DE69832982T2 - Dolastatin 15 derivate - Google Patents
Dolastatin 15 derivate Download PDFInfo
- Publication number
- DE69832982T2 DE69832982T2 DE69832982T DE69832982T DE69832982T2 DE 69832982 T2 DE69832982 T2 DE 69832982T2 DE 69832982 T DE69832982 T DE 69832982T DE 69832982 T DE69832982 T DE 69832982T DE 69832982 T2 DE69832982 T2 DE 69832982T2
- Authority
- DE
- Germany
- Prior art keywords
- group
- methyl
- alkyl
- hydrogen
- formula
- 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
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- -1 methoxy, ethoxy Chemical group 0.000 claims description 191
- 150000001875 compounds Chemical class 0.000 claims description 90
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 61
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 60
- 150000003254 radicals Chemical class 0.000 claims description 59
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 38
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 31
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 22
- 125000003277 amino group Chemical group 0.000 claims description 22
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 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 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 125000004122 cyclic group Chemical group 0.000 claims description 15
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 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
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 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
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 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
- 239000011737 fluorine Substances 0.000 claims description 9
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- 241000124008 Mammalia Species 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
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 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 8
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 7
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 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
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 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
- 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 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 5
- 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 5
- 150000003147 proline derivatives Chemical class 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 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
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000005309 thioalkoxy group 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
- MLLSSTJTARJLHK-UHFFFAOYSA-N 3-aminocyclopentane-1-carboxylic acid Chemical group NC1CCC(C(O)=O)C1 MLLSSTJTARJLHK-UHFFFAOYSA-N 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
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 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
- 239000003814 drug Substances 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
- 150000002431 hydrogen Chemical class 0.000 claims 37
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 11
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims 10
- 125000003107 substituted aryl group Chemical group 0.000 claims 10
- 235000008206 alpha-amino acids Nutrition 0.000 claims 4
- 125000000539 amino acid group Chemical group 0.000 claims 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 4
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 claims 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims 1
- 125000002015 acyclic group Chemical group 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 229920002554 vinyl polymer Polymers 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
- 238000000034 method Methods 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 102000004196 processed proteins & peptides Human genes 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 150000001413 amino acids Chemical class 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 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 compound 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 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 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 9
- 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
- 108010045552 dolastatin 15 Proteins 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 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
- 239000002253 acid Substances 0.000 description 6
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000010647 peptide synthesis reaction Methods 0.000 description 5
- 229960002429 proline Drugs 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 0 *N(*)C1(Cc2ccccc2C1)C=O Chemical compound *N(*)C1(Cc2ccccc2C1)C=O 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 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-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
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- AKCRVYNORCOYQT-YFKPBYRVSA-N N-methyl-L-valine Chemical compound CN[C@@H](C(C)C)C(O)=O AKCRVYNORCOYQT-YFKPBYRVSA-N 0.000 description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-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
- 230000000118 anti-neoplastic effect Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
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- 239000012507 Sephadex™ Substances 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- CWUYOSYHUNLLRT-UHFFFAOYSA-N [2h-benzotriazol-4-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical class CN(C)C(=[N+](C)C)OC1=CC=CC2=C1N=NN2 CWUYOSYHUNLLRT-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 238000011717 athymic nude mouse Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
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- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 1
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- ZICBNHLULHJETL-UHFFFAOYSA-N ethyl 1-methylpiperidine-2-carboxylate Chemical compound CCOC(=O)C1CCCCN1C ZICBNHLULHJETL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical class C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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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)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Hematology (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 (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/896,394 US6143721A (en) | 1997-07-18 | 1997-07-18 | Dolastatin 15 derivatives |
| US896394 | 1997-07-18 | ||
| PCT/US1998/013901 WO1999003879A1 (en) | 1997-07-18 | 1998-07-07 | Dolastatin 15 derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69832982D1 DE69832982D1 (de) | 2006-02-02 |
| DE69832982T2 true DE69832982T2 (de) | 2006-08-24 |
Family
ID=25406130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69832982T Expired - Lifetime DE69832982T2 (de) | 1997-07-18 | 1998-07-07 | Dolastatin 15 derivate |
Country Status (32)
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US6686336B2 (en) | 2000-02-08 | 2004-02-03 | Federal Government As Represented By The Department Of Veterans Affaires | N-terminal D(-)-penicillamine peptides as aldehyde sequestration agents |
| US6884869B2 (en) * | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
| US7256257B2 (en) * | 2001-04-30 | 2007-08-14 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
| JP5042444B2 (ja) | 2002-03-22 | 2012-10-03 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 癌の処置におけるヘミアスタリン誘導体およびその利用法 |
| US7064211B2 (en) * | 2002-03-22 | 2006-06-20 | Eisai Co., Ltd. | Hemiasterlin derivatives and uses thereof |
| EP2353611B1 (en) * | 2002-07-31 | 2015-05-13 | Seattle Genetics, Inc. | Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease |
| KR101520209B1 (ko) | 2003-11-06 | 2015-05-13 | 시애틀 지네틱스, 인크. | 리간드에 접합될 수 있는 모노메틸발린 화합물 |
| WO2006063135A2 (en) * | 2004-12-09 | 2006-06-15 | Eisai R & D Management Co., Ltd. | Tubulin isotype screnning in cancer therapy using hemiasterlin analogs |
| CA2607940C (en) | 2005-05-18 | 2009-12-15 | Aegera Therapeutics Inc. | Bir domain binding compounds |
| SG171682A1 (en) | 2006-05-16 | 2011-06-29 | Aegera Therapeutics Inc | Iap bir domain binding compounds |
| SG183044A1 (en) | 2007-07-16 | 2012-08-30 | Genentech Inc | Humanized anti-cd79b antibodies and immunoconjugatesand methods of use |
| JP5469600B2 (ja) | 2007-07-16 | 2014-04-16 | ジェネンテック， インコーポレイテッド | 抗ＣＤ７９ｂ抗体及びイムノコンジュゲートとその使用方法 |
| DE102007039706A1 (de) | 2007-08-22 | 2009-02-26 | Erhard Prof. Dr.-Ing. Kohn | Chemischer Sensor auf Diamantschichten |
| UA106586C2 (uk) | 2008-01-31 | 2014-09-25 | Дженентек, Інк. | Анти-cd79b антитіла, і імунокон'югати та способи їх застосування |
| NZ600608A (en) | 2009-12-18 | 2015-01-30 | Idenix Pharmaceuticals Inc | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
| TW201129384A (en) | 2010-02-10 | 2011-09-01 | Immunogen Inc | CD20 antibodies and uses thereof |
| EP3263583A1 (en) | 2010-02-12 | 2018-01-03 | Pharmascience Inc. | Iap bir domain binding compounds |
| AU2012395148B2 (en) | 2012-11-24 | 2016-10-27 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
| PT3122757T (pt) | 2014-02-28 | 2023-11-03 | Hangzhou Dac Biotech Co Ltd | Ligantes carregados e as suas utilizações em conjugação |
| EP3689910A3 (en) | 2014-09-23 | 2020-12-02 | F. Hoffmann-La Roche AG | Method of using anti-cd79b immunoconjugates |
| NZ737471A (en) | 2015-06-15 | 2022-02-25 | Hangzhou Dac Biotech Co Ltd | Hydrophilic linkers for conjugation |
| WO2015151081A2 (en) | 2015-07-12 | 2015-10-08 | 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 |
| WO2018086139A1 (en) | 2016-11-14 | 2018-05-17 | Hangzhou Dac Biotech Co., Ltd | Conjugation linkers, cell binding molecule-drug conjugates containing the likers, methods of making and uses such conjugates with the linkers |
| AU2022338463A1 (en) | 2021-09-03 | 2024-03-21 | Toray Industries, Inc. | Pharmaceutical composition for cancer treatment and/or prevention |
| JP2024541058A (ja) | 2021-11-03 | 2024-11-06 | ハンジョウ ディーエーシー バイオテック シーオー．，エルティディ． | 抗体の特異的共役 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| ES2144421T3 (es) * | 1991-08-09 | 2000-06-16 | Teikoku Hormone Mfg Co Ltd | Nuevo derivado tetrapeptidico. |
| 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 |
| WO1993017388A1 (en) | 1992-02-26 | 1993-09-02 | Clark Paul C | System for protecting computers via intelligent tokens or smart cards |
| JP3523253B2 (ja) * | 1992-05-20 | 2004-04-26 | アボット ゲーエムベーハー ウント カンパニー カーゲー | ドラスタチン誘導体 |
| US5831002A (en) * | 1992-05-20 | 1998-11-03 | Basf Aktiengesellschaft | Antitumor peptides |
| DE69329425T2 (de) * | 1992-12-16 | 2001-01-18 | 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 |
| AU728161B2 (en) | 1997-01-10 | 2001-01-04 | Silicon Gaming, Inc. | Method and apparatus using geoographical position and a universal time to determination means to provide authenticated, secure, on-line communication between remote gaming 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 |
-
1997
- 1997-07-18 US US08/896,394 patent/US6143721A/en not_active Expired - Lifetime
-
1998
- 1998-07-07 IL IL13378498A patent/IL133784A/xx not_active IP Right Cessation
- 1998-07-07 CZ CZ20000176A patent/CZ303045B6/cs not_active IP Right Cessation
- 1998-07-07 CA CA002296036A patent/CA2296036C/en not_active Expired - Fee Related
- 1998-07-07 WO PCT/US1998/013901 patent/WO1999003879A1/en not_active Ceased
- 1998-07-07 PT PT98935531T patent/PT991658E/pt unknown
- 1998-07-07 PL PL338144A patent/PL197884B1/pl unknown
- 1998-07-07 ID IDW20000322A patent/ID24669A/id unknown
- 1998-07-07 AT AT98935531T patent/ATE314387T1/de active
- 1998-07-07 HU HU0004234A patent/HU228996B1/hu not_active IP Right Cessation
- 1998-07-07 CN CNB988073595A patent/CN1268636C/zh not_active Expired - Fee Related
- 1998-07-07 JP JP2000503101A patent/JP4508413B2/ja not_active Expired - Fee Related
- 1998-07-07 RU RU2000103960/04A patent/RU2195462C2/ru not_active IP Right Cessation
- 1998-07-07 DE DE69832982T patent/DE69832982T2/de not_active Expired - Lifetime
- 1998-07-07 BR BR9810911-1A patent/BR9810911A/pt not_active Application Discontinuation
- 1998-07-07 DK DK98935531T patent/DK0991658T3/da active
- 1998-07-07 TR TR2001/03545T patent/TR200103545T2/xx unknown
- 1998-07-07 NZ NZ502296A patent/NZ502296A/en not_active IP Right Cessation
- 1998-07-07 SK SK1879-99A patent/SK286581B6/sk not_active IP Right Cessation
- 1998-07-07 TR TR2000/00132T patent/TR200000132T2/xx unknown
- 1998-07-07 EP EP98935531A patent/EP0991658B1/en not_active Expired - Lifetime
- 1998-07-07 AU AU84758/98A patent/AU750120B2/en not_active Ceased
- 1998-07-07 KR KR1020007000565A patent/KR100579748B1/ko not_active Expired - Fee Related
- 1998-07-07 ES ES98935531T patent/ES2258819T3/es not_active Expired - Lifetime
- 1998-07-15 AR ARP980103445A patent/AR018501A1/es active IP Right Grant
- 1998-07-16 HR HR08/896,394A patent/HRP980397A2/hr not_active Application Discontinuation
- 1998-07-17 CO CO98040961A patent/CO4990967A1/es unknown
- 1998-07-17 ZA ZA9806358A patent/ZA986358B/xx unknown
- 1998-07-18 TW TW087111729A patent/TW533217B/zh active
- 1998-07-18 MY MYPI98003298A patent/MY135057A/en unknown
-
2000
- 2000-01-17 BG BG104089A patent/BG65212B1/bg unknown
- 2000-01-17 NO NO20000231A patent/NO326827B1/no not_active IP Right Cessation
- 2000-07-18 US US09/618,694 patent/US6458765B1/en not_active Expired - Lifetime
-
2002
- 2002-09-25 US US10/255,118 patent/US7084110B2/en not_active Expired - Lifetime
-
2006
- 2006-03-13 CY CY20061100348T patent/CY1107047T1/el unknown
- 2006-04-18 US US11/406,512 patent/US7662786B2/en not_active Expired - Fee Related
-
2008
- 2008-12-11 JP JP2008315269A patent/JP5047935B2/ja not_active Expired - Fee Related
- 2008-12-11 JP JP2008315263A patent/JP5122429B2/ja not_active Expired - Fee Related
-
2009
- 2009-12-29 US US12/648,446 patent/US8163698B2/en not_active Expired - Fee Related
-
2012
- 2012-04-16 US US13/447,529 patent/US20130046077A1/en not_active Abandoned
- 2012-06-20 JP JP2012138485A patent/JP2012211164A/ja active Pending
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