CN116135855A - 孟鲁斯特酸小檗碱类季铵盐化合物、复盐组合物及其合成方法和用途 - Google Patents
孟鲁斯特酸小檗碱类季铵盐化合物、复盐组合物及其合成方法和用途 Download PDFInfo
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Abstract
Description
本发明要求享有于2021年11月16日向中国国家知识产权局提交的,专利申请号为202111358162.9,名称为“孟鲁斯特酸小檗碱类季铵盐化合物、复盐组合物及其合成方法和用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本发明中。
技术领域
本发明属于医药化学领域,具体包括具有式(I)结构的新型孟鲁斯特酸小檗碱类季铵盐化合物、复盐组合物,包含该类化合物的组合物及以及将该类化合物、组合物或复盐应用于制备用于预防、缓解和/或治疗与过敏、炎症、脉管畸形、感染、免疫等相关疾病(如溃疡性结肠炎、鼻炎、哮喘、脉管畸形/脉管炎、干眼、眼部感染和炎症等)的药物中的应用。
背景技术
小檗碱是从毛莨科黄连属植物黄连的根和皮中提取的异喹啉类生物碱。小檗碱为中药黄连主要成分,以往多认为口服后不易吸收,对大肠杆菌、金黄色葡萄球菌引起的肠道感染、眼结膜炎、化脓性中耳炎等有效,临床上主要用于肠道感染的治疗。近年来发现小檗碱具有降血糖、降血脂、抗炎等药理作用。研究发现在动脉粥样硬化动物模型中,小檗碱治疗后可明显降低血清中LDL-C和TC水平,抑制炎性因子IL-6分泌,降低血清和组织中的ALP、BMP-2、OPG、OCN、RUNX2和钙含量,抑制血管炎性浸润并提高斑块稳定性。同时发现小檗碱具有一定抗血管生成作用,其作用主要是通过抑制各种促炎和促血管生成因子来调节的,主要包括HIF、VEGF、COX-2、NO、NF-κB以及促炎等细胞因子。小檗碱抗炎机制可总结为通过对NF-κB、MAPK、PPARγ信号等通路的调节,影响免疫细胞Treg和Th17细胞之间的平衡,抑制IL-1β、IL-6、IL-8、IL-17、TNF-α、ICAM-1等炎性因子的分泌和表达,从而阻碍白细胞与内皮的黏附、迁移,减轻中性粒细胞浸润,促进细胞凋亡,减轻组织损伤。当前临床研究已初步发现小檗碱在代谢、自身免疫等的炎症相关疾病中发挥一定的治疗作用。
以往由于小檗碱水溶性差,口服生物利用度低等原因,一般将小檗碱做成盐酸盐来使用。而广泛应用的盐酸小檗碱水溶性,脂溶性均不佳,胃肠道吸收不良,导致其口服生物利用度低,影响了它的全身治疗作用。
孟鲁斯特酸或其钠盐是一种强选择性白三烯受体拮抗剂。白三烯系花生四烯酸5-脂氧化酶的代谢产物,是强效炎性递质,可介导一系列免疫反应。孟鲁斯特可与白三烯受体高选择性结合,阻断白三烯的致炎作用,从而发挥抗炎、抗过敏作用,临床广泛应用于多种呼吸道过敏性疾病的治疗。近期动物和临床研究发现,孟鲁斯特也具有较好的抗氧化功能。
尽管小檗碱与孟鲁斯特酸在抗炎及抗感染和免疫调节方面可能具有协同作用,但以往没有任何这方面的相关研究报道。本申请人创新性地将小檗碱与孟鲁斯特酸制成相应的小檗碱孟鲁斯特酸盐,不仅提高了两者的溶解度,增加了其溶液稳定性以及生物利用度,同时也显示了更强的抗炎效果,减少了副作用,特别是避免了盐酸盐的潜在高氯血症风险,提高了安全性。
技术效果
本发明人意外地发现部分本发明的式(I)结构新型季铵盐化合物或其复盐组合物不仅提高了小檗碱/孟鲁斯特的溶解度,不仅提高了两者的溶解度,增加了其溶液稳定性以及生物利用度,同时也显示了更强的抗炎效果,减少了副作用,特别是避免了小檗碱盐酸盐的潜在高氯血症风险,提高了安全性,更适合制备用于预防、缓解和/或治疗与过敏、炎症、脉管畸形、感染、免疫等相关疾病(如溃疡性结肠炎、鼻炎、哮喘、脉管畸形/脉管炎、干眼、眼部感染和炎症等)的药物或各种制剂。
发明内容
本发明的目的在于提供式(I)所示季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐。
其中,
R1和R2各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R1或任意两相邻的R2与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
R3和R4各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R3或任意两相邻的R4与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
m任意地选自0、1、2、3和4中的整数;
n任意地选自0、1、2、3和4中的整数;
P任意地选自0、1、2、3、4和5中的整数;
t任意地选自0、1、2、3、4和5中的整数。
本发明的一个方案中,所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物、组合物或其复盐,其具有式(IA)结构,
其中,
R1和R2各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R1或任意两相邻的R2与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
m任意地选自0、1、2、3和4中的整数;
n任意地选自0、1、2、3和4中的整数;
本发明的一个方案中,所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物、组合物或其复盐,其具有式(IB)结构,
其中,
R1各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R1与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
m任意地选自0、1、2、3和4中的整数;
本发明的一个方案中,所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物、组合物或其复盐,其具有式(IC)结构,
其中,
R2各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R2与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
n任意地选自0、1、2、3和4中的整数;
本发明的一个方案中,所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物、组合物或其复盐,其具有式(ID)结构,
其中,
R3和R4各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R3或任意两相邻的R4与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
P任意地选自0、1、2、3、4和5中的整数;
t任意地选自0、1、2、3、4和5中的整数。
根据本发明的实施方案,每个R1相同或不同,彼此独立地选自氢、C1-6烷基、C1-6烷氧基;或者两个R1与其各自连接的碳形成3-8元杂环;
根据本发明的实施方案,每个R2相同或不同,彼此独立地选自氢、C1-6烷基、C1-6烷氧基;或者两个R2与其各自连接的碳形成3-8元杂环;
根据本发明的实施方案,每个R3相同或不同,彼此独立地选自氢、卤素、C1-6烷基、C1-6烷氧基;
根据本发明的实施方案,每个R3相同或不同,彼此独立地选自氟、氯、溴或碘;优选为氯。
根据本发明的实施方案,每个R4相同或不同,彼此独立地选自氢或羟基C1-6烷基;
根据本发明的实施方案,m选自0、1、2或3;
根据本发明的实施方案,n选自0、1、2或3;
根据本发明的实施方案,t选自0或1;
根据本发明的实施方案,p选自0或1。
本发明的某些方案中,所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物、组合物或其复盐,其选自如下结构:
本发明的的另一目的在于提供上述季铵盐共轭化合物、溶剂合物、对映异构体和同位素取代物、复盐组合物的合成方法,其包括如下步骤:
1)各种游离型小檗碱生物碱丙酮加成产物制备:按需称取各种酸根的小檗碱型生物碱季铵盐类化合物于反应瓶中,加入无机碱(通常为氢氧化钠或KOH水溶液),随后逐滴加入丙酮,搅拌反应至原料反应完全。将反应混合液抽滤,并水洗滤饼至中性,干燥得到各种游离型小檗碱生物碱丙酮加成产物;
2)所述季铵盐共轭化合物、溶剂合物或组合物的制备:按需称取孟鲁斯特酸于反应瓶中,加入乙酸乙酯,完全溶解后于搅拌下加入8-丙酮基二氢小檗碱型生物碱化合物进行反应,至原料反应完全,减压浓缩或析晶;或向反应混合物中添加适当反溶剂获得小檗碱孟鲁斯特酸复盐组合物;
本发明的的另一目的在于提供式(I)所示的化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐中的至少一种在制备预防、缓解和/或治疗与过敏、炎症、脉管畸形、感染、免疫等相关疾病(如溃疡性结肠炎、鼻炎、哮喘、脉管畸形/脉管炎、干眼、眼部感染等)的药物中的应用。
根据本发明的实施方案,所述疾病包括但不限于超重、肥胖、糖尿病(T1 D及/或T2DM,包括糖尿病前期)、特发性T1 D(1B型)、潜伏性自身免疫性糖尿病成人(LADA)、早发性T2DM(EOD)、青年期非典型糖尿病(YOAD)、成熟期青年糖尿病(MODY)、营养不良相关糖尿病、妊娠期糖尿病、高血糖、胰岛素抵抗、肝胰岛素抵抗、糖耐量受损、糖尿病神经病变、糖尿病肾病、肾脏疾病(例如。,急性肾脏疾病、肾小管功能障碍、近端小管的促炎性改变)、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪沉积、睡眠呼吸暂停、肥胖(包括下丘脑肥胖和单基因肥胖)以及相关的共病(如骨关节炎和尿失禁),饮食失调(包括暴饮综合征、神经性贪食症和综合征性肥胖症,如Prader-Willi和Bardet-Biedl综合征)、使用其他药物导致的体重增加(例如,使用类固醇和抗精神病药)、过度嗜糖、血脂异常(包括高脂血症、高甘油三酯血症、总胆固醇增加,高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、高胰岛素血症、NAFLD(包括脂肪变性、NASH、纤维化、肝硬化、肝细胞癌等相关疾病)、心血管疾病、动脉粥样硬化(包括冠状动脉疾病)、外周血管疾病、高血压、内皮功能障碍,血管顺应性受损、充血性心力衰竭、心肌梗死(如坏死和凋亡)、中风、出血性中风、缺血性中风、创伤性脑损伤、肺动脉高压、血管成形术后再狭窄、间歇性跛行、餐后血脂、代谢性酸中毒、酮症、关节炎、骨质疏松症,帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、干眼症、肾小球硬化、慢性肾功能衰竭、代谢综合征、X综合征、经前综合征、心绞痛、血栓形成、动脉粥样硬化、短暂性缺血发作、血管再狭窄、糖代谢受损,空腹血糖受损、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织疾病、牛皮癣、足部溃疡、溃疡性结肠炎、高载脂蛋白B脂蛋白血症、阿尔茨海默病、精神分裂症、认知障碍、炎性肠病、短肠综合征、克罗恩病、结肠炎,肠易激综合征、多囊卵巢综合征的预防或治疗以及成瘾治疗(如酗酒和/或吸毒)等病症。
本发明还提供一种药物组合物,其包含治疗有效量的式(I)所示的化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐中的至少一种和药学上可接受的载体或赋形剂。
根据本发明的实施方案,所述药物组合物经配制而通过选自以下的途径给药:口服、注射、直肠、经鼻、经肺、局部、口腔和舌下、阴道、肠胃外、皮下、肌肉内、静脉内、皮内、鞘内和硬膜外。
根据本发明的实施方案,所述药物组合物优选以口服方式给药。
所述口服剂型没有特别限定,可以采用本领域熟知的任意口服剂型,优选包括片剂、胶囊、混悬剂或者口服溶液等本领域已知的口服剂型。作为口服剂型时,使用的剂量标准例如为500-1500mg/天,优选用量为700-1200mg/天,优选800-1000mg/天,最优选为1000mg/天。
根据本发明的药物组合物的用药时间可以视病情程度而定,优选至少为1个月,例如可以为1、2、3、4、5或6个月,最长可能因病情需要而终身服药。
根据本发明的实施方案,所述药物组合物还可以包含药学上可接受的辅料,其选自包括但不限于下列辅料中的至少一种:填充剂、崩解剂、粘合剂、润滑剂、表面活性剂、矫味剂、湿润剂、pH调节剂、增溶剂或助溶剂、渗透压调节剂。本领域技术人员根据具体剂型的需要,可以容易地确定如何选择相应的辅料及其相应用量。
根据本发明的实施方案,所述药物组合物还可以进一步含有一种或多种额外的治疗剂。
本发明的的另一目的在于提供—种小檗碱孟鲁斯特酸复盐组合物,,所述小檗碱孟鲁斯特酸复盐组合物由小檗碱孟鲁斯特酸复盐作为有效成分加入适当的辅料和载体制成临床上可以接受的药物制剂。
本发明还提供所述式(I)所示的化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐,以及所述药物组合物在预防或治疗与炎症、免疫、感染、过敏、代谢等相关的疾病中的用途。所述的与炎症、免疫、感染、过敏、代谢等相关的疾病具有上文所述的定义。
本发明还提供一种预防或治疗与炎症、免疫、感染、过敏、代谢等相关的疾病的方法,包括给予患者预防或治疗有效量的式(I)所示的化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐中的至少一种,或者给予患者预防或治疗有效量的上述药物组合物。所述的与炎症、免疫、感染、过敏、代谢等相关的疾病具有上文所述的定义。
在一些实施方案中,所述患者哺乳动物,优选是人。
本发明现在进一步通过实施例描述。下面给出的实施例仅用于说明目的,而不是仅限于此发明的范围。本发明的化合物可以用有机合成领域中许多已知的方法来制备。本发明的实施例可以使用下面描述的方法来合成,以及有机合成化学领域中已知的合成方法,或在其基础上通过改进的方法。优选的方法包括,但不限于以下描述方法。
说明书附图
图1为实施例3中不同浓度复盐化合物的抗炎效果对照图。
图2为实施例4中复盐与其单体的抗炎效果对照图。
具体实施方式
为了更详细地说明本发明,给出下列实例,但本发明的范围并非限定于此。
实施例1、孟鲁斯特酸小檗碱复盐(复盐1)的制备:
1. 1-(9,10-二甲氧基-5,8-二氢-6H-[1,3]二氧杂环[4,5-g]异喹啉基[3,2-a]异喹啉-8-基)丙-2-酮的合成
在室温条件下,向溶有9,10-二甲氧基-5,6-二氢-[1,3]二氧杂环[4,5-g]异喹啉基[3,2-a]异喹啉-7-氯化铵(1.00g,2.70mmol)丙酮溶液中(2mL)滴加氢氧化钠(5M,6mL)水溶液。滴加完毕,室温反应4小时。反应结束,反应液直接浓缩得到粗产品。粗产品用甲醇(30mL)打浆30分钟,然后过滤,收集滤饼并干燥得到黄色固体化合物1-(9,10-二甲氧基-5,8-二氢-6H-[1,3]二氧杂环[4,5-g]异喹啉基[3,2-a]异喹啉-8-基)丙-2-酮(830mg,2.11mmol,收率:78.1%)。
产物NMR:1H NMR(400MHz,DMSO-d6)δ7.25(s,1H),6.86(d,J=8.4Hz,1H),6.76(s,1H),6.72(d,J=8.4Hz,1H),6.00(s,1H),5.99(s,2H),5.22-5.19(m,1H),3.76(d,J=2.4Hz,6H),3.30–3.26(m,1H),3.20-3.19(m,1H),2.96-2.90(m,1H),2.78-2.76(m,2H),2.33-2.29(m,1H),2.03(s,3H).
2.(R,E)-2-(1-(((1-(3-(2-(7-氯喹啉-2-基)乙烯基)苯基)-3-(2-(2-羟丙-2-基)苯基)丙基)硫代)甲基)环丙基)乙酸9,10-二甲氧基-5,6-二氢-[1,3]二氧杂环[4,5-g]异喹啉并[3,2-a]异喹啉-7-鎓偶合物的合成
将化合物1-(9,10-二甲氧基-5,8-二氢-6H-[1,3]二氧杂环[4,5-g]异喹啉基[3,2-a]异喹啉-8-基)丙-2-酮(791mg,2.01mmol)和化合物(R,E)-2-(1-(((1-(3-(2-(7-氯喹啉-2-基)乙烯基)苯基)-3-(2-(2-羟丙-2-基)苯基)丙基)硫代)甲基)环丙基)乙酸(1.18g,2.01mmol)的含有甲醇(8mL)和水(0.1mL)的密封管中,然后反应液溶液升温80℃反应2小时。反应结束,将反应液除去溶剂得到黄色固体化合物(11.90g,2.06mmol,粗品)。然后将粗品化合物(600mg,0.65mmol)加入到(氯仿(6.5mL),甲醇(3.5mL)和水(0.1mL)混合溶剂中,升温80℃直至粗产品全部溶解,80℃继续搅拌1小时。反应结束,反应液自然冷却至室温,反应液直接浓缩除去溶剂得到(R,E)-2-(1-(((1-(3-(2-(7-氯喹啉-2-基)乙烯基)苯基)-3-(2-(2-羟丙-2-基)苯基)丙基)硫代)甲基)环丙基)乙酸9,10-二甲氧基-5,6-二氢-[1,3]二氧杂环[4,5-g]异喹啉并[3,2-a]异喹啉-7-鎓偶合物(复盐1,600mg,0.65mmol,收率:100%)保留时间:1.271min.LCMS:[M+H]+336.1.保留时间:1.853min.LCMS:[M+H]+586.3.
产物NMR:1H NMR(400MHz,DMSO)δ9.89(s,1H),8.93(s,1H),8.40(d,J=8.8Hz,1H),8.20(d,J=9.2Hz,1H),8.03(d,J=2.4Hz,1H),8.01-7.94(m,3H),7.89(d,J=16.4Hz,1H),7.80(s,1H),7.73(s,1H),7.62-7.57(m,2H),7.51(d,J=16.4Hz,1H),7.40-7.33(m,3H),7.11-7.00(m,4H),6.17(s,2H),4.94-4.91(m,2H),4.08(d,J=10.0Hz,6H),4.02(t,J=8.0Hz,1H),3.25-3.19(m,2H),3.13-3.06(m,1H),2.75-2.65(m,2H),2.54(s,1H),2.29-2.20(m,1H),2.10-2.06(m,2H),1.95-1.91(m,1H),1.45(d,J=8.4Hz,6H),0.41-0.30(m,2H),0.25-0.14(m,2H).
斯特
实施例2、孟鲁斯特酸小檗碱类似物复盐(复盐2-15)的制备:
实施例3、高渗炎症细胞模型评价受试化合物对抗炎效果
3.1细胞与培养
3.2试剂、仪器及耗材
3.3实验方法和过程
SV40细胞培养:SV40细胞培养于含10%胎牛血清的DMEM/F12培养基中,同时加入胰岛素和人表皮生长因子,使胰岛素在培养基里的终浓度为5μg/mL,人表皮生长因子的终浓度为10ng/mL。并将其置于温度为37℃、含5%CO2、湿度为90%的细胞培养箱内常规传代培养。待细胞生长至70%~90%的融合状态用于实验。
人原代细胞培养:将手术使用的供体角膜剩余角膜缘用眼科器械处理为携带角膜干细胞的组织块,将组织块贴于细胞培养皿底部,培养于SHEM培养基中,将其置于温度为37℃、含5%CO2、湿度为90%的细胞培养箱内,3~5天后可见由角膜缘干细胞爬出的人角膜原代上皮细胞,待细胞生长至70%~90%的融合状态用于实验。
溶液的配制:①高渗液(500mOsm)的配制:向无血清的培养基中加90mmol/L NaCl溶液配制而成。②被试药物溶液配置:将10mg的上述制备产物溶于1mL的37℃DMSO溶液中,配制成104μg/mL的母液,-20℃冰箱保存备用;用不含血清的培养基稀释母液,配制成终浓度为1μmol/L,10μmol/L的药物溶液用于实验。
高渗炎症细胞模型的建立与用药:弃旧培养基,给含500mOsm高渗液的高渗培养基和正常等渗培养基,培养细胞四小时后,药物组换用药物溶液,对照组(含高渗模型对照,正常细胞对照)换用正常等渗培养基,继续培养四小时后取材。
实时荧光定量PCR(RT-PCR):使用RT-PCR检测不同组IL-6,IL-1β,IL-17A,IL-18,TNF-α和NLRP3的mRNA表达。取不同时间点(高渗炎症细胞模型造模后,用药后四小时)的接种于12孔板的SV40和人角膜上皮原代细胞,收集细胞备用。相同实验重复3次。按RNA提取试剂盒说明书提取细胞的RNA,并根据所测浓度计算出合成cDNA模板所需的总RNA量。利用M-MLV反转录试剂盒合成cDNA,将反转录得到的cDNA-20℃保存,后续进行PCR的扩增。基因引物序列如下:
RT-PCR检测采用SYBR Green荧光染料法。计算出目的基因mRNA相对定量的表达量。每组均设3个重复孔,最终结果取3次的平均值。
两组间比较采用t检验,P<0.05为显著性差异
3.4结果
实验结果显示(图1:NC:正常对照,HS:高渗模型,HS-1:高渗模型加1μmol/L孟鲁斯特酸小檗碱复盐复盐药物治疗组,HS-10:高渗模型加10μmol/L孟鲁斯特酸小檗碱复盐复盐药物治疗组),在人角膜上皮原代细胞和SV40角膜上皮细胞高渗模型中,1μmol/L与10μmol/L浓度斯特药物治疗均能对各炎症相关细胞因子产生显著的降低作用(图1:A-H,HS组对比HS-1,HS-10组,Ps<0.01)。提示孟鲁斯特酸小檗碱复盐具有良好的抗炎效果,对相关疾病有治疗潜力。
实施例4、高渗炎症细胞模型评价受试化合物与其单体抗炎效果比较
4.1实验方法和过程
该实施例试剂、仪器及耗材与实施例3相同,所用对比药物为小檗碱碱基(阿拉丁,B414323),孟鲁斯特(阿拉丁,M421902)
人原代细胞培养:将手术使用的供体角膜剩余角膜缘用眼科器械处理为携带角膜干细胞的组织块,将组织块贴于细胞培养皿底部,培养于SHEM培养基中,将其置于温度为37℃、含5%CO2、湿度为90%的细胞培养箱内,3~5天后可见由角膜缘干细胞爬出的人角膜原代上皮细胞,待细胞生长至70%~90%的融合状态用于实验。
溶液的配制:①高渗液(500mOsm)的配制:向无血清的培养基中加90mmol/L NaCl溶液配制而成。②被试药物溶液配置:将10mg的上述制备产物溶于1mL的37℃DMSO溶液中,配制成104μg/mL的母液,-20℃冰箱保存备用;用不含血清的培养基稀释母液,配制成终浓度为0.5μmol/L的药物溶液用于此次实验。③小檗碱,孟鲁斯特药物溶液配置:将10mg的小檗碱或孟鲁斯特分别溶于1mL的37℃DMSO溶液中,分别配制成104μg/mL的母液,-20℃冰箱保存备用;用不含血清的培养基稀释母液,配制成终浓度为0.5μmol/L的药物溶液用于此次实验。
实时荧光定量PCR(RT-PCR):使用RT-PCR检测不同组IL-6,IL-1β,IL-17A,IL-18,TNF-α和NLRP3的mRNA表达。取不同时间点(高渗炎症细胞模型造模后,用药后四小时)的接种于12孔板的SV40和人角膜上皮原代细胞,收集细胞备用。相同实验重复3次。按RNA提取试剂盒说明书提取细胞的RNA,并根据所测浓度计算出合成cDNA模板所需的总RNA量。利用M-MLV反转录试剂盒合成cDNA,将反转录得到的cDNA-20℃保存,后续进行PCR的扩增。基因引物序列与实施例3相同。
两组间比较采用t检验,P<0.05为显著性差异
4.2结果
实验结果显示(图2:UT:正常对照,HS:高渗细胞模型,HS-0.5:高渗细胞模型加0.5μmol/L孟鲁斯特酸小檗碱复盐药物治疗组,A:高渗细胞模型加0.5μmol/L孟鲁斯特,B:高渗细胞模型加0.5μmol/L小檗碱碱基),在人角膜上皮原代细胞高渗模型中,相比较与同浓度小檗碱与孟鲁斯特单药,所得复盐药物均能对各炎症相关细胞因子产生显著更强的降低作用(图2:A-D,HS-0.5组分别对比A,B组,Ps<0.01)。提示孟鲁斯特酸小檗碱复盐的抗炎效果优于孟鲁斯特或小檗碱单体抗炎效果。
实施例5、孟鲁斯特酸小檗碱复盐与孟鲁斯特,小檗碱碱基在高湿环境稳定性比较
5.1实验方法和过程
该实施例中使用万分之一电子天平(Sartorius,德国),所用对比药物为小檗碱碱基(阿拉丁,B414323),孟鲁斯特(阿拉丁,M421902)。
分别取孟鲁斯特酸小檗碱复盐(复盐1),孟鲁斯特和小檗碱一克各三份,分别置平面皿内,精密称定,供试品置恒湿密闭容器中,于25℃、RH90%±5%条件下放置10天,分别于第5天和第10天精密称定,记录称定结果。计算吸湿增重比。
5.2结果
孟鲁斯特酸小檗碱复盐在高湿环境下,吸湿增重比小于孟鲁斯特以及小檗碱碱基。更便于化合物储存。
化合物 | 5天增重百分比(%) | 10天增重百分比(%) |
孟鲁斯特酸小檗碱复盐 | 3.3 | 4.9 |
孟鲁斯特 | 4.5 | 6.3 |
小檗碱碱基 | 4.2 | 6.7 |
实施例6、孟鲁斯特酸小檗碱复盐与孟鲁斯特,小檗碱碱基在溶剂中溶解度比较
6.1实验方法和过程
溶媒的制备:1)羧甲基纤维素CMC(麦克林:C889437)的溶解:取1个2L烧杯量取约1500mL 80℃的超纯水,用LED顶置式搅拌器边搅拌边缓慢加入羧甲基纤维素CMC(3.75g,0.25%),搅拌约7h后继续加入其他辅料。2)加入羟丙基-β-环糊精HPBCD(毕得:BD44359):缓慢加入羟丙基-β-环糊精HPBCD(82.5g,5.5%)搅拌至溶解,搅拌约1h。3)调节pH值:调节pH值前测量pH值,然后再加入1mol/L的NaOH溶液或者1mol/L的HCl溶液,将pH值调节至约7.5-8。
对照品的制备:1)孟鲁斯特酸小檗碱盐对照品溶液:精密称取孟鲁斯特酸小檗碱盐适量于量瓶中,用甲醇溶解并稀释至刻度。2)小檗碱碱基对照品溶液:精密称取小檗碱对照品适量于量瓶中,加甲醇溶解并稀释至刻度。3)孟鲁斯特对照品溶液:精密称取孟鲁斯特对照品适量于量瓶中,用DMSO溶解并稀释至刻度。4)供试品溶液:分别向溶媒中加入孟鲁斯特酸小檗碱盐,小檗碱碱基、孟鲁斯特至过饱和,过滤,用氢氧化钠或盐酸溶液调节pH至7.5-8。
色谱条件:1)孟鲁斯特酸小檗碱盐色谱条件:所用色谱柱为Agilent ZORBAX SB-C18(4.6×250mm,5μm);流动相:0.01mol/L磷酸二氢铵溶液(用磷酸调节pH值至2.8)-乙腈(75:25);检测波长:345nm;进样体积:10μL;柱温:25℃;流速:1.0mL/min。精密量取孟鲁斯特酸小檗碱盐供试品溶液与对照品溶液,分别注入液相色谱仪。2)孟鲁斯特色谱条件:所用色谱柱:Agilent Eclipse XDB-C18(4.6×150mm,5μm),流动相A:称取3.85g乙酸铵用1000mL水溶解,加入1mL三乙胺,用冰醋酸调节pH值至5.5,过滤,超声;流动相B:甲醇;检测波长:240nm;进样体积:20μL;柱温:25℃;流速:1.0mL/min。测定法:精密量取孟鲁斯特对照品溶液,注入液相色谱仪;孟鲁斯特各供试品溶液经适当稀释后,注入液相色谱仪。3)小檗碱碱基色谱条件:所用色谱柱为Agilent ZORBAX SB-C18(4.6×250mm,5μm);流动相:0.01mol/L磷酸二氢铵溶液(用磷酸调节pH值至2.8)-乙腈(75:25);检测波长:345nm;进样体积:10μL;柱温:25℃;流速:1.0mL/min。精密量取小檗碱碱基供试品溶液与对照品溶液,分别注入液相色谱仪。
两组间比较采用t检验,P<0.05为显著性差异
6.2结果
化合物 | 溶剂中浓度(μg/ml) |
孟鲁斯特酸小檗碱复盐 | 31.51 |
孟鲁斯特 | 极微量未检出 |
小檗碱碱基 | 24.45 |
结果可见孟鲁斯特酸小檗碱复盐的在该溶媒中溶解度优于小檗碱碱基,且大幅优于孟鲁斯特单体(Ps<0.05)。
实施例7、孟鲁斯特酸小檗碱复盐与孟鲁斯特,小檗碱碱基在溶媒中稳定性比较
7.1实验方法和过程
该实施例试剂、仪器及耗材与实施例6相同,由于孟鲁斯特在该溶媒中溶解度极差,无法检出,故使用其钠盐(阿拉丁:M129586)与孟鲁斯特酸小檗碱复盐对比其在溶媒中稳定性。
溶媒的制备:1)羧甲基纤维素CMC(麦克林:C889437)的溶解:取1个2L烧杯量取约1500mL 80℃的超纯水,用LED顶置式搅拌器边搅拌边缓慢加入羧甲基纤维素CMC(3.75g,0.25%),搅拌约7h后继续加入其他辅料。2)加入羟丙基-β-环糊精HPBCD(毕得:BD44359):缓慢加入羟丙基-β-环糊精HPBCD(82.5g,5.5%)搅拌至溶解,搅拌约1h。3)调节pH值:调节pH值前测量pH值,然后再加入1mol/L的NaOH溶液或者1mol/L的HCl溶液,将pH值调节至约7.5-8。
对照品的制备:1)孟鲁斯特酸小檗碱盐对照品溶液:精密称取孟鲁斯特酸小檗碱盐适量于量瓶中,用甲醇溶解并稀释至刻度。2)小檗碱碱基对照品溶液:精密称取小檗碱对照品适量于量瓶中,加甲醇溶解并稀释至刻度。3)孟鲁斯特钠对照品溶液:精密称取孟鲁斯特钠对照品适量于量瓶中,用DMSO溶解并稀释至刻度。4)供试品溶液:分别向溶媒中加入孟鲁斯特酸小檗碱盐,小檗碱碱基、孟鲁斯特钠至过饱和,过滤,用氢氧化钠或盐酸溶液调节pH至7.5-8。
色谱条件:1)孟鲁斯特酸小檗碱盐色谱条件:所用色谱柱为Agilent ZORBAX SB-C18(4.6×250mm,5μm);流动相:0.01mol/L磷酸二氢铵溶液(用磷酸调节pH值至2.8)-乙腈(75:25);检测波长:345nm;进样体积:10μL;柱温:25℃;流速:1.0mL/min。精密量取孟鲁斯特酸小檗碱盐供试品溶液与对照品溶液,分别注入液相色谱仪。2)孟鲁斯特钠色谱条件:所用色谱柱:Agilent Eclipse XDB-C18(4.6×150mm,5μm),流动相A:称取3.85g乙酸铵用1000mL水溶解,加入1mL三乙胺,用冰醋酸调节pH值至5.5,过滤,超声;流动相B:甲醇;检测波长:240nm;进样体积:20μL;柱温:25℃;流速:1.0mL/min。测定法:精密量取孟鲁斯特钠对照品溶液,注入液相色谱仪;孟鲁斯特钠各供试品溶液经适当稀释后,注入液相色谱仪。3)小檗碱碱基色谱条件:所用色谱柱为Agilent ZORBAX SB-C18(4.6×250mm,5μm);流动相:0.01mol/L磷酸二氢铵溶液(用磷酸调节pH值至2.8)-乙腈(75:25);检测波长:345nm;进样体积:10μL;柱温:25℃;流速:1.0mL/min。精密量取小檗碱碱基供试品溶液与对照品溶液,分别注入液相色谱仪。
实验流程:1)光稳定性实验:分别取孟鲁斯特酸小檗碱盐0小时供试品溶液,小檗碱碱基0小时供试品溶液、孟鲁斯特钠0小时供试品溶液,将上述溶液置于光照条件下,分别于8小时、5天、10天取样,得各物质各条件下供试品溶液,与标准品溶液进行比较。2)热稳定性实验:分别取孟鲁斯特酸小檗碱盐0小时供试品溶液,小檗碱碱基0小时供试品溶液、孟鲁斯特钠0小时供试品溶液,将上述溶液置于40℃(避光)和60℃(避光)条件下,分别于8小时、5天、10天取样,得各物质各条件下供试品溶液,与标准品溶液进行比较。
两组间比较采用t检验,P<0.05为显著性差异
7.2结果
结果可见孟鲁斯特酸小檗碱复盐的在该滴眼液常用溶媒中在8小时,5天,10天等三个时间点,整体光热稳定性优于孟鲁斯特(Ps<0.05),光热稳定性与小檗碱碱基相当(Ps>0.05)。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.式(I)所示季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐;
其中,
R1和R2各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R1或任意两相邻的R2与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
R3和R4各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R3或任意两相邻的R4与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
m任意地选自0、1、2、3和4中的整数;
n任意地选自0、1、2、3和4中的整数;
P任意地选自0、1、2、3、4和5中的整数;
t任意地选自0、1、2、3、4和5中的整数。
2.根据权利要求1所述的季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐,其具有式(IA)结构,
其中,
R1和R2各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R1或任意两相邻的R2与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
m任意地选自0、1、2、3和4中的整数;
n任意地选自0、1、2、3和4中的整数。
3.根据权利要求1或2所述的季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐,其具有式(IB)结构,
其中,
R1各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R1与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
m任意地选自0、1、2、3和4中的整数。
4.根据权利要求1-3任一项所述的季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐,其具有式(IC)结构,
其中,
R2各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R2与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
n任意地选自0、1、2、3和4中的整数;
优选地,所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐,其具有式(ID)结构,
其中,
R3和R4各自独立地选自氢、氘、卤素、-CN、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基;其中所述C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、6-10元芳基、5-8元杂芳基、3-8元饱和或部分饱和环烷基和3-8元饱和或部分饱和杂环基任选地最佳被1至多个取代基团取代,所述的取代基团任意选自氢、氘、卤素、烷基、卤代烷基、烷氧基、烷胺基、O=、CN、OH、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、6-10元芳基和5-8元杂芳基;
或者任意两相邻的R3或任意两相邻的R4与其附着的碳一起形成5-6元芳基或杂芳基,3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基,其中,所述环烷基、杂环基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代;
所述的杂芳基、杂环基中的杂原子代表着任意独立地选自O、N、S、P的杂原子及其同位素;
所述的卤素任意独立地选自F、Cl、Br、I及其同位素;
P任意地选自0、1、2、3、4和5中的整数;
t任意地选自0、1、2、3、4和5中的整数。
5.根据权利要求1-4任一项所述的季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐,其特征在于,每个R1相同或不同,彼此独立地选自氢、C1-6烷基、C1-6烷氧基;或者两个R1与其各自连接的碳形成3-8元杂环;
优选地,每个R2相同或不同,彼此独立地选自氢、C1-6烷基、C1-6烷氧基;或者两个R2与其各自连接的碳形成3-8元杂环;
优选地,每个R3相同或不同,彼此独立地选自氢、卤素、C1-6烷基、C1-6烷氧基;
优选地,每个R3相同或不同,彼此独立地选自氟、氯、溴或碘;优选为氯;
优选地,每个R4相同或不同,彼此独立地选自氢或羟基C1-6烷基;
优选地,m选自0、1、2或3;
优选地,n选自0、1、2或3;
优选地,t选自0或1;
优选地,p选自0或1。
7.权利要求1-6任一项所述季铵盐共轭化合物、溶剂合物、对映异构体和同位素取代物的合成方法,其包括如下步骤:
1)各种游离型小檗碱生物碱丙酮加成产物制备:按需称取各种酸根的小檗碱型生物碱季铵盐类化合物于反应瓶中,加入无机碱(通常为氢氧化钠或KOH水溶液),随后逐滴加入丙酮,搅拌反应至原料反应完全;将反应混合液抽滤,并水洗滤饼至中性,干燥得到各种游离型小檗碱生物碱丙酮加成产物;
2)所述季铵盐共轭化合物、溶剂合物或组合物的制备:按需称取孟鲁斯特酸于反应瓶中,加入乙酸乙酯,完全溶解后于搅拌下加入8-丙酮基二氢小檗碱型生物碱化合物进行反应,至原料反应完全,减压浓缩或析晶;或向反应混合物中添加适当反溶剂获得小檗碱孟鲁斯特酸复盐组合物。
8.一种药物组合物,其特征在于,所述药物组合物包含治疗有效量的权利要求1-6任一项的所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体、同位素取代物、复盐中的至少一种和药学上可接受的载体或赋形剂。
9.权利要求1-6中任一项所述季铵盐共轭化合物或其药学上可接受的盐、溶剂合物、组合物、对映异构体和同位素取代物或其复盐在制备用于预防、缓解和/或治疗与过敏、炎症、脉管畸形、感染、免疫等相关疾病(如溃疡性结肠炎、鼻炎、哮喘、脉管畸形/脉管炎、干眼、眼部感染等)的药物中的应用。
10.一种小檗碱孟鲁斯特酸复盐组合物,其特征在于:所述小檗碱孟鲁斯特酸复盐组合物由权利要求1-6中任一项所述季铵盐共轭化合物的复盐作为有效成分加入适当的辅料和载体制成临床上可以接受的药物制剂。
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