CN115785079B - 4-(1h-吲哚-5-基)氨基呋喃-2(5h)-酮类化合物及其制备和应用 - Google Patents
4-(1h-吲哚-5-基)氨基呋喃-2(5h)-酮类化合物及其制备和应用 Download PDFInfo
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- CN115785079B CN115785079B CN202211502441.2A CN202211502441A CN115785079B CN 115785079 B CN115785079 B CN 115785079B CN 202211502441 A CN202211502441 A CN 202211502441A CN 115785079 B CN115785079 B CN 115785079B
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- 238000002360 preparation method Methods 0.000 title abstract description 35
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- -1 1H-indole-5-yl Chemical group 0.000 claims abstract description 26
- 201000007270 liver cancer Diseases 0.000 claims abstract description 13
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 13
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 11
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 230000035755 proliferation Effects 0.000 claims 2
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical compound O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 abstract description 20
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002474 experimental method 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
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- LUMLZKVIXLWTCI-NSCUHMNNSA-N (e)-2,3-dichloro-4-oxobut-2-enoic acid Chemical compound OC(=O)C(\Cl)=C(/Cl)C=O LUMLZKVIXLWTCI-NSCUHMNNSA-N 0.000 abstract description 2
- 238000006000 Knoevenagel condensation reaction Methods 0.000 abstract description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 abstract description 2
- ZAKLKBFCSHJIRI-UHFFFAOYSA-N mucochloric acid Natural products OC1OC(=O)C(Cl)=C1Cl ZAKLKBFCSHJIRI-UHFFFAOYSA-N 0.000 abstract description 2
- 238000007344 nucleophilic reaction Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 17
- 239000011734 sodium Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 8
- JZQBAGOECGRTSA-UHFFFAOYSA-N 3-hydroxy-2h-furan-5-one Chemical compound OC1=CC(=O)OC1 JZQBAGOECGRTSA-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- RENLGFYEYNCZFJ-UHFFFAOYSA-N CC(C)OC1OC(=O)C(Cl)=C1 Chemical compound CC(C)OC1OC(=O)C(Cl)=C1 RENLGFYEYNCZFJ-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- 229930182821 L-proline Natural products 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- 239000012074 organic phase Substances 0.000 description 5
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- HUEWZXDISSFEPL-UHFFFAOYSA-N 4-chloro-2-ethoxy-2h-furan-5-one Chemical compound CCOC1OC(=O)C(Cl)=C1 HUEWZXDISSFEPL-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 4
- 229940008406 diethyl sulfate Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical group 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Chemical group CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
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- VVDUZZGYBOWDSQ-UHFFFAOYSA-M eschenmoser's salt Chemical compound [I-].C[N+](C)=C VVDUZZGYBOWDSQ-UHFFFAOYSA-M 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CYBOJGGUHAUMKT-UHFFFAOYSA-N 3,4-dichloro-5-methoxy-3H-furan-2-one Chemical compound COC1=C(Cl)C(Cl)C(=O)O1 CYBOJGGUHAUMKT-UHFFFAOYSA-N 0.000 description 2
- QSYHSDNIQZDYGF-UHFFFAOYSA-N 4-bromo-2h-furan-5-one Chemical compound BrC1=CCOC1=O QSYHSDNIQZDYGF-UHFFFAOYSA-N 0.000 description 2
- WMRFBVADMRJNDA-UHFFFAOYSA-N 4-chloro-2-methoxy-2h-furan-5-one Chemical compound COC1OC(=O)C(Cl)=C1 WMRFBVADMRJNDA-UHFFFAOYSA-N 0.000 description 2
- GCVGDGFZLSSUIO-UHFFFAOYSA-N 4-chloro-2h-furan-5-one Chemical compound ClC1=CCOC1=O GCVGDGFZLSSUIO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
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- ULWRZZDLLPNFEW-UHFFFAOYSA-N 3,4-dichloro-2h-furan-5-one Chemical group ClC1=C(Cl)C(=O)OC1 ULWRZZDLLPNFEW-UHFFFAOYSA-N 0.000 description 1
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- PSWCIARYGITEOY-UHFFFAOYSA-N 6-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2C=CNC2=C1 PSWCIARYGITEOY-UHFFFAOYSA-N 0.000 description 1
- KYFZSGBVGJNEPN-UHFFFAOYSA-N 6-nitro-1h-indole-3-carbaldehyde Chemical compound [O-][N+](=O)C1=CC=C2C(C=O)=CNC2=C1 KYFZSGBVGJNEPN-UHFFFAOYSA-N 0.000 description 1
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- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
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- 238000010009 beating Methods 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical group BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
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- LUCKBIGWTFTDTL-UHFFFAOYSA-N ethyl 3-(5-nitro-1h-indol-3-yl)prop-2-enoate Chemical compound C1=C([N+]([O-])=O)C=C2C(C=CC(=O)OCC)=CNC2=C1 LUCKBIGWTFTDTL-UHFFFAOYSA-N 0.000 description 1
- FGBJXOREULPLGL-UHFFFAOYSA-N ethyl cyanoacrylate Chemical group CCOC(=O)C(=C)C#N FGBJXOREULPLGL-UHFFFAOYSA-N 0.000 description 1
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- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
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- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Substances CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明属于医药技术领域,具体涉及一种4‑(1H‑吲哚‑5‑基)氨基呋喃‑2(5H)‑酮类化合及其制备和在抗肿瘤中的应用。化合物为通式Ⅰ所示化合物,本发明4‑(1H‑吲哚‑5‑基)氨基呋喃‑2(5H)‑酮类化合物是以5‑硝基吲哚为原料经Vilsmeier‑Haack反应、Knoevenagel缩合反应、还原反应及与粘氯酸的亲核反应合成了含2(5H)‑呋喃酮的吲哚类化合物,通过细胞活性实验,可见所得化合物对结肠癌细胞和肝癌细胞具有显著的抑制作用。
Description
技术领域
本发明属于医药技术领域,具体涉及一种4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合及其制备和在抗肿瘤中的应用。
背景技术
癌症是全球疾病负担的主要贡献者,据预测,全球癌症负担至少在未来20年将继续增长。严重影响着人们的生命健康,(JAMA oncology,2022,8(3):420-444.);全世界每年因恶性肿瘤死亡的人数约占总死亡人数的25%。其中原发性肝癌(Hepatocellularcarcinoma,HCC)在我国发病率及死亡率长期处于居高不下的地位,据全球最新癌症大数据统计,肝癌在我国恶性肿瘤发病率位居第四位,病死率居第三位,每年平均新增病例约39.3万人,发病人数不低于全球的50%(CA Cancer J Clin,2018,68(6):394-424.);肝癌的主要病因是由乙型肝炎病毒、丙型肝炎病毒、酗酒或血色素沉着病等引起的慢性肝脏肿瘤性疾病。现阶段,仅可为大约1/3的肝癌患者提供诸如肝切除术和肝移植之类的治疗程序,并且患者术后复发率高,5年生存率低。而结肠癌作为目前我国最常见的消化系统恶性肿瘤之一,其发病率位列恶性肿瘤第三位,死亡率逐年上升,严重威胁结肠癌患者的生命安全,中晚期结肠癌一般采用化疗的方法治疗,然而,耐药性的影响通常使治疗效果不佳(中国比较医学杂志,2019,29(2):43-50.);因此,开发出可有效对抗此类癌的治疗药物迫在眉睫且至关重要。
吲哚类化合物凭借其显著的生理活性而被广泛应用于靶向抗癌药物的研究,近年来,对于吲哚类抗癌药物的研究取得了较大的进展。2(5H)-呋喃酮环属于a,b-不饱和内酯类化合物,广泛存在于许多天然产物中。结构中含有2(5H)-呋喃酮骨架的化合物具有显著抗肿瘤活性(Eur.J.Med.Chem.2017,139:84-94.);但同时具备较强选择性和细胞活性的的吲哚类化合物报道较少,一些常规的抗癌药在癌症治疗中通常会存在脱靶效应,使进入癌细胞药物浓度较低,从而减弱其药效作用,本发明提供一种具有可逆共价作用的吲哚类化合物(J.Med.Chem.2011,54:1347–1355.);在提高对癌细胞选择性的同时可有效减少脱靶效应。
发明内容
本发明目的在于提供一种4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物及其制备和在抗肿瘤中的应用。
为实现上述目的,本发明采用技术方案为:
一种4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物,化合物为通式Ⅰ所示化合物,
式中,R选自氢、卤素、或二甲胺亚甲基;R1选自氢、C1-C8烷基、未取代或至少一个卤素取代的苄基;R2选自氢、C1-C8烷基;R3选自C1-C8烷基。
所述式Ⅰ中,R选自氢、卤素或二甲胺亚甲基;R1选自氢、C1-C4烷基、未取代或至少一个卤素取代的苄基;R2选自氢、C1-C6烷氧基;R3选自C1-C4烷基
所述式Ⅰ中,R选自氢、氯、溴、或二甲胺亚甲基;R1选自氢、甲基、乙基、苄基、或对氯苄基;R2选自氢、甲氧基、乙氧基、正丙氧基、正丁氧基、异丙氧基或新戊氧基;R3选自甲基或乙基。
所述化合物为下述结构之一,
其中,K-29为2-氰基-3-[5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;K-37为2-氰基-3-[1-乙基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;K-38为2-氰基-3-[1-苄基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;K-40为2-氰基-3-[1-甲基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;C6为2-氰基-3-[6-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;C7为2-氰基-3-[7-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;K-47为2-氰基-3-[5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸乙酯;M-34为2-氰基-3-[5-(4-溴-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-35为2-氰基-3-[5-(4-(二甲基氨基)甲基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-38为2-氰基-3-[5-(4-氯-2-甲氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-39为2-氰基-3-[5-(4-氯-2-乙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-40为2-氰基-3-[5-(4-氯-2-异丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-41为2-氰基-3-[5-(4-氯-2-正丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-42为2-氰基-3-[5-(4-氯-2-正丁氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-43为2-氰基-3-[1-甲基-5-(4-氯-2-异丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-44为2-氰基-3-[5-(4-氯-2-新戊氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-45为2-氰基-3-[1-苄基-5-(4-氯-2-乙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-46为2-氰基-3-[1-苄基-5-(4-氯-2-正丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-47为2-氰基-3-[1-苄基-5-(4-氯-2-异丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;为M-49为2-氰基-3-[1-对氯苯基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯;M-50为2-氰基-3-[5-(4-氯-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯。
一种4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物的制备方法,按照上述中取代基的记载,根据反应式分别获得通式Ⅰ所示化合物:
(1)制备上述化合物a
将反应原料5-硝基吲哚加入新鲜制备的Vilsmeier试剂中,35℃条件下,反应1h后,反应结束自然升温到室温后,调节体系pH值8~9,析出沉淀,得到化合物a;所述的5-硝基吲哚、三氯氧磷、DMF的摩尔比为1:1~1.5:5~10;
(2)制备上述化合物b
将化合物a和L-脯氨酸于无水乙醇中混匀,混匀后加入结构式为的氰基乙酸酯类,78~80℃条件下,反应1~1.5h,反应后重结晶得到化合物b;所述化合物a、L-脯氨酸与/>的摩尔比为1:0.5:1.5,其中R3取代基与权利要求1中一致;
(3)制备上述化合物c
化合物b在醇和氯化铵混合,在78~80℃温度下,再加入铁粉还原反应3.5~6h后,纯化得化合物c;所述化合物b、铁粉、氯化铵的摩尔比为1:3~5:6~10;
(4)制备上述化合物d
将反应原料化合物c和4-羟基-2(5H)-呋喃酮加入二氧六环中,室温条件下,搅拌反应3~7d,加水静置,过滤、干燥得化合物d;所述的化合物c与4-羟基-2(5H)-呋喃酮的摩尔比为1:1~1.2;
(5)制备上述化合物e
将反应原料化合物c和加入至N,N-二甲基甲酰胺和甲醇体积比为1:4~5的混合溶液中,90~95℃条件下,反应24~48h得化合物e;所述化合物c与/>的摩尔比为1:1.3,其中R2选自甲氧基、乙氧基、正丙氧基、正丁氧基、异丙氧基或新戊氧基;
(6)制备上述化合物f
将化合物e/d、碳酸钾和四丁基碘化铵(TABI)加入乙腈中,室温条件下搅拌15~30min,再加入N-烷基化试剂,室温条件下,反应12~24h,经萃取、干燥、浓缩、柱分离得化合物f:所述化合物e/d、碳酸钾、四丁基碘化铵(TBAI)与N-烷基化试剂摩尔比为1:5:0.3:1.5~10。
所述步骤(5)N,N-二甲基甲酰胺和甲醇的混合溶液中N,N-二甲基甲酰胺和甲醇的体积比为1:4~5;所述步骤(6)中N-烷基化试剂选自硫酸二甲酯、硫酸二乙酯或溴苄。
当式Ⅰ结构始中R2选自氢,二甲胺亚甲基时,相应化合物的制备为:
所述制备上述化合物g
将化合物c和加入甲醇中,室温条件下,搅拌24~48h,经纯化得化合物g;所述化合物c与/>摩尔比为1:2.5~3,X选自氯或溴;
所述制备上述化合物h
将化合物d、碳酸钾和N,N-二甲基亚甲基碘化铵加入DME中,通入氮气,室温条件下,反应1.5~3h后得化合物h;所述化合物d、碳酸钾与N,N-二甲基亚甲基碘化铵的摩尔比为1:2~2.5:3~3.5。
所述的步骤(1)反应体系中5-硝基吲哚浓度为0.01mol/L;所述的步骤(2)反应体系中化合物a的浓度为0.5mol/L;所述的步骤(3)反应体系中化合物b的浓度为0.1mol/L;所述的步骤(4)、步骤(5)和制备化合物g的反应体系中化合物c的浓度为0.03~0.05mol/L;所述的步骤(6)和制备化合物h的反应体系中化合物d的浓度为0.01~0.03mol/L。
一种所述的4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物的应用,所述通式Ⅰ所示化合物在制备肝癌细胞和/或结肠癌细胞的增殖抑制中的应用。
通式Ⅰ所示化合物经细胞活性测试,对HepG2和Hep3B肝癌细胞半数抑制浓度分别达到0.9μmol、0.055μmol,对SW480、HCT116结肠癌细胞半数抑制浓度分别达到2.88μmol、0.47μmol,可以作为治疗肝癌和结肠癌的潜力备选化合物。
本发明所具有的优点:
本发明4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物是以5-硝基吲哚为原料经Vilsmeier-Haack反应、Knoevenagel缩合反应、还原反应及与粘氯酸的亲核反应合成了含2(5H)-呋喃酮的吲哚类化合物,通过细胞活性实验,可见所得化合物对结肠癌细胞和肝癌细胞具有显著的抑制作用,尤其是化合物M-44对Hep3B肝癌细胞的IC50值甚至达到了55nmol,具有成为治疗肝癌的小分子的潜力,本发明为此类作为一种可能的抗癌药物治疗肝癌和结肠癌提供了强有力的基础。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为市售。
化合物具体实施方式
实施例1 2-氰基-3-[5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物K-29)的制备
步骤1)在0℃下(冰水浴),量取21mL的N,N-二甲基甲酰胺于500mL反应瓶中,用滴液漏斗将5.6mL三氯氧磷缓慢滴加至反应瓶中(至少30min滴完),将5-硝基吲哚(9.8g,60.4mmol)溶于7mLN,N-二甲基甲酰胺中,通过滴液漏斗缓慢滴加至反应瓶中(至少10min滴完)。将混合物于35℃下搅拌60min,直至溶液变成粘稠状,加冰水溶解,加10%氢氧化钠溶液碱化,调PH至8-9,35℃继续回流30min,室温冷却,抽滤得粗品,乙酸乙酯重结晶得黄色固体化合物a 11.2g,收率97.5%。
步骤2)将化合物a(4.15g,21.82mmol)加入250mL圆底烧瓶中,再加入1.88g L-脯氨酸作为催化剂,最后加入40mL无水乙醇,室温下搅拌15min,缓慢滴加氰乙酸甲酯3.24g,在温度为78℃条件下搅拌反应1.2h,TLC点板监测,反应结束后冷却至室温,加入适量冷水析出产物,抽滤,再真空干燥,得黄色固体粉末化合物b 5.12g,收率为86.5%。
步骤3)称取化合物b(5.96g,21.97mmol)加入到500mL圆底烧瓶中,在加入200mL无水乙醇搅拌溶解,搅拌下加入还原铁粉(6.14g,0.11mol),称取氯化铵(11.75g,0.22mmol)于100mL烧杯中,加入60mL水搅拌溶解,再加反应瓶中,回流反应4h,TLC点板监测,反应完全,冷却至室温,用硅藻土过滤除去铁渣,用乙酸乙酯洗涤滤饼,回收滤液,水洗,饱和食盐水洗,有机相用无水硫酸镁干燥,过滤,经硅胶柱层析(DCM:MeOH=100:1,v/v)得黄色固体化合物c纯品4.10g,收率为77.4%。步骤4)称取化合物c(0.98g,4.06mmol)于250mL茄形瓶中,加120mL二氧六环溶剂,搅拌15min后,加入4-羟基-2(5H)-呋喃酮(0.41g,4.06mmol)于反应瓶中,室温搅拌6d,有黄色固体析出,原料基本反应完成后,边搅拌便加入等体积的水,抽滤得黄色固体(K-29)0.83g。收率63.4%。
ESI-MS m/z:346.0[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.57(s,1H),9.68(s,1H),8.63(s,1H),8.55(d,J=3.0Hz,1H),7.72(s,1H),7.55(d,J=8.6Hz,1H),7.12(dd,J=8.7,2.0Hz,1H),5.42(s,1H),4.87(s,2H),3.82(s,3H).13C-NMR(151MHz,DMSO)δ175.20,163.83,147.28,135.29,133.36,132.81,127.65,118.15,116.87,113.89,110.15,108.33,91.82,82.93,67.89,52.61.
实施例2 2-氰基-3-[6-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物C6)的制备
与实施例1不同之处在于:将实施例1步骤1中的原料5-硝基吲哚以6-硝基吲哚(9.8g,60.4mmol)替换按上述步骤反应,碱化后,乙酸乙酯萃取(20mL×3),有机相用饱和食盐水洗涤,无水硫酸镁干燥,过滤,蒸除溶剂,柱层析(石油醚:乙酸乙酯=5:1,v/v),得6-硝基吲哚-3-甲醛(7.37g,38.8mmol),收率64.2%。而后在L-脯氨酸催化作用下得6-硝基吲哚-3-丙烯酸甲酯(10.00g,36.87mmol)收率95.2%。再经还原铁粉、氯化铵作用将硝基还原得6-氨基吲哚-3-丙烯酸甲酯(4.05g,16.79mmol),收率45.6%。最后与4-羟基-2(5H)-呋喃酮经亲核取代反应得1.52黄色固体化合物C6,收率30.3%。
ESI-MS m/z:324.12[M-H]-,346.13[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.65(s,1H),10.21(s,1H),8.51(s,2H),7.94(d,J=8.6Hz,1H),7.45(s,1H),7.17–7.11(m,1H),5.26(s,1H),4.90(s,2H),3.82(s,3H).13C-NMR(151MHz,DMSO-d6)δ175.01,163.80,163.06,146.85,136.93,136.76,133.19,122.68,119.63,118.04,114.84,110.14,102.46,92.00,82.93,68.12,52.64.
实施例3 2-氰基-3-[7-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物C7)的制备
与实施例1不同之处在于:将实施例1步骤1中的原料5-硝基吲哚以7-硝基吲哚(9.8g,60.4mmol)替换按上述步骤反应,碱化后,乙酸乙酯萃取(20mL×3),有机相用饱和食盐水洗涤,无水硫酸镁干燥,过滤,蒸除溶剂,柱层析(石油醚:乙酸乙酯=5:1,v/v),得7-硝基吲哚-3-甲醛(5.58g,29.3mmol),收率48.6%。而后在L-脯氨酸催化作用下得7-硝基吲哚-3-丙烯酸甲酯7.35g,收率92.3%。再经还原铁粉、氯化铵作用将硝基还原得7-氨基吲哚-3-丙烯酸甲酯(2.43g,10.07mmol),收率37.2%。最后与4-羟基-2(5H)-呋喃酮经亲核取代反应得0.59g黄色固体化合物C7,收率18.1%。
ESI-MS m/z:324.12[M-H]-,346.13[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.27(s,1H),9.61(s,1H),8.61(s,1H),8.57(s,1H),7.80(d,J=7.8Hz,1H),7.27(t,J=7.7Hz,1H),7.22(d,J=7.5Hz,1H),4.94(s,2H),4.89(s,1H),3.83(s,3H).13C-NMR(151MHz,DMSO-d6)δ174.58,164.82,163.58,146.62,132.49,129.02,128.74,125.59,122.87,117.78,115.87,115.39,110.47,93.12,83.87,67.69,52.74.
实施例4 2-氰基-3-[5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸乙酯(化合物K-47)的制备
与实施例1不同之处在于:将实施例1步骤2中的原料氰基丙烯酸甲酯以氰基丙烯酸乙酯(3.70g,32.74mmol)替换按上述步骤制备获得5-硝基吲哚-3-丙烯酸乙酯(5.90g,20.68mmol),收率94.7%,再经还原铁粉、氯化铵作用将硝基还原得5-氨基吲哚-3-丙烯酸乙酯(4.93g,19.31mmol),收率93.3%。最后与4-羟基-2(5H)-呋喃酮经亲核取代反应得3.14g黄色固体化合物K-47,收率48.2%。
1H-NMR(600MHz,DMSO-d6)δ12.56(s,1H),9.69(s,1H),8.62(s,1H),8.55(d,J=3.2Hz,1H),7.71(d,J=1.6Hz,1H),7.55(d,J=8.6Hz,1H),7.12(dd,J=8.7,1.9Hz,1H),5.41(s,1H),4.87(s,2H),4.28(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).13C-NMR(151MHz,DMSO-d6)δ175.17,163.31,147.17,135.26,133.34,132.82,127.63,118.15,116.83,113.89,110.13,108.35,92.11,82.89,67.89,61.40,14.21.
实施例5 2-氰基-3-[1-乙基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物K-37)的制备
将化合物K-29(0.032g,0.1mmol),碳酸钾(0.074g,0.5mmol)和四丁基碘化铵(0.011g,0.03mmol)溶于3mL乙腈中,搅拌15min,再将硫酸二乙酯(0.154g,1mmol)溶于2mL乙腈,补加到反应体系,室温反应2.5h,TLC监测反应中无原料剩余,且有少量黄色固体析出,加20mL水搅拌,静置析出沉淀,抽滤并用水洗涤得0.027g黄色固体化合物K-37,收率79.4%。
1H-NMR(600MHz,DMSO-d6)δ9.73(s,1H),8.60(d,J=17.6Hz,2H),7.75(d,J=1.8Hz,1H),7.69(d,J=8.8Hz,1H),7.17(dd,J=8.8,2.0Hz,1H),5.46(s,1H),4.89(s,2H),4.41–4.36(m,2H),3.83(s,3H),1.43(t,J=7.2Hz,3H).13C-NMR(151MHz,DMSO-d6)δ175.18,163.86,163.35,146.60,135.67,134.85,132.53,128.38,118.08,116.80,112.48,109.27,108.53,91.61,83.15,67.90,52.63,41.97,15.03.
实施例6 2-氰基-3-[1-甲基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物K-40)的制备
与实施例5不同之处在于:将实施例5中原料硫酸二乙酯以硫酸二甲酯(0.037g,0.3mmol)替换按上述步骤制备获得0.027g黄色固体化合物K-40,收率81.7%。
1H-NMR(600MHz,DMSO-d6)δ9.72(s,1H),8.61(s,1H),8.54(s,1H),7.73(d,J=1.7Hz,1H),7.63(d,J=8.7Hz,1H),7.18(dd,J=8.8,1.9Hz,1H),5.45(s,1H),4.88(s,2H),3.96(s,3H),3.82(s,3H).13C-NMR(151MHz,DMSO-d6)δ175.17,163.86,163.35,146.51,136.34,135.71,133.55,128.20,118.03,116.76,112.46,109.06,108.33,91.50,83.14,67.90,52.62,33.99.
实施例7 2-氰基-3-[1-苄基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物K-38)的制备
与实施例5不同之处在于:将实施例5中原料硫酸二乙酯以苄溴(0.026g,0.15mmol)替换按上述步骤制备经硅胶柱层析(二氯甲烷:甲醇=80:1,v:v)纯化获得0.020g淡黄色固体化合物K-38,收率61.2%。
1H-NMR(600MHz,DMSO-d6)δ9.73(s,1H),8.69(s,1H),8.64(s,1H),7.74(d,J=1.7Hz,1H),7.62(d,J=8.8Hz,1H),7.37–7.33(m,2H),7.30(t,J=6.2Hz,3H),7.12(dd,J=8.8,1.9Hz,1H),5.63(s,2H),5.45(s,1H),4.87(s,2H),3.83(s,3H).13C-NMR(151MHz,DMSO-d6)δ175.16,163.73,146.61,136.36,135.73,135.52,132.73,128.83,128.45,127.95,127.34,117.86,116.89,112.83,109.58,108.44,92.42,83.23,67.89,52.69,50.25.
实施例8 2-氰基-3-[1-对氯苯基-5-(5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-49)的制备
将化合物K-29(0.1g,0.31mmol)溶于20mLN,N-二甲基甲酰胺中,冰浴条件下,加入氢化钠(0.008g,0.33mmol)于反应瓶中,搅拌30min,反应液由黄色变成红色,称量并加入4-氯苄溴(0.1g,0.46mmol),室温反应12h,TLC监测,待原料消耗完全,向反应液中补加乙酸乙酯,水洗,饱和食盐水洗,真空浓缩并硅胶柱层析(二氯甲烷:甲醇=50:1→30:1)得0.09g黄色固体(M-49),收率65.0%。
ESI-MS m/z:446.25[M-H]-,470.10[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ9.72(s,1H),8.70(s,1H),8.64(s,1H),7.74(s,1H),7.59(d,J=8.8Hz,1H),7.42(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),7.12(dd,J=8.8,1.8Hz,1H),5.64(s,2H),5.47(s,1H),4.87(s,2H),3.83(s,3H).13C-NMR(151MHz,DMSO-d6)δ175.16,163.70,146.55,135.78,135.48,135.40,132.60,132.57,129.22,128.80,128.46,117.81,116.92,112.76,109.67,108.43,92.61,83.26,67.90,52.69,49.51.
实施例9 2-氰基-3-[5-(4-溴-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-34)的制备
将实施例1步骤3中的化合物c(0.2g,0.83mmol)溶于30mL甲醇中,再补加3,4-二溴呋喃-2(5H)酮(0.6g,2.49mmol),室温搅拌24h,有大量黄色固体析出,待原料反应完全后,加水于反应液中,抽滤得粗品,乙酸乙酯打浆得纯品0.21g化合物(M-34)。收率63.6%。
ESI-MS m/z:402.14[M]-,424.02[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.59(s,1H),8.63(s,1H),8.60(d,J=3.1Hz,1H),7.95(s,1H),7.57(d,J=8.6Hz,1H),7.21(dd,J=8.6,1.6Hz,1H),5.05(s,2H),3.83(s,3H).13C-NMR(151MHz,DMSO-d6)δ169.78,163.67,162.40,146.81,134.10,133.36,132.77,127.53,120.39,118.04,113.56,113.48,110.16,92.40,72.90,67.19,52.66.
实施例10 2-氰基-3-[5-(4-氯-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-50)的制备
与实施例9不同之处在于:将实施例9中原料3,4-二溴呋喃-2(5H)-酮以3,4-二氯呋喃-2(5H)-酮(0.35g,2.07mmol)替换按上述步骤制备获得0.15g黄色固体化合物(M-50),收率47.5%。
ESI-MS m/z:356.09[M-H]-,380.00[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.69(s,1H),8.65–8.58(m,2H),7.91(d,J=1.5Hz,1H),7.56(d,J=8.6Hz,1H),7.20(dd,J=8.6,1.9Hz,1H),5.08(s,2H),3.82(s,3H).13C-NMR(151MHz,DMSO-d6)δ169.21,163.69,159.53,146.81,133.98,133.37,132.89,127.55,120.02,118.05,113.59,112.92,110.14,92.36,85.51,66.11,52.66.
实施例11 2-氰基-3-[5-(4-(二甲基氨基)甲基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-35)的制备
将实施例1中的化合物K-29(0.2g,0.62mmol),碳酸钾(0.17g,1.24mmol)和N,N-二甲基亚甲基碘化铵(0.34g,1.86mmol)于100mL双颈瓶中,补加乙二醇二甲醚40mL,氮气氛围下,室温搅拌1.5h,待原料消耗完全,向反应液中补加乙酸乙酯,将有机相用水洗3次,饱和食盐水洗2次,加无水硫酸钠干燥并过滤,真空浓缩后,加甲醇溶解固体,适当的补加水,析出黄色固体抽滤并干燥得0.16g淡黄色固体(M-35),收率68.0%。
ESI-MS m/z:379.30[M-H]-,381.20[M+H]+.
1H-NMR(600MHz,DMSO-d6)δ8.61(d,J=26.3Hz,2H),7.89(s,1H),7.54(d,J=8.5Hz,1H),7.12(d,J=8.1Hz,1H),4.97(s,2H),3.82(s,3H),3.09(s,2H),2.16(s,6H).
实施例12 2-氰基-3-[5-(4-氯-2-甲氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-38)的制备
步骤1)将3,4-二氯-5-羟基-5H-呋喃-2-酮(粘氯酸)(0.5g,2.96mmol)溶于55mL甲苯,补加浓硫酸相当于0.25当量,搅拌15min后,向反应液中补加甲醇(1.42g,44.39mmol),回流12h,待原料消耗完全后,真空浓缩,硅胶柱层析(PE:EA=10:1v:v)得0.32g油状液体3,4-二氯-5-甲氧基呋喃酮,收率58.2%。
步骤2)将实施例1步骤3中的化合物c(0.32g,1.33mmol)溶于甲醇和N,N-二甲基甲酰(v:v=2:1)混合溶液中,再补加3,4-二氯-5-甲氧基呋喃酮(0.32g,1.75mmol)于反应瓶中,90℃回流24h,TLC监测,待原料消耗完全,向反应液中补加乙酸乙酯,摇匀,将有机相用水洗3次,饱和食盐水洗2次,无水硫酸镁干燥并过滤,真空浓缩得粗品,乙酸乙酯打浆得0.26g黄色固体化合物(M-38),收率50.6%。
ESI-MS m/z:386.19[M-H]-,410.07[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.85(s,1H),8.60(s,2H),7.88(s,1H),7.60–7.52(m,1H),7.17(d,J=8.5Hz,1H),6.29(s,1H),3.83(s,3H),3.34(s,3H).13C-NMR(151MHz,DMSO)δ167.03,163.72,146.65,134.07,133.40,132.39,127.18,120.67,118.03,113.79,113.12,110.12,98.03,92.28,87.02,54.63,52.67.
实施例13 2-氰基-3-[5-(4-氯-2-乙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-39)的制备
与实施例12不同之处在于:将实施例12中原料甲醇以无水乙醇(2.05g,44.39mmol)替换按上述步骤制备获得(0.42g,2.18mmol)油状液体3,4-二氯-5-乙氧基呋喃酮,收率72.0%。而后按上述步骤与化合物c(0.34g,1.41mmol)发生亲核取代再加成反应制备获得0.27g黄色固体化合物(M-39),收率47.7%。
ESI-MS m/z:400.20[M-H]-,424.08[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.80(s,1H),8.62(s,1H),8.60(d,J=3.0Hz,1H),7.89(s,1H),7.56(d,J=8.6Hz,1H),7.17(dd,J=8.6,1.6Hz,1H),6.33(s,1H),3.83(s,3H),3.45(dd,J=14.0,7.1Hz,2H),0.91(t,3H).13C-NMR(151MHz,DMSO-d6)δ167.08,163.72,146.70,134.07,133.36,132.55,127.22,120.87,118.05,113.95,113.09,110.12,97.40,92.31,64.19,52.68,14.66.
实施例14 2-氰基-3-[5-(4-氯-2-异丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-40)的制备
与实施例12不同之处在于:将实施例12中原料甲醇以异丙醇(2.67g,44.39mmol)替换按上述步骤制备获得(0.41g,1.93mmol)油状液体3,4-二氯-5-异丙氧基呋喃酮,收率65.7%。而后按上述步骤与化合物c(0.31g,1.28mmol)发生亲核取代再加成反应制备获得0.32g黄色固体化合物(M-40),收率77.0%。
ESI-MS m/z:414.22[M-H]-,438.09[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.71(s,1H),8.65(s,1H),8.60(d,J=3.1Hz,1H),7.93(s,1H),7.56(d,J=8.6Hz,1H),7.17(dd,J=8.6,1.7Hz,1H),6.44(s,1H),3.83(s,3H),3.67(s,1H),1.02(d,J=6.1Hz,3H),0.62(t,3H).13C-NMR(151MHz,DMSO)δ167.07,163.70,146.78,134.05,133.32,132.82,127.32,121.01,118.06,114.03,113.12,110.11,96.89,92.29,86.98,73.11,52.66,22.89,21.40.
实施例15 2-氰基-3-[5-(4-氯-2-正丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-41)的制备
与实施例12不同之处在于:将实施例12中原料甲醇以正丙醇(2.67g,44.39mmol)替换按上述步骤制备获得(0.38g,1.80mmol)油状液体3,4-二氯-5-正丙氧基呋喃酮,收率60.8%。而后按上述步骤与化合物c(0.29g,1.20mmol)发生亲核取代再加成反应制备获得0.32g黄色固体化合物(M-41),收率63.3%。
ESI-MS m/z:414.22[M-H]-,438.10[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.79(s,1H),8.63(s,1H),8.60(d,J=3.1Hz,1H),7.91(s,1H),7.55(d,J=8.6Hz,1H),7.18(dd,J=8.6,1.6Hz,1H),6.39(s,1H),3.83(s,3H),3.58–3.34(m,2H),1.30(dd,J=12.5,5.8Hz,2H),0.61–0.48(m,3H).13C-NMR(151MHz,DMSO)δ166.98,163.71,146.72,134.06,133.35,132.71,127.30,120.69,118.05,113.70,113.13,110.11,97.47,92.25,87.07,69.90,52.66,22.01,10.00.
实施例16 2-氰基-3-[5-(4-氯-2-正丁氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-42)的制备
与实施例12不同之处在于:将实施例12中原料甲醇以正丁醇(3.29g,44.39mmol)替换按上述步骤制备获得(0.46g,2.05mmol)油状液体3,4-二氯-5-正丁氧基呋喃酮,收率69.1%。而后按上述步骤与化合物c(0.33g,1.37mmol)发生亲核取代再加成反应制备获得0.23g黄色固体化合物(M-42),收率53.5%。
ESI-MS m/z:428.26[M-H]-,452.12[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.79(s,1H),8.63(s,1H),8.60(d,J=3.0Hz,1H),7.92(s,1H),7.56(d,J=8.6Hz,1H),7.17(dd,J=8.6,1.6Hz,1H),6.40(s,1H),3.83(s,3H),3.55(t,J=6.3Hz,2H),1.20(s,2H),0.92(d,J=40.8Hz,2H),0.59(t,J=7.1Hz,3H).13C-NMR(151MHz,DMSO)δ166.96,163.71,146.77,134.10,133.35,132.76,127.34,120.72,118.06,113.75,113.16,110.15,97.44,92.24,87.08,68.10,52.66,30.65,18.16,13.31.
实施例17 2-氰基-3-[5-(4-氯-2-新戊氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-44)的制备
与实施例12不同之处在于:将实施例12中原料甲醇以新戊醇(3.91g,44.39mmol)替换按上述步骤制备获得(0.53g,2.18mmol)油状液体3,4-二氯-5-新戊氧基呋喃酮,收率75.0%。而后按上述步骤与化合物c(0.35g,1.45mmol)发生亲核取代再加成反应制备获得0.35g黄色固体化合物(M-44),收率54.3%。
ESI-MS m/z:442.30[M-H]-,466.15[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ12.59(s,1H),9.77(s,1H),8.63(s,1H),8.60(d,J=3.0Hz,1H),7.95(s,1H),7.55(d,J=8.6Hz,1H),7.19(dd,J=8.6,1.6Hz,1H),6.49(s,1H),3.83(s,3H),3.24(d,J=8.4Hz,1H),2.95(d,J=8.2Hz,1H),0.56(s,9H).13C-NMR(151MHz,DMSO-d6)δ166.85,163.72,146.77,134.06,133.38,132.97,127.44,120.50,118.07,113.44,113.22,110.11,97.26,92.20,87.35,77.39,52.64,30.99,25.94.
实施例18 2-氰基-3-[1-甲基-5-(4-氯-2-异丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-43)的制备
与实施例6不同之处在于:将实施例6中原料K-29以化合物M-40(0.042g,0.1mmol)替换按上述步骤制备经硅胶柱层析(二氯甲烷:甲醇=100:1→50:1,v:v)纯化获得0.016g黄色固体化合物(M-43),收率36.7%。
ESI-MS m/z:428.28[M-H]-,452.12[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ9.73(s,1H),8.60(s,1H),8.57(s,1H),7.93(s,1H),7.64(d,J=8.7Hz,1H),7.23(dd,J=8.7,1.9Hz,1H),6.46(s,1H),3.98(s,3H),3.82(s,3H),3.72(s,1H),1.03(d,J=6.1Hz,3H),0.67(s,3H).
实施例19 2-氰基-3-[1-苄基-5-(4-氯-2-乙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-45)的制备
与实施例7不同之处在于:将实施例7中原料K-29以化合物M-39(0.040g,0.1mmol)替换按上述步骤经硅胶柱层析(二氯甲烷:甲醇=100:1→50:1,v:v)纯化制备获得0.016g黄色固体化合物(M-45),收率32.9%。
ESI-MS m/z:490.26[M-H]-,514.18[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ9.81(s,1H),8.73(s,1H),8.60(s,1H),7.91(s,1H),7.62(d,J=8.7Hz,1H),7.35(t,J=7.4Hz,2H),7.29(t,J=9.2Hz,3H),7.18(dd,J=8.7,1.7Hz,1H),6.34(s,1H),5.66(s,2H),3.83(s,3H),3.61(dt,J=14.1,7.0Hz,1H),3.44–3.38(m,1H),0.84(t,J=6.3Hz,3H).
实施例20 2-氰基-3-[1-苄基-5-(4-氯-2-正丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-46)的制备
与实施例7不同之处在于:将实施例7中原料K-29以化合物M-41(0.042g,0.1mmol)替换按上述步骤制备经硅胶柱层析(二氯甲烷:甲醇=100:1→50:1,v:v)纯化获得0.017g黄色固体化合物(M-46),收率32.9%。
ESI-MS m/z:504.28[M-H]-,528.21[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ9.80(s,1H),8.73(s,1H),8.62(s,1H),7.95(s,1H),7.62(d,J=8.8Hz,1H),7.35(t,J=7.3Hz,2H),7.31–7.26(m,3H),7.20(dd,J=8.7,1.9Hz,1H),6.42(s,1H),5.66(s,2H),3.83(s,3H),3.51(dt,J=9.1,6.3Hz,1H),3.28–3.22(m,1H),1.21(d,J=7.7Hz,2H),0.44(t,J=6.6Hz,3H).13C-NMR(151MHz,DMSO-d6)δ166.92,163.63,145.97,136.39,135.52,134.01,133.30,128.80,128.10,127.94,127.26,120.68,117.78,113.72,112.16,109.60,97.49,92.90,87.39,70.04,52.74,50.29,21.93,9.91.
实施例21 2-氰基-3-[1-苄基-5-(4-氯-2-异丙氧基-5-氧亚基-2,5-二氢呋喃)氨基]-1H-吲哚-3-基丙烯酸甲酯(化合物M-47)的制备
与实施例7不同之处在于:将实施例7中原料K-29以化合物M-40(0.042g,0.1mmol)替换按上述步骤制备经硅胶柱层析(二氯甲烷:甲醇=100:1→50:1,v:v)纯化获得0.018g黄色固体化合物(M-47),收率35.4%。
ESI-MS m/z:504.27[M-H]-,527.23[M+Na]+.
1H-NMR(600MHz,DMSO-d6)δ9.74(s,1H),8.74(s,1H),8.64(s,1H),7.96(d,J=2.0Hz,1H),7.62(d,J=8.7Hz,1H),7.34(t,J=7.3Hz,2H),7.29(t,J=7.3Hz,1H),7.24(d,J=7.2Hz,2H),7.19(dd,J=8.8,1.9Hz,1H),6.44(s,1H),5.68(s,2H),3.84(s,3H),3.64–3.57(m,1H),0.99(d,J=6.1Hz,3H),0.51(s,3H).13C-NMR(151MHz,DMSO-d6)δ167.02,163.61,146.02,136.44,135.53,134.05,133.37,128.78,128.11,127.89,127.12,121.11,117,77,114.21,112.18,109.61,96.93,92.97,87.24,73.19,52.73,50.28,22.87,21.26.
本发明产物的药理研究。
将2mL的0.25%胰酶溶液预先在37℃水浴中加热,选取对数期生长的HepG2细胞、Hep3B细胞、SW480细胞和HCT116细胞,并移除其培养液,加入消化液盖住细胞,静置,显微镜下观察待细胞间隙明显时,加入培养液终止消化。轻轻吹打细胞至脱落,形成细胞悬液后转移至离心管内离心,除去上清,用含大约10mL血清培养基(4.5g/L高糖DMEM+10%胎牛血清+1%青霉素100U/mL+1%链霉素100U/mL)重悬后接种于细胞培养皿中,于37℃、5% CO2培养箱中培养,并定期更换培养液。
将化合物以100μmol 4倍系列稀释,共制备6个浓度梯度备用。消化并稀释对数期生长的HepG2细胞、Hep3B细胞、SW480细胞和HCT116细胞,种于96孔板中,密度为1×104个/孔,每孔加入100μL培养液(10%FBS DMEM),于37℃、5% CO2培养箱中培养24h。弃去上清液,加入100μL培养液(3%FBS DMEM)作为对照组,实验组分别加入100μL含以上浓度梯度化合物的培养液(3%FBS DMEM),继续培养48h。然后在避光状态下,每孔加入20μL的MTT溶液(5mg/mL),37℃、5% CO2条件下培继续孵育4h,孵育结束后,吸除上清,并于每孔中加入150μL DMSO,震荡5min至蓝紫色结晶完全溶解后,于酶标仪490nm处测定吸光值。绘制曲线,计算出不同化合物对HepG2细胞、Hep3B细胞、SW480细胞和HCT116细胞的IC50值。其结果如下表一、表二、表三、表四所示。
表一部分化合物对HepG2细胞细胞毒性测试结果(IC50值)
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表二部分化合物对Hep3B细胞的细胞毒性测试结果(IC50值)
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表三部分化合物对SW480细胞的细胞毒性测试结果(IC50值)
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表四部分化合物对HCT116细胞的细胞毒性测试结果(IC50值)
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Claims (3)
1.一种4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物,其特征在于:化合物为下述结构之一;
2.一种权利要求1所述的4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物的应用,其特征在于:所述化合物M40、M41、M43、M44、K37、K40、K47在制备肝癌细胞的增殖抑制药物中的应用。
3.一种权利要求1所述的4-(1H-吲哚-5-基)氨基呋喃-2(5H)-酮类化合物的应用,其特征在于:所述化合物M38、M39、M40、M41、M42、K38在制备结肠癌细胞的增殖抑制药物中的应用。
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