CN107540636A - 一种含氮杂环衍生物及其应用 - Google Patents
一种含氮杂环衍生物及其应用 Download PDFInfo
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- CN107540636A CN107540636A CN201610495032.2A CN201610495032A CN107540636A CN 107540636 A CN107540636 A CN 107540636A CN 201610495032 A CN201610495032 A CN 201610495032A CN 107540636 A CN107540636 A CN 107540636A
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Abstract
一种含氮杂环衍生物及其应用。本发明涉及式(V)化合物和制备方法及其在医药上的应用。具体而言,本发明涉及通式为(V)化合物的衍生物和制备方法以及其作为治疗剂,在预防和治疗高脂血症,高胆固醇血症,高甘油三酯血症,肝脂肪变性,II型糖尿病,高血糖症,肥胖症或胰岛素抵抗症,代谢综合征和抗肿瘤药物中的用途。本文公开的化合物还能降低总胆固醇,LDL‑胆固醇和甘油三酯,并且增加肝LDL受体表达,抑制PCSK9表达。
Description
技术领域
本发明的技术涉及用于治疗高脂血症(包括高甘油三酯血症和高胆固醇血症),肝脂肪变性,II型糖尿病,高血糖症,胰岛素抵抗症,肥胖症,代谢综合征和抗肿瘤中的用途、化合物和组合物。
背景技术
代谢综合征(Metabolic Syndrome,MS)是多种代谢成分异常聚集的病理状态,是一组复杂的代谢紊乱症候群,是导致糖尿病,心脑血管疾病的危险因素。
心脑血管疾病是危害人类健康的头号杀手,其病因非常复杂,高血脂又作为其非常关键的危险因子而受到大多数人的关注,而且随着生活水平的改善和老龄化的加速,高血脂症的发生率与死亡率明显提升,更有相关文献报道,血脂异常是引起动脉粥样硬化、冠心病、心肌梗死等的主要原因。肪的代谢或者运转异常使得血浆中一种或多种脂质高于正常。而且高血脂症是种全身性的疾病,通常指血清中总胆固醇(TC),甘油三酯(TG)过高或高密度脂蛋白胆固醇(HDL-C)过低,现代医学称之为血脂异常。脂质是不溶或微溶于水,所以必须与蛋白质结合形成脂蛋白,因此,高血脂症通常也称为高脂蛋白血症。
高血脂症定义为血脂紊乱或血脂异常。通常指人体内血脂浓度超出了正常范围。包括甘油三酯(TG)、血清总胆固醇(TC)、极低密度脂蛋白胆固醇(VLDL-C)或低密度脂蛋白胆固醇(LDL-C)水平升高和高密度脂蛋白胆固醇(HDL-C)水平降低随着高血脂与心血管疾病的深入研究,人们开始认识到降血脂对减少心血管疾病的风险具有非常重要的意义。
低密度脂蛋白(LDL)水平过高能致动脉粥样硬化,降低血浆LDL水平对预防和治疗心脑血管等疾病具有重要的意义。血液中大约70%的LDL是通过低密度脂蛋白受体(LDLR)介导的内吞作用完成清除的,LDLR的表达受到前蛋白转化酶枯草杆菌蛋白酶/kexin9型(proprotein convertase subtilisin/kexin type9)(PCSK9)的影响,PCSK9是一个丝氨酸蛋白酶,主要在肝脏合成,它能够减少肝细胞中LDLR数量。PCSK9与位于细胞表面的LDLR结合后,内化至细胞里,促进溶酶体中LDLR降解。抑制PCSK9的活性可以增加LDLR数量,降低血浆中LDL水平。
PCSK9抑制剂的开发是当今大型跨国制药公司努力研发新型心血管疾病药物的重要方向,期待这类药物超越他汀类成熟的降脂药物。大型制药公司正密锣紧鼓地推动PCSK9抑制剂药物开发工作,目前的研究工作主要集中在生物制品药物(包括蛋白药物和长链核酸药物)的开发(如下表),生物制品药物与小分子药物针对治疗同一病症时,生物药具有成本高昂,只能采用注射制剂等有限的制剂方式等缺点,目前,还没有小分子PCSK9抑制剂成为临床候选药物。
目前公开了一系列PCSK9抑制剂的小分子化合物专利申请,其中包括WO2010075469,WO2011006000,WO2011051961,WO2011152508,WO2012090220,JP2013136572,WO2013132509,WO2013137371,WO2014017569,WO2014002105,WO2014002106,WO2014150326,WO2014150395,WO2014139008等。
尽管目前已经公开了一系列的具有抑制PCSK9表达和降脂效果的化合物,但是,仍然需要开发新的具有更好药效,药代结果的化合物,经过不断努力,本发明设计具有通式(V)结构的化合物并发现具有此类结构的化合物表现出优异的效果和作用,在更大范围内,更加深入和全面地揭示和阐明了结构和活性效能的关系,具有重要的应用价值。
发明内容
本发明的目的在于提供一种通式(V)所示化合物,以及它们的互变异构体、对映体、非对映体、消旋体和可药用的盐,以及代谢产物和代谢前体或前药。式V的化合物
其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中:
R5,R6,R7,R8独立地是氢,卤,经取代的或未经取代的硅基,氨基,硝基,氧代基,硫基,砜基,氰基,羰基,磺酰氧基,磷酰氧基,烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R9,R10,R11,R12,R13,R14,R15,R16独立地是氢,卤,经取代的或未经取代的硅基,氨基,硝基,氧基,硫基,砜基,氰基,羰基,磺酰氧基,磷酰氧基,烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R17,R18,R19,R20,R21,R22,R23,R24,R25,R26独立地是氢,卤,-OH,-NR′R″,-NO2,-Si(R′)3,-CN,-(CH2)0-6COOR′,-C(O)R′,-OC(O)R′,-C(O)NR′R″,-OC(O)OR′,-OC(O)NR′R″,-S(O)mR′,-S(O)nNR′R″,-OS(O)nR′,-OS(O)nNR′R″,-OS(O)nNH(C=O)NR′R″,-S(O)nNH(C=O)NR′R″,-NR′S(O)nR″,-NR′S(O)nNR′R″,经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R′和R″独立的是氢或者经取代的或未经取代的烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
M为氮原子,或者碳原子;
m=0,1,2;
n=1,2,3;
q=0,1,2,3,4,5,6;
t=0,1,2。
本发明化合物(V),其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中包括通式化合物化合物(VI),
其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中:
R27独立地是-OH,-NR′R″,-CN,-(CH2)0-6COOR′,经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R5,R6,R17,R18,R20,R21,R22,R23,R24,R25,R26,R′,R″,M同权利要求1。
本发明化合物(VI),其中,R27独立地是经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基。
本发明化合物(VI),其中,R27独立地是经取代的或未经取代的芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基。
本发明化合物(VI),其中,R27选自以下基团:
本发明化合物(VI),其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中包括通式化合物(VII),
其中,R22,R23,R24,R25,R26独立地是氢,卤,经取代的或未经取代的硅基,氨基,硝基,氧代基,硫基,砜基,氰基,羰基,磺酰氧基,磷酰氧基,烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R27独立地是经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基。
本发明化合物(VII),其中,R27选自以下基团:
本发明的化合物,该化合物选自以下化合物,但不局限于以下化合物范围:
或其药用可接受的盐。
本发明化合物在制备用于治疗II型糖尿病,高血糖症,肥胖症,胰岛素抵抗症,抗肿瘤,以及治疗高脂血症,高胆固醇血症,高甘油三酯血症,肝脂肪变性和代谢综合征构成的疾病或病况的药物中的用途。
本发明化合物在制备用于降低患者血浆和/或肝的脂类水平的药物中的用途。
本发明涉及通式(V)所示化合物,本发明公开的化合物具有以下有益效果:
1、本发明公开的具有通式(V)小分子化合物,在抑制PCSK9基因表达,增加细胞LDLR的表达,增强肝细胞对LDL的摄取能力中的显著作用,有望成为新一代降脂药。
PCSK9抑制剂作为降脂药物的开发是当今大型跨国制药公司努力研发新型心血管疾病药物的重要方向,期待这类药物超越他汀类成熟的降脂药物。大型制药公司正密锣紧鼓地推动PCSK9抑制剂药物开发工作,目前的研究工作主要集中在生物制品药物(包括蛋白药物和长链核酸药物)的开发,目前,还没有小分子PCSK9抑制剂成为临床候选药物。
生物制品药物与小分子药物针对治疗同一病症时,生物药具有成本高昂,只能采用注射制剂等有限的制剂方式等缺点,而小分子药物具有制造成本低廉,制剂方法多样等优点,本发明公开的有通式(V)小分子化合物,在细胞水平表现出显著的抑制PCSK9基因表达,增强肝细胞对LDL的摄取能力中的显著作用,有望成为具有新一代降脂药。另一方面,小分子药物的制剂方案比生物大分子药物选择面更加广泛,有利于后期药物开发多种剂型药物的开发,相比生物大分子药物而言,可以提供给为广泛的制剂类型,满足人们的需求。
2、与现有的专利文献公开的以PCSK9为作用的靶点的化合物相比,本发明公开的具有通式(V)化合物,结构新颖,具有崭新的结构特征,有望成为对PCSK9具有新颖作用机理的候选药物,并最终成为新一代具有新颖作用机制的降脂药物。
现有公开专利文献报道了几类作用于PCSK9靶点的小分子化合物,以专利申请人分类总结如下:
a、CVI Pharmaceutical Limited的申请专利WO2010075469,WO2011006000中报道了基于天然产物紫堇碱结构改造得到的小分子化合物,该类基于天然产物结构的小分子化合物,其制造工艺较为复杂,部分合成方法需要使用剧毒的化学试剂,会给操作工人和自然环境带来巨大的危害。
b、Cadila Healthcare Limited的申请专利WO2011051961,WO2012090220,WO2013132509,WO2014002105,WO2014002106中报道了几类小分子化合物,这几类小分子化合物在分子结构特点上主要含有一个共同的化学结构片段——六氢吡喃甲基氨基结构片段。该结构片段可能在化合物结构与生物活性中扮演着重要的角色。
c、Kowa Company Limited申请专利WO2011152508,JP2013136572,WO2013137371,WO2014017569中报道了几类小分子化合物,这类小分子化合物分子结构相对复杂,一般的实施例化合物还含有三个手性中心,其制造难度相对较大,实施例化合物一般需要六步化学反应(不包括含有手性中心的结构片段的构建)才能制备得到目标化合物。
d、Amorchem Holdings INC.申请专利WO2014139008中报道了一类小分子化合物,该类小分子化合物的部分实施例化合物主要结构特点在于含有“硼酸酯和硼酸”结构片段,尽管目前已经上市多发性骨髓瘤治疗药物——硼替佐米(含有“硼酸”结构片段),但是“硼酸类”药物在非肿瘤治疗领域(例如:糖尿病,高脂血症等等)的应用仍然受到限制,主要原因在于含硼药物的潜在的神经毒性副作用,以及其潜在的与生物机体“不可逆结合”的化学特性(Chem.Res.Toxicol.,2013,26(4),pp 608–615),该化学特性的在药物分子设计中可能造成的潜在的“致癌性”,“生殖毒性”已经广泛受到药物化学家的重视。
e、Shifa Biomedical Corporation申请专利WO2014150326,WO2014150395中报道了两类小分子化合物,这些小分子化合物的制备方法相对复杂,某些活性比较优秀的化合物的制备需要使用重金属催化反应,并且使用异氰酸酯化合物。
以上总结的就是目前公开的文献中以PCSK9为作用靶点的小分子化合物。本发明公开的化合物同样以PCSK9为作用靶点,该类化合物与上述总结的几类小分子化合物均可能成为未来基于PCSK9作用靶点的新型药物。
与现有的专利文献公开的以PCSK9为作用的靶点的化合物相比,本发明公开的具有通式(V)化合物,结构新颖,具有崭新的独特结构特征,预示着本发明公开的化合物其新颖的分子结构特点,有可能带来意想不到“类药性特点”,有望成为对PCSK9具有新颖作用机理的候选药物,并最终成为新一代具有新颖作用机制的降脂药物。
3、本发明公开的具有通式(V)化合物,具有原料易得,制备过程操作简单,成本低廉优势。
本发明公开的具有通式(V)的小分子化合物,主要采用市售中间体,然后采用简单的化学反应进行片段偶联反应制备得到。例如采用市售的具有“胺”,“醛”,“卤代烃”等官能团的起始物料,然后进行一步化学反应即可以制备得到目标化合物。因此,本发明公开的具有通式(V)化合物,具有原料易得,制备过程操作简单,成本低廉的优势。
4、本发明公开的具有通式(V)化合物具有活化AMPK激酶的活性,提示本发明化合物不但可以开发成为新一代降脂药,而且可以起到较好控制血糖的作用,为广大的代谢综合征患者在降脂和降糖方面获得综合的收益比现有单一作用药物更具优势。
本发明公开的通式化合物(V)制备主要参照以下的方案进行制备,
本发明所述通式(V)所示的化合物,其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类的方法,其中一种制备方法包括以下步骤:
X5和X8为该方案的起始物料,可以通过市售产品获得,或者根据文献报道的方法制备获得。X5和X8在一定的反应温度条件下,在一定的碱性试剂存在的条件下,通过偶联得到化合物V;
另一种制备方法包括以下步骤:
X5和X9为该方案的起始物料,可以通过市售产品获得,或者根据文献报道的方法制备获得。将X5和X9在一定的反应条件下,通过还原氨化的反应制备得到V。
发明详述
在多个方面,本发明的技术提供了新颖的化合物,以及该化合物在降低血浆和/或肝的脂类水平的用途以及治疗高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性、II型糖尿病、高血糖症、胰岛素抵抗症、肥胖症和代谢综合征中的用途。本文提供的化合物可被配制用于本文公开的方法中的药物组合物和药剂。本发明还提供了所述化合物用于制备药物配制物和药剂的用途,所述化合物在降低血浆和/或肝的脂类水平中的用途以及所述化合物在治疗高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性、II型糖尿病、高血糖症,胰岛素抵抗症、肥胖症和代谢综合征中的用途。
下述术语在本文通篇中参照下述定义来使用。
通常,提到某个元素,例如氢或H,表示包括该元素的所有同位素。例如,如果R基团被定义为包括氢或H,其还包括氘和氚。包含放射性同位素(例如氚、C14、P32和S35)的化合物因此也在本发明的范围。用于将此类标记插入本发明的化合物中的手段是本领域技术人员基于本文公开的内容显而易见的。
通常,“经取代的”表示这样的如下文定义的有机基团(例如烷基),其中含有的一个或多个连接氢的键被连接非氢原子或非碳原子的键替换。经取代的基团还包括这样的基团:其中一个或多个连接碳原子或氢原子的键被一个或多个连接杂原子的键(包括双键或三键)替换。由此,除非另有指明,被取代的基团被一个或多个取代基取代。在一些实施方式中,取代基被1、2、3、4、5或6个取代基取代。取代基的例子包括卤(即,F,Cl,Br和I)、羟基、烷氧基、烯氧基、芳基氧基、芳烷基氧基、杂环基氧和杂环基烷氧基、羰基、羧基、酯、氨基甲酸盐/酯、肟、羟基胺、烷氧基胺、芳烷氧基胺、硫醇、硫化物、亚砜、砜、磺酰基、磺酰胺、胺、N-氧化物、肼、酰肼、腙、叠氮化物、酰胺、脲、脒、胍、烯胺、酰亚胺、异氰酸盐/酯、异硫代氰酸盐/酯、氰酸盐/酯、硫代氰酸盐/酯、亚胺、硝基、腈等等。
经取代的环基,例如经取代的环烷基、芳基、杂环基和杂芳基,还包括其中连接氢原子的键被连接碳原子的键替换的环和环系统。经取代的环烷基、芳基、杂环基和杂芳基还可被下文定义的经取代的或未经取代的烷基、烯基和炔基取代。
烷基包括包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代、-C(O)R′、-C(O)OR′、-S(O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR″或-S(O)mNR′R″。
环烷基烷基是指饱和或部分不饱和单环或多环环状烃取代的烷基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至10个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
烯基指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的不饱和烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-C(O)R′、-C(O)OR′、-S(O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR″或-S(O)mNR′R″。
环烯基指包括具有至少一个处于两个碳原子之间的双键的,如上文定义的不饱和环烷基。在一些实施方式中,环烯基可具有一个、两个或三个双键但是不包括芳香族化合物。环烯基包含4至14个碳原子,或在一些实施方式中,包含5至14个碳原子,优选包含5至10个碳原子,更优选包含5、6、7或8个碳原子。环烯基的例子包括环己烯基、环戊烯基、环己二烯基、丁二烯基、戊二烯基和己二烯基。
炔基指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的不饱和烷基,例如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-C(O)R′、-C(O)OR′、-S(O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR″或-S(O)mNR′R″。
芳基是不含杂原子的环状芳香烃。芳基在本文中包括单环、二环和三环系统。因此,芳基包括但不限于苯基、茂并芳庚基、二苯基、芴基、菲基、蒽基、茚基、茚满基、并环戊二烯基和萘基。在一些实施方式中,芳基在基团的环的部分中含有6-14个碳,优选6至12个,更优选6-10个碳原子。在一些实施方式中,芳基是苯基或萘基。虽然词组“芳基”包括含有稠合的环(例如稠合的芳香族-脂肪族环系统)的基团(例如茚满基、四氢萘基等等),但其不包括具有与环成员之一键合的其它基团(例如烷基或卤代基团)的芳基。甲苯基等基团被称为经取代的芳基。代表性的经取代的芳基可以是经单取代的或被取代超过一次的。例如,经单取代的芳基包括但不限于2-、3-、4-、5-或6-取代的苯基或萘基,其可被例如上文列出的取代基取代。
芳烷基是如上文定义的烷基,其中,烷基的氢或碳键被连接上文定义的芳基的键所替换。在一些实施方式中,芳烷基含有7至16个碳原子,优选7至14个碳原子,更优选7至10个碳原子。经取代的芳烷基可在烷基、芳基的部分被取代,或在烷基和芳基部分均被取代。代表性的芳烷基包括但不限于苄基和苯乙基和稠合的(环烷基芳基)烷基(例如4-茚满基乙基)。代表性的经取代的芳烷基可被例如上文列出的取代基取代一次或数次。
杂环基包括含有3个或多个环成员的芳香族(也被称为杂芳基)和非芳香族环状化合物,其中环成员中的一个或多个是杂原子,例如但不限于N、O和S。在一些实施方式中,杂环基含有1、2、3或4个杂原子。在一些例子中,杂环基包括具有3至16个环成员的单、二和三环。杂环基包括芳香族的、部分未饱和的和饱和的环系统,例如,咪唑基、咪唑啉基和咪唑烷基。词组“杂环基”包括稠合的环种类,这包括包含稠合的芳香族和非芳香族基团的那些,例如苯并三唑基、2,3-二氢苯并[1,4]二噁烷基和苯并[1,3]二氧杂环戊烯基。该词组还包括桥联的含有杂原子的多环系统,例如但不限于奎宁环基。但是,该词组不包括具有与环成员之一键合的其它基团(例如烷基、氧代或卤代基团)的杂环基。相反,这些被称为“经取代的杂环基”。杂环基包括但不限于吖丙啶基、吖丁啶基、吡咯烷基、咪唑烷基、吡唑烷基、噻唑烷基、四氢硫代苯基、四氢呋喃基、二氧杂环戊烯基、呋喃基、硫代苯基、吡咯基、吡咯啉基、咪唑基、咪唑啉基、吡唑基、吡唑啉基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、噻唑啉基、异噻唑基、噻重氮基、噁二唑基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、四氢吡喃基、四氢硫代吡喃基、氧硫杂环己烷、二氧六环基、二噻烷基、吡喃基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、二氢吡啶基、二氢二噻嗯基、二氢二硫酮基、高哌嗪基、奎宁环基、吲哚基、吲哚啉基、异吲哚基、氮杂吲哚基(吡咯并吡啶基)、吲唑基、吲哚嗪基、苯并三唑基、苯并咪唑基、苯并呋喃基、苯并硫代苯基、苯并噻唑基、苯并噁二唑基、苯并噁嗪基、苯并二噻嗯基、苯并噁噻嗯基、苯并噻嗪基、苯并噁唑基、苯并噻唑基、苯并噻重氮基、苯并[1,3]二氧杂环戊烯基、吡唑并吡啶基、咪唑并吡啶基(氮杂苯并咪唑基)、三唑并吡啶基、异噁唑并吡啶基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、喹嗪基、喹喔啉基、喹唑啉基、酞嗪基、萘啶基、硫杂萘基、二氢苯并噻嗪基、二氢苯并呋喃基、二氢吲哚基、二氢苯并二噁烷基、四氢吲哚基、四氢吲唑基、四苯并咪唑基、四氢苯并三唑基、四氢吡咯并吡啶基、四氢吡唑并吡啶基、四氢咪唑并吡啶基、四氢三唑并吡啶基和四氢喹啉基。代表性的经取代的杂环基可经单取代或被取代超过一次,例如但不限于2-、3-、4-、5-或6-取代的或被例如上文列出的多种取代基二取代的吡啶基或吗啉基。
杂芳基是含有5个或更多个环成员原子的芳香族环化合物,其中一个或多个环成员是杂原子,例如但不限于N、O和S。杂芳基包括但不限于下述基团,例如,吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、硫代苯基、苯并硫代苯基、呋喃基、苯并呋喃基、吲哚基、氮杂吲哚基(吡咯并吡啶基)、吲唑基、苯并咪唑基、咪唑并吡啶基(氮杂苯并咪唑基)、吡唑并吡啶基、三唑并吡啶基、苯并三唑基、苯并噁唑基、苯并噻唑基、苯并噻重氮基、咪唑并吡啶基、异噁唑并吡啶基、硫杂萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。杂芳基包括其中所有环都是芳香族的稠合环化合物,例如吲哚基,其还包括其中仅一个环是芳香族的稠合环化合物,例如2,3-二氢吲哚基。虽然词组“杂芳基”包括稠合的环化合物,但该词组不包括具有与环成员之一键合的其它基团(例如烷基)的杂芳基。相反,具有此类取代的杂芳基被称为“经取代的杂芳基”。代表性的经取代的杂芳基可被例如上文列出的多种取代基取代一次或数次。
杂环基烷基是如上文定义的烷基,但其中,烷基的氢或碳键被连接上文定义的杂环基的键所替换。经取代的杂环基烷基可在烷基、杂环基的部分被取代,或在烷基和杂环基部分均被取代。代表性的杂环基烷基包括但不限于吗啉-4-基-乙基、呋喃-2-基-甲基、咪唑-4-基-甲基、吡啶-3-基-甲基、四氢呋喃-2-基-乙基和吲哚-2-基-丙基。代表性的经取代的杂环基烷基可被例如上文列出的取代基取代一次或数次。
杂芳烷基是如上文定义的烷基,其中,烷基的氢或碳键被连接上文定义的杂芳基的键所替换。经取代的杂芳烷基可在烷基、杂芳基的部分被取代,或在烷基和杂芳基部分均被取代。代表性的经取代的杂芳烷基可被例如上文列出的取代基取代一次或数次。
本发明的化合物中,具有两个或多个连接点(即二价、三价或多价)的本文描述的基团被用前缀“亚”来命名。例如,二价烷基是亚烷基,二价芳基是亚芳基,二价杂芳基是杂亚芳基,等等。与本发明的化合物具有单个连接点的经取代的基团不使用“亚”命名。因此,例如,氯乙基在本文中不被称为氯亚乙基。
氧代基是指通过与氧原子相连构成的取代基团,其中与氧原子相连接的基团为经取代或者未经取代的烷基,芳基,杂芳基,环烷基,烷基酰基,芳基酰基,杂芳基酰基。以上的基团与氧原子连接即可以构成烷氧基,芳氧基,杂芳氧基,环烷基氧基,烷基酰氧基,芳基酰氧基,杂芳基酰氧基,环烷基酰氧基。
烷氧基是羟基(-OH)中连接氢原子的键被连接上文定义的经取代的或未经取代的烷基的碳原子的键替换的取代基。线性烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等等。带支链的烷氧基的例子包括但不限于异丙氧基、仲丁氧基、叔丁氧基、异戊氧基、异己氧基等等。环烷氧基的例子包括但不限于环丙基氧、环丁基氧、环戊基氧、环己基氧等等。代表性的经取代的烷氧基可被例如上文列出的取代基取代一次或数次。
术语“烷酰基”和“烷酰基氧”在本文中使用时分别指-C(O)-烷基和-O-C(O)-烷基,它们每个含有2-5个碳原子。
术语“芳基氧”和“芳基烷氧基”分别指经取代的或未经取代的芳基与氧原子键合构成的取代基,经取代的或未经取代的芳烷基与氧原子键合构成的取代基。例子包括但不限于苯氧基、萘基氧和苄氧基。代表性的经取代的芳基氧和芳基烷氧基可被例如上文列出的取代基取代一次或数次。
术语“羧酸”在本文中使用时指-COOH基团。
术语“羧酸酯”在本文中使用时指-COOR′基团。R′是如本文定义的经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基、芳烷基、杂环基烷基或杂环基。
术语“酰胺”(或“酰胺基”)包括C-酰胺基团和N-酰胺基团,即分别是-C(O)NR′R″和-NR′C(O)R″基团。R′和R″独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。酰胺基因此包括但不限于氨基甲酰基(-C(O)NH2)和甲酰胺基团(-NHC(O)H)。在一些实施方式中,酰胺是-NR′C(O)-(C1-5烷基),该基团被称为“羰基氨基”,在另一些实施方式中,酰胺是-NHC(O)-烷基,该基团被称为“烷酰基氨基”。
术语“腈”或“氰基”在本文中使用时指-CN基团。
氨基甲酸盐/酯包括N-氨基甲酸盐基团和O-氨基甲酸盐基团,即分别是-NR′C(O)OR″和-OC(O)NR′R″基团。R′和R″独立地是如本文定义的经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。R′还可以是H。
术语“胺”(或“氨基”)在本文中使用时指-NR′R″基团,其中R′和R″独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。在一些实施方式中,胺是烷基氨基、二烷基氨基、芳基氨基或烷基芳基氨基。在其它一些实施方式中,胺是NH2、甲基氨基、二甲基氨基、乙基氨基、二乙基氨基、丙基氨基、异丙基氨基、苯基氨基或苄基氨基。
术语“磺酰胺”包括S-磺酰胺基团和N-磺酰胺基团,即分别是-SO2NR′R″和-NR′SO2R″基团。R′和R″独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基烷基或杂环基。磺酰胺基团因此包括但不限于磺酰基(-SO2NH2)。在本文的一些实施方式中,磺酰胺是-NHSO2-烷基,其被称为“烷基磺酰基氨基”。
术语“硫醇”指-SH基团,而硫化物包括-SR′基团,亚砜包括-S(O)R′基团,砜包括-SO2R′基团,以及磺酰氧基包括-OSO2R′,磺酸氧基包括-OSO2OR′。R′独立地是如本文定义的经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。在一些实施方式中,硫化物是烷基硫醇基团,-S-烷基。
术语“脲”指-NR′-C(O)-NR′R″基团。R′和R″基团独立地是如本文定义的氢或者经取代的或未经取代的烷基、烯基、炔基、环烷基、芳基、芳烷基、杂环基或杂环基烷基。
术语“脒”指-C(NR′)NR′R″和-NR′C(NR′)R″,其中,R′和R″每个独立地是如本文定义的氢或者经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。
术语“胍”指-NR′C(NR′)NR′R″,其中R′和R″每个独立地是如本文定义的氢或者经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。
术语“烯胺”指-C(R′)=C(R′)NR′R″和-NR′C(R′)=C(R′)R″,其中R′和R″每个独立地是如本文定义的氢、经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。
术语“卤”或“卤代”在本文中使用时指溴、氯、氟或碘。在一些实施方式中,卤是氟。在其它一些实施方式中,卤是氯或溴。
术语“羟基”在本文中使用时可以指-OH或其离子化形式-O-。
术语“酰亚胺”指-C(O)NR′C(O)R″,其中R′和R″每个独立地是如本文定义的氢或者经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基。
术语“含氮杂环基”指含有氮原子的环系,该环系可以“骈合”芳香和非芳香环系,或者通过“螺碳原子”链接其他环系。
术语“亚胺”指-CR′(NR″)和-N(CR′R″)基团,其中R′和R″每个独立地是如本文定义的氢或经取代的或未经取代的烷基、环烷基、烯基、炔基、芳基芳烷基、杂环基或杂环基烷基、并且满足:R′和R″不同时是氢。
术语“硝基”在本文中使用时指-NO2。
术语“三氟甲基”在本文中使用时指-CF3。
术语“三氟甲氧基”在本文中使用时指-OCF3。
本文描述的化合物的可药用盐在本发明的范围内,其包括这样的酸加成盐或碱加成盐,所述盐保持了预期的药理学活性并且从生物学角度而言不是具有潜在不良效果的(例如盐没有过分的毒性、致敏性或刺激性,并且是生物可利用的)。当本发明的化合物具有碱性基团(例如,氨基)时,可与无机酸(例如盐酸、氢硼酸、硝酸、硫酸和磷酸)、有机酸(例如藻酸盐、甲酸、乙酸、苯甲酸、葡糖酸、延胡索酸、草酸、酒石酸、乳酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸、萘磺酸和对甲苯磺酸)或酸性氨基酸(例如天冬氨酸和谷氨酸)形成可药用盐。当本发明的化合物具有酸性基团,例如羧酸基团时,其可与金属,例如碱金属和碱土金属(例如Na+、Li+、K+、Ca2+、Mg2+、Zn2+)、氨或有机胺(例如二环己基胺、三甲基胺、三乙基胺、吡啶、乙醇胺、二乙醇胺、三乙醇胺)或碱性氨基酸(例如精氨酸、赖氨酸和鸟氨酸)形成盐。此类盐可在对化合物的分离和纯化期间“一锅法”制备,或者可通过将游离碱或游离酸经纯化后化合物分别与合适的酸或碱单独反应并且分离由此形成的盐来制备此类盐。
本领域技术人员已知的,本发明的化合物可展示出互变异构、构象异构、几何异构和/或立体异构的现象。虽然本说明书和权利要求中的式图仅代表可能的互变异构、构象异构、立体异构或几何异构形式之一,但是应当理解,本发明包括化合物的具有本文描述的一种或多种用途的任何互变异构、构象异构、立体异构和/或几何异构形式以及这些多种不同形式的混合物。
本领域技术人员易于理解的,大范围的官能团和其它结构可展示出互变异构体,本文描述的化合物的所有互变异构体都在本发明的范围内。
除非明确指示了立体化学,化合物的立体异构体,包括结构的所有手性、非对映异构和外消旋形式。因此,用于本发明中的化合物包括在任何或所有非对称原子处富集或拆分的光学异构体。外消旋和非对映异构混合物,以及各光学异构体,均可被分离或合成,以基本上不含其对应异构体或非对映异构体,这些立体异构体也在本发明的范围内。
本发明的化合物可作为溶剂化物存在,尤其是作为水合物。水合物可在化合物或包含化合物的组合物的制造期间形成,或者水合物可随着时间由于化合物的吸湿性质而形成。本发明的化合物还可作为有机溶剂化物存在,包括醚和醇溶剂化物等等。对任何特定的溶剂化物的鉴定和制备都是合成有机或药物化学领域普通技术人员已知的。
脂类包括合成的和天然存在的脂溶性化合物,其包括中性和两性分子。两性脂类典型地包含亲水组分和疏水组分。示例性脂类包括脂肪酸、甘油三酯、中性脂肪、磷脂、醣脂、脂肪醇、蜡、萜、类固醇(例如胆固醇)和表面活性剂。
在一个方面,本发明提供了利用本发明化合物制造在降低患者血浆和/或肝的脂类水平的药物中的用途,包括向所述患者施用脂类降低有效量的如本文所述的化合物或组合物。降低的脂类水平可以是总胆固醇、LDL-胆固醇(LDL-C)、甘油三酯(TG)和未酯化的长链脂肪酸中的一种或多种。
本文描述的化合物和组合物可用于预防或治疗下述疾病,包括例如,高脂血症,高胆固醇血症,高甘油三酯血症,脂肪肝(肝脂肪变性),II型糖尿病,高血糖症,肥胖症或胰岛素抵抗症和代谢综合征。治疗的方法包括向需要治疗的受试者施用治疗有效量的本文所述的化合物或组合物。本发明的化合物还可用于治疗或预防特征在于升高的血浆或肝胆固醇或甘油三酯或与升高的血浆或肝胆固醇或甘油三酯相关的疾病状态或病态。本发明的技术还提供使用本发明化合物制造治疗或预防疾病(例如,高脂血症、高胆固醇血症、高甘油三酯血症、脂肪肝、II型糖尿病,高血糖症,肥胖症或胰岛素抵抗症或代谢综合征)的有效量药物的用途。
本文公开的化合物和组合物通过增加LDLR的肝表达,通过增加LDLRmRNA的稳定性,通过增加LDLR基因转录,通过抑制前蛋白转化酶枯草杆菌蛋白酶/kexin9型(proprotein convertase subtilisin/kexin type9)(PCSK9)介导的LDLR蛋白的降解或上述可能的细胞机制的全部,来降低脂类水平。肝中增加的LDLR水平增加了血浆LDL-C的摄取和加工,从而导致胆固醇、LDL-C和甘油三酯的血浆水平降低。此外,化合物可通过活化AMP活化的蛋白激酶(AMPK)(生物能量代谢调节的关键分子)来增加乙酰CoA羧化酶(ACC)的磷酸化。ACC的增加的磷酸化增强了肝中的脂肪酸氧化,导致肝的TG积累降低,以及导致TG以VLDL形式分泌,这还有助于减少TG、LDL-C、总胆固醇和未酯化的长链脂肪酸的血浆水平,从而防止或治疗与高脂血症相关的疾病。另一方面,我们相信,遗传学和药理学研究表明,AMPK是机体保持葡萄糖平衡所必需的,化合物通过活化AMPK,最终起到治疗II型糖尿病,高血糖症,肥胖症或胰岛素抵抗症或代谢综合征。
在另一个方面,本发明提供的化合物具有增加LDLR表达的用途,包括向需要其的受试者施用治疗有效量的本文所述的化合物或组合物,由此增加所述受试者中的LDLR表达。在本发明的另一方面,本发明提供了一种利用本发明化合物减少血浆LDL-胆固醇和/或血浆甘油三酯的用途,包括向需要其的患者施用治疗有效量的本文所述的化合物或组合物,由此减少所述患者的血浆LDL-胆固醇。
在另一个方面,本发明提供了包括化合物及其组合物的脂类降低试剂。化合物和组合物可用于本文所述的降低脂类的方法和治疗中。在一种实施方式中,本发明提供了式V化合物,其立体异构体、其互变异构体、其溶剂化物和/或其可药用盐。
在另一个方面,本发明的技术提供了包含本文公开的任何化合物和可药用载体或一种或多种赋形剂或填料的药物组合物和药剂。在一些实施方式中,提供了治疗选自由高脂血症、高胆固醇血症、高甘油三酯血症、肝脂肪变性和代谢综合征构成的组的病况的药物组合物。此类组合物包括脂类降低有效量的本文所述的任何化合物。在一种实施方式中,将药物组合物包装成单位剂量形式。在施用给需要其的受试者时,单位剂量形式能有效降低血流和/或肝中的脂类水平(例如总胆固醇、LDL-胆固醇、甘油三酯和未酯化的长链脂肪酸中的至少一种)。
可通过将本发明的一种或多种化合物、其可药用盐、其立体异构体、其互变异构体或其溶剂化物与可药用载体、赋形剂、粘合剂、稀释剂等等混合,来制备药物组合物,以防止或治疗与增加的血浆和/或肝的脂类水平相关的病症。本文所述的化合物和组合物可用于制备防止或治疗与增加的血浆和/或肝脂类水平相关的多种病症(例如高脂血症、高胆固醇血症、肝脂肪变性和代谢综合征)的配制物和药剂。此类组合物可以是例如颗粒、粉末、片剂、胶囊、糖浆、栓剂、注射剂、乳液、酏剂、悬浮液或溶液的形式。本发明的组合物可被配制成用于多种施用途径的各种形式,例如,通过口服、肠胃外、局部、直肠、经鼻、阴道施用或者通过植入的贮器来施用。肠胃外或全身性施用包括但不限于皮下、静脉内、腹膜内和肌内、注射。下述剂量形式作为例子给出,其不应被解释为限制本发明的技术。
含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。可参照本领域任何已知制备药用组合物的方法制备口服组合物,此类组合物可含有一种或多种选自以下的成分:甜味剂、矫味剂、着色剂和防腐剂,以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸;粘合剂,例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收,因而在较长时间内提供缓释作用的已知技术将其包衣。例如,可使用水溶性味道掩蔽物质,例如羟丙基甲基纤维素或羟丙基纤维素,或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊,或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂,例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶;分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂,或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七碳亚乙基氧基鲸蜡醇,或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物,例如聚环氧乙烷山梨醇单油酸酯,或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物,例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种娇味剂和一种或多种甜味剂,例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油,或矿物油例如液体石蜡中配制而成。油悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和娇味剂,以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水可使适用于制备水混悬也的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、娇味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油,或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂,例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单油酸酯,和所述偏酯和环氧乙烷的缩合产物,例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、娇味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
药物组合物可以是无菌注射水溶液形式。可在使用的可接受的溶媒和溶剂中有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射,将注射液或微乳注入患者的血流中。或者,最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度,可使用连续静脉内递药装置。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液,例如1,3-丁二醇中制备的溶液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。为此目的,可使用包括合成甘油单或二酯在内的任何调和固定油。此外,脂肪酸例如油酸也可以制备注射剂。
用于局部(包括经颊和舌下)或透皮施用本发明的化合物的剂量形式包括粉末、喷雾、油膏、糊剂、乳膏、洗液、凝胶、溶液和贴片。活性组分可在无菌条件下与可药用载体或赋形剂以及与可能需要的任何防腐剂或缓冲剂混合。粉末和喷雾可例如用赋形剂(例如糖、云母、硅酸、氢氧化钠、硅酸钙和聚胺粉末或这些物质的混合物)来制备。油膏、糊剂、乳膏和凝胶还可含有下述赋形剂,例如,动物和植物脂肪、油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅酮、斑脱土、硅酸、云母和氧化锌或其混合物。还可使用吸收增强剂,来增加本发明的化合物穿透皮肤的流动。可通过提供速率控制膜(例如作为透皮贴片的一部分)或将化合物分散于聚合物基质或凝胶中来控制此类流动的速率。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体,因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本发明的化合物还可与可用于治疗或预防高脂血性疾病的其它传统治疗剂一起施用。用于与本发明的一种或多种化合物的组合疗法的示例性治疗试剂包括但不限于抗炎性药、治疗性抗体和胆固醇降低药,例如,他汀。可用于组合配制物和协作治疗的有用的附加治疗试剂包括,例如,抗高脂血症试剂;抗血脂异常试剂;抗糖尿病试剂,包括但不限于胆固醇生物合成抑制剂,例如HMG-CoA还原酶抑制剂(也被称为他汀,洛伐他汀,辛伐他汀,普伐他汀,氟伐他汀,瑞舒伐他汀,匹伐他汀和阿托伐他汀);HMG-CoA还原合酶抑制剂;角鲨烯环氧酶抑制剂或角鲨烯合成酶抑制剂(还被称为角鲨烯合酶抑制剂);微粒体甘油三酯转移蛋白(MTP)抑制剂;胆酸螯合剂阴离子交换树脂,包括但不限于消胆胺,降胆宁,考来维仑或经交联葡聚糖的二烷基氨基烷基衍生物;LDL受体诱导剂;贝特类,包括但不限于安妥明,苯扎贝特,非诺贝特和吉非贝齐;二甲双胍,罗格列酮,血浆HDL-升高试剂,包括但不限于烟酸,贝特类;抗高胆固醇血症试剂,包括但不限于胆固醇-摄取抑制剂;酰基辅酶A胆固醇酰基转移酶(ACAT)抑制剂,包括但不限于美林那胺;普罗布考;烟酸及其盐;烟酰胺;胆固醇吸收抑制剂,包括但不限于β-谷甾醇或依替米贝;维生素B6(吡哆醇)及其可药用盐,例如HCl盐;维生素B12(氰钴胺);维生素B3(烟酸和烟酰胺);抗氧化剂维生素,包括但不限于维生素C和维生素E和β胡萝卜素;β阻断剂;血管紧张素II受体(AT1)拮抗剂;血管紧张素转化酶抑制剂,肾素抑制剂;血小板聚集抑制剂,包括但不限于纤维蛋白原受体拮抗剂,即,糖蛋白IIb/IIIa纤维蛋白原受体拮抗剂;激素,包括但不限于雌激素;胰岛素;离子交换树脂;Ω-3油;苯氟雷司;廿六碳五烯酸乙酯和氨氯地平。附加疗法还可包括增加锻炼、手术和改变膳食(例如变为低胆固醇膳食)一些植物药品也可有效用于组合配制物和协作疗法,以治疗高脂血症,例如姜黄素,香胶甾酮,大蒜,大豆,可溶纤维,鱼油,绿茶,肉毒碱,铬,辅酶Q10,葡萄籽提取物,二聚泛酸,红曲米和蜂王浆。
小檗碱和相关化合物也可作为第二治疗试剂,与本发明的脂类降低试剂一起使用。例如,可使用硫酸小檗碱、盐酸小檗碱、氯化小檗碱、氧小檗碱、二氢小檗碱、8-氰基二氢小檗碱、四氢小檗碱N-氧化物、四氢小檗碱、原小檗碱、9-乙氧基羰基小檗碱、9-N,N-二甲基氨基甲酰基小檗碱和12-溴代小檗碱、小檗碱叠氮化物和小檗碱甜菜碱。
还可修饰本发明的化合物,例如通过共价联接有机结构片段或缀合物来进行,以改善药代动力学性质、毒性或生物利用性(例如增加的体内半衰期)。缀合物可以是线性的或带支链的亲水性聚合基团、脂肪酸基团或脂肪酸酯基团。聚合基团可包含可被本领域技术人员调节的分子量,以改善,例如药代动力学性质、毒性或生物利用性。示例性的缀合物可包括聚烷醇(例如聚乙二醇(PEG)、聚丙二醇(PPG)),碳水化合物聚合物,氨基酸聚合物或聚乙烯吡咯烷酮和脂肪酸或脂肪酸酯基团,它们每个均可独立包含大约8至大约70个碳原子。用于与本发明的化合物一起使用的缀合物还可用作为接头,例如用于任何合适的取代基或基团、放射性标记(标志物或标签)、卤、蛋白、酶、多肽、其它治疗试剂(例如药物或药品)、核苷、染料、寡核苷酸、脂类、磷脂和/或脂质体。在一个方面,缀合物可包括聚乙烯胺(PEI)、多聚甘氨酸、PEI和多聚甘氨酸的杂交体、聚乙二醇(PEG)或甲氧基聚乙二醇(mPEG)。缀合物还可将本发明的化合物连接至,例如,标记(发荧光的或发光的)或标志物(放射性素、放射性同位素和/或同位素),以包含本发明的探针。与本发明的化合物一起使用的缀合物在一个方面可改善体内半衰期。
术语“连结”和/或“结合”可表示化学或物理相互作用,例如本发明的化合物和感兴趣的目标之间的。连结或相互作用的例子包括共价键、离子键、亲水-疏水相互作用、疏水-疏水相互作用和复合体。“连结”一般还可称作“结合”或“亲和性”,它们每个均可用于描述多种化学或物理相互作用。测量结合或亲和性也是本领域技术人员的常规技术。
本文提供下面的实施例来阐述本发明的优点,以及进一步协助本领域普通技术人员制备或使用本发明的化合物或其盐、药物组合物、衍生物、代谢产物、前药、外消旋混合物或互变异构形式。本文的实施例还用于阐述本发明优选方面。实施例不应以任何方式被解释为限制由所附权利要求定义的本发明的范围。
具体实施方式
以下进一步解释本发明的一般方法,本发明的化合物可以通过本领域中公知的方法来制备,下面以本发明的优选化合物的制备流程为例详细进行说明但本发明化合物的制备方法不局限于此。
本发明公开的通式化合物(V)制备主要参照以下的方案进行制备,
本发明所述通式(V)所示的化合物,其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类的方法,其中一种制备方法包括以下步骤:
X5和X8为该方案的起始物料,可以通过市售产品获得,或者根据文献报道的方法制备获得。X5和X8在一定的反应温度条件下,在一定的碱性试剂存在的条件下,通过偶联得到化合物V;
另一种制备方法包括以下步骤:
X5和X9为该方案的起始物料,可以通过市售产品获得,或者根据文献报道的方法制备获得。将X5和X9在一定的反应条件下,通过还原氨化的反应制备得到V。
下面通过具体的实施例来进一步说明本发明,但本领域技术人员应知,本发明并不仅限于这些实施例。
化合物的结构是通过核磁共振(NMR)或质谱(MS)确定的。NMR的测定是用BrukerAVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thremo型号:Finnigan LCQadvantage MAX)
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm硅胶板。
柱层析一般使用烟台黄海200~300目硅胶为载体。
本发明的已知的起始原料可以采用或参照本领域已知的方法来合成,或可购买自GmbH&Co.KG,Acros Organnics,Aldrich Chemical Company,TCI Chemicals,安耐吉化学等公司。
实施例中如无特殊说明,反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气球或氮气球。
氢气氛是指反应瓶连接一个约1L容积的氢气球。
氢化反应常抽真空,充入氢气,反复操作3次。
实施例中如无特殊说明,反应的温度为室温,温度范围是20℃~30℃
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂的体系有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:正己烷和丙酮体系,D:正己烷,E:乙酸乙酯,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:正己烷和丙酮体系,D:正己烷,E:乙酸乙酯,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
实施例1
将化合物1A(150mg,0.458mmol)溶于二氯甲烷(20mL)中,然后加入三乙胺(70μL,0.504mmol),室温下搅拌,再分批加入1B(128mg,0.504mmol),加毕,室温下反应过夜。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣加入二氯甲烷,析出固体,搅拌30min,抽滤,二氯甲烷洗涤,收集滤饼,干燥得到白色固体化合物1(61mg,产率24.4%)。1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.14–8.07(m,2H),7.96–7.89(m,2H),6.95–6.86(m,4H),6.85–6.77(m,3H),3.73(s,6H),3.42(s,2H),3.29(s,3H),3.10–2.99(m,4H),2.49–2.40(m,4H).MS(ESI)m/z[M+H]+,546.1。
实施例2
将化合物1A(600mg,1.83mmol)溶于二氯甲烷(15mL)中,然后加入三乙胺(286μL,2.01mmol),室温下搅拌,再滴入2B(609mg,2.01mmol)的二氯甲烷溶液,滴毕,室温下反应过夜。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣加入二氯甲烷,析出固体,抽滤,二氯甲烷洗涤,收集滤饼,干燥得到类白色固体2C(510mg,产率47.0%)。
25mL圆底烧瓶中加入化合物2C(150mg,0.253mmol),2D(44mg,0.253mmol),Pd(dppf)2Cl2(18mg,0.025mmol),醋酸钾(74mg,0.759mmol),THF/EtOH/水(3mL/3mL/3mL)混合溶剂,氮气保护下在80℃油浴中反应过夜,反应液旋干,残渣中加入饱和碳酸氢钠水溶液,乙酸乙酯萃取,合并有机相,水洗涤,无水硫酸钠干燥,旋干后得到的残渣经硅胶柱层析(二氯甲烷:甲醇50:1)分离纯化,得到的流份旋干后加入二氯甲烷,静置析晶,抽滤,二氯甲烷洗涤,收集滤饼,干燥后得到类白色固体化合物2(93mg,产率61.5%)。1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),7.94–7.86(m,2H),7.86–7.72(m,4H),7.00–6.85(m,4H),6.84–6.75(m,3H),3.73(s,6H),3.41(s,2H),3.08–2.97(m,4H),2.48–2.35(m,4H).MS(ESI)m/z[M+H]+,598.0。
实施例3
25mL圆底烧瓶中加入化合物2B(150mg,0.253mmol),3B(56mg,0.278mmol),Pd(dppf)2Cl2(18mg,0.025mmol),醋酸钾(74mg,0.759mmol),THF/EtOH/水(3mL/3mL/3mL)混合溶剂,氮气保护下在80℃油浴中反应过夜,反应液旋干,残渣中加入饱和碳酸氢钠水溶液,乙酸乙酯萃取,合并有机相,水洗涤,无水硫酸钠干燥,旋干后得到的残渣经硅胶柱层析(二氯甲烷:甲醇50:1)分离纯化,得到的流份旋干后加入二氯甲烷,静置析晶,抽滤,二氯甲烷洗涤,收集滤饼,干燥后得到类白色固体化合物3(65mg,产率41.3%)。1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.07–7.96(m,4H),7.95–7.90(m,2H),7.85–7.77(m,2H),6.99–6.91(m,2H),6.91–6.85(m,2H),6.85–6.76(m,3H),3.72(s,6H),3.41(s,2H),3.27(s,3H),3.10–2.95(m,4H),2.49–2.38(m,4H).MS(ESI)m/z[M+H]+,622.2。
实施例4
50mL圆底烧瓶中加入4A(290mg,1.88mmol),溶于DMF(2mL),再加入碳酸钾(390mg,2.82mmol),4B(265mg,1.88mmol),氮气保护下在50℃油浴中搅拌反应过夜,反应液加水,石油醚,搅拌30min,抽滤,依次用水,石油醚洗涤,得到的滤饼用硅胶柱层析(二氯甲烷:甲醇100:1)纯化得到黄色固体4C(382mg,产率73.8%)。
100mL圆底烧瓶中加入4D(2g,12.0mmol),溶于甲醇(30mL),室温下分批加入硼氢化钠(454mg,12.0mmol),加毕,室温下反应1h,反应液浓缩至小体积,加入水和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干得到无色油状物4E,4E溶于乙醚(25mL),室温下逐滴加入三溴化磷(712μL,7.50mmol),加毕,室温下反应1h。反应液置于冰浴中,加入饱和碳酸氢钠淬灭反应,再加入乙酸乙酯萃取,无水硫酸钠干燥,旋干得到白色固体4F(1.48g,产率53.4%)
100mL圆底烧瓶中加入4G(183mg,0.430mmol),铁粉(96mg,1.72mmol),乙醇(15mL),水(3mL),饱和氯化铵(430μL),氮气保护下在90℃油浴中搅拌2h,抽滤,二氯甲烷:甲醇(20:1)洗涤,合并滤液,旋干,得到的残渣用二氯甲烷:甲醇(20:1)溶解,抽滤,收集滤液,蒸除溶剂,得到4H,该固体溶于二氯甲烷(5mL),依次加入TEA(52μL,0.373mmol),对甲苯磺酰氯(71mg,0.373mmol),搅拌反应过夜,反应液旋干,加入饱和碳酸氢钠和乙酸乙酯,萃取分层,收集有机相,水洗,无水硫酸钠干燥,蒸除溶剂,得到的残渣经硅胶柱层析(石油醚:乙酸乙酯10:1)分离纯化得到无色油状物,加入氯化氢甲醇溶液成盐,再滴加乙醚,析出固体,抽滤,收集滤饼,干燥后得到白色固体化合物4(29mg,产率11.5%)。1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.57(d,J=8.2Hz,2H),7.33(d,J=8.1Hz,2H),6.98–6.84(m,5H),6.78(d,J=8.9Hz,2H),3.93–3.80(m,2H),3.73(d,J=0.9Hz,6H),3.66(s,1H),3.54(d,J=9.6Hz,1H),3.28–3.11(m,2H),2.99–2.81(m,2H),2.65(d,J=11.1Hz,1H),2.34(s,3H).MS(ESI)m/z[M+H]+,549.9。
实施例5
将化合物1A(150mg,0.458mmol)溶解于二氯甲烷(10mL)中,然后加入DIPEA(96μL,0.550mmol),冰浴下搅拌,再滴加5B(143mg,0.550mmol)的二氯甲烷/THF溶液,滴毕,冰浴下反应2h。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇50:1)纯化得到类白色固体化合物5(52mg,产率20.6%)。1H NMR(400MHz,DMSO-d6)δ11.60–11.46(m,2H),9.84(s,1H),8.17(d,J=2.1Hz,1H),7.83(dd,J=8.6,2.1Hz,1H),7.22(d,J=8.6Hz,1H),6.91–6.85(m,4H),6.83–6.74(m,3H),3.72(s,6H),3.41(s,2H),3.07–2.97(m,4H),2.48–2.38(m,4H).MS(ESI)m/z[M+H]+,552.19。
实施例6
将化合物1A(150mg,0.458mmol)溶解于二氯甲烷(10mL)中,然后加入DIPEA(96μL,0.550mmol),冰浴下搅拌,再滴加6B(141mg,0.550mmol)的二氯甲烷/THF溶液,滴毕,冰浴下反应2h。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇50:1)纯化得到类白色固体化合物6(37mg,产率14.8%)。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.99–7.92(m,2H),7.89–7.82(m,2H),7.57(s,2H),6.94–6.85(m,4H),6.84–6.75(m,3H),3.72(s,6H),3.41(s,2H),3.10–2.96(m,4H),2.49–2.38(m,4H).MS(ESI)m/z[M+H]+,547.16。
实施例7
将化合物7A(150mg,0.311mmol)溶解于二氯甲烷(15mL)中,然后加入DIPEA(59μL,0.342mmol),室温下搅拌,再滴加7B(68mg,0.342mmol)的二氯甲烷溶液,室温下反应过夜。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇100:1)纯化得到白色固体化合物7(67mg,产率33.4%)。1H NMR(400MHz,CDCl3)δ8.00–7.86(m,2H),7.58(s,1H),7.37–7.27(m,2H),7.04–6.67(m,8H),3.88(s,3H),3.87(s,3H),3.48(s,2H),3.20–3.04(m,4H),2.62–2.48(m,4H),2.13–2.03(m,3H),1.99–1.86(m,6H),1.78–1.70(m,6H).MS(ESI)m/z[M+Na]+,667.0。
实施例8
将化合物8A(150mg,0.311mmol)溶解于二氯甲烷(15mL)中,然后加入DIPEA(59μL,0.342mmol),室温下搅拌,再滴加8B(74mg,0.342mmol)的二氯甲烷溶液,室温下反应过夜。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇100:1)纯化得到白色固体化合物8(71mg,产率34.4%)。1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.11–8.06(m,1H),7.84–7.76(m,1H),7.43–7.31(m,2H),7.02–6.69(m,8H),3.88(s,3H),3.86(s,3H),3.48(s,2H),3.16–3.08(m,4H),2.64–2.49(m,5H),2.07–1.93(m,2H),1.78–1.67(m,1H),1.15(s,6H),0.98(s,3H).MS(ESI)m/z[M+Na]+,685.0。
实施例9
将化合物9A(150mg,0.311mmol)溶解于二氯甲烷(15mL)中,然后加入DIPEA(59μL,0.342mmol),室温下搅拌,再滴加9B(95mg,0.342mmol)的二氯甲烷溶液,室温下反应过夜。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇100:1)纯化得到白色固体化合物9(83mg,产率36.9%)。1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.36(s,2H),8.20–8.11(m,1H),8.07–7.96(m,2H),7.44–7.29(m,2H),6.97–6.76(m,5H),6.75–6.65(m,2H),3.86(s,3H),3.85(s,3H),3.46(s,2H),3.16–3.02(m,4H),2.59–2.45(m,4H).MS(ESI)m/z[M+Na]+,744.9。
实施例10
将化合物10A(600mg,1.83mmol)溶解于二氯甲烷(20mL)中,然后加入DIPEA(352μL,2.02mmol),室温搅拌,再滴加10B(406mg,2.02mmol)的二氯甲烷溶液,滴毕,室温搅拌2h。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇100:1)纯化得到浅黄色固体10C(508mg,产率56.4%)。
100mL圆底烧瓶中加入C(100mg,0.203mmol),盐酸羟胺(21mg,0.305mmol),碳酸钾(42mg,0.305mmol),乙醇(15mL),在90℃油浴中反应4h,反应液旋干,加水,用稀盐酸调节pH至中性,抽滤,水洗涤,收集滤饼,干燥,经硅胶柱层析(石油醚:乙酸乙酯1:4)纯化得类白色固体化合物10(72mg,产率67.5%)。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.84(s,1H),7.84–7.76(m,2H),7.71–7.62(m,2H),6.95–6.85(m,4H),6.85–6.75(m,3H),5.95(s,2H),3.73(s,6H),3.42(s,2H),3.08–2.98(m,4H),2.49–2.39(m,4H).MS(ESI)m/z[M+H]+,526.1。
实施例11
将化合物11A(150mg,0.458mmol)溶解于二氯甲烷(10mL)中,然后加入DIPEA(96μL,0.550mmol),冰浴下搅拌,再滴加11B(147mg,0.550mmol)的二氯甲烷溶液,滴毕,冰浴下反应2h。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇100:1)纯化得到类白色固体化合物11(109mg,产率42.7%)。1H NMR(400MHz,CDCl3)δ7.74–7.64(m,2H),7.39(d,J=8.3Hz,1H),7.02–6.75(m,7H),4.41(s,2H),4.37(s,2H),3.90(s,3H),3.89(s,3H),3.51(s,2H),3.26–3.09(m,4H),2.66–2.50(m,4H).MS(ESI)m/z[M+H]+,558.1。
实施例12
将化合物12A(163mg,0.310mmol)溶解于DMF(2mL)中,然后加入TEA(65μL,0.465mmol),冰浴下搅拌,再滴加12B(56mg,0.341mmol)的二氯甲烷溶液,滴毕,冰浴下反应1h。反应液中加入饱和碳酸氢钠水溶液,乙酸乙酯萃取,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇50:1)纯化得到类白色固体化合物12(49mg,产率24.2%)。1H NMR(400MHz,CDCl3)δ7.78–7.57(m,4H),7.02–6.65(m,7H),4.34–4.16(m,2H),3.87(s,3H),3.87(s,3H),3.48(s,2H),3.22–3.02(m,4H),2.65–2.43(m,4H),1.77–1.65(m,2H),1.35–1.20(m,6H),0.93–0.85(m,3H).MS(ESI)m/z[M+H]+,554.1。
实施例13
100mL圆底烧瓶中加入13A(150mg,0.285mmol),Pd/C(50mg),甲酸铵(54mg,0.856mmol),乙酸(2mL),氮气保护下在120℃油浴中反应4h,反应液抽滤,二氯甲烷:甲醇(10:1)洗涤,合并滤液,旋干,加入水,用饱和碳酸氢钠调节pH至中性,乙酸乙酯萃取,无水硫酸钠干燥,旋干,得到的残渣中加入乙酸乙酯,搅拌,抽滤,乙酸乙酯洗涤,收集滤饼,干燥得浅黄色固体化合物13(53mg,产率36.5%)。1H NMR(400MHz,DMSO-d6)δ10.16(brs,4H),7.96–7.79(m,4H),7.00–6.85(m,4H),6.84–6.70(m,3H),3.72(s,6H),3.41(s,2H),3.08–2.92(m,4H),2.48–2.35(m,4H).MS(ESI)m/z[M+H]+,510.1。
实施例14
将化合物14A(200mg,0.381mmol)溶解于无水THF(20mL)中,然后加入DIPEA(80μL,0.457mmol),冰浴下搅拌,再滴加14B(45mg,0.152mmol)的THF溶液,滴毕,冰浴下反应2h。抽滤,水洗涤,收集滤饼,干燥,经硅胶柱层析(二氯甲烷:甲醇10:1)纯化得到白色固体化合物14(39mg,产率18.6%)。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),7.94-7.87(m,2H),7.80-7.74(m,2H),6.98-6.76(m,8H),3.73(s,6H),3.64(s,2H),3.14-3.05(m,4H),2.71-2.57(m,4H).MS(ESI)m/z[M-H]-,550.1。
实施例15
将化合物15A(130mg,0.255mmol)溶解于DMF(2mL)中,然后加入DIPEA(67μL,0.383mmol),冰浴下搅拌,再滴加15B(46mg,0.281mmol)的二氯甲烷溶液,滴毕,冰浴下反应1h。反应液中加入饱和碳酸氢钠水溶液,乙酸乙酯萃取,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇50:1)纯化得到类白色固体化合物15(49mg,产率30.1%)。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.11(s,2H),8.11–7.97(m,2H),7.83–7.69(m,2H),6.98–6.72(m,7H),4.00(t,J=6.3Hz,2H),3.72(s,6H),3.41(s,2H),3.13–2.93(m,4H),2.48–2.38(m,4H),1.66–1.50(m,2H),1.39–1.17(m,6H),0.94–0.78(m,3H).MS(ESI)m/z[M+H]+,638.0。
实施例16
将化合物16A(150mg,0.458mmol)溶解于二氯甲烷(10mL)中,然后加入DIPEA(96μL,0.550mmol),冰浴下搅拌,再滴加16B(156mg,0.550mmol)的二氯甲烷溶液,滴毕,冰浴下反应2h。反应液旋干,加入饱和碳酸氢钠水溶液和乙酸乙酯,萃取分层,收集有机相,无水硫酸钠干燥,旋干,得到的残渣经硅胶柱层析(二氯甲烷:甲醇100:1)纯化得到类白色固体化合物16(59mg,产率21.4%)。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),7.56–7.45(m,2H),7.13–7.00(m,2H),6.97–6.85(m,4H),6.84–6.71(m,3H),3.94–3.80(m,4H),3.72(s,6H),3.41(s,2H),3.16–2.95(m,8H),2.50–2.37(m,4H).MS(ESI)m/z[M+H]+,601.0。
实施例17
将1-(4-硝基苯基)哌嗪17A(1.036g,5mM)溶于甲醇(10mL)中,于0℃条件下慢滴入二碳酸二叔丁酯(1.24mL,5.4mM)的甲醇(5mL)溶液。经TLC监测反应完全,浓缩去除溶剂,用石油醚/乙酸乙酯(20/1)打浆,过滤,干燥得产品17B。
将以上产品17B溶于甲醇(15mL)中,加入10%钯/碳(150mg),在氢气条件下反应过夜。经TLC监测反应完全,硅藻土过滤,浓缩滤液得产品17C。
取以上产品17C(460mg,1.66mM)溶于二氯甲烷(10mL)中,加入三乙胺(347μL,2.49mM)和对甲苯磺酰氯(317mg,1.66mM),反应过夜。经TLC监测反应完全,加入5%柠檬酸水溶液,用二氯甲烷萃取,饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析(石油醚/乙酸乙酯=2/1)得到17D(600mg,产率84%)。
将以上产品17D溶于甲醇(4mL)中,滴入4M HCl/甲醇(8mL),反应半小时,经TLC监测反应完全,浓缩得到产品17E。
将产品17E溶于二氯甲烷(15mL)中,加入三乙胺(146μL,1.05mM)和2-溴-4′-甲氧基苯乙酮(318mg,1.39mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物17(350mg,产率52.5%)。1H NMR(400MHz,CDCl3)δ8.03(d,J=8.9Hz,2H),7.59(d,J=8.2Hz,2H),7.22(d,J=8.1Hz,2H),6.96(d,J=8.8Hz,4H),6.79(d,J=8.9Hz,2H),6.47(s,1H),3.90(s,3H),3.84(s,2H),3.29–3.15(m,4H),2.81–2.69(m,4H),2.40(s,3H).MS(ESI)m/z[M+H]+,480.4。
实施例18
将1-(4-硝基苯基)哌嗪18A(414mg,2mM)和3,4-二甲氧基苯甲醛(332mg,2mM)溶于二氯甲烷(50mL)中,滴入醋酸(100μL),搅拌半小时后,分批加入三乙酰氧基硼氢化钠(848mg,4mM),室温搅拌过夜。TLC监测反应完全,加入饱和碳酸氢钠水溶液,二氯甲烷萃取,合并有机层,分别用5%柠檬酸水溶液、水和饱和食盐水洗涤,无水硫酸钠干燥,浓缩干燥得到油状产品。静置2h后析出固体,用乙酸乙酯打浆,过滤,干燥得产品18B(435mg,产率60.9%)。
将以上产品18B溶于乙醇(30mL)和四氢呋喃(30mL)中,加入10%钯/碳(60mg),在氢气条件下反应过夜。经TLC监测反应完全,硅藻土过滤,浓缩滤液得产品18C(365mg,产率91.5%)。
将产品18C溶于二氯甲烷(20mL)中,加入三乙胺(167μL,1.2mM)和4-联苯磺酰氯(283mg,1.12mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物18(158mg,产率26.2%)。1H NMR(400MHz,CDCl3)δ7.77(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.62–7.56(m,2H),7.53–7.45(m,2H),7.46–7.39(m,1H),6.99(d,J=8.9Hz,2H),6.95–6.91(m,1H),6.91–6.76(m,4H),6.40(s,1H),3.91(s,3H),3.90(s,3H),3.51(s,2H),3.22–3.11(m,4H),2.69–2.50(m,4H).MS(ESI)m/z[M+H]+,544.7。
实施例19
将3-氯磺酰基苯甲酸19F(252mg,1.17mM)溶于二氯甲烷(10mL)中,于0℃条件下滴加草酰氯(198μL,2.34mM)和N,N-二甲基甲酰胺(20μL),转移至30℃继续搅拌反应。TLC监测反应完全,浓缩,加入二氯甲烷(15mL)并搅拌,于0℃条件下滴入三乙胺(326μL,2.34mM)和甲醇(49μL,1.2mM),TLC监测反应完全,将其滴加入到搅拌状态下的19C(225mg,0.687mM)与三乙胺(115μL,0.824mM)的二氯甲烷溶液中,经TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1-100/1)得到化合物19(222mg,产率61.5%)。1H NMR(400MHz,CDCl3)δ8.50–8.41(m,1H),8.21(d,J=7.8Hz,1H),7.84(d,J=7.9Hz,1H),7.51(t,J=7.8Hz,1H),6.97–6.90(m,3H),6.89–6.81(m,2H),6.77(d,J=8.9Hz,2H),6.65(s,1H),3.94(s,3H),3.90(s,3H),3.89(s,3H),3.51(s,2H),3.23–3.07(m,4H),2.63–2.53(m,4H).MS(ESI)m/z[M+H]+,526.7。
实施例20
将3-氯磺酰基苯甲酸20F(252mg,1.17mM)溶于二氯甲烷(10mL)中,于0℃条件下滴加草酰氯(198μL,2.34mM)和N,N-二甲基甲酰胺(20μL),转移至30℃继续搅拌反应。TLC监测反应完全,浓缩,加入二氯甲烷(15mL)并搅拌,于0℃条件下滴入三乙胺(326μL,2.34mM)和氨水(122μL,1.6mM),TLC监测反应完全,将其滴加入到搅拌状态下的20C(225mg,0.687mM)与三乙胺(115μL,0.824mM)的二氯甲烷溶液中,经TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1-20/1)得到化合物20(167mg,产率47.6%)。1H NMR(400MHz,CDCl3)δ8.39–8.28(m,1H),7.98(d,J=7.8Hz,1H),7.69(d,J=7.9Hz,1H),7.40(t,J=7.8Hz,1H),6.95(d,J=8.8Hz,2H),6.93–6.89(m,1H),6.89–6.78(m,3H),6.73(d,J=8.9Hz,2H),6.53(s,1H),3.88(s,3H),3.88(s,3H),3.49(s,2H),3.19–3.02(m,4H),2.63–2.47(m,4H).MS(ESI)m/z[M+H]+,511.6。
实施例21
将1-(4-硝基苯基)哌嗪21A(828mg,4mM)和吡啶-4-甲醛(764μL,4mM)溶于二氯甲烷(100mL)中,滴入醋酸(200μL),搅拌半小时后,分批加入三乙酰氧基硼氢化钠(1.696g,8mM),室温搅拌过夜。TLC监测反应完全,加入饱和碳酸氢钠水溶液,二氯甲烷萃取,合并有机层,分别用5%柠檬酸水溶液、水和饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析(二氯甲烷/甲醇=50/1)得产品21B(653mg,产率54.7%)。
将以上产品21B溶于乙醇(40mL)和四氢呋喃(60mL)中,加入10%钯/碳(70mg),在氢气条件下反应过夜。经TLC监测反应完全,硅藻土过滤,浓缩滤液得产品21C(135mg,产率23.0%)。
将产品21C溶于二氯甲烷(20mL)中,加入三乙胺(77μL,0.553mM)和4-联苯磺酰氯(127mg,0.503mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=100/1-50/1)得到化合物21(125mg,产率51.2%)。1H NMR(400MHz,CDCl3)δ8.58(d,J=5.9Hz,2H),8.05(s,1H),7.79(d,J=8.4Hz,2H),7.61(d,J=8.5Hz,2H),7.59–7.52(m,2H),7.46(t,J=7.3Hz,2H),7.43–7.37(m,1H),7.32(d,J=5.8Hz,2H),7.05(d,J=8.9Hz,2H),6.79(d,J=9.0Hz,2H),3.56(s,2H),3.28–3.04(m,4H),2.68–2.53(m,4H).MS(ESI)m/z[M+H]+,485.6。
实施例22
将1-(4-硝基苯基)哌嗪22A(414mg,2mM)溶于乙醇(15mL)和四氢呋喃(15mL)中,加入10%钯/碳(50mg),在氢气条件下反应3小时。经TLC监测反应完全,硅藻土过滤,浓缩滤液得产品22B(319mg,产率90.0%)。
将产品22B溶于二氯甲烷(20mL)中,加入三乙胺(348μL,2.5mM)和4-联苯磺酰氯(455mg,1.8mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物22(215mg,产率19.6%)。1H NMR(400MHz,CDCl3)δ7.86(d,J=8.3Hz,2H),7.83–7.71(m,4H),7.66–7.57(m,4H),7.58–7.36(m,8H),7.13(s,1H),7.04(d,J=8.8Hz,2H),6.74(d,J=8.8Hz,2H),3.39–3.04(m,8H).MS(ESI)m/z[M+H]+,610.8。
实施例23
将4-苯基哌啶23A(2.0g,12.4mM)溶液醋酸(10mL)中,分别滴加浓硫酸(663μL)的醋酸(10mL)溶液和浓硝酸(525μL)的醋酸(5mL)溶液(内部温度不低于20℃),然后,再加入浓硫酸(10mL)(内部温度达到60℃),让其恢复到室温,将其倒入冰水(25g)中,并加入碳酸氢钠固体(37.5g)调至中性,用二氯甲烷萃取,用饱和食盐水洗涤,无水硫酸钠干燥,用乙醚分散得到黄色固体23B(675mg),不需纯化直接进行下一步。
将化合物23B(675mg,3.3mM)和3,4-二甲氧基苯甲醛(548mg,3.3mM)溶于二氯甲烷(80mL)中,滴入醋酸(100μL),搅拌半小时后,分批加入三乙酰氧基硼氢化钠(1.25g,5.9mM),室温搅拌过夜。TLC监测反应完全,加入饱和碳酸氢钠水溶液,二氯甲烷萃取,合并有机层,分别用5%柠檬酸水溶液、水和饱和食盐水洗涤,无水硫酸钠干燥,浓缩干燥得到油状产品23C。静置2h后析出固体,用乙酸乙酯打浆,过滤,干燥得产品23C(633mg,产率53.8%)。
将以上产品23C溶于乙醇(40mL)和四氢呋喃(40mL)中,加入10%钯/碳(70mg),在氢气条件下反应过夜。经TLC监测反应完全,硅藻土过滤,浓缩滤液得产品23D。
将产品23D溶于二氯甲烷(30mL)中,加入三乙胺(237μL,1.7mM)和4-联苯磺酰氯(359mg,1.42mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物23(128mg,产率16.6%)。1H NMR(400MHz,CDCl3)δ7.90(d,J=8.4Hz,2H),7.59(d,J=8.4Hz,2H),7.52(d,J=7.1Hz,2H),7.43(t,J=7.3Hz,2H),7.41–7.34(m,1H),7.31(s,1H),7.15(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,2H),6.96(d,J=8.1Hz,1H),6.84(d,J=8.2Hz,1H),4.02–3.90(m,5H),3.87(s,3H),3.48–3.24(m,2H),2.64–2.42(m,3H),2.12(t,J=19.1Hz,2H),1.80(d,J=13.1Hz,2H).MS(ESI)m/z[M+H]+,543.7。
实施例24
将产品24C(490mg,1.5mM)溶于二氯甲烷(25mL)中,加入三乙胺(230μL,1.65mM)和4-硝基苯磺酰氯(332mg,1.5mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物24D(356mg,产率46.3%)。
将化合物24D(356mg,0.69mM)溶于乙醇(20mL)和四氢呋喃(20mL)中,加入10%钯/碳(40mg),在氢气条件下反应过夜。经TLC监测反应完全,硅藻土过滤,浓缩滤液得化合物24E。
将化合物24E溶于二氯甲烷(15mL)中,加入三乙胺(106μL,0.76mM),在0℃下滴加甲磺酰氯(54μL,0.7mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物24(68mg,产率15.4%)。1H NMR(400MHz,CDCl3)δ7.82(d,J=8.7Hz,2H),7.27(d,J=8.7Hz,2H),7.00(d,J=8.8Hz,2H),6.94(s,1H),6.92–6.79(m,4H),3.90(s,3H),3.88(s,3H),3.51(s,2H),3.48(s,3H),3.35–3.20(m,4H),3.10(s,3H),2.70–2.38(m,4H).MS(ESI)m/z[M+H]+,561.7。
实施例25
将化合物25A(96mg,0.2mM)溶于二氯甲烷(4mL)中,加三乙胺(31μL,0.22mM)和3-氯磺酰基苯甲酸(44mg,0.2mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物25(32mg,产率24.0%)。1H NMR(400MHz,DMSO)δ10.83(s,1H),9.98(s,1H),9.08(s,1H),8.45–8.29(m,1H),8.28–8.18(m,1H),7.99–7.89(m,1H),7.89–7.83(m,1H),7.68(t,J=7.9Hz,1H),7.58(s,1H),7.54–7.47(m,1H),7.43(d,J=7.9Hz,1H),7.40–7.33(m,1H),7.33–7.25(m,1H),6.94(d,J=8.5Hz,3H),6.80(d,J=8.1Hz,2H),6.78–6.69(m,1H),3.87(s,1H),3.75(s,6H),3.66–3.54(m,5H),3.17–3.06(m,4H).MS(ESI)m/z[M+H]+,667.8。
实施例26
将化合物26A(96mg,0.2mM)溶于二氯甲烷(4mL)中,加三乙胺(31μL,0.22mM)和4-氯磺酰基苯磺酰胺(84mg,0.33mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物26(26mg,产率18.5%)。1H NMR(400MHz,DMSO)δ10.83(s,2H),9.92(s,1H),8.14–8.09(m,2H),7.98–7.94(m,2H),7.93(s,1H),7.78(s,2H),7.36(t,J=7.9Hz,1H),7.33–7.26(m,1H),7.24–7.16(m,1H),6.96–6.79(m,5H),6.80–6.72(m,2H),3.75–3.73(m,6H),3.44(s,2H),3.16–2.90(m,4H),2.52–2.38(m,4H).MS(ESI)m/z[M+H]+,702.8。
实施例27
将化合物27A(77mg,0.16mM)溶于乙腈(3mL)中,加对甲苯磺酰异氰酸酯(28μL,0.18mM),搅拌1小时后,TLC监测反应完全,过滤并洗涤得到化合物27(46mg,产率42.3%)。1H NMR(400MHz,DMSO)δ9.85(s,1H),8.97(s,1H),8.00(s,1H),7.76(d,J=8.1Hz,2H),7.41(d,J=8.2Hz,1H),7.35–7.24(m,3H),7.16(d,J=7.8Hz,1H),7.05–6.84(m,5H),6.79(d,J=9.0Hz,2H),3.86(s,2H),3.76(s,3H),3.76(s,3H),3.24–3.01(m,4H),2.95–2.72(m,4H),2.35(s,3H).MS(ESI)m/z[M+H]+,680.8。
实施例28
将产品28C(96mg,0.29mM)溶于二氯甲烷(3mL)中,加入N,N-二异丙基乙基胺(77μL,0.44mM)和4-((甲砜基)甲基)苯磺酰氯(86mg,0.32mM),搅拌过夜。TLC监测反应完全,浓缩,柱层析(二氯甲烷/甲醇=200/1)得到化合物28(48mg,产率29.6%)。1H NMR(400MHz,CDCl3)δ7.76(d,J=8.2Hz,2H),7.74–7.69(m,1H),7.66(d,J=7.7Hz,1H),7.51(d,J=8.3Hz,2H),6.95(d,J=9.1Hz,2H),6.86(d,J=7.0Hz,2H),6.82–6.72(m,1H),6.34(s,1H),4.30(s,2H),3.91(s,3H),3.90(s,3H),3.51(s,2H),3.22–3.11(m,4H),2.81(s,3H),2.62–2.51(m,4H).MS(ESI)m/z[M+H]+,560.7。
实施例29
将化合物29A 300mg(0.917mmol)溶于5ml CH2Cl2中,加入Et3N 190μl(1.376mmol),冰水浴下滴加29B 202.5mg(0.917mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物29(80.4mg,收率:17.1%),1H NMR(400MHz,CDCl3)δ8.58(s,1H),8.40(d,J=8.3Hz,1H),7.99(d,J=7.8Hz,1H),7.65(t,J=8.0Hz,1H),7.00–6.76(m,7H),3.91(d,J=5.4Hz,6H),3.53(d,J=8.7Hz,2H),3.19(s,4H),2.61(s,4H).MS(ESI)m/z[M+H]+,513.1。
实施例30
将化合物30C100mg(0.195mmol)溶于5ml MeOH中,加入20mg Pd/C,在氢气保护下室温反应过夜,反应液用硅藻土过滤,浓缩,得到粗产品,经硅胶柱层析得到类白色固体产物30(64mg,收率:68.2%)。1H NMR(400MHz,CDCl3)δ7.19(t,J=7.9Hz,1H),7.05(d,J=7.9Hz,1H),7.02–6.75(m,9H),6.24(s,1H),5.32(s,1H),3.91(d,J=4.8Hz,6H),3.51(s,2H),3.22–3.08(m,4H),2.63–2.53(m,4H).MS(ESI)m/z[M+H]+,483.1。
实施例31
将化合物31A300mg(0.917mmol)溶于5ml CH2Cl2中,加入Et3N 190μl(1.376mmol),冰水浴下滴加31B 243.8mg(0.917mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物31(100mg,收率:19.6%),1H NMR(400MHz,CDCl3)δ8.68(d,J=2.2Hz,1H),8.38(d,J=7.1Hz,1H),7.99(d,J=8.5Hz,1H),7.13–6.74(m,8H),3.91(d,J=3.5Hz,6H),3.51(s,2H),3.18(s,4H),2.58(s,4H).MS(ESI)m/z[M+H]+,558.0。
实施例32
将化合物32A300mg(0.917mmol)溶于5ml CH2Cl2中,加入Et3N 190μl(1.376mmol),冰水浴下滴加32B 202.5mg(0.917mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物32(102mg,收率:21.7%),1H NMR(400MHz,CDCl3)δ7.87(d,J=7.9Hz,1H),7.77(d,J=7.8Hz,1H),7.70(t,J=7.2Hz,1H),7.57(t,J=7.3Hz,1H),7.06(d,J=8.9Hz,3H),6.92(s,1H),6.89–6.75(m,4H),3.90(d,J=4.1Hz,6H),3.51(s,2H),3.23–3.12(m,4H),2.58(s,4H).MS(ESI)m/z[M+H]+,513.1。
实施例33
将化合物33A 300mg(0.917mmol)溶于5ml CH2Cl2中,加入Et3N 190μl(1.376mmol),冰水浴下滴加33B 207.8mg(0.917mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析纯化得到类白色固体产物化合物33(125.7mg,收率:26.5%)。1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.90(d,J=8.2Hz,3H),7.73–7.56(m,3H),6.95(d,J=8.9Hz,3H),6.85(d,J=6.8Hz,2H),6.76(d,J=9.0Hz,2H),3.90(d,J=5.5Hz,6H),3.51(s,2H),3.15(m,4H),2.58(m,4H).MS(ESI)m/z[M+H]+,518.1。
实施例34
将化合物34D 100mg(0.207mmol)溶于5ml CH2Cl2中,加入Et3N 43μl(0.31mmol),冰水浴下滴加联苯磺酰氯52.2mg(0.207mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物34(45mg,收率:31.2%)。1H NMR(400MHz,CDCl3)δ8.08–7.87(m,3H),7.71(ddd,J=22.8,14.1,6.4Hz,5H),7.51(ddd,J=26.7,17.0,8.0Hz,5H),7.02–6.68(m,7H),3.91(d,J=6.3Hz,6H),3.58(s,2H),3.26(d,J=24.1Hz,4H),2.61(s,4H).MS(ESI)m/z[M+H]+,699.3.。
实施例35
将化合物35A 300mg(0.917mmol)溶于5ml CH2Cl2中,加入Et3N 190μl(1.376mmol),冰水浴下滴加C10 202.6mg(0.917mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物35(236mg,收率:50.2%),1H NMR(400MHz,CDCl3)δ8.28(d,J=8.8Hz,2H),7.88(d,J=8.8Hz,2H),7.07–6.71(m,7H),3.91(d,J=5.9Hz,6H),3.58(d,J=4.9Hz,2H),3.21(s,4H),2.63(s,4H).MS(ESI)m/z[M+H]+,513.2。
实施例36
将化合物36D100mg(0.207mmol)溶于5ml CH2Cl2中,加入Et3N 43μl(0.31mmol),冰水浴下滴加甲基磺酰氯71.13mg(0.621mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物36共计49.6mg(42.7%),1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.00(d,J=8.4Hz,2H),7.52(d,J=8.5Hz,2H),6.93(dd,J=55.2,8.6Hz,7H),3.92(d,J=8.9Hz,6H),3.58(s,2H),3.52(s,3H),3.46(s,6H),3.29(m,4H),2.60(m,4H).MS(ESI)m/z[M+H]+,717.1。
实施例37
将化合物37A 300mg(0.917mmol)溶于5ml CH2Cl2中,加入Et3N 190μl(1.376mmol),冰水浴下滴加37B共计202.5mg(0.917mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物37C。
将化合物37C共计200mg(0.39mmol)溶于5ml MeOH中,加入Pd/C 40mg,氢气保护下反应过夜,硅藻土过滤,甲醇和二氯甲烷依次洗涤滤饼,合并有机相,浓缩得化合物37D,投下一步。
化合物37D溶于5ml CH2Cl2中,加入Et3N(1.5eq),冰水浴下滴加甲基磺酰氯(1eq),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物37共计41mg(收率28.9%)。1H NMR(400MHz,CDCl3)δ8.62(s,1H),7.88(d,J=8.4Hz,1H),7.78–7.55(m,2H),7.19(t,J=7.7Hz,1H),7.05(d,J=8.8Hz,2H),6.97–6.78(m,5H),3.91(d,J=6.5Hz,6H),3.52(s,2H),3.47(s,3H),3.30(s,4H),3.08(s,3H),2.59(s,4H).MS(ESI)m/z[M+H]+,639.0。
实施例38
将化合物38D共计100mg(0.207mmol)溶于5ml CH2Cl2中,加入Et3N 43μl(0.31mmol),冰水浴下滴加对甲基苯磺酰氯39.5mg(0.207mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物38(43mg,收率:32.7%)。1H NMR(400MHz,CDCl3)δ7.77(dd,J=55.0,7.7Hz,3H),7.35(s,2H),7.03–6.72(m,10H),3.91(d,J=6.1Hz,6H),3.52(s,2H),3.27(s,4H),2.59(s,4H),2.48(s,3H).MS(ESI)m/z[M+H]+,637.1。
实施例39
将化合物39D 100mg(0.207mmol)溶于5ml CH2Cl2中,加入Et3N 43μl(0.31mmol),冰水浴下滴加甲基磺酰氯47.4mg(0.414mmol),滴加完毕后转至室温反应3h,用CH2Cl2萃取,有机相用水洗,然后用饱和食盐水洗涤后合并有机相层,无水硫酸钠干燥,浓缩,经硅胶柱层析得到类白色固体产物化合物39共计68.4mg(51.7%),1H NMR(400MHz,CDCl3)δ8.02(t,J=3.7Hz,1H),7.91(s,1H),7.65(d,J=4.8Hz,2H),6.90(ddd,J=14.5,12.0,5.9Hz,7H),5.32(s,1H),3.91(d,J=6.6Hz,6H),3.51(s,2H),3.48–3.37(m,6H),3.28(s,4H),2.59(s,4H).MS(ESI)m/z[M+H]+,638.9。
本发明部分化合物生物测试结果
一、荧光定量PCR实验检测药物对肝细胞PCSK9基因表达水平的影响
本实验目的是反映化合物对PCSK9基因表达的抑制作用,化合物对PCSK9基因表达的抑制作用越强烈,表明化合物潜在的降脂功效越强。
检测药物对HepG2细胞PCSK9mRNA的作用:
将HepG2细胞(ATCC),按每孔7×105细胞/孔的密度接种至6孔板,37℃,5%CO2培养过夜。次日,换液并加入待测药物和阳性药处理24小时。用Trizol试剂(Invitrogen)提取总RNA,RNase-Free DNase(Promega)处理。每份样品取1ug RNA,用M-MLV逆转录酶(Promega)反转录成cDNA作为实时荧光定量PCR的模板。使用经过验证的PCSK9定量PCR引物、β-Actin定量PCR引物作为PCSK9及内参基因β-Actin的引物。用模板、引物、Power SYBR Green PCRMaster Mix(Invitrogen)配制各样品的定量PCR反应体系,在定量PCR仪CFX96Real-TimePCR Detection System(Bio-Rad)上按PCR仪器说明书要求进行实时荧光定量PCR反应,获得表达量数据。采用ΔΔCT法处理表达量数据,以β-Actin为内参,空白对照的PCSK9表达量设定为1,求得其余样品中PCSK9相对于对照的相对表达量(相对于对照的倍数),以此评估药物对肝细胞PCSK9基因表达水平的影响。
实验表明:本发明化合物,例如:1,2,3,6,7,8,9,11,16,18,20,23,26,28,29,30,38等,能够对PCSK9mRNA表达起到强烈的抑制作用。
二、LDL摄取率测试实验:
本实验的目的是在细胞水平上反映化合物对降低LDL的作用。LDL水平过高能致动脉粥样硬化。本实验从细胞水平直接检测肝细胞摄取LDL的能力,可直接反映化合物的降脂效果。
LDL摄取率细胞模型:
肝细胞表面表达LDL受体,具有摄取LDL的能力。在培养基中添加荧光物质Dil标记的LDL(Dil-LDL),在荧光显微镜下可观察到HepG2肝癌细胞将Dil-LDL摄取到细胞内。药物可使肝细胞表面LDL受体的量增多从而增强肝细胞对LDL的摄取能力,因此可用在显微镜下观察到的荧光强度评价样品对肝细胞摄取LDL能力的影响。
常规培养HepG2细胞(ATCC),按每孔2.5×104个细胞的密度接种至96孔板,37℃,5%CO2培养过夜。次日,弃上清,加入样品和阳性药处理20小时。弃上清,每孔加入含2μg/ml荧光性的Dil-LDL(Invitrogen)的新鲜培养基,在37℃,5%CO2条件下继续孵育4小时。弃上清,用PBS洗涤细胞2次,换新鲜培养基,在荧光显微镜(Leica DM IL LED Microsystems)下观察每孔细胞的荧光强度。以不加样品及Dil-LDL处理的正常细胞作为阴性对照。用在显微镜下观察到的荧光强度评价样品对肝细胞摄取LDL能力的影响,并加以分级,便于比较。分级方法如下:
-表示较正常细胞对照而言,无增加的荧光强度;
+表示较正常细胞对照而言,略微增加的荧光强度;
++表示较正常细胞对照而言,中等增加的荧光强度;
+++表示较正常细胞对照而言,强烈增加的荧光强度;
++++表示较正常细胞对照而言,非常强烈增加的荧光强度。
实验结果表明:本发明化合物能够显著地增强肝细胞对LDL的摄取能力。说明本发明化合物具有增加肝细胞摄取LDL的活性。
Claims (10)
1.式V的化合物
其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中:
R5,R6,R7,R8独立地是氢,卤,经取代的或未经取代的硅基,氨基,硝基,氧代基,硫基,砜基,氰基,羰基,磺酰氧基,磷酰氧基,烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R9,R10,R11,R12,R13,R14,R15,R16独立地是氢,卤,经取代的或未经取代的硅基,氨基,硝基,氧基,硫基,砜基,氰基,羰基,磺酰氧基,磷酰氧基,烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R17,R18,R19,R20,R21,R22,R23,R24,R25,R26独立地是氢,卤,-OH,-NR′R″,-NO2,-Si(R′)3,-CN,-(CH2)0-6COOR′,-C(O)R′,-OC(O)R′,-C(O)NR′R″,-OC(O)OR′,-OC(O)NR′R″,-S(O)mR′,-S(O)nNR′R″,-OS(O)nR′,-OS(O)nNR′R″,-OS(O)nNH(C=O)NR′R″,-S(O)nNH(C=O)NR′R″,-NR′S(O)nR″,-NR′S(O)nNR′R″,经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R′和R″独立的是氢或者经取代的或未经取代的烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
M为氮原子,或者碳原子;
m=0,1,2;
n=1,2,3;
q=0,1,2,3,4,5,6;
t=0,1,2。
2.根据权利要求1的通式化合物(V),其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中包括通式化合物化合物(VI),
其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中:
R27独立地是-OH,-NR′R″,-CN,-(CH2)0-6COOR′,经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R5,R6,R17,R18,R20,R21,R22,R23,R24,R25,R26,R′,R″,M同权利要求1。
3.根据权利要求2的通式化合物(VI),其中,R27独立地是经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基。
4.根据权利要求2的通式化合物(VI),其中,R27独立地是经取代的或未经取代的芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基。
5.根据权利要求2的通式化合物(VI),其中,R27选自以下基团:
6.根据权利要求2的通式化合物(VI),其立体异构体,其互变异构体,其溶剂化物及其药用可接受的盐类,其中包括通式化合物(VII),
其中,R22,R23,R24,R25,R26独立地是氢,卤,经取代的或未经取代的硅基,氨基,硝基,氧代基,硫基,砜基,氰基,羰基,磺酰氧基,磷酰氧基,烷基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基;
R27独立地是经取代的或未经取代的烷基,烷氧基,烯基,炔基,环烷基,环烷基烷基,芳基,芳烷基,杂芳基,杂芳基烷基,杂环基或杂环基烷基。
7.根据权利要求6的通式化合物(VII),其中,R27选自以下基团:
8.根据权利要求1~7的化合物,该化合物选自以下化合物,但不局限于以下化合物范围:
或其药用可接受的盐。
9.权利要求1至8中任意一项化合物在制备用于治疗II型糖尿病,高血糖症,肥胖症,胰岛素抵抗症,抗肿瘤,以及治疗高脂血症,高胆固醇血症,高甘油三酯血症,肝脂肪变性和代谢综合征构成的疾病或病况的药物中的用途。
10.权利要求1至8中任意一项化合物在制备用于降低患者血浆和/或肝的脂类水平的药物中的用途。
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US10800757B2 (en) | 2017-10-27 | 2020-10-13 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
US12059408B2 (en) | 2020-08-13 | 2024-08-13 | Boehringer Ingelheim International Gmbh | Treatment of cognitive impairment associated with schizophrenia |
US12275722B2 (en) | 2020-10-13 | 2025-04-15 | Boehringer Ingelheim International Gmbh | Process of reworking a crystalline form of a glycine transport inhibitor |
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US10800757B2 (en) | 2017-10-27 | 2020-10-13 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
US10889568B2 (en) | 2017-10-27 | 2021-01-12 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
USRE49699E1 (en) | 2017-10-27 | 2023-10-17 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
US12059408B2 (en) | 2020-08-13 | 2024-08-13 | Boehringer Ingelheim International Gmbh | Treatment of cognitive impairment associated with schizophrenia |
US12275722B2 (en) | 2020-10-13 | 2025-04-15 | Boehringer Ingelheim International Gmbh | Process of reworking a crystalline form of a glycine transport inhibitor |
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