CN110746396A - 含硒异唑胺类化合物及其制备方法和用途 - Google Patents
含硒异唑胺类化合物及其制备方法和用途 Download PDFInfo
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- CN110746396A CN110746396A CN201910660653.5A CN201910660653A CN110746396A CN 110746396 A CN110746396 A CN 110746396A CN 201910660653 A CN201910660653 A CN 201910660653A CN 110746396 A CN110746396 A CN 110746396A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/80—Compounds with a nitrogen-containing hetero ring, attached with the ring nitrogen atom in position 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明提供一类具有式I所示结构的含硒异唑胺类化合物,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TNF-α和或铁死亡调节活性的含硒异唑胺类化合物及其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物。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TNF-α及铁死亡通路相关的疾病或病症的治疗和/或预防中作为TNF-α和或铁死亡调节剂的用途。
背景技术
TNF-α(肿瘤坏死因子)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。TNF-α也可以由肿瘤产生,并且可以起到促肿瘤形成的作用,也可引起肿瘤细胞的程序性死亡。此外,TNF-α也影响诸如细胞凋亡、坏死、血管生成、免疫细胞活化、分化和细胞迁移过程,所有这些过程在肿瘤发生和肿瘤进展中发挥着重要作用。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)、脑型疟疾、糖尿病、肿瘤、骨质疏松症、同种异体移植排斥、HBV、HCV和HIV等 (Brenner D. et. al. Nat Rev Immunol. 2015, 15(6), 362; J. Blake Bartlett. et. al. Nat Rev Cancer. 2004, 4, 314.)。因此降低或调节TNF-α水平是许多免疫学、炎症性、神经退行性和恶性疾病等很有前途的治疗策略(Front. Biosci. 2008, 13, 5094;Results Prob. Cell Differ. 2009, 49, 1)。
到目前为止,已有数个以TNF-α为靶点的药物开发上市,如生物大分子药物Infliximab,CD571,Etanercept,Onercept,Adalimmab (D2E7),CDP870等;小分子药物如沙利度胺、泊马度胺和来那度胺。临床应用研究显示生物大分子TNF-α抑制剂对类风湿性关节炎、强制性脊柱炎、干藓性关节炎、银屑病、炎性肠病的疗效显著(80%)且快速,往往在两周左右有明显的改善。然而这类生物大分子TNF-α抑制剂,虽然具有特异性强、结合能力强和疗效显著的优点,但也存在稳定性较差,使用不方便,在患者体内易降解,长期使用易导致患者免疫耐受及临床治疗费用高昂的缺点。此外,小分子TNF-α抑制剂如沙利度胺和来那度胺因证明其能够抑制TNF-α和其他促炎性细胞因子分泌,而被广泛用于红斑结节性麻风、一些血液及实体肿瘤,如骨髓增生异常综合征、骨髓纤维化症、套细胞淋巴瘤、急性髓系白血病以及急/慢性移植物抗宿主反应、卵巢癌、肾细胞癌等疾病的治疗,并取得了不错的临床治疗效果(Palladino M. A. et. al. Anti-TNF-α therapies: the next generation.Nat Rev Drug Discov. 2003, 2, 737)。然而,虽然它们具有这些临床益处,但是长期使用却受到限制,主要体现在其临床上的毒性反应,包括周围神经病、嗜睡、便秘以及血栓栓塞和致畸风险,因而大大降低了它们的综合治疗指数。因此,本领域亟需一种改良结构的度胺类衍生物,以优化其性能。
铁死亡是近年发现的一种铁依赖性脂质过氧化和活性氧(ROS)诱导的调节性细胞死亡,在细胞形态特征和生化指标等方面与细胞凋亡、自噬和程序性坏死等死亡方式存在较大差别,主要表现为细胞质和脂质活性氧增多、线粒体变小以及线粒体膜密度较大。这种坏死受细胞内信号通路的严密调节,包括铁稳态的调节通路、RAS通路以胱氨酸转运通路,广泛涉及肿瘤、神经系统、冠心病、组织缺血再灌注损伤、急性肾功能衰竭、衰老等多种疾病。谷胱甘肽过氧化酶(GPX4)和硫氧蛋白还原酶(TrxR),是生物体氧化还原系统中两种重要含硒蛋白酶,在细胞铁死亡过程起重要作用(DIXON, S.J. et al. Cell. 2012, 5,1060;IIngold, I. et. al. Cell. 2018, 172, 409; Llabani, E. et al. Nat Chem.2019, 11, 521.)。例如,GPX4能保护正常细胞避免氧化应激和铁死亡,当GPX4缺乏、功能不足或者被抑制时,则会导致正常细胞铁死亡。此外,TrxR是各种血液瘤(如淋巴瘤、多发性骨髓瘤)和实体瘤(如肺癌、肝癌、乳腺癌、神经胶质细胞瘤)相关性蛋白,在肿瘤细胞的增殖和分化中起着重要的作用,而抑制TrxR则会促进肿瘤细胞发生铁死亡。
本发明针对沙利度胺类药物仍然存在的问题,结合不同硒酶在细胞铁死亡调控中的作用,创造性的设计并合成了系列新型含硒异唑胺类化合物,以期在提高的TNF-α抑制活性的同时,抑制正常细胞的铁死亡,促进肿瘤细胞发生铁死亡,从而最终达到提高疾病综合治疗指数的要求。
发明内容
本发明的目的是提供一类新型的含硒异唑胺结构类化合物。
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提供含硒异唑胺结构类化合物的用途,该类化合物对TNF-α表达和细胞铁死亡的有明显的干预作用,可用于预防和/或治疗TNF-α过表达相关疾病以及细胞铁死亡引起相关疾病。
本发明提供一类新型结构的含硒异唑胺类化合物或其可药用的盐一种通式(I)所示结构的含硒异唑胺类化合物或其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物:
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、氨基、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、C0~C8烷胺甲酰基、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、C1~C8烷胺基、C0~C8烷硒甲酰胺基、芳硒C1~C8酰胺基、氰硒C1~C8酰胺基、苯并硒唑基、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、C0~C8烷胺磺酰基、C1~C8烷磺酰胺基、C1~C8烷基、卤代C1~C8烷氧基、C1~C8烷氧基中的基团所取代的苯基;
Z可任意为:、、、、、或;其中Z选自、、基团时,R5为H、D、C1~C8烷基、C1~C8烷硒C1~C8烷基、C2~C8烯烷硒C1~C8烷基、氰硒酸C1~C8烷基、、;Z选自或基团时,R5为卤素、羟基、硝基、氰基、氨基、三氟甲基、羧基、C1~C8烷基磺酰基、胺磺酰基、C1~C8烷基、卤代C1~C8烷氧基、C1~C8烷氧基;
W为:C或Se;其中,W为C时,R1、R2、R3、R4和R5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;
X为:O或不存在;
虚线为:化学键或不存在。
优选的,本发明提供通式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)和(I-f)结构化合物或其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物:
R1、R2、R3、R4分别独立地为选自下组基团:H、D、卤素、羟基、氨基、硝基、氰基、羧基、C0~C8烷胺C1~C8烷硒基、C0~C8烷胺甲酰基、C0~C8烷氧甲酰基C1~C8烷氧基、脒基、胍基、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、芳磺酰胺基、芳胺基磺酰基、芳甲酰基、芳甲胺基、芳甲酰胺基、脒基、C0~C8烷氧甲酰基、C1~C8烷酰胺基、C1~C8烷胺基、C0~C8烷胺基甲酰胺基、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、三氟甲基、羧基、胺磺酰基、C1~C6烷基、C1~C6烷氧基中的基团所取代的苯基;
其中Z选自、、基团时,R5为H、D、C1~C8烷基;Z选自或基团时,R5为卤素、羟基、硝基、氰基、氨基、三氟甲基、羧基、C1~C8烷基磺酰基、胺磺酰基、C1~C8烷基、卤代C1~C8烷氧基、C1~C8烷氧基。
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“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、其药学上可接受的盐、晶型、立体异构体、同位素化合物或代谢物的一种晶体形式,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。
本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物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-exo isomers)、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。
如本文所用,术语“药学上可接受的盐”是指通式I化合物的非毒性酸盐。这些盐可在最终分离和纯化通式I化合物时原位制得、或分别将合适的有机或无机酸与碱性官能团反应制得。代表性的盐包括,但不限于:乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡萄糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘基磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、硫氰酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一烷酸盐。
本发明的部分优选的新型含硒异唑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。
本发明还提供上述新型苯并硒唑类化合物可药用的盐。
根据本发明的第二方面,提供上述含硒异唑胺类化合物或其可药用的盐的制备方法,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:
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
HA 有机酸或者无机酸,如盐酸、硫酸、马来酸、酒石酸等
H2O2 双氧水
HOBt 1-羟基苯并三氮唑
OMs 甲磺酰氧基
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:
式I-a、I-b、I-c、I-d和I-e结构系列中苯并异硒唑酮类化合物合成是以取代苯甲酰氯为原料,在碱性(Base)条件下如三乙胺、二异丙基乙胺等叔胺,分别与3-氨基-2,6-哌啶二酮或3-氨基-1,4-二氢吡啶-2-(1H)-酮或3-胺基-1-金刚烷醇或2-苯并噻唑胺或3-氨基-2,5-吡咯二酮加热(rt~120℃)反应得到,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:Heteroatom Chemistry. 2014, 35, 320);其中,当取代苯甲酰氯邻位Y=SeCl时,与上述底物反应可直接得到目标产物I-a、I-b和I-e(参考文献: J. Med. Chem. 2013, 56, 9089);当取代苯甲酰氯邻位Y=I或Br时,与上述底物反应则首先分别得到取代邻卤苯甲酰胺中间体,然后再经[Se]化反应如得到目标化合物I-a、I-b、I-c和I-d(参考文献:Org. Lett. 2010, 12, 23;J. Org. Chem. 2017, 82, 3844;Tetrahedron . 2011, 67, 9565)。
式I-a、I-b、I-c、I-d和I-e结构系列中苯并异硒唑类化合物合成是以取代2,2’-二硒化双苯甲醛为原料,分别与3-胺基-1-金刚烷醇、2-苯并噻唑胺、3-氨基-2,6-哌啶二酮、3-氨基-1,4-二氢吡啶-2-(1H)-酮和3-氨基-2,5-吡咯二酮反应得到相应的烯亚胺中间体;烯亚胺中间体经还原胺化成环得到苯并异硒唑类化合物(参考文献:Angew. Chem. Int. Ed. 2015, 54, 1)。
式I-a、I-b、I-c、I-d和I-e结构系列中四价硒类型化合物合成是以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-a、I-b、I-c、I-d和I-e结构类型化合物含-NH2、烷胺基或芳胺基与HA成盐后得到苯并硒唑类化合物可药用的盐。HA为盐酸、氢溴酸、硫酸、磷酸、乙酸、柠檬酸、草酸、丙二酸、水杨酸、苹果酸、富马酸、琥珀酸、扁桃酸、抗坏血酸、马来酸、酒石酸、苯磺酸、甲磺酸或羟乙磺酸。
根据本发明的第三方面,式I结构的化合物具有抑制过TNF-α表达和正常细胞铁死亡的作用。相应地,它们可作为TNF-α和或细胞铁死亡抑制剂用于治疗(包括联合治疗)TNF-α过表达和或细胞铁死亡引起的相关疾病,如自身免疫性疾病、血液肿瘤、实体肿瘤、组织缺血再灌注损伤、急性肾功能衰竭以及衰老疾病的药物中的应用。所述自身免疫性疾病包括骨髓纤维化症以及急/慢性移植物抗宿主反应病、风湿性关节炎、炎性肠道疾病、糖尿病、银屑病、强制性脊柱炎、麻风结节性红斑以及包括HBV、HCV、HIV在内的其他一些传染疾病;所述神经退行性疾病包括阿尔茨海默病、老年痴呆、多发性硬化症、运动神经元病;所述血液肿瘤指的是多发性骨髓瘤、骨髓增生异常综合征;所述实体肿瘤指的是肝癌、肾癌、胃癌、结肠癌、卵巢癌、胰腺癌、前列腺癌、乳腺癌、黑色素瘤、脑神经胶质细胞瘤;所述组织缺血再灌注损伤指的是脑卒中、冠心病、心肌梗塞、肺栓塞、急性冠脉综合征。
有益效果
本发明设计并合成了一类新型含硒异唑胺结构类化合物,相对于现有度胺类药物,该类化合物不仅对TNF-α有明显的抑制作用,而且具有模拟硒酶调节氧化应激并抑制正常细胞铁死亡作用,更加契合于临床复杂性疾病如神经退行性疾病、自身免疫性疾病等复杂的病理过程。
附图说明
图1是本发明式I化合物结构通式。
图2是本发明式I化合物对ox-LDL诱导人血管内皮细胞保护作用。
图3是本发明式I化合物对Erastin诱导HT22发生铁死亡的保护作用。
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
制备方法步骤1:2-氯硒基苯甲酰氯的制备
冰浴下将邻氨基苯甲酸(1.37 g,10 mmol)加入到3 N的盐酸水溶液(4 ml)中,然后在搅拌的条件下缓慢滴加含有690 mg的亚硝酸钠(10 mmol)水溶液2 ml,反应1小时至澄清,备用。
在氮气的保护下,称取硒粉790 mg(10 mmol)和十六烷基三甲基溴化铵20 mg加入到2 N的氢氧化钠水溶液中(5 ml),得到Se-NaOH溶液。然后在冰浴下将含有NaOH(40 mg,1mmol)和NaBH4(49 mg,1.3 mmol)的水溶液(1 ml)加入到上述Se-NaOH溶液中,并在室温下搅拌1小时,然后升温到90 oC继续搅拌反应半小时,得二硒化钠溶液。冷却至室温后,将前述制备的2-苯甲酸重氮盐溶液缓慢滴加到二硒化钠溶液中,加热至40 oC反应2小时。反应结束后,过滤。滤液加入6 N HCl酸化至沉淀不再析出,过滤,滤饼用水洗涤,干燥,得到土黄色固体2,2’-二硒化双苯甲酸,收率80%,m.p. 295-296 oC。
氮气保护下,将2,2’-二硒化双苯甲酸(800 mg,2 mmol)加入到5 ml的氯化亚砜溶液中,加热回流3小时,减压蒸掉氯化亚砜,剩余固体用正己烷提取,所得固体再经乙醚重结晶,得到淡黄色固体2-氯硒基苯甲酰氯,收率81%,m.p. 60-62 oC。
制备方法步骤2:目标化合物合成
在氮气和冰浴条件下,将(254 mg, 1 mmol)二氯硒基苯甲酰氯(制备方法参照上述方案及J. Med. Chem. 2016, 59, 8125−8133)的乙腈溶液(2 mL)缓慢加入到含有3-氨基-2,6-哌啶二酮(128 mg, 1 mmol)和三乙胺(151 mg, 1.5 mmol)的乙腈溶液(10 mL)中,然后继续反应至完全。TLC检测反应完成后,加水20 ml,然后加入乙酸乙酯 (20 mL×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1(260 mg,收率85%)。HRMS-ESI: m/z calcd forC12H10N2O3Se: 309.9857, found [M+H]+ 310.9927;1H NMR (400 MHz, DMSO-d 6 ) δ 10.98(s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.68 – 7.62 (m,1H), 7.45 (t, J = 7.4 Hz, 1H), 5.26 (dd, J = 12.8, 5.3 Hz, 1H), 2.92 – 2.83(m, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.48 – 2.36 (m, 1H), 2.13– 2.05 (m, 1H);13C NMR (126 MHz, DMSO) δ 173.2, 171.3, 167.5, 140.4, 132.25, 128.0, 127.9,126.3, 126.2, 53.7, 31.7, 25.1。
实施例2至实施例21的制备参考实施例1操作,其中取代2-氯硒基苯甲酰氯制备方法参照J. Med. Chem. 2016, 59, 8125−8133或Bioorg Med Chem. 2012, 20, 3816–3827所述方法,以取代2-氨基苯甲酸为原料(市售)经二硒醚化和氯化反应得到。实施例15~16所列化合物合成按上述路线并用青霉胺替代3-氨基-2,6-哌啶二酮;实施例17~21所列化合物合成按上述路线并用3-氨基-2,5-吡咯二酮替代3-氨基-2,6-哌啶二酮,所得实施例结果如下:
实施例22化合物19的合成
合成路线1:
制备步骤1:中间体a19合成
在冰浴搅拌的条件下,向含有3-胺基-1-金刚烷醇(167 mg, 1 mmol)和三乙胺(151mg, 1.5 mmol)的四氢呋喃溶液(10 mL)中慢慢加入邻碘苯甲酰氯(266 mg, 1 mmol)并继续反应1~2 h至完全。TLC检测反应完成后,加水20 ml,然后加入乙酸乙酯 (20 mL×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),反应定量得到a19。MS-ESI [M+H]+ 398.0 (397.0)。
制备步骤2:化合物19的合成
向含有a19(397 mg, 1 mmol)、硒粉(0.15 g, 1.9 mmol)、K2CO3 (276 mg, 2 mmol)的DMF溶液(5 mL)中加入CuI (154 mg, 0.8 mmol), 1,10-邻二氮杂菲(146 mg, 0.8mmol),然后置于氮气氛围中于110℃反应24小时至完全。TLC检测反应完成后,加水20 ml,然后加入乙酸乙酯 (20 mL×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19(251 mg,收率72%)。HRMS-ESI: m/z C17H19NO2Se: 349.0581, found [M+H]+ 350.0655; 1H NMR(400 MHz, CDCl3) δ8.04 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.68 –7.60 (m, 1H), 7.43 (t, J = 7.4 Hz, 1H), 2.48 – 1.60 (m, 15H)。
实施例23至实施例29的制备参考实施例22操作,所得实施例结果如下:其中实施例24~26所列化合物合成按上述路线并用2-胺基-苯并噻吩替代3-胺基-1-金刚烷醇。
实施例30 化合物3的合成
向含有化合物2(72 mg, 0.2 mmol)的甲醇溶液(1 mL)中加入10%的Pd/C,然后置于H2氛围中加热至70℃反应48小时至完全。TLC检测反应完成后,过滤,所得滤液减压蒸干后经柱层析纯化得到化合物6(25 mg,36%)。HRMS-ESI: m/z calcd for C12H10N2O3Se:324.9966, found [M+H]+ 326.0040;1H NMR (400 MHz, DMSO-d 6 ) δ10.97 (s, 1H), 7.47– 7.34 (m, 1H), 7.05 – 6.83 (m, 2H), 6.33 (brs, 2H), 5.23 (dd, J = 12.8, 5.3Hz, 1H), 2.92 – 2.83 (m, 1H), 2.59 (d, J = 17.3 Hz, 1H), 2.45 – 2.35 (m, 1H),2.12– 2.02 (m, 1H)。
实施例31化合物6的合成
氮气保护下,冰浴下向含有化合物5(72 mg, 0.2 mmol)的甲醇溶液(1 mL)中加入10%的Pd/C和80%的水合肼(40 mg),然后升温至40 oC下反应8小时。TLC检测反应完成后,过滤,所得滤液减压蒸干后经柱层析纯化得到化合物6(15 mg,22%)。HRMS-ESI: m/z calcd forC12H11N3O3Se: 324.9966, found [M+H]+ 326.0040;1H NMR (400 MHz, DMSO-d 6 ) δ10.97(s, 1H), 7.29 – 6.91 (m, 3H), 6.12 (brs, 2H), 5.21 (dd, J = 12.8, 5.3 Hz,1H), 2.94 – 2.82 (m, 1H), 2.59 – 2.52 (m, 1H), 2.43 – 2.29 (m, 1H), 2.12–2.01 (m, 1H)。
实施例32 化合物32的合成
在冰浴搅拌的条件下,向含有化合物19(35 mg, 0.1 mmol)的甲醇溶液(2 mL)中慢慢加入30%过氧化氢(0.12 mmol),然后升温至室温并继续反应12 h至完全。TLC检测反应完成后,加水5 ml,然后加入乙酸乙酯 (5 mL×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32(27 mg,收率75%)。HRMS-ESI: m/z calcd for C17H19NO3Se: 365.0530, found [M+H]+366.0609;1H NMR (400 MHz, DMSO-d 6 )δ8.24 – 7.96 (m, 2H), 7.83 – 7.62 (m, 2H),2.76 – 1.71 (m, 15H)。
实施例33~42的制备参考实施例32操作,所得实施例结果如下:
编号 | 化合物信息 | 编号 | 化合物信息 |
实施例33 | 化合物33,收率26%,分子式:C<sub>14</sub>H<sub>8</sub>N<sub>2</sub>O<sub>2</sub>SSe,HRMS-ESI: m/z347.9472, found [M+H]<sup>+</sup>348.9548; <sup>1</sup>H NMR (400 MHz,DMSO-<i>d</i><sub><i>6</i></sub>): <i>δ</i> 8.18 – 7.95(m, 6H), 7.62 (t, <i>J</i> = 7.1Hz, 1H), 7.52 (t, <i>J</i> = 7.1Hz, 1H)。 | 实施例38 | 化合物39,收率29%,分子式:C<sub>12</sub>H<sub>9</sub>FN<sub>2</sub>O<sub>4</sub>Se, HRMS-ESI: m/z343.9712, found [M+H]<sup>+</sup> 344.9784;<sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub><i>6</i></sub>): <i>δ </i>11.08 (s, 1H), 8.12 –8.08 (m,1H), 7.42 – 7.23 (m, 2H), 5.31 –5.27 (m, 1H), 2.96 – 2.87 (m,1H), 2.64 – 2.53 (m, 1H), 2.48 –2.35 (m, 1H), 2.17– 2.02 (m,1H)。 |
实施例34 | 化合物34,收率21%,分子式:C<sub>15</sub>H<sub>7</sub>F<sub>3</sub>N<sub>2</sub>O<sub>3</sub>SSe, MS-ESI [M+H]<sup>+</sup> 432.9。 | 实施例39 | 化合物40,收率51%,分子式:C<sub>13</sub>H<sub>12</sub>N<sub>2</sub>O<sub>5</sub>Se, MS-ESI [M+H]<sup>+</sup> 357.0。 |
实施例35 | 化合物36,收率43%,分子式:C<sub>12</sub>H<sub>9</sub>FN<sub>2</sub>O<sub>4</sub>Se, MS-ESI [M+H]<sup>+</sup>345.0。 | 实施例40 | 化合物41,收率39%,分子式:C<sub>11</sub>H<sub>8</sub>N<sub>2</sub>O<sub>4</sub>Se, HRMS-ESI: m/z311.9649, found [M+H]<sup>+</sup> 312.9724;<sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub><i>6</i></sub>): <i>δ</i>11.49 (s, 1H), 8.28 – 7.82 (m,3H), 7.59 (t, <i>J</i> = 7.4 Hz, 1H),5.33– 5.27 (m, 1H), 3.02 – 2.95(m, 1H), 2.89 – 2.82 (m, 1H)。 |
实施例36 | 化合物37,收率47%,分子式:C<sub>14</sub>H<sub>13</sub>N<sub>3</sub>O<sub>5</sub>Se, MS-ESI [M+H]<sup>+</sup>384.0。 | 实施例41 | 化合物42,收率42%,分子式:C<sub>12</sub>H<sub>10</sub>N<sub>2</sub>O<sub>4</sub>Se,MS-ESI [M+H]<sup>+</sup> 327.0。 |
实施例37 | 化合物38,收率35%,分子式:C<sub>13</sub>H<sub>9</sub>N<sub>3</sub>O<sub>4</sub>Se, MS-ESI [M+H]<sup>+</sup>352.0。 | 实施例42 | 化合物43,收率34%,分子式:C<sub>12</sub>H<sub>10</sub>N<sub>2</sub>O<sub>5</sub>Se,MS-ESI [M+H]<sup>+</sup> 343.0。 |
实施例43 化合物35的合成
按照实施例32所述合成方法经过氧化反应获得化合物a5。化合物a5(37 mg, 0.1mmol)溶于1 ml四氢呋喃溶液中,然后升温至60℃,在氮气保护下滴加含有亚硫酸氢钠(52mg, 0.5 mmol)的水溶液(0.7 ml),并继续反应至完全。TLC检测反应完成后,冷却至室温,然后加入乙酸乙酯 (5 mL×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,得到化合物35(27 mg,收率79%)。分子式: C12H11N3O4Se, HRMS-ESI:m/z calcd for 340.9915, found [M+H]+ 341.9984。
实施例44 化合物44的合成
制备方法步骤1:2,2’-二硒化双苯甲醛的制备
冰浴下将3-甲氧基-2-氨基苯甲醛(1.51 g,10 mmol)加入到3 N的盐酸水-DMSO(V:V=1:1)混合溶液4 ml中,然后在搅拌的条件下缓慢滴加含有690 mg的亚硝酸钠(10 mmol)水溶液2 ml,反应1小时至澄清,备用。
在氮气的保护下,称取硒粉790 mg(10 mmol)和十六烷基三甲基溴化铵20 mg加入到2 N的氢氧化钠水溶液中(5 ml),得到Se-NaOH溶液。然后在冰浴下将含有NaOH(40 mg,1mmol)和NaBH4(49 mg,1.3 mmol)的水溶液(1 ml)加入到上述Se-NaOH溶液中,并在室温下搅拌1小时,然后升温到90 oC继续搅拌反应半小时,得二硒化钠溶液。冷却至室温后,将前述制备的2-苯甲酸重氮盐溶液缓慢滴加到二硒化钠溶液中,加热至40 oC反应2小时。反应结束后,1 N HCl调节pH至中性,然后加入乙酸乙酯萃取2次,所得有机相经二氯甲烷:甲醇洗脱,得到土黄色固体2,2’-二硒化双苯甲醛,收率45%。分子式: C16H14O4Se2, HRMS-ESI:m/z calcd for 428.9223, found [M+H]+ 430.9298; 1H NMR (CDCl3), δ (ppm): 3.78(s, 6H), 7.09-7.13 (dd, J = 7.6 Hz, 2H), 7.42-7.50 (m, 4H), 10.20 (s, 2H)。
制备方法步骤2:目标化合物44合成
向含有2,2’-二硒化双苯甲醛(429 m g, 1 mmol)的20 ml乙腈溶液中加入加入50 μL的conc HCl并继续搅拌15 min,然后加入3-氨基-2,6-哌啶二酮(128 mg, 1 mmol)并继续反应6小时至完全,得到烯胺中间体。然后将上述混合液减压浓缩至干,并用10 ml甲醇重新溶解,然后于冰浴条件下加入硼氢化钠 (38 mg, 1 mmol)并继续反应6 h。反应完成后经常归乙酸乙酯萃取、硫酸镁干燥和减压浓缩及硅胶柱层析后处理得到化合物44。收率36%,117mg。HRMS-ESI: m/z calcd for C13H14N2O3Se: 326.0170, found [M+H]+ 327.0245; 1H NMR(DMSO-d 6 ), δ (ppm): 10.91 (s, 1H), 7.85-7.69 (t, J = 7.8 Hz, 1H), 7.58-7.31(m, 2H), 4.75-4.62 (m, 3 H), 3.89 (s, 3H), 2.78 – 2.42 (m, 2H), 2. 31 – 1.91(m, 2H)。
实施例45~48的制备参考实施例44操作,所得实施例结果如下:
实施例49 TNF-α 活性抑制实验
方法: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10 μl本发明通式(I)化合物的DMSO (Sigma,产品目录号D2650,USA)溶液处理,DMSO 的终浓度为0.2%。在37℃,5% CO2培养箱中孵育60 min后,于反应体系中加入10 μl LPS (Sigma,产品目录号L-2880,USA),终浓度10 ng/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,实验结果见表1。
表1. TNF-α 抑制活性
注:A:<1 μM; B:1~10 μM;C:10~100 μM;D:>100 μM。
实施例50 硫氧还蛋白还原酶1(TrxR1)抑制实验
实验工作液的配制:TrxR工作液:精密量取175 μl浓度为0.34 mg/mL的TrxR储备液,将其稀释到500 μl,将其配制成浓度为0.119 mg/ml TrxR工作液;NADPH工作液:精密称取5mg NADPH,将其溶解于12 ml磷酸钾缓冲液中,将其配制成浓度为1 mM的工作液;DTNB工作液:精密称取25 mg DTNB,将其溶解于63 ml DMSO中,将其配制成浓度为1 mM的工作液;磷酸钾缓冲液体系:将0.2 mg/ml的牛血清白蛋白(BSA)和1 mM的EDTA加入到pH7.4的磷酸钾缓冲液中(磷酸氢二钾/磷酸二氢钾),即得。
方法:采用DTNB还原法研究部分具有代表性结构的含硒异唑胺类化合物体外对硫氧还蛋白还原酶1(TrxR1)的抑制活性。在0.5 ml的微量比色皿中,依次加入胰岛素、NADPH、Trx和含硒异唑胺类待测样品,补充反应缓冲液(0.1 mol/l 磷酸钾/2 mmol/l EDTA)至总体积0.5 ml,所得反应体系中各成分的浓度为:胰岛素130 μmol/l、NADPH 0.4 mol/l(购自Sigma公司)、Trx 4 μmol/l和含硒异唑胺类待测样品,将其置入紫外分光光度计中,连续检测反应体系在340 nm处的吸光度变化。酶活力活性单位定义为:1U=△A340 nm/min×1000,样品中TR活性以U/L计,实验结果见表2。
表2. 式I化合物TrxR抑制作用
注:A:<5 μM; B:5~50 μM;C:50~100 μM;D:>100 μM。
实施例51 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硒类化合物的GPX活性。将谷胱甘肽(2.0 mM)、EDTA(1mM)、谷胱甘肽二硫化物还原酶(1.7 units mL-1)和烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NADPH;0.4 mM)混合于pH=7.5的0.1 M的磷酸钾缓冲液中。在室温下(25 oC),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 (1.6 mM)开始反应。初始还原速率(v 0)通过测定NADPH的氧化速率计算得出,用摩尔消光系数(6.22 mM-1cm-1)表示NADPH,连续检测反应体系在340 nm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化合物抗过氧化作用
实验结果表明,含硒异唑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52 对氧化低密度脂蛋白引起的内皮细胞损伤的影响
药品:受试化合物,DMSO溶解。
试剂:氧化低密度脂蛋白ox-LDL购自北京协和三友科技公司; DMEM培养基(低糖)购自GIBCO,UK;HMEC细胞购自中科院上海生物化学与细胞生物学研究所细胞库;ThiazolylBlue (MTT) 购自Sigma公司;其余化学试剂均为国产分析纯。
实验方法:内皮细胞培养,人微血管内皮细胞 (HMEC) 用含10%胎牛血清的DMEM培养液在37℃、5%CO2湿热培养箱中培养。MTT法测定细胞存活率,对数生长期细胞用10%FCS DMEM培养液按104/孔种于96孔培养板,37℃,5%CO2培养48小时,待细胞长成单层融合后,换无血清DMEM培养液,及含终浓度2.0 mg/ml待测样品培养液100 ml与细胞预孵育1小时。1小时后,损伤组加入ox-LDL使终浓度为100 mg/ml,置于培养箱中继续培养24小时。弃上清,细胞数量通过MTT法测定:每孔加入100 ml 含0.5 mg/ml MTT的培养液,于37℃继续培养4小时。弃培养液,加入DMSO 150 ml/孔,震荡5分钟令染料释出,酶标仪测定570 nm OD值,以正常细胞对照组吸光度为100%,计算各组细胞存活率。
实验结果:如附图2所示,Ox-LDL对血管内皮细胞具有毒性作用,可引起内皮细胞损伤。含硒异唑胺类化合物可显著减轻ox-LDL引起的内皮细胞损伤,提高细胞存活率。
实施例53 含硒异唑胺类化合物对Erastin诱导HT22发生铁死亡的影响
药品:受试含硒异唑胺类化合物,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 oC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(5 μM),再加入0.5 μmol/L Erastin作用8小时;然后每孔分别加入CCK-8溶液10 μL,培养箱内孵育3小时,酶标仪上读取450 nm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3所示,铁死亡促进剂Erastin可引起HT22细胞凋亡。含硒异唑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 (10)
1.一种通式(I)所示结构的含硒异唑胺类化合物或其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物:
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、氨基、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、C0~C8烷胺甲酰基、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、C1~C8烷胺基、芳硒C1~C8酰胺基、氰硒C1~C8酰胺基、苯并硒唑基、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、C0~C8烷胺磺酰基、C1~C8烷磺酰胺基、C1~C8烷基、卤代C1~C8烷氧基、C1~C8烷氧基中的基团所取代的苯基;所述苯并硒唑C1~C8烷酰胺基为;
Z可任意为:、、、、、或;其中Z选自、、基团时,R5为H、D、C1~C8烷基、C1~C8烷硒C1~C8烷基、C2~C8烯烷硒C1~C8烷基、氰硒酸C1~C8烷基、、;Z选自或基团时,R5为卤素、羟基、硝基、氰基、氨基、三氟甲基、羧基、C1~C8烷基磺酰基、胺磺酰基、C1~C8烷基、卤代C1~C8烷氧基、C1~C8烷氧基;
W为:C或Se;其中,W为C时,R1、R2、R3、R4和R5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;
X为:O或不存在;
虚线为:化学键或不存在。
2.根据权利要求1所述的通式(I)化合物或其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物,其特征在于,所述化合物如通式(I-a)、(I-b)、(I-c) 和(I-d)中所示:
式(I-a)、(I-b)、(I-c)、(I-d)和(I-e)中,
R1、R2、R3、R4和R5分别独立地为选自下组基团:H、D、卤素、羟基、氨基、硝基、氰基、羧基、C0~C8烷胺C1~C8烷硒基、C0~C8烷胺甲酰基、C0~C8烷氧甲酰基C1~C8烷氧基、脒基、胍基、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、芳磺酰胺基、芳胺基磺酰基、芳甲酰基、芳甲胺基、芳甲酰胺基、脒基、C0~C8烷氧甲酰基、C1~C8烷酰胺基、C1~C8烷胺基、C0~C8烷胺基甲酰胺基、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、三氟甲基、羧基、胺磺酰基、C1~C6烷基、C1~C6烷氧基中的基团所取代的苯基;其中Z选自、、基团时,R5为H、D、C1~C8烷基;Z选自或基团时,R5为卤素、羟基、硝基、氰基、氨基、三氟甲基、羧基、C1~C8烷基磺酰基、胺磺酰基、C1~C8烷基、卤代C1~C8烷氧基、C1~C8烷氧基;
X为:O或不存在;
虚线为:化学键或不存在。
4.一种药物组合物,其包含至少一种如权利要求1-4之一所述的式I的化合物或其药学可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物,以及一种或多种药学可接受的载体、稀释剂或赋形剂。
5.一种根据权利要求1-4中任意一项所述的含硒异唑胺类化合物或其可药用的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物,通过下述方法得到:
一种根据权利要求1-4中任意一项所述的丹参酮IIA哌嗪类化合物或其可药用的盐的制备方法,通过下述方法得到:
式I-a、I-b、I-c和I-d结构系列中苯并异硒唑酮类化合物合成主要是以取代邻卤苯甲酰氯为原料,分别与3-胺基-1-金刚烷醇和2-苯并噻唑胺反应得到取代苯甲酰胺中间体,中间体再经[Se]化反应得到目标化合物;
式I-a、I-b、I-c、I-d和I-e结构系列中苯并异硒唑酮类化合物合成也可以是以取代邻硒氯苯甲酰氯为原料,分别与3-氨基-2,6-哌啶二酮、3-氨基-1,4-二氢吡啶-2-(1H)-酮和3-氨基-2,5-吡咯二酮反应得到目标化合物;
式I-a、I-b、I-c、I-d和I-e结构系列中苯并异硒唑类化合物合成是以取代2,2’-二硒化双苯甲醛为原料,分别与3-胺基-1-金刚烷醇、2-苯并噻唑胺、3-氨基-2,6-哌啶二酮、3-氨基-1,4-二氢吡啶-2-(1H)-酮和3-氨基-2,5-吡咯二酮反应得到相应的烯亚胺中间体;烯亚胺中间体经还原胺化成环得到苯并异硒唑类化合物;
式I-a、I-b、I-c、I-d和I-e结构系列中四价硒类型化合物合成是以取代苯并异硒唑为原料,经[O]过氧化反应得到。
6.权利要求1-3中任意一项所述的含硒异唑胺类化合物或其可药用的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物在制备预防或治疗TNF-α过表达引起的自身免疫性疾病、神经系统退行性疾病、血液肿瘤、实体肿瘤、骨髓纤维化症以及急/慢性移植物抗宿主反应疾病的药物中的应用。
7.权利要求1-3中任意一项所述的含硒异唑胺类化合物或其可药用的盐、溶剂化物、晶型、立体异构体、同位素化合物或代谢物在制备预防或治疗硒酶依赖的细胞铁死亡引起的神经系统退行性疾病、血液肿瘤、实体肿瘤、组织缺血再灌注损伤、急性肾功能衰竭以及衰老疾病的药物中的应用。
8.一种治疗TNF-α过表达和或细胞铁死亡导致相关疾病患者的方法,包括给于患者治疗有效量的根据权利要求1-3任一项的含硒异唑胺类化合物或其药学可接受的盐。
9.作为TNF-α抑制剂和或铁死亡调节剂的权利要求1-3任一项的含硒异唑胺类化合物或其药学可接受的盐。
10.根据权利要求7、8或9的用途、方法或含硒异唑胺类化合物,其中所述自身免疫性疾病包括:骨髓纤维化症以及急/慢性移植物抗宿主反应病、风湿性关节炎、炎性肠道疾病、糖尿病、银屑病、强制性脊柱炎、麻风结节性红斑以及包括HBV、HCV、HIV在内的其他一些传染疾病;所述神经系统退行性疾病指的是阿尔茨海默症、老年痴呆、多发性硬化症、运动神经元病;所述血液肿瘤指的是多发性骨髓瘤;所述实体肿瘤指的是肝癌、肺癌、肾癌、胃癌、结肠癌、卵巢癌、胰腺癌、前列腺癌、乳腺癌、黑色素瘤、脑神经胶质细胞瘤;所述组织缺血再灌注损伤指的是脑卒中、冠心病、心肌梗塞、肺栓塞、急性冠脉综合征。
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