CN104023715B - 激酶抑制剂的副作用降低剂 - Google Patents
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Abstract
本发明涉及以选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐作为有效成分,使激酶抑制剂的副作用降低的副作用降低剂,以及含有选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐、和激酶抑制剂的抗癌用药物。
Description
技术领域
本发明涉及使激酶抑制剂的副作用降低的副作用降低剂、将支链氨基酸和激酶抑制剂组合而成的抗癌用药物、和它们的药物试剂盒等。本申请基于2011年12月2日在日本申请的特愿2011-264687号而主张优先权,其内容在本文中引用。
背景技术
与肿瘤细胞的增殖、血管新生等有关的各种激酶的抑制剂可以期待作为抗癌剂的功能。例如,对于生物体内的多种多样的激酶具有抑制活性的激酶抑制剂索拉非尼,特别可作为肝细胞癌和肾细胞癌的抗癌剂在临床上被使用。
另一方面,抗癌剂多具有严重的副作用,根据副作用的症状、重症度,有不得不放弃给药的情况。例如由于索拉非尼的服用,导致高频率地产生手足综合症或各组织的出血。手足综合症是由于抗癌剂的服用而导致在手、脚的皮肤、指甲上产生的副作用的总称。作为初期症状,在手、脚上产生麻木、刺痛之类的异常感觉、或如烧伤时的疼痛,重症化时,有时由于强烈疼痛,导致不能进行日常生活。这样由于患者的QOL显著受损,因此在手足综合症发病时,将索拉非尼的给予减量、停药或中止。因此,需求一种发挥充分的抗癌效果、同时减轻副作用的方法。
通过将作用机制不同的多种抗癌剂组合使用,与分别单独给药的情况相比,有能够以低容量得到相同程度的抗癌效果的情况。例如在专利文献1中,作为抗癌剂,公开了将VEGFR酪氨酸激酶抑制剂或其药学上可接受的盐、与mTOR选择性激酶抑制剂或其药学上可接受的盐组合来使用,作为VEGFR酪氨酸激酶抑制剂的一个例子,可以列举索拉非尼。
另一方面,对于肝癌等肝病,已知支链氨基酸(BCAA)是有效的。例如,在非专利文献1中,记载了在小鼠非酒精性脂肪性肝炎(NASH)模型中,BCAA不仅改善胰岛素抵抗性,而且可抑制肝的脂肪化,因此,通过BCAA的给药,对于非酒精性脂肪性肝疾病的预防、向NASH的恶化抑制是有用的。另外,在专利文献2中,记载了通过BCAA的给药,可以抑制肝癌的发生和恶化。进而,通过将BCAA和干扰素联合给药,由干扰素产生的抗丙型肝炎病毒活性被增强,而且由干扰素导致的发热等的副作用也可减轻。
另外,在专利文献4中,记载了为了改善由癌引起的恶病质(以厌食症,即食欲的缺乏或重度的减少、体重减少和肌肉萎缩为特征的、重度的营养失调和负氮平衡的状态)或体重减少,含有至少2种以上的必须氨基酸,且游离型或盐型的亮氨酸以基于全部氨基酸的重量为至少约10~35重量%的量存在的组合物是有效的。
现有技术文献
专利文献
专利文献1 : 日本特表2011-512395号公报
专利文献2 : 国际公开第2004/058243号
专利文献3 : 国际公开第2007/013677号
专利文献4 : 日本特表2006-503105号公报
非专利文献
非专利文献1 : 根本等、“小鼠非酒精性脂肪性肝炎(NASH)模型中的支链氨基酸(BCAA)的有用性的研究”、日本消化器病学会杂志、第105卷、临时增刊号、A832(2008年)。
发明内容
上述专利文献1~4和非专利文献1中,对于可使以索拉非尼为代表的激酶抑制剂的副作用直接降低的方法,完全没有公开。
本发明的目的是提供使以索拉非尼为代表的激酶抑制剂的副作用降低的副作用降低剂。
本发明人等为了解决上述课题而进行了努力研究,结果发现通过将作为抗癌剂的激酶抑制剂索拉非尼、和选自异亮氨酸、亮氨酸和缬氨酸中的至少1种的支链氨基酸或其盐一起服用,可降低由索拉非尼导致的副作用,从而完成了本发明。
即,本发明提供以下(1)~(9)的副作用降低剂、(10)~(17)的抗癌用药物、和(18)~(19)的药物试剂盒;
(1)副作用降低剂,其以选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐作为有效成分,使激酶抑制剂的副作用降低;
(2)根据(1)所述的副作用降低剂,其中,上述激酶抑制剂为选自KIT、FLT-3、RET、VEGFR-1、VEGFR-2、VEGFR-3、PDGFR-β和Raf中的至少一种激酶抑制剂;
(3)根据上述(1)所述的副作用降低剂,其中,上述激酶抑制剂为
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
(4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺)、
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
(4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺)、
N-(2-Chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea
(N-(2-氯-4-((6,7-二甲氧基-4-喹唑啉基)氧基)苯基)-N´-丙基脲)、
N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
(N-[3-[5-(2-氨基吡啶-4-基)2-叔丁基-1,3-噻唑-4-基]-2-氟苯基]-2,6-二氟苯磺酰胺)、
1-[1-[(2-aminopyridin-4-yl)methyl]indol-4-yl]-3-(5-bromo-2-methoxyphenyl)urea hydrochloride
(1-[1-[(2-氨基吡啶-4-基)甲基]吲哚-4-基]-3-(5-溴-2-甲氧基苯基)脲盐酸盐)、
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
(N-[4-(3-氨基-1H-吲哚-4-基)苯基]-N´-(2-氟-5-甲基苯基)脲)
1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea
(1-[2-氯-4-(6,7-二甲氧基喹啉-4-基)氧基苯基]-3-(5-甲基-1,2-噁唑基-3-基)脲)、
1-N'-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(1-N´-[3-氟-4-[6-甲氧基-7-(3-吗啉-4-基丙氧基)喹啉-4-基]氧基苯基]-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)、
N-[[3-fluoro-4-[2-(1-methylimidazol-4-yl)thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-phenylacetamide
(N-[[3-氟-4-[2-(1-甲基咪唑-4-基)噻吩并[3,2-b]吡啶-7-基]氧基苯基]硫代氨基甲酰基]-2-苯乙酰胺)、
1-N'-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(1-N´-[2-氟-4-[2-[[4-甲基哌嗪-1-基]哌啶-1-羰基]氨基]吡啶-4-基]氧基苯基-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)、
4-[3-chloro-4-[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-,monomethanesulfonate (4-[3-氯-4-[[环丙基氨基]羰基]氨基]苯氧基]-7-甲氧基一甲磺酸盐)、
1-N'-(4-fluorophenyl)-1-N-[4-[[2-(2-morpholin-4-ylethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide
(1-N´-(4-氟苯基)-1-N-[4-[[2-(2-吗啉-4-基乙基氨基甲酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氧基]苯基]环丙烷-1,1-二甲酰胺)、
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine
(1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺)、
6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide
(6-[7-[(1-氨基环丙基)甲氧基]-6-甲氧基喹啉-4-基]氧基-N-甲基萘-1-甲酰胺)、或
2-dimethyl-6-[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy-1-benzofuran-3-carboxamide
(2-二甲基-6-[7-(2-吗啉-4-基乙氧基)喹啉-4-基]氧基-1-苯并呋喃-3-甲酰胺);
(4)根据上述(1)所述的副作用降低剂,其中,上述激酶抑制剂为
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
(4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺);
(5)根据上述(1)~(4)中任一项所述的副作用降低剂,其包含异亮氨酸、亮氨酸和缬氨酸这3种支链氨基酸;
(6)根据上述(1)~(5)中任一项所述的副作用降低剂,其中,异亮氨酸、亮氨酸和缬氨酸的重量比为1∶1.5~2.5∶0.8~1.7;
(7)根据上述(1)~(6)中任一项所述的副作用降低剂,其中,上述副作用选自手足综合症和出血中的1种以上;
(8)根据上述(1)~(7)中任一项所述的副作用降低剂,其被给予肝癌患者;
(9)根据上述(1)~(8)中任一项所述的副作用降低剂,其被给予肝硬化的分级为child A级的患者;
(10)抗癌用药物,其特征在于,将选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐与激酶抑制剂组合而成;
(11)根据上述(10)所述的抗癌用药物,其中,上述激酶抑制剂为
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
(4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺)、
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
(4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺)、
N-(2-Chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea
(N-(2-氯-4-((6,7-二甲氧基-4-喹唑啉基)氧基)苯基)-N´-丙基脲)、
N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
(N-[3-[5-(2-氨基吡啶-4-基)2-叔丁基-1,3-噻唑-4-基]-2-氟苯基]-2,6-二氟苯磺酰胺)、
1-[1-[(2-aminopyridin-4-yl)methyl]indol-4-yl]-3-(5-bromo-2-methoxyphenyl)urea hydrochloride
(1-[1-[(2-氨基吡啶-4-基)甲基]吲哚-4-基]-3-(5-溴-2-甲氧基苯基)脲盐酸盐)、
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
(N-[4-(3-氨基-1H-吲哚-4-基)苯基]-N´-(2-氟-5-甲基苯基)脲)
1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea
(1-[2-氯-4-(6,7-二甲氧基喹啉-4-基)氧基苯基]-3-(5-甲基-1,2-噁唑基-3-基)脲)、
1-N'-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(1-N´-[3-氟-4-[6-甲氧基-7-(3-吗啉-4-基丙氧基)喹啉-4-基]氧基苯基]-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)、
N-[[3-fluoro-4-[2-(1-methylimidazol-4-yl)thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-phenylacetamide
(N-[[3-氟-4-[2-(1-甲基咪唑-4-基)噻吩并[3,2-b]吡啶-7-基]氧基苯基]硫代氨基甲酰基]-2-苯乙酰胺)、
1-N'-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(1-N´-[2-氟-4-[2-[[4-甲基哌嗪-1-基]哌啶-1-羰基]氨基]吡啶-4-基]氧基苯基-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)、
4-[3-chloro-4-[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-,monomethanesulfonate
(4-[3-氯-4-[[环丙基氨基]羰基]氨基]苯氧基]-7-甲氧基一甲磺酸盐)、
1-N'-(4-fluorophenyl)-1-N-[4-[[2-(2-morpholin-4-ylethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide
(1-N´-(4-氟苯基)-1-N-[4-[[2-(2-吗啉-4-基乙基氨基甲酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氧基]苯基]环丙烷-1,1-二甲酰胺)、
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine
(1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺)、
6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide
(6-[7-[(1-氨基环丙基)甲氧基]-6-甲氧基喹啉-4-基]氧基-N-甲基萘-1-甲酰胺)、或
2-dimethyl-6-[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy-1-benzofuran-3-carboxamide
(2-二甲基-6-[7-(2-吗啉-4-基乙氧基)喹啉-4-基]氧基-1-苯并呋喃-3-甲酰胺);
(12)根据上述(10)所述的抗癌用药物,其中,上述激酶抑制剂为
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
(4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺);
(13)根据上述(9)~(11)中任一项所述的抗癌用药物,其包含异亮氨酸、亮氨酸和缬氨酸这3种支链氨基酸;
(14)根据上述(10)~(13)中任一项所述的抗癌用药物,其中,异亮氨酸、亮氨酸和缬氨酸的重量比为1∶1.5~2.5∶0.8~1.7;
(15)根据上述(10)~(14)中任一项所述的抗癌用药物,其被给予肝癌患者;
(16)根据上述(10)~(15)中任一项所述的抗癌用药物,其被给予肝硬化的分级为child A级的患者;
(17)根据上述(10)~(16)中任一项所述的抗癌用药物,其中,上述支链氨基酸或其盐与上述激酶抑制剂一起服用;
(18)药物试剂盒,其含有
选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐、和
激酶抑制剂;
(19)根据上述(18)所述的药物试剂盒,其中,进一步含有记载物,该记载物记载了为了使上述激酶抑制剂的副作用降低,可以使用或应该使用上述支链氨基酸或其盐。
本发明的副作用降低剂可以有效地降低由以索拉非尼为代表的激酶抑制剂导致的副作用。因此,通过使用本发明的副作用降低剂、以及含有该副作用降低剂的抗癌用药物和药物试剂盒,可以在各种激酶抑制剂适应的疾病、特别是癌的治疗中,改善患者的QOL(生活质量),得到更高的治疗效果。
附图说明
[图1] 表示在实施例1中各组的生存率的经时变化的图;
[图2] 表示在实施例2中各组的细胞增殖抑制作用的图;
[图3] 表示在实施例3中各组的抗肿瘤作用增强效果的图。
具体实施方式
<支链氨基酸>
作为本发明的有效成分(支链氨基酸)的、异亮氨酸、亮氨酸和缬氨酸分别能够以L型、D型、DL型的任一者使用,优选为L型、DL型,进而优选为L型。另外,异亮氨酸、亮氨酸和缬氨酸各自不仅能够以游离体的形式使用,还能够以盐的形式使用。盐的形式也可以列举酸加成盐、与碱的盐等,优选选择异亮氨酸、亮氨酸和缬氨酸的作为药物可接受的盐。可分别与异亮氨酸、亮氨酸和缬氨酸加成而形成作为药物可接受的盐的酸,可以列举例如氯化氢、溴化氢、硫酸、磷酸盐等无机盐、醋酸、乳酸、柠檬酸、酒石酸、马来酸、富马酸或单甲基硫酸等有机盐。作为异亮氨酸、亮氨酸和缬氨酸的作为药物可接受的碱的例子,可以列举例如与钠、钾、钙等金属的氢氧化物或碳酸化物、或氨等无机碱的盐、与乙二胺、丙二胺、乙醇胺、单烷基乙醇胺、二烷基乙醇胺、二乙醇胺、三乙醇胺等有机碱的盐。
<激酶抑制剂>
在本发明和本申请说明书中,激酶抑制剂是指KIT、FLT-3、RET、VEGFR-1、VEGFR-2、VEGFR-3和PDGFR-β等细胞表面激酶、以及Raf等细胞内激酶的抑制剂。
作为可利用本发明的副作用降低剂降低副作用的激酶抑制剂,具体地可以列举下述化合物:
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
(4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺)(索拉非尼)、
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
(4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺)、
N-(2-Chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea
(N-(2-氯-4-((6,7-二甲氧基-4-喹唑啉基)氧基)苯基)-N´-丙基脲)、
N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
(N-[3-[5-(2-氨基吡啶-4-基)2-叔丁基-1,3-噻唑-4-基]-2-氟苯基]-2,6-二氟苯磺酰胺)、
1-[1-[(2-aminopyridin-4-yl)methyl]indol-4-yl]-3-(5-bromo-2-methoxyphenyl)urea hydrochloride
(1-[1-[(2-氨基吡啶-4-基)甲基]吲哚-4-基]-3-(5-溴-2-甲氧基苯基)脲盐酸盐)、
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
(N-[4-(3-氨基-1H-吲哚-4-基)苯基]-N´-(2-氟-5-甲基苯基)脲)
1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea
(1-[2-氯-4-(6,7-二甲氧基喹啉-4-基)氧基苯基]-3-(5-甲基-1,2-噁唑基-3-基)脲)、
1-N'-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(1-N´-[3-氟-4-[6-甲氧基-7-(3-吗啉-4-基丙氧基)喹啉-4-基]氧基苯基]-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)、
N-[[3-fluoro-4-[2-(1-methylimidazol-4-yl)thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-phenylacetamide
(N-[[3-氟-4-[2-(1-甲基咪唑-4-基)噻吩并[3,2-b]吡啶-7-基]氧基苯基]硫代氨基甲酰基]-2-苯乙酰胺)、
1-N'-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(1-N´-[2-氟-4-[2-[[4-甲基哌嗪-1-基]哌啶-1-羰基]氨基]吡啶-4-基]氧基苯基-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺)、
4-[3-chloro-4-[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-,monomethanesulfonate
(4-[3-氯-4-[[环丙基氨基]羰基]氨基]苯氧基]-7-甲氧基一甲磺酸盐)、
1-N'-(4-fluorophenyl)-1-N-[4-[[2-(2-morpholin-4-ylethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]cyclopropane-1,1-dicarboxamide
(1-N´-(4-氟苯基)-1-N-[4-[[2-(2-吗啉-4-基乙基氨基甲酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氧基]苯基]环丙烷-1,1-二甲酰胺)、
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine
(1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺)、
6-[7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl]oxy-N-methylnaphthalene-1-carboxamide
(6-[7-[(1-氨基环丙基)甲氧基]-6-甲氧基喹啉-4-基]氧基-N-甲基萘-1-甲酰胺)、和
2-dimethyl-6-[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy-1-benzofuran-3-carboxamide
(2-二甲基-6-[7-(2-吗啉-4-基乙氧基)喹啉-4-基]氧基-1-苯并呋喃-3-甲酰胺)。
在本发明中,更优选上述激酶抑制剂为索拉非尼。
激酶抑制剂也可以是作为药物可接受的盐。与激酶抑制剂形成作为药物可接受的盐的酸可以列举例如上述支链氨基酸中列举的物质。
<副作用降低剂>
本发明的副作用降低剂的特征在于,以选自异亮氨酸、亮氨酸、和缬氨酸中的至少1种支链氨基酸或其盐作为有效成分,使激酶抑制剂的副作用降低。本发明的副作用降低剂可含有异亮氨酸、亮氨酸、缬氨酸的任意1种以上作为支链氨基酸,优选异亮氨酸、亮氨酸、缬氨酸这三种全部含有。
作为本发明的有效成分的异亮氨酸、亮氨酸和缬氨酸可以分别单独地、或以任意组合的方式含在制剂中,或可以全部含在1种制剂中。分别进行制剂化并给药时,它们的给药途径、给药剂型可以相同,也可以不同,另外各自给药的时机可以是同时给药,也可以是分别给药。根据并用的药剂的种类、效果而适当决定。
在本发明的副作用降低剂含有3种支链氨基酸时,异亮氨酸、亮氨酸、缬氨酸的配合比(重量比)优选为1∶1~3∶0.5~2.0,更优选为1∶1.5~2.5∶0.8~1.7,进而优选为1∶1.5~2.5∶0.8~1.5,更进而优选为1∶1.9~2.2∶1.1~1.3,特别优选为1∶2∶1.2。
在本发明中,“重量比”表示制剂中各成分的重量之比。例如在1个制剂中含有异亮氨酸、亮氨酸和缬氨酸各有效成分时,“重量比”是各自的含量之比,将各有效成分分别单独或以任意的组合含在多个制剂中时,是指各制剂中所含的各有效成分的重量之比。
另外在本发明中,实际的给药量的比例是指每位给药对象(即患者)的各有效成分1次给药量或1日给药量的比例。例如在1个制剂中含有异亮氨酸、亮氨酸和缬氨酸各有效成分,并将其向给药对象给药时,重量比相当于给药量比。将各有效成分以单独或任意组合的方式含在多个制剂中来给药时,1次或1日给药的各制剂中的各有效成分的合计量的比例相当于重量比。
异亮氨酸、亮氨酸和缬氨酸已经在药物、食品领域广泛使用,安全性是确定的,例如以1∶2∶1.2的比例含有这些氨基酸的本发明的药物组合物的急性毒性(LD50)在小鼠的口服给药中为10g/Kg以上。
本发明的副作用降低剂可以利用通常的方法制成散剂、颗粒剂、胶囊剂、片剂、咀嚼剂等固体制剂、溶液剂、糖浆剂等液体制剂、或注射剂、喷雾剂等。这些制剂可以通过口服、注射、或局部给药等任意的给药方法来给药。
本发明的副作用降低剂可在作为有效成分的支链氨基酸中,根据制剂上的需要,配合适当的药学上可接受的载体、例如赋形剂、粘合剂、润滑剂、溶剂、崩解剂、溶解助剂、悬浮剂、乳化剂、等渗剂、稳定剂、止痛剂、防腐剂、抗氧化剂、矫味矫臭剂、着色剂等来形成制剂。
赋形剂可以列举乳糖、葡萄糖、D-甘露醇等糖类、淀粉类、结晶纤维素等纤维素类等有机系赋形剂、碳酸钙、白陶土等无机系赋形剂等。粘合剂可以列举α化淀粉、明胶、***胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、结晶纤维素、D-甘露醇、海藻糖、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇等。润滑剂可以列举硬脂酸、硬脂酸盐等脂肪酸盐、滑石、硅酸盐类等。溶剂可以列举纯化水、生理盐水等。崩解剂可以列举低取代羟丙基纤维素、化学修饰的纤维素、淀粉类等。溶解助剂可以列举聚乙二醇、丙二醇、海藻糖、苯甲酸苄酯、乙醇、碳酸钠、柠檬酸钠、水杨酸钠、醋酸钠等。悬浮剂或乳化剂可以列举十二烷基硫酸钠、***胶、明胶、卵磷脂、单硬脂酸甘油酯、聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠等纤维素类、聚山梨醇酯类、聚氧乙烯氢化蓖麻油等。等渗剂可以列举氯化钠、氯化钾、糖类、甘油、尿素等。稳定剂可以列举聚乙二醇、右旋糖酐硫酸酯纳、其它的氨基酸类等。止痛剂可以列举葡萄糖、葡萄糖酸钙、盐酸普鲁卡因等。防腐剂可以列举对羟基苯甲酸酯类、氯代丁醇、苯甲醇、苯乙醇、脱氢醋酸、山梨酸等。作为抗氧化剂,可以列举亚硫酸盐、抗坏血酸等。作为矫味矫臭剂,可以列举在药物和食品领域通常使用的甜味料、香料等。作为着色剂,可以列举在药物和食品领域通常使用的着色料。
通过服用本发明的副作用降低剂,可以降低激酶抑制剂的副作用。本发明的副作用降低剂优选为了降低由上述具体列举的激酶抑制剂组的至少1种导致的副作用而被服用,优选为了降低由在上述激酶抑制剂组中作为抗癌剂服用的激酶抑制剂导致的副作用而被服用,更优选为了降低由索拉非尼导致的副作用而被服用。支链氨基酸其本身具有抑制肝癌的发生和恶化的作用(参照专利文献2。),因此本发明的副作用降低剂特别优选为了降低由作为肝癌的抗癌剂给予的索拉非尼导致的副作用而被服用。
作为可以利用本发明的副作用降低剂而降低的副作用,可以列举例如手足综合症、剥脱性皮炎、粘膜皮肤眼综合征(Stevens-Johnson综合征,史-约综合征)、多形性红斑、出血(胃肠出血、呼吸道出血、脑出血、口腔内出血、鼻出血、甲床出血、血肿、肿瘤出血)、急性肝炎、肝功能障碍-黄疸、肝衰竭、肝性脑病、急性肝炎、伴随AST(GOT)或ALT(GPT)上升的肝功能障碍、黄疸、肝衰竭、肝性脑病、急性肺障碍、间质性肺炎、高血压危象、可逆性后白质脑病(reversible posterior leukoencephalopathy)、心肌缺血-心肌梗塞、充血性心力衰竭、胃肠穿孔、胃肠溃疡、出血性肠炎、缺血性肠炎、白细胞减少、中性白细胞减少、淋巴细胞减少、血小板减少、贫血、胰腺炎、肾衰竭、休克、过敏反应、横纹肌溶解。其它可以列举超敏反应(包括皮肤反应和荨麻疹)、INR升高、凝血酶原时间延长、疹、脱发、瘙痒、红斑、皮肤干燥、痤疮、皮肤脱屑(skin scale)、湿疹、潮红、抑郁、周围感觉神经病(sensory peripheralneuropathy)、耳鸣、头晕、关节痛、肌肉痛、声嘶、鼻漏、高血压、QT延长、腹泻、恶心、呕吐、淀粉酶升高、脂肪酶升高、便秘、口炎(包含口干和舌痛)、消化不良、吞咽困难、厌食症、胃食管反流病、胃炎、AST(GOT)升高、ALT(GPT)升高、胆红素升高、Al-P升高、胆囊炎、胆管炎、LDH升高、疲劳、疼痛(包含口内疼痛、腹痛、骨痛、头痛和癌疼痛)、低磷酸盐血症、无力、发热、流感样症状、体重减少、***功能障碍、毛囊炎、感染、女样***症、甲状腺功能减退、低钠血症、脱水、味觉障碍、甲状腺功能亢进、辐射回忆反应(radiation recall reaction)、高钾血症和水肿。
本发明的副作用降低剂特别优选以下列目的而服用:降低手足综合症、剥脱性皮炎、粘膜皮肤眼综合征(Stevens-Johnson综合征)、多形性红斑、疹、脱发、瘙痒、红斑、皮肤干燥、痤疮、皮肤脱屑、湿疹、潮红等皮肤症状、以及出血(胃肠出血、呼吸道出血、脑出血、口腔内出血、鼻出血、甲床出血、血肿、肿瘤出血)的至少一种以上。
通过将本发明的副作用降低剂与索拉非尼等激酶抑制剂一并服用,可以降低由激酶抑制剂导致的副作用。因此,通过服用本发明的副作用降低剂,可以改善激酶抑制剂服用者的QOL。另外,对于激酶抑制剂的给药量,即使对于以往由于副作用而仅可少量给药的患者,也可以为了得到药效而更为安全地给予充分的量。特别地,优选向肝硬化的分级为child A级的患者给药。child A级的患者是指胆红素值低于2.0mg/dl、白蛋白值高于3.5g/dl的患者,没有表现腹水和脑病的症状的营养状态较为良好的患者。
例如,使用索拉非尼作为抗癌剂时,通过并用本发明的副作用降低剂,可使手足综合症、出血等副作用显著降低,因此对于由于这些副作用而不得不放弃或中断治疗的患者,也可以不过大地损害QOL而给予索拉非尼。另外,通过副作用的减轻,增加给药量或延长给药期间这样的给药方式的选择也成为可能,因此还可以扩大治疗方针的范围。
本发明的副作用降低剂除了含有支链氨基酸或其盐作为有效成分以外,还可以含有其它的药效成分。作为其它的药效成分,可以列举例如上述激酶抑制剂以外的抗癌剂、维生素类等营养剂等。
<抗癌用药物>
本发明的抗癌用药物的特征在于,将选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐(即,本发明的副作用降低剂)、和激酶抑制剂组合而成,并为了治疗癌症而向给药对象给药。本发明的抗癌用药物可以是将本发明的副作用降低剂和激酶抑制剂制成一个制剂的药物,也可以是各自作为个别的制剂组合而成的药物。
在本发明的抗癌用药物中,不仅含有治疗癌症的药物,还含有抑制癌症的发病/恶化的药物。
激酶抑制剂可以使用药理学上可接受的载体、添加剂,利用本身公知的方法形成各种制剂,进行制剂化。根据制剂的种类、制剂上的需要,作为适当的药学上可接受的载体,可以列举例如上述副作用降低剂中列举的载体。
作为激酶抑制剂,可以使用市售的各种激酶抑制剂制剂。例如,索拉非尼作为甲苯磺酸盐,市售有ネクサバール(注册商标)片(バイエル薬品社制)。
本发明的抗癌用药物所针对的治疗对象的疾病只要是人或动物的癌(恶性肿瘤),就没有特别限定。例如可以是原发性癌,也可以是转移性癌。另外,可以是早期癌,也可以是晚期癌(advanced cancer)。例如激酶抑制剂为索拉非尼时,优选为了治疗肾细胞癌、肝细胞癌而给药,更优选向不能切除的肝细胞癌、且肝硬化的分级为child A级的患者给药。
<给药方法、给药量>
对于本发明的副作用降低剂和抗癌用药物,支链氨基酸的给药量(摄入量)根据患者的病症、年龄、给药方法等而不同,通常是每1人、1天,异亮氨酸为0.5~30.0g、亮氨酸为1.0~60.0g、缬氨酸为0.5~30.0g。普通成人的情况下,优选每1人、1天,异亮氨酸为2.0~10.0g、亮氨酸为3.0~20.0g、缬氨酸为2.0~10.0g,更优选异亮氨酸为2.5~3.5g、亮氨酸为5.0~7.0g、缬氨酸为3.0~4.0g。异亮氨酸、亮氨酸、缬氨酸全部含有时,成人每1天的给药量以3种支链氨基酸的合计量计,通常优选为2.0~50.0g左右,根据需要将其分为1~6次、优选1~3次来给药。
每1次给药的支链氨基酸的配合量通常为0.5~50.0g左右,优选1.0~20.0g左右,更优选2.0~6.0g左右。
激酶抑制剂的给药量、给药期间、给药时间表、给药途径等只要是可发挥该激酶抑制剂的药效的范围内,就没有特别限定。例如上述具体列举的各激酶抑制剂的给药量根据各种给药途径,可以是每1天为0.01~200mg/kg(体重)/天。激酶抑制剂为索拉非尼时,对于成人,优选的是,将索拉非尼1剂400mg隔日或1天1~2次口服给药。
在本发明中,支链氨基酸和激酶抑制剂可以作为各自分开的制剂,以相同或不同的给药方式给药。或者可以作为同时含有支链氨基酸和激酶抑制剂的药物、即复合药来给药。
支链氨基酸和激酶抑制剂为各自分开的制剂时,只要支链氨基酸和激酶抑制剂这两者在体内同时存在,就不特别限定给药方式,例如可以将支链氨基酸与激酶抑制剂同时或在激酶抑制剂给药前后的任一时候给药。并用时的给药方法和给药量根据并用的药剂的种类、效果而适当决定。
隔着时间差给予支链氨基酸和激酶抑制剂时,时间差根据给予的有效成分、剂型、给药方法而不同,例如先给予支链氨基酸时,可以列举在给予支链氨基酸后,在5分钟~14天以内、优选10分钟~7天以内给予激酶抑制剂的方法。先给予激酶抑制剂时,可以列举在给予激酶抑制剂后,在5分钟~120小时以内、优选10分钟~80小时以内给予支链氨基酸的方法。
对于本发明中使用的作为有效成分的支链氨基酸的给药量(摄入量)进行计算时,作为以激酶抑制剂的副作用降低为目的使用的药剂的有效成分来决定上述的估算范围,对于以与其不同的目的、例如通常的饮食生活的需要、或以其它疾病的治疗目的而被摄取或给予的支链氨基酸,不需要将其含在上述估算中。例如,不需要将由通常的饮食生活摄取的每一日的支链氨基酸的量从上述本发明中的有效成分的每一日的给药量中扣除来估算。
<药物试剂盒>
可以将选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐(即,本发明的副作用降低剂)与例如有效量的激酶抑制剂制剂、以各自单一成分的方式组合而形成一体包装这样的药物用试剂盒。
该药物试剂盒优选进一步含有记载物,该记载物记载了为了使上述激酶抑制剂的副作用降低,可以使用或应该使用本发明的副作用降低剂。该记录物可以作为印刷在纸等上的记录物而附在药物试剂盒中,也可以直接印刷到收纳了本发明的副作用降低剂的容器上,还可以直接印刷到同时收纳了本发明的副作用降低剂和激酶抑制剂的箱或塑料包装等上。应予说明,在容器、箱等上印刷时,也可以贴附印刷的封条。
实施例
接着,用实施例等进而详细地说明本发明,但本发明不限于这些例子。
[实施例1]
使用CDAA(胆碱缺乏氨基酸添加)饮食诱发肝癌模型大鼠,研究由一并摄入索拉非尼和支链氨基酸(BCAA)带来的效果。作为CDAA饮食,使用市售品胆碱缺乏饮食(♯518753:胆碱缺乏且铁补充的L-氨基酸规定的大鼠饮食(Choline Deficient and ironSupplemented L-Amino Acid Defined Rat Diet)、Dyets社制)。
将6周龄的Fischer344系大鼠分为CDAA饮食摄入组、索拉非尼单独摄入组、和BCAA并用摄入组(各组:N=15),自由喂食实验饮食。作为实验饮食,对于CDAA饮食摄入组仅提供CDAA饮食。对于索拉非尼单独摄入组,提供在CDAA饮食中以单位体重的索拉非尼的摄入量为16mg/kg/日(800mg/50kg/日)的方式混合了索拉非尼甲苯磺酸盐片(ネクサバール(注册商标)片200mg、バイエル薬品社制)而成的物质(以下称为“CDAA/索拉非尼饮食”)。对于BCAA并用摄入组,提供在索拉非尼单独摄入组中所提供的CDAA/索拉非尼饮食中进而以使含量为2.5质量%的方式混合了BCAA制剂(リーバクト(注册商标)颗粒、味之素公司制)而成的物质(以下称为“CDAA/索拉非尼/BCAA饮食”)。应予说明,该BCAA制剂的异亮氨酸、亮氨酸、缬氨酸的重量比为1∶2∶1.2(异亮氨酸:0.952g、亮氨酸:1.904g、缬氨酸:1.144g)。
对于各个体,在死亡时、或试验(提供实验饮食)开始后56周后进行剖检,研究基于肝纤维化抑制效果、肝癌发生率和生存率的治疗持续效果。
另外,肝纤维化的有无基于下述两结果来判断:将肝脏的组织切片进行Azan染色的结果、和进行肝中HYP(羟脯氨酸,hydroxyproline)浓度的测定的结果。肝癌发生的有无如下述这样评价,即,将肝脏的组织切片用对抗癌前标记物GST-P(谷胱甘肽S-转移酶胎盘型,glutathione S-transferase placental form)的抗体进行免疫染色,利用染色的有无来评价。
各组的生存率的经时变化示于图1。对于CDAA饮食摄入组和BCAA并用摄入组,在试验开始后20周后的时候,全部大鼠都存活,相对于此,对于索拉非尼单独摄入组,在试验开始后第16~20周,呈现皮肤症状、全身出血,全部个体死亡,死亡率显著增加。即,对于BCAA并用摄入组,与索拉非尼单独摄入组相比,生存率远远得到改善。另外,对于观察到肝纤维化和癌前病变的大鼠,与CDAA饮食摄入组相比,索拉非尼单独摄入组和BCAA并用摄入组较少,在这两组中,确认可抑制肝癌的发病。另外,对于索拉非尼单独摄入组,确认除了四肢发红,而且躯干部和皮肤也发红,且在还包含***部的胃肠道观察到出血倾向。进而,还观察到由胃狭窄导致的食欲降低。相对于此,对于BCAA并用摄入组,发红、出血、和食欲降低的任一症状也得到显著改善。
由这些结果可以清楚地获知,在摄入胆碱欠乏氨基酸添加饮食的肝纤维化/生癌大鼠模型中,通过一并给予索拉非尼和BCAA,可以得到肝纤维化抑制效果和肝癌前病变抑制效果,而且与单独给予索拉非尼时相比,可以显著改善生存率和副作用,可以稳定地使治疗持续。
[实施例2]
(细胞增殖抑制作用)
将Huh7细胞以6×103细胞/各孔播种到96孔板中,第二天置换为LC(含10%FBS)培养基,在浓度为0、1、2、4、8μM的索拉非尼中分别添加2mM的BCAA,进行48小时的培养。另外,将在不添加BCAA的条件下进行48小时培养的情况作为对照。
在48小时后,除去培养基,将4%仲甲醛添加到各孔中,固定15分钟。除去仲甲醛后,将5% 霍赫斯特(Hoechst)溶液添加到各孔中,放置1分钟。除去5% Hoechst溶液后,将PBS溶液200μl添加到各well中。
对于该板,利用阵列扫描(array scan)分析细胞数,将对照(LC10%)设为100时,将各组中的细胞数作为增殖的百分数(% of proliferation)算出。结果示于图2。
由图2可以清楚地得知,在索拉非尼+BCAA组中,特别地,在索拉非尼的浓度为2、4、8μM刺激下的BCAA并用刺激中,与索拉非尼单独刺激相比,观察到显著的细胞增殖抑制作用。
[实施例3]
(抗肿瘤作用增强效果)
将Huh7细胞以1x107细胞/小鼠向BALB/c裸鼠的皮下移植。
1周后,以肿瘤直径进行分组,实施2周(索拉非尼给药5天/周)的5mg/kg索拉非尼口服给药±含3%BCAA的饲料供给。
第3周给药是将索拉非尼给药量从5mg/kg增加至30mg/kg,并口服给药5天。其间,持续供给含3%BCAA的饲料。
测定从给药开始至3周后的各组的肿瘤直径,算出肿瘤体积的平均值+SE。肿瘤体积根据肿瘤的长径/2x(短径)2来算出。
结果示于图3。
由图3的结果可以清楚地知道,在索拉非尼+BCAA组中,与对照组给药相比,肿瘤体积的缩小程度大,可以观察到由2种药物并用带来的抗肿瘤效果增强效果的倾向。
对于索拉非尼单独组、BCAA单独组,与对照组相比,肿瘤体积的缩小程度没有变化。
产业上的可利用性
本发明的副作用降低剂可以有效地减少由以索拉非尼为代表的激酶抑制剂导致的副作用。因此,本发明的副作用降低剂、以及含有该副作用降低剂的抗癌用药物和药物试剂盒作为用于治疗各种激酶抑制剂适应的疾病、特别是索拉非尼适应的癌的医疗用是合适的。
Claims (20)
1.药物试剂盒,该试剂盒含有:
选自异亮氨酸、亮氨酸和缬氨酸中的至少1种支链氨基酸或其盐,和
激酶抑制剂,
所述激酶抑制剂为:
4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺、
4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺、
N-(2-氯-4-((6,7-二甲氧基-4-喹唑啉基)氧基)苯基)-N'-丙基脲、
N-[3-[5-(2-氨基吡啶-4-基)-2-叔丁基-1,3-噻唑-4-基]-2-氟苯基]-2,6-二氟苯磺酰胺、
1-[1-[(2-氨基吡啶-4-基)甲基]吲哚-4-基]-3-(5-溴-2-甲氧基苯基)脲盐酸盐、
N-[4-(3-氨基-1H-吲哚-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲、
1-[2-氯-4-(6,7-二甲氧基喹啉-4-基)氧基苯基]-3-(5-甲基-1,2-噁唑-3-基)脲、
1-N'-[3-氟-4-[6-甲氧基-7-(3-吗啉-4-基丙氧基)喹啉-4-基]氧基苯基]-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
N-[[3-氟-4-[2-(1-甲基咪唑-4-基)噻吩并[3,2-b]吡啶-7-基]氧基苯基]硫代氨基甲酰基]-2-苯乙酰胺、
1-N'-[2-氟-4-[2-[[4-甲基哌嗪-1-基]哌啶-1-羰基]氨基]吡啶-4-基]氧基苯基-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
4-[3-氯-4-[[环丙基氨基]羰基]氨基]苯氧基]-7-甲氧基一甲磺酸盐、
1-N'-(4-氟苯基)-1-N-[4-[[2-(2-吗啉-4-基乙基氨基甲酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氧基]苯基]环丙烷-1,1-二甲酰胺、
1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺、
6-[7-[(1-氨基环丙基)甲氧基]-6-甲氧基喹啉-4-基]氧基-N-甲基萘-1-甲酰胺、或
2-二甲基-6-[7-(2-吗啉-4-基乙氧基)喹啉-4-基]氧基-1-苯并呋喃-3-甲酰胺。
2.根据权利要求1所述的药物试剂盒,其中,进一步含有记载物,该记载物记载了为了使上述激酶抑制剂的副作用降低,使用上述支链氨基酸或其盐。
3.支链氨基酸或其盐、和激酶抑制剂的组合在制备用于治疗癌症的药物中的用途,其中,
所述支链氨基酸是选自异亮氨酸、亮氨酸和缬氨酸中的至少1种,
所述激酶抑制剂为:
4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺、
4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺、
N-(2-氯-4-((6,7-二甲氧基-4-喹唑啉基)氧基)苯基)-N'-丙基脲、
N-[3-[5-(2-氨基吡啶-4-基)-2-叔丁基-1,3-噻唑-4-基]-2-氟苯基]-2,6-二氟苯磺酰胺、
1-[1-[(2-氨基吡啶-4-基)甲基]吲哚-4-基]-3-(5-溴-2-甲氧基苯基)脲盐酸盐、
N-[4-(3-氨基-1H-吲哚-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲、
1-[2-氯-4-(6,7-二甲氧基喹啉-4-基)氧基苯基]-3-(5-甲基-1,2-噁唑-3-基)脲、
1-N'-[3-氟-4-[6-甲氧基-7-(3-吗啉-4-基丙氧基)喹啉-4-基]氧基苯基]-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
N-[[3-氟-4-[2-(1-甲基咪唑-4-基)噻吩并[3,2-b]吡啶-7-基]氧基苯基]硫代氨基甲酰基]-2-苯乙酰胺、
1-N'-[2-氟-4-[2-[[4-甲基哌嗪-1-基]哌啶-1-羰基]氨基]吡啶-4-基]氧基苯基-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
4-[3-氯-4-[[环丙基氨基]羰基]氨基]苯氧基]-7-甲氧基一甲磺酸盐、
1-N'-(4-氟苯基)-1-N-[4-[[2-(2-吗啉-4-基乙基氨基甲酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氧基]苯基]环丙烷-1,1-二甲酰胺、
1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺、
6-[7-[(1-氨基环丙基)甲氧基]-6-甲氧基喹啉-4-基]氧基-N-甲基萘-1-甲酰胺、或
2-二甲基-6-[7-(2-吗啉-4-基乙氧基)喹啉-4-基]氧基-1-苯并呋喃-3-甲酰胺。
4.根据权利要求3所述的用途,其中,上述激酶抑制剂为4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺。
5.权利要求3或4所述的用途,其中,所述支链氨基酸包含异亮氨酸、亮氨酸和缬氨酸这3种。
6.根据权利要求5所述的用途,其中,异亮氨酸、亮氨酸、和缬氨酸的重量比为1∶1.5~2.5∶0.8~1.7。
7.根据权利要求3或4所述的用途,其中,所述药物是治疗癌症、同时降低选自手足综合症和出血的至少一种副作用的药物。
8.根据权利要求3或4所述的用途,其中,所述药物是用于治疗肝癌患者的药物。
9.根据权利要求3或4所述的用途,其中,所述药物是用于治疗不能切除的肝细胞癌、且肝硬化的分级为child A级的患者的药物。
10.支链氨基酸或其盐在制备激酶抑制剂的副作用降低剂中的用途,其中,
所述支链氨基酸是选自异亮氨酸、亮氨酸和缬氨酸中的至少1种,
所述激酶抑制剂为:
4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺、
4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺、
N-(2-氯-4-((6,7-二甲氧基-4-喹唑啉基)氧基)苯基)-N'-丙基脲、
N-[3-[5-(2-氨基吡啶-4-基)-2-叔丁基-1,3-噻唑-4-基]-2-氟苯基]-2,6-二氟苯磺酰胺、
1-[1-[(2-氨基吡啶-4-基)甲基]吲哚-4-基]-3-(5-溴-2-甲氧基苯基)脲盐酸盐、
N-[4-(3-氨基-1H-吲哚-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲、
1-[2-氯-4-(6,7-二甲氧基喹啉-4-基)氧基苯基]-3-(5-甲基-1,2-噁唑-3-基)脲、
1-N'-[3-氟-4-[6-甲氧基-7-(3-吗啉-4-基丙氧基)喹啉-4-基]氧基苯基]-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
N-[[3-氟-4-[2-(1-甲基咪唑-4-基)噻吩并[3,2-b]吡啶-7-基]氧基苯基]硫代氨基甲酰基]-2-苯乙酰胺、
1-N'-[2-氟-4-[2-[[4-甲基哌嗪-1-基]哌啶-1-羰基]氨基]吡啶-4-基]氧基苯基-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
4-[3-氯-4-[[环丙基氨基]羰基]氨基]苯氧基]-7-甲氧基一甲磺酸盐、
1-N'-(4-氟苯基)-1-N-[4-[[2-(2-吗啉-4-基乙基氨基甲酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氧基]苯基]环丙烷-1,1-二甲酰胺、
1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺、
6-[7-[(1-氨基环丙基)甲氧基]-6-甲氧基喹啉-4-基]氧基-N-甲基萘-1-甲酰胺、或
2-二甲基-6-[7-(2-吗啉-4-基乙氧基)喹啉-4-基]氧基-1-苯并呋喃-3-甲酰胺。
11.根据权利要求10所述的用途,其中,上述激酶抑制剂为4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺。
12.根据权利要求10或11所述的用途,其中,所述支链氨基酸包含异亮氨酸、亮氨酸和缬氨酸这3种。
13.根据权利要求12所述的用途,其中,异亮氨酸、亮氨酸、和缬氨酸的重量比为1∶1.5~2.5∶0.8~1.7。
14.根据权利要求10或11所述的用途,其中,所述副作用是选自手足综合症和出血的至少一种症状。
15.根据权利要求10或11所述的用途,其中,所述副作用降低剂是用于肝癌患者的副作用降低剂。
16.根据权利要求10或11所述的用途,其中,所述副作用降低剂是用于肝硬化的分级为child A级的患者的副作用降低剂。
17.根据权利要求10或11所述的用途,其中,所述副作用降低剂是与所述激酶抑制剂同时给药的激酶抑制剂的副作用降低剂。
18.根据权利要求10或11所述的用途,其中,所述副作用降低剂是在所述激酶抑制剂的给药前、给药后、或给药前后的两者进行给药的激酶抑制剂的副作用降低剂。
19.支链氨基酸或其盐在制备用于降低激酶抑制剂的副作用的食品中的用途,其中,
所述支链氨基酸是选自异亮氨酸、亮氨酸和缬氨酸中的至少1种,
所述激酶抑制剂为:
4-[4-[[4-氯-3-(三氟甲基)苯基]氨基甲酰基氨基]苯氧基]-N-甲基吡啶-2-甲酰胺、
4-[4-({[4-氯-3-(三氟甲基)苯基]氨基甲酰基}氨基)-3-氟苯氧基]-N-甲基吡啶-2-甲酰胺、
N-(2-氯-4-((6,7-二甲氧基-4-喹唑啉基)氧基)苯基)-N'-丙基脲、
N-[3-[5-(2-氨基吡啶-4-基)-2-叔丁基-1,3-噻唑-4-基]-2-氟苯基]-2,6-二氟苯磺酰胺、
1-[1-[(2-氨基吡啶-4-基)甲基]吲哚-4-基]-3-(5-溴-2-甲氧基苯基)脲盐酸盐、
N-[4-(3-氨基-1H-吲哚-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲、
1-[2-氯-4-(6,7-二甲氧基喹啉-4-基)氧基苯基]-3-(5-甲基-1,2-噁唑-3-基)脲、
1-N'-[3-氟-4-[6-甲氧基-7-(3-吗啉-4-基丙氧基)喹啉-4-基]氧基苯基]-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
N-[[3-氟-4-[2-(1-甲基咪唑-4-基)噻吩并[3,2-b]吡啶-7-基]氧基苯基]硫代氨基甲酰基]-2-苯乙酰胺、
1-N'-[2-氟-4-[2-[[4-甲基哌嗪-1-基]哌啶-1-羰基]氨基]吡啶-4-基]氧基苯基-1-N-(4-氟苯基)环丙烷-1,1-二甲酰胺、
4-[3-氯-4-[[环丙基氨基]羰基]氨基]苯氧基]-7-甲氧基一甲磺酸盐、
1-N'-(4-氟苯基)-1-N-[4-[[2-(2-吗啉-4-基乙基氨基甲酰基)-1H-吡咯并[2,3-b]吡啶-4-基]氧基]苯基]环丙烷-1,1-二甲酰胺、
1-甲基-5-[2-[5-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基]氧基-N-[4-(三氟甲基)苯基]苯并咪唑-2-胺、
6-[7-[(1-氨基环丙基)甲氧基]-6-甲氧基喹啉-4-基]氧基-N-甲基萘-1-甲酰胺、或
2-二甲基-6-[7-(2-吗啉-4-基乙氧基)喹啉-4-基]氧基-1-苯并呋喃-3-甲酰胺。
20.根据权利要求19所述的用途,其中,所述食品是容器包装食品。
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2014
- 2014-05-29 US US14/290,275 patent/US20140275183A1/en not_active Abandoned
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2015
- 2015-04-27 JP JP2015090705A patent/JP2015131865A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1582207A1 (en) * | 2002-12-26 | 2005-10-05 | Ajinomoto Co., Inc. | Inhibitor for liver cancer onset and progress |
CN101868235A (zh) * | 2007-11-26 | 2010-10-20 | 雀巢产品技术援助有限公司 | 抑制dsRNA-依赖性蛋白激酶激活和抑制肿瘤生长的组合物和方法 |
Non-Patent Citations (1)
Title |
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Effect of branched-chain amino acids on muscle atrophy in cancer cachexia;Helen L. ELEY,et al.;《Biochem. J.》;20071231;第407卷;全文 * |
Also Published As
Publication number | Publication date |
---|---|
EP2786750B2 (en) | 2023-06-28 |
KR101909433B1 (ko) | 2018-10-18 |
EP2786750A4 (en) | 2015-04-08 |
CN104023715A (zh) | 2014-09-03 |
KR20140087037A (ko) | 2014-07-08 |
US20140275183A1 (en) | 2014-09-18 |
JP5788527B2 (ja) | 2015-09-30 |
EP2786750B1 (en) | 2016-06-08 |
WO2013081154A1 (ja) | 2013-06-06 |
JPWO2013081154A1 (ja) | 2015-04-27 |
EP2786750A1 (en) | 2014-10-08 |
JP2015131865A (ja) | 2015-07-23 |
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