CN114989131A - N’-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物及其合成和用途 - Google Patents
N’-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物及其合成和用途 Download PDFInfo
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- CN114989131A CN114989131A CN202210596849.4A CN202210596849A CN114989131A CN 114989131 A CN114989131 A CN 114989131A CN 202210596849 A CN202210596849 A CN 202210596849A CN 114989131 A CN114989131 A CN 114989131A
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- pepper
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- 125000002252 acyl group Chemical group 0.000 title claims abstract description 21
- 125000003435 aroyl group Chemical group 0.000 title claims abstract description 19
- -1 benzo [1,3] dioxolane-5-yl Chemical group 0.000 title claims description 25
- 230000015572 biosynthetic process Effects 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 22
- 235000002566 Capsicum Nutrition 0.000 claims description 18
- 239000006002 Pepper Substances 0.000 claims description 18
- 241000722363 Piper Species 0.000 claims description 18
- 235000016761 Piper aduncum Nutrition 0.000 claims description 18
- 235000017804 Piper guineense Nutrition 0.000 claims description 18
- 235000008184 Piper nigrum Nutrition 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 241000725619 Dengue virus Species 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000005251 aryl acyl group Chemical group 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
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- 238000000034 method Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims description 6
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
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- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
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- RHBGITBPARBDPH-UHFFFAOYSA-N (2E,4E)-5-(3,4-methylenedioxyphenyl)-2,4-pentadienoic acid Natural products OC(=O)C=CC=CC1=CC=C2OCOC2=C1 RHBGITBPARBDPH-UHFFFAOYSA-N 0.000 claims description 3
- RHBGITBPARBDPH-ZPUQHVIOSA-N (E,E)-piperic acid Chemical compound OC(=O)\C=C\C=C\C1=CC=C2OCOC2=C1 RHBGITBPARBDPH-ZPUQHVIOSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical group COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- PFWYHTORQZAGCA-UHFFFAOYSA-N Piperonyl acetate Chemical compound CC(=O)OCC1=CC=C2OCOC2=C1 PFWYHTORQZAGCA-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
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- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
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- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 abstract description 10
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 14
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 11
- VDVJGIYXDVPQLP-UHFFFAOYSA-N piperonylic acid Chemical compound OC(=O)C1=CC=C2OCOC2=C1 VDVJGIYXDVPQLP-UHFFFAOYSA-N 0.000 description 10
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 208000009714 Severe Dengue Diseases 0.000 description 6
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
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- 229920000936 Agarose Polymers 0.000 description 2
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 241000710842 Japanese encephalitis virus Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- SUCHFQLAEJRLOS-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)propanoyl chloride Chemical compound COC1=CC=C(CCC(Cl)=O)C=C1OC SUCHFQLAEJRLOS-UHFFFAOYSA-N 0.000 description 1
- UOVBAZLLBRLOTA-UHFFFAOYSA-N 4-methyl-1,3-benzodioxole-5-carboxylic acid Chemical compound C1=C(C(O)=O)C(C)=C2OCOC2=C1 UOVBAZLLBRLOTA-UHFFFAOYSA-N 0.000 description 1
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- 238000010521 absorption reaction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
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- QCHGUEIECOASJU-UHFFFAOYSA-N methyl 1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC=C2OCOC2=C1 QCHGUEIECOASJU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种N'‑(2‑(苯并[1,3]二氧戊烷‑5‑基)酰基)芳酰肼类化合物及其制备方法和用途，所述N'‑(2‑(苯并[1,3]二氧戊烷‑5‑基)酰基)芳酰肼类化合物结构式如下式所示：
Description
技术领域
本发明属于药物制备技术领域，涉及一种N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物及其制备方法和用途。
背景技术
登革热病毒(DENV)是由埃及伊蚊和白纹伊蚊叮咬传播的虫媒病毒，它们与黄热病病毒(YFV)、西尼罗病毒(WNV)、日本脑炎病毒(JEV)、丙型肝炎病毒(HCV)等同属于黄病毒科病毒。登革热病毒感染的潜伏期为4-7天，疾病范围从无症状感染和中度发热性疾病 (登革热)到更严重的表现，如登革热出血热(DHF)和登革热休克综合征(DSS)。后两者称重症登革热，造成多达20％的患者死亡。重症登革热的致病机制目前尚不明确，二次感染登革热病毒会导致机体产生更严重的疾病，并且重症登革热的病死率也较高。在登革热治疗方面，目前尚无特效药物上市，登革热患者仅能通过对症治疗缓解临床症状。利巴韦林是广谱核苷类抗病毒药物，对多种RNA和DNA病毒的复制有一定抑制作用，有文献报道利巴韦林能够抑制登革病毒的复制，但确切的作用机制尚不明确。2015年末，由赛诺菲巴斯德公司开发的首个登革热疫苗Dengvaxia(CYD-TDV)在菲律宾、巴西、墨西哥等国家注册，供流行区的9～45岁居民使用，但该疫苗的安全性和有效性仍有待于观察研究。迄今为止DENV药物和疫苗的研制尚无重大突破，安全有效的抗登革药物的研发迫在眉睫。
胡椒环广泛存在于天然产物中，并且具有多种活性，多个含有胡椒环的药物已经上市，例如抗癌药、抗癫痫药、抗菌药、抗抑郁药、抑制胃酸分泌药等。
目前未见与本发明化合物的相关报道。
发明内容
针对现有技术的不足，本发明的目的在于提供一种N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基) 芳酰肼类化合物及其制备方法和用途。
为达此目的，本发明采用以下技术方案：
本发明N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物结构式如式Ⅰ所示：
式Ⅰ中，n1＝0或1；n2为0～3之间的任一整数；R为甲氧基、三氟甲基、氟基中的任意一种或至少两种的组合。
本发明把胡椒环这一结构单元引入到化合物结构中，并导入酰胺基团，合成了系列链式 N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物，体外实验证明该类化合物具有明显的抗 DENV活性。
本发明所述N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物为表1所示结构之一：
表1
本发明另一目的是提供上述N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物的制备方法，步骤如下：
(1)在溶剂存在、强酸催化下，胡椒甲酸或胡椒乙酸与C1-C5醇发生酯化反应制得式Ⅱ所示的胡椒乙酸酯或胡椒甲酸酯，反应式如下：
其中n1为0或1，R1为C1-C5烷基；
所述C1-C5醇为甲醇、乙醇、丙醇、丁醇、戊醇中的任意一种，胡椒乙酸或胡椒甲酸:C1-C5 醇的摩尔比为1:(5-40)，在本发明中，醇既作为反应原料也作为反应溶剂，因此需要较多的醇；强酸作为催化剂，优选98％的浓硫酸；在50-80℃下反应1-8小时；
(2)在溶剂存在条件下，胡椒乙酸酯或胡椒甲酸酯与水合肼反应制得式Ⅲ所示的胡椒乙酰肼或胡椒甲酰肼，反应式如下：
所述胡椒乙酸酯或胡椒甲酸酯:水合肼的摩尔比为1:(1-4)；溶剂为乙二醇甲醚；反应在 110-130℃下进行5-24小时；
(3)在溶剂存在条件下，由式Ⅳ所示的芳香羧酸与氯化试剂反应制备得到式Ⅴ所示芳基酰氯，反应式如下：
其中n2为0～3之间的任一整数；
所述氯化试剂为二氯亚砜、三氯化磷、五氯化磷中的一种或几种，芳香羧酸与氯化试剂的摩尔比为1:(2-6)；反应中所用溶剂为四氢呋喃，优选地在四氢呋喃中加入1-3滴DMF；反应在0-30℃下进行1-4小时；
(4)在溶剂、碱性试剂存在下，式Ⅲ所示的胡椒乙酰肼或胡椒甲酰肼与式Ⅴ所示的芳基酰氯反应制得式Ⅰ所示N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物，反应式如下：
所述胡椒乙酰肼或胡椒甲酰肼:芳基酰氯的摩尔比为1:(1-2)，碱性试剂为三乙胺；碱性试剂:胡椒乙酰肼或胡椒甲酰肼的摩尔比为1:(1-3)；反应在0-30℃下进行2-24小时。
本发明另一目的是将上述N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物应用在制备抗登革病毒药物中，实验证明该类化合物具有明显的抗DENV活性，可作为抗登革病毒药物的活性成分候选物。
本发明所述的抗登革病毒药物的成分(或有效成分)为N′-(2-(苯并[1,3]二氧戊烷-5-基) 酰基)芳酰肼类化合物，还可以加入一种或多种药物上可接受的辅料，以改善药物吸收效果或便于服用，如制成胶囊或丸剂、粉剂、片剂、粒剂、口服液和注射液等，即制成药剂学上适宜的使用剂型；还可以与其他活性成分组合制得抗登革病毒的药物。
相对于现有技术，本发明具有以下有益效果：
本发明制备的N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物对DENV病毒具有明显的抑制作用，抗DENV病毒治疗指数高于现临床药物利巴韦林(Ribavirin)，可作为抗DENV 药物候选物，并且本发明的制备方法简单、产率高，适用于工业生产。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
实施例1，在本实施例中，通过以下方法制备式Ⅰ-1化合物：
(1)在500mL干燥圆底烧瓶中，依次加入8.3g胡椒甲酸(50mmol)、60mL甲醇、3mL98％浓硫酸，在70℃油浴中反应，反应约1-3小时，薄层色谱(TLC)跟踪反应进度至完全反应后，0℃下加入饱和碳酸氢钠溶液淬灭反应，减压蒸馏除去甲醇，加入50mL水，用乙酸乙酯萃取三次，合并有机相，依次用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤无水硫酸钠，减压蒸馏除去溶剂，得到式Ⅱ胡椒甲酸甲酯粗产物，本品无需纯化直接用于下一步反应；
(2)在500mL圆底烧瓶中加入胡椒甲酸甲酯(48mmol)，并用40mL乙二醇甲醚溶解，随后加入5mL水合肼，在油浴115℃中加热回流反应约20小时，薄层色谱(TLC)跟踪反应进度至完全反应后，冷却至室温，加入50mL水，静置析出白色固体，抽滤得到粗产物，用乙醇重结晶得到式Ⅲ白色固体胡椒甲酰肼；
(3)在50mL干燥圆底烧瓶中，依次加入1.5mmol取代芳香羧酸、5mL无水四氢呋喃(滴加一滴DMF)，在0℃冰浴条件下加入0.5mL氯化亚砜，室温下反应1h，TLC跟踪反应进度至完全反应后，减压蒸馏除去溶剂，得式Ⅴ所示芳基酰氯粗产物，可直接用于下一步反应；
(4)在50mL干燥圆底烧瓶中，依次加入1mmol胡椒甲酰肼、5mL无水四氢呋喃，然后加入1.5mL经无水处理的三乙胺，在0℃冰浴条件下缓慢滴加入含3,4二甲氧基苯丙酰氯(1.5mmol)的无水四氢呋喃溶液(将步骤(3)芳基酰氯溶解在少量的无水四氢呋喃溶液)，产生沉淀，继续室温下反应12h，TLC跟踪反应进度至完全反应后，减压蒸馏除去溶剂，乙酸乙酯溶解，有机相用依次用水和饱和氯化钠溶液洗涤，减压浓缩得到粗产物，用乙醇重结晶得到白色或淡黄色Ⅰ-1固体产物，产率：68％。mp：185.7℃；
对得到的产物进行核磁氢谱和质谱表征，结果如下：
1H NMR(400MHz,DMSO-d6)δ(ppm):10.16(s,1H,NH),9.86(s,1H,NH),7.49(d,J＝8.1, 1H,ArH),7.40(s,1H,ArH),7.02(d,J＝8.1Hz,1H,ArH),6.88–6.83(m,2H,ArH),6.76(d,J＝ 2.2Hz,1H,ArH),6.11(s,2H,CH2),3.75(s,3H,CH3),3.72(t,J＝7.7Hz,2H,CH2),2.81(t,J＝ 7.7Hz,2H,CH2)；m/z 372.1[M++1]。
实施例2
在本实施例中，制备式Ⅰ-2到式Ⅰ-12的化合物，制备方法与实施例1式Ⅰ-1化合物的制备方法相同，不同在于：步骤(4)中使用的芳基酰氯分别为
在本实施例中，制备式Ⅰ-13到式Ⅰ-26的化合物，制备方法与实施例1式Ⅰ-1化合物的制备相同，不同在于，步骤(1)中使用的是胡椒乙酸，步骤(2)中使用的是胡椒乙酸甲酯，步骤(4)中使用的芳基酰氯分别为
制备得到的式Ⅰ-2到式Ⅰ-26化合物的性状、产率以及结构表征结果如下：
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-2-甲氧基-苯丙酰肼(式Ⅰ-2)：白色固体，产率： 81％，mp:135.9℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.17(s,1H,NH),9.86(s,1H,NH), 7.50(d,J＝8.2Hz,1H,ArH),7.41(s,1H,ArH),7.23-7.19(m,2H,ArH),7.03(d,J＝8.2Hz,1H, ArH),6.97(d,J＝8.1Hz,1H,ArH),6.88(t,J＝7.4Hz,1H,ArH),6.13(s,2H,CH2),3.82(s,3H, CH3),2.84(t,J＝7.9Hz,2H,CH2),2.49–2.42(t,J＝7.9Hz,2H,CH2)；m/z342.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-4-甲氧基-苯丙酰肼(式Ⅰ-3)：白色固体，产率： 61％，mp:176.81℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.17(s,1H,NH),9.87(s,1H,NH), 7.49(d,J＝8.3Hz,1H,ArH),7.40(s,1H,ArH),7.21–7.14(m,2H,ArH),7.02(d,J＝6.5Hz,1H), 6.89–6.83(m,2H,ArH),6.12(s,2H,CH2),3.72(s,3H,CH3),2.81(t,J＝7.8Hz,2H,CH2),2.46 (t,J＝7.8Hz,2H,CH2)；m/z 342.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-4-甲氧基苯乙酰肼(式Ⅰ-4)：白色固体，产率： 72％，mp:197.5℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.17(s,1H,NH),10.07(s,1H,NH), 7.46(dd,J＝8.1,1.8Hz,1H,ArH),7.38(d,J＝1.8Hz,1H,ArH),7.26–7.21(m,2H,ArH),6.99 (d,J＝8.1Hz,1H,ArH),6.89–6.84(m,2H,ArH),6.09(s,2H,CH2),3.72(s,3H,CH3),3.44(s, 2H,CH2)；m/z 328.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-3-甲氧基苯乙酰肼(式Ⅰ-5)：白色固体，产率：70％，mp:161.2℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.22(s,1H,NH),10.13(s,1H,NH), 7.48(dd,J＝8.1,1.8Hz,1H,ArH),7.39(d,J＝1.8Hz,1H,ArH),7.22(d,J＝7.9Hz,1H,ArH), 7.01(d,J＝8.1Hz,1H,ArH),6.95(s,1H,ArH),6.91(d,J＝7.6Hz,1H,ArH),6.11(s,2H,CH2), 3.75(s,3H,CH3),3.50(s,2H,CH2)；m/z 328.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-2-三氟甲基苯丙酰肼(式Ⅰ-6)：白色固体，产率： 54％，mp:192.88℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.18(s,1H,NH),9.93(s,1H,NH), 7.70(dd,J＝7.9,1.3Hz,1H,ArH),7.64(t,J＝7.7Hz,1H,ArH),7.56(d,J＝7.7Hz,1H,ArH), 7.50(dd,J＝8.2,1.8Hz,1H,ArH),7.44(t,J＝7.7Hz,1H,ArH),7.40(d,J＝1.7Hz,1H,ArH), 7.02(d,J＝8.1Hz,1H,ArH),6.12(s,2H,CH2),3.05(t,J＝8.0Hz,2H,CH2),2.53(t,J＝8.0Hz, 2H,CH2)；m/z 380.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-2-三氟甲基苯乙酰肼(式Ⅰ-7)：白色固体，产率： 65％，mp:239.1℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.27(s,1H,NH),10.19(s,1H,NH), 7.71(d,J＝7.7Hz,1H,ArH),7.65(d,J＝7.5Hz,1H,ArH),7.61(d,J＝7.4Hz,1H,ArH),7.49(m, 2H,ArH),7.41(d,J＝1.7Hz,1H,ArH),7.02(d,J＝8.2Hz,1H,ArH),6.11(s,2H,CH2),3.77(s, 2H,CH2)；m/z 366.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-3,5-二甲氧基苯乙酰肼(式Ⅰ-8)：白色固体，产率：42％，mp:190.9℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.21(s,1H,NH),10.10(s,1H, NH),7.49(dd,J＝8.2,1.8Hz,1H,ArH),7.40(d,J＝1.8Hz,1H,ArH),7.02(d,J＝8.2Hz,1H, ArH),6.55(d,J＝2.3Hz,2H,ArH),6.38(t,J＝2.3Hz,1H,ArH),6.12(s,2H,CH2),3.74(s,6H, 2CH3),3.46(s,2H,CH2)；m/z 358.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-3,4-二甲氧基苯乙酰肼(式Ⅰ-9)：白色固体，产率：51％，mp:185.3℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.21(s,1H,NH),10.08(s,1H, NH),7.49(dd,J＝8.2,1.7Hz,1H,ArH),7.39(d,J＝1.7Hz,1H,ArH),7.04–6.98(m,2H,ArH), 6.92–6.83(m,2H,ArH),6.11(s,2H,CH2),3.76(s,3H,CH3),3.73(s,3H,CH3),3.45(s,2H,CH2)； m/z 358.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-2-氟苯乙酰肼(式Ⅰ-10)：白色固体，产率：60％， mp:195.8℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.27(s,1H,NH),10.21(s,1H,NH),7.49 (dd,J＝8.2,1.8Hz,1H,ArH),7.47–7.42(m,1H,ArH),7.41(d,J＝1.7Hz,1H,ArH),7.30(d,J＝ 2.2Hz,1H,ArH),7.20–7.14(m,2H,ArH),7.02(d,J＝8.2Hz,1H,ArH),6.11(s,2H,CH2),3.60 (s,2H,CH2)；m/z 316.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-3-甲氧基苯丙酰肼(式Ⅰ-11)：白色固体，产率：65％，mp:146.1℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.16(s,1H,NH),9.86(s,1H,NH), 7.49(dd,J＝8.2,1.8Hz,1H,ArH),7.40(d,J＝1.7Hz,1H,ArH),7.20(t,J＝8.1Hz,1H,ArH), 7.01(d,J＝8.2Hz,1H,ArH),6.85–6.81(m,2H,ArH),6.76(dd,J＝8.2,1.5Hz,1H,ArH),6.11(s, 2H,CH2),3.74(s,3H,CH3),2.85(t,2H,CH2),2.53–2.47(m,2H,CH2)；m/z342.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)甲酰基)-2-氟苯丙酰肼(式Ⅰ-12)：白色固体，产率：54％， mp:187.6℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.19(s,1H,NH),9.92(s,1H,NH),7.49(dd, J＝8.1,1.7Hz,1H,ArH),7.40(d,J＝1.7Hz,1H,ArH),7.36(td,J＝7.8,1.6Hz,1H,ArH),7.30– 7.23(m,1H,ArH),7.19–7.12(m,2H,ArH),7.02(d,J＝8.1Hz,1H,ArH),6.12(s,2H,CH2),2.90 (t,J＝7.8Hz,2H,CH2),2.51(t,J＝7.8Hz,2H,CH2)；m/z 330.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-3,4-二甲氧基苯丙酰肼(式Ⅰ-13)：白色固体，产率：92％，mp:217.4℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.03(s,1H,NH),9.85(s,1H,NH), 6.88(d,J＝1.6Hz,1H,ArH),6.85–6.81(m,3H,ArH),6.73(ddd,J＝12.8,8.0,1.7Hz,2H,ArH), 5.98(s,2H,CH2),3.72(s,3H,CH3),3.70(s,3H,CH3),3.38(s,2H,CH2),2.76(t,J＝7.7Hz,2H, CH2),2.41(t,J＝7.7Hz,2H,CH2)；m/z 386.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-2-甲氧基苯丙酰肼(式Ⅰ-14)：白色固体，产率： 53％，mp:211.4℃；1H NMR(400MHz,DMSO-d6)δ(ppm):9.95(s,1H,NH),9.78(s,1H,NH), 7.23–7.15(m,2H,ArH),6.96(d,J＝8.1Hz,1H,ArH),6.91–6.83(m,3H,ArH),6.77(d,J＝8.0, 1H,ArH),5.99(s,2H,CH2),3.81(s,3H,CH3),3.40(s,2H,CH2),2.81(t,J＝9.1,2H,CH2),2.40(t, J＝9.1,2H,CH2)；m/z 356.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-3-甲氧基苯丙酰肼(式Ⅰ-15)：白色固体，产率： 37％，mp:179.3℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.01(s,1H,NH),9.85(s,1H,NH), 7.20(t,J＝8.1Hz,1H,ArH),6.90–6.84(m,2H,ArH),6.83–6.79(m,2H,ArH),6.77(m,2H, ArH),6.00(s,2H,CH2),3.75(s,3H,CH3),3.40(s,2H,CH2),2.83(t,J＝7.7Hz,2H,CH2),2.46(t, J＝7.7Hz,2H,CH2)；m/z 356.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-4-甲氧基苯丙酰肼(式Ⅰ-16)：白色固体，产率： 63％，mp:222.7℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.01(s,1H,NH),9.85(s,1H,NH), 7.16(d,J＝8.2Hz,2H,ArH),6.91(d,J＝1.6Hz,1H,ArH),6.89–6.84(m,3H,ArH),6.78(dd,J ＝8.0,1.6Hz,1H,ArH),6.00(s,2H,CH2),3.74(s,3H,CH3),3.41(s,2H,CH2),2.80(t,J＝7.7Hz, 2H,CH2),2.42(t,J＝7.7Hz,2H,CH2)；m/z 356.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-2-三氟甲基苯丙酰肼(式Ⅰ-17)：白色固体，产率： 41％，mp:234.9℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.04(s,1H,NH),9.93(s,1H,NH), 7.70(d,J＝7.9Hz,1H,ArH),7.63(t,J＝7.5Hz,1H,ArH),7.54(d,J＝7.7Hz,1H,ArH),7.44(t, J＝7.6Hz,1H,ArH),6.90(d,J＝1.6Hz,1H,ArH),6.86(d,J＝7.9Hz,1H,ArH),6.77(dd,J＝8.0, 1.7Hz,1H,ArH),6.00(s,2H,CH2),3.40(s,2H,CH2),3.03(t,J＝8.0Hz,2H,CH2),2.48(t,J＝ 8.0Hz,2H,CH2)；m/z 394.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-2-氟苯丙酰肼(式Ⅰ-18)：白色固体，产率：46％， mp:247.6℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.00(s,1H,NH),9.87(s,1H,NH),7.33(d, J＝7.7Hz,1H,ArH),7.29–7.23(m,1H,ArH),7.18–7.11(m,2H,ArH),6.90(d,J＝1.7Hz,1H, ArH),6.85(d,J＝7.9Hz,1H,ArH),6.77(d,J＝7.9Hz,1H,ArH),5.99(s,2H,CH2),3.40(s,2H, CH2),2.88(t,J＝7.8Hz,2H,CH2),2.47(t,J＝7.8Hz,2H,CH2)；m/z 344.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-2-甲氧基苯乙酰肼(式Ⅰ-19)：白色固体，产率： 67％，mp:202.9℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.01(s,1H,NH),9.90(s,1H,NH), 7.24(t,J＝7.3Hz,2H,ArH),6.97(d,J＝7.7Hz,1H,ArH),6.92–6.87(m,2H,ArH),6.85(d,J＝ 8.0Hz,1H,ArH),6.76(dd,J＝7.9,1.7Hz,1H,ArH),5.99(s,2H,CH2),3.77(s,3H,CH3),3.45(s, 2H,CH2),3.39(s,2H,CH2)；m/z 342.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-3-甲氧基苯乙酰肼(式Ⅰ-20)：白色固体，产率： 66％，mp:187.8℃；1H NMR(600MHz,DMSO-d6)δ(ppm):10.14(s,1H,NH),10.12(s,1H,NH), 7.20(t,J＝7.9Hz,1H,ArH),6.90(t,J＝2.0Hz,1H,ArH),6.88–6.85(m,2H,ArH),6.83(d,J＝ 7.9Hz,1H,ArH),6.79(dd,J＝8.2,2.6Hz,1H,ArH),6.74(dd,J＝7.9,1.7Hz,1H,ArH),5.97(s, 2H,CH2),3.73(s,3H,CH3),3.43(s,2H,CH2),3.38(s,2H,CH2)；m/z 342.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-4-甲氧基苯乙酰肼(式Ⅰ-21)：白色固体，产率： 59％，mp:210.8℃；1H NMR(600MHz,DMSO-d6)δ(ppm):10.05(s,2H,2NH),7.20(d,J＝8.2Hz, 2H,ArH),6.92–6.80(m,4H,ArH),6.74(dd,J＝8.0,1.6Hz,1H,ArH),5.97(s,2H,CH2),3.72(s, 3H,CH3),3.38(s,2H,CH2),3.36(s,2H,CH2)；m/z 342.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-3,4-二甲氧基苯乙酰肼(式Ⅰ-22)：白色固体，产率：60％，mp:214.6℃；1H NMR(600MHz,DMSO-d6)δ(ppm):10.05(s,2H,2NH),6.93(d,J＝2.0 Hz,1H,ArH),6.87–6.85(m,2H,ArH),6.83(d,J＝7.9Hz,1H,ArH),6.79(dd,J＝8.2,2.0Hz, 1H,ArH),6.74(dd,J＝8.0,1.7Hz,1H,ArH),5.97(s,2H,CH2),3.73(s,3H,CH3),3.71(s,3H, CH3),3.37(s,2H,CH2),3.36(s,2H,CH2)；m/z 372.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-3,5-二甲氧基苯乙酰肼(式Ⅰ-23)：白色固体，产率：51％，mp:210.6℃；1H NMR(600MHz,DMSO-d6)δ(ppm):10.11(s,2H,2NH),6.88(d,J＝1.7 Hz,1H,ArH),6.83(d,J＝8.0Hz,1H,ArH),6.74(dd,J＝8.0,1.7Hz,1H,ArH),6.49(d,J＝2.3 Hz,2H,ArH),6.35(t,J＝2.3Hz,1H,ArH),5.97(s,2H,CH2),3.71(s,6H,2CH3),3.39(s,2H, CH2),3.38(s,2H,CH2)；m/z 372.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-2-氟苯乙酰肼(式Ⅰ-24)：白色固体，产率：48％， mp:230.4℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.13(s,1H,NH),10.10(s,1H,NH),7.42– 7.36(m,1H,ArH),7.35–7.26(m,1H,ArH),7.20–7.12(m,2H,ArH),6.90–6.82(m,2H,ArH), 6.75(d,J＝8.0Hz,1H,ArH),5.98(s,2H,CH2),3.54(s,2H,CH2),3.38(s,2H,CH2)；m/z 330.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-4-氟苯乙酰肼(式Ⅰ-25)：白色固体，产率：51％， mp:228.4℃；1H NMR(400MHz,DMSO-d6)δ(ppm):10.18(s,1H,NH),10.13(s,1H,NH),7.37 (dd,J＝8.4,5.6Hz,2H,ArH),7.18(t,J＝8.8Hz,2H,ArH),6.93–6.87(m,2H,ArH),6.79(dd,J ＝7.9,1.6Hz,1H,ArH),6.02(s,2H,CH2),3.51(s,2H,CH2),3.42(s,2H,CH2)；m/z 330.1[M++1]。
N′-(2-(苯并[1,3]二氧戊烷-5-基)乙酰基)-3-氟苯乙酰肼(式Ⅰ-26)：白色固体，产率：53％， mp:224.4℃；1H NMR(600MHz,DMSO-d6)δ(ppm):10.17(s,1H,NH),10.11(s,1H,NH),7.36– 7.33(m,1H,ArH),7.14–7.12(m,2H,ArH),7.10–7.04(m,1H,ArH),6.87(d,J＝1.6Hz,1H, ArH),6.83(d,J＝7.8Hz,1H,ArH),6.74(dd,J＝8.0,1.8Hz,1H,ArH),5.97(s,2H,CH2),3.51(s, 2H,CH2),3.38(s,2H,CH2)；m/z 330.1[M++1]。
实施例4
在本实施例中，对式Ⅰ-1到式Ⅰ-26化合物的体外抗DENV活性进行评价，采用Vero细胞，DENV-II D01090(GenBank:KY882458)病毒株进行体外细胞水平抗DENV活性评价，方法如下：
MTT法检测药物细胞毒性：在96孔细胞培养板内，将Vero细胞按3×105个/孔接种，37℃、 5％CO2培养24h；待细胞长成单层后，弃去培养上清液，加入含梯度稀释待测化合物的DMEM 培养基，每个浓度设置3个复孔，并设正常细胞对照、溶剂对照、空白对照，培养3天后，每孔添加20μL 5mg/mL MTT，在37℃恒温培养箱中继续孵育4h，弃去100μL上清液，加入100μL 12％SDS-50％DMF溶液，继续37℃孵育过夜，待结晶完全溶解后，震荡混合均匀，Bio-TEK酶标仪检测OD值(检测波长570nm，参考波长630nm)；根据实验结果绘制剂量反应曲线，使用Reed&Muench法计算得到50％抑制细胞生长浓度(CC50)值。
噬斑法测定化合物对病毒的抑制活性：在12孔细胞培养板内，将Vero细胞按3×105个/ 孔接种,37℃、5％CO2培养24h；待细胞长成单层后，弃培养上清，1×PBS洗1遍。在含2％新生牛血清(NCS)的DMEM细胞维持液中加入DENV-2(MOI.＝0.05)，每孔加入400μL，设3个重复孔，并设正常细胞对照组、阴性对照、溶剂对照、阳性对照，37℃、5％CO2培养箱培养4h后，加入适量的1×PBS洗涤12孔板。待测样品用4％NCS DMEM培养基浓度梯度稀释后，每孔各加入1mL待测样品稀释液和1mL 2％低熔点琼脂糖混合培养基；待琼脂糖凝固后，转移至培养箱中倒置细胞板，连续培养5d后记录并观察细胞的病变程度。4％多聚甲醛固定琼脂块10-15min后，将其轻轻吹掉，用0.8％结晶紫染色20min，清水洗涤残余结晶紫溶液后烘干，酶联荧斑点分析仪(CTL)进行噬斑数统计，根据实验结果绘制剂量反应曲线，计算出待测样品的EC50。
抗DENV药效评价：治疗指数(TI)为药物对细胞的半数抑制浓度CC50和对病毒的半数效应浓度EC50的比值，代表药物的安全性，此数值越大越安全。
以临床治疗药物利巴韦林(Ribavirin)作为阳性对照，将上述方法合成的化合物进行了药物细胞毒性和抗DENV病毒活性实验，表1中大部分化合物在50μM有效抑制DENV的复制，表2中所列15个化合物治疗指数高于阳性对照Ribavirin，其中活性最好的3个化合物式Ⅰ-4、式Ⅰ-7和式Ⅰ-8治疗指数比Ribavirin高15-25倍，可作为抗DENV的先导化合物加以利用。
表2
| 编号 | CC<sub>50</sub>(μM) | EC<sub>50</sub>(μM) | TI |
| 式I-1 | >200 | 7.39±0.04 | >27.06 |
| 式I-2 | >200 | 12.50±0.09 | >16 |
| 式I-3 | >200 | 17.67±0.12 | >11.32 |
| 式I-4 | >200 | 2.94±0.10 | >68.02 |
| 式I-5 | >200 | 33.03±0.26 | >6.06 |
| 式I-6 | >200 | 23.24±0.11 | >8.06 |
| 式I-7 | >200 | 2.23±0.46 | >89.69 |
| 式I-8 | >200 | 1.86±0.06 | >107.53 |
| 式I-9 | >200 | 25.0±0.18 | >8 |
| 式I-13 | >200 | 17.88±0.27 | >11.19 |
| 式I-14 | >200 | 19.86±0.37 | >10.07 |
| 式I-16 | >200 | 25.0±0.23 | >8 |
| 式I-17 | >200 | 40.0±0.08 | >5 |
| 式I-21 | >200 | 17.63±0.16 | >11.34 |
| 式I-23 | >200 | 13.37±0.25 | >14.96 |
| Ribavirin | >200 | 45.73±0.34 | >4.37 |
申请人声明，本发明通过上述实施例来说明本发明的N′-(2-(苯并[1,3]二氧戊烷-5-基)酰基) 芳酰肼类化合物及其制备方法和用途，但本发明并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围内。
Claims (8)
1.结构式如式Ⅰ所示的N'-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物：
式中，n1为0或1，n2为0～3之间的任一整数；
R为H、卤素、取代的或未取代的C1-C6烷基、取代的或未取代的C1-C6烷氧基中的一种或至少两种的组合。
2.根据权利要求1所述的N'-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物，其特征在于，N'-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物为如下结构：
3.权利要求1或2中所述的N'-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物的制备方法，其特征在于，步骤如下：
(1)在溶剂存在、强酸催化下，胡椒甲酸或胡椒乙酸与C1-C5醇发生酯化反应制得式Ⅱ所示的胡椒乙酸酯或胡椒甲酸酯，反应式如下：
其中n1为0或1，R1为C1-C5烷基；
(2)在溶剂存在条件下，胡椒乙酸酯或胡椒甲酸酯与水合肼反应制得式Ⅲ所示的胡椒乙酰肼或胡椒甲酰肼，反应式如下：
(3)在溶剂存在条件下，由式Ⅳ所示的芳香羧酸与氯化试剂反应制备得到式Ⅴ所示芳基酰氯，反应式如下：
其中n2为0～3之间的任一整数，R为甲氧基、三氟甲基、氟基中的任意一种或至少两种的组合；
(4)在溶剂、碱性试剂存在下，式Ⅲ所示的胡椒乙酰肼或胡椒甲酰肼与式Ⅴ所示的芳基酰氯反应制得式Ⅰ所示N'-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物，反应式如下：
4.根据权利要求3所述的制备方法，其特征在于：步骤(1)中C1-C5醇为甲醇、乙醇、丙醇、丁醇、戊醇中的一种，胡椒乙酸或胡椒甲酸:C1-C5醇的摩尔比为1:(5-40)；强酸为浓硫酸；在50-80℃下反应1-8小时。
5.根据权利要求3或4所述的制备方法，其特征在于：步骤(2)中胡椒乙酸酯或胡椒甲酸酯:水合肼的摩尔比为1:(1-4)；溶剂为乙二醇甲醚；反应在110-130℃下进行5-24小时。
6.根据权利要求5中所述的制备方法，其特征在于：步骤(3)中氯化试剂为二氯亚砜、三氯化磷、五氯化磷中的一种或几种，芳香羧酸与氯化试剂的摩尔比为1:(2-6)；反应中所用溶剂为四氢呋喃；反应在0-30℃下进行1-4小时。
7.根据权利要求6所述的制备方法，其特征在于：步骤(4)中胡椒乙酰肼或胡椒甲酰肼:芳基酰氯的摩尔比为1:(1-2)，碱性试剂为三乙胺；碱性试剂:胡椒乙酰肼或胡椒甲酰肼的摩尔比为1:(1-3)；反应在0-30℃下进行2-24小时。
8.权利要求1或2所述的N'-(2-(苯并[1,3]二氧戊烷-5-基)酰基)芳酰肼类化合物在制备抗登革热病毒药物中的应用。
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