CN1295215C - 黄皮酰胺的光学活性衍生物、其制法和其药物组合物与用途 - Google Patents
黄皮酰胺的光学活性衍生物、其制法和其药物组合物与用途 Download PDFInfo
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- CN1295215C CN1295215C CNB2003101238752A CN200310123875A CN1295215C CN 1295215 C CN1295215 C CN 1295215C CN B2003101238752 A CNB2003101238752 A CN B2003101238752A CN 200310123875 A CN200310123875 A CN 200310123875A CN 1295215 C CN1295215 C CN 1295215C
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Abstract
本发明公开了羟苄基、羟基、苯基取代γ-内酰胺(黄皮酰胺)的立体异构体,光活的立体异构体,及它们的制备方法,以它们作为活性物质的药物组合物,和它们在制备治疗智力衰退、抗脑缺氧缺氧、神经退行性疾病、老年性痴呆、早老性痴呆、血管性痴呆的药物中的应用。
Description
技术领域
本发明涉及羟苄基、羟基、苯基取代γ-内酰胺(黄皮酰胺)的立体异构体,光活的立体异构体,及它们的制备方法,以它们作为活性物质的药物组合物,和它们在制备治疗智力衰退、抗脑缺血缺氧、神经退行性疾病、老年性痴呆、早老性痴呆、血管性痴呆的药物中的应用。
背景技术
目前我国人口的平均寿命已超过70岁,比解放时的人均寿命增加了一倍。国外一项科学研究预测:到2025年时,15岁以下儿童的比例将占总人口的18.6%,而65岁及65岁以上的老年人将超过童数,达到18.8%,这个数字表明,再过20余年,每5个人中就有1个老年人。早老性痴呆症(Alzheimer’s Disease)多发生在50余岁。因脑血管病变引发的多发性栓塞性痴呆或老年性痴呆多发生在60岁以后。可见,由于人口的老龄化,早老性痴呆症和老年性痴呆症的发病率也必将增加。老年人及其特有的神经退化性疾病——各种痴呆症要经历两种死亡,首先是精神上的死亡,后是肉体上的死亡,苦不堪言,更给社会和家庭带来沉重负担。人口老龄化被认为是仅次于战争,瘟疫,饥荒,资源能源短缺而影响社会发展和安定的不利因素。
防治衰老和治疗老年痴呆的药物种类繁多。脑血管扩张药,通过改善脑血流量有助于提供能量和改善智能,但真正有价值的脑血管扩张药必须具有高度选择性,不影响脑代谢,无“窃血”现象,有抗血小板聚集和抗血栓作用。钙拮抗剂尼莫地平虽符合上述某些条件,但它仅作用于电压依赖性钙通道中的L-通道,对N型和T型钙通道无影响。增强胆碱系统功能的药物中,Ach前体仅有微弱的治疗作用,Ach受体激动剂和胆碱脂酶抑制剂虽有一定效果,但作用较短暂,毒副作用较大。多种神经肽和神经生长因子曾被认为有治疗痴呆症的希望,但临床效果不佳,可能主要归因于这类物质难以通过血脑屏障进入脑内发挥作用,2-吡咯烷酮乙酰胺(piracetam国内已生产,商品名脑复康)问世后,在早期文献中属没有争论的一类新型促智药(nootropil,该词是从希腊词noo(脑)和tropein(向)衍化而来),近几年来国内外报道,该药对各类型的记忆障碍和老年痴呆作用轻微或尚无定论,一个主要原因是该药为水溶性化合物,通过血脑屏障率低,不易集中到靶点发挥作用。
本发明人从芸香科植物黄皮[Clausena Lansium(lour.)Skells]中第一次分离出含有脑复康药的γ-内酰胺骨架的化合物,称之为黄皮酰胺(黄皮酰胺)。黄皮酰胺是具有四个手性中心的γ-内酰胺,天然品为消旋体,消旋黄皮酰胺的合成方法曾申请欧洲专利,其申请号为EP0414020,中国专利申请为86107090,90107145.5和90107144.7。左旋黄皮酰胺具有较好的促智作用,该化合物的纯物质、制备方法及其潜在的医药应用本发明人已申请专利,CN00124630.5。
黄皮酰胺分子中有4个手性中心,应有16个光活的立体异构体,组成互为非对映关系的8对对映异构体(其构型与命名如表1)
表1 8对光活立体异构体
其中黄皮酰胺的一对对映体(I1)本发明人已申请专利(专利申请号:CN00124630.5)。消旋的新黄皮酰胺(I2)和消旋的表新黄皮酰胺(I4)是公知的,但光活新黄皮酰胺(I2)和表新黄皮酰胺(I4)及其制备方法未见文献报道。(-)和(+)黄皮酰胺(I1)的体内、外代谢的研究结果表明:两者的代谢物的种类基本相同,而(-)黄皮酰胺的代谢物中(-)N-羟甲基去甲黄皮酰胺[(-)-CM1]和(-)-5-羟基黄皮酰胺[(-)-CM2]的含量明显高于(+)黄皮酰胺的代谢产物中相应的[(+)-CM1]和[(+)-CM2]的含量。其母体(-)黄皮酰胺的药理试验表明,具有明显的促智抗细胞凋亡作用,而(+)黄皮酰胺无此作用,并有拮抗作用,据此合成了代谢物CM1和CM2的一对对映体及其衍生物,其中CM11的制备本发明人已发表。
黄皮酰胺(I1)(-)3S,4R,5R,6S(+)3R,4S,5S,6R | 新黄皮酰胺(I2)(-)3S,4R,5S,6R(+)3R,4S,5R,6S | |
C6异构体 | 表黄皮酰胺(I3)(-)3S,4R,5R,6R(+)3R,4S,5S,6S | 表新黄皮酰胺(I4)(-)3S,4R,5S,6S(+)3R,4S,5R,6R |
C3异构体(C3/C4顺式) | 顺黄皮酰胺(I5)(+)3S,4S,5S,6R(-)3R,4R,5R,6S | 顺新黄皮酰胺(I6)(-)3S,4S,5R,6S(+)3R,4R,5S,6R |
顺表黄皮酰胺(I7)(+)3S,4S,5S,6S(-)3R,4R,5R,6R | 顺表新黄皮酰胺(I8)(-)3S,4S,5R,6R(+)3R,4R,5S,6S |
现有技术不能直接用于制备本发明所述的具有光学活性黄皮酰胺及其衍生物。
发明内容
本发明的目的是提供一类新的光活的手性药物黄皮酰胺衍生物。
本发明的另一目的在于提供制备本发明的光学活性黄皮酰胺衍生物的方法;
本发明的另一目的在于提供一种新的光学活性黄皮酰胺衍生物在制备促智,抗脑缺血缺氧,神经变性疾病药物的应用。
具体讲,本发明涉及如通式(I)所示的黄皮酰胺光活衍生物中的另外14个立体异构体,组成互为非对映关系的7对对映异构体,(其构型与命名如表2)
其中,各个碳原子的立体构型为
(+)-I2 (3R,4S,5R,6S) (+)新黄皮酰胺
(-)-I2 (3S,4R,5S,6R) (-)新黄皮酰胺
(+)-I3 (3R,4S,5S,6S) (+)表黄皮酰胺
(-)-I3 (3S,4R,5R,6R) (-)表黄皮酰胺
(+)-I4 (3R,4S,5R,6R) (+)表新黄皮酰胺
(-)-I4 (3S,4R,5S,6S) (-)表新黄皮酰胺
(+)-I5 (3S,4S,5S,6R) (+)顺黄皮酰胺
(-)-I5 (3R,4R,5R,6S) (-)顺黄皮酰胺
(+)-I6 (3R,4R,5S,6R) (+)顺新黄皮酰胺
(-)-I6 (3S,4S,5R,6S) (-)顺新黄皮酰胺
(+)-I7 (3S,4S,5S,6S) (+)顺表黄皮酰胺
(-)-I7 (3R,4R,5R,6R) (-)顺表黄皮酰胺
(+)-I8 (3R,4R,5S,6S) (+)顺表新黄皮酰胺
(-)-I8 (3S,4S,5R,6R) (-)顺表新黄皮酰胺
根据本发明,还涉及黄皮酰胺光活衍生物中I2、I4、I5、I6、I7和I8的制备方法,反应路线如路线1所示。
路线1
其中:
(a)碱催化环合:可用NaOCH3、(CH3)4NOH或二异丙基胺基锂(LDA);
(b)拆分剂:(-)-薄荷醇氧乙酰氯、N保护的氨基酸酰氯;
(c)羟基的保护,二氢吡喃,乙酰氯/吡啶或乙酸酐/吡啶;
(d)还原C6酮的还原剂:NaBH4或L-selectride;
(e)还原C6酮的还原剂:Al(i-C3H7O)3;
(f)氧化C3-OH的氧化剂:K2Cr2O7/H+、或KMnO4+CuSO4、MnO2 orDMSO/(COCl)2;
(g)还原Δ3,4双键的还原剂:NaBH4/H+、NaBH4/AlCl3或催化氢化;
(h)C3-OH的构型反转,用偶氮甲酸二异丙酯(DIAD)或偶氮甲酸二乙酯(DEAD)/TPP,H+(Mitsunobu method)或以CsOAc/18-冠醚-6完成。
本路线均以已知的消旋或光活的N-甲基-N-苯甲酰基-3-苯基缩水甘油酰胺(A)为原料。若以光活的化合物A为原料,则可略去步骤2(b)拆分这一步。
本发明化合物中黄皮酰胺的光活立体异构体中I3(C6差向异构体表黄皮酰胺)的制备方法如路线2所示。
路线2
本路线原料的原料消旋3-去氧表黄皮酰胺(3-去氧-I3)为已知化合物,是拜尔药厂合成消旋黄皮酰胺的中间体[Walfgang Hartwig,Liborrious Born,J.Org.Chem.,1987,52,4352.]的副产物。本路线经化合物3-去氧-I3引入C3位羟基得到消旋表黄皮酰胺(I3)。或先拆分得到3-去氧-I3的光活体,然后引羟得到光活的表黄皮酰胺(I3)。
(1)3-去氧表黄皮酰胺(3-去氧-I3)中引入3位羟基,采用的条件是选自二异丙基胺基锂(LDA)/O2/亚磷酸三乙酯(P(OEt)3)/六甲基磷酰胺(HMPT)/THF。
(2)3-去氧表黄皮酰胺(3-去氧-I3)的拆分,拆分剂选自O-乙酰-R-扁桃酸、O-乙酰-S-扁桃酸、薄荷醇氧乙酸、N-保护的氨基酸。
(3)水解拆分剂采用K2CO3/CH3OH的条件。
本发明因此还涉及含有作为活性成份的本发明化合物和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1-95重量%的本发明化合物。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时,如果需要,可将本发明化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射和皮内注射埋植等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、缓释、贴剂、埋植剂、冻干粉针剂等。
本发明化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
例如为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊,将有效成分本发明化合物与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明化合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数、治疗目的,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围本发明的化合物的用量为0.001-150mg/Kg体重,优选为0.01-100mg/Kg体重,更优选为0.01-60mg/Kg体重,最优选为0.1-10mg/Kg体重。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用并调整剂量。
在对人胚胎脑神经干细胞克隆形成率的试验中本发明的化合物具有明显促进人胚胎脑神经干细胞扩增和克隆形成的作用,说明本发明的化合物具有治疗老年性神经退行性疾病如老年性痴呆的作用。
在对神经细胞胞浆游离钙的影响的试验中本发明的化合物有升高神经细胞胞浆游离钙水平的趋势。钙作为第二信使在细胞活动中起着重要作用,胞浆游离钙浓度的变化与许多生理/病理刺激和细胞内效应器的反应具有密切关系。
在对大鼠海马长时程增强(LTP)的试验中本发明化合物对大鼠海马长时程增强(LTP)具有明显的增强作用,(P<0.05vs control,n=5)。本发明化合物对神经细胞基础突触传递有增强作用,说明本发明的化合物有促智作用。
附图说明
图1. 16种光学活性黄皮酰胺对人胚脑神经干细胞的影响
具体实施方式
实施例1 光活新黄皮酰胺(I2)的制备(见路线1)
消旋新黄皮酰胺酮的拆分:
消旋新黄皮酰胺酮2.7g,加至由2.7g(-)-薄荷醇氧乙酸制备的(-)-薄荷醇氧乙酰氯的30mL的二氯甲烷溶液,以冰水浴冷却,然后加入1.5mL吡啶,室温搅拌至反应完全,反应液以50mL的二氯甲烷稀释,依次以2N盐酸,饱和碳酸钠溶液和食盐水洗,有机层用无水硫酸钠干燥。浓缩后得6g油状物,加入己烷固化,固体过滤,以甲醇重结晶得1.48g 3-O-[(-)薄荷醇氧乙酰基]--(3R,4S,5R)-新黄皮酰胺酮[酯(a)],mp:170-172℃,[α]D 15=-50.9(c,1.25,CHCl3),收率33.8%。滤液柱层析得到3-O-[(-)薄荷醇氧乙酰基]--(3S,4R,5S)-新黄皮酰胺酮[酯(b)],mp:104-105℃,[α]D 15=-31.2(c,1.40,CHCl3),收率31.8%。酯(a)和酯(b)分别以对甲苯磺酸的甲醇溶液水解,蒸去甲醇,残余物溶于二氯甲烷,溶液依次以碱和酸的水溶液洗,从6g酯(a)得到3.25g的(-)-(3R,4S,5R)-新黄皮酰胺酮,收率86%,mp:164-167℃,[α]D 15=-14.9(c,0.60,CHCl3);5.5g酯(b)得到3.0g的(+)-(3S,4R,5S)-新黄皮酰胺酮,收率89%,mp:167-169℃,[α]D 15=+14.1(c,0.54,CHCl3)。
光活新黄皮酰胺(I2)由光活新黄皮酰胺酮的3-O-四氢吡喃醚还原得到。
(+)-3-O-四氢吡喃基新黄皮酰胺酮0.45g(1.19mmol)的10ml无水四氢呋喃液注入到-25--30℃的2.5ml 1.0M LTBB/THF中,反应1小时后,用40ml冰水(含2ml,30% H2O2)分解,用二氯甲烷提取,合併提取液,依次用2N NaOH、饱和NaHCO3及NaCl水溶液洗涤(PH≈8),无水硫酸鈉干燥,浓缩得油状物,用3ml无水乙醇及25mg TSOH·H2O,60℃反应30分钟,稍冷后加乙醚5ml,续冷析出(+)-(3R,4S,5R,6S)-新黄皮酰胺(+)-(I2),mp:186-187℃,[α]D 18=+89.5(c,0.20,MeOH),收率77.9%。
(-)-3-O-四氢吡喃基新黄皮酰胺酮0.379g(1.0mmol),同上法还原去保护得(-)-(3S,4R,5S,6R)-新黄皮酰胺((-)-I2),mp:186-187℃,[α]D 18=-88.6(c,0.18,MeOH),收率77.4%。
实施例2 光活表新黄皮酰胺(I4)的制备
(+)-(3S,4R,5S)-新黄皮酰胺酮1.05g(3.56mmol.),异丙醇铝2.4g(11.75mmol.)溶于30ml无水无水异丙醇中,加热搅拌,慢慢蒸出异丙醇及丙酮,并同时等速滴加无水异丙醇,约6.5小时反应完成,蒸除大部分溶剂,冷至室温加60ml水及20ml 3N盐酸室温搅拌,析出大量白色固体,用甲醇重结晶,得(-)-(3S,4R,5S,6S)-表新黄皮酰胺,收率85%,m.p.217-219℃,[α]D 24=-36.5(c,0.128,MeOH)。用甲醇再次重结晶,m.p.221-222℃,[α]D 20=-37.3(c,0.15,MeOH)。
(-)-(3R,4S,5R)-新黄皮酰胺酮为原料,同上操作,以异丙醇铝还原,得(+)-(3R,4S,5R,6R)-表新黄皮酰胺,m.p.220-222℃,[α]D 20=+36.5(c,0.16,MeOH)。
实施例3 表黄皮酰胺(I3)的制备(见路线2)
A:(±)-表黄皮酰胺((±)-I3)的制备
将(±)-(4R*,5R*,6R*)-3-去氧表黄皮酰胺(3-去氧I3)90mg(0.032mmol.),用2.5mL无水THF和0.7mL六甲基磷酰胺溶解(N2保护下),冷至-70℃,搅拌5分钟,用注射器加入1mL(0.32mmol.)新制的二异丙基氨基锂THF溶液,-60℃至-70℃下搅拌1小时,加入亚磷酸三乙酯53ul,通入依次经过氢氧化钾、浓硫酸、无水氯化钙处理过的O2,保持温度在-60℃至-70℃,2小时后停止通气,反应液用0.5mol/L盐酸在冰水浴下调至PH值=3-4,再依次用乙酸乙酯洗、水洗、氯化钠水溶液洗,无水硫酸钠干燥,蒸发溶剂后柱层析得到标题化合物40mg,回收原料40mg,收率40%,重结晶mp:193-195℃。
B:(-)-(3S,4R,5R,6R)-表黄皮酰胺((-)-I3)和(+)-(3R,4S,5S,6S)-表黄皮酰胺((+)-I3)的制备
将(±)-3-去氧表黄皮酰胺(3-去氧I3)600mg溶于30mL无水二氯甲烷中,再将O-乙酰-(-)-R-扁桃酸621mg,4-(二甲基氨基)吡啶26mg及1,3-二环己基碳酰亚胺880mg依次加入,室温下搅拌1小时,滤去不溶物,20mL二氯甲烷洗涤滤饼,有机相用2mol/L盐酸洗至偏酸,再用饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗,无水硫酸钠干燥过夜,蒸去溶剂得油状物930mg。硅胶H乙酸乙酯∶石油醚=1∶2。纯化得(4R,5R,6R)-5-O-乙酰-R-扁桃酰基-3-去氧表黄皮酰胺452mg,收率46%,mp:212-215℃;和(4S,5S,6S)-5-(O-乙酰-R-扁桃酰)-O-3-去氧表黄皮酰胺370mg,mp 206-209℃,收率40%。
将(4S,5S,6S)-5-(O-乙酰-R-扁桃酰基)-O-3-去氧表黄皮酰胺234mg溶于20mL甲醇和10mL二氯甲烷中,加入碳酸钾141mg,室温搅拌12小时。用2mol/L盐酸中和后减压蒸去溶剂,再用二氯甲烷溶解,水洗后用饱和氯化钠水溶液洗一次,无水硫酸钠干燥,蒸发溶剂得150mg固体。柱层析纯化得(+)-(4S,5S,6S)-3-去氧表黄皮酰胺(3-去氧I3)134mg,白色固体,收率93%。mp:239-242℃[α]30 D=+137(c,0.465,甲醇)
按上步反应同样的方法,将(4R,5R,6R)-5-O-乙酰-R-扁桃酰基-3-去氧表黄皮酰胺以K2CO3/CH3OH处理得到(-)-(4R,5R,6R)-3-去氧表黄皮酰胺(3-去氧I3),白色固体,收率与上相近,mp:237-240℃,[α]30 D=-136(c,0.480,甲醇)。
以(-)-(4R,5R,6R)-3-去氧表黄皮酰胺(3-去氧I3)或(+)-(4S,5S,6S)-3-去氧表黄皮酰胺(3-去氧I3)为原料,应用消旋3-去氧表黄皮酰胺(3-去氧I3)引入3位羟基的方法,可分别得到(-)-(3S,4R,5R,6R)-表黄皮酰胺((-)-I3),mp:107-109℃,[α]29 D=-204(c,0.445,甲醇)或(+)-(3R,4S,5S,6S)-表黄皮酰胺((+)-I3),mp:108-110℃[α]29 D=+201(c,0.245,甲醇)。
实施例4 顺黄皮酰胺(I5)的制备
路线5 顺黄皮酰胺(I5)的制备
酸性重铬酸钠溶液(0.7g重铬酸钠,0.7g浓硫酸和5mL水配成)加至0.25g的(+)-(3S,4R,5S)新黄皮酰胺酮的10ml二氯甲烷溶液,在室温搅拌5小时,加入二氯甲烷提取,提取液依次以碳酸氢钠溶液和水洗,蒸去溶剂,残留物以甲醇重结晶得0.19g,收率78%,mp:157-159℃,[α]D 15=-199.6(c,0.75,CHCl3)的(-)-(5S)Δ3,4-新黄皮酰胺酮
(-)-(5S)-Δ3,4-新黄皮酰胺酮0.1克溶于含有1ml醋酸,0.0lmol硼氢化钠的10ml二氯甲烷,搅拌,以薄层跟踪反应完毕后,滴入醋酸以分解剩余的硼氢化钠,然后加入20ml二氯甲烷,反应液倾至50ml冰水中,分离出有机层,依次以饱和碳酸氢钠水溶液和水洗,蒸去二氯甲烷,残留物柱层折得0.074g的(-)-(3S,4S,5S)-顺黄皮酰胺酮,收率73%,mp:145-147℃,[α]D 20=-111.0(C,0.48,CHCl3)。
(-)-(3S,4S,5S)-顺黄皮酰胺酮0.08g溶于10ml二氯甲烷,以0.01g硼氢化钠/甲醇还原,在反应完毕后加入30ml二氯甲烷,然后以乙酸处理剩余硼氢化钠,用碳酸氢钠和水洗,蒸去溶剂得油状物,以丙酮和石油醚重结晶,得(+)-(3S,4S,5S,6R)-顺黄皮酰胺((+)-I5)的晶体0.59g,收率77%,mp:197-199.5℃,[α]D 22=+6.30(c,0.46,CHCl3)。
以(-)-(3R,4S,5R)-新黄皮酰胺酮为原料,按上述方法反应得(+)-(5R)-Δ3,4-新黄皮酰胺酮,收率75%,m.p.154-156℃,[α]15 D=+206.8(c,0.90,CHCl3);(+)-(3R,4R,5R)-顺黄皮酰胺酮,收率76%,m,p,130-132℃,[α]D 20=+116.5(c,0.40,CHCl3);(-)-(3R,4R,5R,6S)-顺黄皮酰胺((-)-I5),产率69%,m,p,196-198℃,[α]D 22=-6.07(c,0.67,CHCl3)。
实施例5 顺表黄皮酰胺(I7)的制备
R=-CO-R’(R’=C1-C6),四氢吡喃,MEM[(2-甲氧基-乙氧基)-亚甲基),MOM(甲氧基亚甲基)
路线6 顺表黄皮酰胺(I7)的制备
将0.2克6-O-乙酰表新黄皮酰胺溶于20ml二氯甲烷溶剂中,分批滴加重铬酸钠的酸性水溶液(Na2Cr2O7/H2SO4=20mol/7mol)5ml,室温搅拌至原料点消失,加入20mlCH2Cl2稀释,分去水层,用水和饱和碳酸氢钠水溶液分别洗涤有机层,无水硫酸钠干燥,蒸去溶剂后得浅棕色固体,柱层折分离(CH2Cl2/CH3OH 50/1)得产物0.163g,mp:166.5-168℃,产率65%。
本方法亦适用于相应光活体的合成.
由(+)-(3R,4S,5R,6R)-表新黄皮酰胺得(5R,6R)-6-O-乙酰-Δ3,4-表黄皮酰胺,[α]D 22=+80.4°(c,0.47,CHCl3),mp:170-172℃,由(-)-(3S,4R,5S,6S)-表新黄皮酰胺得(5S,6S)-6-O-乙酰-Δ3,4-表黄皮酰胺,[α]D 22--83.4°(c,0.37,CHCl3),mp:168-170℃。
将0.1g 6-O-乙酰-Δ3,4-表黄皮酰胺溶于20mL二氯甲烷中,室温下滴加冰醋酸0.5mL,分批加入0.2g硼氢化钠,搅拌至原料点消失,再加入20mL二氯甲烷稀释,倾入50mL冰水中,搅拌数分钟后分去水层,有机层用饱和碳酸氢钠水溶液洗涤2次,无水硫酸钠干燥,蒸干溶剂得到白色固体,用乙醚/石油醚重结晶得到白色丝状晶体0.073g,mp:128-130℃,收率71%。
本方法同样适用于光活体的合成,由光活的原料分别得到(+)-(3R,4R,5R,6R)-6-O-乙酰顺表黄皮酰胺,mp:128-130℃,[α]D 16=+13.8(c,0.50,CHCl3);(-)-(3S,4S,5S,6S)-6-O-乙酰顺表黄皮酰胺,mp:126-128℃,[α]D 16=-14.3(c,0.43,CHCl3)。
将0.07g 6-O-乙酰顺表黄皮酰胺溶于10mL甲醇中,加入0.05g无水碳酸钾,室温下搅拌至原料点消失,蒸去大部分溶剂后,加入30mL二氯甲烷稀释,分别用0.1N盐酸、水和饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,蒸去溶剂得到白色固体,用丙酮/乙醚/石油醚重结晶得到白色丝状固体0.04g,mp:191-193℃,收率65%。
本方法同样适用于光活体的合成,由光活的原料可得到(-)-(3R,4R,5R,6R)顺表黄皮酰胺((-)-I7),mp:197-199℃,[α]D 15=-38.7(c,0.385,CHCl3);(+)-(3S,4S,5S,6S)顺表黄皮酰胺((+)-I7),mp:199-202℃,[α]D 16=+39.7(c,0.785,CHCl3)。
实施例6 顺新黄皮酰胺(I6)和顺表新黄皮酰胺(I8)的制备
路线7 顺新黄皮酰胺(I6)和顺表新黄皮酰胺(I8)的制备
A:顺新黄皮酰胺酮的制备
方法一,以偶氮二甲酸二乙酯/氯乙酸/三苯磷转位的方法制备顺新黄皮酰胺酮
将2.10g mL的偶氮二甲酸二乙酯(DEAD)渐渐滴入1.5g(-)-(3R,4S,5R)-新黄皮酰胺酮,2.6g三苯磷和0.99g氯乙酸的甲苯溶液中,反应液在室温下搅拌12小时,然后加入乙酸乙酯和石油醚的混合液,过滤,滤饼以乙酸乙酯洗涤,合并滤液和洗涤液,以水洗后蒸去溶剂,残余物以750mg对甲苯磺酸的3mL甲醇溶液在室温下搅拌18小时,蒸去甲醇,残余物溶于二氯甲烷,有机层依次用碳酸氢钠水溶液、饱和氯化钠水溶液洗,蒸去溶剂,残余物经柱层析分离后重结晶得到1.05g(-)-(3S,4S,5R)-顺新黄皮酰胺酮,mp:145.8-146.9℃,[α]D 25=-138.6(c,0.81,CHCl3)。
以(+)-(3S,4R,5S)-新黄皮酰胺酮为原料,按上述方法,得到(+)-(3R,4R,5S)-顺新黄皮酰胺酮,mp:143.8-145.7℃,[α]D 25=+139.8(c,1.74,CHCl3)。
方法二,以碳酸铯/冠醚转位的方法制备顺新黄皮酰胺酮
消旋新黄皮酰胺酮1g溶于10mL无水吡啶中,冰水浴冷却下加入0.42g甲磺酰氯,然后在室温下搅拌至反应完全,加入50mL二氯甲烷稀释反应液,以稀盐酸中和,然后水洗,无水硫酸钠干燥,蒸去溶剂得到残余物1.18g,收率94%。
取上述磺酸酯0.5g溶于30mL无水苯中,加入4.1g醋酸铯和2.4g二苯酰-18-冠醚-6,加热洄流至反应完全,冷却浓缩除去苯,柱层析得3-O-乙酰顺新黄皮酰胺酮0.39g,油状物,收率87%。
以上述3-O-乙酰顺新黄皮酰胺酮0.27g溶于40mL甲醇中,加入对甲苯磺酸118mg,加热洄流至反应完全,蒸去甲醇,残余物溶于二氯甲烷,依次以饱和碳酸氢钠,饱和食盐水溶液洗,无水硫酸钠干燥,浓缩得到固体0.21g收率89%,乙酸乙酯/石油醚重结晶得到消旋顺新黄皮酰胺酮,mp:189.3-192.4℃。
本法以光活新黄皮酰胺酮为原料得到光活顺新黄皮酰胺酮,结果与方法一相同。
B:顺新黄皮酰胺酮还原制备顺表新黄皮酰胺(I8)
消旋顺新黄皮酰胺的制备:
将0.15g(0.5mmol)(±)顺新黄皮酰胺酮溶于20ml甲醇中,搅拌下分批加入0.41g(1.1mmol)硼氢化钠,室温搅拌3小时,TLC(乙酸乙酯/石油醚=2∶1)监测原料点消失,并有Rf值0.26和0.33两点生成,用醋酸中和,并倾入到50mlCH2Cl2/20ml冰水搅拌液中,然后分出有机层,分別用水、飽和NaHCO3洗涤,无水Na2SO4干燥,蒸除溶剂得白色固体0.134g,柱层分离,得前组分(±)顺新黄皮酰胺0.04g,收率26.5%,用乙醚重结晶,得白色丝状结晶,m.p164.5-166℃,和后组分(±)顺表新黄皮酰0.075g,收率49.7%,甲醇重结晶得白色片晶,m.p252-254℃,
光活顺新黄皮酰胺的制备:
以250mg(+)-3R,4R,5S-顺新黄皮酰胺酮为原料,同上操作,用硼氢化钠还原,得(+)-(3R,4R,5S,6R)-顺新黄皮酰胺73mg,收率29%,m.p164.5-166℃,[α]D 20=+66.7(c,0.525,MeOH);同时还得到3R,4R,5S,6S-顺表新黄皮酰胺132mg,收率52.45%,m.p248-250℃,[α]D22+19.2(c,0.525,MeOH)
以250mg(-)-3S,4S,5R-顺新黄皮酰胺酮为原料,同上操作,用硼氢化钠还原,得(-)-(3S,4S,5R,6S)-顺新黄皮酰胺67mg,收率26.6%,m.p168-170℃,[α]D 22=-65.3(c,0.32,MeOH);同时还得到(-)-(3S,4S,5R,6R)-顺表新黄皮酰胺134mg,收率53.24%m.p250-252℃,[α]D 22=-20.75(c,0.265,MeOH)
上述(-)-(3S,4S,5R)-顺新黄皮酰胺酮100mg溶于5mL异丙醇铝中,加入160mg异丙醇铝,在100℃的油浴中加热,搅拌蒸出异丙醇和丙酮,并等速补加无水异丙醇,历时数小时后反应完毕,蒸去大部分异丙醇,加水以分解异丙醇铝,以6N的盐酸酸化,冰水浴冷却析出90mg的片晶,薄层层析显示产物中顺表新黄皮酰胺(I8)和顺新黄皮酰胺(I6)的比率约为3/1,总收率90%,以甲醇重结晶得到(-)-(3S,4S,5R,6R)-顺表新黄皮酰胺((-)-I8),mp:271.1-273℃,[α]D 30=-33.3(c,0.34,DMSO)
以(+)(3R,4R,5S)-顺新黄皮酰胺酮为原料,按上述方法还原可得到(+)-(3R,4R,5S,6S)-顺表新黄皮酰胺((+)-I8),mp:275-277℃,[α]D 30=+31.2(c,0.31,DMSO)
表二 黄皮酰胺16个光活异构体的常数
编号 | 异构体名称 | 绝对构型 | Mp℃ | [α]1 D(c,溶剂) |
(+)-I1(-)-I1 | (+)黄皮酰胺 | 3R,4S,5S,6R | 161-162 | +144(0.26,MeOH) |
(-)黄皮酰胺 | 3S,4R,5R,6S | 161-162 | -146(0.21,MeOH) | |
(+)-I2(-)-I2 | (+)新黄皮酰胺 | 3R,4S,5R,6S | 186-187 | +89.5(0.2,MeOH) |
(-)新黄皮酰胺 | 3S,4R,5S,6R | 186-187 | -88.6(0.18,MeOH) | |
(+)-I3(-)-I3 | (+)表黄皮酰胺 | 3R,4S,5S,6S | 108-110 | +201(0.245,MeOH) |
(-)表黄皮酰胺 | 3S,4R,5R,6R | 107-109 | -204(0.445,MeOH) | |
(+)-I4(-)-I4 | (+)表新黄皮酰胺 | 3R,4S,5R,6R | 220-222 | +36.5(0.15,MeOH) |
(-)表新黄皮酰胺 | 3S,4R,5S,6S | 221-222 | -37.7(0.16,MeOH) | |
(+)-I5(-)-I5 | (+)顺黄皮酰胺 | 3S,4S,5S,6R | 197-199 | +6.30(0.46,CHCl3) |
(-)顺黄皮酰胺 | 3R,4R,5R,6S | 196-198 | -6.07(0.675,CHCl3) | |
(+)-I6(-)-I6 | (+)顺新黄皮酰胺 | 3R,4R,5S,6R | 164-166 | +66.7(0.46 MeOH), |
(-)顺新黄皮酰胺 | 3S,4S,5R,6S | 168-170 | -65.3(0.32,MeOH) | |
(+)-I7(-)-I7 | (+)顺表黄皮酰胺 | 3S,4S,5S,6S | 198-199 | +39.7(0.785,CHCl3) |
(-)顺表黄皮酰胺 | 3R,4R,5R,6R | 199-202 | -38.7(0.385,CHCl3) | |
(+)-I8(-)-I8 | (+)顺表新黄皮酰胺 | 3R,4R,5S,6S | 275-277 | +31.2(0.31,DMSO) |
(-)顺表新黄皮酰胺 | 3S,4S,5R,6R | 271-273 | -33.3(0.34,DMSO) |
药理实验
实验例1 本发明化合物对人胚胎脑神经干细胞克隆形成率的影响
目的和意义:
神经干细胞数量的增加或寿命的延长对增加神经元和防止神经元丢失具有特别重要的意义。我们建立人胚胎脑神经干细胞的特殊培养结合细胞克隆形成的方法检测黄皮酰胺16个光活异构体是否具有促进神经干细胞增殖的作用。
方法:
人胚胎脑神经干细胞在含有表皮生长因子(EGF)20ng/ml、碱性成纤维细胞生长因子(FGF-2)20ng/ml、N-2添加剂的DMBM/F12培养基(购于BIBCO公司)和在5% CO2和37℃培养箱中连续培养。用0.1%胰蛋白酶溶液将人胚胎脑神经干细胞的神经球消化成单细胞悬液,离心1000rpm×5min,再用培养基冲洗,细胞经接种于96孔培养板中,神经干细胞1×103细胞/孔,每组4孔,连续培养。24h后加药,16种光学活性的黄皮酰胺异构体(No.1-No.16名称见表1)的给药剂量为1μM,每周换一次含药的低营养培养基(FGF-22ng/ml、EGF 2ng/ml和N-2添加剂的DMEM/F12培养基),每周两次在显微镜下观测细胞生长状态,在第3周,4周,6周分别在显微镜下计数细胞克隆数,用t检验与对照组进行统计学处理。
结果见表三和附图1
表三-A.16种化合物对人胚胎脑神经干细胞克隆形成的影响
编号 | 化合物名称 | N | 剂量 | 3周 | 4周 | 6周 |
μM | 克隆数Mean±SD | 克隆数Mean±SD | 克隆数Mean±SD | |||
对照(DMSO) | 4 | 0 | 43.00±4.97 | 30.33±4.99 | 22.25±4.86 | |
(-)-I2(+)-I2 | (-)新黄皮酰胺 | 4 | 1 | 53.00±6.71 | 37.50±4.15 | 24.5±4.43 |
(+)新黄皮酰胺 | 4 | 1 | 49.00±8.86 | 39.75±7.50 | 30.00±4.40* | |
(-)-I4(+)-I4 | (-)表新黄皮酰胺 | 4 | 1 | 58.0±13.02 | 36.75±7.59 | 32.50±7.05* |
(+)表新黄皮酰胺 | 4 | 1 | 49.75±10.26 | 38.50±5.02 | 26.00±2.94 | |
(-)-I6(+)-I6 | (-)顺新黄皮酰胺 | 4 | 1 | 49.50±5.43 | 35.25±7.46 | 33.50±4.20# |
(+)顺新黄皮酰胺 | 4 | 1 | 47.00±9.03 | 42.50±10.01 | 24.00±4.69 |
●p<0.05(single tail T test);#p<0.05(double tail T test)
表三-B.本发明化合物对人胚胎脑神经干细胞克隆形成的影响
代号 | 化合物 | N | 剂量μM | 第6周克隆形成数 | 细胞克隆形成率% |
DMSO | 对照组 | 4 | 1 | 22.25±4.86 | 100 |
(+)-I1(-)-I1 | (+)黄皮酰胺 | 4 | 1 | 27.00±5.48 | 121.35 |
(-)黄皮酰胺 | 4 | 1 | 26.50±4.12 | 119.1 | |
(+)-I2(-)-I2 | (+)新黄皮酰胺 | 4 | 1 | 30.00±4.40* | 134.83 |
(-)新黄皮酰胺 | 4 | 1 | 24.5±4.43 | 110.11 | |
(+)-I3(-)-I3 | (-)表黄皮酰胺 | 4 | 1 | 25.00±3.16 | 112.36 |
(+)表黄皮酰胺 | 4 | 1 | 28.75±3.59 | 129.21 | |
(+)-I4(-)-I4 | (+)表新黄皮酰胺 | 4 | 1 | 26.00±2.94 | 116.85 |
(-)表新黄皮酰胺 | 4 | 1 | 32.50±7.05* | 146.07 | |
(+)-I5(-)-I5 | (+)顺黄皮酰胺 | 4 | 1 | 23.75±6.70 | 106.74 |
(-)顺黄皮酰胺 | 4 | 1 | 24.50±3.11 | 110.11 |
(+)-I6(-)-I6 | (+)顺新黄皮酰胺 | 4 | 1 | 24.00±4.69 | 107.87 |
(-)顺新黄皮酰胺 | 4 | 1 | 33.5±4.20# | 150.56 | |
(+)-I7(-)-I7 | (+)顺表黄皮酰胺 | 4 | 1 | 23.00±0.82 | 103.37 |
(-)顺表黄皮酰胺 | 4 | 1 | 29.25±6.85 | 131.46 | |
(+)-I8(-)-I8 | (+)顺表新黄皮酰胺 | 4 | 1 | 27.50±5.26 | 123.60 |
(-)顺表新黄皮酰胺 | 4 | 1 | 25.00±3.56 | 112.36 |
●*P<0.05;#P<0.01。
结论:本发明的16种光学活性黄皮酰胺异构体中有三种黄皮酰胺(异构体(+)-I2((+)新黄皮酰胺));(-)-I4((-)表新黄皮酰胺)和(-)-I6((-)顺新黄皮酰胺)具有明显促进人胚胎脑神经干细胞克隆形成的作用,这对老年性神经退行性疾病如老年性痴呆等具有特别重要的意义。
实验例2、化合物对神经细胞胞浆游离钙的影响
目的和意义
钙作为第二信使在细胞活动中起着重要作用,胞浆游离钙浓度的变化是联系许多生理/病理刺激和细胞内效应器反应之间的枢纽,化合物对胞浆游离钙浓度的影响在药物筛选中有着重要意义。
取新生大鼠,分离大脑皮层神经细胞,制备单细胞悬液106细胞/ml,在37度条件下,细胞经荧光探针(Fura-2/AM,购于SIGMA公司)5μM剂量进行负载40min,在日本SHIMADZU RF-5000荧光光密度测定仪中测定细胞内钙离子的荧光强度,在静息时和加入药物37℃温育5分钟,以及50mM KCl刺激后的胞浆游离钙浓度,分别计算加药5分钟和加入KCl后的胞浆游离钙升高幅度,每种化合物重复做5-8次(N=5-8),结果合并计算出每个化合物的细胞内游离钙浓度。
结果见表2.
表2.本发明化合物对神经细胞胞浆游离钙的影响
化合物代号 | 16种黄皮酰胺中文名 | (% basal level)X±SD(n=5-8) |
对照组 | DMSO | 17.82±3.84 |
对照组 | KCl | 67.58±6.48 |
(+)-I1 | (+)黄皮酰胺 | 22.05±3.84 |
KCl | 60.99±10.32 | |
(-)-I1 | (-)黄皮酰胺 | 20.99±4.91 |
KCl | 66.35±9.38 | |
(+)-I2 | (+)新黄皮酰胺 | 26.39±3.39 |
KCl | 69.99±9.05 | |
(-)-I2 | (-)新黄皮酰胺 | 19.49±4.51 |
KCl | 59.82±8.32 | |
(-)-I3 | (-)表黄皮酰胺 | 25.80±4.93 |
KCl | 65.53±9.08 | |
(+)-I3 | (+)表黄皮酰胺 | 17.79±3.40 |
KCl | 58.72±7.50 | |
(+)-I4 | (+)表新黄皮酰胺 | 16.79±6.13 |
KCl | 70.60±7.94 | |
(-)-I4 | (-)表新黄皮酰胺 | 16.79±6.13 |
KCl | 70.60±7.94 | |
(+)-I5 | (+)顺黄皮酰胺 | 20.13±4.94 |
KCl | 65.13±15.48 | |
(-)-I5 | (-)顺黄皮酰胺 | 17.85±4.97 |
KCl | 55.69±7.43 | |
(+)-I6 | (+)顺新黄皮酰胺 | 14.09±5.81 |
KCl | 55.22±8.04 | |
(-)-I6 | (-)顺新黄皮酰胺 | 23.64±4.96 |
KCl | 76.40±12.76 | |
(+)-I7 | (+)顺表黄皮酰胺 | 18.82±3.53 |
KCl | 65.52±7.28 | |
(-)-I7 | (-)顺表黄皮酰胺 | 22.80±4.30 |
KCl | 65.67±6.99 | |
(+)-I8 | (+)顺表新黄皮酰胺 | 15.86±5.55 |
KCl | 50.71±10.70 | |
(-)-I8 | (-)顺表新黄皮酰胺 | 25.90±5.54 |
KCl | 64.16±7.97 |
本发明的化合物中有6种黄皮酰胺((+)-I1(+)黄皮酰胺);((+)-I2(+)新黄皮酰胺);((-)-I3(-)表黄皮酰胺);((-)-I6(-)顺新黄皮酰胺);((-)-I7(-)顺表黄皮酰胺);((-)-I8(-)顺表新黄皮酰胺)有升高胞浆游离钙水平的趋势。钙作为第二信使在细胞活动中起着重要作用,胞浆游离钙浓度的变化与许多生理/病理刺激和细胞内效应器的反应具有密切关系。
实验例3 本发明化合物对大鼠海马长时程增强(LTP)的影响
目的和意义
黄皮酰胺在多种行为学实验中表现出明显的促智作用,但其对突触传递活动的影响目前还不清楚,而突触是神经系统中细胞间信息传递和加工的基础环节,其功能活动和形态结构上的改变是学习记忆活动的神经生物学基础,因此,本实验采用电生理学技术从突触水平对黄皮酰胺的促智作用进行研究。
方法
成年雄性SD大鼠(5只/组)以20%(w/v)乌拉坦(1.0g·kg-1,ip)麻醉并固定于立体定位仪上。参照Pellegrino大鼠脑立体定位图谱,在海马齿状回颗粒细胞层埋藏记录电极(外覆绝缘层,尖端裸露0.2mm,直径0.2mm的不锈钢针)。侧脑室给予表9所示的4对光学活性的黄皮酰胺。刺激电极(两枚间距0.5mm,外覆聚四氟乙烯绝缘层,尖端裸露0.2mm,直径0.15mm的不锈钢针构成)埋植于大鼠内嗅区穿通路(perforant path,PP)纤维间。电子刺激器产生持续的电流刺激后,经刺激隔离器和刺激电极输向PP。调整刺激电极的位置,直到观察到典型的兴奋性突触后电位(EPSP)。电流通过放大器放大后,经过计算机DataWave软件处理。刺激强度则采用引起最大群峰电位(Population spike,PS)所需刺激强度的1/2。在整个实验过程中,每30秒钟给予一次测试刺激频率,记录群峰电位幅度(Populationspike amplitude,PSA),根据公式(PSA/基础幅度值)计算出相对的PSA百分率。
结果见表3
表3. 16种光学活性黄皮酰胺对大鼠海马长时程增强(LTP)的结果
代号 | 黄皮酰胺名称 | LTP 15分钟X±SD | LTP 30分钟X±SD | LTP 60分钟X±SD |
(+)-I1(-)-I1 | (+)黄皮酰胺 | 90.6±0.3 | 110.1±13.1 | 106.4±4.1 |
(-)黄皮酰胺 | 131.8±0.4 | 138.5±8.9 | 158.1±4.2* | |
(+)-I2(-)-I2 | (+)新黄皮酰胺 | 99.3±29.6 | 70.9 | 97 |
(-)新黄皮酰胺 | 81.8±14.0 | 65.5±4.3 | ||
(+)-I3(-)-I3 | (-)表黄皮酰胺 | 97.8±21.7 | 91.2±22.5 | 117.3±22.5 |
(+)表黄皮酰胺 | 136.0±22.8 | 147.5±15.0 | 207.8±12.8* | |
(+)-I4(-)-I4 | (+)表新黄皮酰胺 | 104.7±8.0 | 94.7±10.3 | 101.1±28.5 |
(-)表新黄皮酰胺 | 90.6±11.9 | 91.9±15.2 | 118.2±15.4 | |
(+)-I5(-)-I5 | (+)顺黄皮酰胺 | 87.3±4.4 | 102.9±5.9 | 122.5±14.5 |
(-)顺黄皮酰胺 | 126.2±2.3 | 141.2±8.6 | 205.4±24.7* | |
(+)-I6(-)-I6 | (+)顺新黄皮酰胺 | 135.0±12.9 | 150.9±19.9 | 192.3±22.4* |
(-)顺新黄皮酰胺 | 94.1±6.7 | 98.2±6.6 | 94.9 | |
(+)-I7(-)-I7 | (+)顺表黄皮酰胺 | 101.7±5.2 | 109.7±11.7 | 109.6 |
(-)顺表黄皮酰胺 | 107.2 | 100.3 | 105.4 | |
(+)-I8(-)-I8 | (+)顺表新黄皮酰胺 | 97.0±18.9 | 110.1±25.7 | 121.7±37.1 |
(-)顺表新黄皮酰胺 | 88.5±10.2 | 88.1±9.4 | 84.6 |
结论 由实验结果(表达)可知,本发明16种光学活性黄皮酰胺异构体中有4种黄皮酰胺异构体(((+)-I6(+)顺新黄皮酰胺);((-)-I5(-)顺黄皮酰胺);((-)-I1(-)黄皮酰胺);((+)-I3(+)表黄皮酰胺))对大鼠海马长时程增强(LTP)具有明显的增强作用,(P<0.05vs control,n=5)。本发明化合物对神经细胞基础突触传递有增强作用,说明本发明的化合物有促智作用。
Claims (5)
1、如通式(I)所示的黄皮酰胺光活立体异构体化合物
选自:
(+)-I2 (3R,4S,5R,6S) (+)新黄皮酰胺
(-)-I2 (3S,4R,5S,6R) (-)新黄皮酰胺
(+)-I3 (3R,4S,5S,6S) (+)表黄皮酰胺
(-)-I3 (3S,4R,5R,6R) (-)表黄皮酰胺
(+)-I4 (3R,4S,5R,6R) (+)表新黄皮酰胺
(-)-I4 (3S,4R,5S,6S) (-)表新黄皮酰胺
(+)-I5 (3S,4S,5S,6R) (+)顺黄皮酰胺
(-)-I5 (3R,4R,5R,6S) (-)顺黄皮酰胺
(+)-I6 (3R,4R,5S,6R) (+)顺新黄皮酰胺
(-)-I6 (3S,4S,5R,6S) (-)顺新黄皮酰胺
(+)-I7 (3S,4S,5S,6S) (+)顺表黄皮酰胺
(-)-I7 (3R,4R,5R,6R) (-)顺表黄皮酰胺
(+)-I8 (3R,4R,5S,6S) (+)顺表新黄皮酰胺
(-)-I8 (3S,4S,5R,6R) (-)顺表新黄皮酰胺
2、如权利要求1所述光活立体异构体化合物I2、I4、I5、I6、I7和I8的制备方法,其特征在于,包括如下步骤
路线1
其中:
(a)碱催化环合:可用NaOCH3、(CH3)4NOH或二异丙基胺基锂;
(b)拆分剂:(-)-薄荷醇氧乙酰氯、N保护的氨基酸酰氯;
(c)羟基的保护,二氢吡喃,乙酰氯/吡啶或乙酸酐/吡啶;
(d)还原C6酮的还原剂:NaBH4或L-selectride;
(e)还原C6酮的还原剂:Al(i-C3H7O)3;
(f)氧化C3-OH的氧化剂:K2Cr2O7/H+、或KMnO4+CuSO4、MnO2 orDMSO/(COCl)2;
(g)还原Δ3,4双键的还原剂:NaBH4/H+、NaBH4/AlCl3或催化氢化;
(h)C3-OH的构型反转,用偶氮甲酸二异丙酯或偶氮甲酸二乙酯/TPP,H+或以CsOAc/18-冠醚-6完成;
本路线均以已知的消旋或光活的N-甲基-N-苯甲酰基-3-苯基缩水甘油酰胺(A)为原料;若以光活的化合物A为原料,则可略去步骤2(b)拆分这一步。
4、药物组合物,其特征在于,含有有效剂量的如权利要求1所述的任一化合物,以及药效学上可接受的载体。
5、如权利要求1所述的化合物在制备促智、抗脑缺血缺氧、神经退行性疾病的药物中的应用。
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CN1040440C (zh) * | 1989-08-19 | 1998-10-28 | 拜尔公司 | 去氢环黄皮酰胺衍生物的制备方法 |
CN1345721A (zh) * | 2000-09-28 | 2002-04-24 | 中国医学科学院药物研究所 | 光活(一)黄皮酰胺制备方法 |
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