CN114736202A - 具有ido1/tdo抑制活性的小檗碱衍生物的制备及用途 - Google Patents
具有ido1/tdo抑制活性的小檗碱衍生物的制备及用途 Download PDFInfo
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- CN114736202A CN114736202A CN202210415635.2A CN202210415635A CN114736202A CN 114736202 A CN114736202 A CN 114736202A CN 202210415635 A CN202210415635 A CN 202210415635A CN 114736202 A CN114736202 A CN 114736202A
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- berberine
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Abstract
本发明公开一种小檗碱衍生物及其制备方法,和其作为IDO1/TDO抑制剂的用途。本发明结合C‑H活化/环化的方法高效制备了一系列含杂原子的高B环小檗碱衍生物,包括A或D环为噻吩环的新型异喹啉季铵碱衍生物,另外,利用环氧丙烷引入羟乙基的新方法制备了小檗碱衍生物,所制备的小檗碱衍生物对IDO1/TDO酶具有很高的抑制活性。可用于治疗或预防癌症或肿瘤、代谢紊乱疾病、自身免疫病、阿尔茨海默氏症、帕金森氏症、抑郁症等相关疾病。
Description
技术领域
本发明属于药物化学领域,具体涉及一种具有IDO1/TDO抑制活性的小檗碱衍生物及其制备方法和应用。
背景技术
色氨酸(Trp)是蛋白质合成所必须的氨基酸,是人体所必需的氨基酸。色氨酸在体内的代谢途径主要有犬尿氨酸途径和5-羟色胺途径两种代谢途径。其中犬尿氨酸途径是色氨酸代谢的最主要途径,约95%的色氨酸都是通过该途径进行代谢[1-2]。IDO1/TDO与肿瘤的免疫逃逸相关。肿瘤免疫治疗通过激活或调动机体自身的免疫系统,从而控制与清除肿瘤,是继手术、放疗和化疗后又一重要肿瘤治疗手段,包括免疫检查点抑制剂、肿瘤疫苗、过继免疫细胞治疗等多种方法[3]。
IDO1是催化色氨酸代谢的限速酶,色氨酸的过度消耗会抑制T细胞免疫反应。IDO1在多种肿瘤组织中过度表达,诱发机体免疫系统对其免疫耐受,发生免疫逃逸[4]。IDO1和TDO催化色氨酸分解代谢,可以维持机体正常的免疫反应幅度和持续时间,防止健康细胞产生不受抑制的免疫激活[5]。但在恶性肿瘤中IDO1和TDO的表达上调,导致色氨酸耗竭和犬尿氨酸等下游产物的积累,创造了一个免疫抑制微环境,使肿瘤细胞逃避有效的免疫应答。研究表明 IDO1 和 TDO 在多种癌症细胞如乳腺癌、宫颈癌、脑癌等上调表达,与肿瘤的侵袭性和患者的不良预后相关[6,7],其抑制剂已成为癌症免疫治疗的新策略。在过去的 20多年里,通过高通量筛选、天然产物结构修饰、基于结构的药物设计等方式,已经有多种结构类型的 IDO1抑制剂被报道,基本骨架种类包括如:吲哚、芳基咪唑、N-羟基脒、喹啉、醌等。并且有多个 IDO1 抑制剂进入临床研究,如 Indoximod、PF-06840003、Navoximod、Epacadostat、Linrodostat等。
IDO1/TDO活化与多种疾病发病机制密切相关,是肿瘤、阿尔茨海默氏症、帕金森氏症、抑郁症等相关疾病领域的重要靶点,因此在治疗广泛类型肿瘤方面具有的极大潜力,但至今仍没有IDO/TDO抑制剂上市,因此,寻找和开发新型高效的IDO抑制剂具有重要的理论意义和应用价值。
小檗碱是中药黄连中的主要药效成分,作为抗菌药物已拥有悠久的药用历史[8]。随着研究水平的不断提高以及分子生物技术的发展,人们逐渐发现小檗碱还具有降血糖[9]、降血脂[10]、抗炎[11]、抗肿瘤[12]等多种药理活性,其中小檗碱的抗肿瘤活性一直被广为研究,作为具有多靶点的天然产物,其具体的作用靶点和机制还尚待阐明。IDO1和TDO是肿瘤免疫治疗的重要靶标。我们通过活性筛选技术发现小檗碱类衍生物具有很好的IDO1/TDO酶抑制活性,因此对小檗碱进行更多的结构修饰和改造,对开发新的IDO1/TDO抑制剂具有重要研究价值。
发明内容
本发明的目的是提供一种小檗碱衍生物及其制备方法和其作为IDO1/TDO抑制剂的用途。
本发明提供一种小檗碱衍生物,其立体异构体、溶剂合物或其药学上可接受的盐,或同位素标记化合物,所述结构通式如结构I-VI所示:
其中,
R1和R2各自独立地为氢、羟基或甲氧基、C2-C6的烷基链;
R3和R4各自独立地为氢、甲氧基,或R3和R4连接为亚甲二氧基;
A环独立地为未取代的或取代的苯环或者噻吩环;
D环独立地为未取代的或取代的苯环或者噻吩环;
B环为六元碳环或者含N、O、S杂原子的七元环。
本发明提供一种制备合成如结构式V所示小檗碱衍生物的方法,其特征在于,它包括如下工艺流程:
本发明还提供一种小檗碱类衍生物在制备TDO和/或IDO1抑制剂上的用途,其特征在于,所述的小檗碱类衍生物为权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂合物。
进一步地,所述抑制剂是用于预防或治疗由IDO1/TDO介导的肿瘤、代谢紊乱疾病、自身免疫病、阿尔茨海默氏症、帕金森氏症、抑郁症等相关疾病的药物。
实验结果证明,本发明所制备的化合物对IDO1/TDO酶具有较好的抑制效果,在制备用于预防或治疗由IDO1/TDO介导的相关疾病领域具有广阔的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其他多种形式的修改、替换或变更。
附图说明
图1 为本发明化合物Ber-1的核磁氢谱图。
图2 为本发明化合物Ber-5的核磁氢谱图。
具体实施方式
下面详细描述本发明的实施例,需要说明的是下面描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。另外,如果没有明确说明,在下面实施例中所采用的所有试剂均为市场上可以购得的,或者可以按照本文或已知的方法合成的,对于没有列出的反应条件也均为本领域技术人员容易获得的。
实施例1:化合物Ber-1的合成
参照文献(New J. Chem., 2020, 44, 1761--1771)的方法:将市售的盐酸小檗碱置于烧瓶中,在20-30mmHg 的减压条件下190度加热搅拌得红棕色粉末。1H NMR (400 MHz,DMSO-d 6) δ 9.11 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.24 (d, J = 7.8 Hz,1H), 6.96 (s, 1H), 6.40 (d, J = 7.8 Hz, 1H), 6.10 (s, 2H), 4.50 (t, J = 6.1Hz, 2H), 3.74 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H)。
实施例2-4:化合物Ber-2、Ber-3和Ber-4的合成
实施例2:化合物Ber-2的合成
参照我们之前的发明的方法合成(CN 111808121 A)。所合成的化合物数据及图谱与其一致。
以2,3-二甲氧基苄胺和3,4-亚甲二氧基溴苯为初始原料,经过酰化、碘代、Sonogashira偶联、C-H活化/环化、亲核取代、环合等步骤得到目标化合物5-氧杂高B环小檗碱(Ber-2)。
(1)化合物3的合成:
向干燥的50 mL双颈瓶中加入2,3-二甲氧基苄胺1(4 mmol)和2-吡啶羧酸2(4mmol,1.0 equiv.),氩气置换3次,注入DCM(20 mL)溶解,将反应液至于-10 °C预冷5分钟。加入Et3N(8 mmol,2.0 equiv.),搅拌均匀后,缓慢滴加POCl3(8 mmol,2.0 equiv.)。滴毕,于-10°C反应5小时后移至室温过夜。TLC监测反应完毕后,移入分液漏斗,依次用饱和Na2CO3溶液、H2O、饱和NaCl溶液反洗,经无水Na2SO4干燥、减压浓缩得粗品。粗品经柱层析纯化(洗脱剂为石油醚/乙酸乙酯 = 5/1)得化合物3,收率为84 %,白色固体。
(2)化合物5的合成:
向500 mL圆底瓶中加入3,4-亚甲二氧基溴苯4(6.0 g,3.0 mol)、AgTFA(7.24 g,3.3 mol),注入70 mL DCM溶解。降温至-20 °C,向反应体系缓慢滴加I2的DCM/Et2O(150 mL/ 70 mL)溶液,滴毕室温过夜。反应液经减压浓缩、柱层析(洗脱液为石油醚)得目标化合物5,收率为85 %,化合物5为白色固体。
(3)化合物6的合成:
向100 mL双颈瓶中加入化合物5(13.2 mmol)、Pd(PPh3)2Cl2(0.66 mmol,0.07equiv.)、CuI(1.3 mmol,0.1 equiv.),Ar换气3次。注入干燥的Et3N (40 mL),室温搅拌均匀后,加入三甲基硅乙炔(14.5 mmol,1.1 equiv.)。室温过夜反应。TLC监测反应完成后,直接减压浓缩除去溶剂。然后向残留物中加入水和乙酸乙酯进行萃取,合并乙酸乙酯层,并用饱和NaCl溶液反洗、无水Na2SO4干燥,减压浓缩后得到深棕色油状物。最后通过硅胶柱层析(洗脱液为石油醚)分离纯化得到目标化合物6,收率为58%,白色固体。
(4)化合物7的合成:
于15 mL封管中依次加入化合物3(0.2 mmol)、化合物6(0.3 mmol)、Co(OAc)2·4H2O (0.31 mmol)、KPF6(0.1 mmol)和2.5 mL PEG-400。反应液氧气置换3次后置于140 °C油浴反应24小时。TLC监测反应完成后,加入乙醚萃取。合并乙醚层,无水硫酸钠干燥,经减压蒸馏除去溶剂,残留物采用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯 = 20/1)分离纯化得目标产品7,收率为51%,黄色固体。
(5)化合物8的合成:
将化合物7(0.26 mmol)、CuCl2(0.013 mmol,0.05 equiv.)、K2CO3(0.78 mmol,3.0equiv.)、乙二醇4.0 mL依次加入到10 mL圆底瓶中。反应液置于130 °C反应20小时。TLC监测反应完成后,直接柱层析(洗脱剂为石油醚/乙酸乙酯 = 2/1)分离纯化得化合物8,收率为60%,黄色固体。
(6)化合物Ber-2的合成:
向圆底瓶中加入化合物8(0.283 mmol)、SOCl2(3 mL),室温搅拌3小时。搅拌下将反应液缓慢倾倒入冰水中,室温搅拌5分钟。然后加入乙酸乙酯萃取,乙酸乙酯层用饱和NaCl溶液反洗,无水Na2SO4干燥。减压浓缩后通过硅胶柱层析(洗脱剂为二氯甲烷/甲醇 =10/1)分离纯化得目标产品Ber-2,收率为63%,黄色固体。
实施例3:化合物Ber-3的合成
如上合成路线所示,以关键中间体7为原料,经亲核取代、环合等步骤得到目标化合物5-氮杂高B环小檗碱(Ber-3)。
(1)化合物9的合成:
将化合物7(0.26 mmol)、CuCl(0.026 mmol,0.1 equiv.)、KOH(0.52 mmol,2.0equiv.)和4.0 mL氨基乙醇依次加入到10 mL圆底瓶中。反应液置于90 °C反应8小时。TLC监测反应完成后,直接柱层析(洗脱剂为石油醚/乙酸乙酯 = 2/1)分离纯化得化合物9,收率为45%,黄色固体。
(2)化合物Ber-3的合成:
向圆底瓶中加入化合物9(0.283 mmol)、SOCl2(3 mL),室温搅拌3小时。搅拌下将反应液缓慢倾倒入冰水中,室温搅拌5分钟。然后加入乙酸乙酯萃取,乙酸乙酯层用饱和NaCl溶液反洗,无水Na2SO4干燥。减压浓缩后通过硅胶柱层析(洗脱剂为二氯甲烷/甲醇 =10/1)分离纯化得目标产品Ber-3,收率为50%,黄色固体。
实施例4:5-硫杂高B环小檗碱(Ber-4)的合成
如上合成路线所示,以关键中间体7为原料,经亲核取代、环合等步骤得到目标化合物5-硫杂高B环小檗碱(Ber-4)。
(1)化合物10的合成:
将化合物7(0.13 mmol)、CuO(0.26 mmol,2.0 equiv.)、巯基乙醇(1.3 mmol,10.0equiv.)和二氧六环2.0 mL依次加入到15 mL封管中。反应液于130°C反应24小时。TLC监测反应完成后,加入水和乙酸乙酯萃取,有机层浓缩后柱层析(洗脱剂为石油醚/乙酸乙酯 =2/1)得化合物10,收率为85%,化合物10为黄色固体。
(2)化合物Ber-4的合成:
向圆底瓶中加入化合物10(0.283 mmol)、SOCl2(3 mL),室温搅拌3小时。搅拌下将反应液缓慢倾倒入冰水中,室温搅拌5分钟。然后加入乙酸乙酯萃取,乙酸乙酯层用饱和NaCl溶液反洗,无水Na2SO4干燥。减压浓缩后通过硅胶柱层析(洗脱剂为二氯甲烷/甲醇 =10/1)分离纯化得目标产品Ber-4,收率为85%,黄色固体。
实施例5-6:化合物Ber-5和化合物Ber-6的合成
实施例5:化合物Ber-5的合成
(1)中间体N-(噻吩2-苄基)吡啶酰胺(11)的合成
以2-噻吩甲胺为原料,参照实施例2(1)化合物3的合成方法合成。黄色固体,收率60%。
(2)中间体3-(2-溴-4,5-亚甲二氧基苯基)-噻唑并[2,3-c]吡啶(12)的合成
参照实施例2(4)化合物7的合成方法合成。黄色固体,收率58%。1H NMR (400 MHz,DMSO-d 6) δ 9.19 (s, 1H), 8.05 (d, J = 5.3 Hz, 1H), 7.88 (d, J = 1.1 Hz, 1H),7.47 (d, J = 5.3 Hz, 1H), 7.21 (s, 1H), 7.01 (s, 1H), 6.02 (s, 2H)。
(3)化合物13的合成
参照化合物8的合成方法合成。黄色固体,收率35%。1H NMR (400 MHz,Chloroform-d) δ 9.26 (s, 1H), 8.50 (d, J = 1.1 Hz, 1H), 8.09 (d, J = 5.3 Hz,1H), 7.51 (d, J = 5.3 Hz, 1H), 7.44 (s, 1H), 6.94 (s, 1H), 6.04 (s, 2H), 5.01(t, J = 5.4 Hz, 1H), 4.06 (t, J = 4.9 Hz, 2H), 3.72 (q, J = 5.1 Hz, 2H)。
(4)化合物Ber-5的合成
参照实施例2(6)化合物Ber-2的合成。与实施例2(6)的区别仅在于:将实施例2(6)的原料化合物8替换为化合物13。1H NMR (400 MHz, DMSO-d 6) δ 9.28 (s, 1H), 8.49 (d,J = 1.0 Hz, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.49 (dd, J = 5.4, 0.8 Hz, 1H),7.46 (s, 1H), 6.96 (s, 1H), 6.05 (s, 2H), 4.32–4.28 (m, 2H), 3.97–3.93 (m,2H)。
实施例6:化合物Ber-6的合成
参照实施例3的方法合成。本实例的合成示意图与步骤与实施例3的区别仅在于:将实施例3的原料化合物7替换为化合物12,化合物9替换为化合物14。黄色固体,收率50%。1H NMR (400 MHz, DMSO-d 6) δ 9.23 (s, 1H), 8.44 (t, J = 6.0 Hz, 1H), 8.21 –8.16 (m, 1H), 8.13 (d, J = 5.4 Hz, 1H), 7.54 (d, J = 5.4 Hz, 1H), 7.27 (s,1H), 6.54 (s, 1H), 5.96 (s, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.49 (q, J = 5.9Hz, 2H).13C NMR (151 MHz, DMSO-d 6) δ 153.0, 149.1, 146.7, 143.5, 142.88,139.0, 134.7, 133.2, 123.9, 116.2, 114.6, 109.4, 101.0, 94.3, 45.6, 44.6。
实施例7:化合物Ber-7的合成
参照化合物Ber-1的合成方法。将所合成的化合物Ber-2置于烧瓶中,在20-30mmHg的减压条件下190度加热搅拌得红棕色粉末,收率86%。1H NMR (400 MHz, DMSO-d 6) δ 9.44(d, J = 4.4 Hz, 1H), 7.75 (d, J = 3.9 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.24(s, 1H), 6.88 (s, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H), 4.57 (dd, J =13.1, 5.0 Hz, 2H), 3.80 (s, 3H), 3.59 – 3.46 (m, 2H)。
实施例8:化合物Ber-8的合成
将市售的盐酸小檗碱1g置于烧瓶中,在20-30mmHg 的减压条件下190度加热搅拌得红棕色粉末。然后不经纯化直接将该粗品溶于无水乙醇20 mL中,室温搅拌下加入4-甲基哌嗪1.54 g及37%甲醛水溶液1.26 mL并升温至80℃反应24 h。减压浓缩除去溶剂,快速硅胶柱层析(二氯甲烷:甲醇=20:1)纯化后得暗红色固体,将此固体溶于二氯甲烷中,0℃下缓慢滴加氯化氢的乙醇溶液,室温搅拌1 h,抽滤,滤饼干燥可得橙色固体508 mg。1H NMR(400 MHz, DMSO-d 6) δ 9.96 (s, 1H), 8.74 (s, 1H), 8.58 (s, 1H), 8.10 (s, 1H),7.09 (s, 1H), 6.19 (s, 2H), 4.88 (d, J = 8.7 Hz, 4H), 4.11 (s, 3H), 3.22 –3.14 (m, 3H), 3.13 – 3.06 (m, 2H), 1.76 (d, J = 12.9 Hz, 2H), 1.68 – 1.46 (m,4H), 0.91 (d, J = 5.8 Hz, 3H)。
实施例9:化合物Ber-9的合成
(1)化合物15的合成
于15 mL封管中依次加入化合物3(0.2 mmol)、2-乙炔噻吩(0.3 mmol)、Co(OAc)2·4H2O (0.1 mmol)、KPF6(0.1 mmol)和2.5 mL PEG-400。反应液氧气置换3次后置于140 °C油浴反应24小时。TLC监测反应完成后,加入乙醚萃取。合并乙醚层,无水硫酸钠干燥,经减压蒸馏除去溶剂,残留物采用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯 = 20/1)分离纯化得目标产品,收率为58%。1H NMR (400 MHz, DMSO-d 6) δ 9.36 (s, 1H), 8.26 (s,1H), 7.80 (dd, J = 3.7, 1.1 Hz, 1H), 7.76 (s, 2H), 7.60 (dd, J = 5.1, 1.1 Hz,1H), 7.19 (dd, J = 5.1, 3.7 Hz, 1H), 3.98 (d, J = 2.9 Hz, 6H)。
(2)化合物16的合成
于15 mL封管中依次加入化合物15(0.2 mmol),米氏酸重氮(0.32 mmol),[Cp*IrCl2]2(0.005 mmol), AgNtf2(0.02 mmol)和1 mL甲醇。将反应液于100 °C油浴反应 20h, TLC监测反应完成后,经减压蒸馏除去溶剂,残留物采用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯 = 5/1)分离纯化得目标产品,收率为77%。1H NMR (400 MHz, Chloroform-d) δ9.54 (s, 1H), 7.88 (s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 9.0 Hz,1H), 7.33 (d, J = 5.1 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 4.08 (s, 3H), 4.07(s, 2H), 4.02 (s, 3H), 3.72 (s, 3H)。
(3)化合物17的合成
将LiAlH4分散于20 mLTHF中并于0 °C下搅拌,向其中逐滴滴加溶有化合物16(100mg)的THF溶液,滴加完毕后室温搅拌12 h。反应结束后加水淬灭,用1 M HCl调节pH至中性,EA萃取,合并EA层,无水硫酸钠干燥,经减压蒸馏除去溶剂,残留物采用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯 = 20/1)分离纯化得目标产品,收率为79%。
(4)化合物Ber-9的合成
向圆底瓶中加入化合物17(100 mg)、SOCl2(3 mL),室温搅拌3小时。搅拌下将反应液缓慢倾倒入冰水中,室温搅拌5分钟。然后加入乙酸乙酯萃取,乙酸乙酯层用饱和NaCl溶液反洗,无水Na2SO4干燥。减压浓缩后通过硅胶柱层析(洗脱剂为二氯甲烷/甲醇 = 10/1)分离纯化得目标产品Ber-9,收率为85%。1H NMR (400 MHz, Chloroform-d) δ 9.86 (s,1H), 8.07 (s, 1H), 7.92 – 7.78 (m, 2H), 7.54 (d, J = 5.0 Hz, 1H), 7.14 (d, J= 5.1 Hz, 1H), 4.19 (s, 3H), 4.09 (s, 3H), 3.77 (t, J = 6.5 Hz, 2H), 3.39 (t,J = 6.6 Hz, 2H)。
实施例10:化合物Ber-10的合成
参照化合物Ber-1的合成方法,将市售的化合物18置于烧瓶中,在20-30mmHg 的减压条件下190度加热搅拌得红棕色粉末。1H NMR (400 MHz, DMSO-d 6) δ 9.81 (s, 1H),8.83 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 8.7 Hz,1H), 7.06 (s, 1H), 4.85 (t, J = 6.2 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.86(s, 3H), 3.20 (t, J = 6.3 Hz, 2H)。
实施例11:化合物Ber-11的合成
(1)化合物19的合成
将2 g化合物4溶于THF,冷却至-78℃,缓慢滴加正丁基锂4.5 mL(2.5 M的正己烷溶液),搅拌1.5 h后加入过量的环氧乙烷,搅拌0.5 h后,缓慢升至室温。反应结束后加入饱和氯化铵溶液,乙醚萃取,合并有机层,无水硫酸钠干燥,经减压蒸馏除去溶剂,残留物采用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯 = 10/1)分离纯化得目标产品,收率为89%。1H NMR(400 MHz, Chloroform-d) δ 6.78 – 6.65 (m, 3H), 5.93 (s, 2H), 3.81 (t, J = 6.5Hz, 2H), 2.78 (t, J = 6.5 Hz, 2H)。
(2)化合物20的合成
将1.4 g化合物19和3 g AgTFA溶于60 mLTHF,0℃滴加I2(2.4 g)的THF溶液90mL,滴毕后移至室温过夜反应。反应结束后加入Na2S2O3溶液搅拌,EA萃取,有机层用饱和食盐水反洗。合并有机层,无水硫酸钠干燥,经减压蒸馏除去溶剂,残留物采用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯 = 10/1)分离纯化得目标产品,收率为53%。
(3)化合物21的合成
向100 mL双颈瓶中加入化合物20(2.6 g)、Pd(PPh3)2Cl2(140 mg)、CuI(58 mg),Ar换气3次。注入干燥的Et3N (40 mL),室温搅拌均匀后,加入三甲基硅乙炔(1.6 mL)。室温过夜反应。TLC监测反应完成后,直接减压浓缩除去溶剂。然后向残留物中加入水和乙酸乙酯进行萃取,合并乙酸乙酯层,并用饱和NaCl溶液反洗、无水Na2SO4干燥,减压浓缩后得到黄色油状物。最后通过硅胶柱层析(洗脱液为石油醚)分离纯化得到目标化合物21,收率为85%。
(4)化合物22的合成
将0.5 g化合物21溶于THF中,加入四丁基氟化铵溶液(1M in THF)110μL,反应结束后加入稀盐酸溶液和EA,有机层用纯水和饱和食盐水洗涤,合并有机层,无水硫酸钠干燥,经减压蒸馏除去溶剂,残留物采用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯 = 10/1)分离纯化得目标产品,收率为89%。
(5)化合物24的合成
向50 mL双颈瓶中加入140 mg市售的化合物23、 Pd(PPh3)2Cl2(9 mg,0.02equiv.)、CuI(3.7 mg,0.03 equiv.),Ar换气3次。注入干燥的Et3N (20 mL),室温搅拌均匀后,加入化合物22(14.5 mmol,1.1 equiv.)。室温过夜反应。TLC监测反应完成后,直接减压浓缩除去溶剂。然后向残留物中加入水和乙酸乙酯进行萃取,合并乙酸乙酯层,并用饱和NaCl溶液反洗、无水Na2SO4干燥,减压浓缩后得到深棕色油状物。最后通过硅胶柱层析(洗脱液为石油醚/乙酸乙酯 = 2/1)分离纯化得到目标化合物24,收率为36%。
(6)化合物25的合成
向50 mL双颈瓶中加入76.4 mg化合物24,27.2 mg乙酸铵,4 mg硝酸银和叔丁醇2mL,Ar换气3次,室温搅拌过夜。反应结束后加入饱和NH4Cl溶液,EA萃取,合并乙酸乙酯层,无水Na2SO4干燥,减压浓缩后通过硅胶柱层析(洗脱液为石油醚/乙酸乙酯 = 2/1)分离纯化得到目标化合物24,收率为88%。1H NMR (400 MHz, Chloroform-d) δ 9.62 (t, J = 0.9Hz, 1H), 7.74 (d, J = 1.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.2Hz, 1H), 6.97 – 6.86 (m, 3H), 6.00 (s, 2H), 4.05 (s, 3H), 3.98 (t, J = 5.7Hz, 2H), 2.82 (t, J = 5.7 Hz, 2H)。
(7)化合物Ber-11的合成
参照实施例2(6)化合物Ber-2的合成,本实例的合成步骤与实施例2(6)的区别仅在于:将实施例2 (6)的原料化合物8替换为化合物25,收率为80%。1H NMR (400 MHz,DMSO-d 6) δ 9.94 (s, 1H), 8.96 (s, 1H), 8.13 (t, J = 8.0 Hz, 1H), 7.86 (s,1H), 7.75 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.10 (s, 1H), 6.19(s, 2H), 4.93 (d, J = 6.7 Hz, 2H), 4.14 (s, 3H), 3.17 (d, J = 4.9 Hz, 2H). 13CNMR (100 MHz, DMSO-d 6) δ 157.7, 150.7, 148.2, 146.1, 140.45, 139.7, 139.0,131.8, 120.7, 120.4, 119.2, 118.2, 109.3, 108.9, 106.2, 102.7, 57.2, 55.3,26.8。
实施例12:化合物Ber-12和Ber-13的合成
参照文献(European Journal of Medicinal Chemistry, 157, 2018, 877-886)的合成方法。将溶有0.6g NaBH4的5ml 5%NaOH溶液逐滴滴加入含小檗碱(3.7g,11.01mmol),4.2g K2CO3的甲醇溶液 (125ml) 中,室温搅拌2小时,抽滤,收集固体。滤饼依次用蒸馏水,80%乙醇洗涤,得到黄绿色粉末二氢小檗碱2.57g (26)。收率70%。将二氢小檗碱(4g, 11.8mmol) 2与40%乙二醛 (3ml) 加入CH3CN (160ml)和HOAc (40ml)的搅拌溶剂混合物中反应,85-95℃加热反应6h,旋干后的深红色油状物27。向上一步旋干后的残渣中添加10%盐酸100ml,反应混合物在室温下搅拌过夜,真空蒸发掉溶剂,在95%乙醇中重结晶,得橙色固体环小檗碱(Ber-12)2.6g。收率62%。1H NMR (400 MHz, DMSO-d 6) δ 10.15 (s,1H), 8.84 (dd, J = 14.4, 9.3 Hz, 2H), 8.29 (d, J = 9.2 Hz, 1H), 8.17 (d, J =9.2 Hz, 1H), 7.59 (s, 1H), 6.40 (s, 2H), 5.25 (t, J = 6.7 Hz, 2H), 4.18 (s,3H), 4.12 (s, 3H), 3.63 (t, J = 6.7 Hz, 2H)。
将2.6g环小檗碱(Ber-12)置于圆底烧瓶中,抽真空至压力为10 mmHg,190 °C下反应2h至原料完全由橙色转变为暗红色。得到的粗品用快速柱层析(二氯甲烷/甲醇=50:1)纯化,得到2.4g暗红色固体Ber-13。收率96%。1H NMR (400 MHz, DMSO-d 6) δ 9.15 (s, 1H),8.39 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.38 (s, 1H), 7.23 (d, J= 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.30 (s, 2H), 4.71 (t, J = 6.5 Hz,2H), 3.77 (s, 3H), 3.42 (t, J = 6.5 Hz, 2H)。
实施例13:化合物Ber-14的合成
将暗红色固体产物Ber-13 (1g, 2.78mmol)与1,6-二溴己烷(1.28ml, 8.34mmol)溶于60ml DMF中,在80℃下搅拌反应18小时。旋干溶剂,得到深红色油状物粗品,用快速柱层析(二氯甲烷/甲醇=50:1)纯化,得到420mg橙色固体28。收率30%。将200mg固体28,28%氨水(6ml),NH4Cl固体(100mg)溶于10ml甲醇溶液中,室温搅拌过夜。用快速柱层析(二氯甲烷/甲醇=40:1)纯化,得到60mg橙色固体Ber-14。收率34%。1H NMR (400 MHz, DMSO-d 6) δ10.00 (s, 1H), 8.88 (dd, J = 20.8, 9.3 Hz, 2H), 8.31 (d, J = 9.2 Hz, 1H),8.22 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 6.41 (s, 2H), 5.26 (t, J = 6.7 Hz,2H), 4.37 (td, J = 6.8, 5.9, 3.3 Hz, 2H), 4.11 (s, 3H), 3.63 (t, J = 6.8 Hz,2H), 3.43 (q, J = 5.9 Hz, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.50 (dd, J = 13.0,6.4 Hz, 4H), 1.42 (d, J = 6.9 Hz, 2H), 1.34 (s, 2H)。
实施例14:化合物Ber-15的合成
参照文献(Bioorg. Med. Chem. 2013, 21, 62–69.)的方法合成。将1.5 g化合物Ber-1溶于甲醇中,加热回流至溶解,室温下分批加入0.76 g NaBH4,搅拌2 h后过滤,滤饼用甲醇冲洗得到粗品,用乙酸乙酯重结晶得到白色固体,收率76%。1H NMR (400 MHz,Chloroform-d) δ 6.76 – 6.71 (m, 2H), 6.67 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H),5.92 (s, 2H), 5.67 (s, 1H), 4.25 (d, J = 15.6 Hz, 1H), 3.87 (s, 3H), 3.54 (d,J = 18.7 Hz, 2H), 3.28 – 3.13 (m, 3H), 2.85 (s, 1H), 2.67 (d, J = 13.8 Hz,2H)。
实施例15:本发明化合物对IDO1/TDO酶抑制活性评价
1.实验方法
人N末端IDO1和TDO在大肠杆菌中表达,镍亲合层析纯化而得。使用重组hIDO1,hTDO和L-色氨酸作为底物通过紫外吸收进行测定。为了检测化合物对TDO和IDO1酶的抑制活性,将重组hTDO(100nM)和hIDO1(100nM)与一定浓度的化合物在室温下在含有400mM色氨酸,40mM抗坏血酸,200μg/ml的过氧化氢酶,20μM亚甲基蓝,Ca2+,Mg2+-无磷酸钾缓冲液培育系统中培养。对于阴性对照(空白),加入5μL测定缓冲液代替酶,加入10%DMSO代替抑制剂。对于阳性对照,加入Epacadostat代替抑制剂。温育1小时后,向每个系统中加入30%三氯乙酸,并在65℃温育15分钟以终止酶反应并将N-甲酰基犬尿氨酸转化为犬尿氨酸。然后,将来自各系统的100μL上清液与等体积的含有DMAB(二甲基氨基苯甲醛,3%,w/v)的乙酸混合,并使用Multiscan光谱Mk3(Thermo Fisher)在480nm波长下检测光密度。从L-犬尿氨酸标准曲线确定犬尿氨酸浓度。最后,使用GraphPad Prism 5 .0软件处理数据。通过以上实验方法,测试了各化合物针对TDO和IDO1的抑制活性。
2.实验结果
表1所示为本发明合成的化合物对IDO1/TDO酶的抑制活性数据。可以看出,本发明制备的化合物能够有效地抑制TDO和IDO1,特别是化合物Ber-1和Ber-7,对TDO和(或)IDO1具有明显的抑制效果。
表1.本发明化合物对IDO1/TDO抑制活性数据
综上所述,本发明成功制备了如式I-VII所示的小檗碱衍生物,其立体异构体、溶剂合物或其药学上可接受的盐,或同位素标记化合物。本发明所制备的化合物对IDO1和/TDO具有明显的抑制效果,可用于预防或治疗由IDO1/TDO介导的肿瘤、代谢紊乱疾病、自身免疫病、阿尔茨海默氏症、帕金森氏症、抑郁症等相关疾病,在药物制备领域具有广阔的应用前景。
以上内容仅是对本发明结构所做的举例和说明,所属本领域的技术人员不经创造性劳动即对所描述的具体实施实例做的修改或补充或采用类似的方式替代仍属于本专利的保护范围。
参考文献
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Claims (5)
3.根据权利要求1所述的一种小檗碱衍生物的药物组合物,其特征在于,包括治疗有效剂量的权利要求1所述的化合物,其立体异构体、溶剂合物或其药学上可接受的盐,或同位素标记化合物,和可药用载体、稀释剂和赋形剂。
4.根据权利要求1所述的一种小檗碱类衍生物在制备TDO和/或IDO1抑制剂上的用途,其特征在于,所述的小檗碱类衍生物为权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂合物。
5.根据权利要求4所述的用途,其特征在于:所述抑制剂是用于预防或治疗由IDO1/TDO介导的肿瘤、代谢紊乱疾病、自身免疫病、阿尔茨海默氏症、帕金森氏症、抑郁症等相关疾病的药物。
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