CN105906665A - 咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用 - Google Patents
咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用 Download PDFInfo
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- CN105906665A CN105906665A CN201610323767.7A CN201610323767A CN105906665A CN 105906665 A CN105906665 A CN 105906665A CN 201610323767 A CN201610323767 A CN 201610323767A CN 105906665 A CN105906665 A CN 105906665A
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- carbazole
- sulfonamide
- methyl
- pyridine
- dimethoxy
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- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Abstract
本发明提供一种咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用。该咔唑磺酰胺衍生物前药或其药用盐具有如下通式(1),其中,R1为氢、低级烷基、苄基或钠。本发明提供的咔唑磺酰胺衍生物前药作为小分子的微管蛋白抑制剂不仅具有抗微管作用,还具有显著的抗肿瘤活性,同时该咔唑磺酰胺衍生物前药或其药用盐合成简单且毒副作用小。
Description
技术领域
本发明涉及一种咔唑磺酰胺衍生物前药或其可药用盐及其制备方法和应用,属于生物制药技术领域。
背景技术
随着肿瘤生物学研究的飞速发展以及科学家对肿瘤致病机制认识的不断深入,新的抗肿瘤治疗靶点和具有新型作用机制的抗肿瘤药物日益成为研发的热点。这些新型的抗肿瘤药物,如化疗增敏剂、蛋白酶抑制剂、血管生成抑制剂、受体拮抗剂等,利用肿瘤生长和转移过程中的生物学特性,选择性的抑制肿瘤细胞生长和转移过程,可以在一定程度上克服细胞毒性药物在治疗实体瘤方面的局限性,从而在肿瘤治疗中显示出广泛的应用前景。肿瘤细胞具有快速增殖能力,通过有丝分裂来维持细胞的形态、功能和增殖,若阻断有丝分裂的过程即可导致肿瘤细胞增值受阻,基于微管在有丝分裂过程中发挥的重要作用,以微管为靶点的抗肿瘤药物成为研究的热点。
微管(Microtubule,MT)是由微管蛋白(Tubulin)装配而成的长丝管状结构,广泛存在于真核细胞中,呈网状和束状分布。微管与其他蛋白共同组装成纺锤体、基粒、中心粒、纤毛、鞭毛、轴突和神经管等结构,在维持细胞形态、细胞增殖、物质运输及信号转导等方面扮演着重要角色,是抗肿瘤药物重要靶点之一。
微管蛋白抑制剂可以通过与微管蛋白的特殊位点相结合,抑制微管的聚合或解聚,使肿瘤细胞有丝分裂过程中纺锤体难以形成,细胞周期阻断在M期,并进一步诱导肿瘤细胞凋亡。按其与微管蛋白的结合位点不同大致分为三类:紫杉醇位点抑制剂、长春新碱位点抑制剂和秋水仙碱位点抑制剂。目前,紫杉醇和长春碱类抗肿瘤药物在癌症治疗方面占据了重要地位,但也存在以下弊端:作为一种大的天然产物,其合成的难度很大,生物利用度差,有较大的毒副作用。
发明内容
本发明提供一种咔唑磺酰胺衍生物前药及其制备方法,作为小分子的微管蛋白抑制剂不仅具有抗微管作用,还具有显著的抗肿瘤活性,同时该咔唑磺酰胺衍生物前药或其药用盐合成简单且毒副作用小。
本发明还提供了该咔唑磺酰胺衍生物或其药用盐作为微管蛋白抑制剂的应用,及在制备抗肿瘤药物中的应用。
本发明还提供了一种抗肿瘤药物组合物,其包括治疗有效量的上述咔唑磺酰胺衍生物或其药用盐及药学上可接受的药用辅料。
为实现上述目的,本发明提供一种咔唑磺酰胺衍生物前药或其药用盐,具有如下通式(1):
其中,R1为氢、低级烷基、苄基或钠。
以上定义中所述的“低级烷基”尤其是指碳原子数在1-6的直链烷基或碳原子数在3-6的支链烷基或环烷基。碳原子数在1-6的直链烷基例如可列举甲基、乙基、丙基、烯丙基、正丁基、正戊基、正己基或正庚基等;碳原子数在3-6的支链烷基例如可列举异丙基、异丁基、仲丁基、叔丁基、异戊基或异己基等;碳原子数在3-6的环烷基例如可列举环丙基、环丁基、环戊基或环己基等。
进一步地,-OPO(OR1)2为6位或7位的取代基。
进一步地,所述低级烷基为甲基或乙基。
进一步地,所述咔唑磺酰胺衍生物前药或其药用盐为:
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑-二乙基磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑-二苄基磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑-二苄基磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑磷酸二钠盐;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑磷酸二钠盐。
作为一类新的小分子微管蛋白抑制剂,经药理实验表明,该类化合物不仅能将肿瘤细胞阻断在有丝分裂(M)期,还具有显著的抗肿瘤活性。
本发明进一步提供了该咔唑磺酰胺衍生物或其药用盐作为微管蛋白抑制剂的应用,及在制备抗肿瘤药物中的应用。
本发明另一方面还提供了一种抗肿瘤药物组合物,其包括治疗有效量的上述咔唑磺酰胺衍生物或其药用盐及药学上可接受的药用辅料,可将化合物本身或其药用盐与可药用赋形剂、稀释剂等混合制备成片剂、胶囊、颗粒剂、散剂、糖浆剂或注射剂等剂型。
上述制剂可通过常规制药方法制备。可用的药用辅剂的例子包括赋形剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇;淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉;纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠;阿拉伯胶;右旋糖酐;硅酸盐衍生物如偏硅酸镁铝;磷酸盐衍生物如磷酸钙;碳酸盐衍生物如碳酸钙;硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)、稀释剂和注射液用溶剂(例如水、乙醇和甘油等)。
本发明化合物的给药量随患者的年龄、性别和病情等的不同而不同。一般成人的给药量为大约50-5000mg/次,优选100-3000mg/次。
另一方面,本发明还提供上述咔唑磺酰胺衍生物前药或其药用盐的制备方法,该方法至少包括利用化合物(1)和化合物(2)进行反应的过程,
上述方法中,当R1为低级烷基时,上述方法包括在碱性条件下,化合物(1)和化合物(2)进行反应,反应溶剂可为CBr4,以及无水DCM、无水THF、无水乙腈或三氯乙腈,可通过例如DIEA、TEA、NaH或吡啶等提供碱性环境。
其中,化合物(1)可以通过参考文献(Mitsumori,Susumu;Tsuri,Tatsuo;Honma,Tsunetoshi;et al.Journal of Medicinal Chemistry(2003),46(12),(2436-2445)的方法或其它相关报道的方法合成;化合物(2)可通过商购得到。
当R1为氢、苄基或钠时,可参照以下合成路线进行制备:
其中,反应a为在DIEA、TEA、NaH或吡啶等提供的碱性条件下,化合物(1)13l或13g和亚磷酸二苄酯进行反应,反应溶剂为CBr4,以及无水DCM、无水THF、无水乙腈或三氯乙腈,获得化合物20或21;化合物20或21进一步进行脱苄基反应,例如可在在H2和Pd/C的催化作用下进行反应(反应b),生成化合物22或23,化合物22或23进一步在CH3OH以及NaOCH3的作用下生成化合物24或25。
本发明化合物的抗肿瘤活性和药理实验
利用本发明所制备出的部分咔唑磺酰胺化合物前药及其药用盐,发明人同时提供了以下的实验结果,旨在说明本发明化合物的药用功效。
一、体外抗肿瘤活性测定
取培养瓶中指数生长期细胞(人肝癌细胞HepG2和Bel-7402、人乳腺癌细胞MCF-7、人胰腺癌细胞MIA PaCa-2)接种于96孔板中,每孔中的细胞数在4000-8000之间,置37℃,5%CO2,培养24小时;加入不同浓度的药物(DMSO的浓度不超过0.5%,v/v),药物组一般设立5个浓度梯度,设3-4个复孔;继续培养48小时后,贴壁细胞用经4℃预冷的50%TCA固定,96孔板置于4℃冰箱放置1小时;1小时后,用蒸馏水或者自来水洗涤细胞孔5次,以除去TCA、培养液、低分子量代谢物以及血清蛋白等;待其细胞板晾干后,用0.4%的SRB染色15-30分钟;用1%的乙酸洗涤5次,晾干;加入10mmol/L Tris溶液150μL溶解,低速震荡5-10分钟,用酶联免疫检测仪在波长490nm处测定吸收值。
根据所测得的OD值,按照下列公式计算药物对细胞的抑制率IC50。
抑制率=(对照孔OD值-加药孔OD值)/(对照孔OD值-空白孔OD值)×100,结果参见表1。
表1
表1的活性数据表明,本发明提供的咔唑磺酰胺衍生物前药对四种肿瘤细胞都有很好肿瘤抑制活性,22和24的抗肿瘤活性与IMB-105活性相当;而23和25的抗肿瘤活性显著强于IMB-105,尤其是对HepG2细胞和MCF-7细胞,IC50值在10nM左右,并且22和23都较相应的钠盐24和25抗肿瘤活性稍强。
二、小鼠体内急性毒性试验
本发明化合物用生理盐水稀释至所需体积。给药剂量为1000mg/kg-25mg/kg(不同的化合物设计了不同的给药计量);对照组给予等量的生理盐水。
昆明种小鼠(18-20g)按体重平均分组,记录体重,每组6只,雌雄各半或所为雌性,给药前禁食5小时。腹腔注射给药,给药体积为0.2mL/只;静脉注射给药,给药体积为0.2mL/只。
观察给药后的一般情况,记录体重,记录死亡情况,观察7天后称重,结果如表2所示。
表2
由表2可知,化合物24的LD50值在600mg/kg左右。而本领域公知的是,作为对照药的紫杉醇的LD50值35mg/kg。因此本发明化合物与对照药紫杉醇相比,具有较小的毒性。
三、体内抗肿瘤活性测定
抗人体肝癌BALB/c裸鼠10只(雌性,4-6周龄,体重18-20g),均采用肝癌HepG2细胞,裸鼠右侧腋窝皮下接种,10天后瘤体积长到100mm3左右开始分组给药,对照组隔天给以溶剂,治疗组隔天给药(ip)。
每周测量肿瘤体积直到超过2000mm3时,结束试验。肿瘤体积=长×宽2×0.52。按照下式计算给药组与对照组的肿瘤生长抑制率:
生长抑制率(%)=(C-T)/C×100
T:给药组平均肿瘤体积-给药前平均肿瘤体积
C:对照组平均肿瘤体积-给药前平均肿瘤体积
根据初步得到的本发明化合物的LD50值,我们进行了三批小鼠体内的抑瘤试验。在BALB/c(nu/nu)裸鼠右侧腋窝皮下接种的人肝癌HepG2细胞,给药方式都是腹腔注射。
表3
表3为本发明化合物对人肝癌Hep-G2裸鼠移植瘤模型的作用。选择了化合物24和25的两个剂量。表3和图1的数据表明,与空白对照组相比,本发明的咔唑磺酰胺化合物前药具有显著的体内抗肿瘤活性,肿瘤体积得到明显抑制。
以上结果已经初步验证了本发明的小分子咔唑磺酰胺化合物或其药用盐在抗肿瘤及抑制微管方面的作用,应该具有良好的应用前景。
附图说明
图1为本发明的咔唑磺酰胺衍生物前药用于治疗人肝癌HepG2时肿瘤体积随接种后天数的变化曲线。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
下面通过实施例进一步详细说明本发明,但本发明的实施并不仅限于这些实施例。
实施例1
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑-二乙基磷酸酯(19)
氮气保护下,N-(2,6-二甲氧基吡啶-3-基)-6-羟基-9-甲基-3-咔唑磺酰胺(13l)(207mg,0.5mmol)溶于约8mL无水DCM中,亚磷酸二乙酯(0.3mL,2.3mmol),四溴化碳(700mg,2.1mmol)以及N,N-二异丙基乙胺(DIEA,0.45mL,2.6mmol)分别加入上述溶液,室温下搅拌约2h。反应液倒入适量冰水中,1N盐酸溶液调其pH值至中性。用DCM萃取三次,有机层分别用清水和饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(DCM/AcOEt=9/1)得类白色固体270mg,产率:49%,熔点:198-200℃。
1HNMR(DMSO-d6,400MHz)δppm1.28(6H,t,J=7.2Hz),3.43(3H,s),3.73(3H,s),3.93(3H,s),4.19(6H,t,J=7.2Hz),6.29(1H,d,J=8.4Hz),7.41(2H,m),7.69(1H,d,J=8.8Hz),7.74(1H,d,J=8.8Hz),7.77(1H,J=8.4Hz),8.11(1H,s),8.53(1H,s),9.34(1H,s);
13CNMR(DMSO-d6,101MHz)δppm16.40,16.46,29.98,53.40,53.86,64.65,64.71,101.15,109.98,111.18,112.26,112.30(J c-p=4Hz),112.64,119.85,119.89(J c-p=4Hz),120.83,121.16,122.48,125.23,131.01,139.03,139.80,143.38,144.57,144.65(J c-p=8Hz),157.22,160.70;
31PNMR(DMSO-d6,162MHz)δppm-5.66(1P,s);
HRMS(ESI+)550.14081,Calcd for C24H29O8N3PS 550.14075[M+H]+.
实施例2
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑-二苄基磷酸酯(20)
氮气保护下,化合物13l(250mg,0.6mmol),四溴化碳(794mg,2.4mmol)溶于约8mL无水DCM中,亚磷酸二苄酯(0.67mL,3.0mmol)以及N,N-二异丙基乙胺(DIEA,0.52mL,3.0mmol)分别加入上述溶液,室温下搅拌约2h。反应液倒入适量冰水中,1N盐酸溶液调其pH值至中性。用DCM萃取三次,有机层分别用清水和饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(PE/AcOEt=1/1)得类白色固体200mg,产率约49.5%,熔点:198-200℃。
1HNMR(DMSO-d6,400MHz)δppm3.41(3H,s),3.72(3H,s),3.91(3H,s),5.21(4H,d,J=8.4Hz),6.30(1H,d,J=8.4Hz),7.35-7.39(11H,m),7.44(1H,d,J=8.4Hz),7.66(1H,d,J=8.8Hz),7.74(1H,d,J=8.8Hz),7.79(1H,d,J=8.8Hz),7.95(1H,s),8.45(1H,s),9.35(1H,s);
13CNMR(DMSO-d6,101MHz)δppm29.98,53.39,53.85,69.78,69.84,101.16,110.02,111.17,112.31,112.35(J c-p=4Hz),112.61,119.90,119.94(J c-p=4Hz),120.77,121.06,122.41,125.27,128.50×4,128.97×4,131.03,136.22×2,136.29×2,139.10,139.91,143.36,144.38,144.46(J c-p=8Hz),157.29,160.73;
31PNMR(DMSO-d6,162MHz)δppm:-5.61;
HRMS(ESI+)674.17215,Calcd for C34H33O8N3PS 674.17205[M+H]+.
实施例3
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑-二苄基磷酸酯(21)
氮气保护下,N-(2,6-二甲氧基吡啶-3-基)-7-醛基-9-甲基-3-咔唑磺酰胺(13e)(220mg,0.53mmol),四溴化碳(660mg,2.0mmol)溶于约8mL无水DCM中,亚磷酸二苄酯(0.55mL,2.5mmol)以及N,N-二异丙基乙胺(DIEA,0.43mL,2.5mmol)分别加入上述溶液,室温下搅拌约2h。反应液倒入适量冰水中,1N盐酸溶液调其pH值至中性。用DCM萃取三次,有机层分别用清水和饱和食盐水洗涤,无水Na2SO4干燥,过滤,浓缩,柱层析分离纯化(PE/AcOEt=3/2)得类白色固体140mg,产率:39.2%,熔点:140-142℃。
1HNMR(DMSO-d6,400MHz)δppm3.42(3H,s),3.73(3H,s),3.84(3H,s),5.23(4H,d,J=8.4Hz),6.30(1H,d,J=8.4Hz),7.11-7.14(1H,m),7.34-7.41(10H,m),7.43(2H,m),7.74(2H,m),8.24(1H,d,J=8.4Hz),8.47(1H,s),9.35(1H,s);
13CNMR(DMSO-d6,101MHz)δppm 29.46,39.51,52.92,53.38,54.91,69.43,69.49,100.68,101.54,101.59(J c-p=5Hz),109.28,112.14,112.54,112.58(J c-p=4Hz),118.98,119.70,120.80,121.79,124.21,128.03×4,128.49×4,130.95,135.66×2,135.73×2,139.42,141.93,142.83,149.39,149.46(J c-p=7Hz),156.81,160.25;
31PNMR(DMSO-d6,162MHz)δppm-6.18;
HRMS(ESI+)674.17554,Calcd for C34H33O8N3PS 674.17205[M+H]+.
实施例4
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑磷酸酯(22)
化合物20(200mg,0.30mmol)溶于约15mL甲醇中,加入过催化剂量的Pd/C,在50PSI氢气压力下反应约1.0h。将Pd/C过滤,浓缩后,加入适量乙醚搅拌约30min,过滤得类白色固体120mg,产率约81.1%,mp.192-194℃;1HNMR(DMSO-d6,400MHz)δppm 3.43(3H,s),3.72(3H,s),3.89(3H,s),6.29(1H,d,J=8.4Hz),7.36(1H,d,J=8.8Hz),7.43(1H,d,J=8.4Hz),7.59(1H,d,J=8.4Hz),7.68(1H,d,J=8.8Hz),7.71(1H,d,J=8.8Hz),7.99(1H,s),8.48(1H,s),9.36(1H,s);13CNMR(DMSO-d6,101MHz)δppm29.87,53.43,53.85,101.12,109.64,110.69,111.71,111.75(J c-p=4Hz),112.69,120.35,120.50,120.55(J c-p=4Hz),121.39,122.21,124.84,130.66,138.36,139.65,143.23,146.28,146.34(J c-p=6Hz),157.14,160.64;31PNMR(DMSO-d6,162MHz)δppm-5.01;HRMS(ESI+)494.07808,Calcdfor C20H21O8N3PS 494.07815[M+H]+.
实施例5
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑磷酸酯(23)
化合物21(200mg,0.30mmol)溶于约15mL甲醇中,加入过催化剂量的Pd/C(5%),在50PSI氢气压力下反应约1.0h。将Pd/C过滤,浓缩后,加入适量乙醚搅拌约30min,过滤得类白色固体480mg,产率约91%,熔点:137-139℃。
1HNMR(DMSO-d6,400MHz)δppm3.39(3H,s),3.72(3H,s),3.82(3H,s),6.29(1H,d,J=8.4Hz),7.07(1H,d,J=8.4Hz),7.41(1H,d,J=8.4Hz),7.46(1H,s),7.62-7.65(2H,m),8.06(1H,d,J=8.4Hz),8.37(1H,s),9.29(1H,s);
13CNMR(DMSO-d6,101MHz)δppm29.74,53.40,53.85,101.11,109.13,112.72,113.94,113.99(J c-p=5Hz),116.83,116.87(J c-p=4Hz),119.39,121.19,121.89,123.67,124.63,130.77,139.83,142.82,142.97,153.83,153.89(J c-p=6Hz),157.27,160.68;
31PNMR(DMSO-d6,162MHz)δppm-4.98.
HRMS(ESI+)494.07813Calcd for C20H21O8N3PS 494.07815[M+H]+.
实施例6
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑磷酸二钠盐(24)
化合物2275mg(0.15mmol)溶于约15mL甲醇中,加入4倍当量的甲醇钠,室温下搅拌约10h。将反应液浓缩后,加入适量无水乙醇搅拌约30min,过滤得类白色固体65mg,产率约80.7%,熔点:212-214℃。HRMS(ESI+)538.04205,Calcd for C20H19O8N3Na2PS 538.04204[M+H]+.
实施例6
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑磷酸二钠盐(25)
化合物24 75mg(0.15mmol)溶于约15mL甲醇中,加入4倍当量的甲醇钠,室温下搅拌约10h。将反应液浓缩后,加入适量无水乙醇搅拌约30min,过滤得类白色固体65mg,产率:80.7%,熔点:210-212℃。
HRMS(ESI+)538.04205,Calcd for C20H19O8N3Na2PS 538.04204[M+H]+.
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (8)
1.一种咔唑磺酰胺衍生物前药或其药用盐,其特征在于,具有如下通式(1):
其中,R1为氢、低级烷基、苄基或钠。
2.根据权利要求1所述的咔唑磺酰胺衍生物前药或其药用盐,其特征在于,-OPO(OR1)2为6位或7位的取代基。
3.根据权利要求1或2所述的咔唑磺酰胺衍生物前药或其药用盐,其特征在于,所述低级烷基为甲基或乙基。
4.根据权利要求1所述的咔唑磺酰胺衍生物前药或其药用盐,其特征在于,所述咔唑磺酰胺衍生物前药或其药用盐为:
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑-二乙基磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑-二苄基磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑-二苄基磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑磷酸酯;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-3-咔唑磷酸二钠盐;
6-(N-(2,6-二甲氧基吡啶-3-基)-磺酰胺)-9-甲基-2-咔唑磷酸二钠盐。
5.权利要求1-4任一项所述咔唑磺酰胺衍生物前药或其药用盐作为微管蛋白抑制剂的应用。
6.权利要求1-4任一项所述咔唑磺酰胺衍生物前药或其药用盐在制备抗肿瘤药物中的应用。
7.一种抗肿瘤药物组合物,其包括治疗有效量的权利要求1-4任一项所述的咔唑磺酰胺衍生物前药或其药用盐和药学上可接受的药用辅料。
8.权利要求1-4任一项所述的咔唑磺酰胺衍生物或其药用盐的制备方法,其特征在于,所述方法至少包括利用化合物(1)和化合物(2)在碱性条件下进行反应的过程,
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