CN105616391A - 使用异紫苏醇的方法和装置 - Google Patents
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- CN105616391A CN105616391A CN201610009982.XA CN201610009982A CN105616391A CN 105616391 A CN105616391 A CN 105616391A CN 201610009982 A CN201610009982 A CN 201610009982A CN 105616391 A CN105616391 A CN 105616391A
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Abstract
本发明提供一种治疗疾病如癌症的方法,其包括向患者施用治疗有效量的单萜或倍半萜的异构体或类似物(或其衍生物)如异紫苏醇的步骤。本发明还提供一种治疗疾病的方法,其包括向患者施用治疗有效量的单萜或倍半萜的异构体或类似物的衍生物如异紫苏醇氨基甲酸酯的步骤。所述衍生物可以是与治疗剂如化疗剂偶联的异紫苏醇。施用途径可以变化,包括吸入、鼻内、口服、经皮、静脉内、皮下或肌内注射。
Description
本申请是申请日为2011年12月16日、申请号为201180066892.X、发明名称为“使用异紫苏醇的方法和装置”的发明专利申请的分案申请。
相关申请的交叉引用
本申请要求美国临时申请第61/424,332号(2010年12月17日提交)和第61/436,365号(2011年1月26日提交)的优先权。这些申请以其全部内容通过引用结合于此。
技术领域
本发明涉及异紫苏醇(iso-POH)和异紫苏醇衍生物。异紫苏醇包括紫苏醇的任何异构体或类似物。本发明进一步涉及使用异紫苏醇和异紫苏醇衍生物如异紫苏醇氨基甲酸酯来治疗癌症的方法。
背景技术
恶性神经胶质瘤,中枢神经系统(CNS)癌症的最常见形式,当前被认为是基本上不能治愈的。在各种恶性神经胶质瘤之中,间变性星形细胞瘤(III期)和多形性成胶质细胞瘤(GBM;IV期)具有特别差的预后,这是由于它们的侵袭性生长和对当前可用疗法的抗性。恶性神经胶质瘤的现有标准治疗由外科手术、电离辐射和化疗组成。尽管医学上有最新的进展,但过去的50年在恶性神经胶质瘤的预后上并未看到任何明显改善。Wen等,Malignantgliomasinadults.NewEnglandJMed.359:492-507,2008.Stupp等,Radiotherapyplusconcomitantandadjuvanttemozolomideforglioblastoma.NewEnglandJ Med.352:987-996,2005。
肿瘤(包括恶性神经胶质瘤)对各种类型化疗剂的较差反应性通常是由于内在的抗药性。另外,初始反应良好的肿瘤的获得性抗性和不希望的副作用是经常阻碍使用化疗剂进行长期治疗的其它问题。因此,已经制备了化疗剂的各种类似物以试图克服这些问题。所述类似物包括作为至少两种现有治疗剂的杂化分子(hybridmolecules)的新型治疗剂。例如,顺铂与细胞毒性共药(codrug)偶联,或与生物活性穿梭组分如卟啉、胆汁酸、激素或加快跨膜输送或细胞内药物积聚的调节剂偶联。在一组人肿瘤细胞系上测试了用萜烯醇酯化的(6-氨基甲基烟酸酯)二氯合铂(II)((6-Aminomethylnicotinate)dichloridoplatinum)复合物。这些复合物中的萜烯基部分似乎实现了跨膜穿梭功能,并且增加了这些偶联物摄取进入各种肿瘤细胞系中的速率和程度。Schobert等,MonoterpenesasDrugShuttles:Cytotoxic(6-minomethylnicotinate)dichloridoplatinum(II)ComplexeswithPotentialToOvercomeCisplatinResistance.J.Med.Chem.2007,50,1288-1293。
紫苏醇(POH),一种天然存在的单萜,已经被认为是抗多种癌症的有效药剂,包括CNS癌症、乳腺癌、胰腺癌、肺癌、黑素瘤和结肠癌。Gould,M.Cancerchemopreventionandtherapybymonoterpenes.EnvironHealthPerspect.1997June;105(Suppl4):977-979。已经制备了含紫苏醇和类视黄醇的杂化分子以增加诱导细胞凋亡的活性。Das等,Designandsynthesisofpotentialnewapoptosisagents:hybridcompoundscontainingperillylalcoholandnewconstrainedretinoids.TetrahedronLetters2010,51,1462-1466。
为了改善紫苏醇及其衍生物的性能,需要制备包括与其它治疗剂偶联的异紫苏醇的异构体或类似物,并在癌症如恶性神经胶质瘤及其它脑疾病如帕金森病和阿尔茨海默病的治疗中使用该物质。这些化合物可以单独施用,或与包括放疗、标准化疗和外科手术的其它治疗方法联合施用。所述施用还可以通过包括鼻内、经口、用于肺部递送的口腔气管和经皮的各种途径。
发明内容
本发明提供一种治疗哺乳动物的疾病的方法,其包括向所述哺乳动物递送治疗有效量的异紫苏醇的步骤。本发明还提供一种治疗哺乳动物的疾病的方法,其包括向所述哺乳动物递送治疗有效量的异紫苏醇氨基甲酸酯的步骤。所述方法可进一步包括用放射治疗所述哺乳动物的步骤,和/或进一步包括向所述哺乳动物递送化疗剂的步骤。所治疗的疾病可以是癌症,包括神经系统的肿瘤如胶质母细胞瘤。施用途径包括吸入、鼻内、口服、静脉内、皮下或肌内施用。
本发明进一步提供一种包含异紫苏醇氨基甲酸酯的药物组合物。所述异紫苏醇氨基甲酸酯可以是与治疗剂如化疗剂偶联的异紫苏醇。可用于本发明的所述化疗剂包括DNA烷化剂、拓扑异构酶抑制剂、内质网应激诱导剂、铂化合物、抗代谢物、酶抑制剂和受体拮抗剂。在某些实施方式中,所述治疗剂是二甲基塞来昔布(DMC)、替莫唑胺(TMZ)或咯利普兰。本发明提供一种包含与治疗剂共混或联合配制的异紫苏醇的药物组合物。本发明的所述药物组合物可以在放射之前、期间或之后施用。所述药物组合物可以在施用化疗剂之前、期间或之后施用。
本发明还提供一种制备异紫苏醇氨基甲酸酯的方法,其包括使第一反应物异紫苏基氯甲酸酯与第二反应物反应的步骤,所述第二反应物可以是二甲基塞来昔布(DMC)、替莫唑胺(TMZ)或咯利普兰。当所述第二反应物是二甲基塞来昔布时,该反应可以在丙酮和碳酸钾催化剂存在下进行。当所述第二反应物是咯利普兰时,该反应可以在四氢呋喃和正丁基锂存在下进行。还可以通过使异紫苏醇与光气反应来制备所述异紫苏基氯甲酸酯。
附图简要说明
图1显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死LN229人神经胶质瘤细胞的效力。
图2显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死U251人神经胶质瘤细胞的效力。
图3显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死A172人神经胶质瘤细胞的效力。
图4A和4B显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死A172人神经胶质瘤细胞(对替莫唑胺敏感的)(图4A)和替莫唑胺抗性的A172细胞(图4B)的效力。SGP-527-155是纯化至GLP质量(具有约98.7%的GC相对面积纯度(曲线下面积))的POH。SGP-561-79P和SGF-561-65P是两个不同批次的异-POH。SGP-561-79P比SGP-561-65P更纯,且其细节如下。
*NA:未分析
注解:由于所述样品经GC分析降解,我们通过HPLC分析了异-POH,并将其与作为wt%分析的标准物的Sigma-AldrichPOH比较。SigmaPOH是购自SigmaChemicals的POH。
图5A和5B显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死U251人神经胶质瘤细胞(对替莫唑胺敏感的)(图5A)和替莫唑胺抗性的U251细胞(图5B)的效力。
图6A和6B显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死LN229人神经胶质瘤细胞(对替莫唑胺敏感的)(图6A)和替莫唑胺抗性的LN229细胞(图6B)的效力。
图7A和7B显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死U87人神经胶质瘤细胞(对替莫唑胺敏感的)(图7A)和替莫唑胺抗性的U87细胞(图7B)的效力。
图8A、8B和8C显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死U251人神经胶质瘤细胞(对替莫唑胺敏感的)(图8A)和替莫唑胺抗性的U251细胞(图8B和8C)的效力。U251-TR1和U251-TR2指的是两种替莫唑胺抗性的U251细胞系。SigmaPOH是购自SigmaChemicals的POH。GLPPOH是纯化至GLP质量(具有约98.7%的GC相对面积纯度(曲线下面积))的POH。异-POH65和异-POH79是不同批次的异-POH(参见以上图4A和4B的详述)。
图9显示MTT细胞毒性试验的结果,表明POH和异-POH杀死USC04胶质母细胞瘤癌症干细胞系的效力。
图10A和10B显示在TMZ敏感的U251细胞和TMZ抗性的U251(U251-TR1、U251-TR2)细胞中用SigmaPOH(1.5mM;纯度为约95%(AUC))或超纯POH(“GLP-POH”,1.5mM;纯度为约98.7%(AUC))处理U251神经胶质瘤细胞18小时后进行的蛋白质印迹,其表明增加了葡萄糖-调节蛋白78(GRP-78)和细胞凋亡标志物CHOP的表达,显示处理后增强了内质网(ER)应激。在相同条件下,异-POH(异-POH65、异-POH79)也增强了ER应激(图10B)。
图11显示用500μMSigmaPOH、GLPPOH或异-POH(异POH65、异POH79)处理U251神经胶质瘤细胞24小时之后进行的蛋白质印迹,其表明所有处理均减少了Kras表达。
发明详述
本发明提供使用异紫苏醇或异紫苏醇的衍生物治疗疾病如癌症的方法。施用途径包括吸入、鼻内、口服、经皮、静脉内、皮下和肌内注射。
在本方法中,向患者施用治疗有效量的单萜或倍半萜的异构体或类似物如异紫苏醇。本发明还提供一种治疗疾病的方法,其包括向患者施用治疗有效量的单萜或倍半萜的异构体或类似物的衍生物如异紫苏醇氨基甲酸酯的步骤。所述衍生物可以是与治疗剂如化疗剂偶联的异紫苏醇。
例如,所述单萜或倍半萜的异构体或类似物可以是异紫苏醇(异-POH)。异紫苏醇包括紫苏醇的任何异构体或类似物。在一个实施方式中,所述异紫苏醇是(4-异亚丙基环己-1-烯基)甲醇。异紫苏醇的其它实例包括但不限于,(4-异丙基环己-1,3-二烯基)甲醇、(4-异丙基环己-1,4-二烯基)甲醇、(4-异丙基苯基)甲醇和(4-异丙烯基苯基)甲醇。
示例性的异紫苏醇,(4-异亚丙基环己-1-烯基)甲醇,显示如下:
本发明所述化合物可用于治疗神经系统癌症,如恶性神经胶质瘤(例如星形细胞瘤、间变性星形细胞瘤、多形性胶质母细胞瘤)、视网膜母细胞瘤、毛细胞性星形细胞瘤(I期)、脑膜瘤、转移性脑肿瘤、成神经细胞瘤、垂体腺瘤、颅底脑膜瘤和颅底癌症。本发明还提供治疗CNS(中枢神经系统)紊乱的方法,所述CNS紊乱包括但不限于,诸如阿尔茨海默病的原发性退行性神经系统紊乱、帕金森病、心理疾病、精神病和抑郁症。
本发明还包括单萜或倍半萜的异构体或类似物的衍生物如异紫苏醇衍生物。例如,所述异紫苏醇衍生物可以是异紫苏醇氨基甲酸酯、酯或醚。单萜或倍半萜的异构体或类似物的衍生物可以是与治疗剂如化疗剂偶联的单萜或倍半萜的异构体或类似物。所述异紫苏醇衍生物可以是与治疗剂如化疗剂偶联的异紫苏醇。
因此,本发明的化合物包括单萜或倍半萜的异构体或类似物、和单萜或倍半萜的异构体或类似物的衍生物。所述单萜或倍半萜的异构体或类似物(或所述单萜或倍半萜的异构体或类似物的衍生物)可配制成药物组合物,其中所述单萜或倍半萜的异构体或类似物(或所述单萜或倍半萜的异构体或类似物的衍生物)以约0.01%(w/w)至约100%(w/w),约0.1%(w/w)至约80%(w/w),约1%(w/w)至约70%(w/w),约10%(w/w)至约60%(w/w),或约0.1%(w/w)至约20%(w/w)的量存在。本发明的组合物可以单独施用,或可以与放射或其它药剂(例如化疗剂)一起施用,以治疗疾病如癌症。治疗可以是相继的,其中单萜或倍半萜的异构体或类似物(或单萜或倍半萜的异构体或类似物的衍生物)在施用其它药剂之前或之后施用。例如,异紫苏醇(或异紫苏醇氨基甲酸酯、酯或醚)可用于使癌症患者对放射或化疗敏感。或者,可同时施用多种药剂。施用途径可以变化,并可包括吸入、鼻内、口服、经皮、静脉内、皮下或肌内注射。
本发明的组合物可含有一种或多种类型的单萜或倍半萜的异构体或类似物(或所述单萜或倍半萜的异构体或类似物的衍生物)。单萜包括由两个异戊二烯单元组成的萜烯。单萜可以是线性的(非环状的)或含有环。类单萜的衍生物也包括在本发明中。可以通过单萜的生物化学修饰如氧化或重排来制备类单萜。单萜和类单萜的实例包括紫苏醇(S(-))和(R(+))、罗勒烯、月桂烯、香叶醇、柠檬醛、香茅醇、香茅醛、芳樟醇、蒎烯、萜品醇、萜品烯、柠檬烯、松油烯、水芹烯、萜品油烯、萜品烯-4-醇(或茶树油)、蒎烯、萜品醇、萜品烯;诸如对-伞花烃的类萜,其源于单环萜烯如薄荷醇、百里酚和香芹酚;双环类单萜如樟脑、冰片和桉树脑。
单萜可以通过碳骨架的结构来区分,且可以被分组为非环状的单萜(例如月桂烯、(Z)-和(E)-罗勒烯、芳樟醇、香叶醇、橙花醇、香茅醇、月桂烯醇、香叶醛、柠檬醛a、橙花醛、柠檬醛b、香茅醛等)、单环单萜(例如柠檬烯、松油烯、水芹烯、萜品油烯、薄荷醇、香芹醇等)、双环单萜(例如蒎烯、桃金娘烯醇、桃金娘烯醛、马鞭草烷醇、马鞭烷酮、松香芹醇、蒈烯、桧烯、莰烯、侧柏烯等)和三环单萜(例如三环烯)。参见EncyclopediaofChemical Technology,第4版,23卷,834-835页。
本发明的倍半萜包括由三个异戊二烯单元组成的萜烯。倍半萜可以是线性的(非环状的)或含有环。类倍半萜的衍生物也包括在本发明中。可以通过倍半萜的生物化学修饰如氧化或重排来制备类倍半萜。倍半萜的实例包括法尼醇、法尼醛、法尼酸(famesylicacid)和橙花叔醇。美国临时申请第61/310,231号(2010年3月3日提交)、第61/377,747号(2010年8月27日提交)、第61/471,402号(2011年4月4日提交)和第61/562,105号(2011年11月21日提交)。PCT申请号PCT/US2011/027051(2011年3月3日提交)和PCT/US2011/049392(2011年8月26日提交)。美国申请第13/040,059号(2011年3月3日提交)。所有这些申请以其全部内容通过引用结合于此。
单萜或倍半萜的异构体或类似物的衍生物包括但不限于,所述单萜(或倍半萜)的氨基甲酸酯、酯、醚、醇和醛。醇可以衍生成氨基甲酸酯、酯、醚、醛或酸。
氨基甲酸酯是指共有基于通过氧和氮侧接的羰基的官能团的一类化合物。
R1、R2和R3可以是可被取代的基团诸如烷基、芳基等。所述氮和氧上的R基团可以形成环。R1-OH可以是单萜例如POH。R2-N-R3部分可以是治疗剂。
可通过使异氰酸酯和醇反应或通过使氯甲酸酯与胺反应来合成氨基甲酸酯。可通过利用光气或光气等同物的反应来合成氨基甲酸酯。例如,可通过使光气气体、双光气或固体光气前体如三光气与两个胺或与一个胺和一个醇反应来合成氨基甲酸酯。也可以由脲中间体与醇的反应来制备氨基甲酸酯(也称为脲烷)。碳酸二甲基酯和碳酸二苯酯也用于制备氨基甲酸酯。或者,可通过醇和/或胺前体与酯取代的碳酸二芳基酯如碳酸二甲基水杨基酯(BMSC)的反应来合成氨基甲酸酯。美国专利公开20100113819号。
氨基甲酸酯可通过以下途径合成:
适合的反应溶剂包括但不限于,四氢呋喃、二氯甲烷、二氯乙烷、丙酮和二异丙醚。该反应可在约-70℃至约80℃或约-65℃至约50℃的温度下进行。异紫苏基氯甲酸酯与底物R-NH2的摩尔比可以是约1:1至约2:1,约1:1至约1.5:1,约2:1至约1:1,或约1.05:1至约1.1:1。适合的碱包括但不限于,有机碱如三乙胺、碳酸钾、Ν,Ν'-二异丙基乙胺、丁基锂和叔丁醇钾。
或者,氨基甲酸酯可通过以下途径合成:
适合的反应溶剂包括但不限于,二氯甲烷、二氯乙烷、甲苯、二异丙醚和四氢呋喃。该反应可在约25℃至约110℃、或约30℃至约80℃或约50℃的温度下进行。异紫苏醇与底物R-N=C=O的摩尔比可以是约1:1至约2:1,约1:1至约1.5:1,约2:1至约1:1,或约1.05:1至约1.1:1。
所述单萜或倍半萜的异构体或类似物的醇的酯可以衍生自无机酸或有机酸。无机酸包括但不限于,磷酸、硫酸和硝酸。有机酸包括但不限于,羧酸如苯甲酸、脂肪酸、乙酸和丙酸,以及带有至少一个羧酸官能团的任何治疗剂。所述醇的酯的实例包括但不限于,羧酸酯(如苯甲酸酯、脂肪酸酯(例如,棕榈酸酯、亚油酸酯、硬脂酸酯、丁酰基酯和油酸酯)、乙酸酯、丙酸酯(或丙烷酸酯)和甲酸酯)、磷酸酯、硫酸酯和氨基甲酸酯(例如,Ν,Ν-二甲氨基羰基酯)。维基百科-酯。由URL:http://en.wikipedia.org/wiki/Ester得到。
所述异紫苏醇的衍生物包括异紫苏醇氨基甲酸酯、异紫苏醇酯、异紫苏醛、异紫苏酸、异紫苏醛衍生物和异紫苏酸酯。异紫苏醇的衍生物还可以包括其氧化性的和亲核/亲电加成衍生物。异紫苏醇的衍生物的少数实例报道在化学文献中。参见美国专利第5,994,598号和日本专利第07048264A号。
在某些实施方式中,可通过包括使第一反应物异紫苏基氯甲酸酯与第二反应物例如二甲基塞来昔布(DMC)、替莫唑胺(TMZ)或咯利普兰反应的步骤的方法来合成异-POH氨基甲酸酯。该反应可在四氢呋喃和碱如正丁基锂存在下进行。可通过使异-POH与光气反应来制备异紫苏基氯甲酸酯。例如,可通过使替莫唑胺与草酰氯反应,再与异紫苏醇反应来合成通过氨基甲酸酯键与替莫唑胺偶联的异-POH。该反应可在1,2-二氯乙烷存在下进行。
本发明涵盖的异-POH氨基甲酸酯包括但不限于,(3-甲基4-氧代-3,4-二氢咪唑并[5,1-d][1,2,3,5]四嗪-8-羰基)-氨基甲酸-4-异亚丙基环己-1-烯基甲基酯、4-(3-环戊基氧基-4-甲氧基苯基)-2-氧代-吡咯烷-1-羧酸4-异亚丙基环己-1-烯基甲基酯、4-(双-N,N'-4-异亚丙基环己-1-烯基甲氧基羰基[5-(2,5-二甲基苯基)-3-三氟甲基吡唑-1-基]苯磺酰胺。生成这些化合物的化学反应的细节描述在以下实施例中。
在某些实施方式中,异紫苏醇衍生物可以是异紫苏醇脂肪酸酯,如异-POH的棕榈酰基酯和异-POH的亚油酰基酯。
单萜或倍半萜的异构体或类似物的衍生物可以是与治疗剂偶联的单萜或倍半萜的异构体或类似物。本发明涵盖的偶联物是具有通过化学连接基团共价连接至治疗剂的单萜或倍半萜的异构体或类似物的分子。在偶联物中,单萜或倍半萜的异构体或类似物与治疗剂的摩尔比可以是1:1、1:2、1:3、1:4、2:1、3:1、4:1或任何其它适合的摩尔比。单萜或倍半萜的异构体或类似物和治疗剂可通过氨基甲酸酯键、酯键、醚键或任何其它适合的化学官能团共价连接。当所述单萜或倍半萜的异构体或类似物与所述治疗剂通过氨基甲酸酯键偶联时,所述治疗剂可以是带有至少一个羧酸官能团的任何药剂或带有至少一个胺官能团的任何药剂。在具体实例中,异紫苏醇偶联物是通过化学连接基团共价连接化疗剂的异紫苏醇。
根据本发明,可与单萜或倍半萜的异构体或类似物偶联的治疗剂包括但不限于,化疗剂、用于治疗CNS紊乱(包括但不限于,原发性退行性神经系统紊乱诸如阿尔茨海默病、帕金森病、多发性硬化症、注意缺陷多动障碍或ADHD、心理疾病、精神病和抑郁症)的治疗剂、免疫治疗剂、血管生成抑制剂和抗高血压剂。可与单萜或倍半萜偶联的抗癌剂可以具有一项或多项以下对癌细胞或受试者的效应:细胞死亡;减少的细胞增殖;减少的细胞数量;细胞生长的抑制;细胞凋亡;坏死;有丝分裂崩溃;细胞周期停滞;减小的细胞大小;减少的细胞分裂;降低的细胞存活率;降低的细胞代谢;细胞损害或细胞毒性的标志物;细胞损害或细胞毒性的间接指示如肿瘤收缩;提高的受试者存活率;或与不希望有的、不需要的或异常的细胞增殖有关的标志物的消失。美国专利公开第20080275057号。
本发明还涵盖单萜或倍半萜的异构体或类似物与至少一种治疗剂的共混物和/或联合配制剂(coformulations)。
化疗剂包括但不限于,DNA烷化剂、拓扑异构酶抑制剂、内质网应激诱导剂、铂化合物、抗代谢物、长春花生物碱类(vincalkaloids)、紫杉烷类、埃博霉素、酶抑制剂、受体拮抗剂、酪氨酸激酶抑制剂、硼放射致敏剂(即万珂)和化疗联合疗法。
DNA烷化剂的非限制性实例是氮芥类如环磷酰胺(异环磷酰胺、曲磷胺)、苯丁酸氮芥(美法仑、松龙苯芥)、苯达莫司汀、尿嘧啶氮芥和雌氮芥;亚硝基脲类如卡莫司汀(BCNU)、洛莫司汀(司莫司汀)、福莫司汀、尼莫司汀、雷莫司汀和链脲霉素;烷基磺酸酯类如白消安(甘露舒凡、苏消安);氮丙啶类如卡波醌、三乙撑亚胺苯醌、三亚乙基蜜胺;肼类(甲基苄肼);三氮烯类如氮烯咪胺和替莫唑胺;六甲蜜胺和二溴甘露醇。
拓扑异构酶I抑制剂的非限制性实例包括喜树碱衍生物,包括如PommierY.(2006)Nat.Rev.Cancer6(10):789-802和美国专利公开200510250854号中描述的SN-38、APC、NPC、喜树碱、拓扑替康、依喜替康甲磺酸盐、9-硝基喜树碱、9-氨基喜树碱、勒托替康、鲁比替康、silatecan、吉马替康(gimatecan)、二氟替康(diflomotecan)、依喜替康(extatecan)、BN-80927、DX-8951f和MAG-CPT;原小檗碱生物碱及其衍生物包括如Li等.(2000)Biochemistry39(24):7107-7116和Gatto等.(1996)CancerRes.15(12):2795-2800中描述的小檗红碱和甲氧檗因;菲咯啉衍生物包括如Makhey等.(2003)Bioorg.Med.Chem.11(8):1809-1820中描述的苯并[i]菲啶、两面针碱和花椒宁碱(fagaronine);如Xu(1998)Biochemistry37(10):3558-3566中描述的Terbenzimidazole及其衍生物;和蒽环类化合物衍生物包括如Foglesong等.(1992)Cancer Chemother.Pharmacol.30(2):123-125,Crow等.(1994)J.Med.Chem.37(19):3191-3194和Crespi等.(1986)Biochem.Biophys.Res.Commun.136(2):521-8描述的阿霉素、柔红霉素和米托蒽醌。拓扑异构酶II抑制剂包括但不限于依托泊苷和替尼泊苷。拓扑异构酶I和II双重抑制剂包括但不限于,如Denny和Baguley(2003)Curr.Top.Med.Chem.3(3):339-353中描述的圣特平(Saintopin)和其它萘并萘二酮(Naphthecenediones)、DACA和其它吖啶-4-羧酰胺、茚托利辛和其它苯并吡啶并吲哚、TAS-I03和其它7H-茚并[2,1-c]喹啉-7-酮类、吡唑啉吖啶(pyrazoloacridine)、XR11576和其它苯并吩嗪类、XR5944和其它二聚化合物、7-氧代-7H-二苯并[f,ij]异喹啉类和7-氧代-7H-苯并[e]嘧啶类和蒽-氨基酸偶联物。一些药剂抑制拓扑异构酶II并具有DNA嵌入活性,例如但不限于,蒽环类化合物(阿柔比星、柔红霉素、阿霉素、表柔比星、伊达比星、氨柔比星、吡柔比星、戊柔比星、佐柔比星)和蒽二酮类(米托蒽醌和匹杉琼)。
内质网应激诱导剂的实例包括但不限于,二甲基-塞来昔布(DMC)、奈非那韦、塞来昔布和硼放射致敏剂(即万珂(硼替佐米))。
铂基化合物是DNA烷化剂的亚类。此类药剂的非限制性实例包括顺铂、奈达铂、奥沙利铂、四硝酸三铂、赛特铂、阿罗铂(Aroplatin)、洛铂和JM-216。(参见McKeage等.(1997)J.Clin.Oncol.201:1232-1237,并且一般说来,参见CHEMOTHERAPYFORGYNECOLOGICALNEOPLASM,CURRENTTHERAPYANDNOVELAPPROACHES,SeriesBasicandClinicalOncology,Angioli等编辑,2004)。
“FOLFOX”是用于治疗结肠直肠癌的一种联合治疗类型的缩写。它包括5-FU、奥沙利铂和甲酰四氢叶酸。与此治疗有关的信息可以在国家癌症研究所的网站(cancer.gov)上得到,最后一次访问于2008年1月16日。
“FOLFOX/BV”是用于治疗结肠直肠癌的一种联合治疗类型的缩写。该治疗包括5-FU、奥沙利铂、甲酰四氢叶酸和贝伐单抗。此外,“XELOX/BV”是用于治疗结肠直肠癌的另一联合疗法,其包括被称为卡培他滨(希罗达)的5-FU的前药与奥沙利铂和贝伐单抗的组合。与这些治疗有关的信息可以从国家癌症研究所的网站(cancer.gov)上或国家综合癌症网络的网站(nccn.org)上得到,最后一次访问于2008年5月27日。
抗代谢物药剂的非限制性实例包括基于叶酸的药剂,即二氢叶酸还原酶抑制剂,如氨蝶呤、氨甲喋呤和培美曲塞;胸苷酸合酶抑制剂,如雷替曲塞、培美曲塞;基于嘌呤的药剂,即腺苷脱氨酶抑制剂如喷司他丁、硫嘌呤如硫鸟嘌呤和巯基嘌呤,卤化/核苷酸还原酶抑制剂,如克拉屈滨、氯法拉滨、氟达拉滨,或鸟嘌呤/鸟苷:硫嘌呤如硫鸟嘌呤;或基于嘧啶的药剂,即胞嘧啶/胞苷:低甲基化剂如阿扎胞苷和地西他滨,DNA聚合酶抑制剂如阿糖胞苷,核糖核苷酸还原酶抑制剂诸如吉西他滨,或胸腺嘧啶/胸苷:胸苷酸合酶抑制剂如氟尿嘧啶(5-FU)。5-FU的等同物包括其前药、类似物和衍生物,如例如在Papamicheal(1999)TheOncologist4:478-487中所描述的5'-脱氧-5-氟尿苷(去氧氟尿苷)、1-四氢呋喃基-5-氟尿嘧啶(呋氟脲嘧啶)、卡培他滨(希罗达)、S-I(MBMS-247616,由替加氟和两种调节剂,5-氯-2,4-二羟基吡啶和氧嗪酸钾组成)、雷替曲噻(拓优得)、诺拉曲特(诺拉曲塞(Thymitaq),AG337)、LY231514和ZD9331。
长春花生物碱类的实例包括但不限于长春花碱、长春新碱、长春氟宁、长春地辛和长春瑞滨。
紫杉烷类的实例包括但不限于多西他赛、莱龙泰素(Larotaxel)、奥他赛(Ortataxel)、紫杉醇和替司他赛(Tesetaxel)。埃博霉素的实例是伊沙匹隆(iabepilone)。
酶抑制剂的实例包括但不限于,法尼基转移酶抑制剂(替吡法尼(tipifamib);CDK抑制剂(阿伏昔地(Alvocidib)、塞利西利(Seliciclib));蛋白酶体抑制剂(硼替佐米);磷酸二酯酶抑制剂(阿那格雷;咯利普兰);IMP脱氢酶抑制剂(噻唑呋林);和脂氧合酶抑制剂(马索罗酚)。受体拮抗剂的实例包括但不限于ERA(阿曲生坦);类视黄醇X受体(蓓萨罗丁);和性类固醇(睾内酯)。
酪氨酸激酶抑制剂的实例包括但不限于,ErbB:HER1/EGFR的抑制剂(埃罗替尼、吉非替尼、拉帕替尼、凡德他尼、舒尼替尼、来那替尼(Neratinib));HER2/neu的抑制剂(拉帕替尼、来那替尼);第III类RTK:C-kit的抑制剂(阿西替尼、舒尼替尼、索拉非尼)、FLT3抑制剂(来他替尼(Lestaurtinib))、PDGFR抑制剂(阿西替尼、舒尼替尼、索拉非尼);和VEGFR抑制剂(凡德他尼、司马沙尼、西地尼布、阿西替尼、索拉非尼);bcr-abl抑制剂(伊马替尼、尼罗替尼、达沙替尼);Src抑制剂(博舒替尼)和Janus激酶2抑制剂(来他替尼)。
“拉帕替尼”是EGFR和erbB-2双重抑制剂。拉帕替尼已经在许多临床试验中作为抗癌单一疗法以及与曲妥珠单抗、卡培他滨、来曲唑、紫杉醇和FOLFIRI(伊立替康、5-氟尿嘧啶和甲酰四氢叶酸)结合进行了研究。目前正对转移性乳房癌、头颈癌、肺癌、胃癌、肾癌和膀胱癌的口服治疗进行III期测试。
拉帕替尼的化学等同物是作为酪氨酸激酶抑制剂(TKI)或者HER-1抑制剂或HER-2抑制剂的小分子或化合物。已经发现几种TKI具有有效的抗癌活性并已经得到批准或在临床试验中。这样的实例包括但不限于,Zactima(ZD6474)、易瑞沙(吉非替尼)、伊马替尼甲磺酸盐(STI571;格列卫)、埃罗替尼(OSI-1774;特罗凯)、卡奈替尼(CI1033)、司马沙尼(semaxinib)(SU5416)、瓦他拉尼(PTK787/ZK222584)、索拉非尼(BAY43-9006)、索坦(SUI1248)和来氟米特(SU101)。
PTK/ZK是靶向于所有VEGF受体(VEGFR)、血小板源生长因子(PDGF)受体、c-KIT和c-Fms的具有广泛特异性的酪氨酸激酶抑制剂。Drevs(2003)Idrugs6(8):787-794。PTK/ZK是通过抑制结合VEGF的所有已知受体的活性来阻断血管生成和淋巴管生成的靶向药物,所述受体包括VEGFR-1(Flt-1)、VEGFR-2(KDR/Flk-1)和VEGFR-3(Flt-4)。PTK/ZK的化学名称是1-[4-氯苯胺基]-4-[4-吡啶基甲基]酞嗪琥珀酸酯或1-酞嗪基胺,N-(4-氯苯基)-4-(4-吡啶基甲基)-丁二酸酯(1:1)。PTK/TK的异名同物和类似物被称为瓦他拉尼、CGP79787D、PTK787/ZK222584、CGP-79787、DE-00268、PTK-787、PTK787A、VEGFR-TK抑制剂、ZK222584和ZK。
可用于单萜或倍半萜的异构体或类似物的共混物和/或联合配制剂中和/或与单萜或倍半萜的异构体或类似物偶联的化疗剂还可以包括安吖啶、曲贝替定、类视黄醇(阿利维A酸、维甲酸)、三氧化二砷、天冬酰胺消耗剂(天冬酰胺酶/培门冬酶)、塞来昔布、地美可辛、伊利司莫、依沙芦星、乙环氧啶、氯尼达明、硫蒽酮、丙脒腙、米托坦、奥利默森、替西罗莫司和伏立诺他。
单萜或倍半萜的异构体或类似物可与血管生成抑制剂偶联和/或可用于与血管生成抑制剂的共混物和/或联合配制剂中。血管生成抑制剂的实例包括但不限于,血管抑素、血管酶(angiozyme)、抗凝血酶III、AG3340、VEGF抑制剂、巴马司他、贝伐单抗(阿瓦斯丁)、BMS-275291、CAI、2C3、HuMV833血管能抑素(canstatin)、卡托普利、羧胺三唑、软骨源抑制剂(CDI)、CC-5013、6-O-(氯乙酰基-羰基)-烟曲霉醇、COL-3、考布他汀、考布他汀A4磷酸盐、达肝素、EMD121974(西仑吉肽)、内皮抑素、埃罗替尼、吉非替尼(易瑞沙)、染料木素、氢溴酸卤夫酮、Id1、Id3、IM862、伊马替尼甲磺酸盐、IMC-IC11诱导蛋白10、干扰素α、白细胞介素12、熏草菌素A、LY317615或AE-941、马立马司他、mspin、乙酸甲羟孕酮(medroxpregesteroneacetate)、Meth-1、Meth-2、2-甲氧雌甾二醇(2-ME)、新伐司他、骨桥蛋白裂解产物(oteopontincleavedproduct)、PEX、色素上皮生长因子(PEGF)、血小板因子4、催乳素片段、增殖蛋白相关蛋白(PRP)、PTK787/ZK222584、ZD6474、重组人血小板因子4(rPF4)、网状内皮系统刺激素、角鲨胺、SU5416、SU6668、SU11248苏拉明、紫杉醇、替康兰(Tecogalan)、萨立多胺、凝血栓蛋白、TNP-470、肌钙蛋白-1、血管抑制因子、VEG1、VEGF-Trap和ZD6474。
血管生成抑制剂的非限制性实例还包括,酪氨酸激酶抑制剂,如酪氨酸激酶受体Flt-1(VEGFRl)和Flk-1/KDR(VEGFR2)的抑制剂、表皮源、成纤维细胞源或血小板源生长因子的抑制剂、MMP(基质金属蛋白酶)抑制剂、整联蛋白阻断剂、戊聚糖多硫酸酯、血管紧张素II拮抗剂、环加氧酶抑制剂(包括非甾体抗炎药(NSAID)如阿斯匹林和布洛芬,以及选择性环加氧酶-2抑制剂如塞来昔布和罗非昔布),和甾类抗炎药(如皮质类固醇、盐皮质激素、地塞米松、强的松、强的松龙、甲泼尼龙(methylpred)、倍他米松)。
调节或抑制血管生成并且还可与单萜或倍半萜的异构体或类似物偶联和/或共混和/或联合配制的其它治疗剂包括调节或抑制凝血和纤维蛋白溶解体系的试剂,其包括但不限于,肝素、低分子量肝素和羧肽酶U抑制剂(也称为活性凝血酶可活化纤维蛋白溶解抑制剂[TAFIa]的抑制剂)。美国专利公开第20090328239号。美国专利第7,638,549号。
抗高血压剂的非限制性实例包括血管紧张素转化酶抑制剂(例如卡托普利、依那普利、地拉普利等)、血管紧张素II拮抗剂(例如坎地沙坦酯、坎地沙坦、氯沙坦(或科素亚)、氯沙坦钾、依普沙坦、缬沙坦(或代文)、泰米沙坦(termisartan)、厄贝沙坦、他索沙坦、奥美沙坦、奥美沙坦酯等)、钙拮抗剂(例如马尼地平、硝苯吡啶、氨氯地平(或Amlodin)、依福地平、硝吡胺甲酯等)、利尿剂、肾素抑制剂(例如阿利克仑等)、醛固酮拮抗剂(例如安体舒通、依普利酮等)、β-阻断剂(例如美托洛尔(或Toporol)、阿替洛尔、普萘洛尔、卡维地洛、吲哚洛尔等)、血管舒张剂(例如硝酸盐、可溶性鸟苷酸环化酶刺激剂或活化剂、环前列腺素等)、血管紧张素疫苗、可乐宁等等。美国专利公开第20100113780号。
可与单萜或倍半萜的异构体或类似物偶联和/或共混和/或联合配制的其它治疗剂包括但不限于,舍曲林(左洛复)、托吡酯(妥泰)、度洛西汀(欣百达)、舒马普坦(舒马曲坦)、普瑞巴林(利痛抑)、拉莫三嗪(利必通)、伐昔洛韦(维德思)、坦索罗辛(坦洛新)、齐多夫定(可比韦)、拉米夫定(益平维(Combivir))、依法韦仑(依非韦伦)、阿巴卡韦(Epzicom)、洛匹那韦(Kaletra)、吡格列酮(爱妥糖)、地氯雷他定(地洛他定)、西替利嗪(仙特明)、潘托拉唑(泮托拉唑)、兰索拉唑(Prevacid)、雷贝拉唑(Aciphex)、莫西沙星(拜复乐)、美洛昔康(莫比可)、多佐胺(Truspot)、双氯芬酸(扶他林)、依那普利(Vasotec)、孟鲁司特(顺尔宁)、西地那非(万艾可)、卡维地洛(Coreg)、雷米普利(Delix)。
表1列出了能够与单萜或倍半萜的异构体或类似物偶联的药剂,包括所述药剂的结构和优选的用于偶联的衍生物。
表1
例如,L-DOPA异-POH偶联物显示如下:
单萜或倍半萜的异构体或类似物或者其衍生物的纯度可通过气相色谱法(GC)或高压液相色谱法(HPLC)来分析。用于分析本发明化合物的纯度和确定杂质存在的其它技术包括但不限于,核磁共振(NMR)谱、质谱(MS)、GC-MS、红外光谱(IR)和薄层色谱(TLC)。手性纯度可以通过手性GC或旋光度的测量来确定。
单萜或倍半萜的异构体或类似物(或其衍生物)可通过例如结晶的方法来纯化,或根据所述单萜或倍半萜的异构体或类似物(或其衍生物)独特的物理化学性质(例如溶解性或极性)将所述单萜或倍半萜的异构体或类似物(或其衍生物)与杂质分离。因此,单萜或倍半萜的异构体或类似物(或其衍生物)可通过本领域已知的适合的分离技术如制备型色谱法、(分级)蒸馏法或(分级)结晶法分离。
本发明还提供使用单萜或倍半萜的异构体或类似物以及使用单萜或倍半萜的异构体或类似物的衍生物治疗疾病如癌症或其它神经系统紊乱的方法。本发明的化合物可以单独施用,或与放疗、外科手术或化疗剂联合施用。单萜或倍半萜的异构体或类似物或其衍生物还可以与抗病毒剂、消炎药或抗生素共同施用。所述药剂可以同时或顺序施用。本发明的化合物可以在施用其它活性剂之前、期间或之后施用。
本发明的化合物和方法可用于抑制Ras蛋白。Ras家族是参与细胞信号转导的小GTP酶的蛋白质家族。Ras信号传导的激活引起细胞生长、分化和存活。ras基因中的突变可永久激活ras基因,并甚至在不存在细胞外信号的情况下引起细胞内不适宜的传输。因为这些信号导致细胞生长和分裂,异常的Ras信号最终会导致肿瘤形成和癌症。在20-25%的所有人类肿瘤和高达90%的特定肿瘤类型中发现了Ras的激活突变。GoodsellDS(1999),DownwardJ.,"Themolecularperspective;therasoncogene",Oncologist4(3):263-4,(January2003),"TargetingRASsignallingpathwaysincancertherapy".Nat.Rev.Cancer3(1):11-22。Ras家族成员包括但不限于,HRAS、KRAS、NRAS、DIRAS1、DIRAS2、DIRAS3、ERAS、GEM、MRAS、NKIRAS1、NKIRAS2、NRAS、RALA、RALB、RAP1A、RAP1B、RAP2A、RAP2B、RAP2C、RASD1、RASD2、RASL10A、RASL10B、RASL11A、RASL11B、RASL12、REM1、REM2、RERG、RERGL、RRAD、RRAS和RRAS。WennerbergK,RossmanKL,DerCJ(March2005)."TheRassuperfamilyataglance",J.Cell.Sci.118(Pt5):843-6。
所述单萜或倍半萜的异构体或类似物,或单萜或倍半萜的异构体或类似物的衍生物,可与放射疗法联合使用。在一个实施方式中,本发明提供采用放射处理肿瘤细胞如恶性神经胶质瘤细胞的方法,其中用有效量的单萜或倍半萜的异构体或类似物(或其衍生物)如异紫苏醇处理所述细胞,然后进行放射处理。本发明化合物的处理可以在放射之前、期间和/或之后。例如,本发明化合物可以从放疗开始之前一星期开始连续施用,并且在放疗完成之后持续两个星期。美国专利第5,587,402和5,602,184号。
在一个实施方式中,本发明提供采用化疗处理肿瘤细胞如恶性神经胶质瘤细胞的方法,其中用有效量的单萜或倍半萜的异构体或类似物(或所述单萜或倍半萜的异构体或类似物的衍生物)如异紫苏醇处理所述细胞,然后进行化疗。本发明化合物的处理可以在化疗之前、期间和/或之后。
本发明化合物可用于治疗神经系统癌症,如恶性神经胶质瘤(例如星形细胞瘤、间变性星形细胞瘤、多形性胶质母细胞瘤)、视网膜母细胞瘤、毛细胞性星形细胞瘤(I期)、脑膜瘤、转移性脑肿瘤、成神经细胞瘤、垂体腺瘤、颅底脑膜瘤和颅底癌症。本文中使用的术语“神经系统肿瘤”是指其中受试者具有神经系统细胞的恶性增殖的病症。
可通过本发明化合物治疗的癌症包括,但不限于,肺癌、耳鼻喉癌、白血病、结肠癌、黑素瘤、胰腺癌、乳癌、前列腺癌、乳腺癌、造血系统癌症、卵巢癌、基底细胞癌、胆管癌;膀胱癌;骨癌;乳腺癌;宫颈癌;绒毛膜癌;结肠和直肠癌;结缔组织癌;消化系统的癌症;子宫内膜癌;食管癌;眼癌;头颈癌;胃癌;上皮内瘤;肾癌;喉癌;包括急性骨髓性白血病、急性淋巴细胞性白血病、慢性骨髓性白血病、慢性淋巴细胞性白血病的白血病;肝癌;包括霍奇金和非霍奇金淋巴瘤的淋巴瘤;骨髓瘤;纤维瘤、成神经细胞瘤;口腔(例如唇、舌、口和咽)癌;卵巢癌;胰腺癌;前列腺癌;视网膜母细胞瘤;横纹肌肉瘤;直肠癌;肾癌;呼吸系统癌症;肉瘤;皮肤癌;胃癌;睾丸癌;甲状腺癌;子宫癌;泌尿系统癌症,以及其它癌瘤和肉瘤。美国专利第7,601,355号。
本发明还提供治疗CNS紊乱的方法,所述CNS紊乱包括但不限于,诸如阿尔茨海默病的原发性退行性神经系统紊乱、帕金森病、心理疾病、精神病和抑郁症。本发明的组合物和方法还可治疗孤独症。治疗可包括单独使用本发明的化合物,或与目前用于治疗帕金森病、阿尔茨海默病或心理疾病的药物联合使用。
本发明还提供提高免疫调节疗法反应的方法,其包括在免疫调节治疗之前或期间将细胞暴露于有效量的本发明化合物如异紫苏醇的步骤。优选的免疫调节剂是细胞因子,如白细胞介素、淋巴因子、单核因子、干扰素和趋化因子。
本发明的组合物可通过现有技术已知的任何方法施用,包括但不限于,鼻内、口服、经皮、经眼、腹膜内、吸入、静脉内、ICV、脑池内注射或输注、皮下、植入、阴道、舌下、尿道(例如尿道栓剂)、皮下、肌肉内、静脉内、直肠、舌下、粘膜、眼部、脊髓、鞘内、关节内、动脉内、蛛网膜下、支气管和淋巴管施用。局部制剂可以是凝胶、膏剂、乳膏剂、气雾剂等的形式;鼻内制剂可以以喷雾或液滴形式递送;经皮制剂可以通过透皮贴剂或离子电渗施用;吸入制剂可以利用喷雾器或类似装置施用。组合物还可以采用片剂、丸剂、胶囊、半固体、粉末、缓释制剂、溶液、悬浮液、酏剂、气雾剂或任何其它合适的组合物的形式。
为了制备这种药物组合物,可以根据常规药物配制技术将一种或多种本发明的化合物与药学上可接受的载体、助剂和/或赋形剂混合。可用于本发明的组合物中的药学上可接受的载体包括任何标准的药用载体,如磷酸盐缓冲盐水溶液、水和乳液如油/水或水/油乳液,以及各种类型的润湿剂。所述组合物可另外含有固体药物赋形剂如淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、氯化钠、脱脂奶粉等。液体和半固态赋形剂可以选自甘油、丙二醇、水、乙醇和各种油类,包括石油、动物、植物或合成来源的那些油类,例如花生油、豆油、矿物油、芝麻油等。液体载体,特别是注射液用液体载体,包括水、盐水、水化葡萄糖和二醇类。载体、稳定剂和助剂的实例,参见E.W.Martin编辑的Remington'sPharmaceuticalSciences,(MackPublishingCompany,18thed.,1990)。所述组合物还可包括稳定剂和防腐剂。
如在本文中使用的术语“治疗有效量”是足以治疗特定紊乱或疾病的量,或者足以获得治疗紊乱或疾病的药理学反应的量。确定最有效的施用方式和剂量的方法可以随着用于治疗的组合物、治疗的目的、治疗的靶细胞和治疗的受试者而变化。治疗剂量通常可以通过逐步增加剂量的方式确定以优化安全性和效力。单次或多次施用可以根据治疗医生选择的剂量水平和方式来进行。本领域技术人员能够容易确定施用药剂的合适剂量制剂和方法。例如,所述组合物以约0.01mg/kg至约200mg/kg、约0.1mg/kg至约100mg/kg、或约0.5mg/kg至约50mg/kg施用。当在本文中描述的化合物与另一试剂或疗法共同施用时,所述有效量可以低于所述试剂单独使用时的有效量。
经皮制剂可通过将活性剂并入触变性或凝胶状载体如纤维素介质(例如甲基纤维素或羟乙基纤维素)中,然后将所形成的制剂装进适合于在与佩戴者皮肤的皮肤接触时固定的透皮装置中来制备。如果所述组合物是凝胶的形式,可将所述组合物涂在患者的表层例如肩部或上臂和/或上半身的皮肤上,优选完整、干净和干燥的皮肤,并在其上保持一段足以将本发明的化合物递送至患者的血清的时间。凝胶形式的本发明组合物可以包含在管、药囊或计量泵中。这种管或药囊可含有一个单位剂量或超过一个单位剂量的所述组合物。计量泵能够分配一个定量剂量的组合物。
本发明还提供如上所述的鼻内施用的组合物。如此,所述组合物可以进一步包含渗透促进剂。Southall等.DevelopmentinNasalDrugDelivery,2000。本发明的化合物可以以液体形式如溶液、乳液、悬浮液、滴剂,或固体形式如粉末、凝胶或膏剂鼻内施用。
递送鼻内药物的装置是本领域中众所周知的。可利用下述装置进行经鼻药物的递送,包括但不限于,鼻内吸入器、鼻内喷雾装置、雾化器、鼻喷雾瓶、单位剂量容器、泵、点滴器、挤压瓶、喷雾器、定量吸入器(MDI)、加压剂量吸入器、吹药器和双向装置。可以对所述经鼻递送装置可以定量以向鼻腔施用精确的有效剂量的量。所述经鼻递送装置可用于单一单位递送或多单位递送。在具体的实例中,来自KurveTechnology(Bethell,Washington)的ViaNaseElectronicAtomizer可用于本发明中(http://www.kurvetech.com)。本发明化合物还可以通过管、导管、注射器、包装尾(packtail)、小拭子、鼻塞或通过粘膜下输注递送。美国专利公开第20090326275、20090291894、20090281522和20090317377号。
本发明的化合物可利用标准程序配制成气雾剂。所述化合物可与溶剂一起配制或不与溶剂一起配制,以及与载体一起配制或不与载体一起配制。所述制剂可以是溶液,或可以是含有一种或多种表面活性剂的水性乳液。例如,可以由带有合适推进剂如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、烃类、压缩空气、氮气、二氧化碳或其它合适气体的加压容器来产生气溶胶喷雾。可通过提供阀门来确定剂量单位以递送定量的量。泵喷雾分配器可以分配定量的剂量或具有特定的粒径或液滴尺寸的剂量。如在本文中使用的术语“气溶胶”是指处于气体中的细小固体颗粒或液体溶液小滴的悬浮液。具体地说,气溶胶包括单萜(或倍半萜)小滴的气载悬浮液,其可以在任何适合装置如MDI、喷雾器或弥雾机中制备。气溶胶还包括悬浮在空气或其它载气中的本发明组合物的干粉组合物。Gonda(1990)Critical ReviewsinTherapeuticDrugCarrierSystems6:273-313.Raeburn等,(1992)Pharmacol.Toxicol.Methods27:143-159。
本发明的化合物可以作为以如通过经鼻吹药器递送的微球的形式的粉末递送到鼻腔。本发明的化合物可以吸附至固体表面例如载体上。所述粉末或微球可以以干燥的、空气可分配的形式施用。所述粉末或微球可以储存在吹药器的容器中。或者,所述粉末或微球可以装填到胶囊如明胶胶囊或其它适合于经鼻施用的单剂量单元中。
药物组合物可以通过在鼻腔中直接放置所述组合物来递送到鼻腔,例如以凝胶、膏剂、经鼻乳剂、洗剂、乳膏剂、鼻棉塞、点滴器或生物粘附条的形式。在某些实施方式中,例如为了提高吸收,可能希望的是延长药物组合物在鼻腔中的停留时间。因此,药物组合物可任选与生物粘性聚合物、树胶(例如黄原胶)、壳聚糖(例如高纯度阳离子型多糖)、果胶(或像凝胶一样稠化或当施加到鼻粘膜时乳化的任何碳水化合物)、微球(例如淀粉、白蛋白、右旋糖酐、环糊精)、明胶、脂质体、卡波姆(carbamer)、聚乙烯醇、藻酸盐、阿拉伯胶、壳聚糖和/或纤维素(例如甲基或丙基;羟基或羧基;羧甲基或羟丙基)一起配制。
含有本发明化合物的组合物可以通过口腔吸入进入呼吸道(即肺)施用。
用于可吸入剂的典型递送系统包括雾化吸入器、干粉吸入器(DPI)和定量吸入器(MDI)。
喷雾器装置产生高速空气流,其使液体形式的治疗剂以轻雾的形式喷射。所述治疗剂配制成液体形式,例如溶液或具有合适大小的颗粒的悬浮液。在一个实施方案中,所述颗粒是微粉化的。术语“微粉化”定义为具有约90%或更多的颗粒直径小于约10微米。适合的喷雾器装置是商业上提供的,例如,由PARIGmbH(Starnberg,德国)提供。其它喷雾器装置包括Respimat(BoehringerIngelheim)以及在例如美国专利第7,568,480和6,123,068号以及WO97/12687中公开的那些。本发明的化合物可以配制以作为水性溶液或液体悬浮液用在喷雾器装置中。
DPI装置通常以自由流动粉末形式施用治疗剂,所述粉末可分散在患者吸气过程中的气流中。使用外部能量源的DPI装置也可以用于本发明中。为了得到自由流动的粉末,本发明的化合物可与适合的赋形剂(例如乳糖)一起配制。例如,可以通过将颗粒大小为约1μm至100μm的干燥乳糖与本发明化合物的微粉化颗粒混合并干混制得干粉制剂。或者,所述化合物可不与赋形剂一起配制。将所述制剂装入干粉分配器中,或装入与干粉递送装置一起使用的吸入盒或胶囊中。商业上提供的DPI装置的实例包括Diskhaler(GlaxoSmithKline,ResearchTrianglePark,N.C.)(参见,例如美国专利第5,035,237号);Diskus(GlaxoSmithKline)(参见,例如美国专利第6,378,519号);Turbuhaler(AstraZeneca,Wilmington,Del.)(参见,例如美国专利第4,524,769号);和Rotahaler(GlaxoSmithKline)(参见,例如美国专利第4,353,365号)。适合的DPI装置的其他实例描述在美国专利第5,415,162、5,239,993和5,715,810号以及其中的参考文献中。
MDI装置通常利用压缩的推进剂气体释放出测定量的所储存组合物。用于MDI施用的制剂包括在液化推进剂中的活性成分的溶液或悬浮液。推进剂的实例包括氢氟烷烃(HFA)例如1,1,1,2-四氟乙烷(HFA134a)和1,1,1,2,3,3,3-七氟-正丙烷(HFA227),和氯氟烃例如CCl3F。用于MDI施用的HFA制剂的其他组分包括共溶剂如乙醇、戊烷、水和表面活性剂如去水山梨糖醇三油酸酯、油酸、卵磷脂和甘油。(参见,例如美国专利第5,225,183号、EP0717987和WO92/22286)。将制剂装入气溶胶罐中,其构成MDI装置的一部分。美国专利第6,006,745和6,143,227号中提供了为与HFA推进剂一起使用而特别开发的MDI装置的实例。制备适合制剂的方法和适合于吸入给药的装置的实例参见美国专利第6,268,533、5,983,956、5,874,063和6,221,398号,以及WO99/53901、WO00/61108、WO99/55319和WO00/30614。
为了通过吸入递送,本发明的化合物可以包封在脂质体或微胶囊中。脂质体是由脂质双层膜和水性内部组成的囊泡。所述脂质膜可以由磷脂制成,其实例包括磷脂酰胆碱如卵磷脂和溶血卵磷脂,酸性磷脂如磷脂酰丝氨酸和磷脂酰甘油,及鞘磷脂如磷脂酰乙醇胺和神经鞘磷脂。或者,可以添加胆固醇。微胶囊是包有涂层材料的颗粒。例如,所述涂层材料可以由成膜聚合物、疏水性增塑剂、表面活性剂或/和润滑剂含氮聚合物的混合物组成。美国专利第6,313,176和7,563,768号。
本发明的化合物也可以单独或与其它化疗剂联合通过局部施用于治疗局部癌症如乳房癌或黑素瘤而使用。本发明的化合物也可以与镇静剂或止痛药联合用于疼痛药物的经皮递送。
本发明还提供如上所述的眼部施用的组合物。如此,所述组合物可进一步包含渗透促进剂。对于眼部施用而言,本文描述的组合物可以配制成溶液、乳液、悬浮液等。多种适用于将化合物施用于眼睛的媒介是本领域已知的。具体的非限制性实例描述在美国专利第6,261,547;6,197,934;6,056,950;5,800,807;5,776,445;5,698,219;5,521,222;5,403,841;5,077,033;4,882150和4,738,851号中。
本发明的化合物可单独或与用于上述疾病治疗的其它药物联合给予短或较长的时间。本发明的组合物可施用于哺乳动物,优选人类。哺乳动物包括,但不限于,鼠科动物、大鼠、兔、猿、牛、绵羊、猪、狗、猫、农畜、运动动物(sportanimals)、宠物、马和灵长类动物。
本发明还提供在体外、离体或在体内抑制细胞生长的方法,其中使细胞如癌细胞与有效量的本文中描述的化合物接触。
病理细胞或组织如过度增殖的细胞或组织可通过使所述细胞或组织接触有效量的本发明组合物来处理。所述细胞如癌细胞可以是原发性癌细胞,或可以是能从组织库如美国典型培养物保藏中心(ATCC)获得的培养细胞。所述病理细胞可以是全身性癌症、神经胶质瘤、脑膜瘤、垂体腺瘤、或来自全身性癌症、肺癌、前列腺癌、乳腺癌、造血系统癌症或卵巢癌的CNS转移的细胞。所述细胞可以来自于脊椎动物,优选哺乳动物,更优选人类。美国专利公开第2004/0087651号。Balassiano等.(2002)Intern.J.Mol.Med.10:785-788。Thorne等.(2004)Neuroscience127:481-496。Fernandes等.(2005)OncologyReports13:943-947。DaFonseca等.(2008)SurgicalNeurology70:259-267。DaFonseca等.(2008)Arch.Immunol.Ther.Exp.56:267-276。Hashizume等.(2008)Neuroncology10:112-120。
本发明组合物的体外效力可利用本领域众所周知的方法测定。例如,可以通过MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴化物]细胞毒性试验来研究本发明化合物的细胞毒性。MTT试验基于以下原理:新陈代谢活跃细胞摄取MTT(四氮唑盐),其在细胞中被代谢成可通过光谱读取的蓝色甲瓒产物。J.ofImmunologicalMethods65:55-63,1983。可以通过集落形成试验研究本发明化合物的细胞毒性。用于VEGF分泌和IL-8分泌的抑制的功能性试验可以通过ELISA进行。可以通过标准化碘化丙啶(PI)染色法和流式细胞术研究本发明化合物引起的细胞周期阻滞。可以通过博伊登室(Boydenchambers)研究侵袭抑制。在此试验中,将一层重构的基底膜—基质胶(Matrigel)—涂覆到趋化作用过滤器上,并作为博伊登室中细胞迁移的屏障。只有具有侵袭能力的细胞能够穿过所述基质胶屏障。其它试验包括但不限于,细胞存活力试验、细胞凋亡试验和形态学分析。
以下是本发明的实施例,其不应解释为限制性的。
实施例
实施例1:异-POH的合成
反应流程如下:
4-异亚丙基-1,4-二氧杂-螺[4.5]癸烷(2)的制备:
在氮气气氛下在室温下,将异丙基三苯基碘化膦(83.02g,192mmol)加入至无水二甲亚砜(120mL)中的NaH(60%,在矿物油中,8.38g,192mmol)。将反应混合物在15分钟内缓慢加热至50℃,并保持在50℃直到反应物质变成红色(大约30分钟)。在保持温度低于50℃的同时,在45分钟内加入1,4-环己二酮单乙二醇缩酮(1,30g,192mmol)的无水二甲亚砜溶液,并将反应物在50℃保持16小时。将反应混合物冷却至室温,用冷水(150ml)淬灭,再用乙酸乙酯(2×160mL)萃取。用水(2×200mL)、接着用盐水(10%,250mL)洗涤合并的有机层,并用硫酸钠干燥。浓缩所过滤的有机层以得到固体,其用己烷(300mL)研磨,滤出所沉淀的三苯基氧化膦。浓缩己烷层以得到油,其用柱色谱法纯化。[柱尺寸:直径:6.0cm,高度:12cm,二氧化硅:200目,用己烷(1.0L)、接着用己烷:乙酸乙酯(97:3,2.0L)洗脱]。合并己烷:乙酸乙酯级分,在真空下浓缩以得到油。重量:23.36g,重量产率:66.7%。1H-NMR(400MHz,CDCl3):δ1.61-1.63(t,4H),1.64(s,6H),2.29(m,4H),3.97(s,4H)。
MS(APCI法):未观察到分子离子峰。
4-异亚丙基环己酮(3)的制备:
将对甲苯磺酸(31.16g,164mmol)加入至缩酮(2,23.0g,126mmol)在丙酮(2.3L)和水(138mL)的溶液中。将反应混合物加热至回流,并保持回流3.5小时。将混合物冷却至室温,用饱和碳酸氢钠(60mL)处理,并在真空下浓缩。用乙酸乙酯(2×130ml)萃取所得到的油状残留物,用水(100mL)洗涤,然后用盐水(100mL)洗涤,并用硫酸钠干燥。在真空下浓缩所过滤的有机层以得到油。重量:16g,重量产率:92%。1H-NMR(400MHz,CDCl3):δ1.69(s,6H),2.35(t,4H),2.50(t,4H)。MS(APCI法):未观察到分子离子峰(注解:1H-NMR显示存在约2%的缩酮2,但不纯化直接使用)。
4-异亚丙基-1-氧杂-螺[2.5]辛烷(4)的制备:
在氮气气氛下在室温下,将叔丁醇钾(3.3g,29.4mmol)加入至酮(3,2.5g,18.1mmol)和三甲基碘化亚砜(6.45g,29.4mmol)在无水二甲亚砜(40ml)的混合物中。在室温下搅拌混合物4.0小时。通过加入冷水(40mL)淬灭反应,并用乙酸乙酯(2×60mL)萃取。用水(75mL)、接着用盐水(75mL)洗涤合并的有机层,并用硫酸钠干燥。在真空下浓缩所过滤的有机层以得到油。重量:2.13g,重量产率:77%。1H-NMR(400MHz,CDCl3):δ1.42-1.50(m,2H),1.55-1.61(m,2H),1.65(s,6H),2.31(t,4H),2.61(s,2H)。MS(APCI法):未观察到分子离子峰。
3,5-二硝基苯甲酸4-异亚丙基环己-1-烯基甲基酯(6)的制备:
将异丙醇铝(5.93g,29.0mmol)加入至环氧化物(4,4.0g,26.2mmol)在甲苯(80mL)的混合物中,并将混合物加热至回流持续7.0小时。将混合物冷却至室温,并用饱和酒石酸钠钾溶液淬灭。分离有机层,用水(40mL)、接着用盐水(40mL)洗涤,并用硫酸钠干燥。在真空下浓缩所过滤的有机层以得到油状的粗异紫苏醇(5)。重量:4.0g,重量产量:100%,纯度:约85-90%(根据GC面积百分比,实际产率约:85%)。
将三乙胺(5.1mL,36.6mmol)加入至粗异紫苏醇(5,4.0g,26.2mmol)的二氯甲烷(50mL)溶液中。搅拌15分钟后,在0.25小时内加入3,5-二硝基苯甲酰氯(6.3g,27.5mmol)。将反应混合物搅拌3.0小时,用水(30mL)淬灭。分离有机层,用水(40mL)洗涤,并用硫酸钠干燥。在真空下浓缩所过滤的有机层以得到浅黄色固体(8.5g),所述固体从丙酮中再结晶以得到浅黄色固体的纯酯6。熔点:138-140℃(丙酮);重量:5.7g;产率:62%(来自环氧化物)。1H-NMR(400MHz,CDCl3):δ1.68(s,3H),1.71(s,3H),2.18(t,2H),2.40(t,2H),2.87(brs,2H),4.85(s,2H);5.88(s,1H),9.17(t,1H),9.24(s,1H)。MS(APCI法):m/e:247.1(5%),149.07(7%),135.1(100%),107.1(9%)。
异紫苏醇(7)的制备
在0.25小时内,将氢氧化钠水溶液(1.43g,35.7mmol,溶于12.5mL水中)加入冰冷的3,5-二硝基苯甲酸4-异亚丙基-环己-1-烯基甲基酯(6,5.63g,16.2mmol)的甲醇(56mL)溶液中。使反应混合物升温到室温,然后搅拌3.0小时。在真空下浓缩甲醇至最小搅拌体积,再将混合物悬浮于水(40mL)中。用乙酸乙酯(2×50mL)萃取所得到的混合物。用水(2×50mL)洗涤有机层,然后用盐水(50mL)洗涤,并用硫酸钠干燥。在真空下浓缩所过滤的有机层以得到油状的纯异紫苏醇。重量:2.35g,产率:95%,纯度:97%(根据GCAUC)。1H-NMR(400MHz,CDCl3):δ1.65(s,3H),1.69(s,3H),1.77(bs,OH),2.09(m,2H),2.33(t,2H),2.79(brs,2H);13C-NMR:δ20.38,20.80,26.95,27.60,29.86,67.49,122.88,123.04,127.92,138.37。MS(APCI法):m/e:152(M+,3.5%),135.07(100%),107.12(5%)。然而,所述质谱显示未鉴定的在M+:207.06、269.1、287.09&301处的四个小峰(约5%)。
实施例2:异-POH的可选合成
反应流程如下:
三氟甲烷磺酸4-异亚丙基环己-1-烯基酯(8)的制备:
在-78℃下,在0.5小时内,将2.5M正丁基锂的己烷(5.6mL,14.1mmol)溶液加入二异丙胺(1.98mL,14.1mmol)的无水THF(30ml)溶液中。在-78℃下搅拌1.0小时后,在保持温度低于-78℃的同时,在10分钟内加入酮(3,1.3g,9.4mmol)的无水THF(10mL)溶液。在-78℃下搅拌反应混合物1.0小时。在保持温度低于-78℃的同时,缓慢加入苯基三氟甲磺酰亚胺(3.53g,9.86mmol)的THF(15ml)溶液。将反应混合物缓慢升温至0℃,在0℃下保持2.0小时,然后用饱和氯化铵溶液淬灭。用水(15mL)、盐水(15mL)洗涤所分离的有机层,并用硫酸钠干燥。在真空下浓缩所过滤的有机层,再用柱色谱法纯化所得到的残留物。[柱尺寸:直径:6.0cm,高度:12cm,二氧化硅:200目,用己烷(200mL)洗脱]。合并类似级分,在真空下浓缩,这得到油。重量:0.9g,重量产率:38%。1H-NMR(400MHz,CDCl3):δ1.68(s,3H),1.71(s,3H),2.37(m,2H),2.46(m,2H),2.91(m,2H),5.73(m,1H)。MS(APCI法):未观察到分子离子峰。
注解-1:1H-NMR表明在δ7.42-7.57之间存在芳族峰(5%),其归因于副产物三氟-N-苯基甲磺酰胺。
注解-2:在作为碱的2,6-二叔丁基-4-甲基吡啶存在下,也使用三氟甲磺酸酐以低产率(28%)合成了化合物8。
4-异亚丙基环己-1-烯羧酸甲酯(9)的制备:
将甲醇(1.0mL)、三乙胺(0.17mL,1.2mmol)、1,3-双(二苯基膦基)丙烷(0.03g,0.07mmol)和乙酸钯(0.04g,0.07mmol)加入至化合物8(0.2g,0.74mmol)的N'N-二甲基甲酰胺(1.5mL)溶液中。将所述反应混合物脱气,然后在室温下和一氧化碳气氛(球囊压力)下搅拌5小时。用乙酸乙酯(15mL)稀释反应混合物,用0.5NHCl(15mL)、盐水(15mL)洗涤,并用硫酸钠干燥。在真空下浓缩所过滤的有机层,并用柱色谱法纯化所得到的残留物。[柱尺寸:直径:6.0cm,高度:12cm,二氧化硅:200目,用己烷(100ml)、接着用乙酸乙酯:己烷(2%,150mL)洗脱]。合并类似级分,并在真空下浓缩得到油。虽然TLC分析显示只有单一点,但1H-NMR和GC分析表明所分离的物质是通过TLC共洗脱的两种主要成分的混合物。重量:0.11g,重量产率:82%。1H-NMR(400MHz,CDCl3)表明存在带有未知杂质的对应于甲酯(9)的峰。GC分析证实其主要是比例为3:1的两种化合物的混合物。MS(APCI法):m/e:180(M+,5%),180.9(M+1,100%)。未鉴定在M+:197.8、247.0&274.0处的其他峰(≤5%)。在未纯化的情况下,进一步使用所述粗混合物。
异紫苏醇(7)的制备:在2分钟内,将在无水THF(10mL)中的甲酯(9,0.11g,0.6mmol)加入LAH(0.03g,0.78mmol)在无水THF(10mL)中的冷溶液中。将反应混合物缓慢加热至回流,并保持3.0小时。将混合物冷却至5℃,并用饱和硫酸钠(1.5mL)淬灭。滤出所沉淀的锂盐,并用热的乙酸乙酯(20mL)洗涤。用硫酸钠干燥滤液。在真空下浓缩所过滤的有机层得到油。重量:74mg,重量产率:79%。虽然TLC分析显示只有单一点,但1H-NMR和GC分析表明所分离的物质是通过TLC共洗脱的两种主要成分的混合物。1H-NMR(400MHz,CDCl3)表明存在带有未知杂质的对应于异紫苏醇(7)的峰。MS(APCI法):m/e:153(M+1,40%),152(M+,13%),135.09(M-OH)。未鉴定在M+:169.03(10%)、255.20(13%)、285.25(15%)、287.19(70%)、290(68%)&397.24(15%)的其他峰。GC分析证实,与从环氧化物途径获得的带有未知杂质的异-POH(67.5%,(AUC))相比,存在异紫苏醇(20.5%,(AUC))。
实施例3:异-POH((4-异亚丙基环己-1-烯基)-甲醇)的体外细胞毒性研究
细胞在用异-POH(例如,通过实施例1方法合成的)或具有不同纯度的其它类型POH处理之后,进行MTT细胞毒性试验。图1显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死LN229人神经胶质瘤细胞的效力。SigmaPOH是从SigmaChemicals购买的具有约96%纯度的POH。SGP-527-155通过二异丙醚溶剂的两次结晶由WAKOPOH制得,其具有约98.7%的GC相对面积纯度(曲线下面积)。KWH0744是从Wako购买的具有约89.5%纯度的粗POH。SGP-527-130通过二异丙醚溶剂的单次结晶由WAKOPOH制得,其具有约97.1%的GC相对面积纯度(曲线下面积)。图2显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死U251人神经胶质瘤细胞的效力。图3显示MTT细胞毒性试验的结果,其表明不同类型的POH和异-POH杀死A172人神经胶质瘤细胞的效力。所述结果表明异-POH显示出比具有不同纯度的POH强得多的细胞毒性。
还研究了异-POH在替莫唑胺敏感的细胞或替莫唑胺抗性的细胞中的体外细胞毒性。用SigmaPOH、合成至具有约98.7%纯度的GLP质量的POH(SGP-527-155)和异-POH(SGP-561-79P、SGP-561-65P)处理神经胶质瘤细胞48小时,并进行MTT试验。图4表明,与GLPPOH和SigmaPOH相比,A172细胞具有最大的对异-POH的细胞毒性反应(图4A)。在替莫唑胺抗性的A172细胞中也看到这种反应模式(图4B)。类似地,图5表明U251细胞具有对异-POH的最大反应(图5A),并且在替莫唑胺抗性的U251细胞中也看到了该反应(图5B)。在替莫唑胺敏感的LN229细胞(图6A)和替莫唑胺抗性的LN229细胞(图6B)中看到了相同的对异-POH的反应。虽然低于LN229和U251细胞,但替莫唑胺敏感的U87细胞(图7A)和替莫唑胺抗性的U87细胞(图7B)均具有对异-POH的最大反应。
图8显示使用在24小时内用SigmaPOH、具有约98.7%纯度的GLPPOH、异-POH(异-POH65、异-POH79(全部在0mM-3mM浓度下)处理的TMZ敏感的U251神经胶质瘤细胞进行MTT试验的结果。与SigmaPOH和GLPPOH相比,异-POH具有更大的细胞毒性(图8A)。在相同条件下处理的替莫唑胺抗性的U251细胞系(U251-TR2)表明,与SigmaPOH和GLPPOH相比,异-POH具有更大的细胞毒性(图8B)。在相同条件下处理的另一种替莫唑胺抗性的U251细胞系(U251-TR1)也表明,与GLPPOH或SigmaPOH相比,异-POH(异-POH65、异-POH79)具有更大的细胞毒性(图8C)。
图9显示在24小时内用GLP-POH和异-POH(异-POH65)两者处理的胶质母细胞瘤癌症干细胞系USC04进行的MTT试验的结果。GLPPOH和异-POH在所述细胞上显示类似的细胞毒性。
用SigmaPOH(1.5mM)或GLPPOH(1.5mM)处理TMZ敏感的U251细胞和TMZ抗性的U251细胞(U251-TR1、U251-TR2)18小时,然后进行蛋白质印迹。结果显示,SigmaPOH和GLPPOH增加了葡萄糖-调节蛋白78(GRP-78)和细胞凋亡标记物CHOP的表达,这表明处理后增强了内质网(ER)应激(图10a)。在相同条件下,异-POH(异-POH65、异-POH79)也增强了ER应激(图10b)。
用500μMSigmaPOH、GLPPOH或异-POH(异POH65、异POH79)处理U251神经胶质瘤细胞24小时,然后进行蛋白质印迹分析。结果(图11)表明所有处理均降低了Kras表达。
实施例4:与替莫唑胺(TMZ)偶联的异-POH的合成
反应流程如下:
(3-甲基4-氧代-3,4-二氢咪唑并[5,1-d][l,2,3,5]四嗪-8-羰基)-氨基甲酸-4-异亚丙基环己-1-烯基甲基酯的制备:
在N2下,在保持在10℃温度的同时,在5分钟内将草酰氯(0.26g,2.0mmol)缓慢加入替莫唑胺(来源:OChemIncorporation,Lot#0711185A;0.2g,1.0mmol)在1,2-二氯乙烷(15mL)中的混合物中。使所述反应混合物升温到室温,然后加热至回流2.5小时。过量的草酰氯和1,2-二氯乙烷将通过真空下浓缩除去。将所得到的残留物再溶解在1,2-二氯乙烷(20mL)中,并在N2下将反应混合物冷却至5℃。在10分钟内加入异紫苏醇(0.17g,1.12mmol)的1,2-二氯乙烷(5mL)溶液。使反应混合物升温到室温并搅拌12小时。在真空下浓缩1,2-二氯乙烷以得到残留物,其用己烷研磨。过滤所得到的浅黄色固体并用己烷洗涤。
实施例5:与咯利普兰偶联的异-POH的合成
反应流程如下。
4-(3-环戊氧基-4-甲氧基苯基)-2-氧代-吡咯烷-1-甲酸4-异亚丙基环己-1-烯基甲基酯的制备:
在将温度保持在10-12℃的同时,在45分钟内将光气(甲苯中20%,19.5ml,39.4mmol)加入异紫苏醇(3.0g,19.7mmol)和碳酸钾(8.1g,58.6mmol)在无水甲苯(45mL)中的混合物中。使反应混合物升温到室温,并在N2下搅拌10小时。用水(40ml)淬灭反应混合物,并分离有机层。用甲苯(30mL)萃取水层,用水(40ml×2)、盐水(10%,40mL)洗涤合并的有机层,并用硫酸钠(25g)干燥。在真空下浓缩所过滤的有机层以得到油状的异紫苏基氯甲酸酯。
在N2下在-72℃下,在10分钟内将丁基锂(2.5M,0.36mL,0.90mmol)加入至咯利普兰(来源:GLsynthesis,inc.Lot#GLS-SH-110809;0.2g,0.72mmol)的无水THF(8mL)溶液中。在-72℃下搅拌反应混合物1.0小时后,在保持温度在-72℃的同时,在10分钟内加入异紫苏基氯甲酸酯(0.16g,0.76mmol,溶于4mLTHF中)。搅拌反应混合物3小时,并用饱和氯化铵(10mL)淬灭。使反应混合物升温到室温,并用乙酸乙酯(2×20mL)萃取。用水(20mL)、盐水(10%,25mL)洗涤合并的有机层,并用硫酸钠干燥。浓缩所过滤的有机层以得到油,其用柱色谱法[柱尺寸:直径:1.5cm,高度:15cm,二氧化硅:230-400目]纯化,用5%的乙酸乙酯/己烷混合物(120ml)、接着用10%的乙酸乙酯/己烷(150ml)洗脱。合并10%的乙酸乙酯/己烷级分,并在真空下浓缩以得到胶粘性固体。
实施例6:二甲基塞来昔布双异-POH氨基甲酸酯偶联物的合成
反应流程如下。
4-(双-N,N'-4-异亚丙基环己-1-烯基甲氧基羰基[5-(2,5-二甲基苯基)-3-三氟甲基吡唑-1-基]苯磺酰胺的制备:
在温度保持在10-12℃的同时,在45分钟内将光气(甲苯中20%,19.5ml,39.4mmol)加入至异紫苏醇(3.0g,19.7mmol)和碳酸钾(8.1g,58.6mmol)在无水甲苯(45mL)中的混合物中。使反应混合物升温到室温,并在N2下搅拌10小时。用水(40ml)淬灭反应混合物,并分离有机层。用甲苯(30mL)萃取水层,用水(40ml×2)、盐水(10%,40mL)洗涤合并的有机层,并用硫酸钠(25g)干燥。在真空下浓缩所过滤的有机层以得到油状的异紫苏基氯甲酸酯。
在N2下,在5分钟内,将异紫苏基氯甲酸酯(0.22g,1.0mmol)缓慢加入至二甲基塞来昔布(0.2g,0.50mmol)和碳酸钾(0.14g,1.0mmol)在无水丙酮(25mL)中的混合物中。将反应混合物加热至回流,并保持4小时。冷却反应混合物,并在真空下浓缩丙酮。将所得到的残留物悬浮于水(25mL)中,用乙酸乙酯(3×20ml)萃取。用水(40mL)、接着用盐水(10%,30mL)洗涤合并的有机层,并用硫酸钠干燥。在真空下浓缩所过滤的有机层以得到残留物,其用柱色谱法[柱尺寸:直径:1.5cm,高度:15cm,二氧化硅:230-400目]纯化,并用己烷(100ml)、接着用己烷/乙酸乙酯的混合物(95:5,100mL)洗脱。合并己烷/乙酸乙酯级分,并在真空下浓缩得到胶粘性物质。
本发明的范围不受上文中具体显示和描述的内容所限制。本领域技术人员将认识到所描述的材料、构造、结构和尺寸的示例存在合适的替代物。在本发明说明书中引用并讨论了大量参考文献,包括专利和各种出版物。提供这些参考文献的引用和讨论仅仅为了使本发明的描述清楚,并非承认任何参考文献是本文所描述的发明的现有技术。所有在本说明书中引用和讨论的参考文献均以其全部内容通过引用结合到本文中。本领域技术人员将明白在本文中描述的内容的变型、修改及其他实施方式不背离本发明的精神和范围。尽管已经显示和描述了本发明的某些实施方案,但是可在不背离本发明的精神和范围的情况下进行变化和修改,这对本领域技术人员来说是显而易见的。提供上述说明书和附图中所列的事物仅仅为了举例说明而不是作为限制。
Claims (37)
1.一种治疗哺乳动物的疾病的方法,其包括向所述哺乳动物施用治疗有效量的异紫苏醇的步骤。
2.权利要求1所述的方法,其中所述异紫苏醇选自下组:(4-异亚丙基环己-1-烯基)甲醇、(4-异丙基环己-1,3-二烯基)甲醇、(4-异丙基环己-1,4-二烯基)甲醇、(4-异丙基苯基)甲醇和(4-异丙烯基苯基)甲醇。
3.权利要求1所述的方法,其中所述疾病是癌症。
4.权利要求3所述的方法,其中所述癌症是神经系统的肿瘤。
5.权利要求4所述的方法,其中所述肿瘤是胶质母细胞瘤。
6.权利要求1所述的方法,其进一步包括用放射治疗所述哺乳动物的步骤。
7.权利要求6所述的方法,其中所述异紫苏醇在放射之前、期间或之后施用。
8.权利要求1所述的方法,其进一步包括向所述哺乳动物施用化疗剂的步骤。
9.权利要求8所述的方法,其中所述异紫苏醇在施用所述化疗剂之前、期间或之后施用。
10.权利要求1所述的方法,其中所述异紫苏醇通过吸入、鼻内、口服、静脉内、皮下或肌内方式施用。
11.一种治疗哺乳动物的疾病的方法,其包括向所述哺乳动物施用治疗有效量的异紫苏醇氨基甲酸酯的步骤。
12.权利要求11所述的方法,其中所述疾病是癌症。
13.权利要求12所述的方法,其中所述癌症是神经系统的肿瘤。
14.权利要求13所述的方法,其中所述肿瘤是胶质母细胞瘤。
15.权利要求11的方法,其进一步包括用放射治疗所述哺乳动物的步骤。
16.权利要求11所述的方法,其进一步包括向所述哺乳动物施用化疗剂的步骤。
17.权利要求11所述的方法,其中所述异紫苏醇氨基甲酸酯通过吸入、鼻内、口服、静脉内、皮下或肌内方式施用。
18.权利要求11所述的方法,其中所述异紫苏醇氨基甲酸酯是与治疗剂偶联的异紫苏醇。
19.权利要求18所述的方法,其中所述治疗剂是化疗剂。
20.权利要求19所述的方法,其中所述化疗剂选自下组:DNA烷化剂、拓扑异构酶抑制剂、内质网应激诱导剂、铂化合物、抗代谢物、酶抑制剂和受体拮抗剂。
21.权利要求18所述的方法,其中所述治疗剂选自下组:二甲基塞来昔布(DMC)、替莫唑胺(TMZ)和咯利普兰。
22.一种治疗哺乳动物的疾病的方法,其包括使用经鼻递送装置向所述哺乳动物施用治疗有效量的异紫苏醇或异紫苏醇氨基甲酸酯的步骤。
23.权利要求22所述的方法,其中所述经鼻递送装置选自下组:鼻内吸入器、鼻内喷雾装置、雾化器、喷雾器、定量吸入器(MDI)、加压剂量吸入器、吹药器、单位剂量容器、泵、点滴器、挤压瓶和双向装置。
24.一种药物组合物,其包含异紫苏醇氨基甲酸酯。
25.权利要求24所述的药物组合物,其中所述异紫苏醇氨基甲酸酯是与治疗剂偶联的异紫苏醇。
26.权利要求25所述的药物组合物,其中所述治疗剂是化疗剂。
27.权利要求25所述的药物组合物,其中所述治疗剂选自下组:二甲基塞来昔布(DMC)、替莫唑胺(TMZ)和咯利普兰。
28.权利要求25所述的药物组合物,其中所述化疗剂选自下组:DNA烷化剂、拓扑异构酶抑制剂、内质网应激诱导剂、铂化合物、抗代谢物、酶抑制剂和受体拮抗剂。
29.权利要求24所述的药物组合物,其中所述药物组合物通过吸入、鼻内、口服、静脉内、皮下或肌内方式施用。
30.权利要求24所述的药物组合物,其中所述药物组合物与治疗剂共混或联合配制。
31.一种药物组合物,其包含与治疗剂共混或联合配制的异紫苏醇。
32.一种制备异紫苏醇氨基甲酸酯的方法,其包括使第一反应物异紫苏基氯甲酸酯与选自二甲基塞来昔布(DMC)、替莫唑胺(TMZ)和咯利普兰的第二反应物反应的步骤。
33.权利要求32所述的方法,其中所述第二反应物是二甲基塞来昔布。
34.权利要求32所述的方法,其中所述反应在丙酮和催化剂碳酸钾的存在下进行。
35.权利要求32所述的方法,其中所述第二反应物是咯利普兰。
36.权利要求35所述的方法,其中所述反应在四氢呋喃和催化剂正丁基锂的存在下进行。
37.权利要求32所述的方法,其中异紫苏基氯甲酸酯通过使异紫苏醇与光气反应来制备。
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EP2651864B1 (en) | 2016-07-13 |
CN105616391B (zh) | 2021-03-19 |
EP3130579A1 (en) | 2017-02-15 |
DK2651864T3 (en) | 2016-09-05 |
EP4374929A3 (en) | 2024-08-07 |
US20130331422A1 (en) | 2013-12-12 |
EP2651864A1 (en) | 2013-10-23 |
CN103517892A (zh) | 2014-01-15 |
JP2017125024A (ja) | 2017-07-20 |
US20180280317A1 (en) | 2018-10-04 |
US9211269B2 (en) | 2015-12-15 |
EP3130579B1 (en) | 2024-02-07 |
WO2012083178A1 (en) | 2012-06-21 |
EP2651864A4 (en) | 2014-04-30 |
EP4374929A2 (en) | 2024-05-29 |
CN103517892B (zh) | 2016-01-27 |
JP2014507391A (ja) | 2014-03-27 |
BR112013015107A2 (pt) | 2018-01-23 |
US20150359754A1 (en) | 2015-12-17 |
HK1188984A1 (zh) | 2014-05-23 |
US9987237B2 (en) | 2018-06-05 |
US20200170961A1 (en) | 2020-06-04 |
BR112013015107B1 (pt) | 2022-03-22 |
JP6122564B2 (ja) | 2017-04-26 |
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