CN115716829A - 一种喹啉并咪唑酮联氘代吡唑类化合物及其应用 - Google Patents
一种喹啉并咪唑酮联氘代吡唑类化合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种式I所示的喹啉并咪唑酮联氘代吡唑类化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物。本发明提供的式I所示化合物对ATM激酶具有很好的抑制活性，对癌症具有良好的治疗作用。
Description
技术领域
本发明属于创新药物化学领域，涉及一种喹啉并咪唑酮联氘代吡唑类化合物、药物组合物及其应用。
背景技术
共济失调性毛细血管扩张突变激酶(ATM)是一种丝氨酸/苏氨酸激酶，参与DNA损伤应答。它属于磷脂酰肌醇-3激酶样蛋白(PIKK)激酶家族，该家族还包括共济失调-和rad3-相关激酶(ATR)、哺乳动物雷帕霉素靶蛋白(mTOR)和DNA依赖的蛋白激酶(DNA-PK)。ATM识别和修复双链DNA断裂，在维持基因完整性中发挥重要作用。应对DNA损伤，ATM会发生自动磷酸化，从而磷酸化大约700种底物，包括H2AX，P53和KAP1等。由于辐射(IR)或化学诱导DNA损伤剂容易诱导产生双链DNA断裂，因此，抑制ATM活性能够增强辐射或者临床上应用的DNA损伤剂的抗肿瘤活性。因此，ATM是开发抗肿瘤药物的潜在有效靶点。目前，已经有一些ATM抑制剂被报道，但是进展最快的ATM抑制剂，比如M-4076，处于早期临床研究阶段；目前尚无ATM抑制剂批准上市。目前报道的ATM抑制剂大多存在缺乏选择性而存在潜在的毒副作用、活性较差等问题，另外联合用药可能存在不明确的药代动力学性质。因此，新型高效ATM抑制剂的开发具有重要意义。
氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近，氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定，使得氘代药物在化学反应过程中，C-D键更不容易断裂，其半衰期会延长。自2000年以来，氘代策略便被广泛应用于药物的研究中。
发明内容
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，其结构如下：
本发明提供了一种如式I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备ATM激酶抑制剂中的应用。
本发明提供了一种I所示化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备用于预防和/或治疗癌症的药物中的应用。
在一些实施方案中，所述的癌症选自血液癌症或实体瘤。
在一些实施方案中，所述的血液癌症为单核细胞性白血病、急性髓性白血病、慢性髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤。
在一些实施方案中，所述的实体瘤为肺腺癌、小细胞肺癌、胰腺癌、成胶质细胞瘤、肠癌和乳腺癌。
在一些实施方案中，所述的癌症为与ATM激酶酶活性异常相关的癌症。
本发明提供了一种药物组合物，其含有如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，及药学上可接受的载体或辅料。
在所述的药物组合物中，所述的如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物用量为治疗有效量。
本发明提供了一种药物组合物在制备ATM激酶抑制剂中的应用。
本发明提供了一种药物组合物在制备用于预防和/或治疗癌症的药物中的应用。
在一些实施方案中，所述的癌症选自血液癌症或实体瘤。
在一些实施方案中，所述的血液癌症为单核细胞性白血病、急性髓性白血病、慢性髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤。
在一些实施方案中，所述的实体瘤为肺腺癌、小细胞肺癌、胰腺癌、成胶质细胞瘤、肠癌和乳腺癌。
在一些实施方案中，所述的癌症为与ATM激酶酶活性异常相关的癌症。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；有机酸盐还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本发明的“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“异构体”是指具有相同化学式而有不同的原子排列的化合物。
术语“代谢产物”是指式I所示化合物或其盐通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化、酶促裂解等产生。因此，本发明包括本发明的化合物的代谢产物，包括使本发明的化合物与哺乳动物接触足够得到其代谢产物的一段时间的方法而产生的化合物。
代谢产物的鉴定典型地通过制备本发明化合物的放射性标记的同位素、将其以可检测的剂量(例如，大于约0.5mg/kg)非肠道给予动物，例如大鼠、小鼠、豚鼠、猴、或人，允许充分的时间以发生代谢(典型地约30秒到30小时)和从尿、血液或其它生物样本分离其转化产物。这些产物容易分离，因为它们是被标记的(其它通过利用能够结合存在于代谢物中的抗原表位的抗体分离)。以常规的方式确定代谢物结构，例如，通过MS，LC/MS或NMR分析。通常，代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方法进行的。只要代谢物产物不是以其它方式在体内不能被发现，否则它们可用于本发明化合物的治疗剂量给药的检定测定法。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式I所示化合物)的任何化合物是在本发明的范围和主旨内的前药。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。
本发明的积极进步效果在于：
(1)本发明化合物对ATM激酶具有很好的抑制活性和选择性。
(2)本发明化合物的口服生物利用度较高，半衰期延长，可以降低单次给药的剂量。
(3)本发明化合物对癌症具有良好的治疗作用。
(4)本发明化合物对癌细胞具有较高的选择性，毒副作用较小。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：化合物7的合成
步骤一：化合物b的合成
向化合物a(104mg,0.47mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入氢氧化钾(105.5mg,1.88mmol)和碘单质(239mg,0.94mmol)，室温反应3小时，TLC监测反应完全，加入亚硫酸钠饱和溶液淬灭反应，水相用乙酸乙酯(10mL*2)萃取，水(20mL*2)洗，饱和食盐(20mL)水洗无水硫酸钠干燥，浓缩柱层析分离纯化制得碘代化合物b(82mg，50％)。MS(ESI,m/z):349(M++1).
步骤二：化合物c的合成
向化合物b(125mg,0.36mmol)的氘代醋酸溶液(8mL)中加入醋酸钠(97.9mg,0.72mmol)，2小时滴完，室温反应24小时，TLC检测反应完全，减压浓缩，柱层析分离纯化制得化合物c(52mg,64％)。MS(ESI,m/z):224(M++1).
实施例2：化合物I的合成
步骤一：化合物2的合成
将化合物6(494mg，3.48mmol)溶于无水DMF(10mL)中，氮气保护，向上述溶液中加入NaH(630mg，26.3mmol)，室温下搅拌反应10min。然后，将化合物1(1g，3.15mmol)加入到上述混悬液中，室温下搅拌30min，向反应液中加入冰水(100mL)淬灭反应，乙酸乙酯萃取(100mL×3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物2(1.1g，83％)。MS(ESI,m/z):423(M++1).
步骤二：化合物3的合成
将化合物2(1g，2.36mmol)溶乙醇/水(10mL/2mL)中，剧烈搅拌下向上述溶液中加入Fe粉(133mg,23.6mmol)和七水硫酸亚铁(65mg,0.236mmol)，加热回流搅拌反应6h。冷却至室温，硅藻土抽滤，滤液浓缩，柱层析分离纯化制得化合物3(574mg，62％)。MS(ESI,m/z):393(M++1).
步骤三：化合物4的合成
将化合物3(862mg，2.20mmol)溶于无水THF(20mL)中，向上述溶液中加入CDI(1.78g,11.0mol)和DIPEA(1.42mg，11.0mmol)，升高反应液温度至40℃，搅拌反应2h。加入冰水终止反应，乙酸乙酯萃取(20mL×3)，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化制得化合物4(800mg，87％)。MS(ESI,m/z):419(M++1).
步骤四：化合物5的合成
将原料4(861mg，2.06mmol)溶于DMF(10mL)中，向反应液中加入NaH(412mg,17.2mmol)和碘甲烷(1.46g，10.3mmol)。反应在室温下搅拌1小时，加入冰水终止反应，析出大量沉淀，过滤，水洗，收集滤饼，真空干燥制得化合物5，直接投入下一步反应。
步骤五：化合物I的合成
将化合物5(160mg,0.37mmol)、化合物7(100mg，0.45mmol)、碳酸钾(103mg，0.75mmol)和四三苯基膦钯(43mg，0.04mmol)混悬于1,4-二氧六环(10mL)和水(3mL)的混合溶剂中，氮气保护，升高反应液温度至80℃搅拌2h。然后将2M二甲胺的THF溶液(7mL,14mmol)加入到反应液中，继续搅拌1h。停止反应，冷却至室温，减压除掉残留的溶剂，HPLC制备得目标化合物I。1H NMR(500MHz,DMSO-d6)δ8.58(s,1H),8.46(s,1H),8.08(d,J＝7.9Hz,1H),7.89(s,1H),7.69(s,1H),4.01(s,3H),3.91(s,3H),3.85(s,3H),2.88(s,3H),2.36(s,3H).MS(ESI,m/z):450(M++1).
实施例3：激酶抑制活性测试
ATM激酶抑制活性测试：将稀释系列待测化合物加入到96孔板中，ATM激酶的Hepes缓冲液(50mM Hepes pH 7.4,150mM NaCl,10mM,MnCl2 1mM，DTT,5％v/v甘油，0.05％v/v吐温20)与稀释系列待测化合物预孵育30min后，然后加入含有p53和ATP的底物溶液。反应2h后，加入检测试剂(33mM HEPES pH 7.4,20mM EDTA,0.1M KF,0.1mg/mL BSA,13nM D2抗GST抗体，0.5nM Eu3+抗p53phosphos15抗体)终止反应，混合体系孵育过夜，然后采用在Pherastar仪器采用标准HTRF法进行分析。DMSO、ATP和p53的最终浓度含量分别为1％、5μM和50nM。采用数据分析软件
中的智能拟合模型，使用四个参数拟合确定IC50值(测试浓度化合物抑制50％的酶活性)。
ATR激酶抑制活性测试：Hela细胞中提取ATR激酶，与缓冲液混合：25mM HEPES(pH7.4)，2mM MgCl2,250mM NaCl,0.5mM EDTA,0.1mM Na3VO4,10％v/v甘油，0.01％v/v Tween20。10μL含有ATR的琼脂糖珠、1μg底物谷胱甘肽s-转移酶-p53N66的ATR缓冲液(50mM)[HEPES(pH 7.4)，150mM NaCl,6mM MgCl2,4mM MnCl2,0.1mM Na3VO4,0.1mM DTT，10％(v/v)甘油]和系列稀释待测化合物在37℃下共孵育。10分钟后，轻轻摇晃，加入终浓度为3μM的ATP，在37℃下继续反应1h。加入100μL PBS停止反应，将反应转移到白色不透明的谷胱甘肽包被96孔板中，4℃下孵育过夜。然后用PBS/0.05％(v/v)Tween 20清洗孔板，吸干，采用磷酸丝氨酸15p53(16G78)抗体，用标准ELISA试剂盒分析技术进行分析。磷酸化谷胱甘肽S-转移酶-p53N66的检测结合山羊抗小鼠辣根过氧化物酶二抗。增强化学发光溶液用于产生信号，化学发光检测通过TopCount酶标仪检测。
mTOR激酶抑制活性测试：mTOR与缓冲液(50mM HEPES(pH 7.5),1Mm EGTA,0.01％Teen 20,2mg/ml底物，3mM MgCl2)混合，和[γ-33P-ATP]共孵育，加入MgATP启动反应。室温下孵育40min，加入3％的磷酸终止反应。然后将10μL反应溶液逐滴转移至P30滤垫上，用75mM磷酸洗涤三次5分钟，甲醇洗涤一次，干燥，通过液体闪烁技术评价。
PI3K p110α/85α激酶抑制活性测试：PI3K p110α/85α在10μM磷脂酰肌醇4,5-二磷酸和MgATP的测定缓冲液中孵育。加入MgATP溶液启动反应，室温下孵育30min后，加入EDTA和生物素化的磷脂酰肌醇3,4,5-三磷酸的终止液终止反应。最后，加入由铕标记的抗-GST单克隆抗体、GST标记的GRP1 PH结构域和链霉亲和素别藻蓝蛋白组成的检测缓冲液。通过HTRF读取荧光值变化，通过相应的信号值计算每个浓度点下的激酶抑制率，然后拟合获得待测化合物的IC50。
PI3K p110β/85α激酶抑制活性测试：PI3K p110β/85α在10μM磷脂酰肌醇4,5-二磷酸和MgATP的测定缓冲液中孵育。加入MgATP溶液启动反应，室温下孵育30min后，加入EDTA和生物素化的磷脂酰肌醇3,4,5-三磷酸的终止液终止反应。最后，加入由铕标记的抗-GST单克隆抗体、GST标记的GRP1 PH结构域和链霉亲和素别藻蓝蛋白组成的检测缓冲液。通过HTRF读取荧光值变化，通过相应的信号值计算每个浓度点下的激酶抑制率，然后拟合获得待测化合物的IC50。
PI3K p110δ/85α激酶抑制活性测试：PI3K p110δ/85α在10μM磷脂酰肌醇4,5-二磷酸和MgATP的测定缓冲液中孵育。加入MgATP溶液启动反应，室温下孵育30min后，加入EDTA和生物素化的磷脂酰肌醇3,4,5-三磷酸的终止液终止反应。最后，加入由铕标记的抗-GST单克隆抗体、GST标记的GRP1 PH结构域和链霉亲和素别藻蓝蛋白组成的检测缓冲液。通过HTRF读取荧光值变化，通过相应的信号值计算每个浓度点下的激酶抑制率，然后拟合获得待测化合物的IC50。
PI3K p120γ激酶抑制活性测试：PI3K p120γ在10μM磷脂酰肌醇4,5-二磷酸和MgATP的测定缓冲液中孵育。加入MgATP溶液启动反应，室温下孵育30min后，加入EDTA和生物素化的磷脂酰肌醇3,4,5-三磷酸的终止液终止反应。最后，加入由铕标记的抗-GST单克隆抗体、GST标记的GRP1 PH结构域和链霉亲和素别藻蓝蛋白组成的检测缓冲液。通过HTRF读取荧光值变化，通过相应的信号值计算每个浓度点下的激酶抑制率，然后拟合获得待测化合物的IC50。
表1待测化合物对ATR、脂质激酶和其他PIKK激酶家族成员的酶抑制活性(IC50 nM)
| 名称 | ATM | ATR | PI3Kα | PI3Kβ | PI3Kδ | PI3Kγ | DNA-PK |
| I | 0.015 | ＞30000 | ＞30000 | ＞30000 | ＞30000 | ＞30000 | ＞30000 |
| M-4076 | 0.042 | ＞20000 | ＞20000 | ＞20000 | ＞20000 | ＞20000 | ＞20000 |
如表1所述，化合物I对ATM激酶表现出显著的抑制活性，且对脂质激酶和PIKK激酶的其他成员具有较高的选择性。并且，对ATM激酶的抑制活性和选择性具有优于阳性对照M-4076。
实施例3：细胞抗增殖活性测试
细胞抗增殖活性检测采用CTG发光法。ATP是维持正常细胞生命活动的必须因素，是活细胞的新陈代谢的一个关键指标，能够真实反映活细胞的状态以及数量。测试过程中，向培养基中加入CellTiter-GloTM试剂，测量发光值，而发光值与ATP的含量呈正比，因此可以通过测定ATP含量来检测活细胞的数量。
具体的实验操作步骤如下：
1、化合物配置：
1)使用DMSO将化合物配制为10mM的储存浓度；
2)将化合物以10mM的top dose(100％DMSO)，将最高浓度点两倍稀释共十个点，每个浓度设置两个复孔；
3)使用细胞相对应培养基将化合物稀释100倍，使化合物浓度为100μM的top dose(1％DMSO)。
2、细胞铺板：
1)细胞铺板密度为5000cells/well，细胞铺板过夜，体积为20μL；
2)向96孔板中加入20μL待测化合物，此时每个孔中为40μL，化合物最终浓度的topdose为50μM(0.5％DMSO)。加药完成后，37℃，5％CO2孵育72h。
3、细胞检测：每个孔中加入20μL CTG试剂，共孵育20min，使用程序Luminescence进行检测。
4、数据处理：采用Graphpad软件计算IC50值。
表2待测化合物在实体瘤中的抗细胞增殖活性测试结果(IC50μM)
| 名称 | A549 | HCT116 | MDA-MB231 | A2780 | PANC-1 | Hela | Hep-3B | PC-3 | L02 |
| I | 0.22 | 0.35 | 0.56 | 0.45 | 0.38 | 0.22 | 0.15 | 0.18 | ＞30 |
| M-4076 | 0.65 | 0.98 | 1.72 | 1.4 | 1.23 | 0.67 | 0.67 | 0.66 | ＞20 |
如表2所示，化合物I对多种实体瘤细胞，包括非小细胞肺癌(A549)、结肠癌细胞(HCT116)、三阴乳腺癌(MDA-MB-231)、卵巢癌(A2780)、胰腺癌(PANC-1)、宫颈癌(Hela)、肝癌(Hep-3B)和前列腺癌(PC-3)具有显著的抑制活性，并且优于阳性对照M-M-4076；另外，化合物I对正常肝细胞L02细胞毒性较小，表明该化合物具有较小的毒副作用。
表3待测化合物在血液癌症中的抗细胞增殖活性测试结果(IC50μM)
| 名称 | CRO-AP2 | MV-4-11 | K562 | MOLT-3 | Hs 445 | MJ | MEC-1 |
| I | 0.13 | 1.00 | 1.32 | 0.13 | 0.17 | 0.18 | 0.25 |
| M-4076 | 0.60 | 4.20 | 5.40 | 0.57 | 0.62 | 0.76 | 0.73 |
如表3所示，化合物I对多种血液肿瘤细胞，包括B-细胞淋巴瘤(CRO-AP2)、T细胞淋巴瘤(MJ)、霍奇金淋巴瘤(Hs 445)、急性髓性白血病(MV-4-11)、慢性髓性白血病(K562)、慢性B细胞白血病(MEC-1)具有显著的抑制活性，并且优于阳性对照M-4076。
实施例4：待测化合物药代动力学性质检测
选用雄性SD大鼠，口服(10mg/kg)或静脉注射(2mg/kg)给药，于给药后5min，15min，30min，1h，2h，4h，8h，10h，24h，从眼底静脉丛连续取血置于含有肝素的EP管中，离心、取上层血浆进行LC-MS/MS分析，根据测试所得的血药浓度-时间数据，采用WinNonlin软件计算药代动力学参数，计算口服生物利用度。
研究结果表明，M-4076口服生物利用度42％，半衰期为1h，半衰期较短；而化合物I口服生物利用提高至85％，半衰期延长至3h。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，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 (8)
1.一种如式I所示的喹啉并咪唑酮联氘代吡唑类化合物，或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，其结构如下：
2.一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的如权利要求1所述的如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物，及药学上可接受的载体或辅料。
3.一种如权利要求1所述的如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物、或如权利要求2所述的药物组合物在制备ATM激酶抑制剂中的应用。
4.一种如权利要求1所述的如式I所示化合物、或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物、或如权利要求2所述的药物组合物在制备用于治疗和/或预防癌症的药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述的癌症选自血液癌症和实体瘤。
6.根据权利要求5所述的应用，其特征在于，所述的血液癌症包括单核细胞性白血病、急性髓性白血病、慢性髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤。
7.根据权利要求5所述的应用，其特征在于，所述的实体瘤选自肺腺癌、小细胞肺癌、胰腺癌、成胶质细胞瘤、肠癌和乳腺癌。
8.根据权利要求4所述的应用，其特征在于，所述的癌症为与ATM激酶酶活性异常相关的癌症。
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| CN113614083A (zh) * | 2019-03-27 | 2021-11-05 | 默克专利股份公司 | 咪唑酮基喹啉化合物及其治疗用途 |
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