CN117003732A - 一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其应用 - Google Patents
一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其应用 Download PDFInfo
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- CN117003732A CN117003732A CN202310990342.1A CN202310990342A CN117003732A CN 117003732 A CN117003732 A CN 117003732A CN 202310990342 A CN202310990342 A CN 202310990342A CN 117003732 A CN117003732 A CN 117003732A
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- semicarbazone
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Abstract
本发明涉及一种新型含缩氨基脲结构的2‑苯氨基嘧啶类衍生物及其应用,属于医药技术领域,所述含缩氨基脲结构的2‑苯氨基嘧啶类衍生物具有通式(I)所示的结构,其可药用加酸成盐。药理活性筛选结果显示其对人慢性髓原白血病细胞K562和人慢性髓原白血病细胞耐伊马替尼细胞株K562/G01具有显著抑制作用,具有良好的抗肿瘤药物开发应用前景。
Description
技术领域
本发明属医药领域,具体涉及一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该类化合物及其药学上可接受的盐在制备治疗和/或预防癌症药物中的用途。
背景技术
慢性粒细胞白血病(CML)最初发现于1840年。CML是一种白血球骨髓细胞不受控制地生长造成的血液恶性肿瘤。CML属于恶性的血液肿瘤,发病患者表现的症状有贫血、容易出血、感染及器官浸润等。根据骨髓中白血病细胞的数量和症状的严重程度,CML的治疗阶段可分慢性期(CP)、加速期(AP)和急变期(BC),大约90%的CML患者诊断时为该病的慢性期。如果不加以治疗,恶性克隆的分化能力就会在2-4年后丧失,该病会发展到急变期成为急性白血病,而处于急变期的患者生存时间中位少于六个月。在未开发出靶向抑制剂之前,CML的常规治疗手段包括单药化疗、联合化疗、干扰素治疗及骨髓移植等。
慢性粒细胞白血病是一种骨髓造血干细胞恶性克隆性增生疾病,其发病机制是由于9号染色体的c-ABL基因和22号染色体的BCR基因发生平行易位形成一种异常染色体——费城(Philadelphia,Ph)染色体,该染色体中由于易位所导致的融合基因BCR-ABL会编码一种持续处于激活状态的蛋白酪氨酸激酶(Protein tyrosine kinase,PTK),即Bcr-Abl蛋白。Bcr-Abl蛋白这种持续处于激活状态的酪氨酸激酶会通过多种细胞内信号传导途径(例如SRC途径,Ras/Raf途径,MAPK途径,JAK/STAT信号传导途径和PI3K途径)导致细胞分裂加速,控制细胞周期,抑制细胞凋亡,影响细胞粘附转移能力,使细胞发生癌变。因此,Bcr-Abl蛋白被认为是分子靶向治疗CML最为理想的靶标。苯胺嘧啶类小分子药物伊马替尼(Imatinib)作为第一个Bcr-Abl蛋白酪氨酸激酶抑制剂,同时也是全球首个分子靶向抗肿瘤药,该药是由Novartis公司研发,商品名为Gleevec。伊马替尼于2001年被批准上市,用于慢性粒细胞白血病(CML)的治疗。该药物的成功上市也揭开了小分子酪氨酸激酶抑制剂抵抗肿瘤的序幕,并引领了一批批优秀的抗肿瘤药物发展。伊马替尼对BCR-AB激酶具有非常强的抑制作用,到目前为止仍旧是临床治疗CML的主要药物。虽然Imatinib在早期治疗中获得巨大成功,但是在临床应用过程中发现严重的耐药性等问题成为了该药的缺点,其耐药性临床主要表现为病人病情继续恶化,不见好转,使用伊马替尼后疗效不明显,特别是在疾病的晚期阶段。该耐药的主要机制是由于ABL激酶结构域中点突变的发生,即Abl蛋白在第315位的苏氨酸(T)被异亮氨酸(I)取代,故被称为“T315I”突变。该突变导致伊马替尼和Abl激酶活性域间失去形成关键性氢键所需的氧原子氢键供体,从而削弱药物与激酶活性域的亲和力。因此,为了克服伊马替尼耐药后治疗无效的问题,药物化学家们从未放弃对新型的BCR-ABL激酶抑制剂的研究与开发,希望为白血病患者带来福音。
发明内容
本发明的目的在于设计并合成一系列新的含缩氨基脲结构的2-苯氨基嘧啶类衍生物。经过体外活性筛选,表明该类化合物具有抗肿瘤活性。
本发明提供一种具有通式(I)所示的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,
其中:
Ar选自C6-C10芳基或5-10元杂芳基;其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、硝基、酯基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷基硫基、被羟基取代或被氨基取代或被卤代的C1-C6烷基、被羟基取代或被氨基取代或被卤代的C1-C6烷氧基、被单或双C1-C6烷基取代的氨基、C1-C6烷基酰氨基、游离的或成盐的或酯化的或酰胺化的羧基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、C1-C6烷基酰基、氨基甲酰基、和被单或双C1-C6烷基取代的氨基甲酰基。
进一步的,上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,其中,
Ar选自苯基、萘基、或5-10元杂芳基;其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、硝基、酯基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、被卤代的C1-C6烷基、被卤代的C1-C6烷氧基、被单或双C1-C6烷基取代的氨基、C1-C6烷基酰氨基、C1-C6烷基磺酰基、C1-C6烷基酰基、或氨基甲酰基。
进一步的,上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,其中,
Ar选自苯基或5-6元杂芳基;其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、硝基、氨基、氰基、甲基、C1-C6烷氧基、三氟甲基、三氟甲氧基、二氟甲氧基、甲磺酰基、被单或双C1-C6烷基取代的氨基、或C1-C6烷基酰氨基。
进一步的,上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,其中,
Ar为苯基或吡啶基,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、甲氧基、甲磺酰基、二甲氨基、二乙胺基、吗啉基、4-甲基-1-哌啶基或1-甲基哌嗪基。
进一步的,上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,具有如下结构式,但这些化合物并不意味着对本发明的任何限制:
一种药物组合物,包含上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐作为活性成分以及药学上可接受的赋形剂。
上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐或上述的药物组合物在制备治疗和/或预防增生性疾病药物中的应用。
上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐或上述的药物组合物在制备治疗和/或预防癌症药物中的应用。
上述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐或上述的药物组合物在制备治疗和/或预防白血病药物中的应用。
而且,按照本发明所属领域的一些通常方法,本发明中通式(I)所示的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及构型异构体可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐,与下列酸加成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外,本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式Ⅰ的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“亚烷基”是指直链或支链的亚烷基;“环烷基”是指取代或未取代的环烷基;“芳基”是指无取代基或连有取代基的苯基;“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,环状体系是芳香性的,如咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基、噻唑基、苯并噻唑基、噁唑基、异噁唑基、萘基、喹啉基、异喹啉基、苯并咪唑基和苯并噁唑基等;“饱和或部分饱和的杂环基”是指含有一个或多个选自N、O、S的杂原子的单环或多环的环状体系,如吡咯烷基、吗啉基、哌嗪基、哌啶基、吡唑烷基、咪唑烷基和噻唑啉基等。
本发明的有益效果是:
本发明通过体外抑制人慢性髓原白血病细胞K562、人慢性髓原白血病细胞耐伊马替尼细胞株K562/G01活性试验,证明本发明化合物对人慢性髓原白血病细胞和人慢性髓原白血病细胞耐伊马替尼细胞具有显著抑制作用,特别用于制备治疗和/或预防白血病的药物。
具体实施方式
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。化合物的核磁共振氢谱用Bruker ARX-600或Bruker ARX-400测定,质谱用Agilent 6460QQQ测定。所用试剂均为分析纯或化学纯。
下面的合成路线描述了本发明的通式(I)衍生物的制备,所有的原料都是通过下述的合成路线、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过下述的合成路线或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。下述的合成路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
合成路线如下所示:
制备通法
步骤A1-(3-吡啶基)-3-(二甲氨基)-2-丙烯-1-酮(a)
取3-乙酰基吡啶80g和Ν,Ν-二甲基甲酯胺二甲缩醛111g,加热至回流反应4-5h,停止加热,自然冷却至室温,减压浓缩反应液至干,得到深黄色晶体1-(3-吡啶基)-3-(二甲氨基)-2-丙烯-1-酮(a)106g。MS(ESI)m/z:177.1[M+H]+。
步骤B(2-甲基-5-硝基苯基)胍(b)
取2-甲基-5-硝基苯胺80g和50%单氰胺水溶液88.4g,再加入260mL异丙醇,控制上述溶液温度为0℃以下,缓慢滴加72mL浓盐酸,1-1.5h滴加完毕,升温至回流反应1h,补加24mL浓盐酸,继续反应4-5h。将反应液冷却至室温20℃,缓慢滴加发烟硝酸38.4mL,控制滴速使内浴温度不超过20℃。滴加完毕后继续室温搅拌30min后抽滤,2×300mL异丙醇洗,干燥,得白色固体(2-甲基-5-硝基苯基)胍(b)101.5g。MS(ESI)m/z:195.1[M+H]+。
步骤C N-(2-甲基-5-硝基苯基)-4-(3-吡啶基)-2-嘧啶胺(c)
取(2-甲基-5-硝基苯基)胍(b)36.5g,180mL正丁醇,再加入NaOH 3.95g,60℃下搅拌半个小时。向瓶中加入1-(3-吡啶基)-3-(二甲氨基)-2-丙烯-1-酮(a)17.5g,回流搅拌18h。将反应液冷却至50℃以下,加入400mL甲醇,搅拌半个小时,抽滤,2×100mL甲醇洗,得到黄色固体N-(2-甲基-5-硝基苯基)-4-(3-吡啶基)-2-嘧啶胺(c)24.1g。MS(ESI)m/z:308.1[M+H]+。
步骤D N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-氨基嘧啶(d)
取N-(2-甲基-5-硝基苯基)-4-(3-吡啶基)-2-嘧啶胺(c)35g和550mL无水乙醇,再加入活性炭1.3g和六水合三氯化铁15.4g,回流反应半个小时。在回流状态下缓慢滴加水合肼107g。滴加完全部水合肼后,连续反应15h。趁热抽滤,滤饼用100mL热乙醇洗。滤液减压蒸发除去大部分乙醇,析出黄色固体,抽滤,水洗滤饼至滤液呈中性,干燥,得黄色固体N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-氨基嘧啶(d)26.1g。MS(ESI)m/z:278.1[M+H]+。
步骤E苯基(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酸酯(e)
将N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-氨基嘧啶(d)5.00g,三乙胺5.47g,加入到60mL干燥THF中,在0℃-5℃下滴加苯基氯甲酸酯3.38g,添加完毕,室温下反应2h,减压蒸出溶剂,残余物溶于60mL二氯甲烷中,适量水洗4次,分出有机相,无水硫酸钠干燥,过滤,减压蒸干溶剂,得淡黄色固体苯基(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酸酯(e)5.3g,产物直接用于下一步反应。
步骤F N-(4-甲基-3-((4-(吡啶-3-)嘧啶-2-)氨)苯基)氨基脲(f)
将苯基(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)氨基甲酸酯(e)4.00g用20mL 1,4-二氧六环溶解,慢慢加入80%水合肼20mL,回流反应,过夜,反应完毕冷却至10℃以下,过滤出沉淀,水洗,真空干燥,得白色固体N-(4-甲基-3-((4-(吡啶-3-)嘧啶-2-)氨)苯基)氨基脲(f)2.8g。MS(ESI)m/z:336.1[M+H]+。
实施例1-25化合物制备通法:
将N-(4-甲基-3-((4-(吡啶-3-)嘧啶-2-)氨)苯基)氨基脲(f)0.20g和1.2当量的取代芳香醛加入到5mL乙醇中,加入适量冰醋酸,回流反应5-8小时,反应完毕,冷却至室温,过滤出沉淀,干燥得白色固体产物。
按照实施制备通法,分别制得实施例1-25化合物见表1。
表1:
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实施例26本发明含缩氨基脲结构的2-苯氨基嘧啶类衍生物的体外抗肿瘤细胞活性
对部分所合成的含缩氨基脲结构的2-苯氨基嘧啶类衍生物进行了体外抑制人慢性髓原白血病细胞K562和人慢性髓原白血病细胞耐伊马替尼细胞株K562/G01活性筛选。
体外细胞毒活性测试
(1)细胞复苏并传代2-3次稳定后,用胰蛋白酶溶液(0.25%)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中,之后加入培养液以终止消化。将离心管在800r/min下离心10min,弃去上清液后加入5mL培养液,吹打混匀细胞,吸取10μL细胞混悬液加入细胞计数板中计数,调整细胞浓度为104个/孔。96孔板中除A1孔为空白孔不加细胞外,其余皆加入100μL细胞混悬液。将96孔板放入培养箱中培养24h。
(2)用50μL二甲基亚砜溶解受试样品,然后加入适量培养液,使样品溶解成2mg/mL药液,然后在24孔板中将样品稀释为20,4,0.8,0.16,0.032μg/mL。
每个浓度加入3孔,其中周围两行两列细胞长势受环境影响较大,只做为空白细胞孔使用。将96孔板放入培养箱中培养72h。
(3)将96孔板中带药培养液弃去,用磷酸缓冲溶液(PBS)将细胞冲洗两遍,在每孔中加入MTT(四氮唑)(0.5mg/mL)100μL放入培养箱中4h后,弃去MTT溶液,加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解,放入酶标仪中测定结果。通过Bliss法可求出药物IC50值。实施化合物及阳性对照药伊马替尼抑制人慢性髓原白血病细胞K562和人慢性髓原白血病细胞耐伊马替尼细胞株K562/G01活性结果见表2所示。
表2
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从表2可以清楚地看出,本发明所要保护的通式(I)的化合物在体外对人慢性髓原白血病细胞K562和人慢性髓原白血病细胞耐伊马替尼细胞株K562/G01均具有良好的抑制活性。该类化合物具有良好的抗肿瘤药物开发应用前景。
尽管已经通过特定实施方案描述了本发明,但修改和等价变化对于精通此领域的技术人员而言是显见的,且它们都包含在本发明范围之。
Claims (9)
1.通式(I)所示的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,
其中:
Ar选自C6-C10芳基或5-10元杂芳基;其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、硝基、酯基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷基硫基、被羟基取代或被氨基取代或被卤代的C1-C6烷基、被羟基取代或被氨基取代或被卤代的C1-C6烷氧基、被单或双C1-C6烷基取代的氨基、C1-C6烷基酰氨基、游离的或成盐的或酯化的或酰胺化的羧基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、C1-C6烷基酰基、氨基甲酰基、和被单或双C1-C6烷基取代的氨基甲酰基。
2.根据权利要求1所述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,其特征在于,
Ar选自苯基、萘基、或5-10元杂芳基;其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、硝基、酯基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、被卤代的C1-C6烷基、被卤代的C1-C6烷氧基、被单或双C1-C6烷基取代的氨基、C1-C6烷基酰氨基、C1-C6烷基磺酰基、C1-C6烷基酰基、或氨基甲酰基。
3.根据权利要求2所述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,其特征在于,
Ar选自苯基或5-6元杂芳基;其中,所述杂芳基含有1-3个选自N、O或S的杂原子,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、硝基、氨基、氰基、甲基、C1-C6烷氧基、三氟甲基、三氟甲氧基、二氟甲氧基、甲磺酰基、被单或双C1-C6烷基取代的氨基、或C1-C6烷基酰氨基。
4.根据权利要求3所述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,其特征在于,
Ar为苯基或吡啶基,并且Ar被1-3个相同或不同的R1取代;
R1选自氢、羟基、卤素、甲氧基、甲磺酰基、二甲氨基、二乙胺基、吗啉基、4-甲基-1-哌啶基或1-甲基哌嗪基。
5.根据权利要求1所述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐,其特征在于,具有如下结构式:
6.一种药物组合物,其特征在于,包含权利要求1-5任一项所述的含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐作为活性成分以及药学上可接受的赋形剂。
7.权利要求1-5任一项所述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐或权利要求6所述的药物组合物在制备治疗和/或预防增生性疾病药物中的应用。
8.权利要求1-5任一项所述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐或权利要求6所述的药物组合物在制备治疗和/或预防癌症药物中的应用。
9.权利要求1-5任一项所述的一种新型含缩氨基脲结构的2-苯氨基嘧啶类衍生物及其药学上可接受的盐或权利要求6所述的药物组合物在制备治疗和/或预防白血病药物中的应用。
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