JP2015514101A5 - - Google Patents
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- Publication number
- JP2015514101A5 JP2015514101A5 JP2015503835A JP2015503835A JP2015514101A5 JP 2015514101 A5 JP2015514101 A5 JP 2015514101A5 JP 2015503835 A JP2015503835 A JP 2015503835A JP 2015503835 A JP2015503835 A JP 2015503835A JP 2015514101 A5 JP2015514101 A5 JP 2015514101A5
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- indol
- carbonyl
- dihydro
- thieno
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- -1 5-{[(8R) -8- (chloromethyl) -4-hydroxy-1-methyl-7,8-dihydro-6H-thieno [3,2-e] indol-6-yl] carbonyl} -1-methyl-1H-pyrrol-3-yl Chemical group 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 33
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 230000004568 DNA-binding Effects 0.000 claims description 2
- 108010016626 Dipeptides Proteins 0.000 claims description 2
- 239000002202 Polyethylene glycol Chemical group 0.000 claims description 2
- 125000003827 glycol group Chemical group 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229920001223 polyethylene glycol Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 13
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 6
- 150000002431 hydrogen Chemical group 0.000 claims 6
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 5
- 125000000623 heterocyclic group Chemical group 0.000 claims 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 4
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- OERRZAJTKPMGBB-BYPYZUCNSA-N (2s)-2,5-diaminopentanamide Chemical compound NCCC[C@H](N)C(N)=O OERRZAJTKPMGBB-BYPYZUCNSA-N 0.000 claims 2
- ZTOQBFJTKSDMRF-CHIBUHFTSA-N C1=CC=C2NC(C(=O)NC3=CN=C4NC=C(C4=C3)/C=C/C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 Chemical compound C1=CC=C2NC(C(=O)NC3=CN=C4NC=C(C4=C3)/C=C/C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 ZTOQBFJTKSDMRF-CHIBUHFTSA-N 0.000 claims 2
- QNJQVYIXMYRTCY-UHFFFAOYSA-N CN1CCN(CC1)C(=O)OC1=C2C(=C3CC(NC3=C1)=C=O)C=CS2 Chemical compound CN1CCN(CC1)C(=O)OC1=C2C(=C3CC(NC3=C1)=C=O)C=CS2 QNJQVYIXMYRTCY-UHFFFAOYSA-N 0.000 claims 2
- 239000002246 antineoplastic agent Substances 0.000 claims 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims 2
- 229940127089 cytotoxic agent Drugs 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 1
- YSNOHRGMXBLFEQ-NNTXTVRGSA-N (e)-1-[(8r)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indol-6-yl]-3-(1h-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one Chemical compound C1=CC=C2C(/C=C/C(=O)N3C4=CC(O)=C5SC=C(C5=C4[C@@H](CCl)C3)C)=CNC2=N1 YSNOHRGMXBLFEQ-NNTXTVRGSA-N 0.000 claims 1
- FKAVHLMIWRHYKO-LQYUOIDQSA-N (e)-1-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indol-6-yl]-3-(1h-indol-3-yl)prop-2-en-1-one Chemical compound C1=CC=C2C(/C=C/C(=O)N3C4=CC(O)=C5SC=C(C5=C4[C@H](CCl)C3)C)=CNC2=C1 FKAVHLMIWRHYKO-LQYUOIDQSA-N 0.000 claims 1
- YSNOHRGMXBLFEQ-ISZGNANSSA-N (e)-1-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indol-6-yl]-3-(1h-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one Chemical compound C1=CC=C2C(/C=C/C(=O)N3C4=CC(O)=C5SC=C(C5=C4[C@H](CCl)C3)C)=CNC2=N1 YSNOHRGMXBLFEQ-ISZGNANSSA-N 0.000 claims 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- NTSUDTJWQYBXEV-QYWNIODHSA-N 2-[(8S)-8-(chloromethyl)-6-[5-(1H-indole-2-carbonylamino)-1H-indole-2-carbonyl]-1-methyl-7,8-dihydrothieno[3,2-e]indol-4-yl]piperazine-1-carboxylic acid Chemical compound CC1=CSC2=C1C3=C(C=C2C4CNCCN4C(=O)O)N(C[C@H]3CCl)C(=O)C5=CC6=C(N5)C=CC(=C6)NC(=O)C7=CC8=CC=CC=C8N7 NTSUDTJWQYBXEV-QYWNIODHSA-N 0.000 claims 1
- OSRXKJNSSYJDMG-SXEDBCOVSA-N 5-amino-n-[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-5a,7,8,8a-tetrahydrothieno[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]-1h-indole-2-carboxamide Chemical compound NC1=CC=C2NC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@@H](CCl)C4C5=C(C(=CC43)O)SC=C5C)=CC2=C1 OSRXKJNSSYJDMG-SXEDBCOVSA-N 0.000 claims 1
- YAPRKFOSQTXPNL-QTEAWJPNSA-N C1=C2C=CNC2=CC(C(=O)NC=2C3=CC=C(C=C3NC=2)C(=O)N2C[C@H]3C[C@]33C4=C(C(C=C32)=O)SC=C4C)=C1 Chemical compound C1=C2C=CNC2=CC(C(=O)NC=2C3=CC=C(C=C3NC=2)C(=O)N2C[C@H]3C[C@]33C4=C(C(C=C32)=O)SC=C4C)=C1 YAPRKFOSQTXPNL-QTEAWJPNSA-N 0.000 claims 1
- ROEQCXKLBIEWOD-JVUYMAJISA-N C1=CC=C2C(/C=C/C(=O)N3C[C@@H]4C[C@@]44C5=C(C(C=C43)=O)SC=C5C)=CNC2=N1 Chemical compound C1=CC=C2C(/C=C/C(=O)N3C[C@@H]4C[C@@]44C5=C(C(C=C43)=O)SC=C5C)=CNC2=N1 ROEQCXKLBIEWOD-JVUYMAJISA-N 0.000 claims 1
- ROEQCXKLBIEWOD-BKEYBNDJSA-N C1=CC=C2C(/C=C/C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)SC=C5C)=CNC2=N1 Chemical compound C1=CC=C2C(/C=C/C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)SC=C5C)=CNC2=N1 ROEQCXKLBIEWOD-BKEYBNDJSA-N 0.000 claims 1
- WAHUJUOBRIEUQF-MQFAKOPTSA-N C1=CC=C2N(C)C(C(=O)NC=3C=C4C=C(N(C4=CC=3)C)C(=O)N3C[C@@H]4C[C@@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 Chemical compound C1=CC=C2N(C)C(C(=O)NC=3C=C4C=C(N(C4=CC=3)C)C(=O)N3C[C@@H]4C[C@@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 WAHUJUOBRIEUQF-MQFAKOPTSA-N 0.000 claims 1
- OSEFAXCBOSRUPB-NYEHZQRNSA-N CC(C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N(C)CCN(C)C(=O)Oc2cc3N(C[C@@H](CCl)c3c3c(C)csc23)C(=O)c2cc3cc(NC(=O)c4cc5cc(OCCN6CCCC6)ccc5[nH]4)ccc3[nH]2)cc1 Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N(C)CCN(C)C(=O)Oc2cc3N(C[C@@H](CCl)c3c3c(C)csc23)C(=O)c2cc3cc(NC(=O)c4cc5cc(OCCN6CCCC6)ccc5[nH]4)ccc3[nH]2)cc1 OSEFAXCBOSRUPB-NYEHZQRNSA-N 0.000 claims 1
- IIHLTOJHVNXPRZ-VZYDHVRKSA-N Cl.CN1CCN(CC1)C(=O)Oc1cc2N(C[C@@H](CCl)c2c2c(C)csc12)C(=O)c1cc2cc(NC(=O)c3cc4cc(N)ccc4[nH]3)ccc2[nH]1 Chemical compound Cl.CN1CCN(CC1)C(=O)Oc1cc2N(C[C@@H](CCl)c2c2c(C)csc12)C(=O)c1cc2cc(NC(=O)c3cc4cc(N)ccc4[nH]3)ccc2[nH]1 IIHLTOJHVNXPRZ-VZYDHVRKSA-N 0.000 claims 1
- VSRXZPHBLOFJOX-ZQHDKMAOSA-N N-[2-[(1R,12S)-3-methyl-7-oxo-5-thia-10-azatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-10-carbonyl]-1H-indol-5-yl]-5-nitro-1H-indole-2-carboxamide Chemical compound CC1=CSC2=C1[C@@]13[C@@H](CN(C1=CC2=O)C(=O)C=1NC2=CC=C(C=C2C=1)NC(=O)C=1NC2=CC=C(C=C2C=1)[N+](=O)[O-])C3 VSRXZPHBLOFJOX-ZQHDKMAOSA-N 0.000 claims 1
- VSRXZPHBLOFJOX-NOVUIFNWSA-N N-[2-[(1S,12R)-3-methyl-7-oxo-5-thia-10-azatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-10-carbonyl]-1H-indol-5-yl]-5-nitro-1H-indole-2-carboxamide Chemical compound CC1=CSC2=C1[C@]13[C@H](CN(C1=CC2=O)C(=O)C=1NC2=CC=C(C=C2C=1)NC(=O)C=1NC2=CC=C(C=C2C=1)[N+](=O)[O-])C3 VSRXZPHBLOFJOX-NOVUIFNWSA-N 0.000 claims 1
- QJVOTMJXHJCVTN-NOVUIFNWSA-N NC1=CC=C2NC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@@H]4C[C@@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 Chemical compound NC1=CC=C2NC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@@H]4C[C@@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 QJVOTMJXHJCVTN-NOVUIFNWSA-N 0.000 claims 1
- QJVOTMJXHJCVTN-ZQHDKMAOSA-N NC1=CC=C2NC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 Chemical compound NC1=CC=C2NC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)SC=C5C)=CC2=C1 QJVOTMJXHJCVTN-ZQHDKMAOSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- IIHLTOJHVNXPRZ-FTBISJDPSA-N [(8r)-6-[5-[(5-amino-1h-indole-2-carbonyl)amino]-1h-indole-2-carbonyl]-8-(chloromethyl)-1-methyl-7,8-dihydrothieno[3,2-e]indol-4-yl] 4-methylpiperazine-1-carboxylate;hydrochloride Chemical compound Cl.C1CN(C)CCN1C(=O)OC(C=1SC=C(C)C=11)=CC2=C1[C@@H](CCl)CN2C(=O)C1=CC2=CC(NC(=O)C=3NC4=CC=C(N)C=C4C=3)=CC=C2N1 IIHLTOJHVNXPRZ-FTBISJDPSA-N 0.000 claims 1
- DLGMWIQPGAEPPC-SFHVURJKSA-N [(8r)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indol-6-yl]-[5-(2-pyrrolidin-1-ylethoxy)-1h-indol-2-yl]methanone Chemical compound C1([C@@H](CCl)C2)=C3C(C)=CSC3=C(O)C=C1N2C(=O)C(NC1=CC=2)=CC1=CC=2OCCN1CCCC1 DLGMWIQPGAEPPC-SFHVURJKSA-N 0.000 claims 1
- ZAYQWCHJZMUHGQ-QFIPXVFZSA-N [(8r)-8-(chloromethyl)-6-[5-[(5-hydroxy-1h-indole-2-carbonyl)amino]-1h-indole-2-carbonyl]-1-methyl-7,8-dihydrothieno[3,2-e]indol-4-yl] 4-methylpiperazine-1-carboxylate Chemical compound C1CN(C)CCN1C(=O)OC(C=1SC=C(C)C=11)=CC2=C1[C@@H](CCl)CN2C(=O)C1=CC2=CC(NC(=O)C=3NC4=CC=C(O)C=C4C=3)=CC=C2N1 ZAYQWCHJZMUHGQ-QFIPXVFZSA-N 0.000 claims 1
- DLGMWIQPGAEPPC-GOSISDBHSA-N [(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indol-6-yl]-[5-(2-pyrrolidin-1-ylethoxy)-1h-indol-2-yl]methanone Chemical compound C1([C@H](CCl)C2)=C3C(C)=CSC3=C(O)C=C1N2C(=O)C(NC1=CC=2)=CC1=CC=2OCCN1CCCC1 DLGMWIQPGAEPPC-GOSISDBHSA-N 0.000 claims 1
- ZAYQWCHJZMUHGQ-JOCHJYFZSA-N [(8s)-8-(chloromethyl)-6-[5-[(5-hydroxy-1h-indole-2-carbonyl)amino]-1h-indole-2-carbonyl]-1-methyl-7,8-dihydrothieno[3,2-e]indol-4-yl] 4-methylpiperazine-1-carboxylate Chemical compound C1CN(C)CCN1C(=O)OC(C=1SC=C(C)C=11)=CC2=C1[C@H](CCl)CN2C(=O)C1=CC2=CC(NC(=O)C=3NC4=CC=C(O)C=C4C=3)=CC=C2N1 ZAYQWCHJZMUHGQ-JOCHJYFZSA-N 0.000 claims 1
- 238000011319 anticancer therapy Methods 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000006575 electron-withdrawing group Chemical group 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims 1
- ILKNYDYHSDRBKI-FQEVSTJZSA-N n-[2-[(8r)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indole-6-carbonyl]-1-methylindol-5-yl]-1-methylindole-2-carboxamide Chemical compound C1=CC=C2N(C)C(C(=O)NC=3C=C4C=C(N(C4=CC=3)C)C(=O)N3C4=CC(O)=C5SC=C(C5=C4[C@@H](CCl)C3)C)=CC2=C1 ILKNYDYHSDRBKI-FQEVSTJZSA-N 0.000 claims 1
- DKHKILMWOTZNRZ-GHOSXJJBSA-N n-[3-[(e)-3-[(8r)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indol-6-yl]-3-oxoprop-1-enyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]-1h-indole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)NC3=CN=C4NC=C(C4=C3)/C=C/C(=O)N3C4=CC(O)=C5SC=C(C5=C4[C@@H](CCl)C3)C)=CC2=C1 DKHKILMWOTZNRZ-GHOSXJJBSA-N 0.000 claims 1
- DKHKILMWOTZNRZ-OVKVCFKUSA-N n-[3-[(e)-3-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indol-6-yl]-3-oxoprop-1-enyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]-1h-indole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)NC3=CN=C4NC=C(C4=C3)/C=C/C(=O)N3C4=CC(O)=C5SC=C(C5=C4[C@H](CCl)C3)C)=CC2=C1 DKHKILMWOTZNRZ-OVKVCFKUSA-N 0.000 claims 1
- BKBWUCJJECCKNO-LJQANCHMSA-N n-[6-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydrothieno[3,2-e]indole-6-carbonyl]-1h-indol-3-yl]-1h-indole-6-carboxamide Chemical compound C1=C2C=CNC2=CC(C(=O)NC=2C3=CC=C(C=C3NC=2)C(=O)N2C3=CC(O)=C4SC=C(C4=C3[C@H](CCl)C2)C)=C1 BKBWUCJJECCKNO-LJQANCHMSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-M 4-nitrophenolate Chemical compound [O-]C1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-M 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 125000005599 alkyl carboxylate group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- ZSCYJHGJGRSPAB-UHFFFAOYSA-N carbamic acid Chemical compound NC(O)=O.NC(O)=O ZSCYJHGJGRSPAB-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 238000006265 spirocyclization reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12163459.6 | 2012-04-05 | ||
| EP12163459 | 2012-04-05 | ||
| EP12176162.1 | 2012-07-12 | ||
| EP12176162 | 2012-07-12 | ||
| PCT/EP2013/056743 WO2013149948A1 (en) | 2012-04-05 | 2013-03-28 | New alkylating agents |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017199656A Division JP2018070599A (ja) | 2012-04-05 | 2017-10-13 | 新たなアルキル化剤 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2015514101A JP2015514101A (ja) | 2015-05-18 |
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| EP2836493B1 (en) * | 2012-04-05 | 2018-06-20 | Nerviano Medical Sciences S.r.l. | Functionalized thieno-indole derivatives for the treatment of cancer |
| ES2755719T3 (es) | 2012-04-05 | 2020-04-23 | Nerviano Medical Sciences Srl | Nuevos agentes alquilantes |
| ES2738657T3 (es) * | 2013-09-25 | 2020-01-24 | Nerviano Medical Sciences Srl | Derivados de tieno[2,3-e]indol como nuevos antitumorales |
| BR112017018706B1 (pt) | 2015-03-20 | 2023-01-24 | Pfizer Inc | Agentes citotóxicos bifuncionais contendo o farmacoforo cti, composição farmacêutica e uso dos mesmos |
| DK3325489T3 (da) * | 2015-07-21 | 2020-02-17 | Nerviano Medical Sciences Srl | Asymmetrisk fremgangsmåde til fremstilling af thien-indolderivater |
| EP3165532B1 (en) | 2015-11-03 | 2018-12-19 | Industrial Technology Research Institute | Auristatin derivatives, linker-drugs and ligand-drug conjugates |
| ES2902179T3 (es) * | 2016-08-19 | 2022-03-25 | Bristol Myers Squibb Co | Compuestos de seco-ciclopropapirroloindol, conjugados de anticuerpo-fármaco de los mismos y métodos de elaboración y uso |
| WO2022053570A1 (en) * | 2020-09-09 | 2022-03-17 | Clinuvel Pharmaceuticals Ltd (Uk) | Pyrrolidine compounds to treat xeroderma pigmentosum |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE10940T1 (de) * | 1981-05-12 | 1985-01-15 | Imperial Chemical Industries Plc | Pyrrolderivate. |
| 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 |
| US5659022A (en) * | 1996-01-05 | 1997-08-19 | Epoch Pharmaceuticals, Inc. | Oligonucleotide-cyclopropapyrroloindole conjugates as sequence specific hybridization and crosslinking agents for nucleic acids |
| JP3045706B1 (ja) * | 1998-09-14 | 2000-05-29 | 科学技術振興事業団 | Ｄｎａの特定塩基配列をアルキル化する化合物及びその合成法 |
| GB2344818A (en) * | 1998-12-16 | 2000-06-21 | Pharmacia & Upjohn Spa | Anti-tumour thieno-indole derivatives |
| GB0015447D0 (en) * | 2000-06-23 | 2000-08-16 | Pharmacia & Upjohn Spa | Combined therapy against tumors comprising substituted acryloyl derivates and alkylating agents |
| EP1243276A1 (en) | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
| US7129261B2 (en) * | 2001-05-31 | 2006-10-31 | Medarex, Inc. | Cytotoxic agents |
| JP2005502703A (ja) * | 2001-09-07 | 2005-01-27 | ザ スクリプス リサーチ インスティテュート | Ｃｃ−１０６５およびデュオカルマイシンのｃｂｉ類似体 |
| WO2003026577A2 (en) * | 2001-09-24 | 2003-04-03 | Seattle Genetics, Inc. | P-amidobenzylethers in drug delivery agents |
| US6756397B2 (en) * | 2002-04-05 | 2004-06-29 | Immunogen, Inc. | Prodrugs of CC-1065 analogs |
| WO2004043493A1 (en) | 2002-11-14 | 2004-05-27 | Syntarga B.V. | Prodrugs built as multiple self-elimination-release spacers |
| WO2004069201A2 (en) * | 2003-02-03 | 2004-08-19 | Medlogics Device Corporation | Compounds useful in coating stents to prevent and treat stenosis and restenosis |
| TW200526204A (en) * | 2004-02-03 | 2005-08-16 | Pharmacia Italia Spa | 1h-thieno[2,3-c]pyrazole derivatives useful as kinase inhibitors |
| US7282590B2 (en) | 2004-02-12 | 2007-10-16 | The Research Foundation Of State University Of New York | Drug conjugates |
| MXPA06012144A (es) | 2004-04-21 | 2007-01-31 | Alza Corp | Conjugado polimerico liberable bajo condiciones tioliticas suaves. |
| WO2005112919A2 (en) * | 2004-05-19 | 2005-12-01 | Medarex, Inc. | Self-immolative linkers and drug conjugates |
| RU2402548C2 (ru) * | 2004-05-19 | 2010-10-27 | Медарекс, Инк. | Химические линкеры и их конъюгаты |
| US8288557B2 (en) | 2004-07-23 | 2012-10-16 | Endocyte, Inc. | Bivalent linkers and conjugates thereof |
| CN101415679A (zh) * | 2006-02-02 | 2009-04-22 | 辛塔佳有限公司 | 水溶性cc-1065类似物及其缀合物 |
| ES2509820T3 (es) * | 2006-12-20 | 2014-10-20 | Nerviano Medical Sciences S.R.L. | Derivados de indazol como inhibidores de la cinasa para el tratamiento del cáncer |
| JP6067222B2 (ja) | 2008-07-15 | 2017-01-25 | ジェネンテック， インコーポレイテッド | アントラサイクリン誘導体コンジュゲート、その調製方法及び抗腫瘍化合物としてのその用途 |
| ES2755719T3 (es) | 2012-04-05 | 2020-04-23 | Nerviano Medical Sciences Srl | Nuevos agentes alquilantes |
| EP2836493B1 (en) * | 2012-04-05 | 2018-06-20 | Nerviano Medical Sciences S.r.l. | Functionalized thieno-indole derivatives for the treatment of cancer |
-
2013
- 2013-03-28 ES ES13715931T patent/ES2755719T3/es active Active
- 2013-03-28 RU RU2014143994A patent/RU2632206C2/ru active
- 2013-03-28 EP EP19184082.6A patent/EP3587426B1/en active Active
- 2013-03-28 US US14/390,644 patent/US9527863B2/en active Active
- 2013-03-28 JP JP2015503835A patent/JP6314128B2/ja active Active
- 2013-03-28 CN CN201610942350.9A patent/CN107011358B/zh active Active
- 2013-03-28 DK DK13715931T patent/DK2836494T3/da active
- 2013-03-28 ES ES19184082T patent/ES2929759T3/es active Active
- 2013-03-28 WO PCT/EP2013/056743 patent/WO2013149948A1/en not_active Ceased
- 2013-03-28 EP EP13715931.5A patent/EP2836494B1/en active Active
- 2013-03-28 HU HUE19184082A patent/HUE060655T2/hu unknown
- 2013-03-28 HR HRP20221356TT patent/HRP20221356T1/hr unknown
- 2013-03-28 CN CN201380016674.4A patent/CN104220442B/zh active Active
-
2016
- 2016-11-23 US US15/359,703 patent/US10071074B2/en active Active
-
2017
- 2017-10-13 JP JP2017199656A patent/JP2018070599A/ja not_active Withdrawn
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