WO2021244547A1 - 天然化合物及其衍生物在治疗动脉病变中的应用 - Google Patents
天然化合物及其衍生物在治疗动脉病变中的应用 Download PDFInfo
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
式I化合物及其衍生物在治疗动脉病变中的应用,其中动脉病变选自(i)动脉瘤,(ii)动脉壁间血肿,和/或(iii)动脉夹层。
Description
本发明属于医药领域,具体涉及黄酮类化合物及其衍生物在治疗动脉病变中的应用。
动脉病变包括动脉瘤、壁间血肿和动脉夹层等,这些疾病都是由于动脉扩张所致,发展到后期将导致血管破裂,严重者危及患者生命。动脉病变可以在全身所有动脉上出现,其病因非常复杂,糖尿病、高血压、吸烟和动脉粥样硬化等是最常见的诱发因素,症状表现为中层和外膜的细胞外基质降解,动脉壁变薄及炎症细胞的侵入,最终血管破裂,从而导致患者死亡。
临床上,尚无针对动脉瘤、壁间血肿和动脉夹层的预防和治疗药物,除手术治疗外,患者处于无药可医的状态,所以本领域急需能够预防和/或治疗动脉瘤、壁间血肿和/或动脉夹层的药物,给患者提供更多的治疗选择。
发明内容
本发明的目的是提供一种式I化合物在预防和/或治疗动脉瘤、壁间血肿和/或动脉夹层中的应用。
本发明第一方面,提供了一种式I化合物、其药学上可接受的盐、其异构体、其晶型、水合物或溶剂合物的用途,其特征在于,用于制备一药物组合物或制剂;所述药物组合物或制剂用于预防和/或治疗选自下组的动脉病变:(i)动脉瘤;(ii)动脉壁间血肿;和/或(iii)动脉夹层;
其中,X选自下组:O、取代或未取代的-CH
2-;
虚线表示键或不存在;
R
1、R
2、R
3和R
4独立地选自下组:H、卤素、OR
11、-COOH、-CN、-NH
2、糖基、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C
6-C
10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;或者R
1和R
2、R
2和R
3、或R
3和 R
4与相连环碳原子共同构成含1或2个O或S杂原子的5或6元杂环;
Ra和Rb中的一个为
且R
6、R
7、R
8、R
9和R
10独立地选自下组:H、卤素、OR
11、-COOH、-CN、-NH
2、糖基、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C
6-C
10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;或者R
6和R
7、R
7和R
8、R
8和R
9、或R
9和R
10与相连环碳原子共同构成含1或2个O或S杂原子的5或6元杂环;
Ra和Rb中另一个为选自下组的基团:H、卤素、OR
11、-COOH、-CN、-NH
2、糖基、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C
6-C
10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;
Rc选自下组:H、氧代(=O)、或OR
11;
各R
11独立地选自下组:H、糖基、取代或未取代的C
1-C
6烷基、-(C=O)-(取代或未取代的C
1-C
6烷基)、-(C=O)-(取代或未取代的苯基)、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
8环烷基、取代或未取代的苯基,或取代或未取代的苄基;和
所述“取代”是指,基团上的一个或多个(例如2、3或4个)氢原子独立地被选自下组的基团取代:H、卤素、-SH、-OH、-COOH、-CN、-NH
2、-(C=O)-C
1-C
6烷基、-C
1-C
6烷基、-C
1-C
6烷氧基、C
1-C
6卤代烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、C
3-C
8环烷基、苯基或苄基。
在另一优选例中,X为O;且Rc为氧代。
在另一优选例中,所述化合物具有式Ia或式Ib结构:
各式中,各虚线独立地表示键或不存在;
各R
5独立地选自下组:H、OR
11;和
各R
1、R
2、R
3、R
4、R
6、R
7、R
8、R
9、R
10和R
11独立地如上定义。
在另一优选例中,所述化合物具有式Ic结构:
其中,R
b、R
c、R
1、R
2、R
3、R
4、R
6、R
7、R
8、R
9和R
10独立地如上定义。
在另一优选例中,所述化合物具有式Ia结构:
R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9和R
10独立地选自下组:H、卤素、OR
11、-COOH、-CN、-NH
2、糖基、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C
6-C
10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;或者R
1和R
2、R
2和R
3、或R
3和R
4与相连环碳原子共同构成含1或2个O或S杂原子的5或6元杂环;
R
5选自下组:H、卤素、OR
11、-COOH、-CN、-NH
2、糖基、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C
6-C
10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;
R
6、R
7、R
8、R
9和R
10独立地选自下组:H、卤素、OR
11、-COOH、-CN、-NH
2、糖基、取代或未取代的C
1-C
6烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
3-C
8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C
6-C
10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;或者R
6和R
7、R
7和R
8、R
8和R
9、或R
9和R
10与相连环碳原子共同构成含1或2个O或S杂原子的5或6元杂环;
各R
11独立地选自下组:H、糖基、取代或未取代的C
1-C
6烷基、-(C=O)-(取代或未取代的C
1-C
6烷基)、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取 代或未取代的C
3-C
8环烷基、取代或未取代的苯基,或取代或未取代的苄基;和
所述“取代”是指,基团上的一个或多个(例如2、3或4个)氢原子独立地被选自下组的基团取代:H、卤素、-SH、-OH、-COOH、-CN、-NH
2、-(C=O)-C
1-C
6烷基、C
1-C
6烷基、C
1-C
6卤代烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、C
3-C
8环烷基、苯基或苄基。
在另一优选例中,R
1、R
2、R
3、R
4中有1、2或3个为选自下组的基团:卤素、OR
11;
各R
11独立地选自下组:H、糖基、取代或未取代的C
1-C
6烷基、-(C=O)-(取代或未取代的C
1-C
6烷基)。
在另一优选例中,R
6、R
7和R
8中有1、2或3个为选自下组的基团:卤素、OR
11;
各R
11独立地选自下组:H、糖基、取代或未取代的C
1-C
6烷基、-(C=O)-(取代或未取代的C
1-C
6烷基)。
在另一优选例中,R
9和R
10中有1或2个为选自下组的基团:卤素、OR
11;
各R
11独立地选自下组:H、糖基、取代或未取代的C
1-C
6烷基、-(C=O)-(取代或未取代的C
1-C
6烷基)。
在另一优选例中,R
1、R
2、R
3、R
4、R
6、R
7、R
8、R
9和R
10中至少1个,较佳地,2、3、4或5个为-OH或C
1-C
6烷氧基。
在另一优选例中,所述的R
1、R
2、R
3、R
4、R
6、R
7、R
8、R
9和R
10中的其余基团为H或C
1-C
6烷基。
在另一优选例中,R
1、R
3、R
6、R
7、R
9和R
10为H。
在另一优选例中,R
2为OR
11,较佳地,羟基或甲氧基。
在另一优选例中,R
4为OR
11,较佳地,羟基或甲氧基。
在另一优选例中,R
5为H或OR
11,
R
11选自下组:H、糖基、取代或未取代的C
1-C
6烷基、-(C=O)-(取代或未取代的C
1-C
6烷基)。
在另一优选例中,R
8为OR
11,较佳地,羟基或甲氧基。
在另一优选例中,R
2、R
4和R
8为羟基。
在另一优选例中,R
2、R
4、R
8和R
5为羟基。
在另一优选例中,所述的糖基为单糖基、二糖基或三糖基。
在另一优选例中,所述的糖基各自独立地选自下组:葡萄糖基、果糖基、甘露糖基、阿拉伯糖基、鼠李糖基、半乳糖基、木糖基、芹菜糖,或其组合。
在另一优选例中,所述糖基选自下组:单葡糖基或双葡萄糖基。
在另一优选例中,所述R
1选自下组:H、C
1-C
6烷基、环丙基、环丁基、环戊基和环己基。
在另一优选例中,所述式I化合物选自下组:
在另一优选例中,所述化合物为山奈酚。
在另一优选例中,所述化合物不是柚皮苷。
在另一优选例中,所述虚线、Ra、Rb、Rc、R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9和R
10独立地为如上述具体化合物相应的取代基。
在另一优选例中,所述药物组合物还包括药学上可接受的载体。
在另一优选例中,所述动脉选自下组:胸主动脉、腹主动脉、脾动脉、肝动脉、肠系膜上动脉、腹腔干动脉、肾动脉、网膜动脉、肠系膜下动脉、颅内动脉、颈动脉,或其组合。
在另一优选例中,所述动脉瘤包括早期动脉瘤、中期动脉瘤、和/或晚期动脉瘤。
在另一优选例中,所述药物组合物或制剂用于一个或多个选自下组的用途:
(a)抑制动脉瘤的形成和/或生长;
(b)降低血管壁的厚度;
(c)抑制弹力蛋白降解;
(d)保护血管结构的完整性,
(e)抑制壁间血肿的发生;和/或
(f)保护血管外膜胶原。
在另一优选例中,所述药物组合物或制剂的剂型选自下组:液体制剂(如溶液、乳液、悬浮液)、固体制剂(如冻干制剂)。
在另一优选例中,所述药物组合物的剂型选自下组:注射剂(如注射液或粉针剂)、口服制剂(如胶囊剂、片剂、丸剂、散剂、颗粒剂、糖浆、口服液或酊剂),更佳地,所述剂型为口服制剂。
本发明第二方面提供了一种含如本发明第一方面所述的式I化合物的药材和/或含式I化合物的提取物的用途,用于制备一组合物;所述组合物用于预防和/或治疗选自下组的动脉病变:(i)动脉瘤;(ii)动脉壁间血肿;和/或(iii)动脉夹层。
在另一优选例中,所述化合物具有式Ia结构:
在另一优选例中,所述药材选自:山柰(kaempferol galanga L.)、蓝莓(Vaccinium Spp)、窝儿七(DiphylleiasinensisLi.)、白瑞草(Thesium chinense Turcz.)、猫眼草(EuphorbialunulataBge.)、槐树果、银杏,或其组合。
在另一优选例中,所述提取物为选自下组的物质的提取物:山柰(kaempferol galanga L.)、蓝莓(Vaccinium Spp)、窝儿七(DiphylleiasinensisLi.)、白瑞草(Thesium chinense Turcz.)、猫眼草(EuphorbialunulataBge.)、槐树果、茶叶、椰菜、巫榛子、柚子,或其组合。
在另一优选例中,所述提取物中的式I化合物为山奈酚。
在另一优选例中,所述提取的溶剂选自下组:水、有机溶剂,或其组合。
在另一优选例中,所述有机溶剂选自下组:C
1-C
4醇、乙腈,或其组合。
在另一优选例中,所述的组合物选自下组:药物组合物、食品组合物、膳食补充剂、或保健品组合物。
在另一优选例中,所述提取物为蓝莓提取物,较佳地,蓝莓花青素提取物。
在另一优选例中,所述药物组合物用于一个或多个选自下组的用途:
(a)抑制动脉瘤的形成和/或生长;
(b)降低血管壁的厚度;
(c)抑制弹力蛋白降解;
(d)保护血管结构的完整性,
(e)抑制壁间血肿的发生;和/或
(f)保护血管外膜胶原。
本发明第三方面,提供了一种预防和/或治疗(i)动脉瘤;(ii)动脉壁间血肿;和/或(iii)动脉夹层的方法,给予有需要的对象治疗有效量的如本发明第一方面所述的式I化合物、其异构体、其晶型、水合物或溶剂合物,或药学上可接受的盐。
在另一优选例中,所述对象为哺乳动物。
在另一优选例中,所述对象为人、大鼠、小鼠。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
图1为动脉瘤、壁间血肿和动脉夹层模型形成过程示意图。
图2示出了山奈酚抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为各组动脉的代表图;B为主动脉组织染色分析图。
图3为柚皮素和山奈酚的腹主动脉瘤最大直径定量结果。A为各组动脉代表图;B是各组腹主动脉最大直径定量图。
图4示出了儿茶素抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为各组动脉的代表图;B为主动脉组织染色分析图。
图5示出了鹰嘴豆芽素A抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为各组动脉的代表图;B为主动脉组织染色分析图。
图6示出了大豆苷元抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为各组 动脉的代表图;B为主动脉组织染色分析图。
图7示出了表没食子儿茶素没食子酸酯(EGCG)抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为各组动脉的代表图;B为主动脉组织染色分析图。
图8示出了矢车菊-3-葡萄糖苷抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为各组动脉的代表图;B为主动脉组织染色分析图。
图9示出了蓝莓花青素提取物抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为各组动脉的代表图;B为腹主动脉瘤最大直径定量结果。
图10示出了蓝莓花青素提取物抑制动脉瘤、壁间血肿和或动脉夹层的实验结果。A为主动脉组织H&E染色结果图,B为主动脉组织地依红染色结果图,C为腹主动脉壁厚定量结果;D为动脉弹力蛋白降解分数定量结果。
本发明人经过广泛而深入的研究,通过大量筛选和测试,提供了式I化合物在预防或治疗动脉病变中的作用。本发明首次发现式I化合物(典型地,如山奈酚)能够有效的降低血管壁的厚度、减小动脉瘤体积、保护血管结构的完整性,抑制炎症细胞浸润,能够从根本上治疗动脉病变。在此基础上完成了本发明。
术语
除非另有定义,否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用,术语“室温”是指温度为4-40℃,较佳地,25±5℃。
如本文所用,术语“烷基”本身或作为另一取代基的一部分,是指具有指定碳原子数的直链或支链烃基(即C
1-C
6表示1-6个碳),烷基包括1、2、3、4、5或6个碳原子的烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C
2-C
6烯基指具有2-6个碳原子的直链或支链的烯基,烯基包括1、2、3、4、5或6个碳原子的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C
2-C
6炔基是指具有2-6个碳原子的直链或支链的炔基,炔基包括1、2、3、4、5或6个碳原子的炔基,例如 乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C
3-C
8环烷基”包括单环或双环烷基。例如C
3-C
8环烷基指包括3-8个环碳原子的饱和或不超过一个双键的烃环。环烷基包括具有3、4、5、6、7或8个碳原子的环烷基,例如环丙基、环丁基、环戊基、环己基,双环[2.2.1]庚烷、双环[2.2.2]辛烷,或类似基团。
如本文所用,除非另有表述,术语“杂环烷基”是指含有指定个数选自O、N和S的杂原子的环烷基,其中氮和硫原子任选被氧化,且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。杂环原子优选的为3-8元,更优选地为4-6元。杂环烷基的非限制性例子包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、苯邻二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以经环碳或杂原子连接于分子的其余部分。
除非另有表述,术语“芳基”表示多不饱和的(通常芳香性)的烃基,其可以是单环或稠合在一起或共价连接的多环(最多三环),芳基的非限制性例子包括苯基、萘基和联苯基。
术语"杂芳基"是指含有指定个数选自O、N和S的杂原子的芳基(或环),其中氮和硫原子任选被氧化,氮原子任选被季铵化。杂芳基可通过杂原子连接于分子的其余部分。杂芳基的非限制性例子包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基(benzotriazinyl)、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基(isobenzofuryl)、异吲哚基、中氮茚基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
如本文所用,术语“糖基(glycosyl)”指通过从单糖(或双糖、三糖)的环状形式除去半缩醛羟基而形成的一价取代基,如糖基取代式I化合物上一个或多个OH,而形成的-O-糖基。代表性的单糖包括戊糖和己糖,优选的糖基为单葡萄糖基(β-D吡喃葡萄糖基,-glu)或双葡萄糖基。
在一些实施例中,上述术语(如“烷基”,“芳基”和“杂芳基”)将包括指定基团的取代和未取代形式,取代基个数可以为1、2、3或4。如未特别说明,所述“取代”是指基团上的一个或多个氢原子被选自下组的基团取代:基团上的一个或多个(例如2、3或4个)氢原子被选自下组的基团取代:H、卤素、-SH、-OH、-COOH、-CN、-NH
2、 -(C=O)-C
1-C
6烷基、-(C=O)-(取代或未取代的苯基)、C
1-C
6烷基、C
1-C
6卤代烷基、烷基C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、C
3-C
8环烷基、苯基或苄基。
如本文所用,术语“异构体”意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明某些化合物可以非溶剂化形式以及溶剂化形式存在,包括水合形式。通常,溶剂化形式等同于未溶剂化形式,并且旨在包括在发明的范围内。本公开的某些化合物可以以多种结晶或无定形形式存在。通常,所有物理形式对于本公开所考虑的用途是等同的,并且旨在落入本公开的范围内。
本发明的化合物还可以在构成这些化合物的一个或多个原子上含有非天然比例的原子同位素。例如,化合物可以用放射性同位素放射性标记,例如氚(
3H)、碘-125(
125I)或碳-14(
14C)。无论是否具有放射性,本公开化合物的所有同位素变体都包括在本公开的范围内。例如,可以制备化合物,使得任何数量的氢原子被氘(
2H)同位素取代。本发明的化合物还可以在构成这些化合物的一个或多个原子上含有非天然比例的原子同位素。非天然比例的同位素可以定义为从自然界中发现的量到由所讨论的原子的100%组成的量。例如,化合物可以掺入放射性同位素,例如氚(
3H)、碘-125(
125I)或碳-14(
14C),或非放射性同位素,例如氘(
2H)或碳-13(
13C)。
如本文所用,术语“预防”或“治疗”包括疾病调节治疗和对症治疗,其中任一种都可以是预防性的(即,在症状发作之前,以预防、延迟或减轻症状的严重性))或治疗性的(即,在症状发作后,为了减轻症状的严重性和/或持续时间)。本发明所述的“预防”和“治疗”包括延缓和终止疾病的进展,并不需要100%抑制、消灭和逆转。在一些实施方案中,与不存在本发明式I化合物、包含式I化合物的药材或提取物或本发明的药物组合物相比,减轻、预防、抑制和/或逆转了例如至少约1%、10%、至少约30%、至少约50%、或至少约80%。
活性成分
本发明的活性成分包括式I化合物、其药学上可接受的盐、其异构体、其晶型、水合物或溶剂合物;
其中,所述虚线、Ra、Rb、Rc、R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、和R
10如上定义。
如本文所用,“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于:氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱,氨水、三乙胺、二乙胺、哌嗪等有机碱。
本发明化合物可以是无定形的、晶型或其混合物。
本发明的式I化合物可通过醇提、层析方法等从山柰等植物中提取获得,还可通过商业途径购买或者利用市售原料通过现有技术中合成方法合成。本领域的普通技术人员根据现有公知技术可以来提取或合成本发明的化合物。提取物或合成的化合物可以进一步通过柱色谱法、高效液相色谱法或结晶等方式进一步纯化。
合成化学改造、保护官能团方法学对合成应用化合物是很有帮助的,并且是现有技术中公知的技术,可以参见可例如R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989);T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999);L.Fieser and M.Fieser,Fieser and Fieser's Reagents for Organic Synthesis,John Wiley and Sons(1994);和L.Paquette,ed.Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)等文献。
含式I化合物的中药、食材、提取物
本发明另一方面,提供了含式I化合物的药材和/或食材、及含式I化合物的提取物的用途,它们被用于治疗动脉病变或用于制备治疗动脉病变的组合物和/或制剂。典型地,所述的动脉病变包括(但并不限于):(i)动脉瘤;(ii)动脉壁间血肿;和/或(iii)动脉夹层。
在另一优选例中,所述提取物中的式I化合物为山奈酚。
优选的地,含山奈酚的药材包括(但并不限于):姜科植物山柰(kaempferol galanga L)(如根茎),窝儿七(DiphylleiasinensisLi.)、白瑞草(Thesium chinense Turcz.)、猫眼草(EuphorbialunulataBge.)、槐树果,银杏(Ginkgo biloba L.)(如叶、果),或其组合。
山奈酚也广泛存在于食材中,人们已经从茶叶、椰菜、巫榛子和柚子中提取到山奈酚的纯品。本发明中,对所述提取物的提取方法没有特别要求,可以使用本领域常用的提取方法。如:水提、醇提、超临界萃取(CO
2)等。
优选地,所述提取物中包含富集的本发明的活性成分。如所述活性成分占所述提取物干重≥1wt%、≥2wt%、≥5wt%,如1-30wt%或2-20wt%。
在另一优选例中,所述提取物为蓝莓(果实)青花素提取物。所述蓝莓青花素提取物的提取方法没有特别要求,可以使用市售的蓝莓青花素提取物或使用本发明常用的方法提取,获得的富含蓝莓青花素提取物的提取物。
在另一优选例中,所述蓝莓青花素提取物中,总青花素的质量含量≥1%、≥2%、≥5%、≥10%、≥15%、≥20%、≥50%、≥60%、≥70%、≥80%、≥90%、≥100%,以提取物干重计。
优选地,一种蓝莓青花素提取物的制备方法包括步骤:将蓝莓果浆与酸化乙醇(HCl酸化,pH3.0±0.2,乙醇最终体积分数为70-80%)按料液比1∶8-12进行混合,45-55℃浸提2-4h得浸提液,将浸提液离心,得上清液。随后将上清液经弱极性大孔树脂吸附(如AB-8、D101型树脂)、55-65%乙醇洗脱,蒸发溶剂后获得所述蓝莓青花素提取物。
药物组合物、施用方法和应用
本发明的活性成分具有治疗和/或预防动脉病变相关疾病,所以可用于制备用于预防和/或治疗动脉病变相关疾病的药物组合物;优选地,所述动脉病变选自下组:(i)动脉瘤;(ii)动脉壁间血肿;和/或(iii)动脉夹层。
在另一优选例中,所述动脉瘤选自下组:早期动脉瘤、中期动脉瘤、晚期动脉瘤,或其组合。
本发明活性成分可以单独给药,或者与其他药学上可接受的化合物联合给药,包括(但并不限于):降血压药(例如:血管紧张素转换酶抑制剂和/或血管紧张素受体阻断剂(如缬沙坦、氯沙坦、阿利沙坦酯等))、降血脂药(例如:他汀类、贝特类、烟酸类、胆固醇吸收抑制剂)、降糖药(例如:磺脲类促泌剂、胰岛素增敏剂、双胍类)、多聚体丹酚酸、或其组合。
本发明的药物组合物可用于制备治疗和/或预防动脉病变相关疾病,优选地,所述动脉病变选自下组:(i)动脉瘤;(ii)动脉壁间血肿;和/或(iii)动脉夹层。
在另一优选例中,所述药物组合物还包括药学上可接受的载体。
本发明的药物组合物中,第一活性成分和第二活性成分可以分别制成制剂或混合在一起制成制剂。
如本文所用,“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-500mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和式I化合物相互掺和,而不明显降低化合物的 药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及 其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
在本发明中,式I化合物的治疗有效剂量的一般范围将是:约1-2000mg/天、约10-约1000mg/天、约10-约500mg/天、约10-约250mg/天或约10-100mg/天。治疗有效剂量将以一个或多个剂量给予。然而,应理解,对于任何特定患者的本发明活性成分的特定剂量将取决于多种因素,例如,待治疗的患者的年龄、性别、体重、一般健康状况、饮食、个体响应,给予时间、待治疗的疾病的严重性、施用的具体化合物的活性、剂型、应用模式和伴用药物。给定情况的治疗有效量能用常规实验测定,并在临床医生或医师能力和判断范围内。在任何情况中,所述活性成分将基于患者的个体情况以多个剂量给予并以允许递送治疗有效量的方式给予。
本发明的主要优点包括:
1.本发明首次发现式I化合物具有减慢动脉瘤扩张速度,减少动脉壁间血肿,抑制动脉夹层,进而降低动脉破裂的效果,适用于治疗动脉相关疾病。
2.本发明化合物及药物组合物为动脉瘤、动脉壁间血肿和/或动脉夹层患者提供了手术治疗之外的治疗选择。
3.本发明化合物为大多数为已知且安全、毒副作用小的化合物,可以给快速开发有效治疗动脉病变的药物提供方便的选择。
下面结合具体实施,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
试剂
实验仪器
模型制备和样品检测方法
动脉瘤、壁间血肿和或动脉夹层模型的制备
按照小鼠体重按照20mg/kg的剂量,腹腔注射5%舒泰进行麻醉。等待小鼠进入麻醉状态后,剃毛刀剃掉腹毛,在用脱毛膏进一步彻底脱毛,擦净腹部后固定于手术台上,身下用加热垫保持体温。用碘酒擦拭腹部皮肤后用75%乙醇脱碘,在腹部正中剪开约1.5cm的切口,用镊子小心推离脏器,然后用3%青霉素-链霉素润湿的纱布将肠道分至左右两侧,用镊子仔细分离主动脉表面的结缔组织和肌肉组织,使腹主动脉充分暴露。暴露腹主动脉长度约0.5cm左右,近端不超过双侧肾动脉,远端不超过股动脉。
将灭菌吸水纸(0.3cm×0.3cm)在猪胰弹力蛋白酶(PPE)中充分浸润,随即敷在暴露的腹主动脉上,敷育时间为50分钟,在腹腔切口上方放置一块用3%青霉素-链霉素的生理盐水润湿的纱布防止腹腔水分过度流失。50分钟后,小心取出主动脉上的吸水纸,并用含3%青霉素-链霉素的生理盐水,冲洗腹腔,以3/8缝合针、5/0缝合线缝合腹膜及皮肤。缝合完毕后碘酒擦拭创口,1分钟后用75%乙醇脱碘。将小鼠放入干净的饲养笼,进食含1%的β-氨基丙腈(BAPN)的饲料、自由饮水,隔日更换饲料。
取材
按照小鼠体重4ml/kg的剂量,腹腔注射10%水合氯醛进行安乐死,迅速取出从心脏至下肢的整根主动脉,放于盛有生理盐水的容器中,容器置于冰上。在体视显微镜下,小心剔除主动脉周围的肌肉和脂肪组织。
大体形态学观察
将修剪后的主动脉置于黑色板上,用体视显微镜(SZX7,OLYMPUS)进行拍摄。使用Cell Sens标准软件(OLYMPUS,版本1.18)对AAA的最大直径进行测量。按照V=(AAA最大直径×AAA长度
2)/2公式计算AAA的体积。
样品固定、脱水、石蜡包埋、切片
甲醛100ml,磷酸二氢钠4g,磷酸氢二钠6.5g,溶于900mL蒸馏水中,配制成体积比为10%的多聚甲醛固定液。主动脉组织于多聚甲醛固定液中固定72h后,自来水冲洗4-6h,放置于脱水机中设定程序自动脱水,依次经 75%乙醇1.5h,95%乙醇1.5h,100%乙醇1.5h,二甲苯1.5h、石蜡1.5h。提前2h打开石蜡包埋机熔化石蜡,温度控制在60℃。待石蜡融化后,脱水后的主动脉组织进行石蜡包埋,倒入包埋盒,用加热的镊子将浸蜡后的组织块放入包埋框内,轻轻移至冷台,待石蜡凝固后取下石蜡块准备切片。切片前,将蜡块放入冰箱内预冷,冷却后切片机连续切5μm厚度的石蜡切片。切片在摊片机38℃温水上展开,用涂有APES的载玻片捞片,自然风干用于后续的病理组织学染色。
苏木素-伊红(HE)染色
将组织固定包埋,切成4μm的石蜡切片,首先对石蜡切片进行烤片(65℃,60分钟),然后脱蜡至水相(二甲苯15分钟→无水乙醇5分钟→95%乙醇5分钟→75%乙醇5分钟→流水1分钟);放入苏木素染色液中进行染色15分钟后,流水冲洗4分钟;用1%盐酸乙醇分化5秒(分化时间根据分化液配制的时间进行调整),流水冲5分钟;伊红染色液染色1分钟后置于水中1分钟;脱水再经二甲苯透化(75%乙醇5分钟→95%乙醇5分钟→无水乙醇5分钟→二甲苯15分钟),中性树胶封片,BX51显微镜拍摄图片。
地衣红染色
按上述常规脱蜡方式进行脱蜡。地衣红染色液染色1小时,1%盐酸的乙醇溶液分化5分钟,经二甲苯透化,中性树胶封片。用病理评分对弹性蛋白降解进行定量:未降解0分,降解小于25%为1分,降解范围为25%~50%为2分,降解范围为50%~75%为3分,降解大于75%为4分。该过程进行双盲评估,并以两名研究者的平均值表示。
数据统计
数据以平均值±SE表示。使用GraphPad Prism 6进行统计分析。采用单因素方差分析法对各组间差异的统计学意义进行了多次比较。在确定了正态分布和方差齐性后,进行了Tukey检验。P<0.05为具有统计学意义。
实施例1
山奈酚对动脉瘤、壁间血肿和或动脉夹层的治疗作用
动物给药及分组情况:8周龄C57BL/6小鼠进入动物房适应饲养一周,然后随机分为正常对照组、模型对照组、山奈酚25mg/kg(灌胃)组,每组动物10只,用猪胰弹力蛋白酶造模并在造模当天开始用含1%β-氨基丙腈的饲料喂养,从而诱导动脉瘤、壁间血肿和动脉夹层(所述模型对应于动脉瘤晚期,以及壁间血肿和动脉夹层),手术 当天为第0天,从第5天开始对动物分别采用灌胃给药的方式分别给予CMCNa或山奈酚,持续给药10天并且严密观察动物的活动情况,在第15天对动物安乐死后取得动脉组织评价动脉瘤、动脉壁间血肿和动脉夹层破裂的情况。
采用猪胰弹力蛋白酶和1%β-氨基丙腈饲料喂养诱导动脉瘤、壁间血肿和动脉夹层模型既可以考察药物对动脉瘤增长的影响,还可以考察药物对壁间血肿和动脉夹层破裂的影响。
使用与实施例1类似的方法,测试下列化合物的对壁间血肿和或动脉夹层的预防治疗作用,与模型组相比,腹主动脉瘤最大直径结果总结如下表1。
其中*为P<0.05;**为P<0.01;***为P<0.001;****为P<0.0001
表1
注:对于化合物1-2,n=10,对于化合物3-7,n=5。
从表1和图1-8可以看出,与正常对照组小鼠相比,模型对照组的肾下动脉部分有明显的膨出和扩张,而本发明的化合物能够明显降低小鼠动脉瘤的形成、大小和扩张速度。从组织学分析可以看出,本发明的化合物能够降低血管壁的厚度、保护血管结构的完整性,抑制弹力层的降解、抑制壁间血肿的发生、保护血管外膜胶原的形态。
实施例2
蓝莓花青素提取物
新鲜蓝莓果实,经过蒸馏水洗涤干净并晾干表面水分,-20℃的温度冷冻处理后,捣碎直至其呈现匀浆状态。将蓝莓果浆与酸化乙醇(pH3.0,75%乙醇)按料液比1∶10进行混合,50℃浸提3h得浸提液,将浸提液在4 000r/min离心1h,得上清液。随后将上清液经过AB-8大孔树脂吸附、60%乙醇洗脱、旋转蒸发溶剂后获得蓝莓青花素提取物。
经过高效液相色谱分析,所述蓝莓青花素提取物主要成分包括:飞燕草素-3-半乳糖苷氯化物、飞燕草素-3-葡糖苷氯化物、矢车菊素-3-半乳糖苷氯化物、飞燕草素-3-阿拉伯糖苷氯化物、氯化矢车菊素-3-葡萄糖苷、矮牵牛-3-半乳糖苷氯化物、矢车菊素-3-阿拉伯糖苷氯化物、矮牵牛-3-葡糖苷氯化物、飞燕草素氯化物、芍药色素-3-半乳糖苷氯化物、矮牵牛-3-阿拉伯糖苷氯化物、芍药色素-3-葡糖苷氯化物、锦葵色素-3-半乳糖苷氯化物、芍药色素-3-阿拉伯糖苷氯化物、锦葵色素-3-葡糖苷氯化物、矢车菊素氯化物、锦葵色素-3-阿拉伯糖苷氯化物、矮牵牛苷氯化物、芍药色素氯化物、锦葵色素氯化物。
使用与实施例1类似的方法,测试所述蓝莓花青素提取物的对壁间血肿和或动脉夹层的预防治疗作用,n=10,用量以蓝莓花青素提取物干重计。
结果如图9-10所示,蓝莓花青素提取物具有显著的抑制动脉瘤的形成、和扩张速度,抑制动脉壁增厚,和弹力蛋白降解,这提示蓝莓花青素提取物具有显著的抑制动脉瘤、壁间血肿和或动脉夹层的效果。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (15)
- 一种式I化合物、其药学上可接受的盐、其异构体、其晶型、水合物或溶剂合物的用途,其特征在于,用于制备一药物组合物或制剂;所述药物组合物或制剂用于预防和/或治疗选自下组的动脉病变:(i)动脉瘤;(ii)动脉壁间血肿;和/或(iii)动脉夹层;其中,X选自下组:O、取代或未取代的-CH 2-;虚线表示键或不存在;R 1、R 2、R 3和R 4独立地选自下组:H、卤素、OR 11、-COOH、-CN、-NH 2、糖基、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C 6-C 10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;或者R 1和R 2、R 2和R 3、或R 3和R 4与相连环碳原子共同构成含1或2个O或S杂原子的5或6元杂环;Ra和Rb中的一个为 且R 6、R 7、R 8、R 9和R 10独立地选自下组:H、卤素、OR 11、-COOH、-CN、-NH 2、糖基、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C 6-C 10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;或者R 6和R 7、R 7和R 8、R 8和R 9、或R 9和R 10与相连环碳原子共同构成含1或2个O或S杂原子的5或6元杂环;Ra和Rb中另一个为选自下组的基团:H、卤素、OR 11、-COOH、-CN、-NH 2、糖基、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 8环烷基、取代或未取代的具有1-3个选自O、N和S的3-8元杂环烷基、取代或未取代的C 6-C 10芳基,取代或未取代的具有1-3个选自O、N和S的5-10元芳杂环,或取代或未取代的苄基;Rc选自下组:H、氧代(=O)或OR 11;各R 11独立地选自下组:H、糖基、取代或未取代的C 1-C 6烷基、-(C=O)-(取代或未取代的C 1-C 6烷基)、-(C=O)-(取代或未取代的苯基)、取代或未取代的C 2-C 6烯基、 取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 8环烷基、取代或未取代的苯基,或取代或未取代的苄基;和所述“取代”是指,基团上的一个或多个(例如2、3或4个)氢原子独立地被选自下组的基团取代:H、卤素、-SH、-OH、-COOH、-CN、-NH 2、-(C=O)-C 1-C 6烷基、-C 1-C 6烷基、-C 1-C 6烷氧基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 3-C 8环烷基、苯基或苄基。
- 如权利要求1所述的用途,其特征在于,R 1、R 2、R 3、R 4中有1、2或3个为选自下组的基团:卤素、OR 11;各R 11独立地选自下组:H、糖基、取代或未取代的C 1-C 6烷基、-(C=O)-(取代或未取代的C 1-C 6烷基)。
- 如权利要求1所述的用途,其特征在于,R 6、R 7和R 8中有1、2或3个为选自下组的基团:卤素、OR 11;各R 11独立地选自下组:H、糖基、取代或未取代的C 1-C 6烷基、-(C=O)-(取代或未取代的C 1-C 6烷基)。
- 如权利要求2所述的用途,其特征在于,R 5为H或OR 11,R 11选自下组:H、糖基、取代或未取代的C 1-C 6烷基、-(C=O)-(取代或未取代的C 1-C 6烷基)。
- 如权利要求1所述的用途,其特征在于,R 2、R 4和R 8为羟基。
- 如权利要求1所述的用途,其特征在于,所述的糖基各自独立地选自下组:葡萄糖基、果糖基、甘露糖基、阿拉伯糖基、鼠李糖基、半乳糖基、木糖基、芹菜糖,或其组合。
- 如权利要求1所述的用途,其特征在于,所述动脉选自下组:胸主动脉、腹主动脉、脾动脉、肝动脉、肠系膜上动脉、腹腔干动脉、肾动脉、网膜动脉、肠系膜下动脉、颅内动脉、颈动脉,或其组合。
- 如权利要求1所述的用途,其特征在于,所述药物组合物或制剂用于一个或多个选自下组的用途:(a)抑制动脉瘤的形成和/或生长;(b)降低血管壁的厚度;(c)抑制弹力蛋白降解;(d)保护血管结构的完整性,(e)抑制壁间血肿的发生;和/或(f)保护血管外膜胶原。
- 如权利要求1所述的用途,其特征在于,所述药物组合物或制剂的剂型选自下组:注射剂(如注射液或粉针剂)、口服制剂(如胶囊剂、片剂、丸剂、散剂、颗粒剂、糖浆、口服液或酊剂),更佳地,所述剂型为口服制剂。
- 如权利要求14所述的用途,其特征在于,所述药材选自:山柰(kaempferol galanga L.)、蓝莓(blueberry(Vaccinium Spp.)、窝儿七(DiphylleiasinensisLi.)、白瑞草(Thesium chinense Turcz.)、猫眼草(EuphorbialunulataBge.)、槐树果、银杏、或其组合。
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CN115337266A (zh) * | 2022-08-11 | 2022-11-15 | 宁夏医科大学 | 一种纳米载药胶束及其制备方法和应用 |
CN115337266B (zh) * | 2022-08-11 | 2023-09-01 | 宁夏医科大学 | 一种纳米载药胶束及其制备方法和应用 |
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