CN115916206A - 新型化合物及包含其的用于预防或治疗耐受性癌的药物组合物 - Google Patents
新型化合物及包含其的用于预防或治疗耐受性癌的药物组合物 Download PDFInfo
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- CN115916206A CN115916206A CN202180045662.9A CN202180045662A CN115916206A CN 115916206 A CN115916206 A CN 115916206A CN 202180045662 A CN202180045662 A CN 202180045662A CN 115916206 A CN115916206 A CN 115916206A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- C—CHEMISTRY; METALLURGY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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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
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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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
Abstract
本申请涉及一种新型化合物及包含新型化合物或其药学上可接受的盐的用于预防或治疗耐受性癌的药物组合物,当一起施用本申请的组合物与抗癌剂时,可以表现出优异的抗癌效果。
Description
技术领域
本申请要求于2020年6月26日向韩国知识产权局提交的韩国专利申请第10-2020-0078242号的申请日的权益,其全部内容将通过引用并入本文。
本申请涉及新型化合物及包含其的用于预防或治疗癌症的药物组合物。
背景技术
癌症是全球最常见的死亡原因之一,约占死亡原因的12%。作为代表性的抗癌疗法的化学疗法(chemotherapy)目前被用作治疗癌症最有效的治疗方法,其能够被单独使用或能够与放射疗法等其他疗法联合使用。然而,癌症治疗药物在化学疗法中的功效取决于其杀死癌细胞的能力,但存在使用药物时不仅能够作用于癌细胞,还能够作用于正常细胞的问题。
另一方面,癌症干细胞(cancer stem cell)作为一种具有无限再生能力的癌细胞,在20世纪90年代末,发表了将在急性骨髓性白血病中可能成为癌症干细胞的细胞移植给免疫抑制的老鼠,以使人的白血病在小鼠体内再现的内容,从而肿瘤起源于干细胞的假说被确立。随后,通过在乳腺癌中证明癌症干细胞,从而在实体癌中也证实了干细胞的存在。
癌症干细胞是具有自我再生能力并且也具有分化成其他细胞的能力的细胞,其为症复发和转移的原因。特定的患者群体由于癌症干细胞被激活,因此对抗癌剂表现出强烈的抗性,故被归类为难以用常规抗癌疗法治疗的难治性癌症患者。恶性肿瘤呈现出的异质多样性与干细胞的分化多样性一致,并且在诸多靶向治疗下也不断表达的癌细胞的药物抗性与干细胞的基本特性一致。
癌症干细胞能够成为靶向治疗的新领域,为了有效地进行仅以癌症干细胞为靶标而不损害正常干细胞的治疗,需要对癌症干细胞的维持和调节重要的分子生物学特性或其调节途径的相关知识和理解。
基于癌症干细胞的假说已经研究出多种治疗方法,其中,最广为人知的方法是利用癌症干细胞的自我再生途径的方法。在这种治疗中,重点在于维持正常干细胞的自我再生的同时,仅将癌症干细胞的自我再生作为靶标。例如,Notch信号是由一种叫做γ分泌酶(gamma secretase)的酶进行的,当将所述γ分泌酶抑制剂(gamma secretase inhibitor)用于Notch1过表达的乳腺癌时,能够达到抑制肿瘤的效果。最近有报道称,Hedgehog信号体系作为靶标时也表现出抗癌效果,当作为Hedgehog抑制剂的环巴胺(cyclopamine)施用异种移植(tumor xenograft)瘤的动物时,肿瘤显著萎缩。
此外,已知与PI3K/AKT、MAPK和JAK2/STAT3信号通路(signaling pathway)有关。
如此,正在进行许多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通过抑制癌症干细胞的上位信号传递蛋白质来抑制癌症干细胞的相关研究。然而,目前实际几乎没有直接靶向癌症干细胞的抗癌剂或来源于天然产物的提取物相关的研究,而且在大多数肿瘤患者中,由于肿瘤基因突变或蛋白质突变,靶向实验存在很多困难。
因此,需要开发出能够克服由肿瘤基因或蛋白质突变产生的现有的抗癌药物抗性并具有抗癌效果的新型药物。
发明内容
发明要解决的问题
本申请的一方面提供一种新型化合物。
并且,本申请的另一方面提供一种包含新型化合物的用于预防或治疗癌症的药物组合物。
并且,本申请的另一方面提供一种包含新型化合物的用于预防或治疗耐受性癌的药物组合物。
并且,本申请的另一方面提供一种新型化合物在预防或治疗耐受性癌中的用途。
并且,本申请的另一方面提供一种通过向患有耐受性癌的个体施用新型化合物来治疗对肿瘤学疗法表现出耐受性的癌症的方法。
本申请所要解决的问题并不限于以上所述,本领域技术人员通过以下记载将清楚地理解上述未提及的其他问题。
用于解决问题的手段
根据本申请的一实施例,提供一种由下述化学式1表示的化合物或其药学上可接受的盐。
[化学式1]
在所述化学式1中,
L1为直接键合或C1-10亚烷基;
Ar1为C1-12烷基或能够含有0个至3个独立地选自O、N或S的杂原子的5元至16元单环、双环、三环或四环,其可以不被取代或被独立地选自C1-6卤代烷基、卤素、氧代基、-OCHF2、-CN、硝基、-C(=O)NZaZa、-C(=O)Zb、-C(=O)OZb、-C(=NZa)NZaZa、-OZa、-OC(=O)Zb、-OC(=O)NZaZa、-O-C1-6烷基N(Za)C(=O)OZb、-OC(=O)N(Za)S(=O)2Zb、-OC2-6烷基NZaZa、-OC2-6烷基OZa、-SZa、-S(=O)Zb、-S(=O)2Zb、-S(=O)2NZaZa、-S(=O)2N(Za)C(=O)Zb、-S(=O)2N(Za)C(=O)OZb、-S(=O)2N(Za)C(=O)NZaZa、-NZaZa、-NZcZc、-N(Za)C(=O)Zb、-N(Za)C(=O)OZb、-N(Za)C(=O)NZaZa、-N(Za)C(=NZa)NZaZa、-N(Za)S(=O)2Zb、-N(Za)S(=O)2NZaZa、-NZaC2-6烷基NZaZa、-NZaC2-6烷基OZa、C6-10芳基、C5-10杂芳基、-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基(其中,-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基被0个至3个独立地选自C1-6卤代烷基、卤素、氰基、硝基、C6-12芳基或C5-12杂芳基的取代基取代)的基团取代;
Za各自独立地为氢或Zb;
Zb各自独立地为苯基、苄基、C1-6烷基、C4-8杂环烷基或C3-8环烷基,所述苯基、苄基、C1-6烷基、C4-8杂环烷基或C3-8环烷基烷基被0个至3个独立地选自卤素、-OH、-S(=O)2Zb、-OC2-6烷基OZa、C1-6烷基、C1-6卤代烷基、-OC1-4烷基、-NH2、-CN或-NZaZa的取代基取代;
Zc各自独立地为氢或C1-6烷基,或基团CZcZc能够形成C3-8环烷基环;
m和y各自独立地为0至2的整数;
R1或R2各自独立地为氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基羰基、卤代C1-6烷基、C2-6烯基或C4-15单环或双环(其为C3-10环烷基;C6-12芳基;含有0个至3个独立地选自N、O和S的杂原子的5元或6元饱和或部分饱和杂环;含有0个至3个独立地选自N、O和S的杂原子(所述杂原子不会同时具有两个以上O或两个以上S)的5元或6元芳族杂环;或含有0个至3个独立地选自N、O和S的杂原子的7元至15元饱和、部分饱和或不饱和杂环);
所述R1和R2能够以形成5元至12元的单环或双环的方式连接。
本申请的一实施例提供一种包括所述化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的用于预防或治疗癌症的药物组合物。
本申请的一实施例提供一种包括所述化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的用于预防或治疗耐受性癌的药物组合物。
在本申请的一实施例中,所述组合物还可以包括药学上可接受的载体、赋形剂、稀释剂或免疫佐剂。
在本申请的一实施例中,所述组合物能够抑制SERCA蛋白的表达。
在本申请的一实施例中,所述耐受性癌对抗癌药物或放射线具有耐受性。
在本申请的一实施例中,所述抗癌药物为选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、埃罗替尼、来那替尼、拉帕替尼、吉非替尼、凡德他尼、尼洛替尼、塞马西尼、博舒替尼、阿昔替尼、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、普纳替尼、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、白果槲寄生、天冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥单抗、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、丙卡巴肼、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、吉美拉西、奥特拉西、阿扎胞苷、甲氨蝶呤、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、多西他赛、紫杉醇、卡巴他赛、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春碱、替尼泊苷、阿霉素、伊达比星、表柔比星、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素D、吡柔比星、阿柔比星、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、亚叶酸、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、伏罗唑、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。
在本申请的一实施例中,所述抗癌药物能够以1:0.001至1:1000的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。
在本申请的一实施例中,所述耐受性癌可以为选自由卵巢癌、大肠癌、胰腺癌、胃癌、肝癌、乳腺癌、宫颈癌、甲状腺癌、甲状旁腺癌、肺癌、非小细胞肺癌、前列腺癌、胆囊癌、胆道癌、血液癌、膀胱癌、肾癌、黑色素瘤、结肠癌、骨癌、皮肤癌、头颈癌、子宫癌、直肠癌、脑癌、肛周癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、输尿管癌、肾细胞癌、肾盂癌、血液癌、白血病、中枢神经系统(central nervous system;CNS)肿瘤、脊髓肿瘤、脑干神经胶质瘤和脑下垂体腺瘤组成的组中的至少一种。
本申请的一实施例提供一种癌症的治疗方法,包括对患有癌症的个体施用治疗有效量的所述化合物、其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的步骤。
本申请的一实施例提供一种对肿瘤学疗法表现出耐受性的癌症的治疗方法,包括对患有癌症的个体施用治疗有效量的所述化合物、其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的步骤。
本申请的一实施例提供一种对肿瘤学疗法表现出耐受性的癌症的治疗方法,包括同时、分别或依次施用可用于治疗癌症或增殖性疾病的化学用药剂的步骤。
本申请的一实施例提供一种所述化合物或其药学上可接受的盐在制备癌症或耐受性癌治疗用药剂中的用途。
本申请的一实施例提供一种所述化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合在制备干细胞性癌治疗用药剂中的用途。
发明效果
包含根据本申请的一实施例的化合物或其药学上可接受的盐的组合物能够增强抗癌剂或放射线的抗癌活性,并且能够通过抑制癌细胞的增殖和诱导细胞凋亡等,从而有效地治疗癌症。
包含根据本申请的一实施例的化合物或其药学上可接受的盐的组合物能够克服对抗癌剂或放射线具有耐受性的癌症的耐受性,并且有效地治疗耐受性癌。
包含根据本申请的一实施例的化合物或其药学上可接受的盐的组合物即使在单独使用时也具有预防或治疗癌症的效果。
根据本申请的效果不受以上例示的内容的限制,并且更多的各种效果包括在本说明书中。
附图说明
图1的(a)部分示出了SKOV3的紫杉醇和多西他赛抗癌剂IC50值,(b)部分示出了SKOV3-TR的紫杉醇和多西他赛抗癌剂IC50值。
图2至图13示出了紫杉醇相关的SKOV3-TR和SKOV3的WST-1分析结果。
图14至图25示出了多西他赛抗癌剂相关的SKOV3-TR和SKOV3的WST-1分析结果。
具体实施方式
本申请的优点和特征以及实现它们的方法将通过以下详细描述的实施例变得更加明确。然而,本申请不限于以下公开的实施例,而是能够以多种不同的形式实施。提供本实施例只是为了使本申请的公开内容完整,且为使本领域的普通技术人员充分告知本申请属于本发明的范围,本申请受权利要求的范围的限定。
以下,对本申请的实施例进行说明。
本申请的一实施例提供一种由下述化学式1表示的化合物或其药学上可接受的盐。
[化学式1]
在本申请的一实施例中,所述化学式1表示的化合物可以为下述化学式2至10中任意一个化合物或其药学上可接受的盐。
[化学式2]
[化学式3]
[化学式4]
[化学式5]
[化学式6]
[化学式7]
[化学式8]
[化学式9]
[化学式10]
所述化学式2可以为下述化学式2a至化学式2c。
[化学式2a]
[化学式2b]
[化学式2c]
在所述化学式1中,Ar1为C1-12烷基或能够含有0个至3个独立地选自O、N或S的杂原子的5元至16元单环、双环、三环或四环,其可以未被取代或被独立地选自C1-6卤代烷基、卤素、氧代基、-OCHF2、-CN、硝基、-C(=O)NZaZa、-C(=O)Zb、-C(=O)OZb、-C(=NZa)NZaZa、-OZa、-OC(=O)Zb、-OC(=O)NZaZa、-O-C1-6烷基N(Za)C(=O)OZb、-OC(=O)N(Za)S(=O)2Zb、-OC2-6烷基NZaZa、-OC2-6烷基OZa、-SZa、-S(=O)Zb、-S(=O)2Zb、-S(=O)2NZaZa、-S(=O)2N(Za)C(=O)Zb、-S(=O)2N(Za)C(=O)OZb、-S(=O)2N(Za)C(=O)NZaZa、-NZaZa、-NZcZc、-N(Za)C(=O)Zb、-N(Za)C(=O)OZb、-N(Za)C(=O)NZaZa、-N(Za)C(=NZa)NZaZa、-N(Za)S(=O)2Zb、-N(Za)S(=O)2NZaZa、-NZaC2-6烷基NZaZa、-NZaC2-6烷基OZa、C6-10芳基、C5-10杂芳基、-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基(其中,-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基被0个至3个独立地选自C1-6卤代烷基、卤素、氰基、硝基、C6-12芳基或C5-12杂芳基的取代基取代)的基团取代;
Za各自独立地为氢或Zb;
Zb各自独立地为苯基、苄基、C1-6烷基、C4-8杂环烷基或C3-8环烷基,所述苯基、苄基、C1-6烷基、C4-8杂环烷基或C3-8环烷基烷基被0个至3个独立地选自卤素、-OH、-S(=O)2Zb、-OC2-6烷基OZa、C1-6烷基、C1-6卤代烷基、-OC1-4烷基、-NH2、-CN或-NZaZa的取代基取代;
Zc各自独立地为氢或C1-6烷基,或基团CZcZc能够形成C3-8环烷基环;
具体地,所述Ar1为C1-6直链或支链烷基、萘基、苯基、萘基、蒽基、菲基、芘基、呋喃基、吲哚基、色酮基、喹啉基、咔唑基或噻吩基,其可以未被取代或被羟基、卤素、C1 -6烷基、C3-10环烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C2-6烯基、-C2-6炔基、C6-12芳基或C5-12杂芳基中的至少一种取代。
在所述化学式中,
L1可以为直接键合或C1-10亚烷基。具体地,可以为C1-6亚烷基,更具体地,可以为C1-3亚烷基。
所述A1、A2、A3或A4各自独立地可以为CR或N。
所述R或R’各自独立地可以为氢、羟基、卤素、C6-12芳基、C5-12杂芳基、-C1-6烷基、-C3-10环烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基(其中,-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基可以被0个至3个独立地选自C1-6卤代烷基、卤素、氰基、硝基、C6-12芳基或C5-12杂芳基的取代基取代)。
所述n和n’各自独立地可以为0至13的整数。
所述m和y各自独立地可以为0至2的整数。具体地,m为1,y可以为1或2。
所述R1或R2各自独立地为氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基羰基、卤代C1-6烷基、C2-6烯基、C4-15单环或双环(其为C3-10环烷基;C6-10芳基;含有0个至3个独立地选自N、O和S的杂原子的5元或6元饱和或部分饱和杂环;含有0个至3个独立地选自N、O和S的杂原子(所述杂原子中并非有两个以上O或S)的5元或6元芳族杂环;或含有0个至3个独立地选自N、O和S的杂原子的7元至15元饱和、部分饱和或不饱和杂环);并且所述R1和R2能够以形成5元至12元的单环或双环的方式连接。
具体地,R1或R2各自独立地为氢、C1-6烷基、苄基、萘基烷基、苯并呋喃基烷基、喹啉基烷基、吡啶基烷基、环己基烷基、噻吩基烷基、吡咯基烷基、呋喃基烷基或苯并噻吩基烷基,其可以未被取代或各自独立地被C1-6烷基、C3-6环烷基、C6-12芳基、羟基、卤素、C1-6烷氧基、C1-6卤代烷基或C1-6卤代烷氧基中的至少一个取代;并且所述R1和R2能够以形成5元至12元的单环或双环的方式连接。
在本说明书中,术语“独立地”是指独立应用的变量在每次应用时独立地变化。因此,就如RaXYRa之类的化合物而言,若Ra“独立地为碳或氮”,则两个Ra都可以是碳,两个Ra都可以是氮,或者一个Ra可以是碳,另一个Ra可以是氮。
如在本说明书中所使用,除非另有说明,否则术语“烷基”通常是指C1至C10的饱和的直链或支链烃链。具体地,包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、环己基、环己基甲基、3-甲基戊基、2,2-二甲基丁基和2,3-二甲基丁基等。上述术语包括所有取代和未取代的烷基。选择性地,烷基可以被选自由羟基、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸基、硫酸酯(sulfate)基、磷酸基、磷酸酯(phosphate)基、或膦酸酯(phosphonate)基组成的组中的一个以上的部分(moiety)取代。与烷基的碳原子连接的一个以上的氢原子可以被一个以上的卤素原子(例如氟或氯或两者)取代,例如三氟甲基、二氟甲基、氟氯甲基等。上述烃链还可在中间包含N、O或S等杂原子。
如在本说明书中所使用,除非另有说明,否则术语“环烷基”是指具有3-8个碳原子,优选3-6个碳原子的饱和环烷基,例如环丙基、环丁基、环戊基和环己基。所述环烷基的环可以被烷基取代,如环丙基甲基等。
术语“烷基氨基”或“芳基氨基”是指分别具有一个或两个烷基或芳基取代基的氨基。
如在本说明书中所使用,除非另外定义,否则术语“受保护的”是指为了防止进一步反应或出于其他目的而添加到氧、氮或磷原子的基团。有机合成领域的技术人员已知多种氧和氮保护基团。非限制性示例包括:C(O)-烷基、C(O)Ph、C(O)芳基、CH3、CH2-烷基、CH2-烯基、CH2Ph、CH2-芳基、CH2O-烷基、CH2O-芳基、SO2-烷基、SO2-芳基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基和1,3-(1,1,3,3-四异丙基亚二硅氧烷基)(1,3-(1,1,3,3-tetrapropyl disiloxanylidene))。
在本说明书中使用的,术语“芳基”是指C6~C20芳基,具体地,是指C6-C12芳基,包括环中不含杂原子的具有6个至20个碳原子的芳族环基团。芳基具体是指苯基、联苯基、萘基、蒽基、菲基、芘基、屈基或苉基,更具体地是指苯基、联苯基、萘基、蒽基、菲基或芘基。上述术语包括所有取代和未取代的部分。所述芳基根据需要被包括未保护或保护的羟基、卤素、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸基、硫酸酯基、磷酸基、磷酸酯基或膦酸酯基的一个以上的取代基取代,但不限于此。
术语“烷芳基”或“烷基芳基”是指具有芳基取代基的烷基。术语“芳烷基”或“芳基烷基”是指具有烷基取代基的芳基,例如,苄基。
如在本说明书中所使用,术语“卤代”包括氯代、溴代、碘代和氟代。
术语“酰基酯(acyl ester)”或“O-键合的酯”是指式C(O)R’的羧酸酯,其中酯基的非羰基部分R’为直链或分支的烷基、或环烷基或低级烷基,包括甲氧基甲基的烷氧基烷基,包括苄基的芳烷基,芳如苯氧基甲基的氧基烷基,包括任选地被卤素(F、Cl、Br、I)取代的苯基的芳基、包括C1至C4烷基或C1至C4烷氧基、甲磺酰基、单磷酸酯、二磷酸酯或三磷酸酯的如烷基酰基或芳烷基磺酰基的磺酸酯,三苯甲基或单甲氧基三苯甲基,取代的苄基;三烷基甲硅烷基(例如,二甲基叔丁基甲硅烷基)或二苯基甲基甲硅烷基。选择性地,所述酯中的芳基包括苯基。
术语“酰基”是指式R”C(O)-的基团,所述R”为直链或分支的烷基或环烷基,氨基酸,包括苯基的芳基,烷基芳基,包括苄基的芳烷基,包括甲氧基甲基的烷氧基烷基,如苯氧基甲基的芳氧基烷基;或包括烷基(包括低级烷基)、任选地被氯、溴、氟、碘取代的苯基的芳基,包括C1至C4烷基或C1至C4烷氧基、甲磺酰基的如烷基酰基或芳烷基磺酰基的磺酸酯,单磷酸酯、二磷酸酯或三磷酸酯,包括三苯甲基或单甲氧基-三苯甲基,取代的苄基的烷芳基,包括甲氧基甲基的烷氧基烷基,如苯氧基甲基的芳氧基烷基。最优选地,所述酯中的芳基包括苯基。具体地,所述酰基包括乙酰基、三氟乙酰基、甲基乙酰基、环丙基乙酰基、环丙基羧基、丙酰基、丁酰基、异丁酰基、己酰基、庚酰基、辛酰基、新庚酰基、苯基乙酰基、2-乙酰氧基-2-苯乙酰基、二苯基乙酰基、α-甲氧基-α-三氟甲基-苯基乙酰基、溴乙酰基、2-硝基-苯乙酰基、4-氯-苯乙酰基、2-氯-2,2-二苯基乙酰基、2-氯-2-苯基乙酰基、三甲基乙酰基、氯代二氟乙酰基、全氟乙酰基、氟乙酰基、溴代二氟乙酰基、甲氧基乙酰基、2-噻吩乙酰基、氯磺酰基乙酰基、3-甲氧基苯基乙酰基、苯氧基乙酰基、叔丁基乙酰基、三氯乙酰基、一氯乙酰基、二氯乙酰基、7H-十二氟庚酰基、全氟庚酰基、7H-十二-氟庚酰基、7-氯十二氟-庚酰基、7-氯-十二氟-庚酰基、7H-十二氟庚酰基、7H-十二-氟庚酰基、九-氟-3,6-二氧杂-庚酰基、九氟-3,6-二氧杂庚酰基、全氟庚酰基、甲氧基苯甲酰基、甲基3-氨基-5-苯基噻吩-2-羧基、3,6-二氯-2-甲氧基-苯甲酰基、4-(1,1,2,2-四氟-乙氧基)-苯甲酰基、2-溴-丙酰基、ω-氨基辛酰基(capryl)、癸酰基、正十五烷酰基、硬脂酰基、3-环戊基-丙酰基、1-苯-羧基、O-乙酰基扁桃基(mandelyl)、新戊酰基乙酰基、1-金刚烷-羧基、环己烷-羧基、2,6-吡啶二羧基、环丙烷-羧基、环丁烷-羧基、全氟环己基羧基、4-甲基苯甲酰基、氯甲基异恶唑基羰基、全氟环己基羧基、巴豆酰基、1-甲基-1H-吲唑-3-羰基、2-丙烯基、异戊酰基、1-吡咯烷羰基、4-苯基苯甲酰基。当使用术语酰基时,意指特定并独立地公开了乙酰基、三氟乙酰基、甲基乙酰基、环丙基乙酰基、丙酰基、丁酰基、异丁酰基、己酰基、庚酰基、辛酰基、新庚酰基、苯基乙酰基、二苯基乙酰基、ct-三氟甲基-苯基乙酰基、溴乙酰基、4-氯-苯乙酰基,2-氯-2,2-二苯基乙酰基、2-氯-2-苯基乙酰基、三甲基乙酰基、氯代二氟乙酰基、全氟乙酰基、氟乙酰基、溴代二氟乙酰基、2-噻吩乙酰基、叔丁基乙酰基、三氯乙酰基、一氯乙酰基、二氯乙酰基、甲氧基苯甲酰基、2-溴-丙酰基、癸酰基、正十五烷酰基、硬脂酰基、3-环戊基-丙酰基、1-苯-羧基、新戊酰基乙酰基、1-金刚烷-羧基、环己烷-羧基、2,6-吡啶二羧基、环丙烷-羧基、环丁烷-羧基、4-甲基苯甲酰基、巴豆酰基、1-甲基-1H-吲唑-3-羰基、2-丙烯基、异戊酰基、4-苯基苯甲酰基。
在本申请中,术语“C1~C6烷基”是指具有1个至6个碳原子的直链或支链烷基,包括甲基、乙基、丙基、异丙基、丁基、异丁基(isobutyl)、仲丁基(sec-butyl)、叔丁基、戊基(amyl)和己基(hexyl)等,但不限于此,优选为乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本申请中,术语“C1~C6烷氧基”是指具有1个至6个碳原子的直链或支链烷氧基,包括甲氧基(methoxy)、乙氧基(ethoxy)、丙氧基(propoxy)、异丙氧基(isopropoxy)和丁氧基(butoxy)等,但不限于此。
在本申请中,术语“C2~C6烯基”是指具有2个至6个碳原子的含有一个双键的直链或支链烯基,包括乙烯基(vinyl)、丙烯基(propenyl)、丁烯基(Butenyl)、异丁烯基(isobutenyl)、戊烯基(pentenyl)和己烯基(hexenyl)等,但不限于此。
在本申请中,术语“C2~C6炔基”是指2个至6个碳原子的含有一个三键的直链或支链炔基,包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等,但不限于此。
在本申请中,术语“C3~C10环烷基”是指环中具有3个至10个碳原子的环型烷基,包括环丙基(cyclopropyl)、环丁基、环戊基、环己基、环庚基、环辛基(cyclooctyl)及环癸基(cyclodecyl)等,但不限于此。术语“C3~C8环烷基”、“C3~C7环烷基”和“C3~C6环烷基”具有相似的含义。
在本申请中,术语“C3~C10环烯基”是指环中具有3个至10个碳原子的环型烯基,包括环丙烯基(cyclopropenyl)、环丁烯基(cyclobutenyl)、环戊烯基(cyclopentenyl)、环己烯基(cyclohexenyl)、环庚烯(cycloheptene)、环辛烯(cyclooctene)和环癸烯(cyclodecene)等,但不限于此。术语“C3-C7环烯基”具有相似的含义。
在本申请中,术语“3~12元杂环”是指环中含有1~3个选自氧、硫和氮的杂原子的饱和或不饱和的3~12元环基团,例如,二氧杂环戊烯(dioxol)。术语“3~7元杂环”具有相似的含义。
本申请中的“亚烷基”是指二价烃基;这是因为它是二价的,因此可以与其他两个基团一起键合。通常,其为-(CH2)n-,其中n为1~8,优选地n为1~4,但在特定情况下,亚烷基还可以被其他基团取代,且也可以具有不同的长度,开放的化合价也不一定必须位于链的相对侧。
一般而言,取代基中所含的所有烷基、烯基、炔基,酰基、或者芳基或芳基烷基本身可以任选地被其他额外的取代基取代。除非另有对这些取代基的说明,否则这些取代基的性质类似于对一次取代基本身所列举的性质。
在本申请中,术语“杂原子”是指不是碳或氢的原子,例如氮、氧或硫。如果它是链或环的主链或骨架的一部分,则杂原子必须至少是二价的,并且通常选自N、O、P和S。
术语“可取代的”是指可选择性被取代,即特定基团或多个基团不具有非氢取代基,或者上述基团或多个基团可具有一个以上的符合于最终所得分子的化学及药理学活性的非氢取代基。除非另有说明,否者可能存在的这些取代基的总数等于所述基团的未被取代形式中存在的氢原子总数;可以以少于这些取代基的最大数量的方式存在。当任选取代基通过双键(如羰基氧(C=O))键合时,该基团获取该任选取代基所连接的碳原子上可用的两个化合价,因此可以包括的取代基的总数随着可用的化合价的数量而减少。在本申请中,当用于修饰特定基团、部分或基时,无论术语“取代的”被用作术语“可取代的”一部分或以其他方式使用,其是指1个以上的氢原子各自独立地被彼此相同或不同取代基或多个取代基取代。
可用于取代特定的基、部分或基团(radical)中的饱和碳原子的取代基的非限制性示例包括:-Za、=O、-OZb、-SZb、=S-、-NZcZc、=NZb、=N-OZb、三卤甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)2Zb、-S(O)2NZb、-S(O2)O-、-S(O2)OZb、-OS(O2)OZb、-OS(O2)O-、-OS(O2)OZb、-P(O)(O-)2、-P(O)(OZb)(O-),-P(O)(OZb)(OZb)、-C(O)Zb、-C(S)Zb、-C(NZb)Zb、-C(O)O-、-C(O)OZb、-C(S)OZb、-C(O)NZcZc、-C(NZb)NZcZc、-OC(O)Zb、-OC(S)Zb、-OC(O)O-、-OC(O)OZb、-OC(S)OZb、-NZbC(O)Zb、-NZbC(S)Zb、-NZbC(O)O-、-NZbC(O)OZb、-NZbC(S)OZb、-NZbC(O)NZcZc、-NZbC(NZb)Zb、-NZbC(NZb)NZcZc,其中Za选自烷基、环烷基、杂烷基、环杂烷基、芳基、芳基烷基、杂芳基和杂芳基烷基组成的组;每个Zb独立地为氢或Za;以及每个Zc独立地为Zb或者两个Zc能够与它们所连接的氮原子一起形成4-、5-、6-或7-元环杂烷基环结构,并且该环结构能够任选地包括选自N、O和S组成的组中的1至4个相同或不同的杂原子。作为具体示例,-NZcZc旨在包括-NH2、-NH-烷基、-N-吡咯烷基和-N-吗啉基,但不限于特定替代物,并且也包括本领域已知的其他替代物。同样地,作为另一个具体示例,取代的烷基旨在包括-亚烷基-O-烷基、-亚烷基-杂芳基、-亚烷基-环杂芳基、-亚烷基-C(O)OZb、-亚烷基-C(O)NZbZb和-CH2-CH2-C(O)-CH3,但不限于这些特定的替代例,并且也包括本领域已知的其他替代例。一个以上的取代基与它们所结合的原子一起可以形成环状环,包括但不限于环烷基和环杂烷基。
同样地,可用于取代特定基、部分或基团中的不饱和碳原子的取代基的非限制性示例包括:-Za、卤素(halo)、-O-、-OZb、-SZb、-S-、-NZcZc、三卤代甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、-N3、-S(O)2Zb、-S(O2)O-、-S(O2)OZb、-OS(O2)OZb、-OS(O2)O-、-P(O)(O-)2、-P(O)(OZb)(O-)、-P(O)(OZb)(OZb)、-C(O)Zb、-C(S)Zb、-C(NZb)Zb、-C(O)O-、-C(O)OZb、-C(S)OZb、-C(O)NZcZc、-C(NZb)NZcZc、-OC(O)Zb、-OC(S)Zb、-OC(O)O-、-OC(O)OZb、-OC(S)OZb、-NZbc(O)OZb、-NZbc(S)OZb、-NZbc(O)NZcZc、-NZbc(NZb)Zb和-NZbc(NZb)NZcZc,其中Za、Zb和Zc如上所定义。
同样地,可用于取代杂烷基和环杂烷基中的氮原子的取代基的非限制性示例包括:-Za、卤素、-O-、-OZb、-SZb、-S-、-NZcZc、三卤甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、-N3、-S(O)2Zb、-S(O2)O-、-S(O2)OZb、-OS(O2)OZb、-OS(O2)O-、-P(O)(O-)2、-P(O)(OZb)(O-)、-P(O)(OZb)(OZb)、-C(O)Zb、-C(S)Zb、-C(NZb)Zb、-C(O)O-、-C(O)OZb、-C(S)OZb、-C(O)NZcZc、-C(NZb)NZcZc、-OC(O)Zb、-OC(S)Zb、-OC(O)O-、-OC(O)OZb、-OC(S)OZb,、-NZbc(O)OZb、-NZbc(S)OZb、-NZbc(O)NZcZc、-NZbc(NZb)Zb和-NZbc(NZb)NZcZc,其中Za、Zb和Zc如上所定义。
在本申请中,由于所述的化合物可能含有1个以上的手性中心和/或双键,因此,可能以立体异构体形式存在,例如,可以以双键异构体(即几何异构体,例如E及Z)、对映异构体或非对映异构体形式存在。本申请还包括分别分离的立体异构体形式(例如,从对映异构体角度纯的异构体、E和Z异构体以及立体异构体的其他替代物)及手性纯度和E及Z百分比不同的立体异构体的混合物(除非被限定为特定的立体异构体)。因此,本申请中描述的化学结构包括所述化合物的所有可能的对映异构体和立体异构体,包括立体异构体角度上的纯的形式(例如几何异构角度上的纯的形式、对映异构角度上的纯的形式或非对映异构角度上的纯的形式)及对映异构体混合物和立体异构体混合物等。可以使用本领域熟知的分离技术或手性合成技术将对映异构体混合物和立体异构体混合物分成与其相应的对映异构体或立体异构体组分。本申请不仅包括各自分离的立体异构体形式,还包括不同手性纯度的立体异构体的混合物(包括外消旋混合物)。本申请还包括多种非对映异构体。虽然,其他结构可能看起来描述了特定的异构体,但这只是为了方便,并不旨在将本申请限定为具体描述的异构体。当化学名称未明确表示化合物的异构形式时,它应指化合物的异构体形式中的所有可能的异构体形式或其混合物。
在本说明书和权利要求中使用的情况下,词语“包含~”、“包含~的”、“包括~”和“包括~的”旨在用于对所提及的特征、整数、成分、或步骤进行具体化,但不排除另一个以上的其他特征、整数、成分、或步骤、或它们的组合的存在或添加。
当与时间和温度一起使用时,术语“约”是指±5小时,例如±1小时。当与温度一起使用时,术语“大约”是指±5摄氏度,例如±1摄氏度。当与百分比或其他值、温度一起使用时,术语“约”表示所述百分比或值的±10%,例如±5%。
术语“治疗~”或“治疗”是指治疗剂、预防性或临时性处方的方法或预防性方法。对于本申请而言,非限制性地,有益的或期望的临床结果为可被检测或不可检测,且可包括症状缓解、疾病严重程度的减轻、疾病的稳定(即未恶化)状态、疾病的延迟或缓慢进展、疾病状态的改善或临时处方和好转(无论是部分还是全部)。与未接受治疗的预期生存相比,“治疗”也可以指持续生存。需要治疗的不仅包括容易具有病情或障碍的,而且还包括已经具有病情或障碍、或已经预防病情或障碍的。
术语“癌症”和“癌性”表示或表达哺乳动物中通常以异常或不受调节的细胞生长为特征的生理状况。“肿瘤”包括一种以上的癌性细胞。非限制性地,癌症的示例包括癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴恶性肿瘤。此类癌症的更具体示例包括:鳞状上皮细胞癌(squamos cell carcinoma)(例如,上皮性鳞状上皮细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌(“NSCLC”)、肺腺癌及肺鳞状上皮细胞癌)、腹膜癌、肝细胞癌、胃或胃癌(包括胃肠癌)、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝肿瘤、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾或肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、皮肤癌(包括黑色素瘤)以及头颈癌。
表述“药学上可接受的”是指所述物质或组合物在化学和/或毒理学上与由此治疗的哺乳动物和/或包括剂型的其他成分可并存。
如在本说明书中所使用,表述“药学上可接受的盐”是指药学上可接受的本申请的化合物的有机盐或无机盐。
如在本说明书中所使用,表述“药学上可接受的盐”是指本说明书中记载的化合物的药剂学上可接受的有机盐或无机盐。非限制性地,作为示例性的盐可包括硫酸盐,柠檬酸盐、乙酸盐、草酸盐,氯化物、溴化物、碘化物、硝酸盐,硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙醇盐、乙磺酸盐、乙二磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1'-亚甲基双-(2-羟基-3-萘甲酸盐)(1,1'-methylene-bis-(2-hydroxy-3-naphtonate)))。药学上可接受的盐可以包含另一分子的包涵体,例如乙酸根离子、琥珀酸根离子或其他抗衡离子。抗衡离子可以是稳定母体化合物电荷的任何有机或无机部分。并且,药学上可接受的盐在其结构中可以具有超出一个的填充原子。多个填充原子为药学上可接受的盐的一部分情况下的示例,可以具有多个抗衡离子。因此,药学上可接受的盐可以具有一个以上的填充原子和/或一个以上的抗衡离子。
根据本申请的化合物可以是至少一种选自由下述化学式组成的组的化合物,但不限于此。
本申请的一实施例提供一种包括所述化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合;以及药学上可接受的载体、赋形剂、稀释剂或免疫佐剂的用于预防或治疗癌症的药物组合物。当将由所述化学式1表示的化合物或其药学上可接受的盐单独给药时,具有抑制癌症活性的效果。
本申请的一实施例提供一种包括所述化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合;以及药学上可接受的载体、赋形剂、稀释剂或免疫佐剂的用于预防或治疗耐受性癌的药物组合物。当针对耐受性癌将由所述化学式1表示的化合物或其药学上可接受的盐与抗癌药物或放射线疗法联合施用时,具有抑制癌症活性的效果。
本申请的一实施例提供一种包含由式1表示的化合物或其药学上可接受的盐的用于预防或治疗耐受性癌的药物组合物。当针对耐受性癌将由所述化学式1表示的化合物或其药学上可接受的盐与抗癌药物或放射线疗法联合施用时,具有抑制癌症活性的效果。
在本申请的一实施例中,所述癌症或耐受性癌可以为选自由卵巢癌、大肠癌、胰腺癌、胃癌、肝癌、乳腺癌、宫颈癌、甲状腺癌、甲状旁腺癌、肺癌、非小细胞肺癌、前列腺癌、胆囊癌、胆道癌、血液癌、膀胱癌、肾癌、黑色素瘤、结肠癌、骨癌、皮肤癌、头颈癌、子宫癌、直肠癌、脑癌、肛周癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、输尿管癌、肾细胞癌、肾盂癌、血液癌、白血病、中枢神经系统(central nervous system;CNS)肿瘤、脊髓肿瘤、脑干神经胶质瘤及脑下垂体腺瘤组成的组中的至少一种。
根据本申请的一实施例的药物组合物能够以1:0.001至1:1000、1:0.01至1:100、1:0.1至1:50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。
本申请的一实施例的药物组合物可以是胶囊剂、片剂、颗粒、注射剂、软膏剂、粉末或饮料形式,并且能够以口服剂型、外用剂、栓剂等形式剂型化来使用。
本申请的药物组合物的剂型能够通过与药学上可接受的载体混合来以多种方式制备,并且能够口服或非口服给药。就药学上可接受的载体而言,在口服给药时,可以为结合剂、滑泽剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、色素、香料等;作为注射剂时,能够将缓冲剂、保存剂、无痛化剂、增溶剂、等渗剂、稳定剂等混合使用;用于局部给药时,可使用基质、赋形剂、润滑剂、保存剂等。
例如,用于口服给药的制剂能够以片剂、锭剂、胶囊剂、酏剂(elixir)、混悬剂、糖浆剂、薄片(wafer)、丸剂、散剂、颗粒剂、胶囊剂等的形式制备。在所述制剂中,固体制剂能够通过混合至少一种以上的赋形剂,例如淀粉、碳酸钙、蔗糖乳糖明胶等来制备。此外,除赋形剂以外,还可使用如硬脂酸镁、滑石粉的润滑剂。液体制剂除单纯稀释剂水、液体石蜡以外,可使用润湿剂、甜味剂、芳香剂和保存剂等,但不限于此。
例如,用于非口服给药的制剂可以为非水性溶剂、混悬剂、乳剂、冻干制剂、栓剂等。作为注射剂时,能够制备成单位剂量安瓿或多次给药形式,并且可以选择腹腔内注射、直肠内注射、皮下注射、静脉注射、肌肉内注射或胸腔内注射的注入方式。
用于药物组合物剂型化的载体、赋形剂和稀释剂可以为乳糖、右旋糖(dextrose)、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、藻酸盐、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、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁、矿物油、填充剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂或防腐剂等。
本申请药物组合物的给药途径包括但不限于口腔、静脉内、肌肉内、动脉内、髓内、鞘膜内、心内、经皮、皮下、腹腔内、鼻腔内、肠道、局部、舌下或直肠。
作为额外地能够被使用的免疫佐剂(adjuvant),本领域常规使用的免疫佐剂能够不受限制地被使用。在本申请中,免疫佐剂表示如果同时、同时间段或连续施用时,能够产生、加剧或改变对本发明的活性成分的特定反应的任何物质。作为已知的注射液用免疫佐剂,例如包括:铝组合物(如氢氧化铝或磷酸铝);皂苷(如QS21);胞壁酰二肽或胞壁酰三肽;蛋白质(如γ-干扰素或肿瘤坏死因子(TNF));M59;角鲨烯;多元醇。
本申请药物组合物的给药量根据患者的状态和体重,疾病的严重程度,药物形式,给药途径和时间而不同,但可以由本领域技术人员适当地选择。例如,本申请药物组合物可以每天给药0.0001mg/kg至1000mg/kg或0.001mg/kg至500mg/kg。本申请的药物组合物的给药可以每天给药一次,也可以分几次给药。所述给药量不以任何方式限制本申请的范围。
此外,本申请提供一种由化学式1表示的化合物或其药学上可接受的盐在治疗耐受性癌中的用途。
耐受性癌、由化学式1表示的化合物或其药学上可接受的盐与前述内容相同,因此省略具体说明。
本申请提供一种癌症的治疗方法,包括对患有癌症的对象施用治疗有效量的前述的由化学式1表示的化合物、其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的步骤。就所述给药(施用)而言,可以同时、分开或按顺序施用可用于治疗癌症或增殖性疾病的化学治疗剂。
此外,本申请提供一种对肿瘤学疗法表现出耐受性的癌症的治疗方法,包括对患有耐受性癌的对象施用治疗有效量的前述的由化学式1表示的化合物、其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的步骤。就所述给药而言,可以是同时、分开或按顺序施用可用于治疗癌症或增殖性疾病的化学治疗剂。
术语“治疗学上的有效量”或“治疗有效量”指本申请中记载的化学式I的化合物施用于哺乳动物时,足以产生如下效果的量,这种效果为:(i)治疗或预防特定疾病、病情或障碍;(ii)减弱、改善或缓解特定疾病、病情或障碍中的一种以上的症状;或(iii)预防或延迟特定疾病、病情或障碍中的一种以上的症状。与该量相当的化合物的量将根据诸如特定化合物、疾病状态及其严重程度、需要治疗的哺乳动物的共性(例如,重量)等因素而不同,但尽管如此,可以由本领域的普通技术人员常规地确定。
术语“给药(施用)”是指通过适当的方法将预定的物质引入个体。
耐受性癌、由化学式1表示的化合物或其药学上可接受的盐与前述内容相同,因此省略具体说明。
“患有耐受性癌的对象”是指已经发展或很可能发展为耐受性癌而需要适当治疗的个体,可以是接受过抗癌治疗(例如手术切除疗法、使用抗癌剂的化学疗法、放射线疗法或免疫疗法),但由于对其产生耐受性而复发的个体。
患有耐受性癌的个体可包括人、牛、狗、豚鼠、兔、鸡或昆虫等。
此外,本申请提供一种放射线治疗方法,包括对患有耐受性癌的对象施用药由化学式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。
耐受性癌、患有耐受性癌的对象、由化学式1表示的化合物或其药学上可接受的盐与前述内容相同,因此省略具体说明。
作为放射线照射,可应用已经用于癌症的放射线治疗的任何放射线方法或可能以后被开发出的对于癌症的放射线方法。
当联合使用本申请的由化学式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时,通过赋予对于癌细胞或癌症干细胞的生长抑制和/或死亡诱导的协同作用,从而不仅能够有效地预防或治疗癌症,进而还可以防止对放射线的耐受性、或癌症的转移或癌症的复发。
本申请由化学式1表示的化合物或其药学上可接受的盐具有能作为靶向SERCA蛋白的抑制剂的作用。本申请的由化学式1表示的化合物或其药学上可接受的盐能够抑制SERCA蛋白的表达。
此前的研究表明,癌症干细胞所具有的抗癌剂抗性的核心原因在于参与细胞内钙离子运输和储存的蛋白质,即“SERCA(肌浆网/内质网钙ATP酶(sarco/endoplasmicreticulum calcium ATPase))”。
就普通癌细胞而言,当利用抗癌剂进行给药时,会诱发过度的应激,钙离子会从内质网(endoplasmic reticulum,ER)中过度分泌,分泌出来的钙离子会在线粒体内积聚,导致癌细胞凋亡,而就癌症干细胞而言,当利用抗癌剂进行给药时,能减少过量钙离子的分泌,同时通过增加可以使过度分泌的钙离子返回至内质网的SERCA的表达,以控制钙离子浓度,从而实现生存。也就是说,SERCA蛋白可以在内质网应激信号转导过程中发挥生存信号转导作用。
本申请的由化学式1表示的化合物或其药学上可接受的盐具有能够作为靶向SERCA蛋白的抑制剂的作用,其中所述SERCA蛋白是癌症干细胞表现出其所具有的抗癌剂抗性的原因。因此,可增加基于抗癌药物的化疗的疗效,即使使用较低用量的药物也可以表现出优异的抗癌效果。
具体实施例
制备例
通过下述制备例的方法制备了根据本申请的化合物。
1、制备例1:四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)
经以下记载的5个步骤的工序,制备了表示化学式8的骨架的四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(PPD)。下面具体说明每个步骤中的合成方法。
1)步骤1:1,4-双(叔丁氧基羰基)哌嗪-2-甲酸(1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid)
[反应式1]
加入30g哌嗪-2-甲酸(Piperazine-2-carboxylic acid)(231mmol)、150mL四氢呋喃和150mL纯净水。冷却反应产物,并加入26.8g碳酸钠(254mmol)。冷却反应产物并加入110.6g碳酸酐二叔丁酯(di-tert-butyl decarbonate)(506mmol)后,在室温下搅拌。减压浓缩反应产物。向浓缩的残渣中,加入500mL二氯甲烷。冷却反应产物并滴加4M盐酸。提取有机层。用60mL二氯甲烷提取水层。混合有机层并用300mL纯净水洗涤。将有机层用无水硫酸镁干燥并过滤后,减压浓缩反应液。向残渣中加入60mL二氯甲烷和210mL正庚烷,并在室温下搅拌。额外加入210mL正庚烷,并在室温下搅拌。过滤反应产物,并在60℃下热风干燥,从而以固体形式获得目标化合物(70g,收率92%)。
2)步骤2:2-((2-甲氧基-2-氧代乙基)氨基甲酰基)哌嗪-1,4-二羧酸二叔丁酯(di-tert-butyl 2-((2-metoxy-2-oxoethyl)carbamoyl)piperazine-1,4-dicarboxylate)
[反应式2]
加入70g的1,4-双(叔丁氧羰基)哌嗪-2-甲酸(1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid)(212mmol)、28.6g甘氨酸甲酯盐酸盐(glycine methylester hydrochloride)(228mmol)、30.8g羟基苯并三唑(hydroxybenzotriazole)(228mmol)、2.5g的4-二甲基氨基吡啶(4-dimethylaminopyridine)(21mmol)、1400mL二氯甲烷、39mL的N,N-二异丙基乙胺(N,N-diisopropylethylamine)(229mmol)、47.2g的N,N’-二环己基碳二亚胺(N,N’-dicyclohexylcarbodiimide)(229mmol),并在室温下搅拌。过滤反应产物,滤液用700mL纯净水洗涤3次。将有机层用无水硫酸镁干燥并过滤。减压浓缩反应液,从而以残渣形式获得目标化合物,并用于下一个步骤。
3)步骤3:[(哌嗪-2-羰基)氨基]乙酸甲酯(Methyl[(piperazine-2-carbonyl)amino]acetate)2三氟乙酸盐
[反应式3]
加入95.4g的2-((2-甲氧基-2-氧代乙基)氨基甲酰基)哌嗪-1,4-二羧酸二叔丁酯(di-tert-butyl 2-((2-metoxy-2-oxoethyl)carbamoyl)piperazine-1,4-dicarboxylate)浓缩残渣、700mL二氯甲烷和200mL三氯乙酸(TFA)并在45℃下回流搅拌后,减压浓缩二氯甲烷。向浓缩的残渣中加入300mL异丙醇并在45℃下搅拌30分钟。加入100mL异丙醇,将反应液冷却至室温。向反应产物中加入600mL正庚烷并在室温下搅拌。向反应产物中额外加入600mL正庚烷并在室温下搅拌。过滤反应产物后,回收固体,并在60℃下热风干燥,从而以固体形式获得目标化合物(76g,两个步骤的总收率85%)。
4)步骤4:四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)三氟乙酸盐
[反应式4]
加入76g[(哌嗪-2-羰基)氨基]乙酸甲酯2三氟乙酸盐(177mmol)、460mL甲醇、79mL的1,8-二氮杂双环(5.4.0)十一-7-烯(1,8-diazabicyclo(5.4.0)undec-7-ene,DBU)(531mmol),并在室温下搅拌2小时后,减压浓缩反应液。向浓缩的残渣中加入230mL乙酸乙酯,并将反应产物冷却至10℃以下。滴加122mL三氟乙酸(TFA)。在室温下,加入684mL异丙醚并搅拌3小时后,过滤反应产物。回收固体,并在60℃下热风干燥,从而以固体形式获得目标化合物(48g,收率95%)。
[化学式8-2]
四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)
1H NMR(700MHz,D2O)δ4.64-4.61(m,1H),4.51-4.49(m,1H),4.07(d,J=1.0Hz,2H),3.80-3.78(m,1H),3.53-3.50(m,1H),3.29-3.25(m,1H),3.13-3.08(m,1H),3.07-3.03(m,1H).
13C NMR(176MHz,D2O)δ164.62,164.43,53.47,44.48,43.73,42.13,38.04.
C7H11N3O2[M+H]+的MS(ESI)m/z:计算值170.0930,实测值170.0917。
2、制备例2:8-[(萘-2-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-[(naphthalen-2-yl)methyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(化学式N501)
[反应式5]
在室温下,加入了通过制备例1获得的1g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮三氟乙酸盐(3.53mmol)、10mL二氯甲烷、1.0mL三乙胺、0.61g的2-萘甲醛(2-naphthaldehyde)(3.88mmol)。加入1.5g三乙酰氧基硼氢化钠(7.06mmol),并在室温下搅拌4小时,然后将反应液用10mL纯净水洗涤。将反应液依次用10mL的碳酸氢钠水溶液和纯净水洗涤。将有机层用无水硫酸镁干燥并过滤,然后浓缩反应液。向浓缩的残渣中加入6mL二氯甲烷并溶解反应液。缓慢滴加6mL正庚烷,析出结晶,室温搅拌2小时后,过滤反应产物。将固体在60℃下热风干燥,从而以白色固体的形式获得目标化合物(0.95g,收率87%)。
[化学式N501]
8-[(萘-2-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-[(naphthalen-2-yl)methyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(以N501表示)
1H NMR(500MHz,CDCl3)δ7.84-7.80(m,3H),7.72(s,1H),7.49-7.45(m,3H),6.43(s,1H),4.53-4.50(m,1H),4.12-4.04(m,1H),4.04(d,J=1.5Hz,2H),3.81(d,J=13Hz,1H),3.69(d,J=13.5Hz,1H),3.49-3.47(m,1H),2.91(d,J=11.5Hz,1H),2.85-2.79(m,1H),2.17(t,J=11.3Hz,1H),2.13-2.08(m,1H).
13C NMR(176MHz,CDCl3)δ163.41,161.66,134.91,132.92,128.93,128.51,128.17,127.80,127.65,127.11,126.09,125.82,62.69,57.31,56.71,51.30,48.53,41.26.
C18H19N3O2[M+H]+的MS(ESI)m/z:计算值310.1556,实测值310.1550。
3、制备例3:化学式N513
使用实施例2获得的化合物(化学式N501)作为起始物质,进一步进行以下反应式6的步骤,从而获得了化学式N513的化合物。
[反应式6]
加入0.3g的8-[(萘-2-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(0.97mmol)和0.08g氢化钠(1.9mmol),二甲基甲酰胺,并搅拌1小时后,加入0.18mL苄基溴(1.5mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和15mL乙酸乙酯终止反应。提取有机层,并用20mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得2-苄基-8-(萘-2-基甲基)六氢-1H-吡嗪并[1,2-a]吡嗪-1,4(6H)-二酮(2-benzyl-8-(naphthalen-2-ylmethyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione)(0.15g,收率39%)。
[化学式N513]
2-苄基-8-(萘-2-基甲基)六氢-1H-吡嗪并[1,2-a]吡嗪-1,4(6H)-二酮(2-benzyl-8-(naphthalen-2-ylmethyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione)(以N513表示)
1H NMR(500MHz,CDCl3)δ7.83-7.80(m,3H),7.72(s,1H),7.49-7.45(m,3H),7.35-7.30(m,3H),7.24(d,J=7.0Hz,2H),4.59-4.52(m,2H),4.47(d,J=13.5Hz,1H),4.19-4.16(m,1H),3.86(s,2H),3.82(d,J=13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.59(d,J=11.5Hz,1H),2.87(d,J=11.5Hz,1H),2.81-2.76(m,1H),2.16(t,J=11.3Hz,1H),2.09-2.04(m,1H).
13C NMR(176MHz,CDCl3)δ165.84,162.76,134.79,134.57,133.23,132.86,130.73,130.04,128.68,128.08,127.77,127.64,127.35,127.11,126.08,125.80,62.67,57.39,55.94,55.76,51.09,41.50,41.12.
C25H25N3O2[M+H]+的MS(ESI)m/z:计算值400.2025,实测值400.2018。
4、制备例4:化学式S461
[反应式7]
在室温下,加入了通过制备例1获得的1g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(3.53mmol)、10mL二氯甲烷、1.0mL三乙胺、0.6g的苯甲醛(Benzaldehyde)(5.9mmol)。加入1.5g三乙酰氧基硼氢化钠(7.06mmol),并在室温下搅拌4小时,然后将反应液用8mL纯净水洗涤。将反应液依次用8mL的碳酸氢钠水溶液和纯净水洗涤。将有机层用无水硫酸镁干燥并过滤,然后浓缩反应液。向浓缩的残渣中加入6mL二氯甲烷并溶解反应液。缓慢滴加6mL正庚烷,析出结晶,室温搅拌2小时后,过滤反应产物。将固体在60℃下热风干燥,从而以白色固体的形式获得了8-苄基四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-benzyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(0.78g,收率51%)。
[化学式S461]
8-苄基四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-benzyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)
1H NMR(500MHz,CDCl3)δ7.35-7.27(m,5H),7.01(s,1H),4.53-4.50(m,1H),4.11-4.09(m,1H),4.03(s,2H),3.65(d,1H),3.53(d,1H),3.44-3.42(m,1H),2.87-2.85(m,1H),2.83-2.77(m,1H),2.11(t,J=11.5Hz,1H),2.08-2.03(m,1H).
13C NMR(176MHz,CDCl3)δ163.41,161.64,137.89,134.91,128.94,128.51,128.32,128.19,57.27,56.44,51.22,49.31,48.53,41.23.
质量260.13
5、制备例5:化学式S462
使用制备例4获得的化合物(化学式S461)作为起始物质,进一步进行以下反应式8的步骤,从而获得了化学式S462的化合物。
[反应式8]
加入0.5g的8-苄基四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-benzyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(1.95mmol)和0.16g氢化钠(3.9mmol)、10mL二甲基甲酰胺,并搅拌1小时后,加入0.35mL苄基溴(2.9mmol),并在室温下搅拌过夜。用20mL氯化铵水溶液和20mL乙酸乙酯终止反应。提取有机层,并用20mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤,然后浓缩反应液,并通过硅胶层析纯化,从而获得了2,8-二苄基四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(2,8-dibenzyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(0.49g,收率72%)。
[化学式S462]
2,8-二苄基四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(2,8-dibenzyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)
1H NMR(500MHz,CDCl3)δ7.36-7.25(m,10H),4.61-4.54(m,2H),4.47(d,J=13.0Hz,1H),4.15(d,J=9.5Hz,1H),3.90-3.83(m,2H),3.66(d,J=13.0Hz,1H),3.55-3.52(m,2H),2.85-2.75(m,2H),2.11(t,J=11.5Hz,1H),2.06-2.00(m,1H).
13C NMR(176MHz,CDCl3)δ163.43,161.64,137.02,134.93,129.07,128.93,128.50,128.41,128.18,127.44,62.54,57.31,56.61,51.27,49.30,48.53,41.26.
质量350.18
6、制备例6:化学式S471
[反应式9]
在室温下,加入了1g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-[(thiophen-3-yl)methyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)·三氟乙酸盐(3.53mmol)、10mL二氯甲烷、1.0mL三乙胺、0.66g的3-噻吩甲醛(3-Thiophenecarboxaldehyde)(5.9mmol)。加入1.5g三乙酰氧基硼氢化钠(7.06mmol),并在室温下搅拌4小时,然后将反应液用8mL纯净水洗涤。将反应液依次用8mL的碳酸氢钠水溶液和纯净水洗涤。将有机层用无水硫酸镁干燥、过滤,之后,浓缩反应液。向浓缩的残渣中加入6mL二氯甲烷并溶解反应液。缓慢滴加6mL正庚烷,析出结晶,室温搅拌2小时后,过滤反应产物。将固体在60℃下热风干燥,从而以白色固体的形式获得了8-[(噻吩-3-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-[(thiophen-3-yl)methyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(0.75g,收率48%)。
[化学式S471]
8-[(噻吩-3-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-[(thiophen-3-yl)methyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)
1H NMR(500MHz,CDCl3)δ7.31-7.29(m,1H),7.13(m,1H),7.05-7.04(m,2H),4.53-4.51(m,1H),4.10-3.99(m,3H),3.66(d,J=13.5Hz,1H),3.59(d,J=13.5Hz),3.44-3.42(m,1H),2.88(d,J=11.5Hz,1H),2.83-2.77(m,1H),2.11-2.02(m,2H).
13C NMR(176MHz,CDCl3)δ166.09,161.86,137.81,128.30,125.90,123.27,57.09,56.83,55.88,51.35,44.50,41.42.
质量266.09
7、制备例7:化学式S472
使用制备例6获得的化合物(化学式S471)作为起始物质,进一步进行以下反应式8的步骤,从而获得了化学式S472的化合物。
[反应式10]
添加0.5g的8-[(噻吩-3-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(8-[(thiophen-3-yl)methyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(1.87mmol)和0.15g氢化钠(3.75mmol)、10mL二甲基甲酰胺,并搅拌1小时后,加入0.33mL苄基溴(2.81mmol),并在室温下搅拌过夜。用30mL氯化铵水溶液和30mL乙酸乙酯终止反应。提取有机层,并用20mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-苄基-8-[(噻吩-3-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(2-benzyl-8-[(thiophen-3-yl)methyl]tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione)(0.42g,收率62%)。
[化学式S472]
1H NMR(500MHz,CDCl3)δ7.36-7.29(m,4H),7.26-7.25(m,2H),7.14(m,1H),7.06-7.05(m,1H),4.62-4.53(m,2H),4.50-4.47(m,1H),4.15-4.14(m,1H),3.90-3.83(m,2H),3.67(d,J=13.5Hz,1H),3.59(d,J=13.5Hz,1H),3.56-3.54(m,1H),2.87-2.85(m,1H),2.81-2.76(m,1H),2.08(t,J=11.5Hz,1H),2.05-2.00(m,1H).
13C NMR(176MHz,CDCl3)δ166.03,161.88,134.54,133.25,132.90,128.18,127.80,127.71,127.66,127.10,126.13,125.85,62.69,56.85,56.12,51.50,50.58,44.48,41.45.
质量356.14
8、制备例8:化学式N021
[化学式N021]
1H NMR(400MHz,CDCl3)δ8.08(d,J=7.7Hz,1H),7.99(m,1H),7.48-7.44(m,1H),7.41-7.35(m,3H),7.24-7.20(m,1H),6.61(s,1H),4.50(ddd,J=13.1,2.9,1.8Hz,1H),4.36(q,J=7.2Hz,2H),4.14-4.10(m,1H),4.06-3.97(m,2H),3.83(d,J=12.8Hz,1H),3.70(d,J=12.8Hz,1H),3.52-3.48(m,1H),2.94-2.91(m,1H),2.81(td,J=12.8,3.2Hz,1H),2.15(t,J=11.2Hz,1H),2.11-2.50(m,1H),1.45-1.41(m,3H).
13C NMR(101MHz,CDCl3)δ165.78,161.62,140.19,139.45,127.09,127.02,125.71,122.88,122.64,121.20,120.45,118.80,108.50,108.32,77.34,77.03,76.71,63.01,56.93,56.13,51.31,44.63,41.54,37.59,13.85.
质量377.19
9、制备例9:化学式N022
[反应式11]
在室温下,加入了0.15g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(0.53mmol)、15mL二氯甲烷、1.5mL三乙胺、0.15g的9-苄基-9H-咔唑-3-甲醛(9-benzyl-9H-carbazole-3-carbaldehyde)(0.53mmol)。加入0.22g三乙酰氧基硼氢化钠(1.06mmol),并在室温下搅拌过夜。将反应液用10mL纯净水洗涤。将反应液依次用10mL碳酸氢钠水溶液和10mL纯净水洗涤。将有机层用无水硫酸镁干燥并过滤,之后,浓缩反应液。向浓缩的残渣中加入2mL二氯甲烷并溶解反应液。缓慢滴加6mL正庚烷,析出结晶,并过滤反应产物。干燥固体,从而获得了2-((9-苄基-9H-咔唑-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((9-benzyl-9H-carbazol-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.126g,收率54%)。
[化学式N022]
2-((9-苄基-9H-咔唑-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((9-benzyl-9H-carbazol-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.11(d,J=7.7Hz,1H),8.03(s,1H),7.44-7.21(m,8H),7.16-7.14(m,2H),7.00(s,1H),5.50(s,2H),4.52-4.49(m,1H),4.13-4.09(m,1H),4.00(s,2H),3.82(d,J=12.8Hz,1H),3.69(d,J=12.9Hz,1H),3.51-3.48(m,1H),2.93(d,J=11.6Hz,1H),2.80(td,J=12.8,3.2Hz,1H),2.15(t,J=11.3Hz,1H),2.11-2.05(m,1H).
13C NMR(101MHz,CDCl3)δ166.16,161.87,141.12,140.37,137.28,128.98,127.78,127.67,127.48,126.59,126.16,123.19,122.93,121.31,120.60,119.46,109.17,108.95,63.16,57.10,56.32,51.56,46.82,44.77,41.70.
质量439.21
10、制备例10:化学式N024
[化学式N024]
1H NMR(500MHz,CDCl3)δ8.11(brs,1H),7.86(m,1H),7.30-7.24(m,2H),7.12(m,1H),5.89(s,1H),4.54-4.50(m,1H),4.13-4.10(m,1H),4.06-4.05(m,2H),3.73(dd,J=30.4,13.4Hz,2H),3.51-3.48(m,1H),2.96-2.94(m,1H),2.82(td,J=12.7,3.2Hz,1H),2.11-2.04(m,2H).
质量377.06
11、制备例11:化学式N025
[化学式N025]
1H NMR(400MHz,MeOD)δ7.20(d,J=8.8Hz,1H),7.13(m,2H),6.73(dd,J=8.8,2.4Hz,1H),4.41(ddd,J=13.2,3.1,1.8Hz,1H),4.07-4.03(m,1H),3.93-3.90(m,2H),3.78(s,3H),3.74(d,J=4.7Hz,2H),3.44-3.40(m,1H),2.99-2.96(m,1H),2.78(td,J=12.8,3.2Hz,1H),2.09-2.02(m,2H).
13C NMR(101MHz,MeOD)δ167.61,164.81,155.34,133.54,129.58,126.83,113.09,112.92,110.95,102.02,58.15,56.84,56.40,54.33,52.71,45.24,42.54.
质量329.16
12、制备例12:化学式N026
[化学式N026]
1H NMR(500MHz,CDCl3)δ7.58(d,J=8.1Hz,1H),7.30-7.24(m,3H),7.20(s,1H),7.11-7.09(m,3H),7.05-7.04(m,1H),6.52(m,1H),5.31(s,2H),4.46-4.30(m,1H),4.07-4.05(m,1H),3.98(m,1H),3.74(d,J=12.9Hz,1H),3.58(d,J=12.9Hz,1H),3.42(d,J=11.1Hz,1H),2.82(m,1H),2.76-2.70(m,1H),2.11-2.06(m,1H),2.01-1.96(m,1H).
13C NMR(126MHz,CDCl3)δ166.08,161.84,137.53,136.50,130.39,128.85,128.68,128.28,127.71,126.89,121.24,120.91,110.38,101.69,63.22,56.96,56.17,51.27,50.16,44.65,41.54.
质量389.19
13、制备例13:化学式N032
[反应式12]
在室温下,加入1.41g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(1.2当量)、15mL甲醇、1mL三乙胺、0.8g的2-氯-3-喹啉甲醛(2-chloro-3-quinolinecarboxaldehyde)(1当量),并在室温下搅拌过夜。加入3mL二氯甲烷和2.65g三乙酰氧基硼氢化钠后,在室温下搅拌10分钟。将反应液用100mL碳酸氢钠水溶液洗涤,并用无水硫酸镁干燥,过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-((3-氯喹啉-2-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((3-chloroquinolin-2-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.04g,收率3%)。
[化学式N032]
2-((3-氯喹啉-2-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((3-chloroquinolin-2-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.30-8.25(m,1H),8.02-7.96(m,1H),7.91-7.85(m,1H),7.79-7.72(m,1H),7.64-7.55(m,1H),4.58-4.50(m,1H),4.23-4.14(m,1H),4.05-4.00(m,2H),3.87-3.82(m,1H),3.52-3.45(m,1H),3.05-2.85(m,2H),2.38-2.26(m,2H).
13C NMR(126MHz,CDCl3)δ165.74,162.98,151.30,147.00,139.24,130.90,129.35,127.85,127.81,127.64,127.51,59.04,57.09,56.11,51.96,44.44,41.71.
质量345.11
14、制备例14:化学式N033
[反应式13]
在室温下,加入了0.3g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(1.06mmol)、3mL二氯甲烷、0.3mL三乙胺、0.24g的6-氯-2-甲基喹啉-3-甲醛(6-chloro-2-methylquinoline-3-carboxaldehyde)(1.17mmol)。加入0.449g三乙酰氧基硼氢化钠(2.12mmol),并在室温下搅拌1小时。加入醋酸调节pH至4~5,并在室温下搅拌5小时。将反应液用24mL纯净水洗涤。将反应液依次用24mL碳酸氢钠水溶液和24mL纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-((2-氯-6-甲基喹啉-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-chloro-6-mrthylquinolin-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.234g,收率56%)。
[化学式N033]
2-((2-氯-6-甲基喹啉-3-基)甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-((2-chloro-6-mrthylquinolin-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,DMSO)δ8.37-8.23(m,2H),7.87-7.803(m,2H),7.66-7.64(m,1H),4.31(d,J=13.0Hz,1H),4.07-4.04(m,1H),3.91-3.78(m,4H),3.26-3.24(m,1H),2.94-2.92(m,1H),2.75(t,J=11.7Hz,1H),2.17-2.15(m,2H).
13C NMR(101MHz,DMSO)δ164.68,162.63,149.60,144.82,138.34,137.07,132.70,129.40,127.29,126.97,126.64,58.05,56.04,55.31,51.41,43.90,40.66,21.13.
质量359.2
15、制备例15:化学式N034
[化学式N034]
1H NMR(500MHz,CDCl3)δ8.81-8.79(m,1H),8.27-8.24(m,1H),8.10-8.07(m,1H),7.79-7.76(m,1H),7.64-7.61(m,1H),7.50-7.48(m,1H),4.53-4.50(m,1H),4.15-4.10(m,2H),4.03-4.00(m,3H),3.49-3.46(m,1H),2.95-2.93(m,1H),2.88-2.82(m,1H),2.31-2.22(m,2H)
13C NMR(126MHz,CDCl3)δ165.77,163.08,149.87,148.00,144.04,130.08,129.23,127.87,127.17,124.46,121.92,59.37,57.15,56.49,52.15,44.45,41.73.
质量311.14
16、制备例16:化学式N035
[反应式14]
在室温下,加入了0.2g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(0.70mmol)、2mL二氯甲烷、0.2mL三乙胺、0.122g的6-喹啉甲醛(6-quinolinecarboxaldehyde)(0.78mmol)。加入0.3g三乙酰氧基硼氢化钠(1.42mmol),并在室温下搅拌1小时。加入醋酸(Acetic acid)调节pH至4~5,并在室温下搅拌5小时。将反应液用16mL纯净水洗涤。将反应液依次用16mL碳酸氢钠水溶液和16mL纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(喹啉-6-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinoline-6-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.114g,收率52%)。
[化学式N035]
2-(喹啉-6-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinoline-6-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.91(dd,J=4.2,1.6Hz,1H),8.18-8.05(m,2H),7.78-7.67(m,2H),7.41(dd,J=8.3,4.2Hz,1H),7.21(s,1H),4.65-4.44(m,1H),4.19-4.09(m,1H),4.04(m,2H),3.77(dd,J=35.8,13.3Hz,2H),3.47-3.44(m,1H),2.92-2.80(m,2H),2.21-2.09(m,2H).
13C NMR(101MHz,CDCl3)δ165.99,161.95,150.51,148.03,136.11,135.77,130.85,129.82,128.24,127.63,121.50,62.51,57.00,56.30,51.78,44.74,41.63.
质量311.2
17、制备例17:化学式N036
[反应式15]
在室温下,加入了0.3g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(1.06mmol),3mL二氯甲烷,0.3mL三乙胺,0.166g的8-喹啉甲醛(8-quinolinecarboxaldehyde)(1.06mmol)。加入0.449g三乙酰氧基硼氢化钠(2.12mmol),并在室温下搅拌1小时。加入醋酸(Acetic acid)调节pH至4~5,并在室温下搅拌5小时。将反应液用24mL纯净水洗涤。将反应液依次用24mL碳酸氢钠水溶液和24mL纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(喹啉-8-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinoline-8-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.141g,收率43%)。
[化学式N036]
2-(喹啉-8-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinoline-8-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.92(dd,J=4.2,1.8Hz,1H),8.17(dd,J=8.3,1.8Hz,1H),7.85(d,J=7.0Hz,1H),7.76(dd,J=8.1,1.1Hz,1H),7.56(dd,J=7.9,7.3Hz,1H),7.42(dd,J=8.3,4.2Hz,1H),7.15(s,1H),4.54(ddd,J=13.1,2.9,1.8Hz,1H),4.43-4.31(m,2H),4.21-4.14(m,1H),4.03(s,2H),3.55(ddd,J=11.5,3.0,1.8Hz,1H),3.07-2.99(m,1H),2.89(td,J=12.7,3.3Hz,1H),2.34-2.22(m,2H).
13C NMR(101MHz,CDCl3)δ166.20,161.87,149.72,146.98,136.58,135.43,129.46,128.51,127.41,126.52,121.22,57.20,56.75,56.50,52.26,44.76,41.77.
质量311.2
18、制备例18:化学式N054
[化学式N054]
1H NMR(500MHz,CDCl3)δ7.60-7.58(m,2H),7.54-7.49(m,2H),7.47-7.33(m,4H),7.29(d,J=7.5Hz,1H),6.55(s,1H),4.53-4.50(m,1H),4.13-4.11(m,1H),4.04(s,2H),3.71(d,J=13.2Hz,1H),3.60(d,J=13.2Hz,1H),3.51-3.44(m,1H),2.92-2.90(m,1H),2.82(td,J=12.7,3.2Hz,1H),2.18-2.03(m,2H).
13C NMR(126MHz,CDCl3)δ165.87,161.90,141.56,140.99,129.02,128.87,128.19,128.05,127.49,127.27,126.58,62.63,56.77,56.06,51.48,44.66,41.40.
质量336.17
19、制备例19:化学式N301
[反应式16]
在室温下,加入了5.4g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(19.1mmol)、5.5mL二氯甲烷、5.5mL三乙胺、3.0g的3-喹啉甲醛(3-quinolinecarboxaldehyde)(19.1mmol)。加入8.1g三乙酰氧基硼氢化钠(38.2mmol),并在室温下搅拌6小时。将反应液用10mL纯净水洗涤。将反应液依次用10mL的碳酸氢钠水溶液和纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)。
[化学式N301]
2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.90(d,J=2.0Hz,1H),8.11(d,J=8.4Hz,1H),8.06(s,1H),7.81(d,J=7.9Hz,1H),7.75-7.68(m,1H),7.60-7.53(m,1H),7.49(s,1H),4.55-4.49(m,1H),4.17-4.08(m,1H),4.02(s,2H),3.77(dd,J=36.4,13.5Hz,2H),3.47-3.42(m,1H),2.90(d,J=11.6Hz,1H),2.82(td,J=12.9,3.2Hz,1H),2.26-2.10(m,2H).
13C NMR(126MHz,CDCl3)δ165.78,161.95,151.71,147.61,135.86,129.88,129.48,129.12,127.80,127.65,126.93,60.04,56.75,56.00,51.59,44.52,41.37.
质量451.2
20、制备例20:化学式N311
[反应式17]
添加0.25g的2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.65mmol)和0.039g氢化钠(0.97mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.171g的1-(溴甲基)萘(1-(bromomethyl)naphthalene)(0.77mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-(萘-1-基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-1-yl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.212g,收率73%)。
[化学式N311]
8-(萘-1-基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-1-yl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.91(d,J=2.2Hz,1H),8.14-8.10(m,1H),8.06-7.98(m,2H),7.90-7.79(m,3H),7.71(ddd,J=8.4,6.9,1.4Hz,1H),7.58-7.49(m,3H),7.44-7.36(m,2H),5.06(dd,J=35.8,14.5Hz,2H),4.43(ddd,J=13.2,3.1,1.7Hz,1H),4.21-4.16(m,1H),3.84-3.69(m,4H),3.62(ddd,J=11.3,3.2,1.7Hz,1H),2.86-2.81(m,1H),2.78-2.73(m,1H),2.17(t,J=11.2Hz,1H),2.06(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ162.85,161.62,151.77,147.70,135.74,133.96,131.47,130.01,129.90,129.49,129.40,129.22,128.89,128.54,127.79,127.64,126.92,126.86,126.26,125.14,123.53,60.03,57.24,56.57,51.30,48.13,47.23,41.08.
质量451.2
21、制备例21:化学式N312
[反应式18]
添加0.2g的2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.64mmol)和0.039g氢化钠(0.97mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.171mL的2-(溴甲基)萘(2-(bromomethyl)naphthalene)(0.77mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-(萘-2-基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-2-yl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.181g,收率62%)。
[化学式N312]
8-(萘-2-基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-2-yl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.91(d,J=2.1Hz,1H),8.12(d,J=8.5Hz,1H),8.05(d,J=1.5Hz,1H),7.85-7.77(m.4H),7.73-7.67(m,2H),7.55(ddd,J=8.1,6.9,1.1Hz,1H),7.52-7.45(m,2H),7.36(dd,J=8.4,1.7Hz,1H),4.76-4.66(m,2H),4.47(ddd,J=13.2,3.0,1.7Hz,1H),4.21-4.16(m,1H),3.90(s,2H),3.77(dd,J=56.3,13.5Hz,2H),3.59(ddd,J=11.3,3.2,1.7Hz,1H),2.88-2.83(m,1H),2.79(td,J=12.8,3.3Hz,1H),2.19(t,J=11.2Hz,1H),2.10(td,J=11.7,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.43,161.78,151.88,147.80,135.84,133.29,133.11,132.34,129.98,129.50,129.32,129.12,127.89,127.84,127.80,127.74,126.96,126.63,126.46,126.08,60.13,57.31,56.67,51.46,49.63,48.64,41.26.
质量451.2
22、制备例22:化学式N313
[反应式19]
添加0.2g的2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.64mmol)和0.039g的氢化钠(0.97mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.08mL苄基溴(benzyl bromide)(0.71mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-苄基-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-benzyl-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.106g,产率41%)。
[化学式N313]
8-苄基-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-benzyl-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.91(d,J=2.2Hz,1H),8.11(d,J=8.4Hz,1H),8.06(d,J=1.5Hz,1H),7.83-7.79(m,1H),7.71(m,1H),7.56(m,1H),7.37-7.28(m,3H),7.27-7.23(m,2H),4.57(s,2H),4.49(ddd,J=13.2,3.2,1.8Hz,1H),4.20-4.15(m,1H),3.90-3.82(m,3H),3.73(d,J=13.5Hz,1H),3.58(m,1H),2.91-2.85(m,1H),2.80(td,J=12.7,3.4Hz,1H),2.19(t,J=11.2Hz,1H),2.12(td,J=11.7,3.3Hz,1H).
13C NMR(126MHz,CDCl3)δ163.26,161.73,151.80,147.73,135.76,134.85,129.89,129.41,129.25,128.97,128.52,128.24,127.80,127.65,126.87,60.07,57.20,56.59,51.39,49.35,48.53,41.19.
质量401.2
23、制备例23:化学式N322
[反应式20]
添加0.2g的2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.64mmol)和0.077g氢化钠(1.93mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.166g的2-(氯甲基)喹啉盐酸盐(2-(Chloromethyl)quinoline hydrochloride)(0.77mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-(喹啉-2-基甲基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(quinolin-2-ylmethyl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.158g,收率54%)。
[化学式N322]
8-(喹啉-2-基甲基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(quinolin-2-ylmethyl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.91(d,J=2.2Hz,1H),8.16-8.00(m,4H),7.81-7.79(m,2H),7.74-7.67(m,2H),7.54(m,2H),7.37(d,J=8.4Hz,1H),4.85(s,2H),4.53(ddd,J=13.2,3.1,1.7Hz,1H),4.25-4.18(m,3H),3.79(dd,J=51.5,13.4Hz,2H),3.57(m,1H),2.92-2.79(m,2H),2.27-2.11(m,2H).
13C NMR(126MHz,CDCl3)δ163.68,161.94,155.18,151.80,147.70,147.66,137.32,135.77,129.89,129.85,129.40,129.22,127.79,127.65,127.59,127.44,126.86,126.73,120.11,77.32,77.06,76.81,60.07,57.20,56.56,51.55,51.43,49.86,41.24.
质量452.2
24、制备例24:化学式N323
[反应式21]
添加0.2g的2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.64mmol)和0.077g氢化钠(1.93mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.127g的3-(氯甲基)吡啶盐酸盐(3-(Chloromethyl)pyridine hydrochloride)(0.77mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-(吡啶-3-基甲基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(pyridin-3-ylmethyl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.05g,收率19%)。
[化学式N323]
8-(吡啶-3-基甲基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(pyridin-3-ylmethyl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.91(d,J=2.2Hz,1H),8.57(dd,J=4.8,1.6Hz,1H),8.53(d,J=1.8Hz,1H),8.11(d,J=8.5Hz,1H),8.06(d,J=1.6Hz,1H),7.81(dd,J=8.3,1.0Hz,1H),7.71(ddd,J=8.4,6.9,1.4Hz,1H),7.64-7.60(m,1H),7.58-7.54(m,1H),7.32-7.26(m,1H),4.61-4.54(m,2H),4.49(ddd,J=13.2,3.1,1.7Hz,1H),4.21-4.16(m,1H),3.96-3.86(m,2H),3.86-3.70(m,2H),3.55(m,1H),2.92-2.86(m,1H),2.81(td,J=12.7,3.3Hz,1H),2.22-2.09(m,2H).
13C NMR(126MHz,CDCl3)δ163.54,161.31,151.74,149.68,147.67,136.23,135.80,130.76,129.82,129.45,129.18,127.78,127.65,126.90,123.87,77.37,77.12,76.86,60.02,57.11,56.46,51.36,48.72,47.02,41.24.
质量402.2
25、制备例25:化学式N324
[反应式22]
添加0.2g的2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.64mmol)和0.077g氢化钠(1.93mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.196g的2-(溴甲基)吡啶氢溴酸盐(2-(bromomethyl)pyridine hydrobromide)(0.77mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-(吡啶-2-基甲基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(pyridin-2-ylmethyl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.068g,收率26%)。
[化学式N324]
从而获得了8-(吡啶-2-基甲基)-2-(喹啉-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(pyridin-2-ylmethyl)-2-(quinolin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.90(d,J=2.1Hz,1H),8.53(ddd,J=4.9,1.7,0.9Hz,1H),8.11(d,J=8.5Hz,1H),8.05(d,J=1.5Hz,1H),7.80(dd,J=8.2,1.0Hz,1H),7.73-7.63(m,2H),7.55(m,1H),7.26(d,J=7.8Hz,1H),7.21(m,1H),4.67(dd,J=43.5,14.9Hz,2H),4.51(m,1H),4.22-4.06(m,3H),3.77(dd,J=47.4,13.5Hz,2H),3.53(m,1H),2.91-2.86(m,1H),2.82(td,J=12.6,3.3Hz,1H),2.20(t,J=11.2Hz,1H),2.14(td,J=11.7,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.55,161.89,154.98,151.75,149.57,147.63,137.01,135.76,129.89,129.38,129.15,127.77,127.63,126.84,122.86,122.59,60.00,57.09,56.43,51.39,50.97,49.78,41.18.
质量402.2
26、制备例26:化学式N401
[反应式23]
在室温下,加入了8.1g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(28.6mmol)、81mL二氯甲烷、8.1mL三乙胺、4.5g的2-喹啉甲醛(28.6mmol)。加入12.1g三乙酰氧基硼氢化钠(57.3mmol),并在室温下搅拌过夜。将反应液用65mL纯净水洗涤。将反应液依次用65mL碳酸氢钠水溶液和65mL纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(喹啉-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinolin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(5.8g,收率65%)。
[化学式N401]
2-(喹啉-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(quinolin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,MeOD)δ8.30(d,J=8.5Hz,1H),7.98(d,J=8.5Hz,1H),7.89(d,J=8.1Hz,0 1H),7.75-7.67(m,2H),7.57-7.53(m,1H),5.45(d,J=1.9Hz,1H),4.48-4.38(m,1H),4.14-4.10(m,1H),4.00-3.80(m,4H),3.35-3.23(m,1H),2.96-2.79(m,2H),2.28-2.14(m,2H).
13C NMR(101MHz,MeOD)δ167.20,164.67,160.14,148.34,138.76,131.12,129.05,129.01,128.87,127.85,122.56,64.91,58.03,57.02,53.14,45.10,42.43.
质量311.2
27、制备例27:化学式N411
利用制备例26的化学式N401的化合物制备了下述化学式N411的化合物。
[化学式N411]
1H NMR(500MHz,CDCl3)δ8.16(d,J=8.4Hz,1H),8.08(d,J=8.4Hz,1H),8.05-8.00(m,1H),7.88-7.80(m,3H),7.73-7.69(m,1H),7.62(d,J=8.4Hz,1H),7.56-7.49(m,3H),7.45-7.35(m,2H),5.06(dd,J=54.7,14.5Hz,2H),4.48-4.40(m,1H),4.27-4.19(m,1H),3.93(dd,J=42.9,13.8Hz,2H),3.73(s,2H),3.64(m,1H),2.87(m,1H),2.80(m,1H),2.27(t,J=11.3Hz,1H),2.19(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ162.98,161.63,158.35,147.78,136.82,134.05,131.58,130.12,129.66,129.56,129.21,128.96,128.63,127.65,127.56,127.03,126.49,126.35,125.22,123.63,120.99,64.80,57.48,56.96,51.81,48.24,47.31,41.21.
质量451.21
28、制备例28:化学式N412
利用制备例26的化学式N401的化合物制备了下述化学式N412的化合物。
[化学式N412]
1H NMR(400MHz,CDCl3)δ8.18(d,J=8.5Hz,1H),8.08(d,J=8.5Hz,1H),7.84-7.80(m,4H),7.74-7.71(m,2H),7.64(d,J=8.5Hz,1H),7.58-7.47(m,3H),7.37(dd,J=8.4,1.5Hz,1H),4.73(s,2H),4.52-4.48(m,1H),4.27-4.24(m,1H),4.03-3.87(m,4H),3.64-3.56(m,1H),2.95-2.80(m,2H),2.33-2.20(m,2H).
13C NMR(126MHz,CDCl3)δ163.44,161.67,158.33,147.77,136.80,133.28,133.09,132.36,129.65,129.20,129.10,127.87,127.82,127.79,127.64,127.55,126.60,126.48,126.42,126.08,121.00,64.81,57.44,56.98,51.86,49.59,48.63,41.29.
质量451.21
29、制备例29:化学式N413
利用制备例26的化学式N401的化合物制备了下述化学式N413的化合物。
[化学式N413]
1H NMR(400MHz,CDCl3)δ8.17(d,J=8.5Hz,1H),8.08(d,J=8.5Hz,1H),7.82(d,J=8.1Hz,1H),7.72(t,J=7.7Hz,1H),7.63(d,J=8.5Hz,1H),7.56-7.53(m,1H),7.39-7.30(m,3H),7.27-7.24(m,2H),4.63-4.46(m,3H),4.26-4.19(m,1H),4.00-3.88(m,4H),3.58(d,J=11.3Hz,1H),2.95-2.81(m,2H),2.33-2.18(m,2H).
13C NMR(101MHz,CDCl3)δ163.28,161.67,158.24,147.60,136.86,134.83,129.66,128.98,128.52,128.25,127.59,127.49,126.47,120.95,64.64,57.32,56.86,51.78,49.33,48.51,41.22.
质量401.19
30、制备例30:化学式N414
利用制备例26的化学式N401的化合物制备了下述化学式N414的化合物。
[化学式N414]
1H NMR(400MHz,CDCl3)δ8.17(d,J=8.5Hz,1H),8.08(d,J=8.4Hz,1H),7.83-7.81(m,1H),7.74-7.70(m,1H),7.63(d,J=8.5Hz,1H),7.59-7.51(m,5H),7.46-7.43(m,2H),7.38-7.30(m,3H),4.65-4.56(m,2H),4.55-4.48(m,1H),4.27-4.20(m,1H),4.02-3.87(m,4H),3.63-3.56(m,1H),2.96-2.80(m,2H),2.32-2.21(m,2H).
13C NMR(101MHz,CDCl3)δ163.32,161.66,158.23,147.63,141.26,140.47,136.83,133.81,129.65,129.02,128.83,127.71,127.58,127.51,127.49,127.10,126.46,120.95,77.36,77.05,76.73,64.69,57.35,56.88,51.79,49.08,48.58,41.24.
质量477.22
31、制备例31:化学式N422
利用制备例26的化学式N401的化合物制备了化学式N422的化合物。
[化学式N422]
1H NMR(400MHz,CDCl3)δ8.16(t,J=7.8Hz,2H),8.09-8.02(m,2H),7.83-7.80(m,2H),7.75-7.68(m,2H),7.63(d,J=8.5Hz,1H),7.58-7.51(m,2H),7.38(d,J=8.4Hz,1H),4.90-4.80(m,2H),4.57-4.52(m,1H),4.31-4.13(m,3H),3.95(dd,J=30.5,13.8Hz,2H),3.62-3.53(m,1H),2.97-2.82(m,2H),2.38-2.21(m,2H).
13C NMR(101MHz,CDCl3)δ163.72,161.87,158.27,155.21,147.65,137.39,136.82,129.89,129.64,129.21,129.05,127.60,127.58,127.49,127.46,126.75,126.45,120.95,120.11,64.72,57.32,56.89,51.83,51.57,49.83,41.28.
质量452.2
32、制备例32:化学式N423
利用制备例26的化学式N401的化合物制备了下述化学式N423的化合物。
[化学式N423]
1H NMR(400MHz,CDCl3)δ8.61-8.51(m,2H),8.17(d,J=8.5Hz,1H),8.08(d,J=8.5Hz,1H),7.82(d,J=8.1Hz,1H),7.72(t,J=7.7Hz,1H),7.63-7.61(m,2H),7.56-7.53(m,1H),7.32-7.29(m,1H),4.58(s,2H),4.52-4.49(m,1H),4.25-4.21(m,1H),4.01-3.86(m,4H),3.60-3.53(m,1H),2.94-2.82(m,2H),2.30-2.21(m,2H).
13C NMR(101MHz,CDCl3)δ163.57,161.23,158.13,149.73,149.70,147.62,136.86,136.27,130.77,129.67,129.02,127.59,127.48,126.49,123.92,120.94,64.65,57.24,56.79,51.74,48.72,47.02,41.28.
质量402.19
33、制备例33:化学式N424
1H NMR(500MHz,CDCl3)δ8.55-8.53(m,1H),8.15(d,J=8.4Hz,1H),8.07(d,J=8.4Hz,1H),7.81(dd,J=8.1,1.1Hz,1H),7.74-7.64(m,2H),7.61(d,J=8.4Hz,1H),7.55-7.52(m,1H),7.29-7.24(m,1H),7.21(m,1H),4.71-4.63(m,2H),4.55-4.51(m,1H),4.27-4.20(m,1H),4.18-4.06(m,2H),3.93(m,2H),3.55(ddd,J=11.4,3.2,1.7Hz,1H),2.96-2.81(m,2H),2.33-2.21(m,2H).
13C NMR(126MHz,CDCl3)δ163.60,161.84,158.27,155.08,149.62,147.68,137.02,136.74,129.59,129.10,127.57,127.48,126.41,122.87,122.59,120.94,64.72,57.26,56.81,51.81,51.05,49.81,41.26.
质量402.19
34、制备例34:化学式N502
利用制备例2的N501的化合物制备了下述N502化合物。
[化学式N502]
1H NMR(500MHz,CDCl3)δ7.86-7.76(m,3H),7.64(d,J=17.1Hz,1H),7.51-7.43(m,2H),7.43-7.36(m,1H),7.33-7.29(m,2.5H),7.22-7.14(m,2.5H),7.03(s,0.5H),6.90(s,0.5H),4.52-4.40(m,1H),4.38-4.26(m,1H),3.92(dd,J=11.1,2.8Hz,0.5H),3.73-3.43(m,2H),3.29-3.24(m,1H),3.19(dd,J=13.6,5.6Hz,0.5H),3.08-3.01(m,2H),2.82-2.79(m,0.5H),2.72-2.63(m,1H),2.52(td,J=12.8,3.4Hz,0.5H),2.05-1.93(m,1H),1.74(td,J=11.4,3.0Hz,0.5H),0.78(t,J=11.2Hz,0.5H).
13C NMR(176MHz,CDCl3)δ165.06,162.44,135.04,134.68,133.28,132.86,130.78,129.93,129.01,128.93,128.63,128.33,128.05,127.68,127.63,127.11,126.05,125.77,62.15,58.54,55.07,50.82,46.35,41.29,35.98.
质量400.2
35、制备例35:化学式N503
利用制备例35的N502化合物作为起始物质,进一步进行以下反应,从而制备了N503化合物。
[反应式24]
添加0.3g的3-苄基-8-(萘-2-基甲基)六氢-1H-吡嗪并[1,2-a]吡嗪-1,4(6H)-二酮(3-Benzyl-8-(naphthalen-2-ylmethyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione)(0.75mmol)和0.06g氢化钠(1.5mmol)、6mL二甲基甲酰胺,并搅拌1小时后,加入0.13mL苄基溴(1.1mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和15mL乙酸乙酯终止反应。提取有机层,并用20mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2,3-二苄基-8-(萘-2-基甲基)六氢-1H-吡嗪并[1,2-a]吡嗪-1,4(6H)-二酮(2,3-dibenzyl-8-(naphthalen-2-ylmethyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione)(0.28g,收率76%)。
[化学式N503]
1H NMR(500MHz,CDCl3)δ7.87-7.74(m,3H),7.59(s,1H),7.52-7.43(m,2H),7.38-7.28(m,8H),7.17(t,J=7.4Hz,1H),7.09(d,J=7.3Hz,2H),5.70(d,J=14.6Hz,1H),4.47-4.36(m,1H),4.20-4.16(m,1H),4.05-3.89(m,2H),3.39(dd,J=45.5,13.0Hz,2H),3.25(ddd,J=18.2,14.0,3.7Hz,2H),2.91-2.84(m,1H),2.65-2.56(m,2H).
13C NMR(126MHz,CDCl3)δ165.30,162.67,135.60,134.88,134.70,133.47,133.09,131.03,130.18,129.27,129.19,128.99,128.89,128.58,128.40,128.30,128.23,128.04,127.97,127.94,127.88,127.41,126.29,126.02,62.91,59.49,56.67,55.31,51.07,46.94,41.09,37.17.
质量490.24
36、制备例36:化学式N504
利用制备例2的N501化合物制备了下述N504化合物。
[化学式N504]
1H NMR(500MHz,CDCl3)δ7.82-7.74(m,3H),7.64-7.56(m,1H),7.50-7.42(m,2H),7.39-7.23(m,4H),7.06-6.99(m,2H),4.46-4.40(m,0.5H),4.36-4.27(m,1H),4.22(t,J=3.7Hz,0.5H),4.17-4.05(m,1.5H),3.88(dd,J=11.1,3.1Hz,0.5H),3.60(dd,J=107.4,13.1Hz,1H),3.45-3.20(m,2H),3.16-3.06(m,1H),2.84-2.79(m,0.5H),2.76-2.67(m,1H),2.65-2.56(m,1.5H),2.40-2.33(m,0.5H),2.31-2.25(m,0.5H),1.95-1.81(m,1H),1.79-1.56(m,6H),1.31-1.12(m,2H),1.07-0.87(m,2H).
13C NMR(126MHz,CDCl3)δ165.55,162.82,134.88,134.57,133.44,133.07,131.13,130.23,129.11,128.90,128.27,128.17,127.94,127.84,127.70,127.38,126.25,125.98,62.85,61.20,51.04,50.12,37.57,35.92,32.16,31.38,30.77,29.93,29.59,26.55,26.04,25.86.
质量496.29
37、制备例37:化学式N511
利用制备例2的N501化合物制备了下述N511化合物。
[化学式N511]
1H NMR(500MHz,CDCl3)δ8.06-8.01(m,1H),7.90-7.79(m,5H),7.72(s,1H),7.57-7.34(m,7H),5.05(dd,J=34.8,14.5Hz,2H),4.42-4.39(m,1H),4.20-4.17(m,1H),3.82(d,J=13.1Hz,1H),3.71-3.62(m,4H),2.84-2.81(m,1H),2.74(td,J=12.7,3.3Hz,1H),2.14(t,J=11.2Hz,1H),2.01(td,J=11.8,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ163.27,161.81,134.87,134.23,133.53,133.18,131.76,130.36,129.72,129.14,128.81,128.45,128.07,128.00,127.94,127.39,127.17,126.51,126.38,126.10,125.40,123.86,62.95,57.65,57.01,51.50,48.42,47.47,41.45.
质量450.21
38、制备例38:化学式N512
利用制备例2的N501化合物制备了下述N512化合物。
[化学式N512]
1H NMR(500MHz,CDCl3)δ7.90-7.77(m,6H),7.70(d,J=17.1Hz,2H),7.55-7.43(m,5H),7.37-7.34(m,1H),4.80-4.66(m,2H),4.47-4.44(m,1H),4.20-4.17(m,1H),3.88(s,2H),3.83-3.65(m,2H),3.62-3.59(m,1H),2.87-2.74(m,2H),2.17(t,J=11.2Hz,1H),2.05(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.75,161.88,134.86,133.53,133.46,133.27,133.18,132.58,129.26,128.45,128.08,128.05,128.01,128.00,127.98,127.93,127.40,126.78,126.60,126.37,126.29,126.10,62.96,57.61,56.99,51.58,49.76,48.82,41.53.
质量450.21
39、制备例39:化学式N514
利用制备例2的N501化合物制备了下述N514化合物。
[化学式N514]
1H NMR(500MHz,CDCl3)δ7.85-7.80(m,3H),7.73(s,1H),7.57-7.54(m,4H),7.51-7.42(m,7H),7.37-7.31(m,3H),4.64-4.57(m,2H),4.50-4.46(m,1H),4.21-4.17(m,1H),3.96-3.87(m,2H),3.85-3.67(m,2H),3.60(ddd,J=11.4,3.1,1.7Hz,1H),2.92-2.86(m,1H),2.80(td,J=12.7,3.3Hz,1H),2.18(t,J=11.2Hz,1H),2.09(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.70,161.91,141.45,140.72,134.86,134.15,133.53,133.17,129.26,129.08,128.44,128.07,127.99,127.93,127.76,127.39,127.34,126.36,126.09,62.97,57.60,56.98,51.58,49.29,48.86,41.55.
质量476.23
40、制备例40:化学式N522
[反应式25]
添加0.25g的8-[(萘-2-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(0.81mmol)和0.081g氢化钠(2.02mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.208g的2-(氯甲基)喹啉盐酸盐(2-(chloromethyl)quinoline hydrochloride)(0.97mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和10mL乙酸乙酯终止反应。提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤,然后浓缩反应液,并通过硅胶层析纯化,从而获得了2-(萘-2-基甲基)-8-(喹啉-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-2-ylmethyl)-8-(quinolin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.195g,收率53%)。
[化学式N522]
2-(萘-2-基甲基)-8-(喹啉-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-2-ylmethyl)-8-(quinolin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.13(d,J=8.4Hz,1H),8.02(d,J=8.4Hz,1H),7.85-7.77(m,4H),7.75-7.68(m,2H),7.57-7.43(m,4H),7.37(d,J=8.4Hz,1H),4.85(s,2H),4.55-4.45(m,1H),4.27-4.15(m,3H),3.76(dd,J=57.1,13.1Hz,2H),3.60-3.55(m,1H),2.92-2.78(m,2H),2.21(t,J=11.2Hz,1H),2.10(td,J=11.6,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.83,161.87,155.25,147.65,137.28,134.57,133.25,132.90,129.82,129.21,128.16,127.82,127.72,127.65,127.57,127.42,127.13,126.69,126.08,125.81,120.10,62.71,57.30,56.69,51.54,51.34,49.83,41.32.
质量451.4
41、制备例41:化学式N523
[反应式26]
添加0.25g的8-[(萘-2-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(0.81mmol)和0.081g氢化钠(2.02mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.159g的3-(氯甲基)吡啶盐酸盐(3-(chloromethyl)pyridine hydrochloride)(0.97mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和10mL乙酸乙酯终止反应。提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(萘-2-基甲基)-8-(吡啶-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-2-ylmethyl)-8-(pyridin-3-ylmethyl)hexahydro-2H-pyrazino[l,2-a]pyrazine-6,9-dione)(0.201g,收率62%)。
[化学式N523]
2-(萘-2-基甲基)-8-(吡啶-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-2-ylmethyl)-8-(pyridin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.55(dd,J=4.8,1.6Hz,1H),8.51(d,J=1.9Hz,1H),7.84-7.76(m,4H),7.71(s,1H),7.60-7.58(m,1H),7.50-7.41(m,4H),7.29-7.24(m,1H),4.58-4.41(m,3H),4.22-4.19(m,1H),3.90-3.78(m,3H),3.73-3.67(m,1H),3.59-3.54(m,1H),2.95-2.78(m,2H),2.21-2.04(m,2H).
13C NMR(126MHz,CDCl3)δ163.70,161.42,149.74,136.34,133.34,133.06,130.89,128.37,128.16,128.11,127.84,127.76,127.23,127.21,126.27,126.05,123.94,62.70,57.12,56.51,51.31,48.82,47.10,41.25.
质量401.2
42、制备例42:化学式N524
[反应式27]
添加0.25g的8-[(萘-2-基)甲基]四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮(0.81mmol)和0.081g氢化钠(2.02mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.245g的2-(溴甲基)吡啶氢溴酸盐(2-(bromomethyl)pyridine hydrobromide)(0.97mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和10mL乙酸乙酯终止反应。提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤,然后浓缩反应液,并通过硅胶层析纯化,从而获得了2-(萘-2-基甲基)-8-(吡啶-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-2-ylmethyl)-8-(pyridin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.033g,收率10%)。
[化学式N524]
2-(萘-2-基甲基)-8-(吡啶-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-2-ylmethyl)-8-(pyridin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.55-8.52(m,1H),7.84-7.78(m,3H),7.71(s,1H),7.66(m,1H),7.50-7.43(m,3H),7.28-7.24(m,1H),7.20(m,1H),4.75-4.59(m,2H),4.52-4.47(m,1H),4.21-4.17(m,1H),4.17-4.05(m,2H),3.84-3.65(m,2H),3.57-3.53(m,1H),2.91-2.85(m,1H),2.81(td,J=12.6,3.3Hz,1H),2.17(t,J=11.2Hz,1H),2.09(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.72,161.84,155.09,149.60,137.00,134.59,133.26,132.91,128.16,127.82,127.73,127.65,127.13,126.09,125.81,122.85,122.58,62.71,57.25,56.63,51.34,51.02,49.79,41.31.
质量401.2
43、制备例43:化学式N601
[反应式28]
在室温下,加入了1.5g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(5.3mmol)、15mL二氯甲烷、1.5mL三乙胺、0.83g的1-萘甲醛(1-naphthaldehyde)(5.3mmol)。加入2.25g三乙酰氧基硼氢化钠(10.59mmol),并在室温下搅拌过夜。将反应液用10mL纯净水洗涤。将反应液依次用10mL的碳酸氢钠水溶液和纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(1.526g,收率93%)。
[化学式N601]
2-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.24(d,J=7.8Hz,1H),7.86-7.77(m,2H),7.53-7.47(m,2H),7.45-7.35(m,3H),4.48(d,J=13.1Hz,1H),4.08-4.02(m,2H),3.98(s,2H),3.89-3.83(m,1H),3.52-3.46(m,1H),2.91-2.84(m,1H),2.72(td,J=12.8,3.2Hz,1H),2.18(t,J=11.2Hz,1H),2.10(td,J=11.8,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ166.11,161.73,133.90,132.67,132.38,128.50,128.48,127.77,125.89,125.74,125.09,124.62,60.93,56.88,56.37,51.57,44.48,41.47.
质量310.15
44、制备例44:化学式N611
利用制备例43的N601化合物制备了下述N611化合物。
[化学式N611]
1H NMR(500MHz,CDCl3)δ8.27(d,J=8.1Hz,1H),8.06-8.01(m,1H),7.90-7.77(m,4H),7.56-7.47(m,4H),7.44-7.36(m,4H),5.11-5.01(m,2H),4.41-4.36(m,1H),4.18-4.13(m,1H),3.97(dd,J=121.6,12.9Hz,2H),3.73-3.66(m,3H),2.82(d,J=11.6Hz,1H),2.67(td,J=12.7,3.2Hz,1H),2.19(t,J=11.2Hz,1H),2.03(td,J=11.9,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ163.04,161.49,133.95,133.93,132.75,132.41,131.47,130.07,129.45,128.86,128.53,128.48,127.76,126.90,126.23,125.88,125.73,125.12,125.10,124.67,123.56,60.92,57.40,56.95,51.31,48.14,47.22,41.20.
质量450.21
45、制备例45:化学式N612
利用制备例43的N601化合物制备了下述N612化合物。
[化学式N612]
1H NMR(500MHz,CDCl3)δ8.27(d,J=8.1Hz,1H),7.88-7.78(m,5H),7.69(s,1H),7.55-7.45(m,4H),7.42-7.35(m,3H),4.78-4.67(m,2H),4.46-4.40(m,1H),4.18-4.14(m,1H),4.09(d,J=12.7Hz,1H),3.89(s,2H),3.86(d,J=12.9Hz,1H),3.69-3.64(m,1H),2.87-2.83(m,1H),2.71(td,J=12.7,3.3Hz,1H),2.21(t,J=11.2Hz,1H),2.08(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.53,161.57,133.93,133.18,132.99,132.75,132.41,132.30,129.00,128.48,127.77,127.76,127.73,127.69,126.51,126.33,125.98,125.88,125.73,125.10,124.67,60.94,57.36,56.94,51.38,49.49,48.54,41.29.
质量450.21
46、制备例46:化学式N613
利用制备例43的N601化合物制备了下述N613化合物。
[化学式N613]
1H NMR(400MHz,CDCl3)δ8.30-8.24(m,1H),7.89-7.78(m,2H),7.57-7.47(m,2H),7.44-7.28(m,6H),7.28-7.22(m,2H),4.66-4.51(m,2H),4.45(ddd,J=13.1,2.9,1.8Hz,1H),4.18-4.06(m,2H),3.92-3.82(m,3H),3.68-3.61(m,1H),2.91-2.82(m,1H),2.72(td,J=12.7,3.3Hz,1H),2.20(t,J=11.2Hz,1H),2.09(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.46,161.62,134.92,133.94,132.76,132.42,128.94,128.49,128.19,127.78,125.88,125.74,125.10,124.68,60.93,57.32,56.93,51.38,49.29,48.52,41.29.
质量400.2
47、制备例47:化学式N614
利用制备例43的N601化合物制备了下述N614化合物。
[化学式N614]
1H NMR(400MHz,CDCl3)δ8.27(d,J=8.0Hz,1H),7.87-7.84(m,1H),7.82-7.78(m,1H),7.58-7.47(m,6H),7.46-7.38(m,4H),7.37-7.30(m,3H),4.65-4.56(m,2H),4.48-4.42(m,1H),4.18-4.12(m,1H),4.11-4.07(m,1H),3.91(s,2H),3.89-3.84(m,1H),3.67-3.62(m,1H),2.86(d,J=11.8Hz,1H),2.72(td,J=12.7,3.2Hz,1H),2.21(t,J=11.2Hz,1H),2.09(td,J=11.8,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ163.49,161.60,141.20,140.45,133.93,133.88,132.74,132.41,128.96,128.81,128.49,127.77,127.67,127.48,127.07,125.88,125.73,125.10,124.67,60.94,57.35,56.93,51.39,49.03,48.59,41.31.
质量476.23
48、制备例48:化学式N622
利用制备例43的N601化合物制备了下述N622化合物。
[化学式N622]
1H NMR(400MHz,CDCl3)δ8.30-8.24(m,1H),8.15(d,J=8.5Hz,1H),8.03(d,J=8.5Hz,1H),7.89-7.69(m,4H),7.58-7.47(m,3H),7.43-7.36(m,3H),4.86(s,2H),4.53-4.44(m,1H),4.23-4.16(m,3H),3.99(dd,J=88.3,12.9Hz,2H),3.66-3.60(m,1H),2.93-2.83(m,1H),2.75(td,J=12.7,3.2Hz,1H),2.26(t,J=11.4Hz,1H),2.12(td,J=11.8,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ163.85,161.81,155.25,147.61,137.24,133.90,132.74,132.38,129.79,129.17,128.45,127.75,127.54,127.38,126.65,125.85,125.70,125.08,124.65,120.04,77.35,77.10,76.84,60.88,57.26,56.85,51.48,51.40,49.80,41.29,0.00.
质量451.21
49、制备例49:化学式N641
[化学式N641]
1H NMR(400MHz,CDCl3)δ8.28-8.24(m,1H),7.89-7.83(m,1H),7.83-7.72(m,2H),7.71-7.67(m,1H),7.56-7.46(m,2H),7.43-7.36(m,2H),7.36-7.26(m,2H),4.90-4.80(m,2H),4.38(ddd,J=13.2,3.0,1.8Hz,1H),4.16-4.05(m,2H),3.86-3.82(m,1H),3.73-3.70(m,2H),3.69-3.64(m,1H),2.99-2.92(m,2H),2.85-2.78(m,1H),2.66(td,J=12.7,3.3Hz,1H),2.15(t,J=11.2Hz,1H),2.07-1.97(m,1H),1.35(t,J=7.5Hz,3H).
13C NMR(126MHz,CDCl3)δ163.23,161.46,148.25,139.29,138.05,133.98,132.78,132.46,128.53,127.80,125.93,125.78,125.14,124.69,124.64,124.23,123.31,122.39,121.35,60.94,57.38,56.97,51.36,47.65,45.47,41.25,39.39,21.97,16.18.
质量484.4
50、制备例50:化学式N701
[反应式29]
在室温下,加入了0.3g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(1.06mmol)、3mL二氯甲烷、0.3mL三乙胺、0.193g联苯-4-甲醛(biphenyl-4-carboxaldehyde)(1.06mmol)。加入0.245g的0.449g三乙酰氧基硼氢化钠(2.12mmol),并在室温下搅拌3小时。将反应液用24mL碳酸氢钠水溶液,并再用24mL纯净水洗涤,将有机层用无水硫酸镁干燥,过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-([1,1’-联苯基]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.249g,收率70%)。
[化学式N701]
2-([1,1’-联苯基]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dio ne)
1H NMR(400MHz,CDCl3)δ7.64-7.52(m,4H),7.50-7.41(m,2H),7.41-7.31(m,3H),7.15(s,1H),4.59-4.47(m,1H),4.18-4.08(m,1H),4.07-3.99(m,2H),3.63(dd,J=39.7,13.2Hz,2H),3.50-3.42(m,1H),2.98-2.72(m,2H),2.21-2.00(m,2H).
13C NMR(101MHz,CDCl3)δ165.95,161.71,140.78,140.42,135.98,129.50,128.77,127.28,127.19,127.06,62.23,56.88,56.08,51.48,44.57,41.48.
质量336.2
51、制备例51:化学式N711
使用制备例50获得的化学式N701的化合物作为起始物质,进一步进行以下反应式30的步骤,从而获得了化学式N711的化合物。
[反应式30]
添加0.2g的2-([1,1’-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.60mmol)和0.036g氢化钠(0.89mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.158g的1-(溴甲基)萘(1-(bromomethyl)naphthalene)(0.72mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和10mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-([1,1’2-([1,1’-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’2-([1,1’-biphenyl]-4-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.233g,收率81%)。
[化学式N711]
2-([1,1’-联苯]-4-基甲基)-8-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.06-8.02(m,1H),7.92-7.81(m,2H),7.63-7.48(m,6H),7.48-7.30(m,7H),5.13-5.02(m,2H),4.46-4.40(m,1H),4.22-4.16(m,1H),3.77-3.51(m,5H),2.89-2.70(m,2H),2.16-1.95(m,2H).
13C NMR(126MHz,CDCl3)δ163.04,161.54,140.85,140.43,136.08,133.97,131.49,130.07,129.49,128.88,128.75,128.56,127.24,127.19,127.07,126.91,126.25,125.14,123.58,62.21,57.39,56.64,51.27,48.15,47.22,41.19.
质量476.4
52、制备例52:化学式N712
使用制备例50获得的化学式N701的化合物作为起始物质,进一步进行以下反应式31的步骤,从而获得了化学式N712的化合物。
[反应式31]
添加0.2g的2-([1,1’-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.60mmol)和0.036g氢化钠(0.89mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.158g的2-(溴甲基)萘(2-(bromomethyl)naphthalene)(0.72mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和10mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-([1,1’-联苯]-4-基甲基)-8-(萘-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’2-([1,1’-biphenyl]-4-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.250g,收率87%)。
[化学式N712]
2-([1,1’-联苯]-4-基甲基)-8-(萘-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ7.87-7.78(m,3H),7.70(s,1H),7.63-7.54(m,4H),7.53-7.31(m,8H),4.79-4.67(m,2H),4.53-4.43(m,1H),4.24-4.14(m,1H),3.90(s,2H),3.76-3.52(m,3H),2.96-2.73(m,2H),2.20-1.98(m,2H).
13C NMR(126MHz,CDCl3)δ163.62,161.72,140.96,140.54,136.18,133.31,133.12,132.42,129.61,129.11,128.86,127.90,127.85,127.82,127.35,127.30,127.18,126.63,126.45,126.12,62.33,57.46,56.73,51.46,49.62,48.67,41.38.
质量476.23
53、制备例53:化学式N713
使用制备例50获得的化学式N701的化合物作为起始物质,进一步进行以下反应式32的步骤,从而获得了化学式N713化合物。
[反应式32]
添加0.2g的2-([1,1’-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.60mmol)和0.036g氢化钠(0.89mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.08mL苄基溴(Benzyl bromide)(0.72mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和10mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-([1,1’-联苯]-4-基甲基)-8-苄基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-benzylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.228g,收率89%)。
[化学式N713]
2-([1,1’-联苯]-4-基甲基)-8-苄基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-benzylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ7.65-7.53(m,4H),7.48-7.30(m,8H),7.28-7.24(m,2H),4.64-4.45(m,3H),4.22-4.13(m,1H),3.87(s,2H),3.74-3.54(m,3H),2.93-2.86(m,2H),2.17-2.02(m,2H).
13C NMR(126MHz,CDCl3)δ163.52,161.76,140.94,140.52,136.15,135.00,129.60,129.04,128.84,128.61,128.30,127.33,127.28,127.16,62.31,57.41,56.69,51.44,49.41,48.63,41.37.
质量426.21
54、制备例54:化学式N714
使用制备例50获得的化学式N701的化合物作为起始物质,进一步进行以下反应式33的步骤,从而获得了化学式N714的化合物。
[反应式33]
添加0.2g的2-([1,1’-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.60mmol)和0.036g氢化钠(0.89mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.177mg的4-(溴甲基)联苯(4-(bromomethyl)biphenyl)(0.72mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和10mL乙酸乙酯终止反应。提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤,然后浓缩反应液,并通过硅胶层析纯化,从而获得了2,8-双([1,1’-联苯基]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2,8-bis([1,1’-biphenyl]-4-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.261g,收率86%)。
[化学式N714]
2,8-双([1,1’-联苯基]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2,8-bis([1,1’-biphenyl]-4-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ7.63-7.52(m,8H),7.48-7.30(m,10H),4.68-4.55(m,2H),4.54-4.46(m,1H),4.22-4.16(m,1H),3.92(s,2H),3.73-3.55(m,3H),2.93-2.75(m,2H),2.21-2.01(m,2H).
13C NMR(126MHz,CDCl3)δ163.54,161.72,141.28,140.92,140.53,140.49,136.16,133.98,129.58,129.08,128.90,128.83,127.75,127.57,127.32,127.26,127.15,62.29,57.41,56.68,51.43,49.12,48.68,41.36.
质量502.4
55、制备例55:化学式N722
使用制备例50获得的化学式N701的化合物为起始物质,进一步进行以下反应式34的步骤,从而获得了化学式N722的化合物。
[反应式34]
添加0.25g的2-([1,1’-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.75mmol)和0.097g氢化钠(2.42mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.208mg的2-(氯甲基)喹啉盐酸盐(2-(chloromethyl)quinoline hydrochloride)(0.97mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和10mL乙酸乙酯终止反应。提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-([1,1’-联苯]-4-基甲基)-8-(喹啉-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(quinolin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.301g,收率84%)。
[化学式N722]
2-([1,1’-联苯]-4-基甲基)-8-(喹啉-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(quinolin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.15(d,J=8.5Hz,1H),8.02(d,J=8.5Hz,1H),7.80(d,J=8.1Hz,1H),7.75-7.69(m,1H),7.62-7.51(m,5H),7.47-7.32(m,6H),4.86(s,2H),4.58-4.47(m,1H),4.28-4.12(m,3H),3.72-3.53(m,3H),2.97-2.77(m,2H),2.23-2.04(m,2H).
13C NMR(126MHz,CDCl3)δ163.95,161.97,155.37,147.78,140.96,140.52,137.37,136.17,129.91,129.61,129.34,128.85,127.67,127.53,127.34,127.28,127.17,126.79,120.20,62.33,57.42,56.68,51.67,51.50,49.97,41.43.
质量477.4
56、制备例56:化学式N723
使用制备例50获得的化学式N701的化合物为起始物质,进一步进行以下反应式35的步骤,从而获得了化学式N723的化合物。
[反应式35]
添加0.25g的2-([1,1’-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.75mmol)和0.097g氢化钠(2.42mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.159mg的3-(氯甲基)吡啶盐酸盐(3-(chloromethyl)pyridine hydrochloride)(0.97mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和10mL乙酸乙酯终止反应。提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤,然后浓缩反应液,并通过硅胶层析纯化,从而获得了2-([1,1’-联苯]-4-基甲基)-8-(吡啶-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(pyridin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.161g,收率50%)。
[化学式N723]
2-([1,1’-联苯]-4-基甲基)-8-(吡啶-3-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(pyridin-3-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.58(dd,J=4.8,1.6Hz,1H),8.55(d,J=1.7Hz,1H),7.64-7.54(m,5H),7.47-7.41(m,2H),7.41-7.32(m,3H),7.31-7.27(m,1H),4.62-4.54(m,2H),4.50(ddd,J=13.2,3.1,1.8Hz,1H),4.23-4.15(m,1H),3.96-3.85(m,2H),3.73-3.53(m,3H),2.93-2.87(m,1H),2.81(td,J=12.7,3.4Hz,1H),2.16-2.03(m,2H).
13C NMR(126MHz,CDCl3)δ163.74,161.25,149.76,140.84,140.49,136.21,135.99,130.79,129.51,128.77,127.27,127.22,127.08,123.85,62.23,57.28,56.55,51.34,48.75,47.04,41.37.
质量427.2
57、制备例57:化学式N724
使用制备例50获得的化学式N701的化合物作为起始物质,进一步进行以下反应式36的步骤,从而获得了化学式N724的化合物。
[反应式36]
添加0.25g的2-([1,1'-联苯]-4-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.75mmol)和0.097g氢化钠(2.42mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.245mg的2-(溴甲基)吡啶氢溴酸盐(2-(bromomethyl)pyridine hydrobromide)(0.97mmol),并在室温下搅拌过夜。用10mL氯化铵水溶液和10mL乙酸乙酯终止反应。提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-([1,1’-联苯]-4-基甲基)-8-(吡啶-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(pyridin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.172g,收率53%)。
[化学式N724]
2-([1,1’-联苯]-4-基甲基)-8-(吡啶-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-([1,1’-biphenyl]-4-ylmethyl)-8-(pyridin-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.54(ddd,J=4.9,1.7,0.9Hz,1H),7.68-7.63(m,1H),7.60-7.53(m,4H),7.46-7.41(m,2H),7.40-7.31(m,3H),7.28-7.25(m,1H),7.20(ddd,J=7.6,4.9,1.1Hz,1H),4.67(dd,J=50.2,14.9Hz,2H),4.52(ddd,J=13.1,3.1,1.8Hz,1H),4.21-4.05(m,3H),3.72-3.51(m,3H),2.93-2.86(m,1H),2.82(td,J=12.6,3.3Hz,1H),2.17-2.05(m,2H).
13C NMR(126MHz,CDCl3)δ163.73,161.83,155.12,149.61,140.86,140.41,136.97,136.09,129.50,128.74,127.23,127.17,127.06,122.83,122.56,77.32,77.06,76.81,62.22,57.25,56.51,51.38,51.04,49.81,41.30,0.00.
质量427.2
58、制备例58:化学式S2115
[反应式37]
在室温下,加入了0.5g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(1.77mmol)、5mL二氯甲烷、0.5mL三乙胺、0.36g 9-蒽醛(9-Anthracenecarboxaldehyde)(1.77mmol)。加入0.748g三乙酰氧基硼氢化钠(3.53mmol),并在室温下搅拌1小时30分钟。将反应液用10mL纯净水洗涤。将反应液依次用10mL的碳酸氢钠水溶液和纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(蒽-9-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.497g,收率78%)。
[化学式S2115]
2-(蒽-9-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.44(s,1H),8.40(d,J=8.7Hz,2H),8.01(d,J=8.2Hz,2H),7.58-7.41(m,4H),6.65(s,1H),4.62-4.39(m,3H),4.13-3.97(m,3H),3.62-3.54(m,1H),2.85-2.75(m,1H),2.64(td,J=12.8,3.2Hz,1H),2.43(t,J=11.2Hz,1H),2.32(td,J=11.8,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ165.78,161.49,131.40,129.13,128.05,127.97,125.97,124.93,124.62,57.17,56.58,53.85,51.36,44.63,41.65.
质量360.17
59、制备例59:化学式S2120
[反应式38]
添加0.1g的2-(蒽-9-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.25mmol)和0.015g氢化钠(0.38mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.067mg的1-(溴甲基)萘(1-(bromomethyl)naphthalene)(0.30mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(蒽-9-基甲基)-8-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)-8-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.118g,收率93%)。
[化学式S2120]
2-(蒽-9-基甲基)-8-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)-8-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.50-8.37(m,3H),8.06-7.99(m,3H),7.93-7.82(m,2H),7.59-7.36(m,8H),5.07(dd,J=40.3,14.4Hz,2H),4.53(dd,J=40.2,13.0Hz,2H),4.38-4.28(m,1H),4.19-4.13(m,1H),3.83-3.63(m,3H),2.83-2.70(m,1H),2.58(td,J=12.7,3.2Hz,1H),2.40(t,J=11.2Hz,1H),2.24(td,J=11.7,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.20,161.60,134.14,131.64,131.55,130.26,129.66,129.28,129.05,128.78,128.18,127.10,126.42,126.09,125.29,125.07,124.80,123.77,57.82,57.22,53.98,51.30,48.30,47.44,41.48.
质量500.23
60、制备例60:化学式S2121
[反应式39]
添加0.1g的2-(蒽-9-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.25mmol)和0.015g氢化钠(0.38mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.067g的2-(溴甲基)萘(2-(bromomethyl)naphthalene)(0.30mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(蒽-9-基甲基)-8-(萘-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)-8-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.088g,收率69%)。
[化学式S2121]
2-(蒽-9-基甲基)-8-(萘-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)-8-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.48-8.39(m,3H),8.07-7.98(m,2H),7.88-7.77(m,3H),7.71(s,1H),7.58-7.45(m,6H),7.37(dd,J=8.4,1.6Hz,1H),4.74(dd,J=40.8,14.3Hz,2H),4.55(dd,J=43.0,13.0Hz,2H),4.41-4.32(m,1H),4.21-4.15(m,1H),3.91(s,2H),3.79-3.72(m,1H),2.79-2.72(m,1H),2.61(td,J=12.7,3.2Hz,1H),2.46(t,J=11.2Hz,1H),2.28(td,J=11.7,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.71,161.70,133.34,133.15,132.44,131.51,129.24,129.15,128.18,128.14,127.90,127.89,127.85,126.66,126.48,126.12,126.07,125.05,124.78,57.70,57.26,53.93,51.19,49.63,48.68,41.53.
质量500.4
61、制备例61:化学式S2124
[反应式40]
添加0.1g的2-(蒽-9-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.25mmol)和0.015g氢化钠(0.38mmol)、二甲基甲酰胺,并搅拌1小时后,加入0.036mL苄基溴(benzylbromide)(0.30mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(蒽-9-基甲基)-8-苄基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)-8-benzylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.1g,收率87%)。
[化学式S2124]
2-(蒽-9-基甲基)-8-苄基六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(anthracen-9-ylmethyl)-8-benzylhexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.49-8.38(m,3H),8.06-7.98(m,2H),7.57-7.44(m,4H),7.39-7.23(m,6H),4.65-4.46(m,4H),4.40-4.35(m,1H),4.20-4.12(m,1H),3.87(s,2H),3.76-3.70(m,1H),2.80-2.71(m,1H),2.61(td,J=12.7,3.2Hz,1H),2.44(t,J=11.2Hz,1H),2.28(td,J=11.7,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ163.48,161.61,134.91,134.09,131.38,131.37,129.10,128.96,128.49,128.21,128.04,128.01,125.93,124.91,124.64,57.52,57.12,53.78,51.04,49.30,48.51,41.40.
质量450.2
62、制备例62:化学式S2125
[反应式41]
添加0.1g的2-(蒽-9-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.25mmol)和0.015g氢化钠(0.38mmol)、二甲基甲酰胺,并在室温下搅拌1小时后,加入0.075mg的4-溴甲基联苯(4-bromomethyl biphenyl)(0.30mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-([1,1’-联苯]-4-基甲基)-2-(蒽-9-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-(anthracen-9-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.096g,收率72%)。
[化学式S2125]
8-([1,1’-联苯]-4-基甲基)-2-(蒽-9-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-(anthracen-9-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.50-8.36(m,3H),8.07-7.98(m,2H),7.62-7.41(m,10H),7.39-7.29(m,3H),4.70-4.46(m,4H),4.42-4.34(m,1H),4.20-4.13(m,1H),3.92(s,2H),3.78-3.70(m,1H),2.76(d,J=11.5Hz,1H),2.61(td,J=12.7,3.2Hz,1H),2.46(t,J=11.2Hz,1H),2.29(td,J=11.7,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ149.41,147.48,127.13,126.36,119.76,117.26,114.99,114.86,114.71,113.92,113.88,113.57,113.39,112.97,111.82,110.80,110.53,43.44,43.02,39.68,36.93,34.93,34.48,27.30.
质量526.4
63、制备例63:化学式S2139
[反应式42]
在室温下,加入了1.5g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(5.21mmol)、1.5mL二氯甲烷、1.5mL三乙胺、1.2g的1-芘甲醛(1-pyrenecarboxaldehyde)(5.21mmol)。加入2.2g三乙酰氧基硼氢化钠(10.4mmol),并在室温下搅拌过夜。将反应液用10mL纯净水洗涤。将反应液依次用10mL碳酸氢钠水溶液和10mL纯净水洗涤。将有机层用无水硫酸镁干燥并过滤,之后,浓缩反应液。向浓缩的残渣中加入2mL二氯甲烷并溶解反应液。缓慢滴加6mL正庚烷,析出结晶,并过滤反应产物。干燥固体,从而获得了2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)。
[反应式43]
添加0.25g的2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.65mmol)和0.039g氢化钠(0.97mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.172g的1-(溴甲基)萘(1-(bromomethyl)naphthalene)(0.78mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-(萘-1-基)-2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-1-yl)-2-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.344g,收率99%)。
[化学式S2139]
8-(萘-1-基)-2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-1-yl)-2-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyraz ine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.49(d,J=9.2Hz,1H),8.24-8.10(m,4H),8.09-7.98(m,4H),7.94-7.82(m,3H),7.57-7.49(m,2H),7.45-7.34(m,2H),5.13-4.99(m,2H),4.41-4.34(m,2H),4.23-4.16(m,1H),4.10(d,J=12.8Hz,1H),3.80-3.69(m,3H),2.85-2.77(m,1H),2.66(td,J=12.7,3.1Hz,1H),2.27(t,J=11.2Hz,1H),2.09(td,J=11.8,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ163.14,161.63,134.08,131.60,131.37,131.25,130.92,130.58,130.20,130.12,129.58,128.99,128.65,128.40,127.49,127.03,126.36,126.08,125.28,125.24,125.21,124.81,124.52,124.06,123.70,60.96,57.55,57.15,51.37,48.26,47.33,41.33.
质量524.4
64、制备例64:化学式S2140
使用制备例63的反应式42中获得的化合物作为起始物质,进一步进行以下反应式44的步骤,从而获得了化学式S2140的化合物。
[反应式44]
添加0.25g的2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.65mmol)、0.039g氢化钠(0.97mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.172g的2-(溴甲基)萘(2-(bromomethyl)naphthalene)(0.78mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-(萘-2-基)-2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-2-yl)-2-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyraz ine-6,9-dione)(0.321g,收率94%)。
[化学式S2140]
8-(萘-2-基)-2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-(naphthalen-2-yl)-2-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyraz ine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.49(d,J=9.2Hz,1H),8.24-8.10(m,4H),8.08-7.97(m,3H),7.95-7.89(m,1H),7.85-7.77(m,3H),7.69(s,1H),7.53-7.45(m,2H),7.36(dd,J=8.4,1.6Hz,1H),4.77-4.67(m,2H),4.46-4.34(m,2H),4.22-4.16(m,1H),4.10(d,J=12.8Hz,1H),3.96-3.83(m,2H),3.77-3.68(m,1H),2.88-2.81(m,1H),2.69(td,J=12.8,3.2Hz,1H),2.34-2.26(m,1H),2.13(td,J=11.8,3.1Hz,1H).
13C NMR(126MHz,CDCl3)δ163.63,161.71,133.32,133.13,132.43,131.37,131.25,130.92,130.59,130.11,129.12,128.39,127.89,127.86,127.83,127.49,126.64,126.45,126.11,126.08,125.29,125.21,124.81,124.52,124.06,60.98,57.50,57.16,51.42,49.61,48.66,41.41.
质量524.23
65、制备例65:化学式S2141
使用制备例63的反应式42中获得的化合物作为起始物质,进一步进行以下反应式45的步骤,从而获得了化学式S2141的化合物。
[反应式45]
添加0.25g的2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.65mmol)和0.039g氢化钠(0.97mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.09mL的苄基溴(benzyl bromide)(0.78mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-苄基-2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-benzyl-2-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.323g,收率99%)。
[化学式S2141]
8-苄基-2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-benzyl-2-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dio ne)
1H NMR(400MHz,CDCl3)δ8.48(d,J=9.2Hz,1H),8.19(t,J=7.8Hz,2H),8.12(dd,J=8.5,3.0Hz,2H),8.08-7.98(m,3H),7.94-7.88(m,1H),7.39-7.28(m,3H),7.28-7.21(m,2H),4.56(s,2H),4.46-4.35(m,2H),4.22-4.05(m,2H),3.93-3.79(m,2H),3.73-3.68(m,1H),2.88-2.82(m,2H),2.70(td,J=12.7,3.2Hz,1H),2.29(t,J=11.2Hz,1H),2.14(td,J=11.7,3.0Hz,1H).
13C NMR(126MHz,CDCl3)δ163.54,161.75,135.02,131.36,131.23,130.91,130.57,130.10,129.05,128.60,128.39,128.31,127.48,126.07,125.28,125.19,124.79,124.50,124.05,60.95,57.45,57.14,51.41,49.40,48.62,41.40.
质量474.4
66、制备例66:化学式S2142
使用制备例63的反应式42中获得的化合物作为起始物质,进一步进行以下反应式46的步骤,从而获得了化学式S2142的化合物。
[反应式46]
添加0.25g的2-(芘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.65mmol)和0.039g氢化钠(0.97mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.192g的4-溴甲基联苯(4-bromomethyl biphenyl)(0.78mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-([1,1’-联苯]-4-基甲基)-2-(芘-1-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-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.314g,收率87%)。
[化学式S2142]
8-([1,1’-联苯]-4-基甲基)-2-(芘-1-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-(pyren-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ8.47(d,J=9.2Hz,1H),8.20-8.15(m,2H),8.11(dd,J=8.5,4.2Hz,2H),8.06-7.97(m,3H),7.90(d,J=7.8Hz,1H),7.59-7.51(m,4H),7.45-7.40(m,2H),7.37-7.28(m,3H),4.58(s,2H),4.46-4.40(m,1H),4.36(d,J=12.9Hz,1H),4.20-4.14(m,1H),4.10(d,J=12.9Hz,1H),3.89(s,2H),3.73-3.68(m,1H),2.87-2.81(m,1H),2.69(td,J=12.8,3.3Hz,1H),2.28(t,J=11.2Hz,1H),2.13(td,J=11.8,3.2Hz,1H).
13C NMR(126MHz,CDCl3)δ163.47,161.62,141.20,140.46,133.89,131.25,131.12,130.80,130.47,129.99,128.97,128.81,128.27,127.66,127.49,127.37,127.07,125.96,125.16,125.09,124.69,124.39,123.94,60.86,57.37,57.04,51.31,49.03,48.59,41.31.
质量550.4
67、制备例67:化学式S2217
[反应式47]
在室温下,加入了0.5g四氢-2H-吡嗪并[1,2-a]吡嗪-1,4(3H,6H)-二酮·三氟乙酸盐(1.77mmol)、5mL二氯甲烷、0.5mL三乙胺、0.31mL二苯乙醛(diphenylacetaldehyde)(1.77mmol)。加入0.748g三乙酰氧基硼氢化钠(3.53mmol),并在室温下搅拌过夜。将反应液用10mL纯净水洗涤。将反应液依次用10mL的碳酸氢钠水溶液和纯净水洗涤。将有机层用无水硫酸镁干燥并过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(2,2-diphenylethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.748g)。
[化学式S2217]
2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(2,2-diphenylethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(500MHz,CDCl3)δ7.31-7.16(m,10H),6.95(s,1H),4.44(ddd,J=13.1,2.9,1.9Hz,1H),4.24(t,J=7.8Hz,1H),4.00(s,2H),3.98-3.93(m,1H),3.48(ddd,J=11.3,3.1,1.6Hz,1H),3.10-2.98(m,2H),2.93-2.88(m,1H),2.66(td,J=12.7,3.3Hz,1H),2.18-2.08(m,2H).
13C NMR(126MHz,CDCl3)δ166.03,161.75,143.29,143.18,128.55,128.25,128.24,126.53,63.08,56.83,56.34,52.05,48.53,44.68,41.50.
质量350.2
68、制备例68:化学式S2126
使用制备例67的反应式47中获得的化合物S2217作为起始物质,进一步进行以下反应式48的步骤,从而获得了化学式S2126的化合物。
[反应式48]
添加0.1g的2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.29mmol)和0.017g氢化钠(0.43mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.075g的1-(溴甲基)萘(1-(Bromomethyl)naphthalene)(0.34mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(2,2-二苯基乙基)-8-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(2,2-diphenylethyl)-8-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.096g,收率68%)。
[化学式S2126]
2-(2,2-二苯基乙基)-8-(萘-1-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(2,2-diphenylethyl)-8-(naphthalen-1-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ8.05-8.00(m,1H),7.91-7.82(m,2H),7.57-7.49(m,2H),7.45-7.36(m,2H),7.33-7.16(m,10H),5.08(dd,J=43.9,14.5Hz,2H),4.36(d,J=13.1Hz,1H),4.27(t,J=7.8Hz,1H),4.07-4.01(m,1H),3.74-3.61(m,3H),3.12-2.98(m,2H),2.90-2.83(m,1H),2.61(td,J=12.6,3.2Hz,1H),2.17-1.99(m,2H).
质量490.4
69、制备例69:化学式S2127
使用制备例67的反应式47中获得的化合物S2217作为起始物质,进一步进行以下反应式49的步骤,从而获得了化学式S2127的化合物。
[反应式49]
添加0.1g的2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.29mmol)和0.017g氢化钠(0.43mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.075mg的2-(溴甲基)萘(2-(Bromomethyl)naphthalene)(0.34mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了2-(2,2-二苯基乙基)-8-(萘-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(2,2-diphenylethyl)-8-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.077g,收率55%)。
[化学式S2127]
2-(2,2-二苯基乙基)-8-(萘-2-基甲基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(2-(2,2-diphenylethyl)-8-(naphthalen-2-ylmethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ7.87-7.77(m,3H),7.70(s,1H),7.54-7.46(m,2H),7.39-7.17(m,11H),4.80-4.68(m,2H),4.44-4.38(m,1H),4.27(t,J=7.8Hz,1H),4.07-4.01(m,1H),3.88(s,2H),3.67-3.57(m,1H),3.12-2.99(m,2H),2.92-2.86(m,1H),2.65(td,J=12.6,3.2Hz,1H),2.20-2.05(m,2H).
质量490.4
70、制备例70:化学式S2130
使用制备例67的反应式47中获得的化合物S2217作为起始物质,进一步进行以下反应式50的步骤,从而获得了化学式S2130的化合物。
[反应式50]
添加0.168g的2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.481mmol)和0.029g氢化钠(0.73mmol)、二甲基甲酰胺,并在室温下搅拌30分钟后,加入0.069mL的苄基溴(benzyl bromide)(0.58mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-苄基-2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-benzyl-2-(2,2-diphenylethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.058g,收率27%)。
[化学式S2130]
8-苄基-2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-benzyl-2-(2,2-diphenylethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dio ne)
1H NMR(400MHz,CDCl3)δ7.39-7.15(m,15H),4.57(s,2H),4.45-4.37(m,1H),4.26(t,J=7.8Hz,1H),4.06-3.97(m,1H),3.84(s,2H),3.63-3.57(m,1H),3.10-3.00(m,2H),2.93-2.85(m,1H),2.65(td,J=12.6,3.3Hz,1H),2.17-2.06(m,2H).
质量440.2
71、制备例71:化学式S2131
使用制备例67的反应式47中获得的化合物S2217作为起始物质,进一步进行以下反应式51的步骤,从而获得了化学式S2131的化合物。
[反应式51]
添加0.1g的2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(0.29mmol)和0.017g氢化钠(0.43mmol)、二甲基甲酰胺,室温搅拌30分钟后,加入0.085mL的4-溴甲基联苯(4-bromomethyl biphenyl)(0.34mmol),并在室温下搅拌过夜。加入10mL氯化铵水溶液和20mL乙酸乙酯并搅拌,然后提取有机层,并用10mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥、过滤。浓缩反应液,并通过硅胶层析纯化,从而获得了8-([1,1’-联苯]-4-基甲基)-2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-([1,1’-biphenyl]-4-ylmethyl)-2-(2,2-diphenylethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)(0.102g,收率68%)。
[化学式S2131]
8-([1,1’-联苯]-4-基甲基)-2-(2,2-二苯基乙基)六氢-2H-吡嗪并[1,2-a]吡嗪-6,9-二酮(8-([1,1’-biphenyl]-4-ylmethyl)-2-(2,2-diphenylethyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione)
1H NMR(400MHz,CDCl3)δ7.60-7.54(m,4H),7.47-7.41(m,2H),7.39-7.16(m,13H),4.69-4.54(m,2H),4.42(d,J=13.1Hz,1H),4.26(t,J=7.8Hz,1H),4.09-3.98(m,1H),3.89(s,2H),3.67-3.56(m,1H),3.14-2.97(m,2H),2.90(d,J=11.5Hz,1H),2.66(td,J=12.6,3.2Hz,1H),2.19-2.06(m,2H).
质量516.4
72、制备例72:化学式S2204
[化学式S2204]
1H NMR(500MHz,CDCl3)δ7.84-7.78(m,3H),7.71(s,1H),7.50-7.43(m,3H),7.34(s,1H),4.50(ddd,J=13.2,3.0,1.9Hz,1H),4.11(dd,J=11.0,3.3Hz,1H),3.72(dd,J=63.4,13.1Hz,2H),3.47(ddd,J=11.3,3.2,1.7Hz,1H),2.92-2.85(m,1H),2.82-2.75(m,1H),2.15-2.03(m,2H),1.48(s,3H),1.45(s,3H).
13C NMR(126MHz,CDCl3)δ168.25,165.53,134.68,133.26,132.89,128.15,127.75,127.71,127.65,127.11,126.10,125.81,62.71,57.45,56.43,56.03,51.70,41.70,29.16,28.95.
质量338.18
73、制备例73:化学式S2211
[化学式S2211]
1H NMR(500MHz,CDCl3)δ7.83-7.77(m,3H),7.69(s,1H),7.49-7.42(m,3H),4.47(ddd,J=13.1,3.2,1.8Hz,1H),3.92(s,2H),3.96-3.88(m,2H),3.83-3.59(m,1H),3.50(ddd,J=11.4,3.2,1.8Hz,1H),2.90(s,3H),2.88-2.82(m,1H),2.81-2.71(m,1H),2.13-1.99(m,2H).
13C NMR(126MHz,CDCl3)δ163.42,161.37,134.45,133.19,132.83,128.08,127.79,127.66,127.59,127.12,126.03,125.76,62.60,57.12,56.57,51.23,51.10,41.18,33.25.
质量324.17
74、制备例74:化学式S2212
[化学式S2212]
1H NMR(500MHz,CDCl3)δ7.83-7.77(m,3H),7.70(s,1H),7.50-7.42(m,3H),4.48(ddd,J=13.2,3.1,1.8Hz,1H),4.11-4.04(m,1H),4.00-3.88(m,2H),3.72(dd,J=77.0,13.1Hz,2H),3.51(ddd,J=11.4,3.2,1.8Hz,1H),3.46-3.32(m,2H),2.89-2.83(m,1H),2.78(td,J=12.6,3.3Hz,1H),2.14-2.01(m,2H),1.13(t,J=7.2Hz,3H).
13C NMR(126MHz,CDCl3)δ162.98,161.87,134.61,133.29,132.93,128.17,127.86,127.76,127.68,127.20,126.12,125.84,62.72,57.29,56.67,51.33,48.59,41.30,40.89,11.60.
质量338.18
75、制备例75:化学式S2213
[化学式S2213]
1H NMR(500MHz,CDCl3)δ7.83-7.78(m,3H),7.71(s,1H),7.50-7.43(m,3H),4.49(ddd,J=13.2,3.2,1.8Hz,1H),4.12-4.07(m,1H),4.00-3.90(m,2H),3.73(dd,J=77.3,13.1Hz,2H),3.52(ddd,J=11.4,3.3,1.8Hz,1H),3.42-3.29(m,2H),2.90-2.84(m,1H),2.79(td,J=12.6,3.4Hz,1H),2.14-2.03(m,2H),1.57-1.48(m,2H),1.35-1.25(m,2H),0.93(t,J=7.4Hz,3H).
13C NMR(126MHz,CDCl3)δ163.30,161.97,134.69,133.36,133.00,128.24,127.91,127.82,127.74,127.24,126.17,125.90,62.80,57.36,56.82,51.41,49.23,45.86,41.38,28.51,20.01,13.80.
质量366.21
76、制备例76:化学式S2214
[化学式S2214]
1H NMR(500MHz,CDCl3)δ7.85-7.78(m,3H),7.71(s,1H),7.51-7.43(m,3H),4.46(brs,1H),4.14-4.07(m,1H),3.80(dd,J=80.7,13.1Hz,2H),3.59(dd,J=11.9,2.3Hz,1H),3.18(ddd,J=13.5,12.9,4.2Hz,1H),3.01-2.92(m,4H),2.36(d,J=11.9Hz,1H),2.17(ddd,J=12.7,11.8,3.9Hz,1H),1.59(s,3H),1.53(s,3H).
13C NMR(126MHz,CDCl3)δ171.49,163.97,134.07,133.28,132.99,128.41,128.05,127.75,127.70,126.94,126.26,126.01,79.55,62.28,60.94,60.45,50.98,38.55,28.29,26.08,25.57.
质量350.18
77、制备例77:化学式S2215
[化学式S2215]
1H NMR(500MHz,CDCl3)δ7.86-7.78(m,3H),7.71(s,1H),7.51-7.42(m,3H),4.44(s,1H),4.13-4.04(m,1H),3.89-3.51(m,3H),3.46-3.31(m,1H),3.25-3.12(m,1H),3.01-2.93(m,1H),2.35(d,J=11.9Hz,1H),2.22-2.15(m,1H),2.11-2.00(m,1H),1.62-1.50(m,6H),1.24-1.19(m,3H).
13C NMR(126MHz,CDCl3)δ171.81,163.70,134.24,133.40,133.11,128.53,128.17,127.87,127.81,127.06,126.36,126.12,79.51,62.42,61.55,60.46,51.15,38.69,38.26,27.23,25.87,14.57.
质量366.21
78、制备例78:化学式S2216
[化学式S2216]
1H NMR(500MHz,CDCl3)δ7.84-7.77(m,3H),7.70(s,1H),7.50-7.40(m,3H),4.51-4.45(m,1H),4.08-4.04(m,1H),3.81-3.61(m,2H),3.52(ddd,J=11.3,3.2,1.8Hz,1H),3.39-3.17(m,2H),2.90-2.70(m,2H),2.11-2.00(m,2H),1.60-1.52(m,5H),1.48(s,3H),1.37-1.28(m,2H),0.95-0.90(m,3H).
13C NMR(126MHz,CDCl3)δ168.18,163.81,134.76,133.33,132.95,128.18,127.83,127.78,127.69,127.18,126.09,125.81,77.41,77.16,76.90,62.77,61.15,57.02,56.88,51.61,43.08,41.76,31.36,26.62,26.28,20.51,13.80.
质量394.24
79、制备例79:化学式N502
在下述衍生物的合成中,使用相同的4-(萘-2-基甲基)哌嗪-2-甲酸苄酯(benzyl4-(naphthalen-2-ylmethyl)piperazine-2-carboxylate),并且使用以下方法作为合成方法。
[反应式52]
加入0.4g的2-萘甲醛(2-Naphthaldehyde)(2.3mmol)、1.0g的哌嗪-1,2-二羧酸1-((9H-芴-9-基)甲基)酯2-苄酯(1-((9H-fluoren-9-yl)methyl)2-benzyl piperazine-1,2-dicarboxylate)(2.3mmol)、20mL的1,2-二氯乙烷、1.4g三乙酰氧基硼氢化钠(6.8mmol)和3.5g的分子筛(molecular sieve),并在室温下搅拌过夜。向反应产物中加入25mL纯净水,并剧烈搅拌20分钟。提取有机层,并用氯化钠水溶液洗涤。有机层用无水硫酸钠干燥,并进行减压浓缩,从而以残渣的形式获得化合物,并将其用于下一步骤(1.4g)。
[反应式53]
加入1.4g的4-(萘-2-基甲基)哌嗪-1,2-二羧酸1-(9H-芴-9-基)甲基)酯2-苄酯(1-((9H-fluoren-9-yl)methyl)2-benzyl4-(naphthalen-2-ylmethyl)piperazine-1,2-dicarboxylate)、7mL二甲基甲酰胺和3.2mL哌啶,并在室温下搅拌1小时。向反应产物中加入80mL氯化铵水溶液、二氯甲烷并搅拌后,提取有机层。将有机层用无水硫酸镁干燥,然后进行减压浓缩。将浓缩的残渣通过硅胶层析纯化,从而获得了4-(萘-2-基甲基)哌嗪-2-甲酸苄酯(benzyl 4-(naphthalen-2-ylmethyl)piperazine-2-carboxylate)(0.47g,收率54%)。
[反应式54]
添加1.5g的4-(萘-2-基甲基)哌嗪-2-甲酸苄酯(5.3mmol),N-(叔丁氧基羰基)-L-苯丙氨酸(N-(tert-Butoxycarbonyl)-L-phenylalanine)(5.5mmol)、15mL二甲基甲酰胺、2.9g的(苯并三唑-1-基氧基)三吡咯烷基鏻六氟磷酸盐((Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate)(5.5mmol)和1.0g的N,N-二异丙基乙胺(7.9mmol),将混合物在室温下搅拌过夜。向反应产物中加入60mL纯净水和30mL乙酸乙酯并搅拌。提取有机层并用氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥,并进行减压浓缩。浓缩的残渣通过硅胶层析纯化,从而获得了1-(2-((叔丁氧基羰基)氨基)-2-苯基乙酰基)-4-(萘-2-基甲基)哌嗪-2-甲酸苄酯(benzyl1-(2-((tert-butoxycarbonyl)amino)-2-phenylacetyl)-4-(naphthalen-2-ylmethyl)piperazine-2-carboxylate)(2.6g,收率81%)。
[反应式55]
加入2.6g的1-(2-((叔丁氧基羰基)氨基)-2-苯基乙酰基)-4-(萘-2-基甲基)哌嗪-2-甲酸苄酯(Benzyl 1-(2-((tert-butoxycarbonyl)amino)-2-phenylacetyl)-4-(naphthalen-2-ylmethyl)piperazine-2-carboxylate)(4.3mmol)、26mL二氯甲烷、6.5mL三氟乙酸,并在室温下搅拌30分钟。反应液用80mL碳酸钠水溶液中和,并提取有机层。将有机层用无水硫酸镁干燥,并进行减压浓缩,从而以残渣的形式获得了1-(2-氨基-2-苯基乙酰基)-4-(萘-2-基甲基)哌嗪-2-甲酸苄酯(benzyl1-(2-amino-2-phenylacetyl)-4-(naphthalen-2-ylmethyl)piperazine-2-carboxylate),并将其用于下一步骤(1.9g)。
[反应式56]
加入1.9g的1-(2-氨基-2-苯基乙酰基)-4-(萘-2-基甲基)哌嗪-2-甲酸苄酯(Benzyl 1-(2-amino-2-phenylacetyl)-4-(naphthalen-2-ylmethyl)piperazine-2-carboxylate)残渣、10mL异丙醇、3mL乙酸,并在室温下搅拌过夜。加入110mL碳酸氢钠水溶液和30mL乙酸乙酯并搅拌。提取有机层,并用30mL氯化钠水溶液洗涤。将有机层用无水硫酸镁干燥,并进行减压浓缩。浓缩的残渣通过硅胶层析纯化,从而获得了3-苄基-8-(萘-2-基甲基)六氢-1H-吡嗪并[1,2-a]吡嗪-1,4(6H)-二酮(3-benzyl-8-(naphthalen-2-ylmethyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione)(N502)(1.5g,两个步骤的收率88%)。
[化学式N502]
3-苄基-8-(萘-2-基甲基)六氢-1H-吡嗪并[1,2-a]吡嗪-1,4(6H)-二酮(3-benzyl-8-(naphthalen-2-ylmethyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-1,4(6H)-dione)
1H NMR(500MHz,CDCl3)δ7.86-7.76(m,3H),7.64(d,J=17.1Hz,1H),7.51-7.43(m,2H),7.43-7.36(m,1H),7.33-7.29(m,2.5H),7.22-7.14(m,2.5H),7.03(s,0.5H),6.90(s,0.5H),4.52-4.40(m,1H),4.38-4.26(m,1H),3.92(dd,J=11.1,2.8Hz,0.5H),3.73-3.43(m,2H),3.29-3.24(m,1H),3.19(dd,J=13.6,5.6Hz,0.5H),3.08-3.01(m,2H),2.82-2.79(m,0.5H),2.72-2.63(m,1H),2.52(td,J=12.8,3.4Hz,0.5H),2.05-1.93(m,1H),1.74(td,J=11.4,3.0Hz,0.5H),0.78(t,J=11.2Hz,0.5H).
质量400.2
<实验例>
制备例的化合物的抗癌治疗活性增强效果
1、SKOV3和SKOV3-TR的准备
以作为上皮性卵巢癌细胞株的SKOV3和SKOV3-TR为对象进行了细胞实验,其中,SKOV3-TR为衍生自SKOV3的制作成对紫杉醇(Paclitaxel)抗癌剂有耐受性的癌细胞株,图1的(a)部分示出SKOV3的紫杉醇和多西他赛抗癌剂IC50值,(b)部分示出SKOV3-TR的紫杉醇和多西他赛抗癌剂IC50值。
2、根据紫杉醇的处理的WST-1分析
根据用于测定细胞增殖或存活的WST-1分析结果,紫杉醇的处理诱导了在SKOV3和SKOV3-TR中的物质代谢的减少。对于79种SKOV3和79种SKOV3-TR,与紫杉醇一起联合处理后,进行了WST-1分析。
具体而言,对在96孔中生长的两种癌细胞株,将79种类型的化合物以低浓度(0.5μM)和高浓度(2μM)与紫杉醇一起进行处理,而就紫杉醇的浓度而言,对SKOV3-TR细胞株,处理了3μM或4μM,对SKOV3细胞株,处理了2μM或0.05μM。为了分析细胞毒性,利用DMSO(紫杉醇、化合物溶剂)、紫杉醇(Paclitaxel)和79种化合物联合处理3天后进行了WST-1分析,并将结果示于图2至图13中。
图2、图3分别以未处理(None)、DMSO、紫杉醇、S461(0.5μM)、S461(2μM)、S462(0.5μM)、S462(2μM)、S471(0.5μM)、S471(2μM)、S472(0.5μM)、S472(2μM)、N501(0.5μM)、N501(2μM)、N502(0.5μM)、N502(2μM)、N503(0.5μM)、N503(2μM)、N511(0.5μM)、N511(2μM)、N512(0.5μM)、N512(2μM)、N513(0.5μM)、N513(2μM)、N514(0.5μM)、N514(2μM)、N601(0.5μM)、N601(2μM)、N611(0.5μM)、N611(2μM)、N612(0.5μM)、N612(2μM)、N614(0.5μM)、N614(2μM)的顺序表示。
图4、图5分别以未处理(None)、DMSO、紫杉醇、N701(0.5μM)、N701(2μM)、N613(0.5μM)、N613(2μM)、N024(0.5μM)、N024(2μM)、N522(0.5μM)、N522(2μM)、N622(0.5μM)、N622(2μM)、N523(0.5μM)、N523(2μM)、N711(0.5μM)、N711(2μM)、N712(0.5μM)、N712(2μM)、N713(0.5μM)、N713(2μM)、N714(0.5μM)、N714(2μM)、N722(0.5μM)、N722(2μM)、N401(0.5μM)、N401(2μM)、N724(0.5μM)、N724(2μM)、N723(0.5μM)、N723(2μM)、N524(0.5μM)、N524(2μM)、N411(0.5μM)、N411(2μM)、N412(0.5μM)、N412(2μM)、N413(0.5μM)、N413(2μM)的顺序表示。
图6、图7分别以未处理(None)、DMSO、紫杉醇、N414(0.5μM)、N414(2μM)、N422(0.5μM)、N422(2μM)、N423(0.5μM)、N423(2μM)、N641(0.5μM)、N641(2μM)、N311(0.5μM)、N311(2μM)、N312(0.5μM)、N312(2μM)、N313(0.5μM)、N313(2μM)、N322(0.5μM)、N322(2μM)、N323(0.5μM)、N323(2μM)、N324(0.5μM)、N324(2μM)、N301(0.5μM)、N301(2μM)、N424(0.5μM)、N424(2μM)的顺序表示。
图8、图9分别以未处理(None)、DMSO、紫杉醇、N504(0.5μM)、N504(2μM)、N053(0.5μM)、N053(2μM)、N031(0.5μM)、N031(2μM)、N054(0.5μM)、N054(2μM)、N026(0.5μM)、N026(2μM)、N032(0.5μM)、N032(2μM)、N034(0.5μM)、N034(2μM)、N021(0.5μM)、N021(2μM)、N025(0.5μM)、N025(2μM)、N011(0.5μM)、N011(2μM)、N035(0.5μM)、N035(2μM)、S2126(0.5μM)、S2126(2μM)、S2127(0.5μM)、S2127(2μM)、S2130(0.5μM)、S2130(2μM)的顺序表示。
图10、图11分别以未处理(None)、DMSO、紫杉醇、N033(0.5μM)、N033(2μM)、N036(0.5μM)、N036(2μM)、N022(0.5μM)、N022(2μM)、S2115(0.5μM)、S2115(2μM)、S2120(0.5μM)、S2120(2μM)、S2121(0.5μM)、S2121(2μM)、S2124(0.5μM)、S2124(2μM)、S2125(0.5μM)的顺序表示。
图12和图13分别以未处理(None)、DMSO、紫杉醇、S2131(0.5μM)、S2131(2μM)、S2139(0.5μM)、S2139(2μM)、S2140(0.5μM)、S2140(2μM)、S2141(0.5μM)、S2213(0.5μM)、S2213(2μM)、S2214(0.5μM)、S2214(2μM)、S2215(0.5μM)、S2215(2μM)、S2216(0.5μM)、S2216(2μM)、S2217(0.5μM)、S2217(2μM)的顺序表示。
也就是说,与未处理(None)或DMSO处理组相比,在紫杉醇处理组中,由于诱导SKOV3-TR和SKOV3中的细胞凋亡和抑制细胞生长等的现象,450nm处的吸光度降低。当联合处理化合物和紫杉醇时,在耐受性癌细胞株SKOV3-TR中紫杉醇的抗癌功效增强,与紫杉醇处理组相比,显示出较低的吸光度,但在SKOV3中没有使紫杉醇的抗癌功效增强。并且,在SKOV3-TR中,由于2μM的化合物比0.5μM的化合物更能促进基于紫杉醇的物质代谢的减少,由此可知剂量-反应关系(dose-response relationship)成立。在作为比较例的紫杉醇处理组的吸光度上加入了基线。至于紫杉醇抗癌增强功效,与紫杉醇处理组相比,当处理紫杉醇+化合物时,WST-1分析中的吸光度(450nm处的OD值)显著降低。
3、根据多西他赛的处理的WST-1分析
根据测定细胞增殖或存活的WST-1分析结果,多西他赛的处理诱导了SKOV3和SKOV3-TR物质代谢的减少。
对于79种SKOV3和79种SKOV3-TR,与多西他赛联合处理后,进行了WST-1分析。
具体而言,对在96孔中生长的两种癌细胞株,将79种类型的化合物以低浓度(0.5μM)和高浓度(2μM)与多西他赛一起进行处理,对于多西他赛浓度,对SKOV3-TR细胞株,处理了1μM,对SKOV3细胞株,处理了0.75μM。为了分析细胞毒性,利用DMSO(多西他赛、化合物溶剂)、多西他赛(Docetaxel)和80种化合物联合处理3天后进行了WST-1分析,并将结果示于图14至图25中。
图14、图15分别以未处理(None)、DMSO、多西他赛、S461(0.5μM)、S461(2μM)、S462(0.5μM)、S462(2μM)、S471(0.5μM)、S471(2μM)、S472(0.5μM)、S472(2μM)、N501(0.5μM)、N501(2μM)、N502(0.5μM)、N502(2μM)、N503(0.5μM)、N503(2μM)、N504(0.5μM)、N504(2μM)、N511(0.5μM)、N511(2μM)、N512(0.5μM)、N512(2μM)、N513(0.5μM)、N513(2μM)、N514(0.5μM)、N514(2μM)、N601(0.5μM)、N601(2μM)、N611(0.5μM)、N611(2μM)、N612(0.5μM)、N612(2μM)、N614(0.5μM)、N614(2μM)的顺序表示。
图16、图17分别以未处理(None)、DMSO、多西他赛、N622(0.5μM)、N622(2μM)、N523(0.5μM)、N523(2μM)、N711(0.5μM)、N711(2μM)、N712(0.5μM)、N712(2μM),N713(0.5μM)、N713(2μM)、N714(0.5μM)、N714(2μM),N722(0.5μM)、N722(2μM)、N401(0.5μM)、N401(2μM)、N724(0.5μM)、N724(2μM)、N723(0.5μM)、N723(2μM)、N524(0.5μM)、N524(2μM)、N411(0.5μM)、N411(2μM)、N412(0.5μM)、N412(2μM)的顺序表示。
图18、图19分别以未处理(None)、DMSO、多西他赛、N413(0.5μM)、N413(2μM)、N414(0.5μM)、N414(2μM)、N422(0.5μM)、N422(2μM)、N423(0.5μM)、N423(2μM)、N641(0.5μM)、N641(2μM)、N311(0.5μM)、N311(2μM)、N312(0.5μM)、N312(2μM)、N313(0.5μM)、N313(2μM)、N322(0.5μM)、N322(2μM)、N323(0.5μM)、N323(2μM)、N324(0.5μM)、N324(2μM)、N301(0.5μM)、N301(2μM)、N424(0.5μM)、N424(2μM)的顺序表示。
图20、图21分别以未处理(None)、DMSO、多西他赛、N053(0.5μM)、N053(2μM)、N031(0.5μM)、N031(2μM)、N054(0.5μM)、N054(2μM)、N026(0.5μM)、N026(2μM)、N032(0.5μM)、N032(2μM)、N034(0.5μM)、N034(2μM)、N021(0.5μM)、N021(2μM)、N025(0.5μM)、N025(2μM)、N011(0.5μM)、N011(2μM)、N035(0.5μM)、N035(2μM)、N701(0.5μM)、N701(2μM)、N613(0.5μM)、N613(2μM)、N024(0.5μM)、N024(2μM)、N522(0.5μM)、N522(2μM)的顺序表示。
图22、图23分别以未处理(None)、DMSO、多西他赛、N033(0.5μM)、N033(2μM)、N036(0.5μM)、N036(2μM)、N022(0.5μM)、N022(2μM)、S2115(0.5μM),S2115(2μM)、S2120(0.5μM)、S2120(2μM)、S2121(0.5μM),S2121(2μM)、S2124(0.5μM)、S2124(2μM)、S2125(0.5μM)的顺序表示。
图24、图25分别以未处理(None)、DMSO、多西他赛、S2126(0.5μM)、S2126(2μM)、S2127(0.5μM)、S2127(2μM)、S2130(0.5μM)、S2130(2μM)、S2131(0.5μM)、S2204(0.5μM)、S2204(2μM)、S2211(0.5μM)、S2211(2μM)、S2212(0.5μM)、S2212(2μM)、S2213(0.5μM)、S2213(2μM)、S2214(0.5μM)、S2214(2μM)、S2215(0.5μM)、S2215(2μM)、S2216(0.5μM)、S2216(2μM)、S2217(0.5μM)、S2217(2μM)的顺序表示。
也就是说,与未处理(None)或DMSO处理组相比,在多西他赛(Docetaxel)处理组中,由于诱导SKOV3-TR和SKOV3中的细胞凋亡和抑制细胞生长等的现象,450nm处的吸光度降低。当联合处理化合物和多西他赛(Docetaxel)时,在耐受性癌细胞株SKOV3-TR中多西他赛的抗癌功效增强,与多西他赛(Docetaxel)处理组相比,显示出较低的吸光度,但在SKOV3中没有使多西他赛的抗癌功效增强。并且,在SKOV3-TR中,由于2μM的化合物比0.5μM的化合物更能促进基于多西他赛的物质代谢的减少,由此可知剂量-反应关系(dose-responserelationship)成立。在作为比较例的多西他赛(Docetaxel)处理组的吸光度上加入了基线。至于紫杉醇抗癌增强功效,与多西他赛(Docetaxel)相比,当处理多西他赛+化合物时,WST-1分析中的吸光度(450nm处的OD值)显著降低。
本申请所属领域的技术人员将能够理解,在不改变其技术精神或本质特征的情况下,本申请可以以其他具体形式实施。因此,应当理解,上述实施例在所有方面都是示例性的,而不是限定性的。本申请的范围由所附权利要求书而非上述详细说明来表示,由权利要求书的含义和范围及其等同概念衍生的所有变更或修改,均应被解释为包括在本申请的范围内。
Claims (17)
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,其中,
[化学式1]
在所述化学式1中,
L1为直接键合或C1-10亚烷基;
Ar1为C1-12烷基或能够含有0个至3个独立地选自O、N或S的杂原子的5元至16元单环、双环、三环或四环,其未被取代或被独立地选自C1-6卤代烷基、卤素、氧代基、-OCHF2、-CN、硝基、-C(=O)NZaZa、-C(=O)Zb、-C(=O)OZb、-C(=NZa)NZaZa、-OZa、-OC(=O)Zb、-OC(=O)NZaZa、-O-C1-6烷基N(Za)C(=O)OZb、-OC(=O)N(Za)S(=O)2Zb、-OC2-6烷基NZaZa、-OC2-6烷基OZa、-SZa、-S(=O)Zb、-S(=O)2Zb、-S(=O)2NZaZa、-S(=O)2N(Za)C(=O)Zb、-S(=O)2N(Za)C(=O)OZb、-S(=O)2N(Za)C(=O)NZaZa、-NZaZa、-NZcZc、-N(Za)C(=O)Zb、-N(Za)C(=O)OZb、-N(Za)C(=O)NZaZa、-N(Za)C(=NZa)NZaZa、-N(Za)S(=O)2Zb、-N(Za)S(=O)2NZaZa、-NZaC2-6烷基NZaZa、-NZaC2-6烷基OZa、C6-10芳基、C5-10杂芳基、-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基(其中,-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基被0个至3个独立地选自C1-6卤代烷基、卤素、氰基、硝基、C6-12芳基或C5-12杂芳基的取代基取代)的基团取代;
Za各自独立地为氢或Zb;
Zb各自独立地为苯基、苄基、C1-6烷基、C4-8杂环烷基或C3-8环烷基,所述苯基、苄基、C1-6烷基、C4-8杂环烷基或C3-8环烷基烷基被0个至3个独立地选自卤素、-OH、-S(=O)2Zb、-OC2-6烷基OZa、C1-6烷基、C1-6卤代烷基、-OC1-4烷基、-NH2、-CN或-NZaZa的取代基取代;
Zc各自独立地为氢或C1-6烷基,或基团CZcZc能够形成C3-8环烷基环;
m和y各自独立地为0至2的整数;
R1或R2各自独立地为氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基羰基、卤代C1-6烷基、C2-6烯基或C4-15单环或双环(其为C3-10环烷基;C6-12芳基;含有0个至3个独立地选自N、O和S的杂原子的5元或6元饱和或部分饱和杂环;含有0个至3个独立地选自N、O和S的杂原子(所述杂原子不会同时具有两个以上O或两个以上S)的5元或6元芳族杂环;或含有0个至3个独立地选自N、O和S的杂原子的7元至15元饱和、部分饱和或不饱和杂环);
所述R1和R2能够以形成5元至12元的单环或双环的方式连接。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中,
所述由化学式1表示的化合物为下述化学式2至10中的任意一种。
[化学式2]
[化学式3]
[化学式4]
[化学式5]
[化学式6]
[化学式7]
[化学式8]
[化学式9]
[化学式10]
所述化学式2至10中,
L1为直接键合或C1-6亚烷基;
A1、A2、A3或A4各自独立地为CR或N;
R或R’各自独立地为氢、羟基、卤素、C6-12芳基、C5-12杂芳基、-C1-6烷基、-C3-10环烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基(其中,-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基能够被0个至3个独立地选自C1-6卤代烷基、卤素、氰基、硝基、C6-12芳基或C5-12杂芳基的取代基取代);
n和n’各自独立地为0至13的整数;
m和y各自独立地为0至2的整数;
R1或R2各自独立地为氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基羰基、卤代C1-6烷基、C2-6烯基、C4-15单环或双环(其为C3-10环烷基;C6-10芳基;含有0个至3个独立地选自N、O和S的杂原子的5元或6元饱和或部分饱和杂环;含有0个至3个独立地选自N、O和S的杂原子(所述杂原子不会同时具有两个以上O或两个以上S)的5元或6元芳族杂环;或含有0个至3个独立地选自N、O和S的杂原子的7元至15元饱和、部分饱和或不饱和杂环);
所述R1和R2能够以形成5元至12元的单环或双环的方式连接。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中,
所述L1为直接键合或C1-3亚烷基;
所述Ar1为C1-6直链或支链烷基、萘基、苯基、萘基、蒽基、菲基、芘基、呋喃基、吲哚基、色酮基、喹啉基、咔唑基或噻吩基,其未被取代或被羟基、卤素、C1-6烷基、C3-10环烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C2-6烯基、-C2-6炔基、C6-12芳基或C5-12杂芳基中的至少一种取代;
所述m为1,
所述y为1或2,
所述R1或R2各自独立地为氢、C1-6烷基、苄基、萘基烷基、苯并呋喃基烷基、喹啉基烷基、吡啶基烷基、环己基烷基、噻吩基烷基、吡咯基烷基、呋喃基烷基或苯并噻吩基烷基,其未被取代或各自独立地被C1-6烷基、C3-6环烷基、C6-12芳基、羟基、卤素、C1-6烷氧基、C1-6卤代烷基或C1-6卤代烷氧基中的至少一个取代;
所述R1和R2能够以形成5元至12元的单环或双环的方式连接。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其中,
所述L1为C1-3亚烷基;
所述R或R’各自独立地为氢、羟基、卤素、C6-12芳基、C5-12杂芳基、-C1-6烷基、-C3-10环烷基、-C1-6烷氧基、-C2-6烯基或-C2-6炔基(其中,-C1-6烷基、-C3-10环烷基、-C2-6烯基或-C2-6炔基能够被0个至3个独立地选自C1-6卤代烷基、卤素、氰基、硝基、C6-12芳基或C5-12杂芳基的取代基取代);
所述m为1,
所述y为1或2,
所述R1和R2能够以形成5元至12元的单环或双环的方式连接。
6.一种用于预防或治疗癌症的药物组合物,其中,
所述药物组合物包括权利要求1至5中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体或其组合。
7.一种用于预防或治疗耐受性癌的药物组合物,其中,
所述药物组合物包括权利要求1至5中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体或其组合。
8.根据权利要求7所述的用于预防或治疗耐受性癌的药物组合物,其中,
所述组合物抑制SERCA蛋白的表达。
9.根据权利要求7所述的用于预防或治疗耐受性癌的药物组合物,其中,
所述耐受性癌对抗癌药物或放射线具有耐受性。
10.根据权利要求9所述的用于预防或治疗耐受性癌的药物组合物,其中,
所述抗癌药物为选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、埃罗替尼、来那替尼、拉帕替尼、吉非替尼、凡德他尼、尼洛替尼、塞马西尼、博舒替尼、阿昔替尼、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、普纳替尼、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、白果槲寄生、天冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥单抗、替伊莫单抗、庚铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、丙卡巴肼、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、吉美拉西、奥特拉西、阿扎胞苷、甲氨蝶呤、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、多西他赛、紫杉醇、卡巴他赛、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春碱、替尼泊苷、阿霉素、伊达比星、表柔比星、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素D、吡柔比星、阿柔比星、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、亚叶酸、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、伏罗唑、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。
11.根据权利要求9所述的用于预防或治疗耐受性癌的药物组合物,其中,
以所述抗癌药物与由化学式1表示的化合物或其药学上可接受的盐的摩尔浓度比为1:0.001至1:1000的方式包含所述抗癌药物。
12.根据权利要求9所述的用于预防或治疗耐受性癌的药物组合物,其中,
所述耐受性癌为选自由卵巢癌、大肠癌、胰腺癌、胃癌、肝癌、乳腺癌、宫颈癌、甲状腺癌、甲状旁腺癌、肺癌、非小细胞肺癌、前列腺癌、胆囊癌、胆道癌、血液癌、膀胱癌、肾癌、黑色素瘤、结肠癌、骨癌、皮肤癌、头颈癌、子宫癌、直肠癌、脑癌、肛周癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、输尿管癌、肾细胞癌、肾盂癌、血液癌、中枢神经系统肿瘤、脊髓肿瘤、脑干神经胶质瘤和脑下垂体腺瘤组成的组中的至少一种。
13.一种癌症的治疗方法,其中,
包括向患有癌的个体施用治疗有效量的根据权利要求1至5中任一项所述的化合物、其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的步骤。
14.一种对肿瘤学疗法表现出耐受性的癌症的治疗方法,其中,
包括向患有耐受性癌的个体施用治疗有效量的根据权利要求1至5中任一项所述的化合物、其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合的步骤。
15.根据权利要求14所述的对肿瘤学疗法表现出耐受性的癌症的治疗方法,其中,
包括同时、分别或依次施用能够用于治疗癌症或增殖性疾病的化学治疗剂的步骤。
16.一种根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐在制备癌症或耐受性癌治疗用药剂中的用途。
17.一种根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、结构异构体、光学异构体、立体异构体、或其组合在制备干细胞性癌治疗用药剂中的用途。
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