CN110746376B - 苯并异硒唑酮胺类化合物及其制备方法和用途 - Google Patents
苯并异硒唑酮胺类化合物及其制备方法和用途 Download PDFInfo
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- CN110746376B CN110746376B CN201910661992.5A CN201910661992A CN110746376B CN 110746376 B CN110746376 B CN 110746376B CN 201910661992 A CN201910661992 A CN 201910661992A CN 110746376 B CN110746376 B CN 110746376B
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- benzisoselenazolone
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Abstract
本发明提供一类具有式I所示结构的含苯并异硒唑酮胺类化合物，试验表明该类化合物能有效抑制TNF‑α活性和调节细胞铁死亡。本发明还提供了该类抑制剂的制备方法及在制备预防和治疗TNF‑α及细胞铁死亡介导的疾病药物中的应用。
Description
技术领域
本发明属于医药技术领域，涉及一类具有PDE-4和/或TNF-α抑制活性的苯并异硒唑酮胺化合物。本发明还涉及这些化合物的制备方法，以及这些化合物在人类或其它哺乳动物的与PDE-4和/或TNF-α通路相关的疾病或病症的治疗和/或预防中作为PDE-4和/或TNF-α抑制剂的用途。
背景技术
PDE-4(磷酸二酯酶-4)：磷酸二酯酶(PDEs)是一个庞大的家族，能将细胞内两种重要的第二信使环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)水解为无活性的5-磷酸腺苷(5-AMP)和5-磷酸鸟苷(5-GMP)，其中PDE-4是磷酸二酯酶家族重要成员之一，能够选择性的水解cAMP。PDE-4分为PDE-4A～D四种亚型，除PDE-4C外，其余亚型主要分布在气道平滑肌细胞以及淋巴细胞、巨噬细胞、中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、单核细胞、上皮细胞等炎症细胞和T细胞。PDE-4抑制剂可升高cAMP水平，通过抑制多种炎症介质、抑制细胞黏附因子的上调和表达、抑制血白细胞的活化、诱导细胞凋亡、诱导具有抑制活性的细胞因子的生成(如白细胞介素-6)以及诱导儿茶酚胺类物质和内源性激素的释放等途径来抑制这些免疫细胞和炎症细胞的活性，可以用于治疗由炎症引起的疾病，如哮喘、慢性阻塞性肺(COPD)、类风湿性关节炎、多发性硬化症、阿尔兹海默病(AD)和帕金森病(PD)等由潜在的炎症引起神经元受损伤造成的中枢神经系统疾病。
TNF-α(肿瘤坏死因子)：TNF-α是上世纪70年代发现的一类具有多种生物效应的细胞因子，主要由活化的单核细胞/巨噬细胞/T细胞分泌，通过和细胞膜上的特异性受体结合，如通过激活Caspase蛋白酶、JNK和转录因子NF-κB三条信号通路，从而引起多个不同的生物进程，并最终实现其调控细胞的生长凋亡、肿瘤形成、免疫、炎症以及应激反应等生物学功能。而不适当的TNF-α产生以及TNF-α信号的持续激活将导致系统性人类病理进程，包括全身炎症反应综合征、炎性肠病、风湿性关节炎、神经退行性疾病(多发性硬化症、运动神经元病、阿尔茨海默病、帕金森)、银屑病、脑型疟疾、糖尿病、肿瘤、骨质疏松症、同种异体移植排斥、多发性硬化症、HBV、HCV和HIV等(Brenner D.et.al.Regulation of tumornecrosis factor signaling:live or let die.Nat Rev Immunol.2015,15(6),362)。
阿普斯特(Apremilast，Otezla)：一种口服选择性磷酸二酯酶-4(PDE-4)抑制剂，于2014年底和2015年初分别获美国FDA和欧洲监管机构批准用于活动性银屑病关节炎(PSA)和中度至重度斑块型银屑病(Plaque psoriasis)的治疗。阿普斯特通过抑制抑制PDE-4，升高PDE-4表达细胞的环磷酸腺苷(cAMP)水平，从而激活蛋白激酶K(PKA)和磷酸化cAMP反应元件结合蛋白(CREB)，同时抑制核因子-κB(NF-κB)驱动基因转录，进而降低促炎介质的表达如TNF-α,IFN-γ,IL-8,IL-2和IL-23和增加了抗炎细胞因子如IL-10的表达。目前，在银屑病关节炎的治疗上，单一给药阿普斯特疗效不劣于苏金单抗、阿达木单抗(修美乐)、依那西普(恩利)、英夫利西单抗等生物制剂，并明显优于其他传统治疗药物；但在银屑病的治疗上单一给药阿普斯特疗效要弱于生物制剂，且与传统银屑病治疗药物相比优势并不明显，而这也是阿普斯特仅在欧洲批准用于银屑病治疗的主要原因之一。此外，临床服用阿普斯特片仍存在腹泻，恶心和头痛的副作用。因此，本领域亟需一种改良结构的阿普斯特类衍生物，以优化其性能。
值得注意的是，硒(以硒半胱氨酸形式存在)在生物体中是谷胱甘肽过氧化物酶(GSH-Px)、碘化甲状腺氨酸及哺乳动物硫氧还蛋白还原酶(TrxR)的重要活性中心，也是人体必需的微量元素，对人体健康有多种有益作用，如增强机体免疫力、抗氧化和抗肿瘤等。现代流行病学研究亦表明，血浆中硒含量过低是导致癌症(肝癌、胃癌、前列腺癌、肺癌和结直肠癌等)、心脑血管疾病、银屑病、骨关节炎及AIDS发生的危险因素(MarcoVinceti.et.al.Friend or Foe.The Current Epidemiologic Evidence on Seleniumand Human Cancer Risk.J.Environ.Sci.Heal.2013,31,305；Margaret P Rayman.Theimportance of selenium to human health.The Lancet.2000,356,233)。基于硒在自身免疫性疾病、心脑血管疾病及肿瘤等疾病中的重要作用(李峰等.上海医药.2017,21,6；ABSerwin.et.al.Nutrition.2003,19,301；M Wacewicz.et.al.J Trace Elem MedBio.2017,44,109.)，结合阿普斯特临床应用基础，本发明创造性的设计并合成了系列新型苯并异硒唑酮胺类化合物，以期在提高疾病治疗有效性的基础上，进一步降低现有PDE-4和/或TNF-α抑制剂类药物的毒性反应，提高药物的综合治疗指数。
发明内容
本发明的目的是提供一类新型的苯并异硒唑酮胺结构类型化合物。
本发明的另一目的是提供该类化合物的制备方法。
本发明的再一目的是关于一类苯并异硒唑酮胺结构类化合物，该类化合物不仅对PDE-4和/或TNF-α具有抑制作用，而且能抑制正常细胞的铁死亡，具有预防和/或治疗PDE-4和/或TNF-α过表达相关疾病药物中的用途。
本发明提供一类新型结构的苯并异硒唑酮胺类化合物、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药，这些化合物具有通式I所示的结构：
式(I)中，
R1、R2、R3和R4分别独立地选自下组基团：H、D、卤素、羟基、硝基、氰基、羧基、硒基、巯基、C1～C8烷硒基、C1～C8烷硒C1～C8烷胺基、C2～C8烯烷硒基、α-C1～C8烷硒基氨基酸、α-C1～C8烷硒甲酰基氨基酸、C0～C8烷胺C1～C8烷硒基、C0～C8烷胺甲酰硒基、芳硒基、C0～C8烷氧C1～C8烷硒基、C0～C8烷氧甲酰基C1～C8烷硒基、C0～C8烷氧甲酰基C1～C8烷氧基、卤代C1～C8烷硒基、C1～C8烷磺酰基、C1～C8烷磺酰胺基、C0～C8烷胺基磺酰基、C1～C8烷基、卤代C1～C8烷基、卤代C1～C8烷氧基、C0～C8烷乙炔基、C1～C8烷氧基、C1～C8烷酰氧基、C1～C8烷氧C1～C8烷氧基、C1～C8烷氧C1～C8烷基、C1～C8烷胺基、C0～C8烷胺C1～C8烷基、芳基、芳C1～C8烷胺C1～C8烷基、脒基、胍基、芳磺酰胺基、芳胺基磺酰基、芳甲酰基、C0～C8烷硒甲酰基、芳C1～C8烷胺基、芳C1～C8烷酰胺基、C1～C8烷氧甲酰基、C1～C8烷酰胺基、C0～C8烷胺基、芳硒C1～C8酰胺基、氰硒C1～C8酰胺基、苯并硒唑C1～C8烷酰胺基、苯并硒唑C1～C8烷磺酰胺基、C0～C8烷胺甲酰硒基、C0～C8烷胺甲酰胺基、C0～C8烷胺基甲酰基、C1～C8烷胺基甲酰氧基、芳胺基甲酰胺基、芳胺基甲酰基、芳胺基甲酰氧基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、吡啶基、吡嗪基、喹啉基、嘧啶基、嘧啶氨基、噻唑基、噻吩基、呋喃基、吡咯基或不存在；其中，R1、R2、R3和R4所述芳基为苯基或者被1-4个选自卤素、羟基、硝基、氰基、氨基、三氟甲基、羧基、卤代C1～C8烷氧基、C1～C8烷氧基中的基团所取代的苯基；
R5为：C1～C8烷磺酰基、C1～C8烷胺甲酰基、氰基；
R6和R7分别独立地选自下组基团：卤代C1～C8烷氧基、C1～C8烷氧基、卤代C1～C8烷硒基、C1～C8烷硒基；
X为：C或Se；其中，W为C时，R1、R2、R3、R4、R6和R7取代基至少存在一个含硒取代基；W为Se时，R1、R2、R3、R4和R5为任意上述所述基团；
n＝1-4；
虚线为：化学键或不存在。
优选的，本发明提供通式(I-a)和(I-b)结构化合物、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药：
式(I-a)和(I-b)中，
R1、R2、R3和R4分别独立地选自下组基团：H、D、卤素、羟基、硝基、氰基、羧基、硒基、巯基、C1～C8烷硒基、C1～C8烷硒C1～C8烷胺基、C2～C8烯烷硒基、α-C1～C8烷硒基氨基酸、α-C1～C8烷硒甲酰基氨基酸、C0～C8烷胺C1～C8烷硒基、C0～C8烷胺甲酰硒基、芳硒基、C0～C8烷氧C1～C8烷硒基、C0～C8烷氧甲酰基C1～C8烷硒基、C0～C8烷氧甲酰基C1～C8烷氧基、卤代C1～C8烷硒基、C1～C8烷磺酰基、C1～C8烷磺酰胺基、C0～C8烷胺基磺酰基、C1～C8烷基、卤代C1～C8烷基、卤代C1～C8烷氧基、C0～C8烷乙炔基、C1～C8烷氧基、C1～C8烷酰氧基、C1～C8烷氧C1～C8烷氧基、C1～C8烷氧C1～C8烷基、C1～C8烷胺基、C0～C8烷胺C1～C8烷基、芳基、芳C1～C8烷胺C1～C8烷基、脒基、胍基、芳磺酰胺基、芳胺基磺酰基、芳甲酰基、C0～C8烷硒甲酰基、芳C1～C8烷胺基、芳C1～C8烷酰胺基、C1～C8烷氧甲酰基、C1～C8烷酰胺基、C0～C8烷胺基、芳硒C1～C8酰胺基、氰硒C1～C8酰胺基、苯并硒唑C1～C8烷酰胺基、苯并硒唑C1～C8烷磺酰胺基、C0～C8烷胺甲酰硒基、C0～C8烷胺甲酰胺基、C0～C8烷胺基甲酰基、C1～C8烷胺基甲酰氧基、芳胺基甲酰胺基、芳胺基甲酰基、芳胺基甲酰氧基或不存在；其中，R1、R2、R3和R4所述芳基为苯基或者被1-4个选自卤素、羟基、硝基、氰基、氨基、三氟甲基、羧基、卤代C1～C8烷氧基、C1～C8烷氧基中的基团所取代的苯基；(I-b)中，R1、R2、R3、R4、R6和R7取代基至少存在一个含硒取代基；
R5为：C1～C8烷磺酰基、C1～C8烷磺酰基；胺甲酰基、氰基；
R6和R7分别独立地选自下组基团：卤代C1～C8烷氧基、C1～C8烷氧基、卤代C1～C8烷硒基、C1～C8烷硒基；
虚线为：化学键或不存在。
如本文所用，术语“卤素”是指氟、氯、溴和碘。
如本文所用，术语“卤代”可以是单卤代，也可以是多卤代。
如本文所用，术语“烷磺酰基”是指直链或支链或环状饱和烃磺酰基，所述环状饱和烃为3～8碳原子。
如本文所用，术语“C1～C8烷硒基”是指直链或支链或环状饱和烃硒基，所述环状饱和烃为3～8碳原子。
如本文所用，术语“C0～C8烷硒甲酰胺基”是指直链或支链或环状饱和烷烃硒甲酰胺基，所述环状饱和烃为3～8碳原子。
如本文所用，术语“烷磺酰胺基”是指直链或支链或环状饱和烷烃磺酰胺基，所述环状饱和烃为3～8碳原子。
如本文所用，术语“烷胺基磺酰基”是指N-单取代或者二取代的直链或支链或环状饱和烷烃胺基磺酰基，所述环状饱和烃为3～8碳原子。
如本文所用，术语“烷胺基甲酰基”是指N-单取代或者二取代的直链或支链或环状饱和烷烃胺基甲酰基，所述环状饱和烃为3～8碳原子。
如本文所用，术语“烷基”是指直链或支链直链或支链或环状饱和烃基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷氧基”是指直链或支链或环状饱和烃氧基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷乙炔基”是指直链或支链或环状饱和烃乙炔基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷酰氧基”是指直链或支链或环状饱和烃酰氧基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷酰硒基”是指直链或支链或环状饱和烃酰硒基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷胺基”是指N-单取代或者二取代的直链或支链或环状饱和烃胺基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷氧甲酰基”是指直链或支链或环状饱和烃氧甲酰基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷酰胺基”是指直链或支链或环状饱和烃酰胺基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“烷胺基甲酰胺基、”是N-单取代或者二取代指直链或支链或环状饱和烃胺基甲酰胺基，所述环状饱和烷烃为3～8碳原子。
如本文所用，术语“立体异构体”是指一个或多个立体中心的手性不同的化合物。立体异构体包括对映异构体和非对映异构体。
如本文所用，所述“哌嗪基、吗啉基、吡咯基、吡唑基、吡咯基、咪唑基、嘧啶氨基”如无特殊说明，取代连接位点均在N上。
如本文所用，所述“吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡嗪基、喹啉基”如无特殊说明，取代连接位点均在C上。
本发明所述的化合物有立体异构体存在的情况下，本发明包括化合物的所有立体异构体。
本发明还包括所述化合物中的任何一个或多个氢原子被其稳定同位素氘取代而产生的氘代化合物。
如本文所用，术语“代谢物”是指药物分子在体内所经历的化学结构的变化后产生的活性物质，该活性物质一般为前述药物分子的衍生物，其还可被化学修饰。
如本文所用并且除非另有规定，术语“晶型(polymorph)”是指在结晶时，分子在晶格空间的排列不同而形成的一种或多种晶体结构。
如本文所用，术语“溶剂化物”是指通式(I)化合物、晶型、立体异构体、同位素化合物、代谢物或前药的一种晶体形式，它还包含一种或多种融入晶体结构中的溶剂分子。溶剂化物可包括化学计量量或非化学计量量的溶剂，并且溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量量溶剂分子的溶剂化物可能是溶剂化物至少丢失一个(但并非全部)溶剂分子得到的。在一个特定实施例中，一种溶剂化物是一种水合物，意味着化合物的结晶形式进一步包括水分子，以水分子作为溶剂。
如本文所用并且除非另有规定，术语“前药”是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，前药无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，前药可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。有关前药的综述参见，例如，J.Rautio et al.，Nature Reviews Drug Discovery(2008)7，255-270and Prodrugs：Challenges和Rewards(V.Stella et al.ed.，Springer，2007)。
本发明的通式(I)化合物、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药可以含有一个或多个不对称中心(“立体异构体”)。如本文所用，术语“立体异构体”是指对映异构体、非对映异构体、差向异构体(epimers)、内向-外向异构体(endo-exoisomers)、阻转异构体(atropisomers)、位向异构体(regioisomers)、顺式-和反式-异构体等在内的所有立体异构体。本文的“立体异构体”也包括前述各种立体异构体的“纯立体异构体”及“富集立体异构体”或“消旋体”。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。
本发明的部分优选的新型含硒度胺类化合物如下所示。这些实施例举只对本发明做进一步说明，并不对本发明的范围构成任何限制。
其中众所周知任意上述列举的化合物的任意立构中心在未明示时可以是绝对(R)-或(S)-构型，也可以是二者的外消旋体混合物。本发明涉及：这些化合物的外消旋混合物，富集任一种对映体的混合物，以及任一种分离的对映体。对于本发明的范围，应当理解为，所述外消旋混合物指两种R和S对映体50％:50％的混合物，所述分离的对映体应理解为纯的对映体(即100％)或者高度富集某种对映体(纯度≥98％、≥95％、≥90％、≥88％、≥85％、≥80％)的混合物。
根据本发明的第二方面，提供上述苯并硒唑类化合物的制备方法，该方法包括下列方法制备。
以下缩写应用于整个说明书和实施例中：
以下缩写应用于整个说明书和实施例中：
Ac 乙酰基
AcOH 乙酸
Base 有机碱或无机碱
DMF N,N-二甲基甲酰胺
EA 乙酸乙酯
EtOH 乙醇
EDC 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐
H2O2双氧水
HOBt 1-羟基苯并三氮唑
LC-MS液相色谱-质谱
NMR核磁
Pd/C-H2钯碳氢气还原体系
TLC 薄层层析
V 溶液体积
本发明式I化合物可按照如下通用方法制备：
a)本发明I-a结构系列中二价硒类化合物合成路线
b)本发明I-a结构系列中四价硒类化合物合成路线
c)本发明I-b结构类化合物合成路线
式I-a结构系列中二价硒类型化合物合成可以是以取代2-卤苯甲酸为原料，经步骤(1)与(S)-2-(取代酰基)-1-取代苯基乙胺反应得到中间体a’，然后经步骤(2)与硒试剂反应得到；
式I-a结构系列化合物合成也可以直接以邻硒氯苯甲酰氯为原料，直接与(S)-2-(甲磺酰基)-1-取代苯基乙胺得到目标化合物；
在步骤(1)中，以取代2-卤苯甲酸为原料，在常规缩合条件下如DCC、EDCI、HOBT为缩合剂，三乙胺、吡啶、二异丙基乙胺等作碱，与(S)-2-(甲磺酰基)-1-取代苯基乙胺在有机溶剂中反应(rt～120℃)得到中间体a’，所用溶剂包括但不限于N,N-二甲基甲酰胺、二甲基亚砜、乙腈、四氢呋喃、二氯甲烷、氯仿和乙酸乙酯等有机溶剂(参考文献：HeteroatomChemistry.2014,35,320)；
在步骤(2)中，将中间体a’，在硒化试剂如硒粉、LiSeSeLi、NaSeSeNa、KSeSeK、NaSeCN等作用下经硒化偶联成环反应如得到目标化合物I-a，所用溶剂包括但不限于N,N-二甲基甲酰胺、二甲基亚砜、乙腈、四氢呋喃、二氯甲烷、氯仿和乙酸乙酯等有机溶剂(参考文献：Org.Lett.2010,12,23；J.Org.Chem.2017,82,3844；Tetrahedron.2011,67,9565)。
在步骤(3)中，当取代苯甲酰氯邻位为SeCl时，在碱性条件下如三乙胺、二异丙基乙胺、吡啶等叔胺，与(S)-2-(甲磺酰基)-1-取代苯基乙胺(反应rt～120℃)得到目标化合物，所用溶剂包括但不限于N,N-二甲基甲酰胺、二甲基亚砜、乙腈、四氢呋喃、二氯甲烷、氯仿和乙酸乙酯等有机溶剂(参考文献：J.Med.Chem.2013,56,9089)；
式I-a结构系列中四价硒类型化合物合成是以二价取代苯并异硒唑为原料，经[O-]过氧化反应得到，所用溶剂包括但不限于四氢呋喃、二氯甲烷、氯仿和乙酸乙酯等有机溶剂，反应温度-20℃～0℃，所用过氧化试剂包括但不限于H2O2、O3、间氯过氧苯甲酸(参考文献：J.Org.Chem.2005,70,868；J.Org.Chem.2005,70,5023)；
式I-b结构类型化合物中化合物40-45的合成是以4位去乙酰基阿普斯特为原料，依次经反应步骤(a)二硒化、步骤(b)还原、步骤(c)成醚和步骤(d)脱保护基反应得到；化合物46-51的合成是以4位去乙酰基阿普斯特为原料，经步骤(e)得到；
式I-b结构类型化合物是以4位去乙酰基阿普斯特为原料，经步骤(a)酰化反应与N-苯并硒唑-氨基酸或N-苯并硒唑-牛磺酸或N-硒代吗啉-乙酸反应得到(参考文献：J.Org.Chem.2004,46,53；J Med Chem.2001,1021)。
具体地，根据本发明的方法，经反应式a)、b)和c)所示方法，得到系列不同结构类型的苯并异硒唑酮胺类化合物。反应过程通常用TLC和LC-MS来检测反应完成程度，反应完毕后一般用甲基叔丁基醚、乙酸乙酯或二氯甲烷等溶剂萃取，依次用饱和碳酸氢钠、水和饱和食盐水洗，经无水硫酸钠或者硫酸镁干燥，低温减压下除去溶剂。关键中间产物及最终产物用核磁共振及质谱检测确证。
根据本发明的第三方面，式I的化合物具有抑制PDE-4和/或TNF-α过表达作用。相应地，它们可作为PDE-4和/或TNF-α抑制剂用于治疗(包括联合治疗)PDE-4和/或TNF-α过表达引起相关疾病，包括哮喘、关节炎症、类风湿性关节炎、痛风性关节炎、类风湿性脊椎炎、骨关节炎和其他关节炎性病症；脓毒症、败血症性休克、内毒素性休克、革兰氏阴性脓毒症、中毒性休克综合症、急性呼吸窘迫综合症、脑型疟慢性肺炎症性病、硅肺、肺结节病、骨吸收病、移植物抗宿主反应、同种移植排斥、由感染引起的发热和肌痛、继发于感染或恶性肿瘤的恶病质、继发于人获得性免疫缺陷综合症(艾滋病)的恶病质、艾滋病、HIV、HBV、ARC(艾滋病相关复症)、瘢痕瘤形成、瘢痕组织形成、局限性回肠炎、溃疡性结肠炎、多发性硬化、阿尔兹海默病(AD)和帕金森病(PD)、I型糖尿病、自身免疫糖尿病、尿崩症、系统性红斑狼疮、支气管炎、慢性阻塞性气道病、牛皮癣、Bechet氏病、类过敏性紫癜性肾炎、慢性肾小球肾炎、炎症性肠病、白血病、过敏性鼻炎、抑郁、多梗死性痴呆或者皮炎。
有益效果
本发明设计并合成了一类新型结构苯并异硒唑酮胺的类化合物，其对PDE-4和/或TNF-α有明显的抑制作用。相对现有PDE-4抑制剂阿普斯特，本发明苯并异硒唑酮胺抑制剂还可改善哺乳动物因体内硒水平降低而导致和/或加剧的疾病如银屑病，显著提升综合治疗效果。
具体实施方式
下面结合具体实施例对本发明作进一步阐释，但不限制本发明。本发明的实验操作具有通用性，不限于以下实施例中提到的具体化合物。
下述制备例中，1H-NMR用Varian Mercury AMX300型仪测定。MS用VG ZAB-HS或VG-7070型以及Esquire 3000Plus-01005测定。所有反应溶剂在使用前均经过重新蒸馏，所使用的无水溶剂均是按照标准方法干燥处理获得。除说明外，所有反应均是在氩气保护下进行并用TLC跟踪，后处理时均经饱和食盐水和无水硫酸钠干燥过程。产品的纯化除另有说明外均使用硅胶(200-300目)的柱色谱纯化。
实施例1化合物1的合成
合成路线：
(1)中间体1a合成
在冰浴搅拌的条件下，向含有2-溴-3-硝基苯甲酸(246mg，1mmol)、EDCI(384mg，2mmol)、DMAP(12mg，0.1mmol)和N,N-二异丙基乙胺(390mg,3mmol)的DMF溶液(2mL)中加入(S)-2-(甲磺酰基)-1-(3’-乙氧基-4’-甲氧基)苯基乙胺(273mg,1mmol)，然后于室温下反应过夜。反应完成后，加入乙酸乙酯(2ⅹ20ml)和水20mL萃取，有机相依次经饱和食盐水洗涤、无水硫酸钠干燥、减压浓缩至干及常规硅胶柱层析(V乙酸乙酯:V石油醚＝1:4～1:1)，得到中间体1a(400mg，收率80％)。HRMS-ESI:m/z calcd for C19H21BrN2O7S:500.0253,found[M+H]+501.0330；1H NMR(500MHz,MeOD)δ7.89(d,J＝7.4Hz,1H),7.75(d,J＝6.7Hz,1H),7.69-7.62(m,1H),7.15-6.96(m,3H),5.76-5.69(m,1H),4.16-4.09(m,1H),3.86(s,3H),3.78-3.60(m,2H),2.99(s,3H),1.42(t,J＝6.6Hz,3H)。
(2)中间体1b合成
向含有1a(250mg,0.5mmol)和氯化铵(214mg,4mmol)的四氢呋喃-甲醇-水(10ml/8ml/2ml)溶液20ml中加入锌粉(162mg，2.5mmol)，然后缓慢升温至50℃反应1小时至完全。反应完成后经硅藻土过滤，滤液浓缩至干后加水20ml，然后加入乙酸乙酯(20mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，得到中间体1b。(240mg，收率100％)。HRMS-ESI:m/z calcd for C19H23BrN2O5S:470.0511,found[M+H]+471.0588；1H NMR(500MHz,CDCl3)δ7.14(t,J＝7.7Hz,1H),7.01-6.83(m,5H),5.70(dd,J＝13.1,6.4Hz,1H),4.29(brs,2H),4.13(q,J＝6.9Hz,2H),3.89(s,3H),3.78(dd,J＝14.9,6.4Hz,1H),3.58(dd,J＝14.9,5.2Hz,1H),2.69(s,3H),1.49(t,J＝6.9Hz,3H)。
(3)中间体1c合成
将中间体1b(235mg,0.5mmol)加入到乙酸酐(1mL)和吡啶混合溶液中(1ml)，然后升温至80℃反应2小时；反应完成后，加1N盐酸溶液调节pH至3，然后加入乙酸乙酯(20mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥、减压浓缩至干及常规硅胶柱层析(V乙酸乙酯:V石油醚＝1:4～1:1)，得到中间体1c(260mg，收率100％)。HRMS-ESI:m/z calcd forC21H25BrN2O6S:512.0617,found[M+H]+513.0690；1H NMR(500MHz,DMSO)δ9.53(s,1H),9.11(d,J＝8.6Hz,1H),7.65-7.41(m,2H),7.23(d,J＝7.5Hz,1H),7.18-6.95(m,3H),5.60-5.47(m,1H),4.03(dd,J＝13.7,6.8Hz,2H),3.75(s,3H),3.68-3.50(m,2H),2.96(s,3H),2.09(s,3H),1.33(t,J＝6.9Hz,3H)。
(4)化合物1的合成
向含有CuI(38mg,0.2mmol),1,10-邻二氮杂菲(39mg,0.2mmol)的DMF溶液(2mL)中加入a3(256mg,0.5mmol)、硒粉(0.8g,1mmol)、K2CO3(138mg,1mmol)，然后置于氮气氛围中于110℃反应过夜至完全。TLC检测反应完成后，加水20ml，然后加入乙酸乙酯(20mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，过滤，所得滤液减压蒸干后经硅胶柱色谱纯化(V乙酸乙酯:V石油醚＝1:4～1:1)，得到化合物1(84mg，收率33％)。HRMS-ESI:m/z calcd forC21H24N2O6SSe:512.0520,found[M+H]+513.0598；1H NMR(500MHz,CDCl3)δ9.57(s,1H),8.72-7.44(m,3H),7.12(dd,J＝8.3,2.1Hz,1H),7.04-6.94(m,2H),5.99(t,J＝6.8Hz,1H),4.18-4.04(m,3H),3.92(s,3H),3.82(dd,J＝14.6,7.2Hz,1H),2.97(s,3H),2.25(s,3H)1.49-1.42(m,3H)。
实施例2化合物2的合成
在氮气和冰浴条件下，将(254mg，1mmol)二氯硒基苯甲酰氯(制备)方法参照J.Med.Chem.2016，59，8125-8133)的二氯甲烷溶液(2mL)缓慢加入到含有1-(3-乙氧基-4-甲氧基苯基)-2-(甲磺酰基)乙胺(273mg,1mmol)和三乙胺(151mg,1.5mmol)的二氯甲烷溶液(10mL)中，然后继续反应至完全。TLC检测反应完成后，加水20ml，然后加入二氯甲烷(20mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，过滤，所得滤液减压蒸干后经硅胶柱色谱纯化(V丙酮:V石油醚＝1:4～1:1)，得到化合物2(432mg，收率95％)。HRMS-ESI:m/z calcd for C19H21NO5SSe:455.0306,found[M+H]+456.0378；1H NMR(500MHz,CDCl3)δ8.04(d,J＝7.9Hz,1H),7.64-7.52(m,2H),7.44(t,J＝7.3Hz,1H),7.06(dd,J＝8.3,1.9Hz,1H),7.00(d,J＝1.9Hz,1H),6.91(d,J＝8.3Hz,1H),5.98(t,J＝6.8Hz,1H),4.17-4.06(m,3H),3.90(s,3H),3.80(dd,J＝14.8,7.1Hz,1H),2.96(s,3H),1.46(t,J＝7.0Hz,3H)。13CNMR(126MHz,DMSO)δ166.3,149.6,148.4,140.1,132.0,131.5,128.7,127.9,126.3,126.2,120.9,113.2,112.2,64.4,56.8,55.9,52.5,41.8,15.2。
实施例3-6制备参考实施例1操作，变换不同的取代邻溴苯甲酸与(S)-2-(甲磺酰基)-1-取代苯基乙胺反应；实施例7-14的制备参考实施例2操作，所得实施例结果如下：
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实施例15化合物15的合成
(1)中间体15a合成
在冰浴搅拌的条件下，将乙酰氯(316mg，4mmol)加入到含有2-氨基-6-溴苯甲酸(432mg，2mmol)的四氢呋喃饱和乙酸钠混合溶液中(体积比1:1，5ml)，然后升至室温反应0.5小时；反应完成后，加1N盐酸溶液调节pH至3，然后加入乙酸乙酯(20mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥、减压浓缩至干，得到中间体15a(520mg，收率100％)。MS-ESI:m/z[M-H]-256.0。
(2)中间体15b合成
在冰浴搅拌的条件下，向含有15a(258mg，1mmol)、EDCI(384mg，2mmol)、DMAP(240mg，2mmol)的DMF溶液(2mL)中加入(S)-2-(甲磺酰基)-1-(3’-环戊氧基-4’-甲氧基)苯基乙胺(313mg,1mmol)，然后于室温下反应过夜。反应完成后，加入乙酸乙酯(2ⅹ20ml)和水20mL萃取，有机相依次经饱和食盐水洗涤、无水硫酸钠干燥、减压浓缩至干及常规硅胶柱层析(V乙酸乙酯:V石油醚＝1:4～1:1)，得到中间体15b(391mg，收率71％)。MS-ESI:m/z[M+H]+553.1。
(3)化合物15的合成
向含有CuI(38mg,0.2mmol),1,10-邻二氮杂菲(39mg,0.2mmol)的乙腈溶液(2mL)中加入15b(276mg,0.5mmol)、硒粉(0.8g,1mmol)、K2CO3(138mg,1mmol)，然后置于氮气氛围中于110℃反应过夜至完全。TLC检测反应完成后，加水20ml，然后加入乙酸乙酯(20mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，过滤，所得滤液减压蒸干后经硅胶柱色谱纯化(V乙酸乙酯:V石油醚＝1:4～1:1)，得到化合物1(76mg，收率27％)。HRMS-ESI:m/zcalcd for C24H28N2O6SSe:552.0883,found[M+H]+553.0962；1H NMR(500MHz,CDCl3)δ9.53(s,1H),8.71-7.44(m,3H),7.07-6.99(m,2H),6.92(d,J＝7.8Hz,1H),5.98(t,J＝6.8Hz,1H),4.81-4.72(m,1H),4.18-4.05(m,1H),3.86-3.80(m,4H),2.97(s,3H),2.69(s,3H),1.99-1.56(m,8H)。
实施例16化合物16的合成
在氮气和冰浴条件下，将(25mg,0.1mmol)二氯硒基苯甲酰氯的二氯甲烷溶液(1mL)缓慢加入到含有(31mg,0.1mmol)1-(3-乙氧基-4-甲氧基苯基)-2-(甲磺酰基)乙胺(制备方法参见US2006/0084815)和三乙胺(15mg,0.15mmol)的二氯甲烷溶液(2mL)中，然后继续反应至完全。TLC检测反应完成后，加水5ml，然后加入二氯甲烷(5mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，过滤，所得滤液减压蒸干后经硅胶柱色谱纯化(V丙酮:V石油醚＝1:4～1:1)，得到化合物16(44mg，收率90％)。HRMS-ESI:m/z calcd forC22H25NO5SSe:495.0619,found[M+H]+496.0690；1H NMR(500MHz,CDCl3)δ8.06(d,J＝7.9Hz,1H),7.64-7.52(m,2H),7.44(t,J＝7.3Hz,1H),7.08-6.99(m,2H),6.91(d,J＝7.8Hz,1H),5.97(t,J＝6.8Hz,1H),4.81-4.72(m,1H),4.18-4.07(m,1H),3.86-3.79(m,4H),2.96(s,3H),2.64(s,3H),1.97-1.52(m,8H)。
实施例17-20制备参考实施例15操作，变换不同的取代邻溴苯甲酸与(S)-2-(甲磺酰基)-1-取代苯基乙胺或(S)-2-(胺甲酰基)-1-取代苯基乙胺反应；实施例21-24制备参考实施例16操作，变换不同的取代邻溴苯甲酸与2-(甲磺酰基)-1-取代苯基乙胺或2-(胺甲酰基)-1-取代苯基乙胺、或2-(氰基)-1-取代苯基乙胺反应，所得实施例结果如下：
实施例25化合物25的合成
在冰浴搅拌的条件下，向含有化合物1(45mg,0.1mmol)的二氯甲烷溶液(2mL)中慢慢加入30％过氧化氢(0.12mmol)并继续反应2h至完全。TLC检测反应完成后，加水5ml，然后加入乙酸乙酯(5mL×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，过滤，所得滤液减压蒸干后经硅胶柱色谱纯化(V乙酸乙酯:V石油醚＝1:1)，得到化合物25(36mg，收率77％)。HRMS-ESI:m/z calcd for C19H21NO6SSe:471.0255,found[M+H]+472.0730。1H NMR(500MHz,DMSO)δ8.08(d,J＝8.2Hz,1H),7.89(d,J＝7.7Hz,1H),7.63(t,J＝7.6Hz,1H),7.49(t,J＝7.4Hz,1H),7.23(s,1H),7.15-6.98(m,2H),6.07(t,J＝7.0Hz,1H),4.28-4.08(m,4H),3.81(s,3H),2.93(s,3H),1.37(t,J＝6.9Hz,3H)。
实施例26～32的制备参考实施例25操作，所得实施例结果如下：
实施例46化合物46的合成
(1)制备方法步骤1：N-苯并硒唑-甘氨酸的合成
在冰浴剧烈搅拌条件下，向含有甘氨酸(751mg,10mmol)和碳酸钠(2.12g,20mmol)的二氯甲烷/水(50ml/5ml)溶液中加入10mmol的2-氯硒基-苯甲酰氯(按照专利CN101016319A制备方法获得)，滴加完毕后并于室温下反应1h。反应完成后，加水10ml，1N HCl调节pH至4，二氯甲烷(50ml×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，过滤，所得滤液减压蒸干后经硅胶柱色谱纯化(V乙酸乙酯:V石油醚＝1:1～2：1)，得中间体N-苯并硒唑-甘氨酸(1.85g,72％)，MS-ESI[M+H]+258.0(258.0)。按照本方法，以丙氨酸为原料，获得关键中间体N-苯并硒唑-丙氨酸。
按照上述方法，以牛磺酸为原料，获得其他关键中间体N-苯并硒唑-牛磺酸(2.30g,75％)，MS-ESI[M+H]+308.0(308.0)。
(2)制备方法步骤2：化合物33的合成
在氩气条件下，向含有N-苯并硒唑-甘氨酸(26mg,0.1mmol)的DMF溶液1ml中加入HOBt(20mg,0.15mmol)和EDC(29mg,0.15mmol)，反应1小时后，加入4-去乙酰阿普斯特(42mg,0.1mmol)，并于80℃条件下继续反应24h。反应完成后，加饱和氯化铵2ml淬灭，乙酸乙酯(5ml×2)萃取，有机相依次用饱和食盐水洗涤，无水硫酸钠干燥，过滤，所得滤液减压蒸干后经硅胶色谱纯化(V乙酸乙酯:V石油醚＝1:2)，得到化合物33(37mg,收率56％)。HRMS-ESI:m/z calcd for C29H27N3O8SSe:657.0684,found[M+H]+658.0762；1H NMR(500MHz,CDCl3)δ10.41(s,1H),8.78(d,J＝8.0Hz,1H),8.27(d,J＝6.8Hz,1H)，8.13-8.09(d,J＝7.6Hz,1H),7.90-7.60(m,3H),7.45-7.37(m,1H),7.15-6.95(m,3H),5.91-5.80(m,1H),4.67(s,2H),4.38-4.14(m,2H),4.08-4.02(q,J＝7.0Hz,2H),3.78(s,3H),3.03(s,3H),1.35(t,J＝6.9Hz,3H)。
实施例34～40的制备参考实施例33操作，实施例结果如下：
实施例41PDE-4活性抑制实验
方法按Lance cAMP Assay：准确称取供试品，加入DMSO溶解，充分混匀，配成100μM。然后用DMSO将上述母液稀释为1μM，然后4倍稀释至0.0038nM。384孔板中加入2.5μL底物20nM cAMP，50nL化合物DMSO溶液，再加入2.5μL PDE-4酶缓冲液(1×HBSS，5mM Hepes pH7.4，3mM MgCl2，0.1％BSA)室温孵育90min后，加入5μL Alexa647-anti cAMP抗体孵育30min后，加入10μL检测试剂孵育60min后，665nm检测其LANCE信号，通过以下公式计算抑制率，由抑制率用XLfit计算IC50值。
抑制率＝[信号值(MAX)-信号值(样品)]×100/[信号值(MAX)-信号值(MIN)]注：MAX：不加酶的空白对照；MIN：不加化合物的空白对照。具体见表1。
表1.PDE-4抑制活性
注：A:＜100nM；B:100nM～0.99μM；C:＞1μM。
实施例42TNF-α活性抑制实验
采集健康志愿者的外周血并用EDTA抗凝管收集。将血液用1640培养基(Gibco，产品目录号11875-093，USA)稀释5倍后加入到96孔细胞培养板中(Costar，产品目录号3599，USA)，然后用10μl本发明通式(I)化合物的DMSO(Sigma，产品目录号D2650，USA)溶液处理，化合物的终浓度为100nM，DMSO的终浓度为0.2％。在37℃，5％CO2培养箱中孵育60min后，于反应体系中加入10μl LPS(Sigma，产品目录号L-2880，USA)，终浓度10ng/ml，再在37℃，5％CO2条件下继续培养6小时后。收集上清液，TNF-α含量通过ELISA方法(BD Biosciences，产品目录号555212，USA)测定。用读板仪器检测吸收光强度，检测OD450 nm值，以OD650 nm值作为参考，以含0.2％DMSO培养基的溶液对照组作为0％抑制。记录原始数据和标准曲线。通过XL-fit软件，绘制四参数药物抑制曲线并计算每个化合物的抑制率，具体见表2。
表2.TNF-α抑制活性
实施例43拟谷胱甘肽过氧化酶(GPx)活性实验
实验方法：采用分光光度法研究本发明通式(I)化合物的GPX活性。将谷胱甘肽(2.0mM)、EDTA(1mM)、谷胱甘肽二硫化物还原酶(1.7units mL-1)和烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NADPH；0.4mM)混合于pH＝7.5的0.1M的磷酸钾缓冲液中。在室温下(25℃)，将待测样品(50μm)添加到上述混合物中，然后分别添加H2O2，tBuOOH或Cum-OOH(1.6mM)开始反应。初始还原速率(v0)通过测定NADPH的氧化速率计算得出，用摩尔消光系数(6.22mM-1cm-1)表示NADPH，连续检测反应体系在340nm处的吸光度变化，每个初始速率至少测量3次。其中，过氧化物酶活性的校正测定扣除过氧化物和谷胱甘肽之间的背景反应。实验结果见表3。
表3.式I化合物拟Gpx4抗氧化作用
实验结果表明，苯并异硒唑酮胺类化合物拟谷胱甘肽过氧化酶(GPx)活性显著优于阳性对照依布硒。
实施例44苯并异硒唑酮胺类化合物对Erastin诱导HT22发生铁死亡的保护作用
药品：受试苯并异硒唑酮胺类化合物，Erastin，DMSO溶解。
试剂：CCK-8试剂盒、DEME培养基购自Sigma公司；小鼠HT22海马细胞(上海交通大学)。
CCK-8实验：HT22细胞于含5％ CO2、37℃恒温箱中培养，生长在含10％血清的DMEM培养基中。然后在96孔板中种植培养的HT22细胞，预处理药物2小时(5μM)，再加入0.5μmol/L Erastin作用8小时；然后每孔分别加入CCK-8溶液10μL，培养箱内孵育3小时，酶标仪上读取450nm处的吸光值。细胞存活率每组按照以下公式计算：细胞存活率％＝(处理组-空白对照组)/(对照组-空白对照组)*100％。实验重复3次。
实验结果：如附图2所示，铁死亡促进剂Erastin可引起HT22细胞凋亡。苯并异硒唑酮胺类化合物可显著减轻Erastin引起的HT22细胞损伤，提高细胞存活率。
Claims (5)
1.一种通式(I-a)和(I-b)所示结构化合物：
式(I-a)和(I-b)中，
R1、R2、R3和R4分别独立地选自下组基团：H、D、卤素、羟基、硝基、氰基、羧基、C0～C8烷氧甲酰基C1～C8烷氧基、卤代C1～C8烷硒基、C1～C8烷磺酰基、C1～C8烷磺酰胺基、C0～C8烷胺基磺酰基、C1～C8烷基、卤代C1～C8烷基、卤代C1～C8烷氧基、C1～C8烷氧基、C1～C8烷酰氧基、C1～C8烷氧C1～C8烷氧基、C1～C8烷氧C1～C8烷基、C0～C8烷胺C1～C8烷基、C1～C8烷氧甲酰基、C1～C8烷酰胺基、C0～C8烷胺基、苯并硒唑C1～C8烷酰胺基、苯并硒唑C1～C8烷磺酰胺基、C0～C8烷胺甲酰胺基、C0～C8烷胺基甲酰基、C1～C8烷胺基甲酰氧基或不存在；(I-b)中，R1、R2、R3和R4取代基至少存在一个含硒取代基；
R5为：C1～C8烷磺酰基；胺甲酰基、氰基；
R6和R7分别独立地选自下组基团：卤代C1～C8烷氧基、C1～C8烷氧基；
虚线为：化学键或不存在。
2.根据权利要求1所述的苯并异硒唑酮胺类化合物，其特征在于，所述化合物选自下组：
3.一种根据权利要求1-2中任意一项所述的苯并异硒唑酮胺类化合物的制备方法，通过下述方法得到：
a)本发明I-a结构系列中二价硒类化合物合成路线
b)本发明I-a结构系列中四价硒类化合物合成路线
c)本发明I-b结构类化合物合成路线
式I-a结构系列中二价硒类型化合物合成可以是以取代2-卤代苯甲酸为原料，首先步骤(1)与(S)-2-(取代酰基)-1-取代苯基乙胺发生缩合反应得到中间体a’，然后经步骤(2)与硒试剂反应成环得到目标化合物；
式I-a结构系列中二价硒类型化合物合成也可以邻硒氯苯甲酰氯为原料直接与(S)-2-(取代酰基)-1-取代苯基乙胺反应得到目标化合物；
式I-a结构系列中四价硒类型化合物合成以二价取代苯并异硒唑为原料，经[O-]过氧化反应得到；
式I-b结构类型化合物的合成是以4位去乙酰基阿普斯特为原料，经步骤(e)与硒酰类试剂缩合得到。
4.权利要求1-2中任意一项所述的苯并异硒唑酮胺类化合物在制备预防或治疗PDE-4和/或TNF-α过表达引起的疾病的药物中的应用；其中所述PDE-4和/或TNF-α过表达导致的相关疾病包括哮喘、类风湿性关节炎、痛风性关节炎、类风湿性脊椎炎、骨关节炎、急性呼吸窘迫综合症、脑型疟慢性肺炎症性病、硅肺、肺结节病、骨吸收病、移植物抗宿主反应、由感染引起的发热和肌痛、继发于感染或恶性肿瘤的恶病质、继发于人获得性免疫缺陷综合症的恶病质、HIV、HBV、ARC、瘢痕组织形成、系统性红斑狼疮、支气管炎、慢性阻塞性气道病、牛皮癣、Bechet氏病、类过敏性紫癜性肾炎、慢性肾小球肾炎、炎症性肠病、白血病、过敏性鼻炎或者皮炎。
5.权利要求1-2中任意一项所述的苯并异硒唑酮胺类化合物在制备预防或治疗谷胱甘肽过氧化酶不足或缺失引起的细胞铁死亡相关疾病的药物中的应用；其中所述谷胱甘肽过氧化酶不足或缺失引起的细胞铁死亡相关疾病包括脓毒症、败血症性休克、内毒素性休克、中毒性休克综合症、多发性硬化、阿尔兹海默病和帕金森病、自身免疫糖尿病、尿崩症、抑郁或者多梗死性痴呆。
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