CN111925394A - 水飞蓟宾衍生物或其药学上可接受的盐及其制备方法和应用 - Google Patents
水飞蓟宾衍生物或其药学上可接受的盐及其制备方法和应用 Download PDFInfo
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- CN111925394A CN111925394A CN202011022028.7A CN202011022028A CN111925394A CN 111925394 A CN111925394 A CN 111925394A CN 202011022028 A CN202011022028 A CN 202011022028A CN 111925394 A CN111925394 A CN 111925394A
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- silybin
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Abstract
Description
技术领域
本发明涉及药物化学技术领域,特别涉及水飞蓟宾衍生物或其药学上可接受的盐及其制备方法和应用。
背景技术
肝作为人体的重要解毒器官的肝脏,许多物质可通过胃肠道门静脉或体循环进入肝脏进行转化,因此肝脏容易受到毒性物质损害。肝损伤在人群中普遍易感,潜伏期短,病变的过程与感染的剂量直接相关,进而诱发肝炎、肝硬化甚至肝癌,严重影响生活质量和健康水平。
水飞蓟宾是奶蓟(水飞蓟)的种子提取物,具有多种生物活性,可以清除细胞内的自由基而作为一种保护肝脏的药物应用于各种病因的肝损害治疗。虽然在细胞水平上它的治疗效果相当好,但其无法有效地靶向和聚集到肝脏发挥作用,导致生物利用度较低,且由于水飞蓟宾是一种天然的黄酮类产物,其吸收能力差,半衰期短,更进一步地降低了其生物利用度,故而导致水飞蓟宾应用于抗肝损伤的治疗极其有限,严重限制了其应用。
目前较多方法是将水飞蓟宾与羧酸连接形成羧酸酯,以改善水飞蓟宾的生物利用度,但由于水飞蓟宾作用于肝脏,羧酸酯的水解不专一于肝脏中进行,故不具备靶向到肝脏组织富集的能力。
发明内容
基于此,有必要提供一种水飞蓟宾衍生物或其药学上可接受的盐及其制备方法和应用。该水飞蓟宾衍生物具有良好的生物利用度和肝靶向性。
式(I)所示结构的水飞蓟宾衍生物或其药学上可接受的盐:
R1为C1-16烷基、具有3-8个环原子的环烷基或具有6-10个环原子的芳基;
R2为C1-4烷基。
在其中一实施例中,R1为C1-4烷基;R2为甲基。
在其中一实施例中,具有式(II)所示结构:
在其中一实施例中,R1为异丙基。
上述水飞蓟宾衍生物的制备方法,包括以下步骤:
将式(I-1)所示化合物和水飞蓟宾进行偶联反应,制得式(I)所示水飞蓟宾衍生物;
在其中一实施例中,采用以下方法制备所述式(I-1)所示化合物:
式(I-2)所示化合物和式(I-3)所示化合物反应,制得式(I-1)所示化合物;
一种药物组合物,包括第一组分,所述第一组分为上述水飞蓟宾衍生物或其药学上可接受的盐。
在其中一实施例中,上述药物组合物还包括第二组分,所述第二组分为熊去氧胆酸、胆汁酸、s-腺苷蛋氨酸、维生素E、N-乙酰半胱氨酸和肉毒碱中的一种或多种。
上述水飞蓟宾衍生物或其药学上可接受的盐、或上述药物组合物在制备治疗或预防肝损伤疾病药物、抗氧化损伤疾病药物或抗肿瘤药物中的应用。
在其中一实施例中,所述肝损伤疾病为肝炎、脂肪肝或肝硬化。
有益效果
本发明技术人员经过大量实验发现:通过使水飞蓟宾与磷酸酯基团通过酯键偶联,相比于传统的羧酸酯偶联,能够在一定程度上提高水飞蓟宾在肝脏富集作用,但由于动物体内含有各种磷酸酯酶,会加速磷酸酯片段的分解、吸收,故一般的磷酸酯片段循环系统稳定性极差,进而导致在肝脏中富集浓度较低,仍然无法实现真正的肝脏靶向富集;本发明技术人员发现片段与水飞蓟宾偶联后所得到的衍生物具有极高的循环系统稳定性,且能够在肝内富集,有效地解决了上述问题,使得该水飞蓟宾衍生物具有靶向肝脏的作用,生物利用度大幅提高,在肝内特定酶水解下,释放出水飞蓟素,能够有效地提高肝脏内的水飞蓟素含量,进而达到提高药效,降低副作用的目的,为治疗或预防肝损伤药物的制备奠定了基础。
附图说明
图1为水飞蓟宾与化合物(1)给药后在大鼠体内肝脏的分布图;
图2为水飞蓟宾与化合物(1)给药后在大鼠血浆的浓度图。
具体实施方式
为了便于理解本发明,下面将对本发明进行更全面的描述,并给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
本发明中的若化合物存在立体异构体,在没有特别指明时,应理解为包括R构型、S构型以及消旋体。
本发明中所述的“烷基”表示特定原子个数下的饱和的直链和支链烷基,具体地可列举如但不仅限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基等。C1-C6烷基是指含有1至6个碳原子的烷基。非限定性实施例包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基。
“环烷基”指饱和或部分不饱和单环或多环环状烃基取代基。3-20元环烷基是指包括3至20个碳原子,优选为3-8元单环环烷基。在一实施例中,3-8元单环环烷基为环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选被一个或一个以上的取代基取代。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,更优选苯基和萘基,最优选苯基。芳基环可以稠合于杂芳基、杂环基或环烷基环上,芳基可以是取代的或未取代的。
可理解的,本发明的某一基团上含有多个取代基时,多个取代基可以相同或不同。
“药学上可接受的盐”表示式(I)所示的化合物保持了期望的生物活性且具有最小的毒副作用。该药学上可接受的盐可以直接在化合物的制备和纯化过程中得到,也可以间接的通过该化合物的游离酸或游离碱与另外一种合适的碱或酸反应得到。
术语“溶剂合物”在文中用来描述包含本发明化合物和化学计量的一种或多种药学上可接受的溶剂分子(如乙醇)的分子络合物。当所述溶剂是水时采用术语“水合物”。
使用方法
在用于治疗时,本发明内的化合物通常以一种标准药物组合物的形式给药。其中包含一种或多种有效治疗剂量的通式(I)所示的化合物,以及药学上可以接受的辅料。所述药学上可以接受的辅料为药学上可接受的载体、赋形剂或缓释剂等。
本发明所提供的化合物和药物组合物可以是多种形式,如片剂、胶囊剂、散剂、糖浆剂、溶液剂、混悬剂和气雾剂等,并可以存在于适宜的固体或液体载体或稀释液中。本发明的药物组合物也可以储存在适宜的注射或滴注的消毒器具中。该药物组合物中还可包含气味剂、香味剂等。
通式(I)所示的化合物或包含通式(I)所示的化合物的药物组合物可对哺乳动物临床使用,包括人和动物,给药途径可以包括口服、鼻腔吸入、透皮吸收、肺部给药或胃肠道等。优选的给药途径为口服。优选为单位剂型,且每剂包含有效成分0.01mg-200mg,优选0.5mg-100mg,一次或分次服用。不管用何种服用方法,个人的最佳剂量应根据具体治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最合适的剂量。
本发明的药物组合物可通过口服以及静脉内、肌内或皮下等途径给药。从易于制备和给药的立场看,优选的药物组合物是固态组合物,尤其是片剂和固体填充或液体填充的胶囊。药物组合物的口服给药是优选的。
固态载体包括:淀粉、乳糖、磷酸二钙、微晶纤维素、蔗糖和白陶土等,而液态载体包括:无菌水、聚乙二醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油)等,只要适合活性成分的特性和所需的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括,例如调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。
可注射的制剂包括,但不局限于,无菌的、可注射的、含水的、含油的溶液、悬浊液、乳液等。这些制剂还可以被配置胃肠外合适的稀释剂、分散剂、润湿剂、悬浮剂等。这样可注射的制剂可以通过在截留细菌的过滤器中过滤灭菌。这些制剂还可以用杀菌剂配置,所述的杀菌剂溶解或分散在可注射的介质中或用本领域已知的其他方法。
本发明中,用于治疗和/或预防某种疾病时,治疗和/或预防有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。词语“治疗和/或预防有效量”的本发明化合物指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和药物组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体药物组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体药物组合物的给药时间、给药途径和排泄率;治疗持续时间;与所采用的药物组合物组合使用或同时使用的其它药物;及医疗领域公知的类似因素。例如,本领域的做法是,药物组合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
详细说明
本发明一实施方式提供了式(I)所示结构的水飞蓟宾衍生物或其药学上可接受的盐:
R1为C1-16烷基、具有3-8个环原子的环烷基或具有6-10个环原子的芳基;
R2为C1-4烷基;
进一步地,R1为C1-12烷基、或具有3-6个环原子的环烷基;更进一步地,R1为C1-6烷基;更进一步地,R1为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基;更进一步地,R1为含有3至6个碳原子的支链烷烃;更进一步地,R1为异丙基或叔丁基;更进一步地,R1为异丙基;
进一步地,R2为甲基、乙基、丙基或异丙基;进一步地,R2为甲基。
进一步地,上述水飞蓟宾衍生物具有式(II-1)所示结构:
更进一步地,上述水飞蓟宾衍生物具有式(II)所示结构:
R1和R2的定义如上所述;
本发明技术人员经过大量实验发现:通过使水飞蓟宾与磷酸酯基团通过酯键偶联,相比于传统的羧酸酯偶联,能够在一定程度上提高水飞蓟宾在肝脏富集作用,但由于动物体内含有各种磷酸酯酶,会加速磷酸酯片段的分解、吸收,一般的磷酸酯片段循环系统稳定性极差,进而导致在肝脏中富集浓度较低,仍然无法实现真正的肝脏靶向富集;本发明技术人员发现片段与水飞蓟宾偶联后所得到的衍生物具有极高的循环系统稳定性,且能够在肝内富集,有效地解决了上述问题,使得该水飞蓟宾衍生物具有靶向肝脏的作用,生物利用度大幅提高,在肝内特定酶水解下,释放出水飞蓟素,能够有效地提高肝脏内的水飞蓟素含量,进而达到提高药效,降低副作用的目的,为制备治疗或预防肝损伤药物奠定了基础。
本发明还提供了上述水飞蓟宾衍生物的制备方法,包括以下步骤:
S101:式(I-2)所示化合物和式(I-3)所示化合物反应,制得式(I-1)所示化合物;
进一步地,步骤S101中,优选溶剂为二氯甲烷,碱为三乙胺;更进一步地,步骤S101中,式(I-2)所示化合物和式(I-3)所示化合物的摩尔比为1:0.8~1:1.2;更进一步地,式(I-2)所示化合物和式(I-3)所示化合物的摩尔比为1:1;进一步地,式(I-2)所示化合物和三乙胺的摩尔比为1:2.5~1:3.2;
更进一步地,步骤S101的反应温度为-78℃~-60℃;更进一步地,反应温度为-70℃~-65℃;
可理解的,可以将式(I-1)所示化合物进行分离提纯后再进行后续步骤,也可以不进行分离,直接将步骤S101所制得反应液投入后续步骤,不应理解为对本发明的限制;优选,步骤S101的反应液直接进行后续步骤;
S102:将式(I-1)所示化合物和水飞蓟宾进行偶联反应,制得式(I)所示水飞蓟宾衍生物;
步骤S102中可以采用现有的偶联反应条件,在此不进行特别限定,应理解为均在本发明的保护范围内。进一步地,步骤S102在温度为-78℃~-60℃的条件下加入水飞蓟宾,然后缓慢升至室温,在20℃~35℃的条件下反应8h~16h;反应完成后,纯化分离。进一步地,步骤S102中式(I-1)所示化合物和水飞蓟宾的摩尔比为1:0.5~1:2.5。
本发明还提供了一种药物组合物,包括第一组分,第一组分为上述水飞蓟宾衍生物或其药学上可接受的盐。
进一步地,上述药物组合物还包括第二组分,所述第二组分为熊去氧胆酸、胆汁酸、s-腺苷蛋氨酸、维生素E、N-乙酰半胱氨酸和肉毒碱中的一种或多种。水飞蓟宾衍生物与上述第二组分之间协同作用,能够提高治疗或预防肝损伤的疗效。
本发明还提供了上述水飞蓟宾衍生物或其药学上可接受的盐、或上述药物组合物在制备治疗或预防肝损伤疾病药物中的应用。
本发明还提供了一种治疗或预防肝损伤的方法,包括施加有效量的上述水飞蓟宾衍生物或其药学上可接受的盐、或上述药物组合物的步骤。
进一步地,肝损伤疾病为肝炎、脂肪肝或肝硬化。
进一步地,肝损伤疾病为因鬼笔鹅膏引起的急性肝中毒、急慢性肝炎、初期肝硬化、中毒性肝损害、脂肪肝所致肝功能异常、酒精肝所致肝功能异常。
本发明还提供了上述水飞蓟宾衍生物或其药学上可接受的盐、或上述药物组合物在制备抗氧化损伤疾病的药物。
1990年Lotteron等人报道了在小鼠肝微粒体内,水飞蓟素能减少由四氯化碳代谢引起的体外脂质过氧化及由还原型辅酶单独引起的过氧化作用,这些都表明水飞蓟素为链中断抗氧化剂或为自由基清除剂,故上述水飞蓟宾衍生物或其药学上可接受的盐可以用于制备抗氧化损伤疾病的药物。
进一步地,氧化损伤疾病为神经性疾病,包括但不限于阿尔茨海默症、帕金森或通风。
本发明还提供了一种治疗氧化损伤疾病的方法,包括施加有效量的上述水飞蓟宾衍生物或其药学上可接受的盐、或上述药物组合物的步骤。
本发明还提供了上述水飞蓟宾衍生物或其药学上可接受的盐、或上述药物组合物在制备抗肿瘤药物中的应用。
进一步地,肿瘤为胃癌、结肠癌、肺癌、前列腺癌或膀胱癌。
本发明还提供了一种治疗肿瘤的方法,包括施加有效量的上述水飞蓟宾衍生物或其药学上可接受的盐、或上述药物组合物的步骤。
下面列举具体实施例来对本发明进行说明。
实施例1
将化合物L-丙氨酸异丙酯(0.2g,1.52mmol,1eq)和(297.29mg,1.52mmol,213.88μL,1eq)溶于二氯甲烷(DCM)(20mL)中,将体系降温至-70~-65℃,在此温度下,将三乙胺(TEA)(462.85mg,4.57mmol,636.66μL,3eq)滴加到反应体系中,加完后反应在-70~-65℃下搅拌0.5小时。然后再在此温度下将水飞蓟宾(silybin)(735.57mg,1.52mmol,1eq)加入反应体系中,加完后,反应自然回温至20~30℃反应12小时,反应过程中体系由浑浊变为澄清的溶液。将反应体系旋干得到粗品。粗品通过prep-HPLC纯化得到化合物(1)(0.5g,42.6%yield,95.6%purity,白色固体)。
1H-NMR(500MHz,DMSO-d6):7.86~7.91(m,2H);7.52~7.54(m,3H);7.35~7.45(m,1H);7.20(m,1H);7.10(m,1H);6.92~7.05(m,3H);5.82~5.88(m,3H);4.95~5.10(m,2H);4.70~4.80(m,1H);4.55~4.60(m,1H);4.19~4.20(m,1H);3.80~3.90(m,2H);3.75~3.80(m,3H);3.55(m,1H);3.30~3.35(m,4H);1.14~1.18(m,3H);1.05~1.08(m,6H);
实施例2
药物在大鼠体内肝脏药物分布
实验过程:实验采用40只健康大鼠,体重280-320g,每组20只随机分为2组(公母各半),分别灌胃给予30mg/kg水飞蓟宾与化合物(1)。实验前禁食12小时,空腹给药,整个实验过程不禁水,给药后5min,10min,1h,2h,3h,5h,7h和9h处死,立即解剖采集肝脏,用冷生理盐水冲净表面残留血液及内容物,吸干后,贴好标签,以2mL/g生理盐水匀浆,所得组织匀浆液用LC-MS测定,水飞蓟宾与化合物(1)给药后在大鼠体内肝脏药物浓度-时间曲线图见附图1。
由图1结果可以看到,给予化合物(1)后,药物在肝脏聚集的量接近给予水飞蓟宾后的4倍,可见化合物(1)具有靶向聚集肝脏的作用。
实施例3
药物在大鼠血浆中的浓度
实验过程:
1)采用8只健康大鼠,体重280-320g,随机分成2组,每组4只(公母各半)。分别灌胃给予40mg/kg水飞蓟宾与化合物(1)。给药后15min,30min,1.5h,4h,6h,8h,12h,18h,24h分别眼眶采血。血样处理后用LC-MS测定。
图2为水飞蓟宾与化合物(1)给药后在大鼠血浆的浓度比较图;由图2结果可以看到,药物经灌胃给予后,化合物(1)在血浆中的浓度远高于水飞蓟宾,可见化合物1的生物利用度大大高于水飞蓟宾。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
2.根据权利要求1所述的水飞蓟宾衍生物或其药学上可接受的盐,其特征在于,R1为C1-4烷基;R2为甲基。
4.根据权利要求3所述的水飞蓟宾衍生物或其药学上可接受的盐,其特征在于,R1为异丙基。
7.一种药物组合物,其特征在于,包括第一组分,所述第一组分为权利要求1-4任一项所述的水飞蓟宾衍生物或其药学上可接受的盐。
8.根据权利要求7所述的药物组合物,其特征在于,还包括第二组分,所述第二组分为熊去氧胆酸、胆汁酸、s-腺苷蛋氨酸、维生素E、N-乙酰半胱氨酸和肉毒碱中的一种或多种。
9.权利要求1-4任一项所述的水飞蓟宾衍生物或其药学上可接受的盐、或权利要求7或8所述的药物组合物在制备治疗或预防肝损伤疾病药物、抗氧化损伤疾病药物或抗肿瘤药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述肝损伤疾病为肝炎、脂肪肝或肝硬化。
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