CN113912547A - 取代苯丙咪唑类衍生物及其应用 - Google Patents
取代苯丙咪唑类衍生物及其应用 Download PDFInfo
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- CN113912547A CN113912547A CN202010664800.9A CN202010664800A CN113912547A CN 113912547 A CN113912547 A CN 113912547A CN 202010664800 A CN202010664800 A CN 202010664800A CN 113912547 A CN113912547 A CN 113912547A
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- alkyl
- heterocycloalkyl
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Abstract
本发明涉及式(I)所示的取代苯丙咪唑类衍生物,及其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体。所述化合物是PPARα和PPARδ激动剂,因此可用于治疗和/或预防与PPARα和/或PPARδ导致的疾病的方法,例如非酒精性脂肪性肝炎、杜氏肌营养不良综合症、老年痴呆、肿瘤和PBC(原发性胆汁性胆管炎)等疾病的治疗方法中
Description
技术领域
本发明涉及新型有机化合物取代苯丙咪唑类衍生物及其应用,尤其是涉及对δ亚型过氧化物酶增殖物激活受体(PPARδ)有激动作用的化合物及其制备方法及其在治疗心血管疾病方面的应用。
背景技术
肥胖、抗胰岛素(I-型糖尿病)、脂质代谢紊乱、高血压为特征的代谢综合症,对人类的健康特别是老龄社会的健康构成了极大的威胁。
代谢综合症是指脂代谢平衡、能量平衡和糖代谢平衡等死去平衡或者紊乱而引起的各种相应症状。因此,以维持能量平衡、脂肪和糖的体内平衡为目标的治疗方案便成为了治疗代谢综合症的有效方法。亲核受体(Nuclear receptors(NRs)在维持能量平衡、细胞乃至整个个体的脂肪和糖的体内平衡方面起着重要的作用。在亲核受体中,过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)是重要的家族之一(Acta Cryst.,2009,D65,786–795;J.Med.Chem.2012,55,4027-4061;Nature Reviews Cancer,2012,12:181-189;Immunology Letters,2020,220:32-37)。
PPARs主要有三种亚型:α、γ和δ。这些受体属于细胞核受体和转录因子超家族,它们在与某些脂肪酸和/或它们的脂肪代谢产物接触时被激活。激活的PPAR与9-顺式维甲酸受体(RXR或者类视黄质X受体)形成异二聚体并于靶基因启动子的特定应答元件(PPRE或者过氧化物酶体增值物应答元件)结合,由此提供转录控制(Pharmacology & Therapeutics, 2017,179:142–157;The Journal of Biological Chemistry,1999,274:6718-6725;Signal Transduction and Targeted Therapy,2020.5:4-5)。
PPARα控制(肝脏和肌肉的)脂质代谢和葡萄糖的体内稳态,通过直接控制编码涉及脂质体内稳态的蛋白质的基因的转录来影响细胞内脂质和糖类的代谢,具有抗炎和抗增殖效力,并且通过刺激胆固醇流出来防止胆固醇在巨噬细胞中蓄积的致动脉粥样硬化效应(Expert Opinionon Investigational Drugs,2014,23:10,1441-1448;Bioorg.Med.Chem.2007,15,5177-5190)。
PPRAγ是脂肪形成的关键调节剂。而且,它参与成熟脂肪细胞的脂质代谢、葡萄糖体内稳态,特别是胰岛素抵抗、炎症、巨噬细胞胆固醇蓄积和细胞增殖。因此,PPRAγ在肥胖症、胰岛素抵抗和糖尿病的发病机理中起作用(Nature Reviews Cancer,2012,12:181- 189)。此外,PPRAδ还参与脂质和碳水化合物代谢的控制、能量平衡、神经变形、肥胖症、巨噬泡沫细胞的形成和炎症(Scientific Reports,2016,6,1–12)。
最近的动物药理试验模型研究表明,PPARδ能增强脂肪组织和肌肉脂肪酸分解代谢和能量解偶联,抑制巨噬细胞源性炎症。多方面控制体重增加,增强身体耐受力,提高胰岛素敏感度并改善动脉粥样硬化,因而PPARδ配体可能成为治疗高脂血症、肥胖、胰岛素抵抗、动脉粥样硬化的有效药物(Leukemia 2018,32:184–193;Scientific Reports,2019.9:1-12)。
因此,PPAR各亚型特别是PPARα/δ激动剂的研究开发成为了学术界工业界的一个重要领域。
开发较快的有Genfit公司的Elafibranor(FR2864956A1;Expert Opinion on InvestigationalDrugs,2014,23:10,1441-1448)开发较快的。Elafibranor,又名GFT-505并且化学名为1-(4-甲基硫苯基)-3-(3,5-二甲基-4-羧基二甲基甲氧基苯基)丙-2-烯-1-酮(具有如下结构),是Genfit公司研发PPARα/δ激动剂。该化合物作为脂质代谢改善剂,用于治疗血脂异常、2型糖尿病、非酒精性脂肪肝病,已经进入了III-期临床。
另外,WO9728115A1中记载了L-165041(Merck)作为糖尿病治疗药和抗肥胖药的用途;WO WO2004007439A1中记载了作为使联芳衍生物的血中HDL上升的药物的用途。类似的专利还包括:US7781469B2(吡唑衍生物、Lilly)、US20100029949A1(苯并异噁唑衍生物、武田)、WO2003072100A1(噻吩衍生物、Eli、Lilly)、WO2017180818A1(咪唑衍生物,Mitobridge)。
尽管已存在Elafibranor及相关的研究,社会对PPARα/δ介导相关疾病的治疗仍然有较高的期待。特别是提高相关药物的药代动力学特性或/和药效动力学表现,仍然需要不断地努力。
另一方面,本发明人已经对具有苯并异噁唑环的、具有PPARδ的转录激活作用的化合物提出了专利申请(WO 01/79197、WO 03/033493等)。
后述的通式(I)和(II)表示的本发明化合物与上述GW-501516在结构上具有明确的差异,而且在上述的公知文献中并没有明确公开这些化合物。
发明内容
式(I)的化合物,或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体:
其中,
R1选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、卤素、氨基、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烯氧基、炔氧基、氨基、烷基氨基、氨基烷基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基、酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基。
R1可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基。
R2选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、-CONHR5、-CSNHR6、-SR7、卤素、氨基、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烷基氨基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基。
R2可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基。
R3选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、-SR7、卤素、氨基、烷基、烷氧基、烷氧烷基、杂烷基、杂环烷基、芳基烷基、环烷基、杂环芳基烷基、杂环烷基、杂环烯基、烯氧基、炔氧基、烷基氨基、氨基烷基、烷基氨基羰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基。
R3可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基。
R4选自:H、-CN、-NO2、-CF3、-OCF3、-SR7、卤素、氨基、烷基、烷氧基、烷氧烷基、杂烷基、杂环烷基、芳基烷基、环烷基、杂环芳基烷基、杂环烷基、杂环烯基、烯氧基、炔氧基、烷基氨基、氨基烷基、烷基氨基羰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基。
R4可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基。
R5选自:H、烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基。
R6选自:H、烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基。
R7选自:H、烷基、杂环烷基、环烷基、芳基、杂环芳基、杂环烷基、杂环烯基。
m、n和p各自独立选自0-6。
X、Y和Z各自独立选自:共价键、(CH2)q、-O-、-S-、-NH-、-SO2-、-CONH-;其中q为0-4。
在某些具体实施方案中,优选的A为:H、C1-C10烷基、C1-C10链烯基、C1-C10杂烷基、链炔基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基、酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、烷基、链烯基、链炔基、卤代烷基、卤代烯基。
在另一具体实施方案中,优选的X为:共价键。
在另一具体实施方案中,优选的Y为:-O-和-S-。
在另一具体实施方案中,优选的Z为:共价键。
在另一具体实施方案中,优选的Z为:-O-。
在另一具体实施方案中,优选的Y为:共价键、-O和-S-。
在另一具体实施方案中,优选的R1为:-Br,并且优先连接到苯并咪唑环的C5位上,C5-Br。
在另一具体实施方案中,优选的R2为:C1-C4烷基。
除通式(I)所表示的化合物以外,本发明还包括这些化合物的药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体、药学上可接受的前药和医药活性代谢物,和这些代谢物在药学上可接受的盐。
本发明包含了通式(I)所表示的化合物与药学上可接受的稀释剂、赋形剂或载体所形成的任何一种药物剂型。
所述化合物是PPARα和PPARδ激动剂,因此本发明提供使用有效量的通式(I)所表示的化合物单独或者与其它药物联合使用进行治疗治疗和/或预防与PPARα和/或PPARδ导致的疾病的方法,例如非酒精性脂肪性肝炎、杜氏肌营养不良综合症、老年痴呆和肿瘤等疾病的治疗方法中。
由PPAR所介导特别是和PPARα和PPARδ介导的疾病包括但不限于:高脂血症、脂质异常症、高胆固醇血症、高TG血症、低HDL血症、高LDL和/或非HDL血症、高VLDL血症、脂蛋白异常症、低载脂蛋白A-I血症、动脉硬化性疾病、冠状动脉疾病、脑血管疾病、末梢血管疾病、代谢综合症、X综合征、肥胖、糖尿病、高血糖、胰岛素抵抗、糖耐量减低、高胰岛素血症、糖尿病并发症、心力衰竭、心肌梗塞、心肌病、高血压、脂肪肝、非酒精性脂肪肝炎、血栓、阿尔茨海默氏病、神经退行性疾病、脱髓鞘疾病、多发性硬化症、肾上腺脑白质营养不良、皮肤炎、银屑病、痤疮、皮肤老化、毛发异常、炎症、哮喘、过敏性肠综合征、溃疡性大肠炎、克罗恩病、胰腺炎、以及包括结肠癌、大肠癌、皮肤癌、乳腺癌、前列腺癌、卵巢癌、肺癌的癌症。
在另一具体实施方案中,由PPARδ介导的疾病为:各种脂质异常症、代谢综合症、肥胖、动脉粥样硬化症或糖尿病。
在另一具体实施方案中,由PPARδ介导的疾病为:NASH和杜氏肌营养不良综合症。
在另一具体实施方案中,由PPARδ介导的疾病为:原发性胆汁肝硬化和胆管炎,包括老年痴呆和肿瘤。
在另一具体实施方案中,由PPARδ介导的疾病为:增加T淋巴细胞的能量和活化性能而增强免疫功能,还有可转化肿瘤细胞为脂肪细胞,降低癌症转移等。
在另一具体实施方案中,所述肥胖是内脏脂肪型肥胖。
本申请还提供了上述本发明的化合物,其用于治疗和/或预防由PPARα、PPARδ介导的疾病。
本申请还提供了治疗和/或预防由PPARα、PPARδ介导的疾病的方法,其包括向有此需要的对象给予上述本发明的化合物。
实施方案详述
定义
如本文所用,术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
本发明所使用的术语“不被取代”是指无取代基或仅被氢取代。
本发明所使用的部分术语定义如下:
“卤素”是指氟、氯、溴和碘。
“烷基”当作一基团或一基团的部分时是指直链或者带有支链的脂肪烃基团。优选烷基为C1-C14的烷基;更优选为:C1-C10烷基;最优选为C1-C6,除非另有指明。直链或和带有支链的C1-C6烷基的实例包括,但不限于:甲基、乙基、正丙基、2-丙基、正丁基、异丁基、特丁基、己基等。
“烷基氨基”包括单烷基氨基和二烷基氨基两种,除非另有指明。“单烷基氨基”是指:(烷基-NH)-的基团;“二烷基氨基”是指:((烷基)2N)-的基团。其中,烷基见本文有关定义。该烷基基团优选C1-C6的烷基基团。实例包括,但不限于:N-甲胺基、N-乙胺基、N-异丙胺基、N,N-(二乙基)胺基等。
“氨基烷基”是指:(氨基-烷基)-的基团。其中,烷基见本文有关定义。实例包括,但不限于:氨基乙基、1-氨基丙基、1-氨基丙基等。
“芳基氨基”包括单-芳基氨基和二-芳基氨基两种,除非另有说明。单-芳基氨基是指:(芳基-)NH-的基团、二-芳基氨基是指式(芳基)2N-的基团;芳基的定义见本文相关部分。
“酰基“包括(烷基-CO)-的基团和(芳基-CO)-的基团,除非另有说明。其中烷基或芳基均见本文中的有关定义。酰基的实例包括,但不限于:乙酰基、丙酰基、异丁酰基、苯甲酰基等。
“酰胺基“包括(烷基-CONH)-的基团和(芳基-CONH)-的基团,除非另有说明。其中,烷基或芳基均见本文中的有关定义。酰胺基的实例包括,但不限于:乙酰胺基、丙酰胺基、丁酰胺基、异丁酰胺基、苯甲酰胺基等。
“烯基”作为一基团或一基团的一部分时是指至少含有一个碳-碳双键的脂肪烃基团,可为直链也可以带有支链。优选具有C2-C14的烯基。C2-C12则更好;最为优选的是C2-C6的烯基。该基团可在其主链中含有多个双键且其构象可各自为E或Z。烯基基团的例子包括,但不限于:乙烯基、丙烯基等。
“烷氧基”是指(烷基-O)-的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优选的。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基等。
“烯氧基”是指(烯基-O)-的基团。其中,烯基见本文有关定义。C1-C6的烯氧基为优选的。
“炔氧基”是指(炔基-O)-的基团。其中,炔基见本文有关定义。C1-C6的炔氧基为优选的。
“烷氧羰基”是指(烷基-O-C(O))-的基团。其中,烷基见本文有关定义。优选的烷基基团为C1-C6烷基。其实例包括,但不限于:甲氧羰基、乙氧羰基等。
“烷基亚磺酰基”是指(烷基-S(O))-的基团。其中,烷基见本文有关定义。优选的烷基为C1-C6烷基基团。烷基亚磺酰基基团包括,但不限于:甲基亚磺酰基、乙基亚磺酰基等。
“烷基磺酰基”是指(烷基-S(O)2-O)-的基团。其中,烷基见本文有关定义。该优选的烷基为C1-C6烷基基团。其实例包括,但不限于:甲磺酰基、乙磺酰基等。
“烷基氨基羰基”是指烷基氨基-羰基基团。其中,烷基氨基见本文有关定义。
“环烷基”是指饱和或部分饱和的单环、稠环或螺环的碳环。以3-9个(例如3、4、5、6、7、8或9个)碳原子组成的环为优选的。实例包括,但不限于:环丙基、环丁基、环戊基、环己基等。
“环烷基烷基”是指环烷基-烷基基团。其中,环烷基和烷基部分见本文有关定义。单环烷基烷基基团包括,但不限于:环丙基甲基、环戊基甲基,环己基甲基、环庚基甲基等。
“杂环烷基”是指至少含有一个选自N、S、O的杂原子的环烷基。优选含有1、2或3个杂原子。优选的环为3-14员环,更优选的环为4-7员环。杂环烷基包括,但不限于:吡咯烷基、二氢吡咯基、四氢吡咯基、二氢吡唑基、哌啶基、吗啉四氢呋喃基、四氢硫代呋喃基、四氢吡喃基等。
“杂环烯基”是指至少含有一个双键的杂环烷基。杂环烷基见本文有关定义。
“杂环烷基烷基”是指:(杂环烷基-烷基)-的基团。其中,杂环烷基和烷基部分见本文有关定义。杂环烷基烷基基团包括,但不限于:(2-四氢呋喃基)甲基、(2-四氢硫代呋喃基)甲基等。
“杂烷基”是指直链或含有支链烷基的基团,并且在主链中,至少含有一个或多个(例如1、2、3或4个)选自S、O和N的杂原子。优选含有2-14个(例如2、3、4、5、6、7、8、9、10、11或12个)原子链。杂烷基包括但不限于:醚类、硫醚类、烷基酯类,第二或第三烷基胺类、烷基亚磺酸类等。
“芳基”作为一基团或一基团的部分是指:(1)芳香性的单环或稠环;优选具有5-12个(例如5、6、7、8、9、10、11或12个)碳原子的芳香性碳环(环原子均为碳的环状构造)。芳基的实例包括,但不限于:苯基、萘基;(2)可以连接部分饱和的碳环,例如:苯基和C5-7环烷基或C5-7环烯基基团系互相稠合而形成一环状结构。实例包括,但不限于:四氢萘基,茚基或氢茚基等。芳基基团可被一个或多个取代基取代。
“芳基烯基”是指(芳基-烯基)-的基团。其中,芳基和烯基见本文有关定义。示例性的芳基烯基基团包括,但不限于:苯基丙烯基等。
“芳烷基”是指(芳基-烷基)-的基团。其中,芳基和烷基部分见本文有关定义。示例性的芳烷基基团包括,但不限于:苯甲基,苯乙基、1-萘甲基等。
“环烯基”是指非芳香性单环或多环环系。其至少含有一个碳-碳双键且每环优选具有5-10个(例如5、6、7、8、9、10个)碳原子。示例性的单环状环烯基环包括,但不限于:环戊烯,环己烯或环庚烯。环烯基团可被一个或多个取代基取代。
“杂芳基”是指单环性或稠合的多环芳香杂环。优选含有一个或多个(例如1、2、3或4个)选自N、O或/和S的杂原子的5员、6员或7员芳香环。典型的杂芳基取代基包括实例,但不限于:呋喃基、噻吩基、吡咯、吡唑、三唑、噻唑、吡啶、嘧啶、吡嗪、吲哚、苯并咪唑等。
“杂芳烷基”是指(杂芳基-烷基)-的基团。其中,杂芳基和烷基部分见本文有关定义。示例性的杂芳烷基基团包括但不限于:2-呋喃甲基、3-呋喃甲基、2-吡啶甲基等。
本发明包括通式(I)所表示的化合物及其可能的各种异构形式。包括:非镜像异构体、镜像异构体、互变异构体和“E”或“Z”构型异构体的几何异构体等。任何具有一定基础的化学工作者均可以分离出上述光学纯或者立体异构纯的化合物。
本发明包括通式(I)所表示的化合物及其可能的消旋体或/和镜像异构物/或/和非镜像异构物的混合物。
此外,通式(I)所表示的化合物在应用上也涵盖该化合物的溶剂化及非溶剂化形式。因此,各式均包括具有所指明构造的化合物,包括其水合及无水合形式。
如本文所用,术语“药学上可接受的盐”是指,在可靠的医学判断范围内,适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等,并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如,Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐,例如盐酸、氢溴酸、磷酸、硫酸和高氯酸,或与有机酸形成的盐,例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐,例如,离子交换方法。其它药学上可接受的盐包括:已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐,等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐,等等。如果合适的话,其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子,反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”指本发明化合物与水进行配位形成的配合物。
本发明化合物可包括一个或多个不对称中心,且因此可以存在多种“立体异构体”形式,例如,对映异构体和/或非对映异构体形式。例如,本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体),或者可为立体异构体的混合物的形式,包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离,所述方法包括:手性高压液相色谱法(HPLC)以及手性盐的形成和结晶;或者优选的异构体可通过不对称合成来制备。
以下描述本发明的药理效果。
本发明化合物的PPARδ激活作用如下进行测定(测定试验化合物(实施例化合物)的PPAR激活作用)。
将受体表达质粒(pSG5-GAL4-hPPARα或γ或δ(LBD))、荧光素酶表达质粒(pUC8-MH100×4-TK-Luc)和β-半乳糖苷酶表达质粒(pCMX-β-GAL)(Kliewer,S.A.et.al.,(1992)Nature,358:771-774)导入CV-1细胞(ATCC)。使用脂质转染试剂DMRIE-C或Lipofectamin2000(Invitrogen)进行基因导入后,在供试化合物的存在下培养42小时。测定溶解细胞的荧光素酶活性和β-GAL活性。荧光素酶活性用β-GAL活性修正,PPARα、γ和δ各自的相对的配体活性的计算方法如下:以用GW-590735(PPARα选择性激动剂)处理过的细胞的荧光素酶活性值为100%,计算PPARα的相对的配体活性;以用Rosiglitazone处理过的细胞的荧光素酶活性值为100%,计算PPARγ的相对的配体活性;以用GW-501516处理过的细胞的荧光素酶活性值为100%,计算PPARδ的相对的配体活性。
术语“前药”包括其本身可以是具有生物活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式(I)的一类化合物,或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不限于)所属化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
如本文所用,术语“受试者”包括但不限于:人(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻的成人、中年的成人或年长的成人))和/或非人的动物,例如,哺乳动物,例如,灵长类(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中,受试者是人。在另一些实施方案中,受试者是非人动物。
除非另作说明,否则,本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用,它降低疾病、障碍或病症的严重程度,或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”),还包括受试者开始患有具体疾病、障碍或疾病之前发生的作用(“预防性治疗”)。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如,本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药,或与另一治疗剂一起呈单一单位剂型同时给药。
“药学上可接受的赋形剂”是指不会破坏一起调配的化合物的药理学活性的无毒载体、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载体、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、十二指肠、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、干露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如,石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其他本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性释放剂,如水或其他溶剂,增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物。
本发明提供了在需要其的受试者中治疗和/或PPARα和/或PPARδ导致的疾病相关病症的方法,它包括步骤:给需要治疗的受试者给药本发明化合物,或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物,或给药本发明所述的药物组合物。
本发明化合物可用于治疗PPARα和/或PPARδ导致的疾病选自:涉及肝脏细胞的病理破坏、炎症、退化和/或增殖的任何急性或慢性肝病,与代谢综合症相关的并发症、胰岛素抵抗、糖尿病、血脂异常、动脉粥样硬化、心血管疾病、肥胖症、高血压、炎性疾病、纤维化疾病、神经变形疾病或者癌症。
本发明化合物可治疗的纤维化疾病包括但不限于:肺纤维化、特发性肺纤维化、囊性纤维化、心内膜心肌纤维化、纵膈纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化、肾源性系统化纤维化、克罗恩病、陈旧性心肌梗塞、硬皮病/系统性硬化症、关节纤维化或粘连性囊炎。
本发明化合物可治疗由PPARδ介导的疾病,包括但不限于:高脂血症、脂质异常症、高胆固醇血症、高TG血症、低HDL血症、高LDL和/或非HDL血症、高VLDL血症、脂蛋白异常症、低载脂蛋白A-I血症、动脉硬化性疾病、冠状动脉疾病、脑血管疾病、末梢血管疾病、代谢综合症、X综合征、肥胖、糖尿病、高血糖、胰岛素抵抗、糖耐量减低、高胰岛素血症、糖尿病并发症、心力衰竭、心肌梗塞、心肌病、高血压、脂肪肝、非酒精性脂肪肝炎、血栓、阿尔茨海默氏病、神经退行性疾病、脱髓鞘疾病、多发性硬化症、肾上腺脑白质营养不良、皮肤炎、银屑病、痤疮、皮肤老化、毛发异常、炎症、哮喘、过敏性肠综合征、溃疡性大肠炎、克罗恩病、胰腺炎、以及包括结肠癌、大肠癌、皮肤癌、乳腺癌、前列腺癌、卵巢癌、肺癌的癌症。
本发明化合物可治疗的癌症包括但不限于:肾细胞癌、胃肠道间质瘤(GIST)、胃癌、肝癌、与神经纤维瘤相关的脑膜瘤、胰腺神经内分泌肿瘤、胰腺外分泌肿瘤、白血病、骨髓增殖性/骨髓增生异常疾病、肥大细胞增多症、皮肤纤维肉瘤、包括乳腺癌、肺癌、甲状腺癌或结直肠癌的实体癌、或前列腺癌。
取代苯丙咪唑类衍生物的合成
通式(I)所表示的化合物可以用下面讨论的合成路线和合成方法来合成。所用原材料方便易得。但是,本发明所用的合成路线和合成方法,可以广泛应用于类似物的合成,只需要变换起始原材料即可。例如,在本文实例中没有详细描述的化合物的合成,只要把始原材料更换成相应目标化合物的起始原材料,依据化学常识,在有必要时稍为改变一下反应条件即可合成出所需要的目标化合物。
各具体实施方案的试剂可利用说明如下的反应途径或合成流程图,使用此项技艺中可得的技术,以可取得的起始原料加以制备。具体实施方案的特定化合物的制备详细说明于下列实施例中,但熟习此项技术者知道所说明的化学反应可适用于制备不同具体实施方案中的多其他试剂,例如:非示例化合物的合成可成功地藉由精通本领域的熟练技术人员显见的修饰加以施行,例如:藉由适当地保护干扰基团,藉由改变成该项技术中已知的其他适当的试剂,或藉由进行反应条件的例行性修饰。在有机合成中的适当保护基团的列表可参见G.M.Peter的ProtectiveGroups in Organic Synthesis,Wiley,2007或者,本文中揭示或此项技艺中已知的其他反应可被认定为具有用以制备各具体实施方案的其他化合物的适用性。
可用以合成化合物的试剂可根据此项技艺中已知的技术加以取得或制备。
在下列实例中,除非另有指明,所有温度为摄氏度。
各种起始原料和试剂均来自市售。供应商包括但不限于:Aldrich ChemicalCompany、Lancaster Synthesis Ltd等等。市售原料和试剂均不经进一步纯化直接使用,除非另有指明。
玻璃器皿用烘箱干燥和/或加热干燥。反应用玻璃硅胶-60F254平板(0.25mm)(TLC)上进行跟踪。分析性薄层层析并以适当的溶剂比例(v/v)加以展开。以TLC上起始物质耗尽时为反应终点(J.Org.Chem.,Vol.43,No.14,1978 2923-2925)。
通常,后续处理是用反应所用的溶剂将反应液的体积增大一倍,然后用总体积的25%萃取溶剂来进行萃取三次,除非另有指明。将含产物萃取经无水硫酸钠脱水,在加以过滤于旋转蒸发器上,于减压之下将溶剂蒸发并注意溶剂于真空中的去除。最后,用快速柱层析分离得到目标化合物(J.Org.Chem.,1978;43:2923)。
1H NMR图谱是用Bruker仪器(200-400MHz)测定而得,化学位移用ppm表示。使用氯仿作为参照标准(7.25ppm)或四甲基硅烷内标准(0.00ppm)。视需要,也可以使用其它NMR常用的溶剂。1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。所有熔点均未经修正。
下面的实例仅仅是用来说明所发明的具体化合物的合成方法。但在合成方法上并没有任何限制。在下面未列出的化合物,也可以用与下面同样的合成路线与合成方法,选择适当的起始原材料、在有必要的地方稍加适当的常识性的反应条件调整即可加以制备。
合成
在通式(I)中,当R1=C5-Br、R3=H、R4=C”'2-乙基时,相应的化合物明白化合物XVI可以用合成路线1所示的方法来合成。例如,X=键、Y=O、S时,通式(I)中所示的化合物可以用4-溴-2-乙基苯酚为原料,在钯碳的推化下引入甲酰羧基,经过还原、缩合得化合物VI。合适的化合物1-氟-4-取代-2-硝基苯VII与合适的化合物VIII缩合得化合物IX,经过还原、酰化、环合、脱保护,得到化合物XIV。化合物XIV与合适的化合物V缩合,然后水解,得到目标化合物XVI。
合成路线1
具体来说,当R1=C5-Br、R3=H、R4=C”'2-乙基时,通式(I)所示的目标化合物(XVI),可以用合成路线1所示的方法来合成。例如,X=键,Y、Z=O,S时,可以用4-溴-2-乙基苯酚为原料,在钯碳的推化下引入甲酰羧基,得到II。在LAH的还原下,得到羟基衍生物III;后者与合适的溴代衍生物IV在合适的碱的催化下,得到选择性缩合化合物V,再经氯代,就得到VI。与此同时,在合适的碱的催化下,选择合适的化合物1-氟-4-取代-2-硝基苯VII与相对应的化合物VIII缩合得化合物IX。后者在合适还原剂的作用下还原,得到化合物X。化合物XI与合适常见的缩合剂作用,然后与化合物X反应得XII。在加热条件下酸性环合得化合物XII。以二氯甲烷为溶剂,经过BBr3处理,化合物XIII转化为XIV。用二氯甲烷做溶剂,在合适的碱摧化下,化合物V与化合物XIV缩合,所得到的化合物XV经过碱水解,即得到目标化合物XVI。
在通式(I)中,当R3=H、R4=C”'2-乙基时,相应的化合物目标化合物XXXV可以用合成路线2所示的方法来合成。例如,X、Y=键,Z=O、S时,通式(I)中所示的化合物可以用4-溴-2-乙基苯碘为原料,在推化下引入甲醛基,经过缩合、还原得化合物XX。合适的硼烯剂在靶催化下,引入烯基得化合物XXI。后者经氧化、还原、氯代,即得到XXIV。另一方面,还是得1-氟-2-硝基取代苯衍生物XXV经过氨化、还原得化合物XXVIII。在合适的缩合剂的作用下,将相对应的化合物XXIX引入到XXVIII上,得到XXX。后者在酸条件下环合,催化下脱保护,得化合物XXXII。选择合适的化合物XXXIII,与化合物XXXII缩合,然后碱性水解,即得到所需要的明白化合物XXXV。
合成路线2
在通式(I)中,当R3=H,R4=C”'2-乙基时,相应的化合物目标化合物XXXV可以用合成路线2所示的方法来合成。例如,X、Y=键,Z=O、S时,通式(I)中所示的化合物可以用4-溴-2-乙基苯碘为原料,在推化下引入甲醛基,得到化合物XVIII。在合适的碱存在下,化合物XVIII与三乙基膦酰乙酸酯反应,得到化合物XIX。后者经过还原,得到XX。化合物XX与合适的硼烯剂反应,在钯试剂催化下,加热反应得化合物XXI。使用合适的氧化剂,例如锇酸钾,在丙酮水溶液中,XXI可以氧化为XXII。后者通过功能基转化,经羟基衍生物XXIII,得到氯代衍生物XXIV。与此同时,在合适的碱的催化下,选择合适的化合物1-氟-2-硝基苯的衍生物XXV,在合适碱的催化下,与XXVI反应,得到氨化产物XXVII。化合物XXVII经过还原后,在缩合剂的作用下,得到化合物XXX。在酸性条件下,例如在冰乙酸的作用下,发生环合反应,得到化合物XXXI。后者经过还原,例如氢化还原,脱去保护基,得到化合物XXII。在合适碱的作用下,化合物XXXII与化合物XXXIII在DMF中,发生取代反应,所得化合物XXXIV经碱性水解后得到目标化合物XXXV。
下面结合实例进一步阐明本发明的内容。目的在于让具备有本领域相关的基本知识的技术人员更加清楚的了解并实践本发明的具体内容。但是,本发明的保护范围并不仅仅局限于这些实例。
实施例1
2-(4-((2-((5-溴-2-乙基--1H-苯并[d]咪唑-1-基)甲基)-苯氧基)甲基)-2-乙基苯氧基)乙酸(1)的制备。
实例1的化合物1可以用上述合成路线1的方法或者合成路线2的合成方法来实施。具体来说,只要选择需要的原料,合成方法可以用下式表示的具体路来合成。
步骤1 3-乙基-4-羟基苯乙酸甲酯(II-1)的合成
在反应瓶中,依次加入I-1(40.0g,0.2mol)、Pd(dppf)Cl2(14.6g,0.02mol)、乙酸钾(58.8g,0.6mol)和甲醇(200.0mL),用一氧化碳气球置换三次,在一氧化碳环境下70℃搅拌过夜。反应完毕后,减压蒸除溶剂,加入水(100.0mL)中,乙酸乙酯(150.0mL×3)萃取,有机相用饱和食盐水水洗,无水硫酸钠干燥,减压蒸除溶剂,得粗品,经硅胶柱[洗脱剂:石油醚-乙酸乙酯(1:2)]纯化,收集洗提液,减压蒸除溶剂,得黄色固体II-1(18.0g,收率:50.0%)。1H NMR(400MHz,CDCl3)δ:7.85(d,J=2.0Hz,1H),7.80(dd,J=10.4,6.4Hz,1H),6.78(d,J=8.4Hz,1H),5.41(s,1H),3.87(s,3H),2.68(q,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H)。
步骤2 2-乙基-4-羟甲基苯酚(III-1)的合成
在反应瓶中,加入II-1(15.0g,83.3mmol)和干燥的四氢呋喃(200.0mL),在氮气保护下搅拌,冰浴冷却至0℃。将氢化锂铝(3.8g,99.9mmol)分批缓慢加入其中,保持温度在0℃。加料完毕,继续在0℃下搅拌1h。依次将水(15.0mL)、15%氢氧化钠(15.0mL)和水(30.0mL)缓慢滴加到反应液中,保持温度在0℃,滴加完毕,升至室温,继续搅拌1小时。过滤,收集滤液,无水硫酸钠干燥,再过滤,收集滤液,减压蒸除溶剂,得白色固体III-1(8.0g,收率:63.1%)。1H NMR(400MHz,CDCl3)δ:7.16(d,J=2.0Hz,1H),7.10(dd,J=10.4,6.0Hz,1H),6.76(d,J=8.0Hz,1H),4.81(s,1H),4.61(d,J=5.6Hz,2H),2.67(q,J=7.6Hz,2H),1.26(t,J=4.8Hz,3H)。
步骤3 2-(2-乙基-4-羟甲基)苯氧-乙酸乙基(III-1)的合成
在反应瓶中,依次加入III-1(8.0g,52.6mmol)、溴乙酸乙酯(10.6g,63.2mmol,IV-A)、碳酸铯(25.7g,78.9mmol)和乙腈(100.0mL),室温搅拌过夜。反应完毕后,减压蒸除溶剂,加入水(50.0mL),乙酸乙酯(100.0mL×3)萃取,有机相用饱和食盐水水洗,无水硫酸钠干燥,减压蒸除溶剂,得粗品,经硅胶柱[洗脱剂:石油醚-乙酸乙酯(1:2)]纯化,收集洗提液,减压蒸除溶剂,得灰白色固体V-1(7.5g,收率:60.0%)。LCMS(方法B)纯度:90.75%,Rt=1.86min;MS实测值:238.1;MS实测值:221.4[M-17]。
步骤4 2-(2-乙基-4-氯甲基)苯氧-乙酸乙基(VI-1)的合成
在反应瓶中,加入V-1(100mg,0.42mmol)、N,N-二甲基甲酰胺(2滴)和干燥的二氯甲烷(4.0mL),在搅拌下冰浴冷却至0℃。将氯化亚砜(150mg,1.26mmol)缓慢滴加其中,加料完毕后,室温搅拌2小时。反应完毕后,减压蒸除溶剂,得黄色固体VI-1(122mg,收率:100.00%)。LCMS(方法A)纯度:91.98%,Rt=0.83min;MS实测值:256.1;MS实测值:257.2[M+H]+。
步骤5 4-溴-N-(2-甲氧基)苄基氧-2-硝基苯酚(IX-A)的合成
在反应瓶中,依次加入2-甲氧基苄胺(10.0g,73.1mmol)、VII-1(16.0g,73.1mmol)、三乙胺(14.7g,146.2mmol)和四氢呋喃(200.0mL),室温搅拌过夜。反应完毕后,减压蒸除溶剂,加入水(100.0mL)、乙酸乙酯(150.0mL×3)萃取,有机相用饱和食盐水水洗,无水硫酸钠干燥,减压蒸除溶剂,得黄色固体IX-1(22.0g,收率:89.8%)。1H NMR(400MHz,CDCl3)δ:8.49(s,1H),8.31(s,1H),7.43(d,J=2.0Hz,1H),7.41-7.19(m,2H),6.94-6.90(m,2H),6.79(d,J=9.2Hz,1H),4.52(d,J=6.0Hz,2H),8.49(s,3H)。
步骤6 4-溴-N1-(2-甲氧基)苄基-1,2-苯二胺(X-1)的合成
在反应瓶中,依次加入IX-1(22.0g,65.5mmol)、氯化铵(17.7g,327.4mmol)、铁粉(18.3g,327.4mmol)和甲醇(500.0mL),加热到70℃搅拌2h。反应完毕后,过滤,滤饼用甲醇洗,收集滤液,减压蒸除溶剂,加入水(100.0mL)、二氯甲烷(150.0mL×3)萃取,有机相用饱和食盐水水洗,无水硫酸钠干燥,减压蒸除溶剂,得灰白色固体X-1(19.6g,收率:98.0%)。LCMS(方法B)纯度:84.53%.Rt=1.99min;MS实测值:306.0;MS实测值:307.0[M+H]+。
步骤7 N-(5-溴2-(2-甲氧基苄基)苯胺-丙酰胺(X-1)的合成
在反应瓶中,依次加入X-1(1.5g,4.9mmol)、丙酸(0.36g,4.9mmol)、HATU(2.2g,5.9mmol)、三乙胺(0.99g,9.8mmol)和N,N-二甲基甲酰胺(30.0mL),室温搅拌3小时。反应完毕后,将反应液倒入水中,乙酸乙酯(60.0mL×3)萃取,有机相依次用水和饱和食盐水水洗,无水硫酸钠干燥,减压蒸除溶剂,得粗品,经硅胶柱[洗脱剂:石油醚-乙酸乙酯(3:1)]纯化,收集洗提液,减压蒸除溶剂,得灰白色固体XII-1(1.5g,收率:84.7%)。LCMS(方法B)纯度:93.39%.Rt=2.18min;MS实测值:362.1;MS实测值:363.2[M+H]+。
步骤8 5-溴-2-乙基-1-(2-甲氧基)苄基-1H-苯并[d]咪唑(XIII-1)的合成
在反应瓶中,加入XII-1(1.5g,4.14mmol)和冰乙酸(20.0mL),加热到60℃反应2h。反应完毕后,减压蒸除溶剂,得粗品,经硅胶柱[洗脱剂:石油醚-乙酸乙酯(3:1)]纯化,收集洗提液,减压蒸除溶剂,得黄色固体XIII-1(1.2g,收率:84.5%)。LCMS(方法B)纯度:97.21%,Rt=1.68min;MS实测值:344.1;MS实测值:345.2[M+H]+。
步骤9 5-溴-2-乙基-1-(2-羟基)苯基-1H-苯并[d]咪唑(XIV-1)的合成
在反应瓶中,加入XIII-1(1.5g,4.14mmol)和冰乙酸(20.0mL),加热到60℃反应2h。反应完毕后,减压蒸除溶剂,得粗品,经硅胶柱[洗脱剂:石油醚-乙酸乙酯(3:1)]纯化,收集洗提液,减压蒸除溶剂,得黄色固体XIV-1(1.2g,收率:84.5%)。LCMS(方法B)纯度:97.21%,Rt=1.68min;MS实测值:344.1;MS实测值:345.2[M+H]+。
步骤10 2-(4-((2-((5-溴-2-乙基--1H-苯并[d]咪唑-1-基)甲基)-苯氧基)甲基)-2-乙基苯氧基)乙酸乙基(XV-1)的合成
在反应瓶中,依次加入XIV-1(157mg,0.47mmol)、VI-1(122mg,0.47mmol)、碳酸钾(197mg,1.43mmol)和N,N-二甲基甲酰胺(5.0mL),室温搅拌过夜。反应完毕后,将反应液倒入水中,乙酸乙酯(20.0mL×3)萃取,有机相依次用水和饱和食盐水洗,无水硫酸钠干燥,减压蒸除溶剂,得粗品,经硅胶柱[洗脱剂:石油醚-乙酸乙酯(2:1)]纯化,收集洗提液,减压蒸除溶剂,得无色油状物XV-1(231mg,收率:88.2%)。LCMS(方法A)纯度:93.53%.Rt=0.75min;MS实测值:550.2;MS实测值:551.2[M+H]+。
步骤11 2-(4-((2-((5-溴-2-乙基--1H-苯并[d]咪唑-1-基)甲基)-苯氧基)甲基)-2-乙基苯氧基)乙酸(1)的合成
在反应瓶中,依次加入XV-1(231mg,0.42mmol)、甲醇(6.0mL)和2MLiOH(0.63mL,1.26mmol),室温搅拌3h。反应完毕后,减压蒸除溶剂后,加入水(6.0mL),然后用1M HCl调pH至5-6,过滤,滤饼依次用水洗,干燥,得白色固体1(XVI-1)(100mg,收率:45.7%)。HPLC-MS(方法D)纯度:97.10%,Rt=8.36min;MS实测值:522.2;MS实测值:523.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ:13.00(brs,1H,H9),7.79(d,J=1.6Hz,1H,H1),7.37-7.24(m,3H),7.14-7.09(m,2H),7.03(d,J=2.0Hz,1H,H7),6.90-6.84(m,2H),6.79(d,J=8.4Hz,1H),5.41(s,2H,H4),4.99(s,2H,H5),4.70(s,2H,H6),2.82(q,J=7.2Hz,2H,H2),2.58(q,J=7.6Hz,2H,H7),1.17-1.08(m,6H,H3,H8)。
实施例2-12
根据实施例1的方法,只要变换适当的起始原材料,即可以合成出广泛的各种各样的衍生物。实施例2-12是其中的一些代表性的实例(见表1)。
表1
另外,参考实施例1的方法,只要适当选择起始原材料,还可以合成出更加广泛的各种各样的衍生物,例如表2所列的化合物就是其中的一些实例。
表2
药理试验
I.试验方法
采用以下方法测定试验化合物(实施例化合物)的PPAR激活作用。
在CV-1细胞(ATCC)中导入受体表达质粒(pSG5-GAL4-hPPARα、γ或δ(LBD)、荧光素酶表达质粒(pUC8-MH100×4-TK-Luc)和β-半乳糖苷酶表达质粒(pCMX-β-GAL)(Kilewer,S.A.et.al.,(1992)Nature,358:771-774)。使用脂质转染试剂(Lipofectamine 2000(Invitrogen))进行基因导入后,在供试化合物的存在下培养约40小时。将可溶性细胞用于荧光素酶活性和β-GAL活性测定中。用β-GAL活性对荧光素酶活性进行校正,以用GW-590735(PPARα选择性激动剂)处理后的细胞的荧光素酶活性值为100%计算PPARα的相对配体活性、以用Rosiglitazone处理后的细胞的荧光素酶活性值为100%计算PPARγ的相对配体活性、以用GW-501516处理后的细胞的荧光素酶活性值为100%计算PPARδ的相对配体活性,并求出EC50。
II.试验结果
试验结果如表3所示。
表3 PPAR活性
II.试验结果
实验结果如表3所示。
PPAR活性:以对照药为100%时的试验化合物10-7M计的相对值
PPARα:GW-590735 10-6M
PPARγ:Rosiglitazone 10-5M
PPARδ:GW-501516 10-7M
由表3可知,试验化合物表现出优秀的PPARδ激活剂作用,特别是实施例5的化合物表现出强效且选择性的PPARδ激活剂作用。
说明于本发明的特定实例的细节并非用以被推断为其限制。可不离本发明的本质及范围进行各种同义及修饰,且已知这些同义具体实施方案是本发明之一部份。
Claims (13)
1.式(I)的化合物,或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体:
其中,
R1选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、卤素、氨基、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烯氧基、炔氧基、氨基、烷基氨基、氨基烷基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基、酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基;
R1可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基;
R2选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、-CONHR5、-CSNHR6、-SR7、卤素、氨基、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烷基氨基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基;
R2可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基;
R3选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、-SR7、卤素、氨基、烷基、烷氧基、烷氧烷基、杂烷基、杂环烷基、芳基烷基、环烷基、杂环芳基烷基、杂环烷基、杂环烯基、烯氧基、炔氧基、烷基氨基、氨基烷基、烷基氨基羰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基;
R3可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基;
R4选自:H、-CN、-NO2、-CF3、-OCF3、-SR7、卤素、氨基、烷基、烷氧基、烷氧烷基、杂烷基、杂环烷基、芳基烷基、环烷基、杂环芳基烷基、杂环烷基、杂环烯基、烯氧基、炔氧基、烷基氨基、氨基烷基、烷基氨基羰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基;
R4可以为一种取代非氢基,也可以是两种或者多种不同的非氢取代基;
R5选自:H、烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基;
R6选自:H、烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基;
R7选自:H、烷基、杂环烷基、环烷基、芳基、杂环芳基、杂环烷基、杂环烯基;
M、n和p各自独立选自0-6;
X、Y和Z各自独立选自:-O-、-S-、-NH-、-SO2-、-CONH-或(CH2)q,其中q为1-4的整数。
2.如权利要求1所述的化合物,其中R1选自:H、羟基、C1-14烷基、C1-14烷基、C2-14杂烷基、C5-12芳基C1-14烷基、杂芳基C1-14烷基、C1-6烷氧基C1-14烷基、氨基C1-14烷基和C4-7杂环烷基,其各自未被取代或被一个或多个独立地选自下组的取代基取代:卤素、OH、C1-14烷基、C2-14杂烷基、C3-9环烷基、C4-7杂环烷基、C1-6烷氧基、氨基、和C1-14烷基氨基。
3.如权利要求1所述的化合物,其中R2选自:H、羟基、卤素、C1-14烷基、C2-14杂烷基、C1-6烷氧基C1-14烷基,其各自未被取代或被一个或多个独立地选自下组的取代基取代:卤素、-CO2H、OH、C1-14烷基、C2-14杂烷基、C3-9环烷基、C4-7杂环烷基、C1-6烷氧基、C5-12芳基C1-14烷基。
4.如权利要求1所述的化合物,其中R3选自:H、羟基、卤素、C1-14烷基、C2-14杂烷基、C1-6烷氧基C1-14烷基,其各自未被取代或被一个或多个独立地选自下组的取代基取代:卤素、-CO2H、OH、C1-14烷基、C2-14杂烷基、C3-9环烷基、C4-7杂环烷基、C1-6烷氧基、C5-12芳基C1-14烷基。
6.药物组合物,其包括权利要求1-5中任一项所述的化合物及药学上可接受的稀释剂、赋形剂或载体。
7.权利要求1-5中任一项所述的化合物或其药学上可接受的盐或者权利要求6所述的组合物在制备用于治疗和/或预防由PPARα、PPARδ介导的疾病的药物中的用途。
8.如权利要求7所述的用途,其中由PPARδ介导的疾病为:高脂血症、脂质异常症、高胆固醇血症、高TG血症、低HDL血症、高LDL和/或非HDL血症、高VLDL血症、脂蛋白异常症、低载脂蛋白A-I血症、动脉硬化性疾病、冠状动脉疾病、脑血管疾病、末梢血管疾病、代谢综合症、X综合征、肥胖、糖尿病、高血糖、胰岛素抵抗、糖耐量减低、高胰岛素血症、糖尿病并发症、心力衰竭、心肌梗塞、心肌病、高血压、脂肪肝、非酒精性脂肪肝炎、血栓、阿尔茨海默氏病、神经退行性疾病、脱髓鞘疾病、多发性硬化症、肾上腺脑白质营养不良、皮肤炎、银屑病、痤疮、皮肤老化、毛发异常、炎症、哮喘、过敏性肠综合征、溃疡性大肠炎、克罗恩病、胰腺炎、以及包括结肠癌、大肠癌、皮肤癌、乳腺癌、前列腺癌、卵巢癌、肺癌的癌症。
9.如权利要求7所述的用途,其中由PPARδ介导的疾病为各种脂质异常症、代谢综合症、肥胖、动脉粥样硬化症或糖尿病。
10.如权利要求7所述的用途,其中由PPARδ介导的疾病为NASH和杜氏肌营养不良综合症。
11.如权利要求7所述的用途,其中由PPARδ介导的疾病为原发性胆汁肝硬化和胆管炎,包括老年痴呆和肿瘤。
12.权利要求7所述的用途,其中由PPARδ介导的疾病为增加T淋巴细胞的能量和活化性能而增强免疫功能,还有可转化肿瘤细胞为脂肪细胞,降低癌症转移等。
13.如权利要求9或10所述的用途,其中所述肥胖是内脏脂肪型肥胖。
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