CN107137407B - 一种vegfr抑制剂在制备治疗胰腺癌的药物中的用途 - Google Patents
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Abstract
本发明涉及一种VEGFR抑制剂在制备治疗胰腺癌的药物中的用途。该VEGFR抑制剂可以与Hedgehog抑制剂联合使用。本发明还涉及包含上述两种抑制剂的药物组合物。
Description
技术领域
本发明涉及一种VEGFR抑制剂在制备治疗胰腺癌的药物中的用途。
背景技术
胰腺癌是一种恶性程度很高，诊断和治疗都很困难的消化道恶性肿瘤，约90％为起源于腺管上皮的导管腺癌。其发病率和死亡率近年来明显上升。5年生存率<1％，是预后最差的恶性肿瘤之一。胰腺癌早期的确诊率不高，手术死亡率较高，而治愈率很低。本病发病率男性高于女性，男女之比为1.5～2:1，男性患者远较绝经前的妇女多见，绝经后妇女的发病率与男性相仿。胰腺癌由于恶性程度高，手术切除率低，预后不良。尽管手术仍然是首要的治疗方法，但由于胰腺癌常常发现较晚，而丧失根治的机会，因此需要对胰腺癌进行综合治疗。迄今同大多数肿瘤一样，还没有一种高效和可完全应用的综合治疗方案。现在的综合治疗仍然是以外科治疗为主，放疗、化疗为辅，并在探讨结合免疫和分子等生物治疗的新方法。胰腺癌的进展、局部浸润及转移均有赖于新血管的生成。因此，针对血管内皮生长因子受体(VEGFR)或其配体的分子靶向治疗药物目前已成为晚期胰腺癌药物治疗的临床研究重点。
CN101007815A公开了一类多靶点蛋白激酶抑制剂，它们对VEGFR、特别是VEGFR-2具有很强的抑制作用，其中包括下式(I)所示的化合物，其化学名为5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1,2-二氢-吲哚-3-亚基-甲基)-3-甲基-1,5,6,7-四氢-吡咯[3,2-c]吡啶-4-酮，还指出了VEGF的浓度与乳腺癌、肺癌、前列腺癌和结肠癌有关，暗示这些蛋白激酶抑制剂抑制剂可能用于治疗上述肿瘤，但未涉及胰腺癌。
CN103261198A公开了一类Hedgehog信号通路抑制剂，其中包括如下式(II)的化合物，其化学名为N-(2-乙基-5-(6-(2-(三氟甲基)吡啶-3-基)咪唑并[1,2-b]哒嗪-2-基)苯基)-1-甲基环丙基甲酰胺，并公开了Hedgehog信号通路可能与胶质母细胞瘤、基底细胞癌以及胰腺癌有关。
发明内容
本发明惊奇地发现，VEGFR抑制剂、特别是VEGFR-2抑制剂对于胰腺癌具有良好的治疗效果。在本发明优选的实施方案中，所述的VEGFR抑制剂为如下的式(I)所示化合物或其可药用盐。本发明中，所述的VEGFR抑制剂的用量可以在0.1－1000mg/kg，优选1－100mg/kg，更优选5－20mg/kg，所述的用量以化合物(I)的形式计量。
在本发明优选的实施方案中，所述的VEGFR抑制剂与Hedgehog信号通路抑制剂联合使用，二者联用，对于胰腺癌效果更佳，特别优选地，所述的Hedgehog信号通路抑制剂为如下式(II)所示化合物或其可药用盐。本发明中，所述的Hedgehog信号通路抑制剂的用量可以在1－1000mg/kg，优选5－500mg/kg，更优选10－200mg/kg，最优选20－100mg/kg，所述的用量以化合物(II)的形式计量。本发明中，联合使用指是是两种或多种药物在同一给药周期内都施予给药对象，但二者是否同时施用则不受限制，可以有先有后，可以有一定的时间间隔。
本发明中的式(I)化合物的可药用盐选自多种，如无机酸或有机酸盐，优选苹果酸盐。
式(I)和(II)化合物或它们的药学上可接受的盐也可以与药学上可接受的载体一起制成本领域熟知的组合物形式，如片剂、胶囊、颗粒剂、注射剂等。本发明还涉及含有选自式(I)和式(II)化合物或者它们的药学上可接受的盐的组合物在制备治疗前述胰腺癌的药物中的用途。
附图说明
图1显示化合物(I)、(II)单用或二者合用对人胰腺癌PANC05.04裸小鼠移植瘤的疗效。
图2显示化合物(I)、(II)单用或二者合用对人胰腺癌PANC05.04裸小鼠移植瘤的疗效(肿瘤照片)。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
实施例1：评价化合物(I)、化合物(II)单用或二者合用对人胰腺癌PANC05.04裸小鼠移植瘤的疗效。
1受试药物
受试化合物(I)、化合物(II)分别参照CN101007815A和CN103261198A公开的内容合成。配制方法：化合物(I)用蒸馏水配制，化合物(II)用30％PEG 400配制。
2实验动物
BALB/cA-nude裸小鼠，6-7周，♀，购自上海斯莱克实验动物有限责任公司。合格证号：SCXK(沪)2012－0002。饲养环境：SPF级。
3实验步骤
裸小鼠皮下接种人胰腺癌PANC05.04细胞，待肿瘤生长至100-200mm3后，将动物随机分组(D0)。给药剂量和给药方案见表1。每周测2－3次瘤体积，称鼠重，记录数据。肿瘤体积(V)计算公式为：
V＝1/2×a×b2其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100其中T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
4结果
化合物(I)(10mg/kg,PO,QD×14)单用本身明显抑制人胰腺癌PANC05.04裸小鼠皮下移植瘤的生长，抑瘤率为74％；化合物(II)(50mg/kg,PO,QD×14)单用对PANC05.04没有明显疗效，抑瘤率为24％；荷瘤小鼠对以上二药均能较好耐受，没有明显体重减轻等症状发生。二者合用，抑瘤率明显增强，达到95％，并引起2/8小鼠肿瘤部分消退(P<0.01相比于二药单用)。
表1化合物(I)、化合物(II)单用或二者合用对人胰腺癌PANC05.04裸小鼠移植瘤的疗效
D0:第一次给药时间。P值指与对照相比，Student’s t’检验；**P<0.01vs化合物(I)10mg/kg组。对照组n＝10，治疗组n＝8。
5结论
化合物(I)(10mg/kg,PO,QD×14)单用本身明显抑制人胰腺癌PANC05.04裸小鼠皮下移植瘤的生长；化合物(II)(50mg/kg,PO,QD×14)单用对PANC05.04没有明显疗效；二者合用，抑瘤率明显增强，说明化合物(II)对化合物(I)治疗PANC05.04裸小鼠皮下移植瘤有明显的增效作用。
Claims (11)
1.式(I)所示化合物或其可药用盐与式(II)所示化合物或其可药用盐在制备治疗胰腺癌的药物中的用途，
2.根据权利要求1所述的用途，其中所述的式(I)化合物或其可药用盐的用量为0.1－1000mg/kg。
3.根据权利要求1所述的用途，其中所述的式(I)化合物或其可药用盐的用量为1-100mg/kg。
4.根据权利要求1所述的用途，其中所述的式(I)化合物或其可药用盐的用量为5－20mg/kg。
5.根据权利要求1所述的用途，其中所述的式(II)化合物或其可药用盐用量为1－1000mg/kg。
6.根据权利要求1所述的用途，其中所述的式(II)化合物或其可药用盐用量为5－500mg/kg。
7.根据权利要求1所述的用途，其中所述的式(II)化合物或其可药用盐用量为10－200mg/kg。
8.根据权利要求1所述的用途，其中所述的式(II)化合物或其可药用盐用量为20－100mg/kg。
9.根据权利要求1所述的用途，其中所述的式(I)所示化合物的可药用盐为苹果酸盐。
10.一种药物组合物，含有权利要求1所述的式(I)化合物或其可药用盐和式(II)化合物或其可药用盐，以及药学上可接受的载体。
11.权利要求10所述的药物组合物在制备治疗胰腺癌的药物中的用途。
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| CN113491693B (zh) * | 2020-03-19 | 2023-11-14 | 江苏恒瑞医药股份有限公司 | 法米替尼或其可药用盐在制备治疗Ras突变疾病的药物中的用途 |
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