CA2229264A1 - Cyclopropylindoles and their seco precursors, and their use as prodrugs - Google Patents
Cyclopropylindoles and their seco precursors, and their use as prodrugs Download PDFInfo
- Publication number
- CA2229264A1 CA2229264A1 CA002229264A CA2229264A CA2229264A1 CA 2229264 A1 CA2229264 A1 CA 2229264A1 CA 002229264 A CA002229264 A CA 002229264A CA 2229264 A CA2229264 A CA 2229264A CA 2229264 A1 CA2229264 A1 CA 2229264A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- indole
- group
- mmol
- nmr
- 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.)
- Abandoned
Links
- 229940002612 prodrug Drugs 0.000 title description 31
- 239000000651 prodrug Substances 0.000 title description 31
- 244000180577 Sambucus australis Species 0.000 title description 5
- 235000018734 Sambucus australis Nutrition 0.000 title description 5
- INCAQIRDTKGRNM-UHFFFAOYSA-N 2-cyclopropyl-1h-indole Chemical class C1CC1C1=CC2=CC=CC=C2N1 INCAQIRDTKGRNM-UHFFFAOYSA-N 0.000 title description 4
- 239000002243 precursor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 234
- 239000000203 mixture Substances 0.000 claims description 47
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 28
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 239000013598 vector Substances 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 17
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- 108020001162 nitroreductase Proteins 0.000 claims description 16
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- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
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- 125000005843 halogen group Chemical group 0.000 claims description 6
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
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- OKVIIDPNUHUPCM-UHFFFAOYSA-N 2-[3-(chloromethyl)-6-nitro-2,3-dihydroindole-1-carbonyl]-n-(1,3-dihydroxypropan-2-yl)-1h-indole-6-carboxamide Chemical compound C1C(CCl)C2=CC=C([N+]([O-])=O)C=C2N1C(=O)C1=CC2=CC=C(C(=O)NC(CO)CO)C=C2N1 OKVIIDPNUHUPCM-UHFFFAOYSA-N 0.000 claims description 2
- AIRLSJZBUJIUSL-UHFFFAOYSA-N 2-[3-(chloromethyl)-6-nitro-2,3-dihydroindole-1-carbonyl]-n-(2-morpholin-4-ylethyl)-1h-indole-6-carboxamide Chemical compound C12=CC([N+](=O)[O-])=CC=C2C(CCl)CN1C(=O)C(NC1=C2)=CC1=CC=C2C(=O)NCCN1CCOCC1 AIRLSJZBUJIUSL-UHFFFAOYSA-N 0.000 claims description 2
- JGJLIPNDTBGANN-UHFFFAOYSA-N 2-[3-(chloromethyl)-6-nitro-2,3-dihydroindole-1-carbonyl]-n-(2-pyridin-2-ylethyl)-1h-indole-6-carboxamide Chemical compound C12=CC([N+](=O)[O-])=CC=C2C(CCl)CN1C(=O)C(NC1=C2)=CC1=CC=C2C(=O)NCCC1=CC=CC=N1 JGJLIPNDTBGANN-UHFFFAOYSA-N 0.000 claims description 2
- JBMCYARHKHSASM-UHFFFAOYSA-N 2-[[2-[3-(chloromethyl)-6-nitro-2,3-dihydroindole-1-carbonyl]-1h-indole-6-carbonyl]amino]acetic acid Chemical compound C1C(CCl)C2=CC=C([N+]([O-])=O)C=C2N1C(=O)C1=CC2=CC=C(C(=O)NCC(=O)O)C=C2N1 JBMCYARHKHSASM-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 17
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 150000001408 amides Chemical class 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- -1 amine hydrochloride Chemical class 0.000 description 13
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 13
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
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- 238000002560 therapeutic procedure Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 235000019256 formaldehyde Nutrition 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- KJLFFCRGGGXQKE-UHFFFAOYSA-N 1h-indole-6-carboxamide Chemical compound NC(=O)C1=CC=C2C=CNC2=C1 KJLFFCRGGGXQKE-UHFFFAOYSA-N 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 7
- 125000006360 carbonyl amino methylene group Chemical group [H]N(C([*:1])=O)C([H])([H])[*:2] 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 241000701161 unidentified adenovirus Species 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- NVRASMCYDSUFFA-UHFFFAOYSA-N 2-methoxycarbonyl-1h-indole-6-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2NC(C(=O)OC)=CC2=C1 NVRASMCYDSUFFA-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 5
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- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 125000000879 imine group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 1
- 150000002476 indolines Chemical class 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- OGFXBIXJCWAUCH-UHFFFAOYSA-N meso-secoisolariciresinol Natural products C1=2C=C(O)C(OC)=CC=2CC(CO)C(CO)C1C1=CC=C(O)C(OC)=C1 OGFXBIXJCWAUCH-UHFFFAOYSA-N 0.000 description 1
- OZPOOJREXMDOKD-UHFFFAOYSA-N methyl 2-[3-(4-methylpiperidin-1-yl)propanoylamino]-4-phenylthiophene-3-carboxylate;oxalic acid Chemical compound OC(=O)C(O)=O.S1C=C(C=2C=CC=CC=2)C(C(=O)OC)=C1NC(=O)CCN1CCC(C)CC1 OZPOOJREXMDOKD-UHFFFAOYSA-N 0.000 description 1
- RXYCUKSOYJWGPE-UHFFFAOYSA-N methyl 2-azidoacetate Chemical compound COC(=O)CN=[N+]=[N-] RXYCUKSOYJWGPE-UHFFFAOYSA-N 0.000 description 1
- VPUXNIUAFUMVMN-UHFFFAOYSA-N methyl 6-(2-morpholin-4-ylethylcarbamoyl)-1h-indole-2-carboxylate Chemical compound C1=C2NC(C(=O)OC)=CC2=CC=C1C(=O)NCCN1CCOCC1 VPUXNIUAFUMVMN-UHFFFAOYSA-N 0.000 description 1
- GXCBGJZXAKNFBZ-UHFFFAOYSA-N methyl 6-[(2-butoxy-2-oxoethyl)carbamoyl]-1h-indole-2-carboxylate Chemical compound CCCCOC(=O)CNC(=O)C1=CC=C2C=C(C(=O)OC)NC2=C1 GXCBGJZXAKNFBZ-UHFFFAOYSA-N 0.000 description 1
- VKSPAFINSZZWFR-UHFFFAOYSA-N methyl 6-[1,3-bis[[tert-butyl(dimethyl)silyl]oxy]propan-2-ylcarbamoyl]-1h-indole-2-carboxylate Chemical compound C1=C(C(=O)NC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)C=C2NC(C(=O)OC)=CC2=C1 VKSPAFINSZZWFR-UHFFFAOYSA-N 0.000 description 1
- RUUDKWNUIUBVTH-UHFFFAOYSA-N methyl 6-nitro-1h-indole-3-carboxylate Chemical compound [O-][N+](=O)C1=CC=C2C(C(=O)OC)=CNC2=C1 RUUDKWNUIUBVTH-UHFFFAOYSA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 150000008223 ribosides Chemical class 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- UCERYJRYDLVOAD-UHFFFAOYSA-N tert-butyl 2-chloro-5-nitrobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl UCERYJRYDLVOAD-UHFFFAOYSA-N 0.000 description 1
- YRFIRTPJPOONQE-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)-6-nitro-2,3-dihydroindole-1-carboxylate Chemical compound C1=C([N+]([O-])=O)C=C2N(C(=O)OC(C)(C)C)CC(CO)C2=C1 YRFIRTPJPOONQE-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9516943.9 | 1995-08-18 | ||
| GBGB9516943.9A GB9516943D0 (en) | 1995-08-18 | 1995-08-18 | Novel cyclopropylindoles and their secoprecursors,and their use as prodrugs |
| PCT/NZ1996/000083 WO1997007097A1 (en) | 1995-08-18 | 1996-08-19 | Cyclopropylindoles and their seco precursors, and their use as prodrugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2229264A1 true CA2229264A1 (en) | 1997-02-27 |
Family
ID=10779431
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002229264A Abandoned CA2229264A1 (en) | 1995-08-18 | 1996-08-19 | Cyclopropylindoles and their seco precursors, and their use as prodrugs |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5985909A (2) |
| EP (1) | EP0850220A1 (2) |
| JP (1) | JPH11511113A (2) |
| AU (1) | AU707644B2 (2) |
| CA (1) | CA2229264A1 (2) |
| GB (1) | GB9516943D0 (2) |
| NZ (1) | NZ315410A (2) |
| WO (1) | WO1997007097A1 (2) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69734722T2 (de) * | 1996-09-12 | 2006-07-20 | Auckland Uniservices Ltd. | Kondensierte n-acylindole als antitumormittel |
| US6130237A (en) * | 1996-09-12 | 2000-10-10 | Cancer Research Campaign Technology Limited | Condensed N-aclyindoles as antitumor agents |
| GB9712370D0 (en) | 1997-06-14 | 1997-08-13 | Aepact Ltd | Therapeutic systems |
| EP0887348A1 (en) * | 1997-06-25 | 1998-12-30 | Boehringer Mannheim Italia S.p.A. | Bis-Indole derivatives having antimetastatic activity, a process for their preparation and pharmaceutical compositions containing them |
| US6410584B1 (en) * | 1998-01-14 | 2002-06-25 | Cell Pathways, Inc. | Method for inhibiting neoplastic cells with indole derivatives |
| GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
| PT1109812E (pt) | 1998-08-27 | 2005-09-30 | Spirogen Ltd | Pirrolobenzodiazepinas |
| US6909006B1 (en) * | 1999-08-27 | 2005-06-21 | Spirogen Limited | Cyclopropylindole derivatives |
| US7572442B2 (en) | 2002-07-15 | 2009-08-11 | Board Of Regents, The University Of Texas System | Selected antibody compositions for binding to aminophospholipids |
| GB0226593D0 (en) | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
| ZA200507752B (en) * | 2003-03-28 | 2007-01-31 | Threshold Pharmaceuticals Inc | Compositions and methods for treating cancer |
| GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
| US8003625B2 (en) | 2005-06-29 | 2011-08-23 | Threshold Pharmaceuticals, Inc. | Phosphoramidate alkylator prodrugs |
| US8940784B2 (en) * | 2006-02-02 | 2015-01-27 | Syntarga B.V. | Water-soluble CC-1065 analogs and their conjugates |
| GB0619325D0 (en) * | 2006-09-30 | 2006-11-08 | Univ Strathclyde | New compounds |
| US8552048B2 (en) * | 2006-12-26 | 2013-10-08 | Threshold Pharmaceuticals, Inc. | Phosphoramidate alkylator prodrugs for the treatment of cancer |
| US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
| US20090118031A1 (en) * | 2007-11-01 | 2009-05-07 | Qualizza Gregory K | Shaft Structure with Configurable Bending Profile |
| MX2010005104A (es) | 2007-11-09 | 2010-08-04 | Peregrine Pharmaceuticals Inc | Composiciones de anticuerpo anti-factor de crecimiento endotelial vascular y metodos. |
| PE20091445A1 (es) * | 2007-12-03 | 2009-10-19 | Boehringer Ingelheim Int | Derivados de indolinona y procedimiento para su fabricacion |
| 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 |
| US9056874B2 (en) | 2012-05-04 | 2015-06-16 | Novartis Ag | Complement pathway modulators and uses thereof |
| CN105229003B (zh) | 2013-03-14 | 2017-03-15 | 诺华股份有限公司 | 作为补体因子b抑制剂用于治疗眼科疾病的2‑(1h‑吲哚‑4‑基甲基)‑3h‑咪唑并[4,5‑b]吡啶‑6‑甲腈衍生物 |
| CN105849090A (zh) | 2013-10-30 | 2016-08-10 | 诺华股份有限公司 | 2-苄基-苯并咪唑补体因子b抑制剂及其用途 |
| AU2015205574B2 (en) | 2014-01-10 | 2019-08-15 | Byondis B.V. | Method for purifying Cys-linked antibody-drug conjugates |
| CA3213636A1 (en) | 2021-03-18 | 2022-09-22 | Seagen Inc. | Selective drug release from internalized conjugates of biologically active compounds |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX9203200A (es) * | 1986-12-19 | 1992-09-01 | Upjohn Co | Analogos de cc. 1065 novedosos. |
| GB8705477D0 (en) * | 1987-03-09 | 1987-04-15 | Carlton Med Prod | Drug delivery systems |
| GB8919607D0 (en) * | 1989-08-30 | 1989-10-11 | Wellcome Found | Novel entities for cancer therapy |
| KR100208957B1 (ko) * | 1990-04-25 | 1999-07-15 | 로렌스 티. 마이젠헬더 | 신규한 cc-1065 유사체 |
| US5633158A (en) * | 1991-10-23 | 1997-05-27 | Cancer Research Campaign Technology Limited | Bacterial nitroreductase for the reduction of CB 1954 and analogues thereof to a cytotoxic form |
| NZ240785A (en) * | 1991-11-28 | 1995-08-28 | Cancer Res Campaign Tech | Substituted nitro aniline derivatives and medicaments |
| GB9314960D0 (en) * | 1992-07-23 | 1993-09-01 | Zeneca Ltd | Chemical compounds |
| GB9323008D0 (en) * | 1993-11-05 | 1994-01-05 | Connors Thomas | Improvements relating to cancer therapy |
-
1995
- 1995-08-18 GB GBGB9516943.9A patent/GB9516943D0/en active Pending
-
1996
- 1996-08-19 JP JP8531337A patent/JPH11511113A/ja not_active Withdrawn
- 1996-08-19 WO PCT/NZ1996/000083 patent/WO1997007097A1/en not_active Ceased
- 1996-08-19 EP EP96927217A patent/EP0850220A1/en not_active Withdrawn
- 1996-08-19 US US09/011,883 patent/US5985909A/en not_active Expired - Fee Related
- 1996-08-19 CA CA002229264A patent/CA2229264A1/en not_active Abandoned
- 1996-08-19 AU AU67109/96A patent/AU707644B2/en not_active Ceased
- 1996-08-19 NZ NZ315410A patent/NZ315410A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11511113A (ja) | 1999-09-28 |
| AU707644B2 (en) | 1999-07-15 |
| AU6710996A (en) | 1997-03-12 |
| US5985909A (en) | 1999-11-16 |
| GB9516943D0 (en) | 1995-10-18 |
| WO1997007097A1 (en) | 1997-02-27 |
| NZ315410A (en) | 1999-07-29 |
| EP0850220A1 (en) | 1998-07-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |