CN107793365B - 一种化合物及其制备方法和用途 - Google Patents
一种化合物及其制备方法和用途 Download PDFInfo
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- CN107793365B CN107793365B CN201610786956.8A CN201610786956A CN107793365B CN 107793365 B CN107793365 B CN 107793365B CN 201610786956 A CN201610786956 A CN 201610786956A CN 107793365 B CN107793365 B CN 107793365B
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Abstract
本发明公开了一类具有式X结构的化合物或其药学上可接受的盐及其制备方法和用途：
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种可用于药物支架的化合物及其制备方法和用途。
背景技术
血管的内膜主要由内皮细胞构成，中膜主要由平滑肌细胞和纤维细胞构成。在支架植入后，为了防止病变处血管的再狭窄，希望比较大程度地抑制平滑肌细胞向血管内腔的增生；但为了防止血栓的发生，则希望病变处能够尽快实现内皮化，因此不希望药物对内皮细胞的抑制过强。
目前临床中，对抗血管再狭窄通常采用药物支架的方式进行，这就要求药物支架上所携载的该药物具有较小的细胞毒性，同时拥有良好的脂溶性，并能够在植入体内血管后维持长时间的释放，并且该药物对于血管增生的抑制作用更有选择性，即需要该药物对平滑肌细胞的抑制尽可能大于对内皮细胞的抑制。
目前已知常用的抗血管再狭窄药物包括雷帕霉素和紫杉醇。
雷帕霉素(Rapamycin)，又称西罗莫司(Sirolimus)，属大环内酯类抗生素，其透过细胞膜可以与FKBP-12(FK506结合蛋白)结合生成Rapamycin-FKBP-12复合物，抑制mTOR激酶的活性，阻断平滑肌细胞由G1期至S期的进程，从而起到抑制细胞增殖的作用。雷帕霉素分子结构式如下图。
紫杉醇是从紫杉树皮中所提得，主要是通过与微管蛋白的α端和β端同时结合，使大量微管非正常地聚合，从而改变细胞骨架的平衡状态，产生结构的畸变，导致其失去正常的功能，造成细胞发育停止于G0/G1期和G1/M期，细胞的有丝分裂阻止于丝状分裂期，从而抑制血管平滑肌的分裂、增殖，减少再狭窄的发生。紫杉醇的分子结构式如下图。
上述这两种药物都能够抑制平滑肌细胞、内皮细胞、成纤维细胞等的增殖；但是，这两种药物仍无法完全满足上述对于防止支架植入后病变部位血管再狭窄的需求，尤其对于血管内不同类型的细胞增生的抑制作用不具有选择性，即这两种药物在对平滑肌细胞有强大的抑制作用的同时，对内皮细胞也产生很强的抑制作用，这在临床中容易增大患者晚期的血栓风险，导致患者需要在支架植入术后的很长一段时间内持续服用抗血栓和血小板药物。
因此本领域迫切需要提供一类能满足防止支架植入后病变部位血管再狭窄需求的化合物及含有其的药物支架。
发明内容
发明旨在提供一类可有效对抗支架植入血管处再狭窄的化合物及其制备方法和用途。
在本发明的第一方面，提供了一类具有式X结构的化合物或其药学上可接受的盐：
其中R1是至少包含一个五元环或一个六元环的化学结构；
R2是分子量大于100并且含有吸电子基团的化学结构。
在另一优选例中，所述五元环或六元环的结构选自下述结构中的一种：吗啉、苯环、环己烷、环己烯、环己二烯、环戊烷、环戊烯、环戊二烯、1，3，5-三嗪、1，3，5-噻吩、哌嗪、吡嗪、嘧啶、哒嗪、1，4-二氧六环、哌啶、吡啶、4H-吡喃、三氮唑、戊二唑、噻吩、恶唑、咪唑、吡唑烷、吡唑啉、吡唑、1,3-二氧戊环、吡咯烷、吡咯或呋喃。
在另一优选例中，所述R1选自下述结构中的一种：
其中A为下述基团中的一种：卤素、-CN、-OH、-SH、-NO2、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-NH(C1-C6烷基)-OH、-NH(C1-C6烷基)-(C1-C6烷氧基)、-C1-C6烷氧基-OH、-C1-C6烷氧基-(C1-C6烷氧基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基(C1-C6烷基)、(C1-C6烷氧基)C1-C6烷基、氨基(C1-C6烷基)、-S(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)或-CON(H)OR’；
其中R’为下述基团中的一种：氢、-CONH2、-C(＝NH)NH2、-C(＝NH)NH-NH2或-C(＝NOH)NH2。
在另一优选例中，所述R2的结构中包含下述基团中的一种或多种：-NO2、-CO-、-COOH、-CONH-、-CONH2、-CN、-F、-Cl、-Br、-I、-SO2、-SO3、-OCH3。
在另一优选例中，所述R2的结构选自下述结构中的一种：
在本发明的第二方面，提供了一种化合物，选自于下述化合物中的一种：
在本发明的第三方面，提供了一种组合物，所述组合物包括赋形剂和治疗有效量的如上所述的本发明提供的化合物或其药学上可接受的盐。
在本发明的第四方面，提供了一种如上所述的本发明提供的化合物或其药学上可接受的盐在制备抗血管再狭窄的制品中的应用；所述制品为药物或介入医疗器械；所述介入医疗器械选自心脏瓣膜、心脏封堵器、血管支架、球囊、人造血管、导管、起搏器、起搏器导子或除颤器中的一种。
在本发明的第五方面，提供了一种介入医疗器械，所述介入医疗器械包括含有如上所述的本发明提供的化合物或其药学上可接受的盐的药物释放结构。
在另一优选例中，所述介入医疗器械选自心脏瓣膜、心脏封堵器、血管支架、球囊、人造血管、导管、起搏器、起搏器导子或除颤器中的一种。
据此，本发明提供了一种能满足防止介入医疗器械植入后病变部位血管再狭窄需求的化合物及含有其的介入医疗器械。
具体实施方式
发明人经过广泛而深入的研究，发现了一系列结构如式X所示的化合物对于支架植入造成的血管再狭窄有显著的效果。在此基础上完成了本发明。
化合物
如本文所述化合物，可抗血管再狭窄。在本发明的一方面，提供了一种具有式X结构的化合物或其药学上可接受的盐：
其中，R1是至少包含一个五元环或一个六元环的化学结构，所述的五元环或六元环的结构具体可以是下述基团中的一种：：吗啉、苯环、环己烷、环己烯、环己二烯、环戊烷、环戊烯、环戊二烯、1，3，5-三嗪、1，3，5-噻吩、哌嗪、吡嗪、嘧啶、哒嗪、1，4-二氧六环、哌啶、吡啶、4H-吡喃、三氮唑、戊二唑、噻吩、恶唑、咪唑、吡唑烷、吡唑啉、吡唑、1,3-二氧戊环、吡咯烷、吡咯、呋喃。
R1的结构优选为下述基团中的一种：：
其中A是下述基团中的一种：卤素、-CN、-OH、-SH、-NO2、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-NH(C1-C6烷基)-OH、-NH(C1-C6烷基)-(C1-C6烷氧基)、-C1-C6烷氧基-OH、-C1-C6烷氧基-(C1-C6烷氧基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基(C1-C6烷基)、(C1-C6烷氧基)C1-C6烷基、氨基(C1-C6烷基)、-S(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)、-CON(H)OR’
其中R’是下述基团中的一种：氢、-CONH2、-C(＝NH)NH2、-C(＝NH)NH-NH2或-C(＝NOH)NH2
R2是分子量大于100并且含有吸电子基团的化学结构，具体的讲，该结构中可以包含下述基团中的一种或多种：-NO2、-CO-、-COOH、-CONH-、-CONH2、-CN、-F、-Cl、-Br、-I、-SO2、-SO3、-OCH3结构。
其中，优选结构为：
该化合物可以药学上可应用的盐的形式存在。
具有式X结构的化合物包括但不限于表1中的说明。
表1。
在某个具体实施例中，本发明的化合物按照药学上可接受的酸加成盐(一种药学上可接受的盐)来制备，通过化合物的自由碱形式与药学上可接受的无机或有机酸反应，包括但不限于无机酸，如盐酸，氢溴酸，硫酸，硝酸，磷酸，偏磷酸等；有机酸如乙酸，丙酸，己酸，环戊基丙酸，乙醇酸，丙酮酸，乳酸，丙二酸，丁二酸，羟基丁二酸，马来酸，反丁烯二酸，对甲苯磺酸，酒石酸，三氟乙酸，枸橼酸，苯甲酸，3-(4-羟苯甲酰基)苯甲酸，肉桂酸，扁桃酸，芳磺酸，甲磺酸，乙磺酸，1，2-乙二磺酸，2-羟基乙磺酸，苯磺酸，2-萘磺酸，4-甲基双环-[2.2.2]辛-2-烯-1-羧酸，葡庚糖酸，4,4'-亚甲基双-(3-羟基-2-烯-1-羧酸)，3-苯基丙酸，三甲基乙酸，叔丁基乙酸，硫酸十二烷基酯，葡糖酸，谷氨酸，羟萘甲酸，水杨酸，硬脂酸和己二烯二酸。
“本发明化合物”、“本发明的化合物”或“本发明提供的化合物”可互换使用，都是指结构如式X所示的化合物。
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过本发明的化合物与酸反应获得，如硫酸，硝酸，磷酸，甲磺酸，乙磺酸，对甲苯磺酸，水杨酸等。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。本发明化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。
在其他具体实施例中，本发明化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，本发明化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图，红外光谱，熔点，密度，硬度，晶型，光和电的性质，稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、糖化学、生物化学和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
“烷基”指脂肪烃碳氢基团。烷基部分可以是饱和的烷基(指不含有任何不饱和单元，如碳-碳双键或碳-碳三键)或烷基部分可以是不饱和烷基(指至少含有一个不饱和单元)。烷基部分，不管饱和还是不饱和，可以是支链或直链。
“烷基”片断(moiety)可以有1到6个碳原子(只要在这里出现，一个数字范围如“1到6”指在给出范围中的每个整数，如“1到6个碳原子”指可以含有1个碳原子，2个碳原子，3个碳原子等直到包含6个碳原子的烷基，虽然目前的定义在没有指定数字范围的情况下，也包含了术语“烷基”的出现)。本文所述的化合物的烷基可以被指定为“C1-C6烷基”或类似的指定。举例说明“C1-C6烷基”指在烷基链中有一个，两个，三个，四个，五个或六个碳原子。典型的烷基包括但不限于甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，己基等。
术语“烷氧基”指“烷基”O-基团，烷基如本文中定义。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。
“一有效量(an effective amount)”一词意将对于治疗疾病的目的。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”、“药物(medicineor medicament)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于一个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等，而可在施用个体体内形成该活性化合物的一相当用量者。
本文中交替使用“个体(subject)”或“患者(patient)”等词，其是指可接受所述化合物和/或方法治疗的动物(包括人类)。“个体”或“患者”在此涵盖了雄性与雌性两种性别，除非另有具体说明。因此“个体”或“患者”包含任何哺乳类动物，包括，但不限于，人类、非人类的灵长类，如哺乳动物、狗、猫、马、羊、猪、牛等，其可因利用所述化合物进行治疗而获益。适合接受本发明化合物和/或方法治疗的动物较佳为人类。一般来说，“患者”一词及“个体”一词在本文中可彼此交替使用。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解与惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
用途
本发明的化合物可抗血管再狭窄。在另一具体实施例中，所描述的化合物能够在使用介入医疗器械，例如但不限于支架时，防止或减少血管再狭窄的发生。
在一些实施例中，所述方法为使介入医疗器械包括含有本发明的化合物的药物释放结构。本发明提供一种含化合物X的植入式医疗器械，该器械表面分布的化合物X可持续释放来抑制血管壁平滑肌细胞增殖，并促进血管再内皮化，促进损伤血管壁的愈合，防止支架内血栓的发生，减少病人术后服用抗血栓和血小板药物的时间。
本发明同时提供一种化合物X的植入式医疗器械的制备方法。
本发明所述的植入式医疗器械中还可以包含选自于下述各类药物活性组分的一种或几种联合使用：免疫抑制剂及抗炎药物、抗增殖药物、促再内皮化药物、抗细胞迁移药物、细胞间基质调节剂以及其他细胞外基质蛋白。
所述抗增殖药物包括西罗莫司，他克莫司，艾罗莫司，免疫抑制剂ABT-578，地塞米松，咪唑立宾，雷帕霉素，紫杉醇及其衍生物，放线菌素，长春新碱及其衍生物，他汀类药物，2-氯去氧腺苷，核酶，巴马司他，溴氯哌喹酮，普罗布可，可选用其中任一种或几种。
本发明所述医疗器械，其金属材料选自钛、钴、钽、镍钛合金、镍钛锘合金、医用不锈钢、医用可降解合金材料如铝镁合金，也可以选用聚合物材料，其包括可降解或不可降解材料，可降解材料如PCL、PGA、PLLA、PCLA、PLGA等。
所述医疗器械表面均匀分布0.1μm-10μm的微孔。
本发明所述医疗器械的制备方法，包括但不限于：
将化合物X溶于溶剂中，通过直接喷涂、浸涂或者两种方法联用等方法涂覆于医疗器械表面；
或采用静电喷涂或者阳极极化方法喷涂或浸涂到支架表面。浸泡48小时终止吸附，-55℃真空干燥机中冻干。
药物的溶剂为链烷烃、烯烃、醇、醛、胺、酯、醚、酮、芳香烃、氢化烃、萜烯烃、卤代烃、杂环化物、含氮化合物及含硫化合物等，可以优选乙酸乙酯、乙酸正丙酯、丙酮、四氢呋喃、三氯甲烷、二氯甲烷。
本发明所述的医疗器械可以为心脏瓣膜，心脏封堵器，血管支架，球囊，人造血管，导管，起搏器，起搏器导子，除颤器等医疗器械中的一种或多种医疗器械的组合。
本发明通过支架表面分布的化合物X的持续释放来抑制血管壁平滑肌细胞增殖，并促进血管再内皮化，促进损伤血管壁的愈合，防止支架内血栓的发生，减少病人术后服用抗血栓和血小板药物的时间。
本发明还可以采用无载体涂覆技术，避免载体带来的过敏和炎症反应，药物释放后成为裸支架，导致晚期血栓和炎症的可能性更低，安全性高。若是采用完全可降解支架，在介入术后的一段时间内，支架使血管得到机械性支撑，并借助洗脱出的药物，防止再狭窄。之后支架即缓慢降解，并完全被组织完全吸收，晚期支架血栓的发生应该降低，无需长期的抗血小板药物治疗，没有后顾之忧。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
本发明的主要优点在于：
1、本发明提供的结构如式X所示的新结构化合物；
2、本发明提供的化合物在临床上对抗支架植入病人病变处血管再狭窄取得了显著的临床效果；
3、本发明提供的化合物对于血管增生的抑制作用具有更优越的选择性，对于血管内膜的抑制率明显高于中膜，因而在抑制血管壁平滑肌细胞增殖的同时，还能够促进血管内皮化，促进损伤血管壁的愈合，防止血栓的发生，并可以减少病人在支架植入术后服用抗血栓和血小板药物的时间。
下面结合具体实施例，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，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
制备化合物W
A：NH3/MeOH加热回1h
B：光气/THF
C：POCl3、吗啉加热回流5h
D：4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯胺、Pd(Pcy3)2Cl2、CsF、NMP-水(9：1)100℃48h
E：甲氨甲酰氯、TEA、DCM回流36h
产物用LCMS证实，新峰Rf＝15.754,M+＝398。
实施例2
制备化合物V
A：NH3/MeOH加热回1h
B：光气/THF
C：POCl3、吗啉加热回流5h
D：4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯胺、Pd(Pcy3)2Cl2、CsF、NMP-水(9：1)100℃48h
E：CH3COOOH/CH3COOH
产物用LCMS证实，新峰Rf＝12.013,M+＝371。
实施例3
制备化合物Z
A：NH3/MeOH加热回1h
B：光气/THF
C：POCl3、吗啉加热回流5h
D：4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯胺、Pd(Pcy3)2Cl2、CsF、NMP-水(9：1)100℃48h
E：K2S2O8/NaOH/FeSO4 20℃18h
产物用LCMS证实，新峰Rf＝5.951,M+＝476。
实施例4
制备药物洗脱支架(含化合物W)
将300mg化合物W和300mgPLGA混合置于20ml乙酸乙酯中，待溶质完全溶解后，用超声雾化的方式将溶液均匀喷涂在L605钴铬合金金属支架表面，至载药量达到50μg/cm2。室温下待溶剂完全挥发后即制得药物洗脱支架。
实施例5
制备药物洗脱支架(含化合物W与雷帕霉素)
通过摩擦处理使不锈钢裸支架表面形成细微纹痕，将经过微粉化处理后的化合物W与雷帕霉素按照重量比1：1混合均匀，与裸支架置于高压密闭设备内，开启设备，使药物微粒镶嵌于裸支架的细微纹痕之中，待载药量(化合物W和雷帕霉素药量之和)达到25μg/cm2，得到药物洗脱支架。
实施例6
制备药物洗脱支架(含化合物V)
将150mg化合物V和500mgPLA混合置于15ml丙酮中，待溶质完全溶解后，用超声雾化的方式将溶液均匀喷涂在镁合金支架表面，至载药量达到30μg/cm2。室温下待溶剂完全挥发后即制得药物洗脱支架。
实施例7
制备药物洗脱支架(含化合物Z)
将2mg化合物Z和100mgPVP混合置于10ml浓度为75％的乙醇溶液中，待溶质完全溶解后，用超声雾化的方式将溶液均匀喷涂在不锈钢金支架表面，至载药量达到7μg/cm2。室温下待溶剂完全挥发后即制得药物洗脱支架。
实施例8
制备药物球囊(含化合物W-1)
用尼龙球囊制备用于治疗血管狭窄的含有化合物W-1的药物球囊：
W-1的结构式
(1)对尼龙球囊表面进行预处理，采用低温等离子处理，选择氮气，温度-20℃，输出功率为2000W，频率为25Hz，处理时间为30分钟，气压为1Pa；
(2)将聚赖氨酸溶于乙醇中得到60mg/ml溶液，将步骤(1)得到的球囊折翼卷绕，用Hamilton MOD710SYR100μl NR型注射器(东乐自然基因生命科学公司，中国)将上述溶液滴涂于球囊上，自然晾干，得到改性球囊；
(3)将W-1溶于二甲基亚砜/水(体积比为70：30)的混合溶液中配制35mg/ml的W-1溶液，向10ml上述W-1溶液中加入400mg赖氨酸并以10转/分钟搅拌溶解，-5℃环境下放置24小时，过滤得固体，40℃加热60分钟至干燥，得到药物晶体；
(4)在步骤(2)得到的改性球囊表面刷涂步骤(3)得到的药物晶体，称重并重复刷涂5次，1000Pa真空下加热至60℃干燥，折翼卷绕，包装灭菌，得到药物球囊。
经测定，上述备的药物球囊W-1含量为250μg。
实施例9
制备药物洗脱支架(含化合物W-1)
将300mg化合物W-1和300mgPLA混合置于20ml四氢呋喃中，待溶质完全溶解后，用超声雾化的方式将溶液均匀喷涂在L605钴铬合金金属支架表面，至载药量达到50μg/cm2。室温下待溶剂完全挥发后即制得W-1药物洗脱支架。
实施例10
制备药物洗脱支架(含化合物F)
将300mg化合物F和300mgPLA混合置于20ml四氢呋喃中，待溶质完全溶解后，用超声雾化的方式将溶液均匀喷涂在L605钴铬合金金属支架表面，至载药量达到50μg/cm2。室温下待溶剂完全挥发后即制得F药物洗脱支架。
化合物F的结构式
实施例11
药物洗脱支架效果试验
动物实验：
A研究对象：选择巴马小型猪，雄性，月龄1-2月，以诱导饲料配方喂养5个月。诱导饲料配方为：蔗糖30％，牛油15％，胆固醇3％，大豆饼17％，鱼粉5％,玉米20％，小麦次粉5％，捣米糠5％。选择出现高血糖症、高胰岛素血症，并观察到微蛋白尿、尿糖和肾炎等早期糖尿肾病表现的猪作为实验对象。
B实验分组
1、雷帕霉素支架组：动物植入含有雷帕霉素的支架(支架载药量：雷帕霉素140μg/cm2)
2、化合物V支架组：动物植入含有化合物V的支架(支架载药量：100μg/cm2)
3、化合物Z支架组：动物植入含有化合物Z的支架(支架载药量：140μg/cm2)
4、化合物W-1支架组：动物植入含有化合物W-1的支架(支架载药量：140μg/cm2)
5、化合物F支架组：动物植入含有化合物F的支架(支架载药量：140μg/cm2)
C支架植入术
术前3日开始每天喂服阿司匹林和氯吡格雷。术前麻醉动物，使其仰卧固定于手术台，建立静脉通路，气管插管及呼吸机辅助呼吸。冠脉造影局部消毒后，穿刺右股动脉，经穿刺针送入导引导丝，沿导丝送入6F股动脉鞘，经鞘管给以肝素150Ukg。经鞘管送入6F右冠指引导管分别行左右冠脉造影。靶血管选择尽量避开大的血管分支。在体外用压力泵充盈球囊释放支架，待支架完全贴壁并造成损伤后撤出球囊。术后复查造影。撤出导管，拔出股动脉鞘，术区局部加压止血。猪清醒后送回笼中继续喂养。
D实验结果
支架植入后，持续饲养45d。45d后考察损伤部位血管内膜增生情况，测定支架植入出血管内膜(intima)和中膜厚度(media)计算其比值(I/M)ratio，结果见下表。
| 编号 | 实验组 | I/M ratio |
| 1 | 雷帕霉素支架组 | 0.553±0.301 |
| 2 | 化合物V支架组 | 0.427±0.245* |
| 3 | 化合物Z支架组 | 0.487±0.177* |
| 4 | 化合物W-1支架组 | 0.408±0.212* |
| 5 | 化合物F支架组 | 0.355±0.229** |
注：与雷帕霉素支架组比,进行t检验，*P<0.05；**P<0.01
结果表明，本发明所提供的化合物用于药物支架相比于雷帕霉素对于血管增生的抑制作用更有选择性。本类化合物对于血管内膜的抑制比率高于中膜，这使得本类药物在血管中的持续释放在抑制血管壁平滑肌增殖的同时，相对于雷帕霉素能够促进血管内皮化的进程，这样可以促进损伤血管壁的愈合，防止支架内血栓的发生，减少病人术后服用抗血栓和血小板药物的时间。
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。
Claims (5)
1.一种如下式的化合物：
2.一种组合物，其特征在于，所述组合物包括赋形剂和治疗有效量的如权利要求1所述的化合物或其药学上可接受的盐。
3.一种选自于下述的化合物或其药学上可接受的盐在制备抗血管再狭窄的制品中的应用；所述制品为药物或介入医疗器械；所述介入医疗器械选自心脏瓣膜、心脏封堵器、血管支架、球囊、人造血管、导管、起搏器、起搏器导子或除颤器中的一种；
4.一种介入医疗器械，其特征在于，所述介入医疗器械包括含有选自于下述的一种化合物或其药学上可接受的盐的药物释放结构；
5.如权利要求4所述的介入医疗器械，其特征在于，所述介入医疗器械选自心脏瓣膜、心脏封堵器、血管支架、球囊、人造血管、导管、起搏器、起搏器导子或除颤器中的一种。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101014590A (zh) * | 2004-07-09 | 2007-08-08 | 阿斯利康(瑞典)有限公司 | 作为磷脂酰肌醇(pi)3－激酶抑制剂的2,4,6－三取代的嘧啶及其在癌症治疗中的用途 |
| WO2010120994A2 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | Ureidoaryl-and carbamoylaryl-morpholino- pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their synthesis |
-
2016
- 2016-08-31 CN CN201610786956.8A patent/CN107793365B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101014590A (zh) * | 2004-07-09 | 2007-08-08 | 阿斯利康(瑞典)有限公司 | 作为磷脂酰肌醇(pi)3－激酶抑制剂的2,4,6－三取代的嘧啶及其在癌症治疗中的用途 |
| WO2010120994A2 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | Ureidoaryl-and carbamoylaryl-morpholino- pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their synthesis |
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