CN115803327B - Cdk抑制剂 - Google Patents
Cdk抑制剂 Download PDFInfo
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- CN115803327B CN115803327B CN202180046122.2A CN202180046122A CN115803327B CN 115803327 B CN115803327 B CN 115803327B CN 202180046122 A CN202180046122 A CN 202180046122A CN 115803327 B CN115803327 B CN 115803327B
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Abstract
本发明提供了一种可用于治疗癌症的由以下结构式:(I)表示的化合物或其药学上可接受的盐或立体异构体。
Description
相关申请的交叉引用
本申请要求于2020年5月5日提交的国际专利申请第PCT/CN2020/088585号的优先权的权益。前述申请的全部内容以引用的方式并入本文中。
背景技术
细胞周期蛋白依赖性激酶(CDK)是蛋白激酶家族,最初因其在调节细胞周期中的作用而被发现。从那以后,细胞周期蛋白依赖性激酶被鉴定在调节如转录、mRNA加工和神经细胞的分化等许多其它生物功能方面发挥作用。
CDK是分子量介于约34-40kDa之间的相对较小的蛋白质。CDK仅含有激酶结构域,并且在不与一类称为细胞周期蛋白的调节蛋白复合时基本上是无活性的。CDK水平在整个细胞周期中保持相对恒定,并且大多数调节是在翻译后的,最突出的是通过与细胞周期蛋白结合。
像所有激酶一样,CDK的活性位点或ATP结合位点是小的氨基末端叶与较大的羧基末端叶之间的裂缝。人CDK2的结构表明CDK具有可以通过细胞周期蛋白结合进行调节的经修饰的ATP结合位点。CDK活化激酶(CAK)在T环上的Thr 161处的磷酸化增加了复合物的活性。在没有细胞周期蛋白的情况下,称为活化环或T环的灵活环会阻断裂隙,并且几个关键氨基酸残基的位置对于ATP结合不是最佳的。在有细胞周期蛋白的情况下,两个α螺旋会改变位置以允许ATP结合。所述螺旋中的一个螺旋,即刚好在一级序列中的T环之前的L12螺旋变成β链,并且帮助重新排列T环,因此它不再阻断活性位点。另一个称为PSTAIRE螺旋的α螺旋会重新排列,并且帮助改变活性位点中关键氨基酸残基的位置。
因此,只有细胞周期蛋白-CDK复合物具有活性激酶活性,并且大多数已知的细胞周期蛋白-CDK复合物通过细胞周期调节进程。CDK在所有已知的真核生物中无处不在,并且CDK在细胞周期中的调节功能在进化上是保守的。例如,当酵母细胞的CDK基因被人同源基因取代时,酵母细胞可以正常增殖。CDK通过在某些特定的丝氨酸和苏氨酸残基以及[S/T]PX[K/R]的共有序列上磷酸化其底物来发挥其调节功能,其中S/T是用于磷酸化的靶Ser或Thr,P是脯氨酸,X是任何氨基酸,K是赖氨酸,并且R是精氨酸。
在动物细胞中,有至少九种不同的CDK,其中四种(CDK1、2、3和4)直接参与细胞周期调节。在哺乳动物细胞中,CDK1和其结合伙伴细胞周期蛋白A2和B1可以单独驱动细胞周期。早期细胞周期阶段的细胞周期蛋白-CDK复合物可以帮助在后期阶段活化细胞周期蛋白-CDK复合物。
相同的CDK可能与不同的细胞周期蛋白形成复合物以调节细胞周期的不同阶段。例如,CDK2可以与细胞周期蛋白D或E形成复合物以调节G1阶段;与细胞周期蛋白A或E形成复合物以调节S阶段;并且与细胞周期蛋白A形成复合物以调节G2阶段。同时,CDK4和CDK6可以与细胞周期蛋白D1、D2和D3形成复合物。
高度同源的细胞周期蛋白依赖性激酶(CDK)CDK4和CDK6与细胞周期蛋白D组合是通过细胞周期的G1(生长)阶段与S(DNA复制)阶段之间的限制点R转变的关键调节剂。CDK4/6通过视网膜母细胞瘤蛋白(pRb)的磷酸化发挥其作用。一旦磷酸化,pRb就失去了对促进进入S阶段的基因转录的抑制作用。
相比之下,内源性蛋白质调节剂p16INK4或小分子抑制剂对CDK4/6激酶活性的特异性抑制导致低磷酸化pRb和细胞在G1限制点处停滞。作为调节G1限制点的主要机制,这些激酶调节的通路在广谱的人肿瘤中发生改变,因此在这些肿瘤中抑制CDK4/CDK6通过阻止细胞分裂具有治疗益处。
仍然需要提供可以用于治疗如癌症等细胞增殖性病症的CDK4/6抑制剂。
发明内容
本文描述了抑制细胞周期蛋白依赖性激酶(CDK),例如CDK2、CDK4和/或CDK6活性的化合物和其药学上可接受的盐或立体异构体。
一方面,本发明提供了一种由以下结构式表示的化合物:
(化合物A)或其药学上可接受的盐。发现化合物A不仅对CDK2、CDK4和CDK6有积极的抑制作用,而且具有强的抗增殖活性。
另一方面,本发明提供了一种由以下结构式表示的化合物:
(化合物B)或其药学上可接受的盐。发现化合物B选择性地抑制CDK4,但具有极好的脑穿透性。
还提供了包括本文所公开的化合物或其药学上可接受的盐或立体异构体以及药学上可接受的载体的药物组合物。
本公开进一步提供了一种治疗有需要的受试者的癌症的方法,所述方法包括向受试者施用有效量的(1)本文所公开的化合物或其药学上可接受的盐或立体异构体;或(2)包括本文所公开的化合物或其药学上可接受的盐或立体异构体以及药学上可接受的载体的药学上可接受的组合物。在某些实施例中,癌症选自由以下组成的组:结直肠癌、乳腺癌(如绝经后女性中激素受体阳性、HER2/neu阴性晚期或转移性乳腺癌)、肺癌、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病。
在本发明的方法的某些实施例中,可以通过抑制细胞周期蛋白依赖性激酶(CDK),例如CDK2、CDK4和/或CDK6的活性来治疗癌症。
在本发明的方法的某些实施例中,所述癌症是膀胱癌、乳腺癌、结肠癌、肾癌、表皮癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、鼻癌、头颈癌、前列腺癌或皮肤癌;淋巴系造血肿瘤;髓系造血肿瘤;甲状腺滤泡状癌;间充质起源的肿瘤;中枢或外周神经系统肿瘤;黑色素瘤;精原细胞瘤;畸胎瘤;骨肉瘤;着色性干皮病;角化棘皮瘤;甲状腺滤泡状癌;或卡波西氏肉瘤(Kaposi′s sarcoma)。
在本发明的方法的某些实施例中,本文所公开的化合物与如本文所描述的也治疗相同癌症的第二治疗剂中的任何一种第二治疗剂一起施用。
本公开还提供了本文所公开的化合物或其药学上可接受的盐或立体异构体或包括它们的药物组合物在上文所描述的本发明的方法中的任何方法中的用途。在一个实施例中,提供了用于上文所描述的本发明的方法中的任何方法的本文所公开的化合物或其药学上可接受的盐或立体异构体或包括它们的药物组合物。在另一个实施例中,提供了本文所公开的化合物或其药学上可接受的盐或立体异构体或包括它们的药物组合物用于制造用于所描述的本发明的方法中的任何方法的药物的用途。
具体实施方式
1.概述
本发明提供了一种用于如癌症疗法等疗法的本发明的化合物或其药学上可接受的盐。
本发明还提供了一种药物调配物,所述药物调配物包括本发明的化合物或其药学上可接受的盐以及药学上可接受的载体、稀释剂或赋形剂。
本发明提供了一种可用于治疗癌症的本发明的化合物或其药学上可接受的盐。具体地,那些癌症可以是本文下文所描述的癌症中的任何癌症,如结肠直肠癌、乳腺癌(包含ER+HER2-晚期或转移性或复发性乳腺癌发生于成年女性或绝经后女性)、肺癌、特别是非小细胞肺癌(NSCLC)、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤(MCL)、慢性粒细胞白血病(CML)和急性粒细胞白血病(AML)。
本发明进一步提供了一种治疗哺乳动物的癌症的方法,所述癌症选自由以下组成的组:结直肠癌、乳腺癌(包含ER+HER2-晚期或转移性或复发性乳腺癌发生于成年女性或绝经后女性)、肺癌,特别是非小细胞肺癌(NSCLC)、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病,所述方法包括向需要此类治疗的哺乳动物施用有效量的本发明的化合物或其药学上可接受的盐。
另外,本发明提供了本发明的化合物或其药学上可接受的盐用于制备用于治疗癌症的药物的用途。具体地,那些癌症选自由以下组成的组:结肠直肠癌、乳腺癌(包含ER+HER2-晚期或转移性或复发性乳腺癌发生于成年女性或绝经后女性)、肺癌、特别是非小细胞肺癌(NSCLC)、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病。
此外,本发明提供了一种用于疗法的药物调配物,所述药物调配物包括本发明的化合物或其药学上可接受的盐以及药学上可接受的载体、稀释剂或赋形剂。本发明还提供了一种用于治疗结肠直肠癌、乳腺癌(包含ER+HER2-晚期或转移性或复发性乳腺癌发生于成年女性或绝经后女性)、肺癌、特别是非小细胞肺癌(NSCLC)、前列腺癌、胶质母细胞瘤、套细胞淋巴瘤、慢性粒细胞白血病和急性粒细胞白血病的药物组合物,所述药物组合物包括本发明的化合物或其药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
可治疗的疾病适应症和可用于组合疗法的潜在第二治疗剂在以下部分中进一步详细描述。
应当理解,本文所描述的任何实施例,包含仅在以下部分之一中或仅在实例中描述的那些,可以与本发明的任何一个或多个另外的实施例组合,除非明确否认或以其它方式不适当/不适用。
2.定义
本文所描述的化合物可以包括一个或多个不对称中心,因此可以以各种立体异构的形式存在,例如,对映异构体和/或非对映异构体。例如,本文所描述的化合物可以是单独的对映异构体、非对映异构体或几何异构体的形式,或可以是立体异构体混合物的形式,包含外消旋混合物和富集一种或多种立体异构体的混合物。
对映异构混合物及非对映异构混合物可以通过如手性相气相色谱法、手性相高效液相色谱法、使化合物结晶为手性盐复合物或使化合物在手性溶剂中结晶等众所周知的方法解析为其组分对映异构体或立体异构体。对映异构体和非对映异构体也可以通过众所周知的不对称合成方法从非对映异构或对映异构纯中间体、试剂和催化剂中获得。参见例如Jacques等人,《对映体、外消旋体和拆分(Enantiomers,Racemates and Resolutions)》(威利国际科学出版公司(Wiley Interscience),纽约,1981);Wilen等人,《四面体(Tetrahedron)》33:2725(1977);Eliel,E.L.《碳化合物的立体化学(Stereochemistry ofCarbon Compounds)》(纽约麦格劳-希尔出版公司(McGraw-Hill,NY),1962);以及Wilen,S.H.《拆分剂和光学拆分表(Tables ofResolving Agents and Optical Resolutions)》第268页(E.L.Eliel,编辑,印地安纳州诺特丹的圣母大学出版社(Univ.of Notre DamePress,Notre Dame,IN)1972)。
当化合物通过指示单一对映异构体的名称或结构表示时,除非另有说明,否则所述化合物的光学纯度至少为60%、70%、80%、90%、99%或99.9%(也称作“对映异构体纯的”)。光学纯度是混合物中所命名或描绘的对映异构体的重量除以混合物中两种对映异构体的总重量。
当所公开化合物的立体化学通过结构命名或描绘,并且命名或描绘的结构涵盖多于一种立体异构体(例如,如在非对映异构体中)时,应理解包含所涵盖的立体异构体之一或所涵盖的立体异构体的任何混合物。应进一步理解,所命名或描绘的立体异构体的立体异构纯度为至少60重量%、70重量%、80重量%、90重量%、99重量%或99.9重量%。在这种情况下,通过将混合物中所述名称或结构所涵盖的立体异构体的总重量除以混合物中所有立体异构体的总重量来确定立体异构纯度。
当几何异构体通过名称或结构描绘时,应理解命名或描绘的几何异构体的几何异构纯度至少为60%、70%、80%、90%、99%或99.9%的纯度(按重量计)。通过将混合物中命名或描绘的几何异构体的重量除以混合物中两种几何异构体的总重量来确定几何异构体纯度。
外消旋混合物是指50%的一种对映异构体及50%的对应对映异构体。本发明涵盖本发明的化合物的所有对映体纯的、对映体富集的、非对映体纯的、非对映体富集的和外消旋混合物以及非对映体混合物。
本文所描述的化合物还可以包含出现在中间体或最终化合物中的所有原子同位素。同位素包含具有相同原子序数但不同质量数的那些原子。例如,氢的同位素包含氚和氘。
将认识到,根据合成中使用的化学材料的来源,合成化合物中会出现一些天然同位素丰度的变化。因此,本文所公开的化合物的制剂将固有地含有少量的氘化同位素体。与本发明的化合物的稳定同位素取代程度相比,尽管有这种变化,但天然丰富的稳定氢和碳同位素的浓度小且无关紧要。参见例如Wada,E等人,生化学工业株式会社(Seikagaku),1994,66:15;Gannes,LZ等人,《比较生物化学和生理学(Comp Biochem Physiol MolIntegr Physiol)》,1998,119:725。
本文所描述的化合物可以以各种互变异构形式存在。术语“互变异构体”或“互变异构体”是指两个或两个以上可相互转化的化合物/取代基,它们是通过至少一次形式上氢原子迁移和至少一个化合价变化(例如,单键到双键、三键到单键,反之亦然)产生的。示例性互变异构化包含酮-烯醇、酰胺-酰亚胺、内酰胺-内酰胺、烯胺-亚胺和烯胺-(不同的烯胺)互变异构化。本发明的教导涵盖互变异构体形式的化合物,所述化合物包含结构上未描绘的形式。此类化合物的所有此类异构体形式明确地包含在内。如果化合物的互变异构体是芳香族的,则此化合物是芳香族的。类似地,如果化合物的互变异构体是杂芳基,则此化合物是杂芳基。
在某些情况下,存在所公开化合物的互变异构形式,如下文所示出的互变异构结构:
应当理解,当本文的化合物由结构式表示或由本文的化学名称指定时,所述化合物可能存在的所有其它互变异构形式都涵盖在结构式中。
本发明的化合物可以以用于治疗的游离形式存在或在适当时作为药学上可接受的盐形式存在。
术语“药学上可接受的盐”是指在合理医学判断范围内适用于与人和低等动物的组织接触,而没有过度毒性、刺激、过敏反应等并具有合理的效益/风险比的那些。药学上可接受的盐是本领域众所周知的,例如,Berge等人在通过引用并入本文的《药物科学杂志(J.Pharmaceutical Sciences)》,1977,66,1-19中详细描述了药学上可接受的盐。本发明的化合物的药学上可接受的盐包含衍生自合适的无机和有机酸和碱的盐。药学上可接受的酸加成盐的实例是与无机酸如盐酸、氢溴酸、磷酸、硫酸和高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸形成或通过使用本领域中已知的其它方法如离子交换形成的具有氨基的盐。其它药学上可接受的盐包含己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑、磺酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸、己酸盐、氢碘酸、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸钠、十一酸盐、戊酸盐等。衍生自适当碱的盐包含碱金属盐、碱土金属盐、铵盐和N+(C1-4烷基)4 -盐。代表性的碱金属或碱土金属盐包含钠、锂、钾、钙、镁等。另外的药学上可接受的盐包含在适当时使用抗衡离子(如卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐)形成的铵、季铵和胺阳离子。
此类药学上可接受的酸加成盐和制备它们的常用方法是本领域众所周知的。参见例如Stahl等人,《药用盐手册:性质、选择和使用(HANDBOOK OF PHARMACEUTICAL SALTS:PROPERTIES,SELECTION AND USE)》,(VCHA/威利-VCH,2002);Bighley等人,于“药学技术百科全书(Encyclopedia ofPharmaceutical Technology)”中编辑;Swarbrick和Boylan,第13卷,马塞尔德克尔公司(Marcel Dekker,Inc.),纽约,巴塞尔,香港1995,第453-499页;Berge等人,“药物盐(Pharmaceutical Salts)”《药物科学杂志》,66(1):1977。
术语“组合物”和“调配物”可互换使用。
“受试者”是哺乳动物,优选地人,但也可以是需要兽医治疗的动物,例如伴侣动物(例如,狗、猫等)、农场动物(例如,牛、羊、猪、马等)和实验室动物(例如,大鼠、小鼠、豚鼠等)。
术语“施用(administer)”、“施用(administering)”或“施用(administration)”是指将本发明的化合物或其组合物引入受试者体内或受试者上的方法。这些方法包含但不限于关节内(在关节中)、静脉内、肌肉内、肿瘤内、皮内、腹膜内、皮下、口服、局部、鞘内、吸入、经皮、直肠等。可以与本文所描述的药剂和方法一起使用的施用技术见于例如Goodman和Gilman,《治疗学的药理学基础(The Pharmacological Basis of Therapeutics)》,当前版本;Pergamon;和《雷明顿氏药物科学(Remington′s,Pharmaceutical Sciences)》(当前版本),宾夕法尼亚州伊斯顿市的马克出版公司(Mack Publishing Co.,Easton,Pa.)。
术语“治疗(treatment)”、“治疗(treat)”和“治疗(treating)”是指逆转、缓解或抑制如本文所描述的疾病的进展。在一些实施例中,可以在疾病的一种或多种体征或症状已经发展或已经观察到之后施用治疗(即,治疗性治疗)。在其它实施例中,可以在不存在疾病的体征或症状的情况下施用治疗。例如,可以在症状发作之前对易感受试者施用治疗(即,预防性治疗)(例如,根据症状史和/或根据暴露于病原体)。症状消退后,也可以继续治疗,例如延迟或预防复发。
术语“病状”、“疾病”和“病症”可互换使用。
通常,本文教导的化合物的有效量根据如给定的药物或化合物、药物调配物、施用途径、疾病或病症的类型、被治疗的受试者或宿主的身份等各种因素而有所不同,但仍然可以由本领域技术人员常规确定。普通技术人员可以通过本领域已知的常规方法容易地确定本发明的教导的化合物的有效量。
术语“有效量”意指当施用于受试者时,与对照相比,产生有益的或期望的结果,包含临床结果,例如抑制、压制或减轻受试者所治疗病症的症状的量。例如,可以以单位剂型给予有效量(例如,每天1mg到约50g,例如,每天1mg到约5g)。
“治疗有效量”是用于可检测地杀死或抑制癌细胞的生长或扩散;肿瘤的大小或数量;或癌症水平、阶段、进展或严重程度的其它度量的有效量。根据受试者的物种、年龄和一般状况、疾病的严重程度、特定抗癌剂、其施用方式、与其它疗法组合治疗等,需要的精确量将因受试者而异。
上式中使用的一般化学术语具有其通常的含义。
如本文所使用的,“h”是指一个或多个小时,“min”是指一分钟或多分钟,“Cdk”或“CDK”是指细胞周期蛋白依赖性激酶,“pRb”是指视网膜母细胞瘤蛋白,“MCL”是指套细胞淋巴瘤,“AML”是指急性髓性白血病,“CML”是指慢性髓性白血病,“Boc”是指N-叔丁氧基羰基,“EA”是指乙酸乙酯,“DCM”是指二氯甲烷,“DMSO”是指二甲亚砜,“DMA”是指二甲基乙酰胺,“THF”是指四氢呋喃,“MtBE”是指甲基叔丁基醚,“TEA”是指三乙胺,“FBS”是指胎牛血清,“PBS”是指磷酸盐缓冲盐水,“BSA”是指牛血清白蛋白,“RT”是指室温,“mpk”意指毫克/千克,“po”是指口服(口服),“qd”意指每天给药一次,“HPLC”意指高压液相色谱法,“q2d”意指每2天单个剂量,“q2dx10”意指每2天单个剂量乘以10次,“VSMC”是指血管平滑肌细胞,并且“XRD”是指X射线衍射。
3.化合物
本公开的另一方面涉及本发明的标记的化合物(放射性标记的、荧光标记的等),所述标记的化合物不仅可用于成像技术,而且可在体外和体内测定中用于定位和定量组织样品(包含人)中的CDK,并通过抑制标记的化合物的结合来鉴定CDK配体。因此,本公开包含此类标记的化合物。
本公开进一步包含同位素标记的本发明的化合物。“同位素标记的”或“放射性标记的”化合物是本发明的这样一种化合物,其中一个或多个原子被具有不同于典型地在自然界中发现的(即,天然存在的)原子质量或质量数的原子质量或质量数的原子替换或取代。可以掺入本发明的化合物中的合适放射性核素包含但不限于2H(对于氘也写作D)、3H(对于氚也写作T)、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125I和131I。并入本发明放射性标记的化合物中的放射性核素将取决于所述放射性标记的化合物的具体应用。
本发明可以进一步包含用于将放射性同位素掺入本发明的化合物的合成方法。用于将放射性同位素掺入有机化合物的合成方法是本领域众所周知的,并且本领域普通技术人员将容易地认识到适用于本发明的化合物的方法。
本发明的标记的化合物可以用于筛选测定以鉴定/评估化合物。例如,新合成或鉴定的被标记的化合物(即,测试化合物)可以通过借助于跟踪标记来监测其与CDK接触时的浓度变化来评估其结合CDK的能力。例如,可以评估测试化合物(标记的)降低已知与CDK(即标准化合物)结合的另一种化合物的结合的能力。因此,测试化合物与标准化合物竞争结合CDK的能力与其结合亲和力直接相关。相反,在一些其它筛选测定中,标准化合物被标记而测试化合物未被标记。因此,监测标记的标准化合物的浓度以便评估标准化合物与测试化合物之间的竞争,从而确定测试化合物的相对结合亲和力。
在一个实施例中,所述化合物或其药学上可接受的盐或立体异构体,其中一个或多个氢原子被氘替换。
4.可治疗的疾病和治疗方法
本发明的某些化合物是CDK2、CDK4和/或CDK6的选择性抑制剂,因此可用于治疗以异常细胞增殖为特征的疾病或病症,所述异常细胞增殖可以通过降低的涵盖CDK2、CDK4和/或CDK6的CDK-细胞周期蛋白复合物的活性来抑制。
在某些实施例中,本发明的化合物相对于CDK2选择性抑制CDK4/6,后者(CDK2)与前者(CDK4/6)的IC50值的比率为至少约10、20、50、100、200、300、400、500、800、1,000、2,000或更多。
在某些实施例中,本发明的化合物相对于CDK6选择性抑制CDK4,后者(CDK6)与前者(CDK4)的IC50值的比率为至少约2、3、4、5、6、7、8、9、10、15、20、50或更多。
在某些实施例中,本发明的化合物相对于CDK2选择性抑制CDK4,后者(CDK4)与前者(CDK2)的IC50值的比率为至少约2、5、10、15、20、40、50、60、80、100或更多。
在某些实施例中,本发明的化合物以类似的IC50值抑制CDK2/4/6,例如IC50值在10倍、5倍、3倍或2倍内。本发明的此类化合物可用于治疗具有细胞周期蛋白D1或E1或E2扩增或增强表达的癌症。
CDK2是CDK-细胞周期蛋白复合物的催化亚基,其活性仅限于细胞周期的G1-S阶段,在此期间细胞制造有丝分裂所必需的蛋白质并复制其DNA。CDK2与细胞周期蛋白E或A复合。细胞周期蛋白E结合G1阶段CDK2,这是G1到S阶段转变所必需的。另一方面,CDK2与细胞周期蛋白A结合需要通过S阶段。
尽管CDK2在正常功能细胞的细胞周期中几乎是可有可无的,但它对癌细胞的异常生长过程至关重要。细胞周期蛋白E的过表达发生在许多肿瘤细胞中,导致细胞变得依赖CDK2和细胞周期蛋白E。在乳腺癌、肺癌、结肠直肠癌、胃癌和骨癌以及白血病和淋巴瘤中观察到异常的细胞周期蛋白E活性。同样,细胞周期蛋白A2的异常表达与染色体不稳定性和肿瘤增殖相关,而抑制会导致肿瘤生长减少。因此,CDK2和其细胞周期蛋白结合伙伴表示新的癌症疗法的可能治疗靶标。临床前模型在限制肿瘤生长方面示出初步成功,并且还观察到减少当前化疗药物的副作用。
例如,Caldon等人(《分子癌症治疗学(Mol Cancer Ther)》11(7):1488-1499,2012)报道,细胞周期蛋白E2包含在预测它莫西芬(tamoxifen)抗性或转移性乳腺癌疾病进展的若干个基因特征中,并且CycE2的高表达是乳腺癌的luminal B和HER2亚型的特征,并且强烈预测内分泌疗法后更短的无远处转移生存率。进一步地,它莫西芬抗性(MCF-7TAMR)乳腺癌细胞过表达细胞周期蛋白E2;并且T-47D乳腺癌细胞中细胞周期蛋白E1或E2的表达导致急性抗雌激素抗性,表明细胞周期蛋白E过表达有助于它莫西芬抗性细胞的抗雌激素抗性。细胞周期蛋白E1、细胞周期蛋白E2或CDK2的RNAi介导的敲低抑制了它莫西芬抗性细胞的增殖。此外,细胞周期蛋白E1或E2的异位表达也会降低对CDK4抑制的敏感性,但不会降低对CDK2抑制的敏感性。此外,E-细胞周期蛋白过表达细胞和它莫西芬抗性细胞的CDK2抑制恢复了对它莫西芬或CDK4抑制的敏感性。
这些数据表明,细胞周期蛋白E2过表达是对内分泌疗法和CDK4抑制产生抗性的潜在机制,并且CDK2抑制剂可以进而克服此类抗性,并且作为内分泌抗性疾病组合疗法的组分可以是有益的,因为所述抑制剂有效地抑制细胞周期蛋白E1和E2过表达细胞并增强其它疗法的功效。同样,预期对CDK2和CDK4两者具有强抑制活性的主题化合物对于对内分泌疗法或CDK4抑制具有非抗性和抗性的癌细胞有效。
因此,在某些实施例中,本发明的化合物可以对CDK2和CDK4两者具有强抑制作用(例如,独立地<10nM,<5nM,<1nM水平的IC50值),因此可有效治疗如具有CycE过表达的它莫西芬抗性或转移性乳腺癌等它莫西芬抗性或转移性乳腺癌。
本发明的化合物对CDK2/4/6的IC50值可以使用例如实例1到3(通过引用并入本文)中描述的方法测量。
具体地,本发明的化合物可用于治疗癌症。在其它实施例中,本发明的化合物可用于治疗如关节炎和囊性纤维化等慢性炎性疾病。
因此,一方面,本发明提供了一种治疗哺乳动物的癌症,特别是本文所描述的癌症的方法,所述方法包括向需要此类治疗的哺乳动物施用有效量的本发明的化合物。
在相关方面,本发明涉及本发明的化合物在制造用于治疗癌症,特别是本文所描述癌症的药物中的用途。
在另一个相关方面,本发明的化合物可以用于制造用于治疗癌症,特别是本文所描述癌症的药物。
在另一个相关方面,本发明提供了可用于治疗癌症,特别是本文所描述癌症的本发明的化合物。
根据本发明的上述相关方面中的任何相关方面,CDK4和CDK6可以部分地通过pRb磷酸化调节它们对细胞周期的作用。因此,本发明的某些化合物可以通过在任何癌症类型中抑制CDK4/6活性,并且从而抑制细胞增殖和/或肿瘤生长来抑制pRb磷酸化,其中细胞正在增殖并且含有编码pRb的功能性、完整Rb1基因。
因此,在某些实施例中,本发明的化合物可用于治疗哺乳动物的如以下等pRb+癌症:结肠直肠癌、乳腺癌、肺癌、前列腺癌、慢性粒细胞白血病、急性粒细胞白血病(Fry等人,《分子癌症疗法(Mol.Cancer Ther.)》3(11):1427,2004)、套细胞淋巴瘤(Marzec等人,《血液(Blood)》108(5):1744,2006)、卵巢癌(Kim等人,《癌症研究(Cancer Research)》54:605,1994)、胰腺癌(Schutte等人,《癌症研究》57:3126,1997)、恶性黑色素瘤和转移性恶性黑色素瘤(Maelandsmo等人,《英国癌症杂志(British Journal of Cancer)》73:909,1996)。还预期本发明的化合物可用于治疗横纹肌肉瘤(Saab等人,《分子癌症疗法》5(5):1299,2006)和多发性骨髓瘤(Baughn等人,《癌症研究》66(15):7661,2006),包含哺乳动物(例如,人)的复发难治性多发性骨髓瘤。
同时,Zhang等人(Nature dx.doi.org/10.1038/nature25015,2017)报道,体内CDK4/6的抑制可能会导致磷酸化减少,从而增加Cullin 3SPOP E3连接酶(通过APC/Ccdh1)的降解,进而导致增加肿瘤细胞表面的PD-L1水平,并且减少小鼠肿瘤和原发性人前列腺癌样本中肿瘤浸润淋巴细胞(TIL)的数量。换句话说,体内抑制CDK4/6会提高PD-L1蛋白水平,并且有助于增加对靶向PD-1(程序性细胞死亡蛋白1)和PD-L1(PD-1配体)的免疫检查点疗法的抗性。另一方面,将CDK4/6抑制剂治疗与抗PD-1免疫疗法组合会增强肿瘤消退,并且显著提高小鼠肿瘤模型的总体存活率。
因此,在某些实施例中,本发明的化合物可与PD-1/PD-L1免疫检查点抑制剂组合使用以增强对人癌症的治疗功效。
可以与本发明的化合物一起使用的PD-1和PD-L1抑制剂是本领域已知的。PD-1抑制剂包含对PD-1具有特异性的单克隆抗体或其抗原结合片段。示例性PD-1抑制剂包含派姆单抗(Pembrolizumab)(可瑞达(Keytruda))、纳武单抗(Nivolumab)(欧狄沃(Opdivo))和西米普利单抗(Cemiplimab)(利伯塔约(Libtayo))。PD-L1抑制剂包含对PD-L1具有特异性的单克隆抗体或其抗原结合片段。示例性PD-L1抑制剂包含阿特朱单抗(Atezolizumab)(特森特里克(Tecentriq))、阿维鲁单抗(Avelumab)(巴文西亚(Bavencio))和度伐利尤单抗(Durvalumab)(因芬齐(Imfinzi))。
可以与本发明的化合物一起使用以增强对人癌症的治疗功效的另外的免疫检查点抑制剂包含对CTLA-4具有特异性的如易普利姆玛(Ipilimumab)(耶沃伊(Yervoy))等单克隆抗体或其抗原结合片段。
可以与本发明的化合物一起使用以增强对人癌症的治疗功效的另外的免疫检查点抑制剂包含对PD-1和PD-L1具有特异性的双特异性单克隆抗体或其抗原结合片段或对PD-1和PD-L1或PD-1和CTLA-4等具有特异性的单克隆抗体或其抗原结合片段的组合。
在某些实施例中,本发明的化合物可以与Tyr激酶抑制剂,例如受体Tyr激酶(RTK)抑制剂组合使用以增强对人癌症的治疗功效。示例性Tyr激酶抑制剂包含ALK抑制剂(如克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、艾乐替尼(Alectinib)、布加替尼(Brigatinib))、Bcr-Abl抑制剂(如博舒替尼(Bosutinib)、达沙替尼(Dasatinib)、伊马替尼(Imatinib)、尼罗替尼(Nilotinib)、普纳替尼(Ponatinib))、BTK抑制剂(如依鲁替尼(Ibrutinib))、c-Met抑制剂(如克唑替尼、卡博替尼(Cabozantinib))、EGFR抑制剂(如吉非替尼(Gefitinib)、厄洛替尼(Erlotinib)、拉帕替尼(Lapatinib)、凡德他尼(Vandetanib)、阿法替尼(Afatinib)、奥希替尼(Osimertinib))、JAK抑制剂(如鲁索替尼(Ruxolitinib)、托法替尼(Tofacitinib))、MEK1/2抑制剂(如曲美替尼(Trametinib))、PDGFR抑制剂(如阿昔替尼(Axitinib)、吉非替尼、伊马替尼(Imatinib)、乐伐替尼(Lenvatinib)、尼达尼布(Nintedanib)、帕唑帕尼(Pazopanib)、瑞戈非尼(Regorafenib)、索拉非尼(Sorafenib)、舒尼替尼(Sunitinib))、RET抑制剂(如凡德他尼)、Src家族激酶抑制剂(如博舒替尼、达沙替尼、波纳替尼、凡德他尼)和VEGFR家族抑制剂(如阿西替尼、乐伐替尼、尼达尼布、瑞戈非尼、帕唑帕尼、索拉非尼、舒尼替尼)。
可以与主题化合物组合使用的另外的合适激酶抑制剂以及可治疗的癌症适应症,描述于Bhullar等人,《分子癌症(Molecular Cancer)》17:48,2018(通过引用并入本文)。
进一步的另外的RTK抑制剂包含单克隆抗体及其抗原结合片段,包含如西妥昔单抗(cetuximab)等抗EGFR mAB(有效治疗例如肺癌、结肠直肠癌和头颈癌)和如曲妥珠单抗(trastuzumab)等抗HER2mAb(有效治疗,例如乳腺癌)。
在某些实施例中,本发明的化合物可以与如之前描述的用于治疗乳腺癌的那些等激素受体信号传导的拮抗剂组合使用。
可用本发明的化合物治疗的癌症包含:非霍奇金氏淋巴瘤(Non-Hodgkin′slymphoma);恶性间皮瘤;非小细胞肺癌;胆管癌;软组织肉瘤;胶质母细胞瘤;(复发性)脑肿瘤;继发于激素受体阳性乳腺癌、非小细胞肺癌、黑色素瘤的脑转移(包含细胞周期蛋白D1表达的阳性黑色素瘤);(复发性或持续性)子宫内膜癌;(复发性或转移性)头颈部鳞状细胞癌(HNSCC);肝细胞癌;食管鳞状细胞癌(SCC);食管腺癌(ADC);肾细胞癌和尿路上皮癌。
在某些实施例中,可治疗的癌症包含:膀胱癌、乳腺癌、结肠癌、肾癌、表皮癌、肝癌、肺癌(包含SCLC和NSCLC)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、鼻癌、头颈癌、前列腺癌或皮肤癌;淋巴系造血肿瘤;髓系造血肿瘤;甲状腺滤泡状癌;间充质起源的肿瘤;中枢或外周神经系统肿瘤;黑色素瘤;家族性黑色素瘤;精原细胞瘤;畸胎瘤;骨肉瘤;着色性干皮病;角化棘皮瘤;甲状腺滤泡状癌;卡波西氏肉瘤、鳞癌、肉瘤;或间充质起源的肿瘤。
在某些实施例中,所述淋巴系造血肿瘤为白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、多发性骨髓瘤、霍奇金氏淋巴瘤(Hodgkin′slymphoma)、非霍奇金氏淋巴瘤、毛细胞淋巴瘤或伯克特淋巴瘤(Burkett′s lymphoma)。
在某些实施例中,中枢或外周神经系统的肿瘤是星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤。
在某些实施例中,癌症是小细胞肺癌、非小细胞肺癌、胰腺癌、乳腺癌、多形性胶质母细胞瘤、T细胞ALL和套细胞淋巴瘤。
在某些实施例中,所述癌症选自由以下组成的组:结肠直肠癌、套细胞淋巴瘤、乳腺癌(包含晚期或转移性或复发性乳腺癌)、胰腺癌、卵巢癌、胶质母细胞瘤、急性髓性白血病和肺癌,尤其是NSCLC。
在某些实施例中,癌症是NSCLC、胰腺癌、卵巢癌或转移性乳腺癌,并且治疗包括向有需要的哺乳动物施用本发明的化合物和HCl吉西他滨(gemcitabine)的治疗有效组合。
在某些实施例中,癌症为NSCLC、胰腺癌、卵巢癌或转移性乳腺癌,其中包括本发明的化合物的药物还包括HCl吉西他滨或者与HCl吉西他滨同时、分开或依次施用。
在某些实施例中,本发明的化合物可以与其它药剂组合用于治疗NSCLC、胰腺癌、卵巢癌和转移性乳腺癌。例如,本发明的化合物可以与HCl吉西他滨同时、分开或依次组合用于治疗NSCLC、胰腺癌、卵巢癌或转移性乳腺癌。
在某些实施例中,癌症选自由以下组成的组:结肠直肠癌、胶质母细胞瘤、急性髓性白血病和肺癌。
在某些实施例中,癌症是胶质细胞瘤或星形细胞瘤,并且治疗利用本发明的化合物和替莫唑胺(temozolomide)的治疗有效组合。本发明的化合物可以与替莫唑胺同时、分开或依次施用。
乳腺癌治疗
在某些实施例中,本发明的化合物可以用于治疗乳腺癌。
乳腺癌在全球范围内造成了重大的健康负担,并且仅在2016年,乳腺癌就占美国所有癌症相关死亡人数的约7%。在所有乳腺癌中,约75%被诊断为激素受体阳性(HR+)乳腺癌,其表达雌激素受体(ER)和/或孕激素受体(PgR),并且通常依赖于ER信号传导通路生长和存活。也就是说,HR+乳腺癌利用ER通路的生物学功能来促进乳腺癌的生长、发展和进展。同时,HR+乳腺癌对ER信号传导的依赖使得这种乳腺癌成为靶向雌激素信号传导通路的如芳香酶抑制剂(AI;包含来曲唑(letrozole)、阿那曲唑(anastrozole)和依西美坦(exemestane))、选择性ER调节剂(它莫西芬)和选择性ER下调剂(氟维司群(fulvestrant))等内分泌疗法药剂的治疗靶标。
虽然内分泌疗法弥补了HR+乳腺癌治疗主链,但由于替代性存活或“逃逸”通路的存在,内分泌疗法的功效受到先前存在的重新抗性和治疗期间获得的抗性的高比率限制。ER通路和许多已知的逃逸通路通过细胞周期蛋白D-CDK4/6-CDK4抑制剂(INK4)-视网膜母细胞瘤(Rb)通路促进肿瘤生长。因此,组合靶向ER和细胞周期蛋白D-CDK4/6-INK4-Rb通路通常会导致更广泛地抑制肿瘤生长并且阻止逃逸通路的活化,从而防止内分泌疗法抗性的发展。参见Sammons等人,《当前癌症药物靶标(Current CancerDrug Targets)》17:637-649,2017。
因此在某些实施例中,乳腺癌是pRb+乳腺癌。在某些实施例中,乳腺癌是激素受体(HR)阳性(例如,雌激素受体阳性(ER+)、孕激素受体阳性(PR+)或ER+PR+)、HER2/neu阴性癌症,包含HR+HER2-或ER+HER2-、晚期或转移性或复发性乳腺癌。在某些实施例中,HR+HER2-或ER+HER2-晚期或转移性或复发性乳腺癌发生于成年女性或绝经后女性。
在某些实施例中,本发明的化合物单独使用或与芳香酶抑制剂(抑制雌激素产生)一起使用以治疗HR阳性、HER2阴性的晚期或转移性或复发性乳腺癌。在某些实施例中,芳香酶抑制剂使芳香酶(如阿那曲唑和来曲唑(1etrozole)/>)暂时失活。在某些实施例中,芳香酶抑制剂使芳香酶(如依西美坦/>)永久失活。
在某些实施例中,本发明的化合物与如选择性雌激素受体调节剂(SERM)等干扰雌激素刺激乳腺癌细胞生长能力的化合物一起使用,如它莫西芬和托瑞米芬(toremifene)/>等所述选择性雌激素受体调节剂与雌激素受体结合以防止雌激素结合。它莫西芬用于治疗HR+乳腺癌已有30多年。
在某些实施例中,本发明的化合物与如氟维司群等没有雌激素激动剂活性的纯抗雌激素剂一起使用。
在某些实施例中,HR阳性、HER2阴性晚期或转移性或复发性乳腺癌发生于绝经后女性。在某些实施例中,HR阳性、HER2阴性晚期或转移性或复发性乳腺癌在接受改变患者激素(例如,雌激素和/或孕酮)的疗法后有所进展或在用另一种激素疗法治疗后恶化。
在某些实施例中,本发明的化合物用于接受卵巢切除或已接受卵巢切除的患者。在某些实施例中,卵巢切除是通过卵巢切除术或放射治疗进行的。
在某些实施例中,本发明的化合物与暂时压制卵巢功能(例如,雌激素和/或孕酮产生)的化合物一起使用。此类化合物包含促性腺激素释放激素(GnRH)激动剂或促黄体激素释放激素(LH-RH)激动剂,包含戈舍瑞林(goserelin)和亮丙瑞林(leuprolide)/>
在某些实施例中,本发明的化合物与抑制CYP3A4的化合物一起使用,如利托那韦(ritonavir)、茚地那韦(indinavir)、奈非那韦(nelfinavir)、沙奎那韦(saquinavir)、克拉霉素(clarithromycin)、泰利霉素(telithromycin)、氯霉素(chloramphenicol)、酮康唑(ketoconazole)、伊曲康唑(itraconazole)、泊沙康唑(posaconazole)、伏立康唑(voriconazole)、奈法唑酮(nefazodone)、可比司他(cobicistat)、胺碘酮(amiodarone)、阿瑞匹坦(aprepitant)、维拉帕米(verapamil)、地尔硫卓(dilfiazem)、红霉素(erythromycin)、氟康唑(fluconazole)、咪康唑(miconazole)、佛手柑素(bergamottin)、西咪替丁(cimetidine)、环丙沙星(ciprofloxacin)、环孢霉素(cyclosporine)、决奈达隆(donedarone)、氟伏沙明(fluvoxamine)、伊马替尼(imatinib)、缬草(Valerian)、丁丙诺啡(buprenorphine)、咖啡醇(cafestol)、西洛他唑(cilostazol)、福沙吡坦(fosaprepitant)、gabapentin(加巴喷丁)、洛美他派(lomitapide)、奥芬那君(orphenadrine)、雷尼替丁(ranitidine)、雷诺嗪(ranolazine)、他克莫司(tacrolimus)、替格瑞洛(ticagrelor)、丙戊酸(valproic acid)、氨氯地平(amlodipine)、大麻二酚(cannabidiol)、二硫代氨基甲酸酯(dithiocarbamate)、米非司酮(mifepristone)、诺氟沙星(norfloxacin)、地拉夫定(delavirdine)、孕二烯酮(gestodene)、咪拉地尔(mibefradil)、杨桃、奶蓟草、烟酰胺、银杏、胡椒碱、异烟肼和槲皮素。
在某些实施例中,本发明的化合物与如针对IGF-1/IGF-2的单克隆抗体或其抗原结合片段等IGF-1/IGF-2抑制剂一起使用。示例性抗体包含珍妥珠单抗(xentuzumab),即人源化IgG1mAb。
在某些实施例中,本发明的化合物与抑制PI3K的化合物一起使用。据信,抑制PI3K会降低细胞周期蛋白D1和其它G1-S细胞周期蛋白的水平,消除pRb磷酸化,并且抑制S阶段转录程序的活化。与本发明的化合物一起使用的代表性PI3K抑制剂包含艾代拉里斯(idelalisib)、库潘尼西(copanlisib)、杜韦利西布(duvelisib)、塔塞利布(taselisib)、哌立福辛(perifosine)、布帕西布(buparlisib)、阿博利布(alpelisib)、厄布利塞(umbralisib)、库潘尼西、达托里昔布(dactolisib)和沃塔昔布(voxtalisib)。
在某些实施例中,待治疗的哺乳动物是如患有乳腺癌的成年女性等人(例如,具有激素受体(HR)阳性、人表皮生长因子受体2(HER2)阴性的晚期或转移性或复发性乳腺癌的在接受改变患者激素的疗法后有所进展的绝经后女性或成年女性)。
另外,本发明的某些化合物展现出它们能够穿过血脑屏障的有利性质。因此,此类化合物能够穿透大脑,并且因此可用于治疗原发性和转移性脑肿瘤,其中细胞增殖并含有功能性完整Rb1基因。此类pRb+脑肿瘤的实例包含胶质母细胞瘤,以及成神经管细胞瘤和星形细胞瘤(Lee等人,《科学(Science)》235:1394,1987)。
替莫唑胺是用于治疗包含胶质母细胞瘤和星形细胞瘤的脑肿瘤的细胞毒性DNA烷化剂(Friedman等人,《临床癌症研究(Clin.Cancer Res.)》6(7):2585-2597,2000),所述脑肿瘤包含黑色素瘤、乳腺癌和非小细胞肺癌的NSCLC的脑转移(Siena等人,《肿瘤学年鉴(AnnalsofOncology)》,doi:10.1093/annonc/mdp343,2009)。替莫唑胺与DNA相互作用导致化学修饰/损伤(Marchesi等人,《药理学研究(Pharmacol.Res.)》56(4):275-287,2007)。因此,在一些实施例中,本发明的化合物可以与替莫唑胺组合用于治疗如胶质母细胞瘤和星形细胞瘤等原发性和转移性pRb+脑肿瘤,例如其中此类转移源自黑色素瘤、乳腺癌或NSCLC。
5.药物组合物
本发明提供了药物组合物,所述药物组合物包括本文所描述的化合物中的任何一种化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。
“药学上可接受的赋形剂”和“药学上可接受的载体”是指有助于调配和/或向受试者施用活性剂和/或有助于受试者吸收的物质,并且所述物质可以包含在本公开的组合物中而不会对受试者引起显著不良的毒理学作用。药学上可接受的载体和赋形剂的非-限制性实例包含水、NaCl、生理盐水溶液、乳酸化林格氏(Ringer′s)液、普通蔗糖、普通葡萄糖、粘合剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、调味剂、盐溶液(如林格氏溶液)、醇、油、明胶、碳水化合物(如乳糖、直链淀粉或淀粉)、脂肪酸酯、羧甲基纤维素、聚乙烯吡咯烷酮和颜料等。此类制剂可以进行灭菌,并且如果期望的话,可以与不与本文所提供的化合物有害地反应或干扰其活性的助剂混合,所述助剂如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压的盐、缓冲液、着色物质和/或芳香族物质等。本领域普通技术人员将认识到其它药物载体和赋形剂适用于所公开的化合物。
这些组合物任选地进一步包括一种或多种另外的治疗剂。可替代地,本发明的化合物可以与一种或多种其它治疗方案的施用组合施用于有需要的患者(例如,格列卫(Gleevec)或其它激酶抑制剂、干扰素、骨髓移植、法尼基转移酶抑制剂、二膦酸盐、沙利度胺(thalidomide)、癌症疫苗、激素疗法、抗体、放射等)。例如,用于与本发明的化合物联合施用或包含在药物组合物中的另外的治疗剂可以是另一种或多种抗癌剂。
如本文所描述的,本发明的组合物包括本发明的化合物以及药学上可接受的载体,如本文所使用的,所述药学上可接受的载体包含任何和所有溶剂、稀释剂或其它媒剂、分散或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等,适用于期望的特定剂型。《雷明顿氏药物科学》,第五版,E.W.Martin(宾夕法尼亚州伊斯顿市的马克出版公司,1975)公开了用于调配药物组合物的各种载体及其制备的已知技术。除非任何常规的载体介质与本发明的化合物不相容,如通过产生任何不期望的生物学作用或以其它有害的方式与药物组合物的任何其它组分进行相互作用,否则设想其将在本发明的范围内使用。可以充当药学上可接受的载体的材料的一些实例包含但不限于如乳糖、葡萄糖和蔗糖等糖;如玉米淀粉和马铃薯淀粉等淀粉;如羧甲基纤维素钠、乙基纤维素和乙酸纤维素等纤维素和其衍生物;粉状黄蓍;麦芽;明胶;滑石;如可可脂和栓剂蜡等赋形剂;如花生油、棉籽油等油;红花油;芝麻油橄榄油;玉米油和大豆油;乙二醇;如丙二醇;如油酸乙酯和月桂酸乙酯等酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗盐水;林格氏溶液;乙醇和磷酸盐缓冲溶液以及其它无毒相容性润滑剂,如十二烷基硫酸钠和硬脂酸镁、以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和加香剂,防腐剂和抗氧化剂也可能存在于组合物中。
6.调配物
本发明还涵盖一类组合物,所述一类组合物包括本发明的活性化合物以及一种或多种药学上可接受的载体和/或稀释剂和/或佐剂(本文统称为“载体”材料)和,如果期望的话,其它活性成分。
在某些实施例中,本发明提供了用于治疗癌症,特别是本文所描述的癌症的药物调配物,所述药物调配物包括本发明的化合物或其药学上可接受的盐以及药学上可接受的载体。
在某些实施例中,本发明提供了用于治疗癌症的药物调配物,所述癌症选自由以下组成的组:结肠直肠癌、套细胞淋巴瘤、乳腺癌(包含成年女性或绝经后女性的ER+HER2-晚期或转移性或复发性乳腺癌)、胶质母细胞瘤、急性髓性白血病和肺癌,尤其是NSCLC,所述药物调配物包括本发明的化合物或其药学上可接受的盐以及药学上可接受的载体。
在某些实施例中,本发明提供了用于治疗胶质母细胞瘤或星形细胞瘤的药物调配物,所述药物调配物包括本发明的化合物和替莫唑胺以及药学上可接受的载体。
在某些实施例中,本发明还提供了一种药物调配物,所述药物调配物包括本发明的化合物或其药学上可接受的盐和替莫唑胺以及药学上可接受的载体、稀释剂或赋形剂。
在某些实施例中,本发明提供用于治疗NSCLC、胰腺癌,卵巢癌或转移性乳腺癌(包含成年女性或绝经后女性的ER+HER2-晚期或转移性或复发性乳腺癌)的药物调配物,所述药物调配物包括本发明的化合物和HCl吉西他滨以及药学上可接受的载体。
在某些实施例中,本发明还提供了一种药物调配物,所述药物调配物包括本发明的化合物或其药学上可接受的盐和HCl吉西他滨以及药学上可接受的载体、稀释剂或赋形剂。
本发明的活性化合物可以通过任何适合的途径,优选地以适合此类途径的药物组合物的形式,并且以对预期治疗有效的剂量施用。本发明的化合物和组合物可以例如以含有常规药学上可接受的载体、佐剂和赋形剂的剂量单位调配物口服、粘膜、局部、直肠、如通过吸入喷雾等肺部或包含血管内、静脉内、腹膜内、皮下、肌内、胸骨内和输注技术的亲本施用。
本发明的药学活性化合物可以按照常规的药学方法进行加工,以产生用于向包含人和其它哺乳动物的患者施用的药剂。
对于口服施用,药物组合物可以呈例如片剂、胶囊、悬浮液或液体的形式。优选地,所述药物组合物被制成一种剂量单位,所述剂量单位含有特定量的活性成分。
此类剂量单位的实例是片剂或胶囊。例如,人或其它哺乳动物的合适日剂量可以根据患者的状况和其它因素而变化,但是再一次可以使用常规方法确定。
施用的化合物的量和用本发明的化合物和/或组合物治疗疾病的剂量方案取决于多种因素,所述多种因素包含受试者的年龄、体重、性别和医学状况、疾病类型、疾病的严重程度、施用途径和频率以及采用的特定化合物。因此,给药方案可以在很大范围内变化,但是可以使用标准方法常规确定。如先前所述,日剂量可以在一次施用中给予或可以分成2次、3次、4次或更多次施用。
为了治疗目的,本发明的活性化合物通常与一种或多种适合于指定施用途径的佐剂、赋形剂或载体组合。如果口服施用,这些化合物可以与乳糖、蔗糖、淀粉粉末、链烷酸纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐、明胶、阿拉伯胶、海藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇,然后压片或封装以方便施用。此类胶囊或片剂可以含有控释调配物,所述控释调配物可以以活性化合物在羟丙基甲基纤维素中的分散体的形式提供。
在皮肤状况的情况下,可以优选每天将本发明的化合物的局部制剂应用于患处两次到四次。适用于局部施用的调配物包含适用于穿透皮肤的液体或半液体调配物(例如,擦剂、洗剂、软膏、乳膏或糊剂)和适用于向眼、耳或鼻施用的滴剂。对于局部施用,按调配物的重量计,活性成分可以包括0.001%到10%w/w,例如,1%到2%,尽管活性成分可以包括多达10%w/w,但优选地不超过调配物的5%w/w,并且更优选地为0.1%到1%。
本发明的化合物也可以通过经皮装置施用。优选地,将使用储库和多孔膜类型或固体基质种类的贴剂完成经皮施用。在任一情况下,活性剂被连续地从储库或微胶囊通过膜递送到与接受者的皮肤或粘膜接触的活性剂可渗透粘合剂中。如果活性剂通过皮肤吸收,则将活性剂的受控和预定流量施用于接受者。在微胶囊的情况下,包囊剂也可以起到膜的作用。本发明的乳液的油相可以由已知成分以已知方式构成。
虽然所述相可以仅包括乳化剂,但它可以包括至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。优选地,亲水性乳化剂与充当稳定剂的亲脂性乳化剂一起被包含。还优选包含油和脂肪。乳化剂与稳定剂一起或不与稳定剂一起构成所谓乳化蜡,并且蜡与油和脂肪一起构成形成乳膏调配物的油性分散相的所谓乳化软膏基质。适用于本发明的调配物的乳化剂和乳液稳定剂包含Tween 60、Span 80、鲸蜡硬脂醇、肉豆蔻醇、单硬脂酸甘油酯、十二烷基硫酸钠、单独或与蜡一起的二硬脂酸甘油酯或本领域众所周知的其它材料。
为调配物选择合适的油或脂肪基于实现期望的化妆品性质,因为活性化合物在可能用于药物乳液调配物的大多数油中的溶解度非常低。因此,奶油应该优选地是具有合适稠度的不油腻、不染色和可洗涤的产物以避免从管或其它容器中泄漏。可以使用直链或支链、单或二元烷基酯如二异己二酸酯、异鲸蜡醇硬脂酸酯、椰子脂肪酸丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、棕榈酸2-乙基己酯或支链酯的共混物。根据所需的性质,这些可以单独使用或组合使用。
可替代地,可以使用如白色软石蜡和/或液体石蜡等高熔点脂质或其它矿物油。
适用于局部施用于眼睛的调配物还包含滴眼剂,其中活性成分溶解或悬浮在合适的载体中,尤其是活性成分的水性溶剂中。
活性成分优选地以0.5到20%,有利地0.5到10%以及特别是约1.5%w/w的浓度存在于此类调配物中。
用于肠胃外施用的调配物可以是水性或非水性等渗无菌注射溶液或悬浮液的形式。这些溶液和悬浮液可以由无菌粉末或颗粒使用用于口服施用的调配物的提及的载体或稀释剂中的一种或多种载体或稀释剂或通过使用其它合适的分散剂或润湿剂和悬浮剂来制备。化合物可以溶解于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠、黄蓍胶和/或各种缓冲剂中。其它佐剂和施用方式在药学领域是众所周知的。活性成分也可以作为与包含盐水、葡萄糖或水的合适的载体或与环糊精(即卡普索(Captisol))、共溶剂增溶(即丙二醇)或胶束增溶(即Tween 80)的组合物通过注射施用。
无菌可注射制剂还可以是非毒性的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如像1,3-丁二醇中的溶液。可以采用的可接受的媒剂和溶剂有水、林格氏溶液和等渗氯化钠溶液。另外,无菌的不挥发性油常规被用作溶剂或悬浮介质。出于此目的,可以采用包含合成的甘油单酯或甘油二酯的任何温和的固定油。另外,发现如油酸等脂肪酸可用于制备注射剂。
对于肺部施用,药物组合物可以以气雾剂的形式施用或用包含干粉气雾剂的吸入器施用。
用于直肠药物施用的栓剂可以通过将药物与如可可脂和聚乙二醇等合适的无刺激性赋形剂混合来制备,所述栓剂在常温下为固体,但在直肠温度下为液体,因此会在直肠中融化并释放药物。
药物组合物可以进行如灭菌等常规的药物操作和/或可以含有如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等常规的佐剂。片剂和丸剂可以另外地用肠溶衣制备。此类组合物还可以包括如润湿剂、甜味剂、调味剂和加香剂等佐剂。本发明的药物组合物包括本文所描述的式化合物或其药学上可接受的盐;选自激酶抑制剂(小分子、多肽、抗体等)、免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增殖化合物的另外药剂;和任何药学上可接受的载体、佐剂或媒剂。
本发明的替代组合物包括本文所描述的式化合物或其药学上可接受的盐;和药学上可接受的载体、佐剂或媒剂。此类组合物可以任选地包括一种或多种另外的治疗剂,包含例如激酶抑制剂(小分子、多肽、抗体等)、免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增殖化合物。
术语“药学上可接受的载体或佐剂”是指可以与本发明的化合物一起施用于患者并且不破坏其药理活性的载体或佐剂,并且当以足以递送治疗量的化合物的剂量施用时是无毒的。可以在本发明的药物组合物中使用的药学上可接受的载体、佐剂和媒剂包含但不限于:离子交换剂、氧化铝、硬脂酸铝、卵磷脂、如d-a生育酚聚乙二醇1000琥珀酸酯等自乳化药物递送系统(SEDDS)、如Tween或其它类似的聚合物递送基质等用于药物剂型的表面活性剂、如人血清白蛋白等血清蛋白、如磷酸盐等缓冲物质、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、基于纤维素的物质、聚乙二醇、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、聚乙二醇以及羊毛脂。如u-、P-和y-环糊精等环糊精或如羟烷基环糊精等化学修饰的衍生物,包含2和3-羟丙基-环糊精,或其它溶解的衍生物也可以有利地用于增强本文所描述的式化合物的递送。
药物组合物可以以任何口服可接受的剂型口服施用,包含但不限于胶囊、片剂、乳剂和水悬浮液、分散液和溶液。在用于口服使用的片剂情况下,常见使用的载体包含乳糖和玉米淀粉。还典型地添加了润滑剂如硬脂酸镁。对于呈胶囊形式的口服施用,有用的稀释剂包含乳糖和干燥的玉米淀粉。当口服施用水悬浮液和/或乳剂时,活性成分可以悬浮或溶解于油相中,与乳化剂和/或悬浮剂混合。
如果期望的话,可以添加某些甜味剂、调味剂和/或着色剂。药物组合物可以包括利用脂质体或微囊化技术的调配物,其各种实例是本领域已知的。
药物组合物可以通过鼻用气溶胶或吸入剂施用。此类组合物根据药物调配领域中众所周知的技术制备的,并且可以采用苯甲醇或其它合适的防腐剂、用于增强生物利用度的吸收促进剂、氟碳化合物和/或其它增溶剂或分散剂制备成盐水溶液,其实例也是本领域众所周知的。
于治疗试剂盒
本发明的一个方面涉及用于方便且有效地实施根据本发明的方法或用途的试剂盒。通常,药物包或试剂盒包括用本发明的药物组合物的成分中的一种或多种成分填充的一个或多个容器。此类试剂盒特别适用于递送如片剂或胶囊等固体口服剂型。此类试剂盒优选地包含多个单位剂量,并且还可以包含具有按照其预期用途的顺序朝向的剂量的卡片。如果期望的话,可以提供记忆辅助,例如以数字、字母或其它标记的形式或带有日历插入物,指定可以施用剂量的治疗方案中的天数。与此类容器任选地相关联的可以是呈由管理药物产品的制造、使用或销售的政府机构规定的形式的公告,所述公告反映了机构对针对人类施用在制造、使用或销售方面的许可。
以下代表性实例含有重要的另加信息、例示和指导,它们可以适用于本发明在其各种实施例和其等效物中的实践。这些实例旨在帮助说明本发明,并且不旨在也不应该被解释为限制本发明的范围。事实上,除了本文所示出和描述的那些之外,本发明的各种修改和其许多另外的实施例对于本领域技术人员来说在阅读本文件时将变得显而易见,包含以下实例以及对本文引用的科学和专利文献的参考。
引用的参考文献的内容通过引用并入本文以帮助说明现有技术。
另外,出于本发明的目的,化学元素根据元素周期表,CAS版,《化学和物理手册(Handbook of Chemistry and Physics)》,第75版内封面进行标识的。另外,有机化学的一般原理以及具体的官能部分和反应性描述于“有机化学(Organic Chemistry),”ThomasSorrell,《大学科学书籍出版社(University Science Books)》,索萨利托:1999以及“有机化学”,Morrison和Boyd(第3版),两者的全部内容以引用并入本文。
8.合成方案
式I化合物可以由本领域普通技术人员按照本领域公认的技术和程序制备。更具体地,式I化合物可以按照下文所述的方案、方法和实例中所述来制备。本领域技术人员将认识到,可以改变以下方案中的各个步骤以提供式I化合物。本领域普通技术人员容易获得试剂和起始材料。除非另有说明,否则所有取代基如先前所定义。
实例
合成实例
设备描述
在布鲁克(Bruker)Ascend 400分光仪上记录1H NMR光谱。以百万分率(ppm,6单位)表达化学位移。耦合常数以赫兹(Hz)为单位。分裂模式描述了明显的多重性,并且被指定为s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、quint(五重峰)、m(多重峰)、br(宽峰)。
使用沃特世(Waters)CORTECS C18+、2.7μm 4.6×30mm使用梯度洗脱方法,用SQ检测器在沃特世ACQUITY UPLC上记录分析低分辨质谱(MS)。
溶剂A:含0.1%甲酸(FA)的水
溶剂B:含0.1%FA的乙腈
1.0分钟内5%ACN到95%ACN,固持1.0分钟,
总共2.5分钟;流速:1.8毫升/分钟;柱温40度。
中间体
中间体1
步骤1
在25℃下,向4-苄氧基吡啶(185mg,998μmol)于DCM(10mL)的溶液中添加2,4,6-三甲基苯磺酸氨酯(236mg,1.1mmol)。将反应混合物在25℃下搅拌14小时。将混合物在减压下浓缩以得到呈无色油的粗制期望产物(400mg)。LC-MS:m/z 202[M+H]+。
步骤2
向上述产物(187mg,487μmol)于DMF(10mL)中的溶液中添加Cs2CO3(192mg,1.4mmol和丁-3-炔-2-酮(94mg,1.4mmol)。将反应混合物在25℃下搅拌12小时。将反应混合物用水(50mL)淬灭,并且用DCM(2×25mL)萃取。将有机层用盐水(20mL)洗涤,经无水Na2SO4干燥并且在减压下浓缩。将残余物通过柱色谱法纯化(用PE/EA=10/1洗脱),以得到呈黄色固体的期望产物(90mg,35%产率)。LC-MS:m/z 267[M+H]+。
步骤3
在N2下在-20℃下向甲基(三苯基)溴化鏻(241mg,675μmol)于THF(10ml)中的溶液中滴加丁基锂(43.3mg,675μmol)。将反应在-20℃下搅拌1小时。然后在-20℃下滴加1-(5-苄氧基吡唑并[1,5-a]吡啶-3-基)乙酮(90mg,338μmol)于THF(15ml)中的溶液。将反应混合物在10℃下搅拌3小时。将反应混合物用MeOH(3ml)淬灭,并且在减压下浓缩。将残余物通过制备型HPLC(使用PE:EA=1/1)纯化以得到呈黄色固体的粗制期望产物(41mg)。LC-MS:m/z265[M+H]+。
步骤4
向5-苄氧基-3-异丙烯基-吡唑并[1,5-a]吡啶(600mg,2.3mmol)于甲醇(50mL)中的溶液中添加Pd/C(60mg)。将反应混合物在H2下在30℃下搅拌48小时。将反应混合物过滤,并且在减压下浓缩以得到呈黄色固体的期望产物(380mg)。LC-MS:m/z 177[M+H]+。
步骤5
在N2下在0℃下向3-异丙基吡唑并[1,5-a]吡啶-5-醇(650mg,3.7mmol)和DIPEA(410mg,4.1mmol)于DCM(15mL)中的溶液中添加Tf2O(1.1g,4.1mmol)。将反应混合物在0℃下搅拌2小时。将反应混合物用盐水(15mL)洗涤,并且经Na2SO4干燥。将有机层过滤,并且将滤液浓缩以得到呈无色油的期望产物(1.1g)。LC-MS:m/z 309[M+H]+。
步骤6
向(3-异丙基吡唑并[1,5-a]吡啶-5-基)三氟甲磺酸盐(1.1g,3.4mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二二氧杂环戊硼-2-基)-1,3,2-二氧杂戊硼烷(1.3g,5.1mmol)于二噁烷(10mL)中的溶液中添加Pd(dppf)Cl2(249mg,340μmol)和KOAc(1.0g,10.2mmol)。将反应混合物在110℃下在N2下搅拌2小时。将混合物过滤,并且将滤液在减压下浓缩以获得呈深色固体的粗制期望产物(950mg)。LC-MS:m/z 287[M+H]+。
步骤7
向3-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼-2-基)吡唑并[1,5-a]吡啶(950mg,3.3mmol)和2,4-二氯-5-氟-嘧啶(665mg,4.0mmol)于H2O(1mL)和1,4-二噁烷(15mL)中的溶液中添加Na2CO3(1.2g,10mmol)和Pd(dppf)Cl2(242mg,332μmol)。将混合物在N2下在110℃下搅拌6小时。将混合物在减压下浓缩,并且将残余物通过快速柱色谱法(在EA占0-50%的情况下,PE/EA)纯化,以得到呈黄色固体的期望产物(650mg,67%产率)。LC-MS:m/z 291[M+H]+。
中间体2
向3-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼-2-基)吡唑并[1,5-a]吡啶(3.5g,12.2mmol)和2,4-二氯嘧啶(2.7g,18.4mmol)于水(3mL)和1,4-二二噁烷(60mL)中的溶液中添加Pd(dppf)Cl2(0.9g,1.2mmol)和Na2CO3(1.52g,14mmol)。将反应混合物在N2下在110℃下搅拌6小时。将混合物在减压下浓缩,并且将残余物通过快速柱色谱法(在EA占0-50%的情况下,PE)纯化,以得到呈黄色固体的期望产物(2.1g,62%产率)。LC-MS:m/z 273[M+H]+。
中间体3
步骤1
在0℃下在1小时内向2,6-二氯-3-硝基吡啶-4-胺(1500g,7.2mol)和铁粉(1933g,34.6mmol)于乙醇(45L)和水(3L)中的混合物中逐滴添加含HCl(1.5L,H2O中12M)的水(6.5L),将所得混合物在95℃下搅拌16小时。将混合物冷却到室温,然后将其用碳酸氢钠(固体)中和到pH=9。将混合物过滤,并且用乙酸乙酯(500mL)洗涤。将滤液浓缩以去除溶剂。然后将溶液用乙酸乙酯(9L)萃取。将合并的有机层用盐水(1L)洗涤,经无水硫酸钠干燥并过滤。将滤液浓缩以得到呈黄色固体的2,6-二氯吡啶-3,4-二胺(1200g)。
步骤2
将2,6-二氯吡啶-3,4-二胺(1200g,6.74mol)于三乙氧甲烷(3L)中的溶液在氮气气氛下在140℃下搅拌28小时。将反应浓缩。添加甲酸(1.5L)。将所得混合物在120℃下搅拌2小时。将溶液浓缩以得到残余物,将所述残余物与石油醚/乙酸乙酯(1/1,400mL)一起研磨,以得到呈黄色固体的4,6-二氯-1H-咪唑并[4,5-c]吡啶(1360g)。
步骤3
将4,6-二氯-1H-咪唑并[4,5-c]吡啶(1360g,5.8mol)、K2CO3(5680g,17.4mol)和2-碘丙烷(3951g,23.2mol)于DMF(5L)中的混合物在氮气气氛下在20℃下搅拌24小时。将乙酸乙酯(40L)添加到反应中并且将混合物过滤。将滤液浓缩以得到残余物,将所述残余物通过硅胶柱(石油醚/乙酸乙酯为3∶1至1∶1)纯化,以得到呈黄色固体的期望产物(710g)。
步骤4
向4,6-二氯-1-异丙基-咪唑并[4,5-c]吡啶(250mg,1.1mmol)于DMSO(10mL)中的混合物中添加CsF(510mg,3.4mmol),然后将混合物在140℃下搅拌1.5小时。将所得混合物倒入水(100mL)中,并且用EA(3×30mL)萃取。将合并的有机层经Na2SO4干燥并过滤。将滤液浓缩。将残余物通过快速柱(80g 200-300目硅胶,PE/EA=5/1-2/1)纯化,以得到呈乳白色固体的期望产物(210mg,75%产率)。LC-MS:m/z 214.1[M+H]+。
步骤5
向6-氯-4-氟-1-异丙基-咪唑并[4,5-c]吡啶(30mg,140μmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼-2-基)-1,3,2-二氧杂戊硼烷(35.6mg,140μmol)于二噁烷(5mL)中的溶液中的添加乙酸钾(41.3mg,421μmol)和环戊基(二苯基)膦二氯钯铁(15.4mg,21.1μmol)。将混合物用N2脱气并且在110℃下搅拌16小时。将混合物通过硅藻土垫过滤。将滤液在减压下浓缩到呈黑色油的粗制期望产物(50mg),其直接用于下一步骤。LC-MS:m/z224.2[M+H]+。
步骤6
向(4-氟-1-异丙基-咪唑并[4,5-c]吡啶-6-基)硼酸(50mg,224μmol)和2-氯-4-碘-嘧啶(53.9mg,224μmol)于二噁烷(3mL)中的溶液中添加Pd(dppf)Cl2(24.6mg,33.6μmol)和KOAc(66mg,672μmol)。将混合物用N2脱气并且在110℃下搅拌16小时。将混合物在减压下浓缩。将残余物通过快速色谱法使用0-60%乙酸乙酯/石油醚洗脱来进行纯化,以得到呈白色固体的期望产物(30mg,46%产率)。LC-MS:m/z)292.1[M+H]+。
中间体4
步骤1
向5-溴-2-硝基-吡啶(1g,4.9mmol)和1-异丙基哌嗪(631.6mg,4.9mmol)于二噁烷(40mL)中的溶液中添加三(二亚苄基丙酮)二钯(0)(451.1mg,492μmol)、(5-二苯基膦酰基-9,9-二甲基-呫吨-4-基)-二苯基-膦(570mg,985μmol)和碳酸铯(4.8g,14.8mmol)。后将反应混合物在110℃下在N2下搅拌3小时。将反应混合物在减压下浓缩,并且通过硅胶色谱法使用1-100%乙酸乙酯/石油醚洗脱来进行纯化,以得到呈黄色固体的期望产物(850mg,68%产率)。LC-MS:m/z 251.1[M+H]+。
步骤2
向1-异丙基-4-(6-硝基-3-吡啶基)哌嗪(850mg,3.4mmol)于甲醇(30mL)中的溶液中添加Pd/C(412mg,10%)。然后将反应混合物用H2脱气三次,并且在25℃下搅拌3小时。将反应混合物过滤,并且然后用甲醇(20mL)洗涤。将合并的溶剂在减压下浓缩以得到呈棕色固体的期望产物(620mg,82%产率)。LC-MS:m/z 221.2[M+H]+。
中间体5
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步骤1
向哌啶-2,4-二酮(2.1g,18.5mmol)和N-甲基甲胺(3.4g,74.2mmol)于DCM(36mL)和THF(18mL)中的混合物中添加CH3COOH(10mL),将所得混合物在氮气气氛下在25℃下搅拌3小时。将三乙酰氧基硼氢化钠(7.8g,37.1mmol)添加到此混合物中,将所得混合物在氮气气氛下在25℃下搅拌12小时。将反应用水(50mL)淬灭,并且在真空中浓缩以去除DCM和THF。将混合物用DCM(3×100mL)萃取。将有机溶液用盐水(20mL)洗涤。将有机相经Na2SO4干燥,过滤并且在减压下浓缩,以得到期望产物(2.6g),其在无需进行任何纯化的情况下用于下一步骤。LC-MS:m/z 141.2[M+H]+。
步骤2
向4-(二甲氨基)-2,3-二氢-1H-吡啶-6-酮(1.0g,7.1mmol)于甲醇(15mL)中的混合物中添加硼氢化钠(539mg,14.2mmol),将所得混合物在氮气气氛下在25℃下搅拌12小时。将反应用饱和的NH4Cl水溶液(10mL)淬灭,并且然后在真空中浓缩以去除MeOH。将水溶液通过反相柱(C18,40g)使用(MeCN/水(0.1%NH4OH)=1/10)洗脱来进行纯化,以得到呈淡黄色固体的期望产物(0.3g,32%产率)。LC-MS:m/z 143.2[M+H]+。
步骤3
向4-(二甲氨基)哌啶-2-酮(270mg,1.9mmol)、5-碘吡啶-2-胺(1.0g,4.7mmol)和磷酸钾(1.2g,5.7mmol)于二噁烷(26mL)中的混合物中添加(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(162mg,1.1mmol)和CuI(108mg,569μmol),将所得混合物在氮气气氛下在110℃下搅拌12小时。将反应过滤。将滤液在真空中浓缩以得到残余物,所述残余物通过反相柱(C18,20g)使用(MeCN/水(0.1%NH4OH)=1/10)洗脱来进行纯化,以得到呈淡黄色固体的期望产物(272mg,61%产率)。LC-MS:m/z 235.2[M+H]+。
合成实例1
向1-(6-氨基-3-吡啶基)-4-(二甲氨基)哌啶-2-酮(30mg,128μmol)和5-(2-氯嘧啶-4-基)-3-异丙基-吡唑并[1,5-a]吡啶(38.4mg,140.8μmol)于二噁烷(5mL)中的混合物中添加碳酸铯(125.1mg,384.1μmol)、三(二亚苄基丙酮)二钯(0)(11.7mg,12.8μmol)和RuPhos(11.9mg,25.6μmol)。将所得混合物在氮气气氛下在110℃下搅拌4小时。将反应混合物用EA(20mL)萃取。将有机相用水(3×20mL)、盐水(3×20mL)洗涤,并且经Na2SO4干燥。将混合物在减压下浓缩,并且通过快速柱色谱法(DCM/MeOH=10:1)纯化,以得到呈黄色固体的期望产物(23.8mg,39%产率)。LC-MS:m/z 471.2[M+H]+。
合成实例2和3
将N-[5-[4-(二甲氨基)-1-哌啶基]-2-吡啶基]-4-(3-异丙基吡唑并[1,5-a]吡啶-5-基)嘧啶-2-胺(210mg,459.9μmol)通过SFC与流动相(己烷/EtOH/DEA=60/40/0.1)(波长:UV 214nm,柱:CHIRALCEL OD-H 5.0cm I.D.×25cm L,流速:60毫升/分钟)进行手性分离,以得到呈黄色固体的合成实例2(44.2mg,21%产率)(LC-MS:m/z 471.2[M+H]+。ee值>99%)和呈黄色固体的合成实例3(41mg,19%产率)(LC-MS:m/z 471.2[M+H]+。ee值=97%)。
合成实例4
向5-(4-异丙基哌嗪-1-基)吡啶-2-胺(124.6mg,565μmol)和6-(2-氯嘧啶-4-基)-4-氟-1-异丙基-咪唑并[4,5-c]吡啶(150mg,514μmol)于二噁烷(15mL)中的溶液中添加Pd2(dba)3(47.1mg,51μmol)、RuPhos(47.9mg,102μmol)和Cs2CO3(502.6mg,1.5mmol)。将混合物在110℃下在N2下搅拌3小时。将反应混合物在减压下浓缩。将残余物通过硅胶色谱法使用0-10%MeOH/DCM洗脱来进行纯化,以得到呈黄色固体的期望产物(107.2mg,43%产率)。LC-MS:m/z 476.2[M+H]+。
生物实例1.CDK4/CyclinD1抑制测定
如下进行用于IC50测定的CDK4酶测定。微流体激酶检测技术(卡利珀(Caliper))用于监测CDK4/CyclinD1对肽底物的磷酸化。总反应体积为15μL,其含有缓冲液A(100mMHEPES(pH 7.5)、0.1%BSA、0.01%Triton X-100、1mM DTT、10mM MgCl2、10μM原钒酸钠、10μMβ-甘油磷酸)、200μM ATP、1nM CDK4/CyclinD1(赛默飞世尔(Thermofisher),PR8064A)、1μM FL-34(5-FAM-RRRFRPASPLRGPPK)以及在DMSO中适当稀释的测试化合物。将所有组分添加到384孔板(康宁(Coming),4514),并且在室温下温育3小时。通过添加15μL终止缓冲液(180mM HEPES(pH 7.5)、20mM EDTA、涂层-3试剂(珀金埃尔默(PerkinElmer),760050))终止反应。然后将板加载到卡利珀EZ读出器(EZ读出器II,珀金埃尔默,HD-4HYSG2772)上,并且将包含底物和产物的反应混合物吸入微流控芯片进行分离和检测。测试化合物的IC50值通过使用Xlfit5/GraphPad Prism 5软件通过4参数S形剂量反应模型拟合抑制曲线来确定。
生物实例2.CDK6/CyclinD3抑制测定
如下进行用于IC50测定的CDK6酶测定。微流体激酶检测技术(卡利珀)用于监测CDK6/CyclinD3对肽底物的磷酸化。总反应体积为15μL,其含有缓冲液A(100mM HEPES(pH7.5)、0.1%BSA、0.01%Triton X-100、1mM DTT、10mM MgCl2、10μM原钒酸钠、10μMβ-甘油磷酸)、300μM ATP、2nM CDK6/CyclinD3(卡纳(Cama),04-107)、1μM FL-34(5-FAM-RRRFRPASPLRGPPK)以及在DMSO中适当稀释的测试化合物。将所有组分添加到384孔板(康宁,4514),并且在室温下温育3小时。通过添加15μL终止缓冲液(180mM HEPES(pH 7.5)、20mM EDTA、涂层-3试剂(珀金埃尔默,760050))终止反应。然后将板加载到卡利珀EZ读出器(EZ读出器II,珀金埃尔默,HD-4HYSG2772)上,并且将包含底物和产物的反应混合物吸入微流控芯片进行分离和检测。测试化合物的IC50值通过使用Xlfit5/GraphPad Prism 5软件通过4参数S形剂量反应模型拟合抑制曲线来确定。
生物实例3.CDK2/CyclinE1抑制测定
如下进行用于IC50测定的CDK2酶测定。微流体激酶检测技术(卡利珀)用于监测CDK2/CyclinE1对肽底物的磷酸化。总反应体积为15μL,其含有缓冲液A(100mM HEPES(pH7.5)、0.1%BSA、0.01%Triton X-100、1mM DTT、10mM MgCl2、10μM原钒酸钠、10μMβ-甘油磷酸)、100μMATP、5nM CDK2/CyclinE1(新格诺康(SignalChem),C29-18G)、5μMFL-18(5-FAM-QSPKKG-NH2)以及在DMSO中适当稀释的测试化合物。将所有组分添加到384孔板(康宁,4514),并且在室温下温育3小时。通过添加15μL终止缓冲液(180mM HEPES(pH 7.5)、20mMEDTA、涂层-3试剂(珀金埃尔默,760050))终止反应。将板加载到卡利珀EZ读出器(EZ读出器II,珀金埃尔默,HD-4HYSG2772)上,并且将包含底物和产物的反应混合物吸入微流控芯片进行分离和检测。测试化合物的IC50值通过使用Xlfit5/GraphPadPrism 5软件通过4参数S形剂量反应模型拟合抑制曲线来确定。
在下文合成实例中提供了每个示例化合物对CDK2、CDK4和CDK6的IC50值。对于小于或等于10nM;小于或等于100nM;小于或等于1μM;以及大于1μM的值,IC50值分别指示为“A”、“B”、“C”和“D”。
生物实例4.T47D细胞中的抗增殖测定
T47D是人乳腺癌细胞系,常用于涉及癌细胞激素表达的生物医学研究。T47D细胞与其它人乳腺癌细胞的不同之处在于T47D细胞的孕酮受体(PR)不受雌二醇的调节,所述雌二醇是在细胞自身内含量丰富的激素。T47D细胞已被用于研究孕酮对乳腺癌的影响以及由引入的药物引起的对应转录调节。已经注意到所述细胞对雌激素和抗雌激素具有极强的抗性。
来自美国典型培养物保藏中心(American Type Culture Collection)(ATCC,HTB-133)的T47D乳腺癌细胞以3000个细胞/孔接种在96孔板中,并且在37℃、5%CO2下在含有10%胎牛血清(FBS,Biowest公司(Biowest),FB-1058)的RPMI 1640培养基(吉博(Gibco),31800105)中温育。温育过夜后,按照制造商的建议,使用Cyquant试剂(英杰(Invitrogen),C35011)测量来自一个板的样品的基线值。将细胞与检测试剂在37℃下温育1小时,然后使用Spectra Max M5(分子装置公司(Molecular Devices),HD-4HYSG3196)在485nm激发和535nm发射下测量荧光。其它板在3倍稀释方案中以10μM到0.51nM的十点剂量浓度加入化合物。在添加化合物后的第6天,添加Cyquant试剂并且使用Spectra Max M5测量荧光。使用Xlfit5/GraphPad Prism 5软件从减去基线的活力读出曲线确定测试化合物的抗增殖活性的IC50值。
生物实例5.抑制T47D细胞中视网膜母细胞瘤蛋白(pRb)的磷酸化
来自美国典型培养物保藏中心(ATCC,HTB-133)的T47D乳腺癌细胞以40,000个细胞/孔接种在96孔板中,并且在含有10%胎牛血清(FBS,Biowest公司,FB-1058)的RPMI1640培养基(吉博,31800105)中温育。然后使细胞在37℃、5%CO2下粘附过夜。第二天,以3倍稀释方案滴定化合物,并且测试的最高化合物浓度为10μM。与化合物温育24小时后,将细胞在含有磷酸酶抑制剂混合物和1mM PMSF的冰冷裂解缓冲液中裂解。然后将细胞裂解物(50μL/孔)转移到ELISA板(pRb Ser807/811ELISA试剂盒,细胞信号传导公司(CellSignaling),13152或pRb Ser780ELISA试剂盒,细胞信号传导公司,13016))。将板在4℃下温育过夜,并且以恒定的慢速振荡。温育后,按照制造商的建议洗涤板,并且然后将100μL重构的检测抗体添加到每个孔中,并且在37℃下温育1小时。温育后,洗涤板,并且然后将100μL重构的HRP连接的二抗添加到每个孔中,并且在37℃下温育30分钟。温育后,洗涤板。然后,将100μL TMB底物添加到每个孔中,并且在37℃下温育10分钟或在25℃下温育30分钟。最后,将100μL终止溶液添加到每孔中,并且轻轻混合几秒钟。使用96孔发光模式在易美逊(Envision)读板仪(珀金埃尔默,2104-0010)上读取板。使用Xlfit5/GraphPadPrism 5软件的4参数S形剂量反应模型计算IC50值。
从生物实例4和5获得的细胞数据列于下表A中。对于小于或等于100nM的值,IC50值指示为“++++”;对于小于或等于500nM的值,指示为“+++”;对于小于或等于1μM的值,指示为“++”;并且对于大于1μM的值,指示为“+”。
表A
合成实例 | CDK4IC50 | CDK6IC50 | CDK2IC50 | T47D IC50 | Phospho T47D Ser807IC50 |
1 | A | A | B | ++++ | ++++ |
2 | A | B | B | ++++ | ++++ |
3 | A | A | A | ++++ | ++++ |
4 | A | B | C | ++++ | ++++ |
Claims (20)
1.一种由以下结构式表示的化合物:
或其药学上可接受的盐。
2.一种由以下结构式表示的化合物:
或其药学上可接受的盐。
3.一种药物组合物,其包括有效量的根据权利要求1或2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载体。
4.根据权利要求1或2所述的化合物或其药学上可接受的盐或根据权利要求3所述的药物组合物在制备用于治疗癌症的药物中的用途,其中所述癌症是膀胱癌、乳腺癌、结肠癌、肾癌、表皮癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、鼻癌、头颈癌、前列腺癌或皮肤癌;淋巴系造血肿瘤;髓系造血肿瘤;甲状腺滤泡状癌;间充质起源的肿瘤;中枢或外周神经系统肿瘤;黑色素瘤;精原细胞瘤;畸胎瘤;骨肉瘤;着色性干皮病;角化棘皮瘤;甲状腺滤泡状癌;或卡波西氏肉瘤(Kaposi's sarcoma)。
5.根据权利要求1或2所述的化合物或其药学上可接受的盐或根据权利要求3所述的药物组合物在制备用于抑制受试者的细胞周期蛋白依赖性激酶(CDK)活性的药物中的用途。
6.根据权利要求5所述的用途,其中所述受试者患有癌症,如膀胱癌、乳腺癌、结肠癌、肾癌、表皮癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、鼻癌、头颈癌、前列腺癌或皮肤癌;淋巴系造血肿瘤;髓系造血肿瘤;甲状腺滤泡状癌;间充质起源的肿瘤;中枢或外周神经系统肿瘤;黑色素瘤;精原细胞瘤;畸胎瘤;骨肉瘤;着色性干皮病;角化棘皮瘤;甲状腺滤泡状癌;或卡波西氏肉瘤。
7.根据权利要求6所述的用途,其中所述淋巴系造血肿瘤为白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、多发性骨髓瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、毛细胞淋巴瘤或伯克特淋巴瘤(Burkett's lymphoma)。
8.根据权利要求6所述的用途,其中所述癌症为pRb+乳腺癌或激素受体(HR)阳性或HER2/neu阴性癌症。
9.根据权利要求8所述的用途,其中所述激素受体(HR)阳性癌症为雌激素受体阳性(ER+)、孕激素受体阳性(PR+)或ER+PR+癌症。
10.根据权利要求8所述的用途,其中所述癌症是晚期或转移性或复发性乳腺癌。
11.根据权利要求10所述的用途,其中所述乳腺癌发生于成年女性或绝经后女性。
12.根据权利要求8所述的用途,其进一步与以下的第二药剂组合:芳香酶抑制剂、选择性雌激素受体调节剂、无雌激素激动剂活性的纯抗雌激素、暂时抑制卵巢功能的化合物、抑制CYP3A4的化合物或针对IGF-1/IGF-2的单克隆抗体或其抗原结合片段。
13.根据权利要求12所述的用途,其中所述卵巢功能为雌激素和/或孕激素产生。
14.根据权利要求12所述的用途,其中所述暂时抑制卵巢功能的化合物为促性腺激素释放激素激动剂或促黄体激素释放激素激动剂。
15.根据权利要求4至11中任一项所述的用途,其进一步与以下组合:免疫检查点抑制剂、受体Tyr激酶抑制剂和/或激素受体的拮抗剂。
16.根据权利要求15所述的用途,其中所述免疫检查点抑制剂为PD-1抑制剂、PD-L1抑制剂或CTLA-4抑制剂。
17.根据权利要求15所述的用途,其中所述激素受体为雌激素受体。
18.根据权利要求12-14中任一项所述的用途,其进一步与以下组合:免疫检查点抑制剂、受体Tyr激酶抑制剂和/或激素受体的拮抗剂。
19.根据权利要求18所述的用途,其中所述免疫检查点抑制剂为PD-1抑制剂、PD-L1抑制剂或CTLA-4抑制剂。
20.根据权利要求18所述的用途,其中所述激素受体为雌激素受体。
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EA202191938A1 (ru) * | 2019-01-29 | 2021-10-13 | Бета Фарма, Инк. | Производные 2h-индазола в качестве терапевтических средств при видах рака головного мозга и метастазах в головной мозг |
EA202193015A1 (ru) * | 2019-05-05 | 2022-03-17 | Цилу Регор Терапьютикс Инк. | Ингибиторы cdk |
MX2023004931A (es) * | 2020-11-20 | 2023-05-17 | Hefei Inst Physical Sci Cas | Derivados de dihidroisoquinolinona e isoindolinona y usos de los mismos. |
WO2023143482A1 (zh) * | 2022-01-29 | 2023-08-03 | 上海辉启生物医药科技有限公司 | 2-氨基嘧啶类化合物或其盐及其制备方法和用途 |
WO2023196517A1 (en) * | 2022-04-08 | 2023-10-12 | Biolexis Therapeutics, Inc. | Cdk9 inhibitors |
CN117645604A (zh) * | 2022-09-05 | 2024-03-05 | 浙江同源康医药股份有限公司 | 用作cdk4激酶抑制剂的化合物及其应用 |
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JP2023525005A (ja) | 2023-06-14 |
KR20220004755A (ko) | 2022-01-11 |
CO2021016504A2 (es) | 2022-01-17 |
US20230174512A1 (en) | 2023-06-08 |
AU2020269469A1 (en) | 2021-12-09 |
AU2021268648A1 (en) | 2023-01-19 |
US20240033264A1 (en) | 2024-02-01 |
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CA3138973A1 (en) | 2020-11-12 |
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WO2020224568A1 (en) | 2020-11-12 |
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US20240066031A1 (en) | 2024-02-29 |
CN115803327A (zh) | 2023-03-14 |
EA202193015A1 (ru) | 2022-03-17 |
EP3966213A1 (en) | 2022-03-16 |
TW202144351A (zh) | 2021-12-01 |
BR112021022105A2 (pt) | 2021-12-28 |
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