CN113387831A - 酰胺类化合物及其在制备神经炎症抑制剂中的应用 - Google Patents
酰胺类化合物及其在制备神经炎症抑制剂中的应用 Download PDFInfo
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- CN113387831A CN113387831A CN202010167489.7A CN202010167489A CN113387831A CN 113387831 A CN113387831 A CN 113387831A CN 202010167489 A CN202010167489 A CN 202010167489A CN 113387831 A CN113387831 A CN 113387831A
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- 230000016273 neuron death Effects 0.000 description 1
- 230000009223 neuronal apoptosis Effects 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
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- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
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Abstract
本发明涉及药物学领域,尤其涉及一种式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物及其在制备神经炎症抑制剂中的应用。本发明还公开了式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物在制备预防和/或治疗神经炎症导致的神经退行性疾病的药物中的应用。
Description
技术领域
本发明涉及药物学领域,尤其涉及一种酰胺类化合物及其在制备神经炎症抑制剂中的应用。
背景技术
炎症是器官的第一反应发病机制。神经炎症是中枢神经系统(CNS)的自我防御反应,保护人体免受伤害性刺激,并启动愈合过程。但是,慢性神经炎症可能成为一系列神经退行性疾病的致病因素,如帕金森病、阿尔茨海默病、缺血脑脑卒中、多发性硬化和艾滋病相关痴呆症等。
目前已经证明激活的神经胶质细胞在神经退行性疾病中发挥了重要作用。胶质细胞广泛分布于中枢和周围神经系统,在中枢神经系统(CNS)中胶质细胞主要包含星形胶质细胞、少突胶质细胞(与前者合称为大胶质细胞)和小胶质细胞等。其中,小胶质细胞是大脑的旁核巨噬细胞,约占所有胶质细胞的10%,是中枢神经系统的主要免疫细胞,它们是抵御微生物入侵和伤害的第一道防线,在中枢神经固有免疫反应中起着关键作用。
在正常成年脑组织中,小胶质细胞处于静息状态,在神经退行性条件下,小胶质细胞可被损伤的神经元细胞产生的各种神经毒性因子激活,当小胶质细胞被激活时,它们在中枢神经系统中成为炎性细胞,通过产生促炎介质和神经毒性化合物而参与神经元变性。小胶质细胞的活化也可以观察到在脑损伤和暴露于脂多糖(LPS)、干扰素(IFN)-γ或β-淀粉样蛋白后的反应。活化的小胶质细胞具有产生促炎细胞因子和神经毒性介质的能力,如肿瘤坏死因子(TNF-α)、前列腺素E2(PGE2)、白细胞介素(IL-1β)、IL-6和自由基如一氧化氮(NO)和超氧阴离子等,这些促炎细胞因子和神经毒性介质被认为促进神经炎性疾病的神经元损伤。还有研究报道激活的小胶质细胞能促进了发育中小鼠小脑浦肯野细胞的死亡,选择性清除小胶质细胞可强烈抑制浦肯野细胞死亡,这表明小胶质细胞可能在神经退行性疾病条件下可加剧神经元细胞死亡。综上所述,由于小胶质细胞的炎症活化常在神经元损伤中观察到,并积极参与一些神经退行性疾病的发生和发展,因此抑制小胶质细胞活化和及其引起的神经炎症可能是神经退行性疾病的有效治疗途径。
目前文献已经报道了许多化合物如以丙咪嗪、阿米替林和曲唑酮等抗抑郁药,金莲花提取物OGA,m-CPP,非甾体抗炎药和甾体衍生物(最优化合物18b,IC50(μM)=8.546±0.932)等,可抑制LPS诱导NO生成。目前很多科研工作者都致力于开发新型的对细胞安全性高的神经炎症抑制剂。
发明内容
为解决上述技术问题,本发明的目的是提供一种酰胺类化合物及其在制备神经炎症抑制剂中的应用,本发明公开了一类新的式(I)所示的酰胺类化合物及其衍生物,该类化合物可用于制备神经炎症抑制剂,对LPS诱导的NO有着强大的抑制作用,且几乎不产生细胞毒性。
本发明公开了一种式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物:
其中,n1和n2分别独立地选自0或1;
A选自取代或未取代的C6-C10芳环或C4-C8脂族环;其中取代的C6-C10芳环上的取代基为卤素和/或C1-C8烷基;
B选自C6-C10芳环;
R选自C1-C8烷基、C2-C10炔酰基、C2-C8烷酰基或C2-C10烯酰基。
优选地,n1和n2均为0。
优选地,A选自苯环、2,6-二甲基苯环、2,6-二异丙基苯环、2-甲基苯环、2-氯-6-甲基苯环、萘环、1,2,3,5,6,7-六氢-s-引达省、卤素和/或C1-C8烷基取代的1,2,3,5,6,7-六氢-s-引达省、1,2,3,4-四氢萘、茚满、喹啉、异喹啉或C4-C8脂族环。
优选地,B选自苯基、取代苯基、1,2,3,5,6,7-六氢-s-引达省、1,2,3,4-四氢萘或茚满。
优选地,R选自丙烯酰基、(E)-2-甲基-2-烯酰基、烯丙基、(E)-戊-3-烯-2-酰基、(E)-4-苯基-3-烯-2-酰基、丙酰基、苯丙烯酰基、3-甲基-3-烯-2-酰基或C1-C8烷基。
本发明中,以上基团定义如下:
卤素可以为氟,氯,溴,碘;
C1-C8烷基,可以是直链烷基,支链烷基,螺环烷基,桥环烷基,烯烷基,炔烷基,环烷基,环烯基,环炔基,烷氧烷基,烷氧酰基烷基,环烷基烷基;非限制性地包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基、烯丙基或炔丙基;
C2-C8烷酰基,可以是直链酰基,支链酰基,环酰基,烯烷酰基,炔烷酰基,环烷基酰基;非限制性地包括:乙酰基、正丙酰基、异丙酰基、正丁酰基、异丁酰基、叔丁酰基、环丙甲酰基、环丁甲酰基、环戊甲酰基、环己甲酰基、烯丙酰基、炔丙酰基;
C2-C10烯酰基,非限制性地包括:丙烯酰基、苯丙烯酰基、(E)-2-甲基-2-烯酰基、(E)-戊-3-烯-2-酰基、(E)-4-苯基-3-烯-2-酰基、丙酰基、3-甲基-3-烯-2-酰基;
C2-C10炔酰基,非限制性地包括:苯丙炔酰基、丙炔酰基;
C4-C8脂族环,可以是无取代或取代的环烷基,非限制性地包括:环丁烷基、环戊烷基、环己烷基、C1-C3取代的环戊烷基、C1-C2取代的环己烷基;
C6-C10芳环非限制性地包括:单取代的或双取代或未取代的苯基(包括1,2,3,5,6,7-六氢-s-引达省、卤素和/或C1-C8烷基取代的1,2,3,5,6,7-六氢-s-引达省、1,2,3,4-四氢萘、茚满、1,2,3,4-四氢异喹啉、1,2,3,4-四氢喹啉)、萘环;取代基可以是直链烷基,支链烷基,烯烷基,炔烷基,环烷基,烷氧烷基,烷氧酰基烷基,环烷基烷基,酰基,氰基,硝基,羟基,烯基,炔基,卤素;取代基非限制性地包括甲基,乙基,丙基,环丙基,环丙甲基,甲氧基,乙氧基,溴,氯,氟,硝基,三氟甲氧基,三氟甲基,氨甲酰基,羟基,氰基等。
更优选地,本发明中式(I)所示的酰胺类化合物为化合物S2-S27,其结构式如表1所示。
表1化合物S2-S27及其结构式
进一步地,式(I)所示的酰胺类化合物的制备方法包括以下步骤:
(1)将式1所示的化合物与式2所示的化合物在有机溶剂中,在EDCI、HOBt和Et3N,的作用下反应,反应完全后,得到式3所示的化合物;
(2)将式3所示的化合物在酸性条件(优选浓盐酸和乙酸乙酯)下室温反应脱去保护基团,得到式4所示的化合物;
(3)在保护气氛下,将式4所示的化合物在三乙胺的作用下与式5所示的化合物在有机溶剂(优选DCM或DMF)中反应,反应完全后,得到式(I)所示的酰胺类化合物;
反应路线如下:
以上制备方法中,式1所示的化合物与式2所示的化合物为起始原料,可以通过市售产品获得,或者根据文献报道的方法制备获得。式1所示的化合物与式2所示的化合物在室温条件下脱水缩合制备得到式3所示的化合物,式3所示的化合物经过脱(Boc)2O后得到式4所示的化合物,再将化合物4和化合物5通过取代得到通式(I)化合物。
本发明还公开了式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物在制备神经炎症抑制剂中的应用。
进一步地,神经炎症为小胶质细胞神经炎症。
进一步地,小胶质细胞为小胶质细胞系BV2或原代小胶质细胞;神经炎症为LPS诱导的小胶质细胞神经炎症。
本发明还公开了式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物在制备预防和/或治疗神经炎症导致的神经退行性疾病的药物中的应用。
进一步地,神经退行性疾病包括帕金森氏症、阿尔茨海默症、缺血脑脑卒中、多发性硬化和艾滋病相关痴呆症中的一种或几种。
借由上述方案,本发明至少具有以下优点:
本发明公开了一类新的式(I)所示的酰胺类化合物及其衍生物,并公开了该类化合物在制备神经炎症抑制剂及预防和/或治疗神经炎症导致的神经退行性疾病的药物中的应用,该类化合物对LPS诱导的NO有着强大的抑制作用,且几乎不产生细胞毒性,为开发新型的神经炎症抑制剂和神经退行性疾病治疗药物提供了新方向。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合详细说明如后。
具体实施方式
下面结合实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
本发明以下实施例中,化合物的结构是通过核磁共振(NMR)或质谱(MS)确定的。NMR是用安捷伦400MHz或600MHz仪测定,测定溶剂为氘代二甲基亚帆(DMSO-d6),氘代氯仿(CDCl3),内标为四甲基硅烷(TMS),MS用GCT PremierTM(CI)质谱仪测定,除注明外均为CI源(70ev)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板的规格是0.15mm-0.2mm,柱层析使用烟台黄海100~200目或200~300目硅胶为载体。
反应条件“充氮气”是指反应瓶连接一个约1L容积的氮气球。反应条件“充氢气”是指反应瓶连接一个约1L容积的氢气球。反应条件为“室温”,指的是温度范围是10-30℃。
所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得。
如无特殊说明,本发明以下实施例中,化合物S2-S26的结构如上文中表1所示。
实施例1
(1)化合物S1(B)的合成:将4-氨基苯甲酸(200mg,1.45mmol)溶于二恶烷(3.0mL)和0.5M NaOH(3.0mL)的混合物中。向该溶液中加入二碳酸二叔丁酯(0.4mL,2.1mmol),并将得到的混合物在室温下搅拌12小时。减压浓缩反应混合物,用EtOAc(30mL×2)和1M HCl(10mL)稀释。将水溶液用EtOAc(20mL)萃取,并将合并的有机相用盐水(30mL)洗涤,经硫酸钠干燥,并在减压下浓缩。通过硅胶柱色谱(PE/EA=3/1)纯化残余物,得到410mg纯产物。反应路线如下:
(2)化合物S1的合成:向搅拌的4-((叔丁氧基羰基)氨基)苯甲酸(化合物S1(B),50mg,1.5mmol)的DCM(3mL)混悬液中加入EDCI(54mg,2mmol),HOBt(38mg,2mmol),三乙胺(0.05mL,3mmol),室温下混合物反应1小时,然后加入相应的胺1,2,3,5,6,7-六氢-s-茚满-4-胺(化合物A,25mg,1mmol,合成可参考文献ASC.Med.Chem.Lett.2016,7,1034–1038)将澄清溶液在室温下搅拌12小时。待反应后混合物用30mL二氯甲烷稀释,用0.1N HCl和水洗涤。将有机层用无水硫酸钠干燥,过滤,并真空浓缩,得到粗产物。残留物通过硅胶柱色谱纯化(PE/EA:30/10),得到产物。然后将上述粗产物溶于6mL 1:2(v/v)HCl:EA的混合物中,让其在室温下反应1小时。然后将在高真空下浓缩。用氨中和后,将反应混合物用DCM(30mL×2)稀释,用水洗涤。将有机层用无水硫酸钠干燥,过滤,并真空浓缩,得到粗产物。通过硅胶柱色谱(PE/EA:1/1)纯化残余物,得到30mg产物。反应路线如下:
化合物S1的核磁测试结果如下:1H NMR(400MHz,DMSO-D6)δ9.29(s,1H),7.66(d,J=7.9Hz,2H),6.93(s,1H),6.54(d,J=7.9Hz,2H),5.65(s,2H),2.80(t,J=6.7Hz,4H),2.66(t,J=6.7Hz,4H),1.94(dd,J=13.9,6.9Hz,4H)。13C NMR(151MHz,DMSO-d6)δ164.82,152.29,143.09,138.59,131.06,129.68,121.45,118.07,112.96,32.99,30.78,25.52。
实施例2
化合物S5的合成:将实施例1合成的化合物S1(60mg,0.22mmol)和DIEA(0.02mL,0.236mmol)溶解在无水DMF(3mL)中,并混合液的温度降至0℃,逐滴加入丙烯酰氯(化合物B,0.03mL,0.31mmol)溶液。将反应温度从0℃逐渐升至室温,并在室温下继续搅拌3小时。反应完全后混合液加入10%HCl(10mL)中,然后用DCM(30mL×2)萃取。将合并的有机萃取液用饱和碳酸钠溶液(20mL)洗涤,用无水硫酸钠干燥,蒸发,得到粗产物。通过硅胶柱色谱(DCM/MeOH=40/1)纯化残余物得到28mg产品。
化合物S5的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.74(s,1H),7.96(d,J=8.2Hz,2H),7.80(d,J=8.3Hz,2H),6.99(s,1H),6.48(dd,J=16.9,10.1Hz,1H),6.31(d,J=16.8Hz,1H),5.81(d,J=10.2Hz,1H),2.84(t,J=6.7Hz,4H),2.72(t,J=6.7Hz,4H),2.03–1.91(m,4H).13C NMR(151MHz,DMSO-d6)δ164.36,163.87,143.28,142.21,138.59,132.05,130.47,129.63,129.01,127.98,119.03,118.50,40.18,40.04,39.90,39.76,39.62,32.96,30.75,25.53。
实施例3
(1)化合物S2(B)的合成:将化合物A(300mg,1.73mmol)溶于无水DCM(5mL)中,并将混合物降低至0℃,分批加入NBS(309mg,1.73mmol)。将反应温度从0℃逐渐升至室温,并在室温下搅拌过夜。反应完成后旋干溶剂,用水(30mL)和DCM(30mL×2)萃取,然后将有机相用饱和NaCl(30mL)洗涤,将有机层用无水硫酸钠干燥,过滤,并真空浓缩,得到粗产物。通过硅胶柱色谱(PE/EA=40/5)纯化残余物,得到316mg红棕色固体。
(2)化合物S2(C)的合成:将化合物S2(B)(316mg,1.25mmol)溶于水(6mL)和1,4-二氧六环(6mL)的混合物中,依次加入甲基硼酸(112mg,1.88mmol),四苯基磷钯(144mg,0.13mmol),碳酸钾(345mg,2.5mmol),之后混合物在100℃下反应2.5h,TLC显示反应完全。旋干溶剂,用水(30mL)和DCM(30mL×2)萃取,然后将有机相用饱和NaCl(30mL)洗涤,将有机层用无水硫酸钠干燥,过滤,并真空浓缩,得到粗产物。通过硅胶柱色谱(PE/EA=40/4)纯化残余物,得到200mg白色固体。反应路线如下:
(3)化合物S2(D)的合成:向搅拌的实施例1制备的化合物S1(B)(200mg,0.84mmol)的DCM(3mL)混悬液中加入EDCI(215mg,1.12mmol),HOBt(147mg,1.12mmol),三乙胺(0.23mL,1.68mmol),室温下混合物反应1小时,然后加入以上制备的S2(C),将得到的澄清溶液在室温下搅拌24小时。待反应后混合物用30mL二氯甲烷稀释,用0.1N HCl和水洗涤。将有机层用无水硫酸钠干燥,过滤,并真空浓缩,得到粗产物。残留物通过硅胶柱色谱纯化(PE/EA=30/10),得到产物。然后将上述粗产物溶于6mL 1:2(v/v)HCl:EA的混合物中,让其在室温下反应1小时。然后将在高真空下浓缩。用氨中和后,将反应混合物用DCM(30mL×2)稀释,用水洗涤。将有机层用无水硫酸钠干燥,过滤,并真空浓缩,得到粗产物。通过硅胶柱色谱(PE/EA=30/30)纯化残余物,得到134mg白色固体。
反应路线如下:
(4)化合物S2的合成:将化合物S2(D)(134mg,0.44mmol)和三乙胺(0.07mL,0.48mmol)溶解在无水DCM(3mL)中,并混合液的温度降至0℃,逐滴加入丙烯酰氯(0.04mL,0.46mmol)溶液。将反应温度从0℃逐渐升至室温,并在室温下继续搅拌3小时。反应完全后混合液加入10%HCl(10mL)中,然后用DCM(30mL×2)萃取。将合并的有机萃取液用饱和碳酸钠溶液(20mL)洗涤,用无水硫酸钠干燥,蒸发,得到粗产物。通过硅胶柱色谱(DCM/MeOH=40/4)纯化残余物得到65mg白色固体。反应路线如下:
化合物S2的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.66(s,1H),7.95(d,J=8.3Hz,2H),7.78(d,J=8.4Hz,2H),6.47(dd,J=16.9,10.1Hz,1H),6.30(d,J=16.8Hz,1H),5.81(d,J=10.2Hz,1H),2.79(t,J=7.1Hz,4H),2.74(t,J=7.2Hz,4H),2.13(s,3H),2.02–1.95(m,4H).13C NMR(101MHz,DMSO-d6)δ164.39,163.90,143.32,142.17,141.82,138.67,132.11,129.79,129.00,128.01,127.13,119.05,31.58,31.16,25.08,16.35.
实施例4
按照实施例3的方法合成化合物S3,不同之处在于,在实施例3步骤(2)中,合成化合物S2(B)后结束反应,将实施例3步骤(3)中的S2(C)替换为S2(B),得到产物S3(D),将实施例3步骤(4)中的S2(D)替换为S3(D)。S3(D)的结构式如下:
化合物S3的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.79(s,1H),7.95(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),6.47(dd,J=16.9,10.1Hz,1H),6.30(d,J=16.8Hz,1H),5.81(d,J=10.1Hz,1H),2.86(d,J=4.9Hz,8H),2.06–1.99(m,4H).13CNMR(101MHz,DMSO-D6)δ164.48,163.93,142.94,142.38,141.12,132.12,130.11,129.42,129.10,127.99,119.11,114.12,34.59,32.20,24.45.
实施例5
按照实施例3步骤(4)的方法合成S4,不同之处在于,将S2(D)替换为S4(D)。S4(D)的结构式如下:
化合物S4的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.80(s,1H),7.95(d,J=8.5Hz,2H),7.79(d,J=8.5Hz,2H),6.52–6.42(m,1H),6.30(d,J=16.8Hz,1H),5.81(d,J=10.1Hz,1H),2.89(t,J=7.1Hz,4H),2.82(t,J=7.1Hz,4H),2.02(dd,J=14.4,7.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ164.50,163.93,142.37,141.42,140.81,132.11,129.50,129.44,129.09,128.00,123.94,119.11,32.43,31.92,24.76.
实施例6
按照实施例3步骤(4)的方法合成S6,不同之处在于,将S2(D)替换为S6(D)。S6(D)的结构式如下:
化合物S6的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.73(s,1H),7.94(d,J=8.0Hz,2H),7.77(d,J=8.0Hz,2H),7.30(d,J=7.3Hz,1H),7.23(d,J=6.8Hz,1H),7.20–7.10(m,2H),6.49–6.39(m,1H),6.27(d,J=16.9Hz,1H),5.77(d,J=9.9Hz,1H),2.19(s,3H).13C NMR(151MHz,DMSO-d6)δ165.10,163.90,142.31,136.94,134.09,132.05,130.70,129.61,129.02,128.00,126.99,126.39,126.29,
实施例7
按照实施例3步骤(4)的方法合成S7,不同之处在于,将S2(D)替换为S7(D)。S7(D)的结构式如下:
化合物S7的核磁测试结果如下:1H NMR(400MHz,CDCl3)δ10.44(s,1H),9.93(s,1H),8.00(d,J=8.1Hz,2H),7.82(d,J=8.2Hz,2H),7.40(d,J=7.2Hz,1H),7.26(q,J=7.1Hz,2H),6.48(dd,J=16.8,10.1Hz,1H),6.31(d,J=16.9Hz,1H),5.81(d,J=10.0Hz,1H),2.22(s,3H).13C NMR(151MHz,DMSO-d6)δ164.98,163.89,142.49,139.13,134.58,132.83,132.05,129.38,129.04,128.97,128.47,128.01,127.38,119.13,18.72.
实施例8
按照实施例3步骤(4)的方法合成S8,不同之处在于,将S2(D)替换为S8(D)。S8(D)的结构式如下:
化合物S8的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.64(s,1H),7.96(d,J=7.9Hz,2H),7.80(d,J=8.0Hz,2H),7.13(t,J=9.2Hz,2H),6.98(d,J=6.8Hz,1H),6.48(dd,J=16.7,10.1Hz,1H),6.31(d,J=16.9Hz,1H),5.81(d,J=10.0Hz,1H),2.76(s,2H),2.64(s,2H),1.71(s,4H).13C NMR(151MHz,DMSO-d6)δ165.10,163.87,142.26,137.89,136.60,133.29,132.07,129.68,128.97,127.96,127.21,125.52,124.56,119.03,29.61,24.78,22.86.
实施例9
按照实施例3步骤(4)的方法合成S9,不同之处在于,将S2(D)替换为S9(D)。S9(D)的结构式如下:
化合物S9的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),10.03(s,1H),7.94(d,J=8.5Hz,2H),7.80(d,J=8.5Hz,2H),7.67(s,1H),7.47(d,J=7.9Hz,1H),7.17(d,J=8.0Hz,1H),6.47(dd,J=16.9,10.1Hz,1H),6.30(d,J=16.8Hz,1H),5.81(d,J=10.1Hz,1H),2.83(dt,J=14.1,7.2Hz,4H),2.05–1.97(m,2H).13C NMR(151MHz,DMSO-d6)δ165.06,163.88,144.35,142.22,139.17,137.82,132.04,130.12,128.98,127.98,124.42,118.99,117.03,32.95,32.26,25.64.
实施例10
按照实施例3步骤(4)的方法合成S10,不同之处在于,将S2(D)替换为S10(D)。
S10(D)的结构式如下:
化合物S10的核磁测试结果如下:1H NMR(400MHz,CDCl3)δ10.44(s,1H),9.64(s,1H),7.99(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.28(d,J=7.6Hz,1H),7.19(d,J=7.6Hz,2H),6.48(dd,J=16.9,10.1Hz,1H),6.31(d,J=16.7Hz,1H),5.81(d,J=10.2Hz,1H),3.11–3.02(m,2H),1.16(d,J=6.2Hz,6H),1.10(d,J=6.3Hz,6H).13C NMR(151MHz,DMSO-d6)δ166.02,163.86,146.63,142.26,133.30,132.06,129.50,128.87,127.97,123.31,119.18,28.58,23.98,23.73.
实施例11
按照实施例3步骤(4)的方法合成S11,不同之处在于,将S2(D)替换为S11(D)。
S11(D)的结构式如下:
化合物S11的核磁测试结果如下:1H NMR(400MHz,CDCl3)δ10.41(s,1H),10.10(s,1H),7.91(d,J=8.2Hz,2H),7.74(dd,J=18.1,8.1Hz,4H),7.28(t,J=7.5Hz,2H),7.02(t,J=7.0Hz,1H),6.43(dd,J=16.8,10.1Hz,1H),6.25(d,J=16.9Hz,1H),5.75(d,J=10.0Hz,1H).13C NMR(101MHz,CDCl3)δ165.36,163.96,142.44,139.75,132.12,130.01,129.13,129.04,128.03,123.97,120.81,119.06.
实施例12
按照实施例3步骤(4)的方法合成S12,不同之处在于,将S2(D)替换为S12(D)。
S12(D)的结构式如下:
化合物S12的核磁测试结果如下:1H NMR(400MHz,CDCl3)δ10.44(s,1H),9.67(s,1H),7.99(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.12(s,3H),6.48(dd,J=16.9,10.1Hz,1H),6.31(d,J=16.9Hz,1H),5.81(d,J=10.1Hz,1H),2.18(s,6H).13C NMR(101MHz,CDCl3)δ164.91,163.93,142.32,136.15,135.91,132.12,129.54,128.94,128.16,128.02,127.07,119.17,18.56.
实施例13
按照实施例3步骤(4)的方法合成S13,不同之处在于,将S2(D)替换为S13(D)。
S13(D)的结构式如下:
化合物S13的核磁测试结果如下:1H NMR(400MHz,CDCl3)δ10.35(s,1H),8.09(d,J=7.8Hz,1H),7.82(d,J=8.5Hz,2H),7.72(d,J=8.5Hz,2H),6.45(dd,J=16.9,10.1Hz,1H),6.28(d,J=16.4Hz,1H),5.79(d,J=10.3Hz,1H),3.74(s,1H),1.76(d,J=30.5Hz,4H),1.60(d,J=12.0Hz,1H),1.28(dd,J=19.5,10.7Hz,4H),1.13(s,1H).13C NMR(101MHz,CDCl3)δ165.23,163.83,141.81,132.11,130.09,128.61,127.89,118.88,48.73,32.94,25.75,25.44.
实施例14
按照实施例3步骤(4)的方法合成S14,不同之处在于,将S2(D)替换为S14(D)。
S14(D)的结构式如下:
化合物S14的核磁测试结果如下:1H NMR(400MHz,CDCl3)δ10.47(s,1H),10.35(s,1H),8.10(d,J=7.7Hz,2H),7.98(s,2H),7.86(d,J=7.1Hz,3H),7.58(d,J=18.3Hz,4H),6.50(dd,J=16.5,10.2Hz,1H),6.33(d,J=16.8Hz,1H),5.83(d,J=9.8Hz,1H).13C NMR(101MHz,CDCl3)δ166.03,163.97,142.50,134.43,134.24,132.11,129.70,129.57,129.28,128.53,128.09,126.64,126.52,126.40,126.02,124.31,123.85,119.13,40.60,40.39,40.18,39.97,39.76,39.55,39.34.
实施例15
按照实施例3步骤(4)的方法合成S15,不同之处在于,将S2(D)替换为S15(D)。
S15(D)的结构式如下:
化合物S15的核磁测试结果如下:1H NMR(400MHz,DMSO-d6δ10.45(s,1H),10.35(s,1H),8.45(s,1H),8.02(d,J=7.9Hz,2H),7.92–7.82(m,6H),7.49(t,J=6.9Hz,1H),7.42(t,J=6.9Hz,1H),6.48(dd,J=16.6,10.2Hz,1H),6.32(d,J=16.9Hz,1H),5.82(d,J=9.9Hz,1H).13C NMR(151MHz,DMSO-d6)δ165.54,163.94,142.45,137.31,133.77,132.02,130.36,129.89,129.14,128.55,128.08,127.87,127.79,126.80,125.15,121.41,119.07,116.89.
实施例16
按照实施例3步骤(4)的方法合成S16,不同之处在于,将S2(D)替换为S16(D)。
S16(D)的结构式如下:
化合物S16的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.12(s,1H),8.39(d,J=8.0Hz,1H),7.92(d,J=7.3Hz,1H),7.57(t,J=7.4Hz,1H),7.26(t,J=7.1Hz,1H),7.03(s,1H),6.36(dd,J=16.7,10.1Hz,1H),6.22(d,J=16.9Hz,1H),5.78(d,J=10.0Hz,1H),2.85(m,4H),2.75(m,4H),2.03–1.97(m,4H).13C NMR(151MHz,DMSO-d6)δ166.92,163.64,143.45,138.91,138.59,132.87,132.41,129.68,129.10,127.51,123.73,122.81,121.75,118.89,32.93,30.66,25.52.
实施例17
按照实施例3步骤(4)的方法合成S17,不同之处在于,将S2(D)替换为S17(D)。
S17(D)的结构式如下:
化合物S17的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.85(s,1H),8.18(s,1H),7.92(d,J=7.5Hz,1H),7.67(d,J=7.2Hz,1H),7.46(s,1H),7.01(s,1H),6.46(dd,J=16.8,10.2Hz,1H),6.31(s,1H),5.78(d,J=10.2Hz,1H),2.85(t,J=6.6Hz,4H),2.73(t,J=6.3Hz,4H),2.02–1.95(m,4H).13C NMR(151MHz,DMSO-d6)δ164.97,163.74,143.32,139.58,138.57,135.86,132.16,130.37,129.22,127.61,122.75,122.50,119.45,118.58,32.96,30.72,25.52.
实施例18
按照实施例3步骤(4)的方法合成S18,不同之处在于,将S2(D)替换为S18(D)。
S18(D)的结构式如下:
化合物S18的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.36(s,1H),7.84(d,J=8.2Hz,2H),7.70(d,J=8.2Hz,2H),7.11–7.06(m,1H),7.02(d,J=7.0Hz,2H),6.44(dd,J=16.8,10.1Hz,1H),6.28(d,J=16.8Hz,1H),5.78(d,J=10.0Hz,1H),4.47(d,J=3.7Hz,2H),2.35(s,6H).13C NMR(151MHz,DMSO-d6)δ166.11,163.78,141.86,137.86,135.17,132.07,129.62,128.76,128.34,127.83,127.52,118.84,38.46,20.02.
实施例19
按照实施例3步骤(4)的方法合成S19,不同之处在于,将S2(D)替换为S19(D)。
S19(D)的结构式如下:
化合物S19的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.45(s,1H),7.66(d,J=7.7Hz,2H),7.36(d,J=7.8Hz,2H),7.07(s,3H),6.47(dd,J=16.9,10.1Hz,1H),6.29(d,J=16.9Hz,1H),5.78(d,J=10.0Hz,1H),3.63(s,2H),2.11(s,6H).13CNMR(151MHz,DMSO-d6)δ165.10,163.87,142.26,137.89,136.60,133.29,132.07,129.68,128.97,127.96,127.21,125.52,124.56,119.03,29.61,24.78,22.86.
实施例20
按照实施例2的方法合成S20,不同之处在于,将化合物B替换为如下结构式:
化合物S20的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.66(s,1H),7.88(d,J=8.2Hz,2H),7.68(d,J=8.2Hz,2H),6.96(s,1H),2.81(t,J=6.5Hz,4H),2.68(t,J=6.5Hz,4H),2.33(q,J=7.3Hz,2H),1.98–1.90(m,4H),1.06(t,J=7.4Hz,3H).13C NMR(151MHz,DMSO-d6)δ172.82,164.37,143.25,142.59,138.59,130.53,129.03,128.92,118.58,118.45,32.96,30.75,30.00,25.52,9.94.
实施例21
将化合物S1溶于DMF中,然后依次加入碳酸钾,3-溴基-1-丙烯,混合物在65℃下回流过夜。TLC显示反应完全,旋干溶剂,用水(30mL)和DCM(30mL×2)萃取,然后将有机相用饱和NaCl(30mL)洗涤,将有机层用无水硫酸钠干燥,过滤,并真空浓缩,得到粗产物。通过硅胶柱色谱(PE/EA=30/15)纯化残余物,得到31mg白色固体。
化合物S21的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),7.71(d,J=8.3Hz,2H),6.92(s,1H),6.56(d,J=8.3Hz,2H),6.43(s,1H),5.93–5.78(m,1H),5.19(d,J=17.2Hz,1H),5.08(d,J=10.2Hz,1H),3.72(s,2H),2.79(t,J=6.7Hz,4H),2.65(t,J=6.7Hz,4H),1.96–1.88(m,4H).13C NMR(151MHz,DMSO-d6)δ164.81,151.77,143.10,138.59,135.99,131.04,129.56,121.51,118.09,115.88,111.43,45.20,32.99,30.77,25.52.
实施例22
按照实施例21的方法合成S22,不同之处在于,将3-溴基-1-丙烯替换为如下结构式:
化合物S22的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),7.71(d,J=8.3Hz,2H),6.93(s,1H),6.55(d,J=8.3Hz,2H),6.20(s,1H),3.00(dd,J=12.3,6.2Hz,2H),2.80(t,J=6.7Hz,4H),2.66(t,J=6.8Hz,4H),1.97–1.89(m,4H),1.54(dd,J=14.2,7.1Hz,2H),0.91(t,J=7.3Hz,3H).13C NMR(151MHz,DMSO-d6)δ164.82,152.08,143.09,138.59,131.07,129.64,121.04,118.07,111.04,44.69,32.98,30.78,25.51,22.23,12.04.
实施例23
按照实施例2的方法合成S23,不同之处在于,将化合物B替换为如下结构式:
化合物S23的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.72(s,1H),7.94(d,J=8.0Hz,2H),7.82(d,J=8.2Hz,2H),7.00(s,1H),5.86(s,1H),5.57(s,1H),2.84(d,J=6.3Hz,4H),2.71(d,J=6.4Hz,4H),1.98(d,J=10.6Hz,7H).13C NMR(151MHz,DMSO-d6)δ167.46,164.37,143.27,142.31,140.61,138.59,130.50,129.55,128.73,120.93,119.70,118.48,32.96,30.75,25.52,19.12.
实施例24
按照实施例2的方法合成S24,不同之处在于,将化合物B替换为如下结构式:
化合物S24的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.70(s,1H),7.94(d,J=8.7Hz,2H),7.77(d,J=8.7Hz,2H),7.00(s,1H),6.85(dd,J=15.2,6.9Hz,1H),6.16(dd,J=15.2,1.7Hz,1H),2.85(t,J=7.3Hz,4H),2.72(t,J=7.2Hz,4H),2.02–1.95(m,4H),1.89(dd,J=6.9,1.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ164.40,164.21,143.31,142.56,141.15,138.63,130.55,129.34,129.00,126.24,118.90,118.52,33.00,30.78,25.56,18.06.
实施例25
按照实施例2的方法合成S25,不同之处在于,将化合物B替换为如下结构式:
化合物S25的核磁测试结果如下:1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.73(s,1H),7.97(d,J=8.1Hz,2H),7.83(d,J=8.2Hz,2H),7.69–7.59(m,3H),7.45(dd,J=15.1,7.5Hz,3H),7.00(s,1H),6.88(d,J=15.7Hz,1H),2.85(t,J=6.8Hz,4H),2.73(t,J=6.8Hz,4H),2.02–1.93(m,4H).13C NMR(101MHz,DMSO-d6)δ164.32,143.33,142.52,141.25,138.65,135.09,130.56,130.43,129.54,129.10,128.29,122.45,118.96,118.54,40.61,40.40,40.19,39.98,39.77,39.57,39.36,33.01,30.79,25.57.
实施例26
按照实施例2的方法合成S26,不同之处在于,将化合物B替换为如下结构式:
化合物S26的核磁测试结果如下:S27:1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.70(s,1H),7.92(d,J=8.3Hz,2H),7.80(d,J=8.4Hz,2H),6.99(s,1H),6.50(d,J=6.7Hz,1H),2.84(t,J=6.9Hz,4H),2.72(t,J=6.9Hz,4H),2.01–1.93(m,4H),1.85(s,3H),1.79(d,J=6.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ168.46,164.44,143.30,142.77,138.64,132.95,131.53,130.58,129.24,128.76,119.55,118.50,33.00,30.79,25.56,14.36,12.96.
实施例27
以下实施例中,所使用的试剂获得途径如下:
DMEM培养基(Hclone,USA);DMEM/F12培养基(Hyclone,USA);胎牛血清(Hyclone,USA);MTT(Solaibio,China);DMSO(Sigma,USA);LPS(Sigma,USA);尼日利亚菌素(Invitrogen,USA);IL-1β捕获剂(R&D,USA);IL-1β检测抗体(R&D,USA);链酶亲和素-HRP(R&D,USA);染色剂A/B(R&D,USA);胰蛋白酶(Gbico,USA);DNaseⅠ(Sigma,USA)。
细胞系培养:BV2小胶质细胞的培养基为含有10%胎牛血清和1%青霉素/链霉素的完全DMEM培养基,在37℃,5%CO2培养箱中培养。
用Griess试剂测定BV2细胞产生的NO水平。将BV2小胶质细胞以1~2×104个/cm2的密度接种在96孔板中,每个孔中分别加入不同浓度的化合物S1-S26预处理细胞30分钟,然后用LPS(0.1μg/ml)刺激24h。然后将BV2小胶质细胞上清液(50μL)转移到另一个96孔板中,并与50μLGriess试剂混合,最后,在酶标仪上540nm处测试吸光度。同时,除去残留的细胞培养基,向每个孔中加入30μL MTT(0.5mg/mL)溶液。在37℃孵育2~4小时后,向每个孔中加入100μL二甲基亚砜(DMSO)溶解结晶,通过酶标仪在540nm吸光度下测量吸光度。不同化合物对LPS处理的BV-2小胶质细胞中NO生成的抑制IC50活性,及在20μM浓度下细胞的存活度,如表2所示。
表2不同化合物对BV-2小胶质细胞中NO生成的抑制作用测试结果
NO是一种重要的神经炎症因子,通过激活小胶质细胞而分泌产生,会导致神经元损伤和凋亡。已有文献报道的甾体化合物18b(来自于文献ACS Chemical Neuroscience7(2016)305–315)对LPS刺激的BV-2小胶质细胞中NO生成的抑制作用的IC50值为8.546μM;奎尼酸衍生物2和8(来自于文献Bioorganic&Medicinal Chemistry Letters 23(2013)2140–2144)对LPS刺激的BV-2小胶质细胞中NO生成的抑制作用的IC50值分别为4.66和9.04μM;1,7-二羟基-4-甲氧基黄嘌呤17(来自于文献Bioorganic&Medicinal Chemistry Letters 23(2013)5904–5908)对LPS刺激的BV-2小胶质细胞中NO生成的抑制作用的IC50值分别为7.4μM。从表2可以看出,化合物S8,S9,S10,S21,S22,S26,S20,S12,S14对BV-2小胶质细胞中NO生成的抑制作用的IC50值分别为2.257μM,5.782μM,5.245μM,5.354μM,5.219μM,6.762μM,5.418μM,2.323μM,2.521μM,明显强于化合物甾体化合物18b,奎尼酸衍生物8和1,7-二羟基-4-甲氧基黄嘌呤17。并且,化合物S9比已报道的最强神经炎症抑制剂——奎尼酸衍生物2还要强一倍。虽然从BV-2小胶质细胞的存活度可以看出,化合物S21,S22,S26,S20,S12,S14虽具有对BV-2小胶质细胞中NO生成较好的抑制作用,却存在一定的细胞毒性。然而化合物S8,S9,S10不仅有较强的抑制作用,而且细胞毒性也较低。以上结果表明,本发明的式(I)所示的化合物有望制备神经炎症抑制剂或制备预防和/或治疗神经退行性疾病的潜在治疗药物。
以上仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变型,这些改进和变型也应视为本发明的保护范围。
Claims (9)
2.根据权利要求1所述的式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物,其特征在于:A选自1,2,3,5,6,7-六氢-s-引达省、卤素和/或C1-C8烷基取代的1,2,3,5,6,7-六氢-s-引达省、1,2,3,4-四氢萘、茚满、喹啉、异喹啉或C4-C8脂族环。
3.根据权利要求1所述的式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物,其特征在于:B选自苯基、1,2,3,5,6,7-六氢-s-引达省、1,2,3,4-四氢萘或茚满。
4.根据权利要求1所述的式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物,其特征在于:R选自丙烯酰基、(E)-2-甲基-2-烯酰基、烯丙基、(E)-戊-3-烯-2-酰基、(E)-4-苯基-3-烯-2-酰基、3-甲基-3-烯-2-酰基、苯丙烯酰基、丙酰基或C1-C8烷基。
6.权利要求1-4中任一项所述的式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物在制备神经炎症抑制剂中的应用。
7.根据权利要求6所述的应用,其特征在于:所述神经炎症为小胶质细胞神经炎症。
8.权利要求1-4中任一项所述的式(I)所示的酰胺类化合物、其药剂学上可接受的盐、酯、前药或水合物在制备预防和/或治疗神经炎症导致的神经退行性疾病的药物中的应用。
9.根据权利要求8所述的应用,其特征在于:所述神经退行性疾病包括帕金森氏症、阿尔茨海默症、缺血脑脑卒中、多发性硬化和艾滋病相关痴呆症中的一种或几种。
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