CN117580847A - 大环内酯化合物 - Google Patents
大环内酯化合物 Download PDFInfo
- Publication number
- CN117580847A CN117580847A CN202280045862.9A CN202280045862A CN117580847A CN 117580847 A CN117580847 A CN 117580847A CN 202280045862 A CN202280045862 A CN 202280045862A CN 117580847 A CN117580847 A CN 117580847A
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- Prior art keywords
- alkyl
- compound
- aryl
- substituted
- heterocyclyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 161
- 239000003120 macrolide antibiotic agent Substances 0.000 title abstract description 23
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- 238000000034 method Methods 0.000 claims description 67
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- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 44
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 150000003254 radicals Chemical class 0.000 claims description 36
- 125000000304 alkynyl group Chemical group 0.000 claims description 35
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Landscapes
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
本文公开了具有ATP合酶抑制活性的大环内酯化合物。大环内酯类可用于治疗癌症和其他增殖性疾病。大环内酯类可用于治疗白血病,包括急性髓性白血病。大环内酯类可用于治疗已产生多重耐药性的患者的癌症,包括AML。在一些实施例中,大环内酯为阿矛西丁A的衍生物。
Description
相关申请的交叉引用
本申请要求于2021年5月27日提交的美国临时申请63/193,959的权益,该申请的内容全部并入本文。
政府支持声明
本发明是在由美国国立卫生研究院授予的授权号CA226833下由政府支持进行的。政府享有本发明中的某些权利。
技术领域
本发明涉及具有ATP合酶/ATP酶抑制活性的新型大环内酯化合物。这些化合物可用于多种治疗环境,包括作为抗癌剂、抗生素和免疫抑制剂。
背景技术
癌症是一种以异常克隆细胞增殖、不良细胞分化、以及浸润其他组织器官、骨髓和外周血为特征的疾病。急性髓性白血病(AML)是一种起源于造血干细胞和祖细胞的恶性克隆性疾病,5年生存率低于30%。AML通常采用细胞毒性化疗治疗,缓解率可能在30-75%之间,但复发也很常见。白血病细胞对标准细胞毒性化疗药物的耐药性仍然是治疗AML的主要障碍。肿瘤耐药主要分为原发性耐药和获得性耐药。原发性耐药意味着在使用抗肿瘤药物之前对药物治疗天然缺乏敏感性(例如细胞毒性化疗和未能影响非增殖G0期中的非循环细胞)。获得性耐药是指随着时间的推移,由于肿瘤衍生的分子耐药机制而失去对化疗的敏感性,使得先前有效的药物失效。
大环内酯类包括结构和药理学上不同的一类天然产物,选择性地作用于同样多样化的一系列细胞靶标,诸如免疫抑制信号传导(FK-506、FKB12钙调神经磷酸酶)、剪接因子(SF3b、pladienolide)、核糖体(阿奇霉素、红霉素)、以及离子通道(伊维菌素、谷氨酸门控氯离子通道)。此外,结构家族内的变异可以具有完全不同的靶向特性,这激发了针对通过化学合成和生物合成途径工程化生成修饰的大环内酯类的显著活性。相应地,大环内酯类的影响已在临床中和在作为化学生物学工具以揭示对细胞生物学的新见解上得到认识。
凋亡素A(Apoptolidin A)(图1)最初是在筛选E1A癌基因转化细胞系中细胞凋亡的选择性诱导剂时发现的,并且是从一种被命名为Nocardiopsis sp.的菌株中分离得到的。值得注意的是,凋亡素对转化细胞(10nM)的效力为对未转化细胞系(10μM)的效力的1,000倍。对该化合物与NCI-60系列相比的进一步评估表明,不表现出瓦氏效应(Warburgeffect),而是依赖于氧化磷酸化的细胞系中活性最高(低纳摩尔)。一系列间接的细胞和生化研究与凋亡素A的分子靶标为FOF1 ATP合酶一致。然而,与经过验证的FO亚基抑制剂寡霉素相比,凋亡素的细胞系差异选择性和细胞反应曲线有所不同,表明该家族具有不同的作用模式。最近的研究表明,与之前描述的ATP合酶抑制剂相比,凋亡素家族中大环内酯类在不同的变构位点与ATP合酶的F1亚复合物结合。结构相关的天然产物阿矛西丁A(ammocidinA)(图2)是在针对Ras癌基因转化细胞系的筛选中从Saccharothrix sp.AJ9571分离得到的。Amycolatopsin(图3)是另一种结构相关的大环内酯,是从Amycolatopsis sp.MST-108494中分离得到的。
虽然天然存在的大环内酯类具有令人感兴趣的生理特性,但由于溶解度、生物利用度、稳定性或选择性方面的限制,它们不一定是理想的药物物质。仍然需要具有增强的效力、改善的药代动力学特征、化学稳定性和/或降低的毒性的ATP合酶抑制剂。仍然需要改进的治疗方法来治疗增殖性疾病,包括癌症,特别是白血病。仍然需要用于治疗AML和其他癌症的改进的治疗剂,且该治疗剂不会随着时间的推移而丧失功效。仍然需要改进的癌症治疗方法,其不会激活或加剧一般癌症尤其是白血病的多重耐药性。仍然需要改进的癌症治疗方法,其对已产生多重耐药性的癌症是有效的。
发明内容
根据所公开的材料和方法的目的,如本文所体现和广泛描述的,所公开的主题一方面涉及化合物、组合物以及制备和使用化合物和组合物的方法。
另外的优点将部分地在以下描述中阐述,并且将部分地从描述中显而易见,或者可以通过下面描述的方面的实践来获知。下面描述的优点将通过所附权利要求中特别指出的要素和组合来实现和获得。应当理解,前面的一般描述和以下详细描述仅是示例性和说明性的,而不是限制性的。
在以下说明中阐述了一个或多个实施例的细节。其它特征、目标和优点将从说明书以及权利要求书中显而易见。
附图说明
图1描述了凋亡素A(apoptolidin A)的化学结构。
图2描述了阿矛西丁A(ammocidin A)的化学结构。
图3描述了amycolatopsin A的化学结构。
图4a描述了ApoJ/K分析和生化旁路。ApoJ/K是甲氧基丙二酰-ACP加载所必需的,但对于使用起始单位替代物的生化旁路来说则不需要。
图4b描述了与apoJK无效菌株一起合成和孵育的起始单位替代物。
图4c描述了apoJK靶向删除以及与天然负载单元、高级二酮化合物和起始单位类似物的化学互补的HPLC/MS分析。
图5A描述了KK-32-011/VU936203A的结构。
图5B描述了KK-32-011/VU936203B的结构。
图5C描述了KK-32-012/VU936195A的结构。
图5D描述了KK-32-012/VU936195B的结构
图6描述了MTT活力测定中根据阿矛西丁衍生物的MV-4-11人白血病细胞系的活力。
图7描述了MV-4-11细胞系衍生的异种移植模型中阿矛西丁A(方形数据点)、维奈托克+阿扎西丁(三角形数据点)以及维奈托克+阿扎西丁+阿矛西丁(星形数据点)之间的功效相当。
图8描述了以0.25mg/kg剂量施用阿矛西丁A和阿矛西丁衍生物的小鼠中的药代动力学数据。对于类似物VU936195B(195B)和VU936203B(203B),只能检测到游离的阿矛西丁A。
图9A描述了维奈托克和阿矛西丁A针对AML细胞系Molm-13的经72小时对比数据。
图9B描述了维奈托克和阿矛西丁A针对AML细胞系MV-4-11的经72小时对比数据。
图9C描述了维奈托克和阿矛西丁A针对AML细胞系OCI-AML-3的经72小时对比数据。
图9D描述了维奈托克和阿矛西丁A针对AML细胞系KMS-12的经72小时对比数据。
图10A描述了暴露于阿矛西丁A和维奈托克的组合后48小时的Molm-13细胞活力。图10B描述了阿矛西丁A和维奈托克的组合针对Molm-13细胞的协同评分。
图11A描述了暴露于阿矛西丁A和维奈托克的组合后48小时的MV-4-11细胞活力。图11B描述了阿矛西丁A和维奈托克的组合针对MV-4-11细胞的协同评分。
图12A描述了暴露于阿矛西丁A和维奈托克的组合后48小时的原代AML细胞的活力。图12B描述了阿矛西丁A和维奈托克的组合针对源自患者的原代AML细胞的协同评分。
图13A描述了暴露于阿矛西丁A和维奈托克的组合后72小时的KMS-12细胞活力。图13B描述了阿矛西丁A和维奈托克的组合针对KMS-12细胞的协同评分。
图14A使用来自Prism的活力GI50数据(来自双对数回归的GI50)描述了针对三个原代AML患者样品的阿矛西丁A活性。18-12-001=0.0302μM(0.0312μM);17-03-006=0.0103μM(0.0321μM);29-09-002=0.0158μM(0.0217μM)。数据收集于2021年7月8日。
图14B使用来自Prism的活力GI50数据(来自双对数回归的GI50)描绘了针对两个原代AML患者样品的阿矛西丁A活性。18-12-001=0.0284μM(0.07536μM);17-03-006=0.0095μM(0.0308μM)。数据收集于2022年3月8日。
具体实施方式
在公开和描述本发明的方法和系统之前,应理解,所述方法和系统不限于特定的合成方法、特定组分或特定组成物。还应理解,本文所使用的术语仅出于描述特定实施例的目的,而不希望是限制性的。
如在说明书和所附权利要求中所使用的,单数形式“一个”、“一种”和“该”包括复数指示物,除非上下文中另有明确规定。在本文中,范围可以表达为从“约”一个特定值和/或到“约”另一特定值。当表达这样的范围时,另一实施例包括从一个特定值和/或到另一个特定值。类似地,当通过使用先行词“约”将值表达为近似值时,应理解,所述特定值形成另一实施例。应进一步理解,每个范围的端点相对于另一端点,以及独立于另一端点都是显著的。
“任选的”或“任选地”意味着,随后描述的事件或情形可能会或可能不会发生,并且所述描述包含所述事件或情形发生的例项及所述事件或情形未发生的例项。
贯穿本说明书的具体实施方式和权利要求书,词语“包括(comprise)”和该词语的变体,例如“包括(comprising和comprises)”,意指“包含但不限于”,并且不希望排除例如其它添加物、组件、整体或步骤。“示例性”意指“…的实例”并且不希望传达优选的或理想的实施例的指示。“例如(such as)”不是以限制性的意义使用,而是出于解释性的目的。
公开了可以用于执行所公开的方法和系统的组件。本文公开这些和其它组件,且应理解,当公开这些组件的组合、子集、交互、群组等时,尽管可能未明确地公开对这些组件的每一不同的个别和集体组合及排列的具体提及,但针对所有方法和系统,在本文中具体地审慎考虑和描述每一组合和排列。这适用于本申请的所有方面,包含(但不限于)所公开的方法中的步骤。因此,如果存在可以执行的多种另外的步骤,则应理解,可以利用所公开方法的任何特定实施例或实施例的组合来执行这些另外的步骤中的每一个。
除非有相反说明,化学键仅显示为实线而不显示为楔形或虚线的化学式考虑了每种可能的异构体,例如每种对映异构体、非对映异构体和内消旋化合物,以及异构体的混合物,诸如外消旋或比例混合物。除非有相反说明,描述一种或多种立体化学特征的化学式不排除其他异构体的存在。
在整个定义中,术语“Cn-Cm”表示包括端点的范围,其中n和m是整数并表示碳数。示例包括但不限于C1-C4、C1-C6以及诸如此类。
本文使用的术语“烷基”是支链或直链烃基基团,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十二烷基以及诸如此类。在各个方面,烷基基团含有1至24个碳原子(C1-C24)、1至12个碳原子(C1-C12)、1至10个碳原子(C1-C10)、1至8个碳原子(C1-C8)、1至6个碳原子(C1-C6)、1至4个碳原子(C1-C4)、1至3个碳原子(C1-C3)、或1至2个碳原子(C1-C2)。烷基基团也可以是被取代或未被取代的。除非另有说明,术语“烷基”涵盖被取代的和未被取代的烷基。烷基可以被一个或多个基团取代,包括但不限于C1-C10烷氧基、C1-C10烯基、C1-C10炔基、C3-C10环烷基、C1-C10杂环烷基、C6-C18芳基、C1-C10杂芳基、醛、氨基、羧酸、氧代、卤化物、羟基、氰基、硝基、甲硅烷基、磺基-氧代或硫醇。不含碳-碳双键或碳-碳三键的烷基基团称为饱和烷基基团,而具有一个或多个碳-碳键的烷基基团称为不饱和烷基基团。具有双键的不饱和烷基可以指定为烯基,并且具有三键的不饱和烷基可以指定为炔基。
本文所用的术语“环烷基”是由至少三个碳原子组成的非芳族碳基环。环烷基基团的实例包括但不限于环丙基、环丁基、环戊基、环己基等。术语“杂环烷基”是如上所定义的环烷基基团,其中环的至少一个碳原子被杂原子取代诸如但不限于氮、氧、硫、硒或磷。环烷基基团和杂环烷基基团可以是被取代或未被取代的。除非另有说明,术语“环烷基”和“杂环烷基”涵盖被取代的和未被取代的环烷基和杂环烷基。环烷基和杂环烷基可以被一个或多个基团取代,包括但不限于C1-C10烷基、C1-C10烷氧基、C1-C10烯基、C1-C10炔基、C3-C10环烷基、C1-C10杂环烷基、C6-C18芳基、C1-C10杂芳基、醛、氨基、羧酸、卤化物、羟基、氰基、氧代、硝基、甲硅烷基、磺基-氧代或硫醇。不包含碳-碳双键或碳-碳三键的环烷基基团被指定为饱和环烷基基团,而具有一个或多个这样的键(但仍然不是芳族的)的环烷基基团被指定为不饱和环烷基基团。
本文所用的术语“芳基”是由碳原子组成的芳环。芳基基团的实例包括但不限于苯基和萘基等。术语“杂芳基”是如上所定义的芳基基团,其中环的至少一个碳原子被杂原子取代,诸如但不限于氮、氧、硫、硒或磷。芳基基团和杂芳基基团可以是被取代或未被取代的。除非另有说明,术语“芳基”和“杂芳基”涵盖被取代的和未被取代的芳基和杂芳基。芳基和杂芳基可以被一个或多个基团取代,包括但不限于C1-C10烷基、1-C10烷氧基、C1-C10烯基、C1-C10炔基、C3-C10环烷基、C1-C10杂环烷基、C6-C18芳基、C1-C10杂芳基、醛、氨基、羧酸、卤化物、羟基、氰基、氧代、硝基、甲硅烷基、磺基-氧代或硫醇。
示例性的杂芳基和杂环基环包括:苯并咪唑基、苯并呋喃基、苯并亚硫呋喃基、苯并噻吩基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH咔唑基、咔啉基、苯并二氢吡喃基、苯并吡喃基-环啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢糠[2,3b]四氢呋喃、呋喃基、呋山基、咪唑烷基、咪唑啉基、咪唑基、lH-吲唑基、indolenyl、吲哚啉基、吲嗪基、吲哚基、3H-吲哚基、isatinoyl、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲基二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、phenoxathinyl、吩恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、氮苯基、嘧啶基、氮戊环基、吡咯烷基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-quinolizinyl、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑、噻吩并恶唑基、噻吩并咪唑基、噻吩基和呫吨基。
术语“烷氧基”、“环烷氧基”、“杂环烷氧基”、“环烷氧基”、“芳氧基”和“杂芳氧基”具有上述烷基、环烷基、杂环烷基、芳基和杂芳基的含义,进一步提供所述基团通过氧原子连接。
如本文所用,术语“所取代的”预期包括有机化合物的所有可允许的取代基。在广义方面,可允许的取代基包括有机化合物的非环状和环状、支链和非支链、碳环和杂环,以及芳族和非芳族取代基。示例性的取代基包括例如下文所述的那些。对于合适的有机化合物,可允许的取代基可以是一个或多个并且可以相同或不同。出于本公开的目的,如氮等杂原子可以具有氢取代基和/或本文所述的有机化合物的满足杂原子的化合价的任何可允许的取代基。本公开不旨在以任何方式受限于有机化合物的可允许的取代基。此外,术语“取代”或“经……取代”包括隐含的条件,即这种取代与被取代的原子和取代基的允许化合价一致,并且该取代产生稳定的化合物,例如不会自发经历诸如通过重排、环化、消除等转化的化合物。除非特别说明,否则所说的“被取代的”的取代基是指该取代基可以被以下一种或多种取代:烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、磺基-氧代或硫醇。
除非另有说明,术语“患者”是指任何哺乳动物,包括但不限于人类。
如本文所用,“核苷类似物”是具有模拟天然嘌呤或嘧啶核苷的能力的化合物,其可破坏代谢和调节途径。
如本文所用,氮杂核苷是一种修饰的核苷,其中呋喃糖基或芳香环中的一个或多个原子已被氮原子替代。在一些实施例中,氮杂核苷是具有经修饰的胞嘧啶、腺嘌呤、鸟嘌呤、胸腺嘧啶或尿嘧啶环的修饰的核苷,其中环中的一个或多个碳原子已被氮原子替代。除非有相反说明,修饰的核苷和氮杂核苷包括前体药物,例如在5'和/或4'和3'碳处的酯、磷酸酯和氨基磷酸酯。
药学上可接受的盐是保留母体化合物所需的生物活性并且不具有不期望的毒理学作用的盐。这种盐的实例是与无机酸形成的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸和硝酸,以及诸如此类;与有机酸形成的盐,例如乙酸、草酸、酒石酸、琥珀酸、马来酸、富马酸、葡萄糖酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、萘磺酸和聚半乳糖醛酸,以及诸如此类;由元素阴离子形成的盐,例如氯离子、溴离子和碘离子;由金属氢氧化物形成的盐,例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化锂和氢氧化镁;由金属碳酸盐形成的盐,例如碳酸钠、碳酸钾、碳酸钙和碳酸镁;由金属碳酸氢盐形成的盐,例如碳酸氢钠和碳酸氢钾;由金属硫酸盐形成的盐,例如硫酸钠和硫酸钾;以及由金属硝酸盐形成的盐,例如硝酸钠和硝酸钾。药学上可接受的和非药学上可接受的盐可以使用本领域熟知的方法来制备,例如通过使足够碱性的化合物诸如胺与包含生理学上可接受的阴离子的合适的酸反应。还可以制备羧酸碱金属(例如钠、钾或锂)或碱土金属(例如钙)盐。
本文公开了式(1)的化合物:
及它的药学上可接受的盐,
其中
R1选自H、OH、C1-8烷基和OC1-8烷基,优选CH3。
R2选自H、OH、C1-8烷基和OC1-8烷基,优选OCH3。
R3选自H、OH、C1-8烷基和OC1-8烷基,优选H或OH。
R4选自H、OH、C1-8烷基和OC1-8烷基,优选H或OH。
Q1是具有下式的基团:
其中
R2a选自-R2a*、-OR2a*、OP(O)(OR2a*)2、OP(O)(OR2a*)(N(R2a*)2、-N(R2a*)2、-N(R2a*)3、-C(O)R2a*、-C(O)OR2a*、-OC(O)R2a*、-OC(O)OR2a*、-NR2a*C(O)R2a*、-C(O)N(R2a*)2、NR2a*C(O)OR2a*、-OC(O)N(R2a*)2、-NR2a*C(O)N(R2a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-ORp;
R2a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R2a*可被-OH、-COOH、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-ORp;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次,
其中任意两个或更多个R2a*可一起形成环;
R3a选自-R3a*、-OR3a*、OP(O)(OR3a*)2、OP(O)(OR3a*)(N(R3a*)2、-N(R3a*)2、-N(R3a*)3-C(O)R3a*、-C(O)OR3a*、-OC(O)R3a*、-OC(O)OR3a*、-NR3a*C(O)R3a*、-C(O)N(R3a*)2、NR3a*C(O)OR3a*、-OC(O)N(R3a*)2、-NR3a*C(O)N(R3a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-ORp;
R3a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R3a*可被-OH、-COOH、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-ORp;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次,
其中任意两个或更多个R3a*可一起形成环;
R4a选自-R4a*、-OR4a*、OP(O)(OR4a*)2、OP(O)(OR4a*)(N(R4a*)2、-N(R4a*)2、-N(R4a*)3、-C(O)R4a*、-C(O)OR4a*、-OC(O)R4a*、-OC(O)OR4a*、-NR4a*C(O)R4a*、-C(O)N(R4a*)2、NR4a*C(O)OR4a*、-OC(O)N(R4a*)2、-NR4a*C(O)N(R4a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-ORp;
R4a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R4a*可被-OH、-COOH、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-ORp;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次;
其中任意两个或更多个R4a*可一起形成环;
R5a选自-R5a*、-OR5a*、OP(O)(OR5a*)2、OP(O)(OR5a*)(N(R5a*)2、-N(R5a*)2、-N(R5a*)3、-C(O)R5a*、-C(O)OR5a*、-OC(O)R5a*、-OC(O)OR5a*、-NR5a*C(O)R5a*、-C(O)N(R5a*)2、NR5a*C(O)OR5a*、-OC(O)N(R5a*)2、-NR5a*C(O)N(R5a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-ORp;
R5a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R5a*可被-OH、-COOH、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-ORp;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次;
其中Rp在每种情况下选自H、C1-10烷基和芳基;
其中任意两个或更多个R5a*可一起形成环;
其中任意两个或更多个R2a、R3a、R4a和R5a可一起形成环;
Q2是具有下式的基团:
其中:
R1b选自H、OH、C1-8烷基和OC1-8烷基;
R2b选自-R2b*、-OR2b*、OP(O)(OR2b*)2、OP(O)(OR2b*)(N(R2b*)2、-N(R2b*)2、-N(R2b*)3、-C(O)R2b*、-C(O)OR2b*、-OC(O)R2b*、-OC(O)OR2b*、-NR2b*C(O)R2b*、-C(O)N(R2b*)2、NR2b*C(O)OR2b*、-OC(O)N(R2b*)2、-NR2b*C(O)N(R2b*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-ORp;
R2b*在每种情况下独立地选自H、C1-8烷基、C1-8烯基、C1-10炔基、芳基、C3-8环烷基、C3-8环烯基、C7-10环炔基、芳基、C1-8杂环基、C3-8杂芳基;其中每个R2b*可被-OH、-COOH、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-ORp;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次,其中任意两个或更多个R2b*可一起形成环;
R3b选自H或具有下式的基团:
其中
R3d选自H和CH3;以及
R4d选自H和具有下式的基团:
在一些实施例中,该化合物可以是式(2a)、式(2b)或式(2c)化合物:
在一些实施例中,Q1是具有以下构象的(L)糖:
Q1的示例性立体异构体包括
Q2可以具有下式:
根据任一前述权利要求所述的化合物,其中Q2可以具有以下任一式:
R3b可以是具有下式的基团:
R4d可以是具有下式的基团:
本文公开的化合物的特征优选地为R5a选自CH3和CH2OH、最优选CH3。
在一些实施例中,化合物在R3a位置被衍生化,且R4a和R2a均为OH。在其他实施例中,化合物在R4a位置被衍生化,且R3a和R2a均为OH。在进一步的实施例中,化合物在R2a位置被衍生化,且R3a和R4a均为OH。还可考虑其他实施例,其中R4a和R2a两者都被衍生化、R3a和R2a两者都被衍生化、或者R4a和R3a两者都被衍生化。R2a、R3a和R4a都被衍生化的进一步的实施例也在本公开的范围内。预期对于所有这些实施例,R2b可以如阿矛西丁(-CH2CH2CH2OCH3)中天然存在的那样,但所公开的化合物也可以在该位置被衍生化。而在其他实施例中,R2a、R3a和R4a都不被衍生化(即均为OH),但R2b不为-CH2CH2CH2OCH3。
本文公开的大环内酯衍生物的特征可以是其中R2a、R3a和R4a中的至少一者不为OH,或R2b不为-CH2CH2CH2OCH3。
在某些实施例中,大环内酯衍生物可包括叠氮化物、四嗪、环辛炔或反式环辛烯基团。这些基团可用于“点击”环加成反应,该反应可用于进一步精制大环内酯类似物。合适的环辛炔包括双环[6.1.0]壬炔(“BCN”)、二苯并环辛炔、二苯并环辛炔胺、以及这些基团中每一个的取代衍生物。示例性基团包括以下基团:
在某些实施例中,天然存在的(L)-岩藻糖部分上的一个或多个羟基基团可以被修饰。如本文所用,修饰包括氧化、立体化学反转和/或通过化学反应的官能化。这些化合物可以通过利用岩藻糖环中每个羟基的不同化学反应性来获得。一般来说,R3a位置对亲电试剂反应性最强,并且该位置可以选择性地被修饰。为了在其他位置进行修饰,可能需要首先保护R3a羟基(以及其他位置)。此类技术是本领域技术人员已知的。
在一些实施例中,大环内酯衍生物可以包括线粒体靶向部分。示例性部分包括季鏻和铵离子,例如三苯基鏻、三烷基铵(例如三甲基铵、三乙基铵)胍(包括环状和无环胍)、吡啶、罗丹明、地喹鎓、(E)-4-(1H-吲哚-3-乙烯基)-N-甲基吡啶鎓碘化物,以及诸如此类。
在一些实施例中,R3a是-OR3a*、-OC(O)R3a*、OP(O)(OR3a*)2、OP(O)(OR3a*)(N(R3a*)2、-OC(O)OR3a、-OC(O)N(R3a*)2或-(OCH2CH2)m-OR3a*(m为1-100)。在每种情况下,R3a*独立地选自H(当R3a为OR3a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基。这些R3a*基团可以进一步被取代一次或多次,示例性取代基包括COOR、F、Cl、Br、I、SO3R、OSO3R、-PPh3、-CH2NEt3、-CH2NMe3、P(O)(OR)2、OP(O)(OR)2、N3、杂环基、杂芳基、芳基、环烷基,其中R在每种情况下独立地选自H、烷基和环烷基。
在某些实施例中,R3a被衍生为醚或酯,例如,-OR3a*或-OC(O)R3a*,并且其他被衍生为膦酸酯或氨基磷酸酯产物,例如,-OP(O)(OR3a*)2或OP(O)(OR3a*)(N(R3a*)2,其中R3a优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
其中Rp如上所定义。
在一些实施例中,R3a*可以是具有下式的部分:
其中z和z'之和不大于7,Q2a和Q3a均为氢或一起形成C1-8杂环基,并且Q1a选自COOH、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。特别优选地,Q1a基团包括COOH、N3和CF3。在其他实施例中,Q1a选自芳基和C1-10杂芳基,任选地如上所述被取代一次或多次。在其他实施例中,Q1a是二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
在某些实施例中,Q1a可以是具有下式的部分:
其中Xdq是亚烷基链,具有2-12个CH2单元、优选地5-12个CH2单元、更优选地7-11个CH2单元、特别优选地8-10个CH2单元。技术人员将认识到,虽然上述一些部分以电中性形式描述,但这些部分可以被质子化并与适当的抗衡离子配对。同样,上述喹啉鎓阳离子将伴随有一个或多个电荷平衡离子,例如二氯化物、二溴化物、二碘化物、二乙酸盐等。
在一些实施例中,R2a是-OR2a*、-OC(O)R2a*、OP(O)(OR2a*)2、OP(O)(OR2a*)(N(R2a*)2、-OC(O)OR2a、-OC(O)N(R2a*)2或-(OCH2CH2)m-OR2a*(m为1-100)。在每种情况下,R2a*独立地选自H(当R2a为OR2a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基。这些R2a*基团可以进一步被取代一次或多次;示例性取代基包括COOR、F、Cl、Br、I、SO3R、OSO3R、-PPh3、-CH2NEt3、-CH2NMe3、P(O)(OR)2、OP(O)(OR)2、N3、杂环基、杂芳基、芳基、环烷基,其中R在每种情况下独立地选自H、烷基和环烷基。
在某些实施例中,R2a被衍生为醚或酯,例如,-OR2a*或-OC(O)R2a*,并且其他被衍生为膦酸酯或氨基磷酸酯产物,例如,-OP(O)(OR2a*)2或OP(O)(OR2a*)(N(R2a*)2,其中R2a优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
其中Rp如上所定义。
在一些实施例中,R2a*可以是具有下式的部分:
其中y和y'之和不大于7,Q2b和Q3b均为氢或一起形成C1-8杂环基,并且Q1b选自COOH、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。特别优选的Q1b基团包括COOH、N3和CF3。在其他实施例中,Q1b选自芳基和C1-10杂芳基,任选地如上所述被取代一次或多次。在其他实施例中,Q1b是二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
在某些实施例中,Q1b可以是具有下式的部分:
其中Xdq是亚烷基链,具有2-12个CH2单元、优选地5-12个CH2单元、更优选地7-11个CH2单元、特别优选地8-10个CH2单元。技术人员将认识到,虽然上述一些部分以电中性形式描述,但这些部分可以被质子化并与适当的抗衡离子配对。同样,上述喹啉鎓阳离子将伴随有一个或多个电荷平衡离子,例如二氯化物、二溴化物、二碘化物、二乙酸盐等。
在一些实施例中,R4a是-OR4a*、-OC(O)R4a*、OP(O)(OR4a*)2、OP(O)(OR4a*)(N(R4a*)2、-OC(O)OR4a、-OC(O)N(R4a*)2或-(OCH2CH2)m-OR4a*(m为1-100)。在每种情况下,R4a*独立地选自H(当R4a为OR4a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基。这些R4a*基团可以进一步被取代一次或多次,示例性取代基包括COOR、F、Cl、Br、I、SO3R、OSO3R、-PPh3、-CH2NEt3、-CH2NMe3、P(O)(OR)2、OP(O)(OR)2、N3、杂环基、杂芳基、芳基、环烷基,其中R在每种情况下独立地选自H、烷基和环烷基。
在某些实施例中,R4a被衍生为醚或酯,例如,-OR4a*或-OC(O)R4a*,并且其他被衍生为膦酸酯或氨基磷酸酯产物,例如,-OP(O)(OR4a*)2或OP(O)(OR4a*)(N(R4a*)2,其中R4a优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
其中Rp如上所定义。
在一些实施例中,R4a*可以是具有下式的部分:
其中x和x'之和不大于7,Q2c和Q3c均为氢或一起形成C1-8杂环基,并且Q1c选自COOH、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。特别优选地Q1c基团包括COOH、N3和CF3。在其他实施例中,Q1c选自芳基和C1-10杂芳基,任选地如上所述被取代一次或多次。在其他实施例中,Q1c是二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
在某些实施例中,Q1c可以是具有下式的部分:
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其中Xdq是亚烷基链,具有2-12个CH2单元、优选地5-12个CH2单元、更优选地7-11个CH2单元、特别优选地8-10个CH2单元。技术人员将认识到,虽然上述一些部分以电中性形式描述,但这些部分可以被质子化并与适当的抗衡离子配对。同样,上述喹啉鎓阳离子将伴随有一个或多个电荷平衡离子,例如二氯化物、二溴化物、二碘化物、二乙酸盐等。
在一些实施例中,大环内酯衍生物可以在R2b位置被修饰,例如通过如本文所述的发酵条件的修饰。R2b可以是-OR2b*、-OC(O)R2b*、-PPh3、-CH2NEt3、-CH2NMe3、OP(O)(OR2b*)2、OP(O)(OR2b*)(N(R2b*)2、-OC(O)OR2b、-OC(O)N(R2b*)2或-(OCH2CH2)m-OR2b*(m为1-100)。在每种情况下,R2b*独立地选自H(当R2b为OR2b*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基。这些R2b*基团可以进一步被取代一次或多次;示例性取代基包括COOR、F、Cl、Br、I、SO3R、OSO3R、P(O)(OR)2、OP(O)(OR)2、N3、C1-10杂环基、C1-10杂芳基、C6-18芳基、C3-10环烷基,其中R在每种情况下独立地选自H、烷基和环烷基。
在某些实施例中,R2b衍生为醚或酯,例如,-OR2b*或-OC(O)R2b*,并且其他衍生为膦酸酯或氨基磷酸酯产物,例如,-OP(O)(OR2b*)2或OP(O)(OR2b*)(N(R2b*)2,其中R2b优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
其中Rp如上所定义。
在一些实施例中,R2b*可以是具有下式的部分:
其中w和w'之和不大于7,Q2d和Q3d均为氢或一起形成C1-8杂环基,并且Q1d选自COOH、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。特别优选地Q1d基团包括COOH、N3和CF3。在其他实施例中,Q1d选自芳基和C1-10杂芳基,任选地如上所述被取代一次或多次。在其他实施例中,Q1d是二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
在某些实施例中,Q1d可以是具有下式的部分:
其中Xdq是亚烷基链,具有2-12个CH2单元、优选地5-12个CH2单元、更优选地7-11个CH2单元、特别优选地8-10个CH2单元。技术人员将认识到,虽然上述一些部分以电中性形式描述,但这些部分可以被质子化并与适当的抗衡离子配对。同样,上述喹啉鎓阳离子将伴随有一个或多个电荷平衡离子,例如二氯化物、二溴化物、二碘化物、二乙酸盐等。
还公开了式(3a)、(3b)和(3c)的化合物:
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其中R2f是-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或–(OCH2CH2)m-ORf*;
其中R3f是-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或–(OCH2CH2)m-ORf*;
其中R4f是-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或–(OCH2CH2)m-ORf*;
Rf*在每种情况下独立地选自H、被取代或未被取代的C1-8烷基、被取代或未被取代的C1-8烯基、被取代或未被取代的C1-10炔基、被取代或未被取代的芳基、被取代或未被取代的C3-8环烷基、被取代或未被取代的C3-8环烯基、被取代或未被取代的C7-10环炔基、芳基、被取代或未被取代的C1-8杂环基、被取代或未被取代的C3-8杂芳基;
Rs选自H、被取代或未被取代的C1-8烷基、被取代或未被取代的C1-8烯基、被取代或未被取代的C1-10炔基、被取代或未被取代的芳基、被取代或未被取代的C3-8环烷基、被取代或未被取代的C3-8环烯基、被取代或未被取代的C7-10环炔基、被取代或未被取代的芳基、C1-8杂环基、被取代或未被取代的C3-8杂芳基;
条件是当Rs为CH2CH2CH2OCH3时,R2f、R3f和R4f不同时为H。
如本文所用,被取代基团是其中与碳原子结合的一个或多个氢原子被非氢基团取代的基团。示例性的非氢基团包括卤素(F、Cl、Br、I)、羟基、硫氢基、C1-C24烷氧基、C5-C24芳氧基、酰基(包括C2-C24烷基羰基(—CO-烷基)和C6-C24芳基羰基(—CO—C5–C24芳基))、卤代酰基(包括C2–C24卤代烷基羰基(—C)—卤代烷基)和C6-C24卤代芳基羰基(—CO-芳基))、C2-C24硫代酰氧基(包括—O—(CS)-烷基和—O—(CS)-芳基)、C2-C24硫代卤代酰氧基(包括—O—(CS)-卤代烷基和—O—(CS)-卤代芳基))、酰氧基(—O-酰基)、C2-C24烷氧基羰基(—(CO)—O-烷基)、C6-C24芳氧基羰基(—(CO)—O-芳基)、C7-C24烷芳氧基羰基(—(CO)—O-烷芳基)、C7-C24芳烷氧基羰基(—(CO)—O-芳烷基)、C2-C24卤代烷基碳酸酯(—O—(CO)—O-卤代烷基))、C6-C24卤代芳基碳酸酯(—O—(CO)—O-卤代芳基)、C2-C24烷硫基碳酸酯(—O—(CS)—O-烷基))、C6-C24芳基硫代碳酸酯(—O—(CS)—O-芳基)、C2-C24卤代烷硫基碳酸酯(—O—(CS)—O-卤代烷基)和C6-C24卤代芳基硫代碳酸酯(—O—(CS)—O-卤代芳基)、C6-C24芳氧基羰基(—(CO)—O-芳基)、卤代羰基(—CO)—X,其中X是卤素)、C2-C24烷基碳酸根(—O—(CO)—O-烷基)、C6-C24芳基碳酸酯(—O—(CO)—O-芳基)、羧基(—COOH)、羧酸盐(—COO-)、氨基甲酰基(—(CO)—NH2)、单-(C1-C24烷基)-被取代的氨基甲酰基(—(CO)—NH(C1-C24烷基))、二-(C1–C24烷基)-被取代的氨基甲酰基(—(CO)—N(C1–C24烷基)2)、单-(C6-C24芳基)-被取代的氨基甲酰基(—(CO)—NH-芳基)、二-(C6–C24芳基)-被取代的氨基甲酰基(—(CO)—N(芳基)2)、二-N—(C1-C24烷基)、N—(C6-C24芳基)-被取代的氨基甲酰基、硫代氨基甲酰基(—(CS)—NH2)、氨基甲酰(—NH—(CO)—NH2)、甲酰基(—(CO)—H)、硫代甲酰基(—(CS)—H)、氨基(—NH2)、单-(C1-C24烷基)-被取代的氨基、二-(C1–C24烷基)-被取代的氨基、单-(C5-C24芳基)-被取代的氨基、二-(C5-C24芳基)-被取代的氨基、C2-C24烷基酰胺基(—NH—(CO)-烷基)、C6-C24芳基酰胺基(—NH—(CO)-芳基)、亚氨基(—CR═NH其中R=氢、C1-C24烷基、C5-C24芳基、C6-C24烷芳基、C6–C24芳烷基等)、烷基亚氨基(—CR=N(烷基),其中R=氢、C1–C24烷基、C5–C24芳基、C6-C24烷芳基、C6–C24芳烷基等)、芳基亚氨基(—CR=N(芳基),其中R=氢、C1-C24烷基、C5-C24芳基、C6–C24烷芳基、C6–C24芳烷基等)、硝基(—NO2)、亚硝基(—NO)、磺基(—SO2—OH)、磺酰胺基(—SO2—NH2)、磺基(—SO2—O-)、C1-C24烷基硫基(—S-烷基;也称为“烷硫基”)、芳基硫基(—S-芳基;也称为“芳硫基”)、C1–C24烷基亚磺酰基(—(SO)-烷基)、C5-C24芳基亚磺酰基(—(SO)-芳基)、C1-C24烷基磺酰基(—SO2-烷基)、C5–C24芳基磺酰基(—SO2-芳基)、膦酰基(—P(O)(OH)2)、膦酸根(—P(O)(O-)2)、次膦酸根(—P(O)(O-))、磷基(—PO2)和膦基(—PH2);和烃基部分C1-C24烷基(优选C1-C18烷基、更优选C1-C12烷基、最优选C1-C6烷基)、C2-C24烯基(优选C2-C18烯基、更优选C2-C12烯基、最优选C2-C6烯基)、C2-C24炔基(优选C2-C18炔基、更优选C2-C12炔基、最优选C2-C6炔基)、C5-C24芳基(优选C5-C14芳基)、C6-C24烷芳基(优选C6–C18烷芳基)和C6-C24芳烷基(优选C6-C18芳烷基)。
在一些实施例中,R2f是-C(O)R2f*,并且R3f和R4f均为H并且Rs是CH2CH2CH2OCH3。R2f*的示例性基团包括被取代或未被取代的C1-8烷基或被取代或未被取代的C3-8杂芳基。示例性的C3-8杂芳基包括吡啶-2-基、吡啶-3-基和吡啶-4-基。优选的C1-8烷基包括甲基、乙基、异丁基和异戊基。优选的取代基包括氨基、羧基和巯基。
在一些实施例中,R2f具有结构:
其中Raa是H、CH3、CH(CH3)2、CH2-苯基、CH2-4-(羟基苯基)、CH2-(1H-咪唑-4-基)、CH2-(1H-吲哚-3-基)、CH2CH(CH3)2、CH2OH、CH(OH)CH3、CH2SH、CH2COOH、CH2CH2COOH、CH2CONH2、CH2CH2CONH2、(CH2)4NH2、CH2CH2CH2NHC(=NH)NH2或CH2CH2SCH3。
在其他实施例中,R3f是-C(O)Rf*,并且R2f和R4f均为H并且Rs是CH2CH2CH2OCH3。R2f*的示例性基团包括被取代或未被取代的C1-8烷基或被取代或未被取代的C3-8杂芳基。示例性的C3-8杂芳基包括吡啶-2-基、吡啶-3-基和吡啶-4-基。优选的C1-8烷基包括甲基、乙基、异丁基和异戊基。优选的取代基包括氨基、羧基和巯基。
在一些实施例中,R3f具有结构:
其中Raa是H、CH3、CH(CH3)2、CH2-苯基、CH2-4-(羟基苯基)、CH2-(1H-咪唑-4-基)、CH2-(1H-吲哚-3-基)、CH2CH(CH3)2、CH2OH、CH(OH)CH3、CH2SH、CH2COOH、CH2CH2COOH、CH2CONH2、CH2CH2CONH2、(CH2)4NH2、CH2CH2CH2NHC(=NH)NH2或CH2CH2SCH3。
在进一步的实施例中,R4f是-C(O)Rf*,并且R2f和R3f均为H并且Rs是CH2CH2CH2OCH3。R2f*的示例性基团包括被取代或未被取代的C1-8烷基或被取代或未被取代的C3-8杂芳基。示例性的C3-8杂芳基包括吡啶-2-基、吡啶-3-基和吡啶-4-基。优选的C1-8烷基包括甲基、乙基、异丁基和异戊基。优选的取代基包括氨基、羧基和巯基。
在一些实施例中,R4f具有结构:
其中Raa是H、CH3、CH(CH3)2、CH2-苯基、CH2-4-(羟基苯基)、CH2-(1H-咪唑-4-基)、CH2-(1H-吲哚-3-基)、CH2CH(CH3)2、CH2OH、CH(OH)CH3、CH2SH、CH2COOH、CH2CH2COOH、CH2CONH2、CH2CH2CONH2、(CH2)4NH2、CH2CH2CH2NHC(=NH)NH2或CH2CH2SCH3。
在某些实施例中,Rf*选自:
其中n为0、1、2、3、4、6、7、8、9或10,优选0、1、2、3或4,并且Qf为CF3、-C≡CH、N3、-C≡N、COOH、—(CO)—O-烷基、芳基(例如4-氟苯基、3-氟苯基、2-氟苯基)、金刚烷基、C1-10杂环基、被取代或未被取代的C7-10环炔基。在一些实施例中,n为0,而在其他实施例中,n为3。在某些实施例中,n为2、3或4,并且Qf是具有下式的C1-10杂环基:
其中Xf为空、CH2、O、S或NRxf,其中Rxf为H或C1-3烷基,优选甲基。
在某些实施例中,Rf*是—(CO)—O-烷基,其中烷基是甲基或乙基。
在一些实施例中,Rs选自
其中n为0、1、2、3、4、6、7、8、9或10,并且Qs为CF3、-PPh3、-CH2NEt3、-CH2NMe3、-C≡CH、N3、-C≡N、COOH、—(CO)—O-烷基、芳基(例如4-氟苯基、3-氟苯基、2-氟苯基)、金刚烷基、C1-8杂环基、被取代或未被取代的C7-10环炔基。
在某些实施例中,Qf可以是具有下式的部分:
其中Xdq是亚烷基链,具有2-12个CH2单元、优选地5-12个CH2单元、更优选地7-11个CH2单元、特别优选地8-10个CH2单元。技术人员将认识到,虽然上述一些部分以电中性形式描述,但这些部分可以被质子化并与适当的抗衡离子配对。同样,上述喹啉鎓阳离子将伴随有一个或多个电荷平衡离子,例如二氯化物、二溴化物、二碘化物、二乙酸盐等。Nocardiopsis sp.FU40天然存在的凋亡素和相关大环内酯类的生物合成以(R)-甲氧基丙二酸起始,它是(R)-2-甲氧基丙二酰基-酰基载体蛋白(“MeOM-ACP”)的底物。该蛋白由五基因连续基因盒(apoK-M2)编码,可通过apoJK双基因替换来破坏该基因盒,从而完全消除所有凋亡素大环内酯类的产生。用突变Nocardiopsis sp.FU40apoJK::aac(3)IV与N-乙酰半胱胺、(R)-2-甲氧基丙二酸的(NAC)硫酯一起发酵恢复凋亡素生物合成。Nocardiopsissp.FU40 apoJK::aac(3)IV与为式R2b-C(O)SRst或Rs-C(O)SRst(其中Rst是烷基或芳基基团)的硫代酯的发酵产生具有相应R2b或Rs基团的大环内酯类。
如本文所用,短语“治疗剂”是指当给予受试者时具有治疗和/或诊断效果和/或引发期望的生物学和/或药理学效果的任何药剂。
阿矛西丁化合物(例如,阿矛西丁A、阿矛西丁B、阿矛西丁C、阿矛西丁D、阿矛西丁E,特别是阿矛西丁A)和式(1)(及其子式)化合物可有效用于治疗增殖性疾病,包括癌症和类似疾病。该化合物可用于治疗以一种或多种实体瘤为特征的癌症。在其他实施例中,该增殖性疾病是血癌。在一些实施例中,该增殖性疾病是骨髓增生异常综合征。在一些实施例中,该增殖性疾病是白血病。
在优选的实施例中,可以使用天然存在的阿矛西丁(例如,阿矛西丁A)或式(1)、(2a)、(2b)、(2c)、(3a)、(3b)或(3c)化合物治疗增殖性疾病,例如急性髓性白血病、慢性髓性白血病、急性淋巴性细胞白血病、多发性骨髓瘤、混合谱系白血病、脑肿瘤、成胶质细胞瘤或淋巴瘤。优选地,所使用的试剂是阿矛西丁A或式(3c)化合物。
本文公开的化合物可用于治疗急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、肾上腺皮质癌中的癌症、副肾皮质癌、艾滋病相关癌症、卡波西肉瘤、艾滋病相关淋巴瘤、原发性中枢神经系统淋巴瘤、肛门癌、阑尾癌、类癌、星形细胞瘤、非典型畸胎瘤/横纹肌样肿瘤、基底细胞癌、皮肤癌(非黑色素瘤)、胆道癌、肝外膀胱癌、膀胱癌、骨癌(包括尤因肉瘤和骨肉瘤和恶性纤维组织细胞瘤)、脑肿瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤(非霍奇金)、类癌、心脏(心)肿瘤、非典型畸胎瘤/横纹肌样肿瘤、胚胎性肿瘤、生殖细胞肿瘤、淋巴瘤、原发性-宫颈癌、胆管癌、脊索瘤、慢性淋巴细胞白血病(CLL)、慢性粒细胞白血病(CML)、慢性骨髓增生性肿瘤、结直肠癌、结直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、导管原位癌(DCIS)、胚胎性肿瘤、中枢神经系统、子宫内膜癌、室管膜瘤、食道、感觉神经母细胞瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、眼内黑色素瘤、视网膜母细胞瘤、输卵管癌、骨纤维组织细胞瘤、恶性和骨肉瘤、胆囊癌、胃部(胃)癌、胃部(胃)癌、胃肠道类癌、胃肠道间质瘤(GIST)、胃肠道间质瘤(GIST)、生殖细胞肿瘤、中枢神经系统、颅外、性腺外、卵巢睾丸、妊娠滋养细胞疾病、胶质瘤、毛细胞白血病、头和颈部癌症、心脏肿瘤、肝细胞(肝)癌、组织细胞增多症、朗格汉斯细胞、霍奇金淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞肿瘤、胰腺神经内分泌肿瘤、卡波西肉瘤、肾-朗格汉斯细胞组织细胞增多症、喉部癌症、喉部癌症和乳头状瘤病、白血病、唇口癌、肝癌(原发性)、肺癌、肺癌、淋巴瘤-巨球蛋白血症、-非霍奇金淋巴瘤、男性乳癌、骨恶性纤维组织细胞瘤和骨肉瘤、黑色素瘤、眼内(眼)、默克尔细胞癌、间皮瘤、恶性、间皮瘤、转移性鳞状颈癌症伴隐匿原发性、涉及NUT基因的中线束癌、口腔癌、多种内分泌肿瘤综合征、多发性骨髓瘤/浆细胞肿瘤、蕈样真菌病、骨髓增生异常综合征、骨髓增生异常/骨髓增殖性肿瘤和慢性骨髓增生性肿瘤、髓性白血病、慢性(CML)、髓性白血病、急性(AML)、鼻腔和鼻窦癌症、鼻咽癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌癌症、口腔癌、唇口腔癌症和口咽癌症、骨肉瘤和骨恶性纤维组织细胞瘤、卵巢癌、胰腺癌和胰腺神经内分泌肿瘤(胰岛细胞肿瘤)、乳头状瘤病、副神经节瘤、副神经节瘤、副鼻窦和鼻腔癌症、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、嗜铬细胞瘤、垂体瘤、浆细胞肿瘤/多发性骨髓瘤、胸膜肺母细胞瘤、妊娠和乳腺癌、原发性中枢神经系统(CNS)淋巴瘤、原发性腹膜癌、前列腺癌、直肠癌、肾细胞(肾脏)癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、唾液腺肿瘤、尤因肉瘤、卡波西肉瘤、骨肉瘤、横纹肌肉瘤、子宫肉瘤、血管肿瘤、Sézary综合征、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、鳞状颈癌症伴隐匿原发性、转移性、胃部(胃)癌、胃部(胃)癌、T细胞淋巴瘤、皮肤、睾丸癌、喉咙癌、胸腺瘤和胸腺癌、甲状腺癌、输尿管和肾盂、移行细胞癌、尿道癌、子宫癌、子宫内膜和子宫肉瘤、阴道癌、阴道癌、血管肿瘤、外阴癌、/>巨球蛋白血症、维尔姆斯氏瘤(Wilms'tumor)。
在肿瘤医学领域,通常的做法是组合使用不同形式的治疗方法来治疗每位癌症患者。在肿瘤医学中,除了本发明的组合物之外,这种联合治疗的一种或多种其他成分可以是例如手术、放射疗法、化学疗法、信号转导抑制剂和/或单克隆抗体。因此,本文公开的化合物可以作为联合治疗方案的一部分施用,例如在手术之前或之后或者在放射治疗之前或之后。
在一些实施例中,本文公开的化合物可以与一种或多种抗癌剂组合施用,所述抗癌剂例如有丝分裂抑制剂、烷化剂、抗代谢物、反义DNA或RNA、嵌入抗生素、生长因子抑制剂、信号转导抑制剂、细胞周期抑制剂、酶抑制剂、视黄醇受体调节剂、蛋白酶体抑制剂、拓扑异构酶抑制剂、表观遗传抑制剂、生物反应调节剂、抗代谢物、糖酵解抑制剂、谷氨酰胺代谢抑制剂、抗激素、血管生成抑制剂、抗雄激素细胞抑制剂、靶向抗体、HMG-CoA还原酶抑制剂,以及异戊二烯基蛋白转移酶抑制剂。
示例性的抗癌剂包括核苷类似物、抗叶酸剂、抗代谢物、拓扑异构酶I抑制剂、蒽环类、鬼臼毒素、紫杉烷类、长春花生物碱、烷化剂、铂化合物、蛋白酶体抑制剂、氮芥和雌激素类似物、单克隆抗体、酪氨酸激酶抑制剂、mTOR抑制剂、视黄醇、免疫调节剂、组蛋白脱乙酰酶抑制剂、DNA甲基转移酶抑制剂、BCL-2家族蛋白抑制剂及它们的组合。
在一些实施例中,另外的抗癌剂可以是一种或多种核苷类似物,例如一种或多种氮杂核苷。
在某些实施方案中,抗癌剂选自以下中的一个或多个:乙酸阿比特龙、甲氨蝶呤、紫杉醇白蛋白稳定的纳米颗粒、布伦妥昔单抗维多汀、阿多曲妥珠单抗埃坦新、盐酸多柔比星、阿法替尼二马来酸盐、依维莫司、奈妥匹坦、盐酸帕洛诺司琼、咪喹莫特、阿地司白素、阿来替尼、阿仑单抗、盐酸美法仑、美法仑、培美曲塞二钠、苯丁酸氮芥、氨基乙酰丙酸、阿那曲唑、阿瑞匹坦、帕米膦酸二钠、依西美坦、奈拉滨、三氧化二砷、奥法图单抗、菊欧文氏菌天冬酰胺酶、阿特珠单抗、贝伐珠单抗、阿西替尼、阿扎胞苷、卡莫司汀、贝利诺司他、盐酸苯达莫司汀、贝伐珠单抗、贝沙罗汀、托西莫单抗、比卡鲁胺、博来霉素、博纳吐单抗、博纳吐单抗、硼替佐米、博舒替尼、白消安、卡巴齐他塞尔、卡博扎替尼、阿仑单抗、盐酸伊立替康、卡培他滨、氟尿嘧啶、卡铂、卡非佐米、比卡鲁胺、洛莫司汀、色瑞替尼、盐酸柔红霉素、西妥昔单抗、苯丁酸氮芥、环磷酰胺、氯法拉滨、可美替尼、放线菌素、可美替尼、克唑替尼、异环磷酰胺、拉穆丘单抗、阿糖胞苷、达布芬尼、达卡巴嗪、地西他滨、达拉图单抗、达沙替尼、盐酸柔红霉素、地西他滨、去纤维钠、去纤维钠、地加瑞克、地尼白介素、地舒单抗、地塞米松、盐酸右雷佐生、丁妥昔单抗、多西他赛、盐酸多柔比星、达卡巴嗪、尿酸氧化酶、盐酸表柔比星、埃洛妥珠单抗、奥沙利铂、艾曲泊帕乙醇胺、阿瑞匹坦、埃洛妥珠单抗、恩扎鲁胺、盐酸表柔比星、西妥昔单抗、甲磺酸艾瑞布林、维莫德吉、盐酸埃洛替尼、依托泊苷、盐酸雷洛昔芬、盐酸美法仑、托瑞米芬、帕诺司他、氟维司琼、来曲唑、非格拉司汀、磷酸氟达拉滨、氟他胺、甲氨蝶呤、普拉曲沙、重组hpv四价疫苗、重组hpv九价疫苗、奥比努单抗、吉非替尼、盐酸吉西他滨、吉妥珠单抗奥佐米星、阿法替尼二马来酸、甲磺酸伊马替尼、羧肽酶、醋酸戈塞林、甲磺酸艾瑞布林、曲妥珠单抗、盐酸拓扑替康、帕博昔尼、替伊莫单抗、依鲁替尼、盐酸波那替尼、盐酸伊达比星、艾代拉西布、咪喹莫特、阿西替尼、重组干扰素α-2b、托西莫单抗、易普利木单抗、吉非替尼、罗咪酯肽、依沙匹隆、柠檬酸伊沙佐米、磷酸鲁克索利替尼、卡巴齐他塞尔、阿多曲妥珠单抗埃坦新、帕利费明、帕博利珠单抗、醋酸兰瑞肽、二甲苯磺酸拉帕替尼、来那度胺-甲磺酸乐伐替尼、醋酸亮丙瑞林、奥拉帕尼、硫酸长春新碱、盐酸丙卡巴肼、盐酸氮芥、醋酸甲地孕酮、曲美替尼、巯基嘌呤、替莫唑胺、盐酸米托蒽醌、普利沙福、白消安、阿扎胞苷、吉妥珠单抗奥佐米星、酒石酸长春瑞滨、耐昔妥珠单抗、奈拉滨、甲苯磺酸索拉非尼、尼洛替尼、柠檬酸依沙佐米、尼沃单抗、罗米司汀、奥比努单抗、奥法图单抗、奥拉帕尼、高三尖杉酯碱、培门冬酶、盐酸昂丹司琼、奥西替尼、帕尼图单抗、帕诺司他、聚乙二醇干扰素α-2b、帕博利珠单抗、帕妥珠单抗、普利沙福、泊马度胺、盐酸波纳替尼、耐昔妥珠单抗、普拉曲沙、盐酸丙卡巴肼、阿地司白素、地舒单抗、拉穆丘单抗、尿酸氧化酶、瑞戈非尼、来那度胺、利妥昔单抗、盐酸罗匹坦、罗咪酯肽、磷酸鲁克索利替尼、司妥昔单抗、达沙替尼、苹果酸舒尼替尼、沙利度胺、达布芬尼、奥西替尼、talimogene、阿特珠单抗、替西罗莫司、沙利度明、盐酸右雷佐生、曲贝替丁、曲美替尼、曲妥珠单抗、二甲苯磺酸拉帕替尼、丁妥昔单抗、凡德他尼、盐酸罗匹坦、硼替佐米、维奈托克、克唑替尼、恩扎鲁胺、易普利木单抗、曲贝替丁、阿柏西普、艾代拉西布、色瑞替尼及它们的在药学上可接受的盐。
另外的药剂可以与所公开的化合物组合在单一药物配方(如本文所定义)中或者可以单独施用。
在一个优选的实施例中,天然存在的阿矛西丁(例如,阿矛西丁A)或式(1)、(2a)、(2b)、(2c)、(3a)、(3b)或(3c)化合物可以组合与一种或多种治疗白血病,例如急性髓性白血病、慢性髓性白血病、急性淋巴性细胞白血病或混合谱系白血病的药剂一起使用。示例性药剂包括长春新碱、氮胞苷、地西他滨、阿糖胞苷、道诺霉素、维奈托克、依鲁替尼、艾代拉西布、多柔比星、伊达比星(或另一种蒽环类抗生素)、L-天冬酰胺酶、PEG-L-天冬酰胺酶、环磷酰胺、奈拉滨、克拉屈滨、氟达拉滨、米托蒽醌、依托泊苷、羟基脲、甲氨蝶呤、6-巯基嘌呤、氮胞苷、地西他滨、泼尼松、地塞米松或其他皮质类固醇。优选地,一种或多种用于白血病的药剂与阿矛西丁A或式(3c)化合物组合。
在一些优选的实施例中,可以使用天然存在的阿矛西丁(例如,阿矛西丁A)或式(1)、(2a)、(2b)、(2c)、(3a)、(3b)或(3c)化合物与维奈托克、一种或多种核苷类似物或氮杂核苷(例如,氮胞苷、地西他滨、西达嗪)或两者以及维奈托克和一种或多种核苷类似物或氮杂核苷组合来治疗白血病。优选地,氮胞苷、维奈托克、或氮胞苷和维奈托克这两者与阿矛西丁A或式(3c)化合物组合。在其他实施例中,阿矛西丁A或式(3c)化合物与地西他滨和西达嗪组合施用。
在一些实施例中,本文公开的化合物可以施用于有需要的患者,而不会相应增加多重耐药性。在此类实施例中,所公开的化合物可以单独施用或与一种或多种如本文所定义的另外的抗癌剂组合施用。在一些实施例中,所公开的化合物可用于治疗已产生多重耐药性的患者中的癌症,例如白血病如AML。
可以使用本领域已知的方法来鉴定多重耐药性。在一些实施例中,患者可以具有以异常P-糖蛋白水平、包括升高P-糖蛋白(P-gp)水平为特征的多重耐药性。在一些情况下,患者具有多重耐药性,其特征在于P-gp上调、抗凋亡蛋白B细胞淋巴瘤(Bcl-2)下调、或同时出现P-gp上调和Bcl-2下调。患者可能具有多重耐药性,其特征是多重耐药相关蛋白(MRP1)过度表达或ABCC1基因过度表达。患者可能具有以肺耐药蛋白(LRP)过度表达为特征的多重耐药性。患者可能具有以谷胱甘肽S-转移酶(GST)过度表达为特征的多重耐药性,包括GSTα、GSTμ或GSTπ。患者可能具有多重耐药性,其特征是蛋白激酶C(PKC)上调,包括PKCα、PKCe和PKCq。患者可能具有以FMS样酪氨酸激酶3(FLT3)突变为特征的多重耐药性。患者可能具有以肾母细胞瘤(WT1)表达为特征的多重耐药性。患者可以具有以RAS突变为特征的多重耐药性,例如KRAS突变、HRAS突变或NRAS突变。患者可以具有以IDH1、TP53、ASXL1、DNMT3A、CEBPA、IDH2、PTPN11中的一种或多种突变为特征的多重耐药性。患者可以具有以分化状态为特征的多重耐药性,例如FAB分类,包括原始(M0)或单核细胞(M5)分化。
本文描述的药物组合物可以通过药剂学领域已知的或以后开发的任何方法来制备。一般而言,此类制备方法包括将活性成分与一种或多种赋形剂和/或一种或多种其他辅助成分混合的步骤,然后,如果需要和/或期望的话,将产品成型和/或包装成所需的单剂量或多剂量单位。
用于支架的局部和/或经皮施用的剂型可包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、粉末剂、溶液剂、喷雾剂、吸入剂和/或贴剂。一般而言,活性成分在无菌条件下与药学上可接受的赋形剂和/或任何需要的防腐剂和/或可能需要的缓冲剂混合。另外,本发明考虑了透皮贴剂的使用,其通常具有提供活性成分向身体的受控递送的附加优点。此类剂型可以例如通过将活性成分溶解和/或分散在适当的介质中来制备。可选地或另外地,可以通过提供速率控制膜和/或通过将活性成分分散在聚合物基质和/或凝胶中来控制速率。
用于制造药物组合物的药学上可接受的赋形剂包括但不限于惰性稀释剂、分散剂和/或造粒剂、表面活性剂和/或乳化剂、崩解剂、粘合剂、防腐剂、缓冲剂、润滑剂、和/或油。此类赋形剂可以任选地包含在本发明的制剂中。根据配制者的判断,组合物中可以存在赋形剂,例如可可脂和栓剂蜡、着色剂、包衣剂、甜味剂、矫味剂和芳香剂。
示例性稀释剂包括但不限于碳酸钙、碳酸钠、磷酸钙、磷酸二钙、硫酸钙、磷酸氢钙、磷酸钠乳糖、蔗糖、纤维素、微晶纤维素、高岭土、甘露醇、山梨醇、肌醇、氯化钠、干淀粉、玉米淀粉、糖粉等及它们的组合。
示例性的造粒剂和/或分散剂包括但不限于马铃薯淀粉、玉米淀粉、木薯淀粉、羟基乙酸淀粉钠、粘土、海藻酸、瓜尔胶、柑橘果肉、琼脂、膨润土、纤维素和木制品、天然海绵、阳离子交换树脂、碳酸钙、硅酸盐、碳酸钠、交联聚乙烯吡咯烷酮(交聚维酮)、羧甲基淀粉钠(羟基乙酸淀粉钠)、羧甲基纤维素、交联羧甲基纤维素钠(交联羧甲基纤维素)、甲基纤维素、预胶化淀粉(淀粉1500)、微晶淀粉、水不溶性淀粉、羧甲基纤维素钙、硅酸镁铝(Veegum)、十二烷基硫酸钠、季铵化合物等以及它们的组合。
示例性的表面活性剂和/或乳化剂包括但不限于天然乳化剂(例如阿拉伯胶、琼脂、海藻酸、海藻酸钠、黄芪胶、软骨藻、胆固醇、黄原胶、果胶、明胶、蛋黄、酪蛋白、羊毛脂、胆固醇、蜡和卵磷脂)、胶体粘土(例如膨润土[硅酸铝]和Veegum[硅酸铝镁])、长链氨基酸衍生物、高分子量醇(例如硬脂醇、鲸蜡醇、油醇、单硬脂酸三醋酯、乙二醇二硬脂酸酯、甘油单硬脂酸酯和丙二醇单硬脂酸酯、聚乙烯醇)、卡波姆(例如羧基聚亚甲基、聚丙烯酸、丙烯酸聚合物和羧乙烯基聚合物)、角叉菜胶、纤维素衍生物(例如羧甲基纤维素钠、粉状纤维素、羟甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素)、脱水山梨糖醇脂肪酸酯(例如聚氧乙烯脱水山梨糖醇单月桂酸酯[Tween 20]、聚氧乙烯脱水山梨糖醇[Tween60]、聚氧乙烯脱水山梨糖醇单油酸酯[Tween 80]、脱水山梨糖醇单棕榈酸酯[Span 40]、脱水山梨糖醇单硬脂酸酯[Span 60]、脱水山梨醇三硬脂酸酯[Span 65]、单油酸甘油酯、脱水山梨醇单油酸酯[Span 80])、聚氧乙烯酯(例如聚氧乙烯单硬脂酸酯[Myrj 45]、聚氧乙烯氢化蓖麻油、聚乙氧基化蓖麻油、聚氧亚甲基硬脂酸酯和Solutol)、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯(例如Cremophor)、聚氧乙烯醚(例如聚氧乙烯月桂基醚[Brij 30])、聚(乙烯基吡咯烷酮)、二甘醇单月桂酸酯、三乙醇胺油酸酯、油酸钠、油酸钾、油酸乙酯、油酸、月桂酸乙酯、十二烷基硫酸钠、普朗尼克F68、泊洛沙姆188、西曲溴铵、氯化十六烷基吡啶、苯扎氯铵、多库酯钠等和/或它们的组合。
示例性的粘合剂包括但不限于淀粉(例如玉米淀粉和淀粉糊);明胶;糖(例如蔗糖、葡萄糖、右旋糖、糊精、糖蜜、乳糖、乳糖醇、甘露醇);天然和合成胶(例如阿拉伯胶、海藻酸钠、爱尔兰苔藓提取物、潘瓦胶、加蒂胶、伊萨波尔果壳粘液、羧甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、微晶纤维素、醋酸纤维素、聚乙烯吡咯烷酮);硅酸镁铝(Veegum)和落叶松阿拉伯半乳聚糖);海藻酸盐;聚环氧乙烷;聚乙二醇;无机钙盐;硅酸;聚甲基丙烯酸酯;蜡;水;酒精等及它们的组合。
示例性防腐剂可包括抗氧化剂、螯合剂、抗微生物防腐剂、抗真菌防腐剂、醇防腐剂、酸性防腐剂和其他防腐剂。示例性的抗氧化剂包括但不限于α生育酚、抗坏血酸、抗坏血酸棕榈酸酯、丁基化羟基茴香醚、丁基化羟基甲苯、一硫代甘油、焦亚硫酸钾、丙酸、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、焦亚硫酸钠和亚硫酸钠。示例性螯合剂包括乙二胺四乙酸(EDTA)、柠檬酸一水合物、依地酸二钠、依地酸二钾、依地酸、富马酸、苹果酸、磷酸、依地酸钠、酒石酸和依地酸三钠。示例性的抗微生物防腐剂包括但不限于苯扎氯铵、苄索氯铵、苯甲醇、布罗波尔、西曲溴铵、氯化西吡啶、氯己定、氯丁醇、氯甲酚、氯二甲酚、甲酚、乙醇、甘油、己替丁、咪脲、苯酚、苯氧乙醇、苯乙醇、硝酸苯汞、丙二醇和硫柳汞。示例性抗真菌防腐剂包括但不限于对羟基苯甲酸丁酯、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、苯甲酸、羟基苯甲酸、苯甲酸钾、山梨酸钾、苯甲酸钠、丙酸钠和山梨酸。示例性的醇防腐剂包括但不限于乙醇、聚乙二醇、苯酚、酚类化合物、双酚、氯丁醇、羟基苯甲酸酯和苯乙醇。示例性的酸性防腐剂包括但不限于维生素A、维生素C、维生素E、β-胡萝卜素、柠檬酸、乙酸、脱氢乙酸、抗坏血酸、山梨酸和植酸。其他防腐剂包括但不限于生育酚、生育酚乙酸酯、甲磺酸地特肟、西曲溴铵、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、乙二胺、十二烷基硫酸钠(SLS)、十二烷基醚硫酸钠(SLES)、亚硫酸氢盐、焦亚硫酸钠、亚硫酸钾、焦亚硫酸钾、Glydant Plus、Phenonip、对羟基苯甲酸甲酯、Germall 115、Germaben II、Neolone、Kathon和Euxyl。在某些实施例中,防腐剂是抗氧化剂。在其它实施例中,防腐剂是螯合剂。
示例性的缓冲剂包括但不限于柠檬酸盐缓冲溶液、乙酸盐缓冲溶液、磷酸盐缓冲溶液、氯化铵、碳酸钙、氯化钙、柠檬酸钙、葡萄糖酸钙、葡萄糖酸钙、葡萄糖酸钙、D-葡萄糖酸、钙甘油磷酸盐、乳酸钙、丙酸、乙酰丙酸钙、戊酸、磷酸二氢钙、磷酸、磷酸三钙、磷酸氢钙、乙酸钾、氯化钾、葡萄糖酸钾、钾混合物、磷酸氢二钾、磷酸二氢钾、钾磷酸盐混合物、乙酸钠、碳酸氢钠、氯化钠、柠檬酸钠、乳酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钠混合物、氨丁三醇、氢氧化镁、氢氧化铝、海藻酸、无热原水、等渗盐水、林格氏液、乙醇等及它们的组合。
示例性的润滑剂包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸、二氧化硅、滑石粉、麦芽、山萮酸甘油酯、氢化植物油、聚乙二醇、苯甲酸钠、乙酸钠、氯化钠、亮氨酸、十二烷基硫酸镁、十二烷基硫酸钠等及它们的组合。
示例性的油包括但不限于扁桃仁、杏仁、鳄梨、巴巴苏、香柠檬、黑加仑籽、琉璃苣、刺桧、洋甘菊、芥花籽、香菜、巴西棕榈、蓖麻、肉桂、可可脂、椰子、鱼肝、咖啡、玉米、棉籽、鸸鹋、桉树、月见草、鱼、亚麻籽、香叶醇、葫芦、葡萄籽、榛子、海索草、肉豆蔻酸异丙酯、荷荷巴、库库伊坚果、醒目薰衣草、薰衣草、柠檬、山苍子、澳洲坚果、锦葵、芒果籽、白芒籽、水貂、肉豆蔻、橄榄、橙子、橙连鳍鲑、棕榈、棕榈仁、桃仁、花生、罂粟籽、南瓜籽、油菜籽、米糠、迷迭香、红花、檀香、萨斯奎纳、咸香、海沙棘、芝麻、乳木果油、硅酮、大豆、向日葵、茶树、蓟、椿、香根草、核桃和小麦胚芽油。示例性的油包括但不限于硬脂酸丁酯、辛酸甘油三酯、癸酸甘油三酯、环聚二甲基硅氧烷、癸二酸二乙酯、聚二甲基硅氧烷360、肉豆蔻酸异丙酯、矿物油、辛基十二烷醇、油醇、硅油及它们的组合。
用于口服和肠胃外施用的液体剂型包括但不限于药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除了活性成分之外,液体剂型还可包含本领域常用的惰性稀释剂,例如水或其他溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脂肪酸酯脱水山梨糖醇及它们的混合物。除了惰性稀释剂之外,口服组合物还可包括佐剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和芳香剂。在某些用于肠胃外施用的实施例中,缀合物可以与增溶剂例如Cremophor、醇、油、改性油、二醇、聚山梨醇酯、环糊精、聚合物及它们的组合。
可根据已知技术使用合适的分散剂或润湿剂和悬浮剂配制可注射制剂,例如无菌可注射水性或油性混悬剂。无菌注射制剂可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液、悬浮液或乳液,例如作为在1,3-丁二醇中的溶液。可以使用的可接受的媒介物和溶剂有水、林格氏溶液、U.S.P.和等渗氯化钠溶液等。此外,通常使用无菌的不挥发性油作为溶剂或悬浮介质。出于这个目的,可以采用任何温和的不挥发性油,包括合成的单甘油酯或二甘油酯。另外,在制备可注射剂时使用脂肪酸,例如油酸。
为了延长活性成分的作用,通常需要减缓皮下或肌内注射活性成分的吸收。这可以通过使用具有水溶性差的结晶或非晶形材料的液体悬浮液来实现。活性成分的吸收速率取决于其溶解速率,而溶解速率又可能取决于晶体尺寸和晶体形式。在一些实施例中,胃肠外施用的活性成分的延迟吸收通过将药物溶解或悬浮在油载体中来实现。
用于直肠或阴道施用的组合物通常是栓剂,其可以通过将缀合物与合适的非刺激性赋形剂例如可可脂、聚乙二醇或栓剂蜡混合来制备,所述赋形剂在环境温度下为固体但在体温下为液体并因此能够在直肠或阴道腔中熔化并释放活性成分。
用于口服施用的固体剂型包括胶囊、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性成分与至少一种惰性的药学上可接受的赋形剂,例如柠檬酸钠或磷酸二钙和/或(a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;(c)湿润剂,例如甘油;(d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠;(e)溶液阻滞剂,例如石蜡;(f)吸收促进剂,例如季铵化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸收剂,例如高岭土和膨润土;和(i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及它们的混合物混合。在是胶囊、片剂和丸剂的情况下,剂型可以包含缓冲剂。
类似类型的固体组合物可用作软填充明胶胶囊和硬填充明胶胶囊中的填充剂,使用诸如乳糖或奶糖以及高分子量聚乙二醇等赋形剂。固体剂型的片剂、糖衣药丸、胶囊、丸剂和颗粒剂可以用包衣和外壳,例如肠溶包衣和药学配制领域中所熟知的其它包衣来制备。它们可以任选地包含乳浊剂并且可以具有这样的组合物:它们仅或优选地在肠道的特定部分中任选地以延迟的方式释放一种或多种活性成分。可以使用的包埋组合物的示例包含聚合物质和蜡。类似类型的固体组合物可用作软填充明胶胶囊和硬填充明胶胶囊中的填充剂,使用诸如乳糖或奶糖以及高分子量聚乙二醇等赋形剂。
本文公开的化合物可用于治疗抑制ATP合酶有益的各种病症。特别地,所述化合物可用于治疗血液癌症,包括髓性白血病(慢性和急性)、淋巴性白血病,包括慢性淋巴细胞白血病、非霍奇金淋巴瘤和套细胞淋巴瘤、以及骨髓瘤。该化合物还可用于治疗成胶质细胞瘤,包括ENO1缺陷型成胶质细胞瘤、前列腺癌和肺癌。
实例
以下实施例仅用于说明本发明,并不旨在以任何方式限制本发明的范围。
实施例1:阿矛西丁A发酵
阿矛西丁A通过培养Ajinomoto股份有限公司(日本川崎)提供的Saccharothrixsp.AJ9571获得。将微生物接种在Bennett琼脂(0.1%酵母提取物、0.1%牛肉提取物、0.2%A型N-Z胺、1.0%葡萄糖、2.0%琼脂,pH 7.0)上,并在30℃孵育3-7天直至孢子形成。使用从固体培养物刮下的孢子在含有50mL种子培养基(1.0%可溶性淀粉、1.0%糖蜜(PlantationBlackstrap,未硫化)、1.0%蛋白胨、1.0%牛肉提取物,pH 7.0)的250mL锥形烧瓶中开始种子培养,并在30℃孵育7天,同时以220RPM的速度摇动。生产培养在多个含有50mL生产培养基(2.0%甘油、1.0%糖蜜、0.5%酪蛋白氨基酸、0.1%蛋白胨、0.4%碳酸钙,pH 7.2)的250mL锥形烧瓶中进行,并在30℃孵育7天,同时以220RPM的速度摇动。
发酵7天后,通过3000g×30min离心从培养液中分离菌丝体。将培养液用1体积的乙酸乙酯萃取3次,并将合并的有机层用盐水洗涤,用Na2SO4干燥并真空浓缩。然后将粗提取物用LH-20树脂进行色谱法,使用甲醇作为流动相,并通过薄层色谱法鉴定含有糖的大环内酯的级分并合并。然后使用Waters XBridge Prep C18 19×150mm柱对LH-20级分以从70%A/30%B到20%A/80%B(缓冲液A:95%水、5%乙腈、10mM醋酸铵;缓冲液B:5%水、95%乙腈、10mM醋酸铵)的20分钟的梯度进行反相HPLC。阿矛西丁A-RT 9.0min。使用Genevac HT-6将含有纯化合物的级分冻干,得到白色固体。
实施例2:阿矛西丁A衍生化
用3-(3-(丁-3-炔-1-基)-3H-二嗪-3-基)丙酸衍生化
对在冰上的3-(3-(丁-3-炔-1-基)-3H-二嗪-3-基)丙酸(4.5mg,0.027mmol,Enamine,基辅,乌克兰)的二氯甲烷(4.0mL)溶液,加入溴-三-吡咯烷鏻六氟磷酸盐(PyBrop,13.3mg,0.28mmol)和二异丙基乙胺(DIPEA,31μL,0.177mmol)。将所得溶液在0℃搅拌10min。添加阿矛西丁A(20mg 0.018mmol),然后添加4-二甲基氨基吡啶(DMAP)晶体。将所得溶液温热至室温过夜(16h)。通过TLC(90:10CHCl3:MeOH)监测反应并用100μL MeOH猝灭,然后浓缩。将所得残余物稀释于EtOAc(20mL)中并用1M HCl(5mL)洗涤。将水层用EtOAC(2×10mL)萃取两次。合并有机萃取物并用NaHCO3(5mL)和盐水(5mL)洗涤,用无水硫酸钠干燥并真空浓缩。将所得残余物溶解在800μL MeOH中,并使用Waters XBridge Prep C18 19×150mm柱通过反相HPLC进行纯化,使用25mM碳酸氢铵,使用从32%至77%乙腈水溶液的20分钟的梯度。将含有所需产物的级分(rt=16min)合并并冻干,得到白色固体产物(0.6mg,分离收率2.5%)。HRMS(ESI-TOF MS)m/z 1287.6854(M+Na)+计算值1287.6866,观测值(0.9ppm)。
通过多维NMR证实了加成的区域化学。
4-吗啉丁酸衍生化
向冰上的4-吗啉丁酸(2.2mg,0.013mmol)的二氯甲烷(2.0mL)溶液中添加溴代三吡咯烷鏻六氟磷酸盐(PyBrop,7mg,0.14mmol)和二异丙基乙胺(DIPEA,16μL,0.09mmol)。将所得溶液在0℃搅拌10min。添加阿矛西丁A(10mg 0.009mmol),然后添加4-二甲基氨基吡啶(DMAP)晶体。将所得溶液温热至室温过夜(16h)。通过TLC(90:10CHCl3:MeOH)监测反应并用100μL MeOH猝灭,然后浓缩。将所得残余物稀释于EtOAc(20mL)中并用1M HCl(5mL)洗涤。将水层用EtOAC(2×10mL)萃取两次。合并有机萃取物并用NaHCO3(5mL)和盐水(5mL)洗涤,用无水硫酸钠干燥并真空浓缩。将所得残余物溶解在800μL MeOH中,并使用Waters XBridgePrep C18 19×150mm柱通过反相HPLC进行纯化,使用25mM碳酸氢铵,使用从32%至77%乙腈水溶液的20分钟的梯度。两种主要产物被标记为不同的峰并收集在单独的级分中。HRMS(ESI-TOF MS)证实添加了酯(M+H)+的计算值为1312.7412m/z,观察值为1312.7400m/z(0.9ppm)。2DNMR(HSQC,HMBC)证实这两种产物为2'和3'酯。
使用类似方法制备3-(4-甲基哌嗪-1-基)丁酯,并通过HRMS(ESI-TOF MS)(M+H)+确认添加的计算值为1325.7729m/z、观测值为1325.7704(1.9ppm)。
实施例3:凋亡素生物合成修饰
五基因(R)-2-甲氧基丙二酰基-酰基载体蛋白(MeOM-ACP)连续基因盒(apoK-M2)的翻译序列与fkbG-K(编码来自Streptomyces hygroscopicus中的FK520基因簇的该延伸单元的生物合成)具有广泛的序列同一性,ApoJ与延伸单元的酰基载体蛋白具有53%的同一性。然而,虽然MeOMal-ACP已被报道通过拦截反式聚酮化合物合酶而起到延伸单元的作用,但从未报道过它作为链引发剂。
为了破坏该簇中的apoJ,我们采用了两步PCR靶向替换,其中首先用含有apo基因簇的fosmid中的抗生素抗性标记替换基因,然后转移到Nocardiopsis中以选择双交换事件。尝试替换291bp的apoJ并没有产生重组克隆,但是apoJK的双基因替换是成功的,产生了突变株Nocardiopsis sp.FU40 apoJK::aac(3)IV。翻译的apoK基因与FkbK具有65%的同一性,FkbK是一种负责甘油基-ACP的3-OH脱氢途中生成羟基丙二酸的氧化酶,预计其缺失不会影响下游的凋亡素生物合成。该菌株发酵培养物提取物的LC-MS分析表明所有凋亡素的产生完全消失,支持了(R)-2-甲氧基丙二酰-ACP生物合成起始的假设(图4)。
链起始和延伸结构单元和中间体的合成硫酯已被证明可以在体外加载KS活性位点半胱氨酸硫醇结构域,并且也已成功用于受阻聚酮化合物生物合成途径的化学互补研究。使用N-乙酰半胱胺、(R)-2-甲氧基丙二酸的(NAC)硫酯对apoJK敲除菌株进行化学拯救。将合成的MeOMe-SNAC添加到Nocardiopsis早期生长培养物中的初步研究显着恢复了凋亡素A的生物合成。通过评估脉冲给药方案来确定最佳掺入效率,其中在7天的发酵过程中等份加入60ug/mL。确定从种子培养第2天开始脉冲补充含有50μL 8mg/mL的DMSO的MeOMe-SNAC可获得最佳结果,凋亡素A的产量恢复至接近野生型水平。这些结果与第一聚酮合酶蛋白ApoS1的酰化位点是第二KS结构域中的活性引用半胱氨酸的情况一致。
实施例4:使用合成发酵剂单元的旁路发酵
制备甲氧基乙酸9、2-叠氮乙酸10、2-羟基乙酸11和2-溴乙酸12的苯硫基酯,并将其补充到Nocardiopsis sp.FU40 apoJK::aac(3)IV培养物中。提取物的LC/MS分析表明,甲氧基乙酸苯硫酯成功补充了apoJK缺失(图4C,迹线v),并且2-叠氮乙酸旁路产生了m/z=1139的新代谢物,290nm和330nm的UV max与其他凋亡素的特性一致,表明叠氮化物在C28处成功掺入(图4C,迹线vi)。为了确认这种新观察到的化合物的身份,我们对假定的含叠氮化物类似物进行了碰撞诱导解离研究。凋亡素的三种糖提供了用于鉴定的诊断片段。脱水导致C27糖损失,产生m/z 306和835的片段。随后C9糖的损失产生了m/z为163和675的片段。最后,对C22-C23键断裂和脱水(m/z为457)的观察证实了叠氮化物并入了凋亡素末端。
实施例5:细胞增殖测定(CellTitre-Glo)
将化合物稀释在DMSO(<0.05%的DMSO)中,并使用Echo 555液体处理器(Labcyte)将其分配到384孔板中。添加化合物后,将细胞以每孔2,000至8,000个细胞的浓度移入384孔板中的IMDM或RPMI培养基中,如上所述,补充10% FBS,并在37℃、5%CO2的组织培养箱中孵育。将板孵育48小时,并使用CellTiter-Glo试剂(Promega)测量细胞活力。活力百分比定义为每个孔的相对发光单位(RLU)除以DMSO对照中细胞的RLU。使用双对数转换数据的线性回归(GraphPad Prism version 6.0h)确定剂量反应曲线和GI50值。对照购自STEMCELLTechnologies的骨髓来源的CD34+细胞。
将100,000个细胞ml-1的100μl悬浮细胞添加到预先涂有0.5μl测试化合物(200×二甲亚砜)的微量滴定板的孔中,并孵育48-72h。将MTT试剂以1mg ml-1溶解在新鲜培养基中,并向每孔中添加100μl以达到0.5mg ml-1的终浓度,并在37℃孵育2h。将细胞在800g离心5min并倒出。将MTT晶体重新溶解在100μl二甲亚砜中,在室温下孵育5min,并使用SpectraMax plus 384板读数器(Molecular Devices)在560nm处读数。通过背景扣除(没有细胞的孔)将吸光度值归一化,使得载体处理的细胞的活力为1.0。使用具有四参数对数逻辑函数的DRC R软件包拟合浓度响应曲线。使用具有默认参数的EDcomp函数(用于比较半数最大抑制浓度值)和paramcomp函数(用于比较其他参数)对浓度-响应曲线之间的差异进行统计测试。
下表中列出的化合物是使用本文描述的技术制备的:
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实施例6:药代动力学研究
所有动物实验均按照范德比尔特大学医学中心IACUC批准的指南进行。腹膜内单独给药阿矛西丁0.5mg kg-1后,对生物学三次重复的NSGS雄性小鼠的全血中阿矛西丁的药代动力学进行了评估。将全血样本收集到EDTA管中用于血浆分析。将血浆与由PBS中的1μMApop A组成的内标溶液按1:1混合。用200μl乙酸乙酯提取代谢物,蒸发至干并重悬于50μlMeOH中。使用液相色谱-MS(Thermo TSQ Quantum Access Max)测定Ammo A浓度,并在50×1.8mm C18柱上进行技术重复,等度60/40H2O/乙腈+10mM乙酸铵,在电喷雾电离中以250μlmin-1进行测定-正向模式监测Ammo A(1139.7→208.8,碰撞能量(CE)19V,保留时间(RT)=1.00min)和Apop A(1146.68→805.46,CE 19V,RT=1.66min)。
所附权利要求的组合物和方法在范围上不受本文描述的具体组合物和方法的限制,所述具体组合物和方法旨在作为权利要求的几个方面的说明,并且功能上等效的任何组合物和方法旨在落入权利要求的范围内。除了本文所示出和描述的组合物和方法之外,对方法的各种修改旨在落入所附权利要求书的范围内。进一步地,尽管仅具体描述本文公开的某些代表性组合物和方法步骤,但是这些组合物和方法步骤的其它组合也旨在落入所附权利要求书的范围内,即使没有具体叙述。因此,步骤、元件、组分或成分的组合可以在本文明确提及或更少提及,然而,即使未明确说明,也包括步骤、元件、组分和成分的其他组合。如本文中所使用的术语“包括(comprising)”及其变体与术语“包含(including)”及其变体同义地使用并且是开放性的非限制性术语。尽管术语“包含”和“包括”已经在本文中用于描述各个实施例,但是术语“基本上由…组成”和“由…组成”可以用于代替“包括”和“包含”以提供更具体的实施例,并且还被公开。除了在示例中或另外注明的情况下,说明书和权利要求中使用的表示成分的量、反应条件等的所有数字至少应被理解,并且不是试图将等价物原理的应用限制在权利要求的范围内,根据有效数字的数量和普通舍入方法来解释。
Claims (133)
1.一种化合物,其具有下式:
或其药学上可接受的盐,
其中
R1选自H、OH、C1-8烷基和OC1-8烷基,优选CH3.
R2选自H、OH、C1-8烷基和OC1-8烷基,优选OCH3.
R3选自H、OH、C1-8烷基和OC1-8烷基,优选H或OH.
R4选自H、OH、C1-8烷基和OC1-8烷基,优选H或OH.
Q1是具有下式的基团:
其中
R2a选自-R2a*、-OR2a*、OP(O)(OR2a*)2、OP(O)(OR2a*)(N(R2a*)2、-N(R2a*)2、-N(R2a*)3、-C(O)R2a*、-C(O)OR2a*、-OC(O)R2a*、-OC(O)OR2a*、-NR2a*C(O)R2a*、-C(O)N(R2a*)2、NR2a*C(O)OR2a*、-OC(O)N(R2a*)2、-NR2a*C(O)N(R2a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-OH;
R2a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R2a*可被-OH、-COOH、-、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-OH;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次,
其中任意两个或更多个R2a*可一起形成环;
R3a选自-R3a*、-OR3a*、OP(O)(OR3a*)2、OP(O)(OR3a*)(N(R3a*)2、-N(R3a*)2、-N(R3a*)3-C(O)R3a*、-C(O)OR3a*、-OC(O)R3a*、-OC(O)OR3a*、-NR3a*C(O)R3a*、-C(O)N(R3a*)2、NR3a*C(O)OR3a*、-OC(O)N(R3a*)2、-NR3a*C(O)N(R3a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-OH;
R3a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R3a*可被-OH、-COOH、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-OH;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次,
其中任意两个或更多个R3a*可一起形成环;
R4a选自-R4a*、-OR4a*、OP(O)(OR4a*)2、OP(O)(OR4a*)(N(R4a*)2、-N(R4a*)2、-N(R4a*)3、-C(O)R4a*、-C(O)OR4a*、-OC(O)R4a*、-OC(O)OR4a*、-NR4a*C(O)R4a*、-C(O)N(R4a*)2、NR4a*C(O)OR4a*、-OC(O)N(R4a*)2、-NR4a*C(O)N(R4a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-OH;
R4a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R4a*可被-OH、-COOH、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-OH;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次;
其中任意两个或更多个R4a*可一起形成环;
R5a选自-R5a*、-OR5a*、OP(O)(OR5a*)2、OP(O)(OR5a*)(N(R5a*)2、-N(R5a*)2、-N(R5a*)3、-C(O)R5a*、-C(O)OR5a*、-OC(O)R5a*、-OC(O)OR5a*、-NR5a*C(O)R5a*、-C(O)N(R5a*)2、NR5a*C(O)OR5a*、-OC(O)N(R5a*)2、-NR5a*C(O)N(R5a*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-OH;
R5a*在每种情况下独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、芳基、C3-10环烷基、C3-10环烯基、C7-10环炔基、芳基、C1-10杂环基、C1-10杂芳基;其中每个R5a*可被-OH、-COOH、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-OH;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次;
其中Rp在每种情况下选自H、C1-10烷基和芳基;
其中任意两个或更多个R5a*可一起形成环;
其中任意两个或更多个R2a、R3a、R4a和R5a可一起形成环;
Q2是具有下式的基团:
其中:
R1b选自H、OH、C1-8烷基和OC1-8烷基;
R2b选自-R2b*、-OR2b*、OP(O)(OR2b*)2、OP(O)(OR2b*)(N(R2b*)2、-N(R2b*)2、-N(R2b*)3、-C(O)R2b*、-C(O)OR2b*、-OC(O)R2b*、-OC(O)OR2b*、-NR2b*C(O)R2b*、-C(O)N(R2b*)2、NR2b*C(O)OR2b*、-OC(O)N(R2b*)2、-NR2b*C(O)N(R2b*)2;-Cl、-F、-Br、-I、-NO2、-CN、-N3、-(OCH2CH2)m-OH;
R2b*在每种情况下独立地选自H、C1-8烷基、C1-8烯基、C1-10炔基、芳基、C3-8环烷基、C3-8环烯基、C7-10环炔基、芳基、C1-8杂环基、C3-8杂芳基;其中每个R2b*可被-OH、-COOH、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-NH2、-Cl、-F、-Br、-I、-NO2、-CN、-N3、PO(OH)2、-(OCH2CH2)m-OH;C1-8杂环基、芳基、-OC1-8杂环基或C1-8烷氧基取代一次或多次,
其中任意两个或更多个R2b*可一起形成环;
R3b选自H或具有下式的基团:
其中
R3d选自H和CH3;以及
R4d选自H和具有下式的基团:
其中m在每种情况下选自1-100、5-100、10-100、25-100、50-100、1-50、1-25、1-10、1-5、5-50或25-75;
条件是R2a、R3a和R4a全部为OH,R2b不为CH2CH2CH2OCH3。
2.根据权利要求1所述的化合物,其中所述化合物为式(2a)、(2b)或(2c)化合物:
3.根据权利要求1所述的化合物,其中Q1为具有以下构象的(L)糖:
4.根据权利要求1所述的化合物,其中Q1具有以下结构:
5.根据权利要求1所述的化合物,其中Q2具有下式:
6.根据权利要求1所述的化合物,其中Q2具有下式:
7.根据权利要求1所述的化合物,其中R3b具有下式:
8.根据权利要求1所述的化合物,其中R4d具有下式:
9.根据权利要求2所述的化合物,其中R5a选自CH3和CH2OH,最优选CH3。
10.根据权利要求2所述的化合物,其中R4a和R2a均为OH。
11.根据权利要求2所述的化合物,其中R3a和R2a均为OH。
12.根据权利要求2所述的化合物,其中R3a和R4a均为OH。
13.根据权利要求2所述的化合物,其中R4a和R2a均不为OH。
14.根据权利要求2所述的化合物,其中R3a和R2a均不为OH。
15.根据权利要求2所述的化合物,其中R4a和R3a均不为OH。
16.根据权利要求2所述的化合物,其中R2a、R3a和R4a都不为OH。
17.根据权利要求2所述的化合物,其中R3a为-OR3a*、-OC(O)R3a*、OP(O)(OR3a*)2、OP(O)(OR3a*)(N(R3a*)2、-OC(O)OR3a、-OC(O)N(R3a*)2或-(OCH2CH2)m-OR3a*(m为1-100,其中R3a*独立地选自H(当R3a为OR3a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基)。
18.根据权利要求16所述的化合物,其中R3a*被取代一次或多次;示例性取代基包括COOR、F、Cl、Br、I、SO3R、OSO3R、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、P(O)(OR)2、OP(O)(OR)2、N3、杂环基、杂芳基、芳基、环烷基,其中R在每种情况下独立地选自H、烷基和环烷基。
19.根据权利要求16所述的化合物,其中R3a为-OR3a*或-OC(O)R3a*。
20.根据权利要求16所述的化合物,其中R3a为-OP(O)(OR3a*)2或OP(O)(OR3a*)(N(R3a*)2,其中R3a*优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
21.根据权利要求16所述的化合物,其中R3a*具有下式:
其中z和z'之和不大于7,Q2a和Q3a均为氢或一起形成C1-8杂环基,并且Q1a选自-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、COOH、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
22.根据权利要求20所述的化合物,其中Q1a为COOH、N3和CF3。
23.根据权利要求20所述的化合物,其中Q1a选自芳基和C1-10杂芳基,任选地被如上所述取代一次或多次。
24.根据权利要求20所述的化合物,其中Q1a为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
25.根据权利要求2所述的化合物,其中R2a为-OR2a*、-OC(O)R2a*、OP(O)(OR2a*)2、OP(O)(OR2a*)(N(R2a*)2、-OC(O)OR2a、-OC(O)N(R2a*)2或-(OCH2CH2)m-OR2a*(m为1-100),其中R2a*独立地选自H(当R2a为OR2a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基,任选地被COOR、F、Cl、Br、I、SO3R、OSO3R、P(O)(OR)2、OP(O)(OR)2、-PPh3、-CH2NEt3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、N3、杂环基、杂芳基、芳基、环烷基取代,其中R在每种情况下独立地选自H、烷基和环烷基。
26.根据权利要求24所述的化合物,其中R2a为-OR2a*或-OC(O)R2a*。
27.根据权利要求24所述的化合物,其中R2a为-OP(O)(OR2a*)2或OP(O)(OR2a*)(N(R2a*)2,其中R2a优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
28.根据权利要求24所述的化合物,其中R2a*具有下式:
其中y和y'之和不大于7,Q2b和Q3b均为氢或一起形成C1-8杂环基,并且Q1b选自COOH、芳基、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
29.根据权利要求4所述的化合物,其中Q1b选自COOH、N3和CF3。
30.根据权利要求4所述的化合物,其中Q1b选自芳基和C1-10杂芳基。
31.根据权利要求4所述的化合物,其中Q1b为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
32.根据权利要求2所述的化合物,其中R4a为-OR4a*、-OC(O)R4a*、OP(O)(OR4a*)2、OP(O)(OR4a*)(N(R4a*)2、-OC(O)OR4a、-OC(O)N(R4a*)2或-(OCH2CH2)m-OH(m为1-100),其中R4a*独立地选自H(当R4a为OR4a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基,任选地被COOR、F、Cl、Br、I、SO3R、OSO3R、P(O)(OR)2、OP(O)(OR)2、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、N3、杂环基、杂芳基、芳基、环烷基取代,其中R在每种情况下独立地选自H、烷基和环烷基。
33.根据权利要求31所述的化合物,其中R4a为-OR4a*或-OC(O)R4a*。
34.根据权利要求31所述的化合物,其中R4a为-OP(O)(OR4a*)2或OP(O)(OR4a*)(N(R4a*)2,其中R4a优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
其中Rp如上所述定义。
35.根据权利要求31所述的化合物,其中R4a*具有下式:
其中x和x'之和不大于7,Q2c和Q3c均为氢或一起形成C1-8杂环基,并且Q1c选自COOH、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
36.根据权利要求34所述的化合物,其中Q1c选自COOH、N3和CF3。
37.根据权利要求34所述的化合物,其中Q1c选自芳基和C1-10杂芳基。
38.根据权利要求34所述的化合物,其中Q1c为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
39.根据权利要求4所述的化合物,其中R2b独立地选自H、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基,任选地被-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、N3、COOR、F、Cl、Br、I、SO3R、OSO3R、P(O)(OR)2、OP(O)(OR)2、N3、杂环基、杂芳基、芳基、环烷基取代,其中R在每种情况下独立地选自H、烷基和环烷基。
40.根据权利要求4所述的化合物,其中R2b为C1-8烷基,被-OP(O)(OR2b*)2或OP(O)(OR2b*)(N(R2b*)2取代,其中R2b*优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
41.根据权利要求38所述的化合物,其中R2b*具有下式:
其中w和w'之和不大于7,Q2d和Q3d均为氢或一起形成C1-8杂环基,并且Q1d选自COOH、芳基、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
42.根据权利要求40所述的化合物,其中Q1d选自COOH、N3和CF3。
43.根据权利要求40所述的化合物,其中Q1d选自芳基和C1-10杂芳基,任选地被如上所述取代一次或多次。
44.根据权利要求40所述的化合物,其中Q1d为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
45.根据权利要求1所述的化合物,其中所述化合物具有式(3a)、(3b)或(3c):
或其药学上可接受的盐,
其中R2f为-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或-(CH2CH2)m-ORf*;
其中R3f为-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或-(CH2CH2)m-ORf*;
其中R4f为-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或-(CH2CH2)m-ORf*;
Rf*在每种情况下独立地选自H、被取代或未被取代的C1-8烷基、被取代或未被取代的C1-8烯基、被取代或未被取代的C1-10炔基、被取代或未被取代的芳基、被取代或未被取代的C3-8环烷基、被取代或未被取代的C3-8环烯基、被取代或未被取代的C7-10环炔基、芳基、被取代或未被取代的C1-8杂环基、被取代或未被取代的C3-8杂芳基;
Rs选自H、被取代或未被取代的C1-8烷基、被取代或未被取代的C1-8烯基、被取代或未被取代的C1-10炔基、被取代或未被取代的芳基、被取代或未被取代的C3-8环烷基、被取代或未被取代的C3-8环烯基、被取代或未被取代的C7-10环炔基、被取代或未被取代的芳基、C1-8杂环基、被取代或未被取代的C3-8杂芳基;
其中m在每种情况下选自1-100、5-100、10-100、25-100、50-100、1-50、1-25、1-10、1-5、5-50或25-75;
条件是当Rs为CH2CH2CH2OCH3时,R2f、R3f和R4f不同时为H。
46.根据权利要求44所述的化合物,其中R2f为-C(O)R2f*,并且R3f和R4f均为H且Rs为CH2CH2CH2OCH3。
47.根据权利要求44所述的化合物,其中R3f为-C(O)Rf*,并且R2f和R4f均为H且Rs为CH2CH2CH2OCH3。
48.根据权利要求44所述的化合物,其中R4f为-C(O)Rf*,并且R2f和R3f均为H且Rs为CH2CH2CH2OCH3。
49.根据权利要求45至47中任一项所述的化合物,其中Rf*选自:
其中n为0、1、2、3、4、6、7、8、9或10,并且Qf为-PPh3、-CH2NEt3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、CF3、-C≡CH、N3、-C≡N、COOH、—(CO)—O-烷基、芳基、金刚烷基、杂环基、被取代或未被取代的C7-10环炔基。
50.根据权利要求44所述的化合物,其中Rs选自
其中n为0、1、2、3、4、6、7、8、9或10,并且Qs为-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、CF3、-C≡CH、N3、-C≡N、COOH、—(CO)—O-烷基、芳基、金刚烷基、杂环基、被取代或未被取代的C7-10环炔基。
51.一种治疗有需要的患者的癌症的方法,其包括向所述患者施用根据任一前述权利要求所述的化合物。
52.根据任一前述权利要求所述的方法,其中所述患者已产生多重耐药性。
53.根据前述权利要求所述的方法,其中所述癌症包括血液癌、成胶质细胞瘤、前列腺癌或肺癌。
54.根据任一前述权利要求所述的方法,其中所述癌症包括慢性髓性白血病、急性髓性白血病、淋巴性白血病、慢性淋巴细胞白血病、非霍奇金淋巴瘤、套细胞淋巴瘤或骨髓瘤。
55.根据任一前述权利要求所述的方法,其中所述化合物包括式(3c)化合物。
56.根据任一前述权利要求所述的方法,其包括向所述患者施用至少一种另外的抗癌剂。
57.根据任一前述权利要求所述的方法,其中所述至少一种另外的抗癌剂包括长春新碱、阿糖胞苷、道诺霉素、维奈托克、依鲁替尼、艾代拉西布、多柔比星、伊达比星、L-天冬酰胺酶、PEG-L-天冬酰胺酶、环磷酰胺、奈拉滨、克拉屈滨、氟达拉滨、米托蒽醌、依托泊苷、羟基脲、甲氨蝶呤、6-巯基嘌呤、氮胞苷、地西他滨、泼尼松、地塞米松或其组合。
58.根据任一前述权利要求所述的方法,其中所述至少一种另外的抗癌剂包括维奈托克、氮胞苷或其组合。
59.一种治疗有需要的患者的白血病的方法,其包括向所述患者施用阿矛西丁。
60.一种治疗有需要的患者的白血病的方法,其包括向所述患者施用阿矛西丁。
61.根据任一前述权利要求所述的方法,其中所述患者已产生多重耐药性。
62.根据前述权利要求所述的方法,其中所述白血病包括髓性白血病、急性髓性白血病、淋巴性白血病、慢性淋巴细胞白血病、非霍奇金淋巴瘤、套细胞淋巴瘤或骨髓瘤。
63.根据前述权利要求所述的方法,其中所述阿矛西丁包括阿矛西丁A。
64.根据前述权利要求所述的方法,其中所述阿矛西丁与选自以下的至少一种另外的抗癌剂组合施用:长春新碱、阿糖胞苷、道诺霉素、维奈托克、依鲁替尼、艾代拉西布、多柔比星、伊达比星、L-天冬酰胺酶、PEG-L-天冬酰胺酶、环磷酰胺、奈拉滨、克拉屈滨、氟达拉滨、米托蒽醌、依托泊苷、羟基脲、甲氨蝶呤、6-巯基嘌呤、氮胞苷、地西他滨、泼尼松、地塞米松及其组合。
65.根据任一前述权利要求所述的方法,其中所述阿矛西丁与选自氮胞苷、维奈托克及其组合的至少一种另外的抗癌剂组合施用。
66.根据任一前述权利要求所述的方法,其中所述白血病包括急性髓性白血病。
67.根据任一前述权利要求所述的化合物,其中所述化合物为式(2a)、(2b)或(2c)化合物:
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68.根据任一前述权利要求所述的化合物,其中Q1为具有以下构象的(L)糖:
69.根据任一前述权利要求所述的化合物,其中Q1具有以下结构:
70.根据任一前述权利要求所述的化合物,其中Q2具有下式:
71.根据任一前述权利要求所述的化合物,其中Q2具有下式:
72.根据任一前述权利要求所述的化合物,其中R3b具有下式:
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73.根据任一前述权利要求所述的化合物,其中R4d具有下式:
74.根据任一前述权利要求所述的化合物,其中R5a选自CH3和CH2OH,最优选CH3。
75.根据任一前述权利要求所述的化合物,其中R4a和R2a均为OH。
76.根据任一前述权利要求所述的化合物,其中R3a和R2a均为OH。
77.根据任一前述权利要求所述的化合物,其中R3a和R4a均为OH。
78.根据任一前述权利要求所述的化合物,其中R4a和R2a均不为OH。
79.根据任一前述权利要求所述的化合物,其中R3a和R2a均不为OH。
80.根据任一前述权利要求所述的化合物,其中R4a和R3a均不为OH。
81.根据任一前述权利要求所述的化合物,其中R2a、R3a和R4a都不为OH。
82.根据任一前述权利要求所述的化合物,其中R3a为-OR3a*、-OC(O)R3a*、OP(O)(OR3a*)2、OP(O)(OR3a*)(N(R3a*)2、-OC(O)OR3a、-OC(O)N(R3a*)2或-(OCH2CH2)m-OR3a*(m为1-100)。
83.根据任一前述权利要求所述的化合物,其中R3a*独立地选自H(当R3a为OR3a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基。
84.根据任一前述权利要求所述的化合物,其中R3a*被取代一次或多次;示例性取代基包括COOR、F、Cl、Br、I、SO3R、OSO3R、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、P(O)(OR)2、OP(O)(OR)2、N3、杂环基、杂芳基、芳基、环烷基,其中R在每种情况下独立地选自H、烷基和环烷基。
85.根据任一前述权利要求所述的化合物,其中R3a为-OR3a*或-OC(O)R3a*。
86.根据任一前述权利要求所述的化合物,其中R3a为-OP(O)(OR3a*)2或OP(O)(OR3a*)(N(R3a*)2,其中R3a*优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
87.根据任一前述权利要求所述的化合物,其中R3a*具有下式:
其中z和z'之和不大于7,Q2a和Q3a均为氢或一起形成C1-8杂环基,并且Q1a选自-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、COOH、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
88.根据任一前述权利要求所述的化合物,其中Q1a为COOH、N3和CF3。在其他实施例中,Q1a选自芳基和C1-10杂芳基,任选地如上所述被取代一次或多次。
89.根据任一前述权利要求所述的化合物,其中Q1a为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
90.根据任一前述权利要求所述的化合物,其中R2a为-OR2a*、-OC(O)R2a*、OP(O)(OR2a*)2、OP(O)(OR2a*)(N(R2a*)2、-OC(O)OR2a、-OC(O)N(R2a*)2或-(OCH2CH2)m-OR2a*(m为1-100)。
91.根据任一前述权利要求所述的化合物,其中R2a*独立地选自H(当R2a为OR2a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基,任选地被COOR、F、Cl、Br、I、SO3R、OSO3R、P(O)(OR)2、OP(O)(OR)2、-PPh3、-CH2NEt3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、N3、杂环基、杂芳基、芳基、环烷基取代,其中R在每种情况下独立地选自H、烷基和环烷基。
92.根据任一前述权利要求所述的化合物,其中R2a为-OR2a*或-OC(O)R2a*。
93.根据任一前述权利要求所述的化合物,其中R2a为-OP(O)(OR2a*)2或OP(O)(OR2a*)(N(R2a*)2,其中R2a优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
94.根据任一前述权利要求所述的化合物,其中R2a*具有下式:
其中y和y'之和不大于7,Q2b和Q3b均为氢或一起形成C1-8杂环基,并且Q1b选自COOH、芳基、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
95.根据任一前述权利要求所述的化合物,其中Q1b选自COOH、N3和CF3。
96.根据任一前述权利要求所述的化合物,其中Q1b选自芳基和C1-10杂芳基。
97.根据任一前述权利要求所述的化合物,其中Q1b为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
98.根据任一前述权利要求所述的化合物,其中R4a为-OR4a*、-OC(O)R4a*、OP(O)(OR4a*)2、OP(O)(OR4a*)(N(R4a*)2、-OC(O)OR4a、-OC(O)N(R4a*)2或-(OCH2CH2)m-OH(m为1-100)。
99.根据任一前述权利要求所述的化合物,其中R4a*独立地选自H(当R4a为OR4a*时除外)、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基,任选地被COOR、F、Cl、Br、I、SO3R、OSO3R、P(O)(OR)2、OP(O)(OR)2、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、N3、杂环基、杂芳基、芳基、环烷基取代,其中R在每种情况下独立地选自H、烷基和环烷基。
100.根据任一前述权利要求所述的化合物,其中R4a为-OR4a*或-OC(O)R4a*。
101.根据任一前述权利要求所述的化合物,其中R4a为-OP(O)(OR4a*)2或OP(O)(OR4a*)(N(R4a*)2,其中R4a优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
其中Rp如上所述定义。
102.根据任一前述权利要求所述的化合物,其中R4a*具有下式:
其中x和x'之和不大于7,Q2c和Q3c均为氢或一起形成C1-8杂环基,并且Q1c选自COOH、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、芳基、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
103.根据任一前述权利要求所述的化合物,其中Q1c选自COOH、N3和CF3。
104.根据任一前述权利要求所述的化合物,其中Q1c选自芳基和C1-10杂芳基。
105.根据任一前述权利要求所述的化合物,其中Q1c为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
106.根据任一前述权利要求所述的化合物,其中R2b独立地选自H、C1-8烷基、C1-8烯基或C1-10炔基、C7-10环炔基、C7-10环烯基、C1-8杂环基、C1-8烷基C7-10环炔基、C1-8烷基C7-10环烯基或C1-8烷基C1-8杂环基,任选地被-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、N3、COOR、F、Cl、Br、I、SO3R、OSO3R、P(O)(OR)2、OP(O)(OR)2、N3、杂环基、杂芳基、芳基、环烷基取代,其中R在每种情况下独立地选自H、烷基和环烷基。
107.根据任一前述权利要求所述的化合物,其中R2b为C1-8烷基,被-OP(O)(OR2b*)2或OP(O)(OR2b*)(N(R2b*)2取代,其中R2b*优选地选自H、芳基和C1-8烷基,或衍生自氨基酸,例如:
108.根据任一前述权利要求所述的化合物,其中R2b*具有下式:
其中w和w'之和不大于7,Q2d和Q3d均为氢或一起形成C1-8杂环基,并且Q1d选自COOH、芳基、-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、-C≡CH、-CF3、N3、C7-10环炔基、C7-10环烯基、C1-10杂芳基或C1-10杂环基。
109.根据任一前述权利要求所述的化合物,其中Q1d选自COOH、N3和CF3。
110.根据任一前述权利要求所述的化合物,其中Q1d选自芳基和C1-10杂芳基,任选地被如上所述取代一次或多次。
111.根据任一前述权利要求所述的化合物,其中Q1d为二苯并环辛炔、二苯并环辛炔胺或反式环辛烯。
112.一种化合物,其具有式(3a)、(3b)或(3c):
或其药学上可接受的盐,
其中R2f为-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或-(CH2CH2)m-ORf*;
其中R3f为-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或-(CH2CH2)m-ORf*;
其中R4f为-Rf*、-C(O)Rf*、-C(O)ORf*、-OC(O)R2b*、-OC(O)ORf*、C(O)N(Rf*)2或-(CH2CH2)m-ORf*;
Rf*在每种情况下独立地选自H、被取代或未被取代的C1-8烷基、被取代或未被取代的C1-8烯基、被取代或未被取代的C1-10炔基、被取代或未被取代的芳基、被取代或未被取代的C3-8环烷基、被取代或未被取代的C3-8环烯基、被取代或未被取代的C7-10环炔基、芳基、被取代或未被取代的C1-8杂环基、被取代或未被取代的C3-8杂芳基;
Rs选自H、被取代或未被取代的C1-8烷基、被取代或未被取代的C1-8烯基、被取代或未被取代的C1-10炔基、被取代或未被取代的芳基、被取代或未被取代的C3-8环烷基、被取代或未被取代的C3-8环烯基、被取代或未被取代的C7-10环炔基、被取代或未被取代的芳基、C1-8杂环基、被取代或未被取代的C3-8杂芳基;
其中m在每种情况下选自1-100、5-100、10-100、25-100、50-100、1-50、1-25、1-10、1-5、5-50或25-75;
条件是当Rs为CH2CH2CH2OCH3时,R2f、R3f和R4f不同时为H。
113.根据任一前述权利要求所述的化合物,其中R2f为-C(O)R2f*,并且R3f和R4f均为H且Rs为CH2CH2CH2OCH3。
114.根据任一前述权利要求所述的化合物,其中R3f为-C(O)Rf*,并且R2f和R4f均为H且Rs为CH2CH2CH2OCH3。
115.根据任一前述权利要求所述的化合物,其中R4f为-C(O)Rf*,并且R2f和R3f均为H且Rs为CH2CH2CH2OCH3。
116.根据任一前述权利要求所述的化合物,其中Rf*选自:
其中n为0、1、2、3、4、6、7、8、9或10,并且Qf为-PPh3、-CH2NEt3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、CF3、-C≡CH、N3、-C≡N、COOH、—(CO)—O-烷基、芳基、金刚烷基、杂环基、被取代或未被取代的C7-10环炔基。
117.根据任一前述权利要求所述的化合物,其中Rs选自
其中n为0、1、2、3、4、6、7、8、9或10,并且Qs为-PPh3、-CH2NEt3、-CH2NMe3、-NHC(=NH)NH2、罗丹明染料、双喹啉鎓、CF3、-C≡CH、N3、-C≡N、COOH、—(CO)—O-烷基、芳基、金刚烷基、杂环基、被取代或未被取代的C7-10环炔基。
118.一种治疗有需要的患者的癌症的方法,其包括向所述患者施用根据任一前述权利要求所述的化合物。
119.根据任一前述权利要求所述的方法,其中所述患者已产生多重耐药性。
120.根据前述权利要求所述的方法,其中所述癌症包括血液癌、成胶质细胞瘤、前列腺癌或肺癌。
121.根据任一前述权利要求所述的方法,其中所述癌症包括慢性髓性白血病、急性髓性白血病、淋巴性白血病、慢性淋巴细胞白血病、非霍奇金淋巴瘤、套细胞淋巴瘤或骨髓瘤。
122.根据任一前述权利要求所述的方法,其中所述化合物包括式(3c)化合物。
123.根据任一前述权利要求所述的方法,其包括向所述患者施用至少一种另外的抗癌剂。
124.根据任一前述权利要求所述的方法,其中所述至少一种另外的抗癌剂包括长春新碱、阿糖胞苷、道诺霉素、维奈托克、依鲁替尼、艾代拉西布、多柔比星、伊达比星、L-天冬酰胺酶、PEG-L-天冬酰胺酶、环磷酰胺、奈拉滨、克拉屈滨、氟达拉滨、米托蒽醌、依托泊苷、羟基脲、甲氨蝶呤、6-巯基嘌呤、氮胞苷、地西他滨、泼尼松、地塞米松或其组合。
125.根据任一前述权利要求所述的方法,其中所述至少一种另外的抗癌剂包括维奈托克、氮胞苷或其组合。
126.一种治疗有需要的患者的白血病的方法,其包括向所述患者施用阿矛西丁。
127.一种治疗有需要的患者的白血病的方法,其包括向所述患者施用阿矛西丁。
128.根据任一前述权利要求所述的方法,其中所述患者已产生多重耐药性。
129.根据前述权利要求所述的方法,其中所述白血病包括髓性白血病、急性髓性白血病、淋巴性白血病、慢性淋巴细胞白血病、非霍奇金淋巴瘤、套细胞淋巴瘤或骨髓瘤。
130.根据前述权利要求所述的方法,其中所述阿矛西丁包括阿矛西丁A。
131.根据前述权利要求所述的方法,其中所述阿矛西丁与选自以下的至少一种另外的抗癌剂组合施用:长春新碱、阿糖胞苷、道诺霉素、维奈托克、依鲁替尼、艾代拉西布、多柔比星、伊达比星、L-天冬酰胺酶、PEG-L-天冬酰胺酶、环磷酰胺、奈拉滨、克拉屈滨、氟达拉滨、米托蒽醌、依托泊苷、羟基脲、甲氨蝶呤、6-巯基嘌呤、氮胞苷、地西他滨、泼尼松、地塞米松及其组合。
132.根据任一前述权利要求所述的方法,其中所述阿矛西丁与选自氮胞苷、维奈托克及其组合的至少一种另外的抗癌剂组合施用。
133.根据任一前述权利要求所述的方法,其中所述白血病包括急性髓性白血病。
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