CN111170962A - 4-(苯并硒唑-2-基)芳胺类化合物治疗肠癌的用途 - Google Patents
4-(苯并硒唑-2-基)芳胺类化合物治疗肠癌的用途 Download PDFInfo
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- CN111170962A CN111170962A CN201811342014.6A CN201811342014A CN111170962A CN 111170962 A CN111170962 A CN 111170962A CN 201811342014 A CN201811342014 A CN 201811342014A CN 111170962 A CN111170962 A CN 111170962A
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Abstract
本发明公开了一类4‑(苯并硒唑‑2‑基)芳胺类化合物治疗肠癌的用途,其为通式(I)所示的化合物或其药学上可接受的盐。本发明发现了4‑(苯并硒唑‑2‑基)芳胺类化合物在疾病冶疗方面的一种新的用途,为肠癌的治疗提供了一种潜在的药品。
Description
技术领域
本发明属于药物化学领域,具体涉及一类4-(苯并硒唑-2-基)芳胺类化合物在治疗肠癌方面的用途。
背景技术
结直肠癌是消化系统最常见的恶性肿瘤其全球发病率在恶性肿瘤中位居男性第3位和女性第2位(Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012.CA A Cancer Journal for Clinicians,2015,65(2):87-108)。据2012年统计数据,全球共有约140万例新增结直肠癌病例,以及693,900例结直肠癌死亡病例。发病率最高的区域在澳大利亚和新西兰,欧洲与北美也是高发区(Torre LA,Siegel RL,Ward EM,etal.Global Cancer Incidence and Mortality Rates and Trends-an Update.CancerEpidemiology and Prevention Biomarkers,2016,25(1):16-27)。结肠癌在美国是第三大常见癌症,每年新增确诊结肠癌病例高达130,000人(Birt DF,Phillips GJ.Diet,Genes,and Microbes:Complexities of Colon Cancer Prevention.Toxicologic Pathology,2014,42:182-188)。由于结肠癌早期诊断率很低,绝大多数患者确诊时已是中晚期,给根治性手术带来难度,其5年生存率仅为50%-60%(王正康.结肠癌根治术的合理切除范围.国外医学外科学分册,1989,(1):9-10)。
结肠癌发病的高危因素包括以下几个方面。1.饮食因素:高脂高蛋白饮食、缺少蔬菜水果谷物纤维素、钙硒等微量元素摄入不足(Terry P,Giovannuci E.Michels KB,etal.Fruit,Vegetables,Dietary fiber,and Risk of Colorectal Cancer.Journal ofthe National Cancer Institute,2001,93:525)。2.疾病因素:下消化道疾病史、胆囊切除术、阑尾炎、高甘油三酯症(Masafumi T,Joji K,Hirokazu N.Hypertriglyceridemia isPositively Correlated with the Development of Colorectal Tubular Adenoma inJapanese Men.World Journal of Gastroenterology,2006,12(8):1261-1264)等。3.生活方式及其他因素:肥胖与缺少体力锻炼、便秘、遗传等。
结肠癌以手术切除肿瘤为首选治疗手段,辅助以化疗、放疗、靶向治疗和基因治疗等手段。结肠全系膜切除术是手术治疗结肠癌的最主要方法,但有25%的结肠癌患者确诊时已属于中晚期,并且由于结肠癌具有高复发和远端转移的生物学特性,有超过25%的患者在第一次手术后仍将出现复发或转移(王光林,孟泽松,王飞飞等.局部晚期结肠癌术前化疗的研究进展.肿瘤,2018,38:716-722)。且手术治疗仅适用于部分或早期的患者,因为大量的患者已存在更恶性的不可切除的转移,所以选择全身治疗(化疗和靶向治疗)或许可延长患者的整体生存期。
而结肠癌化疗国际上公认的一线方案是5-氟尿嘧啶联合奥沙利铂,或卡培他滨联合奥沙利铂(Andre T,Boni C,Mounedji L,et al.Oxaliplatin,Fluorouracil,andLeucovorin as Adjuvant Treatment for Colon Cancer.New England Journal ofMedicine,2004,350(23):2343-2351;Schmoll HJ,Tabernero J,Maroun J,etal.Capecitabine plus Oxaliplatin Compared with Fluorouracil/Folinic Acid asAdjuvant Therapy for Stage III Colon Cancer:Final Results of theNO16968Randomized Controlled Phase III Trial.Journal of Clinical Oncology,2015,33(32):3733-3740)。肿瘤化疗中的多重药物耐药是导致化疗失败的主要原因,结肠癌癌变组织由于其抗癌药物耐药相关的载体蛋白(如P糖蛋白、多药耐药相关蛋白或乳腺癌耐药蛋白)的过表达(Herraez E,Gonzalez SE,Vaquero J,et al.Cisplatin InducedChemoresistance in Colon Cancer Cells Involves FXR-Dependent and FXR-Independent Up-regulation of ABC Proteins.Molecular Pharmaceutics,2012.9(9):2565-2576),使得结肠癌细胞内的抗癌药物被迅速外排,浓度过低,从而导致化疗的失败。
如今结肠癌的靶向治疗备受关注。但结肠癌是一种高度异质性、分子分型复杂的疾病。目前临床上传统的靶向治疗主要是针对血管内皮生长因子受体(VEGF)和表皮生长因子受体(EGFR),但抗VEGF药物对中晚期结肠癌没有明显作用(Hurwitz HI,LymanGH.Registries and Randomized Trials in Assessing the Effects of Bevacizumabin colorectal cancer:is there a common theme?.Journal of ClinicalOncology.2012,30(6):580-581),且会增加老年患者动脉血管事件的发生率(Ranpura V,Hapani S,Wu S.Treatment-related Mortality with Bevacizumab in CancerPatients:a Meta-analysis.JAMA,2011,305(5):487-494);而抗EGFR药物对于RAS突变型的结肠癌患者是无效的(Vale CL,Tierney JF,Fisher D,et al.Does Anti-EGFR TherapyImprove Outcome in Advanced Colorectal Cancer?A Systematic Review and Meta-analysis.Cancer Treatment Reviews,2012,38(6):618-625)。结肠癌的全基因组研究显示,肿瘤基因突变数量非常高,每个肿瘤平均有75个左右的突变,这表明针对特定分子异常的癌症治疗可能仅在很小一部分结肠癌患者中有效。目前尚无开发出可用于临床治疗的生物标志物,仅依靠微卫星不稳定性(MSI)、RAS突变和BRAF突变这三类标志物用以评估临床诊疗的决策或判断治疗的预后情况(Guinney J,Dienstmann R,Wang X,et al.TheConsensus Molecular Subtypes of Colorectal Cancer.Nat Med.2015,21:1350-1356;Hutchins G1,Southward K,Handley K,et al.Value of Mismatch Repair,KRAS,andBRAF Mutations in Predicting Recurrence and Benefits from Chemotherapy inColorectal Cancer.Journal of Clinical Oncology.2011,29:1261-1270)。
由于世界范围内的结肠癌发病率和死亡率均处于较高水平,已严重危害人们的健康,给家庭和社会造成了沉重的负担,但由于结肠癌具有高复发、远端转移以及高度异质性的生物学特点,因此目前临床现有的治疗手段十分匮乏,无法显著地增加结肠癌患者的临床获益,急需研制新型的治疗方法或药物以应对结肠癌发病率和死亡率日益增长的现状。
含硒药物由于它在抗肿瘤、抗病毒以及治疗神经系统相关疾病等方面的应用(Reeves MA,Hoffmann PR.The human Selenoproteome:Recent Insights intoFunctions and Regulation.Cellular and Molecular Life Sciences,2009,66(15):2457-78),已成为国内外学者研发的热点,药物研究主要集中在抗肿瘤、抗炎和抗高血压等方面(Romualdo C,Stefania C,Marina DG,et al,Novel Selenium-containing Non-natural Diamino acids.Tetrahedron Lett.,2007,48(7):1425-1427)。
Malcolm F.G.Stevens和Tracey D.Bradshaw所申请的美国专利(MalcolmF.G.Stevens,Andrew D.Westwell,Mei-Sze Chua,et al.Substituted 2-arylbenzazolecompounds and their use as antitumour agents.US6858633B1)公布了下式(II)化合物,并指出了这类化合物在癌症方面的用途,但其说明书内容主要针对的是乳腺癌,由于不同癌症之间发病机理和治疗途径基本上并不相同,而且大部分抗癌化合物仅对某些敏感癌症具有治疗作用,因此该类化合物在其他癌症方面是否能起作用实际上仍然是未知的。
本专利发明人史东方已发表了关于苯并噻唑类化合物的合成及其体内外抗乳腺癌作用的文章(Dong-Fang Shi,Tracey D.Bradshaw,Samantha Wrigley,et al.AntitumorBenzothiazoles.3.Synthesis of 2-(4-Aminophenyl)benzothiazoles and Evaluationof Their Activities against Breast Cancer Cell Lines in Vitro and inVivo.Journal of Medicinal Chemistry,1996,39:3375-3384),同时,本专利发明人史东方所申请的中国专利(史东方,傅长金,承曦等.用于治疗或预防乳腺癌的化合物.CN201610299350.1)公布了如式(III)所示苯并硒唑-2-苯类化合物及其抗乳腺癌的药理活性。这两类化合物均对人乳腺癌细胞具有纳摩尔级别的抑制效果,其中苯并噻唑类化合物对ER+(MCF-7和BO细胞株)和ER-(MT-1和MT-3细胞株)的乳腺癌裸鼠移植瘤均表现出十分显著的抑瘤效果,但是这两类化合物对其他如前列腺癌、膀胱癌、黑色素瘤、肺癌、肝癌、食管癌等肿瘤细胞株并无抑制活性。
至今,未见有任何关于4-(苯并硒唑-2-基)芳胺类化合物对肠癌模型有作用的报道。
发明内容
本发明的目的是在现有技术的基础上,提供一类4-(苯并硒唑-2-基)芳胺类化合物在治疗肠癌方面的用途。
本发明的目的可以通过以下措施达到:
通式(I)所示的化合物或其药学上可接受的盐在制备治疗或预防肠癌药物方面的应用,
其中,
R1和R2分别独立地选自H、D、卤素、-CN、C1-3烷基、取代的C1-3烷基、C1-3烷氧基或取代的C1-3烷氧基;
R3选自H、卤素、-OH、-CN、-C(=O)NH2、取代的-C(=O)NH2、C1-3烷基、取代的C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基或取代的C1-3烷氧基;
R4选自H、D、卤素、-OH、-CN、-NH2、取代的-NH2、-C(=O)NH2、取代的-C(=O)NH2、C1-3烷基、取代的C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基或取代的C1-3烷氧基中的一种或两种;
n=1或2;
R5选自H、-CN、-OH、C1-3烷基、C1-3烷氧基或氨基酸残基;
Z选自CH或N;
R1、R2、R3或R4中的取代基选自D、卤素、OH、C1-3烷基或C1-3烷氧基。
在一种优选方案中,本发明中的R1和R2分别独立地选自H、D、卤素、-CN、C1-3烷基、取代的C1-3烷基、C1-3烷氧基或取代的C1-3烷氧基,所述取代基选自D、F或C1-3烷氧基;
在另一种优选方案中,本发明中的R1和R2分别独立地选自H、D、F、Cl、-CN、-CH3、-CF3、-OCF3或-OCHF2。
在另一种优选方案中,本发明中的R1选自D、F、Cl、-CN、-CH3或-CF3。
在另一种优选方案中,本发明中的R2选自H。
在一种优选方案中,本发明中的R3选自H、卤素、-CN、-C(=O)NH2、C1-2烷基、C2-3烯基、C2-3炔基、C1-3烷氧基或取代的C1-3烷氧基。
在另一种优选方案中,本发明中的R3选自H、F、Cl、Br、-CN、-C(=O)NH2、-CH3、-CH2CH3、-CF3、-CH=CH2、-C≡CH、-OCHF2或-OCF3。
在一种优选方案中,本发明中的R4选自H、D、卤素、-CN、C1-3烷基、取代的C1-3烷基、C1-3烷氧基或取代的C1-3烷氧基中的一种或两种。
在另一种优选方案中,本发明中的R4选自H、D、F、Cl、Br、I、-CN、-CH3、-CF3、-OCH3、-OCH2CH3、-OCHF2或-OCF3。
在一种优选方案中,本发明中的R5选自H、C1-3烷基、C1-3烷氧基或氨基酸残基。
在另一种优选方案中,本发明中的R5选自H、-CH3、-CF3、-OCH3或2,6-二氨基-己酰基。
在一种优选方案中,本发明中所涉及的化合物选自:
2-氨基-5-(5-氟苯并硒唑-2-基)苯甲腈,
2-氨基-3-氟-5-(5-氟苯并硒唑-2-基)苯甲腈,
2-乙炔基-4-(5-氟苯并硒唑-2-基)苯胺,
5-氟-4-(5-氟苯并硒唑-2-基)-2-甲基苯胺,
2-溴-6-(5-氟苯并硒唑-2-基)吡啶-3-氨,
3-氨基-6-(5-氟苯并硒唑-2-基)-2-甲酰胺基吡啶,
2-溴-6-氟-4-(5-氟苯并硒唑-2-基)苯胺,
2,6-二氟-4-(5-氟苯并硒唑-2-基)苯胺,
2-氟-4-(5-氟苯并硒唑-2-基)-6-甲基苯胺。
如无特别说明,本发明中所涉及的各基团分别具有如下含义。
“H”,即氢,是指氕(1H),它是氢元素的主要稳定同位素。
“D”,即氘,是指氢的一种稳定形态同位素,也被称为重氢,其元素符号为D。
“卤素”,是指氟原子,氯原子,溴原子或碘原子。
“-OH”,是指羟基基团。
“-NH2”,是指氨基基团。
“-CONH2”,即C(=O)-NH2,是指酰胺基团。
“-CN”,是指氰基基团。
“-NO2”,是指硝基基团。
“烷基”,是指1-10个碳原子的饱和的脂烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“1-10”,是指该基团,此时为烷基,可以含1个碳原子、2个碳原子、3个碳原子等,直至包括10个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时,称其为未取代的低级烷基。烷基可以选用C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-3烷基、C2-4烷基等。具体的烷基包括但不限于甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
“烯基”表示具有至少一个碳碳双键的不饱和烃基基团,包括直链和支链基团(本申请书中提到的数字范围,例如“2-5”,是指该基团,此时为烯基,可以含2个碳原子、3个碳原子、4个碳原子等,直至包括5个碳原子)。本发明中的烯基可以为C2-8烯基、C2-6烯基、C2-5烯基、C2-4烯基、C2-3烯基等,具体的烯基包括但不限于乙烯基、丙烯基和丁烯基。
“炔基”表示具有至少一个碳碳三键的不饱和烃基基团,包括直链和支链基团(本申请书中提到的数字范围,例如“2-5”,是指该基团,此时为炔基,可以含2个碳原子、3个碳原子、4个碳原子等,直至包括5个碳原子)。本发明中的炔基可以为C2-8炔基、C2-6炔基、C2-5炔基、C2-4炔基、C2-3炔基等,具体的烯基包括但不限于乙炔基、丙炔基和丁炔基。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)基团,其进一步表示-O-(未取代的烷基)。代表性实施例包括但不限于甲氧基、乙氧基、丙氧基、环丙氧基等。
“氨基酸残基”是指氨基酸缺少了某一基团(如-OH、-COOH或-NH2)所形成的基团,其中氨基酸包括但不限于通常由三个字母符号指定的20种天然存在的氨基酸,并且还包括β-丙氨酸、瓜氨酸、锁链素(demosine)、γ-氨基丁酸、同型半胱氨酸、同型丝氨酸、4-羟基脯氨酸、羟基赖氨酸、异锁链素(isodemosine)、3-甲基组氨酸、正缬氨酸、甲硫氨酸砜(methioninesulfone)和鸟氨酸等。一种氨基酸残基的例子包括但不限于:2,6-二氨基-己酰基。
“药学上可接受的盐”是包含通式(I)的化合物与有机酸或无机酸形成的盐,表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括:
(1)与酸成盐,通过母体化合物的游离碱与无机酸或有机酸的反应而得,无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等,有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐,金属离子例如碱金属离子、碱土金属离子或铝离子,有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药用组合物”指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐和前药与其它的化学成分,例如药学上可接受的载体和赋形剂的混合物。药用组合物的目的是促进化合物对生物体的给药。
在本发明化合物的应用中,可以将本发明的化合物、药学上可接受的盐或其溶剂合物作为活性成分或主要活性成分,辅以药学上可接受的辅料制成药物组合物,再对病人进行施用。
本发明的化合物可以用本领域已知的方式配制成临床上或药学上可接受的任一剂型。用于口服给药时,可制成常规的固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,可以制成注射剂,包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中常规方法生产,配制注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。
本发明还提供了一种治疗人类肠癌的方法,即对患有肠癌的人施以每次剂量0.1-1000mg的本发明的化合物、药学上可接受的盐或其溶剂合物,或者施以每次剂量0.1-1000mg的本发明的药物组合物。
本专利涉及到的一类4-(苯并硒唑-2-基)芳胺类化合物尽管有抗乳腺癌方面的药理活性,但体外试验表明,对于前列腺癌、膀胱癌、黑色素瘤、肺癌、肝癌、食管癌等肿瘤细胞株均无明显的抑制作用。然而,本专利发现了这些化合物对于结肠癌的治疗效果十分优异:对人结肠癌细胞株HCT116、HT29、HCT15和COLO205具有显著地抑制生长的作用,效果基本接近于阳性对照药物紫杉醇;该类化合物对人结肠癌HCT116和HT29裸鼠异种移植瘤也表现出极佳的抑制肿瘤生长的效果,抑瘤率均大于40%。因此这些化合物可以应用在人类肠癌治疗领域。
本发明发现了4-(苯并硒唑-2-基)芳胺类化合物在疾病冶疗方面的一种新的用途,为肠癌的治疗提供了一种潜在的药物。
附图说明
图1是化合物6对人结肠癌细胞株HT29裸鼠异种移植肿瘤体积的抑制作用;
图2是化合物6对人结肠癌细胞株HCT116裸鼠异种移植肿瘤体积的抑制作用;
图3是化合物20对人结肠癌细胞株HT29裸鼠异种移植肿瘤体积的抑制作用;
图4是化合物20对人结肠癌细胞株HCT116裸鼠异种移植肿瘤体积的抑制作用;
图5是化合物21对人结肠癌细胞株HT29裸鼠异种移植肿瘤体积的抑制作用;
图6是化合物21对人结肠癌细胞株HCT116裸鼠异种移植肿瘤体积的抑制作用。
具体实施方式
以下结合实施例对本发明的内容做进一步说明,但本专利的保护范围并不局限于以下各实施例。
实施例1:2-氨基-5-(5-氟苯并硒唑-2-基)苯甲腈(6)的合成
步骤A:在-20~-25℃下将2-硝基-4-氟苯胺(5.0g,32.0mmol)的二氯甲烷(80mL)溶液滴加到三氟化硼乙醚(6.82g,48.1mmol)中。搅拌15分钟,然后在该温度下滴加亚硝酸异戊酯(4.50g,38.4mmol)的二氯甲烷(20mL)溶液。加完后继续搅拌30分钟,然后在-10~0℃下搅拌30分钟。向反应体系中滴加冷却的石油醚(60mL),过滤,滤饼用冷却的甲基叔丁基醚(10mL)洗涤,得2-硝基-4-氟苯基-氟硼酸重氮盐(1)粗品(8.10g)。该化合物不经纯化直接用于下一步反应。
步骤B:在冰水浴下,向化合物1粗品(8.10g)和水(150mL)的混合物中滴加硒氰酸钾(4.35g,30.2mmol)的水(20mL)溶液,加完后继续搅拌1小时。过滤,滤饼用二氯甲烷(150mL)溶解。过滤除去不溶物,滤液用无水硫酸钠干燥。减压蒸除溶剂,得4-氟-2-硝基-1-硒氰酸苯酯(2)粗品(6.10g)。该化合物不经纯化直接用于下一步反应。
步骤C:室温下将金属钠(3.23g,140mmol)加入到化合物2粗品(6.10g)和无水乙醇(90mL)的混合物中,所得混合物在水浴下搅拌1小时。冷却到0~5℃,过滤,滤饼用少量冷却的乙醇洗涤,得1,2-二(4-氟-2-硝基苯基)-二硒(3)粗品(3.90g)。该化合物不经纯化直接用于下一步反应。
步骤D:将化合物3粗品(3.90g)溶解于乙醇(60mL),加入氯化亚锡(7.90g,41.7mmol),所得混合物在氮气下回流搅拌4小时。减压蒸除大部分溶剂,加入水(120mL)和乙酸乙酯(200mL),用2M氢氧化钠溶液调节pH值至8~9。通过硅藻土过滤除去不溶物,分层,水层用乙酸乙酯(60mL×2)萃取,合并的有机层用无水硫酸钠干燥。然后利用减压法柱层析纯化(200-300目硅胶,乙酸乙酯洗脱),所得产物用石油醚重结晶,得6,6’-二硒基-二(3-氟苯胺)(4)(3.0g)。步骤A、B、C和D四步反应总收率为49.6%。
步骤E:向化合物4(3.0g,7.93mmol)和4-氨基-3-溴苯甲酸(1.70g,7.87mmol)的甲苯(50mL)溶液中加入三丁基膦(8.0g,39.5mmol),所得混合物在氮气下回流搅拌48小时。冷却到室温,加入水(50mL),用2M氢氧化钠溶液调节pH值至9~10。用乙酸乙酯(40mL×3)萃取,合并的有机相用饱和食盐水(25mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200-300目硅胶,乙酸乙酯:石油醚=1:50~1:5洗脱),得2-溴-4-(5-氟苯并硒唑-2-基)苯胺(5)(1.60g)。收率为54.9%。
步骤F:将含有化合物5(400mg,1.08mmol)、氰化亚铜(145mg,1.62mmol)和NMP(10mL)的混合物在150℃搅拌过夜。冷却到室温,加入水(40mL),用2M碳酸钠溶液调节pH值至8~9。用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:二氯甲烷:石油醚=1:1:20~1:1:8洗脱),得2-氨基-5-(5-氟苯并硒唑-2-基)苯甲腈(6)(84mg)。收率为54.9%。1H NMR(DMSO-d6,400MHz)δ8.15-8.12(m,1H),8.06(d,J=2.4Hz,1H),7.98-7.96(m,1H),7.79-7.76(m,1H),7.24-7.19(m,1H),6.90(d,J=8.8Hz,1H),6.83(s,2H)。MS(EI,m/z):316.0[M-H]-。
实施例2:2-氨基-3-氟-5-(5-氟苯并硒唑-2-基)苯甲腈(9)的合成
步骤A:向化合物4(4.30g,11.4mmol)和4-氨基-3-氟苯甲酸(1.76g,11.3mmol)的甲苯(50mL)溶液中加入三丁基膦(11.5g,39.5mmol),所得混合物在氮气下回流搅拌48小时。冷却到室温,加入水(50mL),用2M氢氧化钠溶液调节pH值至9~10。用乙酸乙酯(40mL×3)萃取,合并的有机相用饱和食盐水(25mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200-300目硅胶,乙酸乙酯:石油醚=1:100~1:20洗脱),得2-氟-4-(5-氟苯并硒唑-2-基)苯胺(7)(780mg)。收率为22.3%。
步骤B:将NBS(585mg,3.29mmol)加入到化合物7(780mg,2.52mmol)的DMF(10mL)溶液中,加完后,所得混合物在室温下搅拌30分钟。加入水(40mL),用乙酸乙酯(30mL×2)萃取,合并的有机相依次用水(15mL)、饱和碳酸氢钠水溶液(15mL)和饱和食盐水(15mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物用石油醚/乙酸乙酯重结晶,得2-溴-6-氟-4-(5-氟苯并硒唑-2-基)苯胺(8)(720mg)。收率为73.6%。1H NMR(DMSO-d6,500MHz)δ8.16-8.13(m,1H),7.90(s,1H),7.79(dd,J=2.0,10.0Hz,1H),7.73(dd,J=2.0,10.0Hz,1H),7.24-7.20(m,1H),6.12(s,2H)。MS(EI,m/z):388.9[M+H]+。
步骤C:将含有化合物8(520mg,1.34mmol)、氰化亚铜(180mg,2.01mmol)和NMP(10mL)的混合物在150℃搅拌过夜。冷却到室温,加入水(40mL),用2M碳酸钠溶液调节pH值至8~9。用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:50~1:20洗脱),得2-氨基-3-氟-5-(5-氟苯并硒唑-2-基)苯甲腈(9)(150mg)。收率为33.5%。1HNMR(DMSO-d6,400MHz)δ8.19-8.16(m,1H),7.99-7.94(m,2H),7.80(dd,J=2.4,10.0Hz,1H),7.27-7.23(m,1H),6.99(s,2H)。MS(EI,m/z):336.0[M+H]+。
实施例3:2-乙炔基-4-(5-氟苯并硒唑-2-基)苯胺(12)的合成
步骤A:将含有化合物5(500mg,1.35mmol)、乙酸酐(0.5mL)、吡啶(10mL)和4-二甲胺基吡啶(10mg,0.0819mmol)的混合物在90℃搅拌过夜。冷却到室温,加入水(50mL),用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:二氯甲烷:石油醚=1:1:25~1:1:10洗脱),得N-[2-溴-4-(5-氟苯并硒唑-2-基)苯基]乙酰胺(10)(500mg)。收率为89.8%。
步骤B:通过注射器将三甲基硅烷乙炔(131mg,1.33mmol)加入到含有化合物10(500mg,1.21mmol)、双三苯基磷二氯化钯(40mg,0.0570mmol)、三乙胺(40mL)和DMF(4mL)的混合物中,加完后,所得混合物在50℃搅拌过夜。减压蒸除大部分溶剂,加入水(30mL),用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:50~1:20洗脱),得N-{4-(5-氟苯并硒唑-2-基)-2-[(三甲基硅烷基)乙炔基]苯基}乙酰胺(11)(211mg)。收率为40.6%。
步骤C:将含有化合物11(100mg,0.233mmol)、2M氢氧化钠溶液(10mL)、THF(5mL)和甲醇(10mL)的混合物在80℃搅拌1小时。冷却到室温,加入水(30mL),用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,所得产物用石油醚/乙酸乙酯重结晶,得2-乙炔基-4-(5-氟苯并硒唑-2-基)苯胺(12)。1H NMR(DMSO-d6,400MHz)δ8.13-8.09(m,1H),7.82(d,J=2.0Hz,1H),7.77-7.73(m,2H),7.22-7.19(m,1H),6.81(d,J=8.4Hz,1H),6.20(s,2H),4.48(s,1H)。MS(EI,m/z):315.0[M-H]-。
实施例4:5-氟-4-(5-氟苯并硒唑-2-基)-2-甲基苯胺(16)的合成
步骤A:在冰水浴下,将NBS(3.55g,19.9mmol)分批加入到5-氟-2-甲基苯胺(2.50g,20.0mmol)的DMF(20mL)溶液中,加完后,所得混合物在该温度下继续搅拌1小时。加入水(80mL),用乙酸乙酯(60mL×3)萃取,合并的有机相依次用饱和碳酸氢钠溶液(30mL×2)和饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,得4-溴-3-氟-6-甲基苯胺(13)粗品(4.87g)。该化合物不经纯化直接用于下一步反应。
步骤B:将含有化合物13粗品(4.87g)、氰化亚铜(2.63g,29.4mmol)和NMP(15mL)的混合物在氮气下180℃搅拌7小时。加入水(75mL),用乙酸乙酯(50mL×3)萃取,合并的有机相依次用水(30mL×2)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200-300目硅胶,乙酸乙酯:石油醚=1:30~1:5洗脱),得4-氨基-2-氟-5-甲基苯甲腈(14)(1.74g)。步骤A和B两步反应总收率为58.2%。
步骤C:将含有化合物14(1.74g,11.6mmol)、1M氢氧化钠溶液(50mL)和乙醇(5mL)的混合物在回流下搅拌过夜。冷却到室温,加入水(50mL),用甲基叔丁基醚(20mL×2)萃取,产物在水相。水相用2M盐酸调节pH值至3~4,有固体析出。过滤,滤饼干燥,得4-氨基-2-氟-5-甲基苯甲酸(15)(1.75g)。收率为89.2%。
步骤D:向化合物4(1.0g,2.64mmol)和化合物15(447mg,2.64mmol)的甲苯(30mL)溶液中加入三丁基膦(2.68g,13.2mmol),所得混合物在氮气下回流搅拌36小时。冷却到室温,加入水(40mL),用2M氢氧化钠溶液调节pH值至9~10。用乙酸乙酯(40mL×3)萃取,合并的有机相用饱和食盐水(25mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200-300目硅胶,乙酸乙酯:石油醚=1:50~1:10洗脱),得5-氟-4-(5-氟苯并硒唑-2-基)-2-甲基苯胺(16)(655mg)。收率为72.9%。1H NMR(DMSO-d6,400MHz)δ8.14-8.10(m,1H),7.90(d,J=8.8Hz,1H),7.78(dd,J=2.4,10.0Hz,1H),7.22-7.17(m,1H),6.54-6.51(m,1H),6.08(s,2H),2.13(s,3H)。MS(EI,m/z):323.0[M-H]-。
实施例5:2-溴-6-(5-氟苯并硒唑-2-基)吡啶-3-氨(18)的合成
步骤A:向化合物4(1.80g,4.76mmol)和5-氨基吡啶-2-甲酸(657mg,4.76mmol)的甲苯(50mL)溶液中加入三丁基膦(4.82g,23.8mmol),所得混合物在氮气下回流搅拌36小时。冷却到室温,加入水(40mL),用2M氢氧化钠溶液调节pH值至9~10。用乙酸乙酯(40mL×3)萃取,合并的有机相用饱和食盐水(25mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200-300目硅胶,乙酸乙酯:二氯甲烷:石油醚=1:1:20~1:1:5洗脱),得6-(5-氟苯并硒唑-2-基)吡啶-3-氨(17)(712mg)。收率为51.2%。
步骤B:在冰水浴下,将NBS(61mg,0.343mmol)分批加入到化合物17(100mg,0.342mmol)的二氯甲烷(6mL)溶液中,加完后,所得混合物在该温度下继续搅拌0.5小时。加入水(15mL),用二氯甲烷(60mL×3)萃取,合并的有机相依次用饱和碳酸氢钠溶液(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200-300目硅胶,THF:二氯甲烷:石油醚=1:1:20~1:1:10洗脱),得2-溴-6-(5-氟苯并硒唑-2-基)吡啶-3-氨(18)。1H NMR(DMSO-d6,400MHz)δ8.15-8.11(m,1H),7.98(d,J=8.4Hz,1H),7.80(dd,J=2.4,10.0Hz,1H),7.26-7.19(m,2H),6.37(s,2H)。MS(EI,m/z):369.9[M-H]-。
实施例6:3-氨基-6-(5-氟苯并硒唑-2-基)-2-甲酰胺基吡啶(19)的合成
以化合物18为起始原料,合成化合物19的实验操作按照实施例1中步骤F的方法制备(由于本批次化合物18没有经过柱层析纯化,后处理中有少许碳酸氢钠以及水没有除干净,以致在本反应中生成了化合物19)。1H NMR(DMSO-d6,400MHz)δ8.16-8.12(m,1H),8.08(d,J=8.8Hz,1H),7.82(dd,J=2.4,10.0Hz,1H),7.76(s,1H),7.65(s,1H),7.54(s,2H),7.30(d,J=8.8Hz,1H),7.26-7.21(m,1H)。MS(EI,m/z):335.0[M-H]-。
实施例7:化合物2-溴-6-氟-4-(5-氟苯并硒唑-2-基)苯胺(20)、2,6-二氟-4-(5-氟苯并硒唑-2-基)苯胺(21)以及2-氟-4-(5-氟苯并硒唑-2-基)-6-甲基苯胺(22)可参考现有文献中的方法合成,如CN201610299350.1中的方法。
实施例8:化合物对人结肠癌细胞株HCT116、HCT15、HT29、SW620和COLO205的生长抑制作用
一、实验材料名称及来源
人结肠癌细胞株HCT116、HCT15、HT29、SW620和COLO205购于中国科学院上海生命科学研究院细胞资源中心。紫杉醇、Resazurin和亚甲基蓝购自Sigma-Aldrich Co.,LLC;铁氰化钾和亚铁氰化钾购自阿拉丁试剂股份有限公司;DMEM培养基、无酚红DMEM和胎牛血清购自Thermo Fisher Scientific Inc;青霉素和链霉素购自碧云天生物技术有限公司。
二、实验方法
HCT116、HCT15、HT29、SW620和COLO205细胞用DMEM培养基(含10%胎牛血清,100U/mL青霉素,0.1mg/mL链霉素),在37℃,5%CO2孵箱培养至细胞密度达90%左右。
按3×103/孔细胞数接种于96孔板中,置37℃,5%CO2孵箱中培养24h。
用培养基配制成不同浓度梯度的试验化合物或对照药物紫杉醇,并按100μL/孔加入96孔板中,做为试验化合物孔或对照药物孔;按100μL/孔加入不含试验化合物或对照药物的培养基,做为阴性对照孔。置37℃,5%CO2孵箱中,培养72h。
将Resazurin(15mg/50mL,200×)、亚甲基蓝(25mg/10mL,1000×)、铁氰化钾(0.329g/100mL,100×)和亚铁氰化钾(0.422g/100mL,100×)溶于PBS(0.1M,pH=7.4)中,配制出10×Alamar Blue溶液,再用无酚红DMEM培养基稀释成1×Alamar Blue溶液,临用前配制。
96孔板中的细胞用PBS(0.1M,pH=7.4)小心清洗2次,并吸尽PBS,再按100μL/孔加入1×Alamar Blue溶液;在无细胞的孔中加入100μL 1×Alamar Blue溶液,做为空白对照孔。将96孔板置37℃,5%CO2孵箱中培养3h。
用酶标仪Victor X4(Perkin Elmer)在Ex 530/Em 590nm处检测细胞荧光值。试验化合物孔的荧光值以F(试验化合物)表示;空白对照孔的荧光值以F(空白对照)表示;阴性对照孔的荧光值以F(阴性对照)表示。按以下公式计算不同药物浓度下的细胞存活率,每个浓度设置3个重复孔,得出平均值和标准偏差。
根据细胞存活率利用Prism Graph软件分别计算出试验化合物或对照药物对细胞的半数抑制浓度(IC50)。
三、实验结果
试验结果如表1所示,化合物对人结肠癌细胞株HCT116、HCT15、HT29和COLO205的生长均有明显地抑制作用。其中化合物9、19、20和21的抑制效果较优。
表1.试验化合物对人结肠癌细胞株HCT116、HCT15、HT29、SW620和COLO205的半数抑制浓度(IC50,nM)
实施例9:化合物6、20和21对人结肠癌HT29和HCT116裸鼠异种移植瘤的生长抑制活性研究
一、试验材料
1.试验动物
SPF级BALB/c裸小鼠,雌性,开始给药时为6-8周龄,体重为18-20g。由常州卡文斯实验动物有限公司提供(实验动物生产许可证:SCXK(苏)2016-0010;实验动物使用许可证:SYXK(苏)2017-0007)。所购动物合格证编号:201822212。
2.试验试剂
聚乙二醇400(PEG400),批号为20180412,购自成都市科龙化工试剂厂;氯化钠注射液(生理盐水),批号为A17111105,购自河北天成药业股份有限公司;DMSO,批号为Q6949,购自MP Biomedicals。
3.细胞株
人结肠癌HCT116和HT29细胞购自中国科学院上海生命科学研究院细胞资源中心;HCT116于含10%胎牛血清的1640培养基中培养,HT29于含10%胎牛血清的1640培养基中培养。
二、试验方法
1.受试化合物的制剂配制
低剂量组(给药剂量:4.0mg/kg):给药前称取3.2mg受试化合物,用溶剂溶至8ml(PEG400 50%,DMSO 5%,生理盐水45%),溶液浓度为0.4mg/ml,静脉注射给药,给药体积为0.2ml/20g体重。
高剂量组(给药剂量:8.0mg/kg):给药前称取6.4mg受试化合物,用溶剂溶至8ml(PEG400 50%,DMSO 5%,生理盐水45%),溶液浓度为0.8mg/ml,静脉注射给药,给药体积为0.2ml/20g体重。
2.试验分组与给药方式
取对数生长期的HCT116和HT29细胞,在无菌条件下,分别接种于各60只裸小鼠右侧腋窝皮下,细胞接种量为5×106个/只。用游标卡尺测量移植瘤直径,待肿瘤生长至100mm3左右时,分别挑选生长状态良好且肿瘤大小均一性较好的HCT116和HT29荷瘤裸鼠各56只,随机分成7组,每组8只,即模型组,化合物6、20和21低剂量组及高剂量组。各组均尾静脉注射给药,分别于0、1、2、3、4天连续每天给药一次,共给药5天,模型组给予等容量的溶媒对照。用测量瘤径的方法,动态观察受试化合物的抗肿瘤效应。每两天测量一次肿瘤直径,同时称重。第20天时各组脱颈处死裸鼠,手术剥取并准确称重瘤块。
肿瘤体积(TV)的计算公式为:
其中a、b分别表示长、宽。
抑瘤率%的计算公式为:
三、试验结果
试验结果如表2、表3、图1至图6所示,化合物6、20和21在分别连续5天以4.0mg/kg和8.0mg/kg的给药剂量尾静脉注射后,可显著地抑制结肠癌细胞HT29和HCT116裸鼠移植瘤的肿瘤生长。
表2.化合物对人结肠癌细胞株HT29裸鼠异种移植肿瘤生长的抑制作用(Mean±SD,n=8)
表3.化合物对人结肠癌细胞株HCT116裸鼠异种移植肿瘤生长的抑制作用(Mean±SD,n=8)
Claims (10)
1.通式(I)所示的化合物或其药学上可接受的盐在制备治疗或预防肠癌药物方面的应用,
其中,
R1和R2分别独立地选自H、D、卤素、-CN、C1-3烷基、取代的C1-3烷基、C1-3烷氧基或取代的C1-3烷氧基;
R3选自H、卤素、-OH、-CN、-C(=O)NH2、取代的-C(=O)NH2、C1-3烷基、取代的C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基或取代的C1-3烷氧基;
R4选自H、D、卤素、-OH、-CN、-NH2、取代的-NH2、-C(=O)NH2、取代的-C(=O)NH2、C1-3烷基、取代的C1-3烷基、C2-3烯基、C2-3炔基、C1-3烷氧基或取代的C1-3烷氧基中的一种或两种;
n=1或2;
R5选自H、-CN、-OH、C1-3烷基、C1-3烷氧基或氨基酸残基;
Z选自CH或N;
R1、R2、R3或R4中的取代基选自D、卤素、OH、C1-3烷基或C1-3烷氧基。
2.根据权利要求1所述的应用,其中,R1和R2分别独立地选自H、D、F、Cl、-CN、-CH3、-CF3、-OCF3或-OCHF2。
3.根据权利要求2所述的应用,其中,R1选自D、F、Cl、-CN、-CH3或-CF3,R2选自H。
4.根据权利要求1所述的应用,其中,R3选自H、F、Cl、Br、-CN、-C(=O)NH2、-CH3、-CH2CH3、-CF3、-CH=CH2、-C≡CH、-OCHF2或-OCF3。
5.根据权利要求1所述的应用,其中,R4选自H、D、卤素、-CN、C1-3烷基、取代的C1-3烷基、C1-3烷氧基或取代的C1-3烷氧基中的一种或两种。
6.根据权利要求1所述的应用,其中,R4选自H、D、F、Cl、Br、I、-CN、-CH3、-CF3、-OCHF2或-OCF3;R5选自H或氨基酸残基。
7.根据权利要求1所述的应用,其中,R5选自H或2,6-二氨基-己酰基。
8.根据权利要求1或2所述的应用,其中,所述化合物选自:
2-氨基-5-(5-氟苯并硒唑-2-基)苯甲腈,
2-氨基-3-氟-5-(5-氟苯并硒唑-2-基)苯甲腈,
2-乙炔基-4-(5-氟苯并硒唑-2-基)苯胺,
5-氟-4-(5-氟苯并硒唑-2-基)-2-甲基苯胺,
2-溴-6-(5-氟苯并硒唑-2-基)吡啶-3-氨,
3-氨基-6-(5-氟苯并硒唑-2-基)-2-甲酰胺基吡啶,
2-溴-6-氟-4-(5-氟苯并硒唑-2-基)苯胺,
2,6-二氟-4-(5-氟苯并硒唑-2-基)苯胺,
2-氟-4-(5-氟苯并硒唑-2-基)-6-甲基苯胺。
9.根据权利要求1所述的应用,其中以权利要求1所述的化合物、药学上可接受的盐或其溶剂合物作为活性成分或主要活性成分,辅以药学上可接受的辅料制成药物组合物。
10.一种治疗人类肠癌的方法,其特征在于对患有肠癌的人施以每次剂量0.1-1000mg的权利要求1所述的化合物、药学上可接受的盐或其溶剂合物,或者施以每次剂量0.1-1000mg的权利要求9所述的药物组合物。
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