CN1082051C - 新的环缩肽pf1022物质的衍生物 - Google Patents
新的环缩肽pf1022物质的衍生物 Download PDFInfo
- Publication number
- CN1082051C CN1082051C CN96198101A CN96198101A CN1082051C CN 1082051 C CN1082051 C CN 1082051C CN 96198101 A CN96198101 A CN 96198101A CN 96198101 A CN96198101 A CN 96198101A CN 1082051 C CN1082051 C CN 1082051C
- Authority
- CN
- China
- Prior art keywords
- meleu
- phlac
- lac
- group
- alkylamino
- 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 - Lifetime
Links
- 108010002156 Depsipeptides Proteins 0.000 title claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims description 300
- 150000001875 compounds Chemical class 0.000 claims description 253
- 239000000203 mixture Substances 0.000 claims description 191
- -1 pyrrolidyl Chemical group 0.000 claims description 173
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 118
- 125000003545 alkoxy group Chemical group 0.000 claims description 106
- 229910052757 nitrogen Inorganic materials 0.000 claims description 66
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 59
- 125000000623 heterocyclic group Chemical group 0.000 claims description 44
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 230000000507 anthelmentic effect Effects 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000004122 cyclic group Chemical group 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 20
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 17
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 17
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 244000045947 parasite Species 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- JJBDWBUEPCGFMN-UHFFFAOYSA-N 3-phenyl-1,2,4-oxadiazole Chemical compound O1C=NC(C=2C=CC=CC=2)=N1 JJBDWBUEPCGFMN-UHFFFAOYSA-N 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 10
- 150000002240 furans Chemical class 0.000 claims description 10
- 150000002460 imidazoles Chemical class 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- 125000003418 alkyl amino alkoxy group Chemical group 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 150000003222 pyridines Chemical class 0.000 claims description 5
- 150000005326 tetrahydropyrimidines Chemical class 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 238000011282 treatment Methods 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 2
- 239000000921 anthelmintic agent Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 273
- 239000000243 solution Substances 0.000 description 261
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 219
- 238000006243 chemical reaction Methods 0.000 description 210
- XJODGRWDFZVTKW-LURJTMIESA-N (2s)-4-methyl-2-(methylamino)pentanoic acid Chemical compound CN[C@H](C(O)=O)CC(C)C XJODGRWDFZVTKW-LURJTMIESA-N 0.000 description 141
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 99
- 125000003118 aryl group Chemical group 0.000 description 93
- 238000000034 method Methods 0.000 description 85
- 238000010898 silica gel chromatography Methods 0.000 description 83
- 239000002904 solvent Substances 0.000 description 82
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 78
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 69
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 66
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 66
- 238000001035 drying Methods 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 230000002829 reductive effect Effects 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000007864 aqueous solution Substances 0.000 description 60
- 238000005481 NMR spectroscopy Methods 0.000 description 58
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 57
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 57
- 239000000843 powder Substances 0.000 description 56
- 239000012044 organic layer Substances 0.000 description 50
- 230000006837 decompression Effects 0.000 description 47
- 238000001816 cooling Methods 0.000 description 44
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 43
- 238000000746 purification Methods 0.000 description 42
- 238000005406 washing Methods 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 239000002585 base Substances 0.000 description 38
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
- 238000002360 preparation method Methods 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- 235000002639 sodium chloride Nutrition 0.000 description 28
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 235000015320 potassium carbonate Nutrition 0.000 description 24
- 125000004429 atom Chemical group 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 22
- 229960002668 sodium chloride Drugs 0.000 description 22
- 235000009518 sodium iodide Nutrition 0.000 description 22
- 239000012895 dilution Substances 0.000 description 21
- 238000010790 dilution Methods 0.000 description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- 239000012141 concentrate Substances 0.000 description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 20
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 238000000605 extraction Methods 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 18
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 239000002994 raw material Substances 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- 239000012299 nitrogen atmosphere Substances 0.000 description 16
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 15
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 15
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 15
- 239000010410 layer Substances 0.000 description 14
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000012954 diazonium Substances 0.000 description 12
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 150000001989 diazonium salts Chemical class 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 241001597008 Nomeidae Species 0.000 description 10
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000010531 catalytic reduction reaction Methods 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 8
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 8
- 150000002828 nitro derivatives Chemical class 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 229960005190 phenylalanine Drugs 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 241000244203 Caenorhabditis elegans Species 0.000 description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 230000003071 parasitic effect Effects 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 7
- VOXXWSYKYCBWHO-QMMMGPOBSA-N (S)-3-phenyllactic acid Chemical compound OC(=O)[C@@H](O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-QMMMGPOBSA-N 0.000 description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 235000010288 sodium nitrite Nutrition 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
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 6
- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical compound NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 description 5
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- ILQZHPWFOWCYND-SQZSLCRCSA-N PF1022B Chemical compound CC(C)C[C@@H]1N(C)C(=O)[C@@H](Cc2ccccc2)OC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc2ccccc2)OC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc2ccccc2)OC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc2ccccc2)OC1=O ILQZHPWFOWCYND-SQZSLCRCSA-N 0.000 description 5
- 241001494479 Pecora Species 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000005864 Sulphur Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 238000000855 fermentation Methods 0.000 description 5
- 230000004151 fermentation Effects 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 4
- 239000003377 acid catalyst Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 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 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
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- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 1
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- 229910001487 potassium perchlorate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 150000003304 ruthenium compounds Chemical class 0.000 description 1
- 229910001925 ruthenium oxide Inorganic materials 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000011697 sodium iodate Substances 0.000 description 1
- 235000015281 sodium iodate Nutrition 0.000 description 1
- 229940032753 sodium iodate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- BQPGKWMFPIWAGE-UHFFFAOYSA-N tert-butyl 4-(hydroxymethyl)imidazole-1-carboxylate Chemical class CC(C)(C)OC(=O)N1C=NC(CO)=C1 BQPGKWMFPIWAGE-UHFFFAOYSA-N 0.000 description 1
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- 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)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24405195 | 1995-09-22 | ||
| JP244051/95 | 1995-09-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1201456A CN1201456A (zh) | 1998-12-09 |
| CN1082051C true CN1082051C (zh) | 2002-04-03 |
Family
ID=17113003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96198101A Expired - Lifetime CN1082051C (zh) | 1995-09-22 | 1996-09-20 | 新的环缩肽pf1022物质的衍生物 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6329338B1 (enExample) |
| EP (1) | EP0903347B1 (enExample) |
| KR (1) | KR19990063676A (enExample) |
| CN (1) | CN1082051C (enExample) |
| AT (1) | ATE299871T1 (enExample) |
| AU (1) | AU727532B2 (enExample) |
| BR (1) | BR9610527A (enExample) |
| CA (1) | CA2232668C (enExample) |
| CZ (1) | CZ295705B6 (enExample) |
| DE (1) | DE69634961T2 (enExample) |
| DK (1) | DK0903347T3 (enExample) |
| ES (1) | ES2246496T3 (enExample) |
| HU (1) | HU228004B1 (enExample) |
| IL (1) | IL123776A (enExample) |
| NO (1) | NO310622B1 (enExample) |
| NZ (1) | NZ318515A (enExample) |
| PL (1) | PL186168B1 (enExample) |
| WO (1) | WO1997011064A1 (enExample) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0930304A4 (en) * | 1996-08-07 | 2000-03-01 | Meiji Seika Co | METHOD FOR PRODUCING CYCLODEPSIPEPTID COMPOUNDS AND CYCLODEPSIPEPTID |
| WO1998037088A1 (en) * | 1997-02-19 | 1998-08-27 | Meiji Seika Kaisha Ltd. | Derivatives of cyclodepsipeptide, pf1022 substance |
| DE19811559A1 (de) * | 1998-03-17 | 1999-09-23 | Bayer Ag | Cyclooctadepsipeptide |
| CN100489095C (zh) | 1999-09-29 | 2009-05-20 | 明治制果株式会社 | 生产被官能团修饰的次级代谢产物的转化体和新的生物合成基因 |
| DE10031044A1 (de) * | 2000-06-26 | 2002-01-03 | Bayer Ag | Endoparasitizide Mittel zur freiwilligen oralen Aufnahme durch Tiere |
| DE10104362A1 (de) * | 2001-02-01 | 2002-08-08 | Bayer Ag | Kristallmodifikation eines cyclischen Depsipeptids mit besserer Wirksamkeit |
| DE102004055316A1 (de) * | 2004-11-16 | 2006-05-18 | Bayer Healthcare Ag | Verhinderung vertikaler Endoparasiten-Infektionen |
| DE102008022520A1 (de) | 2008-05-07 | 2009-11-12 | Bayer Animal Health Gmbh | Feste Arzneimittelformulierung mit verzögerter Freisetzung |
| DE102008030764A1 (de) | 2008-06-28 | 2009-12-31 | Bayer Animal Health Gmbh | Kombination von Amidin-Derivaten mit cyclischen Depsipeptiden |
| DE102008031283A1 (de) * | 2008-07-02 | 2010-01-07 | Bayer Schering Pharma Aktiengesellschaft | Neue Bekämpfungsmöglichkeit von durch Trichomonadida hervorgerufenen Krankheiten |
| DE102008031284A1 (de) * | 2008-07-02 | 2010-01-07 | Bayer Schering Pharma Aktiengesellschaft | Neue Bekämpfungsmöglichkeit der Giardiose |
| DE102009012423A1 (de) | 2009-03-10 | 2010-09-16 | Bayer Animal Health Gmbh | Zubereitung auf Ölbasis |
| DE102010064245A1 (de) | 2010-12-28 | 2012-06-28 | Bayer Animal Health Gmbh | Makrocylischen Lactone und deren Verwendung und deren Kombinationen mit anderen Wirkstoffen |
| WO2012028556A1 (en) | 2010-08-31 | 2012-03-08 | Bayer Animal Health Gmbh | Macrocyclic lactones and their use and their combinations with other active substances |
| US10081656B2 (en) | 2015-05-20 | 2018-09-25 | Merial, Inc. | Anthelmintic depsipeptide compounds |
| HUE065907T2 (hu) | 2015-12-28 | 2024-06-28 | Boehringer Ingelheim Vetmedica Gmbh | Anthelmintikus hatású depszipeptid vegyületek |
| EP3541789A1 (en) | 2016-11-16 | 2019-09-25 | Boehringer Ingelheim Animal Health USA Inc. | Anthelmintic depsipeptide compounds |
| MY203299A (en) | 2017-11-07 | 2024-06-21 | The Kitasato Inst | Method for the synthesis of cyclic depsipeptides |
| RU2747149C9 (ru) | 2017-11-29 | 2021-06-29 | ЗОЕТИС СЕРВИСИЗ ЭлЭлСи | Анти-эндопаразитарные депсипептиды |
| SG11202010187RA (en) | 2018-05-10 | 2020-11-27 | Zoetis Services Llc | Endoparasitic depsipeptides |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019053A1 (en) * | 1992-03-17 | 1993-09-30 | Fujisawa Pharmaceutical Co., Ltd. | Depsipeptide derivative, production thereof and use thereof |
| WO1994019334A1 (fr) * | 1993-02-19 | 1994-09-01 | Meiji Seika Kaisha, Ltd. | Derive du pf 1022 utilise comme depsipeptide cyclqiue |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH477172A (de) * | 1965-05-18 | 1969-08-31 | Agripat Sa | Beifuttermittel |
| AU1933583A (en) * | 1982-09-22 | 1984-03-29 | Meiji Seika K.K. | Hydroxylamine derivatives |
| NO176766C (no) * | 1989-02-07 | 1995-05-24 | Meiji Seika Kaisha | Fremgangsmåte for fremstilling av en forbindelse med anthelmintaktivitet |
| JP2873894B2 (ja) * | 1992-10-19 | 1999-03-24 | 明治製菓株式会社 | 環状デプシペプチドおよびその製造法 |
| DE4317432A1 (de) * | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptide mit endoparasitizider Wirkung |
| DE4317457A1 (de) | 1993-05-26 | 1994-12-01 | Bayer Ag | Octacyclodepsipeptide mit endoparasitizider Wirkung |
| JPH07233068A (ja) * | 1993-12-27 | 1995-09-05 | Meiji Seika Kaisha Ltd | 高コレステロール血症、高脂血症又は動脈硬化症の治療薬 |
-
1996
- 1996-09-20 CA CA2232668A patent/CA2232668C/en not_active Expired - Lifetime
- 1996-09-20 US US09/043,558 patent/US6329338B1/en not_active Expired - Lifetime
- 1996-09-20 NZ NZ318515A patent/NZ318515A/xx not_active IP Right Cessation
- 1996-09-20 ES ES96931283T patent/ES2246496T3/es not_active Expired - Lifetime
- 1996-09-20 DE DE69634961T patent/DE69634961T2/de not_active Expired - Lifetime
- 1996-09-20 BR BR9610527-5A patent/BR9610527A/pt not_active Application Discontinuation
- 1996-09-20 IL IL12377696A patent/IL123776A/en not_active IP Right Cessation
- 1996-09-20 EP EP96931283A patent/EP0903347B1/en not_active Expired - Lifetime
- 1996-09-20 AT AT96931283T patent/ATE299871T1/de active
- 1996-09-20 CN CN96198101A patent/CN1082051C/zh not_active Expired - Lifetime
- 1996-09-20 WO PCT/JP1996/002730 patent/WO1997011064A1/ja not_active Ceased
- 1996-09-20 KR KR1019980702138A patent/KR19990063676A/ko not_active Ceased
- 1996-09-20 CZ CZ1998855A patent/CZ295705B6/cs not_active IP Right Cessation
- 1996-09-20 HU HU0001164A patent/HU228004B1/hu unknown
- 1996-09-20 DK DK96931283T patent/DK0903347T3/da active
- 1996-09-20 PL PL96326024A patent/PL186168B1/pl unknown
- 1996-09-20 AU AU70019/96A patent/AU727532B2/en not_active Expired
-
1998
- 1998-03-19 NO NO19981250A patent/NO310622B1/no not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993019053A1 (en) * | 1992-03-17 | 1993-09-30 | Fujisawa Pharmaceutical Co., Ltd. | Depsipeptide derivative, production thereof and use thereof |
| WO1994019334A1 (fr) * | 1993-02-19 | 1994-09-01 | Meiji Seika Kaisha, Ltd. | Derive du pf 1022 utilise comme depsipeptide cyclqiue |
Also Published As
| Publication number | Publication date |
|---|---|
| DK0903347T3 (da) | 2005-11-21 |
| ATE299871T1 (de) | 2005-08-15 |
| DE69634961T2 (de) | 2006-04-20 |
| HUP0001164A2 (hu) | 2000-11-28 |
| KR19990063676A (ko) | 1999-07-26 |
| WO1997011064A1 (en) | 1997-03-27 |
| CA2232668C (en) | 2011-10-18 |
| PL326024A1 (en) | 1998-08-17 |
| NO981250D0 (no) | 1998-03-19 |
| CA2232668A1 (en) | 1997-03-27 |
| BR9610527A (pt) | 1999-12-21 |
| EP0903347A1 (en) | 1999-03-24 |
| AU7001996A (en) | 1997-04-09 |
| DE69634961D1 (de) | 2005-08-25 |
| HUP0001164A3 (en) | 2001-04-28 |
| NO981250L (no) | 1998-05-22 |
| IL123776A0 (en) | 1998-10-30 |
| US6329338B1 (en) | 2001-12-11 |
| NZ318515A (en) | 2000-05-26 |
| ES2246496T3 (es) | 2006-02-16 |
| CZ85598A3 (cs) | 1998-08-12 |
| MX9802268A (es) | 1998-08-30 |
| PL186168B1 (pl) | 2003-11-28 |
| AU727532B2 (en) | 2000-12-14 |
| HU228004B1 (en) | 2012-08-28 |
| JP4001381B1 (enExample) | 2007-10-31 |
| EP0903347A4 (enExample) | 1999-03-24 |
| NO310622B1 (no) | 2001-07-30 |
| CN1201456A (zh) | 1998-12-09 |
| IL123776A (en) | 2002-09-12 |
| EP0903347B1 (en) | 2005-07-20 |
| CZ295705B6 (cs) | 2005-10-12 |
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