CN101528223A - Mdm2的新型小分子抑制剂和其用途 - Google Patents
Mdm2的新型小分子抑制剂和其用途 Download PDFInfo
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- CN101528223A CN101528223A CNA2007800392114A CN200780039211A CN101528223A CN 101528223 A CN101528223 A CN 101528223A CN A2007800392114 A CNA2007800392114 A CN A2007800392114A CN 200780039211 A CN200780039211 A CN 200780039211A CN 101528223 A CN101528223 A CN 101528223A
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Abstract
本发明涉及功能为p53与MDM2之间相互作用的抑制剂的小分子。本发明还涉及这些化合物抑制细胞生长、诱导细胞死亡、诱导细胞周期阻滞和/或使细胞对其它药剂敏感的用途。
Description
本申请要求2006年8月30日提交的美国临时专利申请序列号60/841,150的优先权,其在此通过引用整体被并入。
发明背景
发明领域
本发明属于药物化学领域。特别地,本发明涉及具有p53与MDM2之间相互作用的拮抗物的功能的小分子以及它们治疗癌症和其他疾病的治疗学用途。
相关领域
侵袭性癌细胞表型是多种遗传和表观遗传改变的结果,导致细胞内信号传导途径失调(Ponder,Nature 411:336(2001))。然而,所有癌细胞的共同性是它们不能执行凋亡程序,并且由于正常凋亡体系中的缺陷造成的适当凋亡的缺失是癌症的特点(Lowe等人,Carcinogenesis 21:485(2000))。因此,由于正常凋亡体系中的缺陷造成的癌细胞不能执行凋亡程序经常与对化疗、放射或免疫治疗诱导的凋亡的耐受性的增加相关联。由于凋亡缺陷造成的不同起源人类癌症对当前治疗方案的原发耐受性或获得的耐受性是当前癌症治疗的主要问题(Lowe等人,Carcinogenesis 21:485(2000);Nicholson,Nature 407:810(2000))。因此,对设计和开发新型分子靶特异性抗癌治疗以提高癌症患者的存活率和生命质量的当前和将来的努力必须包括特别地以癌细胞对凋亡的耐受性为目标的策略。在这一点上,以在直接抑制癌细胞凋亡中起重要作用的关键的负调节子为目标代表了新抗癌药物设计的非常有前途的治疗策略。
p53肿瘤阻抑子在控制细胞周期发展和凋亡中起重要作用(Vogelstein等人,Nature 408:307(2000))。它是抗癌药物设计的吸引人的治疗靶,因为可以刺激它的肿瘤阻抑子活性以根除肿瘤细胞(Vogelstein等人,Nature 408:307(2000);Chene,Nat.Rev.Cancer3:102(2003))。一种刺激p53活性的新方法是通过使用非肽的小分子抑制剂抑制p53与蛋白质MDM2的相互作用(Chene,Nat.Rev.Cancer3:102(2003);Vassilev等人,Science 303:844(2004))。MDM2和p53是自动调节反馈环的部分(Wu等人,Genes Dev.7:1126(1993))。MDM2由p53转录地活化,并且反过来,MDM2通过至少三种机理抑制p53的活性(Wu等人,Genes Dev.7:1126(1993))。第一,MDM2蛋白质直接结合到p53的转录激活结构域并且因此抑制p53介导的转录激活。第二,MDM2蛋白质含有核输出信号序列,并且当结合到p53时诱导p53的核输出,阻止p53结合到靶向DNA。第三,MDM2蛋白质是E3泛素连接酶并且当结合到p53时能够促进p53的降解。因此,通过起到p53活性的有效内源细胞抑制剂的作用,MDM2有效地抑制p53介导的凋亡、细胞周期阻滞和DNA修复。因而,结合到MDM2并且阻断MDM2与p53之间相互作用的小分子抑制剂可在具有功能性p53的细胞中促进p53活性并且刺激p53介导的细胞效应,例如细胞周期阻滞、凋亡或DNA修复(Chene,Nat.Rev.Cancer 3:102(2003);Vassilev等人,Science 303:844(2004))。
尽管过去已经成功地设计了高亲和力的基于肽的抑制剂(Garcia-Echeverria等人,Med.Chem 43:3205(2000)),但是由于这些抑制剂的细胞渗透性和体内生物利用度差,它们不是类药的(drug-like)分子。虽然制药工业不懈的努力,高通量筛选策略在鉴别有效的、非肽的小分子抑制剂方面已经获得的成功十分有限。因此,存在对p53-MDM2相互作用的非肽的、类药的、小分子抑制剂的需求。
目前正在进行靶向p53-MDM2相互作用的非肽的小分子抑制剂的设计作为抗癌药物设计的吸引人的策略(Chene,Nat.Rev.Cancer3:102(2003);Vassilev等人,Science 303:844(2004))。这种相互作用的结构基础已经通过X-射线晶体学建立(Kussie等人,Science274:948(1996))。晶体结构表明p53与MDM2之间的相互作用主要由来自p53的三个疏水性残基(Phe19、Trp23和Leu26)以及MDM2中的一个小的深的疏水性裂隙介导。该疏水性裂隙是设计可破坏p53-MDM2相互作用的小分子抑制剂的理想位点(Chene,Nat.Rev.Cancer 3:102(2003))。
发明概述
通常公认癌细胞或它们的支持细胞不能经历响应遗传损伤的凋亡或响应对凋亡诱导物(例如抗癌剂和辐射)的暴露的凋亡是癌症发作和发展的主要因素。认为在癌细胞或它们的支持细胞(例如肿瘤血管中的新生血管细胞)中诱导凋亡是当今市场上或实践中几乎所有的有效癌症治疗药物或放射治疗的普遍的作用机理。细胞不能经历凋亡的一个原因是p53的肿瘤阻抑子活性的减少,在许多例子中其是由于在含有功能性p53的肿瘤细胞中MDM2对p53的抑制作用。p53活性的抑制导致凋亡途径以及细胞周期调控的改变。
本发明涉及将患有癌症的动物暴露于治疗有效量的药物(例如小分子)将抑制癌细胞或支持细胞的完全(outright)生长和/或使所述细胞变为对癌症治疗药物或放射治疗的细胞死亡诱导活性更加敏感的群体,其中所述治疗有效量的药物通过抑制p53或p53相关蛋白质与MDM2或MDM2相关蛋白质(例如MDMX)之间的相互作用增加p53和p53相关蛋白质(例如p63、p73)的功能。特别地,本发明的抑制剂通过干扰通常可促进p53降解的p53-MDM2相互作用可延长p53的半衰期。本发明包括p53或p53相关蛋白质与MDM2和MDM2相关蛋白质之间相互作用的抑制剂,当作为单一治疗施用以诱导癌细胞中的细胞生长抑制、凋亡和/或细胞周期阻滞时,或当与其它药剂(例如其他细胞死亡诱导或细胞周期中断癌症治疗药物或放射治疗)按时间关系施用(组合治疗)时,满足多种癌症类型的治疗中未满足的需要,从而与仅用单独的癌症治疗药物或放射治疗来治疗的动物中相应比例的细胞相比较,使更大比例的所述癌症细胞或支持细胞变得对执行凋亡程序更加敏感。
在本发明的某些实施方案中,与单独用本发明的化合物或抗癌药物/放射治疗的动物相比,用治疗有效量的所述化合物和一个疗程的抗癌剂或放射组合治疗动物在所述动物中产生更大的肿瘤响应(tumorresponse)和临床效益。换言之,因为所述化合物将降低所有细胞的凋亡阈值,因此增加了将成功执行响应抗癌药物/放射的凋亡诱导活性的凋亡程序的细胞的比例。可选地,本发明的化合物将用于允许施用较低(并且因此低毒和更加耐受)剂量的抗癌剂和/或放射以产生与单独的常规剂量的抗癌剂/放射同样的肿瘤响应/临床效益。因为已知所有批准的抗癌药物和放射治疗的剂量,因此本发明包括它们与本化合物的多种组合。同样,由于本发明的化合物可至少部分地通过刺激p53和p53相关蛋白质的促凋亡和/或细胞周期抑制活性起作用,癌症细胞和支持细胞对治疗有效量的化合物的暴露应该被以时间关系地连接以符合细胞执行响应抗癌剂或放射治疗的凋亡程序的尝试。因此,在一些实施方案中,结合某些时间关系施用本发明的组合物提供了特别有效的治疗实践。
在本发明的其他实施方案中,p53或p53相关蛋白质与MDM2和MDM2相关蛋白质之间相互作用的抑制剂可能通过抑制剂诱导细胞周期阻滞的能力可保护正常(例如非过度增殖的)细胞免受某些化疗剂和放射的毒性效应。特别地,本发明的抑制剂可在含有野生型p53的细胞中引起细胞周期阻滞,而对含有突变的p53或缺失p53的癌细胞没有效应。这种不同的保护效应可通过允许使用更大剂量或更长时间的化疗剂或化疗治疗来允许更加有效的癌症治疗而不增加所述治疗的毒副作用。
本发明涉及用于抑制p53或p53相关蛋白质与MDM2或MDM2相关蛋白质之间的相互作用和增加细胞对凋亡和/或细胞周期阻滞的诱导物的敏感性的化合物。在一个特定的实施方案中,所述化合物具有式I:
或其药学上可接受的盐或前药,其中:
X是CH、O、N或S,其中如果X是O或S,则R8不存在;
Y是O、S或NR′;
R1、R2、R3、R4、R5、R6和R7独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂环、CO2R′、OCOR′、CONR′R″、NR″COR′、NR′SO2R″、SO2NR′R″、(C=NR′)NR″R′″或NR′R″;或
R7与R5或R6中之一形成芳基、环烷基或杂环基;
R8是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂环、CO2R′、OCOR′、CONR′R″、SO2NR′R″或(C=NR′)NR″R′″;
R9代表6-氯和5-氟基团;并且
每个R′、R″和R′″独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基或杂环;或
R′和R″、或R″和R′″形成环;
其中R3和R4之一是CONRR′,并且R和R′之一是任选取代的环烷基-烷基或单环-杂环烷基或在烷基3-位上不包含羟基的二羟基烷基氨基。
本发明涉及式I代表的化合物,其是p53或p53相关蛋白质与MDM2或MDM2相关蛋白质之间相互作用的抑制剂。本发明涉及本发明的化合物在含有功能性p53或p53相关蛋白质的细胞中诱导细胞周期阻滞和/或凋亡中的用途。本发明还涉及本发明的化合物使细胞对其它药剂(例如凋亡和/或细胞周期阻滞的诱导物)敏感和通过在用化疗剂治疗前诱导细胞周期阻滞来化学保护正常细胞的用途。在一个实施方案中,本发明涉及使正常细胞变得对化疗剂或化疗治疗耐受的方法,包括用本发明的化合物接触细胞。在一个实施方案中,本发明涉及保护具有过度增殖疾病的动物的正常细胞免受化疗剂或化疗治疗的毒副作用的方法,包括向所述动物施用本发明的化合物。在一个特定的实施方案中,本发明是指通过向经受化学治疗的动物施用本发明的化合物,治疗、改善或预防由向正常的非癌性细胞施用化疗剂引起的病症、副反应或疾患。由化学治疗引起的所述病症和疾患的例子包括但不限于粘膜炎、口腔炎、口腔干燥、肠胃病症和脱发。
本发明的化合物用于治疗、改善或预防病症,诸如响应于凋亡性细胞死亡的诱导的那些病症,例如以凋亡的失调(dysregulation)为特征的病症,包括诸如癌症的过度增殖疾病。在某些实施方案中,所述化合物可用于治疗、改善或预防以耐受癌症治疗(例如化学耐受、放射耐受、激素耐受以及相似耐受的那些癌细胞)为特征的癌症。在其他的实施方案中,所述化合物可用于治疗以功能性p53或p53相关蛋白质的表达为特征的过度增殖疾病。在其他的实施方案中,本发明涉及本发明的化合物通过在正常(例如非过度增殖的)细胞中诱导细胞周期阻滞来保护那些细胞免受化疗剂和化疗治疗的毒副作用的用途。
本发明提供含有以治疗有效量诱导细胞的凋亡或使细胞对凋亡诱导物敏感的式I化合物的药物组合物。
本发明进一步提供含有式I的化合物和向动物施用所述化合物的说明书的药盒。所述药盒可任选地含有其他治疗剂,例如抗癌剂或凋亡调节剂。
本发明还提供制备式I的化合物的方法。
发明详述
本发明涉及式I表示的化合物,其具有p53或p53相关蛋白质与MDM2或MDM2相关蛋白质之间相互作用的抑制剂的功能。通过抑制MDM2或MDM2相关蛋白质对p53或p53相关蛋白质的负效应,这些化合物使细胞对凋亡和/或细胞周期阻滞的诱导物敏感,并且在一些例子中它们自身诱导凋亡和/或细胞周期阻滞。因此,本发明涉及使细胞对凋亡和/或细胞周期阻滞的诱导物敏感的方法并且涉及在细胞中诱导凋亡和/或细胞周期阻滞的方法,包括用式I的化合物单独地或与其它药剂(例如凋亡的诱导物或细胞周期干扰物(disrupter))组合地接触细胞。本发明进一步涉及治疗、改善或预防动物的病症(例如响应凋亡的诱导的那些病症)的方法,包括向动物施用式I的化合物和例如凋亡诱导物的其它药剂。所述病症包括以凋亡的失调为特征的那些病症和以表达功能性p53或p53相关蛋白质的细胞的增殖为特征的那些病症。在其他的实施方案中,本发明涉及保护动物的正常(例如非过度增殖的)细胞免受化疗剂和化疗治疗的毒副作用的方法,包括向动物施用式I的化合物。
如本文所用,术语“抗癌剂”和“抗癌药物”指用于治疗诸如癌症(例如在哺乳动物中)等过度增殖疾病的任何治疗剂(例如化疗化合物和/或分子治疗化合物)、反义治疗、放射治疗或手术介入。
如本文所用,术语“前药”指母体“药物”分子的药理学无活性衍生物,其需要在靶生理系统中生物转化(例如自发的或酶促的)以释放或将前药转化(例如酶促地、生理地、机械地、电磁地)为活性药物。设计前药用于克服与稳定性、毒性、特异性缺失或生物利用度有限相关的问题。示例性的前药包括活性药物分子自身和化学掩蔽基团(例如可逆地抑制药物活性的基团)。一些前药是具有在代谢条件下可裂解的基团的化合物的变体或衍生物。当示例性的前药在生理条件下经历溶剂分解或经历酶促降解或其他生物化学转化(例如磷酸化、氢化、脱氢、糖基化)时,它们变为有体内或体外药学活性。前药通常提供在哺乳动物生物体中的溶解性、组织相容性或缓释的优势。(参见例如Bundgard,Design of Prodrugs(前药设计),第7-9,21-24页,Elsevier,Amsterdam(1985);和Silverman,The Organic Chemistry of DrugDesign and Drug Action(药物设计和药物作用的有机化学),第352-401页,Academic Press,San Diego,CA(1992))。普通的前药包括酸衍生物,例如由母体酸与适当的醇(例如,低级烷醇)反应制备的酯、由母体酸化合物与胺或碱性基团反应制备的酰胺,所述碱性基团被反应以形成酰化碱性衍生物(例如低级烷基酰氨)。
如本文所用,术语“药学上可接受的盐”指本发明化合物的任何盐(例如通过与酸或碱反应获得的),其在目标动物(例如哺乳动物)中是生理学耐受的。本发明化合物的盐可衍生自无机或有机的酸和碱。酸的例子包括但不限于盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、蚁酸、苯甲酸、丙二酸、磺酸、萘-2-磺酸、苯磺酸以及类似物。其他的酸,例如草酸,虽然它们自身不是药学上可接受的,但是可被用来制备在获得本发明的化合物和它们的药学上可接受的酸加成盐中用作中间体的盐。
碱的例子包括但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨和式NW4 +且其中W是C1-4烷基的化合物以及类似物。
盐的例子包括但不限于:乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐(digluconate)、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐(flucoheptonate)、甘油磷酸盐、半硫酸盐(hemisulfate)、庚酸盐、己酸盐、氯化物、溴化物、碘化物、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐(mesylate)、甲烷磺酸盐(methanesulfonate)、2-萘磺酸盐、烟酸盐、草酸盐、棕榈酸盐(palmoate)、果胶酸盐(pectinate)、过硫酸盐、苯丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐以及类似物。盐的其他例子包括本发明化合物的阴离子与合适的阳离子化合,所述阳离子如Na+、NH4 +和NW4 +(其中W是C1-4烷基)以及类似物。为了治疗应用,预期本发明化合物的盐为药学上可接受的。然而,非药学上可接受的酸和碱的盐也可得到应用,例如在药学上可接受的化合物的制备或纯化中。
如本文所用,术语“治疗有效量”指足以引起病症的一种或多种症状的改善或预防病症的发展或引起病症消退的治疗剂的量。例如关于癌症治疗,在一个实施方案中,治疗有效量将指治疗剂降低肿瘤生长率、减少肿瘤质量、减少转移灶的数量、增加肿瘤发展时间或增加生存时间至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少100%的量。
如本文所用,术语“变敏感”和“敏化”指通过施用第一药剂(例如式I的化合物)使动物或动物内的细胞对第二药剂的生物效应(例如促进或延迟细胞功能的一个方面,包括但不限于细胞分化、细胞生长、增殖、侵袭、血管生成、坏死或凋亡)更加敏感或更具有响应性。第一药剂对靶细胞的敏化效应可测量为:当与施用第一药剂一起施用第二药剂时和施用第二药剂而不施用第一药剂时,所观察到的预期生物效应(例如促进或延迟细胞功能的一个方面,包括但不限于细胞生长、增殖、侵袭、血管生成或凋亡)的差异。敏化细胞的响应超过没有第一药剂时的响应可增加至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少100%、至少150%、至少200%、至少350%、至少300%、至少350%、至少400%、至少450%或至少500%。
如本文所用,术语“凋亡的失调”指细胞经由凋亡经历细胞死亡的能力的任何畸变(例如易感性(predisposition))。凋亡的失调与多种疾患有关或由多种疾患引起,所述疾患的非限制性例子包括自身免疫病症(例如全身性红斑狼疮、类风湿性关节炎、移植物抗宿主疾病、重症肌无力或综合征)、慢性炎性病症(例如牛皮癣、哮喘或Crohn病)、过度增殖病症(例如肿瘤、B细胞淋巴瘤或T细胞淋巴瘤)、病毒感染(例如疱疹、乳头状瘤或HIV)和例如骨关节炎和动脉粥样硬化的其他疾患。应注意,当失调由病毒感染引起或与病毒感染有关时,在发生失调或观察到失调时,病毒感染可以是可检测的或是不可检测的。即病毒引起的失调甚至可以在病毒感染的症状消失后发生。
如本文所用,术语“功能性p53”指以正常、高或低水平表达的野生型p53和保留至少5%的野生型p53活性的突变p53,例如保留至少10%、20%、30%、40%、50%或更多的野生型活性。
如本文所用,术语“p53相关蛋白质”指与p53具有至少25%序列同一性、具有肿瘤阻抑子活性和被与MDM2或MDM2相关蛋白质的相互作用所抑制的蛋白质。p53相关蛋白质的例子包括但不限于p63和p73。
如本文所用,术语“MDM2相关蛋白质”指与MDM2具有至少25%序列同一性、并且与p53或p53相关蛋白质相互作用和抑制p53或p53相关蛋白质的蛋白质。MDM2相关蛋白质的例子包括但不限于MDMX和HDM2。
如本文所用,术语“过度增殖疾病”指动物的增殖细胞的局部群体不由正常生长的通常限制所控制的任何疾患。过度增殖病症的例子包括肿瘤、新生物、淋巴瘤以及类似疾病。如果新生物不经历侵袭或转移,那么新生物被称为是良性的,如果其经历这些中的任何一个就被称为是恶性的。“转移的”细胞指细胞可以侵入并破坏相邻的身体结构。增生是涉及组织或器官中细胞数量增加而没有结构或功能的显著变化的细胞增殖的形式。组织转化是受控制的细胞生长形式,其中一种类型的完全分化细胞取代另一种类型的分化细胞。
活化的淋巴样细胞的病理学生长通常导致自身免疫病症或慢性炎性疾患。如本文所用,术语“自身免疫病症”指生物体产生识别生物体自身分子、细胞或组织的抗体或免疫细胞的任何疾患。自身免疫病症的非限制性例子包括自身免疫性溶血性贫血、自身免疫性肝炎、Berger病或IgA肾病、乳糜泻、慢性疲劳综合征、Crohn病、皮肌炎、纤维肌痛、移植物抗宿主病、Grave病、桥本甲状腺炎、先天性血小板减少性紫癜、扁平苔藓、多发性硬化、重症肌无力、牛皮癣、风湿热、风湿性关节炎、硬皮病、综合征、全身性红斑狼疮、1型糖尿病、溃疡性结肠炎、白癜风以及类似疾病。
如本文所用,术语“肿瘤病”指良性(非癌性的)或恶性(癌性的)细胞的任何异常生长。
如本文所用,术语“正常细胞”指没有经历异常生长或分裂的细胞。正常细胞是非癌性的并且不是任何过度增殖疾病或病症的部分。
如本文所用,术语“抗肿瘤剂”指延迟目标(例如恶性的)新生物的增殖、生长或扩散的任何化合物。
如本文所用,术语“预防(prevent)”、“预防(preventing)”和“预防(prevention)”指减少动物中病理细胞(例如过度增殖的或肿瘤细胞)的出现。预防可是完全的,例如受治疗者完全没有病理细胞。预防还可是部分的,以使受治疗者中病理细胞的出现少于未用本发明时将出现的病理细胞。
如本文所用,术语“凋亡调节剂”指参与调节(例如抑制、减少、增加、促进)凋亡的药剂。凋亡调节剂的例子包括含有死亡结构域的蛋白质,所述蛋白质例如但不限于Fas/CD95、TRAMP、TNF RI、DR1、DR2、DR3、DR4、DR5、DR6、FADD和RIP。凋亡调节剂的其他例子包括但不限于TNFα、Fas配体、Fas/CD95的抗体和其他TNF家族受体、TRAIL(也称为Apo2配体或Apo2L/TRAIL)、TRAIL-R1或TRAIL-R2的抗体、Bcl-2、p53、BAX、BAD、Akt、CAD、PI3激酶、PP1和半胱天冬酶蛋白质。调节剂广泛地包括TNF家族受体和TNF家族配体的激动剂和拮抗物。凋亡调节剂可是可溶的或膜结合的(例如配体或受体)。凋亡调节剂包括是凋亡的诱导物的那些,例如TNF或TNF相关配体,特别是TRAMP配体、Fas/CD95配体、TNFR-1配体或TRAIL。
在本发明的一个方面,p53与MDM2之间相互作用的抑制剂是式I的化合物:
或其药学上可接受的盐或前药,其中:
X是CH、O、N或S,其中如果X是O或S,则R8不存在;
Y是O、S或NR′;
R1、R2、R3、R4、R5、R6和R7独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂环、CO2R′、OCOR′、CONR′R″、NR″COR′、NR′SO2R″、SO2NR′R″、(C=NR′)NR″R′″或NR′R″;或
R7与R5或R6之一形成芳基、环烷基或杂环基;
R8是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂环、CO2R′、OCOR′、CONR′R″、SO2NR′R″或(C=NR′)NR″R′″;
R9代表6-氯和5-氟基团;并且
每个R′、R″和R′″独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基或杂环;或
R′和R″、或R″和R′″形成环;
其中R3和R4之一是CONRR′,并且R和R′之一是任选取代的环烷基-烷基或单环-杂环烷基或在烷基3-位上不包含羟基的二羟基烷基氨基。
在一个更加特别的实施方案中,式I的R1和R2之一是取代或未取代芳基(例如苯基)、取代或未取代杂芳基、环烷基、直链或支链烷基、酰胺或酯。
在另一个实施方案中,R5和R6之一是C3-18的烷基(例如丙基、异丙基、仲丁基、叔丁基、异戊基、环戊基、冰片基或金刚烷基)或5元或6元芳基或杂芳基。
在另一个实施方案中,式I的化合物具有如式II或式III所示的立体化学结构:
或其药学上可接受的盐或前药。
在一个实施方案中,式I的化合物具有式IV:
其中R1-R9和Y如上文定义。
在另一个实施方案中,式IV的化合物具有如式V或式VI所示的立体化学结构:
或其药学上可接受的盐或前药。
在一个实施方案中,式I的化合物具有式VII:
其中R1-R9如上文定义。
在另一个实施方案中,式VII的化合物具有如式VIII或式IX所示的立体化学结构:
或其药学上可接受的盐或前药。
在一个实施方案中,式I的化合物具有式X:
其中:
R1、R5、R7和R9如上文定义;
R10是H;并且
R11是任选取代的环烷基-烷基或单环-杂环烷基或在烷基3-位上不包含羟基的二羟基烷基氨基;
或R10和R11一起形成任选取代的单环-杂环烷基。
取代的环烷基-烷基的例子包括由下文描述的环烷基取代的C1-6烷基,所述环烷基进一步由一个或多个羟基取代。杂环烷基的例子包括由下文描述的单环-杂环烷基取代的C1-6烷基。
环烷基-烷基的特别例子包括2-(3-羟基环戊基)乙氨基和3-(3-羟基环戊基)丙氨基。各个羟基可具有R或S构型。
取代的杂环烷基的特别例子包括2-(1-吗啉基)乙氨基和3-(1-吗啉基)丙氨基。
二羟基烷基氨基的特别例子包括R和S的4,5-二羟基戊氨基和4-羟基-3-(甲基羟基)丁氨基。
预期当羟基不存在于烷基的3位时,所述化合物在其制备期间可表现出提高的稳定性。不限于任何特定的理论,提高的稳定性可能是由于没有亲核性3-羟基,亲核性3-羟基可能置换酰胺的氨基从而形成含6元酯的环。认为不含有3-羟基的二羟基烷基将不会参与这一反应并且将更加稳定以及能够以更高产量被制备。
在进一步的实施方案中,式I的化合物具有式XI-XXVI之一:
其中R1、R5、R7、R9、R10和R11如上文定义。
在另一个实施方案中,式I的化合物具有式XXVII和式XXVIII之一:
其中R1、R5、R7、R9、R10和R11如上文定义。
在另一个实施方案中,式I的化合物具有式XLVIII:
其中:
R1、R3、R4、R5和R9如上文定义。
在进一步的实施方案中,式I的化合物具有式XLIX-LXIV之一:
其中:
R1、R3、R4、R5和R9如上文定义。
在进一步的实施方案中,式I的化合物具有式LXV:
其中:
R1、R4、R5、R9、R10和R11如上文定义。
在进一步的实施方案中,式I的化合物具有式LXVI和LXVII之一:
其中:
R1、R4、R5、R9、R10和R11如上文定义。
本发明特别的实施方案包括但不限于以下化合物中的任何一个:
本发明的另一个特别的实施方案包括但不限于以下化合物中的任何一个:
有用的烷基包括直链或支链C1-18烷基,特别地甲基、乙基、丙基、异丙基、叔丁基、仲丁基、3-戊基、金刚烷基、冰片基和3-己基。
有用的烯基包括直链或支链C2-18烃基(alkyl groups),特别地乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基和己烯基。
有用的炔基是C2-18炔基,特别地乙炔基、丙炔基、丁炔基和2-丁炔基。
有用的环烷基是C3-8环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
有用的芳基包括C6-14芳基,特别地苯基、萘基、菲基、蒽基、茚基、甘菊环基、联苯基、亚联苯基(biphenylenyl)和芴基。
有用的杂芳基包括噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、色烯基、呫吨基、吩呫吨基(phenoxanthenyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基(phthalzinyl)、萘啶基、喹喔啉基(quinozalinyl)、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌间二氮杂苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异噁唑基、呋咱基(furazanyl)、吩噁嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、1,2-苯并异噁唑-3-基、苯并咪唑基、2-羟吲哚基和2-氧代苯并咪唑基。在杂芳基的环上含有氮原子时,所述氮原子可是N-氧化物的形式,例如吡啶基N-氧化物、吡嗪基N-氧化物、嘧啶基N-氧化物以及类似物。
有用的杂环基包括单环杂环基,例如四氢呋喃基、吡喃基、哌啶基、哌嗪基(piperizinyl)、吡咯烷基、咪唑烷基、咪唑啉基、吗啉基、吡唑烷基、吡唑啉基以及类似物。多环杂环基包括二氢吲哚基、异二氢吲哚基、奎宁环基、苯并二氢吡喃基、异苯并二氢吡喃基、tetronoyl、四氢异喹啉基以及与杂芳环稠合的杂环基,例如任选取代的5,6-二氢-8H-[1,2,4]三唑[4,3-A]吡嗪基。
任选的取代基包括一种或多种烷基;卤素;卤代烷基;环烷基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的芳基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的芳氧基;芳烷基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的杂芳基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的杂芳氧基;烷氧基;烷硫基(alkylthio);芳硫基(arylthio);酰氨基;氨基;氨基烷基、烷基氨基、酰氧基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的芳基酰氧基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的二苯基氧膦基氧基(diphenylphosphinyloxy);用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基、杂芳基、氨基酸取代的磺酰基或氨基酸衍生物取代的磺酰基任选地取代的杂环;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的杂环酰基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的杂环烷氧基;用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的部分未饱和的杂环烷基;或用一种或多种低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、氨基磺酰基、芳基或杂芳基任选地取代的部分未饱和的杂环烷氧基。
本发明的某些化合物可以立体异构体存在,包括光学异构体。本发明包括所有的立体异构体,纯的单独立体异构体制备物和每种富集的制备物,以及所述立体异构体的外消旋混合物和单独对映体,其可根据本领域技术人员熟知的方法分离。
结合下面的合成路线将更好地理解本发明的化合物和方法,所述路线阐明可制备本发明化合物的方法。起始原料可从商业来源获得或通过本领域普通技术人员已知的公认的文献方法制备。以下对本领域普通技术人员是十分明显的:以上定义的化合物可通过以下所示的合成中的合适试剂和药剂的取代来合成。
具有式X的一般结构的化合物可通过使用不对称1,3-偶极环加成作为关键步骤来合成(路线1)。
路线1
试剂和条件:a)CH2Cl2-CH3CN,KF-Al2O3,微波或甲醇、哌啶回流;b)分子筛,甲苯,70℃;c)胺,室温;d)Pb(OAc)4,CH2Cl2-MeOH(1∶1),0℃,或硝酸铈(IV)铵(CAN),CH3CN,K2CO3,室温。
具有式LXV的化合物通过与制备式X相似的方法制备(路线5)。
路线5
试剂和条件:a)CH2Cl2-CH3CN,KF-Al2O3,微波或甲醇、哌啶回流;b)分子筛,甲苯,70℃;c)胺,室温;d)Pb(OAc)4,CH2Cl2-MeOH(1∶1),0℃,或硝酸铈(IV)铵(CAN),CH3CN,K2CO3,室温。
本发明的一个方面涉及制备MDM2抑制剂化合物的方法。在一个实施方案中,本发明涉及制备具有式X的化合物的方法,包括:
a)缩合式1的化合物和式2的化合物,例如在微波下,在存在催化剂(例如KF-Al2O3)或存在合适溶剂中的碱时,在溶剂或溶剂混合物(例如CH2Cl2和CH3CN)中缩合,以形成式3的化合物;
c)在合适温度(例如约0℃或室温),在溶剂或溶剂混合物(例如CH2Cl2和MeOH、CH3CN)中,用氧化剂(例如Pb(OAc)4、硝酸铈铵)处理式6的化合物以形成式X的化合物。
在另一个实施方案中,本发明涉及制备具有式LXV的化合物的方法,包括:
a)缩合式16的化合物和式2的化合物,例如在微波下,在存在催化剂(例如KF-Al2O3)或存在合适溶剂中的碱时,在溶剂或溶剂混合物(例如CH2Cl2和CH3CN)中缩合,以形成式17的化合物;
b)缩合式17的化合物和式4的化合物以及式5的化合物,例如在高温下(例如约70℃),在存在脱水剂(例如分子筛)时,在非极性溶剂(例如甲苯)中缩合,以形成式18的化合物;以及
c)在合适温度(例如约0℃或室温),在溶剂或溶剂混合物(例如CH2Cl2和MeOH、CH3CN)中,用氧化剂(例如Pb(OAc)4、硝酸铈铵)处理式18的化合物以形成式LXV的化合物;
其中:
R1、R5、R9、R10和R11如上文定义。
本发明的一个重要方面是式I的化合物诱导细胞周期阻滞和/或凋亡并且还单独地或响应其它凋亡诱导信号地加强诱导细胞周期阻滞和/或凋亡。因此,预期这些化合物使细胞对细胞周期阻滞和/或凋亡的诱导敏感,包括对所述诱导刺激耐受的细胞。本发明的p53或p53相关蛋白质与MDM2或MDM2相关蛋白质之间相互作用的抑制剂可用于在可通过诱导凋亡被治疗、改善或预防的任何病症中诱导凋亡。在一个实施方案中,所述抑制剂可用于在含有功能性p53或p53相关蛋白质的细胞中诱导凋亡。
在另一个实施方案中,本发明涉及调节与凋亡相关的状态,其与一种或多种凋亡调节剂相关。凋亡调节剂的例子包括但不限于Fas/CD95、TRAMP、TNF RI、DR1、DR2、DR3、DR4、DR5、DR6、FADD、RIP、TNFα、Fas配体、TRAIL、TRAIL-R1或TRAIL-R2的抗体、Bcl-2、p53、BAX、BAD、Akt、CAD、PI3激酶、PP1和半胱天冬酶蛋白质。还包括牵涉在凋亡的开始、决定性(decision)和降解阶段中的其他药剂。凋亡调节剂的例子包括其活性、存在或浓度的变化可在受治疗者中调节凋亡的药剂。凋亡调节剂包括是凋亡的诱导物的那些药剂,例如TNF或TNF相关配体,特别是TRAMP配体、Fas/CD95配体、TNFR-1配体或TRAIL。
在一些实施方案中,本发明的组合物和方法用于治疗动物(例如哺乳动物受治疗者,包括但不限于人和脊椎动物)的患病的细胞、组织、器官或病理学疾患和/或疾病状态。在这方面,多种疾病和病状顺从于使用本方法和组合物的治疗或预防。这些疾病或疾患的非限制性示例列表包括但不限于乳腺癌症(breast cancer)、前列腺癌症(prostatecancer)、淋巴瘤、皮肤癌、胰腺癌症(pancreatic cancer)、结肠癌症(colon cancer)、黑素瘤、恶性黑素瘤、卵巢癌症(ovarian cancer)、脑癌、原发性脑癌、头颈癌、神经胶质瘤、成胶质细胞瘤、肝癌、膀胱癌、非小细胞肺癌、头或颈癌、乳腺癌(breast carcinoma)、卵巢癌(ovarian carcinoma)、肺癌、小细胞肺癌、维尔姆斯瘤、宫颈癌、睾丸癌、膀胱癌、胰腺癌(pancreatic carcinoma)、胃癌、结肠癌(coloncarcinoma)、前列腺癌(prostatic carcinoma)、泌尿系统肿瘤(genitourinary carcinoma)、甲状腺癌、食道癌、骨髓瘤、多发性骨髓瘤、肾上腺癌、肾细胞癌、子宫内膜癌、肾上腺皮质癌、恶性胰腺胰岛瘤、恶性类癌癌症(malignant carcinoid carcinoma)、绒毛膜癌、蕈样肉芽肿、恶性高钙血症、宫颈增生、白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性粒细胞性白血病、急性粒细胞性白血病、毛细胞白血病、成神经细胞瘤、横纹肌肉瘤、卡波西肉瘤、真性红细胞增多症、原发性血小板增多症、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、骨原性肉瘤、原发性巨球蛋白血症和眼癌以及类似疾病,T细胞和B细胞介导的自身免疫疾病;炎性疾病;感染;过度增殖疾病;AIDS;退行性疾患(degenerative condition)、血管病以及类似疾病。在一些实施方案中,被治疗的癌细胞是转移性的。在其他的实施方案中,被治疗的癌细胞是对抗癌剂耐受的。
在一些实施方案中,适于用本发明的组合物和方法治疗的感染包括但不限于由病毒、细菌、真菌、支原体、朊蛋白以及类似物引起的感染。
本发明的一些实施方案提供施用有效量的式I的化合物和至少一种其它治疗剂(包括但不限于化学治疗抗肿瘤剂、凋亡调节剂、抗菌剂、抗病毒剂、抗真菌剂和抗炎剂)和/或治疗技术(例如手术介入和/或放射治疗)的方法。
许多合适的抗癌剂可考虑用于本发明的方法中。事实上,本发明涉及但不限于施用多种抗癌剂,例如:诱导凋亡的药剂;多核苷酸(例如反义、核酶、siRNA);多肽(例如酶和抗体);生物学模拟物(biological mimetics)(例如棉子酚或BH3模拟物);与诸如Bax等Bcl-2家族蛋白质结合(例如寡聚或复合)的药剂;生物碱;烷化剂;抗肿瘤抗生素;抗代谢物;激素;铂化合物;单克隆抗体或多克隆抗体(例如与抗癌药、毒素、防卫素结合的抗体),毒素;放射性核素;生物应答调节剂(例如干扰素(例如IFN-α)和白介素(例如IL-2));过继性免疫治疗剂;造血生长因子;诱导肿瘤细胞分化的药剂(例如全反式维甲酸);基因治疗剂(例如反义治疗剂和核苷酸);肿瘤疫苗;血管生成抑制剂;蛋白体抑制剂;NF-κB调质;抗-CDK化合物;HDAC抑制剂;以及类似物。适于与所公开的化合物共同施用的化学治疗化合物和抗癌治疗的许多其他例子为本领域技术人员所知。
在某些实施方案中,抗癌剂包括诱导或刺激凋亡的药剂。诱导凋亡的药剂包括但不限于放射(例如X射线、γ射线、UV);肿瘤坏死因子(TNF)相关因子(例如TNF家族受体蛋白质、TNF家族配体、TRAIL、TRAIL-R1或TRAIL-R2的抗体);激酶抑制剂(例如表皮生长因子受体(EGFR)激酶抑制剂、血管生长因子受体(VGFR)激酶抑制剂、成纤维细胞生长因子受体(FGFR)激酶抑制剂、血小板源性生长因子受体(PDGFR)激酶抑制剂和Bcr-Ab1激酶抑制剂(例如GLEEVEC));反义分子;抗体(例如赫赛汀(HERCEPTIN)、RITUXAN、ZEVALIN和AVASTIN);抗雌激素(例如雷洛昔芬和它莫西芬);抗雄激素(例如氟他胺、比卡鲁胺、非那司提、氨鲁米特、酮康唑和皮质类固醇);环氧合酶2(COX-2)抑制剂(例如塞来昔布、美洛昔康、NS-398和非类固醇抗炎药(NSAID));抗炎药(例如保泰松、地卡特隆(DECADRON)、DELTASONE、地塞米松、dexamethasone intensol、DEXONE、HEXADROL、羟化氯喹、METICORTEN、ORADEXON、ORASONE、羟基保泰松、PEDIAPRED、保泰松、PLAQUENIL、泼尼松龙、泼尼松、PRELONE和坦特利尔(TANDEARIL));以及癌症化疗剂(例如依立替康(CAMPTOSAR)、CPT-11、氟达拉滨(福达华(FLUDARA))、达卡巴嗪(DTIC)、地塞米松、米托蒽醌、MYLOTARG、VP-16、顺铂、碳铂、奥沙利铂、5-FU、多柔比星、吉西他滨、硼替佐米、吉非替尼、贝伐单抗、泰索帝(TAXOTERE)或泰素(TAXOL));细胞信号转导分子;神经酰胺和细胞因子;星形孢菌素(staurosporine)以及类似物。
在其他的实施方案中,本发明的组合物和方法提供式I的化合物和选自烷化剂、抗代谢物和天然产物(例如源自草本和其他植物和/或动物的化合物)的至少一种抗过度增殖剂或抗肿瘤剂。
适用于本组合物和方法的烷化剂包括但不限于:1)氮芥(例如二氯甲基二乙胺、环磷酰胺、异环磷酰胺、美法仑(L-溶肉瘤素)和苯丁酸氮芥);2)氮丙啶和甲基蜜胺(例如六甲蜜胺和噻替派);3)磺酸烷基酯(例如白消安);4)亚硝基脲(例如卡莫司汀(BCNU);洛莫司汀(CCNU);司莫司汀(甲基-CCNU);和链佐星(链脲霉素));和5)三氮烯(例如,达卡巴嗪(DTIC;三嗪咪唑胺)。
在一些实施方案中,适用于本组合物和方法的抗代谢物包括但不限于:1)叶酸类似物(例如甲氨蝶呤(氨甲蝶呤));2)嘧啶类似物(例如氟尿嘧啶(5-氟尿嘧啶;5-FU)、氟尿苷(氟脱氧尿苷;FudR)和阿糖胞苷(胞嘧啶阿拉伯糖苷));以及3)嘌呤类似物(例如巯嘌呤(6-巯嘌呤;6-MP)、硫鸟嘌呤(6-硫鸟嘌呤;TG)和喷司他丁(2’-脱氧助间型霉素(Deoxycoformycin)))。
在进一步的实施方案中,适用于本发明的组合物和方法的化疗剂包括但不限于:1)长春花生物碱(例如长春碱(VLB)、长春新碱);2)表鬼臼毒素(例如依托泊苷和替尼泊苷);3)抗生素(例如更生霉素(放线菌素D)、正定霉素(道诺霉素;红比霉素)、多柔比星、博来霉素、光辉霉素(光神霉素)和丝裂霉素(丝裂霉素C));4)酶(例如左旋天冬酰胺酶);5)生物应答调节剂(例如干扰素α);6)铂配位复合体(例如顺铂(顺DDP)和碳铂);7)蒽二酮(例如米托蒽醌);8)取代的脲(例如羟基脲);9)甲基肼衍生物(例如甲基苄肼(N-甲基肼;MIH));10)肾上腺皮质抑制剂(例如米托坦(o,p′-DDD)和氨鲁米特);11)肾上腺皮质类固醇(例如强的松);12)孕激素(例如羟孕酮己酸酯、醋酸甲羟孕酮和醋酸甲地孕酮);13)雌激素(例如己烯雌酚和乙炔雌二醇);14)抗雌激素(例如它莫西芬);15)雄激素(例如丙酸睾酮和氟甲睾酮);16)抗雄激素(例如氟他胺);和17)促性腺激素释放激素类似物(例如亮丙瑞林)。
在癌症治疗背景中例行使用的任何溶瘤剂可用于本发明的组合物和方法。例如,美国食品和药品管理局提供了批准在美国使用的溶瘤剂的处方集。与U.S.F.D.A.相应的国际机构提供了相似的处方集。表1提供了批准在美国使用的示例性的抗肿瘤剂的列表。本领域技术人员应理解所有美国批准的化学治疗剂所需的“产品标签”描述所述示例性的药剂的批准的适应症、剂量信息、毒性资料以及类似资料。
表1
阿地白介素(去丙氨酰-1,丝氨酸-125人白介素-2) | Proleukin | Chiron Corp.,Emeryville,CA |
阿仑单抗(IgG1κ抗CD25抗体) | Campath | Millennium and ILEXPartners,LP,Cambridge,MA |
阿利维A酸(9-顺式视黄酸) | Panretin | Ligand Pharmaceuticals,Inc.,San Diego CA |
别嘌呤醇(1,5-二氯-4H-吡唑[3,4-d]嘧啶-4-酮单钠盐) | Zyloprim | GlaxoSmithKline,ResearchTriangle Park,NC |
六甲蜜胺(N,N,N′,N′,N″,N″,-六甲基-1,3,5-三嗪-2,4,6-三氨) | Hexalen | US Bioscience,WestConshohocken,PA |
氨磷汀(乙醇硫,2-[(3-氨基丙基)氨基]-二氢磷酸(酯)) | Ethyol | US Bioscience |
阿那曲唑(1,3-苯二乙腈,a,a,a’,a’-四甲基-5-(1H-1,2,4-三唑-1-基甲基)) | Arimidex | AstraZenecaPharmaceuticals,LP,Wilmington,DE |
三氧化二砷 | Trisenox | Cell Therapeutic,Inc.,Seattle,WA |
天冬酰胺酶L-天冬酰胺酰氨基水解酶,EC-2型 | Elspar | Merck & Co.,Inc.,Whitehouse Station,NJ |
活BCG牛型结核菌减毒株的冻干制备品(卡介苗[BCG],Montreal亚株) | TICE BCG | Organon Teknika,Corp.,Durham,NC |
贝沙罗汀胶囊(4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸) | Targretin | Ligand Pharmaceuticals |
贝沙罗汀凝胶 | Targretin | Ligand Pharmaceuticals |
博来霉素 | Blenoxane | Bristol-Myers Squibb Co., |
(由轮丝链霉菌生产的细胞毒性糖肽抗生素;博来霉素A2和博来霉素B2) | NY,NY | |
卡培他滨(5’-脱氧-5-氟-N-[(戊氧基)羰基]-胞啶) | Xeloda | Roche |
碳铂(铂,二氨[1,1-环丁烷二羧基(dicarboxylato)(2-)O,O’]-,(SP)-4-2) | Paraplatin | Bristol-Myers Squibb |
卡莫司汀(1,3-二(2-氯乙基)-1-亚硝基脲) | BCNU,BiCNU | Bristol-Myers Squibb |
卡莫司汀和聚苯丙生20植入物 | GliadelWafer | Guilford Pharmaceuticals,Inc.,Baltimore,MD |
塞来昔布(如4-[5-(4-甲苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺) | Celebrex | Searle Pharmaceuticals,England |
苯丁酸氮芥(4-[二(2氯乙基)氨基]苯丁酸) | Leukeran | GlaxoSmithKline |
顺铂PtCl2H6N2 | Platinol | Bristol-Myers Squibb |
克拉屈滨(2-氯-2’-脱氧-b-D-腺苷) | Leustatin,2-CdA | R.W.JohnsonPharmaceutical ResearchInstitute,Raritan,NJ |
环磷酰胺(2-[二(2-氯乙基)氨基]四氢-2H-13,2-噁唑膦2-氧化物一水合物) | Cytoxan,Neosar | Bristol-Myers Squibb |
阿糖胞苷(1-b-D-阿拉伯呋喃糖基胞嘧啶,C9H13N3O5 | Cytosar-U | Pharmacia & UpjohnCompany |
阿糖胞苷脂质体 | DepoCyt | Skye Pharmaceuticals,Inc.,San Diego,CA |
达卡巴嗪(5-(3,3-二甲基-1-三唑)-咪唑-4-羧酰胺(DTIC)) | DTIC-Dome | Bayer AG,Leverkusen,Germany |
更生霉素,放线菌素D(由微小链霉菌(parvullus)产生的放线菌素C62H86N12O16) | Cosmegen | Merck |
阿法达贝汀(重组肽) | Aranesp | Amgen,Inc.,Thousand Oaks,CA |
正定霉素脂质体((8S-顺式)8-乙酰基-10-[(3-氨基-2,3,6-三脱氧-á-L-来苏-己吡喃糖基)氧]-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-并四苯二酮盐酸盐) | DanuoXome | Nexstar Pharmaceuticals,Inc.,Boulder,CO |
正定霉素盐酸盐,道诺霉素((1S,3S)-3-乙酰基-1,2,3,4,6,11-六氢-3,5,12-三羟基-10-甲氧基-6,11-二氧代-1-并四苯3-氨基-2,3,6-三脱氧-α-L-来苏-己吡喃糖苷盐酸盐) | Cerubidine | Wyeth Ayerst,Madison,NJ |
地尼白介素(重组肽) | Ontak | Seragen,Inc.,Hopkinton,MA |
右丙亚胺((S)-4,4’-(1-甲基-1,2-乙二基)二-2,6-哌嗪二酮) | Zinecard | Pharmacia & UpjohnCompany |
多西他奇(2R,3S)-N-羧基-3-苯基异丝氨酸,N-叔丁 | Taxotere | Aventis Pharmaceuticals,Inc.,Bridgewater,NJ |
酯,13-酯和2b-20-环氧-12a,4,7b,10b,13a-六羟基紫杉-11-烯-9-酮-4-乙酸酯2-苯甲酸酯三水合物 | ||
多柔比星盐酸盐(8S,10S)-10-[(3-氨基-2,3,6-三脱氧-a-L-来苏-己吡喃糖基)氧]-8-羟乙酰基-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-并四苯二酮盐酸盐) | Adriamycin,Rubex | Pharmacia & UpjohnCompany |
多柔比星 | AdriamycinPFS静脉注射剂 | Pharmacia & UpjohnCompany |
多柔比星脂质体 | Doxil | Sequus Pharmaceuticals,Inc.,Menlo park,CA |
丙酸甲雄烷酮(17b-羟基-2a-甲基-5a-雄烷-3-酮丙酸酯) | Dromostanolone | Eli Lilly & Company,Indianapolis,IN |
丙酸甲雄烷酮 | Masterone注射剂 | Syntex,Corp.,Palo Alto,CA |
埃利奥特B溶液 | Elliott′s B溶液 | Orphan Medical,Inc |
表柔比星((8S-顺式)-10-[(3-氨基-2,3,6-三脱氧-a-L-阿拉伯己吡喃糖基)氧]-7,8,9,10-四氢-6,8,11-三羟基-8-(羟乙酰基)-1-甲氧基-5,12-并四苯二酮盐酸盐) | Ellence | Pharmacia & UpjohnCompany |
阿法依伯汀(重组肽) | Epogen | Amgen,Inc |
雌莫司汀(雌-1,3,5(10)-三烯-3,17-二醇(17(β))-,3-[二(2-氯乙基)氨基甲酸酯]17-(二氢磷酸酯),二钠盐,一水合物,或雌二醇3-[二(2-氯乙基)氨基甲酸酯]17-(二氢磷酸酯),二钠盐,一水合物) | Emcyt | Pharmacia & UpjohnCompany |
磷酸依托泊苷(4’-去甲基表鬼臼毒素9-[4,6,O-(R)-亚乙基-(β)-D-吡喃葡萄糖苷],4’-(二氢磷酸盐)) | Etopophos | Bristol-Myers Squibb |
依托泊苷,VP-16(4’-去甲基表鬼臼毒素9-[4,6,O-(R)-亚乙基-(β)-D-吡喃葡萄糖苷]) | Vepesid | Bristol-Myers Squibb |
依西美坦(6-甲基雄烷-1,4-二烯-3,17-二酮) | Aromasin | Pharmacia & UpjohnCompany |
非格司亭(r-metHuG-CSF) | Neupogen | Amgen,Inc |
氟尿苷(动脉内)2’-脱氧-5-氟尿苷 | FUDR | Roche |
氟达拉滨(抗病毒剂阿糖腺苷的氟化核苷酸类似物,9-b-D-阿糖呋喃糖腺嘌呤(ara-A)) | Fludara | Berlex Laboratories,Inc.,Cedar Knolls,NJ |
氟尿嘧啶,5-FU(5-氟-2,4(1H,3H)-嘧啶二酮) | Adrucil | ICN Pharmaceuticals,Inc.,Humacao,Puerto Rico |
氟维司群(7-α-[9-(4,4,5,5,5-五氟戊基亚磺酰基)壬基雌-1,3,5-(10)- | Faslodex | IPR Pharmaceuticals,Guayama,Puerto Rico |
三烯-3,17-β-二醇) | ||
吉西他滨(2’-脱氧-2’,2’-二氟胞啶一盐酸盐(b-异构体)) | Gemzar | Eli Lilly |
吉妥珠单抗奥唑米星(抗CD33 hP67.6) | Mylotarg | Wyeth Ayerst |
醋酸戈舍瑞林[D-Ser(But)6,Azgly10]HLRH的乙酸盐;pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2乙酸盐[C59H84N18O14·(C2H4O2)x | Zoladex植入剂 | AstraZeneea Pharmaceuticals |
羟基脲 | Hydrea | Bristol-Myers Squibb |
替伊莫单抗(来自单克隆抗体伊莫单抗和连接螯合剂tiuxetan[N-[2-二(羧甲基)氨基]-3-(对异硫氰基苯基)-丙基]-[N-[2-二(羧甲基)氨基]-2-(甲基)-乙基]-甘氨酸之间的硫脲共价键的免疫轭合物) | Zevalin | Biogen IDEC,Inc.,Cambridge MA |
依达比星(5,12-并四苯二酮,9-乙酰-7-[(3-氨基-2,3,6-三脱氧-(α)-L-来苏-己吡喃糖基)氧]-7,8,9,10-四氢-6,9,11-三羟基盐酸,(7S-顺式)) | Idamycin | Pharmacia & UpjohnCompany |
异环磷酰胺(3-(2-氯乙基)-2-[(2-氯乙基)氨基]四氢-2H-1,3,2-噁唑膦2-氧化物) | IFEX | Bristol-Myers Squibb |
甲磺酸伊马替尼(4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯基苯甲酰胺甲磺酸) | Gleevec | Novartis AG,Basel,Switzerland |
干扰素α-2a(重组肽) | Roferon-A | Hoffmann-La Roche,Inc.,Nutley,NJ |
干扰素α-2b(重组肽) | Intron A(冻干重组β-1b干扰素) | Schering AG,Berlin,Germany |
盐酸伊立替康((4S)-4,11-二乙基-4-羟基-9-[(4-哌啶基哌啶基)羰氧基]-1H-吡喃并[3’,4’:6,7]中氮茚[1,2-b]喹啉-3,14(4H,12H)二酮盐酸盐三水合物) | Camptosar | Pharmacia & UpjohnCompany |
来曲唑(4,4’-(1H-1,2,4-三唑-1-基亚甲基)二氰苯) | Femara | Novartis |
亚叶酸(L-谷氨酸,N[4[[(2氨基-5-甲酰基-1,4,5,6,7,8六氢4氧6-蝶啶基)甲基]氨基]苯甲酰],钙盐(1∶1)) | Wellcovorin,Leucovorin | Immunex,Corp.,Seattle,WA |
盐酸左旋咪唑((-)-(S)-2,3,5,6-四氢-6-苯基咪唑并[2,1-b]噻唑一盐酸盐C11H12N2SHCl) | Ergamisol | Janssen ResearchFoundation,Titusville,NJ |
洛莫司汀(1-(2-氯-乙基)-3-环己基-1-亚硝基脲) | CeeNU | Bristol-Myers Squibb |
甲氯乙胺,氯芥(2-氯-N-(2-氯乙基)-N-甲基乙胺盐酸盐) | Mustargen | Merck |
醋酸甲地孕酮17α(乙酰氧基)-6-甲基孕烷-4,6-二烯-3,20-二酮 | Megace | Bristol-Myers Squibb |
美法仑,L-PAM(4-[双(2-氯乙基)氨基]-L-苯丙氨酸) | Alkeran | GlaxoSmithKline |
巯嘌呤,6-MP(1,7-二氢-6H-嘌呤-6-硫酮一水合物) | Purinethol | GlaxoSmithKline |
美司纳(2-巯基乙烷磺酸钠) | Mesnex | Asta Medica |
甲氨蝶呤(N-[4-[[(2,4-二氨基-6-蝶啶基)甲基]甲基氨基]苯甲酰]-L-谷氨酸) | Methotrexate | Lederle Laboratories |
甲氧沙林(9-甲氧基-7H-氟并[3,2-g][1]-苯并呋喃-7-酮) | Uvadex | Therakos,Inc.,Way Exton,Pa |
丝裂霉素C | Mutamycin | Bristol-Myers Squibb |
丝裂霉素C | Mitozytrex | SuperGen,Inc.,Dublin,CA |
米托坦(1,1-二氯-2-(邻氯苯基)-2-(对氯苯基)乙烷) | Lysodren | Bristol-Myers Squibb |
米托蒽醌(1,4-二羟基-5,8-双[[2-[(2-羟基乙基)氨基]乙基]氨基]-9,10-蒽二酮二盐酸盐) | Novantrone | Immunex Corporation |
苯丙酸诺龙 | Durabolin-50 | Organon,Inc.,West Orange,NJ |
诺非单抗 | Verluma | Boehringer IngelheimPharma KG,Germany |
奥普瑞白介素(IL-11) | Neumega | Genetics Institute,Inc.,Alexandria,VA |
奥沙利铂(顺式-[(1R,2R)-1,2-环己二胺-N,N’][草酸基(2-)-O,O’]铂) | Eloxatin | Sanofi Synthelabo,Inc.,NY,NY |
紫杉醇(5β,20-环氧-1,2a,4,7β,10β,13a-六羟基紫杉-11-烯-9-酮-4,10-二乙酸酯-2-苯甲酸酯13-与(2R,3S)-N-苯甲酰-3-苯基异丝氨酸的酯) | TAXOL | Bristol-Myers Squibb |
帕米磷酸盐(磷酸(3-氨基-1-羟基亚丙基)二-,二钠盐,五水合物(APD)) | Aredia | Novartis |
培加酶((单甲氧基聚乙二醇琥珀酰亚胺基)11-17-腺苷脱氨酶) | Adagen(牛加培酶) | Enzon Pharmaceuticals,Inc.,Bridgewater,NJ |
培门冬酶(单甲氧基聚乙二醇琥珀酰亚胺基L-门冬酰胺酶) | Oncaspar | Enzon |
培非司亭 | Neulasta | Amgen,Inc |
(重组甲二磺酰人G-CSF(非格司亭)和单甲氧基聚乙二醇的共价结合物) | ||
喷司他丁 | Nipent | Parke-Davis PharmaceuticalCo.,Rockville,MD |
哌泊溴烷 | Vercyte | Abbott Laboratories,AbbottPark,IL |
光辉霉素,光神霉素(褶皱链霉菌产生的抗生素) | Mithracin | Pfizer,Inc.,NY,NY |
卟菲尔钠 | Photofrin | QLT Phototherapeutics,Inc.,Vancouver,Canada |
甲基苄肼(N-异丙基-μ-(2-甲基肼基)-对甲苯酰胺一盐酸盐) | Matulane | Sigma Tau Pharmaceuticals,Inc.,Gaithersburg,MD |
奎纳克林(6-氯-9-(1-甲基-4-二乙基胺)丁基氨基-2-甲氧基吖啶) | Atabrine | Abbott Labs |
拉布立酶(重组肽) | Elitek | Sanofi-Synthelabo,Inc., |
利妥昔单抗(重组抗CD20抗体) | Rituxan | Genentech,Inc.,South SanFrancisco,CA |
沙莫司亭(重组肽) | Prokine | Immunex Corp |
链佐星(链佐星2-脱氧-2-[[甲基亚硝胺]羰基]氨基-a(和b)-D-吡喃葡萄糖和220mg无水柠檬酸) | Zanosar | Pharmacia & UpjohnCompany |
滑石(Mg3Si4O10(OH)2) | Sclerosol | Bryan,Corp.,Woburn,MA |
它莫西芬((Z)2-[4-(1,2-二苯基-1-丁烯)苯氧基]-N,N-二甲基乙胺2-羟基-1,2,3-丙三羧酸酯(1∶1)) | Nolvadex | AstraZeneca Pharmaceuticals |
替莫唑胺(3,4-二氢-3-甲基-4-氧代咪唑并[5,1-d]-as-四嗪-8-羧酰胺) | Temodar | Schering |
替尼泊苷,VM-26(4’-去甲基表鬼舀毒素9-[4,6,O-(R)-2-噻吩亚甲基-(β)-D-吡喃葡糖苷]) | Vumon | Bristol-Myers Squibb |
睾内酯(13-羟基-3-氧-13,17-断雄甾-1,4-二烯-17-酸[dgr]-内酯) | Teslac | Bristol-Myers Squibb |
硫鸟嘌呤,6-TG(2-氨基-1,7-二氢-6H-嘌呤-6-硫酮) | Thioguanine | GlaxoSmithKline |
噻替派(氮丙啶,1,1′,1″-硫亚膦基三-(phosphinothioyli-dynetris-),或三(1-氮丙啶基)硫化膦) | Thioplex | Immunex Corporation |
托泊替康盐酸盐((S)-10-[(二甲基氨基)甲基]-4-乙基-4,9-二羟基-1H-吡喃并[3′,4′:6,7]中氮茚[1,2-b]喹啉-3,14-(4H,12H)-二酮一盐酸盐) | Hycamtin | GlaxoSmithKline |
托瑞米芬(2-(对[(Z)-4-氯-1,2-二苯基-1-丁烯基]-苯氧基)-N,N-二甲基乙胺柠檬酸酯(1∶1)) | Fareston | Roberts PharmaceuticalCorp.,Eatontown,NJ |
托西莫单抗,I 131托西莫单抗(重组鼠免疫治疗单克隆IgG2aλ抗CD20抗体(I 131是放射免疫治疗抗体)) | Bexxar | Corixa Corp.,Seattle,WA |
曲妥单抗(重组单克隆IgG1κ抗HER2抗体) | Herceptin | Genentech,Inc |
维甲酸,ATRA(全反式维甲酸) | Vesanoid | Roche |
乌拉莫司汀 | UracilMustard胶囊 | Roberts Labs |
戊柔比星,N-三氟乙酰阿霉素-14-戊酸酯((2S-顺式)-2-[1,2,3,4,6,11-六氢-2,5,12-三羟基-7甲氧基-6,11-二氧代[[42,3,6-三脱氧-3-[(三氟乙酰基)-氨基-α-L-来苏-己吡喃糖基]氧基]-2-并四苯基]-2-氧代乙基戊酸酯) | Valstar | Anthra-->Medeva |
长春碱,新长春碱(C46H56N4O10·H2SO4) | Velban | Eli Lilly |
长春新碱(C46H56N4O10·H2SO4) | Oncovin | Eli Lilly |
长春瑞滨(3′,4′-二脱氢-4′-脱氧-C′-去甲长春碱[R-(R*,R*)-2,3-二羟基丁二酸酯(1∶2)(盐)]) | Navelbine | GlaxoSmithKline |
唑来膦酸盐,唑来膦酸((1-羟基-2-咪唑-1-基-膦酰乙基)-膦酸一水合物) | Zometa | Novartis |
抗癌剂进一步包括已经被鉴别为具有抗癌活性但目前没有被美国食品和药品管理局或其他相应机构批准的或正在经受新用途的评估的化合物。例子包括但不限于3-AP、12-O-四癸酰佛波醇-13-乙酸酯、17AAG、852A、ABI-007、ABR-217620、ABT-751、AD I-PEG 20、AE-941、AG-013736、AGRO 100、阿拉诺新、AMG 706、抗体G 250、抗瘤酮、AP23573、apaziquone、APC 8015、阿替莫德、ATN-161、阿曲生坦(atrasenten)、氮杂胞苷、BB-10901、BCX-1777、贝伐单抗、BG00001、比卡鲁胺、BMS247550、硼替佐米、苔藓抑素1、布舍瑞林、骨化三醇、CCI-779、CDB-2914、头孢克肟、西妥昔单抗、CG0070、西仑吉肽、克罗拉滨、考布他汀A4磷酸酯、CP-675,206、CP-724,714、CpG 7909、姜黄色素、地西他滨、DENSPM、度骨化醇、E7070、E7389、海鞘素743、乙丙昔罗、依洛尼塞、EKB-569、enzastaurin、厄洛替尼、依昔舒林、芬维A胺、夫拉平度、氟达拉滨、氟他胺、福莫司汀、FR901228、G17DT、加利昔单抗、吉非替尼、染料木素、葡磷酰胺、GTI-2040、组氨瑞林、HKI-272、高三尖杉酯碱、HSPPC-96,hu14.18-白介素-2融合蛋白、HuMax-CD4、伊洛前列素、咪喹莫特、英夫利昔单抗、白介素-12、IPI-504、伊罗夫文、伊沙匹隆、拉帕替尼、来那度胺、来妥替尼、亮丙瑞林、LMB-9免疫毒素、洛那法尼、鲁昔单抗(luniliximab)、马磷酰胺、MB07133、MDX-010、MLN2704、单克隆抗体3F8、单克隆抗体J591、莫特沙芬、MS-275、MVA-MUC1-IL2、尼鲁特米、硝基喜树碱、诺拉曲塞二氢氯化物、诺瓦得士(nolvadex)、NS-9、O6-苯甲基鸟嘌呤、奥利默森钠、ONYX-015、奥戈伏单抗、OSI-774、帕尼单抗、铂尔定、PD-0325901、培美曲塞、PHY 906、匹格列酮、吡非尼酮、匹杉琼、PS-341、PSC 833、PXD101、吡唑啉吖啶、R115777、RAD001、豹蛙酶、蝴蝶霉素类似物、rhuAngiostatin蛋白、rhuMab 2C4、罗格列酮、卢比替康、S-1、S-8184、沙铂、SB-,15992、SGN-0010、SGN-40、索拉非尼、SR31747A、ST1571、SU011248、辛二酰苯胺异羟肟酸、苏拉明、talabostat、他仑帕奈、tariquidar、坦西莫司、TGFα-PE38免疫毒素、沙利度胺、胸腺法新、tipifarnib、替拉扎明、TLK286、trabectedin、葡醛酸三甲曲沙、TroVax、UCN-1、丙戊酸、长春氟宁、VNP40101M、volociximab、vorinostat、VX-680、ZD1839、ZD6474、齐留通和zosuquidar三盐酸盐。
对于抗癌剂和其他治疗剂的更加详细的说明,本领域技术人员可参考许多说明手册,包括但不限于Physician′s Desk Reference(医师案头参考)以及Goodman和Gilman的“Pharmaceutical Basis ofTherapeutics(治疗的药物基础)”第10版,Hardman等人编,2002。
本发明提供伴随放射治疗施用式I的化合物的方法。本发明不受用于向动物传递治疗剂量的放射的类型、量或传递和施用系统的限制。例如,所述动物可接受光子放射治疗、粒子束放射治疗、其他类型的放射治疗和其组合。在一些实施方案中,放射通过使用线性加速器传递到动物。在其他的实施方案中,放射使用γ刀传递。
对动物来说放射源可是外部的或内部的。外部放射治疗是最普通的并且包括通过使用例如线性加速器指引一束高能射线穿过皮肤到达肿瘤位点。尽管所述一束射线定位于肿瘤位点,但避免正常健康组织的暴露几乎是不可能的。然而,外部放射通常被动物很好地忍受。内部放射治疗包括植入放射发射源,例如微珠(bead)、金属线、小丸、胶囊、颗粒以及类似物,其在身体内处在肿瘤位点或其附近,包括使用特异性靶向癌细胞的传递系统(例如使用连接到癌细胞结合配体的颗粒)。所述植入物可在治疗后移除,或无活性的留在体内。内部放射治疗的类型包括但不限于短距离放射治疗、间质内照射、腔内照射、放射免疫疗法以及类似方法。
所述动物可任选地接受放射敏化剂(例如甲硝哒唑、米索硝唑、动脉内溴尿苷、静脉内碘脱氧尿苷(IudR)、硝基咪唑、5-取代-4-硝基咪唑、2H-异吲哚二酮、[[(2-溴乙基)-氨基]甲基]-硝基)-1H-咪唑-1-乙醇、硝基苯胺衍生物、DNA-亲缘性缺氧选择细胞毒素(DNA-affinichypoxia selective cytotoxins)、卤化DNA配体、1,2,4苯并三嗪氧化物、2-硝基咪唑衍生物、含氟硝基唑衍生物、苯甲酰胺、烟酰胺、吖啶-嵌入剂、5-硫四唑衍生物(5-thiotretrazole derivative)、3-硝基-1,2,4-三唑、4,5-二硝基咪唑衍生物、羟化得克萨卟啉(texaphrins)、顺铂、丝裂霉素、替拉扎明(tiripazamine)、亚硝基脲、巯嘌呤、甲氨蝶呤、氟尿嘧啶、博来霉素、长春新碱、碳铂、表柔比星、多柔比星、环磷酰胺、长春地辛、依托泊苷、紫杉醇、热(体温过高)以及类似物)、辐射防护剂(例如巯乙胺、氨基烷基二氢硫代磷酸酯、氨磷汀(WR 2721)、IL-1、IL-6以及类似物)。放射敏化剂加强杀死肿瘤细胞。辐射防护剂保护健康组织免受放射的有害作用。
任何类型的放射可施用于动物,只要动物耐受放射的剂量且没有不可接受的负面的副作用。合适类型的放射治疗包括,例如离子化(电磁)放射治疗(例如X射线和γ射线)或粒子束放射治疗(例如高能线性射线)。将离子化放射定义为含有具有足够能量以产生离子化(即获得或失去电子)的颗粒或光子的放射(例如,如美国5,770,581所述,其在此通过引用整体被并入)。放射的效应可由临床医生至少部分地控制。在一个实施方案中,为了最大的靶细胞暴露和减少毒性,将放射的剂量分为几个部分。
在一个实施方案中,施用于动物的放射的总剂量为约.01格雷(Gy)至约100Gy。在另一个实施方案中,在整个治疗疗程中施用约10Gy至约65Gy(例如约15Gy、20Gy、25Gy、30Gy、35Gy、40Gy、45Gy、50Gy、55Gy或60Gy)。尽管在一些实施方案中在一天的疗程中可施用放射的全部剂量,但是理想地将总剂量分为几部分并在几天施用。期望地,放射治疗在至少约3天的疗程中施用,例如至少5、7、10、14、17、21、25、28、32、35、38、42、46、52或56天(约1-8周)。因此,每日的放射剂量将包括大约1-5Gy(例如,约1Gy、1.5Gy、1.8Gy、2Gy、2.5Gy、2.8Gy、3Gy、3.2Gy、3.5Gy、3.8Gy、4Gy、4.2Gy或4.5Gy)或1-2Gy(例如1.5-2Gy)。每日的放射剂量应该足以诱导靶细胞的破坏。在一个实施方案中,如果延伸一段时间,放射不每天施用,从而使动物休息并实现治疗的效应。例如,期望的放射是在每星期的治疗中连续施用5天并停止施用2天,从而允许每星期休息2天。然而,放射可以1天/星期、2天/星期、3天/星期、4天/星期、5天/星期、6天/星期或全部7天/星期施用,其取决于动物的响应性和任何可能的副作用。放射治疗可在治疗期间的任何时间开始。在一个实施方案中,放射在第1星期或第2星期开始,并且在治疗周期的剩余时间施用。例如,放射在含有6个星期用于治疗例如实体肿瘤的治疗周期的第1-6星期或第2-6星期内施用。可选地,放射在含有5个星期的治疗周期的第1-5星期或第2-5星期内施用。然而,这些示例的放射治疗施用方案无意限制本发明。
在本发明中,抗菌治疗剂也可作为治疗剂使用。可杀死、抑制或以其它方式削弱微生物有机体的功能的任何药剂以及预期具有这样的活性的任何药剂可被使用。抗菌剂包括但不限于,单独或组合使用的天然的和合成的抗生素、抗体、抑制蛋白(例如防卫素)、反义核酸、膜破坏剂以及类似物。事实上,可使用任何类型的抗生素,包括但不限于抗细菌剂、抗病毒剂、抗真菌剂以及类似物。
在本发明的一些实施方案中,式I的化合物和一种或多种治疗剂或抗癌剂按一种或多种以下条件施用于动物:以不同的周期、以不同的持续时间、以不同的浓度,通过不同的施用途径等。在一些实施方案中,所述化合物在治疗剂或抗癌剂之前施用,例如在施用治疗剂或抗癌剂前0.5、1、2、3、4、5、10、12或18个小时,1、2、3、4、5或6天,或1、2、3或4星期施用。在一些实施方案中,所述化合物在治疗剂或抗癌剂之后施用,例如在施用抗癌剂后0.5、1、2、3、4、5、10、12或18个小时,1、2、3、4、5或6天,或1、2、3或4星期施用。在一些实施方案中,所述化合物和治疗剂或抗癌剂同时施用,但是按照不同的给药方案,例如所述化合物每天施用而治疗剂或抗癌剂按每周一次、每两周一次、每三周一次或每四周一次施用。在其他的实施方案中,所述化合物按每周一次施用而治疗剂或抗癌剂按每天、每周一次、每两周一次、每三周一次或每四周一次施用。
属于本发明的范围的组合物包括含有有效实现其预期目的的量的本发明化合物的所有药物组合物。尽管个体的需求不同,确定每种组分的有效量的最优范围属于本领域的技术。通常,可以以被治疗响应凋亡的诱导的病症的哺乳动物体重的每天0.0025mg/kg至50mg/kg的剂量或等价量的其药学上可接受的盐将所述化合物口服施用于所述哺乳动物,例如人。在一个实施方案中,口服施用约0.01mg/kg至约25mg/kg以治疗、改善或预防所述病症。对于肌内注射,所述剂量通常是约口服剂量的一半。例如,合适的肌内剂量可是约0.0025mg/kg至约25mg/kg或约0.01mg/kg至约5mg/kg。
单位口服剂量可包括约0.01mg至约1000mg,例如约0.1mg至约100mg的化合物。所述单位剂量可以各含有约0.1mg至约10mg、适宜地约0.25mg至50mg的化合物或其溶剂化物的一个或多个片剂或胶囊每天一次或多次施用。
在局部制剂中,所述化合物可以约0.01mg至100mg每克载体的浓度存在。在一个实施方案中,所述化合物以约0.07-1.0mg/ml,例如约0.1-0.5mg/ml的浓度存在,并且在一个实施方案中,为约0.4mg/ml。
除了将所述化合物作为粗化学品施用外,本发明的化合物还可作为含有合适药学上可接受载体的药物制剂的部分来施用,所述药学上可接受载体包括促进所述化合物加工成可在药学上使用的制剂的赋形剂和辅料。所述制剂,特别是可口服或局部施用的和可用于一种施用类型(例如片剂、糖衣丸、缓释锭剂和胶囊、口腔冲洗剂和漱口剂、凝胶、液体悬浮液、护发液、发胶、洗发剂)的那些制剂和可直肠施用的制剂(例如栓剂)以及用于静脉内输注、注射、局部或口服施用的合适溶液,含有约0.01%至99%的活性化合物,在一个实施方案中为约0.25%至75%的活性化合物,以及赋形剂。
本发明的药物组合物可向可体验本发明化合物的有益效应的任何动物施用。所述动物中最好的是哺乳动物,例如人,尽管本发明无意如此限制。其他的动物包括脊椎动物(牛、羊、猪、马、狗、猫以及类似动物)。
所述化合物和其药物组合物可以通过实现其预期目的的任何方式施用。例如,可通过肠胃外、皮下、静脉内、肌内、腹腔内、透皮、含服、鞘内、颅内、鼻内或局部途径施用。可选地或同时地,可通过口服途径施用。施用的剂量将取决于接受者的年龄、健康状况和体重、同时治疗的种类(如果有)、治疗的频率以及预期效应的性质。
本发明的药物制剂以本身已知的方式来制备,例如通过常规的混合、粒化、糖衣丸制备、溶解或冻干工艺。因此,口服使用的药物制剂可通过以下来获得:结合活性化合物和固体赋形剂,加入合适的辅料后(如果是期望的或必须的)任选地研磨获得的混合物并加工颗粒的混合物,以获得片剂或糖衣丸核。
特别地,合适的赋形剂是诸如糖类(例如乳糖或蔗糖、甘露醇或山梨醇、纤维素制剂)和/或磷酸钙(例如磷酸三钙或磷酸氢钙)等填充剂以及诸如淀粉糊等粘合剂,其使用例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要,可加入崩解剂,例如以上提到的淀粉以及还有羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或海藻酸或其盐,如海藻酸钠。辅料首先是流体调节剂和润滑剂,例如二氧化硅、滑石、硬脂酸或其盐(例如硬脂酸镁或硬脂酸钙)和/或聚乙二醇。如果需要,向糖衣丸核提供耐受胃液的合适的包衣。为这一目的,可使用浓的糖溶液,其可任选地含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。为制备耐受胃液的包衣,使用合适的纤维素制剂(例如邻苯二甲酸乙酰纤维素或邻苯二甲酸羟丙基甲基纤维素)的溶液。例如为了鉴别或为了表征活性化合物剂量的组合,可将染料或色素加入到片剂或糖衣丸包衣。
可口服使用的其他药物制剂包括由明胶制备的推入配合式胶囊以及由明胶和诸如甘油或山梨醇等增塑剂制备的密封的软胶囊。推入配合式胶囊可含有颗粒形式的活性化合物,所述颗粒可与诸如乳糖等填充剂、诸如淀粉等粘合剂和/或诸如滑石或硬脂酸镁等润滑剂混合,以及任选地与稳定剂混合。在软胶囊中,在一个实施方案中,所述活性化合物溶解或悬浮于合适的液体,例如脂肪油或液体石蜡。此外,可加入稳定剂。
可直肠使用的可能的药物制剂包括,例如栓剂,其由一种或多种活性化合物和栓剂基质的组合物组成。合适的栓剂基质是,例如天然的或合成的甘油三酯或烷属烃。此外,使用由活性化合物和基质的组合物组成的明胶直肠胶囊也是可能的。可能的基质材料包括,例如液态甘油三酯、聚乙二醇或烷属烃。
用于肠胃外施用的合适的制剂包括水溶形式(例如水溶性盐和碱性溶液)的活性化合物的水溶液。此外,可施用作为合适的油性注射悬浮液的活性化合物的悬浮液。合适的亲脂性溶剂或媒介物包括例如芝麻油的脂肪油或例如油酸乙酯或甘油三酯或聚乙二醇-400的合成的脂肪酸酯。含水注射悬浮液可包括增加悬浮液粘性的物质,包括,例如羧甲基纤维素钠、山梨醇和/或葡聚糖。任选地,所述悬浮液还可包括稳定剂。
在一个实施方案中,通过选择合适的载体将本发明的局部组合物配制为油状物、乳膏、洗液、软膏以及类似物。合适的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量的醇(大于C12)。所述载体可是活性成分在其中可溶的那些载体。如果需要,还可包括乳化剂、稳定剂、湿润剂和抗氧化剂以及给予颜色或香味的药剂。此外,在这些局部制剂中可使用透皮渗透增强剂。所述增强剂的例子可参见美国专利第3,989,816和4,444,762号。
乳膏可由矿物油、自乳化蜂蜡和水的混合物配制,在所述混合物中混合溶解于少量油(例如杏仁油)的活性成分。所述乳膏的典型例子是含有约40份水、约20份蜂蜡、约40份矿物油和约1份杏仁油的乳膏。
软膏可通过混合活性成分的植物油(例如杏仁油)溶液和热的软石蜡并使混合物冷却来配制。所述软膏的典型例子是含有按重量计约30%杏仁油和约70%白软石蜡的软膏。
洗液可通过将活性成分溶解于例如丙二醇或聚乙二醇的合适的高分子量的醇来方便地制备。
以下的实施例示例本发明的方法和组合物但不限制本发明的方法和组合物。在临床治疗中通常遇到的多种条件和参数的其他合适的修改和调整以及对本领域技术人员来说明显的修改和调整在本发明的主旨和范围内。
实施例1
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺
1H NMR(300MHz,CD3OH),δ7.70(d,1H,J=8.4Hz),7.40-7.20(m,3H),7.09(m,1H),6.88(d,1H,J=6.0Hz),5.22(d,1H,J=11.4Hz),4.39(m,1H),4.11(d,1H,J=11.1Hz),3.65-3.32(m,9H),1.85(m,1H),1.60(m,1H),1.41(m,1H),1.19(m,1H),0.84(s,9H)。
实施例2
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(2,3-二羟基-丙基)-酰胺
1H NMR(300MHz,CD3OH),δ7.74(d,1H,J=7.5Hz),7.35-7.15(m,3H),7.11(m,1H),6.88(d,1H,J=6.0Hz),5.22(d,1H,J=11.4Hz),4.33(m,1H),4.28(d,1H,J=10.5Hz),3.67(m,2H),3.65-3.32(m,4H),2.05(m,1H),1.90(m,1H),1.56(m,1H),0.87(s,9H)。
实施例3
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,5-二羟基-戊基)-酰胺
1H NMR(300MHz,CD3OH),δ7.72(d,1H,J=8.4Hz),7.35-7.15(m,3H),7.10(m,1H),6.88(d,1H,J=6.0Hz),5.23(d,1H,J=11.1Hz),4.65(m,1H),4.13(d,1H,J=11.4Hz),3.61(m,2H),3.65-3.32(m,5H),2.02(m,1H),1.93(m,1H),1.56(m,3H),1.15(m,1H),0.92(s,9H)。
实施例4
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸[2-(3-羟基-环戊基)-乙基]-酰胺
1H NMR(300MHz,CD3OH),δ7.69(d,1H,J=8.4Hz),7.40-7.20(m,3H),7.10(m,1H),6.86(m,1H),5.24(d,1H,J=11.1Hz),4.35(d,1H,J=8.4Hz),4.09(m,1H),3.61-3.32(m,2H),2.96(m,1H),2.21-1.12(m,11H),0.85(s,9H)。
实施例5
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸[2-(3-羟基-环戊基)-乙基]-酰胺
1H NMR(300MHz,CD3OH),δ7.69(d,1H,J=8.4Hz),7.40-7.20(m,3H),7.10(m,1H),6.86(m,1H),5.24(d,1H,J=11.1Hz),4.48(d,1H,J=8.4Hz),4.12(m,1H),3.64-3.32(m,2H),2.96(m,1H),2.20-1.10(m,11H),0.85(s,9H)。
实施例6
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸[2-(3-羟基-环戊基)-乙基]-酰胺
1H NMR(300MHz,CD3OH),δ7.69(d,1H,J=8.4Hz),7.40-7.20(m,3H),7.10(m,1H),6.86(m,1H),5.24(d,1H,J=11.1Hz),4.47(d,1H,J=8.4Hz),4.11(m,1H),3.65-3.32(m,2H),2.96(m,1H),2.20-1.10(m,11H),0.91(s,9H)。
实施例7
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸[2-(3-羟基-环戊基)-乙基]-酰胺
1H NMR(300MHz,CD3OH),δ7.72(d,1H,J=8.4Hz),7.38-7.22(m,3H),7.10(m,1H),6.87(m,1H),5.23(d,1H,J=11.1Hz),4.48(d,1H,J=8.4Hz),4.12(m,1H),3.56-3.25(m,2H),2.98(m,1H),2.20-1.10(m,11H),0.86(s,9H)。
实施例8
6-氯-4′-(3-氯-4-氟-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(4,5-二羟基-戊基)-酰胺
1H NMR(CD3OD,300MHz),δ7.73(d,J=8.4Hz,1H),7.41(d,J=7.0Hz,1H),7.14(d,J=6.7Hz,2H),5.25(d,J=11.3Hz,1H),4.49(d,J=6.6Hz,1H),4.15(d,J=6.4Hz,1H),3.48-3.10(m,5H),1.94(dd,J=8.1,15.4Hz,1H),1.70-1.10(m,5H),0.92(s,9H)。
实施例9
6-氯-4′-(3-氯-4-氟-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3-吗啉-4-基-丙基)-酰胺
1H NMR(CD3OD,300MHz),δ7.82-7.19(m,4H),6.90(d,J=5.56,1H),5.39(d,J=9.9Hz,1H),4.55(d,J=6.9Hz,1H),4.28(d,J=9.3Hz,1H),4.20-3.85(m,4H),3.70-3.40(m,2H),3.25-3.00(m,4H),2.20-1.85(m,3H),1.69(d,J=15.3Hz,2H),0.934(s,9H),0.70(t,J=11.3Hz,1H)。
实施例10
6-氯-4′-(3-氯-2-氟-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(4-羟基-3-羟甲基-丁基)-酰胺
H1(300MHz CD3OD),δ8.56(s br,1H),7.68(t,J=6.6Hz,1H),7.42(t,J =7.2Hz,1H),7.25(t,J=7.8Hz,1H),7.05(d,J=8.7Hz,1H),6.95(d,J=6.0Hz,1H),5.22(d,J=10.5Hz,1H),4.54(d,J=10.5Hz,1H),4.34-4.31(m,1H),3.51-3.49(m,4H),3.36-3.32(m,2H),2.08(dd,J=15.3,7.5Hz,1H),1.53-1.49(m,2H),1.33(dd,J=15.3,2.7Hz,1H),0.93-0.89(m,1H),0.86(s,9H)。
实施例11
H1(300MHz CD3OD),δ8.56(s br,1H),7.65(t,J=6.6Hz,1H),7.45(t,J=7.2Hz,1H),7.26(t,J=7.8Hz,1H),7.01(d,J=8.7Hz,1H),6.95(d,J=6.0Hz,1H),5.14(d,J=10.5Hz,1H),4.51(d,J=10.5Hz,1H),4.26(m,1H),3.55-3.50(m,2H),3.37-3.31(m,3H),2.08-2.02(m,1H),1.71-1.45(m,2H),1.35-1.23(m,3H),0.86(s,9H)。
实施例12
6-氯-4′-(3-氯-2-氟-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺
(MI-419)
H1(300MHz CD3OD),δ8.55(s br,1H),7.66(t,J=6.6Hz,1H),7.42(t,J=7.8Hz,1H),7.28-7.23(m,2H),7.01(d,J=8.7Hz,1H),6.95(d,J=6.0Hz,1H),5.20(d,J=10.5Hz,1H),4.53(d,J=10.5Hz,1H),4.26(m,1H),3.52(m,1H),3.40-3.33(m,4H),2.03(m,1H),1.71-1.45(m,2H),1.35-1.28(m,1H),0.86(s,9H)。
实施例13
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(2-吗啉-4-基-乙基)-酰胺
1H NMR(300MHz,CD3OH),δ7.74(d,1H,J=7.5Hz),7.35-7.15(m,3H),7.11(m,1H),6.88(d,1H,J=6.0Hz),5.22(d,1H,J=11.4Hz),4.55(d,1H,J=9.6Hz),4.24(d,1H,J=6.3Hz),4.20-3.85(m,4H),3.70-3.40(m,4H),3.25-3.00(m,4H),2.09(m,1H),1.27(m,1H),0.934(s,9H)。
实施例14
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3-吗啉-4-基-丙基)-酰胺
1H NMR(CD3OD,300MHz),δ7.72(d,1H,J=8.4Hz),7.38-7.22(m,3H),7.10(m,1H),6.87(m,1H),5.23(d,1H,J=11.1Hz),4.55(d,J=6.9Hz,1H),4.28(d,J=9.3Hz,1H),4.20-3.85(m,4H),3.70-3.40(m,2H),3.25-3.00(m,4H),2.20-1.85(m,4H),1.69(d,J=15.3Hz,2H),0.934(s,9H)。
实施例15
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(4,5-二羟基-戊基)-酰胺
1H NMR(CD3OD,300MHz),δ7.69(d,1H,J=8.4Hz),7.40-7.20(m,3H),7.10(m,1H),6.86(m,1H),5.24(d,1H,J=11.1Hz),4.51(d,J=10.5Hz,1H),4.26(m,1H),3.55-3.50(m,2H),3.37-3.31(m,3H),2.08-2.02(m,2H),1.71-1.45(m,2H),1.35-1.23(m,3H),0.86(s,9H)。
实施例16
6-氯-4′-(3-氯-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(4-羟基-3-羟甲基-丁基)-酰胺
1H NMR(300MHz,CD3OH),δ7.69(d,1H,J=8.4Hz),7.40-7.20(m,3H),7.10(m,1H),6.86(m,1H),5.24(d,1H,J=11.1Hz),4.54(d,J=10.5Hz,1H),4.34-4.31(m,1H),3.51-3.49(m,4H),3.36-3.32(m,2H),2.08(dd,J=15.3,7.5Hz,1H),1.53-1.49(m,2H),1.33(dd,J=15.3,2.7Hz,1H),0.93-0.89(m,1H),0.86(s,9H)。
实施例17
(2′R,3S,3″S,4′R,5′R)6-氯-4′-(3-氯-4-氟-苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺(MI-319)
分子式:C27H31Cl2F2N3O4.HCl(盐酸盐)1H NMR(300MHz,MeOD),δ8.44(m,1H),7.70(d,1H,J=8.4Hz),7.41(m,1H),7.14(m,2H),6.90(d,1H,J=6.0Hz),5.20(d,1H,J=11.1Hz),4.47(d,1H,J=8.1Hz),4.14(d,1H,J=10.8Hz),3.47(m,4H),1.91(dd,1H,J=15.6,8.4Hz),1.57(m,1H),1.43(m,1H),1.21(dd,1H,J=15.6,1.8Hz),0.92(s,9H);13C NMR(75MHz,MeOD),δ176.28,166.52,157.03,153.19,139.65,130.67,129.58,129.48,128.46,128.40,124.54,124.44,122.58,122.33,121.41,121.17,117.21,116.93,113.37,113.03,112.41,69.69,66.05,64.36,62.93,61.91,55.48,42.25,36.99,32.59,29.84,28.40。
实施例18
(MI-219)
实施例19
6-氯-4′-(3-氯-4-氟苯基)-2′-环戊基甲基-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺
(MDM2-319-1)
1H NMR(300MHz,CD3OD),δ7.72(d,1H,J=8.5Hz),7.46-7.40(m,1H),7.23-7.12(m,2H),6.88(d,1H,J=6.0Hz),5.12(d,1H,J=11.3Hz),4.39-4.35(m,1H),4.14(d,1H,J=11.3Hz),3.41-3.28(m,5H),1.92-1.78(m,2H),1.62-1.42(m,8H),1.28(d,1H,J=15.8Hz),1.10-0.90(m,2H)。
实施例20
(MDM2-319-2)
实施例21
(MDM2-319-3)
实施例22
6-氯-4′-(3-氯-4-氟苯基)-2′-环己基-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺
(MDM2-319-4)
1H NMR(300MHz,CD3OD),δ8.54-8.40(m,2H),7.56(d,1H,J=8.4Hz),7.31-7.29(m,1H),7.16-7.11(m,2H),6.82(d,1H,J=6.1Hz),4.99-4.95(m,1H),4.21-4.01(m,2H),3.39-3.19(m,5H),2.50-2.40(m,1H),2.00-1.83(m,2H),1.63-1.54(m,4H),1.44-1.09(m,6H)。
实施例23
(MDM2-319-5)
实施例24
6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸[2-(3-羟基-环戊基)-乙基]-酰胺
(MDM2-319-6)
1H NMR(300MHz,CD3OD),δ8.52-8.49(m,1H),7.72(d,1H,J=8.5Hz),7.40(d,1H,J=10.0Hz),7.16-7.15(m,2H),6.90(d,1H,J=6.0Hz),5.27-5.23(m,1H),4.49(d,1H,J=8.2Hz),4.14-4.07(m,2H),3.24-3.22(m,1H),3.10-3.02(m,1H),1.93-1.83(m,2H),1.75-1.18(m,7H),1.05-0.93(m,1H),0.92(s,9H),0.85-0.81(m,1H)。
实施例25
(MI-319-7)
实施例26
6-氯-4′-(3-氯-4-氟苯基)-2′-环戊基-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺
(MI-319-8)
1H NMR(300MHz,CD3OD),δ7.68(d,1H,J=8.5Hz),7.40-7.37(m,1H),7.16-7.11(m,2H),6.86(d,1H,J=6.0Hz),5.15(d,1H,J=11.6Hz),4.27(d,1H,J=11.0Hz),4.15(d,1H,J=11.6Hz),3.39-3.24(m,5H),2.30-2.28(m,1H),2.10-2.05(m,1H),1.62-1.31(m,7H),1.15-1.12(m,1H),0.78-0.75(m,1H)。
实施例27
6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-5′-(4-甲基-哌嗪-1-羰基)-1H-螺环[吲哚-3,3′-吡咯烷]-2-酮
(MI-319-9)
1H NMR(300MHz,CD3OD),δ7.73-7.70(m,1H),7.58-7.51(m,1H),7.29-7.19(m,2H),6.93-6.89(m,1H),5.83-5.80(m,1H),4.70-4.68(m,1H),4.44-4.25(m,2H),3.98-3.52(m,3H),3.36-3.22(m,2H),2.92-2.85(m,3H),2.40-1.89(m,2H),1.20(d,1H,J=15.3Hz),0.95-0.90(m,9H)。
实施例28
(MI-319-10)
实施例29
(MI-319-11)
实施例30
(MI-319-11-A)
实施例31
(MI-319-12)
实施例32
1′-乙酰基-6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺
(MI-319-13)
1H NMR(300MHz,CD3Cl),δ8.08(s,1H),7.19-7.12(m,1H),6.93-6.77(m,4H),4.93(d,1H,J=10.2Hz),4.75(d,1H,10.2Hz),4.00-3.98(m,1H),3.78-3.30(m,5H),2.80-2.77(m,1H),2.23(s,3H),1.76-1.64(m,1H),1.56-1.52(m,2H),0.92(s,9H)。
实施例33
6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1′-氧-1,2,4′,5′-四氢-螺环[吲哚-3,3′-吡咯]-5′-羧酸(3,4-二羟基-丁基)-酰胺
(MI-319-14)
1H NMR(300MHz,CD3Cl),δ7.35-7.27(m,1H),7.09-7.07(m,1H),6.92-6.89(m,1H),6.79-6.75(m,2H),5.55(d,1H,J=11.0Hz),4.20(d,1H,J=11.0Hz),3.67-3.65(m,2H),3.44-3.32(m,3H),2.80(d,1H,J=13.1Hz),1.80(d,1H,J=13.1Hz),1.70-1.60(m,2H),0.84(s,9H)。
实施例34
{[6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羰基]-氨基}-乙酸
(MI-319-15)
1H NMR(300MHz,CD3OD),δ7.64(d,1H,J=8.4Hz),7.38(d,1H,J=6.2Hz),7.27-7.21(m,1H),7.10-7.07(m,1H),6.90-6.84(m,1H),5.08(d,1H,J=9.9Hz),4.22-3.88(m,4H),1.76-1.68(m,1H),1.12-1.06(m,1H),0.84(s,9H)。
实施例35
(MI-319-16)
实施例36
6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(2-咪唑-1-基-乙基)-酰胺
(MI-319-17)
1H NMR(300MHz,CD3OD),δ8.99(s,1H),7.78(d,1H,J=8.4Hz),7.50-7.45(m,2H),7.37-7.35(m,1H),7.19-7.11(m,2H),6.89(d,1H,J=6.0Hz),5.32(d,1H,J=11.4Hz),4.52(d,1H,J=6.8Hz),4.41-4.36(m,2H),4.19(d,1H,J=11.4Hz),3.73-3.31(m,2H),1.99-1.91(m,1H),1.21-1.16(m,1H),0.92(s,9H)。
实施例37
7-{[6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羰基]-氨基}-3,5-二羟基-庚酸
(MI-319-18)
1H NMR(300MHz,CD3OD),δ7.60(d,1H,J=8.4Hz),7.37(d,1H,J=7.5Hz),7.08-7.06(m,2H),6.87-6.84(m,1H),4.84(d,1H,J=10.2Hz),4.15-4.08(m,1H),4.00-3.96(m,2H),3.80-3.75(m,1H),3.36-3.32(m,2H),2.49-2.43(m,2H),1.65-1.55(m,6H),1.04(m,1H),0.92(s,9H)。
实施例38
6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(2,3,4-三羟基-丁基)-酰胺
(MI-319-19)
1H NMR(300MHz,CD3OD),δ7.83-7.66(m,1H),7.30-7.10(m,3H),6.92-6.88(m,1H),5.30-5.11(m,1H),4.48-4.21(m,1H),4.15-3.95(m,1H),3.64-3.60(m,2H),3.51-3.47(m,2H),3.32-3.24(m,2H),1.95-1.88(m,1H),1.23-1.13(m,1H),0.92-0.82(m,9H)。
实施例39
6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(2-胍基-乙基)-酰胺
(MI-319-20)
1H NMR(300MHz,CD3OD),δ7.69(d,1H,J=8.4Hz),7.39(d,1H,J=6.7Hz),7.14-7.04(m,2H),6.89(d,1H,J=5.8Hz),5.24(d,1H,J=11.3Hz),4.44(d,1H,J=8.0Hz),3.80-3.65(m,2H),3.08-3.00(m,2H),1.89-1.87(m,1H),1.71-1.64(m,2H),1.40-1.33(m,1H),0.91(s,9H)。
实施例40
(MI-319-21)
实施例41
6-氯-4′-(3-氯-4-氟苯基)-5-氟-2′-(2-甲基-丙烯基)-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(3,4-二羟基-丁基)-酰胺
1H NMR(300MHz,CD3Cl),δ8.19-8.11(m,1H),7.28-7.19(m,3H),6.96-6.85(m,2H),6.68(d,1H,J=5.9Hz),4.97(d,1H,J=8.9Hz),4.60-4.55(m,1H),4.30-4.27(m,1H),3.82(d,1H,J=9.2Hz),3.71-3.23(m,4H),1.58-1.54(m,5H),1.46(s,3H)。
实施例42
6-氯-4′-(3-氯-4-氟苯基)-2′-(2,2-二甲基-丙基)-5-氟-2-氧代-1,2-二氢-螺环[吲哚-3,3′-吡咯烷]-5′-羧酸(2-脲基-乙基)-酰胺
1H NMR(300MHz,CD3OD),δ7.71(d,1H,J=8.4Hz),7.43(d,1H,J=6.0Hz),7.15-7.12(m,2H),6.93-6.89(m,1H),5.19(d,1H,J=11.2Hz),4.48(d,1H,J=11.2Hz),4.16-4.13(m,1H),3.32-3.23(m,2H),2.97-2.89(m,2H),1.95-1.90(m,1H),1.57-1.53(m,2H),1.23-1.18(m,1H),0.92(s,9H)。
实施例43
(2′R,3S,4′R,5′R)-6-氯-N-((S)-3,4-二羟基丁基)-5-氟-4′-(3-氟苯基)-2′-新戊基-2-氧代螺环[二氢吲哚-3,3′-吡咯烷]-5′-羧酰胺
(MI-519-1)
1H NMR(300MHz,CD3OD),δ8.43(m,1H),7.72(d,1H,J=8.4Hz),7.30-7.15(m,1H),7.06(d,2H,J=8.88Hz),6.95(d,1H,J=7.8Hz),6.88(d,1H,J=6.0Hz),5.28(d,1H,J=11.3Hz),4.51-4.40(m,1H),4.16(d,J=11.3Hz),3.50-3.20(m,5H),1.93(dd,1H,J=8.3,15.5Hz),1.62-1.36(m,2H),1.23-1.13(m,1H),0.92(s,9H)。
实施例44
(2′R,3S,4′S,5′R)-6-氯-4′-(2,3-二氟苯基)-N-((S)-3,4-二羟基丁基)-5-氟-2′-新戊基-2-氧代螺环[二氢吲哚-3,3′-吡咯烷]-5′-羧酰胺
(MI-519-2)
1H NMR(300MHz,CD3OD),δ8.47(m,1H),7.73(d,1H,J=7.2Hz),7.43-7.30(m,1H),7.23-7.15(m,2H),6.89(d,1H,J=6.0Hz),5.29(d,1H,J=11.1Hz),4.64(d,1H,J=11.4Hz),4.58-4.50(m,1H),3.50-3.20(m,5H),1.93(dd,1H,J=8.3,15.5Hz),1.67-1.36(m,2H),1.23-1.13(m,1H),0.92(s,9H)。
实施例45
(2′R,3S,4′R,5′R)-6-氯-4′-(3,4-二氟苯基)-N-((S)-3,4-二羟基丁基)-5-氟-2′-新戊基-2-氧代螺环[二氢吲哚-3,3′-吡咯烷]-5′-羧酰胺
(MI-519-3)
1H NMR(300MHz,CD3OD),δ8.43(m,1H),7.73-7.69(m,1H),7.27-1.10(m,2H),6.97-6.94(m,1H),6.90(d,1H,J=6.0Hz),5.26-5.23(m,1H),4.49(d,1H,J=7.5Hz),4.16-4.13(m,1H),3.50-3.15(m,5H),1.96-1.88(m,1H),1.62-1.40(m,2H),1.23-1.13(m,1H),0.92(s,9H)。
实施例46
(2′R,3S,4′S,5′R)-6-氯-4′-(2,5-二氟苯基)-N-((S)-3,4-二羟基丁基)-5-氟-2′-新戊基-2-氧代螺环[二氢吲哚-3,3′-吡咯烷]-5′-羧酰胺
(MI-519-5)
1H NMR(300MHz,CD3OD),δ8.49(m,1H),7.71(d,1H,J=7.2Hz),7.45-7.40(m,1H),7.15-7.00(m,2H),6.89(d,1H,J=6.0Hz),5.23(d,1H,J=11.1Hz),4.63(d,1H,J=11.4Hz),4.58-4.50(m,1H),3.50-3.20(m,5H),1.93(dd,1H,J=8.3,15.5Hz),1.67-1.36(m,2H),1.18(dd,1H,J=1.9,15.5Hz),0.92(s,9H)。
实施例47
(2′R,3S,4′S,5′R)-6-氯-N-((S)-3,4-二羟基丁基)-5-氟-4′-(2-氟苯基)-2′-新戊基-2-氧代螺环[二氢吲哚-3,3′-吡咯烷]-5′-羧酰胺
(MI-519-6)
1H NMR(300MHz,CD3OD),δ8.43(m,1H),7.70-7.64(m,2H),7.40-7.18(m,2H),7.01-6.94(m,1H),6.85(d,1H,J=6.0Hz),5.25(d,1H,J=11.3Hz),4.62(d,1H,J=12Hz),4.55-4.52(m,1H),3.50-3.20(m,5H),1.91(dd,1H,J=8.3,15.5Hz),1.62-1.32(m,2H),1.18(dd,1H,J=1.8,15.3Hz),0.92(s,9H)。
实施例48
(2′R,3S,4′R,5′R)-6-氯-N-((S)-3,4-二羟基丁基)-5-氟-4′-(4-氟苯基)-2′-新戊基-2-氧代螺环[二氢吲哚-3,3′-吡咯烷]-5′-羧酰胺
(MI-519-7)
1H NMR(300MHz,CD3OD),δ8.39(m,1H),7.70(d,1H,J=8.5Hz),7.25-7.21(m,2H),7.03-6.96(m,2H),6.87(d,1H,J=6.0Hz),5.26(d,1H,J=11.3Hz),4.48(m,1H,),4.12(d,J=11.4Hz),3.50-3.20(m,5H),1.92(dd,1H,J=8.3,15.5Hz),1.62-1.32(m,2H),1.20(dd,1H,J=2.0,15.3Hz),0.92(s,9H)。
实施例49
细胞生长的抑制
非肽小分子抑制剂优于基于肽的抑制剂的一个主要优点是其较高的细胞渗透性。预期p53-MDM2相互作用的有效的非肽抑制剂通过刺激p53的活性将有效抑制具有野生型形式的p53的癌细胞的细胞生长和分裂。此外,预期它们对具有p53缺失或突变的非功能性形式的p53的癌细胞具有选择性。为了检验这些预测,使用人前列腺癌LNCaP(p53野生型)和PC-3(无p53)细胞系进行了细胞生长测定。检测了本发明化合物的毒性效应。
将细胞以3-4×103个细胞/孔的密度接种于96孔平底细胞培养板并在存在化合物的情况下培养4天。使用WST-8(2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4二磺基苯基)-2H-四唑鎓一钠盐)(Dojindo Molecular Technologies Inc.,Gaithersburg,Maryland)测定用递增浓度的化合物处理后的细胞生长抑制率。WST-8以10%的最终浓度加至每个孔并且所述板在37℃下培养2-3小时。在450nm下,在平板读取器(Molecular Device-TECAN ULTRA)中测量样品的吸光度。通过对比未处理细胞和用化合物处理的细胞的吸光度计算抑制50%细胞生长的化合物的浓度(IC50)。如表2所示,与p53-阴性PC3(p53-negative PC3)细胞相比,本发明的化合物约5倍至约50倍更加有效地抑制p53-阳性LNCaP(p53-positive LNCaP)细胞的细胞生长。
针对HCT116(野生型p53)和HT-29(突变p53)结肠癌细胞系,相似地检测了本发明的化合物。如表2所示,与p53-阴性HCT116细胞相比,大多数所检测的化合物表现出较高的抑制p53-阳性HCT116细胞的细胞生长的效力,效力的最大差异为约25倍。
由于正常细胞也具有野生型p53,发展p53-MDM2相互作用的抑制剂作为新的抗癌药物的潜在担忧是它们可能是非选择性的并且它们杀死癌细胞与杀死正常细胞时具有相等的活性。将在具有野生型p53的正常人前列腺上皮细胞(PrEC)中评估化合物以确定它们是否表现出对癌细胞的良好选择性。
表2
化合物 | IC50±SD(μM)*(Ki±SD)(μM) | LNCaPIC50(μM) | PC3IC50(μM) | HCT116p53WTIC50(μM) | HCT116p53KOIC50(μM) |
MDM2-319 | 0.076(0.0063)0.077(0.006)0.064(0.005)0.0920.1150.1220.130.180.170.160.10 | 0.27380.18390.22910.2289±0.04 | 15.49.081.3511.61±3.3 | 0.71740.61450.24660.52±0.24 | 11.8312.214.2312.75±1.29 |
MDM2-319-1 | 0.1940.072 | 0.26120.3602 | HCT116 | 0.90851.364 | 12.6610.39 |
MDM2-319-2 | 175(16.43)>80 | 3.4743.3784.0053.61±0.3 | 14.3919.6419.5817.87±3.01 | 15.4621.38.50815.08±6.4 | 22.2419.4925.4422.39±2.97 |
MDM2-319-3 | 0.37(0.034)0.450.23 | 1.7581.2410.84721.28±0.4 | 16.6517.4522.1618.75±2.97 | 3.8134.1092.8263.58±0.67 | 13.8424.7816.7218.44±5.67 |
MDM2-319-4 | 0.71(0.066)1.160.46 | 1.4171.2940.89021.21±0.29 | 18.5323.3825.622.5±3.61 | 5.035.8012.4134.41±1.77 | 13.1326.4813.3917.6±7.6 |
MDM2-319-5 | 0.0550.040 | 0.60200.46530.63410.56±0.08 | 9.475.5538.7117.91±2 | 0.99271.2861.5021.23±0.2 | 10.525.398.4038.1±2.5 |
MDM2-319-6 | 0.590.55Flu | 2.5831.2231.9311.91±0.6 | 21.420.8314.1518.7±4 | 5.4527.415.9576.26±1.0 | 14.2916.0614.5814.97±0.9 |
MI-319-7 | 39.33 | 2.171.917 | 39.7434.29 | 8.227.954 | >30>30 |
MI-319-8 | 0.340.53 | 0.96310.89280.66251.46±1.13 | 30.6620.7218.4323.27±6.5 | 4.1144.7322.7383.86±1.02 | 30.9525.4822.6926.3±4.2 |
MI-319-9 | 3.58 | 2.8662.7661.752.46±0.61 | 20.915.5476.0911.12±8.5 | 7.489.1984.6317.1±2.3 | 9.7118.1894.527.47±2.66 |
MI-319-10 | 0.220.26 | 0.77640.82830.44930.68±0.2 | 10.4710.368.0749.63±1.35 | 1.4111.9471.0881.48±0.4 | 11.589.845.4548.9±3.1 |
MI-319-11 | 5.135.395.11 | 2.8463.0784.2193.38±0.73 | 17.2914.7124.2418.7±4.9 | 13.515.8224.8918.4±5.9 | 13.381824.6818.85±5.45 |
MI-319-11-A | 2.241.64 | 0.30780.53130.46240.43±0.11 | 1.7652.7544.0242.84±1.1 | 2.1532.8160.97531.98±0.9 | 3.9662.6274.1823.59±0.84 |
MI-319-12 | 2.302.96 | 1.9742.5711.9312.15±0.35 | 22.3520.8913.3118.85±4.85 | 12.3713.24.3659.97±4.87 | 13.4517.8414.1315.14±2.36 |
MI-319-13 | 5.875.04 | 3.6632.3164.853.6±1.26 | 17.214.4820.2817.32±2.9 | 3.2276.36810.986.85±3.8 | 32.6435.0533.0233.57±1.29 |
MI-319-14 | 2.041.66 | 4.2212.631.9792.94±1.1 | 40.0840.2>30 | 8.0089.2665.7387.67±1.7 | >30>30>30 |
MI-319-15 | 0.350.18 | 4.5224.1256.1134.92±1.05 | >30>30>30 | 12.1312.8913.8912.97±0.88 | >30>30>30 |
MI-319-16 | 0.85(Flu)0.76(Flu) | 24.07 | >30 | >30 | >30 |
MI-319-17 | 0.390.49 | 1.0981.5481.511 | 1422.0223.63 | 2.0963.7923.148 | 25.1322.3325.14 |
MI-319-18 | 3.513.57 | >30>30 | >30>30 | >30>30 | >30>30 |
MI-319-19 | 0.500.49 | 1.2352.3981.2 | 30.68>3041.65 | 2.685.9814.596 | >30>3077.64 |
MI-319-20 | 27.4431.59 | >3066.12 | >3093.54 | >30>100 | |
MI-319-21 | 2.8381.836 | 21.8714.07 | 4.4023.884 | 11.7613.25 |
计算Ki:MDM2[10nM];F-6[1nM];新样品MDM2蛋白质:
Kd:0.88±0.41nM(双曲线方程;使用1nM 6F)
Kd:2.22±0.93nM(Klotz图;使用1nM 6F)
实施例50
MDM2抑制剂对p53和它的靶基因产物MDM2和p21的表达的效应
用检测化合物或0.1%DMSO处理癌细胞24小时。通过胰蛋白酶消化收获细胞,并以pH 7.5的冷磷酸盐缓冲盐溶液(Invitrogen,Carlsbad,CA)洗涤细胞。细胞在冰冷的裂解缓冲液(50mM Tris(pH7.5),150mM NaCl,1mM EDTA(pH 8.0),25mM氟化钠,1%NP-40和0.1%SDS)中裂解30分钟,所述裂解缓冲液含有2mM正钒酸钠、1mM苯甲基磺酰氟和蛋白酶抑制剂混合物(protease inhibitorcocktail)(Roche Applied Science,Indianapolis,IN)。然后,在4℃下细胞提取物以12,000×g离心10分钟以获得澄清的裂解产物。通过Bio-Rad染色评估蛋白质。在4-20%的tris-甘氨酸凝胶(Invitrogen,Carlsbad,CA)上分辨含有35μg蛋白质的细胞裂解产物并且转移到聚偏氟乙烯膜上。通过使用抗p53(Ab-6,OncogeneResearch Products,Boston,MA)、抗MDM2(SMP 14,Santa CruzBiotechnology,Santa Cruz,CA)和抗p21(BD Biosciences,SanDiego,CA)的小鼠单克隆抗体进行转移膜上的蛋白质的免疫检测。使用β-肌动蛋白的抗体(Sigma,St Louis,MO)评估蛋白质负载(protein loading)。当RKO(野生型p53)和HT-29(突变p53)结肠癌细胞系用本发明的化合物处理24小时时,预期所述化合物将仅在表达野生型p53的RKO细胞中诱导p53和它的靶基因产物的积累。
实施例51
由MDM2抑制剂诱导的细胞死亡和凋亡
在6孔皮氏培养皿中,将RKO(野生型p53)和HT-29(突变p53)结肠癌细胞系和CCD-18Co正常结肠成纤维细胞用递增剂量的本发明化合物处理4天。进行台盼蓝染色排除试验以测定所述抑制剂诱导细胞死亡的能力。处理4天后,收获漂浮细胞和粘附细胞并且用0.2%的台盼蓝溶液(Sigma,St Louis,MO)染色。每个处理进行3次,并且计数至少100个细胞。染成蓝色的细胞或形态学不健康的细胞被记为死细胞。为了评估凋亡,通过碘化丙锭(PI)染色来分析用或没用测试抑制剂处理的细胞中的亚二倍体DNA含量。用冷PBS洗涤一次后,细胞在-20℃下用70%的乙醇固定1天。然后,乙醇固定的细胞用PBS洗涤两次,并在暗处在室温下用含有50μg/ml碘化丙锭(PI)和100μg/ml核糖核酸酶A的PBS染色液染色20分钟。通过使用CellQuest软件的流式细胞计进行细胞的获得和亚二倍体DNA含量的分析。预期只有表达野生型p53的癌细胞将经历响应施用所述化合物的凋亡。
实施例52
MDM2抑制剂对结肠癌细胞的细胞周期进程的效应
在RKO(野生型p53)和HT-29(突变p53)结肠癌细胞系和CCD-18Co正常结肠成纤维细胞中,通过确定S-阶段细胞和总DNA含量评估细胞周期进程,其中通过并入溴脱氧尿苷(BrdU)然后用FITC标记的抗BrdU抗体染色确定S-阶段细胞,并且根据生产商的说明书(BDBiosciences,San Jose,CA)通过用7-氨基放线菌素D(7-AAD)染色确定总DNA的含量。简单地说,癌细胞和正常细胞在过夜培养后,用或不用测试化合物处理22小时,然后用10μM BrdU培养额外2个小时。收获细胞,固定并用FITC标记的抗BrdU和7-AAD染色。通过流式细胞计分析细胞周期分布。获得细胞并使用CellQuest软件(BDBiosciences)分析数据。预期,在均表达野生型p53的RKO癌细胞和CCD-18Co正常结肠成纤维细胞中,本发明的化合物将诱导剂量依赖性的S阶段的缺失。还预期,本化合物对表达突变p53的HT-29细胞的细胞周期进程将不具有可评估的效应。
实施例53
使用MDM2抑制剂保护正常细胞不受化学治疗影响
将PrEC正常前列腺上皮细胞接种于6孔板中并且用本发明的化合物培养24小时,然后加入1μM TAXOL(紫杉醇)持续2天。使用台盼蓝测定细胞的存活率。预期数据表示当正常前列腺上皮细胞用本发明的化合物预处理时,细胞被保护免受TAXOL的影响。
尽管现在已经完全描述了本发明,本领域技术人员应理解,在条件、制剂和其他参数的广泛的和等效的范围内,可以进行相同的内容而不影响本发明或其任何实施方案的范围。本文引用的所有的专利、专利申请和出版物的全部内容在此通过引用整体被并入。
Claims (54)
1.一种化合物,其具有式I:
或其药学上可接受的盐或前药,其中:
X是CH、O、N或S,其中如果X是O或S,则R8不存在;
Y是O、S或NR′;
R1、R2、R3、R4、R5、R6和R7独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂环、CO2R′、OCOR′、CONR′R″、NR″COR′、NR′SO2R″、SO2NR′R″、(C=NR′)NR″R′″或NR′R″;或
R7与R5或R6中之一形成芳基、环烷基或杂环基;
R8是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂环、CO2R′、OCOR′、CONR′R″、SO2NR′R″或(C=NR′)NR″R′″;
R9代表6-氯和5-氟基团;并且
每个R′、R″和R′″独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基或杂环;或
R′和R″、或R″和R′″形成环;
其中R3和R4之一是CONRR′,并且R和R′之一是任选取代的环烷基-烷基或单环-杂环烷基或在烷基3-位上不包含羟基的二羟基烷基氨基。
7.如权利要求1所述的化合物,其中R1和R2之一是任选取代的芳基或杂芳基。
8.如权利要求1所述的化合物,其中R1和R2之一是环烷基、直链或支链烷基、酰胺或酯。
9.如权利要求1所述的化合物,其中R5和R6之一是C3-18烷基、芳基或杂芳基。
10.如权利要求1所述的化合物,其具有式X:
或其药学上可接受的盐或前药,其中:
R10是氢;并且
R11是任选取代的环烷基-烷基或单环-杂环烷基或在烷基3-位上不包含羟基的二羟基烷基氨基;
或R10和R11一起形成任选取代的单环-杂环烷基。
11.如权利要求10所述的化合物,其具有式XI-XXVI之一:
或其药学上可接受的盐或前药。
19.如权利要求1所述的化合物,其是
20.一种药物组合物,其包括如权利要求1或18所述的化合物和药学上可接受的载体。
21.一种在细胞中抑制细胞生长和/或分裂,诱导凋亡和/或诱导细胞周期阻滞的方法,其包括用权利要求1或18所述的化合物接触所述细胞。
22.一种使细胞对其它药剂敏感的方法,其包括用权利要求1或18所述的化合物接触所述细胞。
23.如权利要求22所述的方法,其进一步包括用其它药剂接触所述细胞。
24.如权利要求23所述的方法,其中所述其它药剂是化疗剂。
25.如权利要求23所述的方法,其中所述其它药剂是放射。
26.一种治疗、改善或预防动物的病症的方法,其包括向所述动物施用治疗有效量的权利要求1或18所述的化合物。
27.如权利要求26所述的方法,其进一步包括施用其它药剂。
28.如权利要求27所述的方法,其中所述其它药剂是化疗剂。
29.如权利要求27所述的方法,其中所述其它药剂是放射。
30.如权利要求26所述的方法,其中所述病症是过度增殖疾病。
31.如权利要求30所述的方法,其中所述过度增殖疾病是癌症。
32.如权利要求27所述的方法,其中所述权利要求1所述的化合物在所述其它药剂之前施用。
33.如权利要求27所述的方法,其中所述权利要求1所述的化合物在所述其它药剂之后施用。
34.如权利要求27所述的方法,其中所述权利要求1所述的化合物与所述其它药剂同时施用。
35.一种在细胞中抑制p53或p53相关蛋白质与MDM2或MDM2相关蛋白质之间的相互作用的方法,其包括将所述细胞暴露于权利要求1或18所述的化合物。
36.一种抑制含有功能性p53或p53相关蛋白质的过度增殖细胞的生长的方法,其包括将所述细胞暴露于权利要求1或18所述的化合物。
37.一种在动物中治疗、改善或预防以功能性p53或p53相关蛋白质的表达为特征的过度增殖疾病的方法,其包括向所述动物施用治疗有效量的权利要求1或18所述的化合物。
38.一种使正常细胞对化疗剂或化疗治疗耐受的方法,其包括用权利要求1或18所述的化合物接触所述细胞。
39.如权利要求38所述的方法,其中所述正常细胞包含野生型p53。
40.一种保护患有过度增殖疾病的动物中正常细胞免受化疗剂或化疗治疗的毒副作用的方法,其包括向所述动物施用权利要求1或18所述的化合物。
41.如权利要求40所述的方法,其中所述正常细胞包含野生型p53。
42.如权利要求40所述的方法,其中所述过度增殖疾病是癌症。
43.如权利要求42所述的方法,其中所述癌症包括p53的突变或缺失。
44.一种治疗、改善或预防由施用化疗剂或化疗治疗引起的病症或疾患的方法,其包括向经受用化疗剂或化疗治疗来治疗的动物共施用权利要求1或18所述的化合物。
45.如权利要求44所述的方法,其中所述病症或疾患是粘膜炎、口腔炎、口腔干燥、肠胃病症或脱发。
46.如权利要求44所述的方法,其中所述权利要求1或18所述的化合物在施用所述化疗剂或化疗治疗前施用于所述动物。
47.一种药盒,其包括权利要求1或18所述的化合物。
48.如权利要求47所述的药盒,其进一步包括向动物施用所述化合物的说明书。
49.如权利要求47所述的药盒,其进一步包括其它药剂。
50.如权利要求49所述的药盒,其中所述其它药剂是化疗剂。
51.如权利要求48所述的药盒,其中所述说明书是为了向患有过度增殖疾病的动物施用所述化合物。
52.如权利要求51所述的药盒,其中所述过度增殖疾病是癌症。
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BRPI0715506A2 (pt) | 2014-07-08 |
WO2008036168A3 (en) | 2008-11-27 |
EA016145B1 (ru) | 2012-02-28 |
EP2063887A4 (en) | 2010-09-22 |
AU2007297823A1 (en) | 2008-03-27 |
JP5399904B2 (ja) | 2014-01-29 |
CN101528223B (zh) | 2013-05-01 |
AU2007297823B2 (en) | 2012-04-19 |
EA200900360A1 (ru) | 2009-06-30 |
CA2661354A1 (en) | 2008-03-27 |
ZA200901224B (en) | 2010-05-26 |
SG174107A1 (en) | 2011-09-29 |
EP2063887A2 (en) | 2009-06-03 |
MX2009002306A (es) | 2009-05-20 |
WO2008036168A2 (en) | 2008-03-27 |
JP2010502620A (ja) | 2010-01-28 |
CA2661354C (en) | 2012-12-18 |
EP2063887B1 (en) | 2013-05-29 |
ES2425965T3 (es) | 2013-10-18 |
NZ575193A (en) | 2011-12-22 |
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