CN111712247A - sGC刺激剂 - Google Patents
sGC刺激剂 Download PDFInfo
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- CN111712247A CN111712247A CN201880089157.2A CN201880089157A CN111712247A CN 111712247 A CN111712247 A CN 111712247A CN 201880089157 A CN201880089157 A CN 201880089157A CN 111712247 A CN111712247 A CN 111712247A
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- 229960003414 zomepirac Drugs 0.000 description 1
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- 239000002076 α-tocopherol Substances 0.000 description 1
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Abstract
本公开涉及可溶性鸟苷酸环化酶(sGC)的刺激剂,药学上可接受的盐,包含它们的药物制剂以及它们的磷酸酯前药,以及它们单独或与一种或多种其他试剂组合用于治疗各种疾病的用途,其中,一氧化氮(NO)浓度的增加和/或环状鸟苷单磷酸酯(cGMP)的浓度的增加或两者或NO途径的上调是期望的。所述化合物是具有式I的化合物。
Description
相关申请
本申请根据35 U.S.C.§119(e)要求2017年12月19日提交的美国临时申请62/607,619的申请日的权益,其整个内容在此引入作为参考。
技术领域
本发明涉及可溶性鸟苷酸环化酶(sGC)的刺激剂和其药学上可接受的盐。还涉及包含它们的药物制剂及其用途,所述刺激剂单独或与一种或多种其他药剂组合用于治疗多种疾病。该疾病是将从sGC刺激或一氧化氮(NO)和/或环单磷酸鸟苷(cGMP)浓度增加中受益的疾病。
背景技术
sGC是NO在体内的主要受体。与sGC结合后,NO激活其催化结构域,并导致鸟苷5'-三磷酸(GTP)转化为二级信使cGMP。cGMP水平的升高反过来调节了下游效应子的活性,包括蛋白激酶、磷酸二酯酶(PDE)和离子通道。在体内,NO是由精氨酸和氧气通过各种一氧化氮合酶(NOS)和无机硝酸盐的依次还原而合成的。实验和临床证据表明,降低的NO浓度,降低的NO生物利用度和/或降低的对内源性NO的反应性助长了许多疾病的发展。sGC刺激剂是sGC酶的血红素依赖性激动剂,可与不同数量的NO协同作用,以增加其GTP向cGMP的酶促转化。sGC刺激剂与另一类称为sGC激活剂的NO非依赖性,血红素非依赖性的sGC的激动剂有明显区别,并且在结构上不相关。
改善或恢复sGC功能的疗法相对于当前以该途径为靶标或从NO-sGC途径的上调中受益的其它疗法具有相当大的优势。需要开发新的sGC刺激剂。
发明内容
本发明涉及式I化合物,和其药学上可接受的盐,
其中:
Y独立地为N或C;
环B为苯基或5或6-元杂芳基环,该杂芳基环包含1或2个独立选自N、O或S的环杂原子;
n为选自0至3的整数;和各个JB独立地为卤素、-CN、C1-6脂族基团、-ORB或C3-8脂环族环;
其中各个为C1-6脂族基团的JB和各个为C3-8脂环族环的JB任选且独立取代有至多3个R3;
各个RB独立地为氢、C1-6脂族基团或C3-8脂环族环;所述RB任选且独立取代有至多3个R3a;
各个R3和R3a在每种情况独立为卤素、-CN、C1-4烷基、C1-4卤代烷基、-O(C1-4烷基)或-O(C1-4卤代烷基);
Z选自氢、–P(O)(OH)2、–P(O)(OH)O-M+、–P(O)(O-)2(M+)2、–P(O)(O-)2D2+和-P(O)(O-苄基)2;其中M+是药学上可接受的单价阳离子,D2+是药学上可接受的二价阳离子;
m为0或1;
R1为C1-4烷基、C1-4氟代烷基、-C(O)NH2或氢;和
R2为C1-4烷基、C1-4氟代烷基或氢;
两个R4同时为氢或两个R4与它们所连接的碳原子一起形成羰基。
JD为氢、卤素、甲氧基或-CN;
p为1、2或3;和
每个JC独立地为氢、卤素、C1-4脂族基团、C1-4烷氧基或-CN;其中每个所述的C1-4脂族基团和每个所述的C1-4烷氧基任选地且独立地被至多3个C1-4烷氧基、C1-4卤代烷氧基、-OH或卤素取代。
在另一个实施方案中,本发明涉及药物组合物,其包含式I的化合物或其药学上可接受的盐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,本发明涉及一种在有此需要的受试者中治疗疾病的方法,该方法包括对受试者单独给药或在组合疗法中给药治疗有效量的式I的化合物或其药学上可接受的盐或其药物组合物;其中该疾病是将从sGC刺激或从NO和/或cGMP浓度增加中受益的疾病。本发明还提供了式I的化合物或其药学上可接受的盐单独或在组合疗法中用于在有需要的受试者中治疗疾病的方法,其中所述疾病是将从sGC刺激或从NO和/或cGMP浓度增加中受益的疾病。还提供了式I的化合物或其药学上可接受的盐在制备用于单独或在组合疗法中治疗有此需要的受试者中的疾病的药物的用途,其中所述疾病是将从sGC刺激或从NO和/或cGMP浓度增加中受益的疾病。
发明详述
现将详细地参考本发明的某些实施方案,其实例在所附结构和式中说明。尽管将结合所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方案。相反,本发明旨在涵盖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。本发明并不限于本文所述的方法及材料,但包括任何类似或等同于本文所述的可用于本发明实践的方法和材料。如果所包含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)时,以本申请为准。
定义及一般术语
出于本发明的目的,化学元素是根据元素周期表CAS版和Handbook of Chemistryand Physics,第75版,1994确定。另外,有机化学的一般原理描述于"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's AdvancedOrganic Chemistry",第5版,Smith,M.B.和March,J.,eds.John Wiley&Sons,New York:2001中,其全部内容通过引用并入本文。
通常,术语“取代的”是指用不同于氢的另一种特定的自由基取代基取代给定结构的一个或多个氢基团(一些非限制性实例是羟基,苯基或烷基)。如果结构或部分被“任选地取代”,则其可以被取代或未被取代。当给定化学结构的一个或多个位置可以被选自指定基团或列表的一个或多个取代基取代或可选地取代时,除非另有说明,否则每个位置上的一个或多个取代基可以“独立地选择”为在每个位置上和每种情况下是等同或相同的。例如,如果苯基被两个R100取代,并且每个R100独立地选自卤素和甲基,则意味着每个R100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,或者两个都可以是氯,等等。
本公开内容所包括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”是指在出于本文所公开的一个或多个目的而经受其产生、检测,以及在一些实施方案中,它们的回收、纯化和使用的条件时,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的公开内容,并且如果需要,在补充本领域的相关知识下可以制备的化合物。
如本文所用短语“至多”是指0或等于或小于短语后数值的任一整数数值。例如,“至多3”意指0、1、2或3中的任一个。如本文所述,原子或取代基的指定数量范围包括其中的任一整数。例如,具有1-4个原子的基团可具有1个、2个、3个或4个原子。当任一变量在任一位置出现一次以上时,其在每次出现时的定义独立于其他每次出现。当一个基团被某个变量的0个实例取代时,这表示该基团未被取代。
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、阻转异构和顺-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物及对映异构体、非对映异构体和顺-反异构体的混合物在本发明范围内。除非另有说明,否则本发明化合物的所有互变异构形式也在本发明范围内。
在一个实施方案中,本公开可以包括用氘(即2H)代替氢,其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。氘标记的本发明化合物通常可以通过用氘化试剂取代非氘化试剂,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。
术语“脂族基”,(如在“脂族基团”或“脂族链”中),指完全饱和或包含一个或多个不饱和单元的非支链或支链烃(仅由碳和氢形成)链。合适的脂肪族基团包括但不限于直链或支链烷基、烯基或炔基。脂族基团的具体实例包括但不限于:甲基、乙基、丙基、丁基、异丙基、异丁基、乙烯基、仲丁基、叔丁基、丁烯基、炔丙基、乙炔基等。脂族基团将由术语“Cx-y脂族基团”表示;其中x和y是形成脂族链的最小和最大碳原子数。
如本文所用,术语“烷基”(如在“烷基链”或“烷基基团”中)是指饱和的非支链或支链单价烃基。Cx烷基是含有x个碳原子的烷基链,其中x是不同于0的整数。“Cx-y烷基”,其中x和y是两个不同的整数且均不为0,是包含x和y之间的碳原子数的烷基链,包括本数。例如,C1-6烷基是如上所定义的烷基,其包含1-6个碳原子之间的任何数目。烷基的实例包括但不限于:甲基(即,C1烷基)、乙基(即,C2烷基)、正丙基(C3烷基)、异丙基(不同的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“烯基”(如在“烯基链”或“烯基基团”中)是指具有至少一个不饱和位点(即碳-碳sp2双键)的非支链或支链单价烃基,其中烯基包括具有“顺式”及“反式”取向或者使用替代术语“E”及“Z”取向的基团。烯基的实例包括但不限于乙烯基、烯丙基等。Cx烯基是含有x个碳原子的烯基链,其中x是非0的整数。或者,烯基将由术语“Cx-y烯基”表示;其中x和y是形成烯基链的最小和最大碳原子数。
术语“炔基”(如在“炔基链”或“炔基基团”中)是指具有至少一个不饱和位点(即碳-碳sp叁键)的非支链或支链单价烃基。实例包括但不限于乙炔基、丙炔基等。Cx炔基是含有x个碳原子的炔基链,其中x是不同于0的整数。或者,炔基将由术语“Cx-y炔基”表示;其中x和y是形成炔基链的最小和最大碳原子数。
术语“脂环族”,(如在“脂环族环”或“脂环族基团”中)是指完全饱和或含有一个或多个不饱和单元但不为芳香族的仅由碳和氢原子形成的环系统。Cx脂环族是含有x个碳原子的脂环族环,其中x是不同于0的整数。或者,脂环族环将由术语“Cx-y脂环族”表示;其中x和y是形成脂环族环的最小和最大碳原子数。合适的脂环族基团包括但不限于环烷基、环烯基和环炔基。脂肪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、降莰基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基等。术语“脂环族”也包括多环系统(例如,双环、三环或四环)。多环系统可以是桥接、稠合或螺环系统。
“桥接”环系统包括两个环,其共享两个不相邻的环原子。
“融合”环系统包括两个环,其共享两个相邻的环原子。
“螺环”环系统包括两个环,其共享一个相邻的环原子。
如本文所用,术语“环烷基”(例如“环烷基环”或“环烷基基团”中)是指仅由碳和氢原子形成的完全饱和的环系统。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、环庚烯基、降莰基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基等。环烷基环将由术语“Cx-y环烷基”表示;其中x和y是形成环烷基环的最小和最大碳原子数。术语“环烷基”还包括多环系统(例如,双环、三环或四环)。所述多环系统可以是桥接、稠合或螺环系统。
如本文所用,术语“芳基”(如在“芳环”或“芳基基团”中)是指仅由碳和氢原子形成的芳族环系统。该术语还包括多环系统(例如,双环、三环、四环等)。芳基环的实例包括但不限于苯基、萘基、茚基、芴基和蒽基。
术语“杂原子”是指氧、硫、氮、磷或硅中的一种或多种,包括氮、硫、磷或硅的任何氧化形式,并且包括任何碱性氮的季铵化形式。
术语“环原子”是指作为环的一部分的原子,例如C,N,O或S(环包括,例如,脂环族环(例如环烷基环),杂环,芳基环(例如苯环)或杂芳基环)。
术语“环杂原子”是指诸如N、O或S的原子,其为杂环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。“可取代的环原子”不包括下述环碳或氮原子,其结构显示所述环碳或氮原子已经与氢以外的一个或多个部分或取代基连接并且没有氢可用于取代。当某个环被任选地取代时,将理解为,取决于所允许的取代基的数目,它可以在其一个或一些或全部可取代的环原子上被取代。
如本文所用,术语“杂环”(或“杂环基”)(如在“杂环基团”或“杂环状环”中)是指其中一个或多个环成员是独立选择的杂原子的环系统,其是完全饱和或含有一个或多个不饱和单元但不是芳香族。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-硫吗啉代、3-硫吗啉代、4-硫吗啉代、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-咪唑烷基和5-咪唑烷基。双环杂环系统的实例包括但不限于:2-氧杂双环[2.2.2]辛基,1-氮杂双环[2.2.2]辛基。如本文所用,术语“杂环”还包括多环系统(例如,双环、三环或四环)。
如在中那样,术语“杂芳基”(或“杂芳族”)(如在“杂芳基基团”或“杂芳基环”中)是指为芳香族并且包含一个或多个杂原子的环。杂芳基环包括但不限于以下单环:2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(例如,3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(例如,5-四唑基)、三唑基(例如,2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(例如,2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基、吡嗪基、1,3,5-三嗪基。如本文所用,术语“杂芳基”还包括多环系统(例如,双环、三环或四环)。双环杂芳基环的实例包括但不限于:吲唑、吡唑并嘧啶、咪唑并吡啶等。
如本文所用,术语“烷氧基”是指如前定义的烷基,其通过氧原子连接至分子。烷氧基可以由-O-(Cx-y烷基)表示,其中x和y代表烷基链的最小和最大碳数。“烷氧基”的实例包括但不限于甲氧基(-OMe),乙氧基(-OEt)等。
如本文所用术语“卤素”或“卤代”意指F、Cl、Br或I。
术语“卤代烷基”、“卤代烯基”、“卤代脂肪族”和“卤代烷氧基”意指视情况而定可被一个或多个卤素原子取代的烷基、烯基、脂肪族或烷氧基。例如,C1-3卤代烷基可为例如,-CFHCH2CHF2,且C1-2卤代烷氧基可为例如,-OC(Br)HCHF2。
术语“氟代烷基”是指被一个或多个氟原子取代的烷基。该术语包括全氟烷基,例如–CF3和–CF2CF3。
术语“氟代烷氧基”是指被一个或多个氟原子取代的烷氧基。该术语包括全氟烷氧基,例如–OCF3和–OCF2CF3。
如本文所用术语“氰基”是指-CN或-C≡N。
如本文所述,“氨基”是指–NH2。
术语“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)-。
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。在通过化学结构和化学名称二者来提及化合物且化学结构与化学名称相冲突时,化学结构决定化合物的特性。
除非另外说明,否则在引入时通常会定义取代基,例如R1,R2和R3,并在整个说明书和所有独立权利要求中保留该定义。
当Z不是氢时,式I的化合物是用作sGC刺激剂的式II的化合物的磷酸酯前药及其药学上可接受的盐。对于式II,所有变量的定义与对于式I的定义相同。
式I的化合物在给药时表现出的体内生物活性主要是由于式II的母体化合物的存在,其是由给药后前药的裂解产生的。
术语“前药”是指作为药物前体的化合物,其在给药和吸收后通过某些代谢、酶促、水解或快速化学转化过程在体内释放药物。通常,在裂解成母体药物之前,针对靶标前药本身具有比母体化合物更低的生物活性。前药可例如通过控制药物的吸收,血液水平,代谢分布和细胞摄取来降低其毒性和不良副作用,从而改善母体药物的物理性质和/或改善整体药物功效。前药还可以降低受试者间体内药代动力学的变异性。前药还可以表现出更理想的药物特性,因此,前药还可以改善药物的可配制性或促进药物的某些给药方式的可配制性。
术语“母体药物”或“母体化合物”是指在给药前药后通过代谢、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括Na+,K+或有机胺的一价阳离子,例如伯胺,仲胺和叔胺、环胺、精氨酸、咖啡因、胆碱、二乙胺、2-二乙氨基乙醇、2-二甲基氨基乙醇、乙醇胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、组氨酸、异丙胺、赖氨酸、吗啉、哌啶、三乙胺、三甲胺、三丙胺、二异丙基乙胺等。
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,例如N,N1-二苄基乙二胺、乙二胺、哌嗪等。
化合物实施方案
在第一实施方案中,本发明的化合物由式I或其药学上可接受的盐表示。式I的变量的定义如上所述。在具体的实施方案中,对于式I的化合物,环B为苯基或含有1或2个选自N和S的环杂原子的5元或6元杂芳基环;其余变量的定义如上针对式I所述。在另具体的实施方案中,对于式I的化合物,环B是苯基或含有1或2个环氮原子的5或6元杂芳基环。
在第二实施方案中,式I的化合物由式IA、式IB、式II、式IIA或式IIB或其药学上可接受的盐表示:
其中,对于式IA、式IB、式II、式IIA和式IIB变量的定义与针对式I所述的变量相同。在具体的实施方案中,式I的化合物为式IIA或式IIB的化合物或其药学上可接受的盐。在另具体的实施方案中,式I的化合物为式IA或式IB的化合物或其药学上可接受的盐。
在第三实施方案中,对于式I、式IA、式IB、式II、式IIA或式IIB的化合物或其药学上可接受的盐,JD为氢、氯,氟、甲氧基或CN;其余变量的定义为如上所述针对式I中的定义。在具体的实施方案中,JD为氢、氯、氟或-CN。在另具体的实施方案中,JD为氟、氯或氢。在另具体的实施方案中,JD为氢。在另具体的实施方案中,JD为氟。在另具体的实施方案中,JD为氰基。在另具体的实施方案中,JD为甲氧基。在另具体的实施方案中,JD为氯。
在第四实施方案中,对于式I、式IA、式IB、式II、式IIA或式IIB的化合物或其药学上可接受的盐,每个JC独立地选自氢、C1-2烷基、C1-2烷氧基、C1-2氟代烷基、C1-2氟代烷氧基、卤素和-CN,其中每个所述C1-2烷基和C1-2烷氧基任选地和独立地取代有最多3个C1-4烷氧基、C1-4卤代烷氧基、-OH或卤素;其余变量的定义如以上第二或第三实施方案中所述。在具体的实施方案中,每个JC独立地为氢、C1-2烷基、C1-2烷氧基、C1-2氟代烷基、C1-2氟代烷氧基、卤素或-CN。在另具体的实施方案中,JC为氢或卤素。在另具体的实施方案中,JC为氟或氯。在另具体的实施方案中,JC为氢。
在第五实施方案中,式I的化合物由式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA或式VIB表示,或其药学上可接受的盐:
其中变量的定义与式I中的描述相同。在具体的实施方案中,式I的化合物由式VA、式VB、式VIA或式VIB或其药学上可接受的盐表示。在另具体的实施方案中,式I的化合物由式IIIA、式IIIB、式IVA、式IVB或其药学上可接受的盐表示。在另具体的实施方案中,式I的化合物由式VIA或式VIB或其药学上可接受的盐表示。在另具体的实施方案中,式I的化合物由式IVA或式IVB或其药学上可接受的盐表示。
在第六实施方案中,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA或式VIB的化合物或其药学上可接受的盐,环B为苯基;其余变量的定义如第一、第二、第三、第四或第五实施方案中所述。在第六实施方案中还包括,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA或式VIB或其药学上可接受的盐,环B是5或6元杂芳基环,其含有1或2个独立地选自N、O和S的环杂原子。在具体的实施方案中,环B是含有1或2个环氮原子的6元杂芳基环。
在第七实施方案中,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA或式VIB的化合物或其药学上可接受的盐,n为1、2或3,并且JB独立地为卤素或C1-6脂族基团(优选为C1-4烷基);其余变量如第六实施例中所述。在具体的实施方案中,n为1或2,并且JB独立地为卤素或C1-6脂族基团(优选为C1-4烷基)。在具体的实施方案中,n为1或2,并且每个JB为氟。在另具体的实施方案中,n为1且JB为氟。在另具体的实施方案中,n为1;并且JB是C1-4烷基。在另一个具体实施方案中,n为1;JB是甲基。在另具体的实施方案中,n为3;JB独立地为卤素或C1-4烷基。在另一个具体实施方案中,n为3;并且JB独立地为氟或甲基。
在第八实施方案中,本发明的化合物由式VIIA、式VIIIA、式VIIB或式VIIIB的化合物或其药学上可接受的盐表示:
其中变量如在第一或第六实施方案中对式I的描述。在具体实施方案中,本发明的化合物由式VIIA或式VIIB或其药学上可接受的盐表示。在另一具体实施方案中,本发明的化合物由式VIIIA或式VIIIB或其药学上可接受的盐表示。
在第九实施方案中,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA、式VIB、式VIIA、式VIIB、式VIIIA或式VIIIB的化合物或其药学上可接受的盐,R1为C1-2烷基、C1-2氟代烷基、氢或-C(O)NH2;其余变量的定义如第一、第二、第三、第四、第五、第六、第七或第八实施方案中所述。在另一具体实施方案中,R1为C1-2氟代烷基或-C(O)NH2;其余变量的定义如第一、第二、第三、第四、第五、第六、第七或第八实施方案中所述。
在第十实施方案中,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA、式VIB、式VIIA、式VIIB、式VIIIA或式VIIIB的化合物或其药学上可接受的盐,R2为C1-2氟代烷基、C1-2烷基或氢,其余变量的定义如第一、第二、第三、第四、第五、第六、第七、第八或第九实施方案中所述。在另一具体实施方案中,R2为C1-2氟代烷基,其余变量的定义如第一、第二、第三、第四、第五、第六、第七、第八或第九实施方案中所述。
在第十一实施方案中,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA、式VIB、式VIIA、式VIIB、式VIIIA或式VIIIB的化合物或其药学上可接受的盐,R1为C1-2氟代烷基或-C(O)NH2;R2为C1-2氟代烷基;其余变量的定义如第一、第二、第三、第四、第五、第六、第七或第八实施方案中所述。
在第十二实施方案中,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA、式VIB、式VIIA、式VIIB、式VIIIA或式VIIIB的化合物或其药学上可接受的盐,R1为三氟甲基或-C(O)NH2;R2为三氟甲基;其余变量的定义如第一、第二、第三、第四、第五、第六、第七或第八实施方案中所述。
在第十三实施方案中,对于式I、式IA、式IB、式II、式IIA、式IIB、式IIIA、式IIIB、式IVA、式IVB、式VA、式VB、式VIA、式VIB、式VIIA、式VIIB、式VIIIA或式VIIIB的化合物或其药学上可接受的盐,R1和R2都为氢或C1-2烷基;或R1和R2中的一个为氢,另一个为C1-2氟代烷基;其余变量的定义如第一、第二、第三、第四、第五、第六、第七或第八实施方案中所述。在一具体实施方案中,R1和R2均为氢。在另一具体实施方案中,R1和R2均为甲基。在另一具体实施方案中,R1和R2中的一个是氢,另一个是三氟甲基。
在第十四实施方案中,本发明的化合物由下式之一或其药学上可接受的盐表示:
其中变量的定义如第一或第七实施方案中所述。在具体的实施方案中,JD为氢、氯、氟或-CN。在具体的实施方案中,JD为卤素。在具体的实施方案中,JD为氢或氟。在具体的实施方案中,JD为氟。在具体的实施方案中,n为1或2且JB为卤素。
在一些实施方案中,对于在第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三或第十四实施方案中描述的化合物,Z为–P(O)(OH)2。
在一些实施方案中,对于在第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三或第十四实施方案中描述的化合物,Z为–P(O)(OH)O-M+或–P(O)(O-)2(M+);和M+为Na+、K+或有机胺的单价阳离子。在具体的实施方案中,M+为Na+。
在一些实施方案中,对于在第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三或第十四实施方案中描述的化合物,Z为–P(O)(O-)2D2+;和D2+为Ca2+、Cs2+、Zn2+、Mg2+或有机胺的二价阳离子。
在一些实施方案中,式I的化合物选自表I中列出的那些。
表I
本发明的药学上可接受的盐.
本文所述化合物的“药学上可接受的盐”包括衍生自化合物与无机酸、有机酸或碱的那些。在一些实施方案中,盐可在化合物的最终分离及纯化期间原位制备。在其他实施方案中,盐可在单独合成步骤中由化合物的游离形式制备。上文所述药学上可接受的盐及其他典型药学上可接受的盐的制备更全面描述于Berg等人,“Pharmaceutical Salts”,J.Pharm.Sci.,1977:66:1-19,其全文以引用方式并入本文中。
式I的化合物的药学上可接受的盐是可以在医学中使用的那些。但是,药学上不可接受的盐可用于制备式I的化合物或其药学上可接受的盐。
当式I的化合物为酸性时,合适的“药学上可接受的盐”是指由药学上可接受的无毒碱(包括无机碱及有机碱)制备的盐。衍生自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、二价锰盐、钾盐、钠盐、锌盐等。具体的实施方案包括铵盐、钙盐、镁盐、钾盐和钠盐。衍生自药学上可接受的有机无毒碱的盐包括以下的盐:伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代胺)、环胺、精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡萄糖胺、组氨酸、海巴明(hydrabamine)、异丙胺、赖氨酸、甲基还原葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因(procaine)、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
当式I的化合物为碱性时,盐可以从药学上可接受的无毒酸,包括无机酸和有机酸制备。这类酸包括乙酸盐、乙酸、柠檬酸、酸性磷酸盐、抗坏血酸、苯磺酸、苯磺酸盐、苯甲酸盐、苯甲酸盐、溴化物、硫酸氢盐、酒石酸氢盐、樟脑磺酸盐、氯化物、柠檬酸盐、柠檬酸、乙磺酸盐、乙磺酸、甲酸盐、富马酸盐、富马酸、龙胆酸盐、葡萄糖酸盐、葡萄糖酸、葡萄糖醛酸盐、谷氨酸盐、谷氨酸、氢溴酸、盐酸、碘化物、羟乙磺酸、异烟酸盐、乳酸盐、乳酸、马来酸盐、马来酸、苹果酸、扁桃酸、甲磺酸、甲磺酸盐、粘酸、硝酸盐、硝酸、油酸盐、草酸盐、扑酸、扑酸盐(即,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))、泛酸、泛酸盐、磷酸盐、磷酸、糖质酸盐、水杨酸盐、琥珀酸、琥珀酸盐、硫酸、硫酸盐、单宁酸盐、酒石酸盐、酒石酸、对甲苯磺酸盐、对甲苯磺酸等。具体的实施方案包括柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸和酒石酸。
除本文所述的化合物外,它们的药学上可接受的盐也可用于组合物中以治疗或预防本文鉴别出的疾病。
药物组合物和给药方法
本文所公开的化合物及其药学上可接受的盐可配制为药物组合物或“制剂”。
典型制剂通过混合式I的化合物或其药学上可接受的盐和载体、稀释剂或赋形剂制备。合适的载体、稀释剂和赋形剂是本领域技术人员公知的且包括诸如以下等材料:碳水化合物、蜡、水溶性和/或水可膨胀聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。所用的具体载体、稀释剂或赋形剂将取决于配制式I的化合物的方式和目的。溶剂通常基于本领域技术人员公认的安全(GRAS-通常认为是安全的)给药于哺乳动物的溶剂来选择。一般而言,安全溶剂是无毒水性溶剂,例如水和其他可溶于水或可与水混溶的无毒溶剂。合适的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400、PEG300)等及其混合物。制剂也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(例如肠溶或缓慢释放)、防腐剂、抗氧化剂、遮光剂、助流剂、操作助剂、着色剂、甜味剂、芳香剂、调味剂及其他已知添加剂,以提供药物(即式I的化合物或其药物组合物)的美观呈现或有助于制备药物产品(即药剂)。
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,且包括缓冲剂,例如磷酸盐、柠檬酸盐及其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化六甲双铵;苯扎氯铵、苄索氯铵;苯酚、丁醇或苄醇;对羟基苯甲酸烷基酯,例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);蛋白质,例如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,例如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,例如EDTA;糖,例如蔗糖、甘露醇、海藻糖或山梨醇;盐形成抗衡离子,例如钠;金属络合物(例如,Zn-蛋白质络合物);和/或非离子表面活性剂,例如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。活性药物成分也可以包埋在制备的微胶囊中,例如,通过凝聚技术或通过界面聚合,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;所述微胶囊呈胶体药物递送系统(例如脂质体、白蛋白微球体、微乳剂、纳米颗粒和纳米胶囊)形式或呈粗乳状液形式。所述技术公开于Remington's:The Science and Practice of Pharmacy,第21版,University of the Sciences in Philadelphia编辑,2005(下文称“Remington’s”)中。
制剂可使用常规溶解和混合过程来制备。如本文所用术语“治疗有效量”意指研究人员、兽医、医生或其他临床医生正在寻求的在组织、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。化合物的治疗有效量将由这些考虑决定,并且是改善、治愈或治疗该疾病或其一种或多种症状所必需的最小量。
术语“给药(administer)”、“给药(administering)”或“给药(administration)”在提及本发明的化合物、组合物或剂型时意指将化合物引入需要治疗的受试者或患者的系统中。当本发明化合物是与一种或多种其他活性药剂组合提供时,“给药”及其变体各自应理解为包括同时和/或顺序引入该化合物和其他活性剂。
本文所述的组合物可以全身或局部方式给药,例如:经口(包括但不限于固体剂型,包括硬胶囊或软胶囊(例如明胶胶囊),片剂,丸剂,散剂,舌下片剂,糖锭剂,锭剂和颗粒剂;和液体剂型,包括但不限于药学上可接受的乳剂,微乳剂,水溶液或油溶液,悬浮液,糖浆剂和酏剂,通过吸入(例如利用气雾剂、气体、吸入器、雾化器等)、至耳(例如使用滴耳剂)、经局部(例如使用乳膏剂、凝胶、吸入剂、擦剂、洗剂、软膏剂、贴剂、糊剂、粉剂、溶液剂、喷雾剂、经皮贴剂等)、经眼(例如利用滴眼剂、眼用凝胶、眼用软膏剂)、经直肠(例如使用灌肠剂或栓剂)、经鼻、经颊、经阴道(例如使用冲洗器、宫内设备、阴道药栓、阴道环或片剂等)、通过滴耳剂、通过植入型药盒等或肠胃外,其取决于所治疗疾病的严重程度和类型。如本文所用术语“肠胃外”包括但不限于皮下、静脉内、肌内、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,将所述组合物经口、经腹膜内或经静脉内给药。
用于口服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来制备。
在所述固体剂型中,将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/或以下物质混合:a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸,b)粘合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,c)保湿剂,例如甘油,d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠,e)溶液阻滞剂,例如石蜡,f)吸收促进剂,例如季铵化合物,g)润湿剂,例如鲸蜡硬脂醇和单硬脂酸甘油酯,h)吸收剂,例如高岭土及膨润土,和/或i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物。片剂可无包衣或可通过已知技术(包括微囊化)包衣以遮蔽令人不快的味道或延迟在胃肠道中的崩解和吸收并由此提供较长时段的持续作用。例如,可以使用诸如单硬脂酸甘油酯或单独或与蜡一起使用的二硬脂酸甘油酯的延时材料。可以使用水溶性掩味材料,例如羟丙基甲基纤维素或羟丙基纤维素。
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(例如水或其他溶剂)、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及其混合物。除惰性稀释剂外,经口组合物也可包括佐剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂及芳香剂。
口服组合物(固体或液体)也可包含赋形剂和佐剂如分散剂或润湿剂,例如天然磷脂(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)、环氧乙烷与长链脂肪族醇的缩合产物(例如,十七烷基乙氧基鲸腊醇(heptadecaethyleneoxycetanol))、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);乳化剂和悬浮剂,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、黄蓍树胶和阿拉伯树胶;甜味剂、调味剂及芳香剂;和/或一种或多种防腐剂(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、一种或多种调味剂及一种或多种甜味剂(例如蔗糖或糖精)。
药物组合物也可通过鼻气雾剂或吸入来给药。所述组合物是根据药物制剂领域熟知的技术制备且可制备为盐水溶液,其采用苄醇或其他合适的防腐剂、吸收促进剂(用于增强生物利用度)、氟碳化合物和/或其他常规增溶剂或分散剂。适于肺内或经鼻给药的制剂具有例如介于0.1微米至500微米范围内的粒径(包括颗粒的范围在0.1和500微米之间,以微米为单位,增量为例如0.5、1、30、35微米等),所述制剂通过穿过鼻通道快速吸入或通过穿过口到达肺泡囊进行吸入来给药。
本文所述的药物组合物也可经局部给药,尤其在治疗靶标包括可容易地通过局部给药到达的区域或器官(包括眼、耳、皮肤或下肠道的疾病)时。易于制备针对这些区域或器官中的每一个的合适的局部制剂。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可能需要的缓冲剂混合。
对于局部给药,可将药物组合物配制于含有悬浮或溶解于一种或多种载体中的活性组分的合适的软膏中。用于局部给药本发明化合物的载体包括但不限于矿物油、液体石蜡、白软石蜡、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,可将药物组合物配制于含有悬浮或溶解于一种或多种药学上可接受的载体中的活性组分的合适的洗剂或乳膏剂中。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、苄醇和水。
或者,可使用水包油乳膏基质将活性成分配制于乳膏剂中。如果需要,乳膏基质的水相可包括多元醇,即具有两个或更多个羟基的醇,例如丙二醇、丁烷1,3-二醇、甘露醇、山梨糖醇、甘油及聚乙二醇(包括PEG 400)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。所述皮肤渗透促进剂的实例包括二甲亚砜及相关类似物。
使用式I的化合物制备的乳液的油相可以以已知方式由已知成分构成。尽管该相可仅包含乳化剂(emulsifier)(原本称为乳化剂(emulgent)),但其理想地包含至少一种乳化剂与脂肪或油或与脂肪及油二者的混合物。可包括亲水性乳化剂以及用作稳定剂的亲脂性乳化剂。在一些实施方案中,乳化剂包括油和脂肪二者。含有或不含稳定剂的乳化剂一起构成所谓的乳化蜡,且该蜡与油和脂肪一起构成所谓的乳化软膏基,其形成乳膏剂制剂的油性分散相。适用于配制式I的化合物的乳化剂和乳液稳定剂包括TweenTM-60、SpanTM-80、鲸蜡硬脂醇、苄醇、肉豆蔻醇、单硬脂酸甘油酯及月桂基硫酸钠。
另外,本发明包括使用经皮贴片,其具有提供化合物控制递送至身体的附加优点。所述剂型可通过将化合物溶解或分散于适当介质中来制备。也可使用吸收促进剂来增加化合物穿过皮肤的通量。可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中来控制速率。
对于眼部使用,可将药物组合物配制为等渗、pH调节的无菌盐水中的微粉化悬浮液,或优选地配制为等渗、pH调节的无菌盐水中的溶液,含有或不含防腐剂,例如苯扎氯铵。或者,对于眼部使用,可将药物组合物配制于软膏(例如石蜡)中。为治疗眼或其他外部组织(例如,口及皮肤),制剂可以作为局部软膏剂或乳膏剂施用,其含有例如0.075至20%w/w的量的活性成分。当以软膏剂配制时,活性成分可与基于油的石蜡或水可混溶性软膏基质一起使用。
用于直肠或阴道给药的组合物优选的为栓剂,其可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(例如可可脂、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为固体但在体温下为液体,且由此可在直肠或阴道腔内融化并释放活性化合物。适于阴道给药的其他制剂可呈现为子宫托、棉塞、乳膏剂、凝胶、糊剂、泡沫或喷雾剂。
本文所述组合物的无菌可注射形式(例如用于肠胃外给药)可为水性或油性悬浮液。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(包括在上述段落中描述的那些)。无菌可注射制剂也可为无毒肠胃外可接受稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如为1,3-丁二醇中的溶液形式。可以使用的可接受的媒介和溶剂包括水,林格氏溶液和等渗氯化钠溶液。另外,通常采用无菌不挥发性油作为溶剂或悬浮介质。出于此目的,可采用任一温和不挥发性油,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,例如药学上可接受的天然油类,例如植物油,例如花生油,橄榄油,芝麻油或椰子油,尤其呈它们的聚氧乙烯化形式,或矿物油(如液体石蜡)。这些油性溶液或悬浮液也可含有长链醇稀释剂或分散剂,例如羧甲基纤维素或类似分散剂,其通常用于配制包括乳液及悬浮液在内的药学上可接受的剂型。也可将其他常用表面活性剂(例如吐温类、司盘类及通常用于制备药学上可接受的固体、液体或其他剂型的其他乳化剂或生物利用度增强剂)用于可注射制剂的目的。所述油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡硬脂醇。可添加甜味剂(例如,上文所述的那些)及调味剂以提供适口的口服制剂。这些组合物可通过添加抗氧化剂(例如,丁基化羟基茴香醚或α-生育酚)保存。
在另一个方面,式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。兽医载体是可用于给药组合物目的的材料且可为原本呈惰性的固体、液体或气态材料。在兽医领域,与活性成分相容。这些兽医组合物可以肠胃外、经口或通过任何其他期望途径给药。
治疗方法
在另一方面,本发明还提供在需要的受试者中治疗或预防疾病的方法,包括向受试者单独或以组合疗法的形式给药治疗有效量的式I化合物,或其药学上可接受的盐;其中所述疾病为受益于sGC刺激或受益于NO或cGMP或二者的浓度增加,或受益于NO通路的上调的疾病。本发明还提供在需要的受试者中治疗疾病的方法,包括向受试者单独或以组合疗法的形式给药包含式I化合物或其药学上可接受的盐的药物组合物或包含该药物组合物的剂型;其中所述疾病为受益于sGC刺激或受益于NO或cGMP或二者的浓度增加,或受益于NO通路的上调的疾病。
在一些实施方案中,本文所公开的化合物是sGC刺激剂,其可用于预防和/或治疗特征在于NO的生物利用度和/或对于NO的敏感性具有不期望的降低的疾病,例如与氧化性应激或硝化应激病症相关的那些。
cGMP浓度增加会导致血管扩张,抑制血小板聚集和粘附、抗高血压作用、抗重塑作用、抗凋亡作用、抗炎、抗纤维化作用、代谢作用和神经元信号传导作用。因此,sGC刺激剂可用于治疗和/或预防多种疾病。
可以通过给药本发明的sGC刺激剂(例如式I和表I的化合物及其药学上可接受的盐)治疗和/或预防的特定疾病或病症包括但不限于:
无β脂蛋白血症、失弛缓症(例如,食管失弛症)、急性呼吸窘迫综合征(ARDS)、粘连性囊炎、与年龄有关的学习和记忆障碍、与年龄有关的记忆丧失、酒精中毒、秃顶或脱发、高原反应、阿尔茨海默病(包括临床前阿尔茨海默氏病、轻度至中度阿尔茨海默病和中度至重度阿尔茨海默病)、肌萎缩性侧索硬化症(ALS或Lou Gehrig病)、肛裂、动脉瘤、心绞痛(例如,稳定或不稳定型心绞痛、变异型心绞痛、普林兹迈托心绞痛(Prinzmetal’s angina)、微血管性心绞痛)、焦虑症或焦虑障碍、精胺基琥珀酸尿症、动脉和静脉血栓形成、关节炎、亚斯伯格症候群(Asperger's syndrome)、哮喘和哮喘性疾病、共济失调、毛细管扩张、动脉粥样硬化(例如,与内皮损伤、血小板和单核细胞粘附和聚集、平滑肌增生或迁移相关的动脉粥样硬化)、萎缩性阴道炎、注意缺陷障碍(ADD)和注意缺陷性多动症(ADHD)、自闭症和自闭症谱系中的障碍、良性前列腺增生症(BPH)或肥大或肿大、双相情感障碍、膀胱出口梗阻、膀胱疼痛综合征(BPS)、眼睑炎、骨骼和碳水化合物的代谢紊乱、骨愈合(例如,破骨性骨重塑、破骨细胞吸收、新骨形成后的骨愈合)、脑动脉瘤、脑缺氧、癌症转移、脑淀粉样蛋白血管病(CAA)或嗜刚果红血管病(Congophilic angiopathy)、脑常染色体显性动脉病伴皮质下梗死和白质脑病(CADASIL或CADASIL综合征)、脑灌注、脑小血管疾病、脑血管痉挛、化疗头、童年瓦解性障碍、慢性支气管炎、慢性疲劳、慢性创伤脑部病变(CTE)、纤毛疾病、硬化(例如,肝硬变、与慢性肝病相关的肝硬化、原发性胆汁性肝硬化)、中枢神经系统疾病相关的性功能障碍、中枢神经系统疾病相关的睡眠障碍、亨廷顿舞蹈病(Huntington's Disease)相关的认知缺陷、认知功能障碍、认知受损(例如,血管性认知受损、轻度认知受损、糖尿病相关的认知受损、多发性硬化症相关的认知受损、阻塞性睡眠呼吸暂停相关的认知受损、精神分裂症相关的认知受损(CIAS)、镰状细胞病相关的认知受损、脑震荡、先天性肌无力综合征、结缔组织病、脑梗塞的后果(脑卒中)、创伤患者血液替代品的保存、CREST综合征、克罗恩病、囊性纤维化病(CF)、妄想症、痴呆(例如,血管性痴呆、中风后痴呆、路易体痴呆、额叶退化病变痴呆、额颞叶变性痴呆、皮质基底节变性痴呆、Creutzfeldt-Jakob痴呆、HIV痴呆、多发性梗塞性痴呆、术后痴呆、要害单发性痴呆、HIV相关痴呆(包括无症状神经认知障碍(ANI)、轻度神经认知障碍(MND)、HIV相关痴呆(HAD,也称为AIDS痴呆复合症[ADC]或HIV脑病)、早老痴呆症(轻度认知障碍、MCI)、混合性痴呆、宾斯旺格痴呆(Binswanger'sdementia)(皮质下动脉硬化性脑病)、帕金森氏痴呆症)、脱髓鞘、抑郁、抑郁性障碍、皮肌炎、糖尿病性血管病、糖尿病性黄斑水肿、糖尿病性微血管病变、糖尿病性溃疡或伤口(例如,糖尿病足溃疡)、与代谢综合征相关或关联的疾病(例如,肥胖、糖尿病、胰岛素抗药性、空腹血糖过高、空腹胰岛素过高、血脂过高)、涉及神经递质下调的疾病、涉及脑血流受损的疾病、涉及神经变性受损的疾病、涉及突触功能受损的疾病、涉及神经炎症的疾病、涉及神经毒性的疾病、男性和女性泌尿生殖系统器官疾病(良性和恶性)、有学习和记忆障碍的儿童的注意力障碍、唐氏综合症、吸毒成瘾、药物引起的精神病、干眼症、杜兴氏肌营养不良症、掌腱膜挛缩症、运动障碍(例如,急性运动障碍、慢性或迟发性运动障碍、非运动性运动障碍、左旋多巴诱发的运动障碍(LID))、痛经(例如,原发性痛经、继发性痛经)、性交困难、吞咽困难、张力障碍(例如,全身性张力障碍、灶性张力障碍、节段性张力障碍、性张力障碍、中度张力障碍、急性张力障碍反应、遗传性或原发性张力障碍)、水肿、电解质紊乱(例如,高钾血症、低钠血症)、肺气肿、子宫内膜异位症、内皮功能障碍或与内皮功能障碍相关的损伤以及疾病、勃起功能障碍、食管失弛症、法布里病(Fabry Disease)、女性性功能障碍相关的疾病(例如,女性性唤起功能障碍)、纤维肌痛、纤维化(例如,心内膜纤维化、心房纤维化、心脏间质纤维化、心脏纤维化、肺纤维化、眼纤维化、皮肤纤维化、肠纤维化、肾或肾脏纤维化、间质性肾纤维化、肺纤维化、特发性肺纤维化、肺进行性大规模纤维化、肝纤维化、纵隔纤维化、腹膜后纤维化、关节纤维粘连、骨髓纤维化(bone marrow fibrosis)、骨髓纤维变性(myelofibrosis)、骨髓纤维瘤、放射性诱导的纤维化、胰囊性纤维化)、脆性X染色体综合征、功能性消化不良、胃肌轻瘫、高雪病(Gaucher Disease)、一般性注意力障碍、一般性精神病、青光眼、成胶质细胞瘤、肾小球病(例如,肾小球肾炎、急性肾小球肾炎、肾小球硬化、局灶性节段性肾小球硬化)、肉芽肿、头部受伤、听力障碍(例如,部分听力损失、全部听力损失、部分耳聋、完全耳聋、噪声引起的听力损失)、心脏疾病(例如,左室心肌重构、左心室收缩功能障碍、缺血性心肌病、扩张型心肌病、酒精性心肌病、储存型心肌病(storagecardiomyopathies)、先天性心脏缺陷、冠状血流减少、舒张或收缩功能障碍、冠状供血不足、急性冠脉综合征、冠状动脉疾病、心律不齐、心室前负荷降低(reduction ofventricular preload)、心脏肥大、右心肥大、房性节律和室性节律失常以及心脏传导障碍、I-III度房室传导阻滞(AVB I-III)、室上性快速性心律失常、心室早发性收缩、房颤、房扑、室颤、室扑、室性快速型心律失常、尖端扭转型室性心动过速、房性和室性期外收缩、房室交接性早搏(AV-junction extrasystoles)、病窦综合征、房室结折返性心动过速、午-帕-怀三氏综合征(Wolff-Parkinson-White syndrome)、心肌机能不全、慢性、急性或病毒性心肌炎、心源性休克、心脏重构)、心力衰竭(HF;例如:射血分数保留型心衰(HFPEF)、射血分数降低型心衰(HFREF)、急性心力衰竭、慢性心力衰竭、现有慢性心力衰竭的急性期(心衰恶化)、短暂性心力衰竭、急性后心力衰竭、收缩性心力衰竭、舒张性心力衰竭、充血性心力衰竭、急性失代偿性心力衰竭、右心室衰竭、总心力衰竭、高输出量性心力衰竭、具有瓣膜缺损的心力衰竭、糖尿病性心力衰竭、心力衰竭/心肺综合征、右心力衰竭)、高浓度的纤溶酶原激活物抑制剂1(PA-1)、高水平的纤维蛋白原和低密度DLD、组织细胞增多症X、亨廷顿舞蹈病或舞蹈病(HD)、高氨血症及相关疾病、高血压(例如,动脉高血压、顽固性高血压、糖尿病性高血压、特发性高血压、原发性高血压、继发性高血压、妊娠高血压、门静脉高血压、全身性高血压、先兆子痫、急慢性冠状血压升高)、张力亢进、肥厚性瘢痕、活动减退的性苏醒障碍(hypoactive sexual arousal disorder)、灌注不足、阳痿、肠炎(例如,克罗恩病、溃疡性结肠炎)、由脑部疟疾引起的炎症、由传染病引起的炎症、围手术期护理中的炎症反应、血小板聚集、智力障碍、间歇性跛行、间质性膀胱炎(IC)、透析中低血压、缺血(例如,脑缺血、心肌缺血、血栓栓塞性缺血、严重肢体缺血)、瘢痕疙瘩、肾脏疾病(例如,慢性肾脏疾病、急慢性肾功能衰竭、急慢性肾功能不全、肾功能不全的后遗症、与肺水肿相关的肾功能不全、与心力衰竭相关的肾功能不全、与尿毒症或贫血相关的肾功能不全、原发性肾脏疾病、先天性肾脏疾病、多囊性肾脏疾病进展、肾脏移植排斥反应、免疫复合物诱导的肾脏疾病、肌酐和/或水的排泄异常减少、尿素、氮、钾和/或肌酐的血浓度异常升高、肾酶活性改变(例如,谷氨酰合成酶)、尿渗透压或尿液量改变、微量白蛋白尿增加、巨白蛋白尿、肾小球和小动脉病变、肾小管扩张、高磷酸盐血症、血管性肾脏疾病、肾囊肿、心力衰竭导致的肾水肿)、科萨科夫精神病(Korsakoff psychosis)、白细胞活化、左旋多巴引起的成瘾行为、地衣硬化、脂质相关疾病(例如,肥胖过度、皮下脂肪过多、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)水平适度升高、高甘油三酯血症、高甘油酯血症、高脂蛋白血症、谷固醇血症、脂肪肝疾病、肝脂肪变性或肝脏中脂质异常蓄积、心脏、肾脏或肌肉的脂肪变性、谷固醇血症、黄瘤病、丹吉尔病(Tangierdisease))、肝病(例如,血管性肝病、肝星状细胞活化、肝纤维胶原蛋白和总胶原蛋白积累、坏死性炎性和/或免疫性肝病、与肉芽肿性肝病相关的胆汁淤积性肝病、与肝恶性肿瘤相关的胆汁淤积性肝病、与妊娠肝内胆汁淤积相关的胆汁淤积性肝病、与肝炎相关的胆汁淤积性肝病、与败血症相关的胆汁淤积性肝病、与药物或毒素相关的胆汁淤积性肝病、与移植物抗宿主病相关的胆汁淤积性肝病、与肝移植后相关的胆汁淤积性肝病、与胆总管结石病相关的胆汁淤积性肝病、与胆管肿瘤相关的胆汁淤积性肝病、与胰腺癌相关的胆汁淤积性肝病、与Mirizzi综合征相关的胆汁淤积性肝病、与艾滋病相关的胆汁淤积性肝病、胆管病变、与寄生虫相关的胆汁淤积性肝病、与血吸虫病相关的胆汁淤积性肝病、肝炎、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪肝(NAFLD)、肝血管闭塞性疾病(VOD)、肝窦阻塞综合征(SOS)、肝性脑病)、局部血栓形成、下尿道综合征(LUTS)、腰椎管狭窄、狼疮性肾炎、狼疮或系统性红斑狼疮、微量白蛋白尿、微循环异常、偏头痛、轻度神经性认知障碍(MND)、硬斑病、烟雾病、多发性腔隙性脑梗塞、多器官功能障碍综合征(MODS)、多器官衰竭(MOF)、多发性硬化(MS、包括临床孤立综合征(CIS)、复发缓解型MS(RRMS)、原发性进行性MS(PPMS)、继发进行性MS(SPMS))、多系统萎缩(MSA)、心肌梗塞或心脏病发作(例如,ST段抬高型心肌梗塞、非ST段抬高型心肌梗塞、陈旧性心肌梗塞)、近视脉络膜新生血管形成、痣、麻醉品依赖、肾病(例如,糖尿病肾病、非糖尿病肾病、肾炎、毒素引起的肾病、造影剂诱发的肾病、糖尿病性或非糖尿病性肾硬化、肾病综合征、肾盂肾炎、肾原性纤维化)、神经退行性疾病、神经源性膀胱和尿失禁、神经炎症、与一氧化氮产生减少相关的神经系统疾病、神经肌肉疾病(例如,迪谢内肌营养不良(Duchenne muscular dystrophy)(DMD)、贝克肌营养不良(Becker musculardystrophy)(BMD)、肢带肌营养不良、远端肌病、I型和II型营养不良性肌强直、面部-肩胛-腓骨肌营养不良、常染色体和X染色体连锁埃-德二氏肌营养不良(autosomal and X-linked Emery-Dreifuss muscular dystrophy)、眼咽肌营养不良、肌萎缩性侧索硬化症、脊髓性肌萎缩症(SMA))、视神经脊髓炎、神经病(例如,周围神经病、自主神经病、中枢神经系统神经病、化学疗法诱发的神经病、糖尿病性神经病、疼痛性神经病、神经性疼痛、非疼痛性神经病、疼痛性糖尿病性神经病变、非疼痛性糖尿病性神经病变、与中枢神经系统疾病相关的神经病(例如,多发性硬化症、MS)、辐射诱发的神经病)、带状疱疹相关的神经性疼痛、脊柱手术相关的神经性疼痛)、强迫症(OCD)、阻塞性血栓性血管炎、阻塞性尿路病变、嗜酸细胞性筋膜炎、骨质疏松症、膀胱过度活动症、疼痛(例如,急性疼痛、中枢性疼痛综合征、炎症性疼痛、术后疼痛、持续性痛、内脏痛、跛行痛、孤儿病痛症(例如,乙酰唑胺反应性肌强直、自体红细胞致敏综合征、常染色体显性遗传夏科-马里-图斯病2V型(Autosomaldominant Charcot-Marie-Tooth disease type 2V)、常染色体显性遗传中介的夏科-马里-图斯病伴神经性疼痛、常染色体隐性遗传肢带型肌营养不良症2A型、离子信道疾病相关的先天性疼痛不敏感,需要椎管内镇痛的慢性疼痛、复杂性区域疼痛综合征、复杂性区域疼痛综合征1型、复杂性区域疼痛综合征2型、伴有多汗症的先天性疼痛不敏感、伴有严重智力障碍的先天性疼痛不敏感、先天性疼痛不敏感-多汗综合征、伴有疼痛性裂缝的弥漫性掌跖角化病、家族性阵发性疼痛综合征、主要是下肢受累的家族性阵发性疼痛综合征、主要累及上半身的家族性阵发性疼痛综合征、遗传性疼痛性胼胝、遗传性感觉神经和自主神经病4型、遗传性感觉神经和自主神经病5型、遗传性感觉神经和自主神经病7型、间质性膀胱炎、疼痛性眼眶和系统性神经纤维瘤-马凡习惯综合征、阵发性极度疼痛疾病、持续性特发性面部疼痛、卡配因的定性或定量缺陷、Tolosa-Hunt综合征))、胰腺炎、恐慌症、帕金森氏病、帕金森叠加综合征、帕金森氏吞咽困难、病理性进食障碍、骨盆疼痛、周围血管疾病(例如,外周动脉疾病、外周动脉闭塞性疾病、外周血栓塞、外周血灌注障碍)、腹膜炎、广泛性发育障碍、佩罗尼氏病、皮克综合征(Picks syndrome)、多发性软骨炎、多发性肌炎、疱疹后神经痛、创伤后颅脑损伤、创伤后应激障碍(PTSD)、早泄、进行性核麻痹、前列腺肥大、肺部疾病(例如,丛生性肺动脉病、支气管收缩或肺支气管收缩、肺血管疾病、慢性阻塞性肺疾病(COPD)、肺毛细血管血管瘤病、淋巴管瘤病和压缩性肺血管(例如,由于腺病、肿瘤或纤维化性纵隔炎导致的)、肺血管重构、肺张力过高)、肺性高血压(PH,例如,肺动脉高血压(PAH)、原发性PH、继发性PH、散发性PH、毛细血管前PH、特发性PH,与左心室疾病相关的PH、与HIV相关的PH、与SCD相关的PH、与血栓栓塞相关的PH(慢性血栓栓塞性PH或CTEPH)、与结节病相关的PH、与慢性阻塞性肺疾病相关的PH、与急性呼吸窘迫综合征相关的PH(ARDS)、与急性肺损伤相关的PH、与α-1-抗胰蛋白酶缺乏相关的PH(AATD)、与肺气肿相关的PH(例如,吸烟引起的肺气肿)、与肺部疾病相关的PH、与低氧血症相关的PH、与硬皮病相关的PH、与囊性纤维化(CF)相关的PH、与左心室功能不全相关的PH、与低氧血症相关的PH、PH(WHO组I、II、III、IV和V)、与二尖瓣疾病相关的PH、与心包炎相关的PH、与缩窄性心包炎相关的PH、与主动脉狭窄相关的PH、与扩张型心肌病相关的PH、与肥厚型心肌病相关的PH、与限制性心肌病相关的PH、与纵隔纤维变性相关的PH、与肺纤维化相关的PH、与肺静脉畸形引流相关的PH、与肺静脉闭塞性疾病相关的PH、与肺血管炎相关的PH、与胶原血管疾病相关的PH、与先天性心脏病相关的PH、与肺静脉高血压相关的PH、与间质性肺疾病相关的PH、与睡眠障碍性呼吸相关的PH、与慢性气流阻塞相关的PH、与阻塞性睡眠呼吸暂停相关的PH、与中枢性睡眠呼吸暂停相关的PH、与混合性睡眠呼吸暂停相关的PH、与肺泡通气不足相关的PH、与长期暴露于高原相关的PH、与新生儿肺部疾病相关的PH、与肺泡-毛细血管发育不良相关的PH、与镰状细胞病相关的PH、与其他凝血功能障碍相关的PH、与慢性血栓栓塞相关的PH)、神经根病、雷诺氏病、雷诺氏综合征(原发性或继发性)、难治性癫痫、Renpenning综合征、再灌注损伤(例如,缺血-再灌注损伤、与器官移植相关的缺血-再灌注)、再狭窄(例如,溶栓治疗后、经皮经腔血管成形术后(PTA)、腔内冠状动脉成形术后(PTCA)、心脏移植术后或搭桥手术后再狭窄)、视网膜病变(例如,糖尿病性视网膜病变、非糖尿病性视网膜病变、非增生性糖尿病视网膜病变、增生性玻璃体视网膜病变、周围性视网膜变性、视网膜静脉阻塞)、Rhett病、类风湿和风湿病(例如,关节炎、类风湿关节炎)、结节病、肉状瘤、血吸虫病、情感性分裂症、精神分裂症、伴有痴呆的精神分裂症、硬皮病(例如,局部性硬皮病或局限性硬皮病、全身性硬皮病)、硬化症(例如,肾硬化、进行性硬化、肝硬化、原发性硬化性胆管炎、胃肠道硬化、海马硬化、局灶性硬化、原发性外侧硬化、骨硬化、耳硬化、动脉粥样硬化、结节性硬化、全身性硬化)、败血症或败血性休克或过敏性休克、镰状细胞性贫血、镰状细胞性疾病、干燥综合征(Sjogren’s syndrome)、睡眠觉醒障碍、Sneddon综合征、痉挛(例如,冠状动脉痉挛、血管痉挛、外周动脉痉挛)、脊髓损伤、脊髓肌肉萎缩、脊髓半脱位、脊髓小脑共济失调、Steelee-Richardson-Olszewski病(进行性核上麻痹)、中风、蛛网膜下腔出血、皮层下动脉硬化性脑病、晕厥、Tau病、紧张、丘脑变性、血栓栓塞性或血栓形成性疾病、短暂性脑缺血发作(TIA)、外伤性脑损伤、肾小管间质疾病、溃疡、子宫纤维瘤、阴道萎缩、瓣膜缺损(例如,二尖瓣狭窄、二尖瓣回流、二尖瓣闭锁不全或二尖瓣关闭不全、主动脉瓣狭窄、主动脉瓣关闭不全、三尖瓣关闭不全、肺动脉瓣狭窄、肺动脉瓣关闭不全、联合瓣膜缺陷)、脑血管疾病、心脏和肾脏并发症导致的血管疾病、血管渗漏或通透性、血管炎(例如,血栓性血管炎、闭塞性血栓性血管炎、川崎病、动脉炎、主动脉炎)、血管阻塞危象、抗移植失败、湿性老年黄斑变性和威廉综合症(Williams syndrome)。
如本文所用,术语“疾病”是指任何身体部位,器官或系统的正常结构或功能的任何偏离或中断,其由一组症状和体征的特征集以及其可能是已知的或未知的病因、病理和预后来体现。术语疾病包括其他相关术语,例如病症和病状(或医学病状)以及综合征,它们被定义为由单一原因引起的症状的组合,或者通常一起出现以构成不同的临床现象的单一原因引起的症状的组合。在一些实施方案中,术语疾病是指sGC,cGMP和/或NO介导的医学或病理疾病。
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(例如禽类,例如鸡、鹌鹑或火鸡,或哺乳动物),具体而言“哺乳动物”,包括非灵长类动物(例如,牛、猪、马、绵羊、兔、天竺鼠、大鼠、猫、狗及小鼠)及灵长类动物(例如,猴、黑猩猩及人类),且更具体而言人类。在一些实施方案中,受试者是非人类动物,例如农场动物(例如,马、牛、猪或绵羊)或伴侣动物或宠物(例如,狗、猫、大鼠、小鼠、仓鼠、沙鼠、天竺鼠或兔)。在一些实施方案中,受试者为人类。
本发明还提供治疗受试者的上述疾病中的一种的方法,其包括向需要治疗的受试者给药治疗有效量的式I的化合物或其药学上可接受的盐。或者,本发明提供式I的化合物或其药学上可接受的盐,其用于治疗需要治疗的受试者的所述疾病中的一种。本发明还包括式I的化合物或其药学上可接受的盐在制备用于治疗需要治疗的受试者中的上述疾病之一的药物中的用途。本发明进一步提供制备或制造可用于治疗所述疾病中的一种的药物的方法,其包含使用式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,且包括但不限于细胞培养物或其提取物;自哺乳动物获得的活检材料或其提取物;血液、唾液、尿液、粪便、精液、泪液、淋巴液、眼液、玻璃状液、脑脊髓液(CSF)或其他体液或其提取物。
针对疾病的“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”是指缓和或废除疾病的病因和/或效应。在一个实施方案中,术语“治疗(treat)”、“治疗(treatment)”及“治疗(treating)”是指减轻或改善疾病的进展、严重程度和/或持续时间、或改善该疾病的一个或多个症状(即“管控”但不“治愈”该疾病)。在具体实施例中,术语“治疗(treat)”、“治疗(treatment)”及“治疗(treating)”是指改善疾病的至少一个可量测物理参数。在其他实施方案中,术语“治疗(treat)”、“治疗(treatment)”及“治疗(treating)”是指在身体上通过例如稳定可辨别症状或在生理上通过例如稳定生理参数或二者来抑制疾病的进展。
本文所述的化合物及药物组合物可单独或以组合疗法使用来治疗由sGC、cGMP和/或NO介导、调控或影响的疾病。
在其他实施方案中,本发明提供刺激生物样品中的sGC活性的方法,其包括使该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。所述目的的实例包括但不限于生物分析和生物样本储存。
组合疗法
如本文所用,术语“组合”(如短语“组合疗法”中)或“共同给药”可互换使用,以指使用一种以上的疗法(例如,一种或多种治疗剂)。该术语的使用不限制对受试者给药疗法(例如,治疗剂)的顺序。
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组合使用。对于与一种以上活性剂的组合治疗(其中活性剂呈单独剂量制剂形式),活性剂可单独或以组合形式给药。另外,一种要素的给药可在给药另一药剂之前、同时或之后。
当与其他药剂用于组合疗法时,本文所述的化合物和药物组合物以及其他一种或多种药物的“治疗有效量”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量进行调整。在未明确注明量的情形下,应假设为有效量。
在一些实施方案中,共同给药或组合疗法包括以基本上同时的方式给药第一量和第二量的化合物,例如在单一药物组合物(例如,具有固定比例的第一和第二量的胶囊或片剂)中或针对每一种药剂的多个单独胶囊或片剂中。另外,该共同给药也包括以相继方式以任意顺序使用每种化合物。
当共同给药涉及单独给药第一量的式I化合物及第二量的另一治疗剂时,该化合物是在时间上足够接近地给药以具有期望治疗效果。例如,可产生期望治疗效果的每次给药之间的时间段可介于数分钟至数小时范围内,且可根据每个化合物的性质(例如功效、溶解度、生物利用度、血浆半衰期和动力学特征)来确定。例如,式I化合物和第二治疗剂可以任意顺序在彼此相隔约24小时内、彼此相隔约16小时内、彼此相隔约8小时内、彼此相隔约4小时内、彼此相隔约1小时内或彼此相隔约30分钟内给药。
可与式I化合物或其药学上可接受的盐组合以单独或在同一药物组合物中的方式给药的其他治疗剂的实例包括但不限于::
(1)内皮源释放因子(EDRF)或NO气体。
(2)NO供体,例如亚硝基硫醇、亚硝酸盐、斯德酮亚胺(sydnonimine)、NONOate、N-亚硝胺、N-羟基亚硝胺、亚硝亚胺、硝基酪氨酸、二氮杂环丁烯二氧化物、噁三唑5-亚胺、肟、羟胺、N-羟基胍、羟基脲或氧化呋咱。这些类型的化合物的一些实例包括:三硝酸甘油酯(也称为GTN、硝化甘油、硝酸甘油及三硝酸甘油),其是甘油的硝酸酯;硝普钠(SNP),其是其中一氧化氮分子与铁金属配位形成四方双锥络合物;3-吗啉代-斯得酮亚胺(SIN-1),其是由吗啉和斯德酮亚胺的组合形成的两性离子化合物;S-亚硝基-N-乙酰基青霉胺(SNAP),其是含有亚硝基硫醇官能基的N-乙酰化氨基酸衍生物;二亚乙基三胺/NO(DETA/NO),其是一氧化氮共价连接至二亚乙基三胺的化合物;乙酰基水杨酸的间-硝氧甲基苯基酯。一些所述类别的NO供体的更具体实例包括:经典硝基血管扩张剂,例如有机硝酸酯和亚硝酸酯,包括硝酸甘油、亚硝酸异戊酯、二硝酸异山梨醇酯、5-单硝酸异山梨醇酯和尼可地尔(nicorandil);异山梨醇 3-吗啉代-斯得酮亚胺;林西多明(linsidomine)氯水合物(“SIN-1”);S-亚硝基-N-乙酰基青霉胺(“SNAP”);S-亚硝基谷胱甘肽(GSNO)、硝普钠、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-己胺或二乙胺NONOate。
(3)增强cGMP浓度的其他物质,例如原卟啉IX、花生四烯酸和苯基肼衍生物。
(4)一氧化氮合酶底物:例如L-精氨酸、基于N-羟基胍的类似物,例如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(例如高-Arg、高-NOHA、N-叔丁氧基-和N-(3-甲基-2-丁烯基)氧基-L-精氨酸、刀豆氨酸、ε胍-己酸、胍丁胺、羟基-胍丁胺及L-酪氨酰基-L-精氨酸);N-烷基-N’-羟基胍(例如N-环丙基-N’-羟基胍和正丁基-N’-羟基胍)、N-芳基-N’-羟基胍(例如N-苯基-N’-羟基胍及其分别带有-F、-Cl、-甲基、-OH取代基的对位取代的衍生物);胍衍生物,例如3-(三氟甲基)丙基胍。
(5)增强eNOS转录的化合物。
(6)NO非依赖性的血红素非依赖性sGC活化剂,包括但不限于:
BAY 58-2667(描述于专利公开DE19943635中);HMR-1766(阿他西呱(ataciguat)钠,描述于专利公开WO2000002851中);S 3448(2-(4-氯-苯基磺酰基氨基)-4,5-二甲氧基-N-(4-(硫代吗啉硫吗啉-4-磺酰基)-苯基)-苯甲酰胺(描述于专利公开DE19830430和WO2000002851中);和HMR-1069(Sanofi-Aventis)。
(7)血红素依赖性、NO非依赖性的sGC刺激剂,包括但不限于:
YC-1(参见专利公开EP667345和DE19744026);利奥西呱(riociguat)(BAY 63-2521、描述于DE19834044中);奈利西呱(neliciguat)(BAY 60-4552,描述于WO 2003095451中);威利西呱(vericiguat)(BAY1021189);BAY 41-2272(描述于DE19834047和DE19942809中);BAY 41-8543(描述于DE19834044中);依曲西呱(etriciguat)(描述于WO 2003086407中);CFM-1571(描述于专利公开WO2000027394中);A-344905、其丙烯酰胺类似物A-350619和氨基嘧啶类似物A-778935以及描述于以下公开中的任一个的其他sGC刺激剂:US20090209556、US8455638、US20110118282(WO2009032249)、US20100292192、US20110201621、US7947664、US8053455(WO2009094242)、US20100216764、US8507512、(WO2010099054)US20110218202(WO2010065275)、US20130012511(WO2011119518)、US20130072492(WO2011149921)、US20130210798(WO2012058132),和Tetrahedron Letters(2003),44(48):8661-8663;以及IW-1973和IW1701。
(8)抑制cGMP和/或cAMP降解的化合物,例如:
PDE1抑制剂,PDE2抑制剂,PDE-3抑制剂,例如氨力农、米力农、依诺昔酮、维司力农、匹莫苯和奥普力农,PDE4抑制剂,例如鲁米司特,PDE5抑制剂,例如西地那非(sildenafil)及相关药剂,例如阿伐那非(avanafil)、罗地那非(lodenafil)、米罗那非(mirodenafil)、柠檬酸西地那非他达拉非(tadalafil)(或)、伐地那非(vardenafil)和乌地那非(udenafil);前列地尔(alprostadil);双嘧达莫(dipyridamole)和PF-00489791;PDE6抑制剂,PDE9抑制剂,例如,PF-04447943,PDE10抑制剂,例如,PF-02545920(PF-10)和PDE11抑制剂。
(9)以下类型的钙通道阻断剂:
二氢吡啶钙通道阻断剂,例如胺氯地平(asamlodipine)阿雷地平(aranidipine)阿折地平(azelnidipine)巴尼地平(barnidipine)贝尼地平(benidipine)西尼地平(cilnidipine)氯维地平(clevidipine)地尔硫卓(diltiazem)、依福地平(efonidipine)非洛地平(felodipine)拉西地平(lacidipine)乐卡地平(lercanidipine)马尼地平(manidipine)尼卡地平(nicardipine)(Carden)、硝苯地平(nifedipine)尼伐地平(nilvadipine)尼莫地平(nimodipine)尼索地平(nisoldipine) 尼群地平(nitrendipine)普拉地平(pranidipine)和伊拉地平(isradipine)
非选择性钙通道抑制剂,例如咪拉地尔、苄普地尔(bepridil)、氟司必林(fluspirilene)和芬地林(fendiline)。
(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(epoprostenol)(合成性前列环素,)、曲罗尼尔(treprostinil)伊洛前列素(iloprost)伊洛前列素以及处于研发中的经口和吸入形式的
(12)抗高血脂药,例如以下类型:
胆汁酸多价螯合剂,如消胆胺(cholestyramine)、考来替泊(colestipol)、考来替兰(colestilan)、考来维仑(colesevelam)或司维拉姆(sevelamer);
他汀类药物,如阿托伐他汀(atorvastatin)、辛伐他汀(simvastatin)、洛伐他汀(lovastatin)、氟伐他汀(fluvastatin)、匹伐他汀(pitavastatin)、罗舒伐他汀(rosuvastatin)和普伐他汀(pravastatin);
胆固醇吸收抑制剂,例如依泽替米贝(ezetimibe);
其他降脂剂,例如二十碳五烯酸乙酯、ω-3-酸乙酯、reducol;
贝特类衍生物,例如氯贝丁酯(clofibrate)、苯扎贝特(bezafibrate)、克利贝特(clinofibrate)、吉非贝齐(gemfibrozil)、氯烟贝特(ronifibrate)、比尼贝特(binifibrate)、非诺贝特(fenofibrate)、环丙贝特(ciprofibrate)、胆碱非诺贝特;
烟酸衍生物,例如阿西莫司(acipimox)和尼克酸;
他汀类药物、尼克酸和肠胆固醇吸收抑制补充物(依泽替米贝及其他)和贝特类的组合;及
抗血小板疗法,例如氯吡格雷硫酸氢盐(clopidogrel bisulfate)。
(13)抗凝剂,例如以下类型:
肝素及衍生物,例如低分子量肝素、磺达肝素(fondaparinux)和艾卓肝素(idraparinux);
组织纤溶酶原激活剂,其用于溶解凝块和疏通动脉,例如阿替普酶(alteplase)。
(14)抗血小板药物,例如保栓通锭(topidogrel)、噻氯匹定(ticlopidine)、双嘧达莫(dipyridamole)和阿斯匹林。
(15)ACE抑制剂,例如以下类型:
含二羧基的药剂,例如依那普利(enalapril)雷米普利(ramipril)喹那普利(quinapril)培哚普利(perindopril)赖诺普利(lisinopril)和贝那普利(benazepril)
含膦酸酯的药剂,例如福辛普利(fosinopril);
天然ACE抑制剂,例如酪激肽(casokinins)和乳激肽(lactokinins),其是在摄取乳产品、尤其是培养乳后天然存在的酪蛋白和乳清的分解产物;
乳三肽Val-Pro-Pro和Ile-Pro-Pro,其是由益生菌瑞士乳杆菌(Lactobacillushelveticus)产生或衍生自也具有ACE抑制和抗高血压功能的酪蛋白;
其他ACE抑制剂,例如阿拉普利(alacepril)、地拉普利(delapril)、西拉普利(cilazapril)、咪达普利(imidapril)、群多普利(trandolapril)、替莫普利(temocapril)、莫昔普利(moexipril)和螺普利(pirapril)。
(16)补充性氧疗法。
(17)β阻断剂,例如以下类型:
非选择性药剂,例如阿普洛尔(alprenolol)、布新洛尔(bucindolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、拉贝洛尔(labetalol)、纳多洛尔(nadolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、奥普洛尔(oxprenonol)、醋丁洛尔(acebutolol)、索他洛尔(sotalol)、甲吲洛尔(mepindolol)、塞利洛尔(celiprolol)、阿罗洛尔(arotinolol)、特他洛尔(tertatolol)、氨磺洛尔(amosulalol)、尼普地洛(nipradilol)、普萘洛尔(propranolol)和噻吗洛尔(timolol);
β1选择性药剂,例如醋丁洛尔(cebutolol)、阿替洛尔(atenolol)、倍他洛尔(betaxolol)、比索洛尔(bisoprolol)、塞利洛尔(celiprolol)、多巴酚丁胺(dobutamine)盐酸盐、马来酸伊索拉定(irsogladine maleate)、卡维地洛(carvedilol)、他林洛尔(talinolol)、艾司洛尔(esmolol)、美托洛尔(metoprolol)和奈必洛尔(nebivolol);和
β2选择性药剂,例如布他沙明。
(18)抗心律失常剂,例如以下类型:
I型(钠通道阻断剂),例如奎尼定(quinidine)、利多卡因(lidocaine)、苯妥英(phenytoin)、普罗帕酮(propafenone);
III型(钾通道阻断剂),例如胺碘达隆(amiodarone)、多非利特(dofetilide)和索他洛尔;和
V型,例如腺苷和地高辛(digoxin)。
(19)利尿剂,例如噻嗪利尿剂,例如氯噻嗪、氯噻酮和氢氯噻嗪、苄氟噻嗪、环戊噻嗪、甲氯噻嗪、泊利噻嗪、喹噻酮(quinethazone)、希帕胺(xipamide)、美托拉宗(metolazone)、吲达帕胺(indapamide)、西氯他宁(cicletanine);髓袢利尿剂,例如呋塞米(furosemide)和托瑞斯胺(toresamide);保钾利尿剂,例如阿米洛利(amiloride)、螺内酯、坎利酸钾、依普利酮(eplerenone)和三氨蝶呤(triamterene);这些药剂的组合;其他利尿剂,例如乙酰唑胺和卡培立肽(carperitide)。
(20)直接作用性血管扩张剂,例如盐酸肼苯哒嗪(hydralazine hydrochloride)、二氮嗪、硝普钠、卡屈嗪(cadralazine);其他血管扩张剂,例如二硝酸异山梨醇酯和5-单硝酸异山梨醇酯。
(22)α-1-肾上腺素受体拮抗剂,例如哌唑嗪(prazosin)、吲哚拉明(indoramin)、乌拉地尔(urapidil)、布那唑嗪(bunazosin)、特拉唑嗪(terazosin)和多沙唑嗪(doxazosin);心房钠尿肽(ANP)、乙醇、组胺诱导物、四氢大麻酚(THC)和罂粟碱。
(23)以下类型的支气管扩张剂:
长效β2激动剂(LABA),例如沙美特罗(salmeterol)和福莫特罗(formoterol);
抗胆碱能药物,例如异丙托铵(pratropium)及噻托铵(tiotropium);及
茶碱、支气管扩张剂及磷酸二酯酶抑制剂。
(24)皮质类固醇,例如倍氯米松(beclomethasone)、甲基泼尼松龙(methylprednisolone)、倍他米松(betamethasone)、泼尼松(prednisone)、泼尼松龙(prednisolone)、曲安奈德(triamcinolone)、地塞米松(dexamethasone)、氟替卡松(fluticasone)、氟尼缩松(flunisolide)、氢化可的松(hydrocortisone)及皮质类固醇类似物(例如布地奈德(budesonide))。
(25)膳食补充物,例如ω-3油;叶酸、烟酸、锌、铜、韩国高丽红参(Korean redginseng root)、银杏、松树皮、蒺藜(Tribulus terrestris)、精氨酸、燕麦(Avenasativa)、淫羊藿(horny goat weed)、玛卡根(maca root)、巴西榥榥木(muira puama)、沙巴棕(saw palmetto)及瑞典花粉(Swedish flower pollen);维生素C、维生素E、维生素K2;睾酮补充物、睾酮经皮贴剂;佐拉西(zoraxel)、那曲酮、布美诺肽(bremelanotide)及美拉诺坦II(melanotan II)。
(26)PGD2受体拮抗剂。
(28)非类固醇抗哮喘药,例如β2-激动剂,如特布他林、异丙喘宁(metaproterenol)、非诺特罗(fenoterol)、异他林(isoetharine)、沙丁胺醇、沙美特罗、比托特罗(bitolterol)及吡布特罗(pirbuterol);β2激动剂皮质类固醇组合,例如沙美特罗-氟替卡松(fluticasone)福莫特罗-布地奈德茶碱、色甘酸、色甘酸钠、奈多罗米(nedocromil)、阿托品(atropine)、异丙托铵、异丙托溴铵及白三烯生物合成抑制剂(齐留通(zileuton)、BAY1005)。
(29)非类固醇抗发炎剂(NSAID),例如丙酸衍生物,如阿明洛芬(alminoprofen)、苯噁洛芬(benoxaprofen)、布氯酸、卡洛芬(carprofen)、芬布芬(fenbufen)、非诺洛芬(fenoprofen)、氟比洛芬(fluprofen)、夫比普洛芬(flubiprofen)、布洛芬(ibuprofen)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、米洛芬(miroprofen)、萘普生(naproxen)、奥沙普秦(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)及硫噁洛芬(tioxaprofen);乙酸衍生物,例如吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、环氯茚酸(clidanac)、双氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、呋罗芬酸(furofenac)、异丁芬酸(ibufenac)、伊索克酸(isoxepac)、奥匹酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、妥美汀(tolmetin)、齐多美辛(zidometacin)及左美酸(zomepirac);芬那酸(fenamic acid)衍生物,例如氯芬那酸(flufenamic acid)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、尼氟酸(niflumic acid)及托芬那酸(tolfenamic acid);联苯甲酸衍生物,例如二氟尼索(diflunisal)及氟苯柳(flufenisal);奥昔康(oxicam),例如伊素昔康(isoxicam)、吡罗昔康(piroxicam)、舒多昔康(sudoxicam)及替诺昔康(tenoxican);水杨酸盐,例如乙酰基水杨酸及柳氮磺吡啶(sulfasalazine);及吡唑啉酮,例如阿扎丙宗(apazone)、贝哌洛隆(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羟布宗(oxyphenbutazone)及苯基丁氮酮。
(30)环加氧酶-2(COX-2)抑制剂,例如塞来昔布(celecoxib)罗非昔布(rofecoxib)伐地昔布(valdecoxib)、依托昔布(etoricoxib)、帕瑞昔布(parecoxib)及罗美昔布(lumiracoxib);类鸦片止痛药,例如可待因(codeine)、芬太尼(fentanyl)、氢吗啡酮(hydromorphone)、羟甲左吗南(levorphanol)、哌替啶(meperidine)、美沙酮(methadone)、吗啡(morphine)、羟考酮(oxycodone)、羟吗啡酮(oxymorphone)、丙氧芬(propoxyphene)、丁丙诺菲(buprenorphine)、布托啡诺(butorphanol)、地佐辛(dezocine)、纳布啡(nalbuphine)及戊唑辛(pentazocine)。
(31)抗糖尿病剂,例如胰岛素及胰岛素模拟物;磺酰脲,例如格列苯脲(glyburide)、格列本脲(glybenclamide)、格列吡嗪(glipizide)、格列齐特(gliclazide)、格列喹酮(gliquidone)、格列美脲(glimepiride)、美格替耐(meglinatide)、甲苯磺丁脲(tolbutamide)、氯磺丙脲(chlorpropamide)、乙酰苯磺酰环己脲(acetohexamide)及妥拉磺脲(olazamide);双胍,例如二甲双胍α-葡萄糖苷酶抑制剂,例如阿卡波糖(acarbose)、依帕司他(epalrestat)、伏格列波糖(voglibose)、米格列醇(miglitol);噻唑烷酮化合物,例如罗格列酮(rosiglitazone)曲格列酮(troglitazone)环格列酮(ciglitazone)、吡格列酮(pioglitazone)及恩格列酮(englitazone);胰岛素增敏剂,例如吡格列酮及罗格列酮;胰岛素促泌素,例如瑞格列奈(repaglinide)、那格列奈(nateglinide)及米格列奈(mitiglinide);肠促胰岛素模拟物,例如艾塞那肽(exanatide)及利拉鲁肽(liraglutide);淀粉素类似物,例如普兰林肽(pramlintide);葡萄糖降低剂,例如吡啶甲酸铬任选与生物素的组合;二肽基肽酶IV抑制剂,例如西他列汀(sitagliptin)、维格列汀(vildagliptin)、沙格列汀(saxagliptin)、阿格列汀(alogliptin)及利拉利汀(linagliptin)。
(32)HDL胆固醇增加剂,例如安塞曲匹(anacetrapib)及达塞曲匹(dalcetrapib)。
(33)抗肥胖症药物,例如盐酸甲基安非他明、盐酸安非拉酮(amfepramonehydrochloride)芬特明(phentermine)盐酸苄非他明(benzfetamine hydrochloride)酒石酸苯甲曲秦(phendimetrazinetartrate)吗吲哚(mazindol)奥利司他(orlistat)盐酸西布曲明(sibutramine hydrochloride)一水合物利莫那班(rimonabant)安非拉酮、吡啶甲酸铬;组合,例如芬特明/托吡酯(topiramate)、安非他酮(bupropion)/那曲酮(naltrexone)、西布曲明/二甲双胍(metformin)、安非他酮SR/唑尼沙胺(zonisamide)SR、昔萘酸沙美特罗/丙酸氟替卡松(fluticasone propionate);盐酸氯卡色林(lorcaserinhydrochloride)、芬特明/托吡酯、西替利司他(cetilistat)、艾塞那肽(exenatide)、利拉鲁肽、盐酸二甲双胍、西布曲明/二甲双胍、安非他酮SR/唑尼沙胺SR、CORT-108297、卡格列净(canagliflozin)、吡啶甲酸铬、GSK-1521498、LY-377604、美曲普汀(metreleptin)、奥尼匹肽(obinepitide)、P-57AS3、PSN-821、昔萘酸沙美特罗/丙酸氟替卡松、钨酸钠、生长激素(重组体)、替莫瑞林(tesamorelin)、特索芬辛(tesofensine)、韦利贝特(velneperit)、唑尼沙胺、半草酸贝洛拉尼(beloranib hemioxalate)、促胰岛素、白藜芦醇(resveratrol)、索布替罗(sobetirome)、四氢大麻酚及β-拉帕醌(lapachone)。
(34)血管收缩肽受体阻断剂,例如氯沙坦(losartan)、缬沙坦(valsartan)、坎地沙坦(candesartan)、西来替昔(cilexetil)、依普沙坦(eprosaran)、厄贝沙坦(irbesartan)、替米沙坦(telmisartan)、奥美沙坦(olmesartran)、美索巴莫(medoxomil)、阿齐沙坦(azilsartan)及美索巴莫。
(35)肾素抑制剂,例如半富马酸阿利吉仑(aliskiren hemifumirate)。
(36)中枢作用性α-2-肾上腺素受体激动剂,例如甲基多巴(methyldopa)、可乐定(clonidine)及胍法辛(guanfacine)。
(37)肾上腺素性神经元阻断剂,例如胍乙啶(guanethidine)及胍那决尔(guanadrel)。
(38)咪唑啉I-1受体激动剂,例如磷酸二氢利美尼定(rimenidine dihydrogenphosphate)及盐酸莫索尼定(moxonidine hydrochloride)水合物。
(39)醛固酮拮抗剂,例如螺内酯及依普利酮(eplerenone)。
(40)钾通道活化剂,例如吡那地尔(pinacidil)。
(41)多巴胺D1激动剂,例如甲磺酸非诺多潘(fenoldopam mesilate);其他多巴胺激动剂,例如异波帕胺(ibopamine)、多培沙明(dopexamine)及多卡巴胺(docarpamine)。
(42)5-HT2拮抗剂,例如酮色林(ketanserin)。
(43)加压素拮抗剂,例如托伐普坦(tolvaptan)。
(44)钙通道增敏剂(例如左西孟旦(levosimendan))或活化剂(例如尼可地尔)。
(45)腺苷酸环化酶活化剂,例如盐酸考福辛达罗帕特(colforsin dapropatehydrochloride)。
(46)正性肌力剂,例如地高辛及甲地高辛(metildigoxin);代谢强心剂,例如泛醌;脑钠尿肽,例如奈西立肽(nesiritide)。
(47)用于治疗勃起功能障碍的药物,例如前列地尔、阿肽地尔(aviptadil)及甲磺酸酚妥拉明(phentolamine mesilate)
(49)用于治疗阿尔茨海默病及痴呆的药物,例如以下类型:
氧化还原酶抑制剂,例如艾地苯醌(idebenone)。
(50)精神病药剂,例如以下类型:
齐拉西酮(ziprasidone)(GeodonTM)、利培酮(risperidone)(RisperdalTM)、奥氮平(olanzapine)(ZyprexaTM)、丙戊酸盐;
多巴胺D4受体拮抗剂,例如氯氮平(clozapine);
多巴胺D2受体拮抗剂,例如奈莫必利(nemonapride);
混合多巴胺D1/D2受体拮抗剂,例如珠氯噻醇(zuclopenthixol);
GABA A受体调节剂,例如卡巴马平(carbamazepine);
钠通道抑制剂,例如拉莫三嗪(lamotrigine);和
单胺氧化酶抑制剂,例如吗氯贝胺(moclobemide)及茚洛秦(indeloxazine);普马色林(primavanserin)和哌洛匹隆(perospirone)。
(51)用于治疗运动障碍或症状的药物,例如以下类型:
儿茶酚-O-甲基转移酶抑制剂,例如恩他卡朋(entacapone);
单胺氧化酶B抑制剂,例如司来吉兰(selegiline);
多巴胺受体调节剂,例如左旋多巴;
多巴胺D3受体激动剂,例如普拉克索(pramipexole);
去羧酶抑制剂,例如卡比多巴(carbidopa);
其他多巴胺受体激动剂,例如培高利特(pergolide)、罗匹尼罗(ropinirole)、卡麦角林(cabergoline);
瑞替耐得(ritigonide)、依曲茶碱(istradefylline)、他利克索(talipexole);唑尼沙胺(zonisamide)及沙酚酰胺(safinamide);及
突触囊泡胺运输蛋白抑制剂,例如丁苯那嗪(tetrabenazine)。
(52)用于治疗情绪或情感障碍或OCD的药物,例如以下类型
三环抗抑郁药,例如阿米替林(amitriptyline)地昔帕明(desipramine)伊米帕明(imipramine)阿莫沙平(amoxapine)去甲替林(nortriptyline)及氯米帕明(clomipramine);
选择性去甲肾上腺素再摄取抑制剂(SNRI),例如文拉法辛(venlafaxine)、瑞波西汀(reboxetine)及阿托莫西汀(atomoxetine);多巴胺抗抑郁药,例如安非他酮(bupropion)及安咪奈丁(amineptine)。
(53)用于增强突触可塑性的药物,例如以下类型:
烟碱受体拮抗剂,例如美卡拉明(mecamylamine);及
混合5-HT、多巴胺及去甲肾上腺素受体激动剂,例如鲁拉西酮(lurasidone)。
(54)用于治疗ADHD的药物,例如安非他明;5-HT受体调节剂,例如沃替西汀(vortioxetine)及α-2肾上腺素受体激动剂(例如可尼丁)。
(55)中性肽链内切酶(NEP)抑制剂,例如沙库比曲(sacubitril)、奥马曲拉(omapatrilat);及
亚甲基蓝(MB)。
包装和试剂盒
所用药物组合物(或制剂)可根据用于给药药物的方法以多种方式进行包装。通常,用于分配的物品包括其中以适当的形式存放药物制剂的容器。合适的容器是本领域技术人员公知的且包括诸如以下的材料:瓶(塑料及玻璃)、药囊、安瓿瓶、塑料袋、金属圆筒等。容器也可包括防撬配件(tamper-proof assemblage)以防止不慎接触到包装内容物。另外,容器上置有描述容器内容物的标签。该标签也可包括适当的警告。
本文所述的化合物和药物组合物可包含于试剂盒中。该试剂盒可包括单个或多个剂量的各自经单独包装或配制的两种或更多种药剂,或单个或多个剂量的以组合包装或配制的两种或更多种药剂。因此,一种或多种药剂可存在于第一容器中,且试剂盒可任选包括第二容器中的一种或多种药剂。将一个或多个容器置于包装内,且该包装可任选包括给药或剂量说明书。试剂盒可包括其他组件,例如注射器或用于给药药剂以及稀释剂的其他装置或用于配制的其他装置。因此,试剂盒可包括:a)药物组合物,其包含本文所述的化合物及药学上可接受的载体、媒介物或稀释剂;和b)容器或包装。试剂盒可任选地包含描述在一种或多种本文所述方法(例如预防或治疗一种或多种本文所述的疾病和病症)中使用药物组合物的方法的说明书。试剂盒可任选包含第二种药物组合物,其包含一种或多种本文所述的用于共同治疗用途的其他药剂、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含有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。
实施例
实施例中所提供的所有参考文献皆以引用方式并入本文中。如本文所用所有缩写、符号及惯例皆与当前科学文献中所用的那些一致。参见例如Janet S.Dodd编辑,TheACS Style Guide:A Manual for Authors and Editors,第2版,Washington,D.C.:American Chemical Society,1997,其全文以引用方式并入本文中。
本申请中使用的常见缩写
实施例1:化合物合成
中间体-1:8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-甲腈(Int-1)
该中间体根据专利文献中的步骤合成(WO 2015/187470A1)。1H NMR(500MHz,甲醇-d4)δppm 9.09(s,1H),8.14(s,1H),7.91(s,1H),7.35(t,1H),7.28(d,1H),7.10(m,2H),4.60(s,2H).
一般步骤A:中间体-2(Int-2)
分2步合成标题化合物:
步骤1:8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-甲脒的合成
向8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-甲腈(1当量,中间体-1)在甲醇(根据批次使用12ml或4.8ml)中的溶液中加入0.5M甲醇钠溶液(5当量)(注意:也可以使用催化量的甲醇钠)。在室温下搅拌1小时后,加入氨盐酸盐(10当量),并将反应搅拌过夜。将反应混合物真空浓缩,用半饱和NaHCO3(20mL)和1N NaOH(2mL)稀释,并用2×20mL EtOAc萃取。合并的有机相经硫酸钠干燥,过滤并浓缩,得到粗产物,为褐色固体。它无需进一步纯化即可用于下一步。
步骤2:5-氟-2-(8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(Int-2)的合成
向8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-甲脒(1当量)的乙醇(9ml)溶液中加入(Z)-3-乙氧基-2-氟-3-氧代丙-1-烯-1-油酸钠(3当量)。将反应在密封的小瓶中在80℃加热3h。冷却后,真空除去溶剂。
粗制物质通过使用5-95%乙腈/水0.1%TFA梯度的反相HPLC纯化,得到标题化合物(16mg,19%产率),为灰白色固体。1H NMR(500MHz,甲醇-d4)δppm 9.48(s,1H),8.28(s,1H),8.09(d,1H),7.98(s,1H),7.38(s,1H),7.29(d,1H),7.12(m,2H),4.71(s,2H)。当将该化合物大规模制备时,获得灰白色固体(57mg,33%产率)。1H NMR(500MHz,DMSO-d6)δ(ppm)12.5(br s,1H),9.48(s,1H),8.31(s,1H),8.18(m,1H),7.88(s,1H),7.47(m,1H),7.27(q,1H),7.19(t,1H),7.09(t,1H),4.59(s,2H).
中间体-3.6-(4-氯-5-氟嘧啶-2-基)-8-(2-氟苄基)咪唑并[1,2-a]吡嗪(Int-3)
在室温将中间体Int-2(1当量)在POCl3(98当量)中的溶液搅拌过夜。真空除去溶剂,得到粗制中间体Int-3,为棕色固体。它无需进一步纯化即可用于下一步。
化合物I-2
将在微波小瓶中的中间体Int-3(1当量)和2-(氨基甲基)-1,1,1,1,3,3,3-六氟丙-2-醇(3当量)在DMSO(0.5mL)中的溶液通过微波在120℃加热2小时。冷却后,将溶液过滤,并将粗物质通过使用30-60%乙腈/水0.1%甲酸梯度的反相HPLC纯化,得到化合物I-2(10.2mg,产率42%),为白色固体。1H NMR(500MHz,DMSO-d6)δppm 9.43(s,1H),9.22(s,1H),8.46(d,1H),8.38(br.s.,1H),8.28(s,1H),7.84(s,1H),7.53(t,1H),7.23(br.s.,1H),7.14(t,1H),7.04(t,1H),4.53(s,2H),4.07(d,2H).
化合物I-1
分2步合成标题化合物:
步骤1:(1,1,1,3,3,3-六氟-2-(((5-氟-2-(8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-基)氨基)甲基)丙-2-基)磷酸二苄基酯(化合物I-4)的合成
在0℃向1,1,1,3,3,3-六氟-2-(((5-氟-2-(8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-基)氨基)甲基)丙-2-醇(化合物I-2)0.48g,1当量)在THF(9ml)中的溶液中于5分钟内滴加在THF中的1M LiHMDS(1.2ml,1.3当量)。将所得黄色溶液在0℃下搅拌20分钟。在另外的烧瓶中制备二磷酸四苄基酯(0.69g,1.4当量)的THF(5ml)溶液,并冷却至0℃。在15分钟内将烷氧化物溶液滴加到焦磷酸盐溶液中,并使反应在4小时内升温至室温。然后将其在室温搅拌5天。用乙酸乙酯(20ml)稀释反应,并用水(10ml)洗涤。有机层经硫酸钠干燥,过滤并浓缩,得到粗产物,为黄色胶状物。无需进一步纯化即可直接用于下一步。
步骤2:化合物I-1的合成
向粗制(1,1,1,3,3,3-六氟-2-(((5-氟-2-(8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-基)氨基)甲基)丙-2-基)磷酸二苄基酯(化合物I-4)在乙酸乙酯(10ml)和THF(10ml)的溶液中加入5%钯炭(1当量)。将反应在氢气球下在室温搅拌过夜。通过硅藻土垫过滤混合物,并用甲醇(10ml)洗涤。将洗脱液浓缩至干,得到粗制黄色固体。粗物质经使用10-50%乙腈水0.1%TFA梯度的反相HPLC纯化,得到化合物I-1(18mg,13%产率),为白色固体。1H NMR(500MHz,氧化氘)δppm 8.81 9.10(s,1H),8.12(d,1H),8.05(s,1H),7.78(s,1H),7.31(m,2H),7.14(m,2H),4.67(s,2H),4.62(s,2H).
中间体-4(Int-4)
该中间体的制备分为四个步骤:
步骤1:氰化中间体(15)获得2-(溴甲基)-3,3,3-三氟-2-((三甲基甲硅烷基)氧基)丙腈(16)
将三甲基甲硅烷甲腈(153g,1.54mol,0.97当量)和三乙胺(4.44mL,3.22g,0.032mol,0.02当量)装入装有机械搅拌器和数字温度计的合适反应容器中。将混合物冷却至5℃。3-溴-1,1,1-三氟丙-2-酮((15),304g,1.59mol,1.0当量)在35分钟内通过加料漏斗加入,同时保持反应温度在10至20℃之间。
加料后将混合物在20至30℃搅拌3小时,得到稠油状的中间体(16),将其直接用于下一步。1H-NMR(500MHz,CDCl3)δppm 3.68(d,J=11.14Hz,1H);3.57(d,J=11.14Hz,1H),0.34-0.37(m,9H).
步骤2:将腈(16)转化为酰胺以得到2-(溴甲基)-3,3,3-三氟-2-羟基丙酰胺(17)
在装有机械搅拌器,数字温度计和加料漏斗的合适反应容器中搅拌浓硫酸(339mL,6.37mol,4.0当量)。将硫酸加热到45℃。通过加料漏斗在50分钟内添加上述中间体(16),同时保持温度低于75℃。将反应混合物在75℃搅拌2h,然后冷却至室温。1H-NMR表明反应完成。将反应混合物冷却至-15℃,并通过加料漏斗在45分钟内(剧烈放热)用乙酸乙酯(1824mL)稀释,同时保持温度在-15至5℃之间。在-10至0℃之间经由加料漏斗用时1小时20分钟将水(1520mL)缓慢加入(剧烈放热)。分离各层,并将有机层先后用15%氯化钠水溶液(1520mL),25%碳酸钠水溶液(911mL)和15%氯化钠水溶液(911mL)洗涤。过滤有机层并在减压下浓缩以得到348g的中间体(17),为淡黄色油状物。将该油溶于甲醇(1200mL)中并浓缩以提供380g的中间体(17)。(调整后的重量为296g,产率79%)。1H-NMR(500MHz,CDCl3)δ6.61-6.94(m,1H);5.92-6.26(m,1H);3.93-4.00(m,1H);3.68(d,J=11.14Hz,1H).
步骤3:将化合物(17)N-烷基化以得到2-(氨基甲基)-3,3,3-三氟-2-羟基丙酰胺(14)
将7N的氨在甲醇中的溶液(600mL,4.28mol,10当量)装入装有机械搅拌器和数字温度计的合适反应容器中。将溶液冷却至0至5℃。然后在0至5℃在30分钟内经由加料漏斗添加中间体(17)(102g,0.432mol,1当量)。在1小时内将反应混合物加热至20至25℃,并保持72小时。通过HPLC完成反应。将反应混合物冷却至0至5℃,并在2分钟内加入甲醇钠(78mL,5.4M,0.421mol,0.97当量)。然后将反应混合物在减压下浓缩至体积为300mL。加入2L乙酸乙酯,并在减压下继续浓缩至体积至700mL,得到浆液。将700mL乙酸乙酯加入到浆料中,以使最终体积达到1400mL。加入102mL水,搅拌2分钟,得到双相溶液。分离各层。减压浓缩乙酸乙酯层至体积为600mL。然后将乙酸乙酯层加热至>60℃,并在55至60℃之间缓慢添加庚烷(600mL)。将混合物冷却至15至20℃,得到浆液。将浆液在15至20℃下搅拌2h并过滤。将固体在真空下在25℃干燥16h以提供胺(14)(48g,产率64%),为白色固体。1H-NMR(500MHz,MeOH-d4)δppm 2.94(d,J=13.73Hz,1H);3.24(d,J=13.58Hz,1H).
步骤4:将胺(14)手性拆分为(R)-2,2-二甲基-5-(三氟甲基)噁唑烷-5-甲酰胺(R)-2-羟基琥珀酸盐(中间体-4,Int-4)
将胺(14)(105g,0.608mol,1.0当量),(D)-苹果酸(82g,0.608mol,1.0当量)和丙酮(1571mL)装入装有机械搅拌器和数字温度计的合适反应容器中。将反应混合物在20至25℃下搅拌16h。将得到的浆液过滤,并将湿滤饼用丙酮(300mL)洗涤。将湿滤饼装回到反应容器中,并加入丙酮(625mL)。将浆液加热至53℃并保持6小时。将浆液冷却至20至25℃并保持16小时。过滤浆液,并将湿滤饼用丙酮(200mL)洗涤。将湿滤饼在真空下在40℃干燥4小时,得到82.4g的中间体Int-4,为白色固体(82.4g,39%产率,97%ee)。1H-NMR(500MHz,D2O)δppm 4.33(br,s,1H);3.61(br,d,J=13.58Hz,1H);3.40-3.47(m,1H);2.76(br,d,J=15.87Hz,1H);2.53-2.63(m,1H);2.16(br,s,4H).
化合物I-3
将中间体Int-3和Int-4以及N,N-二异丙基乙胺(3当量)在DMSO(0.4mL)和水(0.04mL)中的溶液在微波瓶中于120℃微波加热2小时。冷却后,将混合物过滤并将粗物质通过使用30-60%乙腈/水0.1%甲酸梯度的反相HPLC纯化,以得到化合物I-3(13.1mg,产率32%),为白色固体。1H NMR(500MHz,DMSO-d6)δppm 9.43(s,1H),8.39(d,1H),8.32(br.s.,1H),8.27(s,1H),8.16(d,1H),7.83(s,1H),7.78(br.s.,1H),7.60(br.s.,1H),7.52(t,1H),7.24(d,1H),7.15(d,1H),7.06(t,1H),4.57(s,2H),4.00(d,2H).
通式B1的化合物
与以上针对化合物I-1、I-2、I-3和I-4例示的合成类似,可以通过以下方案合成具有以下式B1的核心的化合物。
可以根据WO2016081668中描述的方案制备中间体Int-M的通式化合物。然后可以通过与上述类似的方案进一步修饰中间体-Int-M,以得到化合物I-1至I-4。
中间体-5:8-(2,5-二氟苄基)咪唑并[1,2-a]吡嗪-6-甲腈(Int-5)
使用2,5-二氟苄基溴化物根据描述用于合成Int-1的专利文献步骤(WO2015/187470A1),从起始溴化物(6,8-二溴咪唑并[1,2-a]吡嗪)制备腈中间体Int-5。MS ES+m/z=271.2[M+H]+.
中间体6:6-(4-氯-5-氟嘧啶-2-基)-8-(2,5-二氟苄基)咪唑并[1,2-a]吡嗪(Int-6).
根据所述用于从Int-1合成中间体Int-3的通用步骤,由中间体Int-5制备中间体Int-6。MS ES+m/z 376.3[M+H]+.
化合物I-5
将中间体Int-6(1当量),Int-4(3当量)和三乙胺(5当量)在二噁烷/水3:1(1.3mL)中的溶液在90℃下加热18小时。冷却至室温后,将反应混合物体积减小至一半,用1N HCl水溶液和乙酸乙酯稀释。分离各层,有机层先后用水和饱和氯化钠水溶液洗涤,干燥(硫酸钠),并真空浓缩,得到粗制固体。通过反相HPLC使用在水中的30至60%乙腈(经0.1%甲酸改性)的梯度来纯化粗制物质,以得到化合物I-5(20.0mg,产率29%),为灰白色固体。1HNMR(500MHz,CD3OD)δ(ppm):9.40(s,1H),8.22-8.25(m,1H),8.18(s,1H),7.83(s,1H),7.15-7.21(m,1H),7.06-7.10(m,1H),6.91-6.98(m,1H),4.65(s,2H),4.26(d,1H),4.05(d,1H).MS ES+m/z 512.2[M+H]+.
中间体-7:8-(2-氟苄基)-[1,2,4]三唑并[1,5-a]吡嗪-6-甲腈(Int-7)
将(2-氟苄基)氯化锌(II)(18.0ml,0.5M于THF中,9.00mmol)溶液添加到PdCl2(PPh3)2(0.253g,0.360mmol)和市售中间体Int-7a(2.00g,7.20mmol)的混合物中。用氮气吹扫反应,密封并加热至50℃保持1小时。将反应混合物冷却至室温,并通过硅胶色谱法,使用0-70%乙酸乙酯的己烷溶液梯度直接纯化,得到中间体Int-7b(1.49g,61%)。1H NMR:(500MHz,DMSO-d6),δ(ppm):9.46(s,1H),8.74(s,1H),7.39-7.42(m,1H),7.30-7.34(m,1H),7.14-7.21(m,2H),4.56(s,2H).MS ES+m/z=307.1[M]+,309.0[M+2]+,
将Int-7b(1.49g,4.85mmol)、氰化锌(II)(0.684g,5.82mmol)、DPPF(0.538g,0.970mmol)、Pd2(dba)3(0.533g,0.582mmol)和锌(0.162g,2.47mmol)在DMA(8mL)中的搅拌混合物在氮气气氛下在120℃加热2h。完成后,将混合物冷却至室温,用乙酸乙酯:二氯甲烷:甲醇(2:1:1,100mL)的混合物稀释,通过硅藻土垫过滤,并浓缩。残余物通过硅胶色谱法纯化,使用0-85%乙酸乙酯的己烷溶液梯度洗脱,得到中间体Int-7(869mg,71%)。1H NMR:(500MHz,MeOH-d4),δ(ppm):9.52(s,1H),8.72(s,1H),7.39-7.42(m,1H),7.28-7.32(m,1H),7.08-7.15(m,2H),4.65(s,2H).MS ES+m/z 254.1[M+H]+,
中间体10:6-(4-氯-5-氟嘧啶-2-基)-8-(2-氟苄基)-[1,2,4]三唑并[1,5-a]吡嗪(Int-10)
向在室温搅拌的中间体Int-7(1.64g,6.48mmol)在MeOH(33mL)中的溶液中加入甲醇钠(4.44ml,25%于MeOH中,19.4mmol)溶液。1小时后,通过LC-MS确认亚氨酸酯的形成。加入固体NH4Cl(1.73g,32.4mmol),搅拌混合物,同时通过LC-MS分析监测反应进程。完成后,将所得沉淀物过滤并真空干燥,得到中间体Int-8(1.63g,93%)。MS ES+m/z 271.1[M+H]+
向在室温下搅拌的中间体Int-8(1.63g,6.03mmol)在无水EtOH(27ml)中的混合物中添加中间体Int-8a(2.82g,18.1mmol)。将混合物在80℃加热30分钟,并通过LC-MS分析监测反应进程。完成后,加入HCl水溶液(18.1ml,1M),并将所得混合物在室温下搅拌30分钟,从而导致沉淀物的形成。将固体过滤并真空干燥。静置30分钟后,从滤液中回收第二批产物。将合并的固体在高真空下干燥,得到中间体Int-9(2.01g,98%)。MS ES+m/z 341.0[M+H]+.
将POCl3(1.96ml,21.0mmol)和中间体Int-9(358mg,1.05mmol)的搅拌混合物在80℃加热30分钟,同时通过LC-MS分析监测反应进程。完成后,将POCl3真空蒸发并将残余物在饱和碳酸氢钠水溶液(20mL)和二氯甲烷(40mL)之间分配。用二氯甲烷(2×40mL)萃取水层,并将合并的有机层干燥(MgSO4),过滤并浓缩,得到粗制残余物。粗制产物通过硅胶色谱法,使用0-50%乙酸乙酯的己烷溶液梯度纯化,得到固体形式的中间体Int-10(200mg,53.0%)。1H NMR(500MHz,DMSO-d6)δppm 9.65(s,1H),9.14(s,1H),8.82(s,1H),7.40(m,1H),7.34-7.26(m,1H),7.23-7.15(m,1H),7.15-7.08(m,1H),4.66(s,2H).MS ES+m/z359.0[M+H]+.
化合物I-6
将中间体Int-10(1当量),2-(氨基甲基)-1,1,1,3,3,3-六氟丙-2-醇(3当量)和N-乙基-N-异丙基丙-2-胺(0.8mL)在DMSO中的溶液在90℃加热1h,然后在70℃加热12小时。冷却至室温后,将反应混合物用1N HCl水溶液稀释至pH=3,导致形成橙色沉淀,将其过滤并干燥。通过硅胶色谱法在25分钟内使用0至20%的7:1乙腈/甲醇的二氯甲烷溶液梯度,然后进行反相HPLC,在25分钟内使用20至70%的乙腈的水溶液梯度(用0.1%三氟乙酸改性)来纯化粗制物质,得到化合物I-6(12.2mg,产率17%),为浅黄色固体。1H NMR:(500MHz,DMSO-d6),δ(ppm):9.57(s,1H),8.83(s,1H),8.80(s,1H),8.49(d,1H),8.31(m,1H),7.48-7.51(t,1H),7.26-7.30(m,1H),7.14-7.18(t,1H),7.07-7.10(t,1H),4.60(s,2H),4.16(d,2H).MS ES+m/z=520.3.
中间体11:3--氯-6-(4--氯-5-氟嘧啶-2-基)-8-(2-氟苄基)咪唑并[1,2-a]吡嗪(Int-11)
在0℃向中间体Int-2(103mg,0.304mmol)在MeOH(5mL)中的溶液中加入N-氯琥珀酰亚胺(NCS)(44.6mg,0.344mmol)。30分钟后,将反应温热至环境温度持续17小时,然后温热至50℃持续2.5小时。将反应混合物浓缩并将得到的残余物通过硅胶色谱法,使用0-20%的乙腈/甲醇(7:1)的二氯甲烷溶液梯度纯化,得到中间体Int-2a(99.6mg,85%)。MS ES+m/z 374.2[M+H]+.
在60℃将中间体Int-2a(47.9mg,0.128mmol)在POCl3(0.836ml,8.97mmol)中的混合物搅拌2.5h,此后通过LCMS分析表明反应完成。将混合物浓缩至干。通过用甲苯(2×1mL)驱除并在真空中进一步干燥来除去残留量的POCl3。所得的Int-11粗品无需纯化即可使用。MS ES+m/z 392.2[M+H]+.
化合物I-7
将中间体Int-11(1.0当量),N-乙基-N-异丙基丙-2-胺(6.0当量)和1-氨基-2-甲基丙-2-醇(1.8当量)在DMSO(1.0mL)中的悬浮液加热至90℃持续16小时。冷却至室温后,将反应混合物通过硅胶色谱法,在75分钟内使用二氯甲烷中的7:1乙腈/甲醇梯度直接纯化洗脱,得到化合物I-7(19.4mg,产率35%),为灰白色固体。1H NMR:(500MHz,DMSO-d6),δ(ppm):8.90(s,1H),8.28(d,1H),8.00(s,1H),7.55-7.57(m,1H),7.44-7.47(m,1H),7.25-7.30(m,1H),7.15-7.19(m,1H),7.09-7.12(m,1H),4.73(s,1H),4.58(s,2H),3.49(d,2H),1.15(s,6H).MS ES+m/z=445.2.
中间体13:6-(4,5-二氯嘧啶-2-基)-8-(2-氟苄基)咪唑并[1,2-a]吡嗪(Int-13)
在5分钟内,在室温向8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-甲脒(5.00g,18.6mmol)和Int-12a(4.19g,27.9mmol)在无水MeOH(100mL)中的搅拌混合物中添加NaOMe(8.49mL,25重量%于MeOH中,37.1mmol)的无水MeOH(24mL)溶液。将所得溶液加热回流。2小时后,反应不完全。因此,添加了更多的Int-12a(900mg,5.98mmol)。再加热2小时后,将混合物冷却至室温并搅拌过夜。将混合物浓缩并将所得残余物在H2O(100mL)中搅拌。用HCl水溶液(2mL,6M)将pH调节至3,将混合物搅拌30分钟,并过滤。将固体用H2O(2×30mL)洗涤,并在高真空下干燥以得到中间体Int-12(5.20g,79%)。MS ES+m/z 356.2[M+H]+
将Int-12(5.20g,14.6mmol)和DMAP(179mg,1.46mmol)在POCl3(27.0mL,292mmol)中的搅拌混合物在90℃加热3h。浓缩混合物,并与甲苯(100mL)共沸除去残留的POCl3。将残余物重新溶解在二氯甲烷(200mL)中,在冰浴中冷却,并用10%的NaHCO3水溶液(150mL)中和。将混合物用DCM(100mL)稀释,并分离各相。有机层用H2O(50mL)和饱和NaHCO3水溶液(2×50mL)洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过硅胶色谱法,使用20-80%乙酸乙酯/己烷的梯度纯化,得到中间体Int-13(2.50g)。1H NMR(500MHz,CDCl3)δ(ppm)9.18(s,1H),8.77(s,1H),7.76(d,1H),7.69-7.73(m,1H),7.30(m,1H),7.08-7.12(m,1H),6.89-7.01(m,2H),4.71(s,2H).MS ES+m/z 374.1[M+H]+
化合物I-8
向中间体Int-13(1.0当量)和外消旋-3-氨基-1,1,1-三氟丙-2-醇(3.0当量)在3:1二噁烷/水(1.3mL)中的溶液中添加三乙胺(5.0当量)。将反应混合物在90℃下搅拌18h。冷却至室温后,将反应混合物体积减小至一半,用1N HCl水溶液和乙酸乙酯稀释。分离各层,有机层先后用水和饱和氯化钠水溶液洗涤,干燥(硫酸钠),并真空浓缩,得到粗制固体。通过反相HPLC使用在水中的30至60%乙腈(经0.1%甲酸改性)的梯度来纯化粗制物质,以得到外消旋化合物I-8(34.5mg,产率55%),为淡黄色固体。1H NMR(500MHz,CD3OD)δ(ppm):9.35(s,1H),8.32(s,1H),8.12(s,1H),7.80(s,1H),7.25-7.30(m,1H),7.17-7.24(m,1H),6.99–7.02(m,1H),7.02–7.07(m,1H),4.66(s,2H),4.33-4.41(m,1H),4.03(dd,1H),3.76(dd,1H).MS ES+m/z=467.2
中间体15:2-(8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(Int 15)
将8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-甲脒(1.00g,3.71mmol),中间体Int-14a(1.21ml,11.1mmol)和N-乙基-N-异丙基丙-2-胺(1.95mL,11.1mmol)在乙醇(14.9mL)中的溶液在80℃搅拌12小时。将反应混合物冷却至室温,向其中加入氯化铵(0.6g),并将所得混合物在室温下静置6小时。然后将反应混合物加热至80℃再保持20小时,此时LCMS表明反应完成。将反应混合物冷却至室温,导致形成沉淀。将该固体过滤并干燥,得到黄色固体(350mg)。将滤液浓缩至干,用乙酸乙酯(100mL)和水(100mL)稀释。分离各层,水层用乙酸乙酯(2×100mL)萃取。合并的有机层用饱和氯化钠溶液洗涤,干燥(硫酸钠),过滤并浓缩,得到另外380mg的所需产物。合并固体产物,得到深黄色固体状的Int-14(730mg,58%产率)。MS ES+m/z 322.1[M+H]+
中间体Int-14(350mg,1.09mmol)和POCl3(2.00mL,21.8mmol)的混合物在90℃搅拌3h,此时LCMS显示完全转化。真空除去POCl3,并将所得残余物在饱和碳酸氢钠水溶液(25mL)和二氯甲烷(50mL)之间分配。将水层用二氯甲烷(2×25mL)萃取,并将合并的有机萃取液干燥(MgSO4),过滤并减压浓缩,得到粗制的Int-15(380mg,产率103%)。其无需纯化即可用于下一步。MS ES+m/z 340.1[M+H]+
化合物I-9
向中间体Int-15(1.0当量)和2-氨基乙-1-醇(3.0当量)的DMSO(1mL)溶液中加入三乙胺(5.0当量),加热至90℃,持续18小时。将反应混合物冷却至室温,导致形成沉淀物,将其收集。通过反相HPLC使用在水中的20至50%乙腈(经0.1%甲酸改性)的梯度来纯化粗制固体产物,以得到化合物I-9,其为透明玻璃状物。1H NMR(500MHz,CD3OD)δ(ppm)9.58(brs,1H),8.26(s,2H),8.21(s,1H),7.87(s,1H),7.18-7.30(m,2H),7.04–7.08(m,1H),7.00–7.04(m,1H),4.67(s,2H),3.81(br s,4H).MS ES+m/z 366.1[M+H]+(观察到次级质子化)。
中间体16:8-(3,5-二氟-4-甲基苄基)咪唑并[1,2-a]吡嗪-6-甲腈(Int-16)
腈中间体Int-16由起始溴化物即6,8-二溴咪唑并[1,2-a]吡嗪,根据描述用于中间体Int-1的合成的专利文献步骤(WO 2015/187470A1),使用3,5-二氟-4-甲基苄基溴制备。MS ES+m/z=285.2[M+H]+.
中间体-19:6-(4,5-二氯嘧啶-2-基)-8-(3,5-二氟-4-甲基苄基)咪唑并[1,2-a]吡嗪(Int-19)
如由Int-1合成Int-2的方法中所述,由Int-16制备脒中间体Int-17。MS ES+m/z=302.2[M+H]+.
如由8-(2-氟苄基)咪唑并[1,2-a]吡嗪-6-甲脒制备Int-13的方法所述,由Int-17制备中间体Int-19。1H NMR(500MHz,CD3OD)δ(ppm):9.88(s,1H),8.79-8.90(m,1H),8.58(d,1H),8.36(d,1H),7.06-7.20(m,2H),4.71(s,2H),2.15(s,3H).MS ES+m/z 406.1[M+H]+
化合物I-10
向Int-19(1.0当量)和2-(氨基甲基)-1,1,1,1,3,3,3-六氟丙-2-醇(3.0当量)在3:1二噁烷/水(1.3mL)中的溶液中加入三乙胺(5.0当量)。将反应混合物在90℃搅拌18h。冷却至室温后,将反应混合物体积减小至一半,用1N HCl水溶液和乙酸乙酯稀释。分离各层,有机层先后用水和饱和氯化钠水溶液洗涤,干燥(硫酸钠),并真空浓缩,得到粗制固体。通过反相HPLC使用在水中的30至60%乙腈(经0.1%甲酸改性)的梯度来纯化粗制物质,以得到化合物I-10(9.7mg,产率14%),为灰白色固体。1H NMR(500MHz,CD3OD)δ(ppm):9.38(s,1H),8.41(s,1H),8.14(s,1H),7.86(s,1H),7.23(d,2H),4.49(s,2H),4.17(s,2H),2.08(s,3H).MS ES+m/z 567.2[M+H]+
中间体-21:6-(4--氯-5-甲氧基嘧啶-2-基)-8-(2-氟苄基)-[1,2,4]三唑并[1,5-a]吡嗪(Int-21)
将甲氧基乙酸乙酯(1.0当量)和叔丁氧基双(二甲基氨基)甲烷(2.0当量)的混合物在110℃加热21小时,此时LCMS表明转化为产物。粗反应混合物通过硅胶色谱法,在30分钟内使用己烷中的0至60%乙酸乙酯的梯度直接纯化,得到3-(二甲基氨基)-2-甲氧基丙烯酸乙酯(Int-20a),为浅黄色油状物。MS ES+m/z 174.0[M+H]+
将中间体Int-8(170mg,0.629mmol),Int-20a(327mg,1.89mmol)和DBU(0.285mL,1.89mmol)在无水乙醇(1.5mL)中的溶液在90℃加热1小时,随后LC-MS分析表明转化已完成。冷却至室温后,将反应混合物用2.5M的HCl乙醇溶液酸化至pH 2-3,导致形成细的沉淀。收集固体并干燥,得到中间体Int-20(109mg,产率49%),其为棕色固体。1H NMR(500MHz,DMSO-d6)δ(ppm):12.30(br s,1H),9.55(s,1H),8.82(s,1H),7.73(s,1H),7.48-7.52(m,1H),7.26-7.34(m,1H),7.18-7.24(m,1H),7.11-7.14(m,1H),4.63(s,2H),3.83(s,3H).MSES+m/z 353.1[M+H]+
将中间体Int-20(108.5mg,0.308mmol)在POCl3(574μL,6.16mmol)中的混合物加热至90℃,保持1小时,此时LC-MS分析表明转化已完成。将反应混合物冷却至室温后,真空除去POCl3,并将所得残余物悬浮在冰水中,并用饱和碳酸氢钠溶液中和。用5∶1的二氯甲烷:异丙醇(3×20mL)萃取含水混合物,干燥(硫酸钠),过滤,浓缩,得到中间体Int-21(94.9mg,产率83%),为棕色固体。该物质无需纯化即可用于后续步骤。MS ES+m/z 371.1[M+H]+
化合物I-11
将中间体Int-21(1.0当量)和外消旋-3-氨基1,1,1-三氟丙-2-醇(3.0当量)和三乙胺(5.0当量)在3:1二噁烷/水中的悬浮液(1.3mL)在90℃加热12小时,随后LC-MS分析表明转化已完成。用水稀释反应混合物,并用1.0N盐酸水溶液调节pH至6-7,导致形成橙色沉淀。将固体过滤并干燥。通过反相HPLC,在20分钟内使用在水中的10%至40%的乙腈梯度(用0.1%三氟乙酸改性)纯化粗制固体,得到外消旋的化合物I-11(57.4mg,产率48%),为白色固体。1H NMR:(500MHz,CD3OD),δ(ppm):9.63(s,1H),8.61(s,1H),7.74(s,1H),7.30-7.33(m,1H),7.15-7.20(m,1H),6.97-7.01(m,2H,重叠的位移),4.67(s,2H),4.28-4.32(m,1H),3.98-4.02(m,4H,重叠的位移),3.86-3.91(m,1H).MS ES+m/z 464.2[M+H]+
中间体-23:4--氯-2-(8-(2-氟苄基)-[1,2,4]三唑并[1,5-a]吡嗪-6-基)嘧啶-5-甲腈(Int-23)
将(乙氧基亚甲基)氰基乙酸乙酯(1.72g,10.2mmol),Int-8(0.917g,3.39mmol)和DBU(1.53mL,10.2mmol)在乙醇(6.8mL)中的溶液加热至100℃持续24小时,随后LC-MS分析表明为产物混合物。然后将反应冷却至室温,并通过添加2.5N的HCl的乙醇溶液(4.07mL,10.2mmol)来酸化。将反应混合物浓缩至干,然后在75分钟内通过硅胶色谱法,使用0至100%的在二氯甲烷中的7:1乙腈/甲醇梯度纯化。需要通过硅胶色谱法在75分钟内用在二氯甲烷中的0-70%的7:1乙腈/甲醇梯度进行第二次纯化,以提供Int-22a(214mg,产率16%)(纯度),为棕色固体。未分离出Int-22b。1H NMR(Int-22a):(500MHz,DMSO-d6),δ(ppm):13.43(br.s,1H),9.78(s,1H),8.88(s,1H),8.80(br.s,1H),7.44-7.53(br.m,1H),7.28-7.32(m,1H),7.19-7.22(m,1H),7.09-7.12(m,1H),4.64(s,2H).MS ES+m/z348.1[M+H]+
将Int-22a(211mg,0.608mmol)的悬浮液在POCl3(1.42mL,15.2mmol)中,于80℃加热。3小时后,LC-MS分析表明转化完成。将反应浓缩至干,得到粗制的Int-23(331mg),为棕色固体。1H NMR:(500MHz,DMSO-d6),δ(ppm):9.84(s,1H),9.49(s,1H),8.88(s,1H),7.40-7.43(m,1H),7.28-7.33(m,1H),7.18-7.21(m,1H),7.11-7.14(m,1H),4.67(s,2H).MS ES+m/z366.1[M+H]+
化合物I-12
将中间体Int-23(1.0当量),N-乙基-N-异丙基丙-2-胺(10.0当量)和2-(氨基甲基)-1,1,1,3,3,3-六氟丙烷-2-醇(2.5当量)在二甲亚砜(1.2ml)中的溶液加热至95℃持续24小时。冷却至室温后,将反应混合物通过反相HPLC,在10分钟内使用在水中的20至60%乙腈梯度(经0.1%甲酸改性)直接纯化,得到化合物I-12(8.6mg,产率8%),为金色固体。1HNMR:(500MHz,DMSO-d6),δ(ppm):9.71(s,1H),8.94(s,1H),8.85(s,1H),8.62(br.s,1H),8.19(s,1H),7.46-7.49(m,1H),7.26-7.30(m,1H),7.15-7.18(m,1H),7.07-7.10(m,1H),4.61(s,2H),4.23-4.26(m,2H).MS ES-m/z 525.4[M-H]-
中间体24:8-(噻吩-3-基甲基)咪唑并[1,2-a]吡嗪-6-甲腈(Int-24)
根据专利文献描述的中间体-1的合成(WO 2015/187470A1)以及参考J.Org.Chem.2018,83,11437-11445中(噻吩-3-基甲基)氯化锌(II)的生成,由起始溴化物6,8-二溴咪唑并[1,2-a]吡嗪使用3-(氯甲基)噻吩制备腈中间体Int-24。分离出中间体Int-24a,为灰白色固体(产率68%),并且分离出Int-24,为黄色固体(产率36%)。Int-24a:MS ES+m/z 295.9[M+H]+.Int-24:MS ES+m/z 241.0[M+H]+.
中间体-26:6-(4--氯-5-氟嘧啶-2-基)-8-(噻吩-3-基甲基)咪唑并[1,2-a]吡嗪(Int-26)
通过与从Int-1制备Int-3的相同方法制备中间体Int-26。Int 25a:MS ES+m/z258.0[M+H]+.Int 25:1H NMR:(500MHz,DMSO-d6),δ(ppm):12.82(br s,1H),9.46(br s,1H),8.30(s,1H),8.22(br s,1H),7.90(s,1H),7.43-7.46(m,2H,重叠的位移),7.30(br s,1H),4.54(s,2H).MS ES+m/z 328.0[M+H]+.Int 26:MS ES+m/z 346.0[M+H]+
化合物I-13
将中间体Int-26(1.0当量)和2-(氨基甲基)-1,1,1,3,3,3-六氟丙-2-醇(3.0当量)和三乙胺(5.0当量)在2:1二噁烷/水(0.6mL)中的溶液在90℃加热22h。之后反应完成。用水稀释反应混合物,并用二氯甲烷:异丙醇(5∶1)(3×25mL)萃取。将合并的有机层干燥(硫酸钠),过滤,并浓缩成棕色残余物。通过硅胶色谱法使用在二氯甲烷中的0至40%的7:1乙腈/甲醇的梯度在12分钟内进行纯化,得到化合物I-13(15mg,产率25%),为灰白色固体。1H NMR:(500MHz,DMSO-d6),δ(ppm):9.57(s,1H),9.42(s,1H),8.48-8.51(m,2H,重叠的位移),8.28(s,1H),7.87(s,1H),7.42(br s,1H),7.38(br s,1H),7.26-7.27(m,1H),4.42(s,2H),4.08-4.09(m,2H).MS ES+m/z 507.1[M+H]+
中间体-27:8-((2-甲基嘧啶-5-基)甲基)咪唑并[1,2-a]吡嗪-6-甲腈(Int-27)
根据Journal of the American Chemical Society,2003,125,8082-8083,通过将起始溴化物6,8-二溴咪唑并[1,2-a]吡嗪锂化并用2-甲基嘧啶-5-甲醛淬灭制备中间体Int-27a。
通过使用三氟乙酸和三乙基甲硅烷的标准还原,得到中间体Int-27b。Int-27b向中间体氰基中间体Int-27的转化可通过描述用于制备Int-1的步骤来实现。
中间体28:6-(4--氯-5-氟嘧啶-2-基)-8-(2,5-二氟苄基)咪唑并[1,2-a]吡嗪(Int-28).
根据描述的从Int-1合成Int-3的一般步骤,从Int-27制备中间体Int-28。
化合物I-14
使用与所述的从Int-3制备化合物I-2的相同条件制备化合物I-14。
化合物I-15
前药I-1的二钠盐是使用NaOMe并进行J.Med.Chem.2008,51,1111-1114的实验中描述的步骤。
化合物I-16
将中间体Int-10(1当量),中间体Int-4(3当量)和三乙胺(6.0当量)在1:1的二噁烷/水(1.2mL)中的溶液在80℃下加热24小时。冷却至室温后,将反应混合物用乙酸乙酯稀释,并将得到的有机层干燥(硫酸钠),过滤并浓缩,得到油状物。通过硅胶色谱法使用在己烷中的0至100%乙酸乙酯的梯度来纯化粗制产物,以得到化合物I-16(64.2mg,产率56%),为浅黄色固体。1H NMR(500MHz,CDCl3)δppm 9.52(s,1H),8.56(s,1H),8.26(s,1H),7.64(app.t,1H),7.20-7.25(m,2H),7.02-7.14(m,2H),4.77(s,2H),4.22-4.28(m,2H)[由于与CDCl3交换未观察到2个酸性质子].化合物I-16:MS ES+m/z 495.1[M+H]+.
实施例2:通过384孔格式的基于cGMP GloSensor细胞的测试测量生物活性
使用表达GloSensorTM 40F cGMP(产品编号:CS182801,Promega)的人类胚肾细胞(HEK293细胞)来评估测试化合物的活性。掺入所述细胞中的发光生物传感器(工程化荧光素酶)检测由化合物刺激sGC酶形成的cGMP且发光。
将cGMP GloSensor细胞维持于补充有胎牛血清(FBS,最终浓度10%)及潮霉素(200ug/ml)的达尔伯克(氏)改良伊格尔(氏)培养基(Dulbecco’s Modification ofEagle’s Medium,DMEM)中。测定的前一天,在50μL含10%FBS的DMEM中将细胞以1.5x104个细胞/孔的密度平铺于聚-D-赖氨酸涂布的384孔白色底平板(Corning目录号35661)中。在含有5%CO2的潮湿室中在37℃将细胞片培养过夜。第二天,去除培养基且将细胞更换为40ul/孔的2mM GloSensorTM(Promega目录号E1291)。在25℃下将细胞处理90分钟以容许底物在细胞中平衡。在无血清CO2非依赖性培养基中将测试化合物和二亚乙基三胺NONOate(DETA-NONOate)稀释至3mM(20×)且以4×稀释连续稀释以产生5×剂量曲线,自其中取出10ul添加至孔中(测试化合物溶液的浓度为xμM,DETA-NONOate溶液的浓度为10μM;其中x是以下最终浓度之一)。
30000nM |
7500nM |
1875nM |
468.75nM |
117.19nM |
29.29nM |
7.32nM |
1.83nM |
0.46nM |
0.114nM |
0.029nM |
对于动力学研究,立即用Envision(Perkin Elmer)以每孔0.2秒测量发光。对于终点SAR筛选,在室温下培养55分钟后收集数据。
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),其中低对照为16个DMSO(1%)对照数据点的平均值,且高对照为16个化合物Y(30μM)数据点的平均值,其中化合物Y在下文中描述。对于所有化合物,使用GraphPadPrism软件v.5.n=2使用4-参数拟合(log(激动剂)相对反应-可变斜率)拟合数据。绝对(Abs)EC50从曲线拟合内插,并定义为给定化合物在如上所述的数据归一化后引发50%的高对照响应的浓度。未能引起50%最小反应的化合物报告为>30μM或ND(未测定)。对于一式两份或n高于2的化合物,本文所给出的结果是若干所获得结果的几何平均值。表II分别总结了表I的所选择的化合物获得的结果。
表II.在384孔格式的基于GloSensor细胞的测定中的全细胞活性(实施例2,表I中的化合物)
化合物 | Glo-sGC绝对EC50(nM) |
I-2 | A |
I-3 | A |
I-5 | A |
I-6 | B |
I-7 | B |
I-8 | B |
I-9 | B |
I-10 | C |
I-11 | C |
I-12 | B |
I-15 | C |
I-16 | B |
通过GloSensor测定法测定HEK细胞中的sGC酶活性值。(~)sGC酶活性值的代码定义,表示为绝对EC50,其定义为给定化合物在数据归一化后引发50%高对照响应(化合物Y)的浓度:EC50Abs≤100nM=A;100nM<EC50Abs≤1000nM=B;1000nM<EC50Abs≤30μM=C;30μM<EC50Abs=D。未能引起小于高对照的50%的最大响应的化合物被报告为>30μM或ND(并且属于D类)。
实施例3:Sprague-Dawley大鼠的血压变化
用氯胺酮/甲苯噻嗪麻醉雄性大鼠(体重250-350g,由Harlan Laboratories提供)并在右股动脉植入填充有肝素化生理盐水的导管。将导管在肩胛骨之间取出,加盖,在进行任何化合物测试之前,让动物在术后至少恢复7天。在测试之前,动物在12小时的明暗周期内保持正常饮食,可以自由饮水。
在实验当天,在使用吸入异氟烷麻醉下,将导管的盖打开,并连接至系绳(InstechLabs)和压力传感器(Harvard Apparatus)。随后收集血压和心率,并使用专用数据收集系统(PowerLab,ADInstruments)进行分析。数据采样率设置为每秒1个周期。连接后,让每只大鼠从麻醉中恢复,并在这些有意识的、自由活动的动物中建立基线血压和心率水平。一旦建立基线,就可以口服给药媒介物(0.5%甲基纤维素或100%PEG400)或测试物(PO,10mg/kg),并在长达24小时监测对血压和心率的影响。
将化合物I-2的磷前药(化合物I-1)的钠盐(化合物I-15)以在水中10mg/kg的剂量口服,以确定化合物I-2对血压的作用。给药后一小时,所给药的化合物I-15中的97.5%转化为化合物I-2。给药后160分钟,化合物I-2使MAP(平均动脉压)值比基线值降低了约10mmHg。
尽管已出于说明的目的阐释典型实施方案,但不应认为上述描述及实例限制本发明的范围。因此,在不背离本发明的精神及范围下,本领域技术人员可进行多种修改、调整及改变。
Claims (61)
1.式I的化合物,或其药学上可接受的盐,
其中:
Y独立地为N或C;
环B为苯基或5或6-元杂芳基环,该杂芳基环包含1或2个独立选自N、O或S的环杂原子;
n为选自0至3的整数;和各个JB独立地为卤素、-CN、C1-6脂族基团或-ORB;
其中各个为C1-6脂族基团的JB任选且独立取代有至多3个R3;
各个RB独立地为氢或C1-6脂族基团;所述RB任选且独立取代有至多3个R3a;
各个R3和R3a在每种情况独立为卤素、-CN、C1-4烷基、C1-4卤代烷基、-O(C1-4烷基)或-O(C1-4卤代烷基);
Z选自氢、–P(O)(OH)2、–P(O)(OH)O-M+、–P(O)(O-)2(M+)2、–P(O)(O-)2D2+和-P(O)(O-苄基)2;其中M+是药学上可接受的单价阳离子,D2+是药学上可接受的二价阳离子;
m为0或1;
R1为C1-4烷基、C1-4氟代烷基、-C(O)NH2或氢;和
R2为C1-4烷基、C1-4氟代烷基或氢;
两个R4同时为氢或两个R4与它们所连接的碳原子一起形成羰基;
JD为氢、卤素、甲氧基或-CN;
p为1或2;和
每个JC独立地为氢、卤素、C1-4脂族基团、C1-4烷氧基或-CN;其中每个所述的C1-4脂族基团和每个所述的C1-4烷氧基任选地且独立地被至多3个C1-4烷氧基、C1-4卤代烷氧基、-OH或卤素取代。
2.根据权利要求1所述的化合物,其中环B为苯基或包含1或2个环氮原子的5-6元杂芳基环。
8.根据权利要求1至7中任一项所述的化合物,其中,JD为氢、氯、氟、甲氧基或-CN。
9.根据权利要求8所述的化合物,其中JD为甲氧基。
10.根据权利要求1至7中任一项所述的化合物,其中,JD为氢、氯、氟或-CN。
11.根据权利要求10所述的化合物,其中,JD为氢、氯或氟。
12.根据权利要求10所述的化合物,其中,JD为氟或氢。
13.根据权利要求10所述的化合物,其中,JD为氢。
14.根据权利要求10所述的化合物,其中,JD为氟。
15.根据权利要求10所述的化合物,其中,JD为-CN。
16.根据权利要求10所述的化合物,其中,JD为氯。
17.根据权利要求1至16中任一项所述的化合物,其中每个JC独立地为氢、C1-2烷基、C1-2烷氧基、C1-2氟代烷基、C1-2氟代烷氧基、卤素或-CN,其中每个所述C1-2烷基和C1-2烷氧基任选且独立地被至多3个C1-4烷氧基、C1-4卤代烷氧基、-OH或卤素取代。
18.根据权利要求17所述的化合物,其中每个JC独立地为氢、C1-2烷基、C1-2烷氧基、C1-2氟代烷基、C1-2氟代烷氧基、卤素或-CN。
19.根据权利要求18所述的化合物,其中每个JC独立地为氢或卤素。
20.根据权利要求18所述的化合物,其中每个JC是氢。
21.根据权利要求18所述的化合物,其中每个JC独立地为氟或氯。
30.根据权利要求1至29中任一项所述的化合物,其中,环B为苯基。
31.根据权利要求1至29中任一项所述的化合物,其中环B为5或6元杂芳基环,其含有独立地选自N、O和S的1或2个环杂原子。
32.根据权利要求31所述的化合物,其中环B是含有1至2个环氮原子的6元杂芳基环。
33.根据权利要求1至32中任一项所述的化合物,其中n为1、2或3,并且每个JB独立地为卤素或C1-6脂族基团。
34.根据权利要求30所述的化合物,其中n为1或2,并且每个JB独立地为卤素或C1-6脂族基团。
35.根据权利要求34所述的化合物,其中n为1或2,并且每个JB为氟。
36.根据权利要求35所述的化合物,其中,n为1,JB为氟。
41.根据权利要求1至40中任一项所述的化合物,其中,R1为C1-2烷基、C1-2氟代烷基、氢或-C(O)NH2。
42.根据权利要求1至41中任一项所述的化合物,其中R1是C1-2氟代烷基或-C(O)NH2。
43.根据权利要求1至42中任一项所述的化合物,其中R2为C1-2氟代烷基、C1-2烷基或氢。
44.根据权利要求1至42中任一项所述的化合物,其中R2为C1-2氟代烷基。
45.权利要求42或权利要求44所述的化合物,其中R1是三氟甲基或-C(O)NH2,R2是三氟甲基。
46.根据权利要求1至41中任一项所述的化合物,其中R1和R2均为氢或C1-2烷基;或R1和R2中的一个是氢,另一个是C1-2氟代烷基。
47.根据权利要求46所述的化合物,其中R1和R2均为氢。
48.根据权利要求46所述的化合物,其中R1和R2均为甲基。
49.根据权利要求46所述的化合物,其中R1和R2中的一个是氢,另一个是三氟甲基。
51.根据权利要求50所述的化合物,其中JD是氟。
53.根据权利要求52所述的化合物,其中JD为氟。
54.根据权利要求1至53中任一项所述的化合物,其中Z为–P(O)(OH)2。
55.根据权利要求1至53中任一项所述的化合物,其中Z为–P(O)(OH)O-M+或–P(O)(O-)2(M+);和M+为Na+、K+或有机胺的单价阳离子。
56.根据权利要求55所述的化合物,M+为Na+。
57.根据权利要求1至53中任一项所述的化合物,其中Z为–P(O)(O-)2D2+;和D2+为Ca2+、Cs2+、Zn2+、Mg2+或有机胺的二价阳离子。
58.根据权利要求1所述的化合物,其选自表I中所述的那些。
59.药物组合物,其包含根据权利要求1-58中任一项所述的化合物和至少一种药学上可接受的赋形剂或载体。
60.一种在需要治疗的受试者中治疗疾病、健康状况或病症的方法,包括向需要治疗的受试者施用治疗有效量的权利要求1至58中任一项的化合物或权利要求59的药物组合物,其中所述疾病、健康状况或病症选自:
无β脂蛋白血症、失弛缓症、食管失弛症、急性呼吸窘迫综合征(ARDS)、粘连性囊炎、与年龄有关的学习和记忆障碍、与年龄有关的记忆丧失、酒精中毒、秃顶或脱发、高原反应、阿尔茨海默病、临床前阿尔茨海默氏病、轻度至中度阿尔茨海默病和中度至重度阿尔茨海默病、肌萎缩性侧索硬化症(ALS或Lou Gehrig病)、肛裂、动脉瘤、心绞痛、稳定或不稳定型心绞痛、变异型心绞痛、普林兹迈托心绞痛、微血管性心绞痛、焦虑症或焦虑障碍、精胺基琥珀酸尿症、动脉和静脉血栓形成、关节炎、亚斯伯格症候群、哮喘和哮喘性疾病、共济失调、毛细管扩张、动脉粥样硬化、与内皮损伤、血小板和单核细胞粘附和聚集、平滑肌增生或迁移相关的动脉粥样硬化、萎缩性阴道炎、注意缺陷障碍(ADD)和注意缺陷性多动症(ADHD)、自闭症和自闭症谱系中的障碍、良性前列腺增生症(BPH)或肥大或肿大、双相情感障碍、膀胱出口梗阻、膀胱疼痛综合征(BPS)、眼睑炎、骨骼和碳水化合物的代谢紊乱、骨愈合、破骨性骨重塑、破骨细胞吸收、新骨形成后的骨愈合、脑动脉瘤、脑缺氧、癌症转移、脑淀粉样蛋白血管病(CAA)或嗜刚果红血管病、脑常染色体显性动脉病伴皮质下梗死和白质脑病(CADASIL或CADASIL综合征)、脑灌注、脑小血管疾病、脑血管痉挛、化疗头、童年瓦解性障碍、慢性支气管炎、慢性疲劳、慢性创伤脑部病变(CTE)、硬化、肝硬化、与慢性肝病相关的肝硬化、原发性胆汁性肝硬化、中枢神经系统疾病相关的性功能障碍、中枢神经系统疾病相关的睡眠障碍、亨廷顿舞蹈病相关的认知缺陷、认知功能障碍、认知受损、血管性认知受损、轻度认知受损、糖尿病相关的认知受损、多发性硬化症相关的认知受损、阻塞性睡眠呼吸暂停相关的认知受损、精神分裂症相关的认知受损(CIAS)、镰状细胞病相关的认知受损、脑震荡、先天性肌无力综合征、结缔组织病、脑梗塞的后果(脑卒中)、创伤患者血液替代品的保存、CREST综合征、克罗恩病、囊性纤维化病(CF)、妄想症、痴呆、血管性痴呆、中风后痴呆、路易体痴呆、额叶退化病变痴呆、额颞叶变性痴呆、皮质基底节变性痴呆、Creutzfeldt-Jakob痴呆、HIV痴呆、多发性梗塞性痴呆、术后痴呆、要害单发性痴呆、HIV相关痴呆、无症状神经认知障碍(ANI)、轻度神经认知障碍(MND)、HIV相关痴呆(HAD,也称为AIDS痴呆复合症[ADC]或HIV脑病、早老痴呆症(轻度认知障碍、MCI)、混合性痴呆、宾斯旺格痴呆(皮质下动脉硬化性脑病)、帕金森氏痴呆症、脱髓鞘、抑郁、抑郁性障碍、皮肌炎、糖尿病性血管病、糖尿病性黄斑水肿、糖尿病性微血管病变、糖尿病性溃疡或伤口、糖尿病足溃疡、与代谢综合征相关或关联的疾病、肥胖、糖尿病、胰岛素抗药性、空腹血糖过高、空腹胰岛素过高、血脂过高、涉及神经递质下调的疾病、涉及脑血流受损的疾病、涉及神经变性受损的疾病、涉及突触功能受损的疾病、涉及神经炎症的疾病、涉及神经毒性的疾病、男性和女性泌尿生殖系统器官疾病(良性和恶性)、有学习和记忆障碍的儿童的注意力障碍、唐氏综合症、吸毒成瘾、药物引起的精神病、干眼症、杜兴氏肌营养不良症、掌腱膜挛缩症、运动障碍、急性运动障碍、慢性或迟发性运动障碍、非运动性运动障碍、左旋多巴诱发的运动障碍(LID)、痛经、原发性痛经、继发性痛经、性交困难、吞咽困难、张力障碍、全身性张力障碍、灶性张力障碍、节段性张力障碍、性张力障碍、中度张力障碍、急性张力障碍反应、遗传性或原发性张力障碍、水肿、电解质紊乱、高钾血症、低钠血症、肺气肿、子宫内膜异位症、内皮功能障碍或与内皮功能障碍相关的损伤以及疾病、勃起功能障碍、食管失弛症、法布里病、女性性功能障碍、女性性唤起功能障碍、纤维肌痛、纤维化、心内膜纤维化、心房纤维化、心脏间质纤维化、心脏纤维化、肺纤维化、眼纤维化、皮肤纤维化、肠纤维化、肾或肾脏纤维化、间质性肾纤维化、肺纤维化、特发性肺纤维化、肺进行性大规模纤维化、肝纤维化、纵隔纤维化、腹膜后纤维化、关节纤维粘连、骨髓纤维化、骨髓纤维变性、骨髓纤维瘤、放射性诱导的纤维化、胰囊性纤维化、脆性X染色体综合征、功能性消化不良、胃肌轻瘫、高雪病、一般性注意力障碍、一般性精神病、青光眼、成胶质细胞瘤、肾小球病、肾小球肾炎、急性肾小球肾炎、肾小球硬化、局灶性节段性肾小球硬化、肉芽肿、头部受伤、听力障碍、部分听力损失、全部听力损失、部分耳聋、完全耳聋、噪声引起的听力损失、心脏疾病、左室心肌重构、左心室收缩功能障碍、缺血性心肌病、扩张型心肌病、酒精性心肌病、储存型心肌病、先天性心脏缺陷、冠状血流减少、舒张或收缩功能障碍、冠状供血不足、急性冠脉综合征、冠状动脉疾病、心律不齐、心室前负荷降低、心脏肥大、右心肥大、房性节律和室性节律失常以及心脏传导障碍、I-III度房室传导阻滞(AVB I-III)、室上性快速性心律失常、心室早发性收缩、房颤、房扑、室颤、室扑、室性快速型心律失常、尖端扭转型室性心动过速、房性和室性期外收缩、房室交接性早搏、病窦综合征、房室结折返性心动过速、午-帕-怀三氏综合征、心肌机能不全、慢性、急性或病毒性心肌炎、心源性休克、心脏重构、心力衰竭(HF)、射血分数保留型心衰(HFpEF)、射血分数降低型心衰(HFrEF)、急性心力衰竭、慢性心力衰竭、现有慢性心力衰竭的急性期(心衰恶化)、短暂性心力衰竭、急性后心力衰竭、收缩性心力衰竭、舒张性心力衰竭、充血性心力衰竭、急性失代偿性心力衰竭、右心室衰竭、总心力衰竭、高输出量性心力衰竭、具有瓣膜缺损的心力衰竭、糖尿病性心力衰竭、心力衰竭/心肺综合征、右心力衰竭、高浓度的纤溶酶原激活物抑制剂1(PA-1)、高水平的纤维蛋白原和低密度DLD、组织细胞增多症X、亨廷顿舞蹈病或舞蹈病(HD)、高氨血症及相关疾病、高血压、动脉高血压、顽固性高血压、糖尿病性高血压、特发性高血压、原发性高血压、继发性高血压、妊娠高血压、门静脉高血压、全身性高血压、先兆子痫、急慢性冠状血压升高、张力亢进、肥厚性瘢痕、活动减退的性苏醒障碍、灌注不足、阳痿、肠炎、克罗恩病、溃疡性结肠炎、由脑部疟疾引起的炎症、由传染病引起的炎症、围手术期护理中的炎症反应、血小板聚集、智力障碍、间歇性跛行、间质性膀胱炎(IC)、透析中低血压、缺血、脑缺血、心肌缺血、血栓栓塞性缺血、严重肢体缺血、瘢痕疙瘩、肾脏疾病、慢性肾脏疾病、急慢性肾功能衰竭、急慢性肾功能不全、肾功能不全的后遗症、与肺水肿相关的肾功能不全、与心力衰竭相关的肾功能不全、与尿毒症或贫血相关的肾功能不全、原发性肾脏疾病、先天性肾脏疾病、多囊性肾脏疾病进展、肾脏移植排斥反应、免疫复合物诱导的肾脏疾病、肌酐和/或水的排泄异常减少、尿素、氮、钾和/或肌酐的血浓度异常升高、肾酶活性改变、谷氨酰合成酶活性改变、尿渗透压或尿液量改变、微量白蛋白尿增加、巨白蛋白尿、肾小球和小动脉病变、肾小管扩张、高磷酸盐血症、血管性肾脏疾病、肾囊肿、心力衰竭导致的肾水肿、科萨科夫精神病、白细胞活化、左旋多巴引起的成瘾行为、地衣硬化、脂质相关疾病、肥胖过度、皮下脂肪过多、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)水平适度升高、高甘油三酯血症、高甘油酯血症、高脂蛋白血症、谷固醇血症、脂肪肝疾病、肝脂肪变性或肝脏中脂质异常蓄积、心脏、肾脏或肌肉的脂肪变性、谷固醇血症、黄瘤病、丹吉尔病、肝病、血管性肝病、肝星状细胞活化、肝纤维胶原蛋白和总胶原蛋白积累、坏死性炎性和/或免疫性肝病、与肉芽肿性肝病相关的胆汁淤积性肝病、与肝恶性肿瘤相关的胆汁淤积性肝病、与妊娠肝内胆汁淤积相关的胆汁淤积性肝病、与肝炎相关的胆汁淤积性肝病、与败血症相关的胆汁淤积性肝病、与药物或毒素相关的胆汁淤积性肝病、与移植物抗宿主病相关的胆汁淤积性肝病、与肝移植后相关的胆汁淤积性肝病、与胆总管结石病相关的胆汁淤积性肝病、与胆管肿瘤相关的胆汁淤积性肝病、与胰腺癌相关的胆汁淤积性肝病、与Mirizzi综合征相关的胆汁淤积性肝病、与艾滋病相关的胆汁淤积性肝病、胆管病变、与寄生虫相关的胆汁淤积性肝病、与血吸虫病相关的胆汁淤积性肝病、肝炎、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪肝(NAFLD)、肝血管闭塞性疾病(VOD)、肝性脑病、局部血栓形成、下尿道综合征(LUTS)、腰椎管狭窄、狼疮性肾炎、狼疮或系统性红斑狼疮、微量白蛋白尿、微循环异常、偏头痛、轻度神经性认知障碍(MND)、硬斑病、烟雾病、多发性腔隙性脑梗塞、多器官功能障碍综合征(MODS)、多器官衰竭(MOF)、多发性硬化(MS、包括临床孤立综合征(CIS)、复发缓解型MS(RRMS)、原发性进行性MS(PPMS)、继发进行性MS(SPMS)、多系统萎缩(MSA)、心肌梗塞或心脏病发作、ST段抬高型心肌梗塞、非ST段抬高型心肌梗塞、陈旧性心肌梗塞、近视脉络膜新生血管形成、痣、麻醉品依赖、肾病、糖尿病肾病、非糖尿病肾病、肾炎、毒素引起的肾病、造影剂诱发的肾病、糖尿病性或非糖尿病性肾硬化、肾病综合征、肾盂肾炎、肾原性纤维化、神经退行性疾病、神经源性膀胱和尿失禁、神经炎症、与一氧化氮产生减少相关的神经系统疾病、神经肌肉疾病、迪谢内肌营养不良(DMD)、贝克肌营养不良(BMD)、肢带肌营养不良、远端肌病、I型和II型营养不良性肌强直、面部-肩胛-腓骨肌营养不良、常染色体和X染色体连锁埃-德二氏肌营养不良、眼咽肌营养不良、肌萎缩性侧索硬化症、脊髓性肌萎缩症(SMA)、视神经脊髓炎、神经病、周围神经病、自主神经病、中枢神经系统神经病、化学疗法诱发的神经病、糖尿病性神经病、疼痛性神经病、神经性疼痛、非疼痛性神经病、疼痛性糖尿病性神经病变、非疼痛性糖尿病性神经病变、与中枢神经系统疾病相关的神经病、多发性硬化症(MS)、带状疱疹相关的神经性疼痛、脊柱手术相关的神经性疼痛、强迫症(OCD)、阻塞性血栓性血管炎、阻塞性尿路病变、嗜酸细胞性筋膜炎、骨质疏松症、膀胱过度活动症、疼痛、急性疼痛、中枢性疼痛综合征、炎症性疼痛、术后疼痛、持续性痛、内脏痛、跛行痛、孤儿病痛症、乙酰唑胺反应性肌强直、自体红细胞致敏综合征、常染色体显性遗传夏科-马里-图斯病2V型、常染色体显性遗传中介的夏科-马里-图斯病伴神经性疼痛、常染色体隐性遗传肢带型肌营养不良症2A型、离子信道疾病相关的先天性疼痛不敏感、需要椎管内镇痛的慢性疼痛、复杂性区域疼痛综合征、复杂性区域疼痛综合征1型、复杂性区域疼痛综合征2型、伴有多汗症的先天性疼痛不敏感、伴有严重智力障碍的先天性疼痛不敏感、先天性疼痛不敏感-多汗综合征、伴有疼痛性裂缝的弥漫性掌跖角化病、家族性阵发性疼痛综合征、主要是下肢受累的家族性阵发性疼痛综合征、主要累及上半身的家族性阵发性疼痛综合征、遗传性疼痛性胼胝、遗传性感觉神经和自主神经病4型、遗传性感觉神经和自主神经病5型、遗传性感觉神经和自主神经病7型、间质性膀胱炎、疼痛性眼眶和系统性神经纤维瘤-马凡习惯综合征、阵发性极度疼痛疾病、持续性特发性面部疼痛、卡配因的定性或定量缺陷、Tolosa-Hunt综合征、胰腺炎、恐慌症、帕金森氏病、帕金森叠加综合征、帕金森氏吞咽困难、病理性进食障碍、骨盆疼痛、周围血管疾病、外周动脉疾病、外周动脉闭塞性疾病、外周血栓塞、外周血灌注障碍、腹膜炎、广泛性发育障碍、佩罗尼氏病、皮克综合征、多发性软骨炎、多发性肌炎、疱疹后神经痛、创伤后颅脑损伤、创伤后应激障碍(PTSD)、早泄、进行性核麻痹、前列腺肥大、肺部疾病、丛生性肺动脉病、支气管收缩或肺支气管收缩、肺血管疾病、慢性阻塞性肺疾病(COPD)、肺毛细血管血管瘤病、淋巴管瘤病和由于腺病、肿瘤或纤维化性纵隔炎导致的压缩性肺血管、肺血管重构、肺张力过高、肺性高血压(PH)、肺动脉高血压(PAH)、原发性PH、继发性PH、散发性PH、毛细血管前PH、特发性PH、与左心室疾病相关的PH、与HIV相关的PH、与SCD相关的PH、与血栓栓塞相关的PH(慢性血栓栓塞性PH或CTEPH)、与结节病相关的PH、与慢性阻塞性肺疾病相关的PH、与急性呼吸窘迫综合征相关的PH(ARDS)、与急性肺损伤相关的PH、与α-1-抗胰蛋白酶缺乏相关的PH(AATD)、与肺气肿相关的PH、吸烟引起的肺气肿、与肺部疾病相关的PH、与低氧血症相关的PH、与硬皮病相关的PH、与囊性纤维化(CF)相关的PH、与左心室功能不全相关的PH、与低氧血症相关的PH、PH(WHO组I、II、III、IV和V)、与二尖瓣疾病相关的PH、与心包炎相关的PH、与缩窄性心包炎相关的PH、与主动脉狭窄相关的PH、与扩张型心肌病相关的PH、与肥厚型心肌病相关的PH、与限制性心肌病相关的PH、与纵隔纤维变性相关的PH、与肺纤维化相关的PH、与肺静脉畸形引流相关的PH、与肺静脉闭塞性疾病相关的PH、与肺血管炎相关的PH、与胶原血管疾病相关的PH、与先天性心脏病相关的PH、与肺静脉高血压相关的PH、与间质性肺疾病相关的PH、与睡眠障碍性呼吸相关的PH、与慢性气流阻塞相关的PH、与阻塞性睡眠呼吸暂停相关的PH、与中枢性睡眠呼吸暂停相关的PH、与混合性睡眠呼吸暂停相关的PH、与肺泡通气不足相关的PH、与长期暴露于高原相关的PH、与新生儿肺部疾病相关的PH、与肺泡-毛细血管发育不良相关的PH、与镰状细胞病相关的PH、与其他凝血功能障碍相关的PH、与慢性血栓栓塞相关的PH、神经根病、雷诺氏病、雷诺氏综合征(原发性或继发性)、难治性癫痫、Renpenning综合征、再灌注损伤、缺血-再灌注损伤、与器官移植相关的缺血-再灌注、再狭窄、溶栓治疗后、经皮经腔血管成形术后(PTA)、腔内冠状动脉成形术后(PTCA)、心脏移植术后或搭桥手术后再狭窄、视网膜病变、糖尿病性视网膜病变、非糖尿病性视网膜病变、非增生性糖尿病视网膜病变、增生性玻璃体视网膜病变、周围性视网膜变性、视网膜静脉阻塞、Rhett病、类风湿和风湿病、关节炎、类风湿关节炎、结节病、肉状瘤、血吸虫病、情感性分裂症、精神分裂症、伴有痴呆的精神分裂症、硬皮病、局部性硬皮病或局限性硬皮病、全身性硬皮病、硬化症、肾硬化、进行性硬化、肝硬化、原发性硬化性胆管炎、胃肠道硬化、海马硬化、局灶性硬化、原发性外侧硬化、骨硬化、耳硬化、动脉粥样硬化、结节性硬化、全身性硬化、败血症或败血性休克或过敏性休克、镰状细胞性贫血、镰状细胞性疾病、干燥综合征、睡眠觉醒障碍、Sneddon综合征、痉挛、冠状动脉痉挛、血管痉挛、外周动脉痉挛、脊髓损伤、脊髓肌肉萎缩、脊髓半脱位、脊髓小脑共济失调、Steelee-Richardson-Olszewski病(进行性核上麻痹)、中风、蛛网膜下腔出血、皮层下动脉硬化性脑病、晕厥、Tau病、紧张、丘脑变性、血栓栓塞性或血栓形成性疾病、短暂性脑缺血发作(TIA)、外伤性脑损伤、肾小管间质疾病、溃疡、子宫纤维瘤、阴道萎缩、瓣膜缺损、二尖瓣狭窄、二尖瓣回流、二尖瓣闭锁不全或二尖瓣关闭不全、主动脉瓣狭窄、主动脉瓣关闭不全、三尖瓣关闭不全、肺动脉瓣狭窄、肺动脉瓣关闭不全、联合瓣膜缺陷、脑血管疾病、心脏和肾脏并发症导致的血管疾病、血管渗漏或通透性、血管炎、血栓性血管炎、闭塞性血栓性血管炎、川崎病、动脉炎、主动脉炎、血管阻塞危象、抗移植失败、湿性老年黄斑变性和威廉综合症。
61.根据权利要求60所述的方法,其进一步包括向所述受试者给药有效量的其他合适的治疗剂。
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Publication number | Publication date |
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MA51305A (fr) | 2020-10-28 |
JP7337067B2 (ja) | 2023-09-01 |
PH12020550956A1 (en) | 2021-03-22 |
AU2018388629B2 (en) | 2023-11-16 |
EA202091502A1 (ru) | 2020-11-12 |
AU2018388629A1 (en) | 2020-07-30 |
IL275415A (en) | 2020-07-30 |
CA3086207A1 (en) | 2019-06-27 |
JP2021508326A (ja) | 2021-03-04 |
US11897887B2 (en) | 2024-02-13 |
US20200377508A1 (en) | 2020-12-03 |
CN111712247B (zh) | 2024-02-09 |
MX2020006433A (es) | 2020-09-17 |
EP3727388A1 (en) | 2020-10-28 |
BR112020012629A2 (pt) | 2020-12-01 |
SG11202005718PA (en) | 2020-07-29 |
KR20200100696A (ko) | 2020-08-26 |
WO2019126354A1 (en) | 2019-06-27 |
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