CN101511375A - 使用l-胞嘧啶核苷类似物治疗癌症和其它病症或疾病状态的方法 - Google Patents
使用l-胞嘧啶核苷类似物治疗癌症和其它病症或疾病状态的方法 Download PDFInfo
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- CN101511375A CN101511375A CNA2006800451940A CN200680045194A CN101511375A CN 101511375 A CN101511375 A CN 101511375A CN A2006800451940 A CNA2006800451940 A CN A2006800451940A CN 200680045194 A CN200680045194 A CN 200680045194A CN 101511375 A CN101511375 A CN 101511375A
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Abstract
本发明涉及式I化合物和其药学可接受盐、溶剂化物或多晶型物用于治疗肿瘤、癌症和过度增生疾病等病症或疾病状态的用途,其中S为(A)或(B);X为H或F;R1为H、酰基、C1-C20烷基或醚基团、磷酸酯、二磷酸酯、三磷酸酯或磷酸二酯基团或(C)或(D)基团;其中Nu为生物学活性化合物如抗癌、抗过度增生、或抗病毒化合物的基团,使得来自所述生物学活性剂的氨基或羟基与相邻部分形成磷酸酯、氨基磷酸酯、碳酸酯或氨基甲酸乙酯基团;每个R8独立地为H或C1-C20烷基或醚基团,优选为H或C1-C12烷基;k为0-12,优选为0-2。R2为H、酰基或C1-C20烷基或醚基团。
Description
发明领域
本发明涉及拉米夫定(3TC)、恩曲他滨(FTC)和艾夫他滨(Elvucitabine)(L-FD4C或LFD4C),前药或包含这些药物单独或与其它活性药物,尤其是抗癌药物或前药一起的共轭物(conjugates)在单独或与其它药物组合治疗肿瘤中的用途,所述肿瘤包括癌症和过度增生疾病(hyperproliferative diseases)、慢性炎性疾病和一些病毒和其它微生物感染。
相关申请
本申请要求于2005年12月2日提交的美国临时申请号US60/741,730的优选权,将该申请全部引入在此作为参考。
发明背景
肿瘤为细胞生长的无规律的分裂增生。如果肿瘤有侵入和转移的特性,那么它就是恶性的,或癌性的。侵入涉及肿瘤进入周围组织的趋势,穿过定义组织边界的基底层,由此通常浸入身体的循环系统。转移涉及肿瘤迁移到身体的其它区域的趋势且从最初出现的位点建立增生区域。
现在在美国癌症是第二大导致死亡的疾病。在美国已经诊断出有超过8,000,000人患有癌症,在1994年预计有1,208,000新诊断出的癌症患者。在这个国家中,每年有超过500,000人死于这种疾病。
癌症还没有完全在分子水平上被理解。已知的是细胞暴露于致癌物,如一些病毒、一些化学试剂或辐射,导致使“抑制”基因失活或活化“制癌基因”的DNA突变。抑制基因是增长调控基因,当变异时,其不再能控制细胞增长。制癌基因最初是正常基因(称作原癌基因),其通过变异或改变表达内容变成转化基因。转化基因产物导致不适当的细胞增长。通过基因突变超过20种不同的正常细胞基因可变为制癌基因。变异细胞在很多方面不同于正常细胞,包括细胞形态学、细胞间的相互作用、细胞膜内含物、细胞骨架结构、蛋白分泌物、基因表达和死亡率(变异细胞可无限增长)。
身体的所有不同细胞类型可变异成良性或恶性肿瘤细胞。最常见的肿瘤位点是肺,然后是结肠直肠、乳腺、前列腺、膀胱、胰腺,且然后是卵巢。其它普遍类型的癌症包括白血病、包括脑癌的中央神经系统癌,黑色素瘤、淋巴瘤、红白血病、子宫癌和头颈癌。
现在主要使用下述3种疗法的一种或组合治疗癌症:手术、放疗和化疗。手术包括大块切除病灶组织。但是手术通常在位于一定位点,例如在乳腺、结肠和皮肤中有效,它不能用于治疗位于其它区域,如骨骼的肿瘤,也不能治疗扩散肿瘤病症,如白血病。
化疗包括中断细胞复制或细胞代谢。通常其用于治疗白血病,以及乳腺、肺和睾丸癌。
用于治疗癌症的有五种主要类型的化疗试剂:天然产物和它们的衍生物;蒽环类抗生素;烷基化剂;抗增生剂(也称抗代谢剂);和激素剂。通常化疗试剂涉及抗肿瘤剂。
认为烷基化剂通过烷化和交联DNA中的鸟嘌呤和其它可能的碱基起作用,而阻止细胞分裂。典型的烷基化剂包括氮芥类、乙撑亚胺类化合物、硫酸酯类、顺铂和多种亚硝基脲。这些化合物的缺点为它们不仅攻击恶性细胞,而且还攻击其它自然分裂的细胞,如骨髓、皮肤、胃肠粘膜和胎儿组织的细胞。
抗代谢剂通常为可逆或不可逆的酶抑制剂或在其它方面干扰核酸复制、翻译或转录的化合物。
已经鉴定出一些合成的核苷表现出抗癌活性。有强抗癌活性的公知的核酸衍生物为5-氟尿嘧啶。临床上已经将5-氟尿嘧啶用于治疗恶性肿瘤,包括例如,癌瘤、肉瘤、皮肤癌、消化器官癌和乳腺癌。然而,5-氟尿嘧啶引起严重的不良作用,如恶心、脱发、腹泻、口炎、白细胞血小板减少、厌食、色素沉积和水肿。有抗癌活性的5-氟尿嘧啶的衍生物已经描述于美国专利号4,336,381和日本专利号50-50383、50-50384、50-64281、51-146482和53-84981。
美国专利号4,000,137公开了肌苷、腺苷或有甲醇或乙醇的胞苷的过氧化氧化产物有抗淋巴细胞性白血病的活性。
阿糖胞苷(也称作Cytarabin、araC和Cytosar)为脱氧胞苷的核苷类似物,其于1950年首次合成且在1963年成为临床药物。现在它是治疗急性髓细胞样白血病的重要药物。它也有抗急性淋巴细胞性白血病,且小范围的用于慢性髓细胞性白血病和非霍奇金氏淋巴瘤。阿糖胞苷的主要作用为抑制核DNA合成。Handschumacher,R.和Cheng,Y.,"Purine and PyrimidineAntimetabolites",Cancer Medicine,XV-1章,第3版,J.Holland,等人编,Lea和Febigol,出版。
5-氮杂胞苷为胞苷类似物,其主要用于治疗急性髓细胞性白血病和骨髓增生异常综合症。
2-氟腺苷-5′-磷酸酯(福达华(Fludara),也称作FaraA)是用于治疗慢性淋巴细胞性白血病活性最强的试剂中的一种。该化合物通过抑制DNA合成起作用。使用F-araA治疗的细胞伴随有在G1/S相界线和在S相时的细胞堆积;因此,它是特异性细胞循环S相药物。活性代谢产物、F-araATP的合并延缓DNA链的延长。F-araA也是有效的负责dATP形成的关键酶,核苷酸还原酶抑制剂。
2-氯脱氧腺苷用于治疗低度B-细胞肿瘤,如慢性淋巴细胞性白血病、非霍奇金氏淋巴瘤和毛细胞白血病。活性范围与福达华的相似。该化合物抑制增长细胞中DNA合成且抑制休止细胞中的DNA修复。
虽然已经确定了许多化疗药物且这些药物现在用于治疗癌症,但是还在寻找有效的且表现出对健康细胞的低毒性的新试剂。
美国专利号5,817,667和6,063,787公开了使用β-LOddC用于治疗肿瘤,包括癌症,或治疗牛皮癣和相关的过度增生疾病/病症。
发明目的
因此,本发明的目的是提供表现出抗肿瘤,且尤其是抗癌和/或抗过度增生增长疾病活性的化合物和药物组合物。
本发明的另一个目的是提供用于治疗癌症和过度增生细胞生长疾病(hyperproliferative cell growth diseases)的药物组合物。
本发明的另一个目的是提供用于治疗癌症和过度增生细胞生长疾病的方法。
本发明的任何一个或多个这些目的可以通过阅读下述本发明的说明书容易地得到。
发明简述
本发明涉及下式I化合物及其药学可接受的盐、溶剂化物或多晶型物的用途,其用于治疗肿瘤、癌症和过度增生疾病:
X为H或F;
R1为H、酰基、C1—C20烷基或醚基团(ether group)、磷酸酯(phosphate)、二磷酸酯(diphosphate)、三磷酸酯(triphosphate)或磷酸二酯(phosphodiester)基团、
其中Nu为生物学活性化合物如抗癌或抗病毒化合物的基团,使得来自所述生物学活性剂的氨基或羟基与相邻部分形成磷酸酯(phosphate)、氨基磷酸酯(phosphoramidate)、碳酸酯或氨基甲酸乙酯(urethane)基团;
每个R8独立地为H或C1-C20烷基或醚基团,优选H或a C1-C12烷基;
k为0-12,优选0-2;
R2为H、酰基或C1-C20烷基或醚基团;
在本发明的优选方面中,R1为H、C2-C18酰基或磷酸酯基且R2为H。
药物组合物,其包括抗癌有效量的一种或多种式1化合物,任选(且优选)与有效量的至少一种本文其它地方所述的其它抗癌药物和至少一种载体、添加剂或赋形剂组合。
本发明的其它方面涉及治疗过度增生疾病,包括肿瘤,尤其是恶性肿瘤和癌症的方法。本发明的这些方法涉及治疗肿瘤、癌症、过度增生疾病的方法,所述过度增生疾病包括牛皮癣、生殖器疣(乳头状瘤)、过度增生细胞生长,如非变异细胞(包括癌前细胞和任何表达异常或外源细胞表面蛋白或抗原的细胞)的异常细胞增生或增长。单独或与其它药物组合用于治疗慢性炎性疾病和病毒或其它微生物感染的方法是本发明的其它方面。
该方法方面包括治疗过度增生疾病,包括牛皮癣、生殖器疣和过渡增生细胞生长疾病,包括过度增生角质化疾病,如角化过度症、鱼鳞病、皮肤角化病或扁平苔藓和慢性炎性疾病,如关节炎,包括类风湿性关节炎和骨关节炎,以及丙肝病毒(HCV)感染,该方法包括给予所需患者有效量的本发明的化合物,任选地与至少一种其它抗癌药物组合,任选与药学可接受的载体、添加剂或赋形剂组合。
基本上,可以使用本发明的组合物和方法治疗任何癌症。可以治疗的示例性癌症包括,例如胃癌、结肠癌、直肠癌、肝癌、胰腺癌、肺癌、乳腺癌、子宫颈癌、子宫体癌、卵巢癌、前列腺癌、睾丸癌、膀胱癌、肾癌、脑癌/CNS癌、头颈癌、咽喉癌、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、白血病、黑色素瘤、急性淋巴细胞性白血病、极性骨髓性白血病、尤因肉瘤、小细胞肺癌、绒毛膜癌、横纹肌肉瘤、维尔姆斯氏肿瘤、成神经细胞瘤、毛细胞白血病、口/咽癌、食道癌、喉癌、肾癌和淋巴瘤等。
注意到使用3TC、FTC或LFD4C或它们的衍生物在治疗癌症中表现出即使有也很低的抗癌活性,且当与另一种抗癌药物共给药(coadminister)治疗受试者的癌症时,与单独使用其它抗癌药物相比基本上有更高的活性,这是出乎意料的结果。而且,在很多例子中,有效量的本发明的一种核苷化合物与另一种抗癌剂组合将协同增强(即高于累加)其它抗癌药物的抗癌活性。宿主防御异常组织(如癌症)的提高是一种可能的解释。因此,本发明的化合物也能够用于治疗患病组织,如病毒感染的细胞等,即使这些化合物可能不直接表现出抵抗微生物感染的那些组织的活性。
附图简述
图1-2表示单独使用3TC、FTC或LFD4C或与其它抗癌药物组合使用对肿瘤/癌症的作用,如图和实验部分所述的。
发明详述
本文所用的术语“化合物”,除另有说明外,表示任何本文公开的具体化学的化合物。在上下文的使用中,该术语一般优选指单个化合物,核苷类似物(3TC、FTC或LFD4C)的L-β异构体或其富含至少75%、85%、95%、98%、99%或99+%对映体的各种消旋体,或各种前药或本文其它地方所述的衍生物形式。本发明中所用的式1的B-L核苷化合物一般指3TC、FTC或LFD4C或其衍生物。出人意料的结果是,在治疗癌症中本发明的化合物表现出即使有也很低的对宿主细胞的毒性。
本文所用的术语“有效的”,除另有说明外,用于描述化合物的量,在文中所述化合物用于产生或到达所预料的结果,如果所述结果涉及对过度增生疾病状态、慢性炎性疾病、病毒感染如HCV感染、包括致癌肿瘤或其它癌瘤的肿瘤治疗、或对癌前损伤或在细胞表面表达异常或表达外源蛋白或免疫原的细胞的治疗。在涉及本发明的化合物与其它抗癌制剂组合使用的一些方面,本发明涉及增强其它抗癌化合物的抗癌作用。该术语包含所有在本发明中所述的其它有效量或有效浓度的术语。对于抗癌作用,作用可以为一种或多种抑制肿瘤或癌细胞进一步增长,降低肿瘤或癌细胞的可能性或消除转移(matastatsis)或导致肿瘤或癌细胞中的细胞死亡,导致肿瘤缩小或减少肿瘤细胞数量或当切除患者的肿瘤或癌瘤后预防肿瘤和癌瘤的再次生长。如本文所述,3TC、FTC或LFD4C或其衍生物可表现出单独的抗癌作用,和/或可能增强其它抗癌药物的作用表现出抗癌作用。
贯穿说明书的术语“患者”或“受试者”用于描述动物,一般为哺乳动物,且优选为人,对其提供了包括用本发明的组合物预防性治疗的治疗。对于治疗那些对具体动物,如人患者具有特异性的感染、病症或疾病状态,术语患者是指具体的动物。
贯穿说明书的术语“药学可接受的盐”用于描述一种或多种本文组合物的盐形式(且尤其本发明的优选方面,磷酸盐),以所述盐形式存在增加化合物在胃肠外给药的盐水或患者胃肠道的胃液中的溶解度,以提高化合物的溶出或生物利用度。药学可接受盐包括衍生自药学可接受的无机或有机碱和酸的那些。合适的盐包括衍生自碱金属如钾和钠,碱土金属如钙、镁和铵盐,在药学领域公知多种其它的酸的盐。钠和钾特别优选的作为包含本本发明的组合物的羧酸中和盐和游离酸磷酸盐。术语“盐”应该指任何与本发明化合物用途一致的盐。当所述化合物用于药学适应症时,术语“盐”应该指与作为药物的用途相符合的药学可接受的盐,所述药学适应症包括治疗瘤形成,包括癌症。
当对患者给药时,贯穿说明书所用术语“药学可接受的衍生物”或“衍生物”以描述任何药学可接受的前药形式(如酯或醚或其它前药基团)直接或间接地提供了本化合物或本化合物的活性代谢产物。
文中术语“烷基”应该指C1-C20,优选为C1-C10的直链、支链或环状全饱和的烃基团,其可任选被取代,如被苯基取代。术语“醚”应该指C1至C20的醚基团,其由氧和在本发明化合物的糖基团位置上的烷基形成,且优选在烷基链中含有至少一个氧基团。术语烷基应该还包括芳烷基,如苄基,其中苯基可任选被取代。
贯穿本说明书所用的术语“酰基”用于描述在核苷类似物的5′位置中(即在糖合成单体中的游离羟基位置)的基团,所述核苷类似物包括C1至C20的直链、支链或环状烷基链或本文其它地方所述的相关基团。给药后,在5′位置(R1)与相应的羟基结合形成酯的酰基可以被切下以产生本发明的游离核苷形式。本发明的酰基可以由下式结构表示:
其中R4为C1至C20的直链、支链或环状烷基、烷氧基烷基、芳氧基烷基,如苯氧基甲基、芳基、烷氧基,其中它们所有都可任选被取代。优选的酰基为那些R4为C1至C10烷基的基团。本发明的酰基还包括,例如,衍生自苯甲酸和相关酸、3-氯苯甲酸、琥珀酸、羊蜡酸和羊油酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸和油酸基团、氨基酸的酰基,其它许多包括一些药学可接受的磺酸盐(sulphonate)基团,所述磺酸盐基团也可认为是用于本文目的的酰基。本领域普通技术人员将理解酰基在本发明的用途,用于合成目标药学化合物或本发明的核苷的前药形式。
贯穿说明书所用的术语“磷酸酯”或“磷酸二酯”用于描述糖合成单体(synthon)5′位置的单磷酸基团,所述单磷酸酯基团被二酯化,使得中和磷酸基团,即带有中性电荷。用于本发明的磷酸酯包括下式结构表示的磷酸酯:
其中R5、R6和R”选自C1至C20的直链、支链或环状烷基、烷氧基烷基、芳氧基烷基如苯氧基甲基、芳基和烷氧基等,并且R7为C1至C20的直链、支链或环状烷基或酰基、烷氧基烷基、芳氧基烷基如苯氧基甲基、芳基和烷氧基等。本发明以前药形式使用的优选的单磷酸酯为那些R5为C1至C20的直链或支链烷基,更优选为C1至C3烷基的基团。
贯穿本说明书所用的术语“瘤形成(neoplasia)”或“癌症”涉及导致癌性或恶性肿瘤,即通过细胞增殖生长的异常组织的形成和生长的病理过程,通常比正常的增长更迅速,并且在受到引发新增长的刺激停止后继续生长。恶性肿瘤表现出局部或全部的与正常组织结构组织和功能协调的缺乏并且大多侵入周围组织,转移到数个位点,且很可能在进行切除后复发且以导致患者的死亡,除非得到充足的治疗。如本文所用的,使用术语“瘤形成”表述所有的癌性疾病状态且包括或包含伴随恶性血原性、腹水和实体瘤的病理过程。典型的癌症包括胃癌、结肠癌、直肠癌、肝癌、胰腺癌、肺癌、乳腺癌、子宫颈癌、子宫体癌、卵巢癌、前列腺癌、睾丸癌、膀胱癌、肾癌、脑癌/CNS癌、头颈癌、咽喉癌、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、白血病、黑色素瘤、急性淋巴细胞性白血病、急性骨髓性白血病、尤因肉瘤、小细胞肺癌、绒毛膜癌、横纹肌肉瘤、维尔姆斯氏肿瘤、成神经细胞瘤、毛细胞性白血病、口/咽癌、食道癌、喉癌、肾癌和淋巴瘤等,它们可以通过本发明的一种或多种化合物治疗。
使用术语“肿瘤(tumor)”描述恶性或良性生长或肿大。
术语“过度增生疾病状态”是指其中细胞以不可控制的方式增长的疾病状态,无论所述增长是癌性的或不是。该疾病状态可反应为牛皮癣、生殖器疣或其它过度增生性细胞生长疾病,包括过度增生角质化疾病,其包括角化过度症、鱼鳞病、皮肤角化病或扁平苔藓,所有这些疾病状态可使用本发明的化合物治疗。
使用术语“抗癌化合物”或“抗癌药物”描述任何可以用于治疗癌症的化合物(包括其衍生物)。本发明使用的抗癌化合物可与一种或多种3TC、FTC或LFD4或它们的衍生物共给药,使每种这些化合物或它们的衍生化合物有增强抗癌化合物在治疗依据本发明患者中的癌症中的作用。在许多情况中,这些化合物或它们的衍生物和其它抗癌化合物的共给药导致协同的抗癌作用。与3TC、FTC或LFD4或它们的衍生物共给药的本发明所用的示例性抗癌化合物包括具有广谱抗代谢物的抗代谢物剂、拓扑异构酶I和II的抑制剂、烷基化剂和微管抑制剂(如紫杉醇)。本发明所用的抗癌化合物包括阿地白介素;阿仑单抗;阿利维A酸;别嘌醇;六甲蜜胺;氨磷汀;阿那曲唑;三氧化二砷;门冬酰胺酶;卡介苗活菌(BCG live);贝沙罗汀胶囊;贝沙罗汀凝胶;博来霉素;静脉注入白消安;口服白消安;卡普睾酮;卡培他滨;卡铂;卡莫司汀;用聚苯丙生20植入的卡莫司汀;塞来考昔;苯丁酸氮芥;顺铂;克拉屈滨;环磷酰胺;阿糖胞苷;阿糖胞苷脂质体;达卡巴嗪;放线菌素;放线菌素D;促红细胞生成素(Darbepoetin alfa);柔红霉素脂质体;柔红霉素(daunorubicin),道诺霉素(daunomycin);地尼白介素-毒素连接物,右雷佐生;多西紫杉醇;多柔比星;多柔比星脂质体;丙酸屈他雄酮;埃利奥特氏B溶液;表柔比星;阿法依伯汀雌莫司汀;磷酸依托泊苷;依托泊苷(VP-16);依西美坦;非格司亭;氟尿苷(动脉注入);氟达拉滨;氟尿嘧啶(5-FU);氟维司群;吉姆单抗奥佐米星;醋酸戈舍瑞林;羟基脲;替伊莫单抗(Ibitumomab Tiuxetan);伊达比星;异环磷酰胺;甲磺酸伊马替尼;干扰素α-2a;干扰素α-2b;伊立替康;来曲唑;亚叶酸;左旋咪唑;洛莫司汀(CCNU);甲基-双(2-氯-乙基)胺(meclorethamine)(氮芥);醋酸甲地孕酮;美法仑(L-PAM);巯嘌呤(6-MP);美司钠;甲氨蝶呤;甲氧沙林;丝裂霉素C;米托坦;米托蒽醌;苯丙酸诺龙;诺非单抗;LOddC;奥普瑞白介素;奥沙利铂;紫杉醇;氨羟二磷酸二钠;培加酶;培门冬酶;聚乙二醇化非格司亭(Pegfilgrastim);喷司他丁;哌泊溴烷;普卡霉素;光辉霉素;卟吩姆钠;丙卡巴肼;奎纳克林;拉布立酶;利妥昔单抗(Rituximab);沙格司亭;链佐星;替比夫定(talbuvidine)(LDT);滑石(talc);他莫昔芬;替莫唑胺;替尼泊苷(VM-26);睾内酯;硫鸟嘌呤(6-TG);塞替派;托泊替康;托瑞米芬;托西莫单抗;曲妥单抗;维A酸(ATRA);乌拉莫司汀;戊柔比星;维托西达定(valtorcitabine)(一价LDC);长春碱;长春瑞滨;唑来膦酸盐(zoledronate);及其混合物等。
术语“生物活性剂”包括任何生物活性剂,其包括活性剂的前药形式,可以与本发明的3TC、FTC或LFD4C或衍生物(如前药形式)组合给药,且可以包括形成双重作用剂的活性剂或它们的衍生物,其中生物活性剂或它的衍生物和核苷化合物或它的衍生物(指共同地如共轭)如本文其它地方所述是化学连接的。除上述的抗癌药物外,生物活性剂可包括许多抗病毒药物,包括例如下述用于治疗HIV、HBV和其它病毒感染的药物以及治疗过度增生疾病和慢性炎性疾病,如关节炎包括风湿性关节炎和骨关节炎的药物,等。
除上述抗癌药物外,可以与本文所述的3TC、FTC或LFD4C或衍生物化学连接的示例性生物活性剂包括,例如,
阿扎那韦(Atazanavir)(BMS-232632)用游离的二位羟基;
Bis(POM)-PMEA(阿德福韦酯(Adefovi dipivoxyl),用游离氨基(aminegroup);
Bis(POC)-PMPA(替诺福韦酯(Tenofovir disoproxil),用游离氨基;
恩替卡韦(Etecavir),用碳环糖合成单体上的一位羟基;
茚地那韦(佳息患,MK-639 L-735,524,来自Merck),用游离的二位羟基;
KHI-227(Nikko Kyodo Co.的Kynostatin),用游离的二位羟基:
2-[3-[3-(S)-[[(四氢呋喃基氧基)羰基]氨基]-4-苯基-2(R)-羟基丁基]]-N-(1,1-二甲基乙基)十氢-3-异喹啉氨甲酰(IsoquinCON呋喃基氨基甲酸乙酯类似物,来自Merck),用游离的二位羟基;
氨基甲酸,[3-{[(4-甲氧基苯基)磺酰基](环戊基甲基)氨基]-2-羟基-1-(苯基甲基)丙基]-,四氢呋喃基酯(Vertex的VB-11,328),用游离的二位羟基;
来自Nikko Kyodo Co.的KNI-174,用游离的二位羟基(或游离氨基);
来自Sandoz(奥地利)的Val-Val-Sta,用游离的二位羟基;
来自Ciba-Geigy的CPG53820,用游离的二位羟基;
二-Val HOEt-N2氮杂-肽同电子等排体(isostere),用游离的二位羟基;
来自Hoechst AG的C2-Sym次膦酸酰胺衍生物,用游离氨基;
来自Abbott的2,5,-二氨基-N,N’-二(N-苯甲氧基羰基uelyl)-1,6-二苯基-3(S),4(S)-己二醇
BzOCValPhe[diCHOH(SS]PheValBzOC,用游离的二位羟基;
来自Abbott的2,5,-二氨基-N,N’-二(N-苯甲氧基羰基uelyl)-1,6-二苯基-3(R),4(R)-己二醇
BzOCValPhe[diCHOH(RR]PheValBzOC,用游离的二位羟基;
ddA的二(S-乙酰基-2-乙硫基)磷酸三酯或[bis(SATE)ddAMP],用游离氨基;
BILA2186BS(Bio-Mega/Boehringer Ingelheim),用游离的二位羟基;
Vertex/Kissei/Glaxo Wellcome的安瑞那韦(Agenerase)(安泼那韦;VX-478;141W94),在游离的二位羟基或氨基;
Abbott的A-98881(氮杂环脲衍生物),用游离的二位羟基或酚羟基;
Abbott的A-83962(奈非即韦(rifonavir)衍生物),用游离的二位羟基;
Abbott的A-80987(奈非即韦衍生物),用游离的二位羟基;
Roche的(2-萘亚甲基羰基)Asn[去羰基Phe-羟基乙基]ProO叔丁基或2NaphCOAsnPhe[CHOHCH2]Pro-OtBu,用游离的二位羟基;
Sandoz的2-氨基苄基抑制素(statine)Valyl Cbz衍生物,用游离的二位羟基或氨基;
Sandoz的2-氨基苄基抑制素Valyl Cbz衍生物,用游离羟基;
Sandoz的10H-2(Cbz-ValNH)3PhPr[14]对环芳(paracyclophane)衍生物,用游离的二位羟基;
Sandoz的10H-2(Cbz-ValNH)3PhPr[13]对环芳衍生物,用游离的二位羟基;
Sandoz的10H-2(Cbz-ValNH)3PhPr[13]间环芳(metacyclophane)衍生物,用游离的二位羟基;
Sandoz的10H-2(Cbz-Tle)3PhPr[14]对环芳衍生物,用游离的二位羟基;
1-(20HPr)-4-取代-哌嗪(环丙基),噻吩基氨基甲酸酯衍生物(来自Merck),用游离的二位羟基;
1-(20HPr)-4-取代-哌嗪(环丁基),噻吩基氨基甲酸酯衍生物(来自Merck),用游离的二位羟基;
1-(20HPr)-4-取代-哌嗪(3-戊基),噻吩基氨基甲酸酯衍生物(来自Merck),用游离的二位羟基;
10H-2(Cbz-ValNH)3PhPr[17]对环芳衍生物(来自Sandoz),用游离的二位羟基;
A-81525(来自Abbott),用游离的二位羟基;
XM323(来自DuPont Merck的DMP-323),用游离的一位或二位羟基;
替拉那韦(来自Pharmacia & Upjohn的U-140690或PHU-140690),用酚羟基;
噻吩并吡啶(Thienopyrid)CON噻吩基氨基甲酸乙酯衍生物(来自Lilly的HOCH2CH2的电子等排体)(苄基被取代的衍生物或甲基巯基苯基被取代的衍生物),用游离的二位羟基;
SDZ PRI 053(Sandoz),用游离的二位羟基;
SD146(DuPont Merck),用任一游离的二位羟基;
替利那韦(来自Searle/Monsanto的SC-52151),用游离的二位羟基或氨基;
(R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu(来自Roche),用游离的二位羟基或氨基;
沙奎那韦(沙奎那韦(inverase)或来自Roche的RO 31-8959),用游离的二位羟基或氨基;
沙奎那韦/Melfinavir衍生物(来自Lilly),用游离的二位羟基;
IsoquinCON Thf-Thf甲酸乙酯类似物(来自Merck),用游离的二位羟基;
IsoquinCON噻吩基氨基甲酸乙酯类似物(来自Merck),用游离的二位羟基;
R-87366(来自Sankyo的AHPBA类似物),用游离氨基;
DMP 460(Dupont Merck/Avid),用游离的二位羟基或任一苯胺的氨基;
L685,434(Merck),用游离的二位羟基;
L685,434-6-羟基衍生物(Merck),用游离的二位羟基;
L685,434-OEtNMe2(Merck),用游离的二位羟基;
L685,434-OPrMorph衍生物(Merck),用游离的二位羟基;
L689,502(Merck),用游离的二位羟基;
拉西那韦(来自CIBA/Novartis的CGP 61755),用游离的二位羟基;
Aluviran(来自Abbott的洛匹那韦,ABT-378,RS-346 A157378),用游离的二位羟基;
那非那韦-八氢-噻吩并吡啶类似物(来自Lilly),用游离的二位羟基;
P9941(来自DuPot Merck),用任一游离的二位羟基;
帕利那韦(BILA 2011 BS来自BIO-MEGA/Boehringer Ingelheim),用游离的二位羟基;
青霉素,2Isoquin-OHPrNH2类似物(来自Glaxo Wellcome),用游离的二位羟基,等。
用于本发明双重拮抗方面的上述活性化合物和其它相关生物活性剂可以在NIH网站www.niaid.nih.gov/daids/dtpdb/中找到,其相关部分在此引入作为参考。
使用术语“共给药”或“组合治疗”描述其中有效量的至少两种活性化合物同时用于治疗癌症或本文所述的其它疾病状态或病症的治疗。该结果可以是附加的或优选的,且在大多数实例中是协同的。虽然术语共给药优选包括同时向患者给予两种活性化合物,虽然患者体内将同时存在有效量的单个化合物,但是没有必要一定同时给予患者所述化合物。优选与一种或多种抗癌剂一起给予本发明的化合物,所述抗癌剂包括抗代谢物、烷基化剂、拓扑酶I和拓扑酶II抑制剂,以及微管抑制剂。本发明所用的抗癌化合物包括,例如阿地白介素;阿仑单抗;阿利维A酸;别嘌醇;六甲蜜胺;氨磷汀;阿那曲唑;三氧化二砷;门冬酰胺酶;卡介苗活菌;贝沙罗汀胶囊;贝沙罗汀凝胶;博来霉素;静脉注入白消安;口服白消安;卡普睾酮;卡培他滨;卡铂;卡莫司汀;有聚苯丙生20植入的卡莫司汀;塞来考昔;苯丁酸氮芥;顺铂;克拉屈滨;环磷酰胺;阿糖胞苷;阿糖胞苷脂质体;达卡巴嗪;放线菌素;放线菌素D;促红细胞生成素;柔红霉素脂质体;柔红霉素(daunorubicin),道诺霉素(daunomycin);地尼白介素-毒素连接物,右雷佐生;多西紫杉醇;多柔比星;多柔比星脂质体;丙酸屈他雄酮;埃利奥特氏B溶液;表柔比星;阿法依伯汀雌莫司汀;磷酸依托泊苷;依托泊苷(VP-16);依西美坦;非格司亭;氟尿苷(动脉注入);氟达拉滨;氟尿嘧啶(5-FU);氟维司群;吉姆单抗奥佐米星;醋酸戈舍瑞林;羟基脲;替伊莫单抗;伊达比星;异环磷酰胺;甲磺酸伊马替尼;干扰素α-2a;干扰素α-2b;伊立替康;来曲唑;亚叶酸;左旋咪唑;洛莫司汀(CCNU);甲基-双(2-氯-乙基)胺(氮芥);醋酸甲地孕酮;美法仑(L-PAM);巯嘌呤(6-MP);美司钠;甲氨蝶呤;甲氧沙林;丝裂霉素C;米托坦;米托蒽醌;苯丙酸诺龙;诺非单抗;LOddC;奥普瑞白介素;奥沙利铂;紫杉醇;氨羟二磷酸二钠;培加酶;培门冬酶;聚乙二醇化非格司亭;喷司他丁;哌泊溴烷;普卡霉素;光辉霉素;卟吩姆钠;丙卡巴肼;奎纳克林;拉布立酶;利妥昔单抗;沙格司亭;链佐星;替比夫定(LDT);滑石;他莫昔芬;替莫唑胺;替尼泊苷(VM-26);睾内酯;硫鸟嘌呤(6-TG);塞替派;托泊替康;托瑞米芬;托西莫单抗;曲妥单抗;维A酸(ATRA);乌拉莫司汀;戊柔比星;维托西达定(一价LDC);长春碱;长春瑞滨;唑来膦酸盐;及其混合物等。
本发明包括含有本发明化合物的药学可接受的盐的组合物。用于制备上述化合物的药学可接受酸加成盐的酸是那些形成无毒酸加成盐,即含有药学可接受阴离子的盐,如盐酸化物、氢溴酸化物、氢碘酸化物、硝酸盐、硫酸盐、硫酸氢盐(bisulfate)、磷酸盐(phosphate)、酸式磷酸盐(acid phosphate)、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸氢盐(bitartrate)、琥珀酸盐、马来酸盐、延胡索酸盐、葡萄糖酸盐、葡糖二酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和扑酸盐[即,1,1′-亚甲基-二-(2-羟基-3萘甲酸)]盐等的酸。
本发明还包括包含本发明的碱加成盐的组合物。可以用作制备本发明酸性化合物的药学可接受的碱盐的试剂的化学碱是那些与这些化合物形成无毒碱盐的碱。这些无毒碱盐包括,但不限于衍生自下述药学可接受阳离子的碱,所述阳离子如碱金属阳离子(如钾离子和钠离子)和碱土金属阳离子(如钙离子和镁离子)、铵离子或水溶性胺加成盐,如N-甲基葡萄糖胺-(葡甲胺),和低级链烷醇铵(alkanolammonium)和其它药学可接受的有机胺的碱盐等。
本发明的化合物主要涉及核苷化合物,其特征为β-L核苷,但可以包括其它相关的立体异构体,包括本发明的光学异构体,以及外消旋体、非对映异构体和这些异构体的其它混合物,以及该化合物的所有溶剂化物和多晶型物。
本发明的组合物可以常规的方法制剂,使用一种或多种药学可接受的载体,且还可以以控释制剂给予本发明的组合物。在这些药物组合物中可使用的药学可接受载体包括,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、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、电解质盐(如硫酸醇溶谷蛋白、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-聚氧丙稀-嵌段聚合物、聚乙二醇和羊毛酯。
本发明的组合物的给药途径有口服、胃肠外给药、可吸入喷雾、局部、经直肠、经鼻、经颊、经阴道或通过植入储库。本文所用的术语“胃肠外给药”包括皮下、静脉、肌内、关节内、滑膜内、胸骨内、鞘膜内、肝内(intrahepatic)、内部损伤(intralesional)和颅内注射或输注技术。优选地,口服、腹膜内或静脉给予该化合物。
本发明组合物的无菌可注射形式可以是水性或油性混悬液。根据本领域已知的方法使用分散或润湿剂和助悬剂可以配制这些混悬液。所述无菌可注射制剂还可以是在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液,例如在1,3-丁二醇中的溶液。在可接受的载体和溶剂中可以使用的是水、林格溶液和等渗氯化钠溶液。而且常规使用无菌混合的油作为溶剂或混悬介质。为达到此目的,可以使用任何温和混合的油,包括合成的单甘油酯或二甘油酯。在可注射制剂中可用的脂肪酸,如油酸和其甘油酯衍生物,为天然的药学可接受的油,如橄榄油或蓖麻油,尤其是它们的聚氧乙基化的形式。这些油溶液或混悬液还可含有长链醇稀释剂或分散剂,如Ph.Helv或类似的醇。
本发明的药物组合物可以任何口服可接受的剂量形式口服给药,包括但不限于胶囊、片剂、含水混悬液或溶液。对于口服使用片剂,通常使用的载体包括乳糖和玉米淀粉。一般也加入润滑剂,如硬脂酸镁。对于胶囊形式的口服给药,可用的稀释剂包括乳糖和无水玉米淀粉。当需要含水混悬液用于口服使用时,活性成分与乳化和助悬剂混合。视需要,也可以加入一些甜味剂、香味剂或着色剂。
或者,本发明的药物组合物可以用于直肠给药的栓剂形式给药。这些栓剂可以通过将该药物与适合的非刺激性赋形剂混合制备,所述赋形剂在室温下为固体,但在直肠温度下为液体,且因此将在直肠中融化以释放药物。这些物料包括可可脂、蜂蜡和聚乙二醇。
还可局部给予本发明的药物组合物,尤其用于治疗皮肤癌、牛皮癣或发生在皮肤中或皮肤上的其它疾病。对于每个这些区域或器官,可以容易地制备适合的局部制剂。用于下肠道(lower intestinal)的局部应用可以直肠栓剂(见上)或以适合的灌肠剂起作用。也可以使用局部可接受的透皮贴片。
对于局部应用,可将药物组合物配制成适合的含有混悬或溶解于一种或多种载体中的活性成分的软膏剂。用于本发明的这些化合物的局部给药的载体包括,但不限于矿物油、液体石蜡、白凡士林、聚乙二醇、聚氧乙烯、聚氧丙稀化合物、乳化蜡和水。
或者,可以将该药物组合物可配制成合适的含有混悬或溶解于一种或多种药学可接受载体中的活性成分的洗剂或乳剂。适合的载体包括,但不限于矿物油、单硬脂酸山梨坦、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇(cetearylalcohol)、2-辛基十二烷醇、苯甲醇和水。
对于眼用,可以将该药物组合物用等渗、调节过pH的无菌盐水配制成微粉化混悬液,或优选用等渗、调节过pH的无菌盐水配制成溶液,其含有或不含防腐剂如氯化苯二甲烃铵(benzylalkonium chloride)。或者,对于眼用该药物组合物可用软膏如凡士林配制。
还可通过鼻气雾剂或吸入剂给予本发明的药物组合物。根据药学制剂领域中公知的技术制备这些组合物,且也可使用苯甲醇或其它适合的防腐剂、用以提高生物利用度的吸收促进剂、碳氟化合物和/或其它常规助溶剂或分散剂制备成盐水溶液。
与载体物料组合制成单剂量形式的本发明药物组合物中的化合物的量可以根据宿主和所治疗的疾病、特定的给药方式改变。优选地,应该将组合物配制成含有0.5毫克至750毫克,更优选约1毫克至约600毫克,且甚至更优选约10毫克至约500毫克的活性成分。
应该理解,用于特定患者的特定剂量和治疗方法将根据各种因素改变,包括所用特定化合物的活性、年龄、体重、一般健康、性别、饮食、给药时间、排泄速度、组合用药和治疗医师的判断及所治疗的具体疾病或病症的严重度。
本发明的其它方面涉及治疗肿瘤、癌症、癌前细胞和损伤、表达异常或外源表面蛋白或抗原的细胞、牛皮癣、生殖器疣(乳头状瘤)、慢性炎性疾病如关节炎、类风湿性关节炎和骨关节炎、过度增生细胞生长疾病和HCV的方法,所述过度增生细胞生长疾病包括过度增生角质化疾病,如角化过度症、鱼鳞病、皮肤角化病或扁平苔藓,所述方法包括给予需要治疗的患者有效剂量的下式化合物和其药学可接受的盐、溶剂化物或多晶型物:
X为H或F;
R1为H、酰基、C1—C20烷基或醚基团、磷酸酯、二磷酸酯、三磷酸酯或磷酸二酯基团、
其中Nu为生物学活性化合物如抗癌或抗病毒化合物的基团,使得来自所述生物学活性剂的氨基或羟基与相邻部分形成磷酸酯、氨基磷酸酯、碳酸酯或氨基甲酸乙酯基团;
每个R8独立地为H或C1-C20烷基或醚基团,优选H或C1-C12烷基;
k为0-12,优选0-2;
R2为H、酰基或C1-C20烷基或醚基团。
在本发明的优选方面中,R1为H、C2-C18酰基或磷酸酯基且R2为H。
在本发明的优选方面中,上述化合物与至少一种其它抗癌药物或有效抵抗过度增生细胞生长疾病的试剂共给药。在本发明其它优选方面中,R1为H、C2-C18酰基或磷酸酯基,且R2为H。在其它优选方面中,本发明的方法中所用的化合物为:
其中X为F或H。
3TC、FTC或LFD4C的药学可接受衍生物的具体实例包括,但不限于:下述化合物,其中R1选自烷基和酰基,尤其包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、戊基、叔戊基、3-甲基丁酰基、琥珀酸基(hydrogen succinate)、3-氯苯甲酰基(chlorobenzoate)、环戊基、环己基、苯甲酰基、乙酰基、特戊酰基、甲磺酰基、丙酰基、丁酰基、戊酰基、己酰基、辛酰基、癸酰基、月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基,和氨基酸,包括但不限于丙氨酰基、缬氨酰基、亮氨酰基、异亮氨酰基、脯氨酰基,苯丙氨酰基、色氨酰基、蛋氨酰基、甘氨酰基、丝氨酰基、苏氨酰基、半胱氨酰基、酪氨酰基、天冬酰胺酰基、谷氨酰胺酰基、天冬氨二酰基、谷氨酰基(glutaoyl)、赖氨酰基、精氨酰基和组氨酰基,且其中R2为H。
可以以药学可接受的盐的形式提供3TC、FTC或LFD4C或它们的衍生物。如本文所用的术语药学可接受的盐或复合物是指保留母体化合物所需的生物活性的并且表现出最小的不需要的毒理学作用(如果有的话)的3TC、FTC或LFD4C的盐和复合物(溶剂化物、多晶型物)。这些盐的非限制性实例为:(a)与无机酸(例如,盐酸、氢溴酸、硫酸、磷酸、硝酸等),和与有机酸(如,乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、扑酸、海藻酸、聚谷氨酸、萘磺酸、萘二磺酸、和聚半乳糖醛酸)形成的酸加成盐;(b)与多价金属阳离子(如锌、钙、铋、钡、镁、铝、铜、钴、镍、铬、钠、钾等)形成的碱加成盐,或与来自N,N-二苄基乙二胺、铵或乙二胺的有机阳离子形成的碱加成盐;或(c),即(a)和(b)的组合;如鞣酸锌等。
活性化合物的修饰,特别是在5′-0和N-4位的修饰,可以影响溶解度、生物利用度和活性物质的代谢速率,因此对活性物质的递送进行控制。而且,所述修饰可影响化合物的抗癌活性,在一些情况中增加本化合物的活性。这可以简单地通过根据本文所述的方法或其它本领域技术人员已知的方法制备衍生物并检测它的抗癌活性而评估。
活性化合物的制备和给药
可以根据本领域详细公开的方法或可以通过本领域技术人员已知的其它方法制备3TC、FTC或LFD4C或它们的衍生物,。在含有两种活性成分的化合物的情况中,3TC、FTC、LFD4C或其衍生物与其它活性试剂的连接可以根据标准技术容易地完成。可以容易地使用适合的封闭基团和形成连接基团的试剂。
患有癌症的人类、马科、犬科、牛科和其它动物,且尤其是哺乳动物可以通过给予患者(受试者)有效量的3TC、FTC、LFD4C或它们的衍生物而治疗,所述的3TC、FTC、LFD4C或它们的衍生物包括其药学可接受的盐、溶剂化物或多晶型物,任选在药学可接受的载体或稀释剂中,各自单独使用或与其它已知抗癌剂或药物组合。该治疗也可与其它常规的癌症治疗,如放疗或手术治疗联合。
这些化合物可以通过适合的途径给药,所述途径如口服、胃肠外给药、静脉注射、皮内注射、皮下注射或局部给药,以溶液、乳膏、凝胶或固体形式或通过气溶胶形式给药。
所述活性化合物包括在药学可接受的载体或稀释剂中,其含量为足以投递给患者用于所需适应症,而对所治疗的患者不引起严重的毒性作用的治疗有效量。用于本文所述的所有病症的活性化合物的优选有效剂量的范围为约每天10ng/kg至300mg/kg,优选为0.1至100mg/kg/每人每天,更通常为0.5至约25mg/kg受试者体重/天。在适合的载体中,一般局部给药的剂量范围为0.01-3%wt/wt。
所述化合物以任何适合单位剂型(unit dosage form)方便地给药,所述单位剂型包括,但不限于每单位剂型中含有少于1mg、1mg至3000mg,优选为5至500mg的活性成分。通常20-250mg的口服剂量是方便的。
优选给药所述活性成分以实现活性化合物的血浆峰浓度为约0.00001-30mM,优选为约0.1-30μM。这可以通过例如活性成分的溶液或制剂的静脉注射实现,任选在盐水中,或含水介质或以快速注射活性成分给药。在药物组合物中的活性化合物的浓度取决于该药物的吸收、分布、失活和排泄速度,以及其它本领域技术人员已知的因素。注意剂量值也将随病症的严重度而提高。应该进一步理解的是对于具体受试者,根据个体需要、给予或管理组合物给药的人的专业判断可以随时间调整特定的剂量方法,且本文所述的浓度范围仅为例示性的不是为了限制所要求的组合物的范围或实际应用。可以一次给予所述活性成分,或以不同的间隔时间分多次小剂量给予。
口服组合物一般将包括惰性稀释剂或可食用的载体。它们可以包封在明胶胶囊中或压在药片中。为达到口服治疗给药的目的,可以将活性化合物或其前药衍生物与用于形成片剂、含片或胶囊的赋形剂混合。可以包括药学兼容的粘合剂和/或佐剂材料作为组合物的一部分。
片剂、丸剂、胶囊、含片(troches)等可以含有任何下述成分或性质相似的化合物:粘合剂,如微晶纤维素、西黄蓍胶或明胶;赋形剂,如淀粉或乳糖;分散剂,如海藻酸、Primogel或玉米淀粉;润滑剂,如硬脂酸镁或氢化植物油(Sterotes);助流剂,如胶体二氧化硅;甜味剂,如蔗糖或糖精;或香味剂,如薄荷、水杨酸甲酯、或橙味剂。当剂型(dosage unit form)为胶囊时,其可以含有除上述类型的物料以外的液体载体,如脂肪油。而且,剂型可以含有各种其它改变剂量单位的物理形式的物料,例如糖衣、虫胶衣或肠衣。
所述活性化合物或其药学可接受的盐可以作为酏剂、混悬液、糖浆剂、薄片(wafer)、咀嚼胶(chewing gum)等的成分给药。糖浆剂可以含有除活性成分外的蔗糖作为甜味剂和一定的防腐剂、干燥剂和着色剂和香味剂。
所述活性化合物或其药学可接受的盐也可以与其它不破坏所需作用的活性物质,或补充所需作用的物质,如其它抗癌剂、抗生素、抗真菌剂、抗炎剂或抗病毒化合物混合。在本发明的优选方面,3TC、FTC或LFD4C或它们的衍生物可以与其它如本文其它部分所述的抗癌药物共给药。
用于胃肠外给药、皮内注射、皮下注射或局部应用的溶液或混悬液可以包括下述成分:无菌稀释剂,如注射用水、盐水溶液、不挥发油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗菌剂,如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二胺四乙酸;缓冲剂,如乙酸盐、柠檬酸盐或磷酸盐和用于调整张力的试剂,如氯化钠或葡萄糖。亲代制剂可以包封在安瓿、一次性注射器或玻璃或塑料制的多剂量小瓶中。
如果经静脉给药,优选的载体为生理盐水或磷酸盐缓冲的盐水(PBS)。
在一个实施方案中,用保护所述化合物抵抗从身体中的快速消除的载体制备所述活性化合物,如控释制剂,所述载体包括埋植剂和微囊化递送系统。可以使用生物可降解、生物兼容的聚合物,如乙烯-醋酸乙烯酯、聚酐、聚乙醇酸、胶原、多正酯类和聚乳酸。用于制备这些制剂的方法对于本领域技术人员是显而易见的。
脂质体混悬液还可以为药学可接受的载体。它们可以根据本领域技术人员已知的方法制备,所述方法例如描述于美国专利号4,522,811(将其全部在此引入作为参考)。例如,可以通过在无机溶剂中溶解合适脂类(如硬脂酰基磷脂酰乙醇胺、硬脂酰基磷脂酰胆碱、arachadoyl磷脂酰胆碱和胆固醇)然后将无机溶剂蒸发,在容器的表面留下一薄层干燥的脂质而制备脂质体制剂。然后将所述容器手动旋转以使脂质物质从容器边释放并分散脂质聚合物,因此形成脂质体混悬液。
生物活性
已经使用了大量的生物检测且所述生物检测被本领域技术人员接受,以评估化合物的抗癌活性。可以使用任何这些方法评估本文所公开的化合物的活性。
测定活性的一种常规方法是通过使用National Cancer Institute(“NCI”)的癌细胞株实验对象。这些实验评估具体化合物的体外抗癌活性,并对于所测定的化合物在体内使用提供预测数据。其它测定方法包括体内评估所述化合物对植入或移植到裸鼠上的人或小鼠的肿瘤细胞的作用。
实施例
在这些实施例中,本发明的物质,3TC、FTC或LFD4C用于测定对多种品系小鼠肿瘤生长的作用。
一般,下述方法用于向小鼠植入肿瘤细胞株并测定药物的抗癌作用。
Colon 38的传代:
将肿瘤从小鼠中生长的实体瘤中移出。将几克(假定每ml为1g)通过无菌筛进行压制并以2ml/g肿瘤的浓度混悬于无酚红或胎牛血清的组织培养基中。然后将0.1ml的该肿瘤混悬液植入小鼠的肋腹。除非另有说明,在植入后10天至2周(当用测径器能够测量肿瘤时),开始药物治疗。
一般,根据下述方案递送药物。每天称量小鼠体重以确定所注射的量并作为毒性指标。
通过下式经测量计算肿瘤体积:长度(mm)X宽度(mm)X宽度(mm)XΠ/6,作为第一天的%。
实验1
设计该实验以检测单独使用3TC、FTC或LFD4C以及与5-氟尿嘧啶组合或与亚叶酸救援(leucovorin rescue)组合对免疫活性小鼠中小鼠肿瘤(colon38)生长的作用。根据下述方案给予小鼠所述药物:
对照组-仅有载体;
5FU/LV-150mg/kg每只腹腔注射第一天1次
3TC-100mg/kg口服每天两次(b.i.d.),给药5天
FTC-100mg/kg口服每天两次,给药5天
LFD4C-20mg/kg口服每天两次,给药5天
组合组接受如上说明的两种治疗。
图1表示3TC、FTC和LFD4C减慢免疫活性小鼠中colon38小鼠肿瘤的生长。经5天治疗效果持续很好。在每个例子中,这些核苷类似物各自对5-FU/LV的抗癌活性产生了显著作用(累加的或协同的)。
图1中,使用下述图例
对照组-仅有载体;
5-FU/LV(150mg/kg每只)腹腔注射第一天1次;
3TC(100mg/kg)口服每天两次(b.i.d.)X5天;
FTC(100mg/kg)口服每天两次×5天;
LFd4C(20mg/kg)口服每天两次×5天;
组合组接受如上说明的两种治疗。
实验2
实验2检测3TC、FTC和LFD4C(与上述方案相同)增强抗癌药物(奥沙利铂10mg/kg腹腔注射,第一天1次)对C57BL6雌性小鼠中colon38生长的作用。图2表明实验结果,其中3TC、FTC和LFD4C各明显提高奥沙利铂对colon38的抗肿瘤作用(累加的或协同的)。在治疗停止后,该效果持续很好。
在图2中,使用下述图例:
对照组-仅有载体;
3TC和FTC(100mg/kg)口服每天两次第1-5天;
LFd4C(15mg/kg)口服每天两次第1-5天;
奥沙利铂(10mg/kg)腹腔注射第一天1次;
组合组接受如上说明的两种治疗。
Claims (55)
2.根据权利要求1的组合物,其中所述抗癌化合物为抗代谢药物、拓扑异构酶I和II抑制剂、烷基化剂或微管抑制剂。
3.根据权利要求1的组合物,其中所述抗癌化合物选自阿地白介素;阿仑单抗;阿利维A酸;别嘌醇;六甲蜜胺;氨磷汀;阿那曲唑;三氧化二砷;门冬酰胺酶;卡介苗活菌;贝沙罗汀胶囊;贝沙罗汀凝胶;博来霉素;静脉给药白消安;口服白消安;卡普睾酮;卡培他滨;卡铂;卡莫司汀;用聚苯丙生20植入的卡莫司汀;塞来考昔;苯丁酸氮芥;顺铂;克拉屈滨;环磷酰胺;阿糖胞苷;阿糖胞苷脂质体;达卡巴嗪;更生霉素;放线菌素D;促红细胞生成素;柔红霉素脂质体;柔红霉素,道诺霉素;地尼白介素-毒素连接物,右雷佐生;多西紫杉醇;多柔比星;多柔比星脂质体;丙酸屈他雄酮;埃利奥特氏B溶液;表柔比星;阿法依伯汀雌莫司汀;磷酸依托泊苷;依托泊苷(VP-16);依西美坦;非格司亭;氟尿苷(动脉内给药);氟达拉滨;氟尿嘧啶(5-FU);氟维司群;吉姆单抗奥佐米星;醋酸戈舍瑞林;羟基脲;替伊莫单抗;伊达比星;异环磷酰胺;甲磺酸伊马替尼;干扰素α-2a;干扰素α-2b;伊立替康;来曲唑;亚叶酸;左旋咪唑;洛莫司汀(CCNU);甲基-双(2-氯-乙基)胺(氮芥);醋酸甲地孕酮;美法仑(L-PAM);巯嘌呤(6-MP);美司钠;甲氨蝶呤;甲氧沙林;丝裂霉素C;米托坦;米托蒽醌;苯丙酸诺龙;诺非单抗;LOddC;奥普瑞白介素;奥沙利铂;紫杉醇;氨羟二磷酸二钠;培加酶;培门冬酶;聚乙二醇化非格司亭;喷司他丁;哌泊溴烷;普卡霉素;光辉霉素;卟吩姆钠;丙卡巴肼;奎纳克林;拉布立酶;利妥昔单抗;沙格司亭;链佐星;替比夫定(LDT);滑石;他莫昔芬;替莫唑胺;替尼泊苷(VM-26);睾内酯;硫鸟嘌呤(6-TG);塞替派;托泊替康;托瑞米芬;托西莫单抗;曲妥单抗;维A酸(ATRA);乌拉莫司汀;戊柔比星;维托西达定(一价LDC);长春碱;长春瑞滨;唑来膦酸盐;及其混合物。
4.根据权利要求1-3中任一项的组合物,其中R1为H、C2-C18酰基或磷酸酯基团且R2为H。
5.根据权利要求1-4中任一项的组合物,其中R1为H且R2为H。
7.根据权利要求6的方法,其中所述肿瘤为良性的。
8.根据权利要求7的方法,其中所述肿瘤为癌性的。
9.根据权利要求6的方法,其中所述癌症选自胃癌、结肠癌、直肠癌、肝癌、胰腺癌、肺癌、乳腺癌、子宫颈癌、子宫体癌、卵巢癌、前列腺癌、睾丸癌、膀胱癌、肾癌、脑癌/CNS癌、头颈癌、咽喉癌、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、白血病、黑色素瘤、急性淋巴细胞性白血病、急性骨髓性白血病、尤因肉瘤、小细胞肺癌、绒毛膜癌、横纹肌肉瘤、维尔姆斯氏肿瘤、成神经细胞瘤、毛细胞性白血病、口/咽癌、食道癌、喉癌、肾癌和淋巴瘤。
10.根据权利要求6的方法,其中所述癌症为白血病。
11.根据权利要求6的方法,其中所述癌症为结肠癌。
12.根据权利要求6的方法,其中所述癌症为膀胱癌。
13.根据权利要求6的方法,其中所述癌症为前列腺癌。
14.根据权利要求6的方法,其中所述癌症为乳腺癌。
15.根据权利要求6的方法,其中所述癌症为肺癌。
16.根据权利要求6的方法,其中所述癌症为鼻咽癌。
17.根据权利要求6的方法,其中所述癌症为卵巢癌。
18.根据权利要求6的方法,其中所述癌症为淋巴瘤。
19.根据权利要求6的方法,其中所述癌症为肝细胞癌。
20.根据权利要求6的方法,其中所述癌症为黑色素瘤。
21.根据权利要求6-20中任一项的方法,其中所述化合物与至少一种有效量的其它抗癌化合物共给药。
22.根据权利要求21的方法,其中所述抗癌化合物为抗代谢药、拓扑异构酶I和II抑制剂、烷基化剂或微管抑制剂。
23.根据权利要求21的方法,其中所述抗癌化合物选自阿地白介素;阿仑单抗;阿利维A酸;别嘌醇;六甲蜜胺;氨磷汀;阿那曲唑;三氧化二砷;门冬酰胺酶;卡介苗活菌;贝沙罗汀胶囊;贝沙罗汀凝胶;博来霉素;静脉注入白消安;口服白消安;卡普睾酮;卡培他滨;卡铂;卡莫司汀;用聚苯丙生20植入的卡莫司汀;塞来考昔;苯丁酸氮芥;顺铂;克拉屈滨;环磷酰胺;阿糖胞苷;阿糖胞苷脂质体;达卡巴嗪;更生霉素;放线菌素D;促红细胞生成素;柔红霉素脂质体;柔红霉素,道诺霉素;地尼白介素-毒素连接物,右雷佐生;多西紫杉醇;多柔比星;多柔比星脂质体;丙酸屈他雄酮;埃利奥特氏B溶液;表柔比星;阿法依伯汀雌莫司汀;磷酸依托泊苷;依托泊苷(VP-16);依西美坦;非格司亭;氟尿苷(动脉注入);氟达拉滨;氟尿嘧啶(5-FU);氟维司群;吉姆单抗奥佐米星;醋酸戈舍瑞林;羟基脲;替伊莫单抗;伊达比星;异环磷酰胺;甲磺酸伊马替尼;干扰素α-2a;干扰素α-2b;伊立替康;来曲唑;亚叶酸;左旋咪唑;洛莫司汀(CCNU);甲基-双(2-氯-乙基)胺(氮芥);醋酸甲地孕酮;美法仑(L-PAM);巯嘌呤(6-MP);美司钠;甲氨蝶呤;甲氧沙林;丝裂霉素C;米托坦;米托蒽醌;苯丙酸诺龙;诺非单抗;LOddC;奥普瑞白介素;奥沙利铂;紫杉醇;氨羟二磷酸二钠;培加酶;培门冬酶;聚乙二醇化非格司亭;喷司他丁;哌泊溴烷;普卡霉素;光辉霉素;卟吩姆钠;丙卡巴肼;奎纳克林;拉布立酶;利妥昔单抗;沙格司亭;链佐星;替比夫定(LDT);滑石;他莫昔芬;替莫唑胺;替尼泊苷(VM-26);睾内酯;硫鸟嘌呤(6-TG);塞替派;托泊替康;托瑞米芬;托西莫单抗;曲妥单抗;维A酸(ATRA);乌拉莫司汀;戊柔比星;维托西达定(一价LDC);长春碱;长春瑞滨;唑来膦酸盐;及其混合物。
24.根据权利要求6-23中任一项的方法,其中R1为H、C2-C18酰基或磷酸酯基且R2为H。
25.根据权利要求6-24中任一项的方法,其中所述化合物为3TC、FTC、LFD4C或其混合物。
27.根据权利要求26的方法,其中R1为H、C2-C18酰基或磷酸酯基团且R2为H。
28.根据权利要求26或27的方法,其中所述化合物为3TC、FTC、LFD4C或其混合物。
29.根据权利要求26-28中任一项的方法,其中所述过度增生疾病为角化过度症、鱼鳞病、皮肤角化病或扁平苔藓。
31.根据权利要求30的方法,其中所述慢性炎性疾病为类风湿性关节炎或骨关节炎。
33.根据权利要求32的化合物,其中Nu为抗癌剂的基团,所述抗癌剂选自阿地白介素;阿仑单抗;阿利维A酸;别嘌醇;六甲蜜胺;氨磷汀;阿那曲唑;三氧化二砷;门冬酰胺酶;卡介苗活菌;贝沙罗汀胶囊;贝沙罗汀凝胶;博来霉素;静脉注入白消安;口服白消安;卡普睾酮;卡培他滨;卡铂;卡莫司汀;用聚苯丙生20植入的卡莫司汀;塞来考昔;苯丁酸氮芥;顺铂;克拉屈滨;环磷酰胺;阿糖胞苷;阿糖胞苷脂质体;达卡巴嗪;更生霉素;放线菌素D;促红细胞生成素;柔红霉素脂质体;柔红霉素,道诺霉素;地尼白介素-毒素连接物,右雷佐生;多西紫杉醇;多柔比星;多柔比星脂质体;丙酸屈他雄酮;埃利奥特氏B溶液;表柔比星;阿法依伯汀雌莫司汀;磷酸依托泊苷;依托泊苷(VP-16);依西美坦;非格司亭;氟尿苷(动脉注入);氟达拉滨;氟尿嘧啶(5-FU);氟维司群;吉姆单抗奥佐米星;醋酸戈舍瑞林;羟基脲;替伊莫单抗;伊达比星;异环磷酰胺;甲磺酸伊马替尼;干扰素α-2a;干扰素α-2b;伊立替康;来曲唑;亚叶酸;左旋咪唑;洛莫司汀(CCNU);甲基-双(2-氯-乙基)胺(氮芥);醋酸甲地孕酮;美法仑(L-PAM);巯嘌呤(6-MP);美司钠;甲氨蝶呤;甲氧沙林;丝裂霉素C;米托坦;米托蒽醌;苯丙酸诺龙;诺非单抗;LOddC;奥普瑞白介素;奥沙利铂;紫杉醇;氨羟二磷酸二钠;培加酶;培门冬酶;聚乙二醇化非格司亭;喷司他丁;哌泊溴烷;普卡霉素;光辉霉素;卟吩姆钠;丙卡巴肼;奎纳克林;拉布立酶;利妥昔单抗;沙格司亭;链佐星;替比夫定(LDT);滑石;他莫昔芬;替莫唑胺;替尼泊苷(VM-26);睾内酯;硫鸟嘌呤(6-TG);塞替派;托泊替康;托瑞米芬;托西莫单抗;曲妥单抗;维A酸(ATRA);乌拉莫司汀;戊柔比星;维托西达定(一价LDC);长春碱;长春瑞滨;唑来膦酸盐;及其混合物。
34.根据权利要求32的化合物,其中Nu为抗病毒剂的基团。
35.根据权利要求26-29中任一项的方法,其中所述化合物与抗过度增生药物共给药。
36.根据下式的化合物和其药学可接受盐、溶剂化物或多晶型物在制备用于治疗下述疾病中的药物中的用途:肿瘤、癌症、癌前细胞和损伤、表达异常或外源表面蛋白或抗原的细胞、牛皮癣、生殖器疣、关节炎、类风湿性关节炎、骨关节炎、过度增生细胞生长疾病和HCV的疾病:
X为H或F;
R1为H、酰基、C1—C20烷基或醚基团、磷酸酯、二磷酸酯、三磷酸酯或磷酸二酯基团、
Nu为生物学活性化合物的基团,使得来自所述生物学活性剂的氨基或羟基与相邻部分形成磷酸酯、氨基磷酸酯、碳酸酯或氨基甲酸乙酯基团;
每个R8独立地为H或C1-C20烷基或醚基团,优选C1-C12烷基;
k为0-12,优选0-2;
R2为H、酰基或C1-C20烷基或醚基团。
37.根据权利要求36的用途,其中所述生物活性化合物选自抗癌化合物、抗病毒化合物和抗过度增生化合物。
38.根据权利要求36的用途,其中所述过度增生细胞生长疾病为角化过度症、鱼鳞病、皮肤角化病或扁平苔藓。
39.根据权利要求36-38中任一项的用途,其中所述化合物与至少一种其它抗癌化合物、抗病毒化合物或抗过度增生化合物共给药。
41.根据权利要求40的用途,其中所述癌症选自胃癌、结肠癌、直肠癌、肝癌、胰腺癌、肺癌、乳腺癌、子宫颈癌、子宫体癌、卵巢癌、前列腺癌、睾丸癌、膀胱癌、肾癌、脑癌/CNS癌、头颈癌、咽喉癌、霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、白血病、黑色素瘤、急性淋巴细胞性白血病、急性骨髓性白血病、尤因肉瘤、小细胞肺癌、绒毛膜癌、横纹肌肉瘤、维尔姆斯氏肿瘤、成神经细胞瘤、毛细胞性白血病、口/咽癌、食道癌、喉癌、肾癌和淋巴瘤。
42.根据权利要求40或41的用途,其中R1为H、C2-C18酰基或磷酸酯基团且R2为H。
43.根据权利要求40-42中任一项上述化合物的用途,所述化合物与至少一种其它对于治疗癌症有效的药物共给药。
45.根据权利要求38的用途,其中所述病毒为HCV。
46.根据权利要求42或43的用途,其中R1为H、C2-C18酰基或磷酸酯基团且R2为H。
47.根据权利要求44-46中任一项上述化合物的用途,所述化合物与至少一种其它对于治疗病毒感染有效的药物共给药。
49.根据权利要求47的用途,其中所述过度增生疾病为角化过度症、鱼鳞病、皮肤角化病或扁平苔藓。
50.根据权利要求48或49的用途,其中R1为H、C2-C18酰基或磷酸酯基团且R2为H。
51.根据权利要求47-49中任一项上述化合物的用途,所述化合物与至少一种其它对治疗过度增生有效的药物共给药。
52.根据权利要求36-51中任一项上述化合物的用途,其中所述X为H。
53.根据权利要求36-51中任一项上述化合物的用途,其中所述X为F。
54.根据权利要求36-51中任一项上述化合物的用途,其中所述X、R1和R2为H。
55.根据权利要求36-51中任一项上述化合物的用途,其中所述X为F,且R1和R2为H。
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CN112955152A (zh) * | 2018-10-31 | 2021-06-11 | 碧欧埃文公司 | 用于预防和/或治疗癌症的黄素腺嘌呤二核苷酸 |
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EP2240176A2 (en) * | 2008-01-03 | 2010-10-20 | Do-Coop Technologies Ltd | Compositions and methods for enhancing the activity of podophyllotoxin |
CN102167696B (zh) * | 2010-02-25 | 2013-09-18 | 南京正大天晴制药有限公司 | 拉米夫定草酸盐及其制备方法 |
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WO2013039920A1 (en) * | 2011-09-12 | 2013-03-21 | Idenix Pharmaceuticals, Inc. | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections |
WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
EP2852605B1 (en) | 2012-05-22 | 2018-01-31 | Idenix Pharmaceuticals LLC | 3',5'-cyclic phosphate prodrugs for hcv infection |
AP3913A (en) | 2012-05-22 | 2016-11-26 | Idenix Pharamaceuticals Inc | D-amino acid compounds for liver disease |
EP2900682A1 (en) | 2012-09-27 | 2015-08-05 | IDENIX Pharmaceuticals, Inc. | Esters and malonates of sate prodrugs |
PE20151318A1 (es) | 2012-10-08 | 2015-10-03 | Idenix Pharmaceuticals Inc | Analogos de 2'-cloro nucleosido para infeccion por vhc |
WO2014137926A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | 3'-deoxy nucleosides for the treatment of hcv |
WO2014160484A1 (en) | 2013-03-13 | 2014-10-02 | Idenix Pharmaceuticals, Inc. | Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv |
EP3004130B1 (en) | 2013-06-05 | 2019-08-07 | Idenix Pharmaceuticals LLC. | 1',4'-thio nucleosides for the treatment of hcv |
WO2015017713A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
EP3131914B1 (en) | 2014-04-16 | 2023-05-10 | Idenix Pharmaceuticals LLC | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
WO2017192502A1 (en) * | 2016-05-03 | 2017-11-09 | The American University In Cairo | Liposomal delivery systems for oxaliplatin and in dual drug delivery in combination with chemo-sensitizing and chemo-therapeutic agents |
WO2018136920A1 (en) * | 2017-01-23 | 2018-07-26 | Health Research, Inc. | Inhibition of endogenous reverse transcriptase and targeting of cells for prophylaxis and therapy of cancer and aging |
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JPS51146482A (en) | 1976-05-28 | 1976-12-16 | Taiho Yakuhin Kogyo Kk | Process for preparing n1-(2- tetrahydrofuryl)-5-fluorouracil |
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US20050059632A1 (en) * | 2003-06-30 | 2005-03-17 | Richard Storer | Synthesis of beta-L-2'-deoxy nucleosides |
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US7837998B2 (en) | 2004-05-21 | 2010-11-23 | Nathaniel Lallatin | Anti-cancer activity of an anti-thymidine kinase monoclonal antibody |
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CN112955152A (zh) * | 2018-10-31 | 2021-06-11 | 碧欧埃文公司 | 用于预防和/或治疗癌症的黄素腺嘌呤二核苷酸 |
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US7951788B2 (en) | 2011-05-31 |
WO2007067364A2 (en) | 2007-06-14 |
CN101511375B (zh) | 2012-09-05 |
EP1968595A2 (en) | 2008-09-17 |
US20090286754A1 (en) | 2009-11-19 |
EP1968595A4 (en) | 2014-05-21 |
HK1129844A1 (en) | 2009-12-11 |
WO2007067364A3 (en) | 2009-05-07 |
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