CN103772176A - Vibsane型二萜衍生物及其药物组合物和应用 - Google Patents
Vibsane型二萜衍生物及其药物组合物和应用 Download PDFInfo
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- CN103772176A CN103772176A CN201410065477.8A CN201410065477A CN103772176A CN 103772176 A CN103772176 A CN 103772176A CN 201410065477 A CN201410065477 A CN 201410065477A CN 103772176 A CN103772176 A CN 103772176A
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- Prior art keywords
- acid
- alkyl
- vibsane
- compound
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Abstract
式(I)所示的vibsane型二萜衍生物及其药用盐,其制备方法,以其为有效成分的药物组合物,它们在制备治疗或预防阿兹海默症及其它神经退行性疾病药物中的应用。
Description
技术领域:
本发明属于药物技术领域,具体地,涉及vibsane型二萜衍生物,以其为活性成分的药物组合物,其制备方法,以及它们在制备治疗或预防阿兹海默症及其它神经退行性疾病药物中的应用。
背景技术:
阿兹海默症(Alzheimer’s disease,AD)是继心脑血管疾病及恶性肿瘤后严重威胁人类健康的神经退行性疾病。据统计,2006年,全球AD患者有2千6百万,预计到2050年,将会有近1亿的AD患者,到那时,每85个人中就一名AD患者(Brookmeyer,R.,Johnson,E.,Ziegler-Graham,K.,Arrighi,M.,Alzheimer’s&Dementia,2007,3,186)。而目前市售防治AD的药物中,没有一种可以治愈AD,根据个体差异,部分药物可以达到缓解AD症状与延缓AD恶化的作用,但是这远不能降低AD患者的增长趋势。因此寻找有效的AD药物是一项历史重任。
AD一个重要的病理学特征是大脑中的神经细胞缺失,目前认为较好的治疗思路是防止神经细胞死亡与在退行区域促进生成新的神经细胞。神经增长因子(nerve growth factor,NGF)是一类存在于神经系统中的神经营养因子,它对神经增长起到重要的调节作用,因此类NGF活性或可以促进NGF发挥其作用的小分子可以作为治疗AD的有效药物(Cowan,W,M.,Annu.Rev.Neurosci.2001,24,551)(Tang,W,X.,Kubo,M.,Harada,K.,Hioki,H.,Fukuyama,Y.,Bioorganic &Medicinal Chemistry Letters,2009,19,882)。
天然产物具有结构复杂性和多样性,是大自然经过几千年甚至上万年漫长的进化选择出来的,因此天然产物来源的具有NGF促进活性的化学小分子可能表现出更为出色的药理活性。
基于此,本发明设计以骨架独特而自然界中含量较大的vibsaninB二萜为模板,通过简单的重排反应(Fukuyama,Y.;Minami,H.;Takaoka,S.;Kodama,M.;Kawazu,K.;Nemoto,H.,Tetrahedron Letters,1997,38,1435)合成具有新颖骨架类型的二萜化合物,以发现具有NGF促进活性的化合物,并充分利用植物资源。
发明内容:
本发明的目的在于:提供一类新的vibsane型二萜衍生物,以其为活性成分的药物组合物,其制备方法,以及vibsane型二萜衍生物及其药物组合物在制备预防或治疗阿兹海默症及其它神经退行性疾病的药物中的应用。
本发明的上述目的是通过如下的技术方案得以实现的:
式(I)所示的vibsane型二萜衍生物或其药用盐,
式中小写字母a、b代表独立的双键或单键,用表示;Y为O或N原子;
其中a为双键时,R2不存在,R1选自醛基、羧基、羟甲基、亚甲基卤素(-CH2X)、C1-10烷氧基、C1-10酯基、-CH2NH2/-CH2NR2,其中R为H和C1-10烷基或都为C1-10烷基;a为单键时,R2为H,R1选自醛基、羧基、羟甲基、亚甲基卤素(-CH2X)、C1-10烷氧基、C1-10酯基、-CH2NH2/-CH2NR2,其中R为H和C1-10烷基或都为C1-10烷基;R2可以是任意具亲核性基团(如,丙二酸酯、丙酮等),R1为亚甲基(CH2);
b为双键时,R5和R6选自H;b为单键时,R5选自=O、-OH、卤素、C1-10烷氧基、C1-10酯基、-NH2/-NR2,其中R为H和C1-10烷基或都为C1-10烷基;R6选自-OH、卤素、C1-10烷氧基、C1-10酯基;
R3选自羟基、醛基、甲酸的C1-10酯基、羟甲基、亚甲基卤素(-CH2X)、烯丙基、异戊烯基、C1-10烷氧基、C1-10酯基、-CH2NH2/-CH2NR2,其中R为H和C1-10烷基或都为C1-10烷基;
R4选自羟基、醛基、卤素(F、Cl、Br)、C1-10烷氧基、C1-10酯基、-NH2/-NR2,其中R为H和C1-10烷基或都为C1-10烷基;
如式(I)所示的vibsane型二萜衍生物,为如下式(II)和式(III)所示的vibsane型二萜衍生物,
其中R1、R2相同或不同,分别选自羟基、醛基、卤素(F、Cl、Br)、C1-10烷氧基、C1-10酯基、-NH2/-NR2,其中R为H和C1-10烷基或都为C1-10烷基;
如上所示的vibsane型二萜衍生物,为如下化合物:
如上所示的vibsane型二萜衍生物的制备方法,包括下述步骤:
将天然产物vibsanin B在甲苯中加热回流,得化合物1,然后将化合物1用碱处理转化为化合物2,其通过还原、TES保护得到化合物5,化合物5经酯化及去保护化得到化合物6;化合物2经氧化得到化合物4,
本发明还提供用于治疗或预防阿兹海默症及其它神经退行性疾病的药物组合物,其中含有治疗有效量的上述的vibsane型二萜衍生物或其药用盐和药学上可接受的载体。
药物组合物,其中含有治疗有效量的vibsane型二萜衍生物或其药用盐和药学上可接受的载体。
如所述的所示的vibsane型二萜衍生物或其药用盐,其中所述的药用盐是指药学上可接受的盐,是与有机酸形成的盐,所述的有机酸为酒石酸、柠檬酸、甲酸、乙酸、乙二酸、丁酸、草酸、马来酸、琥珀酸、己二酸、藻酸、柠檬酸、天冬氨酸、苯苯磺酸、樟脑酸、樟脑磺酸、二葡糖酸、环戊烷丙酸、十二烷基硫酸、乙磺酸、葡庚糖酸、甘油磷酸、半硫酸、庚酸、己酸、延胡索酸、2-羟基乙磺酸、乳酸、马来酸、甲磺酸、烟酸、2-萘磺酸、扑酸、果胶酯酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、琥珀酸、酒石酸、硫代氰酸、对-甲苯磺酸盐和十一烷酸盐。
本发明同时还提供了上面所示的vibsane型二萜衍生物或其药用盐在制备治疗或预防阿兹海默症及其它神经退行性疾病的药物中的应用。
如所述的应用,其中所述的其它神经退行性疾病为帕金森综合症、2型糖尿病、血脂代谢障碍、高血压及心血管并发症、精神性疾病、认知障碍、神经退行性病变、神经内分泌失调。
除非另有说明,本发明使用的术语“烷基”是指直链或者支链的饱和一价烃基,其中烷基可以任选地被一个或多个取代基取代。术语“烷基”也包括直链和支链烷基,除非另作说明。在某些实施方式中,烷基是具有1到20(C1-20)、1到15(C1-15)、1到12(C1-12)、1到10(C1-10)、或者1到6(C1-6)个碳原子的直链饱和的一价烃基,或者具有3到20(C3-20)、3到15(C3-15)、3到12(C3-12)、3到10(C3-10)、或者3到6(C3-6)个碳原子的支链的饱和一价烃基。本发明使用的直链C1-6和支链C3-6烷基也被称为“低级烷基”。烷基的实施方式包括但不限于甲基、乙基、丙基(包括所有同分异构形式)、n-丙基、异丙基、丁基(包括所有同分异构形式)、n-丁基、异丁基、t-丁基、戊基(包括所有同分异构形式)、和己基(包括所有同分异构形式)。例如,C1-6烷基指具有1到6个碳原子的直链饱和一价烃基或者具有3到6个碳原子的支链饱和一价烃基。
除非另作说明,本发明使用的术语“烯基”是指包含一个或多个碳碳双键(在一个实施方式中1至5个)的直链或者支链一价烃基。烯基可以任选地被一个或多个取代基取代。术语“烯基”也包括“顺式(cis)”和“反式(trans)”结构的基团,或者本领域普通技术人员所理解的“E”和“Z”式结构。除非另作说明,本发明使用的术语“烯基”包括直链和支链烯基。例如,C2-6烯基是指2到6个碳原子的直链不饱和一价烃基或者3到6个碳原子的支链不饱和一价烃基。在某些实施方式中,烯基是2到20(C2-20)、2到15(C2-15)、2到12(C2-12)、2到10(C2-10)、或者2到6(C2-6)个碳原子的直链一价烃基,或者3到20(C3-20)、3到15(C3-15)、3到12(C3-12)、3到10(C3-10)、或者3到6(C3-6)个碳原子的支链一价烃基。烯基的实施方式包括但不限于乙烯基、丙烯-1-基、丙烯-2-基、烯丙基、丁烯基、以及4-甲基丁烯基。
除非另作说明,本发明使用的术语“炔基”是指包含一个或多个碳碳三键(在一个实施方式中1到5个)的直链或者支链一价烃基。炔基可以任选地被一个或多个取代基取代。除非另作说明,术语“炔基”也包括直链和支链炔基。在某些实施方式中,炔基是2到20(C2-20)、2到15(C2-15)、2到12(C2-12)、2到10(C2-10)、或者2到6(C2-6)个碳原子的直链一价烃基,或者3到20(C3-20)、3到15(C3-15)、3到12(C3-12)、3到10(C3-10)、或者3到6(C3-6)个碳原子的支链的一价烃基。炔基的实施方式包括但不限于乙炔基(-C≡CH)和炔丙基(-CH2C≡CH)。例如,C2-6炔基指2到6个碳原子的直链不饱和一价烃基或者3到6个碳原子的支链不饱和一价烃基。
除非另作说明,本发明使用的术语“环烷基”是指环状饱和桥和/或非桥的一价烃基,其可以任选地被一个或多个本发明所述的取代基取代。在某些实施方式中,环烷基具有从3到20(C3-20)、从3到15(C3-15)、从3到12(C3-12)、从3到10(C3-10)、或者从3到7(C3-7)个碳原子。环烷烃基的实施方式包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、十氢萘基和金刚烷基。
除非另作说明,本发明使用的术语“杂烷基”、“杂烯基”和“杂炔基”分别是指一个或多个碳原子被杂原子替换的烷基、链烯基和炔基。
除非另作说明,本发明使用的术语“杂原子”是指除了碳或者氢以外的其他任何原子。在某些实施方式中,术语“杂原子”是指N、O、S、Si或P。在其他实施方式中,术语“杂原子”是指N、O或者S。
除非另作说明,本发明使用的术语“芳基”是指单环芳基和/或包含至少一个芳香烃环的多环单价芳基。在某些实施方式中,芳基具有从6到20(C6-20)、从6到15(C6-15)、或者从6到10(C6-10)个环原子。芳基的实施方式包括但不限于苯基、萘基、芴基、薁基(azulenyl)、蒽基、菲基、芘基、联苯基和三联苯基。芳基也指其中一个环是芳香族的和其他环可以是饱和的,部分不饱和的或者芳香族的二环或者三环的碳环,例如二氢萘基、茚基、二氢茚基或者四氢萘基(萘满基(tetralinyl))。在某些实施方式中,芳基也可以任选地被一个或多个取代基取代。
除非另作说明,本发明使用的术语“芳基烷基”或者“芳烷基”是指用芳基取代的单价烷基。在某些实施方式中,烷基和芳基可任选地被一个或多个取代基取代。
本发明的化合物vibsane型二萜衍生物或其盐可经口或不经过口给药,给药量因药物不同而各有不同,对成人来说,每天1-1000mg比较合适。
附图说明:
图1为本发明的化合物vibsane型二萜衍生物NGF的促进活性结果图。
具体实施方式:
下面的试验实施例、实施例和制剂实施例可更详细地说明本发明,但不以任何形式限制本发明。
实施例1:
本发明的化合物vibsane型二萜衍生物具有明显的NGF促进活性,实验方法和结果如下:
一、实验方法:
1.PC12采用Ham's F12K+12.5%HS+2.5%FBS+100U/mL双抗的培养基进行培养,培养箱温度37℃,5%CO2;
2.当PC12细胞长至合适数量时,取PC12细胞,胰酶消化,制成细胞悬液;
3.将细胞悬液吸至15mL离心管中,1500rpm,3min;
4.离心结束后,离心管用酒精消毒后拿进超净台,将上清倒入废液缸;
5.加入新的完全培养基5mL,用移液器吹打十次,尽量吹散细胞,但不能太用力;
6.取0.2ml细胞悬液,加入到细胞计数管中,再加0.8ml PBS,混匀,计数;
7.将细胞浓度调整至5×104cells/ml,加入预先用PLL包被好的48孔板,每孔0.2mL,放入细胞培养箱培养;
8.第二天,将原培养基吸出,然后加入含Ham's F12K+2.5%FBS的培养基(48孔,0.24mL/孔),加入5ng/mL的NGF及待测化合物;
9.实验设计:各组设计各做3个重复
Blank对照:不加NGF,只有细胞和终浓度为0.01%的DMSO;
阴性对照组:含NGF终浓度为5ng/mL和终浓度为0.01%的DMSO;
阳性对照组:含NGF终浓度为50ng/mL和终浓度为0.01%的DMSO;
化合物组:化合物终浓度10μM(含DMSO,DMSO终浓度为0.01%),同时加入终浓度为5ng/mL的NGF诱导72h。
10.细胞放入细胞培养箱中继续培养;
11.每天观察细胞分化情况,在加入化合物72h后统计细胞分化比例,统计方法:
(1)判断标准:突起长度大于细胞直径的细胞,认为是有分化的细胞;
(2)和阴性对照相比,如果化合物组突起长度和数量无明显提高,认为无明显分化活性,不统计分化率。
(3)如果化合物组突起的数量、长度明显比阴性对照多,认为该化合物有分化活性,要求对分化的细胞数量作出统计,每组统计不少于5个视野;
二、结果:(见图1)。本发明对一系列vibsane型二萜衍生物进行了体外NGF促进PC12细胞分化活性评价,结果显示该类化合物对PC12细胞分化具有较明显地分化活性。
实施例2:
化合物1的制备:
将2gvibsanin B溶于50mL甲苯,氩气保护下加热回流反应36h,加入4g200~300目硅胶搅拌均匀,减压蒸除溶剂,剩余物经硅胶柱层析(石油醚:乙酸乙酯=4:1)得到化合物1(产率88%)。1H NMR(400MHz,CDCl3)δ6.98(d,J=12.3Hz,1H),6.56(t,J=7.1Hz,1H),5.67–5.68(m,1H),5.16(t,J=12.3Hz,1H),5.01(ddd,J=7.0,5.8,1.3Hz,1H),4.25(s,2H),3.02(ddd,J=9.6,7.2,4.5Hz,1H),2.93(dd,J=17.6,7.2Hz,1H),2.64(dd,J=17.7,4.5Hz,1H),2.55(br,1H),2.33(d,J=7.1Hz,2H),2.20(d,J=1.0Hz,3H),2.15(s,3H),1.94(d,J=1.0Hz,3H),1.79–1.90(m,2H),1.65(s,3H),1.57(s,3H),1.21(ddd,J=10.2,6.8,3.5Hz,2H),0.90(s,3H).13C NMR(100MHz,CDCl3)δ208.01,205.86,163.29,160.59,142.18,139.10,137.51,131.88,124.30,114.79,112.60,64.31,48.32,46.10,44.23,40.18,39.99,30.29,27.85,25.85,23.98,20.76,17.82.HRMS(EI)calcd for C25H36O5[M]+:416.2563,found416.2558.
实施例3:
化合物2的制备:
将200mg化合物1溶于2.4mL甲醇,0℃下缓慢滴加10eq2NNaOH的甲醇溶液,滴完后室温下搅拌30min,加入0.6mL饱和NH4Cl溶液猝灭反应,乙酸乙酯萃取,有机相用饱和食盐水洗3次,无水NaSO4干燥,减压蒸除溶剂,得到淡黄色油状物,经硅胶柱层析(石油醚:乙酸乙酯=4:1)得到化合物2(产率60%)。1H NMR(400MHz,CDCl3)δ10.00(s,1H),6.82(dd,J=9.7,5.2Hz,1H),5.12–5.18(m,1H),4.27(dd,J=40.1,12.8Hz,2H),3.03–3.17(m,2H),2.95–3.02(m,1H),2.46–2.59(m,4H),2.22(dd,J=14.9,4.9Hz,1H),2.16(d,J=1.3Hz,3H),1.85–2.11(m,5H),1.69(s,3H),1.63(s,3H),1.54–1.62(m,2H),0.80(s,3H).13C NMR(100MHz,CDCl3)δ202.28,189.16,163.24,143.81,141.25,137.00,131.42,124.57,64.28,54.65,51.36,41.06,40.24,39.55,38.06,25.70,23.96,22.89,17.67,15.24;HRMS(EI)calcd for C20H28O3[M]+:316.2038,found316.2046。
实施例4:
化合物4的制备:
将1g化合物2溶于30mL二氯甲烷与二甲亚砜的混合溶剂(5:1),加入2.2g IBX,加后室温下搅拌8h,将反应液用硅藻土过滤,减压蒸除溶剂,得到黄色油状物,该油状物经硅胶柱层析(石油醚:乙酸乙酯=10:1)得到化合物4为白色固体,该固体在石油醚/乙酸乙酯中重结晶可得到无色块状晶体(产率82%)。MP:150–152℃;1H NMR(400MHz,CDCl3)δ9.99(s,1H),6.87(d,J=2.3Hz,1H),3.37(dd,J=11.0,1.5Hz,1H),3.24(dd,J=20.3,9.6Hz,1H),2.80(br,1H),2.58–2.77(m,3H),2.26(dt,J=14.6,3.7Hz,1H),2.12(s,3H),1.49–1.70(m,4H),1.42(dt,J=12.0,4.5Hz,1H),1.36(dd,J=14.6,3.2Hz,1H),1.30(s,3H),1.26(s,3H),1.25–1.19(m,1H),0.76(s,3H).13C NMR(100MHz,CDCl3)δ204.88,189.62,163.01,148.93,138.77,117.32,79.26,51.62,49.54,42.21,40.70,39.48,37.68,34.13,28.91,28.00,25.73,25.61,19.20,15.19;HRMS(EI)calcd for C20H26O3[M]+:314.1882,found314.1888。
实施例5:
化合物5的制备:
将1mmol化合物2溶于10ml二氯甲烷,加入3mmol三乙胺,搅拌均匀后加入2mmol的三乙基氯硅烷,室温下搅拌6h,减压蒸除溶剂,得到淡黄色油状物。将该黄色油状物溶于12mL二氯甲烷与异丙醇的混合溶剂(3:1),置于0℃搅拌10min,分三次加入1mmolNaBH4,加完后在室温下反应24h。0℃下向上述体系加入1ml饱和NH4Cl溶液猝灭反应接着加入50ml乙酸乙酯搅拌分层,有机相用饱和NaCl溶液洗涤3次,无水Na2SO4干燥,减压蒸除溶剂,得到黄色油状物,该油状物经硅胶柱层析(石油醚:乙酸乙酯=20:1)得到化合物5为黄色油状物(产率95%)。1H NMR(600MHz,CDCl3)δ6.83(m,1H),5.12(ddd,J=7.1,5.8,1.3Hz,1H),4.47(dt,J=15.3,2.2Hz,1H),4.35(d,J=10.4Hz,1H),4.25(m,1H),4.10(dd,J=11.5,5.4Hz,1H),2.93(overlap,3H),2.51(dd,J=14.7,9.9Hz,1H),2.38(m,1H),2.18(m,1H),2.10(m,1H),1.95(m,1H),1.74(s,3H),1.68(s,3H),1.63(s,3H),1.61(s,3H),1.60–1.52(m,2H),1.04(br,1H),0.95(t,J=8.0Hz,9H),0.89(s,3H),0.63(q,J=8.0Hz,6H).13C NMR(150MHz,CDCl3)δ202.99,141.14,139.64,139.06,132.93,131.65,124.83,61.24,58.37,54.75,51.52,41.32,40.15,39.85,36.55,25.94,24.16,22.63,17.81,14.50,7.03,4.58.HRMS(EI)calcd for C26H44O3Si[M]+:432.3060,found432.3065。
实施例6:
化合物3的制备:
将0.1mmol化合物5溶于1mL二氯甲烷,0℃下加入0.12mmol3,3-二甲基丙酸与0.05mmol4-二甲胺基吡啶,搅拌10min,加入0.2mmol二环己基碳二酰亚胺,室温搅拌过夜。加入5mL水与5mL乙酸乙酯搅拌分层,有机相用饱和NaCl溶液洗涤3次,无水Na2SO4干燥,减压蒸除溶剂,得到黄色油状物。将该黄色油状物溶于1ml四氢呋喃与水的混合溶剂(8:2),加入0.5mL冰乙酸,室温搅拌8h,乙酸乙酯萃取,有机相用饱和NaCl溶液洗涤3次,无水Na2SO4干燥,减压蒸除溶剂,得到黄色油状物。经硅胶柱层析(石油醚:乙酸乙酯=10:1)得到化合物3为黄色油状物(产率88%)。1H NMR(600MHz,CDCl3)δ6.73(dd,J=9.6,5.2Hz,1H),5.60–5.66(m,1H),5.01(t,J=6.9Hz,1H),4.77(t,J=9.3Hz,1H),4.53(t,J=10.5Hz,1H),4.19–4.34(m,2H),2.98(ddd,J=20.4,12.0,5.3Hz,2H),2.90(dd,J=24.1,7.8Hz,1H),2.39–2.49(m,2H),2.21(dd,J=14.7,5.0Hz,1H),2.16(d,J=1.0Hz,3H),2.01(dt,J=18.9,6.2Hz,1H),1.89–1.94(m,1H),1.88(t,J=4.5Hz,3H),1.75–1.78(m,4H),1.68(t,J=6.5Hz,2H),1.65(s,3H),1.61(d,J=1.3Hz,1H),1.59(s,3H),1.40–1.50(m,2H),0.91(s,3H).13C NMR(150MHz,CDCl3)δ204.56,166.70,157.45,142.81,142.15,141.33,131.75,128.26,124.48,115.81,64.95,59.30,54.70,51.70,41.23,40.36,40.14,36.50,27.62,25.87,24.16,22.85,20.39,17.91,14.72.HRMS(EI)calcd for C25H36O4[M]+:400.2614,found400.2621。
制剂实施例1:
按实施例2-6的方法先制得本发明的上述化合物,以及利用有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,按常规加注射用水,精滤,灌封灭菌制成注射液。
制剂实施例2:
按实施例2-6的方法先制得本发明的上述化合物,以及利用有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,将其溶于无菌注射用水中,搅拌使溶,用无菌抽滤漏斗过滤,再无菌精滤,分装于2安瓿中,低温冷冻干燥后无菌熔封得粉针剂。
制剂实施例3:
按实施例2-6的方法先制得本发明的上述化合物,以及利用有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,与赋形剂重量比为9:1的比例加入赋形剂,制成粉剂。
制剂实施例4:
按实施例2-6的方法先制得本发明的上述化合物,以及利用有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,按其与赋形剂重量比为1:5-1:10的比例加入赋形剂,制粒压片。
制剂实施例5:
按实施例2-6的方法先制得本发明的上述化合物,以及利用有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,按常规口服液制法制成口服液。
制剂实施例6:
按实施例2-6的方法先制得本发明的上述化合物,以及利用有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,按其与赋形剂重量比为5:1的比例加入赋形剂,制成胶囊或颗粒剂或冲剂。
制剂实施例7:
按实施例2-6的方法先制得本发明的上述化合物,以及利用有机酸(酒石酸,柠檬酸,甲酸,乙二酸等)或无机酸(盐酸,硫酸,磷酸等)制成的盐,按其与赋形剂重量比为3:1的比例加入赋形剂,制成胶囊或颗粒剂或冲剂。
Claims (10)
1.式(I)所示的vibsane型二萜衍生物或其药用盐,
其中a为双键时,R2不存在,R1选自醛基、羧基、羟甲基、亚甲基卤素(-CH2X)、C1-10烷氧基、C1-10酯基、-CH2NH2/-CH2NR2,其中R为H和C1-10烷基或都为C1-10烷基;a为单键时,R2为H,R1选自醛基、羧基、羟甲基、亚甲基卤素(-CH2X)、C1-10烷氧基、C1-10酯基、-CH2NH2/-CH2NR2,其中R为H和C1-10烷基或都为C1-10烷基;R2可以是任意具亲核性基团(如,丙二酸酯、丙酮等),R1为亚甲基(CH2);
b为双键时,R5和R6选自H;b为单键时,R5选自=O、-OH、卤素、C1-10烷氧基、C1-10酯基、-NH2/-NR2,其中R为H和C1-10烷基或都为C1-10烷基;R6选自-OH、卤素、C1-10烷氧基、C1-10酯基;
R3选自羟基、醛基、甲酸的C1-10酯基、羟甲基、亚甲基卤素(-CH2X)、烯丙基、异戊烯基、C1-10烷氧基、C1-10酯基、-CH2NH2/-CH2NR2,其中R为H和C1-10烷基或都为C1-10烷基;
R4选自羟基、醛基、卤素(F、Cl、Br)、C1-10烷氧基、C1-10酯基、-NH2/-NR2,其中R为H和C1-10烷基或都为C1-10烷基。
5.用于治疗或预防阿兹海默症及其它神经退行性疾病的药物组合物,其中含有治疗有效量的权利要求1或2或3所示的vibsane型二萜衍生物或其药用盐和药学上可接受的载体。
6.药物组合物,其中含有治疗有效量的权利要求1或2或3所示的vibsane型二萜衍生物或其药用盐和药学上可接受的载体。
7.如权利要求1所述的所示的vibsane型二萜衍生物或其药用盐,其特征在于所述的药用盐是指药学上可接受的盐,是与有机酸形成的盐,所述的有机酸为酒石酸、柠檬酸、甲酸、乙酸、乙二酸、丁酸、草酸、马来酸、琥珀酸、己二酸、藻酸、柠檬酸、天冬氨酸、苯苯磺酸、樟脑酸、樟脑磺酸、二葡糖酸、环戊烷丙酸、十二烷基硫酸、乙磺酸、葡庚糖酸、甘油磷酸、半硫酸、庚酸、己酸、延胡索酸、2-羟基乙磺酸、乳酸、马来酸、甲磺酸、烟酸、2-萘磺酸、扑酸、果胶酯酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、琥珀酸、酒石酸、硫代氰酸、对-甲苯磺酸盐和十一烷酸盐。
8.权利要求1或2或3所示的vibsane型二萜衍生物或其药用盐 在制备治疗或预防阿兹海默症的药物中的应用。
9.权利要求1或2或3所示的vibsane型二萜衍生物或其药用盐在制备治疗或预防其它神经退行性疾病的药物中的应用。
10.如权利要求9所述的应用,其中所述的其它神经退行性疾病为帕金森综合症、2型糖尿病、血脂代谢障碍、高血压及心血管并发症、精神性疾病、认知障碍、神经退行性病变、神经内分泌失调。
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CN105237415A (zh) * | 2015-05-18 | 2016-01-13 | 中国科学院昆明植物研究所 | Vibsanin B衍生物及其药物组合物和其在制药中的应用 |
CN115073355A (zh) * | 2022-07-13 | 2022-09-20 | 中国科学院昆明植物研究所 | 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 |
CN116063315A (zh) * | 2021-11-03 | 2023-05-05 | 沈阳药科大学 | 珊瑚树中具有八元环新骨架的vibsane型二萜类化合物或其盐及其制备方法和应用 |
-
2014
- 2014-02-26 CN CN201410065477.8A patent/CN103772176B/zh active Active
Non-Patent Citations (4)
Title |
---|
MIWA KUBO ET AL.: "Aldovibsanins, Enol Ester Free Vibsane-Type Diterpenes from Viburnum", 《CHEM. PHARM. BULL.》, vol. 47, no. 2, 28 February 1999 (1999-02-28), pages 295 - 296 * |
XIU GAO ET AL.: "Vibsatins A and B, Two New Tetranorvibsane-Type Diterpenoids from Viburnum tinus cv. variegatus", 《ORG. LETT.》, vol. 16, 22 January 2014 (2014-01-22), pages 980 - 983 * |
XUAN-QIN CHEN ET AL.: "Triterpenoids and Diterpenoids from Viburnum chingii", 《CHEM. PHARM. BULL.》, vol. 59, no. 4, 27 January 2011 (2011-01-27), pages 496 - 498 * |
YOSHIYASU FUKUYAMA ET AL.: "Absolute Structure of Vibsanins B and C, and Their Chemical Correlation", 《TETRAHEDRON LETTERS》, vol. 38, no. 8, 31 December 1997 (1997-12-31), pages 1435 - 1438, XP004053080, DOI: doi:10.1016/S0040-4039(97)00041-5 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105237415A (zh) * | 2015-05-18 | 2016-01-13 | 中国科学院昆明植物研究所 | Vibsanin B衍生物及其药物组合物和其在制药中的应用 |
CN116063315A (zh) * | 2021-11-03 | 2023-05-05 | 沈阳药科大学 | 珊瑚树中具有八元环新骨架的vibsane型二萜类化合物或其盐及其制备方法和应用 |
CN116063315B (zh) * | 2021-11-03 | 2024-04-26 | 沈阳药科大学 | 珊瑚树中具有八元环骨架的vibsane型二萜类化合物或其盐及其制备方法和应用 |
CN115073355A (zh) * | 2022-07-13 | 2022-09-20 | 中国科学院昆明植物研究所 | 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 |
CN115073355B (zh) * | 2022-07-13 | 2023-11-10 | 中国科学院昆明植物研究所 | 环庚烯并氮氧杂二萜衍生物及其药物组合物和其在制药中的应用 |
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