CN113260365A - 新型化合物及包含其的用于增强抗癌活性的药学组合物 - Google Patents
新型化合物及包含其的用于增强抗癌活性的药学组合物 Download PDFInfo
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- CN113260365A CN113260365A CN201980086606.2A CN201980086606A CN113260365A CN 113260365 A CN113260365 A CN 113260365A CN 201980086606 A CN201980086606 A CN 201980086606A CN 113260365 A CN113260365 A CN 113260365A
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
Description
技术领域
本发明涉及新型化合物及包含其的用于增强抗癌活性的药学组合物。
背景技术
癌症为全世界中最普遍的死亡原因中的一种,占死亡原因的约12%。
作为代表性抗癌疗法的化学疗法(chemotherapy)单独或与如放射疗法的其他治疗法结合来用作目前用于治疗癌症的最有效的治疗方法。但是,在化学疗法中,癌症治疗药物的功效取决于可杀死癌细胞的能力,当使用药物时,具有不仅作用于癌细胞,还作用于普通细胞的问题。
另一方面,癌症干细胞(cancer stem cell)为具有无限再生能力的癌细胞,肿瘤起源于干细胞的假设通过如下的报告得以确定,即,在90年代末,将可在急性骨髓性白血病中成为癌症干细胞的细胞移植在免疫抑制小鼠中,并在小鼠中复制人的白血病,之后,在乳腺癌中证明癌症干细胞来明确了实体癌症中也存在干细胞。
癌症干细胞为具有自我再生能力和可分化为其他细胞的能力的细胞,是导致癌症复发和转移的原因。在特定患者组中,癌症干细胞被活化,由此示出强的抗癌剂耐药性,从而被分为难以通过现有的抗癌疗法治疗的难治性癌症患者。在恶性肿瘤中观察到的各种异质性与干细胞的各种分化性一致,即使进行许多靶向治疗,仍持续表达的癌细胞的药物耐药性与干细胞的基本特征一致。
癌症干细胞可成为新的靶向治疗领域,为了有效进行不损伤正常干细胞且仅靶向癌症干细胞的治疗,需要与癌症干细胞的保持和调节中重要的分子生物学特性或其调节途径有关的知识和理解。
根据癌症干细胞假设设计了各种治疗方法,其中,最著名的方法为利用癌症干细胞的自我再生途径的方法。在这种治疗中重要的是,保持正常干细胞的自我再生,并仅靶向癌症干细胞的自我再生。例如,Notch信号由称为γ分泌酶(gamma secretase)的酶进行,若将对于其的抑制剂(gamma secretase inhibitor)用于过表达Notch1的乳腺癌,则可实现肿瘤抑制效果。近来,据报道,在靶向刺猬(Hedgehog)信号体系的情况下,也示出抗癌效果,当将作为刺猬抑制剂的环巴胺(cyclopamine)向进行移植瘤(tumor xenograft)的动物给药时,肿瘤明显萎缩。除此之外,以与PI3K/AKT、MAPK、JAK2/STAT3信号通路(signalingpathway)相关而周知。
如上所述,进行了选多研究,通过抑制癌症干细胞的直接靶基因的实验来抑制癌症干细胞,或者,通过抑制癌症干细胞的更高的信号传递蛋白来抑制癌症干细胞。但是,目前为止,几乎没有对于直接靶向癌症干细胞的抗癌剂或源自天然物的提取物的研究,在大部分的肿瘤患者中,由于肿瘤基因的变异或蛋白质的变异,靶向实验存在诸多困难。
另一方面,以往的研究结果表明,癌症干细胞所具有的抗癌剂耐药性的核心原因在于参与细胞内钙离子的运输和存储的蛋白质,即“肌浆网钙泵(SERCA,sarco/endoplasmic reticulum calcium ATPase)”。
在普通癌细胞中,若给药抗癌剂,则诱发过多应激,在内质网(endoplasmicreticulum,ER)中分泌过多的钙离子,所分泌的钙离子积聚在线粒体并导致癌细胞的自杀,相反,在癌症干细胞中,当给药抗癌剂时,减少过多的钙离子的分泌,同时,增加可将分泌的过多的钙离子再次返回到内质网的SERCA表达,由此发现在调节钙离子的浓度的同时存活。即,SERCA蛋白在内质网应激信号传递过程中起到用于传递存活信号的作用。
若研发能够作用为靶向作为癌症干细胞所具有的的抗癌剂耐药性的原因的SERCA蛋白的抑制剂的物质并选择性地抑制癌症干细胞的生长,则增加通过抗癌药物的化学疗法的功效,能够以更少剂量的药物示出优秀的抗癌效果。
发明内容
技术问题
本发明的目的在于,提供新型化合物。
本发明的目的在于,提供用于增强抗癌活性的药学组合物。
用于解决问题的手段
1.一种由下述化学式1表示的化合物或其药学上可接受的盐:
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
2.在上述第1项所述的化合物或其药学上可接受的盐中,
上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
3.在上述第1项所述的化合物或其药学上可接受的盐中,上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
4.一种用于增强抗癌活性的药学组合物,包含由下述化学式1表示的化合物或其药学上可接受的盐:
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
5.在上述第4项所述的药学组合物中,上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
6.在上述第4项所述的药学组合物中,上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
7.在上述第4项所述的药学组合物中,上述抗癌活性增强为抗癌剂或放射线的抗癌活性增强。
8.在上述第7项所述的药学组合物中,上述抗癌剂为紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种。
9.在上述第8项所述的药学组合物中,上述紫杉类抗癌剂为选自由紫杉醇、多西紫杉醇及卡巴他赛组成的组中的至少一种。
10.在上述第8项所述的药学组合物中,上述喜树碱类抗癌剂为选自由伊立替康、拓扑替康及贝洛替康组成的组中的至少一种。
11.在上述第4项所述的药学组合物中,用于增强对于耐药性癌症的抗癌活性。
12.在上述第11项所述的药学组合物中,上述耐药性癌症为对于紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种的耐药性癌症。
13.在上述第11项所述的药学组合物中,上述耐药性癌症为对于放射线的耐药性癌症。
14.在上述第11项所述的药学组合物中,上述耐药性癌症为选自由甲状腺癌、胃癌、大肠癌、卵巢癌、乳腺癌、肺癌、卡波济氏肉瘤、宫颈癌、胰腺癌、头颈部癌、直肠癌、结肠癌、食道癌及前列腺癌组成的组中的至少一种。
15.在上述第4项所述的药学组合物中,还包含抗癌剂。
16.在上述第15项所述的药学组合物中,上述抗癌剂包含选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄洛替尼、来那替尼、拉帕替尼、吉非替尼、凡德他尼、尼罗替尼、司马沙尼、博舒替尼、阿西替尼、马赛替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、帕唑帕尼、托西尼布、尼达尼布、瑞戈非尼、司马沙尼、替沃扎尼、帕纳替尼、卡博替尼、卡铂、索拉非尼、乐伐替尼、贝伐单抗、顺铂、西妥昔单抗、槲寄生、门冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥珠单抗奥唑米星、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、甲基苄肼、前列地尔、硝酸钬·壳聚糖、吉西他滨、去氧氟尿苷、培美曲塞、替加氟、卡培他滨、吉莫斯特、奥替拉西、阿扎胞苷、氨甲喋呤、尿嘧啶、阿糖胞苷、5-氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、卡培他滨、地西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟、雷替曲塞、多西紫杉醇、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春花碱、替尼泊苷、阿霉素、去甲氧柔红霉素、表阿霉素、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素、吡喃阿霉素、阿克拉霉素、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑、六甲蜜胺、达卡巴嗪、塞替派、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、瘤可维、维甲酸、依西美坦、氨鲁米特、阿那格雷、奥拉帕尼、诺维本、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏氯唑、比卡鲁胺、洛莫司汀、伏立诺他、恩替诺特及卡莫司汀组成的组中的至少一种。
17.在上述第15项所述的药学组合物中,以1∶0.001至1∶1000的摩尔浓度比包含上述抗癌剂与由上述化学式1表示的化合物或其药学上可接受的盐。
18.一种癌症治疗方法,包括向患有耐药性癌症的对象给药治疗有效量的由下述化学式1表示的化合物或其药学上可接受的盐的步骤:
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
19.在上述第18项所述的癌症治疗方法中,上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
20.在上述第18项所述的癌症治疗方法中,上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
21.在上述第18项所述的癌症治疗方法中,上述耐药性癌症为对于紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种的耐药性癌症。
22.在上述第18项所述的癌症治疗方法中,上述耐药性癌症为对于放射线的耐药性癌症。
23.在上述第18项所述的癌症治疗方法中,上述耐药性癌症为选自由甲状腺癌、胃癌、大肠癌、卵巢癌、乳腺癌、肺癌、卡波济氏肉瘤、宫颈癌、胰腺癌、头颈部癌、直肠癌、结肠癌、食道癌及前列腺癌组成的组中的至少一种。
24.一种用于治疗耐药性癌症的由下述化学式1表示的化合物的用途:
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
25.在上述第24项所述的化合物的用途中,上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
26.在上述第24项所述的化合物的用途中,上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
27.在上述第24项所述的化合物的用途中,上述耐药性癌症为对于紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种的耐药性癌症。
28.在上述第24项所述的化合物的用途中,上述耐药性癌症为对于放射线的耐药性癌症。
29.在上述第24项所述的化合物的用途中,上述耐药性癌症为选自由甲状腺癌、胃癌、大肠癌、卵巢癌、乳腺癌、肺癌、卡波济氏肉瘤、宫颈癌、胰腺癌、头颈部癌、直肠癌、结肠癌、食道癌及前列腺癌组成的组中的一种。
发明的效果
包含本发明的化合物或其药学上可接受的盐的组合物可增强抗癌剂或放射线的抗癌活性,抑制癌细胞的增殖及诱导细胞凋亡等,从而可有效地治疗癌症。
包含本发明的化合物或其药学上可接受的盐的组合物克服具有对于抗癌剂或放射线的耐性的癌症的耐性,可有效地治疗耐药性癌症。
附图说明
图1为示出对于来源于服用紫杉醇后复发及转移的患者的癌症干细胞性甲状腺癌细胞,进行制备例1-1的化合物单独处理、紫杉醇单独处理或紫杉醇与制备例1-1的化合物的复方剂处理后,测定根据处理时间的细胞数的变化的结果的图。
图2为示出对于来源于服用紫杉醇后复发及转移的患者的癌症干细胞性甲状腺癌细胞,进行制备例1-1的化合物单独处理、紫杉醇单独处理或紫杉醇与制备例1-1的化合物的复方剂处理后,测定根据处理浓度的细胞存活率的变化的结果的图。
图3为示出对于利用来源于服用紫杉醇后复发及转移的患者的癌症干细胞性甲状腺癌细胞进行移植瘤的小鼠模型,将制备例1-1的化合物单独口服给药、将紫杉醇单独腹腔内注射或将制备例1-1的化合物口服给药且将紫杉醇腹腔内注射后,测定根据时间的推移的肿瘤的体积变化的结果的图。
图4为示出对于来源于服用伊立替康后复发及转移的患者的癌症干细胞性胃癌细胞,进行制备例1-1的化合物单独处理、伊立替康单独处理或伊立替康与制备例1-1的化合物的复合剂处理后,测定根据处理时间的细胞数的变化的结果的图。
图5为示出对于利用来源于服用伊立替康后复发及转移的患者的癌症干细胞性胃癌细胞进行移植瘤的小鼠模型,将制备例1-1的化合物单独口服给药、将伊立替康单独口服给药或将制备例1-1的化合物和伊立替康口服给药后,测定根据时间的推移的肿瘤的体积变化的结果的图。
图6为示出对于利用来源于服用伊立替康后复发及转移的患者的癌症干细胞性胃癌细胞进行移植瘤的小鼠模型,将制备例1-1的化合物单独口服给药、将伊立替康单独口服给药或将制备例1-1的化合物和伊立替康口服给药后,测定根据时间的推移的肿瘤的重量变化的结果的图。
图7为示出对于利用来源于服用伊立替康后复发及转移的患者的癌症干细胞性胃癌细胞进行移植瘤的小鼠模型,将制备例1-1的化合物单独口服给药、将伊立替康单独口服给药或将制备例1-1的化合物和伊立替康口服给药后,测定根据时间的推移的肿瘤的小鼠的体重变化的结果的图。
图8为示出对于来源于照射放射线后复发及转移的患者的癌症干细胞性大肠癌细胞,进行制备例1-1的化合物单独处理、放射线照射或制备例1-1的化合物的处理和放射线照射的结合处理后,测定根据处理时间的细胞数的变化的结果的图。
图9为示出对于利用来源于照射放射线后复发及转移的患者的癌症干细胞性大肠癌细胞进行移植瘤的小鼠模型,将制备例1-1的化合物单独口服给药、照射放射线或进行制备例1-1的化合物的口服给药且照射放射线的结合处理后,测定根据时间的推移的肿瘤的体积变化的结果的图。
图10为示出对于利用来源于照射放射线后复发及转移的患者的癌症干细胞性大肠癌细胞进行移植瘤的小鼠模型,将制备例1-1的化合物单独口服给药、照射放射线或进行制备例1-1的化合物的口服给药且照射放射线的结合处理后,测定根据时间的推移的肿瘤的重量变化的结果的图。
图11为示出对于利用来源于照射放射线后复发及转移的患者的癌症干细胞性大肠癌细胞进行移植瘤的小鼠模型,将制备例1-1的化合物单独口服给药、照射放射线或进行制备例1-1的化合物的口服给药且照射放射线的结合处理后,测定根据时间的推移的肿瘤的小鼠的体重变化的结果的图。
图12为示出对于作为上皮性卵巢癌细胞株的SKOV3和由对紫杉醇抗癌剂具有耐药性的耐性细胞株制备的SKOV3-TR分别未进行任何处理(None)、利用乙醇(制备例的化合物溶剂)处理或利用制备例1-2的化合物处理后确认细胞的形态的结果的图。
图13示出对于SKOV3-TR细胞株进行紫杉醇的单独处理或紫杉醇与制备例1-2的化合物的复方剂处理后的72小时之后的图像。
图14示出对于SKOV3细胞株进行紫杉醇的单独处理或紫杉醇与制备例1-2的化合物的复方剂处理后的72小时之后的图像。
图15为示出在SKOV3-TR细胞株中,未进行任何处理(None)、分别利用2μM的乙醇以及制备例的化合物进行处理后的72小时之后的细胞数的图。
图16为示出在SKOV3细胞株中,未进行任何处理(None)、分别利用2μM的乙醇以及制备例的化合物进行处理后的72小时之后的细胞数的图。
图17为示出在SKOV3-TR细胞株中,未进行任何处理(None)、分别利用2μM的乙醇、二甲基亚砜(DMSO)(紫杉醇溶剂)、紫杉醇单独以及紫杉醇和制备例的化合物的复合剂进行处理后的72小时之后的细胞数的图。
图18为示出在SKOV3细胞株中,未进行任何处理(None)、分别利用2μM的乙醇、二甲基亚砜(DMSO)、紫杉醇单独以及紫杉醇和制备例的化合物的复合剂进行处理后的72小时之后的细胞数的图。
具体实施方式
本发明的下述化学式1的化合物和/或其药学上可接受的盐在内质网应激信号传递中,示出抑制负责传递存活信号的SERCA蛋白的效果。
本发明提供由下述化学式1表示的化合物或其药学上可接受的盐:
[化学式1]
在化学式1中,R1可以为氢、C1至C10的烷基或芳基(C1至C4)烷基。
在化学式1中,R1可以为C1至C6的烷基或芳基(C1至C2)烷基。
在化学式1中,R1可以为C1至C6的烷基、苯甲基或苯乙基。
在化学式1中,R1的烷基及芳基烷基各自独立地可被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代。在化学式1中,在R1的烷基和/或芳基烷基被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
在化学式1中,在R1为芳基烷基的情况下,烷基、卤素基、卤代烷基、氰基、硝基或苯基可在对位取代。
术语“烷基”是指直链或支链的未取代或取代的饱和烃基,包含如甲基、乙基、丙基、异丙基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十三烷基、十五烷基及十七烷基等。C1至C10的烷基是指具有碳原子数为1至10的烷基单元的烷基,在C1至C10的烷基被取代的情况下,不包含取代化合物的碳原子数。
术语“芳基”是指完全或部分不饱和的取代或未取代的单环或多环的碳环,例如,可以为取代或未取代的苯基。
术语“芳基烷基”是指被芳基取代的烷基,例如,可以为苄基(苯甲基)、苯乙基或苯基丙基。芳基(C1至C4)烷基是指被芳基取代的C1至C4的烷基。
在化学式1中,R3可以为C1至C6、C1至C4或C1至C2的烷基。
在化学式1中,R3的烷基可被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代。在化学式1中,在R3的烷基被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
在化学式1中,n可以为0至4、0至2或0至1的整数。在化学式1的n为0的情况下,是指不被R3取代。
在化学式1中,R2可以为氢、C1至C10的烷基或芳基(C1至C4)烷基。
在化学式1中,R2可以为氢、C1至C6的烷基或芳基(C1至C2)烷基。
在化学式1中,R2可以为氢、C1至C6的烷基、苯甲基或苯乙基。
在化学式1中,R2的烷基及芳基烷基各自独立地可被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代。在化学式1中,在R2的烷基和/或芳基烷基被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
在化学式1中,在R2为芳基烷基的情况下,烷基、卤素基、卤代烷基、氰基、硝基或苯基可在对位取代。
在化学式1中,R4可以为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基。
在化学式1中,R4可以为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基。
在化学式1中,R4可以为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基。
术语“环烷基”是指非芳香族、饱和或部分不饱和烃环基,例如,环烷基可以为单环或二环。
在化学式1中,R4的烷基、芳基烷基及环烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代。在化学式1中,在R4的烷基、芳基烷基和/或环烷基被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
在化学式1中,在R4为烷基的情况下,可以是烷基硫醇基或芳基烷基硫醇基被取代的。
例如,烷基硫醇基可以为甲基硫醇基、乙基硫醇基等。
例如,芳基烷基硫醇基可以为苯基硫醇基、苄基硫醇基等。
在化学式1中,R2与R4可形成4元环至7元环、4元环至6元环或5元环至6元环并相互连接。即,R2与R4可以为相互连接来形成4元环至7元环、4元环至6元环或5元环至6元环。
R2与R4相连接的4元环至7元环可包含3个至6个碳。
R2与R4相连接的4元环至6元环可包含3个至5个碳。
R2与R4相连接的5元环至6元环可包含4个至5个碳。
在化学式1中,L1可以为直接键或C1至C6、C1至C4或C1至C2的亚烷基。
术语“亚烷基”是指从直链或支链的烃链衍生的2价残基,例如,可以为亚甲基、亚乙基、亚丙基、异亚丙基、正丁烯基、仲丁烯基、叔丁烯基、正戊烯基、正己烯基等。
L1的亚烷基可被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代。在化学式1中,在L-1的亚烷基被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
在化学式1中,n为0至4的整数;R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;L1为直接键或C1至C6的亚烷基;R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者R2与R4形成4元环至7元环并相互连接;在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
在化学式1中,n为0至2的整数;R1为氢、C1至C6的烷基或芳基(C1至C2)烷基;R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;L1为C1至C4的亚烷基;R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者R2与R4形成4元环至6元环并相互连接;在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
在化学式1中,n为0至1的整数;R1为氢、C1至C6的烷基、苯甲基或苯乙基;R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;L1为C1至C2的亚烷基;R2为氢、C1至C6的烷基、苯甲基或苯乙基,R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基、苯乙基或萘甲基,或者R2与R4形成5元环至6元环并相互连接;在上述R1至R4的烷基、上述R1、R2及R4的苯甲基、苯乙基及萘甲基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,各个取代基可以彼此相同或不同。
化学式1的化合物可以为下述表1的化学式2、化学式5、化学式8至化学式9、化学式13至化学式34。
[表1]
例如,药学上可接受的盐可以为酸加成盐或金属盐。
酸加成盐可由如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸或亚磷酸的无机酸以及如脂肪族单羧酸酯和二羧酸酯、苯基-取代的链烷酸酯、羟基链烷酸酯及链烷二酸酯(alkandioate)、芳香族酸、脂肪族磺酸及芳香族磺酸的无毒性有机酸形成。这种药学上无毒的盐可包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、重亚硫酸盐、硝酸盐、磷酸盐、一氢磷酸盐、二氢磷酸盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-l,4-二酸盐、己烷-l,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-l-磺酸盐、萘-2-磺酸盐和扁桃酸盐。例如,由化学式1表示的化合物的酸加成盐可通过在过量的酸水溶液中溶解化合物,并使用水合有机溶剂,如甲醇、乙醇、丙酮或乙腈使盐沉淀来获取。
金属盐可以为钠盐、钾盐或钙盐。金属盐可使用碱来制备,例如,碱金属或碱土金属盐可通过将化合物溶解在过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐并使滤液蒸发和/或干燥来获取。
如上所述的化学式1的化合物和/或其药学上可接受的盐可起到在内质网应激信号传递过程中负责存活信号传递的SERCA蛋白的抑制剂的作用。
并且,本发明提供包含由如上所述的化学式1表示的化合物或其药学上可接受的盐的用于增强抗癌活性的药学组合物。
由化学式1表示的化合物或其药学上可接受的盐与如上所述的说明相同。
抗癌活性增强可以为抗癌剂或放射线的抗癌活性增强。
本发明的组合物可增强对于利用抗癌剂的化学疗法、放射线疗法或免疫疗法等的抗癌疗法的效果。
“抗癌疗法”为用于治疗癌症的方法,例如,可以为外科切除疗法、利用抗癌剂的化学疗法、放射线疗法或免疫疗法。
术语“治疗”是指疑似患有疾病的个体及发病个体的症状好转或变得有利的所有动作。
本发明的组合物可用作对于抗癌疗法的抗癌辅助剂。
抗癌剂可以为选自由紫杉类抗癌剂及喜树碱类抗癌剂组成的组中的至少一种。
紫杉类抗癌剂可以为选自由紫杉醇、多西紫杉醇及卡巴他赛组成的组中的至少一种。
喜树碱类抗癌剂可以为选自由伊立替康、拓扑替康及贝洛替康组成的组中的至少一种。
本发明的组合物可以为用于增强对于耐药性癌症的抗癌活性的药学组合物。
本发明的组合物可增加对于抗癌疗法的癌细胞的敏感性,可以克服耐药性癌症的耐性。
术语“癌细胞的敏感性增加”是指与对于没有耐性的癌细胞表现出生长抑制等的效果的浓度相比,表现出获取耐性的癌细胞的生长抑制及细胞凋亡等的效果的浓度相同或上升为其以上水平。
术语“耐药性癌症”是指通过抗癌疗法不表现出癌症的症状好转、缓解、减轻或治疗症状的癌症。耐药性癌症可一开始对于特定抗癌疗法具有耐性,还可以最初未表现出耐性,但经过长时间的治疗,由于癌细胞内的基因变异等而对于相同的疗法表现出耐性。
耐药性癌症可以为对于通过照射放射线的放射线疗法具有耐性的癌症,即,对于放射线的耐药性癌症。
耐药性癌症可以为对于利用抗癌剂的化学疗法具有耐性的癌症,即,对于抗癌剂的耐药性癌症。
例如,对于抗癌剂的耐药性癌症可以为对于紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种的耐药性癌症。
对于紫杉类抗癌剂的耐药性癌症可能是基于紫杉类抗癌剂的癌细胞凋亡作用被如NF-κB或GRP78等的存活信号传递蛋白抑制而产生。在此情况下,本发明的药学组合物可通过抑制如NF-κB或GRP78等的存活信号传递蛋白的表达或活性来克服对于紫杉类抗癌剂的耐性。
对于喜树碱类抗癌剂的耐药性癌症可能是基于喜树碱类抗癌剂的癌细胞凋亡作用被如PARP或NF-κB等的存活信号传递蛋白抑制而产生。在此情况下,本发明的药学组合物可通过抑制如PARP或NF-κB等的存活信号传递蛋白的表达或活性来克服对于喜树碱类抗癌剂的耐性。
对于紫杉类抗癌剂和/或喜树碱类抗癌剂的耐药性癌症可能是癌细胞凋亡作用被在内质网应激信号传递过程中的负责存活信号传递的SERCA蛋白的过表达和/或过多的活化抑制而产生的。即,作为SERCA蛋白的抑制剂的可抑制SERCA蛋白的表达或活性的本发明的药学组合物可克服对于紫杉类抗癌剂和/或喜树碱类抗癌剂的耐性。
与紫杉类抗癌剂及喜树碱类抗癌剂有关的说明与如上所述的说明相同。
耐药性癌症可以为选自由甲状腺癌、胃癌、大肠癌、卵巢癌、乳腺癌、肺癌、卡波济氏肉瘤、宫颈癌、胰腺癌、头颈部癌、直肠癌、结肠癌、食道癌及前列腺癌组成的组中的至少一种。它们可以是通过被紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种诱发耐性的癌症。
本发明的组合物可与抗癌剂一同结合给药,在此情况下,可表现出克服对于抗癌剂或放射线的耐性的抗癌增强效果(adjuvant effect)。
本发明的组合物可包含由化学式1表示的化合物或其药学上可接受的盐和抗癌剂。
在此情况下,追加包含的抗癌剂可以为选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄洛替尼、来那替尼、拉帕替尼、吉非替尼、凡德他尼、尼罗替尼、司马沙尼、博舒替尼、阿西替尼、马赛替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、帕唑帕尼、托西尼布、尼达尼布、瑞戈非尼、司马沙尼、替沃扎尼、帕纳替尼、卡博替尼、卡铂、索拉非尼、乐伐替尼、贝伐单抗、顺铂、西妥昔单抗、槲寄生、门冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥珠单抗奥唑米星、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、甲基苄肼、前列地尔、硝酸钬·壳聚糖、吉西他滨、去氧氟尿苷、培美曲塞、替加氟、卡培他滨、吉莫斯特、奥替拉西、阿扎胞苷、氨甲喋呤、尿嘧啶、阿糖胞苷、5-氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、卡培他滨、地西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟、雷替曲塞、多西紫杉醇、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春花碱、替尼泊苷、阿霉素、去甲氧柔红霉素、表阿霉素、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素、吡喃阿霉素、阿克拉霉素、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑、六甲蜜胺、达卡巴嗪、塞替派、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、瘤可维、维甲酸、依西美坦、氨鲁米特、阿那格雷、奥拉帕尼、诺维本、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏氯唑、比卡鲁胺、洛莫司汀、伏立诺他、恩替诺特及卡莫司汀组成的组中的至少一种。
除由化学式1表示的化合物或其药学上可接受的盐之外,本发明的组合物还可包含紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种。
例如,本发明的组合物还可包含选自由紫杉醇、多西紫杉醇及卡巴他赛组成的组中的至少一种。
例如,本发明的组合物还可包含选自由伊立替康、拓扑替康及贝洛替康组成的组中的至少一种。
例如,本发明的组合物还可包含选自由紫杉醇、多西紫杉醇、卡巴他赛、伊立替康、拓扑替康及贝洛替康组成的组中的至少一种。
除由化学式1表示的化合物或其药学上可接受的盐以及紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种之外,本发明的组合物还可包含其他抗癌剂。
除紫杉类抗癌剂及喜树碱类抗癌剂之外的其他抗癌剂可以为选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄洛替尼、来那替尼、拉帕替尼、吉非替尼、凡德他尼、尼罗替尼、司马沙尼、博舒替尼、阿西替尼、马赛替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、帕唑帕尼、托西尼布、尼达尼布、瑞戈非尼、司马沙尼、替沃扎尼、帕纳替尼、卡博替尼、卡铂、索拉非尼、乐伐替尼、贝伐单抗、顺铂、西妥昔单抗、槲寄生、门冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥珠单抗奥唑米星、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、甲基苄肼、前列地尔、硝酸钬·壳聚糖、吉西他滨、去氧氟尿苷、培美曲塞、替加氟、卡培他滨、吉莫斯特、奥替拉西、阿扎胞苷、氨甲喋呤、尿嘧啶、阿糖胞苷、5-氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、卡培他滨、地西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟、雷替曲塞、多西紫杉醇、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春花碱、替尼泊苷、阿霉素、去甲氧柔红霉素、表阿霉素、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素、吡喃阿霉素、阿克拉霉素、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑、六甲蜜胺、达卡巴嗪、塞替派、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、瘤可维、维甲酸、依西美坦、氨鲁米特、阿那格雷、奥拉帕尼、诺维本、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏氯唑、比卡鲁胺、洛莫司汀、伏立诺他、恩替诺特及卡莫司汀组成的组中的至少一种。
除了由化学式1表示的化合物或其药学上可接受的盐以及紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种之外,本发明的组合物还可包含其他抗癌剂,由此,可示出更加优秀的抗癌活性增强效果。
本发明的药学组合物能够以1∶0.001至1∶1000的摩尔浓度比、1∶0.01至1∶100的摩尔浓度比、1∶0.1至1∶50的摩尔浓度比或1∶0.1至1∶20摩尔浓度比包含由化学式1表示的化合物或其药学上可接受的盐与抗癌剂。
本发明的药学组合物可以为胶囊、片剂、颗粒、注射剂、软膏剂、粉末或饮料形式。
本发明的药学组合物能够以散剂、颗粒剂、胶囊、片剂、水性悬浮液等的口服型剂型、外用剂、栓剂及注射剂的形态剂型化来使用。
本发明的药学组合物可包含药学上可接受的载体。当口服给药时,药学上可接受的载体可以为结合剂、润滑剂、崩解剂、赋形剂、加溶剂、分散剂、稳定剂、悬浮剂、色素、香料等,在注射剂的情况下,可混合缓冲剂、保存剂、无痛剂、加溶剂、等渗剂、稳定剂等来使用,在局部给药用的情况下,可使用基剂、赋形剂、润滑剂、保存剂等。
本发明的药学组合物的剂型可与药学上可接受的载体混合来以多种形态制备,例如,当口服给药时,能够以片剂、锭剂、胶囊、酏剂(elixir)、混悬剂、糖浆、威化饼等的形态制备,在注射剂的情况下,能够以单位给药安瓶或多次给药形态制备。并且,本发明的药学组合物的剂型可制备为溶液、悬浮液、片剂、胶囊、缓释剂等。
用于制剂化的载体、赋形剂及稀释剂可以为乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、甲基羟苯酸酯、丙基羟苯酸酯、滑石粉、硬脂酸镁、矿物油、填充剂、抗凝剂、润滑剂、湿润剂、香料、乳化剂或防腐剂等。
本发明的药学组合物的给药途径包括口腔、静脉内、肌内、动脉内、骨髓内、鞘内、心内、经皮、皮下、腹腔内、鼻腔内、肠道、局部、舌下或直肠,但并不限定于此。
本发明的药学组合物可口服给药或肠胃外给药,当肠胃外给药时,可选择皮肤外用或腹腔内注射、直肠内注射、皮下注射、静脉注射、肌内注射或胸内注射方式。
本发明的药学组合物的剂量可根据患者的状态及体重、疾病的程度、药物形态、给药途径及时间而不同,但本领域普通技术人员可适当选择。例如,本发明的药学组合物能够以1日0.0001mg/kg至1000mg/kg或0.001mg/kg至500mg/kg的剂量给药。本发明的药学组合物的给药可一日给药一次或一日给药数次。上述剂量在任何方面并不限定本发明的范围。
并且,本发明提供用于治疗耐药性癌症的由化学式1表示的化合物或其药学上可接受的盐的用途。
耐药性癌症、由化学式1表示的化合物或其药学上可接受的盐与如上所述的说明相同,因此,将省略具体说明。
并且,本发明提供癌症治疗方法,其包括向患有耐药性癌症的对象给药治疗有效量的如上所述的由化学式1表示的化合物或其药学上可接受的盐的步骤。
术语“给药”是指通过适当的方法向个体导入规定物质。
耐药性癌症、由化学式1表示的化合物或其药学上可接受的盐与如上所述的说明相同,因此,将省略具体说明。
“患有耐药性癌症的对象”是指耐药性癌症已发病或耐药性癌症的发病可能性高而需要适当的治疗的个体,虽然进行了抗癌疗法如外科切除疗法、利用抗癌剂的化学疗法、放射线疗法或免疫疗法,但由于对其具有耐性而复发的个体。
患有耐药性癌症的对象可包括人、牛、狗、豚鼠、兔、鸡或昆虫等。
并且,本发明提供放射线治疗方法,其包括:向患有耐药性癌症的对象给药如上所述的由化学式1表示的化合物或其药学上可接受的盐的步骤;以及照射放射线的步骤。
耐药性癌症、患有耐药性癌症的对象、由化学式1表示的化合物或其药学上可接受的盐与如上所述的说明相同,因此,将省略具体说明。
放射线照射可适用所有为了癌症的放射线治疗而以往所使用的任意放射线照射方法或之后研发的对于癌症的放射线照射方法。
在结合使用本发明的由化学式1表示的化合物或其药学上可接受的盐的给药和放射线照射的情况下,对于癌细胞或癌症干细胞的生长抑制和/或凋亡诱导赋予协同效应,不仅可有效地预防或治疗癌症,还可防止对于放射线的耐性或癌症的转移或癌症的复发。
以下,为了具体说明本发明,通过实施例详细说明。
制备例
1.制备例1-1:C101、L19031
经过以下记载的10个步骤反应制备了2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(C101)。在下述内容中具体说明各个步骤中的合成方法。
1)步骤1
[反应式1]
如反应式1,在四氢呋喃溶剂中,将苯并呋喃(1.0当量)冷却至-78℃,并添加2.5M的正丁基锂(1.2当量)溶液。在保持-78℃的同时搅拌1小时,滴注碘乙烷(2.0当量)后,在0℃下搅拌1小时。确认反应完成,并使用氯化铵水溶液和乙基乙酸盐结束反应。使用蒸馏水清洗有机层,利用无水硫酸镁干燥后进行减压浓缩。通过硅层析纯化残余物来获取2-乙基苯并呋喃。
2)步骤2
[反应式2]
将2-乙基苯并呋喃(1.0当量)投入至二氯甲烷(MC)后,冷却至0℃,保持0℃,依次投入氯化锡(IV)(1.5当量)、氯甲基甲醚(1.5当量)后,搅拌1小时。确认反应完成,并使用氯化铵水溶液和二氯甲烷结束反应。使用蒸馏水清洗有机层,利用无水硫酸镁干燥后进行减压浓缩。通过硅层析纯化残余物来获取2-乙基苯并呋喃-3-甲醛(2-ethylbenzofuran-3-carbaldehyde)。
3)步骤3
[反应式3]
添加哌嗪-2-羧酸(piperazine-2-carboxylic acid)(1.0当量)、二氧六环及蒸馏水,冷却至5℃以下。之后,将二碳酸二叔丁酯(di-tert-butyl dicarbonate)(1.1当量)保持10℃以下并投入。在室温条件下搅拌5小时后,投入碳酸钠(1.1当量)并搅拌5分钟。投入9-芴甲基氯甲酸酯(9-Fluorenylmethyl chloroformate)(1.2当量)并搅拌整夜后,进行减压浓缩。向残余物添加乙基乙酸盐和1M的盐酸,将pH值调节为2~3,强力搅拌残余物直至所有残余物溶解。使用盐水(brine)清洗有机层,利用无水硫酸镁干燥后进行减压浓缩。利用EA再结晶来获取白色固体粉末1-(((9H-芴-9-基)甲氧基)羰基)-4-(叔丁氧基羰基)哌嗪-2-羧酸(1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid)。
4)步骤4
[反应式4]
在氮气流下,将1-(((9H-芴-9-基)甲氧基)羰基)-4-(叔丁氧基羰基)哌嗪-2-羧酸、苯甲醇(1.02当量)和三苯基膦(1.02当量)的无水二氯甲烷溶液冷却至0℃。在保持0℃以下的同时投入偶氮二甲酸二乙酯(DEAD,Diethyl Azodicar boxylate)(1.02当量)并搅拌1小时。投入水并强力搅拌20分钟后,利用无水硫酸镁干燥有机层后,进行减压浓缩。通过硅层析纯化残余物来获取白色固体粉末1-((9H-芴-9-基)甲基)2-苄基4-(叔丁基)哌嗪-1,2,4-三羧酸盐(1-((9H-fluoren-9-yl)methyl)2-benzyl 4-(tert-butyl)piperazine-1,2,4-tricarboxylate)。
5)步骤5
[反应式5]
如反应式5,在室温条件下,向1-((9H-芴-9-基)甲基)2-苄基4-(叔丁基)哌嗪-1,2,4-三羧酸盐的二氯甲烷(5.0体积)溶液添加三氟乙酸(TFA)(2.0体积),在室温条件下搅拌30分钟。利用碳酸氢钠中和后,提取二氯甲烷,使用盐水(brine)清洗有机层。利用无水硫酸镁干燥并浓缩,由此获取1-((9H-芴-9-基)甲基)2-苄基哌嗪-1,2-二羧酸盐(1-((9H-fluoren-9-yl)methyl)2-benzyl piperazine-1,2-dicarboxylate)。
6)步骤6
[反应式6]
在室温条件下,将通过步骤2获取的2-乙基苯并呋喃-3-甲醛(1.0当量)和通过步骤5获取的1-((9H-芴-9-基)甲基)2-苄基哌嗪-1,2-二羧酸盐(1.2当量)投入至1,2-二氯乙烷(DCE)后,搅拌30分钟。添加三乙酰氧基硼氢化钠(3.0当量),在室温条件下搅拌整夜。向反应液添加二氯甲烷和水,并强力搅拌20分钟。使用盐水(brine)清洗所分离的有机层,利用无水硫酸镁进行干燥并浓缩,由此获取1-((9H-芴-9-基)甲基)2-苄基4-((2-乙基苯并呋喃-3-基)甲基)哌嗪-1,2-二羧酸盐(1-((9H-fluoren-9-yl)methyl)2-benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-1,2-dicarboxylate)。
7)步骤7
[反应式7]
在室温条件下,将1-((9H-芴-9-基)甲基)2-苄基4-((2-乙基苯并呋喃-3-基)甲基)哌嗪-1,2-二羧酸盐(1.0当量)溶解在二甲基甲酰胺后,投入哌啶(10当量,溶剂中的25%的哌啶)并搅拌1小时。在反应过程中,添加乙基乙酸盐后,使用氯化铵水溶液清洗溶液中的哌啶。利用无水硫酸镁干燥后进行减压浓缩,通过硅层析纯化所获取的残余物来获取4-((2-乙基苯并呋喃-3-基)甲基)哌嗪-2-羧酸苄酯(benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate)。
8)步骤8
[反应式8]
在室温条件下,利用二甲基甲酰胺溶解4-((2-乙基苯并呋喃-3-基)甲基)哌嗪-2-羧酸苄酯(1.0当量)、N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine)(1.1当量)以及(苯并三唑-1-酰氧基)六氟磷酸三吡咯烷膦铵((Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate)(1.2当量)后,添加N,N-二异丙基乙胺(1.5当量),并在室温条件下搅拌整夜。使用氯化铵水溶液和乙基乙酸盐结束反应。使用盐水(brine)清洗所获取的有机层后,利用无水硫酸镁干燥并减压浓缩。通过硅层析纯化残余物来获取1-((叔丁氧羰基)甘氨酸)-4-((2-乙基苯并呋喃-3-基)甲基)哌嗪-2-羧酸苄酯(benzyl1-((tert-butoxycarbonyl)glycyl)-4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate)。
9)步骤9
[反应式9]
如反应式9,在室温条件下,将通过步骤8获取的1-((叔丁氧羰基)甘氨酸)-4-((2-乙基苯并呋喃-3-基)甲基)哌嗪-2-羧酸苄酯溶解在二氯甲烷(5.0体积)后,添加三氟乙酸(2.0体积)并在室温条件下搅拌30分钟。反应完成后,利用碳酸氢钠水溶液中和反应液,并利用二氯甲烷提取。利用无水硫酸镁干燥并减压浓缩来获取4-((2-乙基苯并呋喃-3-基)甲基)-1-甘氨酰哌嗪-2-羧酸苄酯(benzyl4-((2-ethylbenzofuran-3-yl)methyl)-1-glycylpiperazine-2-carboxylate)。
10)步骤10
[反应式10]
将通过步骤9获取的4-((2-乙基苯并呋喃-3-基)甲基)-1-甘氨酰哌嗪-2-羧酸苄酯溶解在异丙醇(5.0体积)后,添加乙酸(1.5体积)并加热,搅拌1小时。反应完成后,利用碳酸氢钠水溶液中和。利用二氯甲烷提取反应物,并利用无水硫酸镁干燥。减压浓缩后,通过硅层析纯化残余物来获取2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(化学式2)。
[化学式2]
2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C101、L19031或候选1(candidate1)表达)。
1H-NMR(500MHz,CDCl3)δ7.58(d,J=7.0Hz,1H),7.40(d,J=7.5Hz,1H),7.24-7.17(m,2H),4.50(d,J=13.0Hz,1H),4.06(d,J=11.0Hz,1H),4.00(s,2H),3.64(dd,J=57.5,13.0Hz,1H),3.47(d,J=11.0Hz,1H),2.90(d,J=11.5Hz,1H),2.71-2.81(m,3H),2.11(t,J=11.5Hz,1H),2.07-2.01(m,1H),1.30(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ166.32,161.99,158.34,154.16,129.60,123.65,122.56,119.87,110.94,109.53,57.18,56.42,51.84,51.58,44.75,41.78,20.18,13.10;
C18H21N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)328.1656,实测值(found)328.1655.
2.制备例1-2:C101.HCl、L19001
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的最后使用盐酸来制备化学式3的盐酸盐。
[化学式3]
2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮盐酸盐(2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride)(由C101.HCl或L19001表达)。
3.制备例2:C102、L19002
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-L-丙氨酸(N-(tert-Butoxycarbonyl)-L-alanine)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),最后使用盐酸来制备化学式4的盐酸盐。
[化学式4]
2-((2-乙基苯并呋喃-3-基)甲基)-7-甲基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮盐酸盐(2-((2-ethylbenzofuran-3-yl)methyl)-7-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride)(由C102或L19002表达)。
1H-NMR(500MHz,CD3OD)δ7.78-7.72(m,1H),7.53-7.47(m,1H),7.36-7.29(m,2H),4.69(dd,J=21.3,12.3Hz,1H),4.60-4.46(m,3H),4.13(dq,J=13.8,6.8Hz,1H),3.99-3.91(m,1H),3.66(s,1H),3.20-3.02(m,3H),2.98(dq,J=7.5,2.0Hz,2H),1.46(t,J=7.5Hz,3H),1.38(t,J=7.5Hz,3H);
C19H23N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)342.1812,实测值(found)342.1813.
4.制备例3:C105、L19033
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-L-2-环己基甘氨酸(N-(tert-Butoxycarbonyl)-L-2-cyclohexylglycine)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),由此获取化学式5的化合物。
[化学式5]
7-环己基-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(7-cyclohexyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C105或L19033表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.40(d,J=7.5Hz,1H),7.23-7.17(m,2H),4.53(t,J=12.3Hz,1H),4.06(ddd,J=20.0,11.0,3.0Hz,1H),3.87(d,J=28.0Hz,1H),3.70(dd,J=13.0,5.5Hz,1H),3.58-3.49(m,2H),2.90(d,J=11.5Hz,1H),2.78(q,J=7.5Hz,2H),2.75-2.65(m,1H),2.15-1.93(m,4H),1.83-1.60(m,4H),1.48(dd,J=32.5,12.0Hz,1H),1.34-1.26(m 4H),1.28-1.04(m,3H);
13C-NMR(126MHz,CDCl3)δ167.02,166.42,165.05,163.54,158.33,158.27,154.16,129.62,129.57,128.75,127.80,127.19,123.64,123.63,122.54,119.90,119.87,110.91,109.63,109.57,60.34,59.95,57.52,57.09,56.57,56.50,51.98,51.89,51.78,51.54,43.67,42.11,41.95,41.52,29.49,29.30,26.78,26.56,26.53,26.39,26.08,25.98,25.87,20.16,13.11,13.10;
C24H31N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)410.2438,实测值(found)410.2442.
5.制备例4:C107、L19003
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-L-蛋氨酸(N-(tert-Butoxycarbonyl)-L-methionine)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),最后使用盐酸来制备化学式6的盐酸盐。
[化学式6]
2-((2-乙基苯并呋喃-3-基)甲基)-7-(2-(甲硫基)乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮盐酸盐(2-((2-ethylbenzofuran-3-yl)methyl)-7-(2-(methylthio)ethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride)(由C107或L19003表达).)。
1H-NMR(500MHz,CD3OD)δ7.80-7.76(m,1H),7.50-7.47(m,1H),7.34-7.30(m,2H),4.72-4.57(m,4H),4.25-4.21(m,1H),4.00(t,J=9.8Hz,1H),3.70(s,1H),3.41-3.32(m,1H),3.24-3.07(m,2H),3.00(dq,J=11.0,3.9Hz,2H),2.64-2.50(m,2H),2.28-2.18(m,1H),2.14-2.06(m,1H),2.00(d,J=22.5Hz,3H),1.38(dt,J=7.5,3.5Hz,3H);
C21H27N3O3S[M+H]+的MS(ESI)m/z:计算值(calcd)402.1846,实测值(found)402.1843.
6.制备例5:C108、L19004
通过与制备例1-1相同的方法合成,在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-S-苄基-L-半胱氨酸(N-(tert-Butoxycarbonyl)-S-benzyl-L-cysteine)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),最后使用盐酸来制备化学式7的盐酸盐。
[化学式7]
7-((苄硫基)甲基)-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮盐酸盐(7-((benzylthio)methyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride)(由C108或L19004表达)。
1H-NMR(500MHz,CD3OD)δ7.78-7.69(m,1H),7.49-7.46(m,1H),7.29-7.26(m,7H),4.70-4.64(m,1H),4.59(s,1H),4.53-4.39(m,2H),4.36-4.32(m,1H),3.94(d,J=10.5Hz,1H),3.71(d,J=2.5Hz,1H),3.51(dd,J=42.0,13.2Hz,2H),3.09(dd,J=14.5,4.0Hz,2H),3.03(dd,J=14.5,3.5Hz,1H),2.99-2.88(m,2H),2.80(ddd,J=35.5,14.5,3.8Hz,2H),1.36(dt,J=12.0,7.5Hz,3H);
C26H29N3O3S[M+H]+的MS(ESI)m/z:计算值(calcd)464.2002,实测值(found)464.2001.
7.制备例6:C109、L19035
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-L-脯氨酸(N-(tert-Butoxycarbonyl)-L-proline)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),由此获取化学式8的化合物。
[化学式8]
2-((2-乙基苯并呋喃-3-基)甲基)八氢-6H-吡嗪并[1,2-a]吡咯并[1,2-d]吡嗪-6,11(2H)-二酮(2-((2-ethylbenzofuran-3-yl)methyl)octahydro-6H-pyrazino[1,2-a]pyrrolo[1,2-d]pyrazine-6,11(2H)-dione)(由C109或L19035表达)。
1H-NMR(500MHz,CDCl3)δ7.58(dd,J=13.0,7.5Hz,1H),7.39(d,J=8.0Hz,1H),7.24-7.15(m,2H),4.45(dd,J=59.0,13.0Hz,1H),4.13-3.98(m,2H),3.81-3.66(m,2H),3.62-3.37(m,3H),2.96-2.71(m,4H),2.48-2.40(m,1H),2.15-1.82(m,5H),1.30(dt,J=16.0,8.0Hz,3H);
13C-NMR(126MHz,CDCl3)δ167.19,164.43,163.30,162.81,158.31,158.30,154.16,154.13,129.66,129.62,123.63,123.56,122.58,122.48,119.97,119.85,110.90,110.87,109.75,109.49,61.16,59.10,58.76,57.14,56.28,55.82,52.01,51.91,51.67,51.43,45.51,45.42,42.04,41.75,31.82,30.15,29.96,22.89,22.07,21.92,20.19,20.17,14.37,13.10;
C21H25N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)368.1969,实测值(found)368.1974.
8.制备例7-1:C111、L19037
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-L-苯丙氨酸(N-(tert-Butoxycarbonyl)-L-phenylalanine)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),由此制备化学式9的化合物。
[化学式9]
7-苄基-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(7-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C111或L19037表达)。
1H-NMR(500MHz,CDCl3)δ7.49(dd,J=12.5,7.5Hz,1H),7.40(dd,J=8.0,5.0Hz,1H),7.34-7.16(m,7H),4.46(dd,J=39.5,13.0Hz,1H),4.34(d,J=26.5Hz,1H),3.83(dd,J=10.5,2.5Hz,0.5H),3.55(dd,J=62.5,13.5Hz,1H),3.39(s,1H),3.35(dd,J=13.5,4.0Hz,0.5H),3.30-3.21(m,1H),3.04(dd,J=13.5,4.0Hz,0.5H),2.97(dd,J=13.5,4.0Hz,1H),2.86-2.79(m,1H),2.76-2.69(m,3H),2.59(dd,J=12.5,3.0Hz,0.5H),2.44(dd,J=12.5,3.5Hz,0.5H),1.97-1.90(m,1H),1.69(dd,J=12.0,3.0Hz,0.5H),1.28(dt,J=7.5,7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ167.02,166.39,164.80,162.84,158.28,158.19,154.13,135.21,135.03,131.16,130.32,129.69,129.63,128.89,128.79,127.89,127.52,123.63,123.59,122.53,122.48,119.88,119.82,110.90,110.88,109.58,109.43,57.62,56.35,56.12,55.96,55.91,55.32,51.77,51.40,51.34,51.30,41.08,41.4,40.73,20.16,20.10,13.10,13.07;
C25H27N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)418.2125,实测值(found)418.2129.
9.制备例7-2:C111.HCl、L19005
通过与制备例7-1相同的方法合成,并且在如上所述的制备例7-1的最后使用盐酸来制备化学式10的盐酸盐。
[化学式10]
7-苄基-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮盐酸盐(7-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride)(由C111.HCl或L19005表达)。
10.制备例8:C121、L19006
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-3-(1-萘基)-D-丙氨酸(N-(tert-Butoxycarbonyl)-3-(1-naphthyl)-D-alanine)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),最后使用盐酸来制备化学式11的盐酸盐。
[化学式11]
2-((2-乙基苯并呋喃-3-基)甲基)-7-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮盐酸盐
(2-((2-ethylbenzofuran-3-yl)methyl)-7-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride)(由C121或L19006表达)。
1H-NMR(500MHz,CD3OD)δ8.07(dd,J=18.8,8.5Hz,1H),7.84(dd,J=12.8,8.0Hz,1H),7.64-7.21(m,9H),4.59(s,1H),4.50-4.43(m,1H),4.40(d,J=14.0Hz,0.5H),4.23(bs,1H),4.18(d,J=14Hz,0.5H),4.02(d,J=11.5Hz,0.5H),3.90(dd,J=14.0,3.0Hz,0.5H),3.81(bs,1H),3.74(dd,J=14.0,4.0Hz,0.5H),3.54-3.49(m,1H),3.36-3.20(m,1H),3.09(dd,J=29.0,11.5Hz,1H),2.86-2.70(m,3.5H),2.57(d,J=11.0Hz,0.5H),2.17-2.08(m,0.5H),1.31(dt,J=17.5,7.5Hz,3H);
C29H29N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)468.2282,实测值(found)468.2284.
11.制备例9:C122、L19007
通过与制备例1-1相同的方法合成,并且在如上所述的制备例1-1的步骤8中,使用N-(叔丁氧羰基)-3-(2-萘基)-D-丙氨酸(N-(tert-Butoxycarbonyl)-3-(2-naphthyl)-D-alanine)代替作为反应物质的N-(叔丁氧羰基)甘氨酸(N-(tert-Butoxycarbonyl)glycine),最后使用盐酸来制备化学式12的盐酸盐。
[化学式12]
2-((2-ethylbenzofuran-3-yl)methyl)-7-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione hydrochloride(由C122或L19007表达).
1H-NMR(500MHz,CD3OD)δ8.00-7.15(m,11H),4.64(d,J=15.0Hz,1H),4.59(s,1H),4.52-4.45(m,1H),4.42(s,1H),4.19(d,J=10.5Hz,0.5H),3.65-3.33(m,3.5H),3.27(d,J=11Hz,0.5H),3.19-3.06(m,2H),2.96-2.82(m,2H),2.64-2.52(m,1.5H),2.14(dt,J=12.5,3.0Hz,0.5H),2.14(dt,J=12.5,3.0Hz,0.5H)1.27(dt,J=27.0,7.5Hz,3H);
C29H29N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)468.2282,实测值(found)468.2283.
12.制备例10:C201、L19008
将在制备例1-1中获取的化合物(化学式2)用作起始物质,进一步进行下述反应式11的步骤来获取化学式13的化合物。
[反应式11]
在常温条件下,添加2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[l,2-a]pyrazine-6,9-dione)和氢化钠(2.0当量)、二甲基甲酰胺并搅拌1小时后,添加碘甲烷并在室温条件下搅拌整夜。通过薄层色谱法(TLC)确认反应后,利用氯化铵水溶液和乙基乙酸盐结束反应。使用水溶液清洗有机层后,利用无水硫酸镁干燥并减压浓缩。通过硅层析纯化残余物来获取2-((2-乙基苯并呋喃-3-基)甲基)-8-甲基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)-8-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)。
[化学式13]
2-((2-乙基苯并呋喃-3-基)甲基)-8-甲基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮
2-((2-ethylbenzofuran-3-yl)methyl)-8-methylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione(由C201或L19008表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.0Hz,1H),7.40(d,J=7.5Hz,1H),7.25-7.16(m,2H),4.49(d,J=13.0Hz,1H),4.09-4.03(m,1H),3.97-3.96(m,2H),3.78-3.50(m,3H),2.95(s,3H),2.89(d,J=11.5Hz,1H),2.80-2.70(m,3H),2.11-1.99(m,2H),1.30(t,J=7.5Hz,3H);13C-NMR(126MHz,CDCl3)δ163.73,161.65,158.36,154.15,129.62,123.62,122.56,119.88,110.91,109.49,57.45,56.85,51.76,51.43,51.40,41.56,33.62,20.18,13.08;
C19H23N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)342.1812,实测值(found)342.1802.
13.制备例11:C202、L19009
通过与制备例10相同的方法合成,并且使用碘乙烷代替作为反应物质的碘甲烷,由此获取化学式14的化合物。
[化学式14]
8-乙基-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-ethyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C202或L19009表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.40(d,J=7.5Hz,1H),7.23-7.16(m,2H),4.48(d,J=13.0Hz,1H),4.07-4.03(m,1H),4.01-3.91(m,2H),3.72(d,J=13.5Hz,1H),3.59-3.52(m 2H),3.50-3.35(m,2H),2.88(d,J=11.5Hz,1H),2.81-2.70(m,3H),2.08(t,J=11.5Hz,1H),2.02(dt,J=11.5,3.0Hz,1H),1.30(t,J=7.5Hz,3H),1.15(t,J=7.3Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.20,162.05,158.29,154.15,129.63,123.60,122.53,119.90,110.89,109.60,57.54,56.89,51.81,51.39,48.81,41.59,41.12,20.18,13.08,11.83;
C20H25N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)356.1969,实测值(found)356.1955.
14.制备例12:C203、L19010
通过与制备例10相同的方法合成,并且使用丁基溴代替作为反应物质的碘甲烷来获取化学式15的化合物。
[化学式15]
8-丁基-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮
(8-butyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C203或L19010表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.39(d,J=8.0Hz,1H),7.24-7.16(m,2H),4.48(d,J=13.0Hz,1H),4.06(d,J=11.0Hz,1H),3.95(d,J=4.5Hz,2H),3.72(d,J=13.0Hz,1H),3.60-3.52(m,2H),3.37(t,J=7.5Hz,2H),2.88(d,J=11.5Hz,1H),2.80-2.69(m,3H),2.07(t,J=11.5Hz,1H),2.02(dt,J=11.5,3.3Hz,1H),1.57-1.49(m,2H),1.36-1.28(m,5H),0.93(t,J=7.3Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.43,162.09,158.28,154.15,129.63,123.59,122.52,119.90,110.88,109.59,57.52,56.94,51.80,51.38,49.34,45.97,41.59,28.63,20.17,20.12,13.95,13.07;
C22H29N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)384.2282,实测值(found)384.2260.
15.制备例13:C204、L19011
通过与制备例10相同的方法合成,并且使用己基溴代替作为反应物质的碘甲烷来获取化学式16的化合物。
[化学式16]
2-((2-乙基苯并呋喃-3-基)甲基)-8-己基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮
(2-((2-ethylbenzofuran-3-yl)methyl)-8-hexylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C204或L19011表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.40(d,J=8.0Hz,1H),7.24-7.16(m,2H),4.48(d,J=13.0Hz,1H),4.06(d,J=11.0Hz,1H),3.96(d,J=5.0Hz,2H),3.72(d,J=13.5Hz,1H),3.59-3.52(m,2H),3.37(dd,J=8.8,6.8Hz,2H),2.88(d,J=11.0Hz,1H),2.81-2.70(m,3H),2.07(t,J=11.0Hz,1H),2.02(dd,J=3.5,11.5,Hz,1H),1.57-1.50(m,2H),1.32-1.26(t,J=6.1Hz,9H),0.88(t,J=7.0Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.41,162.11,158.30,154.16,129.63,123.60,122.53,119.89,110.89,109.58,57.53,56.95,51.81,51.38,49.36,46.25,41.60,31.63,26.55,26.52,22.73,20.17,14.22,13.07;
C24H33N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)412.2595,实测值(found)412.2566.
16.制备例14:C206、L19012
通过与制备例10相同的方法合成,并且使用苄基溴代替作为反应物质的碘甲烷来获取化学式17的化合物。
[化学式17]
8-苄基-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮
(8-benzyl-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C206或L19012表达)。
1H-NMR(500MHz,CDCl3)δ7.60(d,J=7.0Hz,1H),7.40(d,J=7.5Hz,1H),7.36-7.29(m,3H),7.26-7.17(m,4H),4.57(q,J=14.5Hz,2H),4.46(d,J=13.0Hz,1H),4.13(d,J=11.0Hz,1H),3.85(s,2H),3.73(d,J=13.5Hz,1H),3.62-3.56(m,2H),2.89-2.85(m,1H),2.78(q,J=7.5Hz,2H),2.73(dd,J=12.5,3.5Hz,1H),2.12(t,J=11.0Hz,1H),2.02(dd,J=11.5,3.5Hz,1H),1.30(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.69,161.91,158.31,154.18,135.15,129.63,129.18,128.72,128.44,123.63,122.55,119.90,110.93,109.59,57.61,56.97,51.82,51.37,49.55,48.77,41.61,20.20,13.10;
C25H27N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)418.2153,实测值(found)418.2093.
17.制备例15:C207、L19013
通过与制备例10相同的方法合成,并且使用4-甲基溴苄代替作为反应物质的碘甲烷来获取化学式18的化合物。
[化学式18]
2-((2-乙基苯并呋喃-3-基)甲基)-8-(4-甲基苄基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-methylbenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C207或L19013表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.40(d,J=8.0Hz,1H),7.26-7.17(m,2H),7.14(s,4H),4.52(dd,J=32.5,14.0Hz,2H),4.45(d,J=13.5Hz,1H),4.12(dd,J=10.5,2.5Hz,1H),3.84(s,2H),3.73(d,J=13.5Hz,1H),3.61-3.56(m,2H),2.89-2.85(m,1H),2.78(q,J=7.5Hz,2H),2.72(dt,J=12.5,3.0Hz,1H),2.33(s,3H),2.20(d,J=11.5Hz,1H),2.01(dt,J=11.5,3.0Hz,1H),1.30(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.60,161.97,158.30,154.18,138.24,132.11,129.83,129.64,128.77,123.63,122.55,119.90,110.92,109.60,57.62,56.97,51.82,51.37,49.28,48.66,41.59,21.36,20.19,13.10;
C26H29N3O3S[M+H]+的MS(ESI)m/z:计算值(calcd)432.2282,实测值(found)432.2240.
18.制备例16:C208、L19014
通过与制备例10相同的方法合成,并且使用4-氯溴苄代替作为反应物质的碘甲烷来获取化学式19的化合物。
[化学式19]
8-(4-氯苄基)-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(4-chlorobenzyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C208或L19014表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.0Hz,1H),7.40(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,2H),7.25-7.17(m,4H),4.52(dd,J=23.5,14.5Hz,2H),4.46(d,J=13.0Hz,1H),4.12(dd,J=11.0,3.0Hz,1H),3.84(d,J=2.0Hz,2H),3.73(d,J=13.5Hz,1H),3.61-3.56(m,2H),2.88(d,J=11.5Hz,1H),2.81-2.70(m,3H),2.10(t,J=11.0Hz,1H),2.02(td,J=11.5,3.5Hz,1H),1.31(t,J=8.0Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.78,161.69,158.32,154.18,134.41,133.73,130.09,129.61,129.37,123.65,122.55,119.88,110.94,109.54,57.56,56.89,51.81,51.35,48.96,48.82,41.64,20.19,13.10;
C25H26ClN3O3[M+H]+的MS(ESI)m/z:计算值(calcd)452.1736,实测值(found)452.1688.
19.制备例17:C209、L19015
通过与制备例10相同的方法合成,并且使用对溴溴苄代替作为反应物质的碘甲烷来获取化学式20的化合物。
[化学式20]
8-(4-溴苄基)-2-((2-乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(4-bromobenzyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C209或L19015表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.46(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,1H),7.25-7.17(m,2H),7.13(d,J=8.5Hz,2H),4.55-4.43(m,3H),4.12(d,J=10.0Hz,1H),3.84(s,2H),3.73(d,J=13.0Hz,1H),3.61-3.55(m,2H),2.88(d,J=10.5Hz,1H),2.81-2.69(m,3H),2.10(t,J=11.0Hz,1H),2.02(dt,J=11.5,3.0Hz 1H),1.31(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.79,161.67,158.32,154.18,134.24,132.33,130.41,129.61,123.65,122.55,122.52,119.88,110.94,109.54,57.55,56.89,51.81,51.35,49.03,48.84,41.64,20.19,13.10;
C25H26BrN3O3[M+H]+的MS(ESI)m/z:计算值(calcd)496.1230,实测值(found)496.1192.
20.制备例18:C210、L19016
通过与制备例10相同的方法合成,并且使用4-氟溴苄代替作为反应物质的碘甲烷来获取化学式21的化合物。
[化学式21]
2-((2-乙基苯并呋喃-3-基)甲基)-8-(4-氟苄基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-fluorobenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C210或L19016表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.40(d,J=8.0Hz,1H),7.25-7.17(m,4H),7.02(t,J=8.5Hz,2H),4.53(dd,J=32.5,14.5Hz,2H),4.46(d,J=13.0Hz,1H),4.12(dd,J=11.0,3.0Hz,1H),3.85(s,2H),3.73(d,J=13.5Hz,1H),3.59(m,2H),2.88(d,J=11.5Hz,1H),2.81-2.70(m,3H),2.11(t,J=11.5Hz,1H),2.02(dt,J=11.5,3.5Hz,1H),1.30(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.72,161.75,158.31,154.18,131.07,131.04,130.56,130.50,129.62,123.64,122.55,119.89,116.20,116.03,110.93,109.56,57.58,56.91,51.82,51.36,48.87,48.74,41.62,20.19,13.10;
C25H26FN3O3[M+H]+的MS(ESI)m/z:计算值(calcd)436.2031,实测值(found)436.1994.
21.制备例19:C211、L19017
通过与制备例10相同的方法合成,并且使用4-三氟甲基苄溴代替作为反应物质的碘甲烷来获取化学式22的化合物。
[化学式22]
2-((2-乙基苯并呋喃-3-基)甲基)-8-(4-(三氟甲基)苄基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-(trifluoromethyl)benzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C211或L19017表达)。
1H-NMR(500MHz,CDCl3)δ7.62-7.58(m,3H),7.41(d,J=7.5Hz,1H),7.37(d,J=8.0Hz,2H),7.26-7.19(m,2H),4.62(s,2H),4.47(d,J=13.5Hz,1H),4.15(dd,J=11.0,3.0Hz,1H),3.87(d,J=4.0Hz,2H),3.73(d,J=13.0Hz,1H),3.62-3.57(m,2H),2.90(d,J=11.5Hz,1H),2.82-2.71(m,3H),2.12(t,J=11.0Hz,1H),2.03(dt,J=11.5,3.5Hz,1H),1.31(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.93,161.55,158.34,154.18,139.28,129.60,128.92,126.21,126.18,126.15,126.12,123.66,122.56,119.87,110.95,109.52,57.55,56.88,51.81,51.35,49.20,49.03,41.67,20.19,13.08;
C26H26F3N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)486.1999,实测值(found)486.1958.
22.制备例20:C212、L19018
通过与制备例10相同的方法合成,并且使用对氰基溴化苄代替作为反应物质的碘甲烷来获取化学式23的化合物。
[化学式23]
4-((8-((2-乙基苯并呋喃-3-基)甲基)-1,4-二氧八氢-2H-吡嗪并[1,2-a]吡嗪-2-基)甲基)苄腈(4-((8-((2-ethylbenzofuran-3-yl)methyl)-1,4-dioxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)methyl)benzonitrile)((由C212或L19018表达)。
1H-NMR(500MHz,CDCl3)δ7.64(d,J=8.5Hz,2H),7.59(d,J=7.5Hz,1H),7.40(d,J=8.0Hz,1H),7.36(d,J=8.5Hz,2H),7.30(dt,J=8.0,1.5Hz,1H),7.19(dt,J=7.5,1.5Hz,1H),4.61(s,2H),4.47(d,J=13.5Hz,1H),4.15(dd,J=11.0,3.0Hz,1H),3.88(d,J=5.5Hz,2H),3.73(d,J=13.5Hz,1H),3.63-3.56(m,2H),2.90(d,J=12.0Hz,1H),2.81-2.72(m,3H),2.12(t,J=11.5Hz,1H),2.04(dt,J=12.0,3.5Hz,1H),1.31(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ164.05,161.42,158.33,154.17,140.63,132.98,129.59,129.16,123.66,122.55,119.85,118.57,112.43,110.95,109.48,57.50,56.81,51.80,51.34,49.33,49.20,41.70,20.19,13.09;
C26H26N4O3[M+H]+的MS(ESI)m/z:计算值(calcd)443.2078,实测值(found)443.2043.
23.制备例21:C213、L19019
通过与制备例10相同的方法合成,并且使用对硝基溴化苄代替作为反应物质的碘甲烷来获取化学式24的化合物。
[化学式24]
2-((2-乙基苯并呋喃-3-基)甲基)-8-(4-硝基苄基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-nitrobenzyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C213或L19019表达)。
1H-NMR(500MHz,CDCl3)δ8.20(d,J=8.5Hz,2H),7.59(d,J=7.5Hz,1H),7.42(d,J=8.5Hz,2H),7.40(d,J=7.5Hz,1H),7.26-7.17(m,2H),4.67(s,2H),4.47(d,J=13.0Hz,1H),4.17(dd,J=11.0,3.0Hz,1H),3.90(d,J=5.5Hz,2H),3.74(d,J=13.0Hz,1H),3.63-3.56(m,2H),2.91(d,J=11.5Hz,1H),2.82-2.73(m,3H),2.13(t,J=11.0Hz,1H),2.04(dd,J=11.5,3.0Hz,1H),1.31(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ164.10,161.37,158.35,154.18,148.02,142.61,129.59,129.30,124.40,123.67,122.56,119.85,110.96,109.47,57.50,56.81,51.80,51.34,49.26,49.11,41.71,20.19,13.09;
C25H26N4O5[M+H]+的MS(ESI)m/z:计算值(calcd)463.1976,实测值(found)463.1939.
23.制备例22:C214、L19020
通过与制备例10相同的方法合成,并且使用4-溴甲基联苯代替作为反应物质的碘甲烷来获取化学式25的化合物。
[化学式25]
8-([1,1'-联苯]-4-基甲基)-2-((2-乙基苯并呋喃-3-基)甲基)六氢2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-([1,1'-biphenyl]-4-ylmethyl)-2-((2-ethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C214或L19020表达)。
1H-NMR(500MHz,CDCl3)δ7.61-7.54(m,5H),7.46-7.39(m,3H),7.37-7.31(m,3H),7.24-7.17(m,2H),4.60(q,J=14.5Hz,2H),4.46(d,J=13.0Hz,1H),4.14(,J=11.0Hz,1H),3.90(s,2H),3.73(d,J=13.5Hz,1H),3.63-3.57(m,2H),2.88(d,J=12.0Hz,1H),2.81-2.70(m,3H),2.14(t,J=11.0Hz,1H),2.02(dt,J=12.0,3.5Hz,1H),1.31(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.73,161.91,158.33,154.19,141.46,140.70,134.13,129.65,129.23,129.08,127.93,127.76,127.33,123.65,122.57,119.92,110.94,109.59,57.63,56.97,51.84,51.38,49.29,48.84,41.63,20.21,13.13;
C31H31N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)494.2438,实测值(found)494.2394.
24.制备例23:C215、L19021
通过与制备例10相同的方法合成,并且使用苯乙基溴代替作为反应物质的碘甲烷来获取化学式26的化合物。
[化学式26]
2-((2-乙基苯并呋喃-3-基)甲基)-8-苯乙基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)-8-phenethylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C215或L19021表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.0Hz,1H),7.40(d,J=8.0Hz,1H),7.31-7.16(m,7H),4.44(d,J=13.0Hz,1H),4.02(dd,J=11.0,3.5Hz,1H),3.78(d,J=7.0Hz,2H),3.70(d,J=13.5Hz,1H),3.65-3.54(m,3H),3.51(d,J=11.0Hz,1H),2.91-2.85(m,3H),2.78(q,J=7.5Hz,2H),2.71(dt,J=12.5,3.0Hz,1H),2.03-1.95(m,2H),1.30(t,J=7.5Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.53,161.89,158.30,154.17,138.14,129.64,128.97,128.94,127.06,123.63,122.55,119.91,110.92,109.59,57.48,56.86,51.82,51.41,50.13,48.14,41.60,33.08,20.19,13.12;
C26H29N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)432.2282,实测值(found)432.2239.
25.制备例24:C216、L19022
通过与制备例10相同的方法合成,并且使用4-氟溴乙基苯(4-fluorophenethylbromide)代替作为反应物质的碘甲烷来获取化学式27的化合物。
[化学式27]
2-((2-乙基苯并呋喃-3-基)甲基)-8-(4-氟苯乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-ethylbenzofuran-3-yl)methyl)-8-(4-fluorophenethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C216或L19022表达)。
1H-NMR(500MHz,CDCl3)δ7.58(d,J=7.0Hz,1H),7.39(d,J=8.0Hz,1H),7.23-7.17(m,2H),7.17-7.12(m,2H),6.97(t,J=8.5Hz,2H),4.44(d,J=13.0Hz,1H),4.01(dd,J=11.0,3.0Hz,1H),3.82(d,J=6.0,2H),3.69(d,J=13.5Hz,1H),3.63-3.47(m,4H),2.88-2.83(m,3H),2.79-2.70(m,3H),2.01-1.95(m,2H),1.29(t,J=7.8Hz,3H);
13C-NMR(126MHz,CDCl3)δ163.57,161.78,158.32,154.16,133.74,133.72,130.41,130.34,129.62,123.63,122.54,119.89,115.88,115.71,110.92,109.55,57.45,56.82,51.80,51.41,50.00,47.95,41.61,32.20,20.18,13.10;
C26H28FN3O3[M+H]+的MS(ESI)m/z:计算值(calcd)450.2188,实测值(found)450.2155.
26.制备例25:C302、L19023
通过与制备例1-1相同的方法合成,并且使用碘甲烷代替作为在步骤1(反应式1)中的反应物质的碘乙烷来获取化学式28的化合物。
[化学式28]
2-((2-甲基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-methylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C302或L19023表达)。
1H-NMR(500MHz,CDCl3)δ7.57(d,J=7.0Hz,1H),7.39(d,J=7.8Hz,1H),7.24-7.17(m,2H),4.50(d,J=13.5Hz,1H),4.06(d,J=11.0Hz,1H),4.00(s,2H),3.64(dd,J=52.0,13.5Hz,2H),3.46(d,J=11.5Hz,1H),2.90(d,J=11.5Hz,1H),2.75(td,J=12.5,3.0Hz,1H),2.42(s,3H),2.12(t,J=11.5Hz,1H),2.06-2.02(td,J=11.5,3.0Hz,1H);
13C-NMR(126MHz,CDCl3)δ166.24,161.97,154.13,153.42,129.60,123.64,122.61,119.68,110.83,110.45,57.17,56.34,51.95,51.60,44.76,41.75,12.48;
C17H19N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)314.1499,实测值(found)314.1508.
27.制备例26:C303、L19024
通过与制备例1-1相同的方法合成,并且购买2-丁基苯并呋喃代替在步骤1(反应式1)中所生成的2-乙基苯并呋喃来进行反应,由此获取化学式29的化合物。
[化学式29]
2-((2-丁基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-butylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C303或L19024表达)。
1H NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.39(d,J=8.0Hz,1H),7.24-7.16(m,2H),4.50(d,J=13.0Hz,1H),4.07(d,J=11.0Hz,1H),4.00(s,2H),3.65(dd,J=66.0,13.5Hz,2H),3.47(d,J=11.5Hz,1H),2.89(d,J=11.5Hz,1H),2.77-2.71(m,3H),2.12(t,J=11.0Hz,1H),2.03(td,J=11.5,3.0Hz,1H),1.74-1.67(m,2H),1.42-1.33(m,2H),0.94(t,J=7.4Hz,3H);
13C-NMR(126MHz,CDCl3)δ166.35,161.98,157.33,154.18,129.57,123.61,122.52,119.88,110.92,110.24,57.20,56.51,51.96,51.56,44.76,41.79,30.60,26.44,22.63,14.10;
C20H25N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)356.1969,实测值(found)356.1979.
28.制备例27:C304、L19025
通过与制备例1-1相同的方法合成,并且使用己基溴代替在步骤1(反应式1)中作为反应物质的碘乙烷来获取化学式30的化合物。
[化学式30]
2-((2-己基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-hexylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C304或L19025表达)。
1H NMR(500MHz,CDCl3)δ7.59(d,J=7.0Hz,1H),7.39(d,J=8.0Hz,1H),7.24-7.16(m,2H),4.65(s,1H),4.47(d,J=13.5Hz,1H),4.04(d,J=11.0Hz,1H),3.96(s,2H),3.64(dd,J=70.0,13.0Hz,2H),3.46(d,J=11.5Hz,1H),2.88(d,J=11.5Hz,1H),2.76-2.72(m,3H),2.10(d,J=11.0Hz,1H),2.01(td,J=11.5,3.0Hz,1H),1.75-1.66(m,2H),1.37-1.28(m,5H),0.88(t,J=7.0Hz,3H);
13C-NMR(126MHz,CDCl3)δ166.27,162.03,157.39,154.18,129.59,123.62,122.53,119.88,110.93,110.20,57.18,56.51,51.94,51.52,44.72,41.78,31.79,29.23,28.48,26.75,22.79,14.32;
C22H29N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)384.2282,实测值(found)384.2292.
29.制备例28:C306、L19026
通过与制备例1-1相同的方法合成,并使用苄基溴代替在步骤1(反应式1)中作为反应物质的碘乙烷来获取化学式31的化合物。
[化学式31]
2-((2-苄基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-benzylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C306或L19026表达)。
1H-NMR(500MHz,CDCl3)δ7.64(d,J=7.0Hz,1H),7.41(d,J=8.0Hz,2H),7.31-7.19(m,6H),4.47(d,J=13.0Hz,1H),4.14(s,2H),4.05(d,J=11.0Hz,1H),4.01(s,2H),3.69(dd,J=73.0,13.5Hz,2H),3.49(d,J=11.0Hz,1H),2.87(d,J=11.5Hz,1H),2.70(dt,J=12.5,3.0Hz,1H),2.13(t,J=11.5Hz,1H),2.00(dt,J=11.5,3.0Hz,1H);
13C-NMR(126MHz,CDCl3)δ166.27,162.01,154.96,154.40,137.71,129.45,128.86,128.79,126.93,124.06,122.73,120.07,111.55,111.23,57.16,56.58,51.92,51.58,44.77,41.73,33.09;
C23H23N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)390.1812,实测值(found)390.1820.
30.制备例29:C308、L19027
通过与制备例1-1相同的方法合成,并使用4-氯溴苄代替在步骤1(反应式1)中作为反应物质的碘乙烷来获取化学式32的化合物。
[化学式32]
2-((2-(4-氯苄基)苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-(4-chlorobenzyl)benzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C308或L19027表达)。
1H-NMR(500MHz,CDCl3)δ7.62(d,J=7.5Hz,1H),7.40(d,J=8.0Hz,1H),7.26-7.15(m,6H),4.48(d,J=13.0Hz,1H),4.09(s,2H),4.05-4.00(m,3H),3.69(dd,J=58.0,13.5Hz,2H),3.46(d,J=11.0Hz,1H),2.87(d,J=11.5Hz,1H),2.70(dt,J=12.5,3.0Hz,1H),2.09(t,J=11.0Hz,1H),2.02(dt,J=11.5,3.0Hz,1H);
13C-NMR(126MHz,CDCl3)δ166.01,161.93,154.40,154.29,136.14,132.75,130.12,129.30,128.96,124.23,122.83,120.07,111.75,111.24,57.12,56.48,51.88,51.69,44.80,41.73,32.43;
C23H22ClN3O3[M+H]+的MS(ESI)m/z:计算值(calcd)424.1423,实测值(found)424.1423.
31.制备例30:C310、L19028
通过与制备例1-1相同的方法合成,并且使用对氟溴苄代替在步骤1(反应式1)中作为反应物质的碘乙烷来获取化学式33的化合物。
[化学式33]
2-((2-(4-氟苄基)苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-(4-fluorobenzyl)benzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C310或L19028表达)。
1H-NMR(500MHz,CDCl3)δ7.65-7.61(m,2H),7.38(d,J=7.5Hz,1H),7.25-7.18(m,3H),6.97(t,J=8.5Hz,2H),4.47(d,J=13.0Hz,1H),4.10(s,2H),4.02(d,J=11.0Hz,1H)3.97(s,2H),3.69(dd,J=50.5,13.5Hz,2H),3.47(d,J=10.5Hz,1H),2.88(d,J=11.0Hz,1H),2.74-2.67(m,1H),2.10(t,J=11.5Hz,1H),2.032.06-2.00(m,1H);
13C-NMR(126MHz,CDCl3)δ165.41,162.72,162.33,160.77,154.50,154.25,133.36,133.34,130.22,130.15,129.28,124.01,122.68,120.06,115.59,115.43,111.60,111.03,57.08,56.42,51.79,51.68,44.65,41.55,32.13;
C23H22FN3O3[M+H]+的MS(ESI)m/z:计算值(calcd)4 08.1718,实测值(found)408.1723.
32.制备例31:C315、L19030
通过与制备例1-1相同的方法合成,并且使用苯乙基溴代替在步骤1(反应式1)中作为反应物质的碘乙烷来获取化学式34的化合物。
[化学式34]
2-((2-苯乙基苯并呋喃-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-phenethylbenzofuran-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(由C315或L19030表达)。
1H-NMR(500MHz,CDCl3)δ7.59(d,J=7.5Hz,1H),7.46(d,J=8.0Hz,1H),7.28-7.24(m,3H),7.23-7.18(m,2H),7.15(d,J=7.0Hz,2H),4.41(d,J=11.5Hz,1H),4.04(d,J=11.0Hz,1H),4.00(s,2H),3.45(dd,J=84.0,13.5Hz,2H),3.42(d,J=11.0Hz,1H),3.03-3.09(m,4H),2.69-2.63(m,2H),2.04(t,J=11.0Hz,1H),1.87-1.80(m,1H);
13C-NMR(126MHz,CDCl3)δ166.24,161.90,155.71,154.27,141.08,129.43,128.72,128.70,126.49,123.84,122.62,120.06,111.15,110.98,57.17,56.49,51.75,51.27,44.77,41.74,34.57,29.10;
C24H25N3O3[M+H]+的MS(ESI)m/z:计算值(calcd)404.1969,实测值(found)404.1972.
将通过如上所述的制备例合成的化学式2至化学式34的化合物结构在下述表2中示出。
[表2]
实验例
1.制备例1-1的化合物的抗癌治疗活性增强效果
1-1.紫杉醇活性增强效果
1-1-1.对于癌细胞的活性增强效果
对于来源于服用紫杉醇后复发及转移的患者的癌症干细胞性甲状腺癌细胞(ATC),进行制备例1-1的化合物(150nM)单独处理、紫杉醇(12nM)单独处理、或者紫杉醇(5nM)与制备例1-1的化合物(70nM)的复方剂处理后,确认了根据处理时间的细胞数的变化。并且,将根据紫杉醇、制备例1-1的化合物以及紫杉醇与制备例1-1的化合物复方剂的处理浓度的细胞存活率的变化在图1中示出。并且,测定根据上述紫杉醇、制备例1-1的化合物以及它们的复方剂的处理浓度的细胞存活率的变化,并将其结果在图2中示出。
如图1及图2所示,在向抗癌剂耐性甲状腺癌细胞单独处理紫杉醇的情况下,与阴性对照组相比,并没有癌细胞数及癌细胞的存活率的变化,但在将制备例1-1的化合物与紫杉醇一同处理的情况下,可确认到干细胞性甲状腺癌细胞的细胞数和细胞存活率显著减少。
1-1-2.癌细胞移植小鼠的肿瘤大小变化的分析
在体外培养来源于服用紫杉醇后复发及转移的患者的癌症干细胞性甲状腺癌细胞后,向BALB/c裸雌小鼠的左上侧肋下的皮下注入所培养的细胞,至达到2.0×107细胞/小鼠。7日后,以每10只分组后,向各个组口服给药单独的制备例1-1的化合物(60mg/kg)、腹腔内注射单独的紫杉醇(25mg/kg)、或者口服给药制备例1-1的化合物(27mg/kg)并腹腔内注射紫杉醇(11mg/kg)后,将小鼠安乐死并利用测径器每日测定肿瘤的体积变化,共测定60日,并将其结果在图3中示出。利用下述数学式1评价肿瘤的体积。
[数学式1]
肿瘤的体积=L×S2/2
(其中,L是指最长的直径,S是指最短的直径。)
如图3,在向利用抗癌剂耐性甲状腺癌细胞进行移植瘤的小鼠模型单独给药紫杉醇的情况下,与阴性对照组相比,并没有肿瘤体积变化,但在将制备例1-1的化合物与紫杉醇一同处理的情况下,可确认肿瘤的体积显著减少。
1-2.伊立替康活性增强效果
1-2-1.对于癌细胞的活性增强效果
对于来源于服用伊立替康后复发及转移的患者的癌症干细胞性胃癌细胞,进行制备例1-1的化合物(170nM)的单独处理、伊立替康(8.9μM)的单独处理、或者伊立替康(4.5μM)与制备例1-1的化合物(75nM)的复方剂处理后,测定根据处理时间的细胞数的变化,并将其结果在图4中示出。
如图4,在向抗癌剂耐性胃癌细胞单独处理伊立替康的情况下,与阴性对照组相比,癌细胞数没有任何变化,但在将制备例1-1的化合物与伊立替康一同处理的情况下,可确认到癌细胞数显著减少。
1-2-2.癌细胞移植小鼠的肿瘤大小变化的分析
在体外培养来源于服用伊立替康后复发及转移的患者的癌症干细胞性胃癌细胞后,向BALB/c裸雌小鼠的左上侧肋下的皮下注入所培养的细胞,至达到2.0×107细胞/小鼠。7日后,以每10只分组后,向各个组口服给药单独的制备例1-1的化合物(70mg/kg)、口服给药单独的伊立替康(75mg/kg)、或者口服给药制备例1-1的化合物(32mg/kg)和伊立替康(55mg/kg)后,将小鼠安乐死并利用测径器每日测定肿瘤的体积变化,共测定40日,并将其结果在图5中示出。通过如上所述的数学式1计算肿瘤的体积。并且,40日后,测定肿瘤的重量并将其结果在图6中示出,测定41日的小鼠的体重并将其结果在图7中示出。
如图5及图6,向利用抗癌剂耐性胃癌细胞进行移植瘤的小鼠模型单独给药伊立替康的情况下,与阴性对照组相比,没有肿瘤体积或重量的变化,但在将伊立替康与制备例1-1的化合物一同处理的情况下,可确认到肿瘤的体积及重量显著减少。
并且,如图7,在向小鼠模型单独给药制备例1-1的化合物或与伊立替康一同结合给药的情况下,与阴性对照组相比,可观察到小鼠的体重没有变化,并可确认没有毒性问题。
1-3.放射线治疗活性增强效果
1-3-1.对于癌细胞的活性增强效果
对于来源于放射线照射治疗后复发及转移的患者的癌症干细胞性大肠癌细胞,进行制备例1-1的化合物(150nM)的单独处理、以5Gy的强度照射FaxitronX射线(FaxitroBioptics,AZ,USA)(RT)、或者处理制备例1-1的化合物(75nM)并以5Gy的强度照射上述X射线后,测定根据处理时间的癌细胞数的变化,并将其结果在图8中示出。
如图8,在向放射线耐性大肠癌细胞仅照射放射线的情况下,与阴性对照组相比,并没有癌细胞数的变化,但在将放射线照射与制备例1-1的化合物一同处理的情况下,可确认癌细胞的数显著减少。
1-3-2.小鼠肿瘤大小变化的分析
在体外培养来源于放射线照射治疗后复发及转移的患者的癌症干细胞性大肠癌细胞后,向BALB/c裸雌小鼠的左上侧肋下的皮下注入所培养的细胞,至达到2.0×107细胞/小鼠。7日后,以每10只分组后,向各个组口服给药制备例1-1的化合物(60mg/kg)、以5Gy的强度照射Faxitron X射线(Faxitro Bioptics,AZ,USA)、或者口服给药制备例1-1的化合物(27mg/kg)并以5Gy的强度照射上述X射线后,将小鼠安乐死并利用测径器每日测定肿瘤的体积变化,共测定40日,并将其结果在图9中示出。通过如上所述的数学式1计算肿瘤的体积。并且,40日后,测定肿瘤的重量并将其结果在图10中示出,测定41日的小鼠的体重并将其结果在图11中示出。
如图9及图10,在向利用放射线耐性大肠癌细胞进行移植瘤的小鼠模型仅单独照射放射线的情况下,与阴性对照组相比,并没有肿瘤体积或重量的变化,但在与照射放射线一同给药制备例1-1的化合物的情况下,可确认肿瘤的体积和重量显著减少。
并且,如图11,在向小鼠模型单独给药制备例1-1的化合物或与放射线照射一同给药的情况下,与阴性对照组相比,可观察到小鼠的体重没有变化,可确认没有毒性问题。
2.制备例化合物的抗癌治疗活性增强效果
2-1.实验方法
为了确认制备例化合物的抗癌治疗活性增强效果,利用通过制备例1-1至制备例31制备的化合物或盐(以下,制备例化合物),以作为上皮性卵巢癌细胞株的SKOV3及来源于其来制备为具有紫杉醇抗癌剂耐药性的耐性细胞株的SKOV3-TR为对象进行细胞实验。
对于向在12孔板(well)生长的两种细胞株中,进行各个制备例的化合物的2μM的单独处理、紫杉醇(在SKOV3的情况下为0.2μM,在SKOV3-TR的情况下为5μM)的单独处理、或者紫杉醇与各个制备例的化合物的复方剂的处理后,72小时后测定存活的细胞数。当进行紫杉醇与制备例的多个化合物的结合处理时,先利用制备例的化合物分别以2μM预处理(pretreatment)4小时后,在SKOV3-TR细胞株中处理5μM的紫杉醇,在SKOV3细胞株中处理0.2μM的紫杉醇。
为了细胞的形态学分析,处理紫杉醇,24小时、48小时、72小时后,获取了进行“None(未进行任何处理的样品)”、“二甲基亚砜(DMSO)(紫杉醇的溶剂)”、“乙醇(制备例的化合物的溶剂)”、“紫杉醇”、“紫杉醇+乙醇”、“紫杉醇+制备例1-2的化合物(L19001)”处理的细胞的图像。
并且,为了分析细胞存活率,单独处理紫杉醇或制备例化合物,或者将紫杉醇与各个制备例化合物结合处理,72小时后,通过Image J分析测定存活的细胞数。
2-2.细胞形态学分析
细胞的形态学分析结果,在单独处理二甲基亚砜(DMSO)及乙醇的组的情况下,与未进行任何处理的组(None)相比,未示出特别差异,由此可知在本实验中所使用的溶剂的量不影响细胞。并且,当将制备例的化合物分别单独处理时,未在SKOV3-TR及SKOV3中引起特别的形态学变化。图12为未进行任何处理(None)、处理乙醇、处理制备例1-2的化合物(L19001,2μM)后,24小时、48小时、72小时后捕捉的图像。
并且,为了确认制备例化合物是否可增强通过紫杉醇的抗癌功效,在处理紫杉醇的4小时之前,对制备例的化合物进行预处理后,评价了紫杉醇对于癌细胞凋亡的影响。当进行紫杉醇处理时,确认了在SKOV3-TR及SKOV3中,由于细胞凋亡诱发及细胞生长抑制现象等,存活的细胞数减少。
具体地,在作为耐性癌细胞株的SKOV3-TR中,通过制备例的化合物的处理,这种现象无一例外地更加明显,相反,在作为普通癌细胞株的SKOV3中,通过制备例化合物的处理的紫杉醇癌细胞凋亡上升效果并未如SKOV3-TR明显。图13及图14示出向两种细胞株进行紫杉醇单独处理或紫杉醇+制备例1-2的化合物(L19001)处理后的72小时后的图像。
2-3.细胞存活率分析
利用Image J程序测定存活的细胞数,由此分析两种癌细胞株的细胞存活率。
如图15至图18,在单独处理二甲基亚砜(DMSO)及乙醇的组的情况下,与未进行任何处理的组(None)相比,在细胞存活率中未示出特别的差异,由此可知在本实验中所使用的溶剂的量不影响细胞存活率。
为了确认制备例化合物是否影响细胞存活率,向SKOV3-TR及SKOV3细胞株,分别以2μM的制备例的化合物进行处理后,测定72小时后的细胞数。其结果,在将制备例的化合物分别单独处理的情况下,在SKOV3-TR及SKOV3中,对细胞存活率没有显著影响。图15及图16示出在SKOV3-TR及SKOV3细胞株中分别未进行任何处理(None)、处理乙醇及处理制备例的化合物处理后,72小时后的细胞数。
并且,为了观察制备例化合物是否可增强通过紫杉醇的抗癌功效,在处理紫杉醇的4小时之前,分别以2μM的制备例化合物进行预处理后,评价了紫杉醇对于癌细胞凋亡的影响。其结果,与单独处理紫杉醇的情况相比,当预处理制备例化合物后进行紫杉醇处理时,确认了在SKOV3-TR及SKOV3中,由于细胞凋亡诱发及细胞生长抑制现象等,细胞数减少。尤其,确认了与作为普通癌细胞株的SKOV3相比,在作为耐药性癌症细胞株的SKOV3-TR中,通过制备例化合物的预处理,细胞数减少的现象无一例外地更加明显。图17及图18示出在SKOV3-TR及SKOV3细胞株中,未进行任何处理(None)、单独处理二甲基亚砜、单独处理乙醇、单独处理紫杉醇及预处理各个制备例的化合物后紫杉醇处理72小时后的细胞数。
Claims (29)
1.一种化合物或其药学上可接受的盐,其特征在于,由下述化学式1表示,
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
4.一种用于增强抗癌活性的药学组合物,其特征在于,包含由下述化学式1表示的化合物或其药学上可接受的盐,
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
5.根据权利要求4所述的用于增强抗癌活性的药学组合物,其特征在于,
上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
6.根据权利要求4所述的用于增强抗癌活性的药学组合物,其特征在于,
上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
7.根据权利要求4所述的用于增强抗癌活性的药学组合物,其特征在于,
上述抗癌活性增强是指,抗癌剂或放射线的抗癌活性增强。
8.根据权利要求7所述的用于增强抗癌活性的药学组合物,其特征在于,
上述抗癌剂为紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种。
9.根据权利要求8所述的用于增强抗癌活性的药学组合物,其特征在于,
上述紫杉类抗癌剂为选自由紫杉醇、多西紫杉醇及卡巴他赛组成的组中的至少一种。
10.根据权利要求8所述的用于增强抗癌活性的药学组合物,其特征在于,
上述喜树碱类抗癌剂为选自由伊立替康、拓扑替康及贝洛替康组成的组中的至少一种。
11.根据权利要求4所述的用于增强抗癌活性的药学组合物,其特征在于,
用于增强对于耐药性癌症的抗癌活性。
12.根据权利要求11所述的用于增强抗癌活性的药学组合物,其特征在于,
上述耐药性癌症为对于紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种的耐药性癌症。
13.根据权利要求11所述的用于增强抗癌活性的药学组合物,其特征在于,
上述耐药性癌症为对于放射线的耐药性癌症。
14.根据权利要求11所述的用于增强抗癌活性的药学组合物,其特征在于,
上述耐药性癌症为选自由甲状腺癌、胃癌、大肠癌、卵巢癌、乳腺癌、肺癌、卡波济氏肉瘤、宫颈癌、胰腺癌、头颈部癌、直肠癌、结肠癌、食道癌及前列腺癌组成的组中的至少一种。
15.根据权利要求4所述的用于增强抗癌活性的药学组合物,其特征在于,
还包含抗癌剂。
16.根据权利要求15所述的用于增强抗癌活性的药学组合物,其特征在于,
上述抗癌剂包含选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄洛替尼、来那替尼、拉帕替尼、吉非替尼、凡德他尼、尼罗替尼、司马沙尼、博舒替尼、阿西替尼、马赛替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、帕唑帕尼、托西尼布、尼达尼布、瑞戈非尼、司马沙尼、替沃扎尼、帕纳替尼、卡博替尼、卡铂、索拉非尼、乐伐替尼、贝伐单抗、顺铂、西妥昔单抗、槲寄生、门冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥珠单抗奥唑米星、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、甲基苄肼、前列地尔、硝酸钬·壳聚糖、吉西他滨、去氧氟尿苷、培美曲塞、替加氟、卡培他滨、吉莫斯特、奥替拉西、阿扎胞苷、氨甲喋呤、尿嘧啶、阿糖胞苷、5-氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、卡培他滨、地西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟、雷替曲塞、多西紫杉醇、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春花碱、替尼泊苷、阿霉素、去甲氧柔红霉素、表阿霉素、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素、吡喃阿霉素、阿克拉霉素、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑、六甲蜜胺、达卡巴嗪、塞替派、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、瘤可维、维甲酸、依西美坦、氨鲁米特、阿那格雷、奥拉帕尼、诺维本、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏氯唑、比卡鲁胺、洛莫司汀、伏立诺他、恩替诺特及卡莫司汀组成的组中的至少一种。
17.根据权利要求15所述的用于增强抗癌活性的药学组合物,其特征在于,
以1∶0.001至1∶1000的摩尔浓度比包含上述抗癌剂与由上述化学式1表示的化合物或其药学上可接受的盐。
18.一种癌症治疗方法,其特征在于,包括向患有耐药性癌症的对象给药治疗有效量的由下述化学式1表示的化合物或其药学上可接受的盐的步骤,
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,在上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
19.根据权利要求18所述的癌症治疗方法,其特征在于,
上述n为0至2的整数;
上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
20.根据权利要求18所述的癌症治疗方法,其特征在于,
上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
21.根据权利要求18所述的癌症治疗方法,其特征在于,
上述耐药性癌症为对于紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种的耐药性癌症。
22.根据权利要求18所述的癌症治疗方法,其特征在于,
上述耐药性癌症为对于放射线的耐药性癌症。
23.根据权利要求18所述的癌症治疗方法,其特征在于,
上述耐药性癌症为选自由甲状腺癌、胃癌、大肠癌、卵巢癌、乳腺癌、肺癌、卡波济氏肉瘤、宫颈癌、胰腺癌、头颈部癌、直肠癌、结肠癌、食道癌及前列腺癌组成的组中的至少一种。
24.一种用于治疗耐药性癌症的化合物的用途,其特征在于,由下述化学式1表示,
[化学式1]
在上述化学式1中,
n为0至4的整数;
R1为氢、C1至C10的烷基或芳基(C1至C4)烷基;
R3为C1至C6的烷基,上述R3为多个的情况下,它们彼此相同或不同;
L1为直接键或C1至C6的亚烷基;
R2为氢、C1至C10的烷基或芳基(C1至C4)烷基,R4为氢、C1至C4的烷基、C3至C8的环烷基或芳基(C1至C4)烷基,或者
R2与R4形成4元环至7元环并相互连接;
在上述R1至R4的烷基、上述R1、R2及R4的芳基烷基、上述R4的环烷基、上述L1的亚烷基各自独立地被C1至C6的烷基、卤素基、芳基、卤代烷基、硝基、氰基、烷基硫醇基或芳基烷基硫醇基的取代基取代或未取代,且在被多个取代基取代的情况下,多个取代基彼此相同或不同。
25.根据其权利要求24所述的用于治疗耐药性癌症的化合物的用途,其特征在于,
上述n为0至2的整数;
上述R1为C1至C6的烷基或芳基(C1至C2)烷基;
上述L1为C1至C4的亚烷基;
上述R2为氢、C1至C6的烷基或芳基(C1至C2)烷基,上述R4为氢、C1至C4的烷基、C3至C6的环烷基或芳基(C1至C2)烷基,或者
上述R2与上述R4形成4元环至6元环并相互连接。
26.根据其权利要求24所述的化合物的用途,其特征在于,
上述n为0至1的整数;
上述R1为C1至C6的烷基、苯甲基或苯乙基;
上述L1为C1至C2的亚烷基;
上述R2为氢、C1至C6的烷基、苯甲基或苯乙基,上述R4为氢、C1至C2的烷基、C5至C6的环烷基、苯甲基或萘甲基,或者
上述R2与上述R4形成5元环至6元环并相互连接。
27.根据其权利要求24所述的用于治疗耐药性癌症的化合物的用途,其特征在于,
上述耐药性癌症为对于紫杉类抗癌剂及喜树碱类抗癌剂中的至少一种的耐药性癌症。
28.根据其权利要求24所述的用于治疗耐药性癌症的化合物的用途,其特征在于,
上述耐药性癌症为对于放射线的耐药性癌症。
29.根据其权利要求24所述的化合物的用途,其特征在于,
上述耐药性癌症为选自由甲状腺癌、胃癌、大肠癌、卵巢癌、乳腺癌、肺癌、卡波济氏肉瘤、宫颈癌、胰腺癌、头颈部癌、直肠癌、结肠癌、食道癌及前列腺癌组成的组中的一种。
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