CN114599352A - 用于治疗癌症的α-甲基-DL-酪氨酸烷基酯 - Google Patents
用于治疗癌症的α-甲基-DL-酪氨酸烷基酯 Download PDFInfo
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- CN114599352A CN114599352A CN202080075256.2A CN202080075256A CN114599352A CN 114599352 A CN114599352 A CN 114599352A CN 202080075256 A CN202080075256 A CN 202080075256A CN 114599352 A CN114599352 A CN 114599352A
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Abstract
提供了包含α‑甲基‑DL‑酪氨酸烷基酯(或其盐)(例如,α‑甲基‑DL‑酪氨酸甲酯盐酸盐)的药物组合物和药盒。还提供了在对象中治疗癌症的方法,其包括向有此需要的对象施用有效量的α‑甲基‑DL‑酪氨酸烷基酯(或其盐),例如α‑甲基‑DL‑酪氨酸甲酯盐酸盐。
Description
相关申请的交叉引用
本申请要求2019年10月15日提交的美国临时专利申请No.62/915,177的权益,其全部内容通过引用并入本文。
技术领域
本发明一般性地涉及用于如例如在癌症治疗中降低细胞增殖的组合物、药盒(kit)和方法。
背景技术
癌症是美国第二大常见的死亡原因,仅次于心脏病,占死亡的四分之一。据估计,每天有约1600名美国人死于癌症。除了癌症的医疗、情感和心理成本之外,癌症对个人和社会都有巨大的经济成本。
目前癌症治疗包括手术、激素治疗、放射、化学治疗、免疫治疗、靶向治疗及其组合。癌症的手术去除已进展显著;然而,依然有高的疾病复发可能性。使用诸如芳香酶抑制剂和促黄体激素释放激素类似物和抑制剂的药物的激素治疗在治疗前列腺癌和乳腺癌中相对有效。放射及适形质子束放射治疗(conformal proton beam radiation therapy)、立体定向放射外科、立体定向放射治疗、术中放射治疗、化学修饰剂和放射增敏剂的相关技术有效杀伤癌细胞,但也可杀伤和改变周围的正常组织。单独和组合的化学治疗药物例如氨基蝶呤(aminopterin)、顺铂(cisplatin)、甲氨蝶呤(methotrexate)、多柔比星(doxorubicin)、柔红霉素(daunorubicin)等通常通过改变DNA复制过程而有效杀伤癌细胞。生物应答调节剂(Biological response modifier,BRM)治疗、生物学治疗、生物治疗或免疫治疗改变癌细胞生长或影响自然免疫应答,并且涉及向患者施用生物制剂例如干扰素、白介素和其他细胞因子,以及抗体例如利妥昔单抗(rituximab)和曲妥珠单抗(trastuzumab),以及甚至癌症疫苗例如Sipuleucel-T。
已开发了新的靶向治疗来对抗癌症。这些靶向治疗与化学治疗不同,因为化学治疗通过杀伤癌细胞和正常细胞二者(对癌细胞具有更大的作用)而发挥作用。靶向治疗通过影响控制癌细胞生长、分裂和扩散的过程和引起癌细胞自然死亡的信号而发挥作用。一种类型的靶向治疗包括生长信号抑制剂,例如曲妥珠单抗(trastuzumab)、吉非替尼(gefitinib)、伊马替尼(imatinib)、西妥昔单抗(centuximab)、达沙替尼(dasatinib)和尼洛替尼(nilotinib)。另一种类型的靶向治疗包括血管生成抑制剂,例如贝伐单抗(bevacizumab),其抑制癌症增多周围血管系统(vasculature)和血液供应。最后一种类型的靶向治疗包括能够诱导直接的癌细胞死亡的诱导凋亡的药物。
尽管所有这些治疗在某种程度上都有效,但它们都具有缺点和限制。除了许多治疗是昂贵的之外,它们通常也太不精确或者癌症能够适应它们并且变得有抗性。
因此,非常需要另外的癌症治疗。特别地,需要用于已经对其他形式的治疗变得有抗性的癌症的治疗。
发明内容
本发明提供了用于降低过度细胞增殖(包括与癌症治疗相关)的组合物、组合治疗、药盒和方法。在一个方面,本发明提供了药物组合物,其包含:至少一种α-甲基-DL-酪氨酸烷基酯(或其可药用盐),例如α-甲基-酪氨酸甲酯盐酸盐。本发明还提供了药物组合物,其还包含:至少一种酪氨酸羟化酶抑制剂;黑素、黑素促进剂、或其组合中的至少一种;至少一种P450 3A4促进剂;至少一种亮氨酸氨肽酶抑制剂;以及任选地至少一种生长激素抑制剂。在另一些方面,本发明提供了包含这些组分和合适的包装的药盒。还提供了降低细胞增殖的方法和/或治疗癌症的方法,其包括向有此需要的对象施用有效量的单独的或与以下组合的α-甲基-DL-酪氨酸烷基酯(或其可药用盐),例如α-甲基-酪氨酸甲酯盐酸盐:黑素、黑素促进剂、或其组合中的至少一种;至少一种P450 3A4促进剂;至少一种亮氨酸氨肽酶抑制剂;以及任选地至少一种生长激素抑制剂。
具体实施方式
通过参考形成本公开内容的一部分的以下详细描述可更容易地理解本主题。应理解,本发明不限于本文中所述和/或示出的特定产品、方法、条件或参数,并且本文中使用的术语仅用于通过实例来描述一些特定实施方案的目的,并非旨在对所要求保护的发明进行限制。
除非本文中另有定义,否则结合本申请使用的科学和技术术语应具有本领域普通技术人员通常理解的含义。此外,除非上下文另外要求,否则没有数量词修饰的名词表示一个/种或更多个/种。
除非另有说明,否则上文和本公开内容通篇中使用的以下术语和缩写应理解为具有以下含义。
除非上下文中另有明确说明,否则在本公开内容中没有数量词修饰的名词表示一个/种或更多个/种,并且对特定数值的提及包括至少所述特定值。因此,例如,提及“化合物”是指一个或更多个这样的化合物和本领域技术人员已知的其等同物等。本文中使用的术语“多个”意指多于一个。当表达值的范围时,另一个实施方案包括从一个特定值和/或至另一个特定值。类似地,当通过使用在前的“约”将值表示为近似值时,应理解特定值形成另一个实施方案。所有范围都包括端值且是可组合的。
术语“烷基”是指具有1至12个碳原子(“C1-C12”),优选地1至6个碳原子(“C1-C6”)的直链或支链烃基团。烷基的实施例包括甲基(Me,C1烷基)、乙基(Et,C2烷基)、正丙基(C3烷基)、异丙基(C3烷基)、丁基(C4烷基)、异丁基(C4烷基)、仲丁基(C4烷基)、叔丁基(C4烷基)、戊基(C5烷基)、异戊基(C5烷基)、叔戊基(C5烷基)、己基(C6烷基)、异己基(C6烷基)等。
本文中使用的术语“组分”、“组合物”、“化合物的组合物”、“化合物”、“药品”、“药理学活性剂”、“活性剂”、“治疗剂”、“疗法”、“治疗”或“药物”在本文中可互换使用,是指当向对象(人或动物)施用时通过局部和/或全身作用诱导期望的药理学和/或生理学效果的化合物或物质的组合物。
本文中使用的术语“治疗”或“疗法”(及其不同形式)包括预防性(例如,预防)、治愈性或姑息性治疗。本文中使用的术语“治疗”包括减轻或降低病症、疾病或障碍的至少一种不利或负面的作用或症状。这种病症、疾病或障碍可以是癌症。
以上和整个公开内容中所采用的术语“有效量”是指在剂量和必要的持续时间下有效地实现关于相关障碍、病症或副作用的治疗的期望结果的量。应当理解,本发明组分的有效量会随患者而不同,不仅与所选的特定化合物、组分或组合物,施用途径以及组分在个体中引起期望结果的能力有关,还与例如以下因素有关:待缓解的病症的严重程度或疾病状态,个体的激素水平、年龄、性别、体重,患者当时的状态以及治疗中的病理性状况的严重程度、同时使用的药物或特殊饮食,然后是特定患者以及本领域技术人员会意识到的其他因素,恰当的剂量由主治医师判断。可调整剂量方案以提供改进的治疗响应。有效量也是其中组分的治疗有益作用胜过任何毒性或有害作用的量。
“可药用”是指在合理的医学判断范围内适合用于与人和动物的组织相接触而没有过度的毒性、刺激、变态反应或其他问题并发症,与合理的收益/风险比匹配的那些化合物、材料、组合物和/或剂型。
在本发明内,所公开的化合物可以以可药用盐的形式制备。“可药用盐”是指所公开的化合物的衍生物,其中母体化合物通过制备其酸式或碱式盐来修饰。可药用盐的实例包括但不限于碱性残基(例如胺)的无机或有机酸盐;酸性残基(例如羧酸)的碱式盐或有机盐;等。可药用盐包括例如由无毒性无机或有机酸形成的母体化合物的常规无毒性盐或季铵盐。例如,这样的常规无毒性盐包括来自于无机酸(例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等)的那些;以及由有机酸(例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸(sulfanilic acid)、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙磺酸(isethionic acid)等)制备的盐。通过本领域中已知的方法来制备这些生理学上可接受的盐,例如通过将游离的胺碱溶解在醇水溶液中的过量酸中,或者通过用碱金属碱(例如氢氧化物)或胺中和游离羧酸。
本文所述的化合物可以以替代形式制备。例如,许多含氨基化合物可以作为酸加成盐使用或制备。这样的盐通常改善了化合物的分离和处理特性。例如,取决于试剂、反应条件等,如本文中所述的化合物可用作或制备成例如其盐酸盐或甲苯磺酸盐。同构的结晶形式、所有手性和外消旋形式、N-氧化物、水合物、溶剂合物和酸式盐的水合物也被考虑在本发明的范围之内。
本发明的某些酸性或碱性化合物可作为两性离子存在。化合物的所有形式(包括游离酸、游离碱和两性离子)被考虑在本发明的范围之内。本领域中公知,含有氨基和羧基二者的化合物经常与其两性离子形式平衡存在。因此,含有例如氨基和羧基二者的任何本文中所述化合物也包括提及其相应的两性离子。
术语“立体异构体”是指具有相同化学组成但在原子或基团的空间排列方面不同的化合物。
术语“施用”意指直接施用本发明的化合物或组合物,或者施用将在体内形成等量的活性化合物或物质的前药、衍生物或类似物。
术语“对象”、“个体”和“患者”在本文中可互换使用,并且是指向其提供用根据本发明的药物组合物进行治疗(包括预防性治疗)的动物(例如人)。本文中使用的术语“对象”是指人或非人动物。术语“非人动物”和“非人哺乳动物”在本文中可互换使用并且包括所有脊椎动物,例如哺乳动物,例如非人灵长类动物(特别是高级灵长类动物)、绵羊、犬、啮齿动物(例如小鼠或大鼠)、豚鼠、山羊、猪、猫、兔、牛、马;以及非哺乳动物,例如爬行动物、两栖动物、鸡和火鸡。
本文中使用的术语“抑制剂”包括抑制蛋白质、多肽或酶的表达或活性(但不一定意味着完全抑制表达和/或活性)的化合物。更确切地,抑制包括抑制蛋白质、多肽或酶的表达和/或活性至足以产生期望效果的程度和时间。
本文中使用的术语“促进剂”包括促进蛋白质、多肽或酶的表达或活性(但不一定意味着完全促进表达和/或活性)的化合物。更确切地,促进包括促进蛋白质、多肽或酶的表达和/或活性至足以产生期望效果的程度和时间。
本发明的α-甲基-DL-酪氨酸烷基酯可以作为其各自的D和L异构体中的任一者或两者存在。根据本发明的α-甲基-酪氨酸甲酯可以作为其各自的D和L异构体中的任一者或两者存在。优选使用α-甲基-DL-酪氨酸甲酯盐酸盐。α-甲基-DL-酪氨酸烷基酯(及其盐)可以单独使用或与其他癌症治疗剂组合使用。α-甲基-DL-酪氨酸甲酯盐酸盐可以单独使用或与其他癌症治疗剂组合使用。
虽然无意于受任何特定操作机制的束缚,但α-甲基-DL-酪氨酸烷基酯通过在癌细胞中积聚(作为烷基酯或游离酸)并防止其形成脂质或透明质酸的包衣而起作用。通过防止癌细胞形成脂质或透明质酸的包衣,癌细胞被认为更容易受到氧化应激。
在一个方面,本发明提供了改变癌细胞对氧化应激的防御的组合治疗。一类这样的治疗提高了对癌细胞的自由基可用性。这样的治疗的代表性的亚类涉及施用包含酪氨酸羟化酶抑制剂、黑素或黑素促进剂、p450 3A4促进剂、亮氨酸氨肽酶抑制剂以及任选地生长激素抑制剂的药物组合物。另一亚类涉及施用包含黑素和酪氨酸羟化酶抑制剂的药物组合物。药物组合物的特定组分如下所述。
本发明还可涉及使用黑素、黑素促进剂、或其组合中的至少一种。因此,可以使用黑素,可以使用一种或更多种黑素促进剂,并且可以使用黑素和一种或更多种黑素促进剂二者(在分开的剂型中或在相同的剂型中)。根据本发明的黑素促进剂是提高黑素的产生和/或活性的化学化合物。代表性的黑素促进剂是甲氧沙林(methoxsalen)和美拉诺坦(melanotan)II。
在一些情况下,α-甲基-DL-酪氨酸烷基酯(或其盐)与黑素在相同剂型中混合。在一些方面,α-甲基-DL-酪氨酸甲酯盐酸盐与黑素在相同剂型中混合。在某些情况下,将黑素溶解在增溶剂中,然后通过本领域已知的方法与α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)混合。可通过标准技术例如蒸发、干燥等除去增溶剂。增溶剂可以是无毒增溶剂,例如过氧化氢或本领域中公知的其他增溶剂。可进一步处理黑素和/或药物组合物以优化药物组合物对癌细胞的作用。在另一方面,药物组合物可包含另外的活性剂和/或药物赋形剂。
本发明的方法还可包括施用p450 3A4促进剂。“细胞色素p450 3A4”(其可以缩写为“p450 3A4”)是细胞色素p450超家族酶的成员,并且是参与体内外源物(xenobiotics)的代谢的混合功能氧化酶。其在所有细胞色素中具有最广泛的底物。本发明药物组合物中p450 3A4促进剂的功能是提高p450 3A4的表达和/或活性。提高的P450 3A4表达和/或活性被认为降低患者的可的松和雌激素水平。此外,提高的P450 3A4的表达和/或活性也轻微降低血液pH,这被认为有助于保持或增强黑素活性。代表性的p450 3A4促进剂是5,5-二苯基乙内酰脲(商业上以例如Dilantin销售)、丙戊酸和卡马西平(carbamazepine),它们被认为诱导p4503A4酶的表达。
本发明方法还包括施用亮氨酸氨肽酶抑制剂(或者称为亮氨酰氨肽酶抑制剂)。亮氨酸氨肽酶是优先催化肽和/或蛋白质的N端的亮氨酸残基水解的酶。代表性的亮氨酸氨肽酶抑制剂是N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸和雷帕霉素(rapamycin)。
本发明方法任选地还可包括施用生长激素抑制剂。生长激素(例如胰腺生长激素)诱导细胞复制。代表性的生长激素抑制剂是奥曲肽(octreotide)、生长抑素和司格列肽(seglitide)。
本发明的方法还可包括施用D-亮氨酸。D-亮氨酸是天然存在的L-亮氨酸的立体异构体,L-亮氨酸是并入到多肽和蛋白质中的亮氨酸形式。D-亮氨酸不能并入到多肽和/或蛋白质中。D-亮氨酸的存在可允许在药物组合物中使用较低剂量的亮氨酸氨肽酶抑制剂。
本文还提供了包含使癌细胞对氧化应激的防御发生改变的组合治疗的药盒。预期的合适的药盒包含提高对癌细胞自由基可用性的组合治疗。代表性的药盒包含单独的或与以下组合的α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)及其包装:上述类型的另一种癌症治疗剂和/或黑素和/或黑素促进剂、p450 3A4促进剂、亮氨酸氨肽酶抑制剂以及任选地生长激素抑制剂。药盒可包含一个或更多个单独的容器、分隔物或隔室,以及任选地信息材料(例如施用说明书)。例如,每种抑制剂或促进剂(或其多种组合)可包含在瓶子、小瓶或注射器中,并且信息材料可包含在塑料套管或包装中或以标签提供。在一些方面,药盒包含多个(例如,一包)单独的容器,每个容器包含本文中所述化合物的一个或更多个单位剂型。例如,药盒可包含多个注射器、安瓿、箔包装或泡罩包装,每个包含单个单位剂量的本文中所述化合物或其多种组合中的任何一种。药盒的容器可以是气密的、防水的(例如,对水分或蒸发的变化不可渗透)和/或不透光的。药盒任选地包含适合于施用所述组合物的装置,例如注射器、吸入器(inhalant)、移液管、镊子、测量匙、滴管(例如,滴眼管)、拭子(例如棉签或木拭子)或任何这样的递送装置。
还提供了在对象中治疗癌症的方法,以及降低过度细胞增殖的方法。这样的方法可包括施用有效量的单独的或作为使癌细胞对氧化应激的防御发生改变的组合治疗的一部分的α-甲基-DL-酪氨酸烷基酯(或其盐),例如α-甲基-DL-酪氨酸甲酯盐酸盐。治疗癌症的代表性的方法包括施用有效量的单独的或作为提高对癌细胞的自由基可用性的组合治疗的一部分的α-甲基-DL-酪氨酸烷基酯(或其盐),例如α-甲基-DL-酪氨酸甲酯盐酸盐。合适的方法包括施用有效量的单独的或与以下一起的α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐):上述酪氨酸羟化酶抑制剂、黑素和/或黑素促进剂、p450 3A4促进剂、亮氨酸氨肽酶抑制剂以及任选地生长激素抑制剂。另一些合适的方法包括施用有效量的黑素和酪氨酸羟化酶抑制剂。
合适的方法包括同时(simultaneous)或至少同时期(contemporaneous)施用α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐),以及黑素或黑素促进剂、p450 3A4促进剂和亮氨酸氨肽酶抑制剂中的至少一者、它们中的至少两者或它们中的每一者(在每种情况下,任选地与生长激素抑制剂一起)。期望数量的抑制剂和促进剂可以以单一剂型或任何数量的期望剂型(包括单独的剂型)提供。
代表性的剂型包括片剂、胶囊剂、囊片剂、无菌水性或有机溶液、可重构的粉末、酏剂、液体、胶体或其他类型的混悬剂、乳剂、珠、珠粒(beadlet)、颗粒、微粒、纳米颗粒及其组合。当然,施用的组合物的量将取决于所治疗对象、对象的重量、所治疗病症的严重程度、施用方式以及处方医师的判断。
α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)的施用可通过多种途径,包括经口、经鼻、皮下、静脉内、肌内、经皮、经阴道、经直肠或以其任意组合进行。α-甲基-DL-酪氨酸甲酯盐酸盐优选地非经口施用,包括皮下、静脉内、肌内或经皮施用,优选地以水溶液的形式。经皮施用可通过使用例如油酸、1-甲基-2-吡咯烷酮或十二烷基壬氧基乙二醇单醚(dodecylnonaoxyethVlene glycol monoether)来实现。
黑素、促进剂和/或抑制剂的施用可以通过多种途径,包括经口、经鼻、皮下、静脉内、肌内、经皮、经阴道、经直肠或以其任意组合进行。经皮施用可以使用例如油酸、1-甲基-2-吡咯烷酮或十二烷基壬氧基乙二醇单醚来实现。
黑素、促进剂和/或抑制剂可以在由施用黑素、促进剂和/或抑制剂五至七天和不施用黑素、促进剂和/或抑制剂一至两天组成的周期期间施用。可以施用黑素、促进剂和/或抑制剂至少六个所述周期的疗程。可能期望在两餐之间约两小时施用这些组分以促进摄取。
施用本发明组合物的对象可以是哺乳动物,优选人。
在另一个代表性的方法中,经口施用60mg的α-甲基-DL-酪氨酸甲酯盐酸盐,并且皮下施用0.25mL的2mg/mL酪氨酸衍生物混悬剂;经口施用10mg甲氧沙林,并且皮下施用0.25mL的1mg/mL甲氧沙林混悬剂;经口施用30mg的5,5-二苯基乙内酰脲;以及经口施用20mg的N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸。
代表性的方法包括其中癌症是非小细胞肺癌的那些。在某些实施方案中,非小细胞肺癌是IV期非小细胞肺癌。在另一些实施方案中,癌症是卵巢癌、乳腺癌、宫颈癌、胰腺癌、胃癌、脑癌、肝癌、睾丸癌、白血病、淋巴瘤、阑尾癌、胆道癌、胆管癌、结肠癌、结肠直肠癌、生殖细胞瘤、胶质瘤、霍奇金淋巴瘤、肺癌、神经母细胞瘤、前列腺癌、肾癌、肉瘤、甲状腺癌、舌癌、扁桃体鳞状细胞癌或尿路上皮癌。可以评估在所述对象中所述癌症的进展。
本发明方法不仅可以包括公开的施用步骤,还可以包括评估所述对象中所述癌症的进展和/或细胞增殖程度的步骤。评估步骤可以在施用步骤之前或之后进行。
包含α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)的药物组合物还可包含生长激素抑制剂。生长激素可以是胰腺生长激素。生长激素抑制剂可以是奥曲肽或生长抑素。
黑素促进剂可以是甲氧沙林或美拉诺坦II。p450 3A4促进剂可以是5,5-二苯基乙内酰脲。p450 3A4促进剂可以是丙戊酸或卡马西平。亮氨酸氨肽酶抑制剂可以是N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸或雷帕霉素。本发明的药物组合物还可包含D-亮氨酸。
还提供了在对象中治疗癌症的方法,其包括施用有效量的单独的或与上述药剂中的一种或更多种组合的α-甲基-DL-酪氨酸烷基酯(或其盐),例如α-甲基-DL-酪氨酸甲酯盐酸盐。在某些方面,α-甲基-DL-酪氨酸甲酯盐酸盐与至少两种药剂(例如,黑素、促进剂和/或抑制剂)同时施用。在另一些方面,α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)与至少三种药剂同时施用。α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)和药剂各自可以同时施用。施用可以是经口、皮下、静脉内、经皮、经阴道、经直肠或以其任意组合。经皮施用可以用油酸、1-甲基-2-吡咯烷酮或十二烷基壬氧基乙二醇单醚进行。α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)与药剂可以在由施用组分的五至七天和不施用组分的一至两天组成的周期期间施用。α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐)与药剂可以在至少六个所述周期的过程中施用。黑素促进剂可以是甲氧沙林。在另一个合适的方法中,经口施用10mg甲氧沙林,并且皮下施用0.25mL的1mg/mL甲氧沙林混悬剂。黑素促进剂也可以是美拉诺坦II。p450 3A4促进剂可以是5,5-二苯基乙内酰脲。在另一个合适的方法中,经口施用30mg的5,5-二苯基乙内酰脲。p450 3A4促进剂也可以是丙戊酸或卡马西平。亮氨酸氨肽酶抑制剂可以是N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸。在另一个合适的方法中,经口施用20mg的N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸。亮氨酸氨肽酶抑制剂也可以是雷帕霉素。生长激素可以是胰腺生长激素。生长激素抑制剂可以是奥曲肽。该方法还可包括施用有效量的D-亮氨酸。
还提供了在对象中降低细胞增殖的方法,其包括向有此需要的对象施用有效量的单独的或与以下组合的α-甲基-DL-酪氨酸烷基酯(或其盐)(例如,α-甲基-DL-酪氨酸甲酯盐酸盐):黑素和/或黑素促进剂、p450 3A4促进剂以及亮氨酸氨肽酶抑制剂。降低细胞增殖的方法还可包括施用生长激素抑制剂。
还提供了施用药物组合物和组合治疗的代表性的方法。本发明的多个方面还涉及向人患者施用药物组合物或组合治疗以用于治疗癌症的方法。该方法可包括通过通常可接受的施用途径(例如经口、皮下、胃肠外、吸入、表面等)施用药物组合物或组合治疗。在一些情况下,药物组合物或组合治疗可经口和/或皮下施用。在一些情况下,药物组合物或组合治疗可在两餐之间向人患者施用。
在本发明的某些方面,药物组合物或组合治疗可每周5天向人患者施用,持续6周,产生30个治疗日的一个周期。根据6周或一个治疗周期之后的结果,可施用药物组合物或组合治疗的另外周期。
在一些实施方案中,本公开内容涉及以下方面:
方面1.用于在患者中治疗癌症的方法,其包括向有此需要的患者施用药物组合物,所述药物组合物包含至少一种α-甲基-DL-酪氨酸烷基酯或其可药用盐。
方面2.方面1所述的方法,其中所述烷基酯是α-甲基-DL-酪氨酸甲酯。
方面3.方面1或方面2所述的方法,其中向所述患者施用至少一种α-甲基-DL-酪氨酸烷基酯的可药用盐。
方面4.方面2所述的方法,其中所述盐是α-甲基-DL-酪氨酸甲酯盐酸盐。
方面5.前述方面中任一项所述的方法,其还包括向所述患者施用以下至少之一:
·黑素,为甲氧沙林或美拉诺坦II的黑素促进剂,或者黑素、甲氧沙林和美拉诺坦II的组合;
·p450 3A4促进剂,其为5,5-二苯基乙内酰脲、丙戊酸或卡马西平;以及
·亮氨酸氨肽酶抑制剂,其为N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸或雷帕霉素。
方面6.前述方面中任一项所述的方法,其中所述药物组合物皮下、静脉内、肌内或经皮施用。
方面7.前述方面中任一项所述的方法,其中所述药物组合物是水溶液。
方面8.前述方面中任一项所述的方法,其中所述癌症是非小细胞肺癌、卵巢癌、乳腺癌、宫颈癌、胰腺癌、胃癌、脑癌、肝癌、睾丸癌、白血病、淋巴瘤、阑尾癌、胆道癌、胆管癌、结肠癌、结肠直肠癌、生殖细胞瘤、胶质瘤、霍奇金淋巴瘤、肺癌、神经母细胞瘤、前列腺癌、肾癌、肉瘤、甲状腺癌、舌癌、扁桃体鳞状细胞癌或尿路上皮癌。
方面9.前述方面中任一项所述的方法,其还包括向所述患者施用用于治疗癌症的另外的治疗剂。
Claims (18)
1.用于在患者中治疗癌症的方法,其包括向有此需要的患者施用药物组合物,所述药物组合物包含至少一种α-甲基-DL-酪氨酸烷基酯或其可药用盐。
2.权利要求1所述的方法,其中所述烷基酯是α-甲基-DL-酪氨酸甲酯。
3.权利要求1或权利要求2所述的方法,其中向所述患者施用至少一种α-甲基-DL-酪氨酸烷基酯的可药用盐。
4.权利要求3所述的方法,其中所述盐是α-甲基-DL-酪氨酸甲酯盐酸盐。
5.前述权利要求中任一项所述的方法,还包括向所述患者施用以下至少之一:
·黑素,为甲氧沙林或美拉诺坦II的黑素促进剂,或者黑素、甲氧沙林和美拉诺坦II的组合;
·p450 3A4促进剂,其为5,5-二苯基乙内酰脲、丙戊酸或卡马西平;以及
·亮氨酸氨肽酶抑制剂,其为N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸或雷帕霉素。
6.前述权利要求中任一项所述的方法,其中所述药物组合物皮下、静脉内、肌内或经皮施用。
7.前述权利要求中任一项所述的方法,其中所述药物组合物是水溶液。
8.前述权利要求中任一项所述的方法,其中所述癌症是非小细胞肺癌、卵巢癌、乳腺癌、宫颈癌、胰腺癌、胃癌、脑癌、肝癌、睾丸癌、白血病、淋巴瘤、阑尾癌、胆道癌、胆管癌、结肠癌、结肠直肠癌、生殖细胞瘤、胶质瘤、霍奇金淋巴瘤、肺癌、神经母细胞瘤、前列腺癌、肾癌、肉瘤、甲状腺癌、舌癌、扁桃体鳞状细胞癌或尿路上皮癌。
9.前述权利要求中任一项所述的方法,其还包括向所述患者施用用于治疗癌症的另外的治疗剂。
10.药物组合物,其包含至少一种α-甲基-DL-酪氨酸烷基酯或其可药用盐,所述药物组合物用于在有此需要的患者中治疗癌症的方法中,其中所述方法包括向所述患者施用所述药物组合物。
11.权利要求10所述的药物组合物,其中所述烷基酯是α-甲基-DL-酪氨酸甲酯。
12.权利要求10或权利要求11所述的药物组合物,其中所述药物组合物包含至少一种可药用的α-甲基-DL-酪氨酸烷基酯盐。
13.权利要求12所述的药物组合物,其中所述盐是α-甲基-DL-酪氨酸甲酯盐酸盐。
14.权利要求10至13中任一项所述的药物组合物,其中用于治疗癌症的所述方法还包括向所述患者施用以下至少之一:
·黑素,为甲氧沙林或美拉诺坦II的黑素促进剂,或者黑素、甲氧沙林和美拉诺坦II的组合;
·p450 3A4促进剂,其为5,5-二苯基乙内酰脲、丙戊酸或卡马西平;以及
·亮氨酸氨肽酶抑制剂,其为N-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基]-L-亮氨酸或雷帕霉素。
15.权利要求10至14中任一项所述的药物组合物,其中所述药物组合物皮下、静脉内、肌内或经皮施用。
16.权利要求10至15中任一项所述的药物组合物,其中所述药物组合物是水溶液。
17.权利要求10至16中任一项所述的药物组合物,其中所述癌症是非小细胞肺癌、卵巢癌、乳腺癌、宫颈癌、胰腺癌、胃癌、脑癌、肝癌、睾丸癌、白血病、淋巴瘤、阑尾癌、胆道癌、胆管癌、结肠癌、结肠直肠癌、生殖细胞瘤、胶质瘤、霍奇金淋巴瘤、肺癌、神经母细胞瘤、前列腺癌、肾癌、肉瘤、甲状腺癌、舌癌、扁桃体鳞状细胞癌或尿路上皮癌。
18.权利要求10至17中任一项所述的药物组合物,其中用于治疗癌症的所述方法还包括向所述患者施用用于治疗癌症的另外的治疗剂。
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PCT/US2020/055727 WO2021076723A1 (en) | 2019-10-15 | 2020-10-15 | Alkylesters of alpha-methyl-dl-tyrosine for use in treating cancer |
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