HRP980397A2 - Dolastatin 15 derivatives - Google Patents
Dolastatin 15 derivativesInfo
- Publication number
- HRP980397A2 HRP980397A2 HR08/896,394A HRP980397A HRP980397A2 HR P980397 A2 HRP980397 A2 HR P980397A2 HR P980397 A HRP980397 A HR P980397A HR P980397 A2 HRP980397 A2 HR P980397A2
- Authority
- HR
- Croatia
- Prior art keywords
- group
- alkyl
- methyl
- hydrogen
- formula
- Prior art date
Links
- LQKSHSFQQRCAFW-CCVNJFHASA-N [(2s)-1-[(2s)-2-benzyl-3-methoxy-5-oxo-2h-pyrrol-1-yl]-3-methyl-1-oxobutan-2-yl] (2s)-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxyl Chemical class C([C@@H]1N(C(=O)C=C1OC)C(=O)[C@@H](OC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C)C(C)C)C1=CC=CC=C1 LQKSHSFQQRCAFW-CCVNJFHASA-N 0.000 title description 9
- -1 2-ethylglycyl residue Chemical group 0.000 claims description 216
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims description 154
- 150000001875 compounds Chemical class 0.000 claims description 88
- 229910052739 hydrogen Inorganic materials 0.000 claims description 71
- 239000001257 hydrogen Substances 0.000 claims description 71
- 150000003254 radicals Chemical class 0.000 claims description 67
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 46
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 29
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 28
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- 125000005843 halogen group Chemical group 0.000 claims description 21
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 20
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 20
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 20
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 20
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 20
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 19
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 19
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 15
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 10
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 10
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 10
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 10
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 10
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 10
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 10
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 10
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 10
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 10
- 229930192474 thiophene Natural products 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 7
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 6
- 125000005002 aryl methyl group Chemical group 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims description 6
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 150000003147 proline derivatives Chemical class 0.000 claims description 5
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 claims description 4
- MLLSSTJTARJLHK-UHFFFAOYSA-N 3-aminocyclopentane-1-carboxylic acid Chemical group NC1CCC(C(O)=O)C1 MLLSSTJTARJLHK-UHFFFAOYSA-N 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 2
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- BMVVXSIHLQYXJJ-UHFFFAOYSA-N 3-azoniabicyclo[2.2.1]heptane-2-carboxylate Chemical class C1CC2C(C(=O)O)NC1C2 BMVVXSIHLQYXJJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000180 D-prolyl group Chemical group N1[C@@H](C(=O)*)CCC1 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000001203 alloisoleucine group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 229920000151 polyglycol Polymers 0.000 claims description 2
- 239000010695 polyglycol Substances 0.000 claims description 2
- 125000001382 thioacetal group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 11
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims 10
- 125000003107 substituted aryl group Chemical group 0.000 claims 10
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims 6
- 125000000539 amino acid group Chemical group 0.000 claims 3
- 235000008206 alpha-amino acids Nutrition 0.000 claims 2
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 1
- NILQLFBWTXNUOE-UHFFFAOYSA-N 1-aminocyclopentanecarboxylic acid Chemical group OC(=O)C1(N)CCCC1 NILQLFBWTXNUOE-UHFFFAOYSA-N 0.000 claims 1
- 125000002015 acyclic group Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 108090000765 processed proteins & peptides Proteins 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 102000004196 processed proteins & peptides Human genes 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- LQKSHSFQQRCAFW-UHFFFAOYSA-N Dolastatin 15 Natural products COC1=CC(=O)N(C(=O)C(OC(=O)C2N(CCC2)C(=O)C2N(CCC2)C(=O)C(C(C)C)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C)C(C)C)C1CC1=CC=CC=C1 LQKSHSFQQRCAFW-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 108010045552 dolastatin 15 Proteins 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- NTWMEKOIKAVWGG-UHFFFAOYSA-N 2-(dimethylazaniumyl)-2-methylpropanoate Chemical compound CN(C)C(C)(C)C(O)=O NTWMEKOIKAVWGG-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/30—Nucleotides
- C12P19/34—Polynucleotides, e.g. nucleic acids, oligoribonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/896,394 US6143721A (en) | 1997-07-18 | 1997-07-18 | Dolastatin 15 derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP980397A2 true HRP980397A2 (en) | 1999-04-30 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HR08/896,394A HRP980397A2 (en) | 1997-07-18 | 1998-07-16 | Dolastatin 15 derivatives |
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US (6) | US6143721A (zh) |
EP (1) | EP0991658B1 (zh) |
JP (4) | JP4508413B2 (zh) |
KR (1) | KR100579748B1 (zh) |
CN (1) | CN1268636C (zh) |
AR (1) | AR018501A1 (zh) |
AT (1) | ATE314387T1 (zh) |
AU (1) | AU750120B2 (zh) |
BG (1) | BG65212B1 (zh) |
BR (1) | BR9810911A (zh) |
CA (1) | CA2296036C (zh) |
CO (1) | CO4990967A1 (zh) |
CY (1) | CY1107047T1 (zh) |
CZ (1) | CZ303045B6 (zh) |
DE (1) | DE69832982T2 (zh) |
DK (1) | DK0991658T3 (zh) |
ES (1) | ES2258819T3 (zh) |
HK (1) | HK1029125A1 (zh) |
HR (1) | HRP980397A2 (zh) |
HU (1) | HU228996B1 (zh) |
ID (1) | ID24669A (zh) |
IL (1) | IL133784A (zh) |
MY (1) | MY135057A (zh) |
NO (1) | NO326827B1 (zh) |
NZ (1) | NZ502296A (zh) |
PL (1) | PL197884B1 (zh) |
PT (1) | PT991658E (zh) |
RU (1) | RU2195462C2 (zh) |
SK (1) | SK286581B6 (zh) |
TR (2) | TR200103545T2 (zh) |
TW (1) | TW533217B (zh) |
WO (1) | WO1999003879A1 (zh) |
ZA (1) | ZA986358B (zh) |
Families Citing this family (26)
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US20010009901A1 (en) * | 1996-12-11 | 2001-07-26 | Basf Aktiengesellschaft Germany | Antineoplastic peptides |
US6143721A (en) * | 1997-07-18 | 2000-11-07 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
WO2001058928A1 (en) * | 2000-02-08 | 2001-08-16 | Nagasawa Herbert T | N-terminal d(-)-penicillamine peptides as aldehyde sequestration agents |
US7256257B2 (en) * | 2001-04-30 | 2007-08-14 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US6884869B2 (en) * | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US7064211B2 (en) * | 2002-03-22 | 2006-06-20 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof |
PL219737B1 (pl) | 2002-03-22 | 2015-07-31 | Eisai R & D Man Co | Pochodne hemiasterliny, środek farmaceutyczny i zastosowanie pochodnych i zastosowanie hemiasterliny |
DK1545613T3 (da) * | 2002-07-31 | 2011-11-14 | Seattle Genetics Inc | Auristatinkonjugater og deres anvendelse til behandling af cancer, en autoimmun sygdom eller en infektiøs sygdom |
KR101520209B1 (ko) | 2003-11-06 | 2015-05-13 | 시애틀 지네틱스, 인크. | 리간드에 접합될 수 있는 모노메틸발린 화합물 |
US20060148014A1 (en) * | 2004-12-09 | 2006-07-06 | Sergei Agoulnik | Tubulin isotype screening in cancer therapy using hemiasterlin analogs |
CA2607940C (en) | 2005-05-18 | 2009-12-15 | Aegera Therapeutics Inc. | Bir domain binding compounds |
BRPI0711591A2 (pt) | 2006-05-16 | 2011-11-16 | Aegera Therapeutics Inc | composto de ligação de domìnio bir da iap |
CN111499748A (zh) | 2007-07-16 | 2020-08-07 | 健泰科生物技术公司 | 抗cd79b抗体和免疫偶联物及使用方法 |
PE20090481A1 (es) | 2007-07-16 | 2009-05-18 | Genentech Inc | Anticuerpos anti-cd79b e inmunoconjugados humanizados y metodos de uso |
DE102007039706A1 (de) | 2007-08-22 | 2009-02-26 | Erhard Prof. Dr.-Ing. Kohn | Chemischer Sensor auf Diamantschichten |
EP3269737B1 (en) | 2008-01-31 | 2024-06-19 | Genentech, Inc. | Anti-cd79b antibodies and immunoconjugates and methods of use |
CA2784748A1 (en) * | 2009-12-18 | 2011-06-23 | Idenix Pharmaceuticals, Inc. | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
AR080154A1 (es) | 2010-02-10 | 2012-03-14 | Immunogen Inc | Anticuerpos cd20 y su utilizacion |
SG182724A1 (en) | 2010-02-12 | 2012-08-30 | Pharmascience Inc | Iap bir domain binding compounds |
US10131682B2 (en) | 2012-11-24 | 2018-11-20 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules |
CN114262344A (zh) | 2014-02-28 | 2022-04-01 | 杭州多禧生物科技有限公司 | 带电荷链接体及其在共轭反应上的应用 |
CA3069221C (en) | 2014-09-23 | 2023-04-04 | Genentech, Inc. | Methods of using anti-cd79b immunoconjugates |
CA2991973C (en) | 2015-07-12 | 2021-12-07 | Suzhou M-Conj Biotech Co., Ltd. | Bridge linkers for conjugation of a cell-binding molecule |
US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
KR20220150408A (ko) | 2016-11-14 | 2022-11-10 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 결합 링커, 그러한 결합 링커를 함유하는 세포 결합 분자-약물 결합체, 링커를 갖는 그러한 결합체의 제조 및 사용 |
JPWO2023033129A1 (zh) | 2021-09-03 | 2023-03-09 |
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US4816444A (en) * | 1987-07-10 | 1989-03-28 | Arizona Board Of Regents, Arizona State University | Cell growth inhibitory substance |
US4879278A (en) * | 1989-05-16 | 1989-11-07 | Arizona Board Of Regents | Isolation and structural elucidation of the cytostatic linear depsipeptide dolastatin 15 |
SG87056A1 (en) * | 1991-08-09 | 2002-03-19 | Teikoku Hormone Mfg Co Ltd | Novel tetrapeptide derivative |
US5533097A (en) * | 1992-02-26 | 1996-07-02 | Motorola, Inc. | Portable communication system comprising a local and wide area communication units which can store a communication when the wide area communication system is not available |
US5448045A (en) * | 1992-02-26 | 1995-09-05 | Clark; Paul C. | System for protecting computers via intelligent tokens or smart cards |
US5831002A (en) * | 1992-05-20 | 1998-11-03 | Basf Aktiengesellschaft | Antitumor peptides |
IL105651A (en) * | 1992-05-20 | 1998-07-15 | Basf Ag | History of dolastatin preparation and pharmaceutical preparations containing them |
ATE196296T1 (de) * | 1992-12-16 | 2000-09-15 | Basf Ag | Dolastatin analog |
US5554993A (en) * | 1994-01-04 | 1996-09-10 | Panasonic Technologies, Inc. | Global position determining system and method |
US5504191A (en) * | 1994-08-01 | 1996-04-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide methyl esters |
US5530097A (en) * | 1994-08-01 | 1996-06-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory peptide amides |
US5554725A (en) * | 1994-09-14 | 1996-09-10 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Synthesis of dolastatin 15 |
US5663149A (en) * | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
US5618232A (en) * | 1995-03-23 | 1997-04-08 | Martin; John R. | Dual mode gaming device methods and systems |
US5970143A (en) * | 1995-11-22 | 1999-10-19 | Walker Asset Management Lp | Remote-auditing of computer generated outcomes, authenticated billing and access control, and software metering system using cryptographic and other protocols |
US5807984A (en) * | 1995-11-09 | 1998-09-15 | Basf Aktienegesellschaft | Oligopeptides, the preparation and use thereof |
TW474946B (en) * | 1995-12-15 | 2002-02-01 | Basf Ag | Novel compounds, the preparation and use thereof |
CA2287379C (en) * | 1997-01-10 | 2005-10-04 | Silicon Gaming-Nevada | Method and apparatus for providing authenticated, secure on-line communication between remote locations |
US6143721A (en) * | 1997-07-18 | 2000-11-07 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
US6554705B1 (en) * | 1997-08-22 | 2003-04-29 | Blake Cumbers | Passive biometric customer identification and tracking system |
US6629591B1 (en) * | 2001-01-12 | 2003-10-07 | Igt | Smart token |
US6438382B1 (en) * | 2001-02-14 | 2002-08-20 | Telefonaktiebolaget Lm Ericsson (Publ.) | Expedited location determination in analog service areas |
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1997
- 1997-07-18 US US08/896,394 patent/US6143721A/en not_active Expired - Lifetime
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1998
- 1998-07-07 CN CNB988073595A patent/CN1268636C/zh not_active Expired - Fee Related
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2002
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2009
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2012
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