CN114340641A - 治疗线粒体dna缺失障碍 - Google Patents
治疗线粒体dna缺失障碍 Download PDFInfo
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- CN114340641A CN114340641A CN202080062159.XA CN202080062159A CN114340641A CN 114340641 A CN114340641 A CN 114340641A CN 202080062159 A CN202080062159 A CN 202080062159A CN 114340641 A CN114340641 A CN 114340641A
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- deficiency
- acid
- pyrimidine
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Abstract
本公开内容描述了用于治疗线粒体DNA缺失综合征的方法,通过施用治疗量的包含二核苷酸化合物或其混合物的组合物来进行。本文还描述了用于治疗TK2缺乏症的化合物、组合物和方法。
Description
相关申请的交叉引用
本申请要求2019年9月5日提交的美国临时申请序列号62/896,218的权益,其公开内容通过引用整体并入。
发明领域
本公开内容描述了用于治疗线粒体DNA缺失综合征(MDS)的方法,通过施用治疗量的包含多核苷酸化合物或其混合物的组合物来进行。本文还描述了用于治疗胸苷激酶2(TK2)缺乏症的化合物、组合物和方法。
背景
线粒体被称作细胞的产生能量的细胞器。这些双膜细胞器的功能独立于它们所在的细胞,且甚至具有自身的基因组,所述自身的基因组与核基因组是分开的。虽然核基因组编码一些线粒体蛋白质,但线粒体基因组专门编码与能量相关的代谢过程(包括电子传递链和ATP的产生)相关的蛋白质。线粒体DNA缺失综合征(MDS)是一个总称,其用于描述范围广泛的以细胞线粒体DNA高度减少为特征的障碍。MDS是涉及线粒体DNA的核苷酸合成或复制的核基因突变的结果,并且与多种基因有关,所述基因包括TK2、SUCLA2、SUCLG1、POLG、DGUOK、MPV17、TYMP和RRM2B。(Chansprasert等人,2017)。因此,这些常染色体隐性障碍导致线粒体DNA(mtDNA)极度缺失,进而对能量生产产生负面影响。(El-Hattab等人,2013)。
症状出现在婴儿期或儿童早期,并且主要影响肌肉、肝脏或脑的组织,且通常表现为肌无力、器官和神经功能障碍以及体重减轻。然而,这些障碍在表型上是异质的。例如,SUCLA2、SUCLG1或RRM2B的突变导致脑肌病性MDS,且临床表现为张力减退和神经学问题。DGUOK、MPV17或POLG的突变表现为早发性肝功能障碍。(El-Hattab等人,2013)。TYMP的突变与进行性胃肠道运动障碍和周围神经病相关。(El-Hattab等人,2013)。这些障碍的严重程度和进展也是高度可变的,从轻微的表现到导致婴儿期和儿童期死亡的严重症状。由于临床表现的这种异质性,治疗选择限于主要通过营养补充来管理症状。
胸苷激酶2(TK2)缺乏症是一种特殊类型的MDS。酶胸苷激酶2是涉及参与核苷酸的再循环的线粒体DNA(mtDNA)合成的核编码的酶。(Genetics Home Reference,2013)。TK2基因的突变会降低酶活性并损害mtDNA核苷酸再循环,导致低水平的脱氧胸苷一磷酸和脱氧胞苷一磷酸。核苷酸库中的这种短缺会影响mtDNA合成,并最终导致可能在儿童早期开始的进行性肌病,最终导致运动技能丧失。(Garone等人,2018)。
目前,不存在针对TK2疾病的疾病改善疗法并且治疗主要是支持性的。尽管口服补充脱氧胸苷一磷酸(dTMP)和脱氧胞苷一磷酸(dCMP)已证明能够在动物模型中恢复mtDNA缺失并提高总体存活率,但这类治疗需要高剂量的每种脱氧核糖核苷一磷酸(dNMP)才能达到整体治疗益处并伴随显著副作用。
概述
本文所述的一个实施方案为在有此需要的受试者中治疗线粒体DNA缺失综合征的方法,包含对所述受试者施用治疗有效量的包含式I的化合物的多核苷酸组合物
其中:
R1为H或OH;
R2为嘌呤衍生物或嘧啶衍生物;
R3为嘌呤衍生物或嘧啶衍生物;且
R4为H或OH。
在一个方面,该组合物包含式I的化合物,其中R1为H,R2为5-甲基-2H-1λ2-嘧啶-2,4(3H)-二酮,R3为4-氨基-2H-1λ2-嘧啶-2-酮,且R4为OH。在另一个方面,该组合物为还包含其中R1为OH,R2为9λ2-嘌呤-6-胺,R3为2-氨基-9λ2-嘌呤-6(1H)-酮,且R4为OH的式I的化合物的混合物。
在一个方面,该组合物通过口服、肠道、静脉内或皮下施用。在另一个方面,该组合物通过静脉内施用。
在一个方面,与口服施用单个单核苷酸后的血浆水平相比,静脉内施用后每种单核苷的血浆水平更高。
在另一个方面,静脉内施用所述组合物导致具有第一AUC0-24h的血浆水平,且口服施用单个单核苷酸导致具有第二AUC0-24h的血浆水平,且其中第一AUC0-24h与第二AUC0-24h之比为约100-约400。
在又一个方面,当以约1mg/kg-约20mg/kg的剂量施用所述组合物时,相应核苷的血浆浓度为约50ng/ml-约5000ng/ml。
在一个方面,线粒体DNA缺失综合征包含胸苷激酶2缺乏症、琥珀酰CoA合成酶缺乏症、脱氧鸟苷激酶缺乏症、琥珀酰CoA连接酶缺乏症、核糖核苷酸-二磷酸还原酶亚单位M2 B酶缺乏症、胸苷磷酸化酶缺乏症和聚合酶γ缺乏症。在另一个方面,线粒体DNA缺失综合征包含胸苷激酶2缺乏症。
在一个方面,所述受试者为人。
本文所述的另一个实施方案为用于在有此需要的受试者中治疗胸苷激酶2(TK2)缺乏症的方法,包含:a)从受试者得到核酸样品;b)确定该受试者是否具有TK2缺乏症;c)施用治疗有效量的包含式1的多核苷酸化合物的组合物:
其中:
R1为H或OH;
R2为嘌呤衍生物或嘧啶衍生物;
R3为嘌呤衍生物或嘧啶衍生物;且
R4为H或OH;和d)测定相应单核苷的血浆水平;
其中相应核苷的血浆水平为约50ng/mL-约5000ng/mL。
本文所述的另一个实施方案为式I的化合物:
其中
R1为H或OH;
R2为嘌呤衍生物或嘧啶衍生物;
R3为嘌呤衍生物或嘧啶衍生物;且
R4为H或OH。
在一个方面,所述化合物基本上不含杂质。在另一个方面,R1为H,R2为胸腺嘧啶,且R3为胞嘧啶,R4为OH。
在另一个方面,药物组合物包含至少一种药学上可接受的赋形剂和治疗有效量的本文所述的化合物的任一种。在另一个方面,该组合物包含化合物,其中R1为H,R2为5-甲基-2H-1λ2-嘧啶-2,4(3H)-二酮,R3为4-氨基-2H-1λ2-嘧啶-2-酮,且R4为OH。
尽管没有具体描述,可以将一个或多个方面和实施方案并入不同的实施方案。即所有的方面和实施方案可以以任意方式或组合来组合。
附图简述
图1描绘测试制品的结构和代谢。
图2描绘直至给药后48h的dT和dC的血浆水平,对标记vs未标记测试制品的量校正并且对施用的测试制品总剂量校准。
图3描绘急性(acute)口服施用标记和未标记的dCMP+dTMP和急性静脉内施用标记和未标记的dC(P2)dT后标记校正的和剂量校准的总dT和dC的AUC0-24h暴露(exposure)。静脉内vs口服施用的血浆AUC0-24h的比对于dT和dC分别高大约350-倍和110-倍。
图4描绘单次静脉内施用和一次和两次皮下施用标记和未标记的dC(P2)dT后直至48h的dT和dC的血浆水平。
图5描绘胃肠外施用dC(P2)dT后标记校正的总dT和dC的AUC0-24h暴露。
详细描述
本公开内容描述了治疗线粒体DNA缺失综合征(MDS)的方法。本文还描述了用于治疗胸苷激酶2(TK2)缺乏症的化合物和方法。
定义
如本文所用的术语“约”是指包括在由术语“约”修饰的值的至多±10%的变化范围内的整数和分数部分的任意值。例如,短语“约50%”等价于≈50±10%的任意值,例如44.6%、45%、46%、47%、48%、49%、49.5%、50%、50.3%、51%、52%、53%、54%、55%等。
除非另有说明,否则如本文所用的“一种(a)”或“一个(an)”是指一个或多个。如本文所用,“有效量”是指当施用于需要治疗的患者时足以实现治疗效果的量。
如本文所用的术语“AUC0→24”是指0-24小时的血液(血浆、血清或全血)浓度相对时间曲线下的面积。
如本文所用的术语“衍生物”是指衍生自嘌呤或嘧啶的化合物,包括分别由嘌呤或嘧啶前体形成的化合物。
术语“剂量(dosage)”或“剂量(dose)”表示含有用单次施用足以产生治疗效果的量的活性成分制剂的任意形式。本文所用的剂型可以用于口服、肠道或静脉内施用。
如本文所用的术语“制剂”或“组合物”是指活性药物成分或药物与药学上可接受的赋形剂的组合。这包括口服可施用的制剂以及可通过其他方式可施用的制剂。
术语诸如“包括(include)”、“包括(including)”、“含有(contain)”、“含有(containing)”、“具有(has)”或“具有(having)”等是指“包含(comprising)”。
术语“或”可以为连接的(conjunctive)或分离的(disjunctive)。
如本文所用的术语“单核苷”是指连接至糖的单一嘌呤或嘧啶碱基。实例包括脱氧胞苷(dC)和脱氧胸苷(dT)。
如本文所用的术语“单核苷酸”是指游离酸或任意盐形式(诸如二钠盐)的连接至糖和磷酸基团的单一嘌呤或嘧啶碱基。实例包括脱氧胞苷一磷酸(dCMP)和脱氧胸苷一磷酸(dTMP)。
如本文所用的术语“二核苷酸”是指游离酸或任意盐形式(诸如二钠盐)的含有两个单核苷酸的化合物。例如,脱氧胞苷-脱氧胸苷二磷酸dC(P2)dT或dC(P2)dT.Na2。
如本文所用的术语“多核苷酸”是指含有一个以上单核苷酸的化合物。例如,多核苷酸化合物可以含有两个核苷酸。构成多核苷酸的单核苷酸可以均相同或不同。
如本文所用的术语“相应的单核苷”是指对应于单核苷酸的单一单核苷,或对应于二核苷酸或多核苷酸的单一单核苷组分。例如,在单核苷酸脱氧胞苷一磷酸(dCMP)中,相应的单核苷为脱氧胞苷(dC)。在另一个实例二核苷酸脱氧胞苷-脱氧胸苷二磷酸(dC(P2)dT)中,相应的单核苷为脱氧胞苷(dC)和脱氧胸苷(dT)。
如本文所用,术语“受试者”和“患者”在本文中可以互换使用。在一个实施方案中,所述受试者为人。
如本文所用的术语“基本上纯”是指具有可以由本领域技术人员识别为“纯”的纯度水平。这种纯度水平可以低于100%。
当涉及本文公开的化合物时,除非另有说明,否则以下术语具有如下含义。以下定义旨在阐明而非限制所定义的术语。如果本文使用的特定术语没有具体定义,则不应认为该术语是不确定的。相反,术语在其公认的含义内使用。
如本文所用的术语“嘌呤”是指杂环芳族有机化合物,其由与咪唑环稠合的嘧啶环组成。
如本文所用的术语“嘧啶”是指芳族杂环有机化合物。
如本文所用的“取代的”是指氢原子的取代,否则其可以存在于取代基上。当讨论环系时,任选的取代典型地为用1、2或3个取代基替代正常存在的氢。然而,当涉及直链和支链部分时,取代的数量可以为多个,发生在通常存在氢的任何地方。取代可以相同或不同。示例性的取代包括硝基、-NR’R”、氰基、-NR’COR”’、烷基、烯基、-C(O)、-SO2R”’、-NR’SO2R”’、-SO2NR’R”、-CONR’R”、-CONHC6H5、羟基、烷氧基、烷基磺酰基、卤代烷基、卤代烯基、卤代烷氧基、巯基(-SH)、硫代烷基、卤素、环烷基、杂环基、芳基或杂芳基,其中R’和R”相同或不同,且各自表示氢或烷基;或当R’和R”各自连接至氮原子时,它们可以形成含有4-6个环原子的饱和或不饱和杂环,且其中R”’为烷基或卤代烷基。
在某些情况中,所描绘的取代基可以促成光学和/或立体异构。具有相同分子式但其原子的键合性质或顺序或它们的原子空间排列不同的化合物称作“异构体”。原子空间排列不同的异构体称作“立体异构体”。彼此不是镜像的立体异构体称作“非对映异构体”,而彼此为不可重叠镜像的立体异构体称作“对映体”。当化合物具有不对称中心时,例如当它与四个不同的基团键合时,可能会出现一对对映体。对映体的特征可以在于其不对称中心的绝对构型且根据Cahn和Prelog规则被命名为(R)或(S)(Cahn等人,1966,Angew.Chem.78:413-447,Angew.Chem.,Int.Ed.Engl.5:385-414(errata:Angew.Chem.,Int.Ed.Engl.5:511);Prelog和Helmchen,1982,Angew.Chem.94:614-631,Angew.Chem.Internat.Ed.Eng.21:567-583;Mata和Lobo,1993,Tetrahedron:Asymmetry4:657-668),或其特征可以在于其中分子旋转偏振光平面的方式,并且被称作右旋或左旋(即,分别为(+)-或(-)-异构体)。手性化合物可以作为单独的对映体或作为其混合物存在。含有等比例对映体的混合物被称作“外消旋混合物”。
在某些实施方案中,本文公开的化合物可以具有一个或多个不对称中心;且这类化合物由此可以作为单独的(R)-或(S)-对映体或作为其混合物产生。除非另有指示,例如,通过指定式任意位置上的立体化学,否则对本说明书和权利要求书中特定化合物的描述或命名旨在包括单独的对映体及其混合物,外消旋的或其他的。用于测定立体化学和分离立体异构体的方法为本领域众所周知的。在具体的实施方案中,本文提供的化合物的立体异构体在用碱处理时被描述。
在某些施方案中,本文公开的化合物为“立体化学纯的”。立体化学纯的化合物具有由本领域技术人员可以识别为“纯”的立体化学纯度水平。当然,这种纯度水平可以低于100%。在某些实施方案中,“立体化学纯的”表示为基本上不含(即至少约85%或以上)可替代的异构体的化合物。在具体的实施方案中,该化合物至少约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%、约99.5%或约99.9%不含其他异构体。
此外,由式I表示的化合物的药学上可接受的前药也被包括在本发明中。药学上可接受的前药是指具有通过溶剂解或在生理条件下可以被转化成氨基、羟基、羧基等的基团的化合物。形成前药的基团的实例包括Prog.Med.,5,2157-2161(1985)或“PharmaceuticalResearch and Development”(Hirokawa Publishing Company,1990),第7卷,DrugDesign,163-198中所述的那些。术语前药贯穿于本说明书使用以描述化合物的任何药学上可接受的形式,在施用于患者时,其提供活性化合物。药学上可接受的前药是指在宿主中代谢(例如水解或氧化)以形成本发明的化合物的化合物。前药的典型实例包括在活性化合物的官能部分上具有生物学不稳定的保护基的化合物。前药包括可以被氧化、还原、胺化、脱氨基化、羟化、脱羟基化、水解、脱水、烷基化、脱烷基化、酰化、脱酰化、磷酸化、脱磷酸化而产生活性化合物的化合物。
如本文所用的“药学上可接受的盐”是指本文公开的化合物的任一盐,其保留了化合物的生物特性并且对于杀虫、兽医学或药物用途而言是无毒性的,或否则是不期望的。这类盐可以衍生自本领域公知的各种有机和无机抗衡离子。这类盐包括:(1)与有机或无机酸形成的酸加成盐,诸如盐酸、氢溴酸、硫酸、硝酸、磷酸、氨基磺酸、乙酸、三氟乙酸、三氯乙酸、丙酸、己酸、环戊基丙酸、乙醇酸、戊二酸、丙酮酸、乳酸、丙二酸、琥珀酸、山梨酸、抗坏血酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、苦味酸、肉桂酸、扁桃酸、邻苯二甲酸、月桂酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-甲酸、葡庚糖酸、3-苯丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、苯甲酸、谷氨酸、羟基萘酸、水杨酸、硬脂酸、环己基氨基磺酸、奎尼酸、黏康酸等酸。
盐还包括(仅作为实例)无毒性的有机或无机酸的盐,诸如卤化物(诸如氯化物和溴化物)、硫酸盐、磷酸盐、氨基磺酸盐、硝酸盐、乙酸盐、三氟乙酸盐、三氯乙酸盐、丙酸盐、己酸盐、环戊基丙酸盐、乙醇酸盐、戊二酸盐、丙酮酸盐、乳酸盐、丙二酸盐、琥珀酸盐、山梨酸盐、抗坏血酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、3-(4-羟基苯甲酰基)苯甲酸盐、苦味酸盐、肉桂酸盐、扁桃酸盐、邻苯二甲酸盐、月桂酸盐、甲烷磺酸盐(甲磺酸盐)、乙磺酸盐、1,2-乙二磺酸盐、2-羟基乙磺酸盐、苯磺酸盐(苯磺酸盐)、4-氯苯磺酸盐、2-萘磺酸盐、4-甲苯磺酸盐、樟脑酸盐、樟脑磺酸盐、4-甲基双环[2.2.2]-辛-2-烯-1-甲酸盐、葡庚糖酸盐、3-苯基丙酸盐、三甲基乙酸盐、叔丁基乙酸盐、月桂基硫酸盐、葡糖酸盐、苯甲酸盐、谷氨酸盐、羟基萘甲酸盐、水杨酸盐、硬脂酸盐、环己基氨基磺酸盐、奎尼酸盐、黏康酸盐等。
本公开内容包括本发明的所有药学上可接受的同位素标记的化合物,其中一个或多个原子被具有相同原子数但原子质量或质量数不同于通常在自然中存在的原子质量或质量数的原子替代。适合于包含在本发明的化合物中的同位素的实例包括如下的同位素,氢,诸如2H和3H,碳,诸如11C、13C和4C,氯,诸如36Cl,氟,诸如18F,碘,诸如123I和125I,氮,诸如13N和15N,氧,诸如15O、17O和18O,磷,诸如32P,和硫,诸如35S。本发明的某些同位素标记的化合物(诸如掺入放射性同位素的那些)可以用于药物或底物组织分布研究。放射性同位素氚,即3H,和碳-14,即14C鉴于其易于掺入和现成的检测方式而特别适用于此目的。用较重的同位素,诸如氘,即2H取代可以提供某些治疗优势,这归因于代谢稳定性更高,例如,体内半衰期增加或剂量需求降低,且由此在某些情况下可能是优选的。用正电子发射同位素诸如11C、18F、15O和13N进行取代可以用于正电子发射体层成像(PET)研究,以检查底物受体的占有率。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与所附实施例和制备中所述的那些类似的方法,使用适合的同位素标记的试剂替代前面采用的未标记的试剂来制备。
本公开内容提供了治疗线粒体DNA缺失综合征的方法。当mtDNA水平极度缺失并对细胞能量生产产生负面影响时,会导致线粒体DNA缺失综合征。(El-Hattab等人,2013)。因此,不预期受任何特定理论的束缚,认为本文提供的化合物代谢成它们相应的单核苷,且由此补充为mtDNA合成提供构建单元所需的核苷库。本公开内容考虑的化合物包括但不限于本文提供的示例性化合物及其盐。
本文所述的一个实施方案为用于治疗线粒体DNA缺失综合征的方法,包含施用治疗有效量的包含式I的化合物或其药学上可接受的盐的多核苷酸组合物:
其中
R1为H或OH;
R2为嘌呤衍生物或嘧啶衍生物;
R3为嘌呤衍生物或嘧啶衍生物;且
R4为H或OH。
嘌呤基团的实例包括、但不限于腺嘌呤、鸟嘌呤、次黄嘌呤、黄嘌呤、可可碱、咖啡因、尿酸、异鸟嘌呤。在一个方面,嘌呤为腺嘌呤或鸟嘌呤。
嘧啶基团的实例包括、但不限于胸腺嘧啶、胞嘧啶和尿嘧啶。在一方面,嘧啶为胸腺嘧啶或胞嘧啶。
多核苷酸组合物可以包含一个以上单核苷酸。在一个方面,多核苷酸为二核苷酸。
在一个方面,多核苷酸组合物包含式I的化合物,其中R1为H,R2为5-甲基-2H-1λ2-嘧啶-2,4(3H)-二酮,R3为4-氨基-2H-1λ2-嘧啶-2-酮,且R4为OH。在另一个方面,该组合物包含混合物,所述混合物进一步包含其中R1为OH,R2为9λ2-嘌呤-6-胺,R3为2-氨基-9λ2-嘌呤-6(1H)-酮,且R4为OH的式I的化合物。
在一个方面,化合物基本上不含杂质。基本上纯的化合物具有可以由本领域技术人员识别为“纯”的纯度水平。当然,这种纯度水平可以低于100%。在某些方面,“基本上纯”表示基本上不含(即至少约85%或以上)其他化合物的化合物。在具体的实施方案,该化合物至少约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%、约99.5%或约99.9%不含其他化合物。
本文所述的一个方面为包含如本文所述的式I的化合物的一种或多种和一种或多种药学上可接受的载体的组合物。
如本文所用的术语“组合物”旨在涵盖包含特定量的特定成分的产品,以及直接或间接由特定量的特定成分的组合产生的任何产品。所谓“药学上可接受的”是指载体、稀释剂或赋形剂必须与制剂的其他成分相容并且对其接受者无害。
用于施用本公开内容的化合物的药物组合物可以方便地以单位剂型的形式存在,并且可以通过制药领域众所周知的任何方法来制备。所有方法均包括使活性成分与构成一种或多种辅助成分的载体混合的步骤。通常,药物组合物通过将活性成分与液体载体或细碎的固体载体或它们两者均匀且紧密地混合,然后,如果必要,使产品成型为期望的制剂来制备。在药物组合物中,以足以对疾病的进程或状况产生期望的效果的量包括活性目标化合物。
含有活性成分的药物组合物可以是适合口服使用的形式,例如,片剂、药片、锭剂、水性或油性混悬液、可分散粉末或颗粒、乳剂和自乳化剂(如美国专利号6,451,339所述)、硬胶囊或软胶囊,或糖浆剂或酏剂。可以根据本领域已知的用于制备药物组合物的任何方法制备预期用于口服使用的组合物。这类组合物可以含有一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的试剂,以提供药学上优雅和可口的制备物。片剂含有活性成分与其他适用于制造片剂的无毒性药学上可接受的赋形剂的混合物。这些赋形剂可以为例如惰性稀释剂,诸如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露糖醇、山梨糖醇、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如PVP、纤维素、PEG、淀粉、明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以为未包衣的,或者它们可以通过已知技术进行肠溶包衣或以其他方式包衣以延迟在胃肠道中的崩解和吸收,从而提供在更长时间期限内的持续作用。例如,可以使用诸如单硬脂酸甘油酯或二硬脂酸甘油酯这样的延时材料。也可以通过美国专利号4,256,108;4,166,452;和4,265,874中所述的技术对它们进行包衣,以形成用于控释的渗透性治疗片剂。
用于口服使用的制剂也可以呈现为硬明胶胶囊,其中活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土混合,或呈现为软明胶胶囊,其中活性成分与水或油性介质(例如花生油、液体石蜡或橄榄油)混合。此外,乳剂可以用非水溶混性成分诸如油来制备并用表面活性剂诸如甘油单-二酯(mono-diglyceride)、PEG酯等来稳定。此外,可以将本文所述的多核苷酸配制成前药,以便以允许用于直接胞内递送多核苷酸至细胞的方式合成化合物。
水性混悬液含有活性物质与适合于制造水性悬浮液的赋形剂诸如含盐的盐(saline salt)或缓冲剂的混合物。这样的赋形剂为助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂可以为天然存在的磷脂,例如卵磷脂,或环氧烷烃与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七乙烯氧基十六烷醇(heptadecaethyleneoxycetanol),或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,诸如聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与衍生自脂肪酸和己糖醇酐(hexitolanhydride)的偏酯的缩合产物,例如聚乙烯脱水山梨糖醇单油酸酯。水性混悬液还可以含有一种或多种防腐剂(例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯)、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂(诸如蔗糖或糖精)。
可以通过将活性成分混悬在植物油(诸如花生油、橄榄油、芝麻油或椰子油)中或在矿物油(诸如液体石蜡)中来配制油性混悬液。油性混悬液可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以添加诸如上述那些的甜味剂和矫味剂以提供适口的口服制备物。这些组合物可以通过添加抗氧化剂诸如抗坏血酸来防腐。
适用于通过添加水来制备水性混悬液的可分散粉末和颗粒提供活性成分与分散剂或润湿剂、助悬剂和一种或多种防腐剂的混合物。适合的分散剂或润湿剂和助悬剂以上述举出的那些为示例。也可以存在其他赋形剂,例如甜味剂、矫味剂和着色剂。
本公开内容的药物组合物还可以为水包油型乳剂的形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡或这些的混合物。适合的乳化剂可以为天然存在的树胶,例如阿拉伯树胶或黄蓍胶,天然存在的磷脂,例如大豆、卵磷脂,以及衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯,以及所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳剂还可以含有甜味剂和矫味剂。
糖浆剂和酏剂可以用甜味剂(例如甘油、丙二醇、山梨糖醇或蔗糖)来配制。这种制剂还可以含有缓和剂、防腐剂。以及矫味剂和着色剂。口服溶液可以与例如环糊精、PEG和表面活性剂组合来制备。
在一个方面,该组合物可以通过静脉内施用。该药物组合物可以为无菌可注射水性或油性混悬液的形式。这种混悬液可以根据已知技术使用上文举出的那些适合的分散剂或润湿剂和助悬剂来配制。无菌可注射制备物也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如作为在1,3丁二醇中的溶液。可以使用的可接受的媒介物和溶剂为水、林格液和等渗氯化钠溶液。此外,无菌固定油(axed oil)通常用作溶剂或助悬介质。为此目的,可以使用任何温和的固定油(fixed oil),包括合成的甘油单或二酯。此外,脂肪酸诸如油酸可以用于制备注射剂。
如实施例所证实的,与口服施用相比,以显著更低的剂量静脉内施用如本文所述的组合物显示出与口服施用单独的单核苷酸疗法相比相应单核苷的血浆浓度改善(实施例1)。
在另一个方面,可以通过皮下施用所述组合物。
本公开内容的化合物也可以以栓剂的形式施用,用于药物的直肠施用。这些组合物可以通过将药物与适合的无刺激性赋形剂混合来制备,该赋形剂在常温下为固体但在直肠温度下为液体,且由此将在直肠中熔化以释放药物。这种材料为可可脂和聚乙二醇。
剂型可以含有约1mg/kg-约20mg/kg的多本文所述的多核苷酸组合物。在一个方面,所述组合物以约1mg/kg-约5mg/kg的剂量施用。在另一个方面,所述组合物以约3mg/kg-约8mg/kg的剂量施用。在另一个方面,所述组合物以约5mg/kg-约10mg/kg的剂量施用。在另一个方面,所述组合物以约8mg/kg-约13mg/kg的剂量施用。在一个方面,所述组合物以约10mg/kg-约15mg/kg的剂量施用。在又一个方面,所述组合物以约13mg/kg-约18mg/kg的剂量施用。在一个方面,所述组合物以约15mg/kg-约20mg/kg的剂量施用。
式I的化合物用于治疗线粒体DNA缺失综合征。这类综合征的实例包括、但不限于胸苷激酶2缺乏症、琥珀酰CoA合成酶缺乏症、脱氧鸟苷激酶缺乏症、琥珀酰CoA连接酶缺乏症、核糖核苷酸-二磷酸还原酶亚单位M2 B酶缺乏症、胸苷磷酸化酶缺乏症和聚合酶γ缺乏症。在本文所述的一个方面,线粒体DNA缺失综合征为胸苷激酶2缺乏症。
式I的化合物可以与一种或多种具有相同活性范围的试剂组合,例如,以增加活性,或与具有另一种活性范围的物质组合,例如,以扩宽活性范围。各自列出的试剂的任一种可以与式I的化合物和任意其他一种或多种独立地列出的试剂联用。
用于联合疗法的适合的试剂包括,其中一种或多种式I的化合物可以照此使用或以其作为与一种或多种其他药学活性物质组合的制备物或制剂的形式使用,所述药学活性物质诸如例如,用于治疗特定形式的MDS的症状的治疗剂,普遍存在的核苷代谢酶的抑制剂,包括、但不限于四氢尿苷、三乙酰尿苷、N-乙酰半胱氨酸、N-乙酰半胱氨酸酰胺、维生素E、免疫霉素(immucillin)H和tipiraci。所述组合可以为同一制剂的组成部分或可以单独或依次施用。
包含式I的化合物或其药学上可接受的盐的用于递送至人或其他哺乳动物的药物制备物优选为单位剂型,其中该制备物再被分成含有适量活性组分的单位剂量。单位剂型可以为包装的制备物,其含有离散量的制备物,诸如在小瓶或安瓿中的包装的片剂、胶囊和粉末。此外,单位剂型可以为胶囊、片剂或注射剂,或可以为包装形式的适当数量的任意这些。
单位剂量制备物中活性成分的量在约0.1mg-约1000mg之间可变或调整,根据特定应用和活性组分的功效的不同而定。如果期望,则组合物还含有其他相容性治疗剂。
在用于在人或其他哺乳动物中治疗线粒体DNA缺失综合征的治疗用途中,在治疗方法中使用的化合物以每间隔约0.1mg/kg-约100mg/kg的初始剂量施用。优选的间隔可以为每天、每周、每半月、每月、每两个月、每季度、每三年、每半年或每年一次。剂量可以一天一次、一天两次、一天三次或根据医师确定的必要次数施用。剂量可以根据患者需要的不同而变化,例如,所治疗的人或哺乳动物的大小、所治疗的病症的严重程度、施用途径和所用化合物的功效。在医师的技能范围内确定针对特定情况的适当剂量和施用途径。通常,治疗将以小于化合物最佳剂量的较小剂量开始,该剂量可以以小增量增加,直至达到特定情况下的最佳效果。为方便起见,如果期望,则总每日剂量可以在白天分成几部分施用。
为了理解本文所述的组合物的代谢,在施用后测定多核苷酸代谢成其相应的单核苷的血浆水平。在本文所述的一个方面,相应的单核苷的血浆水平高于施用单一单核苷酸的血浆水平。在另一个方面,相应核苷的血浆水平为约50ng/mL-约5000ng/mL。在另一个方面,相应的核苷的血浆水平为约75ng/mL-约2500ng/mL。
对于静脉内施用,有关血浆水平的0-约24小时时间的曲线下面积测量值(AUC0-24h)为约5000ng-h/mL-约120,000ng-h/mL。
本文所述的另一个实施方案为用于在受试者中治疗胸苷激酶2的方法,包含从受试者得到核酸样品,测定该受试者是否具有TK2缺乏症,施用治疗有效量的包含式I的化合物的组合物:
其中
R1为H或OH;
R2为嘌呤衍生物或嘧啶衍生物;
R3为嘌呤衍生物或嘧啶衍生物;
R4为H或OH;和
测定相应单核苷的血浆水平,其中相应核苷的血浆水平为约50ng/mL-约5000ng/mL。
可以测试表现出表型TK2缺陷的患者,包括以全身张力减退、近端肌无力、先前获得的运动技能的丧失、喂养不良和呼吸困难为特征的进行性肌病的最典型表现,以明确诊断该疾病。
可以使用一组已知导致mtDNA缺失综合征的基因进行分子遗传学测试。(Chanprasert,等人,2012)。可以通过对TK2编码区的序列分析来进行测试。还可以进行进一步的测试以证实TK2缺乏症的诊断,包括测试血清肌酸激酶浓度、肌电图、骨骼肌的组织病理学、线粒体DNA含量(拷贝数)和骨骼肌中的电子传递链(ETC)活性。
实施例
式I的化合物的制备
本公开的化合物或其药学上可接受的盐的制备可以经由下文所示的途径和中间体来完成。
方案1
方案1描述制备式I的化合物的通用方法。通过使用羰基二咪唑作为偶联试剂偶联相应的核苷酸三丁基铵盐来合成二磷酸核苷酸,得到期望的产物。在形成这种二核苷酸的过程中,也形成不对称化合物,诸如(dC(P2)dC)和(dT(P2)dT),目前使用的工艺足以满足小规模制备(1–5g),而在更大规模(100克)上期望更好的方法。
实施例1
确定口服给药两种单核苷酸(dCMP&dTMP)vs静脉内给药二核苷酸(dC(P2)dT)后两种单核苷酸(dCMP和dTMP)及其相应的单核苷(dC和dT)的全身暴露。如下制备测试制品:
未标记的测试制品:
dC=脱氧胞苷(核苷)
dT=脱氧胸苷(核苷)
dCMP=脱氧胞苷一磷酸(单核苷酸)
dTMP=脱氧胸苷一磷酸(单核苷酸)
dC(P2)dT或dT(P2)dC=脱氧胞苷-脱氧胸苷二磷酸(二核苷酸)
标记的测试制品:
dC*=15N3标记的dC(标记的核苷)
dT**=13C10和15N2标记的dT(标记的核苷)
相应标记的核苷酸为dC*MP和dT**MP
相应标记的二核苷酸为dC*(P2)dT**或dT**(P2)dC*。
这些测试制品的结构和代谢如图1中所示。
确定与单次口服施用dCMP+dTMP的剂量强度相比的单次静脉内注射dC(P2)dT的剂量强度,这导致dC和dT的全身暴露相差无几(comparable),其中将全身暴露定量为AUC0-24h。
核苷(dC和dT)及其相应的一磷酸核苷酸(dCMP和dTMP)在体内天然产生。为了区分天然存在的vs外源施用的dC/dT和dCMP/dTMP,经由口服途径给药标记的dC*MP/dT**MP和未标记的dCMP/dTMP的混合物,并且经由静脉内途径给药标记的dC*(P2)dT**和未标记的dC(P2)dT的混合物。标记的测试制品用作测定给药后外源性dC/dT和dCMP/dTMP的全身水平的示踪剂。
然后分析下列分析物的血浆样品:dT**、dC*、dT**MP、dC*MP以及dC*(P2)dT**。仅可检测到dT**和dC*,这表明dT**MP、dC*MP和dC*(P2)dT**在体内快速代谢。结果如表1中所示。
表1
如表1中所示,标记通过口服途径施用的总测试制品(TA)的10%,并标记通过胃肠外途径(静脉内)施用的总TA的20%。为了校正所施用的总TA(标记的+未标记的),对于口服和静脉内治疗组,分别将标记的分析物的血浆水平乘以10和5。此外,对于口服和静脉内治疗组,总TA剂量分别为1000mg/kg(900mg/kg未标记的+100mg/kg标记的)(通过口服途径施用)和10mg/kg(8mg/kg未标记的和2mg/kg标记的)。为了通过施用的TA的单位剂量进行校准,对于口服和静脉内治疗组,分别用分析物的血浆水平除以1000和10。口服和静脉内施用途径的dT和dC的标记校正和剂量校准的水平的结果如图2中所示。
图3显示给药后最初24h的2种分析物的血浆暴露,通过对来自图2的总剂量校准的dT和dC血浆水平计算曲线下的面积(AUC0-24h)来确定。两种分析物的静脉内vs口服的AUC0-24h差异具有统计学差异(p<0.01,t-检验)。静脉内/口服AUC(0-24h)之比对于dT为大约350且对于dC为大约。因此,基于标记校正的和剂量校准的PK分析,这些数据表明,为了递送dT和dC的相差无几的血浆暴露,与静脉内dC(P2)dT相比,我们可能分别需要口服施用大约350-倍和大约110-倍更高剂量的dTMP和dCMP。
实施例2
比较单次静脉内注射dC(P2)dT vs一次和两次皮下(S.C.)注射dC(P2)dT后dC和dT的全身暴露,其中第二次皮下注射是在第一次后24h施用。将研究设计概括在表2中。
表2
分析如下分析物的血浆样品:dT**、dC*、dT**MP、dC*MP和dC*(P2)dT**,且与实施例1一样,仅可检测到dT**和dC*。单次静脉内和一次和两次皮下施用标记的和未标记的dC(P2)dT组后的标记校准的dT和dC水平的血浆水平如图4中所示。图5显示给药后最初24h的3个治疗组的2种分析物的血浆暴露,通过对来自图4的总剂量校准的dT和dC血浆水平计算平均曲线下的面积(AUC0-24h)来确定。3个治疗组中平均AUC0-24h值无统计学差异,表明静脉内和皮下施用dC(P2)dT导致血浆中dT和dC的暴露相差无几。
本说明书中引用的所有出版物、专利和专利申请通过引用并入本文以用于使用这种引用的教导。
观察到的具体反应可以根据所选的特定活性化合物或是否存在载体,以及所采用的制剂类型和施用模式的不同而变化且取决于它们,并且根据本发明的实施考虑结果中的这种预期变化或差异。
尽管本文详细示例和描述了本发明的具体实施方案,但是本发明不限于此。上述详细描述是作为本发明的示例而提供的,而不应解释为构成对本发明的任何限制。变型对本领域技术人员而言将是显而易见的,并且所有不脱离本发明精神的变型均旨在被包括在所附权利要求的范围内。
参考文献
Chansprasert,S.和Craigen W.J.,(2017)Mitochondrial Disorders CausingCardioskeletal Myopathies in Childhood.Cardioskeletal Myopathies in Childrenand Young Adults.
El-Hattab,A.W.和Scaglia,F.,(2013)Mitochondrial DNA depletionsyndromes:review and updates of genetic basis,manifestations,and therapeuticoptions.Neurotherapeutics.Apr:10(2):186-198.
Garone,C.,Taylor,R.W.,Nascimento,A.,Poulton,J.,Fratter,C.,Domínguez-González,C.,Evans,J.C.,Loos,M.,Isohanni,P.,Suomalainen,A.,Ram,D.,Hughes,M.I.,McFarland,R.,Barca E.,Lopez Gomez,C.,Jayawant,S.,Thomas,N.D.,Manzur,A.Y.,Kleinsteuber,K.,Martin,M.A.,Kerr,T.,Gorman,G.S.,Sommerville,E.W.,Chinnery,P.F.,Hofer,M.,Karch,C.,Ralph,J.,Cámara,Y.,Madruga-Garrido,M.,Domínguez-Carral.J.,Ortez,C.,Emperador,S.,Montoya,J.,Chakrapani,A.,Kriger,J.F.,Schoenaker,R.,Levin,B.,Thompson,J.L.P,Long,Y.,Rahman,S.,Donati,M.A.,DiMauro.S.和Hirano M.,(2018)Retrospective natural history of thymidine kinase2deficiency.J Med Genet.Aug;55(8):515-521.
TK2-related mitochondrial DNA depletion syndrome,myopathic form:National Library of Medicine(US).Genetics Home Reference[Internet].Bethesda(MD):The Library;2013年9月;[2013年9月综述;2013年9月19日引述];[约6个屏].得自:https://ghr.nlm.nih.gov/condition/cystic-fibrosis
Claims (17)
2.权利要求1的方法,其中所述组合物包含式I的化合物,其中R1为H,R2为5-甲基-2H-1λ2-嘧啶-2,4(3H)-二酮,R3为4-氨基-2H-1λ2-嘧啶-2-酮,且R4为OH。
3.权利要求1的方法,其中所述组合物为进一步包含其中R1为OH,R2为9λ2-嘌呤-6-胺,R3为2-氨基-9λ2-嘌呤-6(1H)-酮,且R4为OH的式I的化合物的混合物。
4.权利要求1–3中任一项的方法,其中所述组合物通过口服、肠道、静脉内或皮下施用。
5.权利要求1–4中任一项的方法,其中所述组合物通过静脉内施用。
6.权利要求5的方法,其中与口服施用单个单核苷酸后的血浆水平相比,静脉内施用后每种单核苷的血浆水平更高。
7.权利要求1–6中任一项的方法,其中所述组合物的静脉内施用产生具有第一AUC0-24h的血浆水平,并且单个单核苷酸的口服施用产生具有第二AUC0-24h的血浆水平,且其中第一AUC0-24h与第二AUC0-24h之比在约100-约400。
8.权利要求1–7中任一项的方法,其中当组合物以约1mg/kg-约20mg/kg的剂量施用时,相应核苷的血浆浓度在约50ng/ml-约5000ng/ml。
9.权利要求1–8中任一项的方法,其中所述线粒体DNA缺失综合征包含胸苷激酶2缺乏症、琥珀酰CoA合成酶缺乏症、脱氧鸟苷激酶缺乏症、琥珀酰CoA连接酶缺乏症、核糖核苷酸-二磷酸还原酶亚单位M2 B酶缺乏症、胸苷磷酸化酶缺乏症和聚合酶γ缺乏症。
10.权利要求9的方法,其中线粒体DNA缺失综合征包含胸苷激酶2缺乏症。
11.权利要求1–10中任一项的方法,其中所述受试者为人。
14.权利要求13的化合物,其中该化合物基本上不含杂质。
15.权利要求13或14的化合物,其中当R1为H时,R2为胸腺嘧啶,且R3为胞嘧啶,R4为OH。
16.药物组合物,包含至少一种药学上可接受的赋形剂和治疗有效量的权利要求13–15中任一项的化合物。
17.权利要求16的组合物,其中所述化合物包含:R1为H,R2为5-甲基-2H-1λ2-嘧啶-2,4(3H)-二酮,R3为4-氨基-2H-1λ2-嘧啶-2-酮,且R4为OH。
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