CN112409218A - 含酰肼结构片段的神经氨酸酶抑制剂及其医药用途 - Google Patents
含酰肼结构片段的神经氨酸酶抑制剂及其医药用途 Download PDFInfo
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- CN112409218A CN112409218A CN202011385071.XA CN202011385071A CN112409218A CN 112409218 A CN112409218 A CN 112409218A CN 202011385071 A CN202011385071 A CN 202011385071A CN 112409218 A CN112409218 A CN 112409218A
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- Prior art keywords
- cyclohex
- ene
- acetylamino
- carboxylic acid
- carboxamido
- Prior art date
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- -1 (3R, 4R, 5S) -4-acetylamino-5- (2-butyrylhydrazine-1-carboxamido) -3- (pentan-3-oxy) cyclohex-1-ene-1-carboxylic acid Chemical compound 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 206010022000 influenza Diseases 0.000 claims description 6
- TWHBJZAVBVBZJE-PWRODBHTSA-N (3R,4R,5S)-4-acetamido-3-pentan-3-yloxy-5-[(2-phenylethylamino)carbamoylamino]cyclohexene-1-carboxylic acid Chemical compound C(C)(=O)N[C@H]1[C@@H](C=C(C[C@@H]1NC(=O)NNCCC1=CC=CC=C1)C(=O)O)OC(CC)CC TWHBJZAVBVBZJE-PWRODBHTSA-N 0.000 claims description 5
- VDPOHMWXIJQLRS-BFHYXJOUSA-N (3R,4R,5S)-4-acetamido-5-(methylaminocarbamoylamino)-3-pentan-3-yloxycyclohexene-1-carboxylic acid Chemical compound C(C)(=O)N[C@H]1[C@@H](C=C(C[C@@H]1NC(=O)NNC)C(=O)O)OC(CC)CC VDPOHMWXIJQLRS-BFHYXJOUSA-N 0.000 claims description 5
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- WBVUIPVNOCMTHV-RCCFBDPRSA-N (3R,4R,5S)-4-acetamido-5-[(oxan-4-ylamino)carbamoylamino]-3-pentan-3-yloxycyclohexene-1-carboxylic acid Chemical compound C(C)(=O)N[C@H]1[C@@H](C=C(C[C@@H]1NC(=O)NNC1CCOCC1)C(=O)O)OC(CC)CC WBVUIPVNOCMTHV-RCCFBDPRSA-N 0.000 claims description 5
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- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- GDCXEZBHTKSNCZ-ARFHVFGLSA-N C(C)(=O)N[C@H]1[C@@H](C=C(C[C@@H]1NC(=O)NNCCC)C(=O)O)OC(CC)CC Chemical compound C(C)(=O)N[C@H]1[C@@H](C=C(C[C@@H]1NC(=O)NNCCC)C(=O)O)OC(CC)CC GDCXEZBHTKSNCZ-ARFHVFGLSA-N 0.000 claims description 3
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- OZBDFBJXRJWNAV-UHFFFAOYSA-N Rimantadine hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(C(N)C)C3 OZBDFBJXRJWNAV-UHFFFAOYSA-N 0.000 description 1
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- HDKVSEUEUWKMFS-UHFFFAOYSA-N ethyl cyclohexene-1-carboxylate Chemical compound CCOC(=O)C1=CCCCC1 HDKVSEUEUWKMFS-UHFFFAOYSA-N 0.000 description 1
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
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- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
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- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
-
- 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
- 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
- C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
- C07C281/10—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to an acyclic carbon atom or to a carbon atom of a ring other than a six-membered aromatic ring
-
- 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
- C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
- C07C281/12—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being part of a ring other than a six-membered aromatic ring
-
- 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
- C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
- C07C281/14—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to a carbon atom of a six-membered aromatic ring
-
- 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
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Abstract
本发明涉及药物化学领域，具体是一类含酰肼结构片段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，具体涉及所述的含酰肼结构片段的神经氨酸酶抑制剂奥司他韦衍生物在制备治疗由病毒引起的感染性疾病药物中的应用。所述的的衍生物及其药学上可接受的盐或异构体如通式(I)所示，其中，R如权利要求和说明书所述。
Description
技术领域
本发明涉及药物化学领域，具体是一类含酰肼结构片段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，具体涉及所述的含酰肼结构片段的神经氨酸酶抑制剂奥司他韦衍生物在制备治疗由病毒引起的感染性疾病药物中的应用。
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。时至今日，流感仍然是威胁人类健康的一个疾病。
现今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。
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，同时也是销量最大的抗甲型流感药物。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酰肼结构片段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:R独立的表示氢原子、C1-C10烷基、C3-C6环烷基、5-10元芳基、5-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基含有1-3个N、O或S的杂原子，所述R可以被如下取代基中的一个或多个取代：卤素、C1-C10烷基、C2-C6烯基、C1-C10烷氧基、5-10元芳基。
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，R独立的表示氢原子、C1-C8烷基、C3-C6环烷基、5-6元芳基、5-6元杂环基或5-6元杂芳基，所述R可以被如下取代基中的一个或多个取代：卤素、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、5-6元芳基。
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，R独立的表示氢原子、C1-C8烷基、C3-C6环烷基、苯基、或
所述R可以被如下取代基中的一个或多个取代：卤素、C1-C4烷基、C1-C4烷氧基、C2-C4烯基。
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，R独立的表示氢原子、C1-C8烷基、环丙烷、苯基、或
所述R可以被如下取代基中的一个或多个取代：卤素、C1-C2烷基、C1-C2烷氧基、C2-C4烯基。
本发明优选如下衍生物及其药学上可接受的盐或异构体：
(3R，4R，5S)-4-乙酰氨基-5-(2-甲基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-1)
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-丙基肼-1-甲酰胺基)环己-1-烯-1-羧酸(I-2)
(3R，4R，5S)-4-乙酰氨基-5-(2-丁酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-3)
(3R，4R，5S)-4-乙酰氨基-5-(2-异戊基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-4)
(3R，4R，5S)-4-乙酰氨基-5-(2-庚酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-5)
(3R，4R，5S)-4-乙酰氨基-5-(2-苄基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-6)
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-苯乙基肼-1-甲酰胺基)环己-1-烯-1-羧酸(I-7)
(3R，4R，5S)-4-乙酰氨基-5-(2-(2-氯苄基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-8)
(3R，4R，5S)-4-乙酰氨基-5-(2-(3-甲氧基苄基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-9)
(3R，4R，5S)-4-乙酰氨基-5-(2-肉桂酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-10)
(3R，4R，5S)-4-乙酰氨基-5-(2-(环丙基甲基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-11)
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-(四氢-2H-吡喃-4-基)肼-1-甲酰胺基)环己-1-烯-1-羧酸(I-12)
本发明中的衍生物制备如下：
其中，R如权利要求书所述。
本发明对所述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MUNANA(2’-(4-methylumbelliferyl)-α-Nacetylneuraminic 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 | IC50/μM | 化合物名称 | IC50/μM |
| I-1 | 0.029 | I-7 | 2.462 |
| I-2 | 0.241 | I-8 | 0.586 |
| I-3 | 0.038 | I-9 | 0.326 |
| I-4 | 1.533 | I-10 | 7.845 |
| I-5 | 0.575 | I-11 | 4.111 |
| I-6 | 4.345 | I-12 | 1.207 |
实验结果表明，本发明所述的化合物具有明显的神经氨酸酶抑制活性，尤其是I-1、I-3、I-5、I-8、I-9表现了较强的神经氨酸酶抑制活性，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-(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)
在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，进一步纯化后投入下一步反应。
实施实例2
(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)
在100mL圆底烧瓶中加入化合物500mg(1.23mmol)(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)，加1.92g无水硫酸钠(13.52mmol)，依次加入30mL无水氯仿，132μL水合肼(2.71mmol)，255μL三乙胺(1.85mmol)，室温反应0.5h，而后升温35℃，反应12h。反应结束后，过滤除无水硫酸钠，滤液减压蒸除氯仿，得到粗品，然后加入20mL乙腈打浆，得到白色固体340mg，收率80.0％。
实施实例3
(3R，4R，5S)-4-乙酰氨基-5-(2-亚甲基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(IV-1)
在50mL圆底烧瓶中加入化合物200mg(0.58mmol)(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)，依次加10mL甲醇，加25.86μL甲醛(0.70mmol)，室温搅拌8h。反应结束后，减压蒸除甲醇，经柱层析纯化，得白色固体201mg，收率90.0％。
实施实例4
(3R，4R，5S)-4-乙酰氨基-5-(2-甲基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(V-1)
在50mL圆底烧瓶中加入化合物200mg(0.52mmol)(3R，4R，5S)-4-乙酰氨基-5-(2-亚甲基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(IV-1)，接着加入氰基硼氢化钠164.30mg(2.61mmol)，89.79μL冰乙酸(1.57mmol)，10mL甲醇，室温下搅拌6h,反应结束后，加饱和氯化铵淬灭，减压蒸除甲醇，后用乙酸乙酯萃取，接着减压蒸除乙酸乙酯，经柱层析纯化，得白色固体165mg，收率82.9％。
实施实例5
(3R，4R，5S)-4-乙酰氨基-5-(2-甲基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-1)
在50mL圆底烧瓶中加入化合物200mg(0.52mmol)(3R，4R，5S)-4-乙酰氨基-5-(2-亚甲基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(IV-1)，接着加入10mL甲醇溶液中和1.04mL1N NaOH水溶液，补加0.96mL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，减压旋蒸后纯化得白色固体129.5mg，收率70％。1H NMR(400MHz,CD3OD)δ6.81(t,J＝2.4Hz,1H),4.17–4.12(m,1H),3.96–3.91(m,2H),3.42(p,J＝5.6Hz,1H),2.84(s,3H),2.79–2.68(m,1H),2.38–2.22(m,1H),1.96(s,3H),1.58–1.46(m,4H),0.91(dt,J＝15.3,7.4Hz,6H)；MS(ESI):357.2[M+H]+,379.2[M+Na]+.
实施实例6
3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-丙基肼-1-甲酰胺基)环己-1-烯-1-羧酸(I-2)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用正丙醛替换甲醛，经处理得白色固体80mg，收率56.8％。1H NMR(400MHz,CD3OD)δ6.81(t,J＝2.4Hz,1H),4.21–4.09(m,1H),3.98–3.89(m,2H),3.42(p,J＝5.7Hz,1H),3.03(t,J＝7.7Hz,2H),2.80–2.67(m,1H),2.36–2.21(m,1H),1.95(s,3H),1.66(m,2H),1.58–1.46(m,4H),1.00(t,J＝7.5Hz,3H),0.90(dt,J＝15.0,7.4Hz,6H)；HRMS(ESI):407.2272[M+Na]+.
实施实例7
(3R，4R，5S)-4-乙酰氨基-5-(2-丁酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-3)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用正丁醛替换甲醛，经处理得白色固体90.6mg，收率69.6％。1H NMR(400MHz,CD3OD)δ6.81(d,J＝2.5Hz,1H),4.18–4.11(m,1H),3.98–3.90(m,2H),3.42(p,J＝5.7Hz,1H),3.10(t,J＝7.8Hz,2H),2.80–2.64(m,1H),2.35–2.22(m,1H),1.96(s,3H),1.68–1.39(m,8H),1.02–0.84(m,9H)；HRMS(ESI):399.2604[M+H]+,397.2432[M-H]+.
实施实例8
(3R，4R，5S)-4-乙酰氨基-5-(2-异戊基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-4)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用异戊醛替换甲醛，经处理得白色固体106.3mg，收率75.8％。1H NMR(400MHz,CD3OD)δ6.81(t,J＝2.4Hz,1H),4.14(dt,J＝6.3,3.0Hz,1H),3.97–3.91(m,2H),3.43(p,J＝5.7Hz,1H),3.19–3.03(m,2H),2.80–2.65(m,1H),2.36–2.25(m,1H),1.96(s,3H),1.74–1.63(m,1H),1.59–1.45(m,6H),1.02–0.84(m,12H)；HRMS(ESI):413.2747[M+H]+,435.2581[M+Na]+.
实施实例9
(3R，4R，5S)-4-乙酰氨基-5-(2-庚酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-5)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用正庚醛替换甲醛，经处理得白色固体90.6mg，收率72.1％。1H NMR(400MHz,CD3OD)δ6.81(t,J＝2.4Hz,1H),4.18–4.09(m,1H),3.99–3.88(m,2H),3.42(p,J＝5.7Hz,1H),3.17–3.05(m,2H),2.79–2.69(m,1H),2.36–2.24(m,1H),1.96(s,3H),1.66(p,J＝7.3Hz,2H),1.58–1.47(m,4H),1.41–1.28(m,8H),0.96–0.86(m,9H)；HRMS(ESI):463.2909[M+Na]+.
实施实例10
(3R，4R，5S)-4-乙酰氨基-5-(2-苄基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-6)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用苯甲醛替换甲醛，经处理得白色固体130.2mg，收率80.2％。1H NMR(400MHz,CD3OD)δ7.45–6.78(m,5H),6.80(td,J＝2.6,0.9Hz,1H),4.24–4.04(m,3H),4.00–3.81(m,2H),3.42(p,J＝5.6Hz,1H),2.66(dd,J＝17.7,5.1Hz,1H),2.27–2.09(m,1H),1.95(s,3H),1.59–1.44(m,4H),0.91(dt,J＝14.8,7.4Hz,6H)；HRMS(ESI):455.2266[M+Na]+.
实施实例11
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-苯乙基肼-1-甲酰胺基)环己-1-烯-1-羧酸(I-7)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用苯乙醛替换甲醛，经处理得白色固体102.2mg，收率78.7％。1H NMR(400MHz,CD3OD)δ7.36–7.29(m,2H),7.28–7.21(m,3H),6.83–6.79(m,1H),4.13(dd,J＝6.0,2.7Hz,1H),3.97–3.89(m,2H),3.42(p,J＝5.7Hz,1H),3.29–3.21(m,2H),2.92(dd,J＝9.2,6.7Hz,2H),2.73(dd,J＝17.1,4.1Hz,1H),2.31–2.20(m,1H),1.93(s,3H),1.58–1.49(m,4H),0.91(dt,J＝16.4,7.4Hz,6H)；HRMS(ESI):447.2589[M+H]+,469.2430[M+Na]+.
实施实例12
(3R，4R，5S)-4-乙酰氨基-5-(2-(2-氯苄基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-8)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用邻氯苯甲醛替换甲醛，在IV8到V 8反应时需加热60℃反应，经处理得白色固体127.35mg，收率60.2％。1H NMR(400MHz,CD3OD)δ7.52–7.46(m,1H),7.46–7.39(m,1H),7.37–7.28(m,2H),6.79(td,J＝2.6,1.0Hz,1H),4.22–4.06(m,3H),3.98–3.90(m,1H),3.88–3.79(m,1H),3.42(p,J＝5.6Hz,1H),2.59(dd,J＝17.8,5.2Hz,1H),2.19–2.08(m,1H),1.95(s,3H),1.57–1.44(m,4H),0.95–0.85(m,6H)；HRMS(ESI):489.1873[M+Na]+.
实施实例13
(3R，4R，5S)-4-乙酰氨基-5-(2-(3-甲氧基苄基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-9)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用间甲氧基苯甲醛替换甲醛，在IV9到V 9反应时需加热60℃反应，经处理得白色固体120.6mg，收率65.2％。1H NMR(400MHz,CD3OD)δ7.32(t,J＝7.8Hz,1H),7.07–6.87(m,3H),6.84–6.74(m,1H),4.19–4.04(m,3H),3.97–3.83(m,2H),3.82(s,3H),3.42(p,J＝5.6Hz,1H),2.65(dd,J＝17.7,5.2Hz,1H),2.25–2.11(m,1H),1.95(s,3H),1.58–1.45(m,4H),0.98–0.84(m,6H)；HRMS(ESI):485.2372[M+Na]+.
实施实例14
(3R，4R，5S)-4-乙酰氨基-5-(2-肉桂酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-10)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用反式肉桂醛替换甲醛，经处理得白色固体107mg，收率71.3％。1H NMR(600MHz,CD3OD)δ7.48–7.43(m,2H),7.36–7.32(m,2H),7.31–7.26(m,1H),6.80(t,J＝2.5Hz,2H),6.26(dt,J＝15.8,7.1Hz,1H),4.15–4.11(m,1H),3.98–3.89(m,2H),3.85–3.77(m,2H),3.42(p,J＝5.7Hz,1H),2.74–2.68(m,1H),2.31–2.24(m,1H),1.93(s,3H),1.55–1.48(m,4H),0.95–0.87(m,6H)；HRMS(ESI):481.2422[M+Na]+.
实施实例15
(3R，4R，5S)-4-乙酰氨基-5-(2-(环丙基甲基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸(I-11)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用环丙烷甲醛替换甲醛，经处理得白色固体97.5mg，收率74.5％。1H NMR(400MHz,CD3OD)δ6.81(t,J＝2.4Hz,1H),4.22–4.09(m,1H),3.98–3.91(m,2H),3.42(p,J＝5.6Hz,1H),2.98(d,J＝7.5Hz,2H),2.79–2.63(m,1H),2.39–2.24(m,1H),1.95(s,3H),1.58–1.47(m,4H),1.04(td,J＝7.9,4.1Hz,1H),0.96–0.84(m,6H),0.73–0.62(m,2H),0.38(t,J＝5.1Hz,2H)；HRMS(ESI):397.2488[M+H]+,419.2266[M+Na]+.
实施实例16
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-(四氢-2H-吡喃-4-基)肼-1-甲酰胺基)环己-1-烯-1-羧酸(I-12)
实施操作同实施实例3、实施实例4和实施实例5，以200mg(3R，4R，5S)-4-乙酰氨基-5-(肼甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸乙酯(III)为反应原料，用四氢吡喃酮替换甲醛，经处理得白色固体94.9mg，收率65.1％。1H NMR(400MHz,CD3OD)δ6.81(td,J＝2.6,1.0Hz,1H),4.16–4.10(m,1H),4.02–3.88(m,4H),3.45–3.36(m,3H),3.27–
3.13(m,1H),2.74(ddt,J＝17.6,5.0,1.4 Hz,1H),2.35–2.25(m,1H),1.96(s,3H),1.88–1.77(m,2H),1.62–1.45(m,6H),0.97–0.86(m,6H)；HRMS(ESI):449.2372[M+Na]+。
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，R独立的表示氢原子、C1-C10烷基、C3-C6环烷基、5-10元芳基、5-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基含有1-3个N、O或S的杂原子，所述R可以被如下取代基中的一个或多个取代：卤素、C1-C10烷基、C2-C6烯基、C1-C10烷氧基、5-10元芳基。
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，R独立的表示氢原子、C1-C8烷基、C3-C6环烷基、5-6元芳基、5-6元杂环基或5-6元杂芳基，所述R可以被如下取代基中的一个或多个取代：卤素、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、5-6元芳基。
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，R独立的表示氢原子、C1-C8烷基、C3-C6环烷基、苯基、或
所述R可以被如下取代基中的一个或多个取代：卤素、C1-C4烷基、C1-C4烷氧基、C2-C4烯基。
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，R独立的表示氢原子、C1-C8烷基、环丙烷、苯基、或
所述R可以被如下取代基中的一个或多个取代：卤素、C1-C2烷基、C1-C2烷氧基、C2-C4烯基。
5.如下的衍生物及其药学上可接受的盐和异构体：
(3R，4R，5S)-4-乙酰氨基-5-(2-甲基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-丙基肼-1-甲酰胺基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-丁酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-异戊基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-庚酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-苄基肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-苯乙基肼-1-甲酰胺基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-(2-氯苄基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-(3-甲氧基苄基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-肉桂酰肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-5-(2-(环丙基甲基)肼-1-甲酰胺基)-3-(戊烷-3-氧基)环己-1-烯-1-羧酸
(3R，4R，5S)-4-乙酰氨基-3-(戊烷-3-氧基)-5-(2-(四氢-2H-吡喃-4-基)肼-1-甲酰胺基)环己-1-烯-1-羧酸。
6.如权利要求1所述的衍生物及其药学上可接受的盐的制备方法，其特征在于，
其中，R如权利要求1所述。
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形剂。
8.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1-5中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1-5中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药物中的应用。
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| 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 |
| CN109553554A (zh) * | 2017-09-26 | 2019-04-02 | 沈阳药科大学 | 含脲基的神经氨酸酶抑制剂及其医药用途 |
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