CN113461753B - 2-炔基甘露糖衍生物及其应用 - Google Patents
2-炔基甘露糖衍生物及其应用 Download PDFInfo
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- CN113461753B CN113461753B CN202110345872.1A CN202110345872A CN113461753B CN 113461753 B CN113461753 B CN 113461753B CN 202110345872 A CN202110345872 A CN 202110345872A CN 113461753 B CN113461753 B CN 113461753B
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Abstract
Description
相关申请的引用
本发明要求2020年3月31日在中国提交的,名称为“2-炔基甘露糖衍生物及其应用”、申请号为202010246993.6的发明专利申请的优先权,通过引用的方式将该专利申请的全部内容并入本文。
技术领域
本发明涉及一种2-炔基甘露糖衍生物及其应用,属于医药技术领域。
背景技术
尿路感染(urinary tract infections,UTIs)又称泌尿系统感染,是指病原体侵犯尿路粘膜或组织引起的尿路炎症。尿路感染包括肾盂肾炎、膀胱炎和尿道炎,是最常见的感染性疾病之一。尿路感染会引起疼痛、灼痛和尿频,严重情况还会扩散到肾脏和血液,危及生命。每年全球近1亿人受尿路感染困扰,用于治疗的费用超过25亿美元。尿路感染容易反复复发,尽管接受了抗生素治疗,25-44%的女性患者会在6个月内(一般约1个季度)再次感染。而且,复发的尿路感染容易对抗生素产生耐药,因而急需新的疗法。(Tamadonfar KO等人,Microbiol Spectrum,2019,7(3):BAI-0014-2019.)
80%以上的尿路感染由尿路致病性大肠杆菌(UPEC)引起。FimH蛋白是UPEC I型菌毛的顶端蛋白,是细菌感染尿路细胞的关键因素。FimH蛋白能特异地与膀胱表皮细胞表面的甘露糖糖蛋白结合,使细菌粘附在膀胱表面,避免被尿液冲走。FimH蛋白还诱导宿主细胞局部重排而直接介导UPEC的侵入,引起反复发作的尿路感染。因此,FimH蛋白已经成为预防或治疗细菌性尿路感染的候选靶蛋白。动物实验表明,不同于抗生素治疗对肠道菌群的大规模杀伤和群落的大量变化,FimH蛋白抑制剂可以选择性地清除膀胱和肠道内的UPEC,对其他肠道细菌影响较小,有望用于尿路感染的预防或治疗。(Terlizzi M.E.等人,Front.Microbiol.2017,8,1566.)
炎症性肠病(inflammation bowl disease,IBD)是肠道的一种慢性复发性炎症性疾病,主要包括克罗恩病(Crohn’s disease,CD)和溃疡性结肠炎(ulcerative colitis,UC)。炎症性肠病一般起病缓慢,少数急骤,病情轻重不一,易反复发作。近年来此病的患病率在不断增加,尤其是在亚洲、南美和中东等地区的新兴工业化国家。炎症性肠病的具体发病机制尚不明确,一般认为是免疫系统失调和肠道菌群失调等多方因素共同作用的结果。(de Souza HS等人,Nat Rev Gastroenterol Hepatol.2016,13,13–27.)
近年来对炎症性肠病患者的肠道菌群的研究表明,患者体内的黏附侵袭性大肠杆菌(adherent-invasive Escherichia coli,AIEC)的菌群数量较正常人显著增加,并在炎症性肠病的发生和进展中起到重要作用(Alvarez Dorta,D.等人,ChemBioChem 2016,17,936-952.)。与UPEC类似,AIEC也采用其I型菌毛的顶端FimH蛋白与肠道表皮细胞的受体CEACAM6结合,从而在肠道定殖。依靠FimH蛋白与其受体CEACAM6的结合,AIEC可以进一步进入肠道的表皮细胞和免疫细胞,诱发炎症反应和免疫失调(Mydock-McGrane LK等人,Expert Opin Drug Discov.2017,12,711–731.)。
目前对炎症性肠病的治疗主要采用非甾体抗炎药或者免疫抑制剂,但这些治疗方法只能用于缓解症状,因而疾病还是会反复发作,急需新的治疗方法。采用抗生素清除AIEC用于治疗炎症性肠病在临床上和临床前有少量研究,但由于抗生素对肠道其它菌群尤其是益生菌也有杀伤作用,会进一步导致肠道菌群失调,其效果并不明确。甚至有研究表明,抗生素导致的肠道菌群失调会促进AIEC的进一步感染,是炎症性肠病发生发展的一个诱因(Oberc AM等人,Inflamm Bowel Dis.2019,25(4),711-721.)。动物实验表明,FimH蛋白抑制剂通过拮抗FimH蛋白与其受体CEACAM6的结合阻止AIEC在肠道内的定殖,从而将AIEC从肠道中清除,有望用于炎症性肠病的治疗和预防(Alvarez Dorta,D.等人,ChemBioChem2016,17,936-952.)。
发明内容
本发明的目的是提出一种具有抑制FimH蛋白功能/活性的2-炔基甘露糖衍生物及其应用,该2-炔基甘露糖衍生物能够有效抑制FimH蛋白功能/活性,能够用于治疗或预防通过抑制FimH功能或活性而改善的疾病或病症。
本发明的目的通过以下技术方案得以实现:
一种2-炔基甘露糖衍生物,及其药学上可接受的盐、同位素和异构体,具有通式I所示的结构:
其中,U为氢原子、氘原子、C1-10烷基、C3-10环烷基、C2-10烯基、C2-10炔基、6-10元芳环、5-10元含有1-4个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、烯基、炔基、芳环、杂芳环、杂环未被取代或被1-5个R1基团取代;
X为化学键、氧原子、硫原子、N(R2)、C(R2)(R3)、或--C≡C--;
Y为化学键、C1-10烷基、C3-10环烷基、C2-8烯基、C2-8炔基、6-14元芳环、5-14元含有1-4个选自N、O和S的杂原子的杂芳环、或5-10元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、烯基、炔基、芳环、杂芳环、杂环未被取代或被1-5个R4基团取代;
Z选自氢原子、氘原子、卤素、氰基、C1-10烷基、C3-10环烷基、C1-10烷氧基、C2-8烯基、C2-8炔基、-C(O)OR5、-C(O)NR5R6、-N(R5)C(O)R6、-S(O)2R5、-S(O)2NR5R6、-P(O)R5R6、6-14元芳环、5-14元含有1-4个选自N、O和S的杂原子的杂芳环、或5-10元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、烯基、炔基、芳环、杂芳环、杂环未被取代或被1-5个R7基团取代;
R1选自氢原子、氘原子、卤素、氰基、羟基、氨基、C2-8烯基、C2-8炔基、C1-8砜基、C1-8酰胺基、C1-8脲基、C1-8氧代脲基、C1-8磺酰胺基、C1-8酯基、C1-8烷基、C3-8环烷基、C1-8烷氧基、苯基、5-6元含有1-4个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烯基、炔基、烷基、环烷基、烷氧基、苯基、杂芳环、或杂环未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代;
R2和R3分别独立地选自氢原子、氘原子、卤素、羟基、氨基、C1-8烷基、或C3-8环烷基,所述烷基和环烷基未被取代或被1-3个选自氘原子、卤素、羟基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代;
R4选自氢原子、氘原子、卤素、氰基、羟基、氨基、C2-8烯基、C2-8炔基、C1-8砜基、C1-8酰胺基、C1-8脲基、C1-8氧代脲基、C1-8磺酰胺基、C1-8酯基、C1-8烷基、C3-8环烷基、C1-8烷氧基、苯基、5-6元含有1-4个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烯基、炔基、烷基、环烷基、烷氧基、苯基、杂芳环和杂环未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、C1-3烷氧基、或C5-10酚基的取代基取代;
R5和R6分别独立地选自氢原子、C1-8烷基、或C3-8环烷基,所述烷基和环烷基未被取代或被1-3个选自氘原子、卤素、羟基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代;;
R7选自氢原子、氘原子、卤素、氰基、羟基、氨基、C2-8烯基、C2-8炔基、C1-8砜基、C1-8酰胺基、C1-8脲基、C1-8氧代脲基、C1-8磺酰胺基、C1-8酯基、二甲基氧磷基、C1-8烷基、C3-8环烷基、C1-8烷氧基、苯基、5-6元含有1-4个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烯基、炔基、烷基、环烷基、烷氧基、苯基、杂芳环和杂环未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代。
上述的2-炔基甘露糖衍生物中,优选的,U为氢原子、氘原子、C1-10烷基、C3-10环烷基、6-10元芳环、5-10元含有1-4个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、芳环、杂芳环、杂环,未被取代或被1-5个R1基团取代;
X为氧原子或--C≡C--;
Y为化学键、C1-10烷基、C3-10环烷基、6-10元芳环、5-10元含有1-4个选自N、O和S的杂原子的杂芳环、或5-10元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、芳环、杂芳环、杂环,未被取代或被1-5个R4基团取代;
Z选自氢原子、氘原子、卤素、氰基、C1-10烷基、C3-10环烷基、C1-10烷氧基、C2-8烯基、C2-8炔基、-C(O)OR5、-C(O)NR5R6、-N(R5)C(O)R6、-S(O)2R5、-S(O)2NR5R6、-P(O)R5R6、6-10元芳环、5-14元含有1-4个选自N、O和S的杂原子的杂芳环、或5-10元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、烯基、炔基、芳环、杂芳环、杂环,未被取代或被1-5个R7基团取代;
R1选自氢原子、氘原子、卤素、氰基、羟基、氨基、C2-8烯基、C2-8炔基、C1-8砜基、C1-8酰胺基、C1-8磺酰胺基、C1-8酯基、C1-8烷基、C3-8环烷基、C1-8烷氧基、苯基、5-6元含有1-3个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烯基、炔基、烷基、环烷基、烷氧基、苯基、杂芳环、杂环,未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代;
R4选自氢原子、氘原子、卤素、氰基、羟基、氨基、C1-8砜基、C1-8烷基、C3-8环烷基、C1-8烷氧基、苯基、5-6元含有1-3个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、烷氧基、苯基、杂芳环、杂环,未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、C1-3烷氧基、或C6-10酚基的取代基取代;
R5和R6分别独立地选自氢原子、C1-8烷基、或C3-8环烷基,所述烷基和环烷基未被取代或被1-3个选自氘原子、卤素、羟基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代;
R7选自氢原子、氘原子、卤素、氰基、羟基、氨基、C2-8烯基、C2-8炔基、C1-8砜基、C1-8酰胺基、C1-8酯基、二甲基氧磷基、C1-8烷基、C3-8环烷基、C1-8烷氧基、苯基、5-6元含有1-4个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烯基、炔基、烷基、环烷基、烷氧基、苯基、杂芳环、杂环,未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代。
上述的2-炔基甘露糖衍生物中,优选的,Y为C1-8烷基、C3-10环烷基、6-10元芳环、或5-10元含有1-4个选自N、O和S的杂原子的杂芳环,所述烷基、环烷基、芳环、杂芳环,未被取代或被1-5个R4基团取代;
R4选自氢原子、氘原子、卤素、氰基、羟基、C1-8烷基、C3-8环烷基、或C1-8烷氧基,所述烷基、环烷基、烷氧基,未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代。
R4选自氢原子、氘原子、卤素、氰基、羟基、C1-8烷基、C3-8环烷基、或C1-8烷氧基,所述烷基、环烷基、烷氧基未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代。
上述的2-炔基甘露糖衍生物中,优选的,根据权利要求1-3任一项所述的甘露糖衍生物,其特征在于Y选自未被取代或被1-3个R4基团取代的下列基团,其中,左侧与X相连接,右侧与Z相连接,所述R4基团如上所定义:
上述的2-炔基甘露糖衍生物中,优选的,具有通式Ia所示的结构:
其中,R4选自氢原子、氘原子、卤素、氰基、C1-8烷基、C3-8环烷基、或C1-8烷氧基,所述烷基、环烷基、烷氧基,未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代。
上述的2-炔基甘露糖衍生物中,优选的,U为C1-10烷基、C3-10环烷基、6-10元芳环、或5-10元含有1-4个选自N、O和S的杂原子的杂芳环,所述烷基、环烷基、芳环、杂芳环,未被取代或被1-5个R1基团取代;
R1选自氢原子、氘原子、卤素、氰基、羟基、氨基、C1-8砜基、C1-8酰胺基、C1-8磺酰胺基、C1-8酯基、C1-8烷基、C3-8环烷基或C1-8烷氧基,所述烷基、环烷基、烷氧基,未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代。
上述的2-炔基甘露糖衍生物中,优选的,U选自未被取代或被1-5个R1基团取代的下列基团,所述R1如上所定义:
上述的2-炔基甘露糖衍生物中,优选的,Z选自氢原子、氘原子、卤素、氰基、C1-10烷基、C3-10环烷基、C1-10烷氧基、6-10元芳环、5-14元含有1-4个选自N、O和S的杂原子的杂芳环、或5-10元含有1-2个选自N、O和S杂原子的杂环,所述烷基、环烷基、烷氧基、芳环、杂芳环、杂环,未被取代或被1-5个R7基团取代;
R7选自氢原子、氘原子、卤素、氰基、羟基、氨基、C2-8烯基、C2-8炔基、C1-8砜基、C1-8酰胺基、C1-8酯基、二甲基氧磷基、C1-8烷基、C3-8环烷基、C1-8烷氧基、苯基、5-6元含有1-4个选自N、O和S的杂原子的杂芳环、或5-7元含有1-2个选自N、O和S杂原子的杂环,所述烯基、炔基、烷基、环烷基、烷氧基、苯基、杂芳环、杂环,未被取代或被1-3个选自氘原子、卤素、羟基、氰基、C1-3烷基、C3-5环烷基、或C1-3烷氧基的取代基取代。
上述的2-炔基甘露糖衍生物中,优选的,Z选自未被取代或被1-5个R7基团取代的下列基团,所述R7如上所定义:
上述的2-炔基甘露糖衍生物中,优选的,Y选自未被取代或被1-3个R4基团取代的下列基团,其中,左侧与X相连接,右侧与Z相连接,所述R4基团如上所定义:
上述的2-炔基甘露糖衍生物中,优选的,该甘露糖衍生物包括:
本发明还提供一种药物组合物,其包括上述的2-炔基甘露糖衍生物,或其药学上可接受的盐,与至少一种药学上可接受的载体或稀释剂组成的组合物。
本发明还提供上述的2-炔基甘露糖衍生物及其药学上可接受的盐,或者上述的药物组合物在制备以下药物中的应用,该药物用于预防或治疗通过抑制FimH功能或活性而改善的疾病或病症。
上述的通过抑制FimH功能或活性而改善的疾病或病症,优选的,选自尿路感染、克罗恩病、或溃疡性结肠炎。
上述各基团的说明如下:
烷基是指1-10个碳原子组成的直链或支链的碳氢烷基。
环烷基是指3-10个碳原子组成单环状、双环状、桥环状和螺环状的碳氢烷基。
烷氧基是指-O-C1-10烷基、-O-C3-10环烷基和-O-C3-10杂环。
烯基是指1-10个碳原子组成的直链或支链,环状,双环状和螺环状的碳氢化合物含有至少一个碳碳双键。
炔基是指1-10个碳原子组成的直链或支链,环状,双环状和螺环状的碳氢化合物含有至少一个碳碳三键。
卤素是指氟,氯,溴和碘。
杂原子是指氮,氧,硫,包括它们的各种氧化态,以及氮的季铵盐等。
芳香环是指苯环,萘环及它们的取代衍生物,也指饱和环与芳环的衍生环状取代基。
杂环是指非芳香性的单环,双环,三环和螺环,其中包括至少一个氮、氧、硫及它们的各种氧化态形式的环状取代基。
芳香杂环是指5-14个原子组成的具有芳香性的环,其中包括至少一个氮、氧和硫及它们的各种氧化态形式的环状取代基,如吡啶酮类化合物;也指饱和环与芳香杂环的衍生环状取代基。
本发明的突出效果为:
本发明的2-炔基甘露糖衍生物,对FimH蛋白的功能/活性具有很好的抑制活性,能够用于预防或治疗通过抑制FimH蛋白功能或活性而改善的疾病或病症。
附图说明
图1是化合物A33的测试结果图;
图2是化合物A41的测试结果图;
图3是化合物A66的测试结果图。
具体实施方式
为了对本发明的技术特征、目的和有益效果有更加清楚的理解,现对本发明的技术方案进行以下详细说明,但不能理解为对本发明的可实施范围的限定。下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
在下述的实施例中,所用溶剂和药品均为分析纯或化学纯;溶剂在使用前均经过重新蒸馏;无水溶剂均按照标准方法或文献方法进行处理。柱层析硅胶(100-200目)和薄层层析硅胶(GF254)为青岛海洋化工厂和烟台化工厂产品;如未特别说明,均采用石油醚(60-90℃)/乙酸乙酯(v/v)作为洗脱剂;显色剂用碘或磷钼酸的乙醇溶液;所有萃取溶剂未经说明均用无水Na2SO4干燥。1HNMR用varian-400型核磁共振仪记录,TMS为内标。LC-MS用美国Agilent公司1100型高效液相色谱-离子阱质谱联用仪(LC-MSDTrap)记录,二极管阵列检测器(DAD),检测波长214nm和254nm,离子阱质谱(ESI源)。HPLC柱为AgelaDurashellC18(4.6×50mm,3.5μm);流动相为0.4%醋酸铵水溶液:甲醇(5分钟内从5:95到95:5);流速为1.8mL/min。
中间体合成1
将4-碘吡唑(1.0eq)溶于无水DMF,碳酸铯(1.5eq)和L-R(1.2eq)加入,升到70℃,反应过夜。待冷却到常温,水加入淬灭,乙醚萃取3次,有机相合并,饱和食盐水洗3次,无水Na2SO4干燥,过滤浓缩。残余物经柱层析纯化得产物。
根据该合成方法,从相应的合成原料L-R合成得到下述中间体:
中间体合成2
N2气氛下,将4-碘-1-甲基-1H-吡唑(1.0eq)溶于无水THF,冷到-78℃,LDA(1.0eq)加入,反应1h。六氯乙烷或碘甲烷(1.3eq)加入,慢慢升到常温,反应1h。饱和氯化铵加入淬灭,乙酸乙酯萃取2次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩。残余物经柱层析纯化得产物。
中间体合成3
将(4-碘-1-甲基-1H-吡唑-5-基)甲醇(714mg,3.0mmol)溶于5mL二氯甲烷,0℃下,三乙胺(606mg,6.0mmol)和甲磺酰氯(515mg,4.5mmol)依次加入,升到常温,反应30min。饱和碳酸氢钠加入,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,得到褐色油状物(620mg,65%)。将所得油状物(620mg,2.0mmol)溶于6mL无水乙腈,碳酸钾(414mg,3.0mmol)和对氰基苯酚(357mg,3.0mmol)依次加入,加热到60℃,反应过夜。冷却到常温,乙酸乙酯加入稀释,饱和碳酸钾洗3次,饱和食盐水洗1次,无水Na2SO4干燥,过滤浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=5:1-3:1),得到白色固体(450mg,66%)。
中间体合成4
将4-(4-碘-1H-吡唑-1-基)环己醇(600mg,2.1mmol)溶于5mL THF,置换氮气,0℃下,氢化钠(60%,123mg,E mmol)加入,常温反应30min。碘甲烷(586mg,4.1mmol)加入,常温反应1h。饱和碳酸氢钠加入淬灭,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,得到黄色固体(620mg,99%)。
中间体合成5
将4-(4-碘-1H-吡唑-1-基)环己醇(600mg,2.1mmol)溶于5mL二氯甲烷,0℃下,三乙胺(0.9mL,6.2mmol)、DMAP(24mg,0.2mmol)和和醋酸酐(314mg,3.1mmol)依次加入,常温反应过夜。饱和碳酸氢钠加入淬灭,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,残余物经柱层析纯化(石油醚:乙酸乙酯=5:1-3:1),得到黄色固体(645mg,92%)。
中间体合成6
将4-碘吡唑(5.82g,30mmol)和环己烯环氧化物(2.94g,30mmol)加热至160℃,反应5h。冷到常温,正己烷50mL加入,加热回流10min。将上清液倒出,冷却,有白色固体析出。将固体滤出,干燥,得白色固体(5.3g,61%)。将所得白色固体(1.5g,5.0mmol)溶于15mL二氯甲烷,0℃下,三乙胺(2.8mL,20mmol)、DMAP(61mg,0.5mmol)和和醋酸酐(1.02g,10mmol)依次加入,常温反应过夜。饱和碳酸氢钠加入淬灭,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=10:1-5:1),得到无色液体(1.5g,90%)。
中间体合成7
将4-碘吡唑(1.0eq)和X-Ar(1.1eq)溶于DMA,碳酸铯(1.1eq)加入,100℃反应至原料消失。冷却到常温,水加入,搅拌30min。抽滤,固体用水洗2次,干燥,得产物。
根据该合成方法,从相应的合成原料X-Ar合成得到下述中间体:
中间体合成8
将肼盐酸盐(1.0eq)和1,1,3,3-四甲氧基丙烷(1.0eq)溶于95%乙醇,70℃反应8h。冷到常温,减压浓缩,饱和碳酸氢钠加入,搅拌30min。乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩。残余物溶于醋酸,NIS(1.2eq)加入,常温反应1-2h。饱和亚硫酸氢钠加入淬灭,水加入,搅拌30min。抽滤,固体用水洗两次,干燥,得产物。
根据该合成方法,从相应的肼盐酸盐合成得到下述中间体:
中间体合成9
将1-(4-氯苯基)-1H-吡唑(178mg,1.0mmol)溶于4mL甲苯和0.2mL水,环丙基硼酸(129mg,1.5mmol)、醋酸钯(11mg,0.05mmol)、三环己基磷氟硼酸盐(37mg,0.1mmol)和磷酸钾(954mg,4.5mmol)依次加入,置换氮气,100℃反应18h。冷到常温,水加入,石油醚萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,得到黄色固体(180mg,粗品)。将所得固体溶于1mL冰醋酸,NIS(286mg,1.3mmol)加入,常温反应1h。饱和亚硫酸氢钠水溶液加入淬灭,水加入,搅拌30min。抽滤,滤饼用水洗两次,干燥,得黄色固体(300mg,97%)。
中间体合成10
氮气气氛下,将1-(4-氟苯基)-1H-吡唑(1.0eq)和相应的醇(1.15eq)溶于DMSO,叔丁醇钾(1.1eq)加入,升到100℃反应3h。冷到常温,水加入淬灭,搅拌30min,有固体析出,抽滤干燥。将所得固体溶于冰醋酸,NIS(1.25eq)加入,常温反应1h。饱和亚硫酸氢钠水溶液加入淬灭,水加入,搅拌30min。抽滤,滤饼用水洗两次,干燥,得产物。
根据该合成方法,从相应的起始原料ROH合成得到下述中间体:
中间体合成11
氮气气氛下,将1-(4-氟苯基)-1H-吡唑(2.43g,15mmol)和(S)-丙叉甘油醇(2.28g,17.3mmol)溶于8mL DMSO,叔丁醇钾(2.0g,16.5mmol)加入,升到90℃反应3h。冷到常温,水加入淬灭,搅拌30min,有固体析出,抽滤干燥,得黄色固体(3.85g,94%)。将所得固体溶于10mL THF,2N HCl(5mL)加入,常温搅拌过夜。用乙酸乙酯稀释,饱和碳酸氢钠洗,饱和氯化钠洗,无水硫酸钠干燥,减压浓缩,得白色固体(2.67g,76%)。将所得固体(2.67g,11.4mmol)溶于20mL吡啶,DMAP(139mg,1.14mmol)和醋酸酐(2.9g,28.5mmol)加入,常温搅拌过夜。饱和食盐水加入淬灭,搅拌15min。乙酸乙酯萃取3次,有机相合并,1N HCl洗两次,饱和碳酸氢钠洗,饱和食盐水洗,无水硫酸钠干燥,减压浓缩。将所得黄色液体溶于5mL醋酸,NIS(2.7g,11.8mmol)加入,常温反应1h。饱和亚硫酸氢钠水溶液加入淬灭,水加入,搅拌30min。抽滤,滤饼用水洗两次,干燥,得黄色固体(4.83g,96%)。
中间体合成12
将4-碘吡唑(3.88g,20mmol)和(R)-3-氯-1,2-丙二醇(3.32g,30mmol)溶于60mL乙腈,碳酸钾(5.52g,40mmol)和碘化钾(1.66g,10mmol)加入,加热回流过夜。冷到常温,乙酸乙酯加入,抽滤,滤饼用乙酸乙酯洗2次。滤液合并,无水硫酸钠干燥,减压浓缩。将所得油状物溶于50mL二氯甲烷,三乙胺(10g,100mmol)和DMAP(224mg,2.0mmol)加入,冷到0℃。醋酸酐(8.2g,80mmol)加入,升到常温,搅拌过夜。饱和碳酸氢钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,经柱层析纯化(石油醚:乙酸乙酯=5:1-3:1),得到淡黄色油状物(6.6g,94%)。
中间体合成13
将3-碘苯磺酸(2.84mg,10mmol)溶于20mL二氯甲烷,DMF(15mg,0.2mmol)加入。置换氮气,加热至45℃,草酰氯(1.59g,12.5mmol)逐滴加入,于45℃反应2.5h。冷却到0℃,水9mL加入淬灭,乙酸乙酯萃取。有机相用水洗至pH=4-5,饱和碳酸钾洗3次,无水硫酸钠干燥,减压浓缩,得黄色液体(2.6g,86%)。DIPEA(2.2mL,12mmol)和苯酚(846mg,9.0mmol)的20mL二氯甲烷溶液预搅拌10min,加入上述黄色液体(2.6g)的二氯甲烷溶液30mL加入,常温搅拌至原料消失。1N HCl加入淬灭,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,得到黄色油状物(3.1g,100%)。
中间体合成14
将卤代芳烃(1.0eq)溶于MeCN,醋酸钯(0.025eq)、CuI(0.04eq)、PPh3(0.1eq)和二异丙胺(1.5eq)加入,置换氮气,常温下加入三甲基硅基乙炔(1.4eq),升到80℃反应至原料消失。冷却到常温,乙酸乙酯加入稀释,抽滤,滤饼用乙酸乙酯洗1次。滤液合并,减压浓缩。残余物经柱层析纯化,得产物。
根据该合成方法,从相应的合成原料I-Ar合成得到下述中间体:
根据该合成方法,从相应的合成原料Br-Ar合成得到下述中间体:
中间体合成15
将4-碘-1-(4-三氟甲氧基苯基)-1H-吡唑(390mg,1.1mmol)、三甲基硅基乙炔(220mg,2.2mmol)、二三苯基磷二氯化钯(39mg,0.055mmol)、CuI(11mg,0.055mmol)和二异丙胺(0.46mL,3.3mmol)分散于5mL DMF,氮气气氛下,微波120℃反应1h。冷却到常温,乙醚加入稀释,水洗2次,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩。残余物经柱层析(石油醚:乙酸乙酯=20:1-10:1)纯化,得褐色固体(290mg,81%)。
中间体合成16
将三甲基硅基炔(1.0eq)和醋酸(1.2eq)溶于5mL THF,置换氮气,0℃下,TBAF的1MTHF溶液(1.2eq)加入,升到常温,反应2h。饱和碳酸氢钠加入淬灭,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗3次,无水Na2SO4干燥,过滤浓缩,得到产物。
根据该合成方法,从相应的合成原料合成得到下述中间体:
中间体合成17
将CBr4(3.87g,11.6mmol)溶于50mL二氯甲烷,0℃下,PPh3(6.0g,23.2mmol)加入,再加入3-环丙基苯甲醛(1.7g,11.6mmol)的50mL二氯甲烷溶液,升到常温,反应2h。甲醇加入淬灭,减压浓缩。残余物用石油醚稀释,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,经柱层析纯化(石油醚),得到黄色油状物(2.8g,80%)。将所得油状物(1.4g,4.6mmol)溶于5mL无水THF,置换氮气,-78℃下,丁基锂(2.5M THF溶液,4mL,10mmol)逐滴加入,反应30min。饱和氯化铵淬灭,乙醚萃取3次。有机相合并,饱和食盐水洗1次,无水Na2SO4干燥,过滤浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=1:0-20:1),得到淡黄油状物(620mg,95%)。
实施例1
1)中间体A1-2的合成:
将化合物A1-1(2.8g,7mmol,合成文献见S.Dharuman等人Org.Lett.2014,16,1172–1175.),4-溴-2-甲基苯酚(1.3g,7mmol)溶于6mL无水甲苯,三氟化硼乙醚(200mg,1.4mmol)加入,常温搅拌过夜。饱和NaHCO3加入淬灭,用乙酸乙酯萃取3次。合并有机相,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,残余物经柱层析纯化(石油醚:乙酸乙酯=10:1-5:1),得到黄色油状物(1.2g,34%)。
2)中间体A1-3的合成:
将A1-2(280mg,0.56mmol),苯乙炔(88mg,0.84mmol),醋酸钯(4.8mg,0.02mmol),碳酸铯(272mg,0.84mmol)分散于无水DMF(1.5mL),氮气置换,常温搅拌过夜。饱和NaHCO3加入淬灭,乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗3次。有机相用无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=10:1),得到黄色油状物(200mg,72%)。
3)中间体A1-4的合成:
将A1-3(200mg,0.42mmol)溶于乙酸乙酯/乙腈(4mL/4mL),0℃下加入新配的NaIO4(135mg,0.63mmol)和三氯化钌一水合物(7mg,0.034mmol)溶于1.4mL水的溶液,0℃反应5min。饱和硫代硫酸钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,经无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=3:1-1:1),得到黄色油状物(110mg,52%)。
4)产物A1的合成:
将中间体A1-4(110mg,0.22mmol),A1-5(86mg,0.33mmol,合成文献见WO2017156508)溶于二氧六环/水(1mL/0.2mL),加入碳酸钾(91mg,0.66mmol),Pd(dppf)Cl2(7mg,0.01mmol),氮气置换,100℃搅拌过夜。冷却到常温,2N NaOH水溶液(0.5mL)加入,常温搅拌2h。经biotage反相快速制备色谱纯化,得到黄色固体(20mg,18%)。
实施例2
采用与实施例1类似的合成方法,在第二步用环丙乙炔或4-乙炔基-N-甲基吡唑代替苯乙炔,合成得到化合物A2和A3。
实施例3
1)中间体A6-1的合成:
将化合物A1-1(199mg,0.5mmol)和异丙醇(36mg,0.6mmol)溶于2mL无水甲苯。-15℃下,三氟化硼乙醚(142mg,1.0mmol)逐滴加入,加完升到常温反应2h。饱和NaHCO3加入淬灭,用乙酸乙酯萃取3次。合并有机相,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩,残余物经柱层析纯化(石油醚:乙酸乙酯=10:1-5:1),得到黄色油状物(90mg,45%)。
2)中间体A6-2的合成:
将A6-1(90mg,0.23mmol),苯乙炔(28mg,0.28mmol),醋酸钯(2.7mg,0.012mmol),碳酸铯(113mg,0.35mmol)分散于无水DMF(1mL),氮气置换,常温搅拌1h。饱和NaHCO3加入淬灭,乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗3次。有机相用无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=10:1),得到黄色油状物(80mg,94%)。
3)产物A6的合成:
将A6-2(80mg,0.22mmol)溶于乙酸乙酯/乙腈(2mL/2mL),0℃下加入新配的NaIO4(71mg,0.33mmol)和三氯化钌一水合物(3.5mg,0.017mmol)溶于0.7mL水的溶液,0℃反应5min。饱和硫代硫酸钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,减压浓缩。残余物溶于1mL甲醇,碳酸钾(10mg,0.07mmol)加入,常温搅拌过夜。减压浓缩,经柱层析纯化(石油醚:乙酸乙酯=1:1-乙酸乙酯-乙酸乙酯:甲醇=10:1)得淡黄色固体(20mg,26%)。
实施例4
采用与实施例3类似的合成方法,在第一步用相应的醇或酚代替异丙醇,在第二步用相应的炔代替苯乙炔,合成得到化合物A4、A5、A7-A9、A11-A13和A56-A58。
实施例5
1)中间体A14-1的合成:
将化合物A1-1(199mg,0.5mmol)和双三甲基硅基乙炔(0.24mL,1.0mmol)溶于4mL无水二氯甲烷,-25℃下,四氯化锡(0.09mL,0.75mmol)加入,加完升到-15℃反应2h。饱和NaHCO3(6mL)和水(6mL)加入淬灭,常温搅拌1h。乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=10:1-5:1),得到淡红色油状物(200mg,90%)。
2)中间体A14-2的合成:
将A14-1(1.0g,2.3mmol),苯乙炔(286mg,2.8mmol),醋酸钯(27mg,0.12mmol),碳酸钾(483mg,3.5mmol)分散于无水DMA(10mL),氮气置换,常温搅拌过夜。饱和NaHCO3加入淬灭,乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗3次。有机相用无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=10:1),得到黄色油状物(566mg,60%)。
3)产物A14的合成:
将A14-2(150mg,0.36mmol)溶于乙酸乙酯/乙腈(3mL/3mL),0℃下加入新配的NaIO4(117mg,0.55mmol)和三氯化钌一水合物(6mg,0.03mmol)溶于1.2mL水的溶液,0℃反应5min。饱和硫代硫酸钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,减压浓缩。残余物溶于1mL甲醇,碳酸钾(10mg,0.07mmol)加入,常温搅拌过夜。减压浓缩,经柱层析纯化(石油醚:乙酸乙酯=1:1-乙酸乙酯-乙酸乙酯:甲醇=10:1)得淡黄色固体(12mg,12%)
实施例6
1)中间体A15-1的合成:
将化合物A1-1(300mg,0.75mmol)和三甲硅基丙炔(101mg,0.9mmol)溶于5mL无水1,2-二氯乙烷,常温下,TMSOTf(100mg,0.45mmol)溶于1mL 1,2-二氯乙烷逐滴加入,加完于80℃反应30min。待冷到常温,三乙胺加入淬灭,减压浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=10:1-7:1),得到黄色油状物(260mg,92%)。
2)中间体A15-2的合成:
将A15-1(260mg,0.69mmol),苯乙炔(85mg,0.83mmol),醋酸钯(8mg,0.035mmol),碳酸钾(143mg,1.04mmol)分散于无水DMF(2mL),氮气置换,常温搅拌过夜。饱和NaHCO3加入淬灭,乙醚萃取3次,合并有机相,用饱和食盐水洗3次。有机相用无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=10:1),得到黄色油状物(210mg,86%)。3)产物A15的合成:
将A15-2(210mg,0.60mmol)溶于乙酸乙酯/乙腈(5mL/5mL),0℃下加入新配的NaIO4(193mg,0.9mmol)和三氯化钌一水合物(10mg,0.047mmol)溶于2mL水的溶液,0℃反应5min。饱和硫代硫酸钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,减压浓缩。残余物溶于1mL甲醇,碳酸钾(10mg,0.07mmol)加入,常温搅拌过夜。减压浓缩,经柱层析纯化(石油醚:乙酸乙酯=1:1-乙酸乙酯-乙酸乙酯:甲醇=10:1)得淡黄色固体(30mg,17%)。
实施例7
采用与实施例6类似的合成方法,在第一步用相应的三甲基硅基炔代替三甲硅基丙炔,在第二步用相应的炔代替苯乙炔,合成得到化合物A10、A17-A55、A59-A68、A70-A75、A78-A85、A87、A88、A90和A92-A107。
实施例8
1)中间体A16-1的合成:
将化合物A1-1(800mg,2.0mmol)和环丙乙炔基氟硼酸钾(413mg,2.4mmol)溶于6mL无水乙腈,0℃下,三氟化硼乙醚(341mg,2.4mmol)逐滴加入,加完升至常温反应1h。饱和NaHCO3加入淬灭,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗,无水Na2SO4干燥,过滤浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=10:1-5:1),得到无色油状物(660mg,82%)。
2)中间体A16-2的合成:
将A16-1(202mg,0.5mmol),苯乙炔(61mg,0.6mmol),醋酸钯(6mg,0.025mmol),碳酸铯(245mg,0.75mmol)分散于无水DMF(2.5mL),氮气置换,常温搅拌3h。饱和NaHCO3加入淬灭,乙醚萃取3次,合并有机相,用饱和食盐水洗3次。有机相用无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=10:1-5:1),得到黄色油状物(133mg,70%)。
3)产物A16的合成:
将A16-2(133mg,0.35mmol)溶于乙酸乙酯/乙腈(3.5mL/3.5mL),0℃下加入新配的NaIO4(75mg,0.35mmol)和三氯化钌一水合物(3mg,0.015mmol)溶于1mL水的溶液,0℃反应5min。TLC检测大部分原料未反应,再补加新配的NaIO4(75mg,0.35mmol)和三氯化钌一水合物(3mg,0.015mmol)溶于1mL水的溶液,再反应5min。饱和硫代硫酸钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,减压浓缩。残余物溶于1mL甲醇,碳酸钾(10mg,0.07mmol)加入,常温搅拌过夜。减压浓缩,经柱层析纯化(石油醚:乙酸乙酯=1:1-乙酸乙酯-乙酸乙酯:甲醇=10:1)得淡黄色液体(30mg,26%)。
实施例9
1)中间体A77-2的合成:
将化合物A1-1(2.75g,6.9mmol)和A77-1(2.52g,8.3mmol)溶于30mL无水1,2-二氯乙烷,常温下,TMSOTf(921mg,4.2mmol)溶于3mL 1,2-二氯乙烷逐滴加入,加完于80℃反应30min。待冷到常温,三乙胺加入淬灭,减压浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=5:1-3:1),得到黄色油状物(1.5g,38%)。
2)中间体A77-3的合成:
将A77-2(443mg,0.78mmol),苯乙炔(120mg,1.2mmol),醋酸钯(9mg,0.04mmol),碳酸钾(161mg,1.2mmol)分散于2mL无水DMA,氮气置换,常温搅拌过夜。饱和NaHCO3加入淬灭,乙醚萃取3次,合并有机相,用饱和食盐水洗3次。有机相用无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=5:1-3:1),得到褐色油状物(260mg,61%)。
3)产物A77的合成:
将A77-3(260mg,0.48mmol)溶于乙酸乙酯/乙腈(9mL/9mL),0℃下加入新配的NaIO4(205mg,0.96mmol)和三氯化钌一水合物(9mg,0.045mmol)的3mL水溶液,0℃反应10min。饱和硫代硫酸钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,减压浓缩。残余物溶于1mL甲醇,碳酸钾(10mg,0.07mmol)加入,常温搅拌过夜。减压浓缩,经反相快速制备色谱仪纯化(H2O/MeOH=5%-95%),得淡黄色固体(20mg,9%)。
实施例10
采用与实施例9类似的合成方法,在第一步用相应的三甲基硅基炔代替A77-1,在第二步用相应的炔代替苯乙炔,合成得到化合物A69和A76。
实施例11
1)中间体A89-2的合成:
将化合物A1-1(4.3g,10.8mmol)和A89-1(4.5g,10.8mmol)溶于30mL无水1,2-二氯乙烷,常温下,TMSOTf(1.44g,6.5mmol)溶于3mL 1,2-二氯乙烷逐滴加入,加完于80℃反应30min。待冷到常温,三乙胺加入淬灭,减压浓缩。残余物经柱层析纯化(石油醚:乙酸乙酯=5:1-2:1),得到褐色油状物(2.5g,34%)。
2)中间体A89-4的合成:
将A89-2(340mg,0.5mmol),A89-3(155mg,0.6mmol),醋酸钯(6mg,0.025mmol),碳酸钾(104mg,0.75mmol)分散于1.5mL无水DMF,氮气置换,常温搅拌过夜。饱和NaHCO3加入淬灭,乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗5次。有机相用无水硫酸钠干燥,过滤浓缩。剩余物经柱层析纯化(石油醚:乙酸乙酯=3:1-1:1),得到褐色油状物(360mg,89%)。
3)产物A89的合成:
将A89-4(360mg,0.44mmol)溶于乙酸乙酯/乙腈(8mL/8mL),0℃下加入新配的NaIO4(94mg,0.44mmol)和三氯化钌一水合物(4.6mg,0.022mmol)的1.5mL水溶液,0℃反应10min,再补加新配的NaIO4(47mg,0.22mmol)和三氯化钌一水合物(2.3mg,0.011mmol)的0.75mL水溶液,再反应10min。饱和硫代硫酸钠加入淬灭,乙酸乙酯萃取3次。有机相合并,饱和食盐水洗,减压浓缩。残余物溶于1mL THF,3N氢氧化钠水溶液(1.4mL,4.2mmol)加入,70℃搅拌过夜。冷到常温,2N HCl(2.2mL,4.4mmol)加入,经反相快速制备色谱仪纯化(H2O/MeOH=5%-95%),得淡黄色固体(15mg,6%)。
实施例12
表1.实施例1-12合成得到的2-炔基甘露糖衍生物A1-A107的解析结构和波谱数据
实施例13
本实施例对实施例1-12制备得到的甘露糖衍生物A1-A107进行对血凝抑制(Hemagglutination Inhibition,HAI)测试,测定对化合物对FimH蛋白功能/活性的抑制能力。
1.豚鼠红细胞溶液配制:用乙醚麻醉血成年豚鼠,心脏取血,装入EDTA采血管,2000rpm离心5min,弃去血清,转入15mL离心管,加入灭菌后PBS,1500rpm离心10min,弃去上清,转入50ml离心管,加入PBS,1500rpm离心10min,重复清洗步骤2次,轻轻吸取红细胞转移入新的50mL离心管,配置成5%豚鼠红细胞。
2.菌液配制:将UPEC菌株UTI89接种于培养基平板于37℃培养箱过夜。挑取单菌落接种于灭菌锥形瓶的LB培养液,37℃,170r/min过夜培养。酶标仪测540nm时候的OD约0.8时,细菌浓度约108~109cfu/mL,将菌液2000rpm离心10min,弃去上清,按照1mL菌液配成0.1mL PBS菌液。取50μL PBS菌液加入96孔V型培养板第一孔,第2-12孔加入25μLPBS,第一孔混合后吸出25μl加入第2孔中,对比稀释菌液,依次稀释至第12孔,弃去25μL,留最后一排后为阴性对照,不加细菌,只加红细胞。振荡混匀,置于25℃温箱反应20-40分钟左右,读数时,以出现完全凝集的孔作为细菌的血凝滴度4HAU。例如,如果血凝的终点滴度为1∶256,则4HAU抗原的稀释倍数应是1∶64(256除以4)。根据实验结果配制成相应浓度菌液。
3.活性测定:将待测化合物或标准品加入96孔微量培养板中,第一孔药物的初始浓度为200μM,50μL,第2开始每孔加入25μL PBS,对比稀释药物,第一孔混合后吸出25μL加入第2孔中,依次稀释至最后一孔,弃去25μL。把菌液加入稀释好的药物的培养板中,每孔25μL,37℃培养40min。每孔加入25μL的5%豚鼠红细胞悬液轻轻混匀,4℃静置约1h。判定结果时,将反应板倾斜60°,观察红细胞有无泪珠状流淌。
豚鼠红细胞表面表达有甘露糖基蛋白,可以与UTI89的FimH蛋白结合,引起血凝反应,肉眼表现为红细胞于孔底形成薄膜状凝集,中央可见疏松的红点。而FimH抑制剂与FimH蛋白竞争性结合,抑制血凝反应,肉眼表现为红细胞全部下沉,集中于孔底,形成致密的圆点。抑制血凝反应的最低浓度为该化合物的EC90值。第一孔的化合物最终浓度为66700nM,第二孔浓度为第一孔的一半,第三孔浓度则为第二孔的一半,依次类推。以化合物A33、A41和A66为例,A33和A41抑制血凝反应的最低浓度均为第14孔(图1和图2),对应的EC90值为8nM;A66抑制血凝反应的最低浓度均为第20孔(图3),对应的EC90值为0.13nM。EC90值越低,代表该化合物的活性越高。化合物A1-A107的HAI测试结果如表2所示。
表2.2-炔基甘露糖衍生物A1-A107的HAI测试结果
由上表2可见,本发明中的甘露糖衍生物,能够有效抑制FimH蛋白的功能/活性,能够用于治疗或预防通过抑制FimH功能或活性而改善的疾病或病症。
Claims (4)
1.一种2-炔基甘露糖衍生物或其药学上可接受的盐,所述2-炔基甘露糖衍生物具有通式I所示的结构:
其中,
U选自未被取代或被1-5个R1基团取代的下列基团:
X为氧原子或--C≡C--;
Y为化学键或选自未被取代或被1-3个R4基团取代的下列基团,其中,左侧与X相连接,右侧与Z相连接:
Z选自未被取代或被1-5个R7基团取代的下列基团:
R1选自卤素、C1-8砜基、C1-8烷基、C3-8环烷基或C1-8烷氧基,所述烷基、环烷基和烷氧基未被取代或被1-3个选自羟基的取代基取代;
R4选自卤素、C1-8烷基或C1-8烷氧基,所述烷基和烷氧基未被取代或被1-3个选自卤素的取代基取代;
R7选自卤素、氰基、羟基、C1-8酰胺基、C1-8烷基、C3-8环烷基、C1-8烷氧基或苯基,所述烷基、环烷基、烷氧基和苯基未被取代或被1-3个选自氘原子、卤素、羟基、C3-5环烷基或C1-3烷氧基的取代基取代。
3.一种药物组合物,其包括根据权利要求1或2所述的2-炔基甘露糖衍生物或其药学上可接受的盐与至少一种药学上可接受的载体或稀释剂组成的组合物。
4.根据权利要求1或2所述的2-炔基甘露糖衍生物或其药学上可接受的盐或根据权利要求3所述的药物组合物在制备以下药物中的应用,该药物用于预防或治疗通过抑制FimH蛋白功能或活性而改善的疾病或病症,所述疾病或病症为尿路感染、克罗恩病或溃疡性结肠炎。
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