CN108059635B - 噻吩衍生物 - Google Patents
噻吩衍生物 Download PDFInfo
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- CN108059635B CN108059635B CN201810075755.6A CN201810075755A CN108059635B CN 108059635 B CN108059635 B CN 108059635B CN 201810075755 A CN201810075755 A CN 201810075755A CN 108059635 B CN108059635 B CN 108059635B
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Abstract
Description
领域
本申请涉及有机化学与药物化学领域。
背景
TNFα是一种主要由单核噬菌细胞应答免疫刺激物时释放的细胞因子。TNFα能够促进细胞的分化、募集、增殖和蛋白质降解等大多数过程。在低水平下,TNFα具有防止传染物、肿瘤和组织损伤的保护作用。但TNFα释放过多也会引起疾病,如给予哺乳动物或人TNFα时,会引起或加重炎症、发烧、心血管作用、出血、凝血以及与急性感染和休克状态相类似的急性反应。动物体或人体内产生过量的或不受控制的TNFα常提示患有如下疾病:内毒素血症和/或中毒休克综合症、恶病质、成人呼吸紧张综合症、癌症(如实体瘤和血液性肿瘤)、心脏病(如充血性心力衰竭)、病毒感染、遗传疾病、炎性疾病、变应性疾病或自身免疫疾病。
癌症是具有特别破坏性的疾病,血液中TNFα水平的提高预示存在患有癌症或癌症扩散的危险。通常,癌细胞不能在健康主体的循环系统中存活,其中一个原因在于血管内壁是瘤细胞外渗的屏障。研究表明,内皮细胞上的ELAM-1能介导促进结肠癌细胞黏附在用细胞因子处理的内皮上。
环腺苷酸(cAMP)也在许多疾病和病症中起作用,例如但不限于哮喘、炎症及其它病症。发炎时白细胞中cAMP浓度的升高抑制了白细胞的激活,随后释放出包括TNFα和NF-κB等炎症调控因子。cAMP水平提高也会导致呼吸道平滑肌的松弛。
cAMP失活的主要细胞机制是由于被称为环核苷酸磷酸二酯酶(PDE)的一族同工酶破坏了cAMP。已知有11个PDE家族成员。迄今,已证实抑制PDE4酶对抑制炎症介质的释放及对松弛呼吸道平滑肌特别有效,因此PDE4酶已成为热门的药物靶点之一。抑制PDE4酶,导致cAMP水平的升高,从而调节TNFα水平,达到治疗如脓毒性休克、败血症、内毒素性休克、血液性休克、脓毒病综合症、局部缺血再灌注后损伤、疟疾分枝杆菌感染、脑膜炎、牛皮癣、充血性心力衰竭、纤维化疾病、恶病质、移植排斥、肿瘤、自免疫失调类疾病、AIDS机会感染、风湿性关节炎、风湿性脊椎炎、骨关节炎、其他炎症性疾病、克罗恩病、溃疡性结肠炎、多发性硬化、系统性红斑狼疮、麻风性结节性红斑、辐射损伤、高氧肺损伤等炎症、感染性疾病、免疫性疾病或其它恶性疾病。
目前的PDE4酶抑制剂在临床表现出对数种炎症性疾病有效,包括哮喘、慢性阻塞性肺病(COPD)、过敏性鼻炎和过敏性皮炎等。在动物模型上对其他多种疾病包括关节炎和败血症等也有效,但是都由于不能特异性的抑制PDE4酶而具有恶心、呕吐等不良反应,使得它们的临床应用受到限制。因此,特异性的PDE4酶抑制剂有可能降低药物的不良反应并保持药物的抗炎活性。
概述
一方面,本申请涉及通式(I)化合物、其立体异构体、其药物可接受的盐:
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
另一方面,本申请涉及通式(I)化合物的制备方法,所述方法包括将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物:
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
再一方面,本申请涉及药物组合物,其包括药物可接受的载体以及治疗有效量的通式(I)化合物、其立体异构体、其药物可接受的盐,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
又一方面,本申请涉及通式(I)化合物、其立体异构体、其药物可接受的盐在制备降低PDE4酶活性的药物中的用途,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
再一方面,本申请涉及通式(I)化合物、其立体异构体、其药物可接受的盐在制备治疗PDE4酶介导的疾病或疾病状态的药物中的用途,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
另一方面,本申请涉及药物组合物在制备治疗PDE4酶介导的疾病或疾病状态的药物中的用途,其中所述药物组合物包括药物可接受的载体以及治疗有效量的通式(I)化合物、其立体异构体、其药物可接受的盐,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
详述
在以下的说明中,包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而,相关领域的技术人员会认识到,不采用一个或多个这些具体的细节,而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求,在整个说明书和其后的权利要求书中,词语“包括”和“包含”应解释为开放式的、含括式的意义,即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此,在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外,具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
定义
由表明在所示化学基团中找到的碳原子总数的简化符号在前面标示本文中命名的某些化学基团。例如,C7-C12烷基描述具有总数为7至12个碳原子的如下定义的烷基,并且C4-C12环烃基烷基描述具有总数为4至12个碳原子的如下定义的环烃基烷基。简化符号中碳原子总数并不包含可能存在于所述基团的取代基中的碳。
因此,非另有相反的说明,否则说明书及所附权利要求中所用的下列术语具有以下的意思:
“羟基”是指-OH基团。
“氰基”指-CN基团。
“硝基”指-NO2基团。
本申请所用的术语“烃基”是指脂肪族烃基团。烃基部分可以是“饱和的烷基”基团,意为其不包含任何烯或炔部分。烃基部分还可以是“不饱和的烷基”部分,意为其包含至少一个烯或炔部分。“烯”部分是指由两至八个碳原子和至少一个碳-碳双键组成的基团,并且由单键与分子的其余部分连接的直链或支链烃链基团,例如乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等,并且“炔”部分是指由两至八个碳原子和至少一个碳-碳三键组成的基团,并且由单键与分子的其余部分连接的直链或支链烃链基团。烃基部分,无论饱和的或不饱和的,可以是支链的、直链的。
烃基基团可具有1至8个碳原子(在本申请中每次出现时,诸如“1至8”的数值范围是指给定范围中的每一整数;如“1至8”意为所述烃基基团可由1个碳原子、2个碳原子、3个碳原子等直至并包括8个碳原子,尽管本定义还涵盖未指定数值范围的术语“烃基”的出现)。
本申请所用的“烃氧基”是指通式-OR,其中R是上文所定义的烃基,如甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(异丙氧基)、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、叔戊氧基等等。
本申请所用的“烃硫基”是指通式-SR,其中R是上文所定义的烃基,如甲硫基、乙硫基、正丙硫基、1-甲基乙硫基(异丙硫基)、正丁硫基、异丁硫巯基、仲丁硫基、叔丁硫基等等。
本申请所用的“亚烃基”指仅由碳和氢组成的,并且具有一至八个碳原子,连接分子的其余部分与残基基团的直链或支链二价烃链,例如亚甲基、亚乙基、亚丙基、正亚丁基、亚乙烯基、亚丙烯基、正亚丁烯基。亚烷基链可以通过链中的一个碳或通过链中的任意二个碳与分子的其余部分和残基基团相连。
本申请所用的“芳基”是指具有完全离域的π电子体系的碳环(全碳)或两个或多个稠合环(共享两个相邻碳原子的环)。芳基基团包括但不限于芴基、苯基及萘基。。芳基基团例如可以具有五至十二个碳原子。
本申请所用的术语“卤素”指溴、氯、氟或碘。
“环烃基”指仅由碳和氢原子组成的,具有三至十个碳原子的,尤其具有三至六个碳原子的,并且其为饱和或不饱和的,并且通过单键与分子的其余部分相连的稳定的非芳香族单环或双环烃基团,例如环丙基、环丁基、环戊基、环己基、环癸基等。
本申请所用的“杂环烃基”指由碳原子和一至五个选自氮、氧和硫的杂原子组成的稳定的三至十二员的非芳香族环基团。这样的杂环基基团的实例包括但不限于二氧环戊基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、哌嗪基、4-哌啶酮基、吡咯烷基、吡唑烷基、噻唑烷基、四氢呋喃基、三噻烷基、四氢吡喃基、硫代吗啉基、噻吗啉基、1-氧代-硫代吗啉基和1,1-二氧代-硫代吗啉基。
“药物可接受的载体、稀释剂或赋形剂”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
“药物可接受的盐”包括“药物可以接受的酸加合盐”和“药物可以接受的碱加合盐”。
“药物可接受的酸加合盐”指保持游离碱的生物学有效性和性质的那些盐,所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的,所述无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等,所述有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
“药物可接受的碱加合盐”指保持游离酸的生物学有效性和性质的那些盐,所述碱加成盐是在生物学或其它方面合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。优选的无机盐为铵、钠、钾、钙及镁盐。由有机碱衍生的盐包括但不限于伯、仲和叔胺的盐、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂的盐,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲氨基乙醇、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
“药物组合物”指本申请化合物与通常被本领域所接受的将生物活化化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、稀释剂或赋形剂。
“治疗有效量”指当对哺乳动物例如人类给药时,本申请化合物足以有效治疗(如下定义)哺乳动物的例如人类的PDE4酶介导的疾病或疾病状态的量。根据化合物、疾病状态及其严重性、以及待治疗哺乳动物的年龄,构成“治疗有效量”的本申请化合物的量将会不同,但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本申请化合物的量。
本文所用的“进行治疗”或“治疗”涵盖患有相关疾病或病症的哺乳动物例如人类中治疗相关的疾病或疾病状态,并且包括:
(i)预防疾病或疾病状态在哺乳动物中发生,尤其是当该哺乳动物易感于所述疾病状态,但尚未被诊断出患有这种疾病状态时;
(ii)抑制疾病或疾病状态,即阻止其发生;或者
(iii)缓解疾病或疾病状态,即使疾病或疾病状态消退。
正如本文所用的那样,术语“疾病”和“疾病状态”可以相互交换使用,或者可以是不同的,因为特殊的疾病或疾病状态可能并没有已知的致病因子(因此不能用病因学解释),因此其不被公认为是疾病,而是被认为是不期望的疾病状态或病症,其中临床医生已经鉴定出或多或少的特定系列的症状。
本申请化合物或其药物可接受性盐可以含一个或多个不对称中心,并且因此可以产生对映异构体、非对映异构体、以及其它立体异构形式,可以根据绝对立体化学将其定义为(R)-或(S)-,或氨基酸的(D)-或(L)-。本申请旨在包括所有这些可能的异构体,以及其外消旋形式和光学纯的形式。可使用手性合成子(chiral synthon)或手性试剂制备旋光的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体,或使用常规技术进行拆分,如使用手性柱的HPLC。当本文所述的化合物含有烯双键或其它几何不对称中心时,除非另有说明,否则意味着化合物包括E和Z几何异构体。同样,还意味着包括所有的互变异构形式。
“立体异构体”指由相同的键键合的相同的原子组成的,但具有不可互换的不同三维结构的化合物。本申请涵盖各种立体异构体及其混合物。
具体实施方案
一方面,本申请涉及通式(I)化合物、其立体异构体、其药物可接受的盐:
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
在某些实施方案中,C1-C8烃基选自C1-C4烃基或C1-C6烃基。
在某些实施方案中,C1-C8烃氧基选自C1-C4烃氧基或C1-C6烃氧基。
在某些实施方案中,C1-C8烃硫基选自C1-C4烃硫基或C1-C6烃硫基。
在某些实施方案中,C3-C10环烃基选自C3-C6环烃基。
在某些实施方案中,R1和R2分别选自R1和R2分别选自氢、甲基、乙基、硝基、NH2、NHCH3、CH3C(O)NH、CH3CH2C(O)NH、CH3SO2NH或ClCH2C(O)NH。
在某些实施方案中,R3选自C1-C8烃基。
在某些实施方案中,R3选自甲基、乙基或丙基。
在某些实施方案中,R4和R5分别选自C1-C8烃氧基、卤素取代的C1-C8烃氧基、C5-C12芳基氧基。
在某些实施方案中,R4和R5分别选自甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、丙氧基或苄氧基。
在某些实施方案中,R8选自氢、甲基、乙基、二甲氨基甲基、二乙氨基甲基、哌啶基甲基或吗啡啉基甲基。
在某些实施方案中,通式(I)化合物选自:
N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
(S)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
(R)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
N-(5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
N-(5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
(S)-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
(R)-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
(S)-5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
(S)-5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
N-(5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-甲胺基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
2-氯-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)甲磺酰胺,
(S)-1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
(R)-1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮,
N-(5-(1-(3-乙氧基-4-二氟甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
N-(5-(1-(3-乙氧基-4-三氟甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
(S)-N-(5-(1-(3-乙氧基-4-二氟甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
(R)-N-(5-(1-(3-乙氧基-4-二氟甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
(S)-N-(5-(1-(3-乙氧基-4-三氟甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
(R)-N-(5-(1-(3-乙氧基-4-三氟甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
N-(5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)丙酰胺,
2-(二甲胺基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
2-(二乙胺基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,
2-(哌啶基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺,或
2-(吗啡啉基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺。
另一方面,本申请涉及通式(I)化合物的制备方法,所述方法包括将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物:
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
在某些实施方案中,在将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物的方法中加入三级胺作为催化剂
能够用于本申请的合适的催化剂的实例包括但不限于吡啶、4-二甲胺基吡啶、4-吡咯烷基吡啶及其一种或一种以上的混合物。
在某些实施方案中,在将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物的方法中还可以加入脱水剂。
能够用于本申请的合适的脱水剂的实例包括但不限于DCC、EDC·HCl、CDI、DIC、偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、偶氮二甲酸二苄酯及其一种或一种以上的混合物。
在某些实施方案中,在将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物的方法中还可以加入活化剂。
能够用于本申请的合适的活化剂的实例包括但不限于N-羟基琥珀酰亚胺、HOBt、HOAt、BOP、Cl-HOBt、DEPBT、HATU、HBTU、HCTU、HOOBt、PyBOP、TATU、TBTU及其一种或一种以上的混合物。
在某些实施方案中,将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物的方法是在有机溶剂中进行的。
能够用于本申请的合适的有机溶剂的实例包括但不限于氯仿、二氯甲烷、二氯乙烷、四氢呋喃、乙醚、异丙醚、乙酸乙酯、乙二醇二甲醚、乙二醇二乙醚、苯、甲苯、正己烷、环己烷、DMF、DMSO、甲基乙基醚、甲基丙基醚、甲基叔丁基醚、丙酮、丁酮、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯、乙酸甲酯、乙酸丙酯、乙酸丁酯中及其一种或一种以上的混合物。
在某些实施方案中,在-10°-200℃下将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物。
在某些实施方案中,在-10°-150℃下将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物。
在某些实施方案中,将通式(A-III)化合物脱水得到通式(A-IV)化合物,
能够用于本申请的合适的脱水剂的实例包括但不限于乙酸酐、三氟乙酸酐及其混合物。
在某些实施方案中,将通式(A-III)化合物脱水得到通式(A-IV)化合物的反应是在有机溶剂中进行的。
能够用于本申请的合适的有机溶剂的实例包括但不限于氯仿、二氯甲烷、二氯乙烷、四氢呋喃、乙醚、异丙醚、环己烷、正己烷、乙酸乙酯、乙二醇二甲醚、乙二醇二乙醚、苯、甲苯、DMF、DMSO、丙酮、丁酮、甲基乙基醚、甲基叔丁基醚、甲基丙基醚、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、乙酸、三氟乙酸中及其一种或一种以上的混合物。
在某些实施方案中,将通式(A-II)化合物在酸或碱的作用下得到通式(A-III)化合物,
能够用于本申请的合适的碱的实例包括但不限于氢氧化钠、氢氧化钾、氢氧化锂及其一种或一种以上的混合物。
能够用于本申请的合适的酸的实例包括但不限于盐酸、硫酸、磷酸、甲磺酸、乙磺酸或其一种或一种以上的混合物。
在某些实施方案中,将通式(A-II)化合物在酸或碱的作用下得到通式(A-III)化合物的反应是在溶剂中进行。
能够用于本申请的合适的溶剂的实例包括但不限于氯仿、二氯甲烷、二氯乙烷、四氢呋喃、乙醚、异丙醚、环己烷、正己烷、乙酸乙酯、乙二醇二甲醚、乙二醇二乙醚、苯、甲苯、DMF、DMSO、丙酮、丁酮、甲基乙基醚、甲基叔丁基醚、甲基丙基醚、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、乙酸、三氟乙酸、水及其一种或一种以上的混合物。
在某些实施方案中,在0°-200℃下将通式(A-II)化合物在酸或碱的作用下得到通式(A-III)化合物。
在某些实施方案中,在50°-200℃下将通式(A-II)化合物在酸或碱的作用下得到通式(A-III)化合物。
在某些实施方案中,在80°-180℃下将通式(A-II)化合物在酸或碱的作用下得到通式(A-III)化合物。
在某些实施方案中,将通式(A-I)化合物与氰化物反应得到通式(A-II)化合物,
能够用于本申请的合适的氰化物的实例包括但不限于氰化亚铜、氰化钠、氰化钾和氰化汞。
在某些实施方案中,将通式(A-I)化合物与氰化物反应得到通式(A-II)化合物的反应是在有机溶剂中进行。
能够用于本申请的合适的有机溶剂的实例包括但不限于DMF、DMSO、乙酰胺、N-甲基吡咯烷酮、二缩乙二醇二甲醚、二缩乙二醇二乙醚及其一种或一种以上的混合物。
在某些实施方案中,在50°-250℃下将通式(A-I)化合物与氰化物反应得到通式(A-II)化合物。
在某些实施方案中,在100°-250℃下将通式(A-I)化合物与氰化物反应得到通式(A-II)化合物。
在某些实施方案中,通式(A-VI)化合物在脱保护剂作用下得到通式(A-VII)化合物,
能够用于本申请的合适的脱保护剂的实例包括但不限于四丁基氟化铵、四乙基氟化铵、盐酸、硫酸、磷酸、硝酸、乙酸、三氟乙酸、甲酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸及其一种或一种以上的混合物。
在某些实施方案中,通式(A-VI)化合物在脱保护剂作用下得到通式(A-VII)化合物的反应是在溶剂中进行的。
能够用于本申请的合适的溶剂的实例包括但不限于氯仿、二氯甲烷、二氯乙烷、四氢呋喃、乙醚、异丙醚、乙酸乙酯、乙醇、甲醇、丙醇、丁醇、乙二醇、乙二醇二甲醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇二乙醚、苯、甲苯、正己烷、环己烷、DMF、DMSO、乙酸、三氟乙酸、甲基乙基醚、甲基丙基醚、甲基叔丁基醚、丙酮、丁酮、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、水及其一种或一种以上的混合物。
在某些实施方案中,在-20°-200℃下通式(A-VI)化合物在脱保护剂作用下得到通式(A-VII)化合物。
在某些实施方案中,在0°-200℃下通式(A-VI)化合物在脱保护剂作用下得到通式(A-VII)化合物。
在某些实施方案中,通式(A-V)化合物在强碱的作用下与CH3S(O)2R3和(R14R15R16Si)2NM反应得到通式(A-VII)化合物,
其中,CH3S(O)2R3中的R3所表示的基团与通式(I)化合物中的R3所表示基团相同,其中在(R14R15R16Si)2NM中的R14、R15或R16分别选自烃基或苯基,M选自钠、钾或锂。
能够用于本申请的合适的强碱的实例包括但不限于烷基锂、烷基钠、烷基钾、醇钠、醇钾、醇锂、烷基胺基钠、烷基胺基锂和烷基胺基钾。
能够用于本申请的合适的强碱的实例包括但不限于正丁基锂、叔丁基锂、甲基锂、乙基锂、甲醇钠、甲醇钾、甲醇锂、二甲基胺基锂、二乙基胺基锂、二丙基胺基锂、二异丙基胺基锂及其一种或一种以上的混合物
能够用于本申请的合适的(R14R15R16Si)2NM的实例包括但不限于双三甲基硅基胺基锂、双三乙基硅基胺基锂、双三丙基硅基胺基锂、双三异丙基硅基胺基锂、双(二甲基乙基硅基)胺基锂、双(二甲基丙基硅基)胺基锂、双(二甲基异丙基硅基)胺基锂、双(二甲基苯基硅基)胺基锂、双(二甲基苄基硅基)胺基锂、双(二乙基甲基硅基)胺基锂、双(二乙基丙基硅基)胺基锂、双(二乙基异丙基硅基)胺基锂、双(二乙基苯基硅基)胺基锂、双(二乙基苄基硅基)胺基锂、双(二异丙基甲基硅基)胺基锂、双(二异丙基乙基硅基)胺基锂、双(二异丙基苯基硅基)胺基锂、双(二异丙基苄基硅基)胺基锂、双三甲基硅基胺基钠、双三乙基硅基胺基钠、双三丙基硅基胺基钠、双三异丙基硅基胺基钠、双(二甲基乙基硅基)胺基钠、双(二甲基丙基硅基)胺基钠、双(二甲基异丙基硅基)胺基钠、双(二甲基苯基硅基)胺基钠、双(二甲基苄基硅基)胺基钠、双(二乙基甲基硅基)胺基钠、双(二乙基丙基硅基)胺基钠、双(二乙基异丙基硅基)胺基钠、双(二乙基苯基硅基)胺基钠、双(二乙基苄基硅基)胺基钠、双(二异丙基甲基硅基)胺基钠、双(二异丙基乙基硅基)胺基钠、双(二异丙基苯基硅基)胺基钠、双(二异丙基苄基硅基)胺基钠、双三甲基硅基胺基钾、双三乙基硅基胺基钾、双三丙基硅基胺基钾、双三异丙基硅基胺基钾、双(二甲基乙基硅基)胺基钾、双(二甲基丙基硅基)胺基钾、双(二甲基异丙基硅基)胺基钾、双(二甲基苯基硅基)胺基钾、双(二甲基苄基硅基)胺基钾、双(二乙基甲基硅基)胺基钾、双(二乙基丙基硅基)胺基钾、双(二乙基异丙基硅基)胺基钾、双(二乙基苯基硅基)胺基钾、双(二乙基苄基硅基)胺基钾、双(二异丙基甲基硅基)胺基钾、双(二异丙基乙基硅基)胺基钾、双(二异丙基苯基硅基)胺基钾或双(二异丙基苄基硅基)胺基钾。
在某些实施方案中,通式(A-V)化合物在强碱的作用下与CH3S(O)2R3和(R14R15R16Si)2NM反应得到通式(A-VII)化合物的反应是在催化剂的作用下进行的。
能够用于本申请的合适的催化剂的实例包括但不限于氟化剂。
能够用于本申请的合适的氟化剂的实例包括但不限于三氟化硼。
在某些实施方案中,在-100°-100℃通式(A-V)化合物在强碱的作用下与CH3S(O)2R3和(R14R15R16Si)2NM反应得到通式(A-VII)化合物。
在某些实施方案中,在-100°-50℃通式(A-V)化合物在强碱的作用下与CH3S(O)2R3和(R14R15R16Si)2NM反应得到通式(A-VII)化合物。
又一方面,本申请涉及通式(B-III)化合物的制备方法,所述方法包括将通式(B-II)化合物与通式R11-Y、(R12)2Y或Y-R13-Z化合物进行反应得到通式(B-III)化合物,
其中,
R1选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
在R11-Y中,R11选自C1-C8烃基、C5-C12芳基、C(O)R8或S(O)2R8,Y选自卤素、OMs或OTs;
在(R12)2Y中,R12选自C(O)R8,Y为O;
在Y-R13-Z中,R13选自1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,Y和Z分别选自卤素、OMs或OTs,X表示O、S或NR8。
在某些实施方案中,在将通式(B-II)化合物与通式R11-Y、(R12)2Y或Y-R13-Z化合物进行反应得到通式(B-III)化合物的反应中加入碱性试剂。
能够用于本申请的合适的碱性试剂的实例包括但不限于三乙胺、三甲胺、三丙胺、二异丙基乙基胺、吡啶、N-甲基吗啡啉、N-乙基吗啡啉、N-甲基哌啶、N-乙基哌啶、N-甲基吡咯烷、N-乙基吡咯烷、4-二甲胺基吡啶、4-吡咯烷基吡啶、2-甲基吡啶、3-甲基吡啶、4-甲基吡啶、2,6-二甲基吡啶、2,4,6-三甲基吡啶、氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠、碳酸钾、碳酸锂、碳酸铯、氢化钠、氢化钾、氢化锂、氢化铝锂、甲醇钠、甲醇钾、甲醇锂、乙醇钠、乙醇钾、乙醇锂、异丙醇钠、异丙醇钾、异丙醇锂、(R14R15R16Si)2NM、氨基钠、氨基锂、氨基钾及其一种或一种以上的混合物,其中在(R14R15R16Si)2NM中的R14、R15或R16分别选自C1-8烃基或苯基,M选自钠、钾或锂。
能够用于本申请的合适的(R14R15R16Si)2NM的实例包括但不限于双三甲基硅基胺基锂、双三乙基硅基胺基锂、双三丙基硅基胺基锂、双三异丙基硅基胺基锂、双(二甲基乙基硅基)胺基锂、双(二甲基丙基硅基)胺基锂、双(二甲基异丙基硅基)胺基锂、双(二甲基苯基硅基)胺基锂、双(二甲基苄基硅基)胺基锂、双(二乙基甲基硅基)胺基锂、双(二乙基丙基硅基)胺基锂、双(二乙基异丙基硅基)胺基锂、双(二乙基苯基硅基)胺基锂、双(二乙基苄基硅基)胺基锂、双(二异丙基甲基硅基)胺基锂、双(二异丙基乙基硅基)胺基锂、双(二异丙基苯基硅基)胺基锂、双(二异丙基苄基硅基)胺基锂、双三甲基硅基胺基钠、双三乙基硅基胺基钠、双三丙基硅基胺基钠、双三异丙基硅基胺基钠、双(二甲基乙基硅基)胺基钠、双(二甲基丙基硅基)胺基钠、双(二甲基异丙基硅基)胺基钠、双(二甲基苯基硅基)胺基钠、双(二甲基苄基硅基)胺基钠、双(二乙基甲基硅基)胺基钠、双(二乙基丙基硅基)胺基钠、双(二乙基异丙基硅基)胺基钠、双(二乙基苯基硅基)胺基钠、双(二乙基苄基硅基)胺基钠、双(二异丙基甲基硅基)胺基钠、双(二异丙基乙基硅基)胺基钠、双(二异丙基苯基硅基)胺基钠、双(二异丙基苄基硅基)胺基钠、双三甲基硅基胺基钾、双三乙基硅基胺基钾、双三丙基硅基胺基钾、双三异丙基硅基胺基钾、双(二甲基乙基硅基)胺基钾、双(二甲基丙基硅基)胺基钾、双(二甲基异丙基硅基)胺基钾、双(二甲基苯基硅基)胺基钾、双(二甲基苄基硅基)胺基钾、双(二乙基甲基硅基)胺基钾、双(二乙基丙基硅基)胺基钾、双(二乙基异丙基硅基)胺基钾、双(二乙基苯基硅基)胺基钾、双(二乙基苄基硅基)胺基钾、双(二异丙基甲基硅基)胺基钾、双(二异丙基乙基硅基)胺基钾、双(二异丙基苯基硅基)胺基钾和双(二异丙基苄基硅基)胺基钾。
在某些实施方案中,将通式(B-II)化合物与通式R11-Y、(R12)2Y或Y-R13-Z化合物进行反应得到通式(B-III)化合物的反应是在溶剂中进行的。
能够用于本申请的合适的溶剂的实例包括但不限于氯仿、二氯甲烷、二氯乙烷、四氢呋喃、丙酮、丁酮、乙酸甲酯、乙酸丙酯、乙酸丁酯、乙酸异丙酯、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯、甲酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸丁酯、丙酸异丙酯、甲醚、乙醚、甲基乙醚、甲基叔丁基醚、乙基叔丁基醚、甲基异丙醚、乙基异丙醚、异丙醚、乙酸乙酯、乙醇、甲醇、丙醇、丁醇、乙二醇、乙二醇二甲醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇二乙醚、苯、甲苯、正己烷、环己烷、DMF、DMSO、石油醚、水及其一种或一种以上的混合物。
在某些实施方案中,在-20°-200℃下将通式(B-II)化合物与通式R11-Y、(R12)2Y或Y-R13-Z化合物进行反应得到通式(B-III)化合物。
在某些实施方案中,在-10°-100℃下将通式(B-II)化合物与通式R11-Y、(R12)2Y或Y-R13-Z化合物进行反应得到通式(B-III)化合物。
在某些实施方案中,由通式(B-I)化合物制备通式(B-II)化合物,
其中,
R1选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
在某些实施方案中,由通式(B-I)化合物制备通式(B-II)化合物的反应是在还原剂作用下进行的。
能够用于本申请的合适的还原剂的实例包括但不限于铁粉、保险粉、锌粉和氢气。
在某些实施方案中,由通式(B-I)化合物制备通式(B-II)化合物的反应是在催化剂作用下进行的。
能够用于本申请的合适的催化剂的实例包括但不限于钯、铂、铑、镍、钌或铱等重金属及其的氧化物或盐、盐酸、硫酸、磷酸、甲酸、乙酸、丙酸、甲磺酸、乙磺酸、苯磺酸以及对甲苯磺酸。
在某些实施方案中,由通式(B-I)化合物制备通式(B-II)化合物的反应是在下列催化剂作用下进行的:盐酸、硫酸、磷酸、甲酸、乙酸、丙酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、钯碳、铂碳、二氧化铂、氯化钯、氯化铂、雷尼镍或其一种或一种以上的混合物。
在某些实施方案中,由通式(B-I)化合物制备通式(B-II)化合物的反应是在溶剂中进行的。
能够用于本申请的合适的溶剂的实例包括但不限于甲醇、乙醇、丙醇、丁醇、异丙醇、氯仿、二氯甲烷、四氯化碳、1,2-二氯乙烷、乙二醇二甲醚、乙二醇二乙醚、乙醚、甲基乙基醚、甲基丙基醚、甲基丁基醚、乙基丙基醚、甲基叔丁基醚、四氢呋喃、乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、丙酸甲酯、丙酸乙酯、甲酸甲酯、甲酸乙酯、甲酸丙酯、乙酸异丙酯、丙酮、丁酮、吡啶、DMF、DMSO、乙腈、丙腈、苯、甲苯、水及其一种或一种以上的混合物。
在某些实施方案中,在-20°-250℃下由通式(B-I)化合物制备通式(B-II)化合物。
在某些实施方案中,在0°-150℃下由通式(B-I)化合物制备通式(B-II)化合物。
在某些实施方案中,在1-100个大气压下由通式(B-I)化合物制备通式(B-II)化合物。
在某些实施方案中,在1-20个大气压下由通式(B-I)化合物制备通式(B-II)化合物。
再一方面,本申请涉及药物组合物,其包括药物可接受的载体以及治疗有效量的通式(I)化合物、其立体异构体、其药物可接受的盐,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
能够用于本申请药物组合物中的药物可接受的载体的实例包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
在某些实施方案中,本申请的药物组合物还包含至少一种其他活性成分。
能够用于本申请的合适的活性成分的实例包括但不限于氮芥、氮丙啶、甲基蜜胺、磺酸烷基酯、亚硝基脲、三氮烯、叶酸类似物、嘧啶类似物、嘌呤类似物、长春花生物碱、表鬼臼毒素、抗生素、拓扑异构酶抑制剂、抗癌疫苗、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、安波霉素、醋酸阿美蒽醌、氨鲁米特、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林霉素、阿扎胞苷、阿扎替哌、阿佐霉素、巴马司他、苯佐替哌、比卡鲁胺、盐酸比生群、甲磺酸双萘法德、比折来新、硫酸博来霉素、白消安、放线菌素C、卡普睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡柔比星、苯丁酸氮芥、西罗霉素、克拉屈滨、甲磺酸克立那托、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、盐酸柔红霉素、地西他宾、多西他塞、多柔比星、盐酸多柔比星、屈洛昔芬、盐酸表柔比星、盐酸依索比星、雌莫司汀、依他消唑、依托泊苷、氟尿苷、氟尿嘧啶、氟西他滨、吉西他宾、盐酸依达比星、异环磷酰胺、白介素II、干扰素α-2a、干扰素α-2b、盐酸依立替康、来曲唑、巯嘌呤、甲氨蝶呤、氯苯氨啶、丝列霉素、米托蒽酮、紫杉醇、丙卡巴肼、赛替哌、长春碱、长春新碱、血管生成抑制剂、喜树碱、地塞米松、阿司匹林、乙酰氨基酚、吲哚美辛、布洛芬、酮洛芬、美洛昔康、皮质类固醇和肾上腺皮质类固醇。
在某些实施方案中,本申请的药物组合物被制备为胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
又一方面,本申请涉及通式(I)化合物、其立体异构体、其药物可接受的盐在制备降低PDE4酶活性的药物中的用途,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
另一方面,本申请还涉及通式(I)化合物、其立体异构体、其药物可接受的盐在制备治疗PDE4酶介导的疾病或疾病状态的药物中的用途,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
在某些实施方案中,所述疾病或疾病状态选自炎症性疾病或疾病状态、感染性疾病或疾病状态、免疫类疾病或疾病状态以及癌症类疾病或疾病状态。
在某些实施方案中,所述疾病或疾病状态的实例包括但不限于头部癌、甲状腺癌、颈癌、眼癌、皮肤癌、口腔癌、咽喉癌、食道癌、胸癌、骨癌、血癌、骨髓癌、肺癌、结肠癌、乙状结肠癌、直肠癌、胃癌、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、胰腺癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、色素瘤、恶性神经胶质瘤、HIV、肝炎、成人呼吸窘迫综合症、骨吸收病、慢性阻塞性肺病、慢性肺炎、皮炎、炎性皮肤病、特异性皮炎、囊性纤维变性、败血症性休克、脓毒症、内毒素性休克、血液动力性休克、脓毒病综合症、局部缺血后再灌注损伤、脑膜炎、银屑病、纤维变性疾病、恶病质、移植物抗宿主疾病的移植排斥、自身免疫病、类风湿性脊椎炎、关节炎病症(如类风湿性关节炎或骨关节炎)、骨质疏松症、节段性回肠炎、溃疡性结肠炎、肠炎、多发性硬化病、系统性红斑狼疮、麻风病中的麻风性结节性红斑(ENL)、辐射损伤、哮喘、富氧性肺损伤、微生物感染和微生物感染综合症。
在某些实施方案中,本申请所述的治疗PDE4酶介导的微生物感染和微生物感染综合症的实例包括但不限于细菌感染、真菌感染、疟疾、分枝杆菌感染和HIV引起的机会感染。
在某些实施方案中,向需要治疗PDE4酶介导的疾病或疾病状态的方法的个体给予通式(I)化合物的单位剂量为0.1mg-1000mg。
在某些实施方案中,向需要治疗PDE4酶介导的疾病或疾病状态的方法的个体给予通式(I)化合物的单位剂量为1mg-1000mg。
另一方面,本申请涉及药物组合物在制备治疗PDE4酶介导的疾病或疾病状态的药物中的用途,其中所述药物组合物包括药物可接受的载体以及治疗有效量的通式(I)化合物、其立体异构体、其药物可接受的盐,
其中,
R1和R2分别选自氢、卤素、C1-C8烃基、C1-C8烃氧基、羟基、氰基、硝基或NR6R7;
R3选自羟基、C1-C8烃基、C1-C8烃氧基、C1-C8烃基(C1-C8亚烃基)氧基、C5-C12芳基、C5-C12芳基(C1-C8亚烃基)氧基或NR6R7;
R4和R5分别选自氢、羟基、C1-C8烃基、卤素取代的C1-C8烃基、C1-C8烃氧基、C1-C8烃硫基、氰基、C3-C10环烃基、(C1-C8亚烃基)C3-C10环烃基、C3-C10环烃基(C1-C8亚烃基)氧基、C3-C10环烃基氧基、C5-C12芳基、C5-C12芳基氧基、C5-C12芳基(C1-C8亚烃基)氧基;
R6和R7分别选自氢、C1-C8烃基、C5-C12芳基、C(O)R8或SO2R8,或者R6和R7一起表示1,4-亚丁基、1,5-亚戊基、1,6-亚己基或CH2CH2XCH2CH2,其中X选自O、S或NR8;
R8选自氢、C1-C8烃基、卤素取代的C1-C8烃基、(C1-C8烃基取代的氨基)取代的C1-C8烃基或C3-C12杂环烃基取代的C1-C8烃基。
在某些实施方案中,所述药物组合物还包含至少一种其他活性成分。
能够用于本申请的合适的活性成分的实例包括但不限于氮芥、氮丙啶、甲基蜜胺、磺酸烷基酯、亚硝基脲、三氮烯、叶酸类似物、嘧啶类似物、嘌呤类似物、长春花生物碱、表鬼臼毒素、抗生素、拓扑异构酶抑制剂、抗癌疫苗、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、安波霉素、醋酸阿美蒽醌、氨鲁米特、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林霉素、阿扎胞苷、阿扎替哌、阿佐霉素、巴马司他、苯佐替哌、比卡鲁胺、盐酸比生群、甲磺酸双萘法德、比折来新、硫酸博来霉素、白消安、放线菌素C、卡普睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡柔比星、苯丁酸氮芥、西罗霉素、克拉屈滨、甲磺酸克立那托、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、盐酸柔红霉素、地西他宾、多西他塞、多柔比星、盐酸多柔比星、屈洛昔芬、盐酸表柔比星、盐酸依索比星、雌莫司汀、依他消唑、依托泊苷、氟尿苷、氟尿嘧啶、氟西他滨、吉西他宾、盐酸依达比星、异环磷酰胺、白介素II、干扰素α-2a、干扰素α-2b、盐酸依立替康、来曲唑、巯嘌呤、甲氨蝶呤、氯苯氨啶、丝列霉素、米托蒽酮、紫杉醇、丙卡巴肼、赛替哌、长春碱、长春新碱、血管生成抑制剂、喜树碱、地塞米松、阿司匹林、乙酰氨基酚、吲哚美辛、布洛芬、酮洛芬、美洛昔康、皮质类固醇和肾上腺皮质类固醇。
在某些实施方案中,本申请的药物组合物被制备为胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
实施例
虽然任何本领域技术人员能够依据上述公开的一般技术来制备本申请化合物,但为方便起见,本说明书中的其它地方提供更加详细的本申请化合物的合成技术。另外,本领域技术人员已知合成中所使用的所有试剂及反应条件并且可以由普通的商品来源获得。
缩写语
CDI:1,1’-羰基二咪唑;DCM:二氯甲烷;THF:四氢呋喃;TFA:三氟乙酸;DMAP:4-(N,N-二甲基胺基)吡啶;TEA:三乙胺;DMF:N,N-二甲基甲酰胺;DMSO:二甲基亚砜;HOBt:1-羟基苯并三氮唑;DCC:N,N-二环己基碳二亚胺;TBFA:四丁基氟化铵;EDC·HCl:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;Fmoc:9-芴甲氧羰基;MOM:甲氧甲基;MEM:甲氧基乙氧基甲基;MTM:甲硫基甲基;SEM:2-(三甲基硅基)乙氧基甲基;TMSE:2-(三甲基硅基)乙基;DIC:N,N’-二异丙基碳化二亚胺;HOAt:1-羟基-7-偶氮苯并三氮唑;BOP:卡特缩合剂(苯并三唑-1-基-氧-三-(二甲氨基)鏻六氟磷酸盐);Cl-HOBt:6-氯-1-羟基苯并三氮唑;DEPBT:3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮;HATU:双(二甲基氨基)甲叉-三唑[4,5-B]吡啶-3-氧化物六氟磷酸盐;HBTU:苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸酯;HCTU:6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯;HOOBt:3-羟基-1,2,3-苯并三嗪-4(3H)-酮;PyBOP:六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷;TATU:O-(7-偶氮苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸酯;TBTU:O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸酯;OMS:甲磺酸酯基;OTS:对甲苯磺酸酯基。
通过但不限于以下的实施例说明本申请化合物的合成。
化合物1a:4-甲氧基-3-乙氧基苯甲醛
在装有机械搅拌和惰性气体导管的500ml三口瓶中加入30.5克异香兰素,55.2克碳酸钾,49.9克碘乙烷,140ml DMF,室温搅拌过夜。倾倒入1400ml水中,用乙酸乙酯萃取2次,每次600ml。合并乙酸乙酯层,用饱和Na2CO3洗3次,每次200ml,200ml水洗,200ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,得淡黄色固体,用乙酸乙酯:石油醚=1:4的混合溶剂重结晶,得白色针状晶体32.9克。MS(m/z):181[M+1]+。
用同样方法合成下列化合物1b-1d。
化合物1b:4-乙氧基-3-甲氧基苯甲醛
用香兰素代替异香兰素重复化合物1a的实验步骤得固体产物。MS(m/z):181[M+1]+。
化合物1c:3,4-二甲氧基苯甲醛
用碘甲烷代替碘乙烷重复例1a的实验步骤得固体产物。MS(m/z):167[M+1]+。
化合物1d:3-苯甲氧基-4-甲氧基苯甲醛
用氯化苄代替碘乙烷重复例1a的实验步骤得固体产物。MS(m/z):243[M+1]+。
化合物2a:1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)-N-(三甲基硅基)乙胺
在装有磁力搅拌和惰性气体导管的500ml三口瓶中加入3.7克二甲砜,160ml THF,冷却至-78℃,滴加22ml正丁基锂(2.2M正己烷溶液),滴完后保持-78℃搅拌30分钟,得A。在装有磁力搅拌和惰性气体导管的250ml三口瓶中加入7.1克化合物1a,冰盐浴冷却,滴加43ml双三甲基硅基氨基锂(1.06M THF溶液),滴完后搅拌15分钟,滴加10ml三氟化硼乙醚溶液,滴完后搅拌5分钟,得B。将B转移入A中,转移后缓慢升温至室温(约1.5小时),加入200ml1.6N K2CO3溶液淬灭反应,搅拌30分钟后分液,水层再用乙酸乙酯萃取3次,每次200ml,合并所有有机层,200ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,得淡黄色泡沫状固体10克。
同样方法合成下列化合物2b-2d。
化合物2b:1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)-N-(三甲基硅基)乙胺
化合物2c:1-(3,4-二甲氧基苯基)-2-(甲砜基)-N-(三甲基硅基)乙胺
化合物2d:1-(3-苯甲氧基-甲氧基苯基)-2-(甲砜基)-N-(三甲基硅基)乙胺
化合物3a:1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙胺
在装有磁力搅拌的500ml单口瓶中加入10克化合物2a,100ml乙醚,100ml 4N HCl,室温搅拌30分钟,分液,有机层用4N HCl萃取3次,每次100ml,合并水层,冰浴下用4N Na羟基调节pH=12,用乙酸乙酯萃取3次,每次200ml,合并有机层,200ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,柱色谱纯化后得白色固体1.5克。1H NMR(CDCl3):δ6.93-6.84(m,3H),4.60(d,1H,J=8Hz),4.12(q,2H,J=4Hz),3.87(s,3H),3.37-3.21(m,2H),2.92(s,3H),1.86(s,2H),1.48(t,3H,J=4Hz);MS(m/z):274[M+1]+;手性HPLC(异丙醇/正己烷/二乙胺=35/65/0.1,OJ-H柱,250×4.6mm,1.0mL/min,@234nm):15.2min(R-isomer,49.8%),17.3min(S-isomer,50.2%)。
用同样方法合成下列化合物3b-3d。
化合物3b:1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙胺MS(m/z):274[M+1]+。
化合物3c:1-(3,4-二甲氧基苯基)-2-(甲砜基)乙胺MS(m/z):260[M+1]+
化合物3d:1-(3-苯甲氧基-甲氧基苯基)-2-(甲砜基)乙胺MS(m/z):336[M+1]+
化合物4a:(S)-1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙胺·N-乙酰基-L-缬
氨酸盐
在装有磁力搅拌、回流冷凝装置和惰性气体导管的100ml单口瓶中加入6.920克化合物3a,2.418克N-乙酰基L-缬氨酸,50ml无水甲醇,油浴回流1小时,室温搅拌3小时,抽滤,得白色固体,将此固体再加入无水甲醇25ml回流1小时,室温搅拌3小时,抽滤,得白色固体6.752克。
化合物4b:(S)-1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)-乙胺
在装有磁力搅拌的250ml单口瓶中加入6.752克化合物4a,150ml二氯甲烷和150ml水,冰浴下滴加5%Na羟基水溶液,调节pH=11,分液,水层再用150ml二氯甲烷萃取一次,合并二氯甲烷层,100ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,得白色固体2.855克(99.0%ee)。MS(m/z):274[M+1]+;手性HPLC(异丙醇/正己烷/二乙胺=35/65/0.1,OJ-H柱,250×4.6mm,1.0mL/min,@234nm):15.2min(R-isomer,0.5%),17.3min(S-isomer,99.5%)。
化合物4c:(R)-1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙胺·N-乙酰基-D-亮
氨酸盐
在装有磁力搅拌、回流冷凝装置和惰性气体导管的100ml单口瓶中加入1.365克化合物3a,0.519克N-乙酰基D-亮氨酸,10ml无水甲醇,油浴回流1小时,室温搅拌3小时,抽滤,得白色固体1.290克,将此固体再加入无水甲醇10ml回流1小时,室温搅拌3小时,抽滤,得白色固体1.042克。
化合物4d:(R)-1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙胺
在装有磁力搅拌的250ml单口瓶中加入化合物4c,50ml二氯甲烷和50水,冰浴下滴加5%Na羟基水溶液,调节PH=11,分液,水层再用50ml二氯甲烷萃取一次,合并二氯甲烷层,50ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,得白色固体0.622克(99.0%ee)。MS(m/z):274[M+1]+;手性HPLC(异丙醇/正己烷/二乙胺=35/65/0.1,OJ-H柱,250×4.6mm,1.0mL/min,@234nm):15.2min(R-isomer,99.5%),17.3min(S-isomer,0.5%)。
化合物5:3,4-二氰基噻吩
在装有机械搅拌、回流冷凝装置和惰性气体导管的2000ml三口瓶中加入96.8克3,4-二溴噻吩、104克氰化亚铜和100ml干燥的DMF,加热回流4小时后,冷却至室温,向反应液中加入400克FeCl3·6H2O溶在700ml 1.7N盐酸中的溶液,并维持在60-70℃反应30分钟,充分冷却后加入500ml DCM。将所得反应混合物分成300ml一份,用DCM(300ml×2)萃取,合并所有DCM层。将萃取液分成600ml一份,依次用50ml×26N的盐酸、水、饱和Na2CO3水溶液及饱和食盐水溶液洗,无水MgSO4干燥,过滤,蒸干溶剂得黄色固体,用乙酸乙酯:石油醚=1:1的混合溶剂洗涤,过滤得白色固体21g。1H NMR(CDCl3):δ8.07(s,2H)。
化合物6:噻吩-3,4-二羧酸
在装有电磁搅拌和回流冷凝装置的500ml圆底烧瓶中,加入15.978克化合物5、43.997克K羟基及174ml乙二醇,回流4小时。待冷却后,向反应混合物中加350ml水,用乙醚(100ml×2)萃取,弃去乙醚层,在冰浴冷却下向水层加入过量的浓盐酸直到出现白色沉淀,过滤后将固体溶解于乙醚中(大约需要2000ml),滤液用乙醚(300ml×3)萃取,合并所有乙醚层,无水MgSO4干燥,过滤,蒸干溶剂,得白色固体15克,用水重结晶。1H NMR(DMSO-d6):δ10.35(brs,2H),8.17(s,2H);MS(m/z):171[M-1]+。
化合物7:噻吩[3,4-c]呋喃-1,3-二酮
在装有电磁搅拌、回流冷凝装置和干燥管的250ml圆底烧瓶中,加入15克化合物6和120ml乙酸酐,回流3小时,蒸干溶剂,得褐色固体13克。
化合物8:2-硝基噻吩-3,4-二羧酸
在装有电磁搅拌和干燥管的250ml圆底烧瓶中加入40ml发烟硝酸(含量95%),用冰浴将其冷却至0-5℃,分批(每次1克)加入10克化合物7,加完后,在此温度下反应30分钟(有黄色固体析出)。将反应混合物倒入80克冰水混合液中,用乙酸乙酯(100ml×3)萃取,合并所有乙酸乙酯层,依次用50ml×2水及饱和食盐水溶液洗,无水MgSO4干燥,过滤,蒸干溶剂,得黄色固体10g。MS(m/z):216[M-1]+。
化合物9:4-硝基噻吩[3,4-c]呋喃-1,3-二酮
在装有电磁搅拌、回流冷凝装置和干燥管的250ml圆底烧瓶中加入10克化合物8和100ml乙酸酐,回流3小时,蒸干溶剂,得褐色固体9克。
实施例1
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮
在装有电磁搅拌和干燥管的250ml圆底烧瓶中加入1.99克化合物9,2.73克化合物3a,100ml THF,室温搅拌过夜。加入1.944克CDI,油浴回流2小时。晾至室温,加入200ml乙酸乙酯和150ml水,萃取,分液,有机层用100ml 0.5N HCl洗,100ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,柱色谱纯化后得淡黄色固体3.541克。MS(m/z):453[M-1]+。
实施例2
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮
在装有电磁搅拌、回流冷凝装置和干燥管的250ml圆底烧瓶中加入2.27克5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮和100ml THF,加热回流,加入1.4克还原铁粉,回流2小时。抽滤,滤液蒸干,加入200ml乙酸乙酯和150ml水,萃取,分液,有机层用100ml水洗,100ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,柱色谱纯化后得黄褐色固体1.68克。MS(m/z):425[M+1]+。
实施例3
N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
方法一:在装有电磁搅拌、回流冷凝装置和干燥管的50ml圆底烧瓶中加入0.1克5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮和0.005克DMAP,10ml乙酸酐,加热至60度,搅拌6小时。蒸干溶剂,柱色谱纯化后得白色固体0.02克。
方法二:在装有电磁搅拌、回流冷凝装置和干燥管的50ml圆底烧瓶中加入0.1克5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮和5ml吡啶,冰浴下滴加0.2ml乙酰氯,室温搅拌1小时。蒸干溶剂,加入50ml乙酸乙酯和20ml水,萃取,分液,有机层用20ml 2N HCl洗,20ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,柱色谱纯化后得白色泡沫状固体0.08克。MS(m/z):465[M-1]+。1H NMR(CDCl3):δ9.12(s,1H),7.33(s,1H),7.08(s,1H),7.07(s,1H),6.83(d,1H,J=6Hz),5.82(dd,1H,J=3Hz,J=7Hz),4.56(dd,1H,J=5Hz,J=11Hz),4.12(q,2H,J=3Hz),3.86(s,3H),3.76(dd,1H,J=5Hz,J=11Hz),2.88(s,3H),2.29(s,3H),1.47(t,3H,J=5Hz)。
实施例4
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
在装有电磁搅拌和干燥管的50ml圆底烧瓶中加入0.077克化合物7,0.137克化合物3a,10ml THF,室温搅拌过夜。加入0.122克CDI,油浴回流2小时。晾至室温,加入100ml乙酸乙酯和50ml水,萃取,分液,有机层用20ml 0.5N HCl洗,20ml饱和NaCl洗,无水MgSO4干燥,过滤,蒸干溶剂,得白色固体0.121克。MS(m/z):410[M+1]+。
实施例5
(S)-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物4b代替化合物3a重复实施例4的实验步骤得固体产物。MS(m/z):410[M+1]+。
实施例6
(R)-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物4d代替化合物3a重复实施例4的实验步骤得固体产物。MS(m/z):410[M+1]+。
实施例7
5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物3b代替化合物3a重复实施例4的实验步骤得固体产物。MS(m/z):410[M+1]+。
实施例8
5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物3c代替化合物3a重复实施例4的实验步骤得固体产物。MS(m/z):396[M+1]+。
实施例9
5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物3d代替化合物3a重复实施例4的实验步骤得固体产物。MS(m/z):472[M+1]+。
实施例10
5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物3d代替化合物3a重复实施例1的实验步骤得固体产物。MS(m/z):515[M-1]+。
实施例11
5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮
用实施例10目标化合物代替实施例1目标化合物重复实施2的实验步骤得固体产物。MS(m/z):487[M+1]+。
实施例12
N-(5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用实施例11目标化合物代替实施例2目标化合物重复实施例3的实验步骤得固体产物。MS(m/z):527[M-1]+。
实施例13
5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物3c代替化合物3a重复实施例1的实验步骤得固体产物。MS(m/z):439[M-1]+。
实施例14
5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮
用实施例13目标化合物代替实施例1目标化合物重复实施例2的实验步骤得固体产物。MS(m/z):411[M+1]+。
实施例15
5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物3b代替化合物3a重复实施例1的实验步骤得固体产物。MS(m/z):453[M-1]+。
实施例16
5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮
用实施例15目标化合物代替实施例1目标化合物重复实施例2的实验步骤得固体产物。MS(m/z):425[M+1]+。
实施例17
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-甲胺基-5H-噻吩[3,4-c]吡咯-4,6-二酮
0.085克实施例2目标化合物溶解在10ml丙酮中,加入0.5ml碘甲烷,加热到80℃反应6小时,冷却后加入100ml水,用乙酸乙酯(30ml×3)萃取,合并有机相,依次用30ml水及饱和食盐水洗,无水MgSO4干燥,过滤,蒸干溶剂,硅胶柱色谱分离后得固体0.033克。MS(m/z):439[M+1]+。
实施例18
2-氯-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用化合物氯乙酰氯代替化合物乙酰氯重复实施例3方法二的实验步骤得固体产物。MS(m/z):499[M-1]+。
实施例19
N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)甲磺酰胺
用化合物甲磺酰氯代替化合物乙酰氯重复实施例3方法二的实验步骤得固体产物。MS(m/z):501[M-1]+。
实施例20
(S)-1-硝基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物4b与化合物9重复实施例1的制备方法合成。
实施例21
(S)-1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用实施例20目标化合物重复实施例2的方法制备。MS(m/z):425[M+1]+。
实施例22
(R)-1-硝基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用化合物4d与化合物9重复实施例1的方法制备。
实施例23
(R)-1-氨基-5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-5H-噻吩[3,4-c]吡咯-4,6-二酮
用实施例22目标化合物重复实施例2的方法制备。MS(m/z):425[M+1]+。
实施例24
(S)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用实施例21所得目标化合物重复实施例3的方法合成,MS(m/z):465[M-1]+;手性HPLC(无水乙醇/正己烷/二乙胺=40/60/0.1,OJ-H柱,250×4.6mm,1.0mL/min,@230nm):9.8min(R-isomer,1.2%),13.8min(S-isomer,98.8%)。1H NMR(CDCl3):δ9.27(s,1H),7.30(s,1H),7.07(s,1H),7.05(s,1H),6.81(d,1H,J=6Hz),5.81(dd,1H,J=3Hz,J=7Hz),4.54(dd,1H,J=8Hz,J=11Hz),4.08(q,2H,J=3Hz),3.84(s,3H),3.73(dd,1H,J=8Hz,J=11Hz),2.86(s,3H),2.27(s,3H),1.45(t,3H,J=5Hz)。
实施例25
(R)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用实施例23所得目标化合物重复实施例3的方法合成,465[M-1]+;手性HPLC(无水乙醇/正己烷/二乙胺=40/60/0.1,OJ-H柱,250×4.6mm,1.0mL/min,@230nm):9.8min(R-isomer,99.5%),13.8min(S-isomer,0.5%)。
实施例26
N-(5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用实施例16目标化合物重复实施例3目标化合物的制备方法合成,MS(m/z):465[M-1]+。
实施例27
N-(5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)丙酰胺
用实施例11目标化合物与丙酰氯重复实施例3的实验步骤得固体产物。MS(m/z):541[M-1]+。
实施例28
2-(二甲氨基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
将50mg实施例18目标化合物溶于10ml四氢呋喃,加入2N二甲胺的四氢呋喃溶液0.3ml,室温搅拌过夜,反应结束后加入100ml水,用乙酸乙酯萃取(40ml×3),合并有机相,依次用40ml水和饱和食盐水洗,无水硫酸镁干燥,过滤蒸干溶剂,硅胶柱色谱分离后得固体40mg。MS(m/z):510[M+1]+。
实施例29
2-(二乙氨基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用二乙胺代替二甲胺重复实施例28制备方法得到,MS(m/z):538[M+1]+。
实施例30
2-(哌啶基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用哌啶代替二甲胺重复实施例28制备方法得到,MS(m/z):550[M+1]+。
实施例31
2-(吗啡啉基)-N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)乙酰胺
用吗啡啉代替二甲胺重复实施例28制备方法得到,MS(m/z):552[M+1]+。
实施例32药理学研究
1.LPS刺激单核细胞(PBMCs)对TNFα的影响
在体外可以进行关于脂多糖(LPS)刺激后,人外周血液中的PBMCs释放细胞因子TNFα的研究。本申请涉及的药物活性成分抑制LPS刺激下PBMCs释放细胞因子TNFα的研究方法如下:
PBMCs由至少三名志愿捐献者的经肝素处理的血液中获得。将由至少三名志愿捐献者的经肝素处理的血液,使用已知方法梯度分离得到PBMCs,采集所述的PBMCs并用1640培养基(10%小牛血清,2mML-谷氨酰氨,100mM巯基乙醇,50μg/ml链霉素,50U/ml青霉素)洗涤三次。将所述的PBMCs加入24孔板,用1640培养基调配成1×106细胞/ml的浓度。将待试化合物溶于二甲亚砜,制备成所需浓度的试验物溶液加入到上述细胞培养液中,并将其在CO2培育箱(5%CO2,90%湿度)中培育1小时,然后加入LPS(Sigma)到0.1μg/ml(对照物除外)。
将所述培养基继续培育20小时后,使用商品ELISA试剂盒(美国Genzyme Co)用标准方法测定所述PBMCs培养基上清液中TNFα的含量。由未用活性成分处理的对照孔的测定值和用所述试验物测试孔的测定值计算TNFα抑制率的大小。通过非线性回归分析,计算产生50%TNFα释放抑制的浓度(IC50值)。每个浓度同时测两次并取平均值,部分测试结果见表1。
表1:抑制LPS刺激单核细胞释放TNFα的活性
2.化合物对PDE酶的抑制活性和选择性抑制活性
(1)PDE4酶抑制活性检测化合物对PDE4酶水解cAMP活性的抑制作用,步骤如下:
人源PDE4A1A,PDE4B1,PDE4D2购自BPS bioscience(目录号分别为:60040,60041,60043)。酶反应在10mM Tris-HCl(pH7.4),1mM MgCl2中进行,cAMP浓度为5μM,37℃反应15-30min,使底物的消耗量控制在20%以内,用等体积的乙腈终止反应,HPLC-MS检测底物AMP的生成量。由加化合物的实验组和不加化合物的对照组AMP生成量的比较,得到化合物对PDE4酶的抑制活性,数据见表2。
(2)PDE2抑制活性(PDE酶选择性):
人源PDE2A购自BPS bioscience(目录号:60020)。酶反应在10mM Tris-HCl(pH7.4),1mM MgCl2中进行,cAMP浓度为5μM,37℃反应30min,使底物的消耗量控制在20%以内,用等体积的乙腈终止反应,HPLC-MS检测底物AMP的生成量。由加化合物的实验组和不加化合物的对照组AMP生成量的比较,得到化合物对PDE2的抑制活性,数据见表2。
表2.PDE4酶活性抑制及PDE酶选择性活性抑制
Claims (36)
2.如权利要求1所述的通式(I)化合物,其中R1和R2分别选自氢、硝基、NH2、NHCH3、CH3C(O)NH或、CH3CH2C(O)NH、CH3SO2NH或ClCH2C(O)NH。
3.如权利要求1所述的通式(I)化合物,其中R3选自甲基、乙基或丙基。
4.如权利要求1所述的通式(I)化合物,其中R4选自乙氧基、丙氧基或苄氧基,并且R5选自甲氧基、丙氧基或苄氧基。
5.如权利要求1所述的通式(I)化合物,其中R8选自甲基、乙基、二甲氨基甲基或二乙氨基甲基。
6.化合物,其选自:
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3,4-二甲氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-1-硝基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-甲氧基-4-乙氧基苯基)-2-(甲砜基)乙基)-1-氨基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-1-甲胺基-5H-噻吩[3,4-c]吡咯-4,6-二酮,
N-(5-(1-(3-乙氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二酮-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)甲磺酰胺,或
N-(5-(1-(3-苯甲氧基-4-甲氧基苯基)-2-(甲砜基)乙基)-4,6-二氧-5,6-二氢-4H-噻吩[3,4-c]吡咯-1-基)丙酰胺。
7.通式(I)化合物的制备方法,所述方法包括将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物:
其中,
R1和R2分别选自氢、硝基或NR6R7;
R3选自C1-C8饱和的烷基;
R4选自乙氧基、丙氧基、C5-C12芳基氧基或C5-C12芳基(C1-C8饱和的亚烷基)氧基;
R5选自甲氧基、丙氧基、C5-C12芳基氧基或C5-C12芳基(C1-C8饱和的亚烷基)氧基;
R6和R7分别选自氢、C1-C8饱和的烷基、C(O)R8或SO2R8;
R8选自C1-C8饱和的烷基、卤素取代的C1-C8饱和的烷基、(C1-C8饱和的烷基取代的氨基)取代的C1-C8饱和的烷基、哌啶基甲基或吗啡啉基甲基。
8.如权利要求7所述的方法,其中在将通式(A-IV)化合物与通式(A-VII)化合物进行反应得到通式(I)化合物的方法中加入三级胺作为催化剂。
9.如权利要求8所述的方法,其中所述三级胺选自吡啶、4-二甲胺基吡啶、4-吡咯烷基吡啶中的一种或一种以上的混合物。
10.通式(B-III)化合物的制备方法,所述方法包括将通式(B-II)化合物与通式R11-Y或(R12)2Y化合物进行反应得到通式(B-III)化合物,
其中,
R1选自氢、硝基或NR6R7;
R3选自C1-C8饱和的烷基;
R4选自乙氧基、丙氧基、C5-C12芳基氧基或C5-C12芳基(C1-C8饱和的亚烷基)氧基;
R5选自甲氧基、丙氧基、C5-C12芳基氧基或C5-C12芳基(C1-C8饱和的亚烷基)氧基;
R6和R7分别选自氢、C1-C8饱和的烷基、C(O)R8或SO2R8;
R8选自C1-C8饱和的烷基、卤素取代的C1-C8饱和的烷基、(C1-C8饱和的烷基取代的氨基)取代的C1-C8饱和的烷基、哌啶基甲基或吗啡啉基甲基;
在R11-Y中,R11选自C1-C8饱和的烷基、C(O)R8或S(O)2R8,Y选自卤素、OMs或OTs;
在(R12)2Y中,R12选自C(O)R8,Y为O;
R17选自NH(C1-C8饱和的烷基)、NHC(O)R8或NHS(O)2R8。
11.药物组合物,其包括药物可接受的载体以及治疗有效量的权利要求1-6中任一权利要求所述的化合物、其立体异构体、其药物可接受的盐。
12.如权利要求11所述的药物组合物,其还包含至少一种其他活性成分。
13.如权利要求12所述的药物组合物,其中所述其他活性成分选自氮芥、氮丙啶、甲基蜜胺、磺酸烷基酯、亚硝基脲、三氮烯、长春花生物碱、表鬼臼毒素、抗生素、拓扑异构酶抑制剂、抗癌疫苗、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、安波霉素、醋酸阿美蒽醌、氨鲁米特、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林霉素、阿扎胞苷、阿扎替哌、阿佐霉素、巴马司他、苯佐替哌、比卡鲁胺、盐酸比生群、甲磺酸双萘法德、比折来新、硫酸博来霉素、白消安、放线菌素C、卡普睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡柔比星、苯丁酸氮芥、西罗霉素、克拉屈滨、甲磺酸克立那托、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、盐酸柔红霉素、地西他宾、多西他塞、多柔比星、盐酸多柔比星、屈洛昔芬、盐酸表柔比星、盐酸依索比星、雌莫司汀、依他消唑、依托泊苷、氟尿苷、氟尿嘧啶、氟西他滨、吉西他宾、盐酸依达比星、异环磷酰胺、白介素II、干扰素α-2a、干扰素α-2b、盐酸依立替康、来曲唑、巯嘌呤、甲氨蝶呤、氯苯氨啶、丝列霉素、米托蒽酮、紫杉醇、丙卡巴肼、赛替哌、长春碱、长春新碱、血管生成抑制剂、喜树碱、地塞米松、阿司匹林、乙酰氨基酚、吲哚美辛、布洛芬、酮洛芬、美洛昔康或皮质类固醇。
14.如权利要求11-13中任一权利要求所述的药物组合物,其被制备为片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
15.权利要求1-6中任一权利要求所述的化合物、其立体异构体、其药物可接受的盐在制备降低PDE4酶活性的药物或治疗PDE4酶介导的疾病或疾病状态的药物中的用途。
16.如权利要求15所述的用途,其中所述疾病或疾病状态选自炎症性疾病或疾病状态、感染性疾病或疾病状态、免疫疾病或疾病状态以及癌症疾病或疾病状态。
17.如权利要求16所述的用途,其中所述疾病或疾病状态选自头部癌、甲状腺癌、颈癌、眼癌、皮肤癌、口腔癌、咽喉癌、食道癌、胸癌、骨癌、血癌、骨髓癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、胰腺癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、色素瘤、肝炎、成人呼吸窘迫综合症、骨吸收病、慢性阻塞性肺病、慢性肺炎、炎性皮肤病、囊性纤维变性、败血症性休克、脓毒症、内毒素性休克、血液动力性休克、脓毒病综合症、局部缺血后再灌注损伤、脑膜炎、纤维变性疾病、恶病质、移植物抗宿主疾病的移植排斥、自身免疫病、类风湿性脊椎炎、关节炎病症、骨质疏松症、节段性回肠炎、溃疡性结肠炎、麻风病中的麻风性结节性红斑(ENL)、辐射损伤、哮喘、富氧性肺损伤、微生物感染或微生物感染综合症。
18.如权利要求17所述的用途,其中所述关节炎病症为类风湿性关节炎或骨关节炎。
19.如权利要求16所述的用途,其中所述疾病或疾病状态为皮炎。
20.如权利要求16所述的用途,其中所述疾病或疾病状态为特异性皮炎。
21.如权利要求16所述的用途,其中所述疾病或疾病状态为银屑病、多发性硬化病或系统性红斑狼疮。
22.如权利要求16所述的用途,其中所述疾病或疾病状态为肠炎。
23.如权利要求16所述的用途,其中所述疾病或疾病状态为乙状结肠癌、恶性神经胶质瘤或HIV。
24.如权利要求15所述的用途,其中向需要所述化合物的个体给予通式(I)化合物的单位剂量为0.1mg-1000mg。
25.如权利要求15-24中任一权利要求所述的用途,其中所述药物组合物还包含至少一种其他活性成分。
26.如权利要求25所述的用途,其中所述其他活性成分选自氮芥、氮丙啶、甲基蜜胺、磺酸烷基酯、亚硝基脲、三氮烯、长春花生物碱、表鬼臼毒素、抗生素、拓扑异构酶抑制剂、抗癌疫苗、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、安波霉素、醋酸阿美蒽醌、氨鲁米特、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林霉素、阿扎胞苷、阿扎替哌、阿佐霉素、巴马司他、苯佐替哌、比卡鲁胺、盐酸比生群、甲磺酸双萘法德、比折来新、硫酸博来霉素、白消安、放线菌素C、卡普睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡柔比星、苯丁酸氮芥、西罗霉素、克拉屈滨、甲磺酸克立那托、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、盐酸柔红霉素、地西他宾、多西他塞、多柔比星、盐酸多柔比星、屈洛昔芬、盐酸表柔比星、盐酸依索比星、雌莫司汀、依他消唑、依托泊苷、氟尿苷、氟尿嘧啶、氟西他滨、吉西他宾、盐酸依达比星、异环磷酰胺、白介素II、干扰素α-2a、干扰素α-2b、盐酸依立替康、来曲唑、巯嘌呤、甲氨蝶呤、氯苯氨啶、丝列霉素、米托蒽酮、紫杉醇、丙卡巴肼、赛替哌、长春碱、长春新碱、血管生成抑制剂、喜树碱、地塞米松、阿司匹林、乙酰氨基酚、吲哚美辛、布洛芬、酮洛芬、美洛昔康或皮质类固醇。
27.权利要求11-14中任一权利要求所述的药物组合物在制备降低PDE4酶活性的药物或治疗PDE4酶介导的疾病或疾病状态的药物中的用途。
28.如权利要求27所述的用途,其中所述疾病或疾病状态选自炎症性疾病或疾病状态、感染性疾病或疾病状态、免疫疾病或疾病状态以及癌症疾病或疾病状态。
29.如权利要求27所述的用途,其中所述疾病或疾病状态选自头部癌、甲状腺癌、颈癌、眼癌、皮肤癌、口腔癌、咽喉癌、食道癌、胸癌、骨癌、血癌、骨髓癌、肺癌、结肠癌、乙状结肠癌、直肠癌、胃癌、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、胰腺癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、色素瘤、恶性神经胶质瘤、HIV、肝炎、成人呼吸窘迫综合症、骨吸收病、慢性阻塞性肺病、慢性肺炎、炎性皮肤病、囊性纤维变性、败血症性休克、脓毒症、内毒素性休克、血液动力性休克、脓毒病综合症、局部缺血后再灌注损伤、脑膜炎、纤维变性疾病、恶病质、移植物抗宿主疾病的移植排斥、自身免疫病、类风湿性脊椎炎、关节炎病症、骨质疏松症、节段性回肠炎、溃疡性结肠炎、麻风病中的麻风性结节性红斑(ENL)、辐射损伤、哮喘、富氧性肺损伤、微生物感染或微生物感染综合症。
30.如权利要求29所述的用途,其中所述关节炎病症为类风湿性关节炎或骨关节炎。
31.如权利要求28所述的用途,其中所述疾病或疾病状态为皮炎。
32.如权利要求28所述的用途,其中所述疾病或疾病状态为特异性皮炎。
33.如权利要求28所述的用途,其中所述疾病或疾病状态为银屑病、多发性硬化病或系统性红斑狼疮。
34.如权利要求28所述的用途,其中所述疾病或疾病状态为肠炎。
35.如权利要求28所述的用途,其中所述疾病或疾病状态为乙状结肠癌、恶性神经胶质瘤或HIV。
36.如权利要求27所述的用途,其中所述药物组合物被制备为片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
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