CN114599371A - 作为癌症靶向药物载体的磷脂醚缀合物 - Google Patents
作为癌症靶向药物载体的磷脂醚缀合物 Download PDFInfo
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- CN114599371A CN114599371A CN202080074564.3A CN202080074564A CN114599371A CN 114599371 A CN114599371 A CN 114599371A CN 202080074564 A CN202080074564 A CN 202080074564A CN 114599371 A CN114599371 A CN 114599371A
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Abstract
本文公开的是能够靶向范围广泛的肿瘤细胞的治疗性化合物。本公开进一步涉及包含该治疗性化合物的组合物,制造该治疗性化合物的方法,和包括给予该治疗性化合物的治疗癌症的方法。
Description
相关申请的交叉引用
本申请请求下列的优先权:美国临时专利申请No.62/899,611,2019年9月12日申请;美国临时专利申请No.62/899,615,2019年9月12日申请;美国临时专利申请No.62/899,618,2019年9月12日申请;美国临时专利申请No.62/946,870,2019年12月11日申请;美国临时专利申请No.62/956,844,2020年1月3日申请;和美国临时专利申请No.62/956,907,2020年1月3日申请;这些专利申请的全部内容以引证的方式纳入本文。
技术领域
本公开涉及能够靶向范围广泛的肿瘤细胞的治疗性化合物。本公开进一步涉及包含该治疗性化合物的组合物,制造该治疗性化合物的方法,和包括给予该治疗性化合物的治疗癌症的方法。
背景技术
2018年,世界上有1800万人诊断出癌症,960万人因癌症死亡。在美国,全部人口的40%在其一生中会诊断出癌症。在2018年,肺癌(209万例)、乳腺癌(209万例)、结直肠癌(180万例)、前列腺癌(128万例)、皮肤癌(非黑色素瘤)(104万例)和胃癌(103万例)是最常见类型的癌症。尽管有很多治疗手段,癌症依然是全球第二大死因。
癌症是无限细胞分裂的结果。健康的细胞有检查点来避免无限细胞分裂。这些检查点的几个实例是养分可获得性、DNA损坏和接触抑制(例如,一个细胞接触另一个细胞)。此外,绝大多数细胞只能复制有限次数,因此经过特定次数的细胞分裂后,编程化凋亡。
癌症是当一种细胞克服这些内置检查点并不受控制增殖的结果。所述的不受控增殖导致肿瘤的形成。有两类肿瘤,良性的和恶性的。良性肿瘤无法穿过不同组织类型的自然边界。另一方面,恶性肿瘤可以入侵邻近组织,或进入血流转移至不同区域。只有恶性肿瘤被认为是癌性的。是这种入侵和转移的能力,让癌症成为如此致命的疾病。此外,脂质代谢在癌症转移过程中扮演一个影响深远的角色。癌细胞总是表现出根本不同的细胞代谢。然而,脂质代谢在恶性癌症发展中的角色依然不清楚。
恶性肿瘤具有不相同的细胞类别,这进一步复杂了对癌症的斗争。一种特别麻烦的类别是癌症干细胞(“CSC’s”)。CSC’s可以自我更新并分化为恶性肿瘤中不同癌细胞类别。因此,CSC’s是肿瘤转移能力的主要影响因素。CSC’s经常在放射治疗和化学治疗后存活。现在假设,癌症在放射疗法和化学疗法后的存活,是放射疗法和化学疗法无法杀死所有CSC’s以及CSC’s有能力建立新的肿瘤产生的结果。
化学疗法是用来描述包括使用细胞毒性抗癌药物的一种癌症治疗特殊类型的术语。化学疗法所用的细胞毒性药物可分为几个主要的类别,包括烷化剂、抗代谢物、抗肿瘤抗生素、拓扑异构酶抑制剂和有丝分裂抑制剂。细胞毒性抗癌药物通常会停止细胞分裂,因此影响健康组织和癌变组织。烷化剂通过损坏癌细胞DNA来阻止癌细胞分裂。一些常用于治疗癌症的烷化剂为氮芥类(例如环磷酰胺Cytoxan是Baxter International的注册商标)、亚硝基脲类、烷基磺酸盐类、三氮杂环己烷类(triazeines)和乙烯亚胺类。铂类药物,例如顺铂和卡铂,其作用类似于烷化剂。抗代谢物通过抑制DNA和RNA合成来阻止癌细胞分裂。一些用于治疗癌症的常见抗代谢物为6-巯基嘌呤、吉西他滨(Gemzar是Eli Lilly及公司的注册商标)、甲氨蝶呤和培美曲塞(Alimta是Eli Lilly及公司的注册商标)。拓扑异构酶抑制剂通过抑制拓扑异构酶脱离DNA进行复制来阻止癌细胞分裂。一些常见的拓扑异构酶抑制剂为托泊替康、伊立替康、依托泊苷和替尼泊苷。有丝分裂抑制剂通过抑制关键细胞分裂酶来阻止癌细胞分裂。一些常见的有丝分裂抑制剂为紫杉烷类(例如紫杉醇(Taxol是Bristol-Myers Squibb Company的注册商标))和多西他赛(Taxotere是Aventis Pharma SA的注册商标))、埃坡霉素类和长春花生物碱类。
所有这些抗癌药物的一个缺点是他们对健康组织的损害。因为药物通过抑制正常细胞功能治疗癌症,依赖持续细胞分裂的健康组织细胞例如血细胞、黏膜表面和皮肤,也会被严重损害。这种损害导致明显的发病率,并且限制了化学疗法的安全递送量。在化学疗法治疗中发生副作用的实例包括低血细胞计数、脱发、肌肉和关节疼痛、恶心、呕吐、腹泻、口腔溃疡、发烧和寒战。为了克服这个问题,独特作用机理的新药不断地研发出来,试图提供强化的靶向性,只影响在癌细胞中的蛋白质和细胞功能。例如,抗体药物缀合物(ADC)被设计为结合肿瘤细胞表面特定表位,并提供备选方法靶向肿瘤细胞,来降低相关毒性。尽管具有高选择性,可用于治疗的ADC非常少,因为它们只能达到中等的细胞摄入(<注入药物的1%)以及有限的杀细胞活性。一些具体的癌症药物为伊马替尼(Gleevec是Novartis AG的注册商标)、吉非替尼(lressa是AstraZeneca UK Limited的注册商标)、舒尼替尼(Sutent是CP Pharmaceuticals,International CV的注册商标)、硼替佐米(Velcade是Millennium Pharmaceuticals,Inc.的注册商标)。但是,这些药物并未获准用于治疗所有癌症类型,且都伴随出现治疗抵抗。此外,许多这些化合物依然缺少绝对肿瘤选择性,因脱靶效应,其治疗应用依旧局限。
最近,磷脂醚(“PLE”)类似物展示作为抗癌药物递送的有效分子平台。参见美国专利No.9,480,754和Weichert等人(Sci Transl Med,2014,6(240),240ra75),其中每个都以引证的方式全部纳入本文。可以看出,临床所用大多数抗癌药物的应用,因其对所有增殖细胞的毒性和/或因其无法在所有肿瘤细胞上发挥效果而受限。因此,当前领域中依然需要另一种抗癌药物递送载体,递送强力、有效、光谱抗癌药物至包括CSC’s的癌细胞,同时避免健康细胞对其明显摄入。此外,所述的抗癌药物递送载体应能穿过屏障例如血脑屏障(BBB)。
发明内容
在一个方面,本公开提供式(I)化合物或其药学上可接受的盐,
其中
n是2-20;
Q2是化学键或自分解性间隔子(self-immolative spacer);和
Z是抗癌药物。
在另一个实施方案中,本公开提供治疗有需要的受试者的癌症的方法,包括给予有效量的本文所述化合物或其药学上可接受的盐。
本公开提供了其他方面和实施方案,根据下面详述和附图可看出。
附图说明
图1A-1B示出了磷脂药物缀合物(PDC)向肿瘤细胞系中的摄入。图1A中绿色荧光指示了磷脂醚(PLE)加BODIPY。图1B示出了CLR1502摄入中MFI与自发荧光的比例。
图2A-2B示出了PDC向细胞系(A375和A549细胞系中)中的摄入。图2A示出了细胞质中全缀合PLE的浓度。图2B示出了细胞质中释放的载荷的浓度。
图3示出了CLR1502和CLR1501分别通过肿瘤细胞和原发肿瘤样品上的脂筏的摄入。CLR1502是连接到PLE的近红外分子,且为白色。蓝色的是Hoechst核染色。红色是霍乱毒素单位B,表示脂筏。
图4示出了PDC-SM2对黑色素瘤(A375)和肺癌(A549)细胞的体外疗效。
图5示出了体内可耐受的细胞毒性PDC。对于载荷剂量0.5mg/kg,圆点表示小鼠死亡或牺牲的时间。箭头表示给予剂量的时间。
图6示出了CLR2000045在MCF-7和NHDF细胞系中的体外摄入。
图7示出了CLR2000045在乳腺癌细胞系中的体外细胞毒性。
图8示出了鸡胚绒毛尿囊膜模型(MCF-7)中的体内抗肿瘤活性。
图9示出了植入TNBC(HCC70)异种移植模型中的体内抗肿瘤疗效。
图10示出了TNBC(HCC70)小鼠异种移植模型中的Kaplan-Meier生存曲线。
图11A-11B示出了治疗后(HCC70)小鼠异种移植模型体重的变化。图11A是1mg/kg每周给药3次。图11B是1mg/kg每周给药2次。
图12示出了CLR180099A和CLR180099B在A549和NHDF细胞中的体外摄入。
图13示出了CLR180095在A549(黑线)和HCT116(灰线)细胞中的体外摄入。细胞经过48小时培养,以及初始培养浓度为10nM。通过LC/LC/MS测定摄入。
图14示出了A549细胞中体外释放载荷。
图15示出了CLR180099A在肺癌、乳腺癌和黑色素瘤细胞中的体外细胞毒性。
图16示出CLR180099A在植入结直肠癌异种移植模型中的体内抗肿瘤疗效。
图17示出了结直肠癌异种移植模型中针对CLR180099A的Kaplan-Meier生存曲线。
图18示出了CLR180099A的体内耐受度。
图19A-19F示出了肠道肿瘤中CLR1502的选择性摄入。图19A是在每只小鼠50μgCLR1502给药96小时后尸检切除的整个结肠。图19B是在每只小鼠50μgCLR1502给药96小时后尸检切除的小肠远端段。增加信号强度的面积通过IVIS Spectrum观察。这些区域为非浸润性(结肠,图19C;远端小肠,图19F)和浸润性(结肠,图19D;远端小肠,图19E)肿瘤。图19C、图19D、图19E和图19F在黑框中放大。箭头指出了肠肌肉组织中恶性腺体。短线:1mm。
图20A-20H示出CLR1501在脑中的摄入。图20C、20D和20E示出了U251衍生的原位脑肿瘤,通过磁共振成像确认(MRI;图20C,T2-权重)并使用CLR1501标记(图20E),使用ToPro3核复染(图20D)。图20F、图20G和图20H是使用CLR1501(绿色)标记的22T多形性胶质母细胞瘤来源的原位异种移植物中的脑-肿瘤界面的组织学分析。图20F是异种移植物-脑边界落射荧光可视化,用蓝色DAP1核复染。图20G是用CLR1501标记的异种移植物的共焦视图。图20H是异种移植物和相邻正常脑的共聚焦和明场视图。N表示正常脑;RFU表示相对荧光单位;T表示肿瘤。
图21A示出了可见光下体内CLR1502处理的脑(左)和体内22-CSC衍生的原位异种移植物的CLR1502荧光。
图21B示出了可见光下离体CLR1502处理的脑和肿瘤(上左),和离体22-CSC衍生的异种移植物的CLR1502荧光,证明来自正常脑极好的宏观肿瘤描绘(上右)。该图还示出了通过组织学验证肿瘤(T)(苏木精和伊红;下左)和通过组织学验证正常脑(N)(苏木精和伊红;下右)。
图22示出了肿瘤厚度不能解释肠癌中发现的信号强度增加。图22A示出了结肠的层。图22B示出了各层的总辐射效率。
图23示出了结直肠癌模型中CLR1502摄入的体内光学扫描。随着时间的推移,在体内测定荧光强度(由彩条表示)和生物分布。
图24示出了乳腺癌模型中CLR1502摄入的体内光学扫描。使用Fluoptics和Spectrum系统(黄色和绿色箭头分别表示Fluobeam和IVISSpectrum),在7天的时间(168小时)内,每天对携带原位乳腺癌异种移植物(MDA-MB-231)的无胸腺裸小鼠进行成像。
图25示出了使用IVIS Spectrum对携带肺癌异种移植物(H226肺)的无胸腺小鼠(每个肋腹静脉注射CLR1502)进行成像。在96小时时,恶性组织和正常组织之间辐射效率的差别为肿瘤边缘照明创造了充足的对比度,如黑色箭头所指出的。
具体实施方式
本文记载的是能够靶向范围广泛的肿瘤细胞的治疗性化合物。本文公开的化合物可靶向肿瘤细胞膜中的特化结构,例如脂筏。所以,本文公开的化合物可以以高的特异性靶向肿瘤细胞。特别地,本文公开的化合物可用于治疗癌症。
1.定义
除非另有说明,本文所有技术和科学术语具有领域内普通技术人员通常理解的含义。当有歧义时,本文件,包括定义部分,会进行控制。下面记载了优选的方法和材料,尽管相似或等价于本文记载的那些方法和材料可以用于本发明的实施或测试。本文提及的所有出版物、专利申请、专利和其他引文以引证的方式整体纳入本文。本文公开的材料,方法和实施例仅仅是说明性的,且不意欲限制。
本文使用的术语“包含”和“包括”(comprise、include),“具有”和“有”(having、has),“可以”和“能够”(can),“含有”及其变体,意为开放性过渡短语、术语或词汇,并不排除添加行为或结构的可能性。单数形式“一个”和“一种”(a、an)以及“该”和“所述”(the)包括复数的引用物,除非所处语境清楚指明相反。对于“包括”和“包含”、“由……组成”和“主要由……组成”中出现的实施方案和元素,本公开也考虑其他实施方案,不论是否明确指定。
关于本文引用的数字范围,每个介于其间具有相同精度的数字也被明确地考虑。例如在范围6-9中,除了6和9,数字7和8也被考虑,以及对于6.0至7.0的范围,数字6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9和7.0也被明确地考虑。
本文使用的适用于一个或多个有关值的术语“(大)约”(about、approximately),指一个相似于声明引用值的值,或在本领域普通技术人员可确定的在某特定值的可接受误差区间内,这部分地取决于该值是如何测量或确定的,例如受限于测试系统。在某些方面,术语“(大)约”指值的范围,其落入声明引用值的各个方向(大于或小于)的20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或更小的范围内,除非另有说明,或从语境中得知是显然的(除非当该值会超过某可能值的100%)。此外,“(大)约”可指标准偏差在3以内或超过3,随领域中实践而不同。此外,例如,关于生物系统或方法时,术语“(大)约”可指在某值的一个数量级内,优选在5倍内,更优选在2倍内。
下面更详细地说明特定功能团和化学术语的定义。出于本公开的目的,化学元素根据元素周期表,CAS版本,Handbook of Chemistry and Physics,75th Ed.,内部封面标识,以及特定官能团通常按其中记载的定义。此外,有机化学的通常规则,以及特定官能部分和反应,记载于Organic Chemistry,Thomas Sorrell,University Science Books,Sausalito,1999;Smith and March March's Advanced Organic Chemistry,5thEdition,John Wiley&Sons,Inc.,New York,2001;Larock,Comprehensive OrganicTransformations,VCH Publishers,Inc.,New York,1989;Carruthers,Some ModernMethods of Organic Synthesis,3rd Edition,Cambridge University Press,Cambridge,1987;每个的全部内容以引证的方式纳入本文。
本文使用的术语“癌症”指任何由可转移的细胞不受控分裂导致的疾病。本文使用的术语“癌症”指但不限于多种癌症类型,包括:乳腺癌,包括男性乳腺癌;消化道/胃肠道癌,包括肛门癌、阑尾癌、肝外胆管癌、胃肠道类癌瘤、结肠癌、食道癌、胆囊癌、胃癌、胃肠道间质瘤(“gist”)、胰岛细胞瘤、成人原发性肝癌、儿童肝癌、胰腺癌、直肠癌、小肠癌和胃癌;内分泌和神经内分泌癌,包括胰腺腺癌、肾上腺皮质癌、胰腺神经内分泌瘤、默克尔细胞癌、非小细胞肺神经内分泌瘤、小细胞肺神经内分泌瘤、甲状旁腺癌、嗜铬细胞瘤、垂体瘤和甲状腺癌;眼癌,包括眼内黑色素瘤和视网膜母细胞瘤;泌尿生殖系统癌,包括膀胱癌、肾(肾细胞)癌、阴茎癌、前列腺癌、移行细胞肾盂和输尿管癌、睾丸癌、尿道癌和肾母细胞瘤;生殖细胞癌,包括儿童中枢神经系统癌、儿童颅外生殖细胞瘤、性腺外生殖细胞瘤、卵巢生殖细胞瘤和睾丸癌;妇科癌症,包括宫颈癌、子宫内膜癌、妊娠滋养细胞肿瘤、卵巢上皮癌、卵巢生殖细胞瘤、子宫肉瘤、阴道癌和外阴癌;头颈癌,包括下咽癌、喉癌、唇癌和口腔癌、隐匿性原发性转移性鳞状颈癌、口腔癌、鼻咽癌、口咽癌、鼻窦及鼻腔癌、甲状旁腺癌、咽癌、唾液腺癌、喉癌;白血病,包括成人急性淋巴细胞白血病、儿童急性淋巴细胞白血病、成人急性髓细胞白血病、儿童急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞性白血病和毛细胞白血病;多发性骨髓瘤,包括恶性浆细胞;淋巴瘤,包括艾滋病相关淋巴瘤、皮肤t-细胞淋巴瘤、成人霍奇金淋巴瘤、儿童霍奇金淋巴瘤、妊娠期霍奇金淋巴瘤、蕈样真菌病、成人非霍奇金淋巴瘤、儿童非霍奇金淋巴瘤、妊娠期非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、塞扎里综合征和华氏巨球蛋白血症;肌肉骨骼癌,包括尤文肉瘤、骨肉瘤和骨恶性纤维组织细胞瘤、儿童横纹肌肉瘤和软组织肉瘤;神经系统癌症,包括成人脑肿瘤、儿童脑肿瘤、星形细胞瘤、脑干神经胶质瘤、中枢神经系统非典型畸胎样/横纹肌瘤、中枢神经系统胚胎肿瘤、颅咽管瘤、室管膜瘤、神经母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤;呼吸道/胸部癌症,包括非小细胞肺癌、小细胞肺癌、恶性间皮瘤、胸腺瘤和胸腺癌;和皮肤癌,包括卡波西肉瘤、黑色素瘤和鳞状细胞癌。
本文使用的术语“癌症干细胞”指可以自我更新和分化为恶性肿瘤中发现的不同类型癌细胞的癌细胞。
所用的术语“化学疗法药物”和“抗癌药物”和“抗肿瘤药物”在说明书全文中可相互交换使用。
通常,引用“一个循环肿瘤细胞(a circulating tumor cell)”意指单个细胞,而引用“循环肿瘤细胞(circulating tumor cells)”或“循环肿瘤细胞簇”意指超过一个癌细胞。然而,本领域技术人员能够理解的是,引用“循环肿瘤细胞”意在包括循环肿瘤细胞群,包括一个或多个循环肿瘤细胞,而引用“一个(种)循环肿瘤细胞”可包括超过一个循环肿瘤细胞。本文所用术语“一个(种)循环肿瘤细胞”或“循环肿瘤细胞”指在受试者血液或血浆样品中可见的任何癌细胞或癌细胞簇。CTC也可含有受试者血液或血浆样品中可见的癌干细胞或癌干细胞簇,或者由受试者血液或血浆样品中可见的癌干细胞或癌干细胞簇组成。
本文使用的术语“组合物”意在包括一种产品,所述产品包括特定量的特定成分,以及直接或间接从特定量的特定成分的组合得到的任何产品。
术语“对照(control)”、“参考水平(reference level)”和“参考(reference)”在本文中相互交换使用。参考水平可以是预先指定的量或范围,用作评估测定结果的基准。本文所用的“对照组”指一组对照受试者。预定水平可以是来自对照组的截止值。预定水平可以是来自对照组的平均值。截止值(或预定截止值)可通过自适应指数模型(AdaptiveIndex Model,AIM)方法确定。截止值(或预定截止值)可通过来自患者组的生物样品的接收者操作特性曲线(ROC)分析得到。ROC分析,作为生物学领域中已知的手段,是一种确定一个试验中区分一个条件和其他条件的能力的手段,例如确定每个标记物在识别接受IL-1Ra疗法的理想患者方面的表现。ROC分析的描述提供于P.J.Heagerty等人(Biometrics 2000,56,337-44),该公开以引证的方式全部纳入本文。此外,截止值可通过患者组生物学样品的四分位数分析确定。例如,可以通过选择与第25至第27百分位数范围的任意值对应的值来确定截止值,优选与第25百分位数、第50百分位数或第75百分位数对应的值,以及更优选与第75百分位数对应的值。这种统计分析可以使用本领域任何已知方法进行,以及可以通过任意数量的商用软件包来实现(例如Analyse-it Software Ltd.,Leeds,UK;StataCorpLP,College Station,TX;SAS Institute Inc.,Cary,NC.)。对于标靶或蛋白活性的健康或正常的水平或范围可按标准实践定义。对照可以是没有本文所述的肿瘤的受试者或细胞。对照可以是疾病状况已知的受试者或来自该受试者的样品。该受试者或来自该受试者的样品可以使健康的、患病的、患病于治疗前的、患病于治疗中或患病于治疗后的,或它们的组合。
本文使用的术语“剂量(dose)”指任何形式的活性成分制剂或组合物,其含有的量在至少一次给药下足够产生治疗效果。“制剂”和“化合物”在本文中可相互交换使用。
本文使用的术语“剂量(方案)(dosage)”指在一段特定的时间内,给予任意的含量、数量和频率的多个剂量(dose)。
本文使用的术语“有效量”或”治疗有效量”指所给予的试剂或药学上可接受的组合物或化合物的任何量,其可以一定程度上减轻一种或多种所治疗疾病或病情的症状。结果可能是减轻和/或缓解指征、症状、或疾病病因,或任何其他生物学系统的所需改变。例如,用于治疗用途的“有效量”是包含本文公开的化合物的组合物的量,其提供了临床上显著的疾病症状减轻。合适的“有效”量,在任一单独情况中可通过使用一些技术(例如剂量递增研究)来确定。
本文所用术语“卤素”指Cl、Br、I、F、At,或合成卤素如tennessine(Ts)。
本文所用术语“杂环烷基”指3-24个原子(C3-C24)的环状基团,所述原子选自碳、氮、硫、磷和氧,其中至少一种原子为碳。
如本文所定义,术语“异构体”包括但不限于光学异构体和类似物、结构异构体和类似物、构象异构体和类似物等等。在一个实施方案中,本公开包括使用不同光学异构体,如本文详述。本领域技术人员可以理解的是,本发明中可用的抗癌化合物可能包含至少一个立体手性中心(steriogenic center)。所以,本发明的方法所用化合物可存在并可分离为光活性或外消旋形式。一些化合物也可能表现出多态性。
术语“恶性肿瘤细胞”、“肿瘤细胞”和“癌细胞”在本说明书全文中可相互交换使用。术语“恶性肿瘤干细胞”、“肿瘤干细胞,”和“癌症干细胞”在本说明书全文中可相互交换使用。
本文所用“样品”或“测试样品”指其中存在的标靶和/或标靶的水平待测或已测定的任何样品。样品可包括液体、溶液、乳液或悬浊液。样品可包括医学样品。样品可包括任何生物液体或组织,例如,血液、全血、血液组分(例如血浆和血清)、软骨、韧带、肌腱、肌肉、间质液、汗液、唾液、尿液、泪液、滑液、滑膜、半月板、骨髓、脑脊液、鼻分泌物、痰液、羊水、支气管肺泡灌洗液、洗胃液、呕吐物、粪便物、肺组织、外周血单核细胞、总白细胞、淋巴结细胞、脾细胞、扁桃体细胞、癌细胞、肿瘤细胞、胆汁、消化液、皮肤或它们的组合。在一些实施方案中,样品包括等分试样。在其他实施方案中,样品包括生物流体。样品可以通过本领域已知的任何方式获得。可以直接使用从患者获得的样品,也可以进行预处理,例如通过过滤、蒸馏、提取、浓缩、离心、干扰成分的灭活、添加试剂等,按本文讨论的某种方式或本领域已知的其他方式以改变样品的性质。
本文所用“受试者”和“患者”可相互交换地指任何脊椎动物,包括但不限于需要本文描述的组合物或方法的哺乳动物。受试者可以是人类或非人类。受试者可以是脊椎动物。受试者可以是哺乳动物。该哺乳动物可以是灵长类或非灵长类。该哺乳动物可以是非灵长类,例如牛、猪、骆驼、美洲驼、刺猬、食蚁兽、鸭嘴兽、大象、羊驼、马、山羊、兔、绵羊、仓鼠、豚鼠、猫、狗、大鼠和小鼠。哺乳动物可以是灵长类动物,例如人。哺乳动物可以是非人类灵长类动物,例如,猴、食蟹猴、恒河猴、黑猩猩、大猩猩、红毛猩猩和长臂猿。受试者可以是任何年龄或发育阶段,例如成年、青少年或婴儿。受试者可以是雄性。受试者可以是雌性。在一些实施方案中,受试者患有特定的癌症。受试者可能正在接受其他形式的治疗。
本文使用术语“治疗性化合物”指任何可以提供癌症治疗的化合物。
“治疗”(treat或treating或treatment)指抑制、压制、反转、缓解、改善或阻止疾病的恶化或完全消除所述疾病。治疗可以是急性或慢性的方式。该术语也指降低疾病或该疾病相关症状的严重程度。
除非本文另有定义,与本公开有关的所用的科学和技术术语应具有本领域普通技术人员通常理解的含义。例如,任何与例如细胞和组织培养、分子生物学、免疫学、微生物学、遗传学以及蛋白质和核酸化学和杂交及其技术有关的术语为本领域已知并通常使用的那些。术语的含义和范围应该是清晰的;然而当有任何潜在的混淆时,本文提供的定义优选于任何词典或外部定义。此外,除非所在语境另有要求,单数形式的术语应包括复数含义,以及复数术语应包括单数含义。
2.化合物
在一个方面,本公开提供式(I)化合物或其药学上可接受的盐,
其中
n是2-20;
Q2是化学键或自分解性间隔子;和
Z是抗癌药物。
数字“n”可以是2至20的任何整数。在一些实施方案中,n是2、4、6、8、10、12、14、16、18或20。在特别的实施方案中n是18。
数字“m”可以是0至100的任何整数。在一些实施方案中,m是1、2、3、4、5、6、7、8、9或10。在一些实施方案中,m是10至20、10至40、10至60或10至80的整数。在一些实施方案中m是0,Q1是化学键或
Q2可以是任何已知的自分解性间隔子,包括例如对氨基苄氧羰基(PABC)。
在一些实施方案中,Rx是H。在一些实施方案中,Rx是Cl。
Z可以是任何抗癌药物,包括多种已知的化学疗法药物。
在一些实施方案中,Z是一种Polo样激酶1(PLK-1)抑制剂。合适的PLK-1抑制剂包括,例如BI2536、BI6727(volasertib)、二氨基嘧啶(DAP)衍生物(例如DAP-81和DAP-83)以及公布于Kumar等人(Biomed Res Int.2015,2015:705745)和Peters等人(Nat ChemBiol.2006,2(11):618-26)中的化合物,其内容以引证的方式全部纳入本文中。
在一些实施方案中,Z是微管蛋白聚合酶抑制剂,例如诺考达唑。
在一些实施方案中,Z是微管蛋白稳定剂,例如他卡洛内酯类(taccalonolides)。
在一些实施方案中,Z是抗肿瘤剂,例如单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)、单甲基奥瑞他汀D(MMAD)。
在一些实施方案中,Z是真核翻译起始因子4(EIF4)抑制剂,例如EIF4A和EIF4E抑制剂。在一些实施方案中,Z是EIF4E抑制剂。合适的E1F4抑制剂包括,例如,利巴韦林和公开于D'Abronzo等人(Neoplasia,2018,20(6),563-573)和美国专利第10,577,378号中的化合物,其内容通过引证的方式全部纳入本文。
在一些实施方案中,Z是考布他汀A-4类似物,例如考布他汀A-4磷酸盐或ombrabulin。合适的考布他汀A-4类似物还包括例如Bellina等人(Bioorganic&MedicinalChemistry Letters 2006,16(22),5757-5762)中公开的化合物,其内容通过引证的方式全部纳入本文。
在一些实施方案中,Z是flavagline类似物。合适的flavagline类似物包括,例如,美国专利申请公开US 2018/0086729中公开的化合物,其内容通过引证的方式全部纳入本文。
在某些实施方案中,Z是其他已知的抗癌药物之一,包括例如(i)其他抗增殖/抗肿瘤药物,例如烷化剂、抗代谢物、抗肿瘤抗生素、抗有丝分裂剂;和拓扑异构酶抑制剂;(ii)细胞抑制剂,例如抗雌激素药、抗雄激素药、LHRH拮抗剂或LHRH激动剂、孕激素和芳香酶抑制剂;(iii)抗侵袭剂(例如c-Src激酶家族抑制剂);(iv)生长因子功能抑制剂,例如酪氨酸激酶抑制剂;(v)抗血管生成剂;(vi)血管损伤剂;(vii)内皮素受体拮抗剂。
合适的抗癌药物的实例包括但不限于紫杉醇、伊立替康、拓扑替康、吉西他滨、顺铂、格尔德霉素、mertansine、阿比特龙、阿法替尼、氨基乙酰丙酸、阿瑞匹坦、阿昔替尼、阿扎胞苷、贝利司他、苯达莫司汀、贝沙罗汀、博来霉素、硼替佐米、博舒替尼、白消安、卡巴他赛、卡博替尼、卡培他滨、卡铂、卡非佐米、卡莫司汀、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯法拉滨、克唑替尼、环磷酰胺、阿糖胞苷、达拉非尼、达卡巴嗪、更生霉素、达沙替尼、柔红霉素、地西他滨、地诺单抗、右雷佐生、多西他赛、多拉他汀(如单甲基奥瑞他汀E)、多柔比星、恩杂鲁胺、表柔比星、甲磺酸艾日布林、厄洛替尼、依托泊苷、依维莫司、氟尿苷、磷酸氟达拉滨、氟尿嘧啶、ganetespib、吉非替尼、吉姆单抗奥佐米星、六甲基三聚氰胺、羟基脲、替伊莫单抗、依鲁替尼、idelalisib、异环磷酰胺、伊马替尼、易普利姆玛、伊沙匹隆、拉帕替尼、亚叶酸钙、洛莫司汀、美登素、甲氯乙胺、美法仑、巯基嘌呤、美司钠、甲氨蝶呤、丝裂霉素C、米托坦、米托蒽醌、奈拉滨、奈非那韦、尼罗替尼、奥比妥珠单抗、奥法木单抗、omacetaxinemepesuccinate、奥沙利铂、帕尼单抗、帕唑帕尼、培门冬酶、派姆单抗、培美曲塞、喷司他丁、帕妥珠单抗、plicanycin、泊马度胺、盐酸普纳替尼、普拉曲沙、丙卡巴肼、镭223二氯化物、雷莫芦单抗、瑞戈非尼、瑞他霉素、鲁索替尼、司莫司汀、司妥昔单抗、索拉非尼、链脲佐菌素、苹果酸舒尼替尼、坦斯匹霉素、替莫唑胺、替西罗莫司、替尼泊苷、沙利度胺、硫鸟嘌呤、噻替帕、托瑞米芬、曲美替尼、曲妥珠单抗、凡德他尼、威罗非尼、长春碱、长春新碱、长春瑞滨、vismodegib、伏立诺他和阿柏西普。
在一些实施方案中,式(I)化合物具有式(I-a)的结构或其药学上可接受的盐,其中Q1是L-Q2是 以及Z是PLK-1抑制剂、微管蛋白聚合酶抑制剂、微管蛋白稳定剂、抗肿瘤剂或真核翻译起始因子4(EIF4)抑制剂。式(I-a)具体可以是 或其药学上可接受盐,其中n是2-20以及Z是PLK-1抑制剂、微管蛋白聚合酶抑制剂、微管蛋白稳定剂、抗肿瘤剂或真核翻译起始因子4(EIF4)抑制剂。
在一些实施方案中,化合物具有式(I-a)的结构,其中n是18。在一些实施方案中,化合物具有式(I-a)的结构,其中Z是PLK-1抑制剂或抗肿瘤剂。在一些实施方案中化合物具有(I-a-1)、(I-a-2)或(I-a-3)的结构或者是其药学上可接受盐,其中Z是PLK-1抑制剂。例如,Z可以是
在一些实施方案中,化合物具有(I-a-1)、(I-a-2)或(I-a-3)的结构或者是其药学可接受盐,其中Z是抗肿瘤剂,所述抗肿瘤剂选自下列组成的组:单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)和单甲基奥瑞他汀E(MMAD)。在一些实施方案中,化合物具有式(I-a-3)的结构或者是其药学上可接受的盐,其中Z是MMAE、MMAF或MMAD(如下所示)。
本文公开的合适化合物包括:
所公开的化合物可以药学上可接受的盐存在。术语“药学上可接受的盐”指化合物的盐或两性离子,其是水溶性的或油溶性的或可分散的,适合用于治疗疾病而没有过度毒性、刺激和过敏反应,与合理的收益/风险比相称,并对其预期的用途有效。代表性的盐包括乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,二葡萄糖酸盐,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,甲酸盐,羟乙基磺酸盐,富马酸盐,乳酸盐,马来酸盐,甲磺酸盐,萘磺酸盐,烟酸盐,草酸盐,双羟萘酸盐,果胶酸盐,过硫酸盐,3-苯丙酸盐、苦味酸盐、草酸盐、马来酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、三氯乙酸盐、三氟乙酸盐、谷氨酸盐、对甲苯磺酸盐、十一酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等。化合物的氨基也可以用烷基氯、烷基溴和烷基碘进行季铵化,例如甲基、乙基、丙基、异丙基、丁基、月桂基、肉豆蔻基、硬脂基等。
碱加成盐的制备可在公开化合物最后的分离和提纯中进行,通过羧基和合适的碱反应进行,所述合适的碱例如是金属阳离子(如锂、钠、钾、钙、镁或铝)的氢氧化物、碳酸盐或碳酸氢盐,或有机伯胺、仲胺或叔胺。可以制备季胺盐,例如衍生自下列的那些:甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N-N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、普鲁卡因、二苄胺、N,N-二苄基苯乙胺、1-ephenamine和N,N'-二苄基乙二胺、乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。
化合物可存在为立体异构体,其中存在不对称或手性中心。立体异构体是“R”还是“S”,取决于手性碳原子围绕的取代基的构型。本文使用的术语“R”和“S”是IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,in Pure Appl.Chem.,1976,45:13-30中定义的构型。本公开考虑了多种立体异构体及其混合物,且这些是具体包括在本公开的范围中的。立体异构体包括对映异构体和非对映异构体,以及对映异构体或非对映异构体的混合物。化合物的各个立体异构体可以由含有不对称或手性中心的可商购起始材料合成制备,或通过制备外消旋混合物然后经本领域普通技术人员熟知的拆分方法来制备。这些拆分方法的实例有:(1)将对映异构体混合物连接到手性助剂,通过重结晶或层析分离所得非对映异构体混合物,然后可选释放光学纯的产品,除掉助剂,该方法记载于Furniss,Hannaford,Smith,和Tatchell,“Vogel's Textbook of Practical OrganicChemistry”第5版(1989),Longman Scientific&Technical,Essex CM20 2JE,England;或(2)通过手性层析柱直接分离光学对映异构体混合物;或(3)组分重结晶方法。应当理解的是,化合物可能以互变异构体和几何异构体存在,这些也构成本公开的一个方面。
本公开也包括同位素标记化合物,与式(I)列举的那些相同但事实是,一个或多个原子被原子质量或质量数不同于自然界中常见原子质量或质量数的原子取代。适合包含在本公开化合物中的同位素的实例为氢、碳、氮、氧、磷、硫、氟和氯,分别例如但不限于2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。使用更重的同位素(例如氘,即2H)取代可以提供特定的治疗优势,其源自更大的代谢稳定性,例如增加的体内半衰期,或降低的剂量需求,因此在某些情况下可以是优选的。化合物可结合发射正电子的同位素,用于医学成像和正电子发射断层扫描(PET)研究,来确定受体的分布。可结合至式(I)化合物的合适的正电子发射同位素为11C、13N、15O和18F。同位素标记的式(I)化合物可通过本领域技术人员已知的常规技术制备,或通过类似于所附实施例中描述的方法制备,使用合适的同位素标记试剂替换非同位素标记试剂。
可以根据本文详述的合成方案制备所述化合物。所述化合物和中间体可用有机合成领域技术人员熟知的方法进行分离和提纯。常规分离和提纯化合物方法的实例包括但不限于:固体载体上的层析,例如硅胶、氧化铝或烷基硅烷基团衍生的二氧化硅;通过在高温或低温下重结晶,可选使用活性炭预处理;薄层层析;在多种压力下蒸馏;在真空下升华;和研磨,例如记载于Furniss,Hannaford,Smith,和Tatchell的“Vogel's Textbook ofPractical Organic Chemistry,”第5版(1989),pub.Longman Scientific&Technical,Essex CM20 2JE,England。
每个步骤的反应条件和反应次数可以变化,取决于所用的特定反应物和所用反应物中取代基。具体的步骤提供于实施例章节。反应可按常规方式进行,例如从残余物中出去溶剂,然后进一步根据本领域通常已知的方法提纯,所述的方法包括但不限于结晶、蒸馏、萃取、研磨和层析。除非另有描述,初始原料和试剂可商购获得,或由本领域技术人员从可商购获得的材料使用化学文献记载的方法制备。起始原料如果不可商购获得,则可以通过选自下列的步骤制备:标准有机化学技术,类似于合成已知且结构相似化合物的技术,或类似于上述方案的技术,或制备实施例章节中描述的步骤。
常规实验法,包括适当调控反应条件、试剂和合成路线的顺序,保护与反应条件不兼容的化学功能,以及在该方法的反应顺序中的合适节点去保护,这些都包括在本发明的范围内。合适的保护基以及使用这些合适的保护基来保护和去保护不同取代基的方法为本领域技术人员所熟知;这些方法的实例见于PGM Wuts和TW Greene,在Greene的名为Protective Group in Organic Synthesis(第4版),John Wiley&Sons,NY(2006年)的书中,通过引证的方式将其全部纳入本文。本发明化合物的合成可以通过类似于合成方案和具体实施例中描述的方法来完成。
3.药物组合物
在另一个方面,本公开提供包含本文公开的化合物或其药学上可接受盐和药学上可接受的载体的药物组合物。
本药物组合物可通过本领域已知的方法制造,例如通过常规的混合、溶解、造粒、制成糖衣丸、捻成细粉(levigating)、乳化、包封、包埋(entrapping)或冻干方法。
如本文所描述,药学上可接受的载体包括任何以及全部的溶剂、稀释剂或其他液体载体、分散或悬浮助剂、表面活性剂、等渗剂、稠化或乳化剂、防腐剂、固体粘结剂、润滑剂等,配至所需特定剂量形式。多种制剂药学上可接受的组合物的载体,及所述组合物的制备技术在本领域中是已知的(例如Remington's Pharmaceutical Science,第16版,E.W.Martin(Mack Publishing Co.,Easton,Pa.1980))。
药学上可接受的载体可以是功能性分子,例如载体、佐剂或稀释剂。药学上可接受的载体可以是任何类型的无毒、惰性固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂。药学上可接受的载体包括例如稀释剂、润滑剂、粘合剂、崩解剂、着色剂、调味剂、甜味剂、抗氧化剂、防腐剂、助流剂、溶剂、助悬剂、润湿剂、表面活性剂、软化剂(emollient)、推动剂(propellant)、保湿剂(humectant)、散剂、pH调节剂及其组合。
可用作药学上可接受的载体的材料的一些实例包括但不限于:离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸或山梨酸钾;饱和植物脂肪酸水、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)的部分甘油酯混合物;胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯聚氧丙烯嵌段聚合物、羊毛脂肪、糖类(如乳糖、葡萄糖和蔗糖)、淀粉(如玉米淀粉和马铃薯淀粉)、纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素和醋酸纤维素)、黄蓍胶粉、麦芽、明胶、滑石粉、赋形剂(如可可脂和栓剂蜡)、油类(如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油、大豆油)、二醇类(如丙二醇或聚乙二醇)、酯类(如油酸乙酯和月桂酸乙酯)、琼脂、无毒相容润滑剂(如十二烷基硫酸钠和硬脂酸镁)、着色剂、脱模剂、包衣剂、乳化剂、甜味剂、调味剂、芳香剂、防腐剂、抗氧化剂,也可以存在于组合物中,根据配方设计师的判断。
在一些实施方案中,药物组合物主要由治疗效果量的本文公开化合物或其药学上可接受的盐组成。
液体剂量形式包括但不限于药学上可接受的乳液、微乳液、溶液、悬浊液、糖浆和酏剂。固体剂量形式包括但不限于胶囊、片剂、丸剂、粉剂、胶结剂、腻子(putty)和颗粒剂。本化合物外用和透皮给药包括但不限于软膏、糊剂、乳膏、洗液、凝胶剂、粉末剂、溶液、喷雾剂、吸入剂或贴剂。
液体载体或载剂可以是溶剂或液体分散介质,包括例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯及其合适的混合物。
药物组合物可以是适合注射或输液的剂量形式,例如灭菌水溶液或分散剂,或者是包含一种或多种活性成分的灭菌粉末,所述灭菌粉末适合于立即制备为灭菌可注射或可输液的溶液或分散剂。最终的剂量形式应该是在制造和存储条件下灭菌、流动和稳定的。灭菌可注射溶液可以通过将至少一种所需量的本文公开化合物或其药学是可接受的盐,与多种所需的其他成分结合在合适的溶剂中来制备,可选之后进行过滤灭菌。在用于制备灭菌可注射溶液的灭菌粉剂的情况下,制备的方法可以包括真空干燥和冷冻干燥技术,所述技术可以得到一种或多种活性成分以及任何灭菌溶液中所需的额外成分的粉剂。
在一些实施方案中,组合物是溶液,例如适合用于输液或注射给药的溶液。溶液可以在水中制备,可选使用非毒性表面活性剂混合。也可在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物和油中制备分散剂。这些制剂可能含有防腐剂以防止微生物生长。可以通过各种抗菌剂和抗真菌剂来防止微生物的作用,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。
可注射形式可以通过在可生物降解聚合物(例如聚丙交酯-聚乙交酯)中形成本文公开化合物或其药学上可接受的盐的微胶囊基质来制造。取决于化合物和聚合物的比例,以及所用具体聚合物的性质,可以控制药物释放速率。其他可生物降解的聚合物包括聚(原酸酯)和聚(酸酐)。可注射制剂也可通过将药物包埋在与人体组织相容的脂质体或微乳液中来制备。
在一些实施方案中,组合物可包含至少一种本文记载的化合物和至少一种额外的抗癌药物。可用于本公开的抗癌药物包括但不限于紫杉醇、伊立替康、拓扑替康、吉西他滨、顺铂、格尔德霉素、mertansine、阿比特龙、阿法替尼、氨基乙酰丙酸、阿瑞匹坦、阿昔替尼、阿扎胞苷、贝利司他、苯达莫司汀、贝沙罗汀、博来霉素、硼替佐米、博舒替尼、白消安、卡巴他赛、卡博替尼、卡培他滨、卡铂、卡非佐米、卡莫司汀、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯法拉滨、克唑替尼、环磷酰胺、阿糖胞苷、达拉非尼、达卡巴嗪、更生霉素、达沙替尼、柔红霉素、地西他滨、地诺单抗、右雷佐生、多西他赛、多拉他汀(例如单甲基奥瑞他汀E)、多柔比星、恩杂鲁胺、表柔比星、甲磺酸艾日布林、厄洛替尼、依托泊苷、依维莫司、氟尿苷、磷酸氟达拉滨、氟尿嘧啶、ganetespib、吉非替尼、吉姆单抗奥佐米星、六甲基三聚氰胺、羟基脲、替伊莫单抗、依鲁替尼、idelalisib、异环磷酰胺、伊马替尼、易普利姆玛、伊沙匹隆、拉帕替尼、亚叶酸钙、洛莫司汀、美登素、甲氯乙胺、美法仑、巯基嘌呤、美司钠、甲氨蝶呤、丝裂霉素C、米托坦、米托蒽醌、奈拉滨、奈非那韦、尼洛替尼、奥比妥珠单抗、奥法木单抗、omacetaxine mepesuccinate、奥沙利铂、帕尼单抗、帕唑帕尼、培门冬酶、派姆单抗、培美曲塞、喷司他丁、帕妥珠单抗、plicanycin、泊马度胺、盐酸普纳替尼、普拉曲沙、丙卡巴肼、镭223二氯化物、雷莫芦单抗、瑞戈非尼、瑞他霉素、鲁索替尼、司莫司汀、司妥昔单抗、索拉非尼、链脲佐菌素、苹果酸舒尼替尼、坦斯匹霉素、替莫唑胺、替西罗莫司、替尼泊苷、沙利度胺、硫鸟嘌呤、噻替帕、托瑞米芬、曲美替尼、曲妥珠单抗、凡德他尼、威罗非尼、长春碱、长春新碱、长春瑞滨、vismodegib、伏立诺他和阿柏西普。当前已知或能够充当抗癌药物的任何化合物也可用于本公开。
4.方法
本文详述的化合物选择性靶向肿瘤的基础在于,癌细胞的质膜与大多数正常细胞的质膜之间的差别。磷脂醚(PLE)分子利用了代谢转移,该代谢转移是肿瘤细胞经历的以生成迅速细胞分裂所需的能量。肿瘤增强了β氧化途径的利用,来将长链脂肪酸(LCFA)转化为能量。为了增加LCFA的摄入,肿瘤细胞改变了细胞膜形成专门的微区,称为“脂筏”。脂筏由代谢转移形成,并需要磷脂。在肿瘤细胞中这些区域大量存在并且稳定,使他们成为潜在的肿瘤特异性标靶。具体而言,癌细胞膜高度富含脂筏。在正常组织中,脂筏的存在很有限并且转瞬即逝(~2纳秒)。在肿瘤中,脂筏的存在增强,而且稳定(最高至10天)。癌细胞有比健康细胞多5到10倍的脂筏。此外,脂筏被证明在几乎全部肿瘤类型中丰富存在,并且在测试的单独癌细胞中100%存在。脂筏是膜磷脂双层的高度组织化且特化的区域,含有高浓度的多种信号分子、鞘脂、鞘糖脂和胆固醇,负责管理细胞表面和细胞内信号分子(例如生长因子和细胞因子受体,磷脂酰肌醇3-激酶(PI3K)/Akt生存通道)。数据表明脂筏是磷脂醚(PLE)的进入通道。这些化合物对癌细胞与非癌细胞的显著选择性,归因于PLE对胆固醇的高亲和性以及癌细胞中丰富的富含胆固醇的脂筏。脂筏的关键角色由这样的事实凸显出来:脂筏结构的破坏,可压制癌细胞摄入PLE。已经被证明的是,当阻止形成脂筏时,PLE的摄入可以降低60%。这些特点,结合提供磷脂药物缀合物快速内化的脂筏,使它们成为理想标靶。
本文公开的化合物,例如PLE类似物,可以是LCFA模拟物。本文公开的分子进行了与靶向肿瘤细胞脂筏相关的广泛的结构活性关系分析,并被证明与这些区域特异性结合。本文公开的分子提供直接进入细胞质并沿细胞质内的高尔基体网络转运至内质网和线粒体。在一些实施方案中,本文公开的磷脂药物缀合物(PDC)包括特别设计的磷脂醚,其通过可断裂的接头缀合至新型考布他汀A(CBA)类似物上。CBA是抑制肿瘤细胞内微管蛋白聚合的强效细胞毒素,也展示出扰乱肿瘤周围/内局部脉管系统的能力。在一些实施方案中,本文公开的化合物包括特别设计的磷脂醚,其通过可断裂的接头缀合至flavagline(FLV)类似物上。FLV是阻止翻译、细胞周期进程和诱导细胞凋亡的强效细胞毒素。
本文详述的化合物或其药学上可接受的盐或包含本文详述化合物的组合物可用于治疗癌症。在一个方面,本公开提供治疗有需要的受试者的癌症的方法,包括给予有效量的本文详述的化合物或其药学上可接受的盐或包含文本详述化合物的组合物。
在另一个方面,本公开提供本文公开的化合物或其药学上可接受的盐,用于治疗有需要的受试者的癌症。
在另一个方面,本公开提供本文公开的化合物或其药学上可接受的盐在制造治疗有需要的受试者的癌症的药物中的用途。
可用本文详述化合物或其药学可接受盐或包含本文详述化合物的组合物治疗的癌症,包括但不限于:乳腺癌,包括男性乳腺癌;消化道/胃肠道癌症,包括肛门癌、阑尾癌、肝外胆管癌、胃肠道类癌瘤、结肠癌、食道癌、胆囊癌、胃癌、胃肠道间质瘤(“gist”)、胰岛细胞瘤、成人原发性肝癌、儿童肝癌、胰腺癌、直肠癌、小肠癌和胃癌(胃癌);内分泌和神经内分泌癌,包括胰腺癌、肾上腺皮质癌、胰腺神经内分泌肿瘤、默克尔细胞癌、非小细胞肺神经内分泌肿瘤、小细胞肺神经内分泌肿瘤、甲状旁腺癌、嗜铬细胞瘤、垂体瘤和甲状腺癌;眼癌,包括眼内黑色素瘤和视网膜母细胞瘤;泌尿生殖系统癌,包括膀胱癌、肾(肾细胞)癌、阴茎癌、前列腺癌、移行细胞肾盂和输尿管癌、睾丸癌、尿道癌和肾母细胞瘤;生殖细胞癌,包括儿童中枢神经系统癌、儿童颅外生殖细胞瘤、性腺外生殖细胞瘤、卵巢生殖细胞瘤和睾丸癌;妇科癌症,包括宫颈癌、子宫内膜癌、妊娠滋养细胞肿瘤、卵巢上皮癌、卵巢生殖细胞瘤、子宫肉瘤、阴道癌和外阴癌;头颈癌,包括下咽癌、喉癌、唇癌和口腔癌、隐匿性原发性转移性鳞状颈癌、口腔癌、鼻咽癌、口咽癌、鼻窦及鼻腔癌、甲状旁腺癌、咽癌、唾液腺癌、喉癌;白血病,包括成人急性淋巴细胞白血病、儿童急性淋巴细胞白血病、成人急性髓细胞白血病、儿童急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞性白血病和毛细胞白血病;淋巴瘤,包括艾滋病相关淋巴瘤、皮肤t细胞淋巴瘤、成人霍奇金淋巴瘤、儿童霍奇金淋巴瘤、妊娠期霍奇金淋巴瘤、蕈样真菌病、成人非霍奇金淋巴瘤、儿童非霍奇金淋巴瘤、妊娠期非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、塞扎里综合征和华氏巨球蛋白血症;肌肉骨骼癌,包括尤文肉瘤、骨肉瘤和骨恶性纤维组织细胞瘤、儿童横纹肌肉瘤和软组织肉瘤;神经系统癌症,包括成人脑肿瘤、儿童脑肿瘤、星形细胞瘤、脑干神经胶质瘤、中枢神经系统非典型畸胎瘤/横纹肌瘤、中枢神经系统胚胎肿瘤、颅咽管瘤、室管膜瘤、神经母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤;呼吸道/胸部癌症,包括非小细胞肺癌、小细胞肺癌、恶性间皮瘤、胸腺瘤和胸腺癌;和皮肤癌,包括卡波西肉瘤、黑色素瘤和鳞状细胞癌。在特定实施方案中,癌症可以是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
在另一个实施方案中,癌症可包含一种或多种CTC。一种或多种CTC可选自下列组成的组:乳腺癌、肺癌、甲状腺癌、宫颈癌、黑色素瘤、鳞状细胞癌、前列腺癌、胰腺癌、结直肠癌、癌症干细胞和恶性浆细胞。
在另一个实施方案中,癌症是转移性的。在特别的实施方案中,转移性的癌症可选自下列组成的组:乳腺癌、肺癌、黑色素瘤和结直肠癌。
在另一个实施方案中,癌症可以是癌症干细胞。在特别的实施方案中,癌症干细胞可衍生自下列组成的组:乳腺癌、肺癌、黑色素瘤和结直肠癌。
在一些实施方案中,肺癌可包括小细胞肺癌、非小细胞肺癌或其组合。
在一些实施方案中,黑色素瘤可包括浅表扩散性黑色素瘤、结节性黑色素瘤、恶性雀斑样黑色素瘤、肢端雀斑样黑色素瘤、无色素性黑色素瘤、痣样黑色素瘤、spitzoid黑色素瘤、促纤维增生性黑色素瘤或其组合。
在一些实施方案中,结直肠癌可包括腺癌。
在一些实施方案中,本文详述的式(I-a)、(I-a-1)、(I-a-2)或(I-a-3)化合物或其药学可接受盐或包含本文详述化合物的组合物,可用于治疗黑色素瘤、肺癌、结直肠癌或其组合。
在一些实施方案中,乳腺癌可包括浸润性乳腺导管癌、转移性乳腺癌、炎性乳腺癌、三阴性乳腺癌、导管原位癌或其组合。在其他的实施方案中,癌症是乳腺癌,受试者可以是雌激素受体阳性、雌激素受体阴性和孕激素受体阴性、表达HER2(HER2+)、不表达HER2(HER2-)或其组合。在一些实施方案中,如本文详述的式(I-b)、(I-b-1)、(I-b-2)或(I-b-3)化合物或其药学上可接受的盐或包含如本文详述的化合物的组合物可用于治疗乳腺癌。
在一些实施方案中,本文详述的式(I-c)、(I-c-1)、(I-c-2)或(I-c-3)化合物或药学可接受盐或包含本文详述化合物的组合物可用于治疗黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
在一些实施方案中受试者是人,例如成人和婴儿。在一些实施方案中,受试者是动物,例如哺乳动物。
方法可包括按本文详述的量给予本文详述的化合物或其药学上可接受的盐或包含本文详述化合物的组合物。在一些实施方案中,方法包括给予大约0.0001mg/kg至大约1000mg/kg的文本详述化合物或其药学上可接受的盐。
组合物中一种或多种化合物的可用剂量可通过对比其在动物模型中体外活性和体内活性来确定。从啮齿类、猪和其他动物外推至人的有效剂量的方法为本领域熟知,例如参见美国专利No.4,938,949。
本文详述的治疗组合物中化合物的实际剂量水平可以变化,以得到一种或多种化合物的量,其可以有效达到所需的对特定患者、组合物和给药方式的治疗响应。所述化合物或其药学上可接受的盐用于治疗的所选剂量水平和量可随下列而变化:所选的特定化合物或盐、给药途径、治疗的疾病或病况、被治疗的受试者年龄和病况、被治疗病况的严重性和被治疗的病人的病况及之前医疗历史。当给予药学上可接受的盐时,剂量可按游离碱计算。然而,将化合物的起始剂量控制在低于达到所需治疗效果的水平,然后逐渐增加剂量直到达到所需效果,这是在本领域技术范围内的。在特定的情况下,本公开化合物可以按超过本文详述的剂量范围的量给药,来有效且激进地治疗特别激进的疾病或病况。
在一些实施方案中,本文公开的化合物或其药学上可接受的盐或药物组合物可以通过口服给药或静脉给药的方式给予。然而通常合适的剂量在大约0.0001mg/kg至大约1000mg/kg的范围,例如大约0.001mg/kg至大约10.0mg/kg。例如,合适的剂量可以在每天大约0.001mg/kg体重至大约5.0mg/kg体重,例如每天大约0.01mg/kg接受者体重至1.0mg/kg接受者体重,每天大约0.01mg/kg接受者体重至大约3.0mg/kg接受者体重,每天大约0.1mg/kg接受者体重至大约5.0mg/kg接受者体重,每天大约0.2mg/kg接受者体重至4.0mg/kg接受者体重。化合物可以按单位剂量形式给予;例如在每个剂量形式中包含1mg至100mg、10mg至100mg或5mg至50mg的活性成分。
所需剂量可以方便地以单剂量存在,或以在合适的间隔给予的分剂量存在,例如以每天2个、3个、4个或更多个子剂量存在。子剂量本身可以进一步分开,例如分为某数量的离散、间隔松散的给药。
合适的体内给药剂量和特定的给药方式的变化取决于年龄、体重、痛苦的严重程度、所治疗的哺乳类物种、所用的特定化合物以及这些所用化合物的具体应用。确定有效剂量水平来达到所需效果,可以通过已知方法完成,例如,人体临床试验、体内研究和体外研究。例如,本文公开化合物或其药学上可接受的盐的有效剂量的测定可通过对比其在动物模型中的体外活性和体内活性。这种对比可通过对比已有药物来进行。
剂量的量和间隔可以分别调整来提供活性部分的血浆水平,使之足够保持调控效果,或最小有效浓度(MEC)。对于各个化合物MEC会变化,但可以从体内和/或体外数据估计。达到MEC所必须的剂量取决于每个的特性和给药途径。然而,FIPLC测定或生物测定可以用来测定血浆浓度。剂量间隔也可以使用MEC值确定。组合物的给药应该使用一种方案,其使得在10-90%(优选在30-90%之间,最优选在50-90%之间)的时间内,血浆水平保持超过MEC。在局部给药或选择性摄入的情况下,药物的有效局部浓度可能不与血浆浓度相关。
本文公开的化合物、盐和组合物可以使用已知方法评估药效和毒性。例如,特定化合物或包含特定化学部分的化合物的子集的毒理学可以通过确定对细胞系(例如哺乳动物以及优选人类的细胞系)的体外毒性来建立。这些研究的结果通常可以预测动物中的毒性,例如哺乳动物,或者更具体地说,人类。或者,动物模型中特定化合物的毒性,例如小鼠、大鼠、兔、犬类或猴中,可通过已知手段确定。特定化合物的疗效可通过几种公认的方法确认,例如体外方法、动物模型或人体临床试验。当选择模型确定疗效时,本领域技术人员可在现有技术的指导下选择合适的模型、剂量、给药途径和/或方案。
本文详述的一种或多种化合物或其药学上可接受的盐或包含本文详述的一种或多种化合物的组合物,可以通过多种已知途径给予人类和其他哺乳动物,包括但不限于口服、直肠、肠胃外、脑池内、阴道内、经皮(例如使用贴剂)、经粘膜、舌下、肺部、腹膜内、局部(如通过粉末、软膏或滴剂)、口腔或作为口腔喷雾剂或鼻腔喷雾剂。如本文所用的术语“肠胃外”或“肠胃外地”是指给药方式,包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输注。
本文记载的组合物可以与额外的组分一起给药以延长组合物的稳定性、递及性和/或活性,或与额外的治疗剂组合,或在给予额外的治疗剂之前或之后提供。组合治疗包括:给予单独的药物剂量制剂(其含有一种或多种本所述化合物和一种或多种额外的药剂),以及按各自的药物剂量制剂给予化合物和各种额外的药剂。例如,本文详述的化合物可与本文详述的额外的抗癌药物一起给药。
本文详述的化合物或其药学上可接受的盐可以以脂质体的形式给药。正如本领域已知的,脂质体通常来自磷脂或其他脂质物质。脂质体由分散在水性介质中的单或多层水合液晶形成。任何生理学上可接受的且可代谢的、可以形成脂质体的脂质都可以使用。脂质体形式的本组合物,除了本文记载的化合物之外,可以包含抗癌药物、稳定剂、防腐剂、赋形剂等。优选的脂质是天然和合成的磷脂和磷脂酰胆碱(卵磷脂),单独或一起使用。形成脂质体的方法为本领域已知。参见,例如,Prescott,Ed.,Methods in Cell Biology,卷XIV,Academic Press,New York,N.Y.(1976),页码33及之后。这种组合物会影响物理状态、溶解性、稳定性、体内释放速率和体内清除速率。
在本公开的一个方法中,可在受控释放系统中递送药物组合物。例如,可使用静脉输液、植入式渗透泵、透皮贴剂、脂质体或其他给药方式给予药剂。在一个实施例中,可以使用泵(参见Langer,supra;Sefton CRC Crit.Ref.Biomed.Eng.14:201(1987);Buchwald等人,Surgery 88:507(1980);Saudek等人,N.Engl.J.Med.321:574(1989))。在另一个实施方案中,可以使用聚合物材料。然而在另一个实施方案中,受控释放系统可置于治疗标靶(例如肝脏)附近,因此只需要全身计量的一部分(参见例如Goodson,in MedicalApplications of Controlled Release,supra,卷2,页码115-138(1984))。其他受控释放系统的讨论在Langer的综述中(Science 249:1527-1533(1990))。
5.实施例
通过引用后面的实施例,前述内容会更好理解,提供所述实施例是为了说明但不意图限制本发明的范围。本公开有多种方面和实施方案,由附带的非限制性实施例展示。
实施例1.材料和方法
体外摄入CLR2000045通过使用MCF-7乳腺癌细胞和正常人类真皮成纤维(NHDF)细胞评估,通过LC/MS/MS测量。将乳腺癌细胞保持在补充有10%FBS的最低必需培养基中。所有细胞保持在37℃和5%CO2。细胞使用1μM药物培养,报告的值是三次重复测定的平均值。体外细胞毒性通过Cell Titer-试验测定,使用MCF-7乳腺癌细胞和Hs578T三阴性乳腺癌细胞。
CLR180099体外摄入和释放使用A549肿瘤细胞、HCT116肿瘤细胞和正常人类真皮成纤维(NHDF)细胞评估,通过LC/MS/MS测量。细胞使用1μM药物培养,报告的值是三次重复测定的平均值。体外细胞毒性通过Cell Titer-试验测定。
在使用活体鸡胚胎的疗效筛选模型中,给予72μM的CLR2000045来测定对MCF-7肿瘤的疗效,以及与载体对照和50μM的紫杉醇阳性对照进行比较。CLR2000045局部施用于胚胎外壳。受精白色来亨鸡蛋在37.5℃、50%相对湿度下孵化9天。在那个时刻(E9),通过在蛋壳上钻一个小孔进入气囊,将绒毛尿囊膜(CAM)脱落,在CAM上方的蛋壳切割1cm2的窗口。每组使用至少20个鸡蛋(取决于发展9天后胚胎生存率,每组可以超过20个鸡蛋)。因为在肿瘤移植后或有关于肿瘤移植缺陷,可能发生一些胚胎死亡,每组收集的数据可能少于20个鸡蛋(最少每组15个鸡蛋)。肿瘤细胞在补充有10%FBS和1%青霉素/链霉素的DMEM中培养。在E9日,使用胰蛋白酶脱离细胞,使用完全培养基清洗,然后悬浮在移植培养基中。将3×106个细胞的接种物适当地加入每组每个鸡蛋的CAM上,然后将鸡蛋随机分组。
每日检查胚胎活力。E18日也清点死亡胚胎的数量,以及观察最终可见的严重畸形,来评估治疗导致的胚胎毒性。对于所有组,计算最终死亡率和Kaplan-Meyer曲线。也关注任何观察到的可见畸形。在E18日,从所有带肿瘤的存活胚胎中取下CAM的上部(带肿瘤),使用PBS缓冲液清洗,然后直接转移到PFA中(固化48小时)。之后将肿瘤小心地从正常CAM组织中切除并称重。
进一步在带HCC70三阴性乳腺癌(TNBC)异种移植物的R2G2小鼠中评估体内疗效。3个剂量(1mg/kg)每周给予1、2或3次,持续2周,来评估CLR2000045。CLR2000045通过尾静脉注射的方式全身给药。每组包含10只小鼠。为了疗效监控肿瘤体积,以及为了耐受性监控体重。也监控生存情况。
与单独的FLV分子相比,CLR180099静脉注射(IV)给予健康C57BL/6小鼠来确定最大耐受剂量(MTD)。用于给药CLR180099的载体在这个情况下是PBS,然而任何药学上合适的载体都可以使用。每组包含5只小鼠。在带HCT 116异种移植物的无胸腺裸小鼠中评估体内疗效。小鼠是肋腹模型,其通过向小鼠后肋腹射约1×106在5ml 1.2%甲基纤维素中悬浮的细胞而得到。当组均肿瘤体积达到约120mm3时开始进行研究。使用卡尺测量肿瘤体积——测量肿瘤的长度、宽度和深度来计算肿瘤体积。评估了CLR180099的两个剂量(2mg/kg给予2次或2mg/kg给予3次)。每组包含10只小鼠。为了疗效监控肿瘤体积,以及为了耐受性监控体重。总的缀合CLR180099和游离FLV通过质谱测定。
实施例2.磷脂醚递送载体展示出针对范围广泛的肿瘤细胞的特异性
为了展示多种肿瘤细胞系中PDC的摄入,在37℃下,在完全培养基中,将多种肿瘤细胞系(例如MCT-116、MeS SA/Dx5、MIa PaCa-2、Ovcar-3和U-87MG)用5μM CLR1501(PLE附加BODIPY荧光载荷)培养24小时。各个细胞系的培养基可有轻微不同来优化生长,对每个细胞系可以使用本领域已知的任何合适培养基。所有细胞保持在37℃下,在补充有10%FPS和5%CO2的合适培养基中。激发CLR1501然后使用Alexa-Fluor 488过滤器探测。CLR1501高度聚集在所有不同的肿瘤细胞系中(图1A和图1B)。在超过100种肿瘤细胞系中进行了重复,例如MM.IS、MM.IR、RPM18226、U266和NCIH929、Panc-1、A375、PC-3、Caki-2、HCT-116、A549、转移性PC-3、MDA-MB-231、HT-29、SV-40、CNS-1、BxPC3、MCF-7、LuCap、LNCap、MES SA/Dx5、Capan1、HTB-77、Lan5、CHLA-20、NB1691和SK-N-AS,具有相似结果。CLR1501体外给药于不同癌细胞系和正常人皮肤成纤维细胞系。24小时后,在这些癌细胞系中CLR1501展现5至9重选择性体外摄入,对比正常成纤维细胞系。保留的CLR1501与血浆和细胞器膜有关。
在A375和A549细胞系中测量了体外摄入和细胞毒素载荷的释放,在37℃下,在完全培养基中,将所述细胞系在2μM的带有半稳定接头(CLR2208,“PDC-SM1”)的细胞毒素小分子PDC中培养48小时。PDC-SM1的摄入使用LC/MS/MS测量。PDC-SM1在30分钟内显示了摄入。20-40%暴露于细胞的缀合物在24小时内在肿瘤细胞细胞质中被测到(图2A)。之后使用CLR2206(“PDC-SM2”,除了带可断裂接头外与PDC-SM1相同)测量肿瘤细胞内载荷的释放。也研究了CLR2200(“PDC-SM3”)。小分子载荷的可测量释放在培养后1至2小时发生(图2B)。载荷的可忽略释放在培养基中发生(<1nM)。这些结果说明,磷脂醚分子具有靶向广泛肿瘤的能力,以及PDC具有实现使肿瘤细胞系摄入20-40%的暴露药物的能力。
为了测量在肿瘤细胞上经由脂筏的摄入,在37℃下,用CLR1502(近红外分子连接于PLE)培养多种骨髓瘤细胞24小时。下一天,对细胞进行清洗和并使用核染色剂(Hoescht33342)共染色。使用霍乱毒素单位B进一步染色这些细胞,来呈现脂筏。细胞使用霍乱毒素单位B培养24小时。此外,为了测量经由原发肿瘤样品上脂筏的摄入,来自患者的多种骨髓瘤细胞使用Hoescht 33342染色,并用CLR1501培养(图3)。这些结果说明,在细胞系和原发肿瘤样品中,PDC摄入与肿瘤细胞膜上的脂筏有关联。
测量了细胞毒素载荷的体外疗效。PDC-SM2对黑色素瘤(A375)和肺癌(A549)细胞表现出亚微摩尔活性(浓度测量基于于细胞培养的全缀合物浓度)。PDC-SM2对黑色素瘤表现出比对肺癌更低的活性(IC50 0.131对比0.016),但效果更强(剩余存活细胞0%对比12%,图4)。PDC-SM2对结直肠癌(HCT-116)细胞以及肺癌表现了相似的活性和强度,以及对于正常成纤维细胞没有活性。因此PDC表现出了载荷的释放和对肿瘤细胞的强纳摩尔活性。
为了确定细胞毒性PDC在体内是否耐受,C57BL/6小鼠被给予下列方式的剂量:PDC-SM2在第0、3、7天给予剂量水平0.5mg/kg、1.0mg/kg或2.0mg/kg;载荷单独在第0天给予0.25mg/kg、0.4mg/kg或0.5mg/kg;载体在第0、3、7天给予剂量。通过测量体重的变化,PDC和载体对照在重复给予剂量时没有表现毒性或不良事件(没有体重损失)。载荷剂量0.25mg/kg和0.4mg/kg可耐受,尽管有在小鼠皮肤和毛皮上注意到一些毒性。载荷剂量0.5mg/kg不可耐受,在第4天时两只小鼠在单次输液后死亡,以及所有小鼠在第5天牺牲(图5)。这些PDC在人血浆中表现良好的血浆稳定性。血浆稳定性使用Cyprotex血浆稳定性(Cyprotex'sPlasma Stability)试验测量。样品浓度为1μM,且在0、15、30、60和120分钟培养。使用在血浆中进行降解的阳性对照化合物。在各个培养时间点化合物剩余的百分比被测量。PDC-SM2在小鼠血浆中显示了一些不稳定,这可能导致一些毒性(表1)。当前的PDC在体内良好耐受。总体上,PDC提供了一种新的且独特的方式来将小分子靶向肿瘤。
表1.血浆稳定性评估
还在肠肿瘤中体内测量了CLR1502的选择性摄入。完整的结肠和小肠远端部分在给予50μg CLR1502后96小时的尸检中取出(图19A和图19B)。CLR1502通过尾部静脉注射。使用IVIS Spectrum观察到增加信号强度的面积,这使得可以通过动物皮肤直接视觉化CLR1502。然后,使动物安乐死之后,通过显微解剖切离IVIS系统识别的组织,并进行组织学研究,查看肿瘤与非肿瘤组织,以及出现近红外标记的位置。这些区域表现出非浸润性(结肠,图19C;远端小肠,图19F)和浸润性(结肠,图19D;远端小肠,图19E)肿瘤。
在其他研究中,CLR1502在转移瘤中且在局部淋巴结中积累。切除肠后,整块分离肠系膜脂肪、胰腺和脾。在一种情况下,两个大小~4mm的转移肿瘤沉积物在肠系膜中发现。这些病灶使用Fluobeam近红外成像仪轻松地观察到。这些病灶在H&E上被确认为转移性恶性病灶。局部淋巴结病通过使用Fluobeam也显示累积了CLR1502。在这些增生淋巴结中没观察到恶性细胞。
肿瘤厚度无法解释在肠道癌中注意到的增加的信号强度(图22A和图22B)。在每只小鼠注射50μg CLR1502后96小时进行尸检。为了检查组织厚度的效果,外观正常的结肠片段相互堆叠。测量辐射效率来比较1、2、3层正常结肠和小肠肿瘤的信号强度。应注意,1层正常结肠大约1mm厚。组织厚度可能解释了腺瘤中看到的强度增加,但无法解释腺癌中看到的区别。
体内光学扫描CLR1502在结直肠瘤模型中的摄入展示了,与正常组织相比,在恶性组织中的优先保留。带有结直肠癌(HCT-116)异种移植物的无胸腺裸小鼠经静脉注射1mgCLR1502,使用Li-COR脉冲系统成像(图23)。随时间推移在体内测定荧光强度(彩条表示)和生物学分布。
体内光学扫描CLR1502在乳腺癌模型中的摄入展示了,与正常组织相比,在恶性组织中的优先保留。带有原位乳腺癌异种移植物(MDA-MB-231)的无胸腺裸小鼠经静脉注射约80μg CLR1502,然后在7天内(168hr)使用Fluoptics和Spectrum系统每日成像(图24)。研究结果表明了,在肿瘤内的选择性摄入和延长的保留(黄色和绿色箭头分别指Fluobeam和IVIS Spectrum),以及正常组织随着时间相对增加的清除率。
对于带有肺癌异种移植物(H226肺)的无胸腺裸小鼠,在每个肋腹经静脉注射约50μg的CLR1502,然后使用IVIS Spectrum在落射荧光模式下成像(图25)。应注意,在96小时,恶性组织和正常组织之间辐射效率的差别为肿瘤边缘照明创造了充足的对比度,如黑色箭头所示。
实施例3.带考布他汀A-4类似物的CLR2000045改善乳腺癌治疗
CLR2000045展示了在肿瘤细胞中的明显摄入而正常组织中极少的摄入。弹头的释放表明在各个时间点大约50%的释放。在24和48小时之间,达到了摄入和释放弹头的稳态(图6)。CLR2000045展示了针对两种乳腺癌细胞系(MCF-7和Hs578T)优异的活性和强效,其IC50分别为76nM和51nM(图7)。该分子也展示了对于几种其他固体肿瘤的活性,包括肺癌、黑色素瘤和结直肠癌。在细胞系中测量了半数最大抑制浓度(IC50)(表2)。也测量了CLR2000045的血浆稳定性(表3)。
表2.IC50评估
表3.血浆稳定性评估
受精白色来亨鸡蛋(20/剂量组)在37.5℃下孵化9天。MCF-7移植前在标准条件下培养。3×106MCF-7细胞的接种物在第10天加入到绒毛尿囊膜中。然后将鸡蛋随机分成治疗组,然后按下列条件治疗4次(第11、13、15和17天):载体、每剂量紫杉醇50μM以及每剂量CLR2000045 72μM。CLR2000045在这个筛选模型中表现出与紫杉醇相似的活性(图8)。
当组均肿瘤体积达到约~200mm3(第4天)时开始研究。CLR2000045按下列剂量IV给药:1mg/kg,第5和12天;或第5、8、12和15天;或第5、7、9、12、14和16天。从给药组1至给药组3(每周3次共两周),CLR2000045展示出剂量响应的肿瘤体积减少,所测试的最高剂量显示了几乎100%根除肿瘤。与载体对照相比,2个最高剂量组展示了统计学显著的肿瘤体积降低(分别p≤0.05和p≤0.01)(图9)。Kaplan-Meier曲线表明,与载体和每周1次给药相比,以1mg/kg每周3次进行2周的CLR2000045治疗得到了显著提高的生存(分别p≤0.001和p≤0.05)。与载体相比,1mg/kg每周2次进行两周得到了显著提高(p≤0.05;图10)。治疗后体重的变化在(HCC70)小鼠异种移植模型中测量(图11A和图11B)。
CLR2000045展示了在肿瘤细胞系中显著的摄入并释放载荷(20-40%的暴露药物),同时在正常细胞中发生极少的摄入。CLR2000045对多种乳腺癌细胞系展示了强效的体外活性。CLR2000045展示对三阴性乳腺癌模型(HCC70)和转移性腺癌乳腺癌模型(MCF-7)的强效体内活性。CLR2000045提供了在TNBC(HCC70)模型中统计学显著的生存益处,以及两种最高的剂量被表明可以良好耐受,如体重损失所测量的。这些数据一起表明,CLR2000045针对多种乳腺癌细胞系和动物模型的体内体外的强效活性,保证了该PDC的持续开发。
实施例4.CLR180099提高针对结直肠肿瘤的抗肿瘤药物的安全性和疗效
CLR180099针对乳腺癌和肺癌表现出极好的活性和药效,IC50分别为0.024和0.011(图12)。该化合物也对几种其他固体肿瘤展现出活性,包括黑色素瘤和结直肠癌。CLR1800095、CLR180099A和CLR180099B的血浆稳定性在小鼠和人中测量(表4)。CLR180095在小鼠血浆中表现出一些不稳定性,这可能导致一些毒性。
表4血浆稳定性评估
当组均肿瘤体积达到~120mm3(第1天)时开始研究。CLR180099在第1和4天或第1、3和5天按2mg/kg IV给药。在第1和4天按10mg/kg给予多西他赛。CLR180099展示出与多西他赛相似或更好的肿瘤体积减少,并表现出剂量依赖效应。多西他赛组经历多次死亡,从第18天开始至第26天终止(图16)。Kaplan-Meier曲线表明,与多西他赛相比,在第1和4天或第1、3和5天以2mg/kg CLR180099治疗得到显著增加的生存(图17,对数秩检验,p≤0.001)。通过测量体重损失,所有使用CLR180099(两种剂量)治疗的小鼠在研究全程中表现了正常的体重增长(图18)。在每个剂量水平下,每组给药5只小鼠。两种PDC均耐受高达10mg/kg的剂量,所有小鼠生存且未表现出终末器官毒性(表5)。载荷本身无法在0.5mg/kg以上的剂量下耐受(在0.5mg/kg,所有小鼠死亡)。
表5体内耐受性
mg/kg | 0.1 | 0.5 | 1 | 5 | 10 |
FLV | 5 | 0 | 0 | 0 | 0 |
CLR180099A | 5 | 5 | 5 | 5 | 5 |
CLR180099B | 5 | 5 | 5 | 5 | 5 |
CLR180099在肿瘤细胞系中表现出显著的载荷摄入和释放(20-40%的暴露药物),而在正常细胞中发生极小摄入。CLR180099针对多种固体肿瘤表现出强效体外活性,包括肺癌(A549)、乳腺癌(MCF-7)和黑色素瘤(A375),以及其他肿瘤类型。体内的2种或3种剂量的CLR180099在结直肠癌中表现出与多西他赛相似或更好的活性。此外,与多西他赛相比,CLR180099在两种剂量下展示出显著提高的生存益处。耐受性评估表明,CLR180099在带肿瘤动物和正常动物两者中良好耐受,而FLV载荷对正常小鼠和带肿瘤小鼠两者有毒性。与单独FLV类似物载荷相比,CLR180099表现出无毒效果,说明这种载荷可以从具有磷脂醚(PLE)的靶向递送中获益。
实施例5化合物的合成
化学合成步骤按下列进行。产物的分离使用已知技术,例如HPLC,然后得到的结构通过NMR和MS确认。
CLR2208根据方案1合成。
方案1
CLR2206根据方案2合成。在-40℃下,在Et3N(10当量)和THF中使用次磷酸盐氯化物1A(2.5当量)3小时,以由化合物1制备化合物2。在15℃下,化合物2与2A(1当量)在Et3N(1当量)、CDI(1.5当量)、ZnCl2(2.6当量)和DMF中反应12小时得到化合物3。在哌啶(5当量DMF中,15℃下3小时)中对化合物3进行脱保护得到化合物4。在15℃下,化合物4与4A(1当量)在Et3N(4当量)、COMU(1.15当量)和CHCl3中反应2小时得到CLR2206。
方案2
CLR2200根据方案3合成。在室温下,化合物5与MMAE(0.8当量)在吡啶(Py,20当量)、HOBt(0.5当量)和DMF中反应12小时以得到化合物6。在室温下,化合物6在哌啶(10当量)和DCM:AcN(1:1)中脱保护12小时以提供化合物7。在室温下,化合物7与7A(1当量)在TEA(4.5当量)、COMU(1.2当量)和CHCl3中反应12小时得到CLR2200。
方案3
CLR200045根据方案4制备,或根据方案5制备。
方案4
方案5
CLR2013根据方案6制备。
方案6
CLR1800095根据方案7制备。
方案7
CLR180099B根据方案8制备(LCMS纯度97%)。
方案8
条件:NEt3,DMF,rt,过夜;DIPEA,DCM,rt,过夜。
CLR180099A根据方案9制备。
方案9
出于完整性的原因,在下列编号的条款中限定了本发明的多个方面:
条款1.式(I)化合物或其药学上可接受的盐,
其中
n是2-20;
Q2是化学键或自分解性间隔子,以及
Z是抗癌药物。
条款2.条款1的化合物或其药学上可接受的盐,其中
条款3.条款1-2中任一项的化合物或其药学上可接受的盐,其中Z是一种Polo样激酶1(PLK-1)抑制剂、微管蛋白聚合酶抑制剂、微管蛋白稳定剂、抗肿瘤剂,真核翻译起始因子4(EIF4)抑制剂、考布他汀A-4类似物或flavagline类似物。
条款4.条款1-3中任一项的具有式(I-a)结构的化合物或其药学上可接受的盐,其中
且
Z是PLK-1抑制剂、微管蛋白聚合酶抑制剂、微管蛋白稳定剂、抗肿瘤剂或真核翻译起始因子4(EIF4)抑制剂。
条款5.条款4的化合物,其中Z是PLK-1抑制剂或抗肿瘤剂,所述抗肿瘤剂选自下列组成的组:单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)和单甲基奥瑞他汀D(MMAD)。
条款6.条款1-3中任一项的具有式(I-b)结构的化合物或其药学上可接受的盐,其中
n是18;
Z是考布他汀A-4类似物。
条款7.条款1-3中任一项的具有式(I-c)结构的化合物或其药学上可接受的盐,其中n是18;
Z是flavagline类似物。
条款8.条款1的化合物,选自下列组成的组:
条款9.包含条款1-8中任一项的化合物或其药学上可接受的盐和药学上可接受的载体的药物组合物。
条款10.治疗有需要的受试者的癌症的方法,包括给予有效量的条款1-8中任一项的化合物或其药学上可接受的盐。
条款11.条款10的方法,其中癌症是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
条款12.条款10-11中任一项的方法,其中
肺癌包含小细胞肺癌、非小细胞肺癌或其组合;
黑色素瘤包括浅表扩散性黑色素瘤、结节性黑色素瘤、恶性雀斑样黑色素瘤、肢端雀斑样黑色素瘤、无色素性黑色素瘤、痣样黑色素瘤、spitzoid黑色素瘤、促纤维增生性黑色素瘤或其组合;
结直肠癌包括腺癌;或
乳腺癌包括浸润性乳腺导管癌、转移性乳腺癌、炎性乳腺癌、三阴性乳腺癌、导管原位癌或其组合。
条款13.条款10-12中任一项的方法,其中癌症包括癌症干细胞。
条款14.条款10-13中任一项的方法,其中癌症包括转移性癌细胞。
条款15.条款10-14中任一项的方法,其中癌症包括循环肿瘤细胞。
条款16.款10-15中任一项的方法,其中癌症是黑色素瘤、肺癌、结直肠癌或其组合,以及其中化合物是式(I-a)化合物或其药学上可接受的盐。
条款17.条款10-15中任一项的方法,其中癌症是乳腺癌,其中受试者是:(1)雌激素受体阳性,(2)雌激素受体阴性且黄体酮受体阴性,(3)表达HER2(HER2+),(4)不表达HER2(HER2-),或其组合。
条款18.条款10-15和17中任一项的方法,其中癌症是乳腺癌,且其中所述化合物是式(I-b)化合物或其药学上可接受的盐。
条款19.条款10-15中任一项的方法,其中癌症是癌症是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合,且其中化合物是式(I-c)化合物或其药学上可接受的盐。
前面具体方面的描述非常完整的披露了本发明的一般性质,通过应用现有技术中的知识,其他人可以容易地修改和/或调整至其他应用(例如特定方面),而不需要过度的实验,而不偏离本公开的一般概念。因此,基于本文出现的教导和指导,这些调整和修改旨在落入本公开的方面的等价情况的含义和范围内。应当理解,本文的用词和术语的目的是进行描述而不是限制,使得本说明书的术语和用词在教导和指导下使领域技术人员理解。
本公开的广度和范围不应当受到上述示例性方面中任一项的限制,但应该仅根据下面的权利要求及其等价情况定义。
本申请中为了所有目的引用的所有出版物、专利、专利申请和/或其他文件都以引证的方式全部纳入本文,其程度如将每个单独出版物、专利、专利申请和/或其他文件为了所有目的单独指出通过引证的方式纳入本文一样。
Claims (19)
3.权利要求1-2中任一项所述的化合物或其药学上可接受的盐,其中Z是Polo样激酶1(PLK-1)抑制剂、微管蛋白聚合酶抑制剂、微管蛋白稳定剂、抗肿瘤剂、真核翻译起始因子4(EIF4)抑制剂、考布他汀A-4类似物或flavagline类似物。
5.权利要求4所述的化合物,其中Z是PLK-1抑制剂或抗肿瘤剂,所述抗肿瘤剂选自下列组成的组:单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)和单甲基奥瑞他汀D(MMAD)。
9.包含权利要求1-8中任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体的药物组合物。
10.治疗有需要的受试者的癌症的方法,包括给予有效量的权利要求1-8中任一项的化合物或其药学上可接受的盐。
11.权利要求10所述的方法,其中所述癌症是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合。
12.权利要求10-11中任一项所述的方法,其中
所述肺癌包括小细胞肺癌、非小细胞肺癌或其组合;
所述黑色素瘤包括浅表扩散性黑色素瘤、结节性黑色素瘤、恶性雀斑样黑色素瘤、肢端雀斑样黑色素瘤、无色素性黑色素瘤、痣样黑色素瘤、spitzoid黑色素瘤、促纤维增生性黑色素瘤或其组合;
所述结直肠癌包括腺癌;或
所述乳腺癌包括浸润性乳腺导管癌、转移性乳腺癌、炎性乳腺癌、三阴性乳腺癌、导管原位癌或其组合。
13.权利要求10-12中任一项的所述方法,其中所述癌症包括癌症干细胞。
14.权利要求10-13中任一项所述的方法,其中所述癌症包括转移性癌细胞。
15.权利要求10-14中任一项所述的方法,其中所述癌症包括循环肿瘤细胞。
16.权利要求10-15中任一项所述的方法,其中所述癌症是黑色素瘤、肺癌、结直肠癌或其组合,且其中所述化合物是式(I-a)化合物或其药学上可接受的盐。
17.权利要求10-15中任一项所述的方法,其中癌症是乳腺癌,其中受试者是:(1)雌激素受体阳性,(2)雌激素受体阴性且黄体酮受体阴性,(3)表达HER2(HER2+),(4)不表达HER2(HER2-),或其组合。
18.权利要求10-15和17中任一项所述的方法,其中所述癌症是乳腺癌,且其中所述化合物是式(I-b)化合物或其药学上可接受的盐。
19.权利要求10-15中任一项所述的方法,其中所述癌症是黑色素瘤、肺癌、结直肠癌、乳腺癌或其组合,且其中所述化合物是式(I-c)化合物或其药学上可接受的盐。
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IL291197A (en) | 2022-05-01 |
KR20220062363A (ko) | 2022-05-16 |
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