CN109721596B - 苯基取代的二氢吡啶类化合物及其用途 - Google Patents
苯基取代的二氢吡啶类化合物及其用途 Download PDFInfo
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- CN109721596B CN109721596B CN201711020822.6A CN201711020822A CN109721596B CN 109721596 B CN109721596 B CN 109721596B CN 201711020822 A CN201711020822 A CN 201711020822A CN 109721596 B CN109721596 B CN 109721596B
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Abstract
本发明涉及一种苯基取代的二氢吡啶类化合物及其用途,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盐皮质激素受体拮抗剂。
Description
技术领域
本发明属于医药技术领域,具体涉及苯基取代的二氢吡啶化合物及其用途,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盐皮质激素受体拮抗剂。
背景技术
盐皮质激素受体(Mineralocorticoid Receptor,MR)是醛甾酮活化的核激素受体,其调节许多涉及电解质体内平衡和心血管疾病的基因的表达。循环醛甾酮的增加,通过其对尿钠排泄的影响而提高血压,同时潜在地对脑、心脏和血管系统造成影响。另外,醛甾酮过多症与许多导致肾和心血管疾病的疾病生理过程有关。尽管醛甾酮过多症通常由产生醛甾酮的腺瘤所引起,但顽固性高血压的患者的醛甾酮水平常常升高,通常称为“醛甾酮逃逸”,这是由于血清钾含量提高或残留的AT1R活性所致。醛甾酮过多症和醛甾酮逃逸典型地导致MR活性提高,已经证明,MR拮抗剂可作为有效的抗高血压剂,并且还可以有效的治疗心力衰竭和原发性醛甾酮增多症。
醛甾酮是形成于肾上腺皮质中的甾类激素。它的产生极大地取决于肾血流量而被间接地调节。肾血流量的任何减少都导致肾中的酶肾素释放并进入循环血液。这进而激活血管紧张素II的形成,其一方面对动脉血管具有收缩作用,但是另一方面也刺激肾上腺皮质中醛甾酮的形成。由此,肾用作血液循环中血压传感器,和由此间接用作体积传感器,且经肾素-血管紧张素-醛甾酮体系抵消体积的严重损失,这一方面是通过增加血液压力(血管紧张素II效果),另一方面通过增加肾中钠和水的再吸收来重新平衡血管系统的填充状态(醛甾酮效果)来实现。
该控制系统可能以各种方式发病而受损。例如,肾血流量的慢性减少(例如,由于心力衰竭和由此引起的静脉系中血液阻塞)导致慢性地过量地释放醛甾酮。继之以血容量的膨胀和由此通过增多地供应血容量至心脏而增加了心脏的虛弱。肺中血液的阻塞连同呼吸急促和形成肢体浮肿,并且腹水和胸膜腔积液可能由此产生;肾血流量进一步下降。另外,过量的醛甾酮效果导致血液和细胞外液中钾浓度减少。在以前已经以其它方式受损的心肌中,如果存在低于临界最小值水平的偏差则可能诱发致命的心脏心律不齐。这很可能是患有心力衰竭的患者中经常出现的心源性猝死的主要起因之一。
另外,也有报道认为醛甾酮决定着典型地要在心力衰竭中观察的许多心肌重塑过程。由此,醛甾酮过多症是心力衰竭(其可以最初是由各种类型的损伤例如心肌梗死、心肌炎症或高血压而诱发)的发病机理和预后的决定性组分。该假设得到如下事实的支持:在对患有慢性心力衰竭和后急性心肌梗塞的患者群进行的通过使用醛甾酮拮抗剂的广泛临床研究中,整体死亡率显著减少(B.Pitt,F.Zannad,W.J.Remme等,N.Engl.J.Med.ML 709-717(1999);B.Pitt,W.Remme,F.Zannad等,N.Engl.J.Med 1309-1321(2003))。
另外,在内脏组织中,例如肾和肠管,MR在对醛甾酮响应过程中调节钠潴留、钾排出和水平衡。MR在脑中的表达也似乎起到控制神经元兴奋性、下丘脑-垂体肾上腺轴的负反馈调控和行为表现的认知方面的作用(Castren等人,J.of Neuroendocrinology,3,461-66(1993))。
醛甾酮水平提高或过度刺激盐皮质激素受体与一些生理失调或病理性的疾病状态有关,包括康恩(氏)综合征、原发性和继发性醛甾酮过多症、钠潴留增加、镁和钾排出增加(多尿)、水滞留增加、高血压症(孤立的收缩期高血压症和组合形式的收缩期/舒张期高血压症)、心律失常、心肌纤维化、心肌梗塞、巴特氏综合征和与过量的儿茶酚胺水平相关的病症。(Hadley,M.E.,ENDOCRINOLOGY,2nd Ed.,pp366-81,(1988);以及Brilla等人,Journal of Molecular and Cellular Cardiology,25(5),pp563-75(1993))。起到MR拮抗剂作用的化合物和/或药物组合物对于任何上述病症具有治疗价值。
尽管盐皮质激素受体拮抗剂在治疗高血压症和心力衰竭方面的进展很显著,但护理的现行标准只是接近最佳,并且对于其它治疗/药理干预还存在明显未满足的医学需要。本发明通过提供可以用于治疗或预防高血压症、心力衰竭、其它心血管病症及其它醛甾酮病症的化合物和组合物而解决了那些需要。
发明摘要
本发明提供一种具有盐皮质激素受体(MR)拮抗作用的苯基取代的二氢吡啶类化合物及其药物组合物,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、预防或减轻患者醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭和中风等疾病。
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,
各R1、R2、R3和R4独立地为H、D、卤素、氨基、羟基、巯基、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氨基、羧基、C1-6烷酰基、C1-6烷基磺酰基、氨基酰基、氨基磺酰基、C3-6环烷基、C6-10芳基、3-8个原子组成的杂环基或5-10个原子组成的杂芳基;
R5为氰基或-C(=O)NRaRb;
R6为H、D、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、3-8个原子组成的杂环基或3-8个原子组成的杂芳基;
R7为H、D、氰基、C1-6烷酰基、C1-6烷氧基酰基、羧基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或C1-6烷氨基;
R8为H、D、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氨基、C1-6烷酰基、C1-6烷氧基酰基、羧基、C3-6环烷基、C6-10芳基、3-8个原子组成的杂环基或3-8个原子组成的杂芳基;
各Ra和Rb独立地为H、C1-6烷基、C1-6卤代烷基、C3-6环烷基、C6-10芳基、3-8个原子组成的杂环基或3-8个原子组成的杂芳基。
在一些实施例中,各R1、R2、R3和R4独立地为H、D、F、Cl、Br、氨基、羟基、巯基、氰基、硝基、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、C1-4烷氨基、羧基、C1-4烷酰基、C1-4烷基磺酰基、氨基酰基、氨基磺酰基、C5-6环烷基、C6-10芳基、5-6个原子组成的杂环基或5-6个原子组成的杂芳基。
在一些实施例中,各R1、R2、R3和R4独立地为H、D、氨基、羟基、巯基、氰基、硝基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基、二甲基氨基、羧基、甲基酰基、乙基酰基、甲基磺酰基、氨基酰基或氨基磺酰基。
在一些实施例中,R5为氰基或-C(=O)NH2。
在一些实施例中,R6为H、D、C1-4烷基或C1-4卤代烷基。
在一些实施例中,R6为H、D、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基、二甲基氨基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、吡咯基、噻唑基、吡唑基或嘧啶基。
在一些实施例中,R7为H、D、氰基、C1-4烷酰基、C1-4烷氧基酰基(即,-C(=O)OR7a,其中,R7a为C1-4烷基)、羧基、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基或C1-4烷氨基。
在一些实施例中,R7为H、D、氰基、甲基酰基、乙基酰基、丙基酰基、甲氧基酰基、乙氧基酰基、丙氧基酰基、羧基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基或二甲基氨基。
在一些实施例中,R8为H、D、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、C3-6环烷基、C6-10芳基、3-6个原子组成的杂环基或3-6个原子组成的杂芳基。
在一些实施例中,R8为H、D、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、二氟甲基、一氟甲基、2,2-二氟乙基、1,2-二氟乙基、三氟乙基、三氟甲氧基、二氟甲氧基、一氟甲氧基、甲基氨基、二甲基氨基、甲基酰基、乙基酰基、甲氧基酰基、乙氧基酰基、羧基、环丙基、环丁基、环戊基、环己基、苯基、萘基、环氧乙基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、吡咯基、噻唑基、吡唑基或嘧啶基。
在一些实施例中,本发明所述的化合物为式(II)所示的化合物或式(II)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,R7a为C1-4烷基;R8具有本发明所描述的含义。
在一些实施例中,本发明所述的化合物为以下其中之一的化合物,
或其立体异构体、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。
在一些实施例中,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。
在一些实施例中,本发明所述的药物组合物进一步包含一种或多种其他活性成分,所述其他活性成分选自ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐和抗血栓形成剂。
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,所述药物用于治疗、预防或减轻患者醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭和中风。
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,所述药物用作用作盐皮质激素受体拮抗剂。
本发明详细说明书
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。
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。
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”特指独立公开的甲基、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。
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,丙氧基(包括1-丙氧基或2-丙氧基),丁氧基(包括正丁氧基、异丁氧基、仲丁氧基、叔丁氧基)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“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”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。术语“杂环基”可以与术语“杂环”交换使用。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。
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。除非另外说明,基团“C6-10芳基”表示含有6-10个环碳原子的芳基基团。
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1、2、3或4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,杂芳基为5-10个原子组成的杂芳基,表示杂芳基含有1-9个环碳原子和1、2、3或4个选自O、S和N的环杂原子;在另一些实施方案中,杂芳基为5-6个原子组成的杂芳基,表示杂芳基含有1-5个环碳原子和1、2、3或4个选自O、S和N的环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(包括噻唑-5-基噻唑-2-基或噻唑-4-基)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“3-8个原子组成的”、“5-10个原子组成的”或“5-6个原子组成的”表示所述环状基团由3-8、5-10或5-6个环原子所组成,所述的环原子包括碳原子或O、N、S、P等杂原子。
术语“烷酰基”表示-C(=O)-烷基,其中,所述烷基具有如本发明所述的含义,这样的实例包括,但并不限于,甲基酰基(-C(=O)CH3)、乙基酰基(-C(=O)CH2CH3)、等等。
术语“烷氧酰基”表示-C(=O)-R,其中,R为烷氧基,所述烷氧基具有如本发明所述的含义,这样的实例包括,但并不限于,甲氧基酰基(-C(=O)OCH3)、乙氧基酰基(-C(=O)OCH2CH3)等等。
术语“烷基磺酰基”表示-S(=O)2-烷基,其中,所述烷基具有如本发明所述的含义,这样的实例包括,但并不限于,甲基磺酰基(-S(=O)2CH3)、乙基磺酰基(-S(=O)2CH2CH3)等等。
术语“氨基磺酰基”表示-S(=O)2NH2;术语“氨基酰基”表示-C(=O)NH2。
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的不适当的反应,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。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式(I)所示的化合物。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 as Novel DeliverySystems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,BioreversibleCarriers in Drug Design,American Pharmaceutical Association and PergamonPress,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,NatureReview Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs ofPhosphates 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。本发明式(I)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,均指代本发明中式(I)或式(II)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。同位素富集的式(I)所示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式(I)或式(II)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。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)。
本发明所述化合物竞争性地拮抗醛甾酮受体(MR),并因此它们可以是治疗和预防与醛甾酮水平提高相关的病症的有用药剂。
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与盐皮质激素受体或醛甾酮相关的疾病,包括那些本发明所描述的疾病。本发明包含药物组合物,该药物组合物包括式(I)或式(II)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。
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式(I)或式(II)所示化合物的中间体或式(I)或式(II)所示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MR拮抗活性、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。
本发明化合物的药物组合物、制剂、给药和用途
另一方面,本发明的药物组合物的特点包括式(I)或式(II)所示的苯基取代的二氢吡啶类化合物,本发明所列出的化合物,或实施例1-3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盐皮质激素受体或醛甾酮相关的疾病。
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。
本发明的化合物作为盐皮质激素受体的拮抗剂且显示出不能预知的有价值药理学作用范围。它们因此适于用作用于治疗和/或预防人类和动物疾病的药物。
本发明的化合物适于预防和/或治疗各种病症和疾病的相关状况,特别是特征在于血浆醛甾酮浓度上升或者血浆醛甾酮浓度相对于血浆肾素浓度变化的病症、或与这些变化相关的病症。可被提及的实例是:自发原发性醛甾酮增多症,与肾上腺增生相关的醛甾酮过多症,肾上腺腺瘤和/或肾上腺癌,肝硬化相关的醛甾酮过多症,与心力衰竭相关的醛甾酮过多症,和与原发性高血压相关的(相对的)醛甾酮过多症。
由于其作用机理,本发明的化合物也适用于预防处于死于心源性猝死的增加风险中的患者的心源性猝死。这些特别地为患有如下病症之一的患者:原发性和继发性高血压,有或者没有充血性心力衰竭的高血压心脏病,抵抗疗法的高血压,急性和慢性心力衰竭,冠心病,稳定性和不稳定性心绞痛,心肌缺血,心肌梗死,扩张型心肌病,先天的原发性心肌病(比如Bmgada综合征),通过南美洲锥虫病诱发的心肌病,休克,动脉硬化,心房和心室紊乱心律,瞬时和缺血性发作,中风,炎性的心血管病症,周围和心脏血管病症,外周血流扰动,动脉闭塞疾病比如间歇性跛行,无症状的左心室官能障碍,心肌炎,心脏肥大变化,肺动脉高血压,冠状动脉和外周动脉痉挛,血栓形成,血栓栓塞性病症和血管炎。
本发明的化合物另外可以用于预防和/或治疗浮肿形成,例如肺水肿,肾原性水肿或心力衰竭相关的浮肺,和再狭窄比如在血栓溶解疗法,经皮的穿腔血管成形术(PTA)和冠状血管成形术(PTCA),心脏移植和旁路操作之后。
本发明的化合物进一步适于用作贫钾利尿剂和用于治疗电解质紊乱比如血钙过多,高钠血或低钾血。
本发明的化合物同样适合治疗肾病症比如急性和慢性肾衰竭,高血压肾病,动脉硬化肾炎(慢性的和间质性的),肾硬化,慢性肾衰竭和膀胱肾病症,用于预防肾损伤(例如由与器官移植有关的环孢菌素A的免疫抑制剂引起的肾损伤)和用于肾癌。
本发明的化合物可以另外用于预防和/或治疗糖尿病和糖尿病后遗症,比如肾病。
本发明的化合物可以进一步用于预防和/或治疗的微白蛋白尿,例如由糖尿病或高血压所引起,和蛋白尿。
本发明的化合物也适合预防和/或治疗与血浆糖皮质激素浓度增加或与组织(例如心脏)中糖皮质激素浓度局部增加关联的病症。可辟皮提及的实例是:导致糖皮质激素过量产生的肾上腺功能紊乱(库兴氏综合征),导致糖皮质激素过量产生的肾上腺皮质肿瘤,和垂体瘤,其自发产生ACTH(促肾上腺皮质激素)和由此导致肾上腺增生且结果产生库兴氏病。
本发明的化合物可以另外用于预防和/或治疗肥胖,新陈代谢综合征和阻塞性睡眠呼吸暂停。
本发明的化合物可以进一步用于预防和/或治疗例如由病毒,螺旋体,真菌,细菌或分枝杆菌引起的炎性病症,和病原不明的炎性病症,比如多发性关节炎,红斑狼疮,关节周围炎或多动脉炎,皮肌炎,硬皮病和结节病。
本发明的化合物可以进一步用于治疗的中心神经病症比如抑都,焦虑状态和慢性的疼痛,特别是偏头痛,和用于神经变性的病症比如阿尔茨海默氏病和帕金森氏综合征。
本发明的化合物也适合预防和/或治疗血管损伤,例如在如下程序后比如经皮冠状动脉成形术(PTCA),支架移植,冠状血管透照法,旁路操作后的再阻塞或再狭窄,和用于内皮官能障碍,用于雷诺氏病,用于闭塞性血栓血管炎(Buerger's综合征)和用于耳鸣综合征。
本发明的化合物可以单独使用或,如果需要的话与其它活性成分结合使用。本发明进一步涉及包括至少一种本发明的化合物和一种或多种另一种活性成分(特别是用于治疗和/或预防上述病症)的药物。用于组合的合适的活性成分例如且优选地是:
·降低血压的活性成分,例如和优选地选自钙拮抗剂,血管紧张素II受体拮抗剂,ACE抑制剂,内皮缩血管肽拮抗剂,肾素抑制剂,α-受体阻断剂,β-肾腺素受体阻断剂和ρ-(Rho-)激酶抑制剂;
·利尿剂,特别是袢利尿药,噻嗪和噻嗪样的利尿剂;
·具有抗血栓形成效果的试剂,例如和优选地选自血小板凝聚抑制剂、抗凝剂或纤溶酶原物质;
·改变脂类代谢的活性成分,例如和优选地选自甲状腺受体激动剂,胆甾醇合成抑制剂例如且优选地HMG-辅酶A还原酶抑制剂或角鲨烯合成抑制剂,ACAT抑制剂,CETP抑制剂,MTP抑制剂,PPAR-α,PPAR-γ和/或PPAR-δ激动剂,胆甾醇吸收抑制剂,脂肪酶抑制剂,聚合胆汁吸附剂,胆汁酸再吸收抑制剂和脂蛋白(a)拮抗剂;
·有机硝酸盐/酯和NO供体比如硝普钠,硝酸甘油,单硝酸异山梨酯,二硝酸异山梨酯,吗多明或SIN-1,和吸入的NO;
·具有正性肌力作用的化合物,例如强心苷(地高辛),β-肾上腺素能和多巴胺能的激动剂比如异丙肾上腺素,肾上腺素,去甲肾上腺素,多巴胺和多巴酚丁胺;
·抑制环一磷酸鸟苷(cGMP)和/或环一磷酸腺苷(cAMP)的分解的化合物,例如磷酸二酯酶(PDE)1、2、3、4和/或5抑制剂,特别是PDE5抑制剂比如昔多芬,伐地那非和他达那非,和PDE3抑制剂比如氨力农和米力农;
·促尿钠排泄的肽比如心房促尿钠排泄的肽(ANP,阿那立肽),B型促尿钠排泄的肽或脑促尿钠排泄的肽(BNP,奈西立肽),C型促尿钠排泄的肽(CNP)和尿扩张素;
·钙敏化剂,例如且优选左西孟旦;
·NO-独立性但是血红素-依赖性鸟苷酸环化酶刺激剂,特別地比如描述于WO 00/06568,WO00/06569,WO02/42301和WO03/095451的化合物;
·NO-并且血红素-独立性的鸟苷酸环化酶活化剂,特别地比如描述于WO 01/19355,WO 01/19776,WO01/19778,WO 01/19780,WO 02/070462和WO 02/070510的化合物;
·人类嗜中性的弹性酶(HNE)的抑制剂,例如西维来司他或DX-890(Reltran);
·抑制信号转导级联的化合物,例如酪氨酸激酶抑制剂,特別地索拉非尼,伊马替尼,吉非替尼(Gefitinib)和埃罗替尼(Erlotinib);和/或
·影响心脏能量代谢的化合物,比如乙莫克舍,二氯乙酸盐,雷诺嗪或曲美他嗪。
本发明化合物还可以与上述其他活性成分组合给药。例如,在本发明的优选实施方案中,本发明的化合物与利尿剂(比如且优选腹安酸,布美他尼,托塞米,苄氟噻嗪,克尿塞,双氢氯噻嗪,甲氯噻嗪,泊利噻嗪,三氯噻嗪,氯噻酮,吲达帕胺,美托拉宗,喹乙宗,乙酰唑胺,二氯磺胺,醋甲唑胺,甘油,异山梨醇,甘露醇,阿米洛利或氨苯蝶啶)组合给药。
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)或式(II)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 Avance400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(CH<sub>3</sub>CN,0.1%HCOOH) | B(H<sub>2</sub>O,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:
DMSO-d6氘代二甲基亚砜;g克;mg毫克;mol摩尔;mmol毫摩尔;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,R8具有如本发明所述的含义。
反应方案
反应方案1
化合物(I-A)可以通过反应方案1所描述的方法制备得到。以2,2,6-三甲基-4H-1,3-二英-4-酮为起始原料与3-羟基丙腈反应得到乙酰乙酸2-氰基乙酯,然后与4-氰基-2-甲氧基苯甲醛反应得到式(A-iii)所示化合物。化合物(A-iii)与由式(A-i)化合物经氨化反应制备得到的式(A-ii)化合物在溶剂中反应得到式(A-iv)所示化合物,再经水解反应得到式(A-v)化合物,最后与含氨试剂反应得到式(I-A)化合物。
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 5-氨甲酰基-4-(4-氰基-2-甲氧苯基)-2-异丙基-6-甲基-1,4-二氢吡啶-3-羧酸乙酯
步骤1)乙酰乙酸2-氰基乙酯
2,2,6-三甲基-4H-1,3-二英-4-酮(15.50g,109.0mmol)、3-羟基丙腈(7.75g,109mmol)和邻二甲苯(20mL)在141℃下反应2小时。冷却至室温,旋转蒸掉溶剂,得到淡黄色油状物(16.63g,98.30%)。
MS(ESI,pos.ion)m/z:156.3(M+1).
步骤2)2-(4-氰基-2-甲氧基苯亚甲基)-3-氧代丁酸2-氰基乙酯
向4-氰基-2-甲氧基苯甲醛(2.00g,12.4mmol)和乙酰乙酸2-氰基乙酯(2.21g,14.2mmol)的二氯甲烷(35mL)溶液中加入醋酸(0.14mL,2.4mmol)和六氢吡啶(0.23mL,2.5mmol),然后分水回流23小时。冷却至室温,反应液依次用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥。抽滤,减压蒸掉溶剂,残渣经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)=3/1),得到淡黄色固体(2.98g,80.5%)。
MS(ESI,pos.ion)m/z:299.4(M+1).
步骤3)3-氨基-4-甲基-2-戊烯酸乙酯
向异丁酰乙酸乙酯(2.00g,12.6mmol)的甲苯(20mL)溶液中加入醋酸铵(1.95g,25.3mmol)和醋酸(0.65mL,11mmol),然后分水回流反应过夜。冷却至室温,加入乙酸乙酯稀释(50mL),依次用饱和碳酸氢钠水溶液(50mL)和饱和食盐水洗(50mL)洗涤,无水硫酸钠干燥。抽滤,减压蒸掉溶剂,残渣经真空干燥得到黄色油状物(1.76g,88.6%)。
MS(ESI,pos.ion)m/z:158.3(M+1).
步骤4)4-(4-氰基-2-甲氧苯基)-6-异丙基-2-甲基-1,4-二氢吡啶-3,5-二羧酸3-(2-氰基)乙酯-5-乙酯
2-(4-氰基-2-甲氧基苯亚甲基)-3-氧代丁酸2-氰基乙酯(0.60g,2.0mmol)和3-氨基-4-甲基-2-戊烯酸乙酯(0.38g,2.4mmol)在异丙醇(15mL)中回流过夜。冷却至室温,蒸掉溶剂,残渣经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)=3/1),得到淡黄色固体(0.77g,88%)。
MS(ESI,pos.ion)m/z:438.2(M+1).
步骤5)4-(4-氰基-2-甲氧苯基)-5-(乙氧羰基)-6-异丙基-2-甲基-1,4-二氢吡啶-3-羧酸
向4-(4-氰基-2-甲氧苯基)-6-异丙基-2-甲基-1,4-二氢吡啶-3,5-二羧酸3-(2-氰基)乙酯-5-乙酯(0.77g,1.8mmol)的乙二醇二甲醚(7.5mL)和水(2.5mL)的混合溶液中加入氢氧化钠(3.5mL,3.5mmol,1mol/L),室温下搅拌1小时。加水(60mL),然后用甲基叔丁基醚(30mL)洗一次,水相用1mol/L盐酸调pH=7,再用乙酸乙酯萃取(60mL×2),合并有机相,依次用水(50mL)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥。抽滤,减压蒸掉溶剂,残渣真空干燥得到黄色固体(0.66g,98%)。
MS(ESI,pos.ion)m/z:385.1(M+1).
步骤6)5-氨甲酰基-4-(4-氰基-2-甲氧苯基)-2-异丙基-6-甲基-1,4-二氢吡啶-3-羧酸乙酯
在0℃下,向4-(4-氰基-2-甲氧苯基)-5-(乙氧羰基)-6-异丙基-2-甲基-1,4-二氢吡啶-3-羧酸(0.20g,0.52mmol)和氯化铵(0.083g,1.6mmol)的N,N-二甲基甲酰胺溶液(9mL)中加入N,N-二异丙基乙胺(0.26mL,1.6mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.24g,0.63mmol),反应液室温搅拌过夜。加水淬灭(80mL),乙酸乙酯萃取(50mL×2),合并有机相,依次用水(50mL×2)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥。抽滤,蒸掉溶剂,残渣经硅胶柱层析纯化(二氯甲烷/乙酸乙酯(v/v)=4/1),得到白色固体(0.065g,33%)。
MS(ESI,pos.ion)m/z:384.3(M+1);
1H NMR(400MHz,DMSO-d6)δ(ppm)7.74(s,1H),7.37–7.29(m,2H),7.21(d,J=7.8Hz,1H),6.72(s,2H),5.07(s,1H),4.12–4.00(m,1H),3.98–3.84(m,2H),3.80(s,3H),2.07(s,3H),1.18(d,J=7.1Hz,3H),1.12(d,J=7.0Hz,3H),1.04(t,J=7.1Hz,3H).
实施例2 5-氨甲酰基-4-(4-氰基-2-甲氧苯基)-6-甲基-2-(噻唑-2-基)-1,4-二氢吡啶-3-羧酸乙酯
步骤1)3-氧代-3-(噻唑-2-基)丙酸乙酯
在100mL双口瓶中加入碳酸二乙酯(40mL)和氢化钠(2.24g,56.0mmol,60mass%),缓慢滴加2-乙酰基噻唑(3.00g,23.6mmol),加毕,室温反应1小时,再升至90℃反应2小时。冷却至室温,将反应液倒入冰水(60mL)中,加入醋酸(3mL),乙酸乙酯萃取(90mL×2),合并有机相,依次用水(60mL)和饱和食盐水(60mL)洗涤,无水硫酸钠干燥。抽滤,蒸掉溶剂,残渣经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)=6/1),得到淡黄色油状物(2.51g,53.4%)。
MS(ESI,pos.ion)m/z:200.2(M+1).
步骤2)3-氨基-3-(噻唑-2-基)丙烯酸乙酯
在50mL单口瓶中加入3-氧代-3-(噻唑-2基)丙酸乙酯(0.30g,1.5mmol)、醋酸铵(0.46g,6.0mmol)和乙醇(10mL),混合物加热至回流过夜。冷却至室温,旋掉溶剂,残渣溶于乙酸乙酯(80mL)中,依次用水(80mL)和饱和食盐水(80mL)洗涤,无水硫酸钠干燥,残渣经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)=15/1),得到白色固体(0.22g,74%)。
MS(ESI,pos.ion)m/z:199.1(M+1).
步骤3)4-(4-氰基-2-甲氧苯基)-2-甲基-6-(噻唑-2-基)-1,4-二氢吡啶-3,5-二羧酸3-(2-氰基)乙酯-5-乙酯
在100mL单口瓶中加入2-(4-氰基-2-甲氧基苯亚甲基)-3-氧代丁酸2-氰基乙酯(0.33g,1.1mmol)、3-氨基-3-(噻唑-2基)丙烯酸乙酯(0.22g,1.1mmol)和异丙醇(10mL),混合物在氮气保护下加热至回流过夜。冷却至室温,蒸掉溶剂,残渣经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)=4/1),得到淡黄色固体(0.17g,32%)。
MS(ESI,pos.ion)m/z:479.2(M+1).
步骤4)4-(4-氰基-2-甲氧苯基)-5-(乙氧羰基)-2-甲基-6-(噻唑-2-基)-二氢吡啶-3-羧酸
在50mL单口瓶中加入4-(4-氰基-2-甲氧苯基)-2-甲基-6-(噻唑-2-基)-1,4-二氢吡啶-3,5-二羧酸3-(2-氰基)乙酯-5-乙酯(0.95g,2.0mmol)、乙二醇二甲醚(9mL)和水(3mL),然后滴加氢氧化钠水溶液(3.0mL,3.0mmol,1mol/L),室温搅拌半小时。加水(50mL)稀释,用甲基叔丁基醚洗(60mL×2),水相用2mol/L盐酸调pH=5,再用乙酸乙酯萃取(60mL×2),合并有机相,依次用水(80mL)和饱和食盐水(80mL)洗涤,无水硫酸钠干燥。抽滤,蒸掉溶剂,真空干燥得到黄色固体(0.79g,94%)。
MS(ESI,pos.ion)m/z:426.2(M+1).
步骤5)5-氨甲酰基-4-(4-氰基-2-甲氧苯基)-2-异丙基-6-甲基-1,4-二氢吡啶-3-羧酸乙酯
在50mL双口瓶中加入4-(4-氰基-2-甲氧苯基)-5-(乙氧羰基)-2-甲基-6-(噻唑-2-基)-二氢吡啶-3-羧酸(0.15g,0.35mmol)、氯化铵(0.057g,1.1mmol)和无水N,N-二甲基甲酰胺(9mL),然后在0℃下加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.16g,0.42mmol)和N,N-二异丙基乙胺(0.17mL,1.0mmol),混合溶液升至室温搅拌过夜。加水(50mL)淬灭反应,乙酸乙酯萃取(40mL×2),合并有机相,依次用水(50mL)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥,残渣经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)=60/1),得到黄色固体(0.095g,63%)。
MS(ESI,pos.ion)m/z:425.1(M+1);
1H NMR(400MHz,DMSO-d6)δ(ppm)8.91(s,1H),7.93(s,2H),7.40(d,J=10.8Hz,2H),7.34(d,J=7.8Hz,1H),6.91(d,J=49.1Hz,2H),5.18(s,1H),3.82(s,3H),3.79–3.68(m,2H),2.04(s,3H),0.83(t,J=7.1Hz,3H).
实施例3 5-氨甲酰基-4-(4-氰基-2-甲氧苯基)-6-甲基-2-(噻唑-5-基)-1,4-二氢吡啶-3-羧酸乙酯
步骤1)3-氧代-3-(噻唑-5-基)丙酸乙酯
在100mL双口瓶中加入噻唑-5-甲酸(2.00g,15.5mmol)和无水四氢呋喃(40mL),在0℃下加入N,N'-羰基二咪唑(2.76g,17.0mmol),然后升至室温搅拌2小时。加入丙二酸单乙酯钾盐(2.90g,17.0mmol)和氯化镁(1.62g,17.0mmol),加热至60℃反应过夜。冷却至室温,加水淬灭,用2mol/L盐酸调pH=5,乙酸乙酯萃取(90mL×2),合并有机相,依次用水(60mL)和饱和食盐水(60mL)洗涤,无水硫酸钠干燥。抽滤,蒸掉溶剂,残渣经硅胶柱层析纯化(二氯甲烷/乙酸乙酯(v/v)=20/1),得到淡黄色油状物(2.48g,80.4%)。
MS(ESI,pos.ion)m/z:200.0(M+1).
步骤2)3-氨基-3-(噻唑-5-基)丙烯酸乙酯
在50mL单口瓶中加入3-氧代-3-(噻唑-5-基)丙酸乙酯(0.67g,3.4mmol)、醋酸铵(1.00g,13.0mmol)和乙醇(12mL),混合物加热至回流过夜。冷却至室温,减压蒸掉溶剂,残渣溶于乙酸乙酯(50mL)中,依次用水(50mL)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥。抽滤,减压蒸掉溶剂,残渣经硅胶柱层析纯化(二氯甲烷/乙酸乙酯(v/v)=20/1),得到白色固体(0.61g,91%)。
MS(ESI,pos.ion)m/z:199.0(M+1).
步骤3)4-(4-氰基-2-甲氧苯基)-2-甲基-6-(噻唑-5-基)-1,4-二氢吡啶-3,5-二羧酸3-(2-氰基)乙酯-5-乙酯
在50mL单口瓶中加入2-(4-氰基-2-甲氧基苯亚甲基)-3-氧代丁酸2-氰基乙酯(1.50g,5.03mmol)、3-氨基-3-(噻唑-5-基)丙烯酸乙酯(1.00g,5.04mmol)和异丙醇(30mL),混合物加热至回流过夜。冷却至室温,蒸掉溶剂,残渣经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)=50/1),得到淡黄色固体(0.93g,39%)。
步骤4)4-(4-氰基-2-甲氧苯基)-5-(乙氧羰基)-2-甲基-6-(噻唑-5-基)-1,4-二氢吡啶-3-羧酸
在50mL单口瓶中加入4-(4-氰基-2-甲氧苯基)-2-甲基-6-(噻唑-5-基)-1,4-二氢吡啶-3,5-二羧酸3-(2-氰基)乙酯-5-乙酯(0.079g,0.17mmol)、乙二醇单甲醚(1.5mL)和水(0.5mL),再加入氢氧化钠水溶液(0.50mL,0.50mmol,1mol/L),室温搅拌30分钟。加水(40mL)淬灭,用甲基叔丁基醚(40mL)洗涤,水层用1mol/L升盐酸调pH=6,再用乙酸乙酯萃取(30mL×2),合并有机相,依次用水(40mL)和饱和食盐水(40mL)洗涤,无水硫酸钠干燥。抽滤,蒸掉溶剂,真空干燥得到淡黄色固体(0.062g,88%)。
步骤5)5-氨甲酰基-4-(4-氰基-2-甲氧苯基)-6-甲基-2-(噻唑-5-基)-1,4-二氢吡啶-3-羧酸乙酯
在50mL双口瓶中加入4-(4-氰基-2-甲氧苯基)-5-(乙氧羰基)-2-甲基-6-(噻唑-5-基)-1,4-二氢吡啶-3-羧酸(0.13g,0.31mmol)、氯化铵(0.065g,1.2mmol)和N,N-二甲基甲酰胺(8mL),在0℃下加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.14g,0.37mmol)和三乙胺(0.13mL,0.94mmol),室温搅拌过夜。加水(60mL)淬灭,乙酸乙酯萃取(30mL×2),合并有机相,依次用水(50mL)和饱和食盐水(50mL)洗,无水硫酸钠干燥。抽滤,蒸掉溶剂,残渣经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)=30/1),得到淡黄色固体(0.062g,48%)。
MS(ESI,pos.ion)m/z:425.1(M+1).
1H NMR(400MHz,DMSO-d6)δ(ppm)9.19(s,1H),8.79(s,1H),7.94(s,1H),7.44–7.35(m,2H),7.32(d,J=7.8Hz,1H),6.88(d,J=33.4Hz,2H),5.18(s,1H),3.82(s,3H),3.75(q,J=7.0Hz,2H),2.03(s,3H),0.84(t,J=7.0Hz,3H).
实施例4体外活性测试
实验原理:
利用荧光素酶与底物结合发生化学发光反应的特性,将含有盐皮质激素受体配体结合结构域(LBD)的Gal4DNA结合结构域(DBD)融合的质粒及Gal4UAS(上游激活序列)控制下的萤火虫荧光素酶报告基因质粒转染人胚肾细胞(HEK293)。通过萤火虫荧光素酶活性的高低判断刺激前后或不同刺激对盐皮质激素受体活性的影响。同时,为了减少内在的变化因素对实验准确性的影响,将带有海肾荧光素酶基因的质粒作为对照质粒转染细胞,提供转录活力的内对照,使测试结果不受实验条件变化的干扰。
实验方法:
1)胰蛋白酶消化后收集HEK293细胞并将细胞密度调整至500,000个/ml;
2)向细胞悬浮液中加入FuGENE HD转染试剂;
3)将上述细胞悬浮液按照100μL/孔接种至96孔细胞培养板中,37℃、5%CO2条件下培养24小时;
4)将一系列浓度的待测化合物溶液及EC80浓度的激动剂醛甾酮加入到各孔中,孵育18小时;
5)通过Promega双重荧光素酶报告基因测试系统检测萤火虫及海肾荧光素酶信号。
结果处理:
1)得到萤火虫荧光素酶信号(F)及海肾荧光素酶信号(R)后,使用海肾荧光素酶信号进行校正,即使用F/R值进行后续抑制率计算;
2)%抑制率=(Max-X)/(Max-Min)×100%,其中Max为阳性对照孔F/R值,Min为阴性对照孔F/R值,X为不同浓度待测化合物孔F/R值;
3)通过GraphPrism 5.0作图软件进行IC50计算。
实验结果:
表2
实施例编号 | MR IC<sub>50</sub>(nM) |
实施例1 | 24.7 |
结论:
由表2的实验结果可知,本发明所述化合物(例如,本发明所述实施例1)具有良好的盐皮质激素受体(MR)拮抗活性,其可作为有效的盐皮质激素受体拮抗剂。
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)
2.根据权利要求1所述的化合物,其中,各R1、R3和R4独立地为H或D;
R2为甲氧基、乙氧基、丙氧基或丁氧基。
3.根据权利要求1所述的化合物,其中,R6为甲基、乙基、丙基或丁基。
4.根据权利要求1所述的化合物,其中,R8为甲基、乙基、丙基或丁基。
6.一种药物组合物,其包含权利要求1-5任意一项所述的化合物;任选地,其进一步包含药学上可接受的辅剂。
7.根据权利要求6所述的药物组合物,其进一步包含一种或多种其他活性成分,所述其他活性成分选自ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐和抗血栓形成剂。
8.根据权利要求1-5任意一项所述的化合物或权利要求6或7所述的药物组合物在制备药物中的用途,其中,所述药物用于治疗、预防或减轻患者醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、肾衰竭和中风。
9.根据权利要求1-5任意一项所述的化合物或权利要求6或7所述的药物组合物在制备药物中的用途,其中,所述药物用作盐皮质激素受体拮抗剂。
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