CN114163479A - 一类治疗癌症用的铂类化合物及其制备方法 - Google Patents
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Abstract
本发明公开了一类新颖的式(I)所示的铂类化合物,以及它们作为药剂、特别是用于单独或联合治疗癌症,预防癌症的药剂的用途。实验证明本发明的新式铂类化合物具有优越的体内抗肿瘤作用,显著优于临床药物卡铂;并且显著地改善了铂类药物的水溶性,可以制成冻干粉或注射液,解决了临床上使用不方便的缺陷。综上所述,本发明公布的铂类化合物,具有良好的临床应用前景。
Description
技术领域
本发明涉及到一类新颖的铂类抗癌化合物及其制备方法,属于化学制药领域。
背景技术
癌症是一种严重威胁人类健康和生命的疾病。2015年,我国国内癌症新发病例430万,死亡病例280万。我国癌症发病和死亡人数已居世界第一位,每天约1万人确诊癌症,平均每分钟就有7人。癌症已成为人类亟待攻克的医学难题之一。
目前治疗癌症主要有三大手段:手术治疗、放射治疗和化学治疗。化学治疗的基础是化疗药物,世界各国每年都投入大量人力物力和财力进行抗癌药物的研究。铂类药物在临床癌症治疗中的应用起源于1969年,当时Rosenberg等人发现了铂(II)配合物顺铂的有前景的抗癌活性。以顺铂、卡铂以及奥沙利铂等为代表的铂类药物由于其抗癌活性强、作用谱较广,是治疗许多肿瘤的首选药物,得到广泛使用。据最新统计,现临床使用的联合化疗方案中,有85%的方案是铂类抗肿瘤药物为主药,或有铂类抗肿瘤药物参与配伍。
研究表明铂类药物存在水溶性差的缺陷,顺铂的水溶性为1.0mg/ml,卡铂的水溶性为17.0mg/ml,奥沙利铂的水溶性为6.0mg/ml,给药品制剂的稳定性和临床应用带来了很多的不利影响。铂类药物过低的水溶性,还直接影响到药物在体内的蓄积和代谢,导致其积蓄在肾脏组织和血液里,不能被身体及时排出,很容易产生积累性中毒。
大量临床试验研究证实,抗肿瘤血管生成在癌症的治疗中至关重要,是抑制肿瘤生长过程中的关键一环。肿瘤血管生成被整合素家族中的各种蛋白分子调控,如αvβ3,αvβ6,α5β1等。整合素最早由Richard于1987年提出,是由α和β两个亚基组成的一类异源二聚体跨膜糖蛋白。目前已知至少有25种α亚基和11种β亚基,两者相互连接组成20多种不同的整合素分子。整合素是一种细胞外基质受体,其中整合素αvβ3在新生血管内皮细胞和成神经细胞瘤、骨肉瘤、成胶质细胞瘤、乳腺癌、***癌等肿瘤细胞表面高表达,而在已存在的血管和正常组织中不表达或表达很低;整合素αvβ6在胰腺癌、乳腺癌、肺癌、口腔和皮肤鳞状细胞癌、结肠癌、胃癌和子宫内膜癌中表达上调,在正常成人中的表达下调;整合素α5β1在结直肠癌、乳腺癌、卵巢癌、肺癌、胃癌和神经胶质瘤等多种肿瘤中高表达,在成熟的正常细胞和血管不表达或者低表达。在肿瘤生长和转移过程中的高度限制表达,使整合素成为非常有利于肿瘤靶向治疗的靶点。
发明内容
本发明公开了一类新颖的式(I)所示的铂类化合物,以及它们作为药剂、特别是用于单独或联合治疗癌症,预防癌症的药剂的用途。
本发明公开了一类新颖的式(I)所示的铂类化合物,与现有技术的抗肿瘤铂类相比,本发明公开的铂类化合物,其溶解度和体内抑瘤活性有了极大的改善,产生了意想不到的技术效果。
本发明提供了下式(I)化合物或其药学上可接受的盐,
其中:
R1,R2连接在一起,形成如下结构:
R3为具有一定功能性的基团,其特征在于可有效地增强铂类化合物的靶向性或水溶性。
在本发明某些实施方案中,R1,R2连接在一起,形成(A1),(A2),(A3)或(A4)部分:
在本发明某些实施方案中,R3为具有一定功能性的基团,其特征在于可有效地增强铂类化合物的靶向性或水溶性;
R3选自以下结构:
其中,X选自C或者O;R4为连接臂,具有提高化合物水溶性的功能;R5为具有靶向功能的基团。
在本发明某些实施方案中,R4选自:C1-12烷基,C1-12烷氧基,C1-12烷基羰基,任选被1-2个卤素取代的苯氧基或苯基氨基,C1-12烷基氨基,C1-12烷氧基-C1-12烷基氨基,C1-12烷基羰基氧基,C1-12烷基-C3-8环烷基羰基氧基,(C1-4烷基-O)m-C1-12烷基羰基氧基,C1-12烷基羰基氨基-(C1-4烷基-O)m-C1-12烷基羰基氧基,C1-12烷基羰基氨基和苯基-C1-12烷基羰基氨基。
在本发明某些实施方案中,R4选自以下结构:
在本发明某些实施方案中,R5选自:人血白蛋白HAS;结合肿瘤相关抗原的抗体,如抗叶酸受体α抗体、抗间皮素抗体、抗Her2抗体、抗EGFR抗体、抗VEGFR抗体、抗CD20抗体、抗CD22抗体、抗CD28抗体、抗CD33抗体、抗BR96抗体;可与肿瘤细胞表面整合素受体特异性结合的分子。
在本发明某些实施方案中,R5选自可与肿瘤细胞表面整合素受体特异性结合的分子,其中的整合素受体包括但不限于αvβ3,αvβ6,α5β1。
在本发明某些实施方案中,R5选自:可与整合素特异性结合的分子,在化学结构上都包含精氨酸-甘氨酸-天冬氨酸(RGD)三肽序列,优选但并不限于以下结构:
在本发明某些实施方案中,结构通式如下任一所示:
在本发明某些实施方案中,所述式(I)化合物为:
本发明提供了一种药物组合物,其包含权利要求1-14任一项所述的式(I)化合物或其药学上可接受的盐和可接受载体。
本发明提供了一种上述的式(I)化合物或其药学上可接受的盐,或上述的药物组合物在制备预防和/或治疗癌症药物中的应用。其中癌症优选自胃肠癌、结肠直肠癌、结肠癌、肝癌、肝细胞癌、胰腺癌、胆道癌、胃癌、泌尿生殖***癌症、膀胱癌、睾丸癌、***、恶性间皮瘤、骨原性肉瘤、食管癌、喉癌、***癌、激素抵抗性***癌、肺癌、小细胞肺癌、非小细胞肺癌、乳癌、三阴性乳癌、具有BRCA1和/或BRCA2基因突变的乳癌、血液癌症、白血病、急性原始淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、慢性髓性白血病、淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡型淋巴瘤、弥散性大B-细胞淋巴瘤、卵巢癌、脑癌、成神经细胞瘤、尤因肉瘤、肾癌、表皮样癌、皮肤癌、黑素瘤、头和/或颈癌、头和颈鳞状细胞癌和口癌,更优选自结肠直肠癌、结肠癌、胰腺癌、肺癌、非小细胞肺癌、卵巢癌、***、黑素瘤、头和/或颈癌以及头和颈鳞状细胞癌。
本发明提供了一种上述的式(I)化合物或其药学上可接受的盐,或上述的药物组合物在制备用于预防和/或治疗癌症的药物中的应用,其中所述的式(I)化合物或其药学上可接受的盐,或所述的药物组合物将与抗癌药物联合和/或与放射疗法和/或免疫疗法联合进行施用。
有益成果
本发明公布了一系列式I所示的结构新颖的铂类衍生物并测试了它们的体外水溶性及体内抑瘤活性。这产生了完全不能预见的发现:
1)体外水溶性实验表明,本发明公布的实施例S47,S72,S80,S95,S97的水溶性相比上市药物均有显著的提高。特别是实施例72,实施例S80的水溶性,相比上市药物卡铂,有了将近1倍的提高;实施例S47,实施例S95,实施例S97的水溶性,相比上市药物奥沙利铂,有了3倍以上的提高,可制成冻干粉剂或水溶液剂型,解决了铂类药物水溶性低在临床应用上的不利影响。
2)小鼠体内抑瘤实验表明,本发明的实施例S47,S70等具有比临床用药卡铂更明显的抑制移植性肿瘤S180生长的能力,且有良好的量效关系,具有广阔的抗肿瘤应用前景。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员会理解,下列实施例仅用于说明本发明,而不应视为限制本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
化合物的结构是通过液质联用(HPLC-MS)来确定的。质谱是通过watersZQ2000质谱仪测定的,生产商:Waters,型号:ZQ2000。
采用液质联用进行测定时,采用的液相色谱仪器型号为Water 2695HPLC Waters2998,检测器:紫外检测器,色谱柱:YMC pack ODS-AQ 100*4.6mm*5um。液相色谱仪的检测条件如下:
色谱柱温:35℃;流速:1ml/min;检测波长:214nm;洗脱梯度:(0min:90%(v/v)A,10%(v/v)B;10min:10%(v/v)A,90%(v/v)B;15min:10%(v/v)A,90%(v/v)B;15.1min:90%(v/v)A,10%(v/v)B;20min:90%(v/v)A,10%(v/v)B);流动相A:0.1%甲酸;流动相B:乙腈。
采用液相仪器纯化时,采用的仪器为大连伊力特制备液相色谱仪,型号:P270,检测器:紫外检测器,色谱柱:C18反相硅胶20*250mm。制备型高效液相色谱仪的制备方法如下:
色谱柱温:25℃;检测波长:214nm;洗脱梯度:(0min:85%(v/v)A,15%(v/v)B,流速:25ml/min;8min:20%(v/v)A,80%(v/v)B,流速:25ml/min;8.01min:5%(v/v)A,95%(v/v)B,流速:40ml/min;10min:5%(v/v)A,95%(v/v)B,流速:40ml/min;10.01min:50%(v/v)A,50%(v/v)B,流速:40ml/min;12min:50%(v/v)A,50%(v/v)B,流速:40ml/min);流动相A:0.01%甲酸/H2O;流动相B:乙腈。
反应检测采用薄层色谱法(TLC),使用的展开体系为二氯甲烷:甲醇=10:1(体积比)。
搅拌器使用数显型磁力搅拌器,生产商:大龙兴创实验仪器,型号:MS-H280-Pro。
实施例的通用合成方式,如下所示:
A1-A4与进行偶联,生成(即实施例1,3,5,7,9,11,13,15,17,19,21,22,23,24,25,27,29,30,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63);
A1-A4与进行偶联,生成(即实施例2,4,6,8,10,12,14,16,18,20,26,28,32,34,36,38,40,42,44,46,48,50,52,54,56,58,60,62,64);
以实施例S1及实施例65为例,具体的实施过程如下:
1)于50ml单口烧瓶中,先后称取A1(177.2mg,0.46mmol),2-(aminooxy)-N-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)acetamide(98mg,0.46mmol),加入15ml N,N-二甲基甲酰胺溶解后,再加入4A分子筛(162mg),置换氮气后,室温反应过夜后,将反应液减压旋干,粗产品经硅胶柱层析纯化后,得到白色固体(169.0mg,收率63.3%),即实施例S1。
2)于50ml单口烧瓶中,先后称取实施例S1(151mg,0.26mmol),R5-1(117.5mg,0.26mmol),加入15ml甲醇后,置换氮气后,室温反应过夜后,将反应液减压旋干,用半制备HPLC精制分离并使用冷冻干燥机冻干,得到白色固体(181.2mg,收率65%),即实施例S65。
A、R4、R5分别为不同的取代基时,可得到下表1所示的化合物,即实施例S1-S97。
表1实施例的结构
质谱(MS)检测结果确认化合物S1-S97,分子量依次如下表2所示,与结构计算预测的分子量相一致:
表2实施例的质谱检测结果
实施例的体外水溶性实验
为了比较本发明的铂类化合物与上市药物顺铂,卡铂,奥沙利铂在水溶性方面的不同,进行了室温下水中溶解性测定。室温25℃下,精确称取研成细粉的供试品,于一定容量的蒸馏水中,每隔5分钟强力震荡30秒钟;观察30分钟内的各供试品的溶解情况,如无目视可见的溶质颗粒,即视为完全溶解。实验结果见表3供试品在水中溶解性。
表3供试品在水中溶解性
结论:上市药物顺铂、奥沙利铂的水溶性均较差,均小于6mg/ml。卡铂溶解性稍好,在水中可达到16.6mg/ml。而本发明公布的实施例S47,S72,S80,S95,S97S的水溶性相比上市药物均有显著的提高。特别是实施例72,实施例S80的水溶性,相比卡铂,水溶性有了将近1倍的提高;实施例S47,实施例S95,实施例S97的水溶性,相比奥沙利铂,水溶性有了3倍以上的提高,更容易制成冻干粉剂或水溶液剂型,解决了铂类药物水溶性低在临床应用上的不利影响。
实施例的体内抑瘤实验
实验测试了本发明的实施例S47和实施例S70对动物移植性肿瘤S180的抑制作用。
昆明种小鼠,♀,22±1g,购自上海斯莱克实验动物有限责任公司。合格证号:SCXK(沪)2013-0010-02。饲养环境:SPF级。实施例S47、实施例S70和阳性对照药物卡铂用5%葡萄糖配制成所需浓度。小鼠皮下接种S180肉瘤细胞,接种次日开始给药。给药剂量及方案见表4。第八天处死小鼠,取瘤称重,计算抑瘤率。
抑瘤率=(对照组瘤重-治疗组瘤重)/对照组瘤重×100
表4.实施例S47、实施例S70和卡铂对小鼠S180肉瘤的疗效
*P<0.01与对照组相比较
结论:实施例S47、实施例S70对小鼠S180肉瘤生长有明显的抑制作用,等摩尔浓度时的抑制作用均明显优于临床上广泛使用的抗癌药物卡铂,且有良好的量效关系,具有良好的临床应用前景。
Claims (18)
8.如权利要求1所述的式(I)化合物或其药学上可接受的盐,其特征在于,R4选自:C1-12烷基,C1-12烷氧基,C1-12烷基羰基,任选被1-2个卤素取代的苯氧基或苯基氨基,C1-12烷基氨基,C1-12烷氧基-C1-12烷基氨基,C1-12烷基羰基氧基,C1-12烷基-C3-8环烷基羰基氧基,(C1-4烷基-O)m-C1-12烷基羰基氧基,C1-12烷基羰基氨基-(C1-4烷基-O)m-C1-12烷基羰基氧基,C1-12烷基羰基氨基和苯基-C1-12烷基羰基氨基。
10.如权利要求1所述的式(I)化合物或其药学上可接受的盐,其特征在于,R5选自:人血白蛋白HAS;结合肿瘤相关抗原的抗体,如抗叶酸受体α抗体、抗间皮素抗体、抗Her2抗体、抗EGFR抗体、抗VEGFR抗体、抗CD20抗体、抗CD22抗体、抗CD28抗体、抗CD33抗体、抗BR96抗体;可与肿瘤细胞表面整合素受体特异性结合的分子。
11.如权利要求1所述的式(I)化合物或其药学上可接受的盐,其特征在于,R5选自可与肿瘤细胞表面整合素受体特异性结合的分子,其中的整合素受体包括但不限于αvβ3,αvβ6,α5β1。
15.一种药物组合物,其包含权利要求1-14任一项所述的式(I)化合物或其药学上可接受的盐和可接受载体。
16.一种根据权利要求1-14任一项所述的式(I)化合物或其药学上可接受的盐,或根据权利要求15所述的药物组合物在制备预防和/或治疗癌症药物中的应用,其中癌症优选自胃肠癌、结肠直肠癌、结肠癌、肝癌、肝细胞癌、胰腺癌、胆道癌、胃癌、泌尿生殖***癌症、膀胱癌、睾丸癌、***、恶性间皮瘤、骨原性肉瘤、食管癌、喉癌、***癌、激素抵抗性***癌、肺癌、小细胞肺癌、非小细胞肺癌、乳癌、三阴性乳癌、具有BRCA1和/或BRCA2基因突变的乳癌、血液癌症、白血病、急性原始淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、慢性髓性白血病、淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡型淋巴瘤、弥散性大B-细胞淋巴瘤、卵巢癌、脑癌、成神经细胞瘤、尤因肉瘤、肾癌、表皮样癌、皮肤癌、黑素瘤、头和/或颈癌、头和颈鳞状细胞癌和口癌。
17.根据权利要求16所述的应用,其中癌症选自结肠直肠癌、结肠癌、胰腺癌、肺癌、非小细胞肺癌、卵巢癌、***、黑素瘤、头和/或颈癌以及头和颈鳞状细胞癌。
18.一种根据权利要求1-14任一项所述的式(I)化合物或其药学上可接受的盐,或根据权利要求15所述的药物组合物在制备用于预防和/或治疗癌症的药物中的应用,其中根据权利要求1-14任一项所述的式(I)化合物或其药学上可接受的盐,或根据权利要求15所述的药物组合物将与抗癌药物联合和/或与放射疗法和/或免疫疗法联合进行施用。
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