CN102596905B - 具有促智活性的2-(5-甲基-2-氧代-4-苯基-吡咯烷-1-基)-乙酰胺的4r, 5s -对映异构体 - Google Patents
具有促智活性的2-(5-甲基-2-氧代-4-苯基-吡咯烷-1-基)-乙酰胺的4r, 5s -对映异构体 Download PDFInfo
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- CN102596905B CN102596905B CN201080050216.9A CN201080050216A CN102596905B CN 102596905 B CN102596905 B CN 102596905B CN 201080050216 A CN201080050216 A CN 201080050216A CN 102596905 B CN102596905 B CN 102596905B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
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- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及具有高药理学价值认知促进活性的2-(5-甲基-2-氧代-4-苯基-吡咯烷-1-基)-乙酰胺的5S,4R-对映异构体，并涉及其制备方法，该方法包括合成5S-甲基-4R-苯基吡咯烷-2-酮、用卤代乙酸乙酯将5S-甲基-4R-苯基吡咯烷-2-酮进行N-烷基化以及用氨处理中间体2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酸乙酯。
Description
发明领域
本发明涉及用作促智（nootropic）药物的2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺的4R,5S-对映异构体的制备和医药用途。
背景技术
已知认知促进药物促进注意能力和信息的获得、存储和检索，并减轻与头部外伤、中风、老化和老化相关病状有关的认知功能的损害。
2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺的外消旋分子——比乙酰胺结构衍生物于2001年提及（M.V.Berestovitskaya,M.M.Zobachova,B.M.Novikov,O.S.Vasil′eva,N.V.Usik,S.M.Aleksandrova,I.N.Turenkov.International Conference on the Synthesis of Nitrogen Heterocycles（氮杂环合成国际会议）,Moscov,Oct.9-12,2001,vol.1,pp.229-233）。但是，没有提供该化合物化学结构和生物性质方面的数据。
EP 2013166B(AKCIJU SABIEDRIBA OLAINFARM)于10.03.2010公开了具有向神经活性的N-氨基甲酰基甲基-4-苯基-2-比咯烷酮的R-对映异构体，其与本发明化合物的不同仅在于缺少5-甲基。
发明内容
根据本发明，对在比咯烷酮环的4位和5位含有两个手性中心的外消旋2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺的药理学研究出乎意料地显示出其相当有前景的认知促进特性。但是，当发明人制备出分离的2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺的4R,5S-对映异构体并对其进行促智研究时，其与原外消旋化合物相比，令人吃惊且出人意料地显示出更高的药理学活性。
本发明描述了具有高药理学价值认知促进活性的式1的2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺的4R,5S-对映异构体的制备方法：
其为具有促智活性的新化合物。
根据本发明，制备2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺（1）的化学路线包括合成5-甲基-4-苯基比咯烷-2-酮（2）的4R,5S-对映异构体和在比咯烷酮环的1位插入乙酰胺基团：
外消旋5-甲基-4-苯基比咯烷-2-酮的制备以及将其分离成eritro-和treo-异构体的对映异构混合物的方法记载于文献中（Colonge J.,Pouchol J.M.,Bull.Soc.Chim.,1962,598-603；Langlois M..等人Bull.Soc.Chim.,1971,2976-2982；Lesniak S.,Pasternak B.,Tetrahedron Lett.,2005,46,3093-3095）。但是，尚未发现任何关于将外消旋5-甲基-4-苯基比咯烷-2-酮拆分成分离的对映异构体或者由手性或非手性化学物质直接合成它们的书面证据。
根据本发明，该问题解决如下：2-硝基丙-1-烯基苯（3）与丙二酸二乙酯（3）在由手性2,2′-环亚丙基-二-恶唑啉5、三氟甲基磺酸镁和有机碱组成的复合催化剂的存在下进行不对称迈克尔加成，导致形成2-[2(R,S)-硝基-1R-苯基丙基]-丙二酸二乙酯非对映异构混合物（6）
通过依次进行以下步骤（见下面路线）将中间体6转化成5S-甲基 -4R-苯基比咯烷-2-酮（2）：
a）2-硝基丙-1-烯基苯与丙二酸二乙酯在由手性2,2′-环亚丙基-二-恶唑啉、三氟甲基磺酸镁和有机碱组成的复合催化剂的存在下进行加成；
b）通过2-(2-硝基-1R-苯基丙基)丙二酸二乙酯在雷尼Ni的存在下发生氢化将2-(2-硝基-1R-苯基丙基)丙二酸二乙酯转化成对映异构的5S-甲基-4R-苯基比咯烷-2-酮，将5-甲基-2-氧代-4(R)-苯基比咯烷-3(S)-甲酸乙酯的非对映异构混合物拆分成分离的5S,4R-和5R,4-对映异构体，对5(S)-甲基-2-氧代-4(R)-苯基比咯烷-3(S)-甲酸乙酯进行脱羧；
c）将5S-甲基-4R-苯基比咯烷-2-酮的酰胺基中的氢在适当的有机溶剂中用钠离子置换；
d）将N-金属化的5S-甲基-4R-苯基比咯烷-2-酮在适当的有机溶剂中用卤代乙酸酯进行N-烷基化；
e）将2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯在适当的溶剂的中用氨进行酰胺化。
5S-甲基-4R-苯基比咯烷-2-酮（2）至2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺（1）的转化包括：将2的NH基团中的氢用钠置换；将金属化的比咯烷-2-酮13用卤代乙酸酯进行烷基化；和将中间体 2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯（14）在适当的溶剂的中用氨进行处理。
根据本发明，采用标准的被动回避试验（standard passive avoidance test）对2-(4R-苯基-2-氧代比咯烷-1-基)乙酰胺)、外消旋2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺和2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺的比较药理学评价证实，光学活性的2-(5S-甲基-2-氧代-4R-苯基比咯烷-1-基)-乙酰胺（1）作为学习记忆促进剂具有很高的有效性。
因此，2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺可以作为高度有效的药剂用作具有促智活性的药物。
具体实施方式
本发明的范围不受实施例限制，实施例作说明用途。本领域技术人员可以基于本专利申请的公开内容实施本发明。
对以下实施例进行说明，其不对本发明构成限制。
实施例
实施例1
在室温下将(3aR,3′aR,8aS,8′aS)-2,2′-环亚丙基二-[3a,8a]-二氢-8H-茚并-[1,2-d]-恶唑（420mg,1.18mM）的氯仿（烃稳定化）溶液（5ml）、三氟甲基磺酸镁（378mg,0.1.18mM）和水（25μL）加入到250ml反应瓶中，将混合物在氩气下搅拌1小时。向得到的混合物中加入分 子筛（1.0g）和1,4-二恶烷（30ml），并继续搅拌30分钟。将得到的悬浮液用45ml含有丙二酸二乙酯（1.67g,10.2mM）、2-硝基丙-1-烯基苯（1.63g,10.0mM）和吗啉（46μL）的氯仿溶液稀释。将反应混合物在室温下搅拌。每24小时通过手性HPLC分析[Chiralpak IC，4.6x250mm，1.0ml/min，洗脱剂i-PrOH-己烷（1:9）]测定转化率和选择性。反应完成后，将反应混合物用己烷（50ml）稀释，搅拌20分钟，滤去固体。滤液用5%HCl水溶液（2x50ml）、盐水（2x50ml）洗涤，用无水Na2SO4干燥。过滤除去干燥剂，将溶液减压浓缩。将残余物用乙酸乙酯/己烷（1:10）在硅石上通过柱层析纯化，收集Rf0.28的部分。收率87%（2.8g）。根据手性HPLS，得到的低熔点黄色固体是比率为3:1的2-(2-硝基-1R-苯基丙基)-丙二酸二乙酯的eritro-和treo-异构体的混合物。光学纯度：93%。
1H NMR(CDCl3)，δ，ppm(J，Hz)：0.85(2.25H，t，J＝7.0 eritro-CH2 CH 3)；0.93(0.75H，t，J＝7.0 treo-CH2 CH 3)；1.15-1.27(3H，m，CH2 CH 3)；1.29(0.75H，d，J＝6.8，treo-CH 3CNO2)；1.37(2.25H，d，J＝6.8，eritro-CH 3CNO2)；3.63-3.93(3H，m，CH 2CH3，COCHCO)；4.07-4.29(3H，m，CH 2CH3，PhCH，)；4.29-5.06(0.25H，m，treo-CHNO2)；5.07-5.16(0.75H，m，eritro-CHNO2)；6.99-7.28(5H，m，C6H5).
实施例2
将实施例1中的吗啉用N-甲基吗啉替代，导致形成2-(2-硝基-1R-苯基丙基)-丙二酸二乙酯的eritro-和treo-异构体（比率为3:1）的混合物。光学纯度：94%。收率85%。
实施例3
将实施例1中的吗啉用吗啉（46μL）和四甲基胍（46μL）的混合物替代，导致形成2-(2-硝基-1R-苯基丙基)-丙二酸二乙酯的eritro-和treo-异构体（比率为3:1）的混合物。光学纯度：95%。收率87%。
实施例4
将搅拌下的2-(2-硝基-1R-苯基丙基)-丙二酸二乙酯（2.34g,7.22mM）的乙醇悬浮液（50ml）和1ml 50%雷尼Ni水桨液在50℃、50atm下氢化18小时。反应完成后，将反应混合物冷却，滤去催化剂，并用30ml乙醇洗涤。将滤液减压浓缩。将残余物用CH2Cl2/EtOH （10:1→1:10）在硅胶上通过柱层析纯化，收集Rf 0.28的部分。收率80%（1.43g）。根据1H NMR谱图，得到的白色固体是比率为17:3的5-甲基-2-氧代-4(R)-苯基比咯烷-3(S)-甲酸乙酯的eritro-和treo-异构体的混合物。收率80%（1.43g）。
1H NMR(CDCl3)，δ，ppm(J，Hz)：0.76(2.55H，d，J＝6.3eritro-5-CH3)；1.18-1.23(3.45H，m，treo-5-CH3and CH2 CH 3)；3.73(1H，d，J＝9.0，3-H)；4.02-4.22(4H，m，CH 2CH3，4-H，5-H)；6.23(1H，br.s，NH)；7.09-7.33(5H，m，C6H5).
将得到的产品用乙醇重结晶，结果分离出785mg 5S-甲基-4R-苯基-2-比咯烷酮-3S-甲酸酯。M.p.141-143℃。
C14H17NO3（247.30）的分析计算值：C 68.00;H 6.93;N 5.66。
实测值：C 67.93;H 6.87;N 5.64.
1H NMR(CDCl3)，δ，ppm(J，Hz)：0.76(3H，d，J＝6.3 eritro-5-CH3)；1.18-1.23(3H，m，CH2 CH 3)；3.73(1H，d，J＝9.0，3-H)；4.02-4.22(4H，m， CH 2CH3，4-H，5-H)；6.23(1H，br.s，NH)；7.09-7.33(5H，m，C6H5).
实施例5
将氢氧化钾（672mg,12mM）加入到5S-甲基-4R-苯基-2-比咯烷酮-3S-甲酸乙酯（900mg,4.00mM）的甲醇（50ml）溶液中，得到的混合物回流3小时。将反应混合物冷却，并减压蒸发。残余物溶解在20ml水中，将水溶液用乙酸乙酯（3x30ml）洗涤，用稀HCl将pH调节至pH 2，并减压蒸发。得到的残余物悬浮在EtOH/CH2Cl2（1:1）溶液中，搅拌1小时，过滤，将滤液减压蒸发。将残余物溶解在乙酸异丙酯（40ml）和对甲苯磺酸（100mg）的溶液中。将得到的混合物回流24小时，冷却，并减压浓缩。将残余物用CH2Cl2/EtOH（20:1）在硅胶上通过液相柱层析纯化，收集Rf 0.40的部分。根据手性HPLC，得到的黄色固体是5S-甲基-4R-苯基比咯烷-2-酮的eritro-异构体。收率65%（455mg）。
C11H13NO（175.23）的分析计算值：C 75.40;H 7.48;N 7.99。
实测值：C 75.63;H 7.55;N 8.07。
1H NMR(CDCl3)，δ，ppm(J，Hz)：0.75(3.00H，d，J＝6.55-CH3)；2.55-2.69(2H，m，3-CH2)；3.64-3.72(1H，m，4-H)；3.96-4.04(1H，m，5-H)；6.78(1H，br.s，NH)；7.07-7.33(5H，m，C6H5).
实施例6
将实施例5中的氢氧化钾用氢氧化钠替代，导致形成5S-甲基-4R-苯基-2-比咯烷酮。收率62%。
实施例7
将5S-甲基-4R-苯基-2-比咯烷酮（351mg,2.00mM）的甲苯（30ml）溶液加入到氢化钠（56mg,2.35mM）的甲苯（30ml）悬浮液中。将搅拌下的混合物在80-90℃下加热30分钟，然后冷却至室温。向反应混合物中加入溴乙酸乙酯（368mg,2.20mM），将其在110-120℃下加热6小时，然后减压浓缩。残余物溶解在甲苯（30ml）中。得到的溶液用5%HCl水溶液（2x50ml）、盐水（2x50ml）洗涤，用无水Na2SO4干燥。过滤除去干燥剂，将溶液减压浓缩。将残余物用CH2Cl2/MeOH（20:1）在硅石上通过柱层析纯化，收集Rf0.48的部分，减压蒸发，得到无色油状2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯（381mg,73%）。
1H NMR(CDCl3)，δ，ppm(J，Hz)：0.72(3.00H，d，J＝6.65-CH3)；1.23(3H，t，J＝7.0，CH2 CH 3)；2.60-2.91(2H，d，J＝8.5，3-CH2)；3.65-3.74(1H，m，4-H)；3.66(2H，d，J＝17.7，NCH2COO)；4.01-4.10(1H，m，5-H)；4.10-4.20(2H，m，CH 2CH3)；4.38(1H，d，J＝17.7，NCH2COO)；7.09-7.31(5H，m，C6H5).
实施例8
将实施例7中的氢化钠用乙醇钠替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯，收率68%。
实施例9
将实施例7中的溴乙酸乙酯用氯乙酸乙酯替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯，收率70%。
实施例10
将实施例7中的甲苯用己烷替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯，收率71%。
实施例11
将实施例7中的甲苯用苯替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯，收率70%。
实施例12
将实施例7中的甲苯用1,4-二恶烷替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯，收率72%。
实施例13
将实施例7中的甲苯用二氯甲烷替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯，收率67%。
实施例14
将2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酸乙酯（350mg,1.34mM）的甲醇（30ml）溶液用气态氨饱和5小时。将反应混合物减压浓缩，残余物用CH2Cl2/EtOH（20:1）通过柱层析纯化。收集Rf 0.32的部分，减压蒸发，用水重结晶，得到白色固体状2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1基)-乙酰胺（249mg,80%）。M.p.169-171℃。
C13H16N2O2（232.28）的计算值：C 67.22;H 6.94;N 12.06。
实测值：C 67.31;H 6.99;N 12.10。
1H NMR(CDCl3)，δ：0.77(3.00H，d，J＝6.65-CH3)；2.62-2.81(2H，m，3-CH2)；3.66-3.75(1H，m，4-H)；3.75(1H，d，J＝16，NCH2COO)；3.98-4.08(1H，m，5-H)；4.04(1H，d，J＝16，NCH2COO)；5.48和6.29(2H，br.s，br.s，NH2)；7.07-7.32(5H，m，C6H5).
实施例15
将实施例13中的气态氨用25%的氨水替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺，收率78%。
实施例16
将实施例13中的甲醇用乙醇替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺，收率81%。
实施例17
将实施例13中的甲醇用异丙醇替代，导致形成2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺，收率77%。
实施例18
通过5-甲基-4-苯基比咯烷-2-酮的N-甲基甲氨酰化，制备外消旋 2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺。
1H NMR(CDCl3)，δ：0.77(1.50H，d，J＝6.6eritro-5-CH3)；1.23(1.50H，d，J＝6.3treo-5-CH3)；2.53-2.86(2H，m，3-CH2)；3.66-3.75(1H，m，4-H)；3.75(0.5H，d，J＝16，eritro-NCH2COO)；3.86(0.5H，d，J＝16，treo-NCH2COO)；3.95(0.5H，d，J＝16，treo-NCH2COO)；3.98-4.08(1H，m，5-H)；4.04(0.5H，d，J＝16，erito-NCH2COO)；5.48和6.29(2H，br.s，br.s，NH2)；7.07-7.32(5H，m，C6H5).
生物试验
学习和记忆
在具有两个大小相等（20x10x16cm）的联通隔间和不锈钢格子地板（格栅间距0.7cm）的穿梭箱装置（意大利Ugo Basile）中进行被动回避试验。将右方隔间（电击隔间）涂成黑色，得到暗室。将左方隔间涂成白色，并用安装在树脂玻璃盖上方的灯泡（100W）照明。这些隔间用闸门（5x4cm）分隔。第1天（训练试验），将小鼠置于照明的隔间，60秒后打开两个隔间之间的门。当小鼠四足全部进入暗隔间后，门自动关闭，通过格子地板传输不可避免的足部电击（0.1mA;3秒）。自动测量跨入暗隔间的潜伏时间（latency）（训练潜伏时间）。24小时之后（第2天）进行保持能力（retention）试验。将小鼠置于亮（安全）的隔间，可通向暗隔间（10秒内）时长300秒（截止时间）。自动测量四足全部跨入暗隔间的潜伏时间（保持潜伏时间）。
2-(4R-苯基-2-氧代比咯烷-1-基)乙酰胺)、外消旋2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺和2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺在ICR雄性小鼠中对被动回避反应（记忆）保持能力的影响。
表1所示的数据说明了2-(4R-苯基-2-氧代比咯烷-1-基)乙酰胺)、外消旋2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺和2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺在小鼠的被动回避任务中对记忆力的影响。
表1
给予的化合物对小鼠被动回避任务中记忆力的影响
| 化合物 | 潜伏时间，秒 |
| 对照（盐水） | 62,7±6,2 |
| 2-(4R-苯基-2-氧代比咯烷-1-基)乙酰胺) | 94,9±27,6 |
| 2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺外消旋物 | 74,2±19,9 |
| 2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺 | 170,6±41,9*#$ |
训练试验（第1天）60分钟前，以46μmol/kg的剂量腹膜内给予各化合物。盐水对照组与药物处理组同时进行。数据分析通过学生t检验（Student′s t-test）进行。数据表示平均值±S.EM
*p<0.05、#p<0.05、$p<0.05分别相对于盐水对照组、2-(4R-苯基-2-氧代比咯烷-1-基)乙酰胺处理组和外消旋2-(5-甲基-2-氧代-4-苯基-比咯烷-1-基)-乙酰胺-处理组；n>10
如表1所示，以46μmol/kg的剂量进行2-(5S-甲基-2-氧代-4R-苯基-比咯烷-1-基)-乙酰胺处理在记忆力方面产生了统计学显著的效果。
Claims (14)
1.2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酰胺（I），
2.2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酰胺在制备促智药物中的应用。
3.2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酰胺在制备认知促进剂中的应用。
4.2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酰胺在制备用于治疗认知缺陷的药物中的应用。
5.制备权利要求1所述化合物（I）的方法，其包括以下步骤：
a）2-硝基丙-1-烯基苯与丙二酸二乙酯在由手性2,2'-环亚丙基-二(噁唑啉)、三氟甲基磺酸镁和有机碱组成的复合催化剂的存在下进行加成；
b）通过2-(2-硝基-1R-苯基丙基)丙二酸二乙酯在雷尼Ni的存在下发生氢化将2-(2-硝基-1R-苯基丙基)丙二酸二乙酯转化成对映异构的5S-甲基-4R-苯基吡咯烷-2-酮，其中氢压力为3至60atm，将5-甲基-2-氧代-4(R)-苯基吡咯烷-3(S)-甲酸乙酯的非对映异构混合物拆分成分离的5S,4R-和5R,4R-对映异构体，对5(S)-甲基-2-氧代-4(R)-苯基吡咯烷-3(S)-甲酸乙酯进行水解；
c）将5S-甲基-4R-苯基吡咯烷-2-酮的酰胺基中的氢在适当的有机溶剂中用钠离子置换；
d）将N-金属化的5S-甲基-4R-苯基吡咯烷-2-酮在适当的有机溶剂中用卤代乙酸酯进行N-烷基化；
e）将2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酸乙酯在适当的溶剂的中用氨进行酰胺化，
其中步骤c）、d）、e）的反应中使用的有机溶剂选自甲醇、乙醇、丙醇、氯仿、二氯甲烷、乙酸乙酯和1,4-二噁烷组成的组。
6.根据权利要求5所述的方法，其中在步骤a）中，手性2,2'-环亚丙基-二(噁唑啉)为(3aR,3'aR,8aS,8'aS)-2,2'-环亚丙基二-[3a,8a]-二氢-8H-茚并-[1,2-d]-噁唑。
7.根据权利要求5所述的方法，其中在步骤a）中，有机碱选自吗啉、N-甲基吗啉、1,1,3,3-四甲基胍及其混合物。
8.根据权利要求5所述的方法，其中在步骤b）中，用于通过结晶拆分5(R,S)-甲基-2-氧代-4(R)-苯基吡咯烷-3(S)-甲酸乙酯的非对映异构混合物的有机溶剂选自甲醇、乙醇、异丙醇及其混合物。
9.根据权利要求5所述的方法，其中在步骤b）中，用于5(S)-甲基-2-氧代-4(R)-苯基吡咯烷-3(S)-甲酸乙酯的水解的碱选自氢氧化钠和氢氧化钾。
10.根据权利要求5所述的方法，其中在步骤b）中，5(S)-甲基-2-氧代-4(R)-苯基吡咯烷-3(S)-甲酸酯在对甲苯磺酸的存在下在乙酸异丙醇酯溶液中的脱羧温度为50℃至88℃。
11.根据权利要求5所述的方法，其中在步骤c）中，钠离子通过氢化钠或乙醇钠引入至5S-甲基-4R-苯基吡咯烷-2-酮的酰胺基中。
12.根据权利要求5所述的方法，其中在步骤d）中，卤代乙酸酯选自溴乙酸酯或氯乙酸酯。
13.根据权利要求5所述的方法，其中在步骤e）中，2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酸乙酯的酰胺化在氨水或氨水与所述选自甲醇、乙醇、丙醇、氯仿、二氯甲烷、乙酸乙酯和1,4-二噁烷组成的组的有机溶剂的混合物中进行。
14.根据权利要求5所述的方法，其中在步骤e）中，2-(5S-甲基-2-氧代-4R-苯基-吡咯烷-1-基)-乙酸乙酯的酰胺化在所述选自甲醇、乙醇、丙醇、氯仿、二氯甲烷、乙酸乙酯和1,4-二噁烷组成的组的有机溶剂中通过用气态氨将其饱和来进行。
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| LVP-09-193A LV14346B (lv) | 2009-11-05 | 2009-11-05 | 2-(4-Fenil-5-metil-2-oksopirolidin-1-il)-acetamīda 4R,5S-enantiomērs ar nootropo aktivitāti |
| LVP-09-193 | 2009-11-05 | ||
| PCT/EP2010/066767 WO2011054888A1 (en) | 2009-11-05 | 2010-11-04 | 4r,5s-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide with nootropic activity |
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| RU2711655C1 (ru) * | 2019-09-13 | 2020-01-20 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Российский национальный исследовательский медицинский университет имени Н.И. Пирогова" Министерства здравоохранения Российской Федерации | Способ крупномасштабного синтеза калиевой соли 2-[2-(2-оксо-4-фенилпирролидин-1-ил)ацетамидо]этансульфокислоты |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1120036A (zh) * | 1994-05-07 | 1996-04-10 | 中国科学院昆明植物研究所 | N-取代基-4-取代苯基-5-烷基-5-取代苄基吡咯烷酮-2，其中间体、其合成方法及其应用 |
| CN1484527A (zh) * | 2000-12-28 | 2004-03-24 | ��һ��������ҩ��ʽ���� | 神经性疼痛治疗和预防药 |
| EP1698622A1 (en) * | 2003-12-24 | 2006-09-06 | Hideki Ohyama | Agent or method for treatment for severe aphasia in chronic-stage cerebrovascular disorder |
| CN1960971A (zh) * | 2004-05-28 | 2007-05-09 | 诺瓦提斯公司 | 取代的吡咯烷－2－酮 |
| CN101448786A (zh) * | 2006-03-16 | 2009-06-03 | 奥兰珐姆股份公司 | N-氨基甲酰甲基-4(r)-苯基-2-吡咯烷酮的制备方法及药物用途 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2186236B1 (zh) * | 1972-05-03 | 1975-08-01 | Logeais Labor Jacques |
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2010
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2014
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1120036A (zh) * | 1994-05-07 | 1996-04-10 | 中国科学院昆明植物研究所 | N-取代基-4-取代苯基-5-烷基-5-取代苄基吡咯烷酮-2，其中间体、其合成方法及其应用 |
| CN1484527A (zh) * | 2000-12-28 | 2004-03-24 | ��һ��������ҩ��ʽ���� | 神经性疼痛治疗和预防药 |
| EP1698622A1 (en) * | 2003-12-24 | 2006-09-06 | Hideki Ohyama | Agent or method for treatment for severe aphasia in chronic-stage cerebrovascular disorder |
| CN1960971A (zh) * | 2004-05-28 | 2007-05-09 | 诺瓦提斯公司 | 取代的吡咯烷－2－酮 |
| CN101448786A (zh) * | 2006-03-16 | 2009-06-03 | 奥兰珐姆股份公司 | N-氨基甲酰甲基-4(r)-苯基-2-吡咯烷酮的制备方法及药物用途 |
Non-Patent Citations (4)
| Title |
|---|
| No 115.-PREPARATION DE PYRROLIDONES-2 ET DE GAMMA-AMINOACIDES;par Jean Colonge;《BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE》;19620207;第598-603页 * |
| par Jean Colonge.No 115.-PREPARATION DE PYRROLIDONES-2 ET DE GAMMA-AMINOACIDES.《BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE》.1962,第598-603页. |
| par Michel Langlois.NO 490. - RECHERCHES SUR LES ARYL-3 PYRROLIDINES. I. - PREPARATIONSD"ARYL-4 PYRROLIDONES-2 ET D"ARYL-3 PYRROLIDINES.《BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE》.1971,(第8期),第2976-2982页. |
| par Michel Langlois.NO 490.- RECHERCHES SUR LES ARYL-3 PYRROLIDINES. I.- PREPARATIONSD"ARYL-4 PYRROLIDONES-2 ET D"ARYL-3 PYRROLIDINES.《BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE》.1971,(第8期),第2976-2982页. * |
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| US20140296317A1 (en) | 2014-10-02 |
| DK2496555T3 (da) | 2013-11-11 |
| SI2496555T1 (sl) | 2013-12-31 |
| HRP20131086T1 (hr) | 2013-12-20 |
| PT2496555E (pt) | 2013-12-02 |
| CA2780040A1 (en) | 2011-05-12 |
| EP2496555A1 (en) | 2012-09-12 |
| US20120215010A1 (en) | 2012-08-23 |
| CN102596905A (zh) | 2012-07-18 |
| UA107367C2 (xx) | 2014-12-25 |
| LV14346A (lv) | 2011-05-20 |
| PL2496555T3 (pl) | 2014-01-31 |
| ES2434024T3 (es) | 2013-12-13 |
| EA019890B1 (ru) | 2014-07-30 |
| JP2013510081A (ja) | 2013-03-21 |
| WO2011054888A1 (en) | 2011-05-12 |
| RS53014B (en) | 2014-04-30 |
| AR078904A1 (es) | 2011-12-14 |
| EA201200536A1 (ru) | 2012-09-28 |
| EP2496555B1 (en) | 2013-08-28 |
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