CN102378628A - 改善药物的生物活化的方法 - Google Patents
改善药物的生物活化的方法 Download PDFInfo
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- CN102378628A CN102378628A CN2010800042610A CN201080004261A CN102378628A CN 102378628 A CN102378628 A CN 102378628A CN 2010800042610 A CN2010800042610 A CN 2010800042610A CN 201080004261 A CN201080004261 A CN 201080004261A CN 102378628 A CN102378628 A CN 102378628A
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Abstract
前药,其包含具有通式(I)或(II)的部分结构,其中R1和R2是氢、烷基或芳基。
Description
本发明涉及用于改善药物的生物活性的方法。
对口服施用后药物的治疗效果的要求表现为由胃肠道对其的吸收。此类效果的最重要的机制是被动扩散。通过被动扩散方式的吸收程度尤其取决于亲油性。
通过药物治疗许多疾病时的另一个问题是通过血脑屏障的必要性。血脑屏障是脑中涉及物质吸收的有效屏障。其确保了选择性的摄取并防止物质渗透。此外,血脑屏障不仅作为物理屏障起作用,其也作为酶性屏障起作用。在物质向脑的渗透中涉及许多过程。与其它适应症相比,市场上只有少数药物在中枢神经系统(ZNS)中发挥作用。在这些药物中,大多数通过扩散的方式到达ZNS。以这种方式,治疗了例如癫痫、慢性疼痛或者抑郁的疾病。目前以这种方式很难治疗其它严重的功能性病症,例如脑肿瘤或者肌萎缩侧索硬化。
为了能够通过被动扩散的方式越过生物膜,物质应该是亲脂的、具有小于500Da的分子量、并且其应该不带电而存在。为了特异性吸收小的、高度极性的分子(例如氨基酸或糖),在具有屏障功能(胃肠道,血脑屏障)的生物膜上表达了不同的转运体系统,例如核苷转运体、有机阴离子或阳离子的流入和流出转运体、葡萄糖转运体、肽转运体和氨基酸转运体。
为此,采用了各种前药系统来改善药物动力学特性。前药是没有或仅有很少的药理活性的药物,并且其直至在生物体中经代谢才被转变为活性代谢物。
N-羟基脒(氨肟)和N-羟胍代表已知的用于提高脒(Clement,B.Methodenzur Behandlung und Prophylaxe der Pneumocystis carinii Pneumonie(PCP)und anderen Erkran-kungen sowie Verbindungen und Formulierungen zumGebrauch bei besagten Methoden.[DE 4321444])和胍的口服生物可利用性的前药物质。氨基和亚氨基的氮原子在脒和胍的盐中以中介的平衡态存在,可以将所述概念用于这两种氮原子。
取决于其所基于的前药概念,通过不同的酶系统进行向活性代谢物的转变。几乎在所有的生命形式中都存在的酶系统是细胞色素P450(CYP450),其尤其催化下列反应:
N-氧化,S-氧化,N-脱烷基反应,邻脱烷基反应,S-脱烷基反应,脱氨反应,脱卤反应,以及芳香族和脂肪族化合物的羟基化反应。
CYP450酶系统的多样性所暗示的是:不同的底物和药物在其代谢过程中竞争所述系统。这产生相互作用、交互效应和不希望的相互影响。为此,在前药开发中力求不依赖于CYP450的生物活化作用。
因此,本发明的任务在于提供使用不依赖于细胞色素P450(CYP450)酶的生物活化途径的前药系统。通过权利要求中所描述的主题来完成此任务。从属权利要求提供了本发明的有利实施方式。
根据本发明,一方面通过前药来完成所述任务,所述前药包括具有通式(I)或(II)的部分结构
其中R1和R2是氢、烷基或芳基。
在本发明的优选实施方式中,如本申请中所使用的,术语“部分结构”指在相应式中所表明的结构元素是物质(优选前药)的式的一部分。例如化合物邻羧甲基苄胺肟(1)是药物苯甲脒的相应的前药,其中部分结构是式(II)的部分结构,并且R1和R2分别为氢原子。此部分结构是苯环上的取代基,并且与其共同构成药物苯甲脒。
在本发明的优选实施方式中,如本申请中所使用的,术语“前药”表示本身无活性或药学上仅有很少活性的物质,其直至在生物体中经代谢(Verstoffwechselung)(代谢)才被转变为药学上有活性的药物。相比于实际的活性药物,所述前药可以但是不必须具有改善的口服生物可利用性。备选地,可使用前药是因为,与药物相比,其具有改善的可溶性、生物活化作用、血脑屏障穿越性、物理化学稳定性、更低的毒性和/或可耐受的或更愉悦的味道。如此,将红霉素A的2′-乙基琥珀酸酯作为前药施用给儿童是由于红霉素A的苦味,而可能不是因为其不足的吸收或可溶性(Bhadra et al.(2005),J.Med.Chem.)。
在本发明的另一个优选实施方式中,并非以单步反应、而是通过多个反应步骤的而将原始的前药从前药代谢为药物,其中与原始的前药相比,从反应步骤获得的每一种代谢物可具有一种或多种相同的和/或不同的更有利的性质。由此,有可能不是所有的代谢物相比于前药均具有有利的特性。例如,与所述前药相比,前药的第一种代谢产物可具有更高的药理活性,衍生自第一种代谢产物的第二种代谢产物可类似地具有比前药更高的药理活性,而衍生自第二种代谢产物的第三种代谢产物可具有比前药更高的血脑屏障穿透性和物理化学稳定性。
在本发明的优选实施方式中,如本申请中所使用的,术语“物理化学稳定性”指的是物质(例如前药或药物)以相关水溶液的形式(例如溶解在水、缓冲液或生理盐溶液中)被储存和/或使用而没有化学分解(例如水解)的特性。在本发明的另一个优选的实施方式中,如本申请中所使用的,此术语表示所述物质能够以稳定的和合成的形式被合成。在本发明的另一个优选的实施方式中,如本申请中所使用的,此术语表示在所述物质的合成过程中,与根据类似或相同的合成策略而产生的其它物质的类似产物、前体或中间产物相比,分离的相关合成前体是更稳定的,从而后续的合成产物或合成中间产物才能被产生,或者能够以更加稳定的形式被产生。
在一个实施方式中,所述任务是通过前药而实现的,其特征在于,所述前药所包含的部分结构是羟胺、N-氧化物、硝酮、偶氮鎓二醇(NONOat)或者类似的含有N-O的一氧化氮供体、异羟肟酸、羟基脲、肟、氨肟(N-羟基脒)、N-羟基脒腙或者N-羟胍的组成部分。
例如,在药物苯甲脒的前药羧甲基苄胺肟(1)的情形中,所述部分结构是为式(II)的部分结构,R1和R2分别为氢原子,且前药所包含的部分结构是氨肟(N-羟基脒)的组成部分。
在一个实施方式中,所述任务是通过前药而实现的,其特征在于,所述前药被代谢为用于治疗与一氧化氮缺乏相关的疾病的药物。
在一个实施方式中,所述任务是通过前药而实现的,其特征在于,所述前药或其相应的药物选自:蛋白酶抑制剂,嵌入DNA和嵌入RNA的化合物,病毒酶的抑制剂以及N-甲基-D-天冬氨酸受体拮抗剂。
在本发明的优选实施方式中,如本申请中所使用的,术语“上级的部分结构”应被理解为所述上级的部分结构一方面包含式(I)或(II)的部分结构,并且另一方面是所述及物质的总体结构的一部分。例如在药物苯甲脒(2)的前药羧甲基苄胺肟(1)的情形中,则本申请中标记为(1a)的上级的部分结构包含式(IIa)的部分结构,其中R1和R2为氢,并且在本申请中标记为(1b)的部分结构是为式(II)的部分结构,其中R1和R2也是氢。
在一个实施方式中,通过前药来完成所述任务,其特征在于,所述部分结构具有通式IIa或IIb
例如,在药物苯甲脒的前药羧甲基苄胺肟(1)的情形中,所述上级的部分结构包含式(IIa)的部分结构,其中R1和R2是氢,所述部分结构是为式(II)的部分结构,其中R1和R2也是氢,并且药物在前药中具有结构(IIa-1)而非式(IIa)的部分结构。
在一个实施方式中,所述任务是通过前药而实现的,其特征在于,所述前药是药物的前药,其中通式IIa的部分结构在代谢之后包含具有下式的结构
并且通式IIb的部分结构在代谢之后包含具有下式的结构
在本发明的另一方面,通过形成通式(I)或者(II)的部分结构作为前药总体结构的组成部分的用途而完成所述任务,
所述前药是药物的前药,其中R1和R2是氢、烷基或芳基。
在一个实施方式中,通过前药的用途来完成所述任务,其中所述部分结构具有通式(II)且为上级的部分结构IIa或IIb的一部分
所述部分结构代替药物的脒基或胍基,以改善可溶性、口服生物可利用性、血脑屏障穿透性、味道和/或者物理化学稳定性。
在一个实施方式中,通过前药的用途来完成所述任务,其中所述前药是药物的前药;除了下述之外,所述药物与所述前药具有相同的结构:
所述药物包含部分结构IIa-1或IIa-2之一而不是所述上级的部分结构IIa
或者所述药物包含部分结构IIb-1或IIb-2之一而不是所述上级的部分结构IIb
在一个实施方式中,通过前药用于通过肽酰甘氨酸α-酰胺化单加氧酶(PAM)来活化药物的用途而完成所述任务。
在本发明的优选实施方式中,如本申请中所使用的,表述“通过肽酰甘氨酸α-酰胺化单加氧酶(PAM)来活化前药”、“通过PAM活化途径来活化前药”、生物活化或类似表述指的是所述前药被PAM识别为底物并且被代谢。在本发明的优选实施方式中,如本申请中所使用的,表述“将药物引入PAM活化途径中,包括制备药物的前药”表示生产将被引入PAM活化途径中的药物的相应前药形式,此前药形式被PAM所识别并且被代谢。在优选的实施方式中,与所述药物相比,所述前药对PAM的亲合力为1-1000倍、2-100倍、3-50倍、4-40倍、5-20倍或6~15倍高,如本领域技术人员借助KM值所能够确定的。
在一个实施方式中,通过前药的用途完成了所述任务,其特征在于,所述部分结构是羟胺、N-氧化物、硝酮、偶氮鎓二醇(NONOat)、或含有N-O的类似一氧化氮供体、异羟肟酸、羟基脲、肟、氨肟(N-羟基脒)、N-羟基脒腙或N-羟胍的组成部分。
在本发明的另一个方面,通过用于将包含游离的脒或胍官能团的药物引入PAM活化途径中的方法完成所述任务,所述方法包括制备所述药物的前药。
在本发明的其它方面中,通过用于治疗患者的方法来完成所述任务,所述方法包括向患者施用所述前药。
在本发明的其它方面中,通过所述前药用于生产药物的用途来完成所述任务。
在本发明的优选实施方式中,所述药物或前药是用于防治病毒感染(例如流感)、防治HIV感染、预防和治疗内脏和皮肤利什曼病、预防卡氏肺囊虫肺炎(PcP)、治疗锥虫病(非洲昏睡病)、治疗疟疾、治疗巴贝西虫病、抑制血液凝固(例如初级预防静脉血栓栓塞事件)、预防房颤患者的中风、降血压、抑制恶性肿瘤生长、神经保护、防治病毒感染(例如流感)、(利尿性)除去体内水分,例如心功能不全,肺水肿,中毒,肾功能不全或肝硬化、治疗过敏、治疗哮喘、治疗炎性疾病(例如风湿病或胰腺炎)、预防缺血(供血不足)的药物或前药。
在本发明的其它方面中,通过根据权利要求7-11和权利要求14中任一项所述的前药的用途或者根据权利要求13所述的方法来完成所述任务,其中所述用途或方法是用于治疗与一氧化氮缺乏相关的疾病的用途或方法。
在一个实施方式中,通过前药的用途来完成所述任务,其特征在于所述药物或前药选自:蛋白酶抑制剂,嵌入DNA和嵌入RNA的化合物,病毒酶抑制剂,N-甲基-D-天冬氨酸受体拮抗剂。
在一个实施方式中,通过前药的用途来完成所述任务,其中所述用途是用于预防和/或治疗内脏和/或者皮肤利什曼病、锥虫病、锥虫病的2期或卡氏肺囊虫引起的肺炎、抑制恶性肿瘤生长、抑制血液凝固、降血压、神经保护或者防治病毒感染(包括流感和HIV感染)的用途。
在本发明的其它方面中,通过包含具有通式(I)或(II)的部分结构的药物来完成所述任务
其中R1和R2是氢、烷基或芳基。
在一个实施方式中,通过包含具有通式(I)或(II)的部分结构的药物来完成所述任务,其特征在于所述部分结构是羟胺、N-氧化物、硝酮、偶氮鎓二醇(NONOat)或含有N-O的类似一氧化氮供体、异羟肟酸、羟基脲、肟、氨肟(N-羟基脒)、N-羟基脒腙或者N-羟胍的组成部分。
在一个实施方式中,通过根据前述权利要求中任一项的药物来完成所述任务,其特征在于所述药物被设计为用于治疗与一氧化氮缺乏相关的疾病。
在一个实施方式中,通过药物来完成所述任务,其特征在于所述药物选自:蛋白酶抑制剂、嵌入DNA和嵌入RNA的化合物、病毒酶抑制剂、和N-甲基-D-天冬氨酸受体拮抗剂。
在本发明的其它方面中,通过使用含有N-O的邻羧基烷基化官能团而制备包含形成通式(I)或(II)的部分结构的药物以改善药物的可溶性、生物可利用性、血脑屏障穿透性、生物活化和/或物理化学稳定性来完成所述任务
其中R1和R2是氢、烷基或芳基。
在一个实施方式中,通过包含含有N-O的邻羧基烷基化官能团的药物用于通过肽酰甘氨酸α-酰胺化单加氧酶(PAM)来活化药物的用途而完成所述任务。
在一个实施方式中,通过药物的所述用途来完成所述任务,其特征在于,所述部分结构是羟胺、N-氧化物、硝酮、偶氮鎓二醇(NONOat)、或含有N-O的类似一氧化氮供体、异羟肟酸、羟基脲、肟、氨肟(N-羟基脒)、N-羟基脒腙或者N-羟胍的组成部分。
在一个实施方式中,通过药物的用途来完成所述任务,其特征在于所述药物被设计为用于治疗与一氧化氮缺乏相关的疾病。
在一个实施方式中,通过药物的用途来完成所述任务,其特征在于所述药物选自:蛋白酶抑制剂、嵌入DNA和嵌入RNA的化合物、病毒酶抑制剂、和N-甲基-D-天冬氨酸受体拮抗剂。
在一个实施方式中,通过药物的用途来完成所述任务,其特征在于所述药物被设计为用于预防和/或治疗内脏和/或皮肤利什曼病、锥虫病、锥虫病的2期或卡氏肺囊虫引起的肺炎、抑制恶性肿瘤生长、抑制血液凝固、降血压、神经保护或者防治病毒感染(包括流感和HIV感染)。
在本发明的其它方面中,提供了包含根据本发明的化合物和/或其盐的药物化合物、药物组合物和药物。所述药物组合物优选包含载体和/或助剂,并且理想地,它们是药学上相容的。此类载体和助剂是本领域技术人员通常所熟悉的。也提供了根据本发明的化合物用于医药中。
如果药物含有以所提出的形式存在的至少一种或多种活性脒、N-羟基脒(氨肟)、胍或N-羟胍官能团就是足够的。例如,所述药物因而可含有多个氨肟官能团(例如两个,如对于戊肟酯而言)或N-羟胍官能团,其中这些基团中的至少一个以前述方式被修饰。类似地,也可采用药物混合物,其中至少一个根据本发明被修饰。
可以每天、每周或每月以大丸药施用方式施用一次根据本发明的化合物。也可容易地确定施用途径。通常,所考虑的是口服施用、直肠施用、肠胃外施用(如静脉内、肌内、皮下、透皮施用)、肺内施用和作为气雾剂施用、膀胱内滴注、腹膜内或心内注射、通过粘膜摄取或阴道内应用(例如通过栓剂)。口服形式可以是作为液体、半固体或者固体制剂,尤其是作为片剂、糖衣片、丸剂或微胶囊的形式。为此,对于使用液体制剂的实施方式而言,可使活性成分或活性成分混合物处于适当的非毒性溶剂之中,例如水、一元醇尤其是乙醇、多元醇尤其是甘油和/或者丙二醇、聚二醇尤其是聚乙二醇和/或Miglyol、Glycerinformal、二甲基异山梨醇酯、天然或合成的油。可使用常规的基底物质来生产半固体或固体制备物,例如皂粘土、硅酸铝镁、瓜尔豆粉和/或纤维素衍生物(尤其是甲基纤维素和/或羧甲基纤维素),以及由乙烯醇和/或乙烯基吡咯烷酮制成的聚合物、藻酸盐、果胶、聚丙烯酸酯、固态和/或液态聚乙二醇、石蜡、脂肪醇、凡士林和/或蜡、脂肪酸和/或脂肪酸酯。
此外,固体制剂中也可包含已知的增充剂,例如胶质硅酸、滑石、乳糖、淀粉粉末、糖、明胶、金属氧化物和/或金属盐。作为其它的添加剂,提供稳定剂、乳化剂、分散剂以及防腐剂。
令人惊讶地,已发现通式为(I)或(II)的含有N-O的邻羧基烷基化官能团利用不依赖于细胞色素P450(CYP450)酶的生物活化途径,其中所述官能团通过氮(N)上的键与药物分子结合,
其中(I)和(II)可以是例如羟胺、N-氧化物、硝酮、偶氮鎓二醇(NONOat)、或含有N-O的类似一氧化氮供体、异羟肟酸、肟、氨肟(N-羟基脒)、N-羟基脒腙或N-羟胍的组成部分,而R1(其必须为pro-R构象的)和R2可以是氢、烷基或芳基。这是出人意料的结果,因为已知,CYP450酶通常催化氧化性邻脱烷基反应,其在本申请中所提出前药物质的情形中对于释放真正的药物而言也将是必要的。
所提出的以羧基烷基来醚化含有N-O的官能团产生了下列特别的优势:可利用不同于CYP450酶的酶来进行生物活化,即肽酰甘氨酸α-酰胺化单加氧酶(PAM)。从而可例如,防止副作用以及前述与其它同时施用的药物的相互作用。
肽酰甘氨酸α-酰胺化单加氧酶(PAM)在更高等的生物体(脊椎动物)中是由单加氧酶结构域(PHM,肽酰甘氨酸α-羟基化单加氧酶,EC 1.14.17.3)和裂解酶结构域(PAL,肽基-α-羟基甘氨酸α-酰胺化裂解酶,EC 4.3.2.5)构成的二官能酶。总体而言,通过剪接和表达而使PAM经受强的组织特异性和发育依赖性调控。在翻译后修饰的意义上,PAM能够活化各种生理上存在的肽激素、神经递质和生长因子(例如物质P,神经肽Y,催产素,加压素,降钙素)。在此过程中,在单加氧酶反应中介由氧化性N-脱烷基反应通过裂解末端甘氨酸而使肽在C末端被酰胺化。
如根据本发明所提出的,以羧基烷基来醚化含有N-O的官能团的特别优势是通过插入在生理条件下(pH 6-8)带负电荷的羧酸所产生的改善的可溶性。
另一个优势在于,根据本发明所提出的对含有N-O的官能团的醚化(使用(烷氧基羰基)烷基醚或(芳氧基羰基)烷基醚)提高了亲油性从而使得被动扩散是可能的,并因而改善了生物可利用性和/或血脑屏障穿透性。
类似地下列也是有利的:使用相对较小的残基(在最简单的情况下是羧甲基残基)作为前药基团的可能性使得药物分子的大小仅略微增加。
Wand等人(Metabolism 1985,34,11,1044)研究了不同人组织中的PAM活性,并且在ZNS的组织中(尤其是在垂体中)检测出了最高的活性。相反,在经典的外源物质代谢器官肝脏和肾脏中却没有发现活性。在血浆、心脏和肺中也检测出可被用于所设想的前药概念的活性。
尤其可利用此酶在ZNS中的高活性来将邻羧基烷基化的前药转运通过血脑屏障,从而然后可将它们转化。然而,在口服应用和从肠胃道吸收之后也有可能在心血管系统中进行生物活化。
根据本发明的前药系统可被应用于具有脒或胍官能团的不同药物中。下列药物是特别优选的:
喷他脒,达比加群,BSF 411693(阿博特),盐酸咪唑克生,厄贝沙坦,利诺格列,盐酸洛非西定,盐酸四氢唑林,妥拉唑林,盐酸赛洛唑啉,羟乙磺酸戊氯苯脒,他立韦林,硫胺素(维生素B1),波生坦,羟乙磺酸双溴丙脒,羟乙磺酸羟蔗脒,西拉非班,奥波非班,珍米洛非班,阿加曲班,希美加群,美拉加群,2-哌啶酸,醋酸奥波非班,依匹斯汀(Relestat),RO 43-8857,AB1(苯丁酸氮芥,类似物),AMG-126737,AY-0068,B-623,BABIM,BIBT-986(Boehringer Ingelheim),CI-1031(公司:Biosciences),CJ-1332(公司:Curacyte),CJ-463(公司:Curacyte),CJ-672(公司:Curacyte),CT50728(Portolla Pharmaceuticals),CVS-3983,DX-9065a,拉米非班(Roche),LB-30870(公司:LG LifeSciences Ltd),LY-178550(公司:Lilly),PHA-927F及类似物,RO-44-3888(Roche),司匹司他,FUT-187(Torii),Viramidin(Ribapharm),WX-FX4(Wilex),YM-60828(Yamanouchi Pharmaceutical Co.Ltd),ZK-807191(Berlex Biosciences),NAPAP(SR 25477),BIIL 315(Boehringer Ingelheim),BIIL 260(Boehringer Ingelheim),BIIL 284/260(Boehringer Ingelheim),他诺吉群,莫西卢班,二脒草替,Panamidine,夫雷非班,二脒那秦,罗西非班,Furamidine,PD0313052,PHA 927F,PHA 798,非德沙班,奥米沙班,Thromstop(Thrombstop),扎那米韦,盐酸阿米洛利,盐酸阿那格雷,氯胍,西咪替丁,盐酸可乐定,胍生,培拉米韦,罗米非定,替拉扎明,替扎尼定,硝酸托洛尼定,二甲双胍,二脒那秦,异喹胍,磺胺二甲嘧啶,依替巴肽,法莫替丁,拜尔药物,链霉素,萘莫司他,FUT-175,伊诺加群,胍乙啶(Thilodigon),3DP-10017,APC-366,CVS-1123,二苯基膦酸酯衍生物,E-64,FOY-305,MBGB,MIBG,RWJ-422521,癸烷双胍,WX-293,WX-340,BMS-189090,JTV-803(Japan Tabacco),奈沙加群,依斯迈林,Tan 1057A,Hydika1,Phenformix(苯乙双胍),纺锤菌素(西那诺霉素),BIIB 722(沙泊来德),胍那决尔,脱氧精胍菌素,BMS 262084,Siamformet(Orabet),PPACK(Pebac),MERGETPA(普氏羧肽酶抑制剂),培拉米韦,法莫替丁,唑替丁。
附件中显示具有药物的化学式、CAS编号以及适应症的表格。
以下作为示例显示了4种根据本发明的前药:
扎那米韦的羧乙氧基前药
扎那米韦的羧甲氧基前药
喷他脒的双(羧甲氧基)前药
羧甲基苄胺肟
在根据基于氨肟和N-羟胍的模式化合物的实施例中,显示了含有N-O的非肽邻羧基烷基化官能团作为PAM的底物也被接受这一令人惊讶的发现。
作为氨肟的模式化合物,就邻羧甲基苄胺肟(1)的PAM底物特性对其进行了测试。邻羧甲基苄胺肟是药物苯甲脒的可能的前药。经PAM催化而将邻羧甲基苄胺肟(1)生物活化成为苄胺肟(2)同时伴随乙醛酸的释放而发生。
图1显示了乙醛酸形成的比色法测定的结果。所测定的乙醛酸浓度是平均值±来自两次温育的标准偏差(其中每一次都测量两次)。以浓度依赖性的方式检验了乙醛酸作为1的PAM催化作用的裂解产物而形成。与pH 7.4时的温育相比,PAM在pH值最佳时(pH 6.0)的温育产生了明显更高的转化。在比色测定中,与对1的测试平行进行了对乙醛酸的5点校准。校准在所测定的浓度范围内是线性的(r2=1.000)。
根据这些结果,由于邻羟甲基羧甲基苄胺肟(1)作为PAM的底物是被接受的,因此通过测定KM和Vmax值更详细地表征了所述反应。
为此,开发了HPLC分析。对于苄胺肟的校准线在所测定的浓度范围内是线性的(r2=1.000),并且回收率为130.6%(r2=0.999)。两次触立的实验(n=2)产生了KM值为307±80μM,Vmax值为393±40nmol min-1mg-1PAM。图2是所述测定的代表性表示。
为了CYP450底物的研究,修饰了上述HPLC分析从而还可能检测出作为苄胺肟(2)的N-还原产物的可能的代谢物苯甲脒。在pH 6.0和pH 7.4时,在所有所使用的CYP450酶源中都没有检测到苄胺肟(苯甲脒的可能的前药)或苯甲脒。
基于苄胺肟模式化合物1,在单加氧酶反应的意义上,仅由PAM而没有由细胞色素P450去除了邻羧甲基官能。
作为羟胍的模式化合物,就N-羧甲氧基-N′,N″-二苯胍(3)的PAM底物特性对其进行了测试。
经PAM催化而将N-羧甲氧基-N′,N″-二苯胍(3)生物活化为N,N′-二苯基-N″-羟胍(4),同时伴随乙醛酸的释放而发生。
用3进行的比色测定的结果与氨肟模式化合物1的结果相当。为了测定KM值和Vmax值,开发了能够在15分钟之内在RP柱上分离前药3与羟胍4的HPLC分析。对于N,N′-二苯基-N″-羟胍(4)的校准线在所测定的浓度范围内是线性的(r2=0.999),且回收率为111.7%(r2=0.999)。两次独立的实验(n=2)产生了KM值为37±5μM,Vmax值为373±53μmol min-1mg-1PAM。图3是所述测定的代表性表示。
由所测定的KM值,可得出相比于氨肟前药1约为8倍的更高的对PAM的亲合力,而转化率是相当的。
为了CYP450底物研究,修饰了为PAM底物研究而开发的HPLC分析,从而还可能检测出作为羟胍4的N-还原产物的可能的代谢物N,N′-二苯胍。在pH 6.0和pH 7.4时,在180分钟的温育时间之后,在所有所使用的CYP450酶源中都不能检测到4或N,N′-二苯胍。
与邻羧甲基苄胺肟(1)类似,基于羟胍模式化合物3,在单加氧酶反应的意义中仅由PAM而没有由细胞色素P450去除了邻羧甲基官能。
材料和方法
邻羧甲基苄胺肟一水合物的钠盐(1)
根据Koch(Ber.Dtsch.Chem.Ges.1889,22,3161)的经修改的指导:
将5mL乙醇中的681mg苄胺肟(5.0mmol)、1.04g溴乙酸(7.5mmol)和500mg氢氧化钠丸粒(12.5mmol)的溶液在回流下煮沸5小时。然后,在真空下去除溶剂,直至开始形成沉积物。允许所述沉积物完全沉淀,将其滤出并干燥。从乙醇(96%)/水(95∶5)中重结晶产物。
产率:937mg白色细毡状晶体(80%)
熔点:226℃(dec.)
1H-NMR(DMSO-d6):
δ/ppm=4.13(s,2H,O-CH2),6.09(br s,2H,NH2),7.37(m,3H,3′,4′,5′-CH),7.67(m,2H,2′,6′-CH)。
13C-NMR(CDCl3):
δ/ppm=73.6(O-CH2),125.7,128.0,129.0(ArCH),132.8(ArC),151.4(C=N),173.2(CO)。
MS(ESI):
m/z=217[M+Na]+,195[M+H]+,119[M-C4H2-C2H2+H]+,105[C6H5N2]+。
C9H9N2NaO3·1.0H2O(234.18)
计算的C 46.16 H 4.73 N 11.96
发现的C 46.43 H 4.44 N 11.65
N-羧甲氧基-N′,N″-二苯胍(3)
将546mg氨氧乙酸氯化物(Semichlorid)(5mmol)和697μl三乙胺(5mmol)在10ml的干燥DMF中搅拌30分钟。滤出沉淀,向滤出物中加入970mg N,N′-二苯碳二亚胺(5mmol)。在室温下将此配制物(Ansatz)搅拌四小时,用乙酸乙酯将其取出,并从乙醇中重结晶产物。
产率:285mg白色固体(20%)
熔点:176℃
DC:Rf=0.29(二氯甲烷/甲醇,9∶1)
1H-NMR(DMSO-d6):
δ/ppm=4.37(s,2H,O-CH2),6.75-6.87(m,2H,ArH),7.03-7.20(m,8H,ArH),8.02,8.21(2x br s,1H,NH),12.05(br s,1H,COOH)。
13C-NMR(DMSO-d6):
δ/ppm=70.0(O-CH2),116.7,118.7,119.8,121.0,128.5(ArCH),140.7,142.3(ArC),147.5(C=N),171.8(CO)。
MS(ESI):
m/z=308[M+Na]+,286[M+H]+,210[M-C2H4O3]+。
MS(EI):
m/z(%)=209(38),208(37),119(20),118(38),93(100),91(47),77(43),66(31),51(30)。
C15H15N3O3-0.3H2O(290.71)
计算的 C 61.97 H 5.41 N 14.45
发现的 C 62.18 H 5.72 N 14.57
HPLC系统:
Waters Breeze HPLC系统,具有Waters 1525泵、Waters 2487吸收检测仪、Waters 717 Plus自动进样器以及Breeze记录和分析软件(版本3.30)、Gynkotek STH 585柱温箱。
HPLC柱:
Synergi Max-RP 80A(250x4.6mm,4μm),带有预柱C-18(4x3mm)(公司Phenomenex);
LiChroCART、LiChrospher 100、RP-8(125x4mm,5μm),带有预柱LiChrospher 60、RP-select B(4x4mm,5μm)(公司Merck);
LiChroCART、LiChrospher RP-select B(250x4.6mm,5μm),带有预柱LiChrospher 60、RP-select B(4x4mm,5μm)(公司Merck)。
其它设备和材料:
Cary 50UV-Vis光度计(公司Varian);96孔板(公司Greiner);摇动水浴GFL-1083(Gesellschaft für Labortechnik,Burgwedel);微升离心机(公司Hettich GmbH);pH测量设备InoLab pH Level 1(Wissenschaftlich-TechnischeGmbH,Weilheim),带有pH-电极LiQ Plast(公司Hamilton);Vortexer VF2(Janke und Kunkel GmbH&Co.KG,Staufen);1.5mL的反应容器(Sarstedt AG&Co.,Nümbrecht)。
酶源:
所使用的重组肽酰甘氨酸-α-酰胺化单加氧酶(PAM,大鼠,EC 1.14.17.3)是由Unigene Laboratories,Inc.(New Jersey,USA)公司提供的(比活性=5.8106U/mg蛋白质);牛肝过氧化氢酶(EC 1.11.1.6),比活性=12600U/mg固体(公司Aldrich)。
在Clement von Grünewald工作组中按照以下指导获得了所使用的细胞色素P450酶源:
猪肝微粒体和9000g上清液:
从本地屠宰场(Bordesholm)获得猪肝,屠宰之后直接在经冰冷却的20mM磷酸盐缓冲液(1mM Na2-EDTA,pH 7.4)中运送器官。为了进一步加工,首先用50mM磷酸盐缓冲液(1mM Na2-EDTA,pH 7.4)灌洗肝叶。将组织切成小块,然后使其经过商业上可得的绞肉机处理。用等体积的磷酸盐缓冲液稀释悬浮液,并且使用匀浆器使其均质化。通过差速超速离心进而获得微粒体和9000g上清液。为了储存,将所获得的制备物分为等份并冷冻于-80℃。
人肝微粒体和9000g上清液:
为了获得人的微粒体,从Christian-Albrechts大学大学医院的外科部获得了必须经受半肝切除的癌症患者的人肝组织。
在含有蔗糖的磷酸盐缓冲液(10mM K2HPO4,10mM KH2PO4,250mM蔗糖,1mM Na2-EDTA,pH 7.4,4℃)中将肝组织切块急冻。一旦可获得充足数量的器官部分(>3),就将相应的切块解冻并混合,从而补偿由个体间的差异引起的差别。在4℃下将组织切块切成更小的部分,用缓冲溶液(不含EDTA)洗涤数次,然后用匀浆机将其加工成为悬浮液。通过差速超速离心而从该悬浮液中获得微粒体和9000g上清液。为了储存,将所产生的制备物分成等份,并冷冻于-80℃。
PAM测定:温育条件
300μL(总体积)的典型温育配制物含有25000U/mL肽酰甘氨酸-α-酰胺化单加氧酶(PAM,公司:Unigene Laboratories)、250U/mL过氧化氢酶、1μM铜(II)(作为醋酸盐/一水合物而使用)、2mM抗坏血酸钠、5mM碘化钾,以及浓度为0.1mM或1mM的各底物,在具有不同pH值的缓冲液中。对于pH 6.0下的温育所使用的缓冲系统是30mM MES,对于pH 7.4下的温育所使用的缓冲系统是50mM HEPES。在每种情况下,均用经稀释的氢氧化钠调节pH值。在37℃下、在摇动的水浴中温育60分钟,取出100μL,用50μL 10%的TFA(aq)/乙腈(2∶3)使反应停止。将剩余的配制物在37℃下再温育180分钟,并用100μL10%的TFA(aq)/乙腈(2∶3)使反应停止。
将停止反应后的样品摇动5分钟(Vortexer),并冷冻于-80℃。为了分析样品,将其解冻,摇动5分钟,并以10000U/min离心被沉淀的蛋白质。将上清液用于比色测定乙醛酸和/或HPLC测量。
对于KM值和Vmax值的测定,在上述条件下在pH6.0下处理100μL的配制物,然而区别是温育时间为30分钟。
比色测定乙醛酸
将200μL不含蛋白质的温育配制物与20μL苯肼溶液(20mg在2mL二次蒸馏水中)混合,并在37℃的摇动水浴中摇动5分钟。然后,使所述混合物冷却15分钟至0℃,加入100μL冰冷的6N HCl,并将其在0℃下再静置5分钟。然后,加入20μL六氰合铁(III)化钾溶液(100mg在2mL二次蒸馏水中)。将此配制物在室温下静置15分钟,并取出200μL用于使用酶标仪(Cary50UV-Vis光度计,520nm)进行测量。
校准:
对于5点校准,在测定缓冲液(pH 6.0)(10%TFA(aq)/乙腈(2∶3))的2∶1混合物中,如上所述测量了浓度为2、5、10、50和100μM的乙醛酸。此校准与所进行的测试化合物的每一次测定平行进行。
用于分离邻羧甲基苄胺肟(1)与苄胺肟(2)的HPLC分析
柱: Synergi Max-RP 80 A(250x4.6mm,4μm)
柱温度: 20℃
流动相: 79%(v/v)10mM辛基磺酸盐,pH 2.5(H3PO4)
21%(v/v)乙腈
流速: 1.0mL/分钟
运行时间:20分钟
检测: 在229nm处测定吸收
注射体积:20μL
保留时间:
邻羧甲基苄胺肟(1) 8.9分钟±0.2分钟
苄胺肟(2) 14.4分钟±0.2分钟
校准和回收:
为了校准,将苄胺肟以0.1-500μM的8种浓度溶解于测定缓冲液(30mMMES,1μM醋酸铜(II),2mM抗坏血酸钠,5mM碘化钾,pH 6.0)中,并使用前述的HPLC方法进行测量。
为了测定回收,在测定缓冲液中产生了相同的浓度(终体积=100μL)。此外,加入了邻羧甲基苄胺肟(0.5mM)和250U/mL的过氧化氢酶,继以50μL10%的TFA(aq)/乙腈(2∶3)。使用Vortexer摇动样品,并冷冻于-80℃。为了测量样品,将其解冻,用Vortexer摇动5分钟,并且以10000U/min离心5分钟。
用于分离N-羧甲氧基-N′,N″-二苯胍(3)与N-羟基-N′,N″-二苯胍(4)的HPLC分析
柱: LiChrospher RP-select B(250x4.6mm,5μm)
柱温度: 20℃
流动相: 70%(v/v)40mM乙酸铵,pH 5.2
30%(v/v)乙腈
流速: 1.0mL/分钟
运行时间:15分钟
检测: 在229nm下测量吸收
注射体积:20μL
保留时间:
N-羧甲氧基-N′,N″-二苯胍(3) 5.2分钟±0.1分钟
N-羟基-N′,N″-二苯胍(4) 9.0分钟±0.2分钟
校准与回收:
为了校准,将N-羟基-N′,N″-二苯胍(4)以0.1-500μM的8种浓度溶解于测定缓冲液(30mM MES,1μM醋酸铜(II),2mM抗坏血酸钠,5mM碘化钾,pH 6.0)中,并使用上述的HPLC方法进行测量。为了测定回收,在测定缓冲液中产生了相同的浓度(终体积=100μL)。此外,加入了N-羧甲氧基-N′,N″-二苯胍(3)(0.5mM)和250U/mL的过氧化氢酶,继以50μL 10%的TFA(aq)/乙腈(2∶3)。使用Vortexer摇动样品,并冷冻于-80℃。为了测量样品,将其解冻,用Vortexer摇动5分钟,并且以10000U/min离心5分钟。
CYP450测定:温育条件
500μL(总体积)的典型温育配制物含有0.3mg蛋白质(猪或人肝酶源)、0.1mM(或1mM)100mM磷酸盐缓冲液(pH 6.0或pH 7.4)中的测试化合物以及1mM NADH(或NADPH)。在缓冲液中将酶和测试化合物预温育5分钟后,通过加入NADH(或NADPH)开始温育,并在37℃下在摇动的水浴中摇动60分钟或180分钟。通过加入相同体积的乙腈使配制物停止反应,使用Vortexer进行摇动,并冷冻于-80℃。
为了分析样品,将其解冻,使用Vortexer摇动5分钟,并通过在10000U/min下离心5分钟而分离蛋白质。将上清液用于HPLC分析。
用于分离邻羧甲基苄胺肟(1)、苄胺肟(2)与苯甲脒的HPLC分析
柱: Synergi Max-RP 80 A(250x4.6mm,4μm)
柱温度: 20℃
流动相: 82.5%(v/v)10mM辛基磺酸盐,pH 2.5(H3PO4)
17.5%(v/v)乙腈
流速: 1.0mL/分钟
运行时间:35分钟
检测: 在229nm处测定吸收
注射体积:20μL
保留时间:
邻羧甲氧基苄胺肟(1) 13.6分钟±0.1分钟
苄胺肟(2) 22.8分钟±0.3分钟
苯甲脒 26.0分钟±0.3分钟
用于分离N-羧甲氧基-N′,N″-二苯胍(3)、N-羟基-N′,N″-二苯胍(4)与N,N′-二苯胍的HPLC分析
柱: LiChrospher RP-select B(250x4.6 mm,5μm)
柱温度: 20℃
流动相: 80%20mM乙酸铵,pH 4.3
20%乙腈
流速: 1.25mL/分钟
运行时间:15分钟
检测: 在205nm处测定吸收
注射体积:30μL
保留时间:
N,N′-二苯胍 6.7分钟±0.2分钟
N-羧甲氧基-N′,N″-二苯胍(3) 7.8分钟±0.2分钟
N-羟基-N′,N″-二苯胍(4) 10.7分钟±0.3分钟
以下提供了可优选地应用根据本发明的前药系统的药物的表格:
Claims (19)
2.根据权利要求1的前药,其特征在于,所述前药所包含的所述部分结构是羟胺、N-氧化物、硝酮、偶氮鎓二醇(NONOa t)或含有N-O的类似一氧化氮供体、异羟肟酸、羟基脲、肟、氨肟(N-羟基脒)、N-羟基脒腙或N-羟基胍的组成部分。
3.根据前述权利要求中任一项的前药,其特征在于,所述前药被代谢成为药物,所述药物是用于治疗与一氧化氮缺乏相关的疾病的药物。
4.根据前述权利要求中任一项的前药,其特征在于,所述前药或相应的药物选自:蛋白酶抑制剂,嵌入DNA和嵌入RNA的化合物,病毒酶抑制剂,和N-甲基-D-天冬氨酸受体拮抗剂。
5.根据权利要求1-4中任一项的前药,其特征在于,所述部分结构具有通式IIa或IIb
10.根据权利要求8或9的用途,用于通过肽酰甘氨酸α-酰胺化单加氧酶(PAM)而活化药物。
11.根据权利要求7-10中任一项的用途,其特征在于,所述部分结构是羟胺、N-氧化物、硝酮、偶氮鎓二醇(NONOat)或含有N-O的类似一氧化氮供体、异羟肟酸、羟基脲、肟、氨肟(N-羟基脒)、N-羟基脒腙或N-羟基胍的组成部分。
12.用于将包含游离的脒或胍官能团的药物引入PAM活化途径中的方法,所述方法包括制备根据权利要求1-6中任一项的药物前药。
13.用于治疗患者的方法,其包括向患者施用根据权利要求1-6中任一项的前药。
14.根据权利要求1-6中任一项的前药用于制备药物的用途。
15.根据权利要求7-11和权利要求13中任一项的用途,或根据权利要求14的方法,其中所述用途或方法是用于治疗与一氧化氮缺乏相关的疾病的用途或方法。
16.根据权利要求7-11和15中任一项的用途,其特征在于,所述药物或前药选自:蛋白酶抑制剂,嵌入DNA和嵌入RNA的化合物,病毒酶抑制剂,和N-甲基-D-天冬氨酸受体拮抗剂。
17.根据权利要求7-11和15-17中任一项的用途,其中所述用途是用于下列的用途:预防和/或治疗内脏和/或皮肤利什曼病、锥虫病、锥虫病的2期或者卡氏肺囊虫引起的肺炎、抑制恶性肿瘤生长、抑制血液凝固、降血压、神经保护或者防治病毒感染包括流感和HIV感染。
19.根据权利要求18的方法,其中在碱的存在下进行所述反应,所述的碱优选选自二异丙胺和三乙胺。
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PCT/DE2010/000009 WO2010078867A1 (de) | 2009-01-09 | 2010-01-08 | Verfahren zur verbesserten bioaktivierung von arzneistoffen |
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CA (1) | CA2749009A1 (zh) |
DE (1) | DE102009004204A1 (zh) |
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WO2024089191A1 (en) | 2022-10-27 | 2024-05-02 | Syngenta Crop Protection Ag | Microbiocidal heterobicyclic dihydrooxadiazine derivatives |
WO2024132901A1 (en) | 2022-12-19 | 2024-06-27 | Syngenta Crop Protection Ag | Microbiocidal pyridazine dihydrooxadiazine derivatives |
WO2024132895A1 (en) | 2022-12-19 | 2024-06-27 | Syngenta Crop Protection Ag | Microbiocidal dihydrooxadiazinyl pyridazinone compounds |
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KR20110102506A (ko) | 2011-09-16 |
RU2550969C2 (ru) | 2015-05-20 |
AU2010204395B2 (en) | 2016-04-14 |
IL213955A (en) | 2016-12-29 |
US20120077876A1 (en) | 2012-03-29 |
AU2010204395A1 (en) | 2011-09-01 |
IL213955A0 (en) | 2011-08-31 |
DE102009004204A1 (de) | 2010-07-15 |
CA2749009A1 (en) | 2010-07-15 |
SG10201504075YA (en) | 2015-06-29 |
BRPI1004900A2 (pt) | 2016-04-05 |
WO2010078867A1 (de) | 2010-07-15 |
SG172911A1 (en) | 2011-08-29 |
EP2376074B1 (de) | 2019-03-13 |
JP2012514608A (ja) | 2012-06-28 |
KR20150015002A (ko) | 2015-02-09 |
EP2376074A1 (de) | 2011-10-19 |
JP5918538B2 (ja) | 2016-05-18 |
RU2011133233A (ru) | 2013-02-20 |
KR20160042140A (ko) | 2016-04-18 |
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