JP3380237B2 - ２のｃｐｉサブユニットを有する新規ｃｃ―１０６５アナログ類 - Google Patents
２のｃｐｉサブユニットを有する新規ｃｃ―１０６５アナログ類Info
- Publication number
- JP3380237B2 JP3380237B2 JP50923689A JP50923689A JP3380237B2 JP 3380237 B2 JP3380237 B2 JP 3380237B2 JP 50923689 A JP50923689 A JP 50923689A JP 50923689 A JP50923689 A JP 50923689A JP 3380237 B2 JP3380237 B2 JP 3380237B2
- Authority
- JP
- Japan
- Prior art keywords
- chloromethyl
- dipyrrole
- indole
- compound
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- -1 nitro, amino - carbonyl Chemical group 0.000 claims description 95
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 83
- 229910052757 nitrogen Inorganic materials 0.000 claims description 80
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 76
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 3
- 229940125797 compound 12 Drugs 0.000 claims description 3
- 229940125758 compound 15 Drugs 0.000 claims description 3
- 229940126142 compound 16 Drugs 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000001348 pyrrole-2,5-diyl group Chemical group N1C(=CC=C1*)* 0.000 claims description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 2
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 2
- 150000001408 amides Chemical group 0.000 claims description 2
- 150000001540 azides Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 229940126543 compound 14 Drugs 0.000 claims description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical group [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 2
- 125000004989 dicarbonyl group Chemical group 0.000 claims description 2
- 125000001543 furan-2,5-diyl group Chemical group O1C(=CC=C1*)* 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Chemical group SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012948 isocyanate Chemical group 0.000 claims description 2
- 150000002513 isocyanates Chemical group 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 150000004713 phosphodiesters Chemical class 0.000 claims description 2
- 125000005499 phosphonyl group Chemical group 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 1
- 239000005864 Sulphur Chemical group 0.000 claims 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 abstract description 2
- 239000006096 absorbing agent Substances 0.000 abstract description 2
- 238000010171 animal model Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 105
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 98
- 238000006243 chemical reaction Methods 0.000 description 73
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000000741 silica gel Substances 0.000 description 42
- 229910002027 silica gel Inorganic materials 0.000 description 42
- 239000007787 solid Substances 0.000 description 41
- 239000000243 solution Substances 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 238000002360 preparation method Methods 0.000 description 31
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 26
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 23
- 238000003756 stirring Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 16
- PUBSMDUBHLYMIX-UHFFFAOYSA-N phenol;dihydrochloride Chemical compound Cl.Cl.OC1=CC=CC=C1 PUBSMDUBHLYMIX-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- ULUNQYODBKLBOE-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-1h-pyrrole Chemical compound C1=CNC(C=2NC=CC=2)=C1 ULUNQYODBKLBOE-UHFFFAOYSA-N 0.000 description 13
- PUPKPAZSFZOLOR-UHFFFAOYSA-N n,n-dimethylformamide;toluene Chemical group CN(C)C=O.CC1=CC=CC=C1 PUPKPAZSFZOLOR-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000005119 centrifugation Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WCGCOZXVVVIAEF-UHFFFAOYSA-N ethyl 5-amino-1h-indole-2-carboxylate Chemical compound NC1=CC=C2NC(C(=O)OCC)=CC2=C1 WCGCOZXVVVIAEF-UHFFFAOYSA-N 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- JLUIOEOHOOLSJC-UHFFFAOYSA-N pyrrole-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)N1 JLUIOEOHOOLSJC-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- GGFYNWCTOUIPDE-UHFFFAOYSA-N 2-[(2-carboxy-1h-indol-5-yl)carbamoyl]-1h-indole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)O)=CC2=C1 GGFYNWCTOUIPDE-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- BYQPXOBDTLDUHS-UHFFFAOYSA-N 5H-pyrrolo[3,2-e]indol-4-one Chemical compound C1=CN=C2C1=C1C=CN=C1CC2=O BYQPXOBDTLDUHS-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- ZXRCAYWYTOIRQS-UHFFFAOYSA-N hydron;phenol;chloride Chemical compound Cl.OC1=CC=CC=C1 ZXRCAYWYTOIRQS-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 230000000153 supplemental effect Effects 0.000 description 4
- MUABQYJAPOQWCH-UHFFFAOYSA-N 1h-indole-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CC=C2NC(C(=O)O)=CC2=C1 MUABQYJAPOQWCH-UHFFFAOYSA-N 0.000 description 3
- SHGXCPWOVQDGPW-UHFFFAOYSA-N 5-[(2-carboxy-1h-indol-5-yl)carbamoyl]-1h-indole-2-carboxylic acid Chemical compound C1=C2NC(C(O)=O)=CC2=CC(C(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)O)=C1 SHGXCPWOVQDGPW-UHFFFAOYSA-N 0.000 description 3
- JNDKOANMVLLQKU-UHFFFAOYSA-N 5-[[2-[(2-carboxy-1h-indol-5-yl)carbamoyl]-1h-indole-5-carbonyl]amino]-1h-indole-2-carboxylic acid Chemical compound C1=C2NC(C(O)=O)=CC2=CC(NC(=O)C=2C=C3C=C(NC3=CC=2)C(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)O)=C1 JNDKOANMVLLQKU-UHFFFAOYSA-N 0.000 description 3
- GDNUTGWFGRFLBA-UHFFFAOYSA-N 5-[[3-[(2-carboxy-1h-indol-5-yl)amino]-3-oxopropanoyl]amino]-1h-indole-2-carboxylic acid Chemical compound C1=C2NC(C(O)=O)=CC2=CC(NC(=O)CC(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)O)=C1 GDNUTGWFGRFLBA-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 239000012024 dehydrating agents Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 description 2
- ATFRLAFCRGJKAA-UHFFFAOYSA-N 5-[(2-carboxy-1h-indol-5-yl)carbamoylamino]-1h-indole-2-carboxylic acid Chemical compound C1=C2NC(C(O)=O)=CC2=CC(NC(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)O)=C1 ATFRLAFCRGJKAA-UHFFFAOYSA-N 0.000 description 2
- QWYYDDRIRQHKLO-UHFFFAOYSA-N 5-[[2-[(2-carboxy-1h-indol-5-yl)amino]-2-oxoacetyl]amino]-1h-indole-2-carboxylic acid Chemical compound C1=C2NC(C(O)=O)=CC2=CC(NC(=O)C(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)O)=C1 QWYYDDRIRQHKLO-UHFFFAOYSA-N 0.000 description 2
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- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
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- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- HTWWKYKIBSHDPC-UHFFFAOYSA-N decanoyl decanoate Chemical compound CCCCCCCCCC(=O)OC(=O)CCCCCCCCC HTWWKYKIBSHDPC-UHFFFAOYSA-N 0.000 description 1
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- PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 1
- USSLMJFJRWUITI-UHFFFAOYSA-N ethyl 5-[(2-ethoxycarbonyl-1h-indol-5-yl)carbamoylamino]-1h-indole-2-carboxylate Chemical compound C1=C2NC(C(=O)OCC)=CC2=CC(NC(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)OCC)=C1 USSLMJFJRWUITI-UHFFFAOYSA-N 0.000 description 1
- YIOZTKHJGBFNIO-UHFFFAOYSA-N ethyl 5-[[2-[(2-ethoxycarbonyl-1h-indol-5-yl)amino]-2-oxoacetyl]amino]-1h-indole-2-carboxylate Chemical compound C1=C2NC(C(=O)OCC)=CC2=CC(NC(=O)C(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)OCC)=C1 YIOZTKHJGBFNIO-UHFFFAOYSA-N 0.000 description 1
- JYSYTIUAYLKBCR-UHFFFAOYSA-N ethyl 5-[[3-[(2-ethoxycarbonyl-1h-indol-5-yl)amino]-3-oxopropanoyl]amino]-1h-indole-2-carboxylate Chemical compound C1=C2NC(C(=O)OCC)=CC2=CC(NC(=O)CC(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)OCC)=C1 JYSYTIUAYLKBCR-UHFFFAOYSA-N 0.000 description 1
- SMIURLDKLZNNPU-UHFFFAOYSA-N ethyl 5-[[5-[(2-ethoxycarbonyl-1h-indol-5-yl)carbamoyl]furan-2-carbonyl]amino]-1h-indole-2-carboxylate Chemical compound C1=C2NC(C(=O)OCC)=CC2=CC(NC(=O)C2=CC=C(O2)C(=O)NC=2C=C3C=C(NC3=CC=2)C(=O)OCC)=C1 SMIURLDKLZNNPU-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical class Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 125000004970 halomethyl group Chemical group 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000011487 hemp Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- NONOKGVFTBWRLD-UHFFFAOYSA-N isocyanatosulfanylimino(oxo)methane Chemical group O=C=NSN=C=O NONOKGVFTBWRLD-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- VNXBKJFUJUWOCW-UHFFFAOYSA-N methylcyclopropane Chemical compound CC1CC1 VNXBKJFUJUWOCW-UHFFFAOYSA-N 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- HNPPKZRZKDKXDO-UHFFFAOYSA-N n,n-dimethylformamide;propan-2-one Chemical compound CC(C)=O.CN(C)C=O HNPPKZRZKDKXDO-UHFFFAOYSA-N 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical compound [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- YLZWEPNHBVOIBC-UHFFFAOYSA-N pyrrolo[3,2-e]indole Chemical class C1=CC2=NC=CC2=C2C=CN=C21 YLZWEPNHBVOIBC-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Error Detection And Correction (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Artificial Filaments (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
- Amplifiers (AREA)
- Solid State Image Pick-Up Elements (AREA)
- Semiconductor Integrated Circuits (AREA)
- Television Systems (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Stereophonic System (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Television Receiver Circuits (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24335088A | 1988-09-12 | 1988-09-12 | |
| US243,350 | 1988-09-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04500664A JPH04500664A (ja) | 1992-02-06 |
| JP3380237B2 true JP3380237B2 (ja) | 2003-02-24 |
Family
ID=22918400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50923689A Expired - Fee Related JP3380237B2 (ja) | 1988-09-12 | 1989-08-07 | ２のｃｐｉサブユニットを有する新規ｃｃ―１０６５アナログ類 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5541339A (enExample) |
| JP (1) | JP3380237B2 (enExample) |
| KR (1) | KR0137959B1 (enExample) |
| AT (1) | ATE198335T1 (enExample) |
| AU (1) | AU632288B2 (enExample) |
| CA (1) | CA1340215C (enExample) |
| DE (1) | DE68929275T2 (enExample) |
| DK (1) | DK175458B1 (enExample) |
| FI (1) | FI103668B1 (enExample) |
| GR (1) | GR3035589T3 (enExample) |
| LV (1) | LV12806B (enExample) |
| NO (1) | NO303498B1 (enExample) |
| TW (1) | TW217383B (enExample) |
| WO (1) | WO1990002746A1 (enExample) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2076465C (en) * | 1992-03-25 | 2002-11-26 | Ravi V. J. Chari | Cell binding agent conjugates of analogues and derivatives of cc-1065 |
| US5502068A (en) * | 1995-01-31 | 1996-03-26 | Synphar Laboratories, Inc. | Cyclopropylpyrroloindole-oligopeptide anticancer agents |
| US20100056762A1 (en) | 2001-05-11 | 2010-03-04 | Old Lloyd J | Specific binding proteins and uses thereof |
| US7589180B2 (en) | 2001-05-11 | 2009-09-15 | Abbott Laboratories Inc. | Specific binding proteins and uses thereof |
| BR0214019A (pt) | 2001-11-09 | 2004-10-13 | Boehringer Ingelheim Phamaceut | Benzimidazóis úteis como inibidores de proteìna quinase |
| EP1529046A1 (en) * | 2002-08-08 | 2005-05-11 | Boehringer Ingelheim Pharmaceuticals Inc. | Substituted benzimidazole compounds |
| JP2006505571A (ja) * | 2002-10-15 | 2006-02-16 | リゲル ファーマシューテイカルズ、インコーポレイテッド | 置換されたインドール及びｈｃｖ阻害剤としてのその使用 |
| US20070213374A1 (en) * | 2003-07-07 | 2007-09-13 | Merck Patent Gmbh | Malonamide Derivatives |
| WO2005079791A1 (en) * | 2004-02-12 | 2005-09-01 | Boehringer Ingelheim Pharmaceuticals, Inc. | Thiophene -2- carboxylic acid - (1h - benzimidazol - 2 yl) - amide derivatives and related compounds as inhibitors of the tec kinase itk (interleukin -2- inducible t cell kinase) for the treatment of inflammation, immunological and allergic disorders |
| US7446195B2 (en) * | 2005-08-17 | 2008-11-04 | Schering Corporation | High affinity thiophene-based and furan-based kinase ligands |
| EP2126127B1 (en) | 2007-01-25 | 2016-09-28 | Dana-Farber Cancer Institute, Inc. | Use of anti-egfr antibodies in treatment of egfr mutant mediated disease |
| CA2680854C (en) | 2007-03-15 | 2017-02-14 | Ludwig Institute For Cancer Research | Treatment method using egfr antibodies and src inhibitors and related formulations |
| US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
| US9283276B2 (en) | 2007-08-14 | 2016-03-15 | Ludwig Institute For Cancer Research Ltd. | Monoclonal antibody 175 targeting the EGF receptor and derivatives and uses thereof |
| MX2011004625A (es) | 2008-11-03 | 2011-07-20 | Syntarga Bv | Analogos cc-1065 novedosos y sus conjugados. |
| CA2956934C (en) | 2010-04-21 | 2019-07-09 | Syntarga B.V. | Novel conjugates of cc-1065 analogs and bifunctional linkers |
| WO2014066400A2 (en) | 2012-10-22 | 2014-05-01 | Arnold Glazier | Methods for the effective treatment of metastatic cancer |
| DE102013012622A1 (de) * | 2013-07-30 | 2015-02-05 | Clariant lnternational Ltd | Neue sterisch gehinderte cyclische Amine |
| AU2015205574B2 (en) | 2014-01-10 | 2019-08-15 | Byondis B.V. | Method for purifying Cys-linked antibody-drug conjugates |
| CA2937731C (en) * | 2014-01-27 | 2019-09-24 | Pfizer Inc. | Bifunctional cytotoxic agents |
| EP3160513B1 (en) | 2014-06-30 | 2020-02-12 | Glykos Finland Oy | Saccharide derivative of a toxic payload and antibody conjugates thereof |
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Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169888A (en) * | 1977-10-17 | 1979-10-02 | The Upjohn Company | Composition of matter and process |
| US4301248A (en) * | 1979-12-21 | 1981-11-17 | Bristol-Myers Company | Fermentation process for making rachelmycin |
| US4413132A (en) * | 1980-11-18 | 1983-11-01 | The Upjohn Company | Antibiotic CC-1065 indoline intermediates |
| CA1238907A (en) * | 1984-02-21 | 1988-07-05 | Robert C. Kelly | 1,2,8,8a-tetrahydrocyclopropa¬c|pyrrolo(3,2-e)- indol-4(5h)-ones and related compounds |
| US4912227A (en) * | 1984-02-21 | 1990-03-27 | The Upjohn Company | 1,2,8,8A-tetrahydrocyclopropa(c)pyrrolo(3,2-e)-indol-4-(5H)-ones and related compounds |
| GB8528848D0 (en) * | 1985-11-22 | 1985-12-24 | Davy Mckee Poole | Rolling mills |
| MX9203200A (es) * | 1986-12-19 | 1992-09-01 | Upjohn Co | Analogos de cc. 1065 novedosos. |
-
1989
- 1989-08-07 JP JP50923689A patent/JP3380237B2/ja not_active Expired - Fee Related
- 1989-08-07 WO PCT/US1989/003329 patent/WO1990002746A1/en not_active Ceased
- 1989-08-07 AU AU41922/89A patent/AU632288B2/en not_active Ceased
- 1989-08-07 US US07/659,415 patent/US5541339A/en not_active Expired - Fee Related
- 1989-08-07 KR KR1019900700977A patent/KR0137959B1/ko not_active Expired - Fee Related
- 1989-08-21 CA CA000608908A patent/CA1340215C/en not_active Expired - Fee Related
- 1989-08-23 TW TW078106510A patent/TW217383B/zh active
- 1989-09-04 DE DE68929275T patent/DE68929275T2/de not_active Expired - Fee Related
- 1989-09-04 AT AT89308920T patent/ATE198335T1/de not_active IP Right Cessation
-
1991
- 1991-03-08 DK DK41791A patent/DK175458B1/da not_active IP Right Cessation
- 1991-03-11 NO NO910958A patent/NO303498B1/no unknown
- 1991-03-11 FI FI911193A patent/FI103668B1/fi not_active IP Right Cessation
-
2001
- 2001-03-15 GR GR20010400433T patent/GR3035589T3/el not_active IP Right Cessation
- 2001-12-27 LV LV010180A patent/LV12806B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| LV12806B (lv) | 2002-05-20 |
| CA1340215C (en) | 1998-12-15 |
| DK41791A (da) | 1991-03-08 |
| WO1990002746A1 (en) | 1990-03-22 |
| DE68929275D1 (de) | 2001-02-01 |
| DK41791D0 (da) | 1991-03-08 |
| KR900701801A (ko) | 1990-12-04 |
| ATE198335T1 (de) | 2001-01-15 |
| TW217383B (enExample) | 1993-12-11 |
| NO910958L (no) | 1991-05-10 |
| KR0137959B1 (ko) | 1998-05-15 |
| DK175458B1 (da) | 2004-11-01 |
| DE68929275T2 (de) | 2001-05-23 |
| FI103668B (fi) | 1999-08-13 |
| AU4192289A (en) | 1990-04-02 |
| JPH04500664A (ja) | 1992-02-06 |
| GR3035589T3 (en) | 2001-06-29 |
| LV12806A (en) | 2002-03-20 |
| US5541339A (en) | 1996-07-30 |
| NO910958D0 (no) | 1991-03-11 |
| NO303498B1 (no) | 1998-07-20 |
| AU632288B2 (en) | 1992-12-24 |
| FI103668B1 (fi) | 1999-08-13 |
| FI911193A0 (fi) | 1991-03-11 |
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