CN116323560A - 作为胆汁酸受体和白三烯半胱氨酰受体的选择性和/或双重调节剂的喹啉化合物 - Google Patents
作为胆汁酸受体和白三烯半胱氨酰受体的选择性和/或双重调节剂的喹啉化合物 Download PDFInfo
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- CN116323560A CN116323560A CN202180068308.8A CN202180068308A CN116323560A CN 116323560 A CN116323560 A CN 116323560A CN 202180068308 A CN202180068308 A CN 202180068308A CN 116323560 A CN116323560 A CN 116323560A
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Abstract
本发明涉及式(I)的化合物、其药物组合物和用途,特别涉及治疗和/或预防由胆汁酸受体(FXR和GPBAR1)和半胱氨酰白三烯受体(CysLTR)介导的疾病。
Description
相关申请的交叉引用
本专利申请要求2020年8月4日提交、申请号为102020000019210的意大利专利申请的优先权,其全部公开内容通过引用并入文本。
技术领域
本发明涉及喹啉衍生物及其可以同时调节胆汁酸受体(FXR和GPBAR1)和半胱氨酰白三烯受体(CysLTR)的用途,及其用于治疗和/或预防由后者介导的疾病的用途。
背景技术
识别能够同时作用于多个靶点的小分子的策略被广泛认为可用于识别针对诸如慢性炎症性病症(包括非酒精性脂肪性肝炎、高度流行的炎症性肝脏疾病、代谢综合症和癌症)的多因素疾病的新型药理学方法。
本研究始于我们最近的观察,REV5901(一种半胱氨酰-白三烯受体拮抗剂)能够在肠道炎症的动物模型中调节GPBAR1而具有令人感兴趣的抗炎活性,并且Zafirlukast(一种众所周知的CysLT受体拮抗剂)具有针对FXR的微弱活性(S.Schierle等人.Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology,J Med Chem61(13)(2018)5758-5764)。
白三烯是脂质调节剂的一大家族,其从花生四烯酸通过酶促级联产生并作为炎症的调节剂发挥功能。在白三烯中,半胱氨酰白三烯(CysLT)包括LTC4、LTD4和LTE4,其通过结合至表达于许多促炎性细胞(例如中性粒细胞和嗜酸性粒细胞、肥大细胞和单核/巨噬细胞)的G蛋白相关的跨膜蛋白质家族(CysLTR)而作用于细胞。这些受体通过内源性脂质调节剂的活化在导致微血管通透性、白细胞转运、趋化因子和细胞因子的分泌和组织修复(纤维化)的炎症性反应中发挥重要作用。众所周知的是半胱氨酰白三烯受体介导支气管收缩、肺粘液分泌和水肿,并且由此它们的拮抗剂在治疗哮喘和更普遍地在针对肺部病症的药理学方法中是经过验证的有效药物。半胱氨酰白三烯涉及许多其它疾病,例如心血管病症、癌症、特应性皮炎、类风湿关节炎、克罗恩疾病,还涉及暴发性肝炎的发病机制以及肝脏胆汁淤积、纤维化和肝硬化(Capra V.等人.Cysteinyl-leukotrienes and their receptorsin asthma and other inflammatory diseases:critical update and emergingtrends.(Med Res Rev.2007Jul;27(4):469-527)。
在肝肠组织(肝脏和肠)中高度表达的FXR调控胆汁酸稳态和一些代谢途径,包括脂质代谢和葡萄糖代谢。FXR激动剂已被证明可用于针对代谢性病症(例如胆汁淤积、2型糖尿病、肝脏纤维化和非酒精性脂肪肝综合征(NAFLD)的药理学方法。此外,FXR在肾脏、心血管系统和肿瘤生成中发挥重要作用(Renga等人.PHASEB J.2012,26,3021-3031)。
GPBAR1在肝脏和肠中高表达,在肌肉、脂肪组织、巨噬细胞和内皮细胞中也高表达。在肌肉和棕色脂肪组织中,GPBAR1增加能量支出和氧消耗(Watanabe等人.Nature of2006,439,484)。在肠内分泌L细胞中,GPBAR1活化会刺激胰高血糖素样肽(GLP-1)的分泌,从而调控血糖水平、胃肠运动和食欲(Thomas等人.Cell.Metab.2009,10,167)。
GPBAR1似乎与炎症性过程和免疫功能的调控相关联。许多先天免疫细胞例如单核细胞、巨噬细胞、NKT细胞和树突状细胞都表达这种受体,并且这种受体中的突变与发展出原发性硬化性胆管炎和溃疡性结肠炎的风险增加相关。
发明目的
本发明的目的是识别出能够选择性或同时调节胆汁酸受体(FXR和GPBAR1)和半胱氨酰白三烯受体(CysLTR)的新化合物。
这样的目的通过本发明中有关根据权利要求1的式(I)的化合物、有关根据权利要求8和9的它们的用途、有关根据权利要求10的其组合物得以实现。优选的实施方式在从属权利要求中指出。
附图的简要说明
现在将参照附图中的图对本发明进行详细描述,其中:
-图1显示了用对乙酰氨基酚诱导急性肝炎并随后用CHIN117治疗的小鼠的AST值。
-图2显示了用对乙酰氨基酚诱导急性肝炎并随后用CHIN117治疗的小鼠的ALT值。
-图3显示了用对乙酰氨基酚诱导急性肝炎并随后用CHIN117治疗的小鼠的白细胞(WBC)值。
-图4显示了在模拟NAFLD的小鼠模型中CHIN117施用的结果:(A)每周评估体重的变化(%);(B)体重的曲线下面积(AUC);(C)棕色脂肪组织温度(BAT)(℃);(D)响应于经口葡萄糖耐量试验(OGTT)的葡萄糖水平;(E)OGTT的AUC;(G)AST(U/L)和ALT(U/L)的血浆水平;(H)胆固醇、甘油三酯、高密度脂蛋白(HDL)和低密度脂蛋白(LDL)的血浆水平(mg/100mL)。结果是每组8-12只小鼠的平均值±SEM。*p≤0.05。
-图5显示了在饲喂HFD-F饮食持续8周的C57BL/6小鼠模型中CHIN117施用的结果:(A)对小鼠肝脏组织的苏木精和伊红(H&E)染色(4x-10x)。通过计算以下来评估疾病严重程度:(B)脂肪变性评分(NAS);(C)体重指数(BMI);(D)eWAT重量;(E)eWAT重量/体重的比率;(F)BAT重量(g);(G)BAT重量/体重的比率;(H)肝脏重量;(I)肝脏重量/体重的比率。结果是每组8-12只小鼠的平均值±SEM。*p≤0.05。
具体实施方式
本发明的优选实施方式
以下段落提供了根据本发明的化合物的化学特征,并意图统一应用于整个说明书和所有权利要求,除非另外明确陈述提供更广泛定义的定义。
如本文所用,术语“烷基”是指饱和脂肪族碳氢化合物。该术语包括直(非支化)链或支链。
根据本发明的烷基基团的非限制性实例是,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基等。
如本文所用,术语“羟烷基”是指其中一个或多个氢原子被羟基基团取代的饱和脂肪族碳水化合物。
除非另外说明,如本文所用,术语“取代的”意味着上述基团的一个或多个氢原子被另外的非氢原子或官能团替换,前提是正常的价电子保持不变而且取代产生稳定化合物。
有机化学领域的技术人员将会理解许多有机化合物可以与它们在其中反应、沉淀或结晶的溶剂形成复合物。这些复合物被称为“溶剂合物”。例如,与水的复合物被称为“水合物”。本发明化合物的溶剂合物属于本发明的范围。通过结晶或蒸发合适的溶剂,可以容易地分离出与溶剂分子缔合的式(I)或(Ia)的化合物以提供相应的溶剂合物。
式(I)或(Ia)的化合物可以是结晶形式。在一些实施方式中,式(I)或(Ia)的化合物的结晶形式是多晶型的。
本发明还包括同位素标记的化合物,这些同位素标记的化合物与那些式(I)或(Ia)中给出的化合物相同,但不同之处在于一个或多个原子被原子质量或质量数与通常在自然界中发现的原子质量或质量数不同的原子替换。可以被掺入本发明化合物中的同位素的实例包括氢、碳、氮和氧的同位素,例如2H、3H、11C、13C、14C、15N、17O。
含有上述同位素和/或其它原子的其它同位素的本发明化合物属于本发明的保护范围。本发明的同位素标记的化合物,例如其中掺入放射性同位素例如3H和14C的那些,可用于测定药物和/或底物的组织分布。氚化同位素,即3H,和碳-14,即14C,由于它们易于制备和可检测性而是特别优选的。同位素11C特别可用于PET(正电子发射断层扫描)。此外,用较重的同位素(例如氘,即2H)的取代可以提供由代谢稳定性增加(例如体内半衰期增加或给药需求降低)而产生的某些治疗优势,并且因此在某些情况下可能会被提及。通过进行以下示意图和/或实施例中描述的过程(用容易获得的同位素标记的反应物取代非同位素标记的反应物)通常可以制备本发明的同位素标记的式(I)或(Ia)的化合物。
本发明中包括的一些基团/取代基可以作为异构体存在。因此,在一些实施方式中,式(I)或(Ia)的化合物可以具有轴不对称性,且相应地,可以以光学异构体的形式存在,例如形式(R)、形式构型(S)等。本发明在保护范围内包括所有这些异构体,包括外消旋体、对映(异构)体及其混合物。
特别地,本发明的保护范围包括所有立体异构形式,包括对映(异构)体、非对映异构体及其混合物,包括外消旋体,并且除非另有说明,一般提及的式(I)或(Ia)的化合物包括所有立体异构形式。
一般来说,本发明化合物应被认为不包括那些本身或在水中化学性质非常不稳定的化合物(如果有的话),这些化合物显然不适合所有施用途径的制药用途,无论它是不是经口、肠胃外或其它方式。这样的化合物是熟练化学家已知的。
最后,式(I)或(Ia)的化合物可以形成盐。特别地,喹啉环能够形成盐酸盐,而酚残基或COOH基团形成金属盐。
根据本发明的第一方面,提供式(I)的化合物或其药学上可接受的盐或溶剂合物:
其中:
R1选自由以下组成的组:H、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有一个取代基R8的直链或支链O-C3-6烷基;
R2选自由以下组成的组:H、C1-6羟烷基、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基;
R3选自由以下组成的组:H、COOH、COO-C1-6烷基、CH2OH;
条件是:
-当R2是H,R1或R3不是H;或者
-当R1是任选取代有一个取代基R8的直链O-C3-6烷基,R2和R3之间的至少一者不是H;
R4选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R5选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R6选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基、OH和任选取代有一个取代基R8的直链或支链C1-6烷氧基;
条件是当R4、R5和R6之间的一者是COOH或CH2OH时,R4、R5和R6之间余下者中的至少一者不是H,
R7选自由以下组成的组:
R8选自由以下组成的组:OH、COOH、COO-C1-6烷基;
R9选自由以下组成的组:
其中R10选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R11选自由以下组成的组:H、OH、COOH、COO-C1-6烷基、C1-6羟烷基;
并且R12选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
不包括以下化合物
在第一实施方式中,R1选自由以下组成的组:H、O-异丙基、O-正丙基、O-正丁基、O-仲丁基、O-正戊基、O-2-甲基丁基、-CH2-R7、-O-(CH2)3-4-R8。
在一个实施方式中,R2是任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基。
在另一实施方式中,R2选自由以下组成的组:H、CH2OH、取代有两个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基、-CH2-R9。
在第三实施方式中,
R3选自由以下组成的组:H、COOH、COOCH3、CH2OH;
R4选自由以下组成的组:H、COOH、COOCH3、CH2OH;和
R5选自由以下组成的组:H、COOH、COOCH3、CH2OH。
在另一实施方式中,式(I)的化合物选自由以下组成的组:
优选地,式(I)的化合物选自由以下组成的组:
本发明的第二方面涉及一种药物组合物,包含式(Ia)的化合物或其药学上可接受的盐或溶剂合物和至少一种药学上可接受的辅料。(Ia)式的化合物具有下式:
其中:
R1选自由以下组成的组:H、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有一个取代基R8的直链或支链O-C3-6烷基;
R2选自由以下组成的组:H、C1-6羟烷基、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基;
R3选自由以下组成的组:H、COOH、COO-C1-6烷基、CH2OH;
条件是:
-当R2是H,R1或R3不是H;或者
-当R1是任选取代有一个取代基R8的直链O-C3-6烷基,R2和R3之间的至少一者不是H;
R4选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R5选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R6选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基、OH和任选取代有一个取代基R8的直链或支链C1-6烷氧基;
条件是当R4、R5和R6之间的一者是COOH或CH2OH时,R4、R5和R6之间余下者中的至少一者不是H,
R7选自由以下组成的组:
R8选自由以下组成的组:OH、COOH、COO-C1-6烷基;
R9选自由以下组成的组:
其中R10选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R11选自由以下组成的组:H、OH、COOH、COO-C1-6烷基、C1-6羟烷基;
并且R12选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基。
在一个实施方式中,R1选自由以下组成的组:H、O-异丙基、O-正丙基、O-仲丁基、O-正戊基、O-2-甲基丁基、-CH2-R7、-O-(CH2)3-4-R8。
在一个实施方式中,R2是任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基。
在一个实施方式中,R2选自由以下组成的组:H、CH2OH、取代有两个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基、-CH2-R9。
在一个实施方式中,
R3选自由以下组成的组:H、COOH、COOCH3、CH2OH;
R4选自由以下组成的组:H、COOH、COOCH3、CH2OH;和
R5选自由以下组成的组:H、COOH、COOCH3、CH2OH。
在一个实施方式中,式(Ia)的化合物选自由以下组成的组:
优选地,式(Ia)的化合物选自由以下组成的组:
本领域技术人员知晓适用于配制药物组合物的全部各种这样的辅料化合物。
式(Ia)的化合物与常规采用的辅料一起可以被包含在药物组合物及其剂量单元中并且以使得可以用作固体(例如片剂或填充胶囊剂)或液体(例如溶液剂、混悬剂、乳剂、酏剂或填充有式(Ia)的化合物与常规采用的辅料一起的胶囊剂)的形式,所有都用于经口使用或作为无菌可注射溶液剂用于肠胃外施用(包括皮下和静脉使用)。
这样的药物组合物及其单位剂量形式可以包含以常规百分比的成分,具有或不具有另外的化合物或活性成分,并且这样的单位剂量形式可以包含与待采用的预期日剂量范围相称的任何适当有效量的活性成分。
含有本发明化合物的药物组合物可以以制药领域中众所周知的方式制备,并包含至少一种活性化合物。一般来说,本发明的化合物是按药学有效量施用的。实际施用的化合物的量将通常由医生确定,考虑包括待治疗的病况,选择的施用途径,施用的实际化合物,单个患者的年龄、体重和反应,患者症状的严重程度等在内的相关情况。
本发明的药物组合物可以通过多种途径施用,包括经口、直肠、皮下、静脉内、肌肉内、经鼻腔和肺部途径。用于经口施用的组合物可以采取散装或散装粉末的液体溶液剂或混悬剂的形式。然而,更常见地,组合物以单位剂量形式存在以促进精确配药(dose)。“单位剂量形式”的表达是指适合作为用于人类和其它哺乳动物受试者的单位剂量的物理上离散单元,每个单元含有与药学上可接受的辅料联合的经计算产生所需治疗作用的预定量的活性物质。典型的单位剂量形式包括液体组合物的预填充、预配药的安瓿或注射器,或固体组合物情况下的丸剂、片剂、胶囊剂或类似的剂型。
适合于经口施用的液体形式可以包括具有缓冲剂、助悬剂和分散剂、染料、香料等的合适的含水或无水溶媒。固体形式可以包括例如任何以下成分或类似性质的化合物:粘结剂,例如微晶纤维素、黄芪胶或明胶;赋形剂,例如淀粉或乳糖;崩解剂,例如海藻酸、Primogel或玉米淀粉;润滑剂,例如硬脂酸镁;流动剂,例如胶体二氧化硅;甜味剂,例如蔗糖、乳糖或糖精;或者调味剂,例如薄荷,水杨酸甲酯或桔味调味剂。
可注射组合物通常基于本领域已知的无菌可注射溶液或磷酸盐缓冲溶液或其它可注射溶媒。
药物组合物可以是片剂、丸剂、胶囊剂、溶液剂、混悬剂、乳剂、散剂、栓剂和作为缓释制剂的形式。
如果需要,可以使用标准含水或无水技术对片剂进行包衣。在某些实施方式中,这样的组合物和制剂可以含有至少百分之0.1的活性化合物。当然,这些组合物中活性化合物的百分比可以变化,并且可以适当地介于单位重量的约百分之1至约百分之60之间。这样的治疗有用的组合物中活性化合物的量是使得将获得治疗活性的剂量。活性化合物也可以作为例如液体滴剂或喷雾剂经鼻腔施用。
片剂、丸剂、胶囊剂等还可以含有粘结剂,例如黄芪胶、阿拉伯胶、玉米淀粉或果冻;赋形剂,例如磷酸二钙;崩解剂,例如玉米淀粉、马铃薯淀粉、海藻酸;润滑剂,例如硬脂酸镁;和甜味剂,例如蔗糖,乳糖或糖精。当剂量单位形式是胶囊时,除上述类型的材料外,它还可以含有液体载体例如脂肪油。各种其它材料可以作为包衣或用于改进给药单元的物理形式而存在。例如,片剂可以包衣有虫胶、糖或两者。糖浆剂或酏剂除了活性成分外,还可以含有作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调味剂,例如樱桃或橘子味。为了避免组合物在通过胃肠道上部的运输时破裂,组合物是肠溶包衣制剂。
用于肺部施用的组合物包括但不限于,由式(Ia)的化合物的粉末和合适的溶媒和/或润滑剂的粉末组成的干燥粉末组合物。用于肺部施用的组合物可以通过本领域技术人员已知的任何合适的干燥粉末吸入器装置吸入。
组合物的施用是根据方案进行的并且剂量足以减轻受试者中的炎症和疼痛。在一些实施方式中,在本发明的药物组合物中一种或多种活性成分通常被配制为剂量单元。剂量单元可以以每个用于每日施用的剂量单元含有0.1至1000mg的式(Ia)化合物。
在一些实施方式中,针对具体制剂的有效量将取决于治疗前疾病(disease)、病症(disorder)或病况(condition)的严重程度、个体的健康状况和对药物的反应。在一些实施方式中,剂量在制剂的0.001重量%至约60重量%的范围。
当与一种或多种其它活性成分组合使用时,本发明的化合物和其它活性成分可以以比各自单独使用时更低的剂量使用。
关于与任何各种施用途径有关的制剂,针对药物施用的方法和制剂描述于雷明顿的药物科学,第17版,Gennaro等人,Mack出版公司1985年编;雷明顿的药物科学Gennaro AR编,第20版,2000年,Williams&Wilkins PA,美国;和雷明顿:药学科学与实践,第21版,Lippincott Williams&Wilkins编,2005年;以及描述于Loyd V.Allen e Howard C.Ansel,Ansel的药物剂型和药物递送系统,第10版,Lippincott Williams&Wilkins编,2014年。
如上所述的用于经口施用的或可注射的组合物的成分仅是代表性的。
本发明的化合物也可以以缓释形式或通过缓释药物递送系统施用。
本发明第三方面涉及如上所述的式(Ia)的化合物作为药物的用途。
如上所示,式(Ia)的化合物可以用于预防和/或治疗选自由以下组成的组的病症:胃肠道病症、肝脏病症、心血管病症、代谢性病症、感染性疾病、癌症、肾脏病症、炎症性病症和神经系统病症。
在一个实施方式中,肝脏病症包括原发性胆汁性肝硬化(PBC)、脑腱黄瘤病(CTX)、原发性硬化性胆管炎(PSC)、药物引起的胆汁淤积、妊娠期肝内胆汁淤积、与肠胃外营养相关的胆汁淤积、与细菌过度生长和败血症相关的胆汁淤积、自身免疫性肝炎、慢性病毒性肝炎、酒精性肝脏疾病、非酒精性脂肪性肝脏疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、与肝脏移植相关的宿主疾病、活体供体移植、肝脏再生、先天性肝脏纤维化、肉芽肿性肝脏疾病、肝内或肝外恶性肿瘤、Wilson疾病、血色素沉着症和α-1-抗胰蛋白酶缺乏症。
在一个实施方式中,胃肠道病症包括炎症性肠病(IBD)(包括克罗恩病、溃疡性结肠炎和不确定结肠炎)、肠易激综合征(IBS)、细菌过度生长、急性和慢性胰腺炎、吸收不良、辐射后结肠炎和显微镜下结肠炎。
在一个实施方式中,肾脏病症包括糖尿病肾病、高血压肾病、慢性肾小球肾炎(包括慢性移植性肾小球肾炎)、慢性肾小管间质性疾病和肾脏的血管病症。
在一个实施方式中,心血管疾病选自由以下组成的组:动脉粥样硬化、血脂异常、高胆固醇血症、高甘油三酯血症、高血压(也称为高血压)、炎症性心脏疾病(包括心肌炎和心内膜炎)、缺血性心脏疾病、稳定型心绞痛、不稳定型心绞痛、心肌梗死、脑血管疾病(包括缺血性中风)、肺源性心脏疾病(包括肺动脉高压)、外周动脉疾病(PAD),也称为外周血管疾病(PVD)、外周动脉闭塞性疾病和外周闭塞性动脉病。
在一个实施方式中,代谢疾病选自由以下组成的组:胰岛素抵抗、代谢综合征、I型和II型糖尿病、低血糖症和包括肾上腺皮质功能不全在内的肾上腺皮质病症。
在一个实施方式中,代谢性病症选自由以下组成的组:肥胖和与减肥手术相关的病况。
在一个实施方式中,癌症(cancer)选自包含以下的组:肝脏癌症、胆管癌症、胰腺癌症、胃部癌症、结直肠癌症、乳腺癌症、卵巢癌症和与化疗耐药相关的病变(pathology)。
在一个实施方式中,感染性疾病选自获得性免疫缺陷综合征(艾滋病)及其相关疾病、B病毒和C病毒感染的组。
在一个实施方式中,炎症性病症选自类风湿关节炎、纤维肌痛、干燥综合征、硬皮病、白塞氏综合征、血管炎和系统性红斑狼疮的组。
根据本发明的另一方面,提供了式(Ia)的化合物作为GPBAR1的选择性激动剂的用途。特别是CHIN114。
根据本发明的另一方面,提供了式(Ia)的化合物作为双重CysLT1R/FXR调节剂的用途。这样的式I的化合物中最受欢迎的实例是CHIN104。
根据本发明的另一方面,提供了式(Ia)的化合物作为双重CysLT1R/GPBAR1调节剂的用途。这样的式(Ia)的化合物中的优选实例是CHIN105、CHIN106和CHIN117。
本发明的其它特征将从以下对一些仅仅是说明性和非限制性实施例的描述中变得明显。
以下缩略语用于所附实施例:甲醇(MeOH)、碳酸氢钠(NaHCO3)、乙酸乙酯(EtOAc)、二氯甲烷(DCM)、硫酸钠(Na2SO4)、二甲基甲酰胺(DMF)、二异丁基氢化铝(DIBAL-H)、三苯基膦(PPh3)、偶氮二羧酸二异丙酯(DIAD)、盐酸(HCl)、三乙胺(TEA)、三氟乙酸(TFA)、氢氧化钠(NaOH)、四氢呋喃(THF)、水(H2O)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)、时间(h)、室温(rt)、保留时间(tR)。
实施例
实施例1CHIN104-106的合成
通过用二异丁基氢化铝(DIBAL-H)还原从喹啉-2-羧酸甲酯合成醇1。由此得到的醇1是与3-羟基苯甲酸甲酯进行光延反应的底物(示意图1),从而以高产率合成CHIN104。
分别从CHIN104、羧酸CHIN105和醇CHIN106开始,对提供的甲酯进行碱性水解或者用DIBAL-H还原。
示意图1
试剂和条件a)DIBAL-H,干燥THF,0℃;b)PPh3,DIAD,干燥THF,0℃;c)NaOH,MeOH:H2O 1:1v/v。
一般过程。
反应a).用DIBAL-H还原。在0℃,将DIBAL-H的溶液(2.0当量,THF中1.0M)逐滴添加至喹啉甲基酯的溶液或者无水THF(25mL)中的CHIN104的溶液。在0℃对所得混合物搅拌4小时-8小时。将Rochelle盐(酒石酸钾钠)的饱和水溶液添加至反应混合物,并随后用DCM稀释。使淬灭在搅拌下持续两小时。将水相用DCM(3x 50mL)萃取,然后将汇集的有机相用水洗涤、用Na2SO4脱水、并于真空下在旋转蒸发仪上浓缩,获得粗制残余物,通过色谱柱或HPLC对其进行纯化。
步骤b)光延反应。在0℃,将偶氮二羧酸二异丙酯(DIAD,3.5当量)逐滴添加至干燥THF中的三苯基膦(PPh3,3.5当量)的溶液。10分钟后,添加溶于干燥THF中的醇1的溶液。另外的10分钟后,添加溶解于干燥THF中的3-羟基苯甲酸甲酯的溶液。约12小时后,添加水并将反应混合物干燥以去除THF。将干燥的残余物用EtOAc(3x 50mL)萃取,然后将汇集的有机相用2.5M KOH水溶液和水洗涤、脱水并于真空下在旋转蒸发仪上干燥。在色谱柱和硅胶上进行的纯化提供了CHIN104。
步骤c)碱性水解。将CHIN104酯的小等分式样溶于MeOH:H2O 1:1v/v(30mL)的溶液中,并在碱性环境中进行NaOH处理(5.0当量)。将反应混合物在约150℃的温度回流下搅拌8小时。将所得溶液通过用6M HCl处理而淬灭,然后用EtOAc(3x 50mL)萃取。将汇集的有机相用水洗涤,用无水Na2SO4处理,然后在旋转蒸发仪上干燥而得到作为粗制残余物的CHIN105,对其进行进一步的纯化。
实施例1A.3-(喹啉-2-基甲氧基)苯甲酸甲酯(CHIN104)的合成。
纯化采用作为洗脱液混合物的己烷:EtOAc 9:1v/v和0.1%TEA通过硅胶的方式而获得,提供了CHIN104(78%)。分析样品通过在Nucleodur 100-5C18柱(5μm;10mm i.d.x250mm)并用MeOH/H2O 82:18v/v作为洗脱液(流量3mL/min,tR=14.8min)进行HPLC分离而获得。
CHIN104 C18H15NO3
1H NMR(CDCl3,400MHz):δ8.22(1H,d,J=8.4Hz),8.10(1H,d,J=8.0Hz),7.85(1H,d,J=8.0Hz),7.74(2H,ovl),7.68(2H,ovl),7.57(1H,t,J=8.0Hz),7.37(1H,t,J=7.7Hz),7.24(1H,d,J=7.7Hz),5.44(2H,s),3.91(3H,s)。
13C NMR(CDCl3,100MHz)δ169.6,158.4,157.3,147.5,137.1,131.6,129.8,129.5,128.9,127.7,127.6,126.6,122.4,119.7,119.0,115.6,71.4,52.1。
实施例2A.3-(喹啉-2-基甲氧基)苯甲酸(CHIN105)的合成。
对CHIN105(68%)的纯化采用作为洗脱液的DCM:MeOH 99:1v/v在二氧化硅色谱柱上进行。将分析样品采用Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)和洗脱液混合物己烷/EtOAc 40:60v/v(流量3mL/min,tR=6.9min)通过HPLC进行纯化。
CHIN105 C17H13NO2
1H NMR(CD3OD,400MHz):δ8.40(1H,d,J=8.5Hz),8.06(1H,d,J=8.3Hz),7.95(1H,d,J=8.3Hz),7.80(1H,t,J=8.3Hz),7.74(1H,d,J=8.5Hz),7.70(1H,s),7.64(1H,t,J=8.3Hz),7.62(1H,d,ovl),7.41(1H,t),7.30(1H,dd,J=1.5,8.0Hz),5.42(2H,s)。
13C NMR(CD3OD,100MHz)δ169.4,159.9,158.8,148.4,139.1,133.5,131.3,130.7,129.2,129.1,129.0,128.0,123.7,120.8,120.7,116.6,71.9。
实施例3A.(3-(喹啉-2-基甲氧基)苯基)甲醇(CHIN106)的合成。
采用作为洗脱液的DCM:MeOH 99:1v/v通过二氧化硅柱的纯化提供了CHIN106(60%)。分析样品用作为洗脱液的MeOH/H2O 75:15(流量3mL/min,tR=9.3min)在Nucleodur100-5C18柱(5μm;10mm i.d.x 250mm)上通过HPLC分离而获得。
CHIN106 C17H15NO2
1H NMR(CDCl3,400MHz):δ8.20(1H,d,J=8.4Hz),8.10(1H,d,J=7.4Hz),7.84(1H,d,J=7.4Hz),7.75(1H,t,J=7.4Hz),7.68(1H,d,J=8.4Hz),7.56(1H,t,J=7.4Hz),7.28(1H,dd,J=7.3,8.0Hz),7.08(1H,s),7.0(1H,d,J=8.4Hz),6.95(1H,d,J=7.3Hz),5.40(2H,s),4.68(2H,s)。
13C NMR(CDCl3,100MHz)δ158.6,157.8,147.4,142.8,137.1,129.8,129.6,128.7,127.7,127.6,126.5,119.6,119.1,113.9,113.4,71.1,64.9。
实施例2.CHIN107、CHIN108和CHIN109的合成。
对于化合物CHIN107-CHIN109的合成,第一步包括用TBS对必须与喹啉结合的3,5-二羟基苯甲酸甲酯进行单保护。获得单保护的衍生物后,它将通过(苯)酚与甲磺酰化醇衍生物1之间的威廉姆森反应而与喹啉结合。最后一步是用四丁基氟化铵(TBAF)对TBS进行脱保护以获得CHIN107。对两个等分试样的酯进行碱性水解并用DIBAL-H进行还原以获得CHIN108和CHIN109。
示意图2
试剂和条件:a)TBS-Cl,咪唑,干燥DMF,45%产率;b)甲磺酰基氯,TEA,醚,-20℃,定量产率;c)(苯)酚(化合物3),K2CO3,无水DMF,100℃;d)干燥THF中的1.0M四丁基氟化铵(TBAF),过夜;e)过量的NaOH片,MeOH:H2O 1:1v/v,过夜,回流;f)DIBAL-H,干燥THF,0℃。
一般过程。
反应a).用TBSCl保护。将咪唑(1.5当量)和叔丁基二甲基氯硅烷(1.2当量)添加至干燥DMF中的化合物2的溶液。一小时后去除DMF,用EtOAc/NH4Cl萃取三次,然后将汇集的有机相用H2O洗涤。将有机相脱水(Na2SO4)、过滤、在旋转蒸发仪中浓缩,从而获得粗制状态的化合物3。采用作为洗脱液的己烷/EtOAc 9:1混合物在硅胶上的纯化提供了45%产率的化合物3。
反应b).醇1的甲磺酰化。将化合物1溶解于干燥乙醚中并在-20℃将三乙胺(6当量)和甲磺酰氯(5当量)添加至溶液中。约1小时后,用饱和的NaHCO3水溶液洗涤该溶液,然后将汇集的有机相用水萃取一次。将有机相脱水(Na2SO4)、过滤、在旋转蒸发仪中浓缩,从而获得定量产率的粗制状态的化合物4。
反应c).威廉姆森反应。将碳酸钾(2.5当量)添加至DMF中的(苯)酚溶液(化合物3)中,并留置15分钟。添加溶于干燥DMF中的甲磺酸衍生物(1.2当量,化合物4),并且将该溶液放置在100℃持续约12小时。冷却DMF并在旋转蒸发仪上去除DMF,将固体残余物用水和乙酸乙酯(3x 50mL)萃取。将汇集的有机相用Na2SO4脱水、过滤、然后在旋转蒸发仪上浓缩,从而获得粗制反应产物,将其直接提交给后续反应。
反应d)从TBS中脱保护。在室温,将来自先前反应的粗制产物溶于干燥THF中,并且向该溶液添加THF中的1.0M TBAF四-N-丁基氟化铵溶液(0.63mL,5当量)。反应在8小时后完成,并通过添加AcOEt和用H2O萃取进行处理。将合并的有机相用Na2SO4脱水、过滤、在旋转蒸发仪上浓缩,从而获得其粗制状态的化合物CHIN107。
反应e)碱水解。实施如实施例1步骤c)中的相同合成和检查过程。
反应f)用DIBAL-H进行酯还原。实施与实施例1步骤a)中相同的合成和检查过程。
实施例2A.3-羟基-5-(喹啉-2-基甲氧基)苯甲酸甲酯(CHIN107)的合成。
纯化采用作为洗脱液的DCM/MeOH 998:2混合物在硅胶填充柱上进行,并从而获得85%产率的化合物CHIN107。
分析样品在直接相半制备Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上并采用作为洗脱液混合物的己烷/AcOEt 7:3v/v(流量为3mL/min,tR=23.70min)以HPLC进行分离。
CHIN107 C18H15NO4
1H NMR(400MHz,CDCl3):δ8.17(1H,d,J=8.5Hz),8.00(1H,d,J=8.0Hz),7.79(1H,d,J=8.0Hz),7.68(1H,t,J=8.0Hz),7.62(1H,t,J=8.5Hz),7.54(1H,t,J=8.0Hz),7.28(1H,s),7.21(1H,s),6.76(1H,s),5.38(2H,s),3.89(3H,s)。
13C NMR(100MHz,CDCl3):δ167.2,159.1,157.9,157.3,146.7,137.8,131.8,130.2,127.8,127.7,127.6,126.8,119.2,109.8,107.8,106.8,70.4,52.1。
实施例2B.3-羟基-5-(喹啉-2-基甲氧基)苯甲酸(CHIN108)的合成。
纯化采用作为洗脱液的DCM/MeOH 95:5混合物在硅胶填充柱上进行,并从而获得定量产率的化合物CHIN108。纯分析样品通过在Phenomenex五氟苯基C18反相柱上并采用作为洗脱液混合物的MeOH/H2O 55:45v/v和0.1%TFA(流量为1mL/min,tR=9.25min)以HPLC对混合物进行分离而获得。
CHIN108 C17H13NO4
1H NMR(400MHz,CD3OD):δ8.39(1H,d,J=8.4Hz),8.05(1H,d,J=8.0Hz),7.96(1H,d,J=8.0Hz),7.79(1H,t,J=8.0Hz),7.72(1H,d,J=8.4Hz),7.62(1H,t,J=8.0Hz),7.18(1H,s),7.08(1H,s),6.66(1H,s),5.37(2H,s)。
13C NMR(100MHz,CD3OD):δ160.7,159.7,158.2,148.2,139.1,131.4,131.3,129.2,129.1,129.0,128.9,128.0,120.6,110.8,107.8,107.0,71.8。
实施例2C.3-(羟甲基)-5-(喹啉-2-基甲氧基)苯酚(CHIN109)的合成。
纯分析样品(92%产率)通过在Phenomenex五氟苯基C18反相柱上并采用作为洗脱液混合物的MeOH/H2O 60:40v/v和0.1% TFA(流量为1mL/min,tR=12.24min)以HPLC对混合物进行分离而获得。
CHIN109 C17H15NO3
1H NMR(400MHz,CDCl3):δ8.20(1H,d,J=8.5Hz),8.10(1H,d,J=8.0Hz),7.84(1H,d,J=8.0Hz),7.75(1H,t,J=8.0Hz),7.67(1H,d,J=8.5Hz),7.57(1H,t,J=8.0Hz),6.65(1H,s),6.49(1H,s),6.46(1H,s),5.40(2H,s),4.62(2H,s)。
13C NMR(100MHz,CDCl3):δ161.1,159.8,159.6,148.3,145.5,139.0,131.3,129.1,129.0,128.9,127.9,120.6,107.8,105.5,102.1,71.6,65.1。
实施例3.CHIN111、CHIN112和CHIN114的合成
为了合成化合物CHIN111、CHIN112和CHIN114,必须首先制备取代的苯酚。
可以将如实施例2步骤a)中所述通过光延反应并通过用TBAF进行脱保护所制备的化合物5转化为(苯)酚6-8,然后通过威廉姆森反应将其与喹啉结合,以获得衍生物CHIN110-115。
示意图3
试剂和条件:a)PPh3,DIAD,不同性质的醇,干燥THF,0℃;b)干燥THF中的四丁基氟化铵(TBAF)1.0M,过夜;c)(苯)酚(化合物6-8),K2CO3,无水DMF,100℃。
实施例3A.2-((3-异丙氧基苯氧基)甲基)喹啉(CHIN111)的合成。
对CHIN111(61%)的纯化在直接相半制备Nucleodur 100-5柱(5μm;10mm i.d.x250mm)上并采用作为洗脱液混合物的己烷/EtOAc 95:5v/v(流量为3mL/min,tR=38min)以HPLC进行。
CHIN111 C19H19NO2
1H NMR(400MHz,CDCl3):δ8.19(1H,d,J=8.6Hz),8.09(1H,d,J=7.5Hz),7.84(1H,d,J=7.5Hz),7.74(1H,t,J=7.5Hz),7.68(1H,d,J=8.6Hz),7.56(1H,t,J=7.5Hz),7.17(1H,t,J=8.0Hz),6.61(1H,s),6.60(1H,ovl),6.52(1H,dd,J=8.0,2.0Hz),5.38(2H,s),4.52(1H,七重峰,J=6.0Hz),1.32(6H,d,J=6.0Hz)。
13C NMR(100MHz,CDCl3):δ159.6,159.2,157.9,147.5,136.9,129.9,129.7,128.9,127.7,127.6,126.4,119.1,108.8,106.8,103.0,71.3,69.9,22.0(2C)。
实施例3B.2-((3-(仲丁氧基)苯氧基)甲基)喹啉(CHIN112)的合成。
纯化在直接相半制备Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上并采用作为洗脱液混合物的己烷/EtOAc 9:1v/v(流量为3mL/min,tR=15min)以HPLC进行。获得了具有定量产率的化合物。
CHIN112 C20H21NO2
1H NMR(400MHz,CDCl3):δ8.19(1H,d,J=8.6Hz),8.09(1H,d,J=7.5Hz),7.84(1H,d,J=7.5Hz),7.74(1H,t,J=7.5Hz),7.68(1H,d,J=8.6Hz),7.56(1H,t,J=7.5Hz),7.17(1H,t,J=8.0Hz),6.61(1H,s),6.60(1H,ovl),6.52(1H,dd,J=8.0,2.0Hz),5.37(2H,s),4.27(2H,六重峰,J=6.1Hz),1.73(1H,m),1.60(1H,m),1.27(2H,d,J=6.1Hz),0.96(3H,t,J=7.4Hz)。
13C NMR(100MHz,CDCl3):δ159.7,159.6,158.0,147.5,136.9,129.9,129.7,128.9,127.7,127.6,126.4,119.2,108.9,106.7,103.1,75.2,71.1,29.2,19.2,9.9。
实施例3C.2-((3-(2-甲基丁氧基)苯氧基)甲基)喹啉(CHIN114)的合成。
纯化在直接相半制备Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上并采用作为洗脱液混合物的己烷/EtOAc 9:1v/v(流量为3mL/min,tR=14min)以HPLC进行。获得了90%产率的CHIN114。
CHIN114 C21H23NO2
1H NMR(400MHz,CDCl3):δ8.19(1H,d,J=8.6Hz),8.09(1H,d,J=7.5Hz),7.84(1H,d,J=7.5Hz),7.74(1H,t,J=7.5Hz),7.68(1H,d,J=8.6Hz),7.56(1H,t,J=7.5Hz),7.17(1H,t,J=8.0Hz),6.61(1H,s),6.60(1H,ovl),6.52(1H,dd,J=8.0,2.0Hz),5.38(2H,s),3.80(1H,dd,J=9.0,6.0Hz),3.71(1H,dd,J=9.0,6.6Hz),1.85(1H,七重峰,J=6.6Hz),1.56(1H,m),1.25(1H,m),1.00(3H,d,J=6.6Hz),0.94(3H,t,J=7.3Hz)。
13C NMR(100MHz,CDCl3):δ160.6,159.6,158.0,147.5,136.9,129.9,129.8,128.9,127.8,127.6,126.5,119.1,107.7,106.8,101.8,73.0,71.2,34.6,26.1,16.5,11.3。
实施例4.CHIN116-CHIN121的合成
从2-(氯甲基)喹啉(9)和备选地从4'-羟基-[1,1'-联苯]-3-羧酸甲酯(10)或4'-羟基-[1,1'-联苯]-4-羧酸甲酯(11)开始,采用如实施例2反应c中的相同实验过程,通过威廉姆森合成法合成酯CHIN116和CHIN119。
然后按照先前实施例1步骤a)和步骤c)中描述的实验过程,对酯进行还原和水解。
示意图4.
试剂和条件。a)化合物10或11,K2CO3,干燥DMF,100℃,分别为定量产率和87%;b)过量NaOH,MeOH:H2O 1:1v/v,回流,两个反应都是定量产率;c)DIBAL-H,干燥THF,0℃,分别为定量产率和92%产率。
实施例4A.4'-(喹啉-2-基甲氧基)-[1,1'-联苯]-3-羧酸甲酯(CHIN116)的合成。
将衍生物CHIN116(定量产率)在己烷:EtOAc 9:1v/v的二氧化硅色谱柱上进行纯化。分析样品采用作为洗脱液的己烷混合物:EtOAc 7:3v/v(流量3mL/min,tR=12.1min)在Nucleodur100-5柱(5μm;10mm i.d.x 250mm)上以HPLC而获得。
CHIN116 C24H19NO3
1H NMR(400MHz,CDCl3):δ8.23(1H,t,J=2.0Hz),8.21(1H,d,J=8.4Hz),8.11(1H,d,J=8.6Hz),7.98(1H,d,J=8.0Hz),7.84(1H,d,J=7.9Hz),7.77(1H,t,J=8.6Hz),7.73(1H,d,J=8.4Hz),7.71(1H,d,J=8.0Hz),7.57(1H,t,ovl),7.57(2H,d,J=8.7Hz),7.48(1H,t,J=8.0Hz),7.13(2H,d,J=8.7Hz),5.45(2H,s),3.94(3H,s)。
13C NMR(100MHz,CDCl3):δ167.0,158.2,157.7,147.5,140.8,137.1,133.1,131.0,130.6,129.8,128.9,128.8,128.3(2C),127.8(2C),127.7,127.6,126.5,119.1,115.3(2C),71.4,52.1。
实施例4B.4'-(喹啉-2-基甲氧基)-[1,1'-联苯]-3-羧酸(CHIN117)的合成。
化合物CHIN117在二氧化硅色谱柱(DCM:MeOH 95:5v/v)上纯化后以定量产率获得。
CHIN117 C23H17NO3
1H NMR(400MHz,CDCl3):δ8.29(1H,t,J=1.6Hz),8.23(1H,d,J=8.5Hz),8.14(1H,d,J=8.4Hz),8.03(1H,d,J=7.8Hz),7.85(1H,d,J=8.0Hz),7.79(1H,d,J=7.8Hz),7.77(1H,t,J=8.4Hz),7.72(1H,d,J=8.5Hz),7.58(2H,d,J=8.4Hz),7.57(1H,t,ovl),7.52(1H,t,J=7.8Hz),7.14(2H,d,J=8.4Hz),5.47(2H,s)。
13C NMR(100MHz,DMSO-d6):168.3,159.0,158.5,147.9,141.0,138.2,133.1,132.4,131.0,130.3,129.5,129.0,128.9,128.6,128.3,127.8,127.7,127.6,120.6,116.5(2C),71.9。
实施例4C.4'-(喹啉-2-基甲氧基)-[1,1'-联苯]-3-基)甲醇(CHIN118)的合成。
用作为洗脱液的己烷/EtOAc 1:1v/v(流量3mL/min,tR=20min)在Nucleodur100-5柱(5μm;10mm i.d.x 250mm)上以HPLC进行的纯化为我们提供了定量产率的CHIN118。
CHIN118 C23H19NO2
1H NMR(400MHz,CDCl3):δ8.22(1H,d,J=8.6Hz),8.12(1H,d,J=7.8Hz),7.85(1H,d,J=7.8Hz),7.76(1H,t,J=7.8Hz),7.71(1H,d,J=8.6Hz),7.57(1H,t,J=7.7Hz),7.55(1H,s),7.52(2H,d,J=8.6Hz),7.47(1H,d,J=7.6Hz),7.40(1H,t,J=7.6Hz),7.31(1H,d,J=7.6Hz),7.09(2H,d,J=8.6Hz),5.42(2H,s),4.76(2H,s)。
13C NMR(100MHz,CDCl3):δ158.1,157.8,147.5,141.4,140.9,137.1,133.9,129.8,128.9,128.8,128.3(2C),127.7,127.6,126.6,126.0,125.3(2C),119.1,115.1(2C),71.2,65.4。
实施例4D.4'-(喹啉-2-基甲氧基)-[1,1'-联苯]-4-羧酸甲酯(CHIN119)的合成
将化合物CHIN119(87%产率)采用作为洗脱液的己烷:EtOAc 9:1v/v的混合物通过二氧化硅色谱柱进行纯化。纯分析样品通过以梯度(t0=60% MeOH-t20min=95% MeOH;流量1mL/min,tR=5.5min)在Nucleodur 100-5C18柱(5μm;4.6mm i.d.x 250mm)上以HPLC进行分离而获得。
CHIN119 C24H19NO3
1H NMR(400MHz,CDCl3):δ8.22(1H,d,J=8.6Hz),8.11(1H,d,J=8.2Hz),8.08(2H,d,J=8.6Hz),7.85(1H,d,J=8.2Hz),7.76(1H,t,J=8.2Hz),7.70(1H,d,J=8.6Hz),7.61(2H,d J=8.6Hz),7.58(2H,d,J=8.9Hz),7.57(1H,t,ovl),7.13(2H,d,J=8.9Hz),5.46(2H,s),3.94(3H,s)。
13C NMR(100MHz,CDCl3):δ167.1,158.6,157.6,147.5,145.0,137.1,132.9,130.1(2C),129.8,128.9,128.5(2C),128.3,127.7,127.6,126.6(2C),126.5,119.0,115.3(2C),71.5,52.1。
实施例4E.4'-(喹啉-2-基甲氧基)-[1,1'-联苯]-4-羧酸(CHIN120)的合成。
纯化采用作为洗脱液的DCM:MeOH 95:5v/v在快速色谱柱和硅胶上进行,以获得定量产率的CHIN120。
CHIN120 C23H17NO3
1H NMR(400MHz,CD3OD+0.1% TFA):δ9.23(1H,d,J=8.5Hz),8.42(1H,d,J=8.0Hz),8.39(1H,d,J=7.5Hz),8.24(1H,t,J=7.5Hz),8.23(1H,d,J=8.5Hz),8.10(2H,d,J=8.5Hz),8.03(1H,t,J=8.0Hz),7.76(2H,d,J=8.5Hz),7.73(2H,d,J=8.5Hz),7.32(2H,d,J=8.5Hz),5.80(2H,s)。
13C NMR(100MHz,CDCl3):δ168.7,158.3,157.3,145.7,145.0,138.8,133.2,130.9,130.4(2C),128.5(2C),128.4,128.3,127.8(2C),126.5(3C),119.2,115.3(2C),69.8。
实施例4F.(4'-(喹啉-2-基甲氧基)-[1,1'-联苯]-3-基)甲醇(CHIN121)的合成。
化合物CHIN121采用作为洗脱液的己烷:EtOAc 8:2v/v在硅胶色谱柱上进行纯化后而获得(92的产率)。将分析样品用己烷/EtOAc 1:1v/v(流量3mL/min,tR=18min)在Nucleodur100-5柱(5μm;10mm i.d.x 250mm)上以HPLC进行进一步纯化。
CHIN121 C23H19NO2
1H NMR(400MHz,CDCl3):δ8.22(1H,d,J=8.4Hz),8.11(1H,d,J=8.5Hz),7.85(1H,d,J=8.0Hz),7.76(1H,t,J=8.5Hz),7.71(1H,d,J=8.4Hz),7.57(1H,t,J=8.0Hz),7.55(2H,d,J=8.6Hz),7.53(2H,d,J=8.6Hz),7.42(2H,d,J=8.6Hz),7.10(2H,d,J=8.6Hz),5.44(2H,s),4.74(2H,s)。
13C NMR(100MHz,CDCl3):δ157.9,157.8,157.3,147.5,140.1,137.1,133.9,129.8,128.9,128.5,128.4,127.7,127.6,127.5(2C),126.8(2C),126.5,119.1,115.2(2C),71.3,65.1。
实施例5CHIN125-CHIN127和CHIN131-CHIN133的合成。
对于酯CHIN125和CHIN131的合成,第一步是采用威廉姆森合成法从3,5-二羟基苯甲酸甲酯(2)开始并将其与5-溴戊酸甲酯(14)和4-溴丁酸甲酯(15)交替反应以获得(苯)酚12和13。通过如实施例2反应c中使用的相同实验过程,将所得的单烷基化(苯)酚与2-(氯甲基)喹啉(9)进行进一步的威廉姆森反应。然后按照先前实施例1反应c)中描述的实验过程,对酯进行LiBH4还原和水解。
示意图5
a试剂和条件。a)化合物14或化合物15,K2CO3,干燥DMF,100℃,化合物12和13分别为48%和47%产率;b)化合物12或13,K2CO3,干燥DMF,100℃,分别为80%和74%产率;c)过量NaOH,MeOH:H2O 1:1v/v,回流,分别为98%的定量产率;d)LiBH4,干燥THF,0℃,分别为80%和76%产率。
一般过程。
反应a).威廉姆森反应。将5-溴戊酸甲酯(0.5当量)或4-溴丁酸甲酯和K2CO3(1当量)添加至干燥DMF中的化合物2的溶液,并将该溶液放置在100℃持续约12小时。将其冷却,用6N HCl酸化,并通过旋转蒸发仪去除DMF。将干燥残余物用水和乙酸乙酯(3x 50mL)萃取。将汇集的有机相用Na2SO4脱水、过滤、然后在旋转蒸发仪上浓缩,从而获得粗制反应产物,将其通过开放柱色谱法进行纯化。
反应d).用LiBH4进行还原反应。
在0℃,将干燥甲醇(1当量)和干燥THF中的LiBH4 2M的溶液(2当量)添加至干燥THF中的酯CHIN125或CHIN131的溶液。约5小时后,反应的TLC监测显示底物用尽,通过在0℃添加1N NaOH溶液(2当量)对反应进行处理。淬灭持续1小时,然后将混合物用水和乙酸乙酯(3x 50mL)萃取。将汇集的有机相用Na2SO4脱水、过滤、然后通过旋转蒸发仪浓缩,从而获得粗制反应产物,将其通过HPLC的方式进行纯化。
实施例5A.3-((5-甲氧基-5-氧代戊基)氧基)-5-(喹啉-2-基甲氧基)苯甲酸甲酯(CHIN125)的合成。
将化合物CHIN125(80%产率)采用作为洗脱液的己烷混合物:EtOAc 9:1v/v在二氧化硅色谱柱上进行纯化。纯分析样品用作为洗脱液的己烷:EtOAc 7:3v/v(流速3mL/min,tR=20.4min)在Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上以HPLC进行分离而获得。
CHIN125 C24H25NO6
1H NMR(400MHz,CDCl3):δ8.21(1H,d,J=8.5Hz),8.10(1H,d,J=8.5Hz),7.83(1H,d,J=8.2Hz),7.74(1H,t,J=8.5Hz),7.66(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),7.33(1H,dd,J=1.3Hz,2.3Hz),7.19(1H,dd,J=1.3Hz,2.3Hz),6.78(1H,t,J=2.3Hz),5.40(2H,s),3.98(2H,t,J=6.5Hz),3.89(3H,s),3.67(3H,s),2.38(2H,t,J=7.5Hz),1.81(2H,ovl)。
13C NMR(700MHz,CDCl3):δ173.8,166.7,160.1,159.5,157.3,147.6,137.1,132.1,129.8,129.0,127.7,127.6,126.6,119.1,108.4,108.3,106.7,71.5,67.8,52.3,51.5,33.6,28.5,21.5。
实施例5B.3-(4-羧基丁氧基)-5-(喹啉-2-基甲氧基)苯甲酸(CHIN126)的合成。
纯化以梯度(t0=10% MeCN 0.1% TFA-t20min=70% MeCN 0.1% TFA-t25min=95% MeCN 0.1% TFA;流量3mL/min,tR=16.3min)在Phenomenex Luna C18(2)柱(5μm;10mm i.d.x 250mm)上通过HPLC的方式进行,从而提供化合物CHIN126(定量产率)。
CHIN126 C22H21NO6
1H NMR(400MHz,CD3OD):δ9.17(1H,d,J=8.5Hz),8.38(1H,d,J=8.5Hz),8.34(1H,d,J=8.2Hz),8.20(1H,t,J=8.5Hz),8.18(1H,d,J=8.5Hz),7.98(1H,t,J=8.1Hz),7.38(1H,dd,J=1.3Hz,2.3Hz),7.31(1H,dd,J=1.3Hz,2.3Hz),6.98(1H,t,J=2.3Hz),5.74(2H,s),4.06(2H,t,J=5.5Hz),2.38(2H,t,J=8.0Hz),1.82(2H,ovl)。
13C NMR(700MHz,CD3OD):δ177.3,169.2,161.8,160.4,157.9,143.6,133.5,132.1,129.7,129.5,129.4,129.1,125.9,121.1,109.2,108.9,107.1,70.0,68.9,34.5,29.6,22.7。
实施例5C.5-(3-(羟甲基)-5-(喹啉-2-基甲氧基)苯氧基)戊-1-醇(CHIN127)的合成。
纯化用MeCN/H2O 55:45(流量3mL/min,tR=5.16min)在Phenomenex Luna C18(2)柱(5μm;10mm i.d.x 250mm)上通过HPLC的方式进行,从而提供化合物CHIN127(80%)。
CHIN127 C22H25NO4
1H NMR(400MHz,CDCl3):δ8.21(1H,d,J=8.5Hz),8.11(1H,d,J=8.5Hz),7.84(1H,d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),6.64(1H,dd,J=1.3Hz,2.3Hz),6.55(1H,t,J=2.3Hz),6.52(1H,dd,J=1.3Hz,2.3Hz),5.38(2H,s),4,62(2H,s),3.94(2H,t,J=6.5Hz),3.67(2H,t,J=6.5),1.79(2H,五重峰,J=6.2Hz,7.5Hz),1.63-1.53(4H,ovl)。
13C NMR(700MHz,CDCl3):δ160.3,159.6,157.8,147.2,143.9,137.3,130.0,129.2,127.7,127.6,126.9,119.3,105.9,105.1,100.8,71.9,67.9,64.8,62.5,32.3,28.9,22.3。
实施例5D.3-(4-甲氧基-4-氧代丁氧基)-5-(喹啉-2-基甲氧基)苯甲酸甲酯(CHIN131)的合成。
将衍生物CHIN131(74%)在己烷:EtOAc 9:1v/v的二氧化硅色谱柱上进行纯化。分析样品采用作为洗脱液的己烷:EtOAc 7:3v/v的混合物(流量3mL/min,tR=22.1min)在Nucleodur100-5柱(5μm;10mm i.d.x 250mm)上以HPLC而获得。
CHIN131 C23H23NO6
1H NMR(400MHz,CDCl3):δ8.24(1H,d,J=8.5Hz),8.13(1H,d,J=8.5Hz),7.85(1H,d,J=8.2Hz),7.76(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.58(1H,t,J=8.1Hz),7.34(1H,dd,J=8.1Hz,2.3Hz),7.19(1H,dd,J=2.3Hz),6.78(1H,dd,J=8.1Hz,2.3Hz),5.38(2H,s),4.02(2H,t,J=6.3Hz),3.71(2H,t,J=7.0Hz),2.51(2H,t,J=7.3Hz),2.10(2H,五重峰,J=6.3Hz,7.3Hz)。
13C NMR(700MHz,CDCl3):δ173.6,166.7,160.3,159.6,157.3,147.6,137.2,132.2,129.9,129.1,127.8,127.7,126.7,119.2,108.5,108.3,106.8,71.5,67.1,52.3,51.8,30.5,24.5。
实施例5E.3-(3-羧基丙氧基)-5-(喹啉-2-基甲氧基)苯甲酸(CHIN132)的合成。
将衍生物CHIN132(98%)以梯度(t0=10% MeCN 0.1% TFA-t20min=70% MeCN0.1% TFA-t25min=95% MeCN 0.1% TFA;流量3mL/min,tR=15min)在Phenomenex LunaC18(2)柱(5μm;10mm i.d.x 250mm)上通过HPLC的方式进行纯化。
CHIN132 C21H19NO6
1H NMR(400MHz,CD3OD):δ9.04(1H,d,J=8.5Hz),8.33(1H,d,J=8.5Hz),8.29(1H,d,J=8.2Hz),8.14(1H,t,J=8.5Hz),8.11(1H,d,J=8.5Hz),7.93(1H,t,J=8.1Hz),7.38(1H,dd,J=8.1Hz,2.3Hz),7.28(1H,dd,J=2.3Hz),6.99(1H,dd,J=8.1Hz,2.3Hz),5.69(2H,s),4.09(2H,t,J=6.3Hz),2.50(2H,t,J=7.3Hz),2.08(2H,五重峰,J=6.3Hz,7.3Hz)。
13C NMR(700MHz,CD3OD):δ176.9,169.0,161.3,160.2,159.7,148.1,133.7,132.0,130.1,129.5,129.4,129.1,124.7,121.3,109.3,107.6,107.5,69.6,68.8,33.0,25.7。
实施例5F.4-(3-(羟甲基)-5-(喹啉-2-基甲氧基)苯氧基)丁-1-醇(CHIN133)的合成。
将衍生物CHIN133(76%)采用作为洗脱液的正己烷:EtOAc 4:6v/v的混合物(流量3mL/min,tR=26.32min)在Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上通过HPLC的方式进行纯化。
CHIN133 C21H23NO4
1H NMR(400MHz,CD3OD):δ8.23(1H,d,J=8.5Hz),8.12(1H,d,J=8.5Hz),7.85(1H,d,J=8.2Hz),7.76(1H,t,J=8.5Hz),7.69(1H,d,J=8.5Hz),7.57(1H,t,J=8.1Hz),6.65(1H,dd,J=8.1Hz,2.3Hz),6.55(1H,dd,J=8.1Hz,2.3Hz),6.52(1H,dd,J=2.3Hz),5.39(2H,s),4.64(2H,s),4.07(2H,t,J=6.3Hz),3.86(2H,t,J=6.3Hz),2.49(2H,m),2.02(2H,m)。
13C NMR(700MHz,CD3OD):δ176.9,169.0,161.3,160.2,159.7,148.1,133.7,132.0,130.1,129.5,129.4,129.1,124.7,121.3,109.3,107.6,107.5,69.6,68.8,33.0,25.7。
实施例6CHIN134-CHIN142的合成。
第一个反应步骤是从3,5-二羟基苯甲酸甲酯(2)开始,用丙-2醇(16)、丙-1醇(17)和丁-2醇(18)进行在实施例1步骤b)中描述了过程的光延反应。采用如实施例2反应c中使用的相同实验过程,将所得的单烷基化衍生物与2-(氯甲基)喹啉(9)进行威廉姆森反应。然后分别按照先前实施例5反应d)和实施例1反应c)中描述的实验过程,对这些酯进行还原和水解。
示意图6。
a试剂和条件。a)醇16或17或18,DIAD,PPh3,干燥THF,0℃,化合物19、20和21分别为50%、45%和42%定量产率;b)化合物19-21,K2CO3,干燥DMF,100℃,分别为57%和70%定量产率;c)过量NaOH,MeOH:H2O 1:1v/v,回流,分别为84%、86%和91%产率;d)LiBH4,干燥THF,0℃,分别为88%、94%和89%产率。
实施例6A.3-异丙氧基-5-(喹啉-2-基甲氧基)苯甲酸甲酯(CHIN134)的合成。
将衍生物CHIN134(50%)在己烷:EtOAc 9:1v/v的二氧化硅色谱柱上进行纯化。分析样品采用作为洗脱液的正己烷:EtOAc 7:3v/v的混合物(流量3mL/min,tR=9.9min)在Nucleodur100-5柱(5μm;10mm i.d.x 250mm)上以HPLC而获得。
CHIN134 C21H21NO4
1H NMR(400MHz,CDCl3):δ8.21(1H,d,J=8.5Hz),8.10(1H,d,J=8.5Hz),7.84(1H,d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.67(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),7.31(1H,dd,J=2.4Hz),7.20(1H,dd,J=2.3Hz),6.78(1H,dd,J=2.4Hz,2.3Hz),5.40(2H,s),4.57(1H,五重峰,J=6.1Hz),3.89(3H,s),1.32(6H,d,J=6.1Hz)。
13C NMR(700MHz,CDCl3):δ166.8,159.5,159.1,157.3,147.6,137.1,132.2,129.9,129.0,127.8,127.7,126.7,119.2,109.7,108.2,108.0,71.4,70.4,52.1,21.9(2C)。
实施例6B.3-异丙氧基-5-(喹啉-2-基甲氧基)苯甲酸(CHIN135)的合成。
将衍生物CHIN135(84%)在DCM:MeOH 9:1v/v的二氧化硅色谱柱上进行纯化。
CHIN135 C20H19NO4
1H NMR(400MHz,CD3OD):δ9.21(1H,d,J=8.5Hz),8.39(1H,d,J=8.5Hz),8.37(1H,d,J=8.2Hz),8.22(1H,t,J=8.5Hz),8.20(1H,d,J=8.5Hz),8.01(1H,t,J=8.1Hz),7.38(1H,dd,J=2.4Hz),7.29(1H,dd,J=2.3Hz),6.97(1H,dd,J=2.4Hz,2.3Hz),5.75(2H,s),4.68(1H,五重峰,J=6.1Hz),1.35(6H,d,J=6.1Hz)。
13C NMR(700MHz,CD3OD):δ169.0,160.7,159.8,156.8,148.6,136.6,134.4,131.2,130.5,129.9,129.2,126.2,121.7,111.8,109.1,108.8,71.6,67.7,22.1(2C)。
实施例6C.(3-异丙氧基-5-(喹啉-2-基甲氧基)苯基)甲醇(CHIN136)的合成。
将衍生物CHIN136(88%)采用作为洗脱液的正己烷:EtOAc 7:3v/v的混合物(流量3mL/min,tR=38.79min)在Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上通过HPLC的方式进行纯化。
CHIN136 C20H21NO3
1H NMR(400MHz,CDCl3):δ8.21(1H,d,J=8.5Hz),8.12(1H,d,J=8.5Hz),7.84(1H,d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),6.63(1H,dd,J=2.4Hz),6.54(1H,dd,J=2.3Hz),6.51(1H,dd,J=2.4Hz,2.3Hz),5.38(2H,s),4.61(2H,s),4.52(1H,五重峰,J=6.1Hz),1.30(6H,d,J=6.1Hz)。
13C NMR(700MHz,CDCl3):δ159.8,159.4,157.9,147.5,143.9,137.2,129.9,129.3,127.8,127.7,127.8,127.7,119.3,107.3,105.3,102.2,70.1,65.2,50.6,22.1(2C)。
实施例6D.3-丙氧基-5-(喹啉-2-基甲氧基)苯甲酸甲酯(CHIN137)的合成。
将衍生物CHIN137(50%)在己烷:EtOAc 9:1v/v的二氧化硅色谱柱上进行纯化。分析样本采用作为洗脱液的正己烷:EtOAc 7:3v/v的混合物(流量3mL/min,tR=11.44min)在Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)以HPLC而获得。
CHIN137 C21H21NO4
1H NMR(400MHz,CDCl3):δ8.21(1H,d,J=8.5Hz),8.10(1H,d,J=8.5Hz),7.84(1H,d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.67(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),7.33(1H,dd,J=2.4Hz),7.20(1H,dd,J=2.3Hz),6.80(1H,dd,J=2.4Hz,2.3Hz),5.40(2H,s),3.93(2H,t,J=6.4Hz),3.89(3H,s),1.79(2H,六重峰,J=7.4Hz),1.02(3H,t,J=7.4Hz)。
13C NMR(700MHz,CDCl3):δ166.9,160.3,159.5,157.5,147.5,137.2,132.2,129.9,129.0,127.7,127.6,126.7,119.2,108.5,108.2,106.8,71.5,69.9,52.3,22.6,10.5。
实施例6E.3-丙氧基-5-(喹啉-2-基甲氧基)苯甲酸(CHIN138)的合成。
将衍生物CHIN135(86%)在DCM:MeOH 9:1v/v的二氧化硅色谱柱上进行纯化。
CHIN138 C20H19NO4
1H NMR(400MHz,CD3OD):δ8.40(1H,d,J=8.5Hz),8.06(1H,d,J=8.5Hz),7.96(1H,d,J=8.2Hz),7.80(1H,t,J=8.5Hz),7.73(1H,d,J=8.5Hz),7.62(1H,t,J=8.1Hz),7.28(1H,dd,J=2.4Hz),7.18(1H,dd,J=2.3Hz),6.85(1H,dd,J=2.4Hz,2.3Hz),5.39(2H,s),3.95(2H,t,J=6.4Hz),1.78(2H,六重峰,J=7.4Hz),1.03(3H,t,J=7.4Hz)。
13C NMR(700MHz,CD3OD):δ169.5,161.7,160.8,158.9,148.3,139.0,134.2,131.2,129.2,129.1,129.0,128.0,120.7,109.7,109.2,107.5,72.0,70.8,23.5,10.7。
实施例6F.(3-丙氧基-5-(喹啉-2-基甲氧基)苯基)甲醇(CHIN139)的合成。
将衍生物CHIN139(94%)采用作为洗脱液的正己烷:EtOAc 4:6v/v的混合物(流量3mL/min,tR=24.5min)在Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上通过HPLC的方式进行纯化。
CHIN139 C20H21NO3
1H NMR(400MHz,CD3OD):δ8.38(1H,d,J=8.5Hz),8.05(1H,d,J=8.5Hz),7.95(1H,d,J=8.2Hz),7.80(1H,t,J=8.5Hz),7.73(1H,d,J=8.5Hz),7.62(1H,t,J=8.1Hz),6.65(1H,dd,J=2.4Hz),6.55(1H,dd,J=2.3Hz),6.51(1H,dd,J=2.4Hz,2.3Hz),5.34(2H,s),4.52(2H,s),3.90(2H,t,J=6.4Hz),1.75(2H,六重峰,J=7.4Hz),1.01(3H,t,J=7.4Hz)。
13C NMR(700MHz,CD3OD):δ160.5,159.6,158.0,146.9,144.1,137.5,129.9,129.0,127.7,127.5,126.5,119.3,105.5,104.9,100.2,70.3,69.2,63.7,22.2,09.4。
实施例6G.3-(仲丁氧基)-5-(喹啉-2-基甲氧基)苯甲酸甲酯(CHIN140)的合成。
将衍生物CHIN140(70%)在己烷:EtOAc 9:1v/v的二氧化硅色谱柱上进行纯化。分析样本采用作为洗脱液的正己烷:EtOAc 7:3v/v的混合物(流量3mL/min,tR=11.5min)在Nucleodur100-5柱(5μm;10mm i.d.x 250mm)上以HPLC而获得。
CHIN140 C22H23NO4
1H NMR(400MHz,CDCl3):δ8.21(1H,d,J=8.5Hz),8.10(1H,d,J=8.5Hz),7.84(1H,d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.67(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),7.31(1H,dd,J=2.4Hz),7.20(1H,dd,J=2.3Hz),6.78(1H,dd,J=2.4Hz,2.3Hz),5.40(2H,s),4.32(1H,六重峰,J=6.0Hz),3.88(3H,s),1.72-1.61(2H,ovl),1.26(3H,d,J=6.1Hz),0.95(3H,t,J=7.4Hz)。
13C NMR(700MHz,CDCl3):δ166.9,159.5,159.4,157.3,147.5,137.4,132.5,130.0,128.9,127.8,127.7,126.7,119.2,109.9,108.1,108.0,75.6,71.5,52.3,19.2,09.7。
实施例6H.3-(仲丁氧基)-5-(喹啉-2-基甲氧基)苯甲酸(CHIN141)的合成。
将衍生物CHIN141(91%)在DCM:MeOH 9:1v/v的二氧化硅色谱柱上进行纯化。
CHIN141 C21H21NO4
1H NMR(400MHz,CD3OD):δ8.39(1H,d,J=8.5Hz),8.06(1H,d,J=8.5Hz),7.96(1H,d,J=8.2Hz),7.80(1H,t,J=8.5Hz),7.72(1H,d,J=8.5Hz),7.62(1H,t,J=8.1Hz),7.27(1H,dd,J=2.4Hz),7.16(1H,dd,J=2.3Hz),6.83(1H,dd,J=2.4Hz,2.3Hz),5.39(2H,s),4.36(1H,六重峰,J=6.0Hz),1.69-1.60(2H,ovl),1.24(3H,d,J=6.1Hz),0.96(3H,t,J=7.4Hz)。
13C NMR(700MHz,CD3OD):δ169.4,160.8,158.8,148.3,139.0,134.0,131.3,131.0,129.2,129.1,129.0,128.0,120.7,110.9,109.2,108.6,76.5,72.0,30.0,19.4,09.9。
实施例6I.(3-(仲丁氧基)-5-(喹啉-2-基甲氧基)苯基)甲醇(CHIN142)的合成。
将衍生物CHIN142(89%)采用作为洗脱液的正己烷:EtOAc 4:6v/v的混合物(流量3mL/min,tR=24.74min)在Nucleodur 100-5柱(5μm;10mm i.d.x 250mm)上通过HPLC的方式进行纯化。
CHIN142 C21H23NO3
1H NMR(400MHz,CDCl3):δ8.21(1H,d,J=8.5Hz),8.12(1H,d,J=8.5Hz),7.83(1H,d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),6.63(1H,dd,J=2.4Hz),6.54(1H,dd,J=2.3Hz),6.51(1H,dd,J=2.4Hz,2.3Hz),5.38(2H,s),4.61(2H,s),4.27(1H,六重峰,J=6.0Hz),1.71-1.59(2H,ovl),1.25(3H,d,J=6.1Hz),0.94(3H,t,J=7.4Hz)。
13C NMR(700MHz,CDCl3):δ159.8,159.7,157.9,147.4,143.8,137.1,129.9,128.8,127.7,127.6,126.6,119.2,107.3,105.3,102.1,75.1,71.2,65.1,29.1,19.3,09.8。
实施例7-生物学数据
表1中描述了本发明的化合物对FXR、TGR5/GPBAR1和CysLT1R受体的活性数据。在此表中,将化合物的活性与特定参考化合物(即针对FXR的CDCA、针对TGR5/GPBAR1的TLCA、针对CysLT1R的MK571)进行了比较。每个化合物以10μM的浓度进行测试,并且将参考化合物的活性认为是100%。
表1
对于FXR介导的转录激活,用200ng的含有从热休克蛋白27(hsp27)启动子克隆的FXR反应元件(IR1)的p(hsp27)-TK-LUC报告载体、100ng的pSG5-FXR、100ng的pSG5-RXR和100的编码人类Renilla基因的载体pGL4.70(Promega,Madison WI)转染HepG2细胞。
对于GPBAR1介导的转录激活,用200ng的含有驱动luc2P荧光素酶报告基因转录的cAMP反应原件(CRE)的报告载体pGL4.29(Promega,Madison WI)、100ng的人pCMVSPORT6-GPBAR1和100ng的pGL4.70转染HEK-293T细胞。
转染后24小时,用特异性受体激动剂CDCA(10μM)或TLCA(10μM)或者用衍生物CHIN104-112和CHIN114-121(10μM and 50μM)刺激细胞,持续18小时。在另一实验设置中,转染后24小时,用与10μM的CDCA或TLCA组合的50μM的衍生物CHIN刺激细胞。
对于剂量反应曲线,用递增浓度(0.1-75μM)目标化合物刺激细胞。刺激后十八小时,通过双荧光素酶报告检测(E1980,Promega Madison WI)的方式,将细胞裂解物用于评估荧光素酶和Renilla活性。采用Glomax 20/20光度计(Promega,Madison WI)测量发光,并用Renilla活性将荧光素酶活性归一化。
通过Eurofins Cerep-Panlabs(法国)进行拮抗活性检测。将细胞混悬于DMEM缓冲液(Invitrogen),然后以3×104个细胞/板的密度进行铺板。然后将在补充有20mM Hepes(Invitrogen)(pH 7.4)的HBSS缓冲液(Invitrogen)中的混合有丙磺舒的荧光探针(Fluo4Direct,Invitrogen)添加至每个孔,并与细胞一起留置在37℃持续60min,然后在22℃持续15min。然后将板放置在微孔板读板器(CellLux,PerkinElmer)上,其用于添加待测试化合物或HBSS缓冲液,并继而在5分钟后添加0.1nM LTD4或HBSS缓冲液溶液(用于作为对照)。测量与细胞溶质中游离Ca2+离子的浓度成比例改变的强度和荧光的变化。结果表示为与0.1nMLTD4的对照反应相比的抑制百分比。标准拮抗剂参考是MK571。
CHIN117及其在降低对乙酰氨基酚诱导的肝损伤(APAP)中的作用特别值得关注。在实验设置中,通过经口灌胃而施用浓度为500mg/kg的对乙酰氨基酚(APAP)以在野生型C57/Bl6小鼠中诱导急性肝炎。诱导疾病后45分钟,经口施用浓度为30mg/kg的CHIN117。诱导疾病后24小时处死小鼠,取血并分析血细胞计数以及AST和ALT转氨酶值。
结果显示(图1-3),施用APAP诱导AST和ALT值急剧上升(在3000和4000之间),此外,产生的肝损伤将参与该疾病发病机制的免疫细胞吸引至肝脏,循环白细胞(WBC)值随之下降。如果与单独用APAP处理的小鼠组中记录的AST和ALT值相比,化合物CHIN117的施用能够通过降低AST和ALT值约10倍而缓解APAP诱导的肝损伤。CHIN117还能够保持WBC值与未经处理的小鼠(NT)中存在的WBC值相当。
CHIN117及其在由高脂饮食诱导的慢性肝炎小鼠模型中的功效特别值得关注。这个小鼠模型模拟了NAFLD,其代表工业化国家中迅速增长的流行病,并对医疗保健系统造成了非常高的成本。在这个模型中,给小鼠(雄性C57BL/6小鼠)喂饲富含脂质和胆固醇(2%胆固醇)并在水中添加果糖(3%)的饮食(HFD-F),持续60天。从第7天开始,每天以30mg/kg的剂量施用CHIN117。体重趋势显示CHIN117使体重增长降低约3克(图4A,B)。八周后,小鼠发展出胰岛素抵抗,如OGTT结果所示(图4E,F)。用CHIN117对小鼠的治疗逆转了饮食的作用并降低了OGTT的AUC。此外,CHIN117在统计学上降低了AST、ALT和LDL水平,从而抵消了HFD-F饮食的肝脏毒性作用(图4G-H)。
喂饲HFD-F饮食持续8周的小鼠发展出如肝脏切片中H&E染色所揭示的与人类NASH相似的特征,具有微囊性脂肪变性、肝细胞肿胀、小叶性炎症和巨噬细胞流入(图5A),从而致使肝脏脂肪变性(NAS)评分显著增加(图3B)。此外,HFD-F说明体重指数(BMI)和附睾白色脂肪组织(eWAT)的重量、棕色脂肪组织(BAT)的重量和肝脏的重量都增加(图5C-I)。CHIN117通过降低肝脏脂肪变性、BMI和eWAT、BAT和肝脏重量几乎完全逆转了疾病(图5)。
CHIN117由于其卓越的药代动力学特性(pH7.4的水溶性等于66μM且LogD=2.0)及其有前景的代谢稳定性(在体外暴露于微粒体酶时t1/2=578min(CLint=4),并且在体外暴露于还含有负责第二阶段代谢的酶的S9级分时t1/2=385min(CLint=6))而特别值得关注。
Claims (10)
1.式(I)的化合物或其药学上可接受的盐或溶剂合物:
其中:
R1选自由以下组成的组:H、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有一个取代基R8的直链或支链O-C3-6烷基;
R2选自由以下组成的组:H、C1-6羟烷基、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基;
R3选自由以下组成的组:H、COOH、COO-C1-6烷基、CH2OH;
条件是:
-当R2是H,R1或R3不是H;或者
-当R1是任选取代有一个取代基R8的直链O-C3-6烷基,R2和R3之间的至少一者不是H;
R4选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R5选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R6选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基、OH和任选取代有一个取代基R8的直链或支链C1-6烷氧基;
条件是当R4、R5和R6之间的一者是COOH或CH2OH时,R4、R5和R6之间余下者中的至少一者不是H,
R7选自由以下组成的组:
R8选自由以下组成的组:OH、COOH、COO-C1-6烷基;
R9选自由以下组成的组:
其中R10选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R11选自由以下组成的组:H、OH、COOH、COO-C1-6烷基、C1-6羟烷基;
并且R12选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
不包括以下化合物:
2.根据权利要求1所述的式(I)的化合物,其特征在于,R1选自由以下组成的组:H、O-异丙基、O-正丙基、O-仲丁基、O-正戊基、O-2-甲基丁基、-CH2-R7、-O-(CH2)3-4-R8。
3.根据权利要求1所述的式(I)的化合物,其特征在于,R2是任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基。
4.根据权利要求1所述的式(I)的化合物,其特征在于,R2选自由以下组成的组:H、CH2OH、-CH2-R7、任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:COOH、COO-C1-6烷基、C1-6羟烷基、-CH2-R9。
5.根据权利要求1所述的式(I)的化合物,其特征在于,
R3选自由以下组成的组:H、COOH、COOCH3、CH2OH;
R4选自由以下组成的组:H、COOH、COOCH3、CH2OH;和
R5选自由以下组成的组:H、COOH、COOCH3、CH2OH。
8.式(Ia)的化合物或其药学上可接受的盐或溶剂合物,用于作为药物使用
其中:
R1选自由以下组成的组:H、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有一个取代基R8的直链或支链O-C3-6烷基;
R2选自由以下组成的组:H、C1-6羟烷基、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基;
R3选自由以下组成的组:H、COOH、COO-C1-6烷基、CH2OH;
条件是:
-当R2是H,R1或R3不是H;或者
-当R1是任选取代有一个取代基R8的直链O-C3-6烷基,R2和R3之间的至少一者不是H;
R4选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R5选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R6选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基、OH和任选取代有一个取代基R8的直链或支链C1-6烷氧基;
条件是当R4、R5和R6之间的一者是COOH或CH2OH时,R4、R5和R6之间余下者中的至少一者不是H,
R7选自由以下组成的组:
R8选自由以下组成的组:OH、COOH、COO-C1-6烷基;
R9选自由以下组成的组:
其中R10选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R11选自由以下组成的组:H、OH、COOH、COO-C1-6烷基、C1-6羟烷基;
并且R12选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基。
9.根据权利要求8使用的所述式(Ia)的化合物,用于预防和/或治疗选自由以下组成的组的病症:胃肠道病症、肝脏疾病、心血管疾病、动脉粥样硬化、代谢性疾病、代谢性病症、感染性疾病、癌症、肾脏病症、炎症性病症和神经系统病症。
10.药物组合物,包含:
式(Ia)的化合物或其药学上可接受的盐或溶剂合物:
其中:
R1选自由以下组成的组:H、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有一个取代基R8的直链或支链O-C3-6烷基;
R2选自由以下组成的组:H、C1-6羟烷基、任选取代有一个取代基R7的直链或支链C1-6烷基、任选取代有至少一个独立地选自由以下组成的组的取代基的苯基:H、COOH、COO-C1-6烷基、C1-6羟烷基和任选取代有一个取代基R9的直链或支链C1-6烷基;
R3选自由以下组成的组:H、COOH、COO-C1-6烷基、CH2OH;
条件是:
-当R2是H,R1或R3不是H;或者
-当R1是任选取代有一个取代基R8的直链O-C3-6烷基,R2和R3之间的至少一者不是H;
R4选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R5选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R6选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基、OH和任选取代有一个取代基R8的直链或支链C1-6烷氧基;
条件是当R4、R5和R6之间的一者是COOH或CH2OH时,R4、R5和R6之间余下者中的至少一者不是H,
R7选自由以下组成的组:
R8选自由以下组成的组:OH、COOH、COO-C1-6烷基;
R9选自由以下组成的组:
其中R10选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
R11选自由以下组成的组:H、OH、COOH、COO-C1-6烷基、C1-6羟烷基;
并且R12选自由以下组成的组:H、COOH、COO-C1-6烷基、C1-6羟烷基;
和至少一种药学上可接受的辅料。
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PCT/IB2021/057131 WO2022029640A1 (en) | 2020-08-04 | 2021-08-04 | Quinoline compounds as selective and/or dual modulators of bile acid receptors and leukotriene cysteinyl receptors |
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EP (1) | EP4192815A1 (zh) |
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EP0200101A2 (en) * | 1985-04-16 | 1986-11-05 | Usv Pharmaceutical Corporation | Aryl and heteroaryl ethers as agents for the treatment of hypersensitive aliments |
US4794188A (en) * | 1982-12-01 | 1988-12-27 | Usv Pharmaceutical Corporation | Certain unsymmetrical quinolinyl ethers having anti-inflammatory and anti-allergic activity |
CN1302206A (zh) * | 1997-10-17 | 2001-07-04 | 阿温蒂斯药物制品公司 | 喹啉衍生物的治疗用途 |
CN102131798A (zh) * | 2008-06-25 | 2011-07-20 | 英维沃医药有限公司 | 用作磷酸二酯酶10抑制剂的二取代的苯基化合物 |
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- 2021-08-04 BR BR112023002159A patent/BR112023002159A2/pt unknown
- 2021-08-04 KR KR1020237007773A patent/KR20230066341A/ko unknown
- 2021-08-04 CN CN202180068308.8A patent/CN116323560A/zh active Pending
- 2021-08-04 EP EP21765705.5A patent/EP4192815A1/en active Pending
- 2021-08-04 MX MX2023001448A patent/MX2023001448A/es unknown
- 2021-08-04 WO PCT/IB2021/057131 patent/WO2022029640A1/en active Application Filing
- 2021-08-04 JP JP2023508081A patent/JP2023539034A/ja active Pending
- 2021-08-04 CA CA3187998A patent/CA3187998A1/en active Pending
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US4794188A (en) * | 1982-12-01 | 1988-12-27 | Usv Pharmaceutical Corporation | Certain unsymmetrical quinolinyl ethers having anti-inflammatory and anti-allergic activity |
EP0200101A2 (en) * | 1985-04-16 | 1986-11-05 | Usv Pharmaceutical Corporation | Aryl and heteroaryl ethers as agents for the treatment of hypersensitive aliments |
CN1302206A (zh) * | 1997-10-17 | 2001-07-04 | 阿温蒂斯药物制品公司 | 喹啉衍生物的治疗用途 |
CN102131798A (zh) * | 2008-06-25 | 2011-07-20 | 英维沃医药有限公司 | 用作磷酸二酯酶10抑制剂的二取代的苯基化合物 |
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WO2022029640A1 (en) | 2022-02-10 |
CA3187998A1 (en) | 2022-02-10 |
ZA202301649B (en) | 2024-06-26 |
US20230357159A1 (en) | 2023-11-09 |
KR20230066341A (ko) | 2023-05-15 |
MX2023001448A (es) | 2023-06-22 |
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