CN108938632A - 用于治疗精神疾病的伊潘立酮代谢物及其应用 - Google Patents
用于治疗精神疾病的伊潘立酮代谢物及其应用 Download PDFInfo
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
本发明涉及用于治疗精神疾病的伊潘立酮代谢物R‑P88,以及R‑P88或其药用可接受盐、或者R‑P88的酯或所述酯的药用可接受盐在制备药物组合物中的应用,所述药物组合物用于治疗精神疾病并且每日施用1次至2次而降低QT间期延长和体位性低血压的风险,其中,所述精神疾病选自精神分裂症、分裂情感性障碍、双相情感障碍、抑郁症和重性抑郁症。
Description
本申请是分案申请,其原申请的国际申请号为PCT/US2013/031413,国际申请日为2013年03月14日,中国国家申请号为201380013841.X,进入中国国家阶段的进入日为2014年09月12日,发明名称为“用于治疗精神疾病的伊潘立酮代谢物”。
相关申请的交叉引用
本申请要求于2012年3月14日递交的共同申请的美国临时专利申请第61/610,664号的权益,通过援引将其并入本说明书中。
技术领域
本发明属于适合使用如伊潘立酮等非典型抗精神病药物治疗的疾病的治疗领域。
背景技术
伊潘立酮(1-[4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙酮)在美国专利5,364,866中得到公开,通过援引将其并入本说明书中。伊潘立酮的活性代谢物,例如S-P88(亦称作(S)-P-88-8891)可用于本发明中。参见例如WO2003020707,通过援引将其并入本说明书中。在一些情形中,在具有某些基因型的患者中优先使用伊潘立酮可能是有利的,例如WO2006039663和WO2003054226中所公开的,通过援引将其并入本说明书中。
伊潘立酮目前在美国被批准用于精神分裂症的急性期治疗。片的推荐目标剂量为12mg/日~24mg/日,b.i.d.(即,每日两次)施用。目标剂量范围通过每日剂量调整而实现,提防患者出现体位性低血压症状。必须由低起始剂量缓缓逐步调整,以避免因其α-肾上腺素能阻断特性引起的体位性低血压。片的推荐初始剂量为每日两次服用1mg。增加达到每日两次6mg~12mg目标剂量范围可以如下进行:在第2、3、4、5、6和7日分别将每日剂量调整至每日两次2mg,每日两次4mg,每日两次6mg,每日两次8mg,每日两次10mg、和每日两次12mg。最大推荐剂量为每日两次12mg(24mg/日)。
发明内容
本发明涉及适合使用非典型抗精神病药物、特别是伊潘立酮治疗的疾病的治疗,包括根据由体内R-P88的药代动力学推导的剂量对患者施用R-P88。
在一个特定的示例性实施方式中,本发明提供一种治疗罹患适合使用伊潘立酮治疗的疾病的患者的方法,所述方法包括使患者每日一次体内施用有效量的R-P88。
在另一实施方式中,本发明提供一种治疗罹患适合使用伊潘立酮治疗的疾病的患者的方法,所述方法包括使患者每日两次体内施用有效量的R-P88,其中所述有效量为每日两次3mg~9mg(总计6mg/日~18mg/日)。
本发明的这些示例性方面设计用于解决本文所述的问题和本领域技术人员可发现的未讨论的其他问题。
具体实施方式
人体内清除伊潘立酮的主要代谢途径有三种。具体而言,伊潘立酮被:
(1)转化为S-P88,所述S-P88(a)转化回伊潘立酮,建立动态平衡 和(b)通过CYP2D6途径被进一步代谢和消除;
(2)通过CYP2D6途径代谢为P95,后者然后被消除;
(3)通过CYP3A4途径代谢为P89,后者然后被消除。
本发明涉及一种治疗罹患适合使用如伊潘立酮等非抗精神病药物治疗的疾病的患者的方法,所述方法包括口服R-P88。
P88的化学名称是1-[4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基苯基]乙醇,或者又称作4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基-α-甲基苯甲醇。在人体内,发现P-88仅为S-对映异构形式,其具有以下结构:
然而,P-88也能够以其R对映异构形式合成,其具有以下结构:
P88及其S和R形式描述于美国专利第7,977,356号中,通过援引将其并入本说明书中,如同完全阐述一样。
虽然R-P88未在人体内发现,但是其针对相关受体的受体结合特性与伊潘立酮和S-P88在重要途径中的受体结合特性类似,因此可用作非典型抗精神病药物。
在人血浆中,R-P88体外比S-P88更慢地转化回伊潘立酮。本发明利用这一出乎意料的发现,在需要非典型抗精神病药物治疗的病症的治疗中,使用R-P88代替伊潘立酮,或者代替外消旋P88或S-P88。具体而言,虽然伊潘立酮以24mg/日的最大每日剂量每日两次施用,R-P88可以每日一次施用或者以比伊潘立酮(或S-P88)低的剂量每日两次施用。
因此,在本发明的一个示例性方面中,使罹患精神疾病的人口服有效量的R-P88或者其盐或溶剂化物,所述精神疾病例如为精神分裂症(schizophrenia)、分裂情感性障碍(schizoaffective disorder)、双相情感障碍(躁狂和/或抑郁)(bipolar disorder(maniaand/or depression))、抑郁症(depression)、重性抑郁症(major depression)、精神病发作(psychotic episodes)、孤独症(autism)、自闭症谱系障碍(autism spectrumdisorder)、脆性X染色体综合征(fragile X syndrome)和广泛性发育障碍(pervasivedevelopmental disorder)。有效量是在治疗过程中将对精神疾病具有预防或改善作用的量,所述精神疾病例如为精神分裂症或其症状,或者双相情感障碍。有效量在定量上可以视例如患者、所治疗的疾病或症状的严重程度以及施用途径而变化。
可以理解的是,剂量方案,包括实际施用的R-P88或者其盐或溶剂化物的量,将根据相关情况由合格的健康护理专业人士确定,所述相关情况包括例如所治疗的病症、所选择的施用途径、个体患者的年龄、体重和反应,以及患者症状的严重程度。当然应该对患者监测可能的不良事件,包括例如与伊潘立酮的施用相关的不良事件,例如QT间期延长和体位性低血压。
每日一次(q.d.)剂量方案
在本发明的一个示例性实施方式中,患者例如以下述量每日一次(q.d.)吞服包含有效量R-P88的药物组合物:1mg/日~24mg/日、6mg/日~24mg/日、12mg/日~24mg/日、6mg/日~18mg/日或6mg/日~12mg/日,例如1mg/日、2mg/日、3mg/日、4mg/日、5mg/日、6mg/日、7mg/日、8mg/日、9mg/日、10mg/日、11mg/日、12mg/日、14mg/日、16mg/日、18mg/日、20mg/日、22mg/日或24mg/日。在治疗初始阶段,每日施用的R-P88量可以逐步调整放大直至达到最终剂量,即最大剂量,类似于治疗初始阶段逐步调整伊潘立酮的方式。例如,患者可以按照以下增量方案每日一次施用R-P88:
每日一次1mg、每日一次2mg、每日一次4mg、每日一次6mg、每日一次8mg、每日一次10mg、每日一次12mg,从而达到12mg/日的最大(即,最终)剂量,或者
每日一次2mg、每日一次4mg、每日一次8mg、每日一次12mg、每日一次16mg、每日一次20mg、每日一次24mg,从而达到24mg/日的最大剂量,或者
每日一次2mg、每日一次4mg、每日一次8mg、每日一次12mg,从而达到12mg/日的最大剂量。
在本发明的另一些示例性q.d.剂量方案中,逐步调整放大至最终剂量可更迅速地进行,例如比伊潘立酮更迅速地进行,或者逐步调整放大可以被完全省略,在第一次施用时便对患者施用最终剂量。例如,在本发明的示例性实施方式中,简短的逐步调整放大可以包括:
在第1、2、3和4日每日一次1mg、每日一次4mg、每日一次8mg和每日一次12mg,从而达到12mg/日的最大剂量,或者
在第1、2和3日每日一次2mg、每日一次6mg和每日一次12mg,从而达到12mg/日的最大剂量,或者
在第1、2、3和4日每日一次4mg、每日一次8mg、每日一次16mg和每日一次24mg,从而达到24mg/日的最大剂量,或者
在第1和2日每日一次8mg和每日一次24mg,从而达到24mg/日的最大剂量。
因此,q.d.施用的示例性逐步调整方案包括例如:
第1日1mg q.d.,第2日2mg q.d,第3日4mg q.d.,第4日6mg q.d.,第5日8mg q.d.,第6日10mg q.d.和第7日及之后12mg q.d.,或者
第1日2mg q.d.,第2日4mg q.d.,第3日8mg q.d.,第4日12mg q.d.,第5日16mgq.d.,第6日20mg q.d.和第7日及之后24mg q.d.,或者
第1和2日2mg q.d.,第3和4日4mg q.d.,第5和6日8mg q.d.,和第7日及之后12mgq.d.,
第1日1mg q.d.,第2日4mg q.d.,第3日8mg q.d.和第4日及之后12mg q.d.,或者
第1和2日2mg q.d.,第3和4日6mg q.d.和第5日及之后12mg q.d.,或者
第1日4mg q.d.,第2日8mg q.d.,第3日16mg q.d.和第4日及之后24mg q.d.,或者
第1和2日8mg q.d.和第3日及之后24mg q.d.。
每日两次(b.i.d.)剂量方案
在本发明的一个示例性实施方式中,患者以下述量每日两次(b.i.d.)吞服包含有效量R-P88的药物组合物:1mg/日~24mg/日,例如2mg/日~18mg/日,例如6mg/日~18mg/日,例如6mg/日、12mg/日、16mg/日或18mg/日。在该示例性实施方式中,在治疗的初始阶段,每日施用的R-P88量可以逐步调整放大,直至达到最终剂量。例如,患者可以按照以下增量方案每日一次施用R-P88:
每日两次1mg、每日两次2mg和每日两次3mg,从而达到6mg/日的最大剂量,或者
每日两次1mg、每日两次2mg、每日两次3mg、每日两次4mg、每日两次5mg和每日两次6mg,从而达到12mg/日的最大剂量,或者
每日两次1mg、每日两次2mg、每日两次4mg、每日两次6mg、每日两次8mg,从而达到16mg/日的最大剂量,或者
每日两次1mg、每日两次2mg、每日两次4mg、每日两次6mg、每日两次8mg、每日两次10mg和每日两次12mg,从而达到24mg/日的最大剂量。
在本发明的另一些示例性b.i.d.剂量方案中,逐步调整放大至最终剂量可更迅速地进行,例如比伊潘立酮更迅速地进行,或者逐步调整放大可以被完全省略,在第一次施用时便对患者施用最终剂量。例如,在本发明的示例性实施方式中,简短的逐步调整放大可以包括:
在第1、2、3和4日每日两次1mg、每日两次4mg和每日两次6mg,从而达到12mg/日的最大剂量,或者
在第1和2日每日两次2mg和每日两次6mg,从而达到12mg/日的最大剂量,或者
在第1、2和3日每日两次1mg、每日两次4mg和每日两次12mg,从而达到24mg/日的最大剂量,或者
在第1、2和3日每日两次2mg、每日两次6mg和每日两次12mg,从而达到24mg/日的最大剂量。
因此,b.i.d.施用的示例性逐步调整方案包括例如:
第1日1mg b.i.d.,第2日2mg b.i.d.,第三日及之后3mg b.i.d.,或者
第1日1mg b.i.d.,第2日2mg b.i.d.,第3日3mg b.i.d.,第4日4mg b.i.d.,第5日5mg b.i.d.,第6日及之后6mg b.i.d.,或者
第1日1mg b.i.d.,第2日2mg b.i.d.,第3日4mg b.i.d.,第4日6mg b.i.d.,第5日及之后8mg b.i.d.,或者
第1日1mg b.i.d.,第2日2mg b.i.d.,第3日4mg b.i.d.,第4日6mg b.i.d.,第5日8mg b.i.d.,第6日10mg b.i.d.,第7日及之后12mg b.i.d.。
药物组合物和施用
对于治疗或预防用途,R-P88或者其盐或溶剂化物将作为下述药物组合物以通常方式施用,所述药物组合物采用标准和常规技术包含作为必要活性药物成分的R-P88和固体或液体药用可接受载体,以及可选的药用可接受赋形剂。
可用于本发明的实施中的药物组合物包含适当的口服用剂型。因此,如果使用固体载体,则制剂可以被压片,以粉末或颗粒形式置于硬明胶胶囊中,或者为锭剂或糖锭的形式。固体载体可以含有常规赋形剂,如粘合剂、填充剂、压片润滑剂、崩解剂和润湿剂等。片剂必要时可以通过常规技术包覆膜。如果采用液体载体,则制剂可以为糖浆、乳液、软明胶胶囊、注射用无菌介质、水性或非水性液体悬浮液的形式,或者可以为使用前需用水或其他适当介质重构的干式产品。液体制剂可以含有常规添加剂,如悬浮剂、乳化剂、润湿剂、非水性介质(包括食用油)、防腐剂和香味和/或着色剂。
药物组合物可以通过适于获得含有适当量R-P88的所期望的制剂的常规技术而制备。参见例如Remington's Pharmaceutical Sciences,Mack Publishing Company,Easton,Pa.,第17版,1985。
适当的载体和稀释剂的一些实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯和羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。制品可以另外包含润滑剂、润湿剂、乳化和悬浮剂、防腐剂、增甜剂或香味剂。可以配制本发明的组合物,以提供对患者施用后有效成分的迅速、持续或延迟释放。
可以将组合物以单位剂型配制。术语“单位剂型”是指适于作为用于人类对象和其他哺乳动物的单位剂量的物理离散单元,各单元含有预定量的活性材料以及所需的药物载体,该预定量经计算在治疗期间过程中产生所期望的预防或治疗效果。这种单位剂型可以经配制而具有根据本说明书或权利要求中所述的任意剂量方案施用R-P88所需的R-P88量。例如,如果使用R-P88以6mg/日b.i.d.治疗患者,则各单位剂型可以包含6mg R-P88,并且患者可以在早上服用一个单位剂型,并在下午或晚上服用一个单位剂型。或者,如果使用R-P88以12mg/日b.i.d.治疗患者,则各单位剂型可以包含6mg R-P88,并且患者可以在早上服用两个单位剂型,并在下午或晚上服用两个单位剂型。
在许多因素中,用以消除或减少与较高浓度伊潘立酮或伊潘立酮衍生物相关的校正心电图QT(QTc)间期的延长的伊潘立酮施用方法描述于WO 2006/039663、WO 2008/121899、WO 2009/036056、WO 2009/036100、WO 2010/117931、WO 2010/117937、WO 2010/117941、WO 2010/117943和WO2010/132866中,通过援引将所有这些文献并入本说明书中。这些方法也能够适用于根据本发明的方法施用的R-P88。
本发明因此包括R-P88,以及包含R-P88的药物组合物,它们用于适合根据以上概述和详述的剂量体系治疗使用非典型抗精神病药物治疗的疾病。
合成
R-P88可以通过已知方法合成,所述方法如美国专利第7,977,356号中所公开的那些方法等。如本文所述,R-P88可以通过具有式III的伊潘立酮的立体选择性还原而合成:
所述还原利用式IV的光学活性硼烷络合物进行:
反应可以根据常规方法而实施。可以根据已知程序,加工反应混合物并对由此获得的化合物进行纯化。
酸加成盐可以以已知方式由游离的碱产生,反之亦然。根据本发明使用的适当的酸加成盐包括例如盐酸盐(hydrochloride)。
用作初始材料的硼烷络合物可以根据已知程序,由相应的式Va和Vb的化合物产生:
式Va和Vb的初始材料是已知的。
实施例
本研究的目的是评价(R)-P88和(S)-P88在NAD和NADP存在下在人肝S9组分中向伊潘立酮的可能转化。附上一份来自本研究的标题为“InVitro Metabolism of(R)-P88and(S)-P88in Human Liver S9Fraction(人肝S9组分中(R)-P88和(S)-P88的体外代谢)”(“最终报告”)的最终报告。
在NAD和NADP存在下将三种浓度的(R)-P88和(S)-P88(1μm、10μm和100μM)与人肝S9组分温育。在初始速率条件下,将13种浓度的(R)-P88和(S)-P88(1μM~100μM)与人肝S9组分温育,以确定形成伊潘立酮的Michaelis-Menten酶动力学常数Km和Vmax。
所获得的数据显示,S-P88比R-P88明显更迅速地转化为伊潘立酮。在一些底物浓度下,R-P88转化为伊潘立酮的速率比S-P88转化为伊潘立酮的两倍还高。在下表中显示出这些统计学上显著的数据。
另外,实验结果包括,(R)-P88向伊潘立酮的转化显示了略微S形方向的曲线和“勾”形Eadie-Hofstee曲线,意味着变构反应。
相反,(S)-P88向伊潘立酮的转化最佳地拟合了双阶段饱和酶模型,这意味着两种酶有助于(S)-P88的代谢,一种是具有正常饱和动力学的高亲合性酶,另一种是具有线性(不饱和)酶动力学的低亲合性酶。
另外,预计R-P88向伊潘立酮的较慢转化将减少P95的形成,P95具有以下结构和化学名称:
4-[3-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]丙氧基]-3-甲氧基-苯甲酸,其牵涉到伊潘立酮的最初施用之后的体位性低血压发生期。
R-P88可以形成药用可接受盐。其也可以例如通过乙醇部分中的羟基形成脂肪酸酯及形成其药用可接受盐,例如US20070197595中所描述,通过援引将其并入本说明书中。本发明包括在R-P88以外使用这些盐、酯或该酯的盐,或者使用它们代替R-P88。
出于说明和描述的目的,已给出了本发明的各个方面的以上描述。其不意在穷举,或使本发明限于所公开的精确形式,而且显而易见的是,可以有许多修改和改变。这些对于本领域技术人员可能是显而易见的修改和改变包括在如所附权利要求所限定的本发明的范围内。
Claims (8)
1.R-P88或其药用可接受盐、或者R-P88的酯或所述酯的药用可接受盐在制备药物组合物中的应用,所述药物组合物用于治疗精神疾病并且每日施用一次而降低QT间期延长和体位性低血压的风险,
其中,所述精神疾病选自精神分裂症、分裂情感性障碍、双相情感障碍、抑郁症和重性抑郁症。
2.如权利要求1所述的应用,其中,所述药物组合物中R-P88或其药用可接受盐,或者R-P88的酯或所述酯的药用可接受盐的含量等于每日剂量为24mg。
3.如权利要求1所述的应用,其中,所述药物组合物中R-P88或其药用可接受盐,或者R-P88的酯或所述酯的药用可接受盐的含量等于每日剂量为12mg。
4.如权利要求1所述的应用,其中,所述精神疾病是精神分裂症。
5.R-P88或其药用可接受盐、或者R-P88的酯或所述酯的药用可接受盐在制备药物组合物中的应用,所述药物组合物用于治疗精神疾病并且每日施用两次而降低QT间期延长和体位性低血压的风险,
其中,所述精神疾病选自精神分裂症、分裂情感性障碍、双相情感障碍、抑郁症和重性抑郁症。
6.如权利要求5所述的应用,其中,所述药物组合物中R-P88或其药用可接受盐,或者R-P88的酯或所述酯的药用可接受盐的含量等于每日剂量为24mg。
7.如权利要求5所述的应用,其中,所述药物组合物中R-P88或其药用可接受盐,或者R-P88的酯或所述酯的药用可接受盐的含量等于每日剂量为12mg。
8.如权利要求5所述的应用,其中,所述精神疾病是精神分裂症。
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