CN109180681A - A kind of DNA toxicity dimer compound - Google Patents
A kind of DNA toxicity dimer compound Download PDFInfo
- Publication number
- CN109180681A CN109180681A CN201810943763.8A CN201810943763A CN109180681A CN 109180681 A CN109180681 A CN 109180681A CN 201810943763 A CN201810943763 A CN 201810943763A CN 109180681 A CN109180681 A CN 109180681A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- added
- pharmaceutically acceptable
- hydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 70
- 239000000539 dimer Substances 0.000 title abstract description 4
- 231100000419 toxicity Toxicity 0.000 title abstract description 4
- 230000001988 toxicity Effects 0.000 title abstract description 4
- -1 substituted-phenyl Chemical group 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 230000007541 cellular toxicity Effects 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 8
- 125000001118 alkylidene group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- QNSCDXFRCKNHSS-UHFFFAOYSA-N [cyano(nitro)amino]oxy-nitrocyanamide Chemical compound C(#N)N([N+](=O)[O-])ON(C#N)[N+](=O)[O-] QNSCDXFRCKNHSS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 229910004749 OS(O)2 Inorganic materials 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- MJYFVDNMTKLGTH-UHFFFAOYSA-N 4-bromo-6-(3,4-dichlorophenyl)sulfanyl-1-[[4-(dimethylcarbamoyl)phenyl]methyl]indole-2-carboxylic acid Chemical compound BrC1=C2C=C(N(C2=CC(=C1)SC1=CC(=C(C=C1)Cl)Cl)CC1=CC=C(C=C1)C(N(C)C)=O)C(=O)O MJYFVDNMTKLGTH-UHFFFAOYSA-N 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 150000002825 nitriles Chemical group 0.000 claims description 2
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000007614 solvation Methods 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 abstract description 4
- 231100000682 maximum tolerated dose Toxicity 0.000 abstract description 2
- 231100001274 therapeutic index Toxicity 0.000 abstract description 2
- 150000001557 benzodiazepines Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 176
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 160
- 238000006243 chemical reaction Methods 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- 239000007787 solid Substances 0.000 description 67
- 239000000243 solution Substances 0.000 description 60
- 239000002994 raw material Substances 0.000 description 56
- 239000012044 organic layer Substances 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 238000003756 stirring Methods 0.000 description 44
- 239000002585 base Substances 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 239000012043 crude product Substances 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 16
- 239000012065 filter cake Substances 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 150000002475 indoles Chemical class 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 239000012266 salt solution Substances 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- FEUXCWOYVOYVBT-UHFFFAOYSA-N methyl formate;pentane Chemical compound COC=O.CCCCC FEUXCWOYVOYVBT-UHFFFAOYSA-N 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 238000012790 confirmation Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000002024 ethyl acetate extract Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 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 4
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 230000004568 DNA-binding Effects 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229940005605 valeric acid Drugs 0.000 description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 2
- QOBNPAKWVHRRJU-UHFFFAOYSA-N 1-(chloromethyl)-9-methyl-5-phenylmethoxy-2,3-dihydro-1h-benzo[e]indole Chemical class C1=C2NCC(CCl)C2=C2C(C)=CC=CC2=C1OCC1=CC=CC=C1 QOBNPAKWVHRRJU-UHFFFAOYSA-N 0.000 description 2
- WJGIYNCROZEFBS-UHFFFAOYSA-N 2-bromoethyl pentanoate Chemical compound CCCCC(=O)OCCBr WJGIYNCROZEFBS-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- URORFKDEPJFPOV-UHFFFAOYSA-N methyl 2,3-dihydro-1h-indole-2-carboxylate Chemical class C1=CC=C2NC(C(=O)OC)CC2=C1 URORFKDEPJFPOV-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
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- 238000007789 sealing Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- LMGGOGHEVZMZCU-FGJMKEJPSA-N (2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,7,12-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-2-carboxylic acid Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(O)=O)C1 LMGGOGHEVZMZCU-FGJMKEJPSA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- RHKRZQHJRZVTBP-UHFFFAOYSA-N 1-(chloromethyl)-2,3-dihydro-1h-benzo[e]indole Chemical class C1=CC=CC2=C3C(CCl)CNC3=CC=C21 RHKRZQHJRZVTBP-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
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- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The invention discloses a kind of DNA toxicity dimer compound, compared with the benzodiazepines conjugate disclosed in the prior art, which shows much higher interior therapeutic index (ratio of maximum tolerated dose and minimum effective dose).
Description
Invention field
Medicine the present invention relates to novel cytotoxic compound and comprising these cytotoxic compounds and cell binding agent
Object.It is more particularly related to Novel benzodiazepine Zhuo dimer compound, its derivative, wherein its pharmacy of mesosome
Upper acceptable salt, they can be used as drug, especially as antiproliferative.
Background of invention
Benzodiazepines derivative has the ability for identifying and combining specific dna sequence, is a kind of highly effective
Interchain linkage agent can be reacted with the guanine in DNA ditch, formed DNA adduct, interfered the processing of DNA, therefore they are made
For anti-tumor drug use.(Rahman et al.(2009)Jour. Amer.Chem.Soc.131(38):13756-13766；
Thurston et al.(1994)Chem.Rev.,94:433-46 5；Bose et al.(1992)
J.Am.Chem.Soc.114:4939-4941；Gregson et al.(2004)Jour.Med. Chem.47(5):1161-
1174)。
The DNA ditch alkylating agent of 1- (chloromethyl) -2,3- dihydro -1H- benzo [e] indoles (CBI) class is strong cell
Toxin (Atwell et al. (1999) J.Med.Chem., 42:3400), and it has been used as effector unit for for cancer
The multiclass pro-drug of therapy design.CBI is connected together with benzodiazepines derivative by alkyl chain
(Tercel et al.(2003)J.Med.Chem.,46:2132-2151)。
Imidazo [1,2-a] pyridine derivatives are a kind of strong DNA adhesive units, have been used to antitumor antibiosis
The synthesis of plain times carcinomycin (duocarmycins) derivative, and show very effective cytotoxicity (Ronald
C.Elgersma et al.(2015)Mol.Pharmaceutics.12:1813-1835)。
Benzodiazepines derivative toxicity disclosed in the prior art is very big, be in very low dose it is toxic, therefore,
Improved low toxicity and still there is therapeutic activity, the benzodiazepines derivative of high therapeutic window is very necessary.
Summary of the invention
The present invention is intended to provide a kind of benzodiazepine dimer derivate of the cytotoxicity with good therapeutic window.
The benzodiazepine dimer derivate of the cytotoxicity of brand-new design have chloromethyl (CBI) and imines (PBD) or
DNA-binding (DB) and imines (PBD) Liang Ge functional group.Chloromethyl is a pro-drug structure, into can be formed in vivo
DNA alkylation may further occur for three-membered ring structures.D NA-binding segment has strong DNA adhesive effect.This
The presence of Liang Ge functional group can enhance the crosslinking of DN A.Design of the invention has been surprisingly found that, with benzo two disclosed in prior art
Azatropylidene class conjugate is compared, the cytotoxic compound show much higher interior therapeutic index (maximum tolerated dose with most
The ratio of low effective dose).
In terms of total, the present invention provide a kind of cell toxicity medicament with formula (I) or formula (II) or its pharmaceutically
Acceptable salt, hydrate or solvate,
Wherein:
Y is selected from one or more H, halogen, C1-4Alkyl, OR4, SR4, NR4R5, SO2R4, CONHR4,
CN or COOR4, wherein R4And R5It is independent to be selected from H, C1-4Alkyl, phenyl or substituted-phenyl；
X2Selected from halogen or OSO2R5, wherein R5It is independent to be selected from H, C1-4Alkyl, phenyl or substituted-phenyl；
X1Selected from O and NR6, wherein R6Selected from H, C1-6Alkyl, the C that one or more F replace1-6Alkyl；
R1Selected from H, P (O)3H2, C (O) NR7R8, wherein R7And R8Selected from H, C1-6Alkyl, what one or more F replaced
C1-6Alkyl or R7And R8Form five yuan or six-membered heterocyclic group group；
R3For optional substituent group.
R2Selected from H, P (O)3H2, C (O) NR7R8, wherein R7And R8Selected from H, C1-6Alkyl, what one or more F replaced
C1-6Alkyl or R7And R8Form five yuan or six-membered heterocyclic group group；
D1Selected from following drug moieties:
Wherein wave indicates the site for being attached to T；
Two-wire between N and CIndicate that singly-bound or double bond, condition are the R when it is double bond9It is not present and R10It is
H, and when it is singly-bound, R9It is H or selected from acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group and 9- fluorenes methoxy
The amido protecting part of carbonyl；R10Selected from OH, by O R11Ether, the inferior sulfate radical SO of expression3-Or OSO3-, wherein R11Selected from having
Straight chain, branch or cyclic alkyl, the alkenyl or alkynyl of 1-10 carbon atom；
Dotted line between c 2 and c 3 indicates being optionally present for double bond；
When there is double bond between c 2 and c 3,
R12Selected from the C optionally substituted by one or more substituent groups5-10Aryl, wherein it includes following that the substituent group, which is selected from,
Group: halogen, nitro, cyano, amino, ether, carboxyl, ester, C1-7Alkyl, C3-7Heterocycle；
When there is singly-bound between c 2 and c 3,
R12It isWherein R14And R15It is independent to be selected from H, F, C1-4Saturated alkyl, C2-3Alkenyl, the alkyl and alkene
Base is optionally substituted by a group, and the group is selected from C1-4Alkylamidoalkyl and C1-4Arrcostab, alternatively, working as R14And R15First is that H
When, another is selected from nitrile and C1-4Arrcostab；
Module D1 " can be by one or more R13It is replaced, wherein R13Selected from H, halogen, nitro, cyano, amino, ether, carboxylic
Base, ester, C1-7Alkyl, C3-7Heterocycle；
Preferably, the drug, R3 are selected from H, OH, SH, NH2、N3、NO2、NO、CF3、 CN、C(O)NH2、C(O)H、C
(O) OH, halogen, Rh、SRh、S(O)Rh、S(O)2Rh、S(O)ORh、 S(O)2ORh、OS(O)Rh、OS(O)2Rh、OS(O)ORh、OS
(O)2ORh、ORh、NHRh、N(Rh)Ri、+N(Rh)(Ri)Rj、P(O)(ORh)(ORi)、OP(O)(ORh)(ORi)、SiRhRiRj、C(O)
Rh、C(O)ORh、 C(O)N(Rh)Ri、OC(O)Rh、OC(O)ORh、OC(O)N(Rh)Ri、N(Rh)C(O)Ri、 N(Rh)C(O)ORi、N
(Rh)C(O)N(Ri)Rj。
Wherein Rh、RiAnd RjIndependently selected from H and optionally substituted C1-15Alkyl, C1-15Miscellaneous alkyl, C3-15Naphthenic base,
C1-15Heterocyclylalkyl, C5-15Aryl or C1-15Heteroaryl.
T is selected from C2-C12Alkyl, Z, (C1-C6Alkylidene)-Z- (C1-C6Alkylidene), (C1-C6Alkylidene)-Z- (C1-C6
Alkylidene)-Z- (C1-C6Alkylidene), (C1-C6Alkenylene)-Z- (C1-C6Alkenylene),
(C1-C6Alkynylene)-Z- (C1-C6Alkynylene)；
Wherein Z is independently selected from O, S, NR1, aryl and heteroaryl；
Wherein alkylidene, alkenylene, aryl and heteroaryl are independent and optionally with F, OH, O (C1-C6Alkyl), NH2,
NHCH3, N (CH3)2And C1-C6Alkyl-substituted, wherein alkyl is replaced with one or more F；
Preferably, the drug, wherein X1For O, R1For H；
Preferably, the drug, wherein D1 is D1 ', and there are double bonds between N and C, and there are double bonds between C2 and C3, and
R12It is methoxy-substituted phenyl；
Preferably, the drug, wherein D1 is D2 ", and there are double bond and R between N and C13It is methoxyl group；
Preferably, the drug, wherein T is selected from the alkylidene of C2-12；
Preferably, the drug, wherein T be
Preferably, the present invention provides a kind of method for treating patient with this need, including gives to the patient aforementioned
Drug described in any one of claim, wherein the patient suffers from tumour, autoimmune disease or infectious diseases.
The present composition can be used for inhibiting abnormal cell growth or treatment appreciation disease in mammal (such as mankind)
Disease.The present composition can be used for treating the disease in mammal (such as mankind), such as cancer.Wherein the cancer is selected from cream
Gland cancer, colorectal cancer in gastrointestinal cancer, such as the group of composition, cancer of pancreas, cholangiocarcinoma, hepatocellular carcinoma, osteosarcoma, lung cancer are preceding
Column gland cancer, squamous cell carcinoma, oophoroma, carcinoma of testis, bladder cancer, gastric cancer, head and neck cancer, cervical carcinoma, kidney, glioma, skin
Skin cancer, such as: malignant mela noma, thyroid cancer, leukaemia, malignant lymphoma.
By reference to a specific embodiment of the invention and the embodiment being included therein, this hair can be more easily to understand
It is bright.
Abbreviation and definition
Unless otherwise stated, following term as used herein and phrase are intended to have following meanings.When herein
When using brand name, unless otherwise indicated in context, otherwise brand name includes that the product of the brand name product is matched
Side, universal medication and active pharmaceutical ingredient.
Unless otherwise indicated, term " aryl " refer to how unsaturated, be usually aromatics hydroxyl groups, it can be monocycle or
It is condensed or polycyclic (at most three rings) that be covalently attached.Term " heterocyclic base " refers to heteroatomic selected from N, O or S containing 1-5
Aryl (or ring), wherein the nitrogen and sulphur atom are optionally oxidized, the nitrogen-atoms is optionally quaternized.Heteroaryl group can pass through
Hetero atom is connected to the rest part of molecule.The non-limitative example of aryl group includes: phenyl, naphthalene and diphenyl, and miscellaneous
The non-limitative example of aryl group includes: pyridyl group, pyridazinyl, pyrazinyl, pyrimidine radicals (pyrimindinyl), triazine radical, quinoline
Quinoline base, quinoxalinyl, quinazolyl, cinnoline base, phthalazinyl (phthalaziniyl), phentriazine base, purine radicals, benzo miaow
Oxazolyl, benzopyrene oxazolyl, benzotriazole base, benzo isoxazolyl, isobenzofuran-base, isoindolyl, indolizine base, phentriazine
Base, thienopyridine base, Thienopyrimidine base, Pyridopyrimidine base, imidazopyridine, benzothiazolyl
(benzothiaxolyl), benzofuranyl, benzothienyl, indyl, quinolyl, isoquinolyl, isothiazolyl, pyrazoles
Base, indazolyl, pteridyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, thiadiazolyl group, pyrrole radicals, thiazolyl,
Furyl and thienyl etc..When being described as " substituted ", the substituent group of above-mentioned aromatic ring and heteroaromatic ring system be selected from it is following can
The substituent group of receiving.
Unless otherwise indicated herein, alkyl (including being typically referred to as those of alkylidene, alkenyl, alkynyl and naphthenic base)
Substituent group can be a variety of groups selected from the group below :-halogen ,-OR ' ,-NR ' R " ,-SR ' ,-SiR ' R " R " ' ,-OC (O) R ' ,-C
(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C (O)R’、-NR’-C(O)NR”R”’、-NR”C(O)2R’、-
NH-C (NH2)=NH ,-NR ' C (NH2)=NH ,-NH-C (NH2)=NR ' ,-S (O) R ' ,-S (O) 2R ' ,-S (O) 2NR ' R " ,-
NR ' S (O) 2R " ,-CN and-NO2, substituent group quantity are 0 to (2m '+1), and wherein m ' is the sum of carbon atom in the group.R',
R " and R " ' it is independent refer to hydrogen, unsubstituted C1-8 alkyl, unsubstituted aryl, by 1-3 halogen substitution aryl,
Unsubstituted C1-8 alkyl, C1-8 alkoxy or C1-8 thio alkoxy or unsubstituted aryl-C1-4 alkyl.R ' and R " is even
When being connected to the same nitrogen-atoms, they can be formed together 3-, 4-, 5-, 6- or 7- member ring with the nitrogen-atoms.For example,-NR ' R " packet
Include 1- pyrrolidinyl and 4- morpholinyl.
" derivative " of compound used herein refers to chemical structure similar with compound but also containing extremely
Lack the chemical group being not present in a compound and/or the substance for lacking chemical group present at least one compound.
The compound that derivative is compared is referred to as " parent " compound.In general, " derivative " can be in one or more chemical reaction step
It is generated in rapid by parent compound.
Term " inhibition " or " inhibition " refer to, reduce detectable amount, or prevent completely.
Term " cancer " refers to the physiological condition or disease characterized by the growth of the cell of imbalance." tumour " includes that cancer is thin
Born of the same parents.
Term " autoimmune disease " is derived from the disease or disorder of tissue or protein for individual itself.
Phrase " pharmaceutically acceptable salt " used herein refer to the pharmaceutical acceptable of compound to organic or
Inorganic salts.The compound can contain at least one amino or carboxyl, and therefore can form addition salts with corresponding acid or alkali.Show
Example property salt include but is not limited to: sulfate, trifluoroacetate, citrate, acetate, oxalates, chloride, bromide,
Iodide, nitrate, disulfate, phosphate, superphosphate, isonicotinic acid salt, lactate, salicylate, acid citrate
Salt, tartrate, oleate, tannate, pantothenate, biatrate, ascorbate, salicylate, formates, Ben Jia
Hydrochlorate, glutamate, mesylate, esilate, benzene sulfonate, tosilate, sylvite, sodium salt etc..In addition, pharmaceutically
Acceptable salt has the band point atom more than one in the structure.Plurality of charge atom is pharmaceutically acceptable salt
The example of a part can have multiple counterions.For example, pharmaceutically acceptable salt have one or more charge atoms and/or
One or more is contended with atom.
Present invention will be further explained below with reference to specific examples, it should be appreciated that these embodiments are served only for illustrating this hair
It is bright, rather than limit the scope of the invention.The test method of actual conditions is not specified in the following example, usually according to routine
Condition or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number
By weight.
Unless otherwise defined, all professions and science as used herein with known to one skilled in the art for anticipating
Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong
The preferred implement methods and materials are for illustrative purposes only.
The general step used in the following example of the present invention is:
General step A
The synthesis one of benzodiazepines derivative
General step B
The synthesis two of benzodiazepines derivative
General step C
The synthesis of CBI derivative
General step D
The synthesis of DNA-binding segment
General step E
CBI- benzodiazepine derivative synthesizing process one
General step F CBI- benzodiazepine derivative synthesizing process two
General step G
Binding- benzodiazepine derivative synthesizing process
Detailed description of the invention
Fig. 1 is hct116 experimental result picture.
Fig. 2 is SKOV3 experimental result picture.
Specific embodiment
The preparation of 1 3- of embodiment (methoxycarbonyl base) two rings [1.1.1] pentane -1- formic acid
Bis- ring of 1.48g [1.1.1] pentane -1,3- dicarboxylic acid methyl ester is added in 50ml there-necked flask, it is molten with 20ml methanol
Solution, methanol (5ml) solution of NaOH (324mg) is slowly added dropwise at room temperature, 80 DEG C of reaction 2h are warming up to after adding.After the reaction was completed
It is concentrated to dryness, 40ml water is added, is extracted with dichloromethane (50ml*3), water layer dilute hydrochloric acid adjusts PH to acidity, and dichloro is added
Methane extracts (40ml*4), merges organic layer, the white solid 925mg after dry concentration, yield 68%.1H NMR(400MHz,
CDCl3)δ3.71(s,3H),2.38(s, 6H)；MS m/z 171(M+1).
The preparation of 2 3- of embodiment (methylol) two ring [1.1.1] pentane -1- methyl formate
6.34g 3- (methoxycarbonyl base) two rings [1.1.1] pentane -1- formic acid, 30ml are sequentially added in 500ml there-necked flask
Tetrahydrofuran, 4.89g triethylamine, reaction system are cooled to -10 DEG C, and 3.87g methylchloroformate is slowly added dropwise, and finish anti-in 0 DEG C
1h is answered, 2.54g NaBH4 is added portionwise, it is complete to raw material to continue at 0 DEG C of reaction.400ml water quenching reaction is added, uses acetic acid
Ethyl ester extracts (600ml*3), merges organic layer, after dry concentration gained residue with column chromatographic purifying (DCM:MeOH=20:
1) 3.83g light yellow oil, yield 66%, are obtained.1H NMR(400MHz,CDCl3)δ3.71(s,3H),2.38(s,6H)；
3.48(s,2H)；MS=157 (M+1)
3 3- of embodiment ((tolysulfonyl oxygroup) methyl) two rings [1.1.1] pentane -1- methyl formate
700mg 3- (methylol) two ring [1.1.1] pentane -1- methyl formate is added in 100ml flask, with 10ml dichloro
Methane is dissolved, and 1.2ml triethylamine and 0.55gDMAP are sequentially added, and the methylene chloride of 0 DEG C of dropwise addition paratoluensulfonyl chloride is molten
Liquid, in room temperature reaction to raw material fully reacting after finishing.Organic layer successively uses dilute hydrochloric acid, and saturated common salt water washing is anhydrous
Na2SO4 is dry, is concentrated to give 1.4g yellow solid, is directly used in without purifying and reacts in next step.
The preparation of 4 compound 002 of embodiment
Compound 001 (29g, 67.38mmol) and 400ml DCM, stirring and dissolving, ice bath cooling are added in 1L single port bottle
Under be added portionwise sym-closene (23.45g, 101.07mmol, TCCA) and tetramethyl piperidine nitrogen oxides (0.32g,
2.03mmol, TEMPO), it finishes, moves to reaction at room temperature overnight, TLC shows raw material fully reacting.It is concentrated under reduced pressure at 40 DEG C,
Residue is dissolved in 500ml ethyl acetate and 500ml water, separates organic layer, successively with saturation NaHCO3Solution, water, saturation food
Salt water is respectively washed once, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure at 45 DEG C, and yellow solid 34.0g, crude product 40g are obtained
Silica gel mixed sample, column chromatography, solvent (DCM:MeOH=40:1-20:1) obtain yellow solid 17.8g, yield 61.68%.
The preparation of 5 compound 003 of embodiment
Compound 002 (15.0g, 35.01mmol) and dry DCM 300ml are added in 500ml single port bottle, stirs molten
Xie Hou, N2It protects and is cooled to -50 DEG C hereinafter, addition 2,6- lutidines (16.3ml, 139.95mmol), then drips again
Add trifluoromethanesulfanhydride anhydride (17.7ml, 105.21mmol, Tf2O), finish, 1.5h is reacted under equality of temperature, TLC shows that raw material has reacted
Entirely.Ice water 300ml is added into reaction solution, separates organic layer, successively with saturation NaHCO3Solution, water, saturated salt solution are respectively washed
Once, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure at 45 DEG C, obtains brown oil 21.5g, and crude product is mixed with 25g silica gel
Sample, column chromatography, solvent (PE:EA=5:1-2:1) obtain yellow oil 15.8g, yield 80.5%.
The preparation of 6 compound 004 of embodiment
Compound 003 (13.8g, 24.62mmol), 200ml EtOH, 200ml toluene and water are added in 1L three-necked bottle
60ml is sequentially added triethylamine (7.0ml, 49.85mmol) under stirring, 4- methoxyphenylboronic acid (5.24g, 34.5mmol), N2
Pd (PPh is added after displacement3)4, finish, N2It is protected at 30 DEG C and reacts overnight, TLC shows raw material fully reacting.At 45 DEG C
It is concentrated under reduced pressure, residue is dissolved in 300ml ethyl acetate and 300ml water, separates organic layer, water layer uses 100ml ethyl acetate again
Extraction merges organic layer, is successively respectively washed once with water, saturated salt solution, anhydrous sodium sulfate dries, filters, and depressurizes at 45 DEG C
Concentration obtains brown solid 18.2g, crude product 20g silica gel mixed sample, and column chromatographs, and solvent (PE:EA=4:1-1:1) obtains Huang
Color solid 11.2g, yield 87.8%.
The preparation of 7 compound 005 of embodiment
Compound 004 (10.5g, 20.25mmol) and 5% formic acid/methanol solution are added in 500ml single port bottle
250ml, ice bath are slowly added to zinc powder (26.32g, 404.92mmol) under being cooled to 5 DEG C hereinafter, stirring, finish, under nitrogen protection
It is warming up to 70 DEG C of back flow reactions 8h, TLC and shows raw material fully reacting.It filters while hot, filter cake is washed with a small amount of methanol, and filtrate is with full
It with sodium bicarbonate solution tune pH to 7, is then concentrated under reduced pressure at 50 DEG C, removes solvent, obtain pale tan oil, be added
300ml DCM, separates organic layer, is washed once with saturated common salt, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure at 40 DEG C,
Yellow-brown solid 11.9g, crude product 15g silica gel mixed sample are obtained, column chromatographs, and solvent (DCM:MeOH=50:1) obtains yellow
Solid 8.9g, yield 96.3%.
The preparation of 8 compound 006 of embodiment
60%NaH (0.96g, 24.0mmol) and 15ml DMF are added in 250ml single port bottle, is cooled to -10 under stirring
DEG C, the mixed solution of compound 005 (8.4g, 18.4mmol) and 50ml DMF is added dropwise, finishes, 2h is stirred under equality of temperature, then will
The mixed solution of 2- (trimethylsilyl) ethoxymethyl chlorine (4.0g, 24.0mmol) and 15ml DMF instill in reaction solution, add
Finish, is reacted at -5 DEG C overnight, TLC shows raw material fully reacting.Reaction solution is poured into 300ml ice water, with 200ml DCM extraction
It takes, organic layer is successively with saturation NaHCO3Solution, water, saturated salt solution are respectively washed once, and anhydrous sodium sulfate dries, filters, in 40
It is concentrated under reduced pressure at DEG C, obtains brown oil 10.5g, crude product 15g silica gel mixed sample, column chromatography, solvent (DCM:MeOH=
600:1-400:1), yellow solid 6.1g, yield 56.5% are obtained.
The preparation of 9 compound 007 of embodiment
It is added compound 006 (2.0g, 3.41mmol) and 30ml MeOH in 250ml single port bottle, after stirring and dissolving, according to
Secondary addition HCO2NH4(2.15g, 34.10mmol) and 5%Pd/BaSO4(0.28g), finishes, and reacts 4h at room temperature, and TLC is shown
Raw material fully reacting.Reaction solution is filtered through diatomite, and filter cake is washed with a small amount of DCM, merging filtrate, is concentrated under reduced pressure at 45 DEG C,
Residue is dissolved in 100ml DCM, is successively respectively washed once with water, saturated salt solution, and anhydrous sodium sulfate dries, filters, in 40 DEG C
Lower reduced pressure obtains faint yellow solid 1.59g, crude product 2.0g silica gel mixed sample, and column chromatographs, solvent (PE:EA=3:1-1:
1) yellow solid 1.45g, yield 85.8%, are obtained.
The synthesis of 10 intermediate 008 of embodiment
3- ((tolysulfonyl oxygroup) methyl) two rings [1.1.1] pentane -1- methyl formate is added in 150ml single port bottle
Cesium carbonate is added after stirring and dissolving in (0.92g, 1.85mmol), intermediate 007 (0.61g, 1.96mmol) and 20ml DMF
(1.21g, 3.71mmol), finishes, and 80 DEG C of reactions 4h, TLC are warming up under nitrogen protection and show raw material fully reacting.Toward reaction solution
Middle addition water 60ml is merged organic layer, is successively respectively washed once, separated organic with water, saturated salt solution with 30ml EA extraction 2 times
Layer, anhydrous sodium sulfate dries, filters, is concentrated under reduced pressure at 45 DEG C, obtains yellow solid 1.4g, crude product 2.0g silica gel mixed sample,
Column chromatography, solvent (PE:EA=4:1-2:1) obtain faint yellow solid 1.08g, yield 92.3%.
The synthesis of 11 intermediate 009 of embodiment
Intermediate 008 (0.9g, 1.42mmol), 15ml THF and 5ml MeOH are added in 100ml single port bottle, under stirring
It is added 1N LiOH (3.0ml, 3.0mmol), finishes, nitrogen protection is reacted overnight at room temperature, and TLC shows that raw material has reacted
Entirely.It is concentrated under reduced pressure at 45 DEG C, residue is dissolved in 100ml DCM, under ice bath is cooling, with 1N HCl solution tune pH to 4-5, is divided
Organic layer out is successively respectively washed once with water, saturated salt solution, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, obtains at 40 DEG C
To faint yellow solid 0.95g, crude product 1.2g silica gel mixed sample, column is chromatographed, and solvent (DCM:MeOH=60:1-30:1) obtains
Off-white powder 0.75g, yield 85.2%.
The synthesis of 12 intermediate 010 of embodiment
Intermediate 009 (650mg, 1.047mmol) and 15ml DMF are added in 100ml single port bottle, be stirred at room temperature down according to
Secondary addition 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (610mg, 3.182mmol) and DMAP
(385mg, 3.151mmol), N21h is stirred in protection at room temperature, CBI-10 (470mg, 1.255mmol) then is added, N2Protection
Overnight, TLC shows that raw material fundamental reaction is complete for reaction at room temperature.Water 40ml is added, into reaction solution with 30ml DCM extraction 2
It is secondary, merge organic layer, is successively respectively washed once with water, saturated salt solution, separate organic layer, anhydrous sodium sulfate dries, filters, in 40
It being concentrated under reduced pressure at DEG C, obtains pale tan oil 1.8g, crude product 2.5g silica gel mixed sample, column chromatographs, solvent (PE:EA=4:
1-1:1), faint yellow solid 0.71g, yield 72.08% are obtained.
The synthesis of 13 intermediate 011 of embodiment
Intermediate 010 (0.6g, 0.638mmol), 10ml THF and 20ml MeOH, stirring are added in 100ml single port bottle
Dissolution, sequentially adds HCO at room temperature2NH4(0.41g, 6.502mmol) and 5%Pd/BaSO4(0.085g), finishes, in room temperature
Lower reaction 5h, TLC show raw material fully reacting.Reaction solution is filtered through diatomite, and filter cake is washed with a small amount of THF and DCM, merges filter
Liquid is concentrated under reduced pressure at 45 DEG C, obtains faint yellow solid 0.78g, crude product 1.0g silica gel mixed sample, and column chromatographs, solvent (EA:
PE=1:1-2:1), faint yellow solid 0.3g, yield 55.35% are obtained.
The synthesis of 14 compound 012 of embodiment
Intermediate 011 (0.13g, 0.153mmol) is added in 50ml three-necked bottle, is vacuumized with oil pump, N2Switching 3 times,
It injects the THF 5ml that new fresh weight steams processing, after stirring and dissolving and is cooled to -78 DEG C hereinafter, 1N Li is then slowly added dropwise
BHEt3(1.2ml, 1.20mmol), finishes, and keeps reacting 2h under equality of temperature, TLC shows that raw material fundamental reaction is complete.20ml is added
DCM dilution, reaction solution moves under ice bath, while 20ml water quenching reaction is added dropwise, and separates organic layer, water layer is again with 10ml DCM
Extraction is primary, merges organic layer, is successively respectively washed once with water, saturated salt solution, anhydrous sodium sulfate dries, filters, at 40 DEG C
It is concentrated under reduced pressure, obtains faint yellow solid 152mg, DCM 3ml, CH are added immediately3OH 6ml and H2O 1ml is added after stirring and dissolving
Silica gel at thick, is stirred overnight at room temperature to mixed liquor after sealing.15ml DCM and 5ml CH is added3OH dilution, mistake
Filter, filter cake are washed with a small amount of DCM, and merging filtrate is concentrated under reduced pressure at 45 DEG C, obtains faint yellow solid 0.12g, crude product 1.0g
Silica gel mixed sample, column chromatography, solvent (DCM:MeOH=60:1-30:1) obtain faint yellow solid 25mg, yield 23.36%.
1H-NMR(CDCl3): δ=8.46 (s, 1H), 8.23 (d, 1H), 7.88 (d, 1H), 7.58 (s, 1H), 7.29-
7.39(m,6H),6.86-6.92(m,3H),4.02-4.61(m,5H),4.00(s,3H),3.83(s,3H), 3.49(s,2H),
2.76(s,3H),1.62(m,8H)。
Embodiment 15:5- ((7- (methoxyl group) -2- (4- anisyl) -5,11-dioxo-10- ((2- (trimethyl silicon substrate)
Ethyoxyl) methyl) -5,10,11,11a- tetrahydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diazepine -8- base) oxygen)
Ethyl valerate (compound 013)
0.1g 7- (methoxyl group) -8- hydroxyl -2- (4- anisyl) -10- ((2- (trimethyl silicane is added in 25ml flask
Base) ethyoxyl) methyl) -1,11a- dihydro -5H- benzo [e] pyrrolo- [1,2-a] [1,4] diazepine -5,11 (10H)-two
Oxo (compound 007) and 4ml DMF sequentially add the bromo- ethyl valerate of 42mg K2CO3 and 0.1ml 5- under stirring, finish in
It reacts at room temperature complete to raw material.15ml water is added, ethyl acetate extracts, and drying is concentrated to give after organic layer saturated common salt water washing
Light yellow oil 0.2g.Without purifying, it is directly used in and reacts in next step.
Embodiment 16: compound 014:5- ((7- (methoxyl group) -2- (4- anisyl) -5,11-dioxo-10- ((2-
(trimethyl silicon substrate) ethyoxyl) methyl) -5,10,11,11a- tetrahydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza
Zhuo -8- base) oxygen) valeric acid
0.2g 5- ((7- (methoxyl group) -2- (4- anisyl) -5,11-dioxo-10- ((2- is added in 50ml flask
(trimethyl silicon substrate) ethyoxyl) methyl) -5,10,11,11a- tetrahydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza
Zhuo -8- base) oxygen) ethyl valerate (compound 013), is dissolved with THF/MeOH (V:V=3:1), is added with stirring 1N
LiOH reacts complete to raw material at room temperature.It is concentrated under reduced pressure at 40 DEG C and removes solvent, residue is dissolved in methylene chloride, uses dilute hydrochloric acid
PH to 5~6 is adjusted, organic layer is separated, water layer is extracted with dichloromethane twice again, merges organic layer, successively use saturated salt solution
Washing, anhydrous sodium sulfate dry, filter, and are concentrated, obtain faint yellow solid 0.18g.Column chromatographic purifying (DCM:MeOH=30:1)
Faint yellow solid 90mg, yield 47%.
The preparation of 17 compound 015 of embodiment
20mg 5- ((7- (methoxyl group) -2- (4- anisyl) -5,11-dioxo-10- ((2- is added in 25ml flask
(trimethyl silicon substrate) ethyoxyl) methyl) -5,10,11,11a- tetrahydro -1H- benzo [e] pyrrolo- [1,2-a] [1,4] diaza
Zhuo -8- base) oxygen) valeric acid (compound 014), 10mg EDCI and 5mg DMAP is added after being dissolved with 1ml DMF, at room temperature
1h is stirred, 14mg 5- (benzyloxy) -1- (chloromethyl) -9- methyl -2,3- dihydro -1H- benzo [e] indoles, room is then added
The lower reaction of temperature is complete to raw material reflection.Water is added in reaction solution, with ethyl acetate extraction 2 times, merges organic layer, organic layer is dry
After yellow solid 0.15g is concentrated under reduced pressure to obtain.Yellow solid 10mg is obtained after column chromatographic purifying (petroleum ether: ethyl acetate=3:1), is received
Rate 30%.
The preparation of 18 compound 016 of embodiment
10mg compound 015 and MeOH/THF (V:V=1:1) are added in 25ml flask, 7mg formic acid is sequentially added under stirring
Ammonium, 5% palladium barium sulfate of 1.4mg react the fully reacting of branch raw material at room temperature.Reaction solution is filtered through diatomite, and filter cake is with a small amount of two
13mg solid is concentrated under reduced pressure to obtain in chloromethanes washing, filtrate after merging, not purified be directly used in is reacted in next step.
The preparation of 19 compound 017 of embodiment
50mg compound 016 is added in 50ml flask, dissolved with 2ml THF and is cooled to -78 DEG C, is slowly added dropwise three
The tetrahydrofuran solution of ethyl lithium borohydride is finished in -78 DEG C of reactions to raw material fully reacting.H is slowly added dropwise in reaction solution2O is broken
Bad, dilute hydrochloric acid adjusts PH to 5~6, then is extracted with dichloromethane 3 times, merges organic layer, and it is solid to obtain yellow after the dry concentration of organic layer
Body 56mg.Obtained solid is dissolved in ethanol/methylene (4ml+1.5ml) mixed solvent, is added with stirring 0.5ml water, then plus
Enter 3g silica gel (300-400 mesh), is stirred to react at room temperature.After the reaction was completed, reaction solution is filtered, filter cake methanol and dichloromethane
Yellow solid is concentrated under reduced pressure to obtain in alkane mixed solvent (V:V=1:1) washing, merging filtrate.Obtained solid is through preparing liquid phase separation
Purifying, obtains 009 12.5mg of compound.
20 compound 018:(S of embodiment) -1- (4- (benzyloxy) -5- methoxyl group -2- nitro benzoyl) -6- methoxyl group
The preparation of indoline-2-methanoic acid methyl esters
4- (benzyloxy) -5- methoxyl group -2- nitrobenzoic acid 110mg is dissolved in 3ml methylene chloride, 62 μ are added at 0 DEG C
L oxalyl chloride is warmed to room temperature reaction 3 hours, reaction solution is concentrated to give faint yellow solid.By (S) -6- melonia indoles -2-
Methyl formate 50mg is dissolved in 5ml methylene chloride, and 0.1ml triethylamine is added at 0 DEG C, the two of above-mentioned obtained solid are slowly added dropwise
Chloromethanes solution, in 0 DEG C of reaction 2h.Reaction solution adjusts PH to 4~5 with dilute hydrochloric acid, is extracted with ethyl acetate 2 times, merges organic
Layer, after saturated common salt water washing, dry concentration.Obtained solid is obtained through column chromatographic purifying (petroleum ether: ethyl acetate=20:1)
107mg yellow solid, yield 89.9%.
Embodiment 21 (S) -9- (benzyloxy) -3,8- dimethoxy -12a, 13- dihydro -6H- benzo [5,6] [1,4] phenodiazine
Miscellaneous tall and erect simultaneously [1,2-a] indoles -6,12 (11H)-diketone (compound 019)
50mg (S) -1- (4- (benzyloxy) -5- methoxyl group -2- nitro benzoyl) -6- methoxyl group is added in 25ml flask
Indoline-2-methanoic acid methyl esters is dissolved with 5ml methanol, is added with stirring 96.4mg stannous chloride, is warming up to 65 DEG C of reactions
It is complete to raw material.After reaction solution cooling, with saturation NaHCO3PH to 7~8 is adjusted, is then filtered with diatomite, filtrate concentration
After be diluted with water, be extracted with ethyl acetate 2 times, merge organic layer, dry concentration, obtains faint yellow solid after saturated common salt water washing
28mg, yield 63%.
Embodiment 22 (S) -9- (benzyloxy) -3,8- dimethoxy -11- ((2- (trimethylsilyl) ethyoxyl) methyl) -
12a, 13- dihydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -6,12 (11H)-diketone (compound 020).
26mg sodium hydride is suspended in anhydrous DMF, 215mg (S) -9- (benzyloxy) -3,8- bis- is added dropwise under nitrogen protection
Methoxyl group -12a, 13- dihydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -6,12 (11H)-diketone DMF
Solution, stirs 30min after adding, the DMF solution of 108mg SEMCl is then slowly added dropwise, and finishes equality of temperature and reacts complete to raw material
Entirely.Reaction solution is poured into ice water, is extracted with ethyl acetate 3 times, merges organic layer, is done after organic layer saturated common salt water washing
Dry concentration, gained residue obtain 195mg grease, yield 72% through column chromatographic purifying (petroleum ether: ethyl acetate=10:1).
Embodiment 23 (S) -9- (hydroxyl) -3,8- dimethoxy -11- ((2- (trimethylsilyl) ethyoxyl) methyl) -12a,
13- dihydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -6,12 (11H)-diketone (compound 021)
190mg (S) -9- (benzyloxy) -3,8- dimethoxy -11- ((2- (trimethylsilyl) ethoxy is added in 25ml flask
Base) methyl) -12a, 13- dihydro -6H- benzo [5,6] [Isosorbide-5-Nitrae] diazepine simultaneously [1,2-a] indoles -6,12 (11H)-diketone adds
Enter 10ml methanol to be dissolved, sequentially add 214mg ammonium formate at room temperature, the palladium barium sulfate of 95mg 5% is anti-under nitrogen protection
It should be complete to raw material.Reaction solution is filtered with diatomite, filter cake is washed with methanol, and merging filtrate is simultaneously concentrated, gained residue warp
Column chromatographic purifying (petroleum ether: ethyl acetate=10:1) is crossed, white solid 135mg, yield 84.9% are obtained.
24 3- of embodiment (((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (trimethyl silicon substrate) ethoxy
Base) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -9- base) oxygen) first
Base) two rings [1.1.1] pentane -1- methyl formate (compound 022)
30mg (S) -9- (hydroxyl) -3,8- dimethoxy -11- ((2- (trimethylsilyl) ethyoxyl) is added in 50ml flask
Methyl) -12a, 13- dihydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -6,12 (11H)-diketone and 2ml
DMF is added with stirring Cs2CO3, finish that be warming up to 80 DEG C of reactions complete to raw material.20ml water is added, ethyl acetate extraction is organic
Drying is concentrated to give yellow solid 36mg after layer saturated common salt water washing.Without purifying, it is directly used in and reacts in next step.
25 3- of embodiment (((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (trimethyl silicon substrate) ethoxy
Base) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -9- base) oxygen) first
Base) two rings [1.1.1] pentane -1- formic acid (compound 023)
36mg 3- (((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (three is added in 25ml flask
Methylsilyl) ethyoxyl) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] Yin
Diindyl -9- base) oxygen) methyl) two rings [1.1.1] pentane -1- methyl formate, is dissolved with THF/MeOH (V:V=3:1), is stirred
Lower addition 1N LiOH, reacts complete to raw material at room temperature.It being concentrated under reduced pressure at 40 DEG C and removes solvent, residue is dissolved in methylene chloride,
PH to 5~6 is adjusted with dilute hydrochloric acid, separates organic layer, water layer is extracted with dichloromethane twice again, merges organic layer, successively with full
And brine It, anhydrous sodium sulfate dry, filter, concentration, gained residue is through column chromatographic purifying (DCM:MeOH=30:1)
Obtain faint yellow solid 20mg.
The preparation of 26 compound 024 of embodiment
20mg 3- (((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (front three is added in 25ml flask
Base silicon substrate) ethyoxyl) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -
9- yl) oxygen) methyl) two rings [1.1.1] pentane -1- formic acid, 20mg EDCI and 3mg are added after being dissolved with 2ml DMF
DMAP stirs 1h at room temperature, and 17mg 5- (benzyloxy) -1- (chloromethyl) -9- methyl -2,3- dihydro -1H- benzo is then added
[e] indoles reacts complete to raw material reflection at room temperature.Water is added in reaction solution, with ethyl acetate extraction 2 times, merges organic layer, has
It is concentrated under reduced pressure after machine layer is dry, gained residue obtains yellow solid after column chromatographic purifying (petroleum ether: ethyl acetate=3:1)
10mg, yield 34%.
The preparation of 27 compound 025 of embodiment
10mg compound 024 and MeOH/THF (V:V=1:1) are added in 25ml flask, 7mg first is sequentially added under stirring
Sour ammonium, 5% palladium barium sulfate of 1.4mg react the fully reacting of branch raw material at room temperature.Reaction solution is filtered through diatomite, and filter cake is on a small quantity
13mg solid is concentrated under reduced pressure to obtain in methylene chloride washing, filtrate after merging, not purified be directly used in is reacted in next step.
The preparation of 28 compound 026 of embodiment
20mg compound 025 is added in 50ml flask, dissolved with 2mlTHF and is cooled to -78 DEG C, is slowly added dropwise three
The tetrahydrofuran solution of ethyl lithium borohydride is finished in -78 DEG C of reactions to raw material fully reacting.It is broken that H2O is slowly added dropwise in reaction solution
Bad, dilute hydrochloric acid adjusts PH to 5~6, then is extracted with dichloromethane 3 times, merges organic layer, and it is solid to obtain yellow after the dry concentration of organic layer
Body 25mg.Obtained solid is dissolved in ethanol/methylene (4ml+1.5ml) mixed solvent, is added with stirring 0.5ml water, then plus
Enter 3g silica gel (300-400 mesh), is stirred to react at room temperature.After the reaction was completed, reaction solution is filtered, filter cake methanol and dichloromethane
Yellow solid is concentrated under reduced pressure to obtain in alkane mixed solvent (V:V=1:1) washing, merging filtrate.Obtained solid is through preparing liquid phase separation
Purifying, obtains 026 8mg of compound.
29 5- of embodiment ((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (trimethyl silicon substrate) ethoxy
Base) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -9- base) oxygen) penta
Acetoacetic ester compound 027
500mg (S) -9- (hydroxyl) -3,8- dimethoxy -11- ((2- (trimethylsilyl) ethyoxyl) is added in 50ml flask
Methyl) -12a, 13- dihydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -6,12 (11H)-diketone and
20ml DMF sequentially adds the bromo- ethyl valerate of 200mg K2CO3 and 0.5ml 5- under stirring, finish in room temperature reaction to raw material
Completely.100ml water is added, ethyl acetate extracts, and drying is concentrated to give light yellow oil after organic layer saturated common salt water washing
0.9g.Without purifying, it is directly used in and reacts in next step.
30 5- of embodiment ((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (trimethyl silicon substrate) ethoxy
Base) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -9- base) oxygen) penta
Sour (compound 028)
0.5g 5- ((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (front three is added in 50ml flask
Base silicon substrate) ethyoxyl) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles -
9- yl) oxygen) ethyl valerate, dissolved with THF/MeOH (V:V=3:1), be added with stirring 1N LiOH, react at room temperature to
Raw material is complete.It is concentrated under reduced pressure at 40 DEG C and removes solvent, residue is dissolved in methylene chloride, adjusts PH to 5~6 with dilute hydrochloric acid, separates
Organic layer, water layer are extracted with dichloromethane twice again, merge organic layer, successively use saturated common salt water washing, and anhydrous sodium sulfate is dry
It is dry, it filters, concentration, gained residue obtains faint yellow solid 230mg, yield through column chromatographic purifying (DCM:MeOH=30:1)
49%.
The preparation of 31 compound 029 of embodiment
200mg 5- ((8- (benzyloxy) -3- methoxyl group -6,12- dioxo -11- ((2- (front three is added in 250ml flask
Base silicon substrate) ethyoxyl) methyl) -11,12,12a, 13- tetrahydro -6H- benzo [5,6] [1,4] diazepine simultaneously [1,2-a] indoles
- 9- base) oxygen) valeric acid, 100mg EDCI and 50mg DMAP is added after being dissolved with 10mlDMF, stirs 1h at room temperature, then
150mg 5- (benzyloxy) -1- (chloromethyl) -9- methyl -2,3- dihydro -1H- benzo [e] indoles is added, is reacted at room temperature to original
Material reflection is complete.Water is added in reaction solution, with ethyl acetate extraction 2 times, merges organic layer, is concentrated under reduced pressure after organic layer is dry, institute
It obtains residue and obtains yellow solid 120mg after column chromatographic purifying (petroleum ether: ethyl acetate=3:1).
The preparation of 32 compound 030 of embodiment
15mg compound 013 and MeOH/THF (V:V=1:1) are added in 25ml flask, 10mg first is sequentially added under stirring
Sour ammonium, 5% palladium barium sulfate of 2mg, reacts at room temperature to raw material fully reacting.Reaction solution is filtered through diatomite, and filter cake is with a small amount of two
20mg solid is concentrated under reduced pressure to obtain in chloromethanes washing, filtrate after merging, not purified be directly used in is reacted in next step.
The preparation of 33 compound 031 of embodiment
30mg compound 030 is added in 25ml flask, dissolved with 2mlTHF and is cooled to -78 DEG C, is slowly added dropwise three
The tetrahydrofuran solution of ethyl lithium borohydride is finished in -78 DEG C of reactions to raw material fully reacting.H is slowly added dropwise in reaction solution2O is broken
Bad, dilute hydrochloric acid adjusts PH to 5~6, then is extracted with dichloromethane 3 times, merges organic layer, and it is solid to obtain yellow after the dry concentration of organic layer
Body 34mg.Obtained solid is dissolved in ethanol/methylene (4ml+1.5ml) mixed solvent, is added with stirring 0.5ml water, then plus
Enter 3g silica gel (300-400 mesh), is stirred to react at room temperature.After the reaction was completed, reaction solution is filtered, filter cake methanol and dichloromethane
Yellow solid is concentrated under reduced pressure to obtain in alkane mixed solvent (V:V=1:1) washing, merging filtrate.Obtained solid is through preparing liquid phase separation
Purifying, obtains 031 8mg of compound.
The synthesis of 34 intermediate 032 of embodiment
In 150ml single port bottle be added 4- benzyloxy -5- methoxyl group -2- nitrobenzoic acid (5.73g, 18.88mmol) and
50ml methylene chloride is added with stirring 0.1ml DMF, and oxalyl chloride (3.2ml, 37.8mmol) is added dropwise under ice cooling, 4, adds
Finish, reaction solution is moved to and reacts 4h at room temperature, TLC shows raw material fully reacting.It is concentrated under reduced pressure at 45 DEG C, removes dichloromethane
Alkane, residue is dissolved in 30ml THF, spare.
Separately take 150ml single port bottle, be added (S) -6- nitro-indole quinoline -2- carboxylate methyl ester (2.8g, 12.6mmol) and
30ml THF, is added with stirring triethylamine (5.3ml, 38.2mmol), and the above-mentioned acyl prepared is then added dropwise under ice cooling, 4
The THF solution of chlorine, finishes, and is warming up to reaction at room temperature overnight, TLC shows raw material fully reacting.It is concentrated under reduced pressure at 45 DEG C, it is residual
Excess is dissolved in 150ml methylene chloride, is successively respectively washed once with 1N HCl, water, saturated salt solution, and organic layer, anhydrous sulphur are separated
Sour sodium dries, filters, and is concentrated under reduced pressure at 40 DEG C, obtains brown solid 9.5g, crude product 11.0g silica gel mixed sample, column chromatography, exhibition
Agent (PE:EA=5:1-1:1) is opened, yellow solid 6.1g, yield 95.4% are obtained.
The synthesis of 35 intermediate 033 of embodiment
Intermediate 32 (4.9g, 9.66mmol) and 5% formic acid/methanol solution 150ml, ice are added in 250ml single port bottle
Bath is slowly added to zinc powder (12.56g, 193.23mmol) under being cooled to 5 DEG C hereinafter, stirring, and finishes, is warming up to 70 under nitrogen protection
DEG C back flow reaction is stayed overnight, and TLC shows raw material fully reacting.It filters while hot, filter cake is washed with a small amount of methanol, and filtrate is with unsaturated carbonate
Hydrogen sodium solution tune pH to 8-9, is then concentrated under reduced pressure at 50 DEG C, removes solvent, obtains pale tan oil 6.2g, crude product is direct
With 7.0g silica gel mixed sample, column chromatography, solvent (DCM:MeOH=60:1-30:1) obtains yellow solid 3.2g, yield
79.8%.
The synthesis of 36 intermediate 034 of embodiment
60%NaH (0.38g, 9.5mmol) and 10ml DMF are added in 250ml single port bottle, under stirring
- 10 DEG C are cooled to, the mixed solution of intermediate 2 (3.0g, 7.23mmol) and 50ml DMF is added dropwise, is stirred under equality of temperature
Then 1h instills the mixed solution of 2- (trimethylsilyl) ethoxymethyl chlorine (1.67ml, 9.41mmol) and 10ml DMF
It in reaction solution, finishes, 5h is reacted under equality of temperature, TLC shows raw material fully reacting.Reaction solution is poured into 250ml water, with 200ml
DCM is extracted 2 times, and organic layer is successively with saturation NaHCO3Solution, water, saturated salt solution are respectively washed once, and organic layer, anhydrous sulphur are separated
Sour sodium dries, filters, and is concentrated under reduced pressure at 40 DEG C, obtains pale tan oil 4.1g, crude product 5.0g silica gel mixed sample, column layer
Analysis, solvent (DCM:MeOH=60:1-40:1) obtain yellow solid 2.7g, yield 68.5%.
The synthesis of 37 intermediate 035 of embodiment
Intermediate 3 (2.5g, 4.59mmol), 30ml THF and 30ml MeOH are added in 150ml single port bottle, stirs molten
Solution, sequentially adds HCO at room temperature2NH4(2.89g, 45.87mmol) and 10%Pd/C (1.25g), finishes, reacts at room temperature
3h, TLC show raw material fully reacting.Reaction solution is filtered through diatomite, and filter cake is washed with a small amount of DCM, merging filtrate, at 45 DEG C
It is concentrated under reduced pressure, obtains yellow-brown solid 4.3g, crude product 5.0g silica gel mixed sample, column chromatography, solvent (DCM:MeOH=60:1-
30:1), yellow solid 1.63g, yield 78.3% are obtained.
The synthesis of 38 intermediate 036 of embodiment
In 100ml single port bottle be added 5- tert-butoxycarbonylamino amylalcohol p-methyl benzenesulfonic acid ester (900mg, 2.52mmol) and
10ml DCM, stirring and dissolving are simultaneously cooled to 5 DEG C hereinafter, addition 25ml 3mol/L HCl/EA solution, finishes, under nitrogen protection
It is warming up to room temperature reaction overnight, TLC shows raw material fully reacting.It is concentrated under reduced pressure at 45 DEG C, obtains white oil object 670mg,
It does not purify, is directly used in and reacts in next step.
The synthesis of intermediate 037
BDN-001 (430mg, 1.11mmol) and 40ml DMF are added in 150ml single port bottle, is stirred at room temperature down and successively adds
Enter 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (640mg, 3.33mmol) and DMAP (410mg,
3.35mmol), 2h is stirred at room temperature, intermediate 5 (660mg, 2.24mmol) then is added, and continues to be stirred to react overnight, TLC is aobvious
Show that raw material fundamental reaction is complete.Into reaction solution be added water 100ml, with 100ml DCM extraction 2 times, organic layer successively use water,
Saturated salt solution is respectively washed once, and organic layer is separated, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure at 40 DEG C, is obtained brown color
Grease 1.5g, crude product 2.0g silica gel mixed sample, column chromatography, solvent (DCM:MeOH=70:1-45:1) obtain faint yellow
Solid 0.42g, yield 60.4%.
The synthesis of 39 intermediate 038 of embodiment
Intermediate 4 (0.29g, 0.637mmol) and 10ml DMF are added in 100ml single port bottle, is added after stirring and dissolving
Cesium carbonate (0.52g, 1.596mmol) stirs 30min, and intermediate 6 (0.4g, 0.638mmol) then is added, finishes, nitrogen
It is warming up to 80 DEG C of reactions 6h, TLC under protection and shows raw material fully reacting.Water 40ml is added, into reaction solution with 50ml DCM extraction
It takes 2 times, organic layer is successively respectively washed once with water, saturated salt solution, and organic layer is separated, and anhydrous sodium sulfate dries, filters, in 40 DEG C
Lower reduced pressure obtains pale tan oil 1.1g, crude product 2.0g silica gel mixed sample, column chromatography, solvent (DCM:MeOH=
60:1-40:1), faint yellow solid 0.3g, yield 51.8% are obtained.
The synthesis of 40 intermediate 039 of embodiment
Addition intermediate 7 (0.3g, the 0.33mmol), 8ml THF and 8ml MeOH in 50ml single port bottle, stirring and dissolving,
HCO is sequentially added at room temperature2NH4(0.21g, 3.33mmol) and 5%Pd/BaSO4(0.06g), finishes, and reacts 3h at room temperature,
TLC shows raw material fully reacting.Reaction solution is filtered through diatomite, and filter cake is washed with a small amount of THF and DCM, merging filtrate, in 45 DEG C
Lower reduced pressure obtains yellow solid 0.5g, crude product 1.0g silica gel mixed sample, column chromatography, solvent (DCM:MeOH=30:1-
10:1), faint yellow solid 0.18g, yield 66.67% are obtained.
The synthesis of 41 compound 040 of embodiment
Intermediate 8 (80mg, 0.098mmol) is added in 50ml three-necked bottle, is vacuumized with oil pump, N2Switching 3 times, injection
New fresh weight steams the THF 4ml of processing, after stirring and dissolving and is cooled to -78 DEG C hereinafter, 1N LiBHEt is then slowly added dropwise3
(0.98ml, 0.98mmol), finishes, and keeps reacting 3h under equality of temperature, TLC shows that raw material fundamental reaction is complete.15ml DCM is added
Dilution, reaction solution moves under ice bath, while 20ml water quenching reaction is added dropwise, and separates organic layer, water layer is again with 10ml DCM extraction
Once, merge organic layer, successively respectively washed once with water, saturated salt solution, anhydrous sodium sulfate dries, filters, and depressurizes at 40 DEG C
Concentration, obtains yellow solid 105mg, and DCM 3ml, CH are added immediately3OH 6ml and H2Silica gel is added extremely after stirring and dissolving in O 1ml
Mixed liquor is stirred overnight at room temperature at thick after sealing.10ml DCM and 3ml CH is added3OH dilution, filtering, filter cake are used
A small amount of DCM washing, merging filtrate are concentrated under reduced pressure at 45 DEG C, obtain faint yellow solid 85mg, crude product 500mg silica gel mixed sample,
Column chromatography, solvent (DCM:MeOH=40:1-15:1) obtain faint yellow solid 27mg, yield 41.03%.
The synthesis of 42 compound 041 of embodiment
It disperses 4g raw material BDN-001 in 50ml anhydrous methylene chloride (brand-new), is added dropwise under ice bath (0 ± 5 DEG C)
2.5ml oxalyl chloride is added dropwise 0.5mlDMF, there is bubble formation.It is to slowly warm up to room temperature, stirs 2h, (TLC monitoring: raw material reaction
Complete DCM/MeOH 10:1) 40 ± 5 DEG C of decompressions steam solvent, and appropriate anhydrous methylene chloride band is added, is concentrated under reduced pressure into faint yellow
Solid powder.
The acyl chlorides of brand-new is mixed with 50ml dehydrated alcohol and 4ml triethylamine under ice bath (0 ± 5 DEG C), stirs 2h under ice bath
(TLC monitoring: raw material fully reacting DCM/MeOH, 10:1), reaction solution 1M dilute hydrochloric acid adjust PH neutrality, filtering, crude product nothing
Water-ethanol recrystallization, 55 ± 5 DEG C of vacuum drying (≤- 0.09MPa) are concentrated to get yellow solid 3.1g, 72% (LC-MS of yield
Confirmation is target product)
The synthesis of 43 compound 042 of embodiment
5g raw material 041 is dissolved in the 5- amino -1- Pentanol 45 ml newly opened, adds 100ml ethyl alcohol, it is to slowly warm up to 78 ±
5 DEG C, stir 4h
(TLC monitoring: raw material fully reacting DCM/MeOH 20:1 is unfolded 4 times) is added suitable quantity of water in reaction solution, ice bath (0 ±
5 DEG C) under with 6M hydrochloric acid adjust PH to 6 or so, ethyl acetate extract 3 times, organic phase uses 5% salt acid elution 1 time again, be saturated NaCl
Washing 1 time, dry 40 ± 5 DEG C of reduced pressures, 55 ± 5 DEG C of vacuum drying (≤- 0.09MPa) are concentrated to get yellow solid 4.1g,
Yield 77% is directly used in without purifying and reacts in next step.
The preparation of 44 compound 043 of embodiment
Vial will be dried, N2 displacement, 5g raw material 042 is scattered in anhydrous methylene chloride (brand-new) 150ml, is added
4mlDMF promotes dissolution, and PBr is slowly added dropwise under ice bath (0 ± 5 DEG C)34.3g, reaction solution gradually dissolved clarification.Temperature is maintained to stir 2h,
PBr is added if raw material has residue3To fully reacting (TLC monitoring: raw material fully reacting DCM/MeOH 20:1 is unfolded 2 times) ice
It bathes and adjusts PH to 7 with saturation NaHCO3 solution under (0 ± 5 DEG C), generate a large amount of solids, filter, column chromatographic purifying (DCM/MeOH
100:1) afford 3g product, yield 54% (LC-MS confirmation is target product).
The preparation of 45 compound 044 of embodiment
Vial drying, by 1g raw material 7- (methoxyl group) -8- hydroxyl -2- (4- anisyl) -10- ((2- (trimethyl silicane
Base) ethyoxyl) methyl) -1,11a- dihydro -5H- benzo [e] pyrrolo- [1,2-a] [1,4] diazepine -5,11 (10H)-two
It oxo (compound 007) and is dissolved with super dry DMF, 0.79g cesium carbonate is added and stirs 30min, 1.5g raw material compound is added
50 ± 5 DEG C of 043 and 0.08g KI is stirred overnight (TLC monitoring: 007 fully reacting DCM/MeOH 30:1 of raw material) and is cooled to room
Suitable quantity of water is added in temperature, and ethyl acetate extracts 4 times, and saturation NaCl is washed 1 time, is concentrated to get crude product.Column chromatographic purifying (DCM/
MeOH 100:1~50:1) obtain 1.2g product, yield 63%, (LC-MS confirmation is target product).
The preparation of 46 compound 045 of embodiment
50ml methanol is dispersed by 1g raw material 044 to dissolve by heating, and is cooled to room temperature and 1.32g ammonium formate, 0.25g is added
5%Pd-BaSO4, PH to 7 is adjusted with appropriate 5% formic acid/methanol, 35 ± 5 DEG C are stirred overnight, and next day adds 0.25g 5%Pd-
BaSO4Continue stirring for 24 hours, (TLC monitoring: raw material about 10% unreacted DCM/MeOH of residue, 20:1 are unfolded 2 times) is cooled to room
Temperature, diatomite filtering, filter cake methanol: methylene chloride 10:1 is washed, and 40 ± 5 DEG C of filtrate are concentrated under reduced pressure to give crude product.Column chromatography
Purifying (DCM/MeOH 40:1~20:1) obtains 0.5g product, and raw materials recovery, yield 56%, (LC-MS confirmation is that target produces
Object).
The preparation of 47 compound 046 of embodiment
30mg raw material 045 is dissolved in absolute tetrahydrofuran (brand-new), drops under absolute N2 protection by vial drying
0.07ml lithium triethylborohydride solution is slowly added dropwise to -78 DEG C in temperature, stirs 1h-2h, optionally adds lithium triethylborohydride
Solution.(1M newly opens 25ml specification packaging), (TLC, HPLC tracing and monitoring: raw material fully reacting DCM/MeOH 10:1 expansion 2
It is secondary) maintain temperature addition suitable quantity of water to be quenched, 5% citric acid solution is added and adjusts PH to 7, ethyl acetate extracts 3 times, is saturated NaCl
Washing 1 time, 40 ± 5 DEG C are concentrated to get 25mg crude product.10mg product BL-BDN-007, yield 35% is partly prepared.(LC-MS
Confirmation is target product).
56 toxin cytoactive detection of embodiment
| Compound | hct116 | SKOV-3 |
| 026(PD-02) | 0.36nm | 1.04nm |
| 040(PD-01) | 209.8m | >2000 |
| 046(PD-03) | 253.0nm | >2000 |
Claims (9)
1. one kind has the cell toxicity medicament or its pharmaceutically acceptable salt, hydrate or solvate of formula (I) or formula (II),
Wherein:
Y is selected from one or more H, halogen, C1-4Alkyl, OR4, SR4, NR4R5, SO2R4, CONHR4, CN or COOR4,
Middle R4And R5It is independent to be selected from H, C1-4Alkyl, phenyl or substituted-phenyl；
X2Selected from halogen or OSO2R5, wherein R5It is independent to be selected from H, C1-4Alkyl, phenyl or substituted-phenyl；
X1Selected from O and NR6, wherein R6Selected from H, C1-6Alkyl, the C that one or more F replace1-6Alkyl；
R1Selected from H, P (O)3H2, C (O) NR7R8, wherein R7And R8Selected from H, C1-6Alkyl, the C that one or more F replace1-6Alkane
Base or R7And R8Form five yuan or six-membered heterocyclic group group；
R3For optional substituent group；
R2Selected from H, P (O)3H2, C (O) NR7R8, wherein R7And R8Selected from H, C1-6Alkyl, the C that one or more F replace1-6Alkane
Base or R7And R8Form five yuan or six-membered heterocyclic group group；
D1Selected from following drug moieties:
Wherein wave indicates the site for being attached to T；
Two-wire between N and CIndicate that singly-bound or double bond, condition are the R when it is double bond9It is not present and R10It is H, and
When it is singly-bound, R9It is H or selected from acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group and 9-fluorenylmethyloxycarbonyl
Amido protecting part；R10Selected from OH, by O R11Ether, the inferior sulfate radical SO of expression3-Or OSO3-, wherein R11Selected from 1-10
Straight chain, branch or cyclic alkyl, the alkenyl or alkynyl of carbon atom；
Dotted line between c 2 and c 3 indicates being optionally present for double bond；
When there is double bond between c 2 and c 3,
R12Selected from the C optionally substituted by one or more substituent groups5-10Aryl, wherein it includes with the following group that the substituent group, which is selected from:
Halogen, nitro, cyano, amino, ether, carboxyl, ester, C1-7Alkyl, C3-7Heterocycle；
When there is singly-bound between c 2 and c 3,
R12It isWherein R14And R15It is independent to be selected from H, F, C1-4Saturated alkyl, C2-3Alkenyl, the alkyl and alkenyl quilt
One group is optionally substituted, and the group is selected from C1-4Alkylamidoalkyl and C1-4Arrcostab, alternatively, working as R14And R15First is that when H,
Another is selected from nitrile and C1-4Arrcostab；
Module D1 " can be by one or more R13It is replaced, wherein R13Selected from H, halogen, nitro, cyano, amino, ether, carboxyl, ester,
C1-7Alkyl, C3-7Heterocycle.
2. cell toxicity medicament as described in claim 1 or its pharmaceutically acceptable salt, hydrate or solvate, feature
It is, R3Selected from H, OH, SH, NH2、N3、NO2、NO、CF3、CN、C(O)NH2, C (O) H, C (O) OH, halogen, Rh、SRh、S(O)
Rh、S(O)2Rh、S(O)ORh、S(O)2ORh、OS(O)Rh、OS(O)2Rh、OS(O)ORh、OS(O)2ORh、ORh、NHRh、N(Rh)Ri、+N
(Rh)(Ri)Rj、P(O)(ORh)(ORi)、OP(O)(ORh)(ORi)、SiRhRiRj、C(O)Rh、C(O)ORh、C(O)N(Rh)Ri、OC
(O)Rh、OC(O)ORh、OC(O)N(Rh)Ri、N(Rh)C(O)Ri、N(Rh)C(O)ORiOr N (Rh)C(O)N(Ri)Rj；
Wherein Rh、RiAnd RjIndependently selected from H and optionally substituted C1-15Alkyl, C1-15Miscellaneous alkyl, C3-15Naphthenic base, C1-15It is miscellaneous
Naphthenic base, C5-15Aryl or C1-15Heteroaryl；
T is selected from C2-C12Alkyl, Z, (C1-C6Alkylidene)-Z- (C1-C6Alkylidene), (C1-C6Alkylidene)-Z- (C1-C6Alkylene
Base)-Z- (C1-C6Alkylidene), (C1-C6Alkenylene)-Z- (C1-C6Alkenylene) or (C1-C6Alkynylene)-Z- (C1-C6Sub- alkynes
Base)；
Wherein Z is independently selected from O, S, NR1, aryl and heteroaryl；
Wherein alkylidene, alkenylene, aryl and heteroaryl are independent and optionally with F, OH, O (C1-C6Alkyl), NH2, NHCH3, N
(CH3)2And C1-C6Alkyl-substituted, wherein alkyl is replaced with one or more F.
3. according to cell toxicity medicament as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, hydrate or solvation
Object, which is characterized in that wherein X1For O, R1For H.
4. cell toxicity medicament as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, hydrate or solvate,
It is characterized in that, wherein D1 is D1 ', and there are double bonds between N and C, and there are double bond and R between C2 and C312It is methoxy-substituted
Phenyl.
5. cell toxicity medicament as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, hydrate or solvate,
It is characterized in that, wherein D1 is D2 ", and there are double bond and R between N and C13It is methoxyl group.
6. cell toxicity medicament as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, hydrate or solvate,
It is characterized in that, wherein T is selected from the alkylidene of C2-12.
7. cell toxicity medicament as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, hydrate or solvate,
It is characterized in that, wherein T is
8. a kind of pharmaceutical composition, it includes cell toxicity medicament as claimed in claim 1 or its is pharmaceutically acceptable
Salt, hydrate or solvate and pharmaceutically acceptable carrier, glidant, diluent or excipient.
9. a kind of cell toxicity medicament as claimed in claim 1 or its pharmaceutically acceptable salt, hydrate or solvent
Compound treats tumour, the purposes of autoimmune disease or infectious diseases.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115192732A (en) * | 2021-04-01 | 2022-10-18 | 成都百利多特生物药业有限责任公司 | DNA toxic dimer compound and conjugate thereof |
| CN115605463A (en) * | 2019-09-27 | 2023-01-13 | 德州大学***董事会（Us） | Inhibitors of receptor interacting protein kinase I for the treatment of diseases |
| WO2023051814A1 (en) | 2021-09-30 | 2023-04-06 | 江苏恒瑞医药股份有限公司 | Pyrrolo benzodiazepine derivative, and conjugate, preparation method and use thereof |
| WO2023178641A1 (en) | 2022-03-25 | 2023-09-28 | 成都百利多特生物药业有限责任公司 | Dna toxic dimer compound and conjugate thereof |
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| WO2019034178A1 (en) | 2019-02-21 |
| CN109180681B (en) | 2021-08-20 |
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