CN116217508A - 一类用于保护β细胞来治疗II型糖尿病的噁二唑类化合物及其制备方法和应用 - Google Patents
一类用于保护β细胞来治疗II型糖尿病的噁二唑类化合物及其制备方法和应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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- A—HUMAN NECESSITIES
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
Description
技术领域
本发明涉及药物化学领域,具体为一类用于保护β细胞来治疗II型糖尿病的噁二唑类化合物及其制备方法和应用。
背景技术
糖尿病是一组长期血糖水平异常高的代谢性疾病,已成为一个严重的公共卫生问题,给社会带来巨大的社会和经济负担。分泌胰岛素的β-细胞的功能障碍或死亡是1型(T1D)和2型(T2D)糖尿病发病机制的关键因素。越来越多的证据表明,内质网(ER)应激引起蛋白质在内质网中的错误折叠,导致β细胞产生功能障碍,进而引起胰岛β细胞功能失调甚至凋亡。因此,通过靶向内质网应激来预防功能性β细胞死亡是治疗糖尿病的一种很有前景的方法。但不幸的是,当前没有抗糖尿病药物能够抑制β细胞功能障碍和死亡。
在T2D中,由于肥胖症和抗胰岛素性的高代谢需求,β细胞被迫合成更多的胰岛素,这会导致蛋白质折叠超出细胞的能力范围,最终导致内质网应激和β细胞功能障碍和死亡。此外,T2D中β细胞功能障碍和死亡的常见原因包括脂肪毒性、糖毒性、氧化应激、淀粉样蛋白沉积和胰岛素突变,这些原因与无法解决的慢性内质网应激有关。
尽管内质网应激是导致β细胞功能障碍和死亡的重要因素,但迄今为止,只有少数小分子被报道出对内质网应激后表现出的β细胞具有保护性,产生这种情况的主要原因可能是β细胞的独特特性,食物摄入后血糖水平的升高时,体内产生β-细胞并迅速分泌胰岛素。为了实现这一功能,在葡萄糖刺激下,胰岛素原蛋白的合成是原来的25倍。胰岛素原合成的激增给内质网的蛋白质折叠能力带来了沉重的负担;因此,β-细胞特别容易受到内质网应激的影响。此外,现有的保护β细胞的小分子仍然存在低效价的问题,EC50值通常从一位数到两位数不等。
噁二唑是具有一个氧,两个氮和两个碳原子的环状化合物。这些化合物在古代文献中被称为“furodiazoles”。芳杂环系统形成许多生物活性药物分子的关键部分。芳杂环具有广泛的重要性,因为它们具有与人体中存在的许多生物部分如核酸,激素,神经递质等的结构相似性。在许多杂环中,许多药物产品构成是以噁二唑作为主要药物组分。噁二唑主要有四种存在形式,分别是1,2,3-噁二唑,1,2,4-噁二唑,1,2,5-噁二唑和1,3,4-噁二唑。其中1,3,4-噁二唑类衍生物具有一定的抗癌活性。1,2,4-噁二唑环对于中枢毒蕈碱受体的亲和力和功效是最佳的且具有一定的抗菌活性。这些活性是由于-N=C-O-键的存在,因此噁二唑及其衍生物引起了化学家的广泛关注,用于制备不同的生物活性药物。
发明内容
发明目的为了解决内质网应激导致β细胞功能障碍或者凋亡进而引发II型糖尿病的问题,本发明利用一类1,2,4-噁二唑化合物抑制内质网应激进而保护β细胞来对糖尿病产生治疗效果。本发明还提供了该化合物的具体制备方法,该化合物及以其为原料制备的产品在抗糖尿病药物开发方面具有潜在的应用前景。
一种通式(I)所示的噁二唑类化合物或其药学上可接受的盐,化合物的结构式如下:
通式(I)中,R1选自下列之一:氢、氘、氯、C1-C4烷基或取代烷基,取代烷基的取代基为卤素;R1选自下列之一:氢、氘、C1-C4烷基或取代烷基。
进一步地,本发明所述化合物选自A1至A8:
所述的噁二唑类化合物的合成方法,包括以下步骤:
(1)以取代苯甲腈和盐酸羟胺为原料合成取代的N'-羟基-苯甲酰亚胺;
(2)以取代苯甲酸和取代的N'-羟基-苯甲酰亚胺为原料合成通式(I)所示的噁二唑类化合物,其中所述取代苯甲酸的苯环上的取代基R1与通式(I)中R1相同,取代的N'-羟基-苯甲酰亚胺的苯环上的取代基R2与通式(I)中R2相同。
进一步地,步骤(1)中取代苯甲腈和盐酸羟胺的摩尔比为1:0.5~2;步骤(2)中取代苯甲酸和取代的N'-羟基-苯甲酰亚胺的摩尔比为1:0.5~2。
进一步地,步骤(1)中反应是在NaOH存在下于乙醇溶剂中进行反应,反应温度55-65℃并用TLC跟踪反应至结束,NaOH与盐酸羟胺原料的摩尔比为4-6:1。
进一步地,步骤(2)中反应是在催化剂存在下于有机溶剂中进行反应,催化剂与取代苯甲酸的摩尔比是1~1.2:1,所述取代苯甲酸在有机溶剂中的浓度为0.2~0.4mmol/mL。
步骤(2)中在进行噁二唑合成时溶剂除了选择二甲基甲酰胺外还可选择二甲基亚砜。由于二甲基亚砜有良好的吸水性,因此更有力于反应的正向进行,从而提高产率。但二甲基亚砜存在一定毒性。在苯甲酸存在时加热会产少量甲基硫醇、甲醛、二甲基硫、甲磺酸等杂质。因此可以用二甲基亚砜替换二甲基甲酰胺。
步骤(2)中在进行噁二唑合成时催化试剂除了选择N'N-羰基二咪唑外还可以选择1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和1-羟基苯并三唑(HOBT)来活化羧基。
本发明所述的噁二唑类化合物或其药学上可接受的盐在制备用于保护β细胞来治疗II型糖尿病的药物中的应用。
与现有技术相比,本发明取得的有益效果是:本发明公开了一种新的通式(I)所示的化合物及其制备方法,能够抑制内质网应激进而保护β细胞来对糖尿病产生治疗效果,可用于制备治疗糖尿病的药物。
附图说明
图1为本发明化合物A6的核磁氢谱表征图;
图2为本发明化合物A5的核磁氢谱表征图;
图3为本发明化合物A4的核磁氢谱表征图;
图4为本发明化合物A3的核磁氢谱表征图;
图5为本发明化合物A8的核磁氢谱表征图;
图6为本发明化合物A1的核磁氢谱表征图;
图7为本发明化合物A2的核磁氢谱表征图;
图8为本发明化合物A7的核磁氢谱表征图。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。
实施例1:
1)N'-羟基-苯甲酰亚胺的合成
在50ml烧杯甲中依次加入称取的盐酸羟胺(1.390g,0.02mol)并加入乙醇(95%)配置成1mol/L溶液。在50ml烧杯乙中依次加入称取的固体氢氧化钠(4.008g,0.10mol)并加入乙醇(95%)配置成1mol/L溶液。甲乙两烧杯中溶液同时用磁力搅拌,将乙烧杯中溶液缓慢加入甲烧杯中,磁力搅拌,产生大量白色沉淀,抽滤后得澄清溶液装于100ml圆底烧瓶中并加入称取的苯甲腈(2.066g,0.02mol),磁力搅拌,60℃油浴加热,同时全程用TLC跟踪反应进程,反复尝试后发现展开剂PE:EA=2:1时可以准确分离,用乙酸乙酯和水萃取三次保留乙酸乙酯层,然后用饱和食盐水洗涤三次并用无水硫酸钠干燥,抽滤出去硫酸钠固体后旋蒸除去有机溶剂。得到淡黄色晶体1.132g,产率为83.5%。
2)5-(3-甲基苯基)-3-苯基-1,2,4-噁二唑的合成
在25ml圆底烧瓶中依次加入称取间甲基苯甲酸(0.068g,0.0005mol)和N'N-羰基二咪唑(0.097g,0.0006mol)并滴加二甲基甲酰胺1.67ml,磁力搅拌,25℃油浴加热反应1h,称取N'-羟基-苯甲酰亚胺(0.00055mol)并在50℃温度下加热。称取氢氧化钠(0.024g,0.0006mol)加入圆底烧瓶内,此时反应液变为淡黄色。用乙酸乙酯和水萃取三次保留乙酸乙酯层,然后用饱和食盐水洗涤三次并用无水硫酸钠干燥,抽滤出去硫酸钠固体后旋蒸除去有机溶剂。通过柱层析分离得到纯产品(固定相:硅胶(200-300目),流动相:正己烷、乙酸乙酯(V/V=15:1)),得到最终产物0.026g,产率为57.6%。
实施例2:5,3-二苯基-1,2,4-噁二唑衍生物的底物拓展
表1
实施例1公开了化学物A2合成的具体内容。
化合物A1-A8的合成重复实施例1,不同之处在于“步骤1)中将苯甲腈替换为同等摩尔量的取代苯甲腈合成取代的N'-羟基-苯甲酰亚胺,步骤2)中将间甲基苯甲酸替换为同等摩尔量的取代苯甲酸,相应的取代基列于表1中”。
在化合物A1与A3的合成时,为提高反应产率,对步骤2)后处理步骤进行一定的改进,具体为:用乙酸乙酯和水萃取三次保留乙酸乙酯层后用饱和食盐水洗涤三次改为直接向反应体系中滴加少量冷蒸馏水,此时淡黄色溶液中瞬间有大量白色晶体析出,通过柱层析分离得到纯产品。
在化学物A5的合成中,在合成好A5后,准备通过柱层析分离时,在一定比例展开剂(PE:EA=5:1)通过TLC发现样品点与杂质点比移值大于0.8,决定通过采用HPTLC分离提纯产品,产率为36.3%。
在合成A4时,将步骤2)的反应时间延长1h提高产率。
按照上述过程,化合物A1-A8的收率列于表1中。
本发明化合物A1-A8的核磁氢谱表征图见图1-图8,以及核磁共振氢谱数据列于表3中。
生物学评价实验
(1)活性分析检测方法
β细胞的检测方法:将INS-13×103细胞/孔接种于384孔板中,并用指定浓度的化合物处理。处理3d后,抽吸培养基,加入20μL/孔的CellTiter-Glo试剂(Promega,WI,USA),检测细胞内ATP水平。使用EnVision微孔板读板仪(PerkinElmer,MA,USA)测量细胞活性。每个实验在每个条件下进行3次,并进行3个独立的实验。
测得的EC50值如下表2,从实验结果可以看出,本发明实例化合物对β细胞活性具有很强的抑制活性。
表2本发明化合物对INS-1β细胞活性的EC50测量值
表3本申请化合物的核磁共振氢谱数据
本说明书所述的内容仅仅是对发明构思实现形式的列举,本发明的保护范围不应当被视为仅限于实施例所陈述的具体形式。
Claims (7)
3.根据权利要求1所述的噁二唑类化合物的合成方法,其特征在于包括以下步骤:
(1)以取代苯甲腈和盐酸羟胺为原料合成取代的N'-羟基-苯甲酰亚胺;取代苯甲腈与取代的N'-羟基-苯甲酰亚胺两者的苯环上的取代基相同;
(2)以取代苯甲酸和取代的N'-羟基-苯甲酰亚胺为原料合成通式(I)所示的噁二唑类化合物,其中所述取代苯甲酸的苯环上的取代基与通式(I)中R1相同,取代的N'-羟基-苯甲酰亚胺的苯环上的取代基与通式(I)中R2相同。
4.根据权利要求3所述的噁二唑类化合物的合成方法,其特征在于步骤(1)中取代苯甲腈和盐酸羟胺的摩尔比为1 : 0.5~2;步骤(2)中取代苯甲酸和取代的N'-羟基-苯甲酰亚胺的摩尔比为1 : 0.5~2。
5.根据权利要求3所述的噁二唑类化合物的合成方法,其特征在于步骤(1)中反应是在NaOH存在下于乙醇溶剂中进行反应,反应温度55-65℃并用TLC跟踪反应至结束,NaOH与盐酸羟胺原料的摩尔比为4-6:1。
6.根据权利要求3所述的噁二唑类化合物的合成方法,其特征在于步骤(2)中反应是在催化剂存在下于有机溶剂中进行反应,催化剂为N'N-羰基二咪唑、1-(3-二甲氨基丙基)-3-乙基碳二亚胺EDC或1-羟基苯并三唑HOBT,催化剂与取代苯甲酸的摩尔比是1~1.2:1,有机溶剂为二甲基甲酰胺或二甲基亚砜,所述取代苯甲酸在有机溶剂中的浓度为0.2~0.4mmol/mL。
7.根据权利要求l所述的噁二唑类化合物或其药学上可接受的盐在制备用于保护β细胞来治疗II型糖尿病的药物中的应用。
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