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Title:
NEW BENZAMIDES AS PPAR&Upsi MODULATORS
Document Type and Number:
WIPO Patent Application WO/2004/110983
Kind Code:
A2
Abstract:
Compounds of general structure (I), wherein the central benzene ring may be substituted in the meta- or para-­position; -A is an optionally substituted hydroxyl, alkoxyl, hydroxylamine, alkoxylamine or amine radical; -W is an N- ­and C-linked biradical selected from several possibilities; and -Z is a carbon radical selected from several possibilities. These compounds are PPAR&Upsi and PPAR&Upsi / PPAR&dgr modulators and, therefore, are useful for the prophylactic and/or curative treatment of a condition or a disease mediated by these recetpcors.

Inventors:
FERNANDEZ SERRAT ANNA (ES)
SERRA COMAS CARME (ES)
BALSA LOPEZ DOLORS (ES)
LLEBARIA SOLDEVILA AMADEU (ES)
FARRERONS GALLEMI CARLES (ES)
MIQUEL BONO IGNACIO JOSE (ES)
CATENA RUIZ JUAN LORENZO (ES)
LAGUNAS ARNAL CARMEN (ES)
CORDOMI MONTOYA ARNAU (ES)
SALCEDO ROCA CAROLINA (ES)
TOLEDO MESA NATIVIDAD (ES)
MARRERO GONZALEZ PEDRO (ES)
HARO BAUTISTA DIEGO (ES)
FERNANDEZ GARCIA ANDRES (ES)
Application Number:
PCT/EP2004/006330
Publication Date:
December 23, 2004
Filing Date:
June 11, 2004
Export Citation:
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Assignee:
S A L V A T LAB SA (ES)
FERNANDEZ SERRAT ANNA (ES)
SERRA COMAS CARME (ES)
BALSA LOPEZ DOLORS (ES)
LLEBARIA SOLDEVILA AMADEU (ES)
FARRERONS GALLEMI CARLES (ES)
MIQUEL BONO IGNACIO JOSE (ES)
CATENA RUIZ JUAN LORENZO (ES)
LAGUNAS ARNAL CARMEN (ES)
CORDOMI MONTOYA ARNAU (ES)
SALCEDO ROCA CAROLINA (ES)
TOLEDO MESA NATIVIDAD (ES)
MARRERO GONZALEZ PEDRO (ES)
HARO BAUTISTA DIEGO (ES)
FERNANDEZ GARCIA ANDRES (ES)
International Classes:
A61P5/00; C07C235/52; C07D209/18; C07D213/30; C07D215/20; C07D215/227; C07D215/26; C07D223/16; C07D233/54; C07D241/44; C07D277/64; C07D333/16; C07D215/22; (IPC1-7): C07C235/00
Domestic Patent References:
WO2000055118A12000-09-21
WO1997027847A11997-08-07
Other References:
None
Attorney, Agent or Firm:
Rambelli, Paolo (Corso Emilia 8, Torino, IT)
Download PDF:
Claims:
CLAIMS
1. A compound of formula (I), its stereoisomers and mixtures thereof, its polymorphs and mixtures thereof, and the pharmaceutically acceptable solvates and addition salts of all of them, wherein the central benzene ring may be substituted in metaor para position and, A is a radical selected from the group consisting of OR1,NR20R1 andNR2R3; wherein R1, R2 and R3 independently representH or (ClC4)alkyl ; Wis a biradical selected from the group:NHCH (E) , N (E) CH2, andN (D)CH2CH2 ; wherein E is a radical of the GIJK type and D is a radical of the GI'JK type where: G is a bond or a (CH2)14 biradical ; Iis a biradical of a cycle selected from the following groups: a) cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all optionally substituted by one or several radicals independently selected fromOH, oxo (=O), CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (C1C4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3,CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; b) a fiveor sixmernbered aromatic heterocycle containing from one to three heteroatoms selected from O, S and N, this heterocycle being optionally substituted by one or several radicals independently selected fromOH, oxo <BR> <BR> <BR> <BR> (=O),CHO,SH,NO2,CN,F,Cl,Br,<BR> <BR> <BR> <BR> <BR> (ClC4)alkanoyl, (ClC4)alkoxycarbonyl,<BR> <BR> <BR> <BR> <BR> (ClC4)alkanoyloxy, (ClC4)alkylsulphinyl,<BR> <BR> <BR> <BR> <BR> (ClC4)alkylsulphenyl, (C1C4)alkylsulphonyl,<BR> <BR> <BR> <BR> <BR> (ClC4)alkyloxyS02, (C1,C4)alkylS02O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or severalOH orF; c) benzene or benzene substituted by one or several radicals independently selected from OH, CHO, SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (ClC4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; and d) a bicyclic system consisting of a benzene fused with a fiveor sixmembered ring optionally containing from one to three heteroatoms selected from O, S and N, this bicyclic system being optionally substituted by one or several radicals independently selected fromOH, oxo (=O), CHO, SH, NO2, CN, F, Cl, Br, (ClC4)alkanoy (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (ClC4)alkylsulphinyl, <BR> <BR> <BR> (CiC4)alkylsulphenyl, (ClC4)alkylsulphonyl,<BR> <BR> <BR> <BR> <BR> (CzC4)alkyloxyS02, (CxC4)alkylSOaO, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; J is a bond or a biradical selected from the following groups: a) (CH2) 14alkylidene ; b) O, S, SO, SO2, CO, OCO, COO, OCONR2,NR2COO,CONR2,NR2CO,NR2, NR2SO2, SO2NR2; and c) O(C1C4), (C1C4)O, S(C1C4), (C1C4)S, SO(C1C4), (C1C4)SO, SO2(C1C4), (C1C4)SO2, OCO(C1C4), COO(C1C4), (C1C4)OCO, (C1C4)COO, OCONR2(C1C4), NR2COO(C1C4), (C1C4)OCONR2, (C1C4)NR2COO, CONR2(C1C4), NR2CO(C1C4), (ClC4)CONR2l(ClC4)NR2COlNR2(ClC4) (C1C4)NR2, SO2NR2(C1C4), NR2SO2(C1C4), (C1C4)SO2NR2, (C1C4)NR2SO2; K is a radical selected from the following groups: a) H; b) (ClC4)alkyl ; c) a radical from a cycle selected from the following: cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all of them optionally substituted by one or several radicals independently selected from OH, oxo (=O), CHO, SH, NO2, CN, F, Cl, Br, (CiC4)alkanoyl, (ClC4)alkoxycarbonyl, (C1C4)alkanoylOxy (ClC4)alkylsulphinyl, (ClC4)alkylsulphenyl, (ClC4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF ; d) a radical from a fiveor sixmembered heterocycle containing from one to three heteroatoms selected from 0, S and N, being this heterocycle optionally substituted by one or several radicals independently selected from OH, oxo (=O), CHO, SH, NO2, CN, F, Cl, Br, (ClC4)alkanoyl, (C1C4)alkoxycarbonyl, (ClC4)alkanoyloxy, (ClC4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxyS02, (CiC4)alkylSO2O, NR2R3,CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; and e) phenyl or phenyl optionally substituted by one or several radicals independently selected from OH,CHO,SH,N02,CN,F,Cl,Br, (C1C4)alkanoyl, (ClC4)alkoxycarbonyl, (C1C4)alkanoyloxy, (C1C4)alkylsulphinyl, (ClC4)alkylsulphenyl, (ClC4)alkylsulphonyl, (ClC4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or severalOH orF; I'is a biradical of a cycle selected from the following groups: a) cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all optionally substituted by one or several radicals independently selected from OH, oxo (=O), CHO, SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (ClC4)alkanoyloxy, (C1C4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (ClC4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or severalOH orF ; b) a fiveor sixmeiDered aromatic heterocycle containing from one to three heteroatoms selected from O, S and N, being this heterocycle optionally substituted by one or several radicals independently selected from OH, oxo (=O), CHO, SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoycarbonyl, (C1C4)alkanoyloxy, (ClC4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (ClC4)alkyloxyS02, (C1C4)alkylSO20, NR2R3,CONR2R3, (ClC4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or severalOH orF; c) benzene substituted by one or several radicals independently selected fromOH,CHO,SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (ClC4)alkoxycarbonyl, (ClC4)alkanoyloxy, (C1C4)alkylsulphinyl, (ClC4)alkylsulphenyl, (ClC4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or or F ; and d) a bicyclic system consisting of a benzene fused with a fiveor sixmembered ring optionally containing from one to three heteroatoms selected from O, S and N, being this bicyclic system optionally substituted by one or several radicals independently selected fromOH, oxo (=O), CHO, SH, NO2, CN, F, Cl, Br, (ClC4)alkanoyl, (ClC4)alkoxycarbonyl, (C1C4)alkanoyloxy, (CiC4)alkylsulphinyl, (ClC4)alkylsulphenyl, (ClC4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; Z is a radical selected from the following groups: a) QIJT wherein Q is a biradical (CH2)13; I is as defined above; Jis as defined above; and T is a radical selected from the following groups: a. a) H ; a. b) (ClC4)alkyl ; a. c) a radical from a cycle selected from the following: cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all of them optionally substituted by one or several radicals independently selected fromOH, oxo (=O),CHO,SH,N02,CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (ClC4)alkylsulphinyl, (C1C4)alkylsulphenyl, (ClC4)alkylsulphonyl, (ClC4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; a. d) a radical from a fiveor sixmembered heterocycle containing from one to three heteroatoms selected from O, S and N, this heterocycle being optionally substituted by one or several radicals independently selected fromOH, oxo (=O),CHO,SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (CiC4)alkoxycarbonyl, (ClC4)alkanoyloxy, <BR> <BR> <BR> (C1C4)alkylsulphinyl,<BR> <BR> <BR> <BR> <BR> (C1C4)alkyl, sulphenyl, (ClC4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO20, NR2R3,CONR2R3, (ClC4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; a. e) phenyl or phenyl optionally substituted by one or several radicals independently selected fromOH,CHO,SH,NO2,CN, F, Cl, Br, (C1C4)alkanoyl, (ClC4)alkoxycarbonyl, (ClC4)alkanoyloxy, (C1C4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or severalOH orF; and a. f) a radical from a bicyclic system consisting of a benzene fused with a five or sixmembered ring optionally containing from one to three heteroatoms selected from O, S and N, being this bicyclic system optionally substituted by one or several radicals independently selected fromOH, oxo (=O),CHO,SH,NO2,CN,F,Cl, Br, (C1C4)alkanoyl, (C1C4)alkylsulphinyl, (C1C4)alkanoyloxy, (C1C4)alkylsulphinyl, (ClC4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; b)(CH2) SXPIJT wherein s is 2 or 3; Xis selected from the group consisting of O, S, SO, SO2 and NR4, being R4 a radical selected from the group : b. a) H ; b. b) (C,Clo)alkyl ; b. c) cycloalkyl, cycloalkylCO, cycloalkyl (C1C3)alkyl and cycloalkyl (CJ,C3)alkanoyl, wherein the cycloalkyl is a fiveor sixmembered ring optionally substituted by one or several radicals selected fromOH, oxo (=O),CHO, SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (ClC4)alkoxycarbonyl, (C1C4)alkanoyloxy, (ClC4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3,CONR2R3, (ClC4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or several OH or F; b. d) phenyl, phenylCO, phenyl(C1C3)alkyl and phenyl (ClC3)alkanoyl, being this aromatic ring optionally substituted by one or several radicals selected fromOH, CHO, SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (ClC4)alkylsulphinyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (ClC4)alkylsulphenyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (ClC4)alkylsulphonyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (C1Ca)alkyloxySO2, (C1C4)alkylS020, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or severalOH orF ; and b. e) a heterocycle, heterocycleCO, heterocycle (C1C3)alkyl and heterocycle (ClC3)alkanoyl, wherein the heterocycle is a fiveor sixmembered ring containing from one to three heteroatoms selected from O, S and N, being this heterocycle optionally substituted by one or several radicals selected fromOH, oxo (=O), CHO, SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (C1C4)alkylsulphinyl, (C1C4)alkylsulphenyl, (ClC4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (C1C4)alkoxyl optionally substituted by one or severalOH orF ; Pis a bond or a (CH2) 14 biradical ; Iis as defined above; J is as defined above; and T is a radical as defined above; c) (CH2)uCONR5PIJT wherein u is 1 or 2; R5is a radical selected from the group: c. a) H ; c. b) (ClCio)alkyl ; c. c) cycloalkyl and cycloalkyl(C1C3)alkyl, wherein the cycloalkyl is a fiveor sixmembered ring optionally substituted by one or several radicals selected fromOH, oxo (=O),CHO,SH,N02,CN,F,Cl, Br, (CiC4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (C1C4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3,CONR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC'4)alkoxyl optionally substituted by one or severalOH or F ; c. d) phenyl and phenyl(C1C3)alkyl, being this aromatic ring optionally substituted by one or several radicals selected from OH,CHO,SH,N02,CN,F,Cl,Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (C1C4)alkylsulphinyl, (C1C4)alkylsulphenyl, (ClC4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3,COMR2R3, (C1C4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; and c. e) a heterocycle and heterocycle (CiC3)alkyi, wherein the heterocycle is a fiveor sixmembered ring containing from one to three heteroatoms selected from 0, S and N, being this heterocyclo optionally substituted by one or several radicals selected fromOH, oxo <BR> <BR> <BR> <BR> (=O),CHO,SH,N02,CN,F,Cl,Br,<BR> <BR> <BR> <BR> <BR> (ClC4)alkanoyl, (ClC4)alkoxycarbonyl,<BR> <BR> <BR> <BR> <BR> (C1C4)alkanozloxy, (C1C4)alkylsulphinyl,<BR> <BR> <BR> <BR> <BR> <BR> (ClC4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (C1C4)alkylSO2O, NR2R3, CONR2R3, (C1C4)alkyl optionally substituted by one or severalseveralOH or F, and (ClC4)alkoxyl optionally substituted by one or severalOH orF; Pis as defined above ; Iis as defined above; Jis as defined above ; and T is as defined above ; d)(CH2) SNR6R7, wherein s is as defined above, and R6 and R7 together with the N are joined forming a fiveor sixmembered cycle optionally containing from one to three additional heteroatoms selected from O, S and N, and that may be fused or substituted by one or two five or sixmembered cycles optionally containing one or several heteroatoms selected from the group composed of O, S and N, all the cycles being optionally substituted by one or several radicals independently selected fromOH, oxo (=O),CHO, SH, NO2, CN, F, Cl, Br, (C1C4)alkanoyl, (C1C4)alkoxycarbonyl, (C1C4)alkanoyloxy, (C1C4)alkylsulphinyl, (C1C4)alkylsulphenyl, (C1C4)alkylsulphonyl, (C1C4)alkyloxySO2, (ClC4)alkylSO20,NR2R3,CONR2R3, (ClC4)alkyl optionally substituted by one or severalOH orF, and (ClC4)alkoxyl optionally substituted by one or severalOH orF ; and e) (CH2) uCONR6R7 wherein u is as defined above, and R6 and R7 are as defined above; with the proviso that compound of formula (I) is neither 2(4benzyloxybenzoylamino)3phenylpropionic acid, nor 2 [4 (4methoxybenzyloxy) benzoylamino]3phenylpropionic acid, nor 2 [4 (4bromobenzyloxy) benzoyla. rnino]3phenylpropionic acid.
2. The compound according to claim 1, wherein W is NHCH (E) .
3. The compound according to claim 2, whereinZ is a radical of theQIJT type.
4. The compound according to claim 2, whereinZ is a radical of the (CH2) SXPIJT type.
5. The compound according to claim 4, whereinXisO.
6. The compound according to claim 4, wherein s is 2 andX isNR4.
7. The compound of claim 1, wherein W isN (E)CH2CH2.
8. The compound according to claim 7, whereinZ is a radical of theQIJT type.
9. The compound according to claim 7, whereinZ is a radical of the (CH2)sXPIJT type.
10. The compound according to claim 9, whereinXisO.
11. The compound according to claim 9, wherein s is 2 andX isNR4.
12. The compound according to claim 1, whereinA is anOR1 type radical.
13. The compound according to claim 1 selected from the group consisting of: <BR> <BR> <BR> <BR> (2S)3 (4benzyloxyphenyl)2 [4 (4butoxybenzyloxy) benzoylami no] propionic acid methyl ester ; (2S)3(4benzyloxyphenyl)2[4(3bromobenzyloxy)benzoylamin o] propionic acid methyl ester; <BR> <BR> <BR> <BR> (2S)3 (4benzyloxyphenyl)2 [4 (2chlorobenzyloxy) benzoylami no] propionic acid methyl ester ; <BR> <BR> <BR> <BR> (2S)3 (4benzyloxyphenyl)2 [4 (2fluorobenzyloxy) benzoylami no] propionic acid methyl ester ; (2S)3(4benzyloxyphenyl)2[4(3methylbenzyloxy)benzoylami no] propionic acid methyl ester ; (2S)3(4benzyloxyphenyl)2[4(3 trifluoromethylbenzyloxy) benzoylamino] propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2[4(2 methoxybenzyloxy) benzoylamino] propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2[4(2methylbenzyloxy)benzoylami no] propionic acid methyl ester ; (2S)3(4benzyloxyphenyl)2[4(2 trifluoromethylbenzyloxy) benzoylamino] propionic acid methyl ester; (2S)3 (4benzyloxyphenyl)2 [4 (2o tolylethoxy) benzoylamino] propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2{4[3(4 propoxyphenoxy) propoxy] benzoylamino} propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2[4(3 methoxybenzyloxy) benzoylamino] propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2[4(2ethoxybenzyloxy)benzoylami no] propionic acid methyl ester ; (2S)3 (4benzyloxyphenyl)2 [4 (4butylbenzyloxy) benzoylamin o] propionic acid methyl ester ; <BR> <BR> <BR> <BR> (2S)2 [4 (4butylbenzyloxy) be n. 2, oylamino]3cycloilexylpropion ic acid methyl ester; (2S)2{4[2(3methylquinoxyalin2yloxy)ethoxy]benzoylamino} 3phenylpropionic acid methyl ester; (2S)3(4benzyloxyphenyl)2[4(2pyridin2ylethoxy)benzoyl amino] propionic acid methyl ester ; (2S)3 (4benzyloxyphenyl)2 {4 [2 (3methylquinoxalin2 yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2{4[2(pyridin2 yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)3 (4benzyloxyphenyl)2 (4 [2 (quinolin8 yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2{4[2(quinolin7 yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2{4[2(quinolin2 yloxy) ethoxy]benzoylamino}propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2[3(3methylquinoxalin2 yloxy) propoxy] benzoylamino} prcDpionic acid methyl ester; (2S)3(4bromophenyl)2{4[2(3methylquinoxalin2 yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)3(4fluorophenyl)2{4[2(3methylquinoxalin2 yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)3(4benzyloxyphenyl)2{4[2(3methylquinoxalin2 yloxy) ethoxy] benzoylamino} propionic acid ethyl ester; (2S)3(4benzyloxyphenyl)2{4[2(3methylquinoxalin2 yloxy) ethoxy] benzoylamino} propionic acid isopropyl ester; (2S)3(4benzyloxyphenyl)2{4[2(3methylquinoxalin2 yloxy) ethoxy] benzoylamino} propionic acid propyl ester; (2S)2 (4benzyloxybenzoylam=Lno)3 (4benzyloxyphenyl) propion ic acid; (2S)2 [4 (3benzyloxybenzylo5cy) benzoylaminol3 (4 benzyloxyphenyl) propionic acid ; 3f (3benzyloxybenzyl) [4 (2 dibenzylaminoethoxy) ben. zoyl] amino} propion. ic acid; 3((3denzyloxybenzyl){3[2(3methylquinoxalin2 yloxy) ethoxy] benzoyl} amino) propionic acid; <BR> <BR> <BR> 3 { (3benzyloxybenzyl) [4 (3benzyloxybenzyloxy) benzoyl] amino } propionic acid; 2 [4 (4benzyloxybenzyloxy) benzoylamino]3 (4benzyloxyphenyl ) propionic acid; (2S)2[3(4benzyloxybenzyloxy)benzoylamino]3(4 benzyloxyphenyl) propionic acid ; 3(4benzyloxyphenyl)2[3(biphenyl4ylmethoxy)benzoylamino ] propionic acid; 2 [4 (3benzyloxybenzyloxy) bensoylamino]3 (4bromophenyl) pro pionic acid ; 3 (4benzyloxyphenyl)2 [4 (4butylbenzyloxy) benzoylamino] pro pionic acid ; 2 [4 (4butylbenzyloxy) benzoylamino]3cyclohexylpropionic acid; <BR> <BR> <BR> { (3benzyloxybenzyl) [4 (4butyibenzyloxy) benzoyl] amino} aceti c acid; 3{(3benzyloxybenzyl)[4(4butylbenzyloxy)benzoyl]amino}pro pionic acid ; 3 (4benzyloxyphenyl)2 [4 (2bromobenzyloxy) benzoylamino] pro pionic acid; 3 (4benzyloxyphenyl)2 [4 (2chlorobenzyloxy) benzoylamino] pr opionic acid; <BR> <BR> <BR> <BR> 3 (4benzyloxyphenyl) 2 [4 (2methylbenzyloy) benzoylamino] pr opionic acid; 3 (4benzyloxyphenyl)2 [4 (3 trifluoromethylbenzyloxy) benzoylamino] propionic acid; and 3 (4benzyloxyphenyl)2 [4 (2 trifluoromethylbenzyloxy) benzoylamino] propionic acid.
14. A pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of the compound according to any one of the claims 1 to 13 together with appropriate amounts of pharmaceutically acceptable excipients.
15. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of diseases in an animal including a human.
16. Use of the compound as defined in any one of claims l to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of PPARy mediated diseases in an animal including a human.
17. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of PPARy/PPAR8 mediated diseases in an animal including a human.
18. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of a condition associated with a metabolic disease in an animal including a human.
19. Use according to claim 18, wherein the metabolic disease is noninsulindependent diabetes mellitus (NIDDM).
20. Use according to claim 18, wherein the metabolic disease is obesity.
21. Use according to claim 18, wherein the metabolic disease is selected from hypercholesterolaemia, and other lipidmediated pathologies.
22. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of a cardiovascular disease associated with metabolic syndrome in an animal including a human.
23. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of inflammation or an inflammatory process in general in an animal including a human.
24. Use according to claim 23, wherein the inflammatory process is selected from rheumatoid arthritis, and atherosclerosis.
25. Use according to claim 23, wherein the inflammatory process is selected from psoriasis, and intestinal inflammatory disease.
26. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of a bone disease, particularly osteoporosis, in an animal including a human.
27. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of cancer in an animal including a human.
28. Use of the compound as defined in any one of claims 1 to 13 for the manufacture of a medicament for the prophylactic and/or curative treatment of skin wound healing or cutaneous disorders associated with an anomalous differentiation of epidermic cells, particularly the formation of keloids, in an animal including a human.
29. Use according to any of the claims 15 to 28, wherein the medicament is administered orally,, parenterally or topically.
30. A method for the prophylactic and/or curative treatment of a condition mediated by PPARy in an animal including a human, comprising administering a therapeutically effective amount of a compound as defined in claim 1 together with an appropriate amount of pharmaceutically acceptable excipients.
31. A method for the prophylactic and/or curative treatment of a condition mediated by both PPARy and PPAR5 in an animal including a human, comprising administering. a therapeutically effective amount of a compound as defined in claim 1 together with an appropriate amount of pharmaceutically acceptable excipients.
32. The method according to any one of claims 30 or 31, wherein the administration is carried out orally, parenterally or topically.
33. A method for the prophylactic and/or curative treatment of an animal including a human, suffering from a condition associated with metabolic diseases, comprising administering a therapeuticaly effective amount of a compound as defined in claim 1 together with an appropriate amount of pharmaceutically acceptable excipients.
34. A method for the prophylactic and/or curative treatment of an animal including a human, suffering from a cardiovascular disease associated with metabolic syndrome, comprising administering a therapeuticaly effective amount of a compound as defined in claim 1 together with an appropriate amount of pharmaceutically acceptable excipients.
35. A method for the prophylactic and/or curative treatment of an animal, including a human, suffering from inflammation or an inflammatory process in general, comprising administering a therapeuticaly effective amount of a compound as defined in claim 1 together with an appropriate amount of pharmaceutically acceptable excipients.
36. A method for the prophylactic and/or curative treatment of an animal, including a human, suffering from bone diseases comprising administering a therapeuticaly effective amount of a compound as defined in claim 1 together with an appropriate amount of pharmaceutically acceptable excipients.
37. A method for the prophylactic and/or curative treatment of an animal, including a human, suffering from cancer, comprising administering a therapeuticaly effective amount of a compound as defined in claim 1 together with an appropriate amount of pharmaceutically acceptable excipients.
38. A method for the prophylactic and/or curative treatment of an animal, including a human, suffering from skin wound healing or cutaneous disorders associated with an anomalous differentiation of epidermic cells, particularly the formation of keloids, comprising administering a therapeuticaly effective amount of a compound as defined in claim. 1 together with an appropriate amount of pharmaceutically acceptable excipients.
Description:
New benzamides as PPARy modulators The present invention relates to new benzamides acting as PPARy and PPARy/PPARb modulators, as well as to processes and intermediates useful for their preparation, and to pharmaceutical compositions containing them.

BACKGROUND ART Peroxisome proliferator activated receptors (PPARs) belong to the superfamily of transcription factors known as nuclear receptors. This family includes steroid, retinoid and thyroid hormone receptors. Three sub-types of PPARs have been identified in humans, rodents and'Xenopus. They are PPARa, PPARß/6 and PPARy, each encoded by a different gene and showing different tissue distribution.

The gene encoding for PPARy is transcribed in humans in three different mRNA isoforms (PPARyl, PPARy2 and PPARy3) through different splicing and promoter usage (Fajas et al., J. Biol.

Chem. 1997, 272, 18779-18789). The PPARy1 isoform shows a wide tissular distribution, while PPARy2 and PPARy3 are confined to certain tissues: PPARγ2 is expressed only in adipose tissue and PPARy3 in adipose tissue as well as in macrophages (Fajas et al., FEBS Lett. 1998, 438,55-60).

X9 Differences detected in tissue distribution as well as in the activation profile of the PPARr isoforms suggest they are involved in a variety of physiological functions playing a central role in homeostasis and lipid metabolism (Vamecg et al., Lancet 1999,354, 141-148). These functions include, for example, lipidic transport in plasma and catabolism of fatty acids, regulation of insulin sensitivity and blood glucose levels, differentiation of macrophages that form atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, and adipocyte differentiation, the latter being the most verified function of the PPARy (Grimaldi, Prog. Lipid Res. 2001,40, 269-281, Schiller et <BR> <BR> <BR> <BR> al. , J. Biol. Chem. 2001, 276, 14133-14137). Thus, the discovery of these transcription factors has provided new pharmacological targets for the development of useful therapeutic agents for the prevention and treatment of metabolic diseases such as diabetes, obesity and dyslipidaemia.

Non-insulin dependent diabetes mellitus (NIDDM) or type 2 diabetes is characterized by an insulin resistance in peripheral tissues, including muscle, liver, and adipose tissue. Glitazones, selective PPARy agonist compounds, are drugs that reduce insulin resistance and lower blood glucose levels. Currently two products belonging to this family, rosiglitazone and pioglitazone, have been approved for the treatment of type 2 diabetes in humans.

A great effort has been made in recent years to design new drugs that improve the side effect profile of the first glitazones, show a greater affinity as a PPARy ligands, and increase their potency in type 2 diabetes. This rational design has yielded structurally diverse compounds that show great potency and selectivity. Among them is interesting to highlight the 2-alkoxyphenylpropionic type derivatives ragaglitazar (1, EP 1049684) and tesaglitazar (2, EP 1084103). These compounds are currently in phase III and II of clinical development, respectively.

(1) (2) The use of compounds totally or partially blocking PPARy activity is useful for the inhibition of adipocyte differentiation, which constitutes an effective treatment for obesity.

PPAR8 activation has been shown to lead to increased levels of HDL cholesterol in db/db mice (Leibowitz et al, FEBS Lett. 2000, 473, 333-336), and in diabetic-obese rhesus monkeys, while lowering the levels of LDL, triglycerides, and insulin (Oliver et al, Proc Nat Acad Sci USA, 2001, 98, 5306-5311). The involvement of PPAR# in fatty acid oxidation in muscles was further sustained in PPARa knock-out mice (Muoio et al., J. Biol. Chem. 2002, 277,26089-26097). A number of PEAR. compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (e. g. WO 02/59098, WO 01/603, WO 01/25181, WO 02/14291, WO 01/79197, WO 99/4815, WO 97/28149, WO 98/27974, WO 97/28115, WO 97/27857, WO 97/28137, WO 97/27847). Taken together, these observations suggest that PPAR6 activation is useful in the treatment and prevention of cardiovascular diseases and conditions including atherosclerosis, hypertriglyceremia and mixed dyslipidemia (WO 01/00603) In vitro studies investigating the pharmacological modulation of PPARB suggest that this kind of ligands may prove to be efficacious drugs for decreasing cardiovascular disease associated with metabolic syndrome, a condition comprised of a cluster of risk factors that also includes insulin resistance, obesity and hypertension (Mukjerheer, Drug News Perspect. 2002,15, 261-267).

Pro-differentiation and lipid accumulation effects have been reported in rodent and cultured human keratinocytes, as well as protection against cell death upon PPARB activation (Tan et al., Genes Dev. 2001,15, 3263-3277; Schmuth et al., J.

Invest. Dermatol. 2004,122, 971-983). Modulators of these activities could be useful for treating a variety of skin disorders.

In addition, PPARS has been implicated as a direct target in colorectal carcinogenesis in mice. All the evidences suggest that PPAR8 expression may promote tumour growth and, thus, may be also a potential target for the treatment of colorectal cancer (e. g. Park et al., Proc Nat Acad Sci USA, 2001, 98, 2598-2603). While PPARy is acknowledged as a master regulator of adipogenesis, PPAR8 may also play a role in adipocyte differentiation, as demonstrated by in vitro and in PPARB-deficient animals, promoting PPARy gene expression, which upon specific ligand activation promotes adipogenesis.

Thus a non-selective PPARy/6 antagonist would be also a potential drug for obesity (Shearer et al., Curr. Med. Chem.

2003,10, 267-280).

This indicate that research for compounds displaying various degrees of PPARy and PPAR5 modulation should lead to the discovery of drugs that have great potential in the treatment of diseases such as type-2 diabetes, dyslipidemia, syndrome X, cardiovascular diseases (including atherosclerosis), hypercholesteremia, colon cancer, skin disorders (including psoriasis, and wound healing, Tan et al., Expert Opín. Ther. Targets, 2004,8, 39), and bone diseases (Pei et al., J. Clin. Invest., 2004, 113, 805-806).

Consequently, it is of great interest to provide new therapeutic agents that selectively modulate PPARy, and PPARy /PPAR8.

Kundu and collaborators have described benzamides (3), (4) and (5) as N-0-glucosidase inhibitors (Comb. Chem. High.

2002,5, 545-550). These compounds are structurally close to those of this invention, but were described for different uses.

SUMMARY OF THE INVENTION One aspect of the present invention relates to the provision of new compounds of formula (I), 0 its stereoisomers and mixtures thereof, its polymorphs and mixtures thereof, and the pharmaceutically acceptable solvates and addition salts of all of them, wherein the central benzene ring may be substituted in meta-or para- position and, - A is a radical selected from the group consisting of -OR1, -NR2OR1 and-NR2R3; wherein R1, R2 and R3 independently represent -H or -(C1-C4)-alkyl ; - W-is a biradical selected from the group:-NH-CH (E) -,- N (E)-CH2-, and-N (D)-CH2-CH2- ; wherein E is a radical of the-G-I-J-K type and D is a radical of the-G-I- J-K type where: -G - is a bond or a -(CH2)1-4- biradical ; -I - is a biradical of a cycle selected from the following groups: a) cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all optionally substituted by one or several radicals independently selected from-OH, oxo (=O),- CHO, -SH, -NO2, -CN, -F, -Cl, -Br, -(C1-C4)- alkanoyl, (C1-C4)-alkoxycarbonyl, (C1-C4)- alkanoyloxy, (Ci-C4)-alkylsulphinyl, (Cl-C4)- alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)- alkyloxy-S02-, (C1-C4)-alkyl-SO2O-, -NR2R3, - CONR2R3, (Cl-C4)-alkyl optionally substituted by one or several-OH or-F, and (C1-C4)- alkoxyl optionally substituted by one or several-OH or-F; b) a five-or six-membered aromatic heterocycle containing from one to three heteroatoms selected from O, S and N, this heterocycle being optionally substituted by one or several radicals independently selected from-OH, oxo (=O),-CHO,-SH,-N02,-CN,-F,-Cl,-Br, (C1- C4) -alkanoyl, (Cl-C4)-alkoxycarbonyl, (C1-C4)- alkanoyloxy, (C1-C4)-alkylsulphinyl, (C1-C4)- alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)- alkyloxy-SO2-, (Cl-C4)-alkyl-S02o-,-NR2R3,- CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (C1-C4)- alkoxyl optionally substituted by one or several-OH or-F; c) benzene or benzene substituted by one or several radicals independently selected from- OH, -CHO, -SH, -NO2, -CN, -F, -Cl, -Br, (Cl-C4)- alkanoyl, (C1-C4)-alkoxycarbonyl, (Cl-C4)- alkanoyloxy, (C1-C4)-alkylsulphinyl, (C1-C4)- alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (C1-C4)- alkyloxy-S02-, (C1-C4)-alkyl-SO2O-, -NR2R3, - CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (C1-C4)- alkoxyl optionally substituted by one or several-OH or-F; and d) a bicyclic system consisting of a benzene fused with a five-or six-membered ring optionally containing from one to three heteroatoms selected from O, S and N, this bicyclic system being optionally substituted by one or several radicals independently selected from-OH, oxo <BR> <BR> <BR> <BR> (=O),-CHO,-SH,-N02,-CN,-F,-Cl,-Br, (Ci-<BR> <BR> <BR> <BR> <BR> <BR> <BR> C4) -alkanoyl, (Ci-C4)-alkoxycarbonyl, (C1-C4)- alkanoyloxy, (C1-C4)-alkylsulphinyl, (Cl-C4)- alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (Ci-C4)- alkyloxy-S02-, (C1-C4)-alkyl-SO2O-, -NR2R3, - CONR2R3, (Cl-C4)-alkyl optionally substituted by one or several-OH or-F, and (C1-C4)- alkoxyl optionally substituted by one or several-OH or-F; - J-is a bond or a biradical selected from the following groups: a)-(CH2)1-4-alkylidene ; <BR> <BR> <BR> <BR> b)-O-,-S-,-SO-,-SO2-,-CO-,,-OCO-,-COO-,-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> OCONR2-,-NR2COO-,-CONR2-,-NR2CO-,-NR2-,- NR2SO2-, -SO2NR2- ; and C)-O-(C1-C40-, -(C1-C4)-O-, -S-(C1-C4)-, -(C1-C4)-S ,-SO- (Cl-C4)-,- (Cl-C4)-SO-,-S02- (C1-C4)-,- (C1-C4)-SO2-, -OCO-(C1-C4)-, -COO-(C1-C4)-, -(C1- 4)-OCQ-,- (C1-C4)-COO-,-OCONR2-(C1-C4)-,- NR2COO-(C1-C4)-, -(C1-C4)-OCONR2-, -(C1-C4)- NR2COO-, -CONR2-(C1-C4)-, -NR2CO-(C1-C4)-, -(C1- C4)-CONR2-, -(C1-C4)-NR2CO-, -NR2-(C1-C4)-, -(C1- <BR> <BR> <BR> <BR> C4)-NR2-,-S02NR2- (Cl-C4)-,-NR2SO2- (Cl-C4)-,-<BR> <BR> <BR> <BR> <BR> <BR> <BR> (Cl-C4)-S02NR2-,-Wl-C4)-NR2S02- ; -K is a radical selected from the following groups: a) -H; b) (C1-C4)-alkyl ; c) a radical from a cycle selected from the following: cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all of them optionally substituted by one or several radicals independently selected from -OH, oxo (=O), -CHO, -SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (Ci-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyl, (C1-C4)-alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (Cl-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; d) a radical from a five-or six-membered heterocycle containing from one to three heteroatoms selected from 0, S and N, being this heterocycle optionally substituted by one or several radicals independently selected from -OH, oxo (=O), -CHO, -SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, <BR> <BR> <BR> (Cl-C4)-alkanoyloxy, (Cl-C4)-alkylsulphinyl,<BR> <BR> <BR> <BR> <BR> (Cl-C4)-alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (Cl-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; and e) phenyl or phenyl optionally substituted by one or several radicals independently selected from - OH,-CHO,-SH,-NO2,-CN,-F,-Cl,-Br, (Cl-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoxyloxy, (C1-C4)-alkylsulphinyl, (Cl-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO20-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; is a biradical of a cycle selected from the following groups: a) cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all optionally substituted by one or several radicals independently selected from-OH, oxo (=O), <BR> <BR> <BR> <BR> -CHO,-SH,-NO2,-CN,-F,-Cl,-Br,<BR> <BR> <BR> <BR> <BR> <BR> (Cl-C4)-alkanoyl, (Cl-C4)-alkoxycarbonyl, (C1-C4)-alkanoxyloxy, (C1-C4)-alkylsulphinyl, (Cl-C4)-alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO20-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; b) a five-or six-membered aromatic heterocycle containing from one to three heteroatoms selected from O, S and N, being this heterocycle optionally substituted by one or several radicals independently selected from -OH, oxo (=O),-CHO,-SH,-N02,-CN,-F,-Cl, -Br, (C1-C4)-alkanoxy, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyl, (Cl-C4)-alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; c) benzene substituted by one or several radicals independently selected from-OH,-CHO,-SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (Cl-C4)-alkoxycarbonyl, (C1-C4)-alkanoyloxy, (Cl-C4)-alkylsulphinyl, (Cl-C4)-alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (Cl-C4)-alkyl-S020-,-NR2R3,-CONR2R3, (Cl-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or - F ; and d) a bicyclic system consisting of a benzene fused with a five-or six-membered ring optionally containing. from one to three heteroatoms selected from 0, S and N, being this bicyclic system optionally substituted by one or several radicals independently selected from-OH, oxo (=O), -CHO, -SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (Cl-C4)-alkanoyloxy, (Cl-C4)-alkylsulphinyl, (C1-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (Cl-C4)-alkyloxy-S02-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F ; -Z is a radical selected from the following groups: a) -Q-I-J-T wherein -Q- is a biradical -(CH2)1-3-; - I-is as defined above; -J-is as defined above; and -T is a radical selected from the following groups: a. a)-H ; a. b) (Cl-C4)-alkyl ; a. c) a radical from a cycle selected from the following : cyclopropane, cyclobutane, cyclopentane, cyclohexane and cyclohexene, all of them optionally substituted by one or several radicals independently selected from-OH, oxo (=O), -CHO, -SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyloxy, (Cl-C4)-alkylsulphinyl, (Cl-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (Cl-C4)-alkyloxy-S02-, (C1-C4)-alkyl-S020-, -NR2R3,-CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (C1-C4)-alkoxyl optionally substituted by one or several-OH or-F; a. d) a radical from a five-or six-membered heterocycle containing from one to three heteroatoms selected from 0, S and N, this heterocycle being optionally substituted by one or several radicals independently selected from-OH, oxo (=O),-CHO,-SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (Cl-C4)-alkanoyloxy, <BR> <BR> <BR> (Cl-C4)-alkylsulphinyl,<BR> <BR> <BR> <BR> <BR> (Cl-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; a. e) phenyl or phenyl optionally substituted by one or several radicals independently selected from-OH,-CHO,-SH,-N02,-CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, <BR> <BR> <BR> <BR> (Cl-C4)-alkoxycarbonyl, (Cl-C4)-alkanoyloxy,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (Cl-C4)-alkylsulphinyl, (C1-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3,-CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; and a. f) a radical from a bicyclic system consisting of a benzene fused with a five- or six-membered ring optionally containing from one to three heteroatoms selected from O, S and N, being this bicyclic system optionally substituted by one or several radicals independently selected from-OH, oxo (=O),-CHO,-SH,-N02,-CN,-F,-C1, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (1-04)-alkanoyloxy, (Cl-C4)-alkylsulphinyl, (C1-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; b) -(CH2)s-X-P-I-J-T wherein s is 2 or 3; -X- is selected from the group consisting of -O-, -S-, -SO-, -SO2- and -NR4-, being R4 a radical selected from the group: b. a) -H ; b. b) (C1-C10)-alk7yl ; b. c) cycloalkyl, cycloalkyl-CO-, cycloalkyl- (Cl-C3)-alkyl and cycloalkyl-(C1-C3)-alkanoyl, wherein the cycloalkyl is a five-or six-membered ring optionally substituted by one or several radicals selected from-OH, oxo (=O), -CHO, -SH, -NO2, -CN, -F, -C1, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (Cl-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyl, (C1-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several -OH or-F, and-(C1-C4)-alkoxyl optionally substituted by one or several OH or F ; b. d) phenyl, phenyl-CO-, phenyl-(Cl-C3)-alkyl and phenyl- (Cl-C3)-alkanoyl, being this aromatic ring optionally substituted by one or several radicals selected from <BR> <BR> <BR> -OH,-CHO,-SH,-NO2,-CN,-F,-Cl,-Br,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (Cl-C4)-alkanoyl, (Cl-C4)-alkoxycarbonyl, (Cl-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyl, (C1-C4)-alkylsulphenyl, (Cl-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO20-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several -OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; and b. e) a heterocycle, heterocycle-CO, heterocycle- (C1-C3)-alkyl and heterocycle-(C1-C3)-alkanoyl, wherein the heterocycle is a five-or six-membered ring containing from one to three heteroatoms selected from O, S and N, being this heterocycle optionally substituted by one or several radicals selected from-OH, oxo (=O),-CHO,-SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyl, (Cl-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO20-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several - OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; - P-is a bond or a -(CH2)1-4- biradical ; -I- is as defined above; - J-is as defined above; and -T is a radical as defined above; c)- (CH2) u-CO-NR5-P-I-J-T wherein u is 1 or 2; - R5is a radical selected from the group: c. a) -H ; c. b) (Cl-Cio)-alkyl ; c. c) cycloalkyl and cycloalkyl-(C1-C3)-alyl, wherein the cycloalkyl is a five-or six-membered ring optionally substituted by one or several radicals-selected from -OH, oxo (=O),-CHO,-SH,-N02,-CN,-F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (Cl-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyul, (C1-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (Cl-C4)-alkyl-SO20-, NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several -OH or-F, and (C1-C4)-alkoxyl optionally substituted by one or several-OH or-F ; c. d) phenyl and phenyl-(Cl-C3)-alkyl, being this aromatic ring optionally substituted by one or several radicals selected from -OH, -CHO, -SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alkanoyl, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyl, <BR> <BR> <BR> <BR> (C1-C4)-alkylsulphenyl,<BR> <BR> <BR> <BR> <BR> <BR> (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or several - OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; and c. e) a heterocycle and heterocycle- (Cl-C3)-alkyl, wherein the heterocycle is a five-or six-membered ring containing from one to three heteroatoms selected from O, S and N, being this heterocyclo optionally substituted by one or several radicals selected from-OH, oxo (=O),-CHO,-SH, -NO2, -CN, -F, -Cl, -Br, (C1-C4)-alanoyl, <BR> <BR> <BR> (Cl-C4)-alkoxycarbonyl,<BR> <BR> <BR> <BR> <BR> (Cl-C4)-alkanoyloxy, (C1-C4)-=alkylsulphinuyl, (C1-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C1-C4)-alkyl-SO2O-, -NR2R3, -CONR2R3, (C1-C4)-alkyl optionally substituted by one or severalseveral-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; -is as defined above; - is as defined above; is as defined above; and is as defined above; -(CH2)s-NR6R7, wherein s is as defined above, and R6 and R7 together with the N are joined forming a five-or six-membered cycle optionally containing from one to three additional heteroatoms selected from O, S and N, and that may be fused or substituted by one or two five-or six-membered cycles optionally containing one or several heteroatoms selected from the group composed of O, S and N, all the cycles being optionally substituted by one or several radicals independently selected from -OH, oxo (=O), -CHO, -SH, -NO2, -CN, -F, -Cl, - Br, (Ci-C4)-alkanoyl, (Cl-C4)-alkoxycarbonyl, (C1-C4)-alkanoyloxy, (C1-C4)-alkylsulphinyl, (C1-C4)-alkylsulphenyl, (C1-C4)-alkylsulphonyl, (C1-C4)-alkyloxy-SO2-, (C,,-C4)-alkyl-S020-,<BR> - NR2R3,-CONR2R3, (C1-C4)-alkyl optionally substituted by one or several-OH or-F, and (Cl-C4)-alkoxyl optionally substituted by one or several-OH or-F; and e)- (CH2) u-CO-NR6R7 wherein u is as defined above, and R6 and R7 are as defined above; with the proviso that compound of formula (I) is neither 2- (4-benzyloxybenzoylamino)-3-phenylpropionic acid, nor 2- [4- (4-methoxybenzyloxy) benzoylamino]-3-phenylpropionic acid, nor 2- [4- (4-bromobenzyloxy) benzoylamino]-3-phenylpropionic acid.

In a particular embodiment of this aspect of the invention, in the compounds of formula (I),-W-is-NH-CH (E) -. In another particular embodiment-W-is-NH-CH (E)-, and-Z is a radical of the-Q-I-J-T type. In another particular embodiment-W-is-NH-CH (E) -, and-Z is a radical of the - (CH2) g-X-P-I-J-T type. In another particular embodiment-W- is-NH-CH (E) -, and-Z is a radical of the -(CH2)s-O-P-I-J-T type. In another particular embodiment-W-is-NH-CH (E) -, and - Z is a radical of the- (CH2) 2-NR4-P-I-J-T type. In another particular embodiment-W-is-N (E)-CH2-CH2-. In another particular embodiment-W-is-N (E)-CH2-CH2-, and-Z is a radical of the-Q-I-J-T type. In another particular embodiment-W-is-N (E)-CH2-CH2-, and-Z is a radical of the -(CH2)s-X-P-I-J-T type. In another particular embodiment-W- is-N (E)-CH2-CH2-, and-Z is a radical of the - (CHZ) s-O-P-I-J-T type. In another particular embodiment-W- is-N (E)-CH2-CH2-, and-Z is a radical of the - (CH2) 2-NR4-P-I-J-T type. In another particular embodiment-A is a radical of the-OR1 type.

Preferred compounds of the present invention include: (2S)-3-(4-benzyloxyphenyl)-2-[4-(4-butoxybenzyloxy)benzoylam i no] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (3-bromobenzyloxy) benzoylamin o] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (2-chlorobenzyloxy) benzoylami no] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (2-fluorobenzyloxy) benzoylami no]propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-[4-(3-methylbenzyloxy)benzoylam i no] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (3- trifluoromethylbenzyloxy) benzoylamino] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (2- methoxybenzyloxy) benzoylamino] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (2-methylbenzyloxy) benzoylami no] propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-[4-(2- trifluoromethylbenzyloxy) benzoylamino] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (2-o- tolylethoxy) benzoylamino] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2-{4- [3- (4- propoxyphenoxy) propoxy] benzoylamino} propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (3- methoxybenzyloxy) benzoylamino] propionic acid methyl ester; (2S)-3- (4-benzyloxyphenyl)-2- [4- (2-ethoxybenzyloxy) benzoylami no] propionic acid methyl ester; <BR> <BR> <BR> <BR> (2S)-3- (4-benzyloxyphenyl)-2- [4- (4-butylbenzyloxy) benzoylamin o] propionic acid methyl ester; <BR> <BR> <BR> <BR> (2S)-2- [4- (4-butylbenzyloxy) benzoylamino]-3-cyclohexylpropion ic acid methyl ester; (2S)-2-{4-[2-(3-methylquinoxalin-2yloxy)ethoxy]benzoylamino} - 3-phenylpropionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-[4-(2-pyridin-2-ylethoxy) benzoyl amino] propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[2-(pyridin-2- yloxy) ethoxy] benzoylamino} propionic acid methyl ester ; (2S)-3- (4-benzyloxyphenyl)-2-{4-[2-(quinolin-8- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[2-(quinolin-7- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[2-(quinolin-2- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[3-(3-methylquinoxalin-2- yloxy) propoxy] benzoylamino} propionic acid methyl ester; (2S)-3-(4-bromophenyl)-2-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; (2S)-3-(4-fluorophenyl)-2-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy]benzoylamino}propionic acid methyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid ethyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid isopropyl ester; (2S)-3-(4-benzyloxyphenyl)-2-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid propyl ester; (2S)-2- (4-benzyloxybenzoylamino)-3- (4-benzyloxyphenyl) propion ic acid; (2S)-2-[4-(3-benzyloxybenzyloxy)benzoylamino]-3-(4- benzyloxyphenyl) propionic acid ; 3- { (3-benzyloxybenzyl)- [4- (2- dibenzylaminoethoxy) benzoyl] amino} propionic acid; 3-((3-benzyloxybenzyl)-{3-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoyl} amino) propionic acid; 3-{(3-benzyloxybenzyl)-[4-(3-benzyloxybenzyloxy)benzoyl]amin o } propionic acid; 2-[4-(4-benzyloxybenzyloxy)benzoylamino]-3-(4-benzyloxypheny l ) propionic acid; (2S)-2- [3- (4-benzyloxybenzyloxy) benzoylamino]-3- (4- benzyloxyphenyl) propionic acid ; <BR> <BR> <BR> <BR> 3- (4-benzyloxyphenyl)-2- [3- (biphenyl-4-ylmethoxy) benzoylamino ] propionic acid; 2- [4- (3-benzyloxybenzyloxy) benzoylamino]-3- (4-bromophenyl) pro pionic acid ; <BR> <BR> <BR> <BR> 3- (4-benzyloxyphenyl)-2- [4- (4-butylbenzyloxy) benzoylamino] pro pionic acid; 2- [4- (4-butylbenzyloxy) benzoylamino]-3-cyclohexylpropionic acid ; <BR> <BR> <BR> { (3-benzyloxybenzyl)- [4- (4-butylbenzyloxy) benzoyl] amino} aceti c acid; 3-{(3-benzyloxybenzyl)-[4-(4-butylbenzyloxy)benzoyl]amino}pr o r pionic acid ; 3- (4-benzyloxyphenyl)-2- [4- (2-bromobenzyloxy) benzoylamino] pro pionic acid; 3- (4-benzyloxyphenyl)-2- [4- (2-chlorobenzyloxy) benzoylamino] pr opionic acid; <BR> <BR> <BR> <BR> 3- (4-benzyloxyphenyl)-2- [4- (2-methylbenzyloxy) benzoylamino] pr opionic acid; 3- (4-benzyloxyphenyl)-2- [4- (3- trifluoromethylbenzyloxy) benzoylamino] propionic acid ; and 3- (4-benzyloxyphenyl)-2- [4- (2- trifluoromethylbenzyloxy) benzoylamino] propionic acid.

Throughout, the description and claims, the terms <BR> <BR> <BR> <BR> (Cl-C4)-alkyl, (Cl-Clo)-alkyl, (C1-C4)-alkoxyl, (Cl-C4)-alkanoyl, (Cl-C4)-alkoxycarbonyl and (Cl-C4)-alkanoyloxy shall be construed as straight or branched.

Some of the compounds of formula (I) of the present invention may have one or several chiral centres. The present invention includes each one of the possible stereoisomers and mixtures thereof, particularly racemic mixtures thereof. A single enantiomer may be prepared by any of the commonly used processes, for example, by chromatographic separation of the racemic mixture on a stationary chiral phase, by resolution of the racemic mixture by fractional crystallisation techniques of the diastereomeric salts thereof, by chiral synthesis, by enzymatic resolution or by biotransformation.

Pharmaceutically acceptable salts include, among others, addition salts of inorganic acids such as hydrochloric, hydrobromic, nitric, sulphuric and phosphoric, as well as addition salts of organic acids such as acetic, benzenesulphonic, benzoic, camphorsulphonic, mandelic, methanesulphonic, oxalic, succinic, fumaric, tartaric, and maleic. Likewise, an acid proton in compounds of formula (I) may be substituted by a metallic ion, for example, an alkaline metal ion, an alkaline-earth metal ion or an aluminium ion; or may be coordinated with an organic or inorganic base. An acceptable organic base includes diethylamine and triethylamine. An acceptable inorganic base includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. There may be more than one cation or anion depending on the number of functions with charge and on the valency of cations and anions.

Some of the compounds of formula (I) of the present invention may exist in unsolvated as well as solvated forms such as, for example, hydrates. The present invention encompasses all such above-mentioned forms which are pharmaceutically active.

Some of the compounds of general formula (I) may exhibit polymorphism, encompassing the present invention all the possible polymorphic forms, and mixtures thereof.

Compounds of general structure (I) may be prepared following various processes perfectly known by any skill person in the field of organic synthesis. Compounds of the present invention may be synthesized using the methods described below, as well as other processes known in the field of organic synthesis. Preferred methods include, but are not limited to, the general processes shown in the attached schemes.

Method A o o Coupling agent or O O pH SOCI2/tertiary base WOR 0 9 0 HO Il tOR1 HO O ('") (VII) Z-LG or Z-OH O O Il WOR zy I/ (la) According to a first method (Method A), the phenolic acid (II) is treated with the amine derivative (III) in the presence of a suitable coupling agent, for example the combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT), or with thionyl chloride in the presence of a tertiary base such as triethylamine (Elmore, Amino Acids Pep. Proteins 2001, 32, 107-162). Final compounds (Ia) are obtained by Williamson etherification by displacement of a leaving group (LG) bonded to a type-Z radical with the phenol (IV) (using for example NaH, K2C03 or Cs2CO3 as a base in a solvent such as DMF or acetone; (Bal-Tembe et al., Bioorg. Med. Chem. 1997,5, 1381-1388 ; Cantello et al., J. Med. Chem. 1994,37, 3977-3985, Solar et al., J. Org. Chem. 1966,31, 1996-1997; EP. 875510), or by Mitsunobu reaction between (IV) and a Z-OH type alcohol in the presence of, for example, diethyl azodicarboxylate (DEAD) and triphenylphosphine in tetrahydrofurane as a solvent (Mitsunobu, Synthesis 1981, 1 ; Hughes, Org. React. 1992, 42, 335).

Method B 0 Z-OH OR Z-LG or Z-OH Z\ 0 (oh)' (fla) (VII) (OH)- \ OT 0 o O (Vlb) 0 Coupling agent or SOCl2/tertiary base HW A (III) 0 0 O O ZoJX Z-OH A=OR1 (la) A=OH (lb) An alternative strategy (Method B) involves prior alkylation of the phenolic esters (V). After basic hydrolysis of the resulting ester, the final compounds (I) are synthesized by reaction with the amine derivative (III). Alternatively, and only in the specific case of para substitution of the aromatic ring, the phenolic ether (VI) may be formed by aromatic nucleophilic substitution starting from the fluorinated compound (VII).

When-Z is a radical of the-(CH2) S-X-P-I-J-T type where X is O or S, for the alkylation of the phenol another alternative procedure may be followed (Method C).

Method C 0 0 w'k OR1 HO LG- (CH,)g LG, (IV) w), ORI w oR, I i (VIII) \ O O'' (Vlll) A T-J-I-P-OH T-J-I-P-SH T-J-I-PS"s yac) (lac) 0 0 \ O. O Oxidation W oR1 S 0 oxidation T-J-I-P "S /W-'OR (laa) zozo S (lab) Oxidation O O O HWC1R p 9 ' \ 0 0 HW OR1 T-J-I-P Ms '\ O (OR t O O I/OR (Xa) R=alkyl T J l pSMOvOR (OH)- (Xla) R=al I (OH)- (Xbj R=H T'i-i-P-OH T-J-1- LGI- (CH2).-LG2 OR , HO-OY OR (V) 0 ( ! X) o px) The phenol (IV) or (V) is treated with the suitable doubly functionalised alkylidene derivative (EP 875510) and, then, a nucleophilic substitution reaction with the desired alcohol or thiol is carried out to obtain the compounds (Iaa), and (Iab) or the esters (Xa) and (XIa), depending on the initial phenol. The hydrolysis of'the esters (Xa) and (XIa) and their subsequent reaction with the amine derivative (III) also leads to the compounds (Iaa) and (Iab). The derivatives of the sulphoxide (Iac) and sulphone (Iad) types are obtained by oxidation of the corresponding thioether (Iab) in the presence of oxidizing agents such as, for example, hydrogen peroxide or m-chloroperbenzoic acid.

Method D 0 0 w LGCH,), 7N (PG)-P-1-J-T (Xa LG CH LG HO- (CHZ), bG)-P-tl_T p O i 2a 2 1 (XIb) T-J-I-, T4-1-P-NH+ Xeprotedion \,II . N. O I/WJOR Mu T1-1-P-NHR (faea) R-LG R"-CHO, H R"-COX O O O O R R R j0 j0 c j (y. I T-i-i-P, N'T-i-i-po T-i-i-P, (laeb) (laec) (laed) zozo HW HWOR, HW""OR, (III) (Iil) (III) OR R'R"\T. 0 AIR OR T_ J_I_P. NO T-J_I_P. NMO T_ J_i_P. NMO (XVla) R=alkyi (OH)-qv (XVlla) R=alky Ç (XVlila) R=alkyl (XVIb) R=H (XVllb) R=H (XVlilb) R=H R"-CHO, H R-LG R"-COX 0 \ OR i T-J-1-P-NHR / (XV) N T-J-1-P-NH Deprotection /\ LG,- (CNjs 7LG2 LG- (CH2). 7N (PG)-P-1-J-T 0 OR E 11 OR (XIIa) PG i/OR H-N (PG)-P-1-J-T N 0 13,- o cxne> T-J-I-P Ms (xn> U When-Z is a radical of the-(CH2) S-NR4-P-I-J-T type, the amines (Iae) may be obtained starting from the phenols (IV) or (V) following two alternative alkylation routes in every case (Method D). In the case of phenol (IV), the reaction with a doubly functionalised alkyliden derivative and, then, the nucleophilic substitution with the desired amines; or the etherification with the protected amine compound (XII) (as a trifluoroacetamide derivative, for example), and subsequent functionalisation of the amine released after its deprotection (in a basic medium, or with NaBH4 (Harland and Hodge Synthesis 1984,941-943)) yields the desired compounds.

The tertiary amines of the (Iaeb) and (Iaec) types are obtained by the treatement of the compound (Iaea) with alkylating agents or by reductive alkylation, respectively.

The amides (Iaed) are synthesized by acylation of the compound (Iaea) with the corresponding acid derivative in the presence of a tertiary amine, or by treating the secondary amine with an acid in the presence of a coupling agent such as, for example the combination of EDC and HOBT (Elmore, Amino Acids Pep. Proteins 2001, 32, 107-162). In the case of the phenol (V), the amines (Iae) are obtained by reaction of their precursor acids (XVIb), (XVIIb) and (XVIIIb) with the amine derivatives (III) following the methods outlined above.

These acids, in turn, are obtained from the phenol (V) following an analogous process to that used in the case of the phenol (IV).

The Z-OH or Z-LG type compounds are products that have already been described. Some of them are commercially available or may be prepared following methods analogous to those used to synthesize others that are already known, such as those that are explained in detail in the following documents: EP 03062228; WO 97/31907; WO 01/00603; Daoud et al. , J. Indian Chem. Soc. 1989, 66, 316-318 and Aquino, J. Med. Chem. 1996, 39, 562-569, some of them summarised in Scheme 1.

Scheme 1 0 R O T-J-I-px Xfi, (, 4R 0 R Nu R4 R4 R =-OAc,-COOR1 R4-COR OH Reduction X't°ls- lu N 'Y \NS- R4 R4 Q 0 T-J-i-P tLG P\N<U Nu R5 R5 Some of the compounds (III) are commercially available products, particularly when they are a-amino acids. Others have already been described or may be synthesized following various routes, most of which have been described (March, Advanced Organic Chemistry, 1991, Ed. John Wiley & Sons Juaristi, Enantioselective Synthesis of 8-Amino Acids, 1997, Ed. Wiley-VDH).

An approach for the preparation of the a-amino acids (W is - NH-CH (E) -) is the Sorensen synthesis (Mori, Tetrahedron 1985,2369-2377 ; Scheme 2), wherein dialkyl acyl-amide-malonate is alkylated in a basic medium and, after subsequent hydrolysis and decarboxylation, the desired a-amino acids (IIIa) are obtained.

Scheme 2 J4OR) H2N4 "-f 0 0 The Oh 2) E-LG 0 a OR 3) Hydrolisis/decarboxilation (XIX) (Illa) N-Substituted glycines and P-alanines (W is-N (E)-CH2-or -N (D)-CH2-CH2-) may be synthesized by the methods shown bellow, either by reductive amination of the corresponding glycine or alanine with the suitable aldehyde (Scheme 3) using reducing agents such as NaBH4, NaBH3CN or NaBH (AcO) 3, or by nucleophilic substitution of the esters (XX) or (XXI) with the suitable amine (Scheme 4).

Scheme 3 I (1) E'-CHO, H OR 2) Reduction OR (Illb) (Ilic) 0 1) D'-CHO H, Reduction H HZN OR) H (Ilid) (Ille) Scheme 4 An alternative process for the synthesis of a-alanines (III) would be the addition of the corresponding amine to the a, 3-unsaturated ester of interest (Scheme 5) Scheme 5 (XXII) (Ilig) Conversion of a compound of formula (I) into a different one involves transforming the-CO-A group into a different group.

The modifications considered are: the hydrolysis of the - COOR1 substituent, wherein-R1 represents a- (Cl-C4)-alkyl moiety, to yield the corresponding carboxylic acid; the esterification of the carboxylic acids (Ib) with the R10H alcohols ; and, lastly, the amination of the-COOR1 group to obtain the corresponding amides. The hydrolysis methods used are the usual ones, for example, using an alkaline hydroxide in aqueous methanol. The amination and esterification processes are those commonly used (Scheme 6).

Scheme 6 0 0 0 W (. E) I \ W OH sO a) R, OH/H+ Z\o or (la) b) R OH, coupling agent (lb) a) SOCI2, NHR2R3 a) SOCI2, NHR2OR, or or b) NHR2R3, coupling agent b) NHR2OR, coupling agent 00 00 O O O O ZX W NR2R3 i \ W NR20R (id) Cc) ('d) The compounds of the present invention are ligands of the PPARy and PPAR6. Therefore, they are expectedly useful for the prophylactic and/or curative treatment of a condition mediated by PPARy or PPARy/PPARb in an animal including a human. Thus, an aspect of the present invention relates to the use of these compounds for the preparation of a medicament for the prophylactic and/or curative treatment of a condition associated with metabolic diseases, particularly non-insulin-dependent diabetes mellitus, obesity, hypercholesterolaemia, and other lipid-mediated pathologies, cardiovascular diseases associated with metabolic syndrome, inflammation and inflammatory processes in general, such as rheumatoid arthritis, atherosclerosis, psoriasis, and intestinal inflammatory disease, bone diseases, particularly osteoporosis, cancer, skin wound healing, and cutaneous disorders associated with an anomalous differentiation of epidermic cells, particularly the formation of keloids.

Therefore, this aspect of the invention is related to a method for the prophylactic and/or curative treatment of an animal, including a human, suffering from the above-mentioned pathologies, which comprises administering a therapeutically effective amount of a formula (I) compound.

Another aspect of the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compound (I), as the active ingredient, together with appropiate amounts of pharmaceutically acceptable excipients. Preferably, the compound is administered orally, parenterally or topically.

Throughout the description and claims the word"comprise"and variations of the word, such as"comprising", is not intended to exclude other additives, components, elements or steps.

The disclosures in the abstract accompanying this application and in the application from which priority is claimed, are incorporated herein as reference.

Additional objects, advantages and novel features of the invention will be set forth in part in the description, and in part will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The present invention will be further illustrated by the following examples. The examples are given by way of illustration only and are not to be construed as limiting.

EXAMPLES 1H-NMR spectra of the compounds have been recorded using a VARIAN GEMINI-200 MHz and a VARIAN UNITY-300 MHz equipment and chemical shifts are expressed as ppm (o) from the internal reference TMS. Mass spectra have been obtained with an Agilent 1100 VL mass spectrometer. The nomenclature of the different compounds used in the present document is based on the software AUTONOM (Automatic Nomenclature) from the Beilstein Institute, which uses the IUPAC systematic nomenclature.

INTERMEDIATES (IV) METHOD A: To a solution of 1 eq of the aminic derivative (III), 1 eq of the acid (II), 1.3 eq of HOBT, and 1.3 eq of EDC in tetrahydrofurane, the solution being 0.2 M in the aminic derivative, 2 eq of triethylamine were added. The reaction mixture was stirred at room temperature for 18h, and. then water and dichloromethane were added. The organic layer was separated, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography.

METHOD B: To a solution 0.1 M of 1 eq of the aminic derivative (III) in anhydrous dichloromethane, 2 eq of triethylamine, and 1.2 eq of the corresponding acid chloride, were added. The reaction mixture was either refluxed with stirring (secondary amines) or stirred at room temperature (primary amines) for 18h, then treated with water, twice with sodium bicarbonate and, finally, with a brine. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography.

METHOD C: To a solution of 1 eq of the aminic derivative (III), and 1 eq of the corresponding acid chloride in ethyl acetate, the solution being 0.05 M in the aminic derivative, Amberlyst 21 (200 mg/mmol acid chloride) was added. The reaction mixture was either refluxed with stirring (secondary amines) or stirred at room temperature (primary amines). Then, the resin was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography.

TABLE 1 INTERM IV. 1 (2S)-3- (4-Benzyloxyphenyl)-2- (4-hydroxybenzoylami no) propionic acid methyl ester ; 1H-NMR : 7.52 (d, 2H), 7. 31-7. 20 (m, 5H), 6.97 (d, 2H), 6.81 (d, 2H), 6. 74 (d, 2H), 4.94 (s, 2H), 4.86 (m, 1H), 3.66 (s, 3H), 3.06 (m, 2H) IV. 2 (2S)-3- (4-Benzyloxyphenyl)-2- (3-hydroxybenzoylami no) propionic acid methyl ester; MS: 406 IV. 3 (25)-3-Cyclohexyl-2- (4-hydroxybenzoylamino) propio nic acid methyl ester; MS: 306 INTERMEDIATES (VIa) METHOD D: A suspension of 1 eq of phenol (V), 3 eq of anhydrous potassium carbonate, and 1.3 eq of the Z-LG derivative in ethyl acetate, the suspension being aproximately 0. 5 M in the phenol (V), was refluxed for 18h. Then, the suspension was allowed to cool down and the white solid was filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

METHOD E: A suspension of 1 eq of phenol (V), 3 eq of cesium carbonate, 1.3 eq of the Z-LG derivative, and a catalythic amount of potassium iodide in anhydrous, dimethylformamide (DMF), the suspension being 0.1 M in the phenol (V), was heatet at 80°C for 18h. Then, the suspension was allowed to cool down at room temperature, and then water and ethyl acetate were added. The organic layer was washed three times with brine, then dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

METHOD F: To a solution 0.1 M of 1 eq of phenol (V) in anhydrous DMF, containing a catalythic amount of potassium iodide, 1.1 eq of 60% sodium hydride in paraffin were added. The suspension was stirred at room temperature for 10 minutes and then 1.1 eq of the Z-LG derivative were added. The resulting solution was stirred at 80°C for 18h, and then allowed to cool down to room temperature. After treating with water and ethyl acetate, the organic layer was washed three times with brine, then dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

METHOD G: To a solution of 1 eq of phenol (V), 2.2 eq of the Z-OH derivative, and 2. 2 eq of triphenylphosphine in tetrahydrofurane, the solution being 0.2 M in the phenol, 2.2 eq of DEAD were added under inert atmosphere. The reaction mixture was stirred at room temperature for 18h.

Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

METHOD H: To a solution 0. 01 M of 1 eq of the Z-OH derivative in anhydrous DMF, 1.1 eq of 60% sodium hydride in paraffine were added slowly with stirring until bubbling was finished. Then, 1.2 eq of 4-fluorobenzoic acid methyl ester were added, and the mixture was heated at 80°C for 20h. The resulting solution was carefully poured over water/ice, and the mixture formed was extracted four times with ethyl acetate. The organic extracts were washed five times with brine, then dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

TABLE 2 INTERM VIa. 1 4-[2-(Dibenzylamino) ethoxy] benzoic methyl ester; H-NMR : 8.00 (d, 2H), 7.45-7. 20 (m, 10H), 6.85 (d, 2H), 4.05 (t, 2H), 3.90 (s, 3H), 3.75 (s, 4H), 2.91 (t, 2H) VIa. 2 4- [2- (2-Phenyloxazol-4-yl-5-methyl) ethoxy] benzoic acid methyl ester ; 1H-NMR : 7.99-7. 85 (m, 4H), 7.44-7. 38 (m, 3H), 6.88 (d, 2H), 4.23 (t, 2H), 3.85 (s, 3H), 2.98 (t, 2H), 2.36 (s, 3H) VIa. 3 3-[2-Dibenzylamino) ethoxy] benzoic acid methyl ester ; 1H-NMR : 7.65-7. 00 (m, 14H), 4.09 (t, 2H), 3.92 (s, 3H), 3.74 (s, 4H), 2.93 (t, 2H) VIa. 4 3- (4-Butylbenzyloxy) benzoic acid methyl ester; MS: 299 VIa. 5 4- (2-Pyridin-2-ylethoxy) benzoic acid methyl ester; MS: 258 VIa. 6 4- (2-Naphthalen-2-ylethoxy) benzoic acid methyl ester; MS: 307 VIa. 7 4- (4-Butylbenzyloxy) benzoic acid methyl ester; MS: 299 VIa. 8 3- (4-Benzyloxybenzyloxy) benzoic acid methyl ester; MS: 349 VIa. 9 4- (3-Benzyloxybenzyloxy) benzoic acid methyl ester; MS: 349 VIa. 10 3- (3-Benzyloxybenzyloxy) benzoic acid methyl ester; MS: 349 INTERMEDIATES (VIb) METHOD J: To a solution 0.1 M of 1 eq of intermediate (VIa) in a mixture of 3: 1 tetrahydrofurane: methanol, between 1. 5 and 10 eq of lithium hydroxide 1 M in water were added. The resulting mixture was stirred at room temperature for 18h, then treated with HC1 1 N until pH=5-6, and extracted twice with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

METHOD K: To a solution 0.05 M of 1 eq of intermediate (VIa) in methanol, 5 eq of potassium hydroxide 1.4 M were added. The resulting solution was stirred at room temperature for 18h, then treated with HC1 1 N until acid pH, and extracted with ethyl acetate twice. The organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

TABLE 3 INTERM VIb. 1 4-[2-(DiDenzylamino) ethoxy] benzoic acid ; lH-NMR : 7.98 (d, 2H), 7.47-7. 27 (m, 10H), 6.91 (d, 2H), 4.14 (t, 2H), 3.78 (s, 4H), 2.95 (t, 2H) VIb. 2 4- [2- (2-Phenyloxazol-4-yl-5-methyl) ethoxy] benzoic acid; 1H-NMR : 7.95-7. 83 (m, 4H), 7.50-7. 46 (m, 3H), 7.01 (d, 2H), 4. 28 (t, 2H), 2.95 (t, 2H), 2.35 (s, 3H) VIb. 3 3-[2-(Dibenzylamino) ethoxy] benzoic acid ; 1H-NMR : 7.54-7. 00 (m, 14H), 4.40 (t, 2H), 4.31 (s, 4H), 3.39 (t, 2H) VIb. 4 4- (3-Benzyloxybenzyloxy) benzoic acid; MS: 335 VIb. 5 3- (3-Benzyloxybenzyloxy) benzoic acid; MS: 335 VIb. 6 4-(2-Pyridin-2-ylethoxy) benzoic acid; MS: 244 VIb. 7 3- (4-Butylbenzyloxy) benzoic acid; MS: 285 VIb. 8 4- (2-Naphthalen-2-ylethoxy) benzoic acid; MS: 293 VIb. 9 4- (4-Butylbenzyloxy) benzoic acid; MS: 285 VIb. 10 3- (4-Benzyloxybenzyloxy) benzoic acid ; lH-NMR : 7.60 (br s, 2H), 7.43-7. 22 (m, 8H), 7.10 (dd, 1H), 6.94 (d, 2H), 5.02 (s, 2H), 4.97 (s, 2H) INTERMEDIATES (VIII) METHOD L: To a suspension of 1 eq of phenol (IV), and 2 eq of cesium carbonate in anhydrous DMF, the suspension being 0.4 M in the phenol, 100 eq of LGl-(CH2) s-LG2 were added. The reaction mixture was heated at 90°C for 18h, and then treated with water and 1,2-dichloroethane. The organic layer was washed three times with brine, then dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

TABLE 4 INTERM VIII. 1 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (2-chloroethoxy) b enzoylamino] propionic acid methyl ester ; 1H-NMR : 7.71 (d, 2H), 7.50-7. 33 (m, 5H), 7.06 (d, 2H), 6.93-6. 89 (m, 4H), 6.58 (d, 1H), 5.07-5. 01 (m, 3H), 4.25 (t, 2H), 3.82 (t, 2H), 3.76 (s, 3H), 3.20 (m, 2H) VIII. 2 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (2-chloroethoxy) b enzoylamino] propionic acid methyl ester ; 1H-NMR : 7.50-7. 25 (m, 8H), 7.10-7. 00 (m, 3H), 6.91 (d, 2H), 6.57 (d, 1H), 5.10-5. 00 (m, 3H), 4.27 (t, 2H), 3.83 (t, 2H), 3.78 (s, 3H), 3.24 (dd, 1H), 3.16 (dd, 1H) INTERMEDIATE (Xa), (XVIa) and (XIa) The following compounds were synthesized according to any of methods D, E or F, starting from intermediates (IX).

TABLE 5 INTERM Xa. 1 4- [2- (3-Methylquinoxalin-2-yloxy) ethoxy] benzoic acid methyl ester ; 1H-NMR : 8.02 (d, 2H), 7.95 (d, 1H), 7. 88 (d, 1H), 7. 65-7. 48 (m, 2H), 7. 00 (d, 2H), 4. 87 (t, 2H), 4. 48/t, 2H), 3. 89 (s, 3H), 2.64 (s, 3H) Xa. 2 3- [2- (3-Methylquinoxalin-2-yloxy) ethoxy] benzoic acid methyl ester; MS: 339 XVIa. 1 3- [2- (3-Methyl-2-oxo-2H-quinoxalin-1-yl) ethoxy] be nzoic acid methyl ester; MS: 339 XVIa. 2 4- [2- (3-Methyl-2-oxo-2H-quinoxalin-1-yl) ethoxy] be nzoic acid methyl ester; MS: 339 XIa. 1 3-[2-(Thiophen-2-ylsulfanyl) ethoxy] benzoic acid methyl ester; MS: 295 INTERMEDIATE (Xb), (XVIb) and (XIb) The following compounds were synthesized according to any of methods J or K, starting from intermediates (Xa), (XVIa) or (XIa).

TABLE 6 INTERM Xb. 1 4- [2- (3-Methylquinoxalin-2-yloxy) ethoxy] benzoic acid; MS: 325 Xb. 2 3- [2- (3-Methylquinoxalin-2-yloxy) ethoxy] benzoic acid; MS: 325 XVIb. 1 3- [2- (3-Methyl-2-oxo-2H-quinoxalin-1-yl) ethoxy] be nzoic acid; MS: 325 XVIb. 2 4- [2- (3-Methyl-2-oxo-2H-quinoxalin-1-yl) ethoxy] be nzoic acid; MS: 325 XIb. 1 3-[2-(Thiophen-2-ylsulfanyl) ethoxy] benzoic acid; MS: 281 INTERMEDIATE (XIV) The following compounds were synthesized according to any of methods D to G, starting from phenol (V) and amines (XIIa) or (XIIb).

TABLE 7 INTERM XIV. 1 3-{2-[Benzyl-(2, 2,2-trifluoroacetyl) amino] ethoxy} benzoic acid methyl ester; MS: 382 XIV. 2 4-{2-[Benzyl-(2, 2,2-trifluoroacetyl) amino] ethoxy} benzoic acid methyl ester; MS: 382 INTERMEDIATE (XV) The following compounds were synthesized either according to any of methods D to F, starting either from intermediate (IX), and the corresponding amines, or according to method M, from intermediate (XIV).

METHOD M: To a solution 0.1 M of 1 eq of intermediate (XIV) (PG trifluoroacetyl) in a mixture of tetrahydrofurane: methanol (3: 1), 5 eq of lithium hydroxide 1 M in water were added. The solution was stirred until complete dissolution, then diluted with a mixture of water/ethyl acetate, and then acidified to pH=5 with HC1 1 N. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was disolved in methanol 0.1 M and treated with 3.2 eq of thionyl chloride. The solution was refluxed for 18h, and then allowed to cool down to room temperature. The solvent was distilled off under reduced pressure and the residual solid was broken up with hexane.

TABLE 8 INTERM XV. 1 4- (2-Benzylaminoethoxy) behzoic acid methyl ester; 1H-NMR : 7.96 (d, 2H), 7.34-7. 21 (m, 5H), 6.89 (d, 2H), 4.12 (t, 2H), 3.87 (s, 2H), 3.85 (s, 3H), 3.10 (t, 2H); MS: 286 XV. 2 3- (2-Benzylaminoethoxy) benzoic acid methyl ester; MS: 286 INTERMEDIATE (XVIIIa) The following compounds were synthesized according to any of methods A to C, starting from intermediate (XV) and the corresponding acids.

TABLE 9 INTERM XVIIIa. 1 4- [2- (N-Benzyl-N-benzoylamino) ethoxy] benzoic acid methyl ester ; 1H-NMR : 7.99 (d, 2H), 7.43-6. 77 (m, 12H), 4.91-4. 70 (m, 2H), 4.35-3. 65 (m, 4H), 3.90 (s, 3H) XVIIIa. 2 4-{2-[N-Bénzyl-N-(pyridin-3-ylcarbonyl) amino] et hoxy} benzoic acid methyl ester ; 1H-NMR : 8.80-6. 85 (m, 13H), 4.91-4. 69 (m, 2H), 4.36-3. 60 (m, 4H), 3.86 (s, 3H) INTERMEDIATE (XVIIIb) The following compounds were synthesized according to methods J or K, starting from intermediate (XVIIIa).

TABLE 10 INTER M XVIII 4- [2- (N-Benzyl-N-benzoylamino) ethoxy] benzoic ; b. 1'H-NMR : 8. 06 (d, 2H), 7.41-6. 81 (m, 12H), 4.94-4. 71 (m, 2H), 4.37-3. 67 (m, 4H) XVIII 4- {2- [N-Benzyl-N- (pyridin-3-ylcarbonyl) amino] ethox b. 2 y} benzoic acid ; 1H-NMR : 8.75-6. 85 (m, 13H), 4.91-4. 72 (m, 2H), 4.36-3. 60 (m, 4H) EXAMPLE (Ia) : The compounds of formula (Ia) shown in Table 11 were synthesized according to any of methods D to G, starting from intermediate (IV): TABLE 11 Ex. 1 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-phenylallyloxy ) benzoylamino] propionic acid methyl ester; H-NMR-7. 73 (d, 2H), 7.43-7. 25 (m, 10H), 7.07 (d, 2H), 6. 98 (d, 2H), 6.92 (d, 2H), 6.76 (d, 1H), 6.57 (d, 1H), 6.42 (dt, 1H), 5.10-5. 00 (m, 3H), 4.75 (dd, 2H), 3.77 (s, 3H), 3.28-3. 16 (m, 2H) 2 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (4-phenoxybenzylo xy) benzoylamino] propionic acid methyl ester; H-NMR : 7.71 (d, 2H), 7.42-6. 88 (m, 20H), 6.48 (d, 1H), 5.07-5. 04 (m, 5H), 3.77 (s, 3H), 3.25-3. 10 (m, 2H) 3 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (biphenyl-4- ylmethoxy) benzoylamino] propionic acid methyl ester ; 1H-NMR : 7.72 (d, 2H), 7.65-7. 26 (m, 14H), 7.07-7. 00 (m, 4H), 6.90 (d, 2H), 6.48 (d, 1H), 5.16 (s, 2H), 5.10-5. 00 (m, 3H), 3.77 (s, 3H), 3.30-3. 10 (m, 2H) 4 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3- phenoxybenzyloxy) benzoylamino] propionic acid methyl ester; 1H-NMR : 7.70 (d, 2H), 7.43-6. 92 (m, 20H), 6.48 (d, 1H), 5.08-5. 04 (m, 5H), 3.77 (s, 3H), 3.30-3. 10 (m, 2H) 5 (2S)-2- [4- (3-Benzyloxybenzyloxy) benzoylamino]-3- ( 4-benzyloxyphenyl) propionic acid methyl ester; H-NMR : 7.70 (d, 2H), 7.43-6. 92 (m, 20H), 6.48 (d, 1H), 5.09 (s, 2H), 5.08 (s, 2H), 5.06-5. 02 (m, 3H), 3.77 (s, 3H), 3.27-3. 14 (m, 2H) 6 (2S)-3- (4-Benzyloxyphenyl)-2- (4-phenethyloxybenzo ylamino) propionic acid methyl ester ; H-NMR : 7.69 (d, 2H), 7.42-7. 30 (m, 10H), 7.04 (d, 2H), 6.92-6. 88 (m, 4H), 6.45 (d, 1H), 5.06-5. 00 (m, 3H), 4.22 (t, 2H), 3.77 (s, 3H), 3.27-3. 10 (m, 4H) 7 (2, S)-3- (4-Benzyloxyphenyl)-2- [4- (3-phenylpropoxy) benzoylamino] propionic acid methyl ester ;'H-NMR : 7.70 (d, 2H), 7.43-7. 22 (m, 10H), 7.06 (d, 2H), 6.93-6. 89 (m, 4H), 6.51 (d, 1H), 5.10-5. 02 (m, 3H), 4. 00 (t, 2H), 3.77 (s, 3H), 3.25-3. 15 (m, 2H), 2.83 (t, 2H), 2.12 (m, 2H) 8 (2S)-2- [4- (4-Benzyloxybenzyloxy) benzoylamino]-3- ( 4-benzyloxyphenyl) propionic acid methyl ester. -NR : 7. 70 (d, 2H),'7. 46-7.35 (m, 13H), 7.06-6. 97 (m, 7H), 6.89 (d, 2H), 6.49 (d, 1H), 5.09-5. 00 (m, 7H), 3.76 (s, 3H), 3.26-3. 11 (m, 2H) 9 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (biphenyl-2-ylmet hoxy) benzoylamino] propionic acid methyl ester; MS: 572 10 (25)-3- (4-Benzyloxyphenyl)-2- [3- (3-phenylallyloxy ) benzoylamino] propionic acid methyl ester; MS: 522 11 (2S)-2- [3- (4-Benzyloxybenzyloxy) benzoylamino]-3- ( 4-benzyloxyphenyl) propionic acid methyl ester; H-NMR : 7.47-7. 26 (m, 15H), 7.13-7. 00 (m, 5H), 6.93 (d, 2H), 6.61 (d, 1H), 5.09-5. 00 (m, 7H), 3.78 (s, 3H), 3.29-3. 15 (m, 2H) 12 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (biphenyl-4-ylmet hoxy) benzoylamino] propionic acid methyl ester; MS: 572 13 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (3-phenoxybenzylo xy) benzoylamino]propionic acid methyl ester; MS: 588 14 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (3-phenylpropoxy) benzoylamino] propionic acid. methyl ester; MS: 524 15 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (4-butoxybenzylox y) benzoylamino] propionic acid methyl ester; MS: 568 16 (25)-2- [4- (4-Butoxybenzyloxy) benzoylamino]-3-cycl ohexylpropionic acid methyl ester; MS: 468 17 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (thiophen-3-ylmet hoxy) benzoylamino] propionic acid methyl ester ; MS: 488 18 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-bromobenzyloxy ) benzoylamino] propionic acid methyl ester; MS: 575 19 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-bromobenzyloxy ) benzoylamino] propionic acid methyl ester; MS: 575 20 (25)-3- (4-Benzyloxyphenyl)-2- [4- (2-chlorobenzylox y) benzoylamino] propionic acid methyl ester; MS: 530 21 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-chlorobenzylox y) benzoylamino] propionic acid methyl ester; MS: 530 22 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-fluorobenzylox y) benzoylamino] propionic acid methyl ester; MS: 514 23 (2S)-3-(4-Benzyloxyphenyl)-2-[4-(3-methylbenzylox y) benzoylamino] propionic acid methyl ester; MS: 496 24 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-trifluoromethy lbenzyloxy)-benzoylaminogpropionic acid methyl ester; MS: 564 25 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-methoxybenzylo xy) benzoylamino] propionic acid methyl ester; MS: 526 26 (2S)-2- [4- (3-Bromobenzyloxy) benzoylaminol-3-cyclo hexylpropionic acid methyl ester; MS: 475 27 (2S)-3- (4,-Benzyloxyphenyl)-2- [4- (2-methylbenzylox y) benzoylamino] propionic acid methyl ester; MS: 510 28 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-trifluoromethy lbenzyloxy)-benzoylaminopropionic acid methyl ester; MS: 564 29 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-o-tolylethoxy) benzoylamino] propionic acid methyl ester; MS: 524 30 (2S)-3-(4-Benzuyloxyphenyl)-2-{4-[3-(4- propoxyphenoxy) propoxy] benzoylamino} propionic acid methyl ester; MS: 598 31 (2S)-3-(4-Benzyloxyphenyl)-2-[4-(3-methoxybenzylo xy) benzoylamino] propion. ic acid methyl ester; MS: 526 32 (2S)-3-(4-Benzyloxyphenyl)-2-[4-(2-ethoxybenzylox y) benzoylamino] propionic acid methyl ester; MS: 540 33 3-(4-Benzyloxyphenyl)-2-{4-[ (diphenylcarbamoyl) me thoxy]-benzoylamino} propionic acid methyl ester; 1H-NMR : 7.64 (d, 2H), 7. 41-7. 26 (m. 15H), 7.03 (d, 2H), 6.91-6. 81 (m, 4H), 6.55 (d, 1H), 5. 08-4. 95 (m, 3H), 4.61 (s, 2H), 3.74 (s, 3H), 3.26-3. 06 (m, 2H) 34 3-(4-Benzyloxyphenyl)-2-{4-[(benzylphenylcarbamoy 1) methoxy]-benzoylamino} propionic acid methyl ester ; 1H-NMR : 7.65 (d, 2H), 7.40-6. 77 (m, 21H), 6. 54 (d, 1H), 5.08-4. 95 (m, 3H), 4.90 (s, 2H), 4.42 (s, 2H), 3.74 (s, 3H), 3.25-3. 06 (m, 2H) 35 3-(4-Benzyloxyphenyl)-2-{4-[(dibenzylcarbamoyl) me thoxy]-benzoylamino} propionic acid methyl ester; 1H-NMR : 7.69 (d, 2H), 7.42-7. 16 (m, 15H), 7.05 (d, 2H), 6.90 (d, 4H), 6.53 (d, 1H), 5.09-4. 97 (m, 3H), 4.83 (s, 2H), 4.62 (s, 2H), 4.51 (s, 2H), 3.76 (s, 3H), 3.29-3. 10 (m, 2H) 36 3-(4-Benzyloxyphenyl)-2-{4-[2-(10,11-dihydrodiben zo [b, f] azepin-5-yl)-2- oxoethoxy] benzoylamino} propionic acid methyl ester; 1H-NMR : 7.65 (d,'2H), 7.41-6. 81 (m, 19H), 6.49 (d, 1H), 5.09-4. 97 (m, 3H), 4.80 (d, 1H), 4.45 (d, 1H), 3.75 (s, 3H), 3.45-3. 17 (m, 4H), 2.93-2. 81 (m, 2H) 37 3-(4-Benzyloxyphenyl)-2-{4-[(diphenylcarbamoyl) me thoxy]-benzoylamino} propionic acid ; 1H-NMR : 7.61 (d, 2H), 7.37-6. 66 (m, 22H), 5.00-4. 85 (m, 3H), 4.59 (s, 2H), 3.30-3. 10 (m, 2H) 38 3-(4-Benzyloxyphenyl)-2-(4-{[(3-methoxyphenyl) phe nylcarbamoyl] methoxy}-benzoylamino) propionic acid methyl ester; MS: 645 39 3-(4-Benzyloxyphenyl)-2-{4-[(cyclohexylphenylcarb amoyl) methoxy]-benzoylamino} propionic acid methyl ester; MS: 621 The compounds of formula (Ia) shown in Table 12 were synthesized according to any of methods A to C, starting from intermediate (VIb): TABLE 12 Ex. 40 {[4-(2-Dibenzylaminoethoxy) benzoyl]-(3-phenoxyben zyl) amino} acetic acid ethyl ester; 1H-NMR : 7.42-6. 75 (m, 23H), 4.80-4. 65 (m, 2H), 4.30-3. 99 (m, 6H), 3.72 (s, 4H), 2.90 (t, 2H), 1.27 (m, 3H) 41 { (3-Benzyloxybenzyl)- [3- (2-dibenzylaminoethoxy) be nzoyl] amino} acetic acid ethyl ester ; 1H-NMR : 7.42-6. 89 (m, 23H), 5.07-5. 03 (m, 2H), 4.74-4. 53 (m, 2H), 4. 30-3. 82 (m, 6H), 3.70 (s, 4H), 2.87 (t, 2H), 1.32-1. 19 (m, 3H) 42 {[3-(2-Dibenzylaminoethoxy)benzoyl}-(3-phenoxyben zyl) amino} acetic acid ethyl ester; 1H-NMR : 7.40-6. 84 (m, 23H), 4.78-4. 56 (m, 2H), 4.30-3. 85 (m, 6H), 3.70 (s, 4H), 2. 86 (t, 2H), 1.33-1. 19 (m, 3H) 43 {[3-(2-Dibenzylaminoethoxy) benzoyl]-(4-phenoxyben zyl) amino} acetic acid ethyl ester ; 1H-NMR : 7.41-6. 90 (m, 23H), 4.77-4. 57 (m, 2H), 4.30-3. 85 (m, 6H), 3.71 (s, 4H), 2.88 (t, 2H), 1.33-1. 19 (m, 3H) 44 { (4-tert-Butylbenzyl)- [3- (2-dibenzylaminoethoxy) b enzoyl] amino} acetic acid ethyl ester ;'H-NMR : 7.41-6. 80 (m, 18H), 4.78-4. 57 (m, 2H), 4.25-3. 42 (m, 10H), 2.87 (m, 2H), 1.32-1. 19 (m, 12H) 45 {[3-(2-Dibenzylaminoethoxy)benzoyl]-(3-benzyloxyb enzyl) amino} acetic acid ethyl ester ; 1H-NMR : 7.41-6. 80 (m, 23H), 5. 07-5.03 (m, 2H), 4.78-4. 57 (m, 2H), 4.30-3. 68 (m, 10H), 2.86 (m, 2H), 1.33-1. 19 (m, 3H) 46 {(4-Benzyloxybenzyl)-[4-(2-dibenzylaminoethoxy) be nzoyl] amino} acetic acid ethyl ester ; 1H-NMR : 7.47-7. 23 (m, 19H), 6.97 (d, 2H), 6.79 (d, 2H), 5.08 (s, 2H), 4.71-4. 62 (m, 2H), 4.22-3. 99 (m, 6H), 3.72 (s, 4H), 2.89 (t, 2H), 1. 27 (m, 3H) 47 3- (5-Benzyloxy-lH-indol-3-yl)-2- [4- (2-dibenzylami noethoxy)-benzoylamino] propionic acid methyl ester ; 1H-NMR: 8. 01 (s, 1H), 7.64 (d, 2H), 7. 41-7. 22 (m, 14H), 7.00 (dd, 2H), 6.90 (dd, 1H), 6.74 (d, 2H), 6.64 (d, 1H), 5. 17 (m, 1H), 4.85 (d, 1H), 4.62 (d, 1H), 3. 94 (t, 2H), 3.74 (s, 3H), 3.70 (s, 4H), 3.45 (dd, 1H), 3.35 (dd, 1H), 2.86 (t, 2H) 48 2- [4- (2-Dibenzylaminoethoxy) benzoylamino]-3- (1-me thyl-lH-indol-3-yl) propionic acid methyl ester; H-NMR : 7.60 (d, 2H), 7.53 (d, 1H), 7. 41-7. 21 (m, 12H), 7.08 (t, 1H), 6.85 (s, 1H), 6.77 (d, 2H), 6.56 (d, 1H), 5.12 (m, 1H), 4.03 (t, 2H), 3.75-3. 72 (m, 10H), 3.43 (d, 2H), 2. 90 (t, 2H) 49 3- (5-Benzyloxy-lH-indol-3-yl)-2- [3- (2-dibenzylami noethoxy) benzoylamino]-propionic acid methyl ester ; 1H-NMR : 7.95 (s, 1H), 7. 41-7.19 (m, 14H), 7.04-6. 88 (m, 4H), 6.69 (d, 1H), 5.16 (m, 1H), 4.89 (d, 1H), 4. 71 (d, 1H), 3.98 (t, 2H), 3.74 (s, 3H), 3.69 (s, 4H), 3. 45 (dd, 1H), 3. 35 (dd, 1H), 2.86 (t, 2H) 50 {(3-Benzyloxybenzyl)-[4-(3-benzyloxybenzyloxy) ben zoyl] amino} acetic acid ethyl ester ; 1H-NMR : 7.45-7. 28 (m, 14H), 7.06-6. 81 (m, 8H), 5. 08 (s, 4H), 5. 06 (s, 2H), 4. 77-4. 66 (m, 2H), 4.21 (m, 2H), 4.11-3. 88 (m, 2H), 1.26 (m, 3H) 51 3-{(3-Benzyloxybenzyl)-[4-(3-benzyloxybenzyloxy) b enzoyl] amino} propionic acid ethyl ester; 1H-NMR : 7.45-7. 26 (m, 14H), 6. 96-6.82 (m, 8H), 5.08 (s, 4H), 5.05 (s, 2H), 4.63 (br s, 2H), 4.12 (m, 2H), 3.66 (m, 2H), 2.67 (m, 2H), 1. 26 (m, 3H) 52 3-{(4-Benzyloxybenzyl)-[4-(3-benzyloxybenzyloxy) b enzoyl] amino} propionic acid ethyl ester ; 1H-NMR : 7.46-7. 27 (m, 13H), 7. 13-6.93 (m, 9H), 5.08 (s, 2H), 5.07 (s, 2H), 5.06 (s, 2H), 4.60 (br s, 2H), 4.13 (m, 2H), 3.65 (m, 2H), 2.67 (m, 2H), 1.27 (m, 3H) 53 { (4-Benzyloxybenzyl)- [3- (3-benzyloxybenzyloxy) ben zoyl] amino} acetic acid ethyl ester; 1H-NMR : 7.42-7. 28 (m, 13H), 7. 11-6. 95 (m, 9H), 5. 07-4.99 (m, 6H), 4.75-4. 53 (m,. 2H), 4.23 (q, 2H), 4.13-3. 84 (m, 2H), 1. 26 (m, 3H) 54 { (3-Benzyloxybenzyl)- [3- (3-benzyloxybenzyloxy) ben zoyllamino} acetic acid ethyl ester ;'H-NMR : 7.46-7. 26 (m, 13H), 7.11-6. 80 (m, 9H), 5.09-4. 94 (m, 6H), 4. 79-4.57 (m, 2H), 4.23 (q, 2H), 4.14-3. 84 (m, 2H), 1.26 (m, 3H) 55 3- { (3-Benzyloxybenzyl)- [3- (3-benzyloxybenzyloxy) b enzoyl] amino} propionic acid ethyl ester ; 1H-NMR : 7.45-7. 25 (m, 13H), 7.02-6. 90 (m, 7H), 6.78 (m, 2H), 5.07-4. 94 (m, 6H), 4.75-4. 52 (m, 2H), 4. 15 (m, 2H), 3.71-3. 50 (m, 2H), 2.72-2. 39 (m, 2H), 1.26 (m, 3H) 56 3- [ (4-Benzyloxybenzoyl)- (3-benzyloxybenzyl) amino] propionic acid ethyl ester; MS: 524 57 3-{(4-Benzyloxybenzyl)-[3-(3-benzyloxybenzyloxy) b enzoyl] amino} propionic acid ethyl ester; MS: 631 58 (2S)-2- [3- (4-Butylbenzyloxy) benzoylamino] -3-cyclo hexylpropionic acid methyl ester ; 1H-NMR : 7.45 (s, 1H), 7.35 (d, 4H), 7.20 (d, 2H), 7.12 (m, 1H), 6.47 (d, 1H), 5.06 (s, 2H), 4.87 (m, 1H), 3.76 (s, 1H), 2.62 (t, 2H), 1. 78-0.90 (m, 20H) 59 2- [4- (3-Benzyloxybenzyloxy) benzoylamino]-3- (4-bro mophenyl) propionic acid methyl ester; 1H-NMR : 7.69 (d, 2H), 7.45-7. 20 (m, 8H), 7.06-6. 93 (m, 7H), 6. 50 (d, 1H0, 5. 09-5. 03 (m, 5H), 3. 77 (s, 3H), 3.25 (dd, 1H), 3.16 (dd, 1H) 60 2- [4- (3-Benzyloxybenzyloxy) benzoylamino]-3- (4-flu orophenyl) propionic acid methyl ester ;'H-NMR : 7.69 (d, 2H), 7.45-7. 20 (m, 6H), 7.11-6. 93 (m, 9H), 6.49 (d, 1H), 5.09-5. 02 (m, 5H), 3. 76 (s, 3H), 3.27 (dd, 1H), 3.18 (dd, 1H) 61 3- (4-Benzyloxyphenyl)-2- [4- (2-naphthalen-2-yl-eth oxy) benzoylamino] propionic acid methyl ester; MS: 560 62 3-{[4-(2-Dibenzylaminoethoxy)benzoyl]-(3-phenoxyb enzyl) amino} propionic acid methyl ester ; 1H-NMR : 7.40-7. 23 (m, 16H), 7. 13 (t, 1H), 7.01 (d, 2H), 6.90 (dd, 2H), 6.75 (d, 2H), 4.60 (br s, 2H), 4.01 (t, 2H), 3.71-3. 62 (m, 9H), 2.88 (t, 2H), 2.67 (m, 2H) 63 3-{[3-(2-Dibenzylaminoethoxy)benzoyl]naphthalen-2 -ylmethylamino} propionic acid methyl ester; 1H-NMR : 7.80 (m, 3H), 7.50-7. 47 (m, 2H), 7.32-7. 22 (m, 13H), 7.00 (d, 1H), 6.93 (s, 1H), 6.84 (d, 1H), 4.93-4. 70 (m, 2H), 4.03-3. 91 (t, 2H), 3.80-3. 55 (m, 9H), 2. 81-2. 50 (m, 4H) 64 3-{(4-tert-Butylbenzyl)-[3-(2-dibenzylaminoethoxy ) benzoyl] amino} propionic acid methyl ester; H-NMR : 7.39-7. 20 (m, 14H), 7.10 (m, 1H), 6.95 (d, 1H), 6.91 (s, 1H), 6.85 (d, 1H), 4.72-4. 50 (m, 2H), 3.97 (m, 2H), 3.70-3. 55 (m, 9H), 2.86 (m, 2H), 2.71-2. 48 (m, 2H), 1.30 (s, 9H) 65 3-{(4-Bromobenzyl)-[3-(2-dibenzylaminoethoxy) benz oyl] amino} propionic acid methyl ester ;'H-NMR : 7.47 (d, 2H), 7.39-7. 20 (m, 12H), 7.05 (m, 1H), 6.93 (d, 1H), 6.86-6. 80 (m, 2H), 4.68-4. 50 (m, 2H), 3. 97 (m, 2H), 3. 70-3.55 (m, 9H), 2.87 (m, 2H), 2.72-2. 46 (m, 2H) 66 3-{[3-(2-Dibenzylaminoethoxy) benzoyl]-(3-phenoxyb enzyl) amino} propionic acid methyl ester ; 1H-NMR : 7.45-7. 22 (m, 16H), 7.11 (t, 1H), 7.00 (m, 2H), 6. 90-6.84 (m, 4H), 4.72-4. 49 (m, 2H), 3.96 (m, 2H), 3.70-3. 60 (m, 9H), 2.87 (m, 2H), 2.72-2. 45 (m, 2H) 67 3-{[4-(2-Dibenzylaminoethoxy) benzoyl]-(4-phenoxyb enzyl) amino} propionic acid methyl ester; 1H-NMR : 7.40-7. 14 (m, 17H), 7.02-6. 97 (m, 4H), 6.78 (d, 2H), 4.61 (br s, 2H), 4. 01 (t, 2H), 3.71-3. 65 (m, 9H), 2.89 (t, 2H), 2.66 (m, 2H) 68 (2S)-2- [4- (4-Butylbenzyloxy) benzoylamino]-3-pheny lpropionic acid methyl ester; MS: 446 69 S)-3-(4-Benzyloxyphenyl)-2-[4-(4-butylbenzyloxy ) benzoylamino] propionic acid methyl ester; MS: 552 70 (2S)-2- [4- (4-Butylbenzyloxy) benzoylamino]-3-cyclo hexylpropionic acid methyl ester; MS: 452 71 { (3-Benzyloxybenzyl)- [4- (4-butylbenzyloxy) benzoyl ] amìno} acetic acid methyl ester; 1H-NMR : 7. 45-7. 18 (m, 12H), 6. 93-6. 80 (m, 5H), 5.07 (s, 2H), 5.03 (s, 2H), 4. 74-4. 65 (m, 2H), 4.11-3. 90 (m, 2H), 3.75 (s, 3H), 2.62 (t, 2H), 1.59 (m, 2H), 1. 35 (m, 2H), 0.92 (t, 3H) 72 { (4-Benzyloxybenzyl)- [4- (4-butylbenzyloxy) benzoyl ] amino} acetic acid methyl ester; IH-NMR : 7.50-7. 12 (m, 13H), 6.95 (d, 4H), 5.07 (s, 2H), 5.03 (s, 2H), 4.70-4. 62 (m, 2H), 4. 11-3.92 (m, 2H), 3.74 (s, 3H), 2.61 (t, 2H), 1.59 (m, 2H), 1.35 (m, 2H), 0.92 (t, 3H) 73 3- { (3-Benzyloxybenzyl)- [4- (4-butylbenzyloxy) benzo yl] amino} propionic acid methyl ester; ME : 566 74 3-{(4-Benzyloxybenzyl)-[4-(4-butylbenzyloxy) benzo yl] amino} propionic acid methyl ester ; 1H-NMR : 7.45-7. 13 (m, 13H), 6.95 (d, 4H), 5.06 (s, 2H), 5.03 (s, 2H), 4.58 (br s, 2H), 3.66-3. 60 (m, 5H), 2.62 (m, 4H), 1.59 (m, 2H), 1.35 (m, 2H), 0.92 (t, 3H) 75 (2S)-2- 4- (3-Benzyloxybenzyloxy) benzoylamino]-3-c yclohexylpropionic acid methyl ester ; 1H-NMR : 7.72 (d, 2H), 7.44-7. 28 (m, 6H), 7.06-6. 92 (m, 5H), 6. 40 (d, 1H), 5.09 (s, 2H), 5.07 (s, 2H), 4.87 (s, 1H), 3.76 (s, 1H), 1.77-0. 95 (m, 13H) 76 (2S)-2- [3- (3-Benzyloxybenzyloxy) benzoylamino]-3-c yclohexylpropionic acid methyl ester ;'H-NMR : 7.44-7. 28 (m, 9H), 7.10-6. 93 (m, 4H), 6.50 (d, 1H), 5.08 (s, 4H), 4.87 (s, 1H), 3.76 (s, 1H), 1.81-0. 91 (m, 13H) 77 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (4-butylbenzyloxy ) benzoyl zoylamino]propionic acid methyl ester; MS: 552 78 (25)-2- [3- (4-Benzyloxybenzyloxy) benzoylamiiio]-3-p henylpropionic acid methyl ester; MS: 496 79 (25)-2- [3- (4-Benzyloxybenzyloxy) benzoylamino]-3-c yclohexylpropionic acid methyl ester; MS: 502 80 { (3-Benzyloxybenzyl)- [3- (4-butylbenzyloxy) benzoyl ] amino} acetic acid methyl ester; 1H-NMR : 7.41-7. 16 (m, 12H), 7.10-6. 80 (m, 5H), 5.06-4. 92 (m, 4H), 4.78-4. 57 (m, 2H), 4. 14-3. 90 (m, 2H), 3.77-3. 68 (m, 3H), 2.61 (t, 2H), 1.59 (m, 2H), 1.35 (m, 2H), 0.93 (t, 3H) 81 3- { (3-Benzyloxybenzyl)- [3- (4-butylbenzyloxy) benzo yl] amino} propionic acid methyl ester; 1H-NMR : 7.41-7. 17 (m, 10H), 7.01-6. 77 (m, 7H), 5.05-5. 04 (m, 4H), 4.91-4. 71 (m, 2H), 4.66-4. 48 (m, 2H), 3.69-3. 60 (m, 3H), 2.72 (m, 2H), 2. 61 (t, 2H), 1.59 (m, 2H), 1. 35 (m, 2H), 0.93 (t, 3H) 82 (2S)- [3- (4-Benzyloxybenzyloxy) benzoylamino], phenyl acetic acid methyl ester; MS: 482 83 (2S)-2-{4-[2-(3-Methylquinoxalin-2-yloxy) ethoxy] b enzoylamino}-3-phenylpropionic acid methyl ester; MS: 486 84 (2S)-[3-(3-Benzyloxybenzyloxy)benzoylamino]phenyl acetic acid methyl ester; MS: 482 85 (2S)-2- [3- (3-Benzyloxybenzyloxy) benzoylamino]-3-p henylpropionic acid methyl ester; MS: 496 86 { (3-Benzyloxybenzyl)- [3- (4-benzyloxybenzyloxy) ben zoyl] amino} acetic acid methyl ester; 1H-NMR : 7.45-7. 25 (m, 14H), 7.10-6. 75 (m, 8H), 5.08-4. 89 (m, 6H), 4.78-4. 57 (m, 2H), 4.14-3. 85 (m, 2H), 3.77-3. 68 (m, 3H) 87 3- { (3-Benzyloxybenzyl)- [3- (4-benzyloxybenzyloxy) b enzoyl] amino} propionic acid methyl ester ;'H-NMR : 7.45-7. 24 (m, 14H), 7.00-6. 77 (m, 8H), 5.08-4. 88 (m, 6H), 4.71-4. 51 (m, 2H), 3.69-3. 50 (m, 5H), 2.72-2. 39 (m, 2H) 88 (2S)- [4- (4-Butylbenzyloxy) benzoylamino] phenylacet ic acid methyl ester; MS: 432 89 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-pyridin-2-yl-e thoxy) benzoylamino] propionic acid methyl ester; MS : 511 90 {[4-(3-Benzyloxybenzyloxy)benzoyl]-(4-benzoyloxyph enyl) amino} acetic acid ethyl ester; MS: 602 91 { [4- (3-Benzyloxybenzyloxy) ben. zoyl]- (3-benzyloxyph enyl) amino} acetic acid ethyl ester; MS: 602 3- (4-Benzyloxyphenyl)-2- {3- [(benzylphenethylcarbamoyl) methoxy] benzoylamino} p ropionic acid methyl ester ; 1H-NMR : 7.41-7. 23 (m, 16H), 7.16-7. 05 (m, 5H), 6.98-6. 98 (m, 2H), 6.60-6. 55 (m, 14H), 5.06-4. 93 (m, 3H), 4.70 (d, 1H), 4.43 (d, 1H), 3.76 (s, 3H), 3.64-3. 40 (m, 92 2H), 3.26-3. 11 (m, 2H), 2.85 (t, 2H); MS: 657 {3-[(Benzylphenylcarbamoyl) methoxybenzoylamino} th iophen-3-ylacetic acid methyl ester; 1H-NMR : 7.40-7. 31 (m, 5H), 7. 29-7. 15 (m, 6H), 7.15-7. 09 (m, 1H), 7.09-6. 95 (m, 4H), 5.88 (d, 1H), 5.30 (s, 1H), 4.90 (s, 2H), 4.43 (s, 2H), 3.80 (s, 3H) ; 93 MS: 515 The compounds of formula (Iaa), (Iab) and (Iae) shown in Table 13 were synthesized according to any of methods D to F, starting from intermediate (VIII) and the corresponding alcohols, thiols or amines: TABLE 13 Ex. 94 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(3-bromophenox y) ethoxy]-benzoylamino} propionic acid methyl ester ; 1H-NMR : 7.72 (d, 2H), 7.42-6. 88 (m, 15H), 6.51 (d, 1H), 5.10-5. 03 (m, 3H), 4.33 (s, 4H), 3.77 (s, 3H), 3.29-3. 11 (m, 2H) 95 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(3-methylquino xalin-2-yloxy) ethoxy] benzoylamino} propionic acid methyl ester ; 1H-NMR : 7. 99-6. 87 (m, 17H), 6.54 (d, 1H), 5.10-5. 02 (m, 3H), 4.88 (t, 2H), 4.47 (t, 2H), 3.77 (s, 3H), 3.29-3. 11 (m, 2H), 2.64 (s, 3H) 96 (2S)-3-(4-Benzyloxyphenyl)-2-{3-[2-(2, 6-dimethylp henoxy) ethoxy]-benzoylamino} propionic acid methyl ester; 1H-NMR : 7.44-7. 36 (m, 9H), 7. 14-6.90 (m, 7H), 6. 57. (d, 1H), 5.07-5. 03 (m, 3H), 4.36-4. 33 (m, 2H), 4.18-4. 15 (m, 2H), 3.78 (s, 3H), 3.26-3. 10 (m, 2H), 2.32 (s, 6H) 97 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(pyridin-2-ylo xy) ethoxy]-benzoylamino} propionic acid methyl ester; MS: 527 98 (25)-3-(4-Benzyloxyphenyl)-2-{4-[2-(quinolin-8-yl oxy) ethoxy]-benzoylamino} propionic acid methyl ester; MS: 577 99 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(4-imidazol-1- yl-phenoxy) ethoxy] benzoylamino} propionic acid methyl ester; MS: 592 100 (2S)-3- (4-Benzyloxyphenyl)-2- {4- [2- (2-methylbenzo thiazol-5-yloxy) ethoxy] benzoylamino} propionic acid methyl ester; MS: 597 101 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(5, 6,7, 8-tetra hydronaphthalen-2- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; MS: 580 102 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(quinolin-7-yl oxy) ethoxy]-benzoylamino} propionic acid methyl ester; MS: 577 103 (2S)-3- (4-Benzyloxyphenyl)-2- 4- [2- (quinolin-2- yloxy) ethoxy]-benzoylamino} propionic acid methyl ester; MS: 577 104 (2)-3- (4-Benzyloxyphenyl)-2- {4- [3- (3-methylquino xalin-2-yloxy) propoxy] benzoylamino} propionic acid methyl ester; MS: 606 105 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(1-methyl-1H-i midazol-2- ylsulfanyl) ethoxy] benzoylamino} propionic acid; MS : 532 106 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(2-fluoropheny lsulfanyl) ethoxy]-benzoylamino} propionic acid methyl ester ; 1H-NMR : 7.66 (d, 2H), 7.50-7. 25 (m, 7H), 7.25-7. 08 (m, 2H), 7.03 (d, 2H), 6.90 (d, 2H), 6.86 (d, 2H), 6.45 (d, 1H), 5.08-6. 98 (m, 3H), 4.17 (t, 2H), 3.76 (s, 3H), 3.28 (t, 2H), 3.25-3. 10 (m, 2H); MS: 560 107 (2S)-2-f4- [2- (4-Bromophenylsulfanyl) ethoxy] benzoy lamino}-3-cyclohexylpropionic acid methyl ester; H-NMR : 7.74 (d, 2H), 7.43 (d, 2H), 7. 28 (d, 2H), 6.87 (d, 2H), 6.39 (d, 1H), 4.95-4. 80 (m, 1H), 4.17 (t, 2H), 3.76 (s, 3H), 3.28 (t, 2H), 1.90-1. 50 (m, 5H), 1. 50-1.20 (m, 5H), 1.20-0. 85 (m, 3H); MS: 521 108 (25)-3-Cyclohexyl-2-{4-[2-(2-methoxyphenylsulfany 1) ethoxy]-benzoylamino} propionic acid methyl ester ; 1H-NMR : 7.73 (d, 2H), 7.38 (d, 1H), 7.30-7. 20 (m, 1H), 7.00-6. 83 (m, 4H), 6.39 (d, 1H), 4.95-4. 80 (m, 1H), 4.17 (t, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 3.28 (t, 2H), 1.90-1. 50 (m, 5H), 1.50-1. 20 (m, 5H), 1.20-0. 85 (m, 3H); MS: 472 109 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(2-methoxyphen oxy) ethoxy]-benzoylamino]propionic acid methyl ester ; 1H-NMR : 7.70 (d, 2H), 7.48-7. 30 (m, 4H), 7.20 (t, 1H), 7.04 (d, 2H), 6.97 (d, 2H), 6.90 (d, 2H), 6.60-6. 50 (m, 4H), 6.48 (d, 1H), 5.10-5. 00 (m, 3H), 4. 40-4. 28 (m, 4H), 3.79 (s, 3H), 3.76 (s, 3H), 3.26-3. 12 (m, 2H); MS : 556 110 (2S)-2- [4- (2-N-benzylaminoethoxy) benzoylamino]-3- (4-benzyloxyphenyl) propionic acid methyl ester; 1H-NMR : 7.68 (d, 2H), 7.41-7. 30 (m, 10H), 7.05 (d, 2H), 6.90 (d, 4H), 6.51 (d, 1H), 5.10-5. 00 (m, 3H), 4.14 (t, 2H), 3.90 (s, 2H), 3.76 (s, 3H), 3.19 (m, 2H) 3.06 (t, 2H) The compounds of formula (Iaa) y (Iab) shown in Table 14 were synthesized according to methods A or C, starting from intermediate (Xb) or (XIb) : TABLE 14 Ex. 111 ((4-Benzyloxybenzyl)-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoyl} amino) acetic acid ethyl ester; 1H-NMR : 7.94 (d, 1H), 7.80 (d, 1H), 7.63-7. 52 (m, 4H), 7.46-7. 31 (m, 6H), 7.14 (d, 1H), 7.00-6. 96 (m, 4H), 5.07 (s, 2H), 4. 86 (t, 2H),-4. 73-4.62 (m, 2H), 4.44 (t, 2H), 4.30-4. 18 (m, 2H), 4.11-3. 89 (m, 2H), 2. 64 (s, 3H), 1. 26 (m, 3H) 112 (2S)-3- (4-Benzyloxyphenyl)-2-f 3- [2- (3-methylquinox alin-2-yloxy) ethoxylbenzoylamino} propionic acid methyl ester ;'H-NMR : 7.94 (dd, 1H), 7.81 (d, 1H), 7.60-7. 52 (m, 2H), 7.43-7. 25 (m, 8H), 7.13 (dd, 1H), 7.04 (d, 2H), 6.90 (d, 2H), 6.57 (d, 1H), 5.08-5. 03 (m, 3H), 4.87 (t, 2H), 4.48 (t, 2H), 3. 77 (s, 3H), 3.28-3. 14 (m, 2H), 2.64 (s, 3H) 113 3-((3-Benzyloxybenzyl)-{3-[2-(3-methylquinoxalin-2- -yloxy)ethoxy]benzoyl}amino) propionic acid ethyl ester ; 1H-NMR : 7.95 (d, 1H), 7.79 (d, 1H), 7.64-7. 52 (m, 2H), 7.41-7. 25 (m, 8H), 7.03-6. 78 (m, 5H), 5.04 (s, 2H), 4.81 (m, 2H), 4.55-4. 00 (m, 6H), 3.72 (m, 2H), 2.72-2. 63 (m, 5H), 1.27 (m, 3H) 114 ((3-Benzyloxybenzyl)-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoyl} amino) acetic acid ethyl ester ; 1H-NMR : 7.94 (d, 1H), 7.80 (d, 1H), 7.61-7. 29 (m, 10H), 6.97-6. 82 (m, 5H), 5.08 (s, 2H), 4.86 (t, 2H), 4.78-4. 66 (m, 2H), 4.44 (t, 2H), 4.30-4. 18 (m, 2H), 4. 12-3. 89 (m, 2H), 2.64 (s, 3H), 1.28 (m, 3H) 115 3-((3-Benzyloxybenzyl)-{4-[2-(3-methylquinoxalin-2 -yloxy) ethoxy] benzoyl} amino) propionic acid ethyl ester ; 1H-NMR : 7.94 (d, 1H), 7.80 (d, 1H), 7.64-7. 52 (m, 2H), 7.45-7. 24 (m, 8H), 6.97-6. 78 (m, 5H), 5. 07 (s, 2H), 4.86 (t, 2H), 4.62 (br s, 2H), 4.43 (t, 2H), 4.20-4. 05 (m, 2H), 3.67 (m, 2H), 2.75-2. 64 (s, 5H), 1.25 (m, 3H) 116 ((3-Benzyloxybenzyl)-{3-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoyl} amino) acetic acid ethyl ester ; 1H-NMR : 7.94 (d, 1H), 7.81 (d, 1H), 7.65-7. 50 (m, 2H), 7. 43-7.25 (m, 8H), 7.12-6. 80 (m, 5H), 5.05 (m, 2H), 4.86-4. 79 (m, 2H), 4.60-4. 53 (m, 2H), 4.44-4. 30 (m, 2H), 4.24-4. 15 (m, 2H), 4.14-3. 85 (m, 2H), 2.63 (s, 3H), 1.32-1. 20 (m, 3H) 117 (2S)-3-(4-Bromophenyl)-2-{4-[2-(3-methylquinoxalin -2-yloxy) ethoxy] benzoylamino} propionic acid methyl ester ; 1H-NMR : 7.94 (dd, 1H), 7.81 (d, 1H), 7.72 (d, 2H), 7. 60-7. 52 (m, 2H), 7.40 (d, 2H), 7.02-6. 98 (m, 4H), 6.52 (d, 1H), 5.06 (m, 1H), 4. 88 (t, 2H), 4. 47 (t, 2H), 3. 77 (s, 3H), 3. 26 (dd, 1H), 3.17 (dd, 1H), 2.64 (s, 3H) 118 (2S)-3- (4-Fluorophenyl)-2- {4- [2- (3-methylquinoxali n-2-yloxy) ethoxy]benzoylamino}propionic acid methyl ester; 1H-NMR : 7.92 (d, 1H), 7.80 (d, 1H), 7.72 (d, 2H), 7.65-7. 52 (m, 2H), 7.11-6. 94 (m, 6H), 6.51 (d, 1H), 5.06 (m, 1H), 4.88 (t, 2H), 4.47 (t, 2H), 3.77 (s, 3H), 3.27 (dd, 1H), 3.18 (dd, 1H), 2.64 (s, 3H) 119 (2S)-3-Cyclohexyl-2-4- [2- 3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; 1H-NMR : 7. 94 (d, 1H), 7.81-7. 77 (m, 3H), 7. 64-7.51 (m, 2H), 7. 02 (d, 2H), 6.44 (d, 1H), 4.90-4. 83 (m, 3H), 4.47 (t, 2H), 3.76 (s, 3H), 2.64 (s, 3H), 1.90-0. 95 (m, 13H) 120 (2S)-3-Cyclohexyl-2- {3- [2- (3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid methyl ester; H-NMR : 7. 93 (d, 1H), 7.80 (d, 1H), 7.64-7. 51 (m, 2H), 7. 46 (s, 1H), 7. 36 (d, 2H), 7.12 (m, 1H), 6.54 (d, 1H), 4.90-4. 83 (m, 3H), 4.47 (t, 2H), 3.76 (s, 3H), 2.63 (s, 3H), 1. 90-0. 95 (m, 13H) 121 {Thiophen-3-ylmethyl- {3-E2-(thiophen-2-ylsulfanyl) ethoxy] benzoyl} amino} acetic acid methyl ester ; 1H-NMR : 7.40-7. 25 (m, 4H), 7.25-7. 05 (m, 2H), 7. 05-6. 85 (m, 2H), 7.78-4. 55 (m, 2H), 4.20-4. 04 (m, 4H), 3.78-3. 65 (m, 2H), 3.15-3. 05 (m, 2H); MS: 448 122 {Thiophen-2-yl{3-[2-(thiophen-2-ylsulfanyl)ethoxy] benzoyl}amino}acetic acid methyl ester; 1H-NMR : 7.40-7. 25 (m, 4H), 7.25-7. 05 (m, 2H), 7.05-6. 90 (m, 2H), 6.05 (d, 1H), 4.17 (t, 2H), 4.00-3. 54 (m, 4H), 3.14 (t, 2H); MS: 434 123 (2S)-3-(4-Benzyloxyphenyl)-2-{3-[2-(3-methyl-2-oxo -2H-quinoxalin-l-yl) ethoxy] benzoylamino} propionic acid methyl ester; MS: 592. 124 (2S)-3-((4-Benzyloxybenzyl)-3{3-[2-(3-methyl-2-oxo- 2H-quinoxalin-1-yl) ethoxy] benzoyl} amino) propionic acid methyl ester; MS: 606 The compounds of formula (Ia) shown in Table 16 were synthesized according to methods N or P, starting from compounds of formula (Ib) METHOD N: To a solution of 1 eq of the compound of formula (Ib), 1.3 eq of HOBT and 1.3 eq of EDC in tetrahydrofurane, the solution being 0.2 M in the compound of formula (Ib), 2 eq of triethylamine and 5 eq of the corresponding alcohol were added. The reaction mixture was stirred at room temperature for 18h, and then water and dichloromethane were added. The organic layer was separated, and the aquous layer was extracted once with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered.

The solvent was distilled off under reduced pressure.

METHOD P: 1 Eq of the compound of formula (Ib) was dissolved in the corresponding alcohol, and 2 drops of H2SO4 conc. were added. The solution was stirred over night at room temperature, and the solvent was-distilled off at reduced pressure.

TABLE 15 Ex. 125 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(3-methylquinox alin-2-yloxy) ethoxy3benzoylamino} propionic acid ethyl ester; 1H-NMR : 7.95 (d, 1H), 7.82 (d, 1H), 7.73 (d, 2H), 7.65-7. 52 (m, 2H), 7.45-7. 30 (m, 5H), 7.05 (d, 2H), 7. 00 (d, 2H), 6.89 (d, 2H), 6.52 (d, 1H), 5.03 (m, 3H), 4.88 (t, 2H), 4.47 (t, 2H), 4.22 (q, 2H), 3.20 (m, 2H), 2.65 (s, 3H), 1.29 (t, 3H) 126 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(3-methylquinox alin-2-yloxy) ethoxy] benzoylamino} propionic acid isopropyl ester; MS: 620 127 (25)-3-(4-Benzyloxyphenyl)-2-{4-[2-(3-methylquinox alin-2-yloxy) ethoxyzbenzoylaminopropionic acid propyl ester ; MS: 620 EXEMPLE (Ib): METHOD Q: To a solution 0. 1 M of 1 eq of the corresponding acid chloride in tetrahydrofurane or dioxane, an aqueous solution of 1 eq of the aminoacidic derivative, and 2 eq of sodium hydroxide was added. The resulting mixture was stirred for 18h at room temperature. Then, HCl 1 N was added dropwise until pH acid was reached, and the solution was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

METHOD R: To a mixture of 1 eq of acid of formula (II), 1.3 eq of HOBT and 1.3 eq of EDC, tetrahydrofurane or dioxane were added, and the resulting solution (0.2 M in the acid of formula (II) ) was stirred during 2h at room temperature. Then, an aquous solution of 1 eq of the aminoacidic derivative, and 2 eq of sodium hydroxide was added. The solution was stirred over night at room temperature. Then, HC1 1 N was added dropwise until pH acid was reached, and the solution was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography.

The compounds of formula (Ib) shown in Table 16 were synthesized according to methods Q or R, starting from intermediates (VIb): TABLE 16 Ex. 128 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(5-methyl-2-phe nyloxazol-4-yl) ethoxy] benzoylamino} propionic acid; 1H-NMR : 7.90-6. 80 (m, 18H), 5.00 (s, 2H), 4.45 (m, 1H), 4.26 (m, 2H), 3.40 (m, 2H), 2.95 (m, 2H), 2.35 (s, 3H) 129 (2S)-2- (4-Benzyloxybenzoylamino)-3- (4-benzyloxyphe nyl) propionic acid; 1H-NMR : 7.66 (d, 2H), 7.37-7. 31 (m, 10H), 7. 08 (d, 2H); 6. 95 (d, 2H), 6.86 (d, 2H), 5.07 (s, 2H), 4. 99 (s, 2H), 4.93 (t, 1H), 3.23-3. 15 (m, 2H) 130 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-dibenzylaminoet hoxy) benzoyiamino] propionic acid; 1H-NMR : 8.00-6. 75 (m, 24H), 4.88 (m, 3H), 4. 15 (t, 2H), 3.98 (s, 4H), 3.35-3. 14 (m, 2H), 3. 08 (t, 2H) 131 (2R)-2- [4- (2-Dibenzylaminoethoxy) benzoylamino]-3- ( lH-indol-3-yl) propionic acid ; 1H-NMR : 7.72-6. 74 (m, 20H), 4.80 (m, 1H), 4.02 (t, 2H), 3.72 (s, 4H), 3.55-3. 25 (m, 2H), 2.89 (t, 2H) 132 3- (4-tert-Butylphenyl)-2- [4- (2-dibenzylaininoethoxy ) benzoylamino] propionic acid ; 1H-NMR : 7.62 (d, 2H), 7.50-7. 11 (m, 14H), 6. 83 (d, lH), 6.76 (d, 2H), 4.91 (m, 1H), 4. 10 (t, 2H), 3. 94 (s, 4H), 3.38-3. 16 (m, 2H), 3.05 (t, 2H), 1. 20 (s, 9H) 133 3- (4-Bromophenyl)-2- [4- (2-dibenzylaminoethoxy) benz oylamino] propionic acid ;'H-NMR : 7.62 (d, 2H), 7.43-7. 24 (m, 12H), 7. 04 (d, 2H), 6.85 (d, lH), 6.77 (d, 2H), 4.86 (m, 1H), 4. 12 (t, 2H), 3. 98 (s, 4H), 3.36-3. 13 (m, 2H), 3. 07 (t, 2H) 134 3-Biphenyl-2-yl-2- [4- (2-dibenzylaminoethoxy) benzoy lamino]propionic acid ; 1H-NMR : 7.46-7. 17 (m, 21H), 6.72 (d, 2H), 6.36 (d, 1H), 4. 66 (m, 1H), 4.07 (t, 2H), 3.84 (s, 4H), 3.44-3. 09 (m, 2H), 2.98 (t, 2H) 136 3-Biphenyl-4-yl-2- [4- (2-dibenzylaininoethoxy) benzoy lamino] propionic acid; 1H-NMR : 7.63 (d, 2H), 7.45-7. 22 (m, 19H), 6. 93 (d, 1H), 6.74 (d, 2H), 4.95 (m, lH), 4.08 (t, 2H), 3. 93 (s, 4H), 3.44-3. 23 (m, 2H), 3. 03 (t, 2H) 137 3- (4-tert-Butylphenyl)-2- [3- (2-dibenzylaminoethoxy ) benzoylamino] propionic acid ; 1H-NMR: 7.45-6. 82 (m, 19H), 4.90 (m, 1H), 4. 19 (t, 2H), 3.96 (s, 4H), 3.36-3. 02 (m, 4H), 1.16 (s, 9H) 138 3- (4-Bromophenyl)-2- [3- (2-dibenzylaminoethoxy) benz oylamino] propionic acid ; 1H-NMR : 7.52-6. 85 (m, 19H), 4.98 (m, 1H), 4.20 (t, 2H), 3.99 (s, 4H), 3.51-3. 03 (m, 4H) 139 3- (3-Bromophenyl)-2- [3- (2-dibenzylaminoethoxy) benz oylamino] propionic acid; 1H-NMR : 7. 60-6.88 (m, 19H), 4.83 (m, 1H), 4.29 (t, 2H), 4.11 (s, 4H), 3.32-3. 05 (m, 4H) 140 3-Biphenyl-2-yl-2- [3- (2-dibenzylaminoethoxy) benzoy lamino] propionic acid ; 1H-NMR : 7.50-6. 88 (m, 24H), 4.93 (m, 1H), 4.29 (m, 2H), 4.13 (s, 4H), 3.40-3. 20 (m, 4H) 141 2- [4- (2-Dibenzylaminoethoxy) benzoylamino]-3- (3-phe noxyphenyl) propionic acid ; 1H-NMR : 8.06-6. 74 (m, 24H), 4.90 (m, 1H), 4.10 (t, 2H), 3.89 (s, 2H), 3.76 (s, 2H), 3. 40-2. 92 (m, 4H) 142 3- (5-Bromo-lH-indol-3-yl)-2- [4- (2-dibenzylaminoeth oxy) benzoylamino] propionic acid ; 1H-NMR : 7.81-7. 20 (m, 17H), 6.90 (d, 2H), 4.94 (m, 1H), 4.17 (t, 2H), 3.97 (s, 4H), 3.58-3. 31 (m, 2H), 3. 11 (t, 2H) 143 2- 3- (2-Dibenzylaminoethoxy) benzoylamino]-3- (3-phe noxyphenyl) propionic acid ; 1H-NMR : 7.44-6. 88 (m, 24H), 4.87 (m, 1H), 4.16 (t, 2H), 3.94 (s, 4H), 3.34-3. 03 (m, 4H) 144 3- (5-Bromo-lH-indol-3-yl)-2- [3- (2-dibenzylaminoeth oxy) benzoylamino] propionic acid ; 1H-NMR : 7.79-7. 20 (m, 19H), 4.96 (m, 1H), 4.23 (m, 6H), 3.52-3. 24 (m, 4H) 145 (2S)-2-[3-(3-Benzyloxybenzyloxy)benzoylamino]-3-(4 -benzyloxyphenyl) propionic acid ;'H-NMR : 7.45-7. 21 (m, 14H), 7.13-7. 07 (m, 4H), 7.01 (d, 1H), 6.96-6. 89 (m, 3H), 6.58 (d, 1H), 5.06-4. 99 (m, 7H), 3.31 (dd, 1H), 3.21 (dd, 1H) The compounds of formula (Ib) shown in Table 17 were synthesized according to methods J or K, starting from compounds of formula (Ia) : TABLE 17 Ex. 146 {[4-(2-Dibenzylaminoethoxy)benzoyl]-(3-phenoxybenz yl) amino} acetic acid ; 1H-NMR : 7.66-6. 88 (m, 23H), 4.81-4. 68 (m, 2H), 4.57 (s, 4H), 4.40 (m, 2H), 4.18-4. 00 (m, 2H), 3.63 (m, 2H) 147 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-phenylallyloxy) benzoylamino]propionic acid ; 1H-NMR : 7.66 (d, 2H), 7.40-6. 84 (m, 17H), 6. 71 (d, 1H), 6.36 (dt, 1H), 4.98 (s, 2H), 4.92 (t, 1H), 4.70 (d, 2H), 3.30-3. 08 (m, 2H) 148 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (4-phenoxybenzylox y) benzoylamino] propionic acid ; 1H-NMR : 7.62 (d, 2H), 7.34-6. 79 (m, 20H), 4.99 (s, 2H), 4.94 (s, 2H), 4.84 (t, 1H), 3.25-3. 02 (m, 2H) 149 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (biphenyl-4-ylmeth oxy) benzoylamino] propionic acid ; 1H-NMR : 7.82-6. 91 (m, 22H), 5.28 (s, 2H), 5.02 (s, 2H), 4.75 (t, 1H), 3. 40-3. 10 (m, 2H) 150 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-phenoxybenzylox y) benzoylamino] propionic acid ; 1H-NMR : 7.61 (d, 2H), 7.36-6. 77 (m, 20H), 4.97 (s, 2H), 4.91 (s, 2H), 4.76 (t, 1H), 3.25-3. 02 (m, 2H) 151 (2S)-2- [4- (3-Benzyloxybenzyloxy) benzoylamino]-3- (4 -benzyloxyphenyl)propionic acid ; 1H-NMR : 7.61 (d, 2H), 7.34-6. 77 (m, 20H), 5.00 (s, 2H), 4.97 (s, 2H), 4.91 (s, 2H), 4.77 (m, 1H), 3.25-3. 04 (m, 2H) 152 (2S)-3- (4-Benzyloxyphenyl)-2- (4-phenethyloxybenzoy lamino) propionic acid; 1H-NMR :, 63 (d, 2H), 7.39-7. 24 (m, 10H), 7.19 (d, 2H), 6.92-6. 86 (m, 4H), 6.47 (d, 1H), 5.01-4. 92 (m, 3H), 4.19 (t, 2H), 3.26-3. 07 (m, 4H) 153 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-phenylpropoxy) b enzoylamino] propionic acid ; 1H-NMR : 7.66 (d, 2H), 7.39-7. 18 (m, 10H), 7.10 (d, 2H), 6.89-6. 86 (m, 4H), 5. 00 (s, 2H),. 4.94 (t, 1H), 4.97 (t, 2H), 3. 30-3. 13 (m, 2H), 2.80 (t, 2H), 2.10 (m, 2H) 154 { (4-Benzyloxybenzyl)- [4- (2-dibenzylaminoethoxy) ben zoyl] amino} acetic acid ; 1H-NMR : 7.31-6. 40 (m, 23H), 4.90-4. 50 (m, 4H), 3.90-3. 60 (m, 8H), 2.74 (m, 2H) 155 { (3-Benzyloxybenzyl)- [3- (2-dibenzylaminoethoxy) ben zoyl] amino} acetic acid ; 1H-NMR : 7.60-6. 91 (m, 23H), 5.04-5. 01 (m, 2H), 4.76-3. 68 (m, 10H), 3.40-3. 20 (m, 2H) 156 {[3-(2-Dibenzylaminoethoxy)benzoyl]-(3-phenoxybenz yl) amino} acetic acid ; 1H-NMR : 7.58-6. 88 (m, 23H), 4.79-3. 71 (m, 10H), 3.32-3. 17 (m, 2H) 157 {[3-(2-Dibenzylaminoethoxy)benzoyl]-(4-phenoxybenz yl) amino} acetic acid ; 1H-NMR : 7.61-6. 94 (m, 23H), 4.80-3. 71 (m, 10H), 3.35-3. 15 (m, 2H) 158 { (4-tert-Butylbenzyl)- [3- (2-dibenzylaminoethoxy) be nzoyl] amino} acetic acid; 7. 65-6. 92 (m, 18H), 4.78-3. 38 (m, 12H), 1.35-1. 20 (m, 9H) 159 {[3-(2-Dibenzylaminoethoxy)benzoyl]-(3-benzyloxybe nzyl) amino} acetic acid; 1H-NMR : 7.60-6. 76 (m, 23H), 5.03-4. 99 (m, 2H), 4.74-3. 15 (m, 12H) 160 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(3-methylquinox alin-2-yloxy) ethoxy]benzoylamino}propionic acid; H-NMR : 7.99-6. 86 (m, 17H), 6.57 (d, lH), 4. 99 (m, 3H), 4.86 (t, 2H), 4.44 (t, 2H), 3.39-3. 12 (m, 2H), 2.63 (s, 3H) 161 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(3- bromophenoxy) ethoxy] benzoylamino} propionic acid; 1H-NMR : 7.62 (d, 2H), 7.33-6. 79 (m, 15H), 4.95 (s, 2H), 4.83 (t, 1H), 4.26 (s, 4H), 3.25-3. 02 (m, 2H) 162 3- { (3-Benzyloxybenzyl)- [4- (2-dibenzylaminoethoxy) b enzoyl] amino} propionic acid; MS: 629 163 3- { (3-Benzyloxyben. zyl)- [3- (2-dibenzylaminoethoxy) b enzoyl] amino} propionic acid ; lH-NMR : 7.52-7. 16 (m, 17H), 7.05-6. 62 (m, 6H), 5.03 (s, 2H), 4.75-4. 51 (m, 2H), 4.07-3. 85 (m, 2H), 3.75-3. 66 (m, 6H), 3.14-2. 83 (m, 2H), 2.78-2. 33 (m, 2H) 164 3-{(4-Benzyloxybenzyl)-[3-(2-dibenzylaminoethoxy) b enzoyl] amino} propionic acid ; 1H-NMR : 7.38-7. 15 (m, 17H), 7.06-6. 71 (m, 6H), 4. 95 (s, 2H), 4.66-4. 38 (m, 2H), 4.10-3. 92 (m, 2H), 3.81-3. 44 (m, 6H), 2.95-2. 73 (m, 2H), 2. 54-2.40 (m, 2H) 165 2-[4-(2-Dibenzylaminoethoxy)benzoylamino]-3-(1-met hyl-lH-indol-3-yl) propionic acid; 1H-NMR : 7.50-7. 47 (m, 3H), 7.38-7. 24 (m, 9H), 7.09-6. 83 (m, 5H), 6.53 (d, 2H), 4.93 (m, 1H), 3.83-3. 72 (m, 6H), 3.39 (m, 5H), 2.83 (m, 2H) 166 3- (5-Benzyloxy-lH-indol-3-yl)-2- [4- (2- dibenzylaminoethoxy) benzoylamino] propionic acid; 1H-NMR : 7.40-7. 19 (m, 15H), 6.97 (m, 3H), 6.80-6. 72 (m, 2H), 6.40 (m,. 2H), 4.92 (m, 1H), 4.69 (d, 1H), 4.46 (d, lH), 3.68 (m, 6H), 3.26 (m, 2H), 2.76 (m, 2H) 167 3- (5-Benzyloxy-lH-indol-3-yl)-2- [3- (2- dibenzylaminoethoxy) benzoylamino] propionic acid; 1H-NMR : 7.27-7. 05 (m, 15H), 6.92-6. 85 (m, 4H), 6.72-6. 50 (m, 4H), 4.82 (m, 1H), 4.64 (d, 1H), 4.43 (d, 1H), 3.67 (m, 2H), 3.56 (s, 4H), 3.20 (m, 2H), 2.66 (m, 2H) 168 { (4-Benzyloxybenzyl)- 4- [2- (3-methylquinoxalin-2- yloxy) ethoxy] benzoyl} amino} acetic acid ; 1H-NMR : 7.87 (d, 1H), 7.74 (d, 1H), 7.60-7. 25 (m, 10H), 7.06 (d, 1H), 6.90-6. 88 (m, 4H), 5.00 (s, 2H), 4.80 (t, 2H), 4.68-4. 55 (m, 2H), 4. 38 (t, 2H), 4.04-3. 79 (m, 2H), 2.58 (s, 3H) 169 (2S)-3-(4-Benzyloxyphenyl)-2-{3-[2-(2, 6- dimethylphenoxy) ethoxy] benzoylamino} propionic acid ; 1H-NMR : 7.43-7. 30 (m, 9H), 7.24-6. 91- (m, 7H), 6.58 (d, 1H), 5.07-5. 00 (m, 3H), 4.35-4. 32 (m, 2H), 4.17-4. 14 (m, 2H), 3.30 (dd, 1H), 3.21 (dd, 1H), 2.32 (s, 6H) 170 3- { (3-Benzyloxybenzyl)- {4- [2- (3-methylquinoxalin-2 -yloxy) ethoxy] benzoyl} amino} propionic acid; MS: 592 171 { (3-Benzyloxybenzyl)- {4- [2- (3-methylquinoxalin-2- yloxy) ethoxy] benzoyl} amino} acetic acid; MS : 578 172 {(3-Benzyloxybenzyl)-{3-[2-(3-methylquinoxalin-2- yloxy) ethoxy]benzoyl}amino}acetic acid; MS: 578 173 3-{(3-Benzyloxybenzyl)-{3-[2-(3-methylquinoxalin-2 -yloxy) ethoxy] benzoyl} amino} propionic acid; MS: 592 174 { (3-Benzyloxybenzyl)- [4- (3-benzyloxybenzyloxy) benz oyl] amino} acetic acid ;'H-NMR : 7.45-7. 30 (m, 14H), 7.05-6. 81 (m, 8H), 5.08 (s, 2H), 5.07 (s, 2H), 5. 05 (s, 2H), 4.67 (br s, 2H), 4.15 (br s, 2H) 175 3-{(3-Benzyloxybenzyl)-[4-(3-benzyloxybenzyloxy) be nzoyl] amino} propionic acid ; lH-NMR : 7.46-7. 25 (m, 13H), 7.06-6. 78 (m, 9H), 5.07 (s, 4H), 5.04 (s, 2H), 4.62 (br s, 2H), 3.66 (m, 2H), 2.73 (m, 2H) 176 3-{(4-Benzyloxybenzyl)-[4-(3-benzyloxybenzyloxy) be nzoyl] amino} propionic acid; 1H-NMR : 7.46-7. 27 (m, 13H), 7.11-6. 93 (m, 9H), 5.07 (s, 2H), 5.06 (s, 2H), 5 5. 04 (s, 2H), 4.59 (br s, 2H), 3.66 (m, 2H), 2.70 (m, 2H) 177 { (4-Benzyloxybenzyl)- [3- (3-benzyloxybenzyloxy) benz oyl] amino} acetic acid ;'H-NMR : 7.44-7. 26 (m, 13H), 7.11-6. 91 (m, 9H), 5.08-4. 98 (m, 6H), 4.75-4. 52 (m, 2H), 4. 16-3. 86 (m, 2H) 178 { (3-Benzyloxybenzyl)- [3- (3-benzyloxybenzyloxy) benz oyl] amino} acetic acid ; 1H-NMR : 7.44-7. 26 (m, 13H), 7.07-6. 80 (m, 9H), 5.09-4. 93 (m, 6H), 4.79-4. 57 (m, 2H), 4.17-3. 86 (m, 2H) 179 3- ( (3-Benzyloxybenzyl)- [3- (3-benzyloxybenzyloxy) be nzoyl] amino} propionic acid ; lH-NMR : 7.45-7. 23 (m, 13H), 7.03-6. 89 (m, 8H), 6.75 (m, 1H), 5.06-4. 93 (m, 6H), 4.73-4. 50 (m, 2H), 3.69-3. 47 (m, 2H), 2.73-2. 35 (m, 2H) 180 (2S)-3- (4-Benzyloxyphenyl)-2- {3- [2- (3-methylquinox alin-2-yloxy) ethoxylbenzoylamino} propionic acid ; MS: 578 181 3- [ (4-Benzyloxybenzoyl)- (3-benzyloxybenzyl) amino] p ropionic acid; MS: 496 182 3-f (4-Benzyloxybenzyl)- [3- (3-benzyloxybenzyloxy) be nzoyl] amino} propionic acid ; 1H-NMR : 7.41-7. 26 (m, 13H), 7.02-6. 92 (m, 9H), 5.06-4. 98 (m, 6H), 4.69-4. 46 (m, 2H), 3.68-3. 48 (m, 2H), 2.71-2. 43 (m, 2H) 183 (2S)-2- [4- (4-Benzyloxybenzyloxy) benzoylamino]-3- (4 -benzyloxyphenyl) propionic acid ; 1H-NMR : 7.68 (d, 2H), 7.44-7. 30 (m, 12H), 7.10 (d, 2H), 7.00-6. 90 (m, 4H), 6.89 (d, 2H), 5.08 (s, 2H), 5.02 (s, 4H), 4.95 (t, 1H), 3.27 (dd, 1H), 3. 17 (dd, 1H) 184 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (biphenyl-2-ylmeth oxy) benzoylamino] propionic acid ; 1H-NMR : 7.64-7. 55 (m, 3H), 7.42-7. 33 (m, 13H), 7.10 (d, 2H), 6.89-6. 84 (m, 4H), 5.02 (s, 2H), 4.97 (s, 2H), 4.95 (t, 1H), 3.26 (dd, 1H), 3.17 (dd, 1H) 185 (2S)-2-[3-(4-Benzyloxybenzyloxy)benzoylamino]-3-(4 -benzyloxyphenyl) propionic acid ; 1H-NMR : 7.46-7. 18 (m, 15H), 7.14-7. 07 (m, 3H), 6.97 (d, 2H), 6.57 (d, 2H), 5.05-4. 97 (m, 5H), 3.30 (dd, 1H), 3.19 (dd, 1H) 186 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (3-phenylallyloxy) benzoylamino] propionic acid ; 1H-NMR : 7.41-7. 18 (m, 13H), 7.10-7. 04 (m, 3H), 6.85 (d, 2H), 6.71 (d, 1H), 6. 38 (dt, 1H), 4.98 (s, 2H), 4.95-4. 87 (m, 1H), 4.69 (dd, 1H), 3. 25 (dd, 1H), 3.15 (dd, 1H) 187 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (biphenyl-4-ylmeth oxy) benzoylamino] propionic acid ; 1H-NMR : 7.50-6. 75 (m, 22H), 4.98 (s, 2H), 4.86 (s, 2H), 4.78 (m, 1H), 3. 22-3.00 (m, 2H) 188 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (3-phenoxybenzylox y)benzoylamino]propionic acid ; 1H-NMR : 7.40-7. 20 (m, 11H), 7.12-6. 89 (m, 11H), 6.55 (d, 1H), 5.04-5. 00 (m, 5H), 3.29 (dd, 1H), 3.20 (dd, 1H) 189 (2S)-3- (4-Benzyloxyphenyl)-2- [3- (3-phenylpropoxy) b enzoylamino]propionic acid; 1H-NMR: 7. 40-7.16 (m, 13H), 7.06 (d, 2H), 7.00 (dd, 1H), 6.86 (d, 2H), 4. 98 (s, 2H), 4. 92 (t, 1H), 3. 96 (t, 2H), 3. 25 (dd, 1H), 3.14 (dd, 1H), 2.78 (t, 2H), 2.08 (m, 2H) 190 (2S)-2- [3- (4-Butylbenzyloxy) benzoylamino]-3-cycloh exylpropionic acid; MS: 438 191 (2S)-3-(4-Bromophenyl)-2-{4-[2-(3-methylquinoxalin -2-yloxy)ethoxy]benzoylamino} propionic acid; MS: 551 192 (2S)-3-(4-Fluorophenyl)-2-{4-[2-(3-methylquinoxali n-2-yloxy) ethoxy] benzoylamino} propionic acid; MS: 490 193 (2S)-2-[4-(3-Benzyloxybenzyloxy)benzoylamino]-3-(4 -bromophenyl) propionic acid ; MS: 561 194 (2S)-2- [4- (3-Benzyloxybenzyloxy) benzoylaminol-3- (4 -fluorophenyl) propionic acid; MS: 500 195 3- { [4- (2-Dibenzylaminoethoxy) ben. zoyl]- (3-phen. oxybe nzyl) amino} propionic acid; MS : 615 196 3-{[4-(2-Dibenzylaminoethoxy)benzoyl] (4-phenoxyben zyl) amino} propionic acid; MS: 615 197 3- { [3- (2-Dibenzylaminoethoxy) benzoyll naphthalen-2- ylmethylamino} propionic acid; MS: 573 198 3-{(4-tert-Butylbenzyl)-[3-(2-dibenzylaminoethoxy) benzoyl] amino} propionic acid; MS: 579 199 3- {Biphenyl-4-ylmethyl- [3- (2-dibenzylaminoethoxy) b enzoyl] amino} propionic acid; MS: 599 200 3-{(4-Bromobenzyl)-[3-(2-dibenzylaminoethoxy)benzo yl] amino} propionic acid; MS: 601 201 3- { 3- (2-Dibenzylaminoethoxy) benzoyl]- (3- phenoxybenzyl) amino} propionic acid; MS: 615 202 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(pyridin-2- yloxy) ethoxy]benzoylamino}propionic acid ; MS: 513 203 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(quinolin-8- yloxy) ethoxy] benzoylamino} propionic acid; MS: 563 204 (2S)-3- (4-Benzyloxyphenyl)-2- {4- [2- (4-imidazol-1-y 1-phenoxy)ethoxy]benzoylamino}propionic acid; MS: 578 205 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-naphthalen-2-yl - ethoxy) benzoylaminolpropionic acid; 1H-NMR : 7.80-7. 76 (m, 3H), 7.69-7. 62 (m, 3H), 7.46-7. 25 (m, 8H), 7.06 (d, 2H), 6.89-6. 83 (m, 4H), 4.97 (s, 2H), 4.90 (t, 1H), 4.25 (t, 2H), 3. 24-3. 20 (m, 3H), 3. 11 (dd, 1H) 206 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(2-methylbenzot hiazol-5-yloxy) ethoxy] benzoylamino} propionic acid; MS: 583 207 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(5,6,7,8-tetrah ydronaphthalen-2- yloxy) ethoxy] benzoylamino} propionic acid; MS: 566 208 (2S)-2- [4- (4-Butylbenzyloxy) benzoylamino]-3-phenyl propionic acid; MS: 432 209 (2S)-3-(4-Benzyloxyphenyl)-2-[4-(4-butylbenzyloxy) benzoylamino] propionic acid ; MS: 538 210 (2S)-2- [4- (4-Butylbenzyloxy) benzoylamino]-3-cycloh exylpropionic acid; MS: 438 211 (2S)-3-Cyclohexyl-2-{4-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid; MS: 478 212 (25)-3-Cyclohexyl-2-{3-[2-(3-methylquinoxalin-2- yloxy) ethoxy] benzoylamino} propionic acid; MS: 478 213 (2S)-2- [4- (3-Benzyloxybenzyloxy) benzoylamino]-3-cy clohexylpropionic acid; MS: 488 214 (2S)-2- [3- (3-Benzyloxybenzyloxy) benzoylamino]-3-cy clohexylpropionic acid; MS: 488 215 (2S)-3- (4-Benzyloxyphenyl)-2- (3- (4-butylbenzyloxy) benzoylamino] propionic acid; MS: 538 216 { (3-Benzyloxybenzyl)- [4- (4-butylbenzyloxy) benzoyl] amino} acetic acid ; MS: 538 217 { (4-Benzyloxybenzyl)- [4- (4-butylbenzyloxy) benzoyl] amino} acetic acid ;'H-NMR : 7.50-7. 10 (m, 13H), 6.97 (d, 4H), 5.06 (s, 2H), 5.03 (s, 2H), 4.63 (br s, 2H), 4.15 (br s, 2H), 2.61 (t, 2H), 1. 59 (q, 2H), 1.36 (m, 2H), 0. 92 (t, 3H) 218 3- { (3-Benzyloxybenzyl)- [4- (4-butylbenzyloxy) benzoy llamino} propionic acid; MS: 552 219 3-{(4-Benzyloxybenzyl)-[4-(4-butylbenzyloxy)benzoy l] amino} propionic acid; MS: 552 220 [3-(4-Benzyloxybenzyloxy)benzoylamino]phenylacetic acid; MS : 468 221 (2S)-2- [3- (4-Benzyloxybenzyloxy) benzoylamino]-3-ph enylpropionic acid; MS : 482 222 (2S)-2- [3- (4-Benzyloxybenzyloxy) benzoylamino]-3-cy clohexylpropionic acid; MS : 488 223 {(3-Benzyloxybenzyl)-[3-(4-butylbenzyloxy)benzoyl] amino} acetic acid; MS : 538 224 3-{(3-Benzyloxybenzyl)-[3-(4-butylbenzyloxy)benzoy l] amino} propionic acid; MS: 552 225 (2S)-2-{4-[2-(3-Methylquinoxalin-2-yloxy)ethoxy]be nzoylamino}-3-phenylpropionic acid; MS: 472 226 [3- (3-Benzyloxybenzyloxy) benzoylamino] phenylacetic acid; MS: 468 227 (2S)-2-f3-(3-Benzyloxybenzyloxy) benzoylamino]-3-ph enylpropionic acid; MS: 482 228 { (3-Benzyloxybenzyl)- [3- (4-benzyloxybenzyloxy) benz oyl] amino} acetic acid; MS: 588 229 3- ( (3-Benzyloxybenzyl)- [3- (4-benzyloxybenzyloxy) be nzoyl] amino} propionic acid; MS: 602 230 (2S)-3- (4-Benzyloxyphenyl)-2- {4- [2- (quinolin-2- yloxy) ethoxy] benzoylamino} propionic acid; MS: 563 231 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(quinolin-7-ylo xy) ethoxy]benzoylamino}propionic acid; MS: 563 232 [4- (4-Butylbenzyloxy) benzoylamino] phenylacetic acid; MS: 418 233 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (4-butoxybenzyloxy ) benzoylamino] propionic acid; MS: 554 234 {[4-(3-Benzyloxybenzyloxy)benzoyl]-(4-benzyloxyphe nyl) amino} acetic acid ; MS : 574 235 {[4-(3-Benzyloxybenzyloxy)benzoyl]-(3-benzyloxyphe nyl) amino} acetic acid ; MS: 574 236 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-pyridin-2-yl-et hoxy) benzoylamino] propionic acid; MS: 497 237 (2S)-2- [4- (4-Butoxybenzyloxy) benzoylamino]-3-cyclo hexylpropionic acid; MS: 454 238 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-bromobenzyloxy) benzoylamino] propionic acid; MS: 561 239 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-bromobenzyloxy) benzoylamino] propionic acid; MS: 561 240 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-chlorobenzyloxy ) benzoylamino] propionic acid; MS: 516 241 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3-chlorobenzyloxy ) benzoylamino] propionic acid; MS: 516 242 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-fluorobenzyloxy ) benzoylamino] propionic acid; MS: 500 243 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-methylbenzyloxy ) benzoylamino] propionic acid; MS: 496 244 (25)-3- (4-Benzyloxyphenyl)-2- [4- (3- methylbenzyloxy) benzoylamino] propionic acid; MS: 496 245 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (3- trifluoromethylbenzyloxy) benzoylamino] propionic acid; MS: 550 246 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2- trifluoromethylbenzyloxy) benzoylaminolpropionic acid; MS: 550 247 (2S)-2- [4- (3-Bromobenzyloxy) benzoylamino]-3-cycloh exylpropionic acid ; MS: 461 248 (2S)-3- (4-Benzyloxyphenyl)-2- [4- (2-methoxybenzylox y) benzoylamino] propionic acid; MS: 512 249 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[(benzylphenylcarb amoyl) methoxy]-benzoylamino} propionic acid; 1H-NMR : 7. 60 (d, 2H), 7.38-6. 99 (m, 17H), 6.87 (d, 2H), 6.75 (d, 2H), 6.63 (d, 1H), 5.10-4. 90 (m, 5H), 4.41 (s, 2H), 3.32-3. 10 (m, 2H) 250 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[(dibenzylcarbamoy 1) methoxy]-benzoylamino} propionic acid ;'H-NMR : 7.64 (d, 2H), 7.41-6. 84 (m, 21H), 6.64 (d, 1H), 5.03-4. 91 (m, 3H), 4.81 (s, 2H), 4.61 (s, 2H), 4.50 (s, 2H), 3.33-3. 12 (m, 2H) 251 (2S)-3-(4-Benzyloxyphenyl)-2-{4-[2-(10,11-dihydrod ibenzo [b, f] azepin-5-yl)-2- oxoethoxy] benzoylamino} propionic acid ; 1H-NMR : 7.60 (d, 2H), 7.38-7. 06 (m, 15H), 6. 87 (d, 2H), 6.79 (d, 2H), 6.60 (d, 1H), 5.04-4. 93 (m, 3H), 4.77 (d, 1H), 4.46 (d, 1H), 3.37-3. 20 (m, 4H), 2.89-2. 74 (m, 2H) 252 (2S)-2-{4-[2-(Benzoylbenzylamino)ethoxy]benzoylami no}-3- (4-benzyloxyphenyl) propionic acid ; 1H-NMR : 7.65 (d, 2H), 7. 38-6. 61 (m, 22H), 4.98 (m, 3H), 4.69-3. 63 (m, 6H), 3.34-3. 13 (m, 2H) 253 (2S)-3- (4-Benzyloxyphenyl)-2- (4- {2- [benzyl (pyridin e-3-carbonyl) amino] ethoxy} benzoylamino) propionic acid ; 1H-NMR : 8.70-6. 74 (m, 23H), 5.01-4. 89 (m, 3H), 4.88-3. 61 (m, 6H), 3.35-3. 14 (m, 2H) 254 [ {4- [2- (Benzoylbenzylamino) ethoxy] benzoyl}- (4- benzyloxybenzyl) amino] acetic acid; 1H-NMR: 7. 79-6. 74 (m, 23H), 5.06 (s, 2H), 4.89-3. 61 (m, 10H) 255 [ (4-Benzyloxybenzyl)- (4-2- [benzyl (pyridine-3- carbonyl) amino] ethoxy} benzoyl) amino] acetic acid; H-NMR :: 8.64 (d, 1H), 7.79-6. 80 (m, 21H), 5.06 (s, 2H), 4.87-3. 65 (m, 10H) 256 {Thiophen-3-ylmethyl-{3-[2-(thiophen-2-ylsulfanyl) ethoxy] benzoyl} amino} acetic acid; MS: 434 257 {Thiophen-2-yl- 3- [2- (thiophen-2-ylsulfanyl) ethoxy ]benzoylamino}acetic acid ; MS: 420. 258 {3-[(Benzylphenylcarbamoyl) methoxy] benzoylamino} th iophen-3-yl-acetic acid; MS : 501 259 3-(4-Benzyloxyphenyl)-2-{3-[benzylphenethylcarbam oyl) methoxy]-benzoylamino} propionic acid ; lH-NMR : 7.41-7. 00 (m, 21H), 6.90-6. 75 (m, 2H), 4.85-4. 75 (m, 3H), 4.67-4. 55 (m, 2H), 4.45-4. 25 (m, 2H), 3.60-3. 35 (m, 2H); 3.35-3. 05 (m, 2H), 2.60-2. 05 (m, 2H); MS: 643 260 3-(4-Benzyloxyphenyl)-2-t4-[(phenylpyridin-2-yl-ca rbamoyl) methoxy]-benzoylamino} propionic acid; H-NMR : 9.92 (d, 1H), 7.62-7. 40 (m, 6H), 7.35 (d, 2H), 7.30-7. 10 (m, 7H), 7.12 (d, 1H), 6.97 (d, 2H), 6.90 (2H), 6.75 (d, 2H), 5.27 (s, 2H), 4.89 (s 2H), 4.76 (t, 1H), 3.11 (dd, 1H), 3.01 (dd, 1H) 261 3- (4-Benzyloxyphenyl)-2- {4- [ (cyclohexylphenylcarba moyl) methoxy] benzoylamino} propionic acid ; MS: 607 262 3-(4-Benzyloxyphenyl)-2-{4-[(tert-butylcyclohexylc arbamoyl) methoxy]-benzoylamino} propionic acid; MS: 587 263 3-(4-Benzyloxyphenyl)-2-(4-{[(2-fluorophenyl) thiop hen-2- ylmethylcarbamoyl] methoxy} benzoylamino) propionic acid; MS: 639 264 (2S)-3-(4-Benzyloxphenyl)-2-{3-[2-(3-methyl-2-oxo - 2H-quinoxalin-l-yl) ethoxy] benzoylamino} propionic acid; MS: 578 265 (2S)-3-((4-Benzyloxybenzyl)-{3-[2-(3-methyl-2-oxo 2H-quinoxalin-1-yl) ethoxy]benzoyl}amino) propionic; MS: 592 EXAMPLES (Ic) and (Id) The compounds of formula (Ic) and (Id) shown in Table 18 were synthesized either according to any of methods A to C, starting from compounds of formula (Ib) and the aminic derivatives HNR2R3 oR HNR2ORl : TABLE 18 Ex. 266 N- [ (1S)-2-(4-Benzyloxyphenyl)-1-dimethylcarbamoyle thyl]-4- phenetyloxybenzamide ; 1H-NMR : 7.75 (d, 2H), 7. 44-6. 88 (m, 16H), 5.30 (m, 1H), 5.05 (s, 2H), 4.22 (t, 2H), 3.25-2. 90 (m, 4H) 2.88 (s, 3H), 2.67 (s, 3H) 267 N- [(1S)-2-(4-Benzyloxyphenyl)-1-dimethylcarbamoyle thyl]-4- [2- (3-methylquinoxalin-2-yloxy) ethoxy] benzamide ; 7.96-7. 29 (m, 9H), 7.14-7. 09 (m, 4H), 7.00 (d, 2H), 6.89 (d, 2H), 1H-NMR : 5.30 (m, 1H), 5.05 (s, 2H), 4. 88 (t, 2H), 4. 47 (t, 2H), 3. 30-2. 95 (m, 2H), 2.88 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H) 268 N-[(1S)-2-(4-Benzyloxyphenyl)-1-hydroxycarbamoylet hyl]-4- [2- (3- methylquinoxalin-2-yloxy) ethoxy] benæåmide ; MS: 593 269 N-[(1S)-2-(4-Benzyloxyphenyl)-1-methoxycarbamoylet hyll-4- [2- (3- methylquinoxalin-2-yloxy) ethoxygbenzamide ; MS: 607 270 N-[(1S)-2-(4-Benzyloxyphenyl)-1-(methoxymethylcarb amoyl) ethyl]-4- [2- (3-methylquinoxalin-2-yloxy) etho xylbenzamide ; MS: 621 Assay of binding to the PPARy2 The cDNA encoding for the open reading frame of the hPPARy2 is amplified by PCR (polymerase chain reaction) and inserted in the plasmid pGEX-4T-2. This construction (pGEX-hPPARγ) is introduced into E. coli where it is overexpressed and semipurified as a fusion protein with glutathione S-transferase (GST) (Elbrecht et al., J. Biol. Chem. 1999, 274, 7913-7922).

The binding of the compounds to the GST-hPPARy2 s is determined by modifications in the method described by Lehmann et al. (J. Biol. Chem. 1995,270, 12953-12957). The receptors (2.5 Ag) were incubated in 96-well plates in the presence or in the absence of the products with [3H] BRL-49853 (100 nM) for 3 h at 4°C, in a final volume of 200 HL of buffer Tris-HCl 10 mM pH: 8.0, containing KC1 50 mM and DTT 10 mM. Non-specific binding was determined in the presence of BRL-49853 100 MM. The reaction mixture was transferred to a Multiscreen Durapore (Millipore) microplate containing glutathione-Sepharose 4B in every well. The reaction mixture was left to incubate with the resin during 10 min, and then centrifuged at 735 g during 2 min. To dissociate the receptor bound to the resin, reduced glutathione 10 mM is added and incubated during 10 min. The receptor was eluted by centrifugation. Then, 800 AL of scintillation liquid were added to the elution and the contained radioactivity was quantified by liquid scintillation spectroscopy (Microbeta Wallac, Perkin Elmer).

LBD-hPPARs transactivation assay COS-7 cells were cultivated in 24-well plates and transfected with the pFACMV plasmids that encode the chimeric proteins containing the GAL4 DNA binding domain fused to the PPARy LBD. The reporter plasmid for the foregoing constructions was pFR-Luc, which contains five repetitions of the GAL4-response element in front of a promoter that controls the transcription of the luciferase gene. Lipofectamine was used as a transfection agent.

The plasmids of the chimeric receptors and the reporter gene were inserted in the cells by transitory transfection in COS-7 cells in culture. When the products were added to the culture for 48 h, the luciferase activity showed the effect of the PPAR activity modulation on the transcription of the reporter construction (Wright et al., J. Biol. Chem. 2000, 275,1873).

Cloning of human PPARa, PPARb and PPARy2 The human PPARs cDNAs were amplified through RT-PCR. For hPPARa, RNA was obtained from HepG2 cells treated with linoleic acid; for h PPARb, RNA was obtained from untreated HepG2 cells; for hPPARy2, RNA was obtained from human white adipose tissue. Each amplified fragment was cloned into pBluescript (Stratagene@) and sequenced. One clone for each construction was selected and used as template for further subcloning and PCR amplifications.

GST-fused protein construction To generate these chimeric proteins, the complete cDNA of the four human PPARs were cloned into pGEX4T2 (Amersham Biosciences). The fragment was obtained from the pBluescript-cDNAs clones digested with endonucleases. To assess the plasmid identity and to ensure the in-phase cloning of the proteins, pGEXs constructions were sequenced.

GST-hPPARy2, GST-hPPARa or GST-h PPAR5 fusion proteins were generated in Escherichia coli (BL21 strain DE3). Cells were cultured in LB medium to a density of A600= 1.6 odu, and induced for by addition of isopropyl-l-thio-p-D-galactopyranoside (IPTG) -induced cultures to a final concentration of 0.5 mM. The IPTG-induced cultures were grown at room temperature o/n, before cells were harvested by centrifugation at 5000 g for 15 min. After sonication, the GST-fusion proteins were purified from the cell pellet using glutathione-Sepharose beads, following the procedure recommended by the manufacturer (Amersham Pharmacia Biotech). Excess of gluthatione was removed o/n by dyalisis at 4°C. Receptor purity was visualized by SDS-PAGE and protein content was determined by Bradford method. Receptor aliquots were stored at-80°C until use.

GST-hPPARa and GST-hPPARo binding Using 96-well culture plates, PPARa or PPARS (5 yg) were diluted to a total volume of 100 AL with buffer consisting of 50 mM HEPES (pH: 7.0), 50 mM KCl, 5 mM EDTA andlO mM DTT, in the presence of [3H] -GW2433 (100 and 50 nM for PPARa and PPARb, respectively). Nonspecific binding was estimated in parallel incubations containing 50 AM of GW-2433. Plates were incubated for 2 h at room temperature. Free radioligand was separated from receptor-bound ligand by size exclusion chromatography using. Sephadex G-25 in 96-wells spin plates, using the Multiscreen Column Loader (Millipore). Eluted radioactivity was quantitated by liquid scintillation counting in a Microbeta counter (Perkin Elmer).

In Table 19, affinity and functional activity data of some of the compounds of the present invention are shown.

TABLE 19 Affinity Functional activity ffinity Affinity Ex. PPARγ (1) PPARγ PPARγ (1) PPARγ ( 20 +++ Partial agonist + + 21 +++ Partial agonist + + 27 +++ Antagonist + + 95 +++ Agonist + + 98 +++ Antagonist + + 129 +++ Partial agonist + + 131 ++ Partial agonist + + 136 ++ Antagonist + ++ 141 ++ Antagonist + ++ 142 ++ Antagonist + ++ 145 ++ Antagonist + + 146 ++ Antagonist + + 153 ++ Partial agonist + + 160 + Partial agonist + + 161 ++ Antagonist + + 162 +++ Antagonist + + 163 +++ Antagonist + + 164 ++ Antagonist + + 170 ++ Antagonist + + 176 +++ Antagonist ++ + 180 +++ Partial agonist ++ + 183 +++ Partial agonist + + 184 +++ Antagonist + 185 +++ Partial agonist + + 187 +++ Agonist + + 188 +++ Partial agonist + + . 192 + Partial agonist + + 210 +++ Agonist + + 218 +++ Antagonist + + 237 +++ Partial agonist + + 238 +++ Antagonist 243 +++ Antagonist + + 267 ++ Partial agonist + + (1) +++ : Ki < 1000 nM, ++ 1000 nM< Ki <3000 nM, + : Ki >3000 nM