CN115536637A - 一种均三嗪类衍生物及其合成方法与用途 - Google Patents
一种均三嗪类衍生物及其合成方法与用途 Download PDFInfo
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- CN115536637A CN115536637A CN202211299153.1A CN202211299153A CN115536637A CN 115536637 A CN115536637 A CN 115536637A CN 202211299153 A CN202211299153 A CN 202211299153A CN 115536637 A CN115536637 A CN 115536637A
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- triazine derivative
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Abstract
本发明公开了一种均三嗪类衍生物及其合成方法与用途,具体涉及药物化学领域,现有的AG‑221出现了临床的一些缺陷,例如疗效不是特别明显,部分患者出现了耐药,因此结构新颖的IDH2抑制剂的研究显得尤为迫切的问题。利用化合物的理性设计策略,合成了一系列新型的均三嗪类衍生物,采用人源化的AM7577细胞模型进行体外活性筛选,发现两个活性强于AG‑221的药物,同时采用HuKemia Acute Leukemia xenograft模型验证了体内活性,此类化合物能明显增强老鼠的生存期。优选化合物在10μM的浓度下能明显抑制IDH2(R140Q)的表达。
Description
技术领域
本发明属于药物化学领域,更具体地说,本发明涉及一种均三嗪类衍生物及其合成方法与用途。
背景技术
急性髓系白血病(AML)是造血干细胞的恶性克隆性疾病。近几年在AML中发现了许多干扰细胞的自我更新、增殖、分化等关键过程的基因,如FLT3内部基因串联重复(FLT3internal tandem duplication,FLT3-ITD)、核磷蛋白1(Nucleophosmin1,NPM1)、髓系转录因子CCAAT增强子结合蛋白-A(CCAAT-en-hancer binding-alpha,CEBPA)等。目前认为AML的发生是多因素过程,而单独的分子异常不足以引起造血干细胞的恶性转化。自2009年Mardis等第一次报道了AML患者存在异柠檬酸脱氢酶1(isocitrate dehychogenase1,IDH1)突变以来,多个研究报道了有关IDH1突变对AML患者的诊断、临床特征、预后及治疗的影响。IDH2是IDH1的同源基因,在AML中的发生率比IDH1常见。AML作为最常见的一种急性白血病,疾病发展迅速,并且预后较差。它每年在美国带来超过21000个新病例,大部分患者会最终出现疾病复发,他们的治疗前景也极不乐观。在AML中,大约有8%-19%的患者带有IDH2突变。这种突变会抑制正常的血细胞发育,带来过多不成熟的血细胞。并且也有研究发现在儿童AML中也存在IDH2突变。
IDH2基因位于人类15号染色体的长臂15q26.1,其编码的蛋白位于线粒体中,与IDH1催化同一化学反应,即两者都可以催化异柠檬酸脱氢脱羧生成α-酮戊二酸(α-ketoglutaric acid,α-KG),同时伴随还原型烟酰胺二核苷酸磷酸(Nicotinamide AdenineDinucleotide Phosphate,NADPH)的生成。α-KG参与体内葡萄糖、蛋白质、脂肪的代谢,而NADPH是体内许多合成代谢的供氢体、参与体内羟化反应及维持谷胱甘肽(Glutataione,GSH)的还原性。
IDH突变体将α-KG转化生成肿瘤代谢物2-羟戊二酸(2-hydroxyglutarate,2-HG),促使一类依赖于α-KG的双加氧酶反应紊乱,而从激活细胞下游的信号通路。2-HG积累将引发细胞代谢问题,促使正常细胞转化为癌细胞。
其中IDH2突变主要发生在IDH2R140Q(79%)和IDH2R172Q(21%)。此外,IDH2突变在胆管癌、软骨肉瘤、乳腺癌、T细胞淋巴瘤等肿瘤中也有报道。自从确定了IDH2突变与AML的发生发展有着密切的关系,IDH2抑制剂的研究就取得了科学家的研究兴趣,目前已经取得不错的进展。Fang Wang等对尿素磺酰胺系列的药物设计和修饰得到了AGI-6780,可以有效并选择性的抑制IDH2R140Q突变,并得到了复合物晶体结构(PDB:4JA8)。Wenyuan Lee等以PDB:4JA8为靶标从TCM数据库中进行虚拟筛选,希望筛选出具有抑制R140Q突变的IDH2抑制剂的传统中药成分,虚拟对接中发现相思碱和相思豆碱与目的蛋白结合更为牢固。Enasidenib(AG-221)是Katharine Yen等通过高通量筛选出针对IDH2R140Q突变蛋白的小分子抑制剂,并且得到了小分子和IDH2R140Q突变蛋白的复合物晶体结构(PDB:5196),通过阻断突变蛋白2-HG的产生达到抑制肿瘤的目的。2017年8月,FDA批准了AG-221上市,它的疗效也在临床试验中得到了验证。它曾获美国FDA颁发的优先审评资格和孤儿药资格。该药物作用机制是将AML患者体内的异柠檬酸(IDH2)转变成2羟戊二酸(2-HG),而非通常的α-酮戊二酸,AG-221可以抑制这一过程,缓解率达到56%。如果2-HG的产生能够被取消,可以让恶性细胞返回到正常分化及成长为正常健康成人中性粒细胞的过程。
截至目前,只有Enasidenib(AG-221)一个上市药物,近期Andrew M.Intlekofer等已经发现AG-221出现了临床的一些缺陷,例如疗效不是特别明显,部分患者出现了耐药,因此结构新颖的IDH2抑制剂的研究显得尤为迫切。本发明利用化合物的理性设计策略,发明了一系列新型的均三嗪类衍生物,采用人源化的AM7577细胞模型进行体外活性筛选,发现两个活性强于AG-221的药物,并进行了体内活性验证,新合成的两个均三嗪类化合物明显能够延长老鼠的中位生存期。Western Bloting实验表明,化合物T-33能在10μM的浓度下能明显抑制IDH2(R140Q)的表达。
发明内容
为了克服现有技术的上述缺陷,本发明的实施例提供一种均三嗪类衍生物及其合成方法与用途,以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:
本发明的一个目的在于提供一种具有能够治疗IDH2突变的新型化合物。该类化合物具有如下所示的结构:
其中,R具有手性的取代五元环胺或六元环胺。
优选的,本发明的化合物为选自下表中的一种:
本发明的另一个目的在于提供一种用于治疗IDH2基因突变的药物组合物,该药物组合物包含本发明所述的化合物或者其水合物、溶剂化物、晶型盐、代谢产物、或者药学上可接受的盐或酯或前药,以及药学上可接受的载体。
优选地,本发明所述的药用组合物的剂型选自片剂、胶囊剂、丸剂、颗粒剂、糖浆剂、注射剂和外用剂型的剂型。
优选地,所述外用剂型为溶液剂、悬浮剂或者气雾剂。
本发明的所述化合物可以单独或者相互结合给药,也可以与其他药学上可接受的活性化合物联合给药。所述化合物可以药物组合物的形式通过口服、直肠、肠胃外、局部给药施予有需要的人或动物。
所述药物组合物通常根据常规方法将活性化合物与一种或多种药学上可接受的载体混合,制成合适的剂型。所述药学上可接受的载体指药学领域常规的惰性载体。
除了活性化合物外,药物组合物可包含以下一种或多种载体:稀释剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇或硅酸;粘合剂,如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;分散剂,如聚乙二醇、聚乙烯吡咯烷酮;保湿剂,例如甘油;崩解剂,如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠;缓溶剂,如石蜡;吸收加速剂,如季胺化合物;润湿剂,如鲸蜡醇和单硬脂酸甘油酯;吸附剂,如高岭土;润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠;其他辅剂,如缓冲剂、着色剂、芳香剂、甜味剂等。此外,可包含包衣材料制备包衣制剂。可包含聚合物质和蜡类物质等制备缓释制剂,使活性化合物以延迟的方式在消化道内的某一部分中释放。
用于口服给药的液体剂型包括乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,药物组合物可包含以下一种或多种载体:稀释剂如水或其它溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物;助悬剂,如乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂。此外可包含辅剂,如润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂和香料。
用于肠胃外给药的剂型包括静脉内、皮下、肌内注射制剂。除了活性化合物外,药物组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的剂型包括软膏剂、散剂、喷射剂、滴剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明所述的药学上可接受的盐或酯指的是可以根据本领域技术人员熟知的方法制备的药物工业中通常使用的无毒的盐或酯或其衍生物;一方面,基于碱性基团的盐优选氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐之类的氢齿酸盐、硝酸盐、高氯酸盐、硫酸盐、磷酸盐等无机酸盐;甲磺酸盐、三氟甲磺酸盐、乙磺酸盐之类的低级链烷磺酸盐、苯磺酸盐、对甲苯磺酸盐之类的芳磺酸盐、马来酸盐、乙酸盐、苹果酸盐、琥珀酸盐、富马酸盐、半富马酸盐、枸橼酸盐、丁二酸盐、抗坏血酸盐、酒石酸盐、丙二酸盐、醋酸盐、三氟醋酸盐、乳酸盐、对甲苯磺酸盐、草酸盐等有机酸盐;以及精氨酸盐、赖氨酸盐、甘氨酸盐、鸟氨酸盐、谷氨酸盐、天门冬氨酸盐之类的氨基酸盐;另一方面,基于酸性基团的盐优选钠盐、钾盐、锂盐之类的碱金属盐、钙盐、镁盐之类的碱土金属盐、铝盐,铁盐等金属盐;铵盐之类的无机盐、叔辛胺盐、二苄胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己胺盐、N,N-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基苯乙胺盐、哌嗪盐、四甲基铵盐、三(羟甲基)氨基甲烷盐之类的有机盐等胺盐;以及精氨酸盐、赖氨酸盐、甘氨酸盐、鸟氨酸盐、谷氨酸盐、天门冬氨酸盐之类的氨基酸盐;应当理解的是所述的无毒的盐或酯包括本发明所述化合物的药学上可接受的药理学活性衍生物,或与其显著相关的化合物,包括但不限于盐或酯、药学上可接受的盐或酯、前体药物、活性代谢产物、各种异构体或这些异构体的任何比例的混合物、结晶、部分结晶、非晶形形式或多晶形式、溶剂合物、水合物或氧化物。
本发明所述的药学上可接受的载体是本领域公认的,并指参与运载或转运任何主体组合物或其组分从一个器官或身体的部分至另一个器官或身体的部分的药学上可接受的物质、组分或载体,如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。所述的药学上可接受的载体可以选自填充剂、粘合剂、崩解剂、润滑剂、助流剂、湿润剂、矫味剂、芳香剂、着色剂、溶解度促进剂或其混合物。药学上可接受的每种载体在药物组合物中的量可在本领域常规范围内变化:
附图说明
图1为本发明在HuKemia急性白血病异种移植模型AM7577中,不同组别小鼠在试验品治疗期间的体重图;
图2为本发明在HuKemia急性白血病异种移植模型AM7577试验品治疗期间不同组小鼠的体重变化图;
图3为本发明在HuKemia急性白血病异种移植模型AM7577中不同组别小鼠的肿瘤负荷;
图4为本发明不同组别AM7577小鼠的PB、SP和BM的FACS显示图;
图5为本发明各组AM7577小鼠的生存曲线图;
图6为本发明不同组别AM7577小鼠PB、SP和BM中的2-HG水平图;
图7为本发明通过Western Blotting检测外源性表达的IDH2的表达水平图。
具体实施方式
以下结合实施例来进一步说明本发明,其目的是能更好地理解本发明的内容乃体现本发明的实质性特点,因此所举之例不应视为对本发明保护范围的限制。
实施例1
目标化合物T2的合成路线:
操作步骤:将Y1A(100g,523.26mmol,1eq)和甲醇(800mL)加入到2L的圆底烧瓶,然后缓慢的加入SOCl2(124.50g,1.05mol,2eq)。混合物在70℃搅拌反应12h。直到全部生成Y1,减压除去溶剂得到灰白色中间体Y1(100g,粗品),LC-MS:205.8。
中间体Y3的合成:
操作步骤:Na(13.45g,584.99mmol,1.2eq)加入到EtOH(1.50L),混合物在15℃条件下搅拌直到Na溶解完全。在50℃的条件下往乙醇钠溶液中加入缩二脲Y2(50.25g,487.50mmol,1eq),搅拌10min,紧接着加入Y1,混合液加热至回流48h。原料消失,反应液浓缩加入到冰水(100mL),然后浓盐酸(2.5mL,0.03mol)中和至pH到6~7。真空干燥沉淀得到灰白色固体Y3(40g,粗品),产率:32.0%;LC-MS:302.9;1H NMR(400MHz,DMSO-d6)δppm8.09-8.56(m,3H),11.55(br s,1H),12.38(br s,1H)。
中间体Y4的合成:
操作步骤:缓慢地将POCl3(175mL)加入到含有Y3(30.0g,116.21mmol,1eq)的圆底烧瓶中。混合物在100℃条件下搅拌48h。除去溶剂0℃条件下用乙酸乙酯溶解(200mL),缓慢地加入冰水,有机层用饱和冰食盐水洗涤,然后Na2SO4干燥,得到棕色固体的Y4(40.0g,crude),产率:87.79%,LCMS:294.9,直接用于下一步。
中间体Y6的合成:
操作步骤:将Y4(30.0g,101.68mmol,1eq)溶解在THF(150mL),然后Y5(9.06g,101.68mmol,1eq)和NaHCO3(12.81g,152.52mmol,1.5eq)加入到上述混合液中,混合物在30℃的条件下搅拌12h。过滤固体,滤液浓缩,柱层析分离(石油醚:乙酸乙酯=3:1-1:1),得到淡黄色固体Y6(14.0g,40.26mmol),产率:39.60%,1H NMR(400MHz,CDCl3-d)δppm 1.28-1.34(m,6H),3.51-3.68(m,2H),6.65(br t,J=5.77Hz,1H),7.01(br t,J=5.77Hz,1H),7.84(dd,J=6.78,1.25Hz,1H),8.05(t,J=8.03Hz,1H),8.52-8.66(m,1H)。
中间体Y7的合成:
操作步骤:将Y6(3.0g,8.63mmol,1eq)溶解在MeOH(50mL)中,TEA(837.2mg,8.63mmol,1.2mL,1eq)和Pd(dppf)Cl2.CH2Cl2(704.76mg,863umol,0.1eq)加入到上述溶液中,混合液在8atm、60℃反应16h。过滤滤液浓缩,柱层析纯化(石油醚:乙酸乙酯=5:1~1:1),得到淡黄色化合物Y7(2.0g,5.39mmol,62.41%yield)。
中间体Y8的合成:
操作步骤:Y7(2.0g,5.39mmol,1eq)溶解在THF(15mL)中,LiOH.H2O(339.02mg,8.08mmol,1.5eq)和H2O(15mL)加入上述溶液中,混合物在20℃条件下搅拌16h。除去溶剂加入1当量的稀盐酸到pH~5,水相冻干之后得到Y8(2.0g,粗品),产率:99%,LCMS:358.1,直接用于下一步。
目标化合物T2的合成:
操作步骤:将Y8(200mg,559.77umol,1eq)溶于DCM(15mL)and DMF(5.00mL)中,加入HATU(319.26mg,839.66umol,1.5eq),在0℃条件下搅拌10min,然后加入取代氨胺(839.66umol,1.5eq)和DIEA(144.69mg,1.12mmol,2eq),混合物在20℃条件下搅拌反应3h。加入盐水,混合物用DCM萃取,有机相用无水Na2SO4干燥,浓缩之后用制备液相纯化,得到目标化合物。所有目标化合物都采用相同的合成方法,唯一的区别是最后一步所用的胺不同,表征数据见图表备注。
实施例2
利用本发明提供的衍生物进行测试,验证对人源化的AM7577细胞活性。AG-221作为阳性对照。
1)试验材料
CellTiter-发光细胞活力检测法(Promega,Cat.No.G7572);X-vivo 15基础生长培养基(Lonza,Cat.No.04-744Q);96孔板(Corning,Cat.3603);Backseal黑色胶底密封条(Perkin Elmer,Cat.No.6005189);二甲基亚砜DMSO(Sigma,Cat.No.D2650);CellTiter-缓冲液、CellTiter-底物(冻干)和阳性对照AG-221均购自Sigma。奥林巴斯(CKX41SF);微板阅读器(EnVision PerkinElmer,2104-0010A);二氧化碳培养箱(Thermo Scientific,Model 3100Series);AM7577细胞来源于Crown Bioscience。
2)试验步骤
细胞活性测试采用CTG方法,简述如下:用CountStar细胞计数仪计数AM7577细胞悬液,用培养基稀释细胞悬液浓度至1.1×105cells/mL。将AM7577细胞悬液分别以指定浓度的90μL细胞悬液接种到96孔板中。在37℃加5% CO2的加湿培养箱中培养24小时后。每孔加入100μL反应液(50%新鲜培养基,添加50%反应物质)。该化合物溶解在DMSO中,并使用整个介质稀释。然后在96孔板中加入25uL/孔化合物,最终得到的化合物浓度为10μM、2.5μM、625nM、156.25nM、39.06nM、9.77nM、2.44nM、0.61nM、0.15nM。细胞孵育72h后转移到96孔板上,用微板阅读器测量发光信号。抑制率(%)的计算方法为:
所有的数据采用GraphPad prism处理。部分化合物的活性数据表1所示:表1表明T9和T33对AM7577具有和阳性对照相当的抑制作用,并且T9具有三倍的抑制率。
表1化合物对AM7577的抑制情况
实施例3体内活性筛选
由于化合物T9和T33表现出明显的细胞抑制作用,为了深入研究它们的活性,进行了体内活性测试,HuKemia急性白血病异种移植模型(AM7577)来自Crown Bioscience,操作过程简述如下:
NOD/SCID;年龄:3~4周;性别:女;共45只小鼠(1-5组30只+10只备用小鼠,6组5只);动物供应商:北京恒基生物科技有限公司;动物用途申请ID:AN-1507-005-38。
每只老鼠从液氮中解冻1~2x106(约12瓶),然后迅速放入37℃的水浴中;将所有细胞转移到50mL管和40mL预热完全培养基中;1000rpm离心7min;用冰冷的PBS清洗细胞两次;用2.5mL冰冷PBS重新悬浮细胞;每只小鼠体内注射100uL含100~200万个肿瘤细胞的PBS,进行肿瘤生长。
接种后采集动物眼血,人CD45染色,流式细胞仪(FACS)分析,监测PB中肿瘤负荷。当平均肿瘤负荷量达到2~10%时,将小鼠随机分为6组。同时在接种肿瘤后,每天检查动物的发病率和死亡率。在常规监测的同时,检查动物的肿瘤生长和治疗对正常行为的任何影响,如活动能力、食物和水的消耗、体重的增加/减少、眼睛/头发的纠结和任何其他异常影响。根据每个亚群内的动物数量记录死亡和观察到的临床体征。
所有的动物都被一直研究到死亡。在下列情况下,在动物死亡或达到昏迷状态之前,通过人道安乐死终止个体或整个群体的活体实验。
脾、骨髓切成2块;一份消化成单细胞进行FACS分析,另一份保存于-80℃至2-HG分析;同时,每只小鼠采集2份血液样本,一份用于FACS分析,另一份(至少30uL)在-80℃保存,直到2-HG分析。2-HG分析采用API4000+Agilent 1200+CTC(TLCM0008),MS条件:CUR:20,GS1:70,GS2:70,is:-4500,TEM:550,ihe:ON,CAD:5,EP:-10,CXP:19。分子离子峰:2-HG,Q1质量(amu):147.0;Q3质量(amu):128.9。HPLC条件:A:0.1%甲酸在水中,B:0.1%甲酸在乙腈中,HPLC柱:EC-C18 4.0um 2.1X50mm,总时间:2.51min,流速:300μL/min,A%:B%=85:15。
计算各组的中位生存时间(MST)。延长寿命(ILS)的计算方法如下:
ILS(%)=100×[(药物治疗组中位生存时间/载药组中位生存时间)-1](%)。
各组小鼠体重及体重变化如图1、图2所示。随着疾病的发展,小鼠的体重逐渐下降,但第5组(Compound Th),特别是第1组(Vehicle)的体重下降比其他组更快、更严重,在接种后第55天早期终止。分组后PB小鼠的肿瘤负荷(人CD45阳性白血病细胞)和研究终止时PB、SP、BM小鼠的肿瘤负荷(人CD45阳性和CD45/CD15双阳性白血病细胞)分别如图3、图4所示。随着疾病进展,各组PB中人CD45+白血病细胞百分比增加,当小鼠数量减少时,百分比曲线最终下降。AG-221处理诱导人CD45+母细胞中单核细胞表面标记物CD15+的表达,表明分化的开始。5组小鼠的生存曲线如图5所示。1~5组的中位生存时间分别为55、56、57、58和57.5天。2-5组与1组比较,相应的ILS分别为1.82%、3.64%、5.45%、4.55%,见表2。小鼠2-HG浓度如图6所示。AG-221能有效降低AM7577小鼠PB、SP和BM中的2-HG。综上所述,合成的化合物可以提高动物存活率。AG-221诱导人CD45+母细胞中单核细胞表面标记物CD15+的剂量依赖性表达,提示分化的开始。AG-221还能有效降低AM7577小鼠PB、SP和BM中的2-HG。从动物实验来看,Ta和Th能提高动物存活率。
表2.各组小鼠的存活率
实施例4
为了确定T9和T33是否能调控mIDH2R140Q的表达,我们在TF-1(IDH2/R140Q)细胞中进行western blotting试验(图7)。结果表明,10μM Th能显著降低mIDH2R140Q的表达水平,而10μM AG-221和T9则不能。当最终浓度增加到20μM和50μM时,所有这些化合物对mIDH2R140Q的表达水平均无影响,化合物T33z在低浓度是明显抑制了mIDH2R140Q的表达,但是高浓度没有出现明显的抑制,可能原因是高浓度出现了其他代偿途径,此现象还有待于深入研究。
最后:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (7)
5.根据权利要求1-4任意一项所述的均三嗪类衍生物的用途,其特征在于,用于治疗IDH2(R140q)基因突变或过表达的髓系白血病。
7.一种用于治疗IDH2(R140q)基因突变或过表达的药物组合物,其特征在于,包含权利要求1-4任一项所述的均三嗪类衍生物或者其水合物、溶剂化物、晶型盐、代谢产物、或者药学上可接受的盐或酯或前药,以及药学上可接受的载体。
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