CN112336726A - 治疗结直肠癌的联用药物组合物 - Google Patents
治疗结直肠癌的联用药物组合物 Download PDFInfo
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- CN112336726A CN112336726A CN201910733293.7A CN201910733293A CN112336726A CN 112336726 A CN112336726 A CN 112336726A CN 201910733293 A CN201910733293 A CN 201910733293A CN 112336726 A CN112336726 A CN 112336726A
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- acid
- colorectal cancer
- pharmaceutical composition
- raltitrexed
- compound
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
本发明属于医药领域,提供治疗结直肠癌的联用药物组合物,具体涉及治疗有效量的1‑[[[4‑(4‑氟‑2‑甲基‑1H‑吲哚‑5‑基)氧基‑6‑甲氧基喹啉‑7‑基]氧基]甲基]环丙胺或其药学上可接受的盐与雷替曲塞的联用药物组合物在制备用于治疗结直肠癌药物的应用。
Description
技术领域
本申请属于医药领域,涉及治疗结直肠癌的联用药物组合物。
背景技术
结直肠癌是世界上最常见的恶性肿瘤之一,其发病率在世界不同地区差异很大,以北美洲、大洋洲最高,欧洲居中,亚非地区较低。在美国,结直肠癌的发病率和死亡率居所有肿瘤的前列;在中国,结直肠癌的发病率和死亡率也日益上升。随着人们生活方式、饮食结构的改变,平均寿命的提高,结直肠癌的发病率可能还将进一步上升。
结直肠癌发生部位包括直肠、乙状结肠、盲肠、升结肠、降结肠、横结肠等。常见的结直肠癌组织学类型包括腺癌、腺鳞癌、梭形细胞癌、鳞状细胞癌和未分化癌等;其中腺癌最为常见,可分为筛状粉刺型腺癌、髓样癌、微乳头癌、粘液腺癌、锯齿状腺癌和印戒细胞癌。
Invest New Drugs,2011,29(5):1038-1044公开了Viéitez等将76例晚期结直肠癌患者随机分为两组,实验组应用雷替曲塞联合吉非替尼,对照组单用雷替曲塞,结果提示两组PFS无显著差异。其较大的毒副作用是阻碍临床推广的重要因素。
尽管对增殖性疾病(癌症)患者而言有许多治疗选择,仍需要更为有效的治疗剂以供临床使用,尤其是一种以上药物的组合使用。
发明概述
一方面,本申请提供用于治疗结直肠癌的联用药物组合物,其包括化合物I或其药学可接受的盐和雷替曲塞。
另一方面,本申请还提供联用药物组合物在制备用于治疗结直肠癌的药物的用途。
再一方面,本申请还提供治疗结直肠癌的方法,其包括向受试者给予有效量的本申请的联用药物组合物。所述药物组合物包括化合物I或其药学可接受的盐和雷替曲塞。
发明内容
一方面,本申请提供用于治疗结直肠癌的联用药物组合物,其包括化合物I或其药学上可接受的盐和雷替曲塞,
在一些实施方案中,所述结直肠癌为结直肠腺癌;
在一些实施方案中,所述结直肠癌为筛状粉刺型腺癌、髓样癌、微乳头癌、粘液腺癌、锯齿状腺癌或印戒细胞癌。
在本申请的一些实施方案中,所述联用药物组合物包括化合物I或其药学上可接受的盐的药物组合物和雷替曲塞药物组合物。
另一方面,本申请还提供联用药物组合物在制备用于治疗结直肠癌的药物的用途。在一些实施方案中,所述联用药物组合物包括化合物I或其药学上可接受的盐药物的组合物和雷替曲塞药物组合物。
再一方面,本申请还提供治疗结直肠癌的方法,其包括向受试者给予有效量的本申请的联用药物组合物。在一些实施方案中,所述联用药物组合物包括化合物I或其药学上可接受的盐药物的组合物和雷替曲塞药物组合物。
在本申请的一些实施方案中,上述用途或者治疗方法中,所述化合物I或其药学上可接受的盐和雷替曲塞各自呈药物组合物,可同时、顺序或间隔给药。
在本申请的一些实施方案中,上述用途或者治疗方法中,所述化合物I或其药学上可接受的盐和雷替曲塞各自呈药物组合物,给药方式为顺序给药。
化合物I或其药学上可接受的盐
化合物I的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺,其具有如下的结构式:
本申请中,凡是涉及安罗替尼,均是指化合物I。
化合物I可以以它的游离碱形式给药,也可以以其盐、水合物和前药的形式给药,该前药在体内转换成化合物I的游离碱形式。例如,化合物I药学上可接受的盐在本发明的范围内,可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
进一步的,所述其药学上可接受的盐为化合物I与任意如下酸所形成的盐:盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸;优选为盐酸盐或马来酸盐的形式,更优选为二盐酸盐。
在一些实施方案中,以化合物I盐酸盐的形式给药。在一些实施方案中,以化合物I一盐酸盐的形式给药。在一些实施方案中,以化合物I二盐酸盐的形式给药。在一些实施方案中,以化合物I盐酸盐的晶体形式给药。在特定的实施方案中,以化合物I二盐酸盐的晶体形式给药。
定义和说明
除非另有说明,本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照本领域普通的含义去理解。
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”,包括碱根离子与自由酸形成的盐或酸根离子与自由碱形成的盐,例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐,优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。本申请中,当形成药学上可接受的盐时,所述自由酸与碱根离子的摩尔量之比为约1:0.5~1:5,优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。本申请中,当形成药学上可接受的盐时,所述自由碱与酸根离子的摩尔量之比为约1:0.5~1:5,优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。
术语“约”应理解为包括在平均值的三个标准偏差内或特定领域中的标准公差范围内。在某些实施方式中,约应理解为不超过0.5的变异。“约”修饰其后所有列举的值。例如,“约1、2、3”表示“约1”、“约2”、“约3”。
如本文所用,“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
“AL3818”是指化合物I。
“CCK8”是Cell Counting Kit-8的简称,是一种基于WST-8而广泛应用于细胞增殖和细胞毒性的快速、高灵敏度检测的试剂盒。
具体实施方式
下述是结合具体实施例和实验例,进一步阐述本发明。但这些实施例仅限于说明本发明而不是用于限制本发明的范围。下列实施例中未注明具体实验条件的实验方法,按照常规条件。
实施例1
CCK8检测HCT116和DLD-1细胞增殖实验
实验步骤
1)消化细胞,完全培养基重悬细胞,计数,接种至96孔板,每孔铺5000个。
2)种板24h后加药,用完全培养基配制不同终浓度的含药培养基,给细胞换液,药物终浓度分别为安罗替尼(400μΜ,100μΜ,25μΜ,0μΜ),雷替曲塞(256nM,64nM,16nM,0nM),每种细胞都分这些药物终浓度,每个浓度3个复孔。
3)药物处理24和48h后,吸去培养基,每孔换成含有10%的CCK8的完全培养基,继续培养1h。
4)1h后,在酶标仪上检测450nm处的吸光值。
5)数据处理,计算IC50对应的浓度(安罗替尼处理DLD-1的IC50是通过ELISA Calc回归/拟合计算程序v1.0四参数拟合曲线的方式得到的)。
表1作用于HCT116细胞24h后的检测结果
表2作用于HCT116细胞48h后的检测结果
表3作用于DLD-1细胞24h后的检测结果
表4作用于DLD-1细胞48h后的检测结果
结果:
1)HCT116的实验结果(表1和表2)中可以直接得到IC50对应的浓度,即安罗替尼是25μΜ处理24h,雷体曲塞是64nM处理48h。
2)DLD-1的实验结果(表3和表4)
安罗替尼的IC50浓度为47μΜ,处理24h。雷替曲塞在256nM处理48h后很接近IC50,因此,采用这个浓度进行后续试验。
实施例2
CCK8检测不同分组给药方式作用于HCT116和DLD-1细胞增殖实验
1)CCK8检测不同分组给药方式作用于HCT116细胞增殖实验(AL3818即安罗替尼)
实验中采用5种给药方式作用于HCT116细胞进行细胞增殖实验,5种给药方式分别为:25μΜ的安罗替尼处理78h;64nM的雷替曲塞处理78h;25μΜ的安罗替尼和64nM的雷替曲塞同时处理78h;先使用25μΜ安罗替尼处理30h不清洗直接使用64nM雷替曲塞处理48h;先使用25μΜ安罗替尼处理30h清洗后再使用64nM雷替曲塞处理48h。
实验结果显示:在HCT116细胞中,联合用药(3种方式)的抑制效果均高于单独用药并具有显著性差异(*p<0.05,**p<0.01,***p<0.001)。其中,先使用安罗替尼处理不清洗直接使用雷替曲塞的方式,抑制效果最好,约86%,与其余两种方式均有显著性差异。次之是先使用安罗替尼处理清洗后再使用雷替曲塞的方式,抑制率约80%,再次是同时给药,抑制率约76%。安罗替尼和雷替曲塞先后用药对HCT116的抑制效果明显好于同时用药,并具显著性差异(***p<0.001)。
2)CCK8检测不同分组给药方式作用于DLD-1细胞增殖实验
实验中采用5种给药方式作用于HCT116细胞进行细胞增殖实验,5种给药方式分别为:47μΜ的安罗替尼处理78h;256nM的雷替曲塞处理78h;47μΜ的安罗替尼和256nM的雷替曲塞同时处理78h;先使用47μΜ安罗替尼处理30h不清洗直接使用256nM雷替曲塞处理48h;先使用47μΜ安罗替尼处理30h清洗后再使用256nM雷替曲塞处理48h。
实验结果显示:在DLD-1细胞中,同样的,联合用药(3种方式)的抑制效果均高于单独用药并具有显著性差异(**p<0.01,***p<0.001)。其中,先使用安罗替尼处理不清洗直接使用雷替曲塞的方式,抑制效果最好,约93%,与其余两种方式均有显著性差异。次之是先使用安罗替尼处理清洗后再使用雷替曲塞的方式,抑制率约91%,再次是同时给药,抑制率约89%。安罗替尼和雷替曲塞先后用药对DLD-1的抑制效果明显好于同时用药,并具显著性差异(***p<0.001)。
Claims (6)
2.根据权利要求1所述的联用药物组合物,其特征在于,所述结直肠癌为结直肠腺癌,优选的,所述结直肠腺癌为筛状粉刺型腺癌、髓样癌、微乳头癌、粘液腺癌、锯齿状腺癌或印戒细胞癌。
3.根据权利要求1或2所述的联用药物组合物,其特征在于,所述其药学上可接受的盐为化合物I与任意如下酸所形成的盐:盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸;优选为盐酸盐或马来酸盐的形式,更优选为二盐酸盐。
4.权利要求1或2所述的联用组合物在制备用于治疗结直肠癌药物的用途。
5.根据权利要求4所述的用途,其特征在于,所述化合物I或其药学上可接受的盐和雷替曲塞各自呈药物组合物,给药方式为可同时、顺序或间隔给药。
6.根据权利要求5所述的用途,其特征在于,给药方式为顺序给药。
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