JP6258332B2 - 固形腫瘍の治療手段及び方法 - Google Patents
固形腫瘍の治療手段及び方法 Download PDFInfo
- Publication number
- JP6258332B2 JP6258332B2 JP2015533011A JP2015533011A JP6258332B2 JP 6258332 B2 JP6258332 B2 JP 6258332B2 JP 2015533011 A JP2015533011 A JP 2015533011A JP 2015533011 A JP2015533011 A JP 2015533011A JP 6258332 B2 JP6258332 B2 JP 6258332B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- compounds
- esi
- present
- methyl
- 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.)
- Active
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 36
- 238000000034 method Methods 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims description 67
- 201000011510 cancer Diseases 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 7
- 239000008103 glucose Substances 0.000 claims description 7
- 230000001472 cytotoxic effect Effects 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 231100000433 cytotoxic Toxicity 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000002950 deficient Effects 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000012822 autophagy inhibitor Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 206010009944 Colon cancer Diseases 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000004900 autophagic degradation Effects 0.000 description 7
- 210000002236 cellular spheroid Anatomy 0.000 description 7
- 230000003013 cytotoxicity Effects 0.000 description 7
- 231100000135 cytotoxicity Toxicity 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 5
- 208000029742 colonic neoplasm Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- -1 methoxy, methoxy Chemical group 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 230000030833 cell death Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- OCQLMDPIQPPKEB-UHFFFAOYSA-N (8-methyl-8a,9-dihydro-8h-pyrido[2,3-b]indol-2-yl)hydrazine Chemical compound NNC1=CC=C2C3=CC=CC(C)C3NC2=N1 OCQLMDPIQPPKEB-UHFFFAOYSA-N 0.000 description 3
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 3
- YLPMAXDBFIGJGF-UHFFFAOYSA-N 5h-[1,2,4]triazino[5,6-b]indol-3-ylhydrazine Chemical compound C1=CC=C2C3=NN=C(NN)N=C3NC2=C1 YLPMAXDBFIGJGF-UHFFFAOYSA-N 0.000 description 3
- 102000013563 Acid Phosphatase Human genes 0.000 description 3
- 108010051457 Acid Phosphatase Proteins 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 230000002123 temporal effect Effects 0.000 description 3
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical group ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 2
- RPEJKVRRTJDBSN-UHFFFAOYSA-N 2,5-dihydro-[1,2,4]triazino[5,6-b]indole-3-thione Chemical class C12=CC=CC=C2NC2=C1N=NC(=S)N2 RPEJKVRRTJDBSN-UHFFFAOYSA-N 0.000 description 2
- VYFARFQBIAKMJE-UHFFFAOYSA-N 2,6-dichloro-3-(3-methyl-2-nitrophenyl)pyridine Chemical compound CC1=CC=CC(C=2C(=NC(Cl)=CC=2)Cl)=C1[N+]([O-])=O VYFARFQBIAKMJE-UHFFFAOYSA-N 0.000 description 2
- XKSDJDFAYWBTDP-UHFFFAOYSA-N 2-(2,6-dichloropyridin-3-yl)-6-methylaniline Chemical compound CC1=CC=CC(C=2C(=NC(Cl)=CC=2)Cl)=C1N XKSDJDFAYWBTDP-UHFFFAOYSA-N 0.000 description 2
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 description 2
- WDTVDUFAOUKAMN-UHFFFAOYSA-N 2-chloro-8-methyl-8a,9-dihydro-8h-pyrido[2,3-b]indole Chemical compound ClC1=CC=C2C3=CC=CC(C)C3NC2=N1 WDTVDUFAOUKAMN-UHFFFAOYSA-N 0.000 description 2
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
- FSASIHFSFGAIJM-UHFFFAOYSA-N 3-methyladenine Chemical compound CN1C=NC(N)=C2N=CN=C12 FSASIHFSFGAIJM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 102100033421 Keratin, type I cytoskeletal 18 Human genes 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229960003677 chloroquine Drugs 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 231100000682 maximum tolerated dose Toxicity 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 238000004264 monolayer culture Methods 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- IENCLQAXYAPTJO-UHFFFAOYSA-N (6-methyl-5h-[1,2,4]triazino[5,6-b]indol-3-yl)hydrazine Chemical compound N1C2=NC(NN)=NN=C2C2=C1C(C)=CC=C2 IENCLQAXYAPTJO-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XDKMDDOCVPNVMB-UHFFFAOYSA-N 1-bromo-3-methyl-2-nitrobenzene Chemical compound CC1=CC=CC(Br)=C1[N+]([O-])=O XDKMDDOCVPNVMB-UHFFFAOYSA-N 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical class CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- ZFQAIGYRDWCYQK-ZVBGSRNCSA-N 7-chloro-n-[(e)-1-pyridin-2-ylethylideneamino]-5h-[1,2,4]triazino[5,6-b]indol-3-amine Chemical compound N=1N=C(C2=CC=C(Cl)C=C2N2)C2=NC=1N\N=C(/C)C1=CC=CC=N1 ZFQAIGYRDWCYQK-ZVBGSRNCSA-N 0.000 description 1
- VZEGDLZLFZWBDJ-UFFVCSGVSA-N 8-methoxy-n-[(e)-1-pyridin-2-ylethylideneamino]-5h-[1,2,4]triazino[5,6-b]indol-3-amine Chemical compound N=1N=C2C3=CC(OC)=CC=C3NC2=NC=1N\N=C(/C)C1=CC=CC=N1 VZEGDLZLFZWBDJ-UFFVCSGVSA-N 0.000 description 1
- JXJSMBAZFVMFCT-QRVIBDJDSA-N 8-methyl-n-[(z)-1-pyridin-3-ylethylideneamino]-8a,9-dihydro-8h-pyrido[2,3-b]indol-2-amine Chemical compound CC1C=CC=C(C2=CC=3)C1NC2=NC=3N\N=C(\C)C1=CC=CN=C1 JXJSMBAZFVMFCT-QRVIBDJDSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- AKXYZCUDWWCLSO-ZVBGSRNCSA-N BrC=1C=2C3=C(NC=2C=CC=1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1 Chemical compound BrC=1C=2C3=C(NC=2C=CC=1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1 AKXYZCUDWWCLSO-ZVBGSRNCSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- URUYUCOJVNBUDX-UHFFFAOYSA-N CC1=CC(=CC=2C3=C(NC12)N=C(N=N3)NN=C(/C)C3=NC=CC=C3)C Chemical compound CC1=CC(=CC=2C3=C(NC12)N=C(N=N3)NN=C(/C)C3=NC=CC=C3)C URUYUCOJVNBUDX-UHFFFAOYSA-N 0.000 description 1
- SSAOUPUCOCKEMH-LPYMAVHISA-N CC1=CC=CC=2C3=C(NC1=2)N=C(N=N3)N\N=C(/CC)\C1=NC=CC=C1 Chemical compound CC1=CC=CC=2C3=C(NC1=2)N=C(N=N3)N\N=C(/CC)\C1=NC=CC=C1 SSAOUPUCOCKEMH-LPYMAVHISA-N 0.000 description 1
- BCMXUKBWDVMYSX-QRVIBDJDSA-N CC1C=CC=C(c2cc3)C1Nc2nc3N\N=C(\C)c1ccccn1 Chemical compound CC1C=CC=C(c2cc3)C1Nc2nc3N\N=C(\C)c1ccccn1 BCMXUKBWDVMYSX-QRVIBDJDSA-N 0.000 description 1
- NLZIWECGXQOQTB-SRZZPIQSSA-N CC=1C=2C3=C(NC=2C=CC=1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1 Chemical compound CC=1C=2C3=C(NC=2C=CC=1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1 NLZIWECGXQOQTB-SRZZPIQSSA-N 0.000 description 1
- ORHOKWAVUSBQJL-ZVBGSRNCSA-N ClC1=CC=2C3=C(NC=2C=C1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1 Chemical compound ClC1=CC=2C3=C(NC=2C=C1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1 ORHOKWAVUSBQJL-ZVBGSRNCSA-N 0.000 description 1
- SXXBYTOPBAFDRD-UHFFFAOYSA-N ClC1=CC=CC=2C3=C(NC12)N=C(N=N3)NN=C(/C)C3=NC=CC=C3 Chemical compound ClC1=CC=CC=2C3=C(NC12)N=C(N=N3)NN=C(/C)C3=NC=CC=C3 SXXBYTOPBAFDRD-UHFFFAOYSA-N 0.000 description 1
- 102000007493 Class III Phosphatidylinositol 3-Kinases Human genes 0.000 description 1
- 108010085715 Class III Phosphatidylinositol 3-Kinases Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- ZCPPLAKKDWTORG-PGGKNCGUSA-N FC(OC1=CC=2C3=C(NC=2C=C1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1)(F)F Chemical compound FC(OC1=CC=2C3=C(NC=2C=C1)N=C(N=N3)N\N=C(/C)\C1=NC=CC=C1)(F)F ZCPPLAKKDWTORG-PGGKNCGUSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 108010066327 Keratin-18 Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- RTRQQBHATOEIAF-UUOKFMHZSA-N acadesine Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RTRQQBHATOEIAF-UUOKFMHZSA-N 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000004103 aerobic respiration Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 101150117004 atg18 gene Proteins 0.000 description 1
- 230000009789 autophagic cell death Effects 0.000 description 1
- 230000007455 autophagic response Effects 0.000 description 1
- XDHNQDDQEHDUTM-JQWOJBOSSA-N bafilomycin A1 Chemical compound CO[C@H]1\C=C\C=C(C)\C[C@H](C)[C@H](O)[C@H](C)\C=C(/C)\C=C(OC)\C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-JQWOJBOSSA-N 0.000 description 1
- XDHNQDDQEHDUTM-ZGOPVUMHSA-N bafilomycin A1 Natural products CO[C@H]1C=CC=C(C)C[C@H](C)[C@H](O)[C@H](C)C=C(C)C=C(OC)C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-ZGOPVUMHSA-N 0.000 description 1
- XDHNQDDQEHDUTM-UHFFFAOYSA-N bafliomycin A1 Natural products COC1C=CC=C(C)CC(C)C(O)C(C)C=C(C)C=C(OC)C(=O)OC1C(C)C(O)C(C)C1(O)OC(C(C)C)C(C)C(O)C1 XDHNQDDQEHDUTM-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- LLVVIWYEOKVOFV-UHFFFAOYSA-L copper;diiodate Chemical compound [Cu+2].[O-]I(=O)=O.[O-]I(=O)=O LLVVIWYEOKVOFV-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 235000019000 fluorine Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000007946 glucose deprivation Effects 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000006540 mitochondrial respiration Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 108700025694 p53 Genes Proteins 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明の化合物
一般式Iの本発明の例示的化合物(表1)を調製した。
使用した溶媒は全てHPLC等級又はそれ以上であった。無水条件は、使用から少なくとも24時間前に、過剰量の3オングストローム分子篩を溶媒に加えることにより創設した。低解像電子スプレーイオン化質量スペクトルを、アジレント(Agilent)質量分析計を使用して正のイオン化モードで得た。フラッシュクロマトグラフィーをメルク(Merck)シリカゲル60(230−400メッシュ)上で行った。分析LC/MSデータを、アジレント質量分析計;Agilent1100システムを用いて得た。(a)ACE C8カラム、(50×3.0mm,5μM);勾配:水/0.1%TFA中10-97%アセトニトリル、3分、1.0ml/分。(b):Xbridge C18カラム、(3.5μm,50×3.0mm);勾配:10mMのNH4HCO3(pH10)中10-97%アセトニトリル、3分、1mL/分。化学構造の命名はMarvin Sketch 5.2.6、ChemAxonにより決定した。
チオセミカルバジド(50 mg, 0.11 mmol)、それぞれのイサチン類(0.12 mmol)及びK2CO3 (23.4 mg, 0.17 mmol)を水(1 mL)に溶かし、そして1.5時間還流した。次に温度をRTに調整した。混合物を、HOAcを使用して酸性化し、そして沈殿物を濾取した。母液を濃縮した。粗製の2H,3H,5H-[1,2,4]トリアジノ[5,6-b]インドール-3-チオン誘導体を精製せずに下記のステップで使用した。
それぞれ5H-[1,2,4]トリアジノ[5,6-b]インドール-3-イルヒドラジン中間体(0.1 mmol)を5%酢酸水溶液(1 mL)に懸濁し、そして50℃に加熱した。この温かい懸濁液に2-アセチルピリジン(0.50 mL)を加え、反応を50℃で3時間保持した。反応混合物を濾過した。固体生成物をEtOHで十分洗い、そしてRTで乾燥した。
5%酢酸水溶液(0.67 mL)中の3-ヒドラジニル-6-メチル-5H-[1,2,4]トリアジノ[5,6-b]インドール(20 mg, 0.09 mmol)の攪拌懸濁液に、それぞれのケトン(0.47 mmol)を加え、そして反応物を50℃で、以下に特定した時間攪拌した。冷却後、水(1 mL)を加え、沈殿物を濾取し、そして水/アセトニトリル1:1及び2:1で、又はジエチルエーテルで洗った。
2,6-ジクロロ-3-(3-メチル-2-ニトロフェニル)ピリジン。電子レンジ用小瓶に、270 mgの2-ニトロ-3-ブロモ-トルエン(1.25 mmol)及び240 mgの2,6-ジクロロ-ピリジン-3-ホウ酸(240 mg)を4mlの溶媒混合物(1,4-ジオキサン/H2O, 4:1)中に溶解し、それに炭酸カリウム(345 mg)を加え、次いで28 mgのテトラキスPd(PPh3)4 (0.025 mmol)を加え、窒素で5分間、マイクロ波反応器中で100oCにて15分間脱ガスし、そして蒸発させて溶媒の殆どを除去した。残滓を50 mlの酢酸エチル中に溶解し、3 x10 mlの塩水で洗い、そしてMgSO4上で乾燥した。溶媒の蒸発後、残滓をフラッシュクロマトグラフィー(ヘプタン/酢酸エチル,85:15)で精製した。純粋な標題化合物(99 mg, 28 %)を白色粉末として得た。LC-MS: rt 1.803; MS ESI+/MS ESI+ ms/z 283 [M+H]+。
HCT116結腸癌細胞をマッコイの(McCoy’s)5A修飾媒体/10%ウシ胎児血清中に37℃で5%CO2中に維持した。MCSを、Herrmann R外の方法(Screening compounds that induce apoptosis of cancer cells grown as multicellular spheroids.J Biomol Screen 2008;13:108)の変形を用いて調製した。10,000個の細胞を含む細胞懸濁液(200μl)をポリ−HEMA被覆96穴プレートの各穴に加えた。該穴を次ぎに追加の170μlの媒体を加えることによりいっぱいにして、凸表面曲線を得た。塑像用粘土スペーサー(3mm)を各プレートの隅に置いて、蓋が該媒体に触れるのを防止した。該プレートを次ぎに逆にして該細胞を液体/空気界面に沈殿させ、そして静かに振って培養した。24時間の培養後、該プレートを正常状態に戻した。第1の過剰媒体を吸引により除去し、次ぎに塑像用粘土スペーサーを除去した。該プレートを薬物処理前に4日間培養した。薬物処理24時間の後、NP40を該培養媒体に加えて0.1%の濃度にして、カスパーゼ分割K18をMCSから抽出し、そして死んだ細胞から媒体に放出された物質を含ませた。カスパーゼ分割ケラチン−18(K18−Asp396)を25mLの媒体/抽出物を用い、M30 CytoDeath ELISAアッセー(生体外使用に開発されたM30−Apoptosense(登録商標)ELISA(Hagg M et al., A novel high-through-put assay for screening of pro-apoptotic drugs. Invest New Drugs 2002;20:253-9)の変形)(Peviva AB,ブロマ、スエーデン)を用いて測定した。生存率測定を、Friedrich外によるA reliable tool to determine cell viability in complex 3-d culture: the acid phosphatase assay. J Biomol Screen 2007;12:92537に記載されたアシッドホスファターゼ(APH)法により行った。背景活性を差し引いた。本発明の化合物の細胞毒性(図1a−1l)、及び本発明に含まれない構造的に関連する化合物の細胞毒性(図2a−2h)を、HCT116結腸癌細胞モデルにおいて測定し、そして該化合物の濃度に依存する細胞の生存インデックスにより表現した。
本発明の化合物(化合物11)をNMR1マウスに静脈注射した。16mg/kgの最大許容用量(MTD)にて、〜100μMの初期血漿濃度が観察され、インビトロにおける腫瘍細胞系及び主要な患者結腸直腸癌細胞のIC50の>10倍である。該化合物は急速に分配されそして最後に4〜5時間の半減期で除かれた。本発明の化合物の全身的毒性は低い。4.5mg/kgまでの用量は動物の血漿パラメータ、例えば肝臓ALT、血液グルコース及び全タンパク質、に注目すべき変化を生ぜず、動物が体重増加するのを防止しなかった。
本発明の化合物の細胞毒性活性が鉄枯渇に依存性であるか否かを試験するために、本発明の化合物の添加前に塩化鉄をHCT116細胞に添加した。塩化鉄は、wtp53を発現するHCT116細胞とp53遺伝子が崩壊したHCT116細胞の両方に対して、本発明の化合物の効果を全く無効にすることが見出された。
本発明の化合物を有機溶媒、例えば、塩酸を少なくとも2モル当量含むメタノール、に溶解する。第2の溶媒、例えばエタノール、を添加することにより、該化合物の二塩酸塩が該溶液から、そのままで又は沈殿する溶媒との複合体として、例えば化合物2HCl・EtOHとして、沈殿する。該二塩酸塩/エタノール複合体は、薬学的組成物に使用するためには、本発明の化合物の好ましい態様である。それは寒冷沈殿物の形態で使用されるのが好ましい。所望により、該寒冷沈殿物は、標準的な粉末状薬学的賦形剤、例えばマンニトール、澱粉及びミクロセルロース、と組み合わせて錠剤に混入することができる。該賦形剤は低塩基性でなければならない。水に懸濁した場合、該賦形剤はpHを7.0超に上昇させてはならず、5.0−7.0のpHを与えなければならない。
Claims (11)
- 一般式Iの細胞毒性化合物:
- R2がHである、請求項1の化合物。
- R=H,R1=6−CH3,R2=H,X及びY=CH;R=CH2C(CH3)3,R1=6−CH3,R2=H,X及びY=N;R=CH2CH3;R1=6−CH3,R2=H,X及びY=Nから成る群から選ばれる、請求項2の化合物。
- R=CH2C(CH3)3,R1=6−CH3,R2=H,X及びY=Nである、請求項3の化合物。
- R=CH2CH3,R1=6−CH3,R2=H,X及びY=Nである、請求項3の化合物。
- 請求項1〜5のいずれか1項の化合物のシス−,トランス−異性体の混合物。
- 請求項1〜6のいずれか1項の化合物の薬学的許容塩、塩/溶媒複合体、金属複合体(Fe2+,Fe3+,Co2+のいずれかとの金属複合体を除く)、又は溶媒複合体。
- 塩酸塩及び二塩酸塩から選ばれる、請求項7の薬学的許容塩。
- 請求項1〜8のいずれか1項の化合物と薬学的に許容される担体とを含む、薬学的組成物。
- 薬理学的有効量を投与することを特徴とする、ヒトにおける固形癌腫瘍の治療に使用するための請求項1〜8のいずれか1項の化合物。
- ヒトにおける固形癌腫瘍の治療に使用するために、該腫瘍を薬理学的有効量の投与前にグルコース欠乏にする、請求項1〜8のいずれか1項の化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE1200571 | 2012-09-21 | ||
SE1200571-6 | 2012-09-21 | ||
PCT/SE2013/000142 WO2014046589A1 (en) | 2012-09-21 | 2013-09-17 | Means and method for treating solid tumours |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015529244A JP2015529244A (ja) | 2015-10-05 |
JP6258332B2 true JP6258332B2 (ja) | 2018-01-10 |
Family
ID=50342515
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015533011A Active JP6258332B2 (ja) | 2012-09-21 | 2013-09-17 | 固形腫瘍の治療手段及び方法 |
Country Status (20)
Country | Link |
---|---|
US (1) | US9562046B2 (ja) |
EP (1) | EP2900667B1 (ja) |
JP (1) | JP6258332B2 (ja) |
KR (1) | KR102190768B1 (ja) |
CN (1) | CN104662022A (ja) |
AU (1) | AU2013318672B2 (ja) |
BR (1) | BR112015006370B1 (ja) |
CA (1) | CA2884832C (ja) |
DK (1) | DK2900667T3 (ja) |
EA (1) | EA026465B1 (ja) |
ES (1) | ES2734479T3 (ja) |
HK (1) | HK1206352A1 (ja) |
HU (1) | HUE044767T2 (ja) |
IL (1) | IL237569B (ja) |
MX (1) | MX369470B (ja) |
PL (1) | PL2900667T3 (ja) |
PT (1) | PT2900667T (ja) |
SG (1) | SG11201502209PA (ja) |
WO (1) | WO2014046589A1 (ja) |
ZA (1) | ZA201501558B (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG10201605083SA (en) | 2011-03-21 | 2016-08-30 | Vivolux Ab | Treatment of solid tumours |
WO2016131945A1 (en) | 2015-02-20 | 2016-08-25 | Transgene Sa | Combination product with autophagy modulator |
CA3008084A1 (en) | 2015-12-18 | 2017-06-22 | Vivolux Ab | Pharmaceutical composition comprising indole derivatives, process for preparation and use thereof |
CN106831776B (zh) * | 2017-03-16 | 2018-12-07 | 河北科技大学 | 5,10-二氢吡啶并吡嗪并三嗪类化合物及其应用 |
WO2019101897A1 (en) * | 2017-11-23 | 2019-05-31 | Deutsches Krebsforschungszentrum | Iron chelators in tumor therapy |
CN110964018B (zh) * | 2019-12-03 | 2022-03-11 | 华侨大学 | 一种吲哚类衍生物及其应用 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0233101A1 (fr) | 1986-01-13 | 1987-08-19 | Ire-Celltarg S.A. | Dérivés de vinblastine et composition pharmaceutique les contenant |
US5480906A (en) | 1994-07-01 | 1996-01-02 | Eli Lilly And Company | Stereochemical Wortmannin derivatives |
IL121272A (en) | 1997-07-10 | 2000-06-01 | Can Fite Technologies Ltd | Pharmaceutical compositions comprising adenosine and their use for treating or preventing leukopenia |
US6660737B2 (en) | 2001-05-04 | 2003-12-09 | The Procter & Gamble Company | Medicinal uses of hydrazones |
GB0300804D0 (en) * | 2003-01-14 | 2003-02-12 | Novo Pharmaceuticals De Ltd | Compounds and their use |
US8076352B2 (en) * | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
US7767689B2 (en) * | 2004-03-15 | 2010-08-03 | Ptc Therapeutics, Inc. | Carboline derivatives useful in the treatment of cancer |
ITMI20040874A1 (it) * | 2004-04-30 | 2004-07-30 | Ist Naz Stud Cura Dei Tumori | Derivati indolici ed azaindolici con azione antitumorale |
JP2008520669A (ja) | 2004-11-19 | 2008-06-19 | シバ バイオメディカル,エルエルシー | エリスロポエチン抵抗性を治療する方法 |
MX2008014292A (es) | 2006-05-09 | 2008-11-18 | Novartis Ag | Combinacion que comprende un quelante de hierro y un agente anti-neoplastico, y uso de la misma. |
WO2009035534A2 (en) * | 2007-09-07 | 2009-03-19 | The Cleveland Clinic Foundation | Treatment of ischemic eye disease by the systematic pharmaceutical activation of hypoxia inducible factor (hif) |
KR101208587B1 (ko) | 2009-06-24 | 2012-12-06 | 여오영 | 하이드록시클로로퀸을 포함하는 항암 치료를 위한 국소 투여용 주사제 조성물 |
SG10201605083SA (en) * | 2011-03-21 | 2016-08-30 | Vivolux Ab | Treatment of solid tumours |
-
2013
- 2013-09-17 HU HUE13839817 patent/HUE044767T2/hu unknown
- 2013-09-17 PL PL13839817T patent/PL2900667T3/pl unknown
- 2013-09-17 CN CN201380049080.3A patent/CN104662022A/zh active Pending
- 2013-09-17 SG SG11201502209PA patent/SG11201502209PA/en unknown
- 2013-09-17 WO PCT/SE2013/000142 patent/WO2014046589A1/en active Application Filing
- 2013-09-17 EP EP13839817.7A patent/EP2900667B1/en active Active
- 2013-09-17 PT PT13839817T patent/PT2900667T/pt unknown
- 2013-09-17 KR KR1020157010109A patent/KR102190768B1/ko active IP Right Grant
- 2013-09-17 US US14/435,707 patent/US9562046B2/en active Active
- 2013-09-17 JP JP2015533011A patent/JP6258332B2/ja active Active
- 2013-09-17 CA CA2884832A patent/CA2884832C/en active Active
- 2013-09-17 EA EA201590315A patent/EA026465B1/ru not_active IP Right Cessation
- 2013-09-17 ES ES13839817T patent/ES2734479T3/es active Active
- 2013-09-17 DK DK13839817.7T patent/DK2900667T3/da active
- 2013-09-17 MX MX2015003607A patent/MX369470B/es active IP Right Grant
- 2013-09-17 BR BR112015006370-5A patent/BR112015006370B1/pt active IP Right Grant
- 2013-09-17 AU AU2013318672A patent/AU2013318672B2/en active Active
-
2015
- 2015-03-04 IL IL237569A patent/IL237569B/en active IP Right Grant
- 2015-03-06 ZA ZA2015/01558A patent/ZA201501558B/en unknown
- 2015-07-22 HK HK15107010.4A patent/HK1206352A1/xx unknown
Also Published As
Publication number | Publication date |
---|---|
EP2900667B1 (en) | 2019-06-05 |
AU2013318672A1 (en) | 2015-03-19 |
HUE044767T2 (hu) | 2019-11-28 |
CN104662022A (zh) | 2015-05-27 |
ZA201501558B (en) | 2016-01-27 |
US9562046B2 (en) | 2017-02-07 |
ES2734479T3 (es) | 2019-12-10 |
BR112015006370A8 (pt) | 2019-10-08 |
EA201590315A1 (ru) | 2015-08-31 |
DK2900667T3 (da) | 2019-08-26 |
CA2884832C (en) | 2020-09-15 |
MX369470B (es) | 2019-11-08 |
IL237569A0 (en) | 2015-04-30 |
PT2900667T (pt) | 2019-09-04 |
JP2015529244A (ja) | 2015-10-05 |
CA2884832A1 (en) | 2014-03-27 |
BR112015006370B1 (pt) | 2022-04-12 |
EP2900667A4 (en) | 2016-06-15 |
WO2014046589A1 (en) | 2014-03-27 |
EA026465B1 (ru) | 2017-04-28 |
EP2900667A1 (en) | 2015-08-05 |
AU2013318672B2 (en) | 2017-09-28 |
HK1206352A1 (en) | 2016-01-08 |
US20150259349A1 (en) | 2015-09-17 |
KR102190768B1 (ko) | 2020-12-14 |
BR112015006370A2 (pt) | 2017-07-04 |
KR20150058441A (ko) | 2015-05-28 |
PL2900667T3 (pl) | 2019-11-29 |
MX2015003607A (es) | 2015-06-05 |
SG11201502209PA (en) | 2015-05-28 |
IL237569B (en) | 2020-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6258332B2 (ja) | 固形腫瘍の治療手段及び方法 | |
US11866432B2 (en) | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors | |
CN102203101B (zh) | 作为p38激酶抑制剂的吡咯并[2,3-c]吡啶衍生物 | |
TWI335919B (en) | Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors | |
TW202102482A (zh) | 囊腫纖維化跨膜傳導調節蛋白調節劑 | |
CN105555786A (zh) | 作为BET蛋白和极体样激酶的双重抑制剂的取代的二氢吡啶并[3,4-b]吡嗪酮 | |
CN105461694B (zh) | 取代的杂芳基化合物及其组合物和用途 | |
JP2016053078A (ja) | がん及び非新生物性状態の治療方法 | |
CN104725249B (zh) | 苄胺类衍生物及其在药物上的应用 | |
TWI415613B (zh) | Anti-cancer agent resistance to overcome the agent | |
KR20220113771A (ko) | 마크로사이클릭 구조를 갖는 불소-함유 헤테로사이클릭 유도체 및 이의 용도 | |
CN104557939A (zh) | 吡咯并吡嗪化合物的盐酸盐及其应用 | |
US20150306070A1 (en) | Use of maleimide derivatives for preventing and treating leukemia | |
JP5117377B2 (ja) | 抗腫瘍化合物及びその医薬組成物 | |
CN110272425A (zh) | 吡啶酰基八氢吡咯并[3,4-c]吡咯衍生物及其用途 | |
CN108658937A (zh) | 一种双环生物碱类化合物及其制备方法和应用 | |
TW202132285A (zh) | 經取代異吲哚啉基2,2’-聯嘧啶基化合物、其類似物及使用其之方法 | |
CN104650092A (zh) | 取代的杂芳基化合物及其组合物和用途 | |
KR20150041786A (ko) | 암치료 및 면역억제를 위한 조합요법 | |
CN113493469A (zh) | 可作为免疫调节剂的化合物、其制备方法和应用 | |
US11548891B1 (en) | Quaternary ammonium salts of phenanthroindolizidine and phenanthroquinolizidine alkaloids as hypoxia-targeted anticancer agents | |
CN116789642A (zh) | 一类诱导肿瘤细胞发生methuosis死亡的三芳香杂环哌嗪类化合物及其应用 | |
CN116528866A (zh) | Fgfr4抑制剂的盐的晶型 | |
KR20240066906A (ko) | 퀴놀린 아마이드 구조를 갖는 이소인돌리논 유도체 및 이의 용도 | |
WO2024051795A1 (zh) | 用作泛素-特异性蛋白酶抑制剂的取代嘌呤酮衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150727 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160714 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20161122 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170518 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20170518 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170713 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20170713 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20171201 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20171206 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6258332 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |