HRP20040426A2 - Oligopeptides and compositions containing them as cathepsin s inhibitors - Google Patents

Oligopeptides and compositions containing them as cathepsin s inhibitors Download PDF

Info

Publication number: HRP20040426A2
Authority: HR; Croatia
Prior art keywords: alkyl; carbonyl; ethyl; hetero; amide
Prior art date: 2001-11-14

Application number

HR20040426A

Other languages

English (en)

Croatian (hr)

Inventor

Jiayao Li

David John Aldous

Sukanthini Thurairatnam

Original Assignee

Aventis Pharma Inc

Axys Pharmaceuticals

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2001-11-14

Filing date

2004-05-13

Publication date

2004-10-31

2004-05-13 Application filed by Aventis Pharma Inc, Axys Pharmaceuticals filed Critical Aventis Pharma Inc

2004-10-31 Publication of HRP20040426A2 publication Critical patent/HRP20040426A2/hr

Links

239000000203 mixture Substances 0.000 title claims description 107
229940122805 Cathepsin S inhibitor Drugs 0.000 title description 4
102000015636 Oligopeptides Human genes 0.000 title 1
108010038807 Oligopeptides Proteins 0.000 title 1
-1 2-difluoromethoxyphenyl Chemical group 0.000 claims description 291
150000001875 compounds Chemical class 0.000 claims description 219
125000000217 alkyl group Chemical group 0.000 claims description 168
125000005842 heteroatom Chemical group 0.000 claims description 77
125000003118 aryl group Chemical group 0.000 claims description 76
125000000753 cycloalkyl group Chemical group 0.000 claims description 69
239000001257 hydrogen Substances 0.000 claims description 62
229910052739 hydrogen Inorganic materials 0.000 claims description 62
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 51
238000000034 method Methods 0.000 claims description 41
150000003839 salts Chemical class 0.000 claims description 37
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
150000001204 N-oxides Chemical class 0.000 claims description 33
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
201000010099 disease Diseases 0.000 claims description 27
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 27
239000000651 prodrug Substances 0.000 claims description 27
229940002612 prodrug Drugs 0.000 claims description 27
238000006243 chemical reaction Methods 0.000 claims description 25
125000005843 halogen group Chemical group 0.000 claims description 24
STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims description 24
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 22
125000004429 atom Chemical group 0.000 claims description 20
125000004432 carbon atom Chemical group C* 0.000 claims description 20
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 19
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 19
125000004093 cyano group Chemical group *C#N 0.000 claims description 16
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
239000012453 solvate Substances 0.000 claims description 15
108090000613 Cathepsin S Proteins 0.000 claims description 14
230000000694 effects Effects 0.000 claims description 14
238000002360 preparation method Methods 0.000 claims description 14
241001465754 Metazoa Species 0.000 claims description 13
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 claims description 11
102100035654 Cathepsin S Human genes 0.000 claims description 11
230000007170 pathology Effects 0.000 claims description 11
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
125000002723 alicyclic group Chemical group 0.000 claims description 10
125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 10
239000000546 pharmaceutical excipient Substances 0.000 claims description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
125000001931 aliphatic group Chemical group 0.000 claims description 9
125000002947 alkylene group Chemical group 0.000 claims description 9
230000005764 inhibitory process Effects 0.000 claims description 9
125000001424 substituent group Chemical group 0.000 claims description 9
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 9
150000002148 esters Chemical class 0.000 claims description 8
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
238000007254 oxidation reaction Methods 0.000 claims description 8
229910052799 carbon Inorganic materials 0.000 claims description 7
230000003647 oxidation Effects 0.000 claims description 7
125000001118 alkylidene group Chemical group 0.000 claims description 6
150000002431 hydrogen Chemical class 0.000 claims description 6
ZZUHYMXJXMISDV-UHFFFAOYSA-N n-[3-(2-methylpropylsulfonyl)-1-oxo-1-[[1-oxo-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(C=2C=CC=CC=2)=NOC=1C(=O)C(CC)NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1 ZZUHYMXJXMISDV-UHFFFAOYSA-N 0.000 claims description 6
VYGILIBOTJZKIF-UHFFFAOYSA-N n-[3-[[2-(difluoromethoxy)phenyl]methylsulfonyl]-1-[[2-methyl-1-oxo-1-(5-pyridin-3-yl-1,3,4-oxadiazol-2-yl)propan-2-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1N=C(C=2C=NC=CC=2)OC=1C(=O)C(C)(C)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1=CC=CC=C1OC(F)F VYGILIBOTJZKIF-UHFFFAOYSA-N 0.000 claims description 6
PTWWETUOTKEJSZ-UHFFFAOYSA-N n-[3-benzylsulfonyl-1-oxo-1-[[1-oxo-1-(5-phenyl-1,3,4-oxadiazol-2-yl)hexan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical compound N=1N=C(C=2C=CC=CC=2)OC=1C(=O)C(CCCC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1=CC=CC=C1 PTWWETUOTKEJSZ-UHFFFAOYSA-N 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 5
239000005977 Ethylene Substances 0.000 claims description 5
JLXDNLTXRVYJBV-OALUTQOASA-N n-[(2r)-3-benzylsulfonyl-1-[[(2s)-1-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)N[C@@H](CC)C(=O)C=1N=C(ON=1)C(C)(C)C)NC(=O)N1CCOCC1)S(=O)(=O)CC1=CC=CC=C1 JLXDNLTXRVYJBV-OALUTQOASA-N 0.000 claims description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
125000002993 cycloalkylene group Chemical group 0.000 claims description 4
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
YGKXYRCIFJXEPD-HOTGVXAUSA-N n-[(2r)-1-[[(2s)-1-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-3-(cyclopropylmethylsulfonyl)-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)N[C@@H](CC)C(=O)C=1ON=C(N=1)C(C)(C)C)NC(=O)N1CCOCC1)S(=O)(=O)CC1CC1 YGKXYRCIFJXEPD-HOTGVXAUSA-N 0.000 claims description 4
POWUAQMSRKQQGK-STQMWFEESA-N n-[(2r)-3-(cyclopropylmethylsulfonyl)-1-oxo-1-[[(2s)-1-oxo-1-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]butan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical compound C([C@@H](C(=O)N[C@@H](CC)C(=O)C=1N=C(ON=1)C(F)(F)F)NC(=O)N1CCOCC1)S(=O)(=O)CC1CC1 POWUAQMSRKQQGK-STQMWFEESA-N 0.000 claims description 4
CTPHYVJVZVLRRR-UHFFFAOYSA-N n-[1-[[1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-3-(2-methylpropylsulfonyl)-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(C2CC2)=NOC=1C(=O)C(CC)NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1 CTPHYVJVZVLRRR-UHFFFAOYSA-N 0.000 claims description 4
DWKDLQJJNMNOGO-UHFFFAOYSA-N n-[1-[[1-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-3-(2-methylpropylsulfonyl)-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(C(C)(C)C)=NOC=1C(=O)C(CC)NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1 DWKDLQJJNMNOGO-UHFFFAOYSA-N 0.000 claims description 4
DRUOIQODUQUYBK-UHFFFAOYSA-N n-[3-(2-methylpropylsulfonyl)-1-oxo-1-[[1-oxo-1-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)butan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(C=2SC=CC=2)=NOC=1C(=O)C(CC)NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1 DRUOIQODUQUYBK-UHFFFAOYSA-N 0.000 claims description 4
ZNFDPHHSWIPGCV-UHFFFAOYSA-N n-[3-(cyclopropylmethylsulfonyl)-1-[[1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(C2CC2)=NOC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1 ZNFDPHHSWIPGCV-UHFFFAOYSA-N 0.000 claims description 4
GSEBSAIWYYUYFP-UHFFFAOYSA-N n-[3-(cyclopropylmethylsulfonyl)-1-[[1-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(CC)=NOC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1 GSEBSAIWYYUYFP-UHFFFAOYSA-N 0.000 claims description 4
YHMPUPPIKYOEFG-UHFFFAOYSA-N n-[3-(cyclopropylmethylsulfonyl)-1-oxo-1-[[1-oxo-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(C=2C=CC=CC=2)=NOC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1 YHMPUPPIKYOEFG-UHFFFAOYSA-N 0.000 claims description 4
AZPDRLCJPXQSIZ-UHFFFAOYSA-N n-[3-(cyclopropylmethylsulfonyl)-1-oxo-1-[[1-oxo-1-(5-phenyl-1,2,4-oxadiazol-3-yl)butan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical compound N=1OC(C=2C=CC=CC=2)=NC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1 AZPDRLCJPXQSIZ-UHFFFAOYSA-N 0.000 claims description 4
IOMKJMGYNMKIDF-UHFFFAOYSA-N n-[3-benzylsulfonyl-1-[[1-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(CC)=NOC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1=CC=CC=C1 IOMKJMGYNMKIDF-UHFFFAOYSA-N 0.000 claims description 4
NDMDDXDZHTVIMJ-UHFFFAOYSA-N n-[3-benzylsulfonyl-1-oxo-1-[[1-oxo-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(C=2C=CC=CC=2)=NOC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1=CC=CC=C1 NDMDDXDZHTVIMJ-UHFFFAOYSA-N 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
239000000825 pharmaceutical preparation Substances 0.000 claims description 4
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 3
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 3
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
UDOGYHRFAHGGEX-STQMWFEESA-N CC(C)CS(=O)(=O)C[C@H](N)C(=O)N[C@@H](CC)C(=O)C1=NOC(C2=CSC=C2)=N1 Chemical compound CC(C)CS(=O)(=O)C[C@H](N)C(=O)N[C@@H](CC)C(=O)C1=NOC(C2=CSC=C2)=N1 UDOGYHRFAHGGEX-STQMWFEESA-N 0.000 claims description 3
125000003545 alkoxy group Chemical group 0.000 claims description 3
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
125000006588 heterocycloalkylene group Chemical group 0.000 claims description 3
125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
UNBCTIBIDDXRGC-UHFFFAOYSA-N n-[3-benzylsulfonyl-1-[[1-(5-ethyl-1,3,4-oxadiazol-2-yl)-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1N=C(CC)OC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1=CC=CC=C1 UNBCTIBIDDXRGC-UHFFFAOYSA-N 0.000 claims description 3
YILJXJHOJTWBDI-UHFFFAOYSA-N n-[3-benzylsulfonyl-1-[[1-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1N=C(C(C)(C)C)OC=1C(=O)C(CC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1=CC=CC=C1 YILJXJHOJTWBDI-UHFFFAOYSA-N 0.000 claims description 3
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
125000003373 pyrazinyl group Chemical group 0.000 claims description 3
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
229920002554 vinyl polymer Chemical group 0.000 claims description 3
125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[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
125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 claims description 2
125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 claims description 2
125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 2
125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 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
239000004305 biphenyl Chemical group 0.000 claims description 2
235000010290 biphenyl Nutrition 0.000 claims description 2
125000001072 heteroaryl group Chemical group 0.000 claims description 2
QSPDGSWHFFUJFF-UHFFFAOYSA-N n-[1-[[1-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-oxobutan-2-yl]amino]-3-(2-methylpropylsulfonyl)-1-oxopropan-2-yl]morpholine-4-carboxamide Chemical compound N=1C(CC)=NOC=1C(=O)C(CC)NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1 QSPDGSWHFFUJFF-UHFFFAOYSA-N 0.000 claims description 2
WOYSQEBASFGSRZ-UHFFFAOYSA-N n-[3-[[2-(difluoromethoxy)phenyl]methylsulfonyl]-1-oxo-1-[[1-oxo-1-(5-pyridin-3-yl-1,3,4-oxadiazol-2-yl)hexan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide Chemical class N=1N=C(C=2C=NC=CC=2)OC=1C(=O)C(CCCC)NC(=O)C(NC(=O)N1CCOCC1)CS(=O)(=O)CC1=CC=CC=C1OC(F)F WOYSQEBASFGSRZ-UHFFFAOYSA-N 0.000 claims description 2
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
125000002098 pyridazinyl group Chemical group 0.000 claims description 2
125000004076 pyridyl group Chemical group 0.000 claims description 2
125000001544 thienyl group Chemical group 0.000 claims description 2
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 209
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
239000000243 solution Substances 0.000 description 82
239000011541 reaction mixture Substances 0.000 description 40
238000005160 1H NMR spectroscopy Methods 0.000 description 36
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 32
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
239000007787 solid Substances 0.000 description 22
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
150000003254 radicals Chemical class 0.000 description 20
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
229910052757 nitrogen Inorganic materials 0.000 description 19
125000006239 protecting group Chemical group 0.000 description 19
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 18
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WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000019833 protease Nutrition 0.000 description 1
235000018102 proteins Nutrition 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000001422 pyrrolinyl group Chemical group 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
230000006340 racemization Effects 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
235000009566 rice Nutrition 0.000 description 1
125000006413 ring segment Chemical group 0.000 description 1
150000003873 salicylate salts Chemical class 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000008159 sesame oil Substances 0.000 description 1
235000011803 sesame oil Nutrition 0.000 description 1
235000020183 skimmed milk Nutrition 0.000 description 1
230000037394 skin elasticity Effects 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
239000012439 solid excipient Substances 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
150000003890 succinate salts Chemical class 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
125000004434 sulfur atom Chemical group 0.000 description 1
239000000829 suppository Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
201000000596 systemic lupus erythematosus Diseases 0.000 description 1
239000003826 tablet Substances 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
150000003892 tartrate salts Chemical class 0.000 description 1
PJSJCQBVNWSBQK-UHFFFAOYSA-N tert-butyl n-(1-amino-2-hydroxy-1-hydroxyiminopentan-3-yl)carbamate Chemical compound ONC(=N)C(O)C(CC)NC(=O)OC(C)(C)C PJSJCQBVNWSBQK-UHFFFAOYSA-N 0.000 description 1
AMWBULKKLCAABK-UHFFFAOYSA-N tert-butyl n-(1-cyano-1-hydroxybutan-2-yl)carbamate Chemical compound N#CC(O)C(CC)NC(=O)OC(C)(C)C AMWBULKKLCAABK-UHFFFAOYSA-N 0.000 description 1
WOBIIRJDZNFYHU-RGURZIINSA-N tert-butyl n-[(2s)-1-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-1-hydroxybutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](CC)C(O)C1=NOC(C(C)(C)C)=N1 WOBIIRJDZNFYHU-RGURZIINSA-N 0.000 description 1
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
125000004385 trihaloalkyl group Chemical group 0.000 description 1
125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 description 1
235000013311 vegetables Nutrition 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1
238000005406 washing Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Epidemiology (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Orthopedic Medicine & Surgery (AREA)
Physical Education & Sports Medicine (AREA)
Neurology (AREA)
Urology & Nephrology (AREA)
Immunology (AREA)
Rheumatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Peptides Or Proteins (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

HR20040426A 2001-11-14 2004-05-13 Oligopeptides and compositions containing them as cathepsin s inhibitors HRP20040426A2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US33260501P	2001-11-14	2001-11-14
PCT/US2002/036396 WO2003042197A1 (fr)	2001-11-14	2002-11-14	Nouveaux composes et compositions jouant le role d'inhibiteurs de cathepsine s

Publications (1)

Publication Number	Publication Date
HRP20040426A2 true HRP20040426A2 (en)	2004-10-31

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ID=23298977

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR20040426A HRP20040426A2 (en)	2001-11-14	2004-05-13	Oligopeptides and compositions containing them as cathepsin s inhibitors

Country Status (21)

Country	Link
US (3)	US6977256B2 (fr)
EP (1)	EP1446392A1 (fr)
JP (1)	JP2005514353A (fr)
KR (1)	KR20050044497A (fr)
CN (1)	CN1324018C (fr)
BR (1)	BR0214104A (fr)
CA (1)	CA2467391A1 (fr)
CO (1)	CO5640128A2 (fr)
HK (1)	HK1073840A1 (fr)
HR (1)	HRP20040426A2 (fr)
HU (1)	HUP0401906A3 (fr)
IL (1)	IL161950A0 (fr)
MA (1)	MA27140A1 (fr)
MX (1)	MXPA04004450A (fr)
NO (1)	NO20041909L (fr)
NZ (1)	NZ532167A (fr)
PL (1)	PL372105A1 (fr)
RU (1)	RU2004117877A (fr)
WO (1)	WO2003042197A1 (fr)
YU (1)	YU34604A (fr)
ZA (1)	ZA200403602B (fr)

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2002
- 2002-11-14 CN CNB028226879A patent/CN1324018C/zh not_active Expired - Fee Related
- 2002-11-14 CA CA002467391A patent/CA2467391A1/fr not_active Abandoned
- 2002-11-14 JP JP2003544033A patent/JP2005514353A/ja active Pending
- 2002-11-14 PL PL02372105A patent/PL372105A1/xx not_active Application Discontinuation
- 2002-11-14 YU YU34604A patent/YU34604A/sh unknown
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- 2002-11-14 KR KR1020047007466A patent/KR20050044497A/ko not_active Application Discontinuation
- 2002-11-14 WO PCT/US2002/036396 patent/WO2003042197A1/fr active Application Filing
- 2002-11-14 BR BR0214104-3A patent/BR0214104A/pt not_active IP Right Cessation
- 2002-11-14 MX MXPA04004450A patent/MXPA04004450A/es not_active Application Discontinuation
- 2002-11-14 RU RU2004117877/04A patent/RU2004117877A/ru not_active Application Discontinuation
- 2002-11-14 EP EP02792253A patent/EP1446392A1/fr not_active Withdrawn
- 2002-11-14 IL IL16195002A patent/IL161950A0/xx unknown
- 2002-11-14 HU HU0401906A patent/HUP0401906A3/hu unknown
2004
- 2004-04-06 MA MA27611A patent/MA27140A1/fr unknown
- 2004-05-10 NO NO20041909A patent/NO20041909L/no not_active Application Discontinuation
- 2004-05-11 ZA ZA200403602A patent/ZA200403602B/xx unknown
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2005
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2007
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Publication number	Publication date
MXPA04004450A (es)	2004-08-11
US20070203138A1 (en)	2007-08-30
NZ532167A (en)	2006-11-30
PL372105A1 (en)	2005-07-11
US20030199506A1 (en)	2003-10-23
NO20041909L (no)	2004-05-10
HK1073840A1 (en)	2005-10-21
CN1324018C (zh)	2007-07-04
US6977256B2 (en)	2005-12-20
WO2003042197A1 (fr)	2003-05-22
HUP0401906A2 (hu)	2004-12-28
JP2005514353A (ja)	2005-05-19
KR20050044497A (ko)	2005-05-12
CO5640128A2 (es)	2006-05-31
ZA200403602B (en)	2005-08-31
MA27140A1 (fr)	2005-01-03
CA2467391A1 (fr)	2003-05-22
IL161950A0 (en)	2005-11-20
RU2004117877A (ru)	2006-01-10
US7226921B2 (en)	2007-06-05
YU34604A (sh)	2006-08-17
CN1585757A (zh)	2005-02-23
HUP0401906A3 (en)	2008-07-28
EP1446392A1 (fr)	2004-08-18
US20050267044A1 (en)	2005-12-01
BR0214104A (pt)	2004-09-28

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