MXPA06009777A - Use of methylene amide derivatives in cardiovascular disorders - Google Patents
Use of methylene amide derivatives in cardiovascular disordersInfo
- Publication number
- MXPA06009777A MXPA06009777A MXPA/A/2006/009777A MXPA06009777A MXPA06009777A MX PA06009777 A MXPA06009777 A MX PA06009777A MX PA06009777 A MXPA06009777 A MX PA06009777A MX PA06009777 A MXPA06009777 A MX PA06009777A
- Authority
- MX
- Mexico
- Prior art keywords
- benzyl
- amino
- acid
- oxo
- acetic
- Prior art date
Links
- BUKKEXYZFWWAOA-UHFFFAOYSA-N methylideneazanide Chemical class [N-]=C BUKKEXYZFWWAOA-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 208000008787 Cardiovascular Disease Diseases 0.000 title claims abstract description 15
- 206010007554 Cardiac failure Diseases 0.000 claims abstract description 33
- 206010019280 Heart failure Diseases 0.000 claims abstract description 32
- 230000002265 prevention Effects 0.000 claims abstract description 14
- 206010048554 Endothelial dysfunction Diseases 0.000 claims abstract description 13
- -1 diphenyl-ethyl Chemical group 0.000 claims description 824
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 520
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 451
- 239000002253 acid Substances 0.000 claims description 420
- 125000004043 oxo group Chemical group O=* 0.000 claims description 348
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 282
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 264
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 250
- HHLFWLYXYJOTON-UHFFFAOYSA-N Glyoxalate, Glyoxylate Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 161
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 132
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 90
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 85
- 150000004715 keto acids Chemical class 0.000 claims description 78
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 75
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 58
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 57
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 25
- 239000004305 biphenyl Substances 0.000 claims description 23
- 125000003431 oxalo group Chemical group 0.000 claims description 23
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 22
- 239000011780 sodium chloride Substances 0.000 claims description 21
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 19
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecan-1-amine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 15
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 235000010290 biphenyl Nutrition 0.000 claims description 13
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 13
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 12
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000000301 2-(3-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 9
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000005418 aryl aryl group Chemical group 0.000 claims description 9
- 235000010233 benzoic acid Nutrition 0.000 claims description 9
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000000579 2,2-diphenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 7
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- QDXQAOGNBCOEQX-UHFFFAOYSA-N 1-methylcyclohexa-1,4-diene Chemical compound CC1=CCC=CC1 QDXQAOGNBCOEQX-UHFFFAOYSA-N 0.000 claims description 6
- 125000006481 2-iodobenzyl group Chemical group [H]C1=C([H])C(I)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000006483 4-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1I)C([H])([H])* 0.000 claims description 6
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 claims description 6
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 5
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 5
- 125000005312 heteroarylalkynyl group Chemical group 0.000 claims description 5
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- BTGJVYOHBIOMKK-UHFFFAOYSA-N 2-[2-(3-chlorophenyl)ethyl-[(4-dodec-1-ynylphenyl)methyl]amino]-2-oxoacetic acid Chemical compound C1=CC(C#CCCCCCCCCCC)=CC=C1CN(C(=O)C(O)=O)CCC1=CC=CC(Cl)=C1 BTGJVYOHBIOMKK-UHFFFAOYSA-N 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 4
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 4
- FJMQXAJQFNWGKL-UHFFFAOYSA-N 2,3-dihydro-1$l^{6}-benzothiepine 1,1-dioxide Chemical compound O=S1(=O)CCC=CC2=CC=CC=C12 FJMQXAJQFNWGKL-UHFFFAOYSA-N 0.000 claims description 3
- LDGBYTHFGXYESV-UHFFFAOYSA-N 2-[(3-chlorophenyl)methyl-[(4-dec-1-ynylphenyl)methyl]amino]-2-oxoacetic acid Chemical compound C1=CC(C#CCCCCCCCC)=CC=C1CN(C(=O)C(O)=O)CC1=CC=CC(Cl)=C1 LDGBYTHFGXYESV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000006267 biphenyl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- NTGZYEIFZWYKFV-WLDMJGECSA-N (2R,3S,4R,5R)-1-(methylamino)hexane-1,2,3,4,5,6-hexol Chemical compound CNC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO NTGZYEIFZWYKFV-WLDMJGECSA-N 0.000 claims description 2
- 125000004512 1,2,3-thiadiazol-4-yl group Chemical group S1N=NC(=C1)* 0.000 claims description 2
- RUYZJEIKQYLEGZ-UHFFFAOYSA-N 1-fluoro-4-phenylbenzene Chemical group C1=CC(F)=CC=C1C1=CC=CC=C1 RUYZJEIKQYLEGZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- QEFGLGISUDUOQS-UHFFFAOYSA-N 2-[(4-bromophenyl)methyl-[(4-oct-1-ynylphenyl)methyl]amino]-2-oxoacetic acid Chemical compound C1=CC(C#CCCCCCC)=CC=C1CN(C(=O)C(O)=O)CC1=CC=C(Br)C=C1 QEFGLGISUDUOQS-UHFFFAOYSA-N 0.000 claims description 2
- IGMGHQLOMREYTO-UHFFFAOYSA-N 2-[(4-dodec-1-ynylphenyl)methyl-[(4-fluorophenyl)methyl]amino]-2-oxoacetic acid Chemical compound C1=CC(C#CCCCCCCCCCC)=CC=C1CN(C(=O)C(O)=O)CC1=CC=C(F)C=C1 IGMGHQLOMREYTO-UHFFFAOYSA-N 0.000 claims description 2
- AXHBAIVLWPDEOY-UHFFFAOYSA-N 2-[2-(3-chlorophenyl)ethyl-[(4-oct-1-ynylphenyl)methyl]amino]-2-oxoacetic acid Chemical compound C1=CC(C#CCCCCCC)=CC=C1CN(C(=O)C(O)=O)CCC1=CC=CC(Cl)=C1 AXHBAIVLWPDEOY-UHFFFAOYSA-N 0.000 claims description 2
- OWORKUNNEDPQHS-UHFFFAOYSA-N 2-[4-(trifluoromethyl)-N-[[4-(3-undecyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]anilino]acetic acid Chemical compound CCCCCCCCCCCC1=NOC(C=2C=CC(CN(CC(O)=O)C=3C=CC(=CC=3)C(F)(F)F)=CC=2)=N1 OWORKUNNEDPQHS-UHFFFAOYSA-N 0.000 claims description 2
- IVRABFQCXXALAV-UHFFFAOYSA-N 2-[[2-bromo-4-[2-(4-phenoxyphenyl)ethylcarbamoyl]phenyl]methyl-[(2-iodophenyl)methyl]amino]-2-oxoacetic acid Chemical compound C=1C=CC=C(I)C=1CN(C(=O)C(=O)O)CC(C(=C1)Br)=CC=C1C(=O)NCCC(C=C1)=CC=C1OC1=CC=CC=C1 IVRABFQCXXALAV-UHFFFAOYSA-N 0.000 claims description 2
- CEYVUCRKOPEAPK-UHFFFAOYSA-N 2-[[2-bromo-4-[2-(4-phenoxyphenyl)ethylcarbamoyl]phenyl]methyl-[(3-phenoxyphenyl)methyl]amino]-2-oxoacetic acid Chemical compound C=1C=C(C(=O)NCCC=2C=CC(OC=3C=CC=CC=3)=CC=2)C=C(Br)C=1CN(C(=O)C(=O)O)CC(C=1)=CC=CC=1OC1=CC=CC=C1 CEYVUCRKOPEAPK-UHFFFAOYSA-N 0.000 claims description 2
- BRVGHMFYSBKRKH-UHFFFAOYSA-N 2-[[4-(3-octyl-1,2,4-oxadiazol-5-yl)phenyl]methyl-(5,6,7,8-tetrahydronaphthalen-1-yl)amino]-2-oxoacetic acid Chemical compound CCCCCCCCC1=NOC(C=2C=CC(CN(C(=O)C(O)=O)C=3C=4CCCCC=4C=CC=3)=CC=2)=N1 BRVGHMFYSBKRKH-UHFFFAOYSA-N 0.000 claims description 2
- GZSDREMLVCXNNG-UHFFFAOYSA-N 2-[[4-(dodecylcarbamoyl)phenyl]methylamino]-2-oxoacetic acid Chemical compound CCCCCCCCCCCCNC(=O)C1=CC=C(CNC(=O)C(O)=O)C=C1 GZSDREMLVCXNNG-UHFFFAOYSA-N 0.000 claims description 2
- ZMTSKQJIPAEOQZ-UHFFFAOYSA-N 2-[bis[(4-oct-1-ynylphenyl)methyl]amino]-2-oxoacetic acid Chemical compound C1=CC(C#CCCCCCC)=CC=C1CN(C(=O)C(O)=O)CC1=CC=C(C#CCCCCCC)C=C1 ZMTSKQJIPAEOQZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims description 2
- YZKNKZILWJSSPT-UHFFFAOYSA-N C(CCCCCCCCCCC)NC(=O)C1=CC=C(CNC(CC(=O)O)C2=CC=CC=C2)C=C1 Chemical compound C(CCCCCCCCCCC)NC(=O)C1=CC=C(CNC(CC(=O)O)C2=CC=CC=C2)C=C1 YZKNKZILWJSSPT-UHFFFAOYSA-N 0.000 claims description 2
- UEGMDAUBBRYWCJ-HHHXNRCGSA-N C(CCCCCCCCCCC)NC(=O)C1=CC=C(CN[C@H](CC2=CC=CC=C2)C(=O)O)C=C1 Chemical compound C(CCCCCCCCCCC)NC(=O)C1=CC=C(CN[C@H](CC2=CC=CC=C2)C(=O)O)C=C1 UEGMDAUBBRYWCJ-HHHXNRCGSA-N 0.000 claims description 2
- OPJQDVOJLASNSL-UHFFFAOYSA-N FC(C1=CC=C(CC(C(=O)O)CC2=CC=C(C=C2)C=2SC=C(N2)CCCCCCCCCCC)C=C1)(F)F Chemical compound FC(C1=CC=C(CC(C(=O)O)CC2=CC=C(C=C2)C=2SC=C(N2)CCCCCCCCCCC)C=C1)(F)F OPJQDVOJLASNSL-UHFFFAOYSA-N 0.000 claims description 2
- 235000019766 L-Lysine Nutrition 0.000 claims description 2
- 235000014852 L-arginine Nutrition 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
- 229960003646 lysine Drugs 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005038 alkynylalkyl group Chemical group 0.000 claims 2
- STTMRQGOPWEJLY-UHFFFAOYSA-N octylazanide Chemical group [CH2+]CCCCCCC[NH-] STTMRQGOPWEJLY-UHFFFAOYSA-N 0.000 claims 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- AHPFWFWNZWBTJU-UHFFFAOYSA-N 11-[4-[[oxalo-[[4-(trifluoromethyl)phenyl]methyl]amino]methyl]phenyl]undecanoic acid Chemical compound C1=CC(CCCCCCCCCCC(=O)O)=CC=C1CN(C(=O)C(O)=O)CC1=CC=C(C(F)(F)F)C=C1 AHPFWFWNZWBTJU-UHFFFAOYSA-N 0.000 claims 1
- OPROHMRMQPERQH-UHFFFAOYSA-N 2-[(2-methoxyphenyl)methyl-[[3-(3-undecyl-1,2,4-oxadiazol-5-yl)phenyl]methyl]amino]-2-oxoacetic acid Chemical compound CCCCCCCCCCCC1=NOC(C=2C=C(CN(CC=3C(=CC=CC=3)OC)C(=O)C(O)=O)C=CC=2)=N1 OPROHMRMQPERQH-UHFFFAOYSA-N 0.000 claims 1
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Abstract
The present invention is related to the use of substituted methylene amide derivatives of Formula (I) for the treatment and/or prevention of cardiovascular disorders such as coronary obstruction and heart failure. In particular, the present invention is related to the use of substituted methylene amide derivatives of Formula (I) in particular for the treatment and/or prevention of endothelial dysfunction in heart failure.
Description
USE OF MET1LENAMIDE DERIVATIVES IN CARDIOVASCULAR DISORDERS
FIELD OF THE INVENTION
The present invention relates to the use of methylenamide derivatives of the formula (I) for the prevention and / or treatment of cardiovascular disorders such as coronary obstruction and heart failure, in particular for the prevention and / or treatment of Endothelial dysfunction in heart failure. The compounds of this invention are particularly useful in the treatment of increased peripheral vasoconstriction in chronic heart failure.
BACKGROUND OF THE INVENTION
Despite important advances in the fields of cardiology and cardiac surgery in recent decades, heart failure is still a cause of high morbidity and mortality. About 5 million Americans suffer from heart failure, with an incidence of about 10 per 1000 people in the population over 65 years of age (Jessup et al., 2003, N. Engl. J. Med, 348 (20 ), 2007-2018). Over the past decade, the proportion of hospitalizations for heart failure has increased by 159 percent (Jessup et al., 2003, above). Some reasons for this progressive incidence are the aging of the population, the best treatment of heart diseases such as acute myocardial infarction and non-cardiac diseases, such as cancer. Heart failure is a constellation of signs and symptoms caused by inadequate heart performance. Its evolutionary and progressive nature has led specialists to define four stages of heart failure (from 1 to 4), from the high risk of developing heart failure to progressive structural abnormalities of the heart, to the symptoms of the terminal stage (Hunt). et al., 2001, J. Am. Coil, Cardiol., 38, 2101-13). Mainly, heart failure is defined by the heart's inability to eject blood and to provide adequate perfusion of peripheral organs. Heart failure not only affects the myocardium, but also has many consequences in the peripheral circulation. Especially, heart failure is associated with increased peripheral vascular resistance secondary to peripheral vasoconstriction. This vasoconstriction is heterogeneous, and affects above all the "non-essential" territories such as the skin, the intestine and the skeletal muscles, to maintain perfusion in the "essential" territories such as the brain or the heart in a context of cardiac output. diminished. However, this initially adaptive mechanism may increase the long-term cardiac load (resistance to ventricular contraction) and cardiac work in the long term, and thereby aggravate contractile dysfunction and contribute to the transition from compensated to decompensated heart failure. . Long-term deterioration or loss of cardiac muscle activity leads to the development of Chronic Heart Failure (CHF). The endothelium is made up of a monolayer of cells located at the interface between the blood and the vascular wall. Endothelium plays an important role in the control of human vascular tone and in the regulation of platelet and leukocyte functions by releasing nitric oxide
(NO) derived from the endothelium. An endothelial dysfunction, commonly evaluated by decreased endothelial production of NO in response to blood flow, induces increased peripheral vasoconstriction and therefore increased peripheral resistance. It has been shown that endothelial dysfunction occurs both experimentally and clinically in early cardiovascular diseases, including heart failure with long-term duration. NO is a local factor that plays a major role in the control of vascular tone, regional blood flow and blood pressure. NO is continuously released by endothelial cells through the activation of endothelial NO synthesis (eNOS). Blood flow is the main physiological stimulus for the permanent release of NO that leads to flow-dependent vasodilation or flow-mediated vasodilation (FMD, acronym in English). Fluid-mediated vasodilatation is achieved through the activation of eNOS mediated by the flow. The constitutive production of NO is opposed to vasoconstrictor influences such as those of the sympathetic system, or vasoconstrictor peptides angiotensin II or endothelin, and is now universally considered responsible for the existence of a permanent strong vasodilator tone in the circulation . The physiological roles of NO are not limited to vasodilation.
In fact, NO derived from the endothelium is a potent inhibitor of agglutination and platelet adhesion, through increased platelet cGMP (Radomski et al., 1987, Br. J. Farmacol., 92, 639-646 ). When produced at physiological concentrations, NO also exerts a potent anti-inflammatory effect, and especially inhibits the adhesion of leukocytes to endothelial cells. Decreased NO endothelial production induces an increase in peripheral vasoconstriction and platelet agglutination, leading to subsequent increased risks of vasospasm and thrombosis, respectively. Furthermore, given the inhibitory effects of NO on the activation and adhesion of leukocytes, endothelial dysfunction is considered as one of the triggers of local vascular inflammatory responses that lead to the development of atherosclerosis (Ross, 1993, Nature, 362: 801-809). Several recent clinical data insist on the role of endothelial dysfunction, in the deterioration in the production of NO, or in the mutation or deficiency of the eNOS gene, in cardiovascular diseases. The hypothesis of a link between endothelial dysfunction and the progression of atherosclerosis is supported by several epidemiological studies that show that early endothelial dysfunction predicts the development of atherosclerosis and coronary artery disease (Suwaidi et al., 2000, Circulation, 101 , 948-954; Scacinger et al., 2000, Circuiation, 101, 1899-1906; Perticone et al., 2001, Circulation, 104, 191-196). A recent clinical study reported that a mutation of the eNOS gene that decreases the half-life of NOS in the patient is associated with poorer event-free survival in patients with heart failure (McNamara et al., 2003, Circulation, 107, 1598-1602), in accordance with deficient eNOS data in mice (Scerrer-Crosbie et al, 2001, Circulation, 104, 1286-1291). The substituted methyleneamide derivatives of the formula (I) have been developed as inhibitors of Tyrosine Protein Phosphatase (PTP), particularly of the Tyrosine Phosphatase Inhibitors of Protein 1 B (PTP1 B), for the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia (WO 03/064376). Protein tyrosine phosphatases (PTPs) play an important role in the regulation of protein phosphorylation and represent the counterpart of the kinases. PTPs modulate the interaction of insulin with its receptor and the post-receptor signaling pathway, catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase. PTP-1 B inhibitors are known in the treatment of diabetes (Moller et al., 2000, Current Opinion in Drug Discovey &Development 3 (5), 527-540). Various treatments for cardiac failure have been developed, such as β-blockers, diuretics, angiotensin receptor blockers, Angiotensin Conversion Enzyme (ACE) inhibitors (Chin et al., 2001, Current Opinion in Investigational Drugs,
2 (7), 923-928). However, the multifactorial and progressive nature of heart failure provides multiple opportunities for therapeutic intervention and the need for new treatments for heart failure, especially for chronic heart failure. The clinical evidence listed above suggests that the increased peripheral resistance is partially due to decreased vasodilatory influences, and particularly the permanent release of nitric oxide (NO) induced by the flow. Therefore, the deterioration of peripheral production of NO could contribute to worsening heart failure, and therefore pharmacological interventions that restore NO production in heart failure should have beneficial effects in this disease.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to the use of substituted methyleneamide derivatives of the formula (I):
for the treatment and / or prevention of cardiovascular disorders such as coronary obstruction and heart failure, in particular for the treatment and / or prevention of endothelial dysfunction in chronic heart failure. The compounds of this invention are particularly useful in the treatment of increased peripheral vasoconstriction in chronic heart failure.
DETAILED DESCRIPTION OF THE INVENTION
The following paragraphs provide definitions of the various chemical portions that make up the compounds according to the invention, which are designed to be applied uniformly throughout the specification and the claims; unless otherwise expressly stated, the established definitions provide a broader definition "PTP" are protein tyrosine phosphatases and include, for example, PTP1 B, TC-PTP, PTP-β, DEP-1, LAR, SHP -1, SHP-2, GLEPP-1, PTP-K, PTP-μ, VHR, hVH5, LMW-PTP, PTEN. "Alkyl of C" -C, 2"or" C 1 -C 15 alkyl "refers to straight or branched monovalent alkyl groups having 1 to 12 or 1 to 15 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, n-nonyl, n-dodecyl, tridecyl, pentadecyl, n- pentyl and the like in the straight or branched forms thereof. "Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or condensed multiple rings (e.g., naphthyl). The preferable aryl includes phenyl, naphthyl, phenanthrenyl and the like. "CrC12 aryl" refers to C -? - C-? 2 alkyl groups having an aryl substituent, including benzyl, phenethyl and the like. "Heteroaryl" refers to a monocyclic heteromatic group or a bicyclic or tricyclic fused ring heteroaromatic group. Particular examples of heteroaromatic groups include pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,2,3-oxazolyl. 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl optionally substituted; 1, 3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2 -a] pyridyl, benzothiazolyl, benzoxazolyl, quinolicinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinolinyl, naphthyridinyl, pyrid [3,4-b] pyridyl, pyrido [3,2, -b] pyridyl, pyrido [4.3, -b] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenoyl or benzoquinolyl. "C 12 alkyl heteroaryl" refers to C C 2 alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2- (1H-indol-3-yl) ethyl and the like. "Alkenyl" refers to alkenyl groups preferably having 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. Preferably the alkenyl groups include ethenyl (-CH = CH2), n-propenyl (allyl, -CH2CH = CH2) and the like. "Alkynyl" refers to alkynyl groups having from 2 to 18 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, e.g. eg, ethynyl (-C = CH), propargyl (-CH2C = CH), or -C = CH-alkyl
"Acyl" refers to the group -C (0) R where R includes "d-C12 alkyl", "aryl", "heteroaryl", "aryl C12 alkyl", or "C12 alkyl heteroaryl".
"Acyloxy" refers to the group -OC (0) R where R includes "C? -C? 2 alkyl", "aryl", "heteroaryl", "aryl CrC12 alkyl", or "heteroaryl CC? " "Alkyloxy" refers to the group -OR, where R includes "C 1 -C 2 alkyl," or "aryl," or "heteroaryl," or "aryl C 1 -C 2 alkyl," or "heteroaryl" C C12". Preferred alkoxy groups include, by way of example, methoxy, ethoxy, phenoxy and the like. "Alkoxycarbonyl" refers to the group -C (0) OR, where R includes "C12 alkyl", or "aryl", or "heteroaryl", or "C12 alkyl aryl", or "C12 alkyl heteroaryl" " "Aminocarbonyl" refers to the group -C (0) NRR ', wherein each R, R' independently includes hydrogen or C C 2 alkyl, or aryl, or heteroaryl, or aryl CrC 12 alkyl, or heteroaryl C 12 alkyl. "Acylamino" refers to the group -NR (CO) R ', where each R, R' is independently hydrogen or "C 1 -C 2 alkyl", or "aryl", or "heteroaryl", or "C 1 -C aryl alkyl" ? -C? 2", or" heteroaryl C? .- C12 alkyl ". "Halogen" refers to fluorine, chlorine, bromine and iodine atoms. "Substituted or unsubstituted", unless otherwise defined by the definition of the individual substituent, the groups set forth above, such as the groups "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl" ", etc., may optionally be substituted with from 1 to 5 substituents selected from the group consisting of" C?-C6 alkyl "," C2-C6 alkenyl "," C2-C6 alkynyl "," cycloalkyl " , "heterocycloalkyl; "aryl C" -C6 alkyl "," CrC6 heteroaryl alkyl "," C6 cycloalkyl alkyl "," CrC6 heterocycloalkyl "," amino "," ammonium "" acyl "," acyloxy "," acylamino " , "aminocarbonyl", "alkoxycarbonyl", "ureido", "aryl", "carbamate", "heteroaryl", "sulfinyl", "sulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", trihalomethyl , cyano, hydroxy, mercapto, nitro and the like. Alternatively, the substitution could also comprise situations in which neighboring substituents have undergone ring closure, mainly when vicinal functional substituents are involved, thereby forming, e.g. eg, lactams, lactones, cyclic anhydrides, but also acetals, thioacetals, aminals, formed by ring closure, for example, in an effort to obtain a protection group. "Sulfonyl" refers to the group "-S02-R", wherein R is selected from H, "aryl", "heteroaryl", "C12 alkyl", "C12 alkyl" substituted with halogens, e.g. eg, a group -S02-CF3, "aryl C 1, -C 2 alkyl" or "C 12 alkyl heteroaryl". "Sulfoxy" refers to a group "-S (O) -R", where R is selected from H, "CrC 12 alkyl", "CrC 2 alkyl" substituted with halogens, e.g. eg, a group -SO-CF3, "aryl", "heteroaryl", aryl C 1 -C 2 alkyl, or heteroaryl CrC 12 alkyl ". "Thioalkoxy" refers to the groups -S-R, where R includes "C C 2 alkyl" or "aryl" or "heteroaryl" or "C 1 -C 12 alkyl aryl" or "C 12 C heteroaryl alkyl". Preferred thioalkoxy groups include thiomethoxy, thioethoxy and the like.
"Resistance artery" refers to an artery with a diameter that is sufficiently small (<300 μm) for the vessel to significantly influence local resistance to blood flow and its regulation. The resistance arteries provide the main peripheral resistance to blood flow, and therefore are important in the control and regulation of blood pressure, and blood flow in the systems of the main organs. The term "heart failure" includes several stages of evolution and progression as described in Jessup et al, 2003, supra. It includes, for example, structural heart abnormalities, diastolic heart failure and systolic heart failure. "Pharmaceutically acceptable salts or complexes" refers to salts or complexes of the above-specified compounds of Formula (I). Examples of these salts include, but are not restricted to, the base addition salts formed by the reaction of the compounds of the Formula (I) with organic or inorganic bases such as hydroxide, carbonate or bicarbonate of a metal cation such such as those selected from the group consisting of alkali metals (sodium, potassium or lithium), earthy-alkaline metals (eg, calcium or magnesium), or with a primary, secondary or tertiary alkyl amine. The amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-Me-D-glucamine, N, N'-bis (phenylmethyl) -1,2-ethanediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like are contemplated within the competence of the current invention. Also included are salts that are formed from acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), as well as salts formed with acids organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid and polygalacturonic acid. "Pharmaceutically active derivative" refers to any compound which, upon its administration to the recipient, is capable of providing, directly or indirectly, the activity described herein. The term "indirectly" also encompasses prodrugs that can be converted to the active form of the drug via endogenous enzymes or metabolism. The prodrug is composed of the drug compound itself and a chemical masking group. "Enantiomeric excess" (ee) refers to products that are obtained by an asymmetric synthesis, p. eg, a synthesis involving start materials and / or non-racemic reagents or a synthesis comprising at least one enantioselective step, where a surplus of one enantiomer is produced, in the order of at least about 52% ee. In the absence of an asymmetric synthesis, p. The corresponding esters of the substituted methylene amides of the Formula (I), usually yield racemic products which, however, also have an inhibitory activity of PTP. That Formula also comprises its tautomers, its geometric isomers, its optically active forms as enantiomers, diastereomers and their racemate forms, as well as the pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts of Formula (I) are base addition salts formed by the reaction of compounds of Formula (I) with pharmaceutically acceptable bases such as N-methyl-D-glucamine, tromethamine, carbonate salts , bicarbonates or hydroxides of sodium, potassium or calcium. The methylenamide derivatives according to the present invention are those of Formula (I):
Formula (I) also comprises geometric isomers, optically active forms, including enantiomers, diastereoisomers and racemate forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives thereof. The substituents R1, R2a, R2b and Cy within Formula (I) are defined as follows:
R1 is selected from the group consisting of (C1-C-? 5) alkyl, substituted or unsubstituted (C1-C-? 2) alkyl, substituted or unsubstituted (C1-C6) alkyl, alkenyl of ( C1-C-? 2), substituted or unsubstituted, unsubstituted or substituted (C1-C? 2) alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl or heterocycloalkyl (3 to 8 members) substituted or unsubstituted, aryl, unsubstituted or substituted (C 1 -C 2) alkyl, heteroaryl substituted or unsubstituted (C 1 -C 2) alkyl, aryl or heteroaryl (C 2 -C 2) substituted alkenyl or unsubstituted, substituted or unsubstituted aryl or heteroaryl alkynyl of (C2-C-? 2); R 2a and R 2b are, independently of one another, selected from the group comprising or consisting of H or substituted or unsubstituted (C C 2) alkyl, preferably R 2a and R 2b are each H; Cy is selected from D and E; D is selected from substituted thienyl and substituted phenyl, wherein substituents are selected from phenyl, oxadiazole and 1 or 2 portions selected from the group consisting of -NH-CO-R3, -S02-NR3R3 ', and -CO- NR3R3 ', wherein R3, R3' are independently selected from H, substituted or unsubstituted (CrC15) alkyl, unsubstituted or substituted (C2-C12) alkenyl, substituted or unsubstituted (C2-C12) alkynyl, aryl substituted or unsubstituted or substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl (3-8 members) or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted (C 12 alkyl) aryl, aryl or heteroaryl (C 2 -C 12) alkenyl ) substituted or unsubstituted, substituted or unsubstituted (C2-C-? 2) aryl or heteroaryl alkynyl; E is selected from aryl, heteroaryl, (3-8 membered cycloalkyl) and heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl (3-8 membered) and heterocycloalkyl are substituted by (C2-C-? 8) optionally substituted; Aryl or heteroaryl includes phenyl, naphthyl, phenanthrenyl, pyrrolyl, furyl, thienyl, imidazolyl, pyridyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,2,3. -oxadiazolyl, benzo (1, 2,5) oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, tetrazolyl, 1,4-triazinyl, 1, 2 , 3-triazinyl, benzopyrimidinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridazinyl, pyrimidyl, quinolicinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinolinyl, naphthyridinyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, xanthenyl, benzoquinolyl, oxolanyl, pyrolidinyl, pyrazolidinyl, 2H-benzo [ d] 1,3-dioxolenyl, indanyl, imidazolidinyl, 1,4-oxadiazolidinyl, 1, 2,5-oxadiazolidinyl, 1,4-oxadiazolidinyl or isoxazolidinyl. In a preferable embodiment, R2a and R2b are H. In another preferred embodiment of the present invention, R1 is A, wherein A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, (3-8 membered) heterocycloalkyl. substituted or unsubstituted and substituted or unsubstituted (3-8 membered) cycloalkyl, in particular a substituted or unsubstituted phenyl. In another preferable embodiment, R1 is a portion of the formula -CH2-A or -CH2-CH2-A, where A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted (3-8 membered) heterocycloalkyl or unsubstituted and substituted or unsubstituted (3-8 membered) cycloalkyl. In particular, A can be a phenyl, pyridinyl, benzo-1,3-dioxoleyl, biphenyl, naphthyl, quinoxalinyl, thiazolyl, thienyl, furanyl or piperidinyl group, which is optionally substituted by 1 or 2 portions selected from the group consisting of cyano, halogen, NO2, alkoxy, aryloxy or heteroaryloxy of (CC? 2), thioalkoxy of (CrC6), alkyl of (CC? 2), alkyl of (C12) optionally halogenated, alkenyl of (C2-C12), alkynyl of (C2-C? 2), aryl, heteroaryl, cycloalkyl or heterocycloalkyl of (3-8 members), aryl or heteroaryl (C 12 alkyl), aryl or heteroaryl alkenyl of (C 2 -C 2), aryl or heteroaryl alkynyl of (C 2 -C 12) ), -COR3, -COOR3, -CO-NR3R3 ', -NHCOR3 where R3 is (C12 alkyl) or (C2-C12) alkenyl, -SOR3, S02R3, -S02NR3R3' where R3, R3 are independently selected from the group another, from the group consisting of H, straight or branched (CrC12) alkyl, (C2-C2) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or (3-8 membered) heterocycloalkyl . According to one modality, Cy is D.
According to another embodiment, R3 is H and R3 is selected from the group consisting of diphenyl-ethyl, dodecyl, octyl, 4-pentyl-benzyl, 4-phenoxy-phenethyl, ethyl-thiophen-2-yl, pentadecyl, tridecyl. , hexyloxy-phenyl, (2-ethyl) -hexyl. According to another embodiment, Cy is E. According to a further embodiment, Cy is E wherein E is selected from the group phenyl, pyridinyl, naphthyl and benzofuranyl; the phenyl, pyridinyl, naphthyl and benzofuranyl group being substituted by B-R4, where B is ethyl group and R4 is substituted or unsubstituted (C6-C6) alkyl, (3-8 membered) cycloalkyl substituted or not substituted, substituted or unsubstituted (C 1 -C 12) -cycloalkyl (3-8 membered) alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenyl (C 1 -C 12) alkyl. More particularly, E is phenyl which is substituted by B-R4, where B is ethynyl group and R4 is unsubstituted or substituted (C6-C-? 6) alkyl. According to another embodiment, R2a and R2b are each H, R1 is -CH2-A, or -CH2-CH2-A, where A is phenyl or thienyl, optionally substituted by cyano, halogen, methoxy, hydroxy, phenoxy, -N02 , trifluoromethyl, while Cy is D, where D is selected from thienyl, phenyl and biphenyl; being thienyl, phenyl and biphenyl substituted by S02R3, -CO-NR3R3 ', where R3' is H and R3 is (C7-C12) alkyl, particularly (C8-C12) alkyl and more particularly a dodecyl group. According to another embodiment, R2a and R2b are each H, R is -CH2-A, or -CH2-CH2-A, where A is phenyl or thienyl, optionally substituted by cyano, halogen, methoxy, hydroxy, phenoxy, -N02 , trifluoromethyl, while Cy is D, where D is selected from thienyl, phenyl and biphenyl; being thienyl, phenyl and biphenyl substituted by S02R3, -CO-NR3R3 ', where R3' is H and R3 is (C7-C-? 5) alkyl, particularly (C8-C-? 5) alkyl and more preferably a dodecyl group. According to another embodiment, R2a and R2b are each H; R1 is selected from phenyl, benzyl, phenethyl, 1-methylbenzyl which may be optionally substituted by a (C1-C6) alkyl group or a cycloalkyl group; Cy is D, where D is selected from a phenyl and biphenyl group; phenyl and biphenyl being substituted with a portion selected from -NH-CO-R3, -CO-NH-R3, and an oxadiazole group substituted with R3, where R3 is (C7-C15) alkyl, particularly alkyl (C8-C-? 5) and more particularly a dodecyl group. More preferable compounds are those of the Formula (i1):
wherein: R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which can be substituted by an alkyl group of (d-C6) or a cycloalkyl group; Cy is D, where D is selected from phenyl and biphenyl; phenyl and biphenyl being substituted with a group selected from -NH-CO-R3, -CO-NH-R3, and an oxadiazole group substituted with R3, where R3 is (C7-C5 alkyl), particularly alkyl of (C8-C15) and more particularly a dodecyl group. The compounds of the present invention include in particular those of the group consisting of: (benzyl) {4 - [(dodecylamino) carbonyl] benzyl] amino) (oxo) acetic acid; Oxo acid { . { 4 - [(pentadecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} acetic; (benzyl) {. 4 - [(pentadecylamino) carbonyl] benzyl} amino) (oxo) -acetic acid; (benzyl) {.4 - [(tridecylamino) carbonyl] benzyl} amino) (oxo) acetic acid; [benzyl (4- {[[dodecyl (methyl) amino] carbonyl} benzyl) amino] (oxo) acetic acid; acid { (4-. {[[Dodecyl (methyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} - (oxo) acetic; ([1- (tert-butoxycarbonyl) -4-piperidinyl] { 4 - [(dodecylamino) -carbonyl] benzyl} -amino- (oxo) acetic acid; {. { 4 - [(dodecylamine) carbonyl] benzyl] - [4- (trifluoromethyl) benzyl] -amino} - (oxo) acetic acid: {. { 4 - [(dodecylamino) carbonyl] benzyl} . [3- (trifluoromethyl) benzyl] -amino] - (oxo) acetic;
( { [1 - (tert-butoxycarbonyl) -4-piperidinyl] methyl}. {4 - [(dodecylamino) carbonyl] -benzyl} amino (oxo) acetic acid, oxo acid {. 4- (tridecar? Oylamino) benzyl] [4- (trifluoromethyl) benzyl] -amino} acetic acid; [benzyl (4. {[[4- (hexyloxy) benzoyl] amino] benzyl) amino] - (oxo) acetic acid; Oxo acid { 4- (trifluoromethyl) benzyl] [4- (10-undecenoylamino) benzyl] amino} acetic; Oxo acid { 4 - [(9E) -9-tetradecenylamino] benzyl} [4- (trifluoromethyl) -benzyl-amino} acetic; acid { benzyl [4- (tridekanoylamino) benzyl] amino} (oxo) acetic; acid { . { 4 - [(2-hydroxydodecyl) amino] benzyl} [4- (trifluoromethyl) benzyl] -amino} - (oxo) -acetic; Oxo acid { [4- (trifluoromethyl) benzyl] [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] -amino} -acetic; acid { ( {5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (trifluoromethyl) benzyl] amino) - (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} ( { 1 - [(4-methoxyphenyl) -sulfonyl] -4-piperidinyl}. Methyl) amino] (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-carboxy-1-phenylethyl) -aminoj (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-methoxy-1-methylethyl) -amino] (oxo) acetic;
(4-bromo. {4 - [(dodecylamino) carbonyl] benzyl] anilino) (oxo) acetic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl} anilyl) (oxo) acetic acid; ([2- (3-chlorophenyl) ethyl] - {4 - [(dodecylamino) carbonyl] benzyl] - amino) (oxo) acetic acid; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [2- (3-methoxyphenyl) ethyl] -amino} (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [(d, 1) -trans-2-phenylcyclopropyl] amino} (oxo) acetic; acid ([(d, 1) -trans-2- (benzyloxy) cyclopentyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid; ( {4 - [(dodecylamino) carbonyl] benzyl} -4-phenoxyanilino) (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (1, 2,3,4-tetrahydro-1-naphthalenyl) amino] - (oxo) acetic; ((1-benzyl-4-piperidinyl) - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid { . { 4 - [(dodecylamino) carbonyl] benzyl} [2- (4-phenoxyphenyl) etl] amino} (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [2- (2-phenoxyphenyl) ethyl] -amino} (oxo) acetic; ((2- [1, 1 '-biphenyl] -4-ethyl). {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid;
(([1, 1'-biphenyl] -3-ylmethyl) - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; (3- (benzyloxy). {4 - [(dodecylamino) carbonyl] benzyl] anilino) (oxo) acetic acid; ([4- (Benzoylamino) benzyl] - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; N- (carboxycarbonyl) -N-. { 4 - [(Dodecylamino) carbonyl] benzyl} 3-phenyl-beta-alanine; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [4- (1, 2,3-thiadiazol-4-yl) benzyl] amino} (oxo) acetic; acid[. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-pentylbenzyl) amino] - (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (1-phenylethyl) amino] (oxo) acetic; acid. { . { 4 - [(Dodecylamino) carbonyl] benzyl} [1- (1-naphthyl) ethyl] amino} - (oxo) acetic; acid (benzyl. {3 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid; acid { . { 3 - [(dodecylamino) carbonyl] benzyl} [4- (methylsulfonyl) benzyl] -amino} (oxo) acetic; {(3-cyanobenzyl). {3 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid;
acid { . { 3 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; [(4-chlorobenzyl) (3- {[[(4-pentylbenzyl) amino] carbonyl} benzyl) -amino] (oxo) acetic acid; Oxo acid { [4- ( { [2- (2-thienyl) ethyl] amino.} Carbonyl) benzyl] [4- (trifluoromethyl) benzyl] amino} acetic; acid { benzyl [(3'-. {[[(2,2-diphenylethyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) methyl] -amino} (oxo) acetic; acid { (3-cyanobenzyl) [(3, -. {[[(2,2-diphenylethyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic; acid { (4-chlorobenzyl) [(3, -. {[[(2,2-diphenylethyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic; acid { [(3'- { [(2,2-diphenylethyl) amino] carbonyl]. [1, 1'-biphenyl] -4-yl) methyl] - [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; ((3-cyanobenzyl) { [3, - ( { [2- (4-phenoxyphenyl) ethyl] amino.} carbonyl) - [1,1'-b-phenyl] -4- il] methyl.}. -amino) (oxo) acetic; Oxo acid { [3 '- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Carbonyl) [1,1'-b-phenyl] -4-yl] methyl} - [4- (trifluoromethyl) benzyl] amino} acetic; [(3-cyanobenzyl) (. {3 '- [(octylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) amino] (oxo) acetic acid; [(4-chlorobenzyl) (. {3 '- [(octylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) amino] - (oxo) acetic acid;
acid { (. {3 '- [(octylamino) carbonyl] [1,1'-biphenyl] -4-yl.} Methyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; acid { (3-cyanobenzyl) [(3'-. {[[(3-phenylpropyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic; [(3-cyanobenzyl) (. {3 '- [(dodecylamino) carbonyl] [1, 1'-biphenyl] -4-yl} methyl) -amino] - (oxo) acetic acid; [(4-chlorobenzyl) (. {3 '- [(dodecylamino) carbonyl] [1,1-, 7-phenyl] -4-yl} methyl) -amino] - (oxo) acetic acid; acid { (. {3 '- [(dodecylamino) carbonyl] [1,1'-biphenyl] -4-yl.} Methyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; acid { benzyl-1-yl-pentylbenzaminocarbonyljfl. 1'-biphenyl] ^ -yl) methyl] amino} - (oxo) acetic; acid { (3-cyanobenzyl) [(3, - { [(4-pentylbenzyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) -methyl] amino} - (oxo) acetic; ^ -chlorobenz acid KS '- ^ - pentylbenz aminocarbonylIfl. 1' -biphenyl] -4-yl) -methyl] amino} (oxo) acetic; Oxo acid { [(3'- { [(4-pentylbenzyl) amino] carbonyl] [1, 1'-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl] amino} acetic; Oxo acid { [(3, - { [(4-f? Nyl-butyl) amino] carbonyl}. [1, 1 '-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl] amino} acetic; acid { (3-cyanobenzyl) [(3'-. {[[(2-mesitylethyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) -methyl] amino} (oxo) acetic;
acid { (4-chlorobenzyl) [(3'-. {[[(2-mesitylethyl) amino] carbonyl] - [1 _ '-biphenyl] -4-yl) -methyl] amino} (oxo) acetic; acid { [(3'-. {[[(2-mesyl-ethyl) amino] carbonyl}. [1, 1'-biphenyl] -i-methyl] ^ - (trifluoro-methyl) benzyl] amino.} (Oxo) acetic acid ((4-chlorobenzyl) { [3, - ( { [2- (4-methoxyphenyl) ethyl] amino.} carbonyl) - [1,1 '-biphenyl] -4-yl] methyl.}. amino) (oxo) acetic acid [ { 4 - [(dodecylamino) carbonyl] benzyl] - (4-methoxybenzyl) amino] (oxo) acetic acid; (dodecylamino) carbonyl] benzyl}. [4- (methylsulfonyl) benzyl] -amino} (oxoacetic acid [. {3 - [(dodecylamino) carbonyl] benzyl] - (4-methoxybenzyl) -amino] (oxo) acetic acid; {. { 3 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] -amino}. (oxo) acetic acid (. 4 - [(dodecylamino) carbonyl] benzyl]. {[[6- (trifluoromethyl) -3-pyridinyl] methyl} -amino) (oxo) acetic acid 4 - [((carboxycarbonyl)} {3} - [(dodecylamino) carbonyl] benzyl] -amino) methyl] benzoic acid (. {3 - [(dodecylamino) carbonyl] benzyl] - {. 4- [hydroxy (oxide) amino] -benzyl} -amino) (oxo) acetic acid [ { 3 - [(Dodecylamino) carbonyl] benzyl} (2-fluorobenzyl) amino] - (oxo) acetic;
acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (2-pyridinylmethyl) -amino] (oxo) acetic; acid [. { 13 - [(dodecylamino) carbonyl] benzyl} (3-thienylmethyl) -amino] (oxo) acetic; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (4-hydroxybenzyl) -amino] (oxo) acetic acid; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) amino] (oxo) acetic; ( {3 - [(Dodecylamino) carbonyl] benzyl} { [6- (trifluoromethyl) -3-pyridinyl] methyl} -amino) (oxo) acetic acid; 3 - [((carboxycarbonyl) { 3 - [(dodecylamino) carbonyl] benzyl] -amino) methyl] benzoic acid; 5 - [((carboxycarbonyl) {3 - [(dodecylamino) carbonyl] benzyl} -amino) methyl-2-thio-phenocarboxylic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl] - {4- [hydroxy (oxide) amino] -benzyl] -amino) - (oxo) acetic acid; ((1,3-benzodioxol-5-ylmethyl) - {4 - [(dodecylamino) carbonyl] -benzyl} amino) - (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-fIuorobenzyl) -amino] (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) -amino] (oxo) acetic;
4 - [((carboxycarbonyl). {4 - [(dodecylamino) carbonyl] -benzyl} amino) methyl] benzoic acid; 5 - [((carboxycarbonyl). {4 - [(dodecylamino) carbonyl] benzyl] -amino) methyl] -2-thiophene carboxylic acid; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (2-thienylmethyl) amino] (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (isopropyl) amino] (oxo) acetic; ((3,5-dichlorobenzyl) - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; [(3,5-dichlorobenzyl) (4. {[[(3,3-diphenylpropyl) amino] carbonyl} -benzyl) amino] (oxo) acetic acid; [(4- {[[2- [1, 1'-biphenylH-iletyl aminojcarbonylbenzyl-XS.d-dichlorobenzyl) -amino] (oxo) acetic acid [(1,3-benzodioxol-5-ylmethyl)] - { [(2- [1, 1-biphenyl] -4-ylethyl) amino] -carbonyl.} Benzyl) amino] (oxo) acetic acid (2,3-dihydro-1 H-inden- 1 -yl {4 - [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid; {2,3-dihydro-1 H-inden-1-yl [4- (. { [2- (4-phenoxyphenyl) ethyl] amino] -carbonyl) -benzyl] amino} (oxo) acetic acid [. {4 - [(dodecylamino) carbonyl] benzyl]. pyridinylmethyl) amino] - (oxo) acetic;
([4- (dimethylamino) benzyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (3-pyridinylmethyl) amino] - (oxo) acetic; ((4-cyanobenzyl) - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (1,3-thiazol-2-ylmethyl) amino] (oxo) acetic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl} { [2- (4-morpholinyl) -1, 3-thiazol-5-yl] methyl} -amino) (oxo) acetic acid; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (4-pyridinylmethyl) amino] - (oxo) acetic; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (3-pyridinylmethyl) amino] - (oxo) acetic; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (3-hydroxybenzyl) amino] - (oxo) acetic; ((4-cyanobenzyl). {3 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (1,3-tiazol-2-ylmethyl) -amino] (oxo) acetic acid; ( {3 - [(Dodecylamino) carbonyl] benzyl} { [2- (4-morpholinyl) -1, 3-thiazol-5-yl] methyl} -amino) (oxo) acetic acid;
((1,3-benzodioxol-5-ylmethyl) {3 - [(dodecylamino) carbonyl] -benzyl} amino) - (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-thienylmethyl) amino] (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-pyridinylmethyl) amino] - (oxo) acetic; acid [. { 4 - [(dodecylamino) carbonyl] benzyl} (3-thienylmethyl) amino] (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-hydroxybenzyl) -amino] (oxo) acetic; 3 - [((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl] -amino) methyl] benzoic acid [cyclopentyl (5 - [(dodecylamino) sulfonyl] -2-thienyl} acid. methyl) amino] - (oxo) acetic acid [benzyl (. {5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) amino] (oxo) acetic acid ((. {5 - [(dodecylamino) sulfonyl] -2-tertiary} methyl). {3- [hydroxy (oxido) -amino] -benzyl} amino) (oxo) acetic acid [(. { 5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) (4-methoxybenzyl) amino] - (oxo) acetic acid [(. {5 - [(dodecylamino) sulfonyl] -2- thienyl, methyl) (2-fluorobenzyl) amino] (oxo) acetic;
acid { ( {5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (methylsulfonyl) -benzyl] -amino} (oxo) acetic; [( { 5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) (4-phenoxybenzyl) -amyr? o] (oxo) acetic acid; 4 - [(carboxycarbonyl) (. {5 - [(dodecylamino) sulfonyl] -2-thienyl} -methyl) amino] -methyl} benzoic; (( {5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) { [6- (trifluoromethyl) -3-pyridinyl] -methyl} amino) (oxo) acetic acid; acid { ( {5 - [(Dodecylamino) sulfonyl] -2-thyl) .methyl) [3- (trifluoromethyl) -benzyl] amino} - (oxo) acetic; acid { [(3-chlorobenzyl) (. {5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) -amino] (oxo) acetic acid; [(5- {[[(3,3-diphenylpropyl) amino] sulfonyl} -2-thienyl) methyl] [3- (trifluoromethyl) benzyl] amino]} (oxo) acetic; acid { (3-chlorobenzyl) [(5- {[[(3,3-diphenylpropyl) amino] sulfonyl} -2-thienyl) methyl] -amino} (oxo) acetic; Oxo acid { . { [5- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Sulfonyl) -2-thienyl] methyl} - [3- (trifluoromethyl) benzyl] amino} acetic; ((3-chlorobenzyl) { [5- ( { [2- (4-phenoxyphenyl) ethyl] amino} sulfosyl) -2-thienyl] -methyl} amino) (oxo) acetic acid; acid { [(5- { [(2- [1, r-biphenyl] -4-ylethyl) amino] sulfonyl} -2-thienyl) methyl] [3- (trifluoromethyl) benzyl] amino} (oxo) acetic;
(( { 1 - [(Cyclohexylamino) carbonyl] -4-p-peridinyl} methyl]) {4 - [(dodecylamino) -carbonyl] benzyl} amino) (oxo) acetic acid; ([(1- {[[4- (dimethylamino) anilino] carbonyl} -4-piperidinyl) methyl]. {4 - [(dodecyl-amino) carbonyl] benzyl} amino) (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [(1-hexanoyl-4-piperidinyl) methyl] -amino} - (oxo) acetic; ( {4 - [(Dodecylamino) carbonyl] benzyl] - {. [1- (3-iodobenzoyl) -4-piperidinyl] methyl} -amino) (oxo) acetic acid; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [(1- {(2 E) -3- [3- (trifluoromethyl) phenyl] -2-propenoyl} -4- piperidinyl) methyl] amino} (oxo) acetic; ( {4 - [(Dodecylamino) carbonyl] benzyl] - {. [1 - (2-quinoxalylcarbonyl) -4-piperidinyl] -methyl} amino) (oxo) acetic acid; [( { 1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinyl} methyl) (4. {[[(4-phenoxybenzyl) amino] carbonyl} benzyl) amino] (oxo) acetic; acid [. { [1- (3-iodobenzoyl) -4-piperidinyl] methyl} (4-. {[[(4-phenoxybenzyl) amino] -carbonyl} benzyl) amino] (oxo) acetic; Oxo acid { (4- { [(4-phenoxybenzyl) amino] carbonyl} benzyl) [(1- {(2 (E) -3- [3- (trifluoromethyl) phenyl] -2-propenoyl} -4 -piperidinyl) methyl] amino} acetic; acid { . { 4 - [(dodecylamino) carbon] phenyl} [2- (methoxycarbonyl) benzyl] -amino} (oxo) acetic; [[4- ( { [2- (1, 1 '-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] - (4-iodobenzyl) -amino] (oxo) acetic acid;
[(2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-iodobenzyl) amino] - (oxo) acetic acid; acid [. { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} (4-iodobenzyl) -amino] (oxo) acetic; [(2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-iodobenzyl) amino] - (oxo) acetic acid; ((4-iodobenzyl) { [4 '- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1, 1'-biphenyl-4-yl] methyl}. amino) (oxo) acetic; acid { [2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Carbonyl) benzyl] - [(4'-fluoro-1, 1'-biphenyl-3-yl) methyl] Not me} (oxo) acetic; acid { [4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] - [(4'-fluoro-1.l'- biphenyl-Si methyl-amino-oxo) -acetic; acid { (2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl] benzyl) [(4'-fluoro-1, 1 '-biphenyl-3-yl) methyl] Not me} (oxo) acetic; acid { [2,6-dibromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino.}. CarboniI) -benzyl] [(4'-fluoro-1,1 '-biphenyl-3-yl) methyl] amino} (oxo) acetic; acid { [4- ( { [2- (1, 1 '-biphenyl-4-yl) ethyl] amino.} Carbonyl) -2,6-dibromobenzyl] [(4'-fluoro-1,1' -biphenyl) -3-yl) methyl] amino} (oxo) acetic; acid { (2,6-dibromo-4- { [(4-pentylbenzyl) amino] carbonyl, benzyl) [(4'-fluoro-1, 1 '-biphenyl-3-yl) methyl] amino} (oxo) acetic; acid { . { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [(4'-fluoro-1, 1'-biphenyl-3-yl) methyl] amino} (oxo) acetic;
acid ([(4'-fluoro-1,1-b-phenyl-3-yl) methyl] { [4 '- ( { [2- (4-phenoxyphenyl) ethyl] amino.} - carbonyl) -1, 1'-biphenyl-4-yl.} methyl.} amino) (oxo) acetic; acid { ( {4 '- [(dodecylamino) carbonyl] -1, 1' -b, phenyl-4-yl}. Methyl) [(4'-fluoro-1, 1'-biphenyl-3-yl. ) methyl] amino} (oxo) acetic; acid { (2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [2- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [2- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; oxo [4 '- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1, 1' -biphenyl-4-yl] methyl} - [2- (trifluoromethoxy) benzyl] amino} acetic; acid { ^ '- [(dodecylaminojcarbonylj-1 .l'-biphenyl ^ -ylmethyl) ^ - (trifluoromethoxy) -benzyl] amino} (oxo) acetic; [[2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (3-phenoxy-benzyl) amino] (oxo) acetic acid; acid [^ - ( { ^ - (l. 1'-biphenyl) -i-etipamino-carbonyl) ^ -bromobenzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid [(2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl, benzyl) (3-phenoxybenzyl) -amino] (oxo) acetic acid [[2,6-dibromo-4- ( { [2- (4-phenoxyphenyl)] ethyl] amino.} carbonyl) -benzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid [[4- ( { [2- (1,1'-biphenyl-4-yl) eyl.} amino.} carbonyl) -2,6-dibromobenzyl] (3-phenoxy-benzyl) amino] (oxo) acetic;
[(2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl] (3-phenoxybenzyl) -amino] (oxo) acetic acid; acid [. { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} (3-phenoxybenzyl) amino] (oxo) acetic; oxo ((3-phenoxybenzyl)) {. [4 '- ( { [2- (4-phenoxyphenyl) etl] amino.}. -carbonyl) -1, 1' -biphenyl-4-yl] methyl.}. amino) acetic; oxo [[(4'- { [(4-pentylbenzyl) amino] carbonyl] -1, 1'-biphenyl-4-yl) methyl] (3-phenoxybenzyl) amino] acetic acid; [(. {4 '- [(dodecylamino) carbonyl] -1,1' -biphenyl-4-yl.} Methyl) (3-phenoxybenzyl) amino] (oxo) acetic acid; [[2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (2-iodobenzyl) amino] (oxo) acetic acid; [[4- ( { [2- (1, 1 '-bifeniI-4-yl) ethyl] amino.} carbonyl) -2-bromobenzyl] - (2-iodobenzyl) -amino] (oxo) acetic acid; [(2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (2-iodobenzyl) amino] (oxo) acetic acid; acid [. { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} (2-iodobenzyl) amino] (oxo) acetic acid ([2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Carbonyl) benzyl] - { [2 '- (trifluoro-methyl) -, 1' -biphenyl-4-yl] methyl.} amino) (oxo) acetic; ([4- ( { [2- (1, 1 '-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] - { [2' - (trifluoro-methyl)] -1, 1 '-biphenyl-4-ylmethylaminooxoxo) acetic;
((2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl, benzyl) - {. [2 '- (trifluoromethyl) -l, 1'-biphenyl-4-yl] methyl} amino) (oxo) acetic; ((2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl, benzyl) - {- [2 '- (trifluoromethyl) -l, 1'-biphenyl} -ylmethylmethyloxy) acetic acid; ( {2-Bromo-4 - [(dodecylamino) carbonyl] benzyl} { [2'- (trifluoromethyl) -l, 1'-biphenyl-4-yl] methyl} amino) ( oxo) acetic; ([4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino.} carbonyl) -2,6-dibromobenzyl JIPXtrifluoromethyl-1, 1'-biphenyl-4-yl] methyl.} amino) (oxo) acetic; ((2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) { [2 '- (trifluoromethyl) -l, 1'-biphenyl-4-) il] methyl.} amino) (oxo) acetic; (. {2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl] - {. [2'- (trifluoromethyl) -l. 1'-biphenyl} -ylmethyl-JaminoXoxo) acetic acid; (( {4, - [(dodecylamino) carbonyl] -1, 1'-biphenyl-4-yl.} methyl) { [2'- (trifluoromethyl) -1, 1'-biphenyl-4 -yl] amino) (oxo) acetic; [[4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] (1,1'-biphenol-2-ylmethyl) ) amino] (oxo) acetic; [(1,1-biphenyl-2-ylmethyl) (2-bromo-4-. {((4-pentylbenzyl) amino] -carbonyl} benzyl) -amino] (oxo) acetic acid; ((1,1'-biphenyl-2-ylmethyl). {2-bromo-4 - [(dodecylamino) carbonyl] -benzyl} amino) (oxo) acetic acid; acid { (1,1 '-biphenyl-2-ylmethyl) [2,6-dibromo-4- ( { [2- (4-phenoxyphenyl) etl] -amino.} Carbonyl) benzyl] amino} (oxo) acetic;
[[4 - ([2- (1,1'-biphenyl-4-yl) ethyl] amino.} carbonyl) -2,6-dibromobenzyl] (1,1 '-biphenyl-2-methyl) amino] (oxo) acetic; [(1,1'-biphenyl-2-ylmethyl) (2,6-dibromo-4-. {[[(4-pentylbenzyl) -amino] carbonyl] benzyl) amino] (oxo) acetic acid; ((1,1'-biphenyl-2-ylmethyl). {2,6-dibromo-4 - [(dodecylamino) -carbonyl] benzyl} amino) (oxo) acetic acid; acid { (2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; acid { . { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethoxy) benzyl] amino} (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethoxy) benzyl] amino} (oxo) acetic; acid { (2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl} benzyl) [3- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; acid { . { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethoxy) benzyl] amino} - (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [3- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; acid { . { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethoxy) benzyl] -amino} (oxo) acetic; acid { ( {4 '- [(dodecylamino) carbonyl] -1, 1' -biphenyl-4-yl}. Methyl) [3- (trifluoromethoxy) -benzyl] amino} (oxo) acetic;
[[2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (4-phenoxy-benzyl) aminoj (oxo) acetic acid; [[4- ( { [2- (1, 1'-biphenyl-1-ethylphenyl] -bromobenzyl] - (4-phenoxy-benzyl) amino] (oxo) acetic acid [(2-bromo-4)] - { [(4-Pentylbenzyl) amino] carbonyl.} Benzyl) (4-phenoxybenzyl) -amino] (oxo) acetic; acid [. { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) amino] (oxo) acetic; [[4- ( { [2- (1,1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2,6-dibromobenzyl] (4-phenoxy-benzyl) amino] (oxo) ) acetic; [(2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-phenoxybenzyl) -aminoj (oxo) acetic acid; acid { [4- ( { [2- (1, 1 '-biphenyl-4-yl) ethyl] amino.} Carbonyl) -2-bromobenzyl] [4- (trifluoro-methyl] benzyl] amino} (oxo) acetic; acid { (2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) -benzyl] -amino} (oxo) acetic; acid { . { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl, benzyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; acid { . { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic;
Oxo acid { [(4'- { [(4-Pentylbenzyl) amino] carbonyl] -1, 1'-biphenyl-4- [1] methyl] [4- (trifluoromethyl) benzyl] amino} acetic acid acid { {2-bromo-4 - [(dodecylamino) carbonyl] benzyl}. [3- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid; 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl] - [3- (trifluoromethyl) benzyl] -amino} - (oxo) acetic acid oxo. {[[(4'- { [(4-Pentylbenzyl) amino] carbonyl] -1, 1'-biphenyl-4-yl) methyl] [3- (trifluoromethyl) benzyl] amino} acetic acid; -dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic acid; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { (4-dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; ( {4 - [(Dodecylamino) carbonyl] benzyl}. {- 1- [4- (trifluoromethyl) phenyl] -ethyl} amino) - (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1 - (methylamino) glucitol) of (. {4 - [(dodecylamino) carbonyl] benzyl} {1 •• [4- ( trifluoromethyl) phenyl] ethyl} amino) - (oxo) acetic; acid { ( {4 '- [(octylamino) carbonyl] -1, 1' -biphenyl-4-yl.} Methyl) [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic acid; Oxo acid { (4-tetradec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] amino} acetic;
acid { (4-dodec-1-ynylbenzyl) [4- (trif [uoromethyl) benzyl] amino} (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) phenyl] amino} (oxo) acetic; acid [. { 4 - [(dodecylamino) carbonyl] benzyl} (2-methoxyphenyl) amino- (oxo) acetic; ((1,2-diphenylethyl) {4 - [(dodecylamine) carbonyl] benzyl] -amino) (oxo) acetic acid; N- (carboxycarbonyl) -N-. { 4 - [(Dodecylamino) carbonyl] benzyl} -1-phenylalanine; acid [. { 4 - [(dodecylamino) carbonyl] benzyl} (3-phenoxyphenyl) amino] - (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-isopropoxyphenyl) -amino] (oxo) acetic; acid [. { 4 - [(dodecylamine) carbonyl] benzyl} (4-iodophenyl) amino] (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [3-fluoro-4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; ((3-chloro-2-methylphenyl). {4 - [(dodecylammonyl) carbonyl] benzyl] -amino) (oxo) acetic acid; 4 '- ((carboxycarbonyl). {4 - [(dodecylamino) carbonyl] benzyl] -amino) -1, 1'-biphenyl-2-carboxylic acid;
((2,4-dichlorobenzyl) - {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid; acid [. { 4 - [(dodecylamino) carbonyl] benzyi? I -phenylpropyl) amino] - (oxo) acetic; ([2- (4-chlorophenif) propyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-isopropoxyphenyl) -amino] (oxo) acetic; ([4- (benzyloxy) phenyl]. {4 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [2- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid [. { 4 - [(dodecylamino) carbonyl] benzyl] 2-methoxybenzyl) amino] - (oxo) acetic; ([(1 R) -1 - (4-chlorophenyl) ethyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ((3,4-dichlorobenzyl) { 4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ((1-benzothien-3-ylmethyl). {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ([2- (2,6-Dichlorophenyl) ethyl] - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid;
( {4 - [(Dodecylamino) carbonyl] benzyl] -. {2- [3- (trifluoromethyl) phenyl] -ethyl} amino) (oxo) acetic acid; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [2- (3-fluorophenyl) ethyl] -amino} (oxo) acetic; ([(1S) -1- (4-chlorophenyl) ethyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [(1 S) -1-phenylethyljamino} - (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [(1 R) -1-phenylethyl] aminoXoxo) acetic; ([3- (benzyloxy) phenyl]. {4 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid; N- (carboxycarbonyl) -N-. { 4 - [(Dodecylamino) carbonyl] benzyl} -D-phenylalanine; acid { . { 4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic; Oxo acid { . { 1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic;
N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) of oxo acid. { . { 1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; ([(2-Butyl-1-benzofuran-3-yl) methyl]. {4 - [(dodecylamino) -carbonyl] benzyl} amino) (oxo) acetic acid; acid { (1- { 4 - [(dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) -benzyl] amino) - (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1 - (methylamino) glucitol) acid. { (l- { 4 - [(Dodecylamino) carbonyl] phenyl] ethyl) [4- (trifluoromethyl) benzyl] amine} (oxo) acetic; acid { (4-. {[[(4-octylphenyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) -benzyl] amino-oxo) acetic acid; acid { (3-chlorobenzyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] aminooxo) acetic acid; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { (3-chlorobenzyl) [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] -amino) (oxo) acetic acid; acid { . { cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (tridecanoyl-amino) benzyl] -aminoXoxo) acetic; oxo ([4- (trifluoromethyl) benzyl] { [4- (3-undecyl-1,4-oxadiazol-5-yl) -1-naphthyl] -methyl} amino) acetic acid;
N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) -glucitol) of oxo ([4- (trifluoromethyl) benzyl] { [4- (3-undecyl-1,2, 4-oxadiazol-5-yl) -1-naphthyl] -methyl} amino) acetic acid; acid { . { cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] aminooxo) acetic acid; N-methyl-D-glucamine salt (i.e. 1-deoxy-1 - (methyl-amino) glucitol) acid. { . { cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; acid { (4-dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { (4-dibenzo [b, d] furan-4-phenyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { [4- (octyloxy) benzyl] [4- (trifluoromethyl) benzyl] aminooxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { [4- (octyloxy) benzyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; [[2- (3-chlorophenyl) ethyl] (4-dec-1 -inylbenzyl) amino] (oxo) acetic acid; ([2- (3-chlorophenyl) ethyl]. {4 - [(1 Z) -dec-1-ynyl] benzyl} amino) (oxo) acetic acid; acid { [2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] aminoXoxo) acetic;
N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { [2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic; Oxo acid { . { (1 R) -1 - [4- (trifluoromethyl) pheny] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (Le. 1-deoxy-1- (methylamino) -glucitol) of oxo acid. { . { (1 R) -1- [4- (Trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzylamino} acetic; Oxo acid { [4- (trifluoromethyl) phenyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; Oxo acid { [4- (trifluoromethyl) phenyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic acid, N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) of oxo acid. { . { (1S) -1- [4- (Trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) -glucitol) of oxo acid. { . { (1 S) -1- [4 (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; [(3-chlorobenzyl) 4-dec-1-ynylbenzyl) amino] (oxo) acetic acid; N-methyl-D-glucamine salt (i.e. 1 (deoxy-1- (methylamino) -glucitol) of [(3-chlorobenzyl) (4-dec-1-ynylbenzyl) amino] (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol) of [[2- (3-chlorophenyl) ethyl] (4-oct-1-ynylbenzyl) amino] (oxo) acetic acid;
acid { (4-dec-1-ynylbenzyl) [4- (trifluoromethyl) pheny] amino} (oxo) acetic; ((4-dec-1-ynylbenzyl) - {. l- [4- (trifluoromethyl) phenyl] ethyl} amino) (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol) of ((4-dec-1-ynylbenzyl) { 1- [4- (trifluoromethyl) phenyl] ethyl]. amino) (oxo) acetic; acid { . { 1-methyl-1 - [4- (trifluoromethyl) phenyI] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 1-methyl-1 - [4- (trifluoromethyl) pheny] etl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; acid { [2- (3-chlorophenyl) ethyl] [4- (3-octyl-1,2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { [2- (3-chlorophenyl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] aminooxo) acetic acid; acid { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) -benzyl] amine} - (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { . { [4- (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic;
N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { [4- (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; [(4-bromobenzyl) (4-oct-1-ynylbenzyl) amino] (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-Hydroxy-1-phenylethyl) -amino] (oxo) acetic; ((4-dec-1-ynylbenzyl). {1-methyl-1 - [4- (trifluoromethyl) phenyl] ethyl} -amino) (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1 - (methylamino) glucitol) of ((4-dec-1-ynylbenzyl). {1-methyl-1 - [4- (trifluoromethyl)} phenyl] ethyl} amino) (oxo) acetic; Oxo acid { 4 - [(9Z) -tetradec-9-enoylamino] benzyl} [4- (trifluoromethyl) -benzyl] amino} acetic; acid { [4-dec-1-ynylbenzyl] [4- (trifluoromethyl) benzyl] amino? Oxo) acetic; oxo [4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) of oxo acid. { [4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] -amino} acetic; acid { (4-dodecylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic;
N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { (4-dodecylbenzyl) [4- (trifluoromethyl) benzyl] amine} (oxo) acetic; acid { [4- ( { [(2-Butyl-1-benzofuran-3-yl) methyl] amino.} Carbonyl) benzyl] - [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { (4- { [4- (benzyloxy) benzoyl] amino.} Benzyl) [4- (trifluoromethyl) -benzyl] amino} - (oxo) acetic; acid { (3,5-dichlorobenzyl) [4- (tridekanoylamino) benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { (3,5-dichlorobenzyl) [4- (tridekanoylamino) benzyl] amino} (oxo) acetic; acid { . { 4 - [(4-octylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; Oxo acid { [4- (trifluoromethyl) benzyl] [4- (5-undecyl-1,4-oxadiazol-3-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylaminoglucitol) of oxo acid { [4- (trifluoromethyl) benzyl] [4- (5-undecyl-1, 2,4- oxadiazol-3-yl) benzyl] amino} acetic acid {. {4- [2- (4-octylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino}. (oxo) acetic acid: {. (4- {[4- (heptyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic acid; [4 - [(4-Butylphenyl) ethynyl] benzyl] - [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic;
acid { . { 4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (Trifluoromethyl) benzyl] -amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino? Oxo) acetic; Oxo acid { (4- { [4- (Pentyloxy) phenyl] ethynyl} - benzyl) [4- (trifluoromethyl) -benzyl] amino} acetic; Oxo acid { . { 4 - [(4-propylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} acetic; [[2- (3-chlorophenyl) ethyl] (4-dodec-1-ynylbenzyl) amino] (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol) of [[2- (3-chlorophenyl) ethyl] (4-dodec-1-ynylbenzyl) amino] (oxo) acetic acid; acid { (4-oct-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] aminooxoxo) acetic acid; acid { [4- (11-hydroxyundec-1-ynyl) benzyl] [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic acid; acid { [4- (11-methoxy-11-oxoundec-1-ynyl) benzyl] [4- (trifluoromethyl) -benzyl] aminooxo) acetic acid; 11- [4- ( { (carboxycarbonyl) [4- (trifluoromethyl) benzyl] amino] -methyl) phenyl] undec-10 -noic acid; acid { (4- { [4- (benzyloxy) pheny] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic;
acid { (4-. {2- 2- [4- (heptyloxy) phenyl] ethyl} benzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { . { 4- [2- (4-butylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { . { 4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; Oxo acid { (4-2- [4- (Pentyloxy) phenyl] ethyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} acetic; Oxo acid { . { 4- [2- (4-propylphenyl) ethyl] benzyl} [4- (Trifluoromethyl) benzyl] -amino} acetic; 11 - [4- ( { (carboxycarbonyl) [4- (trifluoromethyl) benzyl] amino]} - methyl) phenyl] undecanoic acid; acid { [4- (11-hydroxyundecyl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { (4-dodec-1-ynylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { (4-dodec-1-ynylbenzyl) [4- (trifluoromethyl) pheny] aminoamino) acetic acid; oxo ([4- (trifluoromethyl) benzyl]. {4- [2- (3-undecyl-1, 2,4-oxadiazol-5-yl) ethyl] benzyl] -amino) acetic acid;
N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol) of oxo ([4- (trifluoromethyl) benzyl]. {4- [2- (3-undecyl-1, 2 , 4-oxadiazol-5-yl) ethyl] benzyl] -amino) acetic acid; acid { . { 4- [2- (3-octyl-1, 2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (Trifluoromethyl) benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1 - (methylamino) glucitol) acid. { . { 4- [2- (3-octyl-1, 2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { . { 4 - [(4-octylbenzoyl) amino] benzyl} [4- (Trifluoromethyl) benzyl] -amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) of acid. { . { 4 - [(4-octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] aminoXoxo) acetic; Oxo acid { (1-tridecanoylpiperidin-4-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} acetic; acid { . { [1- (4-octylbenzoyl) piperdin-4-yl] methyl} [4- (trifluoromethyl) -benzyl] amino? Oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { . { [1- (4-octylbenzoyl) p -peridin-4-yl] methyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { [(3-dec-1-ynyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino-oxo) acetic;
acid { [(3-dodec-1-ynyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; Oxo acid { ( { 3 - [(4-propylphenyl) ethynyl] -1-benzofuran-5-yl}. Methyl) [4- (trifluoromethyl) -benzyl] amino} acetic; [(4-dodec-1-ynylbenzyl) (4-fluorobenzyl) amino] (oxo) acetic acid; [bis (4-oct-1-ynylbenzyl) amino] (oxo) acetic acid; acid { [(6-dodec-1-ynylpyridin-3-yl) methyl] [4- (trifluoromethyl) benzyl] aminooxo) acetic; acid { (3-dodec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] aminooxo) acetic acid; acid { [2- (2-fluorophenyl) ethyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; acid { [2- (2-fluorophenyl) ethyl] [3- (3-undecyl-1,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; acid { [2- (2-fluorophenyl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -aminoXoxo) acetic acid; acid { [2- (3,4-dichlorophenyl) ethyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyljaminooxoxo) acetic; acid { [2- (3,4-dichlorophenyl) ethyl] [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic; acid { [2- (3,4-dichlorophenyl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic;
acid { ^ (1. r-bifeniM-i ethyl J XS-undecyl-I ^ -oxadiazol-d-yl) -benzyl] amino} (oxo) acetic; acid { [2- (1, 1'-biphenyl-4-yl) ethyl] [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl-oxino-oxo) -acetic; acid { [2- (1, 1 '-biphenyl-4-yl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; Oxo acid { 5,6,7,8-tetrahydronaphthalen-1-yl [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} acetic; Oxo acid { 5,6,7,8-tetrahydronaphthalen-1-yl [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} acetic; [[4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] (5,6,7,8-tetrahydro-naphthalen-1-yl) amino] (oxo) acetic acid; acid { (1,1'-biphenyl-3-ylmethyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; acid { (1,1 '-biphenyl-3-ylmethyl) [3- (3-undecyl-1, 2,4-oxadiazoI-5-yl) -benzyl] amino} (oxo) acetic; acid { (1,1 '-biphenyl-3-ylmethyl) [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -aminoXoxo) acetic acid; acid { (1-benzothien-3-ylmethyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic; acid { (1-benzothien-3-ylmethyl) [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic;
acid { (1-benzothien-3-ylmethyl) [4- (3-octyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic; Oxo acid { [2- (trifluoromethyl) benzyl] [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] amino} acetic; Oxo acid { [2- (trifluoromethyl) benzyl] [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; acid { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [2- (trifluoromethyl] -benzyl] aminooxo) acetic acid; Oxo acid { [3- (trifluoromethyl) benzyl] [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] -amino} acetic; Oxo acid { [3- (trifluoromethyl) benzyl] [3- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] -amino} acetic; acid { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [3- (trifluoromethyl) -benzyl] aminooxo) acetic acid; acid { (2-methoxybenzyl) [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -aminoXoxo) acetic acid. { (2-methoxybenzyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino-oxo) acetic acid; acid { [2- (methoxybenzyl) [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic; Oxo acid { . { 4 - [(trifluoromethyl) sulfonyl] benzyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} acetic; Oxo acid { . { 4 - [(trifluoromethyl) sulfonyl] benzyl} [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} acetic;
([4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] - {4 - [(trifluoromethyl) -sulfonyl] benzyl] amino) (oxo) acetic acid; acid { 1,3-benzodioxol-5-yl [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; acid { 1,3-benzodioxol-5-yl [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino-oxo) acetic acid; acid { 1,3-benzodioxol-5-yl [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -aminoXoxo) acetic acid; acid { [(4-dodec-1-ynyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic; acid { [(4-dec-1-ynyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { [(4-dec-1-ynyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; Oxo acid { [4- (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) -benzyl] acetic acid; acid { (4-dec-1-in-1-benzyl) [2- (2-fluorophenyl) ethyl] aminoXoxo) acetic acid; acid { (4-dodec-1-ynylbenzyl) [2- (2-fluorophenyl) ethyl] amine} (oxo) acetic; acid { . { [4- (dodecyloxy) -1-naphthyl] methyl} [2- (2-fluorophenyl) ethyl] amino} - (oxo) acetic; acid { [2- (2-fluorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic;
acid { (4-dec-1-ynylbenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { (4-dodec-1-iniibenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { . { [4- (dodecyloxy) -1-naphthyl] methyl} [2- (trifluoromethyl) benzyl] -aminoXoxo) acetic; acid { [4- (octyloxy) benzyl] [2- (trifluoromethyl) benzyl] aminooxo) acetic; acid { (4-dec-1-ynylbenzyl) [2- (3,4-dichlorophenyl) ethyl] amino} (oxo) acetic; [[2- (3,4-Dichlorophenyl) ethyl] (4-dodec-1-nylbenzyl) amino] (oxo) acetic acid; ([2- (3,4-Dichlorophenyl) ethyl] - {[[4- (dodecyloxy) -1-naphthyl] methyl] -amino) (oxo) acetic acid; acid { [2- (3,4-Dichlorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic; ( {4 - [(4-hexylphenyl) ethynyl] benzyl}. {1-methyl-1 - [4- (trifluoromethyl) -phenyl} ethyl} amino) (oxo) acetic acid; acid { [4- (5 ~ cyclohexylpent-1-ynyl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { . { 3 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic;
acid { [4- (4-etl-3-hydroxyoct-1-ynyl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { (2-dec-1-nylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; salt of L-lysine acid. { (4-dec-1-inylbenzyl) [4- (trifluoromethyl) -benzyl] amine} (oxo) acetic; trometamine salt (i.e. (2-amino-2-hydroxymethyl) -1, 3-propanediol) of acid. { (4-dec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] amino-oxo) acetic acid; salt of L-arginine acid. { (4-dec-1-ynylbenzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; . { Sodium (4-dec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] amino? Oxo) acetate. The compounds of Formula (I) are useful in the prevention and / or treatment of cardiovascular disorders such as coronary obstruction and heart failure. The compounds of Formula (I) are particularly useful in the prevention and / or treatment of chronic heart failure. In particular, the compounds of the invention are particularly useful in the prevention and / or treatment of a cardiovascular disorder selected from endothelial dysfunction, deterioration in endothelial NO production and increased peripheral vasoconstriction in heart failure.
According to another embodiment, there is provided a use of a compound of the Formula (I) for the preparation of a medicament for the prevention and / or treatment of cardiovascular disorders. According to a preferable embodiment, there is provided a use of a compound of the Formula (I) for the preparation of a medicament for the prevention and / or treatment of heart failure, particularly chronic heart failure. According to another embodiment, there is provided a use of a compound of Formula (I) for the preparation of a medicament for the prevention and / or treatment of endothelial dysfunction, impairment in endothelial NO production and peripheral vasoconstriction. increased in heart failure, particularly in chronic heart failure. According to another embodiment, a method for the prevention and / or treatment of cardiovascular disorders such as coronary obstruction, heart failure, including chronic heart failure, which comprises administering a compound of the Formula (I) to a patient is provided. with the need of it. The methylenamide derivatives of the present invention can be prepared from readily available starting materials using general methods and procedures such as those described in WO 03/064376. The compounds of the invention, together with an adjuvant, carrier, diluent or excipient conventionally employed, can be put in the form of pharmaceutical compositions and unit dosages thereof, and in that form they can be used as solids, such as tablets or filled capsules. , or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled therewith, all for oral use, or in the form of sterile injectable solutions for parenteral use (including subcutaneous). Those pharmaceutical compositions and the unit dosage forms thereof may comprise ingredients in the conventional proportions, with or without additional active compounds or principles, and those unit dosage forms may contain any suitable effective amount of the active ingredient provided with the daily dosage amount to be employed. The methylenamide derivatives of this invention are typically administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically active amount. The amount of the compound currently administered will typically be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the route of administration chosen, the current compound administered, the age, the weight, and the patient's response. individual, the severity of the patient's symptoms, and the like.
The pharmaceutical compositions of these inventions can be administered through a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Compositions for oral administration may take the form of liquid solutions or suspensions by volume, or powders by volume. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical dosage unit forms include pre-filled ampoules or syringes, pre-measured liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions. In those compositions, the substituted methyleneamide derivative according to the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) the remainder being various vehicles or carriers and processing aids useful to form the desired dosage form. Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with regulators, suspending and dispersing agents, colorants, flavors and the like. The solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a slip agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. Injectable compositions are typically based on sterile injectable saline or phosphate buffered saline or other injectable carriers known in the art. As mentioned above, the substituted methyleneamide derivatives of Formula (I) in those compositions are typically a minor component, often in the proportion of between 0.05 to 10% by weight, the remainder being the injectable carrier, and the like. The components described above for the orally administrable or injectable compositions are merely representative. Other materials, as well as processing techniques and the like, are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Marck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of the representative materials of sustained release can also be found in the materials incorporated in Remington's Pharmaceutical Sciences. The preparation of the formulations of the methylenamide derivatives of the present invention is described in WO 03/064376. In the following, the present invention will be illustrated by means of some examples that are not designed to be considered as limiting the competence of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1 a-1 b show the response of the dilation mediated by the flow of the mesenteric arteries (dilation%) against the intravascular flow (μl / min) in mice, after preconstriction with phenylephrine. The response to flow-mediated dilation in a normal mouse (open circles) is compared to the response to flow-mediated dilation of the mesenteric arteries either in a normal mouse subjected to an inhibitor of NO synthesis (left , black circles) or in a mouse in which chronic heart failure (CHF) has been induced as described in example 1 (right, black circles).
Figures 2a-2b show the response to dilation induced by the flow of the mesenteric arteries (% dilation) against intravascular flow (μl / min) after preconstriction with phenylephrine, in mice in which heart failure has been induced chronic (CHF). The response to flow-mediated dilation in an untreated mouse that presents CHF (open left and right circles) is compared to the response to flow-mediated dilation of the mesenteric arteries in a mouse that presents CHF after treatment with 10 ~ 5 M of the compound (I) of the invention (black circles on the left) and with 10"6 M of the compound (I) of the invention (black circles on the right) as described in example 1. hereinafter the following abbreviations are used in the accompanying examples: min (minute), μm (micrometer), M (molar, ACE (Angiotensin Conversion Enzyme, acronym in English), CHF (Chronic Heart Failure, acronym in English) , FMD (Flow-mediated Dilation), NO (Nitric Oxide), PTP's (Protein Tyrosine Phosphatases, acronym in English).
EXAMPLES Biological tests
To show the activity of the compounds of Formula (I) in the restoration of flow-mediated vasodilation after chronic heart failure, the compounds of Formula (I) can be subjected to the following test. Experimentally, the release of NO induced by the flow in the small peripheral arteries (ie, arteries that contribute to increased resistance in heart failure) can be evaluated in vitro in perfused, pressurized isolated arteries such as small arteries (<300 μm in diameter) mesenteric or of the hindquarters.
EXAMPLE 1 Model of coronary artery occlusion
Chronic heart failure is induced in C57BL6 mice (n = 12) through coronary ligation according to the model developed in rats by Varin et al., 1999, Circulation, 99, 2951-2957. This model shows that chronic heart failure eliminates NO-mediated vasodilation induced by the flow of small peripheral arteries, in a context of preserved response to acetylcholine, mediated by NO. The mice are anesthetized, ventilated, and a tracheotomy is performed (incision in the pleural cavity). The main left coronary artery is ligated near its origin. This procedure leads to the development of a heart attack that involves around 40% of the left ventricle. Post-infarction mortality in the mouse model is around 40-50%. The development of heart failure is evaluated by electrocardiography in the closed state of the chest, 7 days and 2 months after the coronary ligation. Simulated (normal) mice are subjected to the same protocol, except that the artery will not be ligated. In each group there are six mice present and the mice that survived the myocardial infarction are later used in the study. After two months, the mice are anesthetized and subjected to laparotomy (incision in the stomach cavity). A portion of the mesenteric artery (diameter 250-350 μm) is carefully isolated under a dissecting microscope, and a segment of 1.5 to 2.0 mm in length is cannulated at both ends, transferred to an arteriograph (Living Systems Instrumentation) and pressurized at 60 mm Hg. Fluid-mediated vasodilatation (FMD), i.e. changes in vessel diameter in response to the cut, which increases in intraluminal flow (0-200 μl / min), is evaluated after preconstriction with phenylephrine (incubated 2 min at 10"5 M) after it is reached a contraction plateau, at the baseline and after incubation with a compound of the invention:
1) Endothelial dysfunction in mouse heart failure In this model of chronic heart failure, the response of dilation to an increase in blood flow (flow-mediated dilation) is severely eliminated (flow dilation of 200 ml / min: simulation: 24 ± 2% and CHF: 5 ± 1%). The inhibition of the response to dilation is similar to the case of the administration of an inhibitor of NO synthesis (NG-nitro-L-arginine at 10"5 M) in normal arteries, as shown in Figure 1a -1 B.
2) Restoration of flow-mediated dilation In these arteries in which chronic heart failure has been induced, flow-mediated dilation can be restored to the normal level with in vitro (30 min) incubation of the arteries with acid. . { . { 4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic acid (1) of the invention, diluted in perfusion buffer (regulator Krebs) from a solution at 10"3 M to a final concentration of 10" 5 M and 10" 6 M, respectively, as shown to the left and right of Figure 2a-2b. This example illustrates that the compounds of the invention are capable of acutely restoring endothelial function in mice with chronic heart failure.
Claims (19)
1. - Use of a methylenamide derivative of the formula (I): as well as their geometric isomers, their optically active forms as enantiomers, diastereomers and their racemate forms, as well as the pharmaceutically acceptable salts and pharmaceutically acceptable derivatives thereof, wherein: R1 is selected from (C -? - C15) alkyl ), (C2-C-? 2) alkenyl, (C2-C? 2) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3 to 8 members), aryl (CC? 2) alkyl, or heteroaryl (C C12), aryl or heteroaryl alkenyl of (C2-C12), aryl and heteroaryl alkynyl of (C2-C12); R2a and R2b are, independently of one another, selected from H and (C12 alkyl); Cy is selected from D and E; D is selected from substituted thienyl and substituted phenyl, wherein substituents are selected from phenyl, oxadiazole and 1 or 2 portions selected from the group consisting of -NH-CO-R3, -S02-NR3R3 ', and -CO- NR3R3 '; E is selected from aryl, heteroaryl, (3-8 membered) cycloalkyl and heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl (3-8 membered) and heterocycloalkyl are substituted by (C2-C18) alkynyl; R3, R3 are independently selected from H, (C1.-C15) alkyl, (C2-C? 2) alkenyl, (C2-C? 2) alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl (3-8) members), aryl or heteroaryl (C 1 -C 12) alkyl, aryl or heteroaryl (C 2 -C 2) alkenyl, aryl or heteroaryl (C 2 -C 12) alkynyl; for the preparation of a medicament for the treatment and / or prevention of cardiovascular disorders.
2. The use as claimed in claim 1, wherein R2a and R2b are each H.
3.- The use as claimed in claim 1 or 2, where Cy is D.
4. - The use as claimed in any of the preceding claims, wherein R3 is H and R3 is selected from the group consisting of diphenyl-ethyl, dodecyl, octyl, 4-pentyl-benzyl, 4-phenoxy-phenethyl , ethyl-thiophen-2-yl, pentadecyl, tridecyl, hexyloxy-phenyl or (2-ethyl) -hexyl.
5. The use as claimed in claim 1, wherein Cy is E.
6. The use as claimed in claim 5, wherein E is a phenyl, pyridinyl, naphthyl or benzofuranyl group, being substituted by B-R4 where B is ethynyl group and R4 is (C6-C16) alkyl, cycloalkyl (3-8 members), cycloalkyl (3-8 members) of (C1-C12) alkyl, phenyl or phenyl alkyl of (CC? 2).
7. - The use as claimed in claim 6, wherein E is phenyl which is substituted by B-R4, wherein B is an ethynyl group and R4 is (C6-d6) alkyl.
8. The use as claimed in any of the preceding claims, wherein R1 is a portion -CH2-A, or -CH2-CH2-A, where A is an aryl, heteroaryl, heterocycloalkyl of (3-8 members ) or (3-8 membered) cycloalkyl.
9. The use as claimed in any of claims 1 to 7, wherein R1 is A, where A is aryl, heteroaryl, heterocycloalkyl (3-8 members) or cycloalkyl (3-8 members).
10. The use as claimed in claims 8 or 9, wherein A is selected from the group consisting of a phenyl, pyridinyl, benzo-1,3-dioxolenyl, biphenyl, naphthyl, quinoxalinyl, thiazolyl group, thienyl, furanyl or piperidinyl, which is optionally substituted by 1 or 2 cyano, halogen, N02, alkoxy, aryloxy or heteroaryloxy of (d-C6), thioalkoxy of (d-C6), alkyl of (CrC12), X of alkyl of (d-d2) wherein X is halogen, (C2-C2) alkenyl, (C2-C12) alkynyl, aryl, heteroaryl, cycloalkyl or (3-8 membered) heterocycloalkyl, aryl or heteroaryl alkyl ( CrC-? 2), aryl or heteroaryl alkenyl of (C2-C12), aryl or heteroaryl alkynyl of (C2-C12), -COR3, -COOR3, -CO-NR3R3 ', -NHCOR3 where R3 is (C12 alkyl) ) or alkenyl of (C1-C12), -SOR3, S02R3, -S02NR3R3 'with R3, R3' being independently selected from the other, from the group consisting of H, straight or branched (dC? 2) alkyl, alkenyl (C2-C12), alkynyl (C2-C2), aryl , heteroaryl, cycloalkyl or heterocycloalkyl of (3-8 members).
11. The use as claimed in any of claims 1 to 4 or 8 to 10, wherein: R2a and R2b are each H; R1 is -CH2-A, where A is phenyl or thienyl, optionally substituted by cyano, halogen, methoxy, hydroxy, phenoxy, -N02, trifluoromethyl; Cy is a thienyl, phenyl or biphenyl which is substituted by -S02R3, -CO-NR3R3 ', where R3' is H and R3 is alkyl of (C7-C12).
12. The use as claimed in any of claims 1 to 4 or 8 to 10, wherein: R2a and R2b are each H; R1 is -CH2-A, where A is phenyl or thienyl, optionally substituted by cyano, halogen, methoxy, hydroxy, phenoxy, -N02, trifluoromethyl; Cy is a thienyl, phenyl or biphenyl which is substituted by -S02R3, -CO-NR3R3 ', wherein R3' is H and R3 is (C7-C15) alkyl.
13. The use as claimed in any of claims 1 to 4 or 8 to 10, wherein the methylenamide derivative is from the formula (I '): R1 Cy- • C-H, < o O OH wherein: R1 is selected from the group consisting of phenyl, benzyl, phenethyl, 1-methylbenzyl which may be substituted by an alkyl group of (dC6) or a cycloalkyl group; Cy is a phenyl or biphenyl group substituted with a portion selected from the group consisting of -NH-CO-R3, -CO-NH-R3, or an oxadiazole group substituted with R3, wherein R3 is (C7-C15) alkyl ).
14. The use as claimed in claim 13, wherein R3 is (C8-d5) alkyl.
15. The use as claimed in claims 13 and 14, wherein R3 is dodecyl.
16. The use as claimed in any of the preceding claims, wherein the methylenamide derivative is selected from the following group: acid (benzyl. {4 - [(dodecylamino) carbonyl] benzyl} amino. ) (oxo) -acetic; Oxo acid { . { 4 - [(pentadecylamine) carbonyl] benzyl} [4- (trifluoro-rnethyl) benzyl] amino} acetic; (benzyl) {. 4 - [(pentadecylamino) carbonyl] benzyl} amino) (oxo) -acetic acid; acid (benzyl. {4 - [(tridecylamino) carbonyl] benzyl] amino) (oxo) -acetic acid; [benzyl (4- {[[dodecyl (methyl) amino] carbonyl} benzyl) amino] (oxo) acetic acid; acid { (4-. {[[Dodecyl (methyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} - (oxo) acetic; ([1 - (tert-butoxycarbonyl) -4-p-pentyldinyl]. {4 - [(dodecylamine) -carbonyl] benzyl] -amino- (oxo) acetic acid; {4- [(Dodecylamino) carbonyl] benzyl] - [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic acid; acid { . { 4 - [(dodecylamine) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] -amino} (oxo) acetic; ( { [1 - (tert-butoxycarbonyl) -4-piperidinyl] methyl}. {4 - [(dodecylamino) carbonyl] -benzyl} amino (oxo) acetic acid, oxo acid {. 4- (Tridekanoylamino) benzyl] [4- (trifluoromethyl) benzyl] -amino} acetic acid [benzyl (4- {[[4- (hexyloxy) benzoyl] amino} benzyl) amino] - (oxo) acetic acid, oxo- {4- (trifluoromethyl) benzyl] [4- (10-undecenoylamino) benzyl] amino} acetic acid, oxo acid {4 - [(9E) -9-tetradecenoylamino] benzyl} [4- (trifluoromethyl) -benzyl] amino} -acetic acid, benzyl [4- (tridekanoylamino) benzyl] amino] - (oxo) acetic acid; (2-hydroxydecyl) amino] benzyl} - [4- (trifluoromethyl) benzyl] -amino} - (oxo) -acetic acid, oxo { [4- (trifluoromethyl) benzyl] [4- ( 3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} -acetic acid: {. (. {5 - [(dodecylamino) sulfonyl] -2-thienyl}. L) [4- (trifluoromethyl) benzyl] amino) - (oxo) acetic; acid [. { 4- [(dodecylamino) carbonyl] benzyi ?. { 1 - [(4-methoxyphenyl) -sulfonyl] -4-piperidinyl} methyl) amino] (oxo) acetic; acid [. { 4- [(dodecylamino) carbonyl] benzyl] 2-carboxy-1-phenylethyl) -amino] (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-methoxy-1-methylethyl) -amino] (oxo) acetic; (4-bromo- {4 - [(dodecylamino) carbonyl] benzyl} anilino) (oxo) acetic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl} anilino) (oxo) acetic acid; ([2- (3-chlorophenyl) ethyl] - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid { . { 4 - [(dodecylamino) carbonyl] benzyl} [2- (3-methoxyphenyl) ethyl] -aminoxoxo) acetic; acid { . { 4 - [(dodecylamine) carbonyl] benzyl} [(d, 1) -trans-2-phenylcyclopropyl] amino} (oxo) acetic; acid ([(d, 1) -trans-2- (benzyloxy) cyclopentyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl} -4-phenoxyanilino) (oxo) acetic acid; acid [. { 4 - [(dodecylamino) carbonyl] benzyl?, 2,3,4-tetrahydro-1-naphthalenyl) amino] - (oxo) acetic; ((1-benzyl-4-piperidinyl) { 4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid { . { 4- [(dodecylamino) carbonyl] benzyl} [2- (4-phenoxyphenyl) ethyl] amino} (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [2- (2-phenoxyphenyl) ethyl] -aminoXoxo) acetic; ((2- [1, 1'-biphenyl] -4-ylethyl) - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; (([1,1'-biphenyl] -3-ylmethyl) - {4 - [(dodecylamino) carbonii] benzyl] -amino) (oxo) acetic acid; (3- (benzyloxy)). {4 - [(dodecylamino) carbonyl] benzyl] anionic) (oxo) acetic acid; ([4- (Benzoylamino) benzyl] - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; N- (carboxycarbonyl) -N-. { 4 - [(Dodecylamino) carbonyl] benzyl} 3-phenyl-beta-alanine; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [4- (1, 2,3-thiadiazol-4-yl) benzyl] amino} (oxo) acetic; acid[. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-pentylbenzyl) amino] - (oxo) acetic; acid [. { 4 - [(dodecylamino) carbonyl] benzyi? I-phenylethyl) amino] (oxo) acetic; acid. { . { 4 - [(Dodecylamino) carbonyl] benzyl} [1 - (1 -naphthyl) ethyl] amino} - (oxo) acetic; (benzyl) {3- [(dodecylamino) carbonyl] benzyl] amino) (oxo) acetic acid; acid { . { 3- [(dodecylamino) carbonyl] benzyl} [4- (methylsulfonyl) benzyl] -aminoXoxo) acetic acid; {(3-cyanobenzyl). {3 - [(dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid; acid { . { 3 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] -aminooxo) acetic acid; [(4-chlorobenzyl) (3- {[[(4-pentyl-benzyl) amino] carbonyl] benzyl] -amino] (oxo) acetic acid; Oxo acid { [4- ( { [2- (2-thienyl) ethyl] amino.} Carbonyl) benzyl] [4- (trifluoromethyl) benzyl] amino} acetic; acid { benzyl [(3'-. {[[(2,2-diphenylethyl) amino] carbonyl] [1, 1'-biphenyl] -4-yl) methyl] -aminoXoxo) acetic acid; { (3-cyanobenzyl) [(3'-. {[[(2,2-diphenylethyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) methyl] amino} (oxo) acetic; acid { (4-chlorobenzyl) [(3'-. {[[(2,2-diphenylethyl) amino] carbonyl} [1, 1'-biphenyl] -4-yl) methyl] amino? Oxo) acetic acid; { [(3'- { [(2,2-diphenylethyl) amino] carbonyl.]. [1, 1 '-biphenyl] -4-yl) methyl] - [4- (trifluoromethyl) benzyl] Not me} (oxo) acetic; ((3-cyanobenzyl) { [3 '- ( { [2- (4-phenoxyphenyl) ethyl] amino.} carbonyl) - [1,1' -biphenyl] -4-yl] methyl.}. -amino) (oxo) acetic; Oxo acid { [3 '- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Carbonyl) [1,1'-b-phenyl] -4-yl] methyl} - [4- (trifluoromethyl) benzyl] amino} acetic; [(3-cyanobenzyl) ( {3'- [(octylamino) carbonyl] [1,1'-biphenyl] -4-yl} methyl) amino] (oxo) acetic acid; [(4-chlorobenzyl) (. {3, - [(octylamino) carbonyl] [1, 1'-biphenyl] -4-yl} methyl) amino] - (oxo) acetic acid; acid { ( {3 '- [(octylamino) carbonyl] [1,1'-biphenyl] -4-yl.} Methyl) [4- (trifluoromethyl) -benzyl] aminooxo) acetic acid; acid { (3-cyanobenzyl) [(3'-. {[[(3-phenylpropi aminocarbonyl] -biphenyl] -i-methylmethyl) -acetic acid [(3-cyanobenzyl) (. {3 '- [(dodecylamino) carbonyl]] 1, 1 '-biphenyl] -4-yl.} Methyl) -amino] - (oxo) acetic acid [(4-chlorobenzyl) (. {3' - [(dodecylamino) carbonyl] [1, 1 ' -biphenyl] -4-yl.} methyl) -amino] - (oxo) acetic acid; {. (. {3 '- [(dodecylamino) carbonyl] [1,1'-biphenyl] -4-yl. Methyl) [4- (trifluoromethyl) -benzyl] amino} - (oxo) acetic acid, benzyl [(3'-. {[[(4-pentylbenzyl) amino] carbonyl]. [1] , 1'-biphenyl] -4-yl) methyl] amino.} - - (oxo) acetic acid: {. (3-cyanobenzyl) [(3 - [(4-pentylbenzyl) amino] carbonyl]. [1, 1 '-bifenl] -4-yl) -methyl] amino.} - - (oxo) acetic acid: {(4-chlorobenzyl) [(3'-. {[[(4-pentylbenzyl) amino]] carbonyl.]. [1, 1 '-biphenyl] -4-yl) -methyl] aminooxoxo) acetic acid; Oxo acid { [(3'- { [(4-Pentylbenzyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl] amino} acetic; Oxo acid { [(3'- { [(4-phenylbutyl) amino] carbonyl]. [1, 1'-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl] amino} acetic; acid { (3-cyanobenzyl) [(3'-. {[[(2-mesitylethyl) amino] carbonyl] [1, 1'-biphenyl] -4-yl) -methyl] amino-oxo) acetic acid; acid { (4-chlorobenzyl) [(3'-. {[[(2-mesitylethyl) amino] carbonyl] - [1, 1'-biphenyl] -4-yl) -methyl] amino} (oxo) acetic; acid { [(3, - { F (2-mesitylethyl) amino] carbonyl.]. [1, r-biphenyl] -4-yl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; ((4-chlorobenzyl) { [3 '- ( { [2- (4-methoxyphenyl) ethyl] amino} carbonyl) - [1,1'-biphenyl] -4-yl] methyl} amino) (oxo) acetic; acid [. { 4 - [(dodecylamine) carbonyl] benzyl} (4-methoxybenzyl) amino] (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [4- (Methylsulfonyl) benzyl] -amino? Oxo acetic; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (4-methoxybenzyl) -amino] (oxo) acetic; acid { . { 3 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] -aminoXoxo) acetic; ( {4 - [(Dodecylamino) carbonyl] benzyl} { [6- (trifluoromethyl) -3-pyridinyl] methyl} -amino) (oxo) acetic acid; 4- [((carboxycarbonyl) { 3 - [(dodecylamino) carbonyl] benzyl] -amino) methyl] benzoic acid; ( {3 - [(Dodecylamino) carbonyl] benzyl} - {4- [hydroxy (oxide) amine] -benzyl} -amino) (oxo) acetic acid; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (2-fluorobenzyl) amino] - (oxo) acetic; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (2-pyridinylmethyl) -amino] (oxo) acetic; acid [. { 13 - [(dodecylamino) carbonyl] benzyl} (3-thienylmethyl) -amino] (oxo) acetic; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (4-hydroxybenzyl) -amino] (oxo) acetic acid; acid [. { 3 - [(dodecylamino) carbonyl] benzyl-4-phenoxybenzyl) amino] (oxo) acetic acid; ( {3 - [(Dodecylamino) carbonyl] benzyl] - { [6- (trifluoromethyl) -3-pyridinyl] methyl} -amino) (oxo) acetic acid; 3 - [((carboxycarbonyl) { 3 - [(dodecylamino) carbonyl] benzyl] -amino) methyl] benzoic acid; 5 - [((carboxycarbonyl) {3 - [(dodecylamino) carbonyl] benzyl} -amino) methyl-2-thio-phenocarboxylic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl} {4- [hydroxy (oxide) amine] -benzyl] -amino) - (oxo) acetic acid; ((1,3-benzodioxol-5-ylmethyl). {4 - [(dodecylamino) carbonyl] -benzyl} amino) - (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-fluorobenzyl) -amino] (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) -amino] (oxo) acetic; 4 - [((carboxycarbonyl). {4 - [(dodecylammonyl) carbonyl] -benzyl} amino) methyl] benzoic acid; 5 - [((carboxycarbonyl). {4 - [(dodecylamino) carbonyl] benzyl] -amino) methyl] -2-thiophene carboxylic acid; acid [. { 3 - [(dodecylamine) carbonyl] benz [} (2-thienylmethyl) amino] (oxo) acetic; acid [. { 4- [(dodecylamino) carbonyl] benzyl} (isopropyl) amino] (oxo) acetic; ((3,5-dichlorobenzyl) { 4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; [(3,5-dichlorobenzyl) (4. {[[(3,3-diphenylpropyl) amino] carbonyl} -benzyl) amino] (oxo) acetic acid; [(4- {[[2- [1, 1'-biphenyl-1-ethyl-1-aminolcarbonyl-benzyl-XS-dichlorobenzyl] -amino] (oxo) -acetic acid [(1,3-benzodioxol-5-ylmethyl)] (4- {[[2- [1, r-biphenyl] -4-ylethyl) amino] -carbonyl} benzyl) amino] (oxo) acetic acid (2,3-dihydro-1 H) -inden-1-yl {4 - [(dodecylamino) carbonyl] benzyl} -amino) (oxo) acetic acid; {2,3-dihydro-1 H-inden-1-yl [4- ( { [2- (4-phenoxyphenyl) ethylamino.}. -carbonyl) -benzyl-oxinoXoxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-pyridinylmethyl) amino] - (oxo) acetic; ([4- (dimethylamino) benzyl] - {4 - [(dodecylamino) carboni [] benzyl] - amino) (oxo) acetic acid; acid [. { 4- [(dodecylamino) carbonyl] benzyl-3-pyridinylmethyl) amino] - (oxo) acetic; ((4-cyanobenzyl) - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid [. { 4 - [(dodecylamino) carbonyl] benzyl], 3-thiazol-2-ylmethyl) amino] (oxo) acetic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl} { [2- (4-morpholinyl) -1, 3-thiazol-5-yl] methyl} -amino) (oxo) acetic acid; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (4-pyridinylmethyl) amino] - (oxo) acetic; acid [. { 3 - [(dodecylamine) carbonyl] benzyl} (3-pyridinylmethyl) amino] - (oxo) acetic; acid [. { 3 - [(dodecylamino) carbonyl] benzyl} (3-hydroxybenzyl) amino] - (oxo) acetic; ((4-cyanobenzyl). {3- [3- ((dodecylamino) carbonyl] benzyl} amino) - (oxo) acetic acid; acid [. { 3- [(dodecylamino) carbonyl] benzyl} (1,3-thiazol-2-ylmethyl) -amino] (oxo) acetic acid; ( {3 - [(Dodecylamino) carbonyl] benzyl} { [2- (4-morpholinyl) -1, 3-thiazol-5-yl] methyl} -amino) (oxo) acetic acid; ((1,3-benzodioxol-5-ylmethyl) - {. 3- [(dodecylamino) carbonyl] -benzyl} amino) - (oxo) acetic acid; acid [. { 4- [(dodecylamino) carbonyl] benzyl] 2-thienylmethyl) amino] (oxo) acetic; acid [. { 4 - [(dodecylamine) carbonyl] benzyl} (2-pyridinylmethyl) amino] - (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (3-thienylmethyl) amino] (oxo) acetic; acid [. { 4 - [(dodecylamino) carbonyl] benzyi? 4-hydroxybenzyl) -amino] (oxo) acetic acid; 3 - [((carboxycarbonyl) {4 - [(dodecylamino) carbonyl] benzyl] -amino) methyl] benzoic acid [cyclopentyl (5 - [(dodecylamino) sulfonyl] -2-thienyl] methyl] amino] - (oxo) acetic acid [benzyl (. {5 - [(dodecylamine) sulfonyl] -2-thienyl} methyl) amino] (oxo) acetic acid; (( {5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl). {3- [hydroxy (oxide) -amino] -benzyl] amino) (oxo) acetic; [( { 5 - [(Dodecylamino) sulfonyl] -2-thylphenyl} methyl) (4-methoxybenzyl) amino] - (oxo) acetic acid; [( { 5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) (2-fluorobenzyl) amino] (oxo) acetic acid; acid { ( {5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) [4- (methylsulfonyl) -benzyl] -aminooxo) acetic acid; [( { 5 - [(Dodecylamino) sulfonyl] -2-thienyl] methyl) (4-phenoxybenzyl) -amino] (oxo) acetic acid; 4 - [(carboxycarbonyl) (. {5 - [(dodecylamino) sulfonyl] -2-thienyl} -methyl) amino] -methyl} benzoic; (( {5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) { [6- (trifluoromethyl) -3-pyridinyl] -methyl} amino) (oxo) acetic acid; acid { ( {5 - [(Dodecylamino) sulfonyl] -2-thienyl} methyl) [3- (trifluoromethyl) -benzyl] amino} - (oxo) acetic; acid { [(3-chlorobenzyl) (. {5 - [(dodecylamino) sulfonyl] -2-thienyl} methyl) -amino] (oxo) acetic acid; [(5- {[[3,3-diphenylpropyl) amino] sulfonyl} -2-thienyl) methyl] [3- (trifluoromethyl) benzyl] amino]} (oxo) acetic; acid { (3-chlorobenzyl) [(5- {[[3,3-diphenylpropyl) amino] sulfonyl} -2-thienyl) methyl] -aminoXoxo) acetic acid; Oxo acid { . { [5- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Sulfonyl) -2-thienyl] methyl} - [3- (trifluoromethyl) benzyl] amino} acetic; ((3-chlorobenzyl) { [5- ( { [2- (4-phenoxyphenyl) ethyl] amino} sulfosyl) -2-thienyl] -methyl} amino) (oxo) acetic acid; acid { [(5-. {[[2- [1, 1'-biphenyiO ^ -ethylamino-sulfonyl-J-thieni-methyl] ^ - (trifluoromethyl) -benzyl] -aminoXoxo) -acetic acid (( { 1 - [(cyclohexylamino) carbonyl] -4-pyridinyl.} methyl). {4 - [(dodecylamino) -carbonyl] benzyl} amino) (oxo) acetic acid ([(1- {[4- (dimethylamino ) anilino] carbonyl.] -4-piperidinyl) methyl]. {4 - [(dodecyl-amino) carbonyl] benzyl} amino) (oxo) acetic acid; {. { 4 - [(dodecylamino carbonyl] benzyl.}. [(1-hexanoyl-4-piperidinyl) methyl] -amino.} - (oxo) acetic acid (. {4 - [(dodecylamine) carbonyl] benzyl} { [1- (3-iodobenzoyl) -4-piperidinyl] methyl} -amino) (oxo) acetic acid; {. { 4- [(dodecylamine) carbonyl] benzyl}. [(1- {(2 E) -3- [3- (trifluoromethyl) phenyl] -2-propenoyl} -4-piperidinyl) methyl] aminoXoxo) acetic; ( {4 - [(Dodecylamino) carbonyl] benzyl} { [1- (2-quinoxalinylcarbonyl) -4-piperidinyl] -methyl} amino) (oxo) acetic acid; [( { 1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinyl} methyl) (4. {[[(4-phenoxybenzyl) amino] carbonyl} benzyl) amino] (oxo) acetic; acid [. { [1- (3-iodobenzoyl) -4-piperidinyl] methyl} (4-. {[[(4-phenoxybenzyl) amino] -carbonyl} benzyl) amino] (oxo) acetic; Oxo acid { (4- { [(4-phenoxybenzyl) amino] carbonyl] benzyl) [(1- {(2 E) -3- [3- (trifluoromethyl) phenyl] -2- propenoyl) -4-piperidinyl) methyl] amino} acetic; acid { . { 4- [(dodecylamino) carbonyl] phenyl} [2 - (? -carbonylcarbonyl) benzyl] -aminoxoxo) acetic; [[4- ( { [2- (1, 1'-b-phenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] - (4-iodobenzyl) -amino] (oxo) ) acetic; [(2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-iodobenzyl) amino] - (oxo) acetic acid; acid [. { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl-4-iodobenzyl) -amino] (oxo) acetic acid; [(2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-iodobenzyl) amino] - (oxo) acetic acid; ((4-iodobenzyl) { [4 '- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1, 1'-biphenyl-4-yl] methyl}. amino) (oxo) acetic; acid { [2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Carbonyl) benzyl] - [(4'-fluoro-1,1-b-phenyl-3-yl) methyl] amino} (oxo) acetic; acid { [4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino.} Carbonyl) -2-bromobenzyl] - [(4'-fluoro-1,1 '-biphenyl-) 3-yl) methyl] amino} (oxo) acetic; acid { (2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl, benzyl) [(4'-fluoro-1,1 '-biphenyl-3-yl) methyl] amino} (oxo) acetic; acid { [2,6-dibromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino.} Carbonyl) -benzyl] [(4, -fluoro-1, 1'-biphenyl-3-yl) methyl] aminoXoxo) acetic; acid { [4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino.} Carbonyl) -2,6-dibromobenzyl] [(4'-fluoro-1, 1-bifen L-3-yl) methyl] aminoXoxo) acetic; acid { (2,6-dibromo-4- { [(4-pentylbenzyl) amino] carbonyl, benzyl) [(4, -fluoro-1, 1'-biphenyl-3-yl) methyl] amino} (oxo) acetic; acid { . { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [(4'-fluoro-1, 1'-biphenyl-3-yl) methyl] amino} (oxo) acetic; ([(4, -fluoro-1, 1'-biphenyl-3-yl) methyl] { [4'- ( { [2- (4-phenoxyphenyl) ethyl] amino.}. -carbonyl) -1, 1 '-biphenyl-4-yl.}. Methyl.} Amino) (oxo) acetic; acid { ( { 4 '- [(dodecylamino) carbonyl] -1, 1'-biphenyl-4-yl.} Met.l) [(4, -fluoro-1, 1'-b-phenyl-3-p! l) metyr] amino} (oxo) acetic; acid { (2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [2- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [2- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; oxo [4 '- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -1, 1' -biphenyl-4-yl] methyl} - [2- (trifluoromethoxy) benzyl] amino} acetic; acid { ( { 4, - [(dodecylamine) carbonyl] -1 I'-biphenyl-4-yl.] Methyl) [2- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; [[2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (3-phenoxy-benzyl) amino] (oxo) acetic acid; [[4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino.} carbonyl] -2-bromobenzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid; [(2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (3-phenoxybenzyl) -amino] (oxo) acetic acid; [[2,6-dibromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) -benzyl] (3-phenoxybenzyl) amino] (oxo) acetic acid; [[4- ( { [2- (1,1'-biphenyl-4-yl) ethyl] amino] carbonyl) -2,6-dibromobenzyl] (3-phenoxy-benzyl) amino] (oxo) acetic; [(2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (3-phenoxybenzyl) -amino] (oxo) acetic acid; acid [. { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} (3-phenoxybenzyl) amino] (oxo) acetic; oxo ((3-phenoxybenzyl) { [4 '- ( { [2- (4-phenoxyphenyl) ethyl] amino.}. -carbonyl) -1, 1'-b-phenyl-4-yl] methyl.}. amino) acetic; Oxo [[(4'-. {[[(4-pentylbenzyl) amino] carbonyl] -1, 1, -biphenyl-4-yl) methyl] (3-phenoxybenzyl) amino] acetic acid; [(. {4 '- [(dodecylamino) carbonyl] -1, 1'-biphenyl-4-ii.} Methyl) (3-phenoxybenzyl) amino] (oxo) acetic acid; [[2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (2-iodobenzyl) amino] (oxo) acetic acid; [[4- ( { [2- (1, 1, -biphenyl-4-yl) ethyl] amino.} carbonyl) -2-bromobenzyl] - (2-iodobenzyl) -amino] (oxo) acetic acid; [(2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (2-iodobenzyl) amino] (oxo) acetic acid; acid [. { 2- bromo-4 - [(dodecylamino) carbonyl] benzyi? 2-iodobenzyl) amino] (oxo) acetic; ([2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] - { [2 '- (trifluoromethylene) -1, 1 β-phenyl-4-yl] methyl.} amino) (oxo) acetic; ([4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] - { [2 '- (trifluoromethyl) ) -1, 1'-biphenyl-4-yl] methyl} amino) (oxo) acetic acid ((2-bromo-4- {[[4-pentylbenzyl) amino] carbonyl} benzyl) {. [2 '- (trifluoromethyl) -1, 1'-biphenyl-4-yl] methyl} amino) (oxo) acetic acid ((2-bromo-4-. {[[(4-pentylbenzyl)] amino) carbonyl, benzyl) { [2 '- (trifluoromethyl) -1, 1'-biphenyl-4-yl] methyl} amino) (oxo) acetic acid (. {2-bromine) -4- [(dodecylamine) carbonyl] benzyl, {. [2 '- (trifluoromethyl) -1, 1'-biphenyl-4-yl] methyl} amino) (oxo) acetic acid; [4- ( { [2- (1, 1 '-biphenyl-4-yl) ethyl] amino.} Carbonyl) -2,6-dibromobenzyl] { [2' - (trifluoromethyl) -1, 1 '-biphenyl-4-yl] methyl.} Amino) (oxo) acetic acid ((2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl). { [2'- (trifluoromethyl-l .l'-biphenyl] -illmethylJaminoJioxo) acetic acid (. {2,6-dibromo-4- [(dodecylamino) carbonyl] benzyl} { [2, - (trifluoromethyl) -1, 1 ' -biphenyl-4-yl] methyl} amino) (oxo) acetic; (( { 4 '- [(dodecylamino) carbonyl] -1, 1'-b-phenyl-4-IJmethyl-XP'-trifluoromethyl-1, 1'-biphenyl-amino-oxo) -acetic acid [[4-] ( { [2- (1, 1 '-biphenyl-4-yl) ethyl] amino} carbonyl) -2-bromobenzyl] (1,1' -biphenyl-2-ylmethyl) amino] (oxo) ) acetic acid [(1,1'-biphenyl-2-ylmethyl) (2-bromo-4- ({((4-pentylbenzyl) amino] -carbonyl} benzyl) -amino] (oxo) acetic acid; ((1,1 '-biphenyl-2-ylmethyl) {2-bromo-4 - [(dodecylamine) carbonyl] -benzyl} amino) (oxo) acetic acid; {. (1, rb Phenyl-2-ylmethyl) [2,6-dibromo-4- ( { [2- (4-phenoxyphenyl) ethyl] -amino} carbonyl) benzyl] amino} (oxo) acetic; [[4 - ([2- (1, 1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2,6-dibromobenzyl] (1,1'-biphenyl-2-methyl) amino] (oxo) acetic acid [(1,1'-biphenyl-2-ylmethyl) (2,6-dibromo-4-. {[[(4-pentylbenzyl) -amino] carbonyl} benzyl) amino] (oxo) acetic acid ((1, -biphenyl-2-ylmethyl). {2,6-dibromo-4 - [(dodecylamino) -carbonyl] benzyl} amino) (oxo) acetic acid; -bromo-4- { [ (4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethoxy) -benzyl] -aminoxoxo) acetic; acid { . { 2-bromo-4- [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethoxy) benzyl] amino} (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethoxy) benzyl] amino} (oxo) acetic; acid { (2-bromo-4- { [(4-pentylbenzyl) amino] carbonyl} benzyl) [3- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; acid { . { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethoxy) benzyl] amino} - (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl] benzyl) [3- (trifluoromethoxy) -benzyl] aminooxo) acetic acid; acid { . { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethoxy) benzyl] -amino? Oxo) acetic; acid { (. {4 '- [(dodecylamino) carbonyl] -1,' r-biphenyl-4-yl.} Methyl) [3- (trifluoromethoxy) -benzyl] amino} (oxo) acetic; [[2-bromo-4- ( { [2- (4-phenoxyphenyl) ethyl] amino} carbonyl) benzyl] (4-phenoxy-benzyl) amino] (oxo) acetic acid; [[4- ( { [2- (1,1'-biphenyl-4-y!) ethyl] amino.} carbonyl) -2-bromobenzyl] - (4-phenoxy-benzyl) amino] (oxo) ) acetic; [(2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) (4-phenoxybenzyl) -amino] (oxo) acetic acid; acid [. { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} (4-phenoxybenzyl) amino] (oxo) acetic; [[4- ( { [2- (1, 1'-biphenyl-4-yl) ethyl] amino} carbonyl) -2,6-dibromobenzyl] (4-phenoxy-benzyl) amino] (oxo) ) acetic; [(2,6-dibromo-4-. {[[4-pentylbenzyl) amino] carbonyl} benzyl) (4-phenoxybenzyl) -amino] (oxo) acetic acid; acid { [4- ( { [2- (1, 1, -biphenyl-4-yl) ethyl] amino.} Carbonyl) -2-bromobenzyl] [4- (trifluoromethyl) benzyl] aminooxo) acetic; acid { (2-bromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) -benzyl] -aminoXoxo) acetic acid; acid { . { 2-bromo-4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { (2,6-dibromo-4-. {[[(4-pentylbenzyl) amino] carbonyl} benzyl) [4- (trifluoromethyl] -benzyl] amino} (oxo) acetic; acid { . { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic; Oxo acid { [(4'- { [(4-Pentylbenzyl) amino] carbonyl] -1, 1'-biphenyl-4-yl] methyl] [4- (trifluoromethyl) benzyl] amino} acetic acid; acid { {2-bromo-4 - [(dodecylamino) carbonyl] benzyl} - [3- (trifluoromethyl) benzyl] -amino-oxo) acetic acid; acid { . { 2,6-dibromo-4 - [(dodecylamino) carbonyl] benzyl} [3- (trifluoromethyl) benzyl] -aminoXoxo) acetic; Oxo acid { [(4'- { [(4-Pentylbenzyl) amino] carbonyl] -1, 1'-biphenyl-4-yl) methyl] [3- (trifluoromethyl) benzyl] amino} acetic; acid { (4-dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1 - (methylamino) glucitol) acid. { (4-dibenzo [b, d] furan-4-ylbenzyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; ({4- [(dodecylamino) carbonyl] benzyl}. {- 1- [4- (trifluoromethyl) phenyl] -ethyl} amino) - (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1 - (methylamino) glucitol) of (. {4 - [(dodecylamide) carbonyl] benzyl]. (trifluoromethyl) phenyl] ethyl.}. amino) - (oxo) acetic; acid { ( {4 '- [(octylamino) carbonyl] -1, 1, -biphenl-4-yl}. Methyl) [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; Oxo acid { (4-tetradec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] amino} acetic; acid { (4-dodec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { . { 4- [(dodecylamino) carbonyl] benzyl} [4- (trifluoromethyl) phenyl] amino} (oxo) acetic; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (2-methoxyphenyl) amino- (oxo) acetic; ((1,2-diphenylethyl) { 4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; N- (carboxycarbonyl) -N-. { 4 - [(Dodecylamino) carbonyl] benzyl} - phenylalanine; acid [. { 4 - [(dodecylamino) carbonyl] benzyl-3-phenoxyphenyl) amino] - (oxo) acetic; acid [. { 4 - [(dodecylamino) carbonyl] benzyl] 2-isopropoxyphenyl) -amino] (oxo) acetic acid; acid [. { 4 - [(dodecylamino) carbonyl] benzyl? 4-iodophenyl) amino] (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [3-fluoro-4- (trifluoromethyl) benzyl] -amino-oxo) acetic acid; ((3-chloro-2-methylphenyl). {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; 4 '- ((carboxycarbonyl). {4- [(dodecylamino) carbonyl] benzyl] -amino) -1,1-b-phenyl-2-carboxylic acid; ((2,4-dichlorobenzyl). {4 - [(dodecylamino) carbonyl] benzyl} amino) (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyi? I-phenylpropyl) amino] - (oxo) acetic; ([2- (4-chlorophenyl) propyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid [. { 4 - [(Dodecylamino) carbonyl] benzyl} (4-isopropoxyphenyl) -amino] (oxo) acetic; ([4- (benzyloxy) phenyl] - {4 - [(dodecylamino) carbonyl] benzyl] -amino) - (oxo) acetic acid; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [2- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid [. { 4 - [(dodecylamino) carbonyl] benzyl] 2-methoxybenzyl) amino] - (oxo) acetic; ([(1 R) -1- (4-chlorophenyl) ethyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ((3,4-Dichloxybenzyl) { 4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ((1-benzothien-3-ylmethyl). {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ([2- (2,6-Dichlorophenyl) ethyl] - {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; ( {4 - [(Dodecylamino) carbonyl] benzyl] -. {2- [3- (trifluoromethyl) phenyl] -eti !.} amino) (oxo) acetic acid; acid { . { 4 - [(dodecylamino) carbonyl] benzyl} [2- (3-fluorophenyl) ethyl] -amino} (oxo) acetic; ([(1S) -1- (4-chlorophenyl) ethyl]. {4 - [(dodecylamino) carbonyl] benzyl] -amino) (oxo) acetic acid; acid { . { 4- [(dodecylamino) carbonyl] benzyl} [(1S) -1-phenylethyl] amino} - (oxo) acetic; acid { . { 4 - [(Dodecylamino) carbonyl] benzyl} [(1 R) -1-phenylethyl] amino} (oxo) acetic; ([3- (benzyloxy) phenyl] - {4 - [(dodecylamino) carbonyl] benzyl] amino) - (oxo) acetic acid; N- (carboxycarbonyl) -N-. { 4 - [(Dodecylamino) carbonyl] benzyl} -D-phenylalanine; acid { . { 4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 4 - [(dodecylamino) carbonyl] phenyl} [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic; Oxo acid { . { 1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) of oxo acid. { . { 1- [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; ([(2-Butyl-1-benzofuran-3-yl) methyl]. {4 - [(dodecylamino) -carbonyl] benzyl} amino) (oxo) acetic acid; acid { (1- { 4 - [(dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) -benzyl] amino) - (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1 - (methylamino) glucitol) acid. { (l- { 4 - [(Dodecylamino) carbonyl] phenyl} ethyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { (4-. {[[(4-octylphenyl) amino] carbonyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; acid { (3-chlorobenzyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { (3-chlorobenzyl) [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] -amino) (oxo) acetic acid; acid { . { cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (tridecanoyl-amino) benzyl] -amino} (oxo) acetic; oxo ([4- (trifluoromethyl) benzyl] - {. [4- (3-undecyl-1,4-oxadiazol-5-yl) -1-naphthyl] -methyl] -amino) acetic acid; N-methyl-D-glucamine salt (Le. 1-deoxy-1- (methylamino) -glucitol) of oxo ([4- (trifluoromethyl) benzyl] { [4- (3-undecyl-1,2) , 4-oxadiazol-5-yl) -1-naphthyl] -methyl} amino) acetic acid; acid { . { cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1 - (methyl-amino) glucitol) acid. { . { cyclopentyl [4- (trifluoromethyl) phenyl] methyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; acid { (4-dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl] benzyl] -aminoXoxo) acetic acid; N-methyl-D-glucamine salt (Le. 1-deoxy-1- (methylamino) glucitol) acid. { (4-dibenzo [b, d] furan-4-ylphenyl) [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { [4- (octyloxy) benzyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { [4- (octyloxy) benzyl] [4- (trifluoromethyl) benzyl] aminooxo) acetic; [[2- (3-chlorophenyl) ethyl] (4-dec-1-ynylbenzyl) amino] (oxo) acetic acid; ([2- (3-chlorophenyl) ethyl] - {4 - [(1Z) -dec-1-enyl] -benzyl] -amino) (oxo) -acetic acid; acid. { [2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] aminooxoxo) acetic acid; N-methyl-D-gucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { [2- (3-chlorophenyl) ethyl] [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] amino} - (oxo) acetic; Oxo acid { . { (1 R) -1- [4- (Trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) -glucitol) of oxo acid. { . { (1 R) -1 - [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzylamino} acetic; Oxo acid { [4- (trifluoromethyl) phenyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; Oxo acid { [4- (trifluoromethyl) phenyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic acid, N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) of oxo acid. { . { (1S) -1- [4- (Trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) -glucitol) of oxo acid. { . { (1 S) -1- [4 (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} acetic; [(3-chlorobenzyl) (4-dec-1-ynylbenzyl) amino] (oxo) acetic acid; N-methyl-D-glucamine salt (Le. 1-deoxy-1- (methylamino) -glucitol) of [(3-chlorobenzyl) (4-dec-1-ynylbenzyl) amino] (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) gIucitol) of [[2- (3-chlorophenyl) ethyl] (4-oct-1-ynylbenzyl) amino] (oxo) acetic acid; acid { (4-dec-1-ynylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic; ((4-dec-1-ynylbenzyl). {l- [4- (trifluoromethyl) phenyl] ethyl} aminooxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-l- (methylamino) glucitol) of ((4-dec-1-ynylbenzyl) - {. 1- [4- (trifluoromethyl) phenyl] ethyl]. amino) (oxo) acetic; acid { . { 1-methyl-1 - [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] amino? Oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 1-methyl-1 - [4- (trifluoromethyl) phenyl] ethyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] aminooxo) acetic acid; acid { [2- (3-chlorophenyl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -aminoXoxo) acetic acid; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { [2- (3-chlorophenyl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] amino} (oxo) acetic; acid { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) -benzyl] amino} - (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { . { [4- (dodecyloxy) -1-naphthyl] methyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { [4- (dodecyloxy) -1-naphthyl] metii} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; [(4-bromobenzyl) (4-oct-1-ynylbenzyl) amino] (oxo) acetic acid; acid [. { 4 - [(dodecylamino) carbonyl] benzyl] 2-hydroxy-1-phenylethyl) -amino] (oxo) acetic acid; ((4-dec-1-ynylbenzyl). {1-methyl-1 - [4- (trifluoromethyl) phenyl] ethyl} -amino) (oxo) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1 - (methylamino) glucitol) of ((4-dec-1-innylbenzyl). {1-methyl-1 - [4- (trifluoromethyl) phenyl} ] ethyl.} amino) (oxo) acetic; Oxo acid { 4 - [(9Z) -tetradec-9-enoylamino] benzyl} [4- (trifluoromethyl) -benzyl] amino} acetic; acid { [4-dec-1-ynylbenzyl] [4- (trifluoromethyl] benzyl] amino} (oxo) acetic; oxo [4- (trifluoromethyl) benzyl] [3- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) of oxo acid. { [4- (trifluoromethyl) benzyl] [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} acetic; acid { (4-dodecylbenzyl) [4- (trifluoromethyl] benzyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { (4-dodecylbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { [4- ( { [(2-Butyl-1-benzofuran-3-yl) methyl] amino.} Carbonyl) benzyl] - [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { (4- { [4- (benzyloxy) benzoyl] amino.} Benzyl) [4- (trifluoromethyl) -benzyl] amino} - (oxo) acetic; acid { (3,5-dichlorobenzyl) [4- (tridecanelamino) benzyl] amino-oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { (3,5-dichlorobenzyl) [4- (tridekanoylamino) benzyl] aminooxido) acetic acid; acid { . { 4 - [(4-octylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; Oxo acid { [4- (trifluoromethyl) benzyl] [4- (5-undecyl-1,4-oxadiazol-3-yl) benzyl] amino} acetic; N-methyl-D-glucamine salt (Le. 1-deoxy-1- (methylaminoglucitol) of oxo acid { [4- (trifluoromethyl) benzyl] [4- (5-undecyl-1, 2,4-oxadiazole -3-yl) benzyl] amino.} Acetic acid, {. {4- [2- (4-octylphenyl) ethyl} benzyl} [4- (trifluoromethyl) benzyl] amino}. - (oxo) acetic acid: {. (4- {[[4- (heptyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -aminooxo) acetic acid; acid { . { 4 - [(4-Butylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { . { 4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (Trifluoromethyl) benzyl] -amino-oxo) acetic acid; N-methyl-D-glucamine salt (Le. 1-deoxy-1- (methylamino) glucitol) acid. { . { 4 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] aminoXoxo) acetic; Oxo acid { (4- { [4- (Pentyloxy) phenyl] ethynyl}. Benzyl) [4- (trifluoromethyl) -benzyl] amino} acetic; Oxo acid { . { 4 - [(4-propylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} acetic; [[2- (3-chlorophenyl) ethyl] (4-dodec-1-ynylbenzyl) amino] (oxo) acetic acid; N- methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol) of [[2- (3-chlorophenyl) ethyl] (4-dodec-1-ynylbenzyl) amino] (oxo) acetic acid; acid { (4-oct-1-nilbenzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { [4- (11-hydroxyundec-1-ynyl) benzyl] [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic acid; acid { [4- (11-methoxy-11-oxoundec-1-ynyl) benzyl] [4- (trifluoromethyl) -benzyl] amino-oxo) acetic acid; 11- [4- ( { (carboxycarbonyl) [4- (trifluoromethyl) benzyl] amino] -methyl) phenyl] undec-10 -noic acid; acid { (4- { [4- (benzyloxy) phenyl] ethynyl} benzyl) [4- (trifluoromethyl) benzyl] -aminooxoxo) acetic acid; acid { (4-. {2- 2- [4- (heptyloxy) phenyl] ethyl} benzyl) [4- (trifluoromethyl) benzyl] -aminooxo) acetic acid; acid { . { 4- [2- (4-Butylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { . { 4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 4- [2- (4-hexylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] amino? Oxo) acetic; Oxo acid { (4-2- [4- (Pentyloxy) phenyl] ethyl} benzyl) [4- (trifluoromethyl) -benzyl] amino} acetic; Oxo acid { . { 4- [2- (4-propylphenyl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} acetic; 11- [4- ( { (carboxycarbonyl) [4- (trifluoromethyl) benzyl] amino} -methyl) phenyl] undecanoic acid; acid { [4- (11-hydroxy-indecyl) -benzyl] [4- (trifluoromethyl) -benzyl] -amino} - (oxo) acetic; acid { (4-dodec-1-ynylbenzyl) [4- (trifluoromethyl) phenyl] amino} (oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-l- (methylamino) glucitol) acid. { (4-dodec-1-ynylbenzyl) [4- (trifluoromethyl) phenyl] amine} (oxo) acetic; oxo ([4- (trifluoromethyl) benzyl]. {4- [2- (3-undecyl-1, 2,4-oxadiazol-5-yl) ethyl] benzyl] -amino) acetic acid; N-methyl-D-glucamine salt (ie 1-deoxy-1- (methylamino) glucitol) of oxo ([4- (trifluoromethyl) benzyl]. {4- [2- (3-undecyl-1 , 2,4-oxadiazol-5-yl) ethyl] benzyl] -amino) acetic acid; acid { . { 4- [2- (3-octyl-1, 2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] aminoXoxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1 - (methylamino) glucitol) acid. { . { 4- [2- (3-octyl-1, 2,4-oxadiazol-5-yl) ethyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { . { 4 - [(4-octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] -aminooxo) acetic acid; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { 4 - [(4-octylbenzoyl) amino] benzyl} [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; Oxo acid { (1-Trdecanoylpiperidin-4-yl) methyl] [4- (trifluoromethyl] -benzyl] amino} acetic; acid { . { [1- (4-octylbenzoyl) piperidin-4-yl] methyl} [4- (trifluoromethyl) -benzyl] amino? Oxo) acetic; N-methyl-D-glucamine salt (i.e. 1-deoxy-1- (methylamino) glucitol) acid. { . { [1- (4-octylbenzoyl) piperidin-4-yl] methyl} [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { [(3-dec-1-ynyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; acid { [(3-dodec-1-ynyl-1-benzofuran-5-yl) methyl] [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; Oxo acid { ( { 3 - [(4-propylphenyl) ethynyl] -1-benzofuran-5-yl}. Methyl) [4- (trifluoromethyl) -benzyl-amino} acetic; [(4-dodec-1-ynylbenzyl) (4-fluorobenzyl) amino] (oxo) acetic acid; [bis (4-oct-1-ynylbenzyl) amino] (oxo) acetic acid; acid { [(6-dodec-1 ~ inylpyridin-3-yl) methyl] [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { (3-dodec-1-benzyl) [4- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { [2- (2-fluorophenyl) ethyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; acid { [2- (2-fluorophenyl) ethyl] [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino-oxo) acetic acid; acid { [2- (2-fluorophenyl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic; acid { [2- (3,4-dichlorophenyl) ethyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino-oxo) acetic acid; acid { [2- (3,4-Dichlorophenyl) ethyl] [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino-oxo) acetic acid; acid { [2- (3,4-dichlorophenyl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; acid { [2- (1, 1 '-biphenyl-4-yl) ethyl] [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; acid { [2- (1, 1 '-biphenyl-4-yl) ethyl] [3- (3-undecyl-, 2,4-oxadiazol-5-yl) -benzyl] amino-oxo) acetic acid; acid { [2- (1, 1 '-biphenyl-4-yl) ethyl] [4- (3-octyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic; Oxo acid { 5,6,7,8-tetrahydronaphthalen-1 -yl [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} acetic; Oxo acid { 5,6,7,8-tetrahydronaphthalen-1 -yl [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} acetic; [[4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] (5,6,7,8-tetrahydro-naphthalen-1-yl) amino] (oxo) acetic acid; acid { (1,1'-biphenyl-3-ylmethyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino-oxo) acetic acid; acid { (1,1 '-biphenyl-3-ylmethyl) [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic; acid { (1,1 '-biphenyl-3-ylmethyl) [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic; acid { (1-benzothien-3-ylmethyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino-oxo) acetic acid; acid { (1-benzothien-3-ylmethyl) [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] aminooxo) acetic acid; acid { (1-benzothien-3-ylmethyl) [4- (3-octyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic; Oxo acid { [2- (trifluoromethyl) benzyl] [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] amino} acetic; Oxo acid { [2- (trifluoromethyl] benzyl] [3- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] amino} acetic; acid { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [2- (trifluoromethyl) -benzyl] amino} (oxo) acetic; Oxo acid { [3- (trifluoromethyl) benzyl] [4- (3-undecyl-1,4-oxadiazol-5-yl) benzyl] -amino} acetic; Oxo acid { [3- (trifluoromethyl) benzyl] [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} acetic; acid { [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] [3- (trifluoromethyl) -benzyl] -aminoXoxo) acetic; acid { (2-methoxybenzyl) [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -amino} (oxo) acetic acid. { (2-methoxybenzyl) [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] -aminoXoxo) acetic acid; acid { [2- (methoxy-benzyl) [4- (3-octyl-1, 2,4-oxadiazol-5-yl) -benzyl] -amino-oxo) -acetic acid; Oxo acid { . { 4 - [(trifluoromethyl) sulfonyl] benzyl} [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} acetic; Oxo acid { . { 4 - [(trifluoromethyl) sulfonyl] benzyl} [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} acetic; ([4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] - {4 - [(trifluoromethyl) -sulfonyl] benzyl] amino) (oxo) acetic acid; acid { 1,3-benzodioxol-5-yl [4- (3-undecyl-1, 2,4-oxadiazol-5-yl) benzyl] aminooxo) acetic acid; acid { 1,3-benzodioxol-5-yl [3- (3-undecyl-1, 2,4-oxadiazol-5-yl) -benzyl] amino} (oxo) acetic; acid { 1,3-benzodioxol-5-yl [4- (3-octyl-1, 2,4-oxadiazol-5-yl) benzyl] -aminoXoxo) acetic acid; acid { [(4-dodec-1-ynyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] -aminoXoxo) acetic; acid { [(4-dec-1-ynyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; acid { [(4-dec-1-ynyl-1-naphthyl) methyl] [4- (trifluoromethyl) benzyl] amino} - (oxo) acetic; Oxo acid { [4- (trifluoromethyl) benzyl] [4- (4-undecyl-1,3-thiazol-2-yl) -benzyl] acetic acid; acid { (4-dec-1-nylbenzyl) [2- (2-fluorophenyl) ethyl] amino} (oxo) acetic; acid { (4-dodec-1-ynylbenzyl) [2- (2-fluorophenyl) ethyl] amino} (oxo) acetic; acid { . { [4- (dodecyloxy) -1-naphthyl] methyl} [2- (2-fluorophenyl) ethyl] amino} - (oxo) acetic; acid { [2- (2-fluorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic; acid { (4-dec-1- inylbenzyl) [2- (trifluoromethyl) benzyl] aminooxoxo) acetic acid; acid { (4-dodec-1-inylbenzyl) [2- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { . { [4- (dodecyloxy) -1-naphthyl] methyl} [2- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { [4- (octyloxy) benzyl] [2- (trifluoromethyl) benzyl] amino} (oxo) acetic; acid { (4-dec-1-ynylbenzyl) [2- (3,4-dichlorophenyl) ethyl] amino} (oxo) acetic; [[2- (3,4-Dichlorophenyl) ethyl] (4-dodec-1-ynylbenzyl) amino] (oxo) acetic acid; ([2- (3,4-Dichlorophenyl) ethyl] - {[[4- (dodecyloxy) -1-naphthyl] methyl} -amino) (oxo) acetic acid; acid { [2- (3,4-Dichlorophenyl) ethyl] [4- (octyloxy) benzyl] amino} (oxo) acetic; ( {4 - [(4-hexylphenyl) ethynyl] benzyl}. {1-methyl-1 - [4- (trifluoromethyl) -phenyl} ethyl} amino) (oxo) acetic acid; acid { [4- (5-cyclohexylpent-1-ynyl) benzyl] [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { . { 3 - [(4-hexylphenyl) ethynyl] benzyl} [4- (trifluoromethyl) benzyl] -amino} (oxo) acetic; acid { [4- (4-ethyl-3-hydroxyoct-1-ynyl) -benzyl] [4- (trifluoromethyl) -benzyl] -amino-oxo) -acetic acid; acid { (2-dec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] aminoXoxo) acetic; salt of L-lysine acid. { (4-dec-1-n-benzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; trometamine salt (i.e. (2-amino-2-hydroxymethyl) -1,3-propanediol) of acid. { (4-dec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] aminooxo) acetic acid; salt of L-arginine acid. { (4-dec-1-inylbenzyl) [4- (trifluoromethyl) -benzyl] amino} (oxo) acetic; . { (4-dec-1-ynylbenzyl) [4- (trifluoromethyl) benzyl] aminooxo) sodium acetate.
17. The use as claimed in any of the preceding claims, wherein the cardiovascular disorder is heart failure.
18. - The use as claimed in any of the preceding claims, wherein the cardiovascular disorder is chronic heart failure.
19. The use as claimed in any of the preceding claims, wherein the cardiovascular disorder is endothelial dysfunction.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04100778.2 | 2004-02-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06009777A true MXPA06009777A (en) | 2007-04-10 |
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