RU2233269C2 - Substituted anilides, pharmaceutical composition and method for treatment - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new physiologically active compounds of the formula (I), its N-oxides, ester derivatives and their pharmaceutically acceptable salts and solvates also that elicit valuable pharmaceutical properties, in particular, the ability to control the interaction of VCAM-1 and fibronectin with integrin VLA-4 (α4β1) and they can be used in treatment of inflammatory diseases and asthma. In compound of the general formula (I):

X¹ and X² mean independently CR¹⁰; R⁴ means hydrogen atom or (C₁-C₄)-alkyl group; R¹⁰ means hydrogen atom, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-group, (C₁-C₄)-alkylthio-group, (C₁-C₄)-alkylsulfinyl group or (C¹-C⁴)-alkylsulfonyl group; R¹² means hydrogen atom, (C₁-C₄)-alkyl or benzyl; R¹³ means (C₁-C₆)-alkyl optionally substituted with carboxy-group, (C₁-C₄)-alkoxyalkoxy-group, -OCH₂CO₂H, -NY¹Y² or with one or more hydroxy-groups; heteroaryl taken among imidazolyl, oxazolyl, pyridyl, thienyl and pyridazinyl each of that is substituted optionally with carboxy-group or (C₁-C₄)-alkyl; heterocycloalkyl, such as tetrahydropyranyl; or aryl taken among phenyl and naphthyl each of that can be substituted with carboxy-group, -NY⁴Y⁵ or one or more (C₁-C₄)-alkoxy-group wherein Y⁴ and Y⁵ represent independently (C₁-C)-alkyl; R¹⁵ means -N(R¹²)-C(=O)-R¹³, -N(R¹²)-SO₂-R₁₃ or -NY¹Y² wherein Y¹ and Y² represent independently hydrogen atom, (C₁-C₄)-alkyl or aryl-(C₁-C₄)-alkyl, or the group -NY¹Y² can form 5-6-membered cyclic amine that can comprise additional heteroatom taken among oxygen atom or NY³ [wherein Y³ means -C(=O)-OR¹⁴ (wherein R¹⁴ means (C₁-C₄)-alkyl) or (C-C₄)-alkyl]; Ar¹ means unsubstituted phenylene. Invention relates also to a pharmaceutical composition and a method for treatment using compounds of the present invention.

EFFECT: improved treatment method, valuable medicinal properties of compounds.

16 cl, 51 ex

Description

This invention relates to substituted anilides, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states that can be modulated by inhibiting cell adhesion.

Cell adhesion is a process in which cells connect to each other, migrate towards a specific object, or localize inside an extracellular matrix. Many of the cell-cell or cell-extracellular matrix interactions are mediated by protein ligands (eg, fibronectin, vitronectin and VCAM-1) and their integrin receptors [eg, VLA-4 (α ₄ β ₁ )]. Recent studies have shown that these interactions play an important role in many physiological (e.g., embryonic development and wound healing) and pathological conditions (e.g., invasion (germination) of tumor cells and metastases, inflammatory disease, atherosclerosis, and autoimmune disease).

A wide variety of proteins serve as ligands for integrin receptors. Basically, proteins recognized by integrins are divided into three classes: extracellular matrix proteins, plasma proteins, and cell surface proteins. Extracellular matrix proteins such as fibronectin, collagen, fibrinogen, laminin, thrombospondin and vitronectin bind a number of integrins. Many adhesive proteins also circulate in plasma and bind to activated blood cells. Additional plasma components that are ligands for integrins include fibrinogen and factor X. Cellular bound complement C3bi and some transmembrane proteins, such as an Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM- 1), which are members of the Ig superfamily, also serve as cell surface ligands for some integrins.

Integrins are heterodimeric cell surface receptors that include two subunits called α and β. There are at least twelve different α-subunits (α 1-α 6, α -L, α-m, α -X, α -Iib, α -V and α -E) and at least nine different β subunits (β 1-β 9). The integrin family is divided into classes of β-subunits that are associated with one or more α-subunits. The most widely distributed are integrins belonging to the β 1 class, also known as very late antigens (VLA). The second class of integrins is leukocyte-specific receptors, including one of the three α-subunits (α-L, α-M, or α-X), complexed to the β 2 protein. The cytoadhesins α-IIβ 3 and α -Vβ 3 comprise the third class of integrins.

The present invention mainly relates to agents that modulate the interaction of the VCAM-1 ligand with the α 4β 1 integrin receptor (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T-lymphocytes, B-lymphocytes , monocytes, thymocytes and eosinophils.

Integrin α 4β 1 mediates both cell-cell and cell-extracellular matrix interactions. Cells expressing α 4β 1 bind to the carboxy-terminal cellular binding domain of the extracellular matrix protein, fibronectin, the cytokine activated endothelial cell surface protein, VCAM-1, and with each other, which promotes homotypic aggregation. The expression of VCAM-1 by endothelial cells is regulated by pro-inflammatory cytokines such as INF-γ, TNF-α and LI-1β.

Control of α 4β 1 mediated cell adhesion is important in many physiological processes, including T cell proliferation, B cell localization at germinal centers, and adhesion of activated T cells and eosinophils to endothelial cells. Data on the involvement of VLA-4 / VCAM-1 in the pathological process in various diseases, such as those collected in the study of the role of CS-1 protein (the variable region of fibronectin, with which α 4β 1 binds through the Leu-Asp-Val sequence) and antibodies, specific for VLA-4 or VCAM-1 in various experimental models of inflammation in vitro and in vivo. For example, in an experimental model of rat-induced streptococcal sheath arthritis, the administration of CS-1 when stimulating arthritis suppresses both acute and chronic inflammation (SMWahl et al. J. Clin. Invest., 1994, 94, pages 655 -662). In the oxazolone-sensitized model of inflammation (contact allergic reaction) in mice, the intravenous administration of specific monoclonal antibodies to α 4 significantly suppresses (50-60% attenuation of the ear swelling reaction) the efferent response (PLChisholm et al. J. Immmunol., 1993, 23, pages 682-688).

The authors found a new group of substituted anilides with valuable pharmaceutical properties, in particular, the ability to regulate the interaction of VCAM-1 and fibronectin with integrin VLA-4 (α 4β 1).

So, one aspect of the present invention is directed to compounds of the general formula A

where R ¹ represents hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy;

X ¹ , X ² and X ^{6 are} independently N or CR ¹⁰ and one of X ³ , X ⁴ and X ⁵ is CR ¹¹ and the others are independently N or CR ¹⁰ , where R ¹⁰ is hydrogen, amino, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro or trifluoromethyl, and R ¹¹ denotes a group-L ¹ -Ar ¹ -L ² -Y, in which

L ¹ is an —R ² -R ³ bridge, where R ² is a straight or branched C _1-6 alkylene chain, a straight or branched C _2-6 alkenylene chain or a straight or branched C _2-6 alkynylene, and R ³ is direct chemical bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, -C (= Z) -NR ⁴ -, -NR ⁴ -C (= Z) -, -Z ¹ -, -C (= O) -, -C ( = NOR ⁴ ) -, -NR ⁴ -C (= Z) -NR ⁴ -, -SO ₂ -NR ⁴ -, -NR ⁴ -SO ₂ -, -OC (= O) -, -C (= O) —O—, —NR ⁴ —C (= O) —O— or —OC (= O) —NR ⁴ - (where R ⁴ represents a hydrogen atom or lower alkyl group; Z represents O or S; Z ¹ represents O, S (O) _n , or NR ⁴ and n is zero or an integer o 1 or 2), but with the exception of compounds in which the oxygen, nitrogen or sulfur atom in R ^{3 is} directly bonded to the carbon atom of the multiple bond in R ³ ;

Ar ¹ is arylene or heteroaryldiyl;

L ² means

(i) direct chemical bonding;

(ii) a bridge of alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene, each of which is optionally substituted

(a) an acid functional group (or a corresponding protected derivative), R ⁵ , —ZH, —ZR ⁵ , —C (= O) —R, —N (R ¹² ) —C (= O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , —NY ¹ Y ^2, or - [C (= O) —N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] pC (= O) -NY ¹ Y ² or

(b) an alkyl substituted with an acidic functional group (or a corresponding protected derivative), or —ZH, —ZR ⁵ , —C (═O) —NY ¹ Y ² or —NY ¹ Y ² ;

(iii) - [C (= O) —N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] _p- bridge;

(iv) -Z ² -R ⁹ bridges;

(v) -C (= O) -CH ₂ -C (= O) -bridge;

(vi) -R ⁹ -Z ² -R ⁹ bridge, or

(vii) -C (R ⁴ ) (R ⁸ ) - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] p-bridge,

where R ⁵ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkylalkyl,

R ⁶ is hydrogen, R ⁵ or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or —NY ¹ Y ² ;

each of R ⁷ and R ^{8 is} independently selected from hydrogen or a group comprising amino acid side chains and corresponding protected derivatives, an acid functional group (or a corresponding protected derivative), R ⁵ , —ZR ⁵ , —C (= O) —R ^5, or —C (= O) —NY ¹ Y ² , or alkyl substituted with an acid functional group (or a corresponding protected derivative), or substituted with R ⁵ , —ZR ⁵ , —NY ¹ Y ² , —NH-C (= O) - R ⁵ , —C (= O) —R ² —NH ₂ , —C (= O) —Ar ¹ —NH ₂ , —C (= O) —R ² —CO ₂ H, or —C (= O) - NY ¹ Y ² ;

or R ⁶ and R ⁷ , or R ⁶ and R ^8, together with the atoms to which they are attached, form a 3-6 membered heterocycloalkyl ring;

R ⁹ is C _1-6 alkylene optionally substituted with R ⁵ ;

R ¹² is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;

R ¹³ is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted with aryl, an acid functional group (or a corresponding protected derivative), cycloalkyl, heteroaryl, heterocycloalkyl, -ZH, -ZR ⁵ , -C (= O) -NY ¹ Y ² or -NY ¹ Y ² ;

Y ¹ and Y ^{2 are} independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl or alkyl substituted with alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, —NY ¹ Y ² or one or more groups —CO ₂ R ¹² or —C (═O) —NY ¹ Y ² ;

or the group —NY ¹ Y ² can form a 5-7 membered cyclic amine, which

(i) optionally may be substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or an acetal derivative with a 5, 6 or 7 membered ring), R ¹³ ;

(ii) may also contain an additional heteroatom selected from O, S, SO ₂ or NY ³ [where Y ³ is hydrogen, alkyl, aryl, arylalkyl, —C (= O) —R ¹⁴ , —C (= O) —OR ¹⁴ or —SO ₂ R ¹⁴ (where R ¹⁴ is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl) and

(iii) can also be condensed to form additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl cycles, which leads to the formation of a cyclic system of two or three rings;

Z ² is O, S (O) n, NR ⁴ , SONR ⁴ , C (= O) NR ⁴ or C (= O);

p is zero or an integer from 1 to 4 and

Y is carboxy (or an acid bioisoster) or —C (= O) —NY ¹ Y ² ],

and corresponding N-oxides and their prodrugs; pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs;

the exception is compounds: (2- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} thiazol-4-yl) acetic acid, 2-phenylacetylamino-3- {4- [4- (3 - (2-methylphenyl) ureido) benzyloxy] phenyl} propionic acid, 2-phenylacetylamino-3- (4- {2- [4- (3- (2-methylphenyl) ureido) phenyl] ethoxy} phenyl) propionic acid, 2 -benzylsulfonylamino-3- {4- [4- (3- (2-methylphenyl) ureido) benzyloxy] phenyl} propionic acid, (butane-1-sulfonylamino) - {2- [4- (3- (2-methylphenyl) ureido) benzyl] benzofuran-6-yl} acetic acid, 3- (benzylaminocarbonyl) - (4- {2- [4- (3- (2-methylphenyl) ureido) phenyl] ethoxy} benzyl) propionic acid ota and 2-benzyloxycarbonylamino-3- (5- {3- [4- (3- (2-methylphenyl) ureido) phenyl] propyl} thiophen-2-yl) propionic acid,

and provided that L ¹ cannot denote C _1-6 alkylene-C (= O) -NH- or C _1-6 alkylene when Ar ¹ is optionally substituted phenylene, Y is —CO ₂ H, —CO ₃ H , —PO ₄ H ₂ or tetrazole, and L ² is

(i) direct chemical bonding,

(ii) a bridge of alkylene or alkenylene, each of which is optionally substituted

(a) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; or

(b) alkyl substituted with alkoxy, hydroxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl or —C (═O) —NH ₂ ,

(iii) - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] p-bridge, where R ⁴ is hydrogen or lower alkyl, R ⁶ is hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted with alkoxy, hydroxy or alkylthio, R ⁷ represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, , arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted with al enyl, alkynyl, alkoxy, hydroxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl or carboxamide, and p is one,

(iv) -Z ² -R ⁹ bridge, where Z ² is O, S, NR ⁴ , SO ₂ NR ⁴ or C (= O) NR ⁴ and R ⁹ is C _1-4 alkylene, optionally substituted with alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl, or

(v) —CH ₂ —Z ² —R ⁹ —bridge, where Z ² is O, NR ⁴ or C (= O) NR ⁴ and R ⁹ is C _1-4 alkylene, optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl , cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl.

As used herein, the term “compounds of the invention” and equivalent expressions are intended to encompass compounds of general formula (I) as defined above and, where the context allows, this expression includes prodrugs, pharmaceutically acceptable salts and solvates, for example hydrates. Similarly, with respect to intermediates, regardless of whether or not they are listed in the attached paragraphs, where the context permits, it is understood that the concepts include their salts and solvates. For clarity, individual examples, when the context allows it, are included in the text, but these examples are purely illustrative and do not mean that they exclude other examples when the context allows them.

As used above and in the subsequent text of the description of the invention, it is understood that, unless otherwise indicated, the following terms have the following meanings

"Patient" includes both humans and other mammals.

"Acidic bioisostere" means a group that has chemical and physical similarities to a carboxy group, giving a close similarity of biological properties (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, page 283, "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993 33, pages 576-579, "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38, "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem., 1995, 343, 105-109, Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres "). Examples of acceptable acidic bioisosteres include -C (= O) -NHOH, -C (= O) -CH ₂ OH, -C ( = O) —CH ₂ SH, —C (= O) —NH — CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, aryl sulfonylcarbamoyl, hetero-arylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy -1-methylpyrazolyl.

"Acid functional group" means a group with acidic hydrogen. “Corresponding protected derivatives” are derivatives in which the acidic hydrogen atom is substituted with a suitable protecting group. For suitable protecting groups see T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991. Illustrative examples of acidic functional groups include carboxyl (and acidic bioisosteres), hydroxy, mercapto, and imidazole. Illustrative examples of protected derivatives include esters of carboxy groups, ethers of hydroxy groups, thioethers of mercapto groups and N-benzyl derivatives of imidazoles.

“Acyl” means an H — CO— or alkyl — CO— group in which the alkyl group is as defined above.

“Acylamino” means an acyl NH group wherein acyl is as defined above.

"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond, this group may be linear or branched and with about 2-15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to 12 carbon atoms in the chain, more preferably about 2-4 carbon atoms in the chain. “Branched”, as used hereinafter in the text, means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear chain, here a linear chain of alkenyl. "Lower alkenyl" means that in the chain, which may be linear or branched, about 2-4 carbon atoms. Representative examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

"Alkenylene" means an aliphatic divalent radical derived from a linear or branched alkenyl group in which the alkenyl group is as defined above. Illustrative examples of alkenylene radicals include vinylene and propylene.

“Alkoxy” means an alkyl-O-group in which the alkyl group is as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and heptoxy.

“Alkoxyalkoxy” means an alkyl-O-alkyl-O-group in which the alkyl groups are independently as defined above. Examples of alkoxyalkoxy groups include methoxymethoxy, methoxyethoxy and the like.

“Alkoxycarbonyl” means an alkyl-O — CO— group in which the alkyl group is as defined above. Representative examples of alkoxycarbonyl groups include methoxy and ethoxycarbonyl.

"Alkyl" means, unless otherwise indicated, an aliphatic hydrocarbon group, which may be linear or branched, with about 1-15 carbon atoms in the chain, optionally substituted with alkoxy or one or more halogen atoms. Noteworthy alkyl groups have from about 1 to 6 carbon atoms.

"Lower alkyl" as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means, unless otherwise indicated, an aliphatic hydrocarbon group which may be linear or branched with about 1-4 carbon atoms in the chain. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

“Alkylene” means an aliphatic divalent radical derived from a linear or branched alkyl group in which the alkyl group is as defined above. Illustrative examples of alkylene radicals include methylene, ethylene and trimethylene.

“Alkylenedioxy” means an —O-alkylene-O-group in which alkylene is as defined above. Representative examples of alkylenedioxy groups include methylenedioxy and ethylenedioxy.

“Alkylsulfinyl” means an alkyl-SO— group in which the alkyl group is as defined above. Preferred alkylsulfinyl groups are those in which the alkyl group is C _1-4 alkyl.

“Alkylsulfonyl” means an alkyl-SO ₂ group in which the alkyl group is as defined above. Preferred alkylsulfonyl groups are those in which the alkyl group is C _1-4 alkyl.

"Alkylsulfonylcarbamoyl" means an alkyl-SO ₂ —NH — C (= O) group in which the alkyl group is as defined above. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C _1-4 alkyl.

“Alkylthio” means an alkyl S group in which the alkyl group is as defined above. Representative examples of alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.

"Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be linear or branched, with about 2-15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to 12 carbon atoms in the chain, more preferably about 2-4 carbon atoms in the chain. Representative examples of alkynyl groups include ethynyl, propynyl, n-butynyl, iso-butynyl, 3-methylbut-2-ynyl and n-pentynyl.

“Alkynylene” means an aliphatic divalent radical derived from a linear or branched alkyl group in which the alkynyl group is as defined above. Illustrative examples of alkynylene radicals include ethynylene and propynylene.

The term “amino acid side chains” means a substituent on a carbon located between amino and carboxy groups in α-amino acids. For examples of "corresponding protected derivatives" of amino acid side chains, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

"Aroyl" means an aryl-CO group in which the aryl group is as defined above. Representative examples of groups include benzoyl and 1- and 2-naphthoyl.

“Aroylamino” means an aroyl-NH group, wherein aroyl is as defined above.

"Aryl" as a group or part of a group means

(i) an optionally substituted monocyclic or polycyclic aromatic hydrocarbon radical with about 6-14 carbon atoms, such as phenyl or naphthyl,

or (ii) an optionally substituted partially saturated multinuclear aromatic carbocyclic radical in which the aryl and cycloalkyl or cycloalkenyl group are fused together to give a cyclic structure such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where the term “aryl group substituent” includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino , aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halogen, heteroaryl, heteroaryl, heteroarylalkyloxy, heteroaryo droksi, nitro, trifluoromethyl, Y ⁴ Y ⁵ N-, Y ⁴ Y ⁵ NCO-, Y ⁴ Y ⁵ NSO ₂ - (where Y ⁴ and Y ⁵ are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl), Y ⁴ Y ⁵ NC _2-6 alkylene-Z ³ -, {where Z ³ is O, NR ⁶ or S (O) _n }, alkylC (= O) -Y ⁴ N-, alkyl SO ₂ -Y ⁴ N- or alkyl optionally substituted with aryl, heteroaryl, hydroxy or Y ⁴ Y ⁵ N-. When L ² contains an optionally substituted aryl group, it can in particular be represented by optionally substituted phenyl.

“Arylalkenyl” means an arylalkenyl group in which aryl and alkenyl are as defined above. Preferred arylalkenyls contain a lower alkenyl group. Illustrative examples of arylalkenyl groups include styryl and phenylallyl.

“Arylalkyl” means an arylalkyl group in which the aryl and alkyl groups are as defined above. Preferred arylalkyl groups contain a C _1-4 alkyl radical. Representative examples of arylalkyl groups include benzyl, 2-phenethyl and naphthalenmethyl.

“Arylalkyloxy” means an arylalkyl-O— group in which the arylalkyl groups are as defined above. Representative examples of arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

“Arylalkyloxycarbonyl” means an arylalkyl-O — CO— group in which the arylalkyl groups are as defined above. A representative example of an arylalkyloxycarbonyl group is benzyloxycarbonyl.

“Arylalkylthio” means an arylalkyl-S-group in which the arylalkyl group is as defined above. A typical example of an arylalkylthio group is benzylthio.

“Arylalkynyl” means an arylalkynyl group in which aryl and alkynyl are as defined above. Representative examples of arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.

“Arylene” means an optionally substituted divalent radical derived from an aryl group. Illustrative examples of arylene groups include optionally substituted phenylene, naphthylene and indanylene. When Ar ¹ is arylene, it can, in particular, be an optionally substituted phenylene. Suitable substituents include one or more “aryl group substituents” as defined above, in particular halogen, methyl or methoxy.

"Aryloxy" means an aryl-O-group in which the aryl group is as defined above. Representative examples of aryloxy groups include optionally substituted phenoxy or naphthoxy.

“Aryloxycarbonyl” means an aryl-O — C (═O) group in which the aryl group is as defined above. Representative examples of aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

“Arylsulfinyl” means an aryl-SO group in which the aryl group is as defined above.

“Arylsulfonyl” means an aryl-SO ₂ group in which the aryl group is as defined above.

"Arylsulfonylcarbamoyl" means an aryl-SO ₂ —NH — C (= O) group in which the aryl group is as defined above.

“Arylthio” means an aryl-S group in which the aryl group is as defined above. Representative examples of arylthio groups include phenylthio and naphthylthio.

“Azaheteroaryl” means an aromatic carbocyclic radical with about 5-10 ring members in which one of the ring members is nitrogen and the other ring members are selected from carbon, oxygen, sulfur, or nitrogen. Examples of azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl and benzimidazolyl.

"Cycloalkenyl" means a non-aromatic mononuclear or polynuclear ring system containing at least one carbon-carbon double bond and having about 3-10 carbon atoms. Representative examples of mononuclear cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

“Cycloalkenylalkyl” means a cycloalkenylalkyl group in which the cycloalkenyl and alkyl groups are as defined above. Representative examples of cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.

“Cycloalkenylene” means a divalent radical derived from an unsaturated monocyclic hydrocarbon with about 3-10 carbon atoms, by cleaving a hydrogen atom from each of two different carbon atoms in the ring. Illustrative examples of cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.

“Cycloalkyl” means a saturated system of monocyclic or polycyclic rings, with about 3-10 carbon atoms optionally substituted with oxo. Representative examples of mononuclear cycloalkyl rings include C _3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

“Cycloalkylalkyl” means a cycloalkylalkyl group in which cycloalkyl and alkyl radicals are as defined above. Representative examples of monocyclic cycloalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

“Cycloalkylene” means a divalent radical derived from a saturated monocyclic hydrocarbon with about 3-10 carbon atoms, by cleaving a hydrogen atom from each of two different carbon atoms in the ring. Illustrative examples of cycloalk (en) ylene radicals include cyclopentylene and cyclohexylene.

"Halogen" or "halogen" means fluorine, chlorine, bromine or iodine. Fluorine or chlorine are preferred.

"Heteroaroyl" means a heteroaryl-C (= O) group in which the heteroaryl group is as defined above. Representative examples of groups include pyridylcarbonyl.

“Heteroaroylamino” means a heteroaroyl-NH group in which the heteroar (o) yl group is as defined above.

“Heteroaryl” as a group or part of a group means

(i) an optionally substituted aromatic mononuclear or polynuclear organic radical with approximately 5-10 ring members, in which one or more ring members is / are carbon-different element (s), for example nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl- , benzthiazolyl-, furyl-, imidazolyl-, indolyl-, indolisinyl-, isoxazolyl-, isoquinolinyl-, isothiazolyl-, oxadiazolyl-, pyrazinyl-, pyridazinyl-, pyrazolyl-, pyridyl-, pyrimidinyl-chirin -, 1,3,4-thiadiazolyl- thiazolyl, thienyl and thiazolyl groups optionally substituted with one or more of the above “aryl group substituents”);

(ii) an optionally substituted partially saturated polynuclear heterocarbocyclic radical in which heteroaryl and cycloalkyl or cycloalkenyl groups are fused together, resulting in a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more of the above “aryl group substituents”. When L ² contains an optionally substituted heteroaryl group, it may, in particular, mean an optionally substituted “azaheteroaryl” group.

“Heteroarylalkenyl” means a heteroarylalkenyl group in which the heteroaryl and alkenyl radicals are as defined above. Preferred heteroarylalkenyl groups contain a lower alkenyl radical. Representative examples of heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.

“Heteroarylalkyl” means a heteroarylalkyl group in which the heteroaryl and alkyl radicals are as defined above. Preferred heteroarylalkyl groups contain a C _1-4 alkyl radical. Representative examples of heteroarylalkyl groups include pyridylmethyl.

“Heteroarylalkyloxy” means a heteroarylalkyl-O— group in which the heteroarylalkyl group is as defined above. Representative examples of heteroaryloxy groups include optionally substituted pyridylmethoxy.

“Heteroarylalkynyl” means a heteroarylalkynyl group in which the heteroaryl and alkynyl groups are as defined above. Representative examples of heteroarylalkenyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl.

“Heteroaryldiyl” means a divalent radical derived from an aromatic monocyclic or polycyclic organic radical with about 5-10 members, in which one or more members of the cycle are / are other than carbon, for example nitrogen, oxygen or sulfur, and optionally substituted with one or more of the above “aryl group substituents”. When Ar ¹ is a heteroaryldiyl radical, it may, in particular, be optionally substituted pyridinediyl.

“Heteroaryloxy” means a heteroaryl-O— group in which the heteroaryl group is as defined above. Representative examples of heteroaryloxy groups include optionally substituted pyridyloxy.

“Heteroarylsulfonylcarbamoyl” means heteroaryl-SO ₂ —NH — C (= O) —the group in which the heteroaryl group is as defined above.

"Heterocycloalkyl" means

(i) a cycloalkyl group with about 3-7 members of the cycle containing one or more heteroatoms selected from O, S or NY ⁶ (where Y ⁶ is hydrogen, alkyl, arylalkyl and aryl);

(ii) an optionally substituted partially saturated multinuclear heterocyclic radical in which the aryl (or heteroaryl ring) heterocycloalkyl group is fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyridolinyl groups.

“Heterocycloalkylalkyl” means a heterocycloalkylalkyl group in which the heterocycloalkyl and alkyl groups are as defined above.

“Heterocycloalkylene” means a divalent radical derived from a saturated monocyclic hydrocarbon of about 5-7 atoms, containing one or more heteroatoms selected from O, S or NY ⁶ (where Y ⁶ is hydrogen, alkyl, arylalkyl and aryl) and optionally substituted oxo, by cleaving a hydrogen atom from each of two different carbon atoms in a cycle, or when NY ⁶ is NH, by cleaving a hydrogen atom from one carbon atom in a cycle and a hydrogen atom from NH, or when a cycle contains two NY ⁶ heteroatoms and NY ⁶ denotes r NH, splitting off a hydrogen atom from both nitrogen atoms.

"Y ⁴ Y ⁵ N" means a substituted or unsubstituted amino group, where Y ⁴ and Y ⁵ are as defined above. Representative examples of groups include amino (H ₂ N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.

“Y ⁷ Y ⁸ NCO—” means a substituted or unsubstituted carbamoyl group, wherein Y ⁴ and Y ⁵ are as defined above. Typical examples of groups are carbamoyl (H ₂ NCO-) and dimethylcarbamoyl (Me ₂ NCO-).

"Y ⁴ Y ⁵ NSO ₂ -" means a substituted or unsubstituted sulfamoyl group, where Y ⁴ and Y ⁵ are as defined above. Representative examples of groups are sulfamoyl (H ₂ NSO ₂ -) and dimethylsulfamoyl (Me ₂ NSO ₂ -).

"Prodrug" means a compound converted by metabolic pathways (for example, hydrolysis) in vivo to a compound of formula (A), including its N-oxides. For example, an ester of a compound of formula (I) containing a hydroxyl group can be converted by in vivo hydrolysis to the parent molecule. Alternatively, an ester of a compound of formula (I) containing a carboxyl group can be converted by in vivo hydrolysis to the parent molecule.

Suitable esters of compounds of formula (I) containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, silicates, propionates, succinates, fumarates, maleates, methylene bis-β-hydroxy naphthoates, gentisates, isoethionates , di-p-toluoyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and hinates.

A particularly useful class of esters of compounds of formula (A) containing a hydroxyl group can be formed from acid residues selected from the ones described by Bundgaard etal., J. Med. Chem., 1989, 32, page 2503-2507, and includes substituted (aminomethyl) benzoates, for example dialkylaminomethyl benzoates, in which two alkyl groups can be joined together and / or can be broken by an oxygen atom or an optionally substituted nitrogen atom, for example an alkyl atom nitrogen, in particular (morpholinomethyl) benzoates, for example 3- or 4- (morpholinomethyl) benzoates and (4-alkylpiperazin-1-yl) benzoates, for example 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

When the compounds of the invention contain a carboxyl group or a sufficiently acidic bioisostere, basic addition salts can be prepared which are simply a more convenient form for use, but in practice the use of the salt form is essentially equivalent to using the free acid form. Bases that can be used to prepare basic addition salts include preferably those which, when combined with free acid, give pharmaceutically acceptable salts, i.e. salts whose cations are not toxic to the patient at pharmaceutical doses of salts, so that the beneficial inhibitory effects inherent free base, were not spoiled by the side effects associated with cations. Pharmaceutically acceptable salts, including salts derived from alkali and alkaline earth metal salts and falling within the scope of the invention, include salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide , ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chlorprocain, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydro Methyl) aminomethane, tetramethylammonium hydroxide, and the like.

Some of the compounds of this invention are basic, and such compounds are useful in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt thereof.

Additive acid salts are a more convenient form for use, and in practice, using a salt form is essentially equivalent to using a free base form. Acids that can be used to prepare acid addition salts include predominantly those that give pharmaceutically acceptable salts in combination with the free base, i.e. salts whose anions are non-toxic to the patient at pharmaceutical doses of salts so that the beneficial inhibitory effects inherent in the free base are not spoiled by side effects associated with the anions. Although pharmaceutically acceptable salts of these basic compounds are preferred, all acid addition salts are suitable as sources for the free base form, even if a particular salt, by itself, is only required as an intermediate, such as when the salt is obtained only for purification purposes and identification, or when it is used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange. Pharmaceutically acceptable salts falling within the scope of the invention include those derived from inorganic and organic acids and include hydrogen halides, for example hydrochloric and hydrobromic salts, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis-β-hydroxynaphthoates, gentisates, isoethionates, di-p-toluoyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfate and Hinata.

Along with their suitability as active compounds, the salts of the compounds of the invention are useful for the purification of compounds, for example, based on the use of differences in solubility between salts and parent compounds, by-products and / or starting materials, according to methods well known to those skilled in the art. area.

With respect to the above formula (A), the following groups are deserving of attention and are preferred.

R ¹ may in particular be hydrogen, especially when X ¹ is CR ¹⁰ , where R ¹⁰ is lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl.

R ¹ may also, in particular, be halogen, in particular fluorine and chlorine.

R ¹ may also, in particular, be lower alkyl (e.g. methyl), especially when X ¹ is N.

R ¹ may also, in particular, be lower alkoxy (e.g. methoxy), in particular when X ¹ is N.

X ¹ may in particular be CR ¹⁰ , in particular where R ¹⁰ is lower alkyl or lower alkoxy (e.g. methyl or methoxy).

X ¹ may also, in particular, denote N.

X ² may in particular be CR ¹⁰ , in particular where R ¹⁰ is lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), lower alkylthio (e.g. methylthio), lower alkylsulfinyl (e.g. , methylsulfinyl) or lower alkylsulfonyl (e.g. methylsulfonyl).

X ³ may, in particular, mean CH.

X ³ may also, in particular, mean N.

X ⁶ may in particular be CR ¹⁰ and preferably CH.

One of X ⁴ and X ⁵ may, in particular, denote CR ¹¹ , and the other denotes CR ¹⁰ , in particular CH.

Within R ^{11, the} group L ¹ may, in particular, be an —R ² -R ³ -bridge, where R ² is a straight or branched chain C _1-6 alkylene, especially a straight or branched chain C _1-4 alkylene, and R ³ denotes (a) —C (= Z) —NR ⁴ -, preferably —C - (= O) —NH—, or (b) —Z ¹ -, preferably —O—.

Within R ¹¹ , the Ar ¹ group may, in particular, mean (a) optionally substituted arylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, or (b) optionally substituted heteroaryldiyl, such as optionally substituted pyridinediyl preferably p-pyridinediyl, more preferably pyridin-2,5-diyl. Preferred optional substituents include C _1-4 alkyl, especially methyl, and C _1-4 alkoxy, especially methoxy.

Within R ¹¹ , the L ² group may, in particular, mean (a) a direct chemical bond, (b) an optionally substituted alkylene bridge, in particular an optionally substituted ethylene, (c) an unsubstituted alkenylene bridge, in particular vinyl, or (d) -Z ^{A 2} -R ⁹ bridge, such as —O — CH ₂ -, —S (O) _n —CH ₂ -, —S (O) _n —CH ₂ —CH ₂ -, or, in particular, —NH — CH ₂ -. Preferred optional substituents in (b) include lower alkyl (e.g. methyl), aryl, heteroaryl, —N (R ¹² ) —C (= O) —R ¹³ , —N (R ¹² ) —C (= O) - OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , —NY ¹ Y ^2, and - [C (= O) —N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] pC (= O ) -NY ¹ Y ² . L ² preferably denotes a group

where R ⁴ is hydrogen or lower alkyl (e.g. methyl) and R ¹⁵ is lower alkyl (e.g. methyl) or where R ⁴ is hydrogen and R ¹⁵ is aryl, heteroaryl, -N (R ¹² ) -C (= O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , - [C (= O) —N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] pC (= O) -NY ¹ Y ² . L ² more preferably denotes a group

in particular

where K ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —NT (R ¹² ) —SO ₂ —R ^13, or - NY ¹ Y ² .

Within R ¹¹ , the Y group may, in particular, mean a carboxy or acidic bioisostere.

It will be appreciated that the present invention encompasses all suitable combinations of the particular merits and preferred groups mentioned herein.

A particular group of compounds of the invention are compounds of formula (Ia)

where R ¹ , R ² , L ² , X ¹ , X ² , X ³ and Y are as defined above, Ar ¹ is arylene and —R ² —C (═O) —NH — Ar ¹ —L ² —Y is attached to the ring at position 3 or 4, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of the compounds of formula (Ia) and their prodrugs.

Compounds of formula (Ia) in which R ¹ is hydrogen are preferred.

Compounds of formula (Ia) in which R ² is a straight or branched C _1-6 alkylene chain, especially a straight or branched C _1-4 alkylene chain, more particularly methylene, are preferred.

Compounds of formula (Ia) in which Ar ¹ is optionally substituted arylene, in particular optionally substituted m- or p-phenylene, in particular optionally substituted p-phenylene, are preferred. Preferred substituents for Ar ¹ include C _1-4 alkyl and C _1-4 alkoxy, in particular methyl or methoxy.

Compounds of formula (Ia) in which L ² is an optionally substituted alkylene bridge, in particular ethylene or substituted ethylene, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), aryl, heteroaryl, -N (R ¹² ) -C (= O) -R ¹³ , -N (R ¹² ) -C (= O) -OR ¹³ , - N (R ¹² ) -SO ₂ -R ¹³ , -NY ¹ Y ² or - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] pC (= O) -NY ¹ Y ² . Particularly preferred are compounds of formula (Ia) in which L ² is

where R ⁴ is hydrogen or lower alkyl (for example methyl) and R ¹⁵ is lower alkyl (for example methyl), or where R ⁴ is hydrogen and R ¹⁵ is aryl, heteroaryl, —N (R ¹² ) —C ( = O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , —NY ¹ Y ^2, and - [C (= O) - N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] pC (= O) -NY ¹ Y ² .

Particularly preferred are compounds of formula (Ia) in which L ² is

especially

where R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ^13, or - NY ¹ Y ² .

Compounds of formula (Ia) in which X ¹ is CR ¹⁰ , in particular where R ¹⁰ is lower alkyl or lower alkoxy (e.g. methyl or methoxy), are preferred.

Also preferred are compounds of formula (Ia) in which X ² is CR ¹⁰ , in particular where R ¹⁰ is lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), lower alkylthio (e.g. methylthio), lower alkylsulfinyl (e.g. methylsulfinyl) or lower alkylsulfonyl (e.g. methylsulfonyl).

Compounds of formula (Ia) in which X ³ is CH are also preferred.

Compounds of formula (Ia) in which Y is carboxy are also preferred.

The group —R ² —C (═O) —NH — Ar ¹ —L ² —Y may preferably be attached to the ring at position 4.

A preferred group of compounds of the invention are compounds of formula (Ia) in which R ¹ is hydrogen; R ² is a straight or branched chain C _1-4 alkylene (especially methylene), Ar ¹ is an optionally substituted arylene [in particular p-phenylene and methyl (or methoxy) substituted p-phenylene]; L ² denotes a substituted alkylene bridge [in particular,

where R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ^13, or - NY ¹ Y ² ]; X ¹ and X ² are CR ¹⁰ (especially where R ¹⁰ is methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl); X ³ is CH; Y is carboxy and the group —R ² —C (═O) —NH — Ar ¹ —L ² —Y is attached to the ring at position 4, and the corresponding N-oxides and their prodrugs; pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds, their N-oxides and prodrugs.

Also preferred are compounds of formula (Ia) in which R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , in particular where R ¹² is hydrogen or lower alkyl (e.g. methyl) and R ¹³ is lower alkyl (e.g. methyl), aryl (e.g., optionally substituted phenyl), heteroaryl (e.g., optionally substituted pyridyl, optionally substituted thienyl, optionally substituted isoxazolyl, optionally substituted pyridazyl), heterocycloalkyl (e.g. tetrahydropyran-4- sludge), alkyl substituted with carboxy (for example, —CH ₂ —CH ₂ —CO ₂ H and —CH ₂ —CH ₂ —CH ₂ —CO ₂ H), al a keel substituted with —NY ¹ Y ² (for example, aminomethyl and morpholin-1-ylmethyl) or alkyl substituted with alkoxyalkoxy (for example, —CH ₂ —O — CH ₂ —CH ₂ —O — CH ₃ ).

Also preferred are compounds of formula (Ia) in which R ¹⁵ is —N (R ¹² ) —C (═O) —OR ¹³ , in particular where R ¹² is hydrogen or lower alkyl (e.g. methyl) and R ¹³ is lower alkyl (e.g. ethyl) or alkyl substituted with aryl (e.g. benzyl).

Also preferred are compounds of formula (Ia) in which R ¹⁵ is —N (R ¹² ) —SO ₂ —R ¹³ , especially where R ¹² is hydrogen or lower alkyl (e.g. methyl) and R ¹³ is lower alkyl ( for example methyl), aryl [for example, optionally substituted phenyl or optionally substituted naphthyl (in particular dimethylaminonaphth-1-yl)]), heteroaryl (for example, optionally substituted pyridyl or optionally substituted imidazolyl).

Also preferred are compounds of formula (Ia) in which R ¹⁵ is —NY ¹ Y ² , in particular where Y ¹ and Y ² are hydrogen.

Also preferred are compounds of formula (Ia) in which R ¹⁵ is —NY ¹ Y ² , in particular where Y ¹ is hydrogen and Y ² is either lower alkyl (e.g., propyl) or alkyl substituted with aryl (e.g. , —CH ₂ —Ph, —CH (CH ₃ ) —Ph or —CH ₂ —CH ₂ —Ph).

Particularly preferred are those compounds of formula (Ia) in which R ¹⁵ is —NH ₂ ,

Another particular group of compounds of the invention are compounds of formula (Ib)

where R ¹ , R ² , L ² , X ¹ , X ² , X ^3, and Y are as defined above, Ar ¹ is heteroaryldiyl and —R ² —C (═C) —NH — Ar ¹ —L ² —Y is attached to the ring at position 3 or 4, their prodrugs and pharmaceutically acceptable salts, solvates (e.g. hydrates) of the compounds of formula (Ib) and their prodrugs.

Compounds of formula (Ib) in which R ¹ is hydrogen are preferred.

Compounds of formula (Ib) are preferred in which R ² is a straight or branched C _1-6 alkylene chain, especially a straight or branched C _1-4 alkylene chain, more particularly methylene.

Compounds of formula (Ib) are also preferred in which Ar ¹ is optionally substituted heteroaryldiyl, in particular optionally substituted pyridinediyl, especially optionally substituted p-pyridinediyl, preferably pyridin-2,5-diyl. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, in particular methyl or methoxy.

Preferred are compounds of formula (Ib) in which L ² is an optionally substituted alkylene bridge, in particular ethylene or substituted ethylene. Preferred optional substituents include lower alkyl (e.g. methyl), aryl, heteroaryl, -N (R ¹² ) -C (= O) -R ¹³ , -N (R ¹² ) -C (= O) -OR ¹³ , - N (R ¹² ) —SO ₂ —R ¹³ , —NY ¹ Y ² or - [C (= O) —N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] _p —C (= O) - NY ¹ Y ² .

Particularly preferred are compounds of formula (Ib) in which L ² is

where R ⁴ is hydrogen or lower alkyl (for example methyl) and R ¹⁵ is lower alkyl (for example methyl) or where R ⁴ is hydrogen and R ¹⁵ is aryl, heteroaryl, —N (R ¹² ) —C (= O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ¹³ , —NY ¹ Y ^2, and - [C (= O) —N (R ⁶ ) —C (R ⁴ ) (R ⁷ )] _p —C (= O) —NY ¹ Y ² .

Particularly preferred are compounds of formula (Ib) in which L ² is

especially

where R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —C (= O) —OR ¹³ , —N (R ¹² ) —SO ₂ —R ^13, or - NY ¹ Y ² .

Compounds of formula (Ib) in which X ¹ is CR ¹⁰ , in particular where R ¹⁰ is lower alkyl or lower alkoxy (e.g. methyl or methoxy), are preferred.

Also preferred are compounds of formula (Ib) in which X ² is CR ¹⁰ , in particular where R ¹⁰ is lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), lower alkylthio (e.g. methylthio), lower alkylsulfinyl (e.g. methylsulfinyl) or lower alkylsulfonyl (e.g. methylsulfonyl).

Compounds of formula (Ib) in which X ³ is CH are also preferred.

Compounds of formula (Ib) in which Y is carboxy are also preferred.

The group —R ² —C (═O) —NH — Ar ¹ —L ² —Y may preferably be attached to the ring at position 4.

A preferred group of compounds of the invention are compounds of formula (Ib) in which R ¹ is hydrogen; R ² is a straight or branched chain C _1-4 alkylene (in particular methylene), Ar ¹ is an optionally substituted heteroaryldiyl (in particular pyridin-2,5-diyl); L ² denotes a bridge of optionally substituted alkylene (especially ethylene) or

especially

where R ¹⁵ is methyl, aryl, heteroaryl, -N (R ¹² ) -C (= O) -R ¹³ , -N (R ¹² ) -C (= O) -OR ¹³ , -N (R ¹² ) -SO ₂ -R ¹³ or -NY ¹ Y ² and - [C (= O) -N (R ⁶ ) -C (R ⁴ ) (R ⁷ )] _p -C (= O) -NY ¹ Y ² [in particular , -N (R ¹² ) -C (= O) -R ¹³ , -N (R ¹² ) -C (= O) -OR ¹³ , -N (R ¹² ) -SO ₂ -R ¹³ or -NY ¹ Y ² ]; X ¹ and X ² are CR ¹⁰ (especially where R ¹⁰ is methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl); X ³ is CH; Y is carboxy and the group —R ² —C (═O) —NH — Ar ¹ —L ² —Y is attached to the ring at position 4, the corresponding N-oxides and their prodrugs, pharmaceutically acceptable salts and solvates (e.g. hydrates) such compounds and their N-oxides and prodrugs.

Compounds of formula (Ib) in which R ¹⁵ is —N (R ¹² ) —C (═O) —R ^{13 are} preferred, in particular where R ¹² is hydrogen or lower alkyl (e.g. methyl) and R ¹³ is lower alkyl (e.g. methyl), aryl (e.g., optionally substituted phenyl), heteroaryl (e.g., optionally substituted pyridyl, optionally substituted thienyl, optionally substituted isoxazolyl, optionally substituted pyridazyl), heterocycloalkyl (e.g. tetrahydropyran-4-yl ), alkyl, substituted carboxy (for example, —CH ₂ —CH ₂ —CO ₂ H and —CH ₂ —CH ₂ —CH ₂ —CO ₂ H), alkyl l substituted with —NY ¹ Y ² (for example, aminomethyl and morpholin-1-ylmethyl) or alkyl substituted with alkoxyalkoxy (for example, —CH ₃ —O — CH ₂ —CH ₂ —O — CH ₃ ).

Also preferred are compounds of formula (Ib) in which R ¹⁵ is —N (R ¹² ) —C (═O) —OR ¹³ , in particular where R ¹² is hydrogen or lower alkyl (e.g. methyl) and R ¹³ is lower alkyl (e.g. ethyl) or alkyl substituted with aryl (e.g. benzyl).

Also preferred are compounds of formula (Ib) in which R ¹⁵ is —N (R ¹² ) —SO ₂ —R ¹³ , in particular where R ¹² is hydrogen or lower alkyl (eg methyl), and R ¹³ is lower alkyl (for example methyl), aryl [for example, optionally substituted phenyl or optionally substituted naphthyl (especially dimethylaminonaphth-1-yl)], heteroaryl (for example, optionally substituted pyridyl or optionally substituted imidazolyl).

Also preferred are compounds of formula (Ib) in which R ¹⁵ is —NY ¹ Y ² , in particular where Y ¹ and Y ² are hydrogen.

Also preferred are compounds of formula (Ib) in which R ¹⁵ is —NY ¹ Y ² , in particular where Y ¹ is hydrogen and Y ² is either lower alkyl (e.g., propyl) or alkyl substituted with aryl (e.g. , —CH ₂ —Ph or —CH ₂ —CH ₂ —Ph).

Also preferred are compounds of formula (Ib) in which R ¹⁵ is —NY ¹ Y ² , in particular where Y ¹ and Y ^{2 are} both aryl substituted alkyl (eg, —CH ₂ —Ph or —CH (CH ₃ ) -Ph).

Particularly preferred are those compounds of formula (Ib) in which R ¹⁵ is —NH ₂ ,

More specifically, the invention relates to compounds of the general formula (I)

where X ¹ and X ² independently represent CR ¹⁰ ; R ⁴ represents a hydrogen atom or a C _1-4 alkyl group; R ¹⁰ is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl; R ¹² is hydrogen, C _1-4 alkyl or benzyl; R ¹³ is optionally substituted with C _1-6 carboxy alkyl, C _1-4 alkoxyalkoxy, —OCH ₂ CO ₂ H, —NY ¹ Y ² or one or more hydroxy groups; heteroaryl selected from imidazolyl, oxazolyl, pyridyl, thienyl and pyridazinyl, each of which is optionally substituted with carboxy or C _1-4 alkyl; heterocycloalkyl, such as tetrahydropyranyl, or aryl selected from phenyl and naphthyl, each of which may be substituted with a carboxy group, —NY ⁴ Y ^5, or one or more C _1-4 alkoxy groups, where Y ⁴ and Y ⁵ independently represent C _1-4 alkyl; R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —SO ₂ —R _13, or —MY ¹ Y ² , where Y ¹ and Y ² independently represent hydrogen, C _{1 -4} alkyl or arylC _1-4 alkyl, or the group -NY ¹ Y ² may form a 5-6 membered cyclic amine which may contain an additional heteroatom selected from O or NY ³ [where Y ³ is —C (= O) - OR ¹⁴ (where R ¹⁴ is C _1-4 alkyl) or C _1-4 alkyl]; Ar ¹ denotes unsubstituted phenylene, their N-oxides, ester derivatives, as well as their pharmaceutical salts and solvates.

Noteworthy compounds of the invention are selected from the group consisting of the following compounds:

(5- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) thioacetic acid;

3- (5- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) propanoic acid;

3- (5- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) -2-methylpropanoic acid;

3- (6- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-3-yl) propanoic acid;

3-acetylamino-3- (6- {2-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (3,4-dimethoxybenzoylamino) -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid ;

N- [2-carboxy-1- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethyl] terephthalamic acid ;

3-benzoylamino-3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3 - [(tetrahydropyran-4-carbonyl) amino ] propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3 - [(pyridazine-3-carbonyl) amino ] propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3 - [(thiophen-2-carbonyl) amino ] propionic acid;

N- [2-carboxy-1- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethyl] succinic acid ;

4- [2-carboxy-1- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethylcarbamoyl] butyric acid ;

3- (2-aminoacetylamino) -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid ;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- (2-morpholin-4-ylacetylamino) - propionic acid;

3- [2- (2-methoxyethoxy) -acetylamino] -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl ) -propionic acid;

3-methanesulfonylamino-3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- (pyridin-3-sulfonylamino) propionic acid ;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- (1-methyl-5H-imidazole-4 -sulfonylamino) -propionic acid;

3-acetylamino-3- {6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl} propionic acid;

3- (3,4-dimethoxy-benzoylamino) -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl ] propionic acid;

N- {2-carboxy-1- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] ethyl } Lamic acid terefta;

3-benzoylamino-3- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] propionic acid;

3- [6- {2 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3 - [(tetrahydro-pyran -4-carbonyl) amino] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3 - [(pyridazin-3-carbonyl) amino] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3 - [(thiophen-2-carbonyl) amino] propionic acid;

N- {2-carboxy-1- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] ethyl} - succinic acid;

4- {2-carboxy-1- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] ethylcarbamoyl} - butyric acid;

3- (2-aminoacetylamino) -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- (2-morpholin-4-yl-acetylamino ) -propionic acid;

3- [2- (2-methoxyethoxy) -acetylamino] -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3 -yl] propionic acid;

3-methanesulfonylamino-3- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- (pyridin-3-sulfonylamino) - propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- (1-methyl-5H-imidazole -4-sulfonylamino) propionic acid;

3- (acetylmethylamino) -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3 - [(3,4-dimethoxybenzoyl) methylamino] -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl ) -propionic acid;

N- [2-carboxy-1- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethyl] -N- methyl terephthalamic acid;

3- (benzoylmethylamino) -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- [methyl (tetrahydropyran-4-carbonyl) - amino] propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- [methyl (pyridazin-3-carbonyl) - amino] propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- [methyl (thiophen-2-carbonyl) - amino] propionic acid;

N- [2-carboxy-1- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethyl] -N- methyl succinic acid;

4 - {[2-carboxy-1- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethyl] methylcarbamoyl } butyric acid;

3- (aminoacetylmethylamino) -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- [methyl (morpholin-4-ylacetyl) - amino] propionic acid;

3 - {[(2-methoxyethoxy) acetyl] methylamino} -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3 -yl) propionic acid;

3- (methanesulfonylmethylamino) -3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- [methyl (pyridin-3-sulfonyl) - amino] propionic acid;

3- (6- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) -3- [methyl (1-methyl-5H-imidazole -4-sulfonyl) amino] propionic acid;

3-acetylamino-3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (3,4-dimethoxybenzoylamino) -3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

N- [2-carboxy-1- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethyl] terephthalamic acid;

3-benzoylamino-3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3 - [(tetrahydropyran-4-carbonyl) amino] -3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid ;

3 - [(pyridazine-3-carbonyl) amino] -3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid ;

3 - [(thiophen-2-carbonyl) amino] - (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

N- [2-carboxy-1- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethyl] succinic acid;

4- [2-carboxy-1- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) ethylcarbamoyl] butyric acid;

3- (2-aminoacetylamino) -3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (2-morpholin-4-ylacetylamino) -3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- [2- (2-methoxyethoxy) acetylamino] -3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid ;

3-methanesulfonylamino-3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (pyridin-3-sulfonylamino) - (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) propionic acid;

3- (1-methyl-5H-imidazole-4-sulfonylamino) -3- (6- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-3-yl) - 3-propionic acid;

3- (acetylmethylamino) -3- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] propionic acid;

3 - [(3,4-dimethoxybenzoyl) methylamino] -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3 -yl] propionic acid;

N- {2-carboxy-1- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] ethyl} - N-methyl terephthalamic acid;

3- (benzoylmethylamino) -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- [methyl (tetrahydropyran-4-carbonyl ) amino] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- [methyl (pyridazin-3-carbonyl ) amino] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- [methyl (thiophen-2-carbonyl ) amino] propionic acid;

N- {2-carboxy-1- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] ethyl} -N methyl succinic acid;

4 - ({2-carboxy-1- [6 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] ethyl} -methylcarbamoyl) -butyric acid;

3- (aminoacetylmethylamino) -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- [methyl- (morpholin-4- ethylacetyl) amino] propionic acid;

3 - {[(2-methoxyethoxy) -acetyl] methylamino} -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridine -3-yl] propionic acid;

3- (methanesulfonylmethylamino) -3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- [methyl (pyridin-3-sulfonyl ) amino] propionic acid;

3- [6 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-3-yl] -3- [methyl- (1-methyl- 5H-imidazole-4-sulfonyl) amino] propionic acid;

3-acetylamino-3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (3,4-dimethoxybenzoylamino) -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid ;

N- [2-carboxy-1- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethyl] terephthalamic acid ;

3-benzoylamino-3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3 - [(tetrahydropyran-4-carbonyl) amino] propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3 - [(pyridazine-3-carbonyl) amino ] propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3 - [(thiophen-2-carbonyl) amino ] propionic acid;

N- [2-carboxy-1- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethyl] succinic acid ;

4- [2-carboxy-1- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethylcarbamoyl] butyric acid ;

3- (2-aminoacetylamino) -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- (2-morpholin-4-yl-acetylamino) - propionic acid;

3- [2- (2-methoxyethoxy) -acetylamino] -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl ) -propionic acid;

3-methanesulfonylamino-3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- (pyridin-3-sulfonylamino) propionic acid ;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- (1-methyl-5H-imidazole-4 -sulfonylamino) -propionic acid;

3-acetylamino-3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid;

3- (3,4-dimethoxybenzoylamino) -3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] - propionic acid;

N- {2-carboxy-1- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] ethyl} - terephthalamic acid;

3-benzoylamino-3- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3 - [(tetrahydropyran-4-carbonyl) amino] propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3 - [(pyridazin-3-carbonyl) amino] propionic acid;

3- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3 - [(thiophen-2-carbonyl) amino] propionic acid;

N- {2-carboxy-1- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] ethyl} - succinic acid;

4- {2-carboxy-1- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] ethylcarbamoyl} - butyric acid;

3- (2-aminoacetylamino) -3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid ;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- (2-morpholin-4-yl-acetylamino ) -propionic acid;

3- [2- (2-methoxy-ethoxy) -acetylamino] -3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridine -2-yl] propionic acid;

3-methanesulfonylamino-3- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- (pyridin-3-sulfonylamino) - propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- (1-methyl-5H-imidazole -4-sulfonylamino) propionic acid;

3- (acetylmethylamino) -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3 - [(3,4-dimethoxybenzoyl) methylamino] -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl ) -propionic acid;

N- [2-carboxy-1- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethyl] -N- methyl terephthalamic acid;

3- (benzoylmethylamino) -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- [methyl (tetrahydropyran-4-carbonyl) - amino] propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- [methyl (pyridazin-3-carbonyl) - amino] propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- [methyl (thiophen-2-carbonyl) - amino] propionic acid;

N- [2-carboxy-1- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethyl] -N- methyl succinic acid;

4 - {[2-carboxy-1- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethyl] methylcarbamoyl } butyric acid;

3- (aminoacetylmethylamino) -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- [methyl (morpholin-4-ylacetyl) - amino] propionic acid;

3 - {[(2-methoxyethoxy) acetyl] methylamino} -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2 -yl) propionic acid;

3- (methanesulfonylmethylamino) -3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (5- (2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- [methyl (pyridin-3-sulfonyl) - amino] propionic acid;

3- (5- {2- [3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) -3- [methyl- (1-methyl-5H- imidazole-4-sulfonyl) amino] propionic acid;

3-acetylamino-3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (3,4-dimethoxybenzoylamino) -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

N- [2-carboxy-1- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethyl] terephthalamic acid;

3- (benzoylamino) -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3 - [(tetrahydropyran-4-carbonyl) amino] -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid ;

3 - [(pyridazin-3-carbonyl) amino] -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid ;

3 - [(thiophen-2-carbonyl) amino] -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid ;

N- [2-carboxy-1- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethyl] succinic acid;

4- [2-carboxy-1- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) ethylcarbamoyl] butyric acid;

3- (2-aminoacetylamino) -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (2-morpholin-4-yl-acetylamino) -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- [2- (2-methoxyethoxy) acetylamino] -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid ;

3-methanesulfonylamino-3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (pyridin-3-sulfonylamino) -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) propionic acid;

3- (1-methyl-5H-imidazole-4-sulfonylamino) -3- (5- {2- [4- (3- (2-methylphenyl) ureido) phenyl] acetylamino} pyridin-2-yl) - propionic acid;

3- (acetylmethylamino) -3- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid;

3 - [(3,4-dimethoxybenzoyl) methylamino] -3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2 -yl] propionic acid;

N- {2-carboxy-1- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] ethyl} - N-methyl terephthalamic acid;

3- (benzoylmethylamino) -3- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- [methyl (tetrahydropyran-4-carbonyl ) amino] propionic acid;

3- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- [methyl (pyridazin-3-carbonyl ) amino] propionic acid;

3- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- [methyl (thiophen-2-carbonyl ) amino] propionic acid;

N- {2-carboxy-1- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] ethyl} - N-methylsuccinamic acid;

4 - ({2-carboxy-1- [5 - ({[[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] ethyl} -methylcarbamoyl) -butyric acid;

3- (aminoacetylmethylamino) -3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- [methyl (morpholin-4-yl -acetyl) -amino] propionic acid;

3 - {[(2-methoxyethoxy) acetyl] methylamino} -3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridine -2-yl] propionic acid;

3- (methanesulfonylmethylamino) -3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- [methyl (pyridin-3-sulfonyl ) amino] propionic acid;

3- [5 - ({[3-methoxy-4- (3- (2-methylphenyl) ureido) phenyl] acetyl} methylamino) pyridin-2-yl] -3- [methyl- (1-methyl- 5H-imidazole-4-sulfonyl) amino] propionic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (methanesulfonylamino) propanoic acid;

3- (acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (benzoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (3-pyridylacetylamino) propanoic acid;

3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (n-butylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3-benzylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (2-phenylethylamino) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (morpholin-4-yl) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (4-methylpiperazin-1-yl) propanoic acid;

3- (N-acetyl-N-methylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetyl-N-methylamino} phenyl) propionic acid;

3-benzyloxycarbonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3-phenylsulfonylamino-3- (4- (3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (pyridin-3-sulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (5-dimethylamino-1-naphthalenesulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (3-carboxypropanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (1-methylimidazol-4-ylsulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (N-acetylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (N-methanesulfonylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (morpholin-1-yl-acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (acetylamino) -3- (4- {3-methylthio-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (acetylamino) -3- (4- {3-methylsulfinyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (acetylamino) -3- (4- {3-methylsulfonyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- [2- (2-methoxyethoxy) acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(5-methylisoxazole-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(4-carboxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(pyridazine-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(pyridazin-3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4-carboxy-3,3-dimethylbutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (benzoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4-carboxybutanoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- [4 - ({3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetyl} -N-methylamino) phenyl] butanoic acid;

3 - [(4-carboxypyridin-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- [2,2-di (hydroxymethyl) propanoylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- [2- (carboxymethyloxy) -acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(1-carboxymethyl-piperidin-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- [2- (4-methylpiperazin-1-yl) -acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (pyrrolidin-1-yl) -3- [4 - ({4- [3- (2-methylphenyl) ureido] phenylacetyl} methylamino) phenyl] propanoic acid;

3- (N-acetylmethylamino) -3- [4 - ({4- [3- (2-methylphenyl) ureido] phenylacetyl} methylamino) phenyl] propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -5- (4-methylpiperazin-1-yl) -5-oxopentanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -5- (morpholin-4-yl) -5-oxo-pentanoic acid

and corresponding N-oxides and their prodrugs; pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

A group of preferred compounds of the invention includes:

3- (5- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) propanoic acid;

3- (6- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-3-yl) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (methanesulfonylamino) propanoic acid;

3- (acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (benzoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (3-pyridylacetylamino) propanoic acid;

3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (n-butylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3-benzylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (2-phenylethylamino) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (morpholin-4-yl) propanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (4-methylpiperazin-1-yl) propanoic acid;

3- (N-acetyl-N-methylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetyl-N-methylamino} phenyl) propionic acid;

3-benzyloxycarbonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3-phenylsulfonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (pyridin-3-sulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (5-dimethylamino-1-naphthalenesulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (3-carboxypropanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (1-methylimidazol-4-ylsulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (N-acetylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propionic acid;

3- (N-methanesulfonylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propionic acid;

3- (morpholin-1-yl-acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (acetylamino) -3- (4- {3-methylthio-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (acetylamino) -3- (4- {3-methylsulfinyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (acetylamino) -3- (4- {3-methylsulfonyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- [2- (2-methoxyethoxy) acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(5-methylisoxazole-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(thiophen-2-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(4-carboxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(pyridazin-3-carbonyl) amino] -3- (4- (3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3 - [(pyridazin-3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4-carboxy-3,3-dimethylbutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (benzoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- (4-carboxybutanoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

3- [4 - ({3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetyl} -N-methylamino) phenyl] butanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -5- (4-methylpiperazin-1-yl) -5-oxopentanoic acid;

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -5- (morpholin-4-yl) -5-oxopentanoic acid

and corresponding N-oxides and their prodrugs; pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of the invention include

(R) -3-acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenyl] acetylamino} phenyl) propanoic acid;

(R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3- (3-carboxypropanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3-benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3- [2- (2-methoxyethoxy) acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3 - [(5-methylisoxazole-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid ;

(R) -3 - [(thiophen-2-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3 - [(4-carboxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3- (4-carboxy-3,3-dimethylbutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3- (benzoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid;

(R) -3- (4-carboxybutanoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid

and corresponding N-oxides and their prodrugs; pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

The compounds of the invention have beneficial pharmacological effects and are therefore included in pharmaceutical compositions and are used to treat patients suffering from a particular disease. Thus, according to another aspect, the present invention discloses the use in the treatment of the compounds of the invention and compositions containing the compounds of the invention.

Compounds covered by the scope of the present invention and the attached items, according to the tests described in the literature and the in vitro and in vivo test methods described here, block the interaction of the VCAM-1 ligand with its integrin receptor VLA-1 (α 4β 1), these test results correlate with pharmacological activity in humans and other mammals. Thus, in a further embodiment of the practical embodiment, the present invention provides compounds of the invention and compositions containing the compounds of the invention for use in the treatment of patients suffering from diseases or prone to diseases that can be facilitated by the administration of an α 4β 1 mediated cell adhesion inhibitor. For example, the compounds of the invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritis conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, arthritis after measles, rubella, psoriatic arthritis and osteoarthritis. In addition, the compounds are suitable for the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriatic restenosis, myocarditis, inflammatory bowel disease and melanoma cell division metastases.

A particular embodiment of the therapeutic methods of this invention is the treatment of asthma.

Another particular embodiment of the therapeutic methods of this invention is the treatment of joint inflammation.

Another particular embodiment of the therapeutic methods of this invention is the treatment of inflammatory bowel diseases.

According to another distinctive feature of the present invention, a method for treating patients, humans or animals suffering from diseases or prone to diseases, the symptoms of which can be improved by the introduction of an inhibitor of the interaction of the ligand VCAM-1 with its integrin receptor VLA-1 (α 4β 1), as for, for example, the above diseases, the method comprises administering to the patient an effective amount of a compound of the invention or a composition containing a compound of the invention. It is understood that an “effective amount” corresponds to an amount of a compound of the invention effective in inhibiting the interaction of the VCAM-1 ligand with its integrin receptor VLA-1 (α 4β 1), and therefore, in providing the desired therapeutic effect.

It is understood that the reference to treatment includes, in addition to preventive therapy, treatment of existing conditions.

The present invention also encompasses pharmaceutical compositions comprising at least one of the compounds of the invention in combination with a pharmaceutically acceptable carrier or excipient.

The compounds of the invention may be administered by any suitable means. In practice, the compounds of the invention can be administered parenterally, topically, rectally, orally or by inhalation, especially by oral route.

The compositions of the invention can be prepared by conventional methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, but are not limited to, diluents, a sterile aqueous medium, and various non-toxic organic solvents. The compositions may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, solutions for injection, elixirs or syrups, and may contain one or more agents that are selected from the group consisting of sweeteners, flavoring agents, coloring agents or stabilizers, to get pharmaceutically acceptable drugs. The choice of the environment for the drug and the content of the active substance in it is usually carried out in accordance with the solubility and chemical properties of the active compound, the specific route of administration and taking into account the precautions that must be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc. To obtain capsules, it is convenient to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used, they may contain emulsifying agents or suspension promoting agents. Diluents, such as sucrose, ethanol, polyethylene glycol, glycerin and chloroform, or mixtures thereof, may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products of the invention in vegetable oil are used, for example, sesame oil, peanut oil or olive oil, or aqueous-organic solutions, such as in water and propylene glycol, in injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of pharmaceutically acceptable salts. The salt solutions of the products of the invention are particularly suitable for administration by intramuscular or subcutaneous injection. Aqueous solutions, including salt solutions in pure distilled water, can be used for intravenous administration provided that their pH is adjusted to a reasonable extent, that they contain a reasonable buffer and are isotonic with sufficient glucose or sodium chloride and that they sterilized by heating, irradiation or microfiltration.

For topical administration, gels (with an aqueous or alcoholic base), creams or ointments containing the compounds of the invention can be used. The compounds of the invention can also be incorporated into a gel or matrix base for application to a patch, which enables controlled release of the compound through the transdermal barrier.

For administration by inhalation, the compounds of the invention may be dissolved or suspended in a suitable vehicle for use in a nebulizer or aerosol suspension or solution, or may be absorbed or adsorbed on a suitable solid vehicle for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositories formulated in accordance with well-known methods and containing at least one compound of the invention.

The percentage of active ingredient in the compositions according to the invention may vary, it is necessary that it be an amount that allows you to get a suitable dosage. Obviously, several forms of standardized, unit doses can be administered at approximately the same time. The dose used is determined by the attending physician and depends on the desired therapeutic effect, method of administration and duration of treatment and the patient's condition. For adults, the dose is usually from about 0.001 to 50, preferably from about 0.001 to 5, mg / kg of body weight per day with inhalation, from about 0.01 to 100, preferably from about 0.1 to 70, in particular from 0, 5 to 10 mg / kg body weight per day for oral administration and from about 0.001 to 10, preferably about 0.01 to 1 mg / kg body weight per day for intravenous administration. In each case, the dose is determined in accordance with factors specific to the patient in need of treatment, such as age, weight, general health and other characteristics that may affect the effectiveness of the drug.

The compounds of the invention can be administered as often as necessary in order to obtain the desired therapeutic effect. Some patients may respond quickly to a larger or smaller dose and may find a weaker maintenance dose sufficient. For other patients, it may be necessary to undergo prolonged treatment at a rate of 1 to 4 doses daily, according to the physiological needs of each individual patient. Typically, the active product can be administered orally 1-4 times a day. Of course, some patients need to prescribe no more than one or two doses per day.

The compounds of the invention can be prepared by the application or adaptation of known methods, which are understood to mean the methods previously used or described in the literature, for example, the methods described by R. C. Larok in Comprehensive Organic Transformations, VCH publishers, 1989.

In the reactions described below, it may be necessary to protect reactive functional groups, for example, hydroxy, amino, imino, thio or carboxy groups, when they need to be stored in the final product in order to avoid their undesirable participation in the reactions. Conventional protecting groups can be used according to standard procedures, for example, see T.W. Green and P.G. M. Wuts in "Protective Groups in Organic Chemestry" by John Wiley and Sons, 1991.

The compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical Y in one of X ³ , X ⁴ and X ⁵ denotes carboxy, may be obtained by hydrolysis of an ester of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical Y in one of X ³ , X ⁴ and X ⁵ denotes - A CO ₂ R ¹⁶ group (where R ¹⁶ is alkyl, alkenyl or arylalkyl). The hydrolysis is conveniently carried out by alkaline hydrolysis using a base such as an alkali metal hydroxide, for example lithium hydroxide, or an alkali metal carbonate, for example potassium carbonate, in the presence of a mixture of aqueous organic solvents using organic solvents such as dioxane, tetrahydrofuran or methanol , at a temperature of approximately from ambient temperature to the distillation temperature. The hydrolysis can also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, and in the presence of a mixture of water-organic solvents using organic solvents, such as dioxane or tetrahydrofuran, at a temperature of from about 50 to 80 ° C.

As another example, the compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical Y is in one of X ³ , X ⁴ and X ⁵ denotes carboxy, can be obtained by acid-catalyzed cleavage of the tert-butyl group from the tert-butyl ester of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above meanings and where the radical Y in one of X ³ , X ⁴ and X ⁵ is a —CO ₂ R ¹⁶ group (where R ¹⁶ is tert-butyl) using standard reaction conditions, for example, by reaction with trifluoroacetic acid at tempera atura close to room.

As another example, the compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical Y in one of X ³ , X ⁴ and X ⁵ denotes carboxy can be obtained by hydrogenation of compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical Y is in one of X ³ , X ⁴ and X ⁵ represents a —CO ₂ R ¹⁶ group (wherein R ¹⁶ represents benzyl). The reaction can be carried out in the presence of ammonium formate and a suitable metal catalyst, for example palladium supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature close to the distillation temperature. Alternatively, the reaction can be carried out in the presence of a suitable metal catalyst, for example palladium, optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. This reaction is most convenient for compounds of formula (I), where L ¹ and L ² do not contain multiple carbon-carbon bonds.

As another example of a compound of formula (Ia) or (Ib), wherein R ¹ , R ² , Ar ¹ , L ² , X ¹ and X ² are as defined above, X ³ is CR ¹⁰ (where R ¹⁰ is as defined above) and Y denotes carboxy represented by formula (II) can be obtained using the method using the resins shown in scheme 1.

For example, Wang'a resin can be treated in step 1 with acids of formula (III)

O ₂ N-Ar ¹ -L ² -CO ₂ N (III)

where Ar ¹ and L ² take the above values, and with diisopropylbodiimide in dimethylformamide in the presence of dimethylaminopyridine at room temperature. The obtained esters (resin 2), where Ar ¹ and L ² take the above values, can then be treated in stage 2 with tin chloride in dimethylformamide at room temperature, which gives resin 3, where Ar ¹ and L ² take the above values. Resin 3 may then be subjected in a step 3 to a coupling reaction with an acid of general formula (IV)

where R ¹ , R ² , X ^x and X ² take the above values, and X ³ denotes CR ¹⁰ (where R ¹⁰ takes the above values), in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3 , 3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide at room temperature. The resulting resin 4, where R ¹ , R ² , Ar ¹ , L ² , X ¹ and X ² take the above values and X ³ denotes CR ¹⁰ (where R ¹⁰ takes the above values), can then be treated in stage 4 with trifluoroacetic acid in an inert solvent, such as dichloromethane, at room temperature, which results in the evolution of acids of the general formula (II), where R ¹ , R ² , Ar ¹ , L ² , X ¹ and X ² are as defined above and X ³ is CR ¹⁰ (where R ¹⁰ takes the above values).

As another example, the compounds of formula (Ib), where R ¹ , R ² , Ar ¹ , X ¹ and X ² take the above values, L ² denotes a -Z ² -R ⁹ bridge [where R ⁹ takes the above values and Z ² is O, S or NR ⁴ (where R ⁴ is as defined above)], X ³ is CR ¹⁰ (where R ¹⁰ is as above) and Y is carboxy represented by formula (V) can be prepared using a resin technique shown in diagram 1.

Scheme 2

For example, the Wang resin of Scheme 2 can be treated in step 1 with acids of formula (VI)

where R ¹⁷ denotes Br-R ⁹ - [where R ⁹ takes the above values], and with diisopropylbodiimide in dimethylformamide or a mixture of dimethylformamide and tetrahydrofuran in the presence of dimethylaminopyridine at room temperature. The esters obtained (resin 5, where R ¹⁷ is Br-R ⁹ -) can be reacted in step 2 with compounds of formula (VII)

where Ar ¹ is heteroaryldiyl, and Z ² is O, S or NR ⁴ (where R ⁴ is as defined above), in the presence of a base such as a tertiary organic base, for example diisopropylethylamine, in dimethyl sulfoxide and at a temperature close to room temperature, which gives a resin 6, where R ⁹ and Ar ¹ denotes heteroaryldiyl, and Z ² denotes O, S or NR ⁴ (where R ⁴ takes the above values). Resin 6 can then be subjected, in step 3, to a coupling reaction with an acid of general formula (IV), where R ¹ , R ² , X ¹ and X ² are as defined above and X ³ is CR ¹⁰ (where R ¹⁰ is as defined above) ), in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hessafluorophosphate and diisopropylethylamine in dimethylformamide at room temperature. The resulting resin 7 [where R ¹ , R ² , R ⁹ , X ¹ and X ² take the above values, Ar ¹ denotes heteroaryldiyl, X ³ denotes CR ¹⁰ (where R ¹⁰ takes the above values) and Z ² denotes O, S or NR ⁴ (where R ⁴ takes the above values)], can then be treated in stage 4 with trifluoroacetic acid in an inert solvent such as dichloromethane and at a temperature close to room temperature, which leads to the liberation of acids of the general formula (V), where R ¹ , R ^2, R ^9, X ¹ and X ² are ^as hereinbefore defined, Ar ¹ is a heteroaryldiyl, X ³ is CR ¹⁰ (where R ^10, n inimaet defined above) and Z ² is O, S or NR ⁴ (wherein R ⁴ is as defined above). This method is particularly suitable for preparing compounds of formula (V) wherein L ² is an —S — CH ₂ bridge.

As another example, the Wang resin of Scheme 2 can be treated in step 1 with acid chlorides of formula (VIII)

wherein R ¹⁷ is a vinyl group optionally substituted with R ⁵ in the presence of a tertiary amine such as diisopropylethylamine in an inert solvent such as dichloromethane at a temperature close to room temperature. The resulting optionally substituted vinyl ester (resin 5, where the vinyl group is optionally substituted with R ⁵ ) can then be reacted with compounds of formula (VII), wherein Ar ¹ is heteroaryldiyl and Z ² is S, in the presence of a base such as a tertiary organic base, to for example, diisopropylethylamine, in dimethyl sulfoxide and at room temperature, to form resin 6 [where Ar ¹ is heteroaryldiyl, R ⁹ is ethylene (optionally substituted with R ⁵ ) and Z ² is S]. Resin 6 may then undergo a coupling reaction with an acid of general formula (IV), wherein R ¹ , R ² , X ¹ and X ² are as defined above and X ³ is CR ¹⁰ (where R ¹⁰ is as defined above) in the presence of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium gesafluorophosphate and diisopropylethylamine in dimethylformamide at room temperature. The resulting resin 7 [where R ¹ , R ² , X ¹ and X ² are as defined above, Ar ¹ is heteroaryldiyl, R ⁹ is ethylene (optionally substituted by R ⁵ ), X ³ is CR ¹⁰ (where R ¹⁰ is as above) and Z ² denotes S] can then be treated with trifluoroacetic acid in an inert solvent, such as dichloromethane, and at a temperature close to room temperature, which results in the isolation of acids of the general formula (V), where R ¹ , R ² , X ¹ and X ² take the above values, Ar ¹ is heteroaryldiyl, R ⁹ is ethylene (optionally substituted R ⁵ ), X ³ is CR ¹⁰ (where R ¹⁰ is as defined above) and Z ² is S.

As another example, the compounds of formula (Ia) or (Ib), where R ¹ , R ² , L ² , Ar ¹ , X ¹ and X ² take the above values and X ³ denotes CR ¹⁰ (where R ¹⁰ takes the above values) , a Y is carboxy, can be obtained by the reaction of a combination of acids of formula (IV), where R ¹ , R ² , X ¹ and X ² take the above values and X ³ is CR ¹⁰ (where R ¹⁰ takes the above values) with amines of the formula (Ix)

H ₂ N-Ar ¹ -L ² -CO ₂ H (IX)

where Ar ¹ and L ² take the above values, using standard conditions of combination, for example, the conditions indicated above.

As another example, the compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ² and Y in one of X ³ , X ⁴ and X ⁵ represent an alkylene bridge substituted with —CONY ¹ Y ² and carboxy, respectively, and can be prepared by the reaction of compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ^5, and X ⁶ are as hereinbefore defined and where the radicals L ² and Y in one of X ^3, X ⁴ and X ⁵ represent an alkylene bridge substituted with -CO ₂ H and carboxy respectively, with anhydride, such as trifluoroacetic anhydride, in an inert solvent, for example tet agidrofurane, followed by treatment with NNY ¹ Y ^2.

According to another aspect of the present invention, the compounds of the invention can be prepared by interconversion of other compounds of the invention.

For example, the compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical Y in one of X ³ , X ⁴ and X ⁵ means - C (= O) -NHOH can be obtained by the reaction of compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical Y is in one of X ³ , X ⁴ and X ⁵ are carboxy, with hydroxylamine using standard peptide coupling (condensation) techniques, such as treatment with carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine in an inert solvent such as di chloromethane or tetrahydrofuran, at a temperature close to room temperature. The combination can also be carried out using 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in dichloromethane at room temperature. The preparation of the compound can also be carried out using an O-protected hydroxylamine such as O- (trimethylsilyl) hydroxylamine, O- (tert-butyldimethylsilyl) hydroxylamine or O- (tetrahydropyranyl) hydroxylamine, followed by acid treatment.

As an example of the interconversion process, compounds of formula (I) containing sulfoxide bridges can be obtained by oxidation of the corresponding compounds containing —S-bridges. For example, oxidation is usually carried out by reaction with an acid, for example 3-chloroperbenzoic acid, preferably in an inert solvent, for example dichloromethane, preferably at a temperature close to room temperature, or otherwise, by reaction with potassium peroxomonosulfate in an environment, such as methanol, adjusted to pH 5 with a buffer, at temperatures from 0 ° C to room temperature. This latter method is preferred for compounds containing a labile acid group.

As another example of an interconversion process, compounds of formula (I) containing sulfoxide bridges can be prepared by oxidizing the corresponding compounds containing —S— or sulfoxide bridges. For example, oxidation is usually carried out by reaction with an acid, for example 3-chloroperbenzoic acid, preferably in an inert solvent, for example dichloromethane, preferably at a temperature close to room temperature.

As another example of a method of interconversion, the compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical L ² in one of X ³ , X ⁴ and X ⁵ denotes an optionally substituted alkylene bridge, can be obtained by hydrogenation of the corresponding compounds of formula (I), where the radical L ² in one of X ³ , X ⁴ and X ⁵ denotes an optionally substituted alkenylene bridge. Hydrogenation can be carried out using hydrogen (optionally under pressure) in the presence of, for example, platinum or palladium, optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature close to room temperature.

As another example of an interconversion process, a compound of formula (I) wherein R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ^5, and X ^{6 have the} above meanings and where the radical L ^{1 is} in one of X ³ , X ⁴ and X ⁵ is an —R ² —R ³ bridge, where R ² is a straight or branched chain C _2-6 alkylene and R ³ is a direct chemical bond, can also be obtained by hydrogenation of the corresponding compounds of formula (I), in which L ¹ radical in one of X ³ , X ⁴ and X ⁵ denotes a -R ² -R ³ bridge, where R ² denotes a straight or branched chain C _2-6 alkenylene and R ³ denotes direct chemical bond.

As another example of a method of interconversion, the compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical L ² in one of X ³ , X ⁴ and X ⁵ contains an amino group, can be obtained by the reaction of compounds of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radical L ² in one of X ³ , X ⁴ and X ⁵ contain an acetamido group, with a base such as aqueous alkali metal hydroxide, for example sodium hydroxide.

As an example of the interconversion method, compounds of the invention containing a heterocyclic group, where the heteroatom is a nitrogen atom, can be oxidized to the corresponding N-oxides. The oxidation can usually be carried out by reaction with a mixture of hydrogen peroxide and an organic acid, for example acetic acid, preferably at a temperature of room temperature or higher, for example at a temperature of about 60-90 ° C. Alternatively, the oxidation can be carried out by reaction with a peracid, for example peracetic acid or m-chloroperbenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to the temperature of distillation, preferably at elevated temperature. Or, the oxidation can be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and approximately 60 ° C.

It will be appreciated that the compounds of the invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also possess geometric isomerism. It is understood that the present invention includes the individual geometric isomers and stereoisomers of the compounds of the above formula (I) and mixtures thereof, including racemic mixtures. Such isomers can be isolated from their mixtures by the application or adaptation of known methods, for example, chromatographic methods and recrystallization methods, or they can be obtained separately from the corresponding isomers of their intermediates.

According to another distinguishing feature of the invention, acid addition salts of the compounds of the invention can be prepared by reacting the free base with an appropriate acid using or adapting known methods. For example, acid addition salts of the compounds of this invention can be prepared either by dissolving the free base in water or an aqueous alcoholic solution, or in other suitable solvents containing the corresponding acid, and isolating the salt by evaporating the solution, or by reacting the free base and the acid in an organic solvent, in this case, the salts are separated directly or they can be obtained by concentration of the solution.

The compounds of the invention can be reduced from their salts using or adapting known methods. (The compounds of the invention can be reduced from their acid addition salts using or adaptation of known methods.) For example, the starting compounds of the invention can be reduced from their acid addition salts by treatment with alkali, for example, aqueous sodium bicarbonate or aqueous ammonia .

The compounds of the invention may be reduced from their basic addition salts using or adapting known methods. For example, the starting compounds of the invention can be reduced from their basic addition salts by treatment with an acid, for example hydrochloric acid.

The compounds of the present invention are conveniently prepared, or they form upon receipt according to the method of the invention, in the form of solvates (for example, hydrates). The hydrates of the compounds of this invention are conveniently prepared by recrystallization from a mixture of water and organic solvents using organic solvents such as dioxane, tetrahydrofuran or methanol.

According to another aspect of the invention, basic addition salts of the compounds of the invention can be prepared by reacting the free acid with an appropriate base using or adapting known methods. For example, basic addition salts of the compounds of this invention can be prepared either by dissolving the free acid in water or an aqueous alcoholic solution, or in other suitable solvents containing the appropriate base, and isolating the salt by evaporating the solution, or by reacting the free acid and the base in an organic solvent, in this case, the salts are separated directly or they can be obtained by concentration of the solution.

Starting materials and intermediates can be obtained by the application or adaptation of known methods, for example, by the methods described in standard examples or their obvious chemical equivalents.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above meanings and where the radicals L ¹ and Y in one of X ³ , X ⁴ and X ⁵ denote The —R ² —R ³ bridge (where R ² is as defined above and R ³ is —C (= O) —NH—) and —CO ₂ R ^{16 is a} group (where R ¹⁶ is as defined above) can be obtained respectively reactions of compounds of formula (1)

where R ¹ , X ¹ , X ² and X ⁶ take the above values and one of X ⁷ , X ⁸ and X ⁹ denotes CR ¹⁸ [where R ¹⁸ denotes -R ² -C (= O) X ¹⁰ (where R ² takes the above values and X ¹⁰ denotes a hydroxyl group or a halogen atom, preferably a chlorine atom)], and others independently represent N or CR ¹⁰ (where R ¹⁰ takes the above values), with amines of the formula (2)

where R ¹ , R ¹⁶ , Ar ¹ and L ² take the above values. When X ¹⁰ is a hydroxyl group, the reaction can be carried out using the above standard peptide coupling techniques. When X ¹⁰ is a halogen atom, the reaction can be carried out with a base such as pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature close to room temperature.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above meanings and where the radicals L ¹ and Y in one of X ³ , X ⁴ and X ⁵ denote —R ² —R ^{3 is a} bridge [where R ² is as defined above and R ³ is —NR ⁴ —C (= O) - (where R ⁴ is as defined above) and —CO ₂ R ^{16 is a} group (where R ¹⁶ is as the above values), respectively, can be obtained by the reaction of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is -R ⁴ -NHR ² (wherein R ² and R ⁴ are as defined above)], and others Irrespective denote N or CR ¹⁰ (where R ¹⁰ is as defined above) with compounds of formula (3)

where R ¹⁶ , Ar ¹ , L ² , and X ¹⁰ take the above values, using the above methods for the combination of acid halides with amines.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —O—] and —CO ₂ R ¹⁶ (where R ¹⁶ is as defined above), respectively, can be prepared by the reaction of compounds of formula (1 ), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² —OH) and the others are independently N or CR ¹⁰ (wherein R ¹⁰ is as defined above) with compounds Formula (4)

where R ¹⁶ , Ar ¹ and L ² are as defined above, in the presence of a dialkyl azodicarboxylate such as diethyl azodicarboxylate and triphenylphosphine, preferably in a dry ether solvent, for example diethyl ether or tetrahydrofuran, preferably at a temperature close to room temperature. Or, esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of X ³ , X ⁴ and X ⁵ is an —R ² —R ³ bridge [where R ² is as defined above and R ³ is —O—] and a —CO ₂ R ¹⁶ group (where R ¹⁶ is as defined above), respectively, can also be prepared by alkylation of compounds of formula (4) where R ¹⁶ , Ar ¹ and L ² take the above values. The reaction can be carried out using standard alkylation conditions, for example, reaction with the corresponding alkyl bromides of the formula (I), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ denotes CR ¹⁸ [where R ¹⁸ is —R ² —Br (where R ² is the above], and others are independently N or CR ¹⁰ (where R ¹⁰ is the above).

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above meanings and where the radicals L ¹ and Y in one of X ³ , X ⁴ and X ⁵ denote —R ² —R ^{3 is a} bridge [where R ² is as defined above and R ³ is —S—] and the group is —CO ₂ R ¹⁶ (where R ¹⁶ is as defined above), respectively, can be prepared in a similar way by alkylating compounds of formula ( 5)

where R ¹⁶ , Ar ¹ and L ² take the above values.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above meanings and where the radicals L ¹ and Y in one of X ³ , X ⁴ and X ⁵ denote —R ² —R ^{3 is a} bridge [where R ² takes the above values and R ³ is —NR ⁴ - (where R ⁴ takes the above values)] and the group —CO ₂ R ¹⁶ (where R ¹⁶ takes the above values), respectively, may be obtained in a similar way by alkylation of compounds of formula (2), where R ⁴ , R ¹⁶ , Ar ¹ and L ² take the above values.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —C (= O) -] and —CO ₂ R ¹⁶ (where R ¹⁶ is as defined above), respectively, can be obtained by reaction compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² —CO ₂ R ¹⁶ (where R ² and R ¹⁶ are as defined above)] with a Grignard reagent obtained by rea ii the compounds of formula (6)

where R ¹⁶ , Ar ¹ and L ² take the above indicated values, with magnesium using standard reaction conditions.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —NR ⁴ —C (= O) —NH— (where R ⁴ is as defined above)] and —CO ₂ R ^{16 are} (where R ¹⁶ takes the above values), respectively, can be obtained by the reaction of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² —NHR ⁴ (where R ² and R ⁴ are as defined above)], and others are independently N or CR ¹⁰ (where R ¹⁰ is as defined above), with isocyanates of the formula (7)

where R ¹⁶ , Ar ¹ and L ² take the above values. The reaction is preferably carried out with a base such as a tertiary amine, for example triethylamine, preferably in a solvent such as dichloromethane and at a temperature close to room temperature.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —NH-C (= O) —NR ⁴ - (where R ⁴ is as defined above)] and —CO ₂ R ^{16 are} (where R ¹⁶ takes the above values), respectively, can also be obtained by the reaction of amines of the formula (2), where R ⁴ , R ¹⁶ , Ar ¹ and L ² take the above values, with compounds of the formula (I), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ designates Starts with CR ¹⁸ [where R ¹⁸ is —R ² —N = C = O (where R ² is as defined above)], and others are independently N or CR ¹⁰ (where R ¹⁰ is as defined above).

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —SO ₂ —NR ⁴ - (where R ⁴ is as defined above)] and the group is —CO ₂ R ¹⁶ (where R ¹⁶ is as defined above) ) respectively, can be obtained by the reaction of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² -SO ₂ Cl (wherein R ² is as defined above) and each e independently represent N or CR ¹⁰ (where R ¹⁰ is as defined above) with amines of formula (2) wherein R ^4, R ^16, Ar ¹ and L ² are ^as hereinbefore defined. The reaction is preferably carried out with a base such as a tertiary amine, for example triethylamine, preferably in a solvent such as tetrahydrofuran and at a temperature close to room temperature.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ represent -R ² -R ³ -mostik [wherein R ² is as defined above and R ³ represents -NR ⁴ -SO- (wherein R ⁴ is as defined above)] and a group of -CO ₂ R ¹⁶ (wherein R ¹⁶ is as defined above) respectively, can be obtained by the reaction of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² -NHR ⁴ (wherein R ² and R ⁴ are as defined above), and Drew s independently represent N or CR ¹⁰ (where R ¹⁰ is as defined above) with sulfonyl chlorides of formula (8)

where R ¹⁶ , Ar ¹ and L ² take the above values.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —OC (= O) —O—] and —CO ₂ R ^{16 is} (where R ¹⁶ is as defined), respectively, can also be obtained by O-acylation of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ are as defined above, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ^2- OH (where R ² takes the above values), and the others independently represent N il and CR ¹⁰ (where R ¹⁰ is as defined above), with compounds of formula (3), where R ¹⁶ , Ar ¹ and L ² are as defined above, X ¹⁰ is a halogen atom. The reaction can be carried out using standard O-acylation conditions, for example, a reaction with acid chlorides of the formula (3), wherein X ¹⁰ represents a chlorine atom.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —O — C (= O) —O—] and —CO ₂ R ¹⁶ (where R ¹⁶ is as defined above), respectively, may also be obtained by O-acylation of compounds of formula (4), where R ¹⁶ , Ar ¹ and L ² take the above values, with compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² —C (= O ) X ¹⁰ (where R ² takes the above values and X ¹⁰ represents a halogen atom)], and the others independently represent N or CR ¹⁰ (where R ¹⁰ takes the above values).

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —O — C (= O) —NH—] and —CO ₂ R ^{16 is} (where R ¹⁶ is as defined), respectively, be obtained by the reaction of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² —OH ( where R ² takes the above values)], and others independently represent N or CR ¹⁰ (where R ¹⁰ when takes the above values), with isocyanates of the formula (7), where R ¹⁵ , Ar ¹ and L ² take the above values. The reaction is preferably carried out with a base such as a tertiary amine, for example triethylamine, preferably in a solvent such as dichloromethane and at a temperature close to room temperature.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where the radicals L ¹ and Y in one of the groups X ³ , X ⁴ and X ⁵ are —R ² —R ³ —bridge [where R ² is as defined above and R ³ is —NH — C (= O) —O—] and —CO ₂ R ^{16 is} (where R ¹⁶ is as defined above), respectively, can also be obtained by the reaction of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² - N = C = O (where R ² takes the above values)], and others independently represent N or CR ¹⁰ (g de R ¹⁰ takes the above values), with isocyanates of the formula (4), where R ¹⁶ , Ar ¹ and L ² take the above values.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values and where one of X ³ , X ⁴ and X ⁵ denotes C-R ² -R ³ -Ar ¹ L ² -CO ₂ R ¹⁶ , where R ³ denotes a direct chemical bond, R ² denotes a straight or branched chain C _2-6 alkenylene, where the carbon-carbon double bond is directly connected to Ar ¹ , and R ¹⁶ accepts the above values can be obtained from compounds of formula (9)

where R ¹⁶ , Ar ¹ and L ² take the above values, using standard Wittig coupling techniques with the corresponding phosphorane obtained by the reaction of the corresponding compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the indicated values, one of X ⁷ , X ⁸ and X ⁹ is CR ¹⁸ [where R ¹⁸ is —R ² -Br (where R ² is a straight or branched chain C _1-5 alkenylene)], and the others are independently N or CR ¹⁰ (where R ¹⁰ takes the above values), with triphenylphosphine and subsequent base treatment using standard techniques .

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ is an alkylene bridge substituted with —NY ¹ Y ² (where one of Y ¹ and Y ² is hydrogen and the other is alkyl or alkyl substituted with alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo , —NY ¹ Y ² or one or more —CO ₂ R ¹² or —C (= O) —NY ¹ Y ² ) groups can be prepared by the reaction of esters of formula (1), where R, X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y designate starts with —CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ denotes an alkylene bridge substituted with —NH ₂ with aldehydes of the formula (10)

where R ¹⁹ denotes alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, —NY ¹ Y ² or one or more groups —CO ₂ R ¹² or —C (= O) —NY ¹ Y ² in the presence of sodium cyanoborohydride. The reaction can usually be carried out in methanol, optionally in the presence of sodium acetate and molecular sieves A4 and at a temperature close to room temperature.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ contains the group —N (R ⁴ ) —C (═O) —R ¹³ , which can be obtained by the reaction of amines of the formula (1), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y is —CO ₂ R ^16, and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ contains the group —NH (R ⁴ ), with compounds of formula (11)

where R ¹³ and X ¹⁰ take the above values. When X ¹⁰ is a hydroxyl group, the reaction can be carried out using the above standard peptide coupling techniques. When X ¹⁰ is a halogen atom, the reaction can be carried out using a base such as pyridine, preferably in a solvent such as tetrahydrofuran, and at a temperature close to room temperature.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ³ and X ⁶ take the above values, Y represents —CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ contains the group —N (R ⁴ ) —C (═O) —OR ¹³ , which can be obtained by the reaction of amines of the formula (1), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y is —CO ₂ R ^16, and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ contains the group —NH (R ⁴ ), with the corresponding chloroformate, for example, ethyl compounds (or benzyl-) chloroformate, under standard reaction conditions.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -COsR ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ contains the group —N (R ⁴ ) —SO ₂ —R ¹³ , can be prepared by the reaction of amines of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y is —CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ contains the group —NH (R ⁴ ), with the corresponding sulfonyl chloride, for example phenyl- (or pyridyl-) sulfonyl chloride , in standard reaction conditions.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ denotes

can be obtained by hydrogenation of esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of groups X ³ , X ⁴ and X ⁵ denotes

The reaction can be carried out in the presence of formic acid and a suitable metal catalyst, for example, palladium supported on an inert carrier such as carbon, at a temperature of about 60 ° C. The reaction can usually be carried out in the presence of a suitable metal catalyst, for example platinum or palladium, optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ denotes

the above values, Y is —CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ is

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ denotes

or

can also be obtained by subsequent standard recrystallization of the salts of the racemic mixture, for example, recrystallization of the salt of tartrate.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁰ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ denotes

or

can also be obtained using standard enzymatic separation techniques, for example those described by Soloshonok V.A. et.al., Tetrahedrone: Asymmetry 6 (1995), 7, 1601-1610.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ denotes

or

can be obtained by the reaction of esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one from the groups X ³ , X ⁴ and X ⁵ denotes a —CH = CH bridge, with an alkali metal hydride such as sodium hydride, in an inert solvent, for example tetrahydrofuran, at a temperature close to room temperature and subsequent reaction with the anion obtained when processing dibenzylamine, or (3) -N-benzyl-α-methylbenzylamine, butyl lithium, at a temperature of about -78 ° C.

Esters of formula (I), where R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ take the above values, Y denotes -CO ₂ R ¹⁶ and the radical L ² in one of the groups X ³ , X ⁴ and X ⁵ denotes -CH = CH-bridge, can be obtained by the reaction of compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ denotes CR ¹⁸ [where R ¹⁸ denotes -R ² -R ³ -Ar-I (where R ² , R ³ , and Ar ¹ take the above values), and others independently represent N or CR ¹⁰ (where R ¹⁰ takes the above values) with an acrylic acid ester such as tert-butyl acrylate in the presence of acetate Allada, a triarylphosphine, such as tri (2-methylphenyl) phosphine and a tertiary amine such as tributylamine, in an inert solvent such as dimethylformamide, and at a temperature of about 100 ° C.

The compounds of formula (1), where R ¹ , X ¹ , X ² and X ⁶ take the above values, one of X ⁷ , X ⁸ and X ⁹ denotes CR ¹⁸ [where R ¹⁸ takes the above values or denotes a correspondingly protected derivative), and others independently denote N or CR ¹⁰ (where R ¹⁰ takes the above values), can be obtained as described in the description of international patent application No. WO 96/22966.

The compounds of formula (2), where R ¹⁶ , Ar ¹ and L ² take the above values and R ⁴ denotes hydrogen, can be obtained by reduction of the corresponding nitro compounds. Recovery can be carried out using iron in powder and ammonium chloride in aqueous ethanol at a temperature close to the distillation temperature. Recovery can be carried out by hydrogenation using standard conditions, for example, the conditions indicated above.

Intermediate compounds of the formulas (resin 3), (resin 4), (resin 6) and (resin 7) are new compounds and as such they and the methods for their preparation described herein constitute an additional aspect of the present invention.

The present invention is further disclosed, but not limited, by the following illustrative examples and standard (reference) examples.

The mass spectrum was recorded on a Micromass Platform II mass spectrometer with an integrated electrospray source and an HP1100 liquid chromatograph using a mixture of acetonitrile and water (1: 1, with respect to volumes) as a mobile phase, flow rate 0.3 ml / min, injected volume 20 μl, working time 2.0 minutes, scanning interval 150-850 daltons positive / negative, scanning time 2.0 seconds, ESI voltage 3.5 kilovolts, ESI nitrogen pressure 20 n / m ² . Positive ions are recorded.

EXAMPLE 1

(5- {4- [3- (2-Methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) thioacetic acid

A mixture of 5-amino (pyrid-2-yl) thioacetic acid methyl ester [930 mg, standard (reference) example 1 (a)], 4- [3- (2-methylphenyl) ureido] phenylacetic acid (1, 26 g, obtained according to the description of Example 21 of international patent application No. WO 96/22966), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.69 g) and diisopropylethylamine (1, 2 g) in dimethylformamide (50 ml) was stirred at ambient temperature for 1 hour. The mixture was evaporated and then poured into water (500 ml). The resulting solid was washed with water (50 ml) and then washed twice with diethyl ether (50 ml). The solid product is suspended in methanol (100 ml), and then treated with a solution of sodium hydroxide (10 ml, 1 M). The mixture is heated at the boiling temperature under reflux for 5 hours, then cooled and evaporated. The resulting residue was treated with hydrochloric acid (200 ml, 1 M). The resulting solid was filtered, washed with water (20 ml) and then washed twice with diethyl ether (20 ml), after which it was recrystallized from ethanol to give the title compound (220 mg) as a yellow solid, mp > 235 ° C (with decomposition). MS: NH ⁺ 451.

EXAMPLE 2

(a) 3- (5- {3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) propanoic acid

A stirred mixture of ethyl 3- (5- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) propanoic acid [0.62 g, standard example 3 (a) ] and ethanol (40 ml) are treated with 4% aqueous sodium hydroxide solution (3.2 ml) and then heated to 50 ° C. After stirring at 50 ° C. for 7 hours, the reaction mixture was cooled and then left to stand at room temperature overnight. The reaction mixture was partially concentrated in vacuo, washed with diethyl ether and then acidified to pH 1.0 by adding hydrochloric acid (1 M). The resulting white solid was collected, washed with water and then dried in vacuo. Recrystallization from aqueous acetonitrile afforded the title compound (0.32 g) as a white crystalline solid, mp. 191-192 ° C (with decomposition). MS: NH ⁺ 463.

(b) By processing in a manner analogous to Example 2 (a), but using 3- (5- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) methylpropane ethyl ester acids [standard example 3 (b)], 3- (5- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) methylpropanoic acid is obtained, m.p. 196-197 ° C (with decomposition). MS: NH ⁺ 477. Elemental analysis: C 65.2; H 6.1; N, 11.6%. Calculated for C ₂₆ H ₂₈ N ₄ O ₅ : C 65.5; H 5.9; N 11, 8%].

(c) By processing in a manner analogous to Example 2 (a), but using ethyl 3- (6- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-3-yl) propane acids [standard example 3 (c)], 3- (6- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-3-yl) -propanoic acid, m.p. 175-176 ° C (with decomposition). MS: NH ⁺ 463. Elemental analysis: C 64.9; H 5.7; N, 12.1%. Calculated for C ₂₅ H ₂₆ N ₄ O ₅ : C 64.9; H 5.7; N, 12.0%].

EXAMPLE 3

(a) (R) -3- (4- {3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid

(R) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (methanesulfonylamino) propanoic acid tert-butyl ester [55 mg, standard example 6 (a)] is dissolved in anhydrous trifluoroacetic acid (2 ml) and left to stand at room temperature for 30 minutes. The reaction mixture was evaporated and the residue was triturated with diethyl ether to give the title compound (42 mg) as an amorphous white substance. MS: NH ⁺ 555. Elemental analysis: C 55.3; H 5.1; N, 9.2%. Calculated for C ₂₇ H ₃₀ N ₄ O ₇ S: C 58.5; H 5.45; N, 10.1%.

(b) By processing in a manner analogous to Example 3 (a), but using 3- (acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino tert-butyl ester} phenyl) propanoic acid [standard example 6 (b)], get 3- (acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid. MS: NH ⁺ 519.

Elemental analysis: C 61.9; H 5.05; N, 10.1%. Calculated for C ₂₈ H ₃₀ N ₄ O ₆ : C 64.8; H 5.8; N, 10.8%.

(c) By processing in a manner analogous to Example 3 (a), but using 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (tert-butyl ether) benzoylamino) propanoic acid [standard example 6 (c)], 3- (benzoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid is obtained acid. MS: MNa ⁺ 603.

Elemental analysis: C, 66.65; H 5.05; N, 9.35%. Calculated for C ₃₃ H ₃₂ N ₄ O ₆ : C 68.3; H 5.55; N, 9.65%.

(d) By processing in a manner analogous to Example 3 (a), but using 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (tert-butyl ether) pyridine-3-carbonylamino) propanoic acid [standard example 6 (d)], the trifluoroacetate salt of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3 is obtained - (pyridine-3-carbonylamino) propanoic acid. MS: MH ⁺ 582. Elemental analysis: C 56.85; H 4.4; N, 9.65%. Calculated for C ₃₂ H ₃₁ N ₅ O ₆ · CF ₃ CO ₂ H: C 58.7; H 4.6; N, 10.05%.

(e) By processing in a manner analogous to Example 3 (a), but using (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] tert-butyl ether] - phenylacetylamino} phenyl) propanoic acid [standard example 7 (a)], the trifluoroacetate salt of (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] - is obtained phenylacetylamino} phenyl) propanoic acid. MS:

MH ⁺ 477. Elemental analysis: C 55.55; H 5.15; N, 9.3%. Calculated for C ₂₆ H ₂₈ N ₄ O ₅ · CF ₃ CO ₂ H: C 56.9; H 4.95; N, 9.5%.

(f) By processing in a manner analogous to Example 3 (a), but using 3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl tert-butyl ether) -propanoic acid [standard example 7 (b)], get 3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] -phenylacetylamino} phenyl) -propanoic acid di-trifluoroacetate salt acids. MS: MH ⁺ 477. Elemental analysis: C, 51.95; H 4.3; N, 8.4%. Calculated for C ₂₆ H ₂₈ N ₄ O ₅ · 2CF ₃ CO ₂ H: C, 51.1; H 4.5; N, 7.95%.

(g) By processing in a manner analogous to Example 3 (a), but using 3- (n-butylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] tert-butyl ester] - phenylacetylamino} phenyl) propanoic acid [standard example 10 (a)], the trifluoroacetate salt of 3- (n-butylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] - is obtained phenylacetylamino} phenyl) -propanoic acid, so pl. 110-130 ° C (amorphous.). MS: MH ⁺ 533.

(h) By processing in a manner analogous to Example 3 (a), but using 3-benzylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl tert-butyl ether) of propanoic acid [standard example 10 (b)], the trifluoroacetate salt of 3-benzylamino-3- (4- (3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid is obtained. MS: MH ⁺ 566. Elemental analysis: C 61.05; H 5.05; N 8.0%. Calculated for C ₃₃ H ₃₄ N ₄ O ₅ · CF ₃ CO ₂ H: C 61.75; H 5, 2; N 8.2%.

(i) By processing in a manner analogous to Example 3 (a), but using 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (tert-butyl ether) 2-phenylethylamino) propanoic acid [standard example 10 (c)], the trifluoroacetate salt of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- ( 2-phenylethylamino) -propanoic acid, mp 105-140 ° C (amorph.). MS: MH ⁺ 580.

(j) By processing in a manner analogous to Example 3 (a), but using (R) -3 - [(1-tert-butoxycarbonylmethylpiperidin-4-carbonyl) amino-3- (4- {3-methoxy-4-) methyl ester [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 37 (b)], the trifluoroacetate salt of (R) -3 - [(1-carboxymethylpiperidin-4-carbonyl) amino-3 - (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid. MS: MH ⁺ 660.

EXAMPLE 4

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (morpholin-4-yl) -propanoic acid hydrochloride salt

(a) A mixture of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (morpholin-4-yl) -propanoic acid [100] tert-butyl ester mg, standard example 11 (a)], anhydrous trifluoroacetic acid (3 ml) and dichloromethane (5 ml) were allowed to stand at ambient temperature for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 1.0 M hydrochloric acid. The aqueous layer was evaporated and the residue was triturated with a mixture of methanol and diethyl ether to give the title compound (46 mg) as a white solid, mp. 164-171 ° C (amorphous). MS: MH ⁺ 547.

(b) By processing in a manner analogous to Example 4 (a), but using 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (tert-butyl ether) 4-methylpiperazin-1-yl) -propanoic acid [standard example 11 (b)], the hydrochloride salt of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) is obtained -3- (4-methylpiperazin-1-yl) -propanoic acid, mp 174-184 ° C (amorphous). MS: MH ⁺ 560.

(c) Processing in a manner analogous to Example 4 (a), but using (R) -3- (N-acetyl-N-methylamino) -3- (4- {4- [3- (2-methylphenyl) tert-butyl ether ) ureido] phenylacetyl-N-methylamino} phenyl) propionic acid (0.65 g, standard example 21), (R) -3- (N-acetyl-N-methylamino) -3- (4- {4 - [3- (2-methylphenyl) ureido] phenylacetyl-N-methylamino} phenyl) propionic acid as a white foam. HPLC: retention time (RT) = 11.9 minutes. M ^- 515 (ES ^- ).

EXAMPLE 5

(R) -3-Benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid

A mixture of (R) -3-benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid methyl ester [4.08 g, standard example 12 ( a)] and methanol (40 ml) are heated to 40 ° C and then treated with a 10% aqueous solution of sodium hydroxide (34 ml). After stirring at 40 ° C for 2.5 hours, the reaction mixture was cooled and then acidified to pH 1.0 by adding hydrochloric acid (1 M). The resulting white solid was collected, washed with water and then dried in vacuo. Recrystallization from acetic acid gave the title compound as a white crystalline solid (3.2 g), mp. 220-222 ° C. MS: MH ⁺ 581. [Elemental analysis: C, 68.0; H 5.4; N, 9.5%. Calculated for C ₃₃ H ₃₂ N ₄ O ₆ : C 68.3; H 5.6; N, 9.65%.

99% of it (excluding errors) by HPLC analysis on a CHIRALPAK AD F294 column, elution with heptane: isopropanol: ethanol: trifluoroacetic acid (200: 25: 25: 1) at a speed of 0.7 ml / min.

(b) (R) -3-Acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid hemihydrate

By processing in a manner analogous to Example 5 (a), but using (R) -3-acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propane methyl ester acids [standard example 12 (b)] and lithium hydroxide instead of sodium hydroxide give (R) -3-acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenyl- hemihydrate acetylamino} phenyl) propanoic acid; mp. 244 ° C (with decomposition). MS: MH ⁺ 519. Elemental analysis: C, 63.8; H 5.5; N 10.5%. Calculated for C ₂₈ H ₃₀ N ₄ O ₆ · 0.5 H ₂ O: C 63.75; H 5.9; N, 10.6%.

99% by HPLC analysis on a CHIRALPAK AD F294 column, eluting with heptane, isopropanol, ethanol and trifluoroacetic acid (200: 25: 25: 1 in terms of volume) at a rate of 0.7 ml / min (RT R-isomer = 36, 5 minutes; RT enantiomer = 47.4 minutes).

(c) By processing in a manner analogous to Example 5 (a), but using (R) -3-benzyloxycarbonylamino-3- (4 {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl methyl ester ) -propanoic acid [standard example 12 (c)], (R) -3-benzyloxycarbonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) - is obtained propanoic acid, mp 170-173 ° C (with decomposition). MS: MH ⁺ 611. Elemental analysis: C, 65.7; H 5.4; N, 8.9%. Calculated for C ₃₄ H ₃₄ N ₄ O ₇ · 0.5 H ₂ O: C 65.9; H 5.7; N, 9.0%.

d) By processing in a manner analogous to Example 5 (a), but using (R) -3-phenylsulfonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl methyl ester ) -propanoic acid [standard example 12 (d)], (R) -3-phenylsulfonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) -ureido] phenylacetylamino} phenyl) -propanoic acid, mp 181-184 ° C (with decomposition). MS: MH ⁺ 617. Elemental analysis: C 61.6; H 5.1; N, 9.0%. Calculated for C ₃₂ H ₃₂ N ₄ O ₇ S · 0.25 H ₂ O: C 61.9; H 5.3; N, 9.0%.

(f) By processing in a manner analogous to Example 5 (a), but using (R) -3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) methyl ester ) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (e)], (R) -3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3] is obtained - (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 218-220 ° C. MS: MH ⁺ 582. Elemental analysis: C, 62.3; H 5.1; N, 11.1%. Calculated for C ₃₂ H ₃₁ N ₅ O ₆ S · 2 H ₂ O: C 62.2; H 5.8; N, 11.4%.

(f) By processing in a manner analogous to Example 5 (a), but using (R) -3- (pyridin-3-sulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) methyl ester ) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (f)], (R) -3- (pyridin-3-sulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, mp. 191-193 ° C. MS: MH ⁺ 618. Elemental analysis: C, 58.5; H 5.1; N 11.0%. Calculated for C ₃₁ H ₃₁ N ₅ O ₇ S · H ₂ O: C 58.6; H 5.0; N 11.0%.

(g) By processing in a manner analogous to Example 5 (a) but using (R) -3- (5-dimethylamino-1-naphthalenesulfonylamino) -3- (4- {3-methoxy-4- [3- (2) methyl ester -methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 29 (a)], (R) -3- (5-dimethylamino-1-naphthalenesulfonylamino) -3- (4- {3-methoxy-4) is obtained - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 160 ° C (with decomposition). MS: MH ⁺ 710. Elemental analysis: C, 62.8; H 6.2; N, 9.3%. Calculated for C ₃₈ H ₃₉ N ₅ O ₇ S · H ₂ O · C ₃ H ₈ O: C, 62.5; H 6.3; N, 8.9%.

(h) By processing in a manner analogous to Example 5 (a), but using (R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido methyl ester ] -phenylacetylamino} phenyl) -propanoic acid [standard example 28 (a)], (R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) is obtained ) ureido] phenylacetylamino} phenyl) propanoic acid; mp. 217-219 ° C. MS: MH ⁺ 591. Elemental analysis: C, 62.3; H 5.4; N, 9.45%. Calculated for C ₃₁ H ₃₄ N ₄ O ₈ · 0.5 H ₂ O: C 62, 1; H 5, 9; N, 9.3%.

(i) Processing in a manner analogous to Example 5 (a), but using (R) -3- (3-carboxypropanoylamino) -3 (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] methyl ester] -phenylacetylamino} phenyl) -propanoic acid [standard example 28 (b)], (R) -3- (3-carboxypropanoylamino) -3- (4- (3-methoxy-4- [3- (2-methylphenyl)) is obtained ureido] phenylacetylamino} phenyl) propanoic acid, mp 177-180 ° C. MS: MH ⁺ 577. Elemental analysis: C 60.6; H 5.3; N 9.2%. Calculated for C ₃₂ H ₃₂ N ₄ O ₈ · H ₂ O: C 60, 6; H 5.75; N 9.4%.

(j) By processing in a manner analogous to Example 5 (a), but using methyl ester (R) -3- (1-methylimidazol-4-ylsulfonylamino) -3- (4- {3-methoxy-4- [3- (2 -methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [Standard Example 29 (b)], (R) -3- (1-methylimidazol-4-ylsulfonylamino) -3- (4- {3-methoxy-4) is obtained - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 194-195 ° C. MS: MH ⁺ 621.

(k) Processing in a manner analogous to Example 5 (a), but using (R) -3- (N-acetyl-N-methylamino) -3- (4- {3-methoxy-4- [3- (2) methyl ester -methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (g)], (R) -3- (N-acetyl-N-methylamino) -3- (4- {3-methoxy-4) is obtained - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, mp. 227-229 ° C. MS: MH ⁺ 533.

(l) Processing in a manner analogous to Example 5 (a), but using (R) -3- (N-methanesulfonylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido methyl ester ] -phenylacetylamino} phenyl) -propanoic acid [standard example 12 (h)], get (R) -3- (N-methanesulfonylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl ) ureido] phenylacetylamino} phenyl) propanoic acid; mp. 201-203 ° C. MS: MH ⁺ 569.

(m) By processing in a manner analogous to Example 5 (a), but using methyl ester of (R) -3 - [(morpholin-1-yl) -acetylamino)] - 3- (4- {3-methoxy-4- [3 - (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 37 (a)], (R) -3- (morpholin-1-ylacetylamino) -3- (4- {3-methoxy- 4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 183-184 ° C. MS: MH ⁺ 604.

(n) By processing in a manner analogous to Example 5 (a), but using (R) -3-acetylamino-3- (4- {3-methylthio-4- [3- (2-methylphenyl) ureido] phenylacetylamino} methyl ester} phenyl) propanoic acid [standard example 12 (m)], (R) -3-acetylamino-3- [4- {3-methylthio-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) is obtained) -propanoic acid, mp 205-207 ° C. MS: MH ⁺ 535. Elemental analysis: C 61.4; H 5.6; N, 10.0%. Calculated for C ₂₈ H ₃₀ N ₄ O ₅ S: C 62.9; H 5.6; N 10.5%.

(o) Processing in a manner analogous to Example 5 (a) but using (R) -3-acetylamino-3- (4- {3-methylsulfinyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} methyl ester} phenyl) propanoic acid [standard example 12 (n)], (R) -3-acetylamino-3- (4- {3-methylsulfinyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) is obtained) -propanoic acid, so pl. 202-295 ° C. MS: MH ⁺ 551. Elemental analysis: C 56.3; H 5.2; N, 9.4%. Calculated for C ₂₈ H ₃₀ N ₄ O ₆ S · 0.25 H ₂ O: C 56.5; H 5.9; N, 9.4%.

(p) Processing in a manner analogous to Example 5 (a), but using (R) -3-acetylamino-3- (4- {3-methylsulfonyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} methyl ester} phenyl) propanoic acid [standard example 12 (o)], (R) -3-acetylamino-3- (4- {3-methylsulfonyl-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) is obtained) -propanoic acid, so pl. 220-223 ° C. MS: MH ⁺ 567.

(q) Processing in a manner analogous to Example 5 (a) but using (R) -3- [2- (2-methoxyethoxy) acetylamino] -3- (4- {3-methoxy-4- [3- ( 2-methylphenyl) ureido] phenylacetylamino} phenylpropanoic acid [standard example 12 (p)], (R) -3- [2- (2-methoxyethoxy) acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, mp 193-195 ° C. MS: MH ⁺ 593.

Elemental analysis: C 62.5; H 6.5; N, 9.4%. Calculated for C ₃₁ H ₃₆ N ₄ O ₈ : C 62.8; H 6.1; N, 9.45%.

(r) Processing in a manner analogous to Example 5 (a) but using (R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- ( 2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (q)], (R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- (3-methoxy) is obtained -4- [3- (2-methylphenyl) ureido] phenylacetyl-but} phenyl) propanoic acid, mp 227-230 ° C (decomposition.) MS: MH ⁺ 589. Elemental analysis: C 64, 9; H 6.5; N 9.4%. Calculated for C ₃₂ H ₃₆ N ₄ O ₇ : C 65.3; H 6.2; N 9.5%.

(s) By processing in a manner analogous to Example 5 (a) but using (R) -3 - [(5-methylisoxazole-3-carbonyl) amino] -3- (4- {3-methoxy-4- [ 3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (i)], (R) -3 - [(5-methylisoxazole-3-carbonyl) amino] -3- ( 4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 200 ° C. MS: MH ⁺ 586. Elemental analysis: C 63.6; H 5.15; N, 12.0%. Calculated for C ₃₁ H ₃₁ N ₅ O ₇ : C 63.6; H 5.3; N, 12.0%.

(t) By processing in a manner analogous to Example 5 (a), but using (R) -3 - [(thiophen-2-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (j)], (R) -3 - [(thiophen-2-carbonyl) amino] -3- (4- {3 -methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 222-224 ° C (decomposition). MS: MH ⁺ 587. Elemental analysis: C, 63.1; H 5.3; N, 9.5%. Calculated for C ₃₁ H ₃₁ N ₄ O ₆ S: C 63.5; H 5.15; N, 9.55%.

(u) By processing in a manner analogous to Example 5 (a), but using (R) -3 - [(4-methoxycarbonylbenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2) methyl ester -methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (k)], (R) -3 - [(4-carboxybenzoyl) amino] -3- (4- {3-methoxy-4) is obtained - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 178-180 ° C (decomposition). MS: MH ⁺ 625. Elemental analysis: C, 62.0; H 5.1; N, 8.6%. Calculated for C ₃₄ H ₃₂ N ₄ O ₈ · 2H ₂ O: C 62.0; H 5.5; N 8.5%.

(v) By processing in a manner analogous to Example 5 (a), but using (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenylpropanoic acid [standard example 12 (r)], (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {3-methoxy- 4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, mp 190 ° C (decomposition) MS: MH ⁺ 583. Elemental analysis: C 61.1; H 5.1 ; N 13.5%. Calculated for C ₃₁ H ₃₀ N ₆ O ₆ · 1.5 H ₂ O: C 61.1; H 5.5; N 13.8%.

(w) By processing in a manner analogous to Example 5 (a), but using methyl ester (R) -3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (1)], (R) -3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3 -methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 184-186 ° C (decomposition). MS: MH ⁺ 641. Elemental analysis: C, 62.6; H 5.45; N, 8.3%. Calculated for C ₃₅ H ₃₆ N ₄ O ₈ · 1.75H ₂ O: C 62.5; H 5.9; N, 8.3%.

(x) Processing in a manner analogous to Example 5 (a) but using (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) methyl ester ) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (s)], (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, mp. 231-234 ° C (decomp.). MS: MH ⁺ 553.

(y) Processing in a manner analogous to Example 5 (a), but using methyl ester (R) -3 - [(4-carboxy-3,3-dimethylbutanoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 28 (c)], (R) -3 - [(4-carboxy-3,3-dimethylbutanoyl) amino] - is obtained 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 164 ° C. MS: MH ⁺ 619. Elemental analysis: C 62.0; H 5.7; N, 8.9%. Calculated for C ₃₃ H ₃₈ N ₄ O ₈ · 1.25H ₂ O: C, 61.8; H 6.3; N, 8.7%.

(z) By processing in a manner analogous to Example 5 (a) but using (R) -3- (benzoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl methyl ester) -propanoic acid [standard example 12 (t)], (R) -3- (benzoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid is obtained, so pl. 203-204 ° C (decomposition). MS: MH ⁺ 551. Elemental analysis: C, 66.9; H 5.5; N, 9.7%. Calculated for C ₃₂ H ₃₀ N ₄ O ₅ · 1.2 H ₂ O: C 67.2; H 5.5; N, 9.8%.

(aa) Processing in a manner analogous to Example 5 (a) but using (R) -3- [4-carboxybutanoyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] methyl ester phenylacetylamino} phenyl) propanoic acid [standard example 12 (y)], (R) -3- (4-carboxybutanoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} is obtained phenyl) -propanoic acid, mp 233-235 ° C. MS: MH ⁺ 561. Elemental analysis: C 63.7; H 5.95; N, 9.85%. Calculated for C ₃₀ H ₃₂ N ₄ O ₇ · 0.35H ₂ O: C 63.6; H 5.8; N, 9.9%.

(ab) By processing in a manner analogous to Example 5 (a) but using ethyl 3- [4 - ({3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetyl} -N-methylamino) phenyl] -butanoic acid [standard example 12 (w)], 3- [4 - ({3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetyl} -N-methylamino) phenyl] butanoic acid is obtained. MS: MH ⁺ 490. GHUR-RT = 14.46 minutes [gradient elution using a mixture of acetonitrile and water (1: 4-4: 1, in terms of volume)].

(ac) By processing in a manner analogous to Example 5 (a), but using dimethyl ether (R) -3 - [(4-carboxypyridin-3-carbonyl) amino] -3- (4- {3-methoxy-4- [ 3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (y)], (R) -3 - [(4-carboxypyridin-3-carbonyl) amino] -3- ( 4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 293-295 ° C. MS: MH ⁺ 626. Elemental analysis: C 56.5; H 5.3; N, 9.8%. Calculated for C ₃₃ H ₃₁ N ₅ O ₈ · H ₂ O: C 56.8; H 5.6; N, 10.0%.

(ad) By processing in a manner analogous to Example 5 (a) but using (R) -3- [2,2-di (hydroxymethyl) propanoylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (z)], (R) -3- [2,2-di (hydroxymethyl) propanoylamino] -3- (4- {3 -methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 194 ° C. MS: MH ⁺ 593.

(ae) Processing in a manner analogous to Example 5 (a), but using (R) -3- [2- (4-methylpiperazin-1-yl) -acetylamino] -3- (4- {3-methoxy-4) methyl ester - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (aa)], (R) -3- [2- (4-methylpiperazin-1-yl) -acetylamino] is obtained -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, MS: MH ⁺ 617.

(af) Processing in a manner analogous to Example 5 (a), but using (R) -3 - [(1-carboxymethylpiperidin-4-carbonyl) amino] -3- (4- {3-methoxy-4- [ 3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 3 (k)], (R) -3 - [(1-carboxymethylpiperidin-4-carbonyl) amino] -3- ( 4- (3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid MS: MH ⁺ 646.

(ae) Processing in a manner analogous to Example 5 (a), but using dimethyl ether (R) -3- [2- (carboxymethyloxy) -acetylamino] -3- (4- {3-methoxy-4- [3- (2 -methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [standard example 12 (ab)], (R) -3- [2- (carboxymethyloxy) -acetylamino] -3- (4- {3-methoxy-4) is obtained - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, m.p. 181-183 ° C. MS: MH ⁺ 593. Elemental analysis: C 59.5; H 5.6; N, 9.2%. Calculated for C ₃₀ H ₃₂ N ₄ O ₉ : C 59.5; H 5.6; N, 9.3%.

EXAMPLE 6

(R) -3-Acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenyl] acetylamino} phenyl) propanoic acid sodium hydrate

Suspension of (R) -3-acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [260 mg, example 5 (b)] in water (5 ml) is treated with an aqueous solution of sodium hydroxide (0.6 ml, 1 M). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was recrystallized from 5% aqueous isopropanol to give the title compound (200 mg) as a white crystalline solid, mp. 214-217 ° C (with decomposition). Elemental analysis: C 60.0; H 5.8; N, 9.8%. Calculated for C ₂₈ H ₂₉ N ₄ O ₆ Na · H ₂ O · 0.25 C ₃ H ₈ O: C, 60.2; H 5.6; N, 9.8%.

EXAMPLE 7

(a) 3- (4- {3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -5- (4-methylpiperazin-1-yl) -5-oxopentanoic acid

A mixture of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) pentadionic acid [740 mg, standard example 34], dichloromethane (50 ml) and tetrahydrofuran (10 ml) treated with trifluoroacetic anhydride (84 mg). After stirring at ambient temperature for 3 hours, the reaction mixture was evaporated. The residue was taken up in dichloromethane (20 ml), then N-methylpiperazine (80 mg). The mixture was stirred at ambient temperature for 2 hours, then evaporated. The residue was triturated with diethyl ether to give the title compound (35 mg) as a light brown amorphous. MS: MH ⁺ 602.

(b) Processing in the same manner as in Example 7 (a), but using morpholine instead of N-methylpiperazine, 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -5- (morpholin-4-yl) -5-oxopentanoic acid. MS: MH ⁺ 589.

EXAMPLE 8

(R) -3-benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid triethanolamine salt

A mixture of (R) -3-benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid [1.0 g, example 5 (a)] , Tris (hydroxymethyl) aminomethane (0.208 g), tetrahydrofuran (80 ml) and water (15 ml) are stirred at 50 ° C. for 1.5 hours, then cooled to room temperature and evaporated. The residue was recrystallized from ethanol to give the title compound as a white crystalline solid (1.1 g), mp. 135-140 ° C (with decomposition). Elemental analysis: C 61.6; H 6.1; N, 9.5%. Calculated for C ₃₃ H ₃₂ N ₄ O ₆ Na · C ₄ H ₁₁ NO ₃ · H ₂ O: C 61.75; H 6.3; N, 9.7%.

EXAMPLE 9

(a) Trifluoroacetate salt of (R) -3 - [(S) -N-benzyl-α-methylbenzylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl ) -propanoic acid

A stirred suspension of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propenoic acid tert-butyl ester (1.0 g, standard Example 8) in anhydrous tetrahydrofuran (50 ml) is treated with sodium hydride (0.23 g, 60% dispersion in mineral oil) in a nitrogen atmosphere. After stirring for 30 minutes, the resulting yellow solution was added dropwise to a solution of (S) -N-benzyl-α-methylbenzylamine (0.82 g) in anhydrous tetrahydrofuran (50 ml), cooled to -78 ° C under nitrogen and then treated with a solution of n-butyllithium in hexane (1.55 ml, 2.5 M). This mixture was further stirred for 15 minutes at -78 ° C, then poured into a mixture of ethyl acetate (200 ml) and a saturated aqueous solution of ammonium chloride (200 ml). The organic layer was separated, then dried over magnesium sulfate and then evaporated. The residue was flash chromatographed on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1: 4, v / v), to give a yellow foam (840 mg). A portion of this product (100 mg) was treated with trifluoroacetic acid (2 ml) and allowed to stand at ambient temperature for 30 minutes. The reaction mixture was evaporated and the residue was evaporated, the residue was triturated with diethyl ether to give the title compound as a pale yellow solid (20 mg). MS: MH ⁺ 671.

(b) Processing in the same manner as in Example 9 (a), but using dibenzylamine instead of (S) -N-benzyl-α-methylbenzylamine, the trifluoroacetate salt of 3- (N, N-dibenzylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid. MS: MH ⁺ 657.

EXAMPLE 10

(R) -3 - [(2-aminoacetyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenyl] acetylamino} phenyl) propanoic acid

Mixture of (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenylacetylamino} phenyl) propanoic acid methyl ester (1.0 g, standard example 30 ), N- (tert-butoxycarbonyl) glycine (0.36 g), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (0.81 g) and diisopropylethylamine (0.75 ml) in dry dimethylformamide (20 ml) was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into hydrochloric acid (25 ml, 0.1 M) and then extracted twice with ethyl acetate (50 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (25 ml), then with water (25 ml), then dried over magnesium sulfate and evaporated. The residue was flash chromatographed on silica gel, eluting with dissolved in tetrahydrofuran (10 ml), then treating with an aqueous solution of sodium hydroxide (1.5 ml, 1.0 M). The reaction mixture was heated to 40 ° C. for 4 hours, then evaporated. The residue is treated with water (30 ml) and the mixture is acidified to pH 1 by adding concentrated hydrochloric acid. The resulting solid was filtered, dried in vacuo, then treated with a chilled (0 ° C) solution of trifluoroacetic acid (4 ml) in dichloromethane (9 ml). The mixture was warmed to ambient temperature, then stirred for 4.5 hours, then evaporated. The residue was triturated with diethyl ether to give the title compound as a white solid (150 mg), mp. 105-108 ° C (with decomposition). MS: MH ⁺ 534.

EXAMPLE 11

(R) -3 - [(1-Oxidopyridin-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenylacetylamino} phenyl) propanoic acid

Mixture of (R) -3 - [(pyridin-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenylacetylamino} phenyl) propanoic acid methyl ester [0.4 g, example 5 (e)] and hydrogen peroxide (0.75 ml) in dry dimethylformamide (0.5 ml) were stirred at 80 ° C for 6 hours. The reaction mixture was evaporated and the residue was triturated with water. The resulting solid was flash chromatographed on silica gel, eluting with a mixture of dichloromethane, methanol and acetic acid (9: 1: 0.5, in terms of volume), to give the title compound as a light brown solid (50 mg), t .pl. 190 ° C (with decomposition). MS: MH ⁺ 598.

EXAMPLE 12

(R) -3- (4-Carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetamino} phenyl) propanoic acid

A mixture of methyl ester of (R) -3-amino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid [1.5 g, standard example 7 (c)], monomethylglutarate (0.7 ml), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (2.05 g), diisopropylethylamine (1.8 ml) and dimethylformamide (40 ml) were stirred at ambient temperature for 18 hours. The reaction mixture was evaporated to dryness and diluted with water (75 ml), the resulting mixture was acidified to pH 1.0 by adding concentrated hydrochloric acid. The mixture was extracted twice with ethyl acetate (75 ml). The combined extracts were washed with water (75 ml), then dried over magnesium sulfate and evaporated. The resulting waxy yellowish-brown product (3.8 g) was dissolved in dichloromethane (20 ml), cooled to 0 ° C and the solution was treated with trifluoroacetic acid (4 ml). After stirring at ambient temperature for 2 hours, the mixture was evaporated and the residue was taken up in ethyl acetate (50 ml). The resulting solution was treated with ice-cold saturated aqueous potassium carbonate solution (20 ml) with stirring for 5 minutes at ambient temperature. The organic layer was separated, washed with water (30 ml), dried over magnesium sulfate and then evaporated to give (R) -3- (4-carboxybutanoylamino) -3- (4-aminophenyl) propanoic acid methyl ester (1.32 g) in the form of a yellow oil.

A solution of 3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid (1.28 g, obtained as described in standard example 31) in anhydrous dimethylformamide (50 ml) in an argon atmosphere is treated sequentially with O- ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.55 g), diisopropylethylamine (1.35 ml) and (R) -3- (4-carboxybutanoylamino) -3- methyl ester solution (4-aminophenyl) propanoic acid (1.25 g, obtained as indicated directly above) in dimethylformamide (5 ml). After stirring for 2 hours at ambient temperature, the reaction mixture was evaporated. The residue was treated with hydrochloric acid (50 ml, 1 M) and extracted with ethyl acetate (100 ml). Before drying over magnesium sulfate and evaporating to dryness, the combined organic extracts are washed with water (50 ml) and a saturated aqueous solution of potassium carbonate (50 ml). The residue was flash chromatographed on silica gel, eluting with a mixture of methanol and dichloromethane (1:29, v / v) to give (R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4) methyl ester - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid as a tan solid (1.32 g). A solution of this product in tetrahydrofuran (40 ml) is heated to the boiling point under reflux and treated with an aqueous solution of sodium hydroxide (34 ml, 2 M). After further stirring at the boiling point for 2.5 hours, the reaction mixture was cooled and then evaporated. The residue was diluted with water and the mixture was acidified to pH 1.0 by adding concentrated hydrochloric acid. The resulting white solid was washed with water, then dried in vacuo, and then recrystallized from a mixture of ethanol and water (9: 1, in terms of volumes) to obtain the title compound as a white crystalline solid (3.2 g), mp . 220-222 ° C. MS: MH ⁺ 591. Elemental analysis: C 63.1; H 5.3; N, 9.3%. Calculated for C ₃₁ H ₃₄ N ₄ O ₈ : C 63.0; H 5.8; N, 9.5%. > 99 by HPLC analysis on CHIRALPAK AD F294, elution with heptane: isopropanol: ethanol: trifluoroacetic acid (200: 25: 25: 1) at a rate of 0.7 ml / min.

STANDARD EXAMPLE 1

Methyl 5-amino (pyrid-2-yl) thioacetate

A mixture of methyl 5-nitro (pyrid-2-yl) thioacetate (6.3 g, standard example 2), iron powder (12 g), ammonium chloride (1 g), ethanol (150 ml) and water ( 150 ml) is heated to reflux for 2 hours. The reaction mixture is cooled and then filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue was flash chromatographed on silica gel, eluting with a mixture of ethyl acetate and pentane (1: 1, v / v), to give a yellow foam (840 mg). The title compound is obtained as a yellow oil (3.0 g).

STANDARD EXAMPLE 2

Methyl 5-nitro (pyrid-2-yl) thioacetate

A mixture of methylthioacetate (3 g), iron powder (12 g), diisopropylethylamine (8.14 g), 2-chloro-5-nitropyridine (5 g) and dimethylformamide (50 ml) was heated to 80 ° C for 18 hours. The reaction mixture was cooled and poured into water (500 ml). After stirring for 1 hour at ambient temperature, the mixture was filtered to give the title compound (2.03 g) as a brown solid.

STANDARD EXAMPLE 3

(a) 3- (5- {3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-2-yl) propanoic acid ethyl ester

A solution of 3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid (0.7 g, standard example 31) in anhydrous dimethylformamide (25 ml) is treated sequentially with O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium gesafluorophosphate (0.85 g), diisopropylethylamine (0.54 g), 3- (5-aminopyrid-2-yl) propanoic acid ethyl ester solution [0.42 g, standard example 4 (a)] in dimethylformamide (5 ml). After stirring at room temperature for 5 hours and holding overnight, the reaction mixture was evaporated. The residue was taken up in ethyl acetate and the resulting solution was washed three times with water, then with brine and then evaporated. The residue was flash chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol (97: 3, v / v), to give the title compound (0.68 g) as a white foam.

(b) Processing in the same manner as in Standard Example 3 (a), but using ethyl 3- (6-aminopyrid-3-yl) -propanoic acid [Standard Example 4 (c)], 3- ( 6- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} pyrid-3-yl) propanoic acid.

STANDARD EXAMPLE 4

(a) 3- (5-aminopyrid-2-yl) -propanoic acid ethyl ester

A mixture of 3- (5-nitropyrid-2-yl) propenoic acid ethyl ester [0.8 g, standard example 5 (a)], ethanol (930 ml) and 5% palladium on carbon (0.13 g) was stirred at ambient temperature in a hydrogen atmosphere for 7 hours, left to stand overnight and then further stirred for 24 hours. The reaction mixture is filtered through a small layer of diatomaceous earth. The filtrate was evaporated to give the title compound (0.7 g) as a green oil.

(b) Processing in the same manner as in standard example 4 (a), but using ethyl 3- (5-nitropyrid-2-yl) -2-methylpropenoic acid [standard example 5 (b)], ethyl ester 3 is obtained - (5-aminopyrid-2-yl) methylpropanoic acid.

(c) Processing in the same manner as in standard example 4 (a), but using ethyl 3- (6-aminopyrid-3-yl) -propenoic acid [standard example 5 (c)], ethyl 3- ( 6-aminopyrid-3-yl) propanoic acid.

STANDARD EXAMPLE 5

(a) Ethyl 3- (5-nitropyrid-2-yl) -propenoic acid

A mixture of 5-nitro-2-pyridinecarbaldehyde (2.85 g, prepared according to the procedure described in J. Med. Chem., 1992, 35, 3675) and (carboxymethylene) triphenylphosphorane (6.0 g) in dry toluene (120 ml ) in a nitrogen atmosphere, stirred and heated at the boiling temperature under reflux for 6 hours. After standing at room temperature overnight, the reaction mixture was evaporated. The residue was flash chromatographed on silica gel, eluting with dichloromethane, to give the title compound (0.8 g) as a yellow solid.

(b) Processing in the same manner as in Standard Example 5 (a) above, but using (carbethoxyethylidene) triphenylphosphorane, 3- (5-nitropyrid-2-yl) methylpropenoic acid ethyl ester is obtained.

(c) Processing in the same manner as in the above standard example 5 (a), but using 6-amino-3-pyridinecarbaldehyde (obtained by a method similar to that described in Dolk. Akad. Nauk. SSSR, 1949, 65, 843), 3- (6-aminopyrid-3-yl) -propenoic acid ethyl ester is obtained.

STANDARD EXAMPLE 6

(a) (R) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (methanesulfonylamino) propanoic acid ethyl ester

A mixture of (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid ester [100 mg, standard example 7 (a)], dichloromethane (10 ml) and triethylamine (38 mg) was stirred at ambient temperature and then treated with methanesulfonyl chloride (22 mg). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane (20 ml) and then washed with hydrochloric acid (20 ml, 1 M), then with saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was dried over magnesium sulfate and then evaporated to give the title compound (55 mg) as a white solid.

(b) By processing in a manner analogous to standard Example 6 (a), but using 3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl tert-butyl ester ) -propanoic acid [standard example 7 (b)] and acetyl chloride instead of methanesulfonyl chloride, 3- (acetylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] tert-butyl ester] phenylacetylamino} phenyl) propanoic acid.

(c) By processing in a manner analogous to standard Example 6 (a), but using 3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl tert-butyl ester ) -propanoic acid [standard example 7 (b)] and benzoyl chloride instead of methanesulfonyl chloride, 3- (benzoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] tert-butyl ester] phenylacetylamino} phenyl) propanoic acid.

(a) By processing in a manner analogous to standard example 6 (a), but using 3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl tert-butyl ester ) -propanoic acid [standard example 7 (b)] and pyridine-3-carbonyl chloride instead of methanesulfonyl chloride give 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino tert-butyl ester } phenyl) -3- (pyridinecarbonylamino) propanoic acid.

STANDARD EXAMPLE 7

(a) (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid tert-butyl ester

Suspension of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propenoic acid tert-butyl ester (1.0 g, standard example 8) in anhydrous tetrahydrofuran (50 ml ) is treated with sodium hydride (0.23 g, 60% dispersion in mineral oil) and then stirred for 30 minutes under nitrogen atmosphere to give a yellow solution. This solution was added dropwise to a solution of (S) -N-benzyl-α-methylbenzylamine (0.82 g) in anhydrous tetrahydrofuran (50 ml), cooled to -78 ° C in a nitrogen atmosphere, treated with a solution of n-butyllithium in hexane (1 55 ml, 2.5 M). After further stirring for 15 minutes at −78 ° C., the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and a saturated aqueous solution of ammonium chloride (200 ml). The organic layer was separated, then dried over magnesium sulfate and then evaporated. The residue was flash chromatographed on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1: 4, v / v), to give a yellow foam (840 mg). This product is dissolved in ethanol (50 ml), then treated with formic acid (3 ml), heated to 60 ° C, and then treated with 10% palladium on carbon (0.5 g). The mixture was stirred at 60 ° C for 15 minutes, then filtered through a small layer of diatomaceous earth. The filtrate was evaporated, reducing the volume, and the residue was partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic phase was dried over magnesium sulfate and then evaporated to give the title compound (360 mg) as a white solid.

(b) Processing in the same manner as in Standard Example 7 (a), but using N, N-dibenzylamine instead of (S) -N-benzyl-α-methylbenzylamine, 3-amino-3- (4 - {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(c) By processing in a manner similar to standard example 7 (a), but using methyl 3- [4- (tert-butoxycarbonylamino) phenyl] propenoic acid (standard example 35) instead of tert-butyl ether 3- (4- {3 -methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propenoic acid, (R) -3-amino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid methyl ester

(d) By processing in a manner similar to standard example 7 (a), but using methyl 3- [4- (tert-butoxycarbonylamino) phenyl] propenoic acid (standard example 35) instead of tert-butyl ether 3- (4- {3 -methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propenoic acid and (S) -N, α-dimethylbenzylamine instead of (S) -N-benzyl-α-methylbenzylamine, get methyl ester (R) -3-methylamino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid

STANDARD EXAMPLE 8

3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propenoic acid tert-butyl ester

A mixture of 4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} iodobenzene [4.0 g, standard example 9 (a)], palladium acetate (50 mg), tri- (o -tolyl) phosphine (125 mg) and tributylamine (1.85 g) in anhydrous dimethylformamide (10 ml) are treated with tert-butyl acrylate (1.0 g). The reaction mixture was stirred at 100 ° C. under nitrogen for 4 hours, then cooled to room temperature and then poured into a mixture of ethyl acetate (50 ml) and hydrochloric acid (50 ml, 1 M). The resulting solid was filtered and washed successively with 50 ml portions of saturated aqueous sodium bicarbonate, water and diethyl ether. The residue was dried in vacuo to give the title compound (3.6 g) as a white solid.

STANDARD EXAMPLE 9

(a) 4- {3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} iodobenzene

A mixture of 3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid (2.9 g, standard example 31), 1-hydroxybenzotriazole (2.13 g), 1- (3-dimethylaminopropyl) -3 ethylcarbodiimide (2.67 g) and diisopropylethylamine (93.6 g) in anhydrous dimethylformamide (30 ml) are treated with 4-iodaniline (2.43 g). After stirring at ambient temperature for 18 hours, the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and hydrochloric acid (50 ml, 1 M). The resulting solid was filtered and then washed successively with 50 ml portions of saturated aqueous sodium bicarbonate, water and diethyl ether. The residue was dried in vacuo to give the title compound (4.05 g) as a light brown solid, mp. > 200 ° C.

(b) Processing in the same manner as in standard example 9 (a), but using 4- [3- (2-methylphenyl) ureido] phenyl-acetic acid (2.9 g, obtained as described in example 21 of the international patent Application No. WO 96/22966) instead of 3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid, 4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} iodobenzene is obtained.

STANDARD EXAMPLE 10

(a) 3- (n-Butylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid tert-butyl ester

(0,2 г) в метаноле (5 мл) перемешивают при температуре окружающей среды в атмосфере азота и затем обрабатывают цианоборогидридом натрия (13 мг). После перемешивания в течение 1 часа реакционную смесь обрабатывают, добавляя по каплям соляную кислоту (0,5 мл, 1 М), затем выливают в 10% водный раствор карбоната калия (10 мл). Смесь экстрагируют этилацетатом (30 мл). Органическую фазу сушат над сульфатом магния и затем упаривают. Остаток подвергают флэш-хроматографии на силикагеле, элюируя этилацетатом, что дает указанное в заглавии соединение (44 мг) в виде желтой пены.Mixture of 3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid tert-butyl ester [53 mg, standard example 7 (b)] , butyraldehyde (14 mg), sodium acetate (16 mg) and molecular sieves 4

(0.2 g) in methanol (5 ml) was stirred at ambient temperature under nitrogen and then treated with sodium cyanoborohydride (13 mg). After stirring for 1 hour, the reaction mixture was treated by adding dropwise hydrochloric acid (0.5 ml, 1 M), then poured into a 10% aqueous solution of potassium carbonate (10 ml). The mixture was extracted with ethyl acetate (30 ml). The organic phase is dried over magnesium sulfate and then evaporated. The residue was flash chromatographed on silica gel, eluting with ethyl acetate, to give the title compound (44 mg) as a yellow foam.

(b) Processing in the same manner as in Standard Example 10 (a) but using benzaldehyde instead of butyraldehyde, 3-benzylamino-3- (4- {3-methoxy-4- [3- (2- methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid

(c) Processing in the same manner as in Standard Example 10 (a) but using phenylacetaldehyde instead of butyraldehyde, 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] tert-butyl ester] phenylacetylamino} phenyl) -3- (2-phenylethylamino) propanoic acid.

STANDARD EXAMPLE 11

(a) 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -3- (morpholin-4-yl) propanoic acid tert-butyl ester

A solution of morpholine (87 mg) in anhydrous tetrahydrofuran (10 ml), cooled to -78 ° C, and treated with a solution of n-butyllithium in hexane (0.4 ml, 2.5 M) under nitrogen atmosphere. After stirring at -78 ° C for 15 minutes, the solution obtained by treating a stirred suspension of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} dropwise was added to the mixture dropwise. phenyl) propenoic acid (0.25 g, standard example 8) in anhydrous tetrahydrofuran (10 ml) with sodium hydride (58 mg of a 60% dispersion in mineral oil), in a nitrogen atmosphere. The resulting mixture was further stirred for 30 minutes at -78 ° C, then poured into a mixture of ethyl acetate (50 ml) and a saturated aqueous solution of sodium chloride (50 ml). The organic layer was separated, then dried over magnesium sulfate and then evaporated. The residue was triturated with diethyl ether to give the title compound (165 mg) as a white solid.

(b) Processing in the same manner as in Standard Example 11 (a) but using N-methylpiperazine instead of morpholine, 3- (4- {3-methoxy-4- [3- (2-methylphenyl)) tert-butyl ester is obtained ureido] phenylacetylamino} phenyl) -3- (4-methylpiperazin-1-yl) propanoic acid.

STANDARD EXAMPLE 12

(a) (R) -3-Benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid methyl ester

A solution of 3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid (1.52 g, obtained as described in standard example 31) in anhydrous dimethylformamide (40 ml) under nitrogen atmosphere is treated sequentially with O- ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium gesafluorophosphate (1.84 g), diisopropylethylamine (3.4 ml) and (R) -3-benzoylamino-3- (4-aminophenyl methyl ester solution ) -propanoic acid [2.0 g, standard example 13 (a)] in dimethylformamide (10 ml). After stirring for 45 minutes at ambient temperature, the reaction mixture was evaporated. The residue was taken up in water (150 ml) and hydrochloric acid (10 ml, 1 M) was added to the aqueous suspension. The mixture was filtered and the insoluble matter was washed three times with water (50 ml), then dried in vacuo to give the title compound as a white solid (2.53 g).

(b) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3-acetylamino-3- (4-aminophenyl) propanoic acid [standard example 13 (b)], methyl is obtained (R) -3-acetylamino-3- (4- (3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid ester.

(c) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3-benzyloxycarbonylamino-3- (4-aminophenyl) propanoic acid [standard example 13 (c)], methyl (R) -3-benzyloxycarbonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid ester.

(d) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3-phenylsulfonylamino-3- (4-aminophenyl) propanoic acid [standard example 13 (d)], methyl is obtained (R) -3-phenylsulfonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid ester.

(e) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3- (pyridin-3-carbonylamino) -3- (4-aminophenyl) propanoic acid [standard example 13 ( e)], methyl (R) -3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) -propanoic ester is obtained acids.

(f) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3- (pyridin-3-sulfonylamino) -3- (4-aminophenyl) propanoic acid [standard example 13 ( f)], methyl (R) -3- (pyridin-3-sulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] -phenylacetylamino} phenyl) propane is obtained acids.

(g) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3- (N-acetylmethylamino) -3- (4-aminophenyl) propanoic acid [standard example 13 (g) ], methyl (R) -3- (N-acetylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid methyl ester is obtained.

(h) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3- (N-methanesulfonylmethylamino) -3- (4-aminophenyl) propanoic acid [standard example 13 (h) ], methyl (R) -3- (N-methanesulfonylmethylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid is obtained.

(i) Processing in the same manner as in Standard Example 12 (a), but using methyl ester of (R) -3 - [(5-methylisoxazole-3-carbonyl) amino] -3- (4-aminophenyl) propane acids [standard example 13 (i)], get the methyl ester of (R) -3 - [(5-methylisoxazole-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2 methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(j) Processing in the same manner as in Standard Example 12 (a) but using (R) -3 - [(thiophen-2-carbonyl) amino] -3- (4-aminophenyl) propanoic acid methyl ester [ standard example 13 (j)], receive the methyl ester of (R) -3 - [(thiophene-2-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido ] phenylacetylamino} phenyl) propanoic acid.

(k) Processing in the same manner as in Standard Example 12 (a), but using (R) -3 - [(4-methoxycarbonylbenzoyl) amino] -3- (4-aminophenyl) propanoic acid methyl ester [standard example 13 (k)], methyl (R) -3 - [(4-methoxycarbonylbenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenidacetylamino} - phenyl) propanoic acid.

(1) Processing in the same manner as in Standard Example 12 (a), but using methyl ester of (R) -3 - [(3,4-dimethoxybenzoyl) amino] -3- (4-aminophenyl) propanoic acid [ standard example 13 (1)], receive methyl ester (R) -3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido ] phenylacetylamino} phenyl) propanoic acid.

(m) Processing in the same way as in standard example 12 (a), but using methyl ester of (R) -3-acetylamino-3- (4-aminophenyl) propanoic acid [standard example 13 (b)] and 3- methylthio-4- [3- (2-methylphenyl) ureido] phenylacetic acid (standard example 15), methyl ester (R) -3-acetylamino-3- (4- {3-methylthio-4- [3- (2 methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(n) Processing in the same way as in standard example 12 (a), but using methyl ester of (R) -3-acetylamino-3- (4-aminophenyl) propanoic acid [standard example 13 (b)] and 3- methylsulfinyl-4- [3- (2-methylphenyl) ureido] phenylacetic acid [standard example 16 (a)], methyl (R) -3-acetylamino-3- (4- {3-methylsulfinyl-4- [ 3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(o) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3-acetylamino-3- (4-aminophenyl) propanoic acid [standard example 13 (b)] and 3- methylsulfonyl-4- [3- (2-methylphenyl) ureido] phenylacetic acid [standard example 16 (b)], methyl (R) -3-acetylamino-3- (4- {3-methylsulfonyl-4- [ 3- (2-methylphenyl) ureido] phenylacetamino} phenyl) propanoic acid.

(p) Processing in the same manner as in Standard Example 12 (a), but using (R) -3- [2- (2-methoxyethoxy) -acetylamino] -3- (4-aminophenyl) propanoic acid methyl ester [ standard example 17 (a)], methyl (R) -3- [2- (2-methoxyethoxy) -acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) - ureido] phenylacetylamino} phenyl) propanoic acid.

(q) Processing in the same manner as in Standard Example 12 (a), but using (R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4-aminophenyl) propanoic acid methyl ester [standard Example 17 (b)], methyl ester (R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) -ureido] phenylacetylamino} phenyl) propanoic acid.

(r) Processing in the same manner as in Standard Example 12 (a), but using methyl ester of (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4-aminophenyl) propanoic acid [ standard example 17 (c], get the methyl ester of (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) -ureido ] phenylacetylamino} phenyl) propanoic acid.

(s) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4-aminophenyl) propanoic acid [ standard example 17 (c)] and 4- [3- (2-methylphenylureido)] phenylacetic acid (obtained as described in Example 21 of International Patent Application No. WO 96/22966), methyl ester (R) -3 - [(pyridazine -3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(t) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3- (benzoylamino) -3- (4-aminophenyl) propanoic acid [standard example 13 (a)] and 4- [3- (2-methylphenylureido)] - phenylacetic acid (obtained as described in Example 21 of International Patent Application No. WO 96/22966), methyl ester (R) -3- (benzoylamino) -3- (4- {4 - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(u) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3 - [(4-methoxycarbonylbutanoyl) amino] -3- (4-aminophenyl) propanoic acid [standard example 18 ] and 4- [3- (2-methylphenylureido)] phenylacetic acid (obtained as described in Example 21 of International Patent Application No. WO 96/22966), methyl ester (R) -3 - [(4-methoxycarbonylbutanoyl) amino] - 3- (4- {4- [3- (2-methylphenyl) ureido] phenidacetylamino} phenyl) propanoic acid.

(v) Processing in the same manner as in standard example 12 (a), but using 4- (4-aminophenyl) -tetrahydropyran-2-one (standard example 20), 4- (4- {3-methoxy-4 - [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) tetrahydropyran-2-one.

(w) Processing in the same manner as in standard example 12 (a), but using ethyl 3- [4- (N-methylamino) phenyl] butanoate (standard example 33), ethyl 3- (4- { 3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetyl} -N-methylamino) phenyl] butanoic acid.

(x) Processing in the same manner as in Standard Example 12 (a) but using 3- (4-aminophenyl) -pentanedioic acid diethyl ester (standard example 36), 3- (4- {3-methoxy- 4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) pentanedioic acid.

(y) Processing in the same way as in standard example 12 (a), but using dimethyl ether (R) -3 - [(4-carboxypyridin-3-carbonyl) amino] -3- (4-aminophenyl) propane acids [standard example 17 (d)], get dimethyl ether (R) -3 - [(4-carboxypyridin-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2 methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(z) Processing in the same manner as in Standard Example 12 (a), but using (R) -3- [2,2-di (hydroxymethyl) propanoylamino] -3- (4-aminophenyl) propanoic acid methyl ester [ standard example 17 (e)], methyl ester (R) -3- [2,2-di (hydroxymethyl) propanoylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido ] -phenylacetylamino} phenyl) -propanoic acid.

(aa) Processing in the same manner as in Standard Example 12 (a) but using (R) -3- [2- (4-methylpiperazin-1-yl) -acetylamino] -3- (4-aminophenyl) methyl ester -propanoic acid [standard example 17 (f)], methyl (R) -3- [2- (4-methylpiperazin-1-yl) -acetylamino] -3- (4- {3-methoxy-4- [ 3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(ab) Processing in the same manner as in standard example 12 (a), but using methyl ester of (R) -3- [2- (carboxymethyloxy) -acetylamino] -3- (4-aminophenyl) propanoic acid [standard example 17 (g)], receive (R) -3- [2- (carboxymethyloxy) -acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] -phenylacetylamino} dimethyl ester} phenyl) propanoic acid.

STANDARD EXAMPLE 13

(a) Methyl ester of (R) -3-benzoylamino-3- (4-aminophenyl) propanoic acid

A solution of methyl ester of (R) -3-amino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid [3.0 g, standard Example 7 (c)] in dimethylformamide (50 ml) is treated with benzoyl chloride ( 1.24 ml) and triethylamine (1.56 ml). After stirring at ambient temperature for 2.25 hours, the mixture was evaporated to dryness and the resulting solid was washed with water before drying in vacuo. The resulting solid product (3.8 g) was dissolved in dichloromethane (70 ml) and the solution was treated with trifluoroacetic acid (20 ml). After stirring at ambient temperature for 45 minutes, the reaction mixture was evaporated. The residue is taken up in toluene (70 ml), concentrated to dryness and the obtained product is taken up in dichloromethane (200 ml). The resulting suspension is treated with stirring with a saturated aqueous solution of potassium carbonate (20 ml) at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate and then evaporated to give the title compound as a white foam (2.0 g).

(b) Methyl ester of (R) -3-acetylamino-3- (4-aminophenyl) propanoic acid

A solution of methyl ester of (R) -3-amino-3- [4- (tert-butocarbonylamino) phenyl] propanoic acid [7.2 g, standard example 7 (c)] in dimethylformamide (30 ml) is treated with acetic anhydride (2.4 ml) and diisopropylethylamine (4.6 ml). After stirring at ambient temperature for 10 minutes, the mixture was poured into water (500 ml) and then extracted twice with ethyl acetate (200 ml). The combined organic extracts were washed with brine (200 ml), then dried over magnesium sulfate and evaporated. The resulting white foam (8.5 g) was dissolved in dichloromethane (75 ml) and the solution was treated with trifluoroacetic acid (17 ml). After stirring at ambient temperature for 3 hours, the reaction mixture was evaporated. The residue is taken up in toluene (70 ml), concentrated to dryness and the resulting product is treated with stirring with dichloromethane (200 ml) at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulfate and then evaporated to give the title compound (4.1 g) as a white foam.

(c) Processing in the same manner as in Standard Example 13 (b), but using N- (benzyloxycarbonyloxy) succinimide instead of acetic anhydride, methyl (R) -3-benzyloxycarbonylamino-3- (4-aminophenyl) propanoic acid is obtained .

(d) Processing in the same manner as in Standard Example 13 (a), but using phenylsulfonyl chloride instead of benzoyl chloride, (R) -3-phenylsulfonylamino-3- (4-aminophenyl) propanoic acid methyl ester is obtained.

(e) Processing in the same manner as in Standard Example 13 (a), but using pyridine-3-carbonyl chloride instead of benzoyl chloride, (R) -3- (pyridin-3-carbonylamino) -3- (4-aminophenyl) methyl ester is obtained ) -propanoic acid.

(f) Processing in the same manner as in standard example 13 (a), but using pyridin-3-sulfonyl chloride (standard example 14) instead of benzoyl chloride, methyl ester (R) -3- (pyridin-3-sulfonylamino) -3 - (4-aminophenyl) propanoic acid.

(g) Processing in the same manner as in standard example 13 (b), but using methyl ester of (R) -3-methylamino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid [standard example 7 (d )] instead of 3-amino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid methyl ester, (R) -3- (N-acetylmethylamino) -3- (4-aminophenyl) propanoic acid methyl ester is obtained .

(h) Processing in the same manner as in standard example 13 (a), but using methyl ester of (R) -3-methylamino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid [standard example 7 (d )] instead of 3-amino-3- [4- (tert-butoxycarbonylamino) phenyl] propanoic acid methyl ester and methanesulfonyl chloride instead of acetic anhydride, (R) -3- (N-methanesulfonylmethylamino) -3- (4- aminophenyl) propanoic acid.

(i) Processing in the same manner as in Standard Example 13 (a), but using 5-methylisoxazole-3-carbonyl chloride instead of benzoyl chloride, (R) -3 - [(5-methylisoxazole-3-carbonyl) -amino methyl ester is obtained ] -3- (4-aminophenyl) propanoic acid.

(j) Processing in the same manner as in Standard Example 13 (a), but using 2-thiophenecarbonyl chloride instead of benzoyl chloride, (R) -3 - [(thiophen-2-carbonyl) amino] -3- (4) methyl ester is obtained aminophenyl) propanoic acid.

(k) Processing in the same manner as in Standard Example 13 (a), but using 4-chlorocarbonylbenzoic acid methyl ester instead of benzoyl chloride, (R) -3 - [(4-methoxycarbonylbenzoyl) amino] -3- ( 4-aminophenyl) propanoic acid.

STANDARD EXAMPLE 14

Pyridine-3-sulfonyl chloride

A mixture of pyridine-3-sulfonic acid (5.0 g), phosphorus pentachloride (8.0 g), phosphorus oxychloride (30 ml) and chloroform (30 ml) was stirred at 120 ° C for 18 hours. The reaction mixture was cooled to room temperature, then diluted with chloroform (30 ml) and then filtered. Hydrogen chloride gas was bubbled through the filtrate for 15 minutes and a precipitate formed. This product was dried in vacuo to give the title compound as a white solid.

STANDARD EXAMPLE 15

3-Methylthio-4- [3- (2-methylphenyl) ureido] phenylacetic acid

A stirred suspension of potassium tert-butylate (16 g) in dry dimethylformamide (50 ml) was cooled to 0 ° C and treated, dropwise added over 2 hours, with a solution of methyldichloroacetate (12 ml) and 2-methylthionitrobenzene (10.5 g, obtained according to the method described in J. Org. Chem., 1993, 21, 5628) in dimethylformamide (50 ml). After stirring for another 1 hour, the mixture was warmed to ambient temperature and then quenched by adding water (10 ml) and hydrochloric acid (10 ml, 1 M). The mixture was partitioned between ethyl acetate (600 ml) and hydrochloric acid (100 ml, 1 M). The organic phase is separated, then dried over magnesium sulfate and then evaporated. The residue was flash chromatographed on silica gel, eluting with a mixture of pentane and diethyl ether (7: 3, v / v) to give a yellow solid (7.55 g). This product was dissolved in acetic acid (100 ml) and zinc powder (16 g) was added portionwise to the solution, then it was heated to reflux for 90 minutes. After cooling, the mixture is filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue was dissolved in ethyl acetate (500 ml). The solution was washed three times with saturated aqueous sodium bicarbonate (100 ml), then three times with hydrochloric acid (100 ml, 1 M). The pH of the combined hydrochloric acid washings was adjusted to 10 by adding sodium hydroxide (3 M). The solution was extracted three times with ethyl acetate (200 ml). The combined organic extracts were washed with brine (200 ml), then dried over magnesium sulfate and evaporated. The residue was flash chromatographed on silica gel, eluting with a mixture of pentane and diethyl ether (80:20, v / v) to give a yellow oil (1.35 g). The product is treated with a solution of 2-methylphenyl isocyanate (0.8 ml) in ethyl acetate (30 ml) and the mixture is heated to reflux for 2 hours. After cooling, the precipitate formed is filtered and then dissolved in dichloromethane (100 ml). This solution was washed with hydrochloric acid (20 ml, 1 M), then with brine (20 ml), then dried over magnesium sulfate and evaporated to give the title compound (1.2 g) as a white solid.

STANDARD EXAMPLE 16

(a) 3-Methylsulfinyl-4- [3- (2-methylphenyl) ureido] phenylacetic acid

A mixture of 3-methylthio-4- [3- (2-methylphenyl) ureido] phenylacetic acid (0.2 g, standard example 15), meta-chloroperbenzoic acid (61 mg) and methanol (25 ml) was stirred at ambient temperature for 1 hour and then evaporated. The residue was triturated with ethyl acetate to give the title compound (0.17 g) as a white solid.

(b) Processing in the same manner as in standard example 16 (a), but using 3-methylsulfinyl-4- [3- (2-methylphenyl) ureido] phenylacetic acid [standard example 16 (a)], 3- methylsulfonyl-4- [3- (2-methylphenyl) ureido] phenylacetic acid.

STANDARD EXAMPLE 17

(a) Methyl ester of (R) -3- (2-methoxyethoxy) -acetylamino-3- (4-aminophenyl) propanoic acid

A mixture of methyl ester of (R) -3-amino-3- [4- (tert-butocarbonylamino) phenyl] propanoic acid [0.75 g, standard example 7 (c)], 2- (2-methoxyethoxy) acetic acids (0.3 ml), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.02 g), diisopropylethylamine (0.9 ml) and dimethylformamide (25 ml) are mixed at ambient temperature for 2 hours. The reaction mixture was poured into water (150 ml) and the resulting solid was collected. The resulting tan solid was dissolved in dichloromethane (15 ml) and the solution was treated with trifluoroacetic acid (3 ml). After stirring at ambient temperature for 2 hours, the reaction mixture was evaporated. The residue is taken up in toluene (50 ml), concentrated to dryness and the obtained product is taken up in ethyl acetate (50 ml). The resulting suspension is treated with stirring with a saturated aqueous solution of potassium carbonate (20 ml) at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulfate and then evaporated to give the title compound (0.5 g) as a yellow oil.

(b) Processing in the same way as in standard example 17 (a), but using tetrahydropyran-4-carboxylic acid (obtained by the method described in J. Med. Chem., 1994, Vol. 37 (26), 4538- 4553) instead of 2- (2-methoxyethoxy) acetic acid, methyl ester of (R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4-aminophenyl) propanoic acid is obtained.

(c) Processing in the same way as in standard example 17 (a), but using pyridazine-3-carboxylic acid (obtained by the method described in J. Het. Chem., 1975, Vol. 12 (5), 957- 961) instead of 2- (2-methoxyethoxy) acetic acid, methyl (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4-aminophenyl) propanoic acid methyl ester is obtained.

(d) Processing in the same manner as in standard example 17 (a), but using 2-methoxycarbonylpyridin-5-carboxylic acid (standard example 38) instead of 2- (2-methoxyethoxy) acetic acid, dimethyl ether (R) - is obtained 3 - [(4-carboxypyridin-3-carbonyl) amino] -3- (4-aminophenyl) propanoic acid.

(e) Processing in the same manner as in Standard Example 17 (a), but using 2,2-bis (hydroxymethyl) propionic acid instead of 2- (2-methoxyethoxy) acetic acid, (R) -3- [ 2,2-di (hydroxymethyl) propanoylamino] -3- (4-aminophenyl) propanoic acid.

(f) Processing in the same manner as in standard example 17 (a), but using 2- (4-methylpiperazin-1-yl) acetic acid (standard example 39) instead of 2- (2-methoxyethoxy) acetic acid, methyl is obtained (R) -3- [2- (4-methylpiperazin-1-yl) -acetylamino] -3- (4-aminophenyl) propanoic acid ester.

(g) Processing in the same manner as in Standard Example 17 (a), but using diglycolic acid monomethyl ether (obtained by heating to the boiling point of diglycolic anhydride in methanol) instead of 2- (2-methoxyethoxy) acetic acid, methyl is obtained ester of (R) -3- [2- (carboxymethyloxy) -acetylamino] -3- (4-aminophenyl) propanoic acid.

STANDARD EXAMPLE 18

(R) -3 - [(4-methoxycarbonylbutanoyl) amino] -3- (4-aminophenyl) propanoic acid methyl ester

Concentrated nitric acid (50 ml) was cooled to -30 ° C and (R) -3- (4-carboxybutanoylamino) -3-phenylpropanoic acid (27 g, standard example 19) was added in portions. The resulting solid was filtered and dried, yielding a white solid (13 g). A part of this substance (15 g) was dissolved in methanol (375 ml) and the solution was treated with concentrated sulfuric acid (7.5 ml), then heated at the boiling temperature under reflux for 90 minutes. After cooling to room temperature, the mixture was evaporated. The residue was dissolved in ethyl acetate (250 ml) and the solution was washed with water (200 ml), saturated aqueous sodium bicarbonate (200 ml) and brine (200 ml). The organic layer was dried over magnesium sulfate and then evaporated to give a white solid (16 g). A solution of this product in ethyl acetate (450 ml) was treated with 10% palladium on carbon (2.5 g) and then stirred at ambient temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered by passing through a pad of diatomaceous earth and the filtrate was evaporated, yielding the title compound (15 g) as a pale yellow oil.

STANDARD EXAMPLE 19

(R) -3- (4-Carboxybutanoylamino) -3-phenylpropanoic acid

A solution of (R) -3-amino-3-phenylpropanoic acid (10 g, obtained mainly by the method described in Tetrahedron Letters, 1972, 27, 2789-92) in dichloromethane (150 ml) is treated with methyl 4- ( chloroformyl) butyrate (7.9 ml) and subsequently triethylamine (8.6 ml). The reaction mixture was stirred at ambient temperature for 90 minutes and the reaction was terminated by adding water (50 ml). The organic layer was washed with hydrochloric acid (1 M), dried over magnesium sulfate and evaporated to give a white solid (17 g). A solution of this product in methanol (50 ml) is treated with sodium hydroxide (90 ml, 1 M) and heated to 40 ° C for 1 hour. After this time, the reaction mixture is cooled, concentrated to a low volume and acidified to pH 1.0 with concentrated hydrochloric acid. The resulting solid was collected, washed with water and dried to give the title compound (6 g) as a white solid.

STANDARD EXAMPLE 20

4- (4-aminophenyl) tetrahydropyran-2-one

3-Phenylglutaric acid (23.3 g) was added to concentrated sulfuric acid (90 ml) at 10 ° C, and then fuming nitric acid (4.7 ml) was added dropwise to the stirred mixture over 20 minutes, making sure that the temperature of the reaction mixture did not exceed 10 ° C. The resulting solution was stirred at ambient temperature for 1 hour and then poured onto excess ice. The resulting solid product is collected and recrystallized from a mixture of toluene and cyclohexane, which leads to the formation of a light brown solid (27.1 g). A part of this substance (13.0 g) was suspended in acetic anhydride (70 ml) and the mixture was heated to 85 ° C. After stirring at 85 ° C for 150 minutes, the mixture was cooled to room temperature and evaporated. The residue was taken up in toluene (100 ml) and the mixture was evaporated, yielding 3- (4-nitrophenyl) glutaric acid anhydride as a light brown solid (14.2 g). A portion of this substance (10 g) was dissolved in tetrahydrofuran (50 ml) and the solution was added dropwise to a stirred, cooled (0 ° C.) suspension of sodium borohydride (1.77 g) in tetrahydrofuran (50 ml). Then the reaction mixture was stirred at 0 ° C for 4 hours, after which the reaction was quenched by adding dropwise hydrochloric acid (70 ml, 6 M). The mixture was extracted three times with ethyl acetate (200 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue is treated with toluene (500 ml), then p-toluenesulfonic acid (600 mg). The mixture was warmed to ambient temperature for 18 hours, then cooled to room temperature, then washed with saturated aqueous sodium bicarbonate (200 ml) and then evaporated. The residue was flash chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (2: 3, v / v) to give a white solid (3.0 g). This material was dissolved in ethyl acetate (200 ml) and the solution was treated with 10% palladium on carbon (0.35 g) and stirred at ambient temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a small pad of diatomaceous earth and the filtrate was evaporated, yielding the title compound (2.5 g) as a white solid.

STANDARD EXAMPLE 21

(R) -3 - [(N-Acetyl-N-methyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetyl-N-methylamino} phenyl tert-butyl ether) propionic acid

(R) -3- [4- (N-benzyloxycarbonyl-N-methyl) aminophenyl] -3 - [(N-acetyl-N-methyl) amino} -propionic acid tert-butyl ester (1 g, standard example 22) dissolved in a mixture of trifluoroacetic acid in dichloromethane (40 ml, 5%) at room temperature. After 2 hours, the mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was separated, then dried over magnesium sulfate and then evaporated. The residue was dissolved in dimethylformamide (5 ml) and 4- [3- (2-methylphenyl) ureido] phenylacetic acid (74 mg), O- (7-azabenzotriazol-1-yl) -1.1, 3,3-tetramethyluronium hexafluorophosphate (1.0 g) and diisopropylethylamine (670 mg) in dimethylformamide (15 ml). After stirring for 4 hours, the mixture was partitioned between ethyl acetate and aqueous hydrochloric acid (1 M). The organic phase is washed with an aqueous solution of sodium bicarbonate, then dried over magnesium sulfate and then evaporated. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate, to give the title compound (650 mg) as a colorless oil.

STANDARD EXAMPLE 22

(R) -3- [4- (N-benzyloxycarbonyl-N-methyl) aminophenyl] -3 - [(N-acetyl-N-methyl) amino} -propionic acid tert-butyl ester

To (R) -3- [4- (N-benzyloxycarbonyl-N-methyl) aminophenyl] -3- (N-methylamino) propionic acid tert-butyl ester (6 g, standard example 23) dissolved in a mixture of tetrahydrofuran ( 100 ml) and triethylamine (5.4 g), acetyl chloride (2.12 g) is added dropwise, resulting in an immediate precipitate. The mixture was stirred for 30 minutes, then partitioned between ethyl acetate and aqueous hydrochloric acid (1 M). The organic phase is separated, washed with an aqueous solution of sodium bicarbonate, then dried over magnesium sulfate and then evaporated, obtaining the title compound (6 g) as a pale yellow oil.

STANDARD EXAMPLE 23

(R) -3- [4- (N-benzyloxycarbonyl-N-methyl) aminophenyl] -3- (N-methylamino) propionic acid tert-butyl ester

A solution of (R) -3- [4- (N-benzyloxycarbonyl-N-methyl) aminophenyl] -3- [N - ((S) alpha-methylbenzyl) methylamino] propionic acid tert-butyl ester (6.5 g , standard example 24) in ethanol (50 ml) is heated to 60 ° C, then sequentially treated with formic acid (4 ml) and 10% palladium on carbon (2 g). The mixture was stirred at 60 ° C for 1 hour, then cooled to room temperature, then filtered through a filter accelerator to remove spent catalyst, and then evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate and then evaporated to give the title compound (6 g) as a colorless oil.

STANDARD EXAMPLE 24

(R) -3- [4- (N-benzyloxycarbonyl-N-methyl) aminophenyl] -3- [N - ((S) -alpha-methylbenzyl) methylamino] propionic acid tert-butyl ester

A solution of (S) -N- (alpha-methylbenzyl) methylamine (3.8 g) in tetrahydrofuran (60 ml) is cooled below -70 ° C under a layer of nitrogen, then treated with a solution of butyllithium in hexane (11.3 ml, 2.5 M), maintaining the temperature at about -60 ° C or lower. 10 minutes after completion of the treatment, a solution of 3- [4- (N-benzyloxycarbonyl-N-methyl) aminophenyl] acrylic acid tert-butyl ester (4.7 g, standard example 25) in tetrahydrofuran is slowly added. (40 ml). After another 20 minutes at a temperature below -70 ° C, the cooled reaction mixture was poured directly into a mixture of ethyl acetate and brine, then the layers were separated and the organic phase was dried over magnesium sulfate and then evaporated. The residue was flash chromatographed on silica, eluting with a mixture of ethyl acetate and cyclohexane (3: 7, v / v), which afforded the title compound (5.5 g) as a colorless oil.

STANDARD EXAMPLE 25

3- [4- (N-Benzyloxycarbonyl-N-methyl) aminophenyl] acrylic acid tert-butyl ester

N-Benzyloxycarbonyl-N-methyl-4-iodaniline (11 g, standard example 26), tert-butyl acrylate (8.4 g), tris - [(2-tolyl) phosphine] (0.5 g) and palladium acetate ( 0.15 g) was dissolved in a mixture of dimethylformamide (20 ml) and triethylamine (7.1 g) and stirred at 90 ° C. under nitrogen overnight. The reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid (1 M). The organic phase is washed with an aqueous solution of sodium bicarbonate (5%), then dried over magnesium sulfate and then evaporated. The residue was recrystallized from cyclohexane to give the title compound (7.4 g) as an off-white solid.

STANDARD EXAMPLE 26

N-Benzyloxycarbonyl-N-methyl-4-iodaniline

A stirred solution of N-benzyloxycarbonyl-4-iodaniline (11.5 g, standard example 27) in dimethylformamide (70 ml) is treated by adding portionwise sodium hydride (1.6 g of a 60% dispersion in oil), in a nitrogen atmosphere, at room temperature . After the bubbling ceased, methyl iodide (6.3 g) was added and the mixture was stirred at room temperature for 2 hours, after which it was partitioned between ethyl acetate and water. The organic phase was separated, then dried over magnesium sulphate and then evaporated to give the title compound (11.5 g) as a pink oil.

STANDARD EXAMPLE 27

N-Benzyloxycarbonyl-4-iodaniline

A solution of 4-iodaniline (10 g) in tetrahydrofuran (100 ml) was treated at one time with benzyloxycarbonyl anhydride (12 g). The mixture is stirred by heating to reflux overnight, then evaporated to a small volume. The residue was partitioned between ethyl acetate and aqueous hydrochloric acid (1 M). The organic phase is washed with an aqueous solution of sodium bicarbonate (5%), then dried over magnesium sulfate and then evaporated. The residue was recrystallized from cyclohexane to give the title compound (12.4 g) as pale violet crystals.

STANDARD EXAMPLE 28

(a) (R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid methyl ester

A stirred suspension of (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid methyl ester (0.75 g, standard example 30) in anhydrous tetrahydrofuran (25 ml) in an argon atmosphere is treated with glutaric anhydride (0.18 g). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated, yielding the title compound (1.0 g) as a white solid.

(b) Processing in the same manner as in Standard Example 28 (a), but using succinic anhydride instead of glutaric anhydride, (R) -3- (3-carboxypropanoylamino) -3- (4- {3-methoxy- 4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

(c) Processing in the same manner as in Standard Example 28 (a), but using 3,3-dimethylglutaric anhydride instead of glutaric anhydride, (R) -3 - [(4-carboxy-3,3-dimethylbutanoyl) methyl ester is obtained amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

STANDARD EXAMPLE 29

(a) (R) -3- (5-Dimethylamino-1-naphthalenesulfonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid methyl ester

Mixture of (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenylacetylamino} phenyl) propanoic acid methyl ester (0.75 g, standard example 30) , anhydrous tetrahydrofuran (25 ml), dansyl chloride (0.62 g) and triethylamine (1.0 ml) are placed in a nitrogen atmosphere and stirred at ambient temperature for 4 hours, then heated to reflux for 2 hours. The reaction mixture is cooled, then filtered. The filtrate was evaporated and the residue was flash chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol (49: 1, v / v), to give the title compound (0.89 g) as a yellow solid.

(b) Processing in the same manner as in Standard Example 29 (a), but using 1-methylimidazole-4-sulfonyl chloride instead of dansyl chloride, (R) -3- (1-methylimidazol-4-ylsulfonylamino) methyl ester is obtained - 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

STANDARD EXAMPLE 30

(R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenylacetylamino} phenyl) propanoic acid methyl ester

A mixture of methyl ester of (R) -3-benzyloxycarbonylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenylacetylamino} phenyl) propanoic acid (18.55 g), ethanol ( 750 ml) and formic acid (18 ml) in a hydrogen atmosphere are heated to the boiling temperature under reflux. 10% palladium-carbon (3.0 g) was added portionwise to the reaction mixture over a period of 1 hour, and then further heated to boiling point for another 1 hour. The reaction mixture was filtered through a small layer of diatomaceous earth and the filter layer was washed three times with ethanol (75 ml) and water (75 ml). The combined filtrate and washings were evaporated. The residue was carefully treated with an aqueous solution of sodium bicarbonate (600 ml, 0.6 M), followed by stirring for 15 minutes. The white solid formed is collected, washed twice with water (100 ml), then boiled in acetonitrile in the presence of activated carbon (150 mg). The still hot mixture was filtered through a small layer of diatomaceous earth and the filtrate was cooled on ice to give the title compound (7.6 g) as a white solid, mp. 189-191 ° C.

STANDARD EXAMPLE 31

3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid

A suspension of 3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid methyl ester (19.43 g, standard example 32) in methanol (195 ml) was treated with a solution of sodium hydroxide (65 ml, 1 N.) and the mixture was heated to reflux for 1 hour to give a clear solution. The reaction mixture was cooled to room temperature and filtered. The filtrate is diluted with water to 390 ml, then heated to 50 ° C and then acidified to pH 1 by adding hydrochloric acid (80 ml, 1 N.) for 1 hour. The resulting suspension is stirred for an additional 30 minutes at 50 ° C, then allowed to cool to room temperature and then filtered. The solid product is washed twice with water (200 ml), then dried, obtaining mentioned in the title compound (15.72 g) as a white solid, so pl. 179-181 ° C (with decomposition).

STANDARD EXAMPLE 32

3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetic acid methyl ester

A suspension of potassium tert-butylate (1.44 kg) in dimethylformamide (6.6 L) is cooled to a temperature of from -5 to -10 ° C and treated with a mixture of 2-nitroanisole (690 g) and methyldichloroacetate (915 g) for 4 hours, while maintaining the temperature below -5 ° C. Then the reaction mixture was treated with acetic acid (770 ml) and then with water (6.6 L), and then extracted three times with tert-butyl methyl ether (5.5 L). The combined extracts were washed with water (5.5 L), then with saturated sodium bicarbonate solution (5.5 L), then with saturated brine (5.5 L), and then dried over magnesium sulfate to give methyl α-chloro-3-methoxy -4-nitrophenyl acetate. This solution was concentrated to half volume under reduced pressure and then treated with tetrahydrofuran (2 L), followed by triethylamine (751 ml), then 10% palladium on carbon (58.4 g) and the mixture was hydrogenated at 50 ° C for 8 hours at hydrogen pressure 50 psi. The mixture was cooled to room temperature and filtered. The filtrate was dried over magnesium sulfate to give a solution of methyl 4-amino-3-methoxyphenyl acetate, which was heated to reflux and then treated with o-tolyl isocyanate (598.5 g) for 30 minutes. After heating to a distillation temperature for another 3 hours (during which time a solid product precipitates), the mixture is cooled to room temperature. The solid product was collected, washed twice with tert-butyl methyl ether (4 L), then dried in a vacuum oven at 60 ° C. to give the title compound (764.8 g) as a white solid, mp. 167-168 ° C.

STANDARD EXAMPLE 33

Ethyl 3- [4- (N-methylamino) phenyl] butanoate

A mixture of (E) -ethyl-3-methyl-3- (4-nitrophenyl) -propenoate (11.5 g, obtained by a method similar to that described in J. Med. Chem. 1968, 11, 672), ethanol (200 ml ), acetic acid (200 ml) and 10% palladium on carbon (1 g) was stirred at ambient temperature in a hydrogen atmosphere (2 bar) for 6 hours. The reaction mixture is filtered through a small layer of diatomaceous earth. The filtrate was evaporated and the residue was flash chromatographed on silica gel, eluting with a mixture of pentane and ethyl acetate (4: 1, v / v) to give a yellow oil (6.5 g). A portion of this product (3.0 g) was dissolved in tetrahydrofuran (20 ml) and the solution was added dropwise to methane ethane anhydride [previously prepared by mixing 90% formic acid (2.4 g) and acetic anhydride (3.8 g), followed by heating the mixture to 55 ° C and then cooling to ambient temperature]. The mixture was stirred at ambient temperature for 18 hours and then evaporated to give an oil (3.5 g). A stirred solution of this oil in tetrahydrofuran (20 ml) in a nitrogen atmosphere is treated by adding dropwise a solution of a complex of borane with dimethyl sulfide in tetrahydrofuran (3.7 ml, 1 M), and then the mixture is heated to reflux for 90 minutes. The reaction mixture was cooled, treated with methanol (2 ml) and then stirred at ambient temperature for 30 minutes. The pH of the mixture was adjusted to 2.0 by adding concentrated hydrochloric acid, then the mixture was heated to reflux for 1 hour. The reaction mixture was poured into a 10% aqueous potassium carbonate solution (100 ml) and then extracted three times with ethyl acetate (100 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was flash chromatographed on silica gel, eluting with a mixture of pentane and ethyl acetate (4: 1, v / v) to give the title compound as a white solid (0.15 g).

STANDARD EXAMPLE 34

3- (4- {3-Methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) pentanedioic acid

Mixture of 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) pentanedioic acid diethyl ester [8.40 g, standard example 12 (x)] and methanol (400 ml ) is heated to 40 ° C and then treated with 10% aqueous sodium hydroxide solution (110 ml). After stirring at 40 ° C for 1 hour, the reaction mixture was cooled and then acidified to pH 1.0 by adding hydrochloric acid (1 M). The resulting white solid was collected, washed with water and then dried in vacuo. Recrystallization from ethanol afforded the title compound as a white crystalline solid (4.7 g), mp. 218-220 ° C. Elemental analysis: C 64.5; H 5.6; N, 7.9%. Calculated for C ₂₈ H ₂₉ N ₃ O ₇ : C 64.7; H 5.6; N 8.1%.

STANDARD EXAMPLE 35

3- [4- (tert-Butoxycarbonylamino) phenyl] propenoic acid methyl ester

A solution of 4-aminocinnamic acid hydrochloride (50 g) in water (800 ml) is treated with a solution of sodium carbonate (33.2 g) and subsequently with a solution of di (tert-butoxy) carbonate (77.5 ml) in tetrahydrofuran (300 ml). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated to a small volume (500 ml). This mixture was acidified to pH 2.0 by adding concentrated hydrochloric acid, and then extracted twice with ethyl acetate (500 ml). The combined organic extracts were washed twice with water (500 ml), then with brine (500 ml), then dried over magnesium sulfate and then evaporated. The remaining white solid (47 g) was dissolved in dimethylformamide (240 ml) and the solution was stirred, then successively treated with potassium carbonate (24.8 g) and methyl iodide (11.2 ml). After stirring at ambient temperature for another 2 hours, the reaction mixture was evaporated. The residue is treated with water (500 ml), then filtered. The resulting solid was washed with water (200 ml), then with 10% aqueous potassium carbonate (200 ml), then with water (200 ml), and then dried in vacuo to give the title compound as a white solid (46.5 g) .

STANDARD EXAMPLE 36

3- (4-aminophenyl) pentanedioic acid dimethyl ester

Concentrated sulfuric acid (100 ml) was cooled to 10 ° C and then treated with 3-phenylglutaric acid (24 g). Fuming nitric acid (5 ml) was then added dropwise to the stirred mixture over a period of 20 minutes, ensuring that the temperature of the reaction mixture did not exceed 10 ° C. The resulting solution was stirred at ambient temperature for 1.5 hours and then poured onto excess ice. The resulting solid product is collected and washed with water. The residue was triturated with acetonitrile (100 ml) and dried in vacuo to give a white solid (26.5 g). This product was dissolved in methanol and treated with concentrated sulfuric acid (1.0 ml) and then heated to reflux for 4 hours. After cooling to room temperature, the mixture was evaporated to dryness. The residue was treated with saturated aqueous sodium bicarbonate (100 ml) and the resulting solid was collected and washed with water. The product was recrystallized from diisopropyl ether to give an unpainted solid (14 g). A solution of this substance in ethyl acetate (550 ml) was treated with 10% palladium on carbon (1.4 g) and then stirred at ambient temperature for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered through a small pad of diatomaceous earth and the filtrate was evaporated to give the title compound as an unpainted solid (2.33 g).

STANDARD EXAMPLE 37

(R) -3 - [(morpholin-1-yl) -acetylamino) methyl ester] - 3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) - propanoic acid

Mixture of (R) -3-amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido) phenylacetylamino} phenyl) propanoic acid methyl ester (1.0 g, standard example 30) , (morpholin-1-yl) -acetic acid (0.33 g, obtained according to the procedure described in Zh. Obshch. Khim, 1953, 23, 794), O- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (0.76 g), diisopropylethylamine (1.1 ml) and dimethylformamide (6 ml) were stirred at ambient temperature for 2 hours. Then the reaction mixture was poured into water (150 ml). The resulting solid was dried in vacuo to give the title compound as a green solid (1.31 g).

(b) Processing in the same manner as in Standard Example 37 (a), but using N- (tert-butoxycarbonylmethyl) isonipecotinic acid [obtained by hydrolysis of N- (tert-butoxycarbonylmethyl) isonipecotinic acid ethyl ester with sodium hydroxide (J.Med .Chem., 1982, Vol. 25 (3), 256)] instead of (morpholin-1-yl) -acetic acid, methyl (R) -3 - [(1-tert-butoxycarbonylmethylpiperidine-4-carbonyl) - amino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid.

STANDARD EXAMPLE 38

2-methoxycarbonylpyridine-5-carboxylic acid

A mixture of pyridine-2,5-dicarboxylic acid (8.4 g) and concentrated sulfuric acid (1.7 ml) was heated to reflux for 2 hours, cooled and poured into water (1 L). The resulting precipitate was collected and recrystallized from ethanol, which afforded the title compound as a white solid, mp. 222-223 ° C.

STANDARD EXAMPLE 39

2- (4-Methylpiperazin-1-yl) -acetic acid

A mixture of 1-methylpiperazine (10.7 g), benzyl bromoacetate (24 g), triethylamine (28 ml) and dichloromethane (100 ml) was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to dryness, taken up in tetrahydrofuran (100 ml), filtered and the filtrate was evaporated to dryness. The residue was taken up in methanol (100 ml), treated with an aqueous solution of sodium hydroxide (100 ml, 1 M) and stirred, heating to reflux for 24 hours. The reaction mixture was concentrated to dryness, diluted with water (100 ml) and then acidified to pH 6.0 by adding concentrated hydrochloric acid. The mixture is evaporated. A portion of the resulting brown oil (2.0 g) was taken up in water (100 ml), treated with Dowex 50WX8 resin (80 g) and stirred at ambient temperature for 10 minutes. The mixture is filtered and the resin washed with water until the washings are neutral. Then the resin is mixed with 2.0 M aqueous ammonia (3 × 100 ml) for 5 minutes and filtered. The combined ammonia washings were concentrated to afford the title compound as a white gummy solid (0.8 g).

IN VITRO AND IN VIVQ TEST METHODS

1. Inhibitory effects of the compounds of the invention on VLA-4-dependent cell adhesion to fibronectin and VCAM.

1.1. Metabolic labeling of RAMOS cells.

RAMOS cells (pre-B cell line from ECACC, Porton Down, UK) are grown in RPMI nutrient medium (Gibco, UK) supplemented with 5% fetal calf serum (FCS, Gibco, UK). Before testing, cells are suspended at a concentration of 0.5 × 10 ⁶ cells / ml RPMI and labeled with [ ³ H] -methionine (Amersham, UK) with 400 μCi / 100 ml · sec for 18 hours at 37 ° C.

1.2. Preparation of a 96-cell plate (plate) for adhesion testing.

Labeled cell plates (Amersham, UK) cover 50 μl / well of either 3 μg / ml of soluble human VCAM-1 (R&D Systems Ltd, UK) or 28.8 μg / ml of human tissue fibronectin (Sigma, UK). 50 μl of saline phosphate buffer solution is added to the control cells of non-specific binding. Then the plates are allowed to dry overnight in an incubator at 25 ° C. The next day, the plates were filled with 200 μl / well of Pucks'a buffer (Gibco, UK) supplemented with 1% BSA (Sigma, UK). The plates are left in the dark at room temperature for 2 hours. Then the buffer filling them is removed and the plates are dried, turning over and carefully wetting with a paper towel. 50 μl / well of 3.6% dimethyl sulfoxide in Pucks buffer supplemented with 5 mM manganese chloride (to activate Sigma integrin receptor UK) and 0 , 2% BSA (Sigma, UK). 50 μl / well of test compounds were added to the sample cells at appropriate concentrations, diluting them with 3.6% dimethyl sulfoxide in Pucks buffer supplemented with 5 mM manganese chloride and 0.2% BSA.

Metabolically labeled cells are suspended at 4 × 10 ⁶ cells / ml in Pucks buffer supplemented with manganese chloride and BSA, as described above. 50 μl / well of cells in 3.6% dimethyl sulfoxide in Pucks buffer and complementary materials are added to all plate wells.

The same procedure is used for both VCAM-1 coated plates and fibronectin coated plates, and data are obtained on the inhibition of cell binding compounds with both substrates.

1.3. Testing and analysis of the data.

Plates containing cells in cells with control samples and samples containing compounds are incubated in the dark at room temperature for 1 hour.

Then the plates are counted on a Wallac Microbeta scintillation counter (Wallac, UK) and the data are recorded and processed using Microsoft Excel (Microsoft, US). Data is expressed through an IC50, i.e. inhibitor concentration at which 50% controlled binding is observed. The percentage of binding is determined by the equation

{[(C _TB -C _NS ) - (C _I -C _NS )]} / (C _TB -C _NS )]} × 100 =% binding

where Stv is the count of pulses associated with cells coated with fibronectin (or VCAM-1) in the absence of an inhibitor, c _ns is the count of pulses observed in cells without a substrate and C _I is the count of pulses observed in cells containing a cell adhesion inhibitor.

Data for the compounds of the invention are expressed in terms of IC50 values for inhibiting cell adhesion to both fibronectin and VCAM-1. Noteworthy compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with an IC50 ranging from 100 micromolar to 0.01 nanomolar. Preferred compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with an IC50 in the range of 1.0 micromolar to 0.01 nanomolar. Particularly preferred compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with an IC50 ranging from 10 nanomolar to 0.01 nanomolar.

2. Inhibition of antigen-induced airway inflammation in mice and rats.

2.1. Sensitization of animals.

Rats (Brown Norway, Harland Olac, UK) are sensitized on days 0, 12, and 21 by administering ovalbumin (100 μg, intraperitoneally [ip], Sigma, UK) with adjuvant, aluminum hydroxide (100 mg, ip, Sigma, UK), in physiological saline (1 ml, ip).

In addition, the sensitivity of mice (C57) is increased on days 0 and 12 by administering ovalbumin (10 μg, i.p.) with adjuvant, aluminum hydroxide (20 mg, i.p.), in physiological saline (0.2 ml, i.p.).

2.2. The introduction of antigen.

Rats are given antigen on one of the days, between 28-38, while mice are given antigen on one of the days, between 20-30.

Animals are challenged with the antigen by exposing them to 30 minutes (rats) or 1 hour (mice) with ovalbumin (10 g / L) generated by an ultrasonic inhaler (de Vilbiss Ultraneb, US) and transferred to a treatment chamber.

2.3. The procedure for the introduction of drugs.

Animals are injected with drugs, depending on the circumstances (as needed), before or after administration of the antigen. The water-soluble compounds of this invention can be prepared in water (for oral, r.o.dosing) or physiological saline (for intratracheal (i.t.) dosing). Insoluble compounds are obtained in the form of suspensions, by grinding and dispersing a solid using ultrasound in 0.5% methylcellulose / 0.2% polysorbate 80 in water (for rd dosage, both substances Merck UK Ltd., UK) or physiological solution (for dosing). Volumes of doses administered: for rats, 1 ml / kg, r.o., or 0.5 mg / kg / i.t .; for mice 10 ml / kg, p.o., or 1 ml / kg, i.t.

2.3. A study of airway inflammation. The accumulation of cells in the lungs is determined 24 hours after administration of the antigen (rats) or 48-72 hours after administration of the antigen (mice). Animals are sacrificed with sodium pentobarbitone (200 mg / kg, i.p., Pasteur Merieux, France) and the catheter is immediately catheterized. Cells are isolated from the airways by means of bronchoalveolar lavage (BAL) and from lung tissue by enzymatic (collagenase, Sigma, UK) disaggregation as follows.

BAL is performed by rinsing the airways with 2 aliquots (10 ml / kg each) of RPMI 1640 growth medium (Gibco, UK) containing 10% fetal calf serum (FCS, Serotec Ltd., UK). The isolated BAL aliquots are pooled, and cell counts are performed as described below.

Immediately after BAL, the pulmonary vasculature is washed with RPMI 1640 / FCS to remove the blood depot cells. Lobes of the lung are separated and cut into pieces of 0.5 mm. Samples (rats: 400 mg, mice: 150 mg) of homogeneous lung tissue were incubated in RPMI 1640 / FCS with collagenase (20 units / ml for 2 hours, then 60 units / ml for 1 hour, 37 ° C) to isolate cells from tissue. The isolated cells were washed in RPMI 1640 / FCS.

The total number of leukocytes isolated from the cavity of the respiratory tract and lung tissue was calculated using an automatic cell counter (Cobas Argos, US). Differential counting of eosinophils, neutrophils and mononuclear cells is performed using light microscopy of cytocentrifuged preparations stained with Wright-Giemza stain (Sigma, UK). T lymphocytes are counted by cytometry in an EPICS XL stream. Coulter Electronics, US, using fluofor-labile antibodies to CD2 (a pan-T lymphocyte marker used to quantify the total number of T lymphocytes), CD4, CD8, and CD25 (activated T-lymphocyte marker). All antibodies are supplied by Serotec Ltd., UK).

2.4. Analysis of the results.

Cell data are expressed as the average number of cells, taking into account the standard measurement error, in groups: without the introduction of antigens, with the introduction of antigens and treatment with a solvent, with the introduction of antigens and treatment with compounds. Statistical analysis of differences in groups with different processing is carried out using a monovariant analysis according to the Mann-Whitney test method. Data are not considered statistically unreliable at p values <0.05.

The inhibitors of the invention cause a statistically significant decrease in the number of eosinophils and lymphocytes in BAL and respiratory tract tissue at doses in the range of 100-0.01 mg / kg.

3. Inhibition of antigen-induced airway sensitivity in sheep with allergies.

The experiment is carried out mainly as described in W. M. Abraham et al., J. Clin. Invest. (1994), Vol. 93, 776-787. In the experiment, sheep with allergies are used, which, as previously established, develop reactions of an early or late stage to the administration by inhalation of the Ascaris suum antigen. The inhibitors of the invention are administered to the sheep as an aerosol and cause statistically significant attenuation of Ascaris suum-induced airway reactions.

In the examples of activity tests described in the description, the following compounds of the invention were tested and the following results were obtained.

In the first test to determine cell adhesion to 1) VCAM and 2) fibronectics, all compounds of the invention were tested, showing activity in a wide range of values from 100 μm to 0.01 nm.

The second test tested the compounds of examples 5 (a), (b), (d), (f), (h), (r), (s), (y) and (aa), and example 8. All tested compounds met the requirement indicated on page 190 of the description, namely, showed a statistically significant decrease in the number of eosinophils and lymphocytes in BAL tissue and respiratory tract tissue at doses from 0.01 to 100 mg / kg.

The third in vivo test was conducted only with compound 5 (h), which showed excellent results, allowing to include this compound among the preferred compounds of the invention.

Claims (16)

1. The compound of General formula (I)

where X ¹ and X ² independently represent CR ¹⁰ ; R ⁴ represents a hydrogen atom or a C _1-4 alkyl group; R ¹⁰ is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl; R ¹² is hydrogen, C _1-4 alkyl or benzyl; R ¹³ is C _1-6 alkyl optionally substituted carboxy, C _1-4 alkoxyalkoxy, —OCH ₂ CO ₂ H, —NY ¹ Y ^2, or one or more hydroxy groups; heteroaryl selected from imidazolyl, oxazolyl, pyridyl, thienyl and pyridazinyl, each of which is optionally substituted with carboxy or C _1-4 alkyl; heterocycloalkyl, such as tetrahydropyranyl, or aryl selected from phenyl and naphthyl, each of which may be substituted with a carboxy group, —NY ⁴ Y ^5, or one or more C _1-4 alkoxy groups, where Y ⁴ and Y ⁵ independently represent C _1-4 alkyl; R ¹⁵ is —N (R ¹² ) —C (═O) —R ¹³ , —N (R ¹² ) —SO ₂ —R _13, or —NY ¹ Y ² , where Y ¹ and Y ² independently represent hydrogen, C _{1 -4} alkyl or arylC _1-4 alkyl, or the group -NY ¹ Y ² may form a 5-6 membered cyclic amine that may contain an additional heteroatom selected from O or NY ³ , where Y ³ is —C (= O) -OR ¹⁴ where R ¹⁴ is C _1-4 alkyl, or C _1-4 alkyl; Ar ¹ is unsubstituted phenylene, its N-oxides, ester derivatives, and their pharmaceutically acceptable salts and solvates. 2. The compound according to claim 1, where X ¹ is CR ¹⁰ , where R ¹⁰ is C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl. 3. The compound according to claim 2, where X ¹ is CR ¹⁰ , where R ¹⁰ is C _1-4 alkyl or C _1-4 alkoxy. 4. The compound according to claim 3, where X ¹ denotes CR ¹⁰ where R ¹⁰ denotes methyl. 5. The compound according to any one of claims _{1 to 4} , where X ² denotes CR ¹⁰ where R ¹⁰ denotes C _1-4 alkoxy. 6. The compound according to any one of claims 1 to 5, where R ⁴ denotes hydrogen or methyl. 7. The compound according to any one of claims 1 to 6, wherein Ar ¹ is p-phenylene. 8. The compound according to any one of claims 1 to 7, where the group

denotes a group

9. The compound according to claim 1, selected from among the following compounds: (R) -3-acetylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3- (3-carboxypropanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3- (pyridin-3-carbonylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3-benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3- [2- (2-methoxyethoxy) acetylamino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3 - [(tetrahydropyran-4-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3 - [(5-methylisoxazole-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3 - [(thiophen-2-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3 - [(4-carboxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3 - [(3,4-dimethoxybenzoyl) amino] -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3 - [(pyridazine-3-carbonyl) amino] -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3- (4-carboxy-3,3-dimethylbutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3- (benzoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid; (R) -3- (4-carboxybutanoylamino) -3- (4- {4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid, their N-oxides and ester derivatives; and pharmaceutically acceptable salts and solvates of such compounds. 10. The compound according to claim 1, which is (R) -3- (4-carboxybutanoylamino) -3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid and its N-oxide, ester derivatives, pharmaceutically acceptable salts and solvates. 11. The compound according to claim 1, which is (R) -3-benzoylamino-3- (4- {3-methoxy-4- [3- (2-methylphenyl) ureido] phenylacetylamino} phenyl) propanoic acid and its N- oxide, ester derivatives, pharmaceutically acceptable salts and solvates. 12. A pharmaceutical composition exhibiting anti-inflammatory and anti-asthma activity, comprising an effective amount of a compound according to claim 1, or its N-oxide, or an ester derivative, or a pharmaceutically acceptable salt or solvate of such a compound, in combination with a pharmaceutically acceptable carrier or excipient. 13. The compound according to claim 1, or its N-oxide, or an ester derivative, or a pharmaceutically acceptable salt, or a solvate of such a compound exhibiting anti-inflammatory and anti-asthma activity and is suitable for the treatment of patients suffering from or prone to painful conditions that may be alleviated the introduction of an inhibitor of cell adhesion mediated a4β1. 14. The compound according to claim 1, or its N-oxide, or an ester derivative, or a pharmaceutically acceptable salt, or a solvate of such a compound, exhibiting anti-inflammatory and anti-asthma activity and suitable for the treatment of inflammatory diseases. 15. The compound according to claim 1, or its N-oxide, or an ester derivative, or a pharmaceutically acceptable salt, or a solvate of such a compound, exhibiting anti-inflammatory and anti-asthma activity and suitable for the treatment of asthma. 16. A method of treating a person or animals suffering or prone to diseases, the symptoms of which can be improved by the administration of an A4β1 mediated cell adhesion inhibitor, comprising administering to said patient an effective amount of a compound according to claim 1, or its N-oxide, or ester derivative, or pharmaceutically an acceptable salt or solvate of such a compound.