CN116655635A - 黑茶茶碱衍生物及在制备药物中的应用 - Google Patents
黑茶茶碱衍生物及在制备药物中的应用 Download PDFInfo
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- CN116655635A CN116655635A CN202310570718.3A CN202310570718A CN116655635A CN 116655635 A CN116655635 A CN 116655635A CN 202310570718 A CN202310570718 A CN 202310570718A CN 116655635 A CN116655635 A CN 116655635A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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Abstract
本发明公开了一种黑茶茶碱衍生物及在在制备药物中的应用,所述黑茶茶碱衍生物具有式(I)结构,其制备方法为茶碱乙酸与苯胺衍生物发生酰胺化反应得到。本发明黑茶茶碱衍生物具有更好的抗肿瘤疗效,体外细胞活性抑制测试表明,本发明的黑茶茶碱衍生物具有优异的抗肿瘤活性、毒副作用低,能制备成抗肿瘤药物应用于临床抗肿瘤治疗,对抗肿瘤活性药物的研究具有重要意义。
Description
技术领域
本发明属于药物合成领域,涉及黑茶茶碱衍生物及在制备药物中的应用。
背景技术
黑茶为六大茶类之一,属于后发酵茶,黑茶主要分布在南方地区,其中主要以安化黑茶最为出名,黑茶含有的成分丰富,其中主要以茶多酚、茶碱、茶色素以及他汀类化合物为主,在众多茶类中黑茶含有的茶碱衍生物及其丰富。
恶性肿瘤(Cancer)是一组严重威胁人类健康的疾病,由100多种不同部位肿瘤组成。近年来,恶性肿瘤的总体发病情况在世界各国多呈上升趋势,但其中个别癌种在部分国家和人群中有所下降。受生活环境、方式的变化和生存压力的增大等各种客观因素的影响,恶性肿瘤的发病率不断上升,预计将取代心血管疾病成为全球第一大死亡原因,成为严重威胁人们生命健康的疾病。根据中国医学科学院北京协和医院国家癌症中心专家团队在权威期刊上公布的数据显示,我国的癌症状况正在发生转变,癌症的发病率更高。在我国,最常见的癌症是肺癌,而在美国则是乳腺癌。但是不论是在中国还是美国,肺癌都是主要的癌症死亡原因。肿瘤治疗是一个世界性的难题,目前治疗手段主要以外科手术、化疗和放疗为主。化疗是肿瘤治疗最广泛使用的方法,但具有不良反应大、易产生耐药性等缺点,因此设计一种安全、有效、副作用小的肿瘤药物具有很好的应用前景。
茶碱(Theophylline),是一种有机化合物,化学式为C7H8N4O2,可使平滑肌张力降低,呼吸道扩张;可促进内源性肾上腺素、去甲肾上腺素的释放,气道平滑肌松弛;抑制钙离子由平滑肌内质网释放,降低细胞内钙离子浓度而产生呼吸道扩张作用。茶碱对平滑肌的松弛作用较强,但不及β受体激动剂。茶碱属于嘌呤类化合物,因其结构稳定性强并含有多个氢键供体和受体原子,存在与保守氨基酸形成氢键相互作用的可能性。黑茶茶碱衍生物因其生物效应而被广泛研究。它们代表了一类重要的治疗药物,具有多种生物活性,如抗肿瘤活性、抗微生物、抗炎、中枢神经系统兴奋剂、腺苷受体拮抗、磷酸二酯酶(PDE)抑制、平喘镇咳、免疫调节和降血糖活性。此外,对改善窒息新生儿肾功能和慢性支气管、慢性阻塞性肺疾病也有显著的治疗作用。
茶碱与卡氮芥或环磷酰胺合并用药,通过提高环磷腺苷可产生协同的抗肿瘤作用。茶碱和咖啡因可以增强阿霉素对肿瘤细胞的毒性。当茶碱与吉西他滨或顺铂联合使用时,发现茶碱在多种人类癌细胞系和恶性转化的颗粒细胞系中诱导细胞程序性死亡。黑茶茶碱衍生物二羟丙茶碱联合吗啡对肺癌呼吸困难患者进行联合治疗,可以有效改善患者的呼吸困难程度,提高治疗效果,是常用的临床呼吸困难缓解药物。此外,采用多索茶碱治疗肺癌呼吸困难是一种有效、安全的方法,可显著改善患者肺功能,减轻临床症状,降低不良反应发生率,有较好临床推广价值。
发明内容
为解决现有技术存在的问题,提供一种对于肿瘤药物治疗安全有效的方法,本发明的目的之一是提供一类具有抗肿瘤活性的黑茶茶碱衍生物;本发明的目的之二是提供一种制备和纯化上述黑茶茶碱衍生物的方法;本发明的目的之三是将上述黑茶茶碱衍生物应用于制备成临床用抗肿瘤药物;本发明上述目的是通过以下技术方案来实现的:
具有抗肿瘤活性黑茶茶碱衍生物,其结构式为式(I)所示:
其中R基团为: 中的一种。
本发明目的之二是提供一种制备上述式化合物(I)的方法,该方法包括:由茶碱乙酸和苯胺衍生物在溶剂中,缩合剂作用下发生酰胺化反应得到,反应结束后降至设定温度,加入水,搅拌析晶,过滤得到粗产品,粗产品经过混合溶剂重结晶得到纯品黑茶茶碱衍生物(I)。
上述步骤中,所述缩合剂为EDCI,HATU,DCC,DIC,COMU,CDI,PyBOP中的一种,优选为EDCI;所述反应溶剂为DMF,DMAC,DMSO中的一种,优选为DMF,加入质量为茶碱乙酸的5倍;所述茶碱乙酸与苯胺衍生物的摩尔比为1:1.05-1.1;所述设定温度为0-5℃,加入水的量为反应溶剂量的5倍;所述重结晶混合溶剂为乙醇和水,体积比优选为7:3。
本发明通过把茶碱乙酸和其他苯胺衍生物活性基团连接起来,得到了一系列结构新颖的化合物(I),该类化合物具有优异的抗肿瘤性能,能够较好地应用于药物中,并且该类化合物制备过程中工艺简单,产物收率高,纯度好。
本发明提供的通式(I)的化合物或其药学上可接受的盐,溶剂化物和水合物可以与药学上可以接受的载体或稀释剂联合应用组成药物制剂。药学上可接受的适当的载体包括惰性固体填充剂或稀释剂和无菌水溶液或有机溶液。
本发明所述的通式(I)的化合物或其药学上可接受的盐在发挥制备治疗肿瘤疾病药物的用途作用时,通式(I)的化合物或其药学上可接受的盐在制备的制剂中的用量为0.1mg-1000mg之间,优选为5-200mg,更优选的为5mg、15mg和20mg。
本发明提供的化合物可与适当的固体或液体载体或稀释剂组合形成胶囊、片剂、丸剂、散剂、糖浆剂、溶液剂等,在制剂中含有0.1-90的活性成分,其他为药学上可接受的辅料,其中辅料包含填充剂、崩解剂、润滑剂、稀释剂、崩解剂、赋形剂以及矫味剂中的一种或多种。
本发明还提供一种药物组合物,该药物组合物含有通式(I)的黑茶茶碱衍生物或其药学上可接受的盐,以及一种或多种药填充剂、崩解剂。
本发明的有益效果:
(1)本发明提供的黑茶茶碱衍生物制备方法简单,反应收率高,并且所得产物纯度高,适合大规模化工业化生产。
(2)实验证明本发明提供的黑茶茶碱衍生物或其药学上可接受的盐能够有效抑制癌症细胞,尤其对肺癌细胞的作用显著,在降低细胞内抗凋亡介质Bcl-2的水平,增强对癌症细胞的凋亡作用上效果显著。
附图说明
图1为实施例1所得黑茶茶碱衍生物对于A549的活死实验结果图。
具体实施方式
下面通过实施例来进一步说明本发明。应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
本实施例中核磁数据使用四甲基硅烷作为内标,在DMSO-d6中在Bruker AV 600上测量1H NMR和13C NMR光谱。在Varian QFT-ESI上测量HRMS数据。
一:化合物的制备
具有通式(I)结构的黑茶茶碱衍生物(I)的制备
其中通式(I)结构式为:
其中R为:
上述黑茶茶碱衍生物(I)由茶碱乙酸和苯胺衍生物在溶剂中,缩合剂作用下发生酰胺化反应得到,反应结束后降至设定温度,加入水,搅拌析晶,过滤得到粗产品,粗产品经过混合溶剂重结晶得到纯品黑茶茶碱衍生物(I),其中缩合剂为EDCI,HATU,DCC,DIC,COMU,CDI,PyBOP中的一种;所述反应溶剂为DMF,DMAC,DMSO中的一种,反应溶剂质量为茶碱乙酸的5倍;所述茶碱乙酸与苯胺衍生物的摩尔比为1:1.05-1.1;所述设定温度为0-5℃,加入水的量为反应溶剂量的5倍;所述重结晶混合溶剂为乙醇和水。
实施例1:2-(1,3-二甲基-2,6-二氧代-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(4-(二甲基氨基)-3-氟苯基)乙酰胺的制备
具体的,以代替通式(I)结构式的R,得到
该化合物的具体制备步骤为:
茶碱乙酸,二甲胺,3,4-二氟硝基苯,HATU,三乙胺购买自安耐吉,N,N-二甲基甲酰胺购买自国药集团化学试剂有限公司。
将3,4-二氟硝基苯(10mmol)加入二甲胺(11mmol)和三乙胺(11mmol)在四氢呋喃(20mL)中的溶液,并将混合物在20℃下搅拌过夜。蒸干溶剂浓缩反应,将黄色溶液浓缩并再溶于100毫升乙酸乙酯中,然后用饱和碳酸氢钠溶液50mL洗涤。将有机相干燥用无水硫酸镁干燥并浓缩,柱层析(石油醚:乙酸乙酯=8:1)得到2-氟-N,N-二甲基-4-硝基苯胺1.6g,产率。272的数据:1HNMR(400MHz,CDC13):7.96(dd,J=2.8Hz,1H),7.88(dd,J=3.2Hz,1H),6.73(t,J=8.8Hz,1H),3.10(s,6H)。
25℃下,将2-氟-N,N-二甲基-4-硝基苯胺(8mmol)溶于50mL无水乙醇中,加入0.3g新鲜制备的雷尼镍催化剂,氢气氛围下反应6h,硅藻土过滤除去催化剂,有机相蒸干得到产物2-氟-N1,N1-二甲基苯-1,4-二胺1.2g,产率98%。1H NMR(400MHz,DMSO-d6):6.82(t,J=12Hz,1H),6.46-6.37(m,2H),4.65(s,2H)2.73(s,6H).
将1g(0.0042mol)茶碱乙酸缓慢加入到5gDMF中,向体系中加入0.712g(0.00462mol)上述步骤得到的2-氟-N1,N1-二甲基苯-1,4-二胺,同时加入EDCI,进行反应,反应结束后将体系温度调节至3℃,加入DMF体积5倍量的水,搅拌体系析晶,过滤得粗产品,粗产品经过乙醇/水(体积比为7:3)的混合溶液重结晶得到2-(1,3-二甲基-2,6-二氧代-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(4-(二甲基氨基)-3-氟苯基)乙酰胺,产率95.2%,产品纯度99.2%。1H NMR(600MHz,DMSO-d6)δ=10.04(s,1H),8.06(s,1H),7.08(t,J=12Hz,1H),6.98-6.77(m,2H),5.13(s,2H),3.45(s,3H),3.20(s,3H),2.80(s,6H)。
本发明采用的苯胺衍生物可以是自制,也可以通过购买途径得到,其中当R为时,对应的苯胺衍生物为,/>得到化合物为:
依次类推,分别得到本发明要求保护的各黑茶茶碱衍生物。具体所得化合物编号以及结构式如下:
表1化合物编号及其结构式
对比实施例1
将1g(0.0042mol)茶碱乙酸缓慢加入到5gDMF中,向体系中加入0.841g(0.00546mol)上述步骤得到的2-氟-N1,N1-二甲基苯-1,4-二胺,同时加入EDCI,进行反应,反应结束后将体系温度调节至3℃,加入DMF,搅拌体系析晶,过滤得粗产品,粗产品经过乙醇/水的混合溶液重结晶得到2-(1,3-二甲基-2,6-二氧代-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(4-(二甲基氨基)-3-氟苯基)乙酰胺,产率78.5%,产品纯度92.7%。
对比实施例2
取实施例1所得粗产品,粗产品经过乙醇/水(体积比为5:5)的混合溶液重结晶得到2-(1,3-二甲基-2,6-二氧代-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(4-(二甲基氨基)-3-氟苯基)乙酰胺,产率82.8%,产品纯度95.2%。
二:细胞实验
RPMI-1640培养基、DMEM、FBS、胰蛋白酶和PBS购自Gibco(美国)。CCK-8购自Abmole(美国)。细胞来自ATCC China(中国细胞资源库)
实施例1:
(1)细胞复苏
小皿:在融化开的细胞液中加入3mL培养液;贴壁后中间换液,吸出皿内液体,加入4mL培养液;
(2)细胞传代
取出小皿细胞,将皿中4mL培养液吸出弃掉,加入PBS缓冲液1mL,接着吸出弃掉,加1mL胰酶液消化1-2min(此等待过程中,可拿1个新的大皿加入7mL培养液备用),吸出弃掉,加入1mL培养液,洗下贴壁细胞后,吹打使悬浮,转移至已加入培养液的新皿中,稍晃均匀,可在显微镜下观察,放入培养箱。
取出大皿细胞,将皿中8mL培养液吸出弃掉,加入PBS缓冲液3mL,接着吸出弃掉,加入2mL胰酶液消化1-2min(此等待过程中,可拿3个新皿各加入7mL培养液备用),吸出弃掉,加入3mL培养液,洗下贴壁细胞后,吹打使其悬浮,转移至已加入培养液的新皿中,每个转移1mL,稍晃均匀,可在显微镜下观察,放入培养箱。
(3)铺96孔板
取传代好的1皿细胞,用细胞计数器计数(一般为25×105个),取适量至加样稀释槽中,加入培养液稀释至2~5×105个,用移液排枪吸取100加入96孔板每孔中,其中第二行不加作为空白,周围一圈的孔加入后防止边缘效应,后期不加药。每个96孔板需要用液体10mL。
(4)加药
依次取化合物编号为1、3、5、7、9的样品5mg,分别加到5mL离心管中,放入密封袋,置细胞房内紫外箱中灭菌(20min),根据取样量及分子量,按照下列公式,以培养液(非水溶性样品,先以30~50μl DMSO溶解后,再加培养液)配置成2mmol/L母液,备用;取100μl母液,置5mL离心管中,加入1.9mL培养液,配置成100μmol/L样品液,取500μl置2mL管中,加500μl培养液,配置成50μmol/L样品液,依次稀释配置成25、12.5、6.25、3.125、1.5625μmol/L样品液,阴性对照为2μlDMSO+2mL培养液;配好样品溶液后,取出96孔板,将4~11行液体吸出弃掉,依次加入上述样品溶液及阴性溶液各100μl,每个浓度溶液加3~6个孔。
(5)CCK-8检验
取CCK-8溶液与培养液按1:9比例进行混合,配制成检测液,备用(每2个板配15mL检测液);将4~11行液体吸出弃掉,用移液排枪加CCK-8检测液100μl至第2行和4~11行中(第三行及周围一圈不动),待2小时后酶标仪测吸光度,分别计算化合物编号为1、3、5、7、9的化合物IC50值。
表2实施例所得黑茶茶碱衍生物对癌细胞IC50值
实施例1所得黑茶茶碱衍生物化2-(1,3-二甲基-2,6-二氧代-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(4-(二甲基氨基)-3-氟苯基)乙酰胺对于A549的活死实验。
操作:
将细胞暴露于化合物中48小时,并用LIVE/DEAD试剂盒染色。NC为阴性对照,DMSO为溶剂,具体实验结果见图1
三、制剂实施例
处方量称取黑茶茶碱衍生物超微粉碎成直径小于10μm的微粉,备用。将上述备用混合物料与处方量填充剂、崩解剂混合均匀后,置于干法制粒机中造粒。然后再加入处方量的润滑剂混合均匀,压制成片。
上述虽然对本发明的具体实施方式进行了描述,但并非对本发明保护范围的限制,所属领域技术人员应该明白,在本发明的技术方案的基础上,本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。
Claims (7)
1.一种具有通式(I)所述的黑茶茶碱衍生物或其药学上可接受的盐,其特征在于,通式(I)结构式为:
其中R为:
2.根据权利要求1中所述的具有通式(I)所述的黑茶茶碱衍生物,其特征在于,所述黑茶茶碱衍生物(I)由茶碱乙酸和苯胺衍生物在溶剂中,缩合剂作用下发生酰胺化反应得到,反应结束后降至设定温度,加入水,搅拌析晶,过滤得到粗产品,粗产品经过混合溶剂重结晶得到纯品黑茶茶碱衍生物(I)。
3.根据权利要求2中所述的具有通式(I)所述的黑茶茶碱衍生物的制备方法,其特征在于,所述缩合剂为EDCI,HATU,DCC,DIC,COMU,CDI,PyBOP中的一种;所述反应溶剂为DMF,DMAC,DMSO中的一种。
4.根据权利要求3中所述的具有通式(I)所述的黑茶茶碱衍生物的制备方法,其特征在于,所述反应溶剂质量为茶碱乙酸的5倍;所述茶碱乙酸与苯胺衍生物的摩尔比为1:1.05-1.1;所述设定温度为0-5℃,加入水的量为反应溶剂量的5倍;所述重结晶混合溶剂为乙醇和水。
5.权利要求1-2任意一项的所述的通式(I)的黑茶茶碱衍生物或其药学上可接受的盐在制备治疗肿瘤疾病药物中的用途。
6.根据权利要求5所述用途,其特征在于,所述肿瘤疾病为乳腺癌、卵巢癌、宫颈癌、前列腺癌、结肠癌、支气管癌、肺癌。
7.一种药物组合物,其包含权利要求1-2任意一项的所述的通式(I)的黑茶茶碱衍生物或其药学上可接受的盐,以及一种或多种药填充剂、崩解剂。
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