CN118103378A - 盐霉素的含氮衍生物、其合成和用途 - Google Patents
盐霉素的含氮衍生物、其合成和用途 Download PDFInfo
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Abstract
本发明涉及具有式(I)的盐霉素的含氮衍生物，以及其合成和用途，特别是用于治疗和/或预防癌症的用途。
Description
技术领域
本发明涉及盐霉素的新颖含氮衍生物、它们的合成以及它们在疗法中的用途，特别是在癌症治疗中的用途。
背景技术
对化学疗法和放射疗法的抗性仍然是成功治疗癌症的主要障碍。由于许多原因，诸如一些未被杀死的癌细胞可能突变并且变得有抗性，可能发生导致使治疗无效的蛋白质过表达的基因扩增，或者癌细胞可能发展出使治疗失活的机制，所以在癌症治疗期间可能发生抗性。
已经证明癌症干细胞(CSC)是常规治疗剂难治的，可以促进转移，并且已与癌症复发相关联。盐霉素可以选择性地杀伤CSC。盐霉素衍生物在溶酶体中积累并且螯合该细胞器中的铁。因此，铁的积累导致反应性氧物质(ROS)产生和溶酶体膜透化，这又通过铁死亡(最近表征的细胞凋亡机制，即依赖于铁并且由ROS介导)促进细胞凋亡。因此，CSC中的铁稳态是关键的。该机制为开发下一代治疗剂创造了机会。
盐霉素是治疗耐药性癌细胞系的有效抗增殖药物。但是，该分子包含负责其在细胞中降解的羧基基团。
因此，需要开发新颖并且有效的抗癌药物，其将是有效的同时对肿瘤组织具有特异性。特别地，需要能够杀伤癌症干细胞和治疗抗性癌细胞两者的新颖并且有效的抗癌药物。
还需要能够靶向溶酶体铁并且还诱导治疗抗性癌细胞的细胞死亡的新分子。
发明内容
因此，本发明的目标是提供能够靶向溶酶体铁并且还能够诱导治疗抗性癌细胞的细胞死亡的盐霉素衍生物。
本发明的另一个目标是提供具有抗癌活性，并且优选地能够杀伤癌症干细胞和治疗抗性癌细胞两者的盐霉素衍生物。
因此，本发明涉及一种具有式(I)的化合物：
其中：
-R1和R2是相同或不同的并且独立地选自由以下组成的组：H、(C1-
C20)烷基基团、(C3-C6)环烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：氨基、羟基、巯基、卤素、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷基氨基、卤代(C1-C6)
烷基、羧基和羧基(C1-C6)烷基；
-X是H、K或Na，
条件是R1和R2中的至少一者不是H，并且
排除以下化合物：
具体实施方式
阐述以下定义以说明和定义用于在本文中描述本发明的各种术语的含义和范围。
表述“Ct-Cz”意指可以具有t至z个碳原子的基于碳的链，例如C1-C3意指可以具有1至3个碳原子的基于碳的链。
术语“烷基基团”意指：除非另有提及，否则包含1至20个碳原子、优选地1至15个碳原子、更优选地3至10个或1至6个碳原子的直链或支链饱和烃基脂族基团。作为示例，可以提及甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、辛基或十二烷基，并且优选乙基、正丙基、正丁基、异丁基、正戊基、正己基或十二烷基。
术语“芳基基团”意指包含6至10个碳原子的环状芳族基团。作为芳基基团的示例，可以提及苯基或萘基。
术语“环烷基基团”意指：除非另有提及，否则包含3至6个碳原子的环状碳基基团。作为示例，可以提及环丙基、环丁基、环戊基、环己基等基团。优选地，(C3-C6)环烷基是环丙基。
如本文所用，术语“炔基”包括具有2至20个碳、优选地2至6个碳并且包含至少一个三键的不饱和非芳族烃基。优选地，炔基基团是直链的。优选地，炔基基团是-(CH2)n-C≡CH基团，n是包含1至4的整数。
优选地，炔基基团包含2至10个碳原子，优选地2至6个碳原子。优选地，炔基基团包含3个碳原子。优选地，炔基是丙炔基。
当烷基基团被芳基基团取代时，使用术语“芳基烷基”或“芳烷基”基团。“芳基烷基”或“芳烷基”基团是芳基-烷基-基团，芳基和烷基如上所定义。在芳基烷基基团中，可特别提及苄基或苯乙基基团。
优选地，根据本发明的芳基烷基是基团-(CH2)n-芳基，其中n是1至5的整数，并且芳基如上所定义。
芳基可被至少一个选自由以下组成的组的取代基取代：氨基(-NH2)、羟基(-OH)、巯基(-SH)、卤素、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷基氨基、卤代(C1-C6)烷基、羧基和羧基(C1-C6)烷基。
优选地，芳基可被至少一个选自由以下组成的组的取代基取代：羟基、(C1-C20)烷基基团(优选地(C1-C6)烷基基团)和卤素。
术语“卤素”意指氟、氯、溴或碘。
根据本发明，术语“烷氧基”意指：-O-烷基基团，其中烷基基团如先前所定义。作为示例，可以提及-O-(C1-C4)烷基基团，并且特别是-O-甲基基团、-O-乙基基团、-O-丙基基团、-O-异丙基基团、-O-丁基基团、-O-异丁基基团或-O-叔丁基基团。
根据本发明，术语“烷基氨基”意指：-NH-烷基基团，该烷基基团如上所定义。
根据本发明，术语“烷硫基”意指：-S-烷基基团，该烷基基团如上所定义。
根据本发明，术语“卤代烷基”意指：如上所定义的烷基基团，其中一个或多个氢原子被卤素原子置换。作为示例，可以提及氟代烷基，特别是CF3或CHF2。
根据本发明，术语“羧基烷基”意指：HOOC-烷基基团，该烷基基团如上所定义。作为羧基烷基基团的示例，可以特别提及羧甲基或羧乙基。
根据本发明，术语“羧基”意指：COOH基团。
优选地，芳基优选地在对位位置中被至少一个选自羟基基团、(C1-C6)烷基基团(诸如甲基)和卤素(诸如F或Cl)的基团取代。优选地，芳烷基基团是未被取代或优选地在对位位置中被至少一个选自羟基基团、(C1-C6)烷基基团(诸如甲基)和卤素(诸如F或Cl)的基团取代的苄基。
如上所述，R1和R2不同时是H。因此，当R1是H时，则R2不是H，并且当R2是H时，则R1不是H。
根据一个实施方案，在式(I)中，R1和R2是不同的。
根据一个实施方案，在式(I)中，R1选自由以下组成的组：(C1-C20)烷基基团、(C3-C6)环烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：(C1-C6)烷基、卤素、羟基、氨基、巯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷基氨基、卤代(C1-C6)烷基、羧基和羧基(C1-C6)烷基，并且R2是H。
根据一个实施方案，在式(I)中，R1选自由以下组成的组：(C1-C20)烷基基团、(C3-C6)环烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：(C1-C6)烷基、卤素和羟基，并且R2是H。
因此，根据本发明的一组优选的化合物由具有式(II)的化合物组成：
R1和X如上所定义。
根据一个实施方案，在式(I)或(II)中，X是H。
根据一个实施方案，在式(I)或(II)中，X是Na。
根据一个实施方案，在式(I)中，R1选自由以下组成的组：(C1-C20)烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：(C1-C6)烷基、卤素和羟基，并且R2是H。
在式(II)中，R1选自由以下组成的组：(C1-C20)烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：(C1-C6)烷基、卤素和羟基。
根据一个实施方案，在式(I)中，R1是直链(C2-C12)烷基基团、丙炔-1-基基团或苄基基团，其优选地在对位位置中任选地被羟基、甲基或卤素取代，并且R2是H。
优选地，在式(II)中，R1是直链(C2-C12)烷基基团、丙炔-1-基基团或苄基基团，其优选地在对位位置中任选地被羟基、甲基或卤素取代。
根据一个实施方案，在式(I)中，R1和R2是相同的。
根据该实施方案，R1和R2选自由以下组成的组：(C1-C20)烷基基团，优选地直链(C2-C12)烷基基团，和(C2-C20)炔基基团，优选地丙炔基基团。
因此，根据本发明的一组优选的化合物由具有式(III)的化合物组成：
R1和X如上所定义。
根据一个实施方案，在式(III)中，X是H。
根据一个实施方案，在式(III)中，X是Na。
优选地，在式(III)中，R1选自由以下组成的组：(C1-C20)烷基基团，优选地直链(C2-C12)烷基基团，和(C2-C20)炔基基团，优选地丙炔基基团。
作为优选的化合物，可以提及以下化合物：
如实施例中所示，与非癌细胞系相比，本发明的式(I)化合物对各种癌症的癌细胞系非常具有特异性。
此外，如表1所示，本发明的式(I)化合物显示出选择性的抗癌活性。
本发明的化合物的制备
本发明的化合物可通过以下方法制备，该方法在实施例中说明。
式(I)化合物由化合物C20-epi-氨基盐霉素或其钠盐制备。
因此，本发明还涉及一种用于制备如上所定义的式(II)或(III)化合物的方法，该方法包括以下步骤：
-向C20-epi-氨基盐霉素的钠盐于溶剂中的溶液中添加醛R1CHO，R1如上所定义，以便获得对应的亚胺，随后将所述亚胺还原成对应的式(II)或(III)的胺化合物，或者
-使溴化合物R1Br与化合物C20-epi-氨基盐霉素优选地在溶剂中反应，R1如上所定义。
C20-epi-氨基盐霉素具有下式：
例如，将醛R1CHO添加到C20-epi-氨基盐霉素的钠盐于溶剂诸如二氯甲烷中的溶液中。然后优选地将该溶液在室温下搅拌24h，并且在这之后逐滴添加NaBH3CN于甲醇中的溶液。进一步搅拌反应混合物，并且然后在减压下蒸发溶剂。
例如，当R1＝R2＝炔基时，使化合物C20-epi-氨基盐霉素与溴化合物R1Br诸如炔丙基溴在溶剂诸如乙腈中，优选地在60℃下反应。
组合物和用途
本发明还涉及用作药物的如上所定义的化合物，特别是具有式(I)或(II)的化合物。
本发明还涉及包含如上所定义的化合物，特别是具有式(I)或(II)的化合物或其药学上可接受的盐的药剂。
本发明还涉及一种药物组合物，该药物组合物包含至少一种如上所定义的化合物，特别是具有式(I)或(II)的化合物，或其药学上可接受的盐，以及至少一种药学上可接受的赋形剂。
抗癌用途
本发明的式(I)化合物可用于预防和/或治疗癌症。
“预防”意指避免癌症发生。
“治疗”意指癌症的治愈性治疗。治愈性治疗被定义为完全治疗(治愈)或部分治疗癌症(即诱导肿瘤生长稳定、延缓或消退)的治疗。
“受试者”是指任何受试者，并且通常表示患者，优选地经历癌症治疗诸如免疫疗法、化学疗法和/或放射疗法的受试者。在任何情况下，受试者优选地是脊椎动物，更优选地是哺乳动物，甚至更优选地是人。
“癌症”意指任何类型的癌症。癌症可以是实体癌或非实体癌，并且可以例如选自结肠癌、结肠直肠癌(诸如具有BRAF突变(特别是BRAF V600E)的结肠直肠癌)、黑素瘤、骨癌、乳腺癌(诸如三阴性乳腺癌(即测试为对雌激素受体、孕酮受体和过量HER2蛋白呈阴性的乳腺癌))、甲状腺癌、前列腺癌、卵巢癌、肺癌、胰腺癌、胶质瘤(诸如成胶质细胞瘤)、宫颈癌、子宫内膜癌、头颈癌、肝癌、膀胱癌、肾癌、皮肤癌、胃癌、睾丸癌、尿路上皮癌或肾上腺皮质癌、白血病(诸如急性髓样白血病)以及非实体癌诸如淋巴瘤或多发性骨髓瘤。
优选地，癌症是结肠癌、结肠直肠癌(诸如具有BRAF突变(特别是BRAF V600E)的结肠直肠癌)、乳腺癌(诸如三阴性乳腺癌(即测试为对雌激素受体、孕酮受体和过量HER2蛋白呈阴性的乳腺癌))、胰腺癌、胶质瘤(诸如成胶质细胞瘤)、白血病(诸如急性髓样白血病)、淋巴瘤或多发性骨髓瘤。
癌症可以是或不是转移性癌症。典型的癌症是对一线化学疗法有抗性的癌症。
因此，本发明涉及一种用于预防和/或治疗癌症的如上所定义的化合物，特别是具有式(I)、(II)或(III)的化合物，或其药学上可接受的盐。
优选地，癌症选自由以下组成的组：结肠癌、结肠直肠癌、黑素瘤、骨癌、乳腺癌、甲状腺癌、前列腺癌、卵巢癌、肺癌、胰腺癌、胶质瘤、宫颈癌、子宫内膜癌、头颈癌、肝癌、膀胱癌、肾癌、皮肤癌、胃癌、睾丸癌、尿路上皮癌或肾上腺皮质癌、白血病、淋巴癌和多发性骨髓瘤。
本发明还涉及至少一种式(I)化合物用于增加癌症对化学治疗药物的敏感性的用途。
本发明的另一个目的是至少一种式(I)化合物用于降低癌症对化学治疗药物的抗性的用途。
本发明还涉及一种产品，该产品包含：
a)至少一种本发明的式(I)化合物，和
b)至少一种附加疗法，
作为同时、分开或相继使用的组合产品，在受试者中用于治疗癌症，和/或用于预防癌症转移，和/或用于预防癌症复发，和/或用于降低对附加疗法b)的抗性。
本发明还涉及至少一种本发明的式(I)化合物与至少一种附加疗法组合或联合用于预防和/或治疗癌症的用途。
本发明还涉及至少一种本发明的式(I)化合物用于预防和/或治疗通过至少一种附加疗法治疗的受试者的癌症的用途。本发明还涉及至少一种本发明的式(I)化合物，其用作辅助癌症疗法。辅助疗法是用于治疗癌症的疗法，其与主要或初始疗法(“一线疗法”)一起给予以使其有效性最大化。
所述附加疗法b)可以是免疫疗法、化学疗法和/或放射疗法。优选地，附加疗法b)是免疫疗法和/或化学疗法。
“免疫疗法”意指能够诱导、增强或抑制免疫应答的疗法。所述免疫疗法优选地选自细胞因子、趋化因子、生长因子、生长抑制因子、激素、可溶性受体、诱骗受体；单克隆抗体或多克隆抗体、单特异性抗体、双特异性抗体或多特异性抗体、单体(monobody)、多体(polybody)；疫苗接种；或过继性特异性免疫疗法。
优选地，免疫疗法选自单克隆抗体或多克隆抗体、单特异性抗体、双特异性抗体或多特异性抗体、单体、多体，诸如抗血管生成剂如贝伐珠单抗(Bevacuzimab)(mAb，抑制VEGF-A，基因泰克(Genentech))；IMC-1121B(mAb，抑制VEGFR-2，英克隆系统公司(ImCloneSystems))；CDP-791(聚乙二醇化DiFab，VEGFR-2，希尔泰克公司(Celltech))；2C3(mAb，VEGF-A，百瑞勤医药公司(Peregrine Pharmaceuticals))；VEGF-捕获剂(可溶性杂合受体VEGF-A、PIGF(胎盘生长因子)安内特/瑞泽恩公司(Aventis/Regeneron))。
优选地，免疫疗法是单克隆抗体，优选地抗检查点抗体。
抗检查点抗体包括针对免疫检查点的抗体，该免疫检查点可以选自PD1、PDL1、PDL2、CTLA4、BTLA、CD27、CD40、OX40、GITR(也称为“肿瘤坏死因子受体超家族成员18”或TNFRSF18)、CD137(也称为4-1BB或TNFRS9)、CD28、ICOS、IDO(吲哚胺2,3-双加氧酶)、B7H3(也称为CD276)、KIR2DL2(也称为杀伤细胞免疫球蛋白样受体2DL2)、NKG2(C型凝集素受体家族)、LAG3(也称为淋巴细胞活化基因-3)和CD70。优选地，抗检查点抗体是抗PD1、抗PDL1、抗PDL2或抗CTLA4抗体。抗PD1抗体包括纳武单抗(nivolumab)和派母单抗(pembrolizumab)。抗CTLA4抗体包括伊匹单抗(ipilimumab)和曲美木单抗(tremelimumab.)。
“化学疗法”或“化学治疗剂”是指用于治疗癌症并且具有抑制人的肿瘤，特别是恶性(癌性)病变的发展或进展的功能特性的化合物。
化学治疗剂具有不同的作用模式，例如通过影响DNA或RNA以及干扰细胞周期复制。
在DNA水平或在RNA水平上起作用的化学治疗剂的示例是：
-抗代谢药，诸如硫唑嘌呤、阿糖胞苷、磷酸氟达拉滨、氟达拉滨、吉西他滨、阿糖胞苷、克拉屈滨、卡培他滨、6-巯基嘌呤、6-硫鸟嘌呤、氨甲蝶呤、5-氟尿嘧啶和羟基脲；
-烷化剂，诸如美法仑、白消安、顺铂、卡铂、环磷酰胺、异环磷酰胺、达卡巴嗪(Dacarabazine)、福莫司汀、丙卡巴肼、苯丁酸氮芥、噻替派、洛莫司汀、替莫唑胺；
-抗有丝分裂剂，诸如长春瑞滨、长春新碱、长春碱、多西他赛、紫杉醇；
-拓扑异构酶抑制剂，诸如多柔比星、安吖啶、伊立替康、柔红霉素、表柔比星、丝裂霉素、米托蒽醌、伊达比星、替尼泊苷、依托泊苷、拓扑替康；
-抗生素，诸如放线菌素和博来霉素；
-门冬酰胺酶；
-蒽环霉素或紫杉烷。
其它化学治疗剂是酪氨酸激酶抑制剂(TKI)。许多TKI在晚期和早期开发中用于治疗各种类型的癌症。示例性TKI包括但不限于：BAY 43-9006(索拉非尼，)和SU11248(舒尼替尼，)、甲磺酸伊马替尼(诺华公司(Novartis))；吉非替尼(阿斯利康有限公司(AstraZeneca))；盐酸埃罗替尼(基因泰克)；凡德他尼(阿斯利康有限公司)、替吡法尼(Tipifarnib)(杨森制药(Janssen-Cilag))；达沙替尼(百时美施贵宝公司(Bristol Myers Squibb))；洛那法尼(Lonafarnib)(先灵七星公司(Schering Plough))；琥珀酸瓦他拉尼(诺华公司，先灵制药公司(Schering AG))；拉帕替尼(葛兰素史克公司(GlaxoSmithKline))；尼洛替尼(诺华公司)；来他替尼(赛福伦公司(Cephalon))；盐酸帕唑帕尼(葛兰素史克公司)；阿西替尼(辉瑞公司(Pfizer))；卡奈替尼二盐酸盐(辉瑞公司)；培利替尼(Pelitinib)(国家癌症研究所(National Cancer Institute)，惠氏公司(Wyeth))；坦度替尼(千禧公司(Millennium))；博舒替尼(惠氏公司)；司马沙尼(Semaxanib)(索元公司(Sugen)，大鹏公司(Taiho))；AZD-2171(阿斯利康有限公司)；VX-680(默克公司(Merck)，沃泰克斯公司(Vertex))；EXEL-0999(埃克塞里艾克西斯公司(Exelixis))；ARRY-142886(阿雷生物药品公司(Array BioPharma)，阿斯利康有限公司)；PD-0325901(辉瑞公司)；AMG-706(安进公司(Amgen))；BIBF-1120(勃林格殷格翰公司(Boehringer Ingelheim))；SU-6668(大鹏公司)；CP-547632(OSI)；(AEE-788(诺华公司)；BMS-582664(百时美施贵宝公司)；JNK-401(新基生物制药(Celgene))；R-788(瑞吉尔公司(Rigel))；AZD-1152HQPA(阿斯利康有限公司)；NM-3(建新肿瘤公司(Genzyme Oncology))；CP-868596(辉瑞公司)；BMS-599626(百时美施贵宝公司)；PTC-299(PTC医疗公司(PTC Therapeutics))；ABT-869(雅培公司(Abbott))；EXEL-2880(埃克塞里艾克西斯公司)；AG-024322(辉瑞公司)；XL-820(埃克塞里艾克西斯公司)；OSI-930(OSI)；XL-184(埃克塞里艾克西斯公司)；KRN-951(麒麟控股株式会社(Kirin Brewery))；CP-724714(OSI)；E-7080(卫材公司(Eisai))；HKI-272(惠氏公司)；CHIR-258(赛伦公司(Chiron))；ZK-304709(先灵制药公司)；EXEL-7647(埃克塞里艾克西斯公司)；BAY-57-9352(拜耳公司(Bayer))；BIBW-2992(勃林格殷格翰公司)；AV-412(AVEO)；YN-968D1(爱德程医药公司(Advenchen Laboratories))；星形孢菌素、米哚妥林(PKC412，诺华公司)；哌立福新(Perifosine)(阿特纳赞塔里斯公司(AEterna Zentaris)，凯克斯公司(Keryx)，国家癌症研究所)；AG-024322(辉瑞公司)；AZD-1152(阿斯利康有限公司)；ON-01910Na(安哥洛华公司(Onconova))；和AZD-0530(阿斯利康有限公司)；
本文还描述了(i)一种用于预防或治疗癌症的方法，(ii)一种用于增加癌症对化学治疗剂的敏感性的方法，和(iii)一种用于降低癌症对化学治疗药物的抗性的方法，所述方法各自包括向有需要的受试者施用有效量的至少一种如上所定义的式(I)化合物，优选地与化学治疗药物一起施用。
本发明的式(I)化合物优选地以治疗有效量或剂量施用。如本文所用，“治疗有效量或剂量”是指本发明的化合物在受试者(优选为人)中预防、去除、减缓疾病或减少或延迟由所述疾病引起或与所述疾病相关的一种或数种症状或病症的量。本发明的化合物及其药物组合物的有效量，并且更通常为剂量方案可以由本领域技术人员确定和调整。有效剂量可以通过使用常规技术和通过观察在类似情况下获得的结果来确定。本发明的化合物的治疗有效剂量将根据待治疗或预防的疾病、其严重程度、施用途径、所涉及的任何共同治疗、患者的年龄、体重、一般医学状况、医疗史等而变化。
通常，向患者施用的化合物的量对于人患者可以在约0.01至500mg/kg体重的范围内。在一个具体实施方案中，根据本发明的药物组合物包含0.01mg/kg至300mg/kg的本发明的化合物，优选地0.01mg/kg至3mg/kg，例如25至300mg/kg。
在一个具体方面，本发明的化合物可以通过肠胃外途径、局部途径、口服途径或静脉内注射向受试者施用。本发明的化合物或纳米颗粒可以在连续数天期间，例如在连续2至10天期间，优选地在连续3至6天期间，每天施用于受试者(例如每天1、2、3、4、5、6或7次)。所述治疗可在1、2、3、4、5、6或7周，或每两或三周或每一、二或三个月期间重复。或者，可以进行数个治疗周期，任选地在两个治疗周期之间具有间歇期，例如1、2、3、4或5周。本发明的化合物可以例如作为单剂量每周一次、每两周一次或每月一次施用。治疗可以每年重复一次或数次。
剂量以技术人员可确定的适当间隔施用。所选量将取决于多种因素，包括施用途径、施用持续时间、施用时间、化合物或与所述化合物组合使用的各种产品的消除速率、患者的年龄、体重和身体状况以及他/她的医疗史以及医学中已知的任何其它信息。
施用途径可以是口服、局部或肠胃外，通常是直肠、舌下、鼻内、腹膜内(IP)、静脉内(IV)、动脉内(IA)、肌肉内(IM)、小脑内、鞘内、瘤内和/或皮内。药物组合物适于一种或数种上述途径。药物组合物优选地通过注射或通过合适的无菌溶液的静脉内输注来施用，或以液体或固体剂型经由消化道施用。
本发明还涉及一种组合物，该组合物在药学上可接受的介质中包含至少一种根据本发明的式(I)化合物。这种组合物包含药学上可接受的介质(或载体)。
载体在与配制品的其它成分相容的意义上必须是“可接受的”，并且对其接受者无害。
药物组合物可以本领域已知的方式(可能通过提供持续和/或延迟释放的剂型或装置)配制为在药学上相容的溶剂中的溶液，或配制为在合适的药学溶剂或媒介物中的凝胶、油、乳液、悬浮液或分散体，或配制为含有固体媒介物的丸剂、片剂、胶囊、粉剂、栓剂等。对于这种类型的配制品，有利地使用诸如纤维素、脂质、碳酸盐或淀粉的剂。
可以用于配制品(液体和/或可注射物和/或固体)的剂或媒介物是赋形剂或惰性媒介物，即药学上无活性并且无毒的媒介物。
可以提及例如盐水、生理溶液、等渗溶液和/或缓冲溶液，其与药物用途相容并且是本领域技术人员已知的。组合物可以含有一种或多种选自分散剂、增溶剂、稳定剂、防腐剂等的剂或媒介物。
具体示例是甲基纤维素、羟甲基纤维素、羧甲基纤维素、环糊精、聚山梨醇酯80、甘露糖醇、明胶、乳糖、脂质体、植物油或动物、阿拉伯胶等。优选地，使用植物油。
适用于口服施用的本发明的配制品可以呈离散单元的形式，如胶囊、药囊、片剂或锭剂，其各自含有预定量的活性成分；呈粉末或颗粒形式；呈水性液体或非水性液体中的溶液或悬浮液的形式；或呈水包油乳液或油包水乳液的形式。
适用于肠胃外施用的配制品便利地包含活性成分的无菌油性或水性制剂，其优选地与接受者的血液等渗。每种此类配制品还可以含有其它药学上相容并且无毒的助剂，诸如例如稳定剂、抗氧化剂、粘合剂、染料、乳化剂或调味物质。
现在通过以下实施例说明本发明。
该研究是由欧洲研究委员会(European Research Council)根据欧盟的Horizon2020研究和创新项目拨款协议号647973、查尔斯·迪佛瑞研究所基金会-法国抗癌学会法案(欧洲实验室)(Foundation Charles Defforey-Institut de France,Ligue Contre leCancer(Equipes Labellisées))资助的。
实施例
实施例1：盐霉素的单取代和二取代的C20-epi-胺类似物的制备
方案1.盐霉素的单取代和双取代的C20-epi-胺类似物的合成。
用于制备C20-epi-氨基盐霉素类似物的钠盐的一般程序
步骤1.C1官能团的封闭
在冰浴中向盐霉素(3.00g，1.0当量)于50mL CH2Cl2中的搅拌溶液中添加：DMAP(2.38g，5.0当量)、TMSEtOH(2.77g，6.0当量)和TCFH(1.31g，1.2当量)。将所得混合物在室温下搅拌过夜。然后将反应混合物在减压下浓缩。使用CombiFlash系统在硅胶上纯化(0％→40％EtOAc/正己烷)，得到呈黄色油状物的反应产物(1.70g，50％产率)。
步骤2.一锅光延/施陶丁格(Mitsunobu/Staudinger)反应
在冰浴中向盐霉素-EtTMS酯(1.70g，1.0当量)于20mL无水THF中的溶液中添加PPh3(784mg，1.5当量)。20分钟后，将DIAD(481mg，1.2当量)缓慢添加到混合物中，随后添加DPPA(605mg，1.1当量)。将溶液在室温下搅拌24h。此后，一次性添加PPh3(1.57g，3.0当量)，随后添加0.5mL水。将混合物在室温下搅拌下24h，并且通过TLC监测反应进程。然后将反应混合物在减压下浓缩。使用CombiFlash系统在硅胶上纯化(0％→50％丙酮/CHCl3)，得到呈黄色油状物的反应产物(716mg，42％产率)。
步骤3.C1官能团的解封闭
在室温下将C20-epi-氨基盐霉素的C1-EtTMS酯(716mg，1.0当量)溶解于15mL无水THF中。然后逐滴添加TBAF于THF中的1.0M溶液(2.53mL，3.0当量)。将该溶液在室温下搅拌下24h。然后将反应混合物在减压下浓缩。使用CombiFlash系统在硅胶上纯化(0％→50％丙酮/CHCl3)，得到呈黄色油状物的反应产物。然后将产物溶解于CH2Cl2中并且用0.1M的Na2CO3溶液洗涤。将分离的有机层在减压下浓缩。然后将残余物用正戊烷蒸发数次，定量地得到呈白色无定形固体的C20-epi-氨基盐霉素的钠盐(648mg)。
用于制备盐霉素的C20-epi-胺类似物(式(I)化合物，其中X＝Na)的一般程序
向C20-epi-氨基盐霉素的钠盐(100mg，0.13mmol，1.0当量)于5mL CH2Cl2中的搅拌溶液中，添加对应的醛(对于单取代的类似物为1.0当量，对于双取代的类似物为5.0当量)。将溶液在室温下搅拌24h，并且在这之后逐滴添加NaBH3CN(10mg，0.16mmol，1.2当量)于2mLMeOH中的溶液。将反应混合物再搅拌30分钟。之后，在减压下蒸发溶剂。使用CombiFlash系统在硅胶上纯化过滤的残余物，得到呈白色无定形固体的对应的反应产物。
实施例1.1：化合物(1)的制备：
产率：35mg，70％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在60％丙酮/CHCl3中为0.57。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.31(dd,J＝10.7,5.6Hz,1H),6.12(d,J＝10.8Hz,1H),4.29(q,J＝6.8Hz,1H),4.12(d,J＝10.4Hz,1H),3.77(dt,J＝13.8,6.9Hz,1H),3.64(dd,J＝10.1,2.1Hz,1H),3.60(d,J＝10.2Hz,1H),3.37(dd,J＝11.9,2.1Hz,1H),2.86(d,J＝5.6Hz,1H),2.81-2.73(m,2H),2.72-2.68(m,1H),2.67-2.57(m,2H),2.00-0.50(m,60H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.4,184.1,129.9,122.7,110.1,99.7,89.2,76.4,76.3,75.5,75.1,71.8,70.2,67.7,56.1,55.5,51.6,50.9,42.8,40.7,39.5,37.5,36.5,33.4,33.1,33.0,29.8,28.6,28.3,27.4,24.2,21.4,20.6,17.9,17.3,16.5,16.4,15.1,13.5,12.8,12.4,11.0,7.0,6.8ppm。
FT-IR(KBr)：3319(br,m),2963(s),2935(s),2875(m),1714(s),1568(s),1460(s),1407(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C44H75NO10Na+计算值880.5283；实测值880.5270；[M-Na+2H]+C44H76NO10 +计算值778.5464；实测值778.5460。
实施例1.2：化合物(2)的制备：
产率：35mg，66％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在66％EtOAc/正己烷中为0.23。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.27(dd,J＝10.7,5.6Hz,1H),6.08(d,J＝10.8Hz,1H),4.28(q,J＝6.7Hz,1H),4.11(d,J＝10.2Hz,1H),3.78(dd,J＝11.1,4.8Hz,1H),3.64(dd,J＝16.6,6.3Hz,2H),2.97-2.87(m,2H),2.79-2.68(m,2H),2.68-2.61(m,2H),2.11-2.04(m,2H),2.00-0.50(m,61H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.6,184.1,130.3,122.0,110.4,99.6,89.22,76.5,76.4,75.4,75.1,71.8,70.2,67.8,56.1,53.3,51.6,50.9,47.6,40.7,39.5,37.7,36.5,33.3,33.2,33.0,30.0,28.6,28.2,27.5,24.8,24.1,23.2,21.3,20.6,17.9,17.4,16.6,15.1,13.5,12.8,12.4,11.0,7.1,6.8ppm。
FT-IR(KBr)：3289(br,m),2962(s),2933(s),2874(m),1713(s),1660(w),1568(s),1459(s),1407(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C45H77NO10Na+计算值814.5440；实测值814.5426；[M-Na+2H]+C45H78NO10 +计算值792.5620；实测值792.5619。
实施例1.3：化合物(3)的制备：
产率：36mg，68％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在66％EtOAc/正己烷中为0.29。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.31(dd,J＝10.7,5.6Hz,1H),6.11(d,J＝10.8Hz,1H),4.29(q,J＝6.7Hz,1H),4.12(d,J＝10.4Hz,1H),3.78(dd,J＝11.1,4.8Hz,1H),3.64(dd,J＝9.9,1.8Hz,1H),3.60(d,J＝10.2Hz,1H),3.37(dd,J＝11.9,2.1Hz,1H),2.84(d,J＝5.6Hz,1H),2.80-2.69(m,3H),2.68-2.62(m,1H),2.60-2.52(m,1H),2.00-0.50(m,64H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.4,184.1,130.0,122.6,110.1,99.7,89.2,76.5,76.3,75.5,75.1,71.8,70.2,67.7,56.1,55.8,51.6,50.9,48.27,40.7,39.4,37.5,36.5,33.5,33.4,33.2,33.0,29.8,28.6,28.3,27.4,24.2,21.4,20.8,20.6,17.9,17.3,16.5,15.1,14.3,13.5,12.8,12.4,11.0,7.0,6.8ppm。
FT-IR(KBr)：3288(br,m),2960(s),2931(s),2873(m),1713(s),1661(w),1567(s),1459(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C46H79NO10Na+计算值828.5596；实测值828.5577；[M-Na+2H]+C46H80NO10 +计算值806.5777；实测值806.5772。
实施例1.4：化合物(4)的制备：
产率：40mg，74％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在66％EtOAc/正己烷中为0.50。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.35(dd,J＝10.7,5.6Hz,1H),6.15(d,J＝10.8Hz,1H),4.33(q,J＝6.8Hz,1H),4.16(d,J＝9.4Hz,1H),3.81(dd,J＝11.1,4.9Hz,1H),3.72-3.60(m,2H),3.41(dd,J＝12.0,2.1Hz,1H),2.85(d,J＝5.6Hz,1H),2.82-2.73(m,2H),2.72-2.65(m,1H),2.62(dd,J＝11.3,6.7Hz,1H),2.41(dd,J＝11.3,6.6Hz,1H),2.15-2.09(m,2H),2.05-0.50(m,62H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.3,184.1,130.0,122.5,110.2,99.7,89.2,76.4,76.3,75.5,75.0,71.8,70.2,67.7,56.7,56.0,56.0,51.6,50.8,40.8,39.4,37.6,36.5,33.4,33.2,33.0,29.8,29.7,28.6,28.3,27.4,24.2,21.3,20.8,20.7,20.5,17.9,17.4,16.5,15.1,13.5,12.8,12.4,11.0,7.0,6.8ppm。
FT-IR(KBr)：3289(br,m),2960(s),2931(s),2874(m),1713(s),1660(w),1568(s),1459(s),1407(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C46H79NO10Na+计算值828.5596；实测值828.5578；[M-Na+2H]+C46H80NO10 +计算值806.5777；实测值806.5771。
实施例1.5：化合物(5)的制备：
产率：45mg，82％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在66％EtOAc/正己烷中为0.30。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.23(dd,J＝10.7,5.6Hz,1H),6.03(d,J＝10.8Hz,1H),4.21(q,J＝6.7Hz,1H),4.04(d,J＝10.4Hz,1H),3.70(dd,J＝11.1,4.8Hz,1H),3.62-3.49(m,2H),3.29(dd,J＝11.9,2.1Hz,1H),2.76(d,J＝5.6Hz,1H),2.71-2.60(m,1H),2.60-2.53(m,3H),2.48(ddd,J＝11.3,7.5,6.4Hz,1H),2.02-1.96(m,2H),1.90-0.50(m,64H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.4,184.1,130.0,122.6,110.1,99.7,89.2,76.5,76.3,75.5,75.1,71.8,70.2,67.7,56.1,55.8,51.6,50.9,48.6,40.7,39.5,37.5,36.5,33.4,33.2,33.0,31.1,29.9,29.8,28.6,28.3,27.5,24.2,23.1,21.4,20.6,17.9,17.4,16.6,15.1,14.4,13.5,12.8,12.4,11.0,7.0,6.8ppm。
FT-IR(KBr)：3292(br,m),2961(s),2932(s),2873(m),1713(s),1660(w),1567(s),1459(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C47H81NO10Na+计算值842.5753；实测值842.5728；[M-Na+2H]+C47H82NO10 +计算值820.5933；实测值820.5925。
实施例1.6：化合物(6)的制备：
产率：37mg，70％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在66％EtOAc/正己烷中为0.31。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.31(dd,J＝10.7,5.6Hz,1H),6.11(d,J＝10.7Hz,1H),4.29(q,J＝6.7Hz,1H),4.12(d,J＝10.3Hz,1H),3.78(dd,J＝11.0,4.9Hz,1H),3.64(dd,J＝10.0,1.7Hz,1H),3.60(d,J＝10.1Hz,1H),3.37(dd,J＝11.9,1.7Hz,1H),2.84(d,J＝5.6Hz,1H),2.79-2.69(m,3H),2.68-2.62(m,1H),2.56(dt,J＝11.3,6.8Hz,1H),2.08-2.02(m,2H),2.00-0.50(m,66H)ppm。
13C NMR(101MHz,CD2Cl2)δ217.8,183.5,129.4,122.0,109.5,99.1,88.6,75.9,75.7,74.9,74.5,71.2,69.6,67.1,55.5,55.2,51.0,50.3,48.0,40.1,38.9,36.9,35.9,32.8,32.6,32.4,31.7,30.7,29.2,28.0,27.7,26.9,26.8,23.6,22.6,20.8,20.0,17.3,16.8,16.0,14.5,13.8,12.9,12.3,11.8,10.4,6.5,6.20ppm。
FT-IR(KBr)：3297(br,m),2958(s),2930(s),2872(m),2858(m),1714(s),1668(w),1565(s),1459(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C48H83NO10Na+计算值856.5909；实测值856.5889；[M-Na+2H]+C48H84NO10 +计算值834.6090；实测值834.6084。
实施例1.7：化合物(7)的制备：
产率：60mg，85％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在66％EtOAc/正己烷中为0.40。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.31(dd,J＝10.7,5.6Hz,1H),6.11(d,J＝10.8Hz,1H),4.28(dd,J＝13.5,6.7Hz,1H),4.12(d,J＝10.4Hz,1H),3.77(dd,J＝11.1,4.7Hz,1H),3.64(dd,J＝10.1,2.0Hz,1H),3.59(d,J＝10.2Hz,1H),3.37(dd,J＝11.9,2.1Hz,1H),2.83(d,J＝5.6Hz,1H),2.79-2.73(m,1H),2.74-2.68(m,2H),2.68-2.61(m,1H),2.55(ddd,J＝11.3,7.4,6.3Hz,1H),2.10-2.03(m,2H),2.00-0.50(m,78H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.1,183.9,129.8,122.4,109.9,99.5,89.0,76.2,76.0,75.3,74.8,71.6,70.0,67.4,55.8,55.5,51.4,50.6,48.3,40.5,39.2,37.3,36.3,33.2,32.9,32.8,32.3,31.2,30.03,30.01,30.00,29.9,29.7,29.6,28.4,28.1,27.5,27.2,24.0,23.1,21.1,20.3,17.7,17.2,16.3,14.9,14.3,13.3,12.6,12.2,10.8,6.8,6.6ppm，一个重叠的信号。
FT-IR(KBr):3288(br,m),2960(s),2927(s),2854(m),1713(s),1568(s),1459(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C54H95NO10Na+计算值940.6848；实测值940.6829；[M-Na+2H]+C54H96NO10 +计算值918.7029；实测值918.7024。
实施例1.8：化合物(8)的制备：
产率：41mg，76％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在33％EtOAc/正己烷中为0.42。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.28(dd,J＝11.0,1.6Hz,1H),5.98(dd,J＝11.0,4.2Hz,1H),4.22(q,J＝6.7Hz,1H),4.11(d,J＝10.2Hz,1H),3.79(dd,J＝11.1,4.8Hz,1H),3.63(d,J＝10.1Hz,2H),3.38(dd,J＝12.0,2.1Hz,2H),2.75(td,J＝11.2,3.3Hz,1H),2.69-2.64(m,2H),2.56-2.43(m,3H),2.31(dq,J＝13.4,6.7Hz,2H),2.20-0.50(m,61H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.4,183.7,125.6,123.9,110.9,98.1,87.3,76.1,75.8,75.1,74.9,71.2,69.5,67.1,56.4,55.7,51.0,50.1,44.4,40.4,38.6,36.7,35.9,33.0,32.6,32.4,29.8,28.0,27.6,26.9,23.6,21.1,19.9,17.3,16.8,15.7,14.6,13.7,12.8,12.2,12.0,10.4,6.5,6.2ppm。
FT-IR(KBr)：3300(br,m),2962(s),2933(s),2874(m),1714(s),1566(s),1458(s),1405(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C46H79NO10Na+计算值828.5596；实测值828.5582；[M-Na+2H]+C46H80NO10 +计算值806.5777；实测值806.5774。
实施例1.9：化合物(9)的制备：
产率：45mg，79％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在33％EtOAc/正己烷中为0.57。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.28(dd,J＝11.0,1.7Hz,1H),6.00(dd,J＝11.0,4.2Hz,1H),4.22(q,J＝6.8Hz,1H),4.11(d,J＝10.3Hz,1H),3.79(dd,J＝11.1,4.8Hz,1H),3.68-3.59(m,2H),3.37(dd,J＝12.0,2.1Hz,1H),3.30(dd,J＝4.2,1.8Hz,1H),2.77-2.70(m,1H),2.69-2.63(m,2H),2.52-2.41(m,1H),2.40-2.25(m,4H),2.00-0.50(m,65H)ppm。
13C NMR(101MHz,CD2Cl2)δ219.0,184.2,126.3,124.4,111.6,98.7,87.9,76.7,76.4,75.6,75.4,71.8,70.0,67.7,57.9,56.3,53.7,51.6,50.8,41.1,39.2,37.3,36.5,33.6,33.3,33.0,30.4,28.6,28.2,27.5,24.1,22.2,21.7,20.5,17.9,17.5,16.3,15.2,13.4,12.8,12.6,12.1,11.0,7.1,6.7ppm。
FT-IR(KBr)：3297(br,m),2960(s),2933(s),2873(m),1714(s),1566(s),1459(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C48H83NO10Na+计算值856.5909；实测值856.5892；[M-Na+2H]+C48H84NO10 +计算值834.6090；实测值834.6089。
实施例1.10：化合物(10)的制备：
产率：30mg，55％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在33％EtOAc/正己烷中为0.59。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.29(dd,J＝11.0,1.7Hz,1H),6.01(dd,J＝11.0,4.2Hz,1H),4.20(q,J＝6.7Hz,1H),4.11(d,J＝10.2Hz,1H),3.79(dd,J＝11.1,4.8Hz,1H),3.66-3.60(m,2H),3.37(dd,J＝12.0,2.1Hz,1H),3.30(dd,J＝4.2,1.7Hz,1H),2.77-2.64(m,3H),2.51-2.35(m,3H),2.34-2.25(m,2H),2.00-0.50(m,69H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.9,184.2,126.1,124.4,111.6,98.7,87.9,76.9,76.4,75.6,75.3,71.8,69.9,67.6,57.7,56.3,51.6,51.4,50.8,41.1,39.2,37.4,36.5,33.6,33.3,32.9,31.5,30.2,28.6,28.2,27.5,24.2,21.7,21.2,20.5,17.9,17.5,16.3,15.2,14.5,13.4,12.9,12.6,11.0,7.1,6.7ppm。
FT-IR(KBr)：3300(br,m),2960(s),2933(s),2873(m),2860(m),1712(s),1566(s),1457(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C50H87NO10Na+计算值884.6222；实测值884.6212；[M-Na+2H]+C50H88NO10 +计算值862.6403；实测值862.6410。
实施例1.11：化合物(11)的制备：
产率：35mg，60％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在33％EtOAc/正己烷中为0.62。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.29(dd,J＝11.0,1.6Hz,1H),6.01(dd,J＝11.0,4.2Hz,1H),4.19(q,J＝6.7Hz,1H),4.11(d,J＝10.3Hz,1H),3.79(dd,J＝11.0,4.7Hz,1H),3.69-3.60(m,2H),3.37(dd,J＝12.0,1.9Hz,1H),3.29(dd,J＝4.1,1.6Hz,1H),2.70(tdd,J＝10.3,9.3,3.1Hz,3H),2.45(ddd,J＝22.3,13.0,7.1Hz,2H),2.39-2.25(m,3H),2.00-0.50(m,73H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.9,184.2,126.1,124.4,111.6,98.7,87.9,77.0,76.4,75.6,75.3,71.8,69.9,67.7,57.8,56.3,51.7,51.6,50.8,41.1,39.2,37.4,36.5,33.6,33.3,32.9,30.3,30.1,29.0,28.6,28.2,27.5,24.2,23.3,21.7,20.5,17.9,17.5,16.3,15.2,14.5,13.4,12.9,12.6,11.0,7.1,6.8ppm。
FT-IR(KBr)：3297(br,m),2959(s),2931(s),2872(m),2860(m),1714(s),1567(s),1459(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C52H91NO10Na+计算值912.6535；实测值912.6524；[M-Na+2H]+C52H92NO10 +计算值890.6716；实测值890.6724。
实施例1.12：化合物(12)的制备：
产率：50mg，82％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在33％EtOAc/正己烷中为0.64。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.29(dd,J＝11.0,1.6Hz,1H),6.01(dd,J＝11.0,4.2Hz,1H),4.20(q,J＝6.7Hz,1H),4.12(d,J＝10.3Hz,1H),3.78(dt,J＝13.2,6.5Hz,1H),3.68-3.59(m,2H),3.38(dd,J＝12.0,1.9Hz,1H),3.29(dd,J＝4.1,1.6Hz,1H),2.72(ddd,J＝11.4,8.5,3.4Hz,2H),2.68-2.63(m,1H),2.52-2.43(m,1H),2.43-2.36(m,2H),2.36-2.27(m,2H),2.00-0.50(m,77H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.9,184.2,126.2,124.4,111.6,98.7,87.9,77.0,76.4,75.6,75.3,71.8,69.9,67.7,57.8,56.3,51.7,51.6,50.8,41.1,39.2,37.4,36.5,33.6,33.3,33.0,32.5,30.0,29.3,28.6,28.2,27.8,27.5,24.2,23.4,21.7,20.5,18.0,17.6,16.3,15.2,14.5,13.5,12.9,12.6,11.0 7.1,6.8ppm。
FT-IR(KBr)：3286(br,m),2960(s),2931(s),2873(m),2859(m),1713(s),1568(s),1459(s),1407(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C54H95NO10Na+计算值940.6848；实测值940.6839；[M-Na+2H]+C54H96NO10 +计算值918.7029；实测值918.7038。
实施例1.13：化合物(13)的制备：
产率：21mg，45％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在33％EtOAc/正己烷中为0.79。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ6.28(dd,J＝11.0,1.6Hz,1H),6.00(dd,J＝11.0,4.2Hz,1H),4.20(q,J＝6.6Hz,1H),4.11(d,J＝10.3Hz,1H),3.79(dd,J＝11.0,4.6Hz,1H),3.71-3.59(m,2H),3.38(dd,J＝12.0,1.9Hz,1H),3.29(dd,J＝4.1,1.5Hz,1H),2.75(dd,J＝11.1,3.2Hz,1H),2.71-2.64(m,2H),2.47(dd,J＝12.5,3.6Hz,1H),2.43-2.38(m,1H),2.36(d,J＝8.1Hz,1H),2.34-2.25(m,2H),2.00-0.50(m,101H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.9,184.2,126.1,124.4,111.6,98.7,87.9,76.9,76.4,75.6,75.3,71.8,69.9,67.7,57.7,56.3,51.7,51.6,50.8,41.1,39.2,37.4,36.5,33.6,33.3,32.9,32.1,30.6,30.4,30.3,30.24,30.22,30.0,29.9,29.3,28.6,28.2,28.1,27.5,24.2,23.3,21.7,20.5,17.9,17.6,16.3,15.2,14.5,13.4,12.9,12.6,11.0,7.1,6.8ppm。
FT-IR(KBr)：3295(br,m),2958(s),2926(s),2872(m),2854(m),1714(s),1566(s),1459(s),1405(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C66H119NO10Na+计算值1108.8726；实测值1108.8715；[M-Na+2H]+C66H120NO10 +计算值1086.8907；实测值1086.8920。
实施例1.14：化合物(14)的制备：
产率：48mg，75％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在50％EtOAc/正己烷中为0.65。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ7.19(d,J＝4.4Hz,4H),7.12(dt,J＝5.9,4.2Hz,1H),6.28(dd,J＝10.7,5.6Hz,1H),6.09(d,J＝10.7Hz,1H),4.18(q,J＝6.7Hz,1H),4.04(d,J＝10.4Hz,1H),3.83(d,J＝12.7Hz,1H),3.74-3.63(m,2H),3.61-3.50(m,2H),3.26(dd,J＝11.8,1.8Hz,1H),2.90(d,J＝5.5Hz,1H),2.73-2.65(m,1H),2.64-2.54(m,2H),2.00-0.50(m,57H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.4,184.1,141.5,129.3,128.8,127.3,123.1,110.0,99.7,89.3,76.5,76.3,75.5,75.0,71.8,70.2,67.7,56.1,55.1,52.5,51.6,50.9,40.7,39.4,37.6,36.5,33.4,33.1,33.0,29.7,28.6,28.3,27.4,24.2,21.3,20.5,17.8,17.4,16.5,15.1,13.5,12.9,12.4,11.0,7.0,6.8ppm。
FT-IR(KBr)：3317(br,m),2961(s),2933(s),2874(m),1713(s),1567(s),1495(s),1458(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C49H77NO10Na+计算值862.5440；实测值862.4532；[M-Na+2H]+C49H78NO10 +计算值840.5620；实测值840.5628。
实施例1.15：化合物(15)的制备：
产率：43mg，76％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在50％EtOAc/正己烷中为0.60。具有PMA的绿色品系。
1H NMR(400MHz,CD2Cl2)δ7.12(td,J＝7.9,1.6Hz,1H),6.98(d,J＝6.3Hz,1H),6.77-6.72(m,2H),6.43(dd,J＝10.7,5.5Hz,1H),6.29(d,J＝10.8Hz,1H),4.29(q,J＝6.7Hz,1H),4.13(d,J＝10.5Hz,1H),3.77(dd,J＝11.1,4.8Hz,1H),3.63(dd,J＝16.2,6.0Hz,2H),3.38(dd,J＝11.9,1.9Hz,1H),3.10(d,J＝5.4Hz,1H),2.78(dd,J＝11.0,2.9Hz,1H),2.73(dd,J＝10.8,2.4Hz 1H),2.66(dd,J＝10.2,7.4Hz,1H),2.00-0.50(m,60H)ppm。
13C NMR(101MHz,CD2Cl2)δ218.4,184.3,158.4,129.4,129.1,127.7,125.1,123.5,119.7,116.7,108.8,99.8,89.8,76.5,76.2,75.8,75.0,71.8,70.2,67.8,56.0,55.1,51.6,51.2,50.8,40.6,39.3,37.8,36.5,33.4,33.1,32.9,29.7,28.6,28.3,27.4,24.3,21.4,20.5,17.8,17.4,16.5,15.1,13.5,12.9,12.4,11.0,7.0,6.7ppm。
FT-IR(KBr)：3433(br,m),3320(br,m),2953(s),2932(s),2872(m),1713(s),1563(s),1456(s),1428(s),1405(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C49H77NO10Na+计算值878.5389；实测值878.5381；[M-Na+2H]+C49H79NO10 +计算值856.5569；实测值856.5575。
实施例1.16：化合物(16)的制备：
产率：51mg，89％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在50％EtOAc/正己烷中为0.63。具有PMA的绿色品系。
1H NMR(400MHz,CDCl3)δ7.15(d,J＝7.9Hz,2H),7.08(d,J＝8.2Hz,2H),6.49(dd,J＝10.7,5.6Hz,1H),6.19(d,J＝10.8Hz,1H),4.39(dd,J＝13.8,6.9Hz,1H),4.24(d,J＝10.3Hz,1H),3.90(dd,J＝11.0,4.9Hz,1H),3.85(d,J＝12.5Hz,1H),3.72(dd,J＝15.5,7.2Hz,2H),3.56(d,J＝10.0Hz,1H),3.34-3.29(m,1H),3.03(d,J＝5.7Hz,1H),2.87(td,J＝11.0,3.3Hz,1H),2.68(dd,J＝11.0,2.6Hz,1H),2.64-2.59(m,1H),2.31(s,3H),2.20-0.50(m,57H)ppm。
13C NMR(101MHz,CDCl3)δ216.8,184.1,137.7,136.3,129.0,129.0,128.2,122.6,109.3,99.1,88.7,75.7,75.6,74.9,74.5,71.5,69.8,67.1,55.2,54.6,51.6,51.2,50.4,40.1,38.9,37.2,36.0,32.9,32.5,32.4,29.7,29.0,27.9,26.9,23.9,21.1,20.8,19.9,17.5,17.0,16.0,14.6,13.2,12.5,11.8,10.6,6.7,6.5ppm。
FT-IR(KBr)：3295(br,m),2961(s),2931(s),2874(m),1713(s),1567(s),1458(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C50H79NO11Na+计算值876.5596；实测值876.5593；[M-Na+2H]+C50H80NO11 +计算值854.5777；实测值854.5777。
实施例1.17：化合物(17)的制备：
产率：70mg，88％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在50％EtOAc/正己烷中为0.67。具有PMA的绿色品系。
1H NMR(400MHz,CDCl3)δ7.22(dd,J＝8.5,5.6Hz,2H),6.95(dd,J＝12.0,5.3Hz,2H),6.48(dd,J＝10.7,5.6Hz,1H),6.20(d,J＝10.8Hz,1H),4.37(q,J＝6.6Hz,1H),4.23(d,J＝10.3Hz,1H),3.89(dd,J＝11.1,4.9Hz,1H),3.85(d,J＝11.9Hz,1H),3.74-3.68(m,1H),3.56(d,J＝10.1Hz,1H),3.30(dd,J＝11.9,1.9Hz,1H),3.00(d,J＝5.6Hz,1H),2.87(td,J＝10.9,3.1Hz,1H),2.67(dt,J＝7.1,3.6Hz,1H),2.62(dd,J＝10.2,7.4Hz,1H),2.20-0.50(m,58H)ppm。
13C NMR(101MHz,CDCl3)δ216.8,184.1,162.8,160.9,136.4,129.9,129.9,128.8,122.8,115.2,115.0,109.3,99.1,88.8,75.7,75.7,74.9,74.5,71.6,69.8,67.2,55.3,54.3,51.3,51.0,50.4,40.1,38.9,37.3,36.0,34.1,32.9,32.5,32.4,29.0,27.9,26.9,24.0,22.3,20.9,20.0,17.5,17.0,16.1,14.6,14.1,13.2,12.5,11.8,10.6,6.7,6.5ppm。
FT-IR(KBr)：3321(br,m),2962(s),2932(s),2874(m),1713(s),1567(s),1510(s),1459(s),1406(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C49H76FNO10Na+计算值880.5345；实测值880.5337；[M-Na+2H]+C49H77FNO10 +计算值858.5526；实测值858.5532。
实施例1.18：化合物(18)的制备：
产率：34mg，58％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点。
Rf：在50％EtOAc/正己烷中为0.58。具有PMA的绿色品系。
1H NMR(400MHz,CDCl3)δ7.18(d,J＝8.8Hz,2H),7.13(d,J＝8.5Hz,2H),6.42(dd,J＝10.7,5.6Hz,1H),6.14(d,J＝10.8Hz,1H),4.30(q,J＝6.7Hz,1H),4.17(d,J＝10.2Hz,1H),3.83(dd,J＝10.6,4.2Hz,1H),3.78(d,J＝12.9Hz,1H),3.68-3.61(m,2H),3.49(d,J＝10.1Hz,1H),3.23(d,J＝11.6Hz,1H),2.93(d,J＝5.6Hz,1H),2.80(td,J＝10.9,3.1Hz,1H),2.61(dd,J＝11.0,2.4Hz,1H),2.55(dd,J＝10.2,7.4Hz,1H),2.20-0.50(m,57H)ppm。
13C NMR(101MHz,CDCl3)δ216.8,184.2,139.1,132.5,129.7,128.7,128.4,122.8,109.2,99.0,88.8,75.7,75.6,74.9,74.5,71.5,69.8,67.1,55.2,54.3,51.2,51.0,50.4,40.1,38.8,37.3,36.0,32.9,32.5,32.4,29.7,28.9,27.9,27.9,26.9,23.9,20.8,19.9,17.5,17.0,16.0,14.6,13.2,12.5,11.8,10.6,6.7,6.5ppm。
FT-IR(KBr)：3322(br,m),2962(s),2932(s),2874(m),1713(s),1663(s),1567(s),1492(s),1459(s),1407(m)cm-1。
HRMS-ESI(m/z)：[M+H]+C49H76ClNO10Na+计算值896.5050；实测值869.5046；[M-Na+2H]+C49H77ClNO10 +计算值874.5231；实测值874.5238。
实施例2：C20-epi-二铁霉素的制备
方案2.C20-epi-二铁霉素的合成。对于C20-epi-氨基盐霉素epi-NH2的合成，参见上文。
C20-epi-二铁霉素的合成
方法A：在室温下向C20-epi-氨基盐霉素(50mg，0.07mmol，1.0当量)于无水MeOH(2mL)中的搅拌溶液中添加丙醛(MA-I-073，新鲜制备的)(8.8mg，0.16mmol，2.2当量)和冰乙酸(2滴)，并将所得混合物搅拌4h。之后，逐滴引入溶解于无水MeOH(1mL)中的NaBH3CN(9.0mg，0.15mmol，2.0当量)。将混合物搅拌过夜，然后将溶剂在真空中蒸发至干。使用装备有C18-反相柱的HPLC纯化残余物(梯度：ACN/H2O 1/1至ACN)。获得呈白色无定形固体的纯反应产物。
方法B：在室温下向C20-epi-氨基盐霉素(50mg，0.07mmol，1.0当量)和K2CO3(10mg，0.07mmol，1.0当量)于无水ACN(2mL)中的搅拌溶液中逐滴添加炔丙基溴(80重量％，在甲苯中)(28mg，0.24mmol，3.5当量)。然后将反应混合物加热至60℃，并且再剧烈搅拌20h。之后，将反应混合物过滤并且将滤液在真空中蒸发。将油状残余物溶解于CH2Cl2(10mL)中，并且用H2SO4水溶液(15mM，2×7mL)和水(7mL)萃取两次。将有机层在减压下蒸发，并且使用配备有C18-反相柱的HPLC进行色谱纯化(梯度：ACN/H2O 1/1至ACN)。获得呈白色无定形固体的纯反应产物。
C20-epi-二炔丙基氨基盐霉素epi-diAM5(化合物19)：产率：1.4mg，3％。分离为白色无定形固体，通过NMR测定纯度>95％，并且通过TLC测定为单个斑点；Rf：在CH2Cl2/EtOAc50％中为0.70。具有PMA的绿色品系；1H NMR(500MHz,CD2Cl2)δ6.10(dd,J＝10.4,1.6Hz,1H),5.54(dd,J＝10.4,2.9Hz,1H),4.01(dd,J＝8.7,8.2Hz,2H),3.78(ddd,J＝17.5,15.3,6.1Hz,4H),3.70-3.60(m,3H),3.57(dd,J＝11.2,1.3Hz,1H),3.46-3.40(m,1H),3.14-2.92(m,3H),2.85(dd,J＝8.5,4.3Hz,1H),2.77(dd,J＝11.3,7.2Hz,1H),2.34-2.26(m,2H),2.16(dd,J＝11.3,8.6Hz,1H),2.10-0.60(m,53H)ppm；13C NMR(126MHz,CD2Cl2)δ217.6,177.2,130.9,127.2,109.9,99.0,85.3,81.2,78.2,76.6,75.3,72.5,72.1(2C),71.7,71.3,71.1,60.8,56.4,49.6,48.3,41.4,39.5,36.8,36.1,34.8,33.2,31.0,29.7,29.4,28.7,26.4,22.8,22.7,21.2,21.0,20.2,18.6,16.2,14.6,13.9,13.5,12.1,11.5,7.4,6.5ppm，两个重叠的信号；HRMS(ESI+)m/z[M+H]+C48H76NO10计算值826.5469，实测值826.5467。
实施例3：本发明的化合物的IC50
已针对乳腺癌症干细胞(HMLER)模型和匹配的非干细胞(即HMLER CD24high/CD44high/low的ID2)以及在MCF10A细胞(正常乳腺细胞系)中评价这些化合物。
下表1表示对应的结果。
选择性被计算为IC50 ID2与IC50 HMLER的比率。
每个IC50值以生物一式三份进行测定(三个独立的生物实验)，并且每个一式三份以至少技术一式两份进行测定。
细胞培养
在补充有10％FBS、10μg/mL胰岛素(西格玛奥尔德里奇公司(Sigma-Aldrich)，I0516)、0.5μg/mL氢化可的松(西格玛奥尔德里奇公司，H0888)和0.5μg/mL嘌呤霉素(生命技术公司(Life Technologies)，A11138-02)的DMEM/F12(Gibco，31331-028)中培养从携带hTERT、SV40和致癌等位基因H-rasV12的逆转录病毒感染的人乳腺上皮细胞获得的天然抑制E-钙粘蛋白的HMLER细胞；细胞是来自Alain Puisieux(INSERM)的慷慨馈赠。所有细胞在37℃和5％CO2下进行温育。使用Aria IIu(BD生物科学公司(BD Biosciences))通过FACS分选用CD24-APC和CD44-PE抗体染色的HMLER CD44low/high细胞，以获得分离的CD24low/CD44high和CD24high/CD44low细胞群。向HMLER CD24low/CD44high细胞中补充10ng/mL人表皮生长因子(EGF，美天施生物科技公司(Miltenyi Biotec)，130-093-750，100ng/mL)，而使HMLER CD24high/CD44low细胞在没有EGF的情况下生长。将MCF10A细胞(ATCC，CRL-10317)在补充有10％马血清(英杰公司(Invitrogen)，16050-122)、10μg/mL胰岛素、10ng/mL EGF、0.5μg/mL氢化可的松、100ng/mL霍乱毒素(西格玛奥尔德里奇公司，C8052)和1×PenStrep(英杰公司，15070-063)的DMEM/F12中培养。
细胞活力测定(IC50)
通过在96孔板中每孔铺板1000个细胞来进行细胞活力测定。遵循制造商的方案在12nM与50μM之间或0.3nM与4μM之间的范围内使用系列稀释液将细胞处理72h。简言之，在处理72h后，将CellTiter-Blue试剂(G8081，普洛麦格公司(Promega))添加到孔中，并且将细胞温育3h，之后使用PerkinElmer Wallac 1420Victor2微孔板读数器记录荧光强度(λex＝560/20nm；λem＝590/10nm)。使用Prism 8软件绘制合成的化合物针对HMLER CD24low/CD44high和同基因细胞系HMLER CD24high/CD44low的IC50细胞活力曲线。
评估所有衍生物的抗增殖活性和对良好建立的间充质CSC模型(HMLER CD24low/CD44high)以及它们的缺乏CSC特性的上皮对应物(HMLER CD24high/CD44low)的选择性。发现与参考物Sal和铁霉素相比，大多数这些衍生物对间充质状态更有效并且更具选择性。具体而言，化合物6、8和9被鉴定为在此背景下特别令人感兴趣，其IC50值分别为30nM、3nM和9nM，以及它们的突出选择性(SI在20.0与90.0之间)。关于构效关系(SAR)，我们发现如下：(i)Sal的单取代C20-epi-氨基衍生物的活性基本上大于它们的对应的双取代对应物；(ii)对于仲胺产物，正戊基和正己基取代基对间充质状态更有效，(iii)对于叔胺衍生物，脂肪链的延长导致抗增殖活性降低；以及(iv)在苄基基序的对位位置中引入非极性或极性取代基提高了选择性。
Claims (15)
1.一种具有式(I)的化合物：
其中：
-R1和R2是相同或不同的并且独立地选自由以下组成的组：H、
(C1-C20)烷基基团、(C3-C6)环烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：(C1-C6)烷基、卤素、羟基、氨基、巯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷基氨基、卤代(C1-C6)烷基、羧基和羧基(C1-C6)烷基；
-X是H、K或Na，
条件是R1和R2中的至少一者不是H，并且
排除以下化合物：
2.根据权利要求1所述的化合物，其中R1和R2是不同的。
3.根据权利要求1或2所述的化合物，其中R1选自由以下组成的组：
(C1-C20)烷基基团、(C3-C6)环烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：(C1-C6)烷基、卤素、羟基、氨基、巯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷基氨基、卤代(C1-C6)烷基、羧基和羧基(C1-C6)烷基，并且R2是H。
4.根据权利要求3所述的化合物，其中R1选自由以下组成的组：(C1-C20)烷基基团、(C2-C20)炔基基团和(C6-C10)芳基(C1-C6)烷基基团，所述(C6-C10)芳基任选地被至少一个选自由以下组成的组的取代基取代：
(C1-C6)烷基、卤素和羟基。
5.根据权利要求3或4所述的化合物，其中R1是直链(C2-C12)烷基基团、丙炔-1-基基团或苄基基团，其优选地在对位位置中任选地被OH、甲基或卤素取代。
6.根据权利要求1所述的化合物，其中R1和R2是相同的，并且优选地选自由以下组成的组：(C1-C20)烷基基团，优选地直链(C2-C12)烷基基团，和(C2-C20)炔基基团，优选地丙炔基基团。
7.根据前述权利要求中任一项所述的化合物，所述化合物选自以下化合物：
8.一种用于制备根据权利要求1至7中任一项所述的化合物的方法，所述方法包括以下步骤：
-向C20-epi-氨基盐霉素的钠盐于溶剂中的溶液中添加醛R1CHO，R1如式(I)中所定义，以便获得对应的亚胺，随后将所述亚胺还原成对应的式(I)的胺化合物，或者
-使溴化合物R1Br与化合物C20-epi-氨基盐霉素优选地在溶剂中反应，R1如式(I)中所定义。
9.根据权利要求1至7中任一项所述的化合物，所述化合物用作药物。
10.一种药剂，所述药剂包含根据权利要求1至7中任一项所述的化合物或其药学上可接受的盐。
11.一种药物组合物，所述药物组合物包含至少一种根据权利要求1至7中任一项所述的化合物或其药学上可接受的盐，以及至少一种药学上可接受的赋形剂。
12.根据权利要求1至7中任一项所述的化合物，所述化合物用于预防和/或治疗癌症。
13.根据权利要求12所述的供使用的化合物，其中所述癌症选自由以下组成的组：结肠癌、结肠直肠癌、黑素瘤、骨癌、乳腺癌、甲状腺癌、前列腺癌、卵巢癌、肺癌、胰腺癌、胶质瘤、宫颈癌、子宫内膜癌、头颈癌、肝癌、膀胱癌、肾癌、皮肤癌、胃癌、睾丸癌、尿路上皮癌或肾上腺皮质癌、白血病、淋巴癌和多发性骨髓瘤。
14.根据权利要求1至7中任一项所述的化合物，所述化合物在受试者中用于预防癌症转移和/或用于预防癌症复发和/或用于降低对化学疗法的抗性，优选地其中所述癌症选自实体癌和非实体癌，优选地选自结肠癌、结肠直肠癌诸如具有BRAF突变特别是BRAF V600E的结肠直肠癌、黑素瘤、骨癌、乳腺癌诸如三阴性乳腺癌、甲状腺癌、前列腺癌、卵巢癌、肺癌、胰腺癌、胶质瘤诸如成胶质细胞瘤、宫颈癌、子宫内膜癌、头颈癌、肝癌、膀胱癌、肾癌、皮肤癌、胃癌、睾丸癌、尿路上皮癌或肾上腺皮质癌、白血病诸如急性髓样白血病、淋巴瘤和多发性骨髓瘤。
15.一种产品，所述产品包含：
a)根据权利要求1至7中任一项所述的化合物，和
b)至少一种附加疗法，
作为同时、分开或相继使用的组合产品，在受试者中用于治疗癌症，和/或用于预防癌症转移，和/或用于预防癌症复发，和/或用于降低对所述附加疗法b)的抗性，所述受试者优选地是罹患癌症并且具有对化学疗法的抗性的人，
所述附加疗法b)优选地是免疫疗法、化学疗法和/或放射疗法。
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