CN115160213B - 一种大黄酸吡啶季铵盐类化合物及其合成方法和应用 - Google Patents
一种大黄酸吡啶季铵盐类化合物及其合成方法和应用 Download PDFInfo
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- CN115160213B CN115160213B CN202210612007.3A CN202210612007A CN115160213B CN 115160213 B CN115160213 B CN 115160213B CN 202210612007 A CN202210612007 A CN 202210612007A CN 115160213 B CN115160213 B CN 115160213B
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- -1 emodic acid pyridine quaternary ammonium salt compound Chemical class 0.000 title claims abstract description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000010189 synthetic method Methods 0.000 title abstract description 3
- ZJXVNNSMRGTDBI-UHFFFAOYSA-N Emodinsaeure Natural products C1=C(O)C=C2C(=O)C3=CC(C(=O)O)=CC(O)=C3C(=O)C2=C1O ZJXVNNSMRGTDBI-UHFFFAOYSA-N 0.000 title description 2
- 241000219061 Rheum Species 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 141
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 239000003814 drug Substances 0.000 claims abstract description 32
- 229940079593 drug Drugs 0.000 claims abstract description 30
- 125000006278 bromobenzyl group Chemical group 0.000 claims abstract description 28
- 241000894006 Bacteria Species 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 95
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 81
- 238000004440 column chromatography Methods 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 241000589516 Pseudomonas Species 0.000 claims description 2
- 241000191940 Staphylococcus Species 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 229960003085 meticillin Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 1
- 230000003213 activating effect Effects 0.000 claims 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 28
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- 150000001412 amines Chemical class 0.000 abstract 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 abstract 2
- 238000006467 substitution reaction Methods 0.000 abstract 1
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- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 4
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/40—Acylated substituent nitrogen atom
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明提供一种大黄酸吡啶季铵盐类化合物及其合成方法和应用,该类化合物的结构式如通式Ⅰ所示,
Description
技术领域
本发明涉及医药化学领域,具体涉及一种大黄酸吡啶季铵盐类化合物及其合成方法和应用。
背景技术
抗生素的过度使用导致耐药细菌和耐药基因的快速进化,滥用抗生素已导致出现抗生素耐药菌株的危机,多重耐药细菌成为一个日益严重的公共卫生问题,给人类健康造成持续不断的威胁。因此,迫切需要开发具有新型作用机制、生物利用度良好且抗菌谱广的新型抗菌药物。
随着大量耐药性病原菌的出现,研究天然产物作为抗菌药物一时成为热点,而大黄酸作为植物抗生素,除了对革兰氏阴性菌如:大肠杆菌、痢疾杆菌、变形杆菌等具有明显抑制作用外,还对革兰氏阳性菌如:金黄葡萄球菌、链球菌、白喉杆菌、破伤风杆菌等也具有较强的抑制作用。经研究发现,大黄酸的抗菌机制主要为:(1)可以抑制细胞进行能量代谢时线粒体呼吸链电子的传递;(2) 能够抑制NADH脱氢酶、细胞色素C氧化酶和琥珀酸脱氢酶等的生物活性,从而抑制细胞内能量的传递,达到抑菌的目的;(3)大黄酸还可以通过影响叶酸的合成,从而影响DNA的复制,导致蛋白质合成受阻,最后影响细菌的增长; (4)大黄酸类化合物还能通过抑制细胞内呼吸酶的活性,从而影响细胞的能量代谢,从而抑制细菌的生长。因此,大黄酸一度成为研究的热点。
大黄酸虽具有广泛的药理活性,但其水溶性差、生物利用度低成为影响其临床广泛应用的主要因素。
发明内容
为了解决现有技术的缺点和不足之处,本发明的首要目的在于提供一种大黄酸吡啶季铵盐类化合物及其药学上可接受的盐;
本发明的另一个目的是提供上述大黄酸吡啶季铵盐类化合物的合成方法;
本发明的再一个目的是提供上述大黄酸吡啶季铵盐类化合物在治疗感染性疾病,特别是耐药菌引起的感染性疾病中的用途。
本发明所述大黄酸吡啶季铵盐类化合物的结构式如通式Ⅰ所示:
其中,X为O或者NH。R为氢原子、甲基、三氟甲基、甲氧基、三氟甲氧基、叔丁基、硝基、氰基、卤素原子或苯基,术语“卤素”表示氟、氯或溴。
本发明代表性化合物结构式如下所示:
所述的药学上可接受的盐为具有如通式Ⅰ所示结构的化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
所述的具有抗耐药菌活性的大黄酸吡啶季铵盐类化合物的合成方法,包含如下步骤:
其中,X为O或者NH。R为氢原子、甲基、三氟甲基、甲氧基、三氟甲氧基、叔丁基、硝基、氰基、卤素原子或苯基。术语“卤素”表示氟、氯或溴。
为了实现上述合成路线,本发明的合成步骤如下:
(1)将一定量大黄酸、EDCI(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)、 HOBT(1-羟基苯并三唑)和适量DIPEA(N,N-二异丙基乙胺)置于反应器中,溶于有机溶剂,室温下活化0.5~1.5小时,后将吡啶烷胺或吡啶烷醇溶于有机溶剂,加入到反应液中,室温下反应6~15小时。反应过程用TLC监测追踪反应终点,反应结束,减压浓缩除去有机溶剂,向所得固体加入饱和氯化钠水溶液,后用乙酸乙酯萃取,收集乙酸乙酯层,无水硫酸钠干燥,柱层析分离得到中间体,洗脱剂为二氯甲烷:甲醇=20∶1。
(2)将上述得到的中间体和一定量不同取代的溴苄溶于有机溶剂,室温下反应6~15小时,反应过程用TLC监测追踪反应终点。反应结束后,减压浓缩除去有机溶剂,柱层析分离得到通式Ⅰ所示产物,洗脱剂比例二氯甲烷∶甲醇=10∶1。
上述步骤(1)中的有机溶剂优选为二氯甲烷。
上述步骤(1)中的活化时间优选为1小时。
上述步骤(1)中的大黄酸与吡啶烷胺或吡啶烷醇摩尔比优选为1∶1.2。
上述步骤(1)中的反应时间优选为12小时。
上述步骤(2)中的有机溶剂优选为乙腈。
上述步骤(2)中的中间体与溴苄摩尔比优选为1∶4。
上述步骤(2)中的反应时间优选为12小时。
本发明提供制备抗菌产品中的应用,可将其与可药用的赋形剂、稀释剂等混合,制成口服给药的片剂、注射剂、脂质体纳米粒、控释剂等。
与现有技术相比,本发明具有如下的有益效果:
本发明通过对大黄酸C3位的羧酸部分进行改造,获得一种大黄酸吡啶季铵盐类化合物,通过对常见革兰氏阳性菌如耐药性金黄色葡萄球菌以及革兰氏阴性菌如耐药型铜绿假单胞菌、耐药型鲍曼不动杆菌和大肠杆菌进行抗菌活性测试,经初步生物活性测试表明该类化合物有优异的抗耐药菌活性,体外细胞毒性实验表明本发明合成的衍生物具有较高的安全性,细胞毒性明显低于大黄酸;此外,溶解性有了显著的改善。因此可用于防治经多药耐药菌感染引起的感染性疾病,在制备抗感染治疗药物方面具有很好的开发价值。
本发明大黄酸吡啶季铵盐类化合物的合成方法安全性高、反应条件温和、产率较高,适合工业化生产。
附图说明
图1为化合物2在氘代DMSO中的核磁氢谱图;
图2为化合物2在氘代DMSO中的核磁碳谱图;
图3为化合物2对MRSA-171的体外抑制活性测定结果;
图4为化合物2对MDR-PA-126的体外抑制活性测定结果;
图5为化合物2对E.coil的体外抑制活性测定结果;
图6为不同浓度大黄酸对HepG2、HEK293和A549细胞处理的细胞存活率测定结果;
图7为不同浓度化合物2对HepG2、HEK293和A549细胞处理的细胞存活率测定结果。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明进行描述,这些描述只是进一步解释本发明的特征和优点,并非用于限制本发明的权利要求。
实施例1
中间体Ⅰ的制备:3-(吡啶-4-基)丙基4,5-二羟基-9,10-二氧代-9,10-二氢蒽 -2-羧酸酯
将284.22mg(1mmol)大黄酸、230.04mg(1.2mmol)EDCI、163.36 mg(1.2mmol)HOBT和0.17mL(2mmol)DIPEA置于烧瓶中,加入50mL 二氯甲烷作溶剂,室温下活化一小时,后将164.62mg(1.2mmol)吡啶丙烷醇溶解在15mL二氯甲烷中,加入到反应液中,常温下搅拌反应12小时。反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,向所得固体中加入20mL饱和氯化钠水溶液,后加入乙酸乙酯进行萃取,收集乙酸乙酯层,接着使用无水硫酸钠干燥,通过柱层析对粗品进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=20∶1。将含有目标化合物的洗脱液收集并浓缩干燥得到中间体Ⅰ211.74mg,收率为52.49%。
实施例2
中间体Ⅱ的制备:4,5-二羟基-9,10-二氧代-N-(3-(吡啶-4-基)丙基)-9,10-二氢蒽-2-甲酰胺
将284.22mg(1mmol)大黄酸、230.04mg(1.2mmol)EDCI、163.36 mg(1.2mmol)HOBT和0.17mL(2mmol)DIPEA置于烧瓶中,加入50mL 二氯甲烷作溶剂,室温下活化一小时,后将163.44mg(1.2mmol)吡啶丙烷醇溶解在15mL二氯甲烷中,加入到反应液中,常温下搅拌反应12小时。反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,向所得固体中加入20mL饱和氯化钠水溶液,后加入乙酸乙酯进行萃取,收集乙酸乙酯层,接着使用无水硫酸钠干燥,通过柱层析对粗品进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=20∶1,将含有目标化合物的洗脱液收集并浓缩干燥得到中间体Ⅱ216.01mg,收率为53.68%。
实施例3
化合物1的制备:(1-苄基-4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2- 羰基)氧基)丙基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和684.16mg(4mmol)的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用 TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到387.79mg化合物1,收率为67.51%。
1H NMR(400MHz,DMSO)δ9.28(d,J=6.4Hz,2H),8.21(d,J=6.3Hz, 2H),7.89–7.48(m,5H),7.38(d,J=7.8Hz,2H),7.28(s,1H),7.14(d,J=7.8Hz,2H),5.75(s,2H),4.30(t,J=6.3Hz,2H),3.01(t,J=7.6Hz,2H),2.13 (t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ189.74,182.85,163.25, 162.83,162.39,148.96,148.82,137.59,137.34,135.52,134.21,133.44,131.43,129.64,127.95,126.23,125.95,123.74,121.42,120.59,118.28,116.81,64.85,62.53,29.69,26.49.
实施例4
化合物2的制备:(4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)-1-(4-甲基苄基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和740.24mg(4mmol)的对位甲烷取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到438.86m化合物2,收率为74.58%。化合物2在氘代DMSO中的核磁氢谱图如图1所示,化合物2在氘代DMSO 中的核磁碳谱图如图2所示。
1H NMR(400MHz,DMSO)δ9.24(d,J=6.4Hz,2H),8.17(d,J=6.3Hz, 2H),7.99–7.58(m,4H),7.48(d,J=7.8Hz,2H),7.38(s,1H),7.24(d,J=7.8Hz,2H),5.85(s,2H),4.40(t,J=6.3Hz,2H),3.11(t,J=7.6Hz,2H),2.30 (s,3H),2.23(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ187.75,180.84, 164.25,162.83,162.37,149.97,149.82,137.79,137.74,135.52,133.91,133.44,131.53,129.24,126.95,125.23,124.95,123.84,120.42,120.09, 118.28,115.81,65.05,62.53,31.69,28.99,22.06.
实施例5
化合物3的制备:(4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)-1-(4-(三氟甲基)苄基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和956.12mg(4mmol)的对位三氟甲基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到446.80mg化合物3,收率为 69.55%。
1H NMR(400MHz,DMSO)δ9.54(d,J=6.4Hz,2H),8.46(d,J=6.3Hz, 2H),8.19–7.78(m,4H),7.58(d,J=7.8Hz,2H),7.53(s,1H),7.44(d,J=7.8Hz,2H),5.97(s,2H),4.62(t,J=6.3Hz,2H),3.46(t,J=7.6Hz,2H),2.58 (t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ186.75,178.84,162.25, 161.83,161.37,147.94,147.82,136.79,135.74,135.52,133.61,133.44,130.53,128.74,127.45,124.93,124.55,123.84,120.62,120.39,119.28,115.41,67.55,63.69,32.69,26.46,21.54.
实施例6
化合物4的制备:(4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)-1-(4-甲氧基苄基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和804.24mg(4mmol)的对位甲氧基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到411.87mg化合物4,收率为 68.14%。
1H NMR(400MHz,DMSO)δ9.44(d,J=6.4Hz,2H),8.45(d,J=6.3Hz, 2H),7.93–7.68(m,4H),7.53(d,J=7.8Hz,2H),7.46(s,1H),7.34(d,J=7.8Hz,2H),5.85(s,2H),4.69(t,J=6.3Hz,2H),3.75(s,3H),3.41(t,J=7.6 Hz,2H),2.31(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ184.75,178.94, 167.15,164.83,164.37,148.87,148.62,136.79,136.54,135.69,134.49,133.72,131.53,127.44,126.75,125.53,124.95,123.44,119.42,119.09, 118.28,116.81,65.05,63.53,38.69,29.99,24.37.
实施例7
化合物5的制备:(4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)-1-(4-(三氟甲氧基)苄基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和1020.12mg(4mmol)的对位三氟甲氧基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到482.56mg化合物5,收率为 73.29%。
1H NMR(400MHz,DMSO)δ9.12(d,J=6.4Hz,2H),8.03(d,J=6.3Hz, 2H),7.84–7.36(m,4H),7.31(d,J=7.8Hz,2H),7.28(s,1H),7.22(d,J= 7.8Hz,2H),5.62(s,2H),4.38(t,J=6.3Hz,2H),3.33(t,J=7.6Hz,2H),2.18 (t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ183.38,178.74,163.25, 162.83,162.37,145.97,145.82,135.49,135.34,134.52,133.91,133.44,131.93,129.64,127.95,126.33,123.95,123.84,119.42,119.09,118.24,116.88,66.05,64.53,41.69,31.99,25.36.
实施例8
化合物6的制备:(1-(4-(叔丁基)苄基)-4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和908.60mg(4mmol)的对位叔丁基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到435.89mg化合物6,收率为 69.13%。
1H NMR(400MHz,DMSO)δ9.04(d,J=6.4Hz,2H),8.12(d,J=6.3Hz, 2H),7.79–7.48(m,4H),7.36(d,J=7.8Hz,2H),7.25(s,1H),7.14(d,J=7.8Hz,2H),5.64(s,2H),4.52(t,J=6.3Hz,2H),3.43(t,J=7.6Hz,2H),2.41 (t,J=7.2Hz,2H).1.23(s,9H).13C NMR(101MHz,DMSO)δ189.85,186.84, 165.25,162.83,162.37,149.57,149.42,137.89,137.84,135.32,133.95,133.54,131.53,129.54,126.85,125.43,124.95,123.84,120.32,119.89, 118.18,115.74,65.25,62.43,31.89,31.42,28.89,22.06.
实施例9
化合物7的制备:(4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)-1-(4-硝基苄基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和864.12mg(4mmol)的对位硝基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到448.21mg化合物7,收率为 72.36%。
1H NMR(400MHz,DMSO)δ9.14(d,J=6.4Hz,2H),8.37(d,J=6.3Hz, 2H),7.88–7.74(m,4H),7.62(d,J=7.8Hz,2H),7.42(s,1H),7.24(d,J= 7.8Hz,2H),5.85(s,2H),4.35(t,J=6.3Hz,2H),3.21(t,J=7.6Hz,2H),2.22(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ187.75,182.84,163.25, 162.83,162.37,149.87,149.42,137.59,137.44,135.47,133.73,133.54,132.53,129.24,126.85,125.23,124.95,123.44,120.12,120.09,118.58,115.64,68.05,65.53,33.69,25.79.
实施例10
化合物8的制备:(1-(4-氰基苄基)-4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和784.20mg(4mmol)的对位氰基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到444.78mg化合物8,收率为 74.20%。
1H NMR(400MHz,DMSO)δ9.22(d,J=6.4Hz,2H),8.56(d,J=6.3Hz, 2H),7.87–7.55(m,4H),7.48(d,J=7.8Hz,2H),7.35(s,1H),7.24(d,J=7.8Hz,2H),5.65(s,2H),4.32(t,J=6.3Hz,2H),3.34(t,J=7.6Hz,2H),2.23(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ190.75,183.84,165.25, 163.83,163.37,149.97,149.82,136.79,136.74,134.52,133.65,133.44,131.73,129.64,126.75,125.33,124.85,123.94,120.82,120.69,118.6,116.28,114.81,66.05,63.53,31.63,28.99.
实施例11
化合物9的制备:(1-([1,1'-联苯]-4-基甲基)-4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和988.56mg(4mmol)的对位苯环取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到478.65mg化合物9,收率为 73.58%。
1H NMR(400MHz,DMSO)δ9.24(d,J=6.4Hz,2H),8.17(d,J=6.3Hz, 2H),7.97–7.79(m,5H),7.63-7.49(m,4H),7.48(d,J=7.8Hz,2H),7.38(s,1H),7.19(d,J=7.8Hz,2H),5.75(s,2H),4.37(t,J=6.3Hz,2H),3.31(t,J= 7.6Hz,2H),2.23(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ188.79, 182.84,164.25,162.63,162.17,147.67,147.52,136.73,136.51,135.52, 133.91,133.44,130.53,129.47,128.35,127.91,127.60,127.30,126.95,125.53,124.75,123.73,121.42,121.09,118.28,115.81,64.05,61.33,32.59, 26.93.
实施例12
化合物10的制备:(4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)-1-(4-氟苄基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和756.12mg(4mmol)的对位氟原子取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到390.46mg化合物10,收率为 65.91%。
1H NMR(400MHz,DMSO)δ9.34(d,J=6.4Hz,2H),8.23(d,J=6.3Hz, 2H),7.89–7.45(m,4H),7.42(d,J=7.8Hz,2H),7.38(s,1H),7.24(d,J=7.8Hz,2H),5.78(s,2H),4.45(t,J=6.3Hz,2H),3.23(t,J=7.6Hz,2H),2.34 (t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ187.78,180.67,164.36, 162.83,162.37,149.93,149.82,137.75,137.71,135.53,133.85,133.45,131.43,129.34,126.12,125.23,124.95,123.84,120.42,120.19,118.18,114.81,65.05,62.53,33.69,28.54.
实施例13
化合物11的制备:(1-(4-氯苄基)-4-(3-((4,5-二羟基-9,10-二氧-9,10-二氢蒽-2-羰基)氧基)丙基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和821.92mg(4mmol)的对位氯原子取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到431.56mg化合物11,收率为 70.88%。
1H NMR(400MHz,DMSO)δ9.30(d,J=6.4Hz,2H),8.13(d,J=6.3Hz, 2H),7.80–7.49(m,4H),7.38(d,J=7.8Hz,2H),7.26(s,1H),7.24(d,J=7.8Hz,2H),5.85(s,2H),4.37(t,J=6.3Hz,2H),3.31(t,J=7.6Hz,2H),2.46(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ189.75,183.84,167.25, 164.83,164.37,148.87,148.82,137.79,137.74,135.72,133.91,133.74,131.73,129.74,126.95,125.73,124.95,123.84,120.72,120.39,118.78,115.71,65.75,62.43,31.79,28.79.
实施例14
化合物12的制备:(1-(4-溴苄基)-4-(3-((4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羰基)氧基)丙基)吡啶-1-鎓)溴盐
将403.39mg(1mmol)的中间体Ⅰ和999.72mg(4mmol)的对位溴原子取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到510.90mg化合物12,收率为 78.20%。
1H NMR(400MHz,DMSO)δ9.64(d,J=6.4Hz,2H),8.57(d,J=6.3Hz, 2H),7.79–7.68(m,4H),7.58(d,J=7.8Hz,2H),7.46(s,1H),7.34(d,J=7.8Hz,2H),5.65(s,2H),4.60(t,J=6.3Hz,2H),3.61(t,J=7.6Hz,2H),2.63 (t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ186.55,180.64,166.25, 163.83,163.37,146.97,146.82,137.79,137.74,136.92,135.91,135.44,132.53,129.24,126.95,125.63,124.65,123.64,120.69,120.49,118.68,115.61,65.65,62.63,31.69,26.66.
实施例15
化合物13的制备:(1-苄基-4-(3-(4,5-二羟基-9,10-二氧基-9,10-二氢蒽- 2-甲酰胺基)丙基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和684.16mg(4mmol)的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用 TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到390.61mg化合物13,收率为69.82%。
1H NMR(400MHz,DMSO)δ9.48(d,J=6.4Hz,2H),8.44(s,1H),8.21 (d,J=6.3Hz,2H),7.84–7.44(m,5H),7.34(d,J=7.8Hz,2H),7.24(s,1H),7.14(d,J=7.8Hz,2H),5.45(s,2H),4.40(t,J=6.3Hz,2H),3.41(t,J=7.6 Hz,2H),2.43(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ184.74,182.45, 163.25,162.83,162.49,148.46,148.12,137.49,137.34,135.42,134.41,133.44,131.43,129.44,127.45,126.24,125.94,123.44,121.42,120.49, 118.48,116.41,64.85,62.53,29.49,26.44.
实施例16
化合物14的制备:(4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)-1-(4-甲基苄基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和740.24mg(4mmol)的对位甲烷取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到413.53mg化合物14,收率为 72.11%。
1H NMR(400MHz,DMSO)δ9.34(d,J=6.4Hz,2H),8.44(s,1H),8.37 (d,J=6.3Hz,2H),7.93–7.58(m,4H),7.38(d,J=7.8Hz,2H),7.31(s,1H),7.24(d,J=7.8Hz,2H),5.83(s,2H),4.40(t,J=6.3Hz,2H),3.13(t,J=7.6 Hz,2H),2.33(s,3H),2.23(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ 187.35,180.34,164.35,162.33,162.17,149.93,149.83,137.73,137.34, 135.32,133.71,133.34,131.33,129.34,126.35,125.23,124.95,123.84,120.32,120.39,118.23,115.31,65.35,62.33,31.69,28.39,22.36.
实施例17
化合物15的制备:(4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)-1-(4-(三氟甲基)苄基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和956.12mg(4mmol)的对位三氟甲基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到469.52mg化合物15,收率为 74.83%。
1H NMR(400MHz,DMSO)δ9.44(d,J=6.4Hz,2H),8.43(s,1H),8.34 (d,J=6.3Hz,2H),8.19–7.74(m,4H),7.55(d,J=7.8Hz,2H),7.53(s,1H),7.44(d,J=7.8Hz,2H),5.95(s,2H),4.65(t,J=6.3Hz,2H),3.45(t,J=7.6 Hz,2H),2.55(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ185.75,175.84, 162.25,161.83,161.37,145.94,145.82,136.79,135.74,135.52,133.65,133.54,130.53,128.54,127.45,124.93,124.51,123.54,120.62,120.59, 119.28,115.51,67.55,63.59,35.69,25.46,21.54.
实施例18
化合物16的制备:(4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)-1-(4-甲氧基苄基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和804.24mg(4mmol)的对位甲氧基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到442.70mg化合物16,收率为 75.10%。
1H NMR(400MHz,DMSO)δ9.44(d,J=6.4Hz,2H),8.45(s,1H),8.43 (d,J=6.3Hz,2H),7.93–7.63(m,4H),7.51(d,J=7.8Hz,2H),7.46(s,1H),7.34(d,J=7.8Hz,2H),5.81(s,2H),4.61(t,J=6.3Hz,2H),3.71(s,3H), 3.41(t,J=7.6Hz,2H),2.31(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO) δ187.71,178.91,167.15,164.83,164.37,148.81,148.61,136.72,136.52, 135.62,134.43,133.72,131.54,127.44,126.75,125.53,123.95,123.44,119.42,119.09,118.28,114.81,65.05,63.52,38.69,29.99,24.57.
实施例19
化合物17的制备:(4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)-1-(4-(三氟甲氧基)苄基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和1020.12mg(4mmol)的对位三氟甲氧基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到430.40mg化合物17,收率为66.89%。
1H NMR(400MHz,DMSO)δ9.22(d,J=6.4Hz,2H),8.45(s,1H),8.03 (d,J=6.3Hz,2H),7.85–7.36(m,4H),7.31(d,J=7.8Hz,2H),7.28(s,1H),7.22(d,J=7.8Hz,2H),5.62(s,2H),4.38(t,J=6.3Hz,2H),3.43(t,J=7.6 Hz,2H),2.38(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ183.38,178.74, 165.25,164.83,164.37,145.97,145.82,137.49,137.34,134.52,133.91,133.44,132.93,129.64,127.95,126.33,122.95,122.84,119.42,119.09, 118.24,115.85,66.05,64.53,41.79,31.99,25.56.
实施例20
化合物18的制备:(1-(4-(叔丁基)苄基)-4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和908.60mg(4mmol)的对位叔丁基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到460.44mg化合物18,收率为 74.80%。
1H NMR(400MHz,DMSO)δ9.04(d,J=6.4Hz,2H),8.45(s,1H),8.12 (d,J=6.3Hz,2H),7.89–7.48(m,4H),7.36(d,J=7.8Hz,2H),7.23(s,1H),7.17(d,J=7.8Hz,2H),5.54(s,2H),4.51(t,J=6.3Hz,2H),3.23(t,J=7.6 Hz,2H),2.41(t,J=7.2Hz,2H).1.22(s,9H).13C NMR(101MHz,DMSO)δ 188.85,186.84,165.25,163.83,163.37,148.57,148.42,137.89,137.64,135.32,133.95,133.54,132.53,129.54,126.85,125.33,124.95,123.84,121.32,119.89,117.18,115.74,65.25,62.43,31.89,31.42,27.89,22.46.
实施例21
化合物19的制备:(4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)-1-(4-硝基苄基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和864.12mg(4mmol)的对位硝基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到442.82mg化合物19,收率为73.26%。
1H NMR(400MHz,DMSO)δ9.44(d,J=6.4Hz,2H),8.54(s,1H),8.37 (d,J=6.3Hz,2H),7.84–7.74(m,4H),7.52(d,J=7.8Hz,2H),7.32(s,1H),7.24(d,J=7.8Hz,2H),5.85(s,2H),4.35(t,J=6.3Hz,2H),3.31(t,J=7.6 Hz,2H),2.22(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ189.75,182.84, 165.25,162.83,162.37,149.87,149.42,137.69,137.34,135.47,133.73, 133.54,132.53,129.24,126.85,125.23,123.95,123.44,121.12,120.09,118.58,113.64,68.05,64.53,33.69,25.79.
实施例22
化合物20的制备:(1-(4-氰基苄基)-4-(3-(4,5-二羟基-9,10-二氧代-9,10- 二氢蒽)-2-甲酰胺基)丙基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和784.20mg(4mmol)的对位氰基基取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到411.70mg化合物20,收率为 70.44%。
1H NMR(400MHz,DMSO)δ9.33(d,J=6.4Hz,2H),8.56(d,J=6.3Hz, 2H),8.45(s,1H),7.87–7.55(m,4H),7.52(d,J=7.6Hz,2H),7.32(s,1H),7.24(d,J=7.8Hz,2H),5.75(s,2H),4.32(t,J=6.3Hz,2H),3.34(t,J=7.6 Hz,2H),2.23(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ190.55,183.74, 165.25,162.83,162.37,148.97,148.82,136.79,136.54,134.52,132.65,132.44,131.73,129.64,126.75,125.33,124.65,123.84,122.62,121.16, 120.67,116.38,114.83,66.45,63.33,31.53,28.79.
实施例23
化合物21的制备:(1-([1,1'-联苯]-4-基甲基)-4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺)丙基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和988.56mg(4mmol)的对位苯环取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到454.54mg化合物21,收率为 71.52%。
1H NMR(400MHz,DMSO)δ9.04(d,J=6.4Hz,2H),8.42(s,1H),8.07 (d,J=6.3Hz,2H),7.90–7.79(m,5H),7.60-7.49(m,4H),7.40(d,J=7.8Hz,2H),7.38(s,1H),7.19(d,J=7.8Hz,2H),5.70(s,2H),4.40(t,J=6.3Hz, 2H),3.30(t,J=7.6Hz,2H),2.23(t,J=7.2Hz,2H).13C NMR(101MHz, DMSO)δ188.79,182.80,164.25,162.60,162.17,147.67,147.50,136.70, 136.50,135.52,133.91,133.44,130.50,129.47,128.35,127.80,127.68,127.60,126.90,125.50,124.75,123.70,120.42,121.10,118.28,115.81, 64.10,61.33,32.50,26.80.
实施例24
化合物22的制备:(4-(3-(4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)-1-(4-氟苄基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和756.12mg(4mmol)的对位氟原子取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到426.45mg化合物22,收率为 73.85%。
1H NMR(400MHz,DMSO)δ9.34(d,J=6.4Hz,2H),8.39(s,1H),8.23 (d,J=6.3Hz,2H),7.89–7.45(m,4H),7.42(d,J=7.8Hz,2H),7.36(s,1H),7.24(d,J=7.8Hz,2H),5.78(s,2H),4.42(t,J=6.3Hz,2H),3.23(t,J=7.6 Hz,2H),2.34(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ189.78,182.67, 164.36,162.83,162.37,149.95,149.86,138.75,138.71,135.53,133.95,133.65,131.45,129.44,126.12,125.23,124.95,123.74,120.62,120.29, 119.18,114.51,65.05,62.53,35.69,28.64.
实施例25
化合物23的制备:(1-(4-氯苄基)-4-(3-(4,5-二羟基-9,10-二氧-9,10-二氢蒽 -2-甲酰胺基)丙基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和821.92mg(4mmol)的对位氯原子取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到444.59mg化合物23,收率为 74.86%。
1H NMR(400MHz,DMSO)δ9.58(d,J=6.4Hz,2H),8.39(s,1H),8.33 (d,J=6.3Hz,2H),7.90–7.49(m,4H),7.38(d,J=7.8Hz,2H),7.26(s,1H),7.24(d,J=7.8Hz,2H),5.75(s,2H),4.37(t,J=6.3Hz,2H),3.67(t,J=7.6 Hz,2H),2.49(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ186.75,178.84, 167.25,164.83,164.37,146.87,146.82,137.83,137.59,135.68,133.91,133.74,132.73,128.74,126.95,125.73,123.95,123.84,120.72,120.39, 116.78,115.71,65.75,62.52,33.79,28.49.
实施例26
化合物24的制备:(1-(4-溴苄基)-4-(3-(4,5-二羟基)-9,10-二氧代-9,10-二氢蒽-2-甲酰胺基)丙基)吡啶-1-鎓)溴盐
将402.41mg(1mmol)的中间体Ⅱ和999.72mg(4mmol)的对位溴原子取代的溴苄置于反应器中,使用50mL乙腈进行溶解,常温下搅拌反应12 小时,反应过程用TLC监测追踪反应终点,反应结束后,对反应液减压浓缩除去溶剂,通过柱层析进一步分离得到产物,洗脱剂为二氯甲烷:甲醇=10:1,将含有目标化合物的洗脱液收集并浓缩干燥得到443.01mg化合物24,收率为 69.40%。
1H NMR(400MHz,DMSO)δ9.78(d,J=6.4Hz,2H),8.57(d,J=6.3Hz, 2H),8.41(s,1H),7.79–7.68(m,4H),7.61(d,J=7.6Hz,2H),7.46(s,1H),7.32(d,J=7.6Hz,2H),5.63(s,2H),4.60(t,J=6.3Hz,2H),3.67(t,J=7.6 Hz,2H),2.82(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO)δ190.55,183.64, 166.25,163.83,163.37,148.87,148.52,137.79,137.74,137.52,136.51,136.24,132.53,129.24,127.95,125.63,124.65,122.64,120.69,120.29, 116.68,115.61,65.68,62.48,31.49,26.36.
实施例27
化合物2体外抗耐药菌活性测定
采用微量肉汤稀释法,以莫西沙星、万古霉素、头孢他啶、左氧氟沙星和头孢曲松为阳性对照品,测试化合物大黄酸吡啶季铵盐类化合物及其原料大黄酸的最低抑菌浓度(Minimum inhibitory concentration,MIC)。
实验菌株包括革兰氏阳性菌:耐甲氧西林金黄色葡萄球菌-171(MRSA- 171);革兰氏阴性菌:多重耐药铜绿假单胞菌-126(MDR-PA-126)、耐碳青霉烯类鲍曼不动杆菌-560(CR-AB-560)和大肠杆菌(E.coil)。
具体操作步骤如下:
(1)MHB培养基配制:称取MHB培养基20.0g,加入到1L蒸馏水中,加热煮沸至完全溶解,分装于锥形瓶中,121℃高压灭菌15min,备用;
(2)实验菌株培养至对数生长期:无菌条件下,将实验菌株接种到100mL MHB培养基中,置于37℃恒温恒湿培养箱中培养20h,备用;
(3)贮存液制备:称取待测样品,用1%DMSO溶液溶解,配置成浓度为 2560μg/mL的贮存液;称取阳性对照品,用无菌蒸馏水溶解待用;
(4)菌悬液制备:无菌条件下,将培养至对数生长期的实验菌株用MHB 培养基校正到0.5麦氏单位浊度标准后按1:200的比例进行稀释,备用;
(5)贮存液稀释和接种实验菌株:取无菌96孔板一个,无菌条件下在第 4~11孔加入10μL MHB培养基;第2孔中加入10μL阳性对照品液,第3、 4孔中加入10μL化合物2样品液;第4孔中样品液与培养基混匀,然后吸取 10μL至第5孔,混匀后再吸取10μL至第6孔,如此连续倍比稀释至第10 孔,并从第10孔中吸取10μL弃去,第11孔为阴性对照;然后,在每孔中加入上述制备好的菌悬液190μL,使每孔最终的菌液浓度为5×105CFU/mL;至此,阳性对照品浓度为256μg/mL,样品液浓度依次为128、64、32、16、8、 4、2、1μg/mL。
(6)孵育:将已接种实验菌株的96孔板盖好盖子,置37℃恒温恒湿箱中培育20-22h;
(7)MIC终点判读:黑色背景下肉眼观察96孔板中所见能完全抑制细菌生长的浓度为该样品对该种细菌的最低抑菌浓度,记录汇总结果见表1。化合物2对MRSA-171的体外抑制活性测定结果如图3所示,化合物2对MDR- PA-126的体外抑制活性测定结果如图4所示,化合物2对E.coil的体外抑制活性测定结果如图5所示。
表1受试化合物的最低抑菌浓度(μg/mL)
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对合成化合物的体外抗菌活性测定结果表明,化合物2、4、20的抗菌活性最佳,测定结果如表1所示,对MRSA-171的MIC值分别达到了8μg/mL、 16μg/mL、16μg/mL,对MDR-PA-126的抑制作用分别为16μg/mL、32μg/mL、 32μg/mL;此外,衍生物4在128μg/mL下也可抑制CR-AB-560,衍生物2 和20在64μg/mL下可抑制E.coil;化合物2、4、20的活性均要优于大黄酸,并且优于或等同于部分受试阳性药。其余化合物对于受试菌株也可以产生不同程度的抑制。其中,化合物7、8、9、14、16和21对MRSA-171的抑制作用要优于大黄酸以及受试阳性药物,化合物7、8、9、14、15、19、21对MDR- PA-126的抑制作用优于大黄酸,化合物8、9、14、17、23对于CR-AB-560 的抑制作用相比大黄酸更强,除化合物3、4、5、8、11、12、18、21外其余化合物对E.coil的抑制作用均优于大黄酸。
综上,本发明的化合物2、4、20可以对耐药型金黄色葡萄球菌、耐药型铜绿假单胞菌、耐药型鲍曼不动杆菌和大肠杆菌产生最佳的抑制效果,可做进一步的研究,为抗耐药菌候选药物的制备奠定基础。
实施例28
采用MTT法测定化合物2、4、20以及原料大黄酸的体外细胞毒性。取处于对数生长期的HepG2、HEK293和A549细胞,胰蛋白酶消化后,制成细胞悬液,接种于无菌96孔细胞培养板,每孔180μL,并且保证细胞个数为1×104个/孔,置于37℃,5%CO2恒温培养箱中培养24h。待细胞贴满孔板底部后,分别在每孔中加入浓度梯度的药液20μL,平行设6个复孔,同时设置调零孔即空白对照组(培养基、MTT、二甲基亚砜),正常对照组(不含药物组),然后置于37℃,5%CO2恒温培养箱内孵育24h后,每孔加入5g/L MTT溶液20 μL(如果药物与MTT能够反应,可先离心后弃去培养液,小心用PBS冲洗2- 3次后,再加入含MTT的培养液),继续培养4h。终止培养,轻轻吸去孔内培养液,每孔加入二甲基亚砜100μL,置摇床上低速振荡10min,使结晶物充分溶解后,于酶联免疫检测仪OD490nm处测量各孔的吸光值,并在光学显微镜下观察细胞的形态学变化情况。根据半抑制浓度(IC50)来评价药物对HepG2、 HEK293和A549细胞的细胞毒性。不同浓度大黄酸对HepG2、HEK293和 A549细胞处理的细胞存活率如图6所示,不同浓度化合物2对HepG2、 HEK293和A549细胞处理的细胞存活率如图7所示。
表2受试药物和原料药的半数抑制浓度(IC50)(μM)
表2列出了大黄酸和化合物2、4、20的半数抑制浓度值(IC50),由表可知,化合物2的毒性最小,对HepG2、HEK293和A549细胞的IC50值均大于 200μM,显著优于大黄酸本身的细胞毒性。化合物4对HepG2和A549细胞的IC50值均大于200μM,对HEK293细胞的IC50值为169.24μM,是大黄酸 (IC50=95.26μM)的1.8倍。化合物20对HEK293和A549细胞的IC50值均大于200μM,对HepG2细胞的IC50值为158.30μM,是大黄酸(IC50=79.21μM) 的2倍。由此可见,经修饰后的化合物2、4、20相比原料大黄酸,安全性显著提高。
实施例29
实验方法:选取代表性化合物2、4、20以及原料大黄酸测定溶解度。分别取过量的样品,加入适量的溶剂,恒温下超声振荡至不再溶解,取饱和溶液采取高效液相色谱法测定其吸收峰面积;再将代表性化合物2、4和20及大黄酸的饱和溶剂稀释10倍体积,采用高效液相色谱法测定其吸收峰面积;通过对吸收峰面积的计算获得其各自溶解度。
实验仪器为岛津LC-16,色谱柱为Hypersil C18 ODS(4.6×250mm×5 μm),流速为1.0mL/min,检测波长为235nm,流动相为水:乙腈=20:80。
表4代表性化合物2、4、20的溶解度(mg/mL)
化合物 | pH=7.0水 | pH=1.5盐酸水溶液 | 正辛醇 |
化合物2 | 0.72 | 0.89 | 5.86 |
化合物4 | 0.54 | 0.72 | 6.84 |
化合物20 | 0.78 | 0.97 | 4.42 |
大黄酸 | <0.01 | <0.01 | 1.02 |
由表4的测试结果显示,所测试的本发明化合物均具有良好的溶解度,在中性水溶液、模拟人体胃酸环境下pH值=1.5的盐酸水溶液以及正辛醇中的溶解性均大幅优于原料药大黄酸。这些结果表明,本发明化合物的水溶性和脂溶性均有显著的改善,具备良好的成药性潜能。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
Claims (8)
1.一种大黄酸吡啶季铵盐类化合物,其特征在于,其为如下所示化合物中的一种或其药学上可接受的盐:
2.根据权利要求1所述的大黄酸吡啶季铵盐类化合物,其特征在于,所述的药学上可接受的盐为所述化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、醋酸、富马酸、马来酸、草酸、丙二酸、琥珀酸、柠檬酸、苹果酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、谷氨酸或天冬氨酸形成的盐。
3.权利要求1-2任一项所述的大黄酸吡啶季铵盐类化合物的合成方法,其特征在于,包括:
(1)将大黄酸、EDCI、HOBT和DIPEA溶于有机溶剂,室温下活化0.5~1.5小时,后加入吡啶烷胺或吡啶烷醇,室温下反应6~15小时,反应结束后,减压浓缩除去有机溶剂,向所得固体加入饱和氯化钠水溶液,后用乙酸乙酯萃取,收集乙酸乙酯层,干燥,柱层析分离得到中间体;
(2)将中间体和溴苄溶于有机溶剂,室温下反应6~15小时,反应结束后,减压浓缩除去有机溶剂,柱层析分离得到所述化合物。
4.根据权利要求3所述的大黄酸吡啶季铵盐类化合物的合成方法,其特征在于,步骤(1)中,有机溶剂为二氯甲烷。
5.根据权利要求3所述的大黄酸吡啶季铵盐类化合物的合成方法,其特征在于,步骤(1)中,大黄酸与吡啶烷胺或吡啶烷醇摩尔比为1∶1.2。
6.根据权利要求3所述的大黄酸吡啶季铵盐类化合物的合成方法,其特征在于,步骤(2)中,有机溶剂为乙腈。
7.根据权利要求3所述的大黄酸吡啶季铵盐类化合物的合成方法,其特征在于,步骤(2)中,中间体与溴苄摩尔比为1∶4。
8.权利要求1-2任一项所述的大黄酸吡啶季铵盐类化合物在制备抗耐药菌药物中的应用,所述耐药菌为耐甲氧西林金黄色葡萄球菌-171或多重耐药铜绿假单胞菌-126。
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