CN105663133B - 一种抑制淋巴瘤细胞增殖的药物组合物及其应用 - Google Patents
一种抑制淋巴瘤细胞增殖的药物组合物及其应用 Download PDFInfo
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Abstract
本发明公开了一种抑制淋巴瘤细胞增殖的药物组合物及其应用,该药物组合物由活性成分和辅料制备而成,其中所述的活性成分包括3‑溴‑N‑{(2S)‑2‑(4‑氟苯基)‑4‑[3‑(4‑乙酰基哌嗪‑1‑基)氮杂环丁烷‑1‑基]丁基}‑N‑甲基‑5‑(三氟甲基)苯甲酰胺。试验显示,该药作用后的淋巴瘤细胞体积较前缩小,折光性和立体感减弱,胞内出现细微黑色颗粒,成团现象不明显或单个细胞悬浮存在,说明该药具有抗淋巴瘤细胞增殖的生物活性,可开发成抗肿瘤的新药。
Description
技术领域
本发明属于医药技术领域,具体而言,涉及一种化合物的治疗活性,尤其涉及一种抑制淋巴瘤细胞增殖的药物组合物及其应用。
背景技术
淋巴瘤是起源于淋巴造血系统的恶性肿瘤,主要表现为无痛性淋巴结肿大,肝脾肿大,全身各组织器官均可受累,伴发热、盗汗、消瘦、瘙痒等全身症状。
根据瘤细胞分为非霍奇金淋巴瘤(NHL)和霍奇金淋巴瘤(HL)两类。病理学特征在霍奇金淋巴瘤为瘤组织内含有淋巴细胞、嗜酸性粒细胞、浆细胞和特异性的里-斯细胞,HL按照病理类型分为结节性富含淋巴细胞型和经典型,后者包括淋巴细胞为主型、结节硬化型、混合细胞型和淋巴细胞消减型。NHL发病率远高于HL,是具有很强异质性的一组独立疾病的总和,病理上主要是分化程度不同的淋巴细胞、组织细胞或网状细胞,根据NHL的自然病程,可以归为三大临床类型,即高度侵袭性、侵袭性和惰性淋巴瘤。根据不同的淋巴细胞起源,可以分为B细胞、T细胞和NK细胞淋巴瘤。
恶性淋巴瘤是具有相当异质性的一大类肿瘤,虽然好发于淋巴结,但是由于淋巴系统的分布特点,使得淋巴瘤属于全身性疾病,几乎可以侵犯到全身任何组织和器官。因此,恶性淋巴瘤的临床表现既具有一定的共同特点,同时按照不同的病理类型、受侵部位和范围又存在着很大的差异。胸部X线片上有圆形或类圆形或分叶状阴影,病变进展可压迫支气管致肺不张,有时肿瘤中央坏死形成空洞。有的肺部病变表现为弥漫性间质性改变,此时临床症状明显,常有咳嗽、咳痰、气短、呼吸困难,继发感染可有发热;恶性淋巴瘤可侵犯心肌和心包,表现为心包积液,淋巴瘤侵犯心肌表现为心肌病变,可有心律不齐,心电图异常等表现;腹部表现脾是HL最常见的膈下受侵部位。胃肠道则是NHL最常见的结外病变部位。肠系膜、腹膜后及髂窝淋巴结等亦是淋巴瘤常见侵犯部位;皮肤表现恶性淋巴瘤可原发或继发皮肤侵犯,多见于NHL;骨髓恶性淋巴瘤的骨髓侵犯表现为骨髓受侵或合并白血病,多属疾病晚期表现之一,绝大多数为NHL;神经系统表现,如进行性多灶性脑白质病、亚急性坏死性脊髓病、感觉或运动性周围神经病变以及多发性肌病等其他表现。恶性淋巴瘤还可以原发或继发于脑、硬脊膜外、睾丸、卵巢、阴道、宫颈、乳腺、甲状腺、肾上腺、眼眶球后组织、喉、骨骼及肌肉软组织等,临床表现复杂多样。
目前淋巴瘤的治疗以化疗为主,但几乎现有的化疗药物都有骨髓抑制、脱发、胃肠道反应、肝肾功能损伤等副反应,只是发生程度和侧重面不同而已。因此,研发新的杜甫作用小的抗淋巴瘤药物具有重要意义。CN101316846A公开了一类氮杂环丁烷化合物及其制备方法,并公开了所述化合物在治疗功能性胃肠疾病、IBS和功能性消化不良中的用途。目前,尚没有文献报道这类化合物具有抑制淋巴瘤细胞增殖的生物活性。
发明内容
本发明的目的在于提供一种抑制淋巴瘤细胞增殖的药物。该药物以3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺为活性成分,可用于抗淋巴瘤药物制剂的制备。
为了实现本发明的目的,发明人通过研究3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺(SD-803)对体外培养人淋巴瘤细胞株Raji增殖的影响试验,采用MTT试验检测SD-803对Raji细胞增殖的影响,并采用光镜观察药物处理后细胞形态学的变化,结果发现SD-803在一定的剂量和时间范围内,能抑制Raji细胞生长;通过光镜观察,SD-803作用后细胞体积较前缩小,折光性和立体感减弱,胞内出现细微黑色颗粒,成团现象不明显或单个细胞悬浮存在。基于上述试验结果,本发明提供的技术方案概括如下:
一种抑制淋巴瘤细胞增殖的药物组合物,由活性成分和药学上可接受的辅料制备而成,所述的活性成分包括3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺。优选地,如上所述抑制淋巴瘤细胞增殖的药物组合物,其中所述的活性成分由3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺作为唯一组分组成。该化合物3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺(SD-803)的结构式如下式所示:
另外,本发明还提供一种化合物新用途,即:3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺在制备抗淋巴瘤细胞增殖的药物中的应用。
与现有技术相比,本发明涉及的3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺,其在一定的剂量和时间范围内,能抑制人淋巴瘤Raji细胞生长;通过光镜观察,SD-803作用后的Raji细胞体积较前缩小,折光性和立体感减弱,胞内出现细微黑色颗粒,成团现象不明显或单个细胞悬浮存在,说明SD-803具有抗淋巴瘤细胞增殖的生物活性,可开发成抗肿瘤的新药。
附图说明
图1为MTT法检测SD-803对人淋巴瘤Raji细胞的抑制曲线图。
具体实施方式
以下是该化合物的具体制备和体外试验过程,对本发明的技术方案做进一步作描述,但是本发明的保护范围并不限于该试验例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1:3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺的制备
(a)3-溴-N-[(2S)-2-(4-氟苯基)戊-4-烯-1-基]-N-甲基-5-(三氟甲基)苯甲酰胺
向[(2S)-2-(4-氟苯基)戊-4-烯-1-基]甲基胺(见Bioorg.Med.Chem.Lett;2001;265-270;0.54克,2.8毫摩尔)和3-溴-5-三氟甲基苯甲酸(0.81克,3.0毫摩尔)的DMF(7毫升)溶液中,加入TBTU(0.96克,3.0毫摩尔)和DIPEA(1.41克,10.9毫摩尔)。于室温氮气下搅拌反应混合物过夜,然后在乙酸乙酯和NaHCO3水溶液中分配。水相用乙酸乙酯萃取三次。合并的有机溶液用水洗涤三次,然后经相分离柱干燥。蒸发除去溶剂,产物经硅胶色谱法纯化(乙酸乙酯-庚烷10%至17%)。获得3-溴-N-[(2S)-2-(4-氟苯基)戊-4-烯-1-基]-N-甲基-5-(三氟甲基)苯甲酰胺0.86克(68%)。1H NMR(500MHz,CDCl3):2.1-3.8(cm,8H),4.9-5.1(m,2H),5.5-5.8(m,1H),6.8-7.4(cm,6H),7.8(s,1H)。
(b)3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺
向3-溴-N-[(2S)-2-(4-氟苯基)戊-4-烯-1-基]-N-甲基-5-(三氟甲基)苯甲酰胺(0.86克,1.9毫摩尔)的丙酮(45毫升)溶液中,加入OsO4(2.5%/叔丁基醇,0.49毫升,0.039毫摩尔)和4-甲基吗啉-4-氧化物(0.41克,3.5毫摩尔)。于室温氮气下搅拌溶液过夜,然后加入NaHSO3(39%,45毫升)水溶液。搅拌混合物2小时,用水稀释,然后用二氯甲烷萃取两次。合并的有机溶液用相分离柱分离,蒸发除去溶剂。将残余物(1.08克)溶于THF(18毫升)和水(4.5毫升)中,向所得溶液中加入NaIO4(0.73克,3.4毫摩尔)。室温氮气下搅拌混合物过夜。混合物在二氯甲烷和水之间分配。水相用二氯甲烷萃取,然后合并的有机溶液用盐水洗涤,并用相分离柱分离。蒸发除去溶剂,获得标题化合物0.78克(90%)。1HNMR(500MHz,CDCl3):2.4-4.4(cm,8H),6.8-7.8(cm,7H),9.8(s,1H);LCMS:m/z 447(M-1)+。
实施例2:3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺(SD-803)的制备
将实施例1制备的3-溴-N-[(2S)-2-(4-氟苯基)-4-氧代丁基]-N-甲基-5-(三氟甲基)苯甲酰胺(11.2克,25毫摩尔)溶于甲醇(50毫升)和三乙胺(3.5毫升,25毫摩尔)中。将溶液和另一部分三乙胺(3.5毫升,25毫摩尔)一起转移至装有1-乙酰基-4-氮杂环丁烷-3-基哌嗪二盐酸盐的烧瓶中(见WO 96/05193;8.4克,32.6毫摩尔)。室温搅拌混合物45分钟,然后用1小时分次加入三乙酰氧基硼氢化钠(8.0克,37.6毫摩尔)。室温搅拌反应混合物45分钟。加入水(0.45毫升),然后蒸发除去大部分溶剂。将残余物溶于甲苯(56毫升)中,然后在加热至40℃的同时,加入10%NaOH水溶液(55毫升)。在45℃剧烈搅拌该混合物5分钟。分离除去水层,有机溶液留在通风橱中过夜。在尝试几次从不同溶剂中使产物结晶之后,经硅胶色谱法纯化化合物(氨饱和的甲醇-二氯甲烷1%至10%)。获得白色泡沫的标题化合物8.3克(54%)。1HNMR(500MHz,CDCl3):1.4-1.8(cm,2H),2.0(s,3H),2.1-3.8(cm,21H),6.8-7.4(cm,6H),7.7(s,1H);LCMS:m/z 614(M+1)+。
本发明通过研究3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺(SD-803)对体外培养人淋巴瘤细胞株Raji细胞增殖的影响试验,MTT实验和形态学观察结果显示,SD-803具有较好的体外抗肿瘤细胞增殖的生物活性。具体地试验过程如下:
实施例3:MTT法分析SD-803对人淋巴瘤细胞株Raji增殖的影响试验研究
将人淋巴瘤细胞株Raji细胞于含10%的胎牛血清、100U/mL青霉素和100μg/mL链霉素的RPMI 1640培养液中,37℃、饱和湿度和5%CO2条件下培养。取处于对数生长期的Raji细胞,加入96孔板,每孔200μL,加入不同浓度的SD-803(终浓度分别为1、5、10、20、40、80nmol/L),同时设对照组。分别于37℃培养24、48、72h,在实验结束前,于每孔加入20μL5mg/mL的MTT,培养4h,1000r/min离心,5min去上清液后每孔加入150μL DMSO,振荡溶解,用酶联免疫检测仪测定每孔吸光度,测定波长570nm,参考波长620nm。抑制率(%)=(1-实验组吸光度值/对照组吸光度值)×100%。以细胞抑制率对剂量的对数作图,通过线性回归拟合法可求出SD-803对Raji细胞的IC50值。
MTT结果显示,5nmol/L以上浓度的SD-803能明显抑制Raji细胞增殖(P<0.01或P<0.05),且随着药物浓度的增加及作用时间延长抑制作用逐渐增强。SD-803作用24、48、72h对Raji细胞的IC50值分别为(395.5±3.3)nmol/L、(201.7±1.8)nmol/L、(23.0±1.4)nmol/L,见图1。另外,通过镜下观察发现,正常对数生长期的人淋巴瘤Raji细胞呈圆形,外观饱满,折光性好,成团悬浮生长。SD-803作用后细胞体积较前缩小,折光性和立体感减弱,胞内出现细微黑色颗粒,成团现象不明显或单个细胞悬浮存在。
Claims (1)
1.3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺在制备抗淋巴瘤细胞增殖的药物中的应用,其特征在于:抗淋巴瘤细胞增殖的药物由活性成分和辅料制备而成,所述的活性成分包括3-溴-N-{(2S)-2-(4-氟苯基)-4-[3-(4-乙酰基哌嗪-1-基)氮杂环丁烷-1-基]丁基}-N-甲基-5-(三氟甲基)苯甲酰胺。
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