CN106361752A - 氟哌噻吨的新用途 - Google Patents
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- NJMYODHXAKYRHW-DVZOWYKESA-N cis-flupenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2/1 NJMYODHXAKYRHW-DVZOWYKESA-N 0.000 title claims abstract description 25
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract
本发明属于药物领域,涉及氟哌噻吨的新用途,具体地,涉及氟哌噻吨或其药学上可接受的盐、酯、溶剂合物在制备真核生物肿瘤细胞增殖抑制剂中的应用,以及氟哌噻吨或其药学上可接受的盐、酯、溶剂合物在制备预防和/或治疗肿瘤药物中的应用。氟哌噻吨能通过血脑屏障,有效抑制肿瘤细胞增殖,引发肿瘤细胞死亡,具有潜在的临床应用前景。
Description
技术领域
本发明属于药物领域,具体地,涉及氟哌噻吨的新用途。
背景技术
氟哌噻吨(Flupentixol)是典型抗精神病药物,分子式为C23H25F3N2OS;化学名称为:顺式(Z)-2-[4-[3-(2-三氟甲基噻吨-(9)-丙基)]哌嗪-(1)]乙醇-1-癸酸酯;英文名称为:(EZ)-2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1y]ethanol;化学结构式如式(I)所示:
作为抗精神病药物,氟哌噻吨目前已应用于精神分裂的临床治疗。
随着新药开发难度的加大、开发费用的高昂,世界各地已将药物开发的重点转移到产品的二次开发,如拓展老药的新适应症、开发新剂型等,以期获得新的有效治疗药物。老药经过上市后长时间的大量病例的临床观察,其安全性得到保证,不良反应认识全面,而且价格便宜。老药开发新用途,其临床前及前期临床试验耗费的成本亦可相对节省。因此,研究老药,拓展其新的适应症,不仅极大地促进临床治疗学的发展,也为节约卫生资源和延长老药生命的周期在市场产生重要的价值。
发明内容
本发明的目的是提供氟哌噻吨的新用途。
根据第一方面,本发明提供氟哌噻吨或其药学上可接受的盐、酯、溶剂合物在制备真核生物肿瘤细胞增殖抑制剂中的应用。
其中,所述真核生物优选为哺乳动物。
优选地,所述肿瘤细胞为癌细胞。
优选地,所述癌细胞选自以下任意一种:胶质瘤细胞、白血病细胞、乳腺癌细胞、肺癌细胞、肝癌细胞、卵巢癌细胞、胃癌细胞、食管癌细胞、肠癌细胞、宫颈癌细胞、恶性淋巴瘤细胞和鼻咽癌细胞中的至少一种。
进一步优选地,所述癌细胞为人乳腺癌细胞SUM159和/或人胶质瘤细胞U-118MG。
根据第二方面,本发明提供氟哌噻吨或其药学上可接受的盐、酯、溶剂合物在制备预防和/或治疗肿瘤药物中的应用。
所述治疗和/或预防肿瘤药物可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹后导入机体。
其中,所述肿瘤优选为癌。
优选地,所述癌为脑瘤、白血病、乳腺癌、肺癌、肝癌、卵巢癌、胃癌、食管癌、肠癌、宫颈癌、恶性淋巴瘤和鼻咽癌中的至少一种。
进一步优选地,所述肿瘤为颅内原发肿瘤或转移瘤。
需要的时候,在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
用氟哌噻吨或其药学上可接受的盐、酯、溶剂合物为活性成分制备颅内原发肿瘤和转移瘤治疗药物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明经过多种细胞系测试证明氟哌噻吨是一种潜在的抗肿瘤药物。以氟哌噻吨作为抗肿瘤药物尤其是针对脑肿瘤具有以下两个优点:(1)临床上使用的大部分药物很难突破血脑屏障,因而对颅内疾病很难发挥作用,而氟哌噻吨作为抗精神病药物可透过血脑屏障,因此可作用于颅内原发瘤或转移瘤。(2)由于氟哌噻吨作为抗精神病药物已经上市,因此作为抗肿瘤制剂,可以大大降低临床前研究中的研究成本,节约资源、缩短研发周期。所有实验数据证明氟哌噻吨能通过血脑屏障,有效抑制肿瘤细胞增殖,引发肿瘤细胞死亡,具有潜在的临床应用前景。
具体实施方式
以下对本发明的具体实施方式进行详细描述。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不用于限制本发明。
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和生物材料,如无特殊说明,均可从商业途径获得。体外细胞增殖抑制实验采用MTT法,以下面2种代表细胞系为例:人乳腺癌细胞SUM159和人胶质瘤细胞U-118MG,以上细胞株均从凯基生物公司购买获得。
实施例1
检测氟哌噻吨对肿瘤细胞增殖抑制活性。
1、SUM159用含体积分数为10%胎牛血清的DMEM-F12培养液,附加5ug/ml胰岛素,1μg/ml氢化可的松,在37℃、体积分数为5%的CO2条件下常规培养。
2、U-118MG用含体积分数为10%的胎牛血清的DMEM培养液,在37℃、体积分数为5%的CO2条件下常规培养。
3、取对数生长期的细胞,接种于96孔板中,密度是5×I03个/ml,99μl/孔,每孔加入氟哌噻吨溶液1μl,使药物作用终浓度为0.5,1,5,10,25,50μΜ。每组设五个复孔,并且设置阳性对照和空白对照。作用48h后加入MTT溶液,10μl/孔,继续培养4小时后,2000rpm,4℃,离心5分钟,吸去上清后加入DMSO,100μl/孔,37℃保温约10分钟,并用微量振荡器振荡约5分钟使结晶溶解完全,用酶标仪于490nm处测量OD值,按如下公式计算细胞增殖抑制率(Inhibition Rate,IR%):
IR%=[(对照OD-空白OD)-(样品OD-空白OD)]/(对照OD-空白OD)×100%
经计算,氟哌噻吨对乳腺癌细胞和脑胶质瘤细胞的半数抑制剂量IC50见表1。
表1
由表1数据可以看出,氟哌噻吨对乳腺癌细胞和脑胶质瘤细胞的增殖具有明显的抑制作用。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (10)
1.氟哌噻吨或其药学上可接受的盐、酯、溶剂合物在制备真核生物肿瘤细胞增殖抑制剂中的应用。
2.根据权利要求1所述的应用,其中,所述真核生物为哺乳动物。
3.根据权利要求1所述的应用,其中,所述肿瘤细胞为癌细胞。
4.根据权利要求3所述的应用,其中,所述癌细胞选自以下任意一种:胶质瘤细胞、白血病细胞、乳腺癌细胞、肺癌细胞、肝癌细胞、卵巢癌细胞、胃癌细胞、食管癌细胞、肠癌细胞、宫颈癌细胞、恶性淋巴瘤细胞和鼻咽癌细胞中的至少一种。
5.根据权利要求4所述的应用,其中,所述癌细胞为人乳腺癌细胞SUM159和/或人胶质瘤细胞U-118MG。
6.氟哌噻吨或其药学上可接受的盐、酯、溶剂合物在制备预防和/或治疗肿瘤药物中的应用。
7.根据权利要求6所述的应用,其中,所述肿瘤为癌。
8.根据权利要求7所述的应用,其中,所述癌为脑瘤、白血病、乳腺癌、肺癌、肝癌、卵巢癌、胃癌、食管癌、肠癌、宫颈癌、恶性淋巴瘤和鼻咽癌中的至少一种。
9.根据权利要求7所述的应用,其中,所述肿瘤为颅内原发肿瘤或转移瘤。
10.根据权利要求6所述的应用,其中,所述药物包括一种或多种药学上可接受的载体。
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