NO20023921L - Derivater av thiazepinylhydroksamisk syre som inhibitorer av matriks metalloproteinase - Google Patents
Derivater av thiazepinylhydroksamisk syre som inhibitorer av matriks metalloproteinase Download PDFInfo
- Publication number
- NO20023921L NO20023921L NO20023921A NO20023921A NO20023921L NO 20023921 L NO20023921 L NO 20023921L NO 20023921 A NO20023921 A NO 20023921A NO 20023921 A NO20023921 A NO 20023921A NO 20023921 L NO20023921 L NO 20023921L
- Authority
- NO
- Norway
- Prior art keywords
- optionally substituted
- alkanoyl
- alkoxy
- substituted
- group containing
- Prior art date
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- 102000002274 Matrix Metalloproteinases Human genes 0.000 title claims abstract description 19
- 108010000684 Matrix Metalloproteinases Proteins 0.000 title claims abstract description 19
- 239000003112 inhibitor Substances 0.000 title claims abstract description 6
- -1 Thiazepinyl hydroxamic Chemical compound 0.000 title claims description 2007
- 239000002253 acid Substances 0.000 title description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 244
- 238000004519 manufacturing process Methods 0.000 claims abstract description 171
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 136
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 125000003118 aryl group Chemical group 0.000 claims abstract description 64
- 125000002252 acyl group Chemical group 0.000 claims abstract description 42
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 35
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 20
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 15
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 241000534944 Thia Species 0.000 claims abstract description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims abstract description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 158
- 125000000217 alkyl group Chemical group 0.000 claims description 153
- 150000001875 compounds Chemical class 0.000 claims description 142
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 138
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 132
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 110
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 89
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 70
- 125000004434 sulfur atom Chemical group 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 61
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 61
- 229920006395 saturated elastomer Polymers 0.000 claims description 57
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 54
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 54
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical group 0.000 claims description 38
- 125000005843 halogen group Chemical group 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 33
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 31
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 29
- 125000001544 thienyl group Chemical group 0.000 claims description 29
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 27
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 27
- 125000003435 aroyl group Chemical group 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 24
- 125000002619 bicyclic group Chemical group 0.000 claims description 23
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 23
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 21
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 21
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 20
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 19
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 19
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 19
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 18
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 17
- 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 17
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 17
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 15
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 15
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 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 13
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 13
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 13
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 13
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 13
- 125000003816 2-hydroxybenzoyl group Chemical group OC1=C(C(=O)*)C=CC=C1 0.000 claims description 12
- 125000006637 cyclobutyl carbonyl group Chemical group 0.000 claims description 12
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims description 12
- 125000006638 cyclopentyl carbonyl group Chemical group 0.000 claims description 12
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 12
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 12
- 125000005493 quinolyl group Chemical group 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 10
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 8
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- 102100037205 Sal-like protein 2 Human genes 0.000 claims description 6
- 101710192308 Sal-like protein 2 Proteins 0.000 claims description 6
- 102100040247 Tumor necrosis factor Human genes 0.000 claims description 6
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 6
- 125000005059 halophenyl group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 102000003390 tumor necrosis factor Human genes 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[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 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
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- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
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- 229940079593 drug Drugs 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 241001465754 Metazoa Species 0.000 claims 1
- 230000010933 acylation Effects 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 229940059260 amidate Drugs 0.000 claims 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 230000017074 necrotic cell death Effects 0.000 abstract 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 196
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- 238000002360 preparation method Methods 0.000 description 163
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 102
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
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- YUQACHZFSVKJGM-BOXHHOBZSA-N tert-butyl 2-[(7s)-1,1-dioxo-7-[5-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]-1,4-thiazepan-7-yl]acetate;hydrochloride Chemical compound Cl.C=1C=C(C=2C=CC(OC(F)(F)F)=CC=2)SC=1[C@@]1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O YUQACHZFSVKJGM-BOXHHOBZSA-N 0.000 description 1
- KTQQEMHRNDYEFW-VWLOTQADSA-N tert-butyl 2-[(7s)-4-methylsulfonyl-1,1-dioxo-7-[5-(4-propylphenyl)thiophen-2-yl]-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(CCC)=CC=C1C1=CC=C([C@]2(CC(=O)OC(C)(C)C)S(CCN(CC2)S(C)(=O)=O)(=O)=O)S1 KTQQEMHRNDYEFW-VWLOTQADSA-N 0.000 description 1
- BNRZKCQOADFPHP-HNNXBMFYSA-N tert-butyl 2-[(7s)-7-(5-bromothiophen-2-yl)-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(Br)SC=1[C@@]1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O BNRZKCQOADFPHP-HNNXBMFYSA-N 0.000 description 1
- HQZDGLUZICPBNK-FQEVSTJZSA-N tert-butyl 2-[(7s)-7-(5-bromothiophen-2-yl)-1,1-dioxo-4-(thiophene-3-carbonyl)-1,4-thiazepan-7-yl]acetate Chemical compound C([C@](S(CC1)(=O)=O)(CC(=O)OC(C)(C)C)C=2SC(Br)=CC=2)CN1C(=O)C=1C=CSC=1 HQZDGLUZICPBNK-FQEVSTJZSA-N 0.000 description 1
- HKUJJAIECIWZNZ-KRWDZBQOSA-N tert-butyl 2-[(7s)-7-(5-bromothiophen-2-yl)-4-(dimethylsulfamoyl)-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound O=S1(=O)CCN(S(=O)(=O)N(C)C)CC[C@]1(CC(=O)OC(C)(C)C)C1=CC=C(Br)S1 HKUJJAIECIWZNZ-KRWDZBQOSA-N 0.000 description 1
- WXKMABZGOPJMMW-NRFANRHFSA-N tert-butyl 2-[(7s)-7-[5-(4-chlorophenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=CC(Cl)=CC=2)SC=1[C@@]1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O WXKMABZGOPJMMW-NRFANRHFSA-N 0.000 description 1
- VXXNTDRTDUUHQQ-QHCPKHFHSA-N tert-butyl 2-[(7s)-7-[5-(4-ethylphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(CC)=CC=C1C1=CC=C([C@]2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 VXXNTDRTDUUHQQ-QHCPKHFHSA-N 0.000 description 1
- XOJSOFMUZKBLNB-MHZLTWQESA-N tert-butyl 2-[(7s)-7-[5-(4-methoxyphenyl)thiophen-2-yl]-1,1-dioxo-4-(thiophene-3-carbonyl)-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(OC)=CC=C1C1=CC=C([C@]2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)C2=CSC=C2)(=O)=O)S1 XOJSOFMUZKBLNB-MHZLTWQESA-N 0.000 description 1
- ZGUUJKXMNYUTMF-UHFFFAOYSA-N tert-butyl 2-[7-(5-naphthalen-2-ylthiophen-2-yl)-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=C3C=CC=CC3=CC=2)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O ZGUUJKXMNYUTMF-UHFFFAOYSA-N 0.000 description 1
- QTPYLKAMTHPFJR-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-cyanophenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=CC(=CC=2)C#N)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O QTPYLKAMTHPFJR-UHFFFAOYSA-N 0.000 description 1
- DJWQDYGQTWFOKQ-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-ethoxyphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate;hydrochloride Chemical compound Cl.C1=CC(OCC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 DJWQDYGQTWFOKQ-UHFFFAOYSA-N 0.000 description 1
- NHGSMAGVPVURCC-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-fluorophenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=CC(F)=CC=2)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O NHGSMAGVPVURCC-UHFFFAOYSA-N 0.000 description 1
- ZODZXGBMXXLPMR-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-methylphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(C)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 ZODZXGBMXXLPMR-UHFFFAOYSA-N 0.000 description 1
- RLBJVYHAAAHBFE-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-methylsulfanylphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(SC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 RLBJVYHAAAHBFE-UHFFFAOYSA-N 0.000 description 1
- YIIKOXFGPQXWDI-UHFFFAOYSA-N tert-butyl 2-[7-[5-(5-chlorothiophen-2-yl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2SC(Cl)=CC=2)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O YIIKOXFGPQXWDI-UHFFFAOYSA-N 0.000 description 1
- KUHPRALEZHEVIH-UHFFFAOYSA-N tert-butyl 2-[7-[5-[4-(1,3-oxazol-2-yl)phenyl]thiophen-2-yl]-1,1-dioxo-4-(thiophene-3-carbonyl)-1,4-thiazepan-7-yl]acetate Chemical compound C1CS(=O)(=O)C(CC(=O)OC(C)(C)C)(C=2SC(=CC=2)C=2C=CC(=CC=2)C=2OC=CN=2)CCN1C(=O)C=1C=CSC=1 KUHPRALEZHEVIH-UHFFFAOYSA-N 0.000 description 1
- FCQUTRVCRRYXLN-UHFFFAOYSA-N tert-butyl 2-[7-[5-[4-(methoxymethyl)phenyl]thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(COC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 FCQUTRVCRRYXLN-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- ZLWCVPBRZFOAIW-UHFFFAOYSA-N tert-butyl 7-(4-phenoxyphenyl)-1,4-thiazepane-4-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCSC1C(C=C1)=CC=C1OC1=CC=CC=C1 ZLWCVPBRZFOAIW-UHFFFAOYSA-N 0.000 description 1
- YQQWIELDAFGSQK-UHFFFAOYSA-N tert-butyl 7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-7-[5-(4-propylphenyl)thiophen-2-yl]-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(CCC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)S1 YQQWIELDAFGSQK-UHFFFAOYSA-N 0.000 description 1
- DJJCQOGHYDXWEI-UHFFFAOYSA-N tert-butyl 7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-7-[5-(4-methylsulfanylphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(SC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)S1 DJJCQOGHYDXWEI-UHFFFAOYSA-N 0.000 description 1
- NKOFHAJWEDHPAA-UHFFFAOYSA-N tert-butyl 7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-7-[5-[4-(1,3-oxazol-5-yl)phenyl]thiophen-2-yl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C=1C=C(C=2C=CC(=CC=2)C=2OC=NC=2)SC=1C1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CCS1(=O)=O NKOFHAJWEDHPAA-UHFFFAOYSA-N 0.000 description 1
- LFMYSIRAEJGKIB-UHFFFAOYSA-N tert-butyl 7-[4-(4-chlorophenoxy)phenyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound O=S1(=O)CCN(C(=O)OC(C)(C)C)CCC1C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 LFMYSIRAEJGKIB-UHFFFAOYSA-N 0.000 description 1
- GPJUCKPDAHIQTB-UHFFFAOYSA-N tert-butyl 7-[4-(4-ethylphenoxy)phenyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(CC)=CC=C1OC1=CC=C(C2S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)C=C1 GPJUCKPDAHIQTB-UHFFFAOYSA-N 0.000 description 1
- MEIDQDOTRGXPRO-UHFFFAOYSA-N tert-butyl 7-[4-(4-ethylphenoxy)phenyl]-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(CC)=CC=C1OC1=CC=C(C2SCCN(CC2)C(=O)OC(C)(C)C)C=C1 MEIDQDOTRGXPRO-UHFFFAOYSA-N 0.000 description 1
- XZWYUPKSJVRRIP-UHFFFAOYSA-N tert-butyl 7-[4-(4-ethylphenoxy)phenyl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(CC)=CC=C1OC1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)C=C1 XZWYUPKSJVRRIP-UHFFFAOYSA-N 0.000 description 1
- KYIIQSWFTICDCS-UHFFFAOYSA-N tert-butyl 7-[4-(4-fluorophenoxy)phenyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound O=S1(=O)CCN(C(=O)OC(C)(C)C)CCC1C(C=C1)=CC=C1OC1=CC=C(F)C=C1 KYIIQSWFTICDCS-UHFFFAOYSA-N 0.000 description 1
- JTDLGLHJQNOOQS-UHFFFAOYSA-N tert-butyl 7-[4-(4-fluorophenoxy)phenyl]-1,4-thiazepane-4-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCSC1C(C=C1)=CC=C1OC1=CC=C(F)C=C1 JTDLGLHJQNOOQS-UHFFFAOYSA-N 0.000 description 1
- MMVKAHBGUOXBOK-UHFFFAOYSA-N tert-butyl 7-[4-(4-fluorophenoxy)phenyl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1C1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CCS1(=O)=O MMVKAHBGUOXBOK-UHFFFAOYSA-N 0.000 description 1
- OOFKXGYLLXHCDB-UHFFFAOYSA-N tert-butyl 7-[4-(4-methoxyphenoxy)phenyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(C2S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)C=C1 OOFKXGYLLXHCDB-UHFFFAOYSA-N 0.000 description 1
- USGIVONBVFZDOD-UHFFFAOYSA-N tert-butyl 7-[4-(4-methoxyphenoxy)phenyl]-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(C2SCCN(CC2)C(=O)OC(C)(C)C)C=C1 USGIVONBVFZDOD-UHFFFAOYSA-N 0.000 description 1
- WORTVDNYFASZEA-UHFFFAOYSA-N tert-butyl 7-[4-(4-methylphenoxy)phenyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(C)=CC=C1OC1=CC=C(C2S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)C=C1 WORTVDNYFASZEA-UHFFFAOYSA-N 0.000 description 1
- YLQWKLWZDNYRLI-UHFFFAOYSA-N tert-butyl 7-[5-(4-cyanophenyl)thiophen-2-yl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C=1C=C(C=2C=CC(=CC=2)C#N)SC=1C1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CCS1(=O)=O YLQWKLWZDNYRLI-UHFFFAOYSA-N 0.000 description 1
- QZCVCAPWEABTKG-UHFFFAOYSA-N tert-butyl 7-[5-(4-ethoxyphenyl)thiophen-2-yl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(OCC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)S1 QZCVCAPWEABTKG-UHFFFAOYSA-N 0.000 description 1
- VXHSTSGFJFBTEM-UHFFFAOYSA-N tert-butyl 7-[5-(4-methylphenyl)thiophen-2-yl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(C)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)S1 VXHSTSGFJFBTEM-UHFFFAOYSA-N 0.000 description 1
- MYLNIOYEBYDTMR-UHFFFAOYSA-N tert-butyl 7-[5-(5-chlorothiophen-2-yl)thiophen-2-yl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C=1C=C(C=2SC(Cl)=CC=2)SC=1C1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CCS1(=O)=O MYLNIOYEBYDTMR-UHFFFAOYSA-N 0.000 description 1
- SLKLHBPXSGUHDJ-UHFFFAOYSA-N tert-butyl 7-[5-[4-(methoxymethyl)phenyl]thiophen-2-yl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(COC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)OC(C)(C)C)(=O)=O)S1 SLKLHBPXSGUHDJ-UHFFFAOYSA-N 0.000 description 1
- WCTQFXGWMOKHLV-UHFFFAOYSA-N tert-butyl 7-[[5-(4-methoxyphenyl)thiophen-2-yl]methyl]-7-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,1-dioxo-1,4-thiazepane-4-carboxylate Chemical compound C1=CC(OC)=CC=C1C(S1)=CC=C1CC1(CC(=O)OC(C)(C)C)S(=O)(=O)CCN(C(=O)OC(C)(C)C)CC1 WCTQFXGWMOKHLV-UHFFFAOYSA-N 0.000 description 1
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Virology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- AIDS & HIV (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Transplantation (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPQ5751A AUPQ575100A0 (en) | 2000-02-21 | 2000-02-21 | Cyclic compound |
AUPQ8603A AUPQ860300A0 (en) | 2000-07-06 | 2000-07-06 | Cyclic compound |
PCT/JP2001/001206 WO2001060808A1 (en) | 2000-02-21 | 2001-02-20 | Thiazepinyl hydroxamic acid derivatives as matrix metalloproteinase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NO20023921D0 NO20023921D0 (no) | 2002-08-19 |
NO20023921L true NO20023921L (no) | 2002-10-11 |
Family
ID=25646264
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20023921A NO20023921L (no) | 2000-02-21 | 2002-08-19 | Derivater av thiazepinylhydroksamisk syre som inhibitorer av matriks metalloproteinase |
Country Status (14)
Country | Link |
---|---|
US (1) | US6967197B2 (es) |
EP (1) | EP1259499A1 (es) |
JP (1) | JP2003523337A (es) |
KR (1) | KR20030000029A (es) |
CN (1) | CN1188404C (es) |
AR (1) | AR027952A1 (es) |
BR (1) | BR0108791A (es) |
CA (1) | CA2400862A1 (es) |
HU (1) | HUP0204501A2 (es) |
IL (1) | IL151197A0 (es) |
MX (1) | MXPA02008175A (es) |
NO (1) | NO20023921L (es) |
PL (1) | PL357084A1 (es) |
WO (1) | WO2001060808A1 (es) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002226464A (ja) * | 2001-01-30 | 2002-08-14 | Sumitomo Pharmaceut Co Ltd | トリアリール類縁体およびその利用 |
AUPR755501A0 (en) * | 2001-09-07 | 2001-09-27 | Fujisawa Pharmaceutical Co., Ltd. | Cyclic compound |
WO2003031431A1 (en) | 2001-10-09 | 2003-04-17 | Bristol-Myers Squibb Company | Cyclic sulfone derivatives as inhibitors of matrix metalloproteinases and/or tnf-$g(a) converting enzyme (tace) |
US8133733B2 (en) | 2003-10-24 | 2012-03-13 | Gencia Corporation | Nonviral vectors for delivering polynucleotides to target tissues |
ES2411962T3 (es) | 2003-10-24 | 2013-07-09 | Gencia Corporation | Métodos y composiciones para suministrar polinucleótidos |
US20090123468A1 (en) | 2003-10-24 | 2009-05-14 | Gencia Corporation | Transducible polypeptides for modifying metabolism |
US8507277B2 (en) | 2003-10-24 | 2013-08-13 | Gencia Corporation | Nonviral vectors for delivering polynucleotides |
US8062891B2 (en) | 2003-10-24 | 2011-11-22 | Gencia Corporation | Nonviral vectors for delivering polynucleotides to plants |
KR100685222B1 (ko) * | 2004-12-03 | 2007-02-22 | 우경건설 주식회사 | 이중 콘크리트 구조물 |
US20100028439A1 (en) * | 2005-05-23 | 2010-02-04 | Elan Pharma International Limited | Nanoparticulate stabilized anti-hypertensive compositions |
CN104926707B (zh) * | 2015-05-12 | 2017-10-27 | 江苏福瑞生物医药有限公司 | 一种药物中间体的合成方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0873183T3 (da) * | 1995-12-29 | 2002-01-21 | Novozymes As | Enzymholdige partikler og væskeformigt detergentkoncentrat |
HUP0000505A3 (en) | 1996-08-28 | 2001-12-28 | Procter & Gamble | Saturated 7-9 membered heterocyclic n-hydroxycarboxamide derivatives and pharmaceutical compositions containing them |
AU734834B2 (en) | 1996-08-28 | 2001-06-21 | Procter & Gamble Company, The | Heterocyclic metalloprotease inhibitors |
US6333324B1 (en) | 1996-12-17 | 2001-12-25 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine compounds as inhibitors of MMP or TNF |
-
2001
- 2001-02-20 KR KR1020027010721A patent/KR20030000029A/ko not_active Application Discontinuation
- 2001-02-20 IL IL15119701A patent/IL151197A0/xx unknown
- 2001-02-20 HU HU0204501A patent/HUP0204501A2/hu unknown
- 2001-02-20 BR BR0108791-6A patent/BR0108791A/pt not_active Application Discontinuation
- 2001-02-20 WO PCT/JP2001/001206 patent/WO2001060808A1/en not_active Application Discontinuation
- 2001-02-20 CA CA002400862A patent/CA2400862A1/en not_active Abandoned
- 2001-02-20 JP JP2001560193A patent/JP2003523337A/ja not_active Withdrawn
- 2001-02-20 PL PL01357084A patent/PL357084A1/xx not_active Application Discontinuation
- 2001-02-20 CN CNB018082432A patent/CN1188404C/zh not_active Expired - Fee Related
- 2001-02-20 US US10/203,627 patent/US6967197B2/en not_active Expired - Fee Related
- 2001-02-20 MX MXPA02008175A patent/MXPA02008175A/es unknown
- 2001-02-20 EP EP01906142A patent/EP1259499A1/en not_active Withdrawn
- 2001-02-21 AR ARP010100781A patent/AR027952A1/es unknown
-
2002
- 2002-08-19 NO NO20023921A patent/NO20023921L/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
PL357084A1 (en) | 2004-07-12 |
HUP0204501A2 (hu) | 2003-04-28 |
CN1425010A (zh) | 2003-06-18 |
KR20030000029A (ko) | 2003-01-03 |
WO2001060808A1 (en) | 2001-08-23 |
US20030134849A1 (en) | 2003-07-17 |
US6967197B2 (en) | 2005-11-22 |
BR0108791A (pt) | 2004-04-27 |
CA2400862A1 (en) | 2001-08-23 |
JP2003523337A (ja) | 2003-08-05 |
NO20023921D0 (no) | 2002-08-19 |
CN1188404C (zh) | 2005-02-09 |
EP1259499A1 (en) | 2002-11-27 |
AR027952A1 (es) | 2003-04-16 |
IL151197A0 (en) | 2003-04-10 |
MXPA02008175A (es) | 2003-05-23 |
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