CN114634503A - 含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物及其制备方法和用途 - Google Patents
含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物及其制备方法和用途 Download PDFInfo
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- CN114634503A CN114634503A CN202210181288.1A CN202210181288A CN114634503A CN 114634503 A CN114634503 A CN 114634503A CN 202210181288 A CN202210181288 A CN 202210181288A CN 114634503 A CN114634503 A CN 114634503A
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- substituted
- indole
- ptp1b
- compound
- alkaloid
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- -1 Heterocyclic substituted-1, 3-thiazolidone Chemical class 0.000 title claims description 52
- 229930005303 indole alkaloid Natural products 0.000 title claims description 12
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- 238000002360 preparation method Methods 0.000 title claims description 5
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- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 claims abstract description 18
- 229930013930 alkaloid Natural products 0.000 claims abstract description 5
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- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 230000008827 biological function Effects 0.000 claims abstract description 3
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- 230000015572 biosynthetic process Effects 0.000 claims description 29
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 22
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- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 16
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 16
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Abstract
本发明属于医药技术领域,具体为一种含生物碱1H‑吲哚‑3‑取代‑1,3‑噻唑烷‑4‑酮类衍生物及其合成方法和应用。本发明利用拼合原理、药效团模型以及PTP1B抑制剂的结构特征,结合PTP1B酶活性位点的特点,设计合成具有生物碱1H‑吲哚‑3‑取代‑1,3‑噻唑烷‑4‑酮基本结构的化合物;本发明还包含其药用盐,水合物及溶剂化物,其多晶或共晶,其同样生物功能的前体和衍生物。测试表明:该化合物体外对PTP1B酶具有良好的抑制活性;实施例合成的14个化合物在浓度为5μg/mL下都显示出优秀的PTP1B抑制活性,其半数抑制浓度(IC50值)在4.56~14.53μM之间,抑制率最高达80.61%,活性最好的IC50值为4.56μM,可成为PTP1B抑制剂的潜在先导化合物。
Description
技术领域
本发明属于医药技术领域,具体涉及一种含新型吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物及其制备方法和用途。
背景技术
蛋白质酪氨酸磷酸酶1B是第一个于1988年被成功分离纯化的蛋白质酪氨酸磷酸酶,它在胰岛素信号转导中起负调节作用,PTP1B作为治疗2型糖尿病和肥胖症的最好的药物靶点之一已得到广泛研究。PTP1B与肿瘤的发生发展也有着密切的关系1。尽管PTP1B也是信号转导途径中的组成成分,但直到近些年,人们才逐渐认识到它在人类健康和疾病中的重要性,从而将PTP1B作为一种新的靶点,开发治疗相关疾病的新药物2。PTP1B作为一个很重要的信号转导酶,通过调节细胞的酪氨酸磷酸化水平而参与多种疾病的发生发展,因此开发小分子PTP1B抑制剂作为治疗多种疾病的药物具有非常诱人前景3。尽管近些年来学者们对于PTP1B抑制剂的研究已越来越热,然而传统意义上的PTP1B抑制剂却存在生物利用度差,选择性差,毒性大等各种各样的问题,使得此类抑制剂的研究也受到极大的挑战,目前PTP1B为靶点治疗各种相关疾病的新药多数还处于临床前研究的阶段,并无上市药物,因此寻找结构新颖,作用位点特异性好,高效低毒的新型PTP1B抑制剂已成为一个必然的研究趋势,也为我们开发具有自主知识产权的创新药物提供了机会。
发明内容
本发明的目的在于提供一种结构新颖、作用位点特异性好、高效低毒的PTP1B抑制剂。
鉴于传统PTP1B抑制剂面临各种各样的问题,很多学者将目光投向了五元杂环。其中噻唑烷-4-酮及吲哚等杂环结构由于其广泛的生物活性及良好的生物兼容性,近些年来得到广泛研究。更重要的是,这些结构片段在近些年来有关新型的PTP1B抑制剂研究的文献报道中也活跃起来。李佳等人表达纯化了人类PTP1B催化结构域,建立了一个分子水平的高通量筛选测试方法,筛选48000个纯化合物,发现一个新型噻唑烷-4-酮的结构片段有效竞争性的PTP1B抑制剂I1(LGH00081),其对PTP1B抑制的IC50为1.6μmol/L4。上述课题组进而进一步设计合成系列3-取代的吲哚2-酮骨架的衍生物5,评价其对PTP1B抑制活性,其中活性最好化合物I2 IC50为3.48μM。这些结构片段对PTP1B抑制活性至关重要。我们也先期设计合成了一系列1,3-噻唑烷-4-酮取代的3-吲哚衍生物(I3)和3-取代芳亚胺基靛红衍生物(I4),并进行PTP1B酶抑制活性筛选,浓度为20μg/mL时,所筛选的44个目标化合物,在一定程度都对PTP1B有抑制活性6,7。
含有噻唑烷-4酮和吲哚片段的PTP1B抑制剂化合物I1、I2、I3、I4的结构式为:
通过对目标化合物PTP1B抑制活性分析,总结其构效关系如下:
(1)以1,3-噻唑烷-4-酮取代的3-吲哚衍生物(I3系列化合物)的抑酶活性明显高于3-取代芳亚胺基靛红衍生物(I4系列化合物),这表明在吲哚的3-位引入1,3-噻唑烷-4-酮杂环有利于抑酶活性的提高;
(2)在1,3-噻唑烷-4-酮的2位和3位引入取代基时有助于活性的提高;
(3)当分子中存在更多氢键供体(如吲哚环的NH,羟肟基上的OH)和氢键受体(如噻唑酮的C=O,吲哚2位上的C=O,1,3-噻唑烷酮的2-位上的亚氨基,吲哚3-位的亚氨基)时,有利于化合物抑酶活性的提高;其次对PTP1B三维晶体结构的考察发现,PTP1B酶总共包含有435个氨基酸残基,PTP1B的潜在活性位点主要有A,B,C三个部位(图1);其中A位点,位于一个浅口袋的底部,由His214–Arg221八个氨基酸残基组成,对酶的催化活性起着至关重要的作用,然而该位点却具有很强的正电性及高度的保守性,导致了针对该单一位点所设计的抑制剂理化性质和选择性均较差;第二结合B位点比A位点大而浅,其与芳基磷酸基的结合能力较低,是非催化活性位点,然而却在决定底物特异性方面起到了非常重要的作用;C位点是一个位于Lys41和Arg47附近的大平坦区域,可容纳一些带负电荷的取代基8;总之,该受体结合腔的拓扑学形状和氨基酸残基的空间配置允许该类抑制剂有较大结构变化;为克服以往针对单一位点所设计的抑制剂所面临的问题,希望通过拼合原理,将不同活性片段通过合适连接基,设计出能同时作用于A,B,C等多个位点的抑制剂(图1)。
本发明利用结构拼合原理、药效团模型以及PTP1B活性位点的特点,选取芳香性的吲哚和1,3-噻唑烷-4-酮五元杂环作为基本活性骨架,通过不同长度的连接基将其融合到一个分子当中,设计出了化合物TM,具体是通过在1H-吲哚-2-酮和1,3-噻唑烷-4-酮的基本母核的不同位置引入各种取代基来调节抑制剂的大小,连接基的设计考虑到构效关系中所提到的目标分子中存在更多潜在的氢键供体有利于酶活性的提高,而选用了具有一定长度的亚肼基作为连接基团,以适应PTP1B受体结合腔各结合位点之间的空间位置与距离要求,以期使得这些小分子抑制剂能伸展至多个位点产生相互作用,目标化合物设计思路见图2。
上述目标分子的设计思想是基于对PTP1B结合腔结构和小分子抑制剂的药效团特征分析,设计化合物能够同时作用与酶的A,B,C甚至更多位点,以下为所设计化合物与酶活性部位作用模拟图(图3),旨在在发现理化性质好,活性高,选择性更好的PTP1B抑制剂候选化合物。
根据上述设计思想,本发明提供的新型PTP1B抑制剂,具体为含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物,记为TM,其结构通式为:
其中,R1为以F,Cl为代表的卤素吸电子基,以甲基(Me)为代表的烷基供电子基,R2为各卤素为代表的各种吸电子和以甲氧基(OMe)为代表的各种供电子基。
典型的,化合物TM有26种,依次记为TM1,TM2,…,TM26;其与R1,R2的对应关系如下:
本发明还包括所述含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物的药用盐,其水合物和溶剂化物,其多晶和共晶,其同样生物功能的前体和衍生物。
本发明中,所述5-取代-3-(芳基取代噻唑烷-4-酮-2-叉基亚肼基)-1H-吲哚-2-酮类衍生物的药用盐,包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、富马酸盐或苹果酸盐。
本发明还提供上述含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物(TM)的合成方法,具体是以各种的廉价易得的取代芳香胺类化合物为起始原料,经过多步骤反应制备得到目标化合物,其合成路线为:
合成的具体步骤为:
(1)首先以各种取代的芳香胺(1,1.0~1.1equiv.)为起始原料,在水合氯醛(1,1.1~1.2equiv.),盐酸羟氨(1,3.0~3.3equiv.)的作用进行反应,经过简单后处理后,分别经过硅胶柱层析分离,制备得到中间体(2),产率介于62.6~87.6%之间;
(2)中间体(2)在浓硫酸的作用下环合得到重要中间体各种5-取代的靛红(3),产率介于70.8~98.3%之间;
(3)与上述合成步骤的同时,以各种取代的苯胺(1.1,1.0~1.1equiv.)和CS2(4,1.8~2.0equiv.)为原料,在碱性条件下合成不稳定的硫代乙酸氨基盐类中间体,稍加分离纯化后,继而采用氯甲酸甲酯(1.0~1.1equiv.)进脱硫反应,简单后处理经过硅胶柱层析分离,即可得到各种取代的芳基异硫氰酸酯(5),产率介于40.6~85.5%之间;
(4)将异硫氰酸酯(5)在水合肼(80%)作用下肼解得到各种芳基取代的氨基硫脲(6),产率介于58.2~87.8%之间,为另一种重要中间体;
(5)将上述两种重要中间体5-取代的靛红(3,1.0~1.1equiv.)和芳基异硫氰酸酯(6,1.0~1.1equiv.)在浓硫酸催化下在乙醇中进行分子间脱水缩合反应,得到各种席夫碱中间体7,产率介于58.3~87.8%之间,分别将席夫碱7中的任意一种化合物(7,1.0~1.1equiv.)与2-氯乙酸乙酯(1.0~1.1equiv.)在无水乙酸钠催化下进行等摩尔比的环合反应,得到目标化合物TM,产率介于72.1~97.7%之间。
典型的,所述取代的芳香胺(1),其中,R1取为F,CH3,Cl,并依次记为取代的芳香胺(1a,1b,1c),与其对应的中间体(2)、中间体5-取代的靛红(3),依次记为中间体(2a,2b,2c),中间体5-取代的靛红(3a,3b,3c)。
所述取代的苯胺(1.1),其中,R2取为4-F,4-CH3,4-Cl,4-OCH3,4-H,4Br,2-Cl,3-Cl,3-CF3,并依次记为取代的苯胺(1.1a,1.1b,…,1.1i),与其对应的中间体芳基异硫氰酸酯(5)、中间体芳基异硫氰酸酯(6),依次记为芳基异硫氰酸酯(5a,5b,…,5i),芳基异硫氰酸酯(6a,6b,…,6i)。
所述的席夫碱7,分为三种,记为席夫碱7-1,7-2,7-3,具体为7-1a--7-1i,7-2a--7-2d,7-2f--7-2i,7-3a--7-3h,其对应的R1,R2如下:
本发明设计合成的结构新颖的含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物,通过NMR和质谱分析表征。体外对PTP1B酶抑制活性表明:具有良好的PTP1B抑制活性;实施例中测试的26个目标化合物中,有14个化合物在浓度为5μg/mL下都显示出了优秀的PTP1B抑制活性,其半数抑制浓度(IC50值)在0.45~14.53μM之间。其中,抑制率最高的达80.61%(化合物TM12),活性最好的IC50值为4.56μM(化合物TM25)。对所有目标化合物在酶分子水平上的生物活性初步筛选实验结果显示,目标产物在体外酶水平的对PTP1B在不同程度上具有明显抑制活性。本发明化合物可成为PTP1B抑制剂的潜在先导化合物。
附图说明
图1为PTP1B潜在活性位点。
图2为目标化合物的设计思路。
图3为化合物与酶的活性部位期望作用的模拟图。
具体实施方式
下面通过具体实施例进一步介绍本发明。
实施例包括相关中间体和目标化合物的合成、生物活性筛选及构效关系研究分析。
实施例1.中间体2a-2c合成
在一干净的500mL单口瓶中,加入水合氯醛(9.0g,55.0mmol),水(240mL),搅拌均匀后依次加入无水硫酸钠(130g),取代苯胺(1a-1c,50.0mmol),盐酸溶液(2.2mL HCl+10.0mL水),盐酸羟氨(10.4g,150.0mmol),加毕,逐渐升温至65℃,反应2h,停止加热,趁热过滤分别得各固体粗品,分别经柱纯化(P:E=5:1~3:1)得乳白色固体(2a,6.68g,73.4%,m.p.158.1~159.7℃);柱纯化(P:E=3:1~2:1)得淡黄色固体(2b,7.33g,87.6%,m.p.155.6~156.9℃);将所得粗品2c热溶于乙酸乙酯中,加入石油醚调节极性,析出大量乳白色固体,抽滤干燥得纯品(2c,6.20g,62.6%,m.p.171.7~173.3℃)。
实施例2.中间体3a-3c合成
在一干净的150mL三口瓶中,加入浓硫酸(24.0mL),升温至50℃,慢慢加入上述合成中间体(2a-2c,30.0mmol),随着量的加入,溶液颜色慢慢加深,变黑,加毕,温度调至80℃,反应20min,取碎冰(100g)慢慢加入反应体系,冰水颜色为红棕色,静置,抽滤,水洗至中性,将该固体溶于90mL10%NaOH中,用浓盐酸调节pH至4,抽滤,滤液继续用浓盐酸调pH至2,有大量砖红色固体析出,抽滤干燥得红棕色固体3a(98.3%,220.1~221.8℃),3b(70.8%,185.3~187.5℃),3c(95.1%,248.4~251.2℃。
实施例3.中间体5a-5i的合成
称取各取代苯1a-1i(50.0mmol)置于一干净100mL三颈瓶,依次加入乙醚(15.0mL)、CS2(4,3.6mL,90.0mmol)以及三乙胺(7.2mL),体系于25~30℃下反应12h。体系中产生大量固体,抽滤,滤饼用无水乙醚(30.0mL)洗涤,得粉末状固体。将该固体置空气中自然干燥10min,挥去其中残存的乙醚后,将其转移至100mL干净三颈瓶中,加氯仿(50.0mL),体系成均相,加入三乙胺(7.2mL),冰盐浴冷却至0℃以下,搅拌下向体系中滴加氯甲酸甲酯(3.9mL,50.0mmol),滴加过程中,体系温度控制在5℃以下。滴加完毕,水浴29~30℃反应1h,TLC监测反应进行程度,待反应完毕,停止反应,向体系中加入硅胶拌样后,柱层析分离(石油醚体系),得无色油状液体或白色固体,即得中间体5a-5i(表1)。
表1中间体5a-5i总结表
实施例4.中间体6a-6i的合成
在一干净的50mL单口瓶中,加入芳基异硫氰酸酯(5a-5i,2.00mmol),加入20mL异丙醇溶解,搅拌下滴加水合肼(85%,2.40mmol),立刻有大量白色沉淀生成,将该体系在室温下继续搅拌30min,过滤,滤饼用异丙醇洗涤3次得中间体产物6a-6i(表2)。
表2中间体6a-6i总结表
实施例5.中间体7-1a--7-1i,7-2a--7-2d,7-2f--7-2i,7-3a--7-3h的合成
在一干净的100mL单口瓶中,分别加入各种5-取代靛红(3a-3c,3.50mmol),95%乙醇(30.0mL),搅拌下加入各种N-取代缩氨基硫脲(6a-6i,3.50mmol),待混合均匀,向体系中滴加一滴浓硫酸,逐渐升温至回流,反应5h,TLC监测,待原料反应完全,停止加热,冷却至室温,析出固体,抽滤,滤饼用冷的无水乙醇洗涤,分别得橘红色固体为各种所需中间体(表3)。
表3中间体7-1a-7-1i,7-2a-7-2d,7-2f-7-2i,7-3a-7-3h总结表
实施例6.目标化合物(TM)的合成
(1)5-氟-3-(2-(3-(4-甲基苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM2)的合成
称取5-氟-2-氧代-1H-吲哚-3-亚氨基-4-(4-甲基苯基)硫脲(7-1b,0.61g,1.85mmol)置于一干净的50mL单口瓶中,加入95%乙醇(25.0mL),搅拌下加入无水乙酸钠(0.61g,7.40mmol),滴加氯乙酸乙酯(0.30g,2.40mmol),逐渐升温至78℃,回流反应约6h,停止加热,冷却至室温,加入适量水稀释,析出固体,抽滤,滤饼用冷的无水乙醇洗涤得橘红色固体,干燥称重(0.65g,95.6%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.71(s,1H,indole-NH),7.41(d,J=8.3Hz,2H,3-N-Ar-3,5-H),7.35(m,2H,3-N-Ar-2,6-H),7.11(td,J=9.0,2.8Hz,1H,indole-6-H),6.92(dd,J=8.9,2.8Hz,1H,indole-4-H),6.78(dd,J=8.5,4.3Hz,1H indole-7-H),4.23(s,2H,thiazolidine-CH2-),2.41(s,3H,3-N-Ar-CH3);
(2)5-氟-3-(2-(3-(4-氯苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM3)的合成
称取5-氟-2-氧代-1H-吲哚-3-亚氨基-4-(4-氯苯基)硫脲(7-2c,1.22g,3.50mmol)置于一干净的100mL单口瓶中,加入95%乙醇(35.0mL),搅拌下加入无水乙酸钠(1.16g,14.0mmol),滴加氯乙酸乙酯(0.51g,4.20mmol),逐渐升温至78℃,回流反应约6h,原料处仍有点,停止加热,冷却至室温,加入适量水稀释,析出固体,抽滤,滤饼用冷的无水乙醇洗涤得橘红色固体,干燥后粗品1.10g,石油醚:乙酸乙酯=3:1~1:1柱纯化,发现溶解度较差,得纯品干燥称重(0.98g,72.1%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.72(s,1H,indole-NH),7.68(d,J=8.6Hz,2H,3-N-Ar-3,5-H),7.55(d,J=8.6Hz,2H,3-N-Ar-2,6-H),7.11(m,1H,indole-6-H),6.92(dd,J=8.8,2.5Hz,1H,indole-4-H),6.79(dd,J=8.5,4.3Hz,1H,indole-7-H),4.21(s,2H,thiazolidine-CH2-);
(3)5-氟-3-(2-(3-(3-氯苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM8)的合成
称取5-氟-2-氧代-1H-吲哚-3-亚氨基-4-(3-氯苯基)硫脲(7-1h,1.04g,3.00mmol)置于一干净250mL单口瓶中,加入95%乙醇(60.0mL),搅拌下加入无水乙酸钠(0.98g,12.0mmol),滴加氯乙酸乙酯(0.7mL,6.00mmol),逐渐升温至78℃,回流反应约5h,停止加热,冷却至室温,加入适量水稀释,析出固体,抽滤,滤饼用冷的无水乙醇洗涤得黄色固体,干燥得纯品(1.13g,97.4%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.74(s,1H,indole-NH),7.70(d,J=1.4Hz,1H,3-N-Ar-4-H),7.66(d,J=1.2Hz,1H,3-N-Ar-2-H),7.64(t,J=5.2Hz,1H,3-N-Ar-6-H),7.52(m,1H,3-N-Ar-5-H),7.14(td,J=9.1,2.8Hz,1H,indole-6-H),6.98(dd,J=8.7,2.8Hz,1H,indole-4-H),6.81(dd,J=8.6,4.3Hz,1H,indole-7-H),4.22(s,2H,thiazolidine-CH2-);
(4)5-甲基-3-(2-(3-(4-氯苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM12)的合成
称取5-甲基-2-氧代-1H-吲哚-3-亚氨基-4-(4-氯苯基)硫脲(7-2c,0.345g,1.00mmol)置于一干净的50mL单口瓶中,加入95%乙醇(20.0mL),搅拌下加入无水乙酸钠(0.34g,4.00mmol),滴加氯乙酸乙酯(0.24mL,2.00mmol),逐渐升温至78℃,回流反应约5h,后续操作同化合物TM10,得橘红色固体,干燥得纯品(0.30g,78.1%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.59(s,1H,indole-NH),7.71(m,2H,3-N-Ar-3,5-H),7.56(m,2H,3-N-Ar-2,6-H),7.08(d,J=8.4Hz,2H,indole-Ar-H),6.69(d,J=7.8Hz,1H,indole-Ar-H),4.21(s,2H,thiazolidine-CH2-),2.01(s,3H,indole-5-CH3);
(5)5-甲基-3-(2-(3-(4-溴苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM14)的合成
称取5-甲基-2-氧代-1H-吲哚-3-亚氨基-4-(4-溴苯基)硫脲(7-2f,0.78g,2.00mmol)置于一干净的100mL单口瓶中,加入95%乙醇(30.0mL),搅拌下加入无水乙酸钠(0.66g,8.00mmol),滴加氯乙酸乙酯(0.48mL,4.00mmol),逐渐升温至78℃,回流反应约5h,后续操作同化合物TM10,得橘红色固体,干燥得纯品(0.76g,88.5%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.59(s,1H,indole-NH),7.85(d,J=8.6Hz,2H,3-N-Ar-3,5-H),7.49(d,J=8.6Hz,2H 3-N-Ar--2,6-H),7.08(d,J=7.0Hz,2H,indole-Ar-H),6.69(d,J=8.5Hz,1H,indole-Ar-H),4.21(s,2H,thiazolidine-CH2-),2.03(s,3H,indole-5-CH3).
(6)5-甲基-3-(2-(3-(2-氯苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM15)的合成
称取5-甲基-2-氧代-1H-吲哚-3-亚氨基-4-(2-氯苯基)硫脲(7-2g,0.52g,1.50mmol)置于一干净的100mL单口瓶中,加入95%乙醇(35.0mL),搅拌下加入无水乙酸钠(0.50g,6.00mmol),滴加氯乙酸乙酯(0.36mL,3.00mmol),逐渐升温至78℃,回流反应约5h,后续操作同化合物TM10,得橘红色固体,干燥得纯品(0.51g,88.4%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.60(s,1H,indole-NH),7.70(d,J=1.7Hz,1H,3-N-Ar-3-H),7.67(dd,J=4.0,1.3Hz,2H,3-N-Ar-4,6-H),7.52(m,1H,3-N-Ar-5-H),7.08(d,J=5.3Hz,2H,indole-4,6-H),6.70(d,J=8.4Hz,1H,indole-7-H),4.21(s,2H,thiazolidine-CH2-),2.02(s,3H,indole-5-CH3);
(7)5-甲基-3-(2-(3-(3-氯苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM16)的合成
称取5-甲基-2-氧代-1H-吲哚-3-亚氨基-4-(3-氯苯基)硫脲(7-2h,0.45g,1.30mmol)置于一干净的50mL单口瓶中,加入95%乙醇(25.0mL),搅拌下加入无水乙酸钠(0.43g,5.20mmol),滴加氯乙酸乙酯(0.32mL,2.60mmol),逐渐升温至78℃,回流反应约5h,后续操作同化合物TM10,得橘红色固体,干燥得纯品(0.48g,96.0%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.60(s,1H,indole-NH),7.70(s,1H,3-N-2-Ar-H),7.67(dd,J=4.0,1.3Hz,2H,3-N-Ar-4,6-H),7.52(m,1H,3-N-5-Ar-H),7.08(d,J=5.0Hz,2H,indole-4,6-H),6.70(d,J=8.4Hz,1H,indole-7-H),4.21(s,2H,thiazolidine-CH2-),2.02(s,3H,indole-5-CH3);
(8)5-氯-3-(2-(3-(4-氟苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM18)的合成
称取5-氯-2-氧代-1H-吲哚-3-亚氨基-4-(4-氟苯基)硫脲(7-3a,0.52g,1.50mmol)置于一干净100mL单口瓶中,加入95%乙醇(50.0mL),搅拌下加入无水乙酸钠(0.50g,6.00mmol),滴加氯乙酸乙酯(0.36mL,3.00mmol),逐渐升温至78℃,回流反应约5h,停止加热,冷却至室温,加入适量水稀释,放置过夜,抽滤,滤饼用冷的无水乙醇洗涤得橘红色固体,干燥得纯品(0.54g,93.1%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H,indole-NH),7.57(dd,J=8.9,5.0Hz,2H,3-N-Ar-3,5-H),7.45(t,J=8.8Hz,2H,3-N-Ar-2,6-H),7.31(dd,J=8.3,2.3Hz,1H,indole-6-H),7.20(d,J=2.2Hz,1H,indole-4-H),6.81(d,J=8.3Hz,1H,indole-7-H),4.23(s,2H,thiazolidine-CH2-);
(9)5-氯-3-(2-(3-(4-甲基苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM19)的合成
称取5-氯-2-氧代-1H-吲哚-3-亚氨基-4-(4-甲基苯基)硫脲(7-3b,0.86g,2.50mmol)置于一干净的100mL单口瓶中,加入95%乙醇(40.0mL),搅拌下加入无水乙酸钠(0.82g,10.0mmol),滴加氯乙酸乙酯(0.60mL,5.00mmol),逐渐升温至78℃,回流反应约5h,后续操作同化合物TM18,得橘红色固体,干燥称重(0.78g,81.2%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H,indole-NH),7.41(d,J=8.2Hz,2H,3-N-Ar-3,5-H),7.35(d,J=8.3Hz,2H,3-N-Ar-2,6-H),7.30(dd,J=8.3,2.3Hz,1H,indole-6-H),7.23(d,J=2.2Hz,1H,indole-4-H),6.80(d,J=8.3Hz,1H,indole-7-H),4.23(s,2H,thiazolidine-CH2-),2.41(s,3H,3-N-Ar-CH3);
(10)5-氯-3-(2-(3-(4-氯苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM20)的合成
称取5-氯-2-氧代-1H-吲哚-3-亚氨基-4-(4-氯苯基)硫脲(7-3c,0.73g,2.00mmol)置于一干净的100mL单口瓶中,加入95%乙醇(30.0mL),搅拌下加入无水乙酸钠(0.66g,8.00mmol),滴加氯乙酸乙酯(0.48mL,4.00mmol),逐渐升温至78℃,回流反应约4h,后续操作同化合物TM18,得橘红色固体,干燥称重(0.70g,86.4%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.83(s,1H,indole-NH),7.69(d,J=8.6Hz,2H,3-N-Ar-3,5-H),7.55(d,J=8.6Hz,2H,3-N-Ar-2,6-H),7.31(dd,J=8.3,2.2Hz,1H,indole-6-H),7.22(d,J=2.1Hz,1H,indole-4-H),6.81(d,J=8.3Hz,1H,indole-7-H),4.23(s,2H,thiazolidine-CH2-);
(11)5-氯-3-(2-(3-(4-甲氧基苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM21)的合成
称取5-氯-2-氧代-1H-吲哚-3-亚氨基-4-(4-甲氧基苯基)硫脲(7-3d,0.61g,1.70mmol)置于一干净的100mL单口瓶中,加入95%乙醇(40.0mL),搅拌下加入无水乙酸钠(0.56g,6.80mmol),滴加氯乙酸乙酯(0.40mL,3.40mmol),逐渐升温至78℃,回流反应约4h,后续操作同化合物TM18,得橘红色固体,干燥称重(0.62g,91.2%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.82(s,1H,indole-NH),7.39(d,J=9.0Hz,2H,3-N-Ar-3,5-H),7.30(d,J=8.2Hz,2H,3-N-Ar-2,6-H),7.28(d,J=2.1Hz,1H,indole-4-H),7.14(d,J=9.0Hz,1H,indole-6-H),6.81(d,J=8.2Hz,1H,indole-7-H),4.22(s,2H,thiazolidine-CH2-),3.83(s,3H,3-N-Ar-OCH3);
(12)5-氯-3-(2-(3-苯基-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM22)的合成
称取5-氯-2-氧代-1H-吲哚-3-亚氨基-4-苯基硫脲(7-3e,0.66g,2.00mmol)置于一干净的100mL单口瓶中,加入95%乙醇(30.0mL),搅拌下加入无水乙酸钠(0.66g,8.00mmol),滴加氯乙酸乙酯(0.48mL,4.00mmol),逐渐升温至78℃,回流反应约6h,后续操作同化合物TM18,得橘红色固体,干燥称重(0.62g,83.8%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.83(s,1H,indole-NH),7.62(t,J=7.3Hz,2H,3-N-Ar-3,5-H),7.57(d,J=7.1Hz,1H,3-N-Ar-4-H),7.49(d,J=7.1Hz,2H,3-N-Ar-2,6-H),7.30(dd,J=8.3,2.2Hz,1H,indole-6-H),7.25(d,J=2.1Hz,1H,indole-4-H),6.81(d,J=8.3Hz,1H,indole-7-H),4.24(s,2H,thiazolidine-CH2-);
(13)5-氯-3-(2-(3-(4-溴苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM23)的合成
称取5-氯-2-氧代-1H-吲哚-3-亚氨基-4-(4-溴苯基)硫脲(7-3f,0.62g,1.50mmol)置于一干净的100mL单口瓶中,加入95%乙醇(30.0mL),搅拌下加入无水乙酸钠(0.50g,6.00mmol),滴加氯乙酸乙酯(0.36mL,3.00mmol),逐渐升温至78℃,回流反应约5h。后续操作同化合物TM18,得橘红色固体,干燥称重(0.62g,92.5%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.83(s,1H,indole-NH),7.82(m,2H,3-N-Ar-3,5-H),7.48(m,2H,3-N-Ar-2,6-H),7.31(dd,J=8.3,2.3Hz,1H,indole-6-H),7.22(d,J=2.2Hz,1H,indole-4-H),6.81(d,J=8.3Hz,1H,indole-7-H),4.23(s,2H,thiazolidine-CH2-);
(14)5-氯-3-(2-(3-(3-氯苯基)-4-氧代噻唑烷-2-叉基)亚肼基)-1H-吲哚-2-酮(TM25)的合成
称取5-氯-2-氧代-1H-吲哚-3-亚氨基-4-(3-氯苯基)硫脲(7-3h,0.73g,2.00mmol)置于一干净100mL单口瓶中,加入95%乙醇(30mL),搅拌下加入无水乙酸钠(0.66g,8.00mmol),滴加氯乙酸乙酯(0.48mL,4.00mmol),逐渐升温至78℃,回流反应约5h,后续操作同化合物TM18,得橘红色固体,干燥称重(0.68g,83.9%),m.p.>300℃。1H NMR(400MHz,DMSO-d6)δ:10.84(s,1H,indole-NH),7.68(m,1H,3-N-Ar-4-H),7.66(s,1H,3-N-Ar-2-H),7.65(d,J=1.3Hz,1H,3-N-Ar-6-H),7.51(m,1H,3-N-Ar-5-H),7.32(dd,J=8.3,2.3Hz,1H,indole-6-H),7.22(d,J=2.2Hz,1H,indole-4-H),6.82(d,J=8.3Hz,1H,indole-7-H),4.22(s,2H,thiazolidine-CH2-)。
实施例6,目标化合物对PTP1B酶的抑制活性评价研究
将被测试样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。采用光吸收检测法,在96孔或384孔平底透明微孔板中检测酶活性。首先在大肠杆菌中表达并纯化得到GST融合蛋白,从中提取纯化用于试验筛选的PTP1B酶,再采用紫外底物pNPP,观察不同化合物对重组酶的活性抑制,以初步评价化合物的药用效果。PTP1B水解底物pNPP的磷酯得到的产物在405nm处有很强的光吸收。因此可以通过酶标仪监测405nm处光吸收强度的变化以观察酶的活性变化以及化合物对其的抑制作用。实验中PTP1B所采用的阳性参照化合物为齐墩果酸,实验结果见表4。
具体方法是采用光吸收检测法评价所合成的目标化合物对PTP1B酶的抑制活性,实验数据处理方法及结果如下:首先计算酶初速度期内单位时间光吸收强度的增量(单位:mO.D./min),以此代表酶初速度,然后依据如下公式计算样品对酶活性的抑制率(%Inhibition)。
式中,VSample——加药组的初速度;
VDMSO——DMSO组(即不加药组)的初速度。
实验初步筛选的纯化合物浓度为5μg/mL(粗提物为100μg/mL),设置3个复孔。所合成的化合物对酶抑制活性的初筛实验结果显示:大多数目标化合物对PTP1B酶都表现出良好的抑制活性(阳性对照齐墩果酸IC50为1.28μg/mL),活性结果见表4。
表4.目标化合物的生物活性表
表4列出了实施例目标化合物的活性测试结果。所合成的14个化合物在5μg/mL浓度下都显示出较好的PTP1B抑制活性,对PTP1B酶的抑制率在50%以上的,并测试了活性计量依赖关系,计算得到了其半数抑制浓度(IC50值),以此半数以上化合物所得的半数有效浓度IC50值在4.56~14.53μM之间,其中活性最好的化合物TM25的IC50值为4.56μM。
通过对目标化合物PTP1B的抑制活性分析,将构效关系总结如下:
(1)当1H-吲哚的5-位被氟,氯原子取代的抑酶活性可以得到普遍提升,略高于亲脂性基团甲基取代的化合物。如5-氯-3-(3-间氯苯基取代1,3-噻唑烷-4-酮-2-叉基亚肼基)-1H-吲哚-2-酮(TM25)和5-氟-3-(3-间氯苯基取代噻唑烷-4-酮-2-叉基亚肼基)-1H-吲哚-2-酮(TM8)的IC50值为分别为4.56μM和7.82μM;
(2)当1H-吲哚的5-位被亲脂性基团,如甲基取代时,生物活性可以得到适当保持,但不如吸电子基,氟,氯原子,而化合物5-甲基-3-(3-间氯苯基取代1,3-噻唑烷-4-酮-2-叉基亚肼基)-1H-吲哚-2-酮(TM16)的IC50值14.27μM;
(3)当目标分子中存在更多潜在的氢键供体(如1H-吲哚环的NH,苯环上的OH)和氢键受体(如1,3-噻唑酮的C=O,1H-吲哚2位上的C=O,1,3-噻唑烷酮2-位上的亚肼基)时,有利于化合物抑酶活性提高。
总之,本发明成功合成26个结构新颖的目标化合物,且都有很好的晶型和纯度,所有新化合物的化学结构均已通过1H NMR或13C NMR确证。对所合成的目标物进行了酶水平的PTP1B抑制活性测试。目标化合物中有14个化合物表现出中等程度以上的抑酶活性,IC50值在4.56~14.53μM之间,活性最好的化合物TM25的IC50为4.56μM。
本发明不限于上述实例。
参考文献:
[1].Chen,J.;Jiang,C.S.;Ma,W.Q.;Gao,L.X.;Gong,J.X.;Li,J.Y.;Li,J.;Guo,Y.W.,The first synthesis of natural disulfide bruguiesulfurol and biologicalevaluation of its derivatives as a novel scaffold for PTP1B inhibitors.Bioorg.Med.Chem.Lett.2013,23(18),5061-5065.
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[3].Lee,S.;Wang,Q.,Recent development of small molecular specificinhibitor of protein tyrosine phosphatase 1B.Medicinal research reviews 2007,27(4),553-573.
[4].Shi,L.;Yu,H.-p.;Zhou,Y.-y.;Du,J.-q.;Shen,Q.;Li,J.-y.;Li,J.,Discovery of a novel competitive inhibitor of PTP1B by high-throughputscreening.Acta Pharmacol Sin 2008,29(2),278-284.
[5].Daia,H.-L.;Shenb,Q.;Zheng,J.-B.;Jing-Ya Lib;Wen,R.;Li,J.,Synthesis and biological evaluation of novel indolin-2-one derivatives asprotein tyrosine phosphatase 1B inhibitors.Lett.org.chem.2011,8(7),526-530.
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Claims (7)
3.根据权利要求1所述的含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物,其特征在于,还包括所述含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物的药用盐,其水合物和溶剂化物,其多晶和共晶,其同样生物功能的前体和衍生物。
4.根据权利要求3所述的含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物,其特征在于,所述含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物的药用盐,包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、富马酸盐或苹果酸盐。
5.如权利要求1-4之一所述的含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物含吲哚生物的制备方法,是以取代芳香胺类化合物为起始原料,经过多步骤反应制备得到目标化合物,其合成路线为:
合成的具体步骤为:
(1)以各种取代的芳香胺(1)为起始原料,在水合氯醛、盐酸羟氨的作用下进行反应,经过后处理后,分别经过硅胶柱层析分离,制备得到中间体(2);这里,取代的芳香胺(1)为1.0~1.1equiv.,水合氯醛为1.1~1.2equiv.,盐酸羟氨为3.0~3.3equiv.;
(2)中间体(2)在浓硫酸的作用下环合,得到中间体5-取代的靛红(3);
(3)与上述合成步骤的同时,以取代的苯胺(1.1)和CS2(4)为原料,在碱性条件下合成不稳定的硫代乙酸氨基盐类中间体,分离纯化后,采用氯甲酸甲酯进脱硫反应,经过硅胶柱层析分离,即得到取代的芳基异硫氰酸酯(5);这里,取代的苯胺(1.1)为,1.0~1.1equiv.,CS2(4)为1.8~2.0equiv.,氯甲酸甲酯为1.0~1.1equiv;
(4)将异硫氰酸酯(5)在水合肼作用下肼解得到各种芳基取代的氨基硫脲(6);
(5)将上述两种重要中间体5-取代的靛红(3)和芳基异硫氰酸酯(6)在浓硫酸催化下在乙醇中进行分子间脱水缩合反应,得到各种席夫碱中间体(7);将席夫碱7中的任意一种化合物与2-氯乙酸乙酯在无水乙酸钠催化下进行等摩尔比的环合反应,即得到目标化合物TM;这里,5-取代的靛红(3)为1.0~1.1equiv.,芳基异硫氰酸酯(6)为1.0~1.1equiv.,席夫碱(7)为1.0~1.1equiv.,2-氯乙酸乙酯为1.0~1.1equiv。
6.根据权利要求5所述的制备方法,其特征在于,所述取代的芳香胺(1),其中,R1取为F,CH3,Cl,并依次记为取代的芳香胺1a,1b,1c,与其对应的中间体(2)、中间体5-取代的靛红(3),依次记为中间体2a,2b,2c,中间体5-取代的靛红3a,3b,3c;
所述取代的苯胺(1.1),其中,R2取为4-F,4-CH3,4-Cl,4-OCH3,4-H,4Br,2-Cl,3-Cl,3-CF3,并依次记为取代的苯胺1.1a,1.1b,…,1.1i,与其对应的中间体芳基异硫氰酸酯(5)、中间体芳基异硫氰酸酯(6),依次记为芳基异硫氰酸酯5a,5b,…,5i,芳基异硫氰酸酯6a,6b,…,6i;
所述的席夫碱7中,分为三种,记为席夫碱7-1,7-2,7-3,具体为:7-1a--7-1i,7-2a--7-2d,7-2f--7-2i,7-3a--7-3h,其对应的R1,R2如下:
7.如权利要求1-4之一所述的含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物含吲哚生物在制备PTP1B抑制剂中的用途。
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