CN118165008A - 二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2h)-酮类化合物及其制备方法和抗肿瘤应用 - Google Patents
二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2h)-酮类化合物及其制备方法和抗肿瘤应用 Download PDFInfo
- Publication number
- CN118165008A CN118165008A CN202410305599.3A CN202410305599A CN118165008A CN 118165008 A CN118165008 A CN 118165008A CN 202410305599 A CN202410305599 A CN 202410305599A CN 118165008 A CN118165008 A CN 118165008A
- Authority
- CN
- China
- Prior art keywords
- compound
- dibenzo
- chloroform
- nmr
- trifluoromethyl
- 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.)
- Pending
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 239000003960 organic solvent Substances 0.000 claims abstract description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 229910052786 argon Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 230000008569 process Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 201000007270 liver cancer Diseases 0.000 claims description 8
- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 2
- 238000005292 vacuum distillation Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 14
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 28
- -1 ruthenium propiolate Chemical compound 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000012512 characterization method Methods 0.000 description 22
- 238000005259 measurement Methods 0.000 description 22
- 238000002844 melting Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- 239000000843 powder Substances 0.000 description 22
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 5
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-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
- 201000011510 cancer Diseases 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 2
- 102000003915 DNA Topoisomerases Human genes 0.000 description 2
- 108090000323 DNA Topoisomerases Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 102000005497 Thymidylate Synthase Human genes 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- LZSYGJNFCREHMD-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)benzene Chemical compound BrCC1=CC=CC=C1Br LZSYGJNFCREHMD-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010061968 Gastric neoplasm Diseases 0.000 description 1
- 239000012825 JNK inhibitor Substances 0.000 description 1
- 102100024930 Melatonin receptor type 1A Human genes 0.000 description 1
- 101710098568 Melatonin receptor type 1A Proteins 0.000 description 1
- 102100024970 Melatonin receptor type 1B Human genes 0.000 description 1
- 101710098567 Melatonin receptor type 1B Proteins 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 239000012327 Ruthenium complex Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 208000026500 emaciation Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Abstract
本发明公开了一类二苯并‑1,3‑氧氮杂环戊烷并异喹啉‑1(2H)‑酮类化合物及其制备方法和抗肿瘤应用,该化合物的结构式为或式中R1、R2、R3各自独立的代表H、C1~C4烷基、C1~C4烷氧基、三氟甲基、氟、氯中任意一种。其制备方法为:将3‑联苯基‑1‑羟乙基吡啶‑2(1H)‑酮类化合物和盐酸溶解在甲苯等有机溶剂中,在氩气保护下用紫外光辐射,反应结束后分离纯化,即得到目标化合物的纯品。本发明合成方法具有工艺简便、操作简单、产品产率高和生产成本低等优点,所得化合物具有良好抗肿瘤细胞活性效果,可开发为具有抗肿瘤细胞活性的新型医药产品。
Description
技术领域
本发明属于杂环化合物技术领域,具体涉及一类二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物,以及该化合物的制备方法和在制备抗肿瘤药物中的应用。
背景技术
异喹啉-1(2H)-酮通常被认为是天然产物化学中具有重要生物活性的骨架结构,在一些天然产物中含有异喹啉-1(2H)-酮类化合物的结构片段,其具有广泛的生理活性,可作NK3拮抗剂、褪黑素MT1和MT2受体激动剂、Rho激酶抑制剂、JNK抑制剂、HT3拮抗剂和胸苷酸合成酶(TS)抑制剂,并显示出较好的抗肿瘤活性。1995年,Monroe Wall等人首次从植物中发现一种名为喜书碱(Camptothecin)的生物碱,该生物碱含有异喹啉-1(2H)-酮骨架并被发现具有抑制拓扑异构酶Ⅰ活性的作用,还对大肠癌、乳腺癌、肺癌和卵巢癌均有较强的抗肿瘤活性,可用于抗肿瘤药物的研究。另外,玫瑰花素对拓扑异构酶Ⅰ(top1)也有显著的抑制活性和抗高血压活性;异喹啉-1(2H)-酮结构片段还存在治疗胃肿瘤和人脑细胞疾病的药物中。异喹啉-1(2H)-酮类化合物的生物学特性刺激了研究人员开发各种合成的方法。
2013年,Fan课题组发展了一种以2-溴苄溴和氰乙酰胺为起始原料,以乙二醇为溶剂,在100℃的温度下,通过铜催化的酰胺N-芳基化反应高效合成了3-氰基异喹啉-1(2H)-酮类化合物。2014年,Jeganmohan研究小组发展了萘胺与丙炔酸酯钌催化的氧化环化反应。该反应是以萘胺和丙炔酸酯为起始原料,以钌配合物作催化剂,在六氟锑酸银、二甲基丙酸的作用下,以异丙醇为溶剂,130℃反应24小时,发生环化反应得到苯并异喹啉-1(2H)-酮类化合物。2018年,Cho课题组利用弱碱促进微波辐射下的内酰胺环化反应合成了苯并异喹啉-1(2H)-酮类化合物。该方法以内酰胺化合物为原料,以碳酸钾作碱,N,N-二甲基甲酰胺为溶剂,150℃条件下进行微波辐射,通过自由基环化的反应进行。这些方法需要昂贵的过渡金属或者强酸作催化剂,回收难而且会对环境造成污染。
肿瘤是一种会危害身体健康,使机体组织受损,发生疼痛感染,导致器官功能下降,甚至造成生命危险疾病。肿瘤分良性肿瘤和恶性肿瘤。良性肿瘤对身体危害性比较小,一般会有压迫和阻塞的现象。但是恶性肿瘤危害性比较大,会使组织结构受到严重破坏,器官功能下降,抵抗力低下,机体疼痛发热感染,发生恶液质的变化,造成极度消瘦,各系统功能衰竭导致死亡。肿瘤对人体的伤害极大,因此,科学家们不断研制出许多抗肿瘤的药物,但是一些药物会对人体产生许多副作用,伤害人体,所以迫切需要新的更安全更高效的抗肿瘤活性药品来取代。
发明内容
本发明的目的在于提供一类具有抗肿瘤细胞活性的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物。
本发明的另一个目的在于提供一种以3-联苯基-1-羟乙基吡啶-2(1H)-酮类化合物为原料制备二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物的方法。
本发明的进一步目的在于提供一种二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物的应用。
针对上述目的,本发明提供的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物的结构式如下所示:
式中R1、R2、R3各自独立的代表H、C1~C4烷基、C1~C4烷氧基、三氟甲基、氟、氯中任意一种。优选R1代表氢、甲基、甲氧基、氯、三氟甲基中任意一种,R2代表氢、甲基、甲氧基、三氟甲基、氟中任意一种,R3代表氢、三氟甲基、甲氧基中任意一种。
本发明的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物进一步优选
上述二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物的制备方法为:将式I所示的3-联苯基-1-羟乙基吡啶-2(1H)-酮类化合物和盐酸溶解在有机溶剂中,在氩气保护及300~365nm的紫外光辐射下反应30~90分钟,反应结束后,将反应液减压蒸馏后经柱层析分离提纯,得到二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物;
上述制备方法中,优选3-联苯基-1-羟乙基吡啶-2(1H)-酮类化合物与盐酸中HCl的摩尔比为1:1~2。
上述制备方法中,优选有机溶剂为甲苯、二氯甲烷、二氧六环中任意一种。
本发明的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物对白血病细胞HL-60、肺癌细胞A549、肝癌细胞SMMC-7721、乳腺癌细胞MDA-MB-231表现出良好的抑制效果,可用于制备抗肿瘤药物,按常规药用制剂,与药学上可接受的载体按照各种制剂的常规制备工艺制成,可以是片剂、颗粒剂、胶囊剂等。所述的肿瘤为白血病、肺癌、肝癌、乳腺癌中任意一种。
本发明的有益效果如下:
1、本发明二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物均具有较强的抗肿瘤细胞活性。以商业化顺铂为对照,本发明化合物2b-α、2b-β对白血病细胞HL-60、肺癌细胞A549、肝癌细胞SMMC-7721表现出良好的抑制效果,2j-β对肝癌细胞SMMC-7721、乳腺癌细胞MDA-MB-231有明显抑制效果,2k-α对乳腺癌细胞MDA-MB-231有抑制效果。而且从实验数据上看,针对这4种肿瘤细胞,本发明二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物中的一些化合物的抑制活性高于或者与顺铂相似,若将它们用于制备抗肿瘤细胞的药品,预期将会有较好的治疗肿瘤效果。
2、本发明采用廉价易得的3-联苯基-1-羟乙基吡啶-1(2H)-酮类化合物为原料,用廉价盐酸做催化剂,利用光化学反应合成一系列二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物,具有合成路线短、工艺简便、所用的设备简单、产品的收率高、生产成本低和环保等优点。
具体实施方式
下面结合实施例对本发明进一步详细说明,但本发明的保护范围不仅限于这些实施例。
实施例1
在光反应管中加入59.2g(0.2mol)3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮、0.3L 1mol/L的盐酸水溶液和40L甲苯,在氩气保护及搅拌下用313nm的紫外光辐射1小时,反应结束后,将反应液减压蒸馏后经柱层析分离提纯(洗脱剂为CH2Cl2与CH3OH体积比20:1的混合液),得到化合物2a-α和2a-β纯品,产率分别为38%和36%。
化合物2a-α为白色粉末;熔点198.5-199.0℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.79(dd,J=17.2,7.6Hz,2H),7.40-7.34(m,3H),7.34-7.27(m,3H),4.62(dd,J=5.2,4.1Hz,1H),4.27-7.15(m,1H),4.12-4.04(m,1H),3.92(d,J=5.4Hz,1H),3.80(q,J=8.4Hz,1H),3.56-3.43(m,1H),3.35-3.31(m,1H),2.41-2.29(m,1H),2.10(dt,J=14.7,4.3Hz,1H);13C NMR(151MHz,Chloroform-d)δ169.3,136.1,133.3,132.9,131.6,128.4,128.2,128.1,128.0,127.9,127.1,124.4,123.8,85.2,63.9,46.8,42.8,33.5,28.9;HRMS(ESI):m/z[M+Na]+理论值C19H17NO2 Na:314.1152;实测值:314.1158。
化合物2a-β为白色粉末;熔点175.6-176.3℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.78(t,J=6.9Hz,2H),7.63(d,J=7.7Hz,1H),7.43-7.32(m,2H),7.32-7.22(m,3H),4.83(dd,J=9.4,4.9Hz,1H),4.16-4.05(m,1H),4.03-3.93(m,2H),3.89(q,J=8.3Hz,1H),3.57-3.46(m,1H),3.36-3.21(m,1H),2.14-2.00(m,1H),1.82-1.69(m,1H);13C NMR(151MHz,Chloroform-d)δ167.5,136.7,133.1,132.8,131.4,128.4,128.2,128.1,127.9,127.7,127.5,124.1,124.0,86.7,64.7,44.7,42.3,36.0,29.7;HRMS(ESI):m/z[M+Na]+理论值C19H17NO2Na:314.1152;实测值:314.1156。
实施例2
本实施例中,用等摩尔3-(4'-甲氧基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2b-α和2b-β纯品,产率均为34%。
化合物2b-α为白色粉末;熔点167.8-168.4℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.74(dd,J=23.0,8.1Hz,2H),7.35(d,J=8.0Hz,2H),7.28(d,J=8.1Hz,1H),6.92(dd,J=8.6,2.4Hz,1H),6.88(d,J=2.3Hz,1H),4.70-4.62(m,1H),4.28-4.20(m,1H),4.14-4.05(m,1H),3.93(d,J=5.2Hz,1H),3.90-3.81(m,4H),3.48-3.40(m,1H),3.36-3.28(m,1H),2.36-2.27(m,1H),2.15-2.06(m,1H);13C NMR(151MHz,Chloroform-d)δ169.5,159.6,137.8,132.9,130.7,128.2,127.9,127.3,126.0,125.7,123.1,113.2,112.6,85.1,63.8,55.3,46.8,42.7,33.9,28.8;HRMS(ESI):m/z[M+Na]+理论值C20H19NO3Na:344.1258;实测值:344.1255。
化合物2b-β为白色粉末;熔点150.2-150.8℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.64(dd,J=15.3,7.9Hz,2H),7.52(d,J=7.2Hz,1H),7.28-7.14(m,2H),6.84(d,J=7.3Hz,1H),6.71(s,1H),4.88-4.68(m,1H),4.14-4.00(m,1H),3.96-3.68(m,6H),3.50-3.39(m,1H),3.16(d,J=10.7Hz,1H),1.99(d,J=10.7Hz,1H),1.70(q,J=12.3Hz,1H);13CNMR(151MHz,Chloroform-d)δ167.6,159.6,138.3,132.8,130.6,127.7,127.5,127.4,126.0,125.5,123.3,113.6,113.1,86.7,64.7,55.4,44.8,42.3,36.5,29.7;HRMS(ESI):m/z[M+Na]+理论值C20H19NO3Na:344.1258;实测值:344.1254。
实施例3
本实施例中,用等摩尔3-(4'-三氟甲基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2c-α和2c-β纯品,产率分别为30%和32%。
化合物2c-α为白色粉末;熔点178.8-179.5℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.90(d,J=8.0Hz,1H),7.80(d,J=7.4Hz,1H),7.61(d,J=8.0Hz,1H),7.58(s,1H),7.44-7.35(m,3H),4.67-4.56(m,1H),4.27-4.15(m,1H),4.09(q,J=8.1Hz,1H),3.94(d,J=5.1Hz,1H),3.83(q,J=7.8Hz,1H),3.59-3.50(m,1H),3.34-3.25(m,1H),2.42-2.30(m,1H),2.13(d,J=14.8Hz,1H);13C NMR(151MHz,Chloroform-d)δ168.7,136.8(q,J=8.8Hz),132.1,131.6,129.7(q,J=33.4Hz),129.4,128.7,128.3,128.0(q,J=25.8Hz),124.8(q,J=3.4Hz),124.7,124.4,124.1,124.0(q,J=272.3Hz),85.0,63.9,46.5,42.8,33.5,28.6;HRMS(ESI):m/z[M+Na]+理论值C20H16F3NO2Na:382.1026;实测值:382.1022。
化合物2c-β为白色粉末;熔点187.2-187.7℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.89(d,J=8.2Hz,1H),7.81(d,J=7.4Hz,1H),7.67(d,J=7.5Hz,1H),7.62(d,J=7.9Hz,1H),7.53(s,1H),7.43-7.33(m,2H),4.87(dd,J=9.3,4.9Hz,1H),4.15-4.07(m,1H),4.02-3.95(m,2H),3.92(q,J=8.1Hz,1H),3.58-3.47(m,1H),3.43-3.33(m,1H),2.15-2.05(m,1H),1.87-1.72(m,1H);13C NMR(151MHz,Chloroform-d)δ167.0,137.2,136.6,132.0,131.6,130.0(q,J=33.0Hz),129.6,128.1,127.9,125.0(q,J=3.9Hz),124.9(q,J=4.1Hz),124.6,124.5,124.0(q,J=271.9Hz),86.6,64.8,44.5,42.4,36.0,29.5;HRMS(ESI):m/z[M+Na]+理论值C20H16F3NO2Na:382.1026;实测值:382.1024。
实施例4
本实施例中,用等摩尔3-(4'-氯-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2d-α和2d-β纯品,产率分别为32%和31%。
化合物2d-α为白色粉末;熔点159.7-160.5℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.73(d,J=7.6Hz,2H),7.40-7.30(m,5H),4.63(t,J=4.7Hz,1H),4.24-4.15(m,1H),4.11-4.06(m,1H),3.90(d,J=5.4Hz,1H),3.82(q,J=8.3Hz,1H),3.49-3.42(m,1H),3.33-3.25(m,1H),2.39-2.29(m,1H),2.10(dt,J=14.6,4.4Hz,1H);13C NMR(151MHz,Chloroform-d)δ168.8,137.8,133.7,132.0,131.9,131.5,128.7,128.5,128.2,128.1,127.1,125.8,123.8,85.0,64.0,46.5,42.8,33.4,28.7;HRMS(ESI):m/z[M+Na]+理论值C19H16ClNO2Na:348.0762;实测值:348.0753。
化合物2d-β为白色粉末;熔点145.5-146.0℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.65(t,J=8.0Hz,2H),7.56(d,J=7.6Hz,1H),7.32-7.20(m,3H),7.19(s,1H),4.77(dd,J=9.3,4.8Hz,1H),4.08-4.00(m,1H),3.96-3.81(m,3H),3.49-3.40(m,1H),3.27-3.17(m,1H),2.10-1.98(m,1H),1.77-1.67(m,1H);13C NMR(151MHz,Chloroform-d)δ167.2,138.3,133.7,131.91,131.7,131.2,128.8,128.3,127.9,127.8,127.7,125.6,124.0,86.6,64.8,44.6,42.4,35.9,29.5;HRMS(ESI):m/z[M+Na]+理论值C19H16ClNO2Na:348.0762;实测值:348.0753。
实施例5
本实施例中,用等摩尔3-(3'-甲氧基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2e-α和2e-β纯品,产率分别为34%和32%。
化合物2e-α为白色粉末;熔点131.2-131.8℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.67(d,J=7.7Hz,1H),7.31-7.28(m,2H),7.27-7.24(m,2H),7.18(d,J=9.0Hz,1H),6.80-6.76(m,1H),4.56(t,J=4.5Hz,1H),4.14-4.08(m,1H),4.04-3.98(m,1H),3.80(s,3H),3.73(d,J=7.9Hz,1H),3.58(s,1H),3.42-3.34(m,1H),3.27-3.17(m,1H),2.33-2.25(m,1H),2.03-1.97(m,1H);13C NMR(151MHz,Chloroform-d)δ169.4,159.4,134.5,132.9,132.8,132.0,128.7,128.3,128.0,127.9,123.8,113.5,110.0,85.2,63.9,55.4,47.0,42.8,32.8,29.1;HRMS(ESI):m/z[M+Na]+理论值C20H19NO3Na:344.1258;实测值:344.1260。
化合物2e-β为白色粉末;熔点129.2-129.8℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.75(d,J=7.3Hz,1H),7.62(d,J=7.3Hz,1H),7.40-7.27(m,3H),7.18(d,J=8.0Hz,1H),6.86(d,J=7.8Hz,1H),4.83(dd,J=8.0,4.2Hz,1H),4.11(s,1H),4.02-3.96(m,1H),3.95-3.89(m,1H),3.88(s,3H),3.65(s,1H),3.55-3.48(m,1H),3.25(d,J=14.2Hz,1H),2.03(d,J=11.7Hz,1H),1.73(q,J=12.3Hz,1H);13C NMR(151MHz,Chloroform-d)δ167.7,159.6,134.2,132.8,131.7,129.1,128.9,128.6,127.7,127.6,124.1,113.9,109.5,86.8,64.7,55.4,45.0,42.4,35.4,30.0;HRMS(ESI):m/z[M+Na]+理论值C20H19NO3Na:344.1258;实测值:344.1260。
实施例6
本实施例中,用等摩尔3-(3'-三氟甲基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2f-α和2f-β纯品,产率分别为29%和27%。
化合物2f-α为白色粉末;熔点208.4-208.9℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ8.01(d,J=7.5Hz,1H),7.64-7.59(m,1H),7.40(dd,J=9.9,2.5Hz,1H),7.35-7.27(m,2H),7.20-7.16(m,1H),6.97(td,J=8.4,2.5Hz,1H),4.86(dd,J=9.5,3.9Hz,1H),4.22(td,J=8.2,2.9Hz,1H),4.03-3.93(m,1H),3.93-3.86(m,1H),3.47-3.93(m,1H),3.23(d,J=13.7Hz,1H),2.92-2.84(m,2H),1.71-1.64(m,1H);13C NMR(151MHz,Chloroform-d)δ166.8,162.5(d,J=244.7Hz),137.0(d,J=7.8Hz),134.9,133.9,133.1(d,J=2.6Hz),128.5,127.6,125.5,124.7,124.4(d,J=21.8Hz),114.2(d,J=21.8Hz),111.6(d,J=22.7Hz),87.3,65.2,46.3,43.1,35.3,30.1;HRMS(ESI):m/z[M+Na]+理论值C19H16FNO2Na:332.1058;实测值:332.1056。
化合物2f-β为白色粉末;熔点191.4-191.9℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(400MHz,Chloroform-d)δ7.71(d,J=7.5Hz,1H),7.64(d,J=7.3Hz,1H),7.47(d,J=9.5Hz,1H),7.40-7.39(m,2H),7.25-7.18(m,1H),6.99(t,J=7.6Hz,1H),4.84(dd,J=9.2,4.8Hz,1H),4.23-4.06(m,1H),4.05-3.84(m,3H),3.52(t,J=10.7Hz,1H),3.36-3.21(m,1H),2.04(d,J=13.3Hz,1H),1.75(q,J=12.7Hz,1H);13C NMR(151MHz,Chloroform-d)δ167.4,162.8(d,J=245.2Hz),135.2(d,J=7.7Hz),132.3(d,J=2.6Hz),132.0(d,J=2.1Hz),131.5,129.4(d,J=8.3Hz),129.1,127.9,127.7,124.2,115.0(d,J=21.9Hz),110.9(d,J=22.7Hz),86.7,64.7,44.8,42.4,35.4,29.8;HRMS(ESI):m/z[M+Na]+理论值C19H16FNO2Na:332.1058;实测值:332.1057。
实施例7
本实施例中,用等摩尔3-(3'-氟-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2g-α和2g-β纯品,产率分别为28%和27%。
化合物2g-α为白色粉末;熔点187.1-187.7℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ8.04(s,1H),7.81(d,J=7.6Hz,1H),7.55(d,J=7.8Hz,1H),7.45(d,J=7.9Hz,1H),7.44-7.33(m,3H),4.62(t,J=4.3Hz,1H),4.27-4.17(m,1H),4.14-4.04(m,1H),3.94(d,J=5.3Hz,1H),3.82(q,J=8.3Hz,1H),3.60-3.50(m,1H),3.38-3.17(m,1H),2.41-3.27(m,1H),2.17-2.07(m,1H);13C NMR(151MHz,Chloroform-d)δ168.8,139.8,134.1,131.7,131.6,130.4(q,J=32.1Hz),129.2,128.6,128.3,127.6,124.7(q,J=4.0Hz),124.1(q,J=272.3Hz),124.0,121.3(q,J=3.7Hz),85.0,63.9,46.4,42.8,33.5,28.5;HRMS(ESI):m/z[M+Na]+理论值C20H16F3NO2Na:382.1026;实测值:382.1025。
化合物2g-β为白色粉末;熔点168.2-168.9℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.96(s,1H),7.74(d,J=7.2Hz,1H),7.59(d,J=7.4Hz,1H),7.48(d,J=7.1Hz,1H),7.34 -7.29(m,2H),7.19(s,1H),4.80(dd,J=8.6,4.5Hz,1H),4.05(q,J=7.7Hz,1H),3.94-83(m,3H),3.51-3.41(m,1H),3.31(d,J=11.7Hz,1H),2.01(d,J=12.0Hz,1H),1.74(q,J=12.2Hz,1H);13C NMR(151MHz,Chloroform-d)δ167.0,140.3,134.0,131.6(q,J=3.2Hz),130.7(q,J=31.0Hz),129.4,128.5,128.1,127.9,124.7(q,J=3.2Hz),124.3,124.1(q,J=272.1Hz),121.1(q,J=3.2Hz),121.1,86.6,64.8,44.5,42.4,36.0,29.4;HRMS(ESI):m/z[M+Na]+理论值C20H16F3NO2Na:382.1026;实测值:382.1026。
实施例8
本实施例中,用等摩尔3-(4-甲氧基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2h-α和2h-β纯品,产率均为31%。
化合物2h-α为白色粉末;熔点149.7-150.3℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.71(dd,J=11.4,8.7Hz,2H),7.36-7.31(m,1H),7.29(d,J=7.2Hz,1H),7.25-7.22(m,1H),6.97-6.87(m,2H),4.64(dd,J=5.3,3.8Hz,1H),4.25-4.16(m,1H),4.10-4.04(m,1H),3.90(d,J=5.4Hz,1H),3.84(s,3H),3.81(q,J=8.4Hz,1H),3.49-3.42(m,1H),3.38-3.23(m,1H),2.37-2.29(m,1H),2.13-1.96(m,1H);13C NMR(151MHz,Chloroform-d)δ169.3,159.7,135.2,133.3,133.2,127.9,127.2,127.0,125.8,125.2,123.7,113.7,113.6,85.2,63.9,55.4,47.1,42.8,33.6,28.8;HRMS(ESI):m/z[M+Na]+理论值C20H19NO3Na:344.1258;实测值:344.1248。
化合物2h-β为白色粉末;熔点159.5-160.3℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.64(d,J=8.7Hz,2H),7.30-7.25(m,1H),7.20-7.15(m,3H),6.81(dd,J=8.6,2.3Hz,1H),4.77(dd,J=9.4,4.8Hz,1H),4.09-4.03(m,1H),3.94-3.81(m,3H),3.76(s,3H),3.49-3.41(m,1H),3.26-3.15(m,1H),1.99(d,J=11.4Hz,1H),1.78-1.67(m,1H);13C NMR(151MHz,Chloroform-d)δ167.6,159.9,135.8,133.1,133.0,128.2,127.9,127.3,125.7,125.3,123.4,113.3,113.2,86.8,64.7,55.3,44.9,42.4,36.2,29.8;HRMS(ESI):m/z[M+Na]+理论值C20H19NO3Na:344.1258;实测值:344.1251。
实施例9
本实施例中,用等摩尔3-(4-三氟甲基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2i-α和2i-β纯品,产率分别为36%和34%。
化合物2i-α为白色粉末;熔点177.7-178.5℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.87(d,J=8.2Hz,1H),7.83(d,J=7.4Hz,1H),7.64(s,1H),7.62(d,J=8.2Hz,1H),7.45-7.34(m,3H),4.66(t,J=4.8Hz,1H),4.24-4.14(m,1H),4.13-4.06(m,1H),3.93(d,J=5.6Hz,1H),3.82(q,J=8.3Hz,1H),3.61-3.50(m,1H),3.38-3.20(m,1H),2.52-2.35(m,1H),2.19-2.07(m,1H);13C NMR(151MHz,Chloroform-d)δ168.2,136.3,136.2,132.5,132.1,129.9(q,J=32.4Hz),129.3,128.2,127.1,125.8(q,J=4.0Hz),125.0(q,J=4.0Hz),124.9,124.1,124.0(q,J=280.4Hz),85.0,64.0,46.5,43.0,33.2,28.8;HRMS(ESI):m/z[M+Na]+理论值C20H16F3NO2Na:382.1026;实测值:382.1020。
化合物2i-β为白色粉末;熔点183.4-183.9℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.95(s,1H),7.89(d,J=8.0Hz,1H),7.82(d,J=7.5Hz,1H),7.61(d,J=7.8Hz,1H),7.47-7.35(m,2H),7.30(d,J=7.1Hz,1H),4.87(dd,J=8.9,4.5Hz,1H),4.23-4.08(m,1H),4.07-3.87(m,3H),3.59-3.47(m,1H),3.42-3.25(m,1H),2.11(d,J=12.0Hz,1H),1.72(q,J=12.7Hz,1H);13C NMR(151MHz,Chloroform-d)δ166.8,137.0,136.3,132.2,131.8,130.2(q,J=32.7Hz),129.4,128.5,128.2,124.8(q,J=2.1Hz),124.7,124.4,124.1(q,J=272.0Hz),86.7,64.8,44.4,42.4,35.8,30.0;HRMS(ESI):m/z[M+Na]+理论值C20H16F3NO2Na:382.1026;实测值:382.1018。
实施例10
本实施例中,用等摩尔3-(4'-甲基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2j-α和2j-β纯品,产率分别为34%和35%。
化合物2j-α为白色粉末;熔点137.7-138.5℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.67(d,J=7.5Hz,1H),7.63(d,J=7.9Hz,1H),7.30-7.25(m,1H),7.21(d,J=7.3Hz,1H),7.19(s,1H),7.10(d,J=7.8Hz,1H),7.06(s,1H),4.55(s,1H),4.14(q,J=8.0Hz,1H),4.01(q,J=8.1Hz,1H),3.84(d,J=4.9Hz,1H),3.74(q,J=7.9Hz,1H),3.42-3.29(m,1H),3.29-3.18(m,1H),2.31(s,3H),2.27-2.20(m,1H),2.01(d,J=14.6Hz,1H);13C NMR(151MHz,Chloroform-d)δ169.8,138.3,136.4,133.3,131.6,130.8,128.9,128.5,128.2,128.1,128.0,124.6,123.8,85.5,64.1,47.2,43.0,33.8,29.2,21.5;HRMS(ESI):m/z[M+H]+理论值C20H20NO2:306.1489;实测值:306.1489。
化合物2j-β为白色粉末;熔点155.2-155.9℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.67(d,J=7.7Hz,1H),7.60(d,J=7.9Hz,1H),7.53(d,J=7.8Hz,1H),7.25(t,J=7.5Hz,1H),7.18(t,J=7.4Hz,1H),7.10(d,J=7.9Hz,1H),6.98(s,1H),4.75(dd,J=9.4,4.8Hz,1H),4.07-3.98(m,1H),3.94-3.87(m,1H),3.87-3.75(m,2H),3.49-3.39(m,1H),3.19-3.10(m,1H),2.30(s,3H),1.96(d,J=12.6Hz,1H),1.71-1.62(m,1H);13C NMR(151MHz,Chloroform-d)δ167.9,138.4,136.9,133.2,131.4,130.6,129.2,128.8,128.3,127.9,127.7,124.3,124.0,87.0,65.0,45.1,42.6,36.4,30.0,21.4;HRMS(ESI):m/z[M+Na]+理论值C20H19NO2Na:328.1308;实测值:328.1306。
实施例11
本实施例中,用等摩尔3-(3',4'-二甲基-[1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮替换实施例1中的3-([1,1'-联苯基]-2-基)-1-(3-羟乙基)吡啶-1(2H)-酮,其他步骤与实施例1相同,得到化合物2k-α和2k-β纯品,产率分别为34%和35%。
化合物2k-α为白色粉末;熔点142.8-143.5℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.68(d,J=7.8Hz,1H),7.50(s,1H),7.26(d,J=7.0Hz,2H),7.19(t,J=7.1Hz,1H),7.01(s,1H),4.55(t,J=4.4Hz,1H),4.17-4.05(m,1H),4.05-3.94(m,1H),3.80(d,J=5.2Hz,1H),3.72(q,J=8.1Hz,1H),3.39-3.27(m,1H),3.25-3.17(m,1H),2.27(d,J=5.8Hz,1H),2.24(s,3H),2.21(s,3H),2.02-1.95(m,1H);13C NMR(151MHz,Chloroform-d)δ169.8,137.0,136.3,133.8,133.3,131.7,131.0,128.7,128.5,128.1,127.9,125.8,123.7,85.5,64.1,47.2,43.0,33.3,29.3,19.9,19.8;HRMS(ESI):m/z[M+Na]+理论值C21H21NO2Na:342.1465;实测值:342.1461。
化合物2k-β为白色粉末;熔点166.9-167.5℃;易溶于甲醇、乙醇、二氯甲烷等有机溶剂,结构表征结果为:1H NMR(600MHz,Chloroform-d)δ7.66(d,J=7.5Hz,1H),7.52(d,J=7.7Hz,1H),7.47(s,1H),7.23(t,J=7.5Hz,1H),7.18-7.14(m,1H),6.92(s,1H),4.72(dd,J=9.5,4.8Hz,1H),4.05-3.97(m,1H),3.92-3.85(m,1H),3.82-3.75(m,2H),3.46-3.88(m,1H),3.14-3.05(m,1H),2.23(s,3H),2.19(s,3H),1.93(d,J=12.4Hz,1H),1.69-1.59(m,1H);13C NMR(151MHz,Chloroform-d)δ168.0,137.0,136.6,134.4,133.2,131.4,130.8,129.3,128.1,127.8,127.7,125.4,123.8,87.0,64.9,45.1,42.5,35.8,30.1,19.9,19.6;HRMS(ESI):m/z[M+Na]+理论值C21H21NO2Na:342.1465;实测值:342.1460。
实施例12
实施例1~11化合物在制备抗肿瘤药物中的应用
以实施例1~11化合物作为有效成分进行了药效试验,具体试验情况如下:
1、受试药物
顺铂、紫杉醇(阳性对照化合物)及实施例1~11化合物。
2、供试细胞
白血病HL-60、肺癌A549、肝癌SMMC-7721、乳腺癌MDA-MB-231。
3、抗肿瘤细胞活性测定
接种细胞:用含10%胎牛血清的培养液(DMEM或者RMPI1640)配成单个细胞悬液,以每孔3000~15000个细胞接种到96孔板,每孔体积100μL,细胞提前12~24小时接种培养。
加入待测化合物溶液:化合物用DMSO溶解,化合物以40μmol/L浓度初筛,每孔终体积200μL,每种处理均设3个复孔。
显色:37℃培养48小时后,贴壁细胞弃孔内培养液,每孔加MTS溶液20μL和培养液100μL;悬浮细胞HL-60弃100μL培养上清液,每孔加20μL MTS溶液;设3个空白复孔(MTS溶液20μL和培养液100μL的混合液),继续孵育2~4小时,使反应充分进行后测定光吸收值。
比色:选择492nm波长,多功能酶标仪(MULTISKAN FC)读取各孔光吸收值,记录结果,数据处理后以化合物编号为横坐标,细胞抑制率为纵坐标绘制细胞的抑制率图。结果见表1。
表1抗肿瘤活性抑制率
/>
由表1可见,化合物2b-α、2b-β、2j-β和2k-α表现出较好的抑制率(>60%),因此进一步测试它们的IC50值(半数抑制浓度)。每次实验均设顺铂(DDP)阳性化合物,以浓度为横坐标,细胞存活率为纵坐标绘制细胞生长曲线,应用两点法(Reed and Muench法)计算化合物的IC50值。结果见表2。
表2抗肿瘤活性的IC50值(IC50±SD(uM))
表中“--”表示未测试。
由表2可见,本发明化合物2b-α、2b-β、2j-β、2k-α对4种供试癌细胞有较好的抑制活性,其中2b-α、2b-β、对白血病细胞HL-60、肺癌细胞A549、肝癌细胞SMMC-7721表现出良好的抑制效果,2j-β对肝癌细胞SMMC-7721、乳腺癌细胞MDA-MB-231有明显抑制效果,2k-α对乳腺癌细胞MDA-MB-231有抑制效果。由此可见,本发明二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物具有良好抗肿瘤活性。
Claims (8)
1.一类二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物,其特征在于该化合物的结构式为:
式中R1、R2、R3各自独立的代表H、C1~C4烷基、C1~C4烷氧基、三氟甲基、氟、氯中任意一种。
2.根据权利要求1所述的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物,其特征在于:所述R1代表氢、甲基、甲氧基、氯、三氟甲基中任意一种,R2代表氢、甲基、甲氧基、三氟甲基、氟中任意一种,R3代表氢、三氟甲基、甲氧基中任意一种。
3.根据权利要求1所述的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物,其特征在于该化合物为
中任意一种。
4.一种权利要求1所述的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物的制备方法,其特征在于:将式I所示的3-联苯基-1-羟乙基吡啶-2(1H)-酮类化合物和盐酸溶解在有机溶剂中,在氩气保护及300~365nm的紫外光辐射下反应30~90分钟,反应结束后,将反应液减压蒸馏后经柱层析分离提纯,得到二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物;
式中R1、R2、R3各自独立的代表H、C1~C4烷基、C1~C4烷氧基、三氟甲基、氟、氯中任意一种。
5.根据权利要求4所述的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物的制备方法,其特征在于:所述3-联苯基-1-羟乙基吡啶-2(1H)-酮类化合物与盐酸中HCl的摩尔比为1:1~2。
6.根据权利要求4所述的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物的制备方法,其特征在于:所述有机溶剂为甲苯、二氯甲烷、二氧六环中任意一种。
7.权利要求1所述的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2H)-酮类化合物在制备抗肿瘤细胞药物中的应用,其特征在于:所述肿瘤为白血病、肺癌、肝癌、乳腺癌中任意一种。
Publications (1)
Publication Number | Publication Date |
---|---|
CN118165008A true CN118165008A (zh) | 2024-06-11 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6494624B2 (ja) | カゼインキナーゼ1d/e阻害剤としての置換された4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピラジン誘導体 | |
CA2829188C (en) | Dispiropyrrolidine derivatives | |
CA3020870A1 (en) | Inhibitors of activin receptor-like kinase | |
JP3514490B2 (ja) | トリフルオロメチルピロロインドールカルボン酸エステル誘導体及びその製造方法 | |
WO2003082830A1 (en) | Novel fused quinazoline derivatives useful as tyrosine kinase inhibitors | |
CN107556318B (zh) | 一种含哌啶的吡咯并嘧啶类化合物及其制备方法与应用 | |
BR112019023918A2 (pt) | Inibidores de quinase e usos dos mesmos | |
EP2373659B1 (en) | Substituted tetrahydropyran spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof | |
CN113527300B (zh) | 布鲁顿酪氨酸蛋白激酶抑制剂 | |
EA007221B1 (ru) | НОВЫЕ СОЕДИНЕНИЯ ПИРИДО-ПИРИДО-ПИРРОЛО[3,2-g]-ПИРРОЛО[3,4-e]ИНДОЛА И ПИРИДО-ПИРРОЛО[2,3-a]ПИРРОЛО[3,4-c]-КАРБАЗОЛА, СПОСОБ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ, СОДЕРЖАЩИЕ ИХ | |
Rassu et al. | Total synthesis of 1, 5-dideoxy-1, 5-iminoalditols | |
WO2006034094A1 (en) | Crystalline form 1 of atrasentan hxdrochloride | |
CA3130253C (en) | Cd73 inhibitor, preparation method therefor and application thereof | |
JP2023535096A (ja) | キナーゼ阻害活性を有する化合物 | |
EP3524602A1 (en) | Pyrido five-element aromatic ring compound, preparation method therefor and use thereof | |
CN118165008A (zh) | 二苯并-1,3-氧氮杂环戊烷并异喹啉-1(2h)-酮类化合物及其制备方法和抗肿瘤应用 | |
CN109942665B (zh) | 雷公藤内酯醇衍生物及其制备方法和应用 | |
EP4055013B1 (en) | Wdr5 inhibitors and modulators | |
CN111423441B (zh) | 一类具有抗肿瘤活性的卤代吲哚苦参碱衍生物及制备方法和应用 | |
CN117486876A (zh) | 作为Akt激酶抑制剂的化合物 | |
Tsai et al. | Synthesis and cytotoxicity of 1, 6, 8, 9-substituted α-carboline derivatives | |
CN104334561B (zh) | 化合物jk12a及其制备 | |
CA2598327A1 (en) | Ocaperidone salts and pharmaceutical compositions containing the same | |
CN114621161B (zh) | 一种大黄酸-哌嗪-二硫代氨基甲酸酯杂化物及其制备方法和应用 | |
CN112250725B (zh) | 一种苯并咪唑衍生物bi345及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication |