CN105641711A - 以有机胺修饰的维生素c为载体的双重脑靶向前药 - Google Patents
以有机胺修饰的维生素c为载体的双重脑靶向前药 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
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Abstract
本发明公开了一种以有机胺修饰的维生素C为载体的双重脑靶向前药,为通式(I)所示结构或其药学上可接受的盐或水合物:其中:X代表-(CH2)n-、-C(O)-(CH2)n-C(O)-或-(CH2)m-O-、-(CH2)m-NH-、-(CH2)m-C(O)-、-C(O)-(CH2)m-、-C(O)-(CH2)m-NH-,n表示0~6,m表示1~4;Drug代表作用于中枢神经系统的药物。本发明提供一系列前药,可提高药物的脑靶向性、药物的中枢浓度,从而增强药物疗效,同时降低了药物在外周器官的分布,减少了药物的毒副作用。
Description
技术领域
本发明涉及一类新化合物,具体涉及一类以有机胺修饰的维生素C为载体的双重脑靶向前药的设计、制备及初步靶向性测定。属于医药技术领域。
背景技术
据统计,全球约有1/5的人口患有不同种类和程度的中枢神经系统(CNS)疾病,这些疾病包括脑肿瘤、急性或慢性疼痛综合症、癫痫、脑炎、脑缺血以及神经衰退性疾病(如:阿尔茨海默症、帕金森氏症等)。随着世界人口的老龄化,这一趋势将会更加严重,并且会对人类的健康造成严重的影响。血脑屏障(BBB)的存在对人类中枢神经系统起到了一定的保护作用,但同时也限制了许多物质从血液中进入脑部。几乎所有大分子和95%的小分子药物都不能有效进入大脑及中枢神经系统,这使得对CNS有效的药物很难进入CNS病灶部位并呈现有效的药物浓度从而达到治疗效果。
据报道非甾体抗炎药(Non-SteroidalAnti-InflammatoryDrugs,NSAIDs)如布洛芬、吲哚美辛等神经保护剂已经被广泛用于治疗CNS疾病,也可用作慢性摄入型非甾体抗炎药。例如,布洛芬能够降低CNS疾病的风险,甚至能够延缓CNS疾病的发病,所以布洛芬在治疗CNS紊乱方面具有广阔发展前景。但是,由于布洛芬的低渗透性,在CNS中的分布有限,有效的治疗浓度低,为了达到较好的治疗效果需要增加药物的剂量,使药物在体内达到一个较高的浓度,但与此同时其它器官的药物浓度也会增加,毒副反应也随之增加,对身体产生更大的危害,长期使用这些药物有不同程度的胃肠道不适、头痛、头晕、甚至肾毒性等不良反应,所以布洛芬的临床应用受到了很大限制。因此,为了治疗CNS疾病,需要找到一种有效的策略以提高布洛芬的在大脑中的输运能力。
维生素C(VitaminC),又名抗坏血酸,具有许多生物学功能,包括:参与氨基酸代谢;神经递质、胶原蛋白和组织细胞间质的合成;增加对感染的抵抗能力;降低毛细血管的通透性,加速血液凝固;并有抗组胺及阻止致癌物质生成的作用等。维生素C在脑内的浓度是其它器官的10倍以上,这源于大脑中GLUT1、SVCT2和少量的SVCT1可以充当维生素C通过血脑屏障的转送体,从而使维生素C在脑内可以维持在一个相对较高的水平。因此,可以将维生素C作为药物脑靶向给药的载体。
ChristopherP.Corpe等人提到维生素C的C2-OH、C3-OH对于维生素的转运至关重要,C2和C3中烯二醇上的羟基是维生素C在氧化还原过程中起到还原能力所必须的重要的反应位点,而维生素C中C5和C6上的羟基在转运过程中所起到的作用很小。而且药物同维生素C的C5-OH相连的前药的脑靶向性较强于药物连接在C6-OH的前药。因此,我们关注的重点是通过修饰维生素C的C6-OH来提高维生素C载体转运介导的脑靶向性。
除了维生素C以外,有机胺类衍生物同样具有很好的脑靶向性。有机胺类衍生物及其相关结构不仅存在于磷脂等的内源性物质内,而且也存在于甲氯芬酯等中枢神经系统治疗药物中。生理条件下,有机胺衍生物是带正电的,它能与带负电的BBB相结合。另外,经过有机胺结构修饰的前药能够作为BBB上的胆碱转运蛋白或者有机阳离子的底物,且经有机胺小分子修饰后的一些非甾体抗炎药衍生物的改性剂,能够显著提高母体化合物的抗炎能力并降低母体化合物的胃肠毒性。一些研究表明,有些小分子有机胺衍生物是较好的脑靶向性修饰基团,其修饰的前药能够被特定的转运到大脑中,然后经进一步水解释放出母体药物,进而提高药物在大脑中的浓度及累计效应,降低药物的使用剂量,从而减少其毒副反应。以上结果表明,有机胺衍生物是一种优异的脑靶向性修饰基团。
发明内容
基于上述研究及假设,本研究的目的是提出一种新型的基于维生素C以及小分子胺类衍生物的具有双重脑靶向功能的药物载体,以提高药物的脑靶向性,增加药物的中枢浓度,从而增强药物疗效,同时降低了药物在外周器官的分布,减少了药物的毒副作用。因此,我们设计了如通式(I)所示的一类前药,旨在合成并探索这类前药的脑靶向性;此外还合成了维生素C-C5-布洛芬(简称prodrug1)为对照化合物,用来考察如通式(I)所示的一类前药的脑靶向性。
本发明提供一类通式(I)所示结构的化合物或其药学上可接受的盐或水合物:
其中:
X代表-(CH2)n-、-C(O)-(CH2)n-C(O)-或-(CH2)m-O-、-(CH2)m-NH-、-(CH2)m-C(O)-、-C(O)-(CH2)m-、-C(O)-(CH2)m-NH-,n表示0~6,m表示1~4;
Drug代表可作用于中枢神经系统的药物。
通式(I)所示化合物的具体制备方法如下所示:
维生素C(L-Ascorbicacid)5,6位羟基先用丙叉基封闭后,苄基保护2,3位羟基,脱去丙叉基,暴露出5,6位羟基;小位阻的6位羟基在碱性条件下与对甲苯磺酰氯反应生成化合物4,通过一锅法反应,与二甲胺反应得到有机胺修饰的中间体6;接着在缩合剂(如N,N'-二环己基碳二亚胺)作用下,5位羟基依次同X、Drug相接,最后氢化脱除苄基保护,得到化合物9即通式(I)所示的结构。
具体实施方法
但以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例1
化合物1的制备
向维生素C(L-Ascorbicacid)(20g,114mmol)的丙酮(重蒸,150ml)混悬液中加入乙酰氯(0.4ml,5.7mmol),室温搅拌20h;过滤反应液,冷丙酮洗涤滤饼,干燥滤饼,得白色固体1(18g),收率73.3%。m.p:202-204℃。
实施例2
化合物2的制备
向1(6g,27.75mmol)、K2CO3粉末(11.3g,81.5mmol)中加入重蒸过的丙酮(100ml),升温回流,向上混悬液中加入BnBr(8.74ml,73.6mmol),4.5h后,减压出去溶剂,依次加入少量水、乙醚,析出白色固体,过滤,冷水、冷乙醚洗涤滤饼;干燥滤饼,得白色固体2(4.85g),收率44.1%。
实施例3
化合物3的制备
向2(4.85g,12.23mmol)的CH3CN(200ml)溶液中,加入HCl溶液(20ml,2mol/L),外温30℃搅拌反应3h。旋去溶剂,加入EA,依次用水洗2遍,饱和食盐水洗2遍,无水Na2SO4干燥,浓缩得黄色油状物3(4.4g),收率100%,后缓慢固化为白色固体。m.p:67-69℃。
实施例4
化合物4的制备
向3(7g,19.64mmol)的CH2Cl2(300ml)溶液中加入Et3N(67.6ml)和TsCl(9.36g,49.1mmol),外温25℃搅拌反应6h。反应液用水洗,分离出有机层,无水Na2SO4干燥,浓缩,柱层析纯化CH2Cl2:CH3OH,得化合物4,收率77.6%。m.p:138-140℃。
目标产物结构表征:
1H-NMR(400MHz,CDCl3,ppm):δ2.45(s,3H,ArCH3),4.11(s,3H,6CH2,5CH),4.65(s,1H,4-CH),5.06-5.21(m,4H,CH2Ar),7.20-7.22(m,2H,Ar-H),7.33-7.37(m,10H,Ar-H),7.80(d,J=8Hz,2H,Ar-H)。
实施例6
化合物6的制备
向4(4g,7.61mmol)的乙腈(150ml)溶液中加入K2CO3(5.27g,38.1mmol),HN(CH3)2(1.24g,15.22mmol)。外温25℃搅拌反应24h。旋去溶剂,反应液用水洗,分离出有机层,无水Na2SO4干燥,浓缩,柱层析纯化CH2Cl2:CH3OH,得化合物5,收率67.6%。m.p:96-97℃。
目标产物结构表征:
1H-NMR(400MHz,CDCl3,ppm):δ2.47(s,6H,N(CH3)2),2.90-2.95(m,2H,6CH2),4.11-4.13(m,1H,5CH),4.51(s,1H,4CH),5.10(s,2H,2COCH2Ar),5.23(s,2H,3COCH2Ar),7.26-7.38(m,10H,OCH2Ar-H)。
实施例7
化合物8的制备
向布洛芬(2.17g,10.51mmol)的CH2Cl2(100ml)溶液中加入二环己基碳二亚胺(DCC)(2.39g,11.56mmol)、4-二甲氨基吡啶(DMAP)(128mg,1.051mmol),室温活化30min后,加入6(1.5g,4.57mmol)的二氯甲烷(10ml)溶液,室温搅拌过夜。滤掉二环己基脲(DCU),浓缩滤液,柱层析纯化石油醚:乙酸乙酯=10:1-4:1,得淡黄色油状化合物8(2.77g,83%)。
目标产物结构表征:
1H-NMR(400MHz,CDCl3,ppm):δ0.81(d,6H,J=4.8Hz,(CH3)2),1.45(d,6H,J=7.2Hz,2×CH3),1.91-1.93(m,1H,CH(CH3)2),2.43(d,4H,J=7.2Hz,2×CH2Ar),2.53-2.56(m,1H,6-CH),2.76-2.81(m,1H,6-CH),3.65-3.68(m,1H,CHCH3Ar),4.60-4.62(m,1H,5-CH),4.87-4.94(m,4H,2×CH2Ar),5.20-5.22(m,1H,4-CH);6.98-7.00(m,2H,Ar-H),7.07-7.09(m,2H,Ar-H),7.16-7.36(m,10H,Ar-H)。
实施例8
化合物9的制备
向化合物8(400mg)的MeOH(28ml)溶液加入Pd/C(10%,60mg),在0.4MPaH2下常温反应5h。滤去Pd/C,浓缩溶剂得化合物9,收率79.2%。m.p:70-74℃。
目标产物结构表征:
1H-NMR(CDCl3,400MHz):δ0.88(d,6H,J=6.4Hz,(CH3)2),1.51(d,3H,J=7.2Hz,CH3),1.83(m,1H,CH(CH3)2),2.43(d,4H,J=7.2Hz,2×ArCH2),2.52(s,6H,N(CH3)2),2.84-2.88(m,1H,6CH),3.05-3.10(m,1H,6CH),3.75(q,1H,J=7.2Hz,CH3CHAr),4.65(d,1H,J=7.6Hz5-CH2),5.11-5.16(m,1H,4-CH),7.09(d,2H,J=8Hz,Ar-H),7.09(d,2H,J=8Hz,Ar-H)。
初步靶向性研究
为了评价此类以有机胺修饰的维生素C为载体的双重脑靶向前药,选择实施例8中的化合物9(简称prodrug2)进行了小鼠脑及血浆中药物浓度的测定,以维生素C-C5-布洛芬(简称prodrug1)为对照药品。结构如下所示:
。
实验动物选择昆明小鼠,雌雄过半,体重18-22g不等,随机分成3组。一组尾静脉注射对照品脑靶向前药(prodrug1),一组尾静脉注射脑靶向前药(prodrug2),另外一组尾静脉注射布洛芬。各组三只小鼠在给药后5、10、30、45、60、90、120、240min后,眼眶取血后处死,同时获得小鼠脑组织,将所取血液样品及脑组织样品处理过后,进入高效液相色谱(HPLC)分析。不同时间点小鼠血浆和脑匀浆中的布洛芬药时曲线如图1、图2所示。
图1和图2显示在血浆及脑内prodrug1与prodrug2中布洛芬的浓度在任何时间段均远高于游离的布洛芬。经过计算还可以得到以下药代动力学参数:
表1血浆中布洛芬的药代动力学参数(n=3)
*P<0.05versusibuprofen
**P<0.01versusibuprofen
***P<0.001versusibuprofen.
表2脑中布洛芬的药代动力学参数(n=3)
*P<0.05versusibuprofen
**P<0.01versusibuprofen
***P<0.001versusibuprofen
由表1、表2可计算出:
血液中,prodrug1和prodrug2中布洛芬的药时曲线下面积AUC0-t分别是游离布洛芬的5.06和5.72倍,而它们的平均滞留时间MRT的比则分别是1.43和1.42,这些数据都有力地说明了经修饰过的布洛芬前药可以延长布洛芬在小鼠血浆内的滞留时间,而延长的滞留时间也为其透过血脑屏障进入中枢神经系统提供了良好的前提条件。
Prodrug1及prodrug2在血浆中的稳定性较脑浆中好,其血浆t1/2分别为51.4min和40.1min,为药物以前药的形式递送入脑提供了保障。小鼠脑匀浆内的稳定性实验表明,prodrug1及prodrug2进入脑部之后均可被快速降解(t1/2<16.7min),并释放出原药发挥作用,避免了前药在脑内的蓄积毒性。
脑内,prodrug1和prodrug2中布洛芬的药时曲线下面积AUC0-t分别是游离布洛芬AUC0-t的2.25和3.16倍,最大浓度Cmax分别是游离布洛芬Cmax的4.19和4.92倍,说明prodrug1和prodrug2都具有脑靶向性。此外,我们还可以计算出,prodrug2的脑靶向性是prodrug1的1.4倍,该数据表明,prodrug2的脑靶向性更好,脑内的布洛芬的有效浓度提高更多。
以上数据表明,本发明的化合物9作为前药可以显著提高药物在脑内的分布,有明显的脑靶向性。具有双重脑靶向功能的小分子胺类所修饰的维生素C载体与单纯的维生素C载体相比,可以进一步提高药物的脑靶向性。
附图说明
图1为血浆中prodrug1、prodrug2中布洛芬和布洛芬的药时曲线。
图2为脑匀浆中prodrug1、prodrug2中布洛芬和布洛芬的药时曲线。
图3为本发明实施例8中prodrug2结构的1HNMR谱图。
图4为本发明实施例8中prodrug2结构的MS谱图。
图5为本发明对照药品prodrug1结构的1HNMR谱图。
Claims (7)
1.一种以有机胺修饰的维生素C为载体的双重脑靶向前药,为通式(I)所示结构或其药学上可接受的盐或水合物:
其中:
X代表-(CH2)n-、-C(O)-(CH2)n-C(O)-或-(CH2)m-O-、-(CH2)m-NH-、-(CH2)m-C(O)-、-C(O)-(CH2)m-、-C(O)-(CH2)m-NH-,n表示0~6,m表示1~4;
Drug代表可作用于中枢神经系统的药物。
2.根据权利要求1所述的以有机胺修饰的维生素C为载体的双重脑靶向前药,其特征在于X的一端以酯键或醚键同维生素C的C5-O相连,另一端以酯键或醚键或酰胺键同药物相连。
3.根据权利要求1所述的以有机胺修饰的维生素C为载体的双重脑靶向前药,其特征在于维生素C的C6-OH被有机胺修饰,形成维生素C的有机胺衍生物。
4.根据权利要求1所述的以有机胺修饰的维生素C为载体的双重脑靶向前药,其特征在于药物可以是但不限于布洛芬、萘普生、文拉法辛、美金刚胺等可作用于中枢神经系统的药物。
5.根据权利要求1所述的以有机胺修饰的维生素C为载体的双重脑靶向前药,其特征在于药物直接以其所含游离羧基、羟基或氨基等作为开放端同X以酯键、醚键、酰胺键等相连。
6.根据权利要求1所述的以有机胺修饰的维生素C为载体的双重脑靶向前药,其特征在于当n=0时,药物直接以其所含游离羧基、羟基等作为开放端同维生素C的C5-O以酯键、醚键等相连。
7.根据权利要求1所述的以有机胺修饰的维生素C为载体的双重脑靶向前药,其特征在于增加药物的脑靶向性,提高药物的中枢浓度,从而降低药物在外周器官的分布,提高药物疗效。
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CN107982541A (zh) * | 2017-11-29 | 2018-05-04 | 四川大学 | 抗坏血酸修饰的新型脑靶向磁性纳米粒的制备 |
CN113577303A (zh) * | 2021-07-05 | 2021-11-02 | 四川大学 | 三分枝rgd修饰的脑胶质瘤靶向脂质材料的制备和应用 |
CN113577303B (zh) * | 2021-07-05 | 2023-06-02 | 四川大学 | 三分枝rgd修饰的脑胶质瘤靶向脂质材料的制备和应用 |
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