CN1168101A - 3，4-二苯基苯并二氢吡喃制备治疗或预防大脑退化性疾病的药物组合物的用途 - Google Patents
3，4-二苯基苯并二氢吡喃制备治疗或预防大脑退化性疾病的药物组合物的用途 Download PDFInfo
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- CN1168101A CN1168101A CN96191516A CN96191516A CN1168101A CN 1168101 A CN1168101 A CN 1168101A CN 96191516 A CN96191516 A CN 96191516A CN 96191516 A CN96191516 A CN 96191516A CN 1168101 A CN1168101 A CN 1168101A
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Abstract
本发明提供了用通式(I)化合物或其药学上可接受的盐其中R1，R4和R5分别是氢、羟基、卤素、三氟甲基、低级烷基或(叔氨基)(低级烷氧基)；而R2和R3分别是氢或低级烷基，与药学上可接受的载体制备治疗或预防大脑退化性疾病的药物组合物的新用途。
Description
发明领域
本发明涉及通式I的化合物对患有大脑退化性疾病例如阿尔茨海默疾病的患者的治疗及其预防的用途。本发明也包括了含有该化合物的药物组合物和使用该化合物及其药物组合物的方法。
发明背景
在给神经系统的疾病分类中，通常把其中的一组定义为退化性，其特征在于基本未知原因的逐渐发展的渐进性神经死亡。这些疾病的识别依赖于排除这些可能因素如感染，代谢紊乱和中毒。归于退化性类的大部分疾病是基因性的。但是，在给定族的分离性例子也偶尔出现其他疾病。退化性疾病的分类不能以病因学或发病机理的任何精确知识为准；把它们进一步细分为单独症状是根据大量神经病理和临床领域为主的描述性标准。许多退化性神经系统疾病的进程不受治疗方法的影响。
因为阿尔茨海默疾病(AD)的频繁发作和毁坏性，它可能是所有退化性疾病中最重要的。AD是一种临床特征为逐渐丧失记忆、认知、推理、判断和感情能力并逐渐导致明显的意识退化而最终死亡的退化性大脑疾病。AD是年龄较大的人渐进性意识丧失(痴呆)的最普遍的原因并且认为它在美国最常规治疗死亡中占第四位。目前估计在美国这种疾病影响了两到三百万人。迄今为止，包括AD的许多退化性神经系统疾病的进程不受任何治疗方法的影响。
显著的病理特征是大脑皮层神经细胞的死亡和消失。这最后导致了大范围的脑回萎缩，特别是在额、顶骨和内侧的颞部区。对该疾病来说两种显微病灶是显著的。阿尔茨海默最早描述的第一种是由环、卷或纠缠的团块形式的神经内累积的丝状物构成的且称作阿尔茨海默神经原纤维紊乱。目前正在积极研究它们的具体性质，但是神经病理证据极大地表明这些淀粉样蛋白性的原纤维团块在引起神经死亡方面起重要作用。AD特征的第二种病理组织学变化是存在增厚的神经突起轴突和树突的皮层内束。
好几方面的证据表明特别是淀粉样基因蛋白、β-淀粉样蛋白(βAP)的渐进性大脑沉淀在AD的发病机理中起关键作用并且几年或几十年后能出现识别症状(Selkoe DJ，Neuron6：487，1991)。最近已经表明βAP是从生长在细胞培养基中的神经细胞中释放的并且存在于正常个体和AD患者的脑脊液(CSF)中(Seubert等，Nature359：325，1992)中。
生物化学研究表明合成乙酰胆碱所需要的关键酶乙酰胆碱转化酶在AD中大脑皮层中下降了。新皮层胆碱能的神经支配的主要来源是位于前脑的基底部分刚好在纹状体、迈内特的核基底下的一组神经元。该核是主要神经元损失和经常性阿尔茨海默神经成纤维紊乱的部位。这样，胆碱能传导的损害在这种疾病的临床表现中占一部分。但是，用类胆碱作用剂所尝试的治疗大多数都不成功。相反，最近的研究表明雌激素通过刺激胆碱乙酰转化酶影响胆碱能的功能(Kaufman H等，Brain Res453：389，1988)并且雌激素也增加了下丘脑烟酸乙酰胆碱受体的结合部位(Morley BJ等，Brain Res278：262，1983)。而且这也表明低剂量的雌激素替代疗法对AD可能具有一种有益的作用(Okura T等，Menopause 1：125，1994)。
尽管如此，雌激素对鼠的作用显示出了性别差异：雌二醇给药增加了经过卵巢切除术的雌性核中胆碱乙酰转化酶的活性，但是对阉割的雄性鼠有一种减弱的作用或没有作用(Luine VN&McEwen BS，Neuroendocrinology 36：36：475，1983)。而且，还存在显著的雌激素替代疗法的副作用，最令人不安的是已确立的与子宫内膜癌和乳腺癌的联系。肿瘤的发病率是与剂量和过程皆有关。
通过伴随雌激素使用孕酮已经实现了避免癌症危险。但是这种组合引起了月经复发，这对许多妇女来说是不可接受的。另外一种缺点是至今没有完全测定出孕酮的长期作用。
在本领域中仍需要用于治疗或预防退化性大脑疾病包括阿尔茨海默疾病的化合物和方法。还需要没有不需要的雌激素副作用的组合物。
星克罗曼(Centchroman)是一种已知抗雌激素活性的非甾体化合物。在印度将其用作口服避孕药(例如，参见，Salman等，美国专利申请号4,447,622；Singh等，Acta Endocrinal(Copenh)126(1992)，444-450；Grubb，Curr Opin Obstet Gvnecol 3(1991)，491-495；Sankaran等，Contraception 9(1974)，279-289；印度专利申请号129187)。人们也已经研究发现星克罗曼作为治疗继发性乳腺癌的抗肿瘤剂(Misra等，Int JCancer43(1989)，781-783)。最近，人们已发现星克罗曼的外消旋盐作为一种降低胆固醇的药物的潜力，它是通过血浆浓度的显著降低所表现的(S.D.Bain等，J Min Bon Res 9(1994)，S394)。
美国专利5,280,040描述了使用3，4-二芳基苯并二氢吡喃及其药学上可接受的盐降低骨损失的方法和药物组合物。
本发明的一个目的就是提供用于治疗或预防例如阿尔茨海默疾病的大脑退化性疾病有效的化合物。
发明的概述
令人惊奇地发现如权利要求1所述的通式I的化合物能够用于例如阿尔茨海默疾病的大脑退化性疾病的治疗或预防。
发明的详细描述
本发明部分基于这样的发现，即代表性的3，4-二芳基苯并二氢吡喃、星克罗曼(3，4-反式-2，2-二甲基-3-苯基-4-〔4-(2-(吡咯烷-1-基)乙氧基)苯基〕-7-甲氧基苯并二氢吡喃)对小鼠或大鼠(例如Fisher大鼠)的例如阿尔茨海默疾病的大脑退化性疾病是有效的。星克罗曼是一种外消旋混合物。这些动物模型一般被认为是例如阿尔茨海默疾病的大脑退化性疾病的识别模型。这些数据表明3，4-二芳基苯并二氢吡喃可用作抗包括象人的灵长目动物的哺乳动物的例如阿尔茨海默疾病的大脑退化性疾病的治疗或预防剂。
在本发明中，权利要求1所述的通式I的化合物可作为抗例如阿尔茨海默疾病的大脑退化性疾病的药物给药。在通式I中，R1，R2和R5分别是氢、卤素、三氟甲基、低级烷基、低级烷氧基或(叔氨基)(低级烷氧基)；R2和R3分别是氢或低级烷基。本文所用的术语“低级烷基”包括含有1到6个碳原子的直链和支链烷基，如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、仲戊基、正己基、2-乙基丁基、2，3-二甲基丁基等。术语“低级烷氧基”包括含有1到6个碳原子的直链和支链烷氧基，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、仲戊氧基、正己氧基、2-乙基丁氧基、2，3-二甲基丁氧基等。术语“卤素”包括氯、氟、溴和碘。叔氨基可以是N，N-二烷基胺，如N，N-二甲基氨基、N，N二乙基氨基、N，N二丙基氨基、N，N二丁基氨基或一种聚亚甲基胺如哌啶、吡咯烷、N-甲基哌嗪或吗啉。本文的术语“(叔氨基)(低级烷氧基)”是被叔氨基取代的低级烷氧基。优选的化合物包括那些其中R1是低级烷氧基；R2和R3是低级烷基，特别是甲基；R4是氢；而R5是聚亚甲基胺型的(叔氨基)(低级烷氧基)。在特别优选的实施方案中，R1在7位并且是低级烷氧基，特别是甲氧基；R2和R3各是甲基，R4是氢和R5在4位并且是(叔氨基)(低级烷氧基)如2-(吡咯烷-1-基)乙氧基。本发明也包括了所提到的通式I化合物的所有药学上可接受的盐。
优选使用反式构型的式I的化合物。这些化合物可以外消旋混合物，分离的对映体，例如d-或L-对映体使用。更优选反式-L-对映体。
本发明所用的特别优选的化合物是由L-星克罗曼和d-星克罗曼组成的星克罗曼。1-星克罗曼可具有通式IV：
按照已知方法如在Carney等，美国专利说明书号3,340,276，Bolger的美国专利说明书号3,822,287和Ray等，J Med Chem19(1976)，276-279(本文将这些内容引用为参考文献)中所公开的方法制备3，4-二芳基苯并二氢吡喃。在美国专利说明书3,822,287中公开了用有机金属为主催化的重排方法把顺式异构体转化为反式构型。按照Salman等的美国专利说明书号4,447,622(本文将这些内容引用为参考文献)所述的通过形成旋光酸盐并将其经过碱水解来生产所需的对映体的方法制备旋光d-和L-对映体。如果R2不同于R3并且R4不同于R5，通式I包括了8种旋光异构体。
在本发明中，式I3，4-二芳基苯并二氢吡喃可以制备成药学上可接受的盐的形式，特别是酸加成盐，其包括有机酸盐和无机酸盐。这些盐的例子包括有机酸如甲酸、富马酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、琥珀酸、苹果酸、酒石酸、柠檬酸、苯甲酸、水杨酸等。适当的无机酸加成盐包括盐酸、氢溴酸、硫酸和磷酸等的盐。可以作为化合物合成的直接产物获得这些酸的加成盐。另一方面，可把游离碱溶于含有适当酸的有机溶剂中，并且通过蒸发溶剂或者其它分离该盐和溶剂的方法分离该盐。
式I的3，4-二芳基苯并二氢吡喃及其盐在人和兽药领域中可用作例如，治疗或预防患有大脑退化性疾病例如阿尔茨海默疾病患者的药物。在本发明的使用中，按照常规方法可以把式I的3，4-二芳基苯并二氢吡喃及其药学上可接受的盐与药学上可接受的载体配制成用于胃肠外、口服、鼻、直肠、皮下或真皮内或经皮给药的药剂。制剂还可以包括一种或多种稀释剂、填充剂、乳化剂、防腐剂、缓冲液、赋型剂等。并可以为液体、粉剂、乳剂、栓剂、脂质体、经皮片、控制释放剂、经皮植入物、片剂等。本领域普通技术人员可用适当的方式并根据所接受的实践配置该化合物，如Remington′s Pharmaceutical Sciences，Gennaro，ed.，Mack PublishingCo.，Easton，PA，1990中所公开的那些。
优选口服给药。这样，把活性化合物制成适合于口服的形式如片剂或胶囊。化合物的药学上可接受的盐一般是与一种载体混合并模压成片。在这方面，适当的载体包括淀粉、蔗糖、磷酸二钙、硬脂酸钙、硬脂酸镁等。该组合物还可以包括一种或多种辅料物质，如润湿剂、乳化剂、防腐剂、稳定剂、着色剂等。
含有式I化合物的药物组合物每天或每周可以给药一次或多次。该药物组合物的有效用量是能够在临床上提供显著抗大脑退化性疾病例如阿尔茨海默疾病作用的用量。这种用量部分取决于治疗的具体症状、年龄、体重和患者的一般健康以及本领域普通技术人员所显知的其它因素。
含有式I化合物的药物组合物可以以单位剂量每天或每周一次或多次给药。另一方面，也可以把它们以适用经皮植入的控制释放剂型提供。配置成植入物可在所需的期间提供活性化合物的释放，该期间可高达几年。例如Sanders等，J Pharm Sci 73(1964)，1294-1297，1984；美国专利说明书号4,489,056以及美国专利说明书号4,210,644中公开了控制释放制剂，上述文献在本文引用为参考。
式I化合物的优选例子是作为外消旋混合物星克罗曼和L-星克罗曼以及d-星克罗曼的星克罗曼。进-步讲，优选化合物是3，4-反式-2，2-二甲基-3-苯基-4-[4-(2-(吡咯烷-1-基)乙氧基]-7-羟基苯并二氢吡喃。更优选的化合物是L-3，4-反式-2，2-二甲基-3-苯基-4-[4-(2-(吡咯烷-1-基)乙氧基)苯基]-7-甲氧基苯并二氢吡喃。
通过下列实施例进一步对本发明进行详细说明，但是，这些实施例不是用来限定保护范围的。
前面说明书和下列实施例中所公开的特征可分开或结合起来从而用不同方式实现本发明。实施例试验1
从美国加利福尼亚旧金山的Athena Neurosciences Inc.购买过表达V717Fβ-淀粉样前体蛋白的突变小鼠。只使用杂交的动物。6-9个月后，对这些动物大脑的病理组织学检查发现在海马、并氐体和大脑皮层有人淀粉样β-肽(Aβ)的沉积。随着年龄肽的累积会增加并且9个月后情况类似于在阿尔茨海默疾病中所看到的。
把10到50只突变小鼠用于研究。按两只一组把动物放入金属编织的笼中并且随意提供食物和水一周。室温保持在20℃±1.5℃，最小相对湿度为40％。室中的光期是12小时有光和12小时黑暗。
在适应一周后，把动物随机按每组2到10只动物分成5个治疗组并开始每天用试验化合物口服治疗。把试验化合物按照0到75mg/kg/天的四种不同剂量给药一个月。给药期后，给动物称重并用CO2窒息杀死。把大脑取出、称重并马上冷冻在冷却的异戊烷中。在低温箱中把大脑连续切片(10-50um厚的切片)并在标记的和聚-L-色氨酸涂覆的玻片上计数。
用抗血浆R1280所产生的抗合成的人Aβ1-40肽给小鼠大脑切片标记。推荐使用过氧化酶标准兔IgG试剂盒(载体实验室)与3，3-二氨基联苯胺(DAB)作色原。对阳性斑计数并用立体学技术定量测定。用大脑中斑大小的体积和数目的减少来表示活性。试验2
选择5到50名妇女进行临床研究。妇女都是月经后，即在开始研究之前月经停止6到12个月，已诊断为阿尔茨海默疾病(AD)的早期，在研究期间可能会有AD变坏的症状，但是其他方面的健康状态是好的。该研究设有安慰的对照组，即，把这些妇女分成两组，一组接受本发明活性药剂而另外一组接受安慰剂。将患有与AD有关的记忆、认知、推理和其他症状的患者做标记。治疗组的妇女每天口服接受1-1000mg的活性剂。她们持续这种治疗6-36月。对两组中已标记的症状的患者进行精确记录并在试验结束后比较这些结果。在每组成员之间比较结果并且也把每个患者的结果与试验开始前的症状进行比较。用在服用该试验药物的患者中AD的任何一种或多种症状的抑制来说明试验结果的活性。
Claims (19)
1.用通式(I)化合物或其药学上可接受的盐
其中R1，R4和R5分别是氢、羟基、卤素、三氟甲基、低级烷基或(叔氨基)(低级烷氧基)；而R2和R3分别是氢或低级烷基，与药学上可接受的载体制备治疗或预防大脑退化性疾病如阿尔茨海默疾病的药物组合物的用途。
2.根据权利要求1的用途，其中化合物具有通式III：
其中R1，R2，R3，R4和R5分别如权利要求1所述的定义。
3.根据权利要求1或2中的用途，其中R1是低级烷氧基，优选甲氧基。
4.根据上述权利要求中的任何一种的用途，其中R2是低级烷基，优选甲基。
5.根据上述权利要求中的任何一种的用途，其中R3是低级烷基，优选甲基。
6.根据上述权利要求中的任何一种的用途，其中R4是氢。
7.根据上述权利要求中的任何一种的用途，其中R5是(叔氨基)(低级烷氧基)，优选2-(吡咯烷-1-基)乙氧基。
8.根据上述任何一种权利要求的用途，其中该化合物是立体异构体，如可分离的d-或L-对映体。
9.根据上述任何一种权利要求的用途，其中该化合物是可分离的L-对映体。
10.根据上述权利要求1的用途，其中该化合物是3，4-反式-2，2-二甲基-3-苯基-4-〔4-(2-(吡咯烷-1-基)乙氧基)苯基〕-7-甲氧基苯并二氢吡喃。
11.根据上述权利要求的用途，其中该化合物是3，4-反式-2，2-二甲基-3-苯基-4-〔4-(2-(吡咯烷-1-基)乙氧基)苯基〕-7-甲氧基苯并二氢吡喃的可分离的d-或L-对映体。
12.根据上述权利要求11的用途，其中该化合物是的L-3，4-反式-2，2-二甲基-3-苯基-4-〔4-(2-(吡咯烷-1-基)乙氧基)苯基〕-7-甲氧基苯并二氢吡喃。
13.根据上述权利要求的任何一种的用途，其中该组合物是适合于口服的形式。
14.根据上述任何一种权利要求的用途，其中该化合物是以每天从大约0.001到75，优选从大约0.01到75，更优选从大约0.01到50并且最佳为从大约0.1到25mg/kg患者体重的剂量给药的。
15.根据上述任何一种权利要求的用途，其中该组合物是每天或每周给药一次或多次。
16.根据上述任何一种权利要求的用途，其中该组合物是经皮植入物形式。
17.一种治疗或预防大脑退化性疾病如阿尔茨海默疾病的方法，它包括给患者服用临床有效量的如上述任何一种用途权利要求中所述的通式I化合物或其药学上可接受的盐，其中的用量为足以治疗或预防大脑退化性疾病例如阿尔茨海默疾病的量。
18.一种治疗或预防防大脑退化性疾病如阿尔茨海默疾病的方法，它包括给需要这种治疗的患者服用临床有效量的式I化合物或其盐和含有这类化合物的药学上可接受的组合物。
19.本文所描述的任何新的特征或特征的组合。
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| US5958967A (en) * | 1996-10-28 | 1999-09-28 | Novo Nordisk A/S | Cis-3,4-chroman derivatives useful in the prevention or treatment of estrogen related diseases or syndromes |
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| ATE532777T1 (de) | 2004-09-21 | 2011-11-15 | Marshall Edwards Inc | Substituierte chromanderivate, medikamente und anwendungen in der therapie |
| US8080675B2 (en) | 2004-09-21 | 2011-12-20 | Marshall Edwards, Inc. | Chroman derivatives, medicaments and use in therapy |
| US20100173983A1 (en) * | 2007-03-16 | 2010-07-08 | David Brown | Method for inducing autophagy |
| WO2010045674A1 (en) * | 2008-10-22 | 2010-04-29 | Novogen Research Pty Ltd | Methods for inducing programmed cell death |
| EP2635121B1 (en) | 2010-11-01 | 2020-01-08 | MEI Pharma, Inc. | Isoflavonoid compounds and methods for the treatment of cancer |
| NZ711603A (en) | 2014-02-07 | 2017-05-26 | Novogen ltd | Functionalised benzopyran compounds and use thereof |
| PL3253208T3 (pl) | 2015-02-02 | 2021-11-08 | Mei Pharma, Inc. | Terapie kombinowane do zastosowania w leczeniu nowotworu piersi |
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| BR9606766A (pt) | 1997-12-30 |
| JPH10512269A (ja) | 1998-11-24 |
| NO973342L (no) | 1997-07-18 |
| MX9705390A (es) | 1997-10-31 |
| HUP9702246A3 (en) | 1999-12-28 |
| US5696149A (en) | 1997-12-09 |
| KR19980701549A (ko) | 1998-05-15 |
| WO1996022091A1 (en) | 1996-07-25 |
| EP0809495A1 (en) | 1997-12-03 |
| IL116828A0 (en) | 1996-05-14 |
| IL116828A (en) | 1999-11-30 |
| NO973342D0 (no) | 1997-07-18 |
| US5827873A (en) | 1998-10-27 |
| CA2208856A1 (en) | 1996-07-25 |
| HUP9702246A2 (hu) | 1998-12-28 |
| AU4328896A (en) | 1996-08-07 |
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