KR19990087415A - 세린 프로테아제 억제제 - Google Patents
세린 프로테아제 억제제 Download PDFInfo
- Publication number
- KR19990087415A KR19990087415A KR1019980706833A KR19980706833A KR19990087415A KR 19990087415 A KR19990087415 A KR 19990087415A KR 1019980706833 A KR1019980706833 A KR 1019980706833A KR 19980706833 A KR19980706833 A KR 19980706833A KR 19990087415 A KR19990087415 A KR 19990087415A
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- pro
- chr
- boc
- cha
- 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.)
- Ceased
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- 239000003001 serine protease inhibitor Substances 0.000 title description 3
- 229940122055 Serine protease inhibitor Drugs 0.000 title 1
- 101710102218 Serine protease inhibitor Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 108090000190 Thrombin Proteins 0.000 claims abstract description 20
- 229960004072 thrombin Drugs 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000002243 precursor Substances 0.000 claims abstract description 11
- -1 C 1 -C 6 alkoxy Chemical group 0.000 claims description 180
- 229910052799 carbon Inorganic materials 0.000 claims description 73
- 238000000034 method Methods 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 230000002209 hydrophobic effect Effects 0.000 claims description 22
- 150000001413 amino acids Chemical class 0.000 claims description 21
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 9
- 150000008574 D-amino acids Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical group OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 7
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical group OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 7
- IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical group OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 claims description 7
- CQYBNXGHMBNGCG-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCCC2NC(C(=O)O)CC21 CQYBNXGHMBNGCG-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 claims description 6
- 229950001139 timonacic Drugs 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 4
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004473 Threonine Substances 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 239000000651 prodrug Substances 0.000 claims description 3
- 229940002612 prodrug Drugs 0.000 claims description 3
- 150000008575 L-amino acids Chemical group 0.000 claims description 2
- JUYPZDAEPYSHNZ-UHFFFAOYSA-N S1C=NC2=C1C=CC=C2.S2C=NCC2 Chemical compound S1C=NC2=C1C=CC=C2.S2C=NCC2 JUYPZDAEPYSHNZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 238000011282 treatment Methods 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 4
- 230000014508 negative regulation of coagulation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 276
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 189
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 168
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 131
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 123
- 239000000243 solution Substances 0.000 description 116
- 239000000203 mixture Substances 0.000 description 83
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 77
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 72
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 56
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 52
- 239000000741 silica gel Substances 0.000 description 51
- 229910002027 silica gel Inorganic materials 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 239000011541 reaction mixture Substances 0.000 description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
- 239000000377 silicon dioxide Substances 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 37
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 229910052938 sodium sulfate Inorganic materials 0.000 description 30
- 235000011152 sodium sulphate Nutrition 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 235000001014 amino acid Nutrition 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000012267 brine Substances 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 230000008878 coupling Effects 0.000 description 16
- 238000010168 coupling process Methods 0.000 description 16
- 238000005859 coupling reaction Methods 0.000 description 16
- 238000010511 deprotection reaction Methods 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 229940122388 Thrombin inhibitor Drugs 0.000 description 8
- 150000008064 anhydrides Chemical class 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000003868 thrombin inhibitor Substances 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- 108010016626 Dipeptides Proteins 0.000 description 5
- 125000006319 alkynyl amino group Chemical group 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 238000007127 saponification reaction Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- HZVTZSFWPLLBRF-UHFFFAOYSA-N 4-chlorobut-2-ynylazanium;chloride Chemical compound Cl.NCC#CCCl HZVTZSFWPLLBRF-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108010022999 Serine Proteases Proteins 0.000 description 3
- 102000012479 Serine Proteases Human genes 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 239000004019 antithrombin Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 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 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- PMLHJHJCNMWPBW-UHFFFAOYSA-N n-(4-chlorobut-2-ynyl)acetamide Chemical compound CC(=O)NCC#CCCl PMLHJHJCNMWPBW-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 3
- ZPRHVPHDENDZTP-CABCVRRESA-N (2s)-1-[(2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@@H](NC(=O)OC(C)(C)C)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZPRHVPHDENDZTP-CABCVRRESA-N 0.000 description 2
- WFPSMPYVXFVVFA-LURJTMIESA-N (2s)-4-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobutanoic acid Chemical compound COC(=O)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C WFPSMPYVXFVVFA-LURJTMIESA-N 0.000 description 2
- IHEPKHXGAAYYQN-UHFFFAOYSA-N 2,6-diaminohex-4-ynoic acid;dihydrochloride Chemical compound Cl.Cl.NCC#CCC(N)C(O)=O IHEPKHXGAAYYQN-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- GYIUDLLQLVWKPP-UHFFFAOYSA-N 2-propylpentanoyl 2-propylpentanoate Chemical compound CCCC(CCC)C(=O)OC(=O)C(CCC)CCC GYIUDLLQLVWKPP-UHFFFAOYSA-N 0.000 description 2
- 125000003974 3-carbamimidamidopropyl group Chemical group C(N)(=N)NCCC* 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
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- 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
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- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- 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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
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- 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
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- 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
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
-
- 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
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP96200543 | 1996-03-01 | ||
| EP96200543.5 | 1996-03-01 |
Publications (1)
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| KR19990087415A true KR19990087415A (ko) | 1999-12-27 |
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| CA2246256A1 (en) * | 1996-02-13 | 1997-08-21 | Akzo Nobel Nv | Serine protease inhibitors |
| US6214841B1 (en) | 1997-05-15 | 2001-04-10 | Eli Lilly And Company | Antithrombotic compound |
| TR200003159T2 (tr) | 1998-04-30 | 2001-09-21 | Agouron Pharmaceuticals,Inc. | Antipicornaviral bileşikler, hazırlanışları ve kullanımları |
| EP1105412A1 (en) * | 1998-08-17 | 2001-06-13 | Cortech, Inc. | Serine protease inhibitors comprising alpha-keto heterocycles |
| AU3731400A (en) | 1999-03-05 | 2000-09-21 | Trustees Of University Technology Corporation, The | Methods and compositions useful in inhibiting apoptosis |
| WO2000051623A2 (en) | 1999-03-05 | 2000-09-08 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of nitric oxide-induced clinical conditions |
| US6849605B1 (en) | 1999-03-05 | 2005-02-01 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of viral infections |
| JP2003506457A (ja) | 1999-08-04 | 2003-02-18 | アグロン・ファーマシュウティカルズ・インコーポレーテッド | 抗ピコルナウィルス化合物及び組成物、その医薬的使用、並びにその合成のための物質 |
| WO2001096297A2 (en) | 2000-06-14 | 2001-12-20 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis |
| SK742003A3 (en) | 2000-07-21 | 2003-06-03 | Schering Corp | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
| US7012066B2 (en) | 2000-07-21 | 2006-03-14 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
| US7244721B2 (en) | 2000-07-21 | 2007-07-17 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
| HUP0304058A2 (hu) | 2001-01-30 | 2004-04-28 | Bristol-Myers Squibb Company | Xa faktor szulfonamid-laktám inhibitorok és alkalmazásuk és ezeket tartalmazó gyógyszerkészítmények |
| US7405210B2 (en) * | 2003-05-21 | 2008-07-29 | Osi Pharmaceuticals, Inc. | Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase |
| ATE483708T1 (de) | 2004-03-08 | 2010-10-15 | Prosidion Ltd | Pyrrolopyridin-2-carbonsäurehydrazide als inhibitoren von glykogenphosphorylase |
| ATE424821T1 (de) | 2004-12-02 | 2009-03-15 | Prosidion Ltd | Pyrrolopyridin-2-karbonsäureamide |
| CA2740197A1 (en) * | 2008-10-15 | 2010-04-22 | Danisco Us Inc. | Modified variant bowman birk protease inhibitors |
| JP7164521B2 (ja) | 2016-06-21 | 2022-11-01 | オリオン・オフサルモロジー・エルエルシー | 炭素環式プロリンアミド誘導体 |
| JP7179721B2 (ja) | 2016-06-21 | 2022-11-29 | オリオン・オフサルモロジー・エルエルシー | 複素環式プロリンアミド誘導体 |
| EP4178955A1 (en) | 2020-07-11 | 2023-05-17 | Pfizer Inc. | Antiviral heteroaryl ketone derivatives |
| US11351149B2 (en) | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
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| US4556655A (en) * | 1984-09-24 | 1985-12-03 | Schering Corporation | Antihypertensive compounds having both diuretic and angiotensin converting enzyme inhibitory activity |
| CA2008116C (en) * | 1989-02-23 | 2001-11-20 | Thomas Weller | Glycine derivatives |
| ZW11290A1 (en) * | 1989-07-14 | 1990-10-31 | Smithkline Beecham Corp | Hemoregulatory peptides |
| EP0699074B1 (en) | 1993-04-30 | 2002-11-13 | Merck & Co. Inc. | Thrombin inhibitors |
| US5672582A (en) * | 1993-04-30 | 1997-09-30 | Merck & Co., Inc. | Thrombin inhibitors |
| SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
| ZA951618B (en) | 1994-03-04 | 1996-08-27 | Lilly Co Eli | Antithrombotic agents |
| ZA951617B (en) | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
| US5561146A (en) | 1994-06-10 | 1996-10-01 | Bristol-Myers Squibb Company | Modified guanidino and amidino thrombin inhibitors |
| JPH10503176A (ja) * | 1994-06-17 | 1998-03-24 | コーバス インターナショナル， インコーポレイテッド | 酵素インヒビターとしての３−アミノ−２−オキソ−１−ピペリジン酢酸誘導体 |
| 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 |
| CN1175259A (zh) | 1994-12-22 | 1998-03-04 | 生化制药有限公司 | 低分子量双环凝血酶抑制剂 |
-
1997
- 1997-02-25 IL IL12031097A patent/IL120310A/en not_active IP Right Cessation
- 1997-02-25 TW TW086102261A patent/TW442452B/zh not_active IP Right Cessation
- 1997-02-26 KR KR1019980706833A patent/KR19990087415A/ko not_active Ceased
- 1997-02-26 ZA ZA9701667A patent/ZA971667B/xx unknown
- 1997-02-26 JP JP9530600A patent/JP2000506837A/ja not_active Ceased
- 1997-02-26 CN CN97192682A patent/CN1212704A/zh active Pending
- 1997-02-26 CZ CZ982778A patent/CZ277898A3/cs unknown
- 1997-02-26 DK DK97905099T patent/DK0886647T3/da active
- 1997-02-26 CA CA002246246A patent/CA2246246A1/en not_active Abandoned
- 1997-02-26 WO PCT/EP1997/000938 patent/WO1997031937A1/en not_active Ceased
- 1997-02-26 ES ES97905099T patent/ES2180933T3/es not_active Expired - Lifetime
- 1997-02-26 PT PT97905099T patent/PT886647E/pt unknown
- 1997-02-26 TR TR1998/01704T patent/TR199801704T2/xx unknown
- 1997-02-26 AU AU18775/97A patent/AU709330B2/en not_active Ceased
- 1997-02-26 HU HU9900390A patent/HUP9900390A3/hu unknown
- 1997-02-26 RU RU98117949/04A patent/RU2178419C2/ru active
- 1997-02-26 EP EP97905099A patent/EP0886647B1/en not_active Expired - Lifetime
- 1997-02-26 US US09/142,110 patent/US6410684B1/en not_active Expired - Fee Related
- 1997-02-26 DE DE69714222T patent/DE69714222T2/de not_active Expired - Fee Related
- 1997-02-26 PL PL97328875A patent/PL328875A1/xx unknown
- 1997-02-26 AT AT97905099T patent/ATE221080T1/de not_active IP Right Cessation
- 1997-02-26 NZ NZ331484A patent/NZ331484A/xx unknown
- 1997-02-26 BR BR9707808A patent/BR9707808A/pt not_active Application Discontinuation
- 1997-03-03 AR ARP970100833A patent/AR006310A1/es unknown
-
1998
- 1998-08-31 NO NO983991A patent/NO983991L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ES2180933T3 (es) | 2003-02-16 |
| EP0886647A1 (en) | 1998-12-30 |
| ATE221080T1 (de) | 2002-08-15 |
| IL120310A (en) | 2002-02-10 |
| HUP9900390A2 (hu) | 1999-06-28 |
| EP0886647B1 (en) | 2002-07-24 |
| HUP9900390A3 (en) | 2000-11-28 |
| CN1212704A (zh) | 1999-03-31 |
| ZA971667B (en) | 1997-09-10 |
| AR006310A1 (es) | 1999-08-25 |
| DE69714222T2 (de) | 2003-02-20 |
| AU709330B2 (en) | 1999-08-26 |
| JP2000506837A (ja) | 2000-06-06 |
| PL328875A1 (en) | 1999-03-01 |
| IL120310A0 (en) | 1997-06-10 |
| NZ331484A (en) | 2000-01-28 |
| DE69714222D1 (de) | 2002-08-29 |
| NO983991L (no) | 1998-10-30 |
| NO983991D0 (no) | 1998-08-31 |
| TW442452B (en) | 2001-06-23 |
| HK1021541A1 (en) | 2000-06-16 |
| CA2246246A1 (en) | 1997-09-04 |
| US6410684B1 (en) | 2002-06-25 |
| PT886647E (pt) | 2002-12-31 |
| TR199801704T2 (xx) | 1998-12-21 |
| AU1877597A (en) | 1997-09-16 |
| CZ277898A3 (cs) | 1999-06-16 |
| RU2178419C2 (ru) | 2002-01-20 |
| DK0886647T3 (da) | 2002-11-04 |
| BR9707808A (pt) | 1999-07-27 |
| WO1997031937A1 (en) | 1997-09-04 |
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