CN114933598B - 6-取代去氢骆驼蓬碱衍生物及其制备方法和应用 - Google Patents
6-取代去氢骆驼蓬碱衍生物及其制备方法和应用 Download PDFInfo
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- CN114933598B CN114933598B CN202210178785.6A CN202210178785A CN114933598B CN 114933598 B CN114933598 B CN 114933598B CN 202210178785 A CN202210178785 A CN 202210178785A CN 114933598 B CN114933598 B CN 114933598B
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- RAYHOJDYVGUYQQ-UHFFFAOYSA-N 7-methoxy-1-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indol-8-amine;hydrochloride Chemical class [Cl-].C1CNC(C)C2=C1C1=CC=C(OC)C([NH3+])=C1N2 RAYHOJDYVGUYQQ-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims description 11
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- 238000000034 method Methods 0.000 claims description 21
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
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- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
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- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 7
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- LJQLTQRHIJBENP-UHFFFAOYSA-N 7-methoxy-1,9-dimethylpyrido[3,4-b]indole Chemical compound N1=CC=C2C3=CC=C(OC)C=C3N(C)C2=C1C LJQLTQRHIJBENP-UHFFFAOYSA-N 0.000 description 5
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- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明公开了一种6‑取代去氢骆驼蓬碱衍生物,其结构如式(I)所示:其中,R为芳香基、取代芳香基、杂芳香基、取代杂芳香基、芳烷胺基、取代芳烷胺基、杂化取代烷胺基、脂烷胺或脂环烷胺中的一种。
Description
技术领域
本发明涉及一种6-取代去氢骆驼蓬碱衍生物及其制备方法和应用。
背景技术
去氢骆驼蓬碱又名哈尔明碱(harmine),其结构式为
去氢骆驼蓬碱是从植物骆驼蓬中分离得到的β-咔啉类生物碱,骆驼蓬全草及种子均可入药,性平,味苦、辛,有毒,素有助阳暖阴、坚固筋脉,消除粘稠体液及消散寒湿之气等功效,是维吾尔族、哈萨克族等民族常用的民族药。特别是骆驼蓬子,去氢骆驼蓬碱的含量高达3.92%,为骆驼蓬全草及种子的主要活性物质之一。研究发现去氢骆驼蓬碱具有抗肿瘤、降低血糖、消炎镇痛、抑菌、杀虫等活性,但活性还不足以达到成药的标准,因此仍然有衍生化的空间和价值。
目前发现的去氢骆驼蓬碱的衍生物大多为7位和9位取代的去氢骆驼蓬碱衍生物等,例如:中国发明专利CN102977096公开了一种制备具有靶向特性的去氢骆驼蓬碱衍生物,并测试了衍生物对癌细胞的毒性。寻找具有良好抗癌活性的去氢骆驼蓬碱的衍生物仍是本领域技术人员不断探索的方向。
发明内容
为解决上述问题,本发明提供一种6-取代去氢骆驼蓬碱衍生物及其制备方法,旨在获得一系列具有良好肿瘤细胞毒性的化合物,用于肺癌、乳腺癌、肝癌、结肠癌或白血病等多种抗肿瘤药物。
本发明的目的是通过以下技术方案实现的。
第一方面,本发明提供一种6-取代去氢骆驼蓬碱衍生物,其结构如式(I)所示:
其中,R为取代或未取代的芳香基、取代或未取代的杂芳香基、取代或未取代的芳烷胺基、杂化取代烷胺基、脂烷胺基或脂环烷胺基中的一种。
在一些实施方案中,6-取代去氢骆驼蓬碱衍生物中的R为
其中,R1为烷基、环烷基、烯基、饱和或不饱和单环杂原子取代的环烃基、取代或未取代的芳香基以及取代或未取代的杂芳香基中的一种。
在一些实施方式中,R1为苯环、取代苯环、吡啶环、嘧啶环、噻唑环、呋喃环、噻吩环、咪唑环、吡唑环、取代吡唑环、C1-10直链或支链烷基、C1-10直链或支链环烷基、C1-10直链或支链取代环烷基中的一种。
在一些实施方案中,6-取代去氢骆驼蓬碱衍生物中的R为
其中,R2为烷基、环烷基、烯基、饱和或不饱和单环杂原子取代的环烃基、取代或未取代的芳香基以及取代或未取代的杂芳香基中的一种。。
在一些实施方案中,R2为苯环、取代苯环、吡啶环、嘧啶环、噻唑环、呋喃环、噻吩环、咪唑环、吡唑环、异噁唑、萘环、喹啉环、异喹啉环、C1-10直链或支链烷基、C1-10直链或支链环烷基、C1-10直链或支链烯基中的一种。
在一些实施方案中,6-取代去氢骆驼蓬碱衍生物中的R为
其中,R3为烷基、环烷基、饱和或不饱和单环杂原子取代的环烃基、苄基、取代或未取代的芳香基以及取代或未取代的杂芳香基中的一种。
在一些实施方案中,R3为苯环、取代苯环、吡啶环、嘧啶环、噻唑环、呋喃环、噻吩环、咪唑环、吡唑环、异噁唑、萘环、喹啉环、异喹啉环、C1-10直链或支链烷基、C1-10直链或支链环烷基、C1-10直链或支链烯基中的一种。
在一些实施方式中,R为苯环、取代苯环、吡啶环、嘧啶环、噻唑环、呋喃环、噻吩环、咪唑环、吡唑环、异噁唑、萘环、喹啉环、异喹啉环、哌嗪环、四氢吡咯环、吗啉或取代吗啉环、环丁胺基、环戊胺基、环己胺基、苄胺基、呋喃甲胺基、噻吩甲胺基中的一种。
根据本发明提供的6-取代去氢骆驼蓬碱衍生物,6-取代去氢骆驼蓬碱衍生物可以为:
7-甲氧基-1,9-二甲基-6-苯基-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(嘧啶-5-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(噻吩-3-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(吡啶-4-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(1-甲基-1H-吡唑-4-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(噻吩-2-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(吡啶-3-基)-9H-吡啶并[3,4-b]吲哚;
1-(5-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)噻吩-2-基)乙-1-酮;
6-(异喹啉-4-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(4-(三氟甲基)苯基)-9H-吡啶[3,4-b]吲哚;
1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)乙烷-1-酮;
7-甲氧基-1,9-二甲基-6-(1-甲基-1H-吡唑-5-基)-9H-吡啶并[3,4-b]吲哚;
6-(呋喃-2-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚;
6-(呋喃-3-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(吡咯烷-1-基)-9H-吡啶并[3,4-b]吲哚;
N-环己基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺;
(2S,6R)-4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)-2,6-二甲基吗啉;
N-环戊基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺;
N-苄基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺;
4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)吗啉;
N-环丁基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺;
7-甲氧基-1,9-二甲基-6-(4-甲基哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚;
N-(呋喃-2-基甲基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺;
7-甲氧基-1,9-二甲基-N-(噻吩-2-基甲基)-9H-吡啶并[3,4-b]吲哚-6-胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)乙酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6基)苯基)丙酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)丁酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)环己烷甲酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)四氢-2H-吡喃-4-甲酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)噻吩-3-甲酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)烟酰胺;
3-(二氟甲基)-N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)-1-甲基-1H-吡唑-4-甲酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)噻唑-4-甲酰胺;
N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)-1-甲基-1H-咪唑-4-甲酰胺;
1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)乙烷-1-酮;
1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)丙烷-1-酮;
1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)丙-2-烯-1-酮;
1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)丁酮;
4-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-羰基)环己烷-1-酮;
(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮;
(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(噻吩-3-基)甲酮;
(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(嘧啶-5-基)甲酮;
(呋喃-2-基)(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)甲酮;
(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(噻吩-2-基)甲酮;
(2-氯吡啶-3-基)(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)甲酮;
(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(2-甲基-4-(三氟甲基)噻唑-5-基)甲酮;
(3-(二氟甲基)-1-甲基-1H-吡唑-4-基)(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)甲酮;
(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(4-甲氧基苯基)甲酮;
(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(苯基)甲酮;
7-甲氧基-1,9-二甲基-6-(4-(苯基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚;
6-(4-(苄基磺酰基)哌嗪-1-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚;
N-(4-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)苯基)乙酰胺;
7-甲氧基-1,9-二甲基-6-(4-(喹啉-8-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(4-((1-甲基-1H-吡唑-4-基)磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(4-(吡啶-3-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(4-(萘-2-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚;
7-甲氧基-1,9-二甲基-6-(4-(噻吩-2-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚;
4-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)-3,5-二甲基异恶唑;
4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)-N,N-二甲基哌嗪-1-磺酰胺;
N-(5-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)-4-甲基噻唑-2-基)乙酰胺;
6-(4-(乙基磺酰基)哌嗪-1-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚;
5-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)-N,N-二甲基萘-1-胺;
7-甲氧基-1,9-二甲基-6-(4-(丙基磺酰基)哌嗪-1-基)-9H吡啶[3,4-b]吲哚;
6-(4-(环丙基磺酰基)哌嗪-1-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚。
第二方面,本发明提供一种6-取代去氢骆驼蓬碱衍生物的合成方法,包括以去氢骆驼蓬碱为原料,先在去氢骆驼蓬碱6号位进行卤代,在通过偶联反应在去氢骆驼蓬碱6号位引入芳基或胺基。
在一些实施方式中,去氢骆驼蓬碱6号位进行偶联反应接入芳基时,采用了碳酸盐以及1,4-二氧六环和水的混合溶剂体系。
在一些实施方式中,去氢骆驼蓬碱6号位引入胺基时,依次进行甲基化、卤代、亲核取代胺基化。
本发明的合成方法中对偶联反应、甲基化、卤代、亲核取代胺基化等没有特殊限制,可以采用本领域中任何已知方式、条件。
第三方面,本发明提供一种6-取代去氢骆驼蓬碱衍生物的应用,应用于抗肿瘤药物中。
在一些实施方案中,所述肿瘤为组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、胃癌、结肠癌、直肠癌、卵巢癌、宫茎癌、脑癌、食道癌、骨癌、睾丸癌、黑色素癌、皮肤癌、上皮细胞癌、前列腺癌、鼻咽癌、口腔癌、白血病,以及脑、生殖系统、淋巴系统、消化系统肿瘤、呼吸系统肿瘤和皮肤肿瘤中的一种或多种;优选地为肺癌、乳腺癌、肝癌、结肠癌或白血病中的一种或多种。
在一些实施方案中,所述肿瘤的肿瘤细胞为白血病细胞HL-60、肺癌细胞A549、肝癌细胞SMMC-7721、乳腺癌细胞MCF-7和结肠癌细胞SW480。
与现有技术相比,本发明的有益效果是:
(1)本发明提供了大量的去氢骆驼蓬碱6号位取代的衍生物,其中首次获得了去氢骆驼蓬碱6号位脂肪胺、脂环胺取代的衍生物;
(2)本发明以去氢骆驼蓬碱为原料,依次采用对去氢骆驼蓬碱6号位进行卤代,在进行偶联的方法制备获得多种去氢骆驼蓬碱6号位取代的衍生物,该合成方法适用性强,可广泛用于对去氢骆驼蓬碱6号位进行取代和修饰以获得更为丰富的6-取代去氢骆驼蓬碱衍生物;
(3)本发明在去氢骆驼蓬碱6号位进行偶联反应接入芳基时,与现有技术不同的是,本发明合成方法的特征在于采用了更为便宜的碱碳酸钾和毒性更小的溶剂1,4-二氧六环+水,具有更高的经济应用性和环境相容性
(4)本发明在去氢骆驼蓬碱6号位进行胺基衍生化时,与现有技术相比,本发明先甲基化,再卤代,最后亲核取代胺基化完全不同的合成路线,能以更短的3步路线合成得到6号位胺基化的去氢骆驼蓬碱衍生物,并且避开了具有高度危险性的浓硫酸、浓硝酸和酸性腐蚀品氯化亚锡的使用,具有较高的生产安全性。
(5)本发明提供的6-取代去氢骆驼蓬碱衍生物具有良好的抗肿瘤的作用,尤其对肺癌、乳腺癌、肝癌、结肠癌或白血病的肿瘤细胞具有良好的抗肿瘤活性,其中的6-(异喹啉-4-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚具有极为增强的抗肝癌细胞(SMMC-7721)的特点,其IC50μM达到了惊人的0.048μM,其抗癌活性远高于去氢骆驼蓬碱(harmine)的17.43μM,甚至高于紫杉醇的0.162μM,具有应用于抗癌药物的广泛前景。
附图说明
图1为化合物62诱导HL-60细胞凋亡流式分布图;
图2为化合物62诱导HL-60细胞凋亡细胞分布直方图。
具体实施方式
为使本发明更加容易理解,下面将结合实施例和附图来详细说明本发明,这些实施例仅起说明性作用,并不局限于本发明的应用范围。
如无具体说明,本发明的各种原料均可以通过市售得到;或根据本领域的常规方法制备得到。除非另有定义或说明,本文中所使用的所有专业与科学用语与本领域技术熟练人员所熟悉的意义相同。此外任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
下面对本发明的6-取代去氢骆驼蓬碱衍生物的制备方法详细进行说明,但本发明化合物的制备方法并不局限于此。
路线1-1:
去氢骆驼蓬碱(1a)在氢化钠的作用下与碘甲烷反应生成7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1b)后,在冰醋酸的作用下与N-溴代琥珀酰亚胺(NBS)反应生成6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c),最后再与硼酸或硼酸酯合成砌块,在四三苯基磷钯(Pd(pph3(4),碳酸钾(K2CO3),1,4-二氧六环和水条件下经suzuki偶联生成目标化合物。在该路线中,R如为苯环、取代苯环、吡啶环、嘧啶环、噻唑环、呋喃环、噻吩环、咪唑环、吡唑环、异噁唑、萘环、喹啉环、异喹啉环等。
上述路线用于合成去氢骆驼蓬碱6号位取代基为芳香基或杂环芳香基的衍生物的制备方法,对于去氢骆驼蓬碱6号位的胺取代化合物通过下面的路线实现,路线1-2:
6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)与胺在醋酸钯(Pd(OAc(2),1,1'-联萘-2,2'-双二苯膦(BINAP),叔丁醇钠(t-BuONa)条件下反应生成目标化合物。在该路线中,R如为环戊胺、环己基胺、环戊基胺、环丁基胺、吗啉环、取代吗啉环、哌嗪环、芳烷胺基等。
路线2,对于合成去氢骆驼蓬碱6号位取代基为酰胺取代的芳香基或杂环芳香基,通过下面的路线实现:
6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)与4-((叔丁氧羰基)氨基)苯硼酸(2a)在四三苯基磷钯(Pd(pph3(4),碳酸钾(K2CO3),1,4-二氧六环和水条件下suzuki偶联生成叔丁基-(4-(7-甲氧基-1 9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(苯基(氨基甲酸酯(2b),然后在三氟乙酸(TFA)的作用下脱叔丁基氧羰基,反应生成4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(苯胺(2c),最后再与羧酸(2d)反应,在1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI),三乙胺,1-羟基-7-氮杂苯并三唑(HOAt)条件下缩合成目标化合物。在该路线中,R1如为链状烃基、环状烃基、饱和或不饱和单环杂环、苯环、取代苯环、吡啶环、嘧啶环、噻唑环、咪唑环、噻唑环、吡唑环等。
路线3-1,对于去氢骆驼蓬碱6号位的脂环胺取代化合物通过下面的路线实现:
6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)与1-叔丁基氧羰基哌嗪(3a)在醋酸钯(Pd(OAc(2),1,1'-联萘-2,2'-双二苯膦(BINAP),叔丁醇钠(t-BuONa)条件下反应生成叔丁基-4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(哌嗪-1-羧酸酯(3b),然后在三氟乙酸(TFA)的作用下脱叔丁基氧羰基,反应生成7-甲氧基-1,9-二甲基-6-(哌嗪-1-基(-9H--吡啶并[3,4-b]吲哚(3c),最后再与羧酸(2d)反应,在1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI),三乙胺,1-羟基-7-氮杂苯并三唑(HOAt)条件下缩合成目标化合物。在该路线中,R2如为链状烃基、环状烃基、饱和或不饱和单环杂环、苯环、取代苯环、吡啶环、嘧啶环、噻唑环、咪唑环、吡唑环等。
路线3-2,若对脂环胺上的胺进一步进行磺酰化可采用的方法为:
7-甲氧基-1,9-二甲基-6-(哌嗪-1-基(-9H--吡啶并[3,4-b]吲哚(3c)与磺酰氯在三乙胺作用下合成目标化合物。在该路线中,R3如为链状烃基、环状烃基、饱和或不饱和单环杂环、苯环、取代苯环、苄基、吡啶环、嘧啶环、噻唑环、咪唑环、吡唑环、萘环、取代萘环、喹啉环等。
通过具体实施例来进一步说明本发明,但本领域的技术人员应知,本发明并不仅限于这些具体实施例。
以下实施例中的化合物结构是通过核磁共振(NMR)和质谱(ESI(来确定的。NMR位移(δ)以10-6(ppm)的单位给出。1H-NMR光谱数据测定使用Bruker AV II-400MHz核磁共振仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),内标为四甲基硅烷(TMS)。
ESI-MS的测定使用SCIEX UPLC(EXion(–QTOF(X500R(质谱仪测定。
薄层层析硅胶板使用烟台黄海HSGF254硅胶板,薄层色谱法(TLC)使用的硅胶板,采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
层析柱一般使用烟台黄海200~300目硅胶为载体。
本发明的已知的起始原料购自南京多隆生物科技有限公司,合成砌块购自TCI、上海泰坦、安徽泽升和上海韶远化学科技公司。
实施例中无特殊说明,反应均在氩气或者氮气气氛下进行。氩气或者氮气气氛是指反应瓶连接一个约1L容积的氩气或者氮气气球。氢化反应通常抽真空,充入氢气,反复操作3次。实施例中无特殊说明,反应温度为室温。室温为最适宜的反应温度,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂体系有:A:二氯甲烷和甲醇体系,B:二氯甲烷和丙酮体系,C:二氯甲烷和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱体系和薄层色谱法的展开剂体系包括A:二氯甲烷和甲醇体系,B:二氯甲烷和丙酮体系,C:二氯甲烷和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
中间体制备例1
6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)的合成
N2保护下,在室温条件下,将去氢骆驼蓬碱(1a,购自南京多隆生物科技有限公司)(10.0g,47.1mmol)加入250mL三口瓶中,然后加入干燥的DMF(100mL)溶解,接下来将NaH(2.3g,94.2mmol)分批缓慢加到反应液中,加完后在室温下反应0.5h,最后将反应液冷却至0℃,碘甲烷(CH3I,8.0g,56.5mmol)缓慢滴加到反应液中,滴加完后移至室温反应2h。薄层层析检测(TLC)反应完后,在0℃下缓慢加水淬灭反应,然后加乙酸乙酯萃取,然后用50mL水洗三次,合并有机层浓缩干,得到7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1b)粗品,类白色固体9.8g(产率92%)。得到的粗品(1b)无需进一步纯化,直接投下一步反应。
将上面反应得到的7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1b)粗品(6.0g,26.5mmol)用100mL冰醋酸溶解后,在搅拌条件下加入NBS(4.72g,26.5mmol),加完后在室温条件下反应过夜。薄层层析检测(TLC)反应完全后,旋出冰醋酸,得到浓缩物。将得到的浓缩物加二氯甲烷溶解,然后用饱和碳酸氢钠溶液洗涤,直到检测有机相为碱性为止。合并有机层浓缩干,柱层析(二氯甲烷:甲醇=20:1)分离得到6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c),白色固体6.1g(产率75%)。1H NMR(400MHz,CDCl3(δ8.22(d,J=5.3Hz,1H(,8.07(s,1H(,7.54(d,J=5.2Hz,1H(,6.62(s,1H(,3.94(s,3H(,3.91(s,3H(,2.96(s,3H(.ESI-MS m/z:计算值305.0284,实测值305.0284[M+H]+。
中间体制备例2
叔丁基-(4-(7-甲氧基-1 9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(苯基(氨基甲酸酯(2b)的制备
将6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)(1.07g,3.5mmol)加入100mL圆底烧瓶中,然后用1,4-二氧六环(50mL)溶解,接下来加入4-((叔丁氧羰基)氨基)苯硼酸(2a)(1.0g,4.2mmol)、碳酸钾(1.45g,10.5mmol)以及水(5mL),最后加入四三苯基磷钯(325mg,0.28mmol),置换氮气三次,105℃条件下反应8h。薄层层析检测(TLC)反应完全后,旋出1,4-二氧六环和水,得到浓缩物。柱层析(二氯甲烷:甲醇=20:1)分离得到叔丁基-(4-(7-甲氧基-1 9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(苯基(氨基甲酸酯(2b),白色固体1.26g(产率86%)。
中间体制备例3
叔丁基-4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(哌嗪-1-羧酸酯(3b)的制备
将6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)(1.5g,4.9mmol)加入150mL圆底烧瓶中,然后用甲苯(80mL)溶解,接下来加入1-叔丁基氧羰基哌嗪(3a)(1.2g,6.4mmol)、1,1'-联萘-2,2'-双二苯膦(BINAP,305mg,0.49mmol)、叔丁醇钠(942mg,9.8mmol),最后加入醋酸钯((56mg,0.25mmol)),置换氮气三次,110℃条件下反应10h。薄层层析检测(TLC)反应完全后,旋出甲苯,得到浓缩物。柱层析(二氯甲烷:甲醇=20:1)分离得到叔丁基-4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(哌嗪-1-羧酸酯(3b),白色固体1.67g(产率83%)。
实施例1
6-取代去氢骆驼蓬碱衍生物为化合物1,7-甲氧基-1,9-二甲基-6-苯基-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物1按照上述方案中路线1-1制备。
将6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)(120mg,0.39mmol)加入50mL圆底烧瓶中,然后用1,4-二氧六环(10mL)溶解,接下来加入苯硼酸(62g,0.51mmol)、碳酸钾(161mg,1.17mmol)以及水(1mL),最后加入四三苯基磷钯(36mg,0.031mmol),置换氮气三次,105℃条件下反应8h。薄层层析检测(TLC)反应完全后,旋出1,4-二氧六环和水,得到浓缩物。柱层析(二氯甲烷:甲醇=20:1)分离得到化合物1,白色固体。1H NMR(400MHz,CDCl3(δ8.28(d,J=5.3Hz,1H(,7.99(s,1H(,7.74(d,J=5.3Hz,1H(,7.60(d,J=7.2Hz,2H(,7.46(t,J=7.5Hz,2H(,7.37(t,J=7.3Hz,1H(,6.90(s,1H(,4.14(s,3H(,3.97(s,3H(,3.11(s,3H(.ESI-MS m/z:计算值303.1492,实测值303.1492[M+H]+。
实施例2
6-取代去氢骆驼蓬碱衍生物为化合物2,7-甲氧基-1,9-二甲基-6-(嘧啶-5-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物2按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为嘧啶-5-基硼酸,得到白色固体。1H NMR(400MHz,CDCl3(δ9.18(s,1H(,8.98(s,2H(,8.32(d,J=4.9Hz,1H(,8.01(s,1H(,7.78(d,J=4.7Hz,1H(,6.95(s,1H(,4.18(s,3H(,4.01(s,3H(,3.12(s,3H(.ESI-MS m/z:计算值305.1397,实测值305.1395[M+H]+。
实施例3
6-取代去氢骆驼蓬碱衍生物为化合物3,7-甲氧基-1,9-二甲基-6-(噻吩-3-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物3按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为噻吩-3-基硼酸,得到白色固体。1H NMR(400MHz,CDCl3(δ9.18(s,1H(,8.98(s,2H(,8.32(d,J=4.9Hz,1H(,8.01(s,1H(,7.78(d,J=4.7Hz,1H(,6.95(s,1H(,4.18(s,3H(,4.01(s,3H(,3.12(s,3H(.ESI-MS m/z:计算值309.1056,实测值309.1053[M+H]+。
实施例4
6-取代去氢骆驼蓬碱衍生物为化合物4,7-甲氧基-1,9-二甲基-6-(吡啶-4-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物4按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为吡啶-4-基硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.60(d,J=3.8Hz,2H(,8.25(s,1H(,8.17(d,J=5.1Hz,1H(,7.93(d,J=5.1Hz,1H(,7.60(d,J=4.7Hz,2H(,7.33(s,1H(,4.15(s,3H(,3.96(s,3H(,3.00(s,3H(.ESI-MS m/z:计算值304.1445,实测值304.1452[M+H]+。
实施例5
6-取代去氢骆驼蓬碱衍生物为化合物5,7-甲氧基-1,9-二甲基-6-(1-甲基-1H-吡唑-4-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物5按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为(1-甲基-1H-吡唑-4-基)硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.40(s,1H(,8.15(d,J=5.2Hz,1H(,8.11(s,1H(,7.96(s,1H(,7.89(d,J=5.2Hz,1H(,7.26(s,1H(,4.14(s,3H(,4.03(s,3H(,3.89(s,3H(,2.99(s,3H(.ESI-MS m/z:计算值307.1554,实测值307.1553[M+H]+。
实施例6
6-取代去氢骆驼蓬碱衍生物为化合物6,7-甲氧基-1,9-二甲基-6-(噻吩-2-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物6按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为噻吩-2-基硼酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.24(d,J=5.2Hz,1H(,8.14(s,1H(,7.64(d,J=5.2Hz,1H(,7.47(dd,J=3.6,1.2Hz,1H(,7.32(dd,J=5.1,1.2Hz,1H(,7.12(dd,J=5.2,3.6Hz,1H(,6.64(s,1H(,3.94(s,3H(,3.89(s,3H(,2.96(s,3H(.ESI-MSm/z:计算值309.1056,实测值309.1053[M+H]+。
实施例7
6-取代去氢骆驼蓬碱衍生物为化合物7,7-甲氧基-1,9-二甲基-6-(吡啶-3-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物7按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为吡啶-3-基硼酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.82(s,1H(,8.59–8.54(m,1H(,8.27(d,J=4.7Hz,1H(,7.96(s,1H(,7.90(d,J=7.2Hz,1H(,7.72(d,J=4.6Hz,1H(,7.39–7.33(m,1H(,6.88(s,1H(,4.11(s,3H(,3.95(s,3H(,3.07(s,3H(.ESI-MS m/z:计算值304.1445,实测值304.1448[M+H]+。
实施例8
6-取代去氢骆驼蓬碱衍生物为化合物8,1-(5-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)噻吩-2-基)乙-1-酮,其结构为:
本发明化合物8按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为(5-乙酰基噻吩-2-基)硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.76(s,1H(,8.20(d,J=5.2Hz,1H(,8.00(d,J=5.2Hz,1H(,7.94(d,J=4.1Hz,1H(,7.81(d,J=4.1Hz,1H(,7.38(s,1H(,4.17(s,3H(,4.10(s,3H(,3.01(s,3H(,2.54(s,3H(.ESI-MS m/z:计算值351.1162,实测值351.1169[M+H]+。
实施例9
6-取代去氢骆驼蓬碱衍生物为化合物9,6-(异喹啉-4-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物9按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为异喹啉-4-基硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ9.34(s,1H(,8.44(s,1H(,8.20–8.18(m,1H(,8.16–8.14(m,2H(,7.90(d,J=5.2Hz,1H(,7.72–7.67(m,2H(,7.51–7.48(m,1H(,7.44(s,1H(,4.24(s,3H(,3.82(s,3H(,3.05(s,3H(.ESI-MS m/z:计算值354.1601,实测值354.1612[M+H]+。
实施例10
6-取代去氢骆驼蓬碱衍生物为化合物10,7-甲氧基-1,9-二甲基-6-(4-(三氟甲基)苯基)-9H-吡啶[3,4-b]吲哚,其结构为:
本发明化合物10按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为(4-(三氟甲基)苯基)硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.20(s,1H(,8.16(d,J=5.2Hz,1H(,7.93(d,J=5.2Hz,1H(,7.78(br s,4H(,7.36(s,1H(,4.18(s,3H(,3.95(s,3H(,3.02(s,3H(.ESI-MS m/z:计算值371.1366,实测值371.1365[M+H]+。
实施例11
6-取代去氢骆驼蓬碱衍生物为化合物11,1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)乙烷-1-酮,其结构为:
本发明化合物11按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为4-乙酰基苯基硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.19(s,1H(,8.16(d,J=5.2Hz,1H(,8.01(d,J=8.4Hz,2H(,7.93(d,J=5.2Hz,1H(,7.71(d,J=8.4Hz,2H(,7.35(s,1H(,4.18(s,3H(,3.95(s,3H(,3.01(s,3H(,2.62(s,3H(.ESI-MS m/z:计算值345.1598,实测值345.1599[M+H]+。
实施例12
6-取代去氢骆驼蓬碱衍生物为化合物12,7-甲氧基-1,9-二甲基-6-(1-甲基-1H-吡唑-5-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物12按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为(1-甲基-1H-吡唑-5-基(硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.16(d,J=5.2Hz,1H(,8.11(s,1H(,7.92(d,J=5.2Hz,1H(,7.46(d,J=1.8Hz,1H(,7.37(s,1H(,6.30(d,J=1.8Hz,1H(,4.18(s,3H(,3.96(s,3H(,3.63(s,3H(,3.02(s,3H(.ESI-MS m/z:计算值307.1554,实测值307.1560[M+H]+。
实施例13
6-取代去氢骆驼蓬碱衍生物为化合物13,6-(呋喃-2-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物13按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为呋喃-2-基硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.48(s,1H(,8.15(d,J=5.2Hz,1H(,7.95(d,J=5.2Hz,1H(,7.74(dd,J=1.7,0.7Hz,1H(,7.26(s,1H(,6.88(dd,J=3.3,0.6Hz,1H(,6.60(dd,J=3.3,1.8Hz,1H(,4.11(s,3H(,4.05(s,3H(,2.97(s,3H(.ESI-MS m/z:计算值293.1285,实测值293.1289[M+H]+。
实施例14
6-取代去氢骆驼蓬碱衍生物为化合物14,6-(呋喃-3-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物14按照方案中路线1-1制备,合成方法参考实施例1,只是代替苯硼酸为呋喃-3-基硼酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.48(s,1H(,8.19(d,J=5.3Hz,1H(,8.15–8.14(m,1H(,8.01(d,J=5.3Hz,1H(,7.76–7.75(m,1H(,7.28(s,1H(,7.17–7.15(m,1H(,4.14(s,3H(,4.05(s,3H(,3.02(s,3H(.ESI-MS m/z:计算值293.1285,实测值293.1292[M+H]+。
实施例15
6-取代去氢骆驼蓬碱衍生物为化合物15,7-甲氧基-1,9-二甲基-6-(吡咯烷-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物15按照方案中路线1-2制备。
将6-溴-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(1c)(150mg,0.49mmol)加入50mL圆底烧瓶中,然后用甲苯(10mL)溶解,接下来加入四氢吡咯(46mg,0.64mmol)、1,1'-联萘-2,2'-双二苯膦(BINAP,30.5mg,0.049mmol),叔丁醇钠(94mg,0.98mmol),最后加入醋酸钯(5.5mg,0.024mmol),置换氮气三次,110℃条件下反应10h。薄层层析检测(TLC)反应完全后,旋出甲苯,得到浓缩物。柱层析(二氯甲烷:甲醇=20:1)分离得到化合物15,白色固体。1H NMR(400MHz,CDCl3(δ8.21(d,J=5.3Hz,1H(,7.68(d,J=5.3Hz,1H(,7.48(s,1H(,6.81(s,1H(,4.06(s,3H(,4.01(s,3H(,3.33–3.26(m,4H(,3.04(s,3H(,2.04–1.98(m,4H(.ESI-MS m/z:计算值296.1758,实测值296.1755[M+H]+。
实施例16
6-取代去氢骆驼蓬碱衍生物为化合物16,N-环己基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺,其结构为:
本发明化合物16按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为环己胺,得到白色固体。1H NMR(400MHz,CDCl3(δ8.18(d,J=5.3Hz,1H(,7.69(d,J=5.3Hz,1H(,7.18(s,1H(,6.71(s,1H(,3.99(s,3H(,3.97(s,3H(,3.41–3.34(m,1H(,3.00(s,3H(,2.20–2.12(m,2H(,1.85–1.76(m,2H(,1.74–1.66(m,1H(,1.51–1.40(m,2H(,1.28–1.19(m,3H(.ESI-MS m/z:计算值324.2071,实测值324.2070[M+H]+。
实施例17
6-取代去氢骆驼蓬碱衍生物为化合物17,(2S,6R)-4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)-2,6-二甲基吗啉,其结构为:
本发明化合物17按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为(2R,6S)-2,6-二甲基吗啉,得到白色固体。1H NMR(400MHz,CDCl3(δ8.24(d,J=5.3Hz,1H(,7.72(d,J=5.3Hz,1H(,7.58(s,1H(,6.84(s,1H(,4.10(s,3H(,4.03(s,3H(,4.00–3.94(m,2H(,3.37–3.32(m,2H(,3.06(s,3H(,2.47–2.42(m,2H(,1.28–1.23(m,6H(.ESI-MS m/z:计算值340.2020,实测值340.2017[M+H]+。
实施例18
6-取代去氢骆驼蓬碱衍生物为化合物18,N-环戊基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺,其结构为:
本发明化合物18按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为环戊胺,得到白色固体。1H NMR(400MHz,CDCl3(δ8.17(d,J=5.3Hz,1H(,7.67(d,J=5.2Hz,1H(,7.17(s,1H(,6.66(s,1H(,3.95(s,3H(,3.94(s,3H(,3.91–3.86(m,1H(,2.98(s,3H(,2.17–2.09(m,2H(,1.82–1.74(m,2H(,1.72–1.64(m,2H(,1.62–1.54(m,2H(.ESI-MS m/z:计算值310.1914,实测值310.1912[M+H]+。
实施例19
6-取代去氢骆驼蓬碱衍生物为化合物19,N-苄基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺,其结构为:
本发明化合物19按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为苯甲胺,得到白色固体。1H NMR(400MHz,CDCl3(δ8.06(d,J=5.3Hz,1H(,7.50(d,J=5.3Hz,1H(,7.37–7.34(m,2H(,7.29–7.25(m,2H(,7.22–7.17(m,1H(,7.06(s,1H(,6.59(s,1H(,4.33(s,2H(,3.86(s,3H(,3.84(s,3H(,2.88(s,3H(.ESI-MS m/z:计算值332.1758,实测值332.1756[M+H]+。
实施例20
6-取代去氢骆驼蓬碱衍生物为化合物20,4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)吗啉,其结构为:
本发明化合物20按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为吗啉,得到白色固体。1H NMR(400MHz,CDCl3(δ8.23(d,J=5.3Hz,1H(,7.69(d,J=5.3Hz,1H(,7.58(s,1H(,6.82(s,1H(,4.05(s,3H(,4.01(s,3H(,3.96–3.93(m,4H(,3.13–3.11(m,4H(,3.02(s,3H(.ESI-MS m/z:计算值312.1707,实测值312.1707[M+H]+。
实施例21
6-取代去氢骆驼蓬碱衍生物为化合物21,N-环丁基-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺,其结构为:
本发明化合物21按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为环丁胺,得到白色固体。1H NMR(400MHz,CDCl3(δ8.19(d,J=5.3Hz,1H(,7.66(d,J=5.3Hz,1H(,7.06(s,1H(,6.70(s,1H(,4.06–4.02(m,1H(,3.98(s,3H(,3.97(s,3H(,3.00(s,3H(,2.58–2.51(m,2H(,1.97–1.85(m,4H(.ESI-MS m/z:计算值296.1758,实测值296.1756[M+H]+。
实施例22
6-取代去氢骆驼蓬碱衍生物为化合物22,7-甲氧基-1,9-二甲基-6-(4-甲基哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物22按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为1-甲基哌嗪,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.14(br s,2H(,7.85(s,1H(,7.28(s,1H(,4.17(s,3H(,4.12(s,3H(,4.17–3.61(m,8H(,3.07(s,3H(,2.77(s,3H(.ESI-MSm/z:计算值325.2023,实测值325.2020[M+H]+。
实施例23
6-取代去氢骆驼蓬碱衍生物为化合物23,N-(呋喃-2-基甲基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-胺,其结构为:
本发明化合物23按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为呋喃-2-基甲胺,得到白色固体。1H NMR(400MHz,CDCl3(δ8.19(d,J=5.3Hz,1H(,7.66(d,J=5.2Hz,1H(,7.41–7.39(m,1H(,7.25(s,1H(,6.73(s,1H(,6.36–6.29(m,2H(,4.63–4.48(m,1H(,4.43(s,2H(,4.00(s,3H(,3.97(s,3H(,3.01(s,3H(.ESI-MS m/z:计算值322.1550,实测值322.1548[M+H]+。
实施例24
6-取代去氢骆驼蓬碱衍生物为化合物24,7-甲氧基-1,9-二甲基-N-(噻吩-2-基甲基)-9H-吡啶并[3,4-b]吲哚-6-胺,其结构为:
本发明化合物24按照方案中路线1-2制备,合成方法参考实施例15,只是代替四氢吡咯为噻吩-2-基甲胺,得到白色固体。1H NMR(400MHz,CDCl3(δ8.18(d,J=5.3Hz,1H(,7.63(d,J=5.2Hz,1H(,7.24(s,1H(,7.22(dd,J=5.1,1.2Hz,1H(,7.08(dd,J=3.4,1.1Hz,1H(,6.98(dd,J=5.1,3.4Hz,1H(,6.71(s,1H(,4.61(s,2H(,4.60–4.54(m,1H(,3.98(s,3H(,3.96(s,3H(,3.00(s,3H(.ESI-MS m/z:计算值338.1322,实测值338.1319[M+H]+。
实施例25
6-取代去氢骆驼蓬碱衍生物为化合物25,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)乙酰胺,其结构为:
本发明化合物25按照方案中路线2制备。
将叔丁基-(4-(7-甲氧基-1 9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(苯基(氨基甲酸酯(2b)(100mg,0.24mmol)溶于二氯甲烷(5mL)后加入三氟乙酸(1mL),室温搅拌至原料反应完后,旋出二氯甲烷,得到浓缩物。然后用二氯甲烷溶解浓缩物,用NEt3调节至碱性,浓缩得到的4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(苯胺(2c),黄色固体备用。1H NMR(400MHz,DMSO-d6(δ8.12(d,J=5.2Hz,1H(,7.98(s,1H(,7.88(d,J=5.2Hz,1H(,7.23–7.21(m,3H(,6.62(d,J=8.5Hz,2H(,5.09(br s,2H(,4.14(s,3H(,3.90(s,3H(,3.00(s,3H(.ESI-MS m/z:计算值318.1601,实测值318.1606[M+H]+。
将乙酸(17mg,0.29mmol)溶于二氯甲烷中,依次加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)(69mg,0.36mmol)、三乙胺(67μL,0.48mmol)、1-羟基-7-氮杂苯并三唑(HOAt)(49mg,0.36mmol),室温搅拌半小时后加入上步所得的4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(苯胺(2c),室温反应过夜后,加入水淬灭反应,用水洗3次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析分离(二氯甲烷:甲醇=20:1)得到白色固体。1H NMR(400MHz,DMSO-d6(δ10.03(s,1H(,8.14–8.09(m,2H(,7.93(s,1H(,7.68–7.60(m,2H(,7.51–7.44(m,2H(,7.27(s,1H(,4.14(s,3H(,3.92(s,3H(,3.00(s,3H(,2.08(s,3H(.ESI-MS m/z:计算值360.1707,实测值360.1709[M+H]+。
实施例26
6-取代去氢骆驼蓬碱衍生物为化合物26,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6基)苯基)丙酰胺,其结构为:
本发明化合物26按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为丙酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ9.94(s,1H(,8.15(d,J=5.3Hz,1H(,8.09(s,1H(,7.93(d,J=5.3Hz,1H(,7.65(d,J=8.3Hz,2H(,7.47(d,J=8.5Hz,2H(,7.29(s,1H(,4.16(s,3H(,3.93(s,3H(,3.01(s,3H(,2.35(q,J=7.5Hz,2H(,1.11(t,J=7.5Hz,3H(.ESI-MS m/z:计算值374.1863,实测值374.1870[M+H]+。
实施例27
6-取代去氢骆驼蓬碱衍生物为化合物27,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)丁酰胺,其结构为:
本发明化合物27按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为丁酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ9.96(s,1H(,8.20(d,J=5.4Hz,1H(,8.15(s,1H(,8.06(d,J=5.5Hz,1H(,7.65(d,J=8.4Hz,2H(,7.47(d,J=8.5Hz,2H(,7.34(s,1H(,4.20(s,3H(,3.94(s,3H(,3.07(s,3H(,2.31(t,J=7.3Hz,2H(,1.68-1.59(m,2H(,0.93(t,J=7.4Hz,3H(.ESI-MS m/z:计算值388.2020,实测值388.2027[M+H]+。
实施例28
6-取代去氢骆驼蓬碱衍生物为化合物28,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)环己烷甲酰胺,其结构为:
本发明化合物28按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为环己甲酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ9.90(s,1H(,8.15(d,J=5.3Hz,1H(,8.09(s,1H(,7.96(d,J=5.3Hz,1H(,7.66(d,J=8.4Hz,2H(,7.46(d,J=8.3Hz,2H(,7.28(s,1H(,4.15(s,3H(,3.92(s,3H(,3.02(s,3H(,2.39–2.33(m,1H(,1.88–1.59(m,6H(,1.48–1.29(m,4H(.ESI-MS m/z:计算值428.2333,实测值428.2329[M+H]+。
实施例29
6-取代去氢骆驼蓬碱衍生物为化合物29,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)四氢-2H-吡喃-4-甲酰胺,其结构为:
本发明化合物29按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为四氢-2H-吡喃-4-羧酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ9.96(s,1H(,8.14(d,J=5.2Hz,1H(,8.08(s,1H(,7.91(d,J=5.2Hz,1H(,7.65(d,J=8.2Hz,2H(,7.47(d,J=8.2Hz,2H(,7.30(s,1H(,4.17(s,3H(,3.96–3.88(m,7H(,3.01(s,3H(,2.66–2.59(m,1H(,1.74–1.67(m,4H(.ESI-MS m/z:计算值430.2125,实测值430.2119[M+H]+。
实施例30
6-取代去氢骆驼蓬碱衍生物为化合物30,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)噻吩-3-甲酰胺,其结构为:
本发明化合物30按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为噻吩-3-羧酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ10.13(s,1H(,8.38(t,J=2.1Hz,1H(,8.15(d,J=5.2Hz,1H(,8.12(s,1H(,7.92(d,J=5.2Hz,1H(,7.81(dd,J=6.6,2.0Hz,2H(,7.67(d,J=2.2Hz,2H(,7.53(dd,J=6.6,2.0Hz,2H(,7.30(s,1H(,4.17(s,3H(,3.94(s,3H(,3.01(s,3H(.ESI-MS m/z:计算值428.1427,实测值428.1422[M+H]+。
实施例31
6-取代去氢骆驼蓬碱衍生物为化合物31,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)烟酰胺,其结构为:
本发明化合物31按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为烟酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ10.53(s,1H(,9.15(d,J=2.2Hz,1H(,8.78(dd,J=4.8,1.7Hz,1H(,8.33(dt,J=8.0,2.0Hz,1H(,8.15(d,J=5.2Hz,1H(,8.13(s,1H(,7.92(d,J=5.2Hz,1H(,7.83(dd,J=6.6,2.0Hz,2H(,7.61–7.55(m,3H(,7.31(s,1H(,4.17(s,3H(,3.95(s,3H(,3.01(s,3H(.ESI-MS m/z:计算值423.1816,实测值423.1809[M+H]+。
实施例32
6-取代去氢骆驼蓬碱衍生物为化合物32,3-(二氟甲基)-N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)-1-甲基-1H-吡唑-4-甲酰胺,其结构为:
本发明化合物32按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ10.10(s,1H(,8.53(s,1H(,8.14(d,J=5.2Hz,1H(,8.11(s,1H(,7.91(d,J=5.2Hz,1H(,7.75(dd,J=6.6,2.0Hz,2H(,7.53(dd,J=6.6,2.0Hz,2H(,7.32(d,J H-F=54.0Hz,1H(,7.28(s,1H(,4.15(s,3H(,3.99(s,3H(,3.93(s,3H(,3.00(s,3H(.ESI-MS m/z:计算值476.1893,实测值476.1899[M+H]+。
实施例33
6-取代去氢骆驼蓬碱衍生物为化合物33,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)噻唑-4-甲酰胺,其结构为:
本发明化合物33按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为噻唑-4-羧酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ10.41(s,1H(,9.29(d,J=2.0Hz,1H(,8.53(d,J=2.0Hz,1H(,8.14(d,J=5.2Hz,1H(,8.12(s,1H(,7.92–7.89(m,3H(,7.53(dd,J=6.6,2.0Hz,2H(,7.30(s,1H(,4.16(s,3H(,3.94(s,3H(,3.01(s,3H(.ESI-MS m/z:计算值429.1380,实测值429.1377[M+H]+。
实施例34
6-取代去氢骆驼蓬碱衍生物为化合物34,N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)-1-甲基-1H-咪唑-4-甲酰胺,其结构为:
本发明化合物34按照方案中路线2制备,合成方法参考实施例25,只是代替乙酸为1-甲基-1H-咪唑-4-羧酸,得到白色固体。1H NMR(400MHz,DMSO-d6(δ9.86(s,1H(,8.14(d,J=5.2Hz,1H(,8.11(s,1H(,7.91(d,J=5.2Hz,1H(,7.87(dd,J=6.6,2.0Hz,2H(,7.83(d,J=1.3Hz,1H(,7.79(d,J=1.2Hz,1H(,7.49dd,J=6.6,2.0Hz,2H(,7.30(s,1H(,4.17(s,3H(,3.94(s,3H(,3.74(s,3H(,3.01(s,3H(.ESI-MS m/z:计算值426.1925,实测值426.1924[M+H]+。
实施例35
6-取代去氢骆驼蓬碱衍生物为化合物35,1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)乙烷-1-酮,其结构为:
本发明化合物35按照方案中路线3-1制备。
将叔丁基-4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(哌嗪-1-羧酸酯(3b)(150mg,0.37mmol)溶于二氯甲烷(5mL)后加入三氟乙酸(1mL),室温搅拌至原料反应完后,旋出二氯甲烷,得到浓缩物。然后二氯甲烷溶解浓缩物,用NEt3调节至碱性,浓缩得到7-甲氧基-1,9-二甲基-6-(哌嗪-1-基(-9H--吡啶并[3,4-b]吲哚(3c),黄色固体备用。
将乙酸(26.4mg,0.44mmol)溶于二氯甲烷中,依次加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)(107mg,0.56mmol)、三乙胺(103μL,0.74mmol)、1-羟基-7-氮杂苯并三唑(HOAt)(76mg,0.56mmol),室温搅拌半小时后加入上步所得的7-甲氧基-1,9-二甲基-6-(哌嗪-1-基(-9H--吡啶并[3,4-b]吲哚(3c),室温反应过夜后,加入水淬灭反应,用水洗3次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析分离(二氯甲烷:甲醇=20:1)得到白色固体。1H NMR(400MHz,CDCl3(δ8.23(d,J=5.3Hz,1H(,7.67(d,J=5.3Hz,1H(,7.56(s,1H(,6.83(s,1H(,4.07(s,3H(,4.03(s,3H(,3.85–3.83(m,2H(,3.70–3.67(m,2H(,3.11–3.05(m,4H(,3.03(s,3H(,2.15(s,3H(.ESI-MS m/z:计算值353.1972,实测值353.1973[M+H]+。
实施例36
6-取代去氢骆驼蓬碱衍生物为化合物36,1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)丙烷-1-酮,其结构为:
本发明化合物36按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为丙酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.25(d,J=5.3Hz,1H(,7.69(d,J=5.3Hz,1H(,7.58(s,1H(,6.85(s,1H(,4.09(s,3H(,4.04(s,3H(,3.86(t,J=4.9Hz,2H(,3.70(t,J=4.8Hz,2H(,3.12–3.06(m,4H(,3.05(s,3H(,2.42(q,J=7.5Hz,2H(,1.20(t,J=7.4Hz,3H(.ESI-MS m/z:计算值367.2129,实测值367.2129[M+H]+。
实施例37
6-取代去氢骆驼蓬碱衍生物为化合物37,1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)丙-2-烯-1-酮,其结构为:
本发明化合物37按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为烯丙酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.25(d,J=5.3Hz,1H(,7.69(d,J=5.3Hz,1H(,7.58(s,1H(,6.85(s,1H(,6.64(dd,J=16.8,10.5Hz,1H(,6.34(dd,J=16.8,2.0Hz,1H(,5.74(dd,J=10.5,2.0Hz,1H(,4.10(s,3H(,4.04(s,3H(,3.93(t,J=4.9Hz,2H(,3.80(t,J=4.9Hz,2H(,3.13–3.11(m,4H(,3.05(s,3H(.ESI-MS m/z:计算值365.1972,实测值365.1970[M+H]+。
实施例38
6-取代去氢骆驼蓬碱衍生物为化合物38,1-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)丁酮,其结构为:
本发明化合物38按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为丁酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.23(d,J=5.3Hz,1H(,7.68(d,J=5.3Hz,1H(,7.57(s,1H(,6.84(s,1H(,4.07(s,3H(,4.03(s,3H(,3.85(t,J=4.8Hz,2H(,3.70(t,J=4.8Hz,2H(,3.11–3.05(m,4H(,3.04(s,3H(,2.37(t,J=7.6Hz,2H(,1.75–1.66(m,2H(,0.99(t,J=7.4Hz,3H(.ESI-MS m/z:计算值381.2285,实测值381.2283[M+H]+。
实施例39
6-取代去氢骆驼蓬碱衍生物为化合物39,4-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-羰基)环己烷-1-酮,其结构为:
本发明化合物39按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为4-氧代环己烷-1-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.22(d,J=5.3Hz,1H(,7.67(d,J=5.3Hz,1H(,7.57(s,1H(,6.84(s,1H(,4.07(s,3H(,4.03(s,3H(,3.92–3.74(m,4H(,3.19–3.06(m,4H(,3.03(s,3H(,2.91–2.79(m,1H(,2.60–2.52(m,2H(,2.41–2.32(m,2H(,2.16–2.03(m,4H(.ESI-MS m/z:计算值435.2391,实测值435.2388[M+H]+。
实施例40
6-取代去氢骆驼蓬碱衍生物为化合物40,(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(四氢-2H-吡喃-4-基)甲酮,其结构为:
本发明化合物40按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为四氢-2H-吡喃-4-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.23(d,J=5.3Hz,1H(,7.67(d,J=5.3Hz,1H(,7.56(s,1H(,6.84(s,1H(,4.07(s,3H(,4.03(s,3H(,3.89–3.83(m,2H(,3.78–3.73(m,2H(,3.50–3.43(m,2H(,3.14–3.06(m,4H(,3.03(s,3H(,2.84–2.73(m,3H(,2.01–1.91(m,2H(,1.70–1.62(m,2H(.ESI-MS m/z:计算值423.2391,实测值423.2389[M+H]+。
实施例41
6-取代去氢骆驼蓬碱衍生物为化合物41,(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(噻吩-3-基)甲酮,其结构为:
本发明化合物41按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为噻吩-3-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.18(d,J=5.3Hz,1H(,7.62(d,J=5.3Hz,1H(,7.53(s,1H(,7.51(dd,J=3.0,1.3Hz,1H(,7.29(dd,J=5.0,3.0Hz,1H(,7.18(dd,J=5.0,1.3Hz,1H(,6.79(s,1H(,4.03(s,3H(,3.97(s,3H(,3.84–3.67(m,2H(,3.16–3.02(m,4H(,2.99(s,3H(,2.44–2.32(m,2H(.ESI-MS m/z:计算值421.1693,实测值421.1694[M+H]+。
实施例42
6-取代去氢骆驼蓬碱衍生物为化合物42,(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(嘧啶-5-基)甲酮,其结构为:
本发明化合物42按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为嘧啶-5-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ9.29(s,1H(,8.88(s,2H(,8.25(d,J=5.3Hz,1H(,7.69(d,J=5.3Hz,1H(,7.60(s,1H(,6.86(s,1H(,4.09(s,3H(,4.04(s,3H(,3.73–3.66(m,2H(,3.27–3.20(m,2H(,3.15-3.05(m,2H(,3.05(s,3H(,2.79–2.69(m,2H(.ESI-MS m/z:计算值417.2034,实测值417.2032[M+H]+。
实施例43
6-取代去氢骆驼蓬碱衍生物为化合物43,(呋喃-2-基)(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)甲酮,其结构为:
本发明化合物43按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为呋喃-2-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.24(d,J=5.3Hz,1H(,7.68(d,J=5.3Hz,1H(,7.60(s,1H(,7.51(br s,1H(,7.05(d,J=3.5Hz,1H(,6.86(s,1H(,6.50(dd,J=3.4,1.8Hz,1H(,4.09(s,3H(,4.07–4.02(m,5H(,3.21–3.15(m,4H(,3.05(s,3H(,2.52–2.40(m,2H(.ESI-MS m/z:计算值405.1921,实测值405.1921[M+H]+。
实施例44
6-取代去氢骆驼蓬碱衍生物为化合物44,(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(噻吩-2-基)甲酮,其结构为:
本发明化合物44按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为噻吩-2-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.25(d,J=5.3Hz,1H(,7.69(d,J=5.3Hz,1H(,7.60(s,1H(,7.46(d,J=5.0Hz,1H(,7.35(d,J=3.7Hz,1H(,7.06(t,J=4.3Hz,1H(,6.85(s,1H(,4.09(s,3H(,4.04(s,3H(,4.02–3.97(m,4H(,3.19–3.13(m,4H(,3.05(s,3H(.ESI-MS m/z:计算值421.1693,实测值421.1693[M+H]+。
实施例45
6-取代去氢骆驼蓬碱衍生物为化合物45,(2-氯吡啶-3-基)(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)甲酮,其结构为:
本发明化合物45按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为2-氯烟酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.46(dd,J=4.9,2.0Hz,1H(,8.24(d,J=5.3Hz,1H(,7.73–7.68(m,2H(,7.59(s,1H(,7.35(dd,J=7.5,4.8Hz,1H(,6.85(s,1H(,4.10(s,3H(,4.03(s,3H(,3.61–3.54(m,1H(,3.49–3.42(m,1H(,3.24–3.15(m,3H(,3.05(s,3H(,2.38–2.25(m,3H(.ESI-MS m/z:计算值450.1692,实测值450.1695[M+H]+。
实施例46
6-取代去氢骆驼蓬碱衍生物为化合物46,(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(2-甲基-4-(三氟甲基)噻唑-5-基)甲酮,其结构为:
本发明化合物46按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为2-甲基-4-(三氟甲基)噻唑-5-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.25(d,J=5.3Hz,1H(,7.69(d,J=5.3Hz,1H(,7.58(s,1H(,6.85(s,1H(,4.08(s,3H(,4.02(s,3H(,4.01–3.98(m,2H(,3.57(t,J=4.9Hz,2H(,3.17(t,J=4.9Hz,2H(,3.09–3.06(m,2H(,3.04(s,3H(,2.76(s,3H(.ESI-MS m/z:计算值504.1676,实测值504.1678[M+H]+。
实施例47
6-取代去氢骆驼蓬碱衍生物为化合物47,(3-(二氟甲基)-1-甲基-1H-吡唑-4-基)(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)甲酮,其结构为:
本发明化合物47按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.22(d,J=5.3Hz,1H(,7.66(d,J=5.3Hz,1H(,7.56(s,1H(,7.54(s,1H(,6.86(t,JH-F=54.6Hz,1H(,6.83(s,1H(,4.06(s,3H(,4.02(s,3H(,3.93(s,3H(,3.92–3.71(m,4H(,3.14–3.07(m,4H(,3.02(s,3H(.ESI-MS m/z:计算值469.2158,实测值469.2157[M+H]+。
实施例48
6-取代去氢骆驼蓬碱衍生物为化合物48,(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(4-甲氧基苯基)甲酮,其结构为:
本发明化合物48按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为4-甲氧基苯甲酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.23(d,J=5.3Hz,1H(,7.67(d,J=5.3Hz,1H(,7.58(s,1H(,7.46–7.42(m,2H(,6.94–6.90(m,2H(,6.83(s,1H(,4.06(s,3H(,4.02(s,3H(,3.97–3.63(m,4H(,3.82(s,3H(,3.21–3.05(m,4H(,3.02(s,3H(.ESI-MS m/z:计算值445.2234,实测值445.2236[M+H]+。
实施例49
6-取代去氢骆驼蓬碱衍生物为化合物49,(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)(苯基)甲酮,其结构为:
本发明化合物49按照方案中路线3-1制备,合成方法参考实施例35,只是代替乙酸为苯甲酸,得到白色固体。1H NMR(400MHz,CDCl3(δ8.23(d,J=5.3Hz,1H(,7.67(d,J=5.3Hz,1H(,7.58(s,1H(,7.47–7.40(m,5H(,6.83(s,1H(,4.05(s,3H(,4.01(s,3H(,4.07–4.00(m,2H(,3.73–3.62(m,2H(,3.22–3.03(m,4H(,3.02(s,3H(.ESI-MS m/z:计算值415.2129,实测值415.2132[M+H]+。
实施例50
6-取代去氢骆驼蓬碱衍生物为化合物50,7-甲氧基-1,9-二甲基-6-(4-(苯基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物50按照方案中路线3-2制备。
将叔丁基-4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基(哌嗪-1-羧酸酯(3b)(150mg,0.37mmol)溶于二氯甲烷(5mL)后加入三氟乙酸(1mL),室温搅拌至原料反应完后,旋出二氯甲烷,得到浓缩物。然后二氯甲烷溶解浓缩物,用NEt3调节至碱性,浓缩得到7-甲氧基-1,9-二甲基-6-(哌嗪-1-基(-9H--吡啶并[3,4-b]吲哚(3c),黄色固体备用。
将上步所得的7-甲氧基-1,9-二甲基-6-(哌嗪-1-基(-9H--吡啶并[3,4-b]吲哚(4c)溶于二氯甲烷中,然后依次加入被苯磺酰氯(78mg,0.44mmol)、NEt3(103μL,0.74mmol),室温反应过夜后,加入水淬灭反应,用水洗3次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,浓缩后柱层析分离(二氯甲烷:甲醇=20:1)得到白色固体。1H NMR(400MHz,CDCl3(δ8.24(d,J=5.3Hz,1H(,7.84–7.78(m,2H(,7.70(d,J=5.3Hz,1H(,7.64–7.53(m,4H(,6.80(s,1H(,4.07(s,3H(,3.96(s,3H(,3.29–3.15(m,8H(,3.04(s,3H(.ESI-MS m/z:计算值451.1799,实测值451.1804[M+H]+。
实施例51
6-取代去氢骆驼蓬碱衍生物为化合物51,6-(4-(苄基磺酰基)哌嗪-1-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物51按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为苯甲磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.12(d,J=5.3Hz,1H(,7.88(d,J=5.3Hz,1H(,7.74(s,1H(,7.47–7.36(m,5H(,7.23(s,1H(,4.49(s,2H(,4.12(s,3H(,3.96(s,3H(,3.34–3.29(m,4H(,3.05–3.01(m,4H(,2.99(s,3H(.ESI-MS m/z:计算值465.1955,实测值465.1958[M+H]+。
实施例52
6-取代去氢骆驼蓬碱衍生物为化合物52,N-(4-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)苯基)乙酰胺,其结构为:
本发明化合物52按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为4-乙酰胺苯磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ10.44(s,1H(,8.10(d,J=5.3Hz,1H(,7.90–7.85(m,2H(,7.84(d,J=5.3Hz,1H(,7.74(s,1H(,7.75–7.70(m,3H(,7.18(s,1H(,4.10(s,3H(,3.88(s,3H(,3.09–2.97(m,8H(,2.97(s,3H(,2.11(s,3H(.ESI-MSm/z:计算值508.2013,实测值508.2018[M+H]+。
实施例53
6-取代去氢骆驼蓬碱衍生物为化合物53,7-甲氧基-1,9-二甲基-6-(4-(喹啉-8-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物53按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为喹啉-8-磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ9.12(dd,J=4.2,1.8Hz,1H(,8.56(dd,J=8.4,1.8Hz,1H(,8.42(dd,J=7.4,1.5Hz,1H(,8.34(dd,J=8.2,1.5Hz,1H(,8.08(d,J=5.2Hz,1H(,7.83(d,J=5.3Hz,1H(,7.80(dd,J=8.2,7.4Hz,1H(,7.72(dd,J=8.3,4.2Hz,1H(,7.69(s,1H(,7.17(s,1H(,4.09(s,3H(,3.87(s,3H(,3.48–3.44(m,4H(,3.04–3.00(m,4H(,2.97(s,3H(.ESI-MS m/z:计算值502.1908,实测值502.1899[M+H]+。
实施例54
6-取代去氢骆驼蓬碱衍生物为化合物54,7-甲氧基-1,9-二甲基-6-(4-((1-甲基-1H-吡唑-4-基)磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物54按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为1-甲基-1H-吡唑-4-磺酰氯,得到白色固体。1H NMR(400MHz,CDCl3(δ8.25(d,J=5.3Hz,1H(,7.77(d,J=1.7Hz,2H(,7.70(d,J=5.2Hz,1H(,7.58(s,1H(,6.82(s,1H(,4.09(s,3H(,3.99(s,3H(,3.97(s,3H(,3.25–3.18(m,8H(,3.05(s,3H(.ESI-MS m/z:计算值455.1860,实测值455.1860[M+H]+。
实施例55
6-取代去氢骆驼蓬碱衍生物为化合物55,7-甲氧基-1,9-二甲基-6-(4-(吡啶-3-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物55按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为吡啶-3-磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.98(dd,J=2.4,0.8Hz,1H(,8.95(dd,J=4.9,1.6Hz,1H(,8.26–8.21(m,1H(,8.10(d,J=5.3Hz,1H(,7.84(d,J=5.2Hz,1H(,7.77–7.74(m,1H(,7.72(s,1H(,7.19(s,1H(,4.10(s,3H(,3.89(s,3H(,3.15–3.06m,8H(,2.97(s,3H(.ESI-MS m/z:计算值452.1751,实测值452.1750[M+H]+。
实施例56
6-取代去氢骆驼蓬碱衍生物为化合物56,7-甲氧基-1,9-二甲基-6-(4-(萘-2-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物56按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为萘-2-磺酰氯,得到白色固体。1H NMR(400MHz,CDCl3(δ8.36(s,1H(,8.23(d,J=5.3Hz,1H(,8.00–7.94(m,2H(,7.91(d,J=7.9Hz,1H(,7.79(dd,J=8.6,1.8Hz,1H(,7.70–7.57(m,3H(,7.54(s,1H(,6.76(s,1H(,4.02(s,3H(,3.91(s,3H(,3.35–3.13(m,8H(,3.01(s,3H(.ESI-MS m/z:计算值501.1955,实测值501.1952[M+H]+。
实施例57
6-取代去氢骆驼蓬碱衍生物为化合物57,7-甲氧基-1,9-二甲基-6-(4-(噻吩-2-基磺酰基)哌嗪-1-基)-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物57按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为噻吩-2-磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.12(dd,J=5.0,1.3Hz,1H(,8.10(d,J=5.3Hz,1H(,7.84(d,J=5.3Hz,1H(,7.74–7.71(m,2H(,7.35(dd,J=5.0,3.7Hz,1H(,7.20(s,1H(,4.11(s,3H(,3.90(s,3H(,3.13–3.08(m,8H(,2.98(s,3H(.ESI-MSm/z:计算值457.1363,实测值457.1361[M+H]+。
实施例58
6-取代去氢骆驼蓬碱衍生物为化合物58,4-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)-3,5-二甲基异恶唑,其结构为:
本发明化合物58按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为3,5-二甲基异恶唑-4-磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.10(d,J=5.2Hz,1H(,7.84(d,J=5.2Hz,1H(,7.74(s,1H(,7.20(s,1H(,4.10(s,3H(,3.92(s,3H(,3.24–3.20(m,4H(,3.12–3.07(m,4H(,2.97(s,3H(,2.67(s,3H(,2.38(s,3H(.ESI-MS m/z:计算值470.1857,实测值470.1856[M+H]+。
实施例59
6-取代去氢骆驼蓬碱衍生物为化合物59,4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)-N,N-二甲基哌嗪-1-磺酰胺,其结构为:
本发明化合物59按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为二甲基氨磺酰氯,得到白色固体。1H NMR(400MHz,CDCl3(δ8.20(d,J=5.3Hz,1H(,7.66(d,J=5.3Hz,1H(,7.56(s,1H(,6.81(s,1H(,4.03(s,3H(,4.00(s,3H(,3.53–3.44(m,4H(,3.18–3.10(m,4H(,3.00(s,3H(,2.87(s,6H(.ESI-MS m/z:计算值418.1908,实测值418.1906[M+H]+。
实施例60
6-取代去氢骆驼蓬碱衍生物为化合物60,N-(5-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)-4-甲基噻唑-2-基)乙酰胺,其结构为:
本发明化合物60按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为2-乙酰胺基-4-甲基噻唑-5-磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.10(d,J=5.3Hz,1H(,7.84(d,J=5.2Hz,1H(,7.73(s,1H(,7.19(s,1H(,4.10(s,3H(,3.91(s,3H(,3.23–3.08(m,8H(,2.97(s,3H(,2.54(s,3H(,2.19(s,3H(.ESI-MS m/z:计算值529.1686,实测值529.1682[M+H]+。
实施例61
6-取代去氢骆驼蓬碱衍生物为化合物61,6-(4-(乙基磺酰基)哌嗪-1-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物61按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为乙基磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.15(d,J=5.5Hz,1H(,7.98(d,J=5.5Hz,1H(,7.80(s,1H(,7.27(s,1H(,4.15(s,3H(,3.98(s,3H(,3.14(q,J=7.3Hz,2H(,3.10–3.06(m,4H(,3.03(s,3H(,1.26(t,J=7.3Hz,3H(.ESI-MS m/z:计算值403.1799,实测值403.1800[M+H]+。
实施例62
6-取代去氢骆驼蓬碱衍生物为化合物62,5-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)-N,N-二甲基萘-1-胺,其结构为:
本发明化合物62按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为5-(二甲氨基)萘-1-磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.55(d,J=8.5Hz,1H(,8.39(d,J=8.7Hz,1H(,8.19(dd,J=7.4,1.3Hz,1H(,8.13(d,J=5.6Hz,1H(,7.98(d,J=5.5Hz,1H(,7.74–7.62(m,3H(,7.28(d,J=7.6Hz,1H(,7.19(s,1H(,4.08(s,3H(,3.87(s,3H(,3.28–3.22(m,4H(,3.05–3.00(m,7H(,2.83(s,6H(.ESI-MS m/z:计算值544.2377,实测值544.2373[M+H]+。
实施例63
6-取代去氢骆驼蓬碱衍生物为化合物63,7-甲氧基-1,9-二甲基-6-(4-(丙基磺酰基)哌嗪-1-基)-9H吡啶[3,4-b]吲哚,其结构为:
本发明化合物63按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为丙基磺酰氯,得到白色固体。1H NMR(400MHz,DMSO-d6(δ8.10(d,J=5.2Hz,1H(,7.84(d,J=5.2Hz,1H(,7.73(s,1H(,7.21(s,1H(,4.10(s,3H(,3.96(s,3H(,3.36–3.32(m,4H(,3.10–3.05(m,6H(,2.97(s,3H(,1.78–1.69(m,2H(,1.02(t,J=7.4Hz,3H(.ESI-MS m/z:计算值417.1955,实测值417.1955[M+H]+。
实施例64
6-取代去氢骆驼蓬碱衍生物为化合物64,6-(4-(环丙基磺酰基)哌嗪-1-基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚,其结构为:
本发明化合物64按照方案中路线3-2制备,合成方法参考实施例50,只是代替苯磺酰氯为环丙烷磺酰氯,得到白色固体。1H NMR(400MHz,CDCl3(δ8.25(d,J=5.2Hz,1H(,7.71(d,J=5.0Hz,1H(,7.60(s,1H(,6.85(s,1H(,4.10(s,3H(,4.04(s,3H(,3.59–3.53(m,4H(,3.24–3.17(m,4H(,3.05(s,3H(,2.36–2.29(m,1H(,1.25–1.20(m,2H(,1.05–0.99(m,2H(.ESI-MS m/z:计算值415.1799,实测值415.1798[M+H]+。
测试例1癌细胞增殖抑制活性测试
下面的体外筛选试验是用来测定本发明化合物对于肿瘤生长半抑制浓度的大小。
MTS法检测细胞活性原理:
MTS为一种全新的MTT类似物,全称为3-(4,5-dimethylthiazol-2-yl(-5(3-carboxymethoxyphenyl(-2-(4-sulfopheny(-2H-tetrazolium,是一种黄颜色的染料。活细胞线粒体中琥珀酸脱氢酶能够代谢还原MTS,生成可溶性的甲臜(Formazan)化合物,甲臜的含量可以用酶标仪在490nm处进行测定。在通常情况下,甲臜生成量与活细胞数成正比,因此可根据光密度OD值推测出活细胞的数目。
实验方法:
1.接种细胞:用含10%胎牛血清的培养液(DMEM或者RMPI1640)配成单个细胞悬液,以每孔3000~15000个细胞接种到96孔板,每孔体积100μl,细胞提前12~24小时接种培养。
2.加入待测化合物溶液:化合物用DMSO溶解,化合物以100μM、20μM、4μM、0.8μM、0.16μM、0.032μM浓度复筛,每孔终体积200μl,每种处理均设3个复孔。
3.显色:37摄氏度培养48小时后,贴壁细胞弃孔内培养液,每孔加MTS溶液20μl和培养液100μl;悬浮细胞弃100μl培养上清液,每孔加20μl的MTS溶液;设3个空白复孔(MTS溶液20μl和培养液100μl的混合液),继续孵育2~4小时,使反应充分进行后测定光吸收值。
4.比色:选择492nm波长,多功能酶标仪(MULTISKAN FC)读取各孔光吸收值,记录结果,数据处理后以浓度为横坐标,细胞存活率为纵坐标绘制细胞生长曲线,应用两点法(Reed and Muench法)计算化合物的IC50值。
5.阳性对照化合物:每次实验均设顺铂(DDP)和紫杉醇(Taxol)两个阳性化合物,以浓度为横坐标,细胞存活率为纵坐标绘制细胞生长曲线,应用两点法(Reed and Muench法)计算化合物的IC50值。
部分化合物活性测试如下表1所示:
测试例2诱导癌细胞凋亡活性
下面的诱导凋亡试验是用来测定本发明的示例化合物62对于HL-60白血病细胞的影响。
检测原理:
FITC Annexin V/PI的双染法双标法染色的原理:用标记了荧光素的FITCAnnexin V作为荧光探针,利用流式细胞仪检测细胞凋亡的发生。PI具有高DNA结合常数,并且被完整细胞有效排除。正常细胞的细胞膜是完整的,PI是核酸染料,不能透过完整的细胞膜(FITC Annexin V阴性,PI阴性)。早期细胞凋亡中,PS外翻暴露于细胞表面,但是细胞膜保持完整性,这些细胞可以被FITC Annexin V染色,从而区分早期凋亡中的细胞(FITCAnnexin V阳性,PI阴性)。在晚期细胞凋亡中,细胞膜丧失完整性,从而允许PI进入并与DNA结合,同时允许FITC Annexin V与细胞膜上的PS结合(FITC Annexin V阳性,PI阳性)。
实验方法:
1.取对数生长期的细胞HL-60(白血病细胞(,以每孔3*105个细胞接种到6孔板,每孔体积2mL,细胞提前24h接种培养。
2.化合物用DMSO溶解,24h后加入化合物,化合物终浓度分别为(0.1μΜ、1μΜ、5μΜ)。
3.24h后收集细胞,300g离心5min,弃上清,用预冷的PBS重悬,300g离心洗涤2次。
4.加入100μL 1×Binding Buffer轻轻重悬细胞。
5.单染管分别加入5μL FITC Annexin V和5μL PI,样本管加入5μL FITCAnnexinV和5μL PI,轻轻混匀,室温避光孵育15min。
6.在1h内进行流式细胞仪检测,检测时,用空白管调节FSC、SSC和荧光通道的电压,并在此电压条件下,用单染管调节荧光通道的补偿并依次收集实验组的数据。
实验结果表明,在1μM、5μM浓度下,化合物62对HL-60(白血病细胞(有明显的促凋亡作用。
图1和图2均展示了化合物62对白血病HL-60细胞的诱导凋亡影响。其中图1为HL-60细胞与不同浓度的化合物62(0.1,1,5μM)进行孵育24h,然后用Annexin V-FITC/PI染色,并用流式细胞仪进行凋亡分析。图1的各象限分别表示:
Q1:机械损伤,坏死细胞等(FITC Annexin V阴性,PI阳性)
Q2:凋亡晚期(FITC Annexin V阳性,PI阳性)
Q3:凋亡早期(FITC Annexin V阳性,PI阴性)
Q4:活细胞(FITC Annexin V阴性,PI阴性)
图2直方图中为细胞分布百分比。Control=DMSO(0.1%(。
由表1可知,本发明的6-取代去氢骆驼蓬碱衍生物对白血病细胞HL-60、肺癌细胞A549、肝癌细胞SMMC-7721、乳腺癌细胞MCF-7和结肠癌细胞SW480等癌细胞表现出较强的抑制活性;由图1和图2可知,本发明的示例化合物之一,化合物62能够明显的诱导HL-60癌细胞凋亡,具有优良的应用前景等优点。
与原始化合物去氢骆驼蓬碱(harmine)相比,抑制癌细胞生长活性明显更好。说明本发明提出的新的化合物,与初始化合物相比,抗肿瘤细胞增殖活性得到明显提升。
以上所述的仅是本发明的优选实例。应当指出对于本领域的普通技术人员来说,在本发明所提供的技术启示下,作为本领域的公知常识,还可以做出其它等同变型和改进,也应视为本发明的保护范围。
Claims (5)
1.一种6-取代去氢骆驼蓬碱衍生物,其结构如式(I)所示:
其中,R为呋喃基、吡唑基、喹啉基、异喹啉基、呋喃甲胺基、噻吩甲胺基中的一种;
或R为
其中,R1为噻吩基、吡唑基中的一种;
或R为
其中,R3为苯基、萘基中的一种。
2.一种6-取代去氢骆驼蓬碱衍生物,其特征在于,所述6-取代去氢骆驼蓬碱衍生物为以下中的一种:
7-甲氧基-1,9-二甲基-6-(1-甲基-1H-吡唑-4-基)-9H-吡啶并[3,4-b]吲哚;
3-(二氟甲基)-N-(4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)苯基)-1-甲基-1H-吡唑-4-甲酰胺;
N-(4-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)苯基)乙酰胺;
5-((4-(7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-6-基)哌嗪-1-基)磺酰基)-N,N-二甲基萘-1-胺。
3.根据权利要求1或2所述的6-取代去氢骆驼蓬碱衍生物的合成方法,其特征在于,所述合成方法包括:以去氢骆驼蓬碱为原料,先在去氢骆驼蓬碱N-9位进行烷基化,再在6号位进行卤代;最后再通过偶联反应在去氢骆驼蓬碱6号位引入芳基或胺基。
4.根据权利要求1或2所述的6-取代去氢骆驼蓬碱衍生物或根据权利要求3的方法合成的6-取代去氢骆驼蓬碱衍生物的应用,其特征在于,应用于制备抗肿瘤药物;所述肿瘤为肺癌、乳腺癌、肝癌、结肠癌或白血病中的一种或多种。
5.根据权利要求4所述的应用,其特征在于,所述肿瘤的肿瘤细胞为白血病细胞HL-60、肺癌细胞A549、肝癌细胞SMMC-7721、乳腺癌细胞MCF-7和结肠癌细胞SW480。
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