CN115745975B - 一种jak激酶结构域和假激酶结构域共抑制前药、制备方法及医药用途 - Google Patents
一种jak激酶结构域和假激酶结构域共抑制前药、制备方法及医药用途 Download PDFInfo
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- CN115745975B CN115745975B CN202211131511.8A CN202211131511A CN115745975B CN 115745975 B CN115745975 B CN 115745975B CN 202211131511 A CN202211131511 A CN 202211131511A CN 115745975 B CN115745975 B CN 115745975B
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种JAK激酶结构域和假激酶结构域共抑制前药、制备方法及医药用途。本发明请求保护一种JAK激酶结构域和假激酶结构域共抑制前药，结构式如式Ⅰ或式Ⅱ所示。活性研究表明，本发明提供的JAK激酶结构域和假激酶结构域共抑制前药对HEL细胞增殖抑制作用强，且具有靶向、可调控的特点，具有开发成抗骨髓增殖性肿瘤的药物的前景。
Description
技术领域
本发明属于药物化学领域，具体涉及一种JAK激酶结构域和假激酶结构域共抑制前药、制备方法及医药用途。
背景技术
JAK是生物体内一类极为重要的非受体型酪氨酸激酶，其能介导细胞因子信号转导，引起下游信号分子STAT磷酸化、聚集，随即入核激活或抑制相关基因，进而调控相关蛋白的表达以发挥生理作用。因此，JAK家族一直是药物开发领域的明星靶点。骨髓增殖性肿瘤(MPNs)是一大类常见的血液肿瘤。MPNs是一系或多系分化相对成熟的骨髓细胞克隆性增殖所致的恶性肿瘤，包括真性红细胞增多症、血小板增多症和原发性骨髓纤维化等多种疾病，各疾病之间可相互转化。这类疾病的患者的临床诊断中都存在一定程度的脾肿大和血细胞分型异常，易转化成急性白血病，严重者甚至会威胁生命。MPNs的典型特征是JAK-STAT信号通路的失调导致巨核细胞、红系和粒细胞祖细胞的过度增殖。
数十年来，研究人员开展了详尽的研究，开发了多种类型的JAK小分子抑制剂。其中多种JAK激酶结构域抑制剂已成功上市并成为MPNs的一线治疗药物。然而，随着JAK激酶结构域抑制剂代表Ruxolitinib在MPNs临床治疗的广泛应用，临床上却发现了新的问题：尽管服用Ruxolitinib能实现患者生存期的延长，但患者的病理状况并没有出现改善。Andraos等人的研究表明，现行主流JAK2激酶结构域抑制剂的“DFG-in”结合模式诱导了JAK2激活环Y1007磷酸化的反常增加，肿瘤过表达的JAK2可以与JAK1或TYK2异二聚，从而转激活JAK-STAT通路，导致对JAK激酶结构域抑制剂的功能性抵抗，MPNs细胞可以继续在JAK2抑制剂的压力下存活，甚至导致耐药等问题一直困扰着医药研究领域。此外，由于JAK及其家族在人体全身的广泛分布及其复杂多样的生理作用，使用JAK抑制剂治疗MPNs时，不可避免会对正常组织产生一定副作用。
为了解决上述问题和不足，特提出本发明创造。
发明内容
为了解决JAK抑制剂在治疗骨髓增殖性肿瘤时存在的问题，本发明旨在采取药物联用的策略共抑制JAK激酶结构域和假激酶结构域以增强对JAK的抑制。为了进一步解决JAK抑制剂因选择性不足而引起的副作用，提高药物针对病灶的靶向性，我们设计并合成了JAK激酶结构域和假激酶结构域拼合而成的前药分子以改善JAK抑制对正常组织的损伤。
本发明上述目的通过如下技术方案实现：
一种JAK激酶结构域和假激酶结构域共抑制前药，为式Ⅰ或式Ⅱ所示化合物或其药学上可接受的盐：
一种上述式Ⅰ化合物的制备方法，合成路线如下：
试剂和反应条件：(a)LiHMDS,THF,-40℃；then NBS,THF,-70℃；(b)H2O/1,4-dioxane,110℃；(c)TBS-Cl,imdazloe,DMF；(d)BTC,DMAP,TEA,0℃,6h；(e)TBAF,THF,r.t.,2h；(f)BTC,DIPEA,THF,0℃,2h；(g)DIPEA,DMAP,TG101209,overnight,r,t.,then NaH,AT-9283,DMAP,THF,r.t.,6h。
一种上述式Ⅱ化合物的制备方法，合成路线如下：
试剂和反应条件：(a)TBS-Cl,Imdazloe,DMF；(b)Cs2CO3,DMF；(c)TBAF,THF；(d)BTC,DIPEA,THF；(e)DIPEA,DMAP,TG101209,thenNaH,AT-9283,DMAP,THF。
上述的化合物用于制备抗骨髓增殖性肿瘤的药物的用途。
进一步地，所述药物以上述的化合物为活性成分，用药学上可以的辅料或载体，制成药学上可以接受的剂型。
更进一步地，所述辅料或载体为固体、液体或半固体。
更进一步地，所述剂型包括片剂、胶囊、注射剂和滴剂。
有益效果：
本发明JAK激酶结构域和假激酶结构域共抑制前药对HEL细胞增殖抑制作用强，且具有靶向、可调控的特点，克服了现有技术的不足，具有开发成抗骨髓增殖性肿瘤药物的前景。
附图说明
图1为在光照或避光状态下，DDO-8441对HEL细胞的增殖抑制活性。
图2为在低氧或常氧状态下，DDO-8442对HEL细胞的增殖抑制活性。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
实施例1：DDO-8441
合成路线1：DDO-8441的合成
Scheme 1Regents and conditions:(a)LiHMDS,THF,-40℃；then NBS,THF,-70℃；(b)H2O/1,4-dioxane,110℃；(c)TBS-Cl,imdazloe,DMF；(d)BTC,DMAP,TEA,0℃,6h；(e)TBAF,THF,r.t.,2h；(f)BTC,DIPEA,THF,0℃,2h；(g)DIPEA,DMAP,TG101209,overnight,r,t.,then NaH,AT-9283,DMAP,THF,r.t.,6h.
4-(溴甲基)-7-(二乙氨基)香豆素(2c)的合成
4-(bromomethyl)-7-(diethylamino)-2H-chromen-2-one(2c)
将7-二乙氨基-4-甲基香豆素(1c)(853mg，4.0mmol)加入到干燥的烧瓶中，并加入无水THF(40ml)中。，将悬浮液冷却至-40℃后，缓慢滴加LiHMDS(10mmol，1M的THF溶液，10ml)。将反应体系缓慢升温至-30℃，然后在低温反应浴中冷却至-78℃，随后向反应体系内缓慢滴加NBS(854.4mg，4.8mmol)的无水THF(10ml)溶液，并将该溶液在-78℃搅拌。30分钟后，加入HCl(0.1M)淬灭反应，并用DCM(10ml×3)萃取，合并有机相，旋干制砂，柱层析得橙色固体2c 662mg，产率58％。1H NMR(300MHz,Chloroform-d)δ:7.51(d,J＝9.3Hz,1H),6.65(dd,J＝9.0,2.5Hz,1H),6.54(s,1H),6.16(s,1H),4.42(s,2H),3.44(q,J＝7.1Hz,4H),1.24(t,J＝6.3Hz,6H).
7-(二乙氨基)-4-(羟甲基)香豆素(3c)的合成
7-(diethylamino)-4-(hydroxymethyl)-2H-chromen-2-one(3c)
将化合物2c(309.0mg，1.0mmol)溶于1，4-二氧六环(5ml)和H2O(5ml)的混合液中，并将混合物加热回流10小时。将得到的悬浮液冷却至室温，并用EtOAc(5ml×3)萃取三次。合并有机相，干燥、旋蒸浓缩制砂，柱层析(PE：EA＝4:1)纯化得橙色固体148.2mg，产率60％。m.p.:127.8-128.9℃。1H NMR(300MHz,Chloroform-d)δ7.36(d,J＝8.9Hz,1H),6.61(dd,J＝9.1,2.6Hz,1H),6.54(d,J＝2.6Hz,1H),6.32(s,1H),4.88(d,J＝4.7Hz,2H),3.45(q,J＝7.1Hz,5H),1.24(t,J＝7.1Hz,7H).
2,6-双(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基苯酚(5d)的合成
2,6-bis(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenol(5d)
将化合物4d(10g，59.5mmol)和咪唑(9.72g，143mmol)溶于50ml DMF中。在该溶液中缓慢加入TBS-Cl(21.5g，143mmol)。室温下搅拌2h，TLC监测反应完全后，加水，并用200ml乙酸乙酯萃取；将有机相浓缩旋干，柱层析得无色油状液体5d 20.8g，产率89％。
2,6-双(羟甲基)-4-甲基苯基((7-(二乙氨基)-2-氧代-2H-4-基)甲基)碳酸酯(7d)的合成
2,6-bis(hydroxymethyl)-4-methylphenyl((7-(diethylamino)-2-oxo-2H-chromen-4-yl)methyl)carbonate(7d)
将化合物5d(475mg，1.2mmol)溶于50ml无水THF中，加入1ml DIPEA，随后在冰浴中缓慢滴加三光气(148mg，0.5mmol)的THF溶液，可见大量白烟；缓慢升至室温并搅拌3h，随后再次降至0℃，向反应液内滴加化合物3c(247mg，1.0mmol)的THF溶液，缓慢升至室温后搅拌过夜，注意此时开始反应容器应注意避光；次日，将反应液旋干，并溶于50ml 1.0M的四丁基氟化铵THF溶液中。TLC监测反应完全后，旋干制砂，柱层析得橙红色化合物7d 235mg，产率52％。1H NMR(300MHz,DMSO-d6)δ7.47(d,J＝9.0Hz,1H),7.20(s,2H),6.71(dd,J＝9.1,2.5Hz,1H),6.59(d,J＝2.5Hz,1H),6.30(s,1H),5.14(t,J＝5.4Hz,2H),4.55(d,J＝5.3Hz,3H),2.33(s,3H),1.14(d,J＝6.9Hz,6H).
3-(((4-(3-环丙基脲基)-3-(5-(吗啉代甲基)-1H-苯并[d]咪唑-2-基)-1H-吡唑-1-羰基)氧基)甲基)-2-(((((7-二乙胺基-2-羰基-2H-酮)甲氧基)羰基)氧基)-5-甲基苄基4-(4-((4-((3-(N-(叔-丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯基哌嗪-1-甲酸(DDO-8441)的合成
3-(((4-(3-cyclopropylureido)-3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazole-1-carbonyl)oxy)methyl)-2-((((7-(diethylamino)-2-oxo-2H-chromen-4-yl)methoxy)carbonyl)oxy)-5-methylbenzyl 4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(DDO-8441)
将化合物7d(1.0g，2.26mmol)溶于50ml无水DCM中，加入1ml DIPEA，冰浴下缓慢滴加三光气(0.85g，2.87mmol)的DCM溶液，有大量白烟生成，缓慢升至室温并搅拌过夜；次日，旋干反应液，并将黄色油状物8d重新溶解至20ml无水THF中，加入DMAP(246mg，2.1mmol)，随后滴入TG101209(430mg，0.87mmol)的20ml THF溶液，搅拌6h，TLC提示反应完全后，滴加1mlDIPEA与AT-9283(381mg，1.0mmol)的20ml THF溶液，搅拌过夜，浓缩反应液，制备板纯化得产物DDO-8441132mg，产率11％。m.p.:165-168℃,1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.58(s,1H),8.18(s,1H),8.09(s,1H),7.93(d,J＝0.9Hz,2H),7.62(s,2H),7.56(s,2H),7.53(d,J＝1.7Hz,2H),7.51(d,J＝1.6Hz,1H),7.45(d,J＝3.8Hz,2H),7.20(s,2H),6.90–6.85(m,4H),5.12–5.09(m,2H),4.55(s,4H),3.59(d,J＝4.9Hz,8H),3.14(s,2H),3.03(s,2H),2.39(t,J＝4.5Hz,7H),2.33(s,1H),2.15(s,3H),1.15(s,15H),0.87(s,2H),0.58(s,2H).13C NMR(75MHz,DMSO-d6)δ161.43,158.21,157.90,156.25,155.89,155.38,153.83,153.45,153.30,152.28,151.43,147.20,146.63,142.96,141.29,141.19,139.99,138.87,138.29,135.78,134.97,132.68,130.51,129.00,127.90,127.24,127.18,125.61,125.35,123.72,123.37,120.63,119.66,117.82,115.20,112.74,112.64,112.29,110.67,109.15,100.95,66.52,64.77,64.51,63.16,55.54,52.78,47.88,45.80,44.92,32.28,30.26,20.30,13.62,12.29,9.47.HRMS(ESI):calcd.For C70H79N15O13S[M+H]+1370.5702,found1370.5852.
实施例2：DDO-8442
合成路线2：7e的合成
Scheme 2Reagents and conditions:(a)EtOCHO,THF,NaH,3h；(b)EtOH,Conc.HCl,90℃,2h；(c)EtOH,H2O,NH2CN,pH＝3,100℃,1.5h；(d)AcOH,NaNO2(aq),r.t.,4h；(e)NaBH4,THF,MeOH,0℃,2h；(f)p-TsCl,CH2Cl2,0℃,2h.
合成路线3：DDO-8442的合成
Scheme 3Regents and conditions:(a)TBS-Cl,Imdazloe,DMF；(b)Cs2CO3,DMF；(c)TBAF,THF；(d)BTC,DIPEA,THF；(e)DIPEA,DMAP,TG101209,then NaH,AT-9283,DMAP,THF.
1-甲基-2-硝基-1H-咪唑-5-羧酸乙酯(5e)的合成
ethyl 1-methyl-2-nitro-1H-imidazole-5-carboxylate(5e)
将肌氨酸乙酯盐酸盐(2g，0.013mol)加入甲酸乙酯(45ml)和THF(45ml)的混合溶剂中形成悬浮液，缓慢加入NaH(60％，5g，0.13mol)，并搅拌3小时。反应会放出大量氢气且形成黄色悬浮液，旋干混合物；将EtOH(40ml)和浓HCl水溶液(8ml)加入到该混合物中，并加热回流2小时。趁热过滤，并用沸腾的EtOH(2×30ml)洗涤滤饼至无色。将滤液真空浓缩，并用用EtOH(70ml)和水(30ml)稀释。使用2M NaOH水溶液将溶液的pH调节至3，并加入氨腈(1.09g，0.026mol)，加热回流1.5小时。冷却溶液并减压浓缩；将该浓缩液溶于30ml冰醋酸，并缓缓滴加进20ml亚硝酸钠(8.97g，0.13mol)水溶液中，室温搅拌3h，TLC监测反应完全，向反应液中加入Na2CO3水溶液，并用DCM(100ml*3)萃取，合并有机相，旋干制砂，柱层析(PE：EA＝15:1)得黄色固体5e 540mg，产率21％，1H NMR(300MHz,Chloroform-d)δ7.76(1H,s),4.40(2H,q,J＝7.3Hz),4.35(3H,s),1.41(3H,t,J＝7.3).
(1-甲基-2-硝基-1H-咪唑-5-基)甲醇(6e)的合成
(1-methyl-2-nitro-1H-imidazol-5-yl)methanol(6e)
在0℃下，向5e(230mg，1.16mmol)的无水THF(6ml)和MeOH(0.5ml)溶液中加入硼氢化钠(131mg，3.47mmol)。将反应混合物在0℃下搅拌45分钟，然后在室温下搅拌1小时。TLC监测到反应结束，将反应混合物冷却至0℃，加入冰淬灭，并用1M HCl水溶液将pH调节至7。将含水混合物用固体NaCl饱和，并用EtOAc(5×15ml)萃取。合并有机层，用硫酸钠干燥并过滤。将滤液旋干制砂，柱层析纯化(PE：EA＝1:1)，得到浅黄色晶体6e 109mg，产率66％。1HNMR(300MHz,DMSO-d6)δ7.12(1H,s),5.50(1H,t,J＝5.4Hz),4.54(2H,d,J＝5.4Hz),3.92(3H,s).
5-(氯甲基)-1-甲基-2-硝基-1H-咪唑(7e)
5-(chloromethyl)-1-methyl-2-nitro-1H-imidazole(7e)
将化合物6e(200mg，1.27mmol)溶于无水DCM(8ml)，并加入DMAP(184mg，1.5mmol)和对甲苯磺酰氯(286mg，1.5mmol)，将反应在室温下搅拌，至TLC提示反应结束。将反应液直接旋干制砂，柱层析(PE：EA＝4:1)得产物用石油醚和EtOAc(梯度；50-100％EtOAc)洗脱，得到浅黄色晶体7e 147mg，产率66％。1H NMR(300MHz,Chloroform-d)δ7.24(s,1H),4.68(s,2H),4.12(s,3H).
5-甲基-2-(((1-甲基-2-硝基-1H-咪唑-5-基)甲氧基)-1,3-亚苯基)二甲醇(4f)的合成(5-methyl-2-((1-methyl-2-nitro-1H-imidazol-5-yl)methoxy)-1,3-phenylene)dimethanol(4f)
将化合物7e(350mg，2.0mmol)、化合物2f(900mg，2.3mmol)与碳酸铯(975mg，3.0mmol)溶于DMF，于室温搅拌过夜，次日TLC提示反应完成后，加水，并用乙酸乙酯萃取，合并有机相，旋干，将粗产物直接溶于TBAF的1.0M THF溶液，室温搅拌2h，旋干制砂，柱层析得淡绿色固体4f298 mg，产率48.5％。1H NMR(300MHz,Chloroform-d)δ7.25–7.20(m,1H),5.19(s,1H),4.46(d,J＝4.9Hz,2H),3.79(s,1H),2.13(s,1H),2.02(t,J＝5.0Hz,1H).
3-(((4-(3-环丙基脲基)-3-(5-(吗啉代甲基)-1H-苯并[d]咪唑-2-基)-1H-吡唑-1-羰基)氧基)甲基)-5-甲基-2-((1-甲基-2-硝基-1H-咪唑-5-基)甲氧基)苄基4-(4-((4-((3-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯基哌嗪-1-羧酸酯(DDO-8442)的合成
3-(((4-(3-cyclopropylureido)-3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazole-1-carbonyl)oxy)methyl)-5-methyl-2-((1-methyl-2-nitro-1H-imidazol-5-yl)methoxy)benzyl4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(DDO-8442)
将化合物4f(614mg，2.0mmol)溶于50ml无水DCM中，加入1ml DIPEA，冰浴下缓慢滴加三光气(600mg，2.1mmol)的DCM溶液，有大量白烟生成，缓慢升至室温并搅拌过夜；次日，旋干反应液，并将黄色油状物5f重新溶解至20ml无水THF中，加入DMAP(307mg，2.5mmol)，随后滴入TG101209(446mg，0.9mmol)的20ml THF溶液，搅拌6h，TLC提示反应完全后，滴加1mlDIPEA与AT-9283(457mg，1.2mmol)的20ml THF溶液，搅拌过夜，浓缩反应液，制备板纯化得产物DDO-8441151mg，产率13％。m.p.：183-185℃；1H NMR(300MHz,DMSO-d6)δ8.13(t,J＝2.2Hz,2H),8.08(s,2H),7.55(d,J＝2.6Hz,1H),7.51(s,1H),7.27(s,2H),7.16(s,3H),6.90(s,1H),6.87(s,1H),5.13(s,4H),5.02(s,3H),4.49(d,J＝3.7Hz,7H),4.05(s,5H),3.72(s,7H),3.25(s,10H),3.18(s,5H),2.62(s,2H),2.29(s,5H),2.13(s,3H),1.13(s,9H),1.06(t,J＝7.0Hz,2H),0.86(s,3H),0.57(s,3H).13C NMR(75MHz,DMSO-d6)δ166.23,158.21,156.25,155.89,153.45,152.50,150.18,147.20,141.29,139.99,139.54,138.29,136.28,135.78,134.92,132.68,132.05,129.00,127.99,127.64,127.24,125.61,123.99,123.72,123.37,120.63,119.66,119.42,117.82,115.20,112.74,66.52,64.51,63.16,60.98,55.54,52.78,47.88,45.80,30.26,29.48,22.70,20.30,13.62,7.76.HRMS(ESI):calcd.For C60H69N17O11S[M+H]+1236.5083,found 1236.5935.
活性测定
1、细胞培养
从中国科学院(上海)细胞库购买得到的HEL细胞在RPMI-1640培养基(GiBco，Invitrogen Corp.，USA)中培养，该培养基包含10％热灭活的胎牛血清(FBS,GiBco，Invitrogen Corp.，USA)，100μg/ml青霉素和100μg/ml链霉素(Thermo Scientific)并在含有5％CO2的加湿37℃恒温孵箱中培养。
2、细胞抗增殖实验
使用CCK-8法开展细胞抗增殖实验。将处于对数期的HEL细胞以每孔5000个的密度接种在96孔板中，培养基体积为100μl，并于37℃，5％CO2的孵箱内过夜孵育。次日，加入100μl培养基配制的药物溶液孵育，每个浓度设三个复孔。DDO-8441处理的细胞分别在405nm光照下或者在避光处理下孵育孵育，DDO-8442处理的细胞分别在常氧三气培养箱(75％N2，5％CO2及20％O2)或低氧三气培养箱(94％N2，5％CO2及1％O2)中孵育，48h后，每孔点入20μlCCK-8溶液，并将细胞在37℃下孵育2小时。通过Multiskan Spectrum Microplate Reader(Thermo，USA)在455nm下测量吸光度。通过下式计算处理的细胞的存活百分比：抑制率计算公式为：抑制率(％)＝[1-(ODtest-ODblank)/(ODcontrol-ODblank)]×100％。Graphpad Prism6.0软件计算IC50。
3、实验结果
DDO-8441对HEL细胞的增殖抑制活性如图1所示，DDO-8442对HEL细胞的增殖抑制活性如图2所示。DDO-8441、DDO-8442对HEL细胞增殖抑制作用强，且具有靶向、可调控的特点，具有开发成抗骨髓增殖性肿瘤的药物的前景。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。
Claims (5)
1.一种JAK激酶结构域和假激酶结构域共抑制前药，为式Ⅰ或式Ⅱ所示化合物或其药学上可接受的盐：
2.权利要求1所述的化合物用于制备抗骨髓增殖性肿瘤的药物的用途。
3.根据权利要求2所述的用途，其特征在于：所述药物以权利要求1所述的化合物为活性成分，用药学上可以的辅料或载体，制成药学上可以接受的剂型。
4.根据权利要求3所述的用途，其特征在于：所述辅料或载体为固体、液体或半固体。
5.根据权利要求3所述的用途，其特征在于：所述剂型包括片剂、胶囊、注射剂和滴剂。
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| CN104797267A (zh) * | 2012-06-26 | 2015-07-22 | 德玛医药 | 使用卫康醇、二乙酰二脱水卫矛醇、二溴卫矛醇或类似物或其衍生物治疗具有基因多型性或ahi1失调或突变患者的抗酪氨酸激酶抑制剂的恶性肿瘤的方法 |
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