CN117915917A - 使用sGC刺激剂的CNS疾病治疗 - Google Patents
使用sGC刺激剂的CNS疾病治疗 Download PDFInfo
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Abstract
本发明是关于可溶性鸟苷酸环化酶(sGC)的刺激剂、其医药学上可接受的盐及包含其的医药制剂或剂型单独或与一或多种额外药物组合用于治疗各种CNS疾病的用途,其中sGC刺激的增加、或一氧化氮(NO)或环状3',5'‑单磷酸鸟苷(cGMP)或两者的浓度的增加或NO‑sGC‑cGMP路径的上调是期望的。适用于本发明的方法中的化合物为式I所示的那些化合物或其医药学上可接受的盐。
Description
相关申请
本申请主张2021年4月20日申请的美国临时申请案第63/177,023号及2021年8月4日申请的美国临时申请案第63/229,251号的优先权益。上述提及的申请案中的每一者的全部内容以引用的方式并入本文中。
技术领域
本发明是关于可溶性鸟苷酸环化酶(sGC)的刺激剂、其医药学上可接受的盐及包含其的医药制剂或剂型单独或与一或多种额外药物组合用于治疗各种CNS疾病的用途,其中sGC刺激增加、或一氧化氮(NO)或环状3′,5′-单磷酸鸟苷(cGMP)或两者浓度的增加,或NO-sGC-cGMP路径的上调是期望的。
背景技术
sGC为体内针对NO的主要受体。在结合至sGC后,NO活化其催化域且使得鸟苷-5′-三磷酸酯(GTP)转化成第二信使cGMP。增加量的cGMP又调节包括蛋白激酶、磷酸二酯酶(PDE)及离子通道的下游效应物的活性。在体内,NO通过各种一氧化氮合成酶(NOS)及通过无机硝酸盐的循序还原由精氨酸及氧合成。实验及临床迹象指示,NO浓度降低、NO生物利用度降低及/或对内源性产生的NO的反应性降低促成众多疾病的发展。sGC刺激剂为sGC酶的血红素依赖性激动剂,所述sGC酶与不同量的NO协同作用以提高其GTP至cGMP的酶促转化。sGC刺激剂与已知为sGC活化剂的另一类NO非依赖性、血红素非依赖性sGC激动剂明显相互区分且在结构上不相关。
改善或恢复sGC功能的疗法提供优于现有替代疗法的相当大的优点,所述替代疗法靶向NO-sGC-cGMP路径或以其他方式得益于NO-sGC-cGMP路径的上调。迫切需要研发出针对具有功能异常或下调NO-sGC-cGMP路径的患者的新颖且安全的疗法。
可跨越血脑屏障(BBB)且可穿透至中枢神经系统(CNS)中的sGC刺激剂提供治疗CNS疾病的额外益处。本文所描述的sGC刺激剂由于其跨越BBB且活化大脑中的靶标的能力而适用于治疗CNS疾病。迫切需要研发用于治疗CNS疾病的额外的新颖治疗剂。在CNS中使用sGC刺激代表一种近年来才开始研究的治疗这些疾病的新颖作用机制,因为过去缺乏具有CNS穿透性质的sGC刺激剂。
发明内容
本发明是基于发现本文所披露的化合物为能够穿透血脑障壁(BBB)的sGC刺激剂且因此适用于治疗CNS疾病。具有相关结构特点,特别是在嘧啶环上具有4-OH取代基的化合物先前仅已知为可用于制备嘧啶环上具有4-胺基取代基的sGC刺激剂的合成中间物。现有公开中之此类别的化合物不具有医疗用途。出乎意料地发现,本发明的化合物具有较强的sGC刺激活性且其能够穿透BBB、增加大脑中的cGMP浓度且在活体外及体内测定中显示CNS活性。
在第一方面中,本发明涉及一种治疗有需要受试者的CNS疾病、CNS健康状况或CNS病症的方法,其包含单独或以组合疗法形式施用治疗有效量的由式I表示的化合物:
或其医药学上可接受的盐,其中:
JC选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
X为N或C(JC1);
JC1选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
各JB独立地选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
JD选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;及
n为选自0、1、2、3或4的整数。在第二方面中,本发明涉及一种治疗有需要受试者的CNS疾病、CNS健康状况或CNS病症的方法,其包含单独或以组合疗法形式向所述受试者施用治疗有效量的包含式I化合物或其医药学上可接受的盐的医药组合物或剂型。
在第三方面中,本发明进一步涉及式I化合物或其医药学上可接受的盐或包含式I化合物或其医药学上可接受的盐的医药组合物或剂型的用途,其用于制造用于治疗有需要受试者的CNS疾病、CNS健康状况或CNS病症的药物。
在第四方面中,本发明进一步涉及式I化合物或其医药学上可接受的盐、包含式I化合物或其医药学上可接受的盐的医药组合物或剂型,其用于治疗有需要受试者的CNS疾病、CNS健康状况或CNS病症。
附图说明
图1显示化合物I-14对雄性血压正常大鼠中的MAP相对于基线的变化(ΔBMAP)的作用。
图2显示化合物I-20对雄性血压正常大鼠中的ΔBMAP的作用。
图3显示在T=0min时PO(3mg/kg)施用化合物I-14之后,成年雄性Sprague-Dawley大鼠大脑的STR及HIPP区域中的化合物I-14的含量。数据表示为平均值±SEM,N=5。
图4显示在施用单次口服剂量的化合物I-20(1mg/kg、3mg/kg或10mg/kg)之后1、2及6小时,大鼠CSF中的cGMP的浓度。
图5显示在施用单次口服剂量的化合物I-14(1mg/kg、3mg/kg或10mg/kg或30mg/kg)之后1、2及6小时,大鼠CSF中的cGMP的浓度。
图6显示化合物I-14在具有帕金森氏病认知缺陷的长期低剂量MPTP-病变猕猴模型中的认知作用。SDR效能在长期低剂量MPTP暴露之后显著减弱(**P<0.01)。在施用媒剂后,SD(简单的辨别)及SDR(简单的辨别逆转)效能与MPTP基线效能无区别。SDR效能在化合物I-14施用之后显著改善(**P<0.01)且在清除期间恶化(**P<0.01对比药物效能)。图6A显示平均值±SEM效能;且图6B为用平均值±SEM显示单独数据的散点图。N=正常,MPTP前;WO=清除。
发明详述
现将详细参考本发明的某些实施方案,其实例在随附结构及式中说明。虽然本发明将结合所列举的实施方案描述,但应了解其不欲将本发明限于这些实施方案。相反地,本发明意欲涵盖所有替代方案、改进及等效物,这些都包括在申请专利范围所界定的本发明范畴内。本发明不限于本文所描述的方法及材料,而是包括类似于或等效于可用于本发明的实践的本文所描述所示的那些方法及材料的任何方法及材料。在所并入的文献参考、专利或类似材料中的一或多者(包括但不限于经定义的术语、术语用法、所描述的技术等)与本申请不同或抵触的情况下,以本申请为准。
定义及通用术语
出于本发明的目的,化学元素系根据元素周期表,CAS版,及Handbook ofChemistry and Physics,第75版,1994来鉴别。另外,有机化学的一般原理描述于“OrganicChemistry”,Thomas Sorrell,University Science Books,Sausalito:1999及“March′sAdvanced Organic Chemistry”,第5版,Smith,M.B.及March,J.编,John Wiley&Sons,NewYork:2001中,其全部内容以引用的方式并入本文中。
当结构中的一或多个位置可经选自指定群组或列举的一个或多于一个取代基取代时,各位置处之一或多个取代基可经“独立地选择”以在各位置处且对于每一次出现为相等或相同的,除非另外规定。举例而言,若苯基经两个R100取代且各R100独立地选自卤素及甲基,则是指R100的每一次出现分别选自卤素或甲基;例如,一个R100可为氟且一个可为甲基,或两者均可为氯等。类似地,若可取代原子结合至多于一个氢(例如CH3或NH2),则取代基可经“独立地选择”以在各位置处且对于每一次出现为相等或相同的,除非另有规定。举例而言,若甲基(例如CH3)经两个R100取代且各R100独立地选自卤素及甲基,则是指R100之每一个例分别选自卤素或甲基;例如,一个R100可为氟且一个可为甲基(例如,CHF(CH3),或两者均可为氯(例如CHCl2),等等。
本发明预想的取代基的选择及组合仅为形成稳定或化学上可行的化合物的那些选择及组合。此类选择及组合对于一般本领域技术人员将为显而易见的,且可在无过度实验的情况下确定。如本文所使用的术语“稳定的”是指在经受允许其生产、检测及在一些实施方案中其回收、纯化的条件时以及用于本文所披露的一或多个目的时实质上不发生改变的化合物。化学上可行的化合物是由本领域技术人员基于本文披露的内容(在必要时辅以本领域的相关知识)可制备的化合物。
除非另外陈述,否则本发明化合物的所有互变异构形式也在本发明的范围内。
在一个实施方案中,本发明可包括用氘(亦即2H)置换氢,如此可得到由更大代谢稳定性带来的某些治疗优势(例如,体内半衰期延长或剂量需求降低)且因此在一些情况下可为较佳的。经氘标记的本发明化合物大体上可通过以下类似于下文方案及/或实例中所示的那些操作来制备,通过用经氘化试剂取代未经氘化的试剂。
如本文所使用,如在(例如)“烷基链”或“烷基基团”中的术语“烷基”是指饱和非支链(例如直链)或支链单价烃基。Cx烷基为含有x个碳原子的烷基链,其中x为不为0的整数。“Cx-y烷基”(其中x及y为两个不同整数,两者均不为0)为含有数目介于x与y之间(包括端点)的碳原子的烷基链。举例而言,C1-6烷基为如上文所定义的含有介于1与6之间的任何数目的碳原子的烷基。烷基的实例包括(但不限于)甲基(亦即C1烷基)、乙基(亦即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、辛基及其类似者。在某些实施方案中,烷基为C1-4烷基。在某些实施方案中,烷基为C1-3烷基或C1-2烷基。在其他实施方案中,烷基为甲基或乙基。
如本文中所使用,术语“氟烷基”是指如上文所定义的烷基,其中在烷基的任一个或多个碳原子处,连接至链碳原子的氢原子中的一或多者已被氟置换。举例而言,经1至3个氟原子取代的氟烷基为其中在烷基链的同一碳原子或不同碳原子上的任何位置处的1至3个氢原子已被氟原子置换的烷基。
如本文中所使用,术语“卤素”或“卤代”是指F、Cl、Br或I。在某些实施方案中,卤代为F或Cl。在其他实施方案中,卤代为F。
术语“羟基(hydroxyl/hydroxy)”是指-OH。
本发明的化合物在本文中通过其化学结构及/或化学名称定义。在通过化学结构与化学名称提及化合物且化学结构与化学名称冲突时,化学结构决定化合物的身分。
化合物及组合物实施方案
本发明涉及式I化合物、其医药学上可接受的盐或包含该化合物或其医药学上可接受的盐的医药组合物的医疗用途。
在第一方面中,本发明涉及一种治疗有需要受试者的CNS疾病、健康状况或病症的方法,其包含单独或以组合疗法形式向所述受试者施用治疗有效量的由式I表示的化合物:
或其医药学上可接受的盐,其中:
JC选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
X为N或C(JC1);
JC1选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
各JB独立地选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
JD选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;及
n为选自0、1、2、3或4的整数。
在第二方面中,本发明涉及一种治疗有需要受试者的CNS疾病、健康状况或病症的方法,其包含单独或以组合疗法形式向所述受试者施用治疗有效量的包含式I化合物或其医药学上可接受的盐的医药组合物或剂型。
在第三方面中,本发明进一步涉及式I化合物或其医药学上可接受的盐或包含式I化合物或其医药学上可接受的盐的医药组合物或剂型的用途,其用于制造用于治疗有需要受试者的CNS疾病、健康状况或病症的药物。
在第四方面中,本发明进一步涉及式I化合物或其医药学上可接受的盐或包含式I化合物或其医药学上可接受的盐的医药组合物或剂型,其用于治疗有需要受试者的CNS疾病、健康状况或病症。
在第一、第二、第三及第四方面的第一实施方案中,对于式I化合物,n为选自1、2、3或4的整数,各JB独立地选自由以下组成的群组:卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基,苯环的所有其他碳原子为未经取代的,且其余变量如上文所定义。
在第一、第二、第三及第四方面的第二实施方案中,对于式I化合物或其医药学上可接受的盐,JC选自由以下组成的群组:氢、卤素及C1-6烷基;JC1选自由以下组成的群组:氢、卤素及C1-6烷基;各JB独立地选自由以下组成的群组:氢、卤素及C1-6烷基;JD选自由以下组成的群组:氢、卤素及C1-6烷基;且其余变量如上文针对第一方面中的式I所定义。
在第一、第二、第三及第四方面的第三实施方案中,式I化合物由式IA表示:
或其医药学上可接受的盐,其中变量如上文针对第一方面或第一或第二实施方案的式I所描述。
在第四实施方案中,对于式IA化合物或其医药学上可接受的盐,JC1为H、F或Cl;且其余变量如第一方面或第一、第二或第三实施方案中所定义。
在第五实施方案中,对于式IA化合物或其医药学上可接受的盐,JC1为H;且其余变量如第一方面或第一至第四实施方案中任一者所定义。
在第六实施方案中,对于式IA的化合物或其医药学上可接受的盐,JC1为F;且其余变量如第一方面或第一至第五实施方案中任一者所定义。
在第七实施方案中,式I化合物由式IB表示:
或其医药学上可接受的盐,其中变量如上文针对根据第一方面或第一至第六实施方案中任一者的式I所描述。
在第八实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,n为2或3,且其余变量如第一方面或第一、第二、第三、第四、第五、第六或第七实施方案中所描述。
在第九实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,n为0或1,且其余变量如第一方面或第一、第二、第三、第四、第五、第六或第七实施方案中所描述。在一些实施方案中,各JB独立地为卤素或C1-6烷基。
在第十实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,各JB独立地为H、F或C1-4烷基;且其余变量如第一方面或第一、第二、第三、第四、第五、第六、第七、第八或第九实施方案中所描述。在一些实施方案中,各JB独立地为F或C1-4烷基。
在第十一实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,n为2或3;各JB独立地为F或甲基;且其余变量如第一方面或第一、第二、第三、第四或第五、第六或第七实施方案中所描述。
在第十二实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,n为2;JB均为F,或JB中之一者为F且另一者为甲基;且其余变量如第一方面或第一、第二、第三、第四、第五、第六或第七实施方案中所描述。在一些实施方案中,一个JB为F且另一者为甲基。
在第十三实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,n为3;JB中的两者为F且另一者为甲基;且其余变量如第一方面或第一、第二、第三、第四、第五、第六或第七实施方案中所描述。在一些实施方案中,JD为H或F。在一些实施方案中,JD为F。在一些实施方案中,JD为H。
在第十四实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,n为1;JB为F;且其余变量如第一方面或第一、第二、第三、第四、第五、第六或第七实施方案中所描述。
在第十五实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,n为0;且其余变量如第一方面或第一、第二、第三、第四、第五、第六或第七实施方案中所描述。
在第十六实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,JD为氢;且其余变量如第一方面或第一、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、第十四或第十五实施方案中所描述。
在第十七实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,JD为F、Cl或甲基;且其余变量如第一方面或第一、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、第十四或第十五实施方案中所描述。
在第十八实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,JD为F;且其余变量如第一方面或第一、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、第十四或第十五实施方案中所描述。
在第十九实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,JC为H、Cl或F;且其余变量如第一方面或第一、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、第十四、第十五、第十六、第十七或第十八实施方案中所描述。
在第二十实施方案中,对于式I、IA或IB的化合物或其医药学上可接受的盐,JC为H;且其余变量如第一方面或第一、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、第十四、第十五、第十六、第十七或第十八实施方案中所描述。
在第二十一实施方案中,式I化合物为表I中显示的化合物或其医药学上可接受的盐。
表I.示例性sGC刺激剂。
或其医药学上可接受的盐。
在第二十二实施方案中,对于本发明的方法及用途,sGC刺激剂为化合物I-14或其医药学上可接受的盐。在一个实施方案中,医药学上可接受的盐为钠盐。在另一实施方案中,sGC刺激剂为由下式表示的化合物I-14的钠盐:
在第二十三实施方案中,对于本发明的方法及用途,sGC刺激剂为化合物I-20或其医药学上可接受的盐。在一个实施方案中,医药学上可接受的盐为钠盐。在另一实施方案中,sGC刺激剂为由下式表示的化合物I-20的钠盐:
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在第二十四实施方案中,本发明的化合物为由式IC表示的化合物:
或其医药学上可接受的盐,其中X为N或C(JC1),其中当X为C(JC1)时,其由下表中的C表示;且变量X、JC1及JB的定义描述于下表中;另外其中Me表示甲基且Me-F表示经1至3个氟原子取代的氟化甲基(亦即,-CH2F、-CHF2或CF3):
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本发明医药学上可接受的盐。
本文所描述的化合物的“医药学上可接受的盐”包括由所述化合物与无机酸或有机酸或碱混合时所得到的那些盐。在一些实施方案中,所述盐可在化合物最终分离及纯化期间原位制备。在其他实施方案中,可在单独的合成步骤中由游离形式的化合物制备盐。上文所描述的医药学上可接受的盐及其他典型医药学上可接受的盐的制备更充分地描述于以全文引用方式并入本文中的Berg等人,“Pharmaceutical Salts”,J.Pharm.Sci.,1977:66:1-19中。式I化合物的医药学上可接受的盐为可用于药物中所示的那些盐。然而,医药学上不可接受的盐可适用于制备I化合物或其医药学上可接受的盐。
当式I化合物为酸性时,适合的“医药学上可接受的盐”是指由包括无机及有机碱的医药学上可接受的无毒性碱制备的盐。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、三价锰(manganic)盐、二价锰(manganous)盐、钾盐、钠盐、锌盐及类似盐。具体实施方案包括铵盐、钙盐、镁盐、钾盐及钠盐。衍生自医药学上可接受的有机无毒性碱的盐包括伯胺、仲胺及叔胺的盐,经取代的胺包括天然存在的经取代的胺、环胺、精氨酸、甜菜碱、咖啡因、胆碱、N,N1-二苯甲基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡糖胺、组氨酸、哈胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多元胺树脂、普鲁卡因(procaine)、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、缓血酸胺及其类似物。
在一些实施方案中,式I化合物具有能够与碱(例如,医药学上可接受的无毒性碱)反应以形成盐(例如,医药学上可接受的盐)的酸性OH基团。在一些实施方案中,盐为铵盐、钙盐、镁盐、钾盐或钠盐。在其他实施方案中,盐为钠盐。
当式I化合物为碱时,能够由医药学上可接受的无毒性酸(包括无机及有机酸)制备盐。此类酸包括乙酸根、乙酸、酸式柠檬酸根、酸式磷酸根、抗坏血酸根、苯磺酸、苯磺酸根、苯甲酸、苯甲酸根、溴离子、硫酸氢根、酒石酸氢根、樟脑磺酸、氯离子、柠檬酸根、柠檬酸、乙磺酸根、乙磺酸、甲酸根、富马酸根、富马酸、龙胆酸根、葡糖酸根、葡糖酸、葡糖醛酸根、谷氨酸根、谷氨酸、氢溴酸、盐酸、碘离子、羟乙基磺酸、异烟碱酸根、乳酸根、乳酸、马来酸根、马来酸、苹果酸、苦杏仁酸、甲磺酸、甲磺酸根、粘酸、硝酸根、硝酸、油酸根、草酸根、扑酸、双羟萘酸根(亦即,1,1′-亚甲基-双-(2-羟基-3-萘甲酸根))、泛酸、泛酸根、磷酸根、磷酸、葡糖二酸根、水杨酸根、琥珀酸、琥珀酸根、硫酸、硫酸根、鞣酸根、酒石酸根、酒石酸、对甲苯磺酸根、对甲苯磺酸及类似者。具体实施方案包括柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸及酒石酸。
除了本文所描述的化合物以外,其医药学上可接受的盐亦可用于组合物中或剂型中以治疗或预防本文中所鉴别的疾病。
医药组合物、剂型及施用方法。
本文所披露的化合物及其医药学上可接受的盐可配制为用于本发明治疗及用途的医药组合物或“制剂”。
通过将式I化合物或其医药学上可接受的盐与载剂、稀释剂或赋形剂混合来制备典型制剂。适合的载剂、稀释剂及赋形剂为本领域技术人员所熟知,且包括诸如碳水化合物、蜡、水溶性及/或可膨胀聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。所使用的载剂、稀释剂或赋形剂将视调配式I化合物或其医药学上可接受的盐的方式及目的而使用。一般基于本领域技术人员公认为施用给哺乳动物安全(GRAS-一般视为安全(GenerallyRegarded as Safe))的溶剂选择溶剂。一般而言,安全溶剂为无毒水性溶剂,诸如水及可溶于水或可混溶于水的其他无毒溶剂。适合的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400、PEG300)等及其混合物。制剂亦可包括其他类型的赋形剂,诸如一或多种缓冲剂、稳定剂、抗粘剂、表面活性剂、湿润剂、润滑剂、乳化剂、粘合剂、悬浮剂、崩解剂、填充剂、吸附剂、包衣(例如肠溶性或缓慢释放)、防腐剂、抗氧化剂、避光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂及用于提供药物(亦即,式I化合物或其医药组合物)的精致外观或帮助制造医药产物(亦即,药物)的其他已知添加剂。
可接受的稀释剂、载剂、赋形剂及稳定剂为在所采用的剂量及浓度下对接受者无毒的那些物质,且包括缓冲液,诸如磷酸盐、柠檬酸盐及其他有机酸;抗氧化剂,包括抗坏血酸及甲硫胺酸;防腐剂(诸如十八烷基二甲基苯甲基氯化铵;氯化六烃季铵;苯扎氯铵、苯索氯铵;苯酚、丁醇或苯甲醇;对羟苯甲酸烷酯,诸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;及间甲酚);蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、双糖及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖,诸如蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子,诸如钠;金属络合物(例如,Zn-蛋白质络合物);及/或非离子表面活性剂,诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。亦可例如通过凝聚技术或通过界面聚合将活性医药成分包埋于所制备的微胶囊中,例如分别包埋于羟基甲基纤维素或明胶微胶囊及聚-(甲基丙烯酸甲酯)微胶囊;包埋于胶状药物传递系统(例如脂质体、白蛋白微球体、微乳液、纳米粒子及纳米囊剂)中或包埋于巨乳液中。此类技术揭示于Remington's:The Science and Practice of Pharmacy,第21版,University of the Sciences in Philadelphia,2005版(下文称为“Remington's”)中。
制剂可使用常规溶解及混合程序制备。
如本文所使用,术语“治疗有效量”是指在组织、系统、动物或人类中引起研究人员、兽医、医生或其他临床医师所寻求的生物或药物反应的活性化合物或医药物的量。待施用的化合物的治疗有效量将由此类考虑因素决定,且为改善、治愈或治疗疾病或其症状中的一或多者所需的最少量。
关于本发明的化合物、组合物或剂型的术语“施用(administer/administering/administration)”是指将化合物引入至个体或需要治疗的患者的系统中。当本发明的化合物与一或多种其他活性剂组合提供时,“施用”及其变化形式各自理解为包括同时及/或依序引入所述化合物及其他活性剂。
视待治疗的疾病的严重程度及类型而定,本文所描述的组合物可全身性或局部施用,例如经口(包括但不限于固体剂型,包括硬或软胶囊(例如明胶胶囊)、片剂、丸剂、粉剂、舌下片剂、糖锭剂、锭剂及颗粒剂;及液体剂型,包括但不限于医药学上可接受的乳液、微乳液、水性或油性溶液、悬浮液、糖浆及酏剂;通过吸入(例如利用气溶胶、气体、吸入器、喷雾器或其类似者);经耳(例如使用滴耳剂);局部(例如使用乳霜、凝胶、吸入剂、擦剂、洗剂、软膏、贴片、糊剂、粉剂、溶液、喷雾、经皮贴片等);经眼(例如利用滴眼剂、经眼凝胶、经眼软膏);经直肠(例如使用灌肠剂或栓剂);经鼻;经颊;经阴道(例如使用冲洗剂、子宫内装置、经阴道栓剂、阴道环或片剂等);经由滴耳剂;经由植入式贮器或其类似者;或非经肠。如本文所使用,术语“非经肠”包括(但不限于)皮下、静脉内、肌肉内、关节内、滑液内、胸骨内、鞘内、肝内、病灶内及颅内注射或输注技术。优选地,组合物经口、腹膜内或静脉内施用。
意欲用于经口使用的化合物的制剂可根据制造医药组合物领域已知的任何方法来制备。
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。
使用表I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
在第一方面中,本发明涉及一种治疗有需要受试者的CNS疾病、健康状况或病症的方法,其包含单独或以组合疗法形式向受试者施用治疗有效量的式I化合物或其医药学上可接受的盐。在某些实施方案中,式I化合物如上文第一至第二十一实施方案中任一者中所描述。
在第二方面中,本发明涉及一种治疗有需要受试者的CNS疾病、健康状况或病症的方法,其包含单独或以组合疗法形式向所述受试者施用治疗有效量的包含式I化合物或其医药学上可接受的盐的医药组合物或剂型。在某些实施方案中,式I化合物如上文第一至第二十一实施方案中任一者中所描述。
在第三方面中,本发明进一步涉及式I化合物或其医药学上可接受的盐或包含式I化合物或其医药学上可接受的盐的医药组合物或剂型的用途,其用于制造用于治疗有需要受试者的CNS疾病、健康状况或病症的药物。在某些实施方案中,式I化合物如上文第一至第二十一实施方案中任一者中所描述。
在第四方面中,本发明进一步涉及式I化合物或其医药学上可接受的盐或包含式I化合物或其医药学上可接受的盐的医药组合物或剂型,其用于治疗有需要受试者的CNS疾病、健康状况或病症。在某些实施方案中,式I化合物如上文第一至第二十一实施方案中任一者中所描述。
在第一、第二、第三及第四方面的一个实施方案中,本文中所披露的化合物为可适用于预防及/或治疗以增加的神经炎症为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来减少所述受试者的神经炎症的方法。
在本发明的第一至第四方面中的另一实施方案中,本文中所披露的化合物为可适用于预防及/或治疗以增加的神经毒性为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来降低或补偿所述受试者的神经毒性的负面作用的方法。
在本发明的第一至第四方面中的另一实施方案中,本文中所披露的化合物为可适用于预防及/或治疗以受损的神经再生为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来恢复所述受试者的神经再生的方法。
在本发明的第一至第四方面中的另一实施方案中,本文中所披露的化合物为可适用于预防及/或治疗由受损的突触功能为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来恢复所述受试者的突触功能的方法。
在本发明的第一至第四方面中的另一实施方案中,本文中所披露的化合物为可适用于预防及/或治疗以下调的神经递质为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来使所述受试者的神经递质正常化的方法。
在本发明的第一至第四方面中的另一实施方案中,本文中所披露的化合物为可适用于预防及/或治疗由受损的大脑血流量为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来恢复所述受试者的大脑血流量的方法。
在本发明的第一至第四方面中的另一实施方案中,本文中所披露的化合物为可适用于预防及/或治疗由增加的神经退化为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来减少所述受试者的神经退化的方法。
在本发明的第一至第四方面中的另一实施方案中,本文中所披露的化合物为可适用于预防及/或治疗由认知障碍为特征的疾病及病症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来改善所述受试者认知的方法。在一些实施方案中,该治疗改善记忆。在其他实施方案中,该治疗提高注意力。在其他实施方案中,该治疗改善执行功能。
在本发明的第一至第四方面的另一实施方案中,本文中披露的化合物为具有神经保护性的sGC刺激剂。具体地,式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型可适用于保护有需要受试者的神经元。
在一些实施方案中,CNS疾病、健康状况或病症选自阿尔茨海默尔病(Alzheimer'sdisease;AD)、血管型痴呆症(VD)、血管型认知障碍、混合型痴呆症、宾斯旺格痴呆(Binswanger's dementia)(皮质下动脉硬化性脑病)、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)、额颞叶退化或痴呆症(FTD)、无症状神经认知障碍(ANI)、主观认知受损或减退(SCD)、认知老化、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)、路易体痴呆、早老性痴呆或轻度认知障碍(MCI)。
在其他实施方案中,所述疾病、健康状况或病症为选自以下的CNS病症或病状:睡眠觉醒障碍及与Sneddon综合征相关的神经异常。
在其他实施方案中,所述疾病、健康状况或病症为选自以下的CNS病症或病状:阿尔茨海默尔病或早期阿尔茨海默尔病、轻度至中度阿尔茨海默尔病或中度至重度阿尔茨海默尔病。
在其他实施方案中,所述CNS疾病选自青光眼、亨廷顿氏病(Huntington'sdisease)(或亨廷顿氏舞蹈病(Huntington's chorea),HD)、多发性硬化症(MS)、多系统萎缩(MSA)、帕金森氏病(PD)、帕金森叠加综合征、脊髓小脑共济失调(SCA)、Steel-Richardson-Olszewski疾病(进行性核上麻痹)、肌肉萎缩性侧索硬化(ALS或Lou Gehrig病)或唐氏综合征(Down's syndrome)。
在其他实施方案中,CNS疾病选自注意缺陷障碍(ADD)和注意缺陷性多动症(ADHD)。
在其他实施方案中CNS病症为创伤性(闭合或开放的)穿透性脑损伤、创伤性脑损伤(TBI)、非创伤性中风(具体地,缺血性中风)、动脉瘤、缺氧或大脑的其他损伤。
在其他实施方案中,CNS病症为选自以下的精神、心理、情绪或情感病症:双相情感障碍、精神分裂症、广泛性精神病、药物诱发的精神病、妄想症、精神分裂型情感障碍、强迫症(OCD)、抑郁症、焦虑症、恐慌症或创伤后应激障碍(PTSD)。
在其他实施方案中,CNS疾病或病症是选自张力障碍,包括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、遗传性或原发性张力障碍或急性张力障碍反应(acute dystonic reaction);或运动障碍,包括例如急性运动障碍、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)。
在其他实施方案中,CNS疾病或病症是选自特征为突触可塑性及突触过程相对减少的病症,包括例如脆性X染色体综合征、瑞特氏症(Rhett's disorder)、威廉综合症(Williams syndrome)、Renpenning综合征、自闭症谱系障碍(ASD)、自闭症、亚斯伯格综合征(Asperger's syndrome)、广泛性发育障碍或童年瓦解性障碍。
在其他实施方案中,CNS病症是选自化学脑、左旋多巴诱发的成瘾行为、酒精中毒、麻醉剂依赖性(包括但不限于安非他明(amphetamine)、鸦片剂或其他物质)及药物滥用。
在一个实施方案中,CNS疾病为由脑损伤、精神病症、神经发育性病症或神经退化性病症引起的认知受损或功能障碍。
在本发明的方法及用途的一些实施方案中,认知障碍(如MCI或痴呆症)与以下相关:阿尔茨海默尔病(AD)、血管型痴呆症、混合型痴呆症、伴有血管病变的AD(ADv)、脑梗塞、大脑缺血、中风、头部损伤、创伤性头部损伤、学习障碍、自闭症、注意力缺陷症、抑郁、脊髓小脑性共济失调、路易体性痴呆、伴有额叶退化的痴呆症、皮克氏综合征(Pick'ssyndrome)、帕金森氏病、进行性核上麻痹、伴有皮质基底核退化的痴呆症、肌肉萎缩性侧索硬化(ALS)、亨廷顿氏病、脱髓鞘病、多发性硬化症(MS)、丘脑变性、克罗伊茨费尔特雅各布布痴呆症(Creutzfeldt-Jakob dementia)、HIV-痴呆症、精神分裂症、卡萨科夫精神病(Korsakoff psychosis)、老年人术后认知减退、双相情感障碍或线粒体疾病。在其他实施方案中,认知障碍与镰状细胞疾病相关。
在本发明的方法及用途的一些实施方案中,MCI、痴呆症、亚临床认知障碍或SCD与以下相关:认知老化、术后认知减退、药物副作用、代谢不平衡、激素问题、维生素或营养物缺陷、谵妄、精神疾病、因一种损伤(例如,中风或其他脑血管疾病或因为创伤性脑损伤)而对大脑神经元造成的损伤、神经退化的早期过程、暴露于毒素、或病毒或细菌感染。
在其他实施方案中,本文所披露的化合物为可适用于预防及/或治疗孤儿疼痛适应症的sGC刺激剂。本发明的一个实施方案为一种通过向有需要受试者施用式I化合物或其医药学上可接受的盐或包含其的医药组合物或剂型中的任一者来治疗孤儿疼痛适应症的方法。具体地,孤儿疼痛适应症选自乙酰唑胺反应性肌强直、自体红血球过敏作用综合征、体染色体显性恰克-马里-杜斯氏病2V型(Autosomal dominant Charcot-Marie-Toothdisease type 2V)、伴有神经痛的体染色体显性中度恰克-马里-杜斯氏病、体染色体隐性肢带型肌肉萎缩症2A型、离子通道病相关的先天性无痛症、需要脊柱内镇痛的慢性疼痛、复杂区域疼痛综合征、复杂区域疼痛综合征1型、复杂区域疼痛综合征2型、伴多汗的先天性无痛症、伴有严重智力缺陷的先天性无痛症、先天性无痛-少汗综合征、伴有疼痛性裂纹的弥漫性掌跖角化病、家族性间歇性疼痛综合征、伴有显著下肢受累的家族性间歇性疼痛综合征、伴有主要上半身受累的家族性间歇性疼痛综合征、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(marfanoid habitussyndrome)、阵发性剧痛症、持久性特发性面部疼痛、卡配因(calpain)的定性或定量缺陷、托洛萨亨特综合征(Tolosa-Hunt syndrome)。
在其他实施方案中,CNS病症为神经痛。在一些实施方案中,疼痛为与CNS疾病相关的神经痛。
在其他实施方案中,疾病或病状选自急性疼痛、中枢性疼痛综合征、化学疗法诱发的神经病变、糖尿病性神经病变、纤维肌痛、炎性疼痛、疼痛性糖尿病性周边神经病、术后疼痛、强直性疼痛及内脏疼痛。
在其他实施方案中,本文所披露的化合物为可适用于预防及/或治疗以下的sGC刺激剂:高海拔(高原)疾病、脑小血管病、脑脉管炎、脑血管痉挛、肝性脑病、烟雾病(moyamoya)、帕金森吞咽困难、毛细血管扩张性运动失调、自闭症谱系障碍、慢性疲劳、慢性创伤性脑病(CTE)、与糖尿病相关的认知障碍、与多发性硬化症相关的认知障碍、与阻塞性睡眠呼吸暂停相关的认知障碍、与精神分裂症相关的认知障碍(CIAS)、与镰状细胞疾病相关的认知障碍、脑震荡、视网膜病变、糖尿病性视网膜病变(包括增生性及非增生性)、吞咽困难。
在其他实施方案中,本文所披露的化合物为可适用于预防及/或治疗以下的sGC刺激剂:眼纤维化、法布里病(Fabry Disease)、高雪病(Gaucher Disease)、胶质母细胞瘤、由脑疟疾引起的脑炎(SoC)、由感染性疾病引起的脑炎、智力缺陷、近视脉络膜新生血管、视神经脊髓炎、伴有多发性硬化症的神经痛、伴有带状疱疹(shingles/herpes zoster)的神经痛、脊椎手术下的神经痛、帕金森痴呆症、周边及自主神经病变、周边视网膜变性、创伤后应激综合征、疱疹后神经痛、术后痴呆症、增生性玻璃体视网膜病变、辐射诱发的脑纤维化、神经根病变、难治性癫痫、视网膜静脉阻塞、脊髓损伤、脊髓性肌萎缩、脊椎半脱位、tau蛋白病及湿性年龄相关黄斑变性。
可得益于用本发明的sGC刺激剂治疗的CNS疾病为这些CNS疾病,其中NO浓度的增加或cGMP浓度的增加或两者,或NO-sGC-cGMP路径的上调是期望的。
作为能够跨越血脑屏障(BBB)的sGC刺激剂的本文所描述的化合物以及其医药学上可接受的盐适用于预防及/或治疗可得益于大脑中的sGC刺激的CNS疾病、病状及病症。
在一些实施方案中,本发明的化合物能够刺激大脑中的sGC而不造成患者较大血压(BP)降低。在一些实施方案中,对于引起所需CNS作用的剂量,化合物使患者BP降低平均低于5mm Hg。在一些实施方案中,平均低于10mm Hg。在其他实施方案中,患者BP降低在临床上不显著。在其他实施方案中,本发明的方法及用途在处理患者的CNS疾病时不会引起与症状性低血压相关的不良事件(AE)的显著发生。
如本文中所使用,不会“引起与症状性低血压相关的不良事件(AE)的显著发生”的剂量为不引起患者过度起立性低血压、过度眩晕、过度体位性眩晕、过度晕厥先兆或过度晕厥的剂量。患者过度起立性低血压、过度眩晕、过度体位性眩晕、过度晕厥先兆或过度晕厥为保证患者停止治疗或医师停止建议的这些情况。
在一些实施方案中,BP被测量为收缩BP。在其他实施方案中,被测量为舒张BP。在其他实施方案中,测量为平均动脉压(MAP)。在其他实施方案中,BP为走动测量的BP。在其他实施方案中,BP为腕部测量的BP。在一些实施方案中,在患者处于仰卧位置的情况下进行BP的测量。在其他实施方案中,患者处于坐立位置。
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。在一些实施方案中,术语疾病是指sGC、cGMP及/或NO介导的影响CNS的医学或病理学疾病。如本文中所使用,“CNS疾病、健康状况或病症”是指与CNS疾病、CNS健康状况或CNS病症相同,且本发明中的术语疾病、病状及病症与其如何使用无关,均指仅影响CNS(中枢神经系统)所示的那些者。
针对障碍、疾病、病症、症状或综合征的“治疗(Treat/treating/treatment)”是指消除或改善该障碍、疾病、病症或综合征的病因及/或影响(亦即,症状、生理学、身体、精神、情感或任何其他临床表现、观测结果或测量结果,或改善病理学评估)。
如本文中所使用,术语“治疗”亦是指延迟或改善或预防疾病的进展(亦即疾病的已知或预期进展)、严重程度及/或持续时间或延迟或改善或预防一或多种症状、临床表现、观测结果或测量结果的进展,或预防或减缓由施用一或多种疗法所引起的病理学评估的负进展(亦即“管控”而不是“治愈”所述病症)。
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。
在其他实施方案中,本发明提供一种刺激生物样本中的sGC活性的方法,其包含使该生物样本与本发明的化合物或组合物接触。在生物样本中使用sGC刺激剂适用于本领域技术人员已知的多种目的。此类目的的实例包括(但不限于)生物测定及生物样本储存。
组合疗法
本文所描述的化合物及医药组合物可单独使用或以组合疗法使用,用于治疗通过sGC、cGMP及/或NO介导、调节或影响的疾病。
如本文所用,术语“组合”(如“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。该术语的使用不限制对受试者给药疗法的顺序。
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,包括但不限于亚硝基硫醇、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,包括但不限于原卟啉IX、花生四烯酸和苯基肼衍生物。
(4)一氧化氮合酶底物,包括但不限于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),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(来自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(nelociguat)(BAY 60-4552,描述于WO 2003095451中);威利西呱(vericiguat)(BAY 1021189,描述于US8420656中);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;
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(praliciguat)、IW1701(olinciguat)和CY6463(之前的IW-6463)。
(8)抑制cGMP和/或cAMP降解的化合物,包括但不限于:
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)、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。
(10)抗凝剂,包括但不限于:
香豆素(维生素K拮抗剂),例如华法林(warfarin)、醋硝香豆素(acenocoumarol)、苯丙香豆素和苯茚二酮(phenindione);
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);
直接凝血酶抑制剂,例如阿加曲班(argatroban)、来匹卢定(lepirudin)、比伐卢定(bivalirudin)、达比加群(dabigatran)和希美加群(ximelagatran);和
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)。
(10)抗血小板药物,包括但不限于保栓通锭(topidogrel)、噻氯匹定(ticlopidine)、双嘧达莫(dipyridamole)和阿斯匹林。
(11)补充性氧疗法。
(12)α-1-肾上腺素受体拮抗剂,包括但不限于哌唑嗪(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。
(13)支气管扩张剂,包括但不限于:
短效β2激动剂,例如沙丁胺醇(albutamol)或舒喘灵(albuterol)和特布他林(terbutaline);
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。
(14)皮质类固醇,包括但不限于倍氯米松(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))。
(15)膳食补充物,包括但不限于ω-3油;叶酸、烟酸、锌、铜、韩国高丽红参(Koreanred ginseng 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)。
(16)PGD2受体拮抗剂。
(17)免疫抑制剂,包括但不限于环孢素、他克莫司(tacrolimus)、雷帕霉素(rapamycin)及其他FK-506型免疫抑制剂麦考酚酯、吗替麦考酚酯。
(18)非类固醇抗哮喘药,包括但不限于:
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;和
白三烯生物合成抑制剂,如齐留通(zileuton)或veliflapon。
(19)非类固醇抗发炎剂(NSAID),包括但不限于:
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);
水杨酸类,例如乙酰基水杨酸及柳氮磺吡啶(sulfasalazine);及
吡唑啉酮,包括但不限于阿扎丙宗(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。
(20)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)。
(21)肾上腺素性神经元阻断剂,例如胍乙啶(guanethidine)及胍那决尔(guanadrel)。
(22)咪唑啉I-1受体激动剂,包括但不限于磷酸二氢利美尼定(rimenidinedihydrogen phosphate)及盐酸莫索尼定(moxonidine hydrochloride)水合物。
(23)钾通道活化剂,包括但不限于吡那地尔(pinacidil)。
(24)多巴胺D1激动剂,包括但不限于甲磺酸非诺多潘(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)。
(25)5-HT2拮抗剂,包括但不限于酮色林(ketanserin)。
(26)加压素拮抗剂,包括但不限于托伐普坦(tolvaptan)。
(27)钙通道增敏剂,包括但不限于左西孟旦(levosimendan))或活化剂(例如尼可地尔)。
(28)腺苷酸环化酶活化剂,包括但不限于盐酸考福辛达罗帕特(colforsindapropate hydrochloride)。
(29)正性肌力剂,包括但不限于地高辛及甲地高辛(metildigoxin);代谢强心剂,例如泛醌;脑钠尿肽,例如奈西立肽(nesiritide)。
(30)用于治疗勃起功能障碍的药物,包括但不限于前列地尔、阿肽地尔(aviptadil)及甲磺酸酚妥拉明(phentolamine mesilate)。
(31)用于治疗阿尔茨海默病及痴呆的药物,包括但不限于:
乙酰胆碱酯酶抑制剂,例如加兰他敏(galantamine)、利凡斯的明(rivastigmine)、多奈派齐(donepezil)及他克林(tacrine);和
NMDA受体拮抗剂,例如美金刚(memantine);及
氧化还原酶抑制剂,例如艾地苯醌(idebenone)。
(32)精神病药剂,包括但不限于:
齐拉西酮(ziprasidone)、利培酮(risperidone)、奥氮平(olanzapine)、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);
GABAA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);
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)。
(33)用于治疗运动障碍或症状的药物,包括但不限于:
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)。
(34)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)、多虑平(doxepin)及氯米帕明(clomipramine);
选择性血清素再摄取抑制剂(SSRI),例如帕罗西汀(paroxetine)、氟西汀(fluoxetine)、舍曲林(sertraline)、曲唑酮(trazodone)及西酞普兰(citralopram);
非典型抗抑郁药,如阿戈美拉汀(agomelatine);
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)。
(35)用于增强突触可塑性的药物,包括但不限于:
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)。
(36)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)。
(37)一氧化氮合酶辅因子,包括但不限于:四氢生物蝶呤,二氢生物蝶呤和沙丙蝶呤。
(38)血糖降低药物(亦称作血糖控制药物或抗糖尿病药物)包括但不限于:
双胍,诸如二甲双胍(metformin);
磺酰脲,诸如格列本脲(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)、与格列美脲组合的阿托伐他汀钙、美格那肽(meglinatide)、甲苯磺丁脲(tolbutamide)、氯磺丙脲、醋磺环已脲及妥拉磺脲(tolazimide);
α-葡萄糖苷酶抑制剂,诸如阿卡波糖(acarbose)、依帕司他(epalrestat)、伏格列波糖(voglibose)及米格列醇(miglitol);
胰岛素促分泌素,诸如瑞格列奈(repaglinide)、米格列奈(mitiglinide)及那格列奈(nateglinide);
噻唑烷二酮,诸如罗格列酮(rosiglitazone)、曲格列酮(troglitazone)、环格列酮(ciglitazone)、吡格列酮(pioglitazone)、恩格列酮(englitazone)、硫酸洛贝格列酮(lobeglitazone sulfate)及巴拉列酮(balaglitazone);
DPP-4抑制剂(或DPP-IV抑制剂),诸如西格列汀(sitagliptin)、维格列汀(vildagliptin)、沙格列汀(saxagliptin)、阿格列汀(alogliptin)、利格列汀(linagliptin)、与二甲双胍或盐酸二甲双胍组合的苯甲酸阿格列汀(alogliptinbenzoate)、阿拉格列汀(anagliptin)、替格列汀(teneligliptin)、阿托伐他汀钙及格列美脲、与利格列汀组合的恩格列净(empagliflozin)、吉格列汀(gemigliptin)、与吡格列酮盐酸盐组合的磷酸西格列汀单水合物、与吡格列酮组合的西格列汀、与阿托伐他汀钙组合的西格列汀及(2S,4S)-1-[2-(1,1-二甲基-3-氧代-3-吡咯烷-1-基-丙胺基)乙酰基]-4-氟-吡咯烷-2-甲腈(DBPR-108);
GLP-1受体激动剂或肠促胰岛素模拟物,诸如艾塞那肽(exenatide)、度拉糖肽(dulaglutide)、利拉鲁肽(liraglutide)、司美鲁肽(semaglutide)、利司那肽(lixisenatide)、与甘精胰岛素组合的利司那肽、阿比鲁肽(albiglutide)及陪阿帕度肽(pegapamodutide)(TT-401)、LY3298176(双葡萄糖依赖性促胰岛素多肽(GIP)及GLP-1受体激动剂);
SGLT2抑制剂(SGLT2i),诸如恩格列净(empagliflozin)、与利格列汀组合的恩格列净、与二甲双胍组合的恩格列净、伊格列净(ipragliflozin)、伊格列净L-脯胺酸、托格列净(tofogliflozin)、依碳酸舍格列净、依碳酸瑞格列净、埃格列净(ertugliflozin)、与西格列汀组合的埃格列净、与二甲双胍组合的埃格列净、索格列净(sotagliflozin)、卡格列净(canagliflozin)、与二甲双胍或盐酸二甲双胍组合的卡格列净、达格列净(dapagliflozin)、与二甲双胍或盐酸二甲双胍及鲁格列净(luseoglifozin)组合的达格列净、与沙格列汀组合的达格列净(dapagliflozin);
SGLT1抑制剂或SGLT1及SGLT2抑制剂的组合,诸如索格列净;
胰岛素疗法,诸如许多类型胰岛素之一:赖谷胰岛素、德谷胰岛素、赖脯胰岛素、门冬胰岛素、甘精胰岛素、地特胰岛素、鱼精蛋白胰岛素、混合胰岛素(insulin mixtard)(含有快速作用(可溶性)及长效(鱼精蛋白)胰岛素两者的人类胰岛素、与门冬胰岛素组合的德谷胰岛素、人类(rDNA来源)吸入粉末胰岛素、重组人类胰岛素、肝导引囊泡胰岛素、特格胰岛素(insulin tregopi)(IN-105)、与利拉鲁肽组合的德谷胰岛素、普赖胰岛素(insulinpeglispro)(LY-2605541)及诺丁(nodlin);及
托利米酮(tolimidone)(lyn激酶活化剂)。
(39)降血压药物(亦称为抗高血压药物),包括但不限于:
利尿剂,诸如噻嗪利尿剂、氯噻嗪、氯噻酮、氢氯噻嗪、苄氟甲噻嗪、环戊噻嗪、甲氯噻嗪、多噻嗪、喹乙唑酮、希伯胺(xipamide)、美托拉宗(metolazone)、吲达帕胺(indapamide)、西氯他宁(cicletanine)、呋喃苯胺酸(furosemide)、托瑞司胺(toresamide)、胺氯吡脒(amiloride)、螺内酯、坎利酸钾、依普利酮、胺苯蝶啶(triamterene)、乙酰唑胺及卡培立肽(carperitide);
β阻断剂,诸如醋丁洛尔(acebutolol)、阿替洛尔(atenolol)、美托洛尔(metoprolol)及奈必洛尔(nebivolol);
血管收缩素转化酶(ACE)抑制剂,诸如含巯基药物(例如,卡托普利(captopril)、佐芬普利(zofenopril))、含二甲酸酯的药物(例如,依那普利(enalapril)、喹那普利(quinapril)、雷米普利(ramipril)、培哚普利(perindopril)、赖诺普利及贝那普利(benazepril))、含膦酸酯的药物(例如,福辛普利(fosinopril))、天然存在的ACE抑制剂(例如,酪激肽、乳激肽、乳三肽Val-Pro-Pro及Ile-Pro-Pro)、阿拉普利(alacepril)、地拉普利(delapril)、西拉普利(cilazapril)、咪达普利(imidapril)、替莫普利(temocapril)、莫西普利(moexipril)、赖诺普利、赖诺普利与氢氯噻嗪的组合、群多普利(trandolapril)及螺普利(spirapril);
血管收缩素II受体阻断剂(ARB),诸如坎地沙坦(candesartan)、氯沙坦(losartan)、氯沙坦钾-氢氯噻嗪、缬沙坦(valsartan)、坎地沙坦酯(candesartancilexetil)、依普沙坦(eprosaran)、依贝沙坦(irbesartan)、替米沙坦(telmisartan)、奥美沙坦美度米(或奥美沙坦)、阿齐沙坦美度米(azilsartan medoxomil)、阿齐沙坦(azilsartan)、与依贝沙坦组合的苯磺酸氨氯地平(amlodipine besylate)、与苯磺酸氨氯地平组合的阿齐沙坦、与缬沙坦组合的西尼地平(cilnidipine)、非马沙坦(fimasartan)、与阿托伐他汀组合的依贝沙坦、与三氯甲噻嗪组合的依贝沙坦、与氢氯噻嗪及/或苯磺酸氨氯地平组合的氯沙坦钾、普特沙坦(pratosartan)、与氯沙坦钾组合的阿托伐他汀钙、硝苯地平(nifedipine)及坎地沙坦酯、与缬沙坦或LCZ-696组合的沙库必曲(sacubitril)、血管紧张素AT2拮抗剂及TAK-591以及奥美沙坦美度米;
内皮素受体拮抗剂(ERA),诸如阿曲生坦(atrasentan)、波生坦(bosentan)、西他塞坦(sitaxentan)、安立生坦(ambrisentan)、爱可泰隆-1(actelion-1)(马西腾坦(macitentan))、环(D-trp-D-asp-L-pro-D-Val-L-leu)(BQ-123)、斯帕森坦(sparsentan)及替唑生坦二钠(tezosentan disodium)。
盐皮质激素受体拮抗剂(MRA),诸如螺内酯、与螺内酯组合的胺氯吡脒盐酸盐、阿帕瑞酮(apararenone)或MT-3995、依普利酮及非瑞酮(finerenone)(BAY-94-8862);
钙通道阻断剂,诸如胺氯地平、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)、硝苯地平、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)、伊拉地平(isradipine)、维拉帕米(verapamil)、加洛帕米(gallopamil)、地尔硫卓、米贝地尔(mibefradil)、苄普地尔(bepridil)、氟斯必灵(fluspirilene)及芬地林;
肾素抑制剂,诸如阿力克伦(aliskiren);
α阻断剂,诸如多沙唑嗪(doxazosin)及哌唑嗪(prazosin);
α-β阻断剂,诸如卡维地洛(carvedilol)及拉贝洛尔(labetalol);
中枢神经药物,诸如可乐定(clonidine)、胍法新(guanfacine)及甲基多巴(methyldopa);
血管扩张剂,诸如硝酸甘油酯、肼酞嗪及敏乐定(minoxidil);及
醛固酮拮抗剂,诸如非瑞酮、螺内酯及依普利酮。
(40)抗高脂质血症药物,包括但不限于:
他汀类(statins),诸如阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、匹伐他汀(pitavastatin)、普伐他汀(pravastatin)、罗素他汀(rosuvastatin)及辛伐他汀(simvastatin);
他汀类与另一药物的组合,诸如胺氯地平/阿托伐他汀、阿司匹林/普伐他汀、依泽麦布(ezetimibe)/辛伐他汀、烟酸/辛伐他汀、洛伐他汀/烟酸、辛伐他汀/西格列汀及阿托伐他汀/依泽麦布;
贝特类或纤维酸衍生物。实例包括但不限于非诺贝特(fenofibrate)、吉非贝齐(gemfibrozil)、苯扎贝特(bezafibrate)、环丙贝特(ciprofibrate)、克利贝特(clinofibrate)及氯贝特(clofibrate);
尼克酸(或烟碱酸);
胆酸螯合剂,诸如消胆胺、考来维仑(colesevelam)、考来替兰(colestilan)及考来替泼(colestipol);
依泽麦布、洛美他哌(lomitapide)、植物固醇或奥利司他(orlistat);及
PCSK9抑制剂,诸如阿利库单抗(alirocumab)及依伏库单抗(evolocumab);
(41)脑啡肽酶抑制剂(亦称为内肽酶抑制剂或NEP抑制剂或脑啡肽酶抑制剂),包括但不限于沙库必曲(sacubitril)、或沙库必曲与缬沙坦的组合;脑啡肽酶抑制剂,研发中的TD-1439或TD-0714。
(42)肾脏保护药物,包括但不限于:
巴多曲龙(Bardoxolone);
ACE抑制剂,诸如卡托普利;
ARB,诸如氯沙坦或依贝沙坦;
SGLT2抑制剂,诸如卡格列净,
GLP1受体激动剂;
MRA,诸如非瑞酮;
ERA,诸如阿曲生坦;及细胞凋亡信号调节激酶1(ASK1)抑制剂,诸如司隆色替(selonsertib)。
(43)羟基脲(HU,羟基尿素)。
(44)抗镰状细胞形成药物,包括但不限于羟基脲、沃塞洛托(voxelotor)或GBT-440。
(45)抗粘附疗法,包括但不限于阻断抗体粘附至P-选择素、E-选择素、VLA-4、VCAM-1。
(46)谷氨酰胺。
(47)红血球生成素(EPO),亦称为造血素(hematopoietin/hemopoietin)包括其所有形式,诸如外源性红血球生成素、重组人类红血球生成素(rhEPO)或其他红血球生成刺激剂(ESA),两个实例为阿法依泊汀(epoetin alfa)及倍他依泊汀(epoetin beta)。
(48)抗生素,包括但不限于:
青霉素及其衍生物,包括但不限于青霉素、阿莫西林(amoxicillin)、安比西林(ampicillin)、阿洛西林(azlocillin)、氯唑西林(cloxacillin)、青霉素G、青霉素V、普鲁卡因青霉素或苄星青霉素等。
头孢菌素,诸如头孢氨苄(cephalexin)、头孢羟胺苄(cefadroxil)、头孢克洛(cefaclor)、头孢呋辛(cefuroxime)及头孢克肟(cefexime);
大环内酯,诸如红霉素、克拉霉素、阿奇霉素及罗红霉素;
四环素及其衍生物,诸如地美环素(demeclocycline)、多西环素(doxycycline)、米诺四环素(minocycline)、土霉素(oxytetracycline)及四环素;
磺酰胺,包括但不限于磺胺米隆(mafenide)、磺胺醋酰胺、磺胺嘧啶、磺胺嘧啶银、达美磺胺、磺胺甲二唑、磺胺甲异唑、柳氮磺胺吡啶、三甲氧苄二胺嘧啶-磺胺甲异/>唑(复方新诺明(Co-trimoxazole))及磺胺异/>唑;及
喹啉酮,包括但不限于环丙沙星(ciprofloxacin)、依诺沙星(enoxacin)、加替沙星(gatifloxacin)、吉米沙星(gemifloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lomefloxacin)、莫西沙星(moxifloxacin)、氧氟沙星(ofloxacin)及萘啶酸(nalidixicacid)。
(49)FXR激动剂,包括但不限于奥贝胆酸(obeticholic acid)、森尼韦若(cenicriviroc)、恩利卡生(emricasan)、GR-MD-02、司隆色替(selonsertib)及埃拉菲诺(elafibranor)。
(50)甲状腺受体-β激动剂,包括但不限于MGL-3196。
(51)乙酰基-CoA羧化酶抑制剂,包括但不限于GS-0976。
(52)用于粒线体病症的治疗剂,包括但不限于维生素及补充剂,包括辅酶Q10;B复合维生素、尤其硫胺(B1)及核黄素(B2);α类脂酸;L-肉碱(Carnitor);肌酸;瓜胺酸及L-精氨酸。
(53)用于癫痫或癫痫发作的治疗剂,包括但不限于苯妥英(phenytoin)、丙戊酸、苯巴比妥、拉莫三嗪(lamotrigine)、卡马西平(carbamazepine)、托吡酯、奥卡西平(oxcarbazepine)、唑尼沙胺(zonisamide)、加巴喷汀(gabapentin)、左乙拉西坦(levetiracetam)、普瑞巴林(pregabalin)、可那氮平(clonazepam)、拉科酰胺(lacosamide)、卢非酰胺(rufinamide)及氨己烯酸(vigabatrin)。
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。
本发明的各种实施方案描述于下文中。
实例部分中使用的缩写的定义提供于下表中。
合成部分
实例1:合成式I化合物
本发明本申请还提供用于合成式I化合物的方法,其代表了本发明的另一实施方案。可根据本文所描述的通用及具体合成方法、化学文献中报导的合成操作或本领域一般技术人员已知的方法制备本发明的式I化合物。如本领域一般技术人员可理解,可在实验期间确定的最佳反应条件可基于反应类型及反应中使用的特定试剂而改变。因此,除非特定描述,否则诸如压力、温度、试剂的相对比率、溶剂及反应时间等反应条件可由本领域一般技术人员容易地选择及改变,而不存在过度实验。
本发明的化合物及中间体可通过本领域一般技术人员已知的纯化方法来制备。这些方法包括但不限于硅胶层析、再结晶、反相HPLC(RP-HPLC)及超临界流体层析(SFC)。RP-HPLC纯化可使用选自0%至100%乙腈于含有诸如0.1%TFA或FA添加剂的水中的适合梯度在适合的反相柱(例如,Waters XBridge OBD C18,5μm,19×150mm)上实现。非对映异构体可通过硅胶层析、RP-HPLC或对手性HPLC分离。离散的对映异构体可通过使用手性HPLC拆分对映异构体的混合物来获得。可通过本领域一般技术人员已知的方法,诸如薄层层析法、反相HPLC或串联反相HPLC-质谱法(LC-MS)来监测反应进程。
本文所描述的合成中使用的起始材料购自市售来源或可由本领域一般技术人员使用化学文献中报导或本文提及的方法来制备。
本文所描述的通用方法可用于制备式I化合物和式I的化合物。本文所描述的通用及特定方法作为实现本发明的解释说明提供。因此,其并不意欲对本发明的主题及所要求保护的化合物的范畴施加任何限制。
实例中所提供的所有参考文献均以引用的方式并入本文中。如本文所使用,所有缩写、符号及常规均与当代科学文献中所使用所示的那些缩写、符号及常规一致。参见例如G.M.Banik,G.Baysinger,P.V.Kamat,N.J.Pienta,编,The ACS Guide to ScholarlyCommunication,Washington,D.C.:American Chemical Society,2020(https;//pub.acs.org/doi/book/10.1021/acsguide),其以全文引用的方式并入本文中。
实施例1:化合物合成
本文所披露的化合物可例如使用下文所描绘的通用程序(通用程序C)由对应的腈中间体制成:
通用程序C
本发明的化合物可通过以下与本文所描述所示的那些类似的程序经由其对应腈来制备。具有不同取代模式的腈可通过以下WO2015187470、WO2016081668、WO2017197555、WO2017200825、WO2018/045276A1及WO2019/126354A1中描述的程序来制备。
以下腈中间物根据WO2018/045276A1及WO2019/126354A1中所描述的文献程序来制备。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。
8-苯甲基咪唑并[1,2-a]吡嗪-6-甲腈;
8-(3-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(2-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(2,3-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(3-氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(3,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(3,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈;
8-(2,5-二氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-甲腈;
8-(3-氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-甲腈;
8-(3,5-二氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-甲腈;
8-(2,3-二氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-甲腈;
8-(2,5-二氟-4-甲基苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-甲腈。
用于合成化合物I-1至I-20的程序描述于下文中。用于合成化合物I-20至I-26的程序描述于专利申请公开文本WO2019/126354中。
通用程序A,适用于合成化合物I-1
以2个步骤合成标题化合物:
步骤1:合成8-(3-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒
向8-(3-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈(220mg,0.87mmol,1.0当量)于甲醇(5.0mL)中的溶液中添加0.50N甲醇钠于甲醇中的溶液(0.17mL,0.087mmol,0.10当量)(注意:亦可使用化学计算量或过量的甲醇钠)。在环境温度下搅拌6h之后,添加氯化铵(280mg,5.2mmol,6.0当量)且搅拌反应物16h。将反应混合物在真空中浓缩,用半饱和NaHCO3溶液(20mL)稀释且用2×20mLCH2Cl2/iPrOH(5:1)萃取。合并的有机相经硫酸钠干燥,过滤,且浓缩,得到呈浅棕色泡沫固体状的粗产物甲脒。其不经进一步纯化即用于下一步骤中。LC/MS ES+m/z=270.2[M+H]+。
步骤2:合成5-氟-2-(8-(3-氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇
向8-(3-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(210mg,0.79mmol,1.0当量)于乙醇(7.0mL)中的悬浮液中添加(Z)-3-乙氧基-2-氟-3-氧代丙-1-烯-1-醇化钠(490mg,3.1mmol,4.0当量)。在90℃下于密封小瓶中加热反应物2.5h。在冷却至环境温度之后,添加1.0N HCl水溶液(3.1mL,3.1mmol,4.0当量)。将所得物混合物在真空中浓缩,用水(50mL)稀释,用饱和NaHCO3溶液调节至pH 6,且用2×50mLCH2Cl2/iPrOH(5:1)萃取。合并的有机相经硫酸钠干燥,过滤,且浓缩。粗制物经由硅胶层析(0至15%乙腈/甲醇(7:1)于CH2Cl2中)纯化以得到呈淡褐色固体状的标题化合物(180mg,64%产率,历经2个步骤)。1H NMR(500MHz,DMSO-d6)δ(ppm)13.1-12.5(单峰对,1H,互变异构体),9.46(s,1H),8.30(s,1H),8.26-8.00(单峰对,1H,互变异构体),7.90(s,1H),7.50(m,1H),7.41(m,1H),7.32(m,1H),7.02(app.t,1H),4.53(s,2H)。
化合物I-2
根据通用程序A合成呈白色固体状的2-(8-苯甲基咪唑并[1,2-a]吡嗪-6-基)-5-氟嘧啶-4-醇(化合物I-2)(25mg,14%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,甲醇-d4)δ(ppm)9.30(s,1H),8.09(s,1H),7.99(d,1H),7.80(s,1H),7.40(d,2H),7.17(t,2H),7.07-7.11(m,1H),4.52(s,2H)。
化合物I-4
根据通用程序A合成呈浅褐色固体状的2-(8-(2,3-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)-5-氟嘧啶-4-醇(化合物4)(150mg,67%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,丙酮-d6)δ(ppm)10.6(s,1H),9.34(s,1H),8.16(s,1H),7.92(s,1H),7.78(s,1H),7.20(t,1H),7.09(q,1H),7.00(q,1H),4.60(s,2H).
化合物I-6
根据通用程序A合成呈淡黄色固体状的5-氟-2-(8-(3-氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(化合物I-6)(200mg,54%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,DMSO-d6)δ(ppm)12.9(br.s,1H),9.44(s,1H),8.29(s,1H),8.16(br.s,1H),7.89(s,1H),7.39(d,1H),7.27(d,1H),7.17(t,1H),4.48(s,2H),2.14(s,3H)。
化合物I-7
根据通用程序A合成呈黄色固体状的2-(8-(3,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)-5-氟嘧啶-4-醇(化合物I-7)(190mg,57%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,DMSO-d6)δ(ppm)13.0(br.s,1H),9.47(s,1H),8.31(s,1H),8.22(br.s,1H),7.91(s,1H),7.36(br.s,2H),7.07(t,1H),4.53(s,2H)。
化合物I-3
根据通用程序A合成呈白色固体状的5-氟-2-(8-(3,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(化合物I-3)67mg,34%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,氯仿-d)δ(ppm)11.1(br.s,1H),9.14(s,1H),8.00-7.91(m,2H),7.87(s,1H),7.00(d,2H),4.56(s,2H),2.14(s,3H)。
化合物I-14
以2个步骤合成标题化合物:
步骤1:合成8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒
向8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈(2.5g,8.9mmol,1.0当量)于甲醇(44mL)中的悬浮液中添加0.50N甲醇钠于甲醇中的溶液(18mL,8.9mmol,1.0当量)。在环境温度下搅拌4h之后,再添加一份含0.50N甲醇钠的甲醇溶液(5.3mL,2.7mmol,0.3当量)且再继续搅拌2h。接着添加氯化铵(470mg,8.9mmol,1.0当量)。16h之后,将反应混合物在真空中浓缩,悬浮于饱和NaHCO3水溶液中,且搅拌20min。通过过滤收集固体且用3体积的水及2体积的醚洗涤。将粗产物在加热下再悬浮于100mL乙腈中,用醚稀释且过滤。滤饼用3体积的醚洗涤且干燥,得到浅棕色固体(2.2g,83%产率)。其不经进一步纯化即用于下一步骤中。LC/MS ES+m/z=302.1[M+H]+。
步骤2:合成5-氟-2-(8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇
向含8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(1.9g,6.2mmol,1.0当量)的乙醇(31mL)中添加(Z)-3-乙氧基-2-氟-3-氧代丙-1-烯-1-醇化钠(2.9g,19mmol,3.0当量)。在90℃下于密封容器中加热溶液18h。在冷却至环境温度之后,添加2.5N乙醇HCl溶液(7.4mL,19mmol,3.0当量)。将所得物混合物在真空中浓缩,在加热下悬浮于乙腈(100mL)中。稍微冷却之后,添加醚(100mL)且搅拌混合物10min。通过过滤收集固体且用3体积的醚洗涤。将所得固体再悬浮于水中,搅拌1h且过滤。粗制物经由制备型反相HPLC(含有0.1%三氟乙酸作为添加剂的10%至70%乙腈/水)纯化。不纯的溶离份经由制备型反相HPLC(含有0.1%三氟乙酸作为添加剂的10%至50%乙腈/水)再纯化,得到呈灰白色固体状的标题化合物(840mg,37%产率)。1H NMR(500MHz,甲醇-d4)δ(ppm)9.43(s,1H),8.21(s,1H),8.08(br.s,1H),7.89(s,1H),7.09(m,1H),7.00(m,1H),4.63(s,2H),2.23(s,3H)。
化合物I-14的Na+盐
在氮气氛围下向5-氟-2-(8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(化合物I-14,10g,27mmol)于450mL无水MeOH中的灰白色悬浮液中添加0.50N甲醇钠于甲醇中的溶液(54mL,27mmol)。在简单超声处理之后,将所得淡黄色溶液在环境温度下搅拌15min且在真空中浓缩至干燥。藉助于超声处理将固体再悬浮于250mL醚且浓缩(两次)。将所得固体再悬浮于650mL醚中且在环境温度下搅拌3h。通过真空过滤收集固体且用醚(3×100mL)洗涤。在过滤器上干燥隔夜之后,将产物盐在真空烘箱中在45℃下干燥4天,得到呈白色固体状的5-氟-2-(8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇化钠(11g,99%产率)。1H NMR(500MHz,D2O)δ(ppm)8.92(s,1H),7.99(d,1H),7.97(d,1H),7.70(d,1H),6.98(dd,1H),6.86(dd,1H),4.48(s,2H),2.14(s,3H)。
化合物I-11
根据通用程序A合成呈黄金色固体状的5-氟-2-(8-(3-氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-基)嘧啶-4-醇(化合物I-11)(61mg,23%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,DMSO-d6)δ(ppm)13.3(br.s,1H),9.60(s,1H),8.86(s,1H),8.24-8.27(m,1H),7.32-7.47(m,3H),7.03-7.06(m,1H),4.59(s,2H)。
化合物I-13
根据通用程序A合成呈棕色固体状的2-(8-(3,5-二氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-基)-5-氟嘧啶-4-醇(化合物I-13)(57mg,17%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,DMSO-d6)δ(ppm)13.2(br.s,1H),9.61(s,1H),8.87(s,1H),8.25(s,1H),7.33(d,2H),7.10(t,1H),4.60(s,2H)。
化合物I-10
根据通用程序A合成呈淡黄色固体状的2-(8-(2,3-二氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-基)-5-氟嘧啶-4-醇(化合物I-10)(85mg,16%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,DMSO-d6)δ(ppm)13.0(br.s,1H),9.62(s,1H),8.85(s,1H),8.23(s,1H),7.29-7.37(m,2H),7.09-7.16(m,1H),4.68(s,2H).
化合物I-12
根据通用程序A合成呈灰白色固体状的2-(8-(2,5-二氟苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-基)-5-氟嘧啶-4-醇(化合物I-12)(75mg,57%产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,甲醇-d4)δ(ppm)9.67(s,1H),8.69(s,1H),8.12(d,1H),7.25(m,1H),7.13(m,1H),7.02(m,1H),4.73(s,2H)。
化合物I-19
根据通用程序A合成呈浅褐色固体状的5-氟-2-(8-(2,5-二氟-4-甲基苯甲基)-[1,2,4]三唑并[1,5-a]吡嗪-6-基)嘧啶-4-醇(化合物I-19)(140mg,66%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,DMSO-d6)δ(ppm)13.1(br.s,1H),9.61(s,1H),8.83(s,1H),8.26(br.s,1H),7.35(br.s,1H),7.17(m,1H),4.57(s,2H),2.18(s,3H)。
通用程序B,适用于合成化合物I-16
以2个步骤合成标题化合物:
步骤1:合成8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒
向8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈(490mg,1.8mmol,1.0当量)于甲醇(5.0mL)中的悬浮液中添加0.50N甲醇钠于甲醇中的溶液(3.6mL,1.8mmol,1.0当量)(注意:亦可使用催化量或过量的甲醇钠)。在环境温度下搅拌3h 45min之后,添加氯化铵(970mg,18mmol,10当量)且搅拌反应物20h。将所得混合物在真空中浓缩至约2mL体积且用EtOAc(20mL)及10%NaHCO3水溶液(10mL)稀释。在搅拌15min之后,通过过滤收集产物,用水(10mL)洗涤且在真空中干燥,得到呈灰白色固体状的标题化合物(420mg,80%产率)。LC/MSES+m/z=287.9[M+H]+。
步骤2:合成5-氯-2-(8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇
向8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(100mg,0.35mmol)及2-氯-3-氧代丙酸乙酯(110mg,0.70mmol)于甲醇(1.7mL)中的悬浮液中添加0.50N甲醇钠于甲醇中的溶液(1.4mL,0.70mmol)。在65℃下于密封小瓶中加热反应物2.5h。在冷却至环境温度之后,将所得混合物在真空中浓缩,用水(10mL)稀释,用6.0NHCl水溶液溶液调节至pH 3,且用2×15mL的CH2Cl2/iPrOH(8:1)萃取。合并的有机相经硫酸钠干燥,过滤且浓缩。粗制物经由硅胶层析(0%至20%乙腈/甲醇(7:1)于CH2Cl2中)纯化且经由硅胶层析(20%至100%EtOAc/CH2Cl2)再纯化,得到呈灰白色固体状的标题化合物(37mg,28%产率)。
1H NMR(500MHz,DMSO-d6)δ(ppm)12.6(br.s,1H),9.54(s,1H),8.36(br.s,1H),8.32(s,1H),7.89(s,1H),7.45(br.s,1H),7.25(m,1H),7.12(m,1H),4.58(s,2H)。
化合物I-17
根据通用程序B合成呈浅棕色固体状的5-氯-2-(8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(化合物I-17)(5.2mg,2.2%总产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。1H NMR(500MHz,DMSO-d6)δ(ppm)9.47(s,1H),8.45(s,1H),8.22(d,1H),7.94(s,1H),7.23(dd,1H),7.16(dd,1H),6.72(d,1H),4.56(s,2H),2.17(br s,3H).LC/MS ES+m/z=388.0[M+H]+。
化合物I-15
以2个步骤合成标题化合物:
步骤1:合成8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒
根据通用程序A或B的步骤1合成呈浅棕色固体状的8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(840mg,76%产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。LC/MS ES+m/z=302.0[M+H]+。
步骤2:合成2-(8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇
向8-(2,5-二氟-4-甲基苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(360mg,1.2mmol)及3-甲氧基丙烯酸甲酯(0.39mL,3.6mmol)于乙醇(6.0mL)中的悬浮液中添加Hunig氏碱(0.63mL,3.6mmol)。在90℃下于密封小瓶中加热反应物3h。在冷却至环境温度之后,用2.5N乙醇HCl溶液(1.4mL,3.6mmol)处理所得混合物且浓缩至干燥。粗制物经由硅胶层析(0%至20%乙腈/甲醇(7:1)于CH2Cl2中)纯化且经由硅胶层析(0至15%MeOH/CH2Cl2)再纯化,得到呈浅棕色固体状的标题化合物(120mg,28%产率)。1H NMR(500MHz,DMSO-d6)δ(ppm)11.9(br.s,1H),9.52(s,1H),8.31(s,1H),8.07(br.d,1H),7.89(s,1H),7.37(dd,1H),7.16(dd,1H),6.38(br.d,1H),4.54(s,2H),2.18(s,3H)。
化合物I-8
以2个步骤合成标题化合物:
步骤1:合成8-(2-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒
根据通用程序A或B的步骤1合成呈奶黄色固体状的8-(2-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(5.1g,91%产率)。视需要改变反应条件(诸如试剂比率、温度及反应时间)及纯化方法。LC/MS ES+m/z=270.2[M+H]+。
步骤2:合成2-(8-(2-氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)-5-甲基嘧啶-4-醇
向8-(2-氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(400mg,1.5mmol)及2-甲基-3-氧代丙酸乙酯(230mg,1.8mmol)于t-BuOH(9.9mL)中的溶液中添加碳酸氢钾(220mg,2.2mmol)。将反应物加热至回流2h。在冷却至环境温度之后,添加水且通过过滤收集产物且干燥,得到呈奶黄色固体状的标题化合物(410mg,82%产率)。1H NMR(500MHz,DMSO-d6)δ(ppm)11.6(br.s,1H),9.48(s,1H),8.30(s,1H),7.94(br s,1H),7.88(s,1H),7.48(app.t,1H),7.29(m,1H),7.19(m,1H),7.11(app.t,1H),4.60(s,2H),1.98(s,3H)。
化合物I-9
含5-氟-2-(8-(2-氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(230mg,0.67mmol)的9.0mL乙腈-THF(2:1)用碳酸氢钠(84mg,1.0mmol)及SelectfluorTM(350mg,1.0mmol)处理且在50℃下加热。在实验过程中,再添加额外份碳酸氢钠(42+28mg)及SelectfluorTM(180+120mg)。在总共49h之后,将反应物冷却至环境温度且添加20mL水。所得混合物用1.0N HCl水溶液酸化至pH 3且用2×25mL的EtOAc萃取。合并的有机相经硫酸钠干燥,过滤,且浓缩。粗制物经由硅胶层析(0%至20%乙腈/甲醇(7:1)于CH2Cl2中)纯化且经由制备型反相HPLC(含有0.1%甲酸作为添加剂的15%至65%乙腈/水)再纯化,得到呈浅棕色固体状的标题化合物(23mg,9.7%产率)。1H NMR(500MHz,DMSO-d6)δ(ppm)12.6(br.s,1H),8.98(s,1H),8.19(br.s,1H),7.74(d,1H),7.48(app.t,1H),7.28(m,1H),7.19(m,1H),7.10(app.t,1H),4.56(s,2H)。
化合物I-5
含5-氟-2-(8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(200mg,0.56mmol)的10mL乙腈-THF(1:1)用碳酸氢钠(94mg,1.1mmol)及SelectfluorTM(400mg,1.1mmol)处理且在50℃下加热。在实验过程中,再添加额外份碳酸氢钠(3×47mg)及SelectfluorTM(3×200mg)。在总共74h之后,将反应物冷却至环境温度且添加40mL水。所得混合物用1.0N HCl水溶液酸化至pH 3且用2×40mL CH2Cl2/iPrOH(6:1)萃取。合并的有机相经硫酸钠干燥,过滤,且浓缩。粗制物通过硅胶层析(0至20%乙腈/甲醇(7:1)于CH2Cl2中)、制备型反相HPLC(具有0.1%TFA作为添加剂的10%至70%乙腈/水)及最终柱层析法(20%至100%EtOAc/己烷)纯化,得到呈白色固体状的标题化合物(24mg,11%产率)。1H NMR(500MHz,DMSO-d6)δ(ppm)12.8(br.s,1H),8.99(s,1H),8.20(br.s,1H),7.75(d,1H),7.42(m,1H),7.25(m,1H),7.13(m,1H),4.54(s,2H)。
化合物I-18
以5个步骤合成标题化合物:
步骤1:合成6,8-二溴-3-氟咪唑并[1,2-a]吡嗪
含6,8-二溴咪唑并[1,2-a]吡嗪(2.4g,8.7mmol)的40mL乙腈用SelectfluorTM(4.6g,13mmol)处理且在50℃下加热。在22h之后,将反应物冷却至环境温度,倾入150mL半饱和NaHCO3溶液中且用2×EtOAc(总共400mL)萃取。合并的有机相经硫酸钠干燥,过滤且浓缩。粗制物通过硅胶层析(0至20%EtOAc/己烷)纯化,得到呈橙色固体状的标题化合物(580mg,23%产率)。
步骤2:合成6-溴-8-(2,5-二氟-4-甲基苯甲基)-3-氟咪唑并[1,2-a]吡嗪
干燥锌粉末(240mg,3.7mmol)于THF(3.0mL)中的悬浮液用1,2-二溴乙烷(30mL,催化剂)处理且在50℃下加热所得混合物。接着添加氯三甲基硅烷(30mL,催化剂)。在15min之后,将混合物冷却至环境温度。添加干燥氯化锂(170mg,3.9mmol),接着逐滴添加1-(溴甲基)-2,5-二氟-3-甲苯(480mg,2.2mmol)于THF(2.0mL)中的溶液(注意:放热反应)。将混合物在环境温度下搅拌1h。同时,6,8-二溴-3-氟咪唑并[1,2-a]吡嗪(580mg,2.0mmol)及Pd(PPh3)2Cl2(41mg,0.059mmol)于THF(3.0mL)中的浆液用氮气脱气。经由注射器将新形成的锌酸盐溶液转移至此浆液中且用2×0.5mL THF冲洗以确保完全转移。将所得混合物在环境温度下搅拌1h 20min且接着在40℃下搅拌4h。在冷却至环境温度之后,反应物用4mL饱和NH4Cl溶液淬灭。有机层经浓缩,用CH2Cl2(10mL)稀释且经由硅藻土床过滤。浓缩滤液,得到棕色残余物,其通过硅胶层析(负载有CH2Cl2的化合物且用0至10%EtOAc/己烷溶离)纯化,得到呈黄色固体状的标题化合物(440mg,63%产率)。
步骤3:合成8-(2,5-二氟-4-甲基苯甲基)-3-氟咪唑并[1,2-a]吡嗪-6-甲腈
由6-溴-8-(2,5-二氟-4-甲基苯甲基)-3-氟咪唑并[1,2-a]吡嗪(440mmol,1.2mmol)、氰化锌(100mg,0.87mmol)、Pd2(dba)3(46mg,0.050mmol)及1,1'-双(二苯基膦基)二茂铁(dppf)(41mg,0.075mmol)于无水DMF(5.0mL)中构成的反应混合物用氮气脱气且接着在90℃下加热6h。将反应物冷却至环境温度且用CH2Cl2(50mL)、水(40mL)及28%氢氧化铵溶液(4.0mL)处理。水层用CH2Cl2(50mL)萃取。合并的有机层经Na2SO4干燥,过滤且浓缩,得到棕色油状物,其通过柱层析(0至20%EtOAc/己烷梯度)进行纯化,得到呈浅褐色固体状的标题化合物(310mg,81%产率)。LC/MS ES+m/z=302.8[M+H]+。
步骤4:合成8-(2,5-二氟-4-甲基苯甲基)-3-氟咪唑并[1,2-a]吡嗪-6-甲脒
向8-(2,5-二氟-4-甲基苯甲基)-3-氟咪唑并[1,2-a]吡嗪-6-甲腈(150mg,0.50mmol)于甲醇(6.0mL)中的悬浮液中添加0.50N甲醇钠于甲醇中的溶液(1.0mL,0.50mmol)。在环境温度下搅拌4h 30min之后,添加氯化铵(270mg,5.0mmol)且搅拌反应物18h。所得混合物在真空中浓缩,用10%NaHCO3水溶液(10mL)处理且进行超声处理,得到悬浮液。在搅拌1h之后,产物通过过滤收集,用水(10mL)洗涤且在真空中干燥,得到呈浅褐色固体状的标题化合物(170mg,>100%产率)。其不经进一步纯化即用于下一步骤中。LC/MSES+m/z=319.7[M+H]+。
步骤5:合成2-(8-(2,5-二氟-4-甲基苯甲基)-3-氟咪唑并[1,2-a]吡嗪-6-氟嘧啶-4-醇
向8-(2,5-二氟-4-甲基苯甲基)-3-氟咪唑并[1,2-a]吡嗪-6-甲脒(0.50mmol,来自前一步骤的理论量)于乙醇(5.0mL)中的悬浮液中添加(Z)-3-乙氧基-2-氟-3-氧代丙-1-烯-1-醇化钠(310mg,2.0mmol)。在90℃下于密封小瓶中加热反应物16h。在冷却至环境温度之后,混合物用水(7.5mL)稀释,用1N HCl水溶液调节至pH 4。所得浅棕色固体通过过滤收集,用水(50mL)及乙醚(30mL)洗涤,且干燥,得到呈棕色固体状的标题化合物(140mg,71%产率,历经2个步骤)。1H NMR(500MHz,DMSO-d6)δ(ppm)12.8(br.s,1H),8.98(s,1H),8.22(br.s,1H),7.74(d,1H),7.35(br.s,1H),7.15(m,1H),4.50(s,2H),2.18(s,3H)。
化合物I-20
以2个步骤合成标题化合物:
步骤1:合成8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒
向8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲腈(500mg,1.9mmol)于甲醇(22mL)中的溶液中添加25wt%甲醇钠于甲醇中的溶液(2.1mL,9.3mmol)。在环境温度下搅拌1h之后,添加氯化铵(1.0g,19mmol)且搅拌反应物隔夜。将反应混合物在真空中浓缩,用半饱和NaHCO3溶液(20mL)及1.0N氢氧化钠溶液(2.0mL)稀释,且用2×20mL EtOAc萃取。合并的有机相经硫酸钠干燥,过滤且浓缩,得到呈棕色固体状的粗产物。其不经进一步纯化即用于下一步骤。LC/MS ES+m/z=288.1[M+H]+。
步骤2:合成5-氟-2-(8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇
向8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-甲脒(500mg,1.7mmol)于乙醇(9.0mL)中的悬浮液中添加(Z)-3-乙氧基-2-氟-3-氧代丙-1-烯-1-醇化钠(820mg,5.2mmol)。在90℃下于密封小瓶中加热反应物2h。在冷却至环境温度之后,逐滴添加浓HCl溶液以将混合物酸化至pH 4。所得混合物在真空中浓缩。通过制备型反相HPLC(乙腈-水梯度,具有0.1%TFA作为添加剂)纯化,得到呈黄色固体状的标题化合物(200mg,28%产率,历经2个步骤)。1H NMR(500MHz,DMSO-d6)δ(ppm)12.6(br.s,1H),9.49(s,1H),8.32(s,1H),8.19(br.s,1H),7.89(s,1H),7.43(s,1H),7.25(m,1H),7.13(m,1H),4.58(s,2H)。
化合物I-20之Na+盐
在氮气氛围下向5-氟-2-(8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇(化合物I-20,10g,28mmol)于450mL无水MeOH中的浅棕色悬浮液中添加0.50N甲醇钠于甲醇中的溶液(57mL,28mmol)。在简单超声处理之后,在环境温度下搅拌所得浅橙色溶液15min且在真空中浓缩至干燥。藉助于超声处理将固体再悬浮于200mL醚且浓缩(两次)。将所得固体再悬浮于500mL醚中且在环境温度下搅拌3h。通过真空过滤收集固体且用醚(3×100mL)洗涤。在过滤器上干燥隔夜之后,将产物盐在真空烘箱中在45℃下干燥5天,得到呈浅褐色固体状的5-氟-2-(8-(2,5-二氟苯甲基)咪唑并[1,2-a]吡嗪-6-基)嘧啶-4-醇化钠(11g,99%产率)。1H NMR(500MHz,D2O)δ(ppm)8.90(s,1H),7.98(d,1H),7.95(d,1H),7.70(d,1H),7.10(m,1H),6.98-6.89(m,2H),4.53(s,2H)。
生物部分
式I化合物的生物特性的评估
本发明本申请还提供对表I化合物的生物特性的评估。在各种细胞及测定中活体外测试本发明的代表性化合物作为sGC刺激剂的活性,以及在体内测试其降低动物血压的能力。血压降低用以表明化合物体内外围地接合目标的能力。使用其他测试用于指示这些化合物跨越BBB、接合CNS中的靶标、增加CNS中的cGMP的含量及由此刺激动物的功能性反应的能力。这些生物特性代表了本发明的另一实施方案。
实例2:通过基于cGMP Glo Sensor细胞的测定、384孔格式进行生物活性测量
表现GloSensorTM 40F cGMP(产品编号:CS182801,Promega)的人类胚胎肾细胞(HEK293)细胞用于评估测试化合物的活性。并入至这些细胞中的发光生物传感器(经工程改造的荧光素酶)检测由刺激sGC酶的化合物形成的cGMP且发射荧光。
将cGMP GloSensor细胞维持在补充有胎牛血清(FBS,10%最终)及潮霉素(200ug/ml)的达尔伯克改良伊格尔培养基(Dulbecco'sModification of Eagle's Medium;DMEM)中。测定前一天,将细胞以1.5×104个细胞/孔的密度接种于聚D-赖氨酸涂布的384孔平坦白底盘(Corning目录号35661)中的50μL体积的具有10%FBS的DMEM中。在37℃下在具有5%CO2的潮湿室中培养细胞隔夜。次日,移除培养基且用40微升/孔的GloSensorTM,2mM(Promega,目录号E1291)替换细胞。在25℃下处理细胞90分钟以允许基质在细胞中平衡。将测试化合物及二亚乙基三胺NONO盐(DETA-NONO盐)在无血清CO2非依赖性培养基中稀释至3mM(20×)且以4×稀释液连续稀释以产生5X剂量曲线,从中将10ul添加至各孔中(针对测试化合物溶液为xμM浓度且对于DETA-NONO盐溶液为10μM浓度;其中x为以下最终浓度之一:30μM、7.5μM、1.9μM、469nM、117nM、29.3nM、7.3nM、1.83nM、0.46nM、0.11nM、0.03nM)。对于动力学研究,立刻用Envision(Perkin Elmer)以0.2秒/孔测量荧光。对于终点SAR筛选,在室温下培育55min之后收集资料。
使用4参数拟合(对数(激动剂)相比于反应-可变斜率)分析浓度应答数据。EC50是有曲线拟合内推得出的且定义为化合物引发其最大反应的50%时的浓度。当对给定化合物进行多次实验时,报导所有实验的几何平均值。
下表A汇总了本发明的化合物的Glo测定中的EC50值。
表A.
化合物编号 | Glo EC50(nM) | 化合物编号 | Glo EC50(nM) |
I-21 | B | I-5 | A |
I-2 | B | I-14* | A |
I-1 | B | I-16 | A |
I-4 | B | I-15 | B |
I-23 | B | I-19 | B |
I-20* | A | I-17 | A |
I-11 | B | I-18 | A |
I-13 | B | I-12 | B |
I-10 | B | I-3 | A |
I-6 | A | I-8 | C |
I-7 | B | I-9 | B |
通过GloSensor测定确定HEK细胞中的sGC酶活性值。sGC酶活性值(表示为EC50,其定义为化合物引发其最大反应的50%时的浓度)的代码定义:EC50≤100nM=A;100nM<EC50≤1000nM=B;1000nM<EC50=C。*对于化合物I-20及I-14,使用游离酸及钠盐两者且此处的结果为独立于形式运行的所有实验的平均值。
实例3.通过基于cGMP神经元细胞的分析进行生物活性测量
自18天怀孕的Sprague-Dawley雌性大鼠的胎儿分离出大鼠原代神经元。将胎儿收集在汉克氏平衡盐溶液(HBSS)中且快速移除大脑。将脑海马区分离且机械地碎裂。在37℃下在不具有Ca2+及Mg2+的HBSS中用0.25%(wt/vol)胰蛋白酶溶液进行进一步组织消化15min。胰蛋白酶化之后,将细胞洗涤且再悬浮于补充有0.5mM L-谷氨酰胺、12.5uM谷氨酸、2%B-27及100U/mL青霉素及100μg/mL链霉素的神经基质培养基中。将细胞以26×103或3×104或4×104个细胞/孔的密度接种于聚D-赖氨酸涂布的384孔平坦透明底盘(Corning目录号354662)中。在37℃下在具有5%CO2的潮湿室中培育细胞6至7天。移除培养基且用含有Ca2+及Mg2+的HBSS洗涤细胞1×,且用40uL含有0.5mM IBMX的HBSS替换,且在37℃下培育15分钟。添加具有二亚乙基三胺NONO盐(DETA-NO)的10uL5×测试化合物储备液。DETA-NO的最终浓度为10μM或30μM。在37℃下培育细胞20min。移除培养基,添加50uL冰冷的10%乙酸,且在4℃下培育60分钟。在4℃下以1000×g离心5分钟以使细胞碎片沉淀之后,将上清液抽吸至清洁盘中且分析样本的cGMP内含物。使用LC-MS/MS自各样本测定cGMP浓度。
使用4参数拟合(对数(激动剂)相对于反应-可变斜率)分析浓度应答数据。EC50是曲线拟合内推得出的且定义为化合物引发其最大反应的50%时的浓度。当对给定化合物进行多次实验时,报导所有实验的几何平均值。
下表B汇总了本发明化合物的神经元测定中的EC50值。
表B.
基于神经元的细胞测定。EC50≤100nM=A;100nM<EC50≤1000nM=B;1000nM<EC50=C。*对于化合物I-20及I-14,使用游离酸及钠盐两者且此处结果为独立于形式运行的所有实验的平均值。
实例4:对CHO-K1细胞中稳定表现之人类α2β1sGC同功酶的生物活性量测
将sGC刺激剂溶解于DMSO中成为10mM溶液并储存于-20℃下。为达成所需测试浓度,将储备液浓度连续稀释至DMSO中且接着在测定缓冲液中稀释至适当浓度。
在37℃下在空气中含有5%CO2的95%潮湿氛围中将稳定转染有人类α2β1sGC同工酶(由Ironwood的GenScript产生)的CHO-K1细胞培养在具有10%胎牛血清、4μg/mL嘌呤霉素(Gibco目录号A11138-03)及0.4mg/mL遗传霉素(Gibco目录号10131-027)的F-12K培养基(ATCC目录号30-2004)中。对于GC活性分析,将细胞分别以3×104个细胞/孔或15×103的密度接种于384孔聚D-赖氨酸涂布的平底盘(Fisher Scientific#08-774-311)中的50μL或70μL培养基中。在37℃下在补充有5%CO2的潮湿室中培养细胞24小时。
对于各测试浓度,将化合物在100%DMSO中稀释至其最终分析浓度的百分之一。就在分析之前,将所述溶液20倍稀释至含有钙、镁及50μM DETA-NONO盐的HBSS中(5×最终分析浓度)。移除培养基且用40μL HBSS洗涤细胞一次。接着在37℃下用HBSS中含有0.5mMIBMX的40μL溶液培育细胞15min。向细胞中添加至10μL来自sGC刺激剂/HBSS/DETA-NONO盐盘的溶液,在37℃下再培育20min。最终DMSO浓度为1%,最终DETA-NONO盐浓度为10μM;且最终化合物浓度为30,000nM、6000nM、1200nM、240nM、48nM、9.6nM、1.92nM、0.384nM、0.077nM、0.015nM或0.003nM。
在与化合物一起培育后,移除测定缓冲液且向各孔中添加50μL冰冷的10%乙酸+150ng/mL内标物(+3cGMP)。将样本在冰上培育30至60min。在4℃下以1000×g离心5min以使细胞碎片沉淀后,将上清液转移至清洁盘中且分析样本的cGMP内含物。
使用GraphPad Prism软件v.8以4参数拟合(对数(激动剂)相比于反应-可变斜率)分析数据。EC50是由曲线拟合内推得出的且定义为化合物引发其最大反应的50%时的浓度。当对给定化合物进行多次实验时,报导所有实验的几何平均值。
下表C汇总了本发明的化合物的CHO分析中的EC50值。
表C
CHO细胞分析。EC50≤100nM=A;100nM<EC50≤1000nM=B;
1000nM<EC50=C。*对于化合物I-20及I-14,使用游离酸及钠盐两者且此处的结果为独立于形式运行的所有实验的平均值。
实例5:本发明代表性化合物在多个浓度的急性剂量后在血压正常大鼠中的血压影响
化合物I-14
血压正常的雄性Sprague Dawley大鼠购自Charles River实验室。这些大鼠已安置有留置股动脉导管。将动物拴在系绳系统且连接至压力传感器以监测心脏血管(CV)参数,具体地监测平均动脉压(MAP)及心率(HR)。使动物适应该系统隔夜且收集基线CV参数。随后向清醒自由移动的大鼠施用1、3、10及30mg/kg单次口服剂量的含化合物I-14的Milli-Q水(由化合物14的钠盐产生的剂量)。在给药前及给药后2小时经由导管线自各动物收集血液样本以用于化合物浓度定量。记录给药后十小时内的血液动力学测量结果。针对这些研究使用五十四只雄性大鼠且将其在250至275克体重范围内排序以收容。根据方案MIL-110,将它们单独圈养在温度(21±1℃)、相对湿度(36±1%)的受控条件下且置放于SmartLabs饲养室(21Erie Street,Cambridge,MA)的12-小时光照-避光循环(在6:00AM开灯且在6:00PM关灯)房间内。允许动物随意获取食物(LabDiet Prolab Isopro RMH 3000,St.Louis,MO)及水。进行两组研究。对于第一组研究,化合物I-14以0.3及1.0mg/ml配制于Milli-Q水中且冷冻在-20℃下。对于第二组研究,在Cyclerion Therapeutics称重化合物I-14的钠盐且在SmartLabs重构以提供化合物I-14于Milli-Q水中的0.1、0.3、1.0及3.0mg/ml溶液。在给药前4小时内将制备的制剂解冻且储存于室温下,或在给药前2小时内制成且储存于室温下。
历经6个独立的阶段进行研究。受试者的总数目及治疗剂分配在下表中列出。动物最初在接收的3天内使用且若导管保持畅通,则在清洗6至7天后再使用一次。没有动物被使用超过两次。
群组 | 动物数目 | 治疗剂 | 剂量体积 | 剂量浓度 |
1 | 13 | 媒剂 | 10mL/kg | - |
2 | 9 | 1mg/kg化合物I-14 | 10mL/kg | 0.1mg/mL |
3 | 6 | 3mg/kg化合物I-14 | 10mL/kg | 0.3mg/mL |
4 | 11 | 10mg/kg化合物I-14 | 10mL/kg | 1.0mg/mL |
5 | 6 | 30mg/kg化合物I-14 | 10mL/kg | 3.0mg/mL |
血压的测量
此研究利用ADInstruments LabChart(v8)自被栓至血压传感器(HarvardApparatus目录号APT300)的清醒自由移动大鼠收集血液动力学数据。在隔夜适应系绳及压力传感器之后,在1小时基线记录时间段之后向动物给药。向动物施用10mL/kg体积剂量的化合物I-14的钠盐形式或媒剂的单一口服(P.O.)剂量。给药后继续收集数据10小时。
使用ADInstruments LabChart(v8)监测且输出血液动力学数据。持续监测血压及心率,且以1000个数据点/秒收集数据,接着平均至10-分钟分组中以用于分析。使用Microsoft 365的Microsoft Excel使用在给药前1小时时间段内平均化的给药前基线计算MAP相对于基线的变化(ΔBMAP)及HR相对于基线的变化(ΔBHR)。使用此10-分钟分组数据集测定ΔVMAP峰、ΔVMAP峰的时间、ΔVHR峰及ΔVHR峰的时间。数据集进一步合并至1-小时分组中以用于MAP及HR图及对ΔBMAP、ΔBMAP及ΔBHR的分析。这些术语/缩写的定义总结于下文:
ΔBMAP,dMAP | 平均动脉压相对于基线的变化 |
ΔBHR,dHR | 心率相对于基线的变化 |
ΔVMAP | 经媒剂调整的平均动脉压 |
ΔVMAP | 经媒剂调整的心率 |
AOC | 曲线上面积 |
在GraphPad Prism(v8)中进行统计分析。通过双因子重复测量ANOVA接着邓尼特多重比较测试来测定与媒剂治疗的大鼠相比,ΔBMAP及ΔBHR数据的显著性,若存在遗漏的数据点,则利用混合效应分析。通过各剂量组在各时间点的ΔBMAP减去媒剂组的ΔBMAP来计算经媒剂调整的MAP(ΔVMAP)。以类似于ΔVMAP的方式计算经媒剂调整的HR(ΔVHR)。
通过单因子ANOVA接着邓尼特多重比较测试来测定与媒剂相比的AOC数据的显著性。
在分析之前移除一些研究数据。由于2-小时血液样本收集,移除给药后130min及140min收集的数据。由于在470分钟开始且持续直至研究结束(600min)的实验期间的信号丢失,排除一只大鼠在1mg/kg下的几个时间点。出于各种原因,自所有数据集排除5只动物的全部时程,包括它们用于特定分析的离群值或因导致异常结果的信号损失。
血压变化
MAP相对于基线的变化(ΔBMAP)以图形方式显示于图1中。相比于媒剂治疗的大鼠,用化合物I-14治疗的大鼠的MAP减少更多(如通过MAP相对于基线的变化,即ΔBMAP,来评定)。通过双因子ANOVA,ΔBMAP数据集为显著的(对于治疗剂及时间,p<0.0001,且对于治疗剂×时间相互作用,p=0.045)。主要治疗作用的邓尼特氏多重比较测试得到:与经媒剂治疗的大鼠相比,对于1mg/kg为p=ns,对于3mg/kg为p=0.0034且对于10及30mg/kg剂量为p<0.0001。相比于媒剂治疗的大鼠,在各时间点及各剂量的单一作用的单独邓尼特氏多重比较测试显示,ΔBMAP在用10及30mg/kg化合物I-14治疗的大鼠中的整个给药后6-小时时间段内减少更多;在用3mg/kg化合物I-14治疗的大鼠中,在给药后1-小时、2-小时及3-小时减少更多;而在用1mg/kg化合物I-14治疗的大鼠中则没有减少。
通过使用10-分钟分组的数据集计算化合物I-14对ΔVMAP的最大作用且显示于下表D中:
表D.化合物I-14对经媒剂调整的MAP(ΔVMAP)的最大作用
化合物I-14 | 峰ΔvMAP(mm Hg) | 到达峰的时间(min) |
1mg/kg | -6.2 | 90 |
3mg/kg | -10.1 | 70 |
10mg/kg | -22.3 | 30 |
30mg/kg | -24.4 | 30 |
如通过主效应分析、单一效应分析及通过AOC评定,对ΔBMAP无作用的剂量为1mg/kg。
结论
相对于基线且如自媒剂调整,化合物I-14在3、10及30mg/kg降低MAP。
b)化合物I-20
用化合物I-20进行于上文所描述的研究类似的研究。向清醒自由移动的大鼠施用1、3、10及30mg/kg单次口服剂量的含化合物I-20(由化合物I-20的钠盐制备的剂量)于Milli-Q水中。在给药前及给药后2小时经由导管线自各动物收集血液样本以用于化合物浓度定量。记录给药后十小时的血液动力学测量结果。
血压变化
MAP相对于基线的变化(ΔBMAP)以图形方式显示于图2中。相比于经媒剂治疗的大鼠,用化合物I-20治疗的大鼠的MAP减少更多(如通过MAP相对于基线的变化,即ΔBMAP,来评定)。通过双因子ANOVA,ΔBMAP数据集为显著的(对于治疗剂及治疗剂×时间相互作用,p<0.0001;且对于时间,p=0.022)。主要治疗作用的邓尼特氏多重比较测试得到:与经媒剂治疗的大鼠相比,对于1mg/kg为p=0.055(ns),对于3mg/kg为p=0.0001且对于10及30mg/kg剂量为p<0.0001。对比媒剂治疗的大鼠,在各时间点及各剂量的单一作用的单独邓尼特氏多重比较测试显示,MAP在用3、10及30mg/kg化合物I-20治疗的大鼠中,在整个给药后6-小时时间段内减少更多;在用1mg/kg化合物I-20治疗的大鼠中,给药后1-小时、2-小时、3-小时、4-小时及5-小时减少更多。
通过使用10-分钟分组的数据集计算化合物I-20对ΔVMAP(经媒剂调整的MAP)的最大作用且显示于下表E中:
表E.化合物I-20对经媒剂调整的MAP(ΔVMAP)的最大作用
化合物I-20 | 峰ΔvMAP(mm Hg) | 到达峰之时间(min) |
1mg/kg | -14.3 | 20 |
3mg/kg | -19.2 | 20 |
10mg/kg | -20.2 | 30 |
30mg/kg | -38.1 | 30 |
结论
相对于基线且如自媒剂调整,化合物I-20在1、3、10及30mg/kg降低MAP。
其他BP测量
在与上文所描述所示的那些研究类似的研究中,在PEG400中配制且以10mg/kg施用的化合物I-4显示,在给药后50min,MAP相对于基线的最大减少(ΔBMAP)为20mm Hg。在与上文所描述所示的那些研究类似的研究中,在PEG400中配制且以10mg/kg施用的化合物I-20显示,在给药后42min,峰ΔBMAP为-26mm Hg。在化合物I-20以1、3或10mg/kg进行测试且在甲基纤维素中配制的另一研究中,化合物在所有测试剂量下均能够使MAP相对于基线降低。
实例6:大鼠原代神经元中sGC刺激剂诱导的CREB磷酸化
目标
为评估本发明的化合物活化大鼠原代神经元中的cAMP反应组件结合蛋白(CREB)的能力。CREB为细胞转录因子。其结合至称作cAMP反应组件(CRE)的DNA序列,且调节下游基因的转录(参见Bourtchuladze R,等人,Cell 1994;79(1):59-68)。有充分证据证明,CREB在大脑的神经元可塑性及长期记忆形成中具有作用,且已显示在空间记忆形成中为不可或缺的(参见Silva AJ,等人,Annual Review of Neuroscience 1998;21:127-148)。CREB蛋白质通过各种激酶对丝胺酸133的磷酸化来活化,所述激酶包括cAMP依赖性蛋白激酶或蛋白激酶A(PKA)、cGMP依赖性蛋白激酶或蛋白激酶G(PKG)及Ca2+/钙调蛋白依赖性蛋白激酶。(参见Shaywitz AJ及Greenberg ME,Annual Review of Biochemistry 1999;68(1):821–861及Wong JC,等人,J Cell Biochem 2012:113(11):3587-98)。CREB的刺激对于其中认知、神经元可塑性及或神经元功能受损的疾病可具有治疗益处。
大鼠原代神经元培养
在胚胎第18天(E18)自Sprague Dawley大白鼠胚胎分离出神经元。自各大鼠获得大致10个胚胎,且自所述胚胎分离出整个大脑。在立体显微镜下使用两个细镊子自大脑剥离海马体及皮质。小心地移除脑膜。剥离之后,将组织切碎且在15-mL锥形管中用10mL不含Ca2+及Mg2+的汉克氏平衡盐溶液(HBSS,Corning目录号21-022-CM)轻缓地洗涤一次。洗涤之后,将0.25%胰蛋白酶(Invitrogen目录号15090-046)及0.1%脱氧核糖核酸酶I(DNase I,Sigma目录号DN-25)的5mL溶液添加至组织中,接着在37℃下培育15min。接着,用冰冷的HBSS洗涤组织3次,添加3mL的0.1%DNase I溶液,接着使用玻璃巴斯德吸管(Pasteurpipette)缓慢地吸取组织12次,接着在500×g下离心10min。将细胞沉淀物再悬浮于培养基(神经基质培养基,Gibco目录号21103-049)、2%B27补充剂(Gibco目录号17504-044)、0.5mM L-谷氨酰胺(Corning目录号25-005-Cl)、25μM L-谷氨酸(Sigma目录号G1251)及1%青霉素/链霉素(Gibco目录号15070-063)中,随后,将细胞悬浮液以100,000个细胞/孔接种于聚-L-赖氨酸涂布的96孔盘中。接种后二十四小时,移除一半培养基且用上文所描述但不含谷氨酸的培养基置换。将细胞维持在具有5%CO2之37℃潮湿培育箱中且在收集后第6天与第10天之间用于测定。
分析条件
对于各测试浓度,将化合物在100%DMSO中稀释至100×其最终测定浓度。就在测定之前,将化合物1/10稀释至含有100μMDETA-NONO盐(10×最终分析浓度)的HBSS(含有钙及镁)(10×最终分析浓度)中。移除培养基,且用90μL HBSS(Corining目录号21-023-CV)洗涤细胞一次。接着在37℃下用90μL HBSS培育细胞30min。向10μL测试物/HBSS/DETA-NONO盐培养盘中添加细胞且在37℃再培育30min。最终DMSO浓度为1%,最终DETA-NONO盐浓度为10μM;且最终化合物浓度为10μM、1μM、0.1μM、0.01μM、0.001μM、0.0001μM、0.00001μM及0.0μM。移除培养基,将细胞溶解且根据Cisbio方案(磷酸化CREB(Ser133)目录号64CREPEG)测定pCREB的含量。使用Envision仪器(PerkinElmer)读取培养盘。
数据分析
测定各孔的pCREB且使用GraphPad Prism软件v.8以3-参数拟合(对数(激动剂)相对于反应-可变斜率)进行分析。EC50由曲线拟合内推且定义为sGC刺激剂化合物引发其最大反应的50%时的浓度。对给定化合物进行多次实验且报导所有实验的几何平均值。对于化合物14及20两者,在这些实验中使用游离酸。
下表F汇总了本发明的化合物的pCREB测定中的EC50值。
表F.
实例7:大鼠脑脊髓液(CSF)药物动力学特性
方案
口服给药后测定大鼠的PK。对于口服(PO)实验,使用置放在小脑延髓池中的具有留置导管的一组6只雄性Sprague-Dawley大鼠。向PO组给与调配为于PEG400中的溶液或于0.5%Tween 80及0.5%甲基纤维素于水中的悬浮液的3.0或10mg/kg化合物。PO剂量通过经口管饲施用且使用注射器及管饲管递送至胃。在口服剂量施用之后,用大致0.5mL水冲洗管饲管以确保完整剂量的完全递送。
如下收集血浆样本:在给药后1小时、2小时及视情况4小时收集CSF及血液的样本。经由脑池内导管收集CSF样本(0.05mL)。经由尾部切口采用收集血液样本(0.25mL)。将这些样本保持在冰上直至处理血浆。在收集1小时内将血液样本在大致5℃下在3200rpm下离心5分钟。将血浆直接转移至单独的埃彭道夫管(Eppendorf tube)(0.125mL)中。将塞帽置于导管上且将导管冷冻在大致-70℃下并且储存直至分析。收集血浆及CSF且分析化合物的存在。
化合物的定量。
所讨论的化合物及内标物通过自血浆中沉淀来提取且通过沉淀或稀释自CSF中提取。使用液相层析(LC)及串联质谱检测(MS/MS)使用电喷雾电离分析样本。标准曲线介于0.1至1000ng/mL范围内。本文所描述的化合物在此测定中的结果说明于下表G(对于10mg/kg剂量及/或3mg/kg的化合物)中。将若干动物的化合物浓度组合以得到各特定剂量及时间点处的几何平均值。
Kp,uu被定义为CSF中的未结合药物与血浆中的未结合药物的浓度比。通过总血浆浓度乘以如通过血浆蛋白质结合所测定的未结合分率来计算血浆中的未结合药物(或游离血浆浓度)。接着,CSF浓度除以游离血浆浓度以测定Kp,uu。(参见例如Di等人,J.Med.Chem.,56,2-12(2013))
表G.
大鼠CSF PK。Kp,uu≤1=A;1<Kp,uu≤2=B;2<Kp,uu≤3=C,3<Kp,uu=D。
实例8:对大鼠大脑的微透析实验
目标
当前研究的目标为评估向Sprague Dawley雄性大鼠施用之后,在海马体及纹状体间质液(ISF)以及循环血浆中本发明的sGC刺激剂的含量。为此,在海马体及纹状体及颈静脉插管(JVC)中向大鼠植入微透析探针。在收集一个给药前ISF样本之后,向动物给与sGC刺激剂。在施用之后,经由海马体及纹状体探针收集样本24小时,以及经由JVC收集连续血浆采样。将所有收集的样本储存于-80℃下等待对渗透液中的化合物含量进行分析。
材料及方法
动物
将预先插入有颈静脉插管的五只Sprague Dawley大白鼠用于此研究。到达之后,将大鼠分组圈养于聚碳酸酯笼(2至3只/笼)中且在开始研究之前适应至少3天。将动物圈养于具有维持在22±2℃下的室温及大致50%湿度的12小时光照/黑暗循环中且随意获得食物及水。经由独特鉴别号对大鼠进行追踪。根据南旧金山市查尔斯河实验室的实验动物照护及使用委员会(Institutional Animal Care and Use Committee of Charles RiverLaboratories South San Francisco)批准的方案进行实验。
配制及给药
在治疗当天新鲜配制sGC刺激剂且如下向动物施用:化合物I-14以3mg/kg的剂量给与,呈其钠盐形式,且浓度为3mg/mL且配制于MilliQ水中。
活体外实验
进行活体外Metaquant微透析(MQ-MD)实验以经由探针的膜测试化合物的回收率。为此,MQ探针(聚丙烯腈,3mm膜)通过入口PEEK导管连接至微灌注泵(Harvard PHD 2000注射泵,Holliston,MA或类似者)。将探针单独地置放于含有50ng/mL sGC刺激剂的人工CSF(aCSF)+0.2%牛血清白蛋白(BSA)浴中。将浴液内含物持续搅拌且保持在37℃下。用aCSF+0.2%β-环糊精(β-CD,缓流)灌注各探针且使用超纯水+0.2%BSA的载流。流动速率对于缓流为0.15μL/min且对于载流为0.8μL/min。探针的出口通过出口PEEK导管连接至自动化流分收集器(820微取样器、Univentor、Malta或类似者)。在灌注稳定之后,将样本在20-分钟时间段内收集至聚丙烯小瓶中。在独立小瓶中,在实验样本收集阶段开始及结束时收集150μL浴液内含物样本。分析活体外透析液及浴液样本的化合物含量。探针回收率经计算为渗透液样本中的化合物浓度相对于浴液浓度的比率且表示为回收百分比。
微透析程序
使用异氟醚(2%,800mL/min O2)麻醉大鼠。使用布比卡因(Bupivacaine)进行局部麻醉且使用卡洛芬(carprofen)进行术前/术后镇痛。将动物置放于立体定位的框架(Kopf仪器,USA)中。接着,将MetaQuant微透析探针(聚丙烯腈;3mm暴露膜)植入纹状体(STR)及海马体(HIPP)中。针对STR的探针尖端的坐标为:前后(AP)距前囟=+0.9mm,侧面(L)距中线=+3.0mm,且腹侧(V)距硬脑膜=-7.0mm,齿条设定为-3.3mm。接着将第二探针植入海马体(HIPP)中。针对HIPP的探针尖端的坐标为:前后(AP)距前囟=-5.3mm,侧面(L)距中线=-4.8mm且腹侧(V)距硬脑膜=-7.0mm,齿条设定为-3.3mm。手术后,将动物单独圈养在笼中且随意提供食物及水。
手术后一天进行微透析实验。将微透析探针用挠性PEEK导管连接至微灌注泵(Harvard PHD 2000注射泵,Holliston MA)。微透析探针用含有147mM NaCl、3.0mM KCl、1.2mM CaCl2及1.2mM MgCl2及0.2%β-环糊精的aCSF以0.15μL/min缓流及H2O+0.2%BSA的载剂以0.8μL/min的速率灌注。通过自动化流分收集器(820微取样器,Univentor,Malta)在30分钟时间段内将微透析样本收集至含有15μL 0.02M甲酸+0.04%抗坏血酸/超纯水的300uL聚丙烯微瓶中。在稳定之后,收集一个基线样本,且在T=0时经口(PO)施用sGC刺激剂且持续收集样本24小时(在1h、2h、3h、4h、5h、6h、8h、12h及24h收集)。将样本等分用于对sGC刺激剂进行分析。将所有ISF样本储存于-80℃下直至进行分析。
除了ISF收集,在治疗之后的T=-0.5h、0.5h、1h、2h、3h、4h、5h、6h、8h、12h及24h经由JVC将血液样本收集至K2+EDTA小瓶中。将血液储存于冰上直至进行血浆处理(在4℃,以2,500g离心10min)。将血浆等分至1.5mL埃彭道夫小瓶中且储存于-80℃下等待分析。
死后组织收集
完成微透析后,经由CO2窒息使动物安乐死。将大脑收集于10%中性缓冲福尔马林中以用于探针置放验证。
生物分析方法
测量渗透液及血浆中的化合物含量
渗透液及血浆样本中的化合物I-14的浓度通过超高效液相层析(UPLC)联合串联质谱法(MS/MS)检测以多重反应监测模式(MRM)进行定量。
首先将血浆样本与含有100ng/mL的地塞米松(dexamethasone)(内标物)的乙腈溶液混合以进行蛋白质沉淀。在室温下培育5分钟之后,将样本离心5分钟(1300rpm,4℃)且将上清液在具有0.1%甲酸的超纯水中稀释100倍。
在分析之前,将未经稀释的渗透液样本(10μL)与含有50ng/mL地塞米松(内标物)溶解于乙腈/超纯水(1:1)及0.1%甲酸中的4μL内标物溶液混合。
通过自动化样本注射器(Shimadzu Sil-30AC自动取样器,Shimadzu,USA)将未经稀释的渗透液样本及经稀释的血浆上清液注射至Shimadzu系统(Shimadzu,USA)中。通过液相层析使用移动相B在0.800mL/min流速下的线性梯度在保持于35℃温度的反相XBridgeBEH C8管柱(2.1*50mm,2.5μm粒度;Waters,USA)上分离分析物。移动相A由具有0.1%甲酸的超纯水组成。移动相B为具有0.1%甲酸的乙腈。
使用配备有涡轮离子喷雾接口的5500质谱仪(Applied Biosystems,USA)以正电离模式实现采集。离子喷雾电压设定为5.5kV且探针温度为600℃。在培养基处保持碰撞气体(氮气)压力。使用以下MRM过渡区进行定量:m/z 372.0/352.0。使用加权(1/x)回归拟合适合的导入校准曲线。使用这些校准曲线测定样本浓度。在各样本系列之后通过质量控制样本验证准确度。使用AnalystTM数据系统(Applied Biosystems,1.5.2版)校准及定量数据。
数据评估
以Windows(GraphPad Software,Inc.)的Prism 8绘制数据。基于探针回收率校正所报导的化合物I-14的渗透液浓度。平均回收率为14.7%(SEM为0.59)。
结果
五只均成功地给药且完成实验。在4小时时间点将一只动物的JVC阻断且不收集额外血液。未观测到治疗的明显副作用。
在纹状体及海马ISF中施用化合物I-14的作用;STI/HIPP与血浆中的化合物的比率
图3显示在T=0min施用(3mg/kg;PO)化合物I-14后,成年雄性Sprague-Dawley大鼠中ISF渗透液中的STR及HIPP部分中的化合物I-14的含量。
微透析允许对脑组织之间质液中的化合物浓度进行取样。鉴于采样位置处的组织具有与脑脊髓液(CSF)相比不同的血液灌注速率、生理组成及清除率机制,我们预期相同动物中的微透析研究与CSF-PK研究之间的分布及测量的浓度会不同。在达至最大浓度的时间、测量的浓度及由量测浓度计算的比率中观测到这些差异(Nagaya Y,Nozaki Y,Takenaka O,等人,Investigation of utility of cerebrospinal fluid drugconcentration as a surrogate for interstitial fluid concentration usingmicrodialysis coupled with cisternal cerebrospinal fluid sampling in wild-type and Mdr1a(-/-)rats.Drug Metab Pharmacokinet.2016;31(1):57-66)。
实例9:单次施用sGC刺激剂之后的大鼠脑脊髓液(CSF)中的cGMP浓度变化(CSF生物标记量测)
进行此实验以测定不同剂量的本发明sGC刺激剂化合物对大鼠CSF中的cGMP含量的影响。
方案
向大鼠施用单剂量的媒剂或sGC刺激剂(1、3、10或30mg/kg)。施用之后一小时、两小时及六小时,收集CSF样本且分析以测定cGMP及化合物浓度,收集血浆样本且分析以测定化合物浓度。对各大鼠采样一次或多次,各给药之间间隔3天或多于三天。实验前一天,使大鼠禁食隔夜,随意获取水。
在实验当天,经口给药之后测定大鼠CSF中的化合物及环单磷酸鸟苷(cGMP)的浓度。将植入有脑池内插管的雄性CD大鼠(250至275g)用于这些研究。根据方案MIL-110,将大鼠单独圈养在温度(21±1℃)、相对湿度(36±1%)的受控条件下且置放于SmartLabs饲养室(21Erie Street,Cambridge,MA)的12-小时光照-黑暗循环(在6:00AM开灯且在6:00PM关灯)房间内。允许动物随意获取食物(LabDiet Prolab Isopro RMH 3000,St.Louis,MO)及水。向大鼠给与0mg/kg(媒剂)、1mg/kg、3mg/kg、10mg/kg或30mg/kg的被配制为于0.5%甲基纤维素、0.5%Tween80中的悬浮液或于MilliQ水中的溶液的本发明的化合物。制剂经制备,冷冻储存于-20℃下且在给药之前在室温下解冻1小时,或经制备且在2小时内使用,或其在给药前一天制备且保持在室温下搅拌隔夜且直至给药。PO剂量通过经口管饲施用且使用注射器及管饲管递送至胃。在口服剂量施用之后,用大致0.5mL水冲洗管饲管以确保完整剂量的完全递送。
在异氟醚麻醉下如下收集血浆及CSF样本:在给药后1、2及6小时收集CSF及血液的样本。经由脑池内导管收集CSF样本。收集大致20μL CSF且丢弃(此包括注射器怠体积(deadvolume)为14至16μL);接着将大致50μL CSF抽取在含有5μL冰乙酸的埃彭道夫管中。CSF样本通过浸没在液氮中进行快速冷冻。接着,使动物保持在麻醉下且经由尾部切口获得血液样本且将其储存于K-EDTA管中。将这些样本保持在冰上直至处理血浆。将血液样本在大致5℃下在收集的1小时内以3200rpm离心10分钟。将血浆直接转移至96孔盘管(0.125mL)中。将塞帽置于导管上且将导管冷冻在大致-70℃下并且储存直至分析。收集血浆及CSF且分析化合物的存在。
化合物及cGMP的定量。
通过沉淀自血浆及CSF中提取本发明的化合物、cGMP及内标物。使用液相层析(LC)及串联质谱检测(MS/MS)使用电喷雾电离分析样本。化合物的标准曲线范围介于0.1至1000ng/mL范围内。cGMP的标准曲线范围介于0.01至40ng/mL范围内。使用GraphPad Prism,8.4.3版绘制CSF cGMP数据且表示为平均值±S.E.M.。用混合型效应分析来分析数据,接着进行邓尼特氏多重比较测试来与时间点内的媒剂治疗的大鼠进行比较。显著性设定为p<0.05。
结果
给药后一小时及两小时,与媒剂治疗的大鼠相比,用1、3及10mg/kg的化合物I-20(以于Tween/MC中的悬浮液形式给与)治疗的大鼠就大鼠CSF中的cGMP浓度方面不具有显著变化。然而,在给药后六小时,与媒剂治疗的大鼠相比,用10mg/kg化合物I-20治疗的大鼠在CSF中具有显著较高的cGMP。(参见图4)
与媒剂治疗的大鼠相比,用化合物I-14(以钠盐形式施用)治疗的大鼠在所有测试剂量下但不在所有测试时间点下在CSF中具有较高cGMP含量。给药后一小时及两小时,施用3mg/kg化合物I-14的大鼠在CSF中具有显著较高的cGMP浓度。给药后两小时,与媒剂治疗的大鼠相比,用1mg/kg化合物I-14治疗的大鼠在CSF中具有显著较高的cGMP。在给药后1、2及6小时,施用10或30mg/kg化合物I-14的大鼠在CSF中具有显著较高的cGMP(参见图5)。
实例10A:非人类灵长类脑脊髓液(CSF)药物动力学特性(研究A)
方案。
口服给药(PO)之后测定NHP中的PK。使用一组4只雌性食蟹猕猴来研究各化合物。化合物I-20钠盐被配制为于MilliQ水中的0.06mg/mL溶液。化合物I-14钠盐被配制为于MilliQ水中的0.2mg/mL溶液。将制剂在干冰上冷冻进行运送,且接着解冻并且在给药之前进行充分地混合。通过经口管饲施用PO剂量1mg/kg的化合物I-14及0.3mg/kg的化合物I-20。
如下收集血浆及CSF样本:在PO给药后3及24小时收集CSF的样本。经由直接针穿刺通过直接稀释在小脑延髓池收集CSF样本(0.125mL)。在0、0.25、0.5、1、2、3、6、8、12、24、32及48小时自周边静脉收集血液样本(0.8mL)。将这些样本保持在冰上直至处理血浆。使用乙腈对血液样本进行蛋白质沉淀。将血浆直接转移至个别导管(0.125mL)中且使用K2EDTA作为抗凝血剂。将塞帽置于导管上且将导管冷冻在大致-70℃下并且储存直至分析。收集血浆及CSF且分析化合物的存在。
化合物的定量。
使用液相层析(LC)及串联质谱检测(MS/MS)使用正电喷雾电离分析血浆及CSF样本。标准曲线范围为0.1至1000ng/mL。
针对各化合物研究中的4只动物获得的所述值的几何平均值分别为CSF及血浆中的浓度。
Kp,uu定义为CSF中未结合的药物与血浆中未结合的药物的浓度比。通过总血浆浓度乘以如通过血浆蛋白质结合所测定的未结合分率来计算血浆中未结合的药物(或游离血浆浓度)。接着,CSF浓度除以游离血浆浓度以测定Kp,uu。(参见例如Di等人,J.Med.Chem.,56,2-12(2013))
本发明的化合物的结果概述于下表H中。
表H.
NHP CSF PK。Kp,uu≤1=A;1<Kp,uu≤2=B;2<Kp,uu≤3=C;
3<Kp,uu=D。
实例10B:非人类灵长类脑脊髓液(CSF)药物动力学特性(研究B)
此研究的目标为研究在第1天向食蟹猕猴施用单一鞘内弹丸或经口管饲剂量之后的化合物I-14的药物动力学及评估当比较小脑延髓池(如同实例10A中)与腰腰椎位置处收集的CSF时的药物动力学值的差异。
研究设计
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No.=编号;F=雌性;CSF=脑脊髓液;No=数目a,各组将使用相同的动物,各组给药日之间将存在最少7天的清除期
测试系统/方法
物种:长尾猕猴(Macaca fascicularis)
品种:食蟹猕猴(Cynomolgus macaque)
雌性数目:4
年龄:成年
体重:2.5-4kg
将动物圈养于配备有不锈钢底纹及自动供水阀的不锈钢笼中。主要外罩如实验室动物管理与使用指南中所描述(国家研究委员会(NRC).Guide for the Care and Use ofLaboratory Animals.Washington,D.C:National Academy Press,第8版.2011;实验动物福利办公室(Office of Laboratory Animal Welfare).Public Health Services Policyon Humane Care and Use of Laboratory Animals.Bethesda,Maryland:NationalInstitutes of Health,2015修订)。除非研究负责人及/或临床兽医认为不适当,否则维持这些圈养条件。将动物进行社会圈养(可能时),除将其分开以用于指定研究程序/活动时的时间之外。
在交叉设计中,单次剂量的化合物I-14以0.15mg/kg的团注溶液形式静脉内施用,且以0.5mg/kg悬浮液形式通过管饲经口施用至一组四只食蟹猕猴。在IV及PO剂量之后0.25(15min)、0.5(30min)、1、2、3、6、8、12、24、32、及48h收集血浆样本。针对所有动物,在3及24h时,自第1组及第2组中之小脑延髓池且自第3组及第4组中的腰椎收集CSF样本。通过蛋白质沉淀制备样本提取物且使用LC-MS/MS来量测化合物I-14浓度。计算药物动力学参数。
总结/结论
总体而言,IV(第2组及第4组)与PO(第1组及第3组)之间的平均药物动力学参数系在彼此的标准偏差内。
在IV及PO施用之后3及24小时使用小脑延髓池及腰椎采样两者观测CSF中的化合物I-14。在IV及口服给药后3小时,在自小脑延髓池采样后以及在腰椎采样后,血浆中的CSF浓度与未结合的浓度的几何平均比率在两种情况下均下降,落入如上文所描述的范围C内,亦即在2与3之间(NHP CSF PK。Kp,uu≤1=A;1<Kp,uu≤2=B;2<Kp,uu≤3=C;3<Kp,uu=D)。在IV及口服给药后24小时,在自小脑延髓池采样后,血浆中的CSF浓度与未结合的浓度的几何平均比率分别下降,落入范围B及C中,且在腰椎采样后分别下降,落入范围B及C中。
实例11:在记忆增强的新对象辨识(NOR)模型中评估本发明的化合物
目标
为评估本发明的CNS渗透剂sGC刺激剂在逆转由MK-801诱导的记忆中断中的疗效,在雄性朗伊凡氏大鼠(Long Evans rat)中使用新对象辨识(NOR)测试。
介绍
NOR为识别学习及记忆提取的测试,其利用啮齿动物的自发偏好来研究与熟悉对象相比的新对象。NOR测试已广泛地用于评估新颖测试化合物的潜在的辨识增强特性。因为NOR范例不涉及奖励或有害刺激,所以其在转换成人类临床试验中进行的类似测试时提供较少的混淆变量。
在本研究中,使用记忆保存模型。NMDA受体的无竞争性拮抗剂MK-801(地佐环平(Dizocilpine))用于造成辨识记忆的缺陷。评估sGC刺激剂预防由MK-801诱导的记忆受损的功效。参考化合物为加兰他敏(galantamine)1mg/kg(腹膜内)显著地逆转由MK-8010.1mg/kg(腹膜内)诱导的辨识缺陷,从而表明该测试的有效性。
材料及方法
动物
在此研究中使用成年雄性朗伊凡氏大鼠(自Envigo,Indianapolis,IN到达时,275至299克)。将大鼠置放于实验房间中且分配独特的标识号(尾部标记)。将大鼠以每笼2只圈养在具有过滤顶的聚碳酸酯笼中,且在测试前适应至少7天。将动物房间维持在12/12h光照/黑暗循环(在07.00EST开灯)、22±1℃及大致50%相对湿度中。随意提供食物及水。在研究之前检查、处置及称重所有动物以确保足够健康且使与测试相关的非特异性应激降至最低。将各动物随机分配在整个治疗组中。在动物之光照循环阶段进行实验。
测试化合物及药物
在这些研究中使用以下化合物及药物:
将MK-801(0.1mg/;Sigma-Aldrich)溶解于生理盐水中且在NOR训练之前15min进行IP注射。剂量体积为1ml/kg。
将加兰他敏(1mg/kg;Tocris)溶解于生理盐水中且在训练之前15分钟进行IP注射。剂量体积为1ml/kg。
将化合物I-20(0.03、0.3及1mg/kg)配制于媒剂(0.5%(w/w)甲基纤维素及0.5%(w/w)Tween 80/超纯水)中且在NOR训练之前60min以2ml/kg剂量体积经口给与。
测试以下组:其中各组N=16,(由于健康问题,在开始测试之前,自化合物I-20-1mg/kg-MK-801组移除一只大鼠):1)媒剂-生理盐水;2)媒剂-MK-801 0.1mg/kg;3)加兰他敏1mg/kg-MK-801;4)化合物I-20,0.03mg/kg-MK-801;5)化合物I-20,0.3mg/kg-MK-801;及6)化合物I-20,1mg/kg-MK-801
化合物I-14(0.01、0.1及1mg/kg)以其Na+盐形式被配制为于MilliQ水中的溶液形式,且以冷冻等分试样形式储存。将化合物溶液及化合物媒剂的等分试样储存于-80℃下且在各测试日新鲜解冻。化合物及媒剂在NOR训练之前60分钟经口给与。剂量体积为10ml/kg。
测试以下组的化合物I-14,其中各组N=16:1)生理盐水-MK-801 0.1mg/kg;2)加兰他敏1mg/kg-MK-801;3)媒剂-生理盐水;4)媒剂-MK-801;5)化合物I-14,0.01mg/kg-MK-801;6)化合物I-14,0.1mg/kg-MK-801;及7)化合物I-14,1mg/kg-MK-801
实验程序
在置于弱光下的静音房间中的开放场所(40×40cm)进行NOR测试。单独地测试各大鼠,且注意通过在试验与大鼠之间用70%酒精清洁场所及测试对象来移除嗅觉/味觉线索。所有训练及测试试验均录入视频且由对治疗不知情的观测者进行评分。
在第1天及第2天,使大鼠自由地探索场所(内部无对象)持续5-分钟适应阶段。在第3天(训练及试验日)根据对应预处理向大鼠施用媒剂、生理盐水及/或化合物溶液,其定义为在注射及开始NOR训练之间的时间。将各动物置放于存在两个相同对象的测试场所中。将各大鼠置放于场所中的相同位置面向同一方向,且记录在3-分钟训练阶段(T1)期间主动探究对象所花费的时间。在训练之后使大鼠返回至其饲养笼中。在T1之后1小时进行NOR测试(T2)。将各大鼠置放回存在一个熟悉对象及一个新颖对象的测试场所中5分钟,且记录探索两个对象所花费的时间。所述对象(左/右)在T2中的呈现顺序及位置在大鼠之间为随机的以防止由于顺序或位置偏好造成的偏差。
组织收集
在T2之后约10分钟(在药物施用之后135分钟),将躯干血液收集在含有K2EDTA的微量离心管中。将血液管保持在冰上进行短期储存。在15分钟内,将试管在冷冻离心机中以10,000RPM离心10分钟。萃取血浆且将样本储存于-80℃冷冻器中直至装运至试验委托者。
统计分析
NOR测试(T2)的数据表示为辨识指数,其定义为在测试阶段期间探索新颖对象所花费的时间相对于探索两种对象所花费的总时间的比率(新颖/(熟悉+新颖)×100%)。
对于化合物I-14,将数据分两批进行单独分析。第1批包括生理盐水-MK-801组及加兰他敏-MK-801组。用t测试分析数据以评估测试的有效性。第2批包括“sGC刺激剂组”,其包括5个含有化合物媒剂(MilliQ水)的治疗组:媒剂-生理盐水、媒剂-MK-801、化合物I-140.01mg/kg-MK-801、化合物I-14 0.1mg/kg-MK-801及化合物I-14 1mg/kg-MK-801。第2批资料通过单因子ANOVA,接着在各别0至1、0至3及0至5分钟时间范围内进行费雪LSD事后分析(Fisher LSD post hoc)比较来分析。显著性设定为P<0.05。辨识指数高于90%或低于30%的十九只动物因为在两个对象之间存在强烈(非记忆)偏差而排除。对两个对象的总探索时间在五分钟少于10秒内的两只大鼠亦由于不可靠的结果而排除(此为我们NOR测试的标准偏差)。基于血浆分析的反馈,一只大鼠由于可疑药物暴露而移除。随后,自进一步分析移除高于或低于平均值两个标准偏差的统计离群值。通过这些标准,自各实验组排除1至6只大鼠(最初N=16)且自所有时间范围(0至1、0至3及0至5分钟)内的统计分析中排除。
对于化合物I-20,通过使用单因子ANOVA,接着费雪LSD事后分析测试在各别0至1、0至3及0至5分钟时间范围内分析数据,其中显著性设定为P<0.05。辨识指数高于90%或低于30%的动物因为在两个对象之间存在强烈(非记忆)偏差而排除。随后,自进一步分析移除高于或低于平均值两个标准偏差的统计离群值。通过这些标准,自各实验组排除2至4只大鼠(最初N=16)且自所有时间范围(0至1、0至3及0至5分钟)内的统计分析中排除。
结果
a)化合物I-14
此研究中的大鼠中无一者在任何剂量下显示明显的副作用。大鼠维持正常警戒、活动及对对象的探索水平。
在0至1分钟时间范围中,t测试显示在生理盐水-MK-801组与加兰他敏-MK-801组之间的显著差异(P<0.01),从而指示此分析的有效性。对化合物组的ANOVA显示对辨识指数的显著主要治疗作用[F(4,56)=4.698,P<0.01]。费雪LSD事后分析比较表明,在此时间范围内,媒剂-生理盐水组及1mg/kg化合物I-14-MK-801组两者均显示与媒剂-MK-801组的显著差异(分别地,P<0.05及P<0.01),从而表明MK-801 0.1mg/kg诱导显著对记忆缺失且1mg/kg的化合物I-14会逆转该缺陷。
在0至3分钟时间范围中,t测试显示在生理盐水-MK-801组与加兰他敏-MK-801组之间的显著差异(P<0.001),从而指示此分析的有效性。对化合物组的ANOVA显示对辨识指数的显著主要治疗作用[F(4,56)=5.113,P<0.01]。事后分析比较表明,在此时间范围内,媒剂-生理盐水组显示与媒剂-MK-801组的显著差异(P<0.01),从而表明MK-801 0.1mg/kg诱导显著记忆缺失。在此时间范围内,1mg/kg的化合物I-14显示具有逆转MK-801诱导的记忆缺失的趋势(P<0.10)。
在0至5分钟时间范围中,t测试显示在生理盐水-MK-801组与加兰他敏-MK-801组之间的显著差异(P<0.001),从而指示此分析的有效性。对化合物组的ANOVA显示对辨识指数的显著主要治疗作用[F(4,56)=2.847,P<0.05]。事后分析比较显示在此时间范围内,1mg/kg的化合物I-14具有相对于媒剂-MK-801组的显著较高的辨识指数(P<0.05)。
b)化合物I-20
此研究中的大鼠中无一者在任何剂量下显示明显的副作用。大鼠维持正常警戒、活动及对对象的探索水平。
ANOVA在0至1min时间范围内显示对辨识指数的显著主要治疗作用[F(5,77)=3.379,P<0.01]。事后分析测试显示在此时间范围内,媒剂-MK-801 0.1mg/kg组及媒剂-生理盐水组未显示显著差异(P>0.05)。化合物I-20 1mg/kg-MK-801组及加兰他敏-MK-801组显示比媒剂-MK-801组显著更高的辨识指数(Ps<0.01)。通常,0至1min时间范围内的数据相对不稳定;0至3min及0至5min时间范围内的治疗提供更可靠的结果。
在0至3min时间范围内,ANOVA发现对辨识指数的显著主要治疗作用[F(5,77)=3.922,P<0.01]。事后分析测试显示,在此时间范围内,MK-801 0.1mg/kg引起显著记忆缺失(媒剂-生理盐水组对比媒剂-MK-801组,P<0.05)。化合物I-20 1mg/kg-MK-801组及加兰他敏-MK-801组显著地逆转MK-801诱导的记忆缺陷(Ps<0.001)。化合物I-20 0.3mg/kg-MK-801组亦在此时间范围内显示逆转MK-801诱导的记忆缺陷的趋势(P<0.10)。
在0至5min时间范围中,ANOVA显示显著主要治疗作用[F(5,77)=5.219,P<0.001]。事后分析测试显示,MK-801 0.1mg/kg引起显著记忆缺失,其中辨识指数接近机会水平(50%)。加兰他敏(1mg/kg)、化合物I-20 0.3mg/kg及1g/kg显著地逆转MK-801诱导的记忆缺陷(与媒剂-MK-801组相比,分别地,Ps<0.05、P<0.01及Ps<0.001)。化合物I-200.03mg/kg-MK-801组亦在此时间范围内显示逆转MK-801诱导的记忆缺陷的趋势(P<0.10)。
实例12:对植入遥测仪的大鼠的睡眠觉醒药物EEG的评估
在PsychoGenics,Inc.进行此研究。程序由实验动物管理及使用委员会根据美国国立卫生研究院实验动物管理及使用指南批准通过。
目标
此研究经设计以评估化合物I-14在无线植入的年轻成年雄性SD大鼠中的睡眠阶段的特定药物EEG(脑电图学)特征。
材料及方法
动物
在研究中使用来自Envigo(Indianapolis,IN)的年轻成年雄性Sprague-Dawley(SD)大鼠(到达时约275至325克)。在接收后,向大鼠指配独特的标识号且以每笼3只大鼠圈养在具有微型隔离过滤顶的聚碳酸酯笼中。在研究开始之前检查及称重所有大鼠以确保足够健康及适合性。在研究过程期间,保持12/12光照/黑暗循环。室温维持在20℃与23℃之间,其中相对湿度维持在约50%。在研究时间随意提供食物及水。手术后,将大鼠单独圈养。在恢复阶段(7至10天)之后,将动物转移至EEG记录室且置放于DSI接收器上进行记录。
研究组
a.媒剂A
i.途径:PO
ii.体积:10ml/kg
iii.制剂:水
b.3mg/kg的化合物I-14
i.途径:PO
ii.体积:10ml/kg
iii.制剂:3mg/kg于水中
c.10mg/kg的化合物I-14
i.途径:PO
ii.体积:10ml/kg
iii.制剂:10mg/kg于水中
d)30mg/kg的化合物I-14
i.途径:PO
ii.体积:10ml/kg
iii.制剂:30mg/kg于水中
手术程序
简言之,动物在3个信道(引线对)结构中植入有DSI遥测装置(F50-EET)。注意各个位置的正及负引线放置。DSI发送器上EEG通道中之每一者充当差动输入,藉此差动输入量测正引线与负引线之间的差异。前额/顶骨(右):前面(+)2mm,侧面2mm;后面(-)4mm,侧面2mm;前额/前额(双侧半球状):前面(+)2mm,侧面2mm(右);前面(-)2mm,侧面2mm(左);及颈部EMG。
总之,在手术之前用4%至5%异氟醚及1L/min氧使动物麻醉以进行诱导且在手术期间维持有1%至2.5%异氟醚/1L/min氧混合物。使用后肢回缩反射及呼吸率测定且监测麻醉的深度。持续性调节异氟醚含量以在整个手术程序中维持手术麻醉平面。用无菌棉签拭子在眼睛上施用眼用润滑剂。通过刮毛且用氯己定擦洗及酒精拭子清洁皮肤三次来准备用于无菌手术的手术部位。对腹部、颈部及头部进行刮毛且用氯己定擦洗及酒精(2%氯己定葡糖酸盐及4%异丙醇)的3次交替作业来杀菌。接着将麻醉的动物置放于温水循环加热垫上以用于手术植入遥测装置。
遥测植入
在颅骨顶部上的中线处进行3至4cm切口,该颅骨自后部约1cm延伸至眼睛的中点至颅骨的基部且延伸至中间背侧颈区域。使用钝器解剖,通过在结缔组织旁边推移至右侧腹区域而自切口的后端形成皮下袋。用无菌生理盐水冲洗该袋状物,接着将发送器置放于该袋状物中,其中引线延伸出颈部切口。量测一条与发送器连接的导线,将其按尺寸切割且插入于背侧颈部肌肉中之一者中且用5-0丝质缝合线固定在适当位置。针对第二引线重复此程序以使得两条引线沿同一肌肉束直线置放且间隔开2至4mm,且提供肌电图学(EMG)信号。随后移除骨膜以显露颅骨标志、前囟及人字缝尖(lambda)。视需要,使用无菌生理盐水擦拭颅骨区域,随后使用纱布或无菌棉签(Q-tip)将其干燥。使用所关注区域(后部及顶叶皮质)的立体定位坐标来标记脑电图(EEG)引线。对于各关注区域,在颅骨上钻凿1至2个孔,确保硬脑膜的暴露。将硬脑膜接触螺杆插入至孔中且将EEG引线缠绕于其周围(最多4个孔)。这些螺杆必须与硬脑膜接触以检测EEG脑信号。穿过硬脑膜的渗透将不引起不良事件且可改善EEG信号(更多大脑与金属接触)。接着使用FLOW-It ALC复合物永久性密封螺杆及周围颅骨表面区域。在充分干燥粘合剂后,使用缝合钉闭合覆盖颅骨的皮肤。
测试计划表
此研究遵循星期一及星期四给药/记录计划表,其中基线EEG记录2小时且接着使大鼠在7:50至8:00AM之间接受0.3、3或10mg/kg的第一剂量化合物I-14或媒剂A(全部经口)且在约12小时后接受第二剂量的相同物质,且随后继续EEG 12小时。
·在6AM(在开灯时)开始EEG记录
·在7:50am AM(在开灯后1小时50分钟)进行给药
·在7:50PM(在关灯后1小时又50分钟)进行第2次给药(相同化合物)
·继续EEG记录直至第二天7:50AM(第1次剂量后24小时及第2次剂量后12小时)。
使用国际数据科学(DSI)数据采集平台记录在饲养笼中自由移动的大鼠的数据。在光照及黑暗循环期间进行记录。在研究期间,维持在6AM开灯及在6PM关灯的光照。在进行数据收集之前使动物适应给药(媒剂给药)。
在各剂量之间具有至少72小时清除期的交叉设计中测试动物。在各测试日,动物在开灯(6:00AM)后刚好2小时(7:50AM)下经口接受化合物或媒剂。在给药前2小时开始记录数据且在给药后持续记录24小时。
EEG信号评估
确保EEG不含有线路噪声(50或60Hz)或将视为来自外部电源之噪声的任何连续非生理频率模式。所有EEG记录均在正常操作范围内(亦即EEG信号早正常操作振幅范围内,通常大于100微伏且小于500微伏,无信号保真度损失,通常通过EEG减少<100μV观测)。
睡眠评分
使用神经评分软件(国际数据科学)对原始EEG记录进行人工评分以鉴别睡眠阶段:主动觉醒、安静觉醒、NREM及REM。使用神经评分(DSI)自数据中脱机移除假影且通过如先前所描述的常规方法使用EEG、EMG及自发活动(LMA)(Ivarsson等人,2005;Parmentier-Batteur等人,2012;Leiser等人,2014,2015)使用前顶骨EEG、LMA及EMG人工地指配每10s期的睡眠阶段:主动觉醒(不太规律的低振幅EEG,及高EMG及LMA活动);安静觉醒(不太规律的低振幅EEG,及低EMG且无LMA活动);NREM(由具有主要δ(1至4Hz)之高振幅不规律波、低EMG且无LMA组成);REM睡眠(由θ(4至8Hz)占主导的稳定低振幅波,几乎不存在EMG且无LMA)。
自每15min(给药前2小时至给药后4小时)的睡眠状态时间的神经评分报导模板导出睡眠阶段数据。亦自神经评分报导模板直接报导第一睡眠及第一REM的发作。潜伏期经计算为在NREM发作后的第一REM回合的发作的时间段(亦即TREM-TNREM=REM潜伏期)。使用每小时时间区间的各睡眠阶段所花费的时间百分比制备睡眠图(Hypnogram)。各睡眠状态中的时间经计算为各睡眠状态的总时间百分比(平均值±平均值的标准误差,SEM)。通过治疗组、睡眠状态、频率分组配置各个动物的数据且导出至GraphPad PRISM中用于统计及图示。
频谱分析
使用Matlab进行频谱分析。将针对多个信道收集的时域信号收集至DSI/神经评分中且随后将EDF档案转移至Matlab中。标记基线及给药后的特定时间戳的Excel档案亦转移至Matlab中用于时间锁定。在Matlab中,使用Welch方法计算功率频谱密度(PSD)。接着,针对六个频带中的每一者(δ、θ、α、β、低γ及高γ)及各1Hz次频带计算原始及相对频谱功率。将在化合物给药之前记录的2小时数据合并且定义为“基线”。基于各通道、受试者、剂量水平、频谱带及时间区段计算相对于基线的变化百分比。计算各组的各频带的平均原始、相对及百分比变化。频谱分析包括针对每只大鼠的每次记录定量传统上定义的EEG频带(δ-0.5至3.9Hz、θ-4至7.9Hz、α-8至11.9Hz、β12至29.9Hz、低γ30至49.9Hz及高γ50至100Hz)的原始频谱功率、相对频谱功率及频谱功率变化百分比。另外,以线图表示1至100Hz EEG频谱。将这些频谱图数据分别提供至客户端且并非所有数据都包括于本文中,这是因为曲线图的数目广泛。为了清楚起见,呈现给药后时间段之时间内的各频带的变化百分比。
结果
睡眠
化合物I-14的睡眠图显示与媒剂(A)组相比,高剂量(30mg/kg)治疗组中的REM及NREM显著减少。在最高剂量的化合物组中观测到安静觉醒的增加。在此治疗组中,NREM、REM及REM潜伏期的发作推迟。化合物I-14最深入的影响在高剂量中出现,其中对安静觉醒的影响(增加)、对REM的影响(减少)及对NREM的影响(减少)在给药后持续几个小时。
频谱分析
在QW中,化合物I-14(3mg/kg)在给药后0至180分钟增加低γ,而在30mg/kg剂量下,其在给药后0至240分钟增加低γ且在给药后0至180分钟增加高γ。在30mg/kg下,在NREM中,化合物在给药后约0至300分钟减少δ、θ、α且增加低及高γ。
实例13:评估化合物I-14在具有帕金森氏病认知缺陷的长期低剂量MPTP病变猕猴模型中的认知作用
此研究为在帕金森氏病的长期低剂量MPTP病变猕猴模型中的非GLP研究。此模型已描述于文献(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282499/)中。该研究经设计以评估作为单一疗法施用的化合物I-14对以下认知任务的表现的作用:可变延迟反应(VDR)、持续性表现(CPT)、视觉辨别逆转学习(SDR)及物体检索(OR)。在先前已接受用低剂量MPTP治疗且已知在上文所提及的任务表现中具有困难的动物中进行该研究。这些研究利用具有MPTP诱导的认知缺陷的四只雄性食蟹猕猴。
该研究具有4个部分。该研究的第一部分为自四只动物收集关于待研究的四个任务的基线数据。该研究的第二部分为施用媒剂(无菌过滤蒸馏水)16天时间段且每周收集关于四个任务的媒剂数据一次持续两周。在该研究的第三部分中,每日经口施用化合物I-14持续五天且随后每周收集关于四个任务的数据一次持续两周,其中在每天测试之前2小时继续每日施用化合物I-14(3.0mg/kg)。在研究的最终部分中,存在9天清除期且随后每周收集关于四个任务的数据一次持续两周。在预给药五天及每日给药持续两周之后,将一个剂量的化合物I-14以单一疗法(3.0mg/kg)形式评定。在每日药物施用之后2小时及在药物清除期间评估治疗对认知表现的作用。
MPTP-HCl通过静脉内注射以0.05mg/kg至0.30mg/kg范围内的剂量施用,每周2至3次持续几个月。MPTP施用持续直至出现认知缺陷,伴有最小/轻度帕金森氏病运动损伤。若动物在相对于MPTP前基线水平的认知任务效能中显示至少15%降低,则其视为“认知受损”。因为对MPTP的反应有些特殊,所以施用MPTP以发挥作用(亦即,出现认知缺陷且随后出现运动缺陷),而非针对特定暴露持续时间或特定MPTP累积剂量给与。
SDR表示对认知灵活性的测试。在此任务中,在屏幕上同时呈现三种刺激且这些刺激中之一者任意地指定为正面(奖励)刺激,且与其接触会产生正型色调及奖励,而在接触负面(非奖励)刺激时会产生不同的色调及屏幕空白。刺激在屏幕上的位置根据不同试验而进行假随机变化。在各阶段中显示最多300个试验。针对各阶段记录的测量为:1)学习初始辨别所需的试验的总数(亦即达到指定的14/16正确标准)及2)学习(亦即,达到如上文所提及的相同准则)逆转所需的试验总数,其中先前的负面(非奖励)刺激现在为正面(奖励)刺激(亦即,达到标准)。达到关于学习辨别逆转的标准所需的试验数目视为对认知灵活性的量度。
化合物I-14单一疗法显著地改善SDR范例中的效能。CY3018显著减少达到学习辨别逆转的标准所需的试验数目,其旨在改善这些动物认知的至少一个方面。简单的辨别效能并未通过施用媒剂或化合物I-14而显著改变。然而,施用化合物I-14使得辨别逆转学习效能显著改善(图6)。
另外,在基线、媒剂及清除试验期间,一些动物未能成功地学习辨别逆转,然而,当通过化合物I-14测试时,动物中全部学会该逆转,从而表明该化合物对所有测试动物具有积极作用。
Claims (34)
1.一种治疗有需要受试者的CNS疾病、健康状况或病症的方法,其包含向所述受试者施用治疗有效量的式I化合物:
或其医药学上可接受的盐,其中:
JC选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
X为N或C(JC1);
JC1选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
各JB独立地选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;
JD选自由以下组成的群组:氢、卤素、C1-6烷基及经1至3个氟原子取代的C1-6氟烷基;及
n为选自0、1、2、3或4的整数。
2.如权利要求1的方法,其中:
JC选自由以下组成的群组:氢、卤素及C1-6烷基;
X为N或C(JC1);
JC1选自由以下组成的群组:氢、卤素及C1-6烷基;
各JB独立地选自由以下组成的群组:氢、卤素及C1-6烷基;
JD选自由以下组成的群组:氢、卤素及C1-6烷基;及
n为选自0、1、2、3或4的整数。
3.如权利要求1或2的方法,其中该化合物由式IA表示:
或其医药学上可接受的盐。
4.如权利要求1至3中任一项的方法,其中JC1为H、F或Cl。
5.如权利要求1至3中任一项的方法,其中JC1为H。
6.如权利要求1至3中任一项的方法,其中JC1为F。
7.如权利要求1或2的方法,其中该化合物由式IB表示:
或其医药学上可接受的盐。
8.如权利要求1至7中任一项的方法,其中n为2或3。
9.如权利要求1至7中任一项的方法,其中n为0或1。
10.如权利要求1至9中任一项的方法,其中各JB独立地为H、F或C1-4烷基。
11.如权利要求10的方法,其中各JB独立地为F或甲基。
12.如权利要求8的方法,其中n为2且JB均为F或JB中之一者为F且另一者为甲基。
13.如权利要求8的方法,其中n为3且JB中的两者为F且另一者为甲基。
14.如权利要求9的方法,其中n为1且JB为F。
15.如权利要求9的方法,其中n为0。
16.如权利要求1至15中任一项的方法,其中JD为氢。
17.如权利要求1至15中任一项的方法,其中JD为F、Cl或甲基。
18.如权利要求1至15中任一项的方法,其中JD为F。
19.如权利要求1至18中任一项的方法,其中JC为H或F。
20.如权利要求1至18中任一项的方法,其中JC为H。
21.如权利要求1至20中任一项的方法,其中该CNS疾病为阿尔茨海默尔病。
22.如权利要求21的方法,其中该阿尔茨海默尔病为轻度至中度阿尔茨海默尔病或中度至重度阿尔茨海默尔病。
23.如权利要求1至20中任一项的方法,其中该CNS疾病为认知障碍。
24.如权利要求1至20中任一项的方法,其中该CNS疾病为痴呆症。
25.如权利要求1至20中任一项的方法,其中该CNS疾病为主观认知障碍(SCI)。
26.如权利要求1至20中任一项的方法,其中该CNS疾病为认知老化。
27.如权利要求1至20中任一项的方法,其中该CNS疾病为血管型痴呆症。
28.如权利要求1至20中任一项的方法,其中该CNS疾病为混合型痴呆症。
29.如权利要求1至20中任一项的方法,其中该CNS疾病为帕金森氏病。
30.如权利要求1至20中任一项的方法,其中该CNS疾病为轻度认知障碍。
31.如权利要求1至20中任一项的方法,其中该CNS疾病为创伤性(闭合或开放的)穿透性脑损伤、创伤性脑损伤(TBI)、非创伤性中风、动脉瘤、缺氧或大脑的其他损伤。
32.如权利要求1至20中任一项的方法,其中该CNS疾病为中风。
33.如权利要求32的方法,其中该CNS疾病为缺血性中风。
34.如权利要求1至33中任一项的方法,其中该方法进一步包括向所述受试者施用额外治疗剂。
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