CN114957137B - N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物及其制备与应用 - Google Patents
N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物及其制备与应用 Download PDFInfo
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- CN114957137B CN114957137B CN202210582327.9A CN202210582327A CN114957137B CN 114957137 B CN114957137 B CN 114957137B CN 202210582327 A CN202210582327 A CN 202210582327A CN 114957137 B CN114957137 B CN 114957137B
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- tetrahydropyrimidin
- phenylacetamide
- compound
- pharmaceutically acceptable
- cancer
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明的N‑(1,2,3,6‑四氢嘧啶‑4‑基)‑2‑苯基乙酰胺类化合物及其制备与应用,属于医药技术领域,具体用于制备抗肿瘤药物。所述的N‑(1,2,3,6‑四氢嘧啶‑4‑基)‑2‑苯基乙酰胺类化合物结构通式如式(I)所示:n=2,3;R1为甲基或氟;R2、R3与各自相连的氮原子组成二甲氨基或吗啉‑4‑基;R4为氢或2,4,5‑三氟。本发明化合物的合成方法简便,适于工业化生产,生物活性测试显示此类化合物具有抗肿瘤活性,可应用于抗肿瘤药物中。
Description
技术领域
本发明属于医药技术领域,具体涉及N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物及其制备与应用,具体作为多靶点抑制剂应用于抗肿瘤方面。
背景技术
癌症是由基因引起的疾病,当调控细胞生长的基因发生突变或损伤时,细胞失去控制,持续地增生及分裂而产生肿瘤;因其无限增殖、可转化和易分散转移的特性,临床表现为较高的复发率和死亡率,现已成为一个困扰全世界的医疗难题。据2020年全球最新癌症负担数据(IARC提供)显示,2020年全球新发癌症病例1929万例,全球癌症死亡病例996万例,其中中国新发癌症457万人,占全球23.7%,远超世界其他国家。
过去对于癌症的治疗方法有手术治疗、放射治疗、化学治疗等。这些治疗方法在杀死癌细胞的同时,还对患者的身体有着不可逆的伤害。随着社会和科学的发展,癌症治疗手段不断改进,由对细胞的毒性攻击治疗已发展到针对癌细胞的靶向治疗。所谓的分子靶向治疗,是指在细胞分子水平上,针对已经明确的致癌位点而设计开发相应的治疗药物。该药物进入人体后会特异性地选择与致癌位点相结合,继而发生特异性作用,使肿瘤细胞死亡,而不会波及肿瘤周围的正常组织细胞。分子靶向性药物的共同特点是对正常组织细胞影响较小,毒性轻微,起效慢,其通过特异性针对肿瘤细胞中的一个或几个靶点抑制肿瘤细胞的恶性生物学行为。
分子靶向药物在化学特性上可以是单克隆抗体和小分子化合物。其作用靶点可以是细胞受体、信号转导和抗血管生成等。在1997年,当时利妥昔单抗(Rituxan)成为第一个获批用于治疗低级别B细胞淋巴瘤的单克隆抗体(mAb)。不久之后,FDA于1999年批准了单克隆抗体药物曲妥珠单抗(赫赛汀),这是第一个用于治疗实体瘤的药物,特别是用于过度表达HER2蛋白的晚期乳腺癌患者。第一个靶向小分子抗癌药物伊马替尼(格列卫)于2001年被FDA批准用于治疗慢性粒细胞白血病(CML)。紧随其后的是批准用于非小细胞肺癌(NSCLC)的蛋白质表皮生长因子受体(EGFR)的首个靶向药物,吉非替尼(Iressa)和厄洛替尼(Tarceva)。进一步的突破性治疗包括FDA批准的贝伐珠单抗(Avastin)是一种抗血管生成药物,通过阻断血管的生长而不是直接靶向肿瘤细胞来靶向肿瘤。它于2004年首次获准用于结直肠癌(CRC)患者,现在可用于治疗多种适应症,包括肺癌、卵巢癌和肾癌(Ward R A,Fawell S,Floc'H N,et al.Challenges and Opportunities in Cancer DrugResistance[J].Chemical Reviews,2020.)。
发明内容
本发明的目的是提供一种N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物及其制备与应用,具体为如式I所示的化合物、其前体药物和药物活性代谢物以及其药学上可接受的盐,并提供所述化合物的制备方法及其作为小分子抑制剂在治疗或/和预防乳腺癌、宫颈癌、结肠癌、非小细胞肺癌、小细胞肺癌、肝癌、黑色素瘤、前列腺癌等多种恶行肿瘤疾病方面的应用。
其中,
n=2,3;
R1为氢、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基或卤素;
R2、R3各自独立地为C1-C3烷基,或R2、R3与各自相连的氮原子组成吗啉环;
R4为氢或卤素。
R1和R4可以为一个或多个。
进一步地,本发明所述的如式I所示化合物、其前体药物和药物活性代谢物以及其药学上可接受的盐:
n=2,3;
R1为甲基或氟;
R2、R3与各自相连的氮原子组成二甲氨基或吗啉-4-基;
R4为氢或2,4,5-三氟。
进一步的,本发明优选如下化合物:
N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA01);
N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-(2,4,5-三氟苯基)乙酰胺(XA02);
N-(2-(二甲氨基)乙基)-N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺(XA03);
N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA04);
N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-(2,4,5-三氟苯基)乙酰胺(XA05);
N-(1,3-双(4-氟苯基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA06)。
一种药物组合物,包括作为活性成分的本发明所述的化合物,其前体药物和药物活性代谢物,以及其在药学上可接受的盐中任何一个的化合物和药学上可接受的载体或稀释剂。
所述的药物组合物为一种抑制丝裂原活化蛋白激酶的药物组合物。
“药学上可接受的盐”指保留了式I化合物的生物效力和性质,并与合适的非毒性有机或无机酸或有机或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐包括盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、磷酸盐、硫酸盐、高氯酸盐、硫氰酸盐、硫酸氢盐、过硫酸盐、硼酸盐、甲酸盐、乙酸盐、丙酸盐、戊酸盐、新戊酸盐、己酸盐、庚酸盐、辛酸盐、异辛酸盐、十一烷酸盐、月桂酸盐、棕榈酸盐、硬脂酸盐、油酸盐、环丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、己二酸盐、壬二酸盐、丙烯酸盐、草莓盐、巴豆酸盐、惕格酸盐、衣康酸盐、山梨酸盐、肉桂酸盐、乙醇酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、亚酒石酸盐、扁桃酸盐、二苯乙醇酸盐、托品酸盐、抗坏血酸盐、葡萄糖酸盐、葡庚糖酸盐、葡萄糖二酸盐、甘露糖酸盐、乳糖酸盐、苯甲酸盐、酞酸盐、对酞酸盐、糠酸盐、烟酸盐、异烟酸盐、水杨酸盐、乙酰水杨酸盐、酪酸盐、没食子酸盐、咖啡酸盐、阿魏酸盐、苦味酸盐、樟脑酸盐、樟脑磺酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、苯磺酸盐、对甲苯磺酸盐、对氨基苯磺酸盐、氨基磺酸盐、牛磺酸盐、2-羟基乙磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、色氨酸盐、酪氨酸盐、天冬氨酸盐、天冬酰胺盐、谷氨酸盐、赖氨酸盐、谷氨酰胺盐、甲硫氨酸盐、丝氨酸盐、苏氨酸盐、半胱氨酸盐、脯氨酸盐、组氨酸盐、精氨酸盐、依地酸盐、丙酮酸盐、α-酮戊二酸盐、藻酸盐、环戊烷丙酸盐、3-苯基丙酸盐、3-环己基丙酸、2-萘甲酸盐、2-萘磺酸盐、双羟萘酸盐、月桂基硫酸盐、甘油磷酸盐、月桂基硫酸盐、果胶脂酸盐等。碱盐包括铵盐,碱金属盐,例如钠和钾盐,碱土金属盐,例如钙和镁盐,有机碱的盐,例如二环己胺盐,N-甲基-D-葡糖胺盐等,而且,碱性含氮基团可以用这样的试剂季铵化,例如低级烷基卤化物,如甲基,乙基,丙基和丁基的氯、溴和碘化物;硫酸二烷基酯,如硫酸二甲酯,二乙酯,二丁酯和二戊酯;长链卤化物,如癸基,月桂基,肉豆蔻基和硬脂酰基的氯、溴和碘化物;芳烷基卤化物,如苄基和苯乙基的溴化物等。优选用于生成酸加成盐的酸包括盐酸、对甲苯磺酸、甲磺酸、顺丁烯二酸、苹果酸、苦味酸、柠檬酸、对氨基苯磺酸。
本发明也涉及抑制MAPK,MEK激酶,ERK MEK和Raf激酶的药用组合物,该组合物含有式I化合物或衍生物或其药学上适用的酸加成盐以及药学上可接受的载体。
“药学上可接受的”如药学上可接受的载体、赋形剂、前体药物等,指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。
“药学活性代谢物”指药学上可接受并有效的式I化合物的代谢产物。
本发明中应用的术语“卤素”包括氟、氯、溴或碘。
本发明化合物可以通过不同的方法给患者服用,例如以胶囊剂或片剂口服,以无菌溶液剂或混悬剂给药,并且在某些情况下,可以以溶液剂形式静脉注射。可以将本发明的游离碱化合物以其药学上适用的酸加成盐形式进行配制和服用。
本发明所述化合物作为全新结构类型的与BRaf激酶,血管内皮生长因子受体(Vascular endothelial growth factor receptor,VEGFR),表皮生长因子受体(epidermal growth factor receptor,EGFR)和丝裂原活化的细胞外信号调节激酶(mitogen-activated extracellular signal-regulated kinase,MEK)等相关的小分子抑制剂,具有结构类型新颖,且能够作用于多个靶点等特点,可用于治疗或预防与BRaf激酶,血管内皮生长因子受体-2(Vascular endothelial growth factor receptor-2,VEGFR-2)血小板衍生生长因子受体-β(Platelet-derived growth factor receptors-β,PDGFR-β)表皮生长因子受体(epidermal growth factor receptor,EGFR)和丝裂原活化的细胞外信号调节激酶(mitogen-activated extracellular signal-regulated kinase,MEK)相关的肿瘤疾病如小细胞肺癌,鳞癌,腺癌,大细胞癌,结肠直肠癌、乳腺癌,卵巢癌,肾细胞癌,具有良好的应用价值和开发应用前景。
本发明化合物的制备路线如下:
本发明所述化合物XA01-XA06及药学上可接受的盐、以及其前体药物,具有丝裂原活化蛋白激酶(MAPK),丝裂原活化蛋白激酶激酶(MEK),细胞外调节蛋白激酶(ERK)和Raf蛋白激酶抑制活性的作用。
本发明有益效果:
本发明提供了一类全新抗肿瘤化合物的结构,具有潜在的成药价值,该化合物制备路线简便,易于合成且成本低廉。与已上市药物相比,具有更加显著的抗肿瘤细胞增殖活性。
具体实施方式
以下述实例详细叙述本发明。但是,应当明白,本发明不限于具体叙述的下述实例。实施例1:N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA01)的制备
步骤A:1,3-二对甲苯脲的制备
称量40mL二氯甲烷溶解固体光气(9.5g,32mmol)于500mL圆底烧瓶内,称量对甲苯胺(8.57g,80mmol)溶于40mL二氯甲烷中,室温下将其用滴液漏斗在30min内滴入瓶内,再称量三乙胺(20.24g,0.2mol)溶于50mL二氯甲烷中,并在30min内滴入瓶内,再次称量对氟苯胺(8.57g,80mmol)溶于40mL二氯甲烷中,按上述再次滴入瓶内。滴完后搅拌反应30min监测对氟苯胺反应完全。减压蒸馏除去约3/4体积的二氯甲烷,再用5%HCl溶液搅拌5-10min后产生大量固体,滤出固体,用乙醚反复洗涤,干燥后得到1,3-二对甲苯脲白色固体18.25g,产率95.01%。
步骤B:6-氯-1,3-双(4-甲基苯基)嘧啶-2,4(1H,3H)-二酮的制备
称量1,3-二对甲苯脲(4.81g,20mmol)、丙二酸(2.7g,26mmol)、三氯氧磷(3.4g,22mmol)和15ml乙腈置于35mL密封管内。密封加热至120℃后反应1h,监测原料1,3-二对甲苯脲反应完全后,将封管内的反应液倒入茄形瓶内,减压蒸馏除去所有溶剂,加入50mL2mol/L NaOH和20mL乙酸乙酯搅拌溶解。再用2mol/L NaOH水溶液萃取有机相三次,合并水层,再用少量乙酸乙酯萃取水层一次,留下的水层用盐酸调pH至产生大量固体。滤出固体,用水洗涤滤饼,干燥后得黄白色固体1,3-双(4-甲基苯基)嘧啶-2,4,6(1H,3H,5H)-三酮3.89g,产率63.11%。步骤C:称量1,3-双(4-甲基苯基)嘧啶-2,4,6(1H,3H,5H)-三酮(4.99g,16.2mmol)、三氯氧磷(4.92g,32.4mmol)和20ml乙腈置于125mL密封管内。密封加热至120℃后反应3h,监测原料反应完全后,将封管内的反应液倒入茄形瓶内,减压蒸馏除去所有溶剂,加入少量乙醇溶解混合物,再加水以析出固体,滤出固体,用水洗涤滤饼,干燥后得到6-氯-1,3-双(4-甲基苯基)嘧啶-2,4(1H,3H)-二酮红棕色固体4.86g,产率92.18%。
步骤D:6-[(3-吗啉丙基)氨基]-1,3-双(4-甲基苯基)嘧啶-2,4(1H,3H)-二酮的制备
称量6-氯-1,3-双(4-甲基苯基)嘧啶-2,4(1H,3H)-二酮(2.70g,8.3mmol)、N-(3-氨丙基)吗啉(2.03g,14.1mmol)、三乙胺(1.84g,18.2mmol)和20mL乙醇于50mL圆底烧瓶内,搅拌回流反应8小时后反应完全。减压蒸馏除去大部分乙醇,加入乙醚搅拌出固体。滤出固体,用乙醚洗涤固体,干燥后得到6-[(3-吗啉丙基)氨基]-1,3-双(4-甲基苯基)嘧啶-2,4(1H,3H)-二酮白色固体2.04g,产率56.60%。
步骤E:N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA01)的制备
称量6-[(3-吗啉丙基)氨基]-1,3-双(4-甲基苯基)嘧啶-2,4(1H,3H)-二酮(1.30g,3mmol)、苯乙酸(0.61g,4.5mmol)、EDCI(0.86g,4.5mmol)和5mL吡啶与25mL圆底烧瓶中,加热至100℃后搅拌回流2h,TLC监测有明显产物点,停止反应。减压蒸馏除去吡啶,加入2mol/L盐酸溶液和乙酸乙酯搅拌2h左右,抽滤除去析出的固体,分离出EA层,再用EA萃取水层3次,收集有机层,用2mol/L盐酸溶液洗1次,再用饱和碳酸氢钠溶液洗3次,饱和食盐水洗1次,干燥有机层,减压蒸馏除去溶剂后进行柱层析纯化得到N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA01)黄色固体,产量0.19g,产率11.47%;m.p.:65.5-68.4℃;MS:553.2([M+H]+);1H NMR(400MHz,DMSO-d6)δ7.43–7.37(m,2H),7.32–7.09(m,12H),4.30(s,2H),3.48(t,J=4.6Hz,4H),2.43(q,J=6.6Hz,2H),2.36(s,3H),2.34(s,3H),2.16(t,J=4.5Hz,4H),2.05(t,J=6.8Hz,2H),1.41(p,J=6.9Hz,2H)。
实施例2:N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-(3-吗啉丙基)-2-(2,4,5-三氟苯基)乙酰胺(XA02)的制备
采用实施例1的方法制得到N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-(3-吗啉丙基)-2-(2,4,5-三氟苯基)乙酰胺(XA02)白色固体,产量0.37g,产率88.40%;m.p.:70.2-73.2℃;MS:607.29([M+H]+);1H NMR(400MHz,DMSO-d6)δ7.52–7.19(m,9H),7.14(d,J=8.2Hz,2H),4.33(s,2H),3.47(t,J=4.6Hz,4H),2.44(td,J=6.9,4.9Hz,2H),2.36(s,3H),2.34(s,3H),2.15(t,J=4.6Hz,4H),2.03(t,J=6.8Hz,2H),1.40(p,J=6.9Hz,2H)。
实施例3:N-[2-(二甲氨基)乙基]-N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺(XA03)制备
采用实施例1的方法制得到N-[2-(二甲氨基)乙基]-N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺(XA03)黄色固体,产量0.17g,产率13.18%;m.p.:132.8-135.7℃;MS:497.25([M+H]+);1H NMR(400MHz,DMSO-d6)δ7.45–7.06(m,14H),4.29(s,2H),2.41(t,J=6.2Hz,2H),2.36(s,3H),2.34(s,3H),2.13(t,J=6.0Hz,2H),1.98(s,6H)。
实施例4:N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA04)的制备
采用实施例1的方法,得到N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA04)黄色固体,产量0.23g,产率15.09%;m.p.:56.0-57.2℃;MS:553.26([M+H]+);1H NMR(400MHz,DMSO-d6)δ7.42–7.12(m,12H),7.09–7.00(m,2H),4.31(s,2H),3.48(t,J=4.6Hz,4H),2.43(s,2H),2.34(s,3H),2.33(s,3H),2.16(t,J=4.6Hz,4H),2.04(t,J=6.8Hz,2H),1.42(p,J=6.9Hz,2H)。
实施例5:N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-(2,4,5-三氟苯基)乙酰胺(XA05)的制备
采用实施例1的方法制得N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-(2,4,5-三氟苯基)乙酰胺(XA05)黄色固体,产量0.22g,产率13.44%;m.p.:67.1-68.9℃;MS:607.32([M+H]+);1H NMR(400MHz,DMSO-d6)δ7.50–7.28(m,8H),7.24–7.18(m,1H),7.11–7.04(m,2H),4.33(s,2H),3.47(t,J=4.6Hz,4H),2.43(s,2H),2.35(s,3H),2.33(s,3H),2.15(t,J=4.8Hz,4H),2.02(t,J=6.8Hz,2H),1.40(p,J=7.0Hz,2H)。
实施例6:N-(1,3-双(4-氟苯基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA06)的制备
采用实施例1的方法,得到N-(1,3-双(4-氟苯基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺(XA06)黄色固体,产量0.25g,产率13.13%;m.p.:60.4-62.9℃;MS:561.1([M+H]+);1H NMR(400MHz,DMSO-d6)δ7.64–7.57(m,2H),7.41–7.14(m,12H),4.31(s,2H),3.48(t,J=4.6Hz,4H),2.44(td,J=6.9,4.8Hz,2H),2.17(dt,J=5.2,2.5Hz,4H),2.08(t,J=6.8Hz,2H),1.45(p,J=6.3,5.8Hz,2H)。
药理实施例
实施例7:受试化合物对MCF7、A375、SK-Mel-2细胞增殖的抑制活性
(1)实验材料
细胞系:MCF7、A375、SK-Mel-2细胞分别以4000、5000、4000个/孔的密度铺于96孔板,每孔100ul,24h后使用。
编号XA01-XA06目标化合物:以DMSO溶解,用培养液稀释配制为100μM、50μM、25μM、12.5μM、6.25μM、3.125μM六个不同浓度保存于-20℃待用,DMSO在培养液中的终浓度低于0.1%。
阳性对照药:5-氟尿嘧啶(5-Fu,Fluorouracil)和奥沙利铂。
MTT:以PBS溶解为2mg/mL,保存于-20℃。
(2)实验方法
利用MTT方法,选取MCF7、A375、SK-Mel-2细胞来评价供试样品的抗肿瘤增值活性。MCF7、A375、SK-Mel-2细胞株在DMEM培养基上进行培养,该培养基包含10%小牛血清(FBS)。当细胞增殖至80-90%时使其合并随后进行不超过20代的传代培养,然后在下一步处置前使它们适应环境达到24h。将这些细胞置于96孔板上,然后在含有5%CO2、恒温37℃的孵箱中培养至细胞贴壁完全。24h过后加入不同浓度的发明代表性化合物。再经过24h的培养,向其中加入MTT(2mg/mL)并继续培养4h。移除培养基质,将晶体溶解于DMSO中,利用酶标仪(Thermo Multiskan GO,Thermo Fisher,美国)在570nm波长下测量吸光度。根据公式:细胞生长抑制率=(1-药物组OD值/对照组OD值)×100%,计算相应浓度下的细胞生长抑制率,以受试化合物的不同浓度及对细胞的抑制率作对数曲线,计算受试化合物相对应的IC50值。按照上述方法测定本发明代表性化合物。
制剂实施例
下列制剂实施例仅举例说明本发明的保护范围,但不以任何方式构成限定。以下实施例中所述的活性化合物即指上述实施例中制得的化合物XA01-XA07。
实施例9:片剂配方
活性化合物25-1000mg,淀粉45mg,微晶纤维素35mg,聚乙烯吡咯烷酮(为10%水溶液)4mL,羧甲基纤维素钠4.5mg,硬脂酸镁0.5mg,滑石1mg。
实施例10:悬浮剂配方
活性化合物0.1-1000mg,羧甲基纤维素钠50mg,糖浆1.25mg,苯甲酸钠0.1mg,矫味剂25mg,着色剂5mg,加纯水至5mL。
实施例11:气溶胶配方
活性化合物0.25mg,乙醇25-75mL,抛射剂22(氯二氟甲烷)70mg。
实施例12:栓剂配方
活性化合物250mg,饱和脂肪酸甘油酯类2000mL。
实施例13:可注射制剂配方
活性化合物50mg,等渗盐溶液1000mL。
实施例14:软膏配方
微粉化活性化合物0.025g,液体石蜡10g,加软白蜡至100g。
实施例15:软膏配方
活性化合物0.025g,丙二醇5g,脱水山梨醇倍半油酸酯5g,液体石蜡10g,加软白蜡至100g。
实施例16:水包油霜剂配方
活性化合物0.025g,十六醇5g,单硬脂酸甘油酯5g,液体石蜡10g,鲸蜡醇聚氧乙烯醚2g,柠檬酸0.1g,柠檬酸钠0.2g,丙二醇35g,加水至100g。
实施例17:水包油霜剂配方
微粉化活性化合物0.025g,软白蜡15g,液体石蜡5g,十六醇5g,Sorbimacrogolstearate(特定药用辅料级的吐温65)2g,脱水山梨醇单硬脂酸酯0.5g,山梨酸0.2g,柠檬酸0.1g,柠檬酸钠0.2g,加水至100g。
实施例18:油包水霜剂配方
活性化合物0.025g,软白蜡35g,液体石蜡5g,脱水山梨醉倍半油酸酯5g,山梨酸0.2g,柠檬酸0.1g,柠檬酸钠0.2g,加水至100g。
实施例19:洗剂配方
活性化合物0.25g,异丙醇0.5mL,羧基乙烯基聚合物3mg,NaOH 2mg,加水至1g。
实施例20:注射用悬浮液配方
活性化合物10mg,羧甲基纤维素钠7mg,NaCl 7mg,聚氧乙烯(20)脱水山梨醇单油酸酯0.5mg,苯甲醇8mg,加无菌水至1mL。
实施例21:用于口腔和鼻吸入的气雾剂配方
活性化合物0.1%w/w,脱水山梨醇三油酸酯0.7%w/w,三氯氟甲烷24.8%w/w,二氯四氟乙烷24.8%w/w,二氯二氟甲烷49.6%w/w。
实施例22:雾化溶液配方
活性化合物7mg,丙二醇5mg,加水至10g。
实施例23:用于吸入的粉剂配方
用下述成份的混合物填充明质胶囊,微粉化活性化合物0.1mg,乳糖20mg,借助于吸入装置吸入该粉末。
实施例24:用于吸入的粉剂配方
球化的粉剂装入多剂粉末吸入器,每剂含有微粉化活性化合物0.1mg。
实施例25:用于吸入的粉剂配方
将球化的粉剂装入多剂粉末吸入器,每剂含有微粉化活性化合物0.1mg,微粉化乳糖1mg。
实施例26:胶囊剂配方
活性化合物1.0mg,小糖球321mg,Aquacoat ECD 30 6.6mg,乙酰柠檬酸三丁酯0.5mg,吐温-80 0.1mg,Eudragit L 100-55 17.5mg,柠檬酸三乙酯1.8mg,滑石粉8.8mg,消泡剂MMS0.lmg。
实施例27:胶囊剂苗体配方
活性化合物2.0mg,小糖球305mg,Aquocoat ECD 30 5.0mg,乙酰柠檬三丁酯0.4mg,吐温-80 0.14mg,Eudragit NE30 D 12.6mg,Eudragit S 100 12.6mg,滑石粉0.l6mg。
实施例28:灌肠剂配方
活性化合物2mg,羧甲基纤维素钠25mg,乙二胺四乙酸二钠0.5mg,对羟基苯甲酸甲酯0.8mg,对羟基苯甲酸丙酯0.2mg,氯化钠7mg,柠檬酸1.8mg,吐温-80 0.01mg,加纯水至1mL。
实施例29:含有脂质体的配方
A.滴注配方的制备
将二棕榈酰基卵磷脂(45mg),二肉豆蔻酰基卵磷脂(7mg),二棕榈酰基磷脂酰甘油(1mg)和活性化合物(5mg)放入玻璃管中,将所有组份溶解在氯仿中,用N2蒸发掉大部分溶剂,然后减压,由此,在玻璃管表面形成脂质薄膜.在该脂质中加入水溶液(0.9%NaCl),在高于脂质的转相温度下形成脂质体,所得悬液含有大小范围为极小囊泡至2μm的脂质体。
B.吸入用配方的制备
按实施例A制备脂质体,其中的水溶液含有10%乳糖,乳糖与脂质之比为7:3。将该脂质体悬液用干冰冷冻,并且进行冷冻干燥,将干燥产物微粉化,所得颗粒的质均空气动力学直径(MMAD)约为2μm。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其他形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (9)
1.一种如式I所示的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物或其药学上可接受的盐,其特征在于,所述式I结构为:
n=2,3;
R1为氢、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基或卤素;
R2、R3各自独立地为C1-C3烷基,或R2、R3与各自相连的氮原子组成吗啉环;
R4为氢或卤素;
R1和R4为一个或多个。
2.根据权利要求1所述的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物或其药学上可接受的盐,其特征在于,式I中:
R1为甲基或氟;
R2、R3与各自相连的氮原子组成二甲氨基或吗啉-4-基。
3.根据权利要求2所述的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物或其药学上可接受的盐,其特征在于,所述化合物为如下化合物中任一个:
N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺;
N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-(2,4,5-三氟苯基)乙酰胺;
N-[2-(二甲氨基)乙基]-N-(2,6-二氧代-1,3-二对甲苯基-1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺;
N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺;
N-(2,6-二氧代-1,3-二间甲苯基-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-(2,4,5-三氟苯基)乙酰胺;
N-(1,3-双(4-氟苯基)-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)-N-[3-(吗啉-4-基)丙基]-2-苯基乙酰胺。
4.一种药物组合物,其特征在于,所述药物组合物包括作为活性成分的权利要求1-3任一项所述的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物或其药学上可接受的盐中任何一个的化合物和药学上可接受的载体或稀释剂。
5.根据权利要求4所述的药物组合物,其特征在于,所述的药物组合物为一种抑制丝裂原活化蛋白激酶的药物组合物。
6.一种权利要求1所述的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物或其药学上可接受的盐的制备方法,其特征在于,所述的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物制备路线如下:
7.一种权利要求1-3任一项所述的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物或其药学上可接受的盐或权利要求4-5任一项所述的药物组合物的应用,其特征在于,应用于制备抑制MCF7、A375、SK-MEL-2肿瘤细胞增长的药物。
8.一种权利要求1-3任一项所述的N-(1,2,3,6-四氢嘧啶-4-基)-2-苯基乙酰胺类化合物或其药学上可接受的盐或权利要求4-5任一项所述的药物组合物的应用,其特征在于,应用于制备治疗肿瘤药物中。
9.根据权利要求8所述的应用,其特征在于,所述的肿瘤为肺癌、肝癌、黑色素瘤、结肠癌、直肠癌、乳腺癌、卵巢癌、宫颈癌及肾癌。
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