CN114920663B - 一种联苯类奥司他韦衍生物及其制备方法与应用 - Google Patents
一种联苯类奥司他韦衍生物及其制备方法与应用 Download PDFInfo
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- -1 Biphenyl oseltamivir derivative Chemical class 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 235000010290 biphenyl Nutrition 0.000 title claims abstract description 20
- 239000004305 biphenyl Substances 0.000 title claims abstract description 20
- 206010022000 influenza Diseases 0.000 claims abstract description 18
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- 238000006243 chemical reaction Methods 0.000 description 17
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- ZDICHAGDCMMAKV-UHFFFAOYSA-N 3-bromo-2-chlorobenzaldehyde Chemical group ClC1=C(Br)C=CC=C1C=O ZDICHAGDCMMAKV-UHFFFAOYSA-N 0.000 description 1
- HHVUFPUWPWOWOA-UHFFFAOYSA-N 3-bromo-2-methylbenzaldehyde Chemical group CC1=C(Br)C=CC=C1C=O HHVUFPUWPWOWOA-UHFFFAOYSA-N 0.000 description 1
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- FAHZIKXYYRGSHF-UHFFFAOYSA-N 3-bromo-4-fluorobenzaldehyde Chemical group FC1=CC=C(C=O)C=C1Br FAHZIKXYYRGSHF-UHFFFAOYSA-N 0.000 description 1
- QMPNFQLVIGPNEI-UHFFFAOYSA-N 3-bromo-4-methoxybenzaldehyde Chemical group COC1=CC=C(C=O)C=C1Br QMPNFQLVIGPNEI-UHFFFAOYSA-N 0.000 description 1
- WTXXUAHMTVAQHW-UHFFFAOYSA-N 3-bromo-4-methylbenzaldehyde Chemical group CC1=CC=C(C=O)C=C1Br WTXXUAHMTVAQHW-UHFFFAOYSA-N 0.000 description 1
- JGMGDYUVFBBCEQ-UHFFFAOYSA-N 3-bromo-5-chlorobenzaldehyde Chemical group ClC1=CC(Br)=CC(C=O)=C1 JGMGDYUVFBBCEQ-UHFFFAOYSA-N 0.000 description 1
- MEFQRXHVMJPOKZ-UHFFFAOYSA-N 3-bromo-5-fluorobenzaldehyde Chemical group FC1=CC(Br)=CC(C=O)=C1 MEFQRXHVMJPOKZ-UHFFFAOYSA-N 0.000 description 1
- DMSLPBFUZSQMQT-UHFFFAOYSA-N 3-bromo-5-methylbenzaldehyde Chemical group CC1=CC(Br)=CC(C=O)=C1 DMSLPBFUZSQMQT-UHFFFAOYSA-N 0.000 description 1
- JKHVNWUVFDFSAZ-UHFFFAOYSA-N 5-bromo-2-fluoro-3-methylbenzaldehyde Chemical group CC1=CC(Br)=CC(C=O)=C1F JKHVNWUVFDFSAZ-UHFFFAOYSA-N 0.000 description 1
- MMFGGDVQLQQQRX-UHFFFAOYSA-N 5-bromo-2-fluorobenzaldehyde Chemical group FC1=CC=C(Br)C=C1C=O MMFGGDVQLQQQRX-UHFFFAOYSA-N 0.000 description 1
- YILPAIKZHXATHY-UHFFFAOYSA-N 5-bromo-2-methylbenzaldehyde Chemical group CC1=CC=C(Br)C=C1C=O YILPAIKZHXATHY-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种联苯类奥司他韦衍生物及其制备方法和应用,所述的衍生物具有通式I所示的结构。本发明还提供了上述化合物以及含有一个或多个此类化合物的组合物在制备抗流感药物中的应用。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域,具体涉及一种联苯类奥司他韦衍生物及其制备方法与应用。
背景技术
流行性感冒(流感)是由流感病毒引起的一种呼吸道传染病,近期研究表明流感可与新冠共存,两者合并感染的死亡风险大大增加,因此流感的防治依然是当前及未来医药卫生领域重点关注的课题。尽管目前已有近十种小分子药物获批用于治疗流感,但是在流感病毒感染过程中,由于抗原漂移/转移、基因适应性突变和重组等因素产生的耐药性,大大削弱了这些上市药物的疗效,因此研发新一代抗流感药物一直是该领域的研究热点。
神经氨酸酶是流感病毒的一种表面糖蛋白,在子代病毒的释放过程中发挥着关键作用,是抗流感药物设计的重要靶点。目前临床治疗流感的首选药物磷酸奥司他韦(oseltamivir phosphate)就是一种神经氨酸酶抑制剂,然而该药物饱受耐药性问题的困扰,特别是临床最常见的NA-H274Y耐药突变株使其基本丧失了原有的疗效,因此开发新型、高效、抗耐药的神经氨酸酶抑制剂具有十分重要的意义。目前已发现的甲型流感病毒神经氨酸酶依据其一级结构序列和进化关系可分为两组:第一组(Group-1)包括N1、N4、N5和N8,第二组(Group-2)包括N2、N3、N6、N7和N9。研究发现,第一组神经氨酸酶的活性中心附近存在一个体积约为的空腔—150-腔,该空腔与活性中心直接连通,可以作为药物设计的辅助结合位点。值得注意的是,奥司他韦与神经氨酸酶的共晶结构显示,奥司他韦的C-5位氨基正对着150-腔。因此,通过该位点对奥司他韦的化学结构进行修饰,以增强小分子与150-腔的结合力,是发现高活性、高选择性及高抗耐药性的新型神经氨酸酶抑制剂的有效途径。
发明内容
本发明提供了一种可以靶向150-腔的联苯类奥司他韦衍生物及其制备方法,本发明还提供了该类化合物的抗流感活性结果及其用途。
本发明的技术方案如下:
一、联苯类奥司他韦衍生物
本发明的联苯类奥司他韦衍生物,或其药学上可接受的盐,具有如下通式I所示的结构:
其中,
R为卤素、硝基、羟基、氰基、酯基、羧基、乙酰氨基、氨基、羟甲基、C1-C12烷基、C1-C12烷氧基、部分或全部氟取代的C1-C3烷基、C3-C12环烷氧基、取代或未取代的苯基、取代或未取代的六元杂环、取代或未取代的五元杂环,所述的苯基、六元杂环、五元杂环上的取代基选自卤素、羟基、巯基、氨基、氰基、硝基、C1-C6的烷基、C1-C3的烷氧基、部分或全部氟取代的C1-C3烷基。
根据本发明优选的,R为卤素、甲基、硝基、甲氧基、羟基、三氟甲基、氰基、酯基、羧基、乙酰氨基、羟甲基、苯基、吡啶基、噻吩基、呋喃基、吡咯基。
根据本发明进一步优选的联苯类奥司他韦衍生物,是下列之一:
二、联苯类奥司他韦衍生物的制备方法
本发明联苯类奥司他韦衍生物的制备方法,以取代的间溴苯甲醛和苯硼酸为起始原料,在四(三苯基膦)钯的催化下发生Suzuki偶联反应得到中间体A,随后与磷酸奥司他韦发生Borch还原反应制得中间体B,最后B在氢氧化钠水溶液中发生水解反应并经稀盐酸酸化得目标化合物;
反应路线如下:
反应试剂与反应条件:i)碳酸钾,四(三苯基膦)钯,二甲基亚砜,N2保护,回流;ii)磷酸奥司他韦,氰基硼氢化钠,甲醇,室温;iii)4M氢氧化钠溶液,甲醇,室温,3M盐酸溶液酸化;
其中,R同上述通式I所示:
所述的取代的间溴苯甲醛为卤素取代的间溴苯甲醛、硝基取代的间溴苯甲醛、羟基取代的间溴苯甲醛、氰基取代的间溴苯甲醛、酯基取代的间溴苯甲醛、乙酰氨基取代的间溴苯甲醛、氨基取代的间溴苯甲醛、羟甲基取代的间溴苯甲醛、C1-C12烷基取代的间溴苯甲醛、C1-C12烷氧基取代的间溴苯甲醛、部分或全部氟取代的C1-C3烷基取代的间溴苯甲醛、C3-C12环烷氧基取代的间溴苯甲醛、取代或未取代的苯基、五元杂环和六元杂环取代的间溴苯甲醛。
本发明所述的室温为20-30℃。
优选的,本发明联苯类奥司他韦衍生物的制备方法,具体步骤如下:
(1)将3.0mmol苯硼酸溶于20mL DMSO中,然后依次加入3.0mmol取代的3-溴苯甲醛,13.5mmol K2CO3和催化量的四(三苯基膦)钯,将反应液在120℃和氮气保护下搅拌12小时。反应完毕后,冷却反应液至室温,加入100mL饱和氯化钠溶液,然后用乙酸乙酯50mL×3萃取。合并有机相,用无水硫酸镁干燥2小时,过滤,将滤液蒸干得白色粉末状固体或透明油状物A,不经纯化直接进行下一步;
(2)将2.0mmol磷酸奥司他韦和2.4mmolA溶于30mL甲醇中,室温下搅拌30分钟,然后加入5.0mmol氰基硼氢化钠,在室温下继续搅拌6小时。TLC检测反应完全后,减压除去溶剂,然后向残余物中加入30mL饱和氯化钠溶液和10mL饱和碳酸钠溶液。将混合液用乙酸乙酯3×30mL萃取,合并有机相,用无水硫酸镁干燥2小时,过滤,将滤液蒸干得白色粉末状中间体B,不经纯化直接进行下一步;
(3)向1mmol中间体B的10mL甲醇溶液中滴加4M的氢氧化钠水溶液至pH为14,然后将反应液在室温下搅拌2小时。TLC检测反应完毕后,减压除去大部分甲醇,将剩余的悬浊液溶于30mL水中,并在磁力搅拌下滴加3M的稀盐酸将pH调至2-3,此过程中有大量白色固体析出,抽滤、洗涤滤饼、干燥得通式I目标化合物。
三、联苯类奥司他韦衍生物的应用
活性测试结果表明,上述联苯类奥司他韦衍生物是一系列结构新颖的流感病毒神经氨酸酶抑制剂,大部分化合物同时具有显著的抑酶活性及细胞水平的抗流感病毒活性,其中化合物C2和C5活性最优,C2对H1N1-NA、H5N1-NA和H5N8-NA的抑制活性分别是奥司他韦活性形式OSC的85倍、51倍和39倍,C5对这三种亚型NA的抑制活性分别是OSC的30倍、11倍和70倍。令人欣喜的是,这两个化合物对奥司他韦耐药的H1N1-H274Y和H5N1-H274YNA同样展现出极强的抑制活性,C2的活性较OSC分别提高了34倍和39倍,C5的活性较OSC分别提高了8倍和51倍。细胞水平的抗流感病毒活性测试表明,C2对禽流感H5N1和H5N8毒株的抑制活性分别是OSC的8.5倍和3.6倍,C5对这两个毒株的抑制活性分别是OSC的8.0倍和1.5倍,且这两个化合物的细胞毒性极低。
药代动力学研究显示,C2和C5在大鼠体内的口服生物利用度分别为11.8%和3.9%,优于或与OSC(4.3%)相当。
综上,该类化合物具有进一步开发的重要价值。
因此,本发明所提供的联苯类奥司他韦衍生物可作为神经氨酸酶抑制剂用于制备抗流感病毒药物。
一种抗流感的药物组合物,含有上述的联苯类奥司他韦衍生物及其药学上可接受的盐与药用辅料,制成不同剂型的药物。
说明书附图
图1:(A)C2的血浆药物浓度-时间曲线;(B)C5的血浆药物浓度-时间曲线。
具体实施方式
通过下述实例有助于理解本发明,但是不能限制本发明的内容。
实例中所涉及的合成路线如下:
反应试剂与反应条件:i)碳酸钾,四(三苯基膦)钯,二甲基亚砜,N2保护,回流;ii)磷酸奥司他韦,氰基硼氢化钠,甲醇,室温;iii)4M氢氧化钠溶液,甲醇,室温,3M盐酸溶液酸化。
实施例1:(3R,4R,5S)-4-乙酰氨基-5-((2-氟-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C1)的制备
(1)将3.0mmol苯硼酸溶于20mLDMSO中,然后依次加入3.0mmol 3-溴-2-氟苯甲醛,13.5mmol K2CO3和催化量的四(三苯基膦)钯,将反应液在120℃和氮气保护下搅拌12小时。反应完毕后,冷却反应液至室温,加入100mL饱和氯化钠溶液,然后用乙酸乙酯50mL×3萃取。合并有机相,用无水硫酸镁干燥2小时,过滤,将滤液蒸干得白色粉末状固体A1,不经纯化直接进行下一步。
(2)将2.0mmol磷酸奥司他韦和2.4mmolA1溶于30mL甲醇中,室温下搅拌30分钟,然后加入5.0mmol氰基硼氢化钠,在室温下继续搅拌6小时。TLC检测反应完全后,减压除去溶剂,然后向残余物中加入30mL饱和氯化钠溶液和10mL饱和碳酸钠溶液。将混合液用乙酸乙酯3×30mL萃取,合并有机相,用无水硫酸镁干燥2小时,过滤,将滤液蒸干得白色粉末状中间体B1,不经纯化直接进行下一步。
(3)向1mmol中间体B1的10mL甲醇溶液中滴加4M的NaOH水溶液至pH为14,然后将反应液在室温下搅拌2小时。TLC检测反应完毕后,减压除去大部分甲醇,将剩余的悬浊液溶于30mL水中,并在磁力搅拌下滴加3M的稀盐酸将pH调至2-3,该过程中有大量白色固体析出,抽滤、洗涤滤饼、干燥得目标化合物C1。
白色粉末,收率63%,mp:195-197℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.80(dd,J=7.1,2.4Hz,1H),7.73(ddd,J=7.8,5.0,2.4Hz,1H),7.63(dd,J=7.6,1.6Hz,2H),7.46(t,J=7.7Hz,2H),7.41–7.34(m,1H),7.31(dd,J=9.8,8.6Hz,1H),6.86(d,J=2.4Hz,1H),4.39(q,J=13.3Hz,2H),4.24(d,J=8.2Hz,1H),4.17(dd,J=10.7,8.0Hz,1H),3.59(td,J=10.1,5.5Hz,1H),3.45(p,J=5.6Hz,1H),3.05(dd,J=17.4,5.6Hz,1H),2.65(ddt,J=17.3,9.8,2.7Hz,1H),2.04(s,3H),1.53(tq,J=13.6,7.0Hz,4H),0.91(dt,J=9.6,7.5Hz,6H).13C NMR(150MHz,CD3OD)δ173.34,167.65,160.85(d,1JCF=247.7Hz),139.21,138.28,136.79,130.13,129.80,128.65,128.03,127.43,126.58,115.95,115.81,74.71,55.49,26.56,25.74,25.26,21.92,8.40,8.13.ESI-MS:m/z 468.96[M+H]+,C27H33FN2O(468.57).
实施例2:(3R,4R,5S)-4-乙酰氨基-5-((2-甲基-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C2)的制备
化合物C2的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-2-甲基苯甲醛,再进行相似的后续步骤。
白色粉末,产率72%,mp:198-199℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.43(t,J=7.3Hz,2H),7.38(t,J=6.0Hz,2H),7.32(t,J=7.6Hz,1H),7.25(t,J=6.7Hz,3H),6.83(s,1H),4.33(dd,J=29.9,13.4Hz,2H),4.24(d,J=7.3Hz,1H),4.21–4.14(m,1H),3.61(td,J=9.8,5.6Hz,1H),3.52–3.40(m,1H),3.01(dd,J=17.5,5.4Hz,1H),2.67(dd,J=17.5,9.4Hz,1H),2.26(s,3H),2.08(d,J=28.6Hz,3H),1.66–1.41(m,4H),0.91(q,J=7.3Hz,6H).13CNMR(150MHz,CD3OD)δ173.33,168.30,143.69,141.68,135.97,134.54,131.41,130.58,128.85,128.69,127.93,126.86,125.85,82.22,74.79,55.70,52.02,46.19,26.64,25.77,25.26,21.94,15.44,8.42,8.15.ESI-MS:m/z 464.98[M+H]+,C28H36N2O4(464.60).
实施例3:(3R,4R,5S)-4-乙酰氨基-5-((2-氯-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C3)的制备
化合物C3的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-2-氯苯甲醛,再进行相似的后续步骤。
白色粉末,产率51%,mp:197-200℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.58(dd,J=6.8,2.6Hz,1H),7.55–7.44(m,3H),7.43(s,1H),7.43–7.24(m,3H),6.88(q,J=5.9,4.2Hz,1H),4.64–4.34(m,2H),4.33–4.21(m,1H),4.20–4.09(m,1H),3.71(td,J=10.1,5.5Hz,1H),3.46(p,J=5.9Hz,1H),3.04(td,J=15.9,14.4,5.6Hz,1H),2.71(ddt,J=17.4,9.8,2.8Hz,1H),2.05(d,J=2.8Hz,3H),1.59–1.47(m,4H),0.91(q,J=7.7Hz,6H).13CNMR(150MHz,CD3OD)δ173.44,167.42,142.18,138.98,136.98,132.65,132.50,130.83,130.75,128.99,127.91,127.73,127.70,127.29,82.29,74.60,55.76,52.03,46.57,26.35,25.76,25.27,22.02,8.42,8.15.ESI-MS:m/z 485.52[M+H]+,C27H33ClN2O4(485.02).
实施例4:(3R,4R,5S)-4-乙酰氨基-5-((6-甲氧基-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C4)的制备
化合物C4的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-4-甲氧基苯甲醛,再进行相似的后续步骤。
白色粉末,产率59%,mp:199-201℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.49(d,J=7.5Hz,2H),7.44(d,J=9.7Hz,2H),7.38(t,J=7.5Hz,2H),7.31(t,J=7.3Hz,1H),7.15(d,J=8.2Hz,1H),6.82(s,1H),4.36(d,J=13.0Hz,1H),4.30–4.08(m,3H),3.57(dt,J=15.2,7.2Hz,1H),3.44(p,J=5.7Hz,1H),3.02(dd,J=17.6,5.6Hz,1H),2.64(dd,J=17.7,9.6Hz,1H),2.03(s,3H),1.51(dp,J=14.0,7.0Hz,4H),0.89(q,J=7.4Hz,6H).13C NMR(150MHz,CD3OD)δ173.39,167.28,157.64,137.74,136.92,132.02,131.60,130.22,129.10,127.64,127.56,126.88,122.83,111.84,82.35,74.40,54.87,54.81,51.45,25.86,25.73,25.25,21.96,8.36,8.11.ESI-MS:m/z 481.18[M+H]+,C28H36N2O5(480.60).
实施例5:(3R,4R,5S)-4-乙酰氨基-5-((6-氟-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C5)的制备
化合物C5的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-4-氟苯甲醛,再进行相似的后续步骤。
白色粉末,产率82%,mp:196-198℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.63(dd,J=7.3,2.3Hz,1H),7.61–7.53(m,2H),7.53–7.44(m,3H),7.44–7.37(m,1H),7.29(dd,J=10.4,8.5Hz,1H),6.86(s,1H),4.42(d,J=13.1Hz,1H),4.28(d,J=13.2Hz,1H),4.19(q,J=8.9,7.9Hz,2H),3.58(td,J=9.5,5.5Hz,1H),3.45(p,J=5.6Hz,1H),3.03(dd,J=17.6,5.6Hz,1H),2.65(dd,J=17.8,9.6Hz,1H),2.03(s,3H),1.52(dp,J=14.0,7.0Hz,4H),1.29(s,1H),0.90(q,J=7.4Hz,6H).13C NMR(150MHz,CD3OD)δ173.32,168.01,160.09(d,1JCF=249.5Hz),136.17,134.91,132.24,130.42,129.82,128.63,128.61,128.42,128.26,127.84,116.59,116.44,82.24,74.53,55.11,51.84,48.16,26.39,25.75,25.23,21.90,8.37,8.13.ESI-MS:m/z469.12[M+H]+,C27H33FN2O(468.57).
实施例6:(3R,4R,5S)-4-乙酰氨基-5-((6-氯-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C6)的制备
化合物C6的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-4-氯苯甲醛,再进行相似的后续步骤。
白色粉末,产率85%,mp:225-227℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.53(d,J=8.2Hz,1H),7.48–7.39(m,5H),7.39(dd,J=8.1,2.3Hz,2H),6.74(d,J=2.5Hz,1H),4.21(d,J=13.2Hz,1H),4.13(d,J=8.2Hz,1H),4.07(dd,J=11.3,7.6Hz,2H),3.42(p,J=5.6Hz,1H),3.30–3.24(m,1H),2.92(dd,J=17.5,5.5Hz,1H),2.58–2.39(m,1H),1.99(s,3H),1.67–1.40(m,4H),0.89(q,J=7.3Hz,6H).13C NMR(100MHz,CD3OD)δ178.24,172.98,141.02,138.92,138.14,134.72,132.27,131.95,130.07,129.15,129.02,127.82,127.55,82.04,74.99,55.01,52.83,48.31,27.92,25.77,25.22,21.76,8.42,8.14.ESI-MS:m/z486.89[M+2]+,C27H33ClN2O4(485.02).
实施例7:(3R,4R,5S)-4-乙酰氨基-5-((6-甲基-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C7)的制备
化合物C7的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-4-甲基苯甲醛,再进行相似的后续步骤。
白色粉末,产率72%,mp:210-212℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.44(t,J=7.4Hz,2H),7.37(d,J=2.5Hz,3H),7.34–7.28(m,3H),6.85(s,1H),4.38(d,J=13.0Hz,1H),4.25(d,J=12.9Hz,1H),4.24–4.15(m,2H),3.60(td,J=9.8,5.7Hz,1H),3.45(p,J=5.8Hz,1H),3.01(dd,J=17.5,5.6Hz,1H),2.70–2.58(m,1H),2.26(s,3H),2.02(s,3H),1.61–1.41(m,J=7.0,6.3Hz,4H),0.89(q,J=7.3Hz,6H).13C NMR(150MHz,CD3OD)δ173.36,167.66,142.94,141.01,136.92,136.44,130.92,130.72,128.71,128.51,128.26,127.98,126.98,82.30,74.40,54.96,51.50,48.17,25.99,25.73,25.23,21.91,18.95,8.37,8.11.ESI-MS:m/z465.12[M+H]+,C28H36N2O4(464.60).
实施例8:(3R,4R,5S)-4-乙酰氨基-5-((5-甲基-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C8)的制备
化合物C8的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-5-甲基苯甲醛,再进行相似的后续步骤。
白色粉末,产率66%,mp:206-208℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.64(dd,J=7.4,1.7Hz,2H),7.53(d,J=7.9Hz,2H),7.44(t,J=7.7Hz,2H),7.39–7.32(m,1H),7.28(s,1H),6.83(s,1H),4.40(d,J=13.0Hz,1H),4.25(d,J=12.9Hz,1H),4.21(d,J=7.6Hz,2H),3.58(d,J=6.4Hz,1H),3.45(p,J=5.7Hz,1H),3.03(dd,J=17.5,5.5Hz,1H),2.72–2.56(m,1H),2.45(s,3H),2.04(s,3H),1.52(tt,J=13.1,6.5Hz,4H),0.90(q,J=7.2Hz,6H).13C NMR(150MHz,CD3OD)δ173.33,168.24,142.18,140.21,139.55,135.94,131.96,128.81,128.64,128.56,128.38,127.39,126.67,125.18,82.26,74.56,55.07,51.66,47.46,26.27,25.75,25.24,21.96,20.05,8.39,8.13.ESI-MS:m/z 465.01[M+H]+,C28H36N2O4(464.60).
实施例9:(3R,4R,5S)-4-乙酰氨基-5-((5-氟-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C9)的制备
化合物C9的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-5-氟苯甲醛,再进行相似的后续步骤。
白色粉末,产率77%,mp:194-197℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.81–7.63(m,2H),7.58(d,J=1.7Hz,1H),7.54–7.32(m,4H),7.23(dt,J=9.1,1.9Hz,1H),6.84(d,J=2.8Hz,1H),4.40(d,J=13.2Hz,1H),4.25(d,J=13.3Hz,1H),4.23–4.11(m,2H),3.51(dt,J=9.8,4.9Hz,1H),3.44(q,J=5.7Hz,1H),3.02(dd,J=17.4,5.5Hz,1H),2.60(ddd,J=17.5,7.5,5.0Hz,1H),2.03(s,3H),1.53(ddd,J=13.3,6.6,3.8Hz,4H),0.90(q,J=7.4Hz,6H).13CNMR(150MHz,CD3OD)δ173.32,168.13,163.33(d,1JCF=245.9Hz),144.42,144.37,138.92,136.33,128.75,128.52,128.06,126.70,123.80,114.69,114.00,82.25,74.75,55.26,52.09,48.18,26.66,25.26,21.97,8.40,8.15.ESI-MS:m/z 468.93[M+H]+,C27H33FN2O(468.57).
实施例10:(3R,4R,5S)-4-乙酰氨基-5-((5-氯-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C10)的制备
化合物C10的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为3-溴-5-氯苯甲醛,再进行相似的后续步骤。
白色粉末,产率59%,mp:207-210℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.64(dt,J=4.1,1.9Hz,4H),7.55–7.42(m,3H),7.39(t,J=7.3Hz,1H),6.78(d,J=2.5Hz,1H),4.26(d,J=13.3Hz,1H),4.16(d,J=8.5Hz,1H),4.12(s,1H),4.09(q,J=3.8,3.0Hz,1H),3.43(p,J=5.6Hz,1H),3.39–3.32(m,1H),2.96(dd,J=17.6,5.5Hz,1H),2.51(ddt,J=17.6,9.6,2.7Hz,1H),2.02(s,3H),1.53(tt,J=7.1,5.2Hz,4H),0.90(q,J=7.1Hz,6H).13C NMR(150MHz,CD3OD)δ173.22,167.04,143.85,138.87,136.04,134.96,128.75,128.04,127.72,127.04,126.71,126.24,82.22,74.77,55.33,52.35,48.16,27.04,25.77,25.27,21.89,8.38,8.14.ESI-MS:m/z487.00[M+2]+,C27H33ClN2O4(485.02).
实施例11:(3R,4R,5S)-4-乙酰氨基-5-((4-氟-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C11)的制备
化合物C11的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为5-溴-2-氟苯甲醛,再进行相似的后续步骤。
白色粉末,产率76%,mp:195-198℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.60–7.52(m,3H),7.53–7.43(m,3H),7.40(t,J=7.3Hz,1H),7.34(t,J=7.7Hz,1H),6.84(s,1H),4.36(dd,J=31.3,13.4Hz,2H),4.22(d,J=7.5Hz,1H),4.18–4.06(m,1H),3.54(td,J=10.1,5.6Hz,1H),3.44(dq,J=11.3,5.7Hz,1H),3.03(dd,J=17.4,5.4Hz,1H),2.61(dd,J=17.5,9.6Hz,1H),2.02(s,3H),1.67–1.40(m,4H),0.90(dt,J=9.6,7.5Hz,6H).13C NMR(150MHz,CD3OD)δ173.28,167.98,158.25(d,1JCF=248.5Hz),136.49,134.97,131.99,130.60,129.74,129.65,128.70,128.41,128.23,127.78,124.76,82.24,74.76,55.36,52.24,42.37,26.85,25.75,25.25,21.87,8.41,8.13.ESI-MS:m/z 468.93[M+H]+,C27H33FN2O(468.57).
实施例12:(3R,4R,5S)-4-乙酰氨基-5-((4-甲基-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C12)的制备
化合物C12的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为5-溴-2-甲基苯甲醛,再进行相似的后续步骤。
白色粉末,产率62%,mp:199-202℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.77–7.61(m,3H),7.59(dd,J=7.9,1.9Hz,1H),7.44(t,J=7.6Hz,2H),7.35(q,J=7.6Hz,2H),6.87(s,1H),4.37(q,J=13.4Hz,2H),4.30–4.17(m,2H),3.69(td,J=9.6,5.5Hz,1H),3.46(p,J=5.6Hz,1H),3.04(dd,J=17.6,5.6Hz,1H),2.73(ddt,J=17.4,9.3,2.4Hz,1H),2.46(s,3H),2.04(s,3H),1.64–1.43(m,4H),0.90(td,J=7.4,5.6Hz,6H).13C NMR(150MHz,CD3OD)δ173.35,167.99,140.00,139.59,136.18,131.29,130.87,128.56,128.47,127.98,127.43,127.19,126.43,82.24,74.66,55.75,51.79,45.51,26.38,25.75,25.25,21.95,17.59,8.40,8.14.ESI-MS:m/z465.12[M+H]+,C28H36N2O4(464.60).
实施例13:(3R,4R,5S)-4-乙酰氨基-5-((4-氟-5-甲基-[1,1'-联苯]-3-基)甲基)氨基-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(C13)的制备
化合物C13的制备,操作步骤同实施例1,所不同的是将实施例1中的原料3-溴-2-氟苯甲醛替换为5-溴-2-氟-3-甲基苯甲醛,再进行相似的后续步骤。
白色粉末,产率56%,mp:196-198℃。波谱数据:1H NMR(400MHz,CD3OD)δ7.62–7.54(m,2H),7.54–7.46(m,2H),7.42(t,J=7.6Hz,2H),7.33(t,J=7.3Hz,1H),6.74(d,J=2.4Hz,1H),4.31–3.90(m,4H),3.40(p,J=5.8Hz,1H),3.25(td,J=9.8,5.4Hz,1H),2.96(dd,J=17.7,5.5Hz,1H),2.47(ddt,J=12.5,9.7,4.9Hz,1H),2.35(d,J=2.1Hz,3H),2.00(s,3H),1.51(h,J=7.1Hz,4H),0.89(q,J=7.7Hz,6H).13C NMR(150MHz,CD3OD)δ172.88,169.67,159.35(d,1JCF=245.0Hz),139.76,137.39,135.05,129.99,128.51,127.09,126.96,126.61,126.53,125.32,114.43,82.02,75.19,55.07,53.36,42.93,28.42,25.80,25.25,21.75,13.18,8.45,8.14.ESI-MS:m/z 483.03[M+H]+,C28H35FN2O4(482.60).
实施例14:神经氨酸酶(NA)抑制活性测试
测试方法:向黑色96孔荧光板中依次加入10μLNA溶液,70μL缓冲液(33mmol/L吗啉乙磺酸,4mmol/L氯化钙),10μL待测化合物的不同浓度溶液,同时设置空白组和对照组。37℃下孵育10分钟后,加入20μmol/L底物MUNANA 10μL,充分混匀。37℃下孵育40分钟,然后加入150μL终止液(20mmol/L氢氧化钠-甘氨酸溶液),测定荧光强度。设定参数:EX=355nM,EM=460nM。计算抑制率并拟合化合物对NA的半数抑制浓度(IC50)。
抑制率=(对照值-测定样品值)/(对照值-空白值)×l00%
表1.化合物的NA抑制活性测试结果
a单位为nM;b单位为μM;cND:未测定;d奥司他韦活性形式。
实验结果:化合物的NA抑制活性测试结果如表1所示,大部分化合物对第一组神经氨酸酶(H1N1、H5N1和H5N8)展现出良好的抑制活性,其中活性最好的化合物为C2(H1N1,IC50=0.47nM;H5N1,IC50=0.12nM;H5N8,IC50=0.91nM)和C5(H1N1,IC50=1.33nM;H5N1,IC50=0.55nM;H5N8,IC50=0.50nM),它们的活性达到了亚纳摩尔级别。C2对H1N1-NA、H5N1-NA和H5N8-NA的抑制活性分别是阳性对照药物OSC(H1N1,IC50=40.07nM;H5N1,IC50=6.19nM;H5N8,IC50=35.12nM)的85倍、51倍和39倍,C5对这三种亚型NA的抑制活性分别是OSC的30倍、11倍和70倍。此外,这两个化合物对耐药突变的H274Y-NA的抑制活性较OSC也有明显提升,C2对H1N1-H274Y和H5N1-H274Y的抑酶活性较OSC分别提高了34倍和39倍,C5对这两个耐药突变亚型的抑酶活性较OSC也分别提高了8倍和51倍。
实施例15:细胞水平抗流感病毒活性测试
测试方法:将制备好的鸡胚成纤维细胞(CEFs)溶液(1×105个细胞/mL)以100μL/孔加入96孔细胞板,在细胞培养箱(37℃,5.0%CO2)中孵育24小时使细胞单层平铺。将50μL100TCID50的H5N1或H5N8病毒液与等体积不同浓度的化合物溶液混合,孵育1小时,然后将混合液接种到96孔细胞板中感染CEFs并在细胞培养箱(37℃,5.0%CO2)中继续孵育48小时。向每个复孔中加入10μL CCK-8试剂,孵育90分钟,在酶标仪上读取450nm处的吸光度。抑制剂的EC50值通过拟合细胞病变效应与化合物浓度的曲线来确定。阳性对照药物为OSC,同时设置病毒对照和细胞空白对照。采用CC50值作为新合成的化合物对CEFs的细胞毒性度量,并用测定EC50相似的方法测定,只是没有进行病毒感染。
实验结果:按照上述实验方法挑选出具有良好NA抑制活性的联苯类奥司他韦衍生物进行细胞水平抗H5N1和H5N8毒株活性测试,测试结果如表2所示。化合物C3、C6、C9和C11的抗H5N1毒株活性与阳性对照OSC相当,而化合物C2和C5的活性则是OSC的8倍左右。此外,化合物C2和C5对H5N8毒株的抑制活性分别是OSC的3.6倍和1.5倍。值得注意的是,所有奥司他韦衍生物的CC50均大于200μM,说明该类化合物的细胞毒性极低,综上,化合物C2和C5的体外抗流感病毒活性最佳,值得被进一步研究。
表2.联苯类奥司他韦衍生物的体外抗流感病毒活性
实施例16:目标化合物的药代动力学实验
试验方法:6只雄性SD大鼠随机分成2组,每组3只。给药前禁食12小时,自由饮水。将化合物C2或C5以20mg/kg的剂量灌胃给药,灌胃后分别在5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时和12小时经锁骨静脉窦采血0.2mL,血样置于肝素化的离心管中,离心15分钟,然后取上清血浆样品保存于-20℃备用。将化合物C2或C5进行剂量为2mg/kg的尾静脉注射,注射后分别在5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时和12小时经锁骨静脉窦采血0.2mL,血样处理同前。
用LC-MS进行血浆样品中化合物浓度的分析测定。使用DAS2.0药代动力学程序的非房室模型对测定的血浆药-时数据进行拟合分析,计算Cmax、AUC、Tmax、T1/2、CL等药代动力学参数,并绘制出平均血药浓度-时间曲线。此外,按照如下公式进行生物利用度的计算:
F(%)=[AUC(po)×Div]/[AUC(iv)×Dpo]×100%
AUC:曲线下面积;D:给药剂量(mg/kg)
实验结果:如表3和图1所示,以2mg/kg的剂量尾静脉注射后,化合物C2和C5的半衰期(T1/2)均为0.4小时左右,清除率分别为15.7和10mL/min/kg。当以20mg/kg的剂量灌胃给药后,C2和C5的半衰期都有所增加,分别为1.41小时和1.16小时,达峰浓度分别为2157和1357ng/mL。此外,化合物C2和C5的绝对口服生物利用度分别为11.8%和3.9%,优于或与OSC(4.3%)相当。综上,这两个化合物在大鼠体内表现出理想的药代动力学性质。
表3.C2和C5的药代动力学参数
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Claims (3)
1.一种联苯类奥司他韦衍生物,或其药学上可接受的盐,其特征在于具有如下所示的结构:
C2 C5。
2.权利要求1所述的联苯类奥司他韦衍生物在制备抗流感病毒药物中的应用。
3.一种抗流感病毒的药物组合物,包含权利要求1所述的联苯类奥司他韦衍生物和一种或多种药学上可接受载体或赋形剂。
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