CN109553554A - 含脲基的神经氨酸酶抑制剂及其医药用途 - Google Patents

含脲基的神经氨酸酶抑制剂及其医药用途 Download PDF

Info

Publication number
CN109553554A
CN109553554A CN201710881483.4A CN201710881483A CN109553554A CN 109553554 A CN109553554 A CN 109553554A CN 201710881483 A CN201710881483 A CN 201710881483A CN 109553554 A CN109553554 A CN 109553554A
Authority
CN
China
Prior art keywords
pharmaceutically acceptable
isomers
acceptable salt
alkyl
derivative
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.)
Granted
Application number
CN201710881483.4A
Other languages
English (en)
Other versions
CN109553554B (zh
Inventor
田永寿
王矿磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Priority to CN201710881483.4A priority Critical patent/CN109553554B/zh
Priority to PCT/CN2018/106952 priority patent/WO2019062661A1/zh
Publication of CN109553554A publication Critical patent/CN109553554A/zh
Application granted granted Critical
Publication of CN109553554B publication Critical patent/CN109553554B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin

Abstract

本发明涉及药物化学领域，具体是一类含脲基的神经氨酸酶抑制剂奥司他韦衍生物、其制备方法及其医药用途，医药用途主要用于治疗由病毒引起的感染性疾病。本发明的化合物为具有如下通式(I)所示的衍生物及其药学上可接受的盐或异构体,其中，R1、R2、R3如权利要求书和说明书所述。

Description

含脲基的神经氨酸酶抑制剂及其医药用途
技术领域
本发明涉及药物化学领域，具体是一类含脲基的神经氨酸酶抑制剂奥司他韦衍生物、其制备方法及其医药用途，医药用途主要用于治疗由病毒引起的感染性疾病。
背景技术
流行性感冒(简称流感)是由流感病毒引起的急性呼吸道感染病，其中甲型流感具有很强的传播性，并且有较高的致病率和致死率，容易造成大流行或大暴发。
抗流感病毒药物主要有两种，M2蛋白抑制剂和神经氨酸酶抑制剂，M2蛋白抑制剂主要有盐酸金刚烷胺和盐酸金刚乙胺，盐酸金刚烷胺口服吸收后，能穿透血脑屏障，引起中枢神经系统毒副反应，并且很容易产生耐药性，美国Centers for Disease Control已经不推荐这两种药物用于甲型流感的预防和治疗(Recommendations and Reports,2007,56,RR-6,1-54)。
神经氨酸酶能促进宿主细胞释放子代病毒，故神经氨酸酶抑制剂能抑制病毒释放，阻断传播途径，从而起到治疗流感的作用。神经氨酸酶活性中心的结构相对比较保守，所以它是一个比较理想的治疗流感的靶点。全世界范围内使用的这一类药物有扎那米韦和磷酸奥司他韦。其中磷酸奥司他韦是唯一的口服用药，它在体内经酯酶水解成为游离酸(GS4071)后才能发挥药效，活性成分分布至所有流感病毒感染的部位，包括肺、气管、鼻黏膜和中耳，从而大大减少并发症的发生，是公认的抗甲型流感、禽流感的特效药之一。但是，临床上不可避免地出现了一些耐药株。
发明内容
本发明中为了克服现有技术的缺陷，提供了一系列奥司他韦的伯胺基团修饰改造的衍生物。药理活性测试结果表明，本发明的衍生物对神经氨酸酶A/Anhui/1/2005(H5N1)有酶抑制活性，部分化合物表现了较强的酶抑制活性。
本发明提供具有通式(I)所示的衍生物及其药学上可接受的盐或异构体：
其中：
R1、R2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C6烷基、取代或未取代的5-10元芳香环，所述取代基为：C1-C6烷基，卤素；
R3表示氢原子、C1-C6烷基。
R1、R2同时为氢时，R3为不能为乙基。
本发明优选通式(I)所示的衍生物及其药学上可接受的盐或异构体：
其中，R1、R2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的5-6元芳香环，所述取代基为C1-C4烷基、卤素。
本发明优选通式(I)所示的化合物及其药学上可接受的盐或异构体：
其中，R1、R2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的苯环，所述取代基为C1-C4烷基，F、Cl、Br。
本发明优选通式(I)所示的化合物及其药学上可接受的盐和异构体：
其中，R1表示氨基、羟基、C1-C4烷基、卤素取代的苯环；R2表示氢原子、C1-C4烷基。
本发明优选如下化合物及其药学上可接受的盐和异构体：
(3R，4R，5S)-4-乙酰胺基-5-(3-酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-1)
(3R，4R，5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-2)
(3R，4R，5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-3)
(3R，4R，5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-4)
(3R，4R，5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-5)
本发明中的化合物制备如下：
当R1、R2同时表示氢原子时，合成方法如下：
当R1和R2不同时表示氢原子时，合成方法如下：
本发明中的化合物进行了神经氨酸酶的抑制活性测试。其中阳性对照药为奥司他韦羧酸(Oseltamivir acid)。测试原理为MUNANA(2’-(4-methylumbelliferyl)-α-N-acetylneuraminic acid)是神经氨酸酶的特异性底物，经神经氨酸酶代谢所生成的物质，在355nm的光照激发下，能够产生460nm的荧光，当测试的化合物与神经氨酸酶作用时，导致该特异性底物的结合率发生变化，从而产生荧光强度的变化，通过荧光强度变化反映神经氨酸酶的活性，从而计算出化合物在特定浓度下对神经氨酸酶的抑制率，根据不同浓度的抑制率得到相应的IC50值。
试验方法：
往96孔板中每孔加入10μL含有酶的溶液，70μL缓冲液(33mM吗啉乙磺酸，4mMCaCl2)，10μL一定浓度的待测化合物，37°条件下孵育十分钟，然后加入100μM的荧光底物10μL，在37°条件下孵育30分钟，加150μL终止液(14mM NaOH的83％乙醇溶液)测定荧光强度，其中激发波长355nm，发射波长460nm。
活性测试结果为：
化合物名称 I-1 I-2 I-3 I-4 I-5
IC<sub>50</sub>/μM 0.254 0.072 4.832 30.8 16.98
实验结果表明I-1和I-2表现了较强的神经氨酸酶抑制活性，优于达菲活性成分——奥司他韦羧酸,有进一步开发的价值。
具体实施方式
实施实例1
(3R，4R，5S)-4-乙酰胺基-5-(3-酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-1)
往50mL圆底烧瓶中加入磷酸奥司他韦(500mg,1.218mmol)、氢氧化钡(355mg,2.071mmol)和尿素(146mg,2.436mmol)，加入10mL去离子水，回流反应。反应结束后，反应液冷却至室温，过滤，滤液的pH值调节至1-2，过滤，干燥得白色固体262mg，收率为65.7％。1HNMR(400MHz,DMSO-d6)δ12.50(br s,1H),7.80(d,J＝8.8Hz,1H),6.60(s,1H),5.69(d,J＝8.2Hz,1H),5.54(s,2H),4.01(d,J＝7.4Hz,1H),3.78–3.57(m,2H),3.40–3.35(m,1H),2.63-2.53(m,1H),2.05–1.92(m,1H),1.80(s,3H),1.49-1.32(m,4H),0.83(t,J＝7.4Hz,3H),0.77(t,J＝7.4Hz,3H)；LC-MS(ESI):350.3[M+Na]+,326.0[M-H]-。
实施实例2
(3R，4R，5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)
往100mL圆底烧瓶中加入500mg(1.60mmol)奥司他韦，加入30mL二氯甲烷溶解，冰水浴下，分批加入260mg(1.60mmol)羰基二咪唑，搅拌。反应结束后，有机相用饱和的氯化铵溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗品530mg，不经纯化直接投入下一步反应。
实施实例3
(3R，4R，5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-2)
取(3R，4R，5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)(600mg,1.477mmol)和2.00g无水Na2SO4加入到圆底烧瓶中，接着加入30mL干燥CHCl3和0.5mL水合肼溶液，室温搅拌0.5h，升温至35℃，随后补加0.3mL水合肼溶液。反应结束后，往反应液中加入适量的饱和氯化钠溶液，搅拌5min，分液，有机相用饱和氯化钠水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，粗产品经柱层析纯化得白色固体334mg，收率61.1％。
实施实例4
(3R，4R，5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(I-2)
取上一步产物(3R，4R，5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-2)(334mg,0.902mmol)，加入10mL甲醇和1.13mL 2N NaOH水溶液，补加0.83mL去离子水，使V甲醇：V水＝5:1，室温搅拌反应。反应结束后，用离子交换树脂(Amberlite IR120,H form)调节反应液pH至6.0–7.0，过滤，纯化得白色固体96mg，收率30.2％。1H NMR(600MHz,Methanol-d4)δ6.79(s,1H),4.13(d,J＝7.3Hz,1H),4.04–3.94(m,2H),3.44(p,J＝5.7Hz,1H),2.82–2.75(m,1H),2.37–2.30(m,1H),2.00(s,2H),1.94(s,3H),1.87(s,2H),1.58–1.46(m,4H),0.93(t,J＝7.4Hz,3H),0.90(t,J＝7.4Hz,3H)；LC-MS(ESI):340.9[M-H]-.
实施实例5
(3R，4R，5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-3)
往50mL圆底烧瓶中加入(3R，4R，5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)(200mg,0.492mmol)和10mL氯仿溶液，接着加入DIPEA(318mg,2.46mmol)和盐酸二甲胺(60mg,0.738mmol)，室温搅拌0.5h，加热至回流。反应结束后，缓慢冷却至室温，反应液依次用3N HCl水溶液、1N NaOH水溶液和饱和氯化钠水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，粗品经柱层析纯化得白色固体72mg，收率38.3％。
实施实例6
(3R，4R，5S)-4-乙酰胺基-5-(3，3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-3)
取上一步产物(3R，4R，5S)-4-乙酰胺基-5-(3，3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-3)(72mg,0.188mmol)加到圆底烧瓶中，接着加入10mL甲醇溶液中和0.47mL1N NaOH水溶液，补加1.53mL去离子水，使V甲醇：V水＝5:1，室温搅拌反应。反应结束后，调节pH至1-2，减压蒸除甲醇，用2×10mL乙酸乙酯萃取水相，合并两次有机相，用饱和氯化钠水溶液洗涤有机相，无水MgSO4干燥，过滤，浓缩得白色固体50mg，收率为74.4％。1H NMR(400MHz,DMSO)δ9.02(s,1H),7.91(d,J＝8.3Hz,1H),6.80(d,J＝7.5Hz,1H),6.71(s,1H),4.15(q,J＝7.0Hz,2H),4.07–4.00(m,1H),3.94–3.87(m,1H),3.86–3.76(m,1H),3.43(p,J＝5.6Hz,1H),2.65(dd,J＝17.8,4.6Hz,1H),2.32–2.19(m,1H),1.84(s,3H),1.80(s,3H),1.77(s,3H),1.52–1.35(m,4H),1.23(t,J＝7.1Hz,3H),0.83(dt,J＝11.3,7.4Hz,6H)；LC-MS(ESI):356.3[M+H]+,354.1[M-H]-.
实施实例7
(3R，4R，5S)-4-乙酰胺基-5-(3，3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-4)
实施操作同实施实例5，以250mg(3R，4R，5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-2-氧代乙基氨基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)反应原料，得到白色固体214mg，收率为79.1％。
实施实例8
(3R，4R，5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-4)
实施操作同实施实例6，以214mg(0.514mmol)(3R，4R，5S)-4-乙酰胺基-5-(3，3-二异丙基酰脲)-2-氧代乙基氨基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-4)为反应原料，经处理得到白色固体154mg，收率为82.4％。1H NMR(400MHz,DMSO-d6)δ12.50(s,br1H),7.86(d,J＝8.4Hz,1H),6.60(s,1H),5.59(d,J＝7.2Hz,1H),4.04(d,J＝3.4Hz,1H),3.85–3.70(m,2H),3.64(dt,J＝13.4,6.7Hz,2H),3.43–3.38(m,1H),2.56–2.50(m,1H),2.29–2.14(m,1H),1.50–1.32(m,4H),1.14(d,J＝6.6Hz,12H),0.83(t,J＝7.4Hz,3H),0.78(t,J＝7.4Hz,3H)；LC-MS(ESI):412.4[M+H]+,410.1[M-H]-。
实施实例9
(3R，4R，5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-5)
实施操作同实施实例5，以280mg(3R，4R，5S)-4-乙酰胺基-5-(1-(咪唑)-胺基甲酰胺基)-2-氧代乙基氨基)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ)反应原料，经处理得到白色固体231mg，收率为65.7％。
实施实例10
(3R，4R，5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-5)
实施操作同实施实例6，以(3R，4R，5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸乙酯(Ⅱ-5)为反应原料，经处理得到白色固体160mg，收率为73.2％。1H NMR(600MHz,DMSO-d6)δ12.58(s,1H),8.92(s,1H),7.93(d,J＝8.7Hz,1H),7.82(t,J＝1.9Hz,1H),7.24–7.11(m,2H),7.08–7.01(m,1H),6.64(t,J＝2.0Hz,1H),6.01(d,J＝7.9Hz,1H),4.07(d,J＝6.4Hz,1H),3.84-3.75(m,2H),3.41(p,J＝5.6Hz,1H),2.68(dd,J＝17.3,4.1Hz,1H),2.12-2.05(m,1H),1.79(s,3H),1.48-1.34(m,4H),0.85(t,J＝7.4Hz,3H),0.78(t,J＝7.4Hz,3H)；LC-MS(ESI):480.0[M-H]-。

Claims (10)

1.通式(I)所示的衍生物及其药学上可接受的盐或异构体：
其中：
R1、R2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C6烷基、取代或未取代的5-10元芳香环；所述取代基为：C1-C6烷基，卤素；
R3表示氢原子、C1-C6烷基；
R1、R2同时为氢时，R3为不能为乙基。
2.如权利要求1所述的衍生物及其药学上可接受的盐或异构体：
其中:
R1、R2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的5-6元芳香环，所述取代基为C1-C4烷基，卤素。
3.如权利要求1或2所述的衍生物及其药学上可接受的盐或异构体：
其中，R1、R2独立的表示氢原子、氨基、羟基、甲基、取代或未取代的C1-C4烷基、取代或未取代的5-6元苯环，所述取代基为C1-C4烷基，F、Cl、Br。
4.如权利要求1-3任何一项所述的衍生物及其药学上可接受的盐或异构体：其中，R1表示氨基、羟基、C1-C4烷基、卤素取代的苯环；R2表示氢原子、C1-C4烷基。
5.如下的化合物及其药学上可接受的盐或异构体：
(3R，4R，5S)-4-乙酰胺基-5-(3-酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-1)
(3R，4R，5S)-4-乙酰胺基-5-(3-胺基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-2)
(3R，4R，5S)-4-乙酰胺基-5-(3,3-二甲基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-3)
(3R，4R，5S)-4-乙酰胺基-5-(3,3-二异丙基酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-4)
(3R，4R，5S)-4-乙酰胺基-5-(3-(3-溴苯基)酰脲)-3-(1-乙基丙氧基)-1-环己烯-1-羧酸(I-5)。
6.权利要求1-5任何一项所述的衍生物或者药学上可接受的盐或异构体，其特征在于，还包括所述化合物的溶剂化物、多晶型体、对映体或外消旋混合物。
7.一种药物组合物，包含权利要求1-5中任何一项的衍生物及其药学上可接受的盐或异构体作为活性成分以及药学上可接受的赋型剂。
8.权利要求1-6任何一项的化合物及其药学上可接受的盐或异构体或权利要求7所述的药物组合物在制备神经氨酸酶抑制剂中的应用。
9.权利要求1-6任何一项所述的衍生物及其药学上可接受的盐或异构体或权利要求7所述的药物组合物在制备治疗流感病毒感染引起的疾病的药物中的应用。
10.权利要求1-6任何一项所述的衍生物及其药学上可接受的盐或异构体或权利要求7所述的药物组合物在制备治疗流感的药物中的应用。
CN201710881483.4A 2017-09-26 2017-09-26 含脲基的神经氨酸酶抑制剂及其医药用途 Active CN109553554B (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201710881483.4A CN109553554B (zh) 2017-09-26 2017-09-26 含脲基的神经氨酸酶抑制剂及其医药用途
PCT/CN2018/106952 WO2019062661A1 (zh) 2017-09-26 2018-09-21 含脲基的神经氨酸酶抑制剂及其医药用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710881483.4A CN109553554B (zh) 2017-09-26 2017-09-26 含脲基的神经氨酸酶抑制剂及其医药用途

Publications (2)

Publication Number Publication Date
CN109553554A true CN109553554A (zh) 2019-04-02
CN109553554B CN109553554B (zh) 2021-12-07

Family

ID=65862889

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710881483.4A Active CN109553554B (zh) 2017-09-26 2017-09-26 含脲基的神经氨酸酶抑制剂及其医药用途

Country Status (2)

Country Link
CN (1) CN109553554B (zh)
WO (1) WO2019062661A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020259471A1 (en) * 2019-06-24 2020-12-30 The Hong Kong Polytechnic University N-substituted oseltamivir derivatives with antimicrobial activity
CN112409218A (zh) * 2020-12-01 2021-02-26 沈阳药科大学 含酰肼结构片段的神经氨酸酶抑制剂及其医药用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102659615A (zh) * 2012-05-09 2012-09-12 中国药科大学 奥司他韦衍生物、其制备方法及其医药用途
CN103845316A (zh) * 2012-11-30 2014-06-11 北京普禄德医药科技有限公司 神经氨酸苷酶抑制剂及其前药的制药用途
CN103848762A (zh) * 2012-11-30 2014-06-11 北京普禄德医药科技有限公司 神经氨酸苷酶抑制剂的前药及其组合物和用途
CN106905193A (zh) * 2017-02-15 2017-06-30 中国药科大学 芳酰基胍基奥司他韦羧酸衍生物及其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102659615A (zh) * 2012-05-09 2012-09-12 中国药科大学 奥司他韦衍生物、其制备方法及其医药用途
CN103845316A (zh) * 2012-11-30 2014-06-11 北京普禄德医药科技有限公司 神经氨酸苷酶抑制剂及其前药的制药用途
CN103848762A (zh) * 2012-11-30 2014-06-11 北京普禄德医药科技有限公司 神经氨酸苷酶抑制剂的前药及其组合物和用途
CN106905193A (zh) * 2017-02-15 2017-06-30 中国药科大学 芳酰基胍基奥司他韦羧酸衍生物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NERI-BAZAN, ROCIO M.等: "Design, in silico studies, synthesis and in vitro evaluation of oseltamivir derivatives as inhibitors of neuraminidase from influenza A virus H1N1", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020259471A1 (en) * 2019-06-24 2020-12-30 The Hong Kong Polytechnic University N-substituted oseltamivir derivatives with antimicrobial activity
CN114286817A (zh) * 2019-06-24 2022-04-05 香港理工大学 具有抗微生物活性的n-取代的奥司他韦衍生物
CN112409218A (zh) * 2020-12-01 2021-02-26 沈阳药科大学 含酰肼结构片段的神经氨酸酶抑制剂及其医药用途

Also Published As

Publication number Publication date
WO2019062661A1 (zh) 2019-04-04
CN109553554B (zh) 2021-12-07

Similar Documents

Publication Publication Date Title
JP6989509B2 (ja) インフルエンザウイルス感染における使用のためのアリール置換ピリミジン
JP7001601B2 (ja) インフルエンザウイルス感染に使用するための官能化ペンタン酸
AU2016359907B2 (en) Heterocyclic indoles for use in influenza virus infection
AU2015298876A1 (en) Indoles for use in influenza virus infection
EP4159211A1 (en) Compound exhibiting physiological activity such as antiviral activity
CN109553554A (zh) 含脲基的神经氨酸酶抑制剂及其医药用途
CN105693665B (zh) 含苯并呋喃环的芳甲酰腙衍生物及其制备方法与医药用途
CN105622558B (zh) 含苯并呋喃环的酰腙衍生物及其制备方法与应用
CN110183433B (zh) 吡唑类化合物及其制备方法与用途
CN102329245A (zh) 具有抗禽流感病毒活性的金刚烷衍生物及其制备方法
US10590167B2 (en) NMDA receptor modulators and prodrugs, salts, and uses thereof
WO2023014758A1 (en) Inhibitors for coronaviruses
CN106748872A (zh) 酰基类神经氨酸酶抑制剂及其医药用途
CN105669589B (zh) 2‑(5‑酰基噻唑‑2‑亚氨基)‑4‑噻唑啉酮及其制备方法与应用
CN108101804B (zh) 羧基修饰的奥司他韦衍生物及其医药用途
JP2009533428A (ja) 筋肉内抗ウイルス処置
CN112409218A (zh) 含酰肼结构片段的神经氨酸酶抑制剂及其医药用途
WO2021188620A1 (en) Peptidomimetic n5-methyl-n2-(nonanoyl-l-leucyl)-l-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds as inhibitors of norovirus and coronavirus replication
CN110272381A (zh) 含吡啶片段的奥司他韦类似物及其应用
WO2020112716A1 (en) Inhibitors of influenza virus replication
JP2023520819A (ja) 抗ウイルス１，３－ジ－オキソ－インデン化合物
CN117586330A (zh) 一种新型核苷衍生物及其药物组合物和用途
EA040080B1 (ru) Функционализированные пентановые кислоты, их фармацевтическая композиция, лекарственное средство и применение
CN107141267A (zh) N‑（5‑酰基噻唑‑2‑基）酰胺及其制备方法与应用
KR20180020119A (ko) 새로운 5형포스포디에스테라아제 억제제 및 그 용도

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant