DE69625691T2 - Verabreichung von peptidylheterocyclen zur behandlung von thrombin in zusammenhang stehenden krankheiten - Google Patents
Verabreichung von peptidylheterocyclen zur behandlung von thrombin in zusammenhang stehenden krankheitenInfo
- Publication number
- DE69625691T2 DE69625691T2 DE69625691T DE69625691T DE69625691T2 DE 69625691 T2 DE69625691 T2 DE 69625691T2 DE 69625691 T DE69625691 T DE 69625691T DE 69625691 T DE69625691 T DE 69625691T DE 69625691 T2 DE69625691 T2 DE 69625691T2
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- amino
- carbonyl
- substituted
- carboxy
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 6
- 201000010099 disease Diseases 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- 108090000190 Thrombin Proteins 0.000 claims abstract description 26
- 229960004072 thrombin Drugs 0.000 claims abstract description 24
- 108090000631 Trypsin Proteins 0.000 claims abstract description 7
- 102000004142 Trypsin Human genes 0.000 claims abstract description 7
- 239000012588 trypsin Substances 0.000 claims abstract description 7
- -1 1-naphthylsulfonyl Chemical group 0.000 claims description 265
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 50
- 150000002367 halogens Chemical class 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 46
- 125000003368 amide group Chemical group 0.000 claims description 43
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 43
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000006531 (C2-C5) alkyl group Chemical group 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 28
- 229940024606 amino acid Drugs 0.000 claims description 28
- 235000001014 amino acid Nutrition 0.000 claims description 28
- 150000001413 amino acids Chemical class 0.000 claims description 28
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 21
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 125000003282 alkyl amino group Chemical group 0.000 claims description 19
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 claims description 17
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 16
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 claims description 12
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 claims description 12
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 11
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 11
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 8
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 7
- 150000008575 L-amino acids Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 claims description 7
- 125000004501 isothiazol-5-yl group Chemical group S1N=CC=C1* 0.000 claims description 7
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 7
- 235000008729 phenylalanine Nutrition 0.000 claims description 7
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 7
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 6
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 6
- 101100311330 Schizosaccharomyces pombe (strain 972 / ATCC 24843) uap56 gene Proteins 0.000 claims description 6
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 6
- 229920001184 polypeptide Polymers 0.000 claims description 6
- 125000004544 purin-8-yl group Chemical group N1=CN=C2N=C(NC2=C1)* 0.000 claims description 6
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 6
- 125000004260 quinazolin-2-yl group Chemical group [H]C1=NC(*)=NC2=C1C([H])=C([H])C([H])=C2[H] 0.000 claims description 6
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 claims description 6
- 101150018444 sub2 gene Proteins 0.000 claims description 6
- 125000004301 thiazolin-2-yl group Chemical group [H]C1([H])SC(*)=NC1([H])[H] 0.000 claims description 6
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 5
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 claims description 5
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- 235000004279 alanine Nutrition 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 210000004899 c-terminal region Anatomy 0.000 claims description 4
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 4
- 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 claims description 4
- 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 235000009582 asparagine Nutrition 0.000 claims description 3
- 229960001230 asparagine Drugs 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 3
- BJBUEDPLEOHJGE-UHFFFAOYSA-N (2R,3S)-3-Hydroxy-2-pyrolidinecarboxylic acid Natural products OC1CCNC1C(O)=O BJBUEDPLEOHJGE-UHFFFAOYSA-N 0.000 claims description 2
- AALYNABLSOHPQK-BYPYZUCNSA-N (2s)-2-(1,3-thiazol-4-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CSC=N1 AALYNABLSOHPQK-BYPYZUCNSA-N 0.000 claims description 2
- YPJJGMCMOHDOFZ-ZETCQYMHSA-N (2s)-2-(1-benzothiophen-3-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CSC2=C1 YPJJGMCMOHDOFZ-ZETCQYMHSA-N 0.000 claims description 2
- CNMAQBJBWQQZFZ-LURJTMIESA-N (2s)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 claims description 2
- WTKYBFQVZPCGAO-LURJTMIESA-N (2s)-2-(pyridin-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CN=C1 WTKYBFQVZPCGAO-LURJTMIESA-N 0.000 claims description 2
- WRQSUCJAKAMYMQ-YFKPBYRVSA-N (2s)-2-(thiophen-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC=1C=CSC=1 WRQSUCJAKAMYMQ-YFKPBYRVSA-N 0.000 claims description 2
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 claims description 2
- CQYBNXGHMBNGCG-FXQIFTODSA-N (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 claims description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 claims description 2
- KFLKTDAONDZLAN-UHFFFAOYSA-N 2-(n-phenylanilino)acetic acid Chemical compound C=1C=CC=CC=1N(CC(=O)O)C1=CC=CC=C1 KFLKTDAONDZLAN-UHFFFAOYSA-N 0.000 claims description 2
- WTOFYLAWDLQMBZ-UHFFFAOYSA-N 2-azaniumyl-3-thiophen-2-ylpropanoate Chemical compound OC(=O)C(N)CC1=CC=CS1 WTOFYLAWDLQMBZ-UHFFFAOYSA-N 0.000 claims description 2
- YXDGRBPZVQPESQ-QMMMGPOBSA-N 4-[(2s)-2-amino-2-carboxyethyl]benzoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(C(O)=O)C=C1 YXDGRBPZVQPESQ-QMMMGPOBSA-N 0.000 claims description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims description 2
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 claims description 2
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229960002591 hydroxyproline Drugs 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- TVIDEEHSOPHZBR-AWEZNQCLSA-N para-(benzoyl)-phenylalanine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1C(=O)C1=CC=CC=C1 TVIDEEHSOPHZBR-AWEZNQCLSA-N 0.000 claims description 2
- 150000002993 phenylalanine derivatives Chemical class 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 2
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 claims description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 1
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 claims 1
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 125000005138 alkoxysulfonyl group Chemical group 0.000 claims 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 214
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 213
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 187
- 239000000203 mixture Substances 0.000 description 129
- 239000007787 solid Substances 0.000 description 128
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 118
- 239000000243 solution Substances 0.000 description 110
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- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 94
- 235000019439 ethyl acetate Nutrition 0.000 description 79
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 74
- 238000006243 chemical reaction Methods 0.000 description 67
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 67
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- 238000000034 method Methods 0.000 description 58
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 36
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 30
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- 238000003756 stirring Methods 0.000 description 29
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- DMPZJACLHDWUFS-UHFFFAOYSA-N 1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CSC2=C1 DMPZJACLHDWUFS-UHFFFAOYSA-N 0.000 description 26
- 239000000284 extract Substances 0.000 description 26
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- 239000000543 intermediate Substances 0.000 description 24
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- 238000004587 chromatography analysis Methods 0.000 description 20
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
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- 150000001299 aldehydes Chemical class 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 150000001412 amines Chemical class 0.000 description 16
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 14
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Classifications
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- 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
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Claims (9)
1. Verbindung der Formel I:
wobei:
A
ausgewählt ist aus der Gruppe bestehend aus 1-Naphthylsulfonyl; 2-Naphthylsulfonyl;
substituiertes Naphthylsulfonyl, wo die Naphtyhlsubstituenten unabhängig gewählt
sind aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy,
Hydroxy, Halogen, Amido, Nitro, Amino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl;
eine D- oder L-Aminosäure ist, die an ihrem Carboxyterminus an den Stickstoff
gebunden ist, der in Formel I dargestellt ist und ausgewählt ist aus der Gruppe bestehend
aus Prolin und Pipecolinsäure,
wo der Aminoterminus der Aminosäure an ein Mitglied gebunden ist, ausgewählt aus
der Gruppe bestehend aus C&sub1;&submin;&sub4;-Alkyl; Tetrazol-5-yl-C&sub1;&submin;&sub2;-Alkyl; Carboxy-C&sub1;&submin;&sub4;-Alkyl;
C&sub1;&submin;&sub4;-Alkoxycarbonyl-C&sub1;&submin;&sub4;-Alkyl; substituiertes Phenyl-C&sub1;&submin;&sub4;-Alkyl, wenn die
Phenylsubstituenten unabhängig ausgewählt sind aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl,
Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-
Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl; 1,1-Diphenyl-C&sub1;&submin;&sub4;-
&sub4;-Alkyl; 3-Phenyl-2-hydroxypropionly; 2,2-Diphenyl-1-hydroxyethylcarbonyl;
[1,2,3,4]-Tetrahydroisochinoline-1-carbonyl; [1,2,3,4]-Tetrahydroisochinolin-3-
carbonyl; 1-Methylamino-1-cyclohexancarbonyl; 1-Hydroxy-1-cyclohexancarbonyl;
1-Hydroxy-1-phenylacetyl; 1-Cyclohexyl-1-hydroxyacetyl; 3-Phenyl-2-
hydroxypropionly; 3,3-Diphenyl-2-hydroxypropionyl; 3-Cyclohexyl-2-
hydroxypropionyl; Formyl; C&sub1;&submin;&sub4;-Alkoxycarbonyl; C&sub1;&submin;&sub1;&sub2;-Alkylcarbonyl; Perfluor-C&sub1;&submin;&sub4;-
Alkyl-C&sub0;&submin;&sub4;-Alkylcarbonyl; Phenyl-C&sub1;&submin;&sub4;-Alkylcarbonyl; substituiertes Phenyl-C&sub1;&submin;&sub4;-
Alkylcarbonyl, wo die Phenylsubstituenten unabhängig voneinander ausgewählt sind
aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy,
Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder
C&sub1;&submin;&sub4;-Alkoxycarbonyl; 1,1-Diphenyl-C&sub1;&submin;&sub4;-Alkylcarbonyl; substituiertes 1,1-Diphenyl-
C&sub1;&submin;&sub4;-Alkylcarbonyl, wo die Phenylsubstituenten unabhängig voneinander ausgewählt
sind aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy,
Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy
oder C&sub1;&submin;&sub4;-Alkoxycarbonyl; Perfluor-C&sub1;&submin;&sub4;-Alkylsulfonyl; C&sub1;&submin;&sub4;-Alkylsulfonyl; C&sub1;&submin;&sub4;-
Alkoxysulfonyl; Phenylsulfonyl; substituiertes Phenylsulfonyl, wo die
Phenylsubstituenten unabhängig voneinander ausgewählt sind aus einem oder mehreren C&sub1;&submin;&sub4;-Alkyl,
Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-
Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl; 10-
Kampfersulfonyl; Phenyl-C&sub1;&submin;&sub4;-Alkylsulfonyl; substituiertes Phenyl-C&sub1;&submin;&sub4;-Alkylsulfonyl;
Perfluor-C&sub1;&submin;&sub4;-Alkylsulfinyl; C&sub1;&submin;&sub4;-Alkylsulfinyl; Phenylsulfinyl; substituiertes
Phenylsulfinyl, wo die Phenylsubstituenten unabhängig voneinander ausgewählt sind aus
einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy,
Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-
Alkoxycarbonyl; Phenyl-C&sub1;&submin;&sub4;-Alkylsulfinyl; substituiertes Phenyl-C&sub1;&submin;&sub4;-Alkylsulfinyl,
wo die Phenylsubstituenten unabhängig voneinander ausgewählt sind aus einem oder
mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy, Halogen,
Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-
Alkoxycarbonyl; 1-Naphthylsulfonyl; 2-Naphthylsulfonyl; substituiertes
Naphthylsulfonyl, wo die Naphthylsubstituenten unabhängig voneinander ausgewählt sind aus
einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy,
Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-
Alkoxycarbonyl; 1-Naphthylsulfinyl; 2-Naphthylsulfinyl; und substituiertes
Naphthylsulfinyl, wo die Naphthylsubstituenten unabhängig voneinander ausgewählt sind aus
einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy,
Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-
Alkoxycarbonyl;
oder ein Polypeptid ist, das zwei Aminosäuren umfaßt,
wo die erste Aminosäure eine D- oder L-Aminosäure ist, gebunden über ihren
Carboxyterminus an den Stickstoff, dargestellt in Formel I und ausgewählt ist aus der
Gruppe bestehend aus Prolin, 3-Hydroxyprolin, 4-Hydroxyprolin, 3-(C&sub1;&submin;&sub4;-
Alkoxy)prolin, 4-(C&sub1;&submin;&sub4;-Alkoxy)prolin, 3,4-Dehydroprolin und Pipecolinsäure,
und die zweite D- oder L-Aminosäure an den Aminoterminus der ersten Aminosäure
gebunden ist und ausgewählt ist aus der Gruppe bestehend aus Phenylalanin; 4-
Benzoylphenylalanin; 4-Carboxyphenylalanin; 4-(Carboxy-C&sub0;&submin;&sub2;-Alkyl)phenylalanin;
substituiertes Phenylalanin, wo die Phenylsubstituenten unabhängig voneinander
ausgewählt sind aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-
Alkoxy, Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-
Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl; 3-Benzothienylalanin; 4-
Biphenylalanin; Homophenylalanin; Octahydroindol-2-carboxylsäure; 2-
Pyridylalanin: 3-Pyridylalanin; 4-Thiazolylalanin; 2-Thienylalanin; 3-(3-
Benzothienly)alanin; 3-Thienylalanin; Tryptophan; Tyrosin; Asparagin; 3-tri-C&sub1;&submin;&sub4;-
Alkylsilylalanin; Cyclohexylglycin; Diphenylglycin; Phenylglycin;
Methioninsulfoxid; Methioninsulfon; 2,2-Dicyclohexylalanin; 2-(1-Naphthylalanin); 2-(2-
Naphthylalanin); phenylsubstituierte Phenylalanine, wo die Substituenten ausgewählt
sind aus C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy, Halogen, Amido,
Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl;
Asparaginsäure, Asparaginsäure-4-C&sub1;&submin;&sub4;-Alkylester; Glutaminsäure, Glutaminsäure-5-
C&sub1;&submin;&sub4;-Alkylester; cyclo-C&sub3;&submin;&sub8;-Alkylalanin; substituiertes cyclo-C&sub3;&submin;&sub8;-Alkylalanin, wo die
Ringsubstituenten Carboxy, C&sub1;&submin;&sub4;-Alkylcarboxy, C&sub1;&submin;&sub4;-Alkoxycarbonyl oder
Aminocarbonyl sind; 2,2-Diphenylalanin und alle alpha-C&sub1;&submin;&sub5;-Alkyle aller Aminosäurederivate
derselben;
wo der Aminoterminus der zweiten Aminosäure nicht substituiert oder einfach
substituiert ist mit einem Mitglied der Gruppe bestehend aus Formyl; C&sub1;&submin;&sub1;&sub2;-Alkyl; Tetrazol-
5-yl-C&sub1;&submin;&sub2;-Alkyl; Carboxy-C&sub1;&submin;&sub8;-Alkyl; Carboalkoxy-C&sub1;&submin;&sub4;-Alkyl; Phenyl-C&sub1;&submin;&sub4;-Alkyl;
substituiertes Phenyl-C&sub1;&submin;&sub4;-Alkyl, wo die Phenylsubstituenten unabhängig voneinander
ausgewählt sind aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-
Alkoxy, Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-
Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl; 1,1-Diphenyl-C&sub1;&submin;&sub4;-Alkyl; C&sub1;&submin;&sub4;-
Alkoxycarbonyl; Phenyl-C&sub1;&submin;&sub6;-Alkoxycarbonyl; C&sub1;&submin;&sub1;&sub2;-Alkylcarbonyl; Perfluor-C&sub1;&submin;&sub4;-
Alkyl-C&sub0;&submin;&sub4;-Alkylcarbonyl; Phenyl-C&sub1;&submin;&sub4;-Alkylcarbonyl; substituiertes Phenyl-C&sub1;&submin;&sub4;-
Alkylcarbonyl, wo die Phenylsubstituenten unabhängig voneinander ausgewählt sind
aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy,
Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder
C&sub1;&submin;&sub4;-Alkoxycarbonyl; 1,1-Diphenyl-C&sub1;&submin;&sub4;-Alkylcarbonyl; C&sub1;&submin;&sub4;-Alkylsulfonyl; C&sub1;&submin;&sub4;-
Alkoxysulfonyl; Perfluor-C&sub1;&submin;&sub4;-Alkylsulfonyl; Phenylsulfonyl; substituiertes
Phenylsulfonyl, wo die Phenylsubstituenten unabhängig voneinander ausgewählt sind aus einem
oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy, Halogen,
Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-
Alkoxycarbonyl; C&sub1;&submin;&sub4;-Kampfersulfonyl; Phenyl-C&sub1;&submin;&sub4;-Alkylsulfonyl; substituiertes
Phenyl-C&sub1;&submin;&sub4;-Alkylsulfonyl; C&sub1;&submin;&sub4;-Alkylsulfinyl; Perfluor-C&sub1;&submin;&sub4;-Alkylsulfinyl; Phenylsulfinyl;
substituiertes Phenylsulfinyl, wo die Phenylsubstituenten unabhängig voneinander
ausgewählt sind aus einem oder mehreren von C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-
Alkoxy, Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-
Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl; Phenyl-C&sub1;&submin;&sub4;-Alkylsulfinyl;
substituiertes Phenyl-C&sub1;&submin;&sub4;-Alkylsulfinyl; 1-Naphthylsulfonly; 2-Naphthylsulfonyl;
substituiertes Naphthylsulfonyl, wo der Naphthylsubstituent ausgewählt ist aus C-Alkyl,
Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-
Alkylamino. C&sub1;&submin;&sub4;-Dialkylamino, Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl; 1-
Naphthylsulfinyl; 2-Naphthylsulfinyl und substituiertes Naphthylsulfinyl, wo der
Napthylsubstituent ausgewählt ist aus C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy,
Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino,
Carboxy oder C&sub1;&submin;&sub4;-Alkoxycarbonyl;
R&sub1; ausgewählt ist aus der Gruppe bestehend aus Wasserstoff und C&sub1;&submin;&sub5;-Alkyl;
R&sub2;
ausgewählt ist aus der Gruppe bestehend aus Amino-C&sub2;&submin;&sub5;-Alkyl, Guanidino-C&sub2;&submin;&sub5;-
Alkyl, C&sub1;&submin;&sub4;-Alkylguanidino-C&sub2;&submin;&sub5;-Alkyl, di-C&sub1;&submin;&sub4;-Alkylguanidino-C&sub2;&submin;&sub5;-Alkyl, Amidino-
C&sub2;&submin;&sub5;-Alkyl, C&sub1;&submin;&sub4;-Alkylamidino-C&sub2;&submin;&sub5;-Alkyl, di-C&sub1;&submin;&sub4;-Alkylamidino-C&sub2;&submin;&sub5;-Alkyl, C&sub1;&submin;&sub3;-
Akoxy-C&sub2;&submin;&sub5;-Alkyl, Phenyl, substituiertes Phenyl (wo die Substituenten unabhängig
voneinander ausgewählt sind aus einem oder mehreren von Amino, Amidino,
Guanidino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Halogen, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkyl,
C&sub1;&submin;&sub3;-Alkoxy oder Nitro), Benzyl, Phenyl-substituiertes Benzyl (wo die Substituenten
unabhängig voneinander ausgewählt sind aus einem oder mehreren von Amino,
Amidino, Guanidino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Halogen, Perfluor-C&sub1;&submin;&sub4;-Alkyl,
C&sub1;&submin;&sub4;-Alkyl,
C&sub1;&submin;&sub3;-Alkoxy oder Nitro), Hydroxy-C&sub2;&submin;&sub5;-Alkyl, C&sub1;&submin;&sub5;-Alkylamino-C&sub2;&submin;&sub5;-Alkyl,
C&sub1;&submin;&sub5;-Dialkylamino-C&sub2;&submin;&sub5;-Alkyl, 4-Aminocyclohexyl-C&sub0;&submin;&sub2;-Alkyl und C&sub1;&submin;&sub5;-Alkyl;
p 0 oder 1 ist
B
ist, wo n 0 bis 3 ist, R3 H oder C&sub1;&submin;&sub5;-Alkyl ist und die Carbonyl-Einheit von B an E
gebunden ist;
E
ein Heterozyklus ist, ausgewählt aus der Gruppe bestehend aus Oxazolin-2-yl, Oxazol-
2-yl, Thiazol-2-yl, Thiazol-5-yl, Thiazol-4-yl, Thiazolin-2-yl, Imidazol-2-yl, 4-Oxo-2-
chinoxalin-2-yl, 2-Pyridyl, 3-Pyridyl, Benzo[b]thiophen-2-yl, Benzoxazol-2-yl,
Benzimidazol-2-yl, Benzothiazol-2-yl, Triazol-4-yl, Triazol-6-yl, Tetrazol-2-yl,
Pyrimidin-2-yl, Chinolin-2-yl, Indol-2-yl, Pyrazol-2-yl, 4,5,6,7-Tetrahydrobenzothiazol-2-yl,
Naphtho[2,1-d]thiazol-2-yl, Naphtho[1,2-d]thiazol-2-yl-chinoxalin-2-yl, Isochinolin-
1-yl, Isochinolin-3-yl, Benzo[b]furan-2-yl, Pyrazin-2-yl, Chinazolin-2-yl, Isothiazol-5-
yl, Isothiazol-3-yl, Purin-8-yl und ein substituierter Heterozyklus, wo die
Substituenten unabhängig voneinander ausgewählt sind aus C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-
Alkoxy, Hydroxy, Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-
Dialkylamino, Carboxy, C&sub1;&submin;&sub4;-Alkoxycarbonyl, Hydroxy oder Phenyl-C&sub1;&submin;&sub4;-
Alkylaminocarbonyl;
oder pharmazeutisch akzeptable Salze derselben.
2. Verbindung nach Anspruch 1, wobei:
A ein Polypeptid ist, das zwei Aminosäuren, wie in Anspruch 1 definiert, umfaßt; und
p 0 ist.
3. Verbindung nach Anspruch 2, wobei:
R&sub2; ausgewählt ist aus der Gruppe bestehend aus Amino-C&sub2;&submin;&sub5;-Alkyl, Guanidino-C&sub2;&submin;&sub5;-
Alkyl, Amidino-C&sub2;&submin;&sub5;-Alkyl, C&sub1;&submin;&sub5;-Alkylamino-C&sub2;&submin;&sub5;-Alkyl, C&sub1;&submin;&sub5;-Dialkylamino-C&sub2;&submin;&sub5;-
Alkyl, 4-Aminocyclohexyl-C&sub0;&submin;&sub2;-Alkyl, 3-Aminocyclohexyl-C&sub0;&submin;&sub2;-Alkyl und C&sub1;&submin;&sub5;-Alkyl.
4. Verbindung nach Anspruch 3, wobei:
E ein Heterozyklus ist, ausgewählt aus der Gruppe bestehend aus Oxazolin-2-yl,
Oxazol-2-yl, Thiazol-2-yl, Thiazol-5-yl, Thiazol-4-yl, Thiazolin-2-yl, Imidazol-2-yl, 4-
Oxo-2-chinoxalin-2-yl, 2-Pyridyl, Benzo[b]thiophen-2-yl, Benzoxazol-2-yl,
Benzimidazol-2-yl, Benzothiazol-2-yl, Triazol-4-yl, Triazol-6-yl, Tetrazol-2-yl, Pyrimidin-2-
yl, Chinolin-2-yl, Indol-2-yl, Pyrazol-2-yl, [4,5,6,7]-Tetrahydrobezonthiazol-2-yl,
Naphtho[2,1-d]thiazol-2-yl, Naphtho[1,2-d]thiazol-2-yl, Chinoxalin-2-yl, Isochinolin-
1-yl, Isochinolin-3-yl, Benzo[b]furan-2-yl, Pyrazin-2-yl, Chinazolin-2-yl, Isothiazol-5-
yl, Isothiazol-3-yl, Purin-8-yl und ein substituierter Heterozyklus, wo die
Substituenten ausgewählt sind aus C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy,
Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy, C&sub1;&submin;&sub4;-
Alkoxycarbonyl, Hydroxy oder Phenyl-C&sub1;&submin;&sub4;-Alkylaminocarbonyl.
5. Verbindung nach Anspruch 4, wobei:
E ein Heterozyklus ist, ausgewählt aus der Gruppe bestehend aus Thiazol-2-yl,
Thiazol-5-yl, Thiazol-4-yl, Thiazolin-2-yl, Benzoxazol-2-yl, Benzimidazol-2-yl, Imidazol-
2-yl, 4-Oxo-2-chinoxalin-2-yl, Benzothiazol-2-yl, Triazol-4-yl, Triazol-6-yl, Tetrazol-
2-yl, Pyrimidin-2-yl, Chinolin-2-yl, Pyrazol-2-yl, [4,5,6,7]-Tetrahydrobenzothiazol-2-
yl, Naphtho[2,1-d]thiazol-2-yl, Naphtho[1,2-d]thiazol-2-yl, Chinazolin-2-yl,
Isothiazol-5-yl, Isothiazol-3-yl, Purin-8-yl und ein substituierter Heterozyklus, wo die
Substituenten ausgewählt sind aus C&sub1;&submin;&sub4;-Alkyl, Perfluor-C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Hydroxy,
Halogen, Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy, C&sub1;&submin;&sub4;-
Alkoxycarbonyl oder Hydroxy.
6. Verbindung nach Anspruch 5, wobei:
E ein Heterozyklus ist, ausgewählt aus der Gruppe bestehend aus Thiazol-2-yl,
Thiazol-5-yl, Thiazol-4-yl, Thiazolin-2-yl, Benzothiazol-2-yl, 4,5,6,7-
Tetrahydrobenzothiazol-2-yl, Naphtho[2,1-d]thiazol-2-yl, Naphtho[1,2-d]thiazol-2-yl,
Isothiazol-5-yl, Isothiazol-3-yl und ein substituierter Heterozyklus, wobei die Substituenten
ausgewählt sind aus C&sub1;&submin;&sub4;-Alkyl, C&sub1;&submin;&sub4;-Alkoxy, Perfluor, Hydroxy, Halogen,
Amido, Nitro, Amino, C&sub1;&submin;&sub4;-Alkylamino, C&sub1;&submin;&sub4;-Dialkylamino, Carboxy, C&sub1;&submin;&sub4;-
Alkoxycarbonyl oder Hydroxy.
7. Verbindung nach Anspruch 1, die
N-Methyl-D-phenylalanyl-N-[4-[aminoiminomethyl)amino]-1S-[(benzothiazol-2-
yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[5-[aminoiminomethyl)amino]-1S-(benzothiazol-2-
yl)carbonyl]phenyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[aminoiminomethyl)amino]-2S-[(6-
methoxycarbonylbenzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-[(6-
carboxybenzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[aminoiminomethyl)amino]-1S-[(6-
carboxamidobenzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[-4-[(aminoiminomethyl)amino]-1S-[(6-
Hydroxymethylbenzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[-4-[(aminoiminomethyl)amino]-1S-[(6-
fluorobenzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-[(4-
ethoxycarbonylthiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-[(4-carboxythiazol-2-
yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-[(6-
methoxybenzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethylamino]-1S-[(6-
Hydroxybenzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-cyclohexylalanyl-N-[4[(aminoiminomethyl)amino]-1S-[(benzothiazol-2-
yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino-1S-[(naptho[2,1-
d]thiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-(4-fluorphenyl)alanyl-N-[4-[(aminoiminomethyl)amino]-1S-
(benzothiazol-2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylglycyl-N-[4-[(aminoiminomethyl)amino]-1S-[benzothiazol-2-
yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-(diphenyl)alanyl-N-(4-[(aminoiminomethyl)amino]-1S-[(benzothiazol-2-
yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-cyclohexylglycyl-N-[4-[(aminoiminomethyl)amino]-1S-[(benzothiazol-
2-yl)carbonyl]butyl]-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-[(4,5,6,7-
tetrahydrobenzothiazol-2-yl)-carbonyl]butyl]-L-prolinamid;
D-Phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-[(benzothiazol-2-
yl)carbonyl]butyl-L-prolinamid;
N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-[(benzothiazol-2-
yl)carbonyl]butyl]-2S-piperidincarboxamid;
2,2-Diphenylglycyl-N-[4-[(aminoiminomethyl)amino-1S-[(benzothiazol-2-
yl)carbonyl]butyl-L-prolinamid;
α-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1S-benzothiazol-2-
yl)carbonyl]butyl]-L-prolinamid; oder
1-(N-Methylamino)-1-cyclohexylcarbonyl-N-[4-[(aminoiminomethyl)amino-1S-
[(benzothiazol-2-yl)carbonyl]butyl]-L-prolinamid ist.
8. Pharmazeutische Zusammensetzung, die einen pharmazeutisch akzeptablen Träger
und eine therapeutisch wirksame Menge einer Verbindung nach einem der Ansprüche
1 bis 7 umfaßt.
9. Verbindung nach einem der Ansprüche 1 bis 7 oder die pharmazeutische
Zusammensetzung nach Anspruch 9 zur Verwendung beim Inhibieren von Thrombin oder
Trypsin in einem Medium oder zur Verwendung bei der Behandlung einer Thrombin- oder
Trypsin-vermittelten Krankheit in einem Säugetier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/486,473 US5523308A (en) | 1995-06-07 | 1995-06-07 | Peptidyl heterocycles useful in the treatment of thrombin related disorders |
| PCT/US1996/008456 WO1996040748A1 (en) | 1995-06-07 | 1996-06-03 | Peptidyl heterocycles useful in the treatment of thrombin related disorders |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69625691D1 DE69625691D1 (de) | 2003-02-13 |
| DE69625691T2 true DE69625691T2 (de) | 2003-10-23 |
Family
ID=23932026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69625691T Expired - Fee Related DE69625691T2 (de) | 1995-06-07 | 1996-06-03 | Verabreichung von peptidylheterocyclen zur behandlung von thrombin in zusammenhang stehenden krankheiten |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5523308A (de) |
| EP (1) | EP0833839B1 (de) |
| JP (1) | JPH11506762A (de) |
| KR (1) | KR100434667B1 (de) |
| CN (1) | CN1146575C (de) |
| AT (1) | ATE230757T1 (de) |
| AU (1) | AU721079B2 (de) |
| CA (1) | CA2224110A1 (de) |
| CZ (1) | CZ386997A3 (de) |
| DE (1) | DE69625691T2 (de) |
| DK (1) | DK0833839T3 (de) |
| ES (1) | ES2191102T3 (de) |
| IL (1) | IL122436A (de) |
| MX (1) | MX9709915A (de) |
| NO (1) | NO975747L (de) |
| NZ (1) | NZ309523A (de) |
| PL (1) | PL184986B1 (de) |
| RU (1) | RU2181125C2 (de) |
| TW (1) | TW470751B (de) |
| WO (1) | WO1996040748A1 (de) |
| ZA (1) | ZA964759B (de) |
Families Citing this family (64)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4857633A (en) * | 1984-06-25 | 1989-08-15 | Exxon Research & Engineering Company | Method for high temperature phase separation of solutions containing polymers |
| US5721214A (en) * | 1995-06-07 | 1998-02-24 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
| US6069130A (en) * | 1995-06-07 | 2000-05-30 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US6022861A (en) * | 1995-06-07 | 2000-02-08 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US5827860A (en) * | 1995-06-07 | 1998-10-27 | Ortho Pharmaceutical Corporation | Peptidyl heterocycles useful in the treatment of thrombin related disorders |
| US6211154B1 (en) | 1995-06-07 | 2001-04-03 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US5827866A (en) * | 1995-06-07 | 1998-10-27 | Ortho Pharmaceutical Corporation | Peptidyl heterocycles useful in the treatment of thrombin related disorders |
| US6046169A (en) * | 1995-06-07 | 2000-04-04 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
| US5919765A (en) * | 1995-06-07 | 1999-07-06 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
| IL119466A (en) * | 1995-11-03 | 2001-08-26 | Akzo Nobel Nv | Thrombin inhibitors, their preparation and pharmaceutical compositions containing them |
| US5811402A (en) * | 1996-03-22 | 1998-09-22 | Eli Lilly And Company | Antithrombotic diamides |
| US6245743B1 (en) | 1996-06-05 | 2001-06-12 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
| US6063794A (en) * | 1996-10-11 | 2000-05-16 | Cor Therapeutics Inc. | Selective factor Xa inhibitors |
| US6194435B1 (en) * | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
| US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| EP0932608A1 (de) * | 1996-10-11 | 1999-08-04 | Cor Therapeutics, Inc. | Selektive factor xa inhibitoren |
| CA2268270A1 (en) * | 1996-10-11 | 1998-04-23 | Cor Therapeutics, Inc. | Heterocyclic derivatives as factor xa inhibitors |
| US6369080B2 (en) | 1996-10-11 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| AU743735B2 (en) * | 1996-10-11 | 2002-02-07 | Millennium Pharmaceuticals, Inc. | Selective factor Xa inhibitors |
| NZ500351A (en) * | 1997-04-14 | 2001-10-26 | Cor Therapeutics Inc | Cyclic diaza compounds as selective factor Xa inhibitors |
| WO1998046627A1 (en) | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | SELECTIVE FACTOR Xa INHIBITORS |
| CA2285685A1 (en) | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | Selective factor xa inhibitors |
| EP0884325A1 (de) * | 1997-04-24 | 1998-12-16 | Akzo Nobel N.V. | Inhibitoren des Thrombins, die einen peptid-Heterocyclus aufweisen |
| US5877156A (en) * | 1997-04-24 | 1999-03-02 | Akzo Nobel, N.V. | Thrombin inhibitors |
| WO1998051684A1 (en) * | 1997-05-15 | 1998-11-19 | Eli Lilly And Company | Antithrombotic compound |
| US8039026B1 (en) * | 1997-07-28 | 2011-10-18 | Johnson & Johnson Consumer Companies, Inc | Methods for treating skin pigmentation |
| AU2006252275A1 (en) * | 1997-07-28 | 2007-01-25 | Johnson & Johnson Consumer Companies, Inc. | Methods for treating skin pigmentation |
| US6228854B1 (en) | 1997-08-11 | 2001-05-08 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6218382B1 (en) | 1997-08-11 | 2001-04-17 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
| US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6323219B1 (en) | 1998-04-02 | 2001-11-27 | Ortho-Mcneil Pharmaceutical, Inc. | Methods for treating immunomediated inflammatory disorders |
| US6750229B2 (en) | 1998-07-06 | 2004-06-15 | Johnson & Johnson Consumer Companies, Inc. | Methods for treating skin pigmentation |
| US8106094B2 (en) | 1998-07-06 | 2012-01-31 | Johnson & Johnson Consumer Companies, Inc. | Compositions and methods for treating skin conditions |
| US8093293B2 (en) * | 1998-07-06 | 2012-01-10 | Johnson & Johnson Consumer Companies, Inc. | Methods for treating skin conditions |
| WO2000044733A1 (en) * | 1999-01-27 | 2000-08-03 | Ortho-Mcneil Pharmaceutical, Inc. | Peptidyl heterocyclic ketones useful as tryptase inhibitors |
| US7985404B1 (en) | 1999-07-27 | 2011-07-26 | Johnson & Johnson Consumer Companies, Inc. | Reducing hair growth, hair follicle and hair shaft size and hair pigmentation |
| US7309688B2 (en) * | 2000-10-27 | 2007-12-18 | Johnson & Johnson Consumer Companies | Topical anti-cancer compositions and methods of use thereof |
| GB0004686D0 (en) * | 2000-02-28 | 2000-04-19 | Aventis Pharma Ltd | Chemical compounds |
| SI20582A (sl) | 2000-05-05 | 2001-12-31 | Univerza V Ljubljani | Novi inhibitorji trombina, njihova priprava in uporaba |
| US6960597B2 (en) * | 2000-06-30 | 2005-11-01 | Orth-Mcneil Pharmaceutical, Inc. | Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists |
| US8431550B2 (en) | 2000-10-27 | 2013-04-30 | Johnson & Johnson Consumer Companies, Inc. | Topical anti-cancer compositions and methods of use thereof |
| US6555143B2 (en) | 2001-02-28 | 2003-04-29 | Johnson & Johnson Consumer Products, Inc. | Legume products |
| US7192615B2 (en) | 2001-02-28 | 2007-03-20 | J&J Consumer Companies, Inc. | Compositions containing legume products |
| KR20030080810A (ko) * | 2002-04-11 | 2003-10-17 | 주식회사 엘지생명과학 | 아미노피리도아릴 그룹을 가진 선택적 트롬빈 억제제 |
| MXPA04010089A (es) * | 2002-04-16 | 2004-12-13 | Axys Pharm Inc | Proceso para preparar reactivos de heteroarilo y heterocicloalquilmagnesio insaturado y sus usos. |
| US7375093B2 (en) * | 2002-07-05 | 2008-05-20 | Intrexon Corporation | Ketone ligands for modulating the expression of exogenous genes via an ecdysone receptor complex |
| US20040063593A1 (en) * | 2002-09-30 | 2004-04-01 | Wu Jeffrey M. | Compositions containing a cosmetically active organic acid and a legume product |
| US7393920B2 (en) | 2003-06-23 | 2008-07-01 | Cem Corporation | Microwave-assisted peptide synthesis |
| US20050176755A1 (en) * | 2003-10-31 | 2005-08-11 | Dyatkin Alexey B. | Aza-bridged-bicyclic amino acid derivatives as alpha4 integrin antagonists |
| MXPA06009099A (es) * | 2004-02-10 | 2007-02-02 | Johnson & Johnson | Piridazinona ureas como antagonistas de las integrinas alfa-4. |
| GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
| AU2007253819B2 (en) | 2006-05-23 | 2011-02-17 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| PT2019837E (pt) * | 2006-05-23 | 2011-07-05 | Irm Llc | Compostos e composições como inibidores das proteases activadoras de canal |
| TWI389899B (zh) * | 2006-08-08 | 2013-03-21 | Msd Oss Bv | 具口服活性之凝血酶抑制劑 |
| WO2008097673A1 (en) * | 2007-02-09 | 2008-08-14 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| CA2677487A1 (en) * | 2007-02-09 | 2008-08-14 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| US9365853B2 (en) * | 2011-06-02 | 2016-06-14 | SOCPRA Sciences Sante et Humaines S.E.C. | Matriptase inhibitors and uses thereof against orthomyxoviridae infections |
| CN104003984B (zh) * | 2014-06-16 | 2016-03-02 | 山东大学 | 噻唑-4-甲酰基哌嗪衍生物及其制备方法与应用 |
| ES2819218T3 (es) | 2014-10-06 | 2021-04-15 | Cortexyme Inc | Inhibidores de lisina gingipaína |
| JP6877424B2 (ja) * | 2015-11-09 | 2021-05-26 | コーテクシーミー， インコーポレイテッド | アルギニンジンジパインの阻害剤 |
| BR112019004864A8 (pt) | 2016-09-16 | 2023-03-07 | Cortexyme Inc | Inibidores cetona de lisina gingipain |
| US20190309020A1 (en) * | 2016-11-22 | 2019-10-10 | Ohio State Innovation Foundation | Cell-penetrating peptide sequences |
| EP3790890A4 (de) | 2018-05-09 | 2022-03-02 | Ohio State Innovation Foundation | Zyklische, zellpenetrierende peptide mit einem oder mehreren hydrophoben resten |
| CN117143179B (zh) * | 2023-09-18 | 2024-07-12 | 安徽峆一药业股份有限公司 | 一种凝血酶发色底物s-2238的合成方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0503203A1 (de) * | 1991-03-15 | 1992-09-16 | Merrell Dow Pharmaceuticals Inc. | Neue Thrombin-Inhibitoren |
| DE69330823T2 (de) * | 1992-02-13 | 2002-05-02 | Merrell Pharmaceuticals Inc., Cincinnati | Thiacyclische piperidinylderivate |
| JPH0820597A (ja) * | 1994-07-07 | 1996-01-23 | Meiji Seika Kaisha Ltd | トロンビン阻害作用を有する複素環カルボニル化合物 |
-
1995
- 1995-06-07 US US08/486,473 patent/US5523308A/en not_active Expired - Lifetime
-
1996
- 1996-06-03 NZ NZ309523A patent/NZ309523A/xx unknown
- 1996-06-03 PL PL96323825A patent/PL184986B1/pl not_active IP Right Cessation
- 1996-06-03 WO PCT/US1996/008456 patent/WO1996040748A1/en not_active Application Discontinuation
- 1996-06-03 JP JP9501056A patent/JPH11506762A/ja not_active Ceased
- 1996-06-03 IL IL12243696A patent/IL122436A/en not_active IP Right Cessation
- 1996-06-03 DK DK96917014T patent/DK0833839T3/da active
- 1996-06-03 CA CA002224110A patent/CA2224110A1/en not_active Abandoned
- 1996-06-03 CZ CZ973869A patent/CZ386997A3/cs unknown
- 1996-06-03 RU RU98100420/04A patent/RU2181125C2/ru not_active IP Right Cessation
- 1996-06-03 AT AT96917014T patent/ATE230757T1/de not_active IP Right Cessation
- 1996-06-03 CN CNB961961031A patent/CN1146575C/zh not_active Expired - Fee Related
- 1996-06-03 ES ES96917014T patent/ES2191102T3/es not_active Expired - Lifetime
- 1996-06-03 DE DE69625691T patent/DE69625691T2/de not_active Expired - Fee Related
- 1996-06-03 EP EP96917014A patent/EP0833839B1/de not_active Expired - Lifetime
- 1996-06-03 AU AU59713/96A patent/AU721079B2/en not_active Ceased
- 1996-06-03 KR KR1019970709049A patent/KR100434667B1/ko not_active IP Right Cessation
- 1996-06-06 ZA ZA9604759A patent/ZA964759B/xx unknown
- 1996-07-08 TW TW085108206A patent/TW470751B/zh not_active IP Right Cessation
-
1997
- 1997-12-05 NO NO975747A patent/NO975747L/no not_active Application Discontinuation
- 1997-12-08 MX MX9709915A patent/MX9709915A/es not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR100434667B1 (ko) | 2004-09-24 |
| WO1996040748A1 (en) | 1996-12-19 |
| EP0833839A1 (de) | 1998-04-08 |
| CA2224110A1 (en) | 1996-12-19 |
| US5523308A (en) | 1996-06-04 |
| JPH11506762A (ja) | 1999-06-15 |
| CN1146575C (zh) | 2004-04-21 |
| NO975747D0 (no) | 1997-12-05 |
| MX9709915A (es) | 1998-08-30 |
| DK0833839T3 (da) | 2003-04-14 |
| AU5971396A (en) | 1996-12-30 |
| ES2191102T3 (es) | 2003-09-01 |
| ZA964759B (en) | 1997-12-08 |
| NO975747L (no) | 1998-02-03 |
| AU721079B2 (en) | 2000-06-22 |
| KR19990022568A (ko) | 1999-03-25 |
| IL122436A (en) | 2004-06-20 |
| CZ386997A3 (cs) | 1998-07-15 |
| TW470751B (en) | 2002-01-01 |
| CN1192747A (zh) | 1998-09-09 |
| DE69625691D1 (de) | 2003-02-13 |
| PL184986B1 (pl) | 2003-01-31 |
| RU2181125C2 (ru) | 2002-04-10 |
| ATE230757T1 (de) | 2003-01-15 |
| PL323825A1 (en) | 1998-04-27 |
| EP0833839B1 (de) | 2003-01-08 |
| NZ309523A (en) | 1999-11-29 |
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