CN101754758B - 一种用于治疗阿尔茨海默氏症的包含喹诺酮衍生物和多奈哌齐的药物 - Google Patents
一种用于治疗阿尔茨海默氏症的包含喹诺酮衍生物和多奈哌齐的药物 Download PDFInfo
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- alzheimer
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Abstract
本发明涉及一种用于治疗阿尔茨海默氏症的药物，其含有下列通式的喹诺酮衍生物或其盐和多奈哌齐或其盐作为活性成分，其中A为低级亚烷基，R为环烷基，在喹诺酮骨架的3-和4-位之间的键是单键或双键。
Description
技术领域
本发明涉及一种用于治疗阿尔茨海默氏症的药物，特别是含有下列通式的喹诺酮衍生物或其盐和多奈哌齐或其盐作为活性成分的用于治疗阿尔茨海默氏症的药物：
其中A为低级亚烷基，R为环烷基，喹诺酮骨架的3-和4-位之间的键是单键或双键。
背景技术
式(1)的喹诺酮衍生物或其盐和其制备方法被公开于JP-63-20235-B和JP-55-35019-A中。并且已知喹诺酮衍生物(1)具有血小板聚集抑制作用、磷酸二酯酶(PDE)抑制作用、抗溃疡、降血压作用和抗炎作用，可以用作抗血栓形成药物、用于改善脑循环的药物、抗炎药物、抗溃疡药物、抗高血压药物、抗哮喘药物、磷酸二酯酶抑制剂等。此外，已知这类化合物也可用作治疗过敏性疾病的药物(JP-5-320050-A)。还已知喹诺酮衍生物(1)是用于治疗阿尔茨海默氏症的药物(JP-2006-518732-A)。
在日本，患有痴呆的患者数估计为1,890,000人，2005年其患病率估计为7.6％，并且患病人数和患病率都会随着社会老龄化的进展而日益增长。可以理解患有阿尔茨海默氏症(AD)的患者数占痴呆患者总数的一半以上。
大部分的AD被认为是散发病例，但是包括大约10％的家族性AD，由于基因例如淀粉样前体蛋白基因、早老素-1和早老素-2的错义突变，其发作伴有常染色体显性遗传。特别地，女性更易罹患AD。AD最重要的危险因素是衰老。AD的患病率随年龄增长而增加，因此大部分的AD是迟发性AD，其在65岁时或65岁后发作。AD患者会表现出不同的病理学状态，取决于神经递质例如乙酰胆碱的紊乱、大脑内淀粉样β蛋白蓄积造成的老年斑的形成、含有磷酸化的π和其他物质的不正常纤丝的神经元内蓄积、通过脱落神经细胞造成的大脑严重萎缩等。AD的核心症状包括记忆损伤、失语症、认知损伤、执行功能紊乱和相关症状；它们中的很多都是精神愉快的。然而，一些AD的症状表现出相反的情况，例如缺乏动力、抑郁、坏情绪、从发作开始的坏脾气。
盐酸多奈哌齐(商品名：安理申)在临床实践中被广泛应用于治疗AD的主要症状(JP-2578475-B)。对于相关症状，例如失眠、坏脾气和妄想症，盐酸多奈哌齐也可用作姑息治疗(Japanese Journal of Psychiatric Treatment，第21卷，增刊，第302-305页，2006年10月15日，Tsuneyoshi Ohta，Heii Arai)。但是，盐酸多奈哌齐姑息治疗的作用在长期使用时容易下降。因此，由于该药物需要被长期给药，盐酸多奈哌齐也具有难以持续和充分抑制病情发展的问题。
发明的公开
如上所述，盐酸多奈哌齐(商品名：
)已经被广泛地用作治疗阿尔茨海默氏症的药物，但是，仍然需要开发治疗阿尔茨海默氏症的更有效的药物，其能够抑制在长期给药时盐酸多奈哌齐治疗效果的降低。
本发明人已经深入研究了一种新的用于治疗阿尔茨海默氏症的药物，并且发现了上述式(1)的喹诺酮衍生物，特别是6-[4-(1-环己基-1H-四唑-5-基)丁氧基]-3，4-二氢喹诺酮(西洛他唑)或其盐与多奈哌齐或其盐的组合或药物组合，对于治疗阿尔茨海默氏症表现出极好的协同作用，从而完成了本发明。特别地，本发明人已发现本发明的组合表现出极好的改善由于盐酸多奈哌齐长期给药而降低的盐酸多奈哌齐活性的作用。此外，本发明的组合或药物组合表现出快速起效和低毒性，因此它可以被长期给药。从安全性的角度考虑，本发明也是治疗阿尔茨海默氏症的有用药物。
本发明提供一种用于治疗阿尔茨海默氏症的药物，其含有下列通式的喹诺酮衍生物或其盐和多奈哌齐或其盐作为活性成分：
其中A为低级亚烷基，R为环烷基，在喹诺酮骨架的3-和4-位之间的键是单键或双键。
本发明还提供一种用于治疗阿尔茨海默氏症的药物，含有6-[4-(1-环己基-1H-四唑-5-基)丁氧基]-3，4-二氢喹诺酮(西洛他唑)或其盐与多奈哌齐或其盐作为活性成分。
本发明还提供一种用于治疗阿尔茨海默氏症的药物，含有喹诺酮衍生物(1)和盐酸多奈哌齐作为活性成分。
本发明还提供一种含有上述活性成分的用于治疗阿尔茨海默氏症的组合物。
本发明还提供喹诺酮衍生物(1)或其盐和多奈哌齐或其盐在制备用于治疗阿尔茨海默氏症的药物中的应用。
本发明还提供用于治疗阿尔茨海默氏症的方法，包括给予需要这种治疗的患者有效量的喹诺酮衍生物(1)或其盐和多奈哌齐或其盐。
根据本发明，喹诺酮衍生物(1)，特别是6-[4-(1-环己基-1H-四唑-5-基)丁氧基]-3，4-二氢喹诺酮或其盐与多奈哌齐的组合对于阿尔茨海默氏症表现出有效的治疗和预防作用。
附图简述
图1表示以组合形式一起使用盐酸多奈哌齐和西洛他唑对阿尔茨海默氏症的治疗效果。
实施本发明的最佳方式
包含在药物组合或以与多奈哌齐或其盐组合方式使用的喹诺酮衍生物是下列通式的四唑烷氧基二氢喹诺酮衍生物或其盐：
其中A为低级亚烷基，R为环烷基，在喹诺酮骨架的3-和4-位之间的键是单键或双键。
在上述式(1)中，环烷基包括C3-C8环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。优选的环烷基是环己基。低级亚烷基包括C1-C6亚烷基，例如亚甲基、亚乙基、亚丙基、四亚甲基、亚丁基和亚戊基，其中优选的是四亚甲基。
优选的喹诺酮衍生物是6-[4-(1-环己基-1H-四唑-5-基)丁氧基]-3，4-二氢喹诺酮，它已经作为抗血小板药物以商品名西洛他唑被投入了市场。
可以通过用药学上可接受的酸处理将喹诺酮衍生物(1)容易地转化为它的盐。所述的酸包括，如，无机酸例如盐酸、硫酸、磷酸和氢溴酸；有机酸例如草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸和苯甲酸。
这些喹诺酮衍生物(1)及其盐和其制备方法被公开于JP-55-35019-A中(与美国专利4,277,479相关)。
另一活性成分是多奈哌齐，其化学名是1-苯甲基-4-[(5，6-二甲氧基茚满-1-酮)-2-基]甲基哌嗪。其盐酸盐已经作为治疗阿尔茨海默氏症的药物被投入了市场(盐酸多奈哌齐，商品名：
)。该化合物被公开于JP-2578475-B中。可以使用药学上可接受的酸将本发明的1-苯甲基-4-[(5，6-二甲氧基茚满-1-酮)-2-基]甲基哌嗪容易地转化为其盐的形式。所述的酸包括，如，无机酸例如盐酸、硫酸、磷酸和氢溴酸；有机酸例如草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸和苯甲酸。其中，其盐酸盐，盐酸多奈哌齐是优选的。
这些活性成分，喹诺酮衍生物(1)或其盐和多奈哌齐或其盐可以同时地或在不同的时间被一起或分开给药。这些成分通常可以被用于常规的药物制剂中。然后，这些成分可以被制成单一剂型或分开的剂型。
含有本发明的喹诺酮衍生物(1)或其盐和多奈哌齐或其盐的药物适用于包括阿尔茨海默氏症在内的普通痴呆病症。因此，本发明药物的应用包括认知损伤，例如阿尔茨海默型痴呆、老年性痴呆和早发性痴呆，以及亨廷顿氏症、皮克病、迟发性运动障碍等。
这些活性成分的剂量不限于特定的范围。喹诺酮衍生物(1)或其盐可以以每个成年人(50kg体重)50-200mg/天的量被使用，每天一次或者每天两次到数次被给药。多奈哌齐可以以每个成年人(50kg体重)大约0.1-300mg/天，优选大约1-10mg/天的量被使用，通常每天被给药一到四次。当这些组分被制成单一剂型时，它们以每1重量份的喹诺酮衍生物(1)或其盐0.025-1.0重量份的多奈哌齐的比例被混合。并且，该药物组合可以包括占制剂的0.1-70％(w/w)的这些成分的总和，但不限于此。
用于本发明的药物组合或组合的每种剂型包括，例如，JP-10-175864-A中例举的剂型，和一般的口服固体剂型，如片剂和胶囊，口服液体剂型，如糖浆和酏剂，非肠道剂型，如注射剂和吸入剂。
本发明的制剂，例如片剂、胶囊、用于口服给药的液体可以通过常规方法被制备。片剂可以通过将活性成分和常规的药用载体，如明胶、淀粉、乳糖、硬脂酸镁、滑石粉、阿拉伯胶等混合来制备。胶囊可以通过将活性成分和惰性药学赋形剂或稀释剂混合并且用混合物填装硬胶囊或软胶囊来制备。口服液体制剂，例如糖浆和酏剂可以通过将活性成分和甜味剂(如蔗糖)、防腐剂(如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯)、着色剂、调味剂等混合来制备。用于非肠道给药的制剂也可以通过常规方法被制备，例如，将本发明的活性成分溶解在无菌水性载体中，优选水或盐水溶液中。优选的适用于非肠道给药的液体制剂可以通过将每日剂量的上述活性成分溶解在水中和有机溶剂中并进一步溶解在分子量为300到5000的聚乙二醇中而被制备，其中优选掺入润滑剂，例如羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮和聚乙烯醇。优选地，上述液体制剂可以进一步含有消毒剂(例如，苯甲醇、苯酚、硫柳汞)、杀真菌剂，以及进一步任选地包含等渗剂(如蔗糖、氯化钠)、局部麻醉剂、稳定剂、缓冲剂等。为了保持稳定，用于非肠道给药的制剂可以被放入胶囊中，然后通过常规的冷冻干燥技术除去水性介质。在使用时可以通过将该制剂溶于水性介质而将其复原成液体制剂。可以通过常规方法制备吸入剂。即，可以通过将活性化合物变成粉末或液体状态，使其混合于供吸入剂用的推进剂和/或载体中，和将该混合物装入合适的喷雾器中来制备吸入剂。通常，当活性化合物是粉末时，可以使用机械式粉末喷雾器，当化合物是液体时，可以使用喷雾器例如雾化器。此外，在必要时吸入剂还可任选地含有已经使用的表面活性剂、油、调味剂、环糊精或其衍生物。
上述添加剂的实例、其制备方法或其他事情包括，但不限于JP-10-175864-A公开的内容。
实施例
两名患有阿尔茨海默氏症的女性(一名63岁，另一名52岁)已经分别以5mg/天的剂量被给药盐酸多奈哌齐
12个月和9个月。在给药期间，对这些女性进行细微精神状态检查(MMSE)(Journal of psychiatric research.1975年11月；12(3)：189-98)，结果如表1和图1中所示。在实验开始的时候(0月)，以100mg/天的剂量以与盐酸多奈哌齐的组合形式开始给药西洛他唑。那时，之前已经降低的MMSE得分迅速被提高。根据上述结果，发现以与盐酸多奈哌齐组合形式给药西洛他唑可以恢复由于盐酸多奈哌齐长期给药而倾向于降低的盐酸多奈哌齐的作用。并且还发现盐酸多奈哌齐和西洛他唑的组合对痴呆例如阿尔茨海默氏症能够提供强效的治疗作用。
表1
M(s)表示“月”。
组合中西洛他唑的给药开始于0月。
Claims (6)
1.一种用于治疗阿尔茨海默氏症的药物，含有6-[4-(1-环己基-1H-四唑-5-基)丁氧基]-3，4-二氢喹诺酮或其盐和多奈哌齐或其盐作为活性成分。
2.权利要求1的药物，其中多奈哌齐的盐是盐酸多奈哌齐。
3.6-[4-(1-环己基-1H-四唑-5-基)丁氧基]-3，4-二氢喹诺酮或其盐和多奈哌齐或其盐在制备用于治疗阿尔茨海默氏症的药物中的应用。
4.权利要求3的应用，其中所述的多奈哌齐的盐是盐酸多奈哌齐。
5.一种用于治疗阿尔茨海默氏症的组合物，包括有效量的6-[4-(1-环己基-1H-四唑-5-基)丁氧基]-3，4-二氢喹诺酮或其盐和多奈哌齐或其盐。
6.权利要求5的组合物，其中所述的多奈哌齐的盐是盐酸多奈哌齐。
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1607952A (zh) * | 2001-12-27 | 2005-04-20 | 大塚制药株式会社 | 包含多官能磷酸二酯酶抑制剂和腺苷吸收抑制剂的药物组合物 |
| WO2004075897A1 (en) * | 2003-02-25 | 2004-09-10 | Otsuka Pharmaceutical Co., Ltd. | Pten inhibitor or maxi-k channels opener |
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