CN102241646B - 己烯酮类化合物及其医药用途 - Google Patents
己烯酮类化合物及其医药用途 Download PDFInfo
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- CN102241646B CN102241646B CN201010172482.0A CN201010172482A CN102241646B CN 102241646 B CN102241646 B CN 102241646B CN 201010172482 A CN201010172482 A CN 201010172482A CN 102241646 B CN102241646 B CN 102241646B
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Classifications
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/194—Radicals derived from thio- or thiono carboxylic acids
Landscapes
- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
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Abstract
本发明涉及通式I化合物,或其异构体、可药用盐及溶剂化物;本发明还涉及包含通式I化合物或其异构体、可药用盐及溶剂化物,以及药学上可接受的载体、赋形剂或稀释剂的组合物;本发明还涉及通式I化合物,或其异构体、可药用盐及溶剂化物,用于抗细胞凋亡、预防或治疗与细胞凋亡有关的疾病或症状的用途;特别是用于保护心肌细胞和预防或治疗与心肌细胞凋亡有关的疾病或症状中的用途。
Description
技术领域
本发明涉及医药化学领域,具体地,本发明涉及己烯酮类化合物及其药物组合物,本发明还涉及所述化合物及其药物组合物用于抗细胞凋亡,预防或治疗与细胞凋亡有关的疾病或症状的用途,特别是用于保护心肌细胞和预防或治疗与心肌细胞凋亡有关的疾病或症状中的用途。
背景技术
细胞凋亡一般是指机体细胞在发育过程中或在某些因素作用下,通过细胞内基因及其产物的调控而发生的一种程序性细胞死亡。细胞凋亡普遍存在于生物界,既发生于生理状态下,也发生于病理状态下。对胚胎发育及形态发生、组织内正常细胞群的稳定、机体的防御和免疫反应、疾病或中毒时引起的细胞损伤、老化、肿瘤的发生进展起着重要作用,一直是生物医学研究的热点。
研究表明,有很多重大疾病的发生都与细胞过度凋亡有关,例如在艾滋病的发展过程中,CD4+T细胞数目的减少;移植排斥反应中,细胞毒性T细胞介导的细胞死亡;缺血及再灌注损伤,心肌细胞和神经细胞的凋亡;神经系统退化性疾病(如阿尔海默次病、帕金森氏症等);暴露于电离辐射引起的多种组织细胞凋亡等。
有证据表明,心肌细胞凋亡与许多心脏疾病的发生、发展和预后有着密切的关系。通过研究心肌细胞凋亡发现梗死的心肌死亡不等于心肌坏死,凋亡是心肌梗死的机制之一,而且是梗死早期心肌死亡及缺血/再灌注所致的心肌死亡的主要方式,此时心肌的大量凋亡,加重了心肌的破坏。1989年,Nepomniashchikh等观察饥饿性心肌萎缩超微结构时发现,心肌细胞结构蛋白合成降低,细胞数减少,但不伴细胞核相应成比例地减少,由此初步提出饥饿性心肌萎缩是由细胞凋亡所致。1994年,Gottlieb和Kawano等采用电镜结合DNA凝胶电泳方法取得了心肌细胞凋亡的直接证据,前者揭示再灌注损伤诱发兔心肌细胞凋亡,后者证实心肌炎患者伴发心肌细胞凋亡。Tanaka等培养的乳鼠心肌细胞中,也证明了凋亡的存在。由于方法学的进步和凋亡的研究深入,已在多种心脏病中发现心肌细胞凋亡的病理作用。研究表明,自发性高血压小鼠(SHR)心脏损害与凋亡有关;晚期由肥厚心脏转向心力衰竭为心肌细胞凋亡所致;急性心梗除坏死外,梗塞早期和再灌注损伤也诱发凋亡;心肌细胞凋亡同样见于移植的心脏和右室发育不良性心肌病,缺氧同样诱导心肌细胞凋亡。
凋亡在某种程度上具有可复性,心肌梗死和缺血/再灌注中的细胞凋亡有其特点和规律,利用其特点可以预防和减少细胞凋亡,为临床预防缺血/再灌注损伤提供启示;在再灌注过程中,产生收缩带区域(梗死灶周围)的细胞凋亡是由一些诱因诱导产生的,可以利用凋亡的抑制因素如药物等来预防凋亡,治疗凋亡引起的相应疾病。
但目前可供临床应用的用于抗细胞凋亡和保护细胞的药物种类和数量还很少,选择性和靶向性都不高,因此不断研究开发新的安全有效的抗细胞凋亡和保护细胞的药物,尤其是具有全新作用机制的药物具有十分重要的意义。
发明内容
为了开发新的安全有效的抗细胞凋亡和保护细胞的药物,发明人经过长期、大量的实验研究,发现了一类己烯酮类化合物,其具有抗细胞凋亡,保护心肌细胞的作用,能够用于预防或治疗与心肌细胞凋亡有关的疾病或症状。具体地,
本发明的第一方面涉及通式I所示的化合物,或其异构体、可药用盐及溶剂化物。
其中
A代表=S、-SR4或=O;
X代表F、Cl、Br或I;
R1代表苯基、苯基-C1-C6烷基-、其中所述的苯基未被取代或被1-4个(例如1-2个、1个、2个、3个或4个)独立地选自下列的取代基取代:卤素、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、和C1-C6卤代烷基,并且其中所述的烷基、烷氧基和卤代烷基可以任选被羟基、-O-(C1-C4)-烷基、氧代、氨基、-NH-(C1-C4)-烷基、或-N-[(C1-C6)-烷基]2所取代,或者所述的烷基、烷氧基和卤代烷基任选被-O-、-S-、-NH-、-COO-、或-CONH-所间隔;五元或六元杂环或取代杂环;其中所述的杂环未被取代或被1-3个(例如1-2个、1个、2个、或3个)独立地选自下列的取代基取代:卤素、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、和C1-C6卤代烷基,并且其中所述的烷基、烷氧基和卤代烷基可以任选被羟基、-O-(C1-C4)-烷基、氧代、氨基、-NH-(C1-C4)-烷基、或-N-[(C1-C6)-烷基]2所取代,或者所述的烷基、烷氧基和卤代烷基任选被-O-、-S-、-NH-、-COO-、,所述杂环可以为氮氮杂环、氮氧杂环、氮硫杂环;
R2、R3代表氢、C1-C6烷基、C3-C6环烷基、取代C3-C6环烷基、C1-C6烷氧基C1-C6烷基、氨基C1-C6烷基、单取代或二取代氨基C1-C6烷基、苯基C1-C6烷基、取代苯基C1-C6烷基、杂环基C1-C6烷基、取代杂环基C1-C6烷基、苯基、取代苯基、C1-C6杂环基或取代C1-C6杂环基,其中R2和R3可以合环;
R4代表C1-C6烷基。
优选如下的通式(I)化合物,或其异构体、可药用盐及溶剂化物,其中:
A代表=S、-SR4或=O;
X代表F、Cl、Br或I;
R1代表苯基、苯基-C1-C6烷基-、其中所述的苯基未被取代或被1-4个(例如1-2个、1个、2个、3个或4个)独立地选自下列的取代基取代:卤素、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、和C1-C6卤代烷基,并且其中所述的烷基、烷氧基和卤代烷基可以任选被羟基、-O-(C1-C4)-烷基、氧代、氨基、-NH-(C1-C4)-烷基、或-N-[(C1-C6)-烷基]2所取代,或者所述的烷基、烷氧基和卤代烷基任选被-O-、-S-、-NH-、-COO-、或-CONH-所取代;噻吩基、噻唑基、其中所述的噻吩基、噻唑基未被取代或被1-3个(例如1-2个、1个、2个、或3个)独立地选自下列的取代基取代:卤素、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、和C1-C6卤代烷基,并且其中所述的烷基、烷氧基和卤代烷基可以任选被羟基、-O-(C1-C4)-烷基、氧代、氨基、-NH-(C1-C4)-烷基、或-N-[(C1-C6)-烷基]2所取代,或者所述的烷基、烷氧基和卤代烷基任选被-O-、-S-、-NH-、-COO-;
R2、R3代表氢、C1-C6烷基、C3-C6环烷基、取代C3-C6环烷基、C1-C6烷氧基C1-C6烷基、氨基C1-C6烷基、单取代或二取代氨基C1-C6烷基、苯基C1-C6烷基、取代苯基C1-C6烷基、杂环基C1-C6烷基、苯基、取代苯基、杂环基或取代杂环基,其中R2和R3可以合环成饱和环烷烃、含氮或含氧杂环;
R4代表甲基、乙基、丙基、异丙基、丁基或戊基。
特别优选如下的通式(I)化合物,或其异构体、药用盐及溶剂化物,其中:
A代表=S、-SR4或=O;
X代表Cl;
R1代表苯基或2-噻吩基;
R2、R3代表氢、甲基、异丙基、2-甲氧基乙基、3-异丙氧基丙基、2-N,N-二甲基乙基、环己基、环庚基、邻甲氧基苯基、邻氟苯基、邻氯苯基、对氯苯基、苄基或8-喹啉基,其中R2和R3可以合环成哌啶环、吗啉环或N-甲基哌嗪环;
R4代表甲基或乙基。
通式(I)化合物,或其异构体、可药用盐及溶剂化物,特别优选下面的化合物:
(1E)-1-苯基-5-(1-吗啉基硫代甲酰氨基)-6,6,6-三氯-1-烯-3-己酮。
本发明通式(I)化合物可通过下述方法制备:
以化合物(1)为例,本发明化合物以苯甲醛为起始原料,与丙酮在氢氧化钠的甲醇溶液中反应生成(1E)-1-苯基1-烯-3-丙酮,再经过LDA催化下与三氯乙醛反应,得到中间体1,经过氯化亚砜氯代,再与硫氰酸钾反应生成中间体2,最后与吗啉在四氢呋喃中回流得到化合物(1)。
本发明另一方面涉及药物组合物,其包含通式(I)所示化合物,或其异构体、可药用盐及溶剂化物,以及药学上可接受的载体、赋形剂或稀释剂。
本发明还涉及第一方面所述通式(I)化合物或其异构体、可药用盐及溶剂化物,用于制备抗细胞凋亡,预防或治疗与细胞凋亡有关的疾病或症状的药物的用途。
本发明还涉及第一方面所述通式(I)化合物或其异构体、可药用盐及溶剂化物,用于制备保护心肌细胞和预防或治疗与心肌细胞凋亡有关的疾病或症状的药物的用途。
本发明还涉及一种抗细胞凋亡、预防或治疗与细胞凋亡有关的疾病或症状的方法,所述方法包括向有此需要的受试者给予治疗有效量的本发明第一方面所述通式(I)化合物或其异构体,可药用盐及溶剂化物。
本发明还涉及一种保护心肌细胞、预防或治疗与心肌细胞凋亡有关的疾病或症状的方法,所述方法包括向有此需要的受试者给予治疗有效量的本发明第一方面所述通式(I)化合物或其异构体,可药用盐及溶剂化物。
本发明所述与细胞凋亡有关的疾病或症状包括:心血管疾病,神经退行性疾病,多发性硬化症,病毒性感染等。
本发明所述与心肌细胞凋亡有关的疾病或症状包括但不限于(i)饥饿性心肌萎缩,(ii)心肌炎,(iii)心力衰竭,(iv)原发性高血压引起的心肌损伤,(v)急性心梗早期引起的心肌损伤,(vi)急性心梗再灌注引起的心肌损伤,(vii)心脏移植引起的心肌细胞病变,(viii)发育不良性心肌病;或缺氧引起的心肌细胞凋亡,或心血管系统硬化。
根据本发明,术语“杂环”包括但不限于:吡啶、吡咯、呋喃、噻吩、吡唑、咪唑、噻唑、唑、异唑、吲哚、苯并呋喃、苯并咪唑、咔唑、哒嗪、嘧啶、吡嗪、喹啉、异喹啉、嘌呤、吩噻嗪、吩嗪。
本领域技术人员应该认识到通式I化合物存在手性中心。当需要通式I化合物为单一的对映体时,可以使用在所有可能的步骤中均处于单一对映异构体形式的反应物来制备,或者在单一对映异构体形式的试剂或催化剂的存在下进行反应来制备,或者通过常规方法拆分立体异构体混合物来制备。一些优选的方法包括使用微生物进行拆分,拆分与手性酸如扁桃酸、樟脑磺酸、酒石酸、乳酸等任何可使用的酸形成的非对映异构体的盐,或者拆分与手性碱如番木鳖碱(bracine)、金鸡纳树生物碱及其衍生物等形成的非对映异构体的盐。常用的方法见Jaques等人编辑的“Enantiomers,Racemates and Resolution”(Wiley Interscience,1981)。
本领域技术人员应该意识到,本发明化合物也可以以其可药用盐或溶剂化物的形式使用。通式I化合物的生理学上可接受的盐包括由药学上可接受的无机酸或有机酸或者无机碱或有机碱形成的常规的盐以及季铵的酸加成盐。合适的酸盐的更具体的例子包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、steroic、鞣酸等的盐。其它的酸,如草酸,虽然其本身并非药学上可接受的,但可以用于制备用作中间体的盐,以获得本发明化合物及其可药用盐。合适的碱盐的更具体的例子包括钠、锂、钾、镁、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因盐。此后涉及到本发明的化合物时,包括通式I化合物及其可药用盐和溶剂化物。
本发明还包括本发明化合物的前药,该前药一经给药,即通过代谢过程进行化学转化,之后变成具有活性的药物。通常,这类前药是本发明化合物的功能性衍生物,其在体内容易转化成所需的式(I)的化合物。例如,在“Design Of Prodrugs”,H Bund Saard,E1sevier编辑,1985中描述了选择和制备适宜前药衍生物的常规方法。
本发明也包括本发明化合物的活性代谢物。
本发明的另一个方面涉及药物组合物,其含有本发明化合物的消旋体或旋光异构体和至少一种药学上可接受的载体,其可用于体内治疗并具有生物相容性。所述药物组合物可以根据不同给药途径而制备成各种形式。本发明所提及的化合物也可以被制备成各种药学可接受的盐。
本发明的药物组合物包括有效剂量的本发明通式I化合物或其可药用盐或水合物和一种或多种适宜的可药用载体。这里的药用载体包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂。
本发明化合物的药物组合物可以以下面的任意方式施用:口服,喷雾吸入,直肠用药,鼻腔用药,颊部用药,局部用药,非肠道用药,如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入,或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。
当口服用药时,本发明化合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体一般包括乳糖和玉米淀粉,另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当局部用药时,特别是治疗局部外敷容易达到的患面或器官,如眼睛、皮肤或下肠道神经性疾病时,可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式,具体说明如下:
当眼部局部施用时,本发明化合物可配制成一种微粉化悬浮液或溶液的制剂形式,所使用载体为等渗的一定pH的无菌盐水,其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用,也可将化合物制成膏剂形式如凡士林膏。
当皮肤局部施用时,本发明化合物可制成适当的软膏、洗剂或霜剂制剂形式,其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于:矿物油,液体凡士林,白凡士林,丙二醇,聚氧化乙烯,聚氧化丙烯,乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油,脱水山梨糖醇单硬脂酸酯,吐温60,十六烷酯蜡,十六碳烯芳醇,2-辛基十二烷醇,苄醇和水。
本发明化合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液或无菌注射溶液。其中,可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
另外需要指出,本发明化合物的使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。
发明的有益效果
本发明提供了一种己烯酮类化合物,并证明其具有抗细胞凋亡和保护细胞的作用,为治疗细胞凋亡引起的疾病或症状,特别是治疗心肌细胞凋亡引起的疾病或症状提供了新的方法和途径。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
化合物的熔点由RY-1熔点仪测定,温度计未较正。质谱由Micromass ZabSpec高分辨率质谱仪(分辨率1000)测定。1H NMR由JNM-ECA-400超导NMR仪测定,工作频率1H NMR 400MHz,13C NMR 100MHz。
实施例1(1E)-1-苯基-5-(1-吗啉基硫代甲酰氨基)-6,6,6-三氯-1-烯-3-己酮
将丙酮3ml加入10%NaOH水溶液4.80g中,30℃搅拌5分钟,滴入苯甲醛1ml,室温搅拌3小时。反应液分层,取有机层用展开剂石油醚∶乙酸乙酯=20∶1洗脱,得黄色晶体(1E)-1-苯基-1-烯-3-丁酮1.00g。氮气保护下将二异丙胺0.64g溶于10ml THF中,降温至-40℃,滴入正丁基锂0.40g,搅拌30分钟再降温至-78℃,将(1E)-1-苯基-1-烯-3-丁酮0.84g溶于15mlTHF中,滴入LDA溶液中,-78℃反应40分钟,将三氯乙醛1.19g溶于15mlTHF中,滴入上述反应液,-78℃反应12小时。升温至-40℃滴入20ml饱和NH4Cl水溶液,搅拌30分钟,升至室温加入20ml乙酸乙酯萃取,将有机层用展开剂石油醚∶乙酸乙酯=6∶1洗脱,得淡黄色晶体(1E)-1-苯基-5-羟基-6,6,6-三氯-1-烯-3-己酮1.49g。将其溶于20mlTHF中加入氯化亚砜1.1ml回流6小时,将反应溶剂蒸干,残余物溶于20ml丙酮中再加入0.74gKSCN,40℃搅拌1.5小时,停止反应后用展开剂石油醚∶乙酸乙酯=30∶1洗脱,得淡黄色固体(1E)-1-苯基-5-异硫氰酸基-6,6,6-三氯-1-烯-3-己酮1.2g。取0.33g与0.06ml吗啉在THF中回流1小时,析出白色固体,用THF重结晶得纯品0.10g。1H-NMR(400MHz,DMSO-d6)δ3.28-3.43(m,4H);δ3.46-3.58(m,4H);δ3.68-3.74(m,2H);δ3.81-3.87(m,2H);δ6.27-6.29(m,1H);δ7.02-7.06(d,1H);δ7.43-7.46(t,3H);δ7.60-7.64(d,1H);δ7.21-7.74(m,2H);δ8.03-8.05(d,1H)。MS(TOF)421.7(M+)。
实施例2化合物保护心肌细胞活性实验
心肌细胞原代培养
心肌细胞的分离和培养参照差速贴壁分离的方法(Kreider,A.Messing,H.Doan,S.U.Kim,R.P.Lisak and D.E.Pleasure,Enrichment of Schwann cell cultures from neonatal rat sciaticnerve by differential adhesion,Brain Res 2(1981),pp.433444.),取24h内新生的Wistar乳鼠,经碘酒酒精消毒胸腹部皮肤,用剪刀在剑突下正中线稍偏左开胸,斜开胸取出心脏置于冰预冷PBS中;用0.01M的PBS轻轻吹打心脏去除血液细胞和其他组织,将心脏剪成0.5mm3大小的碎块,用0.01M PBS反复冲洗2-3次;将碎块置于锥形瓶中,加入4ml 0.125%胰酶,1ml 0.1%胶原酶II(终浓度分别为0.1%和0.02%)37℃水浴震荡10min,弃上清;再次加入4ml 0.125%胰酶,1ml0.1%胶原酶II,37℃水浴震荡消化10min,吸取上清移至离心管,将上清加入含10%FBS的DMEM终止消化;重复水浴震荡消化步骤3-4次,直至组织块完全消化为止;将收集的细胞悬液以1000rpm离心10min后,去上清,再加培养基重悬;将重悬的细胞接种到细胞培养瓶中,置于37℃CO2孵箱中孵育1.5h后将培养液吸出,在显微镜下计数后,用含10%FBS的DMEM培养液调整细胞密度,按1×104接种到96孔板,置于37℃5%CO2孵箱中24h后半量换液,补加含0.1%Brdu的培养基;之后每48h后换液1次,培养4天后即可获得原代心肌细胞。
细胞抑制率(MTT)测定
将分离的原代培养心肌细胞按照每孔104个细胞接种到96孔板,每孔体积100ul(边缘孔用无菌PBS填充)。在5%CO2,37℃孵箱培养4d后,分别加入不同浓度的通式I化合物(0.3μM、1μM、3μM、10μM、30μM、100μM),每个浓度设置3个复孔,同时设置调零孔(培养液、MTT、DMSO),对照孔(培养液、DMSO)。继续孵育处理48h后,每孔加入20ulMTT溶液(5mg/ml,用PBS(pH=7.4)配即0.5%MTT),继续培养4h。终止培养,小心吸去孔内培养液。每孔加入150ulDMSO,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪于波长550nm处测定各孔吸光度(OD)值,每孔重复5次并记录结果。结果见表1。
表1MTT法检测不同浓度化合物对心肌细胞存活率的影响
组别 | 心肌细胞抑制率(%) |
对照组 | 100 |
实施例1化合物 | |
100μM组 | 2.91±1.88 |
300μM组 | 0.76±0.42 |
结果表明:实施例1化合物在300μM浓度内对正常心肌细胞的存活率没有影响。
保护心肌细胞活性测定-保护由TG诱导的心肌细胞凋亡活性
心肌细胞按照上述方法原代培养4天开始加毒胡萝卜内酯(thapsigargin,TG)诱导细胞凋亡,在诱导细胞凋亡前30min加本发明化合物进行预处理。细胞随机分成5组:(1)溶剂对照组(DMSO);(2)TG干预组(0.4uM);(3)TG(0.4uM)+化合物干预组(0.3uM);(4)TG(0.4uM)+化合物干预组(1uM);(5)TG(0.4uM)+化合物干预组(3uM)。TG用DMSO配制,母液为4mM,本发明化合物用DMSO配制,母液为150mM。按照上述MTT法测定细胞存活率,从而测定本发明化合物对TG诱导心肌细胞凋亡的保护作用,结果见表2。
表2MTT法检测不同浓度化合物对TG诱导的心肌细胞存活率的影响
组别 | 心肌细胞存活率(%) |
对照组 | 100 |
TG干预组 | 59±1.1 |
实施例1化合物 | |
0.3μM组 | 76.3±7.6 |
1μM组 | 83.3±7.1 |
10μM组 | 92.2±5.6 |
注:细胞存活率=1-细胞抑制率
实验结果:与单加入TG组相比,在同时加入TG和实施例化合物时,心肌细胞存活率有明显提高,表明表2中所述实施例化合物能够明显改善TG引起的细胞凋亡作用,对心肌细胞具有保护作用。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (6)
2.通式I化合物,或其可药用盐,其中
A代表=S或=O;
X代表Cl;
R1代表苯基;
R2和R3合环成吗啉环。
3.具有下述结构的权利要求1的化合物,或其可药用盐:
(1)(1E)-1-苯基-5-(1-吗啉基硫代甲酰氨基)-6,6,6-三氯-1-烯-3-己酮。
4.药物组合物,其包含权利要求1-3任一项所述化合物或其可药用盐,以及药学上可接受的载体、赋形剂或稀释剂。
5.权利要求1-3任一项所述化合物或其可药用盐用于制备抗细胞凋亡、预防或治疗与细胞凋亡有关的疾病或症状的药物的用途。
6.权利要求1-3任一项所述化合物或其可药用盐用于制备保护心肌细胞、预防或治疗与心肌细胞凋亡有关的疾病或症状的药物的用途。
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