CN114736240A - sGC刺激剂的磷前药 - Google Patents
sGC刺激剂的磷前药 Download PDFInfo
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- CN114736240A CN114736240A CN202111570967.XA CN202111570967A CN114736240A CN 114736240 A CN114736240 A CN 114736240A CN 202111570967 A CN202111570967 A CN 202111570967A CN 114736240 A CN114736240 A CN 114736240A
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Abstract
sGC刺激剂的磷前药。本专利申请公开了如下所示的式I化合物或其药学上可接受的盐,其中JB,n,R1,R2,R3,R4,R5,m和X如本文所定义。
Description
技术领域
本公开涉及可溶性鸟苷酸环化酶(sGC)的刺激剂的含磷前药,包含它们的药物制剂及其单独或与一种或多种另外的药剂组合用于治疗各种疾病的用途,其中所述疾病或病症是受益于sGC刺激或受益于一氧化氮(NO)和/或环鸟苷酸(cGMP)浓度增加的疾病。
背景技术
sGC是体内NO的主要受体。sGC可以通过NO依赖性和NO非依赖性机制激活。响应于这种活化,sGC将鸟苷-5'-三磷酸(GTP)转化为第二信使cGMP。反过来,cGMP水平的增加调节下游效应物的活性,包括蛋白激酶、磷酸二酯酶(PDEs)和离子通道。
在体内,NO由精氨酸和氧通过各种一氧化氮合酶(NOS)和连续还原无机硝酸盐合成。已经鉴定了三种不同的NOS亚型:在活化的巨噬细胞中发现的诱导型NOS(iNOS或NOSII);组成型神经元NOS(nNOS或NOS I),参与神经传递和长时程增强;和组成型内皮NOS(eNOS或NOS III),调节平滑肌松弛和血压。实验和临床证据表明NO的浓度或生物利用度降低和/或对内源性NO的反应性有助于疾病的发展。
当与NO非依赖性、血红素非依赖性sGC激活剂相比时,NO非依赖性血红素依赖性sGC刺激剂显示出几种重要的分化特征。这些包括对减少的假体血红素部分的活性的存在的重要依赖性,当与NO组合时强烈的协同酶活化,并且不依赖于NO通过直接刺激sGC刺激cGMP的合成。苄基吲唑化合物YC-1是第一个待鉴定的sGC刺激剂。此后,开发了对sGC具有改善的效力和特异性的额外sGC刺激剂。
以NO非依赖性方式刺激sGC的化合物提供了超过靶向异常NO途径的其他当前替代疗法的显着优势。需要开发新的sGC刺激剂。特别是,需要开发具有用于临床应用的改善的溶解性和药学性质的sGC刺激剂。
发明内容
在一个实施方案中,本发明涉及式I的化合物:
其中,
X选自–P(O)(OH)2、–P(O)(OH)O-M+、–P(O)(O-)2(M+)2或–P(O)(O-)2D2+;其中M+是药学上可接受的一价阳离子,D2+是药学上可接受的二价阳离子;
每个JB独立地选自卤素;
m选自0或1;
n选自0、1、2、3或4;
R1选自C1-4烷基,C1-4氟代烷基,-C(O)NH2或氢;且
R2选自C1-4烷基,C1-4氟烷基或氢;
或者,
R1和R2与它们所连接的碳原子一起形成C3-7脂环族环,或含有独立地选自N、O或S的至多2个杂原子的3至7元杂环;其中所述C3-7脂环族环或3至7元杂环是未取代的;
R3选自卤素、氢、-CN或-NH2;
R4的两个实例同时为氢,或R4的两个实例与它们所连接的碳原子一起形成羰基;和
R5选自甲基或氢。
在另一个实施方案中,本发明涉及药物组合物,其包含式I化合物和至少一种药学上可接受的赋形剂或载体。在另一个实施方案中,本发明涉及包含所述药物组合物的药物剂型。
在另一个实施方案中,本发明涉及治疗有此需要的受试者的疾病、健康状况或病症的方法,包括单独或联合治疗施用治疗有效量的式I化合物,或其药学上可接受的组合物;其中所述疾病或病症是将受益于sGC刺激或受益于NO和/或cGMP浓度增加的疾病或病症。
具体实施方式
现在将详细参考本发明的某些实施方案,其实例在所附结构和分子式中说明。虽然将结合列举的实施例描述本发明,但是应该理解,它们并不旨在将本发明限制于那些实施例。相反,本发明旨在覆盖可以包括在由权利要求限定的本发明的范围内的所有替代、修改和等同物。本发明不限于本文所述的方法和材料,而是包括与本文所述的那些可用于本发明实践的方法和材料相似或等同的任何方法和材料。如果所结合的一篇或多篇参考文献、专利或类似材料与本申请不同或相矛盾,包括但不限于定义的术语、术语用法、所描述的技术等,以本申请为准。
定义和一般术语
出于本公开的目的,化学元素根据CAS版本元素周期表和Handbook of Chemistryand Physics(第75版)进行鉴定。另外,有机化学的一般原理描述于《有机化学》,ThomasSorrell,University Science Books,Sausalito:1999,和《March's Advanced OrganicChemistry》,5th Ed.,Smith,MB和March,J.,eds.John Wiley&Sons,New York:2001,其全部内容通过引用并入本文。
本公开内容所设想的取代基和组合的选择仅是导致形成稳定或化学上可行的化合物的那些。这些选择和组合对于本领域普通技术人员来说是显而易见的,并且可以在没有过多实验的情况下确定。如本文所用,术语“稳定的”是指当经受允许其生产、检测的条件时基本上不改变的化合物,并且在一些实施方案中,其用于一种或多种在此公开的目的的回收、纯化和用途。在一些实施方案中,稳定的化合物是在不存在水分或其它化学反应性条件的情况下,在25℃或更低的温度下保持至少一周时基本上不改变的化合物。化学上可行的化合物是本领域技术人员基于本文公开的化合物制备的化合物,如果需要,可以通过本领域的相关知识补充。
化合物,例如式I化合物或本文公开的其他化合物,可以其游离形式(例如,无定形形式,或结晶形式或多晶型物)存在。在某些条件下,化合物也可以形成共形式(co-form)。如本文所用,术语共形式与术语多组分结晶形式同义。当共形式中的一种组分明显转移或丢失质子时,所得的共形式称为“盐”。盐的形成取决于形成混合物的配偶体之间pKas的差异有多大。出于本公开的目的,化合物包括其药学上可接受的盐,即使没有明确指出术语“药学上可接受的盐”。
除非仅特异性地绘制或命名一种异构体,否则本文描述的结构也意味着包括该结构的所有立体异构(例如,对映异构、非对映异构、构形异构和顺反异构)形式;例如,每个不对称中心的R和S构型,每个不对称轴的Ra和Sa构型,(Z)和(E)双键构型,以及顺式和反式构象异构体。因此,本发明化合物的单一立体化学异构体以及外消旋体、对映异构体、非对映异构体和顺式-反式异构体(双键或构象)的混合物都在本发明的范围内。
本公开内容还包括同位素标记的化合物,其与本文所述的那些相同,但是因为一个或多个原子被原子质量或质量数不同于原子质量或质量数的原子取代。在大自然中发现。所指出的任何特定原子或元素的所有同位素都涵盖在本发明化合物及其用途的范围内。可掺入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,例如分别为2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I和125I。某些同位素标记的本发明化合物(例如,用3H和14C标记的化合物)可用于化合物和/或底物组织分布测定。氚(即3H)和碳-14(即14C)同位素因其易于制备和可检测性而有用。此外,用较重的同位素例如氘(即2H)取代可以提供某些治疗优势,这是由于更高的代谢稳定性(例如,体内半衰期延长或剂量需求减少),因此在某些情况下可能是优选的。正电子发射同位素如15O,13N,11C和18F可用于正电子发射断层扫描(PET)研究以检查底物受体占有率。同位素标记的本发明化合物通常可以通过用同位素标记的试剂取代非同位素标记的试剂,按照与下文方案和/或实施例中公开的那些类似的方法制备。
如本文所用,术语“适当的”和“合适的”可互换使用。
如本文所用,如果一次允许多于一个取代基的实例,则在每种情况下独立地选择该取代基的每个实例。例如,如果苯基可以被两个R100实例取代,并且R100选自卤素和甲基,那么这意味着R100的每个实例分别选自卤素或甲基;例如,一个R100可以是氟,一个可以是甲基,或者两者都可以是氯等。
基团可以被取代基的“至多”Z个实例取代,其中“n”是整数。例如,如果“Z”为3,则该基团可以被0、1、2或3个取代基取代。除非另有说明,否则每个“Z”实例始终是独立选择的。
本文所用的术语“烷基”(如“烷基链”或“烷基”)是指饱和的直链或支链一价烃基。Cx烷基是含有x个碳原子的烷基链,其中x是不等于0的整数。“Cx-y烷基”,其中x和y是两个不同的整数,两者都不同于0,是含有x的烷基链和y个碳原子,包括端值。例如,C1-6烷基是如上定义的含有1至6个碳原子的任何数目的烷基。烷基的实例包括但不限于甲基(C1烷基),乙基(C2烷基),正丙基(C3烷基),异丙基(C3烷基),正丁基,异丁基,仲丁基,叔丁基,戊基,己基,庚基,辛基等。
术语“脂环族”是指仅由碳和氢原子形成并且完全饱和或含有一个或多个不饱和单元但不是芳香族的环系统。在一个实施方案中,术语“脂环族”是指含有3至7个碳的单环烃环(即C3-7脂环族)。合适的脂环族基团包括但不限于环烷基、环烯基和环炔基。脂环族基团的实例包括环丙基,环丁基,环戊基,环戊烯基,环己基,环己烯基,环庚基,环庚烯基等。
如本文所用,“环烷基”是指完全饱和的脂环族环系。在一个实施方案中,术语“环烷基”是指单环3-至7-元饱和脂环族环(即,C3-7环烷基)。合适的环烷基包括但不限于环丙基,环丁基,环戊基,环己基,环庚基等。
“杂原子”是指氧、硫、氮、磷或硅中的一种或多种,包括任何氧化形式的氮、硫、磷或硅,季铵化形式的任何碱性氮,或可取代的氮杂环或杂芳基环,例如N(如在3,4-二氢-2H-吡咯基中),NH(如在吡咯烷基中)或NR+(如在N-取代的吡咯烷基中)。
术语“环原子”是指诸如C、N、O或S的原子,其是苯基或杂芳基环的一部分。“可取代的环原子”是与至少一个氢原子键合的环碳或氮原子。氢可以任选地被合适的取代基取代。当结构表明它们已经连接到除氢以外的一个或多个部分并且没有氢可用于取代时,“可取代的环原子”不包括环碳或氮原子。当某个环、基团或链任选被取代时,应理解它可以在其任何或部分或全部可取代的环原子中被取代。
如本文所用,术语“杂环”(如以“杂环”或“杂环基团”表示)是指其中一个或多个环原子是独立选择的杂原子的环系统。杂环是完全饱和的或含有一个或多个不饱和单元但不是芳香族的。在一些实施方案中,杂环可以是具有3至7个环原子(2至6个碳原子和1至4个杂原子)的单环。杂环的实例包括但不限于以下单环:2-四氢呋喃基,3-四氢呋喃基,2-四氢噻吩基,3-四氢噻吩基,2-吗啉代,3-吗啉代,4-吗啉代,2-硫代吗啉代,3-硫代吗啉代,4-硫代吗啉代,1-吡咯烷基,2-吡咯烷基,3-吡咯烷基,1-四氢哌嗪基,2-四氢哌嗪基,3-四氢哌嗪基,1-哌啶基,2-哌啶基,3-哌啶基,1-吡唑啉基,3-吡唑啉基,4-吡唑啉基,5-吡唑啉基,1-哌啶基,2-哌啶基,3-哌啶基,4-哌啶基,2-噻唑烷基,3-噻唑烷基,4-噻唑烷基,1-咪唑烷基,2-咪唑烷基,4-咪唑烷基,5-咪唑。
如本文所用,术语“卤素”或“卤代”表示F,Cl,Br或I。
术语“卤代烷基”是指被一个或多个卤素原子取代的烷基。例如,C1-3卤代烷基可以是-CFHCH2CHF2。
术语“氟代烷基”是指被一个或多个氟原子取代的烷基。该术语包括全氟化烷基,例如-CF3和-CF2CF3。
如本文所用,“氨基”基团是指-NH2。
术语“羟基”或“羟基”是指-OH。
如本文所用,单独使用或与另一基团结合使用的“羰基”是指-C(O)-(通过双键与氧结合的碳原子)或-C(O)H(如果是羰基位于链的末端位置)。
本发明化合物在本文中通过其化学结构和/或化学名称来定义。化合物由化学结构和化学名称引用,化学结构和化学名称冲突时,化学结构决定了化合物的特性。
取代基Rn通常在引入时定义,并在整个说明书和所有独立权利要求中保留该定义。
化合物实例
在一个实施方案中,本发明涉及式I的化合物:
其中,
X选自–P(O)(OH)2、–P(O)(OH)O-M+、–P(O)(O-)2(M+)2或–P(O)(O-)2D2+;其中M+是药学上可接受的一价阳离子,D2+是药学上可接受的二价阳离子;
每个JB独立地选自卤素;
m选自0或1;
n选自0、1、2、3或4;
R1选自C1-4烷基,C1-4氟代烷基,-C(O)NH2或氢;且
R2选自C1-4烷基,C1-4氟烷基或氢;或者,
R1和R2与它们所连接的碳原子一起形成C3-7脂环族环,或含有独立地选自N、O或S的至多2个杂原子的3至7元杂环;其中所述C3-7脂环族环或3至7元杂环是未取代的;
R3选自卤素、氢、-CN或-NH2;
R4的两个实例同时为氢,或R4的两个实例与它们所连接的碳原子一起形成羰基;和
R5选自氢或甲基。
式I化合物是式IA化合物的磷酸酯前药及其药学上可接受的盐,其可用作sGC刺激剂。对于式IA,JB、n、R1、R2、R3、R4和R5的定义与上面对式I所示的定义相同。
施用后式I化合物表现出的体内生物活性主要是由于前药裂解得到的式IA的母体化合物的存在。
术语“前药”是指作为药物前体的化合物,其在施用和吸收后通过一些代谢、酶促、水解或快速化学转化过程在体内释放药物。通常,在切割成母体药物之前,前药本身具有比母体化合物更低的针对靶标的生物活性。前药可改善母体药物的物理性质和/或改善总体药物功效,例如通过控制其吸收、血液水平、代谢分布和细胞摄取来降低药物的毒性和不需要的副作用。前药还可以降低体内药代动力学间的可变性。前药也可以显示出更理想的药物性质,因此,前药也可以改善药物的配方性或促进药物的配制性以用于某些给药方式。
术语“母体药物”或“母体化合物”是指在施用前药后通过代谢、酶促、水解或快速化学转化过程释放的生物活性实体。在一些实施方案中,母体化合物也可以是用于制备前药的起始材料。
由M+描述的单价阳离子包含Na+,K+或有机胺的一价阳离子。
由D2+描述的二价阳离子包括Ca2+,Zn2+,Cs2+,Mg2+或有机胺的二价阳离子。
在式I的一些实施方案中,其中R1和R2不同,所述化合物是式IB或IC的那些。
在式I、式IB或式IC的一些实施方案中,n选自1、2或3。在其他实施方案中,n为1或2。在其他实施方案中,n为1。在其他实施方案中,n为2。在其他实施方案中,n为0。
在式I、式IB或式IC的一些实施方案中,JB的所有实例均为氟。在其他实施方案中,JB的所有实例都是氯。在其他实施方案中,JB的一些实例是氟,并且JB的一些实例是氯。在一些实施方案中,n为3,JB的一些实例为氯,JB的其余实例为氟。在其他实施方案中,n为3且JB的所有实例均为氟。在一些实施方案中,n为2且每个JB独立地选自氟或氯。在其他实施方案中,n为2且JB的一个实例为氯,JB的另一个实例为氟。在其他实施方案中,n为2且每个JB为氯。在其他实施方案中,n为2且每个JB为氟。在其他实施方案中,n为1且JB为氯。在其他实施方案中,n为1且JB为氟。
在式I的一些实施方案中,R1和R2同时为氢。
在式I、式IB或式IC的一些实施方案中,R1是氢且R2是C1-4烷基或C1-4氟代烷基。在一些实施方案中,R1是氢且R2是C1-2烷基。在其他实施方案中,R1是氢且R2是甲基。在一些实施方案中,R1是氢且R2是C1-2氟代烷基。在其他实施方案中,R1是氢且R2是三氟甲基。
在式I的一些实施方案中,R1和R2同时是C1-4烷基。在一些实施方案中,它们同时是C1-2烷基。在其他实施方案中,它们同时是甲基。
在式I的一些实施方案中,R1和R2同时是C1-4氟代烷基。在一些实施方案中,它们同时是C1-2氟代烷基。在其他实施方案中,它们同时是三氟甲基。
在式I、式IB或式IC的一些实施方案中,R1是-CONH2且R2是C1-2烷基或C1-2氟代烷基。在其他实施方案中,R1是-CONH2且R2是甲基或三氟甲基。在其他实施方案中,R1是-CONH2且R2是三氟甲基。
在式I的一些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,其含有至多2个独立地选自O或S的杂原子。在这些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,其含有一个选自O或S的环杂原子。在其他实施方案中,所述环杂原子是O。
在式I、式IB或式IC的一些实施方案中,m为1。在其他实施方案中,m为0。
在式I、式IB或式IC的一些实施方案中,R4的两个实例同时为氢。在其他实施方案中,R4的两个实例与它们所连接的碳原子一起形成羰基。
在式I、式IB或式IC的一些实施方案中,R3选自氢、卤素、-CN或-NH2。在一些实施方案中,R3选自氢或卤素。在其他实施方案中,R3选自氢、氯或氟。在其他实施方案中,它选自氢或氟。在其他实施方案中,其选自氟或氯。在其他实施方案中,R3是氯。在其他实施方案中,R3是氟。在其他实施方案中,R3是氢。
在式I、式IB或式IC化合物的一些实施方案中,m为0且化合物分别为式II、式IIB或式IIC之一,或为其药学上可接受的盐。
在式II、式IIB或式IIC的一些实施方案中,n选自1、2或3。在其他实施方案中,n为1或2。在其他实施方案中,n为1。在其他实施方案中,n为2。在其他实施方案中,n为0。
在式II、式IIB或式IIC的一些实施方案中,JB的所有实例均为氟。在其他实施方案中,JB的所有实例都是氯。在其他实施方案中,JB的一些实例是氟,并且JB的一些实例是氯。在一些实施方案中,n为3,JB的一些实例为氯,JB的其余实例为氟。在其他实施方案中,n为3且JB的所有实例均为氟。在一些实施方案中,n为2且每个JB独立地选自氟或氯。在其他实施方案中,n为2且JB的一个实例为氯,JB的另一个实例为氟。在其他实施方案中,n为2且每个JB为氯。在其他实施方案中,n为2且每个JB为氟。在其他实施方案中,n为1且JB为氯。在其他实施方案中,n为1且JB为氟。
在式II的一些实施方案中,R1和R2同时为氢。
在式II、式IIB或式IIC的一些实施方案中,R1是氢且R2是C1-4烷基或C1-4氟代烷基。在一些实施方案中,R1是氢且R2是C1-2烷基。在其他实施方案中,R1是氢且R2是甲基。在一些实施方案中,R1是氢且R2是C1-2氟代烷基。在其他实施方案中,R1是氢且R2是三氟甲基。
在式II的一些实施方案中,R1和R2同时是C1-4烷基。在一些实施方案中,它们同时是C1-2烷基。在其他实施方案中,它们同时是甲基。
在式II的一些实施方案中,R1和R2同时是C1-4氟代烷基。在一些实施方案中,它们同时是C1-2氟代烷基。在其他实施方案中,它们同时是三氟甲基。
在式II、式IIB或式IIC的一些实施方案中,R1是-CONH2且R2是C1-2烷基或C1-2氟代烷基。在其他实施方案中,R1是-CONH2且R2是甲基或三氟甲基。在其他实施方案中,R1是-CONH2且R2是三氟甲基。
在式II的一些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,其含有至多2个独立地选自O或S的杂原子。在这些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,含有一个选自O或S的环杂原子。在其他实施方案中,所述环杂原子是O。
在式II、式IIB或式IIC的一些实施方案中,R4的两个实例同时为氢。在其他实施方案中,R4的两个实例与它们所连接的碳原子一起形成羰基。
在式II、式IIB或式IIC的一些实施方案中,R3选自氢,卤素,-CN或-NH2。在这些实施方案的一些中,R3选自氢或卤素。在其他实施方案中,R3选自氢、氯或氟。在其他实施方案中,它选自氢或氟。在其他实施方案中,其选自氟或氯。在其他实施方案中,R3是氯。在其他实施方案中,R3是氟。在其他实施方案中,R3是氢。
在式I、式IB或式IC化合物的一些实施方案中,m为1且化合物分别为式III、式IIIB或式IIIC中的一种,或为其药学上可接受的盐。
在式III、式IIIB或式IIIC的一些实施方案中,n选自1、2或3。在其他实施方案中,n为1或2。在其他实施方案中,n为1。在其他实施方案中,n为2。在其他实施方案中,n为0。
在式III、式IIIB或式IIIC的一些实施方案中,JB的所有实例均为氟。在其他实施方案中,JB的所有实例都是氯。在其他实施方案中,JB的一些实例是氟,并且JB的一些实例是氯。在一些实施方案中,n为3,JB的一些实例为氯,JB的其余实例为氟。在其他实施方案中,n为3且JB的所有实例均为氟。在一些实施方案中,n为2且每个JB独立地选自氟或氯。在其他实施方案中,n为2且JB的一个实例为氯,JB的另一个实例为氟。在其他实施方案中,n为2且每个JB为氯。在其他实施方案中,n为2且每个JB为氟。在其他实施方案中,n为1且JB为氯。在其他实施方案中,n为1且JB为氟。
在式III的一些实施方案中,R1和R2同时为氢。
在式III、式IIIB或式IIIC的一些实施方案中,R1是氢且R2是C1-4烷基或C1-4氟代烷基。
在式III的一些实施方案中,R1和R2同时是C1-4烷基。在一些实施方案中,它们同时是C1-2烷基。在其他实施方案中,它们同时是甲基。在一些实施方案中,R1是氢且R2是C1-2烷基。在其他实施方案中,R1是氢且R2是甲基。在一些实施方案中,R1是氢且R2是C1-2氟代烷基。在其他实施方案中,R1是氢且R2是三氟甲基。
在式III的一些实施方案中,R1和R2同时是C1-4氟代烷基。在一些实施方案中,它们同时是C1-2氟代烷基。在其他实施方案中,它们同时是三氟甲基。
在式III、式IIIB或式IIIC的一些实施方案中,R1是-CONH2且R2是C1-2烷基或C1-2氟代烷基。在其他实施方案中,R1是-CONH2且R2是甲基或三氟甲基。在其他实施方案中,R1是-CONH2且R2是三氟甲基。
在式III的一些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,其含有至多2个独立地选自O或S的杂原子。在这些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,其含有一个选自O或S的环杂原子。在其他实施方案中,所述环杂原子是O。
在式III、式IIIB或式IIIC的一些实施方案中,R4的两个实例同时为氢。在其他实施方案中,R4的两个实例与它们所连接的碳原子一起形成羰基。
在式III、式IIIB或式IIIC的一些实施方案中,R3选自氢、卤素、-CN或-NH2。在这些实施方案的一些中,R3选自氢或卤素。在其他实施方案中,R3选自氢、氯或氟。在其他实施方案中,它选自氢或氟。在其他实施方案中,其选自氟或氯。在其他实施方案中,R3是氯。在其他实施方案中,R3是氟。在其他实施方案中,R3是氢。
在式I的一些实施方案中,化合物是式IV之一或其药学上可接受的盐。
在式IV的一些实施方案中,n选自1、2或3。在其他实施方案中,n为1或2。在其他实施方案中,n为2。在其他实施方案中,n为1。在其他实施方案中,n是0。
在式IV的一些实施方案中,JB的所有实例均为氟。在其他实施方案中,JB的所有实例都是氯。在其他实施方案中,JB的一些实例是氟,并且JB的一些实例是氯。在一些实施方案中,n为2且每个JB独立地选自氟或氯。在其他实施方案中,n为2且JB的一个实例为氯,JB的另一个实例为氟。在其他实施方案中,n为2且每个JB为氯。在其他实施方案中,n为2且每个JB为氟。在其他实施方案中,n为1且JB为氯。在其他实施方案中,n为1且JB为氟。
在式IV的一些实施方案中,m为1。在其他实施方案中,m为0。
在式IV的一些实施方案中,R4的两个实例同时为氢。在其他实施方案中,R4的两个实例与它们所连接的碳原子一起形成羰基。
在式IV的一些实施方案中,R3选自氢、卤素、-CN或-NH2。在这些实施方案的一些中,R3是氢或卤素。在其他实施方案中,R3选自氢、氯或氟。在其他实施方案中,它选自氢或氟。在其他实施方案中,其选自氟或氯。在其他实施方案中,R3是氯。在其他实施方案中,R3是氟。在其他实施方案中,R3是氢。
在式IV的一些实施方案中,化合物是式V之一或其药学上可接受的盐
在式V的一些实施方案中,n选自0、1、2或3。在其他实施方案中,n选自1或2。在其他实施方案中,n为1。在其他实施方案中,n为2。
在式V的一些实施方案中,JB的所有实例均为氟。在其他实施方案中,JB的所有实例都是氯。在其他实施方案中,JB的一些实例是氟,并且JB的一些实例是氯。在一些实施方案中,n为2且每个JB独立地选自氟或氯。在其他实施方案中,n为2且JB的一个实例为氯,JB的另一个实例为氟。在其他实施方案中,n为2且每个JB为氯。在其他实施方案中,n为2且每个JB为氟。在其他实施方案中,n为1且JB为氯。在其他实施方案中,n为1且JB为氟。
在式V的一些实施方案中,m为1。在其他实施方案中,m为0。
在式V的一些实施方案中,R3选自氢、卤素、-CN或-NH2。在这些实施方案的一些中,R3是氢或卤素。在其他实施方案中,R3选自氢、氯或氟。在其他实施方案中,其选自氢或氟。在其他实施方案中,其选自氟或氯。在其他实施方案中,R3是氯。在其他实施方案中,R3是氟。在其他实施方案中,R3是氢。
在式II的一些实施方案中,化合物是式VI之一,或是其药学上可接受的盐。
在式VI的一些实施方案中,R1和R2同时为氢。在一些实施方案中,R1是氢且R2是C1-4烷基或C1-4氟代烷基。
在式VI的一些实施方案中,R1和R2同时是C1-4烷基。在一些实施方案中,它们同时是C1-2烷基。在其他实施方案中,它们同时是甲基。在一些实施方案中,R1是氢且R2是C1-2烷基。在其他实施方案中,R1是氢且R2是甲基。在一些实施方案中,R1是氢且R2是C1-2氟代烷基。在其他实施方案中,R1是氢且R2是三氟甲基。
在式VI的一些实施方案中,R1和R2同时是C1-4氟代烷基。在一些实施方案中,它们同时是C1-2氟代烷基。在其他实施方案中,它们同时是三氟甲基。
在式VI的一些实施方案中,R1是-CONH2且R2是C1-2烷基或C1-2氟代烷基。在其他实施方案中,R1是-CONH2且R2是甲基或三氟甲基。在其他实施方案中,R1是-CONH2且R2是三氟甲基。
在式VI的一些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,其含有至多2个独立地选自O或S的杂原子。在这些实施方案中,R1和R2与它们所连接的碳原子一起形成未取代的3至7元杂环,含有一个选自O或S的环杂原子。在其他实施方案中,所述环杂原子是O。
在式VI的一些实施方案中,其中R1和R2不同,该化合物是式VIA或式VIB之一。
在式VI、式VIA或式VIB的一些实施方案中,n选自1、2或3。在其他实施方案中,n为2。在其他实施方案中,n为1。在其他实施方案中,n为3。在其他实施方案中,n为0。
在式VI、式VIA或式VIB的一些实施方案中,JB的所有实例均为氟。在其他实施方案中,JB的所有实例都是氯。在其他实施方案中,JB的一些实例是氟,并且JB的一些实例是氯。在一些实施方案中,n为2且每个JB独立地选自氟或氯。在其他实施方案中,n为2且JB的一个实例为氯,JB的另一个实例为氟。在其他实施方案中,n为2且每个JB为氯。在其他实施方案中,n为2且每个JB为氟。在其他实施方案中,n为1且JB为氯。在其他实施方案中,n为1且JB为氟。
在式VI、式VIA或式VIB的一些上述实施方案中,R3选自氢、卤素、-CN或-NH2。在这些实施方案的一些中,R3是氢或卤素。在其他实施方案中,R3选自氢、氯或氟。在其他实施方案中,其选自氢或氟。在其他实施方案中,其选自氟或氯。在其他实施方案中,R3是氯。在其他实施方案中,R3是氟。在其他实施方案中,R3是氢。
在任何上式中的一些实施方案中,化合物是选自下表I中的一种:
表I
在本发明的一个实施方案中,化合物是I-1。在本发明的另一个实施方案中,化合物是I-2。在另一个实施方案中,化合物是I-3。在又一个实施方案中,化合物是I-4。在另一个实施方案中,化合物是I-5。
本发明的前药的特征在于高水溶性。前药的水溶性远高于相应的母体化合物。例如,化合物I-1在pH7下的溶解度为66-1000μg/mL,化合物I-4在pH7时的溶解度为71μg/mL;而母体化合物中间体3的溶解度在pH7时为2-3μg/mL。鉴于与母体化合物相比它们的溶解性提高,本发明的前药可适用于肠胃外给药制剂的开发,用于静脉内递送,或皮下肌内注射、眼内、鞘内、脑内、脑室内或动脉内递送的实例。
本发明的前药的特征还在于在给药后快速裂解成母体药物。例如,它们在离体大鼠肠液测定中快速切割。它们也在临床前动物如大鼠和狗体内快速裂解。更具体地,本发明的前药的特征在于当在体外模型系统中或在临床前动物体内施用时意外的短切割或释放时间。
本发明的药学上可接受的盐。
在本文所述的所有情况中,术语“化合物”还包括化合物的药学上可接受的盐,无论是否实际使用短语“药学上可接受的盐”。本文所用的短语“药学上可接受的盐”是指式I或表I的化合物的药学上可接受的有机或无机盐。式I或表I的化合物的药学上可接受的盐用于医药中。然而,非药学上可接受的盐可用于制备式I或表I的化合物或其他药学上可接受的盐。药学上可接受的盐包括包含另一个充当抗衡离子的原子或分子。抗衡离子可以是稳定母体化合物上的电荷的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电荷的原子。多个带电原子是药学上可接受的盐的一部分的实例可具有多个抗衡离子。在某些情况下,抗衡离子可以是相同的。在其他情况下,它们对于每个带电原子可能是不同的。因此,药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
本文所述化合物的药学上可接受的盐包括衍生自式I或表I化合物与无机或有机碱反应的那些。在一些实施方案中,盐可以在化合物的最终分离和纯化过程中原位制备。在其他实施方案中,盐可以在单独的合成步骤中由游离形式的式I或表I的化合物制备。
对于含有磷酸部分的式I或表I的化合物,术语合适的“药学上可接受的盐”是指由药学上可接受的无毒碱制备的盐,包括无机碱和有机碱。衍生自无机碱的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰盐、亚锰、钾、钠、锌等的盐。具体实施方案包括钙、镁、锌、铯、钾和钠盐以及有机胺盐。衍生自药学上可接受的有机无毒胺的盐包括伯、仲和叔胺的盐,取代的胺,包括天然存在的取代的胺、环胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N1-二苯乙烯二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、氢化胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺三丙胺、氨丁三醇、亮氨酸、异亮氨酸、蛋氨酸、丙氨酸、葡甲胺等。一个具体的实施方案是葡甲胺盐。
Berg等人在“Pharmaceutical Salts,”J.Pharm.Sci.,1977:66:1-19中,更全面地描述了上述药学上可接受的盐和其他典型的药学上可接受的盐的制备,其全部内容通过引用并入本文。
除了本文所述的化合物之外,它们的药学上可接受的盐也可以用于组合物中以治疗或预防本文鉴定的疾病。
药物组合物和给药方法。
本文公开的化合物及其药学上可接受的盐可以配制成药物组合物或“制剂”。
通过混合式I或表I的化合物或其药学上可接受的盐与载体,和稀释剂或赋形剂来制备典型的制剂。合适的载体、稀释剂和赋形剂是本领域技术人员公知的,包括诸如碳水化合物、蜡、水溶性和/或可溶胀聚合物、亲水或疏水材料、明胶、油、溶剂、水等材料。所用的特定载体、稀释剂或赋形剂将取决于配制式I或表I化合物或其药学上可接受的盐的方式和目的。通常基于本领域技术人员认为对哺乳动物施用的安全(GRAS-通常认为是安全的)溶剂来选择溶剂。通常,安全溶剂是无毒的含水溶剂,例如水和其它在水中可溶或可混溶的无毒溶剂。合适的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400,PEG300)等,以及它们的混合物。制剂还可包括其他类型的赋形剂,例如一种或多种缓冲剂、稳定剂、抗粘附剂、表面活性剂、润湿剂、润滑剂、乳化剂、粘合剂、悬浮剂、崩解剂、填充剂、吸附剂、包衣(例如肠溶或缓释剂)、防腐剂、抗氧化剂、不透明剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其它已知的添加剂,以提供药物的优雅呈现(即,式I或表I的化合物或药学上可接受的盐或其药物组合物)或有助于制备药物产品(即药物)。
可以使用常规的溶解和混合程序制备制剂。例如,将原料药物质(即,式I或表I的化合物,其药学上可接受的盐,或该化合物的稳定形式,例如与环糊精衍生物或其它已知络合剂的络合物)溶解于在一种或多种上述赋形剂存在下的合适溶剂。具有所需纯度的化合物任选地与药学上可接受的稀释剂、载体、赋形剂或稳定剂以冻干制剂、研磨粉末或水溶液的形式混合。制剂可以通过在环境温度下在适当的pH下和所需的纯度下与生理学上可接受的载体混合来进行。制剂的pH主要取决于具体用途和化合物的浓度,但可以在约3至约8的范围内。当本文所述的试剂是通过溶剂法形成的固体无定形分散体时,可以将添加剂直接添加到当形成诸如添加剂的混合物时,喷雾干燥溶液作为浆液溶解或悬浮在溶液中,然后可以喷雾干燥。或者,可以在喷雾干燥过程之后添加添加剂以帮助形成最终配制的产品
通常将式I或表I的化合物或其药学上可接受的盐配制成药物剂型,以提供易于控制的药物剂量并使患者符合规定的方案。可以制备式I或表I的化合物或其药学上可接受的盐的药物制剂用于各种途径和类型的给药。对于相同化合物可存在各种剂型,因为不同的医学条件可能需要不同的给药途径。
可以与载体材料组合以产生单一剂型的活性成分的量将根据所治疗的受试者和特定的给药方式而变化。例如,用于口服给予人的时间释放制剂可含有约1至1000mg活性物质,其与适当且方便量的载体物质混合,其可占总组合物的约5至约95%(重量:重量)。可以制备药物组合物以提供易于测量的给药量。例如,用于静脉内输注的水溶液可以含有每毫升溶液约3至500μg的活性成分,以便可以以约30mL/hr的速率输注合适的体积。作为一般提议,所施用的抑制剂的初始药学有效量将在约0.01-100mg/kg每剂量的范围内,即每天约0.1至20mg/kg患者体重,具有典型的初始范围。使用的化合物为0.3至15mg/kg/天。
如本文所用的术语“治疗有效量”是指研究人员、兽医、医学博士或其他临床医生正在寻求的组织、系统、动物或人类中引发生物或药物反应的活性化合物或药剂的量。待施用的化合物的治疗或药学有效量将受这些考虑因素控制,并且是改善、治愈或治疗疾病或病症或其一种或多种症状所需的最小量。
式I或表I的药物组合物或其药学上可接受的盐将以一定的方式(即量、浓度、时间表、疗程、载体和给药途径)配制、制剂和给药,符合良好的医疗实践。在此背景下考虑的因素包括所治疗的特定疾病,所治疗的特定哺乳动物,个体患者的临床状况,疾病的原因,药剂的递送部位,给药方法,给药方案,以及医疗从业者已知的其他因素,例如患者个体的年龄、体重和反应。
术语“预防有效量”是指有效预防或基本上减少获得疾病或病症的机会或在获得疾病或病症之前降低疾病或病症的严重程度或降低一种或多种病症的严重程度的量。在症状出现之前的症状。大致上,预防措施分为一级预防(以防止疾病的发展)和二级预防(由此疾病已经发展并且患者受到保护以防止该过程的恶化)。
可接受的稀释剂、载体、赋形剂和稳定剂是在所用剂量和浓度下对接受者无毒的那些,并且包括缓冲剂,例如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和蛋氨酸;防腐剂(如十八烷基二甲基苄基氯化铵;六甲基氯化铵;苯扎氯铵,苄索氯铵;苯酚,丁基或苄醇;对羟基苯甲酸烷基酯,如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);血清白蛋白、明胶或免疫球蛋白等蛋白质;亲水性聚合物,如聚乙烯吡咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂如EDTA;糖类,如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐抗衡离子如钠;金属配合物(例如,锌-蛋白质配合物);和/或非离子表面活性剂,例如吐温、普朗尼克或聚乙二醇(PEG)。活性药物成分也可以包埋在微胶囊中,例如,通过凝聚技术或通过界面聚合制备,例如分别为羟甲基纤维素或明胶-微胶囊和聚-(甲基丙烯酸甲酯)微胶囊;在胶体药物递送系统(例如,脂质体、白蛋白微球、微乳、纳米颗粒和纳米胶囊)或在粗乳液中。这些技术在Remington's:The Science andPractice of Pharmacy,第21版,费城科学大学,2005(以下称“Remington's”)中公开。
关于本发明的化合物、组合物或制剂,术语“施用”或“给药”是指将化合物引入需要治疗的动物的系统中。当本发明化合物与一种或多种其它活性剂组合提供时,“给药”及其变体各自应理解为包括同时和/或顺序引入化合物和其它活性剂。
取决于所治疗疾病的严重程度和类型,本文所述的组合物可通过全身或局部给药,例如经口(例如,使用胶囊、粉末、溶液、悬浮液、片剂、舌下片剂等),吸入(例如,使用气溶胶、气体、吸入器、雾化器等),耳部给药(例如,使用滴耳液),局部(例如,使用乳膏、凝胶、搽剂、乳液、软膏、糊剂、透皮贴剂等),眼科给药(例如,使用滴眼液、眼药水、眼科凝胶、眼用软膏),直肠给药(例如,使用灌肠剂或栓剂),鼻腔给药,口腔给药,阴道给药(例如,使用冲洗液、子宫内装置、阴道栓剂、阴道环或片剂等),通过植入的储库或类似物,或肠胃外给药。
本文使用的术语“肠胃外”包括但不限于皮下、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。优选地,组合物通过口服、皮下或静脉内给药。
本文所述的药物组合物可以以任何口服可接受的剂型口服给药,包括但不限于胶囊、片剂、水悬浮液或溶液。用于口服给药的液体剂型包括但不限于药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物外,液体剂型可含有本领域常用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄基醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽、花生、玉米、胚芽、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脂肪酸酯脱水山梨糖醇及其混合物。除惰性稀释剂外,口服组合物还可包括佐剂,如润湿剂、乳化剂和悬浮剂,甜味剂,调味剂和芳香剂。
用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这种固体剂型中,活性化合物与至少一种惰性的药学上可接受的赋形剂或载体如柠檬酸钠或磷酸二钙和/或选自下列的辅料混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露醇,b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,c)保湿剂如甘油,d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸某些硅酸盐和碳酸钠,e)溶液延迟剂如石蜡,f)吸收促进剂如季铵化合物,g)润湿剂如鲸蜡醇和甘油单硬脂酸酯,h)吸收剂如高岭土和膨润土,和i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠、以及它们的混合物。片剂可以是未包衣的,或者可以通过已知技术包衣,包括微囊化以掩盖令人不愉快的味道或延迟胃肠道中的崩解和吸附,从而在较长时间内提供持续作用。例如,可以使用延时材料,例如单独的甘油单硬脂酸酯或二硬脂酸甘油酯或与蜡一起使用。可以使用水溶性味道掩蔽材料,例如羟丙基甲基纤维素或羟丙基纤维素。
适于口服给药的式I或表I化合物或其药学上可接受的盐的制剂可以制备成离散的单位,例如片剂,丸剂,锭剂,锭剂,水性或油性悬浮液,可分散的粉末或颗粒,乳液,硬或软胶囊,例如明胶胶囊,糖浆或酏剂。用于口服使用的化合物的制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。
口服使用的制剂也可以作为硬明胶胶囊提供,其中活性成分与惰性固体稀释剂混合,例如碳酸钙、磷酸钙或高岭土,或作为软明胶胶囊,其中活性成分与其混合。水溶性载体如聚乙二醇或油介质,例如花生油、液体石蜡或橄榄油。
活性化合物也可以是具有一种或多种上述赋形剂的微囊化形式。
当口服使用需要含水悬浮液时,将活性成分与乳化剂和悬浮剂混合。如果需要,可以加入某些甜味剂和/或调味剂。糖浆和酏剂可以用甜味剂配制,例如甘油、丙二醇、山梨糖醇或蔗糖。此类制剂还可含有缓和剂、防腐剂、调味剂和着色剂和抗氧化剂。
本文所述组合物的无菌可注射形式(例如,用于肠胃外给药)可以是水性或油性悬浮液。可以根据本领域已知的技术使用合适的分散剂或润湿剂和悬浮剂配制这些悬浮液。无菌可注射制剂还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悬浮液,例如在1,3-丁二醇或PEG400中的溶液。可以使用的可接受的载体和溶剂包括水,林格氏溶液和等渗氯化钠溶液。另外,无菌的固定油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。脂肪酸,例如油酸及其甘油酯衍生物可用于制备注射剂,天然药学上可接受的油,例如橄榄油或蓖麻油,尤其是它们的聚氧乙基化形式。这些油溶液或悬浮液还可含有长链醇稀释剂或分散剂,例如羧甲基纤维素或类似的分散剂,它们通常用于配制药学上可接受的剂型,包括乳液和悬浮液。其他常用的表面活性剂,例如吐温、司盘和其它乳化剂或生物利用度增强剂,其通常用于制备药学上可接受的固体、液体或其它剂型,也可用于可注射制剂的目的。
可以通过将式I或表I的化合物或其药学上可接受的盐悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如矿物油)中来配制油性悬浮液。作为液体石蜡。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可加入如上所述的甜味剂和调味剂以提供适口的口服制剂。这些组合物可以通过加入抗氧化剂如丁基化羟基茴香醚或α-生育酚来保存。
式I或表I化合物或其药学上可接受的盐的水性悬浮液含有活性物质与适于制备水性悬浮液的赋形剂的混合物。这些赋形剂包括悬浮剂,例如羧甲基纤维素钠、交联羧甲基纤维素、聚维酮、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,以及分散或润湿剂,例如天然存在的磷脂(例如,卵磷脂),环氧烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯),环氧乙烷与长链脂族醇的缩合产物(例如十七烷氧基乙醇),环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如,聚氧乙烯脱水山梨糖醇单油酸酯)。含水悬浮液还可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,一种或多种调味剂和一种或多种甜味剂,例如蔗糖或糖精。
可注射制剂可以是灭菌的,例如,通过细菌截留过滤器过滤,或通过掺入无菌固体组合物形式的灭菌剂,其可以在使用前溶解或分散在无菌水或其它无菌可注射介质中。
可通过局部推注注射将可注射溶液或微乳液引入患者的血流中。或者,以保持本发明化合物的恒定循环浓度的方式给予溶液或微乳液可能是有利的。为了保持这种恒定的浓度,可以使用连续的静脉内递送装置。这种装置的一个例子是Deltec CADD-PLUSTM 5400型静脉泵。
用于直肠或阴道给药的组合物优选是栓剂,其可以通过将本文所述的化合物与合适的无刺激性赋形剂或载体如可可脂、蜂蜡、聚乙二醇或栓剂蜡混合来制备,所述赋形剂或载体在环境温度下是固体但是液体在体温下因此在直肠或阴道腔中融化并释放活性化合物。适用于阴道给药的其他制剂可以呈现为阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾剂。
本文所述的药物组合物还可以局部给药,特别是当治疗目标包括局部施用易于接近的区域或器官时,包括眼、耳、皮肤或下肠道疾病。对于这些区域或器官中的每一个,可便利地制备合适的局部制剂。
用于局部或透皮施用本文所述化合物的剂型包括软膏、糊剂、乳膏、洗剂、凝胶、粉末、溶液、喷雾剂、吸入剂或贴剂。在无菌条件下将活性成分与药学上可接受的载体和任何所需的防腐剂或缓冲剂混合。眼科制剂、滴耳剂和滴眼剂也包括在本发明的范围内。另外,本发明考虑使用透皮贴剂,其具有提供化合物控制递送至身体的附加优点。这种剂型可以通过将化合物溶解或分散在适当的介质中来制备。吸收促进剂也可用于增加化合物在皮肤上的通量。可以通过提供速率控制膜或通过将化合物分散在聚合物基质或凝胶中来控制速率。用于下肠道的局部施用可以以直肠栓剂制剂(参见上文)或以合适的灌肠剂制剂实现。也可以使用局部透皮贴剂。
对于局部应用,可以将药物组合物配制成合适的软膏,其含有悬浮或溶解在一种或多种载体中的活性组分。用于局部施用本发明化合物的载体包括但不限于矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,可以将药物组合物配制成合适的洗剂或乳膏,其中含有悬浮或溶解在一种或多种药学上可接受的载体中的活性组分。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。
对于眼科使用,药物组合物可以配制成等渗的、pH调节的无菌盐水中的微粉化悬浮液,或优选地,作为等渗的、pH调节的无菌盐水中的溶液,有或没有防腐剂如苄基氯化铵。或者,对于眼科用途,药物组合物可以配制成软膏如凡士林。为了治疗眼睛或其他外部组织,例如口腔和皮肤,制剂可以作为局部软膏或乳膏施用,其含有活性成分,其量为例如0.075-20%w/w。当配制成软膏时,活性成分可以与油基、石蜡基或水混溶性软膏基质一起使用。
或者,可以将活性成分配制成具有水包油乳膏基质的乳膏。如果需要,乳膏基质的水相可包括多元醇,即具有两个或多个羟基的醇,例如丙二醇、1,3-二醇丁烷、甘露醇、山梨糖醇、甘油和聚乙二醇(包括PEG400)及其混合物。局部制剂可以理想地包括增强活性成分通过皮肤或其他受影响区域的吸收或渗透的化合物。这种皮肤渗透促进剂的实例包括二甲基亚砜和相关的类似物。
使用式I或表I的化合物或其药学上可接受的盐制备的乳液的油相可以以已知方式由已知成分构成。虽然该相可仅包含乳化剂,但理想地包含至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。亲水性乳化剂可与亲脂性乳化剂一起包含,所述亲脂性乳化剂用作稳定剂。在一些实施方案中,乳化剂包括油和脂肪。有或没有稳定剂的乳化剂一起构成所谓的乳化蜡,并且蜡与油脂一起构成所谓的乳化软膏基质,其形成乳膏的油性分散相。适用于配制式I或表I化合物或其药学上可接受的盐的乳化剂和乳液稳定剂包括TweenTM-60、SpanTM-80、十六醇十八醇、苯甲醇、肉豆蔻醇、单硬脂酸甘油酯和月桂基硫酸钠。
药物组合物还可以通过鼻气雾剂或通过吸入给药。此类组合物根据药物制剂领域熟知的技术制备,并且可以制备为盐水溶液,使用苯甲醇或其他合适的防腐剂,吸收促进剂以提高生物利用度,碳氟化合物和/或其他常规增溶剂或分散剂。适用于肺内或鼻内给药的制剂具有例如0.1至500微米的粒度(包括0.1至500微米的微粒,例如0.5、1、30、35微米等的粒子),其中通过鼻腔通道快速吸入或通过口腔吸入给药,以便到达肺泡囊。
取决于用于施用药物的方法,可以以多种方式包装使用的药物组合物(或制剂)。通常,用于分配的制品包括其中以适当的形式沉积药物制剂的容器。合适的容器是本领域技术人员公知的,包括诸如瓶子(塑料和玻璃)、小袋、安瓿、塑料袋、金属圆筒等材料。容器还可以包括防篡改组件,以防止轻易获得包装内容物。另外,容器上沉积有描述容器内容物的标签。标签还可能包含适当的警告。
制剂可以包装在单位剂量或多剂量容器中,例如密封的安瓿和小瓶中,并且可以以仅需要添加无菌液体载体的冷冻干燥(冻干)条件储存,例如水,在使用前立即注射。临时注射溶液和悬浮液由前述类型的无菌粉末、颗粒和片剂制备。优选的单位剂量制剂是含有如上所述的每日剂量或单位每日亚剂量的活性成分或其适当部分的那些。
在另一个方面,式I或表I的化合物或其药学上可接受的盐可以配制在包含兽医载体的兽医用组合物中。兽用载体是可用于施用组合物的材料,并且可以是固体、液体或气体材料,其在惰性或兽医领域中是可接受的并且与活性成分相容。这些兽医用组合物可以胃肠外、口服或任何其他所需途径给药。
治疗方法
增加的NO产生或组织中cGMP浓度的增加导致血管舒张,血小板聚集和粘附的抑制,抗高血压作用,抗重塑作用,抗纤维化,抗细胞凋亡作用,抗炎作用和神经元信号传递效应,以及其他影响。
在另一个方面,本发明涉及通过在有此需要的患者中使用某些sGC刺激剂的某些前药或其药学上可接受的盐或包含它们的药物组合物单独或组合治疗某些病症。
本公开涉及可溶性鸟苷酸环化酶(sGC)刺激剂的某些前药,其药学上可接受的盐和药物制剂以及它们单独或与一种或多种另外的药剂组合用于治疗和/或预防各种疾病的用途,其中可能需要增加NO浓度或增加cGMP浓度。
在其他实施方案中,本文公开的化合物是sGC刺激剂的前药,其可用于预防和/或治疗以生物系统中NO的不希望的生物利用度和/或敏感性降低为特征的疾病和病症(例如,在人体内),例如与氧化应激或亚硝化应激条件有关的那些。
本文所用的术语“心血管疾病”(或“心血管病症”)是指基于循环器官例如心脏、血管(动脉、毛细血管和静脉)或两者的异常症状的疾病,该术语还包括一般影响心血管系统的任何疾病,包括心脏病,脑血管疾病,肾脏、肝脏和相关器官的血管疾病,或肺,以及外周动脉疾病等。
“sGC相关的心血管疾病”是已知或怀疑涉及NO/sGC/cGMP系统的心血管疾病,并且是可以通过sGC激活/刺激,通过NO合酶激活,或通过添加NO或NO供体或NO前体如L-精氨酸或L-瓜氨酸,或通过抑制负责cGMP分解的PDE(磷酸二酯酶)或任何组合以上方法来治疗或预防的心血管疾病。
如本文所用的术语“血管舒张”是指血管扩张。它是由血管壁内的平滑肌细胞松弛引起的,特别是在大静脉、大动脉和较小的小动脉中。实质上,该过程与“血管收缩”相反,后者是血管变窄。当血管扩张时,由于血管阻力的降低,血液流动增加。因此,动脉血管(主要是小动脉)的扩张会降低血压。反应可能是内在的(由于周围组织中的局部过程)或外在的(由于激素或神经系统)。此外,响应可以定位于特定器官(取决于特定组织的代谢需要,如在剧烈运动期间),或者它可以是全身性的(在整个体循环中看到)。
如本文所用的术语“血管收缩”是指由于肌肉收缩导致的血管变窄。血管收缩是身体调节和维持平均动脉压(MAP)的一种机制。广泛性血管收缩通常导致全身血压升高,但也可能在特定组织中发生,导致血流局部减少。
如本文所用,术语“支气管收缩”用于限定由于周围平滑肌收紧导致的肺部气道收缩,随之发生咳嗽、喘息和呼吸短促。这种情况有很多原因,最常见的是哮喘。运动和过敏可以在其他无症状的个体中引起症状。其他病症如慢性阻塞性肺病(COPD)也可伴有支气管收缩。
贯穿本公开内容,术语“高血压”、“动脉高血压”或“HBP”可互换使用,并且指的是极其常见且高度可预防的慢性病症,其中动脉中的血压(BP)高于正常或期望。如果控制不当,它代表了几种严重心血管和肾脏疾病的重要危险因素。高血压可能是一种主要疾病,称为“原发性高血压”或“特发性高血压”,或者可能由其他疾病引起或与之相关,在这种情况下,它被归类为“继发性高血压”。原发性高血压占所有病例的90-95%。
如本文所用,术语“顽固性高血压”是指尽管同时使用属于不同抗高血压药物类别的三种抗高血压药物,但仍高于目标血压的高血压(通常低于140/90mmHg,但对于患有合并糖尿病或肾病的患者,建议低于130/80mmHg的低目标)。需要四种或更多药物来控制血压的人也被认为患有顽固性高血压。高血压是糖尿病中极为常见的合并症,取决于肥胖、种族和年龄,影响约20-60%的糖尿病患者。这种类型的高血压在本文中称为“糖尿病性高血压”。在2型糖尿病中,高血压通常作为胰岛素抵抗的代谢综合征的一部分存在,还包括中心性肥胖和血脂异常。在1型糖尿病中,高血压可能反映了糖尿病肾病的发病。
如本文所用,“肺动脉高血压(PH)”是一种疾病,其特征在于肺血管(肺动脉,肺静脉和肺毛细血管)中的血压持续升高,其导致右心肥大,最终导致右心衰竭和死亡。PH的常见症状包括呼吸短促、头晕和昏厥,所有这些症状都会因劳累加剧而恶化。如果不进行治疗,诊断后的预期寿命中位数为2.8年。PH以许多不同的形式存在,根据其病因分类。类别包括肺动脉高压(PAH),患有左心病的PH,与肺病和/或低氧血症相关的PH,由于慢性血栓形成和/或栓塞性疾病引起的PH和各种PH。PAH在一般人群中很少见,但与某些常见病症如HIV感染、硬皮病和镰状细胞病相关的患病率增加。其他形式的PH通常比PAH更常见,例如,PH与慢性阻塞性肺病(COPD)的关联是特别令人关注的。目前对肺动脉高压的治疗取决于疾病的阶段和机制。
术语“冠状动脉疾病”是指对心肌的血液供应部分或完全阻断(心肌缺血)的病症。这种对心肌的血液供应减少可能导致许多“急性心肌综合征”:胸痛(“心绞痛”,稳定或不稳定)和不同类型的心脏病(“心肌梗塞”或MI)。冠状动脉疾病的一个常见原因是“动脉粥样硬化”,指由于动脉壁中的脂肪沉积导致动脉变硬,然后可能通过动脉粥样硬化斑块的形成进展,缩小并最终阻塞血流到动脉中。这种动脉粥样硬化过程也可能影响其他动脉,而不仅仅是心脏的动脉。血栓是导致动脉阻塞的最常见原因,因为动脉通常由于动脉粥样硬化斑块(动脉粥样硬化斑块)而部分阻塞;动脉粥样硬化可能破裂或撕裂,导致凝块形成。偶尔,冠状动脉疾病是由冠状动脉痉挛引起的,冠状动脉痉挛可以自发发生或由于使用某些药物(例如可卡因、尼古丁)而发生。偶尔,冠状动脉疾病的原因是出生缺陷,病毒感染(例如,川崎病),系统性红斑狼疮(狼疮),动脉炎症(动脉炎),从心室进入其中一个的血凝块冠状动脉或物理损伤(例如,受伤或放射治疗)。
如本文所用,“不稳定型心绞痛”是指心绞痛症状模式的变化,包括心绞痛延长或恶化以及严重症状的新发作。
MI(心肌梗塞)可分为两种类型:“非ST段抬高”MI和“ST段抬高”MI。急性冠状动脉综合征的并发症取决于冠状动脉阻塞的程度、时间和位置。如果阻塞影响大量心肌,心脏将无法有效泵送。如果堵塞阻断了流向心脏电气系统的血流,心脏节律可能会受到影响。当心脏病发作时,部分心肌会死亡。死的组织和取代它的疤痕组织不会收缩。当其余的心脏试图收缩时,疤痕组织有时甚至会扩张或凸出。因此,抽血的肌肉变少。如果足够的肌肉死亡,心脏的抽吸能力可能会降低,心脏无法满足身体对氧气和血液的需求。然后发生心力衰竭、低血压或两者兼而有之。如果超过一半的心肌受损或死亡,心脏通常不能发挥作用,并且可能导致严重的残疾或死亡。
如本文所用,“心力衰竭”(HF)是左心室(LV)心肌重塑的进行性病症,其最终导致复杂的临床综合征,其中心脏功能受损和循环充血是定义的特征,并导致递送不足血液和营养物质对身体组织的影响。当心脏受损或过度劳累并且无法抽出从体循环返回的所有血液时,就会发生这种情况。由于抽出较少的血液,返回心脏的血液会回流,并且身体的其他部位会积聚液体。心力衰竭还会损害肾脏处理钠和水的能力,进一步使液体潴留变得复杂。心力衰竭的特征在于自主神经功能障碍、神经激素激活和细胞因子的过度产生,其导致进行性循环衰竭。心力衰竭的症状包括:运动或休息时呼吸困难(呼吸短促),夜间因突然呼吸困难而醒来,均表明肺水肿;一般疲劳或虚弱;脚、脚踝和腿部水肿;体重迅速增加;或慢性咳嗽,包括产生粘液或血液的咳嗽。根据其临床表现,心力衰竭被分类为新发、短暂、急性、急性后或慢性。急性心力衰竭,即需要紧急治疗的症状的快速或逐渐发作,可能从头开始或由于慢性心力衰竭而失代偿。术语“心力衰竭”通常用于表示“慢性心力衰竭”。术语“充血性心力衰竭(CHF)”或“充血性心力衰竭(CCF)”通常可与慢性心力衰竭互换使用。心力衰竭的常见原因包括冠状动脉疾病,包括先前的心肌梗塞(心脏病发作)、高血压、心房颤动、心脏瓣膜病和心肌病。这些通过改变心脏的结构或功能导致心力衰竭。
有两种主要类型的心力衰竭:“由于射血分数降低引起的心力衰竭(HFREF)”,也称为“由于左心室收缩功能障碍导致的心力衰竭”或“收缩性心力衰竭”,以及“具有保留射血分数的心力衰竭(HFPEF)”,也称为“舒张性心力衰竭”或“具有正常射血分数的心力衰竭(HFNEF)”。射血分数是在单次收缩期间从心脏泵出的心脏中的血液的比例。其正常百分比介于50%和75%之间。
术语“急性”(如“急性HF”)用于表示快速发作,“慢性”表示长持续时间。慢性心力衰竭是一种长期的情况,通常具有稳定的治疗症状。“急性失代偿性”心力衰竭是恶化或失代偿性心力衰竭,指的是一个人可以被描述为心力衰竭体征和症状改变导致需要紧急治疗或住院治疗的事件。在高输出的情况下(然后它被称为“高输出心力衰竭”)也可能发生心力衰竭,其中心室收缩功能正常但心脏不能处理血容量的重要增加。
在心血管生理学中,术语“射血分数(EF)”定义为左心室和右心室中随每次心跳或心动周期抽出的血液分数。在医学成像允许的有限数学中,EF应用于右心室,其通过肺动脉瓣将血液喷射到肺循环中,或左心室,其通过主动脉瓣将血液喷射到脑和体循环中。
术语“具有保留射血分数的心力衰竭(HFPEF)”通常被理解为具有大于55%射血分数的心力衰竭的体征和症状的表现。其特征在于左心室顺应性降低,导致左心室压力增加。由于左心室功能差,HFPEF常见左心房大小增加。充血性心力衰竭、心房颤动和肺动脉高压的风险增加。风险因素是高血压、高脂血症、糖尿病、吸烟和阻塞性睡眠呼吸暂停。在这种类型的心力衰竭中,心肌收缩良好但心室在松弛阶段不能很好地充满血液。
术语“射血分数降低(HFREF)的心力衰竭”是指射血分数小于40%的心力衰竭。
糖尿病是心力衰竭患者的常见合并症,并且与较差的结果相关并且可能损害治疗的功效。其他重要的合并症包括系统性高血压、慢性气流阻塞、睡眠呼吸暂停、认知功能障碍、贫血、慢性肾病和关节炎。慢性左心衰竭通常与肺动脉高压的发展有关。某些合并症的发生频率因性别而异:女性中,高血压和甲状腺疾病更为常见,而男性更常患慢性阻塞性肺病(COPD)、外周血管疾病、冠状动脉疾病和肾功能不全。抑郁症是心力衰竭的常见并发症,这两种情况往往会相互复杂化。恶病质长期以来被认为是心力衰竭的严重且常见的并发症,影响所有心力衰竭患者的高达15%并且预后不良。心脏恶病质定义为在六个月内非体重,非自愿性丧失至少6%的体重。
如本文所用,术语“心律失常”是指在超过90%的心脏病发作的人中发生的异常心律。有时问题在于心脏部分触发心跳并且心率可能太慢,有时问题可能导致心脏过快或不规律地跳动。有时,心跳的信号不是从心脏的一部分传导到另一部分,心跳可能会减慢或停止。此外,心肌的未死但血流不畅的区域可能易激惹。这会导致心律问题,如室性心动过速或心室颤动。如果心脏停止完全抽吸,这可能导致心脏停搏。
“心包”是围绕心脏的袋或膜。“心包炎”或该膜的炎症可能由于心脏病发作而发展,并且可能导致发热,心包积液,覆盖肺部的膜(胸膜)的炎症,胸腔积液和关节疼痛。心脏病发作后的其他并发症可能包括二尖瓣功能障碍、心肌破裂、心室壁膨胀(室性动脉瘤)、血栓和低血压。
术语“心肌病”是指心室肌壁的结构和功能的进行性损害。心肌病的主要类型是扩张的、肥大的和限制性的。心肌病通常会导致心力衰竭的症状,并且还可能导致胸痛、昏厥和猝死。
术语“二尖瓣反流”、“二尖瓣关闭不全”或“二尖瓣功能不全”是指心脏的二尖瓣不紧密闭合,允许血液在心脏中向后流动的情况。结果,血液不能有效地通过心脏或身体的其他部分移动,导致疲劳或呼吸短促。
术语“睡眠呼吸暂停”是指睡眠呼吸障碍中最常见的呼吸障碍。这是一种特征为间歇性、周期性减少或完全停止气流的病症,其可能涉及或可能不涉及阻塞上呼吸道。睡眠呼吸暂停有三种类型:阻塞性睡眠呼吸暂停,为最常见的形式,中枢性睡眠呼吸暂停和混合性睡眠呼吸暂停。
“中枢性睡眠呼吸暂停(CSA)”是由大脑正常呼吸信号的故障引起的,而不是气道的物理阻塞引起的。呼吸努力的缺乏导致血液中的二氧化碳增加,这可能引起患者的注意。CSA在一般人群中很少见,但在收缩性心力衰竭患者中相对常见。
如本文所用,术语“代谢综合征”、“胰岛素抵抗综合征”或“综合征X”是指代谢病症(腹部肥胖,空腹血糖升高,“血脂异常”(即血脂水平升高)和高血压(HBP))的组或聚类,它们一起发生的次数多于偶然发生,并且共同促进2型糖尿病和心血管疾病的发展。代谢综合征的特征在于特定脂质特征:甘油三酯增加,高密度脂蛋白胆固醇(HDL-胆固醇)降低,并且在一些情况下,低密度脂蛋白胆固醇(LDL-胆固醇)水平适度升高,以及由于组成风险因素的压力的“动脉粥样硬化病”加速进展。有几种类型的血脂异常:“高胆固醇血症”是指胆固醇水平升高。家族性高胆固醇血症是由于19号染色体(19p13.1-13.3)上的缺陷的一种特殊形式的高胆固醇血症。“高甘油三酯血症”是指甘油酯水平升高(例如,“高甘油三酯血症”涉及升高的甘油三酯水平)。“高脂蛋白血症”是指脂蛋白水平升高(除非另有说明,通常为LDL)。
术语“脂肪变性”是指细胞内脂质的异常保留。它通常反映了合成和消除甘油三酯的正常过程的损害。多余的脂肪积聚在囊泡中,从而取代细胞的细胞质。在严重的情况下,细胞可能会破裂。通常在肝脏中观察到脂肪变性,因为它是主要与脂肪代谢相关的器官。它也可以在心脏、肾脏和肌肉组织中观察到。
如本文所用,术语“外周血管疾病(PVD)”,通常也称为“外周动脉疾病(PAD)”或“外周动脉闭塞性疾病(PAOD)”,是指阻塞大动脉而非在冠状动脉、主动脉弓血管系统或大脑内。PVD可由动脉粥样硬化、导致狭窄的炎症过程、栓塞、血栓形成或其他类型的闭塞引起。它引起急性或慢性“缺血(缺乏血液供应)”。通常,PVD是用于指下肢中发现的动脉粥样硬化阻塞的术语。PVD还包括归类为由于动脉的间歇性狭窄(例如,“雷诺氏现象”)或其扩大(红斑性肢痛),即血管痉挛引起的微血管疾病的一部分疾病。外周动脉疾病包括闭塞性血栓性血管炎,外周动脉闭塞性疾病,雷诺氏病和雷诺氏综合症。常见的症状是腿或脚发冷,间歇性跛行,下肢疼痛和严重的肢体缺血(下肢溃疡和坏死)。外周动脉疾病的诊断和治疗指南可在Eur.J.Vasco Endovasc.Surg,2007,33(1),Sl中找到。
本文使用的术语“狭窄(stenosis)”是指血管或其他管状器官或结构中的异常变窄。它有时也被称为“狭窄(stricture)”(如在尿道狭窄中)。术语“缩窄(coarctation)”是同义词,但通常仅在主动脉缩窄(aortic coarctation)的情况下使用。术语“再狭窄”是指手术后狭窄的复发。
术语“血栓形成”是指在血管内形成血凝块(“血栓”),阻碍血液流过循环系统。当血管受伤时,身体使用血小板和纤维蛋白形成血凝块以防止失血。或者,即使血管未受伤,如果适当的条件存在,也可在体内形成血凝块。如果凝血太严重并且凝块脱落,那么移动的凝块现在被称为“栓子(embolus)”。术语“血栓栓塞”是指血栓形成与其主要并发症“栓塞”的组合。当血栓占据动脉管腔表面积的75%以上时,供给组织的血流量减少到足以引起症状,因为氧气减少(缺氧)和代谢产物如乳酸(“痛风”)的积累。超过90%的阻塞可导致缺氧、完全缺氧和“梗塞”,这是一种细胞死亡模式。
“栓塞”(复数栓塞)是将栓子(能够在远离其原点的位置堵塞动脉毛细血管床的分离的血管内小块)倒入动脉床的狭窄毛细血管中的事件,其引起阻塞(血管闭塞)在身体的远端。不要将其与在原产地阻塞的血栓相混淆。形成栓塞的材料可以有许多不同的来源:如果材料是血液,“栓子”被称为“血栓”;固体材料还可包括脂肪、细菌残留物、感染组织等。
“局部缺血”是对组织的血液供应的限制,导致细胞代谢所需(以保持组织存活)的氧和葡萄糖的短缺。缺血通常由血管问题引起,导致组织损伤或功能障碍。它还意味着身体某一部分的局部贫血症有时是由于阻塞(如血管收缩、血栓形成或栓塞)引起的。如果在心肌(或“心肌”)中发生“局部缺血”,则缺血被称为心肌缺血。其他类型的局部缺血例如是脑缺血、严重肢体缺血等。
当在局部缺血期后血液供应返回组织时发生“再灌注”。在恢复到组织的循环后,可能发展炎症和氧化应激过程。这一系列事件的一个例子是与器官移植相关的缺血再灌注。
“再灌注损伤”是在局部缺血和炎症和氧化损伤之后血液供应返回组织而不是恢复正常功能时引起的组织损伤。缺血问题的再灌注通常与微血管损伤有关,特别是由于毛细血管和小动脉的渗透性增加导致组织中扩散和流体过滤的增加。活化的内皮细胞在再灌注后产生更多的活性氧物质但NO更少,并且不平衡导致炎症反应。通过新返回的血流携带到该区域的白细胞释放大量炎性因子和自由基以响应组织损伤。恢复的血液流动带来氧气,破坏细胞蛋白质、DNA和质膜。这种缺血-再灌注过程也被认为是导致慢性伤口(例如,压疮或糖尿病性溃疡)愈合形成和失败的原因。
本文使用的术语“血管病”是血管疾病(动脉、静脉和毛细血管)的总称。最常见和最普遍的血管病是“糖尿病性血管病”,慢性糖尿病的常见并发症。另一种常见类型的血管病是“脑淀粉样血管病”(CAA),也称为嗜刚果红血管病(congophilic angiopathy),其中淀粉样沉积物形成在中枢神经系统的血管壁中。使用术语嗜刚果红(congophilic)是因为在应用称为刚果红的特殊染色剂后,通过显微镜检查脑组织可以证明存在淀粉样蛋白的异常聚集。淀粉样物质仅存在于脑中,因此该疾病与其他形式的淀粉样变性无关。
“中风”或脑血管意外(CVA)是由于对脑的血液供应的干扰而导致的脑功能的快速丧失。这可能是由于阻塞(血栓形成、动脉栓塞、脂肪堆积或痉挛)或出血(血液渗漏)引起的“缺血”(缺乏血流,导致组织缺氧和葡萄糖供应不足)。结果,受影响的大脑区域无法发挥作用,这可能导致无法在身体的一侧移动一个或多个肢体,无法理解或制定语言,或者无法看到视野的一侧。中风的危险因素包括老年、高血压、既往卒中或短暂性脑缺血发作(TIA)、糖尿病、高胆固醇、吸烟和心房颤动。高血压是中风最重要的可改变的危险因素。“缺血性中风”偶尔在医院接受溶栓治疗(也称为“凝块破坏者”),并且一些出血性中风可从神经外科手术中获益。预防复发可能涉及给予抗血小板药物,如阿司匹林和双嘧达莫,控制和减少高血压,以及使用他汀类药物。选定的患者可能受益于颈动脉内膜切除术和抗凝血剂的使用。
“血管性痴呆”是老年人中痴呆的第二大常见原因。它在男性中更常见,并且通常在70岁以后开始。在患有血管危险因素(例如,高血压、糖尿病、高脂血症、吸烟)的人和患有几次中风的人中更常发生。许多人患有血管性痴呆和阿尔茨海默病。血管性痴呆通常发生在多个小脑梗塞(或有时是出血)导致足够的神经元或轴突丧失以损害脑功能时。血管性痴呆包括以下类型:多发性腔隙性梗塞(其中小血管受到影响,梗塞发生在半球白色和灰质内深处);多发梗塞性痴呆(其中中型血管受影响);战略性单梗塞性痴呆(其中单个梗塞发生在大脑的关键区域,如角回或丘脑;宾斯万格氏痴呆或皮质下动脉硬化性脑病(其中小血管性痴呆与严重,控制不良的高血压和全身血管相关,这些疾病导致轴突和髓鞘弥漫性和不规则性丧失、伴有广泛的神经胶质增生,由于梗塞引起的组织死亡或脑部白质的血液供应丧失)。
术语“神经胶质瘤”是指在脑或脊柱中起始的一类肿瘤。它被称为神经胶质瘤,因为它来自神经胶质细胞。胶质瘤最常见的部位是大脑。胶质瘤占所有脑和中枢神经系统肿瘤的约30%,占所有恶性脑肿瘤的80%。
根据美国精神病学协会的精神疾病诊断和统计手册,第四版(DSM-IV),术语“性功能障碍”包括一系列“与性反应周期相关的性欲和心理生理变化的紊乱”;虽然这种类型的问题很常见,但只有在问题导致患者痛苦时,才会认为存在性功能障碍。性功能障碍可以是身体上的,也可以是心理上的。它可以作为主要病症存在,通常是激素性的,尽管大多数情况下它是继发于其他医学病症或对所述病症的药物治疗。所有类型的性功能障碍可以进一步分类为终身、获得性、情境性或全身性(或其组合)。
DSM-IV-TR规定了五种主要类别的“女性性功能障碍”:性欲/兴趣障碍;“性唤起障碍(包括生殖器、主观和组合)”;性高潮障碍;性交困难和阴道痉挛;和持续的性唤起障碍。
“女性性唤起障碍(FSAD)”被定义为持续或反复无法达到或维持足够水平的性兴奋,导致个人痛苦。FSAD包括缺乏主观兴奋感(即主观性唤起障碍)和缺乏诸如润滑和肿胀(即生殖器/身体性唤起障碍)的躯体反应。FSAD可能是严格的心理起源,尽管它通常由医学或生理因素引起或复杂化。低雌激素是与FSAD相关的最常见的生理状况,导致泌尿生殖器萎缩和阴道润滑减少。
如本文所用,“勃起功能障碍(ED)”是男性性功能障碍,其特征在于在性表现期间不能发展或维持阴茎的勃起。阴茎勃起是血液进入并保留在阴茎内的海绵状体内的水力效应。当信号从大脑传递到阴茎神经时,这一过程通常是由性唤起引发的。当勃起难以产生时,表明勃起功能障碍。最重要的有机原因是心血管疾病和糖尿病,神经系统疾病(例如,前列腺切除术的创伤),激素不足(性腺机能减退)和药物副作用。
在一个实施方案中,作为sGC刺激剂的式I或表I的化合物或其药学上可接受的盐及其药学上可接受的盐因此可用于预防和/或治疗以下类型的与循环有关的心脏、肺、外周、肝、肾或脑血管/内皮障碍、疾病和病症:
·与高血压和冠状动脉血流减少有关的疾病;急性和慢性冠状动脉血压升高;动脉高血压;心脏和肾脏并发症引起的血管疾病;由心脏病、中风、脑缺血或肾衰竭引起的血管疾病;顽固性高血压(resistant hypertension);糖尿病高血压;原发性高血压;继发性高血压;妊娠期高血压;先兆子痫;门静脉高压;心肌梗死;
·心力衰竭,HFPEF,HFREF;急性和慢性心力衰竭;心力衰竭的更具体形式:急性失代偿性心力衰竭,右心室衰竭,左心室衰竭,全心衰,缺血性心肌病,扩张型心肌病,先天性心脏病,心室瓣缺陷性心力衰竭,二尖瓣狭窄,二尖瓣关闭不全,主动脉瓣狭窄,主动脉瓣不足,三尖瓣狭窄,三尖瓣关闭不全,肺动脉瓣狭窄,肺动脉瓣关闭不全,合并瓣膜缺损;糖尿病心衰;酒精性心肌病或储存心肌病;舒张期心力衰竭,收缩期心力衰竭;现有慢性心力衰竭的急性期(心力衰竭恶化);舒张期或收缩期功能障碍;冠状动脉供血不足心律失常;心室前负荷减少;心脏肥大;心力衰竭/心肾综合征;门静脉高压;内皮功能障碍或损伤;心房和心室节律和传导障碍的紊乱:I-III级房室传导阻滞(AVB I-III),室上性快速性心律失常,心房颤动,心房扑动,心室颤动,心室扑动,室性快速性心律失常,扭转性室性心动过速,心房颤动和室性期前收缩,AV结外期收缩,病态窦房结综合征,晕厥,房室结再入性心动过速;Wolff-Parkinson-White综合征或急性冠状动脉综合征;拳击手心肌病(Boxercardiomyopathy);室性早搏;心肌病;癌症诱发的心肌病;化疗引起的心脏毒性;
·血栓栓塞性疾病和缺血;心肌缺血;梗死;心肌梗死;心脏病发作;心肌功能不全;内皮功能障碍;脑卒中;短暂性脑缺血发作(TIAs);阻塞性血栓性血管炎;稳定或不稳定型心绞痛;冠状动脉痉挛或外周动脉痉挛;变异型心绞痛;Prinzmetal的心绞痛;心脏肥大;先兆子痫;血栓形成疾病;缺血再灌注损伤;器官移植相关的缺血再灌注;肺移植、心脏移植、静脉移植失败相关的缺血再灌注;创伤患者血液替代物的保存;
·外周血管疾病;外周动脉疾病;外周闭塞性动脉疾病;肌张力增高;雷诺综合症或现象(原发性和继发性);雷诺氏病;严重肢体缺血;外周栓塞;间歇性跛行;血管闭塞性风险;肌营养不良症,Duchenne肌营养不良症,Becker肌营养不良症;微循环异常;血管渗漏或渗透的控制;腰椎管狭窄症;闭塞性血栓性血管炎;血栓性血管炎;外周灌注障碍;动脉和静脉血栓形成;微量白蛋白尿;外周和自主神经病;糖尿病神经性疼痛;糖尿病微血管病变;肝血管闭塞性疾病;镰状细胞病的血管闭塞性风险;高血压风险;
·水肿;心力衰竭引起的肾水肿;
·阿尔茨海默氏病;帕金森病;血管性痴呆;血管性认知障碍;脑血管痉挛;先天性肌无力综合征;蛛网膜下腔出血;创伤性脑损伤;认知障碍(如轻度认知功能障碍、年龄相关学习和记忆障碍、年龄相关性记忆丧失、血管性痴呆、颅脑损伤、脑卒中、脑卒中后痴呆、创伤后头部损伤、一般性注意力障碍、和学习记忆障碍儿童的注意力障碍)后的感知、注意能力、学习能力或记忆表现的改善;路易体痴呆;患有额叶变性的痴呆,包括Pick's综合征;进行性核麻痹;伴有皮质基底节变性的痴呆;肌萎缩侧索硬化症(ALS);亨廷顿氏病;脱髓鞘;多发性硬化症;丘脑退化;Creutzfeldt-Jakob痴呆;艾滋病痴呆;伴痴呆精神分裂症或柯萨科夫精神病;多系统萎缩和其他形式的帕金森综合症;运动障碍;神经保护;焦虑,紧张和抑郁或创伤后应激障碍(PTSD);双相情感障碍;精神分裂症;CNS相关的性功能障碍和睡眠障碍;病理性饮食失调和使用昂贵食品和成瘾药物;控制脑灌注;偏头痛;脑梗塞(脑卒中)后果的预防和控制;中风后果的预防和控制,脑缺血和头部损伤;与CNS疾病相关的神经病变;与MS相关的神经性疼痛;化疗引起的神经性疼痛;与带状疱疹相关的神经性疼痛;与脊柱手术相关的神经性疼痛;
·休克;心源性休克;败血症;感染性休克;过敏性休克;动脉瘤;控制白细胞活化;抑制或调节血小板聚集;多器官功能障碍综合征(MODS);多器官功能衰竭(MOF);
·肺/呼吸系统疾病:肺动脉高压(PH);肺动脉高压(PAH)和相关的肺血管重塑;以局部血栓形成和右心肥大形式的血管重塑;肺性高血压;原发性肺动脉高压;继发性肺动脉高压;家族性肺动脉高压;散发性肺动脉高压;毛细血管前肺动脉高压;特发性肺动脉高压;其他形式的PH;与左心室疾病、HIV、SCD、血栓栓塞(CTEPH)、结节病、慢性阻塞性肺病、肺纤维化、急性呼吸窘迫综合征(ARDS)、急性肺损伤、α-1抗胰蛋白酶缺乏症(AATD)、肺气肿、吸烟诱发肺气肿和囊性纤维化(CF)有关的PH;血栓性肺动脉病;丛生性肺动脉病;囊性纤维化;支气管收缩或肺支气管收缩;急性呼吸综合症;肺纤维化,肺移植;哮喘病;
·与以下关联或相关的肺动脉高血压:左心室功能障碍,低氧血症,WHO组I、II、III、IV和V高血压病,二尖瓣瓣膜病,缩窄性心包炎,主动脉瓣狭窄,心肌病,纵隔纤维化,肺纤维化,肺静脉畸形引流,肺静脉闭塞性疾病,肺血管炎,胶原性血管疾病,先天性心脏病,肺静脉高压,间质性肺病,睡眠呼吸紊乱,睡眠呼吸暂停,肺泡通气不足,长期暴露于高原,新生儿肺部疾病,肺泡-毛细血管发育不良,镰状细胞病,其他凝血功能障碍,慢性血栓栓塞,肺栓塞;肿瘤,寄生虫或异物引起的肺栓塞;结缔组织病,狼疮,狼疮性肾炎,血吸虫病,肉状瘤病,慢性阻塞性肺病,哮喘,肺气肿,慢性支气管炎,肺毛细血管瘤,组织细胞增多症X,淋巴管,压缩肺血管;由于腺病,肿瘤或纤维性纵隔炎引起的压缩肺血管;
·动脉硬化疾病或病症:动脉粥样硬化;与内皮损伤、血小板和单核细胞粘附和聚集、平滑肌增殖或迁移有关的动脉粥样硬化;再狭窄;血栓溶解治疗、经皮腔内血管成形术(PTA)、经腔冠状动脉成形术(PTCAs)、心脏移植、旁路手术或炎症过程后发生的再狭窄;
·微血管和大血管损伤(血管炎);纤维蛋白原水平升高和低密度DLD;纤溶酶原激活物抑制剂1(PA-1)的浓度增加;
·代谢综合征;与代谢综合征相关的代谢疾病或疾病:肥胖症;皮下脂肪过多;过度肥胖;糖尿病;高血压;脂质相关疾病,高脂血症,血脂异常,高胆固醇血症,高密度脂蛋白胆固醇(HDL-胆固醇)降低,低密度脂蛋白胆固醇(LDL-胆固醇)水平中度升高,高甘油三酯血症,高甘油酯血症,低脂蛋白血症,谷甾醇血症,脂肪肝疾病,酒精性脂肪肝病(AFLD),非酒精性脂肪性肝病(NAFLD),肝炎;先兆子痫;多囊肾病进展;肝脏脂肪变性或肝脏脂质积聚异常;非酒精性脂肪性肝炎(NASH);心脏、肾脏或肌肉的脂肪变性;alphabeta脂蛋白血症;谷固醇血症;黄瘤病;丹吉尔病;高氨血症及相关疾病;肝性脑病;其他中毒性脑病;雷氏综合症;
·性、妇科和泌尿系统疾病:勃起功能障碍;阳痿;早泄;女性性功能障碍;女性性唤起功能障碍;性欲减退性唤起症;阴道萎缩;性交困难;萎缩性阴道炎;良性前列腺增生(BPH),前列腺肥大,前列腺增生;膀胱出口梗阻;膀胱疼痛综合征(BPS);间质性膀胱炎(IC);膀胱过度活动;神经源性膀胱和尿失禁;糖尿病肾病;原发性和继发性痛经;下尿路综合征(LUTS);子宫内膜异位症;骨盆疼痛;男性和女性泌尿生殖系统器官的良性和恶性疾病;
·慢性肾病;急慢性肾功能不全;急慢性肾功能衰竭;狼疮性肾炎;潜在或相关的肾脏疾病:低灌注,透析低血压,阻塞性尿路病,肾小球病,肾小球肾炎,急性肾小球肾炎,肾小球硬化症,肾小管间质疾病,肾病,原发性和先天性肾病,肾炎;以肌酐和/或水排泄异常减少为特征的疾病;以尿素、氮、钾和/或肌酸酐血浓度异常升高为特征的疾病;以肾酶活性改变为特征的疾病,以谷氨酰合成酶活性改变为特征的疾病;以尿渗透压或尿量改变为特征的疾病;以微量白蛋白尿增加为特征的疾病,以大量白蛋白尿为特征的疾病;以肾小球和小动脉损伤、肾小管扩张、高磷血症和/或透析需要为特征的疾病;肾功能不全后遗症;与肺灌肠有关的肾功能不全;与HF有关的肾功能不全;与尿毒症或贫血有关的肾功能不全;电解质紊乱(高钾血症,低钠血症);骨和碳水化合物代谢紊乱;急性肾损伤;
·眼部疾病或病症,如青光眼、视网膜病变和糖尿病视网膜病变。
术语“炎症”是指血管组织对有害刺激(例如病原体、受损细胞或刺激剂)的复杂生物反应。急性炎症的典型症状是疼痛、发热、发红、肿胀和功能丧失。炎症是有机体去除有害刺激并启动愈合过程的保护性尝试。炎症不是感染的同义词,即使两者经常相关(前者通常是后者的结果)。炎症也可以在没有感染的情况下发生,尽管这种类型的炎症通常是适应不良的(例如在动脉粥样硬化中)。炎症是一种刻板的反应,因此与适应性免疫相比,它被认为是先天免疫的机制,适应性免疫对每种病原体都是特异性的。在没有炎症的情况下逐渐破坏组织会损害生物体的存活。另一方面,慢性炎症可能导致许多疾病,例如枯草热、牙周炎、动脉粥样硬化、类风湿性关节炎、甚至癌症(例如胆囊癌)。因此,炎症通常受到身体的严密调节。炎症可分为急性或慢性。“急性炎症”是身体对有害刺激的初始反应,并且通过血浆和白细胞(尤其是粒细胞)从血液到受损组织的增加的运动来实现。一系列生化事件传播并使炎症反应成熟,涉及局部血管系统、免疫系统和受损组织内的各种细胞。被称为“慢性炎症”的延长的炎症导致炎症部位存在的细胞类型的进行性转变,其特征在于炎症过程中组织的同时破坏和愈合。
在另一个实施方案中,作为sGC刺激剂的式I或表I化合物或其药学上可接受的盐及其药学上可接受的盐因此可用于预防和/或治疗可能涉及炎症或炎症过程的以下类型的心脏、肺、外周、肝、肾、消化或中枢神经系统疾病、情况和病症:
·心肌炎症(心肌炎);慢性心肌炎;急性心肌炎;病毒性心肌炎;
·血管炎;胰腺炎;腹膜炎;类风湿病;
·肾脏炎症性疾病;免疫性肾病:肾移植排斥反应,免疫复合物诱发的肾病,毒素引起的肾病,造影剂诱发的肾病;糖尿病和非糖尿病肾病,肾盂肾炎,肾囊肿,肾硬化,高血压性肾硬化和肾病综合征;
·慢性间质性炎症,炎症性肠病(IBD),克罗恩病,溃疡性结肠炎(UC);
·炎症性皮肤病;
·眼部炎症性疾病,睑缘炎,干眼症和修格兰氏症候群;眼睛纤维化。
术语“伤口愈合”是指复杂的过程,其中皮肤(或另一器官或组织)在受伤后自我修复。例如,在正常皮肤中,表皮(最外层)和真皮(内层或更深层)以稳态平衡存在,形成对外部环境的保护屏障。一旦保护屏障被破坏,伤口愈合的正常(生理)过程立即开始运动。经典的伤口愈合模型分为三个或四个连续但重叠的阶段:(1)止血(一些作者不认为是一个阶段),(2)炎症,(3)增殖和(4)重塑。在皮肤受伤后,一系列复杂的生化事件发生在密切协调的级联中,以修复损伤。在损伤后的最初几分钟内,血小板粘附到损伤部位,被激活,聚集(连接在一起),然后激活凝血级联,在交联的纤维蛋白蛋白网中形成聚集的血小板凝块。该凝块阻止活动性出血(“止血”)。在炎症阶段,细菌和细胞碎片被白细胞吞噬并从伤口中除去。血小板衍生的生长因子(储存在血小板的α颗粒中)释放到伤口中,引起增殖期细胞的迁移和分裂。增殖期的特征在于血管生成、胶原沉积、肉芽组织形成、上皮形成和伤口收缩。在“血管生成”中,血管内皮细胞形成新血管。在“纤维组织形成”和肉芽组织形成中,成纤维细胞通过排泄胶原蛋白和纤连蛋白而生长并形成新的临时细胞外基质(ECM)。同时,发生表皮的“再上皮化”,其中上皮细胞在伤口床上增殖和“爬行”,为新组织提供覆盖。在伤口收缩期间,肌成纤维细胞通过抓住伤口边缘并使用类似于平滑肌细胞中的机制收缩来减小伤口的大小。当细胞的作用接近完成时,不需要的细胞会发生细胞凋亡。在成熟和重塑过程中,胶原蛋白被重塑并沿着张力线重新排列,不再需要的细胞被细胞凋亡除去。然而,该过程不仅复杂而且易碎,并且易于中断或失败,导致形成不愈合的慢性伤口(一个例子包括糖尿病伤口或溃疡,特别是糖尿病足溃疡)。导致不愈合的慢性伤口的因素是糖尿病、静脉或动脉疾病、感染和老年代谢缺陷。
术语“骨愈合”或“骨折愈合”是指增殖性生理过程,其中身体促进骨折的修复。在骨折愈合过程中,几个恢复阶段促进了骨折和脱位周围区域的增殖和保护。该过程的长度取决于受伤的程度,并且对于大多数上身骨折的修复需要通常两到三周的范围;对于下身伤害需要超过四周。愈合过程主要由“骨膜”(覆盖骨骼的结缔组织膜)决定。骨膜是前体细胞的一种来源,其发展成“成软骨细胞”和成骨细胞,其对于骨的愈合是必需的。骨髓(当存在时)、骨内膜、小血管和成纤维细胞是前体细胞的其他来源。
在另一个实施方案中,作为sGC刺激剂及其药学上可接受的盐的式I或I的化合物或其药学上可接受的盐因此可用于治疗以下类型的疾病、状况或病症。哪种刺激伤口或骨愈合过程是可取的:
·糖尿病患者的伤口或溃疡愈合;微血管灌注改善;损伤后微血管灌注改善或抵消围手术期护理中的炎症反应;肛裂;糖尿病溃疡;糖尿病足溃疡);骨愈合;破骨细胞骨吸收和重塑;和新骨形成。
术语“结缔组织”(CT)是指一种支持、连接或分离身体的不同类型的组织和器官的动物组织。它是动物组织的四大类之一,其他是上皮、肌肉和神经组织。随处可见结缔组织,包括中枢神经系统。它位于其他组织之间。所有CT都有三个主要成分——基础物质、纤维和细胞——所有这些成分都浸没在体液中。
术语“结缔组织病症或病症”是指涉及身体的一个或多个部分中的结缔组织异常的任何病症。某些病症的特征在于免疫系统的过度活动,导致对组织的炎症和全身性损伤,通常用结缔组织替换正常组织(例如,某些器官的正常组织)。其他疾病涉及结缔组织本身的生化异常或结构缺陷。其中一些疾病是遗传性的,有些是病因不明。
当结缔组织疾病具有自身免疫起源时,它们被分类为“风湿性疾病”、“自身免疫性风湿性疾病”或“自身免疫性胶原-血管疾病”。
在“自身免疫病症”中,由身体产生的抗体或其他细胞攻击身体自身的组织。许多自身免疫性疾病影响各种器官中的结缔组织。在自身免疫疾病中,炎症和免疫反应可导致结缔组织周围以及其他组织(包括重要器官,例如肾脏或胃肠道器官)的结缔组织损伤。围绕心脏的囊(心包膜),覆盖肺部的膜(胸膜),纵隔(胸腔中的一组未定的结构,被疏松的结缔组织包围,包含心脏、心脏的大血管、食道、气管、膈神经、心脏神经、胸导管、胸腺和中央胸部的淋巴结)甚至大脑都可能受到影响。
如本文所用的术语“纤维化”是指结缔组织或纤维组织(瘢痕组织,胶原)在身体的某个器官或部分中的累积。如果纤维化由单一细胞系产生,则称为“纤维瘤”。当身体试图修复和替换受损细胞时发生纤维化,因此可以是反应性,良性或病理状态。生理性纤维化与瘢痕形成过程相似。当所讨论的组织反复且连续地受损时,病理状态就会发展。即使严重,单次伤害也不会引起纤维化。如果伤害重复或持续(例如在慢性肝炎中发生),身体会试图修复损伤,但这种尝试反而导致疤痕组织的过度积聚。瘢痕组织开始取代器官的规则组织,其执行瘢痕组织不能执行的某些功能;它还可以干扰血液流动并限制其他细胞的血液供应。结果,这些其他功能细胞开始死亡并形成更多的瘢痕组织。当这种情况发生在肝脏时,静脉中的血液从肠道到肝脏(门静脉)的血压增加,从而引起称为“门静脉高压症”的病症。
术语“硬化”是指通常通过用结缔组织替换正常器官特异性组织而通常是柔性的组织或结构或器官的硬化或变硬。
存在许多类型的纤维化或纤维化疾病,包括但不限于肺纤维化(特发性肺纤维化,囊性纤维化),肝纤维化(或“肝硬化”),心内膜纤维化,陈旧性心肌梗塞,心房纤维化,纵隔纤维化,骨髓纤维化(影响骨髓),腹膜后纤维化,进行性大量纤维化(影响肺部),肾性纤维化(影响皮肤),克罗恩病,关节纤维化,佩罗尼氏病(影响阴茎),杜普伊特伦氏挛缩(影响手和手指),某些形式的粘连性囊炎(影响肩部)。
存在许多类型的硬化或“硬化疾病”,包括但不限于肌萎缩性脊髓侧索硬化症(ALS);动脉粥样硬化;局灶性节段性肾小球硬化和肾病综合征;海马硬化(影响大脑);硬化性苔癣(一种硬化阴道和阴茎结缔组织的疾病);肝硬化;多发性硬化症或局灶性硬化症(影响协调的疾病);骨硬化(骨密度显着降低的疾病);耳硬化症(影响耳朵的疾病);结节性硬化症(影响多种系统的罕见遗传病);原发性硬化性胆管炎(胆管硬化);原发性侧索硬化(随意肌肉进行性肌无力);和瘢痕疙瘩。
术语“硬皮病”或“系统性硬化症”或“进行性系统性硬皮病”是指涉及关节、皮肤和内部器官的瘢痕形成以及血管异常的病症。系统性硬化症有时可以以有限的形式发生,例如有时仅影响皮肤或仅主要影响皮肤的某些部分或作为CREST综合征(其中涉及皮肤的外周区域但不涉及躯干)。系统性硬化症的通常初始症状是肿胀,然后在手指末端增厚和收紧皮肤。“雷诺现象”,其中手指突然和暂时变得非常苍白、刺痛或变得麻木、疼痛或两者都很常见。
术语“多发性肌炎”是指肌肉炎症。术语“皮肌炎”是指伴有皮肤炎症的肌肉炎症。术语“多软骨炎”是指软骨炎症。
术语“嗜酸性粒细胞性筋膜炎”是指罕见的紊乱,其中嗜酸性粒细胞免疫细胞被释放并导致“筋膜”的炎症和硬化,“筋膜”是皮肤下、肌肉上方和肌肉之间的坚韧纤维组织层。筋膜疼痛发炎、肿胀,手臂和腿部逐渐变硬。随着手臂和腿部的皮肤逐渐变硬,它们变得难以移动。最终他们陷入了不寻常的位置。有时,如果涉及手臂,该人可能会发展为腕管综合症。
在另一个实施方案中,可通过施用作为sGC刺激剂的式I或表I的sGC刺激剂或其药学上可接受的盐及其药学上可接受的盐来治疗和/或预防的特定疾病疾病,包括但不限于以下类型的疾病,包括炎症、自身免疫或纤维化(即纤维化疾病):
·泌尿生殖系统和肾脏疾病:糖尿病肾病;慢性肾脏疾病或功能不全引起的肾纤维化和肾功能衰竭;由于积聚/沉积和组织损伤引起的肾纤维化和肾衰竭;肾硬化;进行性硬化症;肾小球肾炎;局灶性节段性肾小球硬化;肾病综合征;前列腺肥大;肾纤维化;间质性肾纤维化;
·肺系统疾病:肺纤维化;特发性肺纤维化;囊性纤维化;进行性大块纤维化;进行性大块纤维化(影响肺部);
·影响心脏的疾病:心内膜心肌纤维化;老年心肌梗死;心房纤维化;心脏间质纤维化;心脏重塑和纤维化;心脏肥大;
·肝脏和相关器官紊乱:肝硬化或肝硬化;肝硬化伴慢性肝病;肝纤维化;肝星状细胞活化;NASH;肝纤维胶原和总胶原蛋白积聚;坏死性和/或免疫性肝病;原发性胆汁性肝硬化;原发性硬化性胆管炎;其他胆汁淤积性肝病:与肉芽肿性肝病,肝脏恶性肿瘤,妊娠期肝内胆汁淤积,肝炎,败血症,药物或毒素,移植物抗宿主病,肝移植后,胆总管结石,胆管肿瘤,胰腺癌,Mirizzi相关综合征,艾滋病胆管病或寄生虫;血吸虫病;肝细胞癌;
·消化系统疾病或疾病:克罗恩病;溃疡性结肠炎;胃肠道硬化;贲门失弛缓症;
·皮肤或眼睛疾病:肾源性纤维化;瘢痕疙瘩;纤维化局部或皮肤病或病症;皮肤纤维化;硬皮病,皮肤纤维化;硬斑病;肥厚性疤痕;痣;增殖性玻璃体视网膜病变;结节;肉芽肿;眼睛纤维化;
·影响神经系统的疾病:肌萎缩性脊髓侧索硬化症(ALS);海马硬化,多发性硬化症(MS);局灶性硬化;原发性侧索硬化;
·骨骼疾病;骨硬化;
·耳硬化症;其他听力疾病或紊乱;听力损伤,部分或全部听力损失;部分或全部耳聋;耳鸣;噪音引起的听力损失;
·其他涉及自身免疫,炎症或纤维化的疾病:硬皮病;局限性硬皮病或阿狄森氏瘢痕瘤;纵隔纤维化;纤维化纵隔炎;骨髓纤维化;腹膜后纤维化;关节纤维化;佩罗尼氏病;杜普伊特伦氏挛缩;硬化性苔藓;某些形式的粘连性囊炎;动脉粥样硬化;结节性硬化症;系统性硬化症;多发性肌炎;皮肌炎;多软骨炎;嗜酸性筋膜炎;系统性红斑狼疮或狼疮;骨髓纤维化,骨髓纤维化;结节病;子宫肌瘤;子宫内膜异位症。
在另一个实施方案中,可以通过施用作为sGC刺激剂的式I或表I的sGC刺激剂或其药学上可接受的盐及其药学上可接受的盐来治疗和/或预防的特定疾病,包括但不限于:某些类型的癌症;镰状细胞病;镰状细胞性贫血;癌转移;骨质疏松症;胃轻瘫;功能性消化不良;糖尿病并发症;脱发;与内皮功能障碍有关的疾病;与一氧化氮生成减少有关的神经系统疾病;精氨酸琥珀酸尿症;神经肌肉疾病:杜兴氏肌营养不良(DMD),贝克肌营养不良(BMD),肢带肌营养不良,远端肌病,I型和II型肌强直性营养不良,面-肩胛-腓骨肌营养不良,常染色体和X连锁艾-德肌营养不良,眼咽肌营养不良症,肌萎缩性侧索硬化症和脊髓肌肉萎缩(SMA)。在一些实施方案中,本发明涉及一种治疗受试者的疾病、健康状况或病症的方法,其包括向需要治疗的受试者给予治疗有效量的式I或表I的化合物,或其药学上可接受的盐,其中所述疾病、健康状况或病症选自上文列出的疾病之一。
在另一个实施方案中,本发明的化合物可以以植入装置的形式递送,例如支架。支架是插入体内天然通道/导管中的网状管,以防止或抵消疾病引起的局部流动收缩。该术语还可以指用于暂时保持这种天然导管打开以允许进行手术的管。
药物洗脱支架(DES)是置于狭窄的患病外周或冠状动脉中的外周或冠状动脉支架(支架),其缓慢释放药物以阻断细胞增殖,通常是平滑肌细胞增殖。这可以防止纤维化,再加上凝块(血栓),否则会阻塞支架动脉,这个过程称为再狭窄。在血管成形术过程中,介入心脏病专家或介入放射科医师通常将支架置于外周或冠状动脉内。DES中常用于阻断细胞增殖的药物包括紫杉醇或雷帕霉素类似物。
在本发明的一些实施方案中,本发明的sGC刺激剂可以通过涂有所述sGC刺激剂的药物洗脱支架递送。涂有本发明的sGC刺激剂的药物洗脱支架可用于在经皮冠状动脉介入治疗期间预防支架再狭窄和血栓形成。涂覆有本发明的sGC刺激剂的药物洗脱支架可以能够防止平滑的细胞增殖以及辅助再插入支架的动脉的内皮组织的再血管化和再生。
用于治疗由冠状动脉闭塞性疾病引起的难治性心绞痛的经皮冠状动脉介入治疗的替代方案是称为冠状动脉旁路移植术(CABG)的手术。CABG仅提供缓解正在进行的过程,该过程由于移植物动脉粥样硬化的快速发展而进一步复杂化。隐静脉移植物是CABG手术中最常用的导管。静脉CABG的长期临床成功受到三个主要原因的阻碍:加速移植物动脉粥样硬化,内皮化不完全和血栓形成。
在一些实施方案中,本发明的sGC刺激剂可用于预防CABG期间的隐静脉移植物衰竭。本发明化合物可有助于内皮化过程并有助于预防血栓形成。在该指示中,sGC刺激剂以凝胶形式局部递送。
术语“疾病”,“病症”和“状况”在本文中可互换使用,指的是sGC、cGMP和/或NO介导的医学或病理学病症。
如本文所用,术语“受试者”和“患者”可互换使用。术语“受试者”和“患者”是指动物(例如,诸如鸡,鹌鹑或火鸡或哺乳动物的鸟),特别是包括非灵长类动物的“哺乳动物”(例如,牛、猪、马、绵羊、兔子、豚鼠、大鼠、猫、狗和小鼠)和灵长类动物(例如,猴子、黑猩猩和人类),更具体地说是人类。在一些实施方案中,受试者是非人动物,例如农场动物(例如,马、牛、猪或绵羊),或宠物(例如,狗、猫、豚鼠或兔)。在一些实施方案中,受试者是人。
本发明还提供了治疗受试者的上述疾病、病症和状况之一的方法,包括给予需要治疗的受试者治疗有效量的式I或表I的化合物或其药学上可接受的盐。或者,本发明提供式I或表I化合物或其药学上可接受的盐在需要治疗的受试者中治疗这些疾病、病症和状况之一的用途。本发明进一步提供制备或生产可用于治疗这些疾病、病症和状况之一的药物的方法,包括使用式I或表I的化合物或其药学上可接受的盐。
如本文所用,术语“生物样品”是指体外或离体样品,并且包括但不限于细胞培养物或其提取物;从哺乳动物或其提取物中获得的活检材料;血液、唾液、尿液、粪便、精液、眼泪、淋巴液、眼液、玻璃体液或其他体液或其提取物。
关于病症或疾病的“治疗”或“处理”是指减轻或消除病症或疾病的原因和/或影响。如本文所用,术语“治疗”和“处理”是指减少或改善sGC、cGMP和/或NO介导的病症的进展、严重性和/或持续时间,或改善所述病症的一种或多种症状(优选一种或多种可辨别的症状)(即,“管理”而不“治愈”该病症),其由一种或多种疗法产生。在具体实施方案中,术语“治疗”和“处理”是指改善sGC、cGMP和/或NO介导的病症的至少一种可测量的物理参数。在其他实施方案中,术语“治疗”和“处理”是指物理上通过例如稳定可辨别的症状,或在生理上通过例如稳定物理参数,或全部两者,抑制sGC、cGMP和/或NO介导的病症的进展。
如本文所用的术语“预防”是指预先施用药物以避免或预防疾病或病症的一种或多种症状的出现。医学领域的普通技术人员认识到术语“预防”不是绝对术语。在医学领域中,应理解为预防性施用药物以基本上减少病症的可能性或严重性或病症的症状,这是本公开内容中意图的意义。医师案头参考(Physician's Desk Reference),该领域的标准文本,使用术语“预防”数百次。如其中所使用的,关于病症或疾病的术语“预防”是指在疾病或病症完全表现出来之前避免疾病或病症的原因、作用、症状或进展。
在一个实施方案中,本发明的方法是对患者,特别是人的预防性或“先发制人”措施,其具有发展sGC、cGMP和/或NO相关疾病、障碍或症状的倾向(例如,遗传倾向)。
在其他实施方案中,本发明的方法是对患有疾病、病症或状况的患者,特别是人的预防性或“先发制人”措施,使得其有发展sGC、cGMP和/或NO相关疾病、障碍或症状的风险。
本文所述的化合物和药物组合物可单独使用或组合使用,用于治疗或预防由sGC、cGMP和/或NO介导、调节或影响的疾病或病症。
本文公开的化合物和组合物还可用于兽医治疗伴侣动物、外来动物和农场动物,包括但不限于狗、猫、小鼠、大鼠、仓鼠、沙鼠、豚鼠、兔、马、猪和牛。
在其他实施方案中,本发明提供刺激生物样品中sGC活性的方法,包括使所述生物样品与本发明的化合物或组合物接触。在生物样品中使用sGC刺激剂可用于本领域技术人员已知的各种目的。此类目的的实例包括但不限于生物测定和生物样本储存。
联合疗法
本文所述的化合物和药物组合物可与一种或多种另外的治疗剂联合使用。对于与一种以上活性剂的组合治疗,其中活性剂在分开的剂量制剂中,活性剂可以单独给药或联合给药。另外,一种元素的给药可以在给予另一种药剂之前、同时或之后进行。
当与其他药剂共同给药时,例如当与另一种止痛药共同给药时,第二药剂的“有效量”将取决于所用药物的类型。合适的剂量对于批准的药剂是已知的,并且可以由技术人员根据受试者的状况,所治疗的病症的类型和本文所述的化合物的剂量进行调整。如果没有明确说明剂量,则应假定有效剂量。例如,本文所述的化合物可以以约0.01至约10000mg/kg体重/天,约0.01至约5000mg/kg体重/天,约0.01至约3000mg的剂量范围给予受试者。/kg体重/天,约0.01至约1000mg/kg体重/天,约0.01至约500mg/kg体重/天,约0.01至约300mg/kg体重/天,约0.01至约100毫克/千克体重/天。
当使用“组合疗法”时,可以使用第一剂量的式I或表I的化合物或其药学上可接受的盐和第二剂量的另外的合适的治疗剂来实现有效剂量。
在本发明的一个实施方案中,式I或表I的化合物或其药学上可接受的盐和另外的治疗剂各自以有效剂量施用(即,各自以治疗有效的量施用,如果单独使用)。在另一个实施方案中,式I或表I的化合物或其药学上可接受的盐和另外的治疗剂各自以单独不提供治疗效果(亚治疗剂量)的剂量施用。在另一个实施方案中,式I或表I的化合物或其药学上可接受的盐可以以有效剂量施用,而另外的治疗剂以亚治疗剂量施用。在另一个实施方案中,式I或表I的化合物或其药学上可接受的盐可以亚治疗剂量施用,而另外的治疗剂,例如合适的癌症治疗剂,以有效剂量施用。
如本文所用,术语“组合”或“共同施用”可互换使用,指使用一种以上疗法(例如,一种或多种预防和/或治疗剂)。术语的使用不限制向受试者施用治疗(例如,预防和/或治疗剂)的顺序。
共同施用包括以基本上同时的方式施用第一和第二量的化合物,例如在单一药物组合物中,例如,具有固定比率的第一和第二量的胶囊或片剂,或多个,每个单独的胶囊或片剂。此外,这种共同给药还包括以任何顺序以顺序方式使用每种化合物。当共同施用涉及单独施用第一量的式I或表I的化合物或其药学上可接受的盐和第二量的另外的治疗剂时,所述化合物在足够接近的时间内施用以具有理想的治疗效果。例如,每次给药之间可以产生所需治疗效果的时间可以是几分钟到几小时,并且可以考虑每种化合物的性质如效力、溶解度、生物利用度、血浆半衰期和动力学曲线。例如,式I或表I的化合物或其药学上可接受的盐和第二治疗剂可以在彼此约24小时内,彼此在约16小时内,彼此在约8小时内,彼此在约4小时内,彼此在约1小时内,或彼此在约30分钟内以任何顺序施用。
更具体地,可以在(例如,5分钟,15分钟,30分钟,45分钟,1小时,2小时,4小时,6小时,12小时,24小时,48小时,72小时,96小时,1周,2周,3周,4周,5周,6周,8周或12周前)之前施用第一疗法(例如,预防或治疗剂,例如本文所述的化合物),同时或(例如,5分钟,15分钟,30分钟,45分钟,1小时,2小时,4小时,6小时,12小时,24小时,48小时,72小时,96小时,1周,2周,3周,4周,5周,6周,8周或12周)之后给受试者施用第二疗法(例如,预防或治疗剂,例如抗癌剂)。
可以与式I或表I的化合物或其药学上可接受的盐组合单独给药或者在相同的药物组合物中给药的其他治疗剂的实例,包括但不限于:
(1)内皮衍生释放因子(EDRF);
(2)NO供体,如亚硝基硫醇,亚硝酸盐,悉尼酮亚胺(sydnonimine),NONOate,N-亚硝基胺,N-羟基亚硝胺,亚硝基亚胺,硝基酪氨酸,二氮杂二胺,氧杂三唑5-亚胺,肟,羟胺,N-羟基胍,羟基脲或呋咱。这些类型化合物的一些实例包括:三硝酸甘油酯(也称为GTN,硝酸甘油,硝化甘油和三硝基甘油),甘油的硝酸酯;硝普钠(SNP),其中一氧化氮分子与铁金属配位,形成方形双锥体复合物;3-吗啉代壬亚胺(SIN-1),一种由吗啉和悉尼酮亚胺组合形成的两性离子化合物;S-亚硝基-N-乙酰基青霉胺(SNAP),具有亚硝基硫醇官能团的N-乙酰化氨基酸衍生物;二亚乙基三胺/NO(DETA/NO),一种与二亚乙基三胺共价连接的一氧化氮化合物;和NCX 4016,乙酰水杨酸的间硝基氧基甲基苯基酯。这些类型的NO供体中的一些的更具体的实例包括:经典的硝基类扩张剂,例如有机硝酸盐和亚硝酸酯,包括硝酸甘油,亚硝酸戊酯,硝酸异山梨酯异山梨酯,5-单硝酸异山梨酯和尼可地尔;异山梨醇FK 409(NOR-3);FR144420(NOR-4);3-吗啉悉尼酮亚胺;林西多明氯水合物(“SIN-1”);S-亚硝基-N-乙酰基青霉胺(“SNAP”);AZD3582(CINOD先导化合物),NCX 4016,NCX 701,NCX 1022,HCT 1026,NCX1015,NCX 950,NCX 1000,NCX 1020,AZD 4717,NCX 1510/NCX 1512,NCX 2216和NCX 4040(均可从NicOx SA获得),S-亚硝基谷胱甘肽(GSNO),硝普钠,V-Pyrro-NO,S-亚硝基谷胱甘肽单乙酯(GSNO-酯),6-(2-羟基-1-甲基-亚硝基肼基)-N-甲基-1-己胺(NOC-9)或二乙胺NONOate。一氧化氮供体也如美国专利No.5,199,080、美国专利5,155,137、5,366,997、5,405,919、5,650,442、5,700,830、5,632,981、6,290,981、5,691,423、5,721,365、5,714,511、6,511,911和5,814,666,Chrysselis等(2002)J Med Chem.45:5406-9(例如NO供体14和17),以及《一氧化氮供体:药学和生物学研究(Nitric Oxide Donors forPharmaceutical and Biological Research)》,编辑:Peng George Wang,Tingwei BillCai,Naoyuki Taniguchi,Wiley,2005中所公开。
(3)增强cGMP浓度的其他物质,如原卟啉IX、花生四烯酸和苯肼衍生物;
(4)一氧化氮合酶底物:例如,基于n-羟基胍的类似物,如N[G]-羟基-L-精氨酸(NOHA),1-(3,4-二甲氧基-2-氯亚苄基氨基)-3-羟基胍和PR5(1-(3,4-二甲氧基-2-氯亚苄基氨基)-3-羟基胍);L-精氨酸衍生物(如homo-Arg,homo-NOHA,N-叔丁氧基-和N-(3-甲基-2-丁烯基)氧-L-精氨酸,刀豆氨酸,ε-胍-己酸,胍丁胺,羟基-胍丁胺和L-酪氨酰-L-精氨酸);N-烷基-N'-羟基胍(如N-环丙基-N'-羟基胍和N-丁基-N'-羟基胍),N-芳基-N'-羟基胍(如N-苯基-N'-羟基胍和其对位取代的衍生物分别带有-F,-Cl,-甲基,-OH取代基);胍衍生物如3-(三氟甲基)丙基胍;和其他人在Cali等人(2005,Current Topics in MedicinalChemistry 5:721-736)的评论,以及在其中引用的参考文献中公开;
(5)增强eNOS转录的化合物:例如WO02/064146,WO02/064545,WO02/064546和WO02/064565,和相应的专利文献,例如US2003/0008915,US2003/0022935,US2003/0022939和US2003/0055093中描述的化合物。其他eNOS转录增强子,包括US20050101599中描述的那些(例如,2,2-二氟苯并[1,3]二氧杂环戊烯-5-羧酸茚-2-基酰胺和4-氟-N-(茚满-2-基)-苯甲酰胺)和Sanofi-Aventis化合物AVE3085和AVE9488(CA登记号916514-70-0;等,Journal of Thrombosis and Homeostasis 2005;Volume 3,Supplement 1:abstractnumber P1487);
(6)没有独立的血红素独立的sGC激活剂,包括但不限于:BAY 58-2667(参见专利公开DE19943635)
HMR-1766(ataciguat sodium,参见专利公开WO2000002851)
S 3448(2-(4-氯-苯磺酰基氨基)-4,5-二甲氧基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺(参见专利公开DE19830430和WO2000002851)
HMR-1069(Sanofi-Aventis)。
(7)血红素依赖性sGC刺激剂,包括但不限于:
YC-1(参见专利公开EP667345和DE19744026)
Riociguat(BAY 63-2521,Adempas,商品,描述于DE19834044)
Neliciguat(BAY 60-4552,描述于WO 2003095451)
Vericiguat(BAY 1021189,Riociguat的临床备份),
BAY 41-2272(描述于DE19834047和DE19942809)
BAY 41-8543(描述于DE19834044)
Etriciguat(描述于WO 2003086407)
CFM-1571(参见专利公开WO2000027394)
A-344905,其丙烯酰胺类似物A-350619和氨基嘧啶类似物A-778935。
化合物在以下公开申请之一中公开:US20090209556,US8455638,US20110118282(WO2009032249),US20100292192,US20110201621,US7947664,US8053455(WO2009094242),US20100216764,US8507512,(WO2010099054)US20110218202(WO2010065275),US20130012511(WO2011119518),US20130072492(WO2011149921),US20130210798(WO2012058132),Tetrahedron Letters(2003),44(48):8661-8663中公开的其他化合物。
(8)抑制cGMP降解的化合物,例如:
PDE5抑制剂,例如西地那非(Viagra)和其他相关药剂,例如Avanafil,Lodenafil,Mirodenafil,枸橼酸西地那非(Revatio),他达拉非(Cialisfil)或伐地那非(Udenafil)和乌地那非;前列地尔;和双嘧达莫;PF-00489791
PDE9抑制剂,例如PF-04447943;
(9)钙通道阻滞剂,例如:
二氢吡啶类钙通道阻滞剂:氨氯地平(Norvasc),阿雷地平(Sapresta),阿折地平(Calblock),巴尼地平(HypoCa),贝尼地平(Coniel),西尼地平(Atelec,Cinalong,Siscard),氯维地平(Cleviprex),地尔硫卓,依福地平(Landel),非洛地平(Plendil),拉西地平(Motens,Lacipil),乐卡地平(Zanidip),马尼地平(Calslot,Madipine),尼卡地平(Cardene,Carden SR),硝苯地平(Procardia,Adalat),尼伐地平(Nivadil),尼莫地平(Nimotop),尼索地平(Baymycard,Sular,Syscor),尼群地平(Cardif,Nitrepin,Baylotensin),普拉地平(Acalas),伊拉地平(Lomir);
苯丙氨酰胺钙通道阻滞剂:维拉帕米(Calan,Isoptin)
加洛帕米(Procorum,D600);
苯并硫氮杂卓:地尔硫卓(Cardizem);
非选择性钙通道抑制剂,如:咪拉地尔,苄普地尔和氟司必林,芬地林;
(10)内皮素受体拮抗剂(ERAs):例如双重(ETA和ETB)内皮素受体拮抗剂波生坦(以销售);西他生坦,以的名称销售;安贝生坦在美国以销售;双/非选择性内皮素拮抗剂Actelion-1,于2008年进入临床试验;
(11)前列环素衍生物或类似物:例如前列环素(前列腺素I2),依前列醇(合成前列环素,以销售);曲前列环素IloprostIloprost(以销售);口服和吸入形式的正在开发中;Beraprost是一种口服前列腺素,可在日本和韩国使用;
(12)抗高脂血症,例如:胆汁酸螯合剂(例如,考来烯胺,考来替泊,考来替兰和考来维仑);他汀类药物如阿托伐他汀,辛伐他汀,洛伐他汀,氟伐他汀,匹伐他汀,瑞舒伐他汀和普伐他汀;伊折麦布等胆固醇吸收抑制剂;其他降脂剂如二十碳五烯酸乙酯,Omega-3-酸乙酯,Reducol;纤维酸衍生物如氯贝特,苯扎贝特,克利贝特,吉非贝齐,氯烟贝特,比尼贝特,非诺贝特,环丙贝特,非诺贝特胆碱;烟酸衍生物,如阿西莫司和烟酸;他汀类药物,烟酸,肠道胆固醇吸收抑制补充剂(依泽替米贝等)和贝特类药物的组合;抗血小板治疗,如氯吡格雷硫酸氢盐;
(13)抗凝剂,如下列类型:
·肝素和衍生物质,如:肝素;低分子量肝素,磺达肝素和艾卓肝素;
·组织纤溶酶原激活剂,用于溶解凝块和解除阻塞动脉,如阿替普酶;
(14)抗血小板药物:例如噻吩并吡啶类,例如氯吡格雷和噻氯匹定;潘生丁;阿司匹林;
(15)ACE抑制剂,例如以下类型:
·含膦酸盐的药剂,如:福辛普利;
·天然存在的ACE抑制剂,如:Casokinins和lactokinins,是摄入乳制品,尤其是培养乳后天然存在的酪蛋白和乳清的分解产物;由益生菌瑞士乳杆菌或酪蛋白衍生的乳酸三肽Val-Pro-Pro和Ile-Pro-Pro也具有ACE抑制和抗高血压功能;
·其他ACE抑制剂,如阿拉普利,地拉普利,西拉普利,咪达普利,群多普利,替莫普利,莫昔普利,螺普利,
(16)补充氧疗;
(17)β受体阻滞剂,如下列类型:
·非选择性药物:(具有额外的α-阻断活性),(具有额外的α-阻断活性),(具有内在的拟交感神经活性),(具有内在的拟交感神经活性),Oxprenonol,Acebutolol,Sotalol,Mepindolol,Celiprolol,Arotinolol,Tertatolol,Amosulalol,Nipradilol,和
(18)抗心律失常药如下列类型:
·I型(钠通道阻滞剂):奎尼丁,利多卡因,苯妥英,普罗帕酮
·III型(钾通道阻滞剂):胺碘酮,多非利特,索他洛尔
·V型:腺苷,地高辛
(19)利尿剂如:噻嗪类利尿剂,例如氯噻嗪,氯噻酮和氢氯噻嗪,苄氟甲噻嗪,环噻嗪,甲基噻嗪,聚噻嗪,喹吖啶,西咪酰胺,甲氧苄啶,吲达帕胺,辛可兰;袢利尿剂,如呋塞米和Toresamide;保钾利尿剂如阿米洛利,螺内酯,坎利酸钾,依普利酮和氨苯喋呤;这些药剂的组合;其他利尿剂如乙酰唑胺和卡培立肽
(20a)直接作用的血管扩张剂,例如盐酸肼苯哒嗪,二氮嗪,硝普钠,卡拉嗪;其他血管扩张剂,如硝酸异山梨酯和5-硝酸异山梨酯;
(20b)外源性血管扩张剂,例如:
·阿尔法阻滞剂(阻断肾上腺素的血管收缩作用):
α-1-肾上腺素能受体拮抗剂如哌唑嗪,吲哚拉明,乌拉地尔,布那唑嗪,特拉唑嗪,多沙唑嗪
·心房利钠肽(ANP);
·乙醇;
·组胺诱导剂,补充蛋白质C3a,C4a和C5a通过触发肥大细胞和嗜碱性粒细胞释放组胺起作用;
·四氢大麻酚(THC),大麻中的主要活性化学物质,具有轻微的血管舒张作用;
·罂粟碱,一种在罂粟罂粟中发现的生物碱;
(21)支气管扩张剂:有两种主要类型的支气管扩张剂,β2激动剂和抗胆碱能药,示例如下:
(22)皮质类固醇:如倍氯米松,甲基强的松龙,倍他米松,泼尼松,泼尼松龙,曲安奈德,地塞米松,氟替卡松,氟尼缩松和氢化可的松,以及布地奈德等皮质类固醇类似物
(23)膳食补充剂,例如:ω-3油;叶酸,烟酸,锌,铜,韩国红参,银杏,松树皮,蒺藜(Tribulus terrestris),精氨酸,燕麦,角质山羊杂草,马卡根,巴西榥榥木(muirapuama),锯棕榈和瑞典花粉;维生素C,维生素E,维生素K2;睾酮补充剂,睾酮透皮贴剂;Zoraxel,Naltrexone,Bremelanotide(前身为PT-141),Melanotan II,hMaxi-K;Prelox:天然成分,L-精氨酸天冬氨酸和碧萝芷的专有混合物/组合;
(24)PGD2受体拮抗剂,包括但不限于,在美国公开申请US20020022218,US20010051624和US20030055077,PCT公开申请W09700853,W09825919,WO03066046,WO03066047,WO03101961,WO03101981,WO04007451,WO0178697,WO04032848,WO03097042,WO03097598,WO03022814,WO03022813和WO04058164,欧洲专利申请EP945450和EP944614中描述为具有PGD2拮抗活性的化合物,以及在Torisu等人2004Bioorg Med Chem Lett 14:4557,Torisu等2004 Bioorg Med Chem Lett 2004 14:4891,和Torisu等2004 Bioorg&MedChem 2004 12:4685中列出的那些;
(26)非甾体抗哮喘诸如β2激动剂(例如,特布他林,奥西那林,非诺特罗,乙基异丙肾上腺素,沙丁胺醇,沙美特罗,比托特罗和吡布特罗),β2激动剂,皮质类固醇的组合(例如,沙美特罗,氟替卡松福莫特罗-布地奈德),茶碱,色甘酸,色甘酸钠,奈多罗米,阿托品,异丙托溴铵,异丙托溴铵,白三烯生物合成抑制剂(zileuton,BAY1005);
(27)非甾体抗炎剂(NSAIDS),诸如丙酸衍生物(例如,阿明洛芬,苯恶洛芬,布氯酸,卡洛芬,芬布芬,非诺洛芬,氟洛芬,氟比洛芬,布洛芬,吲哚洛芬,酮洛芬,咪洛芬,萘普生,奥沙普秦,吡罗芬,普拉洛芬,舒洛芬,噻洛芬酸和硫噁洛芬),醋酸衍生物(如吲哚美辛,阿西美辛,阿洛芬,环氯茚酸,双氯芬酸,芬氯酸,芬克洛酸,芬替酸,乙基二氢苯并呋喃乙酸,异丁芬酸,伊索克酸,奥西平酸,舒林酸,二氢氧二苯并硫杂,托麦汀,齐多美辛和佐美酸),芬那酸衍生物(例如,氟芬那酸,甲氯芬那酸,甲芬那酸,尼氟酸和托芬那酸),联苯羧酸衍生物(例如,二氟尼柳和氟苯柳),昔康类(例如,伊索昔康,吡罗昔康,舒多昔康和替诺昔康),水杨酸盐(如乙酰水杨酸和柳氮磺胺吡啶)和吡唑啉酮(如阿帕酮,苯并吡咯烷,芬吡酯,保守霉素,羟基保泰松和保泰松);
(阿片类镇痛药,如可待因,芬太尼,氢吗啡酮,左啡烷,哌替啶,美沙酮,吗啡,羟考酮,羟吗啡酮,丙氧芬,丁丙诺啡,布托啡诺,地佐辛,纳布啡和喷他佐辛;和
(29)抗糖尿病药,如胰岛素和胰岛素模拟物,磺脲类(如格列本脲,格列本脲,格列吡嗪,格列齐特,格列喹酮,格列美脲,Meglinatide,甲苯磺丁脲,氯磺丙脲,乙酰苯磺酰环己脲,甲磺氮草脲),双胍类,例如二甲双胍α-葡萄糖苷酶抑制剂(如阿卡波糖,依帕司他,伏格列波糖,米格列醇),噻唑烷酮类化合物,如罗格列酮(文迪雅),曲格列酮环格列酮,吡格列酮和恩格列酮;胰岛素敏化剂,如吡格列酮和罗格列酮;胰岛素促分泌素如瑞格列奈,那格列奈和米格列奈;包括Exanatide和利拉鲁肽在内的肠促胰岛素模拟物;Amylin类似物如普兰林肽;葡萄糖降低剂如吡啶甲酸铬(任选与生物素结合);二肽基肽酶IV抑制剂,例如西他列汀,维达列汀,沙格列汀,阿格列汀和利格列汀;目前正在开发用于治疗糖尿病的疫苗;AVE-0277,Alum-GAD,BHT-3021,IBC-VS01;用于治疗糖尿病的发展中的细胞因子靶向疗法,例如阿那白滞素,那可马单抗,双醋瑞因,Gevokizumab,LY-2189102,MABP-1,GIT-027;
(30)HDL胆固醇增加剂,例如Anacetrapib,MK-524A,CER-001,DRL-17822,Dalcetrapib,JTT-302,RVX-000222,TA-8995;
(31)抗肥胖药物,如盐酸甲基苯丙胺,盐酸安非拉酮芬特明盐酸苯并噻嗪酒石酸苯二甲吗啉马吲哚奥利司他西布曲明盐酸盐一水合物利莫那班安非泼拉酮,吡啶甲酸铬,RM-493,TZP-301;苯丁胺/托吡酯,安非他酮,西布曲明/二甲双胍,安非他酮SR/唑尼沙胺SR,沙美特罗,昔萘酸盐/丙酸氟替卡松等组合物;盐酸氯卡色林,芬特明/托吡酯,安非他酮,头孢曲坦,艾塞那肽,KI-0803,利拉鲁肽,盐酸二甲双胍,西布曲明/二甲双胍,876167,ALS-L-1023,安非他酮SR/唑尼沙胺SR,CORT-108297,Canagliflozin,吡啶甲酸铬,GSK-1521498,LY-377604,Metreleptin,Obinepitide,P-57AS3,PSN-821,沙美特罗昔萘酸盐/丙酸氟替卡松,钨酸钠,生长激素(重组),TM-30339,TTP-435,替莫瑞林,特索芬辛,韦利贝特,唑尼沙胺,BMS-830216,ALB-127158,AP-1030,ATHX-105,AZD-2820,AZD-8329,Beloranib hemiocaalate,CP-404,HPP-404,ISIS-FGFR4Rx,胰高血糖素,KD-3010PF,05212389,PP-1420,PSN-842,肽YY3-36,白藜芦醇,S-234462;S-234462,Sobetirome,TM-38837,四氢大麻酚,ZYO-1,β-拉帕醌;
(32)血管紧张素受体阻滞剂,如氯沙坦,缬沙坦,坎地沙坦西酯,依普罗沙坦,厄贝沙坦,替米沙坦,奥美沙坦酯,阿齐沙坦酯;
(33)肾上腺素抑制剂,如阿利吉仑半氟双胍;
(34)中枢作用的α-2-肾上腺素能受体激动剂,例如甲基多巴,可乐定,胍法辛;
(35)肾上腺素能神经元阻滞剂,如胍乙啶,胍那决尔;
(36)咪唑啉I-1受体激动剂,例如磷酸二氢嘧啶核苷和盐酸莫索尼定水合物;
(37)醛固酮拮抗剂,如螺内酯和依普利酮
(38)钾通道活化剂,如吡那地尔
(39)多巴胺D1激动剂,例如甲磺酸非诺多泮;其他多巴胺激动剂,如异波帕胺,多培沙明和多卡巴胺;
(40)5-HT2拮抗剂,如酮色林;
(42)加压素拮抗剂,例如托伐普坦;
(43)钙通道敏化剂如左西孟旦或活化剂如尼可地尔;
(44)PDE-3抑制剂,例如氨力农,米力农,依诺莫酮,维纳啉酮,匹莫苯,奥普力农;
(45)腺苷酸环化酶活化剂,例如盐酸柯福辛达洛比;
(46)正性肌力药,如地高辛和甲地高辛;代谢性强心剂,如泛癸利酮;脑神经肽如奈西立肽;
(49)用于治疗勃起功能障碍的药物,如前列地尔,阿肽地尔,甲磺酸酚妥拉明,维格,前列地尔;
(53)抗肥胖药物:
(54)用于治疗阿尔茨海默病的药物:例如,用于轻度至中度阿尔茨海默病的胆碱酯酶抑制剂,包括(加兰他敏),(利凡斯的明)和(多奈哌齐),(他克林);(美金刚),N-甲基D-天冬氨酸(NMDA)拮抗剂和用于治疗中度至重度阿尔茨海默病;维生素E(一种抗氧化剂)。
(55)抗抑郁药:三环类抗抑郁药,如阿米替林地昔帕明丙咪嗪阿莫沙平去甲替林;选择性5-羟色胺再摄取抑制剂(SSRI),如帕罗西汀氟西汀舍曲林和柠檬醛其他如多塞平和曲唑酮SNRIs(例如文拉法辛和瑞波西汀);多巴胺能抗抑郁药(例如安非他酮和安咪奈汀)。
(56)神经保护剂:例如,美金刚,左旋多巴,溴隐亭,培高利特,利克索,普拉克索,卡麦角林,目前正在研究的神经保护剂,包括抗凋亡药物(CEP 1347和CTCT346),拉扎洛依,生物能量学,抗谷氨酸能药物和多巴胺受体。其他临床评价的神经保护剂是例如单胺氧化酶B抑制剂司来吉兰和雷沙吉兰,多巴胺激动剂和复合物I线粒体强化剂辅酶Q10。
(57)抗精神病药物:例如齐拉西酮(Geodon TM),利培酮(Risperdal TM)和奥氮平(Zyprexa TM)。
(58)NEP抑制剂,例如沙卡布曲,奥马曲拉。
(59)亚甲基蓝(MB)。
试剂盒
本文所述的化合物和药物制剂可以包含在试剂盒中。所述试剂盒可包括单剂量或多剂量的两种或更多种药剂,每种药剂单独包装或配制,或单剂量或多剂量的两种或更多种药剂组合包装或配制。因此,一种或多种试剂可以存在于第一容器中,并且试剂盒可以任选地在第二容器中包含一种或多种试剂。一个或多个容器放置在包装内,并且包装可任选地包括给药或剂量说明。试剂盒可以包括其他组分,例如注射器或用于施用药剂的其他装置以及稀释剂或其他配制方法。因此,试剂盒可包含:a)药物组合物,其包含本文所述的化合物和药学上可接受的载体、媒介物或稀释剂;b)容器或包装。试剂盒可任选地包含描述在本文所述的一种或多种方法中使用药物组合物的方法的说明书(例如,预防或治疗本文所述的一种或多种疾病和病症)。所述试剂盒可任选地包含第二药物组合物,其包含一种或多种本文所述的用于共同治疗的其他药剂,药学上可接受的载体、媒介物或稀释剂。包含本文所述化合物和试剂盒中包含的第二药物组合物的药物组合物可任选地组合在同一药物组合物中。
试剂盒包括用于容纳药物组合物的容器或包装,并且还可以包括分开的容器,例如分开的瓶子或分开的箔包。容器可以是例如纸或纸板盒,玻璃或塑料瓶或罐,可重复密封的袋(例如,用于容纳片剂的“再填充物”以放置到不同的容器中)或泡罩包装。根据治疗方案,用个别剂量按压包装。可以在单个包装中一起使用多于一个容器以销售单一剂型。例如,片剂可以包含在瓶子中,瓶子又包含在盒子中。
试剂盒的实例是所谓的泡罩包装。泡罩包装在包装工业中是众所周知的,并且广泛用于药物单位剂型(片剂,胶囊等)的包装。泡罩包装通常由一片相对硬的材料构成,该材料覆盖有优选透明的塑料材料的箔。在包装过程中,在塑料箔中形成凹槽。凹槽具有待包装的单个片剂或胶囊的尺寸和形状,或者可具有尺寸和形状以容纳待包装的多个片剂和/或胶囊。接下来,将片剂或胶囊相应地放置在凹槽中,并且在箔的与形成凹槽的方向相反的面上将相对硬的材料片密封在塑料箔上。结果,片剂或胶囊根据需要单独密封或共同密封在塑料箔和片材之间的凹槽中。优选地,片材的强度使得片剂或胶囊可以通过在凹槽上手动施加压力从泡罩包装中取出,由此在凹槽的位置处在片材中形成开口。然后可以通过所述开口除去片剂或胶囊。
可能需要提供书面记忆辅助,其包含关于何时服用药物的医生,药剂师或受试者的信息和/或指令。“每日剂量”可以是单个片剂或胶囊或在给定的一天服用的几个片剂或胶囊。当试剂盒包含单独的组合物时,试剂盒的一种或多种组合物的日剂量可以由一种片剂或胶囊组成,而试剂盒的另一种或多种组合物的日剂量可以由几种片剂或胶囊组成。试剂盒可以采用分配器的形式,该分配器设计成按照其预期用途的顺序一次一个地分配每日剂量。分配器可以配备记忆辅助装置,以便进一步促进对方案的依从性。这种记忆辅助器的一个例子是机械计数器,它指示已经分配的每日剂量的数量。这种记忆辅助的另一个例子是电池供电的微芯片存储器,其与液晶读出器或听觉提醒信号耦合,例如,读出最后一次每日剂量的日期和/或提醒一个何时服用下一剂。
实施例
实施例1:化合物合成
化合物I-1
标题化合物分2步合成:
步骤1:中间体4和中间体5的合成
将中间体3(0.3g,1当量;该化合物先前如WO2014144100中所述合成)和二氯甲烷(6ml)中的二苄基二异丙基亚磷酰胺(0.38g,2当量)的溶液加入1H-四唑中,作为0.45M乙腈溶液(4.37ml,3.5当量),将反应混合物在室温下搅拌30分钟。然后将反应混合物冷却至0℃,加入间-氯过氧苯甲酸(m-CPBA,0.29g,3当量),并使反应升温至室温并搅拌过夜。将反应物真空浓缩,用甲醇(1ml)稀释,粗物质通过反相HPLC纯化,使用5-75%乙腈:含0.1%甲酸梯度的水,得到二苄基中间体4[LCMS:保留时间=2.02分钟,m/z 795.2(M+H)](3mg,0.6%收率)和苄基中间体5[LCMS:保留时间=1.31分钟,m/z705.2(M+H)](5mg,1.2%收率),为白色固体。
步骤2:化合物I-1的合成
向中间体4和中间体5在甲醇(3ml)中的混合物中加入5%钯碳(10当量)。将小瓶用氮气冲洗并将反应在氢气球下在室温下搅拌3小时。然后过滤反应,真空除去溶剂,得到化合物I-1(6.1mg,79%收率),为白色固体。
1H NMR(500MHz,CD3OD)δppm8.81(s,1H),8.34(d,1H),7.56(s,1H),7.29(d,1H),7.08(m,2H),6.97(m,1H),6.94(t,1H),6.02(s,2H),4.87(s,2H)。LCMS:保留时间=1.11min,MS(ESI pos):m/z=614.8(M+H),MS(ESI neg):m/z=612.8(M-H)
LC-MS方法:
使用配备有Waters BEH C18柱(1.7um,2.1×50mm),Waters TUV检测器(220nm)和具有电喷雾电离的Waters SQ质谱仪的Waters Acuity UPLC系统获得UPLC ESMS。在0.1秒内从200-1000amu以正离子和负离子模式扫描光谱。梯度洗脱使用含有0.1%甲酸的水作为缓冲液A,含有0.1%甲酸的乙腈作为缓冲液B,流速0.6ml/min。在2分钟内从10%至100%B洗脱样品并在100%B下保持1分钟,然后使柱回到初始条件。总运行时间为3.0分钟。
化合物I-1,替代合成方法
以两个步骤合成化合物。
步骤1:中间体4的合成
将中间体3(0.50g,0.94mmol,先前如WO2014144100中所述合成的)在四氢呋喃(10mL)中的溶液在冰中冷却。在5分钟内滴加双(三甲基甲硅烷基)氨基锂(1M的THF溶液,1.2mL,1.2mmol),将得到的亮黄色溶液在0℃下搅拌20分钟。溶解四磷酸二苄酯(0.70g,1.31mmol)在THF(8mL)中并在冰中冷却。在15分钟内将预制的中间体3醇锂溶液滴入二磷酸盐溶液中,随着冰融化,使混合物在3小时内温热至室温。将反应混合物用乙酸乙酯(100mL)稀释,并用pH8的4×10mL NaH2PO4/Na3PO4缓冲液,盐水洗涤,用Na2SO4干燥。滤出干燥剂,得到粗中间体4的溶液(LCMS:m/e 795(M+H))。
步骤2:化合物I-1的合成
将上面制备的中间体4的溶液转移到250mL圆底烧瓶中,加入10%Pd/C(标称50%H2O,0.20g),用N2吹扫溶液和容器,然后用H2吹扫。将烧瓶用橡胶隔膜密封,并将混合物在室温下在充氢气球供应的氢气氛下搅拌5小时。将混合物通过硅藻土过滤,将滤饼用4:1乙酸乙酯/甲醇(40mL)洗涤,并通过旋转蒸发浓缩合并的滤液。将残余物与乙酸乙酯(40mL)和水(30mL)混合,加入浓NH4OH(水溶液),直至混合后pH保持在9。分离各层,水相用2×30mL乙酸乙酯洗涤。过滤水相,用乙腈(50mL)稀释并冻干过夜,得到化合物I-1,为灰白色粉末(0.35g,61%收率)。LCMS:m/e 615(M+H)。1H-NMR(500MHz,D2O)δ8.8.70(s,1H),8.10(d,1H),7.30-7.35(m,1H),7.31(s,1H),7.13(t,1H),7.08(t,1H),6.95(t,1H),6.83(s,1H),5.78(s,2H),4.67(s,2H)ppm。
化合物I-3
该化合物分三步合成。
步骤1:中间体2的合成
中间体1的悬浮液(328mg,0.877mmol,先前如WO2014144100中所述合成),4-(氨基甲基)四氢-2H-吡喃-4-醇盐酸盐(162mg,0.965mmol)和二恶烷(3mL)和水(1.5mL)中的三乙胺(0.611mL,4.38mmol)在90℃下加热3小时,得到浅黄色均匀溶液。将反应混合物冷却至室温,用水(10mL)稀释,然后用1N盐酸溶液(2mL)稀释,用乙酸乙酯(3×30mL)萃取,经硫酸钠干燥,过滤并浓缩,得到得到的中间体2(373mg,91%收率),为白色固体。1H NMR(500MHz,CD3OD):δ(ppm):8.76(d,1H),8.09(d,1H),7.42(s,1H),7.25-7.29(m,1H),7.07-7.11(m,1H),7.02-7.06(m,1H),6.89(d,1H),6.83-6.87(m,1H),5.96(s,2H),3.74-3.80(m,4H),3.71(s,2H),1.74-1.80(m,2H),1.57-1.61(m,2H)。LCMS[ES]-:C23H22F2N6O3的计算值,468.17。实测值:1.07分钟,467.3
步骤2:中间体9的合成
向中间体2(275mg,0.587mmol)的二氯甲烷(8mL)溶液中加入0.45M的1,2,3,4-四唑(3.91mL,1.76mmol)的乙腈溶液,然后加入二苄基。二异丙基亚磷酰胺(0.429mL,1.17mmol)。将反应混合物在室温下搅拌2.5小时,然后将其冷却至0℃。加入3-氯过氧苯甲酸(203mg,0.704mmol)的二氯甲烷(4mL)溶液,并将所得混合物在1.5小时内温热至室温。然后将反应混合物浓缩成残余物,并通过硅胶色谱法纯化,利用1至8%甲醇的二氯甲烷溶液梯度洗脱60分钟,得到两种化合物(288mg粗品)的混合物,其中二苄基(4-(((5-氟-2-(1-(2-氟苄基)-5-(异噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)氨基)甲基)四氢-2H-吡喃(4-中间体)磷酸酯(中间体9)是主要组分。该物质无需进一步纯化即可用于下一步骤。
步骤3:化合物I-3的合成
向二苄基中间体9(280mg)的乙酸乙酯(10mL)和无水乙醇(10mL)的悬浮液中加入10%钯碳(61.3mg,0.0580mmol)。将悬浮液抽空并用氮气回填三次,然后将装有氢气的气球装配到反应小瓶中。将反应混合物在室温下搅拌12小时,然后过滤反应物并浓缩成残余物。通过反相HPLC使用5至95%乙腈水溶液(掺入0.1%三氟乙酸)的梯度在20分钟内实现纯化,得到化合物I-3(103mg,49%产率),为粘性白色固体。
1H NMR(500MHz,CD3OD)δ(ppm):8.81(d,1H),8.23(m,1H),7.65(m,1H),7.28-7.33(m,1H),7.09-7.13(m,1H),7.05-7.08(m,1H),6.99(d,1H),6.94-6.97(m,1H),6.02(s,2H),4.22(s,2H),3.84-3.89(m,2H),3.74-3.82(m,2H),2.04-2.08(m,2H),1.84-1.89(m,2H)。LCMS[ES]+:C23H23F2N6O6P的计算值,548.14。实测值:0.97分钟,549.2
化合物I-4
以2个步骤合成标题化合物。
步骤1:中间体7的合成
将含有碳酸钾(2.0当量)、四丁基碘化铵(1.5当量)、中间体3(340mg,0.636mmol)和二叔丁基(氯甲基)磷酸酯(2.0当量)的混合物在DMF(4.2ml)中在室温下搅拌24小时。将混合物在乙酸乙酯(50ml)中稀释。用水(50ml×3)、盐水(50ml)洗涤有机层,干燥,过滤并蒸发,得到油状物。使用0至100%乙酸乙酯/己烷梯度,通过柱色谱法纯化油状物,得到标题中间体7(201mg,42%收率),为浅黄色油状物。该油状物无需进一步纯化即可用于下一步骤。
1H NMR(500MHz,CDCl3)δppm8.46(d,1H)8.21(d,1H)7.32(s,1H)7.17-7.23(m,1H)7.02(ddd,1H)6.94-7.00(m,1H)6.88-6.93(m,1H)6.62(d,1H)5.97(s,2H)5.49(d,2H)4.56(d,2H)1.51(s,18H)。
步骤2:化合物I-4的合成
将含有中间体7(319mg,1.0当量)和DCM(2.1ml)中的TFA(3.0当量)的混合物在室温下搅拌1小时。将混合物真空浓缩,得到化合物I-4(284mg,定量收率),为浅黄色固体。
1H NMR(500MHz,CD3OD)δppm8.79-8.83(m,1H)8.39(d,1H)7.59(s,1H)7.26-7.35(m,1H)7.05-7.16(m,2H)6.95-7.01(m,2H)5.98-6.04(m,2H)5.56(d,2H)4.75(s,2H)。
化合物I-4的二钠盐
向化合物I-4(50.5mg,1.0当量)在水(980μl)中的悬浮液中加入氢氧化钠的1.0M水溶液(157μl,2.0当量)。加完后,混合物的pH值为pH=7.4。将混合物用冷冻干燥机冷冻干燥,得到化合物I-4的标题二钠盐(40.9mg,76%产率),为白色固体。
1H NMR(500MHz,D2O)δppm8.72(s,1H)8.12(d,1H)7.30-7.38(m,2H)7.06-7.19(m,2H)6.98(t,1H)6.85(s,1H)5.79(s,2H)5.40(d,2H)4.61(s,2H)
化合物I-5
将含有中间体8(392mg,1.0当量,该化合物如WO2014144100中所述制备)和多磷酸(2.8ml,30当量)的混合物在90℃下加热24小时。将混合物在水中稀释并剧烈搅拌3小时直至形成浆液。通过小心加入氢氧化钠(3.7g,120当量),将混合物的pH升至pH=4。通过过滤收集形成的浅棕色沉淀物。获得的沉淀物通过HPLC纯化。将固体溶于1,4-二噁烷和水的混合物中,并在冷冻干燥器中冷冻干燥,得到标题化合物I-5(4.7mg,1.0%收率),为奶油色固体。
1H NMR(D2O)δ:8.76(br.s,1H),8.30(br.s,1H),7.67(s,1H),7.37(br.s,1H),7.10-7.22(m,2H),7.06(d,1H),6.90(br.s.,1H),5.89(br.s.,2H),4.60-4.70(m,2H)。
化合物I-2
将中间体1(26.9mg,0.191mmol)、磷酸乙醇胺(26.9mg,0.191mmol)和三乙胺(0.0970mL,0.695mmol)在二噁烷(1mL)和水(0.5mL)中的溶液加热至100℃,保持16小时,然后将反应冷却至室温,然后在1N盐酸溶液(0.400mL)中稀释,导致形成白色沉淀,其主要是未反应的原料。过滤该固体。静置后,另一种白色固体开始从滤液中沉淀出来,也将其过滤,并显示为含有所需产物的混合物。该混合物通过反相HPLC纯化,利用5至95%乙腈(掺入0.1三氟乙酸)的水溶液梯度洗脱25分钟,得到纯标题化合物I-2(21.3mg,26%收率),为白色固体。
1H NMR(500MHz,CD3OD)δ(ppm):8.81(s,1H),8.22(d,1H),7.66(s,1H),7.28-7.32(m,1H),7.09-7.12(m,1H),7.04-7.07(m,1H),6.99(s,1H),6.92-6.95(m,1H),6.02(s,2H),4.21(app.q,2H),3.99(t,2H)。[ES]+:C19H17F2N6O5P的计算值,478.10。实测值:0.97分钟,479。
实施例2A:通过sGC-HEK-cGMP测定进行的生物活性测量,具有LC/MS检测
使用内源表达可溶性鸟苷酸环化酶(sGC)的人胚肾细胞(HEK293)来评价测试化合物的活性。刺激sGC酶的化合物应引起cGMP细胞内浓度的增加。将HEK 293细胞接种于Dulbecco's改良Eagle's培养基中,补充有胎牛血清(10%终浓度)和青霉素(100U/mL)/链霉素(100μg/mL),体积为50μL,密度为1.5×104细胞/孔在聚-D-赖氨酸涂覆的384孔平底板中。将细胞在37℃下在含有5%CO2的加湿室中温育过夜。吸出培养基,用1x Hank's缓冲盐水溶液(50μL)洗涤细胞。然后将细胞在37℃下与50μL的0.5mM的3-异丁基-1-甲基黄嘌呤(IBMX)溶液一起温育15分钟。测试物品和二亚乙基三胺NONOate(DETA-NONOate)溶液(测试物溶液的xM浓度和DETA-NONOate溶液的10M浓度;其中x是以下浓度之一)
30000nM |
7500nM |
1875nM |
468.75nM |
117.19nM |
29.29nM |
7.32nM |
1.83nM |
0.46nM |
0.114nM |
0.029nM |
然后将其加入到测定混合物中,并将所得混合物在37℃下温育20分钟。孵育20分钟后,吸出测定混合物,向细胞中加入含有150ng/mL+3-cGMP(LCMS内标)(50μL)的10%乙酸。将板在4℃下在乙酸溶液中温育30分钟以终止反应并裂解细胞。然后将板在4℃下以1,000g离心3分钟,并将上清液转移到干净的反应板中进行LCMS分析。
使用下面的LCMS条件(表2)和计算的标准曲线从每个样品确定cGMP浓度。标准曲线在10%乙酸和150ng/mL+3cGMP(同位素标记的cGMP,重量比野生型高3个单位)中制备,其中cGMP的最终浓度为ng/mL:1、5、10、50、100、250、500、1000、2000。
表2:LC/MS条件,实施例2A
使用以下等式将数据标准化为高对照:100×(样品-低对照)/(高对照-低对照),其中低对照是用1%DMSO处理的16个样品的平均值,并且高对照是用30μM下面描述的化合物Y处理的16个样品的平均值。使用GraphPad Prism软件v.5,使用4-参数拟合(log(激动剂)对比响应-可变斜率)拟合数据。所有化合物的n=2。绝对EC50从曲线拟合内插,并定义为给定化合物引发50%高控制响应的浓度。据报道,未能引起50%最小响应的化合物>30μM。对于一式两份或n高于2的化合物,本文给出的结果是获得的几个结果的几何平均值。
表2A总结了在该测定中对于所选择的本发明化合物获得的结果。如所预期的,与其母体药物相比,前药(例如化合物I-1和化合物I-4)没有表现出高度的sGC激动作用。
表2A.用LC/MS检测HEK测定中的全细胞活性
化合物 | 绝对EC50(nM) | 母体化合物 | 绝对EC50(nM) |
I-1 | 12980 | 中间体3 | 220 |
I-4 | 25000 | 中间体3 | 220 |
HEK细胞中的sGC酶活性值,表示为绝对EC50,其定义为在标准化后给定化合物引发用化合物Y获得的50%高对照响应的浓度。
实施例2B:通过基于cGMP GloSensor细胞的测定的生物活性测量,384孔格式
人胚肾细胞(HEK293)细胞表达GloSensorTM 40F cGMP(部件号:CS182801,Promega)用于评估测试化合物的活性。掺入这些细胞中的发光生物传感器(工程荧光素酶)检测由刺激sGC酶并发射发光的化合物形成的cGMP。
将cGMP GloSensor细胞维持在补充有胎牛血清(FBS,10%终浓度)和潮霉素(200ug/ml)的Dulbecco's Eagle of Medium(DMEM)修饰中。在测定前一天,将细胞接种于含有10%FBS的50μL体积的DMEM中,密度为1.5×10 4个细胞/孔,在聚-D-赖氨酸包被的384孔平底白色底板中(Corning目录号35661)。将细胞在37℃下在含有5%CO2的加湿室中温育过夜。第二天,除去培养基,用40ul/孔的GloSensorTM,2mM(Promega Cat No E1291)替换细胞。将细胞在25℃下处理90分钟以使底物在细胞中平衡。将测试化合物和二亚乙基三胺NONOate(DETA-NONOate)在无血清CO 2的培养基中稀释至3mM(20x),并以4x稀释度连续稀释以产生5X剂量曲线,其中向孔中加入10μl(x×M浓度,试验化合物溶液和10 6M浓度的DETA-NONOate溶液;其中x是下列最终浓度之一)。
对于动力学研究,使用Envision(Perkin Elmer)立即测量每孔0.2秒的发光。对于终点SAR筛选,在室温下孵育55分钟后收集数据。
如上文实施例2A中所示进行数据分析。
如所预期的,与其母体药物相比,前药(例如化合物I-1)没有表现出高度的sGC激动作用。
表2B。基于GloSensor细胞的测定中的全细胞活性,384孔格式(实施例2B)
化合物 | 绝对EC50(nM) | 母体化合物 | 绝对EC50(nM) |
I-1 | 4843 | 中间体3 | 72 |
通过GloSensor测定法测定HEK细胞中的sGC酶活性值,表示为绝对EC50,其定义为在标准化后给定化合物引起化合物Y获得的50%高对照响应的浓度。
实施例3:热力学溶解度测量
将约1mg测试化合物称入1.5mL Eppendorf管中,并加入1.5mL给定pH的水性缓冲液。将样品涡旋并以150RPM置于振荡器上2-5天。收获样品,然后以12K RPM离心20分钟。将上清液用乙腈(ACN)稀释两次并通过UPLC分析。为了稀释样品,取出200uL上清液并丢弃。然后,取400μL上清液(间隔200μL)并加入到400μL乙腈(间隔200μL)中。
UPLC条件:流动相A:0.1%TFA水溶液;流动相B:0.1%TFA的乙腈溶液;柱:AcquityBEH C18,1.7微米,2.1x 50毫米;注射量:2-3uL;自动进样器温度:环境温度;柱温:25℃;运行时间:10分钟;流速:0.45mL/min;收集的波长:220nm,245nm,254nm,280nm,PDA光谱(190-400nm);用于分析的波长:254nm
梯度(表3):
在pH 7下,化合物I-1的溶解度=66-1000μg/mL
在pH 7下,化合物I-4的溶解度=71μg/mL
在pH 7下,母体中间体3的溶解度=2-3μg/mL
实施例4:离体大鼠肠液稳定性测定
本文公开的磷酸酯前药被设计为被存在于肠的顶端刷状缘膜上的碱性磷酸酶切割,之后更容易吸收更疏水的母体化合物。磷酸酶也存在于肝脏和体循环中。为了测试前药裂解成母体药物的速度,将每种测试化合物的5μM溶液在大鼠肠(空肠)液中温育。在=0、5、15、30和60分钟时取样,并通过加入含有内标的乙腈淬灭混合物。通过全扫描LC/MS分析样品。使用以下协议:
溶液和材料的制备
将10mM DMSO储备溶液解冻或制备用于阳性对照(依那普利)和每种测试物品。制备具有20ng/ml化合物Z的乙腈(ACN)中的内标(IS)碰撞溶液,如下所述。从10mM在50/50乙腈/H2O中制备原液(250μM)。将大鼠肠液小瓶在室温下在水浴中解冻。
肠液样品制备
在96孔、1ml平板中,每个时间点将48uL大鼠肠液等分三份。通过向48ul肠液中加入450ul IS崩解溶液,然后加入2μL试验化合物,分别制备t0(“0min”)时间点。加入2μl的250μM亚母液(substock)以在5分钟、15分钟、30分钟和60分钟开始反应。将上述步骤中制备的板用塑料或箔密封覆盖,并置于37℃培养箱中,轻轻摇动。对于每个时间点,加入450ulIS崩解溶液以淬灭反应。将板在4℃下以4000RPM离心10分钟。将50μl上清液转移到50μlH2O中并使用LC/MS分析。
随时间监测前药的消失和向母体的转化。使用以下LC/MS方案(表4):
为了比较的目的,在该测定中使用几种市售的磷酸盐前药作为基准:磷苯妥英和fostamatinib(已知在体内快速切割至母体药物)和磷氟康唑(叔醇的磷酸酯前药,已知的缓慢裂解到体内的母体药物)。
在实验条件下,将磷苯妥英快速裂解成其母体药物。在孵育30分钟后,超过80%的前药已转化为其母体药物。孵育60分钟后,未检测到前药。在该大鼠肠液测定中,消失半衰期(T1/2)确定为5分钟。据报道,人的半衰期(来自公开数据)为8-15分钟(Fosphenytoin:anovel phenytoin prodrug.Boucher BA,Pharmacology,1996Sept-Oct;16(5):777-91)。
在实验条件下,将福斯马替尼适度快速切成其母体药物。在孵育30分钟后,约50%的前药已转化为其母体药物。在孵育60分钟后,约80%的前药已转化为其母体药物。在该大鼠肠液测定中,消失半衰期(T1/2)确定为34分钟。当使用人类微粒体时,据报道前药在15分钟后完全水解(Metabolism of Fosfamatinib,the Oral Methylene Phosphat Prodrugof the Spleen Tyrosine Kinase Inhibitor R406 in Humans:Contribution ofHepatic and Gut Bacterial Processes to the Overal Transformacion.DJ Sweeny等人,Drug Metabolism and Disposition,38,1166-1176(2010))。在人体临床试验中,在3小时研究中,在单次和多次口服给药后,在2小时时间点(Pharmacokinetics offostamatinib,a spleen tyrosine kinase(SYK)inhibitor,in healthy human subjectsfollowing single and multiple oral dosing in three phase I studies.MuhammadBaluom,Elliott B Grossbard,Tim Mant和David TW Lau.Br J Clin Pharmacol.2013年7月;76(1):78-88)
在实验条件下,并且如所预期的,由于是空间位阻的叔醇,将磷氟康唑更慢地裂解成其母体药物。孵育60分钟后,约80%的前药保持未切割。在该大鼠肠液测定中,消失半衰期(T1/2)确定为211分钟。据报道,人体半衰期(来自已发表的数据)为1.5-2.5小时(Pharmacokinetics of fosfluconazole and fluconazole following multipleintravenous administration of fosfluconazole in healthy male volunteers.SobueS,Tan K,Layton G,Eve M,和Sanderson JB.Br J Clin Pharmacol 58:20-25,(2004)。
参见“Evaluation of in Vitro Models for Screening AlkalinePhosphatase-Mediated Bioconversion of Phosphate Ester Prodrugs”Haodan Yuan,NaLi和Yurong Lai;Drug Metabolism and Disposition 37:1443-1447,2009用于比较几种体外模型中磷苯妥英与磷氟康唑的切割时间。
出乎意料的是,化合物I-1(叔醇中间体3的磷酸酯前药)非常快速地裂解。在孵育30分钟后,约80%的前药已转化为其母体药物,并且在孵育60分钟后约95%的前药已被切割。在该大鼠肠液测定中,消失半衰期(T1/2)确定为16分钟。
化合物I-4(叔醇中间体3的另一种磷酸酯前药)也非常出乎意料地快速裂解。孵育60分钟后,超过99%的前药已被切割。在该大鼠肠液测定中,消失半衰期(T1/2)确定为9分钟。
还出乎意料地,中间体2的磷酸酯前药化合物I-3(叔醇)快速裂解。孵育30分钟后,约25%的前药已被消耗。孵育60分钟后,少于10%的前药保留在溶液中。
实施例5:大鼠PK化合物I-1(与其母体中间体3相比)
操作步骤
在静脉内和口服给药后测定大鼠中的PK。
对于静脉内(IV)和口服(PO)实验,分别使用两组4只雄性Sprague-Dawley大鼠。PO组给予3.0mg/kg化合物I-1,配制成磷酸盐缓冲盐水(PBS)中的溶液。IV组给予1.0mg/kg化合物I-1,配制成磷酸盐缓冲盐水(PBS)中的溶液。IV剂量通过颈静脉中的留置导管给药。给药后,用大约0.25mL盐水冲洗导管。使用注射器和管饲管将PO剂量递送至胃。口服剂量给药后,用约0.5mL水冲洗管饲管以确保完全递送全剂量。
如下收集血浆样品:对于IV和PO实验,在给药后5分钟、15分钟、30分钟、1小时、2小时、4小时、6小时、8小时、12小时、16小时、20小时和24小时收集样品。从颈静脉收集血样(0.25mL)。将这些样品保持在冰上直至处理成等离子体。在收集1小时内,将血液样品在约5℃下以3200rpm离心5分钟。将血浆直接转移到96孔板管(0.125mL)中。将塞盖置于管上,并将管冷冻至约-70℃并储存直至分析。
收集血浆并分析化合物I-1和衍生自化合物I-1的中间体3的存在。
通过LC-MS/MS定量化合物I-1和中间体3
通过沉淀从血浆中提取中间体3、化合物I-1和内标(IS,化合物Z)。使用液相色谱(LC)使用串联质谱检测(MS/MS)使用电喷雾电离分析样品。标准曲线范围为0.1至400ng/mL。
储备溶液的制备(储存溶液在4℃)
中间体3DMSO储备溶液(1mg/mL):用DMSO溶解至终浓度1mg/mL。
化合物I-1DMSO储备溶液(1mg/mL):用DMSO溶解至终浓度为1mg/mL。
工作溶液的制备(新鲜制备)
中间体3(50ug/mL)工作溶液:通过向950ul ACN中加入50μl,从1mg/mL储备标准溶液制备1mL50μg/mL工作溶液。
化合物I-1(50ug/mL)工作溶液:通过向950ul ACN中加入50μl,从1mg/mL储备标准溶液制备1mL50μg/mL工作溶液。
标准的制定
创建中间体3(在ACN中)和化合物I-1(在ACN中)的100X标准曲线。将解决方案存储在-80℃。
标准品、样品和空白的制备
解冻的血浆样品和用于标准品,空白和稀释液的所需量的血浆。准备好的碰撞溶液:室温ACN含有1ng/mL化合物Z作为内标。通过稀释100X储液(每种100X标准品5uL至495uL血浆)产生1X混合(中间体3和化合物I-1)标准曲线。转移50uL每种血浆样品/稀释液、标准品或空白样品。添加了200uL包含IS的崩溃解决方案。涡旋5分钟。在室温下以16,000g离心10分钟。将200uL每种上清液转移至平板中。在氮气下在TurboVap中在55℃下干燥。将每个样品重新悬浮在50uL0.1%甲酸中,覆盖并涡旋。通过LC-MS/MS分析。
使用以下条件(表5A):
表5A
结果
IV大鼠PK实验的结果总结在下表5B中
当IV给药时,化合物I-1前药干净地转化为其母体中间体3,半衰期为约9分钟。在PBS(磷酸盐缓冲盐水)中静脉内给药的化合物I-1给予与PEG中给药的中间体3(其亲本)相当的PK参数。
口服(PO)大鼠PK实验的结果总结在下表5C中:
在PO给药后,在任何血浆样品中均未观察到前药化合物I-1。观察到由化合物I-1产生的中间体3的Tmax为约7小时,类似于相似给药后母体药物中间体3的Tmax。
实施例6:狗PK化合物I-1(与其母体中间体3相比)
操作步骤
在IV和口服给药后测定狗中的PK。
对于口服(PO)实验,使用两组,每组5只雄性比格犬。一组给予2.5mg/kg化合物I-1,其配制成胶囊中的PEG400溶液。另一组给予2.5mg/kg配制成PBS溶液的化合物I-1。对于IV实验,给5只雄性Beagle犬给予0.5mg/kg配制成PBS溶液的化合物I-1。IV剂量通过头静脉中的留置导管给药。给药后,用大约5小时冲洗导管。3mL盐水。使用注射器和管饲管将口服悬浮剂量递送至胃。口服剂量给药后,用约10mL水冲洗管饲管以确保完全递送全剂量。
如下收集血浆和尿液样品:对于PO实验,在给药后15分钟、30分钟、1小时、2小时、3小时、4小时、6小时、8小时、24小时、32小时和48小时收集样品;对于IV实验,在给药后2分钟、5分钟、15分钟、30分钟、1小时、2小时、3小时、4小时、6小时、8小时、24小时、32小时和48小时收集样品。从颈静脉、头静脉或隐静脉收集血样(2mL)。将这些样品保持在冰上直至处理成等离子体。在收集1小时内,将血液样品在约5℃下以3200rpm离心10分钟。将血浆分成两个大致相等的等分试样,并直接转移到96孔板管(1.1mL)中。将塞盖置于管上,并将管冷冻至约-70℃并储存直至分析。
通过从放置在每只动物的笼子下面的尿液收集盘转移到适当的收集容器中从每只动物收集尿液,在整个收集过程中被湿冰或冰袋包围。测量并记录在每个间隔收集的尿液的总体积,收集单个10mL等分试样并在约-70℃冷冻储存直至分析。
收集血浆和尿液并分析化合物I-1和衍生自化合物I-1的中间体3的存在。
通过LC-MS/MS定量化合物I-1和中间体3
通过沉淀从血浆中提取中间体3、化合物I-1和内标(IS,化合物Z)。使用液相色谱(LC)使用串联质谱检测(MS/MS)使用电喷雾电离分析样品。标准曲线范围为0.1至400ng/mL。
储备溶液的制备(储存溶液在4℃)
中间体3DMSO储备溶液(1mg/mL):用DMSO溶解至终浓度1mg/mL。
化合物I-1DMSO储备溶液(1mg/mL):用DMSO溶解至终浓度为1mg/mL。
工作溶液的制备(新鲜制备)
中间体3(50ug/mL)工作溶液:通过向950ul ACN中加入50μl,从1mg/mL储备标准溶液制备1mL50μg/mL工作溶液。
化合物I-1(50ug/mL)工作溶液:通过向950ul ACN中加入50μl,从1mg/mL储备标准溶液制备1mL50μg/mL工作溶液。
标准品的制备
创建中间体3(在ACN中)和化合物I-1(在ACN中)的100X标准曲线。存储在-80℃。
标准品、样品和空白的制备
解冻的血浆样品和用于标准品、空白和稀释液的所需量的血浆。准备好的碰撞溶液:室温ACN含有1ng/mL化合物Z作为内标。通过稀释100X原液(每个100X标准品5uL到490μL血浆中)产生1X混合(中间体3和化合物I-1)标准曲线。转移50uL每种血浆样品/稀释液、标准品或空白样品。添加了200uL包含IS的崩溃解决方案。涡旋5分钟。在室温下以16,000g离心10分钟。将200uL每种上清液转移至平板中。在氮气下在TurboVap中在55℃下干燥。将每个样品重悬于50uL0.1%甲酸中,盖上并涡旋。通过LC-MS/MS分析。使用以下条件:
表6A
结果
IV Dog PK实验的结果总结在下表6B中:
当IV给药时,化合物I-1前药干净地转化为其母体中间体3,半衰期为约15分钟。转换为母体的速度很快,平均转化率为95%。在PBS中给药IV的化合物I-1给予与PEG中给药的中间体3(其亲本)相当的AUC。
口服(PO)狗PK实验的结果总结在下表6C中:
来自化合物I-1的中间体3在PEG400填充的胶囊中的生物利用度与相同制剂中的母体中间体3的生物利用度相似。PO给药后在血浆中观察到低水平的前药。在该实验中使用的动物的尿液中也发现了可忽略量的前药。
本文使用的术语仅用于描述特定实施方案的目的,并不意图限制本发明。如这里所使用的,单数形式“一”,“一个”和“该”也旨在包括复数形式,除非上下文另有明确说明。将进一步理解,术语“包含”(和任何形式的包括,例如“包含”),“具有”(和任何形式的具有,例如“有”),“包括”(以及任何形式的包括,例如“包括”),“含有”(以及任何形式含有,例如“含有”),以及其他任何语法变体,都是开放的-连接动词。结果,“包含”,“具有”,“包括”或“含有”一个或多个步骤或元素的方法或设备拥有那些一个或多个步骤或元素,但不限于仅拥有那些一个或多个步骤或元素。同样地,“包括”,“具有”,“包含”或“含有”一个或多个特征的设备的方法或元素的步骤拥有那些一个或多个特征,但不限于仅拥有那些特征或者一个或多个特征。更多功能。此外,以某种方式配置的设备或结构至少以这种方式配置,但是也可以以未列出的方式配置。
如本文所用,术语“包含”、“具有”、“包括”、“含有”及其他语法变体包括术语“由......组成”和“基本上由......组成”。
当在本文中使用时,短语“基本上由......组成”或其语法变体应被视为指定所述特征、整数、步骤或组件,但不排除添加一个或多个附加特征、整数、步骤、组件或其组,但仅在其附加特征、整数、步骤、组分或组不会实质上改变所要求保护的组合物、装置或方法的基本和新颖特征时。
本说明书中引用的所有出版物均通过引用并入本文,如同每个单独的出版物被具体和单独地指出通过引用并入本文,如同完全阐述一样。
除非另外明确指出,否则通过引用并入的主题不被认为是任何权利要求限制的替代。
在整个说明书中引用一个或多个范围的情况下,每个范围旨在是用于呈现信息的简写格式,其中该范围被理解为包含该范围内的每个离散点,如同其在本文中完全阐述一样。
虽然本文已经描述和描绘了本发明的若干方面和实施例,但是本领域技术人员可以影响替代方面和实施例以实现相同的目的。因此,本公开和所附权利要求旨在覆盖落入本发明的真实精神和范围内的所有这些进一步和替代方面和实施例。
Claims (10)
1.式I化合物或其药学上可接受的盐:
其中,
X选自–P(O)(OH)2、–P(O)(OH)O-M+、–P(O)(O-)2(M+)2或–P(O)(O-)2D2+;其中M+是药学上可接受的一价阳离子,D2+是药学上可接受的二价阳离子;
每个JB独立地选自卤素;
m选自0或1;
n选自0、1、2、3或4;
R1选自C1-4烷基,C1-4氟代烷基,-C(O)NH2或氢;且
R2选自C1-4烷基,C1-4氟烷基或氢;或者,
R1和R2与它们所连接的碳原子一起形成C3-7脂环族环,或含有独立地选自N、O或S的至多2个杂原子的3至7元杂环;其中所述C3-7脂环族环或3至7元杂环是未取代的;
R3选自卤素、氢、-CN或-NH2;
R4的两个实例同时为氢,或R4的两个实例与它们所连接的碳原子一起形成羰基;和
R5选自氢或甲基。
4.根据权利要求1、2或3所述的化合物,其中X是–P(O)(OH)2。
5.根据权利要求1、2或3中任一项所述的化合物,其中X是–P(O)(OH)O-M+或–P(O)(O-)2(M+);M+选自Na+、K+或有机胺的一价阳离子。
6.根据权利要求1、2或3中任一项所述的化合物,其中X是–P(O)(O-)2D2+;D2+选自Ca2+、Cs2+、Zn2+、Mg2+或有机胺的二价阳离子。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101735267A (zh) * | 2008-11-17 | 2010-06-16 | 上海阳帆医药科技有限公司 | 水溶性(r)-(-)-比卡鲁胺前药、其制备方法及用途 |
WO2014144100A2 (en) * | 2013-03-15 | 2014-09-18 | Takashi Nakai | Sgc stimulators |
Family Cites Families (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5721365A (en) | 1989-09-15 | 1998-02-24 | Us Health | N-substituted piperazine NONOates |
US5155137A (en) | 1990-09-20 | 1992-10-13 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Complexes of nitric oxide with polyamines |
CA2119572C (en) | 1991-09-24 | 2005-07-05 | Larry Kay Keefer | Oxygen substituted derivatives of nucleophile-nitric oxide adducts as nitric oxide donor prodrugs |
US5814666A (en) | 1992-04-13 | 1998-09-29 | The United States As Represented By The Department Of Health And Human Services | Encapsulated and non-encapsulated nitric oxide generators used as antimicrobial agents |
US5405919A (en) | 1992-08-24 | 1995-04-11 | The United States Of America As Represented By The Secretary Of Health And Human Services | Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions and methods of treating biological disorders |
US5910316A (en) | 1992-08-24 | 1999-06-08 | The United States Of America, As Represented By The Department Of Health And Human Services | Use of nitric oxide-releasing agents to treat impotency |
US5632981A (en) | 1992-08-24 | 1997-05-27 | The United States Of America As Represented By The Department Of Health And Human Services | Biopolymer-bound nitric oxide-releasing compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same |
US5691423A (en) | 1992-08-24 | 1997-11-25 | The United States Of America As Represented By The Department Of Health And Human Services | Polysaccharide-bound nitric oxide-nucleophile adducts |
AU685178B2 (en) | 1993-10-08 | 1998-01-15 | United States Of America, Represented By The Secretary, Department Of Health And Human Services, The | Use of nitric oxide-releasing compounds as hypoxic cell radiation sensitizers |
JP2928079B2 (ja) | 1994-02-14 | 1999-07-28 | 永信薬品工業股▲ふん▼有限公司 | 1−(置換ベンジル)−3−(置換アリール)縮合ピラゾール類、その製造法及びその用途 |
US5700830A (en) | 1994-11-22 | 1997-12-23 | The United States Of America As Represented By The Department Of Health And Human Services | Use of nitric oxide-releasing agents for reducing metastasis risk |
EP0837052B1 (en) | 1995-06-21 | 2006-08-23 | Shionogi & Co., Ltd. | Bicyclic amino derivatives and pgd 2 antagonist containing the same |
US5714511A (en) | 1995-07-31 | 1998-02-03 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Selective prevention of organ injury in sepsis and shock using selection release of nitric oxide in vulnerable organs |
ATE295360T1 (de) | 1996-12-12 | 2005-05-15 | Shionogi & Co | Kondensierte heterocyclische benzolcarbonsäureamid-derivate und diese enthaltende pgd2 antagonisten |
NZ336143A (en) | 1996-12-13 | 2002-05-31 | Shionogi & Co | Benzothiophenecarboxamide derivatives and pgd 2 antagonists comprising them |
DE19744026A1 (de) | 1997-10-06 | 1999-04-08 | Hoechst Marion Roussel De Gmbh | Pyrazol-Derivate, ihre Herstellung und ihre Verwendung in Arzneimitteln |
DE19830430A1 (de) | 1998-07-08 | 2000-01-13 | Hoechst Marion Roussel De Gmbh | Schwefelsubstituierte Sulfonylamino-carbonsäure-N-arylamide, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
ID26773A (id) | 1998-07-08 | 2001-02-08 | Aventis Pharma Gmbh | Sulfur tersubstitusi pada asam sulfonilaminokarboksilat n-arilamida, persiapan, penggunaan dan persiapan pembuatan obat yang menyertainya |
DE19834044A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19834047A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
GB9824310D0 (en) | 1998-11-05 | 1998-12-30 | Univ London | Activators of soluble guanylate cyclase |
DE19942809A1 (de) | 1999-09-08 | 2001-03-15 | Bayer Ag | Verfahren zur Herstellung substituierter Pyrimidinderivate |
DE19943635A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
US20010051624A1 (en) | 2000-04-12 | 2001-12-13 | Jones Thomas R. | Method and compositions for the treatment of allergic conditions using PGD2 receptor antagonists |
EP1274457B1 (en) | 2000-04-12 | 2005-11-30 | Merck Frosst Canada & Co. | Method and compositions for the treatment of allergic conditions using pgd2 receptor antagonists |
US6878522B2 (en) | 2000-07-07 | 2005-04-12 | Baiyong Li | Methods for the identification of compounds useful for the treatment of disease states mediated by prostaglandin D2 |
MY136316A (en) | 2001-02-13 | 2008-09-30 | Sanofi Aventis Deutschland | Acylated 6,7,8,9-tetrahydro-5h-benzocycloheptenyl amines and their use as pharmaceutical. |
PE20020856A1 (es) | 2001-02-13 | 2002-11-11 | Aventis Pharma Gmbh | 1,2,3,4-tetrahidronaftil aminas aciladas |
TWI241190B (en) | 2001-02-13 | 2005-10-11 | Aventis Pharma Gmbh | 4-Fluoro-N-indan-2-yl benzamide and its use as pharmaceutical |
TWI243164B (en) | 2001-02-13 | 2005-11-11 | Aventis Pharma Gmbh | Acylated indanyl amines and their use as pharmaceuticals |
US6511911B1 (en) | 2001-04-03 | 2003-01-28 | Advanced Micro Devices, Inc. | Metal gate stack with etch stop layer |
EP1424335A4 (en) | 2001-09-07 | 2005-11-16 | Ono Pharmaceutical Co | INDOLE DERIVATIVES |
EP1424325A4 (en) | 2001-09-07 | 2005-12-21 | Ono Pharmaceutical Co | INDOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICAMENTS CONTAINING THEM AS AN ACTIVE AGENT |
SE0200411D0 (sv) | 2002-02-05 | 2002-02-05 | Astrazeneca Ab | Novel use |
SE0200356D0 (sv) | 2002-02-05 | 2002-02-05 | Astrazeneca Ab | Novel use |
DE10216145A1 (de) | 2002-04-12 | 2003-10-23 | Bayer Ag | Verwendung von Stimulatoren der löslichen Guanylatcyclase zur Behandlung von Glaukom |
DE10220570A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamat-substituierte Pyrazolopyridine |
JPWO2003097042A1 (ja) | 2002-05-16 | 2005-09-15 | 塩野義製薬株式会社 | Pgd2受容体拮抗剤 |
EP2423190A1 (en) | 2002-05-16 | 2012-02-29 | Shionogi&Co., Ltd. | Compounds Exhibiting PGD 2 Receptor Antagonism |
TW200307542A (en) | 2002-05-30 | 2003-12-16 | Astrazeneca Ab | Novel compounds |
SE0201635D0 (sv) | 2002-05-30 | 2002-05-30 | Astrazeneca Ab | Novel compounds |
SE0202241D0 (sv) | 2002-07-17 | 2002-07-17 | Astrazeneca Ab | Novel Compounds |
CA2500582A1 (en) | 2002-10-04 | 2004-04-22 | Millennium Pharmaceuticals, Inc. | Pgd2 receptor antagonists for the treatment of inflammatory diseases |
EP1585511B1 (en) | 2002-12-20 | 2013-01-23 | Amgen Inc. | Asthma and allergic inflammation modulators |
US8309608B2 (en) | 2003-11-06 | 2012-11-13 | Sanofi-Aventis Deutschland Gmbh | Use of eNOS transcription enhancers in the cell therapy of ischemic heart diseases |
MY146042A (en) | 2005-12-27 | 2012-06-15 | Otsuka Pharma Co Ltd | Water-soluble benzoazepine compound and its pharmaceutical composition |
DE102007036075A1 (de) | 2007-08-01 | 2009-02-05 | Bayer Healthcare Ag | Prodrugs und ihre Verwendung |
JP5298129B2 (ja) | 2007-09-06 | 2013-09-25 | メルク・シャープ・アンド・ドーム・コーポレーション | 可溶性グアニレートシクラーゼ活性化因子 |
EP2244575B1 (en) | 2008-01-24 | 2013-07-17 | Merck Sharp & Dohme Corp. | Angiotensin ii receptor antagonists |
CA2743864A1 (en) | 2008-11-25 | 2010-06-10 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
CA2753434C (en) | 2009-02-26 | 2014-07-15 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
WO2011119518A1 (en) | 2010-03-25 | 2011-09-29 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
EA023254B1 (ru) | 2010-05-27 | 2016-05-31 | Мерк Шарп Энд Домэ Корп. | Активаторы растворимой гуанилатциклазы |
US8895583B2 (en) | 2010-10-28 | 2014-11-25 | Merck Sharp & Dohme Corp. | Soluble guanylate cyclase activators |
AU2012205415B2 (en) | 2011-01-14 | 2017-02-02 | Spero Therapeutics, Inc. | Pyrimidine gyrase and topoisomerase IV inhibitors |
CN103288809B (zh) * | 2012-02-24 | 2015-09-23 | 深圳市健元医药科技有限公司 | 葛根素单磷酸盐或单磺酸盐衍生物及其制备方法 |
EP2980087B1 (en) | 2013-03-29 | 2018-06-06 | Xuanzhu Pharma Co., Ltd. | Prodrugs of bicyclic substituted pyrimidine type pde-5 inhibitors |
US20160324856A1 (en) * | 2014-01-13 | 2016-11-10 | Ironwood Pharmaceuticals, Inc. | Use of sgc stimulators for the treatment of neuromuscular disorders |
US10927136B2 (en) * | 2016-07-07 | 2021-02-23 | Cyclerion Therapeutics, Inc. | Phosphorus prodrugs of pyrazolo-substituted pyrimidine sGC stimulators |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101735267A (zh) * | 2008-11-17 | 2010-06-16 | 上海阳帆医药科技有限公司 | 水溶性(r)-(-)-比卡鲁胺前药、其制备方法及用途 |
WO2014144100A2 (en) * | 2013-03-15 | 2014-09-18 | Takashi Nakai | Sgc stimulators |
CN105408328A (zh) * | 2013-03-15 | 2016-03-16 | 铁木医药有限公司 | sGC刺激剂 |
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