CN115850248A - 一种替尼类抗肿瘤药物化合物及其制备方法和应用 - Google Patents
一种替尼类抗肿瘤药物化合物及其制备方法和应用 Download PDFInfo
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- CN115850248A CN115850248A CN202211576464.8A CN202211576464A CN115850248A CN 115850248 A CN115850248 A CN 115850248A CN 202211576464 A CN202211576464 A CN 202211576464A CN 115850248 A CN115850248 A CN 115850248A
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Abstract
Description
技术领域
本发明属于抗肿瘤化合物技术领域,具体涉及一种新的替尼类抗肿瘤药物化合物及其制备方法,该化合物的制剂以及在制备抗癌药物中的应用。
背景技术
肿瘤是一类严重危害人类生命健康的疾病,是机体在致癌因素作用下,局部组织的某个细胞在基因水平上失去对其生长的正常调控,导致其克隆性异常增生而形成的异常病变,表现为细胞过度增殖、分化异常。目前癌症已成为人类第一死因,对人类生存构成最严重的威胁。
替尼类药物的开发,成功的将癌症带入到靶向治疗时代,靶点为人表皮生长因子酪氨酸激酶受体,包括:erbB1(EGFR,HER-1)、erbB2(HER-2,neu)、erbB3(HER-3)、erbB4(HER-4),替尼类药物使患者在延长生存期的同时,也大幅度提高了生存质量。
目前临床上主要使用的替尼类靶向药物为可逆性酪氨酸激酶抑制剂(tyrosinekinase inhibitor,TKI)、厄洛替尼(Erlotinib,商品名为特罗凯)或吉非替尼(Gefitinib,商品名为易瑞沙)、不可逆性酪氨酸激酶抑制剂阿法替尼(Afatinib,2013年FDA批准)、靶向药物奥西替尼(AZD9291,2015年FDA批准)。2018年FDA批准达克替尼(Dacomtinib)用于一线治疗。但是现在临床使用的替尼类抗肿瘤药依然存在耐药性、治疗效果有限和毒副作用较高的缺点,因此开发新型高效低毒的靶向替尼类抗肿瘤药物具有重要的意义。
发明内容
本发明的目的在于提供一种新的靶向替尼类抗肿瘤药物化合物,具有抗肿瘤活性高、毒副作用低的特点。
本发明的另一目的在于提供一种所述的替尼类抗肿瘤药物化合物的合成方法。
本发明的另一目的还在于提供一种所述的替尼类抗肿瘤药物化合物的组合物。
同时,本发明的另一目的还在于提供所述替尼类抗肿瘤药物化合物在制备抗肿瘤药物中的应用。
本发明的替尼类抗肿瘤药物化合物,化学名称为马来酰亚胺烷基酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺。它的分子式可以用通式I表示:
式中,n=0-10的整数。
优选地,所述的替尼类抗肿瘤药物化合物为6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺。
本发明还涉及所述的抗肿瘤药物化合物的制备方法,包括以下步骤:
(1)制备中间体4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5);
(2)4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5)与马来酰亚胺基烷基酸或其衍生物(6)进行N-酰化反应,生成本发明的抗肿瘤药物化合物(I);
其中,n=0-10的整数,X为OH、Cl、Br或OR,R为烃基。
所述的马来酰亚胺基烷基酸或其衍生物(6)优选为马来酰亚胺基烷基酸或马来酰亚胺基烷基酰氯,即X优选为OH或Cl。
优选地,所述的N-酰化反应中,4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5)与马来酰亚胺基烷基酸或其衍生物(6)的摩尔比为1:1~1.5。
优选地,所述的N-酰化反应的缩合剂选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、二环己基碳二亚胺(DCC)、N,N'-羰基二咪唑(CDI)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)或二异丙基碳二亚胺(DIC)中的一种或几种;缚酸剂选自三乙胺、吡啶、二异丙基乙胺、甲醇钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾中的一种或几种。
所述的中间体4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5)的制备可参照WO2005107758A1所公开的方法。或者,参照现有技术中众多有关替尼类化合物的技术文献所披露的方法。
本发明还涉及一种所述替尼类抗肿瘤药物化合物的组合物,其中包含有效治疗量的所述替尼类抗肿瘤药物化合物以及药学上可接受的辅料。
本发明的替尼类抗肿瘤药物化合物的组合物可以制成各种常见的制剂,包括口服制剂、注射剂或外用制剂,如片剂、胶囊剂、脂质体剂、乳剂或微乳液剂、胶束剂和膏剂等。片剂包括所述的替尼类抗肿瘤药物化合物和辅料。胶囊剂包括所述的替尼类抗肿瘤药物化合物和辅料。脂质体剂包括所述的替尼类抗肿瘤药物化合物、磷脂(最具有代表性的是卵磷脂、磷脂酰胆碱)、胆固醇和水相。乳剂包括所述的替尼类抗肿瘤药物化合物、一种或多种表面活性剂、油相(亲脂性介质)和水相。乳剂可以是水包油型或油包水型。胶束剂包括所述的替尼类抗肿瘤药物化合物、助溶剂和一种或多种表面活性剂和水相。膏剂包括所述的替尼类抗肿瘤药物化合物和基质。
本发明还提供了所述的替尼类抗肿瘤药物化合物在制备抗癌药物中的应用。
本发明的替尼类抗肿瘤药物化合物可用于治疗包括血液系统的癌症,如白血病,淋巴瘤,骨髓瘤;和非血液癌症,如实体瘤癌(如乳腺癌、卵巢癌、宫颈癌、胰腺癌、食道癌、结肠癌、直肠癌、肺癌、膀胱癌、胃癌、肝癌、皮肤癌),肉瘤和胶质瘤等。
本发明的替尼类药物化合物的疗效和毒性用体外细胞或体内动物实验来确定,例如,ED50(50%effective dose,半数有效量:50%实验对象出现阳性反应时的药量)、LD50(50%lethal dose,半数致死量,杀死一半试验对象的剂量)和GI50(concentration ofthe anti-cancer drug that inhibits the growth of cancer cells by 50%,抑制50%的实验对象生长的药物浓度)。通常将半数致死量(LD50)/半数有效量(ED50)的比值称为治疗指数,用以表示药物的安全性。治疗指数大的药物相对治疗指数小的药物更安全。所述的替尼类抗肿瘤药物化合物旨在提高治疗指数和药物的安全性,同时也提高治疗效果。这种化合物的剂量最好在很少或根本没有毒性的ED50范围内。剂量变化通常取决于采用的剂型、病人的敏感性和给药途径等。本发明的替尼类抗肿瘤药物化合物可以单独使用,也可与一个或多个其它的治疗药物一起使用。
有益效果:本发明所述替尼类抗肿瘤药物化合物具有良好的抗癌活性,可用于制备治疗血液和淋巴系统的癌症、实体瘤癌的药物。
附图说明
图1抗肿瘤药物化合物6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)的核磁共振氢谱图。
图2抗肿瘤药物化合物6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)的质谱图。
具体实施方式
下面的实施例用来说明本发明的抗肿瘤药物化合物的合成、制剂、体内药效学等。所述的实施例有助于对本发明的理解和实施,并不构成对于本发明的限制。
以下实施例中,本发明所述的替尼类抗肿瘤药物化合物的具体合成步骤包括(参见反应式2):
(1)以7-氟-6-硝基喹唑啉-4(3H)-酮(1)为原料合成7-甲氧基-6-硝基喹唑啉-4(3H)-酮(2);
(2)步骤(1)所得到的7-甲氧基-6-硝基喹唑啉-4(3H)-酮(2)与三氯氧磷反应,生成4-氯-7-甲氧基-6-硝基喹唑啉(3);
(3)4-氯-7-甲氧基-6-硝基喹唑啉(3)与3-氯-4-氟苯胺反应,生成4-(3-氯-4-氟苯胺基)-7-甲氧基-6-硝基喹唑啉(4);
(4)4-(3-氯-4-氟苯胺基)-7-甲氧基-6-硝基喹唑啉(4)与铁粉反应,生成4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5);
(5)4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5)马来酰亚胺基烷基酸或马来酰亚胺基烷基酰氯,生成所述的抗肿瘤药物化合物(I)。
所述替尼类抗肿瘤药物化合物被证明具有良好的抗癌活性,有效治疗量的所述替尼类抗肿瘤药物化合物与药学上可接受的辅料组合可以得到一种抗肿瘤药物组合物。
本发明的替尼类抗肿瘤药物化合物可以制成各种常见的制剂,包括口服制剂、注射剂或外用制剂,如片剂、胶囊剂、脂质体剂、乳剂或微乳液剂、胶束剂和膏剂等。以下结合常见的制剂形式,对包含所述替尼类抗肿瘤药物化合物的各种制剂及辅料的选择进行详细的说明。
一种所述的替尼类抗癌药物化合物的片剂,其成分包括:
(1)本发明的替尼类抗肿瘤药物化合物;
(2)辅料。
常用的辅料包括:①稀释剂(Diluents),如淀粉、糖粉、糊精、乳糖、预胶化淀粉(Pregelatinized starch)、微晶纤维素(Microcrystalline cellulose,MCC)、无机钙盐,如硫酸钙、磷酸氢钙及药用碳酸钙、甘露醇;②粘合剂(Adhesives),如蒸馏水、乙醇、淀粉浆、羧甲基纤维素钠(carboxymethylcellulose sodium,CMC-Na)、羟丙基纤维素(hydroxypropylcellulose,HPC)、甲基纤维素和乙基纤维素(Methylcellulose,MC;Ethylcellulose,EC)、羟丙甲纤维素(Hydroxypropylmethyl cellulose,HPMC)、其它粘合剂(5%~20%的明胶溶液,50%~70%的蔗糖溶液,3%~5%的聚乙烯毗咯烷酮(PVP)的水溶液或醇溶液);③崩解剂(Disintegrants),如干淀粉、羧甲基淀粉钠(Carboxymethylstarch sodium,CMS-Na)、低取代羟丙基纤维素(L-HPC)、交联聚乙烯比咯烷酮(Cross-linked polyvinyl pyrrolidone,亦称交联PVP)、交联羧甲基纤维素钠(Croscarmellosesodium,CCNa是交联化的纤维素羧甲基醚(大约有70%的羧基为钠盐型);④润滑剂(Lubricants),如硬脂酸镁、氢化植物油、聚乙二醇、月挂醇硫酸镁、微粉硅胶(Aerosil)、滑石粉;⑤着色剂;⑥矫味剂等。无论加入何种辅料,都应符合药用的要求,都不能与主药发生反应,也不应妨碍主药的溶出和吸收。
片剂可采用湿法制粒压片、干法制粒压片和直接压片制备。
或者,一种所述的抗癌药物化合物的胶囊剂,包括硬胶囊和软胶囊。其成分包括:
1)本发明的替尼类抗肿瘤药物化合物;
2)辅料。
硬胶囊剂的常用辅料包括但不限于:①稀释剂:用于改善内容物的物理特性和增加体积,往往具有一定的可压性。常用的稀释剂有甘露醇、微晶纤维素、乳糖、预胶化淀粉1500、玉米淀粉等。②润滑剂:以防止粉末与金属材料的黏附。常用有硬脂酸镁、单硬脂酸甘油酯、硬脂酸、滑石粉等。③助流剂:改善内容物的流动性。常用有微粉硅胶和滑石粉等。④崩解剂:保证内容物的崩解。常见有交联纤维素、玉米淀粉、交联聚维酮、预胶化淀粉1500、甘氨酰基淀粉钠、海藻酸等。⑤润湿剂:增加药物与溶出介质的润湿性,保证制剂的效能。常见有吐温80、十二烷基硫酸钠等。
软胶囊剂内容物中的辅料包括但不限于油性分散或PEG分散,内容物可以是溶液、混悬液、乳剂、半固体等。油性分散(亲脂性)内容物辅料包括:①油性载体:大豆油、蓖麻油、中链脂肪酸等;②用于调节粘度的半固体包括氢化蓖麻油、蜂蜡等;③表面活性剂如磷脂可以改善混悬液的混悬稳定性。也可添加其它稳定剂如抗氧剂BHT等。PEG分散(亲水性)内容物辅料通常为PEG400和600,半固体的可以同时使用低分子量的PEG200、300和高分子的PEG4000-10000。
硬胶囊壳与软胶囊壳相似,主要含明胶、阿拉伯胶、水、增塑剂(如甘油,也可以加入适量丙二醇和聚乙二醇200,甘露醇或山梨醇可以替代甘油作为胶皮的增塑剂)、防腐剂(如山梨酸钾、尼泊金等)、遮光剂和色素等,其中水的作用是溶剂。
或者,一种所述的抗肿瘤药物化合物的膏剂,其成分包括:
1)本发明的抗肿瘤药物化合物;
2)基质。
常用的基质包括:烃类(如凡士林、固体石蜡、液体石蜡、硅酮)、类脂类(如羊毛脂、蜂蜡与鲸蜡、二甲硅油)、油脂类(如动植物高级脂肪酸甘油脂及其混合物)。
本发明的抗肿瘤药物化合物可溶于亲脂性介质中,适合的制剂还包括脂质体剂、乳剂或微乳液剂、胶束剂等。
进一步地,一种所述的抗肿瘤药物化合物脂质体制剂,其成分包括:
1)本发明的抗肿瘤药物化合物;
2)磷脂;
3)胆固醇或维生素E及其衍生物;
4)水相。
或者,一种所述的抗肿瘤药物化合物的乳剂或微乳剂,其成分包括:
1)油相,包括:
a)本发明的抗肿瘤药物化合物;
b)生物相容的亲脂性介质;
2)表面活性剂和助溶剂;
3)水相。
或者,一种所述的抗肿瘤药物化合物胶束剂,其成分包括:
1)本发明的抗肿瘤药物化合物;
2)表面活性剂;
3)助溶剂;
4)水相。
所述的亲脂性介质(或载体)可以是任何一种的生物相容的亲脂性介质,具有代表性的生物相容的亲脂性介质包括:
1)可作为亲脂性介质的油脂,包括不同链长的脂肪酸及酯,它们大多是直链的,但也可以是支链的,例如癸酸、辛酸、己酸、月桂酸、肉豆蔻、硬脂酸、油酸、亚油酸、以及其它饱和或不饱和脂肪酸及酯类。
2)脂溶性的维生素E及衍生物。维生素E是指以天然或人工合成的维生素E系列,它们通常称为生育酚和生育三烯酚(tocopherols和tocotrienols),生育酚包括α-生育酚(D型、DL型、L型)、β-生育酚(D型、DL型、L型)、γ-生育酚(D型、DL型、L型)和δ-生育酚(D型、DL型、L型)。生育三烯酚在结构上与生育酚相似,但生育三烯酚在碳-2的侧链植基(phytyl)上有三个双键。生育三烯酚包括α-生育三烯酚(D型、DL型、L型)、β-生育三烯酚(D型、DL型、L型)、γ-生育三烯酚(D型、DL型、L型)和δ-生育三烯酚(D型、DL型、L型)。维生素E衍生物包括所有生育酚和生育三烯酚的衍生物,如维生素E琥珀酸酯,维生素E醋酸酯等。
3)脂肪酸与甘油酯化反应所形成的甘油单酯、甘油二酯或甘油三酯,无论它们是合成的还是天然的,都可作为亲脂性介质,例如,甘油酯,如豆油,棉籽油,菜籽油,鱼油,乙酰化单甘酯,甘油单油酸酯,三醋酸甘油酯,和双乙酰酒石酸酯,单甘酯,蓖麻油等。
4)脂肪醇,如苄醇、硬脂醇、月桂醇等,或是它们的酯或醚,如苯甲酸苄酯。
具有代表性的表面活性剂包括:
1)聚乙二醇表面活性剂,如聚氧乙烯蓖麻油EL(Cremophor EL)、吐温系列表面活性剂等。
2)磷脂表面活性剂(phospholipids),如卵磷脂(lecithin)、大豆磷脂(granulesten or soybean lecithin)、聚乙二醇磷脂(pegylated phospholipids)。
3)聚乙二醇维生素E衍生物,如维生素E琥珀酸酯聚乙二醇(d-α-tocopherolpolyethylene glycol 1000succinate,TPGS)。
4)聚氧乙烯聚氧丙烯嵌段共聚物:POLOXAMERS或PLURONICS的嵌段共聚物(H(OCH2CH2)a(OCH2CH2CH2)b(OCH2CH2)aOH)。
具有代表性的有机助溶剂包括:乙醇、聚乙二醇、丙二醇、甘油、N-甲基吡咯烷酮等。聚乙二醇(PEG)是亲水性的,重复单元的化学结构组成为-CH2CH2O-,通式为H-(CH2CH2)n-OH,分子量范围一般从200至10000。例如,聚乙二醇200、聚乙二醇300、聚乙二醇400等。
此处使用的“乳剂”是指在表面活性剂的作用下,一相液体以液滴状态分散于另一相液体中形成的非均相液体分散体系,如油和水所形成的液滴,其直径一般在0.1至3.0微米。
所述的乳剂可以形成稳定的微乳剂。“微乳”一词是指两个不混溶的液体形成一个热力学稳定的各向同性、透明或半透明的分散体系,如油和水的微乳分散体系是被表面活性剂分子形成的界面膜所稳定。微乳平均液滴直径小于200nm,一般10至50纳米。
乳剂或微乳剂中包括油相和水相。乳剂或微乳剂可以是水包油型乳化或油包水型。
在没有水的情况下,由油相、非离子型表面活性剂和助乳化剂混合所形成的均一透明并包含药物的溶液被称为自乳化释药系统(self-emulsifying drug deliverysystem:SEDDS),自发乳化形成粒径在100nm至500nm的乳剂,可用于提高亲脂性药物溶解度和口服吸收度。
在一个乳剂或微乳剂的实施方案中,亲脂性介质包括豆油,水相介质是水。在另一个乳剂和微乳剂的实施方案中,亲脂性介质包括油溶性维生素E。在另一个乳剂或微乳剂的实施方案中,亲脂性介质包括油溶性维生素E衍生物。
除了本发明的抗肿瘤药物化合物,乳剂或微乳剂配方中还可以包括药物乳剂和微乳剂中常用的其他的成分,这些成分包括表面活性剂和助溶剂。具有代表性的表面活性剂包括非离子表面活性剂,如聚氧乙烯蓖麻油EL(Cremophor EL)、吐温80(Tween 80)、聚乙二醇维生素E衍生物表面活性剂及其它表面活性剂聚合物。
合适的聚乙二醇维生素E衍生物表面活性包括维生素E琥珀酸聚乙二醇衍生物(例如维生素E聚乙二醇琥珀酸酯),在维生素E衍生物分子中,聚乙二醇是由琥珀酸与维生素E的羟基连接而成,这些维生素E的聚乙二醇衍生物中的聚乙二醇包括具有各种分子量(例如,200、300、400、600、1000等)的聚乙二醇。此处的“维生素E聚乙二醇琥珀酸酯”包括维生素E聚乙二醇琥珀酸酯(如D-α生育酚聚乙二醇1000琥珀酸酯,TPGS,一种非离子型表面活性剂(HLB=16-18))和维生素E聚乙二醇的各种酯和醚衍生物。
上述各种制剂其配方中都包含有效治疗量的本发明的替尼类抗肿瘤药物化合物及辅料。
所述的替尼类抗肿瘤药物化合物的片剂包括本发明的抗肿瘤药物化合物和辅料。所述的抗肿瘤药物化合物的在每片中的含量可为1毫克至1000毫克,优选的方案中抗肿瘤药物化合物在每片中的含量为5毫克至500毫克;更优选的方案中,抗肿瘤药物化合物在每片中的含量为10毫克至250毫克。
所述的替尼类抗肿瘤药物化合物的胶囊剂包括本发明的抗肿瘤药物化合物和辅料。所述的抗肿瘤药物化合物的在每颗胶囊中的含量可为1毫克至1000毫克,优选的方案中抗肿瘤药物化合物在每颗胶囊中的含量为5毫克至500毫克;更优选的方案中,抗肿瘤药物化合物在每颗中的含量为10毫克至250毫克。
所述的替尼类抗肿瘤药物化合物的乳剂或微乳剂中,抗肿瘤药物化合物在制剂配方中所占的重量百分比为0.005%至5.0%;优选抗肿瘤药物化合物在制剂配方中所占的重量百分比为0.01%至2.5%;更优选的方案中,抗肿瘤药物化合物在制剂配方中所占的重量百分比为0.1%至1.5%。
所述的乳剂或微乳剂中,亲脂性介质在制剂配方中所占的重量百分比为2%至20%;优选亲脂性介质在制剂配方中所占的重量百分比为4%至12%;更优选的方案中,亲脂性介质在制剂配方中所占的重量百分比为6%至10%。
所述的乳剂或微乳剂中,表面活性剂在配方中的重量百分含量约为1至10%,优选2-6%,更优选4-5%。
所述的乳剂或微乳剂中,助溶剂约占配方重量的0%至20%。
如上文所述的替尼类抗癌药物化合物的胶束制剂包括本发明的抗肿瘤药物化合物、一种或多种表面活性剂、一种或多种助溶剂和水相。
在所述的抗肿瘤药物化合物的胶束剂中,药物化合物在配方中重量百分含量约为0.005%至3.0%,优选药物化合物在配方中重量百分含量约为0.01%至2.5%;更优选,药物化合物在配方中重量百分含量约为0.1%至1.0%。
合适的表面活性剂在本发明的胶束剂配方中的重量百分含量约为1至10%,优选2-6%,更优选4-5%。
胶束剂配方还包括其它的成份,如上面提到的助溶剂。在一个实施例中,胶束剂配方中包含聚乙二醇和较低的烷基醇(如乙醇)。所述的胶束剂中,助溶剂约占配方重量的1%至20%。
所述的替尼类抗肿瘤药物化合物的脂质体剂包括本发明的抗肿瘤药物化合物、一种或多种磷脂(包括PEG化磷脂)、一种或多种亲脂性介质(如胆固醇)和水相。
在所述的替尼类抗肿瘤药物化合物的脂质体剂中,药物化合物在配方中重量百分含量约为0.005%至5.0%,优选药物化合物在配方中的重量百分含量约为0.01%至2.5%;更优选,药物化合物在配方中重量百分含量约为0.1%至1.5%。
合适的磷脂在本发明的脂质体剂配方中的重量百分含量约为1至10%,优选2-6%,更优选4-5%。
脂质体剂配方还包括其它的成份,如上面提到的亲脂性介质(如胆固醇)。在一个实施例中,脂质体剂配方中包含胆固醇或维生素E。所述的脂质体剂中,胆固醇或维生素E约占配方重量的0.1%至20%。
上述乳剂、微乳剂、胶束剂和脂质体剂配方中包含水相。在一个实施例中,水相包括去离子水。在另一个实施例中,水相包括生理盐水。在另一个实施例中,水相中含一种酸(如琥珀酸、柠檬酸、磷酸)的缓冲液。
所述的替尼类抗肿瘤药物化合物的膏剂包括本发明的替尼类抗肿瘤药物化合物、一种或多种基质。
在所述的替尼类抗肿瘤药物化合物的膏剂中本发明的抗肿瘤药物化合物的重量百分含量约为0.01%至30%,优选药物化合物在配方中的重量百分含量约为0.05%至20%;更优选,药物化合物在配方中重量百分含量约为0.1%至10%。
所述的替尼类抗肿瘤药物化合物或者上述制剂,作为抗癌药物应用于癌症的治疗,或者单独使用,或者与其它药物组合使用。其它药物可从以下药物化合物中选择,包括但不限于:雄激素抑制剂,如氟他胺(flutamide)和鲁珀若利得(luprolide);抗雌激素,如他莫昔芬(tomoxifen);抗代谢药物和细胞毒性药物,如道诺红菌素(daunorubicin)、五氟脲嘧啶(fluorouracil)、氟尿苷(floxuridine)、α-干扰素(interferon alpha)、甲氨蝶呤(methotrexate)、光神霉素(plicamycin)、硫基嘌呤(mecaptopurine)、硫鸟嘌呤(thioguanine)、阿霉素(adriamycin)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、阿糖胞苷(cytarabine)、环磷酰胺(cyclophosphamide)、阿霉素(doxorubicin)、雌莫司汀(estramustine)、六甲蜜胺(altretamine)、羟基脲(hydroxyurea)、异环磷酰胺(ifosfamide)、甲基苄肼(procarbazine)、突变霉素(mutamycin)、白消安(busulfan)、米托蒽醌(mitoxantrone)、卡铂carboplatin)、顺铂(cisplatin)、链脲佐菌素(streptozocin)、博莱霉素(bleomycin)、放线菌素(dactinomycin)、和依达比星(idamycin);激素,如甲孕酮(medroxyprogesterone)、炔雌二醇(ethinyl estradiol)、雌二醇(estradiol)、亮丙瑞林(leuprolide)、甲地孕酮(megestrol)、奥曲肽(octreotide)、己烯雌酚(diethylstilbestrol)、氯烯雌醚(chlorotrianisene)、足叶乙甙(etoposide)、鬼臼毒素(podophyllotoxin)和戈舍瑞林(goserelin);氮芥衍生物,如苯丙酸氮芥(melphalan)、苯丁酸氮芥(chlorambucil)和塞替派(thiotepa);类固醇,如倍他米松(betamethasone);和其他抗肿瘤药物,如活牛分枝杆菌(live Mycobacterium bovis)、达卡巴嗪(dicarbazine)、天冬酰胺酶(asparaginase)、甲酰四氢叶酸(leucovorin)、米托坦(mitotane)、长春新碱(vincristine)、长春碱(vinblastine)和多西紫杉醇(taxotere)等。
实施例1
一种替尼类抗肿瘤药物化合物6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺及其合成,包括以下步骤:
(1)7-甲氧基-6-硝基喹唑啉-4(3H)-酮(2)的合成
反应式如下式所示:
实验步骤:
在100ml的圆底烧瓶中加入甲醇约50ml,加入甲醇钠0.760g(20mmol),搅拌至溶解,再加入7-氟-6-硝基喹唑啉1.046g(5mmol),加热回流2h,加入30%的冰醋酸调节PH至6-7,加入水50ml,搅拌20min后,过滤,得淡黄色固体1.087g,产率98.26%。
1H NMR(500MHz,DMSO-d6):δppm:12.4696(s,1H),8.5111(s,1H),8.2161(s,1H),7.4157(s,1H),4.0382(s,3H)。
(2)4-氯-7-甲氧基-6-硝基喹唑啉(3)的合成
反应式如下式所示:
在100mL圆底烧瓶中,加入1.039g(4.70mmol)7-甲氧基-6-硝基喹唑啉-4(3H)-酮(2)和30ml三氯氧磷,加热回流至反应完成,减压蒸馏去除过量的三氯氧磷,加入约150ml的乙酸乙酯搅拌,加入饱和碳酸氢钠水溶液,调节PH至中性,合并有机相,有机相用饱和食盐水洗3次后,无水硫酸钠干燥,减压蒸馏除去乙酸乙酯,得黄色固体产物1.12g,直接用于下一步反应。
(3)4-(3-氯-4-氟苯胺基)-7-甲氧基-6-硝基喹唑啉(4)的合成
反应式如下式所示:
在250mL圆底烧瓶中,加入1.12g(4.674mmol)的4-氯-7-甲氧基-6-硝基喹唑啉(3)、1.40g(9.618mmol)的3-氯-4-氟苯胺和100ml的异丙醇,搅拌,再滴加4滴浓HCl后,在100摄氏度下加热回流1h,冷却至室温后,用TEA(三乙胺)调节PH至7-8,减压蒸馏除去异丙醇,硅胶柱层分离,得到黄色固体产物1.110g,产率=68.10%。
MS(Positive ESI):m/z(M+H+)=349.05373,MS(Negative ESI):m/z(M-H+)=347.03710。
1H NMR(500MHz,DMSO-d6):δppm:10.1139(s,1H),9.2010(s,1H),8.6671(s,1H),8.1602-8.1415(m,1H),7.8129-7.7813(m,1H),7.4714-7.4352(m,2H),4.0615(s,3H)。
(4)4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5)的合成
反应式如下式所示:
在250mL圆底烧瓶中,加入1.90g(5.448mmol)的4-(3-氯-4-氟苯胺基)-7-甲氧基-6-硝基喹唑啉(4)、30ml的乙醇和15ml的水,搅拌,再加入1.50g(26.860mmol)铁粉(铁粉使用前用1N的HCl洗涤活化),然后加入850μl的冰醋酸,升温至100摄氏度回流1小时后,热的反应液用25%的氨水碱化,然后乘热过滤,滤液冷却至室温,再加入盐酸反应液的PH=6,然后用NaHCO3调反应液的PH=7-8,减压蒸馏除去溶剂乙醇,再加入水,过滤,得黄色固体产物1.33g,产率:76.6%,直接用于下一步反应。
(5)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)的合成
反应式如下式所示:
在50ml的圆底烧瓶内,加入0.28g(1.325mmol)6-马来酰亚氨基己酸、0.60g(1.578mmol)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、380μl(2.726mmol)三乙胺(TEA)和10ml DMF,室温搅拌1h,再加入0.20g(0.628mmol)4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5),加热至50℃,搅拌至反应完成,硅胶柱层分离,得固体产物0.236g,产率73.5%。
上述方法合成得到的化合物(记为YY-058-6),其核磁共振氢谱和质谱见图1和图2。
MS(Positive ESI):m/z(M+H+)=512.15045,MS(Negative ESI):m/z(M-H+)=510.13294。
1H NMR(500MHz,DMSO-d6):δppm:10.6854(s,1H),9.5525(s,1H),8.9928(s,1H),8.7665-8.7457(m,1H),8.0166-7.9982(m,1H),7.7153-7.6840(m,1H),7.5266-7.4719(m,1H),7.2736(s,1H),7.0002(s,2H),4.0485(s,3H),3.4257-3.3975(t,2H,J=7.05Hz),2.4969-2.4593(t,2H,J=9.4Hz),1.6657-1.6063(m,2H),1.5725-1.5139(m,2H),1.3346-1.2740(m,2H)。
实施例2
一种替尼类抗肿瘤药物化合物3-马来酰亚胺基丙酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺及其合成,步骤如下:
(1)~(4):按照与实施例1相同的方法制备4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5)。
(5)3-马来酰亚胺基丙酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-7)的合成
反应式如下式所示:
在50ml的圆底烧瓶内,加入0.36g(2.128mmol)3-马来酰亚氨基丙酸、0.90g(2.237mmol)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、570μl(4.10mmol)三乙胺(TEA)和10ml DMF,室温搅拌1h,再加入0.30g(0.941mmol)4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5),加热至50℃,搅拌至反应完成,硅胶柱层分离,得固体产物(记为YY-058-7)0.27g,产率61.4%。
MS(Positive ESI):m/z(M+H+)=470.10539,MS(Negative ESI):m/z(M-H+)=468.08816。
1H NMR(500MHz,DMSO-d6):δppm:10.6834(s,1H),9.7448(s,1H),8.9508(s,1H),8.7366(s,1H),8.0176-7.9991(m,1H),7.7151-7.5054(m,1H),7.2725(s,1H),7.0359(s,2H),4.0330(s,3H),3.7637-3.7350(t,2H,J=7.18Hz),2.8113-2.7830(t,2H,J=7.075Hz)。
实施例3
YY-058-6和YY-058-7对肺癌细胞LLCI小鼠移植肿瘤生长抑制作用的药效学试验
(1)药物配制方法:
①YY-058-6和YY-058-7的配制方法
配制方法:称取13.06mg YY-058-6粉末药物,加入2ml的药用级吐温,充分溶解至微透明后,加入18ml CMCNa水溶液(体积比为0.5%),搅拌至充分溶解。给药体积为0.2ml/20g,即给药剂量为6.54mg/kg。
配制方法:称取12.03mg YY-058-7粉末药物,加入2ml的药用级吐温,充分溶解至微透明后,加入18ml CMCNa水溶液(体积比为0.5%),搅拌至充分溶解。给药体积为0.2ml/20g,即给药剂量为6mg/kg。
②阳性对照药物达可米替尼(Dacomitinib)的配制方法
配制方法:称取12mg达克米替尼粉末,加入2ml的药用级吐温,充分溶解至微透明后,加入18ml CMCNa水溶液(体积比为0.5%),搅拌至充分溶解。给药体积为0.2ml/20g,即给药剂量为6mg/kg。
(2)实验动物来源、种系、品系
品系和来源:C57BL/6小鼠,上海斯莱克实验动物有限责任公司提供,实验动物生产许可证:SCXK(沪)2017-0005。体重:18-22g,性别:雌性,饲料:颗粒饲料,饲养条件:空调房间,温度18-24℃,相对湿度40-70%。
(3)实验动物分组
空白对照组(模型对照组) 8只 达可米替尼(阳性对照药) 8只
药物治疗组(YY-0-58-6) 8只 药物治疗组(YY-0-58-7) 8只
(4)实验方法
取C57BL/6小鼠,按移植性肿瘤研究法接种移植瘤,小鼠移植瘤用游标卡尺测量移植瘤直径,接种14天后,肿瘤生长至90-100mm3时将动物随机分4组,每组8只。同时,各组小鼠开始给药,每天一次,灌胃,剂量为200ul/20g,共给药8次。于接种后第9天(d9)处死荷瘤小鼠称重,并分离瘤块称重,所得数据进行统计学处理(t检验)。
(5)实验结果
结果(表1)表明,与模型对照组相比,YY-058-6、YY-058-7和达可米替尼对小鼠肺癌细胞LLCI移植瘤肿瘤生长的抑制作用(P<0.01)有显著的抑制作用,但相同摩尔浓度下,YY-058-6和YY-058-7对肺癌细胞LLCI移植瘤肿瘤都比达可米替尼强,尤其是YY-058-6显示出对小鼠肺癌细胞LLCI移植瘤肿瘤生长更强的抑制作用,相同摩尔浓度下,比临床替尼类药物达克米替尼抑瘤效果高出13.7%。Dacomitinib是由美国辉瑞公司(Pfizer)研制的第二代多靶点小分子药物,Dacomitinib于2018年9月27日在美国获批上市,是一种新型的酪氨酸激酶抑制剂,用于EGFR敏感突变的局部晚期或转移性非小细胞肺癌(NSCLC)的一线治疗。
表1.YY-058-6和YY-058-7对小鼠肺癌细胞LLCI移植瘤肿瘤生长的影响(X±SD,n=8)
与空白组比较,*P<0.05,**P<0.01
实施例4
抗肿瘤药物化合物6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)的制剂,包括片剂、胶囊剂、乳剂、胶束剂、脂质体剂和膏剂。
(1)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)胶囊剂(湿法制粒)
处方量的YY-058-6与处方量的羟基乙酸淀粉钠、乳糖和硬脂酸镁混合后,加入处方量的吐温80水溶液后进行湿法制粒,制得的湿材料在流化床、干燥盘或其它适当干燥器中干燥,将干燥后的颗粒碾磨至合适的粒径分布,再与处方量的其它组分混合,最后将混合物装入两片硬明胶胶囊壳体中。
组分 | 每颗胶囊的含量(mg) | 每组分的百分含量(%) |
YY-058-6 | 25 | 25 |
吐温80 | 2.5 | 2.5 |
乳糖 | 25 | 25 |
硬脂酸镁 | 2.5 | 2.5 |
羟基乙酸淀粉钠 | 45 | 45 |
每颗胶囊总重量 | 100 |
(2)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)片剂(湿法制粒)
处方量的十二烷基硫酸钠水溶液与处方量的YY-058-6、羟基乙酸淀粉钠、硬脂酸镁和微晶纤维素制粒,制得的湿材料在流化床、干燥盘或其它适当干燥器中干燥,干燥后的颗粒碾磨至所需的粒径分布,然后将混合物压制成片。
组分 | 每片的含量(mg) | 每组分的百分含量(%) |
YY-058-6 | 30 | 47.6 |
十二烷基硫酸钠 | 1.5 | 2.40 |
乳糖 | 4.5 | 7.10 |
硬脂酸镁 | 3 | 4.80 |
羟基乙酸淀粉钠 | 12 | 19.05 |
微晶纤维素 | 12 | 19.05 |
每颗胶囊总重量 | 63 |
(3)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)片剂(干法制粒)
首先将YY-058-6原料粉碎过筛,控制粒径小于80μm,再将处方量的YY-058-6与微粉硅胶混匀,加入处方量的淀粉、蔗糖、交联羧甲基纤维素钠,混匀,干法制粒,制粒后,加入处方量的硬脂酸镁,混匀,压片,包薄膜衣。
组分 | 每片的含量(mg) | 每组分的百分含量(%) |
YY-058-6 | 10 | 50 |
淀粉 | 5 | 25 |
蔗糖 | 1.5 | 7.5 |
交联羧甲基纤维素钠 | 1.5 | 7.5 |
微粉硅胶 | 1.5 | 7.5 |
硬脂酸镁 | 0.5 | 2.5 |
每颗胶囊总重量 | 20 |
(4)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)乳剂
YY-058-6溶解于豆油、吐温80和聚乙二醇PEG(200)的混合物中,再加入去离子水(DI water),然后搅拌和超声乳化或用均质机乳化,所生产的乳剂的组成如下:
制成的乳剂药品通过一个孔径0.2微米的过滤器过滤,再装入无菌的玻璃瓶。
(5)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)乳剂
YY-058-6溶解于D-α-生育酚乙酸酯、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)和聚乙二醇PEG(200)的混合物中,再加入去离子水(DI water),然后搅拌和超声乳化或用均质机乳化,所生产的乳剂的组成如下:
制成的乳液药品通过一个孔径0.2微米的过滤器过滤,再装入无菌的玻璃瓶。
(6)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)胶束剂
YY-058-6溶解于D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)、乙醇和聚乙二醇PEG(200)的混合物中得到一透明的液体,使用前再加入适量的生理盐水,然后搅拌和超声搅拌,得一澄清液体,所生产的胶束剂的组成如下:
制成的胶束剂药品通过一个孔径0.2微米的过滤器过滤,备用。
(7)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)胶束剂
YY-058-6溶解于聚氧乙烯蓖麻油EL(Cremophor EL)、乙醇和聚乙二醇PEG(200)的混合物中得到透明的液体,使用前再加入适量的去离子水(DI water),然后搅拌和超声搅拌,得澄清液体,所生产的胶束剂的组成如下:
制成的胶束剂药品通过一个孔径0.2微米的过滤器过滤,备用。
(8)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)胶束剂
YY-058-6溶解于聚氧乙烯蓖麻油EL(Cremophor EL)、乙醇和聚乙二醇PEG(200)的混合物中得到透明的液体,使用前再加入适量的去离子水(DI water),然后搅拌和超声搅拌,得一澄清液体,所生产的胶束剂的组成如下:
制成的胶束剂药品通过一个孔径0.2微米的过滤器过滤,备用。
(9)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)胶束剂
YY-058-6溶解于吐温80(Tween 80)、乙醇和聚乙二醇PEG(200)的混合物中得到透明的液体,使用前再加入适量的去离子水(DI water),然后搅拌和超声搅拌,得一澄清液体,所生产的胶束剂的组成如下:
制成的胶束剂药品通过一个孔径0.2微米的过滤器过滤,备用
(10)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)脂质体剂
在一个圆底烧瓶中,将100毫克YY-058-6、1600毫克的磷脂(卵磷脂、磷脂酰胆碱)和110毫克的胆固醇溶解于15mL的氯仿(CHCl3),慢慢加热至40℃,用旋转蒸发仪减压蒸发溶剂,形成一层薄的脂质膜,真空干燥过夜,进一步除去脂质膜中的氯仿,加入50ml 5%蔗糖溶液,然后搅拌和超声搅拌,所得脂质体液通过一个孔径0.2微米的过滤器过滤,再装入无菌的玻璃瓶,用干冰和丙酮冷冻,然后冷冻干燥24小时,得6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺(YY-058-6)的脂质体剂。
(11)6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酯(YY-058-6)膏剂
取适量YY-058-6、硬脂酸、单硬脂酸甘油酯、液体石蜡、聚乙二醇200(PEG 200)、吐温-80加热熔化;另取适量甘油、水加热至70-80℃,在搅拌下加入至油相中,继续搅拌至成型,所生产的膏剂的组成如下:
Claims (9)
2.根据权利要求1所述的替尼类抗肿瘤药物化合物,其特征在于,为6-马来酰亚胺基己酸4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉酰胺。
4.根据权利要求3所述的替尼类抗肿瘤药物化合物的制备方法,其特征在于,所述的马来酰亚胺基烷基酸或其衍生物(6)为马来酰亚胺基烷基酸或马来酰亚胺基烷基酰氯。
5.根据权利要求3所述的替尼类抗肿瘤药物化合物的制备方法,其特征在于,所述的N-酰化反应的缩合剂选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、二环己基碳二亚胺、N,N'-羰基二咪唑、1-(3-二甲胺基丙基)-3-乙基碳二亚胺或二异丙基碳二亚胺中的一种或几种;缚酸剂选自三乙胺、吡啶、二异丙基乙胺、甲醇钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾中的一种或几种。
6.根据权利要求3所述的替尼类抗肿瘤药物化合物的制备方法,其特征在于,所述的N-酰化反应中,4-(3-氯-4-氟苯胺基)-7-甲氧基-6-氨基喹唑啉(5)与马来酰亚胺基烷基酸或其衍生物(6)摩尔比为1:1~1.5。
7.根据权利要求1所述的替尼类抗肿瘤药物化合物在制备抗癌药物中的应用。
8.一种替尼类抗肿瘤药物组合物,其特征在于,所述的药物组合物包括有效治疗量的权利要求1所述的替尼类抗肿瘤药物化合物以及药学上可接受的辅料。
9.根据权利要求8所述的抗肿瘤药物组合物,其特征在于,所述药物组合物为片剂、胶囊剂、乳剂、胶束剂、脂质体或膏剂。
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CN113979954A (zh) * | 2021-11-12 | 2022-01-28 | 南京友怡医药科技有限公司 | 一种替尼类抗肿瘤药物化合物及其制备方法和应用 |
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