MXPA00004475A - Chemical compounds - Google Patents

Abstract

Compounds of formula (II) where R1 is in the para or meta position and is (A);R2 and R3 are each independently selected from hydrogen, nitro, C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-4alkoxyl, C1-6alkylamino, C1-6dialkylamino, C1-6alkylC1-4alkoxyl, C1-6alkylaminoC1-6alkyl, amino, cyano, halogeno, trifluoromethyl, -CO2R12 and -CONR12R13, where R12 and R13 are independently selected from hydrogen or C1-6alkyl, or R2 and R3 together with the phenyl to which they are attached form a 9 or 10 membered bicyclic ring system;R4 is C1-4alkyl;R5 is selected from hydrogen and C1-4alkyl;R6 is selected from C1-6alkyl, C1-4alkyl(C4-6)cycloalkyl, C1-6alkyl(C1-6)alkoxyl, C1-6alkylS(C1-6)alkyl, C1-4alkylsulphonyl(C1-4)alkyl;(B) where q is an integer from 1 to 6 and R14 is halogeno;R7 is selected from C1-6alkyl, C1-8alkoxylcarbonyl, C2-6alkenyl, 1,3-benzodioxol-5-yl and aryl each optionally substituted by one or more substituents selected from C1-4alkoxy, C1-6alkyl, cyano, halogeno, and trifluoromethyl;R8 is aryl, heteroaryl, a bicyclic heteroaryl ring system linked to the nitrogen via a ring carbon or a 9 or 10 membered bicyclic ring system linked to the nitrogen via a ring carbon and each ring is optionally substituted with up to two substituents, which may be the same or different, and are selected from C1-6alkyl, C1-4alkoxy, C1-4alkylthio, C1-6alkylC1-4alkoxyl, C1-6alkylaminoC1-6alkyl, hydroxy, -CO2H, -(CH2)pOHwhere p is 1 or 2, cyano, halogeno, and trifluoromethyl;R9 and R10 are each independently selected from hydrogen and C1-4alkyl or R8 and R9 together with the nitrogen to which they are attached form a dihydroindolyl, or a dihidroquinolinyl group;R11 is selected from carboxyl, tetrazolyl, alkyl sulphonylcarbamyl, sulfo and sulfino;Y is oxygen, sulphur or sulfonyl;m is 0 or 1;and n is 0 or an integer from 1 to 4 with the proviso that when m and n cannot both be 0 and when m is 1, n is 0;or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. The compounds inhibit the interaction of vascular cell-adhesion molecule-1 and fibronectin with integrin very late antigen 4 (&agr;4&bgr;1). They have therapeutic applications such as in multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease and psoriasis.

Description

UREA DERIVATIVES AND THEIR USE AS INTEGRINE INHIBITORS DESCRIPTION OF THE INVENTION The present invention relates to compounds that are inhibitors of the interaction between the integrin a4ß ?, also known as Very Late Antigen-4 (AMT-4) or CD49d / CD29 and its protein ligands, for example the Molecule of Vascular Cell Adhesion-1 (MACV-1) and fibronectin. The present invention also relates to processes for the preparation of such compounds, to pharmaceutical compositions containing them and to their use in methods of therapeutic application. The a4ß? is a member of the integrin family of heterodimeric cell surface receptors that are composed of glycoprotein subunits non-covalently associated (a and β) and participate in cell adhesion to other cells or to the extracellular matrix. There are at least 14 different integrin to human subunits and at least at least 8 different subunits ß and each β subunit can form a heterodimer with one or more alpha subunits. Integrins can be subdivided based on their composition of β subunits. The aß? is one of several ßi integrins, also known as Very Late Antigens (AMT).

REF .: 119420 The interactions between the integrins and their protein ligands are fundamental for the maintenance of cellular function, for example when joining cells in a particular location, facilitating cell migration or providing survival signals to cells from their environment. Ligands recognized by integrins include extracellular matrix proteins such as collagen and fibronectin; plasma proteins such as fibrinogen; and cell surface molecules such as the transmembrane proteins of the immunoglobulin superfamily and the cell-binding complement. The specificity of the interaction between the integrin and the ligand is governed by the composition of the a and ß subunits. The integrin a4β? it is expressed in numerous hematopoietic cells and in established cell lines, including hematopoietic precursors, peripheral blood and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils [Hemler, M. E. et al. , (1987), J. Biol. Chem., 262, 11478-11485; Bochner, B. S. et al. , (1991), J. Exp. Med., 173, 1553-1556], Unlike other ßi integrins that bind only to extracellular matrix proteins, a4β? binds to MACV-1, which is a member of the immunoglobulin superfamily expressed on the cell surface, for example in vascular endothelial cells; and to fibronectin containing the alternatively spliced type III (fibronectin CS-1) connecting segment [Elices, M. J. et al. , (1990), Cell, 60, 577-584; Wayner, E. A. et al. , (1989), J. Cell Biol., 109, 1321-1330]. The activation and extravasation of blood leukocytes plays a major role in the development and progress of inflammatory diseases. Cell adhesion to vascular endothelium is required before cells migrate from the blood to the inflamed tissue and is mediated by specific interactions between cell adhesion molecules on the surface of vascular endothelial cells and circulating leukocytes [Sharar, SR et al. al , (1995), Springer Semin. Immunopathol. , 16, 359- 378]. It is believed that the aß? It plays an important role in the recruitment of lymphocytes, monocytes and eosinophils during inflammation. The binding of a4β? / Ligand has also been implicated in the proliferation of T cells, in the location of B cells towards the germinal center, in the location of hematopoietic progenitor cells in the bone marrow, placental development, muscle development and metastasis of tumor cells. The affinity of a4β? its ligands are usually low, but the chemokines expressed by the inflamed vascular endothelium act through receptors on the surface of leukocytes to regulate the function of a4ßa [Weber, C. et al. , (1996), J. Cell Biol., 134, 1063-1073]. The expression of MACV-1 is regulated in endothelial cells in vi tro by inflammatory cytokines [Osborn, L. et al. , (1989), Cell, 59, 1203-1211] and in human inflammatory diseases such as rheumatoid arthritis [Morales-Ducret, J. et al. , (1992), J. Immunol., 149, 1424-1431], multiple sclerosis [Cannella, B. et al. , (1995), Ann. Neurol. , 37, 424-435], allergic asthma [FGBuda, T. et al. , (1996, Am. J. Respir, Cell Mol. Biol., 14, 84-94) and atherosclerosis [O'Brien, K. D. et al., (1993), J.

Clin. Invest., 92, 945-951]. Monoclonal antibodies directed against the integrin α subunit have been shown to be effective in a number of animal models of human inflammatory diseases, including multiple sclerosis, rheumatoid arthritis, allergic asthma, contact dermatitis, transplant rejection , insulin-dependent diabetes, inflammatory bowel disease and glomerulonephritis. Integrins recognize small peptide portions in their ligands. The minimal binding epitope of a4β? in CS-1 is the tripeptide leucine-aspartic acid-yaline (Leu-Asp-Val) [Ko oriya, A., et al. , (1991), J. * k Biol. Chem., 266, 15075-15079], while MACV-1 contains the similar sequence isoleucine-aspartic acid-5 serine [Clements, J. M., et al. , (1994), J. Cell Sci., 107, 2127-2135]. The fragment of fibronectin of 25 amino acids, peptide CS-1, containing the portion Leu-Asp-Val, is a competitive inhibitor of the binding of a4β? to MACV-1 [Makarem, R., et al. , (1994), J. Biol. Chem., 10 269, 4005-4011]. Have been described small inhibitors of the molecule a4ß? with the sequence Leu-Asp-Val in CS-1, for example the linear molecule phenylacetic acid-Leu-Asp-Phe-D-Pro-amide [Molossi, S. et al. , (1995), J. Clin. Invest., 95, 2601-2610] and the cyclic peptide with sources of Cys-Trp-Leu-Asp-Val-Vys disulfide [Vanderslice, P., et al. , (1997), J. Immunol., 158, 1710-1718]. More recently, in International Publication WO 96/00581, published on January 11, 1996 and in International Publication WO 96/20216 published on July 4, 1996, cyclic peptides are described which contain the Leu-Asp-Val sequence to inhibit the binding of the integrin a4β? to MACV-1 or fibronectin. Some small non-peptidic compounds having Leu-Asp-Val have been reported in International Publication WO 94/02445 published on February 3, 1994, to inhibit the adhesion of? -4β? induced. More recently non-peptidic compounds of Formula I that can be administered orally and that inhibit MACV / AMT-4 binding have been reported in PCT Patent Application WO 96/22966.

The preferred compounds are those of the Formula I in which R 1 'is a urea derivative, R 2' - is 3 'hydrogen, R is an alkyl or substituted alkyl radical, R 4 'is a radical dimethoxyphenyl or benzodioxol-5-yl and Y is CO. There is still a need for alternative compounds that inhibit the interaction between sla MACV-1 and fibronectin with the integrin AMT-4 and, in particular, compounds that can be administered orally. A group of compounds containing a substituted phenoxy group have been found that inhibit this interaction. In accordance with one aspect of the present invention, there is provided a compound of Formula (II) wherein: R1 is in the para or meta position and is wherein R and R are each independently selected from the group consisting of a hydrogen atom, a nitro radical, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms , alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, amino, cyano, halogen, trifluoromethyl, -CO2R1"and -CONR12R13, wherein R12 and R are independently selected from the group consisting of of a hydrogen atom or an alkyl radical of 1 •> 3 to 6 carbon atoms, or R "and R together with the phenyl to which they are attached form a 9- or 10-membered bicyclic ring system; R4 is an alkyl radical of 1 to 4 carbon atoms; R is selected from the group consisting of a hydrogen atom and an alkyl radical of 1 to 4 carbon atoms; R is selected from the group consisting of an alkyl radical of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms-cycloalkyl of 4 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-S-alkyl of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, where q is an integer from 1 to 6 and R14 is halogen; R is selected from the group consisting of a radial alkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, 1,3-benzodioxol-5-yl and optionally substituted aryl with one or more substituents that are selected from the group consisting of alkoxy radicals of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl; or R is an aryl radical, heteroaryl, a bicyclic heteroaryl ring system linked to the nitrogen through a carbon ring or a 9 or 10 membered bicyclic ring system attached to the nitrogen through a carbon ring and each ring is optionally substituted with up to two substituents, which may be the same or different, and are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, hydroxy, -C02H, - (CH ^ JpOH, wherein p is 1 or 2, cyano, halogen and trifluoromethyl, R 9 and R 10 are each independently selected from the group consisting of a hydrogen atom and an alkyl radical of 1 to 4 carbon atoms; 8 or R and R together with the nitrogen to which they are bound form a dihydroindolyl group or a dihydroquinolinyl group; R11 is selected from the group consisting of carboxyl, tetrazolyl, alkylsulfonylcarbamoyl, sulfo and sulphino radicals; And it is an atom of oxygen, of sulfur or a sulphonyl radical; m is 0 or 1 and n is 0 or an integer from 1 to 4, provided that m and n can not both be 0 and when m is 1, n is 0; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. The term "alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms" typically means a group - (C? _6) alkyl (C? -4) alkyl, of which a preferred example is the radical -CH2OCH3 The term "C 1-6 alkylamino-C 1-6 -alkyl alkyl" typically means a radical - (Ci-6) alkylNH (C 1-6) alkyl, of which a preferred example is the radical -CH 2 NHC 2 H 5 The term "aryl" typically means a phenyl or naphthyl radical, preferably phenyl The term "heteroaryl" means an aromatic ring of 5 or 6 members with up to four heteroatoms in the ring that are selected from the group consisting of nitrogen, oxygen and sulfur atoms, Examples of "heteroaryl" radicals include pirtolyl, furanyl, thienyl, imidazolyl, thiadiazolyl, iazolyl, isoxazolyl, pyridinyl, pyridyl groups and pyrimidinyl, The term "bicyclic heteroaryl ring system" means a system of fused rings 5,6-, 6,5 or 6,6, wherein one or both rings contain heteroatoms. The ring system may contain up to three heteroatoms, which are selected independently from the group consisting of oxygen, nitrogen and sulfur. When the ring system contains more than one heteroatom, at least one such heteroatom is nitrogen. An example of a heteroaryl ring system is the isoquinolyl, benzothiazolyl or be t.cimidazolyl group. "9- or 10-membered bicyclic" means a 6-membered aromatic ring fused to a 5 or 6 membered ring, preferably a 5 or 6 membered saturated ring, optionally substituted with at least one heteroary atom, preferably oxygen, and which is linked to the nitrogen to which it binds through a ring carbon in the 6-membered aromatic ring. A preferred example for R .8 is tetrahydronaphthalyl. When R, R and the phenyl to which they are linked form a 9 or 10 membered bicyclic ring system, the groups are preferably dihydrobenzofuranyl and dihydrobenzopyranyl. R2 and R3 are preferably independently selected from the group consisting of a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, trifluoromethyl and halogen; and more preferably are independently selected from the group consisting of methyl, methoxy, isopropoxy, trifluoromethyl, fluoro, bromo and chloro radicals. 4 A preferred group for R is alkyl of 1 to 2 carbon atoms. R is preferably selected from the group consisting of a hydrogen atom, a methyl radical and isopropyl. Preferably, R is selected from the group consisting of an alkyl radical of 1 to 4 carbon atoms and a C 1-4 alkyl (C 1-4) alkyl radical and is preferably selected from the group consisting of -CH 2 CH (CH 3) radicals ( CH3) and -CH2CH2SCH3, R7 is preferably selected from the group consisting of alkenyl radicals of 2 to 6 carbon atoms, 1,3-benzodioxol-5-yl and 1-isopropyl-2-methylpropylacetyl and is preferably selected from the group which consists of allyl radicals and 1,3-benzodioxol-5-yl.

R8 is preferably a phenyl, thienyl, pyridyl, thiadiazolyl, isoxazolyl, thiazolyl, 5,6,7,8-tetrahydronaphthalyl, isoquinolyl, 1,3-benzimidazolyl and 1,3-benzothiazolyl group, each optionally substituted with up to two substituents , which preferably and independently are selected from the group consisting of alkyl radicals of 1 to 4 carbon atoms, more preferably methyl, halogen radicals, still more preferably fluorine, chlorine and bromine; -COOH, -CH2OH, hydroxy and thiomethyl. R and R are preferably selected each / independently of hydrogen and methyl or R 8 and R 9 together with the nitrogen to which they are bound, form a group 2, 3-dihydro-1H-indol-1-yl or a 3, 4-dihydro-l (2H) -quinolinyl group. R11 is preferably COOH. In a preferred embodiment, n is 1 and m is 0. And preferably it is an oxygen atom. Preferred compounds according to the present invention are those of Formula (III) where R "" * to R8, Y, m and n are as previously defined. More preferred are those compounds wherein R is alkoxy of 1 to 4 carbon atoms, especially methoxy, R3, R and R1 are each independently hydrogen; R it is alkyl of 1 to 4 carbon atoms; R is selected from the group consisting of alkyl of 1 to 4 carbon atoms and C? _4alkylS (C? _4) alkyl and is especially -CH2CH (CH3) (CH3) or -CH2CH2SCH3; R 7 is 1,3-benzodioxol-5-yl; R8 is aryl or heteroaryl, each optionally substituted with a substituent selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, especially methyl, CH2OH, halogen, especially chloro or fluoro-9-hydroxy; and R is hydrogen or alkyl of 1 to 4 atoms of carbon or R 8 and R 9 together with the nitrogen to which they are bound, form a dihydroindolyl or dihydroquinolinyl group, and m and n are 0 or 1, provided that n and m can not both be 0 or 1 and preferably m is 0 and n is 1 Particularly preferred compounds include 4- (N '- (2-methylphenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid amide; - (N'-phenylurea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid amide of 4- (N '- (2-chlorophenyl) -urea) -3- methoxyphenoxyacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid) 7- (N '- (2-methylphenyl) -urea) -2, 3-dihydrobenzofuranyl-4-oxacetyl- (leucine- 3-amino- (3,4-methylenedioxy) -phenylpropionic acid) 4- (N '- (2-hydroxymethylphenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) amide ) -phenylpropionic acid) 4- [(2, 3-dihydro-lH-indol-1-yl-carbonyl) amide) -amino] -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid); 4- (N '- (2-fluorophenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methi / lenedioxy) -phenylpropionic acid) amide; 4- (N '- (2-hydroxy-6-methylphenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) amide; and 4- (N '- (2-trethylphenyl) -urea) -3-isopropoxyphenoxyacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid) amide. The compounds of Formulas (II) and (III) have chiral centers, in -CHR6 and -CHR7. When R6 is -CH2CH (CH3) (CH3) or -CH2CH2SCH3 and, therefore, the compounds of the present invention of the Formulas (II) and (III) contain leucine or methionine as a subunit, the latter being in its proteogenic (or natural) configuration. The present invention encompasses all diastereomers that inhibit the interaction between MACV-1 and fibronectin with the integrin AMT-4. In accordance with another aspect of the present invention, a compound of the Formula (IV) is provided where: R a is in the position for or goal and is wherein 3 R "a and R a are each independently selected from the group consisting of a hydrogen atom, a nitro radical, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, cyano, halogen, trifluoromethyl, -C? 2R7a and -CONR7aR8a, in Wherein R a and R a are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms; R 4a is selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted-alkyl of 1 to 6 carbon atoms and C? _6alkylS (Ci-β) alkyl; R a is selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, 1,3-benzodioxol-5-yl and aryl, optionally substituted with at least one substituent selected of the group consisting of alkoxy radicals of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl; R a is an aryl or heteroaryl radical and the ring is optionally substituted with up to two substituents, which may be the same or different, which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl; It is already oxygen or sulfur; and na is an integer from 1 to 4; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. In the compounds of Formula (IV), the term "aryl" typically means a phenyl or naphthyl radical, preferably phenyl. The term "heteroaryl" means a 5- or 6-membered aromatic ring with up to four heteroatoms in the ring that are selected from the group consisting of nitrogen, oxygen and sulfur. Examples of "heteroaryl" groups include pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, pyridinyl and pyrimidinyl. - > 3 R "and R a are preferably independently selected from the group consisting of a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, trifluoromethyl and halogen and, more preferably, are independently selected from the group consisting of methyl, trifluoromethyl and chlorine. Ra is preferably selected from the group consisting of alkyl radicals of 1 to 4 carbon atoms and C 4 _4 alkyl (C 1 -4) alkyl and, more preferably, is selected from -CH 2 CH (CH 3) groups ( CH3) and -CH2CH2SCH3 Preferably, R a is selected from alkenyl groups of 2 to 6 carbon atoms, more preferably allyl and 1,3-benxodioxol-5-yl.Ra preferably is phenyl with up to two substituents preferably independently they are selected from alkyl groups of 1 to 4 carbon atoms, more preferably methyl, and halogen, more preferably chlorine and bromine The preferred value for n is 1. The compounds of the formula (IV) of the present invention, have chiral centers in -CHR a and -CHR a.

When R4a is a group -CH2CH (CH3) (CH3) or CH2CH2SCH3 and, therefore, the compound of the present invention of Formula (IV) contains leucine or methionine as a subunit, this being in its proteinogenic (or natural) configuration ). The present invention encompasses all diastereomers that inhibit the interaction between MACV-1 and fibronectin with the integrin AMT-4. The pharmaceutically acceptable salts of the compounds of the formulas (II), (III) and (IV) include acid addition salts such as salts formed with mineral acids, for example hydrogen halides such as hydrogen chloride and hydrogen bromide, acids sulfonic and phosphonic; and salts formed with organic acids, especially citric, maleic, acetic, oxalic, tartaric, mandelic, p-toluenesulfonic, methanesulfonic acid and the like. In another aspect, suitable salts are basic salts such as alkali metal salts, for example sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium; aluminum and ammonium salts; and salts with organic bases such as ethanolamine, methylamine, diethylamine, isopropylamine, trimethylamine and the like. Such salts can be prepared by any suitable method known in the art: In vivo hydrolysable esters are those pharmaceutically acceptable esters that are hydrolyzed in the human body to produce the parent compound. for example intravenously to a test animal, the compound under test and subsequently examining the body fluids of the animal.Inventible hydrolysable esters suitable for hydroxy groups include acetyl / and for the carboxyl group include, for example Ci-β-alkoxymethyl esters , for example methoxymethyl, Ci-galkanoyloxymethyl esters for example -pivaloyloxymethyl, phthalylyl esters, C3-8CycloalkyloxycarbonyloxyC? -alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-yl-methyl esters, for example 5-methyl-l, 3-dioxolan-2-yl-methyl; and C 1-6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl. The activities of the compounds of the present invention to inhibit the interaction between MACV-1 and fibronectin with integrin AMT-4, can be determined using a number of in vitro and in vivo tests. These show a better power compared to the compounds of the prior art. For example, the compounds according to the P > present invention preferably have an IC50 < 10 μM, preferably < 1 μM in the MOLT-5 4 / Fibronectin cell assay, which will be described later. Preferred compounds have demonstrated activity in a number of in vitro tests in mice, for example delayed hypersensitivity (HR) responses induced by ovalbumin in the footpad and in collagen-induced arthritis. In order to be used, a compound of the Formulas (II), (III) or (IV) or a pharmaceutically acceptable salt or an in-hydrolysable ester thereof, is typically formulated as a pharmaceutical composition of compliance with standard pharmaceutical practice. Thus, in accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula (II), (III) or (IV) or a pharmaceutically acceptable salt or a hydrolysable ester in vi thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention may be in a pharmaceutical form suitable for oral administration, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for nasal administration, for example an inhaler, a nasal spray and nasal drops; for vaginal or rectal administration, for example a suppository; for administration by inhalation, for example in the form of a finely divided powder or a liquid aerosol; for sublingual or buccal administration, for example a tablet or capsule; or for parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example an aqueous or oily solution or suspension or a depot formulation with the drug incorporated in a biodegradable polymer. The composition may be a pharmaceutical form suitable for topical administration, such as for example creams, ointments and gels. Skin patches are also contemplated. For these purposes, the composition of the present invention can be formulated by means known in the art, such as, for example, those described in general terms in Chapter 25.2 of Comprehensive Medicinal Chemistry, Volume 5, Editor by Hansch et al. , Pegamon Press, 1990. In addition, the pharmaceutical composition of the present invention may contain one or more additional pharmacological agents for the treatment of one or more diseases as defined above, in addition to the compounds of the present invention. In a further aspect, the additional pharmacological agent or agents can be coadministered, either simultaneously or sequentially, with the pharmaceutical composition of the present invention. The composition of the present invention will normally be administered to humans at a daily dose which will be from 0.01 to 75 mg / kg of body weight and preferably from 0.1 to 15 mg / kg of body weight. A preferred composition of the present invention is one suitable for oral administration in a pharmaceutical form, for example a tablet or a capsule, containing from 1 to 1000 mg and preferably from 10 to 500 mg of a compound according to the present invention. , in each dose unit. ~~ So,, in accordance with still another aspect of the present invention, there is provided a compound of Formulas (II), (III) or (IV) or a pharmaceutically acceptable salt or hydrolysable ester in vi thereof, to be used in a method of therapeutic treatment of the body of a human being or an animal. In yet another aspect of the present invention, the present invention provides a method for the treatment of a disease mediated by the interaction between MACV-1 and / or fibronectin and the integrin receptor AMT-4 in a living being in need of such treatment. , which comprises administering to the warm-blooded mammal an effective amount of a compound of the Formulas (II), (III) or (IV) or a pharmaceutically acceptable salt or a hydrolysable ester in vi thereof. The present invention also provides the use of a compound of Formula (II), (III) or (IV) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in the production of a medicament for use in the treatment of a disease or medical condition mediated by the interaction between fibronectin and / or MACV-1 (especially MACV-1) and the integrin receptor AMT-4. In one embodiment of the present invention, the mammal in need of treatment suffers from "multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease or psoriasis." In another aspect of the present invention, there is provided a process for preparing a compound of Formula (II), wherein R is a COOH group or a pharmaceutically acceptable salt or a hydrolyzable ester in vi ve thereof, wherein the process comprises the steps of, coupling of; i) a compound of Formula (V) with a compound of the Formula (VI) NHR5-CHR6-CONH-CHR7-CH2-COOH (VI) or ii) a compound of the Formula (VII) and a compound of Formula (VIII) NH: -CHR7-CH: -COOH (VIII) wherein L and L1 are leaving groups and any functional group is optionally protected; and then, if necessary: a) remove any protective group; and b forming a pharmaceutically acceptable salt or a hydrolysable ester vi n. The reactions of the compounds (v) and (VI) or (VII) and (VIII), are made under standard coupling conditions to form peptide bonds. These reactions can be carried out either on a solid support (Peptide Synthesis in Solid Phase) or in solution, using the normal techniques used in the synthesis of organic compounds. With the exception of solid support, all other protective groups, coupling agents, unblocking reagents and purification techniques are similar to solid phase and solution phase peptide synthesis techniques. During the reaction, the amino acid functional groups, if necessary, can be protected by protecting groups, for example Boc groups. Such groups can be broken when necessary using standard techniques such as treatment in an acidic or basic medium. Suitable protecting groups for the protection of carboxyl groups include esters. Coupling reagents for the formation of peptide bonds include commonly used compounds such as azide, symmetric anhydride, mixed anhydride and various active esters and carbodiimides. In the case of carbodiimides, additives such as 1-hydroxybenzotriazole and N-hydroxysuccinimide may also be added. Other coupling reagents include 1H-benzotriazol-1-yl-oxy-Tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP), (2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate (TBTU) ), (2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (HBTU)] and O- (7-azabenzotriazol-1-yl) hexafluorophosphate -1, 1, 3 , 3-tetramethyluronium (HATU) .The coupling reactions can be carried out at temperatures between -20 and 40 ° C. The reaction time can vary between 10 minutes and 24 hours.The purification methods suitable for intermediaries and products Finals, include chromatographic techniques such as high pressure liquid chromatography (HPLC), along with many other standard techniques used in organic chemistry (eg, solvent extraction and crystallization) In the present description, the following abbreviations are used: Boc tert-butoxycarbonyl DIPEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulphoxide Et3N triethylamine HATU O- (7-azabenstoriazol-l-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate HOBT 1-hydroxybenzotriazole Your succinimido TFA trifluoroacetic acid THF tetrahydrofuran WSCDI methoiodide or l- (3-dimethylaminopropyl) methochloride -3-ethylcarbodiimide.

The preferred coupling conditions for reacting the compounds of Formula (V) and (VI) or Formula (VII) and (VIII) are, in particular, a) HATU / DIPEA / DMF b) HOBT / WSCDI / DIPEA / DMF c) HOBT / WSCDI / DIPEA / N-methylmorpholine. The compounds of the Formula (VI) can be prepared by reacting a compound of the Formula (IX) NHR5CHR6COL '(IX) with a compound of the Formula (VIII). Preferably, the / Compound of Formula (IX) is in the form of Boc-amino acid or Boc-amino acid-OSu and the coupling reagents are selected from the group consisting of d) HATU / DMF / DIPEA; e) H0BT / WSCDI / DI PEA / DMF / CH2C12; and f) Et3N / CH2Cl2. The protecting group can be removed using any suitable reagent known in the art, a particularly preferred example being trifluoroacetic acid. The compounds of the Formula (VII) can be prepared by reacting a compound of the Formula (V) with a compound of the Formula (IX), in a standard manner. Exemplary methods for preparing the compounds of Formula (VIII) are the following. When R is an aryl or 1,3-benzodioxol-5-yl group, the following method can be used. wherein R, 15 is a substituent selected from the group consisting of alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl; or forms a 1,3-benzodioxol-5-yl and p is an integer from 1 to 4. When R is an alkenyl group of 2 to 6 carbon atoms, the following method can be used As will be appreciated in the art, BF3 * Et2? can be replaced by some other known Lewis acid, the it can be replaced by, for example, an allyl bromide and the HCl / MeOH can be replaced, for example, by HBr / acetic acid. An exemplary method for preparing a compound of Formula (V) wherein Y is oxygen, m is 0, n is 1 and R is a 6-membered aromatic ring, is as follows, wherein R and R are selected independently of the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms carbon, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, hydroxy, -CO2H, - (CH2) pOH, wherein p is 1 or 2, cyano, halogen and trifluoromethyl: In the first step of Other bases other than sodium methoxide and other esters other than t-butyl can be used in the reaction, without this typically requiring basic hydrolysis instead of acid hydrolysis to form the final product. For compounds of Formula (V) wherein m is 0 and n is 2, the phenoxide ion of Formula (XVII) will be added to an acrylic ester. Another route for the preparation of compounds of Formula (XXI) includes reacting a compound of Formula (XIX) with triphosgene and then an amine of Formula (XXII). Alternatively, the triphosgene can be reacted with the amine of the Formula (XXII) and then with the compound of the Formula (XIX).

The compounds of Formula (XXI) can also be prepared in accordance with the following reaction: When Y is sulfur, an exemplary method for preparing the compounds of the present invention is as follows. A compound of Formula (V) can be formed by reacting phenyl isocyanate, optionally substituted on the phenyl ring, with a 2- (4-aminophenylthio) -acetic acid. To this mixture is added a coupling agent and a compound of Formula (VI) and Formula (VII). When Y is sulfonyl, an exemplary method for preparing the compounds of the present invention is next. A compound of Formula (II) wherein Y = S, is oxidized by treatment with oxone, m-chloroperbenzoic acid or other suitable oxidant. In the process, the sulfoxide intermediate (Y = SO) can be isolated initially, and then more vigorous conditions are used to obtain the sulfonyl derivatives. When R 1 is an acyl sulfonamide group (- CONHS02Rx) in a compound of the Formula (II), an exemplary method for preparing these compounds is as follows. A compound of the Formula (II) wherein R is -CO2H, is treated with a sulfonamide of the Formula RXS02 H2 in the presence of 4-dimethylaminopyridine and a carbodiimide. The compounds of the present invention may contain more than two units that are to be bound by the formation of amide bonds. When such units are present, the person skilled in the art will realize the preferred order for joining the units. The present invention is further illustrated with the following methods of biological tests, data and non-limiting examples. Table 1 refers to Examples 13 to 76. It provides the structure of the final materials and their analysis. It also refers to the method by which they were prepared, with reference to a key. EXAMPLES Example 1 - Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methionine-3-amino-3,4- (methylenedioxy) -phenylpropionic acid) amide.

An amide suspension of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) (1.3 g, 2 mmol) in a mixture of methanol (250 ml) and THF (100 ml), was treated with 1 N LiOH (12.3 ml, 12 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (75 ml) and DMF (10 ml) were added and the reaction mixture was stirred for another two hours. Subsequently, the reaction mixture was concentrated to 1/4 volume and the solution was acidified to pH 2 with 1 M citric acid, obtaining a white solid. The solid was filtered, washed with water and then with ether, to obtain the acid (615 mg, 48%) as a white solid. 1 H NMR (DMSO d 6, 300 MHz, ppm) 8.80 (s, 1 H), 8.46 (d, 1H), 8.00 (d, 1H), 7.80 (d, 2H), 7.36 (d, 2H), 7.08-7.18 (m, 2H), 6.72-6.96 (m, 6H), 5.98 (s, 2H) ), 5.10 (q, 1H), 4.48 (s, 2H), 4.40 (q, 1H), 2.56-2.74 (m, 2H), 2.18-2.28 (m, 5H), 1.70-1.90 (m, 2H); ESPMS (M + H) 623; HPLC-Dynamax 60A C18 column, acetonitrile / water / 0.1% TFA, 10/70% over a period of 20 minutes, Rt 17.35 minutes. a) Preparation of N- (t-butoxycarbonyl) -methionine-3-amino-β) methyl 3- (3,4-methylenedioxy) enyl) -propionate. It was prepared according to the method described below (Example 3a) for the preparation of methyl N- (t-butoxycarbonyl) -leucine-3-amino-5-hexanoate, except that 3-amino-3 was used - (3,4-methylenedioxyphenyl) -methyl propionate (prepared according to the method described in International Publication WO 96/22966 (Biogen) on pages 52 to 55 and which is incorporated herein by reference) in place of methyl 3-amino-5-hexanoat / hydrochloride and N- (t-butoxycarbonyl) -methionine was used instead of N- (t-butoxycarbonyl) -leucine. N-methyl (t-butoxycarbonyl) -methionine-3-amino-3- (3, 4-methylenedioxyphenyl) -propionate. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 1.3 (9H, m), 1.6-1.8 (2H, m), 2.0 (3H, s), 2.3-2.4 (2H, t), 2.7-2.8 (2H , m), 3.5 (3H, s), 3.9-4.0 (1H, m), 5.1 (1H, m), 5.9 (2H, s), 6.7-6.9 (4H, m), 8.2 (2H, d): m / Z 455 (M + H). b) Preparation of methyl methionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate. It was prepared according to the method described below (Example 3b) for the preparation of Methyl leucine-3-amino-5-hexanoate, except that N- (t-butoxycarbonyl) -methionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate methyl was used instead of N- ( methyl t-butoxycarbonyl) -leucine-3-amino-5-hexanoate. Methionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate methyl. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 1.8-1.9 (2H, m), 2.0 (3H, s), 2.2-2.4 (2H, m), 2.7-2.9 (2H, m), 3.5 (3H , s), 3.7 (1H, t), 5.1 (1H, b), 6.0 (2H, s), 6.7-6.9 (3H, m), 7.1-7.4 (2H, b), 8.8 (1H, d): m / Z 355 (M + H). c) Preparation of t-butyl 4-nitro enoxyacetate. A stirred solution of 4-nitrophenol (23 g) in methanol (200 / ml) was treated at room temperature with a solution of sodium methoxide (9.3 g) in methanol (50 ml). The solution was evaporated to dryness under reduced pressure and the residue was suspended in toluene (100 ml) The suspension in toluene was evaporated to dryness under reduced pressure and the residue was washed by decantation with isohexane The resulting solid was dissolved in dimethylformamide (250 ml) and the resulting suspension under stirring was treated at room temperature for 10 minutes with undiluted t-butyl bromoacetate (35 g) The mixture was heated at 60 ° C for 2 hours and then diluted with ice and water (400 ml) The mixture was extracted with ethyl acetate (3 x 150 ml) and the combined extracts were washed with 2N potassium hydroxide (2 x 100 ml) at 0 ° C with water (100 ml). The extract was dried (MgSO.sub.4) and evaporated, the residue was triturated with isohexane and the crystals were filtered and washed with isohexane, t-butyl 4-nitrophenoxyacetate, 36.3 g (86%), mp 83-85. 84 ° C. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 1.45 (9H, s), 4.88 (2H, s), 7.10 (2H, d), 8.17 (2H, d): m / Z 254 (M + H). d) Preparation of t-butyl 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate. A solution under rapid stirring at room temperature, of t-butyl 4-pitutophenoxyacetate (10 g) in ethyl acetate (200 ml) containing 5% palladium in carbon (1 g), was exposed to a hydrogen atmosphere. When the hydrogen incorporation had ceased, the solution was filtered and the pellet was washed with ethyl acetate. The filtrates were combined and the combined was cooled to 5 ° C and treated, with stirring, with undiluted 2-ethylphenylisocyanate (7.9 g). The solution was heated at 60 ° C for 2 hours. Then, the solution was cooled to 0 ° C and the precipitate was filtered and washed with cold ethyl acetate, to obtain 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate of t-butyl, 8.1 g ( 57%), pf 177-178 ° C. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 1.43 (9H, s), 2.21 (3H, s), 4.58 (2H, s), 6.83 (2H, d), 6.91 (2H, t), 7.15 ( 2H, q), 7.37 (2H, d), 7.8 (1H, s), 8.8 (1H, s): m / Z 357 (M + H). e) Preparation of 4- (N '- (2-methyl enyl) -urea) -enoxyacetic acid. A stirred solution of t-butyl 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate (5 g) in methylene chloride (50 ml) at 0 ° C was treated with 95% trifluoroacetic acid. (v / v) (50 ml). Stirring continued for 2 hours, during which time the solution reached room temperature. The volatile solvents were removed by distillation under reduced pressure and the residue was diluted with water (200 ml). The precipitate was collected by filtration and washed with water. The crude material was recrystallized from isopropanol, to obtain 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid, 3.1 g (73%), m.p. 216-218 ° C. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 2.21 (3H, s), 4.54 (2H, s), 6.83 (2H, d), 6.90 (2H, t), 7.15 (2H, q), 7.8 ( 1H, s), 8.80 (1H, s): m / Z 301 (M + H). f) Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) amide. A solution of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid (710 mg, 2 mmol) in DMF (6 ml) was treated with methionine-3-amino-3- (3, 4- Methylenedioxyphenyl) -propionate (600 mg, 2 mmol), O- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (760 mg, 2 mmol) and diisopropylethylamine (0.7 mL, 4 mmol). The mixture was stirred at room temperature overnight. The mixture was extracted by partition in EtOAc and water. The EtOAc phase was separated, washed with 1 M citric acid, with a saturated solution of NaHC 3 and concentrated in vacuo to obtain a white solid. The solid was washed with water and with ether, to obtain the coupled product (1.3 g, 100%), in the form of a white solid. NMR (DMSO-do, 300 MHz, ppm): 8.88 (s, 1H), 8.48 (d, 1H), 8.02 (d /, 1H), 7.84 (s, 1H), 7.80 (d, 2H), 7.38 ( d, 2H), 7.06-7.18 (m, 2H), 6.84-6.94 (m, 4H), 6.80 (d, 1H), 6.74 (d, 1H), 5.98 (s, 2H), 5.10 (q, 1H) , 4.48 (s, 2H), 4.38 (q, 1H), 3.52 (s, 3H), 2.70-2.78 (m, 2H), 2.20-2.30 (m, 5H), 1.92 (s, 2H), 1.70-1.88 (m, 2H); ESPMS (M + H); HPLC column-Dynamax 60A C18, acetonitrile / water / TFA 0. 1%, 10-70 ?. in a period of 20 minutes, Rt 19.04 minutes.

Example 2 - Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) amide. This was prepared according to Example 1, except that 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate amide was used. ) instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethiin-3-amino-3- (3, - (methylenedioxy) -phenylpropionate). 1H NMR (DMSO-d6, 300 MHz, ppm): 0.9 (6H, m), 1.2 (3H, m), 2.1 (3H, s), 2.5 (2H, m), 4.3 (1H, m), 4.4 (2H, s), 5.0 (1H, m), 5.9 (2H, s), 6.6 ( 6H, m), 7.0-7.1 < 2H, dd), 7.3-7.4 (2H, d), 7.9 (1H, d), 8.0 (1H, d), 8.2 (lh, s), 8.9 (1H, d), 9.1 (1H, s): m / Z 603 (MH). Column of HPLC-Dynamax 60A C18, acetonitrile / water / TFA 0.1%, 10-70 ?. in a period of 20 minutes, Rt 17.5 minutes. a) Preparation of methyl N- (t-butoxycarbonyl) -leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate. It was prepared according to the method described below (Example 3a) for the preparation of methyl N- (t-butoxycarbonyl) -leucine-3-amino-5-hexenoate, except that 3-amino-3- was used Methyl (3, 4-methylenedioxyphenyl) -propionate (see Example 1) instead of methyl 3-amino-5-hexenoate hydrochloride. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 0.9 (6H,), 1.3-1.5 (3H, m), 2.7 (2H, m), 3.5 (3H, s), 4.8-4.9 (1H, m) , 5.1-5.2 (1H, m), 5.9 (2H, s), 6.7-6.9 (4H, m), 8.2 (lh, d): m / Z 437 (M + H). b) Preparation of methyleucine-3-amino- (3,4-methylenedioxyphenyl) -propionate. It was prepared according to the method described below (Example 3b) for the preparation of methyleucine-3-amino-5-hexenoate, except that N- (t-butoxycarbonyl) -leucine-3-amino-3- was used. Methyl (3-methylenedioxyphenyl) -propionate instead of methyl N- (t-butoxycarbonyl) -leucine-3-amino-5-hexenoate. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 0.8 (6H, m), 1. 3-1.5 (2H, m), 1.5-1.6 (1H, m), 2.7 (2H, -m), 3.3-3.4 (1H, m), 3.5 (3H, s), 4.9-5.3 (2H, b) , 5.1-5.2 (1H, m), 6.0 (2H, s), 6.7-6.9 (3H, m), 8.4-8.5 (1H, d): m / Z 337 (M + H). c) Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) amide. It was prepared according to "Example 1f, except that methyl leucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate was used instead of methionine-3-amino-3- (3,4-methylenedioxyphenyl) ) -methyl propionate.1H NMR (DMSO-d6, 300 MHz, ppm): 0.9 (6H, m), 1.3-1.4 (3H, m), 2.2 (3H, s), 2.7 (2H, m), 3.5 (3H, s), 4.3 (1H, m), 4..4 (2H, S), 5.0 (1H, m), 5.9 (2H, s), 6.7-6.9 (6H,), 7.0-7.1 (2H , q), 7.3-7.4 (2H, d), 7.7-7.8 (2H, m), 8.0 (1H, d), 8.4-8.5 (lh, d), 8.9 (1H, s): m / Z 619 ( M + H) Column HPLC-Dynamax 60A C18, acetonitrile / water / TFA 0.1%, 10-70% over a period of 20 minutes, Rt 19.0 minutes Example 3 - Preparation of amide of acid 4- (N'- (2-methylphenyl) -urea) -phenoxyacetyl- (leucine-3-amino-5-hexenoic) It was prepared according to Example 1, except that 4- (N '- (2-methylphenyl) -urea) was used. -phenoxyacetyl- (methyleucine-3-amino-5-hexenoate) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3, 4- metilend ioxphenyl) -propionate) -amide. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 0.9 (6H, m), 1. 3-1.5 (3H,), 2.0-2.2 (2h, m), 2.2 (3H, s), 2.3 (2H, d), 4. 0 (1H, m), 4.3 (1H, m), 4.4 (2H, S), 4.9-5.0 (2H, dd), 5.6-5.7 (1H, m), 6.8-6.9 (3H, m), 7.1- 7.2 (2H, m), 7.3-7.4 (2H, d), 7.8 (2H, d), 7.9-8.0 (2H,), 8.8 (1H, s), 12.2 (1H, b): m / Z 523 (M-H). Column of HPLC-Dynamax 60A C18, acetonitrile / water / TFA 0.1%, 10/70% in a period of 20 minutes, Rt 16.8 minutes. a) Preparation of methyl N- (t-butoxycarbonyl) -leucine-3-amino-5-hexenoate. HOBT (255 mg) was added to a solution of N- (t-butoxycarbonyl) -leucine (297 mg) in DMF (5 ml), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (273 mg) and the solution was stirred for 15 minutes. Methyl 3-amino-5-hexenoate hydrochloride (185 mg) was dissolved in DMF (5 ml) and triethylamine (140 μl) and the resulting solution was added to the activated ester solution of N- (t-butoxycarbonyl) - leucine, followed by diisopropylethylamine (100 μl). The mixture was stirred ovght at room temperature. The mixture was added to ethyl acetate (30 ml), washed with water (2 x 5 ml), with 5% citric acid (5 ml), with water (5 ml), with saturated sodium bicarbonate solution. ml), with water (5 ml), with saturated brine (5 ml), dried (MgSO 4) and evaporated, to obtain methyl N- (t-butoxycarbonyl) -leucine-3-amino-5-hexenoate (335 mg); NMR (CDC13): 0.9 (6H, d), 1. 4 (10H, m), 1.6-1.8 (2H, m), 2.2-2.3 (2H, m), 2.5 (2H, d), 3.6 (3H, s), 4.0-4.1 (1H, m), 4.2- 4.3 (1H, m), 4.8-4.9 (1H, b), 5.0-5.1 (2H, d), 5.6-5.8 (1H, m), 6.5-6.6 (1H, m): m / Z 357 (M + H). b) Preparation of methyl leucine-3-amino-5-hexenoate. N- (t-butoxycarbonyl) -leucine-3-amino-5-hexenoate methyl (10 g) was treated with TFA a? 90% in water (100 ml).

The mixture was stirred for 30 minutes and the TFA and water were removed by evaporation. The residue was purified by preparative HPLC on a column of C18 silica gel eluting with acetonitrile / water / 0.1% TFA, to obtain a gummy solid by evaporating the appropriate fractions. This was dissolved in ethyl acetate (50 ml) and washed twice with a saturated solution of sodium bicarbonate (10 ml), once with saturated brine 810 ml), dried (MgSO 4) and evaporated to obtain 1.6 g. of a single diastereoisomer of methyl leucine-3-amino-5-hexenoate in the form of a light blue oil. Column of HPLC-Dynamax 60A C18, acetonitrile / water / TFA 0.1%, 10/70% in a period of 20 minutes, Rt 10.7 minutes; 1 H NMR (DMSO-d 6, 300 MHz, ppm): 0.9 (6H, m), 1.4-1.5 (2H, m), 1.5-1.7 (1H,), 2.1-2.3 (2H, m), 2.3-2.5 ( 2H, m), 3.5 (3H, s), 3.6-3.7 (1H,), 4.1-4.2 (1H, m), < 4.4-4.6 '(2H, b), 5.0 5.1 (2H, dd), 5.6-5.8 (1H, m), 8.4 (1H, d): m / Z 257 (M + H). c) Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-5-hexenoate) -amide. It was prepared according to Example lf, except that methyl leucine-3-amino-5-hexenoate was used instead of methyl methionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate. 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methyleucine-3-a-ino-5-hexenoate) -amide. m / Z 539 (M + H). Column of HPLC-Dynamax 60A C18, acetonitrile / water / TFA 0.1%, 10/70% in a period of 20 minutes, Rt 17.7 minutes (92% purity), a rigorous drying and subsequent characterization was used. Example 4 - Preparation of 4- (N '- (2-methylphenyl) -urea) -2-trifluoromethylphenoxyacetyl- (leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionic acid) amide. It was prepared according to Example 1, except that 4- (N '- (2-methylphenyl) -urea) -2-trifluoromethylphenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate was used. ) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 9.35 (d, 1H), 8.50 (d, 2H), 8.30 (d, 1H), 7.75 (d.h.H), 7.60 (d, 1H), 7.05- 7.30 (m, 4H), 6.90-7.00 (, 1H), 6.85 (s, 1H), 6.70-6.80 (m, 2H), 5.95 (s, 2H), 4.88-5.00 (m, 1H), 4.65 (s) , 2H), 4.24-4.40 (m, 1H), 2.35-2.45 (m, 2H), 2.25 (s, 3H), 1.40-1.60 (m, 3H), 0.70-0.90 (m, 6H); ESPMS (M + H) 673; HPLC-Vydac column 201HS54, acetonitrile / water / 0.1% TFA, 10/90% over a period of 20 minutes, Rt 15.94 minutes. a) Preparation of 4- (N '- (2-methylphenyl) -urea) -2- t-butyl trifluoromethylphenoxyacetate. T-butyl 4- (N '- (2-methylphenyl) -urea) -2-trifluoromethylphenoxyacetate analogously prepared to t-butyl 4- (N' - (2-methylphenyl) -urea) -phenoxyacetate (see Examples him and Id). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 8.28 (d, 2H), 7.75 (d, 1H), 7.60 (d, 1H), 7.04-7.22 (m, 4H), 6.92 (t, 1H), 4.72 (s, 2H), 2.20 (s, 3H), 1.40 (s, 9H); ESPMS (M + H) 425. b) Preparation of 4- (N '- (2-methylphenyl) -urea) -2- trifluoromethylphenoxyacetic acid. It was prepared analogously to 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid (see Example le). 1 H NMR (DMS0-d 6, 300 MHz, ppm): 8.30 (d, 2H), 7.75 (d, 1H), 7.60 (d, 1H), 7.04-7.22 (m, 4H), 6.90 (t, 1H), 4.75 (s, 2H), 2.22 (s, 3H); ESPMS (M-H) 367. c) Preparation of 4- (N '- (2-methylphenyl) -urea) -2- trifluoromethylphenoxyacetyl- (methyleucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. It was prepared according to Example lf, except that 4- (N '- (2-methylphenyl) -urea) -2-trifluoromethylphenoxyacetic acid was used instead of 4- (N' - (2-methylphenyl) -urea) -phenoxyacetic acid and leucine-3-amino-3- (3, Methyl 4-methylenedioxyphenyl) -propionate (Examples 2a and 2b) instead of methyl methionine-3-amino-3- (3, -methylenedioxyphenyl) -propionate. 1 H NMR (DMSO-do, 300 MHz, ppm): 8.52 (s, 1H), 8.45 (s, 1H), 8.20 (d, 1H), 7.75. (. D, 1H), 7T58 (d, 1H) ' , 7.05-7.22 (m, 5H), 6.86-6.96 (m, 2H), 6.80 (d, 1H), 6.75 (d, 2H), 5.98 (s, 2H), 5.10 (q, 1H), 4.62 (s) , 2H), 4.30-4.40 (m, 1H), 3.52 (s, 3H), 2.68-2.78 (m, 2H), 2.20 (s, 3H), 1.30-1.50 (m, 3H), 0.72-0.84 (m , 6H); ESPMS (M + H) 687; HPLC column-Dynamax 60A C18, acetonitrile / water / 0.1% TFA, 10-70 ?. in a period of 20 minutes, Rt 20.05 minutes. Example 5 - Preparation of 4- (N '- (2-chlorophenyl) -urea) -phenoxyacetyl- (leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionic acid amide). It was prepared according to Example i, except that 4- (N '- (2-chlorophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-p-methylenedioxyphenyl) -propionate was used. ) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 9.30 (s, 1H), 8.60 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.42 ( d, 1H), 7.35 (d, 2H), 7.25 (t, 1H), 7.00 (t, 1H), 6.75-6.92 (m, 4H), 6.70 (d, 1H), 5.95 (s, 2H), 5.05 (q, 10 1H), 4.50 (s, 2H), 4.30-4.40 (m, 1H), 2.50-2.65 (m, 2H), 1.30-1.50 (m, 3H), 0.70-0.85 (m, 6H); ESPMS (M + H) 625; HPLC-Vydac column 201HS54, acetonitrile / water / 0.1% TFA, 10-90% over a period of 20 minutes, Rt 15.07 minutes. b) Preparation of t-butyl 4- (N '- (2-chlorophenyl) -urea) -15-phenoxyacetate. It was prepared analogously to t-butyl 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate (cf.

Example Id), using t-butyl 4-mtro-2-chlorophenoxyacetate, which was prepared analogously to t-butyl 4- 2C nitrophenoxyacetate (see Example le). 4-nitro-2-chlorophenoxy-t-butyl acetate: 1 H NMR (CDC13, 300 MHz, ppm): 6.32 (d, 1H), 8.15 (d, 1H), 6.85 (d, 1H), 4.72 (s, 2H), 1.45 (s, 9H); ESPMS (M + H) 288. 4- (N '- (2-chlorophenyl) -urea) -phenoxyacetate of t-butyl: 1 H NMR (DMSO-d 6, 300 MHz, ppm): 9.24 (s, 1H), 8.30-8.40 (m, 2H), 7.60 (d, 1H), 7.55 (d, 2H), 7.45 (t, 1H), 7.20 (t, 1H), 7.05 (d, 2H), 4.75 (s, 2H) 1.60 (s, 9H); ESPMS (M + H) 377. c) Preparation of 4- (N '- (2-chlorophenyl) -urea) -phenoxyacetic acid. It was prepared analogously to 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid (see Example le). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 9.20 (s, .1H), 8.20 (s, 1H), 8.15 (d, 1H), 7.40 (d, 1H), 7.35 (d, 2H), 7.25. (t, 1H), 7.00 (t, 1H), 7.00 (t, 1H), 6.82 (d, 2H), 4.60 (s, 2H); ESPMS (M-H) 319. d) Preparation of 4- (N '- (2-chlorophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. It was prepared according to Example lf, except that 4- (N '- (2-chlorophenyl) -urea) -phenoxyacetic acid was used instead of 4- (N' - (2-methylphenyl) -urea) -phenoxyacetic acid and methyl leucine-3-amino-3- (3, 4-methylenedioxyphenyl) -propionate (see Examples 2a and 2b) was used instead of methionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate of methyl. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 9.20 (s, 1 H), 8.45 (d, 1 H), 8.20 (s, 1 H), 8.15 (d, 1 H), 7.95 (d, 1 H), 7.42 ( d, 1H), 7.35 (d, 2H), 7.25 (t, 1H), 7.00 (t, 1H), 6.85-6.95 (m, 3H), 6.80 (d, 1H), 6.75 (d, 1H), 5.98 (s, '2H), 5.10 (q, 1H), 4.45 (s, 2H), 4.30-4.40 (m, 1H), 3.50 (s, 3H), 2.70-2.76 (m, 2H), 1.30-1.50 ( m, 3H), 0.70-0.85 (m, 6H); ESPMS (M + H) 639; HPLC-Dynamax 60A C18 column, acetonitrile / water / 0.1% TFA, 10/70% over a period of 20 minutes, Rt 16.71 minutes. Example 6 - Preparation of 4- (N '- (2-bromophenyl) -urea) -phenoxyacetyl- (leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionic acid amide). It was prepared according to Example 1, except that 4- (N '- (2-bromophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate was used. ) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. 1H NMR (DMSO- d6, 300 MHz «ppm): 9.3 (s, '1H), 8. 62 (d, 1H), 8.10 (s) 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7. 60 (d, 1H), 7.25-7.40 (, 3H), 6.70-7.00 (m, 6H), 5.95 (s, 2H), 5.05 (q, 1H), 4.45 (s, 2H), 4.30-4.40 (m, 1H), 2. 50-2.65 (m, 2H), 1.30-1.50 (m, 3H), 0.70-0.85 (m, 6H); ESPMS (M + H) 671; HPLC-Vydac column 201HS54, acetonitrile / water / 0.1% TFA, 10/90% over a period of 20 minutes, Rt 14.85 minutes. a) Preparation of t-butyl 4- (N '- (2-bromophenyl) -urea) -phenoxyacetate. It was prepared analogously to t-butyl 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate (see Examples le and Id). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 9.15 (s, 1 H), 7.88-7.95 (m, 2 H), 7.45 (d, 1 H), 7.15-7.25 (m, 3 H), 6.78-6.88 ( m, 1H), 6.68-6.75 (m, 2H), 4.45 (s, 2H), 1.30 (s, 9H); ESPMS (M + H) 423. b) Preparation of 4- (N '- (2-bromophenyl) -urea) -phenoxycetic acid. It was prepared analogously to the 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid of (Example le). 1 H NMR (DMS0-d 6, 300 MHz, ppm): 9.25 (s, 1H), 8.00-8.10 (m, 2H), 7.58 (d, 1H), 7.25-7.38 (m, 3H), 6.-90- 6.98 (, 1H), 6.80-6.88 (m, 2H), 4.60 (s, 2H); ESPMS (M + H) 365. c) Preparation of 4- (N, '- (2-bromo-e "nyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) - propionate) -amide was prepared according to Example lf, except that 4- (N '- (2-bromophenyl) -urea) -phenoxyacetic acid was used instead of 4- (N' - (2-methylphenyl)) -urea) -phenoxyacetic acid and methyl leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate (see Examples 2a and 2b) was used instead of methionine-3-amino-3- (3,4). methyl-methylenedioxyphenyl) -propionate. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 9.28 (s, 1H), 8.45 (d, 1H), 8.00-8.10 (m, 2H), 7.95 (d, 1H) , 7.58 (d, 1H), 7.25-7.40 (m, 3H), 6.85-6.95 (m, 4H), 6.8 (d, 1H), 6.72 (d, 1H), 5.98 (s, 2H), 5.10 (q , 1H), 4.44 (s, 2H), 4.35 (q, 1H), 3.50 (s, 3H, 2.70-2.78 (m, 2H), 1.30-1.50 (m, 3H), 0.75 to 0.85 (m, 6H); ESPMS (M + H) 683; HPLC-Dynamax column 60A C18, acetonitrile / water / TFA 0.1%, 20/80% in a period of 20 minutes, Rt 17.87 min Example 7 -. Preparation of amide 4- (N '- (2-methylphenyl) -urea) -3- chlorophenoxyacetyl- (leucine-3-amino-3- (3,4-methylenedioxy) -propionic acid was prepared according to Example 1, except that 4- (N '- (2-methylphenyl) -urea) - 3-chlorophenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylthionine-3-) amino-3- (3, 4-methylenedioxy phenyl) propionate) amide 1H NMR (DMSO-d6, 300 MHz, ppm):. 9.80 (s, 1H), 8.98 (d, 1H), 8.60 (s, 1H ), 7.98 (d, 1H), 7.75 (s, 1H), 7.65 (d, 1H), 7.20 (d, 1H), 7.04-7.15 (m, 2H), 6.85-7.00 (m, 2H), 6.82 ( s, 1H), 6.70-6.80 (m, 2H), 5.90 (s, 2H), 5.00 (q, 1H), 4.58 (s, 2H), 4.35 (q, 1H), 2.20 (s, 3H), 1.38 -1.55 (m, 3H), 0.70-0.90 ( m, 6H); ESPMS (M + H) 639; HPLC-Vydac column 201HS54, acetonitrile / water / 0.1% TFA, 10/90% over a period of 20 minutes, Rt 14.97 minutes. a) Preparation of t-butyl 4- (N '- (2-methylphenyl) -urea) -3- chlorophenoxyacetate. Prepared analogously to t-butyl 4- (N '- (2 - (^, methylphenyl) -urea) -phenoxyacetate (see Examples le and Id). 1H NMR (DMS0-d6, 300 MHz, ppm): 8.95 (s, 1H), 7. 85 (s, 1H), 7.76 (d, 1H), 7.65 (d, 1H), 7.05-7.20 (m, 3H), 6.88-6.95 (m, 2H), 4.65 (s, 2H), 2.20 (s, 3H), 1.40 (s, 9H); ESPMS (M + H) 391. b) Preparation of 4- (N '- (2-methylphenyl) -urea) -3-10-chlorophenoxyacetic acid. It was prepared analogously to 4- (N '- (2'-methylphenyl) -urea) -phenoxyacetic acid (see Example le). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 8.95 (s, 1 H), 7.85 (s, 1 H), 7.78 (d, 1 H), 7.68 (d, 1 H), 7.08-7.20 (m, 15 3 H) , 6.88-7.00 (m, 2H), 4.70 (s, 2H), 2.20 (s, ~ 3H); ESPMS (M + H) 335. c) Preparation of 4- (N '- (2-methylphenyl) -urea) -3-chlorophenoxyacetyl- (methyleucine-3-amino-3- (3,4- (methylenedioxyphenyl) acid amide ) -propionic) 20 Prepared according to Example lf, except that 4- (N '- (2-methylphenyl) -urea) -3-chlorophenoxyacetic acid was used instead of 4- (N' - (2 -methylphenyl) -urea) -phenoxyacetic acid and methyl leucine-3-amino-3- (3, 4-methylenedioxyphenyl) -propionate was used (see Examples 2a and 2b) instead of methyl methionine-3-amino-3- (3, 4-methylenedioxyphenyl) -propionate. 1H NMR (DMS0-d6, 300 MHz, ppm): 9.05 (s, 1H), 8.55 (d, 1H), 7.98 (s, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.70 ( d, 1H), 7.05-7.20 (m, 3H), 6.90-7.00 (m, 2H), 6.85 (s, 1H), 6.80 (d, 1H), 6.75 (d, 1H), 5.95 (s, 2H) , 5.10 (q, 1H), 4.60 (s, 2H), 4.35 (q, 1H), 3.50 (s, 3H), 2.68-2.76 (m, 2H), 2.20 (s, 3H), 1.35-1.45 (m , 3H), 0.75-0.85 (m, 6H); ESPMS (M + H) 653; column HPLC-Dynamax 60A C18, acetonitrile / water / TFA 0.1%, 10/70% in a period of 20 minutes, Rt 20.45 minutes. Example 8 - Preparation of 4- (N '- (2-methyl--chlorophenyl) -urea) -phenoxyacetyl- (leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionic acid) amide. was prepared in accordance with Example 1, except using 4- (N '- (2-methyl-4-clorof'enil) -urea) -fenoxiacetil- (metileucina-3-amino-3- (3, 4- methylenedioxyphenyl) -propionate) amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3,4-methylenedioxy phenyl) -propionate) -amide. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 10.15 (s, 1H), 9. 50-9.60 (m, 1H), 9.10 (s, 1H), 8.25 (d, 1H), 7.90 (d, 2H), 7.60 (d, 1H), 7.30-7.40 (m, 2H), 6.95-7.05 ( , 3H), 6.90 (s, 2H), 6.10 (d, 2H), 5.08-5.18 (m, 1H), 4.65 (s, 2H), 4.42-4.52 (m, 1H), 2.55 (d, 2H), 2.40 (s, 3H), 1.60-1.70 (m, 3H), 0.90-1.10 (, 6H); ESPMS (M + H) 639; HPLC-Vydac column 201HS54, acetonitrile / water / 0.1% TFA, 10/90% over a period of 20 minutes, Rt 15.14 minutes. aj Preparation of 4- (N '- (2-methyl-4-chlorophenyl) -urea) - t-butyl phenoxyacetate. It was prepared analogously to t-butyl 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate (see Examples le and Id). 1 H NMR (DMS0-d 6, 300 MHz, ppm): 8.82 (s, 1 H), 7.82-7.90 (m, 2 H), 7.32 (d, 2 H), 7.22 (s, 1 H), 7.15 (d, 1 H), 6.80 (d.2H), 4.56 (s, 2H), 2.20 (s, 3H); ESPMS (M + H) 391. b) Preparation of 4- (N '- (2-methyl-4-chlorophenyl) -urea) -phenoxyacetic acid. It was prepared analogously to 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid (see Example le). 1 H NMR (DMS0-d 6, 300 MHz, ppm): 8.84 (s, 1 H), 7.82-7.90 (m, 2 H), 7.32 (d, 2 H), 7.22 (s, 1 H), 7.15 (d, 1 H), 6.82 (d, 2H), 4.60 (s, 2H), 2.20 (s, 3H); ESPMS (MH) 335. c) Preparation of 4- (N '- (2-methyl-4-chlorophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. It was prepared according to Example lf, except that 4- (N '- (2-methyl-4-chlorophenyl) -urea) -phenoxyacetic acid was used instead of 4- (N' - (2-methylphenyl) - urea) - phenoxyacetic and methyl leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate (see Examples 2a and 2b) was used instead of methionine-3-amino-3- (3, 4- Methylenedioxyphenyl) -propionate. There was obtained 4- (N'- (2-methyl-4-chlorophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate-amide. 1H NMR (DMS0-d6 , 300 MHz, ppm): 9.15 (s, 1H), 8.50 (d, 1H), 8.15 (s, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.38 (d, 2H), 7.20 (s, 1H), 7.15 (d, 1H), 6.70-6.90 (m, 5H), 5.98 (s, 2H), 5.10 (q, 1H), 4.45 (s, 2H), 4.35 (q, 1H), 3.50 (s, 3H), 2.68-2.78 (m, 2H), 2.20 (s, 3H), 1.30-1.50 '(m, 3H), 0.70-0.90 (m, 6H¡; ESPMS (M + H) 653; HPLC-Dynamax 60A C18 column, acetonitrile / water / 0.1% TFA, 10/70% over a period of 20 minutes, Rt 20.53 minutes Example 9 - Preparation of 4- (N '- (2-tnenylphenyl) -urea acid ) -2-methylphenoxyacetyl- (leucine-3-amino-3- (3,4- (methylenedioxyphenyl) -propionic) Prepared according to Example 1, except that 4- (N '- (2-methylphenyl) was used) -urea) -2-methylphenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- ( methylmethionine-3-amin o-3- (3, 4-methylenedioxyphenyl) -propionate) -amide. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 8.90-9.00 (m, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.85 (d, 1H), 7.60 (d, 1H), 7.30 (d, 1H), 6.90-7.04 (m, 2H), 6.50-6.80 (m, 6H), . 78 (s, 2H), 4.72-4.88 (m, 1H), 4.35 (s, 2H), 4.20-4.42 ft (m, 1H), 2.00-2.15 (m, 6H), 1.25-1.42 (m, 3H), 0.60-0.80 (m, 6H); ESPMS (M + H) 619; HPLC-Vydac column 201HS54, acetonitrile / water / 0.1% TFA, 10/90% over a period of 20 minutes, Rt 14.70 minutes. a) Preparation of 4- (N '- (2-methylphenyl) -urea) -2- t-butyl methylphenoxyacetate. It was prepared analogously to t-butyl 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate (see Examples le and Id). 1 H NMR, (DMSO-d 6, 300 MHz, ppm): 8.10 (s, 2H), 8.00 (s, 1H), 7.78 (d, 1H), 7.50 (d, 1H), 7.04-7.18 (m, 2H) , 6.90 (t, 1H), 6.75 (s, 1H), 6.65 (d, 1H), 4.58 (s, 15 2H), 2.20 (d, 6H), 1.40 (s, 9H); ESPMS (M + H) 371. b) Preparation of 4- (N '- (2-methylphenyl) -urea) -2-methylphenoxyacetic acid. It was prepared analogously to 4- (N '- (2-methylphenyl) -urea-phenoxyacetic acid (see Example le). 1 H NMR (DMS0-d 6, 300 MHz, ppm): 1 H NMR (DMSO-d 6, 300 MHz, ppm): 8.10 (s, 2H), 8.00 (s, 1H), 7.75-7.82 (m, 1H), 7.44-7.52 (m, 1H), 7.04-7.20 (m, 2H), 6.84-6.95 (m, 1H), 6.75 (s, 1H), 6.62-6.70 (m, 1H), 4.60 (s, 2H), 2.20 (d, 6H); ESPMS (M-H) '313. 25 c) Preparation of 4- (N '- (2-methylphenyl) -urea) -2- (methylphenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxy enyl) -propionate) -amide. according to Example lf, except that 4- (N '- (2-methylphenyl) -urea) -2-methylphenoxyacetic acid was used instead of 4- (N' - (2-methylphenyl) -urea) -phenoxyacetic acid and methyl leucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate (see Examples 2a and 2b) was used instead of methionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate. methyl. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 8.50 (d, 1H), 8. 18 (s, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.50 (d, 1H), 7.p5-7.18 (m, 2H), 6.82-6.95 ( m, 2H), 6.J0-6.92 (m, 4H), 5.98 (s, 2H), 5.10 (q, 1H), 4.50 (s, 2H), 4.30-4.40 (m, 1H), 3.50 (s, 3H), 2.70-2.78 (m, 2H), 2.20 (d, 6H), 1.30-1.50 (m, 3H), 0.72-0.88 (m, 6H); ? SPMS (M + H) 633; HPLC-Dynamax 60A C18 column, acetonitrile / water / 0.1% TFA, 10/70% over a period of 20 minutes, Rt 18.99 minutes. Example 10 - Preparation of 4 (N '- (2,4-dichlorophenyl) -urea) -phenoxyacetyl- (leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionic acid) amide. It was prepared according to Example 1, except that 4- (N '- (2,4-dichlorophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3, 4-ethylenedioxyphenyl) -propionate was used. ) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3-' (3,4-methylenedioxyphenyl) -propionate) -amide. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 9.70 (s, 1H), 9.15 (d, 1H), 8.68 (s, 1H), 7.95-8.10 (m, 2H), 7.50 (d, 1H), 7.25-7.35 (m, 3H), 6.75-6.85 (, 3H), 6.65-6.72 (m, 2H), 5.88 (s, 2H), 4.85-4.95 (m, 1H), 4.45 (s, 2H) ), 4.20- 4.35 (m, 1H), 2.33-2.40 (, 2H), 1.35-1.50 (m, 3H), 0.70- 0.85 (m, 6H); ESPMS (M + H) 661; HPLC-Vydac column 201HS54, acetonitrile / water / 0.1% TFA, 10/90% over a period of 20 minutes, Rt 15.96 minutes. a) Preparation of t-butyl 4- (N '- (2,4-dichlorophenyl) -urea) -phenoxyacetate. It was prepared analogously to t-butyl 4- (N '- (2-methylphenyl) -urea) -phenoxyacetate (see Examples le and Id). 1 H NMR (DMSO-d 6, 300 MHz, _ ppm): 9.20 (s, 1H), 8. 25 (s, 1H), 8.15 (d; 1H), 7.50-7.60 (m, 1H), 7.22-7.38 (m, 3H), 6.80 (d, 2H), 4.56 (s, 2H), 1.38 (s, 9H); ESPMS (M + H) 411. b) Preparation of 4- (N '- (2,4-dichlorophenyl) -urea) -phenoxyacetic acid). It was prepared analogously to the 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid of Example le. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 9.22 (s, 1H), 8.30 (s, 1H), 8.18 (d, 1H), 7.58 (s, 1H), 7.24-7.40 (m, 3H), 6.80-6.90 (m, 2H), 4.58 (s, 2H); ESPMS (M-H) 353. c) Preparation of 4- (N '- (2,4-dichlorophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. It was prepared according to Example lf, except that 4- (N '- (2) acid was used., 4-dichlorophenyl) -urea) -phenoxyacetic acid instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid and leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate was used of methyl (see Examples 2 a and 2b) instead of methionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate methyl. 4- (N '- (2,4-dichlorophenyl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide was obtained. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 9.30 (s, 1H), 8.50 (d, 1H), 8.30 (s, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.58 ( s, 1H), 7.30 (d, 3H), 6.68-6.95 (m, 5Hf, 5.94 (s, 2H), 5.10 (q, 1H), 4.50 (s, 2H), 4.30-4.40 (m, 1H), 3.52 (s, 3H), 2.62-2.82 (m, 2H), 1.30-1.50 (m, 3H), 0.70-0.90 (m, 6H); ESPMS (M + H) 675; HPLC-Dynamax 60A C18 column, acetonitrile / water / 0.1% TFA, 10/70% over a period of 20 minutes, Rt 21.90 minutes. Example 11 - Preparation of 4- (N '- (2-methylphenyl) -urea) -3-chlorophenoxyacetyl- (methionine-3-amino-3- (3, -methylenedioxyphenyl) -propionic acid amide was prepared in accordance with Example 1, except that 4- (N '- (2-methylphenyl) -urea) -3- chlorophenoxyacetyl- (methylmethionine-3-amino-3- (3-ethylenedioxyphenyl) -propionate) -amide was used instead of 4- (N '- (2-f <' methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. 1H NMR (DMSO-d6, 300 MHz, ppm): 8.95 (s, 1H), 8. 50 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.05-7.20 (m, 3H), 6.98 (d, 1H) , 6.90 (t, 1H), 6.82 (s, 1H), 6.80 (d, 1H), 6.75 (d, 1H), 5.95 (s, 2H), 5.05 (q, 1H), 4.60 (s, 2H), 4.40 (q, 1H), 2.60-2.75 (m, 2H), 2.15-2.30 (m, 5H), 1.95 (s, 3H), 1-70-1.90 (m, 2H); ESPMS (M + H) 657; HPLC-Dynamax 60A C18 column, acetonitrile / water / 0.1% TFA, 10/70% over a period of 20 minutes, Rt 17.43 minutes. a) Preparation of 4- (N '- (2-methylphenyl) -urea) -3- 15 chlorophenoxyacetyl- (methylmethionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. It was prepared according to Example lf, except that 4- (N '- (2-methylphenyl) -urea) -3-chlorophenoxyacetic acid was used (see Examples 7a and 7b) instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 8.98 (s, 1H), 8.52 (d, 1H), 8.00 (d, 1H), 7.85 (s, 1H), 7.75 (d, 1H), 7.68 ( d, 1H1, 7.05-7.20 (m, 3H), 6.98 (d, 1H), 6.92 (t, 1H), 6.85 (s, 1H), 6.80 (d, 1H), 6.75 (d, 1H), 5.96 ( s, 2H), 5.10 (q, 1H), 4.60 (s, 2H), 4.40 (q, 1H), 3.52 (s, 3H), 2.70-2.78 (m, 2H), 2.25 (t, 2H), 2.20 ( s, 3H), 1.94 (s, 3H), 1.70-1.90 (m, 2H); ESPMS (M + H) 671; column of HPLC-Dynamax 60A C18, acetonitrile / water / 0.1% TFA, 10-70% over a period of 20 minutes, Rt 19.47 minutes. Example 12 - Preparation of 4- (N '- (2-methylphenyl) -urea) -phenothioacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid). A mixture of (4- (N '- (2-methylphenyl) -urea) -phenothioacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionate) -amide (150 mg), MeOH (5 ml) , THF (2 ml) and 2N NaOH (2 ml) was stirred at 50 ° C for 2 hours and then acidified with HOAc The mixture was concentrated to about 3 ml in vacuo and then diluted with water and the more soluble solid was collected and washed with water and EtOAc to obtain 4- (N '- (2-trethylphenyl) -urea) -phenothioacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid amide ( 110 mg, 74%), mp 207-210 ° C. 1 H NMR (DMS0-d 6, 300 MHz, ppm): 9.05 (s, 1H), 8.4 (d, 1H), 8.05 (d, 1H), 7.9 ( s, 1H), 7.8 (d, 1H), 7.4 (d, 2H), 7.3 (d, 2H), 6.95 (m, 1H), 6.7-6.9 (m, 3H), 5.95 (s, 2H), 5.05 (m, 1 HOUR); 4.25 (m, 1H); 3.6 (dd, 2H); 2.6 (m, 2H); 2.2 (s, 3H); 1. 2-1.4 (m, 3H); 0.75 (m, 6H). MS: (ES-) m / e 619.5 (M + H) -. a) Preparation of 4-N '- (2-methylphenyl) -urea) -phenylthioacetic acid. A suspension of 2- (4-aminophenylthio) -acetic acid (3.07 g) in acetonitrile (120 ml) was stirred at reflux while adding 2-methylphenyl isocyanate (2.1 ml) and the mixture was stirred at reflux for 1 hour. The resulting solution was cooled and the light gray solid which crystallized was collected to obtain 4-N '- (2-methylphenyl) -urea) -phenylthioacetic acid (4.93 g, 93%), m.p. 182- 183 ° C. b) Preparation of (4- (N '- (2-methylphenyl) -urea) -phenothioacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionate) -amide A mixture of 4-N' - (2-methylphenyl) -urea) -phenylthioacetic acid 364 mg), DMF (7 ml), methyl 2- (1,3-benzodioxol-5-yl) -2- (leucinylamino) -propionate (336 mg), 1- hydroxybenzotriazole (156 mg), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (220 mg) and N-methylmorpholine (116 mg) was stirred at room temperature for 4 days. The mixture was diluted with EtOAc and water and the precipitate was collected and washed with water and EtOAc, to obtain (4- (N '- (2-methylphenyl) -urea) -phenothioacetyl- (leucine-3-amino- ( 3,4-methylenedioxy) -phenylpropionate) -amide (500 mg, 79%), as an off-white solid Examples 13 to 76 were prepared in the manner described below and in Table 1. Example 14 - Preparation of 4- (N '- (2-methylphenyl) -urea) -phenylsulfonylacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid amide was prepared according to Example 1, except that used methyl 2- (1,3-benzodioxol-5-yl) -2- (2- {[[4- (2-methylphenylureido) -phenylsulfonyl] -acetyleucinylamino} -propionate instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. a) Preparation of methyl 2- (1,3-benzodioxol-5-yl) -2- (2- {[[4- (2-methylphenylureido) -phenylsulfonyl] -acetyleucinylamino} - propionate. 2- (1,3-benzodioxol-5-yl) -2- (2- {[[4- (2-methylphenylureido) -phenylthio] -acetyleucylamino} -propionate methyl (Example 12b, 0.35 g) DMF (2 ml), methanol (8 ml), Oxone® (1 g) and water (4 ml) were stirred at room temperature for 24 hours, the mixture was diluted with water and extracted with ethyl acetate. and the organic phase was dried and evaporated to dryness.The residue was triturated with ether and the insoluble solid was collected to obtain 2- (1,3-benzodioxol-5-yl) -2- (2- { [4- Methyl (2-methyl phenylureido) -phenylsulfonyl] -acetyleucinylamino] -propionate (0.32 g) [m / e 667 (M + H) +] Example 16 - Preparation of 2- (4- (N) amide '- (2-methylphenyl) -urea) -phenoxy) -butyryl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) It was prepared according to Example 2, except that in part 2c and in lf, 2- (4- (N '- (2-methylphenyl) -urea) -phenoxy) -butyric acid was used instead of 4- (N' - (2-methylphenyl) - urea) -phenoxyacetic acid. a) Preparation of ethyl 2- (4- (N '- (2-methylphenyl) -urea) -phenoxy) -butyrate. Potassium carbonate (5.5 g, 0.04 mol) was added to a stirring solution of 4-nitrophenol (5.56 g, 0.04 mol) in DMF (20 ml). Ethyl 2-bromobutyrate /.8 g, 0.04 mol) was added and the mixture was stirred for 48 hours at room temperature. The mixture was poured into water (60 ml) and extracted with diethyl ether (2 times, 70 ml). The organic phase was separated, washed with brine, dried and evaporated to dryness to obtain an oil (9 g). 10% Pd / C (0.2 g) was added to this oil (2 g, 0.008 mol). In ethanol (20 mol) and the mixture was stirred under a hydrogen atmosphere for 2 hours, filtered and evaporated to dryness. The residue in dichloromethane (20 ml) was treated with 2-methylphenylisocyanate (1.05 g, 0.008 mol) and the mixture was allowed to stand for 18 hours. The solution was filtered and evaporated to dryness and the residue was recrystallized from ethanol to obtain the product (1.3 g). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 1.0 (t), 3 H; 1.2 (t), 3H; 2.2 (s), 3H; 4.1 (q), 2H; 4.65 (t), 1H; 6.8 (d), 2H; 6.9. (T), 1H; 7.1 (m), 2H; 7.35 (d), 2H; 7.8 (m), 2H, 8.8 (s), 1H ESPMS (M + H) 357. - ßS - fo) Preparation of 2- (4- (N '- (2-methylphenyl) -urea) -phenoxy) -butyric acid. An aqueous solution of 2 M sodium hydroxide (3 ml) was added to ethyl 2- (4- (N '- (2-methylphenyl) -urea) -phenoxy) -butyrate (1.2 g, 0.0034 mol) in dimethyl sulfoxide ( 7 ml), the mixture was stirred for 1 hour at room temperature. Water (10 ml) was added and the pH was adjusted to -2 with 2 N hydrochloric acid and the product was filtered, washed with water and dried, to obtain the title product (1.0 g). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 1.0 (t), 3H; 2.2 (s), 3H; 4.5 (t), 1H; 6.8 (d), 2H; 6.9 (t), - 1H; 7.1 (m), 2H; 7.35 (d), 2H; 7.8 (m), 2H, 8.8 (s), 1H; 1H ESPMS (M-H) 327. EXAMPLE 23 Preparation of 4- (2-methylphenylureido) -phenylacetylamino- (2- [methylsulfonylethyl] -glycinyl) -aspartic acid- (2,5-dimethylpentyl) ester. A mixture of 4- (2-methylphenylureido) -phenylacetylamino-S- (2- [methylsulfonylethyl] -glycinyl) -aspartic acid (2, 5-dimethylpentyl) -β-benzyldiester (65 mg), DMF (5 ml) ) and 10% Pd on carbon as a catalyst (20 mg), was stirred under a hydrogen atmosphere at room temperature and at atmospheric pressure for 4 hours. The mixture was filtered, the filtrate was evaporated to dryness and the residue was triturated with ethyl acetate, to obtain 2- (2-phenylaminobenzoxazol-6-yl) -acetylamino- (2,5-dimethylpentyl) -esteric acid ester. (2- [Methylsulfonylethyl] -glycyl) -aspartic (52 mg, 91%) as a whitish solid. a) Preparation of a- (2,5-dimethylpentyl) -β-benzyldiester of BOC-aspartic acid. A mixture of β-benzyl ester of BOC-aspartic acid (3.23 g), dichloromethane (20 ml), 2,4-dimethylpentanol (1.51 g) and dicyclohexylcarbodiimide (2.06 g) was stirred and treated with 4-dimethylaminopyridine (20 mg). . The mixture was stirred for 1 hour, filtered and the filtrate was evaporated to dryness. The residue was purified by flash chromatography on silica gel, using a mixture of fresh polarity of dichloromethane and ethyl acetate, and the appropriate fractions were combined and the combined was evaporated to dryness to obtain the product as a gum (3.55 g. ). [m / e 422 (M + H) +]. b) Preparation of α- (2,5-dimethylpentyl) -β-benzyldiester of aspartic acid. A solution of α- (2, 5-dimethylpentyl) -β-benzyldiester of BOC-aspartic acid (3.4 g) in dichloromethane (10 ml) was treated with trifluoroacetic acid (10 ml) and the mixture was stirred at room temperature during 2 hours and then evaporated to dryness. The residue was stirred with a mixture of water (10 ml) and ethyl acetate 830 ml) and alkalized with potassium hydrogen carbonate. The organic phase was separated, washed with brine, dried and evaporated to dryness to obtain the α- (2,5-dimethylpentyl) -β-benzyldiester of aspartic acid in the form of a gum (2.7 g). [m / e 322 (MH) +]. c) Preparation of α- (2,5-dimethylpentyl) -β-benzyldiester of BOC-methioninilaspartic acid. a mixture of a- (2,5-dimethylpentyl) -β-benzyldi-ester of aspartic acid (0.64 g), BOC-methionine (0.75 g), hydroxybenzotriazole (0.41 g), N-methylmorpholine (1 ml), dichloromethane (10 ml), and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.57 g) was stirred for 18 hours. The. mixture was diluted to 30 ml with dichloromethane and the solution was washed successively with an aqueous solution of sodium hydrogencarbonate (2 times) and with brine, and then dried and evaporated to dryness to obtain the α- (2, 5). -dimethylpentyl) -β-benzyldiester of BOC-methioninilaspartic acid in the form of a gum (1.5 g), which was used without further purification. d) Preparation of a- (2, 5-dimethylpentyl) -β-benzyldiester of methionisol tetrapartic acid. A mixture of α- (2,5-dimethylpentyl) -β-benzyldi-ester of BOC-methioninilaspartic acid (1 g), dichloromethane (5 ml), triethylsilane (0.5 ml) and trifluoroacetic acid (5 ml) was stirred at room temperature for 1 hour and then evaporated to dryness. The residue was subjected to extraction by partition in an aqueous solution of potassium carbonate and ethyl acetate, and the organic phase was separated, dried and evaporated to dryness. The residue was purified by flash chromatography eluting with a 1% solution of triethylamine in ethyl acetate, to obtain the α- (2,5-dimethylpentyl) -β-benzyldiester of methioninesilic acid in the form of a gum (0.32 g) [m / e 453 (MH) +]. e) Preparation of 4- (2-methylphenylureido) -phenylacetylamino-methioninelaspartic acid- (2, 5-dimethylpentyl) -β-benzyldiester. A mixture of a- (2, 5-dimethylpentyl) -β-benzyldi-ester of methioninesilic acid (0.3 g), 4- (2-methylphenylureido) -phenylacetic acid (0.28 g), hydroxybenzotriazole (0.13 g), N-methylmorpholine (0.1 ml), dichloromethane (5 ml) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.19 g) was stirred for 18 hours. The mixture was diluted with ethyl acetate and washed successively with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, then dried and evaporated to dryness. The residue was triturated with ethyl acetate to obtain a- (2,5-dimethylpentyl) -β-benzyldiester.

V # 'of 4- (2-methylphenylureido) -phenylacetylamino-methioninilaspartic acid in the form of a white solid (0.4 g). [m / e 719 (MH) +]. f) Preparation of 4- (2-methylphenylureido) -phenylacetylamino- (2- [methylsulfonylethyl] -glycinyl) -aspartic acid- (2,5-dimethylpentyl) -β-benzyldiester. A mixture of 4- (2-methylphenylureido) -phenylacetylamino-methioninilaspartic acid (2-5-dimethylpentyl) -β-benzyldi-ester (0.12 g), DMF (1 ml), Oxone © [Aldrich] '(0.25 g) and water (0.5 ml) was stirred at room temperature for 72 hours. The mixture was diluted with water and the insoluble solid was collected to obtain the a- (2, 5-dimethylpentyl) -β-benzyldiester of 4- (2-methylphenylureido) -phenylacetylamino- (2- [methylsulfonylethyl] -glycinyl) -aspartic acid as a white solid. [m / e 719 (MH) +]. Example 28 - Preparation of 6- (N '- (2-methylphenyl) -urea) -chroman-2-carboxyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) amide. It was prepared according to Example 2, except that in step 2c and in lf 6- (N'-2-methylphenyl) -urea) -chroman-2-carboxylic acid was used instead of 4- (N ') acid. - (2-methylphenyl) -urea) -phenoxyacetic acid. a) Preparation of 2- (4 ~ (N '- (2-methylphenyl) -urea) -chroman-2-ethyl carboxylate 2-methylphenylisocyanate (0.32 g, 0.0024 mol) was added to a stirred solution of 6 ethyl aminocrom-4-one-2-carboxylate (0.5 g, 0.0022 mol), prepared in the manner described in Barker, G., Ellis, GP; J. Chem. Soc. C, 1970, 2230 (which is incorporated in the present as reference), in THF (5 ml) at room temperature The mixture was stirred for 18 hours and the product was recovered by filtration, washed with ether to obtain 0.64 g, which were hydrogenated in a mixture of N- methylpyrrolidinone (20 ml) and acetic acid (20 ml) at 60 ° C, in the presence of the Pd / C catalyst (0.4 g), for 10 hours, filtered and evaporated to dryness and the residue was triturated with water. solid residue was dried to obtain the product 2- (4- (N '- (2-methylphenyl) -urea) -chroman-2-carboxylic acid ethyl ester (0.45 g). NMR (DMSO-d6, 300 MHz, ppm): 1.2 (t), 3H, 2.1 (m), 2H, 2.2 (s), 3H, 2.7 (m), 2H, 4.1 (q) , 2H; 4.8 (m), 1H; 6.7 (d), 1H; 6.9 (t), 1H; 7.1 (m), 4H; 7.8 (m), 2H; 8.7 (s), 1H ESPMS (M + H) 355. b) Preparation of 6- (N '- (2-methylphenyl) -urea) - chroman-2-carboxylic acid. 2- (4- 'N' - (2-methylphenyl) -urea) -chroman-2-ethyl carboxylate (0.43 g, 0.0012 mol) in dimethylsulfoxide (5 ml) was treated with an aqueous solution of $ f, sodium hydroxide (1.2 ml) and the mixture was stirred for 2 hours, water (10 ml) was added and the pH was adjusted to -2 with 5 N hydrochloric acid. The product was filtered, washed with water and dried air, to obtain the title compound (0.35 g). NMR (DMSO-d6, 300 MHz, ppm): 2.1 (m), 2H, 2.2 (s), 3H; 2.7 (m), 2H; 4.7 (m), 1H; 6.7 (d), 1H; 6.9 (t), 1H; 7.1 (m), 4H, 7.8 (), 2H; 8.7 (s), 1H, ESPMS (M + H) 327. EXAMPLE 29 Preparation of 4- (N '- (2-thienyl) -urea) -phenoxyacetyl- (leucine-3-amino- (3, 4- methylenedioxy) -phenylpropionic acid). It was prepared according to Example 1, except that 4- (N '- (2-thienyl) -urea) -phenoxyacetyl- (methyleucine-3-amino- (3, -methylenedioxy) -phenylpropionate) -amide was used. instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. A) Preparation of 4- (N '- (2-thienyl) -urea) -phenoxyacetyl- (methyleucine-3-amino- (3,4-methylenedioxy) -phenylpropionate) -amide. Proton-Sponge® (Aldrich) (102 mg) was added to a stirring solution of thiophene-2-carboxylic acid (61 mg). mg) in THF (3 ml) at room temperature under an argon atmosphere. After 20 minutes, diphenylphosphorylazide (131 mg) was added and the mixture was heated to reflux for 5 hours. The solution was cooled to room temperature and a solution of 4-aminophenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide (243 mg), prepared according to Example 30b, was added. , in THF (5 ml), with stirring at room temperature and the mixture was refluxed for 12 hours. The cooled mixture was partitioned into ethyl acetate (50 ml) and water (50 ml) and the ethyl acetate phase was washed with 1 M citric acid, with an aqueous-saturated solution of sodium bicarbonate and with brine. After evaporation a brown solid was obtained, which was triturated with ether. The product was isolated by filtration. Yield, - 43 mg. m / Z (+ ve) 611.3 (M + H) m / Z (-ve) 611.3. Example 30 - Preparation of 4- (N'-phenylurea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionic acid amide was prepared according to Example i, but using - (N'-phenylurea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl - (methylmethionine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide a) Preparation of -nitrophenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide . HOBT (1.5 g) was added to a solution of 4-nitrophenoxyacetic acid (1.97 g) in DMF (10 ml), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodimide hydrochloride (2.14 g) and the solution was stirred during 15 minutes. Methyl leucine-3-amino-3- (3, 4-methylenedioxyphenyl) -propionate (Example 2b) (2.69 g) was dissolved in DMF (10 ml) and the resulting solution was added to the solution of the activated ester. The mixture was stirred overnight at room temperature. The mixture was poured into ethyl acetate (100 ml), washed with water (2 times, 10 ml), with 5% citric acid (10 ml), with water (10 ml), with a saturated solution of bicarbonate. Sodium (10 ml), with water (10 ml), with saturated brine (10 ml), dried (MgSO 4> and evaporated, to obtain 4-nitrophenoxyacetyl- (methyeucine-3-amino-3- (3, 4-methylenediox? Phenyl) -propionate) -amide, 3.02 g- 1 H NMR (DMSO-d 6, 300 MHz, ppm): 0.9 (6H, m), 1. 3-1.4 (3H, m), 2.7 (2H, m), 3.5 (3H, s), 4.3-4.4 (1H, s), 4.7 (2H, m), 5.1 (1H, m), 5.9 (2H, s), 6.7-6.9 (3H, m), 7.1 (2H, d), 8.2 (3H, m), 8.4-8.5 (1H, d): m / Z 516 (M + H). b) Preparation of -aminophenoxyacetyl- (methyleucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. At room temperature, a rapid stirring solution of 4-nitrophenoxyacetyl- (methyleucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide (3.02 g) in ethyl acetate (60 ml) containing 5% of Palladium on carbon (0.3 g), was exposed to a hydrogen atmosphere. When the hydrogen incorporation was complete, the solution was filtered and the filtrate was washed with ethyl acetate. The filtrates were combined and the combined was evaporated to dryness to obtain 2.7 g of 4-aminophenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 0.9 (6H, m), 1. 3-1.4 (3H, m), 2.7 (2H, m), 3.5 (3H, s), 4.3-4.4 (3H, m), 4.7 (2H, m), 5.1, (1H, m), 5.9 (2H , s), 6.5 (2H, d), 6.7-6.9 (5H, m), 7.8 (1H, d), 8.4-8.5 (1H, d): m / Z 486 (M + H). HPLC-Dynamax 60A C18 column, acetonitrile / water / 0.1% TFA, 20/80% over a period of 20 minutes, Rt 9.7 minutes, and this compound was used without further purification in the next step. c) Preparation of 4- (N'-phenylurea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxy phenyl) -propionate) -amide. 4-aminophenoxyacetyl- (methyleucine-3-amino-3- (3, 4-methylenedioxyphenyl) -propionate) -amide (727 mg) and diisopropylethylamine (0.282 ml) were dissolved in dichloromethane (2 ml) and added to a solution of triphosgene (165 mg) in dichloromethane (2 ml) under an argon atmosphere for a period of 30 minutes. The resulting solution was stirred for 5 minutes and then collected with a syringe and a third of the total volume was added to a solution of aniline (0.042 ml) and diisopropylethylamine (0.093 ml) in dichloromethane (2 ml) under an argon atmosphere . The mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and then taken up with ethyl acetate (30 ml), washed with water (5 ml), with 5% citric acid (5 ml), with water (5 ml), with a saturated solution of sodium bicarbonate (5 ml), with water (5 ml), with saturated brine (5 ml), dried (MgSO 4).

The evaporation left The solvent and the trituration with ether yielded 212 mg of 4- (N '-phenylurea) -phenoxyacetyl- (methyleucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide as a white solid, which was "hydrolyzed without further purification m / Z 605 (M + H) HPLC Column-Dynamax 60A C18, acetonitrile / water / 0.1% TFA, 20/80% in a period of 20 minutes, Rt 15.8minutes (95% purity) Example 54 - Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (N- (2-methylpropyl) glycine-3-amino-3- (3,4-) acid amide methylenedioxyphenyl) -propionic) was prepared according to Example 1, but using 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methyl-propyl) -glycine-3-amino-3- (3 , 4-methylenedioxyphenyl) -propionate) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- ((3,4-methylenedioxyphenyl) -propionate) -amide a) Preparation of t-butyl-N- (2-methylpropyl) -glycine T-butyl bromide acetate (8.4 ml, 10.1 g) was added under an atmo from argon to a solution of isobutilaiha (50 ml, 36.8 g) in diethyl ether (100 ml) at -40 ° C, with stirring for 5 minutes. The solution was stirred at this temperature for 1 hour and then at room temperature for 18 hours. The mixture was filtered and the filtrate was distilled at ambient pressure to remove the ether and subsequently the excess of isobutylamine (e.g., 64-66 ° C) and then under reduced pressure to obtain the product. Performance, 82%. P.e. 68 ° C / 3 mm. NMR (CDC13, 300 MHz, ppm): 3.28 (2H, s), 2.4 (2H, d), 1.72 (1H, m), 1.48 (9H, s), 0.92 (6H, d). m / Z 188.3 (M + H). b) Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl-. { t-butyl-N- (2-methylpropyl) -glycine} - amide. A solution of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetic acid (1.5 g, 5 mmol) in DMF (6 ml) was treated with t-butyl-N- (2-methylpropyl) glycine ) (936 mg, 5 mmol), (O- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate) (2.28 g, 6 mmol) and diisopropylethylamine (1.9 mL, 11 mmol) . The mixture was stirred at room temperature overnight. The mixture was extracted by partition in EtOAc and water. The EtOAc phase was separated, washed with 1 M citric acid, with a saturated solution of NaHCO 3 and concentrated in vacuo to obtain a white solid. The solid was purified by chromatography on KP-SilO (Biotage GB Ltd.), eluting with ethyl acetate, to obtain the coupled product (1.8 g, 76%) as a white solid. NMR (lOOdegC, DMSO-d6, 300 MHz, ppm): 8.52 (1H, s), 7.73 (1H, d), 7.66 (1H, s), 7.33 (2H, d), 7.1 (2H, q), 6.92. (1H, t), 6.8.4 (2H, d), 4.7 (2H, broad s), 4.0 (2H, s broad), 3.18 (2H, d), 2.24 (3H, s), 1.88 (1H, m), 1.48 (9H, s), 0.85-0.96 (6H, broad s), ESPMS (M + NH4) 487.5 c) Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl-N - (2-methylpropyl) -glycine Prepared according to Example LE, using 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl-. {T-butyl-N- (2-methylpropyl) -glycine.} -amide instead of 4- (N '- (2-methylphenyl) -urea) -t-butyl phenoxyacetate 4- (N' - (2-methylphenyl) -urea) -phenoxyacetyl-N- (2-methylpropyl) -glycine m / Z 414.3 (M + H) d) 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methyl-N- (2-methylpropyl) -glycine- 3-amino-3- (3,4-methylenedioxyphenyl) -propionate-amide.

A solution of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl-N- (2-methylpropyl) -glycine (1.5 g, 3.6 mmol) in a mixture of methylene chloride and DMF, 9: 1, v / v (70 ml), was treated with methyl 3-amino-3- (3,4-methylenedioxyphenyl) -propionate (prepared according to the method described in International Publication WO 96/22966 (Biogen) on the pages 52 to 55 and which is incorporated herein by reference) (1.6 g, 7.2 mmol), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.22 g, 7.2 mmol), HOBT (972 mg, 7.2 mmol) and diisopropylethylamine (1.3 ml, 7.2 mmol). The mixture was stirred at room temperature overnight. The mixture was subjected to extraction by partition in EtOAc and water. The EtOAc phase was separated, washed with 1 M citric acid, with a saturated solution of NaHCO3 and concentrated in vacuo, to obtain a translucent gum. The gum was purified by chromatography on KP-SilO (Biotage GB Ltd.) eluting with toluene / ethyl acetate, to obtain the coupled product (1.3 g, 58%) as a white solid. 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methyl-N- (2-methylpropyl) -glycine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide. NMR (DMSO-d6, 300 MHz, ppm): 0.73-0.93 (6H, m), 1.75-1.83 (1H, m), 2.21 (3H, s), 2.75 (2H, t), 3.0-3.2 (2H, m), 3.52 (3H, s), 3.82 (2H, d), 4.70 (2H, d), 5.18 (1H,), 5.95 (2H, s), 6.7-6.9 (6H,), 7.0-7.1 (2H , q), 7.3 (2H, d), 7.8 (2H, d), 8.24-8.67 (lh, dd), 8.79 (1H, d). m / Z 619. 4 (M + H). Example 66 - Preparation of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (2- (2-methoxyethyl) -glycine-3-amino-3- (3,4-methylenedioxyphenyl) - amide propionic). It was prepared according to Example 54, except that in step 54b methyl-2- (2-methoxyethyl) -glycine was used instead of t-butyl-N- (2-methylpropyl) glycine. Methyl-2- (2-methoxyethyl) -glycine was prepared by the method described in European Patent Application No. 618,221. Hydrolysis of the substituted glycine ester of Example 54c was carried out using LiOH in the manner described in Example 1. Example 67 - 4- (N '- (2-methylphenyl) -urea) -3-methoxyphenoxyacetyl acid amide - (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid). Prepared according to Example 1, except that 4- (N '- (2-methyl phenyl) -urea) -3-methoxyphenoxyaceti1- (methyleucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate was used. ) -amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amiT? o -3- (3,4- (methylenedioxy) phenylpropionate) -amide and in step 4-nitro-3-methoxyphenol was used instead of 4-nitrophenol a) 4-nitro-3-methoxyphenol.

A sodium hydroxide solution was poured into a stirred solution of 4-fluoro-2-methoxynitrobenzene (11.1 g) in DMSO (60 ml) at room temperature and the mixture was heated at 85 ° C for 2.5 hours. The solution was cooled and diluted with water (100 ml) and subjected to extraction with ether (3 x 100 ml). The combined ether solution was extracted with 2 N NaOH (3 x 75 mL) and the combined aqueous phases were brought to pH 2 by the addition of 2 N HCl. The precipitated product was collected and washed with water. The product was dried over phosphorus pentoxide. Yield, 7.4 g. m / Z 170.1 (M + H). This product was used without further purification in the next stage (cf. Example le). Example 69 - Preparation of 4- (N '-pyrid-3-yl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionic acid amide). It was prepared according to Example 1, but using 4- (N '- (pyrid-3-yl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) - amide instead of 4- (N '- (2-methylphenyl) -urea) -phenoxyacetyl- (methylmethionine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. a) Preparation of 4- (N (pyrid-3-yl) -urea) -phenoxyacetyl- (methyleucine-3-amino-3- (3, -methylenedioxyphenyl) -propionate) -amide. 3-Pyridyl isocyanate (75 mg, 0.62 mmol) was added to a stirring solution of 4-aminophenoxyacetyl- (methyleucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate) -amide (see Example 30b) ) (280 mg, 0.58 mmol) in anhydrous ethyl acetate, at room temperature. The mixture was refluxed for 2 hours and the product was collected by filtration. Yield, 200 mg (56%). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 0.78 (6H, t); 1.39 (3H, m); 2.73 (2H, q); 3.52 (3H, s); 4.37 (1H, m); 4.47 (2H, s); 5.11 (1H, q); 5.96 (2H, s); 6.72 (1H, d); 6.81 (1H, d); 6.87 (3H, d); 7.26-7.38 (3H, m); 7.92 (2H, m); 8.15 (1H, d); 8.45 (1H, d); 8.60 (2H, d); _ 8.76 (1H, -s); ESPMS 606.4 (M + H) +. Example 71 - Preparation of 7- (N '- (2-methylphenyl) -urea) -2,3-dihydrobenzofuranyl-4-oxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) . It was prepared according to Example 1, but in step it was used 7- (N '- (2-methylphenyl) -urea) -2, 3-dihydrobenzofuranyl-4-oxyacetate of t-butyl instead of 4- ( N '- (2-methylphenyl) -urea) -phenoxyacetate of t-butyl and in part lf methyl leucine-3-amino-3- (3,4-methylenedioxyphenyl) -propionate was used instead of methionine-3- methyl-3- (3, -methylenedioxyphenyl) -propionate. a) Preparation of 4-hydroxydihydrobenzofuran.

At room temperature, a rapid stirring solution of 4-hydroxybenzofuran (2.0 g) (prepared by the method of G. Keen and P. Maddocks Syn. Comm., 16 (13), 1635-1640 (1986)) in acetic acid glacial (30 ml) containing 30% palladium on carbon (0.2 g), was exposed to a hydrogen atmosphere. When the hydrogen incorporation was complete, the solution was filtered and the filtrate was washed with glacial acetic acid. The filtrates were combined and the combined was evaporated to dryness to obtain 4-hydroxydihydrobenzofuran (2.05 g). 1 H NMR (DMSO-d 6, 300 MHz, ppm): 3.0 (2H, t), 4.5 (2H, t), 6.2 (1H, d), 6.3 (1H, d), 6.8 (lH, t), 9.5 ( 1H, b); m / Z 135 (M-H). b) Preparation of bis- (2,2,2-trifluoroethylester) -2,3-dihydrobenzofuran of 4-hydroxy-7- (hydrazine-1,2-dicarboxylic acid). Trifluorosulfonic acid (0.114 ml) was added to a solution of 4-hydroxydihydrobenzofuran (1.77 g) in dichloromethane (80 ml) at -70 ° C under an argon atmosphere, followed by bis- (2, 2, 2-trichloroethyl) - azodicarboxylate (BTEAD) (6 g). The mixture was stirred at -60 ° C for 30 minutes and then the reaction was stopped by adding a solution of 25% ammonium acetate (30 ml), allowing it to cool to room temperature and the mixture was subjected to extraction with acetate. ethyl acetate (2 times, 100 ml), the organic extracts were combined and the combined was washed with a saturated solution of brine (20 ml), dried (MgSO4), evaporated and purified using the Biotage 40M system, eluting with 5% ethyl acetate / toluene, to obtain bis- (2, 2, 2-tricycloester) -2, 3-dihydrobenzofuran of 4-hydroxy-7- (hydrazine-1,2-dicarboxylic acid) (4.73 g) . 1 H NMR (DMSO-d 6, 300 MHz, ppm): 3.0 (2H, t), 4.5 (2H, t), 4.8 (4H, s), 6.2 (1H, d), 7.0 (1H, d), 9.6 ( 1H, s), 10.75 (1H, s), m / Z 515 (MH). c) Preparation of t-butyl-7- (hydrazine-1,2-dicarboxylic acid bis- (2,2,2-trichloroethyl ester) -2,3-dihydrobenzpfuranyl-4-oxyacetate). T-butyl bromoacetate (1.62 ml) was added to a solution of bis- (2, 2, 2-trifluoroeti ester) -2, 3-dihydrobenzofuran of 4-hydroxy-7- (hydrazine-1,2-dicarboxylic acid ) in butan-2-one (50 ml) containing powdered potassium carbonate (1.63 g) and the mixture was stirred overnight at 80 ° C. The mixture was evaporated to dryness and then taken up with ethyl acetate (50 ml), washed with water (20 ml), the aqueous phase was extracted again with ethyl acetate (20 ml), the organic extracts were combined and the combined was washed with a saturated solution of sodium bicarbonate (20 ml) and with a saturated solution of brine (20 ml), and then dried (MgSO 4) *. Evaporation produced bis- (2,2,2-trichloroethyl ester) -2,3-dihydrobenzofuranyl-4-oxyacetatp of the t-butyl-7- (hydrazine-1,2-dicarboxylic acid) (5.4 g), m / Z 266 (M + H), where this compound was used without further purification in the next step. i d) Preparation of t-butyl 7-amino-2,3-dihydrobenzofuranyl-4-oxyacetate. I I I Added zinc grit (2 g) to a stirring solution i of bis- (2, 2, 2-trichloroethyl ester) -2, 3-dihydrobenzofuranyl-4-oxyacetate of t-butyl-7- (hydrazine- 1,2-dicarboxylic acid) (2 g) in glacial acetic acid I (20 ml), under an argon atmosphere. After 1 hour, a solution of 5 N sodium hydroxide (70 ml) was added and the mixture was extracted with ethyl acetate (3 times, 100 ml), dried (a2S? 4). The evaporation and purification by chromatography on a i 40S Biotage system, eluting with 10% ethyl acetate / toluene, produced t-butyl 7-amino-2,3-dihydrobenzofuranyl-4-oxyacetate as a light yellow solid , (341 mg). 1 H NMR (CDC 13, 300 MHz, ppm): 1.5 (9H, s), 3.2 (2H, t), 4.4 (2H, s), 4.6 (2H, t), 6.1 (1H, d), 6.5, (1H, d),: m / Z 266 (M + H). e) Preparation of 7- (N '- (2-methylphenyl) -urea) -2, 3- dihydrobenzofuranyl-4-oxyacetate of t-butyl. 2-Methylphenylisocyanate (171 mg, 160 μl) was added undiluted to a stirred solution of t-butyl 7-amino-2,3-dihydrobenzofuranyl-4-oxyacetate (341 mg) in methylene chloride (5 ml). under an argon atmosphere, at room temperature for a period of 2 minutes. The mixture was stirred for 18 hours and then evaporated. The residue was triturated with ether and the solid was filtered. This product was used without further purification. Performance, 74%. 1 H NMR (DMSO-d 6, 300 MHz, ppm): 1.4 (9H, s), 2.2 (3H, s), 3.2 (2ft, t), 4.6 (2H, s), 4.7 (2H, ~ "t), 6.3 (1H, d), 6.9 (1H, t), 7.1 (1H, t), 7.7 (1H, d), 7.8 (1H, d), 8.2 (1H, s), 8.4 (1H, s). 77 Pharmaceutical Compositions The compounds of the present invention can be formulated into tablets together with, for example, lactose Ph.Eur, Croscarmellose sodium, corn starch paste (5% w / v paste) and magnesium stearate, for therapeutic applications. or prophylactics in humans In Vitro and In Vivo Assays The following abbreviations were used: Sources of suitable materials are listed below.

MOLT-4 cells - human T lymphoblastic leukemia cells (European Collection of Animal Cell Culture, Porton Down). Fibronectin - purified from human plasma by affinity chromatography in gelatin / sepharose, according to the methods described in E. Nengvall, E. Ruoslahti, Int. J. Cancer, 1977, 2_0, pages 1-5 and J. Forsyth et al. , Methods in Enzymology, 1992, 215, pages 311-316). RPMI 1640 - cell culture medium (Life Technologies, Paisley GB). PBS - Dulbecco phosphate buffer (Life Technologies). ASB - bovine serum albumin, fraction V (ICN, Thame, GB). ACF - Freund's Complete Adjuvant (Life Technologies). In the following tests and models, references to or to the compounds refer to the compounds of Formulas (II), (III) and (IV), in accordance with the present invention. 1.1 Test xn vxtro. 1.1.1 MOLT-4 / Fibronectin cell adhesion assay. The MOLT-4 / Fibronectin cell adhesion assay was used to investigate the interaction of the αβ integrin. expressed in the membrane of MOLT-4 cells with fibronectin. 96-well polystyrene plates were coated, overnight at 4 ° C, with fibronectin, 100 μl of 10 μg / ml in PBS. The non-specific adhesion sites were blocked by adding 100 μl of ASB, 20 mg / ml. After incubation for 1 hour at room temperature, the solutions were aspirated. MOLT-4 cells were suspended in RPMI-1640 medium, 2E6 cells / ml (50 μl) and solutions of the compound diluted in the same medium (50 μl) were added to each well. After incubating for 2 hours at 37 ° C in a humidified atmosphere of 5% (v / v) CO2, the non-adherent cells were removed by gentle agitation-followed by vacuum aspiration. The adherent cells were quantified by a colorimetric assay of acid phosphatase. To each well was added 100 μl of p-nitrophenyl phosphate (6 mg / ml) in 50 mM sodium acetate buffer, pH 5.0, containing 1% Triton X-100. After incubating for 1 hour at 37 ° C, 50 μl of sodium hydroxide (1 M) was added to each well and the absorbance at 405 nm was measured on a microplate spectrophotometer. Compounds that inhibited adhesion gave a lower absorbance reading. Standard, control and test conditions were tested in triplicate. The percent inhibition was calculated with respect to the total (non-inhibitory) and non-specific standard (without fibronectin) in each plate. 1.2 Inflammation models in vivo. The activity of a compound can be tested in the following models. 1.2.1 Delayed hypersensitivity of ovalbumin in mice. Female Balb / c mice (20 to 25 g body weight) were immunized on the flank, with a 1: 1 emulsion. (v / v) ovalbumin (2 mg / ml) with ACF. "Seven days later, the mice were challenged by a subplant injection of 1% ovalbumin added by heat in saline (30 μl) in the foot pad of the right hind paw, and inflammation of the paw developed in a 24-hour period. after which the thickness of each leg was measured and compared to the thickness of the contralateral non-injected leg, the percentage increase in thickness of the footpad of each foot was calculated. The compounds were administered orally in groups of 5. mice, at doses ranging from 0.001 mg / kg to 100 mg / kg Inhibition of the inflammatory response was calculated by comparing vehicle-treated animals and groups of animals treated with the compound. 1. 2.2 Arthritis induced by collagen in mice. Male DBA / 1 mice were immunized with 0.1 ml of an emulsion prepared with equal volumes of bovine collagen type II in 0.05 M acetic acid (2 mg / ml) and ACF. This mixture was injected at the base of the tail. Twenty days later, the compounds were administered orally at doses ranging from 0.001 mg / kg / day to 100 mg / kg / day. The day after the first dose, each animal received an intraperitoneal booster injection of 0.1 ml of type II collagen in acetic acid. Mice were evaluated for the incidence and severity of arthritis in the four limbs for up to 28 days.

Inhibition of arthritis was calculated by comparing vehicle-treated mice and mice treated with the compound. or Cp or Cp TABLE 1 or NJ cp Cp Cp O I vo or cp Cp cp cp or cp ro (i cn or Cp ft or cp p VO (You *) or Cp Cp OR O Cp Cp VD 00 Cp or cp n O o • ^ o Cp p I O í Cn or n Cp t- »o .c- Faith C "O Cp Cp O n ft Cn O Cp Cp O ? r Cp O Cp Cp OR ? Cp s cp Cp O 00 - 1 (0 - 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 (10)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. A compound of the Formula (II) characterized because: R is in position for or goal and is
2. R 2 and R 3 are each independently selected from the group consisting of a hydrogen atom, a nitro radical, alkyl of 1 to 6 carbon atoms, cycloalkyl 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms carbon, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, amino, cyano, halogen, trifluoromethyl, -C02R12 and -CONR12R13, wherein R12 and R13 are independently selected from the group consisting of of a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms, or R 2 and R 3 together with the phenyl to which they are linked, form a 9 or 10 membered bicyclic ring system; R is an alkyl radical of 1 to 4 carbon atoms; R is selected from the group consisting of a hydrogen atom and an alkyl group of 1 to 4 carbon atoms; R is selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms-cycloalkyl of 4 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxyl of 1 to 6 carbon atoms, Ci-βalkylS (Ci-β) alkyl, alkylsulfonyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms; ' where q is an integer from 1 to 6 and R14 is a halogen; fc R is selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, 1,3-benzodioxol-5-yl and aryl, each optionally substituted with one or more substituents which are selected from the group consisting of alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl; R is an aryl radical, heteroaryl, a bicyclic heteroaryl ring system linked to nitrogen through a ring carbon or a 9- or 10-membered bicyclic ring system bonded to nitrogen through
3. L5 of a ring carbon, and each ring is optionally substituted with up to two substituents, which may be the same or different, and are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 4 atoms carbon, thioalkyl from 1 to 4 20 carbon atoms, alkyl of 1 to 6 carbon atoms- alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, hydroxy, -C02H, - (CH2) p0H, wherein p is 1 or 2, cyano, halogen and trifluoromethyl;
4. R and R1 are each independently selected from the group consisting of hydrogen atoms and alkyl radicals of 1 to 4 carbon atoms or R8 and R9 together with the nitrogen to which they are attached, form a dihydroindolyl group or a dihydroquinolinyl group; R is selected from the group consisting of carboxyl, tetrazolyl, alkylsulfonylcarbamoyl, sulfo and sulfino radicals; And it's oxygen, sulfur or sulfonyl; m is 0 or 1; and n is 0 or an integer from 1 to 4, provided that m and n can not both be 0 and when m is 1, n is 0; or a pharmaceutically acceptable salt or hydrolysable ester in vi ve. 2. A compound according to claim 1, having the Formula characterized in that: R "is an alkoxy radical of 1 to 4 carbon atoms, R and R are each independently hydrogen, R4 is an alkyl radical of 1 to 4 carbon atoms, R6 is selected from the group consisting of alkyl radicals of 1 to 4 carbon atoms and C1-4 alkyl (C 1-4) alkyl;
5. R is selected from the group consisting of alkenyl radicals of 2 to 6 carbon atoms and 1,3-benzodioxol-5-yl, optionally substituted by at least one substituent selected from the group consisting of alkoxy radicals of 1 to 4 atoms of carbon, alkyl of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl; R is an aryl or heteroaryl radical, each optionally substituted with a substituent selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, CH 2 OH, halogen and hydroxy; and 9 R is hydrogen or alkyl of 1 to 4 atoms of carbon or R and R together with the nitrogen to which they are bound, form a dihydroindolyl group or a dihydroquinolinyl group; and m and n are 0 or 1, provided m and n can not both be 0 or 1; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 3. A compound according to claim 2, characterized in that R is methoxy. 4. A compound according to any of claims 1 or 2, characterized in that the compound is selected from the group consisting of 4- (N '- (2-methylphenyl) -urea) -3-methoxyphenoxyacetyl- (leucine) amide. 3-amino- (3,4-methylenedioxy) -phenylpropionic acid); 4- (N'-phenylurea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) amide; 4- (N '- (2-chlorophenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) amide; 7- (N '- (2-methylphenyl) -urea) -2,3-dihydrobenzofuranyl-4-oxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) amide; 4- (N '- (2-hydroxymethylphenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3,4-methylenedioxy) -phenylpropionic acid) amide; 4 - [(2, 3-dihydro-lH-indol-1-yl-carbonyl) -amino] -3-methoxyphenoxyacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid) amide; 4- (N '- (2-fluorophenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid) amide; 4- (N '- (2-hydroxy-6-methylphenyl) -urea) -3-methoxyphenoxyacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid) amide; and 4- (N '- (2-methylphenyl) -urea) -3-isopropoxyphenoxyacetyl- (leucine-3-amino- (3, -methylenedioxy) -phenylpropionic acid) amide. 5. A compound of the Formula (IV) characterized because: R a is in position for or goal and is 2 3 R a and R a are each independently selected from the group consisting of a hydrogen atom, a nitro radical, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms carbon, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, "7 7 8 cyano, halogen, trifluoromethyl, -C02R to Y -CONR aR a, in wherein R7a and R8a are independently selected from the group consisting of hydrogen atoms or alkyl radicals of 1 to 6 carbon atoms; R a is selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted-alkyl of 1 to 6 carbon atoms and Ci-βalkylS (C? _) Alkyl;
6. R a is selected from the group consisting of alkyl radicals having 1 to 6 carbon atoms, alkenyl 2 to 6 carbon atoms, 1,3-benzodioxol-5-yl and aryl, optionally substituted with at least one substituent selected from the group consisting of alkoxy radicals of 1 to 4 carbon atoms, alkyl of 1 to 6 atoms carbon, cyano, halogen and trifluoromethyl; R a is an aryl or heteroaryl radical and the ring optionally is substituted with up to two substituents, which may be the same or different, which are selected from the group consisting of alkyl radicals of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, cyano, halogen and trifluoromethyl; It is already oxygen or sulfur; and na is an integer from 1 to 4; or a pharmaceutically acceptable salt or hydrolysable ester in vi thereof. 6. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
7. 7. A process for preparing a compound of the Formula (II) or a pharmaceutically acceptable salt or hydrolysable ester thereof, characterized in that it comprises coupling of, i) a compound of the Formula (V) with a compound of the Formula (VI) NHR5-CHR6-CONH-CHR7-CHr-COOH (VI \ or ii) a compound of the Formula (VII) and a compound of the Formula (VIII) NH2-CHR7-CH2-COOH (VIII) wherein L and L1 are leaving groups and any functional group is optionally protected; and then, if necessary: a) remove any protective group; and b) forming a pharmaceutically acceptable salt or a hydrolysable ester in vi vo.
8. 8. A method for inhibiting the interaction between MACV-1 and / or fibronectin and the integrin receptor AMT-4 in mammals in need of such treatment, characterized in that it comprises administering to the warm-blooded mammal an effective amount of a compound of according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 6.
9. 9. A method according to claim 8, characterized in that it is used for the treatment of multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease or psoriasis.
10. 10. The use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in the production of a medicament for use in the treatment of a disease or disorder mediated by the interaction between MACV-1 and / or fibronectin and the integrin receptor AMT-4. SUMMARY OF THE INVENTION The present invention relates to compounds of the Formula (II) wherein R. is in the para or meta position and is (A); R 2 and R 3 are each independently selected from the group consisting of hydrogen, nitro, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 4 carbon atoms, alkylamino from I to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, amino, cyano, halogen, trifluoromethyl, -CO2 1"and -CONR12R13, wherein R12 and R13 are independently selected from hydrogen or alkyl of 1 to 6 atoms • > 3 carbon; or R "and R together with the phenyl to which they are attached, form a 9- or 10-membered bicyclic ring system; R 4 is alkyl of 1 to 4 carbon atoms; R5 is selected from hydrogen and alkyl of 1 to 4 carbon atoms; R is selected from alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms-cycloalkyl of 4 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-alkoxy of 1 to 6 carbon atoms, C S6alkyl (C2) nitrogen to which they are bonded, form a dihydroindolyl group or a dihydroquinolinyl group, R is selected from carboxyl, tetrazolyl, alkylsulfonylcarbayl, sulfo and sulfino, and is oxygen, sulfur or sulfonyl, m is 0 or 1; and n is 0 or an integer from 1 to 4, provided that m and n can not both be 0 and when m is 1, n is 0, or a pharmaceutically acceptable salt or hydrolysable ester in vi thereof. the interaction of the vascular cell adhesion molecule-1 and fibronectin with the very late integrin antigen-4 (a4β?). They have therapeutic applications such as in multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease and psoriasis.