CN105585570B - 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 - Google Patents
异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 Download PDFInfo
- Publication number
- CN105585570B CN105585570B CN201510929055.5A CN201510929055A CN105585570B CN 105585570 B CN105585570 B CN 105585570B CN 201510929055 A CN201510929055 A CN 201510929055A CN 105585570 B CN105585570 B CN 105585570B
- Authority
- CN
- China
- Prior art keywords
- compound
- nmr
- yield
- cdcl
- mhz
- 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.)
- Expired - Fee Related
Links
- -1 pyrrole spiro-epoxy indole compound Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 210000004881 tumor cell Anatomy 0.000 abstract description 63
- 210000004027 cell Anatomy 0.000 abstract description 32
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 abstract description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract description 8
- 239000003960 organic solvent Substances 0.000 abstract description 7
- 230000004071 biological effect Effects 0.000 abstract description 6
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 abstract description 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract description 5
- 108010077895 Sarcosine Proteins 0.000 abstract description 5
- 229940043230 sarcosine Drugs 0.000 abstract description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 abstract description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 4
- 208000032839 leukemia Diseases 0.000 abstract description 4
- 201000005202 lung cancer Diseases 0.000 abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 abstract description 4
- 210000002307 prostate Anatomy 0.000 abstract description 4
- 238000012216 screening Methods 0.000 abstract description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006352 cycloaddition reaction Methods 0.000 abstract description 3
- 238000007877 drug screening Methods 0.000 abstract description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 3
- 238000010992 reflux Methods 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000004614 tumor growth Effects 0.000 abstract description 2
- 125000002971 oxazolyl group Chemical group 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 116
- 238000004896 high resolution mass spectrometry Methods 0.000 description 40
- 238000002844 melting Methods 0.000 description 40
- 230000008018 melting Effects 0.000 description 40
- 239000007787 solid Substances 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 231100000135 cytotoxicity Toxicity 0.000 description 11
- 230000003013 cytotoxicity Effects 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
- 229960004316 cisplatin Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 125000000842 isoxazolyl group Chemical group 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VCYBVWFTGAZHGH-UHFFFAOYSA-N 1-methylindole-2,3-dione Chemical compound C1=CC=C2N(C)C(=O)C(=O)C2=C1 VCYBVWFTGAZHGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- TVIKMEWXHYDWEQ-LKWCPCFXSA-M (e,3r,5s)-7-[2,4-bis(4-fluorophenyl)-5-propan-2-ylimidazol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound [O-]C(=O)C[C@H](O)C[C@H](O)/C=C/N1C(C(C)C)=C(C=2C=CC(F)=CC=2)N=C1C1=CC=C(F)C=C1 TVIKMEWXHYDWEQ-LKWCPCFXSA-M 0.000 description 2
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 2
- JUWMPKQYUSKQSY-KHLSADDPSA-N Alstonisine Natural products O=C(C)C=1[C@H]2[C@H]([C@@H]3N[C@@H]([C@]4(C(=O)N(C)c5c4cccc5)C3)C2)COC=1 JUWMPKQYUSKQSY-KHLSADDPSA-N 0.000 description 2
- JUWMPKQYUSKQSY-UHFFFAOYSA-N Alstonisine Chemical compound C12=CC=CC=C2N(C)C(=O)C11C(CC2C(=COCC32)C(C)=O)NC3C1 JUWMPKQYUSKQSY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- ZJQHPWUVQPJPQT-UHFFFAOYSA-N muscimol Chemical compound NCC1=CC(=O)NO1 ZJQHPWUVQPJPQT-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- BKQVCDGQNOKQNF-KFFVICKMSA-N Corynoxine B Natural products O=C(OC)/C(=C\OC)/[C@@H]1[C@H](CC)C[N+]2[C@H]([C@@]3(C(=O)Nc4c3cccc4)CC2)C1 BKQVCDGQNOKQNF-KFFVICKMSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- VCNYNWHVJKWJRQ-UHFFFAOYSA-N Isorhynchophylline Natural products CCC1=CN2CCC3(C2CC1C(=COC)C(=O)OC)C(=O)Nc4ccccc34 VCNYNWHVJKWJRQ-UHFFFAOYSA-N 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- DAXYUDFNWXHGBE-KAXDATADSA-N Rhynchophylline Chemical compound O=C1NC2=CC=CC=C2[C@@]11CCN2C[C@H](CC)[C@@H](\C(=C/OC)C(=O)OC)C[C@H]21 DAXYUDFNWXHGBE-KAXDATADSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 229940118537 p53 inhibitor Drugs 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229930195380 spirotryprostatin Natural products 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/20—Spiro-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
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/20—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种异恶唑拼接吡咯螺环氧化吲哚化合物，本发明以各种取代的靛红、(E)‑硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸或肌氨酸，在有机溶剂中回流，进行1,3‑偶极子3+2环加成反应，获得异恶唑拼接吡咯螺环氧化吲哚化合物，该类骨架包含潜在的生物活性异恶唑基团，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。且该化合物对三种肿瘤细胞株如人前列腺（PC‑3）,人肺癌细胞（A549）以及人白血病细胞（K562）所进行的肿瘤生长抑制活性筛选。
Description
技术领域
本发明涉及化学技术领域，尤其是一种异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用。
背景技术
把具有生物活性基团拼接到具有活性分子骨架中在有机化学和医药化学中是极其重要的研究领域。（1）多官能团氧化吲哚广泛存在天然产物和合成药物分子中，其中，尤其3-吡咯螺环氧化吲哚因为具有广泛的生物活性，吸引了许多化学工作者及医药化学团队的广泛关注，例如，MI-219 I是一种MDM2-p53抑制剂，可以抑制癌细胞生长和促进凋亡；Spirotryprostatins B (II)是从烟曲霉的发酵液中分离得到，已被证明完全抑制tsFT210细胞，在阻断细胞分裂的G2 / M期；并且，天然产物台钩藤碱III已被证明具有调节大脑皮层M受体亚型和5-羟色胺受体的功能；此外，alstonisine VI，天然生物碱，是首先从灯台muelleriana和几种alstonisine仿生类似物的分离出来。（2）异恶唑基团也普遍存在天然产物和药物分子中。例如: 异噁唑基团也普遍存在天然产物和药物分子中。如: 许多天然产物和药物（Cloxacillin V, muscimol VI,Isoxicam VII, leflunomide VIII, 等）共享一个异恶唑分子单元，这些化合物在解除病痛、经济发展中起着重大作用。鉴于3-吡咯螺环氧化吲哚骨架化合物具有潜在的生物活性，异恶唑基团属于潜在的生物活性官能团。因此，把异恶唑基团拼接到3-吡咯螺环氧化吲哚骨架，合成一系列新的潜在多活性官能团的氧化吲哚衍生物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值(如附图8所示)。
发明内容
本发明的目的是：提供一种异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。
本发明还发现该类化合物在制备防治肿瘤疾病药物中的应用。
本发明是这样实现的：异恶唑拼接吡咯螺环氧化吲哚化合物，该化合物具有如下通式（Ⅰ）的结构：
式中，R1为烷基或芳基；R2为烷基或卤素；R3为烷基或卤素；R4为不同取代的芳基；R5为H或烷基；R6为H或芳基。
异恶唑拼接吡咯螺环氧化吲哚化合物的制备方法，由各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸、硫代脯氨酸或肌氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接吡咯螺环氧化吲哚化合物；
合成路线如下：
其中各种取代的靛红的结构式合成路线中的化合物1，其取代基满足R1为烷基或芳基；R2为烷基或卤素；R3为烷基或卤素。
所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸、硫代脯氨酸或肌氨酸，在有机溶剂中反应温度为50-100℃，反应时间为5-20小时。
异恶唑拼接吡咯螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
通过采用上述技术方案，以各种取代的靛红、(E)-硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸或肌氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接吡咯螺环氧化吲哚化合物，该类骨架包含潜在的生物活性异恶唑基团，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。且该化合物对三种肿瘤细胞株如人前列腺（PC-3），人肺癌细胞（A549）以及人白血病细胞（K562）具有抑制活性的作用。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。
附图说明，
附图1及附图2为本发明的实施例1的化合物3aa谱图数据；
附图3及附图4为本发明的实施例2的化合物4aa谱图数据；
附图5及附图6为本发明的实施例3的化合物5aa谱图数据。
附图7为本发明的实施例2和实施例3的化合物4ah和5dc单晶图；
附图8为本发明的合成路线图。
具体实施方式，
本发明的实施例1：在反应管中依次加入64.4 mg N-甲基靛红1a (0.4 mmol)，138.0 mg (E)-硝基异恶唑烯烃化合物2a (0.6 mmol)，92.0 mg 脯氨酸(0.8 mmol)和15ml甲苯溶液，80 oC反应24 h，TLC检测基本反应完全，直接上样经柱层析（洗脱剂：V（石油醚）：V（乙酸乙酯）= 4:1）纯化得159.8 mg化合物3aa，黄色固体，熔点：237.1-237.6 oC，dr：20:1；产率90.0 %。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ:1.62-1.75 (m, 1H), 1.80-1.83 (m, 1H), 1.95-1.99 (m, 2H), 2.21 (s, 3H), 2.58-2.62 (m, 1H), 2.98-3.04 (m, 1H), 3.16 (s, 3H), 3.87 (t, J = 10.0 Hz, 1H),4.41-4.46 (m, 1H), 4.90 (d, J = 12Hz, 1H ), 6.67-6.78 (m, 3H), 7.13-7.28 (m,2H), 7.21-7.29 (m, 2H), 7.49 (d, J = 8.0 Hz, 2H ); 13C NMR (CDCl3, 100 MHz)δ:11.3, 25.3, 26.5, 27.9, 49.2, 52.9, 56.7, 71.3, 73.9, 108.6, 121.7, 124.7,125.7, 127.5, 128.3, 129.0, 130.0, 138.5, 144.7, 155.8, 172.7, 178.5; HRMS(ESI-TOF) m/z: Calcd. for C25H25N4O4 [M+H]+: 445.1875; Found: 445.1881.
化合物3ab-3gc的制备方法同化合物3aa，投料比与化合物3aa相同，可得到化合物化合物3ab-3gc，反应产率和反应时间见表1，但需强调的是本发明的化合物不限于表1所表示的内容。
表1为一种异恶唑拼接吡咯螺环氧化吲哚化合物的化学结构，
本实施例制备化合物3ab：黄色固体; 熔点：164.7-165.4 oC; 产率：86%, >20:1dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.74-1.77(m, 1H), 1.88-1.93 (m, 1H), 2.00-2.10 (m, 2H), 2.28 (s, 3H), 2.52 (s, 3H),2.67-2.72 (m, 1H), 3.09-3.15 (m, 1H), 3.24 (s, 3H), 4.37 (t, J = 10.0 Hz,1H), 4.47-4.52 (m, 1H), 4.99 (d, J = 12.0 Hz, 1H ), 6.75-6.86 (m, 3H), 7.10-7.13 (m, 2H), 7.21-7.29 (m, 2H), 7.89 (d, J = 8.0 Hz, 1H ); 13C NMR (CDCl3,100 MHz) δ: 11.3, 20.0, 25.3, 26.5, 27.8, 47.0, 49.1, 57.3, 72.6, 74.0,108.6, 121.7, 124.7, 125.6, 126.9, 127.1, 127.6, 130.0, 130.5, 136.7, 137.0,144.0, 155.9, 173.0, 178.5; HRMS (ESI-TOF) m/z: Calcd. for C26H26N4NaO4 [M+Na]+:481.4988; Found: 481.4990.
本实施例制备化合物3ac：黄色固体; 熔点：177.2-178.1 oC; 产率：82%, 20:1dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.76-1.82(m, 1H), 1.88-1.96 (m, 1H), 2.03-2.10 (m, 2H), 2.31 (s, 3H), 2.66-2.70 (m,1H), 3.03-3.10 (m, 1H), 3.24 (s, 3H), 3.94 (t, J = 10.0 Hz, 1H), 4.47-4.52(m, 1H), 4.92 (d, J = 12.0 Hz, 1H ), 6.74-6.78 (m, 2H), 6.81-6.85 (m, 1H),6.91-6.96 (m, 1H), 7.22-7.36 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ: 11.3, 25.3,26.5, 27.8, 49.2, 52.5, 56.7, 71.1, 73.9, 108.7, 114.4 (d, J CF = 21.0 Hz),115.1 (d, J CF = 21.6 Hz), 121.7, 123.8 (d, J CF = 2.8 Hz), 125.6, 130.1, 130.5,141.2, 141.3, 144.7, 155.9, 163.1 (d, J CF = 245.5 Hz), 172.4, 178.4; HRMS(ESI-TOF) m/z: Calcd. for C25H23FN4NaO4 [M+Na]+: 485.1601; Found: 485.1602.
本实施例制备化合物3ad：黄色固体; 熔点：161.7-162.8 oC; 产率：Yield 64%,18:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.72-1.79 (m, 1H), 1.92-1.95 (m, 1H), 2.06-2.09 (m, 2H), 2.32 (s, 3H), 2.69-2.73(m, 1H), 3.06-3.12 (m, 1H), 3.26 (s, 3H), 4.07 (t, J = 10.0 Hz, 1H), 4.53-4.57 (m, 1H), 4.95 (d, J = 12.0 Hz, 1H ), 6.72 (d, J = 8.0 Hz, 1H ), 6.78-6.86 (m, 2H), 7.24-7.28 (m, 1H), 7.77 (d, J = 8.0 Hz, 2H ), 8.20 (d, J = 8.0Hz, 2H ); 13C NMR (100 MHz, CDCl3) δ: 11.3, 25.2, 26.5, 27.8, 49.2, 52.6,56.8, 71.3, 74.1, 108.8, 121.8, 124.2, 124.3, 125.5, 129.2, 130.3, 144.7,146.6, 147.4, 156.0, 172.0, 178.3; HRMS (ESI-TOF) m/z: Calcd. for C25H23N5NaO6 [M+Na]+: 512.1546; Found: 512.1550.
本实施例制备化合物3bc：黄色固体; 熔点：168.2-169.1 oC; 产率：Yield 81%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.67-1.71 (m, 1H), 1.85-1.88 (m, 1H), 1.95-2.02 (m, 2H), 2.22 (s, 3H), 2.57-2.62(m, 1H), 2.92-2.98 (m, 1H), 3.85-3.91 (m, 1H), 4.38-4.41 (m, 1H), 4.72-4.76(m, 1H), 4.95-5.02 (m, 2H), 6.52-6.56 (m, 1H), 6.72-6.77 (m, 2H), 6.84-6.88(m, 1H), 7.00-7.04 (m, 1H), 7.16-7.28 (m, 8H); 13C NMR (CDCl3, 100 MHz) δ:11.4, 25.7, 28.1, 44.3, 48.6, 52.9, 56.5, 71.1, 73.7, 109.7, 114.5 (d, J CF =20.8 Hz), 115.2 (d, J CF = 21.4 Hz), 121.8, 123.7 (d, J CF = 2.7 Hz), 124.6,125.8, 127.4, 127.7, 128.8, 129.9, 130.5, 130.6, 135.6, 141.3, 143.8, 155.9,163.3 (d, J CF = 245.1 Hz), 172.1, 178.3; HRMS (ESI-TOF) m/z: Calcd. forC31H27FN4NaO4 [M+Na]+: 561.1914; Found: 561.1915.
本实施例制备化合物3bf：黄色固体; 熔点：88.7-89.2 oC; 产率：Yield 71%, >20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz)δ: 1.76-1.80 (m, 1H), 1.93-1.98 (m, 1H), 2.04-2.09 (m, 2H), 2.31 (s, 3H), 2.68-2.74(m, 1H), 3.01-3.07 (m, 1H), 4.03 (t, J = 10.1 Hz, 1H), 4.50-4.54 (m, 1H),4.83 (d, J = 16.0 Hz, 1H), 5.05 (d, J = 16.2 Hz, 1H), 5.10 (d, J = 8.1 Hz,1H), 6.64 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 4.3 Hz, 2H), 7.10-7.14 (m, 1H),7.25-7.29 (m, 1H), 7.30-7.35 (m, 4H), 7.60 (d, J = 8.3 Hz, 2H), 7.70 (d, J =8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 11.3, 25.5, 28.0, 44.3, 48.7, 53.0,56.5, 71.2, 73.8, 109.7, 121.8, 125.7, 125.9, 127.3, 127.6, 128.6, 128.8,130.0, 142.7, 143.7, 155.9, 171.8, 178.3; HRMS (ESI-TOF) m/z: Calcd. forC32H27F3N4NaO4 [M+Na]+: 611.1882; Found: 611.1887.
本实施例制备化合物3cb：黄色固体; 熔点：213.5-213.9 oC; 产率：Yield 88%,>20: dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.65-1.70 (m, 1H), 1.94-2.00 (m, 3H), 2.26 (s, 3H), 2.27 (s, 3H), 2.62-2.67 (m,1H), 2.82-2.88 (m, 1H), 3.79 (t, J = 12.0 Hz, 1H), 4.26-4.31 (m, 1H), 5.05(d, J = 12.0 Hz, 1H ), 6.65-6.68 (m, 1H), 6.70-6.73 (m, 1H), 6.82-6.87 (m,1H), 6.99 (d, J = 8.0 Hz, 1H ), 7.12-7.22(m, 4H), 8.26 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 11.4, 21.5, 26.4, 28.9, 48.3, 53.1, 56.2, 71.5, 74.3, 111.1,114.0 (d, J CF = 35.8 Hz), 116.5 (d, J CF = 20.6 Hz), 125.1, 126.6, 128.5,128.7, 128.9, 137.7, 138.7, 155.7, 158.2 (d, J CF = 236.1 Hz), 171.1, 180.1;HRMS (ESI-TOF) m/z: Calcd. for C25H23FN4NaO4 [M+Na]+: 485.1601; Found: 485.1601.
本实施例制备化合物3dc：黄色固体; 熔点：214.7-215.4 oC; 产率：Yield 88%,19:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz)δ: 1.72-1.78 (m, 1H), 1.90-1.98 (m, 3H), 2.20 (s, 3H), 2.33 (s, 3H), 2.68-2.72 (m,1H), 2.97-3.03 (m, 1H), 3.93 (t, J = 10.0 Hz, 1H), 4.37-4.41 (m, 1H), 5.01(d, J = 12.0 Hz, 1H), 6.60 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.92-6.99 (m,2H), 7.23-7.31 (m, 4H), 7.79 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.3,21.0, 25.8, 28.4, 48.6, 52.6, 56.4, 71.1, 74.2, 110.1, 114.4 (d, J CF = 21.0Hz), 115.1(d, J CF = 22.3 Hz), 126.8, 130.4, 130.5, 130.6, 131.2, 139.1, 141.1,155.8, 163.1 (d, J CF = 244.0 Hz), 171.9, 179.8; HRMS (ESI-TOF) m/z: Calcd. forC25H23FN4NaO4 [M+Na]+: 485.1601; Found: 485.1600.
本实施例制备化合物3ee：黄色固体; 熔点：157.8-158.6 oC; 产率：Yield 72%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz)δ: 1.71-1.74 (m, 1H), 1.97-2.08 (m, 3H), 2.34 (s, 3H), 2.59-2.64 (m, 1H), 2.87-2.93(m, 1H), 3.83 (s, 3H), 3.90 (s, 3H), 4.36-4.41 (m, 1H), 5.13 (d, J = 12.0 Hz,1H), 5.28-5.44 (m, 2H), 6.79-6.89 (m, 3H), 7.01-7.13 (m, 3H), 7.24-7.29 (m,5H); 13C NMR (100 MHz, CDCl3)δ: 11.5, 26.4, 28.5, 45.4, 47.7, 53.1, 55.9,56.0, 56.8, 71.0, 72.5, 110.6, 111.4, 115.9, 120.3, 122.7, 124.5, 126.5,127.1, 127.9, 128.5, 130.4, 132.5, 137.5, 139.8, 148.5, 149.3, 155.8, 171.5,179.0; HRMS (ESI-TOF) m/z: Calcd. for C33H31ClN4NaO6 [M+Na]+: 637.1829; Found:637.1831.
本实施例制备化合物3fb：黄色固体; 熔点：209.7-210.5 oC; 产率：Yield 81%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz)δ: 1.74-1.78 (m, 1H), 1.86-1.91 (m, 1H), 2.00-2.07 (m, 2H), 2.29 (s, 3H), 2.33 (s,3H), 2.34 (s, 3H), 2.67-2.71 (m, 1H), 2.97-3.02 (m, 1H), 3.90 (t, J = 12.2Hz, 1H), 4.38-4.42 (m, 1H), 5.09-5.12 (m, 1H), 6.73-6.79 (m, 2H), 6.99-7.06(m, 2H), 7.20-7.26 (m, 1H), 7.29-7.33 (m, 2H), 9.86 (br s, 1H); 13C NMR (100MHz, CDCl3) δ: 11.5, 16.6, 21.6, 25.9, 28.7, 49.1, 53.5, 55.9, 71.5, 75.1,120.3, 121.6, 123.6, 124.7, 125.3, 12.8.4, 128.9, 129.0, 130.6, 131.4, 138.7,140.9, 155.9, 172.1, 181.4; HRMS (ESI-TOF) m/z: Calcd. for C26H26N4NaO4 [M+Na]+:481.1851; Found: 481.1854.
本实施例制备化合物3gc：黄色固体; 熔点：166.4-166.7 oC; 产率：Yield 83%,19:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz)δ: 1.77-1.81 (m, 1H), 1.94-1.98 (m, 1H), 2.07-2.11 (m, 2H), 2.35 (s, 3H), 2.75-2.80(m, 1H), 3.13-3.17 (m, 1H), 3.99 (t, J = 8.5 Hz, 1H), 4.52-4.55 (m, 1H), 5.01(d, J = 8.1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 4.2 Hz, 1H),6.83-6.86 (m, 1H), 6.91-6.95 (m, 1H), 7.13-7.16 (m, 1H), 7.26-7.31 (m, 2H),7.36-7.45 (m, 2H), 7.50-7.57 (m, 4H); 13C NMR (100 MHz, CDCl3) δ: 11.3, 25.1,27.5, 48.9, 52.3, 57.3, 71.0, 74.0, 109.9, 114.4 (d, J CF = 17.0 Hz), 115.2 (d,J CF = 17.2 Hz), 122.0, 125.7, 126.9, 128.3, 129.7, 129.9, 141.4 (d, J CF = 5.1Hz), 144.9, 156.0, 163.1 (d, J CF = 196.7 Hz), 172.8, 177.8; HRMS (ESI-TOF) m/z: Calcd. for C30H25FN4NaO4 [M+Na]+: 547.1757; Found: 547.1759.
本发明的实施例2：在反应管中依次加入64.4 mg N-甲基靛红1a (0.4 mmol)，138.0 mg (E)-硝基异恶唑烯烃化合物2a (0.6 mmol)，106.4 mg 硫代脯氨酸(0.8 mmol)和15 ml甲苯溶液，80 oC反应24 h，TLC检测基本反应完全，直接上样经柱层析（洗脱剂：V（石油醚）：V（乙酸乙酯）= 4:1）纯化得140.5 mg化合物4aa，黄色固体; 熔点：181.3-181.9oC; 产率：Yield 76%, 17:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3,400 MHz) δ: 2.23 (s, 3H), 2.94-3.00 (m, 1H), 3.02-3.06 (m, 1H), 3.19 (s, 3H),3.61 (d, J = 8.2 Hz, 1H), 3.84 (d, J = 8.1 Hz, 1H), 4.00-4.03 (m, 1H), 4.49-4.53 (m, 1H), 5.05 (d, J = 12.3 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.93-6.95(m, 1H), 7.22-7.30 (m, 2H), 7.31-7.37 (m, 3H), 7.52 (d, J = 8.2 Hz, 2H); 13CNMR (CDCl3, 100 MHz) δ: 11.2, 26.5, 34.8, 50.8, 51.9, 56.2, 73.0, 73.9,108.3, 122.3, 123.5, 126.2, 127.9, 128.1, 129.1, 130.3, 137.3, 143.9, 155.4,170.2, 177.3; HRMS (ESI-TOF) m/z: Calcd. for C24H22N4NaO4S[M+Na]+: 485.1259;Found: 485.1261.
化合物4aa-4gk的制备方法同化合物4aa，投料比与化合物4aa相同，可得到化合物化合物4aa-4gk，反应产率和反应时间见表2，但需强调的是本发明的化合物不限于表2所表示的内容。
表2为一种异恶唑拼接吡咯螺环氧化吲哚化合物的化学结构，
本实施例制备化合物4ag：黄色固体; 熔点：202.5-203.7 oC; 产率：Yield 82%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.26(s, 3H), 2.91-3.01 (m, 1H), 3.02-3.06 (m, 1H), 3.20 (m, 3H), 3.60 (d, J = 8.1Hz, 1H), 3.82 (d, J = 8.3 Hz, 1H), 3.95-4.00 (m, 1H), 4.46-4.49 (m, 1H), 4.98(d, J = 12.4 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.91-6.95 (m, 1H), 7.23-7.29(m, 3H), 7.42 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H); 13CNMR (CDCl3, 100 MHz) δ: 11.2, 26.5, 34.6, 50.2, 51.6, 56.2, 72.9, 73.7,108.4, 122.4, 123.1, 123.3, 126.1, 126.7, 130.4, 130.7, 131.2, 131.3, 139.8,143.9, 155.6, 169.9, 177.2; HRMS (ESI-TOF) m/z: Calcd. for C24H21BrN4NaO4S[M+Na]+: 563.036; Found: 563.038.
本实施例制备化合物4ah：黄色固体; 熔点：217.2-218.1 oC; 产率：Yield 83%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.27 (s,3H), 3.00-3.03 (m, 1H), 3.04-3.06 (m, 1H), 3.21 (s, 3H), 3.59 (d, J = 7.2 Hz,1H), 3.79 (d, J = 7.3 Hz, 1H), 4.40-4.43 (m, 1H), 4.74-4.78 (m, 1H), 5.04 (m,1H), 6.75 (d, J = 6.4 Hz, 1H), 6.92-6.96 (m, 1H), 7.23-7.31 (m, 3H), 7.40 (d,J = 1.6 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.2,26.5, 34.4, 45.0, 51.3, 55.7, 72.9, 74.4, 108.4, 122.5, 123.2, 126.2, 128.1,129.7, 130.5, 133.9, 134.1, 135.3, 144.0, 155.5, 169.9, 177.2; HRMS (ESI-TOF)m/z: Calcd. for C24H20Cl2N4NaO4S[M+Na]+: 553.0480; Found: 553.0480.
本实施例制备化合物 4bi：黄色固体; 熔点：108.1-108.7 oC; 产率：Yield 81%,19:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.26(s, 3H), 2.92-2.95 (m, 1H), 3.00-3.04 (m, 1H), 3.58 (d, J = 8.4 Hz, 1H), 3.84(d, J = 8.4 Hz, 1H), 3.99-4.03 m, 1H), 4.48-4.51 (m, 1H), 4.66 (d, J = 16.0Hz, 1H), 5.11 (d, J = 16.0 Hz, 2H), 6.64 (d, J = 8.1 Hz, 1H), 6.88-6.92 (m,1H), 7.11-7.33 (m, 1H), 7.26-7.33 (m, 6H), 7.43 (d, J = 8.8 Hz, 2H), 7.48 (d,J = 8.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 11.3, 34.4, 44.3, 50.5, 51.3,56.0, 72.6, 73.6, 109.4, 122.4, 126.4, 127.3, 127.7, 128.8, 129.8, 130.4,132.3, 135.4, 136.3, 143.1, 155.6, 169.8, 177.2; HRMS (ESI-TOF) m/z: Calcd.for C30H25BrN4NaO4S[M+Na]+: 639.0677; Found: 639.0679.
本实施例制备化合物4da：黄色固体; 熔点：131.5-131.9 oC; 产率：Yield 67%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.23 (s,3H), 2.27 (s, 3H), 2.97-3.06 (m, 2H), 3.67 (d, J = 8.1 Hz, 1H), 3.90-3.97 (m,2H), 4.42-4.47 (m, 1H), 5.10 (d, J = 12.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H),6.95-6.99 (m, 1H), 7.24-7.28 (m, 1H), 7.30-7.35 (m, 3H), 7.48 (d, J = 8.3 Hz,2H), 8.97 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 21.2, 35.4, 51.6,53.6, 55.0, 55.1, 74.5, 110.4, 123.6, 127.9, 128.1, 128.2, 129.2, 130.8,131.8, 137.1, 138.9, 155.5, 169.7; HRMS (ESI-TOF) m/z: Calcd. for C24H22N4NaO4S[M+Na]+: 485.1259; Found: 485.1262.
本实施例制备化合物 4dc：黄色固体; 熔点：227.9-228.7 oC; 产率：Yield 79%,19:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.27(s, 3H), 2.29 (s, 3H), 2.98-3.01 (m, 1H), 3.06-3.11 (m, 1H), 3.70 (d, J = 8.0Hz, 1H), 3.93-4.03 (m, 2H), 4.43-4.47 (m, 1H), 5.10 (d, J = 12.0 Hz, 1H),6.80 (d, J = 8.0 Hz, 1H ), 6.95-7.00 (m, 2H), 7.21-7.32 (m, 4H), 9.2 (s, 1H);13C NMR (CDCl3, 100 MHz)δ: 11.3, 21.1, 35.2, 51.0, 52.9, 55.0, 74.1, 74.2,110.5, 115.0 (d, J CF = 22.0 Hz), 123.5 (d, J CF = 21.7 Hz), 127.6, 130.6,130.8, 130.9, 131.8, 138.9, 139.7 (d, J CF = 8.6 Hz), 155.5, 163.1 (d, J CF =246.2 Hz), 169.4, 179.9; HRMS (ESI-TOF) m/z: Calcd. for C24H21FN4NaO4S[M+Na]+:503.1165; Found: 503.1168.
本实施例制备化合物4dk：黄色固体; 熔点：272.3-273.1 oC; 产率：Yield 70%,19:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.24 (s,3H), 2.27 (s, 3H), 2.53 (s, 3H), 2.92-2.96 (m, 1H), 3.00-3.02 (m, 1H), 3.69(d, J = 8.2 Hz, 1H), 3.90-3.93 (m, 1H), 4.37-4.42 (m, 2H), 5.15 (d, J = 12.4Hz, 1H), 6.73-6.77 (m, 1H), 6.96-6.99 (m, 1H), 7.11-7.15 (m, 2H), 7.22-7.28(m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 8.78 (br s, 1H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 20.1, 21.2, 29.8, 35.0, 45.8, 53.6, 55.7, 75.6, 110.2, 123.8, 123.9,124.0, 127.0, 127.5, 127.6, 127.7, 130.8, 131.0, 131.9, 132.0, 135.5, 137.1,155.6, 170.2; HRMS (ESI-TOF) m/z: Calcd. for C25H24N4NaO4S[M+Na]+: 499.1416;Found: 499.1419.
本实施例制备化合物4gb：黄色固体; 熔点：213.1-213.5 oC; 产率：Yield 65%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.27 (s,3H), 2.32 (s, 3H), 2.90-2.95 (m, 1H), 2.96-3.00 (m, 1H), 3.68-3.71 (m, 1H),3.86-3.89 (m, 1H), 4.00-4.06 (m, 1H), 4.52-4.57 (m, 1H), 5.11-5.16 (m, 1H),6.67-6.70 (m, 1H), 6.90-6.95 (m, 1H), 7.05-7.08 (m, 1H), 7.11-7.16 (m, 1H),7.18-7.25 (m, 2H), 7.33 (s, 2H), 7.41-7.44 (m, 3H), 7.51-7.56 (m, 2H); 13C NMR(CDCl3, 100 MHz) δ: 11.5, 21.5, 21.6, 34.1, 50.3, 57.4, 72.4, 73.7, 109.9,122.9, 123.8, 125.5, 126.2, 126.6, 128.5, 128.9, 129.1, 129.8, 130.3, 137.5,139.0, 144.2, 155.8, 171.1, 176.8; HRMS (ESI-TOF) m/z: Calcd. for C30H26N4NaO4S[M+Na]+: 561.1572; Found: 561.1572.
本实施例制备化合物4gj：黄色固体; 熔点：193.1-193.6 oC; 产率：Yield 65%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.28 (s,9H), 2.29 (s, 3H), 2.92-3.03 (m, 2H), 3.70 (d, J = 8.3 Hz, 1H), 3.90 (d, J =4.5 Hz, 1H), 4.05 (t, J = 10.0 Hz, 1H), 4.54-4.58 (m, 1H), 5.15 (d, J = 12.3Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H ), 6.93 (t, J = 8.0 Hz, 1H), 7.15 (t, J =6.8 Hz, 1H), 7.23 (d, J = 4.4 Hz, 1H), 7.33-7.56 (m, 9H); 13C NMR (CDCl3, 100MHz) δ: 11.4, 31.3, 34.1, 34.5, 49.8, 50.2, 57.4, 72.3, 73.6, 109.7, 122.8,126.0, 126.1, 126.6, 127.8, 128.4, 129.7, 130.2, 133.9, 134.4, 144.1, 150.9,155.7, 171.1, 176.7; HRMS (ESI-TOF) m/z: Calcd. for C33H32N4NaO4S[M+Na]+:603.2042; Found: 603.2048.
本实施例制备化合物4gk：黄色固体; 熔点：236.3-236.8 oC; 产率：Yield 71%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.28 (s,3H), 2.54 (s, 3H), 2.91-2.94 (m, 1H), 2.95-2.98 (m, 1H), 3.71 (d, J = 7.8 Hz,1H), 3.86-3.88 (m, 1H), 4.47-4.56 (m, 2H), 5.20 (d, J = 9.2 Hz, 1H), 6.68-6.71 (m, 1H), 6.93-6.95 (m, 1H), 7.12-7.15 (m, 4H), 7.17-7.25 (m, 1H), 7.42-7.45 (m, 3H), 7.51-7.55 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 100MHz) δ: 11.5, 20.1, 33.8, 44.8, 49.9, 57.9, 72.3, 74.9, 109.9, 123.0, 126.7,127.1, 127.5, 127.6, 128.5, 129.8, 130.8, 136.0, 144.2, 155.9, 171.4, 176.9;HRMS (ESI-TOF) m/z: Calcd. for C30H26N4NaO4S[M+Na]+: 561.1572; Found: 561.1575.
本发明的实施例3：在反应管中依次加入64.4 mg N-甲基靛红1a (0.4 mmol)，138.0 mg (E)-硝基异恶唑烯烃化合物2a (0.6 mmol)，71.2 mg 肌氨酸(0.8 mmol)和15ml甲苯溶液，80 oC反应24 h，TLC检测基本反应完全，直接上样经柱层析（洗脱剂：V（石油醚）：V（乙酸乙酯）= 4:1）纯化得140.4 mg化合物5aa，黄色固体; 熔点：121.1-121.7 oC;产率：Yield 84%, 12:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400MHz) δ: 2.19 (s, 3H), 2.27 (s, 3H), 3.23 (s, 3H), 3.42-3.46 (m, 1H), 3.79-3.84 (m, 1H), 4.44-4.48 (m, 1H), 4.68 (d, J = 10.2 Hz, 1H), 6.70-6.76 (m,2H), 6.82-6.85 (m, 1H), 7.18-7.25 (m, 2H), 7.26-7.33 (m, 2H), 7.55 (d, J =7.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz)δ: 11.4, 26.2, 34.8, 45.5, 55.0, 60.4,74.6, 108.2, 122.7, 124.5, 126.2, 127.6, 128.4, 128.9, 129.0, 129.9, 139.4,144.6, 155.9, 172.8, 177.9; HRMS (ESI-TOF) m/z: Calcd. for C23H22N4NaO4 [M+Na]+:441.1538; Found: 441.1541.
化合物5aa-5ih的制备方法同化合物5aa，投料比与化合物5aa相同，可得到化合物化合物5aa-5ih，反应产率和反应时间见表3，但需强调的是本发明的化合物不限于表3所表示的内容。
本实施例制备化合物5ab：黄色固体; 熔点：171.2-171.7 oC; 产率：Yield 82%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.19(s, 3H), 2.27 (s, 3H), 2.33 (s, 3H), 3.23 (s, 3H), 3.39-3.43 (m, 1H), 3.78-3.83 (m, 1H), 4.40-4.44 (m, 1H), 4.68 (d, J = 10.1 Hz, 1H), 6.70 (d, J = 8.1Hz, 1H), 6.75-6.77 (m, 1H), 6.81-6.84 (m, 1H), 7.04-7.06 (m, 1H), 7.17-7.25(m, 2H), 7.36 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 100 MHz)δ: 11.4, 21.5,26.2, 34.8, 45.5, 54.9, 60.4, 74.5, 108.2, 122.7, 124.5, 125.5, 126.3, 128.4,128.9, 129.0, 129.9, 138.6, 139.3, 144.6, 155.8, 172.9, 177.9; HRMS (ESI-TOF)m/z: Calcd. for C24H24N4NaO4 [M+Na]+: 455.1695; Found: 455.1698.
本实施例制备化合物5ag：黄色固体; 熔点：187.9-188.3 oC; 产率：Yield 81%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.17(s, 3H), 2.29 (s, 3H), 3.23 (s, 3H), 3.39-3.44 (m, 1H), 3.75-3.81 (m, 1H),4.38-4.41 (m, 1H), 4.61-4.64 (m, 1H), 6.69-6.72 (m, 2H), 6.81-6.85 (m, 1H),7.17-7.25 (m, 2H), 7.35-7.37 (m, 1H), 7.51-7.53 (m, 1H), 7.64 (s, 1H); 13C NMR(CDCl3, 100 MHz)δ: 11.4, 26.3, 34.8, 45.1, 54.8, 60.1, 74.5, 108.3, 122.7,122.9, 124.5, 126.0, 127.0, 130.0, 130.6, 130.8, 131.5, 141.9, 144.6, 155.9,172.4, 177.8; HRMS (ESI-TOF) m/z: Calcd. for C23H21BrN4NaO4 [M+Na]+: 519.0643;Found: 519.0647.
本实施例制备化合物5ak：黄色固体; 熔点：192.4-192.7 oC; 产率：Yield 77%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.19(s, 3H), 2.26 (s, 3H), 2.49 (s, 3H), 3.24 (s, 3H), 3.40-3.44 (m, 1H), 3.68-3.73 (m, 1H), 4.76-4.80 (m, 2H), 6.71-6.77 (m, 2H), 6.82-6.86 (m, 1H), 7.10-7.12 (m, 2H), 7.17-7.21 (m, 1H), 7.24-7.27 (m, 1H), 7.84 (d, J = 7.8 Hz, 1H);13C NMR (CDCl3, 100 MHz)δ: 11.4, 20.0, 26.2, 34.8, 40.6, 54.8, 60.8, 74.5,108.3, 122.7, 124.5, 127.1, 127.2, 127.9, 129.9, 130.4, 136.8, 137.6, 144.6,155.9, 173.0, 178.0; HRMS (ESI-TOF) m/z: Calcd. for C24H24N4NaO4 [M+Na]+:455.1695; Found: 455.1698.
本实施例制备化合物 5ba：黄色固体; 熔点：175.4-175.8 oC; 产率：Yield 87%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.25(s, 3H), 2.29 (s, 3H), 3.45-3.49 (m, 1H), 3.83-3.88 (m, 1H), 4.75-4.79 (m,1H), 4.58 (d, J = 15.8 Hz, 1H), 4.76-4.79 (m, 1H), 5.27-5.31 (m, 1H), 6.58(d, J = 8.1 Hz, 1H), 6.77-6.80 (m, 2H), 7.05-7.07 (m, 1H), 7.24-7.26 (m, 2H),7.30-7.35 (m, 6H), 7.56-7.58 (m, 2H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 34.9,44.3, 45.7, 54.9, 60.4, 74.5, 109.3, 122.8, 124.7, 126.2, 127.5, 127.6,127.8, 128.4, 128.9, 129.0, 129.9, 135.9, 139.4, 143.9, 155.9, 172.8, 177.9;HRMS (ESI-TOF) m/z: Calcd. for C29H26N4NaO4 [M+Na]+: 517.1851; Found: 517.1855.
本实施例制备化合物5bg：黄色固体; 熔点：187.1-187.4 oC; 产率：Yield 88%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.23(s, 3H), 2.31 (s, 3H), 3.44-3.48 (m, 1H), 3.79-3.83 (m, 1H), 4.41-4.45 (m,1H), 4.58 (d, J = 16.1 Hz, 1H), 4.72 (d, J = 11.5 Hz, 1H), 5.28 (d, J = 15.8Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 6.72-6.74 (m, 1H), 6.78-6.82 (m, 1H),7.05-7.09 (m, 1H), 7.19-7.39 (m, 7H), 7.55 (d, J = 8.1 Hz, 1H), 7.66-7.67 (m,1H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 34.9, 44.3, 45.3, 54.7, 60.1, 74.5,109.4, 122.8, 122.9, 124.7, 127.0, 127.5, 127.8, 128.9, 130.0, 130.7, 130.8,131.5, 135.8, 141.9, 156.0, 172.4, 177.8; HRMS (ESI-TOF) m/z: Calcd. forC29H25BrN4NaO4 [M+Na]+: 595.0956; Found: 595.0956.
本实施例制备化合物5dc：黄色固体; 熔点：230.1-230.4 oC; 产率：Yield 84%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.12(s, 3H), 2.27 (s, 3H), 2.32 (s, 3H), 3.43-3.47 (m, 1H), 3.73-3.79 (m, 1H),4.42-4.50 (m, 1H), 4.71-4.74 (m, 1H), 6.50 (s, 1H), 6.67 (d, J = 8.1 Hz, 1H),6.92-6.94 (m, 2H), 7.24-7.30 (m, 3H), 8.40 (br s, 1H); 13C NMR (CDCl3, 100MHz)δ: 11.4, 20.9, 34.8, 45.1, 54.4, 59.9, 74.8, 100.0, 109.9, 114.5 (d, J CF =21.1 Hz), 115.3 (d, J CF = 21.5 Hz), 125.5, 126.5, 130.3, 132.3, 139.3, 142.1(d, J CF = 7.3 Hz), 155.9, 163.1 (d, J CF = 245.2 Hz), 172.5, 179.8; HRMS (ESI-TOF) m/z: Calcd. for C23H21FN4NaO4 [M+Na]+: 459.1444; Found: 459.1448.
本实施例制备化合物5df：黄色固体; 熔点：190.1-191.2 oC; 产率：Yield 71%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz)δ: 2.07 (s,3H), 2.22 (s, 3H), 2.26 (s, 3H), 3.42 (t, J = 8.2 Hz, 1H), 3.75 (t, J = 10.1Hz, 1H), 4.44-4.51 (m, 1H), 4.70 (d, J = 12.2 Hz, 1H), 6.46 (s, 1H), 6.62 (d,J = 8.3 Hz, 1H ), 6.88 (d, J = 4.3 Hz, 1H ), 7.50-7.63 (m, 4H), 8.42 (s, 1H);13C NMR (CDCl3, 100 MHz) δ: 11.2, 20.8, 34.8, 45.2, 54.4, 59.9, 74.8, 109.8,125.5, 125.8, 125.9, 126.4, 128.7, 129.6, 130.0, 130.3, 132.3, 139.3, 143.6,155.9, 172.3, 179.8; HRMS (ESI-TOF) m/z: Calcd. for C24H21F3N4NaO4 [M+Na]+:509.1412; Found: 509.1415.
本实施例制备化合物5dg：黄色固体; 熔点：168.7-169.3 oC; 产率：Yield 85%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.15(s, 3H), 2.29 (s, 3H), 2.34 (s, 3H), 3.45-3.49 (m, 1H), 3.79 (t, J = 10.2 Hz,1H), 4.42-4.48 (m, 1H), 4.75 (d, J = 12.1 Hz, 1H), 6.52 (s, 1H), 6.72 (d, J =8.3 Hz, 1H ), 6.95 (d, J = 8.2 Hz, 1H ), 7.21 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 8.61 (s, 1H); 13C NMR(CDCl3, 100 MHz) δ: 11.3, 20.8, 34.8, 45.0, 54.3, 60.0, 74.9, 109.9, 122.8,125.5, 126.4, 126.9, 130.2, 130.5, 130.7, 131.4, 132.2, 139.3, 141.9, 155.8,172.4, 179.8; HRMS (ESI-TOF) m/z: Calcd. for C23H21BrN4NaO4 [M+Na]+: 519.0643;Found: 519.0642.
本实施例制备化合物5dk：黄色固体; 熔点：221.7-222.1 oC; 产率：Yield 77%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.14(s, 3H), 2.29 (s, 3H), 2.51 (s, 3H), 3.42-3.46 (m, 1H), 3.66-3.71 (m, 1H),4.78-4.82 (m, 1H), 4.89 (d, J = 6.4 Hz, 1H), 6.56 (s, 1H), 6.69 (d, J = 8.0Hz, 1H), 6.92-6.95 (m, 1H), 7.11-7.13 (m, 2H), 7.24-7.26 (m, 1H), 7.84 (d, J = 7.8 Hz, 1H), 8.44 (br s, 1H); 13C NMR (CDCl3, 100 MHz)δ: 11.4, 20.0, 20.9,34.9, 40.7, 54.3, 60.7, 74.8, 109.8, 125.6, 126.8, 127.0, 127.2, 127.7,130.2, 130.5, 132.3, 136.9, 137.6, 139.4, 155.9, 173.1, 180.0; HRMS (ESI-TOF)m/z: Calcd. for C24H24N4NaO4 [M+Na]+: 455.1695; Found: 455.1691.
本实施例制备化合物5dl：黄色固体; 熔点：191.7-192.5 oC; 产率：Yield 85%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (DMSO-d 6 , 400 MHz) δ: 2.07(s, 3H), 2.12 (s, 3H), 2.26 (s, 3H), 3.50-3.61 (m, 2H), 4.56-4.61 (m, 1H),4.65 (d, J = 8.6 Hz, 1H), 6.31 (s, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.65-7.69 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.11-8.14 (m,1H), 8.40 (s, 1H), 10.56 (br s, 1H); 13C NMR (DMSO-d 6 , 100 MHz)δ: 11.2, 20.8,34.8, 44.4, 53.6, 59.9, 74.9, 109.9, 122.7, 123.2, 125.4, 126.5, 130.4,130.6, 130.8, 130.9, 135.3, 140.9, 142.7, 148.5, 156.3, 172.3, 179.2; HRMS(ESI-TOF) m/z: Calcd. for C23H21N5NaO6 [M+Na]+: 486.1389; Found: 486.1386.
本实施例制备化合物5gc：黄色固体; 熔点：145.6-146.4 oC; 产率：Yield 90%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.34 (s,6H), 3.47-3.51 (m, 1H), 3.86 (t, J = 10.2 Hz, 1H), 4.49-4.55 (m, 1H), 4.78(d, J = 12.3 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H ), 6.78 (d, J = 8.1 Hz, 1H ),6.86-6.95 (m, 2H), 7.13 (t, J = 8.3 Hz, 1H), 7.24-7.30 (m, 2H), 7.34-7.36 (m,1H), 7.47-7.58 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 34.6, 45.0, 54.9,60.0, 74.6, 109.5, 114.5 (d, J CF = 21.3 Hz), 115.4 (d, J CF = 21.5 Hz), 123.1,124.8, 126.8, 128.4, 129.8, 129.9, 142.0 (d, J CF = 8.2 Hz), 144.7, 156.0,163.0 (d, J CF = 245.7 Hz), 172.5, 177.2; HRMS (ESI-TOF) m/z: Calcd. forC28H23FN4NaO4 [M+Na]+: 521.1601; Found: 521.1600.
本实施例制备化合物5gj：黄色固体; 熔点：165.4-166.3 oC; 产率：Yield 74%,>20:1; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.28 (s,9H), 2.33 (m, 6H), 3.44-3.48 (m, 1H), 3.87 (t, J = 10.0 Hz, 1H), 4.48-4.55(m, 1H), 4.81 (d, J = 12.0 Hz, 1H), 6.66 (d, J = 4.6 Hz, 1H ), 6.79-6.89 (m,2H), 7.11 (t, J = 8.3 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.41-7.57 (m, 7H);13C NMR (CDCl3, 100 MHz) δ: 11.4, 31.3, 34.5, 34.7, 44.9, 55.0, 60.3, 74.7,109.4, 123.0, 124.8, 125.8, 125.9, 126.9, 128.0, 128.4, 129.7, 130.5, 134.0,136.3, 144.7, 150.4, 155.9, 173.0, 177.3; HRMS (ESI-TOF) m/z: Calcd. forC32H32N4NaO4 [M+Na]+: 559.2321; Found: 559.2323.
本实施例制备化合物5gk：黄色固体; 熔点：191.4-191.8 oC; 产率：Yield 78%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.31(s, 3H), 2.33 (s, 3H), 2.51 (s, 3H), 3.44-3.48 (m, 1H), 3.72-3.78 (m, 1H),4.81-4.91 (m, 2H), 6.65-6.68 (m, 1H), 6.78-6.80 (m, 1H), 6.85-6.90 (m, 1H),7.11-7.12 (m, 3H), 7.20-7.25 (m, 1H), 7.42-7.57 (m, 5H), 7.86 (d, J = 7.8 Hz,1H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 20.0, 34.7, 40.4, 55.0, 60.8, 74.7,109.5, 123.2, 126.9, 127.1, 127.2, 128.0, 128.5, 129.8, 129.9, 130.4, 144.7,156.0, 173.1, 177.5; HRMS (ESI-TOF) m/z: Calcd. for C29H26N4NaO4 [M+Na]+:517.1851; Found: 517.1857.
本实施例制备化合物5ha：黄色固体; 熔点：235.1-236.0 oC; 产率：Yield 72%,17:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.29(s, 3H), 2.36 (s, 3H), 3.43-3.49 (m, 1H), 3.75-3.79 (m, 1H), 4.45-4.49 (m,1H), 4.77 (d, J = 8.2 Hz, 1H), 6.74-6.76 (m, 2H), 7.12-7.15 (m, 1H), 7.25-7.37 (m, 3H), 7.53 (d, J = 8.2 Hz, 2H), 8.43 (s, 1H); 13C NMR (CDCl3, 100 MHz)δ: 11.2, 34.8, 45.4, 54.6, 60.1, 74.8, 111.0, 125.4, 127.6, 128.0, 128.2,128.6, 128.9, 129.1, 129.8, 139.0, 140.2, 155.8, 172.2, 179.5; HRMS (ESI-TOF)m/z: Calcd. for C22H19ClN4NaO4 [M+Na]+: 461.0992; Found: 461.0994.
本实施例制备化合物5hc：黄色固体; 熔点：209.4-209.9 oC; 产率：Yield 75%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.28(s, 3H), 2.35 (s, 3H), 3.44-3.48 (m, 1H), 3.74-3.79 (m, 1H), 4.42-4.49 (m,1H), 4.75 (d, J = 9.8 Hz, 1H), 6.67 (d, J = 3.8 Hz, 1H), 6.81-6.83 (m, 1H),6.97-7.01 (m, 1H), 7.14-7.17 (m, 1H), 7.26-7.31 (m, 3H), 8.54 (br s, 1H); 13CNMR (CDCl3, 100 MHz)δ: 11.3, 34.7, 45.2, 54.4, 59.7, 75.4, 114.5 (d, J CF =20.0 Hz), 115.2 (d, J CF = 22.2 Hz), 123.3 (d, J CF = 26.0 Hz), 123.8, 129.9,130.4, 139.5, 141.6 (d, J CF = 7.0 Hz), 155.9, 163.0 (d, J CF = 245.0 Hz),171.8, 178.9; HRMS (ESI-TOF) m/z: Calcd. for C22H18ClFN4NaO4 [M+Na]+: 479.0898;Found: 479.0896.
本实施例制备化合物5hh：黄色固体; 熔点：146.2-146.9 oC; 产率：Yield 88%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (DMSO-d 6 , 400 MHz) δ: 2.10(s, 3H), 2.27 (s, 3H), 3.32-3.44 (m, 1H), 3.45-3.50 (m, 1H), 4.65 (d, J = 4.6Hz, 1H), 4.81-4.85 (m, 1H), 6.51 (s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 7.20-7.23(m, 1H), 7.52-7.59 (m, 2H), 7.83 (d, J = 8.1 Hz, 1H), 10.85 (br s, 1H); 13CNMR (DMSO-d6, 100 MHz)δ: 10.8, 34.3, 40.1, 52.5, 59.0, 74.2, 111.3, 124.4,125.7, 127.8, 128.3, 128.8, 129.8, 130.2, 130.4, 132.6, 134.2, 136.1, 141.8,155.8, 171.2, 178.4; HRMS (ESI-TOF) m/z: Calcd. for C22H17Cl3N4NaO4 [M+Na]+:529.0213; Found: 529.0215.
本实施例制备化合物5ib：黄色固体; 熔点：198.4-198.9 oC; 产率：Yield 73%,>20:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.27(s, 3H), 2.30 (s, 3H), 2.34 (s, 3H), 3.40-3.44 (m, 1H), 3.74-3.77 (m, 1H),4.41-4.44 (m, 1H), 4.77-4.81 (m, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.73-6.76 (m,1H), 6.95-6.97 (m, 1H), 7.04-7.08 (m, 1H), 7.19-7.25 (m, 1H), 7.25-7.37 (m,2H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 16.3, 21.6, 34.9, 45.6, 54.5, 60.3,75.2, 122.3, 122.6, 125.4, 126.4, 126.5, 128.3, 128.8, 129.0, 130.4, 131.2,138.6, 139.5, 155.9, 172.8; HRMS (ESI-TOF) m/z: Calcd. for C24H24N4NaO4 [M+Na]+:455.1695; Found: 455.1698.
本实施例制备化合物5ih：黄色固体; 熔点：207.4-208.6 oC; 产率：Yield 86%,19:1 dr; 核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.26(s, 3H), 2.27 (s, 3H), 2.34 (s, 3H), 3.50-3.54 (m, 1H), 3.63-3.67 (m, 1H),4.77 (d, J = 8.3 Hz, 1H), 5.04-5.07 (m, 1H), 6.58 (d, J = 4.3 Hz, 1H), 6.75-6.79 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 7.25-7.30 (m, 1H), 7.36 (s, 1H), 7.89(d, J = 4.5 Hz, 1H), 8.82 (br s, 1H); 13C NMR (CDCl3, 100 MHz)δ: 11.4, 16.1,34.7, 40.6, 53.4, 59.7, 75.2, 119.2, 122.4, 122.7, 125.7, 127.9, 129.3,130.2, 131.3, 133.6, 135.1, 136.0, 140.3, 155.7, 172.1, 180.5; HRMS (ESI-TOF)m/z: Calcd. for C23H20Cl2N4NaO4 [M+Na]+: 509.0759; Found: 509.0758.
本发明的式（1）化合物具有重要的生物活性，体外对人前列腺（PC-3）, 人肺癌细胞（A549）以及人白血病细胞（K562）共三株肿瘤细胞的细胞毒性试验表明：此类式（1）所示的结构的异恶唑拼接吡咯螺环氧化吲哚化合物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人前列腺（PC-3）, 人肺癌细胞（A549）以及人白血病细胞（K562）表示的细胞毒性。
药理实施例1：化合物3fb, 4da, 4dc, 4dk, 5dc, 5df, 5dg, 5dk, 5ha, 5hh和5ib对PC-3细胞的细胞毒性
PC-3（人前列腺癌）细胞用RPMI-1640培养基培养，培养基中含10%的胎牛血清，100U/mL 青霉素及100U/mL的链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37oC 含5% CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后，分别将新配的化合物3fb, 4da, 4dc, 4dk, 5dc, 5df, 5dg, 5dk, 5ha, 5hh和5ib的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度分别为5 μmol/L, 10 μmol/L, 20 μmol/L, 40 μmol/L 和80 μmol/L。48小时后，每孔加入10 μL MTT （5 mg/mL) 的磷酸盐缓冲液，再继续在37 oC 培养4小时后，离心5分钟除去未转化的MTT，每孔中加入150 μL 二甲基亚砜。以溶解还原的MTT 晶体甲臜（formazan），用酶标仪在490 nm波长测定OD值。其中化合物3fb,4da, 4dc, 4dk, 5dc, 5df, 5dg, 5dk, 5ha, 5hh和5ib对PC-3细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3fb对PC-3肿瘤细胞的IC50为28.8 μmol/L；化合物4da对PC-3肿瘤细胞的IC50为32.2 μmol/L；化合物4dc对PC-3肿瘤细胞的IC50为26.4 μmol/L；化合物4dk对PC-3肿瘤细胞的IC50为13.7 μmol/L；化合物5dc对PC-3肿瘤细胞的IC50为25.8 μmol/L；化合物5dg对PC-3肿瘤细胞的IC50为14.1 μmol/L；化合物5dk对PC-3肿瘤细胞的IC50为18.7 μmol/L；化合物5ha对PC-3肿瘤细胞的IC50为19.8 μmol/L；化合物5hh对PC-3肿瘤细胞的IC50为13.1 μmol/L；化合物5ib对PC-3肿瘤细胞的IC50为58.4 μmol/L；而阳性对照顺铂对PC-3肿瘤细胞的IC50为27.9 μmol/L。
实验结论：PC-3细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式（1）所示的异恶唑拼接吡咯螺环氧化吲哚化合物对PC-3细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级或活性比顺铂更好，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例2：化合物3fb, 4da, 4dc, 4dk, 5dc, 5df, 5dg, 5dk, 5ha, 5hh和5ib对A549细胞的细胞毒性
A549（人非小细胞肺癌肺癌）用DMEM培养基培养，培养基中含10%的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔4000个细胞的浓度加入到96孔中，在37℃含5%CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3fb对A549肿瘤细胞的IC50为65.9 μmol/L；化合物4da对A549肿瘤细胞的IC50为68.7μmol/L；化合物4dc对A549肿瘤细胞的IC50为44.1 μmol/L；化合物4dk对A549肿瘤细胞的IC50为54.4μmol/L；化合物5dc对A549肿瘤细胞的IC50为62.8 μmol/L；化合物5df对A549肿瘤细胞的IC50为27.6 μmol/L；化合物5dg对A549肿瘤细胞的IC50为22.7 μmol/L；化合物5dk对A549肿瘤细胞的IC50为46.2 μmol/L；化合物5ha对A549肿瘤细胞的IC50为26.9 μmol/L；化合物5hh对A549肿瘤细胞的IC50为21.5 μmol/L；化合物5ib对A549肿瘤细胞的IC50为37.1 μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为25.2 μmol/L。
实验结论：A549细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式（1）所示的异恶唑拼接吡咯螺环氧化吲哚化合物对PC-3细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级或活性比顺铂更好，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例3：化合物3aa, 3ad, 3bf, 3cb, 3dc, 3ee, 3fb, 4aa, 4ag, 4ah,4bi, 4da, 4dc, 4dk, 4gb, 4gk, 5aa, 5ab, 5ag, 5ak, 5bg, 5dc, 5df, 5dg, 5dk,5gc, 5ha, 5hc, 5hh, 5ib, 5ih对K562细胞的细胞毒性
K562（人慢性髓系白血病细胞）用RPMI-1640培养基培养，培养基中含10%的胎牛血清，100 U/mL的青霉素和100 U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5% CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3aa对K562肿瘤细胞的IC50为74.7 μmol/L；化合物3ad对K562肿瘤细胞的IC50为62.7 μmol/L；化合物3bf对K562肿瘤细胞的IC50为65.3μmol/L；化合物3cb对K562肿瘤细胞的IC50为33.5 μmol/L；化合物3dc对K562肿瘤细胞的IC50为30.4 μmol/L；化合物3ee对K562肿瘤细胞的IC50为77.4 μmol/L；化合物3fb对K562肿瘤细胞的IC50为13.2 μmol/L；化合物4aa对K562肿瘤细胞的IC50为25.9 μmol/L；化合物4ag对K562肿瘤细胞的IC50为43.0 μmol/L；化合物4ah对K562肿瘤细胞的IC50为43.5 μmol/L；化合物4bi对K562肿瘤细胞的IC50为40.1 μmol/L；化合物4da对K562肿瘤细胞的IC50为16.1 μmol/L；化合物4dc对K562肿瘤细胞的IC50为20.5 μmol/L；化合物4dk对K562肿瘤细胞的IC50为11.8 μmol/L；化合物4gb对K562肿瘤细胞的IC50为85.2 μmol/L；化合物4gk对K562肿瘤细胞的IC50为88.7 μmol/L；化合物5aa对K562肿瘤细胞的IC50为37.1 μmol/L；化合物5ab对K562肿瘤细胞的IC50为34.2 μmol/L；化合物5ag对K562肿瘤细胞的IC50为54.0 μmol/L；化合物5ak对K562肿瘤细胞的IC50为54.1 μmol/L；化合物5bg对K562肿瘤细胞的IC50为83.1μmol/L；化合物5dc对K562肿瘤细胞的IC50为12.5 μmol/L；化合物5df对K562肿瘤细胞的IC50为19.2 μmol/L；化合物5dg对K562肿瘤细胞的IC50为12.4 μmol/L；化合物5dk对K562肿瘤细胞的IC50为14.5 μmol/L；化合物5gc对K562肿瘤细胞的IC50为71.0 μmol/L；化合物5ha对K562肿瘤细胞的IC50为14.2 μmol/L；化合物5hc对K562肿瘤细胞的IC50为75.8 μmol/L；化合物5hh对K562肿瘤细胞的IC50为10.4 μmol/L；化合物5ib对K562肿瘤细胞的IC50为22.1 μmol/L；化合物5ih对K562肿瘤细胞的IC50为43.1 μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为23.2 μmol/L。
实验结论：K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式（1）所示的异恶唑拼接吡咯螺环氧化吲哚化合物对K562细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级或活性比顺铂更好，有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些化合物对这三株肿瘤细胞都显示有一定的细胞毒性。可见这些化合物具有开发成为抗肿瘤药物的潜力，值得继续深入研究下去。
Claims (2)
1.一种异恶唑拼接吡咯螺环氧化吲哚化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
该结构式为如下结构式之一：
2.一种如权利要求1所述的异恶唑拼接吡咯螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510929055.5A CN105585570B (zh) | 2015-12-15 | 2015-12-15 | 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510929055.5A CN105585570B (zh) | 2015-12-15 | 2015-12-15 | 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105585570A CN105585570A (zh) | 2016-05-18 |
| CN105585570B true CN105585570B (zh) | 2019-10-15 |
Family
ID=55925511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510929055.5A Expired - Fee Related CN105585570B (zh) | 2015-12-15 | 2015-12-15 | 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105585570B (zh) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008532B (zh) * | 2016-07-20 | 2019-06-07 | 贵州大学 | 烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物及其制备方法及应用 |
| CN106866686B (zh) * | 2017-03-30 | 2019-03-29 | 贵州大学 | 异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物及其制备方法及应用 |
| CN107235969B (zh) * | 2017-08-04 | 2021-07-06 | 贵州大学 | 合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用 |
| CN107778320A (zh) * | 2017-10-23 | 2018-03-09 | 青岛大学 | 一种螺环异恶唑啉类化合物的合成方法 |
| CN107935910B (zh) * | 2017-11-23 | 2021-10-19 | 贵州大学 | 含1′-茚醇拼接3-氧化吲哚类化合物及其制备方法及应用 |
| CN107857766B (zh) * | 2017-12-11 | 2020-12-22 | 皖南医学院 | 一种基于苯丙氨酸和多羰基类环酮化合物的螺旋吲哚类化合物的合成方法及其应用 |
| CN107857765B (zh) * | 2017-12-11 | 2020-03-13 | 皖南医学院 | 一种基于肌氨酸和多羰基类环酮化合物的螺旋吲哚类化合物的合成方法及其应用 |
| EP3511334A1 (en) * | 2018-01-16 | 2019-07-17 | Adamed sp. z o.o. | 1,2,3',5'-tetrahydro-2'h-spiro[indole-3,1'-pyrrolo[3,4-c]pyrrole]-2,3'-dione compounds as therapeutic agents activating tp53 |
| CN108586437B (zh) * | 2018-05-30 | 2021-05-07 | 贵州大学 | 色酮拼接3-羟甲基氧化吲哚衍生物及其制备方法及应用 |
| CN110183456A (zh) * | 2019-07-11 | 2019-08-30 | 河南师范大学 | 一种2-芳基吲唑琥珀酰亚胺螺环化合物的合成方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102627649A (zh) * | 2005-02-22 | 2012-08-08 | 密执安州立大学董事会 | Mdm2 的小分子抑制剂以及其应用 |
-
2015
- 2015-12-15 CN CN201510929055.5A patent/CN105585570B/zh not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102627649A (zh) * | 2005-02-22 | 2012-08-08 | 密执安州立大学董事会 | Mdm2 的小分子抑制剂以及其应用 |
Non-Patent Citations (3)
| Title |
|---|
| Catalytic asymmetric construction of spiro[pyrrolidine-2,30-oxindole] scaffolds through chiral phosphoric acid-catalyzed 1,3-dipolar cycloaddition involving 3-amino oxindoles;Guodong Zhu, et al.;《ChemComm》;20150826;第51卷;第15510-15513页 * |
| 无催化剂合成吡咯螺环氧化吲哚;景德红等;《遵义医学院学报》;20140831;第37卷(第4期);第442-444、448页 * |
| 通过1,3-偶极环加成反应合成3-吡咯螺环氧化吲哚的研究进展;周英等;《山地农业生物学报》;20150428;第34卷(第2期);第9-13页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105585570A (zh) | 2016-05-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105585570B (zh) | 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用 | |
| CN111153901B (zh) | 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途 | |
| CN110248926B (zh) | Lsd1抑制剂及其制备方法和应用 | |
| TW202136275A (zh) | 嗒𠯤基─噻唑甲醯胺化合物 | |
| CN104276994B (zh) | 3,3′‑双取代氧化吲哚与3‑烯键氧化吲哚拼接衍生物及其制备方法及应用 | |
| EP3848371A1 (en) | Tricyclic furan-substituted piperidinedione compound | |
| AU2016382372B2 (en) | Sulfonamide derivative and preparation method and use thereof | |
| AU2020401999B2 (en) | Compound as cyclin-dependent kinase 9 inhibitor and use thereof | |
| CA3104757A1 (en) | Cell necrosis inhibitor, preparation method therefor and use thereof | |
| WO2020188467A1 (zh) | 作为激酶抑制剂的稠合三环化合物 | |
| CN107383030B (zh) | 姜黄酮拼接3,3’-吡咯双螺环氧化吲哚化合物及其制备方法及应用 | |
| EP3689860A1 (en) | Sulfonyl-substituted bicyclic compound which acts as ror inhibitor | |
| CN106008532A (zh) | 烷氧基嘧啶拼接3-吡咯螺环氧化吲哚衍生物及其制备方法及应用 | |
| AU2025203069A1 (en) | Aromatic molecules for use in the treatment of pathological conditions | |
| CN109705130B (zh) | 二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物及其制备方法及应用 | |
| CN109641909A (zh) | 雷帕霉素信号通路抑制剂的机理靶标及其治疗应用 | |
| JP2021509399A (ja) | インドールアミン−２，３−ジオキシゲナーゼ阻害剤およびその調製方法と使用 | |
| CN110092793B (zh) | 山酮素骨架和异噁唑螺环氧化吲哚拼接衍生物及其制备方法及应用 | |
| CN105949180B (zh) | 治疗中枢神经系统退行性疾病的化合物及其应用 | |
| CN110684032B (zh) | 山酮素异恶唑骨架拼接吡唑啉酮或苯并呋喃酮类化合物及其制备方法及应用 | |
| Aaseng et al. | Synthesis of (S)-2-amino-7-methoxytetralin and isoindolo [1, 2-a] isoquinolinone derivatives from l-aspartic acid | |
| CN104693194B (zh) | 3‑(2‑丙烯酸酯)‑3ˊ‑硝基异噁唑氧化吲哚化合物及其制备方法及应用 | |
| WO2013114040A1 (fr) | Nouveaux composes et compositions utilises comme anticancereux | |
| FR2999575A1 (fr) | 3,5-diaryl-azaindoles comme inhibiteurs de la proteine dyrk1a pour le traitement des deficiences cognitives liees au syndrome de down et a la maladie d'alzheimer | |
| CN107188924B (zh) | 一种丹参酮骨架拼接双吲哚或双吡咯类化合物及其制备方法及应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Liu Xiongli Inventor after: Yu Zhangbiao Inventor after: Yao Zhen Inventor after: Qian Yuxin Inventor after: Liu Xiongwei Inventor after: Zhang Wenhui Inventor after: Chen Zhiyong Inventor after: Zhou Gen Inventor after: Zhou Ying Inventor after: Feng Tingting Inventor before: Liu Xiongli Inventor before: Yao Zhen Inventor before: Liu Xiongwei Inventor before: Zhang Wenhui Inventor before: Chen Zhiyong Inventor before: Zhou Gen Inventor before: Zhou Ying Inventor before: Feng Tingting Inventor before: Yu Zhangbiao |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20191015 Termination date: 20211215 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |