CN111484504A - Acc抑制剂的光学异构体及其应用 - Google Patents
Acc抑制剂的光学异构体及其应用 Download PDFInfo
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- CN111484504A CN111484504A CN201910071777.XA CN201910071777A CN111484504A CN 111484504 A CN111484504 A CN 111484504A CN 201910071777 A CN201910071777 A CN 201910071777A CN 111484504 A CN111484504 A CN 111484504A
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Abstract
本发明属于医药化学领域,涉及一类ACC抑制剂的光学异构体及其应用,具体地,本发明提供式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐,它们的制备方法以及含有这些光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐的药物组合物和它们用于治疗肿瘤的用途。本发明的化合物对ACC具有好的抑制活性,非常有希望成为疗效更高、副作用更小的ACC表达相关疾病,例如纤维化疾病、代谢性疾病、癌症或者组织增生类疾病的治疗剂,
Description
技术领域
本发明属于医药化学领域,具体涉及一类ACC抑制剂的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐,它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗ACC表达相关疾病的用途。
背景技术
乙酰辅酶A羧化酶(ACC)是催化乙酰辅酶A反应生成丙二酰辅酶A的生物素酶,该催化反应是制约脂肪酸合成第一阶段的限速步骤。在哺乳动物中,ACC以两种组织特异性同功酶的形式存在,其中ACC1主要存在于脂质生成组织,如肝脏和脂肪,而ACC2主要存在于氧化组织,如肝脏、心脏和骨胳肌。ACC1和ACC2是由独立基因编码,虽然呈现不同的细胞分布,但二者共有75%的总体氨基酸序列一致性。在肝脏中,脂肪酸(FA)的合成和伸长是通过ACC1催化乙酰辅酶A生成的丙二酰基辅酶A,从而促使三酸甘油酯形成和极低密度脂蛋白(VLDL)产生。在合成脂肪酸能力有限的心脏和骨胳肌中,由ACC2形成的丙二酰基辅酶A发挥调控FA氧化的功能[Tong L,Harwood HJ Jr.J Cell Biochem.2006,99(6):1476-1788.]。
非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪肝炎(NASH)被认为是肝脏代谢异常的两种表现,是目前最为常见的慢性肝病,而且其发病率正在逐年攀升。其中NASH可能会进一步发展为肝硬化和肝癌,可能引起由肝脏疾病引起的死亡。目前该类疾病缺乏有效的治疗策略,现有治疗药物仍然是以噻唑烷二酮类为代表的胰岛素增敏剂和抗氧化剂(如维生素E),此外包括降脂药物、血管紧张素受体拮抗剂、多不饱和脂肪酸等,治疗效果非常有限。在目前的多项研究中,ACC1和ACC2被认为是有望治疗NAFLD和NASH的药物作用靶点[Geraldine Harriman,Jeremy Greenwood,Sathesh Bhat,et al.Proc NatlAcadSciU.S.A.2016,113(13):E1796-E1805.]。
对于靶向ACC途径的药物研究已有一定进展和研究基础,通过抑制ACC1和ACC2可以抑制肝脏细胞内脂肪的从头(de novo)合成,该治疗方案可显著降低肝脏脂肪含量和硬化程度,同时较早降低肝纤维化标志物水平。另有研究表明,对ACC1和ACC2同时抑制可降低肿瘤组织中重新产生FA的能力,具有抑制肿瘤细胞生长的作用[Svensson RU,Parker SJ,Eichner LJ,et al.NatMed.2016,22(10):1108-1119.]。不过,仍然需要开发更优异的ACC抑制剂,以便获得活性更优且安全性更高的药物,从而用于治疗ACC介导的事件相关的疾病,如纤维化疾病、代谢性疾病、肿瘤和增生性疾病。
此外,大量文献数据表明,手性药物的光学异构体具有不同的药效学、药代动力学和毒理学性质。而本申请的发明人前期通过一系列药理研究表明,本发明的ACC抑制剂具有良好的成药性,因此,合成其光学异构体,并对它们进行生物活性、毒性和副作用的研究,对于该类化合物的成药性研究具有重要的指导意义,值得进行深入的开发。
发明内容
本发明的一个目的是提供式I或式II所示的具有ACC抑制活性的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐,
本发明的另一个目的是提供制备本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐的方法。
本发明的再一个目的是提供包含本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐和药学可接受的载体的组合物,以及包含本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐和另一种或多种ACC抑制剂的组合物。
本发明的还一个目的是提供本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐治疗ACC表达相关疾病的方法,以及本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐在制备用于治疗ACC表达相关疾病的药物中的应用。
针对上述目的,本发明提供以下技术方案:
第一方面,本发明提供式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐:
在一些实施方案中,本发明的式I或II的化合物为基本上纯的异构体形式,异构体纯度为至少60%ee。在一个具体的实施方案中,本发明的式I或II的化合物的异构体纯度为至少90%ee。在另一个具体的实施方案中,本发明的式I或II的化合物的异构体纯度为至少98%ee。在一个优选的实施方案中,本发明的式I或II的化合物的异构体纯度为至少99%ee。对映体过量(ee)值提供的是主要对映体的百分量超过与其同时存在的次要对映体的百分量的定量测量,可容易地通过本领域所建立的和公知的适当方法进行测量,例如手性高压液相色谱法(HPLC)、手性气相色谱法(GC)、使用手性位移试剂的核磁共振(NMR)等。
在一些优选的实施方案中,本发明提供式I或式II的化合物的药学上可接受的盐,其中所述药学上可接受的盐包括来源于适合无机和有机酸和碱的药学上可接受的盐。例如,适合无机和有机酸和碱的药学上可接受的盐包括药学上可接受的无毒酸加成盐,实例为由例如盐酸、氢溴酸、磷酸、硫酸和高氯酸的无机酸或由例如乙酸、草酸、顺丁烯二酸、酒石酸、柠檬酸、丁二酸或丙二酸的有机酸形成或通过使用此项技术中所用的其它方法(例如离子交换)而形成的氨基的盐。适合无机和有机酸和碱的药学上可接受的盐还包括其它药学上可接受的盐,例如己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、反丁烯二酸盐、葡糖庚酸盐、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-乙烷磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲烷磺酸盐、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、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、特戊酸盐、丙酸盐、硬脂酸盐、丁二酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐和其类似盐。
适合无机和有机酸和碱的药学上可接受的盐还包括来源于适当碱的药学上可接受的盐,例如碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4盐。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐和其类似盐。适当时,适合无机和有机酸和碱的药学上可接受的盐还包括其它药学上可接受的盐,例如无毒铵、季铵,和使用例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低碳数烷基磺酸根和芳基磺酸根的相对离子形成的胺阳离子。
另一方面,本发明提供本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐的制备方法:
a)式(1)的化合物与三光气、式(2)的化合物在碱性试剂的作用下经反应制得式(3)的化合物;
b)式(3)的化合物在碱性试剂的作用下经反应制得式(4)的化合物;
c)式(4)的化合物与式(5)的化合物在碱性试剂的作用下经反应制得式(6)的化合物;
d)式(6)的化合物经卤代反应制得式(7)的化合物;
e)式(7)的化合物与式(8)的化合物经缩合反应得到式(9)的化合物;
f)式(9)的化合物经酯水解反应制得式I的化合物;
其中,X1、X2各自独立的选自氟、氯、溴和碘;X3为离去基团,优选为三丁基甲锡烷基;R1、R2各自独立地选自烷基,优选为C1-6烷基,更优选为甲基、乙基、丙基、丁基或叔丁基。
本发明的式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐的制备方法与式I所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐的制备方法相似,不同的是将式(5)的化合物替换成其对映异构体。
第三方面,本发明提供药物组合物,其包含本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐和药学上可接受的载体。
在一些实施方案中,本发明提供药物组合物,其包含本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐,还包含选自下列组成的一种或多种:ACC抑制剂、ASK1抑制剂、FGFR抑制剂、PI3K抑制剂、酪氨酸蛋白酶抑制剂、EGFR抑制剂、VEGFR抑制剂、Bcr-Abl抑制剂、c-kit抑制剂、c-Met抑制剂、Raf抑制剂、MEK抑制剂、组蛋白去乙酰酶抑制剂、VEGF抗体、EGF抗体、HIV蛋白激酶抑制剂、HMG-CoA还原酶抑制剂等。
可以将本发明的式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂,以适合于经口或胃肠外给药。给药方法包括,但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用,例如通过输注或推注,通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型,具体而言,包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备,且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
根据本发明,在一些实施方案中,本发明提供式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐,
其中所述式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐富含式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐。在一些实施方案中,本发明的式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐含有基本上为纯的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐。在一个具体的实施方案中,本发明的式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐含有大于60%的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐。在另一个具体的实施方案中,本发明的式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐含有大于90%的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐。在另一个具体的实施方案中,本发明的式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐含有大于98%的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐。在一个优选的实施方案中,本发明的式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐含有大于99%的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐。
在一些实施方案中,本发明的式A的化合物为基本上纯的异构体形式,其基本上不含其它异构体。例如,在一个具体实施方案中,本发明的式A的化合物基本上不含式II的异构体。在另一个具体实施方案中,本发明的式A的化合物为纯的异构体形式。
第四方面,本发明提供本发明式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐,式A所示的化合物或其水合物、溶剂合物、结晶或其药学上可接受的盐或包含它们的药物组合物在制备治疗ACC表达相关疾病的药物中的用途,例如纤维化疾病、代谢性疾病、肿瘤和增生性疾病的药物中的用途,其中所述纤维化疾病选自肝纤维化,其中所述代谢性疾病选自肥胖、糖尿病、非酒精性脂肪性肝病或非酒精性脂肪肝炎,其中所述肿瘤和增生性疾病选自肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤,膀胱、前列腺和胰腺的癌和肉瘤,以及皮肤、结肠、甲状腺和卵巢的原发和复发性实体瘤。
在一个优选的实施方案中,一种具有式I或式II所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐,式A所示的化合物或其水合物、溶剂合物、结晶或其药学上可接受的盐或包含它们的药物组合物治疗和/或预防ACC表达相关疾病的方法和在制备治疗和/或预防ACC表达相关疾病药物中的应用,其中所述的纤维化疾病选自肝纤维化,其中所述代谢性疾病选自肥胖、糖尿病、非酒精性脂肪性肝病或非酒精性脂肪肝炎,其中所述肿瘤和增生性疾病选自肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤,膀胱、前列腺和胰腺的癌和肉瘤,以及皮肤、结肠、甲状腺和卵巢的原发和复发性实体瘤。
术语说明
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明“光学异构体”是指分子结构完全相同,物理化学性质相近,但旋光性不同的物质。在光学活性化合物的描述中,前缀D和L或R和S用于表示与分子的手性中心有关的绝对构型。前缀(+)和(-)或d和l用于指定化合物引起的平面偏振光的旋转方向。用(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。许多有机化合物以光学活性形式存在,即它们能使平面偏振光的平面旋转。对于给定的化学结构,不同的光学活性化合物被称为立体异构体,除了彼此互为镜像之外,它们是相同的。一个具体的立体异构体也可称作对映异构体,这些异构体的混合物被称为对映异构体混合物或外消旋混合物。
在本发明中,当特定异构体在混合物的组成中超过50%时,为外消旋混合物“富含”该特定异构体。“基本上不含”是指当使用本领域技术人员常规使用的传统分析方法确定时,该化合物包括少于大约10%不需要的异构体,例如不需要的异构体的量可以少于10%,例如,9%、8%、7%、6%、5%、4%、3%、2%、1%或甚至更少。含有大约95%或更多的所需异构体的富含异构体的化合物在此被称为“基本上纯的”异构体。含有大约99%或更多的所需异构体的富含异构体的化合物在此被称为“纯的”立体异构体。任何富含异构体的化合物的纯度可以使用传统的分析方法来确认。
本发明“药物组合物”是指包含任何一种本文所述的化合物,包括对应的异构体、前药、溶剂化物、药学上可接受的盐或其化学的保护形式,和一种或多种药学上可接受载体的混合物。药用组合物的目的是促进化合物对生物体的给药。所述组合物通常用于制备治疗和/或预防由一种或多种激酶介导的疾病的药物。
本发明“药学上可接受的载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体,包含所有的溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括,但不限于糖类,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、以及纤维素和乙酸纤维素;麦芽、明胶等。
本发明“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。
本发明“药学上可接受的盐”是指在合理医学判断的范畴内适用于与人类和低等动物的组织接触而无不当毒性、刺激性、过敏反应和其类似反应,并且与合理效益/风险比相匹配的那些盐。药学上可接受的盐在此项技术中为熟知的。举例而言,S.M.伯奇(Berge)等人于药物制剂科学杂志(J.Pharmaceutical Sciences),1977,66,1-19中详细描述药学上可接受的盐,所述文献以引用的方式并入本文中。本发明化合物的药学上可接受的盐包括来源于适合无机和有机酸和碱的盐。
本发明“碱性试剂”是指能够使羟基或氨基去质子化的化合物。碱的实例包括但不限于,与醇溶剂组合的(C1-6烷基)氧化物((C1-6烷基)OM),其中(C1-6烷基)氧化物包括但不限于MeO-、EtO-、n-PrO-、i-PrO-、t-BuO-、i-AmO-(异戊氧基)等,且其中M是碱金属阳离子,例如Li+、Na+、K+等。醇溶剂包括(C1-6烷基)OH,例如,诸如甲醇、乙醇、正丙醇、异丙醇、叔丁醇、异戊醇等。还可以使用非烷氧基碱,例如氢氧化钠、氢氧化钾、氢化钠、六甲基二甲硅基胺钠、六甲基二甲硅基胺锂、二异丙基酰胺锂、氢化钙、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸铯、DBU(1,8-二氮杂二环[5.4.0]十一碳-7-烯)、DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)、格氏试剂例如(C1-6烷基)Mg(卤素),其包括但不限于甲基氯化镁、甲基溴化镁、叔丁基氯化镁、叔丁基溴化镁等。
本发明的“离去基团”,具有本领域的通常含义,是指可以容易地置换的基团,当形成新键时,由分子发生置换反应的分子上的活性官能团。具有此功能的基团是本领域技术人员众所周知的,其具体实例可进一步参考本领域常见的有机合成手册。例如,所述离去基团可以是卤素原子、氨基、烷氧基、酰氧基、芳氧基、杂芳氧基、烷基磺酰氧基、芳基磺酰氧基、羟基、羟基的活性酯,例如羧酸酯、磺酸酯、磷酸酯或硼酸酯、烷基锡基,例如三丁基甲锡烷基等。
本发明化合物中的“氢”、“碳”、“氧”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子,例如氢的同位素包括氕、氚和氘,碳的同位素包括12C、13C和14C,氧的同位素包括16O和18O等。
具体实施方式
下面代表性的实施例是为了更好地说明本发明,而非用于限制本发明的保护范围。以下实施例中使用的材料如无特殊说明均为商购获得。
实施例1:3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸的制备
步骤1:2-(3-(3-(乙氧羰基)苯基)脲基)-4-甲基噻吩-3-羧酸乙酯的合成
将2-氨基-4-甲基噻吩-3-甲酸乙酯(10g,54.05mmol),三光气(6.4g,21.60mmol)加入两口瓶中,氩气保护下,-20℃下滴加二氯甲烷(200mL),原料溶解后,将三乙胺(2.09g,20.7mmol)的二氯甲烷溶液缓慢滴入反应液。该反应混合物在0℃下反应4h后,加入3-氨基苯甲酸乙酯(8.93g,54.05mmol),反应液至于室温搅拌12个小时。加水(200mL)淬灭反应,反应液分层,分出有机相,水相再用二氯甲烷(200mL)萃取两遍,有机相合并,干燥,浓缩。柱层析纯化得到标题化合物17.20g。ESI-MS[M+H]+m/z:377.
步骤2:3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成
将钠块(1.4g,60.86mmol)称入干燥的两口瓶中,氩气保护下,加入无水乙醇。待钠块反应完以后,加入2-(3-(3-(乙氧羰基)苯基)脲基)-4-甲基噻吩-3-羧酸乙酯(9.17g,24.39mmol),室温反应2小时。将反应液滴入的盐酸水溶液(40mL,2mol/L)中,搅拌2个小时,过滤出得到标题化合物7.5g。ESI-MS[M+H]+m/z:331.
步骤3:3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成
3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(963mg,2.92mmol),4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃(1.1g,3.5mmol)和碳酸钾(807mg,5.84mmol)溶于N,N-二甲基甲酰胺(20mL)中,110℃反应12个小时。反应液饱和食盐水洗,乙酸乙酯萃取,有机相再用饱和氯化钠溶液洗两遍。有机相干燥,浓缩。柱层析分离纯化得到标题化合物730mg。ESI-MS[M+H]+m/z:565.
步骤4:3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯
3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(730mg,1.29mmol)溶于N,N-二甲基甲酰胺(10mL)中,-20℃下加入N-溴代丁二酰亚胺(230mg,1.29mmol)。加入完毕后,反应混合物在-20℃下搅拌1个小时。反应液中加入饱和氯化钠溶液(20mL)并用乙酸乙酯萃取。有机相干燥,浓缩。柱层析分离纯化得到标题化合物800mg。ESI-MS[M+H]+m/z:643.
步骤5:3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成
将3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(800mg,1.25mmol),2-(三丁基甲锡烷基)噁唑(1.8g,5mmol),三(二亚苄基丙酮)二钯(115mg,0.125mmol),2-二环己基磷-2,4,6-三异丙基联苯(238mg,0.5mmol)溶于无水二氧六环(15mL)中。在氩气保护下,反应混合物加热至90℃并搅拌12个小时。减压蒸馏出溶剂后柱层析分离纯化得到标题化合物500mg。ESI-MS[M+H]+m/z:632.
步骤6:3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸的制备
3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯溶解(200mg,0.316mmol)甲醇(10mL)中,0℃下向其中滴加氢氧化锂(107mg,4.45mol)的水(3mL)溶液。室温反应3个小时。盐酸(2mol/L)酸化反应液至pH为3-4后蒸干甲醇,并用乙酸乙酯(10mL)萃取三遍,干燥有机相,浓缩,柱层析分离纯化得到标题化合物130mg。ESI-MS[M+H]+m/z:604。1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.25(s,1H),8.04(d,1H),7.83(d,1H),7.67(t,1H),7.52(t,2H),7.42(s,1H),7.32(t,1H),7.04(dd,2H),5.35-5.32(m,1H),4.17-4.14(m,1H),4.04-3.98(m,1H),3.80(s,3H),3.62-3.59(m,2H),3.44-3.41(m,1H),3.31-3.24(m,2H),2.79(s,3H),1.72-1.65(m,2H),1.30-1.24(m,2H)。
实施例2:(R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸
制备方法同实施例1,不同的是实施例1步骤3中将原料由4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃替换为(R)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃,制得标题化合物。1HNMR(400MHz,DMSO-d6)δ13.11(s,1H),8.25(s,1H),8.04(d,1H),7.83(d,1H),7.67(t,1H),7.52(t,2H),7.42(s,1H),7.32(t,1H),7.04(dd,2H),5.35-5.32(m,1H),4.17-4.14(m,1H),4.04-3.98(m,1H),3.80(s,3H),3.62-3.59(m,2H),3.44-3.41(m,1H),3.31-3.24(m,2H),2.79(s,3H),1.72-1.65(m,2H),1.30-1.24(m,2H)。ESI-MS[M+H]+m/z:604。
实施例3:(S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸
步骤1:(S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙-1-醇的制备
称取2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙-1-醇(306g,1214.3mmol)放置2L单口瓶中,加入1.5L乙腈溶解,称取丁酸乙烯酯(76.23g,668mmol),CAL-B脂肪酶(20g)于反应瓶中,25℃搅拌24h。过滤除去酶催化剂,滤液真空浓缩。400g硅胶拌料,3kg硅胶填充柱,柱层析纯化(石油醚:乙酸乙酯=4:1)得到标题化合物136g。ESI-MS[M+H]+m/z:253。
步骤2:(S)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃的制备
将(S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙-1-醇(4.44g,17.5mmol)和四溴化碳(8.72g,26.3mmol)溶于干燥的二氯甲烷溶液中,氩气保护下0℃滴加三苯基膦(6.89g,26.3mmol)的二氯甲烷溶液,反应过夜。反应液浓缩,柱层析分离得到标题化合物4.52g。ESI-MS[M+H]+m/z:315,317。
步骤3:(S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸的合成
制备方法同实施例1步骤3-6,不同的是将实施例1步骤3中的原料由4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃替换为(S)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃,制得标题化合物。1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.25(s,1H),8.04(d,1H),7.83(d,1H),7.67(t,1H),7.52(t,2H),7.42(s,1H),7.32(t,1H),7.04(dd,2H),5.35-5.32(m,1H),4.17-4.14(m,1H),4.04-3.98(m,1H),3.80(s,3H),3.62-3.59(m,2H),3.44-3.41(m,1H),3.31-3.24(m,2H),2.79(s,3H),1.72-1.65(m,2H),1.30-1.24(m,2H)。ESI-MS[M+H]+m/z:604。
实验例1体外乙酰基-CoA羧化酶(ACC)抑制实验
1实验材料
1.1化合物
对照化合物为专利WO2013/071169实施例I-181中公开的化合物ND-630(其为目前临床中最有希望的用于此类疾病的药物),化学名为(2-[1-[2-(2-甲氧基苯基)-2-(氧杂环己烷-4-基氧基)乙基]-5-甲基-6-(1,3-噁唑-2-基)-2,4-二氧代-1H,2H,3H,4H-噻吩并[2,3-d]嘧啶-3-基]-2-甲基丙酸),参照专利WO2013/071169中描述的方法制备并通过氢谱和质谱鉴定。
化合物准备:以上实施例制备的本发明的化合物和对照化合物,每个化合物用DMSO配制成10mM备用,实验时从1000nM开始3倍稀释依次为1000nM、333.3nM、111.1nM、37.1nM、12.3nM、4.12nM、1.37nM、0.46nM、0.15nM、0.05nM。
1.2主要试剂
HEPES缓冲液购自Invitrogen公司;MgCl2、柠檬酸钾缓冲溶液、DTT、乙酰基-CoA和NaHCO3购自Sigma公司;BRIJ-35购自MERCK公司;ACC1和ACC2酶均购自BPS生物公司;ADP-GloTM激酶试剂盒购自Promega公司。
1.3耗材和仪器:
96孔聚丙烯板购自Nunc公司;振荡器购自QILINBEIER公司;离心机购自Eppendorf公司;384孔白板和Envision 2104读板器购自Perkin Elmer公司。
2实验方法
2.1.试剂配制
1×反应缓冲液(PH=7.4)配制:用HEPES(1M)、MgCl2(1M)、BRIJ-35(10%)、柠檬酸钾缓冲溶液(1M)、BSA(10mg/mL)和DTT(500mM)的储备液配制酶活反应缓冲液:包含HEPES(50mM)、MgCl2(2mM)、BRIJ-35(0.01%)、柠檬酸钾缓冲溶液(2mM)、BSA(50μg/mL)和DTT(2mM)。
2.2.ACC酶活实验
1)ACC1酶活测试
将4.5μL 2.2×的ACC1酶(2nM)工作液加入384孔板中;然后加入0.5μL的不同浓度的化合物,室温孵育15min。
用2.1中配制的缓冲液配制2×的底物(40μMATP,20μM乙酰CoA,60mM NaHCO3);向384孔板中加入5μL的2×底物,室温孵育30min;然后加入10μLADP-Glo试剂,室温孵育40min,终止反应;最后加入20μL酶检测试剂,室温孵育40min,用Envision 2104仪器读取荧光值信号(RLU)。
2)ACC2酶活测试
将4.5μL 2.2×的ACC2酶(1.1nM)工作液加入384孔板中;然后加入0.5μL的不同浓度的化合物,室温孵育15min。
用2.1中配制的缓冲液配制2×的底物(40μMATP,40μM乙酰CoA,24mM NaHCO3);向384孔板中加入5μL的2×底物,室温孵育30min;然后加入10μLADP-Glo试剂,室温孵育40min,终止反应;最后加入20μL酶检测试剂,室温孵育40min,用Envision 2104仪器读取荧光值信号(RLU)。
3实验数据处理
阴性对照组:含5%DMSO的溶媒;阳性对照组:含100nM的ND-630。求取各浓度以及阳性和阴性对照的数据的平均值,并且计算标准差。由下式计算抑制百分比:抑制率(100%)=100×(RLU阴性对照-RLU化合物)/(RLU阴性对照-RLU阳性对照)。抑制率数据用非线性回归方程式拟合计算各化合物的IC50,非线性回归方程为Y=最低值+(最高值-最低值)/(1+10((LogIC50 -X)×HillSlope)),其中X为化合物浓度的对数,Y为抑制百分比(100%)。
4实验结果
表1
以上实验结果表明,本发明的化合物对ACC1和ACC2均具有好的抑制活性。
实验例2大鼠肝脏分布评价
1.实验材料
1.1动物
雄性SD大鼠,SPF级,购自上海西普尔必凯实验动物有限公司;220-250g,许可证号:SCXK(沪)2013-0016。实验前给予2-3天适应期。给药前禁食8~12h,给药2h后给水,4h后给食。
1.2主要试剂
甲醇、乙腈购自Merck公司;无水乙醇、PEG400和生理盐水购自南京凯基生物科技发展有限公司;邻甲苯海拉明购自上海子起生物科技有限公司。
1.3仪器
API 4000型三重四级杆液质联用仪、Analyst QS A01.01色谱工作站均购自美国AB SCIEX公司;Milli-Q超纯水器购自Millipore公司;CF16R XII台式高速冷冻离心机购自Hitachi公司;Qilinbeier Vortex-5振荡器购自德国IKA公司;电热恒温水浴锅购自常州国华电器有限公司;电动移液器购自美国Thermo公司;微量分析天平购自上海梅特勒有限公司。
2.实验方法
2.1供试药物配制
称取供试化合物6mg(以游离碱计),加入至20mL乙醇-PEG400-生理盐水(10:30:60)中,涡旋2min,超声3min,配制浓度为0.3mg/mL的供试品溶液,用于口服给药;取供试品溶液100μL用甲醇定容至10ng/mL,同时配制等浓度的对照品,HPLC上进样检测供试品及对照品溶液浓度,计算供试品准确度。
2.2样品采集
单次口服给予SD大鼠供试化合物3mg/kg,给药体积为10mL/kg,大鼠给药后,分别于0.25h、1h和4h颈动脉取血,安乐死取肝脏,立即收集肝脏和血液(用肝素钠抗凝),置于冰上。
2.3肝脏样品处理和分析
称取0.4g肝脏,剪碎,于2mL 75%甲醇-水中匀浆,将匀浆液离心(离心条件:8000rpm/min,5min,4℃),转移上清液冻存,进样前复溶、离心,取上清,用LC-MS/MS分析上清样品中化合物的含量。
2.4血浆样品处理和分析
采集后的全血样品置于冰盒中,于30min以内离心(离心条件:8000rpm/min,5min,4℃)并转移上层血浆100μL,加300μL甲醇沉淀,振荡、离心,加入流动相稀释,取上清,用LC-MS/MS分析上清样品中化合物的含量。
3实验结果
表2
化合物在肝脏中的浓度越高,治疗肝脏疾病的效价越高,同等剂量下疗效越好,而肝脏/血浆比越高,表明供试化合物的靶器官选择性越强,化合物的安全性可能越好。从以上结果可以看出,本发明的化合物在肝脏中有较高的分布,肝脏选择性及靶向性良好(肝/血比>50),因此,本发明化合物有望成为更优效更安全的治疗脂肪肝、非酒精性脂肪肝肝炎(NASH)等代谢性肝脏疾病的药物。
实验例3:体外人肝脏星状细胞LX-2激活抑制实验
1实验材料
1.1化合物制备
以上实施例制备的本发明的化合物和对照化合物,每个化合物用DMSO配制成60mM,备用。
1.2细胞株
人肝星状细胞LX-2,由徐列明教授在美国西奈山医学院肝病中心建立,上海肝病研究所细胞库保存。
1.3主要试剂
DMEM培养基、FBS、胰酶、磷酸盐缓冲液(DPBS)和青霉素-链霉素双抗购自美国GIBCO公司;重组人TGF-β1细胞因子(PeproTech公司,货号:100-21);TransZOL Up PlusRNA抽提试剂盒(全式金,货号:ER501-01);cDNA逆转录试剂盒(全式金,货号:AH341-01);5×SYBR Green qPCR试剂盒(QuantiNovaTM,货号:154045739)。
1.4耗材和仪器:
CKX41倒置显微镜,日本Olympus公司产品,多功能酶标仪,美国MolecularDevices公司产品,Thermo Nano Drop 2000核酸定量分析仪,ABI 9700PCR扩增仪,ABI7500PCR荧光定量,Thermo高速离心机(MEGAFUGE8);全自动制冰机(雪科,IMS-30)。
2实验方法
2.1.试剂配制
将本发明实施例的化合物和对照化合物DMSO母液用培养基依次稀释到30μM、10μM、3μM。按照PeproTech试剂盒说明书将TGF-β1用试剂盒配制的10mM的枸橼酸缓冲液溶解至1μg/mL,备用。
2.2.LX-2细胞处理
LX-2细胞传代后以的2×105个/mL密度接种于6孔培养板内,每孔含10%FBS的DMEM 2mL,5%CO2培养箱内37℃培养,记为Day1。24h后(Day2),融合度达到70-80%,吸弃旧培养液,换以无血清的DMEM对细胞作低血清饥饿处理。于Day3吸弃旧培养液,加入培养液或含有不同浓度药物的培养液继续温育培养,分为对照组(无血清DMEM培养液),TGFβ1组,TGFβ1+化合物组,TGFβ1工作浓度10ng/mL。药物作用24h后(Day4),吸弃细胞上清,预冷1×PBS洗涤细胞1次,用于抽提总RNA。
2.3.总RNA抽提
2.3.1样品前处理:于细胞培养6孔板中每孔加入1mL的TransZOL Up试剂,水平放置片刻,使裂解液均匀分布于细胞表面并裂解细胞,使用移液枪吹打细胞使得细胞完全脱落,将裂解液转移至2mL RNase free离心管中,反复吹吸直至裂解液无明显沉淀。
2.3.2抽提步骤:根据TransZOLUp总RNA抽提试剂盒说明书进行操作。
2.4.总RNA浓度及纯度测定
取2μL总RNA置于NanoVue分光光度计检测A260nm波长吸光度,算出RNA浓度。RNA样品的纯度根据260nm及280nm吸光值比值(A260/A280)计算,比值在1.8~2.1范围,说明RNA无污染也无降解,方可用于后续试验。
2.5.cDNA的合成
将提取的RNA按照等质量稀释到相应的浓度为0.1μg~0.5μg(Total RNA≤1μg)之间,实验各个样本逆转录体系中总RNA的质量为~500ng。
按照逆转录试剂盒说明书(TransScriptⅡAll-in-One First-Strand cDNASynthese kit,Lot:AH341-1),进行如下操作。合成的cDNA-70℃保存备用。
将以上体系轻轻混匀,以上体系液体放入ABI 9700 PCR仪器中,设置如下程序:50℃×15min→85℃×5s→4℃×10min,将获得的cNDA贮存于-20℃或者立即使用。
2.6.Real-time PCR反应
所用Real-Time PCR引物:
PCR样本体系:
加样后轻轻混匀,离心,将PCR管置于PCR仪中,设置程序如下。
PCR仪器循环设置:
每样本设2个复孔,PCR仪器设定程序,计算目的基因相对表达量。
3实验数据处理
Real Time PCR结果的阈值由Real Time PCR detector system自动设置,按如下方法计算Col1A1基因的相对含量。
ΔCt(药物处理组Col1A1基因)=Avg.Ct(药物处理组Col1A1基因)-Avg.Ct(药物处理组GAPDH基因);
ΔCt(TGF组Col1A1基因)=Avg.Ct(TGF组Col1A1基因)-Avg.Ct(TGF组GAPDH基因);
ΔCt(对照组Col1A1基因)=Avg.Ct(对照组Col1A1基因)-Avg.Ct(对照组GAPDH基因);
ΔΔCt=ΔCt(TGF组/药物处理组Col1A1基因)–ΔCt(对照组Col1A1基因)的平均值;
Col1A1基因的相对含量计算公式:RQ=2-ΔΔCt
相对定量的结果由ABI 7500实时定量荧光PCR仪器自动分析所得。
4实验结果
表3 Col1A1基因的相对含量计算
化合物 | 抑制率(%) |
实施例2 | 82.11 |
ND-630 | 42.06 |
Collagen 1是肝纤维化形成过程的关键的信号因子,其表达由Col1A1基因含量所代表。实验结果表明,本发明的化合物对TGF-β1诱导的LX-2细胞的Collagen 1基因的表达具有显著的抑制活性。与ND-630相比,本发明的化合物对肝细胞纤维化形式的抑制活性更强,可用于ACC介导的纤维化疾病、增生性疾病等。
实验例4 HFD-CCL4诱导的NASH及肝纤维化药效评价
先用高脂饮食(HFD)诱导动物肝脏脂肪变性,在此基础上再用四氯化碳(CCL4)诱导肝脏炎症、坏死,发生肝纤维化,该模型与人NASH疾病发生过程以及病理现象类似。本项实验目的是在HFD-CCL4诱导的C57BL/6小鼠的NASH模型中评价本发明的化合物的药效,以ND-630作为对照化合物。HFD-CCL4诱导10周,药物干预4周,观察药物对NASH及肝纤维化的治疗作用。
1.实验材料
1.1仪器
脱水机Leica HistoCore PEARL;石蜡包埋机Leica HistoCore Arcadia C&H;石蜡切片机Leica RM2235;自动染色剂Leica ST5020;扫描仪HAMAMATSU NANO Zoomer S210;SR染色分析软件VisiopharmVIS 6.6.0.2516。
1.2动物
C57BL/6小鼠(雄性,18-20g)购于北京维通利华有限公司。实验动物饲养所有实验操作都经过KCI动物使用和福利委员会(IACUC)批准。小鼠饲养条件如下:温度20–25℃,湿度40%–70%,昼夜明暗交替时间12小时/12小时。每周换2次垫料。
2.实验方法
2.1化合物配制
本发明实施例的待测化合物和ND-630采用PEG200:0.2M Na2HPO4-NaH2PO4缓冲液(35:65)溶液稀释至0.3mg/mL,1mg/mL,3mg/mL,备用给药,现配现用。
2.2动物造模
HFD-CCL4诱导C57BL/6小鼠NASH模型:动物在KCI实验动物中心SPF屏障内进行3-7天的适应性饲养后,动物更换HFD饲料饲养,饲养周期为10周。HFD饲养第6周结束时,根据动物体重将HFD组随机分组,每组10只,口服给予CCL4(一周三次,上午9-10点),并持续4周。详细建模方法根据KCI已建立的方法建立HFD-CCL4诱导的雄性C57BL/6小鼠NASH模型,造模剂为Olive Oil+CCL4溶液(由KCI配制)。其余10只动物给予正常维持饲料伴随饲养作为正常对照动物。
动物分为正常对照组、HFD-CCL4模型组(模型组)和化合物组(本发明的测试化合物组、ND-630组)。
2.3化合物的给药方案
HFD饲养第6周结束后开始灌胃给予本发明的待测化合物和ND-630,每日一次,持续4周,第10周结束给药。本发明的待测化合物组和ND-630组的剂量均为30mg/kg/d。
2.4实验样本收集
末次给药结束后翌日即CCL4最后一次给予48h后各组动物禁食六小时,按照KCI标准操作规程将动物进行安乐死。根据KCI动物解剖实验操作规程将动物进行解剖,动物经低温PBS全身灌流后,采集肝脏,将部分动物肝脏(固定选择每个动物左侧同一肝叶)液氮迅速冷冻,-80℃低温保存。余下动物肝脏经福尔马林后固定(肝脏与固定液的体积比例为1:10),进行相关病理相关检测。
2.5苏木素-伊红染色
肝左叶经10%福尔马林固定后,用石蜡包埋,制成5μm切片,用于苏木素-伊红(haematoxylin-eosin,H&E)染色。苏木素-伊红染色反映组织炎症,脂肪沉积,空泡变性和组织纤维化的程度,对病变程度进行半定量分析。
2.6天狼猩红染色
肝组织制成5μm切片,干燥2h,复水后用天狼猩红(北京海德创业,货号26357)室温染色30min,再脱水封片,用于图像分析。用Aperio ScanScope CS2(莱卡),200×倍数扫描病理切片,再在Aperio ImageScope程序中打开扫描的图片,去除血管,剩下目标图像用Color Deconvolution v9分析算法。使用软件将被染为红色的纤维化部分识别为阳性信号,并计算出纤维化的百分率。
3.统计学分析
数据以均值±标准误表示。显著性分析采用学生t-test,one way ANOVA或者twoway ANOVA及post-hoc Dunnett′s test。
4.实验结果
4.1肝脏脂肪变性
实验动物给予高脂饮食10周,与正常对照组比,模型组肝脏脂肪变性程度显著加深。实施例2的化合物组(30mg/kg/d)较模型组脂肪变性明显消失,与正常对照组无差异,明显优于ND-630组(30mg/kg/d)。实验结果见表4。
表4肝脏脂肪变性
由此可见,本发明的化合物对HFD-CCL4诱导的小鼠NASH模型有一定的治疗作用;在组织病理上,与模型组相比可有效降低肝脏脂肪变性。
尽管以上已经对本发明作了详细描述,但是本领域技术人员理解,在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述,而应归属于权利要求书。
Claims (10)
2.根据权利要求1所述的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐,其中所述式I或式II的光学异构体纯度为至少60%,优选90%,更优选99%。
3.根据权利要求1所述的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐,其中所述式I或式II的化合物的药学上可接受的盐包括来源于适合无机和有机酸和碱的盐。
4.一种权利要求1所述的式I所示的光学异构体或其水合物、溶剂合物、结晶或其药学上可接受的盐的制备方法,其包括:
a)式(1)的化合物与三光气、式(2)的化合物在碱性试剂的作用下经反应制得式(3)的化合物;
b)式(3)的化合物在碱性试剂的作用下经反应制得式(4)的化合物;
c)式(4)的化合物与式(5)的化合物在碱性试剂的作用下经反应制得式(6)的化合物;
d)式(6)的化合物经卤代反应制得式(7)的化合物;
e)式(7)的化合物与式(8)的化合物经缩合反应得到式(9)的化合物;
f)式(9)的化合物经酯水解反应制得式I的化合物;
其中,X1、X2各自独立地为卤素;X3为离去基团;R1、R2各自独立地为烷基。
5.根据权利要求4所述的制备方法,其中所述的X1、X2各自独立地为氟、氯、溴或碘,X3为三丁基甲锡烷基。
6.根据权利要求4所述的制备方法,其中所述的R1、R2各自独立地选自C1-6烷基,优选为甲基、乙基、丙基、丁基或叔丁基。
8.根据权利要求7所述的式A所示的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐,其含有大于60%的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐;优选地,含有大于90%的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐;更优选地,含有大于99%的式I的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐。
9.一种药物组合物,其包含权利要求1或2所述的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐或者权利要求7或8所述的式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐和药学上可接受的载体。
10.根据权利要求1或2所述的光学异构体或其水合物、溶剂合物、结晶或药学上可接受的盐或者根据权利要求7或8所述的式A的化合物或其水合物、溶剂合物、结晶或药学上可接受的盐或权利要求9所述的药物组合物在制备用于治疗ACC表达相关疾病的药物中的用途。
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