CN107074827B - 普拉二烯内酯吡啶化合物和使用方法 - Google Patents
普拉二烯内酯吡啶化合物和使用方法 Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供了新的普拉二烯内酯吡啶化合物,含有这种化合物的药物组合物,和使用作为治疗剂的所述化合物的方法。这些化合物可用于治疗癌症,尤其是其中靶向剪接体及其中突变的药物已知对其是有用的癌症。
Description
背景技术
本发明提供了新的有机化合物和含有这种化合物的药物组合物。这些化合物可用于治疗癌症,尤其是靶向剪接体及其中的突变的药物被证明对其有用的癌症。
在真核生物中,新合成的信使RNA通常具有多个内含子,其被切除以提供成熟mRNA。所述剪接体是完成此任务的多亚基复合体。所述剪接体由五个小核RNA(snRNA;U1-6)以及多种蛋白组成。在剪接体基因中的突变已见于各种类型的癌症中。
例如,在剪接体的剪接因子3B亚基1(SF3B1)中的突变存在于多种癌症中并包含抗癌剂的靶标。这种癌症包括,但不限于,骨髓增生异常综合征(MDS)、白血病(例如慢性淋巴细胞性白血病(CLL)、慢性粒-单核细胞性白血病(CMML)和急性髓细胞性白血病(AML))和实体瘤(例如乳腺癌和葡萄膜黑色素瘤)。
从细菌普拉特链霉菌(Streptomyces platensis)分离出的化合物(Sakai,Takashi;Sameshima,Tomohiro;Matsufuji,Motoko;Kawamura,Naoto;Dobashi,Kazuyuki;Mizui,Yoshiharu。Pladienolides,New Substances from Culture of Streptomycesplatensis Mer-11107.I.Taxonomy,Fermentation,Isolation and Screening。TheJournal of Antibiotics。2004,第57卷,No.3.),其被称为普拉二烯内酯(pladienolide)并且在筛选血管内皮生长因子(VEGF)启动子的抑制剂时被发现,抑制由人VEGF启动子控制的报道基因的表达,其中已知该抑制是抗癌剂有用的作用机制。
这些化合物还在体外抑制U251人神经胶质瘤细胞的增殖。这些化合物中最有效的普拉二烯内酯B,其抑制VEGF-促进基因表达的IC50为1.8nM,和抑制神经胶质瘤细胞增殖的IC50为3.5nM。普拉二烯内酯B的结构是已知的(Sakai,Takashi;Sameshima,Tomohiro;Matsufuji,Motoko;Kawamura,Naoto;Dobashi,Kazuyuki;Mizui,Yoshiharu.Pladienolides,New Substances from Culture of Streptomyces platensisMer-11107.II.Physico-chemical Properties and Structure Elucidation.TheJournal of Antibiotics.第57卷,No.3.(2004))且已知普拉二烯内酯B靶向SF3b剪接体以抑制剪接并改变基因表达的模式(Kotake等人,"Splicing factor SF3b as a target ofthe antitumor natural product pladienolide",Nature Chemical Biology 2007,3,570-575)。
一些普拉二烯内酯B化合物以及其他普拉二烯内酯化合物同样是已知的,如以下专利申请中所公开的:WO 2002/060890;WO 2004/011459;WO 2004/011661;WO 2004/050890;WO 2005/052152;WO 2006/009276;和WO 2008/126918。例如,普拉二烯内酯化合物,(8E,12E,14E)-7-((4-环庚基哌嗪-1-基)羰基)氧基-3,6,16,21-四羟基-6,10,12,16,20-五甲基-18,19-环氧二十三-8,12,14-三烯-11-内酯,也称为E7107,是天然产物普拉二烯内酯D的半合成衍生物,且其I期研究结果已经被报道。
但是,需要用于治疗癌症(尤其是靶向所述剪接体及其中的突变的药物已被证明对其有用的癌症)的其他药物。
发明内容
本发明的目的是提供式1化合物(“化合物1”)、式2化合物(“化合物2”)、式3化合物(“化合物3”)和式4化合物(“化合物4”):
及其药学上可接受的盐。
本发明的其他目的是提供药物组合物,其包含化合物1、化合物2、化合物3、化合物4,或其药学上可接受的盐。这种药物组合物可用一种或多种药学上可接受的载体配制。这种组合物被配制用于各种常规给药途径,包括静脉内给药、口服给药、皮下给药或肌内给药。
本发明还可涉及治疗癌症受试者的方法,其包括向所述受试者给药有效产生治疗有益响应的量的化合物1、化合物2、化合物3、化合物4,或其药学上可接受的盐。所述癌症可为骨髓增生异常综合征、白血病(例如慢性淋巴细胞性白血病(chronic lymphocyticleukemia)、急性成淋巴细胞性白血病(acute lymphoblastic leukemia)、慢性粒-单核细胞性白血病(chronic myelomonocytic leukemia)或急性髓细胞性白血病(acute myeloidleukemia))或实体瘤(例如结肠癌(colon cancer)、胰腺癌(pancreatic cancer)、子宫内膜癌(endometrial cancer)、卵巢癌(ovarian cancer)、乳腺癌(breast cancer)、葡萄膜黑色素瘤(uveal melanoma)、胃癌(gastric cancer)、胆管癌(cholangiocarcinoma)、肺癌(lung cancer)或其任意亚型)。所述癌症可对剪接体基因或蛋白中的一种或多种突变(例如表1中所列的那些)测试呈阳性。
本发明还可涉及化合物1、化合物2、化合物3、化合物4或其药学上可接受的盐在治疗性治疗(例如,治疗癌症)的方法中的用途。所述癌症可为骨髓增生异常综合征、白血病(例如慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性粒-单核细胞性白血病或急性髓细胞性白血病)或实体瘤(例如结肠癌、胰腺癌、子宫内膜癌、卵巢癌、乳腺癌、葡萄膜黑色素瘤、胃癌、胆管癌、肺癌或其任意亚型)。所述癌症可对剪接体基因或蛋白中的一种或多种突变(例如表1中所列的那些)测试呈阳性。
本发明还可涉及化合物1、化合物2、化合物3、化合物4或其药学上可接受的盐在制备药物中的用途。具体地,所述药物可用于治疗癌症。所述癌症可为骨髓增生异常综合征、白血病(例如慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性粒-单核细胞性白血病或急性髓细胞性白血病)或实体瘤(例如结肠癌、胰腺癌、子宫内膜癌、卵巢癌、乳腺癌、葡萄膜黑色素瘤、胃癌、胆管癌、肺癌或其任意亚型)。所述癌症可对剪接体基因或蛋白中的一种或多种突变(例如表1中所列的那些)测试呈阳性。
本发明还可涉及化合物1、化合物2、化合物3、化合物4或其药学上可接受的盐在靶向剪接体(例如SF3B剪接体的亚基1)中的用途。
附图说明
图1显示了在以5mg/kg静脉内(IV)或10mg/kg口服给药(PO)的剂量给药化合物2的CD-1小鼠中的药物代谢动力学(PK)研究的结果。
图2显示了在具有工程化SF3B1K700E突变的Nalm-6(人前B-细胞系)小鼠异种移植模型中化合物2的效力。向小鼠给药2.5mg/kg、5mg/kg或10mg/kg化合物2,每日一次(QD)持续14天,并在40天时间内测量肿瘤体积。
图3显示了在具有工程化SF3B1K700E突变的Nalm-6(人前B-细胞系)小鼠异种移植模型中化合物2的药代动力学和药效学分析。向小鼠给药10mg/kg PO剂量的化合物2,并确定肿瘤浓度(μg/g)和相对于载剂而言Pre-EIF4A1(EIF4A1转录物的前-mRNA)和SLC25A19(SLC25A19转录物的成熟mRNA)在表达上的倍数变化。
图4显示了相比于野生型SF3B1胰腺癌细胞系BXPC3、HPAFII、PANC0403、PANC1005、CFPAC1和MIAPACA2而言,在使用化合物2的情况下,在PANC0504癌症细胞系(SF3B1MUT)(突变体PANC 05.04)中细胞存活力的测定结果。
图5显示了基于Nanostring分析,E7107和化合物2(cmpd 2)对交替剪切的调节。在阴影键(shade key)中的所述“+”和“-”分别表示正值或负值,其以表示不同剪接点的不同表达水平。
图6显示了在以5mg/kg静脉内(IV)或12mg/kg口服给药(PO)的剂量给药化合物1的CD-1小鼠中的PK研究结果。
图7显示了在具有工程化SF3B1K700E突变的Nalm-6小鼠异种移植模型中化合物1的效力。向小鼠给药7.5或10mg/kg的化合物1,每日一次(QD)持续14天,并测定30天时间内的肿瘤体积。
图8显示了在具有工程化SF3B1K700E突变的Nalm-6异种移植模型中化合物1的药物代谢动力学和药效学分析。向小鼠给药单一PO剂量的化合物1,并确定肿瘤浓度(μg/g)和相对于载剂而言Pre-EIF4A1(EIF4A1转录物的前-mRNA)和SLC25A19(SLC25A19转录物的成熟mRNA)在表达上的倍数变化。
图9显示了在以5.964mg/kg静脉内(IV)或13.307mg/kg口服给药(PO)的剂量给药化合物3的CD-1小鼠中的PK研究结果。
图10显示了在以5mg/kg静脉内(IV)或10mg/kg口服给药(PO)的剂量给药化合物4的CD-1小鼠中的PK研究结果。
一些实施方案的详述
A.定义
如本文所用,除非另外提及,否则应使用以下定义。
“异构体”是指具有相同数目和种类的原子并因此具有相同分子量的化合物,但对于原子的排列或构型而言是不同的。“立体异构体”是指具有相同原子连接性但它们的原子在空间上具有不同排列的化合物。“非对映异构体”或“非对映体”是指不是对映异构体的立体异构体。“对映异构体”是指为彼此不重叠的镜像的立体异构体。“几何异构体”是指相对于双键或环或中心原子而言具有不同基团位置的顺式-反式异构体。
本文教导的对映异构体可包括“对映异构体纯的”异构体,其在特定的不对称中心处基本上包含单一对映异构体,例如,大于或等于90%、92%、95%、98%或99%或等于100%的单一对映异构体。“不对称中心”或“手性中心”是指四面体碳原子,其包含四个不同的取代基。
本文所用“立体异构体纯的”是指化合物或其组合物,其包含化合物的一种立体异构体且基本上不含该化合物的其他立体异构体。例如,具有一个手性中心的化合物的立体异构体纯的组合物基本上不含该化合物的相反的对映异构体。具有两个手性中心的化合物的立体异构体纯的组合物基本上不含该化合物的非对映异构体且基本上不含该化合物的相反的对映异构体。典型的立体异构体纯的化合物包含大于约80重量%的所述化合物的一种立体异构体和小于约20重量%的所述化合物的其他立体异构体,更优选大于约90重量%的所述化合物的一种立体异构体和小于约10重量%的所述化合物其他立体异构体,甚至更优选大于约95重量%的所述化合物的一种立体异构体和小于约5重量%的所述化合物其他立体异构体,且最优选大于约97重量%的所述化合物的一种立体异构体和小于约3重量%的所述化合物其他立体异构体。参见,例如,US专利7,189,715。
描述异构体的术语“R”和“S”是描述不对称取代的碳原子的立体化学构型的符号。用“R”或“S”来命名不对称取代的碳原子是通过采用Cahn-Ingold-Prelog优先级规则进行的,正如本领域技术人员熟知的并描述于International Union of Pure and AppliedChemistry(IUPAC)Rules for the Nomenclature of Organic Chemistry.Section E,Stereochemistry。
“治疗”癌症是指逆转(例如,克服细胞的分化阻滞)、减轻(例如,减轻一种或多种症状,例如贫血引起的疲劳、低血细胞计数等)和/或延迟本文所述癌症的进展(例如,延迟病症的进展,例如转化成AML)。
本文所用“受试者”是指动物受试者,优选哺乳动物受试者,且特别是人。
本文所用的“药学上可接受的载体”是指无毒载体、佐剂或媒介物,将其与化合物共同配制时不会破坏所述化合物的药理学活性。可用于本发明组合物中的药学上可接受的载体、佐剂或媒介物包括,但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人血清白蛋白)、缓冲剂(例如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、环糊精、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
“药学上可接受的盐”是指保留母体化合物所需的生物活性并且不产生不希望的毒理学作用的盐。这种盐的实例是:(a)与无机酸形成的酸加成盐,所述无机酸例如,盐酸、氢溴酸、硫酸、磷酸、硝酸等;和与有机酸形成的盐,所述有机酸例如,乙酸、草酸、酒石酸、琥珀酸、马来酸、富马酸、葡糖酸、柠檬酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、棕榈酸、海藻酸、聚谷氨酸、萘磺酸、甲磺酸、对甲苯磺酸、萘二磺酸、多聚半乳糖醛酸等;和(b)由元素的阴离子(例如氯、溴和碘)形成的盐。参见,例如,Haynes等人,“Commentary:Occurrence ofPharmaceutically Acceptable Anions and Cations in the Cambridge StructuralDatabase,”J.Pharmaceutical Sciences,第94卷,no.10(2005),和Berge等人,“Pharmaceutical Salts”,J.Pharmaceutical Sciences,第66卷,no.1(1977),将其引入本文作为参考。
B.化合物
除非另外提及,本文所述化合物可包括本文所述化合物的混合物,和该结构的任意对映异构体、非对映异构体和几何(或构象)形式;例如,各不对称中心的R和S构型、(Z)和(E)双键异构体和(Z)和(E)构象异构体。除非另外提及,与互变异构形式共存的本文所述化合物在本发明的范围内。此外,除非另外提及,本文所述结构也旨在包括这样的化合物,其区别仅在于一种或多种同位素富集的原子的存在。例如,除了用氘或氚替代了氢或用13C-或14C-富集的碳替代了碳之外,具有本发明结构的化合物在本发明的范围内。这种化合物可在生物学测试中用作,例如,分析工具或探针。
根据一些实施方案,本文提供了式1化合物(“化合物1”)、式2化合物(“化合物2”)、式3化合物(“化合物3”)和式4化合物(“化合物4”):
及其药学上可接受的盐。
C.药物制剂
本发明化合物可与药学上可接受的载体组合以提供其药物制剂。载体和制剂的具体选择将取决于所述化合物预期的具体给药途径。
本发明的药物组合物可适当地配制用于胃肠外、口服、吸入喷雾、局部、直肠、鼻内、含服、阴道内或植入型储库给药等。本文所用术语“胃肠外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。在具体实施方案中,所述化合物通过静脉内、口服、皮下或通过肌内进行给药。无菌可注射形式的本发明组合物可为水性或油性混悬液。这些混悬液可根据本领域已知的技术使用合适的分散剂或润湿剂和悬浮剂进行配制。所述无菌可注射制剂也可为在无毒胃肠外的可接受稀释剂或溶剂中的无菌可注射溶液或混悬液,例如,其为在1,3-丁二醇中的溶液。可使用的可接受的媒介物和溶剂为水、林格氏溶液和等渗氯化钠溶液。此外,无菌不挥发油通常用作溶剂或悬浮介质。
为此目的,可以使用任意温和的不挥发油,包括合成的甘油单甘油酯或甘油二脂。脂肪酸,例如油酸及其甘油酯衍生物可用于制备注射剂,其用作天然药学上可接受的油,例如橄榄油或蓖麻油,特别是其聚氧乙基化形式。这些油溶液或混悬液也可含有长链醇稀释剂或分散剂,例如羧甲基纤维素或通常用于配制药学上可接受的剂型(包括乳液和混悬液)中的类似的分散剂。其他常用的表面活性剂,例如Tweens、Spans和通常用于制备药学上可接受的固体、液体或其他剂型的其他乳化剂或生物利用度增强剂,也可用于配制的目的。
对于口服给药,化合物可以以可接受的口服剂型提供,包括,但不限于,胶囊、片剂、水性混悬液或溶液。在口服使用的片剂的情况下,通常使用的载体包括乳糖和玉米淀粉。也可加入润滑剂,例如硬脂酸镁。对于胶囊形式的口服给药,有用的稀释剂包括乳糖和干玉米淀粉。当需要水性混悬液用于口服使用时,将所述活性成分与乳化剂和/或混悬剂组合。如果需要,也可加入一些甜味剂、矫味剂或着色剂。
D.受试者和使用方法
本发明化合物可用于治疗各种类型的癌症,包括对靶向SF3B1的药剂有响应的那些癌症。如上所述,普拉二烯内酯B的抗肿瘤活性据报道与其靶向所述SF3b复合物有关,从而抑制剪接并改变基因表达的模式(Kotake等人,"Splicing factor SF3b as a targetof the antitumor natural product pladienolide,"Nature Chemical Biology 2007,3,570-575)。在剪接体基因(例如剪接因子3B亚基1(SF3B1)蛋白)上的突变已知涉及许多癌症,例如血液恶性肿瘤和实体瘤。Scott等人,"Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors,"JNCI 105,20,1540-1549。
血液恶性肿瘤可包括血液癌症(白血病)或淋巴结癌症(淋巴瘤)。白血病可包括急性成淋巴细胞性白血病(ALL)、急性髓细胞性白血病(AML)、慢性淋巴细胞性白血病(CLL)、慢性髓细胞性白血病(CML)、慢性粒-单核细胞性白血病(CMML)、急性单核性细胞白血病(AMoL)等。淋巴瘤可包括霍奇金淋巴瘤和非霍奇金淋巴瘤。其他血液恶性肿瘤可包括骨髓增生异常综合征(MDS)。
实体瘤可包括癌,例如腺癌,例如,乳腺癌、胰腺癌、前列腺癌、结肠或结肠直肠癌、肺癌、胃癌、子宫颈癌、子宫内膜癌、卵巢癌、胆管癌、神经胶质瘤、黑素瘤等。
本发明化合物也可用于治疗可能对靶向SF3B1之外的剪接体基因或蛋白的药剂有响应的癌症。以下实例说明了不同癌症中的一些,所述癌症可能对靶向剪接体的药剂有响应,且不旨在以任何方式限制本发明的范围。因此,本发明化合物可给药至受试者以治疗各种这样的癌症或病症,例如患有以下疾病的患者或受试者:
a)骨髓增生异常综合征(MDS):参见,例如,"SF3B1mutations inmyelodysplastic syndromes:clinical associations and prognostic implications,"Damm F.等人,Leukemia,2011,1-4;"Frequent pathway mutations in splicingmachinery in myelodysplasia,"Yoshida K.等人,Nature,2011,478,64-69;"Clinicalsignificance of SF3B1mutations in myelodysplastic syndromes andmyelodysplastic/myeloproliferative neoplasms,"Malcovati L.等人,Blood,2011,118,24,6239-6246;"Mutations in the spliceosome machinery,a novel andubiquitous pathway in leukemogenesis,"Makishima等人,Blood,2012,119,3203-3210;"Somatic SF3B1mutation in myelodysplasia with ring sideroblasts,"Pappaemannuil,E.等人,New England J.Med.2011,DOI 10.1056/NEJMoa1103283。
b)慢性淋巴细胞性白血病(CLL):参见,例如,"Defects in the spliceosomalmachinery:a new pathway of leukaemogenesis,"Maciejewski,J.P.,Padgett,R.A.,Br.J.Haematology,2012,1-9;"Mutations in the SF3B1splicing factor in chroniclymphocytic leukemia:associations with progression and fludarabine-refractoriness,"Rossi等人,Blood,2011,118,6904-6908;"Exome sequencingidentifies recurrent mutations of the splicing factor SF3B1 gene in chroniclymphocytic leukemia,"Quesada等人,Nature Genetics,2011,44,47-52。
c)慢性粒-单核细胞性白血病(CMML):参见,例如,Yoshida等人,Nature 2011;"Spliceosomal gene mutations are frequent events in the diverse mutationalspectrum of chronic myelomonocytic leukemia but largely absent in juvenilemyelomonocytic leukemia,"Kar S.A.等人,Haematologia,2012,DOI:10.3324/haematol.2012.064048;DeBoever等人,"Transcriptome sequencing reveals potentialmechanism of cryptic 3'splice site selection in SF3B1-mutated cancers,"PLOSComputational Biology,2013,DOI:10.1371/journal.pcbi.1004105。
d)急性髓细胞性白血病(AML):参见,例如,Malcovati等人,Blood 2011;Yoshida等人,Nature 2011。
e)乳腺癌:参见,例如,"Whole genome analysis informs breast cancerresponse to aromatase inhibition,"Ellis等人,Nature,2012,486,353-360;DeBoever等人,"Transcriptome sequencing reveals potential mechanism of cryptic 3'splice site selection in SF3B1-mutated cancers,"PLOS Computational Biology,2013,DOI:10.1371/journal.pcbi.1004105;Maguire等人,"SF3B1 mutations constitutea novel therapeutic target in breast cancer,"J Pathol 2015,235,571-580。
f)葡萄膜黑色素瘤:参见,例如,"SF3B1mutations are associated withalternative splicing in uveal melanoma,"Furney等人,Cancer Disc.2013,10,1122-1129;DeBoever等人,"Transcriptome sequencing reveals potential mechanism ofcryptic 3'splice site selection in SF3B1-mutated cancers,"PLOS ComputationalBiology,2013,DOI:10.1371/journal.pcbi.1004105。
g)子宫内膜癌:参见,例如,Tefferi等人,"Myelodysplastic syndromes."N EnglJ Med.2009;361:1872–85。
h)胃癌:参见,例如,Int J Cancer.2013Jul;133(1):260-5,"Mutationalanalysis of splicing machinery genes SF3B1,U2AF1 and SRSF2 in myelodysplasiaand other common tumors."Je等人
i)卵巢癌:参见,例如,Int J Cancer.2013Jul;133(1):260-5,"Mutationalanalysis of splicing machinery genes SF3B1,U2AF1and SRSF2 in myelodysplasiaand other common tumors."Je等人
j)胆道癌症,例如胆管癌和胰腺癌:参见,例如,Biankin等人,"Pancreaticcancer genomes reveal aberrations in axon guidance pathway genes,"Nature2012,491,399-405。
k)肺癌:参见,例如,"Exome sequencing identifies recurrent mutations ofthe splicing factor SF3B1 gene in chronic lymphocytic leukemia,"Quesada等人,Nature Genetics 44,47–52(2012);Scott等人,"Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors,"JNCI 105,20,1540-1549。
此外,癌症体细胞突变目录(COSMIC)(Wellcome Trust Sanger Institute,Genome Research Limited,England)报道了已在各种类型的癌症样品中发现的SF3B1突变。
本发明化合物可以治疗有效量(treatment effective或therapeuticallyeffective amount)给药至受试者。可与载体材料组合以产生单一剂量的组合物的本发明化合物的量将根据所治疗的受试者和具体给药途径而变化。优选地,所述组合物应当配制成使得约0.01-100mg/kg体重/天剂量的活性剂给药至接受这些组合物的受试者。在一些实施方案中,本发明组合物提供约0.01mg至50mg的剂量。在其他实施方案中,提供了约0.1mg至25mg或约5mg至40mg的剂量。
还应当理解,针对任意特定患者的具体剂量和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、排泄速率、药物组合、治疗医师的判断和所治疗的特定疾病的严重性。在该组合物中的本发明活性剂的量还将取决于该组合物中的特定化合物/盐。
在一些实施方案中,检测所述癌症在剪接体基因或蛋白中的一种或多种突变和/或所述癌症对在剪接体基因或蛋白中的一种或多种突变呈阳性,其中所述突变("阳性")的存在可指示所述受试者的癌症对治疗方法有响应,所述方法包括给药靶向这个蛋白和/或剪接体的化合物。这种剪接体基因的实例包括,但不限于,表1中所示的那些。
表1:剪接体基因和受影响的潜在疾病
关键词:
MDS=骨髓增生异常综合征
AML=急性髓细胞性白血病
CMML=慢性粒-单核细胞性白血病
LUAD=肺腺癌
UCEC=子宫体子宫内膜癌
PMF=进行性巨状纤维变性
PRAD=前列腺腺癌
COAD=结肠腺癌
OV=卵巢浆液囊腺癌
SKCM=皮肤黑色素瘤
LUSC=肺鳞状细胞癌
STAD=胃腺癌
GBM=多形性胶质母细胞瘤
LGG=较低级别脑胶质瘤
DLBCL=弥漫性大B细胞淋巴瘤
在一些实施方案中,所述受试者的癌症可响应于治疗方法,其包括给药靶向这个蛋白和/或剪接体的化合物,即使是在剪接体基因或蛋白上不存在此突变。
可通过任意已知的方法筛选或测试所述突变,例如,基因分型、表型等,利用核酸扩增、电泳、微阵列、印记、功能测定、免疫测定等。筛选方法可包括,例如,从含有癌细胞/组织的所述受试者中收集生物样品。
为了可以更充分地理解本文所述的本发明,提出了以下实施例。应理解,这些实施例仅用于说明的目的,而不应被解释为以任意方式限制本发明。
实施例
化合物1、2、3和4的制备
概述:
使用Biotage Emrys Liberator或Initiator微波进行微波加热。柱色谱是使用Isco Rf200d进行的。使用Büchi旋转蒸发仪或Genevac离心蒸发仪除去溶剂。在酸性移动相条件下,使用Waters自动纯化器和19x 100mm XTerra 5micron MS C18柱进行制备型LC/MS。使用Varian 400MHz光谱仪记录NMR光谱。
当使用术语“惰性的”来描述反应器(例如,反应器、烧瓶、玻璃反应器等)时,其是指反应器中的空气已被基本上无水或干燥的惰性气体(例如氮气、氩气等)所替代。
用于制备本发明化合物的一般方法和实验如下所述。
本文使用以下缩写:
MeOH:甲醇
DMF:二甲基甲酰胺
KHMDS:双(三甲基甲硅烷基)氨基钾
LCMS:液相色谱–质谱
TBSCl:叔丁基二甲基氯硅烷
THF:四氢呋喃
TLC:薄层色谱
材料:以下化合物是市售可得的和/或可以以有机合成领域技术人员熟知的多种方法进行制备。更具体地,所公开的化合物可使用本文所述的反应和技术进行制备。在下述合成方法的描述中,应当理解,除非另外提及,否则可选择所有提出的反应条件(包括溶剂、反应气氛、反应温度、实验的持续时间和后处理过程的选择)为用于该反应的标准条件。有机合成领域的技术人员应当理解,存在于分子各部分上的官能团应当与所提出的试剂和反应相容。与反应条件不相容的取代基对本领域技术人员是显而易见的,并因此指出了替代方法。实施例的起始材料是市售可得的或通过标准方法由已知的材料容易地制备。
LCMS信息
移动相:A(0.1%甲酸在H2O中)和B(0.1%甲酸在乙腈中)。
梯度:B 5%→95%,1.8分钟。
柱:Acquity BEH C18柱(1.7um,2.1x 50mm)。
美国专利号7,884,128和7,816,401,两专利的发明名称都为:Process for TotalSynthesis of Pladienolide B and Pladienolide D,其描述了本领域已知的用于合成普拉二烯内酯B和D的方法。普拉二烯内酯B和D的合成也使用本领域已知的方法进行并描述于Kanada等人,"Total Synthesis of the Potent Antitumor Macrolides Pladienolide Band D,"Angew.Chem.Int.Ed.46:4350-4355(2007)。Kanada等人和PCT申请公开WO 2003/099813,发明名称为:Novel Physiologically Active Substances,描述了本领域已知的由普拉二烯内酯D(WO'813的11107D)合成E7107(WO'813的化合物45)的方法。相应的美国专利为Kotake等人的7,550,503。
化合物的示例性合成
化合物1的合成
步骤1:4-环庚基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-((R,2E,4E)-7-((2R,3R)-3-((2S,3S)-3-((叔丁基二甲基甲硅烷基)氧基)戊-2-基)-6-羟基-6-甲基庚-2,4-二烯-2-基)-7-羟基-3,7-二甲基-12-氧代氧杂环十二-4-烯-6-基酯的合成。
在0℃,将在氮气下的E7107(A,3.7g,5.1mmol,1.0当量)在DMF(100mL,0.05M)中的溶液用咪唑(2.5g,36.1mmol,7.0当量)处理并加入TBSCl(3.9g,25.7mmol,5.0当量)。将该反应温热至室温并搅拌20小时或直至通过LCMS或TLC确定该反应完成。将该反应用乙酸乙酯稀释且所述有机层用盐水洗涤,用硫酸钠干燥,过滤,并真空干燥。将所得油用硅胶柱色谱纯化(己烷/乙酸乙酯作为洗脱剂),得到所需产物(B,4.7g,5.0mmol,96%)。
步骤2:4-环庚基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-2-((6R,E)-7-((2R,3R)-3-((2S,3S)-3-((叔丁基二甲基甲硅烷基)氧基)戊-2-基)环氧乙烷-2-基)-4,5,6-三羟基-6-甲基庚-2-烯-2-基)-7-羟基-3,7-二甲基-12-氧代氧杂环十二-4-烯-6-基酯的合成。
在0℃和氮气下,向烯烃B(4.7g,5.0mmol,1.0当量)在THF:H2O(10:1,133mL:13mL,0.03M)中的溶液中加入四氧化锇(12.4mL,1.0mmol,0.2当量,2.5%溶液),然后加入N-甲基吗啉N-氧化物(1.16g,9.9mmol,2.0当量)。将该反应温热至室温和搅拌13小时或直至通过LCMS或TLC确定该反应完成。将该反应用亚硫酸钠淬灭,用乙酸乙酯稀释,且所述有机层用水洗涤,用硫酸镁干燥,过滤,和真空干燥。将所得油用硅胶柱色谱纯化(二氯甲烷/甲醇作为洗脱液),得到所需产物(C,4.8g,4.9mmol,99%)。
步骤3:4-环庚基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基-7-羟基-3,7-二甲基-12-氧代-2-((E)-4-氧代丁-2-烯-2-基)氧杂环十二-4-烯-6-基酯的合成。
在室温和氮气下,向二醇C(4.4g,4.5mmol,1.0当量)在苯(100mL,0.05M)中的溶液中加入四醋酸铅(4.0g,9.0mmol,2.0当量)。将该反应搅拌30分钟或直至通过LCMS或TLC确定该反应完成。将该反应用亚硫酸钠淬灭并用二氯甲烷稀释。将该有机层用水洗涤,用硫酸钠干燥,过滤,和真空干燥。所述所需产物(D,1.5g,2.3mmol,52%)是粗制的。
步骤4:4-环庚基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基-7-羟基-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯的合成。
注意:(S)-2-(1-((1-苯基-1H-四唑-5-基)磺酰基)丙-2-基)吡啶的合成如下所述并描述于反应式V中。
在-78℃和氮气下,向(S)-2-(1-((1-苯基-1H-四唑-5-基)磺酰基)丙-2-基)吡啶(1.67g,5.08mmol,2.5当量)在无水THF(30.0mL,0.05M)中滴加KHMDS(8.53ml,4.265mmol,2.1当量)并将该反应搅拌10分钟。然后滴加在THF(10mL)中的醛D 4-环庚基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-7-羟基-3,7-二甲基-12-氧代-2-((E)-4-氧代丁-2-烯-2-基)氧杂环-十二-4-烯-6-基酯(1.318g,2.031mmol,1.0当量)。将该反应在-78℃搅拌1小时,然后温热至室温,过夜。将该反应用水淬灭并用乙酸乙酯稀释。将该有机层用水和盐水洗涤,用硫酸镁干燥,过滤,和真空干燥。将所得油用硅胶柱色谱纯化(己烷/乙酸乙酯作为洗脱液),得到所述所需产物(E,1.20g,2.03mmol,79%)。
步骤5:4-环庚基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羟基-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯(化合物1)的合成。
在室温和氮气下,将甲硅烷基醚E(1.80g,2.39mmol,1.0当量)在MeOH(10.0mL,0.24M)中的溶液用pTsOH(1.14g,5.98mmol,2.5当量)处理。将该反应搅拌2小时或直至通过LCMS或TLC确定该反应完成。然后将该反应用乙酸乙酯稀释并用盐水洗涤,用硫酸镁干燥,过滤,并真空干燥。将所得油用制备型TLC(二氯甲烷/甲醇作为洗脱剂)纯化,得到所述所需产物(化合物1,1.19g,1.83mmol,76%)。1H NMR(400MHz,氯仿-d)δ:0.88(d,J=6.65Hz,6H)1.23(s,3H)1.34-1.78(m,12H)1.44(d,J=7.03Hz,3H)1.73(s,3H)2.28-2.39(m,1H)2.45-2.66(m,8H)3.48(br.s.,5H)3.72(m,2H)5.01(d,J=9.54Hz,1H)5.14(d,J=10.67Hz,1H)5.55-5.72(m,2H)6.00(dd,J=15.00,7.47Hz,1H)6.11(d,J=11.29Hz,1H)6.28-6.35(m,1H)7.12(ddd,J=7.47,4.89,1.07Hz,1H)7.16(d,J=7.78Hz,1H)7.61(t,J=7.65Hz,1H)8.55(d,J=4.91Hz,1H)。MS(ES+)=638.4[M+H]+。
化合物2的合成
步骤1:乙酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-2-((R,2E,4E)-7-((2R,3R)-3-((2S,3S)-3-((叔丁基二甲基甲硅烷基)氧基)戊-2-基)环氧乙烷-2-基)-6-羟基-6-甲基庚-2,4-二烯-2-基)-7-羟基-3,7-二甲基-12-氧代氧杂环十二-4-烯-6-基酯的合成。
在0℃和氮气下,将普拉二烯内酯D(F,5.3g,9.7mmol,1.0当量)在DMF(80mL,0.1M)中的溶液用咪唑(4.6g,67.8mmol,7.0当量)和TBSCl(7.3g,48.4mmol,5.0当量)处理。将该反应温热至室温并搅拌20小时或直至通过LCMS或TLC确定该反应完成。将该反应用乙酸乙酯萃取并将有机层用盐水洗涤,用硫酸钠干燥,过滤,和真空干燥。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱剂)纯化,得到所述所需产物(G,7.5g,9.6mmol,99%)。
步骤2:乙酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-2-((6R,E)-7-((2R,3S)-3-((叔丁基二甲基甲硅烷基)氧基)戊-2-基)环氧乙烷-2-基)-4,5,6-三羟基-6-甲基庚-2-烯-2-基)-7-羟基-3,7-二甲基-12-氧代氧杂环十二-4-烯-6-基酯的合成。
在0℃和氮气下,向烯烃G(7.6g,9.7mmol,1.0当量)在脱气的THF:H2O(210mL:21mL,0.01M)中的溶液中加入四氧化锇(24.4mL,1.9mmol,0.2当量,2.5%在叔丁醇中的溶液),然后加入N-甲基吗啉N-氧化物(2.3g,19.5mmol,2.0当量)。将该反应温热至室温并搅拌13小时或直至通过LCMS或TLC确定该反应完成。将该反应用亚硫酸钠淬灭,用乙酸乙酯稀释,并将有机层用水洗涤,用硫酸镁干燥,过滤,和真空干燥。将所得油用硅胶柱色谱(二氯甲烷/甲醇作为洗脱液)纯化,得到所需产物(H,6.8g,8.3mmol,86%)。
步骤3:乙酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-7-羟基-3,7-二甲基-12-氧代-2-((E)-4-氧代丁-2-烯-2-基)氧杂环十二-4-烯-6-基酯的合成。
在室温和氮气下,向二醇H(7.9g,9.7mmol,1.0当量)在苯(350mL,0.03M)中的溶液中加入四醋酸铅(8.6g,19.4mmol,2.0当量)。将该反应搅拌30分钟或直至通过LCMS或TLC确定该反应完成。将该反应浓缩并用硅胶柱色谱(己烷/乙酸乙酯作为洗脱液)纯化,得到所需产物(I,2.5g,5.26mmol,54%)。
步骤4:乙酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-氧代-2-((E)-4-氧代丁-2-烯-2-基)氧杂环十二-4-烯-6-基酯的合成。
在室温,向醛I(1.4g,2.9mmol,1.0当量)在THF(9.5mL,0.5M)中的溶液中加入乙氧基乙烯(11.1mL,40.0当量)和对甲苯磺酸吡啶鎓(0.07g,0.3mmol,0.1当量)。将该反应搅拌24小时或直至通过LCMS或TLC确定该反应完成。将该反应用碳酸氢钠淬灭并用乙酸乙酯稀释。将所述乙酸乙酯用水、盐水洗涤,用硫酸镁干燥,过滤,并真空干燥。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱液)纯化,得到所需产物(J,1.2g,2.2mmol,75%)。
步骤5:乙酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基)酯的合成。
在-78℃氮气下,向(S)-2-(1-((1-苯基-1H-四唑-5-基)磺酰基)丙-2-基)吡啶(695.0mg,2.1mmol,1.5当量)在THF(20mL,0.06M)中的溶液中滴加KHMDS(4.2mL,2.1mmol,1.5当量)并将该反应搅拌20分钟。然后滴加在THF(1.0mL)中的醛J(780.0mg,1.4mmol,1.0当量)。将该反应在-78℃搅拌90分钟并温热至-20℃持续1小时。将该反应用氯化铵淬灭,用乙酸乙酯稀释,并温热至室温。将该有机层用水、盐水洗涤,用硫酸镁干燥,过滤并真空干燥。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱液)纯化,得到所需Julia产物(K,490mg,0.7mmol,53%)。
步骤6:(4R,7R,8S,11S,E)-4-((叔丁基二甲基甲硅烷基)氧基)-7-(1-乙氧基乙氧基)-8-羟基-7,11-二甲基-12-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-9-烯-2-酮的合成。在室温,向乙酸酯K(490mg,0.7mmol,1.0当量)在甲醇(15mL,0.05M)中的溶液中加入碳酸钾(155mg,0.4mmol,1.5当量)。将该反应进行24小时或直至通过LCMS或TLC确定该反应完成。将该反应用水淬灭,用乙酸乙酯稀释,用盐水洗涤,用硫酸镁干燥,过滤,和真空干燥。将所得泡沫状固体(L,459mg,0.7mmol,100%)直接用于下一步而无需进一步纯化。
步骤7:4-甲基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯的合成。在室温下,向醇L(459mg,0.7mmol,1.0当量)在二氯甲烷(0.5mL,0.1M)中的溶液中加入N,N-二甲基氨基吡啶(27.3mg,0.2mmol,0.3当量)和三乙胺(1.0mL,7.4mmol,10.0当量),然后加入氯甲酸4-硝基苯基酯(451mg,02.2mmol,3.0当量)。将该反应在室温搅拌3小时。接下来,在室温加入N-甲基-哌嗪(299mg,2.98mmol,4.0当量)。搅拌1小时后,将该反应用水淬灭并用二氯甲烷稀释。将该有机层用1N氢氧化钠溶液洗涤,并将所述有机层浓缩。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱剂)纯化,得到所需产物(M,553mg,0.75mmol,100%)。
步骤8:4-甲基哌嗪-1-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羟基-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯(化合物2)的合成。在室温,向甲硅烷基醚(M,553mg,0.74mmol,1.0当量)在甲醇(20mL,0.04M)中的溶液中加入对甲氧基甲苯磺酸(425mg,2.2mmol,3.0当量)。将该反应搅拌3小时或直至通过LCMS或TLC确定该反应完成。将该反应用碳酸氢钠淬灭并用乙酸乙酯稀释。将该有机层用水、盐水洗涤,用硫酸镁干燥,过滤,和真空干燥。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱液)纯化,得到所需产物(化合物2,184mg,0.33mmol,44%)。1H NMR(400MHz,氯仿-d)δ:0.82-1.00(m,3H)1.22-1.48(m,8H)1.50-1.63(m,1H)1.66-1.83(m,4H)1.97(s,1H)2.07(s,1H)2.33(s,3H)2.40(br.s.,3H)2.45-2.68(m,3H)3.44-3.61(m,5H)3.74(dd,J=14.2,7.2Hz,2H)5.04(d,J=9.3Hz,1H)5.17(d,J=10.5Hz,1H)5.57-5.76(m,2H)6.02(dd,J=15.1,7.5Hz,1H)6.13(d,J=10.8Hz,1H)6.34(ddd,J=15.1,10.7,1.0Hz,1H)7.14(t,J=6.2Hz,1H)7.18(d,J=7.4Hz,1H)7.63(t,J=7.3Hz,1H)8.57(d,J=5.1Hz,1H)。MS(ES+)=556.4[M+H]。
化合物3的合成
步骤1–6如上述化合物2的合成所提供,得到醇L。
步骤7:4-(氮杂环庚烷-1-基)哌啶-1-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯的合成。在室温,向醇L(300mg,0.49mmol,1.0当量)在二氯甲烷(3.0mL,0.15M)中的溶液中加入N,N-二甲基氨基吡啶(71.4mg,0.58mmol,1.2当量)和三乙胺(0.27mL,1.95mmol,4.0当量),然后加入氯甲酸4-硝基苯基酯(196mg,0.97mmol,2.0当量)。将该反应在室温搅拌3小时。接下来,在室温下加入1-(哌啶-4-基)氮杂环庚烷(265mg,1.46mmol,3.0当量)。搅拌1小时后,将该反应用水淬灭并用二氯甲烷稀释。将该有机层用1N氢氧化钠溶液洗涤,并将所述有机层浓缩。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱剂)纯化,得到所需产物(N,400mg,0.48mmol,100%)。
步骤8:4-(氮杂环庚烷-1-基)哌啶-1-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羟基-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯(化合物3)的合成。在室温,向甲硅烷基醚(N,400mg,0.48mmol,1.0当量)在甲醇(4.0mL,0.1M)中的溶液中加入对甲氧基甲苯磺酸(231mg,1.2mmol,2.5当量)。将该反应搅拌3小时或直至通过LCMS或TLC确定该反应完成。将该反应用碳酸氢钠淬灭并用乙酸乙酯稀释。将该有机层用水、盐水洗涤,用硫酸镁干燥,过滤,和真空干燥。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱液)纯化,得到所需产物(化合物3,226mg,0.35mmol,73%)。1HNMR(400MHz,氯仿-d)δ:0.88(d,J=6.53Hz,3H)1.20-1.28(m,4H)1.35(s,3H)1.45(d,J=7.03Hz,4H)1.59(br.s.,10H)1.74(d,J=0.75Hz,3H)1.75-1.83(m,2H)1.99(s,1H)2.46-2.62(m,3H)2.62-2.71(m,4H)2.79(br.s.,2H)3.51(d,J=9.79Hz,1H)3.63-3.82(m,2H)4.03-4.26(m,2H)5.01(d,J=9.54Hz,1H)5.16(d,J=10.79Hz,1H)5.54-5.64(m,1H)5.65-5.75(m,1H)6.01(dd,J=15.06,7.53Hz,1H)6.12(d,J=11.04Hz,1H)6.25-6.39(m,1H)7.12(ddd,J=7.47,4.83,1.25Hz,1H)7.17(dt,J=8.03,1.00Hz,1H)7.62(td,J=7.65,1.76Hz,1H)8.56(ddd,J=4.96,1.82,1.00Hz,1H)。MS(ES+)=638.6[M+H]。
化合物4的合成
步骤1–6如上文化合物2的合成所提供,得到醇L。
步骤7:[1,4'-联哌啶]-1'-甲酸(2S,3S,6S,7R,10R,E)-10-((叔丁基二甲基甲硅烷基)氧基)-7-(1-乙氧基乙氧基)-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯的合成。在室温,向醇L(20mg,0.032mmol,1.0当量)在二氯甲烷(0.3mL,0.1M)中的溶液中加入N,N-二甲基氨基吡啶(4.8mg,0.04mmol,1.2当量)和三乙胺(0.02mL,0.13mmol,4.0当量),然后加入氯甲酸4-硝基苯基酯(13.1mg,0.065mmol,2.0当量)。将该反应在室温搅拌3小时。接下来,在室温加入1,4'-联哌啶(16.4mg,0.97mmol,3.0当量)。搅拌1小时后,将该反应用水淬灭并用二氯甲烷稀释。将该有机层用1N氢氧化钠溶液洗涤,并将有机层浓缩。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱剂)纯化,得到所需产物(N,18mg,0.22mmol,68.4%)。
步骤8:[1,4'-联哌啶]-1'-甲酸(2S,3S,6S,7R,10R,E)-7,10-二羟基-3,7-二甲基-12-氧代-2-((R,2E,4E)-6-(吡啶-2-基)庚-2,4-二烯-2-基)氧杂环十二-4-烯-6-基酯(化合物4)的合成。在室温,向甲硅烷基醚(N,18mg,0.022mmol,1.0当量)在甲醇(0.5mL,0.04M)中的溶液中加入对甲氧基甲苯磺酸(10.6mg,0.56mmol,2.5当量)。将该反应搅拌3小时或直至通过LCMS或TLC确定该反应完成。将该反应用碳酸氢钠淬灭并用乙酸乙酯稀释。将该有机层用水、盐水洗涤,用硫酸镁干燥,过滤,和真空干燥。将所得油用硅胶柱色谱(己烷/乙酸乙酯作为洗脱液)纯化,得到所需产物(化合物4,4.0mg,0.006mmol,29%)。1H NMR(400MHz,氯仿-d)δ:0.90(d,J=6.8Hz,3H)1.17-1.42(m,5H)1.46(d,J=7.0Hz,6H)1.51-1.65(m,6H)1.65-1.78(m,5H)1.85(d,J=11.5Hz,2H)2.44(d,J=11.3Hz,2H)2.49-2.66(m,6H)2.80(br.s.,2H)3.42-3.62(m,1H)3.63-3.82(m,2H)4.18(br.s.,2H)5.02(d,J=9.5Hz,1H)5.17(d,J=10.8Hz,1H)5.57-5.75(m,2H)6.02(dd,J=15.2,7.4Hz,1H)6.14(d,J=11.0Hz,1H)6.34(ddd,J=15.1,10.8,1.0Hz,1H)7.14(t,J=6.1Hz,1H)7.18(d,J=7.5Hz,1H)7.29(s,2H)7.63(td,J=7.7,1.9Hz,1H)8.57(d,J=5.1Hz,1H)。MS(ES+)=624.6[M+H]。
(S)-2-(1-((1-苯基-1H-四唑-5-基)磺酰基)丙-2-基)吡啶的合成
步骤1:在0℃,向2-(吡啶-2-基)乙酸盐酸盐MMMMMM(50.0g,288.0mmol,1.0当量)在甲醇(500mL,0.5M)中的溶液中滴加亚硫酰氯(31.5mL,432.0mmol,1.5当量)。将该反应在0℃搅拌60分钟或直至通过LCMS或TLC确定该反应完成。将该反应小心地用碳酸钠淬灭并将水层用乙酸乙酯萃取。将合并的有机层用水、盐水洗涤,用硫酸镁干燥,过滤,和真空干燥。所得产物(NNNNNN,41.5g,275.0mmol,95%)用于下一步而无需进一步纯化。
步骤2:在0℃,向酯NNNNNN(41.5g,275.0mmol,1.0当量)在THF(1500mL,0.2M)中的溶液中加入2-甲基丙-2-醇钠(28.6g,288.3mmol,1.05当量)并将该反应混合物在0℃搅拌30分钟,然后加入碘甲烷(34.3mL,549.1mmol,2.0当量)。将该反应在室温搅拌1小时或直至通过LCMS或TLC确定该反应完成。将该反应用氯化铵淬灭并将过量的溶剂真空除去。然后将粗制物用乙酸乙酯萃取。将合并的有机层用盐水洗涤,并用硫酸镁干燥。过滤后,将所述混合物真空干燥。直接使用所得的甲酯(OOOOOO,41.3g,250mmol,91%)而无需纯化。
步骤3:在0℃,向甲酯OOOOOO(43.0g,260.3mmol,1.0当量)在THF(1500mL,0.1M)中的溶液中滴加氢化铝锂(312mL,312.4mmol,1.2当量,在THF中的溶液)。将该反应逐渐温热至0℃持续30分钟和然后温热至室温持续1小时或直至通过LCMS或TLC确定该反应完成。将该反应小心地用水、氢氧化钠和水淬灭。搅拌该混合物30分钟后,将该白色沉淀物过滤掉并将该溶剂真空除去。然后将该反应用乙醚萃取并将合并的有机级分用水、盐水洗涤,用硫酸镁干燥,过滤,和真空干燥。直接使用所得醇(PPPPPP,30.0g,219.0mmol,84%)而无需纯化。
步骤4:在0℃,向醇PPPPPP(30.0g,219.0mmol,1.0当量)在二氯甲烷(700mL,0.3M)中的溶液中加入三乙胺(61.5mL,437.4mmol,2.0当量)和DMAP(2.7g,21.9mmol,0.1当量)。加入醋酸酐(24.8mL,262.4mmol,1.2当量)并将该反应混合物搅拌30分钟或直至通过LCMS或TLC确定该反应完成。将该反应用氯化铵淬灭,将该有机层用盐水洗涤,用硫酸镁干燥并过滤。然后将所得溶液蒸发并在以下步骤中使用该粗制乙酸酯(QQQQQQ,37.0g,206.0mmol,94%)而无需进一步纯化。
步骤5:将乙酸酯QQQQQQ(39.4g,219.8mmol,1.0当量)的溶液溶于乙醚(100mL)和然后加入118g的硅胶。将过量的乙醚真空除去并然后将该粗制固体稀释于pH 7水性缓冲液中(1970mL,0.1M)(氢氧化钠/磷酸二氢钠/水)。加入II型猪胰脂肪酶(3.3g,(15mg/mmol))并将该反应在37℃搅拌4小时或直至TLC或LCMS确定反应完成。(4小时后,根据ELSD,转达率达到40%并通过手性SFC确定对映异构体过量,和显示出13:1S:R的对映异构比率)。(SFC条件:SFC Investigator(Waters/Thar),软件:Chromscope v1.2,方法:Isocratic 15%共溶剂95:5庚烷:IPA+0.1%DEA持续10分钟,柱:Lux-Amylose-2,4.6x250mm,5m,总流量:4ml/min(3.80ml来自CO2泵,0.20ml来自改性剂泵),烘箱温度设定为35℃和系统压力设定为100bar,保留时间:所需和主要的(S)-对映异构体6.9min,次要的(R)-对映异构体8.4min)。将所述硅胶过滤掉并将水层用乙酸乙酯萃取三次。将该合并的有机层用盐水洗涤,用硫酸镁干燥并浓缩。将产物用硅胶柱色谱(己烷:乙酸乙酯作为洗脱剂)纯化,得到所需醇(RRRRRR,12.5g,91mmol,41%)。
步骤6:在室温,向醇RRRRRR(12.5g,91.0mmol,1.00当量)在二氯甲烷(570mL,0.16M)中的溶液中加入三乙胺(13.9mL,100.1mmol,1.1当量)。将该反应冷却至0℃和然后加入甲磺酰氯(7.44mL,95.5mmol,1.05当量)。将该反应在0℃搅拌30分钟或直至用TLC或LCMS确定反应完成。将该反应用碳酸氢钠淬灭并分离层。然后将水层用二氯甲烷萃取。将合并的有机层用盐水洗涤,用硫酸镁干燥,并真空干燥。直接使用所得磺酸酯SSSSSS(19.2g,89mmol,98%)而无需额外的纯化。
步骤7:在室温,向磺酸酯SSSSSS(19.2g,89mmol,1.0当量)在DMF(120mL,0.1M)中的溶液中加入碳酸铯(40.7g,125.0mmol,1.4当量)和1-苯基-1H-四唑-5-硫醇(19.1g,107.1mmol,1.2当量)。将所得混合物在50℃搅拌48小时或直至用TLC或LCMS确定反应完成。将所述混合物冷却至室温,加入盐水并将水层用乙醚萃取三次。将合并的有机层用水、盐水洗涤,并用硫酸镁干燥。过滤后,将溶剂真空除去并将残余物使用硅胶柱色谱(己烷/乙酸乙酯)纯化,得到所需产物(TTTTTT,28.9g,88mmol,99%)。
步骤8:在-10℃,向硫化物TTTTTT(31.5g,105.9mmol,1.0当量)在EtOH(700mL,0.1M)中的溶液中加入四水合钼酸铵(6.5g,5.3mmol,0.05当量)和过氧化氢(108mL,1060mmol,5.0当量,33%水溶液)。将该反应在-10℃搅拌4小时或直至用TLC或LCMS确定反应完成。将该反应用水和焦亚硫酸钠溶液淬灭。将粗制产物通过过滤收集并用硅胶柱色谱(己烷:乙酸乙酯作为洗脱剂)纯化,得到所需产物(UUUUUU,23.2g,70.4mmol,66%)。1H NMR(400MHz,氯仿-d)δ:1.50(d,J=7.03Hz,3H)1.66(br.s.,1H)3.75(m,1H)3.94(dd,J=14.81,5.02Hz,1H)4.55(dd,J=14.68,7.91Hz,1H)7.14-7.22(m,2H)7.29(s,1H)7.57-7.70(m,6H)8.44-8.49(m,1H)。
然后将该无色油使用甲苯/庚烷(1/1)(每100mg化合物用1mL甲苯和1mL庚烷)进行重结晶。轻轻加热该混合物以混合这两种溶剂。将该混合物冷却至室温持续12h。(如果没有观察到重结晶,则向该溶液中加入一种晶体。该晶体将有助于通过引晶过程得到晶体。)该晶体随时间缓慢形成。它们可通过过滤分离或通过移液管除去液体层。然后将该晶体用庚烷洗涤和然后用甲苯快速洗涤。在重结晶之前和之后分析该砜。(SFC条件:SFC条件:SFCInvestigator(Waters/Thar),软件:Chromscope v1.2,方法:Isocratic 10%共溶剂MeOH持续10分钟,柱:ChiralPak IC,4.6x250mm,5um,总流量:4ml/min(3.80ml来自CO2泵,0.20ml来自改性剂泵),烘箱温度设定为35℃和系统压力设定为100bar,保留时间:所需且主要的(S)-对映异构体3.5min,次要的(R)-对映异构体3.8min)。
pH稳定性测量
将化合物提供于96孔板中并以一式三份进行测试。将4微升10mM化合物在DMSO中的储备溶液分配于三个孔中的每个孔中。在分析前将该板在-20℃或低于-20℃进行储存,然后分析。使用甲醇(HPLC级)和0.1N HCl(EMD目录HX0603A-6)进行稀释。使用乙腈(HPLC级)、水(Milli-Q过滤的)、三氟乙酸(光谱级)和0.2M磷酸盐缓冲液(Wako,目录号163-14471)以制备用于两种分析的移动相。
使用装备有UV检测器(Waters TUV)和单四极杆MS检测器(Waters SQD)的WatersAcquity UPLC获得稳定性数据。将含有感兴趣化合物的96孔板从冷冻器中取出并使其温热至室温1小时。将该UPLC进行预处理、平衡并通过注射标准品检验该系统性能。1小时后,将三个孔中的各孔用266μL 0.1N HCl稀释以得到pH=1。盖上板并将该板置于振荡器(Eppindorf Thermomixer R)上,以600rpm持续45分钟。将该板从振荡器上取出,并将各孔的内容物通过过滤板(Millipore目录号MSSLBPC50)真空过滤并注入UPLC。大约24小时后,将该孔的内容物重新注入所述UPLC中。
UPLC仪器参量(稳定性和稳定性测量)
通过比较在24小时注射时间点时在乙醇中的分析物的峰面积-%与在相同保留时间在0.1N HCl缓冲液中的分析物的峰面积-%来测量在不同缓冲液中的稳定性。在表2中报道的稳定性测定显示,在24小时内,在pH 1下的化合物1-4比化合物E7107具有更高的稳定性。
表2:稳定性测试结果
化合物 | 母体剩余%(pH=1,24小时) |
E7107 | 44% |
化合物1 | 91% |
化合物2 | 96% |
化合物3 | 98% |
化合物4 | 99% |
生物测试
细胞存活测定方案
将细胞(获自ATCC的WiDr和Panc05.04)以2000个细胞/100μL/孔接种到96孔板中并培养过夜。除去废培养基并加入含有9个不同浓度的化合物(100μL/孔)的新鲜培养基,将化合物储备溶液的DMSO浓度调节至0.1%。将各化合物在各浓度以一式两份或一式三份进行处理。
将接种有细胞的另一板作为时间零点(Tz)板,向其中加入0.1%DMSO在培养基中(100μL/孔),然后加入试剂(Promega Corporation,Madison,Wisconsin)(50μL/孔)用于作为细胞存活替代的ATP测量。将该板多个孔的测量平均值用作Tz。
将用化合物处理的板在37℃培养72小时。然后,加入试剂(50μL/孔)并测量ATP。将用化合物一式二份或一式三份处理的孔的测量平均值用作Ti,并将具有含0.1%DMSO而不含化合物的培养基的接种板用作对照生长(C)。
生长抑制百分比/存活百分比按如下计算:
[(Ti-Tz)/(C-Tz)]x 100,针对其中Ti>/=Tz的浓度
[(Ti-Tz)/Tz]x 100,针对其中Ti<Tz的浓度。
*时间零点(Tz)、对照生长(C)和在化合物的存在下的测试生长(Ti)
将生长抑制百分比/存活百分比对比化合物浓度进行作图以确定Emax。
由[(Ti-Tz)/(C-Tz)]x 100=50计算50%的生长抑制(GI50),其是在化合物处理过程中导致对照生长(C)中ATP的净增加减少50%的药物浓度。
体外剪接(生物化学)测定方案
通过体外转录制备具有缺失间插序列(Ad2)的第二型腺病毒构建体的生物素标记的前-mRNA(Berg,M.G.,等人。2012Mol.Cell Bio.,32(7):1271-83)。通过基因合成产生含有外显子1(41个核苷酸)、内含子(231个核苷酸)和外显子2(72个核苷酸)的Ad2构建体并通过(South Plainfield,New Jersey)克隆至载体(Promega)的EcoRI和XbaI位点。然后通过XbaI消化将该质粒线性化和纯化。根据制造商的说明,分别使用T7转录试剂盒(InvitrogenTM,Life TechnologiesTM,Grand Island,NewYork)和MEGAclearTM转录纯化试剂盒(InvitrogenTM,Life TechnologiesTM,Grand Island,New York)进行转录的前-mRNA的体外转录和纯化。生物素-16-UTP(Roche DiagnosticsCorporation,Indianapolis,Indiana)与冷的UTP的比例为1:13,以使每个剪接的Ad2 mRNA结合大约两个生物素分子。
在30℃,在25μL含有95μg HeLa核提取物(Promega Corporation,Madison,Wisconsin)、47nM Ad2前-mRNA、25U RNasin RNA酶抑制剂(Promega Corporation,Madison,Wisconsin)、1X SP缓冲液(0.5mM ATP,20mM磷酸肌酸,1.6mM MgCl2)和在DMSO中的化合物(1%最终浓度的DMSO)的反应混合物中进行体外剪接测试。培养90min后,通过加入18μL的5M NaCl将该反应终止,并在室温将该混合物用10μL的M-280抗生蛋白链菌素包被的磁珠(InvitrogenTM,Life TechnologiesTM,Grand Island,New York)培养30min以捕获Ad2前-mRNA和已剪接的mRNA。将该珠用含有10mM Tris pH=7.5、1mM EDTA和2M NaCl的100uL缓冲液洗涤两次,并然后在70℃的含有95%甲酰胺的装载RNA凝胶的缓冲液中培养10min以洗脱所述RNA。将Ad2RNA用6%TBE-UREA凝胶溶解,转移到尼龙膜(UV交联的),并用标记的抗生蛋白链菌素(LI-COR,Lincoln,Nebraska)探测。通过使用LI-CORImage Studio软件测量条带的荧光强度(band fluorescent intensity)来定量剪接RNA的量。
结果
数据报道于下面的表3中。Emax是指在测试剂量范围内对化合物的最大可实现响应(maximum achievable response),其具有指示细胞死亡的负值。较大的负数Emax值表示对特定化合物较大的细胞死亡。例如,在Panc 05.04细胞(突变体SF3B1细胞系)中,较大的负数Emax值表示化合物1比化合物2具有更大的细胞死亡。
WiDr-R细胞是结肠癌细胞,其具有化学诱导的R1074H突变并且已显示出在生长抑制方面对普拉二烯内酯B具有抗性(Yokoi,A.,等人.,2011FEBS Journal,278:4870-4880)。在这个存活力测试中用“抗性”WiDr-R细胞系对化合物的反向筛选可指示这些化合物是否具有脱靶效应。在抗性WiDr-R细胞系中缺乏生长抑制(GI50)活性但在亲本WiDr细胞系中维持活性的化合物表明机制中的(on-mechanism)剪接调节是在亲本WiDr细胞系中观察到的生长抑制的原因。
上述体外剪接(IVS)测定是监测对示例性前-mRNA剪接成mRNA的抑制的生物化学测定。这种生物化学测定使研究人员能够评估这个具体转录物的剪接在非细胞环境中被抑制的化合物浓度,且用于证明机械性剪接抑制活性。
表3:化合物1、2、3和4的生物活性
关键词
Panc 05.04细胞:胰腺癌细胞,突变体SF3B1细胞系(在SF3B1中的Q699H和K700E突变)
WiDr细胞:结肠癌细胞(野生型SF3B1)
WiDr-R细胞:结肠癌细胞(化学诱导的SF3B1突变体,其对E7107(R1074H突变)有抗性)
化合物的其他测试
小鼠药物代谢动力学(PK)研究
以5mg/kg IV(静脉内)或10mg/kg PO(口服给药)的剂量将化合物2给药至CD-1小鼠。给药后,在预定时间点,通过尾静脉的连续抽血,从五只小鼠收集血液样品。在给药后0.083(对于PO仅0.167)、0.5、1、2、4、6、8和24小时收集血液。在血液收集的30分钟内将该血液样品以5000RPM离心5分钟,以收集血浆。萃取后,使用LCMS测定样品。使用在WinNonlinv6.3中的非房室分析(non-compartmental analysis)计算PK参量。
该数据表明,化合物2在小鼠模型中显示出口服生物利用度和有利的药物代谢动力学性质(图1,表4)。
表4
小鼠异种移植模型
化合物2的效力在小鼠异种移植模型中进行测定。将Nalm-6SF3B1K700E等基因细胞(人前B-细胞系,10x106个细胞)皮下植入雌性CB17-SCID小鼠的侧腹。将小鼠用化合物2(10%乙醇,5%TWEEN-80,85%盐水)或媒介物对照进行处理。将该动物以图2所示的量每日口服给药,持续14天(QDx14PO)并监测直至它们达到以下终点之一:1)每周测量三次过度的肿瘤体积(使用椭圆体公式:(长×宽2)/2计算肿瘤体积);或2)任何健康问题的发展,例如麻痹或过度的体重减轻。所有的动物研究是根据实验动物的护理和使用的H3生物医学指南进行的。
该结果表明,当通过口服途径给药化合物2时,其是有效的,且所述化合物2在异种移植小鼠模型中降低肿瘤生长(图2)。
小鼠异种移植模型中的PK/PD测试
还在Nalm-6小鼠异种移植模型中分析化合物2的药物代谢动力学(PK)/药效学(PD)。将Nalm-6SF3B1K700E等基因细胞(人前B-细胞系,10x106个细胞)皮下植入雌性CB17-SCID小鼠的侧腹。向小鼠单次口服剂量给药10mg/kg化合物2(10%乙醇,5%TWEEN-80,85%盐水),并在给药后指定的时间收集肿瘤用于分析。
将RNA使用RiboPureTM RNA纯化试剂盒进行分离并用于qPCR分析。将所述RNA根据VILOTM cDNA合成试剂盒(InvitrogenTM)的说明书进行逆转录,并使用0.04μl的cDNA进行定量PCR(qPCR)。前-mRNA EIF4A1和成熟mRNA SLC24A19的qPCR和PK评估按先前报道进行(Eskens,F.A.等人。Phase I pharmacokinetic andpharmacodynamic study of the first-in-class spliceosome inhibitor E7107 inpatients with advanced solid tumors.Clin Cancer Res.19,6296-6304,doi:10.1158/1078-0432.CCR-13-0485(2013))。所有的动物研究是根据实验动物的护理和使用的H3生物医学指南进行的。
图3中所示的结果指明,通过口服给药途径的化合物2在耐受剂量下显示出PD响应。
细胞存活能力测定
为了评估在化合物2的存在下Panc 05.04癌细胞(SF3B1MUT)(在SF3B1上的Q699H和K700E突变)的存活力,将细胞以每孔750个细胞接种到384孔板上并在37℃以图4中所指定浓度的化合物2处理72小时。使用发光细胞存活测试(Promega),通过发光测定存活的或凋亡的细胞的相对数目。
该结果显示出在突变体SF3B1胰腺癌细胞系中的细胞死亡与在野生型SF3B1胰腺癌细胞系中的细胞死亡的差异(图4)。
针对E7107和化合物2的替代剪接的比较
使用分析系统(NanoString Techologies,Inc.,Seattle,Washington)确定针对E7107和化合物2的替代剪接的调节。将Nalm-6等基因细胞用10x GI50的化合物2或E7107(获自Eisai,Inc.)处理6小时。将RNA用RiboPureTM RNA纯化试剂盒进行分离并用于分析。根据VILOTM cDNA合成试剂盒(InvitrogenTM)的说明书将所述RNA进行逆转录并使用0.04μl的cDNA进行qPCR。
图5中所示的结果表明针对化合物2的剪接调节概况与E7107的概况不同。
化合物1的小鼠药物代谢动力学(PK)研究
向CD-1小鼠给药5mg/kg IV或12mg/kg PO剂量的化合物1。给药后,在预定时间点,通过尾静脉的连续抽血,从五只小鼠收集血液样品。在给药后0.083(对于PO仅0.167)、0.5、1、2、4、6、8和24小时收集血液。在血液收集的30分钟内将该血液样品以5000RPM离心5分钟,以收集血浆。萃取后,使用LCMS分析样品。使用在WinNonlin v6.3中的非房室分析计算PK参量。
该数据表明,化合物1在小鼠模型中显示出口服生物利用度和有利的药物代谢动力学性质(图6,表5)。
表5
化合物1在小鼠异种移植模型中的效力
化合物1的效力在小鼠异种移植模型中进行测定。将Nalm-6SF3B1K700E等基因细胞(人前B-细胞系,10x106个细胞)皮下植入雌性CB17-SCID小鼠的侧腹。将小鼠用化合物1(10%乙醇,5%TWEEN-80,85%盐水)或媒介物对照进行处理。将该动物以7.5mg/kg或10mg/kg化合物1或媒介物的量每日口服给药,持续14天(QDx14PO)并监测直至它们达到以下终点之一:1)每周测量三次过度的肿瘤体积(使用椭圆体公式:(长×宽2)/2计算肿瘤体积);或2)任何健康问题的发展,例如麻痹或过度的体重减轻。所有的动物研究是根据实验动物的护理和使用的H3生物医学指南进行的。
该结果表明,当通过口服途径给药化合物1时,其是有效的,且所述化合物1在异种移植小鼠模型中降低肿瘤生长(图7)。
化合物1在小鼠异种移植模型中的PK/PD测试
化合物1的药物代谢动力学(PK)/药效学(PD)还在Nalm-6小鼠异种移植模型中进行分析。将Nalm-6SF3B1K700E等基因细胞(人前B-细胞系,10x106个细胞)皮下植入雌性CB17-SCID小鼠的侧腹。向小鼠单一口服剂量给药化合物1(10%乙醇,5%TWEEN-80,85%盐水),并在给药后的指定时间收集肿瘤用于分析。
将RNA使用RiboPureTM RNA纯化试剂盒分离并用于qPCR分析。将所述RNA根据VILOTM cDNA合成试剂盒(InvitrogenTM)的说明书进行逆转录,并使用0.04μl的cDNA进行定量PCR(qPCR)。前-mRNA EIF4A1和成熟mRNA SLC24A19的qPCR和PK评估按先前报道进行(Eskens,F.A.等人。Phase I pharmacokinetic and pharmacodynamicstudy of the first-in-class spliceosome inhibitor E7107 in patients withadvanced solid tumors.Clin Cancer Res.19,6296-6304,doi:10.1158/1078-0432.CCR-13-0485(2013))。所有的动物研究是根据实验动物的护理和使用的H3生物医学指南进行的。
图8中所示的结果指明,通过口服给药途径的化合物1在耐受剂量下显示出PD响应。
化合物3的小鼠药物代谢动力学(PK)研究
以5.964mg/kg IV或13.307mg/kg PO的剂量将化合物3给药至CD-1小鼠。给药后,在预定时间点,通过尾静脉的连续抽血,从五只小鼠收集血液样品。在给药后0.083(对于PO仅0.167)、0.5、1、2、4、6、8和24小时收集血液。在血液收集的30分钟内将该血液样品以5000RPM离心5分钟,以收集血浆。萃取后,使用LCMS分析样品。使用在WinNonlin v6.3中的非房室分析计算PK参量。
该数据表明,化合物3在小鼠模型中显示出口服生物利用度和有利的药物代谢动力学性质(图9,表6)。
表6
化合物4的小鼠药物代谢动力学(PK)研究
以5mg/kg IV或10mg/kg PO的剂量将化合物4给药至CD-1小鼠。给药后,在预定时间点,通过尾静脉的连续抽血,从五只小鼠收集血液样品。在给药后0.083(对于PO仅0.167)、0.5、1、2、4、6、8和24小时收集血液。在血液收集的30分钟内将该血液样品以5000RPM离心5分钟,以收集血浆。萃取后,使用LCMS分析样品。使用在WinNonlin v6.3中的非房室分析计算PK参量。
该数据表明,化合物4在小鼠模型中显示出口服生物利用度和有利的药物代谢动力学性质(图10,表7)。
表7
上文所示结果证明化合物1、2、3和4各自具有口服生物利用度和有利的药物代谢动力学性质。这是优于E7107的改进,所述E7107由于其不足的口服生物利用度而以静脉内输注形式给药至患者(Hong等人。(2014),Invest New Drugs 32,436–444)。
Claims (66)
6.权利要求1所述的化合物,其中所述化合物为立体异构体纯的。
7.权利要求1所述的化合物,其中所述化合物包含大于80重量%的该化合物的一种立体异构体。
8.权利要求1所述的化合物,其中所述化合物包含大于90重量%的该化合物的一种立体异构体。
9.权利要求1所述的化合物,其中所述化合物包含大于95重量%的该化合物的一种立体异构体。
10.权利要求1所述的化合物,其中所述化合物包含大于97重量%的该化合物的一种立体异构体。
11.药物组合物,其包含权利要求1所述的化合物和/或其药学上可接受的盐。
12.权利要求11所述的药物组合物,其中所述组合物被配制用于静脉内、口服、皮下或肌内给药。
13.权利要求12所述的药物组合物,其中所述组合物被配制用于口服给药。
14.权利要求1-10中任一项所述的化合物或其药学上可接受的盐或权利要求11-13中任一项所述的药物组合物在制备用于治疗癌症的药物中的用途,所述癌症选自骨髓增生异常综合征、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性粒-单核细胞性白血病、急性髓细胞性白血病、结肠癌、胰腺癌、子宫内膜癌、卵巢癌、乳腺癌、葡萄膜黑色素瘤、胃癌、胆管癌和肺癌。
15.权利要求14所述的用途,其中所述药物用于治疗结肠癌。
16.权利要求14所述的用途,其中所述药物用于治疗胰腺癌。
17.权利要求14所述的用途,其中所述药物用于治疗白血病,所述白血病选自骨髓增生异常综合征、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性粒-单核细胞性白血病、急性髓细胞性白血病。
18.权利要求14所述的用途,所述癌症为骨髓增生异常综合征。
19.权利要求14所述的用途,所述癌症为慢性粒-单核细胞性白血病。
20.权利要求14所述的用途,所述癌症为急性髓细胞性白血病。
21.权利要求14所述的用途,所述癌症为慢性淋巴细胞性白血病。
22.权利要求14所述的用途,所述癌症为急性成淋巴细胞性白血病。
23.权利要求14所述的用途,所述癌症为子宫内膜癌。
24.权利要求14所述的用途,所述癌症为卵巢癌。
25.权利要求14所述的用途,所述癌症为乳腺癌。
26.权利要求14所述的用途,所述癌症为葡萄膜黑色素瘤。
27.权利要求14所述的用途,所述癌症为胃癌。
28.权利要求14所述的用途,所述癌症为胆管癌。
29.权利要求14所述的用途,所述癌症为肺癌。
30.权利要求14所述的用途,所述癌症对剪接体基因或蛋白中的一种或多种突变呈阳性。
31.权利要求30所述的用途,其中所述剪接体基因或蛋白选自:剪接因子3B亚基1(SF3B1)、U2小核RNA辅助因子1(U2AF1)、富含丝氨酸/精氨酸的剪接因子2(SRSF2)、锌指(CCCH型)RNA-结合基序和富含丝氨酸/精氨酸的2(ZRSR2)、前-mRNA-加工-剪接因子8(PRPF8)、U2小核RNA辅助因子2(U2AF2)、剪接因子1(SF1)、剪接因子3a亚基1(SF3A1)、PRP40前-mRNA加工因子40同系物B(PRPF40B)、RNA结合基序蛋白10(RBM10)、聚(rC)结合蛋白1(PCBP1)、弯曲的颈前-mRNA剪接因子1(CRNKL1)、DEAH(Asp-Glu-Ala-His)盒解旋酶9(DHX9)、肽基-脯氨酰基顺-反异构酶-样2(PPIL2)、RNA结合基序蛋白22(RBM22)、小核核糖核蛋白Sm D3(SNRPD3)、可能的ATP-依赖性RNA解旋酶DDX5(DDX5)、前-mRNA-剪接因子ATP-依赖性RNA解旋酶DHX15(DHX15)和聚腺苷酸-结合蛋白1(PABPC1)。
32.权利要求30所述的用途,其中所述剪接体基因或蛋白为剪接因子3B亚基1(SF3B1)。
34.权利要求33所述的药物组合物,其中所述组合物被配制用于静脉内、口服、皮下或肌内给药。
35.权利要求34所述的药物组合物,其中所述组合物被配制用于口服给药。
36.权利要求33-35中任一项所述的药物组合物在制备用于治疗癌症的药物中的用途,所述癌症选自骨髓增生异常综合征、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性粒-单核细胞性白血病、急性髓细胞性白血病、结肠癌、胰腺癌、子宫内膜癌、卵巢癌、乳腺癌、葡萄膜黑色素瘤、胃癌、胆管癌和肺癌。
37.权利要求36所述的用途,其中所述药物用于治疗结肠癌。
38.权利要求36所述的用途,其中所述药物用于治疗胰腺癌。
39.权利要求36所述的用途,其中所述药物用于治疗癌症,所述癌症选自骨髓增生异常综合征、慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性粒-单核细胞性白血病和急性髓细胞性白血病。
40.权利要求36所述的用途,其中所述癌症为骨髓增生异常综合征。
41.权利要求36所述的用途,所述癌症为慢性粒-单核细胞性白血病。
42.权利要求36所述的用途,所述癌症为急性髓细胞性白血病。
43.权利要求36所述的用途,所述癌症为慢性淋巴细胞性白血病。
44.权利要求36所述的用途,所述癌症为急性成淋巴细胞性白血病。
45.权利要求36所述的用途,所述癌症为子宫内膜癌。
46.权利要求36所述的用途,所述癌症为卵巢癌。
47.权利要求36所述的用途,所述癌症为乳腺癌。
48.权利要求36所述的用途,所述癌症为葡萄膜黑色素瘤。
49.权利要求36所述的用途,所述癌症为胃癌。
50.权利要求36所述的用途,所述癌症为胆管癌。
51.权利要求36所述的用途,所述癌症为肺癌。
52.权利要求36所述的用途,所述癌症对在剪接体基因或蛋白中的一种或多种突变呈阳性。
53.权利要求52所述的用途,其中所述剪接体基因或蛋白选自:剪接因子3B亚基1(SF3B1)、U2小核RNA辅助因子1(U2AF1)、富含丝氨酸/精氨酸的剪接因子2(SRSF2)、锌指(CCCH型)RNA-结合基序和富含丝氨酸/精氨酸的2(ZRSR2)、前-mRNA-加工-剪接因子8(PRPF8)、U2小核RNA辅助因子2(U2AF2)、剪接因子1(SF1)、剪接因子3a亚基1(SF3A1)、PRP40前-mRNA加工因子40同系物B(PRPF40B)、RNA结合基序蛋白10(RBM10)、聚(rC)结合蛋白1(PCBP1)、弯曲的颈前-mRNA剪接因子1(CRNKL1)、DEAH(Asp-Glu-Ala-His)盒解旋酶9(DHX9)、肽基-脯氨酰基顺-反异构酶-样2(PPIL2)、RNA结合基序蛋白22(RBM22)、小核核糖核蛋白Sm D3(SNRPD3)、可能的ATP-依赖性RNA解旋酶DDX5(DDX5)、前-mRNA-剪接因子ATP-依赖性RNA解旋酶DHX15(DHX15)和聚腺苷酸-结合蛋白1(PABPC1)。
54.权利要求52所述的用途,其中所述剪接体基因或蛋白为剪接因子3B亚基1(SF3B1)。
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