CN116102555A - 咪唑并芳杂基类衍生物及其应用 - Google Patents
咪唑并芳杂基类衍生物及其应用 Download PDFInfo
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Abstract
本发明公开一种咪唑并芳杂基类衍生物及其应用，所述咪唑并芳杂基类衍生物具有如式I的结构通式，与多肽类激动剂相比，小分子药物口服使用生物利用度具有显著的优势，且服用更为简便，不受食物或服用时间的限制，此外所述咪唑并芳杂基类衍生物作为小分子激动剂在细胞水平上展示出良好的疗效，具备良好的药物应用前景。
Description
技术领域
本发明涉及化学制药技术领域，更具体地说，本发明涉及咪唑并芳杂基类衍生物及其应用。
背景技术
糖尿病是一组代谢性疾病，由胰岛素分泌缺陷，胰岛素作用或两者兼而有之引起的慢性高血糖。在糖尿病患者中观察到的碳水化合物，脂肪和蛋白质代谢异常是胰岛素对靶组织异常作用的结果，并导致身体许多器官系统的结构变化，特别是与血管系统相关的器官系统。糖尿病的慢性高血糖与严重的长期并发症有关，包括微血管(如视网膜病变，肾病和神经病变)和大血管(包括致命和非致死性心肌梗塞，外周血管疾病和中风)疾病。糖尿病不是一种单一的疾病，而是一种慢性综合征，需要积极和长期的药物治疗，以限制其并发症，并在它们发展时有效管理它们，以及防止过早死亡。因此，糖尿病患者除了血糖控制外，还需要持续的医疗护理，包括多因素风险降低策略。
糖尿病分为四大亚型：I型，II型，妊娠期和其他(即，由于其他原因引起的特定类型的糖尿病)。
胰高血糖素样肽-1受体(Glucagon-like peptide-1receptor,GLP-1R)控制着对肠促胰岛素激素胰高血糖素样肽-1(Glucagon-like peptide-1,GLP-1)的生理反应，并且由于其激活时介导的广泛作用，包括促进葡萄糖依赖性胰岛素分泌，增加胰岛素生物合成，保留β细胞质量，改善外周胰岛素作用和促进体重减轻，是治疗2型糖尿病的主要治疗靶点。
GLP-1受体激动剂在糖尿病的治疗中发挥着不可替代的作用。从2005年以来共批准了7种GLP-1受体激动剂，包括艾塞那肽(Exenatide)、利拉鲁肽(Liraglutide)、杜拉鲁肽(Dulaglutide)、阿尔比鲁肽(Albiglutide)、利西那肽(Lixisenatide)、司美格鲁肽(Semaglutide)和替尔泊肽(Tirzepatide)。目前获批上市的GLP-1受体激动剂均为多肽类激动剂，小分子激动剂尚未有上市药物(进展最快的处于II期临床)。与多肽类激动剂相比，小分子药物口服使用生物利用度具有显著的优势，且服用更为简便，不受食物或服用时间的限制。
因此，有必要提出一种咪唑并芳杂基类衍生物，作为GLP-1受体激动剂小分子药物以推广在药物制备中的应用。
发明内容
鉴于此，本发明提供了一种咪唑并芳杂基类衍生物，作为GLP-1受体激动剂小分子药物用于推广在药物制备中的应用。
基于此，本发明的技术方案如下：
咪唑并芳杂基类衍生物，具有如式(I)的结构通式：
其中：
A选自8-10元稠芳环；
R1独立地选自氢、卤素、氰基、烷基或取代烷基、烷氧基、卤代烷基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基；
n＝0，1，2或3；
W为O，NH，S，S(O)2或C(＝O)；
Q1，Q2，Q3，Q4独立地选自CRZ或N，RZ独立的为氢、氟、氰基、甲基或氯；
B为取代或未取代的或为取代苯环，取代基选自氢、氟、氰基、甲基或氯；
G为C(＝O)、或CR3R4；
R3和R4独立地选自氢、甲基或氘代氢；
R2为
X，Y和Z独立地选自CRZ或N，RZ独立地选自氢、氟、氰基、甲基或氯。
进一步地，所述咪唑并芳杂基类衍生物中：
A选自
W选自O，NH或S；
为
B为
为
本发明另一个目的在于提出以上所述咪唑并芳杂基类衍生物的异构体。
进一步地，所述异构体包括互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体中的至少一种。
本发明还一个目的在于提出以上所述咪唑并芳杂基类衍生物药学上可接受的盐。
本发明再一个目的为提出药物组合物在制备用于激动GLP-1受体的药物中的应用，所述药物组合物包含以上所述的咪唑并芳杂基类衍生物，或以上所述异构体，或以上所述药学上可接受的盐，以及药学上可接受的赋形剂、稀释剂或载体。
进一步地，所述药物组合物用于制备治疗糖尿病或肥胖疾病药物。
优选地，所述组合物用于制备治疗和/或预防I型糖尿病、II型糖尿病、年青的成年发病型糖尿病、成人隐匿性免疫性糖尿病、妊娠糖尿病、糖尿病并发症、肥胖症、营养不良相关性糖尿病、高血糖症、葡萄糖耐受不良、心血管疾病、脑梗塞、中风、非酒精性脂肪性肝病、帕金森病、痴呆或胰岛素抗性的药物。
本发明的有益效果在于：
本发明提供的咪唑并芳杂基类衍生物与多肽类激动剂相比，小分子药物口服使用生物利用度具有显著的优势，且服用更为简便，不受食物或服用时间的限制。此外，所述咪唑并芳杂基类衍生物作为小分子激动剂在细胞水平上展示出良好的疗效，具备良好的药物应用前景。
附图说明
图1为本发明所述咪唑并芳杂基类衍生物结构通式。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
在一个实施例中，提出咪唑并芳杂基类衍生物，具有如式(I)的结构通式(如图1所示)：
其中：
A选自8-10元稠芳环；
R1独立地选自氢、卤素、氰基、烷基或取代烷基、烷氧基、卤代烷基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基；
n＝0，1，2或3；
W为O，NH，S，S(O)2或C(＝O)；
Q1，Q2，Q3，Q4独立地选自CRZ或N，RZ独立的为氢、氟、氰基、甲基或氯；
B为取代或未取代的或为取代苯环，取代基选自氢、氟、氰基、甲基或氯；
G为C(＝O)、或CR3R4；
R3和R4独立地选自氢、甲基或氘代氢；
R2为
X，Y和Z独立地选自CRZ或N，RZ独立地选自氢、氟、氰基、甲基或氯。
在优选的实施例中，以上所述咪唑并芳杂基类衍生物中：
A选自
W选自O，NH或S；
为
B为
为
在优选的实施例中，以上所述咪唑并芳杂基类衍生物包括如式(II)至(LXXIII)的结构式(当R2为时，共72个)：
此外，还包括如以上式(II)至(LXXIII)的结构式中，R2由分别替换成时，每种取代基的72种结构式，四种R2取代基共计288种结构式。
在一个实施例中，部分结构合成路径如下：
合成路径(一)，分为两大步：
1.中间体3至5制备路线如下所示：
其中：反应a为2,6-二氯吡啶(1)和4-(叔丁氧羰基氨基)环己烷甲酸甲酯(2)在碱性条件下发生的亲电取代反应生成3；
反应b为脱去酯基的反应，先在碱性条件下酯水解，然后加热脱羧，得中间体4；
反应c为脱boc保护基。
具体如下：
1.1中间体3的合成：
将4-(叔丁氧羰基氨基)环己烷甲酸甲酯(1.2当量)和2,6-二氯吡啶(1.0当量)溶于甲苯中，-78℃下加入LiHMDS(1M,1.4当量)的四氢呋喃溶液。反应10小时后，用稀盐酸调PH。乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，柱层析洗脱得中间体3。
1.2中间体4的合成：
将中间体3(1.0当量)溶于适量MeOH溶液中，60℃下加入适量氢氧化钠溶液(2N)。反应5小时后，让溶液冷却到室温，用稀盐酸(1N)调PH至酸性。乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，减压蒸馏得固体。将固体溶于二氯乙烷中，回流反应2小时，减压浓缩，加入适量的甲醇和水(3/1)，四小时后，抽滤并减压干燥得中间体4。
1.3中间体5的合成：
将中间体4(1.0当量)溶于适量二氯甲烷中，加入适量三氟乙酸，室温反应2小时，减压蒸馏，乙酸乙酯打浆，抽滤得中间体5。
2.中间体8至最终目标产物制备路线为：
其中：反应a为6和7发生胺取代反应得到中间体8；
反应b为中间体8硝基的还原得到中间体9；
反应c为中间体9与正甲酸三甲酯反应成环得到中间体10；
反应d为中间体10与二氧化碳反应生成羧基得到中间体11；
反应e为中间体11与中间体5的酰胺缩合反应得到中间体12；
反应f为中间体12与取代苄醇或取代苄硫醇发生Buchwald反应成醚得到中间体13；
反应g为中间体13碱性条件下酯水解得到目标化合物。
具体如下：
2.1中间体8的合成：
将原料7(1.0当量)溶于乙腈中，搅拌下加入取代甲胺(1.2当量)，然后再加入三乙胺(3.0当量)，反应18小时。反应完成后，将混合物减压浓缩，加入适当量饱和NH4Cl溶液，乙酸乙酯萃取水相，合并有机相，无水硫酸钠干燥，柱层析洗脱得中间体8。
2.2中间体9的合成：
将Pd/C(10％(w/w)，0.5当量)加入到中间体8(1.0当量)的甲醇和四氢呋喃(3/1)的混合溶液中，置于氢气氛(35psi)中反应4小时，硅藻土过滤，甲醇洗涤，减压浓缩得到中间体9。
2.3中间体10的合成：
将中间体(1.0当量)和正甲酸三甲酯(1.4当量)溶于适当量的DMF中，70℃下搅拌12-24小时，反应完成后，减压蒸馏，柱层析洗脱得中间体10。
2.4中间体11的合成：
将中间体10(1.0当量)和双(三甲基硅烷基)氨基钾(KHMDS)(1.0当量)混悬于适量四氢呋喃中，搅拌30分钟，硅藻土过滤，并转移到圆底烧瓶中，将反应置于二氧化碳气氛中，反应3小时，在反应液中加入等体积的乙醚，析出沉淀，抽滤并干燥的中间体11。
2.5中间体12的合成：
将中间体11(1.0当量)，HATU(1.5当量)，中间体5(1.2当量)溶于适量DMF中，加入三乙胺(3.0当量)，室温搅拌3-5小时，待反应结束后，加入DMF五倍体积的水，析出沉淀，抽滤并减压干燥得中间体12。
2.6中间体13的合成：
中间体12(1.0当量)，取代苄醇或取代苄硫醇(1.05当量)，Pd(OAc)2(0.05当量)，Trixiephos(0.05当量)和Cs2CO3(2.0当量)置于装有回流冷凝器的反应容器中，加入适量1,4-二氧六环，于氮气氛，105℃下反应2小时，待反应完成后，冷却至室温，硅藻土抽滤，减压浓缩并柱层析洗脱得中间体13。
2.7目标化合物的合成：
将LiOH(3.0当量)溶于适量水中并加入中间体13(1.0当量)的乙腈溶液(水的5倍体积)中，室温反应2小时，待反应完成后，加入稀盐酸(1N)调PH至酸性析出沉淀，抽滤并真空干燥得目标化合物。
合成路径(二)，路线如下：
其中：反应a为中间体9与取代氯乙酰氯胺取代并环合成吡唑得中间体14；
反应b为中间体14与中间体5的胺取代反应得中间体15；
反应c为中间体15与取代苄醇或取代苄硫醇发生Buchwald反应成醚得到中间体16；
反应d为中间体16碱性条件下酯水解得到目标化合物。
具体步骤为：
中间体14的合成
将中间体9(1.0当量)溶于适量四氢呋喃中，加入三乙胺(1.1当量)和取代氯乙酰氯(1.1当量)，反应1小时，向反应液中加入二氯亚砜(2.1当量)，室温反应15小时，反应完成后，加入甲醇淬灭反应，乙酸乙酯稀释反应液，有机相水洗，饱和碳酸氢钠洗，干燥并柱层析洗脱得中间体14。
中间体15的合成
将中间体14(1.0当量)溶于适量乙腈中，加入碳酸钾(2.5当量)和中间体5(1.0当量)，50℃下反应2小时，待反应完成后，冷却至室温，抽滤并减压浓缩，柱层析洗脱得中间体15。
中间体16的合成
中间体15(1.0当量)，取代苄醇或取代苄硫醇(1.05当量)，Pd(OAc)2(0.05当量)，Trixiephos(0.05当量)和Cs2CO3(2.0当量)置于装有回流冷凝器的反应容器中，加入适量1,4-二氧六环，于氮气氛，105℃下反应2小时，待反应完成后，冷却至室温，硅藻土抽滤，减压浓缩并柱层析洗脱得中间体16。
目标化合物的合成
将LiOH(3.0当量)溶于适量水中并加入中间体16(1.0当量)的乙腈溶液(水的5倍体积)中，室温反应2小时，待反应完成后，加入稀盐酸(1N)调PH至酸性析出沉淀，抽滤并真空干燥得目标化合物。
最后应说明的几点是，虽然上文中已经用一般性说明及具体实施例对本发明作了详尽的描述，但在本发明的基础上，以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (8)
1.咪唑并芳杂基类衍生物，其特征在于，具有如式(I)的结构通式：
其中：
A选自8-10元稠芳环；
R1独立地选自氢、卤素、氰基、烷基或取代烷基、烷氧基、卤代烷基、卤代烷氧基、烷氧烷基、环烷基、杂环烷基；
n＝0，1，2或3；
W为O，NH，S，S(O)2或C(＝O)；
Q1，Q2，Q3，Q4独立地选自CRZ或N，RZ独立的为氢、氟、氰基、甲基或氯；
B为取代或未取代的
或为取代苯环，取代基选自氢、氟、氰基、甲基或氯；
G为C(＝O)、或CR3R4；
R3和R4独立地选自氢、甲基或氘代氢；
R2为
X，Y和Z独立地选自CRZ或N，RZ独立地选自氢、氟、氰基、甲基或氯。
2.根据权利要求1所述的咪唑并芳杂基类衍生物，其特征在于：
A选自
W选自O，NH或S；
B为
3.权利要求1或2所述咪唑并芳杂基类衍生物的异构体。
4.根据权利要求3所述的异构体，其特征在于，包括互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体中的至少一种。
5.权利要求1或2所述咪唑并芳杂基类衍生物药学上可接受的盐。
6.药物组合物在制备用于激动GLP-1受体的药物中的应用，其特征在于，所述药物组合物包含权利要求1或2所述的咪唑并芳杂基类衍生物，或权利要求3所述异构体，或权利要求5所述药学上可接受的盐，以及药学上可接受的赋形剂、稀释剂或载体。
7.根据权利要求6所述的应用，其特征在于，所述药物组合物用于制备治疗糖尿病或肥胖疾病药物。
8.根据权利要求7所述的应用，其特征在于，所述组合物用于制备治疗和/或预防I型糖尿病、II型糖尿病、年青的成年发病型糖尿病、成人隐匿性免疫性糖尿病、妊娠糖尿病、糖尿病并发症、肥胖症、营养不良相关性糖尿病、高血糖症、葡萄糖耐受不良、心血管疾病、脑梗塞、中风、非酒精性脂肪性肝病、帕金森病、痴呆或胰岛素抗性的药物。
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| CN116675680A (zh) * | 2023-08-02 | 2023-09-01 | 药康众拓(北京)医药科技有限公司 | 一种氘代化合物及其制备方法、药物和应用 |
| WO2024051700A1 (zh) * | 2022-09-05 | 2024-03-14 | 德睿智药(苏州)新药研发有限公司 | 作为glp1r激动剂的新型芳基氘代苄醚取代杂环类化合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024051700A1 (zh) * | 2022-09-05 | 2024-03-14 | 德睿智药(苏州)新药研发有限公司 | 作为glp1r激动剂的新型芳基氘代苄醚取代杂环类化合物 |
| CN116675680A (zh) * | 2023-08-02 | 2023-09-01 | 药康众拓(北京)医药科技有限公司 | 一种氘代化合物及其制备方法、药物和应用 |
| CN116675680B (zh) * | 2023-08-02 | 2023-10-20 | 药康众拓(北京)医药科技有限公司 | 一种氘代化合物及其制备方法、药物和应用 |
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