CN109988199B - 红景天苷衍生物及其用途 - Google Patents
红景天苷衍生物及其用途 Download PDFInfo
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- CN109988199B CN109988199B CN201910343379.9A CN201910343379A CN109988199B CN 109988199 B CN109988199 B CN 109988199B CN 201910343379 A CN201910343379 A CN 201910343379A CN 109988199 B CN109988199 B CN 109988199B
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Abstract
本发明涉及天然药物化学研发领域,具体公开了一类红景天苷衍生物,这类化合物脂溶性较好,生物利用度高,可用于制备神经退行性疾病、精神类疾病或CNS神经损伤的治疗药物。
Description
技术领域
本发明属于天然药物化学研发领域,具体涉及一类红景天苷衍生物及其医药用途。
背景技术
红景天苷是我国传统中药红景天的提取物,也是其主要有效成分及药效物质基础的标志物。众多研究表明,红景天苷具有抗炎、抗氧化、抗细胞凋亡的作用,在动脉粥样硬化和心脑血管疾病的治疗上具有广阔的应用前景。在治疗缺血性脑卒中方面,红景天苷具有神经保护作用及长达48小时的治疗时间窗;同时,对氧化应激下血管内皮细胞的凋亡有很好的抑制作用。
然而,红景天苷虽有诸多疗效,但在临床应用上却有诸多缺点。红景天苷是多羟基化合物,分子极性很大,水溶性极好,脂溶性却很差。红景天苷分子的亲水性强而亲脂性弱,一方面不利于药物通过脂质膜,不易被胃肠吸收进入组织细胞,亦不易通过血脑屏障;在另一方面,水溶性强的药物在进入体内后很容易被大量代谢,使药量减少,药效降低,药理活性减弱。由于红景天苷在体内过短的半衰期,需要频繁服药才能保证血药浓度,保持药效。这是开发红景天苷药品所需要面对的问题。
红景天苷是红景天全草或根茎的主要生物活性成分之一,化学名称为2-(4-羟基苯基)乙基-β-D-葡萄糖苷,化学分子式为C14H20O7,相对分子质量为300.3,为类白色或浅黄色针状结晶,是一种苯乙醇类化合物。近年研究发现红景天苷具有神经保护、清除自由基、调节中枢神经递质、促进神经修复及神经细胞分化等多种神经系统方面的作用,且毒副作用小,在神经系统疾病中的应用前景十分广阔。但目前对红景天苷的研究多停留在临床前研究阶段,剂型也较单一,主要为口服保健品,未真正应用于临床治疗。
红景天苷口服吸收差,大鼠口服给药生物利用度仅为32.1%,主要以原形经肾消除,部分经肝脏消除,体内药代动力学研究显示,大鼠静脉给药后,红景天苷主要分布在肝、肾等组织中,红景天苷在脑中的分布极少,仅在5min时能检测出极低的含量,之后就检测不到红景天苷。
从红景天苷分子结构的角度来考察,其主要包含吡喃葡萄糖及游离的酚羟基等官能团,极性大、分子亲水性强而亲脂性弱(ClogP=-0.29),跨膜扩散能力差,不利于通过脂质膜,从而不能有效地分配到肠壁细胞膜,不易被胃肠吸收进入组织细胞和通过血脑屏障,故在体内半衰期短,口服生物利用度差。另一方面,红景天苷进入体内后半衰期短、清除速率较快,进而导致药物在吸收部位的滞留时间减少,甚至在胃肠循环过程中代谢成其苷元对酪醇等物质,从而降低其生物利用度。由此可见,通过结构优化或者剂型改造等手段提高红景天苷在体内吸收的程度是十分必要的。
发明内容
红景天苷药代动力学研究显示,由于红景天苷具有很高的亲水性,导致生物利用度较差,尤其难以通过血脑屏障,在脑中的分布极少,这对于相关神经系统疾病的治疗非常不利。针对现有技术的缺陷,本发明对红景天苷游离酚进行改造,新设计的红景天苷衍生物有较高的血脑屏障透过率,生物利用度提高,可用于开发成各类中枢神经系统疾病的治疗药物。
本发明所提供的化合物为以下通式表示的化合物及其药学上可接受的盐或立体异构体:
其中R0为-C3-8环烷基、4-6元杂环烷基、苯基、萘基或九至十元双环,其中所述的环烷基、杂环烷基、苯基、萘基可被下列取代基所取代:-OH、卤素、三氟甲基或-C1-4烷基;所述的双环,环与环之间是稠合相连的,而且至少有一个环是芳族环,另一个环为芳族环、环烷基或杂环烷基。
R0可进一步为-C3-6环烷基、苯基、萘基或苯并二氧杂环戊烷,所述的-C3-6环烷基、苯基、萘基或苯并二氧杂环戊烷可被-C1-3烷基所取代。
R0还具体为
本发明的通式中具有代表性的化合物如下:
N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)环戊酰胺;
N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)-苯并[d][1,3]二氧杂环戊烷-5-甲酰胺;
N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)-2-萘酰胺;
4-甲基-N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)-苯甲酰胺。
本发明的通式化合物制备总路线如下:
其中R0如上文所定义;R4为R5为/>DIPEA为N,N-二异丙基乙胺。
本发明还包括以上所列化合物的药用可接受的盐和其立体异构体。
本发明的化合物中具有一个或多个不对称碳原子时,它们能够以如下形式存在:光学纯的对映异构体、纯的非对应异构体、对映异构体混合物、非对应异构体混合物、对映异构体外消旋混合物、外消旋物或外消旋物混合物。式(II)的化合物的全部可能的异构体、立体异构体和其混合物也在本发明的范围内。
本发明还提供了上述化合物在用于治疗神经退行性疾病、精神类疾病及CNS神经损伤的应用。
进一步地,所述神经退行性疾病包括阿兹海默症、帕金森、多发性硬化或亨廷顿舞蹈病;所述CNS神经损伤包括由手术、疾病和/或创伤造成神经损伤;所述精神类疾病包括抑郁症、焦虑症、精神分裂症、反应性精神病、偏执性精神病、更年期精神病、儿童精神病、双相情感性精神病、躁狂症感应性精神病、神经衰弱、癔症、恐怖性神经症、强迫性神经症、疑病性神经症;脑器质性及躯体疾病所致的精神病、颅内与躯体感染所致的精神障碍、脑血管病所致的精神障碍、颅脑外伤所致精神障碍、颅内肿瘤所致精神障碍、癫痫性精神障碍、内分泌疾病所致精神障碍、低血糖所致精神障碍;精神活性物质、酒精中毒所致精神障碍、有机磷中毒所致精神障碍与非依赖性精神障碍、肾上腺皮质激素所致精神障碍、镇静催眠剂中毒所致的精神障碍等。
本发明所提供的化合物一般的剂量范围为成人每日0.1mg至15g,或为每日0.5mg至10g,或为每日1mg至5g,或为每日2mg至2g,或为每日5mg至1g,或为每日10mg至500mg,或为每日20mg至200mg,或为每日50mg至100mg,或为每日100mg至300mg,优选为约50mg/kg至400mg/kg,更优选为约150mg至300mg/kg。
本发明还提供了一种医药组合物,其包含上述至少一个化合物以及任选一种或多种医药上可接受的辅料。
进一步地,所述辅料可以包括制药技术常用的填充剂、粘合剂及崩解剂。例如,所述填充剂包括乳糖、甘露醇、微晶纤维素、蔗糖、磷酸二钙或羧甲基纤维素、硬脂酸镁等中的一种或多种;所述粘合剂包括淀粉、天然树胶(例如阿拉伯胶、明胶)、葡萄糖、糖蜜、聚乙烯吡咯烷酮、纤维素及其衍生物、聚维酮、交联聚维酮等中的一种或多种;所述崩解剂包括羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钠以及交聚维酮中的一种或多种。
本发明的药物组合物剂型可以是适用于临床的各类剂型,例如片剂、丸剂、颗粒剂、散装粉剂、硬胶囊剂或软胶囊等口服制剂,也可以是分散片、缓释剂或脂质体制剂等。
其中片剂、丸剂、胶囊剂辅料可以选含有下列成分中的一种或多种的化合物:粘合剂;稀释剂;崩解剂;辅助脂质;润滑剂;湿润剂;助流剂;甜味剂;矫味剂。
可以使用的粘合剂包括但不限于微晶纤维素、黄蓍胶、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊;
可以使用的稀释剂包括但不限于乳糖、蔗糖、淀粉、高岭土、盐、甘露糖醇和磷酸二钙;
可以使用的崩解剂包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、膨润土、甲基纤维素、琼脂和羧甲基纤维素;
可以使用的辅助脂质包括但不限于磷脂酰乙醇胺、磷脂酰胆碱和胆固醇;
可以使用的润滑剂包括但不限于滑石、淀粉、镁或钙的硬脂酸盐、石松子和硬脂酸;
可以使用的湿润剂包括但不限于丙二醇一硬脂酸酯、脱水山梨醇一油酸酯、二甘醇一月桂酸酯和聚氧乙烯月桂基醚。
可以使用的助流剂包括但不限于胶体二氧化硅;
可以使用的甜味剂包括但不限于蔗糖、乳糖、甘露糖醇和人工甜味剂,例如环磺酸钠和糖精,和任意数量的喷雾干燥矫味剂;
可以使用的矫味剂包括但不限于从植物提取的天然矫味剂,例如果实,和产生快感的化合物的合成掺合物,例如但不限于薄荷和水杨酸甲酯;
附图说明
图1:化合物5c对大鼠空间探索的影响,空白组、盐酸多奈哌齐组及5c组与模型组相比,*p<0.05;
图2:化合物5c单次口服给药对小鼠悬尾不动时间的影响,盐酸地昔帕组,5c20mg/kg组2h和空白组相比**p<0.01
具体实施方式
实施例1:N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)环戊酰胺5a的制备方法
步骤1:
将5-1(1.5g,11.3mmol)溶解到30毫升的二氯甲烷中,室温搅拌下加入N,N-二异丙基乙胺(4.2g,32.6mmol),冰浴下滴加环戊基甲酰氯(2.4g,17.5mmol),加毕,室温搅拌过夜。TLC(PE:EA=2:1)原料反应完全,加水和二氯甲烷,分液,有机相减压蒸干,得到3.8g化合物5a-2粗品,直接用于下一步反应。
步骤2:
室温下,将氢氧化钠溶液(15毫升,3M)滴加到5a-2的70毫升的乙醇溶液,反应混合物室温搅拌2小时,TLC(PE:EA=2:1)显示原料反应完全,将反应混合物直接旋干拌硅胶过柱得到5a-3,浅黄色固体2.57g。
步骤3:
室温搅拌下,分别将5-4(1g,2.43mmol)、5a-3(1g,4.29mmol)、4A分子筛(2.5g)加入到含50毫升二氯甲烷的反应瓶中,搅拌溶解,氩气保护下再加入碳酸银(1g,3.62mmol),避光继续搅拌120小时,TLC(PE:EA=2:1)原料部分反应,过滤,滤液减压浓缩后硅胶柱层析,得到产物5a-5,白色固体约300mg。
步骤4:
将5a-5(250mg,0.44mmol)、K2CO3(30mg,0.22mmol)和甲醇(10ml)分别被加入到100毫升的单口反应瓶中,室温搅拌30分钟,TLC(二氯甲烷:MeOH=5:1)原料反应完全,反应混合物被过滤,滤液通过Pre-TLC得100mg的白色固体5a。终产物结构经核磁共振谱图和MS谱图验证,1H NMR(400MHz,CD3OD)δ1.64(s,2H),1.80(d,J=11.0Hz,4H),1.93(s,2H),2.81(d,J=7.7Hz,1H),2.90(s,2H),3.19(s,1H),3.28(s,2H),3.36(s,1H),3.67-3.76(m,2H),3.84-3.88(m,1H),4.03-4.11(m,1H),4.30(d,J=7.8Hz,1H),7.21(d,J=8.3Hz,2H),7.47(d,J=8.3Hz,2H);MS(ESI,m/z)for C20H20NO7[M+H]+:396.18.
实施例2:N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)-苯并[d][1,3]二氧杂环戊烷-5-甲酰胺5b的制备方法
步骤1
将5b-1(4.2g,25mmol)加入到100毫升的二氯甲烷中,室温搅拌下加入DMF(20mg),冰浴下滴加草酰氯(6.4g,50mmol),加毕,室温搅拌3h。反应液变清澈,反应液减压蒸干,得到4.67g的5b-2。
步骤2
将5-1化合物(1.5g,11.3mmol)溶解到50毫升的二氯甲烷中,室温搅拌下加入N,N-二异丙基乙胺(5.7g,44mmol),冰浴下滴加5b-2(4.67g,25mmol)的20毫升二氯甲烷溶液,加毕,室温搅拌2小时。TLC(PE:EA=2:1)原料反应完全,加水和二氯甲烷,分液,有机相减压蒸干,得到5b-4。
步骤3
室温下,将氢氧化钠溶液(15毫升,1mol/L)滴加到上步产物5b-4的40毫升的乙醇溶液,反应混合物室温搅拌2小时,补加氢氧化钠溶液(15毫升,1mol/L),搅拌3小时,TLC(PE:EA=2:1)显示原料反应完全,将反应混合物直接旋干拌硅胶过柱得到5b-5,浅黄色固体2g。
步骤4
搅拌下,分别将5-4化合物(1g,2.43mmol)、5b-5(1.1g,4.3mmol)、4A分子筛(2.5g)加入到含50毫升二氯甲烷的反应瓶中,搅拌溶解,再加入碳酸银(1g,3.63mmol)氩气保护,避光继续搅拌120小时,TLC(PE:EA=2:1)原料部分反应,过滤,滤液旋干过柱,得到产物5b-7,白色固体约300mg。
步骤5
5b-7(150mg,0.25mmol)、K2CO3(14mg,0.1mmol)和甲醇(5ml)分别被加入到100毫升的单口反应瓶中,室温搅拌30分钟,TLC(二氯甲烷:MeOH=5:1)原料反应完全,反应混合物被过滤,滤液通过Pre-TLC得73mg的白色固体5b。终产物结构经核磁共振谱图和MS谱图验证,1H NMR(400MHz,CD3OD)δ2.94(t,J=7.2Hz,2H),3.17-3.22(m,1H),3.29(d,J=6.8Hz,2H),3.35(d,J=9.1Hz,1H),3.67(dd,J=11.9,5.1Hz,1H),3.74-3.80(m,1H),3.84-3.89(m,1H),4.07-4.13(m,1H),4.31(d,J=7.8Hz,1H),6.06(s,2H),6.93(d,J=8.2Hz,1H),7.26(d,J=8.4Hz,2H),7.41(d,J=1.7Hz,1H),7.52-7.61(m,3H);MS(ESI,m/z)forC22H26NO4[M+H]+:448.10.
实施例3:N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)-2-萘酰胺5c的制备方法
步骤1
将5c-1(4.3g,25mmol)加入到100毫升的二氯甲烷中,室温搅拌下加入DMF(20mg),冰浴下滴加草酰氯(6.4g,50mmol),加毕,室温搅拌3h。反应液变清澈,反应液减压蒸干,得到5c-2。
步骤2
将5-1(1.5g,11.3mmol)溶解到50毫升的二氯甲烷中,室温搅拌下加入N,N-二异丙基乙胺(5.7g,44mmol),冰浴下滴加5c-2(4.8g,25mmol)的20毫升二氯甲烷溶液,加毕,室温搅拌过夜。TLC(PE:EA=2:1)原料反应完全,旋干反应液,加碳酸钠水溶液洗,过滤水洗滤饼,固体EA打浆洗,过滤,滤饼干燥得浅黄色固体2g化合物5c-4。
步骤3
搅拌下,分别将5-4(1g,2.43mmol)、5c-4(1.1g,3.77mmol)、4A分子筛(2.5g)加入到含50毫升二氯甲烷的反应瓶中,搅拌溶解,再加入碳酸银(1g,3.63mmol)氩气保护,避光继续搅拌120小时,TLC(PE:EA=2:1)原料部分反应,过滤,滤液旋干过柱,得到产物5c-6,白色固体约160mg。
步骤4
5c-6(100mg,0.16mmol)、K2CO3(11mg,0.08mmol)和甲醇(5ml)分别被加入到50毫升的单口反应瓶中,室温搅拌30分钟,TLC(二氯甲烷:MeOH=5:1)原料反应完全,反应混合物被过滤,滤液通过Pre-TLC得80mg的白色固体5c。终产物结构经核磁共振谱图和MS谱图验证,1H NMR(400MHz,CD3OD)δ2.96(t,J=7.3Hz,2H),3.21(t,J=8.4Hz,1H),3.35-3.42(m,1H),3.65-3.73(m,1H),3.79(dt,J=9.7,7.3Hz,1H),3.84-3.93(m,1H),4.12(dt,J=9.7,7.2Hz,1H),4.33(d,J=7.8Hz,1H),7.30(d,J=8.3Hz,2H),7.52–7.74(m,4H),7.87-8.10(m,4H),8.50(s,1H);MS(ESI,m/z)for C27H30NO8[M+H]+:454.16.
实施例4:4-甲基-N-(4-[2-(β-D-吡喃葡萄糖氧基)-乙基]-苯基)-苯甲酰胺5d的制备方法
步骤1
将5-1(5g,36.4mmol)、N,N-二异丙基乙胺(15g,110mmol)、100ml的二氯甲烷加入反应瓶中,搅拌均匀,然后用冰盐浴降温至0℃左右,开始缓慢滴加对甲苯磺酰氯(11.3g,73mmol),加毕,室温搅拌过夜。TLC(PE:EA=2:1)显示原料反应完全,加适量的水和二氯甲烷。分液,有机相减压浓缩至干,得到8.5g化合物5d-2粗品,
步骤2
室温下,将10ml的氢氧化钠溶液(2M)滴加到8.5g的5d-2粗品乙醇(200ml)溶液中,反应混合物室温下搅拌4小时,TLC(PE:EA=2:1)显示原料反应完全,将反应混合物直接减压浓缩至干,硅胶柱层析得5g浅黄色固体化合物5d-3。
步骤3
室温搅拌下,分别将2.5g的化合物5-4(6.1mmol)、2.5g的化合物5d-3(9.8mmol)和7g的4A分子筛加入到含30ml二氯甲烷的反应瓶中,搅拌至溶解,氩气保护下再加入2.5g碳酸银(9.0mmol),避光条件下继续搅拌120小时,TLC(PE:EA=2:1)显示大部分原料反应转化,过滤。滤液减压浓缩后硅胶柱层析,得到800mg的白色固体化合物5d-5,直接用于下步反应。
步骤4
将764mg的化合物5d-5(1.30mmol 1eq)、180mg的K2CO3(1.30mmol)和25ml的甲醇分别加入到100ml的反应瓶中,室温搅拌15min,TLC(CH3CN:MeOH 9:1)显示原料反应完全,过滤。硅胶柱层析得280mg的白色固体5d。终产物结构经核磁共振谱图和MS谱图验证,1H NMR(400MHz,(CD3)SO)δ2.37(s,3H),2.82(td,J=7.7,7.3,2.6Hz,2H),2.97(dt,J=8.6,4.3Hz,1H),3.02-3.11(m,2H),3.15(td,J=8.4,4.4Hz,1H),3.60-3.69(m,2H),3.93(dt,J=9.9,7.9Hz,1H),4.18(d,J=7.8Hz,1H),4.55(t,J=6.0Hz,1H),5.01(dd,J=11.0,4.4Hz,3H),7.23(d,J=8.4Hz,2H),7.32(d,J=8.0Hz,2H),7.69(d,J=8.4Hz,2H),7.88(d,J=8.1Hz,2H),10.17(s,1H);MS(ESI,m/z)for C22H28NO7[M+H]+:418.20.
实施例5:受试化合物的抗过氧化作用
分别取100μg/ml、200μg/ml、500μg/ml的受试化合物1mL(红景天苷、5a、5b、5c、5d),各加入1mL2.5%(v/v)的亚油酸、2mL的0.05mol/L、pH7.0的磷酸盐缓冲液,1mL蒸馏水,密封后40℃恒温避光氧化,空白对照以反应溶剂代替抗氧化剂,不同时间取0.1mL上述亚油酸乳化液,依次加入9.7mL 75%的乙醇和0.1mL 30%硫氰酸氨,再加入0.1mL 0.02mol/L溶于3.5%盐酸的氯化亚铁,快速混匀,反应3分钟后测定500nm吸光值。
结果显示,与空白对照相比,红景天苷可使体系吸光值维持在较低的水平,反应中发生的过氧化作用受到明显的抑制,100μg/ml各受试化合物的抑制率保持在20%左右,并且随着受试化合物浓度的增加,对亚油酸体系的抗氧化作用增大。
实验结果说明本发明所提供化合物具有显著的抗氧化能力。
实施例6:本发明化合物在大鼠中药物代谢动力学实验
1.摘要
以体重在200-220g、8周龄雄性SD大鼠为实验动物,应用LC/MS/MS法测定灌胃给予实施例5a化合物、实施例5b化合物、实施例5c化合物、实施例5d化合物后,不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为,评价其药动学特征。
2.实验方案
2.1实验用化合物
实施例5a化合物、实施例5b化合物、实施例5c化合物、实施例5d化合物。
2.2血浆采集和处理
以25毫克每千克(mg/kg)的剂量对大鼠口服给予上述化合物,2.5毫克每千克(mg/kg)的剂量对大鼠静脉给予上述化合物。各组大鼠在给药后0.25、0.5、1、2、4、6小时(h)分别通过眼眶静脉收集血液和脑组织,以待测定。
2.3数据分析
大鼠药物代谢动力学相关数据均由软件Analyst 1.6(美国应用生物系统公司,Applied Biosystems)采集得到。所有的药动学参数采用温诺林(WinNonlin,5.2版本,CA)非房室模型进行分析。
2.4实验结果及结论
本发明的化合物给药后药代动力学参数见以下表1。综合化合物的入脑情况及生物利用度数据,本发明的部分化合物药代学参数优于红景天苷。于不同时间点对大鼠血药浓度及脑组织分布情况进行测定结果显示本发明的部分化合物在脑组织中有一定蓄积,可更好发挥中枢活性。
表1.5a-5c单次口服给药后大鼠体内药代动力学参数
实施例7:本发明实施例5c化合物对大鼠空间记忆障碍的影响
1.摘要
以体重在200-220g、8周龄雌雄SD大鼠为实验动物,测定实施例5c化合物给药两周对东莨菪碱造成的大鼠学习记忆障碍的影响。
2.实验方案
2.1给药方案
给药方案见表2。
表2.给药方案
2.2实验操作
适应期结束后,通过可视平台实验对SD大鼠进行筛选,合格的72只SD大鼠按体重均衡分为9组,每组雌雄各半,经口灌胃给药,每天一次,连续给药一周后进行莫里斯(Morris)水迷宫训练及测试(莫里斯(Morris)水迷宫视频分析系统:购自上海吉量科技有限公司)。水迷宫直径160厘米(cm),水深50厘米(cm),平台直径9厘米(cm),置于第III象限正中,没入水下2~3厘米(cm),水温控制在22±2℃。水中加墨汁使其成不透明状,将水池等分成四个象限并于壁上进行标记。除正常对照组以外,其余各组给予受试物后30分钟(min)后大鼠腹腔注射东莨菪碱2.0毫克每千克(mg/kg)造模,造模30分钟(min)后,将受试大鼠按顺时针方向依次由第I、II、III、IV象限入水点放入水中。自由探索120秒(s),若大鼠找到平台,则停止该象限训练,如大鼠没有找到平台,引导其找到平台,并在平台上站立15秒(s),进行空间位置学习。该训练程序每天一次,连续训练7天。在第8天,将位于第III象限的平台撤除,给药后1小时(h)将大鼠从水池的一点面朝池壁放入水中,使其游泳寻找平台2分钟(min),软件自动记录大鼠轨迹。
撤台实验结束后24小时(h),最后一次给药后1小时(h),所有大鼠安乐死后取脑,脑按质量:体积=1:9加入生理盐水,冰水浴条件下机械匀浆,2500转每分钟(r/min)离心10分钟(min),取上清液。测定总蛋白并以超氧化物歧化酶(SOD)试剂盒(南京建成生物工程研究所,20170315)测定脑匀浆中的超氧化物歧化酶活力(U/mgprot)。
2.3数据分析
实验数据以平均值±标准差表示,数据差异统计采用单因素方差分析(ANOVA)或者秩和检验组间差异以P<0.05判断。
2.4实验结果及结论
在第8天进行的撤台实验测试中,20毫克每千克(mg/kg)剂量的5c可明显缩短模型大鼠第一次上台潜伏期及第一次穿台路程(p<0.05,和模型组比较),同时也具有提高大鼠站台穿梭次数的趋势(p=0.08,和模型组比较)。其学习记忆改善强度基本与0.5毫克每千克(mg/kg)的盐酸多奈哌组齐相当。5c的1.25-5毫克每千克(mg/kg)剂量组也有改善模型大鼠撤台表现的作用,但与模型组相比均未出现统计学显著差异。结果见表3,图1。
表3.5c对大鼠空间记忆障碍的影响——撤台空间探索实验结果
注:*p<0.05,**p<0.01.与模型组相比
实施例8:本发明实施例5c化合物单次给药对小鼠尾悬挂不动时间的影响
1.摘要
以体重在18-22g的雄性C57BL/6小鼠为实验动物,测定实施例5c化合物灌胃给予小鼠后对小鼠尾悬挂不动时间的影响。探讨发明化合物的药效。
2.实验方案
2.1给药方案
给药方案见表4。
表4.给药方案
组别 | 动物个数 | 受试药物 | 剂量(毫克每千克) | 给药途径 | 给药日程 |
1 | 9 | 正常对照 | NA | 灌胃 | 给药一次 |
2 | 9 | 盐酸地昔帕明 | 20 | 腹腔 | 给药一次 |
3 | 9 | 5c高剂量 | 12.5 | 灌胃 | 给药一次 |
4 | 9 | 5c中剂量 | 25 | 灌胃 | 给药一次 |
5 | 9 | 5c低剂量 | 50 | 灌胃 | 给药一次 |
6 | 9 | 红景天苷 | 25 | 灌胃 | 给药一次 |
2.2实验操作
空白对照组小鼠给予饮用水后1小时(h)进行悬尾测定,盐酸地昔帕明组小鼠腹腔给药30分钟(min)后进行测试,红景天苷及5c分别于给药后1小时(h)、2小时(h)小鼠悬尾测试,测试方法为将小鼠尾部2厘米(cm)处用胶布固定于实验台侧壁,小鼠头部离台面约30厘米(cm),持续时间为6分钟(min),摄像系统自动采集数据,记录小鼠后4分钟(min)内停止不动的时间。
2.3数据分析
实验数据以平均值±标准差表示,数据差异统计采用单因素方差分析(ANOVA)或者秩和检验组间差异以P<0.05判断。
2.4实验结果及结论
在给药1小时(h)后的测试时间点,红景天苷及5c各剂量组均未能缩短小鼠悬尾不动时间(p>0.05,和空白组比较);在给药2小时(h)的测试时间点,5c化合物在50毫克每千克(mg/kg)剂量下可明显缩短小鼠悬尾绝望不动时间,改善小鼠类抑郁症状(p<0.05,和空白组比较)。红景天苷及5c的25毫克每千克(mg/kg)剂量组也有缩短小鼠悬尾不动时间作用,但与空白组比较均未出现显著差异,结果见如图2。
Claims (7)
1.下列化合物及其药学上可接受的盐或立体异构体:
其中R0为取代或非取代的萘基,其中所述取代的取代基为:三氟甲基或-C1-4烷基。
2.根据权利要求1所述的化合物及其药学上可接受的盐或立体异构体,其特征在于,R0为萘基。
3.根据权利要求1所述的化合物及其药学上可接受的盐或立体异构体,其特征在于,所述的萘基被-C1-3烷基所取代。
4.根据权利要求1所述的化合物及其药学上可接受的盐或立体异构体,其特征在于,其为
5.根据权利要求1-4所述的化合物及其药学上可接受的盐或立体异构体在制备用于治疗认知障碍、神经退行性疾病或精神类疾病的药物中的用途。
6.根据权利要求5所述的用途,其特征在于,所述神经退行性疾病包括阿兹海默症、帕金森或多发性硬化;所述精神类疾病包括抑郁症、焦虑症或精神分裂症。
7.一种药物组合物,其特征在于,包括治疗有效量的权利要求1-4所述的化合物及其药学上可接受的盐或立体异构体,以及任选一种或多种医药上可接受的载剂和/或稀释剂。
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