CN113980075B - 氟铁龙衍生物及其用途 - Google Patents
氟铁龙衍生物及其用途 Download PDFInfo
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- CN113980075B CN113980075B CN202111396282.8A CN202111396282A CN113980075B CN 113980075 B CN113980075 B CN 113980075B CN 202111396282 A CN202111396282 A CN 202111396282A CN 113980075 B CN113980075 B CN 113980075B
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Abstract
本发明提供一种氟铁龙衍生物及其在制备抗肿瘤药物中的用途,具有下述通式(I)。硝基还原酶介导的氟铁龙衍生物的降解研究表明该氟铁龙衍生物在硝基还原酶条件下能够很好降解生成氟铁龙,体内实验表明该氟铁龙衍生物具有较好的抗肿瘤活性,且毒副作用小于氟铁龙和氟尿嘧啶
Description
技术领域
本发明提供一种新型的氟铁龙衍生物以及衍生物在制备抗肿瘤药物中的用途。
技术背景
恶性肿瘤是威胁人类健康的常见疾病之一,肿瘤死亡率居于各种疾病前列。目前临床使用的抗肿瘤药物,其毒副作用是困扰肿瘤化疗的突出问题。提高肿瘤治疗效果同时降低药物毒性,是当前治疗肿瘤药物的重要研究课题。
氟铁龙,中文别名去氧氟鸟苷、多西氟尿啶、5-氟-5'-脱氧尿苷、5'-脱氧-5-氟尿苷、(+)-5-氟-5'-脱氧尿苷,英文名称doxifluridine,化学名为1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟嘧啶-2,4(1H,3H)-二酮,化学式为C9H11FN2O5,分子量246.19,是一种嘧啶衍生物,属于一种抗代谢抗肿瘤药物。氟铁龙在体内逐渐变为氟尿嘧啶而起作用。生成的氟尿嘧啶在体内转变成氟尿嘧啶脱氧核苷酸(FUDRP)后,与胸腺嘧啶合成酶结合,再与辅酶5,10-次甲基四氢叶酸作用,导致不能有效地合成胸腺嘧啶脱氧核苷酸(TDRP),使胸腺嘧啶合成酶失活。从而抑制DNA的合成,导致肿瘤细胞死亡。氟铁龙其作用与氟尿嘧啶相同,主要治疗消化道肿瘤,如胃癌、结肠癌、直肠癌,也可用于治疗乳腺癌、支气管肺癌和肝癌、膀胱癌、前列腺癌、肾癌等。
氟铁龙口服吸收良好,原形药物的血清浓度1-2小时后达到高峰值,之后迅速下降,此外,血中氟尿嘧啶的浓度也在1-2小时达到最高峰值,其浓度为原形药物的约1/10。氟铁龙作为氟尿嘧啶的前药,虽然副作用较氟尿嘧啶有所降低,但是依然缺乏对肿瘤组织和正常组织的选择性,所以毒性较大,会有胃肠道反应,骨髓抑制,精神神经系统损害,肝肾损害,过敏反应等副作用。
肿瘤微环境是肿瘤细胞赖以生存和发展的复杂环境,由细胞成分和非细胞成分组成。其中细胞成分包括肿瘤细胞本身、炎症细胞、免疫细胞、间充质干细胞、内皮细胞、以及与肿瘤相关的成纤维细胞等;非细胞成分主要包括细胞因子,趋化因子等。细胞成分和非细胞成分共同为肿瘤生长起到支撑的作用。肿瘤细胞由于生长失控、基因表达异常等使肿瘤组织表现出与正常组织显著不同的生理特征,如pH低、还原物质浓度和酶浓度升高、活性氧(reactive oxygen species,ROS)和三磷酸腺苷(adenosine-5'-triphosphate,ATP)含量增加等。基于肿瘤微环境研究靶向抗肿瘤药物能够提高药物的选择性,降低毒副作用。
基于肿瘤特有的微环境对上市药物进行潜伏化设计,生成没有活性的前药。该前药在正常人体血液循环中保持相对稳定,将前药运送到肿瘤部位后,在肿瘤组织特定的微环境下才能快速代谢生成具有抗肿瘤活性的原药,实现药物的靶向性,降低因选择性差引起的毒副作用。
低氧是恶性肿瘤发生、发展过程中普遍存在的现象,其产生主要与肿瘤细胞无限制生长、氧耗量增加、血氧供应不足及肿瘤组织血管发育不良等有关。低氧环境下的肿瘤细胞易发生转移,并且能增加对放疗、化疗的抗拒性,从而降低了治疗效果。肿瘤细胞缺氧通常可以导致细胞内的硝基还原酶(Nitroreductase)的增加。基于肿瘤组织中高水平的硝基还原酶,在抗肿瘤药物中引入硝基,使其在肿瘤部位被还原成氨基,重排后释放出原药,发挥抗肿瘤活性。
本发明对上市药物氟铁龙进行潜伏化研究,生物体外没有化学的氟铁龙衍生物,此衍生物在肿瘤微环境高硝基还原酶和嘧啶核苷磷酸化酶作用下分解成氟尿嘧啶,发挥抗肿瘤活性,进一步降低其副作用。
发明内容
本发明所要解决的技术问题是提供一种新型的氟铁龙衍生物以及上述衍生物在制备抗肿瘤药物中的应用。
本发明目的的技术方案是:一种新型的氟铁龙衍生物,具有下述通式(I):
其中A环为苯环、取代苯环、杂环、取代杂环,稠杂环、取代稠杂环;所述的取代苯环,其苯环上独立地由一个或两个或三个或四个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;所述的杂环是咪唑、吡啶、呋喃、噻吩、噻唑、哌嗪或哌啶;所述的取代杂环,其杂环上独立地由一个或两个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;所述的稠杂环是喹啉或吲哚;所述的取代稠杂环,其稠杂环上独立地由一个或两个或三个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;
R为硝基、亚硝基、氨基、羟胺基;
X为CH2、CHD、CD2、X1是A环。
作为优选是通式(II)所示的氟铁龙衍生物:
其中A环为苯环、取代苯环、杂环、取代杂环;所述的取代苯环,其苯环上独立地由一个或两个或三个或四个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;所述的杂环是咪唑、吡啶、呋喃、噻吩、噻唑、哌嗪或哌啶;所述的取代杂环,其杂环上独立地由一个或两个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;
X为CH2、CD2、X1是A环。
作为优选是通式(III)所示的氟尿嘧啶衍生物:
其中苯环、杂环;所述的杂环是吡啶、呋喃、噻吩、噻唑;
X为CH2、CD2、X1是A环。
优选化合物选自但不限于下列化合物:
1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-(4-硝基苄基)嘧啶-2,4(1H,3H)-二酮;
1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-((5-硝基呋喃-2-基)甲基)嘧啶-2,4(1H,3H)-二酮;
1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-((5-硝基噻吩-2-基)甲基)嘧啶-2,4(1H,3H)-二酮;
4-硝基苄基3-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-2,6-二氧代-3,6-二氢嘧啶-1(2H)-碳酸酯;
(5-硝基呋喃-2-基)甲基3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-2,6-二氧代-3,6-二氢嘧啶-1(2H)-碳酸酯;
(5-硝基噻吩-2-基)甲基3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-2,6-二氧代-3,6-二氢嘧啶-1(2H)-碳酸酯。
上述化合物在制备治疗肿瘤药物中的应用。
所述肿瘤为血液肿瘤或恶性实体肿瘤。具体的,肿瘤包括绒毛膜上皮癌、恶性葡萄胎、直肠癌、肺癌、头颈部癌、前列腺癌、乳腺癌、结肠癌、胃癌、胰腺癌、肝癌、食道癌、脑肿瘤、卵巢癌、子宫癌、肾癌、头颈癌、皮肤癌、膀胱癌、外阴癌、睾丸瘤、直肠癌、生殖细胞瘤、恶性淋巴瘤、白血病和多发性骨瘤,并且甚至更优选的肿瘤可包括绒毛膜上皮癌、恶性葡萄胎、结肠癌、直肠癌、胃癌、乳腺癌和头颈部癌。
一种药物组合物,其中含有作为活性成分的通式(I)所示的氟铁龙衍生物以及一种或多种药用载体或赋形剂。
所述组合物的剂型为注射剂或者是口服剂型,其中注射剂为溶液型注射剂、混悬型注射剂、乳剂型注射剂、或注射用无菌粉末,口服剂型为片剂、散剂、颗粒剂、胶囊剂、微丸制剂、溶液剂、混悬剂、乳剂、糖浆剂或酏剂。
除非另有说明,否则说明书和权利要求书中的术语具有下述含义。
“药物组合物”表示含有一种或多种本发明通式(I)所述化合物与其他化学组分的混合物,其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收,利于活性成分在生物体内发挥生物活性。
本发明化合物的合成方案如所述方案一和方案二所示:
方案一:制备式(I)的化合物:
化合物(I)可以通过将氟铁龙和通式(VI)表示的化合物(简称化合物VI)在碱的存在下反应制备。
其中A环为苯环、取代苯环、杂环、取代杂环,稠杂环、取代稠杂环;所述的取代苯环,其苯环上独立地由一个或两个或三个或四个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;所述的杂环是咪唑、吡啶、呋喃、噻吩、噻唑、哌嗪或哌啶;所述的取代杂环,其杂环上独立地由一个或两个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;所述的稠杂环是喹啉或吲哚;所述的取代稠杂环,其稠杂环上独立地由一个或两个或三个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;
R为硝基、亚硝基、氨基、羟胺基;
X为CH2、CHD、CD2,X1是A环;
W表示离去基团,可以提及例如Cl、Br、I、任选卤代的C1-C6烷基磺酰基氧基(例如,甲磺酰基氧基、乙磺酰基氧基、三氯甲磺酰基)、任选具有取代基的的C6-C10芳基磺酰基氧基(例如,苯基磺酰基氧基、对甲苯磺酰基氧基,间-硝基苯磺酰基氧基等)等;
作为所述的碱包括无机碱和有机碱,所述的无机碱可以提及例如,碱金属碳酸盐类例如碳酸钠、碳酸钾、碳酸铯等;碱金属碳酸氢盐类,如碳酸氢钾、碳酸氢钠等;碱金属氢氧化物例如氢氧化锂、氢氧化钠、氢氧化钾等;所述的有机碱可以提及例如三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯、二异丙基乙胺、N,N-二甲基氨基吡啶、正丁基锂、叔丁基钾等。
方案二:制备式(I)的化合物:
化合物(I)可以通过将氟铁龙和通式(V)表示的化合物(简称化合物V)在碱的存在下反应制备。
其中A环为苯环、取代苯环、杂环、取代杂环,稠杂环、取代稠杂环;所述的取代苯环,其苯环上独立地由一个或两个或三个或四个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;所述的杂环是咪唑、吡啶、呋喃、噻吩、噻唑、哌嗪或哌啶;所述的取代杂环,其杂环上独立地由一个或两个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;所述的稠杂环是喹啉或吲哚;所述的取代稠杂环,其稠杂环上独立地由一个或两个或三个氘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、卤素、氰基、羟基取代;
R为硝基、亚硝基、氨基、羟胺基;
X为CH2、CD2、X1是A环;
W表示离去基团,可以提及例如Cl、Br、I、任选卤代的C1-C6烷基磺酰基氧基(例如,甲磺酰基氧基、乙磺酰基氧基、三氯甲磺酰基)、任选具有取代基的的C6-C10芳基磺酰基氧基(例如,苯基磺酰基氧基、对甲苯磺酰基氧基,间-硝基苯磺酰基氧基等)等;
作为所述的碱包括无机碱和有机碱,所述的无机碱可以提及例如,碱金属碳酸盐类例如碳酸钠、碳酸钾、碳酸铯等;碱金属碳酸氢盐类例如碳酸氢钾、碳酸氢钠等;碱金属氢氧化物例如氢氧化锂、氢氧化钠、氢氧化钾等;所述的有机碱可以提及例如三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯、二异丙基乙胺、N,N-二甲基氨基吡啶、正丁基锂、叔丁基钾等。
本发明涉及的氟铁龙衍生物是一种新型的氟铁龙前药,该氟铁龙衍生物在体外没有细胞毒性,进入体内后在肿瘤特有的微环境,高硝基还原酶浓度作用下生成氟尿嘧啶发挥抗肿瘤活性,从而提高氟铁龙的选择性和靶向性,降低氟铁龙的毒副作用。体内外实验表明,该氟铁龙衍生物具有较好的选择性和靶向性,且降低了氟铁龙的毒副作用。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
本实施例的氟铁龙衍生物1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-(4-硝基苄基)嘧啶-2,4(1H,3H)-二酮(编号F-1)经1步反应合成,反应式如下:
将5.0g(20.31mmol)氟铁龙溶于100ml丙酮中,加入碳酸钾5.61g(40.62mmol),冷却至0℃,氮气保护。用注射器缓慢滴20mL丙酮溶解的对硝基溴苄4.39g(20.31mmol)。加完后缓慢升温至56℃,回流12小时。反应结束后,过滤除去碳酸钾,滤液减压浓缩后得粗产品,硅胶柱层析分离,正己烷:乙酸乙酯(1:2)洗脱得白色固体(F-1)7.12g,产率91.94%。
F-1的核磁共振表征:
1H NMR(500MHz,DMSO-d6)δ8.19(d,J=8.8Hz,2H),8.05(d,J=6.6Hz,1H),7.60–7.55(m,2H),5.74(dd,J=4.4,1.6Hz,1H),5.38(d,J=5.3Hz,1H),5.12(s,2H),5.11(d,J=5.9Hz,1H),4.13(td,J=5.4,4.4Hz,1H),3.90–3.84(m,1H),3.72(q,J=5.6Hz,1H),1.31(d,J=6.4Hz,3H);
13C NMR(125MHz,DMSO-d6)δ157.00(d,J=26.1Hz),149.76,147.25,144.60,141.05,139.22,129.12,125.03(d,J=33.8Hz),124.03,90.78,79.85,74.47,73.22,44.45,18.83。
实施例2
本实施例的氟铁龙衍生物1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-((5-硝基呋喃-2-基)甲基)嘧啶-2,4(1H,3H)-二酮(编号F-2)反应合成,反应式如下:
将5.0g(20.23mmol)氟铁龙溶于100mL N,N-二甲基甲酰胺中,加入碳酸钾5.61g(40.62mmol),冷却至0℃,氮气保护。用注射器缓慢滴20mL N,N-二甲基甲酰胺溶解的2-(溴甲基)-5-硝基呋喃4.18g(20.31mmol)。加完后缓慢升温至80℃,回流12小时。反应结束后,过滤除去碳酸钾,滤液减压浓缩后得粗产品,硅胶柱层析分离,正己烷:乙酸乙酯(2:1)洗脱得白色固体(F-2)6.73g,产率89.25%。
F-2的核磁共振表征:
1H NMR(500MHz,DMSO-d6)δ8.01(d,J=6.6Hz,1H),7.62(d,J=3.8Hz,1H),6.79(d,J=3.8Hz,1H),5.73(dd,J=4.4,1.6Hz,1H),5.10(s,2H),4.15–4.10(m,1H),3.87(p,J=6.2Hz,1H),3.71(t,J=5.6Hz,1H),1.30(d,J=6.4Hz,3H);
13C NMR(126MHz,DMSO-d6)δ156.57,154.15,151.41,149.40,140.94,139.11,125.08,114.44,113.14,90.82,79.90,74.44,73.23,38.22,18.79。
实施例3
本实施例的氟铁龙衍生物1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-((5-硝基噻吩-2-基)甲基)嘧啶-2,4(1H,3H)-二酮(编号F-3)反应合成,反应式如下:
将5.0g(20.31mmol)氟铁龙溶于100mL N,N-二甲基甲酰胺中,加入碳酸钾5.61g(40.62mmol),冷却至0℃,氮气保护。用注射器缓慢滴20mL N,N-二甲基甲酰胺溶解的2-(溴甲基)-5-硝基噻吩4.51g(20.31mmol)。加完后缓慢升温至80℃,回流12小时。反应结束后,过滤除去碳酸钾,滤液减压浓缩后得粗产品,硅胶柱层析分离,正己烷:乙酸乙酯(2:1)洗脱得白色固体(F-3)6.23g,产率79.20%。
F-3的核磁共振表征:
1H NMR(500MHz,DMSO-d6)δ8.02(d,J=6.7Hz,1H),7.99(d,J=4.2Hz,1H),7.22(d,J=4.2Hz,1H),5.75(dd,J=4.4,1.6Hz,1H),5.19(s,2H),4.13(t,J=4.9Hz,1H),3.93–3.84(m,1H),3.72(t,J=5.5Hz,1H),1.30(d,J=6.4Hz,4H);
13C NMR(126MHz,DMSO-d6)δ156.60,150.93,149.49,147.09,141.00,139.16,129.82,128.85,125.22,90.87,79.95,74.45,73.19,18.83。
实施例4
肿瘤微环境(硝基还原酶)介导的氟铁龙衍生物的降解研究
将氟铁龙衍生物溶于10mmol/L Tris缓冲液15mL中,加入适量的硝基还原酶和烟酰胺腺嘌呤二核苷酸或烟酰胺腺嘌呤二核苷酸磷酸,用10mmol/L的Tris缓冲液稀释至20mL,用HPLC测定加入硝基还原酶缓冲液后100s,200s,300s,400s,500s,600s……后氟铁龙和氟铁龙衍生物的浓度,以确定目标化合物在硝基还原酶存在条件下是否能够降解。结果表明化合物F-1、F-2和F-3在硝基还原酶条件下能够迅速降解。
实施例5
细胞毒性实验:收集JEG-3细胞系对数期细胞,调整细胞悬液浓度,每孔加入100uL,铺板使待测细胞调密度1000-10000孔,(边缘孔用无菌PBS填充);5%CO2,37℃孵育至细胞单层铺满孔底(96孔平底板),加入浓度梯度的药物,设5-7个浓度梯度,5个复孔,每孔100uL;5%CO2,37℃孵育24h,倒置显微镜下观察;每孔加入20uLMTT溶液(5mg/ml,即0.5%MTT),继续培养4h。若药物与MTT能够反应,可先离心后弃去培养液,小心用PBS冲2-3遍后,再加入含MTT的培养液。终止培养,小心吸去孔内培养液;每孔加入150uL二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪OD 490nm处测量各孔的吸光值,计算细胞存活率。实验组包括氟尿嘧啶组(组1)、氟铁龙组(组2)、F-1组(组3)、F-2组(组4)、F-3组(组5)、F-1+硝基还原酶组(组6)、F-2+硝基还原酶组(组7)、F-3+硝基还原酶组(组8)。结果见表1。
表1
细胞实验结果表明,氟铁龙衍生物F-1、F-2和F-3的细胞毒性降低,在硝基还原酶存在的条件下因为只生成了氟铁龙,所有也没有表现出明显的细胞毒性。
实施例6
根据动物体内抗肿瘤活性测试的标准方法,选用昆明种小鼠,皮下接种肉瘤S180瘤株,对氟铁龙衍生物F-1、F-2和F-3进行体内抗肿瘤活性研究,结果表明通式(I)所示的氟铁龙衍生物能显著降低肿瘤的大小,且未表现出明显的副作用,说明通式(I)所示的氟铁龙衍生物体内具有抗肿瘤活性,且副作用较氟铁龙降低。
Claims (7)
1.一种氟铁龙衍生物,具有下述通式(I)所示:
(I)
其中A环为苯环、呋喃、噻吩;
R为硝基;
X为CH2。
2.根据权利要求1所述的氟铁龙衍生物,选自下列化合物:
1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-(4-硝基苄基)嘧啶-2,4(1H,3H)-二酮;
1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-((5-硝基呋喃-2-基)甲基)嘧啶-2,4(1H,3H)-二酮;
1-((2S,3S,4R,5S)-3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-3-((5-硝基噻吩-2-基)甲基)嘧啶-2,4(1H,3H)-二酮。
3.权利要求1-2任一所述的氟铁龙衍生物在制备硝基还原酶介导的抗肿瘤药物中的用途。
4.根据权利要求3中所述肿瘤为血液肿瘤或恶性实体肿瘤。
5.根据权利要求3中所述肿瘤为绒毛膜上皮癌、恶性葡萄胎、直肠癌、肺癌、前列腺癌、乳腺癌、结肠癌、胃癌、胰腺癌、肝癌、食道癌、脑肿瘤、卵巢癌、子宫癌、肾癌、头颈癌、皮肤癌、膀胱癌、外阴癌、睾丸瘤、直肠癌、恶性淋巴瘤或白血病。
6.一种药物组合物,其中含有作为活性成分的权利要求1所述的氟铁龙衍生物以及一种或多种药用赋形剂。
7.根据权利要求6所述的药物组合物,其特征在于,所述的药物组合物的剂型为注射剂或者是口服剂型,其中注射剂为溶液型注射剂、混悬型注射剂、乳剂型注射剂、或注射用无菌粉末,口服剂型为片剂、散剂、颗粒剂、胶囊剂、微丸制剂、溶液剂、混悬剂、乳剂、糖浆剂或酏剂。
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