CN112424205B - 选择性的雌激素受体降解剂 - Google Patents
选择性的雌激素受体降解剂 Download PDFInfo
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- CN112424205B CN112424205B CN201980046170.4A CN201980046170A CN112424205B CN 112424205 B CN112424205 B CN 112424205B CN 201980046170 A CN201980046170 A CN 201980046170A CN 112424205 B CN112424205 B CN 112424205B
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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Abstract
提供了根据下式的新颖的选择性的雌激素受体降解剂(SERD)、其药学上可接受的盐、药物组合物、用途和使用方法:
Description
背景
选择性的雌激素受体降解剂(SERD)结合雌激素受体(ER)并下调ER介导的转录活性。由SERD引起的这种降解和下调可用于治疗细胞增殖障碍诸如癌症。SERD的一些小分子实例已在文献(参见,例如,WO2005073204、WO2014205136和WO2016097071)中公开。但是,已知的SERD尚未像有效治疗癌症所需的那样有用。例如,具有更好的药代动力学(PK)和药效动力学(PD)特性、更高的临床效率以及良好的口服生物利用度的SERD的发现对治疗癌症非常有帮助。具有ER介导的转录的有效抑制的纯拮抗剂SERD在治疗癌症中将特别有益。需要新的SERD来治疗癌症诸如乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌和肺癌以及由新出现的抗性引起的突变。特别是需要新的SERD来治疗ER阳性的乳腺癌、胃癌和/或肺癌。
概述
本文提供了下式的化合物:
及其药学上可接受的盐和其药物组合物。
还提供了使用本文所述的化合物、其药学上可接受的盐及其药物组合物来治疗乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌或肺癌的方法。所述方法包括向有需要的患者施用治疗有效量的本文所述的化合物或其药学上可接受的盐。
还提供了用于治疗的本文所述的化合物及其药学上可接受的盐。本文所述的化合物、及其药学上可接受的盐可用于治疗乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌或肺癌。
还提供了本文所述的化合物及其药学上可接受的盐用于制备药物的用途,所述药物用于治疗乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌或肺癌。
描述
本文中公开了充当SERD的新颖四环化合物及其药用盐。SERD可以作为单一药剂使用,或与其它类别的药物组合使用,以治疗激素受体-阳性的乳腺癌,所述其它类别的药物包括选择性雌激素受体调节剂(SERM)、芳香酶抑制剂、CDK4抑制剂、CDK6抑制剂、PI3K抑制剂和mTOR抑制剂。
本文描述的新颖的化合物是下式的化合物:
。
还描述了所述化合物的药学上可接受的盐。所述化合物可以使用IUPAC命名法命名为(4-{2-[3-(氟甲基)氮杂环丁烷-1-基]乙氧基}苯基){3-[2-氟-4-(三氟甲基)苯基]-7-羟基喹啉-4-基}甲酮。
本文还描述了药物组合物,其包括本文所述的化合物或其药学上可接受的盐以及药学上可接受的赋形剂、载体或稀释剂。使用药学上可接受的添加剂可以制备本文描述的药物组合物。本文中使用的术语“药学上可接受的添加剂”表示与组合物或制剂的其它添加剂相容且对患者无害的一种或多种载体、稀释剂和赋形剂。本文描述的化合物或其药学上可接受的盐可以配制为通过多种途径(诸如口服或静脉内)施用的药物组合物。生物利用度经常是癌症治疗中的一个因素,且调整施用方法和药物组合物以控制或优化活性成分的生物利用度的能力是有用的。口服地可生物利用的SERD组合物将特别有用。如本文中所述的化合物或其药学上可接受的盐被认为具有口服生物利用度。药物组合物及其制备方法的例子可见于“Remington: The Science and Practice of Pharmacy”, L. V. Allen Jr, 编辑,第22版, Mack Publishing Co., 2012。药学上可接受的载体、稀释剂和赋形剂的非限制性例子包括以下:盐水、水、淀粉、糖、甘露醇和二氧化硅(silica)衍生物;粘合剂诸如羧甲基纤维素和其它纤维素衍生物、海藻酸盐、明胶和聚乙烯基-吡咯烷酮;高岭土和皂粘土;聚乙二醇类。
本文进一步描述了治疗癌症的方法。本文所述的方法包括向需要这种治疗的患者施用有效量的本文所述的化合物或其药学上可接受的盐。例如,施用有效量的本文所述的化合物或其药学上可接受的盐的方法可以是口服施用。所述癌症可以是雌激素响应性癌症。另外,所述癌症可以是乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌或肺癌。例如,所述癌症可以是ER阳性的乳腺癌、ER阳性的胃癌或ER阳性的肺癌。
本文还描述了用于治疗中的本文所述的化合物或其药学上可接受的盐。本文所述的化合物或本文所述的其药学上可接受的盐可以用于治疗乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌或肺癌。具体地,所述癌症可以是ER阳性的乳腺癌、ER阳性的胃癌或ER阳性的肺癌。例如,可以口服施用所述化合物或其药学上可接受的盐。
另外,对于本文所述的化合物或其药学上可接受的盐,可用于制备用于治疗癌症的药物。例如,可以口服施用所述药物。本文所述的药物可用于治疗的癌症的类型包括乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌或肺癌。特别地,所述癌症可以是ER阳性的乳腺癌、ER阳性的胃癌或ER阳性的肺癌。
本文所述的化合物、及其药学上可接受的盐可以作为单一药剂或与其它抗癌剂联合具有临床实用性,用于治疗癌症诸如乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、子宫癌、胃癌和肺癌。当与其它抗癌剂联合使用时,本文所述的化合物或其药学上可接受的盐可以与其它抗癌剂同时、依次或分开使用。可以与本文所述的化合物组合的其它抗癌剂的一个例子是5-(4-{2-[3-(氟甲基)氮杂环丁烷-1-基]乙氧基}苯基)-8-(三氟甲基)-5H-[1]苯并吡喃并[4,3-c]喹啉-2-醇。
本文中使用的术语“有效量”表示本文所述的化合物或其药学上可接受的盐的量或剂量:其在向患者单次或多次施用后,在诊断或治疗的患者中提供期望的效果。优选地,期望的效果是肿瘤细胞增殖的抑制、肿瘤细胞死亡或两者。本文所述的化合物或本文所述的其药学上可接受的盐通常在宽剂量范围内是有效的。例如,每天的剂量通常落在约100mg至约2000 mg的每日范围内。
本文中使用的“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”表示抑制、减慢、停止或逆转现有症状或障碍的进展或严重程度。
本文中使用的术语“患者”表示罹患特定疾病、障碍或病症的人。
本文所述的化合物或本文所述的其药学上可接受的盐可以通过本领域已知的多种程序来制备,其中一些在下文的制备例和实施例中进行了说明。所描述的每种途径的具体合成步骤可以以不同的方式结合,或者与来自不同程序的步骤结合,以制备本文所述的化合物或其药学上可接受的盐。可以通过本领域众所周知的常规方法回收产物,所述方法包括萃取、蒸发、沉淀、色谱法、过滤、研磨和结晶。试剂和起始原料是本领域普通技术人员容易得到的。
在一个任选的步骤中,通过在合适的溶剂中在标准条件下使本发明的适当游离碱与适当的药学上可接受的酸反应,可以形成本文所述的化合物的药学上可接受的盐。另外,在氮保护基去保护时,这些盐的形成可以同时发生。药学上可接受的盐的可能形成是众所周知的。参见,例如,Gould, P.L., “Salt selection for basic drugs,”International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., 等人. “SaltSelection and Optimization Procedures for Pharmaceutical New ChemicalEntities,”Organic Process Research and Development, 4: 427-435 (2000);和Berge, S.M., 等人, “Pharmaceutical Salts,”Journal of Pharmaceutical Sciences,66: 1-19, (1977)。本领域普通技术人员会明白,本文所述的化合物容易转化成且可以分离为药学上可接受的盐。
除非特别指出,否则本文中使用的缩写根据Aldrichimica Acta, 第17卷, 第1期, 1984或本领域技术人员的普遍接受的含义进行定义。其它缩写如下定义:“AUC”表示曲线下面积;“BSA”表示牛血清白蛋白;“DCM”表示二氯甲烷(dichloromethane或methylenechloride);“DMA”表示二甲胺;“DMEM”表示Dulbecco氏改良的伊格尔培养基;“DMF”表示N,N-二甲基甲酰胺;“DMSO”表示二甲亚砜;“DNA”表示脱氧核糖核酸;“cDNA”表示互补DNA;“DNA酶”表示脱氧核糖核酸酶;“DTT”表示二硫苏糖醇;“EC50”表示与预定义的阳性对照化合物相比产生靶活性的50%应答的试剂浓度(绝对EC50);“EDTA”表示乙二胺四乙酸;“ERα”表示雌激素受体α;“EtOAc”表示乙酸乙酯;“EtOH”表示乙醇;“FBS”表示胎牛血清;“HBSS”表示汉克平衡盐溶液;“HEPES”表示4-(2-羟基乙基)-1-哌嗪乙磺酸;“IC50”表示产生该试剂的可能最大抑制性应答的50%的试剂浓度(相对IC50),或与安慰剂对照相比产生靶酶活性的50%抑制的试剂浓度(绝对IC50);“iPrOH”表示异丙醇(isopropanol或isopropyl alcohol);“IV”表示静脉内施用;“Ki”表示抑制常数;“MeOH”表示甲醇(methyl alcohol或methanol);“MTBE”表示甲基叔丁基醚;“PBS”表示磷酸盐缓冲盐水;“PO”表示口服施用;“PRα”表示黄体酮受体α;“QD”表示每天1次定量施用;“RNA”表示核糖核酸;“RNA酶”表示核糖核酸酶;“RT-PCR”表示反转录聚合酶链式反应;“RT-qPCR”表示反转录定量聚合酶链式反应;“THF”表示四氢呋喃;和“XPhos Pd G2”表示氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]钯(II)。
以下制备例和实施例进一步例证本发明。
制备例和实施例
制备例1
2-[3-(氟甲基)氮杂环丁烷-1-基]乙烷-1-醇
在N2下在15分钟的时间段内将三乙酰氧基硼氢化钠(405 g, 1.91 mol)逐份加入搅拌的3-(氟甲基)氮杂环丁烷盐酸盐(160 g, 1.28 mol)在DCM (2.4 L)中的0℃溶液中,并在0℃搅拌10分钟。在1小时的时间段内在0℃加入分成6份的1,4-二氧杂环己烷-2,5-二醇(99 g, 0.83 mol),然后在0-5℃搅拌15分钟。使反应物温热至室温并在N2下搅拌2小时。在20分钟的时间段内将反应物冷却至10-15℃。在10-15℃在25-30分钟的时间段内加入水(800 mL),温热至室温保持5-10分钟,并然后分离各层。用DCM (800 mL)洗涤水层,分离各层,然后将合并的水层冷却至10-15℃并使用50%氢氧化钠溶液(~540 mL)调节pH至13-14。使水层温热至室温,用DCM (4 X 800 mL)萃取,用硫酸钠(80 g)干燥,过滤,并浓缩至干燥以得到标题化合物。该制备以后得到139 g (82%)作为稠黄色油的标题化合物,具有134.1(M+H)的ES/MS (m/z)。
制备例2
2-[3-(氟甲基)氮杂环丁烷-1-基]乙烷-1-醇盐酸盐
将2-[3-(氟甲基)氮杂环丁烷-1-基]乙烷-1-醇(529 g, 4 mol)溶解在MTBE (2.6L)中并冷却至0℃。历时30分钟逐滴加入HCl/EtOH溶液(492 mL, 30重量%),然后在0℃搅拌30分钟。过滤固体并将滤饼用MTBE (2 X 200 mL)洗涤。在N2下干燥8小时以得到标题化合物。该制备以后得到580 g (86%)作为白色固体的标题化合物,具有134.0 (M+H)的ES/MS(m/z)。
制备例3
(3-氯-7-甲氧基喹啉-4-基)-(4-氟苯基)甲酮
在N2下将4-溴-3-氯-7-甲氧基喹啉(70 g, 254 mmol)和THF (1 L)的混合物冷却至-40℃,得到物质的沉淀。历时20分钟加入异丙基氯化镁(2 M的在THF中的溶液,254 mL,509 mmol)并将混合物搅拌1小时。逐滴加入4-氟苯甲酰氯(66 mL, 559 mmol)在THF (140mL)中的溶液,然后将其温热至室温。用饱和氯化铵溶液(300 mL)和水(200 mL)淬灭反应,并分离各层。将有机层用饱和氯化铵溶液(300 mL)洗涤,经MgSO4干燥,过滤,并浓缩以得到油状残余物。将粗制的棕色油穿过硅胶过滤,用MTBE/己烷(1:1)的混合物洗脱,以得到作为黄色固体的粗产物(84 g)。将固体用10%乙酸甲酯/庚烷(800 mL)处理并在室温搅拌过夜。过滤以收集固体并保存。浓缩滤液并在二氧化硅(silica)上纯化,用10-40%EtOAc/己烷类洗脱,然后将产物用10%乙酸甲酯/庚烷(200 mL)处理并在室温搅拌3小时。过滤得到的固体,与来自前一次过滤的固体合并,并在真空下干燥过夜以得到标题化合物。该制备以后得到31 g (38%)作为黄色固体的标题化合物,具有316.0 (M+H)的ES/MS (m/z)。
制备例4
(3-氯-7-羟基喹啉-4-基)-(4-氟苯基)甲酮
将三溴化硼(1 M在DCM中,295 mL, 295 mmol)加入(3-氯-7-甲氧基喹啉-4-基)-(4-氟苯基)甲酮(31 g, 98 mmol)在DCM (217 ml)中的混合物中,并将混合物在室温搅拌3天。将混合物缓慢地倒入磷酸氢二钾(2 M在水中, 700 mL)和水(200 mL)的0℃溶液中。将混合物温热至室温并搅拌1小时。将溶液在真空中浓缩以除去有机溶剂,过滤,收集滤液并将滤液在真空下在45℃干燥过夜。将固体用DCM/庚烷(1:1, 450 mL)处理并搅拌过夜。收集固体并在真空下干燥过夜以得到标题化合物。该制备以后得到32 g (定量收率)作为浅棕色固体的标题化合物,具有302.0 (M+H)的ES/MS (m/z)。
制备例5
(3-氯-7-羟基喹啉-4-基)-(4-{2-[3-(氟甲基)氮杂环丁烷-1-基]乙氧基}苯基)甲酮
将2-[3-(氟甲基)氮杂环丁烷-1-基]乙烷-1-醇盐酸盐(3.90 g, 23.0 mmol)加入(3-氯-7-羟基喹啉-4-基)-(4-氟苯基)甲酮(5.00 g, 15.3 mmol)在DMF (75 ml)中的搅拌溶液中,随后加入氢化钠(60%在矿物油中, 3.07 g, 76.6 mmol)。在N2下搅拌并温热至40℃保持45分钟。将溶液用水淬灭并浓缩。将残余物在20%iPrOH/CHCl3和饱和碳酸氢钠水溶液之间分配并分离,将水相用2 X 20%iPrOH/CHCl3萃取,合并有机萃取物,将合并的有机层经硫酸镁干燥,过滤并浓缩滤液以得到作为暗红色油的粗产物。将粗制物质通过硅胶柱色谱法纯化,用5-10%的7 N NH3在MeOH/DCM中的梯度洗脱以得到标题化合物。该制备以后得到5.31 g (84%)作为黄色固体的标题化合物,具有415.0 (M+H)的ES/MS (m/z)。
制备例6
(4-氟苯基)-[3-[2-氟-4-(三氟甲基)苯基]-7-羟基-4-喹啉基]甲酮
将(3-氯-7-羟基-4-喹啉基)-(4-氟苯基)甲酮(140 g, 440.8 mmol)、2-氟-4-(三氟甲基)苯基硼酸(183.3 g, 881.7 mmol)、碳酸钾(184.6 g, 1.3 mol)、2-甲基-2-丁醇(1.7 L)和水(0.56 L)的混合物用5 X N2脱气/净化。加入XPhos Pd G2 (7.1 g, 8.82mmol)并在80℃加热2小时。将混合物冷却至室温并蒸发有机溶剂。加入EtOAc (1 L)和水(0.2 L)。将有机层分离并将它经硫酸镁干燥。将该物质穿过硅胶过滤并浓缩至干燥。将粗制物质与己烷类(1.25 L)和MTBE (0.25 L)的混合物一起研磨以得到固体。过滤固体并在真空下干燥。将固体溶解在THF (1.5 L)中并加入SiliaMetS®Thiol的清除剂(150 g)。将混合物在室温搅拌过夜。过滤清除剂并蒸发滤液至干燥以得到标题化合物。该制备以后得到185.5 g (96%)作为白色固体的标题化合物,具有430.0 (M+H)的ES/MS (m/z)。
实施例1
(4-{2-[3-(氟甲基)氮杂环丁烷-1-基]乙氧基}苯基){3-[2-氟-4-(三氟甲基)苯基]-7-羟基喹啉-4-基}甲酮
向配有N2入口的容器中加入THF (2.8 L)、叔丁醇钾(274.5 g, 2.45 mol)和2-(3-(氟甲基)氮杂环丁烷-1-基)乙烷-1-醇(168 g, 1.22 mol)。将混合物搅拌10分钟。逐滴加入(4-氟苯基)-[3-[2-氟-4-(三氟甲基)苯基]-7-羟基-4-喹啉基]甲酮(350 g, 0.81mol)在THF (0.7 L)中的溶液。在室温搅拌1小时。用1 N HCl淬灭反应直到pH 8并用EtOAc(4 L)稀释。分离有机层并将它用盐水(2 L)洗涤。将溶液经硫酸镁干燥,过滤溶液,并浓缩至干燥以得到标题化合物。该制备以后得到415 g (93.8%)作为淡棕色固体的标题化合物,具有543.2 (M+H)的ES/MS (m/z)。
替代实施例1
在微波小瓶中将(3-氯-7-羟基喹啉-4-基)-(4-{2-[3-(氟甲基)氮杂环丁烷-1-基]乙氧基}苯基)甲酮(200 mg, 0.48 mmol)、2-氟-4-(三氟甲基)苯基硼酸(158 mg, 0.72mmol)、碳酸钾(202 mg, 1.45 mmol)、2-甲基-2-丁醇(3 ml)和水(1 ml)的混合物用N2 x 5脱气/净化。加入XPhos Pd G2 (12 mg, 0.015 mmol),密封混合物,并在80℃微波2小时。将残余物在MTBE和饱和氯化铵溶液之间分配。分离各层并将水层用MTBE萃取。合并有机萃取物,将它们经硫酸镁干燥,过滤,并浓缩滤液以得到橙色残余物。将粗制物质通过硅胶柱色谱法纯化,用5%MeOH/DCM洗脱,以得到标题化合物。该制备以后得到205 mg (78%)作为黄色固体的标题化合物,具有543.2 (M+H)的ES/MS (m/z)。
实施例2
外消旋的5-(4-{2-[3-(氟甲基)氮杂环丁烷-1-基]乙氧基}苯基)-8-(三氟甲基)-5H-[1]苯并吡喃并[4,3-c]喹啉-2-醇
将(4-{2-[3-(氟甲基)氮杂环丁烷-1-基]乙氧基}苯基){3-[2-氟-4-(三氟甲基)苯基]-7-羟基喹啉-4-基}甲酮(5.27 g, 9.71 mmol)在1,4-二氧杂环己烷(100 mL)中的溶液冷却至5℃。加入三乙基硼氢化锂(1 M在THF中,30.0 mL, 30.0 mmol)。除去冷却浴并在室温搅拌1.5小时。用水淬灭混合物。加入饱和NH4Cl溶液和EtOAc。分离各层并将水层用EtOAc萃取。合并有机萃取物,经无水MgSO4干燥,过滤,并浓缩滤液。将粗残余物溶解在THF(100 mL)中。加入氢化钠(60%在矿物油中, 1.94 g, 48.5 mmol)。将溶液加热回流1.5小时。加入额外的氢化钠(60%在矿物油中, 1.94 g, 48.5 mmol),然后回流另外30分钟。将溶液冷却至室温并用水淬灭。加入EtOAc和饱和NH4Cl溶液。分离各层并将水层用EtOAc萃取。合并有机提取物,经无水MgSO4干燥,过滤,并浓缩滤液。将残余物通过硅胶柱色谱法纯化,用5-7%的MeOH在DCM中的梯度洗脱,以得到作为浅黄色泡沫的标题化合物(3.70 g, 72%)。ES/MS (m/z): 525.2 (M+H)。
生物学测定
雌激素受体表达与某些癌症之间的关联已有文献报道(关于乳腺癌,参见,例如,Puhalla S, Bhattacharya S, Davidson N., Hormonal therapy in breast cancer: Amodel disease for the personalization of cancer care, Molecular Oncology,2012, 6:222-236; Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D,Speers CH, Nielsen TO, Gelmon K, Metastatic behavior of breast cancersubtypes, J Clin Oncol, 2010, 28(20):3271-3277,关于卵巢癌,参见,例如,O'DonnellAJ, Macleod KG, Burns DJ, Smyth JF, Langdon SP, Estrogen receptor-alphamediates gene expression changes and growth response in ovarian cancer cellsexposed to estrogen, Endocr Relat Cancer, 2005;12(4):851–66; Walker G,MacLeod K, Williams AR, Cameron DA, Smyth JF, Langdon SP, Estrogen regulatedgene expression predicts response to endocrine therapy in patients withovarian cancer, Gynecol Oncol, 2007, 106(3):461–8; Smyth JF, Gourley C,Walker G, MacKean MJ, Stevenson A, Williams AR, 等人, Antiestrogen therapy isactive in selected ovarian cancer cases: The use of letrozole in estrogenreceptor-positive patients, Clin Cancer Res, 2007, 13(12):3617–22,关于前列腺癌,参见,例如,Bonkohoff H, Fixemer T, Hunsicker I和Remberger K, Estrogenreceptor expression in prostate cancer and premalignant prostate lesions, AmJ Pathol, 1999, 155:641-647,关于子宫内膜和子宫癌,参见,例如,Krasner C,Aromatase inhibitors in gynecologic cancer, J Steroid Biochem Mol Biol, 2007,Aug–Sep;106(1–5):76–80; Boisen MM, Andersen CL, Sreekumar S, 等人, Treatinggynecologic malignancies with selective estrogen receptor downregulators(SERDs): Promise and challenges, Mol Cell Endocrinol, 2015, 418:322–3330,关于肺癌,参见,例如,Baik CS, Eaton KD等人, Estrogen signaling in lung cancer: Anopportunity for novel therapy, Cancer, 2012, 4:969-988; Marquez-Garban DC,Chen H-W, Goodglick L, Fishbein MC和Pietras RJ, Targeting aromatase andestrogen signaling in human non-small cell lung cancer. Steroid enzymes andcancer, Ann. N. Y. Acad Sci, 2009, 1155:194-205; Hamilton DH, Griner LM,Keller JM, Hu X, Southall N, Marugan J, David JM, Ferrer M和Palena C,Targeting estrogen receptor signaling with fulvestrant enhances immune andchemotherapy mediated cytotoxicity of human lung cancer, Clin Cancer Res,2016, 22(24):6204-16; Rodriguez-Lara V, Hernandez-Martinez JM, Arrieta O,Influence of estrogen in non-small cell lung cancer and its clinicalimplications, J Thoracic Disease, 2018, 10(1):482-497,关于胃癌,参见,例如,TangW, Liu R, Yan Y, Pan X, Wang M, Han X, Ren H, 和Zhang Z, Expression ofestrogen receptors and androgen receptor and their clinical significance ingastric cancer, Oncotarget, 2017, 8(25) 40765-777)。
下述测定证实,举例说明的化合物是ERα野生型和突变蛋白的有效降解剂。测定的结果也证实,举例说明的化合物是ERα野生型和突变体受体的有效拮抗剂并抑制ER介导的转录活性。另外,所述测定证实,实施例1的化合物抑制ER+ 乳腺癌细胞系的增殖以及ERα信号传导和肿瘤生长抑制(在ER-阳性的乳腺癌异种移植物模型中)。
ERα(野生型)和ERα(Y537S突变体)竞争结合测定
以下ER竞争结合测定的目的是确定试验化合物对ERα(野生型)和ERα(Y537S突变体)的结合亲和力。参见Fanning等人, “Estrogen receptor alpha somatic mutationsY537S and D538G confer breast cancer endocrine resistance by stabilizing theactivating function-2 binding conformation,”eLife 2016;5:e12792。
使用0.025 μCi/孔的3H-雌二醇(118 Ci/mmol, 1 mCi/mL)、7.2 ng/孔的ERα(野生型)或7.2 ng/孔的ERα(Y537S突变体),在含有50 mM HEPES(pH 7.5)、1.5 mM EDTA、150mM NaCl、10%甘油、1 mg/mL卵白蛋白和5 mM DTT的缓冲液中进行竞争结合测定。以从10,000 nM至0.5 nM范围内的10种不同浓度加入试验化合物,并确定在有1 μM 17-β雌二醇存在下的非特异性结合。将结合反应物(140 μL)在室温温育4小时,并然后向每份反应物中加入冷的葡聚糖-木炭缓冲液(70 μL) (每50 mL测定缓冲液含有0.75 g木炭和0.25 g葡聚糖)。将板在定轨摇床上在4℃混合8分钟,并然后在3000 rpm在4℃离心10分钟。将混合物的等分试样(120 μL)转移至另一个96-孔白色平底板(Costar),并向每个孔中加入PerkinElmer Optiphase Supermix闪烁液(175 μL)。密封板并在定轨摇床上剧烈摇动。温育2.5小时以后,在Wallac Microbeta计数器上读出板。使用4-参数逻辑曲线拟合计算IC50,并计算在10 μM的%抑制。使用Cheng-Prusoff方程式将化合物的IC50值转化成Ki。该测定的结果证实,实施例1的化合物以3.78±0.74 (n=3)的Ki (nM)结合重组ERα野生型并以21.24±2.12(n=3)的Ki (nM)结合ERα突变体(Y537S)。
该测定的结果证实了举例说明的化合物对ERα野生型和突变体(ESR1 Y537S)蛋白的结合亲和力和效能。
在MCF7细胞中的ERα降解测定
下述ERα降解测定的目的是在ERα阳性的乳腺癌细胞系诸如MCF7中测量试验化合物对ERα的降解。
在补充了10%FBS、0.01 mg/mL人胰岛素1和1%青霉素/链霉素抗生素的DMEM培养基中培养MCF7 (购自ATCC HTB-22)细胞,并以4,000个细胞/孔的密度在含有10%木炭处理的FBS的、不含酚磺酞的DMEM培养基(20µL)中铺板在384-孔平底板中。在细胞培养箱(5%CO2,95%相对湿度和37℃)中温育细胞过夜,并使细胞附着于板。次日,给细胞施用试验化合物。使用Echo 555声学分配器制备在从6 μM至0.0003 μM范围内的试验化合物系列稀释物(1:3)。如下给细胞施用:将来自系列稀释物板的5 μL添加至细胞板,从而产生0.2%的最终DMSO浓度,最终的试验化合物浓度剂量范围是在2-0.0001 μM之间。对于最大点,使用含有0.2%的DMSO的培养基,且对于最小点,使用在含有0.2%DMSO的生长培养基中以2 μM终浓度稀释的氟维司群。定量施用试验化合物以后,将细胞板在37℃和5%CO2下温育24小时。通过加入14%低聚甲醛(10 μL)在室温保持30分钟,固定细胞。将细胞用PBS (20µL)洗涤1次并与含有0.5%(v/v) TWEEN®20的PBS (20µL)一起温育1小时。将细胞用含有0.05%TWEEN®20的PBS(2×)洗涤,并用在含有0.05%TWEEN®20和0.1%TRITON™X-100的PBS (20 μL/孔)中的3%BSA在室温封闭1小时。向每孔加入在含有0.05%TWEEN®20的PBS中的1%BSA中的1:500第一抗体(20 μL) (ERα(克隆SP1)单克隆兔抗体#RM-9101-S, Thermo Scientific)稀释物,密封板并在4℃温育过夜。次日,将细胞用含有0.05%TWEEN®20的PBS (2×)洗涤,并在PBS 1%BSA中与第二抗体(20 μL/孔) (1:1000稀释物,山羊抗-兔IgM ALEXA FLUOR™488)一起在室温温育105分钟。用PBS (2×20µL)洗涤板后,每孔加入RNA酶(Sigma) (20 μL 50 μg/mL)和在PBS中的1:1000碘化丙啶稀释物(20µL)。密封板并在工作台上在室温温育1小时(避光保存)。用ACUMEN EXPLORER™[由TTP LABTECH LTD制造的激光扫描荧光微量培养板细胞计数器]扫描板以测量ERα。图像分析是基于细胞荧光信号以鉴定阳性细胞。通过平均强度鉴定雌激素受体阳性细胞。使用来自碘化丙啶/DNA的在575-640 nm的总强度鉴定单个细胞。测定输出是%雌激素受体阳性细胞。通过使用GENE DATA™向每个输出的四参数逻辑的曲线拟合确定IC50。
该测定的结果证实,式(I)的化合物是在细胞中具有有效ERα降解活性的SERD。具体地,结果表明实施例1的化合物在MCF7乳腺癌细胞中对ERα的有效降解。使用该测定,实施例1的化合物的相对IC50 (µM)值为2.16±0.96 nM (n=15)。
在MCF7细胞中的PRα诱导测定
下述PRα诱导测定的目的是确定试验化合物是否对ERα受体具有激动活性(预期激动剂会激活该受体)。
在补充了10%FBS、0.01 mg/mL人胰岛素1和1%青霉素/链霉素抗生素的DMEM培养基中培养MCF7 (购自ATCC HTB-22),并在含有10%FBS (木炭处理的)的、不含酚磺酞的DMEM培养基中以20 μL体积以4,000个细胞/孔的密度将细胞(在变成70%汇合之前)铺板在384-孔平底板中。在细胞培养箱(5%CO2, 95%相对湿度在37℃)中温育细胞过夜并使细胞附着于板。次日,给细胞施用试验化合物。使用Echo 555声学分配器制备在从6 μM至0.0003 μM范围内的化合物系列稀释物(1:3)。如下给细胞施用:将来自系列稀释物板的试验化合物(5 μL)添加至细胞板,从而产生0.2%的最终DMSO浓度,试验化合物的终浓度剂量范围是在2-0.0001 μM之间。对于最大点,使用含有0.2%的DMSO的培养基,且对于最小点,使用在含有0.2%DMSO的生长培养基中以2 μM终浓度稀释的氟维司群。定量施用试验化合物以后,将细胞板在37℃和5%CO2下温育24小时。通过加入14%低聚甲醛(10 μL)在室温保持30分钟,固定细胞。将细胞用PBS (20µL)洗涤1次,并与含有0.5%(v/v) TWEEN®20的PBS (20µL)一起温育1小时。将细胞用含有0.05%TWEEN®20的PBS (20µL)洗涤2次,并用在含有0.05%TWEEN®20和0.1%TRITON™X-100的PBS (20 μL/孔)中的3%BSA在室温封闭1小时。向每孔加入在1%BSA/PBS(含有0.05 TWEEN®20)中的1:500第一抗体(20 μL) (黄体酮受体单克隆小鼠抗-人抗体, 克隆PgR 636 Dako, M3569)稀释物,密封板并在4℃温育过夜。
次日,将细胞用PBS 0.05%TWEEN®20 (2×20µL)洗涤,并与在PBS 1%BSA中的第二抗体(20 μL/孔) (1:1000稀释物,山羊抗-兔IgM ALEXA FLUOR™488)一起在室温温育105分钟。用PBS (2×20µL)洗涤以后,向每孔加入RNA酶(20 μL 50 μg/mL) (Sigma)和在PBS中的1:1000碘化丙啶稀释物。密封板并在工作台上在室温温育1小时(避光保存)。用ACUMENEXPLORER™[由TTP LABTECH LTD制造的激光扫描荧光微量培养板细胞计数器]扫描板以测量黄体酮受体α。图像分析是基于细胞荧光信号以鉴定阳性细胞。通过平均强度鉴定黄体酮受体阳性细胞。使用来自碘化丙啶/DNA的在575-640 nm的总强度鉴定单个细胞。测定输出是%黄体酮受体阳性细胞。通过使用GENE DATA™向每个输出的四参数逻辑的曲线拟合确定IC50。
使用该测定,实施例1的化合物的相对IC50 (µM) > 2µM。该测定的结果证实了实施例1在MCF7乳腺癌细胞中没有显著激动活性。这些结果也证实,实施例1的化合物在MCF7乳腺癌细胞中是ERα的纯拮抗剂。
在MCF7-ESR1 Y537N 682 CRISPR细胞中的PRα抑制(ERα功能拮抗作用)细胞测定
下述PRα抑制(ERα功能拮抗作用)细胞测定的目的是确定试验化合物对Y537N突变体ERα受体的拮抗活性。预期在该测定中的拮抗剂会阻断ERα受体的功能。PRα(PGR)是ERα的下游转录靶标,且因此预期ERα的拮抗剂会抑制PRα的表达。
在补充了10%FBS和1%青霉素/链霉素抗生素的DMEM培养基中培养MCF7-ESR1Y537N-682 (在MCF7细胞中通过ESR1基因的CRISPR/Cas9基因编辑而产生,克隆#682),并在含有10%FBS (木炭处理的)的、不含酚磺酞的DMEM培养基(20 μL体积)中以4,000个细胞/孔的密度将细胞(在变成70%汇合之前)铺板在384-孔平底板中。在细胞培养箱(5%CO2, 95%相对湿度和37℃)中温育细胞过夜,并使细胞附着于板。次日,给细胞施用试验化合物。使用Echo 555声学分配器制备在从6 μM至0.0003 μM范围内的化合物系列稀释物(1:3)。如下给细胞施用:将来自系列稀释物板的5 μL添加至细胞板,从而产生0.2%的最终DMSO浓度,最终的试验化合物浓度剂量范围是在2-0.0001 μM之间。对于最大点,使用含有0.2%的DMSO的培养基,且对于最小点,使用在含有0.2%DMSO的生长培养基中以2 μM终浓度稀释的氟维司群。定量施用试验化合物以后,将细胞板在37℃和5%CO2下温育72小时。通过加入14%低聚甲醛(10 μL)在室温保持30分钟,固定细胞。将细胞用PBS (1×20µL)洗涤,并与含有0.5%(v/v)TWEEN®20的PBS (20µL)一起温育1小时。将细胞用PBS (2×20µL)、0.05%TWEEN®20洗涤,并用3%BSA/PBS 0.05%TWEEN®20、0.1%TRITON™X-100 (20 μL/孔)在室温封闭1小时。向每孔加入在1%BSA/PBS 0.05 TWEEN®20中的1:500第一抗体(20 μL) (黄体酮受体单克隆小鼠抗-人抗体, 克隆PgR 636 Dako, M3569)稀释物,密封板并在4℃温育过夜。
次日,将细胞用PBS 0.05%®(2×20µL)洗涤,并与在PBS 1%BSA中的第二抗体(20μL/孔) (1:1000稀释物,山羊抗-兔IgM ALEXA FLUOR™488)一起在室温温育105分钟。用PBS (2×20µL)洗涤以后,向每孔加入RNA酶(20 μL 50 μg/mL) (Sigma)和在PBS中的1:1000碘化丙啶稀释物。密封板并在工作台上在室温温育1小时(避光保存)。用ACUMENEXPLORER™[由TTP LABTECH LTD制造的激光扫描荧光微量培养板细胞计数器]扫描板以测量黄体酮受体α。图像分析是基于细胞荧光信号以鉴定阳性细胞。通过平均强度鉴定黄体酮受体阳性细胞。使用来自碘化丙啶/DNA的在575-640 nm的总强度鉴定单个细胞。测定输出是%黄体酮受体阳性细胞。通过使用GENE DATA™向每个输出的四参数逻辑的曲线拟合确定IC50。
使用该测定,实施例1的化合物的相对IC50 (nM)为7.602±4.804 nM (n=14)。这些结果证实了实施例1在MCF7 (ESR1 Y537N, 杂合突变体)乳腺癌细胞中对PRα的有效抑制和功能拮抗作用。这样,实施例1的化合物是ERα突变体(Y537N)的有效拮抗剂和ERα介导的转录的有效抑制剂。PRα(PGR)也是ERα的转录靶标,且来自该测定的结果证实了ERα介导的PRα转录的有效抑制。
在MCF7细胞中的PRα抑制(ERα功能拮抗作用)细胞测定
下述PRα抑制(ERα功能拮抗作用)细胞测定的目的是确定试验化合物对ERα受体的拮抗活性。预期在该测定中的拮抗剂会阻断ERα受体的功能。PRα是ERα的下游转录靶标,且因此预期ERα的拮抗剂会抑制PRα的表达。
使用MCF7细胞系实现在上面ERα降解细胞基础Acumen测定中详述的测定条件,但是,在试验化合物分配之前,从细胞板除去培养基并用含有0.47 nM雌二醇的测定培养基预处理除了阴性对照孔(板的第24列)以外的所有孔30分钟。在该测定中,进行免疫染色以检测PRα,并用ACUMEN EXPLORER™[由TTP LABTECH LTD制造的激光扫描荧光微量培养板细胞计数器]扫描板以测量PRα。图像分析是基于细胞荧光信号以鉴定阳性细胞。通过平均强度鉴定PRα阳性细胞。使用来自碘化丙啶/DNA的在575-640的总强度鉴定单个细胞。测定输出是%PRα阳性细胞。通过使用GENE DATA™向每个输出的四参数逻辑的曲线拟合确定IC50。
使用该测定,实施例1的化合物在该测定中的相对IC50 (nM)为15.75±9.037 nM(n=15)。该测定的结果证实了实施例1在MCF7乳腺癌细胞中对PRα的有效抑制和功能拮抗作用。这样,实施例1的化合物是ERα野生型蛋白的有效拮抗剂和ERα介导的转录的有效抑制剂。PRα(PGR)也是ERα的转录靶标,且来自该测定的结果证实了ERα介导的PRα转录的有效抑制。
在MCF7和MCF7-ESR1 Y537N-682中的细胞增殖测定
下述细胞增殖测定的目的通常是检测试验化合物是否响应于在细胞培养实验中的处理对细胞增殖、细胞生存力和细胞毒性具有作用。通过监测细胞数目随时间的变化来监测细胞增殖,且使用的碘化丙啶测定允许连续测量细胞生存力随时间的变化。
将MCF7 (购自ATCC HTB-22)细胞在含有10%FBS (木炭处理的)的、不含酚磺酞的DMEM培养基(20 μL体积)中以2,000个细胞/孔的密度接种在透明底384-孔细胞培养板中。以1000个细胞/孔的密度在补充了10%FBS和1%青霉素/链霉素抗生素的DMEM培养基中铺板MCF7-ESRY537N -682 (在MCF7细胞中通过ESR1基因的CRISPR/Cas9基因编辑而产生,克隆#682)。在37℃和5%CO2下温育板。次日,给细胞施用试验化合物。使用Echo 555声学分配器制备在60 μM至0.003 μM范围内的试验化合物系列稀释物(1:3)。如下给细胞施用:将来自系列稀释物板的5 μL添加至细胞板,从而产生0.2%的最终DMSO浓度,最终的试验化合物浓度剂量范围是在20-0.001 μM之间。对于最大点,使用含有0.2%的DMSO的培养基,且对于最小点,使用在含有0.2%DMSO的生长培养基中以2 μM终浓度稀释的氟维司群。定量施用试验化合物以后,将细胞板在37℃和5%CO2下温育。在试验化合物添加后7天,将板从培养箱取出,并向每个孔加入冷乙醇96%(65 μL)。30分钟以后,除去培养基并向每个孔加入RNA酶(20 μL50 μg/mL) (Sigma)和在PBS中的1:1000碘化丙啶稀释物。密封板并在工作台上在室温温育1小时(避光保存)。用ACUMEN EXPLORER™[由TTP LABTECH LTD制造的激光扫描荧光微量培养板细胞计数器]扫描板。MCF-7细胞系生长形成聚集体,作为对象数目的细胞数目可能不能用作读出;所以通过估计的细胞数目(通过面积参数(总细胞群体的总面积(FL-1的峰强度的指定范围(PI)和单个细胞群体的平均面积(由周长定义)之比来计算)可以评价细胞数目。通过使用GENE DATA™向每个输出的四参数逻辑的曲线拟合确定IC50。
使用该测定,实施例1的化合物在MCF7 ESR1野生型中的相对IC50 (nM)为9.243±1.741 nM (n=2),且在MCF7-ESR1 Y537N突变细胞中为7.960±3.691 nM (n=6)。这些结果证实了实施例1在MCF7 (ESR1野生型)和MCF7 (ESR1 Y537N突变体)乳腺癌细胞中的有效抗增殖活性和细胞生长抑制。
在MCF7肿瘤中的体内靶抑制(IVTI)测定(PGR RT-qPCR测定)
该IVTI测定的目的是测量试验化合物(SERD)在小鼠所植入的异种移植物肿瘤中抑制ERα的下游PGR (黄体酮受体α)基因表达(转录)的能力。
在1:1 HBSS + MATRIGEL™溶液(200 μL)中将5×10e6个MCF7 ER+ve乳腺癌细胞(ATCC, # HTB-22)皮下地植入来自Envigo RMS, Inc., Madison, Wisconsin的雌性NODSCID小鼠(22-25 g)的右胁腹区域。在肿瘤细胞植入前1天,皮下地植入17- β雌二醇颗粒(0.18 mg/颗粒, 90天释放, 来自Innovative research)。在植入后第七天开始,每周2次测量肿瘤生长和体重。当肿瘤大小达到250-350 mm3时,将动物随机化并分成5只动物的组。给动物口服施用在特定媒介物(在净化水中的1%羟乙基纤维素/0.25%TWEEN®80/0.05%消泡剂)中的试验化合物或单独的媒介物3天,并在最后一次施用后在期望的时间间隔收集肿瘤和血液。使用异氟烷麻醉+ 颈椎脱位处死动物。将肿瘤快速冷冻并在为RNA分离和RT-qPCR测定加工之前在-80℃保存。将血液收集在EDTA试管中,离心获得血浆,并在96-孔板中在-80℃冷冻。使用质谱法确定试验化合物暴露。
将肿瘤在液氮中粉碎,并在FASTPREP-24TM Cell Disrupter机器(MP Biomedical)中使用Matrix D珠子(MP Biomedical, #6913-500)在1×RNA裂解缓冲液(来自RNA分离试剂盒)中裂解。在4℃在14000 rpm离心20分钟以后,将肿瘤裂解物转移至新管。使用PURELINK®RNA Mini Kit (Invitrogen #12183018A)或RNeasy Mini Kit (Qiagen #74104和#74106),从肿瘤裂解物分离RNA。使用PURELINK®DNase Set (Invitrogen #12185010)或RNase-Free DNase Set (Qiagen #79254),除去DNA污染物。如下测量分离的RNA浓度:将样品在不含RNA酶的水中稀释,并在板读数器(SpectraMax190)上测量在260 nm的吸光度。从所有其它RNA样品的260 nm测量结果减去空白(仅不含RNA酶的水)的平均260nm吸光度测量结果。在不含RNA酶的水中稀释RNA样品至相等浓度。使用用于RT-PCR的First-Strand Synthesis System (Invitrogen, #18080-051),从稀释的RNA合成cDNA。为了执行RT-qPCR,首先在不含RNA酶的水中稀释cDNA。为了在PCR板(Applied Biosystems, #4309849)中的每个反应,组合2×Absolute Blue qPCR ROX Mix (Thermo, #AB-4139/A)、PGR引物(Thermo, Hs01556702_m1)和稀释的cDNA。如下扩增cDNA:在热循环仪(ABI Prism7900HT Sequence Detection System)中将样品在50℃温育2分钟,随后在95℃温育15分钟。继续在95℃温育15秒,随后在50℃温育60秒,共40个循环。将循环归一化至持家基因并用于计算相对于单独媒介物的%PGR抑制。一式两份地分析每个样品,并使用平均数进行计算。使用Excel和XL Fit计算靶(PGR)抑制百分比。
该测定的结果证实,实施例1的化合物抑制肿瘤异种移植物模型中的PRα(PGR)表达。另外,当口服施用时,对于30 mg/kg剂量,实施例1的化合物使肿瘤异种移植物模型中的PRα(PGR)表达抑制了57%保持24小时。这些结果证实了在肿瘤异种移植物模型中ERα拮抗活性和ERα-介导的体内转录活性的显著且持续抑制。
在小鼠所植入的MCF7异种移植物肿瘤中的体内肿瘤生长抑制研究
下述异种移植物肿瘤生长抑制测定的目的是测量响应于试验化合物施用的肿瘤体积的减小。
将培养的人乳腺癌细胞MCF7 (ATCC # HTB-22)扩增,收获,并将5×10e6个细胞在1:1 HBSS+MATRIGEL™溶液(200 μL)中皮下地注射到雌性NOD SCID小鼠(22-25 g, EnvigoRMS, Inc)的后右胁腹。在植入MCF7细胞之前24小时,皮下地植入雌激素颗粒(0.18 mg/颗粒, 17β雌二醇, 90-天释放, Innovative Research)。在植入后第七天开始,每周2次测量肿瘤生长和体重。当肿瘤大小达到250-350 mm3时,将动物随机化并分成5只动物的组。在适当的媒介物(在净化水中的1%羟乙基纤维素/0.25%TWEEN®80/0.05%消泡剂)中制备试验化合物,并通过经口管饲法施用42天。在治疗期间通过每周2次进行的肿瘤体积测量,确定肿瘤应答。每当测量肿瘤体积时,取体重作为毒性的一般量度。
当用在该测定中时,发现实施例1的化合物具有下面表6中提供的δT/C%值。这些结果指示,实施例1的化合物在小鼠中表现出好的口服生物利用度,并在MCF7人乳腺癌异种移植物模型中表现出显著的抗肿瘤活性或肿瘤消退。
在小鼠所植入的MCF7异种移植物肿瘤中的体内肿瘤生长抑制研究
表6
肿瘤模型 | 剂量(mg/kg) | 计划 | δT/C%或消退% | p-值 |
MCF7 (乳腺癌异种移植物) | 30 | QD | -36 | <0.001* |
肿瘤体积分析是基于Log 10和SpatialPower协方差结构。
*: 与媒介物对照相比是显著的(p<0.05)。
当治疗组中的端点肿瘤体积是或高于基线肿瘤体积时,计算δT/C%。式是100*(T-T0)/(C-C0),其中T和C分别是治疗组或对照组中的平均端点肿瘤体积。T0和C0是那些组中的平均基线肿瘤体积。
当端点体积低于基线时,计算消退%。式是100*(T-T0)/T0,其中T0是治疗组的平均基线肿瘤体积。
在第32天来自基线(随机化)的所有组的总平均值用于计算T/C的%变化。
大鼠口服生物利用度测定
下述测定的目的是证实试验化合物是否是口服可生物利用的。
如下将试验化合物施用给Sprague-Dawley大鼠:以1 mg/kg静脉内(使用任一以下媒介物:20%CAPTISOL®在25 mM磷酸钠缓冲液中,pH2适量;或25%DMA、15%EtOH、10%丙二醇、25%2-吡咯烷酮和25%净化水),和以10 mg/kg口服(使用以下媒介物:1%羟乙基纤维素、0.25%聚山梨酯80、0.05%消泡剂1510-US和净化水,适量)。对于静脉内推注在施用后0.08、0.25、0.5、1、2、4、8和12小时,和在口服施用后在施用后0.25、0.5、1、2、4、8和12小时,收集系列血液样品。用EDTA促凝剂处理后,通过离心得到血浆,并在通过LC-MS/MS分析之前在-70℃保存。确定血浆中的试验化合物浓度并上载到Watson LIMSTM系统中,在那里使用非房室模型分析计算静脉内组和口服组的曲线下面积(AUC)。通过下述方程式计算口服生物利用度(%F):
%F = (AUC 口服X剂量静脉内)/(AUC 静脉内X剂量口服) X 100。
使用该测定,实施例1的化合物表现出27%的%F值。该测定证实了实施例1具有好的口服生物利用度。
Claims (8)
1.下式的化合物
或其药学上可接受的盐。
2.根据权利要求1所述的化合物,其中所述化合物是
3.一种药物组合物,其包含与一种或多种药学上可接受的赋形剂或载体组合的权利要求1所述的化合物或其药学上可接受的盐或权利要求2所述的化合物。
4.根据权利要求1或权利要求2所述的化合物或其药学上可接受的盐用于制备药物的用途,所述药物用于治疗乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、胃癌或肺癌。
5.根据权利要求4所述的用途,其中所述化合物或其药学上可接受的盐要口服施用。
6.根据权利要求5的用途,其中所述乳腺癌是ER阳性的乳腺癌。
7.根据权利要求5的用途,其中所述胃癌是ER阳性的胃癌。
8.根据权利要求5的用途,其中所述肺癌是ER阳性的肺癌。
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