CN110623952B - 一类吲哚类化合物制备治疗骨髓增殖性肿瘤药物的用途 - Google Patents
一类吲哚类化合物制备治疗骨髓增殖性肿瘤药物的用途 Download PDFInfo
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Abstract
本发明公开了化合物(I)及其药学上可接受的盐，以及其药物组合物在制备治疗骨髓增殖性肿瘤药物中的应用，
Description
技术领域
本发明涉及一种吲哚类化合物及其药学上可接受的盐、它们的制备方法、含有这类化合物的药物组合物，以及这类化合物在治疗骨髓增殖性肿瘤方面的应用，属于医药技术领域。
背景技术
骨髓增殖性肿瘤(Myeloproliferative Neoplasms，MPNs)是一种以一系或多系髓系细胞增殖为主要特征的克隆性造血干细胞疾病。其主要包括真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)等，这三种经典MPN的Ph染色体BCR/ABL融合基因检测为阴性[1]。急变性和迟发性红细胞增多症及迟发性血小板增多症导致的骨髓纤维化(post-ET MF)时有发生[2,3]。
目前已发现与MPN相关的分子标志物主要有JAK2，CARL及MPL等。2005年发现该类疾病中JAK2基因获得性突变-JAK2V617F点突变，该突变被证实在MPN中具有重要的诊断及预后意义。超过90％的PV患者及约60％的ET和PMF患者均具有V617F位点突变。除此以外，近年来多项研究表明在JAK2V617F突变呈阴性的MPN病人中发现红细胞生成素受体(MPL)突变及体细胞钙网蛋白(CALR)突变，如MPL515位点的突变，CALR 9号外显子的移码突变等。
JAK2、MPL和CALR突变在功能上都得到了验证，并且在小鼠中足以产生MPN表型[4,5]。所有这些突变对JAK2信号传导及下游的转录因子STAT都有功能上的作用。基因表达谱的研究明确显示在所有MPN患者中这些突变都能看到激活的JAK2信号。JAK-STAT信号通路在MPNs的主要信号级联中扮演着重要的角色[6]。JAK2基因编码JAK-STAT通路中的酪氨酸激酶受体。人体内的JAK2基因发生V617F突变，可引起JAK2激酶及下游信号转导通路的持续活化和增强，导致细胞恶性增殖和凋亡抑制，最终引起真性红细胞增多症(PV)等的发生。JAK2突变已经被作为原发性红细胞增多症(ET)、许多PMF和PT病例的潜在分子机制。
在发现这些突变之后，制药公司和研究人员得到了JAK2信号传导的小分子抑制剂(JAKi)用于治疗MPNs[7]。JAKi抑制JAK2和STAT磷酸化从而减少肿瘤细胞增殖和诱导细胞凋亡。2011年11月16日，美国食品和药物管理局(FDA)批准ruxolitinib(RUX)用于治疗中度和高度风险性骨髓纤维化(MF)，包括PMF和post-PV/post-ET MF[8]。随后，2014年12月4日，FDA批准RUX治疗对羟基脲(HU)反应不足或不耐受PV患者。
临床试验的JAKs抑制剂揭示了可能与之相关的不同毒性特征，加强特异性的抑制是我们的研究目标。尤其是针对突变位点的特异性JAK2抑制剂近年来受到越来越多的关注，此类JAK抑制剂既能纠正突变导致的活性增强，又不至于对野生型伤害太大，可以较大程度降低临床副作用，是开发的重点方向。
通过分子水平的JAKs激酶筛选，得到具有JAK2抑制活性的苗头化合物，并在各种MPNs类细胞上进行验证，尤其是在带JAK2V617F天然突变的人的红白血病细胞株HEL上进行评价，考察化合物对JAK2V617F突变位点的选择性，寻求对该位点突变后导致的JAK2激酶活性增强有较好抑制效应的化合物，并通过该细胞建立的荷瘤鼠模型进行药效学评价。
参考文献：
1.Passamonti,F.and M.Maffioli,Update from the latest WHOclassification of MPNs:a user's manual.Hematology Am Soc Hematol EducProgram,2016.2016(1):p.534-542.
2.Passamonti,F.,et al.,Driver mutations'effect in secondarymyelofibrosis:an international multicenter study based on 781patients.Leukemia,2017.31(4):p.970-973.
3.Passamonti,F.,et al.,Leukemic transformation of polycythemia vera:asingle center study of 23 patients.Cancer,2005.104(5):p.1032-6.
4.Mullally,A.,et al.,Physiological Jak2V617F expression causes alethal myeloproliferative neoplasm with differential effects on hematopoieticstem and progenitor cells.Cancer Cell,2010.17(6):p.584-96.
5.Elf,S.,et al.,Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation.CancerDiscov,2016.6(4):p.368-81.
6.Rampal,R.,et al.,Integrated genomic analysis illustrates thecentral role of JAK-STAT pathway activation in myeloproliferative neoplasmpathogenesis.Blood,2014.123(22):p.e123-33.
7.Quintas-Cardama,A.,et al.,Preclinical characterization of theselective JAK1/2inhibitor INCB018424:therapeutic implications for thetreatment of myeloproliferative neoplasms.Blood,2010.115(15):p.3109-17.
8.Verstovsek,S.,et al.,The clinical benefit of ruxolitinib acrosspatient subgroups:analysis of a placebo-controlled,Phase III study inpatients with myelofibrosis.Br J Haematol,2013.161(4):p.508-16.
发明内容
本发明解决的技术问题是提供一个吲哚类化合物及其药学上可接受的盐，以及其药物组合物在制备治疗骨髓增殖性肿瘤药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明的技术方案第一方面是提供了一类吲哚类化合物及其药学上可接受的盐制备预防和/或治疗骨髓增殖性肿瘤药物中的应用，其结构式如式(I)所示：
进一步的，式(I)所示的化合物的制备方法，其可以通过以下步骤和方法合成得到：
3-吲哚乙酸(式1)与2-氨基苯甲醚进行酰胺化反应得到式2，式2经过还原得到中间体式3；式3经氧化得到目标物式4。
更进一步的，所述的骨髓增殖性肿瘤包括真性红细胞增多症、原发性血小板增多症、原发性骨髓纤维化。
本发明技术方案的第二方面是提供含有式(I)所示的化合物及其药学上可接受的盐的药物组合物制备预防和/或治疗骨髓增殖性肿瘤药物中的应用，该药物组合物含有治疗有效量的本发明的吲哚类衍生物及其药学上可接受的盐，以及任选的含有药用载体。所述的骨髓增殖性肿瘤包括真性红细胞增多症、原发性血小板增多症、原发性骨髓纤维化；
其中所述的药用载体指药学领域常用的药用载体；该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物及其药学上可接受的盐与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂组合，制成适于人或动物使用的任何剂型。本发明化合物及其药学上可接受的盐在其药物组合物中的含量通常为0.1-95％重量百分比。
本发明化合物及其药学上可接受的盐或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物及其药学上可接受的盐可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物及其药学上可接受的盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。
为将本发明化合物及其药学上可接受的盐制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
因此，本发明的另一目的是提供了本发明吲哚类衍生物及其药学上可接受的盐在制药领域中的应用，特别是本发明吲哚类衍生物及其药学上可接受的盐在制备治疗骨髓增殖性肿瘤中的应用。
在将本发明的吲哚类衍生物及其药学上可接受的盐或本发明的组合物用于治疗上述疾病时，其用药量可参照使用吲哚类衍生物进行治疗时的用量。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.1-100mg/Kg体重，更优选为1-60mg/Kg体重，最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
具体实施方式
下面的实施例可进一步说明本发明，但不以任何方式限制本发明。
实施例1：2-(1-羟基-1H-吲哚-3-基)-N-(2-甲氧基苯基)乙酰胺的制备
第一步，称取吲哚乙酸(1.05g)，加入二氯甲烷(20mL)中悬浮搅拌，室温下加入EDCI(1.27g)，搅拌溶解；加入邻氨基苯甲醚(0.81g)，DMAP(0.15g)，室温搅拌反应3h；加入2N盐酸快速搅拌10min，分相；有机相加入饱和食盐水(10mL)搅拌10min，分相；有机相40℃减压除去溶剂，得到浅棕色胶状物粗品2-(1H-吲哚-3-基)-N-(2-甲氧基苯基)乙酰胺。
第二步，2-(1H-吲哚-3-基)-N-(2-甲氧基苯基)乙酰胺溶于三氟乙酸(10mL)中，加入三乙基硅烷(1.74g)，60℃回流反应1h；反应液回收溶剂，加入乙酸乙酯(30mL)，饱和碳酸氢钠水溶液(30mL)，快速搅拌15min，分相；水相用乙酸乙酯(30mL)萃取，分相；合并有机相，加入饱和食盐水(30mL)搅拌10min，分相；有机相50℃减压除去溶剂，得到浅棕色胶状物粗品2-(吲哚啉-3-基)-N-(2-甲氧基苯基)乙酰胺。
第三步，2-(吲哚啉-3-基)-N-(2-甲氧基苯基)乙酰胺溶于(20mL)甲醇，降温至0～5℃搅拌，缓慢加入85％间氯过氧苯甲酸(1.83g)，加入完毕自然升至室温20～25℃搅拌反应1h，降温至0～5℃搅拌1h；过滤，滤饼用(8mL×2)冷甲醇洗涤，40℃真空干燥得到类白色固体2-(1-羟基-1H-吲哚-3-基)-N-(2-甲氧基苯基)乙酰胺(1.18g)。1H NMR(400MHz,acetone-d6):δ10.22(1H,s,NH-8′),8.43(1H,s,OH-1),8.31(1H,d,J＝7.6Hz,H-3′),7.64(1H,d,J＝8.0Hz,H-4),7.44(2H,m,H-2,6′),7.20(1H,t,J＝7.6Hz,H-5′),7.06(1H,t,J＝7.6Hz,H-4′),6.96(1H,t,J＝7.6Hz,H-6),6.86(2H,m,H-5,7),3.85(2H,s,H-8),3.61(3H,s,OCH3-2′)；13C NMR(100MHz,acetone-d6):δ169.9(C-9),149.0(C-2′),135.1(C-7a),129.1(C-1′),125.6(C-3′),124.5(C-3a),124.2(C-5′),122.9(C-6′),121.4(C-4′),120.1(C-4),120.0(C-5),119.7(C-2),111.3(C-6),109.2(C-7),104.9(C-3),56.0(OCH3-2′),34.8(C-8)；(+)-HR-ESIMS m/z 297.1232[M+H]+(calcd for C17H17N2O3,297.1234)。
药理实验
实验例1、JAKs激酶活性测定
(1)实验方法
试验设计：组别设置分为对照组(control)和样品组(sample)，实验体系设置了4个对照组，分别为激酶完全活性对照(MAX)，无激酶阴性对照(NEG)，纯检测体系对照，缓冲液对照。样品组中包含TK Substrate-biotin,JAK激酶，ATP，化合物I。
实验步骤：本实验选择10μl激酶反应体系，JAK1抑制剂筛选中，每体系含JAK1激酶10ng，ATP 3.92μM。JAK2抑制剂筛选中，每体系含JAK2激酶0.04ng，ATP 3.96μM。JAK3抑制剂筛选中，每体系含JAK3激酶0.12ng，ATP 1.43μM。TK Substrate-biotin底物为1μM，化合物I需配置成所需浓度。具体包括①激酶反应缓冲液的准备：将1ml 5×Kinase Buffer加入4ml双蒸水中稀释至1×，加入5μl 1M DTT及25μl 1M MgCl2(JAK1反应缓冲液加5μl 1M MnCl2)命名为Kinase Buffer室温储存。②待筛选化合物配置：样品化合物按质量，溶于DMSO，配成浓度为40mM的母液，用激酶反应缓冲液稀释和配置化合物，化合物I的反应终浓度为10μM、1μM、0.1μM、0.01μM、0.001μM。③在黑色384孔微量板，依次加入上述组分使反应体系为10μl。荧光检测使用330nm激发光，检测665nm和620nm的发射强度，酶标仪自动计算Ratio＝665/620*10000。④数据分析：抑制率％＝(Ratio MAX-Ratio sample)/(Ratio MAX-RatioNEG)*100。
(2)实验结果
化合物I对JAK2的激酶活性有较好抑制作用，IC50为0.031μM。对JAK1和JAK3的抑制活性均弱于JAK2，结果见表1。
表1、化合物I抑制JAKs激酶活性的IC50
实验例2、抗肿瘤细胞增殖活性
(1)抗肿瘤筛选原理
实验以肿瘤细胞为研究对象，通过MTS比色法检测样品体外抗肿瘤活性。MTS是新一代四氮唑蓝盐化合物，采用比色法检测能够考察细胞的存活和生长。检测原理为：活细胞线粒体中的琥珀酸脱氢酶能使外源性MTS还原为有色的甲臜(Formazan)，该产物水溶性好、稳定性高、显色快，且颜色深浅与敏感细胞株的活细胞数在一定范围内呈高度相关。实验以酶联免疫检测仪在490nm波长处测定吸光值，通过吸光值的变化反应样品对肿瘤细胞存活和生长的影响。
(2)实验方法
1、细胞处理：各类型的血液瘤细胞于37℃、5％CO2及饱和湿度环境下分别培养于含10％胎牛血清1640培养基中，细胞呈对数增长时进行传代，调整细胞浓度至1×105个/mL，接种100μL于96孔培养板，孵育18h-24h后进行后续实验。
2、模型制备：将肿瘤细胞随机分组：①正常对照组(control)：以含10％胎牛血清的1640培养基继续培养，终体积补充至100μL(补充液与样品溶液相同)；②化合物I组(sample)：每孔加入检测样品10μL，终体积达100μL，化合物I终浓度为100μM，30μM，10μM，3μM，1μM，0.3μM，样品与肿瘤细胞共同孵育48h进行相关检测
3、活性检测：模型制备结束时，每孔加入10μL MTS混合液，继续培养4h显色，于酶标仪490nm波长处检测各孔的光吸收值，测量吸光值后计算IC50。
4、计算方法：每组细胞均以MTS法检测吸光值，测量后计算IC50。
样品抑制率％＝[(ODcontrol-OD blank)-(OD sample-OD blank)]/(ODcontrol-OD blank)×100％
*OD sample：样品处理组吸光值；OD control：正常对照组吸光值；OD blank：培养板空白孔(无细胞)吸光值。
(3)实验结果
化合物I在多种癌细胞上进行评价，发现能较强地抑制HEL细胞的增殖，IC50值在MPNs类细胞中最低，是20.91μM，结果见表2。
表2、化合物I抑制各类癌细胞增殖的IC50
实验例3、化合物I对HEL细胞制作的荷瘤裸鼠模型的作用评价
(1)实验方法
BALB/c-nu裸鼠，雌性，5周龄，采用层流盒无菌饲养方式在中国医学科学院药物研究所实验动物中心饲养，温度25℃，湿度40％。荷瘤裸鼠饲料为消毒标准饲料，引用消毒蒸馏水。将裸鼠分为正常对照组，HEL细胞接种组。培养HEL细胞使其处于对数生长期，调整细胞密度为5*107个/ml，用PBS洗一遍，用无血清的培养基重悬，每只鼠接种100μL体积即每只裸鼠接种5*106个HEL细胞。当瘤体积长到100mm3时，将鼠分为模型组和化合物I(100mg/kg)给药组，并开始灌胃给药两周，2天记录一次小鼠体重和瘤体积。观察给药后瘤体积的变化和相应的指标。按照公式计算：①瘤体积＝0.5×(最长直径×最短横径2)，单位为mm3。②去瘤体重＝带瘤体重－(瘤体积×1)。采用SPSS12.0统计软件，运用方差分析，P＜0.05表示在统计上具有显著性差异。
(2)实验结果
化合物I给药组体重指数正常，并能降低模型鼠的瘤体积。给药两周内裸鼠体重变化结果见表3，对瘤体积的影响见表4。
表3、化合物I对裸鼠体重的影响(mean±sd)
表4、化合物I对裸鼠瘤体积的影响(mean±sd)
*vs模型组，p<0.05
实验例4、化合物I对原发性血小板增多症(ET)病人外周血造血干细胞克隆形成实验的影响
(1)实验原理
由于骨髓增殖性肿瘤的最大特征是造血干细胞的恶性克隆形成，因此我们需要收集临床病人血样标本考察化合物I对ET病人造血干细胞克隆形成的影响。
(2)实验方法
收集健康人和ET病人外周血，并进行ET病人的血常规和脾肿大程度及机体各项功能指标和用药情况的数据采集，病人样本基因检测：JAKWT/JAK2V617F/CALR/MPL后选择JAK2V617F位点突变的ET病人。使用人的外周血单核细胞分离试剂盒将符合要求的人外周血进行处理，得到单核细胞层，并将血小板和红细胞保存于-80℃。分离得到的的单核细胞用含2％血清的IMDM培养基重悬，调整细胞密度为1*106个/ml，取100μl该悬液加入1ml含甲基纤维素和EPO等因子的干细胞培养基(M3434)中，均匀地铺在6孔板中，避免出现气泡。每天观察克隆集落的形成情况，考察化合物I对ET病人造血干细胞克隆形成的影响。
(3)实验结果
化合物I能降低JAK2V617F突变的ET病人的BFU-E克隆形成，详细结果见表5。
表5、化合物I对原发性血小板增多症(ET)病人造血干细胞克隆形成的影响(mean±sd)
Claims (4)
1.式(I)所示的化合物及其药学上可接受的盐在制备预防和/或治疗骨髓增殖性肿瘤药物中的应用，其特征在于，所述的化合物如(I)所示：
2.根据权利要求1的应用，其特征在于，所述化合物的制备方法如下：
式1所示的3-吲哚乙酸与2-氨基苯甲醚进行酰胺化反应得到式2，式2经过还原得到中间体式3；式3经氧化得到目标物式4。
3.一种药物组合物在制备预防、缓解和/或治疗骨髓增殖性肿瘤药物中的应用，其特征在于，该药物组合物含有治疗有效量的式(I)所示的化合物及其药学上可接受的盐，以及药学上可接受的载体或赋形剂，
4.根据权利要求1-3任一项的应用，其特征在于，所述的骨髓增殖性肿瘤是指真性红细胞增多症、原发性血小板增多症、原发性骨髓纤维化。
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