CN111712241A - σ-1受体激动剂收缩期血压疗法 - Google Patents
σ-1受体激动剂收缩期血压疗法 Download PDFInfo
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- CN111712241A CN111712241A CN201880076891.5A CN201880076891A CN111712241A CN 111712241 A CN111712241 A CN 111712241A CN 201880076891 A CN201880076891 A CN 201880076891A CN 111712241 A CN111712241 A CN 111712241A
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Abstract
一种用于降低对使用一种或多种药物的抗高血压疗法展现抗性的患者的收缩期血压的方法，所述方法包括以有效提供选自谷值坐位收缩期、24小时动态收缩期和最大昼夜收缩期血压的一个或多个血压参数的至少约3mmHg降低的剂量和频率向所述患者施用
Description
相关申请的交叉引用
本申请要求2017年11月28日提交的美国临时申请号62/591,248的优先权，所述临时申请的全部公开内容以引用的方式并入本文中。
技术领域
本公开大体上涉及用于降低对使用一种或多种药物的抗高血压疗法展现抗性的患者的收缩期血压的方法，所述方法包括向所述患者施用治疗有效量的四氢-N，N-二甲基-2，2-二苯基-3-呋喃甲胺盐酸盐。
背景技术
σ-1受体是与维持细胞钙水平和适当蛋白质折叠相关联的钙敏感性内质网伴侣蛋白。据信这种受体对于在细胞应激和炎症存在下保持细胞内稳态来说是重要的。若干研究证实σ-1受体刺激促进神经保护、神经可塑性、心脏保护和肾脏保护。
已经报道了使用噻嗪利尿剂和钙拮抗剂或钙通道阻断剂治疗ISH。提及使用氯噻酮(chlorothalidone)(并且任选地包括阿替洛尔(atenolol)或利血平(reserpine))、尼群地平(nitrendipine)、硝苯地平(nifedipine)、依普沙坦(eprosartan)和氢氯噻嗪(hydrochlorothiazide)的治疗处理。另外，ACE抑制剂、AT1阻断剂、螺内酯(spironolactone)和奥帕曲特(omapatrilate)是候选治疗剂。
发明内容
本公开提供了一种治疗单纯收缩期高血压的方法，所述方法包括向有需要的受试者施用有效量的A2-73。本公开还包括A2-73的用途，其用于制造用以治疗单纯收缩期高血压的药剂。
本公开另外包括一种用于治疗单纯收缩期高血压的药物组合物，其包含A2-73和药学上可接受的载剂。可以配制包含A2-73的药物组合物以经口施用或适当时藉由静脉内注射施用。
本公开还包括一种用于降低有需要的受试者的收缩期血压的方法，所述方法包括以有效提供选自谷值坐位收缩期、24小时动态收缩期和最大昼夜收缩期血压的一个或多个血压参数的至少约3mmHg降低的剂量和频率向患者施用A2-73，其中所述受试者对使用一种或多种并非A2-73的抗高血压药物的抗高血压疗法展现抗性。
本文所公开的用于降低收缩期血压的方法中的任一者可以涉及施用A2-73与另外一种或多种抗高血压药物的组合，此类药物选自β阻断剂、噻嗪类利尿剂、ACE抑制剂和钙通道阻断剂。组合可以包括所施用的药物中的每一者的同时或单独施用时程。
A2-73的治疗有效剂量为约1mg至约60mg。在一些方面，治疗有效剂量为约30mg至约50mg，特别是用于经口施用。在其它方面，治疗有效剂量为约3mg至约5mg，特别是用于静脉内施用。本公开预期可以至少每日一次施用治疗有效剂量。在其它方面，根据至少两个周期的间歇给药方案施用A2-73，每个周期包括(a)向所述患者施用治疗有效剂量的所述药物组合物的给药时段，以及此后，(b)停药时段。在一些方面，给药时段和停药时段具有相同持续时间或不同持续时间。在一些方面，给药时段和交替停药时段在约1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天和14天的下限至约28天、27天、26天、25天、24天、23天、22天、21天、20天、19天、18天、17天、16天、15天和14天的上限的范围内。
附图说明
图1是跨越多次随访，针对BP测量时间、性别、年龄、身体质量指数和抗高血压药物的先前或并行使用作调整的32名两种性别的人类患者的收缩期血压读数的图。
具体实施方式
下文详细论述本公开的各个方面。虽然论述了具体实施，但应了解，这仅用于说明的目的。相关领域的技术人员将认识到在不脱离本公开的精神和范围的情况下可以使用其它组分和配置。
起初应了解，尽管下文说明了一个或多个方面的说明性实施，但所公开的方法可以使用许多技术来实施。本公开应决不限于本文所说明的说明性实施、图式和技术，而可以在随附权利要求书的范围以及其等同物的完整范围内进行修改。
在以下论述中和权利要求书中，术语“包括”和“包含”以开放性方式使用，并且因此应解释为意谓“包括但不限于...”。下文更详细描述的各种特征将由本领域技术人员借助于本公开在阅读以下详细描述后并且通过参考附图显而易见。
根据本公开的一个方面，可以通过向四氢-N，N-二甲基-2，2-二苯基-3-呋喃甲胺游离碱于乙酸乙酯中的溶液中馈入异丙醇来产生A2-73。通过蒸馏去除乙酸乙酯并且将含有四氢-N，N-二甲基-2，2-二苯基-3-呋喃甲胺游离碱的剩余异丙醇溶液过滤成澄清的。将盐酸水溶液(1.1当量)馈入异丙醇溶液中并且通过过滤分离所形成的结晶四氢-N，N-二甲基-2，2-二苯基-3-呋喃甲胺盐酸盐(A2-73)，并且在55℃下真空干燥3天。
已经在22名健康男性志愿者的随机化、安慰剂对照、单次递增剂量1期A2-73研究中证实A2-73的安全性。(参见Ole Voges，Ingo Weigmann，Norman Bitterlich，ChristophSchindler和Christopher Missling，“用以研究ANAVEX2-73在健康男性受试者中的安全性、耐受性和药物动力学的1期剂量递增研究(A Phase 1 Dose Escalation Study toInvestigate Safety，Tolerability，and Pharmacokinetics of ANAVEX2-73 in HealthyMale Subjects)”，2014年中枢神经系统峰会(CNS Summit 2014)，Boca Raton，FL，其全部公开内容以引用的方式并入本文中)。A2-73的1mg、10mg、30mg、40mg、50mg和55mg的递增单次经口剂量在健康受试者中是安全的并且耐受良好。未发生严重不良事件。基于非治疗紧急不良事件的频率和强度，最大耐受剂量和最小不耐受剂量分别定义为55mg和60mg。在最高剂量下，所观测的不良事件包括靶向中枢神经系统的药物中常见的中度和可逆眩晕和头痛。血压和静息心率以及如生命征象和12导联心电图(ECG)的其它临床参数不显示任何临床上相关或剂量依赖性的变化。发现A2-73的药物动力学适合于每日经口给药。
本公开大体上涉及用于治疗高收缩期血压(SBP)的药物化合物和组合物。更特别地，本公开涉及含有A2-73的药物组合物的用途，其用于治疗高SBP。
SBP在治疗上通过如本文所描述的方法来降低。血压通过本领域中已知的多种方法中的任一者确定，包括通过血压测量法。血压通常在坐位或动态受试者中测量。
血压的另一个量度是“24小时动态”血压。“24小时动态”收缩期或舒张期BP是在动态受试者中在24小时时段的过程中重复获取的收缩期或舒张期测量的平均值。
“最大昼夜”收缩期或舒张期BP是在24小时时段内记录的最高收缩期或舒张期血压的量度。不受任何特定理论约束，据信最大昼夜BP反映自然昼夜血压周期的峰值，其通常在早晨，例如在约上午5时与约上午11时之间出现。通常，第二个峰值在晚间，例如在约下午5时与下午10时之间出现。此种双峰波形昼夜动态BP模式尤其可以是顽固性高血压的特征。
顽固性高血压的共同特征是夜间(本文中定义为2200至0600)平均收缩期动态BP比日间(本文中定义为0600至2200)平均收缩期动态BP约低10％。本文中称为“日/夜动态BP比率”(以百分比表示)的参数以(日间平均值-夜间平均值)/日间平均值×100计算。日/夜ABP比率小于约10％的昼夜动态BP(ABP)模式有时称作“非杓型ABP”。
如本文所论述，在一些方面，根据本发明的方法展现治疗性收缩期血压降低的接受A2-73的受试患者是对使用一种或多种除A2-73以外的药物的抗高血压疗法展现抗性的受试者。
现在在事后评价的临床研究中已经发现收缩期血压(SBP)的意想不到的下降，这在使用A2-73治疗阿尔茨海默氏病的IIa期临床试验中观测到。在研究时段期间的四个时间点测量BP：1)筛选以供录入当天，2)用经口或静脉内药物治疗第一天(在药物施用之前获得BP测量值)，3)治疗第25天(此时患者转换至经口或静脉内接受其先前尚未接受的无论哪种配方)，以及4)第36天(IIa期研究的部分A结束)。统计分析包括比较跨越每次测量的BP变化的配对t检验，以及多变量线性混合效应建模(针对测量时间、性别、年龄、身体质量指数和抗高血压药物的使用作调整)以说明随时间的个体内重复测量。
三十二名阿尔茨海默氏病患者参与IIa期试验。平均年龄为69.5(标准偏差[SD]9.8)岁，60％为男性，平均身体质量指数为26.5(SD 3.9)kg/m2，并且50％在筛选时正服用抗高血压药物。在未作调整的分析中，比较第一次测量(平均SBP 143.3，SD 19.7，mmHg)与所有后续测量的SBP存在显著下降(分别p＝0.007、0.001和0.007)。在第一次与第二次测量之间(即，在即将第一次治疗之前)存在平均8.7(SD 3.0)mmHg SBP下降，但比较第二次测量与所有后续测量并无显著下降(分别p＝0.120和0.972)。在多变量调整模型(图1)中，在第一次与第二次读取之间SBP不存在显著差异(p＝0.211)。然而，如图1中所示，在第一次读取与其它后续读取之间SBP存在显著下降(分别p＝0.048和0.008)。应注意，没有患者报告在参与试验的同时其抗高血压方案有任何变化。
没有先前报道发现在用σ-1受体激动剂治疗之后SBP下降。这类药物因此提供了一种适用于治疗单纯收缩期高血压的用于降低收缩期BP的新颖机制。A2-73的功效以图示方式呈现于图1中，其呈现跨越随访，针对BP测量时间、性别、年龄、身体质量指数和抗高血压药物的使用作调整的重复收缩期BP读数。降低收缩期血压的有益作用包括对许多现有种类的抗高血压药物展现抗性的患者并且因此代表治疗高收缩期血压的显著进步。
在一些方面，包含A2-73和至少一种β阻断剂的组合剂量预期用于降低SBP，所述β阻断剂如普萘洛尔(propanolol)((RS)-1-(1-甲基乙基氨基)-3-(1-萘氧基)丙-2-醇)、布新洛尔(burcindolol)(2-[2-羟基-3-[[2-(1H-吲哚-3-基)-1，1-二甲基-乙基]氨基]丙氧基]苄腈)、卡替洛尔(carteolol)((RS)-5-[3-(叔丁基氨基)-2-羟基丙氧基]-3，4-二氢喹啉-2(1H)-酮)、卡维洛尔(carvedilol)((±)-[3-(9H-咔唑-4-基氧基)-2-羟基丙基][2-(2-甲氧基苯氧基)乙基]胺)、拉贝洛尔(labetalol)((RS)-2-羟基-5-[1-羟基-2-[(4-苯基丁-2-基)氨基]乙基]苄酰胺)、纳多洛尔(nadolol)(rel-(2R，3S)-5-{[(2R)-3-(叔丁基氨基)-2-羟基丙基]氧基}-1，2，3，4-四氢萘-2，3-二醇)、氧烯洛尔(oxprenolol)((RS)-1-[2-(烯丙氧基)苯氧基]-3-(异丙基氨基)丙-2-醇)、喷布洛尔(penbutolol)((S)-1-(叔丁基氨基)-3-(2-环戊基苯氧基)丙-2-醇)、吲哚洛尔(pindolol)((RS)-1-(1H-吲哚-4-基氧基)-3-(异丙基氨基)丙-2-醇)、索他洛尔(sotalol)((RS)-N-{4-[1-羟基-2-(丙-2-基氨基)乙基]苯基}甲磺酰胺)、噻吗洛尔(timolol)((S)-1-(叔丁基氨基)-3-[(4-吗啉-4-基-1，2，5-噻二唑-3-基)氧基]丙-2-醇)、醋丁洛尔(acebutolol)((RS)-N-{3-乙酰基-4-[2-羟基-3-(丙-2-基氨基)丙氧基]苯基}丁酰胺)、阿替洛尔((RS)-2-{4-[2-羟基-3-(丙-2-基氨基)丙氧基]苯基}乙酰胺)、倍他洛尔(betaxolol)((RS)-1-{4-[2-(环丙基甲氧基)乙基]-苯氧基}-3-(异丙基氨基)丙-2-醇)、比索洛尔(bisoprolol)((RS)-1-{4-[(2-异丙氧基乙氧基)甲基]苯氧基}-3-(异丙基氨基)丙-2-醇)、塞利洛尔(celiprolol)((RS)-N′-{3-乙酰基-4-[3-(叔丁基氨基)-2-羟基丙氧基]苯基}-N，N-二乙脲)、美托洛尔(metoprolol)((RS)-1-[4-(2-甲氧基乙基)苯氧基]-3-[(丙-2-基)氨基]丙-2-醇)、奈比洛尔(nebivolol)(1RS，1′RS)-1，1′-[(2RS，2′SR)-双(6-氟-3，4-二氢-2H-1-苯并吡喃-2-基)]-2，2′-亚氨基二乙醇或1-(6-氟色满-2-基)-{[2-(6-氟色满-2-基)-2-羟基-乙基]氨基}乙醇或2，2′-氮烷二基双(1-(6-氟色满-2-基)乙醇)或1-(6-氟-3，4-二氢-2H-1-苯并吡喃-2-基)-2-{[2-(6-氟-3，4-二氢-2H-1-苯并吡喃-2-基)-2-羟基乙基]氨基}乙-1-醇或其组合)、艾司洛尔(esmolol)((RS)-3-{4-[2-羟基-3-(丙-2-基氨基)丙氧基]苯基}丙酸甲酯)、布他沙明(butaxamine)((1S，2S)-1-(2，5-二甲氧基苯基)-2-(叔丁基氨基)丙-1-醇)、ICI-118，551(3-(异丙基氨基)-1-[(7-甲基-4-茚满基)氧基]丁-2-醇)和SR 59230A((2S)-1-(2-乙基苯氧基)-3-{[(1S)-1，2，3，4-四氢萘-1-基]氨基}丙-2-醇)。
在其它方面，包含A2-73和至少一种噻嗪利尿剂的组合剂量预期用于降低SBP，所述噻嗪利尿剂如氯噻酮(chlorthalidone)((RS)-2-氯-5-(1-羟基-3-氧代-2，3-二氢-1H-异吲哚-1-基)苯-1-磺酰胺)、氢氯噻嗪(6-氯-1，1-二氧代-3，4-二氢-2H-1，2，4-苯并噻二嗪-7-磺酰胺)、甲氯噻嗪(methyclothiazide)(6-氯-3-(氯甲基)-2-甲基-3，4-二氢-2H-1，2，4-苯并噻二嗪-7-磺酰胺1，1-二氧化物)、美托拉宗(metolazone)(7-氯-2-甲基-4-氧代-3-邻甲苯基-1，2，3，4-四氢喹唑啉-6-磺酰胺)、吲达帕胺(indapamide)(4-氯-N-(2-甲基-2，3-二氢吲哚-1-基)-3-氨磺酰基-苄酰胺)、苄氟噻嗪(bendroflumethiazide)(3-苄基-1，1-二氧代-6-(三氟甲基)-3，4-二氢-2H-1，2，4-苯并噻二嗪-7-磺酰胺)、泊利噻嗪(polythiazide)(6-氯-2-甲基-3-{[(2，2，2-三氟乙基)硫代]甲基}-3，4-二氢-2H-1，2，4-苯并噻二嗪-7-磺酰胺1，1-二氧化物)和氢氟噻嗪(hydroflumethiazide)(1，1-二氧代-6-(三氟甲基)-3，4-二氢-2H-1，2，4-苯并噻二嗪-7-磺酰胺)。
在其它方面，包含A2-73和至少一种ACE抑制剂的组合剂量预期用于降低SBP，所述ACE抑制剂如依那普利(enalapril)((2S)-1-[(2S)-2-{[(2S)-1-乙氧基-1-氧代-4-苯基丁-2-基]氨基}丙酰基]吡咯烷-2-甲酸)、雷米普利(ramipril)((2S，3aS，6aS)-1-[(2S)-2-[[(2S)-1-乙氧基-1-氧代-4-苯基丁-2-基]氨基]丙酰基]-3，3a，4，5，6，6a-六氢-2H-环戊二烯并[b]吡咯-2-甲酸)、喹那普利(quinapril)((3S)-2-[(2S)-2-[[(2S)-1-乙氧基-1-氧代-4-苯基丁-2-基]氨基]丙酰基]-3，4-二氢-1H-异喹啉-3-甲酸)、培哚普利(perindopril)((2S，3aS，7aS)-1-[(2S)-2-{[(2S)-1-乙氧基-1-氧代戊-2-基]氨基}丙酰基]-八氢-1H-吲哚-2-甲酸)、赖诺普利(lisinopril)((2S)-1-[(2S)-6-氨基-2-[[(1S)-1-羧基-3-苯基丙基]氨基]己酰基]吡咯烷-2-甲酸)、贝那普利(benazepril)(2-[(3S)-3-[[(2S)-1-乙氧基-1-氧代-4-苯基丁-2-基]氨基]-2-氧代-4，5-二氢-3H-1-苯并氮杂卓-1-基]乙酸)、咪达普利(imidapril)((4S)-3-[(2S)-2-[[(2S)-1-乙氧基-1-氧代-4-苯基丁-2-基]氨基]丙酰基]-1-甲基-2-氧代咪唑烷-4-甲酸)、群多普利(trandolapril)((2S，3aR，7aS)-1-[(2S)-2-{[(2S)-1-乙氧基-1-氧代-4-苯基丁-2-基]氨基}丙酰基]-八氢-1H-吲哚-2-甲酸)、西拉普利(cilazapril)((4S，7S)-7-[[(2S)-1-乙氧基-1-氧代-4-苯基丁-2-基]氨基]-6-氧代-1，2，3，4，7，8，9，10-八氢哒嗪并[1，2-a]二氮杂卓-4-甲酸)、福辛普利(fosinopril)((2S，4S)-4-环己基-1-[2-[羟基(4-苯基丁基)磷酰基]乙酰基]吡咯烷-2-甲酸)、卡托普利(captopril)((2S)-1-[(2S)-2-甲基-3-硫烷基丙酰基]吡咯烷-2-甲酸)和佐芬普利(zofenopril)((2S，4S)-1-[(2S)-3-苄酰基硫烷基-2-甲基丙酰基]-4-苯基硫烷基吡咯烷-2-甲酸)。
在其它方面，包含A2-73和至少一种钙通道阻断剂的组合剂量预期用于降低SBP，所述钙通道阻断剂如氨氯地平(amlodipine)((RS)-2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-6-甲基-1，4-二氢吡啶-3，5-二甲酸3-乙酯5-甲酯)、克林地平(clinidipine)(3-(E)-2，6-二甲基-4-(间硝基苯基)-1，4-二氢吡啶-3，5-二甲酸3-苯基-2-丙烯酯5-2-甲氧基乙酯)、氯维地平(clevidipine)((RS)-4-(2，3-二氯苯基)-2，6-二甲基-1.4-二氢吡啶-3，5-二甲酸5-O-(丁酰氧基甲基)酯3-O-甲酯)、非洛地平(felodipine)((RS)-4-(2，3-二氯苯基)-2，6-二甲基-1，4-二氢吡啶-3，5-二甲酸3-乙酯5-甲酯)、依拉地平(isradipine)(4-(2，1，3-苯并恶二唑-4-基)-2，6-二甲基-1，4-二氢吡啶-3，5-二甲酸3-甲酯5-丙-2-基酯)、乐卡地平(lercanidipine)((RS)-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二甲酸2[(3，3-二苯基丙基)(甲基)氨基]-1，1-二甲基乙酯甲酯)、左旋氨氯地平(levamlodipine)((S)-2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-6-甲基-1，4-二氢吡啶-3，5-二甲酸3-乙酯5-甲酯)、尼卡地平(nicardipine)(2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二甲酸2-[苄基(甲基)氨基]乙酯甲酯)、硝苯地平(2，6-二甲基-4-(2-硝基苯基)-1，4-二氢吡啶-3，5-二甲酸3，5-二甲酯)、尼莫地平(nimodipine)(2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二甲酸3-(2-甲氧基乙基)酯5-丙-2-基酯)、尼索地平(nisoldipine)(2，6-二甲基-4-(2-硝基苯基)-1，4-二氢吡啶-3，5-二甲酸异丁酯甲酯)、尼群地平((RS)-2，6-二甲基-4-(间硝基苯基)-1，4-二氢吡啶-3，5-二甲酸3-乙酯5-甲酯)、地尔硫卓(diltiazem)(顺-(+)-乙酸[2-(2-二甲基氨基乙基)-5-(4-甲氧基苯基)-3-氧代-6-硫杂-2-氮杂双环[5.4.0]十一碳-7，9，11-三烯-4-基]酯)和维拉帕米(verapamil)((RS)-2-(3，4-二甲氧基苯基)-5-{[2-(3，4-二甲氧基苯基)乙基]-(甲基)氨基}-2-丙-2-基戊腈)。
在相关方面，预期给药方案包括以至少每日为基础向受试者施用包含A2-73的药物组合物。还明确预期每日两次施用，并且如本文所描述的每日给药可以分成两个相等剂量。施用可以每日一次或每日两次持续至少2、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天的时段，或无限期地持续超过30天，持续2、3、4、5、6、7、8、9、10、11或12个月，或更长时间。在其它方面，根据至少一个或两个周期的间歇给药方案施用A2-73，每个周期包括(a)向所述患者施用治疗有效剂量的所述药物组合物的给药时段，以及此后，(b)停药时段。在一些方面，给药时段和停药时段具有相同持续时间或不同持续时间。在一些方面，在给药时段期间至少每日施用。
在一些方面，给药时段和停药时段在约1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天和14天的下限至约28天、27天、26天、25天、24天、23天、22天、21天、20天、19天、18天、17天、16天、15天和14天的上限的范围内。从前述内容应了解，预期给药时段长度和停药时段长度的各种组合，并且必要时可以针对患者的反应性进行修改。作为一个简单的实例，给药时段和交替停药时段方案各自可以为1天，如下：第1天第1剂量/第2天停药/第3天第2剂量/第4天停药，等等。还注意到介于约1天与12天之间的给药时段与介于约1天与12天之间的停药时段以任何组合形式交替，特别提及12天的给药时段和12天的停药时段。有效地采用间歇给药方案，其中A2-73的所述药物组合物的治疗有效量为约1mg至约60mg并且特别为约30mg至约50mg，特别是用于经口剂型。还预期约3mg至约5mg的A2-73剂量，特别是对于静脉内施用。
应了解，剂量和给药时程可以根据受试者的特征和反应性而变化。可以使用本领域中已知的任何方法容易地监测血压。
本文所公开的所有数值和范围可以有一定量的变化。无论何时公开具有下限和上限的数值范围，均特定公开处于所述范围内的任何数值和任何所包括的范围。特别地，本文所公开的值的每个范围(具有形式“约a至约b”或等同地“约a至b”或等同地“约a-b”)应理解为陈述在值的较宽范围内所涵盖的每个数值和范围。
本文所公开的组合物个别地或以组合形式与常规赋形剂混合采用，所述赋形剂即为适合于肠道外、经肠(例如经口或吸入)或局部应用并且不会与活性组合物发生有害反应的药学上可接受的有机或无机载剂物质。适合的药学上可接受的载剂包括但不限于水、盐溶液、醇、阿拉伯胶、植物油、苄醇、聚乙二醇、明胶、碳水化合物(例如乳糖、直链淀粉或淀粉)、硬脂酸镁、滑石、二氧化钛、硅酸、粘性石蜡、芳香油、脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷酮等等。可以将药物制剂灭菌并且必要时与助剂混合，所述助剂如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色剂、调味剂和/或芳香族物质等等，这些助剂不会与活性组合物发生有害反应。所述药物制剂必要时还可以与其它活性剂，例如维生素组合。
在一些方面，剂型包括此类组合物的使用说明书。对于肠道外应用，特别有可注射剂、无菌溶液，优选油性或水性溶液，以及悬浮液、乳液或植入物，包括栓剂。安瓿、小瓶或注射器筒是方便的单位剂量。“单位剂型”应意谓单一施用实体。举例来说，单一片剂、胶囊、糖衣丸或糖锭、栓剂或注射器。
同样对于经肠应用，特别适合的有片剂、糖衣丸、液体、滴剂、栓剂或胶囊。可以使用糖浆、酏剂等等，其中采用甜味媒剂。还注意到舌下和经颊形式。
可配制持续或直接释放组合物，例如脂质体或其中活性组分受差异性可降解包衣保护(例如通过微囊化、多个包衣等等)的那些。还可能冷冻干燥新组合物并且使用所获得的冻干物，例如用于制备供注射用的产品。
实施例
以下实施例展示A2-73治疗具有高SBP的患者的用途。所述实施例说明本发明并且不意图限制如上文详细描述并且如权利要求书中所陈述的本发明的范围。
实施例1
5mg和30mg每日一次剂量A2-73的作用.
已经每日一次经口服用5mg A2-73的70岁男性展现150mg Hg的24小时动态收缩期血压。然后增加A2-73的剂量以使得以30毫克/日的剂量每日向受试者施用A2-73持续25天的时段。然后测量他的24小时动态收缩期血压为135mg Hg并且用30mg每日经口剂量的A2-73无限期地维持。
实施例2
50mg每日一次剂量A2-73与β1选择剂治疗组合的作用.
已经每日两次服用50mg酒石酸美托洛尔(metoprolol tartrate)的75岁女性展现150mg Hg的24小时最大昼夜收缩期血压。受试者继续服用酒石酸美托洛尔，并且开始以50毫克/日的日剂量口服A2-73持续25天的时段。然后测量她的最大昼夜收缩期血压为135mgHg并且用组合的酒石酸美托洛尔和50mg每日经口剂量的A2-73无限期地维持。
实施例3
10mg每日一次剂量A2-73与噻嗪利尿剂治疗组合的作用.
已经每日一次经口服用25mg氯噻酮的60岁男性展现150mg Hg的谷值(关于氯噻酮)收缩期血压。受试者继续服用氯噻酮，并且开始以10毫克/日的日剂量口服A2-73持续25天的时段。然后测量他的谷值收缩期血压为135mg Hg并且用组合的氯噻酮和10mg每日经口剂量的A2-73无限期地维持。
Claims (15)
1.一种治疗单纯收缩期高血压的方法，所述方法包括向有需要的受试者施用治疗有效量的A2-73。
2.如权利要求1所述的方法，其中A2-73的所述治疗有效量介于1mg与60mg之间。
3.如权利要求2所述的方法，其中A2-73的所述治疗有效量介于30mg与50mg之间。
4.如权利要求3所述的方法，其中经口施用所述治疗有效量的A2-73。
5.如权利要求2所述的方法，其中A2-73的所述治疗有效量介于3mg与5mg之间。
6.如权利要求5所述的方法，其中静脉内施用所述治疗有效量的A2-73。
7.一种A2-73的用途，其用于制造用以治疗单纯收缩期高血压的药剂。
8.如权利要求7所述的药剂，其包含A2-73和药学上可接受的载剂。
9.一种用于降低有需要的受试者的单纯收缩期血压的方法，所述方法包括以有效提供选自谷值坐位收缩期、24小时动态收缩期和最大昼夜收缩期血压的一个或多个血压参数的至少约3mmHg降低的剂量和频率向所述患者施用A2-73，其中所述受试者对使用一种或多种并非A2-73的抗高血压药物的抗高血压疗法展现抗性。
10.一种用于降低有需要的受试者的单纯收缩期血压的方法，所述方法包括以有效提供选自谷值坐位收缩期、24小时动态收缩期和最大昼夜收缩期血压的一个或多个血压参数的至少约3mmHg降低的剂量和频率向所述患者施用与抗高血压药物组合的A2-73。
11.如权利要求9或权利要求10所述的方法，其中所述抗高血压药物选自包括以下的组：β阻断剂、噻嗪类利尿剂、ACE抑制剂和钙通道阻断剂。
12.如权利要求11所述的方法，其中β阻断剂选自包括以下的组：普萘洛尔、布新洛尔、卡替洛尔、卡维洛尔、拉贝洛尔、纳多洛尔、氧烯洛尔、喷布洛尔、吲哚洛尔、索他洛尔、噻吗洛尔、醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、塞利洛尔、美托洛尔、奈比洛尔、艾司洛尔、ICI-118,551和SR 59230A。
13.如权利要求11所述的方法，其中所述噻嗪利尿剂选自由以下组成的组：氯噻酮、氢氯噻嗪、甲氯噻嗪、美托拉宗、吲达帕胺、苄氟噻嗪、泊利噻嗪和氢氟噻嗪。
14.如权利要求11所述的方法，其中所述ACE抑制剂选自由以下组成的组：依那普利、雷米普利、喹那普利、培哚普利、赖诺普利、贝那普利、咪达普利、群多普利、西拉普利、福辛普利、卡托普利和佐芬普利。
15.如权利要求11所述的方法，其中所述钙通道阻断剂选自由以下组成的组：氨氯地平、克林地平、氯维地平、非洛地平、依拉地平、乐卡地平、左旋氨氯地平、尼卡地平、硝苯地平、尼莫地平、尼索地平、尼群地平、地尔硫卓和维拉帕米。
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| WO2001074348A2 (en) * | 2000-04-03 | 2001-10-11 | Bristol-Myers Squibb Co. | Vasopeptidase inhibitors to treat isolated systolic hypertension |
| EP3209289A4 (en) * | 2014-10-20 | 2018-04-11 | Anavex Life Sciences Corp. | A 19-144, a2-73 and certain anticholinesterase inhibitor compositions and method for anti-seizure therapy |
| JP7429942B2 (ja) * | 2015-07-22 | 2024-02-09 | アナベックス ライフ サイエンシズ コーポレイション | テトラヒドロ－ｎ，ｎ－ジメチル－２，２－ジフェニル－３－フランメタンアミン（ａｎａｖｅｘ２－７３）のエナンチオマーならびにシグマ１レセプターにより調節されるアルツハイマー型および他の傷害の処置におけるその使用 |
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2018
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- 2018-11-28 WO PCT/US2018/062853 patent/WO2019108653A1/en unknown
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- 2018-11-28 EP EP18884002.9A patent/EP3716968A4/en active Pending
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2022
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2023
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2024
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| US20070196510A1 (en) * | 2006-02-17 | 2007-08-23 | Gerber Michael J | Method for treating resistant hypertension |
| US20140170157A1 (en) * | 2011-06-15 | 2014-06-19 | Glaxosmithkline Intellectual Property (No.2) Limited | Method of selecting therapeutic indications |
| WO2018022848A1 (en) * | 2016-07-27 | 2018-02-01 | Anavex Life Sciences Corp. | A2-73 as a therapeutic for insomnia, anxiety, and agitation |
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| US20230071766A1 (en) | 2023-03-09 |
| EP3716968A4 (en) | 2021-09-01 |
| US11622955B2 (en) | 2023-04-11 |
| WO2019108653A1 (en) | 2019-06-06 |
| CA3083770A1 (en) | 2019-06-06 |
| EP3716968A1 (en) | 2020-10-07 |
| AU2024202998A1 (en) | 2024-05-23 |
| AU2023203356B2 (en) | 2024-02-08 |
| US20210186920A1 (en) | 2021-06-24 |
| AU2023203356A1 (en) | 2023-06-29 |
| AU2018375667B2 (en) | 2023-03-02 |
| CN111712241B (zh) | 2024-02-13 |
| JP7180673B2 (ja) | 2022-11-30 |
| JP2021504400A (ja) | 2021-02-15 |
| AU2018375667A1 (en) | 2020-06-18 |
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