CN112794848B - N-环-氨基嘧啶衍生物及其用途 - Google Patents
N-环-氨基嘧啶衍生物及其用途 Download PDFInfo
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- CN112794848B CN112794848B CN201911106367.0A CN201911106367A CN112794848B CN 112794848 B CN112794848 B CN 112794848B CN 201911106367 A CN201911106367 A CN 201911106367A CN 112794848 B CN112794848 B CN 112794848B
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Abstract
本发明涉及一种N‑环‑氨基嘧啶衍生物及其用途,进一步涉及包含所述化合物的药物组合物。本发明所述化合物或所述药物组合物可以用作可溶性鸟苷酸环化酶刺激剂。
Description
技术领域
本发明属于医药技术领域,具体涉及N-环-氨基嘧啶衍生物及其用途,进一步涉及包含所述化合物的药物组合物。所述化合物或所述药物组合物可以用作可溶性鸟苷酸环化酶刺激剂(sGC stimulator)。
背景技术
环磷酸鸟苷(cyclic guanosine monophosphate,cGMP)是一种具有细胞内信息传递作用的第二信使(second messenger);其与从内皮组织释放出来并传输激素与机械信号的一氧化氮(NO)一起,形成了NO/cGMP系统。鸟苷酸环化酶催化三磷酸鸟苷(GTP)生物合成cGMP。此族类目前已知的代表可以根据结构特征和配位体类型分为两组:可被利钠肽激活的粒状鸟苷酸环化酶,和可被NO激活的可溶性鸟苷酸环化酶。可溶性的鸟苷酸环化酶由两个亚单元组成,并且每个异源二聚体非常可能包含一个血红素,这是调节中心的一部分。NO能够与血红素的铁原子结合,从而显著地提高酶的活性。相反地,不含血红素的酶则不能被NO激活。一氧化碳(CO)也能够附着到血红素的中心铁原子上,但是CO的激活作用明显低于NO。
通过形成cGMP,和由此所产生的对磷酸二酯酶、离子通道和蛋白激酶的调节,鸟苷酸环化酶在各种生理过程起着重要的作用,特别是在平滑肌细胞的松弛和增殖中、在血小板聚集和血小板粘附和在神经元信号传输中、以及在基于上述过程紊乱的疾病中。在病理生理学条件下,NO/cGMP系统可被抑制,这可导致例如高血压、血小板激活、细胞增生、内皮机能障碍、动脉硬化、心绞痛、心力衰竭、心肌梗死、血栓形成、中风和性功能障碍等疾病。
基于预期的更高有效性和更少副作用,通过不依赖于NO的途径调节cGMP信号通路来治疗这些疾病是非常有前途的。基于NO的化合物,如有机硝酸盐类,对可溶性鸟苷酸环化酶进行治疗性刺激是通过生物转化形成的NO进攻血红素的中心铁原子激活可溶性鸟苷酸环化酶。除了副作用,耐受性的产生也是此类治疗方法的缺点之一。
可溶性鸟苷酸环化酶(soluble guanylate cyclase,sGC)广泛存在于哺乳动物的细胞溶质内,在肺部和脑部的含量相对较高,是一氧化氮(NO)-sGC-环磷酸鸟苷(cGMP)信号通路中关键的信号转导酶,sGC在体内被激活后会催化GTP转化为cGMP。cGMP是一种重要的二级信使分子,通过激活其下游的多种效应分子,如磷酸二酯酶(PDE)、环核苷酸门控离子通道(CNG)和蛋白激酶G(PKG)等,进而引发下游一系列级联反应,在胃肠系统、血液循环系统和神经系统中发挥重要的生理功能,如促进血管和平滑肌舒张,抑制血小板凝聚、血管重塑、细胞凋亡和炎症发生以及参与神经传递等。
sGC是NO的敏感器和受体,其含有α和β两个亚基,每个亚基分别具有3个结构域,包括血红素结构域、中心结构域和催化结构域,其中两个亚基的血红素结构域共享有一个血红素。NO结合到sGC的血红素后,激活sGC,催化其底物GTP转化为二级信号分子cGMP,开启PKG信号通路,导致血管舒张。sGC作为NO的受体,在心血管系统和神经系统中扮演着重要的角色,NO信号发生紊乱会导致生理功能的失调,从而引发各种疾病。因此,sGC刺激剂作为可以直接激活sGC的新型药物,越来越受到人们的关注。
sGC刺激剂在体内对sGC具有双重作用机制,当NO浓度较低时,可以直接激活sGC;当NO具有一定水平时,又可以与NO协同作用,从而激活sGC催化底物三磷酸鸟苷(GTP)转化为二级信使分子环磷酸鸟苷(cGMP),进而参与调节许多重要的生理过程,例如促进血管和平滑肌舒张;抑制血小板凝集、血管重塑等。sGC刺激剂激活sGC还会介导TGF-β等其他信号通路,从而发挥抗纤维化、抗肿瘤等作用。因此,NO/sGC/cGMP通路成为治疗多种心血管疾病,如肺动脉高压、急性心衰、心绞痛和心肌梗死诱发血管重构等的有效靶标。
多年来,众多研究者以此开发了NO供体、磷酸二酯酶抑制剂和非NO依赖性sGC刺激剂等药物,其中非NO依赖性sGC刺激剂能避免传统的NO供体类药物易出现耐受、作用特异性不强和持续时间短等缺点,受到了广泛关注。
发明摘要
本发明提供一种新的作为sGC刺激剂(sGC stimulator)的N-环-氨基嘧啶衍生物及其药物组合物,以及所述化合物或所述药物组合物在制备药物中的用途,所述药物用于治疗和/或预防sGC介导的疾病,例如,心衰,硬化症,系统性硬化症,镰状细胞贫血,贲门弛缓不能,肺纤维化,特发性肺纤维化,囊性纤维化,肺动脉高压等。
一方面,本发明涉及一种化合物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药,
其中,R1、R2、R3、R4、R5、R6、R7、R8和Cy均具有本发明所述的含义。
在一些实施方案中,各R1、R2、R3、R4和R5独立地为H、D、F、Cl、Br、I、CN、NO2、氨基、羟基、巯基、羧基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氨基、羟基C1-6烷基、氰基C1-6烷基、氨基C1-6烷基、羟基C1-6烷氧基、氨基C1-6烷氧基、酰基、磺酰基或C1-6烷氧基。
在另一些实施方案中,各R1、R2、R3、R4和R5独立地为H、D、F、Cl、Br、I、CN、NO2、氨基、羟基、巯基、羧基、甲基、乙基、异丙基、C2-4烯基、C2-4炔基、三氟甲基、二氟甲基、2,2,2-三氟乙基、三氟甲氧基、二氟甲氧基、甲基氨基、二甲基氨基、羟基甲基、羟基乙基、氰基乙基、氰基甲基、氨基甲基、氨基乙基、羟基甲氧基、羟基乙氧基、氨基甲氧基、氨基乙氧基、乙酰基、甲磺酰基、甲氧基、乙氧基或异丙氧基。
在一些实施方案中,各R6和R7独立地为羟基、巯基、氨基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、卤代C1-6烷氧基或卤代C1-6烷基。
在另一些实施方案中,各R6和R7独立地为羟基、巯基、氨基、氰基、甲基、乙基、异丙基、C2-4烯基、C2-4炔基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、二氟甲氧基、三氟甲基、二氟甲基或2,2,2-三氟乙基。
在一些实施方案中,R8为H、D或C1-6烷基。
在另一些实施方案中,R8为H、D、甲基、乙基、异丙基或叔丁基。
在一些实施方案中,Cy为C5-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基;其中Cy任选地被1、2、3或4个Ry所取代;条件是,所述Cy不为哌啶基;其中Ry具有本发明所述的含义。
在另一些实施方案中,Cy为环戊基、环己基、四氢呋喃基、四氢噻吩基、四氢吡咯基、咪唑啉、恶唑啉基、噻唑啉基、异噁唑啉基、吗啉基、四氢吡喃基、哌嗪基、苯基、吡咯基、噻吩基、呋喃基、恶唑基、咪唑基、噻唑基、三唑基、四唑基、吡啶基、嘧啶基或吡嗪基;其中Cy任选地被1、2、3或4个Ry所取代;其中Ry具有本发明所述的含义。
在又一些实施方案中,Cy为其中Cy任选地被1、2、3或4个Ry所取代;其中Ry具有本发明所述的含义。
在一些实施方案中,各Ry独立地为=O、D、F、Cl、Br、I、CN、NO2、氨基、羟基、巯基、羧基、C1-6烷基、C2-6烯基、C2-6炔基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氨基、羟基C1-6烷基、氰基C1-6烷基、氨基C1-6烷基、羟基C1-6烷氧基、氨基C1-6烷氧基、酰基、磺酰基、C1-6烷氧基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基。
在另一些实施方案中,各Ry独立地为=O、D、F、Cl、Br、I、CN、NO2、氨基、羟基、巯基、羧基、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、C2-4烯基、C2-4炔基、三氟甲基、二氟甲基、2,2-二氟乙基、1,2-二氟乙基、2,2,2-三氟乙基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、羟基甲基、羟基乙基、氰基甲基、氰基乙基、氨基甲基、氨基乙基、羟基甲氧基、羟基乙氧基、氨基甲氧基、氨基乙氧基、乙酰基、氨基酰基、甲氧基酰基、甲氨基酰基甲氧基、乙氧基、异丙氧基C3-6环烷基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基。
在一些实施方案中,本发明所述的化合物,其包含以下结构或所示结构的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、酯、药学上可接受的盐或前药:
另一方面,本发明涉及一种药物组合物,其包含本发明所述的化合物。
在一些实施方案中,本发明所述的药物组合物,其进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物的至少一种。
一方面,本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备用于治疗和/或预防下述疾病的药物中的用途:心力衰竭、心绞痛、高血压、肺动脉高压、缺血症、血管疾病、肾病、血栓栓塞疾病、男性性功能障碍、系统性硬化症、镰状细胞贫血、贲门弛缓不能、纤维化疾病和/或动脉硬化。
另一方面,本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途,其中,所述药物用作可溶性鸟苷酸环化酶刺激剂。
本发明包含本发明化合物及其药学上可接受的盐的应用,用于生产医药产品治疗患者sGC介导的疾病,包括那些本发明所描述的疾病。本发明包含药物组合物,该药物组合物包括本发明任意一个通式结构所代表的化合物与至少一种药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物的结合所需的有效治疗量。
一方面,本发明涉及治疗和/或预防下述疾病的方法:心力衰竭、心绞痛、高血压、肺动脉高压、缺血症、血管疾病、肾病、血栓栓塞疾病、男性性功能障碍、系统性硬化症、镰状细胞贫血、贲门弛缓不能、纤维化疾病和/或动脉硬化等,所述方法包括使用本发明所述的化合物或药物组合物的治疗有效剂量对患者进行治疗。
另一方面,本发明涉及刺激和/或激活可溶性鸟苷酸环化酶的方法,所述方法包括使用本发明所述的化合物或药物组合物的有效剂量与生物体(包括体内或体外)接触。
一方面,本发明涉及使用所述化合物或药物组合物来治疗和/或预防下述疾病:心力衰竭、心绞痛、高血压、肺动脉高压、缺血症、血管疾病、肾病、血栓栓塞疾病、男性性功能障碍、系统性硬化症、镰状细胞贫血、贲门弛缓不能、纤维化疾病和/或动脉硬化等。
另一方面,本发明涉及使用所述化合物或药物组合物来刺激和/或激活可溶性鸟苷酸环化酶。
本发明同样包含治疗或减轻患者的sGC介导的疾病,或对这些病症敏感的方法,该方法包含使用本发明化合物的治疗有效量对患者进行治疗。
除非其他方面表明,本发明的化合物所有的水合物、溶剂化物和药学上可接受的盐都属于本发明的范围。
具体地说,盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学的,与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐还包括用于制备或纯化本发明化合物的中间体或本发明化合物分离的对映异构体的盐,但不一定是药学上可接受的盐。
本发明的化合物的盐可以通过文献上提供的任何合适的方法制备得到,例如,使用无机酸,如盐酸,氢溴酸,硫酸,硝酸和磷酸等等。或者使用有机酸,如乙酸,马来酸,琥珀酸,扁桃酸,富马酸,丙二酸,丙酮酸,草酸,羟乙酸和水杨酸;吡喃糖酸,如葡萄糖醛酸和半乳糖醛酸;α-羟酸,如柠檬酸和酒石酸;氨基酸,如天门冬氨酸和谷氨酸;芳香族酸,如苯甲酸和肉桂酸;磺酸,如对甲苯磺酸,乙磺酸,等等。
本发明化合物的生物活性可通过使用任何常规已知方法评定。适当的检测方法是本领域众所周知的。例如,可以通过适当的常规方法检测本发明化合物的sGC激活活性、药代动力学活性和/或肝微粒体稳定性等。本发明提供的检测方法仅作为实例呈现且不限制本发明。本发明化合物在至少一种本发明提供的检测方法中具有活性。例如,本发明化合物对重组鸟苷酸环化酶报告细胞系具有激活作用,例如,本发明化合物可以有效的激活CHO-K1-Rat sGC单克隆细胞株的活性,即,本发明化合物具有较好的sGC激活活性。又如,本发明化合物具有较好的体内药代动力学性质,有较好的吸收和暴露量,生物利用度较高。
定义和一般术语
现在详细描述本发明的某些实施方案,其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案,它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到,许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术,等等),以本申请为准。
应进一步认识到,本发明的某些特征,为清楚可见,在多个独立的实施方案中进行了描述,但也可以在单个实施例中以组合形式提供。反之,本发明的各种特征,为简洁起见,在单个实施方案中进行了描述,但也可以单独或以任意适合的子组合提供。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明,应当应用本文所使用的下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》,第75版,1994一致。此外,有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突,本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此,本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如,“一组分”指一个或多个组分,即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中,“患者”是指人。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱,例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;andEliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物,或者像实施例里面特殊的例子,子类,和本发明所包含的一类化合物。
应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。“任选取代的”是指所给结构或基团未被取代,或所给结构或基团被一个或多个具体取代基所取代。除非其他方面表明,一个任选的取代基团可以在被取代基团的各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是,但并不限于,氧代(=O)、氢、氘、氰基、硝基、卤素、羟基、巯基、氨基、烷基、卤代烷基、羟基烷基、氰基烷基、氨基烷基、烷氧基、卤代烷氧基、酰基、酰氧基、磺酰基、亚磺酰基、羧基、环烷基、环烷基烷基、环烷基氧基、杂环基、杂环基烷基、杂环基氧基、芳基、芳基烷基、芳基氧基、杂芳基、杂芳基烷基、杂芳基氧基等。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。同样的,对于描述方式“…独立任选地”中的“独立”,也应做上述广义理解。
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现,即,该描述包括其中所述事件或情形出现的情况以及不出现的情况。例如,“任选地被1、2、3或4个独立的选自…的取代基所取代”包括该基团被1个、或2个、或3个、或4个所述的取代基所取代的情况,以及该基团不被所述取代基取代的情况。进一步地,当该基团被1个以上所述取代基取代时,所述取代基之间是相互独立,即,所述的1个以上的取代基可以是互不相同的,也可以是相同的。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-C6烷基”或“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基;“C1-4烷基”特指独立公开的C1烷基(即甲基)、C2烷基(即乙基)、C3烷基(即丙基,包括正丙基和异丙基)、C4烷基(即丁基,包括正丁基、异丁基、仲丁基和叔丁基)。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”,则应该理解,该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”,表示含有1至20个碳原子,饱和的直链或支链的一价烃基基团,其中,所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中,烷基基团含有1-12个碳原子;在另一些实施方案中,烷基基团含有1-6个碳原子,即,C1-6烷基;在又一些实施方案中,烷基基团含有1-4个碳原子,即C1-4烷基;还在一些实施方案中,烷基基团含有1-3个碳原子,即C1-3烷基。在一些实施例中,本发明中所述的C1-6烷基可以为C1-4烷基;在另一些实施例中,本发明中所述的C1-6烷基可以为C1-3烷基。
烷基基团的实例包含,但并不限于,甲基,乙基,丙基(包括正丙基和异丙基),丁基(包括正丁基、异丁基、仲丁基、叔丁基),正戊基,2-戊基,3-戊基,2-甲基-2-丁基,3-甲基-2-丁基,3-甲基-1-丁基,2-甲基-1-丁基,正己基,2-己基,3-己基,2-甲基-2-戊基,3-甲基-2-戊基,4-甲基-2-戊基,3-甲基-3-戊基,2-甲基-3-戊基,2,3-二甲基-2-丁基,3,3-二甲基-2-丁基,正庚基,正辛基,等等。
在一些具体的结构中,当烷基基团清楚地表示为连接基团时,则该烷基基团代表连接的亚烷基基团,例如,基团“C3-10环烷基C1-6烷基”中的C1-6烷基应当理解为C1-6亚烷基。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明,亚烷基基团含有1-12个碳原子。在一些实施方案中,亚烷基基团含有1-6个碳原子;在另一些实施方案中,亚烷基基团含有1-4个碳原子;在又一些实施方案中,亚烷基基团含有1-3个碳原子;还在一些实施方案中,亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-),亚乙基(包括-CH2CH2-或-CH(CH3)-),亚异丙基(包括-CH(CH3)CH2-或-C(CH3)2-)等等。其中,所述亚烷基可以任选地被一个或多个本发明所描述的取代基所取代。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个碳-碳sp2双键,其中,所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代,其包括“cis”和“tans”的定位,或者"E"和"Z"的定位。在一些实施方案中,烯基基团包含2-8个碳原子;在另一些实施方案中,烯基基团包含2-6个碳原子;在又一些实施方案中,烯基基团包含2-4个碳原子。烯基基团的实例包括,但并不限于,乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个碳-碳sp三键,其中,所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中,炔基基团包含2-8个碳原子;在另一实施方案中,炔基基团包含2-6个碳原子;在又一实施方案中,炔基基团包含2-4个碳原子。炔基基团的实例包括,但并不限于,乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的含义。烷氧基基团的实例包括,但并不限于,甲氧基,乙氧基,1-丙氧基,2-丙氧基,1-丁氧基等等。
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代,这样的实例包含,但并不限于,三氟甲基、三氟甲氧基、氯乙基(例如,2-氯乙基)、2,2,2-三氟乙基、2,2-二氟乙基、2-氯-1-甲基乙基等。
术语“氨基”表示基团-NH2。术语“羧基”表示基团-COOH。
术语“羟基”、“氰基”、“硝基”、“巯基”分别表示基团-OH、-CN、-NO2、-SH。术语“氧代”代表基团=O。
术语“烷氨基”表示基团-NH2被一个或两个烷基所取代,其中所述烷基具有如本发明所述的含义。烷氨基基团的实例包括,但并不限于,甲氨基,二甲氨基等。
术语“羟基烷基”、“氰基烷基”、“氨基烷基”分别代表被一个或多个羟基(-OH)、氰基(-CN)或氨基(-NH2)所取代的烷基,所述烷基具有本发明所描述的含义。在一些实施例中,本发明所述的“羟基烷基”、“氰基烷基”、“氨基烷基”分别为“羟基C1-6烷基”、“氰基C1-6烷基”、“氨基C1-6烷基”,即,被一个或多个羟基(-OH)、氰基(-CN)或氨基(-NH2)所取代的C1-6烷基。在另一些实施例中,“羟基C1-6烷基”、“氰基C1-6烷基”、“氨基C1-6烷基”各自独立为“羟基C1-4烷基”、“氰基C1-4烷基”或“氨基C1-4烷基”。这样的实例包括,但不限于,羟基甲基、羟基乙基(例如,2-羟基乙基)、氨基甲基、氨基乙基(例如,2-氨基乙基)、氰基甲基、氰基乙基(例如,2-氰基乙基)等。
术语“羟基烷氧基”、“氰基烷氧基”、“氨基烷氧基”分别代表被一个或多个羟基(-OH)、氰基(-CN)或氨基(-NH2)所取代的烷氧基,所述烷氧基具有本发明所描述的含义。这样的示例包括,但不限于,羟基甲氧基、羟基乙氧基、氰基甲氧基、氨基甲氧基等。
术语“环烷基”表示含有3-12个环碳原子的饱和单环、双环或三环体系。在一些实施方案中,环烷基包含3-10个环碳原子,例如C3-10环烷基;在另一些实施方案中,环烷基包含3-8个环碳原子,例如C3-8环烷基;在又一些实施方案中,环烷基包含3-6个环碳原子,例如C3-6环烷基。环烷基基团的实例包括,但并不限于,环丙基、环丁基、环戊基、环己基、环庚基、环辛基,等等;其中,所述的C3-6环烷基包括环丙基、环丁基、环戊基和环己基。所述环烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“杂环基”或“杂环”是指包含3-12个环原子的,饱和或部分不饱和的单环、双环或三环体系,其中至少一个环原子选自氮、硫和氧原子;其中,所述杂环基是非芳香性的,且不包含任何芳香环。除非另外说明,杂环基可以是碳基或氮基,且-CH2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化物。所述杂环基基团可以任选地被一个或多个本发明描述的取代基所取代。
在一些实施方案中,杂环基为3-6个原子组成的杂环基,所述杂环基至少含有一个选自O、S和N的环杂原子;在另一些实施方案中,杂环基为5-6个原子组成的杂环基,所述杂环基至少含有一个选自O、S和N的环杂原子;在另一些实施方案中,杂环基为5个原子组成的杂环基,所述杂环基至少含有一个选自O、S和N的环杂原子。杂环基的实例包括,但不限于:环氧乙烷基,硫杂环丁基,氮杂环丁基,吡咯烷基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,噁唑烷基,四氢呋喃基,二氢噻吩基,二氢吡喃基,哌啶基,吗啉基,四氢嘧啶基,恶嗪烷基,硫代吗啉基和哌嗪基等。杂环基中-CH2-基团被-C(=O)-取代的实例包括,但不限于,2-氧代吡咯烷基、2-哌啶酮基、3-吗啉酮基、3-硫代吗啉酮基和氧代四氢嘧啶基等。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“芳基”表示含有6-14个环原子,或6-12个环原子,或6-10个环原子的单环、双环和三环的碳环体系,其中,至少一个环是芳香族的,且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”或“芳环”交换使用。芳基基团的实例可以包括苯基、2,3-二氢-1H-茚基、萘基和蒽基。所述芳基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子,或5-10个环原子,或5-6个环原子的单环、双环和三环体系,其中至少一个环是芳香族的,且至少一个环包含一个或多个选自氮、氧、硫的环杂原子,同时,所述杂芳基有一个或多个附着点与分子其余部分相连。当杂芳基基团中存在-CH2-基团时,所述的-CH2-基团可以任选地被-C(=O)-替代。除非另外说明,所述的杂芳基基团可以通过任何合理的位点(可以为CH中的C,或者NH中N)连接到分子其余部分(例如通式中的主体结构)上。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中,“5-10个原子组成的杂芳基”表示所述杂芳基由5-10个环原子组成,其中至少一个环原子为选自O、N、S的杂原子。这样的实例包括,但并不限于,呋喃基、咪唑基、异噁唑基、噁唑基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基等;也包括以下的双环,但绝不限于这些双环:苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、氧代吲哚基、二氢吲哚基、咪唑并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、喹啉基、异喹啉基、喹唑啉基等等。所述杂芳基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“x-y个原子组成的”(x、y分别为任意非0的自然数,且y>x)表示所述环状基团由x-y个环原子所组成,所述的环原子包括碳原子和/或O、N、S、P等杂原子,其中“x-y”包括x、y和x至y之间任意的自然数。例如,“3-8个原子组成的”、“3-10个原子组成的”、“3-6个原子组成的”或“6-10个原子组成的”表示所述环状基团由3-8、3-10、3-6或6-10个环原子所组成,所述的环原子包括碳原子和/或O、N、S、P等杂原子。又如,“6-10个原子组成的杂芳基”代表其包括6、7、8、9或10个原子组成的杂芳基。
术语“酰基”表示-C(=O)-R,其中,取代基R通过羰基(-C(=O)-)与分子其余部分相连,其中,R为本发明所描述的取代基,包括但不限于,烷基、烷氧基、羟基、氨基、环烷基、杂环基、芳基、杂芳基等。其中,烷基、烷氧基、羟基、氨基、环烷基、杂环基、芳基和杂芳基具有如本发明所述的含义,这样的实例包括,但并不限于,乙酰基(-C(=O)CH3)、羧基(-C(=O)OH)、甲氧基酰基(-C(=O)OCH3)、氨基甲酰基(-C(=O)NH2)、苯基甲酰基等等。
术语“磺酰基”表示-S(=O)2-R,其中,取代基R通过磺酰基(-S(=O)2-)与分子其余部分相连,其中,R为本发明所描述的取代基,包括但不限于,烷基、烷氧基、羟基、氨基、环烷基、杂环基、芳基、杂芳基等。其中,烷基、烷氧基、羟基、氨基、环烷基、杂环基、芳基和杂芳基具有如本发明所述的含义,这样的实例包括,但并不限于,磺酸基(-S(=O)2OH)、甲基磺酰基(-S(=O)2CH3)、甲氧基磺酰基(-S(=O)2OCH3)、氨基磺酰基(-S(=O)2NH2)、苯基磺酰基等等。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或类似不适当的反应,例如肠胃不适、眩晕等的分子实体和组合物。优选地,本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、特别是在人体中使用的。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体,例如水和油类,包括石油、动物、植物或合成来源的,例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液(例如,盐水溶液、葡萄糖水溶液、甘油水溶液)优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′sPharmaceutical Sciences”中。
术语“sGC刺激剂(sGC stimulator)”是指对可溶性鸟苷酸环化酶(sGC)具有刺激作用的化合物或药剂。在一些实施方案中,“刺激剂”与“激动剂”可以替换使用。
本发明所使用的术语“前药”,代表一个化合物在体内转化为本发明所述化合物(即,式(I)所示化合物)。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.Higuchi and V.Stella,Pro-drugs asNovel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Associationand Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and ClinicalApplications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker etal.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰氨化,脱酰氨作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,无机酸盐,如盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐;有机酸盐,如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐;或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括,己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过与适当的碱反应得到的盐包括碱金属,碱土金属,铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。可以形成盐的碱金属或碱土金属包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明的“酯”是指含有羟基或羧基的化合物形成的体内可水解的酯。这样的酯是,例如在人或动物体内水解产生母体醇或酸的药学上可接受的酯。本发明所述化合物(即,式(I)所示化合物)含有羧基,可以与适当的基团形成体内可水解的酯,这样的基团包括,但不限于,烷基、芳基烷基等。
本发明的“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是,N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514),其中例如在惰性溶剂例如二氯甲烷中,使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
本发明中所使用的“本发明的化合物”、“本发明所描述的化合物”、“本发明所述化合物”或类似的表述,均指代本发明所述的任意一个通式结构所代表的化合物,即指代本发明中式(I)所代表的化合物。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构,除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl和125I。
另一方面,本发明所述化合物包括同位素富集的本发明所定义的化合物,例如,其中存在放射性同位素,如3H,14C和18F的那些化合物,或者其中存在非放射性同位素,如2H和13C。该类同位素富集的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、检测或成像技术,如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT),或可用于患者的放疗中。18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的本发明所述化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外,较重同位素特别是氘(即,2H或D)的取代可提供某些治疗优点,这些优点是由代谢稳定性更高带来的。例如,体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解,本发明中的氘被看作本发明所述化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘,该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5%的氘掺入)、至少4000(60%的氘掺入)、至少4500(67.5%的氘掺入),至少5000(75%的氘掺入),至少5500(82.5%的氘掺入)、至少6000(90%的氘掺入)、至少6333.3(95%的氘掺入)、至少6466.7(97%的氘掺入)、至少6600(99%的氘掺入)或至少6633.3(99.5%的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。
除非其他方面表明,本发明的化合物的所有互变异构形式都包含在本发明的范围之内。例如,本发明所述化合物(1)包含其立体异构体,即,包含所述化合物(1)的S-构型和/或R-构型。另外,除非其他方面表明,本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写,除非另有说明,都以它们通常使用的、公认的缩写为准,或参照IUPAC-IUBCommission on BiochemicalNomenclature(参见Biochem.1972,11:942-944)。
本发明化合物的药物组合物、制剂、给药和用途
根据另一方面,本发明的药物组合物的特点包括本发明所述的N-环-氨基嘧啶衍生物,本发明所列出的化合物,或实施例1的化合物,和药学上可接受的载体,辅剂,或赋形剂。本发明的组合物中化合物的量能有效地治疗或减轻患者的与sGC相关的疾病。
像本发明所描述的,本发明药学上可接受的组合物进一步包含药学上可接受的载体,辅剂,或赋形剂,这些像本发明所应用的,包括任何溶剂,稀释剂,或其他液体赋形剂,分散剂或悬浮剂,表面活性剂,等渗剂,增稠剂,乳化剂,防腐剂,固体粘合剂或润滑剂,等等,适合于特有的目标剂型。如以下文献所描述的:In Remington:The Science and Practiceof Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrickand J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容,表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围,例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用,它们的用途也是本发明所考虑的范围。
可作为药学上可接受载体的物质包括,但并不限于,离子交换剂,铝,硬脂酸铝,卵磷脂,血清蛋白,如人血清蛋白,缓冲物质如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶体硅,三硅酸镁,聚乙烯吡咯烷酮,聚丙烯酸脂,蜡,聚乙烯-聚氧丙烯-阻断聚合体,羊毛脂,糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇,磷酸缓冲溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁,着色剂,释放剂,包衣衣料,甜味剂,调味剂和香料,防腐剂和抗氧化剂。
本发明的药物组合物可直接给药或随同合适的载体或赋形剂以医药组合物或药物形式给药,这是本领域所熟知的。本发明的治疗方法可包含向有需要的个体施以有效的本发明化合物。在一些实施方案中,所述个体是哺乳动物个体,并且在一些优选实施方案中,所述个体是人类个体。
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定,最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放系统形式提供。例如,常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定,可能需要特殊装置来施用或给予药物,例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Special flask)。药物剂型常常由药物、赋形剂和容器/密封系统组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性,并且可提供获得所需药物释放曲线的方法。因此,添加到药物中的赋形剂类型可视各种因素而定,例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(EuropeanPharmacopoeia,EP)和英国药典(British pharmacopoeia,BP);美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物,例如《非活性组分指南》(InactiveIngredient Guide,1996);Ash和Ash编写的《药物添加剂手册》(Handbook ofPharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY;etc.)。
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造,例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。如上文所述,本发明的组合物可包括一种或一种以上生理学上可接受的非活性成分,这些非活性成分会促进活性分子被加工成用于医药用途的制剂。
适当的制剂视所需的给药途径而定。例如,对于静脉注射来说,组合物可配制于水溶液中,必要时使用生理上相容的缓冲剂,包括例如用于调整制剂pH值的磷酸盐、组氨酸或柠檬酸盐,以及诸如氯化钠或右旋糖的张度剂。对于经粘膜或鼻给药来说,可首选半固体、液体制剂或者贴片、可能含有渗透增强剂;所述渗透剂通常为本领域所已知。对于口服给药来说,化合物可配制成液体或固体剂型并作为速释或控释/缓释制剂。用于个体口服摄取的合适剂型包括片剂、药丸、糖衣药丸、硬壳和软壳胶囊、液体、凝胶、糖浆、膏剂、悬浮液和乳液。化合物也可以被配制在直肠组合物中,诸如栓剂或保留灌肠剂,例如含有常规的栓剂基质如可可脂或其它甘油酯。
固体口服剂型可使用赋形剂获得,所述赋形剂包括填充剂、崩解剂、粘合剂(干和湿)、溶解延缓剂、润滑剂、助流剂、抗粘剂、阳离子性交换树脂、湿润剂、抗氧化剂、防腐剂、着色剂和调味剂。这些赋形剂可为合成或天然来源。所述赋形剂的实例包括纤维素衍生物、柠檬酸、磷酸二钙、明胶、碳酸镁、月桂基硫酸镁/月桂基硫酸钠、甘露糖醇、聚乙二醇、聚乙烯吡咯烷酮、硅酸盐、二氧化硅、苯甲酸钠、山梨糖醇、淀粉、硬脂酸或其盐、糖(即右旋糖、蔗糖、乳糖等)、滑石、西黄蓍胶浆(tragacanth mucilage)、植物油(氢化)和蜡。乙醇和水可用作造粒助剂。在某些情况下,需要用例如掩味膜、抗胃酸膜或延缓释放膜来涂覆片剂。常常将天然和合成的聚合物与着色剂、糖和有机溶剂或水组合用于涂覆片剂,从而产生糖衣药丸。当胶囊优于片剂时,可以用兼容的硬壳或软壳胶囊形式递送其药物粉末、悬浮液或溶液。
在一些实施方案中,本发明的化合物可局部给药,例如通过皮肤贴片、半固体或液体制剂,如凝胶、(微)乳液、软膏、溶液、(纳米/微米级)悬浮液或泡沫。药物的皮肤和下层组织渗透可通过以下方式来调节:例如使用渗透增强剂;使用亲脂性、亲水性和两亲性赋形剂的适当选择和组合,包括水、有机溶剂、蜡、油、合成和天然的聚合物、表面活性剂、乳化剂;通过调整pH值;和使用络合剂。例如离子电渗疗法(iontophoresi)的其它技术也可以用于调节本发明的化合物的皮肤渗透。例如在需要以最小全身性暴露局部给药的情形下,将首选透皮或局部给药。
对于通过吸入给药或鼻给药来说,根据本发明使用的化合物以溶液、悬浮液、乳液或半固体气溶胶的形式从加压包或喷雾器中方便地给药,通常借助于推进剂,例如衍生自甲烷和乙烷的卤化碳、二氧化碳或任何其它合适的气体。对于局部气溶胶来说,如丁烷、异丁烯和戊烷等烃是适用的。在加压气溶胶的情况下,适当的剂量单位可通过提供阀门传递计量来测定。可配制用于吸入器或吹入器中的具有例如明胶的胶囊和药筒。这些通常含有化合物与合适粉末基质(如乳糖或淀粉)的粉末混合物。
用于通过注射非经肠给药而配制的组合物通常是无菌的并且可以用单位剂型提供,例如安瓿瓶、注射器、注射笔、或多剂量容器,后者通常含有防腐剂。组合物可采用在油性或水性载体中的悬浮液、溶液或乳液等形式,并且可含有配制试剂,例如缓冲剂、张度剂、粘度增强剂、表面活性剂、悬浮剂和分散剂、抗氧化剂、生物相容性聚合物、鳌合剂和防腐剂。视注射部位而定,所述载体可含有水、合成或植物油和/或有机共溶剂。在某些情况下,例如对于冻干产物或浓缩物,会在给药之前将非经肠制剂重组或加以稀释。提供本发明的化合物的控释或缓释的贮库制剂(depot formulation)可包括纳米/微米级微粒或者纳米/微米级或非微细化晶体的可注射悬浮液。本领域其它熟知的基质,聚(乳酸)、聚(乙醇酸)或其共聚物等聚合物可被用作控释/缓释基质。可以以需要切口的植入物和泵的形式提供其它的贮库型(depot)给药系统。
用于静脉注射的本发明化合物的合适的载体为本领域所熟知并且包括含有碱(如氢氧化钠)的水基溶液,用于形成离子化合物;作为张度剂的蔗糖或氯化钠;例如含有磷酸盐或组氨酸的缓冲剂。可添加如聚乙二醇的共溶剂。这些水基体系能有效溶解本发明的化合物并且在全身性给药后产生低毒性。在不破坏溶解性和毒性特征的情况下,可大大改变溶液体系的组分的比例。此外,可改变组分的特性。举例来说,可使用诸如聚山梨醇酯或泊洛沙姆(poloxamer)的低毒性表面活性剂,也可使用聚乙二醇或其它共溶剂,可添加诸如聚乙烯吡咯烷酮的生物相容性聚合物,并且可用其它糖和多元醇来替代右旋糖。
本发明化合物可全身和/或局部作用。它们可以以适合的方式给药,例如,通过口服给药、经肠胃给药、经肺给药、经鼻给药、舌下给药、经舌给药、含服、直肠给药、真皮给药、经皮给药、结膜给药、耳道给药或作为移植片或支架给药。本发明化合物优选地经口服给药或非经肠给药。
口服给药的适合给药方式如下:根据现有技术工作的方式,迅速释放和/或以改良的方法释放本发明的化合物的给药方式,它们包含结晶和/或无定形和/或溶解的形式的本发明的化合物,例如片剂(未包衣片剂或例如用控制本发明的化合物释放的胃液耐受的或延迟溶解的或不溶性的包衣进行包衣的片剂)、在口腔中迅速碎裂的片剂或薄膜/薄片、薄膜/冻干体、胶囊(例如硬胶囊或软胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、混悬剂、气溶胶或溶液。
非经肠给药可以绕过吸收步骤(例如静脉内、动脉内、贲门内、脊柱内或腰内)或包括吸收(例如:肌内吸收、皮下吸收、皮内吸收、经皮吸收或腹膜内吸收)。适合于非经肠给药的给药形式包括溶液、混悬液、乳液、冻干体或无菌粉体形式的用于注射和输注的制剂。
对于其它给药途径,适合的例子是吸入的药物形式(包括粉体吸入器、喷雾器)、滴鼻剂、溶液或喷雾剂、用于舌、舌下或含服给药的片剂、薄膜/薄片或胶囊、栓剂、耳或眼制剂、阴道胶囊、水混悬液(洗剂、震荡合剂)、亲脂性混悬剂、软膏、霜剂、经皮治疗体系(例如贴片)、乳剂(Milch)、糊剂、泡沫、喷洒粉剂、植入物或支架。
本发明化合物的治疗有效量应当是以整个混合物约0.1至99.5%,优选约0.5至95%重量的浓度存在于上述药物制剂中。
除本发明化合物外,上述药物制剂还可以包含其它药物活性成分。
治疗有效剂量可首先使用本领域中熟知的各种方法来估算。用于动物研究的初始剂量可基于细胞培养测定中所确立的有效浓度。适合于人个体的剂量范围例如可使用从动物研究和细胞培养测定所获得的数据来确定。在某些实施方案中,可以将本发明的化合物制备为用于口服的药剂。本发明的化合物在用于口服的药剂中的示例性的剂量是从约0.01至约100mg/kg(其中kg表示受试者的体重)。在一些实施方案中,药剂包括从约0.01至约20mg/kg(其中kg表示受试者的体重),或者任选地从约0.01至约10mg/kg(其中kg表示受试者的体重),或者任选地从约0.01至约5.0mg/kg(其中kg表示受试者的体重)。在某些实施例中,本发明化合物经肠胃给药,其有效给药剂量为大约0.001-1mg/kg、优选大约0.01-0.5mg/kg(其中kg表示受试者的体重)。
通常用于口服施用的药剂的给药方案是每周三次、每周两次、每周一次、每日三次、每日两次或者每日一次。在某些实施例中,本发明化合物作为活性成分以每24小时约0.001至约50、优选0.001至10mg/kg体重的总量进行给药,为了获得所需的结果,任选可以采用多个单剂量的形式来进行给药。一个单剂量优选地可以包含用量为约0.001至约30、特别是0.001至3mg/kg体重的本发明化合物。
药剂(例如本发明的化合物)的有效量或治疗有效量或剂量指的是引起个体症状改善或存活延长的药剂或化合物的量。所述分子的毒性和治疗功效可在细胞培养物或实验动物中通过标准医药程序来测定,例如通过测定LD50(使群体的50%致死的剂量)和ED50(对群体的50%治疗有效的剂量)。毒性作用与治疗作用的剂量比是治疗指数,可表示为LD50/ED50。优选显示高治疗指数的药剂。
有效量或治疗有效量是将会引发研究人员、兽医、医生或其它临床医生所探求的组织、系统、动物或人类的生物或医学反应的化合物或医药组合物的量。剂量优选在包括极小毒性或无毒性的ED50的循环浓度的范围内。剂量可在这个范围内变化,视所用的剂型和/或所用的给药途径而定。应根据本领域中已知的方法,考虑个体状况的特殊性来选择正确的制剂、给药途径、剂量和给药间隔时间。
剂量和间隔时间可个别地加以调整以提供足以获得所需效果的活性部分的血浆水平;即最小有效浓度(minimal effective concentration,MEC)。各化合物的MEC将有所不同,但可以例如从体外(in vitro)数据和动物实验估算。获得MEC所必需的剂量将视个体特征和给药途径而定。在局部给药或选择性摄取的情况下,药物的有效局部浓度可能与血浆浓度无关。
所施予的药剂或组合物的量可视各种因素而定,包括所治疗个体的性别、年龄和体重、病痛的严重性、给药方式和处方医师的判断。
在需要时,本发明的组合物可以用含有一个或一个以上单位剂型(含有活性成分)的包装或分配装置提供。举例来说,所述包装或装置可包含金属或塑料箔(如发泡包装)或玻璃和橡皮塞。所述包装或分配装置可附有用药说明书。也可以制备包含在相容性医药载体中配制的本发明化合物的组合物,将其置于适当容器中,并且加上用于治疗指定病状的标签。
本发明的化合物可以单独或者,如需要,与其它的活性化合物结合使用。本发明还提供了包括至少一种本发明的化合物和一种或多种进一步的活性物质,特别是用于治疗和/或预防本发明所述的疾病的药物的联合使用。
本发明化合物可用作可溶性鸟苷酸环化酶的刺激剂,并且与现有技术已知的化合物相比具有相同或者改善的治疗性能,例如,具有相同或改善的体内性能、药物代谢动力学和药效学行为和/或剂量-活性关系和/或安全性能。它们适用于治疗和/或预防人和动物的疾病。
本发明化合物可以引起血管舒张、抑制血小板聚集和降低血压、以及增加冠状动脉血流量。这些效果通过可溶性鸟苷酸环化酶的直接刺激和细胞内cGMP增加进行调节。另外,本发明的化合物提高了增加cGMP水平的物质的效果,所述物质包括EDRF(内皮细胞衍生舒张因子)、NO供体、原卟啉IX、花生四烯酸或苯肼衍生物等。
本发明的化合物适用于治疗和/或预防心血管、肺、血栓栓塞和纤维化方面的疾病。
本发明的化合物可以用作治疗和/或预防如下疾病的药物:心血管疾病,例如高血压、急性和慢性心力衰竭、冠心病、稳定型和不稳定型心绞痛、外周血管和心血管疾病、心律失常、房性和室性心律失常及受损传导(例如,I-III度房室性传导阻滞(AB阻滞I-III))、室上性快速型心律失常、心房颤动、心房扑动、心室颤动、心室扑动、室性快速型心律失常、扭转型室性心动过速、房性和室性早搏、AV-结合性早搏、病窦综合征、晕厥、AV-结节复返心动过速、沃-帕-怀氏综合征;急性冠状动脉综合征(ACS)、自身免疫心脏疾患(心包炎、心内膜炎、Valvolitis、主动脉炎、心肌病)、休克如心源性休克、感染性休克和过敏性休克、动脉瘤、拳击者心肌病(心室早发性收缩(PVC));血栓栓塞疾病和缺血症,例如心肌缺血、心肌梗塞、中风、心脏肥厚、暂时性和缺血性发作、先兆子痫、炎症性心血管疾病、冠状动脉和外周动脉痉挛、水肿形成(例如肺水肿、脑水肿、肾水肿或心力衰竭引起的水肿)、末梢循环紊乱、再灌注损伤、动脉和静脉血栓形成、微白蛋白尿、心肌机能不全、内皮机能失常;预防例如在血栓溶解疗法、经皮的腔间血管成形术(PTA)、经腔冠状动脉血管成形术(PTCA)、心脏移植和分流手术之后的再狭窄,以及微血管和大血管损伤(血管炎)、纤维素蛋白原和低密度脂蛋白(LDL)水平增高和血纤维蛋白溶酶原活性剂抑制剂1(PAI-1)的浓度增加;勃起机能障碍和女性性功能障碍。
在本发明的范围内,术语心力衰竭也包括更特殊或相关的疾病类型,如急性代偿失调性心力衰竭、右心衰竭、左心衰竭、整体衰竭、缺血性心肌病、扩张性心肌病、肥厚型心肌病、自发性心肌病、先天性心脏缺损、心瓣膜缺损、心瓣膜缺损伴随的心力衰竭、二尖瓣狭窄、二尖瓣关闭不全、主动脉狭窄、主动脉瓣关闭不全、三尖瓣狭窄、三尖瓣关闭不全、肺动脉瓣狭窄、肺动脉瓣关闭不全、组合性心瓣膜缺损、心肌炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病性心力衰竭、酒精中毒性心肌病、心脏存储疾病和舒张与收缩性心力衰竭。
另外,本发明的化合物也可用于治疗和/或预防动脉硬化、损伤性脂类代谢血症、血脂蛋白过少症、血脂障碍、高甘油三酯血症、高脂血症、高胆固醇血症、无β脂蛋白血症、谷固醇血症、黄瘤症、丹吉尔病、肥胖症、多脂症以及治疗和/或预防组合性高脂血症和代谢综合征。
本发明的化合物还可用于治疗和/或预防原发性和继发性雷诺现象、微循环功能损伤、跛脚、末梢和自主神经病、糖尿病性微血管病、糖尿病性视网膜病、四肢糖尿病性溃疡、坏疽、CREST综合征、红斑病(Erythemitose)、甲癣、风湿病和用于促进创伤愈合。
本发明的化合物另外还适合于治疗如下疾病:泌尿外科疾病,例如良性前列腺综合征(BPS)、良性前列腺增生(BPH)、良性前列腺增大(BPE)、膀胱出口阻塞(BOO)、下泌尿道综合征(LUTS,包括猫尿路综合征(FUS));泌尿生殖系统疾病,包括膀胱神经性活动过度(OAB)和(IC)、失禁(UI)(例如混合性尿失禁、急迫性尿失禁、应激性尿失禁或溢出性尿失禁(MUI,UUI,SUI,OUI))、骨盆痛、男性和女性泌尿生殖系统器官的良性和恶性疾病。
本发明的化合物另外还适合于治疗和/或预防肾病,特别是急性和慢性肾机能不全以及急性和慢性肾衰竭。在本发明的范围内,术语肾机能不全包括其急性和慢性症状以及基本的或相关的肾脏疾病,例如:肾脏血流灌注不足、透析性低血压、阻塞性尿路病、肾小球病、肾小球肾炎、急性肾小球肾炎、肾小球硬化症、小管间质性病、肾病(如原发性和先天性肾脏疾病)、肾炎、免疫性肾脏疾病(如肾脏移植物排斥和免疫复合物诱发的肾脏疾病)、毒性物质诱发的肾病、造影剂诱发的肾病、糖尿病性和非糖尿病性肾病、肾盂肾炎、肾囊肿、肾硬变、高血压肾硬变和肾病变综合征,所述疾病在诊断上可具有如下特征:异常减少的肌酸酐和/或水排泄、异常增高的尿、氮、钾和/或肌酸酐血浓度、改变的肾酶活性(例如谷氨酸合成酶)、改变的尿渗透性或尿量、增加的微白蛋白尿、大蛋白尿、肾小球和微动脉上的损伤、肾小管扩张、高磷酸酯酶血症和/或透析需要。本发明还包括本发明的化合物用于治疗和/或预防肾机能不全后遗症的用途,例如肺水肿、心力衰竭、尿毒症、贫血、电解质紊乱(例如高钙血症、低钠血症)以及骨病和碳水化合物代谢紊乱。
另外,本发明的化合物还适合于治疗和/或预防哮喘病、肺动脉压过高(PAH)和肺动脉高压(PH)的其它形式(包括左心疾病、HIV、镰状细胞贫血、血栓栓塞(CTEPH)、Sarkoidose、COPD或肺纤维化伴随的肺动脉高压)、慢性阻塞性肺疾病(COPD)、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、α-1-抗胰蛋白酶缺乏(AATD)、肺纤维化、肺气肿(例如抽烟诱发的肺气肿)和囊性纤维化(CF)。
本发明描述的化合物还可以用于控制以NO/cGMP系统紊乱为特征的中枢神经系统疾病。它们特别适合在认知缺损后用于提高知觉、注意力、学习或记忆力,所述认知缺损包括伴随着情景/疾病/综合征发生的认知缺损,例如轻度认知缺损、伴随年老而来的学习和记忆力减退、伴随年老而来的记忆丧失、血管性痴呆、颅脑创伤、中风、中风后发生的痴呆(中风后痴呆)、创伤后颅脑创伤、一般性注意集中障碍、儿童学习和记忆力问题方面的注意集中障碍、阿尔茨海默病、路易体痴呆、额叶退化痴呆(包括皮克斯综合症、帕金森病、渐进性核麻痹)、皮质延髓退化痴呆、肌萎缩侧索硬化症(ALS)、亨廷顿舞蹈病、脱髓鞘症、多发性硬化症、丘脑退化、克-雅病痴呆、HIV痴呆、伴有痴呆的精神分裂或柯萨可夫精神病。它们也适合于治疗和/或预防中枢神经系统障碍,如焦虑状态、紧张和抑郁、中枢神经相关的性功能障碍和睡眠障碍、和用于控制食物、兴奋剂和上瘾性物质摄取的病理障碍。
本发明的化合物另外还适合于控制脑血流量,从而可用作控制偏头疼的有效试剂。它们也适合于预防和控制大脑梗死后遗症,如中风、大脑缺血和颅脑创伤。本发明的化合物同样可用于控制疼痛和耳鸣状况。
另外,本发明的化合物有抗炎作用,因此可作为抗炎剂用于治疗和/或预防脓毒症(SIRS)、多器官衰竭(MODS,MOF)、肾脏的炎症性障碍、慢性肠炎(IBD、克罗恩病、UC)、胰腺炎、腹膜炎、类风湿病、炎症性皮肤病和炎症性眼病。
此外,本发明的化合物也可用于自身免疫疾病的治疗和/或预防。
本发明的化合物还适合于治疗和/或预防内脏器官如肺、心、肾、骨髓的纤维化疾病并特别是肝的纤维化疾病,以及皮肤纤维化和纤维化眼病。在本发明的范围内,术语纤维化疾病特别包括下面的术语:肝纤维化、肝硬化、肺纤维化、心肌心内膜纤维化、肾病、肾小球肾炎、间质性肾纤维化、糖尿病引起的纤维化损害、骨髓纤维化和类似的纤维化疾病、硬皮病(又称系统性硬化症)、硬斑病、瘢痕疙瘩、肥厚型疤痕(以及手术操作之后)、痣、糖尿病性视网膜病、增殖性玻璃体视网膜病变和结缔组织疾病(例如结节病)。
本发明的化合物还适合于控制例如由于青光眼手术造成的术后疤痕。本发明的化合物也可在老化和角质化皮肤情况下美容性应用。
另外,本发明的化合物适合于治疗和/或预防肝炎、赘生物、骨质疏松、青光眼和胃轻瘫。
本发明的化合物还适合于治疗和/或预防胃肠道疾病,例如,胃肠道炎症、胃肠道癌症、胃肠功能紊乱等;和食管动力障碍性疾病。胃肠道紊乱包括,例如,过敏性肠综合症(IBS)、非溃疡性消化不良、慢性肠假性梗阻、机能性消化不良、结肠假性梗阻、十二指肠反流、胃食管反流疾病(GERD)、肠梗阻发炎(例如,手术后肠梗阻)、胃轻瘫、胃灼热(在胃肠道中出现高酸性)、便秘(例如,与使用药物有关的便秘,所述药物例如鸦片样物质、骨关节炎药、骨质疏松症药;手术后便秘;与神经性紊乱有关的便秘)。食管动力障碍性疾病包括例如贲门弛缓不能(又称贲门失弛缓症)、弥漫性食管痉挛以及胡桃夹食管等。
本发明进一步提供本发明的化合物在用于治疗和/或预防疾病特别是上述疾病中的用途。
本发明进一步提供本发明的化合物用于治疗和/或预防如下疾病的用途:心力衰竭、心绞痛、高血压、肺动脉高压、缺血症、血管疾病、肾病、血栓栓塞疾病、男性性功能障碍、系统性硬化症、镰状细胞贫血、贲门弛缓不能、纤维化疾病和/或动脉硬化。
本发明进一步提供本发明的化合物在制备用于治疗和/或预防疾病特别是上述疾病的药物中的用途。
本发明进一步提供本发明的化合物在制备用于治疗和/或预防如下疾病的药物中的用途:心力衰竭、心绞痛、高血压、肺动脉高压、缺血症、血管疾病、肾病、血栓栓塞疾病、男性性功能障碍、系统性硬化症、镰状细胞贫血、贲门弛缓不能、纤维化疾病和/或动脉硬化。
本发明进一步提供一种用有效量的至少一种本发明的化合物来治疗和/或预防疾病、特别是上述疾病的方法。
本发明进一步提供一种用有效量的至少一种本发明的化合物治疗和/或预防如下疾病的方法:心力衰竭、心绞痛、高血压、肺动脉高压、缺血症、血管疾病、肾病、血栓栓塞疾病、男性性功能障碍、系统性硬化症、镰状细胞贫血、贲门弛缓不能、纤维化疾病和/或动脉硬化。
本发明的化合物可单独使用,或者,如需要的话,与其它活性物质结合使用。本发明进一步提供尤其是用于治疗和/或预防上述疾病的药物,所述药物包含至少一种本发明的化合物和一种或多种另外的活性物质。适合的活性物质组合优选的例子包括:
(1)有机的硝酸盐和NO供体,例如,硝普钠、硝化甘油、单硝酸异山梨酯、二硝酸异山梨酯、吗多明或SIN-1、和吸入性NO;
(2)抑制环磷酸鸟苷(cGMP)分裂的化合物,例如,磷酸二酯酶(PDE)1,2和/或5抑制剂,特别是PDE5抑制剂,如昔多芬、伐地那非和他达拉非;
(3)具有抗凝血作用的试剂,例如,优选选自血小板凝集抑制剂组、抗凝血剂组或血纤维蛋白溶酶原物质组的试剂;
(4)降低血压的活性物质,例如,优选选自下组的活性物质:钙拮抗剂、血管紧张素II拮抗剂、ACE抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻滞剂、β-受体阻滞剂、矿质皮质激素受体拮抗剂,和利尿剂组;
(5)改变脂类代谢的活性物质,例如,优选选自甲状腺受体激动剂、胆固醇合成抑制剂(例如,优选HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂组的抑制剂)、ACAT抑制剂、CETP抑制剂、MTP抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂、胆固醇吸收抑制剂、脂肪酶抑制剂、多聚胆汁酸吸附剂、胆汁酸重吸收抑制剂和脂蛋白(a)拮抗剂组的活性物质;和/或
(6)具有抗血栓形成活性的试剂,优选指的是选自血小板凝集抑制剂组、抗凝血剂组或血纤维蛋白溶酶原物质组的化合物。
在本发明的一些实施方案中,本发明的化合物与血小板凝集抑制剂(例如,阿司匹林、氯吡格雷、噻氯吡啶、利伐沙班或双嘧达莫)结合给药。
在本发明的一些实施方案中,本发明的化合物与凝血酶抑制剂(例如,希美加群、达比加群、美拉加群、比伐卢定或克赛)结合给药。
在本发明的一些实施方案中,本发明的化合物与GPIIb/IIIa受体拮抗剂(例如,替罗非班或阿昔单抗)结合给药。
在本发明的一些实施方案中,本发明的化合物与Xa因子抑制剂结合给药:所述Xa因子抑制剂优选为利伐沙班、DU-176b、阿哌沙班、奥米沙班、非地沙班、雷扎沙班、磺达肝癸钠、艾卓肝素、PMD-3112、YM-150、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX9065a、DPC906、JTV803、SSR-126512或SSR-128428。
在本发明的一些实施方案中,本发明的化合物与肝素或与低分子量(LMW)肝素衍生物结合给药。
在本发明的一些实施方案中,本发明的化合物与维他命K拮抗剂(例如,香豆素)结合给药。
在本发明的一些实施方案中,本发明的化合物与钙拮抗剂(例如,硝苯地平、氨氯地平、维拉帕米或地尔硫卓)结合给药。
在本发明的一些实施方案中,本发明的化合物与α-1受体阻滞剂(例如,哌唑嗪)结合给药。
在本发明的一些实施方案中,本发明的化合物与β受体阻滞剂结合给药,所述β受体阻滞剂优选为普萘洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、烯丙洛尔、氧烯洛尔、喷布洛尔、布拉洛尔、美替洛尔、纳多洛尔、甲吲洛尔、卡拉洛尔、索他洛尔、美托洛尔、倍他洛尔、塞利洛尔、比索洛尔、卡替洛尔、艾司洛尔、拉贝洛尔、卡维洛尔、阿达洛尔、兰地洛尔、奈比洛尔、依泮洛尔或布新洛尔。
在本发明的一些实施方案中,本发明的化合物与血管紧张素II拮抗剂(例如,氯沙坦、坎地沙坦、缬沙坦、替米沙坦或恩布沙坦)结合给药。
在本发明的一些实施方案中,本发明的化合物与ACE抑制剂结合给药,所述ACE抑制剂优选为依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、奎诺普利、培哚普利或川多普利。
在本发明的一些实施方案中,本发明的化合物与内皮素拮抗剂(例如,波生坦、达卢生坦、安立生坦或西他生坦)结合给药。
在本发明的一些实施方案中,本发明的化合物与肾素抑制剂(例如,阿利吉仑、SPP-600或SPP-800)结合给药。
在本发明的一些实施方案中,本发明的化合物与矿质皮质激素受体拮抗剂(例如,螺内酯或依普利酮)结合给药。
在本发明的一些实施方案中,本发明的化合物与如下物质结合给药:袢利尿剂(例如,呋塞米、托拉塞米、布美他尼和吡咯他尼),保钾利尿剂(例如,阿米洛利和氨苯蝶啶),醛固酮拮抗剂(例如,螺内酯、烯睾丙酸钾和依普利酮)以及噻嗪类利尿剂(例如,氢氯噻嗪、氯噻酮、烯帕胺和吲达帕胺)。
在本发明的一些实施方案中,本发明的化合物与CETP抑制剂(例如,达塞曲匹、BAY60-5521、安塞曲匹或CETP疫苗(CETi-1))结合给药。
在本发明的一些实施方案中,本发明的化合物与甲状腺受体激动剂(例如,D-甲状腺素、3,5,3'-碘塞罗宁(T3)、CGS23425或阿昔替罗(CGS26214))结合给药。
在本发明的一些实施方案中,本发明的化合物与选自他汀类的HMG-CoA还原酶抑制剂结合给药,所述他汀类优选为洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗苏伐他汀或匹伐他汀。
在本发明的一些实施方案中,本发明的化合物与角鲨烯合成抑制剂(例如,BMS-188494或TAK-475)结合给药。
在本发明的一些实施方案中,本发明的化合物与ACAT抑制剂(例如,阿伐麦布、甲亚油酰胺、帕替麦布、依鲁麦布或SMP-797)结合给药。
在本发明的一些实施方案中,本发明的化合物与MTP抑制剂(例如,英普他牌、BMS-201038,R-103757或JTT-130)结合给药。
在本发明的一些实施方案中,本发明的化合物与PPAR-γ激动剂(例如,匹格列酮或罗西格列酮)结合给药。
在本发明的一些实施方案中,本发明的化合物与PPAR-δ激动剂(例如,GW501516或BAY68-5042)结合给药。
在本发明的一些实施方案中,本发明的化合物与胆固醇吸收抑制剂(例如,依泽替米贝、替奎安或帕马苷)结合给药。
在本发明的一些实施方案中,本发明的化合物与脂肪酶抑制剂结合给药,所述脂肪酶抑制剂优选的例子是奥利司他。
在本发明的一些实施方案中,本发明的化合物与多聚胆汁酸吸收剂(例如,考来烯胺、考来替泊、考来索文(Colesolvam)、考来胶或考来替麦(Colestimid))结合给药。
在本发明的一些实施方案中,本发明的化合物与胆汁酸重吸收抑制剂(例如,ASBT(=IBAT)抑制剂,如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635)结合给药。
在本发明的一些实施方案中,本发明的化合物与脂蛋白酯拮抗剂(例如,Gemcabenecalcium(CI-1027)或烟酸)结合给药。
一般合成过程
在本说明书中,如果在化学名称和化学结构间存在任何差异,结构是占优的。
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到:本发明所描述的化学反应可以用来合适地制备本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例,除非其他方面表明,所有的温度定为摄氏度。除非其他方面表明,试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company andAlfa Chemical Company,使用时都没有经过进一步纯化;一般的试剂从汕头西陇化工厂,广东光华化学试剂厂,广州化学试剂厂,天津好寓宇化学品有限公司,青岛腾龙化学试剂有限公司,和青岛海洋化工厂购买得到。
无水四氢呋喃,二氧六环,甲苯,乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯,石油醚,正己烷,N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明),反应瓶都塞上合适的橡皮塞,底物通过注射器打入。玻璃器皿均是经过干燥的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱数据通过Bruker Avance 400核磁共振谱仪或Bruker Avance III HD 600核磁共振谱仪来测定,以CDC13,DMSO-d6,CD3OD或Acetone-d6为溶剂(报导以ppm为单位),用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet,三重峰),m(multiplet,多重峰),q(quartet,四重峰),br(broadened,宽峰),dd(doublet of doublets,双二重峰),dt(doublet of triplets,双三重峰),dq(doublet of quartets,双四重峰),ddd(doublet of doublet of doublets,双双二重峰),ddt(doublet of doublet of triplets,双双三重峰),dddd(doublet ofdoublet of doublet of doublets,双双双二重峰)。偶合常数,用赫兹(Hz)表示。
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的,G1329A自动采样器和G1315B DAD检测器应用于分析,ESI源应用于LC-MS光谱仪。
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的,G1329A自动采样器和G1315D DAD检测器应用于分析,ESI源应用于LC-MS光谱仪。
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱,规格为2.1×30mm,5μm。注射体积是通过样品浓度来确定;流速为0.6mL/min;HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1%的甲酸乙腈溶液(相A)和0.1%的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示:
表1低分辨率质谱流动相的梯度洗脱条件
时间(min) | A(CH3CN,0.1%HCOOH) | B(H2O,0.1%HCOOH) |
0-3 | 5-100 | 95-0 |
3-6 | 100 | 0 |
6-6.1 | 100-5 | 0-95 |
6.1-8 | 5 | 95 |
下面简写词的使用贯穿本发明:
CDC13 氘代氯仿;
DMSO-d6 氘代二甲基亚砜
DMSO 二甲基亚砜
g 克
mg 毫克
mol 摩尔
mmol 毫摩尔
h 小时
min 分钟
mL 毫升
μL 微升
下列反应方案描述了制备本发明公开化合物的步骤。其中,除非另外说明,Cy具有如本发明所述的含义。
反应方案
反应方案1
化合物S2可以按照反应方案1描述的方法制备得到:化合物S1与合适的试剂反应可以得到化合物S2。例如,当Cy为5元环状基团(其中E为CH2、NH、O或S)时,所述化合物S2可以由化合物S1与氧代的5元环状基团(/>其中E为CH2、NH、O或S)在醋酸和氰基硼氢化钠的作用下反应得到。
下面的实施例可以对本发明做进一步的描述,然而,这些实施例不应作为对本发明的范围的限制。
实施例
实施例1 2-(1-(2-氟苄基)-1H-吡唑[3,4-b]吡啶-3-基)-N5-(四氢呋喃-3-基)嘧啶-4,5,6-三胺
在50mL双口瓶中加入2-(1-(2-氟苄基)-1H-吡唑[3,4-b]吡啶-3-基)嘧啶-4,5,6-三胺(参照文献ChemMedChem,2009,4,853–865中描述的化合物51的合成方法制备得到)(0.12g,0.34mmol)、二氢呋喃-3(2H)-酮(0.044g,0.51mmol)和甲醇(10mL),冰浴中加入醋酸(0.20mL,3.5mmol),室温搅拌1小时后再加入氰基硼氢化钠(0.11g,1.8mmol),继续搅拌过夜。蒸掉溶剂,加入饱和碳酸氢钠水溶液,乙酸乙酯萃取(30mL×2),有机相依次用水(50mL)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,滤液减压旋干,残渣经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)=100/1)得到淡黄色固体(0.068g,47%)。
MS(ESI,pos.ion)m/z:421.1(M+1).
1H NMR(400MHz,DMSO-d6)δ(ppm)9.05(dd,J=8.0,1.5Hz,1H),8.59(dd,J=4.5,1.5Hz,1H),7.39–7.30(m,2H),7.26–7.19(m,1H),7.12(dd,J=7.9,4.9Hz,2H),6.10(s,4H),5.78(s,2H),3.94(q,J=7.6Hz,1H),3.80–3.60(m,3H),3.53(dd,J=8.8,3.4Hz,1H),3.47(d,J=6.9Hz,1H),1.97–1.85(m,1H),1.82–1.72(m,1H).
19F NMR(376MHz,DMSO-d6)δ(ppm)-118.35(s).
生物活性检测
实施例A本发明化合物对重组鸟苷酸环化酶报告细胞系的作用
构建可溶性鸟苷酸环化酶(Soluble Guanylate Cyclase,sGC)稳定高表达CHO-K1细胞系:合成RatsGCα1和Rat sGCβ1基因,构建pcDNA3.1(+)-rat sGCα1和pcDNA3.1/Hygro(+)-rat sGCβ1质粒,并将该质粒共转染至CHO-K1细胞,利用Cisbio cGMP HTRF检测试剂盒筛选出CHO-K1-Rat sGC稳定表达的阳性克隆细胞株。
化合物对CHO-K1-Rat sGC单克隆细胞株活性的测定:培养CHO-K1-Rat sGC单克隆细胞株至70%~90%融合度,TrypLE消化处理后将细胞重悬于完全培养基中,接种于384孔(low volume tissuse culture treated)细胞培养板中,接种密度为7.5千/孔(于25μL完全培养基中),于37℃,5%CO2中培养20小时;利用DMSO溶解并稀释待测化合物为10个浓度梯度(2X工作浓度),取出384孔细胞培养板,将其200g,RT倒置离心3秒,吸弃培养基,然后按Cisbio cGMP HTRF检测试剂盒检测步骤向各细胞孔中加入各浓度梯度的待测化合物及相应试液,利用Envision HTRF detector采集数据并计算各化合物激活可溶性鸟苷酸环化酶的EC50值。
表2本发明化合物对重组鸟苷酸环化酶报告细胞系的作用
实施例编号 | EC50(nM) |
实施例1 | 230 |
实验结论:
由表2数据可知,本发明实施例1化合物能较好的激活CHO-K1-Rat sGC单克隆细胞株的活性,即,本发明化合物对重组鸟苷酸环化酶报告细胞系具有激活作用。特别地,相对于现有技术中结构近似的对比化合物(参见专利申请CN108690016A,实施例4,根据记载,同样的测试条件下,该对比化合物的EC50值为350nM),本发明实施例化合物的体外sGC激活活性得到显著提高。
实施例B本发明化合物的药代动力学实验
待测化合物溶液的配制:待测化合物用5%二甲亚砜、5%Solutol HS 15和90%生理盐水配制成溶液,用于口服和静脉注射给药。
取190-250g雄性SD大鼠,随机分为两组,每组3只,一组静脉注射待测化合物,剂量为1.0mg/kg,另一组口服给予待测化合物,剂量为2.5或5.0mg/kg;给药后按时间点0.0833,0.25,0.5,1.0,2.0,4.0,7.0和24小时采血。根据样品浓度建立合适范围的标准曲线,使用AB SCIEX API4000型LC-MS/MS,在MRM模式下测定血浆样品中待测化合物的浓度。根据药物浓度-时间曲线,采用WinNonLin 6.3软件非房室模型法计算药代动力学参数。
实施例C本发明化合物抑制hERG钾通道实验
1、化合物溶液配制:
称取各化合物物分别溶解于DMSO中,并用DMSO稀释成系列浓度溶液(30、10、3.3、1.1、0.37mM),将以上系列浓度溶液用细胞外液稀释1000倍配制成测试溶液(终浓度分别为30、10、3.3、1.1、0.37μM)。
2、稳转细胞培养及准备:
将过表达hERG钾离子通道的HEK293稳转细胞于37℃、5%CO2培养箱中培养,培养基为:DMEM、15%胎牛血清和1%青霉素-链霉素。细胞密度达培养皿80%时,将细胞用胰蛋白酶/EDTA消化转移到离心管中,1000转/分钟离心3分钟,上清液倒掉,加入细胞培养基,轻轻吹打将细胞混匀,随后将细胞滴入爬片待细胞贴壁用于实验,细胞密度低于50%,培养过夜,备用。
3、电生理手动膜片钳系统实验
将爬片后的实验用细胞转移到一个嵌于倒置显微镜平台的细胞浴槽中,灌流细胞外液,灌流速度为2.7mL/分钟。稳定5分钟细胞沉淀后即可开始实验。采用HEKA EPC-10膜片钳放大PATCHMASTER采集系统记录膜电流(HEKA Instruments Inc.,D-67466Lambrecht,Pfalz,Germany)。所有实验均在室温(22-24℃)下完成。实验中使用P-97微电极拉制仪(Sutter Instrument Company,One Digital Drive,Novato,CA 94949)拉直电极(BF150-110-10)。电极内径为1-1.5mm,充满内液后的入水电阻为2-4MΩ。
hERG钾通道的电生理刺激方案是首先将膜电压钳制在-80mV,给予细胞+20mV电压刺激,持续2s,激活hERG钾通道,再复极化至-50mV,持续5s,产生外向尾电流,刺激频率每15s一次,电流值为尾电流的峰值。
实验中采用全细胞记录模式记录通道电流。首先灌流细胞外液(大约每分钟2毫升)并持续记录,并等待电流稳定(5分钟内电流衰减小于5%),此时尾电流峰值即为对照电流值。接着灌流含待测化合物的细胞外液并持续记录直到化合物对hERG电流的抑制作用到达稳定状态,此时尾电流峰值即为加药后电流值。达到稳定态势以后如果以细胞外液灌流冲洗后hERG电流回复或接近加化合物之前的大小,则可以继续灌流测试其它浓度或化合物。30μM Quinidine(奎尼丁)被用于实验中作为阳性对照以保证所使用的细胞反应正常。
本研究通过测量对照组与化合物处理组的电流最大值,计算处理组最大电流值所占对照组最大电流值的比率,评估待测化合物在测试浓度下对hERG钾离子通道的抑制作用。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (9)
1.化合物,其为以下结构或所示结构的立体异构体、几何异构体、互变异构体、药学上可接受的盐:
2.一种药物组合物,其包含权利要求1所述的化合物;其进一步包含药学上可接受的辅剂。
3.权利要求1所述的化合物或权利要求2所述的药物组合物在制备用于治疗和/或预防下述疾病的药物中的用途:心力衰竭、心绞痛、高血压、肾病、血栓栓塞疾病、男性性功能障碍、镰状细胞贫血、贲门弛缓不能、或纤维化疾病。
4.权利要求1所述的化合物或权利要求2所述的药物组合物在制备用于治疗和/或预防肺动脉高压的药物中的用途。
5.权利要求1所述的化合物或权利要求2所述的药物组合物在制备用于治疗和/或预防动脉硬化的药物中的用途。
6.权利要求1所述的化合物或权利要求2所述的药物组合物在制备药物中的用途,所述药物用作可溶性鸟苷酸环化酶刺激剂。
7.权利要求1所述的化合物或权利要求2所述的药物组合物在制备用于治疗和/或预防缺血症的药物中的用途。
8.权利要求1所述的化合物或权利要求2所述的药物组合物在制备用于治疗和/或预防血管疾病的药物中的用途。
9.权利要求1所述的化合物或权利要求2所述的药物组合物在制备用于治疗和/或预防系统性硬化症的药物中的用途。
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