CN116496267B - Cdk9抑制剂及其制备方法和用途 - Google Patents
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
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- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种式(I)所示的化合物或药学上可接受的盐及其制备方法、其用途及包含该化合物的药物组合物,式中,R为氢或‑C 1‑4烷基‑OH,该化合物具有明显的癌细胞生长抑制活性。
Description
技术领域
本发明涉及一类作为CDK9抑制剂的式(I)所示化合物或其药学上可接受的盐、及其制备方法和用途。
背景技术
真核细胞的增殖分裂是一个精确而复杂的调控过程。增殖过程是通过细胞周期来完成的,细胞周期的有序进行是通过其严格的分子调控机制。目前已发现主要有三大类分子参与细胞周期调控:细胞周期蛋白依赖性激酶(cyclin-dependent kinases,CDK)、细胞周期蛋白(cyclins)、细胞周期蛋白依赖性激酶抑制剂(cyclin-dependent kinaseinhibitors,CKI),其中CDK处于中心地位。CDK家族已发现13个成员(CDK1-CDK13),按其胞内功能不同分为两类:控制细胞周期的CDK和控制细胞转录的CDK。CDK9属于丝氨酸类激酶,它与对应细胞周期蛋白(cyclin)结合形成的复合物称为正性转录延长因子b(P-TEFb),该复合物能够磷酸化RNA聚合酶Ⅱ(RNApolymeraseⅡ)和一些负性转录延长因子(NELF和N-rdTEF)从而使转录从起始部位得以延伸,是转录得以延长的核心分子(Sims RJ 3 等GenesDev,2004,18:2437-68;Yamaguchi Y等Mol Cell Biol,2002,22:2918-27)。研究发现CDK9的表达水平或(和)激酶活性的异常会引起细胞内多种蛋白表达或(和)其mRNA水平异常。其中已经证实且与肿瘤密切相关的就有抗凋亡蛋白如Bcl-2、细胞周期相关调节蛋白如cyclin D1、p53途径相关蛋白、NF-κB途径的某些蛋白和以及与肿瘤微环境有关的蛋白如VEGF等。可以说CDK9是肿瘤发生发展过程中最关键分子之一(Shapiro GI.J Clin Oncol,2006,24:1770-83)。
CN201710257652.7公开了一种对于CDK9激酶具备抑制活性的化合物,但仅公开了化合物1、14对于CDK9激酶的抑制活性,且未涉及对化合物的代谢稳定性的研究。
仍需要具有CDK9抑制活性,可用于CDK9介导的癌症疾病且具有足够代谢稳定性的化合物。
发明内容
有鉴于此,本发明提供一种具有癌细胞生长抑制活性的新化合物。
本发明的一方面,提供一种式(I)化合物或其药学上可接受的盐,
(I)
式中,R为氢或-C1-4烷基-OH;
在一实施方式中,所述化合物选自
或
。
本发明的另一方面,提供上述化合物的制备方法,其选自以下合成路线:
合成路线一:
式(e)化合物与式(f)化合物发生取代反应、脱去Boc保护基团得到式(g)化合物,
式(g)化合物在三溴化硼作用下脱甲基得到式(IA)化合物;
其中,R1为二价C1-4烷基;
。
合成路线二:
式(e)化合物与式(f)化合物在三乙胺存在下反应得到式(h)化合物;
式(h)化合物与式(i)化合物发生取代反应得到式(IB)化合物。
。
在一实施方式中,所述式(e)化合物通过包括以下步骤的方法制备得到:
式(a)化合物与式(b)化合物发生缩合反应得到式(c)化合物;
式(c)化合物与式(d)化合物偶联得到式(e)化合物;
。
本发明的另一方面,提供一种药物组合物,其包括前述化合物或其药学可接受的盐。
进一步地,所述药物组合物还包括至少一种药学上可接受的载体。
在一实施方式中,所述药物组合物进一步包含一种或多种其它的用于治疗癌症的药物。
所述其它的用于治疗癌症的药物可以为其它用于治疗白血病或淋巴瘤的药物,例如可以为BTK抑制剂或BCL-2抑制剂。
在一实施方式中,所述其它的用于治疗癌症的药物包括选自依鲁替尼(Ibrutinib)、泽布替尼(Zanubrutinib)、司培替尼(Spebrutinib, AVL-292)、奥莫替尼(Olmutinib, HM-71224)、阿卡替尼(Acalabrutinib)、CNX-774、CGI1746、LFM-A13、CNX-774、ONO-4059、RN486、Navitoclax (ABT-263)、Venetoclax (ABT-199)、Pelcitoclax(APG-1252)、A-1155463、A-1331852、ABT-737、Obatoclax、S44563、TW-37、AT101、HA14-1和Sabutoclax中的一种或多种。
本发明的另一方面,提供前述化合物或其药学可接受的盐或药物组合物在制备预防和/或治疗与CDK9激酶活性相关的疾病或病症的药物中的用途。
在一实施方式中,所述疾病或病症选自癌症。
本发明的另一方面,提供前述化合物或其药学可接受的盐或药物组合物在制备预防和/或治疗癌症的药物中的用途。
在一实施方式中,所述癌症选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、前列腺癌、膀胱癌、肝癌、皮肤癌、神经胶质瘤、乳腺癌、黑色素瘤、恶性胶质瘤、横纹肌肉瘤、卵巢癌、星形细胞瘤、尤因氏肉瘤、成视网膜细胞瘤、上皮细胞癌、结肠癌、肾癌、胃肠间质瘤、白血病、组织细胞性淋巴癌或鼻咽癌。
在一实施方式中,所述癌症为白血病。
本发明的另一方面,提供一种治疗癌症的方法,其包括向有需要的受试者施用治疗有效量的前述的化合物或其药学上可接受的盐,或施用前述的药物组合物的步骤。
在一实施方案中,所述癌症选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、前列腺癌、膀胱癌、肝癌、皮肤癌、神经胶质瘤、乳腺癌、黑色素瘤、恶性胶质瘤、横纹肌肉瘤、卵巢癌、星形细胞瘤、尤因氏肉瘤、成视网膜细胞瘤、上皮细胞癌、结肠癌、肾癌、胃肠间质瘤、白血病、组织细胞性淋巴癌或鼻咽癌。
在一实施方案中,所述癌症为白血病。
本发明的有益效果:
1. 本发明提供一种新的用于癌症的杂环化合物,具有明显的癌细胞抑制活性;
2. 本发明提供的式(I)所代表的化合物,具有令人惊奇的较长的代谢半衰期和较低的肝微粒体固有清除率,预期具有较佳的成药性。
具体实施方式
I.定义
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
如本文使用的和除非另作说明,术语“包含”,“包括”,“具有”,“含有”,包括其语法上的等同形式,通常应当理解为开放式且非限制性的,例如,不排除其他未列举的要素或步骤。
如本文所用,术语“抑制”的使用是相对于对照的。本领域技术人员将容易地确定用于每个实验的适当对照。例如,将用化合物处理的受试者或细胞中的降低了的反应与未用化合物处理的受试者或细胞中的反应进行比较。本发明中所有范围的公开应当视为对范围内所有子范围和所有点值的公开。
如本文所用,“烷基”是指脂肪族烃基团,可以是支链或直链的烷基。在本发明中,C1-4烷基优选是具有1-4个碳原子的“低级烷基”,甚至更优选具有1-3个碳原子的“低级烷基”。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于:(1)酸加成盐,通过将化合物的游离碱形式与药学可接受的无机酸反应形成,所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等;或与有机酸反应形成,所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等;(2)碱加成盐,其在母体化合物中的酸性质子被金属离子置换时形成,例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子;或与有机碱配位。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺,等等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息,可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005),该文献的内容通过引用的方式并入本文。
针对药物或药理学活性剂而言,术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“受试者”是指动物,特别是哺乳动物,优选人。
本申请还提供药物组合物,其包含至少一种式(I)的化合物或所述化合物的药学可接受的盐,以及药学可接受的载体,以及任选的其它治疗癌症的药物。
在治疗过程中,可以根据情况单独或与一种或多种其它治疗癌症的药物组合使用。可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。
在本发明的实施方式中,在根据本发明对患者进行治疗时,给定药物的量取决于诸多因素,如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重),但是,根据特定的周围情况,包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主,施用剂量可由本领域已知的方法常规决定。通常,就成人治疗使用的剂量而言,施用剂量典型地在0.02-5000mg/天,例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量,例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是,尽管给出了上述剂量范围,但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
式(I)化合物或其药学可接受的盐或者包含其的药物组合物可以用于抑制细胞周期蛋白依赖性激酶(cyclin-dependentkinases,CDK)、细胞周期蛋白(cyclins)的活性尤其是CDK9的活性。
II. 实施例
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合,可以合成式(I)的化合物。另外,本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导,也可以利用以下的合成方法。
所述反应可以按顺序使用,以提供本文描述的化合物;或它们可以用于合成片段,所述片段通过本文描述的方法和/或本领域已知的方法随后加入。在某些实施方式中,本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法,通过使用适当的可选择的起始原料,合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应,并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改,以引入本文提供的分子中的各种部分。
如果需要,反应产物可以使用常规技术分离和纯化,包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征,包括物理常数和图谱数据。
以下具体的非限制性实施例将被解释为仅仅是说明性的,并不以任何方式限制本发明。虽然无需进一步详细描述,但是可以相信本领域技术人员能基于本文的描述,完全利用本发明。
实施例1 化合物Z1的合成
步骤一:向100 mL圆底烧瓶中加入化合物1-1(2.8 g,10 mmol,1.0 eq)、化合物1-2(2.123 g,15 mmol,1.5 eq)、三苯基膦(3.93 g,15 mmol,1.5 eq)和四氢呋喃(60 mL),搅拌溶清。冷却至0oC,滴加偶氮二甲酸二异丙酯(3 mL,15 mmol,1.5 eq),滴完升温至搅拌10min,再升温至40oC搅拌过夜。反应液浓缩,经硅胶柱层析纯化(乙酸乙酯/石油醚=1/16),得到白色固体1-3(3.015 g),收率75%。ES-API:[M+Na]+=423.9。
步骤二:氮气保护下,向100 mL圆底烧瓶中加入化合物1-3(475 mg,1.18 mmol,1.0 eq)、化合物1-4(1.22 g,4.72 mmol,4.0 eq)、碳酸钠(315 mg,2.95 mmol,2.5 eq)、PdCl2(dppf).CH2Cl2(CAS: 95464-05-4,97 mg,0.118 mmol,0.1 eq)、DME(30 mL)和水(6mL),升温至80oC,搅拌2 h。冷却至室温,加入水(30 mL),用乙酸乙酯(15 mL x 3)萃取3次,合并有机相,饱和食盐水(15 mL x 3)洗3次,有机相用无水硫酸钠干燥,过滤浓缩,经硅胶柱层析纯化(乙酸乙酯/石油醚=1/20 – 1/15),得到白色固体1-5(369 mg),收率69%。ES-API:[M+H]+=453.0。
步骤三:向100 mL圆底烧瓶中加入化合物1-5(1 g,2.208 mmol,1.0 eq)、化合物1-6(5 g,26.838 mmol,12.1 eq)、二甲基亚砜(10 mL),氮气保护下升温至95oC,搅拌48 h。冷却至室温,加入二氯甲烷(50 mL),水洗一次(50 mL),再用0.5 M 盐酸(50 mL)洗一次。调节水相pH至9-10,用二氯甲烷(50 mL x 2)萃取2次。合并有机相用无水硫酸钠干燥,过滤浓缩,经硅胶柱层析纯化(甲醇/二氯甲烷=0 – 5%),得到黄色固体1-7(815 mg),收率71%。ES-API:[M+H]+=519.2。
步骤四:向100 mL圆底烧瓶中加入化合物1-7(220 mg,0.423 mmol,1.0 eq)、二氯甲烷(10 mL),冷却至-5-0oC。滴加三溴化硼(0.4mL,4 mmol,9.5 eq),搅拌3 h。-20oC下,将反应液滴加至甲醇(20 mL)中进行淬灭,用饱和碳酸氢钠溶液调节至pH >9,二氯甲烷萃取,有机相浓缩后用制备HPLC(Xbridge C18 19*150mm 10μm, ACN:H2O (0.1% NH4HCO3))纯化,得到白色固体(化合物Z1, 61.7 mg),收率23.4%。ES-API:[M+H]+=505.1。1H NMR(DMSO-d6, 400 MHz)δ 8.08-8.05(t, J = 6.4 Hz, 1H), 7.94(s, 1 H),7.31(s, 1H),6.99(s,1H),6.61-6.59(d, J = 7.6 Hz, 1H),4.40(brs, 1H),3.91-3.87(m, 2H),3.64-3.62(d,J = 6.0 Hz, 2H),3.56(m, 1H),3.47-3.41(t, J = 6.8 Hz, 2H),3.17(m, 2H),2.71(m,1H),2.43(m, 1H),1.92-1.79(m, 6H),1.70-1.62(m, 2H),1.23-0.92(m, 5H),0.87(d, J= 6.4 Hz, 3H).
实施例2 化合物Z2的合成
步骤一:向100 mL圆底烧瓶中加入化合物1-5(9 g,19.87 mmol,1.0 eq)、化合物1-6(11.09 g,59.61 mmol,3 eq)、三乙胺(6.02 g,59.61 mmol,3 eq)、二甲基亚砜(85mL),氮气保护下升温至105-110oC,搅拌24 h。冷却至室温,加入水(250 mL),乙酸乙酯(100mL x 3)萃取3次,有机相用饱和食盐水(100 mL x 3)洗3次。合并有机相用无水硫酸钠干燥,过滤浓缩,柱层析纯化(甲醇/二氯甲烷=1/30 – 1/20),得到粗品化合物2-1(7.65 g)。ES-API:[M+H]+=353.1。
步骤二:向100 mL圆底烧瓶中加入化合物2-1(1 g,2.834 mmol,1.0 eq)、化合物2-2(1.943 g,17 mmol,6 eq)、二甲基亚砜(6 mL),升温至110oC,搅拌过夜。冷却至室温,加入乙酸乙酯(20 mL),用水(20 mL x 2)、饱和食盐水(20 mL x 2)各洗2次。有机相用无水硫酸钠干燥,过滤浓缩,经硅胶柱层析纯化(甲醇/二氯甲烷=1/15 – 1/8),得到白色固体(750mg, 粗品)。取220 mg该粗品经制备HPLC(Xbridge C18 19*150mm 10μm, ACN:H2O (0.1%NH4HCO3))纯化得到白色固体(化合物Z2, 136.5 mg)。ES-API:[M+H]+=353.1。1H NMR(DMSO-d6, 400 MHz)δ 8.07(brs, 1H), 7.94(s, 1 H),7.31(s, 1H),6.98(s, 1H),6.62-6.59(d, J = 8.4 Hz, 1H),3.92-3.87(m, 2H),3.63(s, 2H),3.54(m, 1H),3.47-3.41(t, J =12 Hz, 2H),2.53-2.46(m, 1H),1.89-1.63(m, 8H),1.21-1.02(m, 4H).
测试例1:化合物对癌细胞MV-4-11生长的影响
选用急性髓系白血病细胞株MV-4-11(购自ATCC)。收集细胞,用新鲜完全培养基重悬,细胞计数后,按照5000/孔的密度接种到96孔板中,放入37℃,5% CO2培养箱中培养过夜。第二天将化合物加入对应细胞孔中,化合物终浓度为10 μM、3 μM、1 μM、0.3 μM、0.1 μM、0.03 μM、0.01 μM、0.001 μM和0.0001 μM,同时设置细胞加0.1% DMSO的对照组,放入37℃,5% CO2培养箱中继续培养24小时。用Cell Titer-Glo化学自发光法细胞活力检测试剂盒,通过对活细胞中的ATP进行定量测定来检测活细胞数目,基于此结果结合GraphPadPrism 6软件绘制药效抑制率曲线计算IC50,结果如下表1所示。
表1
注:对照化合物A公布于国际申请专利WO2018192273A1 实施例1中。
对照化合物A:
测试例2:小鼠、犬、猴和人肝代谢稳定性
试剂和仪器:
KH2PO4(A600445-0500, 上海生工),K2HPO4·3H2O (A501728-0500, 上海生工),NADPH (C103029, 阿拉丁),甲醇 (01162578, Fisher),乙腈 (01162577, Fisher),二甲基亚砜 (472301, sigmaaldrich)。
肝微粒体样品:
表2
实验过程:
1. 配制内标和对照化合物储备液
睾酮(A81277, innochem),双氯芬酸(D6899, sigma-aldrich)和普罗帕酮(propafenone) (101190, 中检所)作为对照化合物。甲苯磺丁脲 (T1705, TMstandard)作为LC-MS/MS检测的内标。均用DMSO配置成10 mM的储备液,储存在-20℃冰箱。
2.配制 100 mM 磷酸缓冲液(100 mM PB )
称取1.35g KH2PO4和9.15g K2HPO4·3H2O 加入500 mL纯水溶解。pH 用稀盐酸或者1M的氢氧化钾调整到7.40 ± 0.10即可。
3.配制NADPH溶液或NADPH再生反应体系
称取一定量的NADPH粉末,用100 mM PB溶液配成6 mM使用。配制计算方式可根据6.67 mg溶于1 mL 100 mM PB溶液可得换算成6 mM的浓度。
表3
4. 工作液的配制
表4
5. 实验过程
(1)取出分装好冻存于-80℃冰箱的肝微粒体,置于湿冰上解冻备用。
(2)取一块96孔浅孔板作为化合物板,取5 µL的对照化合物/供试品分别加到含195 µL的纯乙腈的孔中,混合均匀,作为工作溶液A(对照化合物/供试品浓度250 µM);
(3)取一块96孔深孔板作为样品板,用肝微粒体(0.75 mg/mL)稀释工作溶液A为1.5μM,如:取2.4 µL工作溶液A与397.6 µL肝微粒体(0.75 mg/mL)混合均匀,得到对照化合物或供试品和肝微粒体混合液;
(4)取5块96孔深孔板作为孵育板,分别命名为T0,T5,T15,T30,T60,对应的孵育时间为0,5,15,30和60min。将混合液分别分装到对应的板中,每孔体积30 µL,n=2。
(5)将配制好的NADPH溶液和T5,T15,T30,T60共同置于37℃水浴锅预热5 min。预热结束后,取NADPH溶液分别加15 µL至T5,T15,T30,T60板中,轻轻晃动使其混匀,再放入37℃水浴锅孵育相应的时间。
(6)T0板,先加入200µL含有内标的乙腈,再加入15 µL的NADPH溶液,封口膜封上,置于摇板仪上振摇10min(800rpm/min)。
(7)最终反应体系中组分的浓度
表5
(8)孵育5,15,30和60 min后,分别加200 µL含内标的乙腈终止反应,用封口膜封板后置于摇板仪上振摇10 min(800 rpm/min)。摇板结束后,再放入离心机内离心15 min(4000 rpm, 20℃)。
(9)离心结束后,所有样品用 LC-MS/MS进行分析,进样体积可根据信号而定,一般进样2μL。
6. 数据分析
通过以下公式中化合物与内标峰面积的比值转化成剩余百分比求得供试品和对照品的体外消除速率常数ke:
注:
ke: 消除速率常数
T1/2:半衰期;
CLint (mic):肝微粒体固有清除率;
CLint (liver):肝脏固有清除率;
公式中参数见表6
表6
7. 实验结论
化合物体外小鼠、犬、猴和人代谢稳定性测试结果见表7。
T1/2是指体外肝微粒体孵育系统里面原型药物浓度下降到初始浓度1/2时需要的时间。根据微粒体体系孵育条件以及原型药物在里面的稳定性数据可以计算出CLint(liver),CLint(liver)是指测试物在肝的清除率,即药物在肝中的清除速度。这两个参数具有相关性。一般来说,T1/2越长,则CLint(liver)越低,表明药物的代谢率越低,药物在体内滞留时间越长,发挥的药效时间越长,药效也越稳定和长久。因此,通过增加T1/2或者减少CLint(liver)有利于有效地控制和治疗患者的疾病。另外,提升T1/2,减少CLint(liver)还可能在药效不改变的情况,减少给药频次从而提高患者的依从性或者在不改变药效的情况下,通过降低剂量减少毒副作用。
表7
如表1及表7中所显示,实施例化合物Z1和Z2在小鼠、犬、猴和人中的肝脏固有清除率及代谢稳定性方面均显示明显优于对照化合物A的效果。
特别地,本发明的实施例化合物Z1、Z2具有低于0.05µM的白血病细胞生长抑制IC50值,与对照化合物A相当;但是,化合物Z1、Z2在人体中的代谢半衰期却可分别达到218.95min和2449.06min,相比之下,对照化合物A在人体中的代谢半衰期仅为约64分钟;并且,化合物Z1、Z2在人肝微粒体中的固有清除率分别为7.32和0.65,相较于对照化合物A在人肝微粒体中的固有清除率(24.88)明显降低,表明化合物Z1、Z2具有更好的肝代谢稳定性。
将本发明化合物(实施例化合物Z1、Z2)与对照化合物A相比较,本发明的化合物具有癌细胞生长抑制活性及优于对照化合物A的药动学性质,例如肝代谢稳定性和半衰期。相较于对照化合物A,可以实现减少给药频次从而提高患者的依从性;或者在不改变药效的情况下,通过降低剂量减少毒副作用,提高用药安全性。可见,化合物Z1、Z2是更适宜临床应用的、可成药化合物。
Claims (6)
1.以下化合物或其药学上可接受的盐,
。
2.一种药物组合物,其包括权利要求1所述的化合物或其药学可接受的盐。
3.根据权利要求2所述的药物组合物,其进一步包含一种或多种其它的用于治疗癌症的药物。
4.根据权利要求3所述的药物组合物,所述其它的用于治疗癌症的药物为用于治疗白血病或淋巴瘤的药物。
5.根据权利要求3所述的药物组合物,所述其它的用于治疗癌症的药物为BTK抑制剂或BCL-2抑制剂。
6.根据权利要求1所述的化合物或其药学可接受的盐或权利要求2-5任一项所述的药物组合物在制备预防和/或治疗白血病的药物中的用途。
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