CN108368134A - 一种取代的硼酸化合物及包含该化合物的药物组合物及其用途 - Google Patents
一种取代的硼酸化合物及包含该化合物的药物组合物及其用途 Download PDFInfo
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- CN108368134A CN108368134A CN201780004824.8A CN201780004824A CN108368134A CN 108368134 A CN108368134 A CN 108368134A CN 201780004824 A CN201780004824 A CN 201780004824A CN 108368134 A CN108368134 A CN 108368134A
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Abstract
涉及一种取代的硼酸化合物及包含该化合物的药物组合物及其用途,所述取代的硼酸化合物如为式(I)所示的化合物,或其晶型、药学上可接受的盐、前药、立体异构体、水合物或溶剂化合物。该硼酸化合物具有蛋白酶体抑制活性,具有更好药效学/药代动力学性能,化合物的适用性好、安全性高,可用于制备治疗与蛋白酶体相关疾病的药物。
Description
本发明属于医药技术领域,尤其涉及一种取代的硼酸化合物及包含该化合物的药物组合物,其可用于制备治疗由蛋白酶体介导的相关疾病的药物。
蛋白酶体(proteasome)是一种庞大的多价复合酶,参与细胞内许多重要的生理和生化过程,如DNA修复,细胞周期的运转,信号传导,抗原的呈递,蛋白的跨膜定位等,在平衡重要的细胞内酶中起主要作用。蛋白酶体的功能是通过泛素一蛋白酶体通路(ubiquitin-proteasome pathway,UPP)实现。UPP不仅催化降解异常蛋白质,并参与许多调控和蛋白质的更新、加工过程。这些蛋白质的催化过程涉及到人类疾病发病的重要生化机制。
蛋白酶体抑制剂(proteasome inhibitor)通过抑制蛋白酶体的活性,进而影响细胞生长相关蛋白、细胞因子和信号分子的表达,干扰细胞原有的增殖、分化和凋亡过程,对肿瘤细胞生长的抑制更为明显。
蛋白酶体抑制剂主要有肽醛类、肽硼酸类、肽环氧酮类、肽乙烯基砜类、β内酯类及其它类化合物。肽硼酸类蛋白酶体抑制剂硼替佐米(Bortezomib,商品名VELCADE)是第一个用于临床的蛋白酶体抑制剂,在200年和2006年分别通过美国食品药品监督管理局(FDA)批准用于治疗多发性骨髓瘤(MM)和套细胞淋巴瘤(MCL)。肽环氧酮类肽蛋白酶体抑制剂卡非佐米(Carfilzomib,商品名Kyprolis)于2012年经FDA批准用于治疗多发性骨髓瘤,成为第二个上市的蛋白酶体类抗肿瘤药物。肽硼酸类蛋白酶体抑制剂埃沙佐米(Ixazomib citrate,商品名Ninlaro)于2015年经FDA批准用于治疗多发性骨髓瘤,成为第二个上市的肽硼酸类蛋白酶体抑制剂。已上市药物及已报道的硼酸类蛋白酶体抑制剂如WO2005/021558,WO2005/016859,WO2006/086600,WO2009/02044,WO2010/012222,WO2011/109355,WO2011/026349,WO2011/087822,WO2013/092979等肽类骨架蛋白酶体抑制剂,体内稳定性不高,在血浆中的半衰期过短,清除率很快(Miller et al.J Med Chem,2015,58:2036-41)。
因此,本领域仍需要开发对蛋白酶体有抑制活性或更好药效学性能的蛋白酶体抑制剂。
发明内容
针对以上技术问题,本发明公开了一种蛋白酶体抑制剂、药物组合物及其应用,其具有更好的蛋白酶体抑制活性和/或具有更好药效学/药代动力学性能。
对此,本发明采用的技术方案为:
一种蛋白酶体抑制剂,如式(I)所示取代的硼酸化合物,或其晶型、药学上可接受的盐、水合物或溶剂化合物,
其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14和R15各自独立地为氢、氘、卤素;
附加条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15中至少一个是氘代的或氘。
作为本发明的进一步改进,R1、R2和R3各自独立地为氘或氢。
作为本发明的进一步改进,R4和R5各自独立地为氘或氢。
作为本发明的进一步改进,R6是氘。
作为本发明的进一步改进,R7和R8各自独立地为氘或氢。
作为本发明的进一步改进,R9、R10、R11、R12、R13、R14和R15各自独立地为氘或氢。
作为本发明的进一步改进,所述化合物可选自下述化合物或其药学上可接受的盐,但不局限于下列化合物:
采用此技术方案,氘在药物分子中的形状和体积与氢基本上相同,如果药物分子中氢被选择性替换为氘,氘代药物一般还会保留原来的生物活性和选择性。同时发明人经过实验证实,碳氘键的结合比碳氢键的结合更稳定,可直接影响一些药物的吸收、分布、代谢和排泄等属性,从而提高药物的疗效、安全性和耐受性。
优选的,氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
具体地说,在本发明中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14和R15各氘代位置中氘同位素含量至少是5%,较佳地大于10%,更佳地大于15%,更佳地大于20%,更
佳地大于25%,更佳地大于30%,更佳地大于35%,更佳地大于40%,更佳地大于45%,更佳地大于50%,更佳地大于55%,更佳地大于60%,更佳地大于65%,更佳地大于70%,更佳地大于75%,更佳地大于80%,更佳地大于85%,更佳地大于90%,更佳地大于95%,更佳地大于99%。
在另一选例中,式(I)中化合物的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14和R15,至少其中一个R含氘,更佳地两个R含氘,更佳地三个R含氘,更佳地四个R含氘,更佳地五个R含氘,更佳地六个R含氘,更佳地七个R含氘,更佳地八个R含氘,更佳地九个R含氘,更佳地十个R含氘,更佳地十一个R含氘,更佳地十二个R含氘,更佳地十三个R含氘,更佳地十四个R含氘,更佳地十五个R含氘。
在另一优选例中,所述化合物不包括非氘代化合物。
本发明还公开了一种药物组合物,其含有药学上可接受的载体和如上所述的所述的蛋白酶体抑制剂,或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体、前药或同位素变体的药物组合物。
作为本发明的进一步改进,所述药学上可接受的载体包括助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂中的至少一种。
作为本发明的进一步改进,所述药物组合物为片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球或气溶胶。
给予本发明药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药,或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选口服给药或注射给药。
本发明的药物组合物可以采用本领域周知的方法制造,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本发明还提供了一种制备药物组合物的方法,包括步骤:将药学上可接受的载体与如上所述的蛋白酶体抑制剂,或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,形成药物组合物。
本发明化合物具有蛋白酶体酶抑制活性,因此预期其适用作治疗罹患通过抑制蛋白酶体或通过增加其肽底物含量而得以治疗的疾病或病症的患者的治疗剂。因此,本发明的一个方面涉及一种治疗罹患通过抑制蛋白酶体而得以治疗的疾病或病症的患者的方法,其包含向患者投与治疗有效量的本发明化合物。本发明的另一方面涉及一种治疗心血管疾病的方法,其包含向患者投与治疗有效量的本发明化合物。本发明的另一方面涉及一种治疗高血方面涉及一种抑制哺乳动物中的蛋白酶体的
方法,其包含向所述哺乳动物投与蛋白酶体抑制量的本发明化合物。
本发明还公开了一种如上所述的取代的硼酸化合物作为蛋白酶体抑制剂的用途,即本发明化合物可用于制备由蛋白酶体介导的疾病的药物。
本发明所述的由蛋白每日介导的疾病包括炎性病症(例如,类风湿性关节炎、炎症性肠病、哮喘、慢性阻塞性肺病(COPD)、骨关节炎、皮肤病(例如,异位性皮炎、牛皮癣))、血管增殖性病症(例如,动脉粥样硬化症、再狭窄)、眼部增殖性病症(例如,糖尿病性视网膜病变)、良性增殖性病变(例如,血管癌)、自身免疫疾病(例如,多发性硬化、组织和器官排斥反应),以及与感染相关的炎症(例如,免疫反应)、神经退行性病症(例如,阿尔兹海默症,Alzheimer’s disease)、帕金森氏病(Parkinson’s disease)、运动神经元疾病、神经病理性疼痛、三联体重复病症(tripletrepeat disorder)、星形细胞瘤和由酒精性肝病导致的神经退化、缺血性损伤(例如,中风)和恶病质(例如,伴随各种生理病理状态的加速肌肉蛋白降解(例如,神经损伤、绝食、发烧、酸中毒、HIV感染、癌症和某些内分泌病))。
本发明化合物特别适用于治疗癌症。本文中所使用的术语“癌症”是指一种细胞病症,其特征为不受控制或失调的细胞增殖、降低的细胞分化、不适当地侵袭周围组织的能力/或在异位位点形成新的生长能力。术语“癌症”包括(但不限于)实体肿瘤或血液肿瘤。术语“癌症”涵盖皮肤、组织、器官、骨、软骨、血液和血管的疾病。术语“癌症”还包括原发癌和转移癌。所述的癌症的肿瘤细胞优选白血病细胞骨髓瘤细胞、非小细胞肺癌细胞、乳腺癌细胞和卵巢癌细胞中的一种或多种。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本文中,如无特别说明,“卤素”指F、Cl、Br、和I。更佳地,卤原子选自F、Cl和Br。
本文中,如无特别说明,“氘代”指化合物或基团中的一个或多个氢被氘所取代;氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中,如无特别说明,“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015%)的化合物。
药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如
钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
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”是指本发明化合物与水进行配位形成的配合物。
与现有技术相比,本发明的有益效果为:本发明的化合物对蛋白酶体具有优异的抑制性;通过氘化这一技术改变化合物在生物体中的代谢,使化合物具有更好的药代动力学参数特性。在这种情况下,可以改变剂量并形成长效制剂,改善适用性;用氘取代化合物中的氢原子,由于其氘同位素效应,提高化合物在动物体内的药物浓度,提高了药物疗效;用氘取代化合物中的氢原子,可以抑制某些代谢产物,提高了化合物的安全性。
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
实施例1制备(R)-(1-(2-(2,5-二氯苯甲酰胺基)-d2-乙酰胺基)-3-甲基丁基)硼酸(化合物I-1)
具体合成步骤如下:
步骤一:2,2-d2-甘氨酸(化合物3)的合成。
在反应瓶中加入甘氨酸(200mg,2.66mmol)和水杨醛(0.04mL,0.376mmol),加入10mL氘代乙酸溶解,氮气保护下加热至100℃搅拌反应2小时,降至室温,浓缩除去乙酸后加入2mL重水,室温下搅拌15分钟,再加入少量水稀释,加入活性炭脱色0.5小时,过滤,滤液浓缩至干。加入少量甲醇,搅拌析出白色固体,过滤,真空干燥后得产物176.7mg,收率:88%。LC-MS(APCI):m/z=78.1(M+1)+。
步骤二:2,5-[(二氯苯甲酰基)氨基]-d2-乙酸(化合物5)的合成。
在反应瓶中加入化合物3(131mg,1.7mmol)和氢氧化钠(212.5mg,5.31mmol),加入2mL水溶解,冰浴下滴加2,5-二氯苯甲酰氯(176.7mg,0.85mmol)的1mL四氢呋喃溶液,加毕,搅拌反应1小时。TLC检测反应完毕后,用稀盐酸调PH至酸性,析出白色固体,过滤,冰水洗涤,真空干燥后得到200mg产物,收率94.5%。LC-MS(APCI):m/z=250.3(M+1)+。
步骤三:2-甲基丙基硼酸-(+)-蒎烷二醇酯(化合物8)的合成。
在反应瓶中加入异丁基硼酸(510.5mg,5mmol)和(1S,2S,3R,5S)-(+)-2,3-蒎烷二醇(850.65mg,5mmol),加入5mL正庚烷溶解,室温下搅拌反应2小时,TCL检测反应完毕后,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,浓缩,真空干燥得1.1g产物,收率93.14%。
步骤四:(S)-1-氯-3-甲基丁基硼酸-(+)-蒎烷二醇酯(化合物9)的合成。
在反应瓶中加入化合物8(1.1g,4.66mmol),加入6.5mL无水四氢呋喃和1.54mL无水二氯甲烷溶解,氮气保护下降温至-78℃,缓慢滴加2M的二异丙基胺基锂溶液(LDA,4.66mL,9.32mmol),加毕,搅拌反应2小时。缓慢滴加氯化锌的1M四氢呋喃溶液烷溶液(8.16mL,8.16mmol),加毕,保持低温反应2小时,TLC检测反应完毕后,加入少量10%稀硫酸淬灭反应,分出有机相,水相用正己烷萃取,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,真空干燥得产物1.31
g,收率98.9%。LC-MS(APCI):m/z=285.5(M+1)+。
步骤五:(R)-1-(六甲基二硅基)氨基-3-甲基丁基硼酸蒎烷二醇酯(化合物10)的合成。
在反应瓶中加入化合物9(1.35g,4.75mmol),加入10mL无水四氢呋喃溶解,氮气保护下降温至-40℃,缓慢滴加双三甲基硅基氨基锂(LiHMDS,5.7mL,5.7mmol),加毕搅拌反应1小时,再升至室温反应1小时,TLC检测反应完毕后,硅胶塞过滤,滤液蒸干后得产物1.9g,收率97.7%,直接投入下一步。
步骤六:L-亮氨硼酸-(+)-蒎烷二醇酯三氟乙酸盐(化合物11)的合成。
在干燥的反应瓶中加入化合物10(1.7g,4.15mmol),加入6mL异丙醚溶解,氮气保护下降温至-15℃,缓慢滴加三氟乙酸(TFA,1.89g,16.6mmol),加毕保温反应2小时后升至室温反应过夜。过滤,滤饼用异丙醚洗涤,真空干燥后得到白色固体620mg,收率39.5%。LC-MS(APCI):m/z=266.2(M+1)+。
步骤七:2,5-二氯-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷基-2-基]丁基}氨基)-2-氧杂-1,1-d2-乙基]苯甲酰胺(化合物12)的合成。
在反应瓶中加入化合物5(100mg,0.402mmol)和化合物11(152.3mg,0.402mmol),氮气保护下加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU,142mg,0.44mmol),加入2ml无水N,N-二甲基甲酰胺(DMF)溶解,冰浴下滴加N,N-二异丙基乙胺(DIPEA,156mg,1.21mmol),加毕,升至室温搅拌反应1小时。TLC检测反应完毕后。加入少量水稀释,用乙酸乙酯萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后硅胶柱层析纯化,得到196mg产物,收率98.2%。LC-MS(APCI):m/z=497.5(M+1)+。
步骤八:(R)-(1-(2-(2,5-二氯苯甲酰胺基)-d2-乙酰胺基)-3-甲基丁基)硼酸(化合物I-1)的合成。
在反应瓶中加入化合物12(196mg,0.395mmol)和异丁基硼酸(104.8mg,1.03mmol),加入2mL甲醇和2mL正己烷溶解,加入1N盐酸(0.5mL,0.5mmol),氮气保护下室温搅拌反应过夜,TLC检测反应完毕后,分出甲醇层,用正庚烷洗涤三次,减压浓缩至干,加入少量2N氢氧化钠溶解,二氯甲烷洗涤三次,水相用浓盐酸调PH至2-3,再用二氯甲烷萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,干燥后称重得85mg,收率:59.4%。LC-MS(APCI):m/z=345.2(M+1-H2O)。1H NMR(400MHz,DMSO)δ8.93(s,1H),8.71(d,J=7.8Hz,1H),7.65(s,1H),7.55(d,J=1.3Hz,2H),2.64(s,1H),1.61(dd,J=13.3,6.5Hz,1H),1.40–1.32(m,1H),1.26(s,1H),0.85–0.80(m,6H)。
实施例2制备(R)-(1-(2-(2,5-二氯苯甲酰胺基)-d2-乙酰胺基)-3-甲基丁基)硼酸(化合物I-2)
具体合成步骤如下:
步骤一:2,5-[(二氯苯甲酰基)氨基]乙酸(化合物13)的合成。
在反应瓶中加入甘氨酸(1.125g,15mmol)和氢氧化钠(750mg,18.75mmol),加入7.5mL水溶解,冰浴下滴加2,5-二氯苯甲酰氯(623.7mg,3.0mmol)的1mL四氢呋喃溶液,加毕,搅拌反应1小时。TLC检测反应完毕后,用稀盐酸调PH至酸性,析出白色固体,过滤,冰水洗涤,真空干燥后得到675mg产物,收率91.1%。LC-MS(APCI):m/z=248.3(M+1)+。
步骤二:(S)-1-氯-1-d-3-甲基丁基硼酸-(+)-蒎烷二醇酯(化合物14)的合成。
在反应瓶中加入化合物8(1.1g,4.66mmol),加入6.5mL无水四氢呋喃(THF)和1.54mL氘代二氯甲烷溶解,氮气保护下降温至-78℃,缓慢滴加2M的LDA溶液(4.66mL,9.32mmol),加毕,搅拌反应2小时。缓慢滴加氯化锌的1M四氢呋喃溶液烷溶液(8.16mL,8.16mmol),加毕,保持低温反应2小时,TLC检测反应完毕后,加入少量10%稀硫酸淬灭反应,分出有机相,水相用正己烷萃取,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,真空干燥得产物1.29g,收率97.0%。LC-MS(APCI):m/z=286.2(M+1)+。
步骤三:(R)-1-(六甲基二硅基)氨基-1-d-3-甲基丁基硼酸蒎烷二醇酯(化合物15)的合成。
在反应瓶中加入化合物14(1.29g,4.52mmol),加入9mL无水四氢呋喃溶解,氮气保护下降温至-40℃,缓慢滴加双三甲基硅基氨基锂(5.4mL,5.4mmol),加毕搅拌反应1小时,再升至室温反应1小时,TLC检测反应完毕后,硅胶塞过滤,滤液蒸干后得产物1.6g,收率86.3%,直接投入下一步。
步骤四:1-d-L-亮氨硼酸-(+)-蒎烷二醇酯三氟乙酸盐(化合物16)的合成。
在干燥的反应瓶中加入化合物15(1.6g,3.8mmol),加入6mL异丙醚溶解,氮气保护下降温至-15℃,缓慢滴加三氟乙酸(1.75g,15.4mmol),加毕保温反应2小时后升至室温反应过夜。过滤,滤饼用异丙醚洗涤,真空干燥后得到白色固体561mg,收率38.9%。LC-MS(APCI):m/z=267.7(M+1)+。
步骤五:2,5-二氯-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷基-2-基]-1-d-丁基}氨基)-2-氧杂乙基]苯甲酰胺(化合物17)的合成。
在反应瓶中加入化合物16(100mg,0.405mmol)和化合物13(154mg,0.405mmol),氮气保护下加入TBTU(143mg,0.46mmol),加入2mL无水DMF溶解,冰浴下滴加DIPEA(157mg,1.21mmol),加毕,升至室温搅拌反应1小时。TLC检测反应完毕后。加入少量水稀释,用乙酸乙酯萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后硅胶柱层析纯化,得到148mg产物,收率73.8%。LC-MS(APCI):m/z=496.5(M+1)+。
步骤六:(R)-(1-(2-(2,5-二氯苯甲酰胺基)乙酰胺基)-1-d-3-甲基丁基)硼酸(化合物I-2)的合成。
在反应瓶中加入化合物17(148mg,0.3mmol)和异丁基硼酸(79.63mg,0.78mmol),加入2mL甲醇和2mL正己烷溶解,加入1N盐酸(0.4mL,0.4mmol),氮气保护下室温搅拌反应过夜,TLC检测反应完毕后,分出甲醇层,用正庚烷洗涤三次,减压浓缩至干,加入少量2N氢氧化钠溶解,二氯甲烷洗涤三次,水相用浓盐酸调PH至2-3,再用二氯甲烷萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,干燥后称重得61mg,收率:56.3%。LC-MS(APCI):m/z=344.3(M+1-H2O)。1H NMR(400MHz,DMSO)δ8.94(t,J=5.9Hz,1H),8.69(s,1H),7.65(s,1H),7.55(d,J=1.4Hz,2H),4.02(d,J=5.8Hz,2H),1.62(dt,J=13.3,6.7Hz,1H),1.35(dd,J=13.0,6.7Hz,1H),1.25(d,J=7.2Hz,1H),0.86–0.79(m,6H)。
实施例3制备(R)-(1-(2-(2,5-二氯苯甲酰胺基)乙酰胺基)-2-d2-3-甲基丁基)硼酸(化合物I-3)
具体合成步骤如下:
步骤一:1,1-d2-2-甲基丙醇(化合物19)的合成。
将异丁酸乙酯(580.8mg,5mmol)溶于无水THF(20mL)中,冰浴下分批加入LiAlD4(230.9mg,5.5mmol),加毕,升至室温反应过夜,TLC检测反应完毕后,冰浴下加入十水合硫酸钠淬灭反应,过滤除去不溶物,滤液浓缩得到246mg产物,收率64.73%。直接投入下一步。
步骤二:1,1-d2-溴代异丁烷(化合物20)的合成。
将化合物19(850mg,11.17mmol)和四溴化碳(3.7g,11.17mmol)溶于二氯甲烷(15mL)中,冰浴下分批加入三苯基膦(PPh3,2.93g,11.17mmol),氮气保护下低温搅拌反应1小时,再升至室温反应1小时。TLC检测反应完毕后,加入少量水淬灭反应,水相用二氯甲烷萃取三次,合并有机相,饱和食盐水洗涤,浓缩后柱层析纯化得到产物865mg,收率:56.2%。
步骤三:1,1-d2-异丁基硼酸(化合物21)的合成。
将化合物20(120mg,0.87mmol)溶于5mL无水THF中,氮气保护下加入镁屑(104.3mg,4.35mmol)和催化量的碘(1粒),加热至50℃搅拌反应3小时。降至室温后,用注射器将格氏试剂取出,-15℃下缓慢滴加至硼酸三甲酯(180.8mg,1.74mmol)的5mL无水THF中,氮气保护下搅拌反应1小时。TLC检测反应完毕后升至室温,加入稀盐酸调PH至2-3,搅拌15分钟,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗涤,浓缩后柱层析纯化得产物64mg,收率:70.7%。
步骤四:1,1-d2-2-甲基丙基硼酸-(+)-蒎烷二醇酯(化合物22)的合成。
在反应瓶中加入化合物21(110mg,1.06mmol)和(1S,2S,3R,5S)-(+)-2,3-蒎烷二醇(179.8mg,1.06mmol),加入3mL正庚烷溶解,室温下搅拌反应2小时,TCL检测反应完毕后,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,浓缩,真空干燥得238mg产物,收率94.2%。
步骤五:(S)-1-氯-2,2-d2-3-甲基丁基硼酸-(+)-蒎烷二醇酯(化合物23)的合成。
在反应瓶中加入化合物22(238mg,1.0mmol),加入2mL无水四氢呋喃和0.5mL无水二氯甲烷溶解,氮气保护下降温至-78℃,缓慢滴加2M的LDA溶液(1.0mL,2.0mmol),加毕,搅拌反应2小时。缓慢滴加氯化锌的1M四氢呋喃溶液烷溶液(1.75mL,1.75mmol),加毕,保持低温反应2小时,TLC检测反应完毕后,加入少量10%稀硫酸淬灭反应,分出有机相,水相用正己烷萃取,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,真空干燥得产物265mg,收率92.6%。LC-MS(APCI):m/z=287.7(M+1)+。
步骤六:(R)-1-(六甲基二硅基)氨基-2,2-d2-3-甲基丁基硼酸蒎烷二醇酯(化合物24)的合成。
在反应瓶中加入化合物23(265mg,0.93mmol),加入3mL无水四氢呋喃溶解,氮气保护下降温至-40℃,缓慢滴加双三甲基硅基氨基锂(1.11mL,1.11mmol),加毕搅拌反应1小时,再升至室温反应1小时,TLC检测反应完毕后,硅胶塞过滤,滤液蒸干后得产物382.5mg,收率100%,直接投入下一步。
步骤七:L-d2-亮氨硼酸-(+)-蒎烷二醇酯三氟乙酸盐(化合物25)的合成。
在干燥的反应瓶中加入化合物24(382.5mg,0.93mmol),加入3mL异丙醚溶解,氮气保护下降温至-15℃,缓慢滴加三氟乙酸(424.1mg,3.72mmol),加毕保温反应2小时后升至室温反应过夜。过滤,滤饼用异丙醚洗涤,真空干燥后得到白色固体202mg,收率57.1%。LC-MS(APCI):m/z=268.2(M+1)+。
步骤八:2,5-二氯-N-[2-({(1R)-2,2-d2-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷基-2-基]丁基}氨基)-2-氧杂乙基]苯甲酰胺(化合物26)的合成。
在反应瓶中加入化合物13(100mg,0.402mmol)和化合物25(152.4mg,0.402mmol),氮气保护下加入TBTU(142mg,0.44mmol),加入2mL无水DMF溶解,冰浴下滴加DIPEA(156mg,1.21mmol),加毕,升至室温搅拌反应1小时。TLC检测反应完毕后。加入少量水稀释,用乙酸乙酯萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后硅胶柱层析纯化,得到183mg产物,收率91.9%。LC-MS(APCI):m/z=497.4(M+1)+。
步骤九:(R)-(1-(2-(2,5-二氯苯甲酰胺基)乙酰胺基)-2,2-d2-3-甲基丁基)硼酸(化合物I-3)的合成。
在反应瓶中加入化合物26(183mg,0.369mmol)和异丁基硼酸(97.9mg,0.96mmol),加入2mL甲醇和2mL正己烷溶解,加入1N盐酸(0.5ml,0.5mmol),氮气保护下室温搅拌反应过夜,TLC检测反应完毕后,分出甲醇层,用正庚烷洗涤三次,减压浓缩至干,加入少量2N氢氧化钠溶解,二氯甲烷洗涤三次,水相用浓盐酸调PH至2-3,再用二氯甲烷萃取3-4次,合并有机相,饱和
食盐水洗涤,浓缩后经硅胶柱层析纯化,干燥后称重得75mg,收率:56.4%。LC-MS(APCI):m/z=345.2(M+1-H2O)。1H NMR(400MHz,DMSO)δ8.94(t,J=5.9Hz,1H),8.69(s,1H),7.65(s,1H),7.55(d,J=1.4Hz,2H),4.02(d,J=5.8Hz,2H),2.64(s,1H),1.26(m,1H),0.86–0.79(m,6H)。
实施例4制备(R)-(1-(2-(2,5-二氯苯甲酰胺基)-d2-乙酰胺基)-1-d1-3-甲基丁基)硼酸(化合物I-4)
具体合成步骤如下:
步骤一:2,5-二氯-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷基-2-基]-1-d1-丁基}氨基)-2-氧杂-1,1-d2-乙基]苯甲酰胺(化合物27)的合成。
在反应瓶中加入化合物5(100mg,0.402mmol)和化合物16(154mg,0.402mmol),氮气保护下加入TBTU(142mg,0.44mmol),加入2mL无水DMF溶解,冰浴下滴加DIPEA(156mg,1.21mmol),加毕,升至室温搅拌反应1小时。TLC检测反应完毕后。加入少量水稀释,用乙酸乙酯萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后硅胶柱层析纯化,得到199mg产物,收率99%。LC-MS(APCI):m/z=498.2(M+1)+。
步骤二:(R)-(1-(2-(2,5-二氯苯甲酰胺基)-d2-乙酰胺基)-1-d1-3-甲基丁基)硼酸(化合物I-4)的合成。
在反应瓶中加入化合物27(203mg,0.408mmol)和异丁基硼酸(108.4mg,1.06mmol),加入2mL甲醇和2mL正己烷溶解,加入1N盐酸(0.5mL,0.5mmol),氮气保护下室温搅拌反应过夜,TLC检测反应完毕后,分出甲醇层,用正庚烷洗涤三次,减压浓缩至干,加入少量2N氢氧化钠溶解,二氯甲烷洗涤三次,水相用浓盐酸调PH至2-3,再用二氯甲烷萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,干燥后称重得96mg,收率:64.8%。LC-MS(APCI):m/z=346.4(M+1-H2O)。1H NMR(400MHz,DMSO)δ8.93(s,1H),8.71(d,J=11.4Hz,1H),7.65(s,1H),7.55(d,J=1.3Hz,2H),1.61(dd,J=13.3,6.6Hz,1H),1.35(dd,J=13.0,7.0Hz,1H),1.25(d,J=7.1
Hz,1H),0.83(dd,J=6.5,1.9Hz,6H)。
实施例5制备(R)-(1-(2-(2,5-二氯苯甲酰胺基)乙酰胺基)-1-d1-2,2-d2-3-甲基丁基)硼酸(化合物
I-5)
具体合成步骤如下:
步骤一:(S)-1-氯-1-d1-2,2-d2-3-甲基丁基硼酸-(+)-蒎烷二醇酯(化合物28)的合成。
在反应瓶中加入化合物22(238mg,1.0mmol),加入2mL无水四氢呋喃和0.5mL氘代二氯甲烷溶解,氮气保护下降温至-78℃,缓慢滴加2M的LDA溶液(1.0mL,2.0mmol),加毕,搅拌反应2小时。缓慢滴加氯化锌的1M四氢呋喃溶液烷溶液(1.75mL,1.75mmol),加毕,保持低温反应2小时,TLC检测反应完毕后,加入少量10%稀硫酸淬灭反应,分出有机相,水相用正己烷萃取,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,真空干燥得产物200mg,收率69.7%。LC-MS(APCI):m/z=288.1(M+1)+。
步骤二:(R)-1-(六甲基二硅基)氨基-1-d1-2,2-d2-3-甲基丁基硼酸蒎烷二醇酯(化合物29)的合成。
在反应瓶中加入化合物28(200mg,0.70mmol),加入3mL无水四氢呋喃溶解,氮气保护下降温至-40℃,缓慢滴加双三甲基硅基氨基锂(0.84mL,0.84mmol),加毕搅拌反应1小时,再升至室温反应1小时,TLC检测反应完毕后,硅胶塞过滤,滤液蒸干后得产物288.6mg,收率100%,
直接投入下一步。
步骤三:L-d3-亮氨硼酸-(+)-蒎烷二醇酯三氟乙酸盐(化合物30)的合成。
在干燥的反应瓶中加入化合物29(288.6mg,0.7mmol),加入3mL异丙醚溶解,氮气保护下降温至-15℃,缓慢滴加三氟乙酸(319.2mg,2.8mmol),加毕保温反应2小时后升至室温反应过夜。过滤,滤饼用异丙醚洗涤,真空干燥后得到白色固体95mg,收率35.6%。LC-MS(APCI):m/z=269.3(M+1)+。
步骤四:2,5-二氯-N-[2-({(1R)-1-d1-2,2-d2-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷基-2-基]丁基}氨基)-2-氧杂乙基]苯甲酰胺(化合物31)的合成。
在反应瓶中加入化合物13(56mg,0.226mmol)和化合物30(86.4mg,0.226mmol),氮气保护下加入TBTU(80mg,0.25mmol),加入2mL无水DMF溶解,冰浴下滴加DIPEA(87.6mg,0.34mmol),加毕,升至室温搅拌反应1小时。TLC检测反应完毕后。加入少量水稀释,用乙酸乙酯萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后硅胶柱层析纯化,得到88mg产物,收率78.6%。LC-MS(APCI):m/z=498.4(M+1)+。
步骤五:(R)-(1-(2-(2,5-二氯苯甲酰胺基)乙酰胺基)-1-d1-2,2-d2-3-甲基丁基)硼酸(化合物I-5)的合成。
在反应瓶中加入化合物31(88mg,0.177mmol)和异丁基硼酸(47mg,0.46mmol),加入1mL甲醇和1mL正己烷溶解,加入1N盐酸(0.3ml,0.3mmol),氮气保护下室温搅拌反应过夜,TLC检测反应完毕后,分出甲醇层,用正庚烷洗涤三次,减压浓缩至干,加入少量2N氢氧化钠溶解,二氯甲烷洗涤三次,水相用浓盐酸调PH至2-3,再用二氯甲烷萃取3-4次,合并有机相,饱和食盐水洗涤,浓缩后经硅胶柱层析纯化,干燥后称重得32mg,收率:50.1%。LC-MS(APCI):m/z=346.4(M+1-H2O)。1H NMR(400MHz,DMSO)δ8.94(t,J=5.9Hz,1H),8.69(s,1H),7.65(s,1H),7.55(d,J=1.4Hz,2H),4.02(d,J=5.8Hz,2H),1.26(m,1H),0.86–0.79(m,6H)。
实施例6:生物活性测试。
(1)20S蛋白酶体分析。
在37℃向384孔黑色微量滴定板中溶于DMSO的1μL测试化合物中添加25μL含有人类PA28活化子(Boston Biochem,终浓度12nM)与Ac-WLA-AMC(β5选择性底物)(终浓度15μM)的测定缓冲液,随后在37℃再添加25μL含有人类20S蛋白酶体(Boston Biochem,终浓度0.25nM)的测定缓冲液。测定缓冲液由20mM HEPES、0.5mMEDTA和0.01%BSA组成,pH值为7.4。用BMG Galaxy读板器(37℃,380nm激发,460nm发射,20增益)跟踪反应。相
对于0%抑制(DMSO)和100%抑制(10μM硼替佐米)对照组计算抑制百分比。
按照上述测定法测试本发明化合物的蛋白酶抑制作用,观察到本发明化合物表现出对蛋白酶体的抑制活性。本发明化合物对蛋白酶体的抑制活性IC50值小于50nM。
(2)代谢稳定性评价。
微粒体实验:人肝微粒体:0.5mg/mL,Xenotech;大鼠肝微粒体:0.5mg/mL,Xenotech;辅酶(NADPH/NADH):1mM,Sigma Life Science;氯化镁:5mM,100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制:精密称取一定量的实施例化合物粉末,并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM,pH7.4)的配制:取预先配好的0.5M磷酸二氢钾150mL和700mL的0.5M磷酸氢二钾溶液混合,再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4,使用前用超纯水稀释5倍,加入氯化镁,得到磷酸盐缓冲液(100mM),其中含100mM磷酸钾,3.3mM氯化镁,pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP,16.5mM G-6-P,3U/mL G-6-P D,3.3mM氯化镁),使用前置于湿冰上。
配制终止液:含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中,分别加入812.5μL人肝微粒体,混匀,得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中,分别加入812.5μL SD大鼠肝微粒体,混匀,得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育:用含70%乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM,作为工作液,备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N=2),分别加入2μL 0.25mM的的工作液中,混匀。
代谢稳定性的测定:在96孔深孔板的每孔中加入300μL预冷的终止液,并置于冰上,作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中,100转/分钟震荡,预孵5min。从孵育板每孔取出80μL孵育液加入终止板,混匀,补充20μL NADPH再生系统溶液,作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液,启动反应,开始计时。相应化合物的反应浓度为1μM,蛋白浓度为0.5mg/mL。分别于反应10、30、90min时,各取100μL反应液,加入终止板中,涡旋3min终止反应。将终止板于5000×g,4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中,混匀,采用LC-MS/MS进行样品分析。
数据分析:通过LC-MS/MS系统检测相应化合物及内标的峰面积,计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率,并根据以下公式计算t1/2和CLint,
其中V/M即等于1/蛋白浓度。
对本发明化合物及其没有氘代的化合物同时测验比较,评价其在人和大鼠肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如表所示。表中采用未经氘代的化合物Ixazomib作为对照品。如表所示,在人和大鼠肝微粒体实验中,通过与Ixazomib对照,本发明化合物可以明显改善代谢稳定性。
表实施例1-4化合物的代谢稳定性的指标对比表
(3)大鼠药代动力学实验。
实验目的:研究大鼠给予Ixazomib、实施例化合物后,考察本发明化合物的药代动力学行为。
实验动物:
种类及品系:SD大鼠等级:SPF级
性别及数量:雄性,6只
体重范围:180~220g(实际体重范围为187~197g)
来源:上海西普尔必凯实验动物有限公司
实验及动物合格证号:SCXK(沪)2013-0016。
实验过程:
在血样采集之前,预先在EDTA-K2抗凝管中加入20L的2M氟化钠溶液(酯酶抑制剂),于80度烘箱内烘干后,置于4度冰箱存放。
大鼠,雄性,体重187~197g,随机分为2组,于实验前一天下午开始禁食过夜但可自由饮水,给药后4h给食物。A组给予Ixazomib 3mg/kg,B组给予实施例化合物3mg/kg,分别于
给药后15min、30min、1、2、3、5、8、10h从大鼠眼眶静脉取血100-200L左右,置于经EDTA-K2抗凝的0.5mL的Eppendorf管中,立即混匀,抗凝后,尽快将试管轻轻颠倒混匀5-6次后,血取好后放置在冰盒中,30min内把血样本在4000rpm,10min,4℃条件下离心分离血浆,收集全部血浆后立即于-20℃保存。所有时间点样品采集后测定每个时间点的血浆中的血药浓度。
根据上述所得的给药后平均血药浓度-时间数据,采用Winnonin软件,按非房室统计矩理论求算雄性SD大鼠分别i.g给予Ixazomib(3mg/kg)、实施例化合物(3mg/kg)后的药代动力学相关参数。
实验表明,与Ixazomib相比,本发明化合物具有具有优异的药代动力学性质,因此更适合作为抑制蛋白酶体的化合物,进而适合制备治疗由蛋白酶体介导疾病的药物。
应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围,实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则份数和百分比为重量份和重量百分比。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (10)
- 一种蛋白酶体抑制剂,其特征在于:如式(I)所示的硼酸化合物,或其晶型、药学上可接受的盐、前药、立体异构体、水合物或溶剂化合物,其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14和R15各自独立地为氢、氘、卤素;附加条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15中至少一个是氘代的或氘。
- 根据权利要求1所述的蛋白酶体抑制剂,其特征在于:R1、R2和R3各自独立地为氘或氢。
- 根据权利要求1所述的蛋白酶体抑制剂,其特征在于:R4和R5各自独立地为氘或氢。
- 根据权利要求1所述的蛋白酶体抑制剂,其特征在于:R6是氘。
- 根据权利要求1所述的蛋白酶体抑制剂,其特征在于:R7和R8各自独立地为氘或氢。
- 根据权利要求1所述的蛋白酶体抑制剂,其特征在于:R9、R10、R11、R12、R13、R14和R15和各自独立地为氘或氢。
- 根据权利要求1所述的蛋白酶体抑制剂,其特征在于:所述化合物可选自下述化合物或其药学上可接受的盐:
- 一种药物组合物,其特征在于:其含有药学上可接受的载体和如权利要求1~7任意一项所述的蛋白酶体抑制剂,或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体、前药或同位素变体的药物组合物。
- 如权利要求1~7任意一项所述的蛋白酶体抑制剂的用途,其特征在于:用于制备治疗蛋白酶体介导的疾病的药物。
- 如权利要求9所述的用途,其特征在于:该蛋白酶体介导的疾病为癌症。
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