JPH10501529A - エラスターゼのパーフルオロアルキルケトン阻害剤およびそれらを製造する方法 - Google Patents
エラスターゼのパーフルオロアルキルケトン阻害剤およびそれらを製造する方法Info
- Publication number
- JPH10501529A JPH10501529A JP8500860A JP50086096A JPH10501529A JP H10501529 A JPH10501529 A JP H10501529A JP 8500860 A JP8500860 A JP 8500860A JP 50086096 A JP50086096 A JP 50086096A JP H10501529 A JPH10501529 A JP H10501529A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- val
- pro
- formula
- alkyl
- 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.)
- Granted
Links
- -1 Perfluoroalkyl ketone Chemical class 0.000 title claims description 180
- 238000000034 method Methods 0.000 title claims description 82
- 102000016387 Pancreatic elastase Human genes 0.000 title abstract description 16
- 108010067372 Pancreatic elastase Proteins 0.000 title abstract description 16
- 239000003112 inhibitor Substances 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- 210000000440 neutrophil Anatomy 0.000 claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 claims abstract description 30
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 25
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 claims abstract description 17
- 102000052502 human ELANE Human genes 0.000 claims abstract description 12
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 51
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 39
- 150000001413 amino acids Chemical class 0.000 claims description 38
- 238000005859 coupling reaction Methods 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 36
- 230000008878 coupling Effects 0.000 claims description 33
- 238000010168 coupling process Methods 0.000 claims description 33
- 244000191761 Sida cordifolia Species 0.000 claims description 29
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 29
- 239000000460 chlorine Substances 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 19
- 125000003277 amino group Chemical group 0.000 claims description 17
- 239000002585 base Substances 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 239000003937 drug carrier Substances 0.000 claims description 17
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 16
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- 238000009833 condensation Methods 0.000 claims description 15
- 230000005494 condensation Effects 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 239000007822 coupling agent Substances 0.000 claims description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 150000001340 alkali metals Chemical class 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 206010014561 Emphysema Diseases 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 10
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 claims description 6
- 239000012351 deprotecting agent Substances 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 5
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 208000007451 chronic bronchitis Diseases 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 230000004224 protection Effects 0.000 claims description 5
- 239000003591 leukocyte elastase inhibitor Substances 0.000 claims description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 229940024606 amino acid Drugs 0.000 description 44
- 235000001014 amino acid Nutrition 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 238000004293 19F NMR spectroscopy Methods 0.000 description 9
- QRSXLMSDECGEOU-UHFFFAOYSA-N 6-methoxycarbonylpyridine-3-carboxylic acid Chemical compound COC(=O)C1=CC=C(C(O)=O)C=N1 QRSXLMSDECGEOU-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000003602 elastase inhibitor Substances 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- JFMNKDRNEZZRBW-VIFPVBQESA-N (3s)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide Chemical compound C1=CC=C2CN[C@H](C(=O)N)CC2=C1 JFMNKDRNEZZRBW-VIFPVBQESA-N 0.000 description 5
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 5
- 102100033174 Neutrophil elastase Human genes 0.000 description 5
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 5
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 5
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 5
- 235000008206 alpha-amino acids Nutrition 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- FAMGJMYDHOESPR-UHFFFAOYSA-M dilithium;carbanide;bromide Chemical compound [Li+].[Li+].[CH3-].[Br-] FAMGJMYDHOESPR-UHFFFAOYSA-M 0.000 description 5
- 238000010647 peptide synthesis reaction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XTGYEAXBNRVNQU-UHFFFAOYSA-N 1,1,1,2,2,3,3-heptafluoro-3-iodopropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)I XTGYEAXBNRVNQU-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 150000001602 bicycloalkyls Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
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- 239000012043 crude product Substances 0.000 description 4
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- 239000000284 extract Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- GYPCWHHQAVLMKO-XXKQIVDLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(e)-n-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-c-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical group Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 description 3
- PBKONEOXTCPAFI-UHFFFAOYSA-N 1,2,4-trichlorobenzene Chemical compound ClC1=CC=C(Cl)C(Cl)=C1 PBKONEOXTCPAFI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 201000005569 Gout Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- 239000004480 active ingredient Substances 0.000 description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 3
- 150000001371 alpha-amino acids Chemical class 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
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- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
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- VUYWLCHFKCFCNH-QWRGUYRKSA-N (2s)-1-[(2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(O)=O VUYWLCHFKCFCNH-QWRGUYRKSA-N 0.000 description 2
- PGRFXXCKHGIFSV-UHFFFAOYSA-N 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I PGRFXXCKHGIFSV-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- WDGXIUUWINKTGP-UHFFFAOYSA-N 3-(3-pyridinyl)propanoic acid Chemical compound OC(=O)CCC1=CC=CN=C1 WDGXIUUWINKTGP-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- XABUQHDIXPOBCU-UHFFFAOYSA-N 5-o-tert-butyl 2-o-methyl pyridine-2,5-dicarboxylate Chemical compound COC(=O)C1=CC=C(C(=O)OC(C)(C)C)C=N1 XABUQHDIXPOBCU-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式 K-P4-P3-P2-NH-CH(R1)-C(=O)-X′ (配列番号:1) の化合物またはその水和物、アイソスターまたは医薬的に許容し得る塩。 上記式において、 P4は、Ala、bAla、Leu、Ile、Val、Nva、bVal、Nleまたは結合手であり; P3は、Ala、bAla、Leu、Ile、Val、Nva、bVal、NleまたはN−メチル誘導体 、Pro、Ind、TicまたはTca、またはイプシロンアミノ基においてモルホリノ−B −基で置換されたLysまたはデルタアミノ基においてモルホリノ−B−基で置換 されたOrnであり; P2は、Pro、Ind、Tic、Pip、Tca、Pro(4-OBzl)、Aze、Pro(4-OAc)またはPro (4-OH)であり; R1は、Ala、Leu、Ile、Val、NvaまたはbValの側鎖であり; X′は、-CF2CF2CF3または-CF2CF2CF2CF3であり; Kは、水素、ホルミル、アセチル、サクシニル、ベンゾイル、t−ブチルオ キシカルボニル、カルボベンジルオキシ、トシル、ダンシル、イソバレリル、メ トキシサクシニル、1−アダマンタンスルホニル、1−アダマンタンアセチル、 2−カルボキシベンゾイル、フェニルアセチル、t−ブチルアセチル、ビス((1 −ナフチル)メチル)アセチル、-C(=O)N-(CH3)2、 -A-Rz 〔式中、 そして Rzは、独立して弗素、塩素、臭素、沃素、トリフルオロメチル、ヒドロキシ 、1〜6個の炭素を含有するアルキル、1〜6個の炭素を含有するアルコキシ、 カルボキシ、アルキル基が、1〜6個の炭素を含有するアルキルカルボニルアミ ノ、5−テトラゾリルおよび1〜15個の炭素を含有するアシルスルホンアミドか らなる群から選択された1〜3個の基によって場合により置換された6、10また は12個の炭素を含有するアリール基(但し、アシルスルホンアミドがアリールを 含有する場合は、アリールはさらに弗素、塩素、臭素、沃素およびニトロから選 択された基によって置換されていてもよい)である〕または 〔式中、 Zは、NまたはCHであり、そして Bは、式 そしてR′は水素またはC1-6アルキル基である〕である。 2.R1が-CH(CH3)2である請求項1記載の化合物。 3.Kがt−ブチルオキシカルボニル、カルボベンジルオキシまたは 〔式中、Zは、Nであり、Bは の基でありそしてR′は水素またはC1-6アルキル基である〕の基で ある請求項2記載の化合物。 4.P3がIle、ValまたはAlaである請求項3記載の化合物。 5.P4がAlaまたは結合手である請求項4記載の化合物。 6.P2がPro、Pip、Pro(4-OBzl)またはAzeである請求項5記載の化合物。 7.P3がValである請求項6記載の化合物。 8.P4が結合手である請求項7記載の化合物。 9.P2がProである請求項8記載の化合物。 10.化合物がN−〔4−(4−モルホリニルカルボニル)ベンゾイル〕−L−バ リル−N′−〔3,3,4,4,5,5,5−ヘプタフルオロ−1−(1−メチルエチル)−2 −オキソペンチル〕−L−プロリンアミドである請求項1記載の化合物。 11.化合物がN−〔4−(4−モルホリニルカルボニル)ベンゾイル〕−L−バ リル−N′−〔3,3,4,4,5,5,6,6,6−ノナフルオロ−1−(1−メチルエチル)− 2−オキソヘキシル〕−L−プロリンアミドである請求項1記載の化合物。 12.化合物がN−〔(1,1−ジメチルエトキシ)カルボニル〕−L−バリル−N′− 〔3,3,4,4,5,5,5−ヘプタフルオロ−1−(1−メチルエチル)−2−オキソペン チル〕−L−プロリンアミドである請求項1記載の化合物。 13.化合物がN−〔(1,1−ジメチルエトキシ)カルボニル〕−L−バリル−N′− 〔3,3,4,4,5,5,6,6,6−ノナフルオロ−1−(1−メチルエチル)−2−オキソヘ キシル〕−L−プロリンアミドである請求項1記載の化合物。 14.請求項1記載の化合物および担体からなる組成物。 15.請求項1記載の化合物および医薬的に許容し得る担体からなる医薬組成物。 16.請求項1記載の化合物の治療的に有効な量を患者に投与することからなる治 療を必要とする患者におけるヒトの好中球エラスターゼを阻害する方法。 17.請求項1記載の化合物の治療的に有効な量を患者に投与することからなる好 中球関連炎症疾患にかかった患者を治療する方法。 18.好中球関連炎症疾患が気腫である請求項17記載の方法。 19.好中球関連炎症疾患が嚢胞性線維症である請求項17記載の方法。 20.好中球関連炎症疾患が慢性気管支炎である請求項17記載の方法。 21.好中球関連炎症疾患が慢性閉塞性肺疾患である請求項17記載の方法。 22.好中球関連炎症疾患が炎症性腸疾患である請求項17記載の方法。 23.(a) 適当なカップリング剤の存在下および適当なカップリング溶剤の存在下 において式NH2-CH(R1)C(=O)OR2(式中、R2は(C1-6)アルキルである)のアミノ酸 エステルを式K′-P4-P3-P2-OHの適当にN−保護されたペプチドとカップリング させて適当にN−保護されたペプチドエステルを得、 (b) 適当なアルカリ金属塩基および適当な無水の溶剤の存在下において、適 当にN−保護されたペプチドエステルを適当な過弗素化剤と反応させる工程から なる式 K′-P4-P3-P2-NH-CH(R1)-C(=O)-X (配列番号:2) {式中、 P4はAla、bAla、Leu、Ile、Val、Nva、bVal、Nleまたは結合手であり; P3は、Ala、bAla、Leu、Ile、Val、Nva、bVal、NleまたはN−メチル誘導体 、Pro、Ind、TicまたはTca、またはイプシロンアミノ基においてモルホリノ−B −基で置換されたLysまたはデルタアミノ基においてモルホリノ−B−基で置換 されたOrnであり; P2は、Pro、Ind、Tic、Pip、Tca、Pro(4-OBzl)、Aze、Pro(4-OAc)またはPro (4-OH)であり; R1は、Ala、Leu、Ile、Val、NvaまたはbValの側鎖であり; Xは、-CF2CF3、-CF2CF2CF3または-CF2CF2CF2CF3であり; K′は、水素、ホルミル、アセチル、サクシニル、ベンゾイル、t−ブチル オキシカルボニル、カルボベンジルオキシ、トシル、ダンシル、イソバレリル、 メトキシサクシニル、1−アダマンタンスルホニル、1−アダマンタンアセチル 、2−カルボキシベンゾイル、フェニルアセチル、t−ブチルアセチル、ビス(( 1−ナフチル)メチル)アセチル、-C(=O)N-(CH3)2、 -A-Rz 〔式中、 そして Rzは、独立して弗素、塩素、臭素、沃素、トリフルオロメチル、ヒドロキシ 、1〜6個の炭素を含有するアルキル、1〜6個の炭素を含有するアルコキシ、 カルボキシ、アルキル基が、1〜6個の炭素を含有するアルキルカルボニルアミ ノ、5−テトラゾリルおよび1〜15個の炭素を含有するアシルスルホンアミドか らなる群から選択された1〜3個の基によって適当に置換された6、10または12 個の炭素を含有するアリール基(但し、アシルスルホンアミドがアリールを含有 する場合は、アリールはさらに弗素、塩素、臭素、沃素およびニトロから選択さ れた基によって置換されていてもよい)である〕である}の化合物を製造する方 法。 24.(a) 適当なカップリング剤の存在下および適当なカップリング溶剤の存在下 において式NH2-CH(R1)C(=O)OR2(式中、R2は(C1-6)アルキルである)のアミノ酸 エステルを、式K′-P4-P3-P2-OHの適当にN−保護されたペプチドとカップリン グさせて、適当にN−保護されたペプチドエステルを得; (b) 適当なアルカリ金属塩基および適当な無水の溶剤の存在下において、適 当にN−保護されたペプチドエステルを適当な過弗素化剤と反応させて、適当に N−保護されたパーフルオロアルキルペプチドを得; (c) 適当な有機溶剤の存在下において、適当にN−保護されたパーフルオロ アルキルペプチドを適当な脱保護剤で脱保護してパーフルオロアルキルペプチド を得; (d) 適当な非−求核性塩基および適当な有機溶剤の存在下において、パーフ ルオロアルキルペプチドを式 (式中、BおよびZは後述する通りである)の化合物と反応させる工程からな る式 K″-P4-P3-P2-NH-CH(R1)-C(=O)-X (配列番号:3) {式中、 P4はAla、bAla、Leu、Ile、Val、Nva、bVal、Nleまたは結合手であり; P3は、Ala、bAla、Leu、Ile、Val、Nva、bVal、NleまたはN−メチル誘導体 、Pro、Ind、TicまたはTca、またはイプシロンアミノ基においてモルホリノ−B −基で置換されたLysまたはデルタアミノ基においてモルホリノ−B−基で置換 されたOrnであり; P2は、Pro、Ind、Tic、Pip、Tca、Pro(4-OBzl)、Aze、Pro(4-OAc)またはPro (4-OH)であり; R1は、Ala、Leu、Ile、Val、NvaまたはbValの側鎖であり; Xは、-CF2CF3、-CF2CF2CF3または-CF2CF2CF2CF3であり; K″は、 〔式中、 Zは、NまたはCHであり、そして Bは、式 の基でありそしてR′は水素またはC1-6アルキル基である〕である} の化合物を製造する方法。 25.(a) 適当なアルカリ金属塩基および適当な無水の溶剤の存在下において、式 Pg-NH-CH(R1)C(=O)OR2(式中、R2は(C1-6)アルキルでありそしてPgは適当な保護 基である)の適当に保護されたアミノ酸エステルを適当な過弗素化剤と反応させ て、適当にN−保護されたパーフルオロアルキルケトンを得; (b) 適当な有機溶剤の存在下において、適当にN−保護されたパーフルオロ アルキルケトンを適当な脱保護剤で脱保護して、パーフルオロアルキルケトンを 得; (c) 適当なカップリング剤の存在下および適当なカップリング溶剤の存在下 において、パーフルオロアルキルケトンを式K′-P4-P3-P2-OHの適当に保護され たペプチドとカップリングさせる工程からなる請求項23記載の化合物を製造する 方法。 26.(a) 適当なアルカリ金属塩基および適当な無水の溶剤の存在下 において、式Pg-NH-CH(R1)C(=O)OR2(式中、R2は(C1-6)アルキルでありそしてPg は適当な保護基である)の適当に保護されたアミノ酸エステルを適当な過弗素化 剤と反応させて、適当にN−保護されたパーフルオロアルキルケトンを得; (b) 適当な有機溶剤の存在下において、適当にN−保護されたパーフルオロ アルキルケトンを適当な脱保護剤で脱保護して、パーフルオロアルキルケトンを 得; (c) 適当なカップリング剤の存在下および適当なカップリング溶剤の存在下 において、パーフルオロアルキルケトンを式K″-P4-P3-P2-OHの適当に保護され たペプチドとカップリングさせる工程からなる請求項24記載の化合物を製造する 方法。 27.式 {式中、 P1は、Ala、Val、Nva、bVal、Leu、IleまたはNleであり; P2は、Ala、bAla、Leu、Ile、Val、Nva、bVal、Met、Nle、Gly、Phe、Tyr、 TrpまたはNal(1)〔アルファ−アミノ基の窒素は、R基(Rは(C1-6)アルキル、( C3-12)シクロアルキル、(C3-12)シクロアルキル(C1-6)アルキル、(C4-11)ビシク ロアルキル、(C4-11)ビシクロアルキル(C1-6)アルキル、(C6-10)アリール、(C6- 10 )アリール(C1-6)アルキル、(C3-7)ヘテロシクロアルキル、(C3-7)ヘテロシク ロアルキル(C1-6)アルキル、(C5-9)ヘテロアリール、(C5-9)ヘテロアリール(C1- 6 )アルキル、縮合(C6-10)アリール− (C3-12)シクロアルキル、縮合(C6-10)アリール−(C3-12)シクロアルキル(C1-6) アルキル、縮合(C5-9)ヘテロアリール(C3-12)シクロアルキルまたは縮合(C5-9) ヘテロアリール(C3-12)シクロアルキル−(C1-6)アルキルである)で置換されて いてもよい〕であるかまたはP2はPro、Ind、TicまたはTcaであり; P3は、Ala、bAla、Leu、Ile、Val、Nva、bValまたはNleであり; P4は、Ala、bAla、Leu、Ile、Val、Nva、bVal、Nleまたは結合手である}を 有する新規な化合物またはその水和物、アイソスターまたは医薬的に許容し得る 塩。 28.P1がValまたはNvaであり;P2がPro、TicまたはTcaであり;P3がVal、Nva、A laまたはbAlaであり;そしてP4がAlaまたは単一の結合である請求項27記載の化 合物。 29.P1がValであり;P3がValであり;そしてP4が結合手である請求項28記載の化 合物。 30.化合物がN−〔3−(3−ピリジル)プロパノイル〕−L−バリル−N′− 〔3,3,4,4,4−ペンタフルオロ−1−(1−メチルエチル)−2−オキソブチル 〕−L−プロリンアミドである請求項27記載の化合物。 31.請求項27記載の化合物および担体からなる組成物。 32.請求項27記載の化合物および医薬的に許容し得る担体からなる医薬組成物。 33.請求項27記載の化合物の治療的に有効な量を患者に投与することからなる治 療を必要とする患者のヒトの好中球エラスターゼを阻害する方法。 34.請求項27記載の化合物の治療的に有効な量を患者に投与することからなる好 中球関連炎症性疾患にかかった患者を治療する方法。 35.好中球関連炎症性疾患が気腫である請求項34記載の方法。 36.好中球関連炎症性疾患が嚢胞性線維症である請求項34記載の方法。 37.好中球関連炎症性疾患が慢性気管支炎である請求項34記載の方法。 38.好中球関連炎症性疾患が慢性閉塞性肺疾患である請求項34記載の方法。 39.好中球関連炎症性疾患が炎症性腸疾患である請求項34記載の方法。 40.医薬的に活性な化合物として使用するための請求項1〜13の何れかの項記載 の化合物の使用。 41.ヒトの好中球エラスターゼ阻害剤を製造するための、場合によっては医薬的 に許容し得る担体と組み合わされた請求項1〜13項の何れかの項記載の化合物の 使用。 42.好中球関連炎症性疾患の治療のための医薬組成物を製造するための場合によ っては医薬的に許容し得る担体と組み合わされた請求項1〜13の何れかの項記載 の化合物の使用。 43.気腫を治療する医薬を製造するための、場合によっては医薬的に許容し得る 担体と組み合わされた請求項1〜13の何れかの項記載の化合物の使用。 44.医薬的に活性な化合物として使用するための請求項27〜30の何れかの項記載 の化合物。 45.ヒトの好中球エラスターゼ阻害剤を製造するための、場合によっては医薬的 に許容し得る担体と組み合わされた請求項27〜30の何れかの項記載の化合物の使 用。 46.好中球関連炎症性疾患の治療用の医薬組成物を製造するための、場合によっ ては医薬的に許容し得る担体と組み合わされた請求項27〜30の何れかの項記載の 化合物の使用。 47.気腫の治療用の医薬組成物を製造するための、場合によっては医薬的に許容 し得る担体と組み合わされた請求項27〜30の何れかの項記載の化合物の使用。
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1995
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- 1995-05-01 CN CNB951933760A patent/CN1152048C/zh not_active Expired - Fee Related
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- 1995-05-01 EP EP95917216A patent/EP0763055B1/en not_active Expired - Lifetime
- 1995-05-01 NZ NZ284766A patent/NZ284766A/en unknown
- 1995-05-01 JP JP50086096A patent/JP3721538B2/ja not_active Expired - Lifetime
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- 1995-05-01 WO PCT/US1995/005363 patent/WO1995033762A1/en active IP Right Grant
- 1995-05-01 KR KR1019960706819A patent/KR100366328B1/ko not_active IP Right Cessation
- 1995-05-01 DK DK95917216T patent/DK0763055T3/da active
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- 1995-05-31 IL IL11394195A patent/IL113941A/xx not_active IP Right Cessation
- 1995-06-01 TW TW084105552A patent/TW376388B/zh active
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Cited By (2)
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JP2005529885A (ja) * | 2002-04-25 | 2005-10-06 | ザ スクリプス リサーチ インスティテュート | 肺病態の治療および予防 |
JP4651946B2 (ja) * | 2002-04-25 | 2011-03-16 | ザ スクリプス リサーチ インスティテュート | 肺病態の治療および予防 |
Also Published As
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FI964789A (fi) | 1996-11-29 |
NO965098D0 (no) | 1996-11-29 |
CA2189526A1 (en) | 1995-12-14 |
IL113941A0 (en) | 1995-08-31 |
JP3721538B2 (ja) | 2005-11-30 |
DE69513167T2 (de) | 2000-06-15 |
DE69513167D1 (de) | 1999-12-09 |
HU221311B1 (en) | 2002-09-28 |
MX9606031A (es) | 1998-05-31 |
CN1149876A (zh) | 1997-05-14 |
NZ284766A (en) | 1998-06-26 |
ATE186305T1 (de) | 1999-11-15 |
HU9603311D0 (en) | 1997-01-28 |
AU690986B2 (en) | 1998-05-07 |
AU2400095A (en) | 1996-01-04 |
US6008196A (en) | 1999-12-28 |
WO1995033762A1 (en) | 1995-12-14 |
NO316706B1 (no) | 2004-04-13 |
EP0763055A1 (en) | 1997-03-19 |
DK0763055T3 (da) | 2000-05-08 |
CN1152048C (zh) | 2004-06-02 |
ES2137509T3 (es) | 1999-12-16 |
TW376388B (en) | 1999-12-11 |
HUT75318A (en) | 1997-05-28 |
GR3032294T3 (en) | 2000-04-27 |
IL113941A (en) | 2000-02-17 |
EP0763055B1 (en) | 1999-11-03 |
FI964789A0 (fi) | 1996-11-29 |
CA2189526C (en) | 2001-02-27 |
NO965098L (no) | 1997-01-31 |
KR100366328B1 (ko) | 2003-03-06 |
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