CN102010422B - 含有胍基的青蒿素类衍生物及其应用 - Google Patents
含有胍基的青蒿素类衍生物及其应用 Download PDFInfo
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- CN102010422B CN102010422B CN201010555294.6A CN201010555294A CN102010422B CN 102010422 B CN102010422 B CN 102010422B CN 201010555294 A CN201010555294 A CN 201010555294A CN 102010422 B CN102010422 B CN 102010422B
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- Prior art keywords
- dihydroartemisinin
- ethyl
- carboxamidine
- phenyl
- guanidine
- Prior art date
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 title abstract description 24
- 229960004191 artemisinin Drugs 0.000 title abstract description 12
- 229930101531 artemisinin Natural products 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 11
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- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims description 79
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 60
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 55
- -1 hydrogen Chemical class 0.000 claims description 34
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 30
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 30
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
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- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- QUUYRYYUKNNNNS-UHFFFAOYSA-N piperidine-1-carboximidamide Chemical compound NC(=N)N1CCCCC1 QUUYRYYUKNNNNS-UHFFFAOYSA-N 0.000 claims description 8
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- NHXIJZTXMUNDFI-UHFFFAOYSA-N pyrrole-1-carboximidamide Chemical compound NC(=N)N1C=CC=C1 NHXIJZTXMUNDFI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 3
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Abstract
本发明涉及通式Ⅰ所示的青蒿素类衍生物、其旋光异构体及其药学上可接受的盐,其中取代基R1、R2、X、Ar具有在说明书中给出的含义。本发明还涉及通式Ⅰ的化合物在制备治疗和/或预防癌症的药物中的用途。
Description
技术领域
本发明属于医药技术领域,涉及新的青蒿素类衍生物及其光学活性体、及其药学上可接受的盐,它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该衍生物用于制备治疗和/或预防癌症和其它增生性疾病的药物中的用途。
技术背景
癌症是一种严重威胁人类生命的疾病,据2008年WHO的统计,2007年癌症死亡人数达790万,约占所有死亡人数的13%。近年来,随着对肿瘤发生机制研究的不断深入,有关癌症发生发展的分子机制不断被揭示,抗肿瘤药物已从最初的细胞毒性药物发展到作用于肿瘤特有靶点药物的研究。
青蒿素(ART)是我国科研人员于1972年首次从菊科植物黄花蒿中分离得到抗疟疾的有效单体,是具有过氧基团的倍半萜内酯类化合物,为我国首先发现的新型的抗疟药。目前,青蒿素及其衍生物作为高效低毒的抗疟药已经得到了全世界的公认,并在其基础上合成了多种衍生物,如双氢青蒿素、蒿甲醚、青蒿琥酯等。青蒿素类药物毒性低、抗疟性强对于疟原虫具有更强和更快的抑制活性,在临床上已经被应用多年。药理学的研究证实青蒿素还具有抗血吸虫、抗孕、抗肿瘤等多方面作用。随着对青蒿素及其衍生物的认识和研究的深入,其在抗肿瘤方面的作用越来越受到关注。1991年我国学者邓安定等首次报道了青蒿素对白血病P388细胞有选择性杀伤活性。Eferth等在研究青蒿琥酯对55种癌细胞株的抗癌活性时发现,青蒿琥酯对白血病细胞和结肠癌细胞的抗癌活性最强,对黑素瘤、乳腺癌、卵巢癌、前列腺癌、中枢神经系统肿瘤及肾癌细胞等有中度活性,对非小细胞性肺癌细胞的活性最弱。近年来,很多实验研究表明,青蒿素类衍生物对多种肿瘤细胞的生长具有显著的抑制作用,而对正常组织细胞的毒性很低。青蒿素已成为发现新型抗癌药物分子的潜在先导化合物。因此,青蒿素衍生物为人们开发新型高效低毒的抗肿瘤药物开辟了新的研究思路。
本发明人在参考文献的基础上,设计合成了一系列青蒿素类衍生物,经体外对多种肿瘤细胞株进行抗肿瘤活性筛选,结果表明具有抗肿瘤活性。
发明内容:
本发明涉及通式Ⅰ所示的青蒿素类衍生物、其旋光异构体及其药学上可接受的盐,
其中,
X为“—”、O(CH2)n;
n为1-4之间的整数;
R1和R2相同或不同,分别为氢、氨基、C1-C10烷基、C3-C7环烷基、C2-C10烯基和C2-C10炔基、
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基,所述杂环基除了与R1和R2连接的氮原子外,任选含有1-4个选自N、O和S的杂原子;
Ar为苯基、萘基、5-10元杂芳基,所述杂芳基含有1-3个选自O、N和S的杂原子,且Ar任选1-4个相同或不同的R3取代;
R3为氢、卤素、三氟甲基、三氟甲氧基、羟基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷氧基乙基、C1-C4烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N,N-二(C1-C4)烷基氨基磺酰基、C1-C3亚烷基二氧基。
本发明优选涉及定义如下的通式Ⅰ的化合物、其旋光异构体及其药学上可接受的盐,
其中,
X为“—”、O(CH2)n;
n为1-4之间的整数;
R1和R2相同或不同,分别为氢、C1-C10烷基、
或R1和R2与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述杂环基除了与R1和R2连接的氮原子外,任选含有1-4个选自N、O和S的杂原子;
Ar为苯基、5-6元杂芳基,所述杂芳基含有1-3个选自O、N和S的杂原子,且Ar任选1-4个相同或不同的R3取代;
R3为氢、卤素、三氟甲基、三氟甲氧基、羟基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷氧基乙基、C1-C4烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N,N-二(C1-C4)烷基氨基磺酰基、C1-C3亚烷基二氧基。
本发明优选还涉及定义如下的通式Ⅰ的化合物、其旋光异构体及其药学上可接受的盐,
其中,
X为“—”、O(CH2)n;
n为1-4之间的整数;
R1和R2相同或不同,分别为氢、C1-C10烷基、
或R1和R2与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述杂环基除了与R1和R2连接的氮原子外,任选含有1-4个选自N、O和S的杂原子;
Ar为苯基,且Ar任选1-4个相同或不同的R3取代;
R3为氢、卤素、三氟甲基、三氟甲氧基、羟基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷氧基乙基、C1-C4烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N,N-二(C1-C4)烷基氨基磺酰基、C1-C3亚烷基二氧基。
本发明特别优选涉及定义如下的通式Ⅰ的化合物、其旋光异构体及其药学上可接受的盐,
其中,
X为“—”、O(CH2)n;
n为1-4之间的整数;
R1和R2相同或不同,分别为氢、C1-C4烷基,
或R1和R2与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述杂环基除了与R1和R2连接的氮原子外,任选含有1-4个选自N、O和S的杂原子;
R1和R2还特别优选与和它们所连接的氮原子一起形成二甲氨基、二乙氨基、哌啶基、吗啉基、4-甲基哌嗪基、吡咯烷基;
Ar为苯基,且Ar任选1-4个相同或不同的R3取代;
R3为氢、卤素、三氟甲基、三氟甲氧基、羟基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷氧基乙基、C1-C4烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N,N-二(C1-C4)烷基氨基磺酰基、C1-C3亚烷基二氧基。
本发明还优选涉及定义如下的通式Ⅰ的化合物、其旋光异构体及其药学上可接受的盐,
其中,
X为O(CH2)n;
n为1-4之间的整数;
R1为氢;
R2为
Ar为苯基,且Ar任选1-4个相同或不同的R3取代;
R3为氢、卤素、三氟甲基、三氟甲氧基、羟基、羧基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、C1-C4烷基硫基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C1-C4烷氧基甲基、C1-C4烷氧基乙基、C1-C4烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、氨基磺酰基、N-(C1-C4)烷基氨基磺酰基、N,N-二(C1-C4)烷基氨基磺酰基、C1-C3亚烷基二氧基。
本发明非常特别优选下列通式Ⅰ的化合物、其旋光异构体及其药学上可接受的盐:
(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)哌啶-1-甲脒;
(Z)-3-(10α-脱氧青蒿素)-2-(4-(三氟甲氧基)苯基)二乙基胍;
(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)吗啉-4-甲脒;
(Z)-N-(10β-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)吗啉-4-甲脒;
(Z)-N-(10β-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)哌啶-4-甲脒;
(Z)-N-(10β-脱氧青蒿素)-N'-(2-氯-5-(三氟甲基)苯基)吡咯-1-甲脒;
(E)-2-(3-溴苯基)-3-[2-(10β-二氢青蒿素)乙基]二乙基胍;
(E)-N'-(3-溴苯基)-N-(2-(10β-二氢青蒿素)乙基)吗啉-4-甲脒;
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)吡咯-1-甲脒;
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)-4甲基哌嗪-1-甲脒;
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)哌啶-1-甲脒;
(E)-2-(3-氯苯基)-3-[2-(10β-二氢青蒿素)乙基]二乙基胍;
(E)-N'-(3-氯苯基)-N-(2-(10β-二氢青蒿素)乙基)-4-甲基哌嗪-1-甲脒;
(E)-N'-(4-三氟甲氧基苯基)-N-(2-(10β-二氢青蒿素)乙基)哌啶-1-甲脒;
(E)-2-(3-三氟甲基苯基)-3-[2-(10β-二氢青蒿素)丙基]二乙基胍;
(E)-N'-(3三氟甲基苯基)-N-(2-(10β-二氢青蒿素)丙基)-4-甲基哌嗪-1-甲脒;
(E)-N'-(3-氯苯基)-N-(2-(10β-二氢青蒿素)丙基)哌啶-1-甲脒;
2-(3-氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(2,4-二氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(4-三氟甲氧基苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(4-三氟甲基苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(3-溴苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(2-氯-5-(三氟甲基)苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(3-氟苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(4-氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(3-氯苯基)-1-(3-(10β-二氢青蒿素)丙基)-3-(2-(10β-二氢青蒿素)乙基)胍;
2-(3-氟苯基)-1-(3-(10β-二氢青蒿素)丙基)-3-(2-(10β-二氢青蒿素)乙基)胍。
而且,按照本发明所属领域的一些通常方法,本发明的通式Ⅰ的含有胍基的青蒿素类化合物可以与酸生成它的药学上可接受的盐。酸可以包括无机酸或有机酸,与下列酸形成的盐是特别优选的:盐酸、草酸、马来酸、富马酸、柠檬酸、洒石酸、苹果酸、羟乙磺酸、酒石酸、甲磺酸、乙磺酸、氢溴酸、硫酸、磷酸、乙酸、丙酸、乳酸、三氟乙酸、苯甲酸或对甲苯磺酸。
此外,本发明还包括本发明衍生物的前药。依据本发明,前药是通式Ⅰ的衍生物,它们自身可能具有较弱的活性或甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
除非另外指出,本发明所用的术语“卤素”是指氟、氯、溴或碘原子;“烷基”是指直链或支链的烷基;“亚烷基”是指直链或支链的亚烷基;“环烷基”是指取代或未取代的环烷基;杂芳基包括含有一个或多个选自O、N和S的杂原子,可以是单环或多环的,环状体系是芳香性的,可以举出例如咪唑基、吡啶基、嘧啶基、(1,2,3)-和(1,2,4)-三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、苯并咪唑基、吡啶并咪唑基、苯并噻吩基、苯并噻唑基、吲哚基、喹啉基、吡啶并嘧啶基等。
本发明包括药物组合物,该组合物含有通式Ⅰ的含有胍基的青蒿素类化合物、其旋光异构体及其药学上可接受的盐作为活性成分,以及药学上可接受的赋型剂。所述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明的药物组合物可配制成若干种剂型,其中含有药学领域中常用的一些赋形剂;例如,口服制剂(如片剂,胶囊剂,溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射用水可立即使用);局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药学领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。
我们已发现本发明化合物体外具有抑制肿瘤细胞生长活性,因此,它可以用作制备治疗和/或预防癌症的药物。尤其治疗乳腺、肺、结肠、直肠、胃、前列腺、膀胱、胰腺和卵巢的癌。本发明化合物也被期望可以用于治疗其他细胞增生疾病如牛皮癣、良性前列腺肥大、动脉粥样硬化和再狭窄。另外预期本发明的含有胍基的青蒿素类化合物将具有抗白血病、恶性淋巴瘤和固体肿瘤如在组织如肝、肾、前列腺和胰腺中的癌和肉瘤范围的活性。
根据本发明的衍生物可作为活性成分用于制备治疗和/或预防各种癌症,本发明也提供治疗或预防上述疾病的方法,包括给予患有或易患有此病的病人治疗有效量的根据本发明的衍生物。通式Ⅰ的含有胍基的青蒿素类化合物用于患者的临床剂量必需依赖被治疗的主体、给药的具体途径、被治疗疾病的严重性而变化,而最佳剂量由治疗具体患者的医生确定。
本发明活性化合物可作为唯一的抗癌药物使用,或者可以与一种或多种其它抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实施例和制备例的范围并不以任何方式限制本发明的范围。
下面合成路线A描述了本发明的通式Ⅰ化合物的制备,所有的原料都是通过这些示意图中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些示意图中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些示意图中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的通式Ⅰ衍生物,在路线A中,Ar、R1、R2、X和n如发明内容所定义。
将化合物A-1经1-2步反应,生成叠氮化合物A-2。将化合物A-2与苯基异氰酸酯、三苯基磷和胺经四组分反应得到通式为Ⅰ所示的衍生物。其中,当X为“—”时,A-2根据路线B描述的方法制备:以A-1为原料,与叠氮化钠反应得到A-2。
当X为O(CH2)n时,A-2根据路线C描述的方法制备:以A-1为原料,经醚化,叠氮化后得到A-2。
当R1为氢、R2为时,NHR1R2根据路线D描述的方法制备:
以A-1为原料,经醚化,叠氮化,最后还原得到HNR1R2。
本发明制备方法简单,制备的化合物均具有显著的抗肿瘤活性。
具体实施方式
实施例旨在阐述而不是限制本发明的范围。衍生物的核磁共振氢谱用Bruker ARX-300测定,质谱用Agilent1100LC/MSD测定;所用试剂均为分析纯或化学纯。
表1.实施例1-32的结构式
实施例1:(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)哌啶-1-甲脒的制备
步骤A:10α-叠氮二氢青蒿素和10β-叠氮二氢青蒿素的制备
将二氢青蒿素(200mmol,56.8g)和叠氮化钠(300mmol,19.5g)加入到(800mL)二氯甲烷溶液中,加料完毕后冷却至0-5℃,分批加入三甲基氯硅烷(300mmol,38.1mL),然后再加入催化量的碘化钠,升温到室温反应28小时,反应完毕后,将反应液倾入800mL水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。抽滤蒸干得油状物,经硅胶柱层析(1%-5%EtOAc/hexanes)分离得到分别得到光学纯的10α-叠氮二氢青蒿素(3.0g,5%)和10β-叠氮二氢青蒿素(29.0g,47%)产品,MS:332.2(M+Na)。
步骤B:4-三氟甲氧基苯基异氰酸酯的制备
将4-三氟甲氧基苯胺42.5g(0.24mol)加入到干燥的二氧六环300ml中,升温至50℃,搅拌下,加入固体光气68.7g(0.24mol),80℃反应12h。反应毕,减压蒸馏,收集馏分b.p.125-128℃/30-40mmHg,得无色液体20.6g,收率:55.9%。
步骤C:(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)哌啶-1-甲脒的制备
将10α-叠氮二氢青蒿素0.29g(0.93mmol)倒入10mL的无水四氢呋喃溶液中,室温下,加入三苯基磷0.24g(0.93mmol),升温至60℃搅拌反应4小时。反应毕,将反应液冷至室温,然后加入已制备好的4-三氟甲氧基苯基异氰酸酯0.19g(0.93mmol),室温反应半小时后,再加入哌啶(0.08g,0.93mmol)继续反应1小时,冷却,倒入水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。抽滤,浓缩得油状物,最后经柱层析分离得白色固体109.0mg,收率:21.2%,
M.p.:101-103℃;MS(ESI,m/z):554.3(M+H)+;1H NMR(300MHz,CDCl3)δ:7.23(d,J=9.0Hz,2H),7.00(d,J=9.0Hz,2H),5.44(s,1H),5.08(d,J=10.9Hz,1H),3.48(s,2H),3.39-3.20(m,2H),2.66(m,1H),2.34(td,J=14.0,3.8Hz,1H),2.06(dq,J=17.7,14.7Hz,1H),1.95-1.82(m,1H),1.80-1.51(m,11H),1.49(s,3H),1.47-1.28(m,3H),1.28-1.14(m,2H),0.96(d,J=5.5Hz,3H),0.93(d,J=4.5Hz,3H)。
按照实施例1的方法,选择合适的原料和试剂,分别制得实施例2-6的化合物。当提到特定的反应原料时,应该理解的是,精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例2:
(Z)-3-(10α-脱氧青蒿素)-2-(4-(三氟甲氧基)苯基)二乙基胍
M.p.:93-95℃;MS(ESI,m/z):542.3(M+H)+;1H NMR(300MHz,CDCl3)δ:7.21(d,J=8.6Hz,2H),7.01(d,J=8.9Hz,2H),5.39(s,1H),5.02(d,J=10.2Hz,1H),3.70-3.55(m,2H),3.41-3.13(m,2H),2.68-2.53(m,1H),2.35(td,J=14.1,3.9Hz,1H),2.09-1.97(m,1H),1.89(m,2H),1.48(s,3H),1.28-1.26(m,2H),1.25-1.15(m,6H),0.94(d,J=6.3Hz,6H)。
实施例3:
(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)吗啉-4-甲脒
M.p.:103-105℃;MS(ESI,m/z):556.3(M+H)+;1H NMR(300MHz,CDCl3)δ:7.19(d,J=9.0Hz,2H),7.01(d,J=9.0Hz,2H),5.36(s,1H),4.80(d,7.4Hz,1H),3.85-3.68(m,4H),3.57-3.43(m,2H),3.37-3.27(m,2H),2.60-2.44(m,1H),2.38(m,1H),2.06(m,1H),1.98-1.83(m,1H),1.48(s,3H),0.97(d,J=6.1Hz,3H),0.86(d,J=6.0Hz,3H)。
实施例4:
(Z)-3-(10α-脱氧青蒿素)-2-(3-氟代苯基)二乙基胍
M.p.:93-95℃;MS(ESI,m/z):476.4(M+H)+。
实施例5:
(Z)-N-(10α-脱氧青蒿素)-N'-(3-氟代苯基)吗啉-4-甲脒
M.p.:100-102℃;MS(ESI,m/z):490.3(M+H)+。
实施例6:
(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲基)苯基)吗啉-4-甲脒
M.p.:88-90℃;MS(ESI,m/z):540.6(M+H)+。
实施例7:(Z)-N-(10β-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)吗啉-4-甲脒的制备
步骤A:(Z)-N-(10β-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)吗啉-1-甲脒的制备
将已制备好的10β-叠氮二氢青蒿素0.29g(0.93mmol)倒入10mL的无水四氢呋喃溶液中,在室温下,加入三苯基磷0.24g(0.93mmol),升温至60℃搅拌反应4小时。经TLC检测,原料反应完全后,降至室温然后加入已制备好的4-三氟甲氧基苯基异氰酸酯0.19g(0.93mmol)反应半小时后,再加入吗啉(0.08g,0.93mmol)继续反应1小时,冷却,倒入水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。抽滤,浓缩得油状物,最后经柱层析分离得白色固体136.0mg,收率:26.4%;m.p.:109-112℃;MS(ESI,m/z):556.3(M+H)+;1H NMR(300MHz,CDCl3)δ:7.19(d,J=8.6Hz,2H),7.01(d,J=8.9Hz,2H),5.44(s,1H),5.10(d,J=9.6Hz,1H),3.86-3.64(m,4H),3.58-3.43(m,2H),3.44-3.24(m,2H),2.55-2.44(m,1H),2.37(m,J=14.4,2.8Hz,1H),2.1-1.99(m,1H),1.97-1.83(m,1H),1.48(s,3H),0.98(d,J=5.9Hz,3H)0.88(d,J=7.1Hz,3H)。
按照实施例7的方法,选择合适的原料和试剂,分别制得实施例8-11的化合物。当提到特定的反应原料时,应该理解的是,精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例8:
(Z)-N-(10β-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)哌啶-1-甲脒
M.p.:100-102℃;MS(ESI,m/z):554.2(M+H)+;1H NMR(300MHz,CDCl3)δ:7.21(d,J=8.7Hz,2H),7.00(d,J=9.0Hz,2H),5.42(s,1H),5.02(d,J=9.1Hz,1H),3.53-3.40(m,2H),3.38-3.21(m,2H),2.68-2.52(m,1H),2.42-2.27(m,1H),2.10-1.96(m,1H),1.95-1.82(m,1H),1.80-1.52(m,11H),1.49(s,3H),0.95(d,J=6.0Hz,3H),0.93(d,J=5.7Hz,3H)。
实施例9:
(Z)-N-(10β-脱氧青蒿素)-N'-(2-氯-5-(三氟甲基)苯基l)吡咯-1-甲脒
M.p.:101-103℃;MS(ESI,m/z):558.1(M+H)+;1H NMR(300MHz,DMSO-d6)δ:7.68-7.55(m,2H),7.42(d,J=8.2Hz,1H),5.26(s,1H),4.70(d,J=9.3Hz,1H),3.56-3.34(m,4H),2.47-2.40(m,1H),2.18(td,J=13.9,3.3Hz,1H),2.06-1.93(m,1H),1.94-1.72(m,4H),1.67-1.39(m,4H),1.30(s,3H),0.88(d,J=6.0Hz,3H),0.75(d,J=7.1Hz,3H)。
实施例10:
(Z)-N-(10β-脱氧青蒿素)-N'-(3-氯苯基)哌啶-1-甲脒
M.p.:94-96℃;MS(ESI,m/z):504.7(M+H)+。
实施例11:
(Z)-N-(10β-脱氧青蒿素)-N'-(2,4-二氯苯基)吗啉-4-甲脒
M.p.:102-105℃;MS(ESI,m/z):540.1(M+H)+。
实施例12:(E)-2-(3-溴苯基)-3-[2-(10β-二氢青蒿素)乙基]二乙基胍的制备
步骤A:2-(10β-二氢青蒿素)溴乙烷的制备
将二氢青蒿素20.0g(70.4mmol)倒入二氯甲烷150mL中,降温至0-5℃,加入2-溴乙醇13.1g(105.6mmol),然后逐渐滴加三氟化硼乙醚(16mL),加料完毕继续反应约1h,反应完毕后,加入饱和碳酸氢钠溶液(60mL),有机层水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤减压得粗品,经乙醇重结晶得白色固体17.0g,收率:61.8%,m.p.:155-158℃;MS(ESI,m/z):413.2(M+Na)+。
步骤B:2-(10β-二氢青蒿素)叠氮乙烷的制备
NaN3(60.2mmol)将2-(10β-二氢青蒿素)溴乙烷8.0g(20.5mmol)倒入DMF(60mL)溶液中,加入叠氮化钠4.0g(60.2mmol)和催化量的碘化钠0.15g,升温至60℃反应3h.将反应液倒入大量冰水中,析出大量固体,抽滤,冷水洗涤滤饼,真空干燥得白色粉末固体7.1g,收率:98.0%,m.p.:86-88℃;MS(ESI,m/z):376.2(M+Na)+。
步骤C:(E)-2-(3-溴苯基)-3-[2-(10β-二氢青蒿素)乙基]二乙基胍的制备
将2-(10β-二氢青蒿素)叠氮乙烷0.3g(0.85mmol)倒入无水四氢呋喃(10mL)溶液中,在室温下,加入三苯基磷0.22g(0.85mmol),升温至60℃搅拌反应4小时。经TLC检测,原料反应完全后,降至室温后加入已制备好的3-溴苯基异氰酸酯0.16g(0.85mmol)反应半小时,再加入二乙胺0.06g(0.85mmol)继续反应1小时,冷却,倒入水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。抽滤,浓缩得油状物,最后经柱层析分离得白色固体102.0mg,收率:20.7%;m.p.:91-93℃;MS(ESI,m/z):580.1(M+H)+;1H NMR(300MHz,CDCl3)δ:7.19-7.09(m,3H),6.94(d,J=6.1Hz,1H),5.36(s,1H),4.79(d,J=3.3Hz,1H),3.96-3.84(m,1H),3.69-3.56(m,1H),3.44-3.27(m,6H),2.73-2.58(m,1H),2.37(td,J=14.0,3.7Hz,1H),2.10-1.99(m,1H),1.96-1.83(m,1H),1.78-1.46(m,5H),1.43(s,3H),1.19(t,J=7.1Hz,6H),0.97(d,J=6.0Hz,3H),0.86(d,J=7.3Hz,3H)。
按照实施例12的方法,选择合适的原料和试剂,分别制得实施例13-19的化合物。当提到特定的反应原料时,应该理解的是,精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例13:
(E)-N'-(3-溴苯基)-N-(2-(10β-二氢青蒿素)乙基)吗啉-4-甲脒
M.p.:86-88℃;MS(ESI,m/z):594.1(M+H)+;1H NMR(300MHz,CDCl3)δ:7.18-7.01(m,3H),6.82(d,J=6.9Hz,1H),5.33(s,1H),4.75(d,J=3.4Hz,1H),3.96-3.81(m,1H),3.81-3.63(m,4H),3.59-3.46(m,1H),3.37-3.20(m,6H),2.70-2.54(m,1H),2.38(td,J=14.2,3.9Hz,1H),2.10-1.99(m,1H),1.98-1.82(m,1H),1.74-1.47(m,4H),1.44(s,3H),0.97(d,J=5.8Hz,3H),0.75(d,J=7.3Hz,3H)。
实施例14:
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)吡咯-1-甲脒
M.p.:97-99℃;MS(ESI,m/z):568.2(M+H)+;1H NMR(300MHz,CDCl3)δ:7.58(d,J=6.2Hz,2H),7.33(d,J=7.5Hz,2H),5.41(s,1H),4.82(d,J=1.5Hz,1H),3.96-3.79(m,2H),3.78-3.43(m,6H),2.76-2.60(m,1H),2.45-2.29(m,1H),2.09-1.83(m,5H),1.38(s,3H),0.95(d,J=6.1Hz,3H),0.93(d,J=7.8Hz,3H)。
实施例15:
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)-4-甲基哌嗪-1-甲脒
M.p.:81-83℃;MS(ESI,m/z):597.2(M+H)+;1H NMR(300MHz,CDCl3)δ:7.42(t,J=7.8Hz,1H),7.31-7.16(m,3H),5.37(s,1H),4.79(d,J=3.3Hz,1H),3.97-3.87(m,1H),3.71-3.44(m,3H),3.44-3.26(m,3H),2.69-2.59(m,1H),2.52-2.35(m,5H),2.32(s,3H),2.09-1.98(m,1H),1.95-1.84(m,1H),1.42(s,3H),1.32-1.18(m,2H),0.96(d,J=6.0Hz,3H),0.81(d,J=7.3Hz,3H)。
实施例16:
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)哌啶-1-甲脒
M.p.:93-95℃;MS(ESI,m/z):582.3(M+H)+;1H NMR(300MHz,CDCl3)δ:7.52(d,J=8.2Hz,1H),7.51-7.44(m,1H),7.38(d,J=6.8Hz,1H),7.32(s,1H),5.41(s,1H),4.84(d,J=3.4Hz,1H),4.05-3.93(m,1H),3.84-3.64(m,3H),3.45-3.32(m,4H),2.73-2.61(m,1H),2.37(td,J=14.1,3.8Hz,1H),2.08-1.98(m,1H),1.94-1.83(m,1H),1.72-1.56(m,8H),1.40(s,3H),1.28-1.17(m,2H),0.94(d,J=6.3Hz,3H),0.91(d,J=7.4Hz,3H)。
实施例17:
(E)-2-(3-氯苯基)-3-[2-(10β-二氢青蒿素)乙基]二乙基胍
M.p.:96-98℃;MS(ESI,m/z):536.4(M+H)+;1H NMR(300MHz,CDCl3)δ:7.28(d,J=16.5Hz,1H),7.21-7.05(m,3H),5.41(s,1H),4.83(d,J=3.4Hz,1H),4.01-3.89(m,1H),3.86-3.76(m,1H),3.75-3.61(m,2H),3.56-3.38(m,4H),2.75-2.55(m,1H),2.37(td,J=14.2,3.8Hz,1H),2.04(dq,J=15.2,4.5,3.2Hz,1H),1.96-1.82(m,1H),1.65-1.43(m,4H),1.41(s,3H),1.24(t,J=7.1Hz,6H),0.95(d,J=4.9Hz,3H),0.93(d,J=5.9Hz,3H)。
实施例18:
(E)-N'-(3-氯苯基)-N-(2-(10β-二氢青蒿素)乙基)-4-甲基哌嗪-1-甲脒
M.p.:71-73℃;MS(ESI,m/z):563.4(M+H)+;1H NMR(300MHz,CDCl3)δ:7.24(d,J=7.9Hz,1H),7.12-6.91(m,3H),5.40(s,1H),4.82(d,J=3.2Hz,1H),4.03-3.88(m,1H),3.80-3.64(m,1H),3.63-3.51(m,2H),3.48-3.32(m,4H),2.72-2.60(m,1H),2.53-2.44(m,4H),2.37-2.31(m,1H),2.32(s,3H),2.11-1.97(m,1H),1.97-1.83(m,1H),1.76-1.46(m,5H),1.42(s,3H),0.96(d,J=6.2Hz,3H),0.88(d,J=7.3Hz,3H)。
实施例19:
(E)-N'-(4-三氟甲氧基苯基)-N-(2-(10β-二氢青蒿素)乙基)哌啶-1-甲脒
M.p.:93-95℃;MS(ESI,m/z):598.4(M+H)+;1H NMR(300MHz,CDCl3)δ:7.23(d,J=9.0Hz,2H),7.19(d,J=9.0Hz,2H),5.42(s,1H),4.84(d,J=3.0Hz,1H),4.08-3.92(m,1H),3.86-3.63(m,3H),3.52-3.29(m,4H),2.72-2.61(m,1H),2.42-2.31(m,1H),2.09-1.97(m,10H),1.97-1.81(m,1H),1.75-1.48(m,10H),1.40(s,3H),1.31-1.19(m,1H),0.94(d,J=4.9Hz,3H),0.92(d,J=6.3Hz,3H)。
实施例20:(E)-2-(3-三氟甲基苯基)-3-[2-(10β-二氢青蒿素)丙基]二乙基胍的制备
步骤A:2-(10β-二氢青蒿素)溴丙烷的制备
将二氢青蒿素20.0g(70.4mmol)倒入二氯甲烷150mL中,降温至0-5℃,加入3-溴丙醇13.2g(105.6mmol),然后逐渐滴加三氟化硼乙醚(17mL),加料完毕继续反应约1h,反应完毕后,加入饱和碳酸氢钠溶液(60mL),有机层水洗,饱和食盐水洗,无水硫酸钠干燥,抽滤减压得粗品,经乙醇重结晶得白色固体16.1g,收率:56.6%,m.p.:161-163℃;MS(ESI,m/z):427.1(M+Na)+。
步骤B:2-(10β-二氢青蒿素)叠氮丙烷的制备
将2-(10β-二氢青蒿素)溴丙烷8.0g(20.5mmol)倒入DMF(60mL)溶液中,加入叠氮化钠4.0g(60.2mmol)和催化量的碘化钠0.15g,升温至60℃反应3h.将反应液倒入大量冰水中,析出大量固体,抽滤,冷水洗涤滤饼,真空干燥得白色粉末固体7.3g,收率:97.0%,m.p.:82-84℃;MS(ESI,m/z):390.1(M+Na)+。
步骤C:(E)-2-(3-三氟甲基苯基)-3-[2-(10β-二氢青蒿素)丙基]二乙基胍的制备
将2-(10β-二氢青蒿素)叠氮丙烷0.3g(0.85mmol)倒入无水四氢呋喃(10mL)溶液中,在室温下,加入三苯基磷0.22g(0.85mmol),升温至60℃搅拌反应4小时。经TLC检测,原料反应完全后,降至室温后加入已制备好的3-三氟甲基苯基异氰酸酯0.15g(0.85mmol)反应半小时,再加入二乙胺0.06g(0.85mmol)继续反应1h,冷却,倒入水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。抽滤,浓缩得油状物,最后经柱层析分离得白色固体131.0mg,收率:26.47%;m.p.:96-98℃;MS(ESI,m/z):584.2(M+H)+。
按照实施例20的方法,选择合适的原料和试剂,分别制得实施例21-22的化合物。当提到特定的反应原料时,应该理解的是,精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例21:
(E)-N'-(3三氟甲基苯基)-N-(2-(10β-二氢青蒿素)丙基)-4-甲基哌嗪-1-甲脒
M.p.:94-96℃;MS(ESI,m/z):611.3(M+H)+;
实施例22:
(E)-N'-(3-氯苯基)-N-(2-(10β-二氢青蒿素)丙基)哌啶-1-甲脒
M.p.:92-95℃;MS(ESI,m/z):562.1(M+H)+;
实施例23:2-(3-氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍的制备
步骤A:2-(10β-二氢青蒿素)乙胺的制备
将已制备好的2-(10β-二氢青蒿素)叠氮乙烷6.0g(17.2mmol)加入到四氢呋喃(100ml)溶液中,在室温条件下,分批加入三苯基磷7.2g(27.3mmol),加料完毕后,搅拌升温至60℃反应2小时,滴加2mL蒸馏水,继续反应3h。反应完毕后,将反应液冷却至室温,减压浓缩,经柱层析分离得到淡黄色油状粘稠物4.1g,收率:73.8%,MS(ESI,m/z):328.1(M+H)+。
步骤B:2-(3-氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍的制备
将2-(10β-二氢青蒿素)叠氮乙烷0.3g(0.85mmol)倒入10mL的无水四氢呋喃溶液中,在室温下,加入三苯基磷0.22g(0.85mmol),升温至60℃搅拌反应4小时。经TLC检测,原料反应完全后,冷却至室温然后加入已制备好的3-溴苯基异氰酸酯0.16g(0.85mmol)反应半小时后,再加入2-(10β-二氢青蒿素)乙胺0.28g(0.85mmol)继续反应1h,冷却,倒入水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。抽滤,浓缩得油状物,最后经柱层析分离得白色固体176.0mg,收率:26.3%.m.p.:98-100℃;MS(ESI,m/z):790.3(M+H)+;1H NMR(300MHz,DMSO-d6)δ:7.39(s,1H),7.31-6.99(m,3H),5.33(s,2H),4.72(d,J=3.1Hz,2H),3.88-3.73(m,2H),3.55-3.37(m,6H),2.46-2.34(m,2H),2.19(td,J=13.6,3.2Hz,2H),2.07-1.94(m,2H),1.90-1.74(m,2H),1.75-1.45(m,10H),1.29(s,6H),0.90(d,J=6.0Hz,6H),0.85(d,J=7.3Hz,6H)。
按照实施例23的方法,选择合适的原料和试剂,分别制得实施例24-30的化合物。当提到特定的反应原料时,应该理解的是,精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例24:
2-(2,4-二氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍
M.p.:100-102℃;MS(ESI,m/z):825.6(M+H)+;1H NMR(300MHz,CDCl3)δ:7.49(d,J=8.0Hz,1H),7.41(s,1H),7.20(d,J=8.0Hz,1H),5.36(s,2H),4.79(d,J=3.2Hz,2H),4.01-3.87(m,2H),3.75-3.58(m,2H),3.56-3.45(m,4H),2.73-2.56(m,2H),2.38(td,J=13.8,3.2Hz,2H),2.10-2.00(m,2H),1.98-1.84(m,2H),1.79-1.55(m,10H),1.42(s,6H),0.98(d,J=5.6Hz,6H),0.81(d,J=7.2Hz,6H)。
实施例25:
2-(4-三氟甲氧基苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍
M.p.:101-104℃;MS(ESI,m/z):840.3(M+H)+;1H NMR(300MHz,DMSO-d6)δ:7.32(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),5.34(s,2H),4.72(d,J=3.0Hz,2H),3.90-3.74(m,2H),3.59-3.38(m,6H),2.46-2.32(m,2H),2.19(td,J=13.4,2.3Hz,2H),2.08-1.93(m,2H),1.89-1.74(m,2H),1.75-1.45(m,8H),1.28(s,6H),0.89(d,J=5.9Hz,6H),0.83(d,J=7.2Hz,6H);Anal.calcd.For C42H60F3N3O11(in%):C,60.06;H,7.20;N,5.00.Found C,60.02;H,7.34;N,4.89.
实施例26:
2-(4-三氟甲基苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍
M.p.:99-101℃;MS(ESI,m/z):824.3(M+H)+;1H NMR(300MHz,DMSO-d6)δ:7.49(d,J=7.8Hz,2H),6.96(d,J=7.5Hz,2H),5.32(s,2H),4.69(d,J=1.6Hz,2H),3.84-3.69(m,2H),3.51-3.39(m,2H),3.38-3.20(m,4H),2.46-2.29(m,2H),2.28-2.08(td,J=12Hz,2.0H),2.04-1.95(m,2H),1.87-1.74(m,2H),1.75-1.44(m,7H),1.28(s,6H),0.88(d,J=5.5Hz,6H),0.81(d,J=7.1Hz,6H)。
实施例27:
2-(3-溴苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍
M.p.:100-102℃;MS(ESI,m/z):834.6.1(M+H)+;1H NMR(300MHz,DMSO-d6)δ:7.25-7.14(m,3H),6.93(s,1H),5.32(s,2H),4.70(d,J=3.3Hz,2H),3.86-3.73(m,2H),3.49-3.40(m,2H),3.35-3.20(m,4H),2.45-2.33(m,2H),2.19(td,J=13.9,3.5Hz,2H),2.07-1.95(m,2H),1.92-1.75(m,2H),1.75-1.46(m,8H),1.29(s,6H),0.89(d,J=6.1Hz,6H),0.82(d,J=7.4Hz,6H)。
实施例28:
2-(2-氯-5-(三氟甲基)苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍
M.p.:106-108℃;MS(ESI,m/z):858.2(M+H)+;1H NMR(300MHz,CDCl3)δ:7.22(s,1H),7.17(d,J=8.3Hz,1H),7.01(d,J=8.0Hz,1H),5.37(s,2H),4.81(d,J=3.3Hz,2H),4.00-3.88(m,2H),3.68-3.60(m,2H),3.48-3.40(m,4H),2.73-2.61(m,2H),2.38(td,J=14.0,3.9Hz,2H),2.05(m,2H),1.98-1.84(m,2H),1.78-1.53(m,8H),1.43(s,6H),0.98(d,J=5.9Hz,6H),0.86(d,J=7.3Hz,6H)。
实施例29:
2-(3-氟苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍
M.p.:108-110℃;MS(ESI,m/z):774.3(M+H)+;1H NMR(300MHz,CDCl3)δ:7.24(m,J=7.7Hz,1H),6.78(m,J=18.3,9.2Hz,3H),5.39(s,2H),4.80(d,J=3.4Hz,2H),4.03-3.84(m,2H),3.63(m,2H),3.50-3.42(m,4H),2.74-2.58(m,2H),2.38(td,J=14.4,3.9Hz,2H),2.12-1.98(m,2H),1.91(m,2H),1.80-1.46(m,10H),1.41(s,6H),0.98(d,J=5.9Hz,6H),0.85(d,J=9.0Hz,6H)
实施例30:
2-(4-氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍
M.p.:101-103℃;MS(ESI,m/z):790.3(M+H)+;1H NMR(300MHz,CDCl3)δ:7.36(d,J=8.5Hz,2H),7.19(d,J=8.6Hz,2H),5.34(s,2H),4.80(d,J=3.2Hz,2H),3.96(m,2H),3.74-3.62(m,2H),3.61-3.47(m,4H),2.75-2.62(m,2H),2.38(td,J=14.0,3.6Hz,2H),2.12-1.98(m,2H),1.98-1.83(m,2H),1.76-1.43(m,10H),1.41(s,6H),0.98(d,J=5.7Hz,6H),0.86(d,J=7.0Hz,6H)。
实施例31:2-(3-氯苯基)-1-(3-(10β-二氢青蒿素)丙基)-3-(2-(10β-二氢青蒿素)乙基)胍的制备
步骤A:2-(3-氯苯基)-1-(3-(10β-二氢青蒿素)丙基)-3-(2-(10β-二氢青蒿素)乙基)胍的制备
将2-(10β-二氢青蒿素)叠氮丙烷0.31g(0.85mmol)倒入10mL的无水四氢呋喃溶液中,在室温下,加入三苯基磷0.22g(0.85mmol),升温至60℃搅拌反应4小时。经TLC检测,原料反应完全后,冷却至室温然后加入已制备好的3-氯苯基异氰酸酯0.16g(0.85mmol)反应半小时后,再加入2-(10β-二氢青蒿素)乙胺0.28g(0.85mmol)继续反应1h,冷却,倒入水中,二氯甲烷提取,合并提取液,水洗,无水硫酸钠干燥。抽滤,浓缩得油状物,最后经柱层析分离得白色固体173.0mg,收率:25.3%.m.p.:101-103℃;MS(ESI,m/z):804.4(M+H)+。
按照实施例31的方法,选择合适的原料和试剂,制得实施例32的化合物。当提到特定的反应原料时,应该理解的是,精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例32:
2-(3-氟苯基)-1-(3-(10β-二氢青蒿素)丙基)-3-(2-(10β-二氢青蒿素)乙基)胍
M.p.:105-108℃;MS(ESI,m/z):788.2(M+H)+。
本发明产物的药理研究
对按照本发明的上式Ⅰ的含有胍基的青蒿素类衍生物进行了体外抗肿瘤活性筛选。
体外抗肿瘤活性测试
(1)将A549人肺腺癌细胞,MDA-MB-231(人乳腺癌细胞)和HT29(人结肠癌细胞)三种细胞株分别复苏并传代2-3次稳定后,用胰蛋白酶溶液(0.25%)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中而后加入培养液以终止消化。将离心管在1300r/min下离心3min,轻轻弃去上清液后加入5mL培养液,吹打混匀细胞,吸取10μL细胞混悬液加入细胞计数板中计数,调整细胞浓度为104个/孔。96孔板中除A1孔为空白孔不加细胞外,其余皆加入100uL细胞混悬液。将96孔板放入培养箱中培养24h。
(2)用50μL二甲基亚砜溶解受试样品,然后加入适量培养液,使样品溶解成2mg/mL药液。然后在24孔板中将样品稀释为100,20,4,0.8,0.16μg/mL。每个浓度加入3孔,其中周围两行两列细胞长势受环境影响较大,只作为空白细胞孔使用。将96孔板放入培养箱中培养72h。
(3)将96孔板中带药培养液弃去,用磷酸缓冲溶液(PBS)将细胞冲洗两遍,在每孔中加入MTT(四氮唑)(0.5mg/mL)100μL放入培养箱中4h后,弃去MTT溶液,加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解,放入酶标仪中测定结果,通过Bliss法可求出药物IC50值。
化合物的体外抗肿瘤细胞活性结果见表2。
表2实施例化合物体外抗肿瘤活性
注:-表示未测活性。
从上述试验结果可以清楚地看出,本发明所要保护的通式Ⅰ的化合物,具有优异的抗癌活性。因此本发明的化合物具有很好的工业应用前景。
Claims (6)
1.通式Ⅰ的化合物及其药学上可接受的盐,
其中,
X为“—”、O(CH2)n;
n为1-4的整数;
R1和R2相同或不同,分别为氢、C1-C4烷基、,
或R1和R2与和它们所连接的氮原子一起形成5-6元饱和杂环基,所述杂环基除了与R1和R2连接的氮原子外,任选含有1-4个选自N、O和S的杂原子;
Ar为苯基,且Ar任选1-4个相同或不同的R3取代;
R3为氢、卤素、三氟甲基、三氟甲氧基。
2.权利要求1的通式Ⅰ的化合物及其药学上可接受的盐,
其中,
R1和R2与和它们所连接的氮原子一起形成二甲氨基、二乙氨基、哌啶基、吗啉基、4-甲基哌嗪基、吡咯烷基。
3.权利要求1的通式Ⅰ的化合物及其药学上可接受的盐,
其中,
R1为氢;
R2为。
4.权利要求1的通式Ⅰ的化合物及其药学上可接受的盐,
(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)哌啶-1-甲脒;
(Z)-3-(10α-脱氧青蒿素)-2-(4-(三氟甲氧基)苯基)二乙基胍;
(Z)-N-(10α-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)吗啉-4-甲脒;
(Z)-N-(10β-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)吗啉-4-甲脒;
(Z)- N-(10β-脱氧青蒿素)-N'-(4-(三氟甲氧基)苯基)哌啶-1-甲脒;
(Z)-N-(10β-脱氧青蒿素)-N'-(2-氯-5-(三氟甲基)苯基)吡咯-1-甲脒;
(E)-2-(3-溴苯基)-3-[2-(10β-二氢青蒿素)乙基]二乙基胍;
(E)-N'-(3-溴苯基)-N-(2-(10β-二氢青蒿素)乙基)吗啉-4-甲脒;
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)吡咯-1-甲脒;
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)-4-甲基哌嗪-1-甲脒;
(E)-N'-(3-三氟甲基苯基)-N-(2-(10β-二氢青蒿素)乙基)哌啶-1-甲脒;
(E)-2-(3-氯苯基)-3-[2-(10β-二氢青蒿素) 乙基]二乙基胍;
(E)-N'-(3-氯苯基)-N-(2-(10β-二氢青蒿素)乙基)-4-甲基哌嗪-1-甲脒;
(E)-N'-(4-三氟甲氧基苯基)-N-(2-(10β-二氢青蒿素)乙基)哌啶-1-甲脒;
2-(3-氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(2,4-二氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(4-三氟甲氧基苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(4-三氟甲基苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(3-溴苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(2-氯-5-(三氟甲基)苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(3-氟苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍;
2-(4-氯苯基)-1,3-双[2-(10β-二氢青蒿素)乙基]胍。
5.一种药用组合物,包含权利要求1-4中任何一项所述化合物及其药学上可接受的盐作为活性成分以及药学上可接受的赋型剂。
6.权利要求1-4中任何一项所述化合物及其药学上可接受的盐在制备治疗和/或预防肺癌、乳腺癌或结肠癌的药物中的应用。
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