JPH11511113A - シクロプロピルインドール類およびそのセコ前駆体、ならびにプロドラッグとしてのこれらの使用 - Google Patents

シクロプロピルインドール類およびそのセコ前駆体、ならびにプロドラッグとしてのこれらの使用

Info

Publication number: JPH11511113A
Authority: JP; Japan
Prior art keywords: formula; indole; group; defined above; mmol
Prior art date: 1995-08-18
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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

JP8531337A

Other languages

English (en)

Japanese (ja)

Other versions

JPH11511113A5 (2

Inventor

アレクサンダーデニー，ウィリアム

ターセル，モーナ

Original Assignee

オークランドディビジョンキャンサーソサエティーオブニュージーランドインコーポレーテッド

Priority date (The priority date 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 date listed.)

1995-08-18

Filing date

1996-08-19

Publication date

1999-09-28

1996-08-19 Application filed by オークランドディビジョンキャンサーソサエティーオブニュージーランドインコーポレーテッド filed Critical オークランドディビジョンキャンサーソサエティーオブニュージーランドインコーポレーテッド

1999-09-28 Publication of JPH11511113A publication Critical patent/JPH11511113A/ja

2004-07-22 Publication of JPH11511113A5 publication Critical patent/JPH11511113A5/ja

Status Withdrawn legal-status Critical Current

Links

229940002612 prodrug Drugs 0.000 title description 31
239000000651 prodrug Substances 0.000 title description 31
INCAQIRDTKGRNM-UHFFFAOYSA-N 2-cyclopropyl-1h-indole Chemical class C1CC1C1=CC2=CC=CC=C2N1 INCAQIRDTKGRNM-UHFFFAOYSA-N 0.000 title description 4
244000180577 Sambucus australis Species 0.000 title description 4
235000018734 Sambucus australis Nutrition 0.000 title description 4
239000002243 precursor Substances 0.000 title description 4
150000001875 compounds Chemical class 0.000 claims abstract description 71
239000000203 mixture Substances 0.000 claims description 49
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 42
239000000460 chlorine Substances 0.000 claims description 41
229910052757 nitrogen Inorganic materials 0.000 claims description 35
206010028980 Neoplasm Diseases 0.000 claims description 30
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 29
238000000034 method Methods 0.000 claims description 27
239000013598 vector Substances 0.000 claims description 26
229910052739 hydrogen Inorganic materials 0.000 claims description 22
125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 21
229910052799 carbon Inorganic materials 0.000 claims description 15
210000004881 tumor cell Anatomy 0.000 claims description 11
102000004459 Nitroreductase Human genes 0.000 claims description 10
108020001162 nitroreductase Proteins 0.000 claims description 10
239000002253 acid Substances 0.000 claims description 9
229910052760 oxygen Inorganic materials 0.000 claims description 9
KJLFFCRGGGXQKE-UHFFFAOYSA-N 1h-indole-6-carboxamide Chemical compound NC(=O)C1=CC=C2C=CNC2=C1 KJLFFCRGGGXQKE-UHFFFAOYSA-N 0.000 claims description 8
201000010099 disease Diseases 0.000 claims description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
125000000217 alkyl group Chemical group 0.000 claims description 7
125000003277 amino group Chemical group 0.000 claims description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
230000001613 neoplastic effect Effects 0.000 claims description 6
239000001301 oxygen Substances 0.000 claims description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
229910052717 sulfur Inorganic materials 0.000 claims description 6
125000004429 atom Chemical group 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 5
125000004432 carbon atom Chemical group C* 0.000 claims description 4
229910052801 chlorine Inorganic materials 0.000 claims description 4
239000001257 hydrogen Substances 0.000 claims description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
125000005843 halogen group Chemical group 0.000 claims description 3
125000000623 heterocyclic group Chemical group 0.000 claims description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
239000011593 sulfur Substances 0.000 claims description 3
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
125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 2
241001465754 Metazoa Species 0.000 claims description 2
125000001309 chloro group Chemical group Cl* 0.000 claims description 2
239000003085 diluting agent Substances 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
125000002837 carbocyclic group Chemical group 0.000 claims 1
125000001041 indolyl group Chemical group 0.000 claims 1
239000002246 antineoplastic agent Substances 0.000 abstract description 5
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
235000019439 ethyl acetate Nutrition 0.000 description 49
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
102000004190 Enzymes Human genes 0.000 description 40
108090000790 Enzymes Proteins 0.000 description 40
239000000243 solution Substances 0.000 description 36
238000005160 1H NMR spectroscopy Methods 0.000 description 33
-1 cyclopropylindole compound Chemical class 0.000 description 28
239000007787 solid Substances 0.000 description 27
239000011734 sodium Substances 0.000 description 26
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 26
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 25
239000000284 extract Substances 0.000 description 23
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
239000003208 petroleum Substances 0.000 description 21
210000004027 cell Anatomy 0.000 description 19
229940079593 drug Drugs 0.000 description 15
150000001408 amides Chemical class 0.000 description 14
239000003814 drug Substances 0.000 description 14
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 14
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 14
238000004440 column chromatography Methods 0.000 description 13
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 12
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
238000004458 analytical method Methods 0.000 description 11
238000006243 chemical reaction Methods 0.000 description 11
239000000047 product Substances 0.000 description 11
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
239000002502 liposome Substances 0.000 description 9
239000000843 powder Substances 0.000 description 9
238000010992 reflux Methods 0.000 description 9
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
239000002245 particle Substances 0.000 description 8
239000000741 silica gel Substances 0.000 description 8
238000003756 stirring Methods 0.000 description 8
238000002560 therapeutic procedure Methods 0.000 description 8
108020004414 DNA Proteins 0.000 description 7
241000700605 Viruses Species 0.000 description 7
230000004913 activation Effects 0.000 description 7
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
239000000306 component Substances 0.000 description 7
238000000354 decomposition reaction Methods 0.000 description 7
239000006260 foam Substances 0.000 description 7
238000009472 formulation Methods 0.000 description 7
239000012634 fragment Substances 0.000 description 7
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 7
150000003839 salts Chemical class 0.000 description 7
229910002027 silica gel Inorganic materials 0.000 description 7
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
241000588724 Escherichia coli Species 0.000 description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 6
201000011510 cancer Diseases 0.000 description 6
238000004587 chromatography analysis Methods 0.000 description 6
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
238000002347 injection Methods 0.000 description 6
239000007924 injection Substances 0.000 description 6
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
125000004744 butyloxycarbonyl group Chemical group 0.000 description 5
235000019253 formic acid Nutrition 0.000 description 5
239000010410 layer Substances 0.000 description 5
238000002360 preparation method Methods 0.000 description 5
108090000623 proteins and genes Proteins 0.000 description 5
241000701161 unidentified adenovirus Species 0.000 description 5
230000003612 virological effect Effects 0.000 description 5
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
108010006303 Carboxypeptidases Proteins 0.000 description 4
102000005367 Carboxypeptidases Human genes 0.000 description 4
OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
229910002651 NO3 Inorganic materials 0.000 description 4
NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
238000001816 cooling Methods 0.000 description 4
150000002148 esters Chemical class 0.000 description 4
108010062699 gamma-Glutamyl Hydrolase Proteins 0.000 description 4
210000004072 lung Anatomy 0.000 description 4
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
239000012044 organic layer Substances 0.000 description 4
YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 4
125000006239 protecting group Chemical group 0.000 description 4
230000009467 reduction Effects 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
KIDSZNLTRZMEIH-UHFFFAOYSA-N tert-butyl 3-(chloromethyl)-6-nitro-2,3-dihydroindole-1-carboxylate Chemical compound C1=C([N+]([O-])=O)C=C2N(C(=O)OC(C)(C)C)CC(CCl)C2=C1 KIDSZNLTRZMEIH-UHFFFAOYSA-N 0.000 description 4
241001430294 unidentified retrovirus Species 0.000 description 4
239000013603 viral vector Substances 0.000 description 4
WPLWCNRGSGEDSC-UHFFFAOYSA-N 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-5-nitrobenzoic acid Chemical compound COC(=O)C(C(=O)OC)C1=CC=C([N+]([O-])=O)C=C1C(O)=O WPLWCNRGSGEDSC-UHFFFAOYSA-N 0.000 description 3
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
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 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
238000005481 NMR spectroscopy Methods 0.000 description 3
108091028043 Nucleic acid sequence Proteins 0.000 description 3
108020004511 Recombinant DNA Proteins 0.000 description 3
241000714474 Rous sarcoma virus Species 0.000 description 3
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
230000029936 alkylation Effects 0.000 description 3
238000005804 alkylation reaction Methods 0.000 description 3
239000003242 anti bacterial agent Substances 0.000 description 3
229940088710 antibiotic agent Drugs 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
239000002585 base Substances 0.000 description 3
SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
210000000481 breast Anatomy 0.000 description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
239000006071 cream Substances 0.000 description 3
238000012217 deletion Methods 0.000 description 3
230000037430 deletion Effects 0.000 description 3
150000005690 diesters Chemical class 0.000 description 3
230000000694 effects Effects 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
150000002306 glutamic acid derivatives Chemical class 0.000 description 3
150000002367 halogens Chemical group 0.000 description 3
239000004615 ingredient Substances 0.000 description 3
238000003780 insertion Methods 0.000 description 3
230000037431 insertion Effects 0.000 description 3
239000012948 isocyanate Substances 0.000 description 3
150000002513 isocyanates Chemical class 0.000 description 3
208000032839 leukemia Diseases 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
150000007523 nucleic acids Chemical group 0.000 description 3
238000007911 parenteral administration Methods 0.000 description 3
WCNLCIJMFAJCPX-UHFFFAOYSA-N pethidine hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 WCNLCIJMFAJCPX-UHFFFAOYSA-N 0.000 description 3
238000011160 research Methods 0.000 description 3
229910000104 sodium hydride Inorganic materials 0.000 description 3
238000006467 substitution reaction Methods 0.000 description 3
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
230000001225 therapeutic effect Effects 0.000 description 3
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
MCRZWYDXIGCFKO-UHFFFAOYSA-N 2-butylpropanedioic acid Chemical compound CCCCC(C(O)=O)C(O)=O MCRZWYDXIGCFKO-UHFFFAOYSA-N 0.000 description 2
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
JZMUJQGIASARGH-UHFFFAOYSA-N 5,6,7-trimethoxy-1h-indole-2-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC2=C1NC(C(O)=O)=C2 JZMUJQGIASARGH-UHFFFAOYSA-N 0.000 description 2
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
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UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
239000012359 Methanesulfonyl chloride Substances 0.000 description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
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PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
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150000001298 alcohols Chemical class 0.000 description 2
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210000004899 c-terminal region Anatomy 0.000 description 2
239000004202 carbamide Substances 0.000 description 2
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
239000000969 carrier Substances 0.000 description 2
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239000002254 cytotoxic agent Substances 0.000 description 2
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BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
150000002012 dioxanes Chemical class 0.000 description 2
MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
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238000005984 hydrogenation reaction Methods 0.000 description 2
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
238000007918 intramuscular administration Methods 0.000 description 2
230000002601 intratumoral effect Effects 0.000 description 2
229910052744 lithium Inorganic materials 0.000 description 2
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238000007327 hydrogenolysis reaction Methods 0.000 description 1
230000001146 hypoxic effect Effects 0.000 description 1
125000000879 imine group Chemical class 0.000 description 1
239000012535 impurity Substances 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
125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
230000006698 induction Effects 0.000 description 1
208000015181 infectious disease Diseases 0.000 description 1
239000000543 intermediate Substances 0.000 description 1
201000009019 intestinal benign neoplasm Diseases 0.000 description 1
230000000968 intestinal effect Effects 0.000 description 1
230000003834 intracellular effect Effects 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 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
230000004807 localization Effects 0.000 description 1
150000002680 magnesium Chemical class 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
239000002609 medium Substances 0.000 description 1
239000012528 membrane Substances 0.000 description 1
230000009401 metastasis Effects 0.000 description 1
NQPIEWBAWBFGOB-UHFFFAOYSA-N methyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OC)=CC2=C1 NQPIEWBAWBFGOB-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
BQIYSNKKJDYYPA-UHFFFAOYSA-N methyl 6-(1,3-dihydroxypropan-2-ylcarbamoyl)-1h-indole-2-carboxylate Chemical compound C1=C(C(=O)NC(CO)CO)C=C2NC(C(=O)OC)=CC2=C1 BQIYSNKKJDYYPA-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
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
238000000520 microinjection Methods 0.000 description 1
238000010369 molecular cloning Methods 0.000 description 1
238000012544 monitoring process Methods 0.000 description 1
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
230000035772 mutation Effects 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
210000005170 neoplastic cell Anatomy 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
229960002715 nicotine Drugs 0.000 description 1
SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
235000001968 nicotinic acid Nutrition 0.000 description 1
229960003512 nicotinic acid Drugs 0.000 description 1
239000011664 nicotinic acid Substances 0.000 description 1
125000006501 nitrophenyl group Chemical group 0.000 description 1
210000004882 non-tumor cell Anatomy 0.000 description 1
230000002611 ovarian Effects 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
238000002161 passivation Methods 0.000 description 1
229940049954 penicillin Drugs 0.000 description 1
230000010412 perfusion Effects 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
239000012071 phase Substances 0.000 description 1
150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
230000002028 premature Effects 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
230000009257 reactivity Effects 0.000 description 1
238000010188 recombinant method Methods 0.000 description 1
230000008439 repair process Effects 0.000 description 1
238000002271 resection Methods 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
238000007363 ring formation reaction Methods 0.000 description 1
238000007142 ring opening reaction Methods 0.000 description 1
230000007017 scission Effects 0.000 description 1
238000013207 serial dilution Methods 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
210000004927 skin cell Anatomy 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000002904 solvent Substances 0.000 description 1
229910052596 spinel Inorganic materials 0.000 description 1
239000011029 spinel Substances 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
150000003432 sterols Chemical class 0.000 description 1
235000003702 sterols Nutrition 0.000 description 1
239000004575 stone Substances 0.000 description 1
229960005322 streptomycin Drugs 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
208000024891 symptom Diseases 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
BRTMDLPSCGNGEC-UHFFFAOYSA-N tert-butyl 4-chloro-3-nitrobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 BRTMDLPSCGNGEC-UHFFFAOYSA-N 0.000 description 1
DUNFNBQQWYQKFE-UHFFFAOYSA-N tert-butyl 4-formylbenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(C=O)C=C1 DUNFNBQQWYQKFE-UHFFFAOYSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000013518 transcription Methods 0.000 description 1
230000035897 transcription Effects 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
230000004614 tumor growth Effects 0.000 description 1
238000011144 upstream manufacturing Methods 0.000 description 1
230000002792 vascular Effects 0.000 description 1
238000005406 washing Methods 0.000 description 1
230000003442 weekly effect Effects 0.000 description 1
239000008096 xylene Substances 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)

JP8531337A 1995-08-18 1996-08-19 シクロプロピルインドール類およびそのセコ前駆体、ならびにプロドラッグとしてのこれらの使用 Withdrawn JPH11511113A (ja)

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 (2)

Publication Number	Publication Date
JPH11511113A true JPH11511113A (ja)	1999-09-28
JPH11511113A5 JPH11511113A5 (2)	2004-07-22

Family

ID=10779431

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP8531337A Withdrawn JPH11511113A (ja)	1995-08-18	1996-08-19	シクロプロピルインドール類およびそのセコ前駆体、ならびにプロドラッグとしてのこれらの使用

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)

Cited By (2)

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JP2009525322A (ja) *	2006-02-02	2009-07-09	シンタルガ・ビーブイ	水溶性ｃｃ−１０６５類似体及びその接合体
JP2015071602A (ja) *	2007-12-03	2015-04-16	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	インドリノン誘導体及びその製造方法

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ATE310725T1 (de) *	1996-09-12	2005-12-15	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
ES2260570T3 (es)	1998-08-27	2006-11-01	Spirogen Limited	Pirrolobenziodiazepinas dimericas.
US6909006B1 (en)	1999-08-27	2005-06-21	Spirogen Limited	Cyclopropylindole derivatives
DE60335383D1 (de)	2002-07-15	2011-01-27	Univ Texas	Antikörper mit bindung an anionische phospholipide und aminophospholipide und ihre verwendung bei der behandlung von virusinfektionen
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
ZA200800314B (en)	2005-06-29	2009-09-30	Threshold Pharmaceuticals Inc	Phosphoramidate alkylator prodrugs
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
WO2009060198A1 (en)	2007-11-09	2009-05-14	Peregrine Pharmaceuticals, Inc.	Anti-vegf antibody compositions and methods
HUE035798T2 (en)	2008-11-03	2018-05-28	Syntarga Bv	CC-1065 analogues and conjugates
NO3056203T3 (2)	2010-04-21	2018-05-12
US9056874B2 (en)	2012-05-04	2015-06-16	Novartis Ag	Complement pathway modulators and uses thereof
US9475806B2 (en)	2013-03-14	2016-10-25	Novartis Ag	Complement factor B inhibitors and uses there of
EP3089963A1 (en)	2013-10-30	2016-11-09	Novartis AG	2-benzyl-benzimidazole complement factor b inhibitors and uses thereof
TR201810856T4 (tr)	2014-01-10	2018-08-27	Synthon Biopharmaceuticals Bv	CYS'le bağlı antikor-ilaç konjugatlarını saflaştırmak için usul.
JP2024510435A (ja)	2021-03-18	2024-03-07	シージェンインコーポレイテッド	生体活性化合物の内部移行複合体からの選択的薬物放出

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AU617304B2 (en) *	1986-12-19	1991-11-28	Pharmacia & Upjohn Company	Novel cc-1065 analogs
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
AU648313B2 (en) *	1990-04-25	1994-04-21	Pharmacia & Upjohn Company	Novel CC-1065 analogs
JP4115514B2 (ja) *	1991-10-23	2008-07-09	キャンサー・リサーチ・キヤンペーン・テクノロジー・リミテツド	Ｃｂ１９５４およびその類似体を細胞障害性の形態に還元するための細菌のニトロリダクターゼ
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1995
- 1995-08-18 GB GBGB9516943.9A patent/GB9516943D0/en active Pending
1996
- 1996-08-19 NZ NZ315410A patent/NZ315410A/xx unknown
- 1996-08-19 EP EP96927217A patent/EP0850220A1/en not_active Withdrawn
- 1996-08-19 AU AU67109/96A patent/AU707644B2/en not_active Ceased
- 1996-08-19 WO PCT/NZ1996/000083 patent/WO1997007097A1/en not_active Ceased
- 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 JP JP8531337A patent/JPH11511113A/ja not_active Withdrawn

Cited By (3)

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Publication number	Priority date	Publication date	Assignee	Title
JP2009525322A (ja) *	2006-02-02	2009-07-09	シンタルガ・ビーブイ	水溶性ｃｃ−１０６５類似体及びその接合体
JP2013227326A (ja) *	2006-02-02	2013-11-07	Syntarga Bv	水溶性ｃｃ−１０６５類似体及びその接合体
JP2015071602A (ja) *	2007-12-03	2015-04-16	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	インドリノン誘導体及びその製造方法

Also Published As

Publication number	Publication date
CA2229264A1 (en)	1997-02-27
WO1997007097A1 (en)	1997-02-27
AU707644B2 (en)	1999-07-15
EP0850220A1 (en)	1998-07-01
NZ315410A (en)	1999-07-29
US5985909A (en)	1999-11-16
AU6710996A (en)	1997-03-12
GB9516943D0 (en)	1995-10-18

Legal Events

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2004-09-24

A761

Written withdrawal of application

Free format text: JAPANESE INTERMEDIATE CODE: A761

Effective date: 20040906

Publication	Publication Date	Title
US5985909A (en)	1999-11-16	Cyclopropylindoles and their seco precursors, and their use as prodrugs
US6130237A (en)	2000-10-10	Condensed N-aclyindoles as antitumor agents
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JP4669611B2 (ja)	2011-04-13	化合物
US5714148A (en)	1998-02-03	Chemical compounds
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JP2987205B2 (ja)	1999-12-06	抗腫瘍剤としてのニトロアニリン誘導体とその使用方法
JPH10512565A (ja)	1998-12-02	新規な親油性保護基を有するナイトロジェンマスタードプロドラッグ及びその製造方法
US7235578B2 (en)	2007-06-26	Processes for preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3H-[ring fused indol-5-yl-(amine-derived)] compounds and analogues thereof, and to products obtained therefrom
JP2005532280A (ja)	2005-10-27	化合物
US6251933B1 (en)	2001-06-26	Seco precursors of cyclopropylindolines and their use as prodrugs
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CA2184604C (en)	1999-05-04	Bicyclic carbamates
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JP2001514653A (ja)	2001-09-11	ヘテロ環状物質
JPH08507551A (ja)	1996-08-13	抗腫瘍剤としての３−（７−オキソ−１−アザ−４−オキサビシクロ［３．２．０］ヘプト−３−イル）アラニン誘導体