CN100441175C - 化合物用于制备预防药物诱导的细胞毒性药物的用途 - Google Patents
化合物用于制备预防药物诱导的细胞毒性药物的用途 Download PDFInfo
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- CN100441175C CN100441175C CNB2004800146578A CN200480014657A CN100441175C CN 100441175 C CN100441175 C CN 100441175C CN B2004800146578 A CNB2004800146578 A CN B2004800146578A CN 200480014657 A CN200480014657 A CN 200480014657A CN 100441175 C CN100441175 C CN 100441175C
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- piperazine
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Abstract
本发明涉及化合物在制备用于预防和/或治疗诱导的细胞毒性的药物中的用途,所述细胞毒性例如肾毒性和耳毒性,特别是所述细胞毒性是由于药物治疗而诱导的。在优选实施方案中,所述化合物具有至少两个氮原子,更优选的至少两个氨基。本发明化合物能阻断细胞毒性化合物与巨蛋白受体的结合,从而抑制该细胞毒性化合物摄入细胞内。本发明还涉及用于所述治疗的新化合物,以及降低细胞毒性化合物更具体而言是庆大霉素的细胞毒性的方法。
Description
发明领域
本发明涉及细胞毒性治疗技术领域并公开了用于上述治疗的化合物和组合药物(combination medicaments)。
发明背景
本发明涉及预防器官损伤,特别是预防由于给予治疗剂而引起的肾脏和内耳器官损伤的化合物。
临床应用的多种药物对诸如肾脏和内耳这样的器官是有毒性的。其中著名的药物有顺铂、异环磷酰胺、环孢素、两性霉素B、丙戊酸盐、多粘菌素B和治疗抗体。但是,特别重要的是氨基糖苷类,其是治疗重度细菌感染的最重要抗生素之一。它们是对抗革兰氏阴性菌的优选药剂。目前,氨基糖苷类在抗感染药剂领域的市场份额正快速增长。最主要的是由于对其它种类抗生素耐药的致病菌株出现的普遍增长。
临床应用上述药物的主要障碍是其严重的耳毒性和肾毒性(耳和肾)副作用,从长远来看,它们会导致听力完全丧失和肾衰竭。从而,使用这些药物不仅伴随着高风险,而且需要承担用于药物监测和诊断的高额费用。因此,在工业国家,这些药物的使用局限于发生最严重感染时。因为其低生产成本,在发展中国家氨基糖苷类使用更为频繁,70%的所有后天性聋归因于氨基糖苷类。
导致毒性的潜在机制并不清楚。到目前为止已知的是药物与肾脏和内耳中细胞的表面结合,并且通过未知的机制吸收进入细胞。由于这些药物在细胞内不易降解,所以它们在细胞内积聚,导致细胞结构破坏,从而导致肾损伤和听力丧失。已经证实多种表面结构或受体是导致该种抗生素结合和摄取的原因。
Moestrup等人认为巨蛋白受体(megalin)(一种肾表面受体)是导致抗生素摄取的原因(Moestrup等人,J.Clin.Invest.96,1404-1413,1995)。巨蛋白受体是低密度脂蛋白(LDL)受体基因家族的600kDa的内吞受体。巨蛋白受体是一种多功能的清除受体,其结合并摄入多种大分子。巨蛋白受体的序列如下所示:cDNA:U33837;基因:NT 002176。
被认为涉及抗生素相互作用的另一种受体是维生素B12受体(cubilin)。维生素B12受体是一种与巨蛋白受体共结构域的460kDa的膜结合蛋白,其可以在巨蛋白受体介导的维生素B12受体结合配体细胞内摄之前,通过在细胞表面隔离抗生素/治疗剂来促进内吞过程。换句话说,治疗剂可以结合到维生素B12受体,也可以直接结合到巨蛋白受体。但是,维生素B12受体显示出不能独自介导内吞,而是与巨蛋白受体物理联合并以含有该受体的复合物形式摄入细胞。维生素B12受体的序列如下所示:cDNA:XM_011904;基因:NT_008682(人类染色体10序列片段草图)。
已经研发出许多用于预防氨基糖苷类毒性副作用的策略。例如研制具有较少副作用的新氨基糖苷类(参见amikacin,a semi-synthetic derivative ofkanamycin(Begg,E.J. & Barclay,M.L.Br.J.Clin.Pharmac.39,597-603,1995)),和氨基糖苷类与其它化合物同时给药,例如与neutrophin-3(Ernfors,P.,Duan,M.L.,ElShamy,W.M. & Canlon,B.Nat.Med.2,463-467(1996))、nitrendipine(Lee,S.M.,Pattison,M.E. & Michael,U.F.J.Cardiovasc.Pharmacol.9,S65-S69(1997))、圆叶鹿蹄草(Xuan,W. & Dong,M.Ann.Otol.Rhinol.Laryngol.104,374-380(1995))或抗氧化剂(Schacht,J.Head and NeckSurgery 118,674-677(1998))同时给药。
Jones等人(Jones,M.M.,Basinger,M.A.,和Holscher,M.A.;Fundamental and applied toxicology,18,181-188(1992))描述了通过临床使用含硫化合物来控制顺铂的肾毒性。Jones等人公开了含硫化合物如何与来自顺铂铂部分的水解产物结合,从而降低了顺铂的肾毒性副作用。该文献没有公开能与维生素B12受体受体和/或巨蛋白受体和/或巨蛋白和维生素B12的共受体结合的降低细胞毒性的化合物或药物。
本发明提供了化合物,当其单独使用或与导致所述细胞毒性的治疗剂联合使用时,具有改善的细胞毒性降低作用。
发明概述
因此,本发明公开了含有通式(I)结构的化合物、或其可药用加成盐或水合物在制备用于预防和/或治疗诱导的细胞毒性的药物中的用途,
-N’-X-Y-N”-(I)
其中X代表一个原子且Y代表至少一个原子,并且X和Y可独立地被取代至少一次,条件是当引发细胞毒性的药剂是顺铂时,该化合物不是生物素。
另外,本发明涉及含有通式(IV)结构的化合物、或其可药用加成盐或水合物在制备用于预防和/或治疗诱导的细胞毒性的药物中的用途,
其中,
各个R1和R2独立地选自C、S、N、O,任选被C、S、N、O、OH、氢、烷基、烯基、炔基、苯基、苄基、胺(NH)、卤素、取代的低级烷基、芳基、杂环烷基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基取代,任选进一步被C、S、N、O、OH、苯基、胺(NH)、卤素、取代的低级烷基、芳基、杂环基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基、烷氧基、羧基、卤素、三氟甲基、氰基、氨基、或硝基一次或多次取代,并且其中
m是1-8的整数,
n是1-8的整数,
N’和N”是氮,
R3、R4、R5和R6独立地选自C、S、N、O、OH、氢、烷基、烯基、炔基、苯基、苄基、胺(NH)、卤素、取代的低级烷基、芳基、杂环烷基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基,任选进一步被C、S、N、O、OH、苯基、胺(NH)、卤素、取代的低级烷基、芳基、杂环基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基、烷氧基、羧基、卤素、三氟甲基、氰基、氨基、或硝基一次或多次取代,
或者R3、R4、R5和R6中的一个或多个是化学键。
当任何组分中任何变量出现不止一次时,每个定义是独立的。
本发明的另一方面,公开了一种组合药物,其包含本发明化合物和在细胞毒性治疗中同时、分别或相继使用的治疗剂,所述细胞具有巨蛋白受体和/或维生素B12受体和/或巨蛋白和维生素B12的共受体。
本发明还公开了是庆大霉素的一部分的化合物用于预防和/或治疗诱导的细胞毒性的用途,其中所述细胞具有巨蛋白受体和/或维生素B12受体,以及被称为Garoseamine、2-脱氧链霉胺和Purpurosamine的化合物用于预防和/或治疗诱导的细胞毒性的用途。
本发明还涉及具有通式(VII)的化合物:
(Aq-X)p (VII)
其中
A独立地或组合选自式(I)和/或式(II)和/或式(III)和/或式(IV)和/或式(V)和/或式(VI)、Garoseamine、Purpurosamine和2-脱氧链霉胺,并且其中
X是间隔基,
q是1-150的整数,
p是1-150的整数,
及其用于预防和/或治疗诱导的细胞毒性的用途。
在另一个实施方案中,本发明涉及一种降低至少一种细胞毒性化合物的细胞毒性的方法。
当局部给药细胞毒性化合物,例如吸入并且不希望全身摄入时,还可以使用本发明。因为细胞毒性化合物的摄入被认为是由于结合了巨蛋白受体,因此阻断所述受体可以预防全身摄入。特别是当治疗肺部和支气管感染时,为了减少全身摄入,将抗生素化合物与本发明的化合物联合给药是有利的。
因此,本发明进一步涉及本发明的化合物在制备用于抑制细胞毒性化合物全身摄入的药物中的用途。本发明的化合物优选以与细胞毒性化合物相同的给药形式局部给药。
附图说明
图:显示了庆大霉素抑制剂化合物的例子。
图2:显示了可能的庆大霉素部分。
图3:显示了庆大霉素的3D结构。
图4:显示了选择的抑制剂对巨蛋白受体的抑制。
图5:显示了选择的抑制剂对巨蛋白受体的抑制。
图6:显示了腹腔注射3mg选择的化合物之后小鼠肾脏中庆大霉素的摄入。
图7:显示了选择的庆大霉素抑制剂。
发明详述
定义:
烷基:术语“烷基”是指饱和的直链或支链烃基,例如甲基、乙基、异丙基、叔丁基、庚基、十二烷基、十八烷基、戊基、2-乙基己基等。
取代的低级烷基是指具有1个至3个取代基的低级烷基,所述取代基选自羟基、烷氧基、氨基、酰氨基、羧基、酰基、卤素、氰基、硝基和巯基。
杂环基是指具有至2个环,每个环具有3至8个原子且并入了1或2个环杂原子(选自N、O或S(O)0-2)的单价饱和环基团,并且该基团可任选地被1个或2个取代基取代,所述取代基选自羟基、氧代、氰基、低级烷基、低级烷氧基、低级卤代烷氧基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基(alkyaminofarbonyl)、芳基氨基羰基、烷基羰基氨基、或芳基羰基氨基。
杂芳基是指具有1至3个环,每个环具有4至8个原子且在环上并入了1或2个杂原子(选自氮、氧或硫)的单价芳香环基团,其可任选地被1个或2个取代基取代,所述取代基选自羟基、氰基、低级烷基、低级烷氧基、低级卤代烷氧基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基和芳基羰基氨基。
环烷基是指具有1至2个环,每个环具有3至8个原子的单价饱和碳环基团,其可任选地被1个或2个取代基取代,所述取代基选自羟基、氰基、低级烷基、低级烷氧基、低级卤代烷氧基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、氨基、烷基氨基、烷基磺酰基、芳基磺酰基、烷基氨基磺酰基、芳基氨基磺酰基、烷基磺酰基氨基、芳基磺酰基氨基、烷基氨基羰基、芳基氨基羰基、烷基羰基氨基和芳基羰基氨基。
诱导的细胞毒性是指治疗剂能在暴露于该治疗剂的细胞中引发毒性反应。
细胞毒性:当一种治疗剂直接能导致细胞死亡时,将其定义为有毒的。
细胞死亡:在本文中细胞死亡以各种方式定义,并涵盖已失去所有功能的细胞、已失去特定功能例如激素合成的细胞、或进一步分化能力降低的细胞。
阳离子基团:当包含一种化学基团的化合物溶于溶剂中时,优选溶于水中时,该化学基团能作为质子供体。
具体化合物的部分包括所述具体化合物的基团或片段。
间隔基,在本文中是指直接连接式(I)、(II)、(III)、(IV)、(V)或(VI)单体的原子。该间隔基还可以直接将式(I)、(II)、(III)、(IV)、(V)和/或(VI)化合物连接到本发明组合药物所述的治疗剂上。
形成环是指当环结构形成时,所述原子通过键连接。
除非另有指示,治疗剂与药物同义。
本发明的原则是减少由治疗剂引起的副作用,尤其是肾脏和内耳器官损伤。治疗剂的毒性可能是由于所述器官的细胞中治疗剂的积聚。因此,本发明集中于抑制治疗剂在细胞内的积聚。
因此,本发明涉及能抑制细胞内积聚的新化合物的用途。其例如可通过如下方式实现:通过阻断足够量的巨蛋白受体上的结合位点和/或阻断治疗剂来抑制治疗剂结合到巨蛋白受体上,从而使其维持正常的治疗作用但抑制与受体结合。
本发明公开了用作拮抗剂的化合物在制备用于预防和/或治疗诱导的细胞毒性的药物中的新用途。另外,还公开了新颖的化合物和已知抗生素庆大霉素的部分,以及其作为细胞毒性减少剂的治疗用途。
化合物的新用途
在本发明的范围内,本发明化合物可结合到与引发细胞毒性有关的任何特定受体以抑制结合和治疗剂任选地摄入细胞。
优选,本发明化合物能结合受体上足够量的结合位点,或者能结合受体并空间阻碍治疗剂的结合。
因此,本发明最广泛的方面涉及含有通式(I)结构的化合物在制备用于预防和/或治疗诱导的细胞毒性的药物中的用途,
-N’-X-Y-N”-(I)
其中X代表一个原子且Y代表至少一个原子,并且X和Y可独立地被取代至少一次,且
N’和N”是氮、硫或磷(在优选实施方案中,N’或N”中至少一个是氮;更优选N’和N”均是氮),条件是该化合物不是生物素。
如上所述,N’和N”之间的原子数至少是两个。但是,N’和N”之间的原子数可以至少三个,例如至少四个,例如至少五个,如至少六个,如至少七个,如至少八个。
但是,在本发明的优选实施方案中,N’和N”之间的原子数是偶数,例如两个原子,如四个原子,如六个原子,如八个原子。在本发明图7中,说明了N’和N”之间有偶数个原子的化合物,其中例如1,6-二氨基己烷在N’和N”之间有六个原子。根据本发明,已经发现了N’和N”之间有偶数个原子的化合物特别有希望作为诱导的毒性的抑制剂。因此,在优选实施方案中,N’和N”间隔两个原子。在另一实施方案中,N’和N”间隔四个原子。在再一实施方案中,N’和N”间隔六个原子。
本发明一个实施方案中,公开了含有通式(II)结构的化合物、或其可药用加成盐或水合物在制备用于预防和/或治疗诱导的细胞毒性的药物中的用途,
-N’-C-C-N”-(II)
其中N’和N”是氮。
在另一个实施方案中,所述化合物包含通式(III)结构,
-N’-C-N-C-N”-(III)
其中N’和N”是氮,
或其可药用加成盐或水合物,用于制备预防和/或治疗诱导的细胞毒性的药物。
在一个实施方案中,本发明涉及含有通式(IV)结构的化合物、或其可药用加成盐或水合物在制备用于预防和/或治疗诱导的细胞毒性的药物中的用途,
其中,
各个R1和R2独立地选自C、S、N、O,任选被C、S、N、O、OH、氢、烷基、烯基、炔基、苯基、苄基、胺(NH)、卤素、取代的低级烷基、芳基、杂环烷基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基取代,任选进一步被C、S、N、O、OH、苯基、胺(NH)、卤素、取代的低级烷基、芳基、杂环基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基、烷氧基、羧基、卤素、三氟甲基、氰基、氨基、或硝基一次或多次取代,并且其中
m是1-8的整数,
n是1-8的整数,
N’和N”是氮,
R3、R4、R5和R6独立地选自C、S、N、O、OH、氢、烷基、烯基、炔基、苯基、苄基、胺(NH)、卤素、取代的低级烷基、芳基、杂环烷基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基,任选进一步被C、S、N、O、OH、苯基、胺(NH)、卤素、取代的低级烷基、芳基、杂环基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基、烷氧基、羧基、卤素、三氟甲基、氰基、氨基、或硝基一次或多次取代,
或者R3、R4、R5和R6中一个或多个是化学键。
在优选实施方案中,所述化合物由通式(IV)的结构构成。
附带条件
但是,当导致细胞损伤的治疗剂是顺铂时,本发明的上述化合物不能是具有下面所示化学式的生物素化合物:
化合物的结构
基团/环形成
本发明涉及具有各种结构的毒性抑制化合物。上述结构可以是线性结构或环状结构。无论本发明化合物的具体结构是什么,所述化合物的原子必须以使得化合物能发挥出其抑制作用的方式排布。上述抑制作用可能是由于化合物对细胞毒性有关的受体的拮抗结合作用和/或由于化合物与治疗剂结合而导致防止治疗剂与其受体之间的功能性结合。“功能结合”是指导致细胞毒性反应的治疗剂与其受体之间的结合。
如上所述的本发明的线性或环状结构取决于如本文中提及的基团的性质。
因此,在本发明的一个实施方案中,基团R6和R2形成环或基团R5和R2形成环。
还有基团形成环状结构的其它实施方案。在一个该种实施方案中,R3和R1形成环或R4和R1形成环;它的一个实例如通式(V)所示。在另一个实施方案中,R4和R6形成环;它的一个实例如通式(VI)所示。
在本发明的范围内,还提供了包含在基团和N’或N”之间成环状结构的化合物。因而,在优选实施方案中,R4和N’形成环。
在另一优选实施方案中,基团R6和N”形成环结构。
术语“环”与术语“环状”同义。
根据环状结构中化学基团的性质,化合物的上述环状结构可以具有多种环原子数。因此,在本发明的一个实施方案中,化合物的环结构是5-元的。在本发明的另一个实施方案中,化合物的环结构是6-元的。另外,在本发明的另一个实施方案中,化合物的环结构是7-元的。优选,所述环结构是6-元的。
电荷
本发明的化合物能供给至少一个质子,更优选至少两个质子,因为已证实这样的化合物结构允许细胞毒性抑制。因此,所述化合物优选具有至少一个能作为质子供体的氨基。更优选,所述化合物具有至少两个能作为质子供体的氨基。
因此,在本发明优选的实施方案中,R3、R4、R5和R6中至少一个是H。
在本发明更优选的实施方案中,R3和R5是H。例如,其中两个基团均代表氢原子的化合物由本发明化合物哌嗪示意说明(参见图1)。
多元电荷分布
根据本发明,已经发现含有多元电荷分布的化合物作为诱导的细胞毒性的抑制剂特别有用。
因此,如上所讨论,在本发明优选的实施方案中,本发明化合物在溶液中具有至少1个,例如2个正电荷,例如至少2个正电荷,例如2个正电荷。
通过在1-300内选择正电荷数,一般能阻断有关介导引发毒性的受体上足够数量的结合位点,所述受体例如为巨蛋白受体和/或维生素B12受体和/或巨蛋白和维生素B12的共受体。这导致抑制有关引发细胞毒性的治疗剂的摄入。
在优选实施方案中,化合物具有至少3个正电荷,例如至少5个正电荷,例如至少10个正电荷。
在一个实施方案中,优选多元电荷分布具有与引发细胞毒性的治疗剂相同的电荷分布。
在维生素B12受体和巨蛋白受体的情况下,为什么优选多元电荷分布的似乎合理的解释是,氨基糖苷庆大霉素对受体的结合并不必然取决于受体的天然构象,因为二硫键的还原没有明显干涉配体结合。而且,加入EDTA,耗尽了钙并影响受体稳定性,但没有破坏结合。这表明,受体与庆大霉素之间的相互作用可能取决于简单的离子相互作用,而不是受体的整体构象。
通式(V)和(VI)
在一个实施方案中,本发明还涉及具有通式(V)
或通式(VI)结构的化合物,或其可药用加成盐或水合物在制备用于预防和/或治疗诱导的细胞毒性的药物的用途,
其中N’和N”、m、n、R1、R2、R3、R4、R5和R6如上述式(IV)所定义。
对于本发明化合物,m和n优选1-7的整数,例如1-6,例如1-5,例如1-4,例如1-3。最优选,m和n均是1。
化学键
本发明的基团可以由上述已经公开的化学基团代表。但是,在本发明中,还提供了含有由化学键代表的基团的化合物。在一个或多个基团是化学键的实施方案中,获得了包含例如上述环状结构之类结构的化合物。
因此,在一个实施方案中,R3、R4、R5和R6中至少三个是化学键。
在另一个实施方案中,R3、R4、R5和R6中至少两个是化学键。
另外,在另一个实施方案中,R3、R4、R5和R6中至少一个是化学键。
本发明的化学键可以是任何化学键,例如共价键。
为了说明基团是化学键的原则,设想上述式(VI)的R6代表化学键。在该具体实施方案中,式(VI)的6-元环结构将变为包含5-元环结构的化合物。根据基团由化学键代替化学基团,同样标记的其它化合物结构会改变。
结合维生素B12受体和/或巨蛋白受体
本发明化合物均能与巨蛋白受体和/或维生素B12受体和/或巨蛋白和维生素B12的共受体结合。另外,本发明化合物能与治疗剂结合。与受体结合的情况下,就阻断治疗剂与受体结合而言,结合有效是很重要的。例如,受体巨蛋白包含50-150个治疗剂庆大霉素的结合位点,并且对于本发明用途的有效性而言,本发明化合物能抑制有效量的这些结合位点是很重要的。
不受理论的束缚,本发明化合物能结合维生素B12受体和/或巨蛋白受体的益处是发现了这些受体与氨基糖苷诱导的肾脏和耳的细胞毒性有关。使用本发明化合物,对细胞毒性如肾毒性和耳毒性具有抑制作用。
本发明化合物可结合巨蛋白受体以抑制内吞作用,或者结合维生素B12受体受体以减少隔离由此抑制或减少内吞作用。
共受体
在本发明的范围内,所述化合物可与巨蛋白和维生素B12的共受体结合。
N原子间距离
已经发现化合物(参见所有的本发明化学式)的N’和N”原子间距在本发明抑制剂的效能方面起着重要的作用。
因此,在本发明的一个重要方面中,本发明化合物的N’和N”原子间距为2.0-9.0,在优选实施方案中,N’和N”原子间距为2.4-8.5,例如2.5-3.5如2.7-3.3,如约2.9,或者例如7.5-8.5,如8.0-8.5。当至少一个N原子是环结构的一部分时,间距优选为2.5-3.5。当所述化合物是线性结构时,间距优选7.5-9.0
R1/R2
根据本发明,基团R1和R2可代表如本发明化学式中定义的化学基团。但是,存在基团R1和R2的具体性质已证实格外成功的化合物。在一个这种优选实施方案中,R1或R2中至少一个基团代表C。
在更优选实施方案中,基团R1和R2均代表C。
还预见到,在另一个实施方案中,本发明化合物包含其中R1或R2中至少一个是S的基团。在更优选实施方案中,基团R1和R2均代表S。
另外,在另一个实施方案中,本发明化合物可含有个R1和R2至少一代表N,例如基团R1和R2均代表N。
本发明化合物还包含其中至少一个R1和R2是O的基团。但是在更优选实施方案中,基团R1和R2均代表O。
化合物
本发明化合物的例子选自二氨基甲烷、1,2-二氨基乙烷、1,3-二氨基丙烷、1,4-二氨基丁烷、1,5-二氨基戊烷、1,6-二氨基己烷、1,7-二氨基庚烷、1,8-2二氨基辛烷、3-甲基氨基-1-(4-甲基哌嗪)-2-丙醇(propanole)、4-哌嗪苯胺、1-(3-氯苯基)哌嗪二盐酸盐(m-CPP)、哌嗪-2-酮-HCl、2-[4-(2-氨基乙基)哌嗪-1-基]乙胺、无水哌嗪、2,4-二氨基-6-苯基-1,3,5-三嗪、3,5-二氨基-1,2,4-三唑、丙二酰胺(melonamide)、精氨酸-HCl、哌啶、2,5-哌嗪二酮、哌嗪、哌嗪-2-酮-HCl、1-(2-嘧啶基)-哌嗪二盐酸盐。
优选化合物的例子选自2-[4-(2-氨基乙基)哌嗪-1-基]乙胺、3-甲基氨基-1-(4-甲基哌嗪)-2-丙醇、和哌嗪、哌嗪-2-酮、或其可药用加成盐或水合物。
在更优选的实施方案中,所述化合物是哌嗪或其可药用加成盐或水合物。
在本发明的另一个实施方案中,所述化合物可以选自1,2-二氨基乙烷、1,3-二氨基丙烷、1,4-二氨基丁烷、1,5-二氨基戊烷、1,6-二氨基己烷、1,7-二氨基庚烷、1,8-二氨基辛烷或其可药用加成盐或水合物。
在再一个实施方案中,所述化合物可以选自1,7-二氨基庚烷、1,2-二氨基乙烷、1,4-二氨基丁烷、1,6-二氨基己烷、1,5-二氨基戊烷或其可药用加成盐或水合物。
在最优选的实施方案中,所述化合物是1,6-二氨基己烷或其可药用加成盐或水合物。
可药用盐是指所述化合物的任意盐。特别是,是指可药用酸加成盐。所述化合物可药用加成盐包括来自下述无毒性无机酸的盐,例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、氢氟酸、亚磷酸等,以及来自无毒性有机酸的盐,例如脂肪族一元或二元羧酸、苯基取代的链烷酸、羟基链烷酸、链烷二羧酸、芳香族酸、脂肪族和芳香族磺酸等。因此,上述盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、一氢磷酸盐、二氢磷酸盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、三氟乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、邻苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、苯基乙酸盐柠檬酸盐、乳酸盐,、马来酸盐、酒石酸盐、甲磺酸盐等。
庆大霉素衍生的化合物的用途
如前面所述,已知庆大霉素结合受体维生素B12受体和巨蛋白受体。在本发明的范围内,描述了衍生自庆大霉素的化合物抗诱导的细胞毒性的作用。
因此,本发明一方面涉及是庆大霉素的一部分的化合物用于预防和/或治疗诱导的细胞毒性的用途,其中所述细胞具有体和/或维生素B12受体受体和/或巨蛋白和维生素B12的共受体。
已经令人吃惊地发现,衍生自常规用作抗生素的氨基糖苷庆大霉素的化合物对庆大霉素诱导的细胞毒性有抑制作用。不受理论束缚,本文预见到,庆大霉素衍生的化合物通过本文较早所描述的机制发挥出抑制作用。
根据本发明,在一个实施方案中,一种庆大霉素衍生的化合物是称为Garoseamine的部分。在另一个实施方案中,庆大霉素衍生的化合物是Purpurosamine部分。在再一个实施方案中,庆大霉素衍生的化合物是2-脱氧链霉胺部分。
因此,在一个实施方案中,被用于预防和/或治疗诱导的细胞毒性的化合物是Garoseamine,其中所述细胞具有巨蛋白受体和/或维生素B12受体和/或巨蛋白和维生素B12的共受体。
在另一个实施方案中,被用于预防和/或治疗诱导的细胞毒性的化合物是Purpurosamine,其中所述细胞具有巨蛋白受体和/或维生素B12受体受体和/或巨蛋白和维生素B12的共受体。
在再一个实施方案中,被用于预防和/或治疗诱导的细胞毒性的化合物是2-脱氧链霉胺,其中所述细胞具有巨蛋白受体和/或维生素B12受体和/或巨蛋白和维生素B12的共受体。
新的聚合物
本发明还提供了被用于降低诱导的细胞毒性的新化合物。
因此,本发明提供了具有通式(VII)的化合物:
(Aq-X)p (VII)
其中
A独立地或组合选自式(I)和/或式(II)和/或式(III)和/或式(IV)和/或式(V)和/或式(VI)、Garoseamine、Purpurosamine和2-脱氧链霉胺,并且其中
X是间隔基,
q是1-150的整数,
p是1-150的整数。
根据本发明,q可以是1-100、2-150、2-100、2-50、2-10或5-95、例如10-90、如15-90、例如20-85、如25-80、例如30-75、如35-70、例如40-65、如45-60、例如50-55的整数。
另外,式中的p可以是1-100、2-150、2-100、2-50、2-10或5-95、如例10-90、如15-90、例如20-85、如25-80、例如30-75、如35-70、例如40-65、如45-60、例如50-55的整数。
在一个实施方案中,A独立地或组合选自式(I)和/或式(II)和/或式(III)和/或式(IV)和/或式(V)和/或式(VI)。
预见到,一个或多个式(I)化合物单体可通过间隔基与一个或多个式(II)化合物单体或一个或多个式(III)化合物单体或一个或多个式(IV)化合物单体或一个或多个式(V)化合物单体或一个或多个式(VI)化合物单体连接。
在另一个实施方案中,一个或多个式(I)化合物单体可通过间隔基与一个或多个式(I)化合物单体连接。同样,式(II)、(III)、(IV)、(V)、和(VI)化合物也可以各自与各自的一个或多个式(II)、(III)、(IV)、(V)、和(VI)化合物单体连接。
在再一个实施方案中,一个或多个式(I)化合物单体可通过间隔基与一个或多个式(II)化合物单体和/或各个一个或多个式(III)、(IV)、(V)、和/或(VI)化合物单体连接,和进一步通过间隔基与各个一个或多个式(III)、(IV)、(V)、和/或(VI)化合物单体连接。
应理解的是,属于相同基团式(即各自是式(I)、(II)、(III)、(II)、(III)、(IV)、(V)、和(VI))的上述实施方案的各个单体通过间隔基连接,正如属于不同基团式的各个单体/聚合物通过间隔基连接一样。
本发明化合物的组合可通过下述例子来说明:
式(I)-式(I)-间隔基-式(I)-式(I)
式(I)-间隔基-式(I)-式(I)-式(I)
式(I)-间隔基-式(I)-间隔基-式(I)-式(I)
式(I)-式(II)-间隔基-式(I)-式(I)
式(I)-间隔基-式(I)-式(II)-式(III)
式(I)-间隔基-式(I)-间隔基-式(I)-式(I)
另外,A可以独立地或组合选自Garoseamine、Purpurosamine和/或2-脱氧链霉胺。
上述组合仅仅是本发明范围内可能的组合的非限制性说明。
间隔基
根据本发明的一个实施方案,所述间隔基是共价键。
在优选实施方案中,所述间隔基由2-12个原子,如C原子,如4-10个原子,如C原子,优选6-8个原子,如C原子组成。
本发明还涉及一种降低包含至少一种细胞毒性化合物的治疗剂的细胞毒性的方法,所述方法包括减少所述至少一种细胞毒性化合物的阳离子基团的数量。特别是,该方法涉及降低肾毒性或耳毒性。如上所讨论,多种治疗剂是肾毒性或耳毒性的,因此限制了该治疗剂的应用。本发明提供了一种降低所述毒性的方法。优选,阳离子基团的数量减少了至少一个基团,更优选至少两个阳离子基团。本方法的基本原理是减少或者甚至消除化合物与巨蛋白受体结合并从而摄入细胞的可能性。
所述阳离子基团优选是氨基。
阳离子基团数量的减少可通过下述方法提供:用非阳离子基团取代阳离子基团或者引入其它基团到化合物,从而抑制从阳离子基团提供质子。
因此,在一个实施方案中,通过用其它基团取代至少一个阳离子基团来减少阳离子基团数量,其中所述其它基团是非阳离子基团。特别是,该其它基团选自H、OH和低级烷基(C1-C4)。
在另一个实施方案中,通过引入其它基团到所述化合物来减少阳离子基团数量,从而抑制从阳离子基团提供质子。特别是,通过引入酰胺基团到所述化合物来获得上述效果。
优选,在合成化合物期间,进行阳离子基团的减少。
待减少的治疗剂的例子可以是任何下述治疗剂:
醋丁洛尔、乙酰唑胺、阿昔洛韦、阿德福韦、白蛋白、阿氯芬酸、阿伦膦酸盐、阿利维A酸、六甲密胺、阿米卡星、阿米洛利、氨鲁米特、胺碘酮、阿莫西林、阿莫西林/克拉维酸、两性霉素b、两性霉素b硫酸胆固醇酯复合物、两性霉素b脂复合物、两性霉素b脂质体、氨托美丁、茴拉西坦、antacids、安他唑啉、蒽醌泻药、抑肽酶、精氨酸、三氧化砷、门冬酰胺酶、阿斯匹林、阿替洛尔、阿托伐醌、金诺芬、金硫葡糖、阿扎胞苷、硫唑嘌呤、阿洛西林、氨曲南、巴氨西林、杆菌肽、贝美噻嗪、苯噁洛芬、甜菜碱、苯扎贝特、次枸橼酸铋、博来霉素、硼酸、溴夫定、溴尿苷、布美他尼、骨化二醇、骨化三醇、坎地沙坦、坎地沙坦/氢氯噻嗪、坎利酸盐、卷曲霉素、卡托普利、羧苄西林、卡铂、卡莫司汀、卡布洛芬、头孢克洛、头孢他美、头孢克肟、头孢美唑、头孢尼西、头孢哌酮、头孢哌酮/舒巴坦、头孢噻肟、头孢替坦、头孢西丁、头孢匹罗、头孢磺啶、头孢他啶、头孢替唑、头孢布坦,、头孢唑肟、头孢曲松、头孢呋新、塞来考昔、头孢氨苄、头孢噻啶、头孢噻吩、头孢匹林、头孢霉定、氯四环素、西多福韦、西拉普利、西米替丁、环丙贝特、西沙必利、顺铂、克拉霉素、氯膦酸盐、氯贝丁酯、氯唑西林、可卡因、可待因、粘菌素、促肾上腺皮质激素、合成促皮质素、复方增效磺胺甲基异噁唑、磺胺甲基异恶唑、克立那托、环青霉素、环孢霉素A、巯乙胺、地西他滨、地拉普利、地拉夫定、地美环素、denileukin diftitox、地氟烷、葡聚糖、泛影葡胺、二氮嗪、地贝卡星、双氯芬酸、双氟芬酸/米索前列醇、双氯西林、双香豆素、地达诺新、双氢麦角胺、双氢麦角胺/肝素、双氢速甾醇、地红霉素、多巴胺、多塞平、盐酸多柔比星脂质体、多西环素、依地酸钙二钠、依地酸二钠、依米丁、恩氟烷、恩莫单抗、肾上腺素、表柔比星、麦角骨化醇、麦角胺、红霉素/磺胺异恶唑、红细胞生成素、乙醇胺油酸酯、氯乙烷、1-羟基-亚乙基-1,1-二膦酸、依托度酸、依托咪酯、依曲替酯、everninomycin、法倔唑、芬布芬、非诺贝特、非诺洛芬、非诺特罗/异丙托铵、氟卡尼、氟罗沙星、氟氯西林、氟吡汀、氟比洛芬、福美坦、膦甲酸、福辛普利、福莫司汀、新霉素B、呋塞米、加贝酯、钆喷酸二甲葡胺、硝酸镓、吉西他滨、吉非贝齐、庆大霉素、甘油、硫代苹果酸金钠、胍那决尔、胍乙啶、瓜尔胶、海罗芬、伦那塞丁、氯高铁血红素、羟乙基淀粉、高三尖杉酯碱、透明质酸酶、氢氯噻嗪、伊达比星、异磷酰胺、伊马替尼、丙咪嗪、吲达帕胺、流感疫苗、干扰素α-2a、干扰素α-2b、干扰素β、天然的干扰素β-1b、干扰素γ、白细胞介素-3、白细胞介素-4、白细胞介素-6、碘苄胍1-131、碘克沙醇、碘海醇、碘帕醇、碘番酸、碘喷托、碘普胺、碘曲仑、碘佛醇、碘克酸、碘昔兰、ioxithalamate、依立替康、伊罗夫文、异帕米星、异氟醚、异烟肼、伊索昔康、卡那霉素、开他敏、酮康唑、酮洛芬、痛力克、来格司亭、左氧氟沙星、林可霉素、制霉素脂质体、赖诺普利、锂、洛铂、洛莫司汀、氯尼达明、氯诺昔康、氯沙坦、洛沙平、淋巴细胞免疫球蛋白、甘露醇、甲苯达唑、甲灭酸、锑酸葡甲胺、美拉胂醇、美罗培南、美司钠、间羟胺、美他环素、甲氧西林、甲巯咪唑、美索巴莫、甲氨蝶呤、甲氧明、甲泛葡胺、甲硝唑、美洛西林、米力农、米替福新、米诺环素、米诺地尔、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、吗茚酮、吗尼氟酯、吗啡、moxatactam、莫罗单抗-CD3、萘丁美酮、萘夫西林、萘普生、奈达铂、新霉素、奈替米星、氯硝柳胺、硝苯地平、尼氟灭酸、硝呋替莫、尼索地平、硝普盐、去甲肾上腺素、诺氟沙星、氧氟沙星、奥沙拉嗪、奥沙利铂、氧雄龙、奥沙普秦、噁喹酸、土霉素、紫杉醇、氨羟二磷酸二钠、甲乙双酮、巴龙霉素、培氟沙星、培美曲塞、吡嘧司特、青霉素G、喷他脒、喷司他丁、培洛霉素、培哚普利、非那吡啶、苯茚二酮、苯巴比妥、保泰松、苯丙醇胺、苯妥英、phosphates、哌拉西林、吡柔比星、吡咯他尼、吡罗昔康、普卡霉素、聚羟亚烃-188、多粘菌素B、高氯酸钾、吡喹酮、丙谷美辛、丙硫氧嘧啶、乙胺嘧啶/磺胺多辛、喹高利特、喹那普利、奎宁、兔抗胸腺细胞球蛋白、雷替曲塞、雷尼替丁、豹蛙酶、重组人血红素、利福平、利托君、利托那韦、罗非考昔、罗利环素、芦氟沙星、双水杨酯、七氟醚、硝化银、磺胺嘧啶银、辛伐他汀、磷酸纤维素钠、氯化钠、氟化钠、葡萄糖酸锑钠、螺内酯、链激酶、链霉素、链佐星、磺胺甲噁唑、柳氮磺吡啶、磺吡酮、磺胺异噁唑、舒林酸、硫前列酮、舒他西林、舒洛芬、他克莫司、他索纳明、替考拉宁、替马沙星、替尼泊苷、替诺昔康、四环素、硫喷妥钠、噻洛芬酸、替卡西林、替尼酸、替鲁膦酸、硫普罗宁、妥布霉素、妥卡尼、妥拉唑林、灭定、托塞米、曲马多、氨苯蝶啶、三甲双酮、曲美芬、甲氧苄啶、三甲曲沙、三甲丙咪嗪、曲格列酮、氨丁三醇、伤寒疫苗、缬沙坦、万古霉素、阿佐莫单抗、佐美酸、佐匹克隆。
优选,所述治疗剂选自阿昔洛维、白蛋白、阿米卡星、阿莫西林、阿莫西林/克拉维酸、两性霉素b、两性霉素b硫酸胆固醇酯复合物、两性霉素b脂复合物、两性霉素b脂质体、抑肽酶、三氧化砷、硫唑嘌呤、阿洛西林、杆菌肽、次枸橼酸铋、博来霉素、溴夫定、骨化二醇、骨化三醇、卡铂、卡莫司汀、卡洛芬、头孢克洛、头孢克肟、头孢美唑、头孢尼西、头孢哌酮、头孢哌酮/舒巴坦、头孢噻肟、头孢替坦、头孢西丁、头孢他啶、头孢替唑、头孢布烯、头孢唑肟、头孢曲松、西多福韦、顺铂、克拉霉素、氯唑西林、磺胺甲基异恶唑、环孢霉素A、地贝卡星、盐酸多柔比星脂质体、多西环素、麦角骨化醇、红霉素/磺胺异噁唑、庆大霉素、硫代苹果酸金钠、异磷酰胺、碘海醇、异烟肼、卡那霉素、林可霉素、锂、淋巴细胞免疫球蛋白、美罗培南、美司钠、甲氧西林、丝裂霉素、甲硝唑、奈达铂、新霉素、奈替米星、奥沙利铂、巴龙霉素、培洛霉素、苯丙醇胺、青霉素G、哌拉西林、吡柔比星、普卡霉素、多粘菌素B、吡喹酮、兔抗胸腺细胞球蛋白、重组人血红素、利福平、硝化银、链霉素、替考拉宁、四环素、替卡西林、妥布霉素和万古霉素。
特别是,所述治疗剂选自氨基糖苷类,例如庆大霉素、卡那霉素、新霉素、对氨水杨酸、核糖霉素、利维霉素、阿米卡星、地贝卡星、butakacin、妥布霉素、链霉素、双氢链霉素、西苏霉素、甲基姿苏霉素、乙基西梭霉素和布替卡星、顺铂、两性霉素B、异磷酰胺、多粘菌素B、环磷酰胺(cyclophosphomide)、甲氨蝶呤、抑肽酶、环孢素和丙戊酸钠以及治疗抗体。更优选,所述治疗剂是一种氨基糖苷,例如庆大霉素。
待本发明修饰的化合物是具有至少一个阳离子基团并因为与巨蛋白受体结合导致该化合物摄入而引起细胞毒性的化合物,更优选所述治疗剂包括含有至少两个氨基的化合物。
一旦所述化合物已经被修饰,该修饰的化合物优选不能与巨蛋白受体结合,从而不能通过如本文所述并且下述实施例所示的方法摄入细胞。
治疗剂
本发明的治疗剂可以是由于器官细胞中细胞内的积聚而引起器官损伤的任何治疗剂。特别是,所述治疗剂能在肾和/或内耳细胞内积聚,从而导致肾脏损伤和内耳损伤。
治疗剂的例子可以是任何下述治疗剂:
醋丁洛尔、乙酰唑胺、阿昔洛韦、阿德福韦、白蛋白、阿氯芬酸、阿伦膦酸盐、阿利维A酸、六甲密胺、阿米卡星、阿米洛利、氨鲁米特、胺碘酮、阿莫西林、阿莫西林/克拉维酸、两性霉素b、两性霉素b胆固醇硫酸酯复合物、两性霉素b类脂复合物、两性霉素b脂质体、氨托美丁、茴拉西坦、antacids、安他唑啉、蒽醌泻药、抑肽酶、精氨酸、三氧化砷、门冬酰胺酶、阿斯匹林、阿替洛尔、阿托伐醌、金诺芬、金硫葡糖、阿扎胞苷、硫唑嘌呤、阿洛西林、氨曲南、巴氨西林、杆菌肽、贝美噻嗪、苯噁洛芬、甜菜碱、苯扎贝特、次枸橼酸铋、博来霉素、硼酸、溴夫定、溴尿苷、布美他尼、骨化二醇、骨化三醇、坎地沙坦、坎地沙坦/氢氯噻嗪、坎利酸盐、卷曲霉素、卡托普利、羧苄西林、卡铂、卡莫司汀、卡布洛芬、头孢克洛、头孢他美、头孢克肟、头孢美唑、头孢尼西、头孢哌酮、头孢哌酮/舒巴坦、头孢噻肟、头孢替坦、头孢西丁、头孢匹罗、头孢磺啶、头孢他啶、头孢替唑、头孢布坦,、头孢唑肟、头孢曲松、头孢呋新、塞来考昔、头孢氨苄、头孢噻啶、头孢噻吩、头孢匹林、头孢霉定、氯四环素、西多福韦、西拉普利、西米替丁、环丙贝特、西沙必利、顺铂、克拉霉素、氯膦酸盐、氯贝丁酯、氯唑西林、可卡因、可待因、粘菌素、促肾上腺皮质激素、合成促皮质素、复方增效磺胺甲基异噁唑、磺胺甲基异恶唑、克立那托、环青霉素、环孢霉素A、巯乙胺、地西他滨、地拉普利、地拉夫定、地美环素、denileukin diftitox、地氟烷、葡聚糖、泛影葡胺、二氮嗪、地贝卡星、双氯芬酸、双氯芬酸/米索前列醇、双氯西林、双香豆素、地达诺新、双氢麦角胺、双氢麦角胺/肝素、双氢速甾醇、地红霉素、多巴胺、多塞平、盐酸多柔比星脂质体、多西环素、依地酸钙二钠、依地酸二钠、依米丁、恩氟烷、恩莫单抗、肾上腺素、表柔比星、麦角骨化醇、麦角胺、红霉素/磺胺异恶唑、红细胞生成素、乙醇胺油酸酯、氯乙烷、1-羟基-亚乙基-1,1-二膦酸、依托度酸、依托咪酯、依曲替酯、eveminomycin、法倔唑、芬布芬、非诺贝特、非诺洛芬、非诺特罗/异丙托铵、氟卡尼、氟罗沙星、氟氯西林、氟吡汀、氟比洛芬、福美坦、膦甲酸、福辛普利、福莫司汀、新霉素B、呋塞米、加贝酯、钆喷酸二甲葡胺、硝酸镓、吉西他滨、吉非贝齐、庆大霉素、甘油、硫代苹果酸金钠、胍那决尔、胍乙啶、瓜尔胶、海罗芬、伦那塞丁、氯高铁血红素、羟乙基淀粉、高三尖杉酯碱、透明质酸酶、氢氯噻嗪、伊达比星、异磷酰胺、伊马替尼、丙咪嗪、吲达帕胺、流感疫苗、干扰素α-2a、干扰素α-2b、干扰素β、天然的干扰素β-1b、干扰素γ、白细胞介素-3、白细胞介素-4、白细胞介素-6、碘苄胍1-131、碘克沙醇、碘海醇、碘帕醇、碘番酸、碘喷托、碘普胺、碘曲仑、碘佛醇、碘克酸、碘昔兰、ioxithalamate、依立替康、伊罗夫文、异帕米星、异氟醚、异烟肼、伊索昔康、卡那霉素、开他敏、酮康唑、酮洛芬、痛力克、来格司亭、左氧氟沙星、林可霉素、制霉素脂质体(liposomal nystatin)、赖诺普利、锂、洛铂、洛莫司汀、氯尼达明、氯诺昔康、氯沙坦、洛沙平、淋巴细胞免疫球蛋白、甘露醇、甲苯达唑、甲灭酸、锑酸葡甲胺、美拉胂醇、美罗培南、美司钠、间羟胺、美他环素、甲氧西林、甲巯咪唑、美索巴莫、甲氨蝶呤、甲氧明、甲泛葡胺、甲硝唑、美洛西林、米力农、米替福新、米诺环素、米诺地尔、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、吗茚酮、吗尼氟酯、吗啡、moxatactam、莫罗单抗-CD3、萘丁美酮、萘夫西林、萘普生、奈达铂、新霉素、奈替米星、氯硝柳胺、硝苯地平、尼氟灭酸、硝呋替莫、尼索地平、硝普盐、去甲肾上腺素、诺氟沙星、氧氟沙星、奥沙拉嗪、奥沙利铂、氧雄龙、奥沙普秦、噁喹酸、土霉素、紫杉醇、氨羟二磷酸二钠、甲乙双酮、巴龙霉素、培氟沙星、培美曲塞、吡嘧司特、青霉素G、喷他脒、喷司他丁、培洛霉素、培哚普利、非那吡啶、苯茚二酮、苯巴比妥、保泰松、苯丙醇胺、苯妥英、phosphates、哌拉西林、吡柔比星、吡咯他尼、吡罗昔康、普卡霉素、聚羟亚烃-188、多粘菌素B、高氯酸钾、吡喹酮、丙谷美辛、丙硫氧嘧啶、乙胺嘧啶/磺胺多辛、喹高利特、喹那普利、奎宁、兔抗胸腺细胞球蛋白、雷替曲塞、雷尼替丁、豹蛙酶、重组人血红素、利福平、利托君、利托那韦、罗非考昔、罗利环素、芦氟沙星、双水杨酯、七氟醚、硝化银、磺胺嘧啶银、辛伐他汀、磷酸纤维素钠、氯化钠、氟化钠、葡萄糖酸锑钠、螺内酯、链激酶、链霉素、链佐星、磺胺甲噁唑、柳氮磺吡啶、磺吡酮、磺胺异噁唑、舒林酸、硫前列酮、舒他西林、舒洛芬、他克莫司、他索纳明、替考拉宁、替马沙星、替尼泊苷、替诺昔康、四环素、硫喷妥钠、噻洛芬酸、替卡西林、替尼酸、替鲁膦酸、硫普罗宁、妥布霉素、妥卡尼、妥拉唑林、灭定、托塞米、曲马多、氨苯蝶啶、三甲双酮、曲美芬、甲氧苄啶、三甲曲沙、三甲丙咪嗪、曲格列酮、氨丁三醇、伤寒疫苗、缬沙坦、万古霉素、阿佐莫单抗、佐美酸、佐匹克隆。
优选,所述治疗剂选自阿昔洛维、白蛋白、阿米卡星、阿莫西林、阿莫西林/克拉维酸、两性霉素b、两性霉素b胆固醇硫酸酯复合物、两性霉素b脂复合物、两性霉素b脂质体、抑肽酶、三氧化砷、硫唑嘌呤、aziocillin、杆菌肽、次枸橼酸铋、博来霉素、溴夫定、骨化二醇、骨化三醇、卡铂、卡莫司汀、卡洛芬、头孢克洛、头孢克肟、头孢美唑、头孢尼西、头孢哌酮、头孢哌酮/舒巴坦、头孢噻肟、头孢替坦、头孢西丁、头孢他啶、头孢替唑、头孢布烯、头孢唑肟、头孢曲松、西多福韦、顺铂、克拉霉素、氯唑西林、磺胺甲基异恶唑、环孢霉素A、地贝卡星、盐酸多柔比星脂质体、多西环素、麦角骨化醇、红霉素/磺胺异噁唑、庆大霉素、硫代苹果酸金钠、异磷酰胺、碘海醇、异烟肼、卡那霉素、林可霉素、锂、淋巴细胞免疫球蛋白、美罗培南、美司钠、甲氧西林、丝裂霉素、甲硝唑、奈达铂、新霉素、奈替米星、奥沙利铂、巴龙霉素、培洛霉素、苯丙醇胺、青霉素G、哌拉西林、吡柔比星、普卡霉素、多粘菌素B、吡喹酮、兔抗胸腺细胞球蛋白、重组人血红素、利福平、硝化银、链霉素、替考拉宁、四环素、替卡西林、妥布霉素和万古霉素。
特别是,所述治疗剂选自氨基糖苷类,例如庆大霉素、卡那霉素、新霉素、对氨水杨酸、核糖霉素、利维霉素、阿米卡星、地贝卡星、butakacin、妥布霉素、链霉素、双氢链霉素、西苏霉素、甲基姿苏霉素、乙基西梭霉素和布替卡星、顺铂、两性霉素B、异磷酰胺、多粘菌素B、环磷酰胺、甲氨蝶呤、抑肽酶、环孢素和丙戊酸钠以及治疗抗体。更优选,所述治疗剂是一种氨基糖苷,例如庆大霉素。
还可以使用用于治疗的融合蛋白质或融合产物,其中所述蛋白质之一能结合巨蛋白受体或维生素B12受体和/或巨蛋白和维生素B12的共受体并且其它的蛋白质/产物当在细胞中积聚时导致细胞毒性。特别地,为了减少器官损伤,尤其是肾脏损伤,本发明化合物可以与下述融合产物联合给药,其中该产物的一部分是抗体或IgG轻链,它们均能非特异地结合维生素B12受体,并且该产物的其它部分是细胞毒性的,例如癌症治疗剂。
剂量
本发明化合物的剂量取决于所述的化合物;但是,化合物的量也与和所述化合物联合给药的治疗剂以及所述治疗剂的剂量密切相关。
对于所述化合物本文所公开的所有用途方法,每日口服给药方案优选为约0.01-约80mg/kg总体重。每日胃肠外给药方案优选为约0.001-约80mg/kg总体重。
本文所用的术语“单位剂型”是指适合作为人类和动物个体单位剂量的物理离散单位,每个单位含有单独地或与其它药剂组合的预定数量的化合物,以足以产生所需效果的量连同可药用稀释剂、载体或赋形剂进行称量。本发明的单位剂型的规格取决于采用的具体化合物和待达到的效果,以及与每个化合物在宿主中相关的药代动力学。给药剂量应是“有效量”或在个体患者中必须达到“有效水平”的量。
因为“有效水平”被用作剂量的优选边界点,所以实际的剂量和方案可根据药代动力学的个体间差异、药物分布和代谢而变化。例如,“有效水平”可定义为个体所需的血液或组织水平,其对应于一种或多种本发明化合物的浓度。并且,有效水平取决于所述治疗剂,尤其是所述有效水平的浓度。
因此,在优选实施方案中,给药化合物与给药治疗剂的比例是200∶1摩尔∶摩尔-1∶200摩尔∶摩尔,例如100∶1摩尔∶摩尔-1∶50摩尔∶摩尔,例如50∶1摩尔∶摩尔-1∶25摩尔∶摩尔。
所述化合物可以任何合适的给药方案给药,但优选与治疗剂相同的间隔给药,优选在治疗剂给药之前不久或给药期间。
本发明的大多数治疗剂胃肠外给药,通常是静脉内给药。本发明化合物可以根据其制剂任何合适的方式给药,但是通常优选,所述化合物胃肠外给药,例如与治疗剂一样静脉内给药。
药物
根据本发明,本发明药物能够与受体巨蛋白受体结合。
在另一实施方案中,所述药物能够与受体维生素B12受体结合。
在再一实施方案中,所述药物能够与巨蛋白和维生素B12的共受体结合。
在另一实施方案中,所述药物能够与能与受体巨蛋白受体和/或维生素B12受体和/或巨蛋白和维生素B12的共受体结合的治疗剂结合。
组合药物
本发明还涉及含有本发明化合物和治疗剂的组合药物。因此,本发明还涉及一种组合药物,其包含如本发明所公开的化合物和在细胞毒性治疗中同时、分别或相继使用的治疗剂。
在一个实施方案中,所述细胞具有巨蛋白受体和/或维生素B12受体和/或巨蛋白和维生素B12的共受体。
给药
当使用本发明药物时,所述化合物和治疗剂可以单独的制剂或单位剂型组合的形式同时给药,或者相继给药。所述组合药物可以通过将本发明化合物与同时给药的治疗剂共同配制而制成。在另一实施方案中,所述组合药物被制成两种单独的药物,用于同时或相继给药。
术语“分离给药”是指起初给药第一种化合物/药物,随后第二次给药化合物/药物。化合物/药物给药的顺序不是重要的,并且第一次给药与第二次给药的时间间隔没有确定。
根据本发明,药物递送的主要途径是静脉内、口服和局部,这将在下面进行描述。也可以采用其它给药方法,例如皮下注射,它对递送药物到靶点或将药物引入血液是有效的。
本发明药物制剂给药的粘膜可以是要给予生物活性化合物的哺乳动物的任何粘膜,例如在鼻、阴道、眼、口、生殖道、肺、胃肠道或直肠中的粘膜。
本发明化合物可以胃肠外给药,通过静脉内、肌内、皮下、鼻内、直肠内、阴道内或腹腔给药。通常优选皮下和肌内形式的胃肠外给药。上述给药方式的合适剂型可以通过常规技术制得。所述化合物还可以通过吸入给药,例如通过鼻内和口内吸入给药。
本发明化合物可以与至少一种其它化合物一起给药。所述化合物可以单独的制剂或单位剂型组合的形式同时给药,或者相继给药。所述组合药物可以通过将本发明化合物与同时给药的治疗剂共同配制而制成。在另一实施方案中,所述组合药物被制成两种单独的药物,用于同时或相继给药。
含有本发明化合物的药物组合物可通过常规技术制备,例如如Remington中所述:The Science and Practice of Pharmacy 1995,E.W.Martin编著,Mack Publishing Company,第19版,Easton,Pa。所述组合物可以呈常规的形式,例如胶囊、片剂、气雾剂、溶液、悬浮液或局部施用。
本发明化合物可以制成用于胃肠外给药(例如注射、例如快速浓注或连续输注)并且可以呈置于安瓿、预装注射器、小容量输液中或者加有防腐剂的多剂量容器中的单位剂型。所述组合物可例如呈油状或含水赋形剂中的悬浮液、溶剂、或乳剂,例如含水聚乙二醇中的溶液。油状或无水载体、稀释剂、溶剂或赋形剂的例子包括丙二醇、聚乙二醇、植物油(如橄榄油),和可注射的有机酯(如油酸乙酯),并且可以含有配制试剂,例如防腐剂、湿润剂、乳化剂或悬浮剂、稳定剂和/或分散剂。另外,活性成分可以呈粉末形式,其通过无菌分离灭菌固体获得,或在与合适的赋形剂如无菌无热原水使用之前,通过冷冻干燥组成溶液获得。
胃肠外制剂通常溶液中含有约0.5-约25%重量的活性成分。可以使用防腐剂和缓冲液。为了最小化或消除注射部位的刺激,上述组合物可含有一种或多种亲水亲油平衡值(HLB)为约12-约17的非离子表面活性剂。表明活性剂在上述制剂中的数量通常为约5-约15%重量。合适的表面活性剂包括聚乙烯去水山梨糖醇脂肪酸酯,例如去水山梨糖醇单油酸酯和环氧乙烷与由环氧丙烷与丙二醇缩合而成的疏水碱的高分子量加成产物。胃肠外制剂可置于单位剂量或多剂量密封的容器,例如,安瓿和药水瓶,并且可以在冻干(低压冻干)条件下存储,在使用之前仅需加入无菌液体赋形剂如注射用水。临时配制的注射溶液和悬浮液可以由前述种类的无菌粉末、颗粒和片剂制成。
实施例
下述是说明本发明的非限制性实施例。
实施例1
在体内测试了本发明化合物2-[4-(2-氨基乙基)哌嗪-1-基]乙胺(Aldrich,D2,340-8,lot 06028BO-332)的作用。测定了在腹腔(i.p.)给药所述化合物之后庆大霉素在小鼠肾脏中的摄入量。
对于放射性庆大霉素的正常施用,实行下述方式:每只小鼠腹腔注射50mg/kg氚标记的庆大霉素和3mg抑制剂或者不注射3mg抑制剂。这等同于1%的患者使用的庆大霉素临床剂量。
为了竞争庆大霉素的临床剂量,每只小鼠注射了总量3mg的2-[4-(2-氨基乙基)哌嗪-1-基]乙胺与50mg/kg氚标记的庆大霉素以及5mg/kg无放射性的庆大霉素(临床剂量)的混合物。对照组仅给予庆大霉素。与对照组相比,抑制率为40%。
实施例2
体外试验
通过在Biacore 2000仪器上进行质子表面共振(SPR)分析评估庆大霉素与抑制剂之间的相互作用。如Birn等人所述(J.Biol.Chem.,1997,第272卷,第42期,26497-26504)从兔肾脏中纯化出巨蛋白受体,固定于28-40fmol/mm2的浓度。样品溶解于10mM Hepes、150mM NaCl、1.5mM CaCl2、1mMEGTA、0.005%Tween-20pH 7.4中。相同的缓冲液用作运行缓冲液。每次分析之后,用1.6M甘氨酸-HCl缓冲液pH 3.0进行传感器芯片的再生。Biacore反应以相对反应单位(RU)来表示,即是蛋白质和对照流体通道之间反应的差异。样品含有2mM庆大霉素和0-10mM或0-20mM抑制剂。在最大值时记录反应,并校正抑制剂反应的影响。
试验检测了3,5-二氨基-1,2,4-三唑、丙二酰胺、哌啶、2,5-哌嗪二酮、哌嗪、3-甲基氨基-1-(4-甲基-哌嗪)-2-丙醇和2-[4-(2-氨基乙基)哌嗪-1-基]乙胺的抑制作用。结果显示在图5中。
实施例3
通过实施例2所述的评估方法,本试验显示了二氨基烷烃的抑制作用。结果显示在图4中。
实施例4
在该实施例中,如实施例1所述,将3mg抑制剂3-甲基氨基-1-(4-甲基-哌嗪)-2-丙醇、4-哌嗪苯胺、哌嗪-2-酮-HCl、2-[4-(2-氨基乙基)哌嗪-1-基]乙胺、无水哌嗪、和0.5mg 1-(3-氯苯基)哌嗪二盐酸盐(m-CPP)分别向小鼠腹腔注射给药(参见图6)。通过实施例1中所述的评估方式确定抑制剂对庆大霉素摄入小鼠肾脏的作用。最强的庆大霉素抑制剂是哌嗪-2-酮-HCl、2-[4-(2-氨基乙基)哌嗪-1-基]乙胺和无水哌嗪。
实施例中所用试剂如下:
2,4-二氨基-6-苯基-1,3,5-三嗪:产品目录:Aldrich;D2,340-8;lot:06028BO-332
2-[4-(2-氨基乙基)哌嗪-1-基]乙胺:产品目录:Interchim;O4386;1ot:未知
4-哌嗪苯胺:产品目录:Interchim;O4388;lot:未知
3-甲基氨基-1-(4-甲基哌嗪)-2-丙醇:产品目录:Interchim;O4176;lot:未知
哌嗪:产品目录:Aldrich;P4,590-7;lot:90907014
哌啶:产品目录:Aldrich;P4,610-5;lot:S11666-372
哌嗪-2-酮:产品目录:Aldrich;S99,763-3;lot:0100945477
3,5-二氨基-1,2,4-三唑:产品目录:Aldrich;D2,620-2;lot:S07917-042
精氨酸:产品目录:Aldrich;13,846-0;lot:01907C0
丙二酰胺:产品目录:Aldrich;12,959-3;lot:3259397
1-(3-氯苯基)哌嗪:产品目录:Sigma;S014;lot:084H4691
2,5-哌嗪二酮:产品目录:Sigma;G6406;lot:12420TI482
二氨基甲烷:产品目录:Fluka;66770;lot:未知
1,2-二氨基乙烷:产品目录:Sigma;E-2126;lot:012K3463
1,3-二氨基丙烷:产品目录:Aldrich;D23807-5G;lot:05516LQ
1,4-二氨基丁烷:产品目录:Aldrich;234001-25G;lot:10203TS
1,5-二氨基戊烷:产品目录:Aldriich;27,182-9;lot:08208P0
1,6-二氨基己烷:产品目录:Sigma;H-2381;lot:12K3452
1,7-二氨基庚烷:产品目录:Sigma;D-3266;lot:81K3670
1,8-二氨基辛烷:产品目录:Aldrich,D2,240-1;lot:33501-030
Claims (20)
1.具有通式(VI)的结构的化合物,或其可药用加成盐或水合物,
或具有通式(VII)的所述化合物的聚合物,
在制备用于预防和/或治疗诱导的细胞毒性的药物中的用途,
其中,
各个R1和R2独立地选自C、S、N、O,任选被C、S、N、O、OH、氢、烷基、烯基、炔基、苯基、苄基、胺(NH)、卤素、取代的低级烷基、芳基、杂环烷基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基取代,任选进一步被C、S、N、O、OH、苯基、胺(NH)、卤素、取代的低级烷基、芳基、杂环基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基、烷氧基、羧基、卤素、三氟甲基、氰基、氨基或硝基一次或多次取代,并且其中
m是1-8的整数,
n是1-8的整数,
N’和N”是氮,
R3、R4、R5和R6独立地选自C、S、N、O、OH、氢、烷基、烯基、炔基、苯基、苄基、胺(NH)、卤素、取代的低级烷基、芳基、杂环烷基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基,任选进一步被C、S、N、O、OH、苯基、胺(NH)、卤素、取代的低级烷基、芳基、杂环基、杂芳基、芳基-(C1-4)-烷基、杂芳基-(C1-4)-烷基、杂环基-(C1-4)-烷基、环烷基烷基、环烷基、烷氧基、羧基、卤素、三氟甲基、氰基、氨基或硝基一次或多次取代,
或者R3、R4、R5和R6中的一个或多个是化学键;
(Aq-X)p (VII)
其中
A为上述定义的式(VI)化合物,并且其中
X是间隔基,
其中所述间隔基为共价键或,
其中所述间隔基由2-12个原子组成,以及
q是1-100的整数,
p是1-100的整数。
2.根据前述权利要求任一项的用途,其中所述细胞具有巨蛋白受体和/或维生素B12受体。
3.根据前述权利要求任一项的用途,其中R1或R2中至少一个是C。
4.根据权利要求1或2的用途,其中R1和R2是C。
5.根据权利要求1或2的用途,其中R1或R2中至少一个是S。
6.根据权利要求1或2的用途,其中R1和R2是S。
7.根据权利要求1或2的用途,其中R1或R2中至少一个是N。
8.根据权利要求1或2的用途,其中R1和R2是N。
9.根据权利要求1或2的用途,其中R1或R2中至少一个是O。
10.根据权利要求1或2的用途,其中R1和R2是O。
11.根据前述权利要求任一项的用途,其中所述药物能结合巨蛋白受体和/或维生素B12受体。
12.根据权利要求1的用途,其中所述化合物选自3-甲基氨基-1-(4-甲基哌嗪)-2-丙醇、4-哌嗪苯胺、1-(3-氯苯基)哌嗪二盐酸盐(m-CPP)、哌嗪-2-酮-HCl、2-[4-(2-氨基乙基)哌嗪-1-基]乙胺、无水哌嗪、2,4-二氨基-6-苯基-1,3,5-三嗪、3,5-二氨基-1,2,4-三唑、2,5-哌嗪二酮、哌嗪、哌嗪-2-酮-HCl、1-(2-嘧啶基)-哌嗪二盐酸盐或其可药用加成盐或水合物。
13.根据权利要求12的用途,其中所述化合物选自2-[4-(2-氨基乙基)哌嗪-1-基]乙胺、3-甲基氨基-1-(4-甲基哌嗪)-2-丙醇和哌嗪。
14.根据权利要求1的用途,其中所述化合物是哌嗪。
15.根据前述权利要求任一项的用途,其中所述细胞来自肾脏和/或内耳。
16.根据前述权利要求任一项的用途,其中所述化合物在溶液中具有至少1个,例如2个正电荷,例如至少20个正电荷。
17.根据前述权利要求任一项的用途,其中所述化合物具有多元电荷分布。
18.一种组合药物,其包含在诱导的细胞毒性治疗中同时、分别或相继使用的如权利要求1-17任一项所定义的化合物和治疗剂。
19.根据权利要求18的组合药物,其中所述细胞具有巨蛋白受体和/或维生素B12受体。
20.一种药物组合物,其包含如权利要求1-20任一项所定义的化合物和可药用载体、赋形剂或稀释剂。
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US9481912B2 (en) | 2006-09-12 | 2016-11-01 | Longhorn Vaccines And Diagnostics, Llc | Compositions and methods for detecting and identifying nucleic acid sequences in biological samples |
US8097419B2 (en) | 2006-09-12 | 2012-01-17 | Longhorn Vaccines & Diagnostics Llc | Compositions and method for rapid, real-time detection of influenza A virus (H1N1) swine 2009 |
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US9683256B2 (en) | 2007-10-01 | 2017-06-20 | Longhorn Vaccines And Diagnostics, Llc | Biological specimen collection and transport system |
US11041215B2 (en) | 2007-08-24 | 2021-06-22 | Longhorn Vaccines And Diagnostics, Llc | PCR ready compositions and methods for detecting and identifying nucleic acid sequences |
US10004799B2 (en) | 2007-08-27 | 2018-06-26 | Longhorn Vaccines And Diagnostics, Llc | Composite antigenic sequences and vaccines |
RU2468034C2 (ru) | 2007-08-27 | 2012-11-27 | ЛОНГХОРН ВЭКСИНС ЭНД ДИАГНОСТИКС ЭлЭлСи | Иммуногенные композиции и способы |
US11041216B2 (en) | 2007-10-01 | 2021-06-22 | Longhorn Vaccines And Diagnostics, Llc | Compositions and methods for detecting and quantifying nucleic acid sequences in blood samples |
AU2008343745B2 (en) | 2007-10-01 | 2012-05-10 | Longhorn Vaccines & Diagnostics Llc | Biological specimen collection and transport system and methods of use |
WO2012151554A1 (en) * | 2011-05-04 | 2012-11-08 | President And Fellows Of Harvard College | Polyamines for treating biofilms |
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US9976136B2 (en) | 2015-05-14 | 2018-05-22 | Longhorn Vaccines And Diagnostics, Llc | Rapid methods for the extraction of nucleic acids from biological samples |
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