MXPA01007395A - Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by vla-4 - Google Patents

Abstract

Disclosed are pyroglutamic acid derivatives and related compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Description

DERIVATIVES OF PIROGLUTAMIC ACID AND COMPOUNDS RELATED THAT INHIBIT THE ACCESSION TO LEUKOCYTES MEDIATED BY ALPHA4 BETA1 INTEGRINE AND CD49d / cd29 (VLA-4) Background of the invention. This invention relates to compounds that inhibit leukocyte adhesion and, in particular, adhesion to leukocytes mediated by VLA-4. References . The following publications, patents and patent applications are cited in this application as numbers in the above index: 1 Hemler and Takada, European Patent Application Publication No. 330,506, published on August 30, 1989. 2 Elices, et al., Cell, 6_0 577-584 (1990) 3 Springer, Nature, 346: 425-434 (1990) 4 Osborn, Cell, 6_2: 3-6 (1990) 5 Vedder, et al., Surgery, 10: 509 (1989) 6 Pretolani, et al., J. Exp. Med., 180: 795 (1994) 7 Abraham, et al., J. Clin. Invest., 9_3: 776 (1994) 8 Mulligan, et al., J. Immunology, 150: 2407 (1993) REF: 131117 9 Cybulsky, et al., Science, 251: 788 (1991) 10 Li, et al., Arterioscler. Thromb. 13_: 197 (1993) 11 Sasseville, et al., Am. J. Path., 144: 27 (1994) 12 'Yang, et al., Proc. Nati Acad. Sci. (USA), 90_: 10494 (1993) 13 Burkly, et al., Diabetes, 43: 529 (1994) 14 Baron, et al., J. Clin. Invest., 9J3_: 1700 (1994) 15 Hamann et al., Immunology, 152: 3238 (1994) 16 Yednock, et al., Nature, 356: 63 (1992) 17 Baron, et al., J. Exp. Med., 177: 57 (1993) 18 van Dinther-Janssen, et al., J. Immunology, 147: 4207 (1991) 19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52_: 672 (1993) 20 Elices, et al., J. Clin. Invest., _93: 405 (1994) 21 Postigo, and collaborators, j. Clin. Invest., 89: 1445 (1991) 22 Paul, et al., Transpl. Procedure , 25: 813 (1993) 23 Okarhara, et al., Can. Res., 54: 3233 (1994) 24 Paavonen, et al., Int. J. Can., 58: 298 (1994) 25 Schadendorf, et al., J. Path., 170: 429 (1993) 26 Bao, et al. , Diff., 52: 239 (1993) 27 Lauri, et al., British J. Cancer, _68_: 862 (1993) 28 Ka aguchi, et al., Japanese J. Cancer Res., 8J3_: 1304 (1992) 29 Kogan, and collaborators, US Patent No. 5,510,332, published April 23, 1996 30 International Patent Appl. Publication No. WO 96/01644 All prior publications, patents and patent applications are hereby incorporated by reference in full to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be fully incorporated as a reference. .

State of Art VLA-4 (also referred to as integrin a4ßl and CD49d / CD29), first identified by Helmer and Takada1, is a member of the ßl integrin family of cell surface receptors, each of which comprises two subunits, one chain a and a string ß. VLA-4 contains an a4 chain and a ßl chain. There are at least nine ßl integrins, all carrying the same ßl chain and each having a different chain. These nine receptors all bind a different complement of the different cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds to non-matrix molecules that are expressed by endothelial cells and other cells. These non-matrix molecules include VCA-1, which is expressed in human cells of the umbilical vein activated by cytosine in culture. Different epitopes of VLA-4 are responsible for the binding activities of fibronectin and VCAM-1, and each activity is shown to be independently inhibited2.

Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a variety of inflammatory responses. At the site of a wound or other inflammatory stimulus, activated vascular endothelial cells, they express molecules that are adhesive to leukocytes. The mechanism of adhesion of leukocytes to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules in endothelial cells. Once bound, the leukocytes migrate through the wall of the blood vessel to enter the damaged site and release chemical mediators to fight the infection. For reviews of adhesion receptors of the immune system, see for example, Springer3 and Osborn4. Inflammatory diseases of the brain, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of diseases of the central nervous system in which the endothelium / leukocyte adhesion mechanism results in the destruction of brain tissue otherwise healthy. Large numbers of leukocytes migrate through the blood-brain barrier (BBB) in subjects with these inflammatory diseases. Leukocytes release toxic mediators that cause extensive tissue damage that results in impaired conduction of the nerves and paralysis. In other organ systems, tissue damage also occurs through an adhesion mechanism that results in the migration or activation of leukocytes. For example, it has been shown that initial trauma to heart tissue following myocardial ischemia can be further complicated by the entry of leukocytes into damaged tissue, causing even greater trauma (Vedder et al.5). Other inflammatory conditions mediated by an adhesion mechanism include, for example, asthma6-8, Alzheimer's disease, atherosclerosis9-10, AIDS dementia11, diabetes12-14 (including early juvenile diabetes), inflammatory bowel disease (including colitis) ulcerative and Crohn's disease), multiple sclerosis16-17, rheumatoid arthritis18"21, tissue transplantation .2'2 tumor metastasis' meningitis, encephalitis, infarction and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, ischemia myocardium and acute damage to the leukocyte-mediated lung such as that which occurs in the adult respiratory distress syndrome In view of the above, tests to determine the level of VLA-4 in a biological sample containing VLA-4 for example , for the diagnosis of conditions mediated by VLA-4 Additionally, independently of these advances in the understanding of leukocyte adhesion, art has barely addressed the use of adhesion inhibitors in the treatment of brain diseases and other inflammatory conditions29'30. The present invention addresses these and other needs. Brief Description of the Invention This invention relates to compounds that bind to VLA-4. Such compounds can be used, for example, for tests for the presence of VLA-4 in a sample and in pharmaceutical compositions for inhibiting cell adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less (as measured using the procedures described in the example below) whose compounds were defined by formula I below. : wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, and -CYOOR1; 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, carbon and from 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have from 2 to 4 atoms in the heteroalkylene chain, and substituted heteroalkylene, in the heteroalkylene chain, from 1 to 3 carbon atoms and from 1 up to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have 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 may be associated with R2 to form a combined cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; R 4 is selected from the group consisting of isopropyl, -CH 2 -X y = CH-X, where 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, carboxy, carboxylalkyl, substituted carboxyl-alkyl, carboxy-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxyheteroaryl, carboxyl-heteroaryl s substituted, carboxyheterocyclic, substituted carboxy-heterocyclic, and hydroxyl with the proviso that when R 4 is = CH-X then (H) is removed from the formula and X is not hydroxyl; W is oxygen or sulfur; and pharmaceutically acceptable salts thereof. In another embodiment, the compounds of this invention can also be provided as pro-drugs that convert (eg, hydrolyze, metabolize, etc.) in vivo to a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid in the compound of formula I is modified within a group which will convert to the carboxylic acid, in vivo, (including salts thereof). In a particularly preferred embodiment, such prodrugs are represented by compounds of the formula IA: R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl and -C (0) ORx; 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, carbon and from 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have from 2 to 4 atoms in the heteroalkylene chain, and substituted heteroalkylene, in the heteroalkylene chain, from 1 to 3 carbon atoms and from 1 up to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have 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 may be associated with R2 to form a combined cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; R 4 is selected from the group consisting of isopropyl, -CH 2 -X y = CH-X, where 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, carboxy, carboxylalkyl, substituted carboxyl-alkyl, carboxy-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxyheteroaryl, substituted carboxyl-heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic, and hydroxyl with the proviso that when R4 is = CH-X then (H) is removed from the formula and 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, -NHOY wherein 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 from 1 to 8; it is oxygen or sulfur; and pharmaceutically acceptable salts thereof; with the condition that; (a) when R1 is benzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 is benzyl, then R5 is not ethyl; (b) when R1 is 3,4-dichlorobenzyl, R2 is CH CH2-, R: is hydrogen, R 'is 4- (phenylcarbonylamino) benzyl, then R is not methyl; (c) when R1 is benzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 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 R4 is not 4-hydroxybenzyl or 4- (4-nitrophenoxycarbonyloxy) benzyl; (e) when R1 is 4-cyanobenzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 is 4-hydroxybenzyl, then R5 is not tert-butyl; and (f) when R1 is benzyloxycarbonyl, R2 is NHCH2-, R3 is hydrogen, R5 is tert-butyl, then R4 is not 4-hydroxybenzyl or 4- (N, N-dimethylcarbamyloxy) benzyl. In a preferred embodiment, R1 is a group having 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. Preferably, Z is CH. Preferably, one of R6 and R7 is hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy, amino, chloro, fluoro, cyano or nitro; or both R6 and R7 are chlorine. In a particularly preferred embodiment, R1 is selected from the group consisting of benzyl, 4-aminobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 4-cyanobenzyl, 4-fluorobenzyl, 4-methylbenzyl, -methoxybenzyl, -nitrobenzyl, benzyloxycarbonyl, (pyridin-3-yl) methyl and the like. Preferably, R 2 is selected from the group consisting of alkylene having 2 6 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 nitrogen, oxygen and sulfur and having 2 or 3 atoms in the heteroalkylene chain, and containing substituted heteroalkylene, in the heteroalkylene chain, 1 or 2 carbon atoms and 1 heteroatom selected • of nitrogen, oxygen and sulfur and have 2 or 3 atoms in the heteroalkylene chain. In a particularly preferred embodiment, R2 is selected from the group consisting of -CH2-CH2-, '-CH2-S-CH2-, -CH2-0-CH2- and -NHCH2-. Accordingly, when R2 is associated with the other atoms of the nitrogen-containing ring structure it preferably forms a ring of 2-pyrrolidinone, 3-oxothiomorpholine, 3-oxomorpholine or 2-imidazolidinone. In another preferred embodiment, R3 was associated with R2 to form a 5-oxo-4-azatricyclo [4.2.1.0 (3.7) ring} nonano Preferably, in the compounds of formula I and IA above, R3 is hydrogen or is associated with R2 to form a 5-oxo-4-azatricyclo [4.2.1.0 (3.7) ring} nonano More preferably, R3 is hydrogen. R4 is preferably selected from all possible isomers presented by substitution with the following groups. 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl, 4-benzyloxybenzyl, 4- [f-CH (CH3) O-] benzyl, 4- [f-CH (COOH) O-] benzyl, 4- [BocNHCH2C (O) NH-] benzyl, 4-chlorobenzyl, 4- [NH2CH2C (O) NH-] benzyl, 4-carboxybenzyl, 4- [CbzNHCH2CH2NH-] benzyl, 3-hydroxy-4- (f-OC (O) H-) benzyl, 4- [HOOCCH2CH2C (O) NH-] benzyl, benzyl, 4- [2'-carboxylphenoxy] -benzyl, 4- [fC (0) NH-] benzyl, 3-carboxybenzyl, -dodobenzyl, 4-hydroxy-3, 5-diiodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxymethyl] -benzyl, 4-nitrobenzyl, 2-carboxybenzyl, 4- [dibenzylamino] -benzyl, 4- [(1'-cyclopropylpiperidin-4 '-yl) C (O) NH-] benzyl, 4- [-NHC (O) CH2NHBoc] benzyl, 4-carboxybenzyl, 4-hydroxy-3-nitrobenzyl, 4- [-NHC (O) CH (CH3) NHBoc] benzyl, 4 - [- NHC (0) CH (CH2f) NHBoc] benzyl, isobutyl, methyl, 4- [CH3C (O) NH-] benzyl, -CH2- (3-indolyl), n-butyl, t-butyl-OC (O) CH2, t-butyl-OC (O) CH2CH2-, H2NC (0) CH2-, H2NC (O) CH2CH2-, BocNH- (CH2) 4-, t- butyl-OC (O) - (CH2) 2 -, HOOCCH2-, HOOC (CH2) 2-, H2N (CH2) 4-, Isopropyl, (1-naphthyl) -CH2-, (2-naphthyl) -CH2-, (2-thiophenyl) -CH2-, (f-CH2-OC (O) NH- (CH2) 4-, cyclohexyl-CH2-, benzyloxy-CH2-, HOCH2-, 5- (3-N -benzyl) imidazolyl- CH2-, 2-pyridyl-CH2-, 3-pyridyl-CH2-, 4-pyridyl-CH2-, 5- (3-N-methyl) imidazolyl-CH2-, N-benzylpiperid-4-yl-CH2-, N -Boc-piperidin-4-yl-CH2-, N- (phenyl-carbonyl) piperidin-4-yl-CH2-, H3CSCH2CH2-, lN-benzylimidazol-4-yl-CH2-, isopropyl-C (O) H- (CH2) 4-, iso-butyl-C (O) H- (CH2) 4-, feni 1-C (O) NH- (CH2) • -, benzyl-C (0) NH- (CH2) 4-, allyl-C (O) NH- (CH2) 4-, 4- (3-N-methylimidazolyl) -CH2 -, 4-imidazolyl, 4- [(CH3) 2NCH2CH2CH2-0-] benzyl, 4- [(benzyl) 2N-] -benzyl, 4-aminobenzyl, allyloxy-C (0) NH (CH2) 4-, allyloxy- C (0) NH (CH2) 3-, allyloxy-C (O) NH (CH2) 2-, NH2C (O) CH2-, 2-pyridyl-C (0) NH- (CH2) 4-, 4 -me tilpir id- 3- i 1-C (O) NH- (CH2) 4-, 3-met iltien-2-yl-C (O) NH- (CH2) 4-, 2-pyrrolyl-C (O) NH- (CH2) 4-, 2-furanyl-C (O) NH- (CH2) 4-, 4-methylphenyl-S02-N (CH3) CH2C (O) NH (CH2) ~, 4- [cyclopentylacetylenyl] - benzyl, 4- [NHC (O) - (N-Boc) -pyrrolidin-2-yl]] benzyl-, 1-N-met unbound zol-4-yl-CH2-, lN-methylimidazol-5-yl-CH2-, imidazol-5-yl-CH2-, 6-methylpyrid-3-yl-C (O) NH- ( CH 2) 4-, 4- [2 '-carboxymethylphenyl] -benzyl, 4- [-NHC (O) NHCH 2 CH 2 CH 2 -f] -benzyl, 4- [-NHC (O) NHCH 2 CH 2 -f] -benzyl, -CH 2 C (O ) NH (CH2) 4f, 4- [f (CH2) 40-] -benzyl, 4- [-CsC-f-4'f] -benzyl, 4- [-C = C-CH2-0-S (0 ) 2-4 '-CH3-f] -benzyl, 4- [-C = C-CH2-NHC (O) NH2] -benzyl, 4- [-C = C-CH2-0-4' -COOCH2CH3-f ] -benzyl, 4- [-C = C-CH (NH2) -cycdohexyl] -benzyl, - (CH2) 4NHC (0) CH2- 3 -indol i lo, - (CH2) 4NHC (O) CH2CH2-3- indolyl, - (CH2) 4NHC (O) -3- (5-methyloxyindolyl), - (CH2) 4NHC (0) -3- (1-methylindolyl), - (CH2) 4NHC (0) -4- ( -S02 (CH3) -f), - (CH2) 4NHC (0) -4- (C (0) CH3) -phenyl, - (CH2) 4NHC (0) -4-fluorophenyl, - (CH2) 4NHC (0 ) CH20-4- fluorophenyl, 4-C = C- (2-pyridyl) benzyl, 4-C = C-CH2-0-phenyl] benzyl, -C3C-CH20CH3] benzyl, 4- -CsC- (3 -hydroxyphenyl)] benzyl, 4-C = C-CH2-0-4 '- (-C (0) 0C2H5) phenyl] benzyl, 4-C = C-CH2CH (C (0) 0CH3) 2] benzyl, 4- [-CsC-CH2NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl), 3 -aminobenzyl, 4- [-CsC-CH2CH (NHC (0) CH3) C (0) OH] -benzyl, -CH2C (0) NHCH (CH3) f, -CH2C (0) NHCH2- (-dimethylamino) -f, -CH2C (0) NHCH2-4-nor trofenyl, -CH2CH2C (0) N (CH3) CH2-f , -CH2CH2C (0) NHCH2CH2- (N-methyl) -2-pyrrolyl, -CH2CH2C (0) NHCH2CH2CH2CH3, -CH2CH2C (Q) NHCH2CH2-3-indolyl, -CH2C (O) N (CH3) CH2phenyl, -CH2C (O) NH (CH2) 2- (N-methyl) -2-pyrrolyl , -CH2C (O) NHCH2CH2CH2CH3, -CH2C (0) NHCH2CH2-3-indolyl, - (CH2) 2C (0) NHCH (CH3) f, - (CH2) 2C (O) NHCH2-4 -dimet i lamino pheni lo, - (CH2) 2C (O) NHCH2-4-nitrophenyl, -CH2C (O) NH-4- [-NHC (O) CH3-phenyl), -CH2C (O) NH -4 -pyridyl, -CH2C (0) NH-4- [dimethylaminophenyl], -CH2C (O) NH- 3 -metoxy phenyl, -CH2CH2C (O) NH-4-chloro phenyl, -CH2CH2C (O) NH-2-pyridyl, -CH2CH2C (O ) NH-4-methoxyfine, -CH2CH2C (O) NH-3-pyridyl lo, 4- [(CH3) 2NCH2CH20-] benzyl, - (CH2) 3NHC ((NH) NH-S02-4-methylphenyl, - ([CH3) 2NCH2CH20-] benzyl, - (CH2) 4NHC (O) NHCH2CH3, - (CH2) 4NHC (O) NH-phenyl, - (CH2) 4NHC (O) NH- 4 -metoxy phenol, 4 - [4'-pyridyl-C (0) NH-] benzyl, 4- [3'-pyridyl-C (0) NH-] benzyl, 4- [-NHC (O) NH-3 '-met i lf eni 1] benzyl, 4- [-NHC (O) CH2NHC (O) NH-3 '-methylphenyl] benzyl, 4 - [- NHC (0) - (2 ', 3' -dihydroindol-2-yl)] benzyl, 4 - [- NHC (0) - (2 ', 3'-dihydro-N-Boc-indol-2-yl) benzyl, p - [- OCH 2 CH 2 -l' - (4'-pyrimidinyl) -piperazinyl] benzyl, 4- [-OCH2CH2- (1'-piperidinyl) benzyl, 4- [-OCH2CH2- (1'-pyrrolidinyl) benzyl, 4- [-OCH2CH2CH2- (1'-piperidinyl)] benzyl, -CH2-3- (1 , 2,4-triazolyl), 4- [-OCH2CH2CH2-4- (3'-chlorophenyl) -piperazin-1-yl] benzyl, 4- [OCH2CH2N (f) CH2CH3] benzyl, 4- [-OCH2-3 ' - (N-Boc) -piperidinyl] benzyl, 4- [di-n-pentylamino] benzyl, 4- [n-pentylamino] benzyl, 4- [di-iso-propylamino-CH2CH20-] benzyl, 4- [-0CH2CH2 - (N-morpholinyl)] benzyl, 4- [-0- (3 '- (N-Boc) -piperidinyl] benzyl, 4- [-OCH 2 CH (NHBoc) CH 2cydohexyl] benzyl, p- [OCH 2 CH 2 - (N-piperidinyl ] benzyl, 4- [-OCH2CH2CH2- (4-m-chlorophenyl) -piperazin-1-yl] benzyl, 4- [-OCH2CH2- (N-homopiperidinyl) benzyl, 4- [-NHC (0) -3 '- (N-Boc) -piperidinyl] benzyl, 4- [-OCH2CH2N (benzyl) 2-benzyl, -CH2-2-thiazolyl, 3-hydroxybenzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, '4- [-NHC ( S) NHCH2CH2- (N-morpholine) ] benzyl4- [-OCH2CH2N (C2H5) 2] benzyl, 4- [-OCH2CH2CH2N (C2H5) 2] benzyl, 4- [CH3 (CH2) 4NH-benzyl, 4- [Nn-butyl, N -n-pentylamino] -] benzyl 4- [-NHC (O) -4'-piperidinyl] benzyl, 4- [-NHC (O) CH (NHBoc) (CH 2) 4 NHCbz] benzyl, 4- [-NHC (0) - (1 ') , 2 ', 3', 4 '- tet rahydro-N-Boc-isoquinolin-1' -yl] benzyl, p- [-OCH2CH2CH2-l '- (4'-methyl) -piperazinyl] benzyl, - (CH2) 4NH-B0C, 3- [-OCH2CH2CH2N (CH3) 2] benzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, 3- [-OCH2CH2- (1'-pyrrolidinyl)] benzyl, 4- [-OCH2CH2CH2N (CH3) benzyl] benzyl, 4- [-NHC (S) NHCH2CH2CH2 (N-morpholino)] benzyl, 4 - [- OCH2CH2- (N-morpholino)] benzyl, 4- [-NHCH2- (4'-chlorophenyl)] benzyl, 4- [-NHC (O) NH- (4'-cyanophenyl)] benzyl, 4- [-OCH2COOH] benzyl, 4- -OCH2) COO-t-butyl] benzyl, 4- NNHC (O) -5 '-fluoroindol-2-yl] encyl, 4-NHC (S) NH (CH2 ) 2-l-piperidinyl] benzyl, 4- N (S02CH3) (CH2) 3-N (CH3) 2] benzyl, 4-NHC (O) CH2CH (C (O) OCH2f) -NHCbz] benzyl, - -NHS (O) 2CF3] benzyl, 3- -O- (N-me ti Ipiper i din -4 '-yl] benzyl, 4-C (= NH) NH2] benzyl, 4-NHS 02-CH2Cl ] benzyl, 4- -NHC (0) -) l ', 2', 3 ', 4' -tetrahydroisoquinolin-2'-yl] benzyl, 4- [-NHC (S) NH (CH2) 3-N-mor fol ino] benci lo, 4- [-NHC (O) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, 4- [-C (O) NH2] benzyl, 4 - [- NHC (0) NH-3 '- met oxy phenyl 1] benzyl, 4- [-0CH2CH2-indol-3' -yl] benzyl, 4- [ -0CH2C (O) NH-benzyl] benzyl, 4- [-OCH2C (O) O-benzyl] benzyl, 4 - [- OCH2C (0) OH] benzyl, 4- [-OCH2-2 '- (4', 5'-dihydro) imidazolyl] benzyl, -CH2C (O) NHCH2- (4-dimethylamino) phenyl, -CH C (0) NHCH2- (4-dimethylamino) phenyl, 4- [-NHC (0) -L-2'-pyrrolidinyl-N-S02-4 '-methylphenyl] benzyl, 4- [-NHC (O) NHCH2CH2CH3] benzyl, 4-aminobenzyl] benzyl, 4- [-OCH2CH2-l- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl] ] benzyl, 4- [-0- (N-methylpiperidin-4 '-yl) benzyl, 3-methoxybenzyl, 4- [-NHC (0) -piperidin-3'-yl] benzyl, 4- [-NHC (0 ) -pyridin-2 '-yl] benzyl, 4- [-NHCH2- (4'-chlorophenyl)] benzyl, 4- [-NHC (0) - (N- (4' -CH3-f-S02) -L -pyrrolidin.2 '-il)] benzyl 4- [-NHC (0) NHCH2CH2-f] benzyl, 4- [-OCH2C (0) H2] benzyl, 4- [-OCH2C (0) NH- t-buil ] benzyl, 4- [-OCH2CH2-I- (4-hydroxy-4-phenyl) -piperidinyl] benzyl, 4- [-NHS02-CH = CH2] benzyl, 4- [-NHS02-CH2CH2C1] benzyl, -CH2C ( 0) NHCH2CH2N (CH3) 2, 4- [(1 '-Cbz -piperidin-4' -yl) C (0) NH-] benzyl, 4- [(1 '-Boc-piperidin-4' -yl) C (0) NH-] benzyl, 4- [(2'-bromophenyl) C (O) NH-] benzyl, 4- [-NHC (0) -pyridin-4'-yl] benzyl, 4 - [(4 '- (CH 3) 2NC (0) 0-) phenyl) -C (0) 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 (0) -pyridin-4'-yl] benzyl, 4- [tert-butyl-0 (O) CCH2-0-benzyl) -NH-] benzyl, [BocNHCH2C (O) NH-] butyl, 4-benzylbenzyl, 2-hydroxyethyl, 4- [(Et) 2NCH2CH2CH2NHC (S) NH-] benzyl, 4 - [(1-Boc-4 '-hydroxypyrrolidin-2' - il) C (0) NH-] benzyl, 4- [fCH2CH2CH2NHC (S) NH-] benzyl, 4- [(perhydroindolin-2'-yl) C (O) NH-] benzyl, 2- [4-hydroxy-4- (3-methoxy-thien-2-yl) piperidin-1-yl] ethyl, 4- [(1 '-Boc-perhydroindolin-2'-yl) -C (0) NH-] benzyl, 4- [N-3-methylbutyl-N-trifluoromethyl sulphonyl) amino] benzyl, 4- [N-vinyl sulphonyl) amino] benzyl, 4- [2- (2-azabicyclo [3.2.2] octane] -2-yl) ethyl-0-] benzyl, 4- [4'-hydroxypyrrolidin-2'-yl) C (0) NH-] benzyl, 4- (fNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl, 4- (f-CH2NHC (S) NH) benzyl, 3 - [(1-Boc-piperidin-2'-il ) C (0) NH-] benzyl, 3-piperidin, 2'-yl-C (0) NH-] benzyl, 4- (3'-Boc-thiazolidin-4'-yl) C (0) NH-] benzyl, 4-pyridin-3'-yl-NHC (S) NH) benzyl, 4-CH 3 -NHC (S) NH) benzyl, 4-H 2 NHCH 2 CH 2 CH 2 C (O) NH) benzyl, 4-BocHNCH 2 CH 2 CH 2 C (O) NH) benzyl 4-pyridin-4 '-il-CH2NH) benzyl, 4- (N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- [(1-Cbz-piperidin-4-yl) ) C (O) NH-] butyl, 4- rfCH20CH2 (BocHN) CHC (O) NH] benzyl, 4- [(piperidin-4'-yl) C (0) NH-] benzyl, 4- [(pyrrole idin-2 '-il) C (O) NH-] benzyl, 4- (pyridin-3'-yl-C (0) NH) butyl, 4- (pyridin-4'-yl-C (0) NH) butyl, 4- (pyridin-3'-yl) -C (0) NH) benzyl, 4- [CH3NHCH2CH2CH2C (O) NH-] benzyl, 4- [CH3N (boc) CH2CH2CH2C (O) NH-] benzyl, 4- (aminomethyl) benzyl, 4- [fCH2OCH2 (H2N ) CHC (O) MH] benzyl, 4-l ', 4'-di (Boc) piperazin-2'-yl) -C (0) NH-] benzyl, 4 - [(piperazin-2'-yl) - C (0) NH-] benzyl, 4 - [(N-toluenesulfonylpyrrolidin-2'-yl) C (0) NH-] butyl, 4- [-NHC (O) -4'-piperidinyl] butyl, 4- [ -NHC (0) -l'-N-Boc-piperidin-2'-yl] benzyl, 4 - [- NHC (0) -piperidin-2'-yl] benzyl, 4- [(1'-N-Boc-2 ', 3'-dihydroindolin-2'-yl) -C (O) NH] benzyl 4- (pyridin-3 '-il-CH2NH) benzyl, 4 - [(piperidin-1 -yl) C (0) CH 2-0-] benzyl, 4- [(CH 3) 2CH) 2NC (O) CH 2 - 0-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [fCH20 (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [-NHC (O) -2 '-me toxy phenyl] benzyl, 4- [(pyrazin-2'-yl) C (0) NH-] benzyl, 4- [HO (O) C (NH2) CHCH2CH2 -C (O) NH-] benzyl, 4- (2'-f ormi 1-1 ', 2', 3 ', 4' -tetrahydroisoquinolin-3 '-il-CH2NH-) benzyl, N-Cbz-NHCH2-, 4- [(4'-methylpiperazin-1 '-yl) C (0) O-] benzyl, 4- [CH 3 (N-Boc) NCH 2 C (O) NH-] benzyl, 4- [-NHC (0) - (1 ', 2', 3 ', 4' -tetrahydro-N-Boc-isoquinolin-3 ' -yl] -benzyl, 4- [CH3NHCH2C (O) NH-] benzyl, (CH3) 2NC (0) CH2-, 4- (N-methylacetamido) benzyl, 4- (1 ', 2', 3 ', 4'-tetrahydroisoquinolin-3'-yl-CH2NH-) benzyl, 4- (CH3) 2NHCH2C (O) NH-] benzyl, (1-toluenesulfoni 1 imidi zol- 4 -i 1) methyl, 4 - [(l ' -Boc-piperidin-4'-yl) C (0) NH-] benzyl, 4-trifluoromethyl-benzyl, • 4- [(2'-bromophenyl) C (O) NH-] benzyl, 4- [(CH3) 2NC (0) NH-] benzyl, 4- [CH30C (O) NH-] benzyl, 4- [(CH3) 2NC (O) O-] benzyl, 4- [(CH3) 2NC (0) N (CH3) - ] benzyl, 4- [CH30C (0) N (CH3) -] benzyl, 4- (N-methyltrifluoroacet amido) benzyl, 4- [(1'-methoxycarboni Ipiperidin-4 '-yl) C (O) H-] benzyl, 4- [(4 '-phenypiperidin-4' -yl) C (0) NH-] benzyl, 4 - [(4'-phenyl-1-Boc-piperidin-4'-yl) -C (0 ) NH-] benzyl, 4- [(piperidin-4'-yl) C (0) O-] benzyl, 4- [(1'-methyl-piperidin-4'-yl) -O-] benzyl, 4- [( 1 '-meti Ipiperidin- 4' -il) C (0) 0-] benzyl, 4- [(4'-methylpipe razin-1 '-il) C (O) NH-] benzyl, 3- [(CH3) 2NC (O) 0-] benzyl, 4 - [(4'-phenyl-1'-Boc-piperidin-4' - il) -C (0) 0-] benzyl, 4- (N-toluenesulfonylamino) benzyl, 4- [(CH3) 3CC (O) NH-] benzyl, 4- [. { morpholin-4'-yl) C (0) NH-] benzyl, 4- [CH3CH2) 2NC (O) NH-] benzyl, 4- [-C (0) H- (4'-piperidinyl) benzyl, 4- [(2'-trifluoromethylphenyl) C (0) NH-] benzyl, 4- [(2'-methylphenyl) C (0) H-] benzyl, 4- [(CH 3) 2 NS (0) 20-] benzyl, 4- [(pyrrolidin-2 '-yl) C (O) NH- ] benzyl, 4- [-NHC (0) -piperidin-1-yl] benzyl, 4- [(thiomorpholin-4'-yl) C (0) NH-] benzyl, 4- [(thiomorpholin-4 '- il sulfone) -C (O) NH-] benzyl, 4- [(morpholin-4'-yl) C (0) 0-] benzyl, 3-nitro-4- (CH3OC (0) CH20-) benzyl, ( 2-benzoxazolinon-d-yl) methyl- _ (2 H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-, 4- [(CH3) 2NS (0) 2NH-] benzyl, 4- [(CH3) 2NS (0) 2N (CH3) -] benzyl, 4- [(thiomorpholin-4 '-yl) C (0) 0- ] benzyl, 4- [(thiomorpholin-4'-yl sulfone) -C (0) 0-] benzyl, 4- [(piperidin-l'-il) C (0) 0-] benzyl, 4- [(pyrrolidin-1-yl) C (0) 0-] benzyl, 4- [(4'-meti Ipipera zin -1 '-yl) C (O) 0-] benzyl, 4- [(2'-methylpyrrolidin-1 '-yl) -, (pyridin-4-yl) methyl-, 4- [(piperazin-4' -yl) -C (0) 0-] benzyl, 4- [ (1-Boc-piperazin-4'-yl) -C (0) 0-] benzyl, 4- [(4-acetylpiperazin-1-yl) C (O) O-] benzyl, p- [(4 '-methanesulfoniIpipera zin-1' -yl) -benzyl, 3-nitro-4- [(morpholin-4 '-yl) -C (O) O-] benzyl, 4-. { [(CH3) 2NC (S)] 2N-} benzyl, N-Boc-2-aminoethyl-, '4- [(1,1-dioxothiomorpholin-4-yl) -C (0) 0-] benzyl, 4- [(CH3) 2NS (0) 2-] benzyl 4- (imidazolid-2 '-one-1'-yl) benzyl, 4- [(piperidin-1-yl) C (0) 0-] benzyl, lN-benzyl-imidazol-4-yl-CH2- , 3,4-dioxyethylenebenzyl, 3,4-dioxymethylenebenzyl, 4- [-N (S02) (CH 3) CH 2 CH 2 CH 2 N (CH 3) 2] benzyl, 4- (3'-formy limide zolid-2 '-one-1' - il) benzyl, 4- [NHC (O) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, [2 '- [4"- idroxy-4" - (3"' -methoxy-2''-yl) piperidin-2"-yl] ethoxy] benzyl, and p- [(CH 3) 2 NCH 2 CH 2 N (CH 3) C (O) O-] benzyl. In a preferred embodiment, R4 is preferably selected from all possible isomers are presented by substitution with the following groups: benzyl, 4-aminobenzyl, 4-hydroxybenzyl, 4-nitrobenzyl, 3-chloro-4-hydroxybenzyl, 4- (phenylC ( O) NH-) benzyl, 4- (pyridin-4-ylC (O) NH-) benzyl, 4- [(CH 3) 2 NC (0) 0-] benzyl, 4- [(1 '-Cbz -piperidin- 4 '-il) C (O) NH-] benzyl, 4- [(piperidin-4' -yl) C (O) NH-] benzyl, 4- [-0- (N-methylpiperidin-4 '-il)] benzyl, 4- [(4'-methylpiperazin-1 '-yl) C (0) 0-] benzyl, 4 - [(4' - (pyridin-2-yl) piperazin-1-yl) C (0) 0-] benzyl, 4- [(thiomorpholin- 'yl) C (0) 0-] benzyl, 3-chloro-4- [(CH3) 2NC (O) 0-] benzyl, and 5- (3-N) -benzyl) imidazolyl-CH2-, In the compounds of formula IA, R5 is preferably 2,4-dioxotetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-cc-iso-propyl-4-β-met ilcyclohexoxy, 2-β-isopropyl -4-β-methylcyclohexoxi, -NH ?, benzyloxy, -NHCH2C00H, -NHCH2CH2C00H, -NH-adamant i 1, -NHCH2CH2COOCH2CH3, -NHS02-p-CH3-f, -NH0R8 wherein R8 is hydrogen, methyl, iso-propyl or benzyl, O- (N-succinimidyl), -0-colest-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. a group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, -NR "C (0) -R 'where R' is aryl, heteroaryl, or heterocyclic and R "is hydrogen or -CH2C (O) OCH2CH3.

In the compounds of formula I and IA • above, W is preferably oxygen. Preferred compounds within the scope of the above formulas I and IA include by way of example: N- (benzyl) -L-pyroglutamyl-L-phenylalanine N- (benzyloxycarbonyl) -L-pyroglutamyl-L-phenylalanine N- (benzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine N- (3,4-dichlorobenzyl) -L-pyroglutamyl-L-4- (phenyl Icarboni lamino) phenylalanine N- (3-chlorobenzyl) -L-pyroglutamyl-L -4 - (phenylcarbonylamino) phenylalanine Methyl ester of N- (3-chlorobenzyl) -L- pyroglutamyl-L-4 - (phenylcarbonylamino) phenylalanine N- (4-chlorobenzyl) -L-pyroglutamyl-L-4 - (phenyl) lcarbonylamino) phenylalanine Methyl ester of N- (4-chlorobenzyl) -L- pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine N- (4-methylbenzyl) -L-pyroglutamyl-L-4- (phenylcanenylamino) phenylalanine Ester of Methyl N- (4-methylbenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine N- (4-methoxybenzyl) -L-pyroglutamyl-L-4 - (phenylcarbonylamino) phenylalanine Methyl ester of N- (4 -methoxybenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine N- (3-chlorobenzyl) -L-pyroglutamyl-L- (N '-benzyl) histidine Methyl ester of N- (4-methylbenzyl) -L -pyroglutamyl-L- (N'-benzyl) histidine N- (4-methylbenzyl) -L-pyroglutamyl-L- (N '-benzyl) histidine N- (benzyl) -D-Pyroglutamyl-L-phenylalanine N- ( -benzyl-3-oxothiomorpholine-5-carbonyl) -L-phenylalanine N- (4-benzyl-3-oxothiomorpholin-5-carbonyl) -L-phenylalanine N- (4-benzyl-3-oxomorpholine-5-ethyl ester -carbonyl) -L-phenylalanine Methyl ester of N- (4-benzyl-3-oxothiomorpholin-5-carbonyl) -L-4-nitrophenylalanine Methyl ester of N- (benzyl) -L-pyroglutamyl-L-4 - ilcarbonylamino) phenylalanine Methyl ester of N- (benzyl) -L-pyroglutamyl-L-4- (1'-benzyloxycarbonylpiperidin-4'-carbonylamino) phenylalanine N- (benzyl) -L-pyroglutamyl-L-4 - (pyridine- 4-ylcarbonylamino) phenylalanine N- (benzyl) -L-pyroglutamyl-L- 4 - (1'-benzyloxycarbonylpiperidin-4'-alkylcarbonylamino) phenylalanine N- (benzyl) -L-pyroglutamyl-L-tyrosine N- (benzyl) -L-pyroglutamyl-L-4 - (piperidin-1-ylcarbonylamino) phenylalanine ethyl ester N- (benzyl) -L- ethyl ester pyroglutamyl-L-4-nitrophenylalanine N- (benzyl) -L-pyroglutamyl-Lt-irosine 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'-methyl-piperazin-1'-yl) -carbonyl-phenylalanine ethyl ester N- ( benzyl) -L-pyroglutamyl-L-4- (1'-methypiperidin-4'-yloxy) phenylalanine N- (benzyl) -L-pyroglute amyl-L-4 - [(4'-methy Ipipera zin-1 '-yl) carbonyloxy] phenylalanine N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbami loxi) phenylalanine ethyl ester N- (benzyl) -L-pyroglutamyl-L- ethyl ester 4-aminophenylalanine N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyoxy) phenylalanine Tert-butyl ester of N- (benzyl) -L-pyroglutamyl-L-4- (N, N- dimethylcarbam iloxy) phenylalanine N-tert-butyl tert-butyl ester (benzyl) -L-pyroglutamyl-L-4- [(4'-met ipiperazin-1'-yl) carbonyloxy] phenylalanine Tert-butyl ester of N- ( benzyl) -L-pyroglutamyl-L-4- [(thiomorpholin-4'-yl) carbonyloxy] phenylalanine Tert-butyl ester of N- (4-fluorobenzyl) -L-pyroglutamyl-L-4- [(thiomorpholine-4 '-yl) carbonyloxy] phenylalanine Isopropyl ester of N- (benzyl) -L-pyroglutamyl-L-4 - (N, N-dimethylcarbamyloxy) phenylalanine Tert-butyl ester of N- (4-fluorobenzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine N- (benzyl) -L-pyroglutamyl-L-3 -chloro-4-hydroxyphenylalanine Tert-butyl ester of N- (4-cyanobenzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyoxy) phenylalanine Methyl ester of N- (benzyl) -L-pyroglutamyl -L-3-chloro-4- (N, N-dimethylcarbamyoxy) phenylalanine N- (4-fluorobenzyl) -L-pyroglutamyl-L- 4 - [(thiomorpholin-4'-yl) carbonyloxy] phenylalanine N- (4 -cyanobenzyl) -L-pyroglute amyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine N- (l-benzyloxycarbonyl-2-imidazolidone-5-carbonyl) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine Tert-butyl ester of N- (4-nitrobenzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine 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 Ester de tert- N- (4-fluorobenzyl) -L-pyroglutamyl-L-4- [(4 '- (pyridin-2-yl) piperazin-1'-yl) carbonyloxy] phenylalanine N-tert-butyl ester -aminobenzyl) -L-pyroglutamyl-L-4- (N, N-dimethexcarbamyloxy) phenylalanine N-tert-butyl ester (pyridin-3-ylmet i 1) -L-pyroglutamyl-L-tyros ina N- ( pyridin-3-ylmethyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyoxy) phenylalanine Tert-butyl ester of N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-4 - (N , N-dimethylcarbamyloxy) phenylalanine Tert-butyl ester of N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-4- [(4 '- (pyridin-2-yl) piperazin-1' -il) carbonyloxy] phenylalanine N- (pyridin-3-ylmethyl) -L-pirog lutamyl-L-4- [(4 '- (pyridin-2-yl) piperazin-1'-yl) carbonyloxy] phenylalanine Tert-butyl ester of N- (4-benzyl-5-oxo-4-azatricyclo [ 4.2.1.0 (3, 7)] nonane-3-carbonyl) -L-tyrosine Tert-butyl ester of N- (4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3, 7)] nonane -3-carbonyl) -L-4 - (N, -dimethylcarbamyloxy) phenylalanine N- (4-benzyl-5-OXO-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carbonyl) -L- 4- (N, N-dimethylcarbamyoxy) phenylalanine N- (4-fluorobenzyl) -L-pyroglutamyl-L-4 - (N, N-dimethylcarbamyoxy) phenylalanine and pharmaceutically acceptable salts thereof as well as any of the ester compounds described 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. This invention also provides methods for binding VLA-4 to a biological sample wherein the method comprises contacting the biological sample with a compound of formula I or IA above, under conditions wherein said compound binds to VLA-4. Certain compounds of the above formulas I and IA are also useful in reducing mediated inflammation of VLA-4 i n vi vo. The invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of one or more of the compounds of formula I or IA above. Alternatively, racemic mixtures can be used. The pharmaceutical compositions can be used to treat disease conditions mediated by VLA-4. Such disease conditions include, by way of example, asthma, Alzheimer's disease, arteriosclerosis, AIDS dementia, diabetes (including the principle of acute juvenile diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, infarction, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury, such as occurs in an adult with a syndrome of respiratory exhaustion. Accordingly, this invention also provides methods for the treatment of a respiratory disease in a patient mediated by VLA-4 whose methods comprise administering to the patient the pharmaceutical compositions described above. Preferred compounds of the above formulas I and IA include those published in Table IA, IB, IC and ID below: TABLE IA ^ - TABLE IB TABLE TABLE ID Detailed Description of the Invention As above, this invention relates to compounds that. inhibit the adhesion of leukocytes and, in particular, the adhesion of leukocytes mediated by VLA-4. However, prior to describing this invention in greater detail, the following terms will be first defined. Definitions As used herein, "alkyl" refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like. "Substituted alkyl" refers to an alkyl group, preferably from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, • hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl - substituted cycloalkyl, carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl or I thioheteroaryl substituted thioheterocyclic, thioheterocyclic substituted heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy substituted, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy substituted, oxycarbonylamino, oxy t iocarbonilamino, -OS (0) 2 - alkyl, -OS (O) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (O) 2 -substituted aryl, -OS (0) 2-heteroaryl, -OS (0) 2 -substituted heteroaryl , -OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -OS02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (O) 2 -substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic, NRS ( O) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (O) 2-NR- substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-heteroaryl sub substituted, -NRS (O) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino , mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, disubstituted asymmetric amines having substituents different selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl / groups substituted alkyl, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, - S02-heteroaryl, -S02- substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, and -S02NRR where R is hydrogen or alkyl. "Alkylene" refers to a divalent hydrocarbon radical of the formula - (CH2) n- where n is an integer in the range from 1 to 10. By way of illustration, the term alkylene includes methylene (-CH2-), ethylene ( -CH2CH2-), propylene (-CH2CH2CH2-) and the like. "Substituted alkylene" refers to an alkylene group, preferably from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidinoaminoacyl, aminocarbonylamino, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl , carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl , substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxy carbonylamino, oxythiocarbonylamino, -OS (0) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (O) 2 -substituted aryl, -0S (0) 2- heteroaryl, -OS (O) 2 -substituted heteroaryl, OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS (O) 2 -alkyl, -NRS (0) 2 -substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2 -heterocyclic, NRS (0) 2 -substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (O) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substi- tuted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono and di-heterocyclic substituted amino, disubstituted asymmetric amines having different substituents selected from alkyl, substituted alkyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted alkyl / alkyl groups, substituted with -S02-alkyl , -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S? 2-heteroaryl, -S02- substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, and -S02NRR where R is hydrogen or alkyl. Additionally, two or more substituents in the substituted alkylene group may also be taken together to form a cross-linked and / or fused cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group, or a fused heteroaryl or aryl group. "Alkoxy" refers to the group "alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n -hexoxy, 1,2-dimethylbutoxy, and the like. "Alkoxy substituted" refers to the group "alkyl-O-substituted". "Alkoxycarbonyl" refers to the group "alkyl-O-C (O) -". "Substituted alkoxycarbonyl" refers to the group "alkyl-0-C (0) -substituted". "Acyl" refers to the groups HC (O) -, alkyl-C (0) -, alkyl-C (O) -substituted, alkenyl-C (O) -, alkenyl-C (0) -substituted, alkynyl- C (O) -, C (O) -substituted alkynyl, C (O) - cycloalkyl, (C) -substituted cycloalkyl, aryl-C (O) -, aryl-C (O) -substituted, heteroaryl -C (O) -, heteroaryl-C (0) -substituted, heterocyclic-C (0) -, and heterocyclic-C (0) -substituted, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , substituted cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Acylamino" refers to the group -C (0) NRR where R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl , heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein each R joins to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, cycloalkyl substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Thiocarbonylamino" refers to the group C (S) NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein each R is associated to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, cycloalkyl substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Acyloxy" refers to the groups alkyl-C (0) 0-, alkyl-C (0) 0-substituted, alkeni 1-C (0) 0-, alkenyl-C (O) O-substituted, alkynyl-C (O) 0-, C (0) 0-substituted alkynyl, aryl-C (0) 0-, aryl-C (0) 0- substituted, cycloalkyl-C (O) 0-, cycloalkyl-C (O) O-substituted, heteroaryl-C (O) O-, heteroaryl-C (O) O-substituted, heterocyclic-C (O) O-, and- (0) -substituted heterocyclic C, wherein alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Alkenyl" refers to the alkenyl group having preferably from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. "Substituted alkenyl" refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino , aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxyl-aryl substituted, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, tiohet substituted erocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (0) 2 -alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS (O) 2 -substituted aryl, -0S (0) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, OS (0) 2-heterocyclic , -OS (0) 2-substituted heterocyclic, -0S02-NRR where R is hydrogen or alkyl, -NRS (O) 2 -alkyl, -NRS (O) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS (O) 2-substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2 -heterocyclic, NRS (0) 2 -substituted heterocyclic, -NRS ( 0) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2- NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-heterocyclic co substituted, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono - and substituted di-heteroarylamino, mono- and di-heterocyclic amino, mono and di-heterocyclic substituted amino, asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted alkenyl / alkenyl groups, substituted with -S02 ~ alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, - S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, and -S02NRR where R is hydrogen or alkyl. "Alkynyl" refers to the alkynyl group preferably having from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. "Substituted alkynyl" refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarboni lamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxyl- substituted aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, uncle substituted heterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (0) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -0S (0) 2 -heteroaryl, -OS (0) 2 -substituted heteroaryl, OS (0) 2 -heterocyclic, -OS (0) 2-substituted heterocyclic, -0S02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, - NRS (0) 2-substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2 -heterocyclic, NRS (0) 2- substituted heterocyclic, -NRS (0 ) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (O) 2-NR-substituted aryl, -NRS (0) 2-NR -heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-heterocyclic substituted alkyl, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono - and substituted di-heteroarylamino, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, disubstituted asymmetric amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted alkynyl / alkynyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S? 2 -substituted aryl, -S? 2 -heteroaryl, -S02 -substituted heteroaryl, -S? 2 -heterocyclic, -S02- hetero substituted alkyl, and -S02NRR where R is hydrogen or alkyl. "Amidino" refers to the group H2NC (= NH) - and the term "alkylamidoino" refers to compounds having from 1 to 3 alkyl groups (eg, alkyl-HNC (= NH) - and the like). "Thioamidino" refers to the group RSC (= NH) - where R is hydrogen or alkyl. "Aminoacyl" refers to the groups -NRC (O) alkyl, -NRC (O) substituted alkyl, -NRC (O) cycloalkyl, -NRC (O) substituted cycloalkyl, -NRC (0) alkenyl, -NRC (0) substituted alkenyl, -NRC (0) alkynyl, -NRC (0) substituted alkynyl, -NRC (O) ) aryl, -NRC (0) substituted aryl, -NRC (0) heteroaryl, -NRC (0) substituted heteroaryl, -NRC (0) heterocyclic, and -NRC (0) substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminocarbonyloxy" refers to the groups -NRC (0) O-alkyl, -NRC (0) O-substituted alkyl, -NRC (0) O-alkenyl, -NRC (O) O -substituted alkenyl, -NRC (0) O-alkynyl, -NRC (O) O-substituted alkynyl, -NRC (0) O-cycloalkyl, -NRC (0) O-cycloalkyl substituted, -NRC (0) 0-aryl, -NRC (0) O- substituted aryl, -NRC (O) O-heteroaryl, NRC (O) O-substituted heteroaryl, -NRC (O) O-heterocyclic, and -NRC (O) O-substituted heterocyclic wherein R is hydrogen or alkyl and wherein alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Oxycarbonylamino" refers to the groups 0C (0) NH2, -OC (0) NRR, -OC (O) R-alkyl, -0C (0) NR-substituted alkyl, -OC (0) NR-alkenyl, - 0C (0) NR-substituted alkenyl, -OC (0) NR-alkynyl, OC (0) NR-substituted alkynyl, -0C (0) NR-cycloalkyl, -OC (0) NR-cycloalkyl susbstue, -OC ( 0) NR-aryl, -OC (0) NR-substituted aryl, OC (0) NR-heteroaryl, -OC (0) -substituted heteroaryl, -OC (0) NR-heterocyclic, and -0C (0) NR -substituted heterocyclic where R is hydrogen, alkyl and wherein each R is associated to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Oxithiocarbonylamino" refers to the groups -OC (S) NH2, = 0C (S) NRR, -OC (S) NR-alkyl, -0C (S) NR-substituted alkyl, -OC (S) NR-alkenyl, -0C (S) NR-substituted alkenyl, -OC (S) NR-alkynyl, substituted OC (S) NR-alkynyl, -0C (S) NR-cycloalkyl, -OC (S) NR-substituted cycloalkyl, -OC ( S) NR-aryl, -OC (S) NR-substituted aryl, OC (S) NR-heteroaryl, -OC (S) NR-substituted heteroaryl, -OC (S) NR-heterocyclic, and -0C (S) NR -substituted heterocyclic where R is hydrogen, alkyl or where each R is associated to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl , substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Aminocarbonylamino" refers to the groups -NRC (0) NRR, -NRC (0) NR-alkyl, -NRC (0) NR-substituted alkyl, -NRC (0) NR-alkenyl, -NRC (0) NR -substituted alkenyl, -NRC (0) NR-alkynyl, NRC (0) NR-substituted alkynyl, -NRC (0) NR-aryl, -NRC (0) NR-substituted aryl, -NRC (0) NR-cycloalkyl, -NRC (0) NR-substituted cycloalkyl, -NRC (0) NR-heteroaryl, and -NRC (0) NR-substituted heteroaryl, -NRC (0) NR-heterocyclic, and -NRC (0) NR-substituted heterocyclic in wherein each R is independently hydrogen, alkyl or where each R is associated to form together with the nitrogen atom a substituted heterocyclic or heterocyclic ring as well as where one of the amino groups are blocked by conventional blocking groups such as Boc, Cbz, formyl , and the like, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, heteroaryl subst substituted, heterocyclic and heterocyclic are as defined herein. "A inot iocarbonylamino" refers to the groups -NRC (S) NRR, -NRC (S) NR-alkyl, -NRC (S) NR-substituted alkyl, -NRC (S) NR-alkene lo, NRC (S) NR-substituted alkenyl, -NRC (S) NR-alkynyl, -NRC (S) NR-substituted alkynyl, NRC (S) NR-aryl, -NRC (S) NR-substituted aryl, NRC (S) NR-cycloalkyl, -NRC (S) R-substituted cycloalkyl, -NRC (S) NR -heteroaryl, and -NRC (S) NR- substituted heteroaryl, -NRC (S) NR-heterocyclic, and -NRC (S) NR-substituted heterocyclic wherein each R is independently hydrogen, alkyl or where each R is associated to form together with the nitrogen atom a substituted heterocyclic or heterocyclic ring as well as where one of the amino groups are blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic n as defined here. "Aryl" or "Ar" refers to an unsaturated carbocyclic group of 2 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl) which may be fused rings or they may not be aromatic (for example, 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H) -one-7-yl, and the like). Preferred aryls include phenyl and naphthyl. Substituted aryl refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkyl amidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl , substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamino, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl , thioaryl substi thyido, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (0) 2 -alkyl, -S (0) 2 -substituted alkyl, -S (O) 2 -cycloalkyl, -S (0) 2 -substituted cycloalkyl, -S (O) 2-alkenyl, -S (0) 2 -substituted alkenyl, -S (0) 2 -aryl, -S (0) 2 -substituted aryl, -S (O) 2 -heteroaryl, -S (0) 2-substituted heteroaryl, -S (O) 2-eterocyclic, -S (0) 2-heterocyclic. substituted, -OS (O) 2-alkyl, OS (O) 2 -substituted alkyl, -OS (O) 2 -aryl, -OS (0) -substituted aryl, -OS (O) 2 -heteroaryl, -OS (0) 2-substituted heteroaryl, -0S (0) 2-heterocyclic, -OS (O) - substituted eterocyclic, -0S02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS ( 0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (O) 2 -substituted heteroaryl, NRS (O) 2 -heterocyclic, -NRS (O) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS ( 0) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, NRS. (O) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (O) 2- NR-substituted heterocyclic, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, disubstituted asymmetric amines having substituents different selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups in the blocked aryl substituted by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with -SO NRR wherein R is hydrogen or alkyl. "Aryloxy" refers to the aryl-O- group which includes, by way of example, phenoxy, naphthoxy, and the like. '"Substituted aryloxy" refers to aryl-O-substituted groups. "Aryloxyaryl" refers to the -aryl-O-aryl group. "Substituted aryloxyaryl" refers to aryloxyaryl groups substituted with, from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkyl amidino, thioamidino, amino, aminoacyl, aminocarboni loxy, aminocarbonylamino, aminotiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy , substituted heterocyclyloxy, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamino, cyano, thiol, thioalkyl, thioalkyl subst ituido, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (O) 2_alkyl, -S (O) 2 -substituted alkyl, -S (O) 2-cycloalkyl, -S (0) 2-substituted cycloalkyl, -S (O) 2-alkene, -S (0) 2-substituted alkenyl, -S (O) 2 -aryl, -S (0) 2 -substituted aryl, -S (0) 2 -heteroaryl, -S (0) 2-substituted heteroaryl, -S (0) 2-heterocyclic, -S (0) 2 -substituted heterocyclic, -OS (O) 2 -alkyl, OS (O) 2 -substituted alkyl, -OS (0) 2-aryl, -OS (0) 2-substituted aryl, -OS (O) 2-heteroaryl, -0S (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic ico, -OS (0) 2-substituted heterocyclic, -0S02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl , -NRS (0) 2-substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, NRS (0) 2 -heterocyclic, -NRS (0) 2 -substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2 -NR-heteroaryl, NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic amino substituted, asymmetdi-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups in the blocked aryl substituted by conventional blocking groups such as Boc, Cbz , formyl, and the like or substituted with -S02NRR wherein R is hydrogen or alkyl. "4-Benzyl-5-oxo-4-azatclo acid [4.2.1.0 (3,7)] nonane-3-carboxylic "refers to a compound of the formula.

"Cycloalkyl" refers to cyclic alkyl groups of 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Excluded from this definition are alkyl groups of multiple rings or fused rings such as adamantanyl, and the like. "Cycloalkenyl" refers to cyclic alkenyl groups of 3 to 8 carbon atoms that have a single or multiple unsaturation but are not aromatic. "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups, preferably from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (= 0), thioxo (= S) ), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminotiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano , halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl , guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioari substituted, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxitiocarbonylamino , -OS (0) 2-alkyl, -OS (0) 2-substituted alkyl, -0S (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2-heteroaryl, -OS (0) 2-substituted heteroaryl, -0S (0) 2-heterocyclic, -0S (0) 2-substituted heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS ( 0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2-heterocyclic, NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS ( 0) 2-NR-aryl subs tituido, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono and di-heterocyclic substituted amino, disubstituted asymmetamines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, CBz, formyl, and the like or substituted alkynyl / alkynyl groups, substituted with -SOa-alkyl , -S02-substituted alkyl, -S02-cycloalkyl, -S? -2-substituted cycloalkyl, -SO2-alkenyl, -S? 2 -substituted alkenyl, -S? 2 ~ aryl, -SO? -aryl substituted, -S? 2-heteroaryl, -SO2-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, and -S02NRR where R is hyrrogen or alkyl.

"Cycloalkoxy" refers to -0-cycloalkyl groups. "Substituted cycloalkoxy" refers to substituted -O-cycloalkyl groups. '"Guanidino" refers to groups NRC (= NR) NRR, -NRC (= NR) NR-alkyl, -NRC (= NR) NR-substituted alkyl, -NRC (= NR) NR-alkenyl, NRC (= NR) NR-substituted alkenyl, -NRC (= NR) NR-alkynyl, -NRC (= NR) NR-substituted alkynyl, RC (= NR) NR-aryl, -NRC (= NR) NR-substituted aryl, -NRC (= NR) NR-cycloalkyl, - NRC (= NR) NR-heteroaryl, -NRC (= NR) NR-substituted heteroaryl, -NRC (= NR) NR-heterocyclic, and -NRC (= NR) NR-substituted heterocyclic where each R is independently hydrogen and alkyl as wherein one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, aryl substituted, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Guanidinosulfone" refers to groups NRC (= NR) NRS02-alkyl -NRC (= NR) NRS02-substituted alkyl, -NRC (= NR) NRS02-alkenyl, NRC (= NR) NRS02-substituted alkenyl, NRC (= NR) ) RS02-alkynyl, -NRC (= NR) NRS02-alkyne substituted, -NRC (= NR) NRS02-aryl, -NRC (= NR) NRS02-substituted aryl, -NRC (= NR) NRS02-cycloalkyl, NRC ( = NR) NRS02-heteroaryl, -NRC (= NR) NRS02-substituted heteroaryl, -NRC (= NR) NRS02-heterocyclic, and -NRC (= NR) NRS02-substituted heterocyclic where each R is independently hydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo and is preferably either chloro or bromo. "Heteroalkylene" refers to an alkylene group in which it is from 1 to 5, preferably from 1 to 3, of the carbon atoms in the alkylene chain had been replaced with a heteroatom selected from nitrogen, oxygen or sulfur By way of illustration, the term "heteroalkylene" includes -CH2-0-CH2-, -CH2-S-CH2-, - NHCH2- and the like. "Substituted heteroalkylene" refers to a heteroalkylene group having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl. amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-alk substituted ilo, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxy iocarbonylamino, -0S (0) 2 -alkyl, -OS (0) 2 -substituted alkyl, -0S (0) 2 -aryl, -OS (0) -substituted aryl, -0S (0) 2 -heteroaryl, - OS (0) 2-substituted heteroaryl, -0S (0) 2 -heterocyclic, -0S (0) 2-substituted heterocyclic, - OSO2-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alky, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2-heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2-heterocyclic, NRS (0) 2 -substituted heterocyclic, -NRS (0) 2-NR-alkyl, - NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- ( substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, amines asymmetric di-substituted having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, CBz, formyl, and the like or substituted alkynyl / alkynyl groups, substituted with -SOa-alkyl, -S0 -substituted alkyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-alkenyl, -S02-substituted alkenyl , -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, and -S02NRR where R is hyrrogen or alkyl. "Heteroaryl" refers to an aromatic carbocyclic group of 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can be a single ring (for example, pyridyl or furyl) or multiple fused rings (for example, indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl. "Substituted heteroaryl" refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl , alkynyl, substituted alkynyl, amidino, alkyl amidino, thioamidino, amino, aminoacyl, aminocarboni loxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxy , carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamino, cyano, thiol, thioalkyl, substituted thioalkyl , thioaryl, tioari substituted, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy , heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (0) 2-alkyl, -S (O) 2 -substituted alkyl, -S (O) 2-cycloalkyl, -S (0) 2-substituted cycloalkyl, -S (0) 2-alkenyl, -S (0) 2 -substituted alkenyl, -S (0) 2 -aryl, -S (0) 2 -substituted aryl, -S (0) 2 -heteroaryl, -S (0) 2-substituted heteroaryl, -S (0) 2-heterocyclic, -S (0) 2-substituted heterocyclic, -OS (O) 2-alkyl, OS (0) 2-substituted alkyl, -OS (0) 2-aryl , -0S (0) 2-substituted aryl, -OS (0) 2-heteroaryl, -0S (0) 2 -substituted heteroaryl, -0S (0) 2-heterocyclic, -OS (0) 2-heterocyclic substituted alkyl, -0S02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2-aryl substituted, -NRS (0) 2-heteroaryl, -NRS (0) 2-substituted heteroaryl, NRS (O) 2-heterocyclic, -NRS (O) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR -aryl, -NRS (0) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, NRS (O) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di- substituted heterocyclic amino, asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups in the blocked aryl substituted by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with -S02NRR wherein R is hydrogen or alkyl.

"Heteroaryloxy" refers to the -0-heteroaryl group and "substituted heteroaryloxy" refers to the -O-substituted heteroaryl group. "Heterocycle" or "heterocyclic" refers to a saturated or unsaturated group having a single ring or multiple fused rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring in where, in fused ring systems, one or more of the rings can be aryl or heteroaryl. "Substituted heterocyclic" refers to heterocycle groups that are substituted with 1 to 3 substituents selected from the group consisting of oxo (= 0), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminotiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl -cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, -cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl , thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, thioheteroaryl substituted, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (0) 2-alkyl, -OS (O) 2-substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -0S (0) 2 -heteroaryl, -OS (0) 2 -substituted heteroaryl, -0S (0 ) 2-heterocyclic, -0S (0) 2-substituted heterocyclic, -0S02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2 -heterocyclic, NRS (0) 2 -heterocyclic substituted , -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS ( 0) 2-NR-heteroaryl, -NRS (O) 2-NR-substituted heteroaryl, -NRS (O) 2-NR-het erocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- -substituted arylamino, mono and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono and di-heterocyclic substituted amino, disubstituted asymmetric amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, CBz, formyl, and the like or substituted alkynyl / alkynyl groups, substituted with -SOa-alkyl, -S02-substituted alkyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, and -S02NRR where R is hyrrogen or alkyl. Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrolo, imidazole, pyrazolo, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, dihydroindol, indazolo, purine, quinolizine, isoquinoline, quinoline, phthalazine, naft ilpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazolo, carboline, phenanthridine, acridine, phenanthroline, isothiazolo, phenazine, isoxazolo, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4- tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidino, tetrahydrofuranyl, and the like. "Heterocyclyloxy" refers to the -0-heterocyclic group and "heterocyclyloxy" refers to the -O-substituted heterocyclic group. "L-pyroglutamic acid" refers to (S) - (-) -2-pyrrolidone-5-carboxylic acid. "Tiol" refers to the group -SH.

"Thioalkyl" refers to the -S-alkyl groups. "Substituted thioalkyl" refers to the group -S-substituted alkyl. '"Thiocycloalkyl" refers to the -S-cycloalkyl groups. "Substituted thiocycloalkyl" refers to the group -S-substituted cycloalkyl. "Thioaryl" refers to the group -S-aryl and "substituted thioaryl" refers to the group -S-substituted aryl. "Thioheteroaryl" refers to the group -S-heteroaryl and "substituted thioheteroaryl" refers to the group -S-substituted heteroaryl. "Thioheterocyclic" refers to the group -S-heterocyclic and "substituted thioheterocyclic" refers to the group -S-substituted heterocyclic. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of formula I whose salts are derived from a variety of organic or inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule comprises a basic functionality, salts of organic or inorganic acids such as hydrochloride, bromohydrate, tartrate, mesylate, acetate, maleate, oxalate and the like. Preparation of the compound. The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reagents, solvents, pressures, etc.) are given, other process conditions may also be used, unless otherwise stated. The optimum reaction conditions may vary with the particular reagents or solvents used, but such conditions may be determined by one skilled in the art, by routine optimization procedure. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from experiencing undesirable reactions. Appropriate protecting groups for various functional groups as well as appropriate conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Pro t ect in g Gro ups in Organ i c Syn th es i s, Second Edition, Wiley, New York, 1991, and references cited therein. Additionally, the compounds of this invention typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as mixtures enriched by stereoisomers. All of these stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be prepared using, for example, chiral column chromatography, chiral resolving agents and the like. In a preferred synthesis method, the compounds of formula I and IA are prepared by a first alkylation of a cyclic compound of formula I I: wherein R 'is alkyl, such as methyl, ethyl and the like, and R2 and R3 are as defined herein, with an appropriate alkylating agent to provide an N-alkylating compound of formula III: wherein R 'and R ^ R3 are as defined herein. This reaction is typically conducted by contacting the cyclic compound of formula II with at least one equivalent of a strong base, such as potassium tert-butoxide, in the presence of at least one equivalent of the alkylating agent. Generally, the reaction is conducted in a diluent insert, such as THF and the like, at a temperature in the range from about 0 ° C to about 40 ° C for about 1 to about 24 hours. When the reaction is complete, the N-alkylating compound III is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. The cyclic compounds of the formula II used in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. Examples of compounds suitable for use in this reaction include, but are not limited to, esters of L-pyroglutamic acid, esters of D-pyroglutamic acid, esters of D, L-pyroglutamic acid, esters of 3-oxomorpholine-5-carboxylic acid lico, esters of 3-oxot iomorpholine-5-carboxylic acid, esters of 5-oxo-4-azatriciclo [4-.2.1.0 (3,7)] nonane-3-carboxylic acid and the like. Any suitable alkylating agent can be employed in this reaction, preferred alkylating agents include benzyl halides, such as benzyl bromide and benzyl chlorides. Particularly preferred alkylating agents include benzyl bromide, 3-chlorobenzyl bromide, 4-chlorobenzyl bromide, 3,4-dichlorobenzyl bromide, 4-methybenzyl bromide, 4-methoxybenzyl bromide, 4-fluorobenzyl bromide, bromide. of 4-cyanobenzyl, 4-nitrobentile bromide and the like. After completing the alkylation reaction, the subsequent hydrolysis of the ester group using conventional reagents and conditions, that is, a treatment with an alkali metal hydroxide and an inert diluent such as methanol / water, provides the corresponding carboxylic acid of the formula IV : where R1-RJ are as defined herein. Alternatively, intermediate IV can be prepared by reductive alkylation of an amino dicarboxylic acid derived from formula IVa: wherein R2 and R3 are as defined herein, with an aldehyde of the formula: R1-CHO, wherein R1 is as defined herein, using conditions and reagents of reductive alkylation, followed by cyclization of the N-alkylating intermediate resulting. The reductive alkylation reaction is typically conducted by contacting the amino compound IVa with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde and at least one apparatus based on the amino compound of a hydride reducing agent. metal, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature in the range from about 0 ° C to about 50 ° C for about 1 to about of 72 hours. The resulting N-alkylated intermediate is then cyclized by acidification and heated to provide intermediate IV. This reaction typically provides products of high optical purity when an optically active amino dicarboxylic acid, such as L-glutamic acid, is used. The compounds of formula I are then prepared by coupling the intermediate of formula IV with an amino acid derived from formula V: wherein R4 and R5 are as defined in the presence. This coupling reaction is typically conducted using well known coupling reagents such as carbodiimides, BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate) and the like. Suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide (DCC), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) and the like. If desired, forms supported on polymers of carbodiimide coupling reagents can be used including, for example, those described in Tetraiiedron Le t t ers, 34 (48), 7685 (1993). Additionally, well-known coupling promoters, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, can be used to facilitate the coupling reaction. This coupling reaction is typically conducted by contacting intermediate IV with about 1 to about 2 equivalents of the coupling reagent and at least one equivalent, preferably about 1 to about 1.2 equivalents, of the amino acid derivative V in an inert diluent. , such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide and the like. Generally, this reaction is conducted at a temperature in the range from about 0 ° C to about 37 ° C for about 12 to about 24 hours. After completion of the reaction, the compound of formula IA is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. Alternatively, intermediate IV can be converted to an acid halide and the acid halide coupled with an amino acid derivative V to provide compounds of formula IA. The acid halide of IV can be prepared by contacting the IV with an inorganic acid halide, such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, or preferably, with oxalyl chloride under conventional conditions. Generally, this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at a temperature in the range of about 0. ° C up to 80 ° C for about 1 to about 48 hours. A catalyst, such as N, N-dimethylformamide, can be used in this reaction.

The acid halide of intermediate IV is then contacted with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of the amino acid derivative V in an inert diluent, such as dichloromethane, at a temperature in the range from about - 70 ° C to around 40 ° C for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of an appropriate base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schottern-Baumann type conditions using an aqueous alkali, such as sodium hydroxide and the like. After completion of the reaction, the compound of formula IA is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. The amino acids derived from the formula V which are used in the above reactions are either known compounds or compounds which can be prepared from known compounds by conventional synthetic methods. For example, amino acids derived from formula V can be prepared by commercially available C-alkylating diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA), with an alkyl or substituted alkyl halide. This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is subsequently deacetylated, hydrolyzed and decarboxylated by heat in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt. Examples of amino acids derived from formula V suitable for use in the above reactions include, but are not limited to, methyl ester of L-alanine, methyl ester of L-isoleucine, methyl ester of L-leucine, methyl ester of L- valine, methyl ester of ß-tert-butyl-L-aspartic acid ester, tert-butyl ester of L-asparagine, methyl ester of e -Boc-L-lysine, methyl ester of e-Cbz-L-lysine, methyl ester of acid? -tert-butyl-L-glutamic acid, tert-butyl ester of L-glutamine, methyl ester of L- (N-met il) histidine, methyl ester of L- (N-benzyl) histidine, methyl ester of L -methionine, methyl ester of L- (O-benzyl) serine, methyl ester of L-tryptophan, methyl ester of L-phenylalanine, isopropyl ester of L-phenylalanine, benzyl ester of L-phenylalanine, L-phenylalaninamide, benzyl ester of N-methyl-L-phenylalanine, methyl ester of 3-carboxy-D, L-phenylalanine, methyl ester of 4-carboxy-D, L-phenylalanine, ester • methyl of L-4-chlorophenylalanine, methyl ester ilo of L-4- (3-dimethylaminopropyloxy) phenylalanine, methyl ester of L-4-iodophenylalanine, methyl ester of L-3, 4-methylenedioxyphenylalanine, methyl ester of L-3, 4-ethylenedioxyphenylalanine, methyl ester of L-4 -nitrophenylalanine, methyl ester of L-tyrosine, methyl ester of D, L-homophenylalanine, methyl ester of L- (O-methyl) tyrosine, methyl ester of L- (O-tert-butyl) tyrosine, methyl ester of L - (0-benzyl) tyrosine, methyl ester of L-3, 5-diisotyrosine, methyl ester of L-3-iodotosin, methyl ester of β- (1-naphthyl) -L-alanine, methyl ester of β- ( 2-naphthyl) -L-alanine, methyl ester of β- (2-thienyl) -L-alanine, methyl ester of β-cyclohexyl-L-alanine, methyl ester of β- (2-pyridyl) -L-alanine, methyl ester of β- (3-pyridyl) -L-alanine, methyl ester of β- (4-pyridyl) -L-alanine, methyl ester of β- (2-thiazolyl) -D, L-alanine, methyl ester of β- (1, 2, 4-t-riazol-3-yl) -D, 'L-alanine, and the like. If desired, of course, other esters or amides of the compounds described above may also be employed. To facilitate synthesis, the compounds of the formula I are typically prepared as an ester, that is, wherein R5 is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolysed using conventional conditions and reagents to provide the corresponding carboxylic acid. Typically, this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperature in the range of from about 0 ° C to about 24 ° C for about 1 to about 12 hours Alternatively, the benzyl esters can be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon, or tert-butyl esters can be hydrolyzed by exposing them to strong acids, such as formic acid or trifluoroacetic acid. The resulting carboxylic acids can be coupled, if desired, to amines such as β-alanine ethyl ester, hydroxyamines such as hydroxylamine and N-hydroxysuccinimide, alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine and 0-benzylhydroxylamine, and the like, using reagents and conventional coupling conditions as described above. As will be apparent to those skilled in the art, other functional groups present in any of the substituents of the compounds of formula I can be easily modified or derived either before or after the coupling reactions described above using well-known synthetic procedures. For example, a nitro group present in a substituent of a compound of the formula I or an intermediate thereof, can be easily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group. This reaction is typically conducted at a temperature from about 20 ° C to about 50 ° C for about 6 to about 24 hours in an inert diluent, such as methanol. Compounds having a nitro group in the substituted R 4 can be prepared, for example, using a 4-nitrophenylalanine derivative and the like in the coupling reactions described above. Similarly, a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acid diluent to provide the corresponding piperidinyl analogue. Generally, this reaction is conducted by treating the pyridine compound with hydrogen at a pressure in the range from about 20 psi to about 60 psi, preferably around 40 psi, in the presence of the catalyst at a temperature of about 20 ° C. about 50 ° C for about 2 to about 24 hours in an acid diluent, such as a mixture of methanol and aqueous hydrochloric acid. Compounds having a pyridyl group can be easily prepared using, for example, β- (2-pyridyl) -, β- (3-pyridyl) - or β- (-pyridyl) -L-alanine derivatives in the coupling reactions above described. Further, when the R4 substituent of a compound of the formula I or an intermediate thereof contains a primary or secondary amino group, such amino groups can, in addition, be derived either before or after the above coupling reactions to provide, as for example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like. Compounds having an amino group first in the substituent R4 can be prepared, for example, by reducing the corresponding nitro compound as described above. Alternatively, such compounds can be prepared using an amino acid derivative of formula VI derived from lysine, -aminophenylalanine and the like in the coupling reactions described above. By way of illustration, a compound of formula I or an intermediate thereof having a substituent containing a primary or secondary group, such as where R 4 is a (4-a-insphenyl) methyl group, can be N-acylated easily using reagents and conventional acylating conditions to provide the corresponding amide. This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 up to about 1.2 equivalents., of a carboxylic acid in the presence of a coupling reagent such as carbodiimide, BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran,, N-dimethylformamide and the like, at a temperature in the range from about 0 ° C to about 37 ° C for about 4 to about 24 hours. Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and the like, is used to facilitate the acylation reaction. Examples of suitable carboxylic acids for use in this reaction include, but are not limited to, N-tert-butoxycarbonylglycine, -tert-butoxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid , N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert-butyloxycarbonylpecotic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N- (toluene-4-sulfonyl) -L-proline and Similar . Alternatively, a compound of the formula I or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperature in the range from around -70 ° C to around 40 ° C for around 1 to around 24 hours. If desired, an acylation catalyst such as 4- (N, N-dimethylamino) pyridine can be used to promote the acylation reaction. The acylation reaction is preferably conducted in the presence of an appropriate base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann type conditions using an aqueous alkali, such as sodium hydroxide and the like. Examples of suitable acyl halides and carboxylic acid anhydrides for use in this reaction include, but are not limited to, 2-methylopropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoromethylbenzoyl chloride, isonicotylolyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N, N-dimethylcarbamyl chloride, N, N-diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas. Similarly, dicarbonates, such as di-tert-butyl dicarbonate, can be used to provide carbamates. Similarly, a compound of the formula I or an intermediate thereof containing a primary or secondary amino group can be N-sulphonated to form a sulfonamide using a sulfonyl halide or sulfonic acid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides, such as dimethylsulphamoyl chloride, can be used to provide sulfonamides (e.g., >; N-S02-N < ). Additionally, a primary or secondary amino group present in a substituent of a compound of formula I or an intermediate thereof, can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperature in the range from about from 24 ° C to around 37 ° C for about 12 to about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or triphosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyano-phenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate. , ethyl thiocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3- (N, N-diethylamino) propyl thioisocyanate, phenyl thiocyanate, benzyl thiocyanate, 3-pyridyl thiocyanate, fluorescein isocyanate (isomer) I) and similar.

Additionally, when a compound of formula I or an intermediate thereof contains a primary or secondary amino group, the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature in the range from about 0 ° C to about 50 ° C for about 1 to about 72 hours . Suitable aldehydes and ketones for use in this reaction include, by way of example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde and the like. Similarly, when a compound of the formula I or an intermediate thereof has a substituent containing a hydroxyl group, the hydroxyl group may further be modified or derived either before or after the above coupling reactions to provide, as 'for example, ethers, carbamates and the like. Compounds having a hydroxyl group in the R4 substituent, for example, can be prepared using an amino acid derivative of the formula V derived from tyrosine and the like in the reactions described above. By way of example, a compound of the formula I or an intermediate thereof having a substituent containing a hydroxyl group, such as where R 4 is a (4-hydroxyphenyl) methyl group, can easily O-alkylated to form ethers. This O-alkylation reaction is typically conducted by contacting the hydroxy compound with an appropriate alkaline or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form a alkali metal or alkaline earth salt of the hydroxyl group. This salt is generally not isolated, but is reacted in situ with at least one equivalent of a substituted alkali or alkali metal halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to provide the ether. Generally, this reaction is conducted at a temperature in the range from • around 60 ° C to around 150 ° C for around 24 hours to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the mixture of • reaction when an alkyl chloride or bromide is used in the reaction. Examples of alkyl or alkyl-substituted halides and sulfones suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl a-bromophenylacetate, 2- (N-Ethyl-N-phenylamino) ethyl, 2- (N, N-ethylamino) ethyl chloride, 2- (N, N-diisopropylamino) ethyl chloride, 2- (N, N-dibenzylamino ) ethyl, 3- (N, N- and ylamino) propyl chloride, 3- (N-benzyl-N-methylamino) propyl chloride, N- (2-chloroethyl) mor folin, 2- (hexamethyliminimino) chloride ) ethyl, 3- (N-methylpiperazine) propyl chloride, 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine, 2- (4-hydroxy-4-phenylpiperidine) ethyl chloride, N- tosylate tert -butyloxycarbonyl 1-3 -piperidinmethyl, and the like. Alternatively, a hydroxyl group present in a substituent of a compound of the formula I or an intermediate thereof may be O-alkylated using the Mitsunobu reaction. In this reaction, an alcohol, such as 3- (N, N-dimethylamino) -1-propanol and the like, is reacted with from about 1.0 to about 1.3 equivalents of triphenylphosphine and from about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperature in the range from about -10 ° C to about 5 ° C for about 0.25 to about 1 hour. It is then added about 1.0 to about 1.3 equivalents of a hydroxy compound, such as a methyl ester of N-tert-butyl tyrosine, and the reaction mixture is stirred at a temperature of from about 0 ° C to about 30 ° C for about 2 to about 48 hours to provide the product O -rented. In a similar manner, a compound of the formula I or an intermediate thereof containing a hydroxy aryl group can be reacted with an aryl iodide to provide a diaryl ether. Generally, this reaction is conducted by forming the alkali metal salt of the hydroxyl group using an appropriate base, such as sodium hydride, in an inert diluent such as xylenes at a temperature of about -25 ° C to about 10 ° C. the salt is then treated with from about 1.1 to about 1.5 equivalents of cuprous bromide complex and dimethyl sulfoxide at a temperature in the range from about 10 ° C to about 30 ° C for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. The reaction is then heated to about 70 ° C to about 150 ° C for about 2 to about 24 hours to provide the diaryl ether. Additionally, a hydroxy-containing compound can also be easily derivatized to form a carbamate. In a method for preparing such carbamates, a hydroxy compound of the formula I or an intermediate thereof, is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, a a temperature in the range from about -25 ° C to about 0 ° C for about 0.5 to about 2.0 hours. The treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary amine or secondary, provides the carbamate. Examples of the appropriate amines for use in this reaction include, but are not limited to, piperazine, 1-methyl-piperazine, 1-acetyl-piperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like. Alternatively, in another method for preparing carbamates, a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as a dichloromethane, at a temperature in the range from about from 25 ° C to around 70 ° C for about 2 to about 72 hours. Typically, this reaction is conducted in the presence of an appropriate base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Additionally, at least one equivalent (based on the hydroxy compound) of 4- (N, N-dimethylamino) pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of suitable carbamyl chlorides for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride, and the like. Similarly, when a compound of formula I or an intermediate thereof contains a primary or secondary hydroxyl group, such as hydroxyl groups, they can easily be converted to a starting group and displaced to form, for example, amines, sulfides and fluorides. For example, the 4-hydroxy-L-proline derivatives can be converted to the corresponding 4-amino, 4-thio or 4-fluoro-L-proline derivatives by means of nucleophilic displacement of the derivatized hydroxyl group. Generally, when a chiral compound is employed in these reactions, the stereochemistry at the carbon atom linked to the hydroxyl derivative group is typically reversed. These reactions are typically conducted by first converting the hydroxyl group to a starting group, such as a tosylate, by treating the hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperature from about 0 ° C to about 70 ° C for about 1 to about 48 hours. The resulting tosylate can then be easily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixture of N, N-dimethylformamide and water, at a temperature in the range from about 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the corresponding azide compound. The azide group can then be reduced, for example, by hydrogenation using a palladium on carbon catalyst to provide the amino compound (-NH2). Similarly, a tosylate group can be easily displaced by a thiol to form a sulfide. This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of an appropriate base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). , in an inert diluent, such as N, N-dimethylformamide, at a temperature from about 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the sulfide. Additionally, treatment of a tosylate with morpholino-sulfur trifluoride in an inert diluent, such as dichloromethane, at a temperature in the range from about 0 ° C to about 37 ° C for about 12 to about 24 hours, provides the corresponding fluorine compound. Additionally, a compound of the formula I or an intermediate thereof having a substituent containing an iodoaryl group, for example, where R 4 is a (4-iodophenyl) methyl group, can be easily converted either before or after the reactions of top coupling in a biaryl compound. Typically, this reaction is conducted by treating the iodoaryl compound with from about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2- (methoxycarbonyl) phenyl zinc iodide, in the presence of a palladium catalyst, such as tetra ( triphenylphosphine) palladium, in an inert diluent, such as tetrahydrofuran, at a temperature in the range from about 24 ° C to about 30 ° C until the reaction is complete. This reaction is also described, for example, in Rieke, J. Org. Ch em. 1991, 56, 1445. In some cases, the compounds of the formula I or intermediates thereof may contain substituents having one or more sulfur atoms. Such sulfur atoms occur, for example, when the cyclic compound of formula II used in the above reactions is derived from 3-oxothiomorpholino-5-carboxylic acid and the like. When present, such, sulfur atoms can be oxidized either before or after the coupling reactions above to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions. Conventional reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MVPBA), sodium periodate, and the like. The oxidation reaction is typically conducted by contacting the sulfide compound with about 0.92 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperature in the range from about 50 ° C to about 75 ° C for 1 to around 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. Such reactions are further described in March, "Advanced Organic Chemistry", 4th Edition, pages 1201-1202, Wiley Publisher, 1992.

Finally, compounds of formula I, wherein W is sulfur, can be prepared using a thiocarbonyl derivative in place of compound II in the synthetic procedures described above. Such thiocarbonyl derivatives can be prepared using, for example, Lawesson's reagent under conventional reaction conditions. Other methods and reaction conditions for preparing the compounds of this invention are described in the examples set forth below. Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of formula I and IA are administered - usually in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions containing, as the active ingredient, one or more of the compounds of formula I and IA above associated with pharmaceutically acceptable carriers. To make the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a carrier, carrier or medium for the active ingredient. In this way, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, example, up to 10% by weight of the active compound, soft and hard gelatine capsules, suppositories, sterile injectable solutions, and sterile packaged powders. To prepare a formulation, it will be necessary to grind the active compound to provide the appropriate particle size before combining with the other ingredients, if the active compound is substantially insoluble, it is ordinarily ground to a particle size of less than 200 mesh. Active compound is substantially soluble in water, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, around 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol , starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated to provide a rapid, sustained or delayed release of the active ingredient after administration to the patient employing procedures known in the art. The compositions are preferably formulated in a unit dose form, each dose containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect, in association with an appropriate pharmaceutical excipient. The active compound is effective over a wide range of doses and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound currently administered as determined by a physician, in light of the relevant circumstances, include the condition to be treated, the chosen route of administration, the current compound administered, the age, weight, and response of the patient individual, the severity of the patient's symptoms, and the like. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, it means that the active ingredient is completely dispersed throughout the composition so that the composition can easily be sub-divided into equally effective unit dose forms such as tablets, pills and capsules. This solid pre-formulation is then sub-divided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be coated, or otherwise made into a compound, to provide a unit dosage form that provides the advantage of a prolonged action. For example, the tablet or pill may comprise an internal dosage and external dosing component, the latter being in the form of a wrapper over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the internal component to pass intact in the duodenum or to slow down in the release. A variety of materials can be used for such enteric coatings or coatings, such materials include a number of polymeric acids and mixtures of polymeric acids with materials such as lacquer, cetyl alcohol, and cellulose acetate. Liquid forms, in which the novel compositions of the present invention can be incorporated, for oral administration or injection, include flavor syrups adapted with aqueous solutions, aqueous or oily suspensions, and emulsions flavored with edible oils such as seed oil. cotton, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in aqueous or organic solvents, pharmaceutically acceptable, or mixtures thereof, and powders. The liquid or solid compositions may contain pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for a local or systemic effect. The compositions preferably in pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulizing solutions can be inhaled directly from the nebulizing device or the nebulizing device can be tentatively attached to a mask, or an intermittent positive pressure inhalation machine. The compositions in solution, suspension, or powder, can be administered, preferably orally or nasally, of devices that deliver the formulation in an appropriate manner. The following formulation examples illustrate the pharmaceutical compositions of the present invention. Formulation Example 1. Hard gelatin capsules containing the following ingredients are prepared: Ingredient Quantity (mg / capsule) Active Ingredient 30.0 Starch 305.0 Magnesium Stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in amounts of 340 mg. Formulation Example 2. A tablet formula is prepared using the ingredients below: Ingredient Amount (mg / tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are ground and compressed to form tablets, each weighing 240 mg. Formulation Example 3. A dry powder inhalation formulation is prepared containing the following components: Ingredient in Weight Active Ingredient 5 Lactose 95 The active mixture is mixed with lactose and the mixture is added to a dry powder inhaler applicator. Formulation Example 4. Tablets are prepared, each containing 30 mg of active ingredient, as follows: Ingredient Quantity (mg / tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4.0 mg Carboxymethyl sodium starch 4.5 mg Magnesium stearate 0.5 mg Talcum 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a U.S. No. 20 mesh and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. 16 mesh. The granules thus produced are dried at 50 ° to 60 ° C and passed through a U.S. of mesh 16. The starch of carboxymethyl sodium, magnesium stearate, and talc, previously passed through a U.S. of 30 mesh, are then added to the granules which, after mixing, are compressed in a tablet machine to produce tablets weighing 150 mg each. Formulation Example 5. Capsules are prepared as follows, each containing 40 mg of the drug: Ingredient Quantity (mg / capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate is ground, passed through a U.S. No. 20 mesh, and filled into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6. Suppositories are made, each containing mg of the active ingredient, as follows: Ingredient Quantity Active Ingredient 25 mg Saturated fatty acid glycerides up to 2,000 mg The active ingredient is passed through a U.S. sieve. No. 60 mesh and suspended in saturated fatty acid glycerides previously melted using the minimum heat required. The mixture is then emptied into a suppository mold of nominal 2.0 g capacity and allowed to cool. Formulation Example 7. Suspensions are prepared, each containing 50 mg of the drug per 5.0 ml dose, as follows: Ingredient Quantity Active Ingredient 50.0 mg Xanthan gum 4.0 mg Carboxymethyl sodium cellulose (11%), microcrystalline cellulose (89 %) 50.0 mg Sucrose 1.75 mg Sodium Benzoate 10.0 mg Flavor and Color cs Purified water up to 5.0 ml The drug, sucrose and xanthan gum are mixed, passed through a U.S. No. 10 mesh, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some water and added with agitation. Sufficient water is then added to produce the required volume. Formulation Example 8 Ingredient Quantity (mg / capsule Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, cellulose, starch, and magnesium stearate are ground, passed through a U.S. sieve. No. 20 mesh, and filled into hard gelatine capsules in amounts of 560 mg. Formulation Example 9. An intravenous formulation is prepared as follows: Ingredient Amount Active Ingredient 250.0 mg Isotonic saline 1000 mlFormulation Example 10. A topical formulation can be prepared as follows: Ingredient Quantity Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g White soft paraffin up to 100 g The white soft paraffin is heated until it melts. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and the agitation continues until it disperses. The mixture is then cooled until solidified.

Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivery of pharmaceutical agents are well known in the art. See, for example, U.S. Pat. No. 5,023,252, published June 11, 1991, incorporated herein by reference. Such patches may be constructed for continuous, pulsed, or in-demand delivery of pharmaceutical agents. When it is desirable or necessary to introduce the pharmaceutical composition to the brain, direct or indirect placement techniques can be used. Live techniques usually involve the placement of a drug delivery catheter into the host ventricular system to connect directly to the blood-brain barrier. One such implantable delivery system used to transport biological factors to specific anatomical regions of the body is described in U.S. Pat. 5,011,472, which is incorporated herein by reference. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide latency to the medicament by converting the hydrophilic medicaments into lipid soluble medicaments. Latency is generally achieved by blocking the hydroxy, carbonyl, sulfate, and primary amine groups present in the drug to make the drug more soluble in lipids and sensitive to transport through the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs can be increased by the intra-arterial infusion of hypertonic solutions that can temporarily open the blood barrier of the brain. Utility. The compounds of this invention can be used to inhibit VLA-4 (integrin a4ßl) in biological samples and, consequently, have utility in, for example, the testing of such samples for VLA-4. in such assays, the compounds can be attached to a solid support and the VLA-4 sample added thereto. The amount of VLA-4 in the sample can be determined by conventional methods such as the use of an interleaved ELISA assay. Alternatively, labeled VLA-4 can be used in a competitive assay to measure the presence of VLA-4 in the sample. Other suitable assays are well known in the art. In addition, some of the compounds of this invention inhibit, in vivo, the adhesion of leukocytes to endothelial cells mediated by VLA-4 and, consequently, can be used in the treatment of diseases mediated by VLA-4. Such diseases include inflammatory diseases in mammalian patients, such as asthma, Alzheimer's disease, arthrosclerosis, AIDS dementia, diabetes (including early juvenile diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease) multiple sclerosis, arthritis rheumatoid, tissue transplantation, tumor metastasis, meningitis, encephalitis, infarction, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury such as that which occurs in the depletion syndrome adult respiratory The biological activity of the compounds identified above can be evaluated in a variety of systems. For example, a compound can be immobilized on a solid surface and the adhesion of cells expressing VLA-4 can be measured. Using such formats, a large number of compounds can be purified. Suitable cells for this assay include any of the leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils. A variety of leukocyte cell lines can also be used, examples include Jurkat and U937. Test compounds can also be tested for the ability to competitively inhibit the binding between VLA-4 and VCAM-1, or between VLA-4 and a known labeling compound for binding VLA-4 such as a compound of this invention or antibodies to VLA-4. In these assays, VCAM-1 can be immobilized on a solid surface. VCAM-1 can also be expressed as a recombinant fusion protein having an Ig terminus (eg, IgG) so that the binding to VLA-4 can be detected in an immunoassay. Alternatively, cells expressing VCAM-1 can be used, such as activated endothelial cells or transfected fibroblasts of VCAM-1. For assays that measure the ability to block adhesion to brain endothelial cells, the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This application is incorporated herein for full reference. Many test formats employ labeled test components. Labeled systems can be in a variety of forms. The label can be coupled directly or indirectly to the desired component of the assay in accordance with methods well known in the art. A wide variety of labels can be used. The component can be labeled by any of several methods. The most common method of detection is the use of autoradiography with compounds labeled with 3 H, 125 I, 35 S, 14 C, or 32 P or the like. Non-radioactive labels include ligands that bind to labeled antibodies, fluorophores, agents Chemiluminescent enzymes and antibodies, which can serve as specific binding pair members for a labeled ligand. The choice of label depends on the required sensitivity, ease of conjugation with the compound, stability requirements, and available instrumentation. Appropriate models in vi to demonstrate efficacy in the treatment of inflammatory responses include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models dependent on a4 integrins. Compounds having the desired biological activity can be modified as necessary to provide the desired properties such as improved pharmacological properties (e.g., in vivo stability, bioavailability), or the ability to be detected in diagnostic applications. For example, the inclusion of one or more D amino acids in the sulfonamides of this invention typically increases the stability in vivo. Stability can be assessed in a variety of media such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A variety of such stability assays of the protein have been described (see, for example, Verhoef et al., Eur. J. Drug Methab. Pharmacokinet., 1990, 15 (2): 83-93). For diagnostic purposes, a wide variety of labels can be linked to the compounds, which can provide, directly or indirectly, a signal that can be detected. In this manner, the compounds of the present invention can be modified in a variety of ways for a variety of final purposes while still maintaining their biological activity. In addition, several reactive sites may be introduced at the end to bind to the particles, solid substrates, macromolecules, or the like. The labeled compounds can be used in a variety of applications in vi ve or in vi t ro. A wide variety of labels may be employed, such as radionucleotides (e.g., gamma-emitting radioisotopes such as technetium-99 or indium-111), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme co-factors, inhibitors. of enzyme, chemiluminescent compounds, bioluminescent compounds, and the like. Those of ordinary skill in the art will have knowledge of other labels to link to the complexes, or will be able to choose them using routine experimentation. The linkage of these labels is done using common standard techniques for those of ordinary skill in the art. In vi tro uses include diagnostic applications such as monitoring of inflammatory responses detected by the presence of leukocytes expressing VLA-4. The compounds of this invention can also be used to isolate or label such cells. In addition, as mentioned above, the compounds of the invention can be used to evaluate the inhibitory potential of VLA-4 / VCAM-1 interactions. For a diagnostic image in vi to identify, for example, sites of inflammation, radioisotopes are typically used in accordance with well-known techniques. The radioisotopes can be linked to the peptide either directly or indirectly using intermediate functional groups. For example, chelating agents such as diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metal ion radioisotopes. The complexes can also be labeled with a paramagnetic isotope for purposes of in vitro diagnostic, such as magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which are well known. In general, any conventional method for viewing a diagnostic image can be used. Usually, radioisotopes that emit gamma and positron are used for the imaging camera and paramagnetic isotopes are used for MRI. In this way, the compounds can be used to monitor the course of the relief of an inflammatory response in an individual. By measuring the increase or reduction in lymphocytes expressing VLA-4, it is possible to determine which particular therapeutic regimen that helps alleviate the disease is effective.

The pharmaceutical compositions of the present invention can be used to block or inhibit cell adhesion associated with a number of diseases and disorders. For example, a number of inflammatory disorders are associated with integrins or leukocytes. The disorders that can be treated include, for example, transplant rejection (for example allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including early juvenile diabetes onset), retinitis, metastatic cancer, rheumatoid arthritis. , acute leukocyte-mediated lung injury (eg, respiratory distress syndrome in adults), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease (including Crohn's disease) and ulcerative colitis). In preferred embodiments, the pharmaceutical compositions are used to treat inflammatory disorders of the brain, such as multiple sclerosis (MS), meningitis and viral encephalitis. Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn's disease and ulcerative colitis. Crohn's disease is an idiopathic, chronic, ulceroconstructive inflammatory disease characterized by defining defined and typically transmural involvement of all the layers of the bowel wall by a granolomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and / or the colon. Ulcerative colitis is an inflammatory response largely limited to the mucosa and colonic submucosa. Lymphocytes and macrophages are numerous in inflammatory bowel disease lesions and may contribute to an inflammatory lesion. Asthma is a disease characterized by an increased response of the tracheobronchial tree to several stimuli that enhance the paroxysmal constriction of the bronchial airways. The stimulus causes the release of several mediators of inflammation from mast cells coated with IgE including histamine, eosinophilic and neutrophilic chemotactic factors, leukocytes, prostaglandin and platelet activation factor. The release of these factors recruits basophils, eosinophils and neutrophils, which cause the inflammatory lesion. Arteriosclerosis is a disease of the arteries (for example, coronary, carotid, aorta and iliac). The basic lesion, the arterioma, consists of a raised focal plate within the intima, which has a lipid core and a fibrous cover plate. Arteries compromise blood flow and weaken the affected arteries. Myocardial and cerebral infarcts are the main consequence of this disease. Macrophages and leukocytes are recruited into arteriomas and contribute to the inflammatory lesion. Rheumatoid arthritis is a disease of inflammatory, chronic release, which first causes a deterioration and destruction of the joints. Rheumatoid arthritis usually affects the small joints of the hands and feet first but then it can involve the wrists, elbows, ankles and knees. Arthritis results from the interaction of synovial cells with leukocytes that infiltrate the circulation in the synovial lines of the joints. See, for example, Paul, Immunol ogy (3rd edition, Raven Press, 1993). Another indication for the compounds of this invention is in the treatment of rejection of an organ or graft mediated by VLA-4. During recent years, there has been a considerable improvement in the efficiency of surgical techniques for the transplantation of tissues and organs such as skin, kidney, liver, heart, lung, pancreas and spinal cord. Perhaps the main notable problem is the lack of satisfactory agents to induce immunotolerance in the recipient for the allograft or transplanted organ. When allogeneic cells or organs are transplanted into a host (this is, the donor and the donee are different individuals of the same species), the immune system of the host is similar to raising an immune response for foreign antigens in the transplant (graft versus host disease) leading to the destruction of the transplanted tissue. CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplanted tissues. The compounds of this invention that bind to the alpha-4 integrin are useful, among other things, to block the immune responses induced by the alloantigen in the donee, thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. . See, for example, Paul et al., Transplant International 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georcyznki et al., Transplant. Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994). A related use for the compounds of this invention that bind to VLA-4 is to modulate the immune response involved in "graft versus host" disease (GVHD). See, for example, Schlegel et al., J. Immunol. 155, 3856-3865 (1995). GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic receptor. In this situation, the immunocompetent cells of the donor can attack tissues in the recipient. The tissues of the skin, epithelial intestine and liver are frequent targets and can be destroyed during the course of GVHD. The disease presents a particularly severe problem when the immune tissue is transplanted, such as in spinal cord transplantation, but less severe GVHD has also been reported in other cases, including heart and liver transplants. The therapeutic agents of the present invention are used, inter alia, to block the activation of donor T cells, thereby interfering with their ability to lyse target cells in the host. An additional use of the compounds of this invention is to inhibit tumor metastasis. Several tumor cells have been reported to express VLA-4 and compounds that bind to VLA-4 block the adhesion of such cells to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Freedman and collaborators, Leuk. Lymphoma 13, 47-52 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994). An additional use of the compounds of this invention is in the treatment of multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States of America. We have the idea that multiple sclerosis is the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the nerve fibers that cover the insulating lining. In an animal model for multiple sclerosis, murine monoclonal antibodies directed against VLA-4 are shown to block the adhesion of leukocytes to the endothelium, and thus prevent inflammation of the central nervous system and subsequent paralysis in animals16. The pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Formulations suitable for use in the present invention are found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th edition (1985). In order to increase the half-life of the serum, the compounds can be encapsulated, introduced into the liposome lumen, prepared as a colloid, or other conventional techniques that provide an extended serum half-life of the compounds can be employed. A variety of methods are available for preparing liposomes, as described in, for example, Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference. The amount administered to the patient varies depending on what is administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the manner of administration, and the like. In therapeutic applications, the compositions are administered to the patient, who already suffers from a disease, in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An adequate amount to accomplish this is defined as "therapeutically effective dose". The effective amounts for this use depend on the disease condition to be treated as well as the judgment of the attending physician, and it depends on factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like. The compositions administered to the patient are in the form of pharmaceutical compositions as described above. These compositions can be sterilized by conventional sterilization techniques, or can be sterilized by filtration. The resulting aqueous solutions can be packaged for use as such, or lyophilized, the lyophilized preparation is combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically between 3 and 11, more preferably from 5 to 9 and even more preferably from 7 to 8. It will be understood that the use of certain of the excipients, carriers, or stabilizers mentioned above results in the formation of pharmaceutical salts. The therapeutic dose of the compounds of the present invention varies according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. . For example, for intravenous administration, the typical dose will be in the range of about 20 μg to about 500 μg per kilogram of body weight, preferably around 100 μg to about 300 μg per kilogram of body weight. The appropriate dose ranges for intranasal administration are generally from about 0.1 pg to 1 mg per kilogram of body weight. Effective doses can be extrapolated from dose-response curves derived from animal or in vitro test systems. The following synthetic and biological examples are offered to illustrate this invention and are not constructed in any way as limiting the scope of this invention. Unless stated otherwise, all temperatures are in degrees centigrade. Eg emplos In the examples below, the following abbreviations have the following meanings. If the abbreviation is not defined, it has a generally accepted meaning. AcOH = acetic acid bd = broad doublet bm = broad multiplet bs = broad singlet Bn = benzyl Boc = N-tert-butoxycarbonyl Boc20 = di-tert-butyl dicarbonate BOP = benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate Cbz = carbobenzyloxy CHC13 = chloroform CH2C12 = dichloromethane (COCL) 2 oxalyl chloride d doublet doublet doublet triplet doublet DBU 1, 8-diazabicyclo [5.4. 0] undec-7- ene DCC 1,3-dicyclohexylcarbodiimide DMAP 4-N, N-dimethylaminopyridine DME ethylene glycol dimethyl ether DMF N, N-dimethylformamide DMSO dimethisulfoxide EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et3N - triethylamine Et20 = diethyl ether EtOAc = ethyl acetate EtOH = ethanol Fmoc = N- (9-fluorenylmethoxycarbonyl) FmocONSu = N- (9-fluorenylmethoxycarbonyl) -succinimide H20 = water HBr = hydrobromide acid HCl = hydrochloric acid HOBT = hydrate 1-hydroxybenzotriazole K2C03 = potassium carbonate L = liter m = multiplet MeOH = methanol mg = milligram MgSO4 = magnesium sulfate mL = milliliter mm = millimeter mM = millimolar mmol = millimole pf = melting point N = normal NaCl = sodium chloride Na2C03 = carbonate sodium NaHCO3 = sodium bicarbonate NaOEt ^ sodium ethoxide NaOH = sodium hydroxide NH4C1 = ammonium chloride "1MMM1X1M i ?? N-methylmorpholine Phe = L-phenylalanine Pro = L-proline psi = pound per square inch Pt02 = oxide platinum q = quartet qquuiinntt .. = = quintet s = singlet t = triplet t-BuOH = tert-butanol TFA = trifluoroacetic acid T THHFF = = tetrahydrofuran TLC or tlc = thin layer chromatography Ts = tosyl TsCl = tosyl chloride TsOH - tosylate μL = microliter The following methods can be used to prepare the compounds of this invention.

Method A Method of Preparation of Methyl Ester. Amino acid methyl esters can be prepared using the method of Brenner and Huber Helv. Chim. Acta 1953, 36, 1109. Method B BOP Coupling Procedure. The desired dipeptide ester is prepared by the reaction of a carboxylic acid (1 equivalent) with the appropriate amino acid ester ester or hydrochloride (1 equivalent), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate [BOP] (2.0 equivalents), triethylamine (1.1 equivalents), and DMF. The reaction mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography to provide the dipeptide ester. Method C Hydrogenation Procedure I. Hydrogenation is carried out using palladium in 10% carbon (10% by weight) in methanol at 30 psi overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to yield the desired compound. Method D Hydrolysis Procedure I. To a cooled solution (0 ° C) of THF / H20 (2: 1, 5-10 mL) of the appropriate ester, LiOH (or NaOH) (0.95 equivalents) was added. The temperature was maintained at 0 ° C and the reaction was completed in 1-3 hours. The reaction mixture was extracted with ethyl acetate and the aqueous phase was lyophilized resulting in the desired carboxylate salt. Method E Process of Hydrolysis of Ester II. To a cooled solution (0 ° C) of THF / H20 (2: 1, 5-10 mL) of the appropriate ester was added LiOH (1.1 equivalents). The temperature was maintained at 0 ° C and the reaction was completed in 1-3 hours. The reaction mixture was concentrated and the residue was taken up in H20 and the pH was adjusted to 2-3 with aqueous HCl. The product was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated to yield the desired acid.

Method F Hydrolysis Procedure of Ester III. The appropriate ester was dissolved in dioxane / H20 (1: 1) and 0.9 equivalents of 0.5 N NaOH was added. The reaction was stirred for 3-16 hours and then concentrated. The resulting residue was dissolved in H20 and extracted with ethyl acetate. The aqueous phase was lyophilized to yield the desired sodium carboxylate salt. Method G BOC Removal Procedure. Chlorhydrate gas was bubbled anhydrous (HCl) through a methanolic solution of the appropriate Boc amino acid ester at 0 ° C for 15 minutes and the reaction mixture was stirred for three hours. The solution was concentrated to a thick syrup and dissolved in Et20 and re-concentrated. This procedure was repeated and the resulting solid was placed under high vacuum overnight. Method H Hydrolysis Procedure of Tert-Butyl Ester I. The tert-butyl ester was dissolved in CH2C12 and treated with TFA. The reaction was completed in 1-3 hours, at which time the reaction mixture was concentrated and the residue was dissolved in H20 and lyophilized to yield the desired acid. Method I Coupling Procedure of EDC I. To a solution of CH2C12 (5-20 mL) of a carboxylic acid (1 equivalent), the appropriate amino acid ester hydrochloride (1 equivalent), N-methylmorpholine (1.1-2.2 equivalents) and 1-hydroxybenzotriazole (2 equivalents) were mixed, placed in an ice bath and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.1 equivalents) was added. The reaction was allowed to reach room temperature and stirred overnight. The reaction mixture was emptied into H20 and the organic phase was washed with saturated NaHCO3, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. The crude product was purified by column chromatography. Method J Coupling Procedure EDC II. To a solution of DMF (5-20 mL) of a carboxylic acid (1 equivalent), the appropriate hydrochloride of the amino acid ester (1 equivalent), Et3N (1.1 equivalent) and 1-hydroxybenzotriazole (2 equivalents) were mixed, placed in a bath with ice and l- (3- (dimethylaminopropyl) -3-ethyl carbodiimide (1.1 equivalents) was added. The reaction was allowed to reach room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and H20 and the organic phase was washed with 0.2 N citric acid, H20, saturated NaHCO3, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. The crude product was purified by column chromatography or preparative TLC. Method K Hydrolysis Procedure of Tert-Butyl II Ester. The tert-butyl ester was dissolved in CH2C12 (5 mL) and treated with TFA (5 mL). The reaction was complete in 1-3 hours, at which time the reaction mixture was concentrated and the residue was dissolved in H20 and concentrated. The residue was redissolved in H20 and lyophilized to yield the desired product. Method L: Carbamate Formation Procedure I. In a reaction vial, 15.2 mmol, 1.0 equivalent of the starting hydroxy compound (typically a tyrosine derivative) and 1.86 g (15.2 mmol, 1.0 equivalent) of DMAP were combined. Methylene chloride (50 mL), triethylamine (2.12 mL, 1.54 g, 15.2 mmol, 1.0 equivalent), and dimethylcarbamyl chloride (1.68 mL, 1.96 g, 18.2 mmol, 1.2 equivalents) were then added. The vial was sealed, and the reaction solution was mixed to obtain a homogeneous solution. The reaction solution was then heated to 40 ° C. After 48 hours, TLC of the resulting colorless solution indicated complete conversion. The work of the reaction solution was as follows: 50 mL of EtOAc and 50 mL of hexanes were added to the reaction mixture, and the resulting mixture was washed with 0.5 M citric acid. (3 x 50 mL), water (2 x 50 mL), 10% K2C03 (2 x 50 mL), and saturated NaCl (1 x 50 mL); it dried up with MgSO 4, filtered and evaporated to provide the desired compound. Method M Carbamate II Formation Procedure. In a small reaction flask, 84.34 mmoles (1.0 equivalent) of the starting hydroxy compound (typically a tyrosine derivative) and 17.0 g (84.34 mmoles, 1.0 equiv) of 4-nitrophenyl chloroformate were combined. Methylene chloride (700 mL) was added and the small vial was capped with a septum. A line of nitrogen was linked and the small bottle was immersed in a thick mixture of water / dry ice of ethanol stirring to cool to -15 ° C. Triethylamine (29.38 mL, 21.33 g, 210.81 mmol, 2.5 equivalents) was added over 5 minutes with stirring and stirring was continued at -10 to -15 ° C for 1 hour. N-methyl piperazine (9.35 L, 8.45 g, 84.34 mmol, 1.0 equivalent) was added for three minutes with stirring and stirring continued while warming to room temperature. The reaction mixture was diluted with 700 mL of hexanes and the resulting mixture was washed repeatedly with 10% K2CO3 until no yellow color (of 4-nitrophenol) was observed in the aqueous layer. The mixture was then washed with saturated NaCl, dried over anhydrous MgSO 4, filtered and evaporated. The residue was redissolved in 500 mL of ethanol and evaporated to remove the triethylamine. The residue was redissolved in 500 mL of ethanol and evaporated to remove the triethylamine. The residue was then dissolved in 400 mL of ethanol and 600 mL of water was added with stirring to precipitate a solid or oil. If an oil is formed, the oil is shaken vigorously to induce its solidification. The solid is then isolated by filtration. The solution, precipitation, and filtration are repeated once and the resulting solid is rinsed with water to remove the yellow traces. The solid is then subjected to high vacuum until the mass remains constant, whereby the desired carbamyloxy compound is provided. Method N Procedure for Hydrolysis of Tert-Butyl Ester. A solution of the tert-butyl ester (typically 0.95 mmol) in 25 mL of formic acid was stirred at 25 ° C for 24 hours. The solvent was removed and the residue was washed with diethyl ether (3x) to provide the desired product as a white solid.

Example 1. Synthesis of N-benzyl-L-pyroglutamyl-L-phenylalanine. Step A - Preparation of the Ethyl Ester of N-benzyl-L-pyroglutamic acid. Place (S) - (+) -2-pyrrolidone-5-carboxylic acid ethyl ester (1 g, 6.36 mmol) and benzyl bromide (0.76 mL, 6.36 mmol) in dry THF (30 mL). The reaction mixture was stirred and cooled to 0 ° C. A 1M tert-BuOK solution was added dropwise (6.36 mL, 6.36 mmol) and the reaction was stirred for an additional 0.5 hours at 0 ° C and allowed to return to room temperature where it was stirred for 24 hours under N2. The reaction was then dissolved in a 1: 1 mixture of H20 / EtOAc. The organic layer was washed with 1M HCl, H20, brine, and then dried over MgSO4 to give the N-benzyl-L-pyroglutamic acid ethyl ester as an oil. Step B - Preparation of N-benzyl-L-pyroglutamic acid. The ester of Step A is then hydrolyzed using the procedure described in Method F to provide N-benzyl-L-pyroglutamic acid.

Step C - Preparation of the Ethyl Ester of N-Benzyl-L pyroglutamyl-L-phenylalanine. The product of Step B is then coupled with ethyl L-phenylalanine ester using the procedure described in Method B (replacing the N-methylmorpholine with triethylamine) to provide the ethyl ester of N-benzyl 1-L-pyroglutamine 1-L-phenylalanine. The NMR data are as follows: 1E NMR (CDC13): d 7.29 (m, 6H), 7.10 (m, 4H), 6.28 (brd, ÍH), 5.13 (d, lH), 4.90 (m, lH), 4.19 (q, 2H), 3.77 (m, 2H), 3.29-2.98 (m, 2H), 2.37 (m, 2H), 2.16 (m, lH), 1.82 (m, lH), 1.28 (t, 3H) . 13 C NMR (CDCl 3): d 176.18, 171.84, 171.49, 136.32, 136.19, 129.67, 129.37, 129.31, 129.25, 129.01, 128.41, 127.87, 62.38, 60.58, 53.24, 45.89, 38.24, 30.12, 23.84, 14.74. Step D Preparation of N-benzyl-L-pyroglutamine 1-L-phenylalanine. The title compound was prepared by hydrolysis of the product from Step C using the procedure described in Method F. The NMR data are as follows: X NMR (CDCl 3): d 7.28 (m, 6H), 7.11 (m, 4H), 6.67 (brd, ÍH), 5.07 (d, lH), 4.97 (m, lH), 3.83 (m, lH), 3.71 (d, lH), 3.30 (m, lH), 3.00 (m, lH ), 2.38 (m, 2H), 2.16 (m, lH), 1.73 (m, lH). Example 2. Synthesis of N-benzyloxycarbonyl-L-pyroglutamyl-L-phenylalanine. The tert-butyl ester of N-benzyloxycarbonyl-L-pyroglutamyl-L-phenylalanine was prepared from appropriate starting materials using the procedure described in Method B. The title compound was then prepared using the procedure described in the Method D. The NMR data are as follows: XH NMR (CDC13): d 7.40-6.92 (m, lH), 5.19 (s, 2H), 4.93 (m, lH), 4.55 (m, lH), 3.25-2.89 (m, 2H), 2.42 (m, 2H), 2.16 (m, lH), 1.94 (m, lH). 13 C NMR (CDCl 3): d 175.1, 174.6, 171.0, 151.8, 136.4, 135.3, 129.9, 129.2, 129.1, 129.1, 128.8, 127.7, 69.2, 60.6, 53.4, 38.0, 31.8, 22.9. Example 3. Synthesis of N-benzyl-L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The title compound was prepared from appropriate starting materials using the procedures described in Examples 1 and 4. The NMR data are as follows: X H NMR (DMSO-d 6): d 10.24 (s, lH), 7.93 (d, 2H), 7. 74 (d, 2H), 7.64-7.49 (m, 3H), 7.35-7.16 (m, 5H), 7. 05 (d, 2H), 4.78 (d, lH), 4.54 (m, lH), 3.88 (m, lH), 3.20-2.78 (m, 2H), 2.22 (m, 2H), 2.12 (m, ÍH), 1.73 (m, ÍH). 13C NMR (DMSO-d6): d 175.0, 172.9, 171.3, 165.8, 137.7, 136.5, 135.0, 132.7, 131.5, 129.2, 128.5, 128.4, 127.8, 127.6, 127.3, 58.8, 53.2, 44.2, 36.0, 29.3, 22.3 . Example 4. Synthesis of N- (3, -dichlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. Step A - Preparation of Methyl Ester of N- (3, -dichlorobenzyl) -L-pyroglutamine 1-L-4-aminophenilanine. The methyl ester of N- (3,4-dichlorobenzyl) -L-pyroglutamine 1-L-4-aminophenylalanine was prepared from the appropriate starting materials using the procedures described in Methods B and C. Step B - Preparation of the Ester Methyl N- (3,4-dichlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The ester from Step A (230 mg, 0.495 mmol) is then placed in pyridine and benzoyl chloride (63.2 mL, 0.545 mmol) is added dropwise and the reaction is stirred for 2 hours. The resulting mixture is evaporated to dryness and taken up in EtOAc. The organic layer is washed with H20, 1M HCl, brine, and dried over MgSO4 to give the methyl ester of N- (3,4-dichlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) -phenylalanine as a solid white. Step C - Preparation of Methyl Ester of N- (3, -dichlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The title compound was prepared by hydrolyzing the product from Step B using the procedure described in Method F. The NMR data are as follows: X H NMR (DMSO-d 6): d 10.22 (s, lH), 8.56 (brd, lH ), 7.93 (d, 2H), 7.68 (d, 2H), 7.56 (m, 4H), 7.31 (s, lH), 7.20 (d, 2H), 7.00 (d, lH), 4.60 (d, lH) , 4.53 (m, lH), 3.96 (m, lH), 3.42 (d, lH), 3.16-2.79 (m, 2H), 2.32 (m, 2H), 2.19 (m, lH), 1.79 (m, ÍH) ). 13 C NMR (DMSO-d 6): d 175.4, 173.0, 171.1, 166.0, 138. 1, 138.0, 135.4, 133.1, 132.0, 131.5, 130.9, 130. 1, 129.8, 129.1, 128.4, 128.3, 127.6, 120.4, 59.4, 53.4, 43.7, 36.5, 29.6, 22.1.

Example 5 Synthesis of Methyl Ester of N- (3-chlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The title compound was prepared from appropriate starting materials using the procedure described in Example 4. The NMR data are as follows: X H NMR (DMSO-d 6): d 10.23 (s, l H), 8.67 (d, lH), 7.92 (d, 2H), 7.70 (d, 2H), 7.52 (m, 3H), 7.31 (m, 2H), 7.19 (m, 3H), 6.98 (m, 2H), 4.68 (d, lH ), 4.58 (m, lH), 3.93 (m, lH), 3.65 (s, 3H), 3.41 (d, lH) ', 3.11-2.82 (m, 2H), 2.30 (m, 2H), 2.15 (m , ÍH), 1.77 (m, ÍH). Example 6. Synthesis of N- (3-chlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The title compound was prepared from the product of Example 5 using the procedure described in Method F. The NMR data are as follows: tE NMR (DMSO-de): d 10.23 (s, lH), 8.67 (d, lH), 7.92 (d, 2H), 7.70 (d, 2H), 7.52 (m, 3H), 7.31 (m, 2H), 7.19 (m, 3H), 6.98 (m, 2H), 4.68 (d, lH ), 4.58 (m, lH), 3.93 (m, lH), 3.41 (d, lH), 3.11-2.82 (m, 2H), 2.30 (m, 2H), 2.15 (m, lH), 1.77 (m, lH). Example 7. Synthesis of N- (4-chlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The title compound was prepared from the product of Example 8 using the procedure described in Method F. The NMR data are as follows: X H NMR (DMSO-de): d 10.25 (s, lH), 8.51 (d, lH), 7.93 (d, 2H), 7.72 (d, 2H), 7.54 (m, 3H), 7.33 (d, 2H), 7.20 (d, 2H), 7.01 (d, 2H), 4.67 (d, lH ), 4.52 (m, lH), 3.85 (m, lH), 3.15-2.77 (m, 2H), 2.30 (m, 2H), 2.11 (m, lH), 1.76 (m, lH). Example 8. Synthesis of Methyl Ester of N- (4-chlorobenzyl) -L-pyroglutamyl-L-4- (enylcarbonylamino) phenylalanine. The title compound was prepared from appropriate starting materials using the procedure described in Example 4. The NMR data are as follows: X H NMR (DMSO-de): d 10.25 (s, lH), 8.51 (d, lH), 7. 93 (d, 2H), 7.72 (d, 2H), 7.54 (m, 3H), 7.33 (d, 2H), 7.20 (d, 2H), 7.01 (d, 2H), 4.67 (d, lH), 4.52 (m, lH), 3.85 (m, lH), 3.65 (s, 3H), 3.15-2.77 (m, 2H), 2.30 (m, 2H), 2.11 (m, lH), 1.76 (m, lH ). Example 9. Synthesis of Methyl Ester of N- (4-methylbenzyl) -L-pyroglutamyl-L- (4-enylcarbonylamino) phenylalanine. The title compound is prepared from appropriate starting materials using the procedure described in Example 4. The NMR data are as follows: XH NMR (DMS0-d6): d 10.25 (s, lH), 8.59 (d, lH), 7.94 (d, 2H), 7.74 (d, 2H), 7.55 (m, 3H), 7.20 (d, 2H), 7.09 (d, 2H), 6.89 (d, 2H), 4.73 (d, lH ), 4.60 (m, lH), 3.82 (m, lH), 3.66 (s, 3H), 3.32 (d, lH), 3.13-2.81 (m, 2H), 2.30 (m, 2H), 2.24 (s, 3H), 2.10 (m, lH), 1.73 (m, lH). Example 10. Synthesis of N- (4-methylbenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The title compound is prepared from the product of Example 9 using the procedure described in Method F. The NMR data are as follows: 1 H NMR (DMSO-d 6): d 10.25 (s, 1 H), 8.59 (d, lH), 7.94 (d, 2H), 7.74 (d, 2H), 7.55 (m, 3H), 7.20 (d, 2H), 7.09 (d, 2H), 6.89 (d, 2H), 4.73 (d, lH ), 4.60 (m, lH), 3.82 (m, lH), 3.32 (d, lH), 3.13-2.81 (m, 2H), 2.30 (m, 2H), 2.24 (s, 3H), 2.10 (m, lH), 1.73 (m, ÍH). Example 11. Synthesis of Methyl Ester of N- (4-methoxybenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine. The title compound is prepared from appropriate starting materials using the procedures described in Example 4. The NMR data are as follows: X H NMR (DMSO-de): d 10.25 (s, lH), 8.59 (d, lH), 7.94 (d, 2H), 7.74 (d, 2H), 7.55 (m, 3H), 7.42 (d, 2H), 6.92 (d, 2H), 6.83 (d, 2H), 4.73 (d, lH ), 4.60 (m, lH), 3.83 (m, lH), 3.70 (s, 3H), 3.65 (s, 3H), 3.32 (d, lH), 3.16-2.81 (m, 2H), 2.30 (m, 2H), 2.10 (m, lH), 1.73 (m, lH). 13C NMR (DMSO-de): d 174.8, 172.2, 171.6, 165.9, 158.9, 138.2, 136.4, 132.7, 131.9, 129.6, 129.6, 128.8, 128.6, 128.0, 120.4, 114.3, 58.8, 55.4, 53.5, 52.5, 44.0 , 36.2, 29.6, 22.8. Example 12. Synthesis of N- (4-methoxybenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) enylalanine.

The title compound is prepared from the product of Example 11 using the procedure described in Method F. The NMR data are as follows: X H NMR (DMSO-d 6): d 10.25 (s, lH), 8.59 (d, lH), 7.94 (d, 2H), 7.74 (d, 2H), 7.55 (m, 3H), 7.42 (d, 2H), 6.92 (d, 2H), 6.83 (d, 2H), 4.73 (d, lH ), 4.60 (m, lH), 3.83 (mlH), 3.70 (s, 3H), 3.32 (d, lH), 3.16-2.81 (m, 2H), 2.30 (m, 2H), 2.10 (m, lH) , 1.73 (m, ÍH). Example 13. Synthesis of N- (3-chlorobenzyl) -L-pyroglutamyl-L- (N '-benzyl) his idine. The N- (3-chlorobenzyl) -L-pyroglutamyl-L- (N '-benzyl) histidine methyl ester was prepared from the appropriate starting materials using the procedure described in Method B. The title compound was prepared then by hydrolysis of the methyl ester using the procedure described in Method E. The NMR data are as follows: X H NMR (DMSO-de): d 8.08 (brd, lH), 7.59 (s, lH), 7.38-7.12 ( m, 8H), 7.05 (s, lH), 6.84 (s, lH), 5.08 (m2H), 4.68 (d, lH), 4.27 (m, lH), 3.97 (m, lH), 3.59 (d, lH ), 3.05-2.70 (m, 2H), 2.26 (m, 2H), 2.08 (m, ÍH), 1.79 (m, ÍH). 13C NMR (DMSO-de): d 175.3, 173.9, 170.5, 139.9, 139.3, 138.1, 136.9, 133.5, 130.7, 129.0, 128.8, 127.8, 127.6, 127.0, 116.7, 59.8, 54.0, 49.8, 44.1, 31.1, 29.6 , 22.8. Example 14. Synthesis of Methyl Ester of N- (4-methylbenzyl) -L-pyroglutamyl-L- (Nf -benzyl) his idine. The title compound was prepared from appropriate starting materials using the procedures described in Examples 1 and 13. The NMR data are as follows: XH NMR (CDC13) d 8.18 (d, lH), 7.42 (s, lH ), 7.33 (m, 3H), 7.16-7.06 (m, 6H), 6.67 (s, lH), 5.14 (d, lH), 5.04 (s, 2H), 4.79 (m, lH), 3.88 (m, lH), 3. 82 (d, lH), 3.64 (s, 3H), 3.15-2.94 (m, 2H), 2.70- 2.57 (m, lH), 2.39 (m, lH), 2.27-2.00 (m, 2H). 13C NMR (CDCI3): d 176.2, 172.1, 172.1, 138.3, 138.0, 137.9, 136.4, 133.5, 130.0, 129.6, 129.2, 120.0, 127.8, 117.5, 60.8, 53.9, 53.9, 51.5, 45.5, 30.9, 29.5, 23.9 , 21.7. Example 15. Synthesis of N- (4-methylbenzyl) -L-pyroglutamyl-L- (N '-benzyl) histidine.

The title compound was prepared from the product of Example 14 using the procedures described in Method E. The NMR data are as follows: XH NMR (D20): d 7.70 (s, lH), 7.35-7.20 (m, 5H), 7.08 (d, 2H), 6.98 (s, lH), 6.74 (d, 2H), 5.05 (s2H), 4.49-4.42 (m, 2H), 3.94 (m, lH), 3.31 (d, lH ), 3.14-2.73 (m, 2H), 2.24 (s, 3H), 2.56-2.11 (m, 3H), 1.91 (m, ÍH). Example 16. Synthesis of N-benzyl-D-pyroglutamyl-L-phenylalanine. The title compound was prepared from appropriate starting materials using the procedures described in Examples 1 and 2. The NMR data are as follows: 1 H NMR (DMSO-de): d 8.52 (d, 1 H), 7.4- 7.1 (m, 10H), 6.97 (d, lH), 4.83 (dd, 2H), 4.73 (dd), 4. 50 (m, lH), 3.84 (m, lH), 3.50 (dd, 2H), 3.40 (dd), 3.13 (2H), 2.85 (2H), 2.19 (m, 2H), 2.03 (m, lH), 1. 48 (m, ÍH). 13C NMR (DMSO-d6): d 175.0, 173.2, 171.3, 138.0, 136.9, 129.5, 129.4, 128.9, 128.9, 128.6, 128.4, 128.2, 127.7, 126.8, 57.1, 53.5, 44.5, 35.8, 29.5, 22.9.

Example 17. Synthesis of N- (4-benzyl-3-oxothiomorpholine-5-carbonyl) -L-phenylalanine. The title compound was prepared from the product of Example 18 using the procedure described in Method F. The NMR data are as follows: X H NMR (CDCl 3): d 7.38-6.98 (m, 10 H), 5.48 (d , lH), 4.97 (m, lH), 4.20 (t, lH), 4.09 (t), 3.67 (d, lH), 3.50-2.78 (m, 6H). 13C NMR (CDCL3): d 175.5, 169.7, 168.0, 136.2, 135.8, 129.9, 129.5, 129.3, 129.0, 128.7, 128.0, 62.5, 53.9, 51.1, 38.0, 31.3, 29.4. Example 18. Synthesis of Ethyl Ester of N- (4-benzyl-3-oxothiomorpholine-5-carbonyl) -L-phenylalanine. Step A - Preparation of N-benzyl-3-oxothiomorpholin-5-carboxylic acid. S- (methocarboxyethyl) cis-tein was placed (Biochemistry, 1989, 28 (2), 465) (1633 g, 7.88 mmol) in MeOH (50 mL) and benzaldehyde was added. (0.8 mL, 7.88 mmol). The mixture was stirred during minutes and then sodium cyanoborohydride (0.594 g, 946 mmol) was added. The reaction was stirred overnight under N2 and then filtered to provide 853 mg of a white solid. This white solid was then heated in water overnight to give N-benzyl-3-oxothiomorpholine-5-carboxylic acid as a white solid Step B - Preparation of N- (4-benzyl-3-oxothiomorpholine) Ethyl Ester -5-carbonyl) -L-phenylalanine The title compound was prepared from the product of Step A and ethyl ester of L-phenylalanine using the procedures described in Method B. The NMR data are as follows: 2H NMR ( CDC13): d 7.38-7.15 (m, 10H), 6.57 (d, lH), 5.54 (d, lH), 4.17 (m, lH), 4.89 (q, lH), 4.20 (q, 2H), 3.09 (d, lH), 3.46 (d, lH), 3.25-2.80 (m, 5H), 1.29 (t, 3H). 13 C NMR (CDCl 3): d 171.6, 169.4, 168.6, 136.3, 136.1, 129.8, 129.7, 129.5, 129.3, 129.0, 128.6, 127.0, 62.4, 62.4, 53.8, 50.7, 38.1, 31.3, 29.4, 14.8. Example 19. Synthesis of Methyl Ester of N- (4-benzyl-3-oxothiomorpholine-5-carbonyl) -L-4-nitrophenylalanine.

The title compound was prepared from the appropriate starting materials using the procedures described in Example 18. The NMR data are as follows: XH NMR (CDC13) d 8.16 (d, 2H), 7.42-7.17 (m, 7H), 6.84 (d, lH), 5.63 (d, lH), 4.99 (m, lH), 4.18 (m, lH), 3.78-3.70 (m, 4H), 3.56 (d, lH), 3.38-3.15 (m, 3H), 3.05-2.87 (m, 2H). 13 C NMR (CDCl 3): d 171.5, 169.7, 166.5, 147.8, 144.1, 136.1, 130.8, 129.5, 128.9, 128.8, 124.4, 62.5, 53.7, 53.5, 50.9, 38.1, 31.5, 29.6. Example 20. Synthesis of the Isopropyl Ester of N-benzyl-L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine. The title compound was prepared from appropriate starting materials using the procedure described in Method L to provide white crystals, mp 167-169 ° C. The physical data are as follows: Analysis calculated for C2 H33N3? 6: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.06; H, 6.73; N, 8.42. MS (+ EI): 495 (M +) +.

Example 21. Synthesis of Methyl Ester of N-benzyl-L-pyroglutamyl-L-3-chloro-4- (N, N-dimethylcarbamyloxy) phenylalanine. The methyl ester of N-benzyl-L-pyroglutamyl-L-3-chloro-4-hydroxy-phenylalanine was prepared from appropriate starting materials using the procedure described in Method B. The title compound was then prepared from the methyl ester using the procedure described in Method L to provide a white solid. The physical data are as follows: Analysis calculated for C25H28C1N306 * 0.1 CH2C12: C, 59.06; H, 5.57; N, 8.33. Found: C, 59.08; H, 5.37; N, 8.24. MS (+ ESI): 502 (M + l) +. Example 22. Synthesis of N- (4-fluorobenzyl) -L-pyroglutamyl-L-4- (N, -dimethylcarbamyoxy) phenylalanine. The title compound was prepared from appropriate starting materials using the sequential application of the procedure described in Methods B, L and N to provide a white solid, mp 227-230 ° C. The physical data is as follows: Analysis calculated for C24H26FN306: C, 61.14; H, 5.56; N, 8.91. Found: C, 60.80; H, 5.48; N, 8.81. MS (+ ESI): 472 (M + 1) +. Example 23. Synthesis of N- (4-fluorobenzyl) -L-pyroglutamyl-L-4- [(thiomorpholin-4 '-11) carbonyloxy) phenylalanine. Tert-butyl ester of N- (4-fluorobenzyl) -L-pyroglutamine 1-L-4 - [(thiomorpholin-4'-yl) carbonyloxy) phenylalanine was prepared from appropriate starting materials using the procedure described in the Method M (thiomorpholine is replaced by N-methylpiperazine). The title compound is then prepared from the tert-butyl ether using the procedure described in Method N to provide a white solid, mp 266-268 ° C (dec.) The physical data are as follows: Analysis calculated for C26H28F 306S: C, 58.97; H, 5.33; N, 7.93. Found: C, 57.98; H, 5.09; N, 7.62. MS (-ESI): 528 (M-1) -. Example 24. Synthesis of N- (4-cyanobenzyl) -L-pyroglutamyl-L-4- (, N-dimethylcarbamyoxy) phenylalanine.

The title compound was prepared from appropriate starting materials using the sequential application of the procedures described in Methods B, L and N to provide a white solid, mp 232-236 ° C (dec).

The physical data are as follows: Analysis calculated for C25H26N 06 # 0.5 H20 * 0.08 C H? Q0: C, 61.63; H, 5.68; N, 11.35. Found: C, 62.01; H, 5.51; N, 11.00 MS (+ APCI): 479 (M + 1) +. Example 25. Synthesis of tert-butyl ester of N- (4-nitrobenzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine. The title compound was prepared from appropriate starting materials using the sequential application of the procedures described in Methods B and L to provide white crystals, mp 159-161 ° C. The physical data are as follows: Analysis calculated for C2sH3 N408: C, 60.64; H, 6.18; N, 10.10. Found: C, 60.41; H, 6.34; N, 9.73. MS (+ ESI): 555 (M + 1) +.

Example 26. Synthesis of N-benzyl-L-pyroglutamyl-L-3-chloro-4- (N, N-dimethylcarbamyloxy) phenylalanine. The title compound was prepared from the product of Example 21 using the procedure described in Method D to provide a white solid. The physical data are as follows: Analysis calculated for C2 H25C1N306LI »2.5 H20: C, 53.49; H, 5.61; N, 7.80. Found: C, 53.18; H, 5.02; N, 7.59. MS (+ ESI): 488 (M + 1) +. Example 27. Synthesis of N- (4-fluorobenzyl) -L-pyroglutamyl-L-4 - [(4'- (pyridin-2'-yl) piperazin-1'-yl) carbonyloxy] phenylalanine. The title compound was prepared from the product of Example 28 using the procedure described in Method N. The physical data are as follows: Analysis calculated for C3iH32FN5? 6ß .2.5 HC02H: C60.47; H, 5.39; N, 11.02. Found: C, 57.31; H, 5.69; N, 9.53. MS (-ESI): 588 (M-1) -.

Example 28. Synthesis of tert-butyl ester of N- (4-fluor'obenzyl) -L-pyroglutamyl-L-4- [(4 '- (pyridin-2'-11) piperazin-1'-yl) carbonyloxy] phenylalanine The title compound was prepared from appropriate starting materials using the procedures of Method M (the 1- (pyridin-2-yl) piperazine is replaced by N-methylpiperazine) to give white crystals, mp 198-199 ° C. The physical data are as follows: Analysis calculated for C35H40FN5? 6 C, 65.10; H, 6.24; N, 10.85. Found: C, 65.04; H, 6.17; N, 10.77. MS (+ ESI): 646 (M + l) +. Example 29. Synthesis of tert-butyl ester of N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-tyrosine. Step A - Preparation of the Methyl Ester of N- (pyridin-3-ylmethyl) -L-pyroglutamic acid. N- (pyridin-3-ylmethyl) -L-pyroglutamic acid methyl ester was prepared by the reductive alkylation of L-glutamic acid with the appropriate aldehyde followed by acid catalyzed cyclization using the procedures described in J. AMER. Chem. Soc. 106, 4539 (1984). The following work procedures were used: after "the aqueous solution (pH = 3) was heated • overnight, the solution was cooled to 25 ° C and the pH adjusted to 7 using 2N NaOH. The aqueous phase was lyophilized to a gummy solid which was treated with methanolic HCl overnight. After • from filtration, the solvent was evaporated to give the crude methyl ester which was taken up in CH2C12 and washed with saturated sodium bicarbonate, followed by saturated brine, and then dried over MgSO4 and evaporated to an oil. This oil was then subjected to flash chromatography on alumina (active grade 3) using ethyl acetate / hexane 1: 1 as the eluent to give the methyl ester of N- (pyridin-3-ylmethyl) -L-pyroglutamic acid as an oil colorless. Step B - Preparation of tert-butyl ester of N- (pyridin-3-ylmethyl) -L-pyroglutamine 1-L-tyros ina. The title compound was prepared by reacting the acid obtained from the hydrolysis of the product of Step A (using Method D) and the tert-butyl ester of L-tyrosine following the procedures described in Method B.

The physical data are as follows: Analysis calculated for C24H29 305 »0.22 C3H7NO« 0.7 H20: C, 63.26; H, 6.87; N, 9.63; Found: C, 63.16; H, 6.60; N, 9.44. 'MS (+ ESI): 440 (M + l) +. Example 30. Synthesis of N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine. The title compound was prepared from the product of Example 31 using the procedure described in Method N to provide a white solid. The physical data are as follows: Analysis calculated for C23H26N4? 6 # 0.12 C4H802 «0.25 H20: C60.05; H, 5.89; N, 11.93. Found: C59.94; H, 5.77; N, 11.91. MS (+ ESI): 455 (M + l) +. Example 31. Synthesis of the tert-butyl ester of N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamoyloxy) phenylalanine. The title compound was prepared from the product of Example 29 using the procedure described in Method M to provide a crystalline solid, mp 157-158 ° C. The physical data are as follows: Analysis calculated for C2 H3 N40e: C, 63.51; H, 6.71; ', 10.9-7. Found: C, 63.35; H, 6.75; N, 10.88. MS (+ ESI): 511 (M + l) +. Example 32. Synthesis of tert-butyl Ester of N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-4- [(4 '- (pyridin-2'-yl) piperazin-1'-yl) carbonyloxy ] phenylalanine. The title compound was prepared from appropriate starting materials using the procedures of Method M (the 1- (pyridin-2-yl) piperazine is replaced by N-methylpiperazine) to give a white solid. The physical data are as follows: Analysis calculated for C34H40NeOe C, 64.95; H, 6.41; N, 13.37. Found: C, 64.94; H, 6.40; N, 13.18. MS (+ ESI): 629 (M + l) +. Example 33 Synthesis of N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-4- [(4 '- (pyridin-2'-yl) piperazin-1'-yl) carbonyloxy] enylalanine.

The title compound was prepared from the product of Example 32 using the procedure described in Method N to provide a white solid. The physical data are as follows: Analysis calculated for C3oH32N6? 6: C, 62.93; H, 5.63; N, 14.68. Found: C, 62.20; H, 5.49; N, 14.22. MS (-ESI): 571 (M-1) -. Example 34. Synthesis of tert-butyl ester of N- (4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carbo -L-tyrosine. Step A - Preparation of 5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carboxylic acid. A solution of endo-6-carboxybicyclo [2.2.1] heptan-2-one (6.72 g, 43.6 mmol (J. Org. Chem. 41: 1233 (1976)), KCN (3.41 g, 52.4 mmol) and (NH4) ) 2C03 (16.77 g, 174.6 mmol) in 206 mL of H20-ethanol 1: 1 was heated 24 hours at 55 ° C. The condenser was then stirred and the reaction mixture was refluxed for 1.5 hours. The reaction was acidified with concentrated HCl and cooled to 5 ° C, a precipitate was obtained which was then washed with H20 and dried to give 1.74 g (18%) of a white solid, mp 286 ° C. This intermediate (1.74 g, 7.76 mmoles) was converted to the title compound by reflux in 30 mL of 2.5 N NaOH for 24 hours.Acidification to pH = 0 gave the desired product as a white solid, mp 298-300 ° C. The physical data is as follow: Analysis calculated for C 9 H 11 NO 3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.39; H, 6.24; N, 7.67. Step B - Preparation of the methyl ester of the -Oxo-4-azatricyclo [4.2.1.0 (3, 7)] nonane-3-carboxylic acid. To a suspension of 5-oxo-4-azatricyclo [4.2.1.0 (3, 7)] nonane-3-carboxylic acid (183 g, 1.0 mmol) in 10 mL of MeOH under nitrogen at -78 ° C was added SOC12 (75 μL, 1.0 mmol). After 169 hours, the solvent was evaporated to give 195 mg of a white solid which was taken in 10 mL of CHC13, washed sequentially with 10 mL of saturated NaHCO 3 and 10 mL of saturated NaCl, dried over MgSO 4 and evaporated to dryness. give 160 mg (81%) of a white solid, mp 142-144 ° C. The physical data is as follows: MS (FI-POS): 196 (M + 1) +. Step C - Preparation of the Methyl Ester of "4-Benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carboxylic acid. To a suspension of the methyl ester of 5-oxo-4-azatricyclo [4.2.1.0 (3 , 7)] nonane-3-carboxylic acid (68.8 mg, 3.52 mmol) in 10 mL of THF under nitrogen at 25 ° C was added with LiHMDS (3.87 mL of IN THF solution, 3.87 mmol) After 15 minutes, it was added Benzyl bromide (0.42 mL, 3.53 mmol) After 169 hours, the reaction was quenched by the addition of 10 mL of saturated NH4C1 solution The reaction mixture was divided between 30 mL of CH2C12 and 10 mL of H2O. The organic phase was separated, washed with 50 mL of saturated NaCl, dried over MgSO4 and evaporated to give 770 mg of an oil, and flash chromatography of 740 mg of this material, eluting with CH2C12-EtOAc 95: 5, gave 510 mg (51%) of the title compound as a colorless oil (solvate CH2C12 0.14) The physical data are as follows: MS (+ ESI): 286 (M + 1) + Step D - Preparation of 4-Benzyl-5 Acid -oxo -4-azatricyclo [4.2.1.0 (3, 7)] nonane-3-carboxylic acid.

A solution of 4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carboxylic acid methyl ester »0.14 of methylene chloride solvate (399 mg, 1.34 mmol) in 13 mL of MeOH under nitrogen at 25 ° C, 1.5 mL of LiOH IN was added. After 117 hours, the majority of the solvent was removed and the residue was taken up in 10 mL of IN NaOH, washed with 2 x 10 mL of Et02, acidified by the addition of 10 mL of 2N HCl, extracted 2x with 10 L 'of Et02, dried over MgSO4 and evaporated to give 225 mg (71%) of a white solid, mp 191-194 ° C. The physical data are as follows: • Analysis calculated for Ci6H? N03: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.56; H, 6.39; N, 5.01. Step E - Preparation of the tert-butyl ester of N- (4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3, 7)] nonane-3-carbonyl) -L-tyrosine. The title compound was prepared from 4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carboxylic acid (0.60 mmol) and tert-butyl ester of L-tyrosine using the procedures described in Example 1 to provide 300 mg (93%) of a white solid. The physical data are as follows: Analysis calculated for C29H3 N205 «0.5 C4H802: C, 69.64; H, 7.16; N, 5.24. Found: C, 69.41; H, 7.02; N, 5.34. MS (+ ESI): 491 (M + l) +. Example 35. Synthesis of tert-butyl ester of N- (4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carbonyl) -L-4- (N, N -dimethylcarbamyloxy) phenylalanine. The title compound was prepared from the product of Example 34 using the procedure described in Method L to provide a white solid. The physical data are as follows: Analysis calculated for C32H39N306: C, 68.43; H, 7.00; N, 7.48. Found: C, 67.98; H, 7.00; N, 7.27. MS (+ ESI): 562 (M + 1) +. Example 36. Synthesis of N- (4-benzyl-5-oxo-4-azatricyclo [.2.1.0 (3,7)] onano-3-carbon! 1) -L-4- (, N-dimethylcarbamyloxy) phenylalanine The title compound was prepared from the product of Example 35 using the procedure described in Method N to provide a white solid. 'The' physical data are as follows: Analysis calculated for C28H3? N3? 6 * 0.5 C4H? 00: C, 66.40; H, 6.69; N, 7.74. Found: C, 65.72; H, 6.42; N, 7.95. MS (+ ESI): 506 (M + l) +. Example 37. Synthesis of Ethyl Ester of N- (benzyl) -L-pyroglutamyl-L-tyrosine. To a solution of N-benzyl-L-pyroglutamic acid (J. Am. Chem. Soc. 106: 4539 '(1984), 1.00 g, 4.56 mmol), ethyl ester hydrochloride of L-tyrosine (1.23 g, 5.01 mmol) and BOP (2.22 g, 5.01 mmol) in DMF (32 mL) under nitrogen, triethylamine (1.14 g, 11.26 mmol) was added. ) dropwise and the resulting solution was stirred at room temperature for 22.5 hours. The reaction was quenched by the addition of 150 mL of saturated sodium bicarbonate and 150 mL of EtOAc. The organic layer was separated and washed sequentially with 150 L of H20, 150 mL of 10% citric acid and 150 mL of saturated brine, dried over MgSO4 and evaporated to 1.6 g (82%) of a white solid, mp 192 -194 ° C. The physical data are as follows: 1st NMR (DMSO-de, 400 MHz) d 9.23 (s, lH); 8.52 (d, lH, j = 7.9 Hz); 7.32-7.23 (m, 3H); 7.03-6.97 (m, 2H); 4.75 (d, ÍH, j = 15.2 Hz); 4.49-4.43 (m, lH); 4. 11-4.01 (m, 2H); 3.88-3.85 (m, lH); 3.37 (d, ÍH, j = 15.2Hz); 2.99-2.94 (m, lH); 2.78-2.72 (m, lH); 2.33-2.08 (m, 3H); 1.98 (s, 0.2H); 1.76-1.70 (m, lH); 1.14 (t, 3H, j = 7.25Hz). IR (KBr, cm-1) 3400; 3250; 3060; 1725; 1680; 1670; 1550; 1510; 1440; 1265; 1220. MS (-FAB) 409.1 (M-H); 381.0; 302.0; 275.0; 257.0; 217.0; 183.0; 91.0. Analysis calculated for C23H26N205 «0.2M EtOAc: C, 66.78; H, 6.50; N, 6.54. Found: C, 66.48; H, 6.35; N, 6.66. Example 38. Synthesis of N- (benzyl) -L-pyroglutamyl-L-tyrosine. To a solution of the ethyl ester of N- (benzyl-L-pyroglutamyl-Lt-irosine and ethyl acetate solvate 0.2 (0.139 g, 0.325 mmol) in MeOH (3.25 mL) under nitrogen, IN aqueous LiOH (0.72 mL) was added. 0.72 mmol) After 3 days, the solvent was evaporated and the residue was partitioned between 10 mL of H20 and 10 mL of CH2C12.The aqueous layer was washed with 10 mL of CH2C12 and acidified to pH = 1 by the addition of 7 mL of 1N HCl The precipitate was filtered, washed with 20 mL of 1: 1 CHC13 / EtOAc and dried to provide 0.0835 g of a white solid (67%) .The physical data are as follows: X H NMR (DMSO-d 6, 400 MHz) d 12.76 (brd s, 1 H); 9.22 (s, lH); 8.40 (d, ÍH, j = 8.35Hz); 7.32-7.23 (m, 3H); 7.02-6.97 (m, 4H); 6.68-6.65 (m, 2H); 4.74 (d, ÍH, j = 14.94Hz); 4.47-4.1 (m, ÍH); 3.87-3.84 (m, lH); 3.40-3.24 (m, lH); 3.03-2.98 (m, lH); 2.75-2.69 (m, lH); 2.35-2.04 (m, 3H); 1.76-1.69 (m, lH). IR (KBr, cm_1) 3280; 1745; 1670; 1660; 1550; 1515; 1255; 1200; 820; 700. MS (+ FAB) 383.1 (M + H); 367.1; 327.0; 311.0; 295.0; 279.0; 237.0; 197.0; 174.1; 136.0; 105.0. Analysis calculated for C2? H22N205 * 0.2M H20: C, 65.35; H, 5.85; N, 7.26. Found: C, 65.14; H, 5.66; N, 7.13. Example 39. Synthesis of Ethyl Ester of N- (benzyl) -L-pyroglutamyl-L-4 [(4'-methylpiperazin-1 '- (11) carbonyloxy] phenylalanine.

To a suspension of the ethyl ester of N- (benzyl-L-pyroglutamyl) -L-tyrosine and ethyl acetate solvate 0.2 (0.894 g, 2.09 mmol) and 4-nitrophenyl chloroformate (0.435 g, 2.09 mmol) in 13 mL of CH3CN / CH2C12 1: 1 under nitrogen at 0 ° C, was added DMAP (0.032 g, 0.26 mmol) followed by TEA (0.529 g, 5.22 mmol). After 30 minutes at 0 ° C, the reaction mixture was warmed to 25 ° C and maintained at this temperature for 30 minutes. The reaction was then cooled down to 0 ° C and 1-methylpiperazine (0.206 g, 1.06 mmol) was added. The ice bath was then stirred and the reaction mixture was stirred at 25 ° C for 3 hours and 15 minutes. The reaction mixture was then diluted with 50 mL of Et20 and washed with 4x25 mL of 10% sodium carbonate, diluted with CH2C12, dried over K2C03 and evaporated to 1.0 g (88%) of crude solid which was recrystallized from toluene / hexane to give white crystals, mp 145-148 ° C. The physical data are as follows: XH NMR (DMSO-de, 400 MHz) d 8.59 (d, lH, j 8.1Hz); 7.31-7.19 (m, 5H); 7.04-7.00 (m, 4H); 4.76 (d, lHj = 15.2Hz); 4.56-4.51 (m, lH); 4.11-4.05 (m, 2H); 3.87-3.84 (m, lH); ); 3.54-3.35 (m, 5H); 3. 10-3.05 (m, lH); 2.90-2.84 (m, lH); 2.32-2.09 (m, 10H); 1.74-1.69 (m, lH); 1.24-1.23 (m, 0.4H); 1.15 (t, 3H, j = 7.0Hz); 0.85 (m, 0.3H). IR (KBr, cm-1) 33.00; 1740; 1720; 1680; 1650; 1550; 1410; 1240; 1210; 1200; 1160; 700. MS (EI) 536 (M +); 491; 2. 3. 4; 174; 127; 91; 83; 70; 58; 44. Analysis calculated for C29H36N406 «O.lM C6H? 4: C, 65.22; H, 6.90; N, 10.28. Found: C, 65.06; H, 6.66; N, 9.88. Example 40. Synthesis of the lithium salt of N- (benzyl) -L-pyroglutamyl-L-4- (1 '-methylpiperidin-4'-yloxy) enylalanine. To a solution of the ethyl ester of N- (benzyl) -L-pyroglutamyl-L-4 - [(4'-methylpiperazin-1'-yl) carbonyloxy] phenylalanine and hexane solvate 0.1 (0.200 g, 0.367 mmol) in MeOH (3.67 mL) under nitrogen, IN aqueous LiOH (0.35 mL, 0.35 mmol) was added. After 28 hours, the solvent was removed, 25 mL of H20 was added, the aqueous solution was washed twice with 25 mL of CH2C12, filtered and lyophilized to provide 0.16 g (77%) of a white solid. The physical data are as follows: 1R NMR (DMSO-de, 400 MHz) d 7.60 (d, 2H, j = 7.3Hz); 7.30-7.21 (m, 3H); 7.13-7.10 (m, 2H); 7.05-7.03 (m, 2H); 6.92-6.88 (m, 2H); 4.75 (d, lHj = 15.2Hz); 4.04-4.01 (m, lH); 3.89-3.86 (m, lH); 3.54-3.33 (m, lH); 3.13-3.09 (m, lH); 2.92-2.87 (m, lH); 2.33-2.05 (m, 10H); 1.79-1.75 (m, lH). IR (KBr, cm "1) 3400; 1720; 1680; 1610; 1420; 1240; 1200; 1160; 1000; 710. MS (+ FAB) 515.0 (M + Li); 471.0; 220.9; 174.0; 91.0. for C2 H3? N406Li «3. OM H20: C, 57.04; H, 6.56; N, 9.85 Found: C, 57.27; H, 5.70; N, 9.59.Example 41. Synthesis of Ester Methyl N- (benzyl) - L-pyroglutamyl-L-4- (pyridin-4-ylcarbonylamino) phenylalanine A solution of N-benzyl-L-pyroglutamic acid (J.Am. Chem. Soc. 106: 4539 (1984), 1.00 g, 4.562 mmol), methyl ester of 4 - [(4-pyridinylcarbonyl) amino] -L-phenylalanine (1532 g, 4. 562 mmol) and BOP (2.018 g, 4.562 mmol) in acetonitrile (30.0 mL) was charged into a 100 mL round bottom flask equipped with a stir bar and a nitrogen inlet. Triethylamine (1272 μL, 9.123 mmol) was added dropwise and the resulting solution was stirred at 25 ° C for 16 hours. The solvent was completely exhausted and the material was taken up in methylene chloride (75 mL) and washed with saturated sodium bicarbonate solution (50 mL x 3), dried (K2C03) and the solvent was removed to give a solid. beige (2,000 g). This material was chromatographed on silica gel (CH2C12: CH30H 9: 1) yielding a white solid which was recrystallized from acetonitrile to provide 1.744 g (76%) of white needles, mp = 204-208 ° C. The physical data are as follows: 1 1 NMR (DMSO-d 6, 400 MHz) d 10.47 (s, 1 H); 8.77 (d, 2H, j = 6.2Hz); 8.60 (d, ÍH, j = 7.9Hz); 7.83 (d, 2H, j = 6.2Hz); 7.71 (d, 2H, j = 8.6Hz); 7.31-7.19 (m, 5H); 7.02 (d, 2H, j = 5.1Hz); 4.76 (d, 1H, j = 14.9Hz); 4.61-4.55 (m, lH); 3.87-3.84 (m, lH); 3.65 (s, 3H); 3.36 (d, ÍH, j = 14. Hz); 3.11-3.06 (m, lH); 2.89-2.83 (m, lH); 2.34-2.21 (m, 2H); 2.17-2.09 (m, lH); 1.76-1.70 (m, 1H). IR (KBr, cm_1) 3400; 3325; 3100; 3030; 2960; 1660; 1625; 1540; 1490; 1425; 1325; 1225; 700. MS (+ FAB) 501.1 (M + H); 485.1; 475.1; 465.1; 451.0; 394.1; 279.0; 174.0; 91.0.

Analysis calculated for C28H28N405 «0.15 CH2C12: C, 65.87; H, 5.56; N, 10.92. Found: C, 65.87; H, 5.70; N, 11.36. Example 42. Synthesis of the lithium salt of N- (benzyl) -L-pyroglutamyl-L-4- (pyridin-4-ylcarbonylamino) phenylalanine. The methyl ester of N- (benzyl) -L-pyroglutamyl-L-4- (pyridin-4-ylcarbonylamino) -phenylalanine and methylene chloride solvate 0.15 (0.400 g, 0.799 mmol) in methanol (15 mL) was taken and the solvent was stripped of electrons completely using a rotary evaporator. This procedure was repeated twice more to remove any acetonitrile residue. The solid was dissolved in methanol (15 mL) and charged to a 25 mL round bottom flask equipped with a magnetic stir bar, air condenser and nitrogen inlet. The mixture was warmed until the ester dissolved (oil bath temperature = 40 ° C) and LiOH IN (759 μL, 0.759 mmol) was added via syringe, and the solution was stirred for 16 hours under nitrogen. . The reaction solution was transferred to a 50 mL round bottom flask and the solvent was completely exhausted yielding a white solid (0.731 g). This solid was taken up in water (50 mL) and washed with methylene chloride (25 mL). An emulsion was formed and allowed to separate. The organic phase was separated and the aqueous phase was filtered, pumped for 3 hours and lyophilized to give 0.353 g (94%) of a white soft solid, mp = 347 ° C (decomposed). The physical data are as follows: X H NMR (DMSO-de, 400 MHz) d 10.48 (s, 1 H); 8.76-8.74 (m, 2H); 7.85-7.83 (m, 2H); 7.60 (t, 2H, j = 8.6Hz); 7.53 (d, lH, j = 6.8Hz); 7.30-7.20 (m, 3H); 7.15-7.09 (m, 2H); 7.04 (d, 2H, j = 7.6Hz); 4.77 (d, lH, j = 15.4Hz); 4.01-3.98 (m, 1 H); 3.90-3.86 (m, lH); 3.43 (d, ÍH, j = 15.2Hz); 3.13-3.08 (m, lH); 2.94-2.89 (m, lH); 2.29-2.19 (m, 2H); 2.11-2.05 (m, ÍH), 1.80-1.77 (m, ÍH). IR (KBr, cm "1) 3325; 3030; 2960; 1660; 1600; 1530; 1425; 1325; 830; 700. MS (+ FAB) 487.0 (M + H); 471.0; 450.9; 429.0; 417.0; 400.9; 385.0; 279.0; 236.9; 91.0 Analysis calculated for C27H26N 05 «3.00 H20 C58.34; H, 5.72; N, 10.25. Found C, 58.45; H, 5.44; N, 9.95.

Example 43. Synthesis of Ethyl Ester of N- (benzyl) -L-pyroglu ami1- - n-rofenylalanine. A solution of N-benzyl-L-pyroglutamic acid (J. Am. Chem. Soc. 106: 4539 (1984), 1. 00 g, 4. 562 mmoles), ethyl ester of (S) -4-nitro-phenylalanine (1262 g, 4.562 mmol) and HOBT (1,233 g, 9,123 mmoles) in methylene chloride (40.0 mL) was charged to a 100 mL round bottom flask equipped with a stir bar and a nitrogen inlet. A Hunig base (3.25 mL, 18.246 mmol) was added dropwise. The solution that was heterogeneous and thus acetonitrile (10 mL) was added, followed by the addition of EDC (1749 g, 9123 mmol) and the resulting milky white mixture was stirred at 25 ° C for 16 hours. The solvent was completely exhausted and the solid was taken up in ethyl acetate (100 mL) and washed with saturated ammonium chloride solution (10Q mL x 2), saturated sodium bicarbonate solution (50 mL x 2), brine ( 50 mL x 2), dried (MgSO 4) and the solvent was removed to yield 1166 g (58%) of a yellow solid. This material was recrystallized from ethyl acetate to give a white solid, mp = 186-187 ° C.

The physical data are as follows: 1R NMR (DMSO-de, 400 MHz) d 8.63 (d, 1H, j = 8.1Hz); 8.15 (d, 2H, j = 9.1Hz); 7.51 - (d, 2H, j = 8.8Hz); 7.29-7.23 (m, 3H); 6.99-6.95 (m, 2H); 4.76 (d, ÍH, j = 15.2Hz); 4.69-4.64 (m, lH); 4. 11 (q, 2H, j = 5.5Hz); 3.82-3.79 (m, 2H); 3.37 (d, lH, j = 15.2Hz); 3.28-3.23 (m, lH); 3.06-3.00 (m, lH); 2.33-2.21 (m, 2H); 2.17-2.09 (m, lH); 1.73- 1.65 (m, lH); 1.16 (t, 3H, j = 7.1Hz). IR (KBr, cm "1) 3300; 3100; 2990; 2900; 1730; 1690; 1600; 1515; 1450; 1350; 1275; 1250; 1175; 1100; 1025; 840; 750; 700. MS (+ FAB) 439.0 (M + H); 422.0; 394.0; 366.0; 176.0; 175.0; 174.0; 165.0; 146.0; 118.0; 106.0; 92.0; 91.0; 90.0; 84.0; 65.0. Analysis calculated for C2 H26 2? 6 »0.09 CH2C12 C, 62.03; H, 5.80; N, 9.59. Found: C, 62.03; H, 5.68; N, 9.40. Example 44. Synthesis of the lithium salt of N- (benzyl) -L-pyroglutamyl-4-nitrophenylalanine. Ethyl ester of N- (benzyl) -L-pyroglutamyl-L-4-nitrophenylalanine and 0.09 methylene chloride solvate (0.100 g, 0.228 mmol) was dissolved in refluxing ethanol (10 mL) and charged to a bottom flask. round of 25 mL equipped with a magnetic stir bar, air condenser and nitrogen inlet. LiOH IN (216 μL, 0.216 mmol) was added via syringe, and the solution was stirred at 70 ° C for 16 hours under nitrogen. The reaction solution was brought from clear to dark during the addition of LiOH and some precipitate was noted. This solution was transferred to a 125 mL separatory funnel with an additional 50 mL of water and washed with methylene chloride (50 mL). An emulsion was formed and allowed to separate. The organic phase was stirred and the aqueous phase was filtered, pumped for 3 hours and lyophilized to give 0.048 g, (53%) of a white soft solid, mp = 285-287 ° C (decomposed). The physical data are as follows: X H NMR (DMSO-d 6, 400 MHz) d 8.07-8.02 (m, 2H); 7.64-7.61 (m, lH); 7.39-7.36 (m, 2H); 7.31-7.21 (m, 3 H); 7.13 (d, lH, j = 7.5 Hz); 7.00 (d, lH, j = 7.6 Hz); 4.75 (d, lH, j = 15.4 Hz); 4.06-4.01 (m, lH); 3.94-3.89 (m, lH); 3.45 (d, ÍH, j = 15.4 Hz); 3.07-2.99 (m, ÍH); 2.29-2.14 (m, 2H); 2.12-2.00 (m, 1H); 1.79-1.73 (m, ÍH); 1.57-1.54 (m, ÍH). IR (KBr, cm "1) 3400; 3100; 2900; 1675; 1600; 1515; 1450; 1425; 1350; 1250; 1100; 840; 690.

MS (-FAB) 410.1 (M-H); 394.0; 337.1; 275.1; 217.1; 183.0; 153.0; 109.0; 91.0. Analysis calculated for C2? H2iN3? 6 »l .25H20 C, 57.34; H, 5.16; N, 9.55. Found: C, 57.44; H, 5.05; N, 9.48. Example 45. Synthesis of the ethyl ester of N- (benzyl) -L-pyroglutamyl-L-4-aminophenylalanine. An ethyl ester solution of N- (benzyl) -L-pyroglutamyl-L-4-nitrophenylalanine and 0.09 methylene chloride solvate (0.900 g, 2048 mmol) and SnC12 * H20 in ethanol (30 mL) was charged to a flask. 100 mL round bottom equipped with a magnetic stir bar and a nitrogen inlet. This solution was stirred at room temperature, under nitrogen, for 16 hours. The reaction solution was transferred to a 125 mL separatory funnel with 50 mL of ethyl acetate. The organic phase was washed with saturated sodium bicarbonate (50 mL), dried (K2CO3), and the solvent was removed to yield 0.702 g of a white solid. This material was chromatographed on silica gel (ethyl acetate giving 0.362 g (39%) of a white solid, mp = 147 ° C. The physical data are as follows: X H NMR (DMSO-de, 400 MHz) d 8.49 (d, ÍH, J = 8.1 Hz); 7.34-7.24 (m, 3H); 7.04 (d, 2H, J = 7.7 Hz); 6.84 (d, 2H, J = 8.3 Hz); 6.48 (d, 2H, J = 9.3 Hz); 4.94 (s, 2H); 4.76 (d, ÍH, J = 14.9 Hz); 4.44-4.38 (m, ÍH); 4.11-4.01 (m, 2H); 3.89-3.86 (m, ÍH); 3.40 (d, ÍH, J = 15.2 Hz); 2.91-2.86 (m, 1H); 2.72-2.66 (m, ÍH); 2.34-2.20 (m, 2H); 2.16-2.08 (m, ÍH); 1.77-1.71 (m, ÍH); 1.16 (t, 3H, J = 7.1 Hz). IR (KBr, cm "1) 3400; 3300; 3040; 3030; 2990; 2950; 1740; 1675; 1550; 1525; 1425; 1225; 1200; 1125; 830; 700. MS (+ FAB) 409.0 (M + H ); 336.0; 253.4; 253.0; 191.0; 174.0; 146.0; 107.0; 106.0; 91.0; 90.0; 77.0; 65.0; 55.0; 46.0; 45.0; 44.0; Analysis calculated for C23H27N304: C, 67.47; H, 6.65; N, 10.26 Found: C, 67.08; H, 6.69; N, 10.20 Example 46. Synthesis of tert-butyl ester of N- (benzyl) -L-pyroglutamyl-L-4- [(thiomorpholin-4'-yl) carbonyloxy] Phenylalanine A solution of N-benzyl-L-pyroglutamic acid (J.Am. Chem. Soc. 106: 4539 (1984), 10.00 g, 45.62 mmoles), tert-butyl ester of L-tyrosine (11.91 g, 50.17 mmol) and BOP (22.19 g, 50.17 mmol) in DMF (250.0 mL) was loaded into a 500 mL round bottom flask equipped with a stir bar and a nitrogen inlet. Triethylamine (7.00 mL, 50.17 mmol) was added dropwise and the resulting solution was stirred at 25 ° C for 16 hours. The solution was transferred to a 1.0 L separatory funnel with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate solution (300 mL x 2), brine (300 mL x 2), dried (MgSO4) and the solvent was removed to give 18. 63 g (93%) of tert-butyl ester of N- (benzyl) -L-pyroglutamyl-L-tyrosine as a white solid. A solution of tert-butyl ester of N- (benzyl) -L-pyroglutamyl-L-tyrosine (1.00 g, 2280 mmol) and 4-nitrophenyl chloroformate (0.442 g, 2. 092 mmol) was dissolved in methylene chloride (5 mL) and charged to a 25 mL round bottom flask equipped with a magnetic stir bar and a nitrogen inlet. The solution was cooled in an ice bath and triethylamine (729 μL, 5.230 mmol) was added via syringe, and the resulting yellow solution was stirred for 30 minutes in an ice bath, and then 30 minutes at room temperature . The solution was re-cooled in an ice bath and thiomorpholine (210 μL, 2092 mmol) was added. The solution was allowed to warm to room temperature and stirred for 16 hours under nitrogen. The solution was transferred to a 250 mL separatory funnel with 100 mL of diethyl ether and this organic phase was washed with 10% K2CO3 (50 mL x 12), dried (K2C03) and the solvent was removed to give a solid. white (0.992 g). This material was recrystallized from ethanol to give 0.411 g (35%) of white crystals, mp = 169-171 ° C. The physical data are as follows: X H NMR (DMSO-de, 400 MHz) d 8.53 (d, H) , J = 8.1 Hz); 7.33-7.21 (m, 5H); 7.07-7.03 (m, 4H); 4.78 (d, ÍH, J = 15.2 Hz); 4.49-4.36 (m, 1H); 3.89-3.86 (m, ÍH); 3.82 (s, 2H); 3.68 (s, 2H); 3.43 (d, ÍH, J = 17.0 Hz); 3.08-3.03 (m, 1 H); 2.89-2.83 (m, ÍH); 2.67 (s, 4H); 2.32-2.26 (m, 2H); 2.17-2.11 (m, ÍH); 1.77-1.73 (m, ÍH); 1.38 (s, 9H). IR (KBr, cm "1) 3400; 3300; 3100; 2910; 1725; 1675; 1660; 1530; 1510; 1460; 1420; 1375; 1300; 1225; 1200; 1100; 960; 800; 760; 700; 650; 550 MS (+ FAB) 635.5 (M + NH 4); 618.4; 562.2; 506.4; 407.8; 344.5; 255.9. EXAMPLE 47 Synthesis of Methyl Ester of N- (Benzyl) -L-pyroglutamyl-L-4 (1'-benzyloxycarbonylpiperidin-4'-alkylcarbonylamino) phenylalanine. To a solution of N-benzyl-L-pyroglutamic acid (0.50 g, 2.275 mmol), methyl ester hydrochloride of L-4- (1-benzyloxycarbonylpiperidin-4'-alkylcarbonylamino) phenylalanine (1.08 g, 2275 mmol) and BOP (1.10 g, 2.48 mmol) in acetonitrile (60 mL) under nitrogen, triethylamine (0.7 mL, 5.005 mmol) was added dropwise. The mixture was stirred 48 hours at room temperature. The reaction was then worked up by evaporation of the solvent, the addition of ethyl acetate, sequential washing with IN HCl solution, water, saturated sodium bicarbonate solution, saturated brine and dried with MgSO4. Evaporation of the solvent gave a crude solid which was purified by flash chromatography using EtOAc / MeOH (99: 1) as eluent, to give the desired product as a solid (0.332 g, mp 223-225 ° C, 23% yield) .

The physical data are as follows: XE NMR (DMSO-de, 400 MHz) d 9.88 (s, ÍH); 8.56 (d, ÍH, J = 8.1 Hz); 7.52 (d, 2H, J = 8.5 Hz); 7.4-7.2 (m, 8H); 7.11 (d, 2H, J = 8.3 Hz); 6.99 (d, 2H, J == 8.1 Hz); 5.07 (s, 2H); 4.73 (d, ÍH, J = 14.7 Hz); 4.54 (m, ÍH); 4.02 (m, 2H); 3.84 (m, ÍH) -; 3.63 (s, 3H); 3.27 (m, 2H); 3.02 (m, ÍH); 2.90-2.79 (brd m, 3H); 2.30-2.23 (brd m, 2H); 2.10 (m, ÍH); 1.80-1.70 (brd m, 3H); 1.55-1.45 (brd m, 2H). IR (KBr, cm -i • 3400 3275 2910 1690, 1550 1435; 1325; 1225; 1120; 1100; 1010; 940; 700. MS (+ FAB) 663.1 ([M + Na] +); 597.1; 507.1; 174.0; 91.0. Analysis calculated for C36H40N4O7 «0.15C4H802: C66.12; H, 6.35; N, 8.56. Found: C, 66.03; H, 5.01; N, 8.56. Example 48. Synthesis of N- (benzyl) -L-pyroglutamyl-L-4- (1'-benzyloxycarbonylpiperidin-4'-carbonylamino) phenylalanine. To a methyl ester suspension of N- (benzyl) -L-pyroglutamyl-L-4 - (1'-benzyloxycarbonyl-piperidin-4'-carbonylamino) phenylalanine (0.30 g, 0.468 mmol) in a solution of aqueous methanol (MeOH) H20, 12 mL / lmL) under nitrogen, solid LiOH (0.039 g, 0.929 mmol) was added. After stirring for 24 hours, the solvent was concentrated to about 3 mL and acidified using a 10% citric acid solution. A white precipitate was filtered thoroughly, washed with water and dried in va cuo to yield the product as an off white solid (0.22 g, mp 193-16 ° C, 75% yield). The physical data are as follows: 1 H NMR (DMSO-de, 400 MHz) d 9.87 (s, ÍH); 8.42 (d, 1H, J = 8.3 Hz); 7.52 (d, 2H, J = 8.5 Hz); 7.4-7.2 (, 8H); 7.11 (d, 2H, J = 8.5 Hz); 6.97 (d, 2H, J = 7.9 Hz); 5.07 (s, 2H); 4.73 (d, 1H, J = 15.1 Hz); 4.49 (m, ÍH); 4.02 (brd d, 2H, J = 12.7 Hz); 3.84 (m, ÍH); 3.26 (s, ÍH); 3.07 (m, ÍH, 2.98-2.7 (brd m, 3H), 2.32-2.20 (brd m, 2H), 2.10 (m, 1H), 1.80-1.70 (brd m, 3H): 1.55-1.45 (brd m, 2H) IR (KBr, cm "1) 3420; 3300; 3050; 2950; 1660; 1550; 1440; 1325;: .225; 1175; 1110; 1060; 950; 820; 760; 700; 510. MS (+ FAB) 625.4 ([MH] -); 491.3; 367.2; 275.1; 183.1; 91.0.

Analysis calculated for C35H38N407 * 1.5H20: C, 64.30; H, 6.32; N, 8.57. Found: C, 64.33; H, 6.09; N, 8.44. Example 49. Synthesis of N- (benzyl) -L-pyroglutamyl-L-4- (piperidin-1-ylcarbonylamino) phenylalanine hydrochloride. Hydrogen bromide in HOAC (33% by weight, 2 mL) was added to a flask containing N- '(benzyl) -L-pyroglutamyl-L-4- (1'-benzyloxycarbonylpiperidin-4'-carbonylamino) phenylalanine (0.10). g, 0.16 mmol) and stirred for 50 minutes. Et20 was added until a precipitate was deposited completely from the solution. the mixture was then stirred for 10 minutes. The precipitate was filtered completely and washed with fresh Et20. The Et20 layers were discarded. The precipitate was then washed with water until all the material in the paper filtered dissolved. This aqueous phase was then lyophilized to generate the product as a solid (0.082 g, mp 191-194 ° C, 81% yield). The physical data are as follows: XH NMR (DMSO-de, 400 MHz) d 9.98 (s, ÍH); 8.48 (m, 2H); 8.25 (brd s, ÍH); 7.52 (d, 2H, J = 8.3 Hz); 7.27-7.20 (m, 3H); 7.13 (d, 2H, J = 8.5 Hz); 6.97 (d, 2H, J = 8.1 Hz); 4.70 (d, ÍH, J = 14.9 Hz); 4.49 (m, ÍH); 3.83 (, ÍH); 3.05 (, ÍH); 2.86-2.94 (m, 2H); 2.89-2.73 (m, ÍH); 2.67-2.57 (m, ÍH); 2.32-2.19 (brd m, 2H); 2.14-2.06 (brd m, ÍH); 1.98-1.90 (m, 2H); 1.83-1.68 (brd m, 2H). MS (+ FAB) 493.2 ([m + H] +); 482.0; 460.1; 307.1; 220.2; 176.0; 154.1. Analysis calculated for C27H32N405 »HBr» 3.3H20: C, 51.23; H, 6.30; N, 8.85. Found: C, 51.19; H, 5.79; 'N, 8.80. Example 50. Synthesis of Ethyl Ester of N- (benzyl) -L-pyroglutamyl-L-4- (1 '-methylpiperidin-4'-yloxy) phenylalanine. To a solution of N- (benzyl) -pyroglutamic acid (0.29 g, 1.32 mmol), ethyl ester dihydrochloride salt of L-4- (1-methyl-piperidin-4'-yloxy) phenylalanine (0.50 g, 1.32 mmol ) and BOP (0.64 g, 1.45 mmol) in DMF (15 mL) under nitrogen, triethylamine (0.64 mL, 4.62 mmol) was added and the mixture was stirred at room temperature for 7 days. The reaction was then quenched by the addition of excess saturated sodium bicarbonate solution and EtOAc. The organic phase was separated and concentrated to an oil which was flash chromatographed using CH2C12 / MeOH (95: 5) as eluent to give the product as a solid (0.15 g, 22% yield). The physical data are as follows: XH NMR (DMSO-de, 400 MHz) d 8.57 (d, ÍH, J = 7.9 Hz); 7.26 (, 3H); 7.11 (d, 2H, J = 8.5 Hz); 7.01 (m, 2H); 6.86 (d, 2H, J = 8.5Hz); 4.72 (d, 1H, J = 15.1 Hz); 4.52 (m, ÍH); 4.33 (brd s, ÍH); 4.0-4.1 (brd m, 3H); 3.85 (m, 1H); 3.02 (m, ÍH); 2.70-2.83 (brd m, 3H); 2.40-2.20 (brd m, 7H); 2.12 (m, ÍH); 1.93-1.85 (brd's, 2H); 1.75-1.50 (brd m, 4 H); 1.21-1.12 (m, 3H). MS (El) 507 ([M + H] +); 421; 174; 133; 107; 98; 700. Analysis calculated for C29H37N305: C, 68.62; H, 7.35; N, 8.28. Found: C, 60.53; H, 6.91; N, 8.20. Example 51 Synthesis of the Lithium Salt of N- (benzyl) -L-pyroglutamyl-L-4- (1 '-methylpiperidin-4'-yloxy) phenylalanine. To a solution of the ethyl ester of N- (benzyl) -L-pyroglutamyl-L-4 - (1'-methypiperidin-4'-yloxy) phenylalanine (0.10 g, 0.197 mmol) in MeOH (3 mL) under nitrogen, a solution of LiOH IN (0.187 mL, 0.187 mmol) was added. After stirring overnight, the solvent was evaporated and a 10% citric acid solution was added. The precipitate was filtered off completely, washed with water and dried in va cuo to produce the product as a solid (0.08 g, mp 232-235 ° C, 83% yield). The physical data are as follows: XH NMR (DMSO-de, 400 MHz) d 7.60 (d, ÍH, J = 7.2 Hz); 7.25 (m, 3H); 7.01 (m, 4H); 6.70 (d, 2H, J = 11.4 Hz); 4.71 (d, ÍH, J = 15.1 Hz); 4.18 (m, ÍH); 4.02 (m, ÍH); 3.87 (m, ÍH); 3.05 (m, ÍH); 2.85 (m, ÍH); 2.57-2.54 (brd m, 2H); 2.28-2.18 (m, 2H); 2.13 (s, 3H); 2.11-2.05 (brd m, 3H); 1.87-1.72 (brd m, 3H); 1.58-1.49 (m, 2H). MS (-ESI) 480.1 ([M + H] +); 352.0; 274.0; 240.9; 179.9. Example 52. Synthesis of Ethyl Ester of N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine. To a solution of ethyl ester of N- (benzyl) -L-pyroglutamyl-L-tyrosine (0.50 g, 1.22 mmol), dimethylaminopyridine (0.146 g, 1.20 mmol), triethylamine (0.25 mL, 1.83 mmol) and pyridine (1.5 mL) ) in CH2C12 (10 mL), dimethylcarbamyl chloride (0.15 mL, 1.70 mmol) was added dropwise. After stirring for 60 hours, the reaction was quenched by the addition of a 10% citric acid solution (40 mL) followed by extraction using ethyl acetate / hexane (65:35) (100 mL). The organic phase was separated and washed sequentially with water, saturated sodium bicarbonate solution, water, saturated brine, dried with MgSO 4 and evaporated in vacuo to give the product as a solid (0.57 g, mp 150-152 °). C, 99% yield). The physical data are as follows: 1 H NMR (DMSO-de, 400 MHz) d 8.59 (d, 1H, J = 8. 1 Hz); 7.25 (m, 3H); 7.18 (d, 2H, J = 8.5 Hz); 7. 02 (, 4H); 4.75 (d, ÍH, J = 15.3 Hz); 4.53 (m, ÍH); 4.10 (m, 2H); 3.85 (m, 1H); 3.40 (d, ÍH, J = 15.1 Hz); 3.09 (m, ÍH); 3.01 (s, 3H); 2.88 (m, 4H); 2.33-2.24 (m, 2H); 2.18-2.08 (m, ÍH); 1.76-1.67 (m, ÍH); 1.14 (t, 3H, J = 7.0 Hz). IR (KBr, cm "1) 3425; 2900; 1725; 1690; 1660; 1525; 1425; 1380; 1210; 1175; 1010; 845; 800; 750; 650; 520.

MS (El) 481 ([M + H] +); 436; 308; 263; 174 91 72 Analysis calculated for C 26 H 31 N 306: C, 64.85; H, 6.49; N, 8.73. Found: C, 65.00; H, 6.55; N, 8.70. Example 53. Synthesis of the Lithium Salt of N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine. To a stirred mixture of ethyl ester of N- (benzyl) -L-pyroglutamyl-L-4- (N, N-di-ethylcarbamyoxy) phenylalanine (0.3 g, 0.62 mmol) in THF (4 mL), a solution of LiOH 1N (0.59 mL, 0.59 mmol) and the mixture was stirred for 72 hours. The reaction was quenched by dilution with water (15-20 mL) and the aqueous phase was extracted with CH2C12 three times. Lyophilization of the aqueous layer produced the product as a solid (0.27 g, 94% yield). The physical data are as follows: XH NMR (DMSO-d6, 400 MHz) d 7.54 (d, ÍH, J = 6. 8 Hz); 7.30-7.20 (brd m, 3H); 7.10 (d, 2H, J = 8. 5 Hz); 7.04 (m, 2H); 6.88 (m, 2H); 4.75 (d, ÍH, J = 15.1 Hz); 3.99 (q, ÍH, J = 6.3 Hz); 3.86 (m, ÍH, 3.41 (d, ÍH, J = 15.3 Hz), 3.11 (m, ÍH), 3.00 (s, 3H), 2.88 (m, 4H), 2.30-2.19 (brd m, 2H), 2.12 -2.05 (m, ÍH); 1.79-1.72 (m, 1H) IR (KBr, cm "1) 3400; 2950; 1660; 1600; 1400; 1220; 1175; 700; 510. IR (KBr, cm" 1 ) 3400; 2950; 1660; 1600; 1400; 1220; 1175; 700; 510. MS (+ FAB) 454.0 ([M + H] +); 460.0 ([M + Li] +); 410.0; 326.9; 279.0; 220.9; 173.9; 130.6; 80.3 Analysis calculated for C24H27N306Li * 3H20: C, 56.14; H, 6.28; N, 8.18, Found: C, 56.07; H, 5.88; N, 7.95, Example 54. Synthesis of Ester tert - N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamoyloxy) phenylalanine butyl BOP coupling of N- (benzyl) -L-pyroglutamic acid (1.96 g, 8.9 mmoles) and tert-ester L-tyrosine butyl (2.32 g, 9.78 mmole) with triethylamine in DMF according to the method of Example 46 followed by quenching with saturated sodium bicarbonate, in addition to EtOAc and extraction with 10% citric acid solution, water , brine, dried (MgSO4), filtration and co Concentration, produces the precursor of the tert-butyl ester of N- (benzyl) -L-pyroglutamyl-L-tyrosine acid (3.59 g, mp 167-169 ° C, 92% yield) as a crystalline solid. The physical data are as follows: Analysis calculated for C25H30N2O5: C, 68.48; H, 6.90; N, 6.39. Found: C, 68.20; H, 6.78; N, 6.75. To a combined tert-butyl ester mixture of N- (benzyl) -L-pyroglutamyl-L-tyrosine (0.5 g, 1. 14 mmol), N, N-dimethylaminopyridine (0.14 g, 1.14 mmol) and triethylamine (0.24 mL, 1.71 mmol) in CH2C12 (8 mL) was added dimethylcarbamyl chloride (0.15 mL, 1.59 mmol) dropwise.

After stirring for 66 hours, the reaction was quenched by the addition of a 10% citric acid solution (30 mL) followed by extraction using a mixture of ethyl acetate / hexane (65:35) (100 mL). The organic phase was separated, washed sequentially with water, saturated sodium bicarbonate solution, water, saturated brine, dried with MgSO 4 and evaporated in vacuo to give the product as a solid (0.52 g, mp 184-185 ° C. , 90% yield). The physical data are as follows: X H NMR (DMS0-d 6, 400 MHz) d 8.52 (d, ΔH, J = 8.1 Hz); 7.32-7.20 (m, 5H); 7.05-7.01 (, 4H); 4. 76 (d, ÍH, J = 15.1 Hz); 4.46 (m, ÍH); 3.88 (m, ÍH); 3.40 (d, ÍH), J = 15.1 Hz); 3.05-3.0 (, 4H); 2.90 (s, 3H); 2.85 (m, ÍH); 2.34-2.26 (m, 2H); 2.18-2.11 (m, ÍH); 1.78-1.71 (m, ÍH); 1.37 (s, 9H). IR (KBr, cm "1) 3410; 3275; 2950; 1725; 1660; 1550; 1430; 1375; 1210; 1150; 750; 690; 520. MS (El), 509 ([M + H] +);; 408; 233; 174; 91; 72. Analysis calculated for C28H35N306: C, 66.00; H, 6.92; N, 8.25, Found: C, 65.88; H, 6.91; N, 8.24, Example 55. Synthesis of Ester's N- (benzyl) -L-pyroglutamyl-L-4- [(4'-methylpiperazin-1'-yl) carbonyloxy] phenylalanine tert-butyl Tert-butyl ester of N- (benzyl) acid was combined L-pyroglutamyl-L-tyrosine (0.50 g, 1.14 mmol) with p-nitrophenyl chloroformate (0.218 g, 1.08 mmol) in CH2C12 (10 mL) and the reaction mixture was cooled to 0 ° C under N2. Triethylamine (0.4 mL, 2.85 mmol), previously dissolved in 2 mL of CH2C12, was added to the mixture and stirred 30 minutes at 0 ° C. The mixture was conducted at room temperature and stirred 30 minutes followed by re-cooling to 0 ° C and the addition of 1-methyl-piperazine (0.12 mL, 1.08 mmol). The reaction mixture was then allowed to warm to room temperature and was stirred for 66 hours. The reaction was quenched by dilution with Et20 and washed sequentially with 10% K2CO3 solution (5X) and IN HCl. The acid layer was removed and the pH adjusted to 8 using saturated sodium bicarbonate solution. Extraction of the aqueous phase with EtOAc and followed by washing with brine, drying over MgSO4, evaporation and recrystallization (CH2C12 / hexane) yielded the product as a solid (0.372 g, mp 113-116 ° C, 58% yield) . The physical data are as follows: XH NMR (DMSO-de, 400 MHz) d 8.52 (d, ÍH, J = 8.1 Hz); 7.30-7.20 (, 5H); 7.03 (m, 4H); 4.76 (d, ÍH, J = 15.1 Hz); 4.46 (m, ÍH); 3.88 (m, ÍH); 3.58 (brd s, 2H); 3.41 (m, 3H); 2.38-2.32 (brd s, 4H); 2.22 (s, 3H); 1.78-1.70 (m, ÍH); 1.37 (s, 9H). IR (KBr, cm "1) 3410; 3275; 2925; 1725; 1690; 1660; 1550; 1475; 1350; 1290; 1220; 1150; 1050; 1000; 850; 700; 510. MS (+ ESI) 565.5 ([ M + H] +), 509.2, 475.5, 344.1, 279.1, 221.0.

Analysis calculated for C31H40N4O6-0.1 CH2C12: C, 64.96; H, 7.06; N, 9.77. Found: C, 64.93; H, 7.10; N, 9.62. Other compounds prepared by the methods described herein include those set forth in Table I above that are not specifically exemplified herein. Example A. In v tro tro Assay to Determine the Link of the Candidate Compounds to VLA-4. An in vi tro assay is used to evaluate the binding of the candidate compounds to the a4ßl integrin. The compounds that bind in this assay can be used to assess the levels of VCAM-1 in biological samples by conventional assays (eg, competitive assays). This assay is sensitive to IC50 values as low as around InM. The activity of integrin 4ßl is measured by the interaction of soluble VCAM-1 with Jurkat cells (e.g., American Type Culture Collection Nos. TIB 152, TIB 153, and CRL 8163), a human T cell line expressing high levels of integrin a4ßl. VCAM-1 interacts with the surface of the cell in a manner dependent on integrin a4ßl (Yednock, et al., J. Biol. Chem., 1995, 270: 28740). The recombinant soluble VCAM-1 is expressed as a chimeric fusion protein containing the seven extracellular domains of VCAM-1 at the N terminus and the human IgGl heavy chain constant region at the C terminus. The VCAM-1 fusion protein is makes and purifies by the way described by Yednock, supra. Jurkat cells grow in RPMI 1640 supplemented with fetal bovine serum, penicillin, streptomycin and glutamine as described by Yednock, supra. Jurkat cells are incubated with 1.5 mM MnC12 and 5 μg / mL 15/7 antibody for 30 minutes on ice. Mn + 2 activates the receptor to increase the binding, and 15/7 is a monoclonal antibody that recognizes an occupied conformation of activating / ligand of integrin a4ßl and secures the molecule in this conformation, thereby stabilizing the VCAM-1 interaction / integrin a4ßl. Yednock, et al., Supra. Antibodies similar to antibody 15/7 have been prepared by other investigators (Luque, et al., 1996, J. Biol. Chem. 271: 11067) and can be used in this assay. The cells are incubated for 30 minutes at room temperature with candidate compounds, in various concentrations in the range from 66 μM to 0.01 μM using a standard 5 point serial dilution. The 15 μL soluble recombinant VCAM-1 fusion protein is then added to the Jurkat cells and incubated for 30 minutes on ice. (Yednock et al., Supra.). The cells are then washed twice and resuspended in goat-conjugated goat F (ab ') 2 anti-mouse IgG Fc (Immunotech, Westbrook, ME) at 1: 200 and incubated on ice, in the dark , for 30 minutes. Cells are washed twice and analyzed with standard fluorescent activated cell sorter ("FACS") analysis as described in Yednock, et al., Supra. Compounds having an IC50 of less than about 15 μM possess a binding affinity to a4ßl.

When tested in this assay, each of the compounds in Examples 1-36 have an IC 50 of 15 μM or less. Example B. Saturation test ± n v. Tro to Determine the Link of the Candidate Compounds for a4ßl. The following describes an in vitro test to determine the plasma levels necessary for a compound to be active in the Experimental Autoimmune Encephalomyelitis ("EAE") model, described in the following example, or in other models in vi vo. Log Jurkat growth cells are washed and resuspended in a normal animal plasma containing 20 μg / ml of antibody 15/7 (described in the previous example). Jurkat cells are diluted twice in either normal plasma samples containing quantities of known candidate compounds in various concentrations ranging from 66 μM to 0.01 μM, using a standard 12-point serial dilution for a standard curve, or plasma samples obtained from peripheral bleeding of the animals treated with candidate compound.

The cells are then incubated for 30 minutes at room temperature, washed twice with phosphate buffered saline ("PBS") containing 2% fetal bovine serum and 1 M 'each of calcium chloride and magnesium chloride. (test medium) to remove the unbound 15/7 antibody. The cells are then exposed to goat F (ab ') 2 anti-mouse IgG Fc conjugated with phycoerythrin (Immunotech, Westbrook, ME), which is absorbed by any nonspecific cross-reactivity by co-incubation with 5% serum. the animal species that are studied, at 1: 200 and incubate in the dark at 4 ° C for 30 minutes. The cells are washed twice with a test medium and resuspended therein. This is then analyzed with a standard fluorescent activated cell sorter ("FACS") analysis as described in Yednock, et al., J. Biol. Chem., 1995, 270: 28740. The data are plotted as fluorescence against dose, for example, in a normal dose response manner. The dose levels that result in the upper plane of the curve represent the levels necessary to obtain efficacy in an in vi vo model. This assay can be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as integrin a9ßl, which is the integrin most closely related to a4ßl (Palmer et al., 1993, J. Cell Bio., 123: 1289). Such binding is predicted from the in vivo utility for inflammatory conditions mediated by an α9β integrin, including, by way of example, hyper-responses and airway occlusion that occurs with chronic asthma, smooth muscle cell proliferation in arteriosclerosis , vascular occlusion followed by angioplasty, fibrosis and glomerular marking as a result of renal disease, aortic stenosis, synovial membrane hypertrophy in rheumatoid arthritis, and inflammation and marking that occurs with the progression of ulcerative colitis and Crohn's disease. Accordingly, the assay described above can be performed with a human colon carcinoma cell line, SW 4801 (ATTC # CCL228) transfected with cDNA encoding a9 integrin (Yokosaki et al., 1994, J. Biol. Chem., 269: 26691), in place of the Jurkat cells, to measure the binding of the a9ßl integrin. As a control, SW 480 cells expressing other subunits a and ßl can be used. Accordingly, another aspect of this invention is directed to a method of treating a disease in a mammalian patient, whose disease is mediated by a9β1, and which method comprises administering to the patient a therapeutically effective amount of a compound of this invention. Such compounds are preferably administered in a pharmaceutical composition described herein. The effective daily dose can be easily guessed by the attending physician. However, in a preferred embodiment, the compounds are administered from about 20 to 500 μg / kg per day. Example C In vivo evaluation. The standard multiple sclerosis model, Experimental Autoimmune (or Allergic) Encephalomyelitis ("EAE"), is used to determine the effect of candidate compounds to reduce motor mismatch in rats or guinea pigs. The reduction in motor mismatch is based on blocking the adhesion between leukocytes and the endothelium and correlates with an anti-inflammatory activity in the candidate compound. This model has been previously described by Kesztjelyi et al., Neurology, 1996, 47: 1053-1059, and measures the delay in the onset of the disease. Brains and spinal cords are homogenized from adult Hartley guinea pigs in an equal volume of phosphate buffered saline solution. An equal volume of Freud's complete adjuvant (100 mg of mycobacterium urea and 10 ml of Freud's incomplete adjuvant) is added to the homogenous. The mixture is repeatedly emulsified by circulation through a 20 ml syringe with a peristaltic pump for about 20 minutes. Female Lewis rats (2-3 months old, 170-220 g) or Hartley guinea pigs (20 days old, 180-200 g) are anesthetized with isoflurane and three injections of the emulsion, 0.1 ml each, are made on each flank. The onset of motor frustration is observed approximately in 9 days. The treatment of the candidate compound starts on Day 8, just before the onset of symptoms.

The compounds are administered subcutaneously ("SC"), orally ("PO") or intraperitonally ("IP"). Doses are given in the range of 10 mg / kg to 200 mg / kg, giving, for five days, with a typical dose of 10 to 100 mg / kg SC, 10 to 50 mg / kg PO, and 10 to 100 mg / kg IP. The GG5 / 3 antibody against integrin a4ßl (Keszthelyi et al., Neurology, 1996, 47: 1053-1059), which delays the onset of symptoms, was used as a positive control and subcutaneously injected at 3 mg / kg on Day 8 and 11. Body weight and motor mismatch were measured daily. The motor mismatch was related to the following clinical marker: 0 unchanged 1 weakened tail or paralysis 2 weakened hind limbs 3 paralyzed hind limbs 4 moribund or dead. A candidate compound is considered active if it delays the onset of symptoms, for example, it produces clinical markers no greater than 2 or reduces the loss of body weight as compared to the control. Example D.

Asthma model. Inflammatory conditions mediated by the a4ßl integrin include, for example, hyperresponsiveness and airway occlusion that occurs with chronic asthma. The following describes an asthma model that can be used to study the in vivo effects of the compounds of this invention for use in the treatment of asthma. Following the procedures described by Abraham et al., J. Clin. Invest. 93: 776-787 (1994) and Abraham et al., Am J. Respir Crit Care Med, 156: 696-703 (1997), both of which are incorporated for full reference, the compounds of the invention are formulated in an aerosol and they are administered to sheep that are hypersensitive to the antigen As ca ri ssu um. Compounds that reduce the early bronchial response induced by the antigen and / or block the last phase of the airway response are considered to be active in this model, for example, they have a protective effect against late responses induced by the antigen. and the hyper-response of the respiratory tract ("AHR").

Allergic sheep that show that they develop both early and late bronchial responses by inhaling the antigen As ca ri s s u um, are used to study the effects on the respiratory tract of candidate compounds. After topical anesthesia of the nasal passages with 2% lidocaine, a balloon catheter is inserted through a nostril into the lower esophagus. The animals are then intubated with an endotracheal tube at the nape through the other nostril with a flexible fiber optic bronchoscope as a guide. Pleural pressure is estimated according to Abraham (1994). The aerosols (see formulation below) are generated using a disposable medical nebulizer that provides an aerosol with an average aerodynamic diameter of 3.2 μm mass as determined with an Andersen cascade impactor. The nebulizer is connected to a dosimeter system consisting of a solenoid valve and a compressed air source (20 psi). The outlet of the nebulizer is directed in a piece of plastic T, one end of which is connected to the inspiratory port of a respiratory piston. The solenoid valve is activated for 1 second at the beginning of the inspiratory cycle of the respirator. The aerosols are delivered to VT of 500 ml and at a ratio of 20 inhalations / minute. Only one solution of sodium bicarbonate is used as a control. To evaluate bronchial responses, cumulative concentration-response curves for carbachol can be generated according to Abraham (1994). Bronchial biopsies can be taken before and after the start of treatment and 24 hours after the immunogenic test on the antigen. Bronchial biopsies can be performed according to Abraham (1994). A study of adhesion within alveolar macrophages can also be performed according to Abraham (1994), and the percentage of adhered cells is calculated. Aerosol formulation. A solution of the candidate compounds in 0.5% sodium bicarbonate / saline (w / v) at a concentration of 30.0-100.0 mg / mL is prepared using the following procedure: A. Preparation of 0.5% sodium bicarbonate / concentrated solution of saline: 100.0 mL. Ingredient Gram / 100.0 mL Final Concentration Procedure: 1. Add 0.5 g of sodium bicarbonate in a 100 mL volumetric flask. 2. Approximately 90.0 mL of saline is added and sonicated until it dissolves. 3. 'C.S. for 100.0 L with saline and mixed thoroughly. B. Preparation of 30.0 mg / mL of the Candidate Compound.

Procedure: 1. 0.300 g of the candidate compound is added in a 10.0 mL volumetric flask. 2. Approximately 9.7 mL of 0.5% sodium bicarbonate / concentrated saline solution is added. 3. It is sonicated until the candidate compound is completely dissolved. 4. C.S. for 10.0 mL with 0.5% sodium bicarbonate / concentrated saline solution and mix thoroughly. Using a conventional oral formulation, the compounds of this invention are active or are expected to be active in this model when employed at the indicated concentrations. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (30)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. 1. A compound of the formula I: characterized in that R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl and -CYOOR1; 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, carbon and from 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have from 2 to 4 atoms in the heteroalkylene chain, and containing substituted heteroalkylene, in the heteroalkylene chain, from 1 to 3 carbon atoms and from 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have 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 may be associated with R2 to form a combined cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; R 4 is selected from the group consisting of isopropyl, -CH 2 -X y = CH-X, where 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, carboxy, carboxylalkyl, carboxy-substituted alkyl , carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic, and hydroxyl with the proviso that when R4 is = CH-X then (H) is remove from the formula and X is not hydroxyl; W is oxygen or sulfur; and pharmaceutically acceptable salts thereof.
2. 2. A compound of the formula IA: characterized in that R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl and -CYOOR1; 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, carbon and from 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have from 2 to 4 atoms in the heteroalkylene chain, and substituted heteroalkylene, in the heteroalkylene chain, from 1 to 3 carbon atoms and from 1 up to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have 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 may be associated with R2 to form a combined cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; R 4 is selected from the group consisting of isopropyl, -CH 2 -X y = CH-X, where 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, carboxy, carboxylalkyl, carboxylalkyl substituted, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic, and hydroxyl with the proviso that when R4 is = CH-X then (H) is removes from the formula and 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, -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 from 1 to 8; W is oxygen or sulfur; and pharmaceutically acceptable salts thereof; with the condition that; (a) when R1 is benzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 is benzyl, then R5 is not ethyl; (b) when R1 is 3,4-dichlorobenzyl, R2 is CH2CH2-, R3 is hydrogen, R4 is 4- (phenylcarbonylamino) benzyl, then R5 is not methyl; (c) when R1 is benzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 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 R4 is not 4-hydroxybenzyl or 4- (4-nitrophenoxycarbonylloxy) benzyl; (e) when R1 is 4-cyanobenzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 is 4-hydroxybenzyl, then R5 is not tert-butyl; and (f) when R1 is benzyloxycarbonyl, R2 is -NHCH2-, R3 is hydrogen, R5 is tert-butyl, then R4 is not 4-hydroxybenzyl or 4- (N, N-dimethylcarbamyloxy) benzyl.
3. 3. The compound according to claim 1 or 2, characterized in that R1 is a group having the formula: characterized in that 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.
4. 4. The compound according to claim 3, characterized in that Z is CH.
5. The compound according to claim 4, characterized in that one of R6 and R7 is hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy, amino, chloro, fluoro, cyano or nitro; or both of R6 and R7 are chlorine.
6. 6. The compound according to claim 1 or 2, characterized in that R1 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, benzyloxycarbonyl and (pyridin-3-yl) methyl.
7. The compound according to claims 1 6 2, characterized in that 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 chain alkylene, heteroalkylene containing 1 or 2 carbon atoms and 1 heteroatom selected from nitrogen, oxygen and sulfur and having 2 or 3 atoms in the alkylene chain, and substituted heteroalkylene containing, in the heteroalkylene chain, 1 or 2 carbon atoms and 1 heteroatom selected from nitrogen, oxygen and sulfur and having 2 or 3 atoms in the heteroalkylene chain.
8. 8. The compound according to claim 7, characterized in that R2 is selected from the group consisting of -CH2CH2-, CH2-S-CH2-, -CH2-0-CH2- and -NHCH2-.
9. 9. The compound according to claim 1 or 2, characterized in that R3 is hydrogen.
10. 10. The compound according to claims 1 6 2, characterized in that R3 is attached to R2 to form a fused and / or bridged ring of cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle or substituted heterocycle.
11. The compound according to claim 10, characterized in that R2 and R3, together with other atoms of the nitrogen-containing ring, form a 5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane ring.
12. 12. The compound according to claim 1 or 2, characterized in that R4 is selected from the group consisting of: 4-methybenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl, 4-benzyloxybenzyl, 4- [ f-CH (CH3) O-] benzyl, 4- [f-CH (COOH) 0-] benzyl, 4- [BocNHCH2C (O) NH-] benzyl, 4-chlorobenzyl, 4- [NH2CH2C (0) NH- ] benzyl, 4-carboxybenzyl, 4- [CbzNHCH CH2NH-] benzyl, 3-hydroxy-4- (f-OC (O) NH-) benzyl, 4- [HOOCCH2CH2C (O) NH-] benzyl, benzyl, 4- [2'-carboxy phenoxy] benzyl, 4- [fC (O) NH-] benzyl, 3-carboxybenzyl, 4-iodobenzyl, 4-hydroxy-3, 5-diiodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxymethyl] benzyl, 4-nitrobenzyl, 2-carboxybenzyl, 4- [dibenzylamino] -benzyl, 4- [(1'-cyclopropylpiperidin-4 '-yl) C (O) NH-] benzyl, 4- [-NHC (O) CH2NHBoc] benzyl, 4-carboxybenzyl, 4-hydroxy-3-nitrobenzyl, 4- [-NHC (O) CH (CH3) NHBoc] benzyl, 4- [-NHC (O) CH (CH2f) NHBoc] benzyl, isobutyl, methyl, 4- [CH3C (O) H-] benzyl, -CH2- (3-indolyl), n-butyl, t-butyl- OC (O) CH2, t-butyl-OC (O) CH2CH2-, H2NC (0) CH2-, H2NC (0) CH2CH2-, BocNH- (CH2) -t-butyl-OC (O) - (CH2) 2 -, HOOCCH2-, HOOC (CH2) 2-, H2N (CH2) 4-, Isopropyl, (1-naphthyl) -CH2-, (2-naphthyl) -CH2-, (2-thiophenyl) -CH2-, (f -CH2-OC (0) NH- (CH2) 4-, cyclohexyl-CH2-, benzyloxy-CH2-, H0CH2-, 5- (3-N-benzyl) imidazolyl-CH2-, Z-pyridyl-CH2-, 3 -pyridyl-CH2-, 4-pyridyl-CH2-, 5- (3-N-methyl) imidazolyl-CH2-, N-benzylpiperid-4-yl-CH2-, N-Boc-piperidin-4-yl-CH2- , N- (phenyl-carbonyl) piperidin-4-yl-CH2-, H3CSCH2CH2-, 1- -benzyl imidazol-4-yl-CH2-, iso-propyl-C (O) MH- (CH2) 4-, iso-butyl-C (O) NH- (CH2) 4-, phenyl 1 -C (0) NH- (CH2) 4-, benz 1-C (0) NH- (CH2) 4-, allyl-C (0) NH- (CH2) 4-, 4- (3-N-methylimidazolyl) ) -CH2-, 4 -imido zolyl, 4- [(CH3) 2NCH2CH2CH2-O-] benzyl, 4- [(benzyl) 2N-] -benzyl, 4-aminobenzyl, allyloxy-C (0) NH (CH2) 4 ~, allyloxy-C (0) NH (CH2) 3-, to the yloxy -C (0) H (CH2) 2-, NH2C (0) CH2-, 2-pyridyl 1-C (O) NH- ( CH2) 4-, 4-methylpyrid-3-yl-C (O) H- (CH2) 4-, 3-met iltien- 2 -i 1-C (O) NH- (CH2) 4-, 2- pyrrolyl-C (O) NH- (CH2) -, 2-furanyl-C (0) NH- (CH2) 4-, 4-methylphenyl-S02-N (CH3) CH2C (O) NH (CH2) 4- 4- [cyclopentylacetylenyl] -benzyl, 4- [NHC (O) - (N-Boc) -pyrrolidin-2-yl)] benzyl-, lN-methylimidazol-4-yl-CH2-, N-methylimidazole-5- il-CH2-, imidazol-5-yl-CH2-, 6-met ilpyrid-3-yl-C (O) NH- (CH2) 4-, 4- [2'-carboxymethylphenyl] -benzyl, 4- [- NHC (O) NHCH2CH2CH2-f] -benzyl, 4- [-NHC (O) NHCH2CH2-f] -benzyl, -CH2C (O) NH (CH2) 4f, 4- [ f (CH2) 40-] -benzyl, 4- [-C = Cf-4'f] -benzyl, 4- [-C = C-CH2-0-S (O) 2-4 '-CH3-f] -benzyl, 4- [-CsC-CH2-NHC (0) NH2] -benzyl, 4- [-C = C-CH2-0-4 '-COOCH2CH3-f] -benzyl, 4- [-C = C- CH (NH2) -cycdohexyl] -benzyl, - (CH2) 4NHC (O) CH2-3 -indolyl, - (CH2) 4NHC (O) CH2CH2-3-indolyl, - (CH2) 4NHC (O) -3- ( 5-methoxyindolyl), - (CH2) 4NHC (O) -3- (1-met i linda Íil), - (CH2) 4NHC (0) -4 - (- S02 '(CH3) -f), - (CH2 ) 4NHC (O) -4- (C (O) CH3) -phenyl, - (CH2) 4NHC (0) -4-fluorophenyl, - (CH2) 4NHC (O) CH20-4 -fluorophenyl, 4-C = C- (2-pyridyl) benzyl, -C = C-CH 2-0 -phenyl] benzyl, 4- • C = C-CH 2 OCH 3] benzyl, -C = C- (3-hydroxyphenyl)] benzyl, -C = C -CH2-0-4 '- (-C (O) OC2H5) phenyl] benzyl, 4-C = C-CH2CH (C (O) OCH3) 2] benzyl, 4-C = C-CH2NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl), 3-aminobenzyl, 4- [-C = C-CH2CH (NHC (0) CH3) C (0) OH] -benzyl ?, -CH2C (O) NHCH (CH3) f, -CH2C (0) NHCH - (4 -dime ti lamino) -f, -CH2C (O) NHCH2-4 -nitrophenyl, -CH2CH2C (O) N (CH3) CH2-f, -CH2CH2C (O) NHCH2CH2- (N-methyl) -2-pyrrolyl, -CH2CH2C (O) NHCH2CH2CH2CH3, -CH2CH2C (O) NHCH2CH2-3-indolyl, -CH2C (O) N (CH3) CH2 phenyl, -CH2C (O) NH (CH2) 2- (N-methyl) -2 - pyrrolyl, -CH2C (O) NHCH2CH2CH2CH3, -CH2C (0) NHCH2CH2-3-indolyl, - (CH2) 2C (0) NHCH (CH3) f, - (CH2) 2C (O) NHCH2-4-dimethylaminofenyl, - (CH2) 2C (O) NHCH2-4-Nitrophenyl, -CH2C (0) NH-4 - [- NHC (0) CH3-phenyl), -CH2C (O) H-4-pyridyl, -CH2C (O) NH -4- [tell me lamino phenyl], -CH2C (O) NH-3-methoxy pheni lo, -CH2CH2C (O) NH- 4 -chloro feni lo, -CH2CH2C (0) NH-2-pyridyl, -CH2CH2C ( O) NH-4-methoxy-phenyl, -CH2CH2C (0) NH-3-pyridyl, 4- [(CH3) 2NCH2CH20-] benzyl, - (CH2) 3NHC ((NH) NH-S02-4-methylphenyl, - ([CH3) 2NCH2CH20-] benzyl, - (CH2) 4NHC (O) NHCH2CH3, - (CH2) NHC (O) NH-phenyl, - (CH2) 4NHC (O) NH-4-methoxyphenyl, 4- [4 '-pyridyl-C (0) NH-] benzyl, 4- [3'-pyridyl-C (O) NH-] benzyl, 4- [-NHC (O) NH-3' -methylphenyl] benzyl, 4-t -NHC (O) CH2NHC (O) NH-3 '-methylphenyl] benzyl, 4 - [- NHC (0) - (2', 3'-dihydroindol-2-yl)] benzyl, 4- [-NHC (O) - (2 ', 3' -dihydro-N-Boc-indol-2-yl) benzyl, p- [-OCH2CH2-l '- (4'-pyrimidinyl) -piperazinyl] benzyl, 4- [-OCH2CH2- (1'-piperidinyl) benzyl, 4- [-OCH2CH2- (1'-pyrrolidinyl) benzyl, 4- [-OCH2CH2CH2- (1'-piperidinyl)] benzyl, -CH2-3- (1 , 2,4-triazolyl), 4- [-OCH2CH2CH2-4- (3'-chlorophenyl) -piperazin-1-yl] benzyl, 4- [OCH2CH2N (f) CH2CH3] benzyl, 4- [-OCH2-3 ' - (N-Boc) -piperidinyl] benzyl, 4- [di-n-pentylamino] benzyl, 4- [n-pentylamino] benzyl, 4- [di-4-propylamino-CH 2 CH 20-] benzyl, 4 - [- OCH 2 CH 2 - (N-morpholinyl)] benzyl, 4 - [-0- (3 '- (N-Boc) -piperidinyl] benzyl, 4- [-OCH2CH (NHBoc) CH2cyclohexyl] benzyl, p- [OCH2CH2- (N-piperidinyl] benzyl, 4- [-OCH2CH2CH2- ( 4-m-chloro phenyl) -piperazin-1-yl] benzyl, 4- [-OCH2CH2- (N-homopiperidinyl) benzyl, 4- [-NHC (O) -3 '- (N-Boc) -piperidinyl] benzyl , 4- [-OCH2CH2N (benzyl) 2-benzyl, -CH2-2-thiazolyl, 3-hydroxybenzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, 4- [-NHC (S) NHCH2CH2- (N-morpholine)] benzyl, 4- [-OCH2CH2N (C2H5) 2] benzyl, 4- [-OCH2CH2CH2N (C2H5) 2] benzyl, 4- [CH3 (CH2) 4NH-benzyl, 4- [N-n-butyl, N-n-pentylamino-] benzyl 4- [-NHC (O) -4'-piperidinyl] benzyl, 4- [-NHC (0) CH (NHBoc) (CH 2) 4 NHCbz] benzyl, 4 - [- NHC (0) - (1 ', 2', 3 ', 4'-tetrahydro-N-Boc-isoquinolin-1' -yl] benzyl, p- [-0CH2CH2CH2-1 '- (4' - methyl) -piperazinyl] benzyl, - (CH2) NH-Boc, 3- -OCH2CH2CH2N (CH3) 2] benzyl, 4- -OCH2CH2CH2N (CH3) 2] benzyl, 3- -OCH2CH2- (l '-pyrrolidinyl)] benzyl , 4- -OCH2CH2CH2N (CH3) benzyl] benzyl, 4-NHC (S) NHCH2CH2CH2 (N-morpholine)] benzyl, 4- -0CH2CH2- (N-morpholino)] benzyl, 4- NHCH2- (4 ' chlorophenyl)] benzyl, 4- N-NH (O) NH- (4'-cyanophenyl)] benzyl, 4- (OCH 2 COOH) benzyl, 4- (OCH 2) COO-t-butyl] benzyl, 4- [-NHC ( 0) -5 '-fluoroindol-2-yl] benzyl, 4- [-NHC (S) NH (CH2) 2-1 -piperidinyl] benzyl, 4- [-N (S02CH3) (CH2) 3-N (CH3 ) 2] benzyl, 4- [-NHC (O) CH2CH (C (O) OCH2f) -NHCbz] benzyl, 4- [-NHS (O) 2CF3] benzyl, 3- [-0- (N-methylpiperidine- '-yl] benzyl, 4- [-C (= NH) NH2] benzyl, 4- [-NHS02-CH2C1] benzyl, 4- [-NHC (0) -) 1', 2 ', 3', 4 ' -tetrahydroisoquinol ind 2 '-yl] benzyl, 4- [-NHC (S) H (CH2) 3-N-morphino] benzyl, 4- [-NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] b encilo, 4- [-C (0) NH2] benzyl, 4 - [- NHC (0) NH-3 '-methoxy phenyl] benzyl, 4- [-0CH2CH2-indol-3'-yl] benzyl, 4- [-0CH2C (0) NH-benzyl] benzyl, 4- [-OCH2C (0) O-benzyl] benzyl, 4- [-OCH2C (0) OH] benzyl, 4 - [- OCH2-2 '- (4', 5 ' dihydro) imidazolyl] benzyl, -CH2C (0) NHCH2- (4-dimethylamino) phenyl, -CH2C (O) NHCH2- (4-dimethylamino) phenyl, 4- [-NHC (0) -L-2-pyrrolidinyl-N-S02-4 '- methylphenyl] benzyl, 4- [-NHC (0) NHCH2CH2CH3] benzyl, 4-aminobenzyl] benzyl, 4- [-OCH2CH2-l- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl] benzyl , 4- [-0- (N -methylpiperidin-4'-yl) benzyl, 3-methoxybenzyl, 4- [-NHC (O) -piperidin-3'-yl] benzyl, 4 - [- NHC (0) -pyridin-2'-yl] benzyl, 4 - [- NHCH2- (4'-chlorophenyl) '] benzyl, 4- [-NHC (O) - (N- (4' -CH3-f-S02) -L -pyrrolidin.2 '-il)] benzyl 4- [-NHC (O) NHCH2CH2-f] benzyl, 4- [-0CH2C (0) NH2] benzyl, 4- [-OCH2C (O) NH-t-butyl] benzyl, 4- [-OCH2CH2-l- (4-hydroxy-4-phenyl) -piperidinyl] benzyl, 4- [-NHS02-CH = CH2] benzyl, 4- [-NHS02-CH2CH2C1] benzyl, -CH2C (O NHCH2CH2N (CH3) 2, 4- [(1'-Cbz-piper idin-4 '-yl) C (0) NH-] benzyl, 4- [(1-Boc-piperidin-4'-yl) C (0) NH-] benzyl, 4- [(2'-bromophenyl) C (0) NH-] benzyl, 4- [-NHC (0) -pyridin-4'-yl] benzyl, 4- [(4 '- (CH3) 2NC (0) 0-) phenyl) -C (O) H-] 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-0 (O) CCH2-O-benzyl) -NH-] benzyl, [BocNHCH2C (O) NH-] butyl, 4-benzylbenzyl, 2-hydroxyethyl, 4- [(Et) 2NCH2CH2CH2NHC (S) NH-] benzyl, 4 - [(1-Boc-4'-hydroxypyrrolidin-2'- il) C (0) NH-] benzyl, 4- [fCH2CH2CH2NHC (S) NH-] benzyl, 4- [(perhydroindolin-2'-yl) C (O) NH-] benzyl, 2- [4-hydroxy-4- (3-methoxy-thien-2-yl) piperidin-1-yl] ethyl, 4- [(1 '-Boc-perhydroindolin-2'-yl) -C (0) NH-] benzyl, 4- [N-3-methylbutyl-N-trifluoromet anosul fonyl) amino] benzyl, 4- [N-vinylsulfonyl) amino] benzyl, 4- [2- (2-azabicyclo [3.2.2] octan-2- il) ethyl-O-] benzyl, 4- [4'-hydroxypyrrolidin-2'-yl) C (0) NH-] benzyl, 4- (fNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl, 4- (f-CH2NHC (S) NH) benzyl, 3- [(1 '-Boc-piperidin-2' -il ) 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- (CH3-NHC (S) NH) benzyl, 4- (H2NCH2CH2CH2C (O) NH) benzyl, 4- (BocHNCH2CH2CH2C (O) NH) benzyl, 4- (pyridin-4 '-il-CH2NH) benzyl, 4- [(N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- [(1-Cbz- piperidin-4-yl) C (O) NH-] butyl, 4- [fCH2OCH2 (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 (0) NH) butyl, 4- (pyridin-4 '-yl-C (O) NH) butyl, 4- (pyridin-3' - il-C (O) NH) benzyl, 4- [CH3NHCH2CH2CH2C (O) NH-] benzyl, 4- [CH3N (boc) CH2CH2CH2C (O) NH-] benzyl, 4- (aminomethyl) benzyl, 4- [fCH2OCH2 ( H2N) CHC (0) MH] benzyl, 4-l ', 4'-di (Boc) piperazin-2'-yl) -C (0) NH-] benzyl, 4 - [(piperazin-2'-yl) -C (0) NH-] benzyl, 4- [(N-toluenesulfonylpyrrolidin-2'-yl) C (O) H-] butyl, 4- [-NHC (O) -4'-piperidinyl] butyl, 4- [-NHC (0) -l'-N-Boc-piperidin-2'-yl] benzyl, 4- [-NHC (O) -piperidin-2'-yl] benzyl, 4- [(1-N-Boc-2 ', 3' -dihydroindol in-2 '-yl) -C (O) NH] benzyl, 4- (pyridin-3 '-il-CH2NH) benzyl, 4- [(piperidin-1-yl) C (O) CH2-0-] benzyl, 4- [(CH3) 2CH) 2NC (0) CH2-0-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [fCH20 (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [-NHC (O) -2 '-methoxy phenyl] benzyl, 4- [(pyrazin-2'-yl) C (0) NH-] benzyl, 4- [HO (O) C (NH2) CHCH2CH2 -C (O) NH-] benzyl, 4- (2'-formyl-1 ', 2', 3 ', 4' -tetrahydroisoquinolin-3 '-il-CH2NH-) benzyl, N-Cbz-NHCH2-, 4- [(4'-methylpiperazin-1 '-yl) C (O) O-] benzyl, 4- [CH3 (N-Boc) NCH2C (O) NH-] benzyl, 4-NHC (0) - (1 ', 2', 3 ', 4'-tetrahydro-N-Boc-isoquinolin-3' - il] -benzyl, 4- [CH3NHCH2C (O) NH-] benzyl, (CH3) 2NC (0) CH2-, 4- (N-methylacetamido) benzyl, 4- (1 ', 2', 3 ', 4 '-tetrahydroisoquinolin-3' -yl- CH2NH-) benzyl, 4- (CH3) 2NHCH2C (0) NH-] benzyl, (l-toluenesulfonylimidizol-4-yl) methyl, 4 - [(1-Boc-piperidin-4'-yl) C (0) NH-] benzyl, 4-trifluoromethylbenzyl, 4- [(2'-bromophenyl) C (0) NH-] benzyl, 4- [(CH3) 2NC (0) NH-] benzyl, 4- [CH3OC (0) NH-] benzyl, - [(CH3) 2NC (O) 0-] benzyl, 4- [(CH3) 2NC (O) N (CH3) -] benzyl, 4- [CH3OC (O) N (CH3) -] benzyl, 4- ( N -methyltrifluoroacetamido) benzyl, 4- [(1'-methoxycarbonylpiperidin-1-yl) C (0) NH-] benzyl, 4- [(4'-phenylpiperidin-4'-yl) C (O) NH-] benzyl, 4- [(4'-phenyl-1-1 '-Boc-piperidin-4' -yl) -C (0) NH-] benzyl, 4- [(piperidin-4 '-yl) C (O) O-] benzyl, 4- [(1 '-met i -piperidin-4' -yl) -0-] benzyl, 4- [(1 '-methylpiperidin-4' -yl) C (O) 0-] benzyl, 4- [(4'-methylpiperazin-1 '-yl) C (O) NH-] benzyl, 3- [(CH3) 2NC (O) O-] benzyl, 4- [(4'-phenyl-l '-Boc-piperidin-4' -yl) -C (0) 0-] benzyl, 4- (N -toluenesulfonylamino) benzyl, 4- [(CH3) 3CC (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (0) NH-] benzyl, 4 - [CH3CH2) 2NC (O) NH -] benzylo, 4- [-C (O) NH- (4'-piperidinyl) benzyl, 4- [(2'-trifluoromethylphenyl) C (O) H-] benzyl, 4- [(2'-methylphenyl) C (O) NH-] benzyl, 4- [(CH3) 2NS (0) 20-] benzyl, 4- [(pyrrolidin-2 '-yl) C (0) NH- ] benzyl, 4 - [- NHC (0) -piperidin-1-yl] benzyl, 4- [(thiomorpholin-4'-yl) C (O) H-] benzyl, 4- [(thiomorpholin-4'- il sulfone) -C (O) NH-] benzyl, 4 - [(morpholin-4'-yl) C (0) 0-] benzyl, 3-nitro-4- (CH3OC (O) CH20-) benzyl, ( 2-benzoxazolinon-6-yl) ethyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-, 4- (CH3) 2NS (0) 2NH-] benzyl, 4- (CH3) 2NS (O) 2N (CH3) -] benzyl, 4- (thiomorpholin-4 '-yl) C (O) O-] benzyl, 4- (thiomorpholin-4 '-yl sulfone) -C (0) O-] benzyl, 4- (p iperidin-1' -yl) C (O) O-] benzyl, 4- (pyrrolidin-l'-il ) C (O) 0-] benzyl, 4- (4 '-methoxypiperazin-1'-yl) C (O) 0-] 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) 0 -] benzyl, 4- [(4'-acetylpiperazin-1'-yl) C (O) 0-] benzyl, p- [(4'-methanesulfonylpiperazin-1'-yl) -benzyl, 3-nitro-4- [(morpholin-4'-yl) -C (0) 0-] benzyl, 4-. { [(CH3) 2NC (S)] 2N-} benzyl, N-Boc-2-aminoethyl-, 4- [(1,1-dioxothiomorpholin-4-yl) -C (O) 0-] benzyl, 4- [(CH3) 2NS (0) 2-] benzyl, 4- (imidazolid-2'-one-l '-yl) benzyl, 4- [(piperidin-1-yl) C (0) 0-] benzyl, lN-benzyl-imidazol-4-yl-CH2-, 3,4-dioxyethylenebenzyl, 3,4-dioxymethylenebenzyl, 4- [-N (S02) (CH3) CH2CH2CH2N (CH3) 2] benzyl, 4- ( 3'-formyl imide zolid-2 '-one-1-yl) benzyl, 4- [NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, [2' - [4"-hydroxy-4" - (3 ' '' -methoxythien-2 '' '- il) piperidin-2"-yl] ethoxy] benzyl, and p- [(CH3) 2NCH2CH2N (CH3) C (0) 0-] benzyl 13.
13. The compound in accordance with claim 2, characterized in that R5 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-a-iso-propyl-4-β-methylcyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2C00H, -NHCH2CH2C00H, -NH-adamantyl, -NHCH2CH2C00CH2CH3, -NHS02-p-CH3-f, -NH0R8 where R8 is hydrogen, methyl, iso-propyl or benzyl, 0- (N-succinimidyl), -0 -cholest-5-en-3-ß-ilo, -0CH2-0C (O) C (CH3) 3, -O (CH2) 2NHC (0) R9 where z is 1 and R9 is selected from the group consisting of pyrid -3-yl, N-met ilpyridyl, 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 (0) 0CH2CH3.
14. The compound according to claims 1 or 2, characterized in that W is oxygen.
15. 15. A compound, characterized in that it is selected from the group consisting of: N- (benzyl) -L-pyroglutamyl-L-phenylalanine N- (benzyloxycarbonyl) -L-pyroglutamyl-L-phenylalanine N- (benzyl) -L-pyroglutamyl -L-4 - (phenylcarbonylamino) phenylalanine N- (3,4-dichlorobenzyl) -L-pyroglutamine L-4 - (phenylcarbonylamino) phenylalanine N- (3-chlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine Methyl ester of N- (3-chlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine N- (4-chlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine Methyl ester of N- (4-chlorobenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine N- (4-methylbenzyl) -L-pyroglutamyl-L-4 - (phenylcarbonylamino) phenylalanine Methyl ester of N- (4-methylbenzyl) - L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine N- (4-methoxybenzyl) -L-pyroglutamyl-L-4- (phenylcarbonylamino) phenylalanine Methyl ester of N- (4-methoxybenzyl) -L-pyroglutamyl-L- 4 - (phenylcarbonylamino) phenylalanine N- (3-chlorobenzyl) -L-pyroglutamyl-L- (N '-benzyl) histidine Methyl ester of N- (4-methylbenzyl) -L-pyroglutamyl-L- (N' -benzyl) histidine N- (4-methylbenzyl) -L-pyroglutamyl-L- (N '-benzyl) his tidine N- (benzyl) -D-pyroglutamyl-L-phenylalanine N- (4-benzyl 1-3-oxot iomorpholin- 5 - carbonyl) -L-phenylalanine N- (4-benzyl-3-oxothiomorpholine-5-carbonyl) -L-phenylalanine N- (4-benzyl-3-oxomorpholine-5-carbonyl) -L-phenylalanine Ester Methyl N- (4-benzyl-3-oxothiomorpholin-5-carbonyl) -L-4-nitrophenylalanine N- (benzyl) -L-pyroglutamyl-L-4-ylcarbonylamine methyl ester) phenylalanine Methyl ester of N- (benzyl) -L-pyroglutamyl-L-4- (1'-benzyloxycarbonylpiperidin-4'-alkylcarbonylamino) phenylalanine N- (benzyl) -L-pyroglutamyl-L-4 - (pyridin-4-ylcarbonylamino) phenylalanine N- (benzyl) ) -L-pyroglutamyl-L-4- (1'-benzyloxycarbonylpiperidin-4'-ylcarbonylamino) phenylalanine N- (benzyl) ethyl ester - L-pyroglutamyl-L-tyrosine N- (benzyl) -L-pyroglutamyl-L-4- (piperidin-4'-ylcarbonylamino) phenylalanine Ethyl ester of N- (benzyl) -L-pyroglutamyl-L-4-nitrophenylalanine N- (benzyl) -L-pyroglutamyl-L-tyrosine Ethyl ester of N- (benzyl) -L-pyroglutamyl-L-4- (1'-methylpiperidin-4'-yloxy) phenylalanine N- (benzyl) -L-pyroglutamyl -L-4-nitrophenylalanine N- (benzyl) -L-pyroglutamyl-L- 4- [(4'-methyIpiperazin-1'-yl) carbonyloxyphenylalanine N- (benzyl) -L-pyroglutamine-L- ethyl ester 4- (1'-metilpiperidin-4'-yloxy) phenylalanine N- (benzyl) -L-pyroglutamine 1-L- 4- [(4'-met ipipera zin-1'-yl) carbonyloxy] phenylalanine Ester of ethyl N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine N- (benzyl) -L-pyroglutamyl-L-4-amino-phenylalanine N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyoxy) phenylalanine ester Tert-Butyl Ester of N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyoxy) phenylalanine Tert-butyl ester of N- (benzyl) -L-pyroglutamyl-L-4 - [( 4 '-methylpiperazin-1' -yl) carbonyloxy] phenylalanine Tert-butyl ester of N- (benzyl) -L-pyroglutamyl-L-4 - [(thiomorpholin-4'-yl) carbonyloxy] phenylalanine Tert-butyl ester of N- (4-fluorobenzyl) -L-pyroglutamyl-L-4 - [(thiomorpholin-4'-yl) carbonyloxy] phenylalanine Isopropyl ester of N- (benzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyl i) phenylalanine Tert-butyl ester of N- (4-f luorobenzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) phenylalanine N- (benzyl) -L-pyroglutamine L-3-chloro-4-hydroxyphenylalanine Tert-butyl ester of N- (4-cyanobenzyl) -L-pyroglutamyl-L-4- (N, N-dimethylcarbamyloxy) Phenylalanine Methyl ester of N- (benzyl) -L-pyroglutamyl-L-3-chloro-4- (N, N-dimethylcarbamyoxy) phenylalanine N- (4-fluorobenzyl) -L-pyroglutamyl-L-4 - [(thiomorpholine) - 4 '-yl) carbonyloxy] phenylalanine N- (4-cyanobenzyl) -L-pyroglutamine 1-L- 4 - (N, N-dimethylcarbamyloxy) phenylalanine N- (1-benzyloxycarbonyl-2-imidazolidone-5-carbonyl ) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine Tert-butyl ester of N- (4-nitrobenzyl) -L-pyroglutamyl-4- (N, N-dimethylcarbamyoxy) phenylalanine N- (benzyl) - L-pyroglutamine 1-L-3-chloro-4- (N, N-dimethylcarbamyloxy) phenylalanine N- (4-fluorobenzyl) -L-pyroglutamyl-L- 4- [(4 '- (pyridin-2-yl) piperazine - 1 '- il) carbonyloxy] phenylalanine Tert-butyl ester of N- (4-fluorobenzyl) -L-pyroglutamyl-L-4 - [(4' - (pyridin-2-yl) piperazin-1-yl) ) carbonyloxy] phenylalanine Tert-butyl ester of N- (4-aminobenzyl) -L- pyroglutamine IL-4- (N, N-dimethylcarbamyloxy) phenylalanine Tert-butyl ester of N- (pyridin-3-ylmet il) - L-pyroglutamyl-L-tyrosine N- (pyridin-3-ylmethyl) -L-pyroglutamyl-L-4 - (N, N-dimethylcarbamyloxy) phenylalanine. Tert-butyl ester of N- (pyridin-3-ylmethyl) - L-pyroglutamyl-L-4- (N, N-dimethylcarbamyoxy) phenylalanine Tert-butyl ester of N- (pyridin-3-ylmethyl) - L-pyroglutamyl-L- 4 - [(4 '- (pyridine- 2-yl) piperazin-1 '-yl) carbonyloxy] phenylalanine N- (pyridin-3-ylmethyl) -L-pyroglutamine 1-L- 4 - [(4' - (pyridin-2-yl) piperazine-1 '- il) carbonyloxy] phenylalanine Tert-butyl ester of N- (4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carbonyl) -L-tyrosine Tert-butyl ester of N- (4-benzyl-5-oxo-4-azatricyclo [4.2.1.0 (3,7)] nonane-3-carbonyl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine 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 was of the ester compounds described 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.
16. 16. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula I: wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, and -C (0) ORx; 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, carbon and from 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have from 2 to 4 atoms in the heteroalkylene chain, and substituted heteroalkylene, in the heteroalkylene chain, from 1 to 3 carbon atoms and from 1 up to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and 'have 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 may be associated with R2 to form a combined cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; R 4 is selected from the group consisting of isopropyl, -CH 2 -X y = CH-X, where 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, carboxy, carboxylalkyl, substituted carboxylalkyl, carboxycycloalkyl, substituted carboxycycloalkyl, carboxylaryl, substituted arylcarboxyl, carboxyheteroaryl, substituted carboxyl-heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic, and hydroxyl with the proviso that when R4 is = CH-X then (H) is removed from the formula and X is not hydroxyl; "W is oxygen or sulfur, and pharmaceutically acceptable salts thereof"
17. 17. A pharmaceutical composition, characterized in that it comprises an effective amount of a compound of the formula IA: wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl and -CFOlOR1; 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, carbon and from 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have from 2 to 4 atoms in the heteroalkylene chain, and substituted heteroalkylene, in the heteroalkylene chain, from 1 to 3 carbon atoms and from 1 up to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, and have 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 may be associated with R2 to form a combined cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; R 4 is selected from the group consisting of isopropyl, -CH 2 -X y = CH-X, where 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, carboxy, carboxylalkyl, substituted carboxyl-alkyl, carboxy-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxyl- substituted aryl, carboxylheteroaryl, substituted carboxyl -heteroaryl, carboxyheterocyclic, substituted carboxy -heterocyclic, and hydroxyl with the proviso that when R4 is = CH-X then (H) is removed from the formula and 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, -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 from 1 to 8; W is oxygen or sulfur; and pharmaceutically acceptable salts thereof; with the condition that; (a) when R1 is benzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 is benzyl, then R5 is not ethyl; (b) when R1 is 3,4-dichlorobenzyl, R2 is CH2CH2-, Rc is hydrogen, R * is 4- (phenylcarbonylamino) benzyl, then R5 is not methyl; (c) when R1 is benzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 is 4-hydroxybenzyl, then R5 is not isopropyl or tert-butyl; (d) when R 1 is 4-fluorobenzyl, R 2 is CH 2 CH 2 -, R 3 is hydrogen, R 5 is tert-butyl, then R 4 is not 4-hydroxybenzyl or 4- (4-nitro phenoxycarbonyloxy) benzyl; (e) when R1 is 4-cyanobenzyl, R2 is -CH2CH2-, R3 is hydrogen, R4 is 4-hydroxybenzyl, then R5 is not tert-butyl; and (f) when R1 is benzyloxycarbonyl, R2 is NHCH2-, R3 is hydrogen, R5 is tert-butyl, then R4 is not 4-hydroxybenzyl or 4- (N, N-dimethylcarbamyloxy) benzyl.
18. 18. The pharmaceutical composition according to claim 16 or 17, characterized in that R1 is a group having 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.
19. 19. The pharmaceutical composition according to claim 18, characterized in that Z is CH.
20. The pharmaceutical composition according to claim 19, characterized in that one of R6 and R7 is hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy, amino, chloro, fluoro, cyano or nitro; or both of R6 and R7 are chlorine.
21. 21. The pharmaceutical composition according to claim 16 or 17, characterized in that R1 is selected from the group consisting of benzyl, 4-aminobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 4-cyanobenzyl, -fluorobenzyl, 4-methybenzyl, 4-methoxybenzyl, 4-nitrobenzyl, benzyloxycarbonyl and (pyridin-3-yl) methyl.
22. The pharmaceutical composition according to claim 16 or 17, characterized in that R 2 is selected from the group consisting of alkylene having 2 or 3 carbon atoms in the alkylene chain, substituted alkylene having 2 6 3 carbon atoms in the alkylene chain, heteroalkylene containing 1 or 2 carbon atoms and 1 heteroatom selected from nitrogen, oxygen and sulfur and having 2 or 3 atoms in the alkylene chain, and substituted heteroalkylene containing, in the heteroalkylene chain, 1 6 2 carbon atoms; carbon and 1 heteroatom selected from nitrogen, oxygen and sulfur and having 2 or 3 atoms in the heteroalkylene chain.
23. 23. The pharmaceutical composition according to claim 22, characterized in that R2 is selected from the group consisting of -CH2CH2-, -CH2-S-CH2-, -CH2-0-CH2- and -NHCH2-.
24. 24. The pharmaceutical composition according to claim 16 or 17, characterized in that R3 is hydrogen.
25. 25. The pharmaceutical composition according to claim 16 or 17, characterized in that R4 is selected from the group consisting of: 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl, 4-benzyloxybenzyl, 4- [f-CH (CH3) O-] benzyl, 4- [f-CH (COOH) O-] benzyl, 4- [BocNHCH2C (O) NH-] benzyl, 4-chlorobenzyl, 4- [NH2CH2C (O) NH] -] benzyl, 4-carboxybenzyl, 4- [CbzNHCH2CH2NH-] benzyl, 3-hydroxy-4- (f-OC (O) NH-) benzyl, 4- [HOOCCH2CH2C (0) NH-] benzyl, benzyl, 4- [2'-carboxylphenoxy] benzyl, 4- [fC (0) NH-] benzyl, 3-carboxybenzyl, 4-iodobenzyl, 4-hydroxy-3,5-diiodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [ 2 '-carboxyphenyl-] benzyl, 4-nitrobenzyl, 2-carboxybenzyl, 4- [dibenzylamino] -benzyl, 4 - [(1-cyclopropylpiperidin-4'-yl) C (0) NH-] benzyl, 4- [ -NHC (O) CH2NHBoc] benzyl, 4-carboxybenzyl, 4-hydroxy-3-nitrobenzyl, 4- [-NHC (0) CH (CH3) NHBoc] benzyl, 4- [-NHC (0) CH (CH2f) NHBoc ] benzyl, isobutyl, methyl, 4- [CH3C (O) NH-] benzyl, -CH2- (3-indolyl), n-butyl, t-butyl-OC (O) CH2, t-butyl-OC (O) CH2CH2-, H2NC ( O) CH2-, H2NC (O) CH2CH2-, BocNH- (CH2) i-, t-butyl-OC (O) - (CH2) 2-, HOOCCH2-, HOOC (CH2) 2-, H2N (CH2) 4 -, Isopropyl, (1-naphthyl) -CH2-, (2-naphthyl) -CH2-, (2-thiophenyl) -CH2-, (f-CH2-OC (O) NH- (CH2) 4-r cyclohexyl-CH2-, benzyloxy-CH2-, HOCH2-, 5- (3-N-benzyl) imidazolyl -CH2-, 2-pyridyl-CH2-, 3-pyridyl-CH2-, 4-pyridyl-CH-, 5- (3-N -methyl) imide zolyl-CH2-, N-benzylpiperid-4-yl-CH2 -, N-Boc-piperidin-4-yl-CH2-, N- (phenyl-carbonyl) piperidin-4-yl-CH2-, H3CSCH2CH2-, lN-benzylimidazol-4-yl-CH2-, iso-propyl-C (O) MH- (CH2) 4", iso-butyl-C (O) NH- (CH2) 4-, phenyl 1-C (O) NH- (CH2) 4-, benzyl-C (O) NH- (CH2) 4-, allyl-C (O) NH- (CH2) 4-, 4- (3-N-methylimidazolyl) -CH2-, 4 -imido zolyl, 4- [(CH3) 2NCH2CH2CH2-0-] benzyl, 4- [(benzyl) 2N-] -benzyl, 4-aminobenzyl, allyloxy-C (O) NH (CH2) 4-, allyloxy-C (O) NH (CH2) 3-, allyloxy-C (O) NH (CH2) 2-, NH2C (O) CH2-, 2-pyridyl-C (0) NH- (CH2) 4-, 4-methylpyrid-3-yl-C (O) NH- (CH2) 4-, 3-methylthien-2-yl-C (0) NH- (CH2) 4-, 2-pyrrolyl-C (0) NH- (CH2) 4-, 2- furani 1-C (O) NH- (CH2) 4-, 4-methylphenyl1-S02-N (CH3) CH2C (O) NH (CH2) 4-, 4- [cyclopentylacetylenyl] -benzyl, 4- [NHC (0) - (N-Bo) c) -pyrrolidin-2-yl)] benzyl-, 1-N-methylimidazol-4-yl-CH2-, 1-N-methylimidazol-5-yl-CH2-, ylidazol-5-yl-CH2-, 6 -methylpyrid-3-yl-C (O) NH- (CH2) 4-, 4- [2 '-carboxymethylphenyl] -benzyl, 4- [-NHC (O) NHCH 2 CH 2 CH 2 -f] -benzyl, 4- [-NHC (0) NHCH2CH2-f] -benzyl, -CH2C (O) NH (CH2) 4f, 4- [f (CH2) 0-] -benzyl, 4- [-C = Cf-4'f ] -benzyl, 4- [-C = C-CH2-0-S (0) 2-4? -CH3-f] -benzyl, 4- [-C = C-CH2-NHC (0) NH2] -benzyl, 4- [-C = C-CH2-0-4 '-COOCH2CH3-f] -benzyl, 4- [-C = C-CH (NH 2) -cydohexyl] -benzyl, - (CH2) 4NHC (0) CH2-3-indolyl, - (CH2) 4NHC (O) CH2CH2-3-indolyl, - (CH2) 4NHC (0) -3- (5 -methylidene), - (CH2) 4NHC (0) -3- (1-methylindolyl), - (CH2) 4NHC (0) -4- (-S02 (CH3) -f), - (CH2) 4NHC (0) -4- ( C (0) CH3) -phenyl, - (CH2) 4NHC (O) -4-fluorophenyl, - (CH2) 4NHC (0) CH20-4-fluorophenyl, 4- [-C = C- (2-pyridyl) benzyl, 4- [-C = C-CH 2-0- phenyl] benzyl, 4- [-C = C-CH 2 OCH 3] benzyl, 4- [-C = C - (3-hydroxyphenyl)] benzyl, 4- [-C = C-CH2-0-4 '- (- C (0) OC2H5) phenyl] benzyl, 4- [-C = C-CH2CH (C (O) OCH3) 2] benzyl, 4- [-C = C-CH2NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl) ), 3-aminobenzyl, 4- [-C = C-CH2CH (NHC (0) CH3) C (0) OH] -benzyl, -CH2C (O) NHCH (CH3) f, -CH2C (O) NHCH2- (4-dimethylamino) -f, -CH2C (O) NHCH2-4-nitrophenyl, -CH2CH2C (0) N (CH3) CH2- f, -CH2CH2C (O) NHCH2CH2- (N-methyl) -2-pyrrolyl, -CH2CH2C (O) NHCH2CH2CH2CH3, -CH2CH2C (O) NHCH2CH2-3-indolyl, -CH2C (O) N (CH3) CH2phenyl, -CH2C (O) NH (CH2) 2- (N-methyl) -2-pyrrolyl , -CH2C (O) NHCH2CH2CH2CH3, -CH2C (O) NHCH2CH2-3-indolyl, - (CH2) 2C (O) NHCH (CH3) f, - (CH2) 2C (O) NHCH2-4-dimethylamino phenyl, - ( CH2) 2C (0) NHCH2-4-nitrophenyl, -CH2C (O) NH-4- [-NHC (O) CH3-phenyl), -CH2C (O) NH-4-pyridyl, -CH2C (0) NH- 4- [dimethylaminophenyl], -CH2C (O) NH-3-methoxy phenyl, -CH2CH2C (0) NH-4-chlorophenyl, -CH2CH2C (O) NH-2-pyridyl, -CH2CH2C (O) NH- 4 - me toxi feni lo, -CH2CH2C (O) NH-3-pyridyl, 4- [(CH3) 2NCH2CH20-] benzyl, - (CH2) 3NHC ((NH) NH-SO2- -methylphenyl, 4- ([CH3) 2NCH2CH2O -] benzyl, - (CH2) 4NHC (O) NHCH2CH3, - (CH2) 4NHC (O) NH-pheni lo, - (CH2) 4NHC (O) NH-4-methoxy-phenyl, 4- [4'-pyridyl -C (0) NH-] benzyl, 4- [3'-pyridyl-C (O) NH-] benzyl, 4 - [- NHC (0) NH-3 '-methylphenyl] benzyl, 4 - [- NHC ( 0) CH2NHC (0) NH-3 '-methylphenyl] benzyl, 4 - [- NHC (0) - (2', 3'-dihydroindo1-2-yl)] benzyl, 4- [-NHC (O) - ( 2 ', 3' -dihydro-N-Boc-indol-2-yl) benzyl, p- [-OCH2CH2-I '- (4'-pyrimidinyl) -piperazinyl] benzyl, 4- [-OCH2CH2- (l' - piperidinyl) b encyl, 4- [-OCH2CH2- (1'-pyrrolidinyl) benzyl, 4- [-OCH2CH2CH2- (1'-piperidinyl)] benzyl, -CH2-3- (1,2,4-triazolyl), 4- [- OCH2CH2CH2-4- (3'-chlorophenyl) -piperazin-1-yl] benzyl, 4- [OCH2CH2N (f) CH2CH3] benzyl, 4- [-OCH2-3 '- (N-Boc) -piperidinyl] benzyl, 4- [di-n-pentylamino] benzyl, 4 - [n-pentylamino] benzyl, 4- [di-iso -propi lami non -CH2CH20-] benzyl, 4- [-OCH2CH2- (N-morpholinyl) ] benzyl, 4- [-0- (3 '- (N-Boc) -piperidinyl] benzyl, 4- [-OCH2CH (NHBoc) CH2cyclohexyl] benzyl, p- [OCH2CH2- (N-piperidinyl] benzyl, 4- [ -OCH2CH2CH2- (4-m-chlorophenyl) -piperazin-1-yl] benzyl, 4- [-0CH2CH2- (N-homopiperidinyl) benzyl, 4- [-NHC (0) -3 '- (N-Boc) - piperidinyl] benzyl, 4- [-OCH2CH2N (benzyl) 2-benzyl, -CH2-2-thiazolyl, 3-hydroxybenzyl, 4- [-0CH2CH2CH2N (CH3) 2] benzyl, 4- [-NHC (S) NHCH2CH2- (N-morpholine)] benzyl, 4- [-OCH2CH2N (C2H5) 2] benzyl, 4- [-0CH2CH2CH2N (C2H5) 2] benzyl, 4- [CH3 (CH2) 4NH-benzyl, 4- [Nn-butyl, Nn-pentylamino-] benzyl 4 - [-NHC (0) -4 '-piperidinyl] benzyl, 4- [-NHC (O) CH (NHBoc) (CH2) 4NHCbz] benzyl, 4- [-NHC (0) - (1', 2 ', 3 ', 4' -tetrahydro-N-Boc-isoquinolin-1 '-yl] benzyl, p- [-OCH2CH2CH2-I' - (4'-methyl) -piperazinyl] benzyl, - (CH2) 4NH-B0C, 3 - -0CH2CH2CH2N (CH3) 2] benzyl, 4- -OCH2CH2CH2N (CH3) 2] benzyl, 3- -OCH2CH2- (1'-pyrrolidinyl)] benzyl, 4- -OCH2CH2CH2N (CH3) benzyl] benzyl, 4- -NHC (S) NHCH2CH CH2 (N-morpholino)] benzyl, 4- -OCH2CH2- (N-morpholino)] benzyl, 4--NHCH2- (4'-chlorophenyl)] benzyl, A- -NHC (O) NH- ( 4'-cyanophenyl)] benzyl, 4- -OCH2COOH] benzyl, 4- -OCH2) COO-t-butyl] benzyl, 4- NHC (O) -5 '-fluoroindol-2-yl] benzyl, 4- NHC (S) NH (CH2) 2-l-piperidinyl] benzyl, -N (S02CH3) (CH2) 3-N (CH3) 2] benzyl, 4-NHC (O) CH2CH (C (O) OCH2f) -NHCbz] benzyl, 4- NHS (O) 2CF3] benzyl, - -O- (N-met i Ipiperidin-4 '-yl] benzyl, 4-C ("NH) NH2] benzyl, 4-NHSO2-CH2Cl] benzyl, 4- [-NHC (O) -) 1 ', 2', 3 ', 4' -tetrahydroisoquinolin-2'-yl] benzyl, 4- [-NHC (S) NH (CH2) 3-N-mor fol ino] benzyl, 4- [-NHC (O) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, 4- [-C (0) NH2] benzyl, 4 - [- NHC (0) NH-3 '-methoxyphenyl] benzyl, 4- [-OCH2CH2-indol-3'-yl] benzyl, 4- [-OCH2C ( O) NH-benzyl] benzyl, 4- [-OCH2C (O) O-benzyl] benzyl, 4 - [- OCH2C (0) OH] benzyl, 4 - [- OCH2-2 '- (4', 5'- dihydro) imidazolyl] benzyl, -CH2C (0) NHCH2- (4-dimethylamino) phenyl, -CH2C (O) NHCH2- (4-dimet i lamino) phenyl, 4 - [- NHC (0) -L-2 '- pyrrolidinyl-N-S02- 4'-methylphenyl] benzyl, 4- [-NHC (O) NHCH 2 CH 2 CH 3] benzyl, 4-aminobenzyl] benzyl, 4- [-OCH 2 CH 2 -I- (4-hydroxy-4- (3-methoxypyrrol-2-yl) - piperazinyl] benzyl, 4- [-0- (N-methylpiperidin-4 '-yl) benzyl, 3-methoxybenzyl, 4- [-NHC (0) -piperidin-3'-yl] benzyl, 4- [-NHC ( 0) -pyridin-2'-yl] benzyl, 4- [-NHCH2- (4'-chlorophenyl)] benzyl, 4- [-NHC (O) - (N- (4 '-CH3-f-S02) - L-pyrrolidin.2 '-yl)] benzyl 4- [-NHC (O) NHCH 2 CH 2 -f] benzyl, 4- [-OCH 2 C (O) NH 2] benzyl, 4- [-OCH 2 C (O) NH-t-butyl ] benzyl, 4- [-OCH2CH2-I- (4-hydroxy-4-phenyl) -piperidinyl] benzyl, 4- [-NHS02-CH = CH2] benzyl, 4- [-NHS02-CH2CH2C1] benzyl, -CH2C ( 0) NHCH2CH2N (CH3) 2, 4- [(1 '-Cbz -piperidin-4' -yl) C (0) NH-] benzyl, 4 - [(1-Boc-piperidin-4'-yl) C (0) NH-] benzyl, 4- [(2'-bromophenyl) C (O) NH-] benzyl, 4- [-NHC (O) -pyridin-4'-yl] benzyl, 4- [(4 '- (CH 3) 2NC (O) O-) phenyl) -C (O) NH-] benzyl, 4- [-NHC (O) -1 '-methylpiperidin-4' -yl-] benzyl, 4 - . 4- (dimethylamino) benzyl, 4- [-NHC (O) - (1 '-N-Boc) -piperidin-2'-yl] benzyl, 3- [-NHC (O) -pyridin-4'-yl] benzyl, 4- [tert-butyl-0 (O) CCH2-0-benzyl) -NH-] benzyl, [BocNHCH2C (O) NH-] butyl, 4-benzylbenzyl, 2-hydroxyethyl, 4- [(Et) 2NCH2CH2CH2NHC (S) NH-] benzyl, 4- [(lr -Boc-4 '-hydroxypyrrolidin-2'-y ) C (0) NH-] benzyl, 4- [fCH2CH2CH2NHC (S) NH-] benzyl, 4- [(perhydroindolin-2'-yl) C (0) NH-] benzyl, 2- [4-hydroxy-4- (3-methoxy-thien-2-yl) -piperidin-1-yl] -ethyl, 4- [(1 '-Boc-perhydroindolin-2'-yl) -C (0) NH -] benzyl, 4- [N-3-methylbutyl-N-trifluoromethanesulfonyl) amino] benzyl, 4- [N-vinylsulfonyl) amino] benzyl, 4- [2- (2-azabicyclo [3.2.2] octane-2- il) ethyl-0-] benzyl, 4- [4 '-hydroxypyrrolidin-2' -yl) C (O) NH-] benzyl, 4- (fNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl, 4- (f-CH2NHC (S) NH) benzyl, 3- [(1 '-Boc-piperidin-2' -il ) C (O) NH-] benzyl, 3- [piperidin, 2 '-yl-C (O) NH-] benzyl, 4 - [(3'-Boc-thiazolidin-4'-yl) C (0) NH -] benzyl, 4- (pyridin-3'-yl-NHC (S) NH) benzyl, 4- (CH3-NHC (S) NH) benzyl, 4- (H2NCH2CH2CH2C (O) NH) benzyl, 4- (BocHNCH2CH2CH2C (O) NH) benzyl, 4- (pyridin-4 '-il-CH2NH) benzyl, 4- [(N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- [(1 -Cbz -piperidin-4-yl) C (O) NH-] butyl, 4- [fCH2OCH2 (BocHN) CHC (O) NH] benzyl, 4 - [(piperidin-4'-yl) C (0) NH-] benzyl, 4 - [(pyrrolidin-2'-yl) C (0) 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- [CH3NHCH2CH2CH2C (O) NH-] benzyl, 4- [CH3N (boc) CH2CH2CH2C (O) NH-] benzyl, 4- (aminomethyl) benzyl, 4- [fCH2OCH2 (H2N ) CHC (O) MH] benzyl, 4-l ', 4'-di (Boc) pipera zin-2'-yl) -C (0) NH-] benzyl, 4 - [(piperazin-2'-yl) -C (0) NH-] benzyl, 4- [(N-toluene sulfoni lpyrrolidin-2 '-yl) C (O) H-] butyl, 4- [-NHC (O) -4'-piperidinyl] butyl, 4- [-NHC (O) -1 '-N-Boc-piperidin-2' -yl] benzyl, 4 - [- NHC (0) -piperidin-2'-yl] benzyl, 4- [(1'-N-Boc-2 ', 3' -dihydroindo lin-2'-yl) -C (O) H] benzyl, 4- (pyridin-3'-yl-CH2NH) benzyl, 4- [(piperidin-1'-yl) C (O) CH2-0-] benzyl, 4- [(CH3) 2CH) 2NC (0) CH2-0-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [fCH20 (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4 - [- NHC (0) -2'-methoxyphenyl] benzyl, 4 - [(pyrazin-2'-yl) C (0) NH-] benzyl, 4- [HO (O) C (NH2) CHCH2CH2-C (0) NH-] benzyl ?, 4- (2'-f ormyl-1 ', 2', 3 ', 4' -tetrahydroisoquinolin-3 '-il-CH2NH-) benzyl, N-Cbz-NHCH2-, 4- [(4'-methyIpipera zin-1 '-yl) C (O) 0-] benzyl, 4- [CH 3 (N-Boc) NCH 2 C (O) NH-] benzyl, 4 - [- NHC (0) - (1 ', 2', 3 ', 4' - tetrahydro-N-Boc-isoquinolin-3 ' -yl] -benzyl, 4- [CH3NHCH2C (0) NH-] benzyl, (CH3) 2NC (0) CH2-, 4 - (N-methylacetamido) benzyl, 4- (1 ', 2', 3 ', 4'-tetrahydroisoquinolin-3'-yl-CH2NH-) benzyl, 4- (CH3) 2NHCH2C (O) NH-] benzyl, (1-toluenesul fonyl imidi zol-4-yl) methyl, 4 - [(1-Boc-piperidin-4'-yl) C (0) NH-] benzyl, 4-trifluoromet-ilbenzyl, 4- [(2'-bromophenyl) C (O) NH-] benzyl, 4- [(CH3) 2NC (O) NH-] benzyl, 4- [CH3OC (0) NH-] benzyl, 4- [(CH3) 2NC (O) O-] benzyl, 4- [(CH3) 2NC (O) N (CH3) -] benzyl, 4- [CH3OC (0) N (CH3) -] benzyl, 4- (N-methylfluoroacetamido) encyl, 4- [(1'-methoxycarboniIpiperidin-4'-yl) C (0) NH-] benzyl, 4 - [(4'-phenylpiperidin-4'-yl) C (0) NH -] benzyl, 4- [(4'-phenyl-1-1 '-Boc-piperidin-4' -yl) -C (0) NH-] benzyl, 4- [(piperidin-4 '-yl) C (0) 0-] benzyl, 4- [(1'-methi Ipiperidin-4 '-yl) -0-] benzyl, 4- [(1'-methyIpiperidin-4' -yl) C (0) 0-] benzyl, 4- [(4 '-met i Ipipera zin-1' -yl) C (0) NH-] benzyl, 3- [(CH 3) 2 NC (0) 0-] benzyl, 4- [(4'-phenyl-1 '-Boc-piperidin-4' -yl) -C (0) 0-] benzyl, 4- (N toluenesulfonylamino) benzyl, 4- [(CH3) 3CC (0) NH-] benzyl, 4 - [(morpholin-4'-yl) C (0) NH-] benzyl, 4- [CH3CH2) 2NC (0) NH -] benzyl, 4- [-C (0) NH- (4'-piperidinyl) benzyl, 4- [(2'-trifluoromethylphenyl) C (0) H-] benzyl, 4- [(2'-methylphenyl) C (O) NH-] benzyl, 4- [(CH3) 2NS (0) 20-] benzyl, 4- [(pyrrolidin-2'-yl) C (0) H- ] benzyl, 4 - [- NHC (0) -piperidin-1-yl] benzyl, 4- [(thiomorpholin-4 '-yl) C (0) NH-] benzyl, 4- [(thiomorpholin-4' - il sulfone) -C (0) NH-] benzyl, 4 - [(morpholin-4'-yl) C (0) 0-] benzyl, 3-nitro-4- (CH3OC (0) CH20-) benzyl, ( 2-benzoxazolinon-6-yl) methyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-, 4- (CH3) 2NS (0) 2NH-] benzyl, 4- (CH3) 2NS (0) 2N (CH3) -] benzyl, 4- (thiomorpholin-4 '-yl) C (0) 0-] benzyl, 4- (thiomorpholin-4'-yl sulfone) -C (0) O-] benzyl, 4- (piperidin-1-yl) C (O) 0-] benzyl, 4- (pyrrolidin-1-iDC ( O) O-] benzyl, 4- (4'-methylpiperazin-1'-yl) C (0) 0-] benzyl, 4- (2'-methylpyrrolidin-1'-yl) -, (pyridin-4-yl) ) methyl-, 4- (piperazin-4 '-yl) -C (0) 0-] benzyl, 4- (1' -Boc-piperazin-4 '-yl) -C (0) 0-] benzyl, - (4 '-acetylpiperazin-1' -yl) C (0) 0-] benzyl, P- (4'-methanesulfoni Ipipera zin-1 '-il). -benzyl, 3-nitro-4 - [(morpholin-4'-yl) -C (0) 0-] benzyl, 4- [(CH3) 2NC (S)] 2N-} benci 1 < N-Boc-2-aminoethyl-, 4- (1, 1-dioxot iomorpholin-4-yl) -C (O) 0-] benzyl, 4- [(CH 3) 2 NS (O) 2-] benzyl, 4- (imide zolid-2 '-one-1' -yl) benzyl, 4- [(piperidin-1-yl) C (0) O-] benzyl, lN-benzyl-imidazol-4-yl-CH2-, 3 4-dioxyethylenebenzyl, 3,4-dioxymethylenebenzyl, 4- [-N (S02) (CH) CH2CH2CH2N (CH3) 2] benzyl, 4- (3'-formyl imidazolid-2 '-one-1'-yl) benzyl, 4- [NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, [2 '- [4"-hydroxy-4" - (3' '' -methoxy-2''-yl) piperidin-2"- il] ethoxy] benzyl, and P- [(CH3) 2NCH2CH2N (CH3) C (O) 0-] benzyl
26. 26. The pharmaceutical composition according to claim 17, characterized in that R5 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- -isopropyl-4-β- methylcyclohexoxy, 2-ß-isopropyl-4-β-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2COOH, NHCH2CH2COOH, -NH-adamant i lo, -NHCH2CH2COOCH2CH3, -NHS02-p-CH3-f, -NHOR8 where R8 is hydrogen, methyl, iso-propyl or benzyl, 0- (N-succinimidyl), -0-cholest-5 -in-3-ß-ilo, -OCH2-OC (O) C (CH3) 3, -O (CH2) 2NHC (O) R9 where z is 1 and R9 is selected from the group consisting of pyrid-3-yl , N-methylpyridyl, and N-met il-1,4-dihydro-pyrid-3-yl, -NR "C (0) -R 'where R' is aryl, heteroaryl or heterocyclic and R "is hydrogen or CH2C (O) OCH2CH3
27. 27. The pharmaceutical composition according to claim 16 or 17, characterized in that W is oxygen
28. 28. A method to bind VLA-4 in a biological sample characterized in that the method comprises contacting the biological sample with a compound according to claim 1 or 2 under conditions wherein the compounds bind to VLA-4
29. 29. A method for treating an inflammatory condition in a mammalian patient whose Condition is mediated by VLA-4, characterized in the method because it comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claims 16 or 17.
30. 30. The method according to claim 29, characterized in that the inflammatory condition it is selected from the group consisting of asthma, Alzheimer's disease, arteriosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, infarction, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute lung injury mediated by leukocytes. DERIVATIVES OF PIROGLUTAMIC ACID AND COMPOUNDS RELATED THAT INHIBIT THE ACCESSION TO LEUKOCYTES MEDIATED BY ALFA4 BETA1 INTEGRINE AND CD49d / cd29 (VLA-4) Summary of the Invention Pyroglutamic acid derivatives and related compounds that bind VLA-4 are described. Some of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian, e.g., human patient, such as asthma, Alzheimer's disease, arteriosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis. , and tumor ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.