CN110467598A - 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 - Google Patents
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 Download PDFInfo
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- CN110467598A CN110467598A CN201810448556.5A CN201810448556A CN110467598A CN 110467598 A CN110467598 A CN 110467598A CN 201810448556 A CN201810448556 A CN 201810448556A CN 110467598 A CN110467598 A CN 110467598A
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- carbazole
- methyl
- dimethoxy
- pyridine
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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,所述咔唑磺酰胺衍生物前药或其可药用盐具有如下通式(Ⅰ)的结构:该式(Ⅰ)中,R–CO‑NH‑连接于咔唑环的2位或3位上,且,R的选择满足以下规则:R–CO‑NH‑为氨基酸分子与‑NH‑结合得到的酰胺结构;或者,R为–(CH2)n‑NR1。本发明提供的咔唑磺酰胺衍生物前药或其可药用盐,作为小分子的微管蛋白抑制剂不仅具有良好的抗微管作用,还具有抗肿瘤活性强,毒副作用小,水溶性高等优点。
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
肿瘤需要功能性的血管网络提供氧气、养料并及时清除代谢产物,尽管肿瘤可以通过与宿主血管整合而获得部分血管,还必须通过形成新生血管网构建自己的血管系统才能持续地生长和发展。如果没有血管系统提供氧气和养料,实体瘤的增长不会超过1mm3。鉴于在肿瘤发生发展中的重要作用,肿瘤血管已成为抗肿瘤治疗的一个重要靶点。
针对肿瘤血管的治疗方案采用的是针对肿瘤血管供应的药物,而非传统的直接针对肿瘤细胞的细胞毒性的药物。这些药物根据作用血管的机制不同分为血管生成抑制剂和血管阻断剂。其中一类重要的血管阻断剂是微管抑制剂。微管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进一步抑制,诱导肿瘤细胞凋亡。这类药物具有血管靶向作用,破坏肿瘤血管内皮钙黏蛋白(VE-cadherin)、β-链蛋白(β-catenin)以及Akt信号通路,激活RhoA和/或者p38MAPK,导致血管渗透性增加、肌动蛋白应力纤维的形成、微管解聚、破坏内皮细胞骨架,从而降低血流,达到阻断血管的目的。
目前,紫杉醇和长春碱类微管抑制剂在肿瘤血管阻断的治疗方面占据了重要地位,但也存在以下弊端:来源于天然产物的大分子化合物,化学结构复杂,很难进行化学全合成。多数紫杉醇类和长春碱类抗肿瘤药物均为多药耐药基因(MDR)表达的P-gp的作用底物,容易产生肿瘤化疗的耐药性,这也是这些药物在临床用于肿瘤化疗存在的主要问题。这些药物普遍存在神经毒性、溶解性差以及生物利用度低等问题。
发明内容
本发明提供一种咔唑磺酰胺衍生物前药或其可药用盐,作为小分子的微管蛋白抑制剂不仅具有良好的抗微管作用,还具有抗肿瘤活性强,毒副作用小,水溶性高等优点。
本发明还提供了所述咔唑磺酰胺衍生物前药或其可药用盐在制备微管蛋白抑制剂中的应用,以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,其包括所述咔唑磺酰胺衍生物前药或其可药用盐,和药学上可接受的药用辅料。
本发明还提供了所述咔唑磺酰胺衍生物前药或其可药用盐的制备方法,该方法步骤简单,能够高效的合成所述咔唑磺酰胺衍生物前药或其可药用盐。
本发明提供的一种咔唑磺酰胺衍生物前药或其可药用盐,具有如下通式(Ⅰ)的结构:
该式(Ⅰ)中,R–CO-NH-连接于咔唑环的2位或3位上,且,R的选择满足以下规则:
R–CO-NH-为氨基酸分子与-NH-结合得到的酰胺结构;或者,
R为–(CH2)n-NR1,其中,-NR1代表C1-C3的烷基叔胺基,或3-7元的含N杂环基团,n为选自1-6的整数,优选1-3。
本发明的实施方案中,所述3-7元的含N杂环基团是指在环上有至少一个N,例如具有2个或3个N,或者同时具有作为杂原子的O或S的3-7元的杂环,其可以是脂杂环、芳杂环等;所述含N杂环基团还可以有取代基,一般为低级烃基(1-6个碳),比较多的可以是低级烷基,例如可以是甲基取代基、乙基取代基、丙基或异丙基取代基等。
在发明的一个具体实施方式中,所述氨基酸至少包括酪氨酸、甘氨酸、丝氨酸、缬氨酸、色氨酸或丙氨酸等。
所述3-7元的含N杂环可以包括:等杂环基团;所述C1-C3的烷基叔胺基可以包括:二甲基胺基、二乙基胺基或甲基乙基胺基等。
本发明提供的咔唑磺酰胺衍生物前药可以是制药学常用的可药用盐,例如,盐酸盐或三氟乙酸盐。
本发明提供的咔唑磺酰胺衍生物前药或其可药用盐的结构中,R–CO-NH-可位于咔唑环的2位或3位。在具体实施方案中,例举了R–CO-NH-位于咔唑环2位的方案,即,为下式(Ⅱ):
在本发明的具体实施方式中,作为非限定性示例,所述的咔唑磺酰胺衍生物前药或其可药用盐的具体化合物,可以包括:
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·三氟乙酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-乙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-羟基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-甲基-丁酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(吲哚-3-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-氨基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-哌啶基-乙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(N,N-二甲胺基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(4-甲基哌嗪基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(4-甲基哌嗪基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(4-(吗啉-4-基)-丁酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(吗啉-4-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(N,N-二甲胺基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-哌啶基-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-哌啶基-乙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(N,N-二甲胺基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(4-甲基哌嗪基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(4-甲基哌嗪基)-乙酰氨基)-N-甲基-3-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(4-(吗啉-4-基)-丁酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(吗啉-4-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(N,N-二甲胺基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺。
本发明提供的咔唑磺酰胺衍生物前药或其可药用盐,例如上述具体化合物,可以包括了它们可能存在的各种异构体,包括立体异构体或旋光异构体。
本发明还提供了所述咔唑磺酰胺衍生物前药或其可药用盐在制备微管蛋白抑制剂中的应用,以及在制备抗肿瘤药物中的应用。
另一发面,本发明还提供了一种抗肿瘤药物组合物,包括所述咔唑磺酰胺衍生物前药或其可药用盐,和药学上可接受的药用辅料。可将所述咔唑磺酰胺衍生物本身或其可药用盐与药物辅料,包括可药用赋形剂、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。具体制剂均可通过常规制药方法得到。
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。
本发明提供所述的咔唑磺酰胺衍生物前药或其可药用盐的制备方法,包括使
与含氮羧酸发生酰胺缩合反应的过程,其中,所述含氮羧酸选自氨基酸,或COOH(CH2)n-NR1,-NR1代表C1-C3的烷基叔胺基,或3-7元的含N杂环基团,n为选自1-6的整数,优选1-3。
上述制备过程所用起始反应物可以商购或按照已经公开的方法自行合成得到。
以前述R–CO-NH-位于咔唑环2位时的产物式(Ⅱ)为例,可以使用作为起始反应物。
(又称9a)可以通过参考文献(Lianqi Sun etal.Bioorganic&Medical Chemistry Letters 27(2017),261-265)的方法或其它相关报道的方法合成。
本发明的实施方案中,公开了制备前述式(Ⅱ)产物的方法所述方法包括:使与Boc-氨基酸发生酰胺缩合反应,以及使反应产物在酸性环境中脱保护基的过程。
更进一步的,所述方法包括所述酰胺缩合反应的产物进一步成盐的过程。
本发明的羟胺缩合反应的具体条件可以按照公知方法操作,例如包括使用适量EDCI、DMF、DMAP等试剂。
以下通过部分氨基酸前药和胺类前药的合成非限定性示例对上述制备方法进行说明。
一、本发明方案中的氨基酸前药可参照以下合成路线进行制备:
试剂和条件:a:HOBt,EDCI,N-Boc-AA,DMF;b:HCl或TFA,CH3COOCH2H3;对于反应中间物10,本申请实施例中10a,10c-10f为其非限定性具体示例;对于反应产物11,本申请实施例中11a-11g为其非限定性具体示例。
步骤(1):冰浴条件下(例如-20℃至-10℃),N-Boc-AA(N端叔丁氧羰基保护的氨基酸)溶于DMF中,加入1-羟基苯并三唑(HOBt),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),搅拌混合(一般0.5h至1h即可),加入反应物9a,维持搅拌一段时间(例如0.5-2小时,例如1h)后转至室温至反应完成(一般情况下4-10小时可以反应完全)。加入乙酸乙酯萃取并同时水洗,进一步将萃取产物以饱和食盐水洗涤,再经无水硫酸钠干燥,浓缩,必要时进一步经柱层析纯化,得到产物10;该反应中投料比可以按照化学计量比控制,为利于反应的进行,可以控制N-Boc-AA相比于反应物9a适当过量,例如二者的物料比(摩尔比或当量比)为大约1.2:1左右。EDCI为缩合剂,可以根据本领域常规使用量进行添加。
步骤(2):无水无氧,冰浴条件下,所述产物10溶于适量甲醇或乙酸乙酯溶液中,加入适量HCl/CH3OH或者HCl/CH3COOCH2CH3溶液,冰浴或低温下反应至白色固体析出(一般情况下3-10小时可以反应完全,可以控制反应过夜),过滤得目标产物11。可选的,还可以加入丙酮或乙醚促进目标产物析晶。
替换的,步骤(2)可以为,无水无氧条件下,将反应物10溶于适量无水二氯甲烷,冰浴条件下,加入约适量三氟乙酸(TFA),冰浴或低温下控制反应完成(一般情况下4-10小时可以反应完全),旋掉部分溶剂,加入甲醇至晶体析出(可以控制反应过夜),过滤得目标产物11。
二、本发明方案中的胺类前药可参照以下合成路线进行制备:
试剂和条件:a:DMAP,EDCI,DCM;反应物R-OOH代表含氮羧酸(即反应物12),R的定义参照本发明上述说明,12a-12h给出了该反应物的具体示例;对于反应产物13,本申请实施例中13a-13i为其非限定性具体示例。
无水,室温或环境温度下加入反应物9a,反应物12,以及4-二甲氨基吡啶(DMAP)溶于适量无水二氯甲烷,转移至0℃或更低温度下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),先维持搅拌反应一段时间(例如5-15分钟),转移至室温,直至反应完成(一般需1-6h)。用二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析得到目标化合物13。
胺类前药的药用盐的合成路线:
试剂和条件:a:HCl/CH3OH,对于反应产物13·HCl,本申请实施例中13a·HCl-13g·HCl为其非限定性具体示例。
冰浴条件下,上述化合物13溶于适量盐酸/甲醇混合溶液,搅拌反应(1至3h)至有晶体析出(若没有析出,加适量无水乙醚,使晶体析出),过滤得晶体,即为盐酸盐化合物13·HCl。
本发明方案具有以下优点:
1、本申请提供的咔唑磺酰胺衍生物前药或其可药用盐,不仅具有抗微管作用,还是一类重要的肿瘤血管阻断剂,作为一种小分子抑制剂,具有毒副作用小,抗肿瘤活性强,水溶性高等优点。
2、本申请提供的咔唑磺酰胺衍生物前药或其可药用盐的制备方法,步骤简单,能够高效的合成所述咔唑磺酰胺衍生物前药或其可药用盐。
附图说明
图1显示了本发明化合物的裸鼠体内抗肿瘤试验中裸鼠体重生长曲线。
图2显示了本发明化合物的裸鼠体内抗肿瘤试验中裸鼠体重生长曲线。
图3显示了本发明化合物的裸鼠体内抗肿瘤试验中裸鼠肿瘤体积变化曲线。
图4显示了本发明化合物的裸鼠体内抗肿瘤试验中裸鼠肿瘤体积变化曲线。
具体实施方式
为使本发明的目的、技术方案和技术效果更加清楚,下面将结合本发明具体实施例及相应附图,对本发明实施例中的技术方案进行清楚、完整地描述,但以下实施例不能理解为对本发明的可实施范围的限定,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的前提下所获得的所有其它实施例,都属于本发明保护的范围。在以下实施例中,如没有特殊说明,化合物、反应物、以及各种试剂的命名或名称同上文。
实施例1
(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11a)的合成
步骤(1),反应中间产物10的合成:冰浴条件下(例如-20℃至-10℃),N-Boc-AA(N端叔丁氧羰基保护的氨基酸)溶于DMF中,加入1-羟基苯并三唑(HOBt),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),搅拌混合(一般0.5h至1h即可),加入反应物9a,维持搅拌一段时间(例如0.5-2小时,例如1h)后转至室温至反应完成(一般情况下4-10小时可以反应完全)。加入乙酸乙酯萃取并同时水洗,进一步将萃取产物用饱和食盐水洗涤,再经无水硫酸钠干燥,浓缩,必要时进一步经柱层析纯化,得到产物10;该反应中投料比可以按照化学计量比控制,为利于反应的进行,可以控制N-Boc-AA相比于反应物9a适当过量,例如二者的物料比(摩尔比或当量比)为大约1.2:1左右。EDCI为缩合剂,可以根据本领域常规使用量进行添加。
在本实施例步骤(1)中,合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-叔丁氧酰胺基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺(10a)具体条件为:
反应物9a(200mg,0.485mmol),Boc-L-酪氨酸(Boc-L-Try,164mg,0.582mmol),HOBt(78.6mg,0.582mmol),EDCI(139mg,0.73mmol),溶于10mLDMF,反应6h,柱层析(PE:EA=1:1)得到311mg产物(10a)。
产率:95%。
1H NMR(500MHz,DMSO-d6)δppm:10.26(s,1H),9.32(s,1H),9.19(s,1H),8.41(s,1H),8.17(d,J=8.4Hz,1H),8.07(s,1H),7.72(s,2H),7.45(d,J=8.3Hz,1H),7.39(d,J=8.1Hz,1H),7.15(d,J=7.7Hz,2H),7.09(d,J=7.8Hz,1H),6.69(d,J=7.9Hz,2H),6.32(d,J=8.3Hz,1H),4.33(s,1H),3.89(s,3H),3.75(s,3H),3.45(s,3H),2.93(d,J=15.8Hz,1H),2.79(dd,J=21.7,8.4Hz,1H),1.37(s,9H)。
步骤(2),反应产物11的合成:无水无氧,冰浴条件下,所述产物10溶于适量甲醇或乙酸乙酯溶液中,加入0.59N HCl/CH3OH或者HCl/CH3COOCH2CH3溶液,冰浴或低温下反应至白色固体析出(可以控制反应过夜),过滤得白色固体为目标产物11。
上述步骤,若析出物不明显,还可以加入丙酮或乙醚促进目标产物析晶。
在本实施例步骤(2)中,合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11a)的具体条件为:
冰浴,将反应物10a(140mg,0.21mmol)溶于约7mL 0.59N HCl/CH3OH溶液,反应约3h,有晶体析出,放至冰箱过夜,将晶体过滤,得到产物71.4mg。产率:60%,熔点:180.1-184.2℃。
1H NMR(500MHz,DMSO-d6)δppm:10.80(s,1H),9.32(s,1H),8.41(s,1H),8.33(s,2H),8.19(d,J=8.4Hz,1H),7.93(s,1H),7.73(s,2H),7.42(d,J=8.3Hz,1H),7.37(d,J=8.2Hz,1H),7.11(d,J=8.2Hz,2H),6.71(d,J=8.2Hz,2H),6.29(d,J=8.3Hz,1H),4.17(s,1H),3.87(s,3H),3.73(s,3H),3.53(s,3H),3.44(s,3H),3.11(d,J=6.0Hz,1H),3.06–2.97(m,1H)。
13C NMR(101MHz,DMSO-d6)δppm:167.39,160.67,157.22,157.01,143.11,142.11,139.70,137.59,131.00,125.13,121.60,119.76,118.54,115.84,113.15,112.65,109.54,101.08,100.78,55.08,53.88,53.42。
MS m/z(%)576(M+1,100)。
实施例2
(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·三氟乙酸盐(11b)的合成
合成过程参见实施例1,具体条件如下:
步骤(1):合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-叔丁氧酰胺基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺(10a)
将反应物9a(200mg,0.485mmol),Boc-L-酪氨酸(Boc-L-Try,164mg,0.582mmol),HOBt(78.6mg,0.582mmol),EDCI(139mg,0.73mmol),溶于10mLDMF,反应6h,柱层析(PE:EA=1:1)得到311mg产物(10a)。
产率:95%。
1H NMR(500MHz,DMSO-d6)δppm 10.26(s,1H),9.32(s,1H),9.19(s,1H),8.41(s,1H),8.17(d,J=8.4Hz,1H),8.07(s,1H),7.72(s,2H),7.45(d,J=8.3Hz,1H),7.39(d,J=8.1Hz,1H),7.15(d,J=7.7Hz,2H),7.09(d,J=7.8Hz,1H),6.69(d,J=7.9Hz,2H),6.32(d,J=8.3Hz,1H),4.33(s,1H),3.89(s,3H),3.75(s,3H),3.45(s,3H),2.93(d,J=15.8Hz,1H),2.79(dd,J=21.7,8.4Hz,1H),1.37(s,9H).
步骤(2):合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·三氟乙酸盐(11b)
无水无氧条件下,将反应物10a(120mg,0.18mmol)溶于约8mL无水二氯甲烷,冰浴条件下,加入约2mL三氟乙酸(TFA),反应约6h,旋掉一部分溶剂,加入甲醇,有晶体析出,冷藏过夜,过滤得产物(11b)78mg。产率:65%,熔点:168.5-169.7℃。
1H NMR(500MHz,DMSO-d6)δppm:10.57(s,1H),9.35(s,1H),8.40(s,1H),8.19(d,J=8.4Hz,2H),7.90(s,1H),7.73(s,2H),7.42(d,J=8.3Hz,1H),7.34(d,J=8.5Hz,1H),7.09(d,J=8.1Hz,2H),6.71(d,J=8.2Hz,2H),6.29(d,J=8.3Hz,1H),3.88(s,3H),3.73(s,3H),3.44(s,3H),3.16–3.05(m,1H),3.04–2.92(m,1H)。
13C NMR(101MHz,DMSO-d6)δppm:167.46,160.67,157.15,143.12,142.12,139.74,137.50,131.16,130.95,125.12,124.38,121.60,119.78,118.61,115.86,113.11,112.68,109.57,101.11,100.82,55.19,53.86,53.41,36.61,14.61–14.41.19F NMR(470MHz,DMSO-d6)δppm-73.42。
MS m/z(%)576(M+1,100)。
实施例3
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-乙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11c)的合成
合成过程参见实施例1,具体条件如下:
步骤(1):合成N-(2,6-二甲氧基吡啶-3-基)-2-(2-叔丁氧酰胺基-乙酰氨基)-N-甲基-6-咔唑磺酰胺(10c)
将反应物9a(200mg,0.485mmol),Boc-甘氨酸(11mg,0.582mmol),HOBt(79mg,0.582mmol),EDCI(139mg,0.727mmol)溶于10mLDMF,反应6h,柱层析(PE:EA=1:3)得到260mg产物(10c)。
产率:96.7%。
1H NMR(500MHz,DMSO-d6)δppm:10.17(s,1H),9.29(s,1H),8.38(s,1H),8.14(d,J=8.3Hz,1H),8.09(s,1H),7.69(s,2H),7.41(d,J=8.3Hz,1H),7.33(s,1H),7.08(s,1H),6.29(d,J=7.9Hz,1H),3.86(s,3H),3.77(d,J=25.1Hz,3H),3.73(s,3H),3.43(s,3H),1.41(s,9H)。
13C NMR(101MHz,DMSO-d6)δppm:172.26,143.02–142.82,139.82–139.62,127.89,119.53,109.49,101.09,100.07,78.52,53.86,53.41,42.24,29.72,28.66.
MS m/z(%)570(M+1,100)。
步骤(2):合成N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-乙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11c)
将反应物10c(200mg,0.36mmol)溶于5mL无水乙酸乙酯中,加入4mL新制HCl/EA(3.72mol/L)溶液,反应6h,有白色晶体析出,过滤得产物(11c)109mg。产率:60%,熔点:221.2-224.0℃。
1H NMR(500MHz,DMSO-d6)δppm:8.38(s,1H),8.15(d,J=8.3Hz,1H),8.10(s,1H),7.69(s,3H),7.41(d,J=8.3Hz,2H),6.29(d,J=8.2Hz,1H),3.86(s,3H),3.73(s,3H),3.43(s,3H),3.42–3.37(m,3H),3.17(s,1H)。
13C NMR(101MHz,DMSO-d6)δppm:160.64,157.22,143.03,142.32,139.67,138.42,130.98,129.13,124.09,121.51,119.59,117.92,112.72,109.40,101.09,100.11,65.50,53.86,53.41,44.60,29.74,14.01。
MS m/z(%)470(M+1,100)。
实施例4
(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-羟基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11d)的合成
合成过程参见实施例1,具体条件如下:
步骤(1):合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-叔丁氧酰胺基-3-羟基-丙酰氨基)-N-甲基-6-咔唑磺酰胺(10d)
将反应物9a(300mg,0.73mmol),Boc-L-丝氨酸(180mg,0.87mmol),HOBt(120mg,0.87mmol),EDCI(210mg,1.095mmol),溶于10mL DMF中,反应4小时,柱层析(PE:EA=1:2)得到产物(10d)330mg。
产率:76%。
1H NMR(400MHz,DMSO-d6)δppm:10.21(s,1H),9.30(s,1H),8.39(s,1H),8.15(s,1H),8.13(s,1H),7.69(d,J=2.1Hz,2H),7.42(d,J=8.3Hz,1H),7.38(d,J=9.9Hz,1H),6.81(d,J=7.8Hz,1H),6.30(d,J=8.3Hz,1H),4.97(s,1H),4.35(s,1H),3.86(s,3H),3.73(s,3H),3.68(s,2H),3.49–3.40(m,3H),1.41(s,9H)。
13C NMR(101MHz,DMSO-d6)δppm:172.26,143.02–142.82,139.82–139.62,127.89,119.53,109.49,101.09,100.07,78.52,53.86,53.41,42.24,29.72,28.66。
步骤(2):合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-羟基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11d)
冰浴,将反应物10d(200mg,0.33mmol)溶于5mL甲醇中,加入新制0.59N HCl/CH3OH混合溶液,反应3h,浓缩,留少量甲醇,加入5mL丙酮,使白色固体析出,过滤,得到产物115mg。产率:65%,熔点:318.0-320.0℃。
1H NMR(500MHz,DMSO-d6)δppm:10.99(d,J=15.9Hz,1H),9.32(s,1H),8.41(s,1H),8.35(s,2H),8.20(d,J=8.4Hz,1H),8.07(s,1H),7.72(s,1H),7.47(d,J=8.1Hz,1H),7.42(d,J=8.2Hz,1H),6.29(d,J=8.3Hz,1H),5.60(s,1H),4.13(s,1H),3.92(s,1H),3.87(s,3H),3.73(s,3H),3.43(s,3H)。
13C NMR(101MHz,DMSO-d6)δppm:165.65,160.09,156.66,142.52,141.60,139.16137.51,130.54,123.68,121.04,119.16,117.77,112.38,112.13,108.93,100.54,99.92,60.25,55.00,53.29,52.83,29.19。
MS m/z(%)500(M+1,100)。
实施例5
(R)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-甲基-丁酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11e)的合成
合成过程参见实施例1,具体条件如下:
步骤(1):合成(R)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-叔丁氧酰胺基-3-甲基-丁酰氨基)-N-甲基-6-咔唑磺酰胺(10e)
将反应物9a(200mg,0.485mmol),Boc-L-缬氨酸(126mg,0.582mmol),HOBt(79mg,0.582mmol),EDCI(139mg,0.728mmol)溶于10mLDMF中,反应4小时,柱层析纯化(PE:EA=1:1)得到220mg产物(10e)。
产率:74%。
1H NMR(500MHz,DMSO-d6)δppm:10.23(s,1H),9.29(s,1H),8.38(s,1H),8.18–8.02(m,2H),7.69(s,2H),7.39(dd,J=29.7,7.9Hz,2H),6.93(s,1H),6.29(d,J=8.0Hz,1H),3.99(s,1H),3.86(s,3H),3.73(s,3H),3.41(s,3H),2.04(s,1H),1.40(s,9H),0.94(s,6H)。
13C NMR(101MHz,DMSO-d6)δppm:171.40,160.67,157.25,156.08,143.02,142.32,139.81,138.66,130.95,124.02,121.72,121.72,121.57,119.54,117.84,112.81,109.35,101.12,100.25,78.54,61.21,54.99–54.00,53.39,30.86,29.73,28.68,28.68,19.70,19.70,19.02。
MS m/z(%)612(M+1,100)。
步骤(2):合成(R)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-甲基-丁酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11e)
冰浴,无水无氧条件,将反应物10e(250mg,0.409mmol)溶于10mL乙酸乙酯中,加入HCl/EA混合溶液10mL,6h后过滤得到产物100mg(11e)。产率:45%,熔点:186.9-191.3℃。
1H NMR(400MHz,DMSO-d6)δppm:11.01(s,1H),9.33(s,1H),8.42(s,1H),8.37(s,2H),8.21(d,J=8.4Hz,1H),8.06(s,1H),7.73(s,2H),7.47(d,J=7.9Hz,1H),7.43(d,J=8.3Hz,1H),6.30(d,J=8.3Hz,1H),3.89(s,6H),3.73(s,3H),3.60–3.41(m,6H),3.18(s,1H),2.28(s,1H)。
13C NMR(101MHz,DMSO-d6)δppm:167.06,160.31,156.88,142.75,141.81,139.42,130.78,123.95,121.20,119.40,112.64,112.32,109.17,100.75,100.28,58.38,53.50,53.03,30.13,29.42,18.60,17.97。
MS m/z(%)512(M+1,100)。
实施例6
(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(吲哚-3-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11f)的合成
合成过程参见实施例1,具体条件如下:
步骤(1):合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-叔丁氧酰胺基-3-(吲哚-3-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺(10f)
将反应物9a(200mg,0.485mmol),N-Boc-色氨酸(177mg,0.582mmol),HOBt(78mg,0.582mol),EDCI(139mg,0.727mmol)溶于7mLDMF中,反应4小时,柱层析(PE:EA=1:1)得到290mg产物(10f)。
产率:86%。
1H NMR(500MHz,CDCl3)δppm:8.34(s,1H),8.12(s,1H),7.95(s,1H),7.81(d,J=8.0Hz,1H),7.77(d,J=8.4Hz,1H),7.71(t,J=8.9Hz,2H),7.47(d,J=8.8Hz,1H),7.40(d,J=8.1Hz,1H),7.22(d,J=7.5Hz,1H),7.16–7.10(m,1H),6.70(d,J=8.1Hz,1H),6.53(s,1H),6.26(d,J=8.4Hz,1H),5.27(s,1H),4.68(s,1H),4.12(q,J=7.1Hz,1H),3.75(s,3H),3.73(s,3H),3.54(s,3H),3.42(s,1H),3.32(d,J=6.7Hz,1H),1.43(s,9H)。
13C NMR(101MHz,CDCl3)δppm:170.34,168.61–118.99,229.45–112.64,168.61–113.05,111.37,108.15,100.98,100.67,60.44,53.75,53.44,29.38,28.35,21.09,14.22。
MS m/z(%)698(M-1,100)。
步骤(2):合成(S)-N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(吲哚-3-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11f)
将反应物10f(290mg,0.41mmol)溶于约12mL HCl/CH3OH混合溶液中,用丙酮、乙醚得到产物(11f)100mg。产率:38%。熔点:120.2-122.4℃。
1H NMR(500MHz,DMSO-d6)δppm:10.86(s,1H),8.38(s,1H),8.13(d,J=8.4Hz,1H),8.10(s,1H),7.69(s,2H),7.62(d,J=7.7Hz,1H),7.42(d,J=7.9Hz,2H),7.33(d,J=7.9Hz,1H),7.21(s,1H),7.06(t,J=7.4Hz,1H),6.97(t,J=7.3Hz,1H),6.29(d,J=8.3Hz,1H),3.86(s,3H),3.73(s,3H),3.43(s,3H),3.22(d,J=14.0Hz,2H),3.17(s,1H),2.99–2.90(m,1H),1.23(s,3H)。
13C NMR(101MHz,DMSO-d6)δppm:205.68,172.11,160.27,156.85,142.65,141.93,139.32,138.16,136.29,130.59,127.50,123.96,121.35,121.02,119.19,118.59,118.36,117.53,112.36,111.45,108.99,100.73,99.99,55.97–55.77,53.48,53.03,29.37,21.16。
MS m/z(%)599(M-1,100)。
实施例7
N-(2,6-二甲氧基吡啶-3-基)-2-(3-氨基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11g)的合成
合成过程参见实施例1,具体条件如下:
步骤(1):合成N-(2,6-二甲氧基吡啶-3-基)-2-(3-叔丁氧酰胺基-丙酰氨基)-N-甲基-6-咔唑磺酰胺(10g)
将反应物9a(100mg,0.24mmol),Boc-β-丙氨酸(55mg,0.29mmol),DMAP(8.79mg,0.072mol),EDCI(92mg,0.48mmol)溶于8mLDCM中,反应4小时,柱层析(DCM:CH3OH=50:1)得到100mg产物(10g)。
产率:70.7%。
1H NMR(500MHz,CDCl3)δ8.69(s,1H),8.24(s,1H),8.12(d,J=8.5Hz,1H),8.02(d,J=8.1Hz,1H),7.56(d,J=8.2Hz,1H),7.45(d,J=8.7Hz,1H),7.08(d,J=7.9Hz,1H),6.45(d,J=8.2Hz,1H),5.15(s,1H),5.04(s,1H),3.98(s,3H),3.90(s,3H),3.86(s,3H),3.56(d,J=5.1Hz,2H),2.70(s,2H),1.56(s,3H),1.46(s,3H),1.36(s,3H).
步骤(2):合成N-(2,6-二甲氧基吡啶-3-基)-2-(3-氨基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(11g)
将反应物10g(100mg,0.17mmol)溶于约12mL HCl/CH3OH混合溶液中,用乙醚得到80mg产物(11g)。产率:89.9%,熔点:164.0℃。
1H NMR(500MHz,DMSO-d6)δ10.63(s,1H),8.70(s,1H),8.28(d,J=8.4Hz,1H),8.19(s,1H),7.99(d,J=8.6Hz,2H),7.80(d,J=8.5Hz,2H),7.71(s,3H),7.42(d,J=8.2Hz,1H),6.60(d,J=8.2Hz,1H),3.97(s,3H),3.90(s,3H),3.53(s,3H),3.13(d,J=5.7Hz,2H),2.84(s,2H)。
13C NMR(101MHz,DMSO-d6)δ170.33,169.08,163.63,159.22,144.04,142.45,139.04,128.52,126.14,122.28,121.75,117.79,113.17,111.39,109.32,102.73,100.33,54.39,49.05,35.39,34.54,33.87,29.84。
MS m/z(%)484(M+1,100)。
实施例8
胺类前药的合成方法包括在无水,室温或环境温度下加入反应物9a,反应物12,以及4-二甲氨基吡啶(DMAP)溶于适量无水二氯甲烷,转移至0℃或更低温度下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),先维持搅拌反应一段时间(例如5-15分钟),转移至室温,直至反应完成(一般需1-6h)。用二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析得到目标化合物13。
本实例中N-(2,6-二甲氧基吡啶-3-基)-2-(2-哌啶基-乙酰氨基)-N-甲基-6-咔唑磺酰胺(13a)合成的具体条件如下:
将反应物9a(300mg,0.73mmol),2-(哌啶-1-基)乙酸·盐酸盐(157mg,0.87mmol),EDCI(280mg,1.46mmol),DMAP(27mg,0.22mmol)溶于15mL二氯甲烷,柱层析(PE:EA=1:1)得到300mg产物13a。产率:77%,熔点:180.1-181.3℃。
1H NMR(500MHz,CDCl3)δppm 9.56(s,1H),8.39(s,1H),8.25(s,1H),7.95(d,J=8.0Hz,1H),7.77(d,J=8.2Hz,1H),7.72(d,J=8.5Hz,1H),7.31(d,J=8.4Hz,1H),7.04(d,J=8.2Hz,1H),6.55(s,1H),6.26(d,J=8.1Hz,1H),3.84(s,3H),3.76(s,3H),3.53(s,3H),3.14(s,2H),2.59(s,4H),1.69(s,4H),1.52(s,2H)。
13C NMR(101MHz,CDCl3)δppm 169.28,160.25,154.55,143.34,142.47,137.13,135.38,128.96,124.12,122.29,120.95,120.05,118.54,112.93,112.39,108.16,100.96,100.08,77.38,77.07,76.75,62.90,55.00,53.74,53.41,29.54,26.37,23.64。
MS m/z(%)538(M+1,100)。
实施例9
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(N,N-二甲胺基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺(13b)的合成
合成过程参见实施例8,具体条件如下:
将反应物9a(160mg,0.388mmol),3-(二甲胺基)丙酸·盐酸盐(70mg,0.466mmol),EDCI(150mg,0.776mmol),DMAP(15mg,0.12mmol)溶于10mL DCM中,柱层析(DCM:CH3OH=10:1)分离得到产物100mg。产率:51%,熔点:97.7-98.9℃。
1H NMR(500MHz,CDCl3)δppm:11.22(s,1H),8.37(s,1H),8.25(s,1H),7.90(d,J=8.2Hz,1H),7.76(d,J=8.4Hz,1H),7.71(d,J=8.6Hz,1H),7.29(d,J=8.6Hz,1H),6.93(d,J=8.2Hz,1H),6.26(d,J=8.3Hz,1H),3.82(s,3H),3.76(s,3H),3.52(s,3H),2.77–2.70(m,2H),2.63–2.55(m,2H),2.44(s,6H)。
13C NMR(101MHz,CDCl3)δppm:170.89,160.25,154.57,143.28,142.48,138.15,135.40,128.81,123.95,122.35,120.76,119.94,118.15,112.90,108.08,100.95,100.50,77.38,77.06,76.74,55.14,53.73,53.40,44.49,33.52,29.49。
MS m/z(%)512(M+1,100)。
实施例10
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(4-甲基哌嗪基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺(13c)的合成
合成过程参见实施例8,具体条件如下:
将反应物9a(200mg,0.48mmol),3-(4-甲基哌嗪-1-基)丙酸·盐酸盐(140mg,0.58mmol),EDCI(280mg,1.44mmol),DMAP(18mg,0.144mmol),溶于14mL DCM,柱层析(DCM:CH3OH=5:1)得到产物80mg。产率:30%。熔点:175.2-180.6℃。
1H NMR(500MHz,CDCl3)δppm:11.14(s,1H),8.37(s,1H),8.32(s,1H),7.92(d,J=8.2Hz,1H),7.77(d,J=8.4Hz,1H),7.72(d,J=8.6Hz,1H),7.31(d,J=8.6Hz,1H),6.93(d,J=8.2Hz,1H),6.55(s,1H),6.26(d,J=8.3Hz,1H),3.83(s,3H),3.76(s,3H),3.53(s,3H),2.81(d,J=5.3Hz,3H),2.67(s,4H),2.64–2.50(m,4H),2.42(s,4H)。
13C NMR(101MHz,CDCl3)δppm:170.74,160.24,154.55,143.32,142.55,138.17,135.37,128.88,124.01,122.33,120.88,119.96,118.18,112.94,112.33,108.14,100.97,100.43,55.22,53.70,53.41,52.13,45.91,32.69,29.52。
MS m/z(%)567(M+1,100)。
实施例11
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(4-甲基哌嗪基)-乙酰氨基)-N-甲基-3-咔唑磺酰胺(13d)的合成
合成过程参见实施例8,具体条件如下:
将反应物9a(200mg,0.48mmol),2-(4-甲基哌嗪-1-基)乙酸·盐酸盐(134mg,0.58mmol),EDCI(277mg,1.44mmol),DMAP(18mg,0.144mmol)溶于14mL二氯甲烷,柱层析(DCM:CH3OH=10:1)得到产物200mg。产率:75%。熔点:173.7-175.9℃。
1H NMR(500MHz,CDCl3)δppm:9.40(s,1H),8.39(s,1H),8.27(s,1H),7.95(d,J=8.2Hz,1H),7.77(d,J=8.3Hz,1H),7.73(d,J=8.6Hz,1H),7.32(d,J=8.6Hz,1H),7.02(d,J=8.2Hz,1H),6.56(s,1H),6.26(d,J=8.3Hz,1H),3.84(s,3H),3.76(s,3H),3.53(s,3H),3.21(s,2H),2.71(s,4H),2.57(s,4H),2.36(s,3H)。
13C NMR(101MHz,CDCl3)δppm:168.62,160.26,154.55,143.35 142.47,136.96,135.39,129.02,124.17,122.25,120.97,120.09,118.65,112.92,112.33,108.20,100.98,100.15,61.99,55.31,53.74,53.44,46.01,29.56。
MS m/z(%)553(M+1,100)。
实施例12
N-(2,6-二甲氧基吡啶-3-基)-2-(4-(吗啉-4-基)-丁酰氨基)-N-甲基-6-咔唑磺酰胺(13e)的合成
合成过程参见实施例8,具体条件如下:
将反应物9a(200mg,0.48mmol),4-吗啉丁酸(120mg,0.58mmol),EDCI(184mg,0.96mmol),DMAP(18mg,0.144mmol)溶于12mL DCM中,柱层析(DCM:CH3OH=10:1)得到产物260mg。产率:95%,熔点:252.8-253.9℃。
1H NMR(500MHz,CDCl3)δppm:8.38(s,1H),8.27(s,1H),7.93(d,J=8.2Hz,1H),7.77(d,J=8.4Hz,1H),7.73(d,J=8.6Hz,1H),7.32(d,J=8.6Hz,1H),6.93(d,J=7.6Hz,1H),6.50(s,1H),6.27(d,J=8.3Hz,1H),3.84(s,3H),3.77(s,3H),3.76(s,3H),3.53(s,2H),3.49(s,2H),2.52(d,J=5.2Hz,8H),1.99(d,J=6.2Hz,2H)。
13C NMR(101MHz,CDCl3)δppm:171.53,160.27,154.56,143.32,142.42,137.53,135.39,128.93,124.12,122.22,120.91,120.03,118.46,112.87,112.36,108.17,100.99,100.56,66.93,57.49,53.74,53.48,35.70,29.47,21.89。
MS m/z(%)568(M+1,100)。
实施例13
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(吗啉-4-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺(13f)的合成
合成过程参见实施例8,具体条件如下:
将反应物9a(150mg,0.364mmol),4-吗啉丙酸(85mg,0.436mmol),EDCI(140mg,0.728mmol),DMAP(13mg,0.109mmol)溶于12mL DCM中,柱层析(DCM:CH3OH=20:1)得到产物140mg。产率:70%,熔点:211.6-212℃.
1H NMR(500MHz,CDCl3)δppm:11.03(s,1H),8.36(s,1H),8.27(s,1H),7.89(d,J=8.2Hz,1H),7.76(d,J=8.3Hz,1H),7.71(d,J=8.5Hz,1H),6.92(d,J=8.1Hz,1H),6.61(s,1H),6.25(d,J=8.3Hz,1H),5.29(s,1H),3.88(s,3H),3.79(s,3H),3.75(s,3H),3.52(s,2H),2.87–2.75(m,2H),2.67(s,4H),2.62(d,J=5.5Hz,4H)。
13C NMR(101MHz,CDCl3)δppm:170.62,160.25,154.58,143.27,142.49,138.03,135.41,128.92,124.02,122.27,120.88,119.93,118.21,112.92,112.28,108.12,100.94,100.37,67.12,54.23,53.73,53.40,52.88,32.44,29.47。
MS m/z(%)554(M+1,100)。
实施例14
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(N,N-二甲胺基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺(13g)的合成
合成过程参见实施例8,具体条件如下:
将反应物9a(200mg,0.48mmol),N,N-二甲基甘氨酸(60mg,0.58mmol),EDCI(184mg,0.96mmol),DMAP(18mg,0.144mmol)溶于14mL DCM中,柱层析(DCM:CH3OH=20:1)得到产物60mg。产率:25%,熔点:175.1-179.0℃.
1H NMR(500MHz,CDCl3)δppm:9.38(s,1H),8.39(s,1H),8.27(s,1H),7.97(d,J=8.3Hz,1H),7.77(d,J=8.4Hz,1H),7.73(d,J=8.7Hz,1H),7.33(d,J=8.6Hz,1H),7.09(d,J=8.2Hz,1H),6.50(s,1H),6.27(d,J=8.3Hz,1H),3.86(s,3H),3.76(s,3H),3.53(s,3H),3.15(s,2H),2.43(s,6H)。
13C NMR(101MHz,CDCl3)δppm:185.91,169.02,160.24,154.51,143.37,142.48,137.13,135.32,128.98,124.16,122.31,120.99,120.10,118.61,112.95,112.40,108.17,100.98,100.13,63.79,53.74,53.41,46.10,36.50,29.64。
MS m/z(%)498(M+1,100)。
实施例15
N-(2,6-二甲氧基吡啶-3-基)-2-(3-哌啶基-丙酰氨基)-N-甲基-6-咔唑磺酰胺(13i)的合成
合成过程参见实施例8,具体条件如下:
将反应物9a(180mg,0.44mmol),3-(哌啶-1-基)丙酸(80mg,0.52mmol),EDCI(170mg,0.88mmol),DMAP(17mg,0.132mmol)溶于15mL DCM中,柱层析(DCM:CH3OH=20:1)得到产物150mg。产率:62%。熔点:178.2-182.3℃。
1H NMR(500MHz,CDCl3)δppm:11.62(s,1H),8.37(s,1H),8.30(s,1H),7.90(d,J=8.2Hz,1H),7.76(d,J=8.4Hz,1H),7.71(d,J=8.6Hz,1H),6.94(d,J=8.2Hz,1H),6.26(d,J=8.4Hz,1H),5.29(s,1H),3.81(s,3H),3.75(s,3H),3.52(s,3H),2.79–2.71(m,2H),2.70–2.50(m,8H),1.84–1.69(m,4H)。
13C NMR(101MHz,CDCl3)δppm:170.80,160.25,154.63,143.23,142.47,138.33,135.47,128.80,123.92,122.33,120.79,119.86,118.03,112.93 112.44,108.07,100.94,100.30,54.25,53.71,53.40,32.60,29.43,25.88,23.96。
MS m/z(%)552(M+1,100)。
实施例16
胺类前药的药用盐的合成方法包括,在冰浴条件下,上述化合物13溶于适量0.8M盐酸/甲醇混合溶液(其中0.8M为盐酸和甲醇混合后,盐酸的浓度),搅拌反应(1-3h)至有晶体析出(若没有析出,加适量无水乙醚,使晶体析出),过滤得晶体,即为盐酸盐化合物13·HCl。
本实施例中N-(2,6-二甲氧基吡啶-3-基)-2-(2-哌啶基-乙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(13a·HCl)合成的具体条件如下:
将13a制成盐酸盐化合物13a·HCl。熔点:176.0-178.3℃。
1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),9.84(s,1H),9.32(s,1H),8.41(s,1H),8.21(d,J=8.4Hz,1H),8.06(s,1H),7.73(s,2H),7.42(d,J=8.3Hz,1H),7.39(s,1H),6.29(d,J=8.3Hz,1H),4.19(s,3H),3.88(s,3H),3.73(s,4H),3.53(d,J=11.4Hz,3H),3.43(s,4H),3.11(s,2H),1.82(s,2H)。
13C NMR(101MHz,DMSO-d6)δ163.47,160.66,157.24,143.11,142.14,139.73,137.65,131.16,124.33,121.61,119.79,118.54,112.97,112.69,109.57,101.11,100.67,57.63,53.87,53.44,29.77,22.71,21.58.
MS m/z(%)538(M+1,100)。
实施例17
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(N,N-二甲胺基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(13b·HCl)的合成
将13b制成盐酸盐化合物13b·HCl。合成过程参见实施例16。熔点:126.6-138.0℃
1H NMR(500MHz,DMSO-d6)δ10.65(s,1H),10.16(s,1H),9.31(s,1H),8.39(s,1H),8.15(d,J=8.4Hz,1H),8.11(s,1H),7.77(s,1H),7.70(s,1H),7.45(s,1H),7.37(d,J=8.3Hz,1H),6.29(d,J=8.2Hz,1H),3.92(s,3H),3.85(s,3H),3.44(s,3H),3.41(s,2H),2.96(s,2H),2.81(d,J=4.2Hz,6H)。
13C NMR(101MHz,DMSO-d6)δ168.57,160.70,157.27,143.31,142.24,141.90,140.00,138.69,131.64,125.19,124.08,122.39,121.68,120.50,117.91,115.37,113.33,110.02,109.41,104.73,101.13,100.27,53.86,31.41,30.04。
MS m/z(%)512(M+1,100)。
实施例18
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(4-甲基哌嗪基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(13c·HCl)的合成
将13c制成盐酸盐化合物13c·HCl。合成过程参见实施例16。熔点:162.6-163.0℃
1H NMR(500MHz,DMSO-d6)δ11.94(s,1H),10.66(s,1H),9.31(s,1H),8.39(s,1H),8.15(d,J=8.4Hz,1H),8.11(s,1H),7.70(s,2H),7.42(d,J=8.3Hz,1H),7.38(d,J=8.0Hz,1H),6.29(d,J=8.3Hz,1H),4.30(s,4H),3.86(s,3H),3.73(s,4H),3.43(s,3H),3.17(s,3H),3.05(s,3H),2.84(s,4H)。
13C NMR(101MHz,DMSO-d6)δ168.20,160.65,157.24,143.02,142.25,139.72,138.71,130.99,124.07,121.69,121.42,119.59,117.90,112.80,109.40,101.10,100.30,53.86,53.41,50.06,50.02–49.15,48.90,29.75。
MS m/z(%)567(M+1,100)。
实施例19
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(4-甲基哌嗪基)-乙酰氨基)-N-甲基-3-咔唑磺酰胺·盐酸盐(13d·HCl)的合成
将13d制成盐酸盐化合物13d·HCl。合成过程参见实施例16。熔点:191.0-191.8℃
1H NMR(500MHz,DMSO-d6)δ10.42(s,1H),9.31(s,1H),8.40(s,1H),8.18(d,J=8.4Hz,1H),8.10(s,1H),7.72(s,2H),7.41(t,J=8.4Hz,2H),6.29(d,J=8.3Hz,1H),4.23(s,3H),3.87(s,3H),3.73(s,3H),3.49(s,2H),3.43(s,4H),3.23(s,4H),2.81(s,3H)。
13C NMR(101MHz,DMSO-d6)δ160.66,157.23,143.08,142.18,139.72,137.91,131.12,124.24,121.60,119.73,118.35,113.05,112.70,109.52,101.11,100.60,53.87,53.40,29.78。
MS m/z(%)553(M+1,100)。
实施例20
N-(2,6-二甲氧基吡啶-3-基)-2-(4-(吗啉-4-基)-丁酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(13e·HCl)的合成
将13e制成盐酸盐化合物13e·HCl。合成过程参见实施例16。熔点:133.0-133.9℃
1H NMR(500MHz,DMSO-d6)δ11.34(s,1H),10.54(s,1H),9.31(s,1H),8.39(s,1H),8.17(s,1H),8.13(d,J=8.3Hz,1H),7.70(s,1H),7.42(d,J=8.1Hz,1H),7.39(d,J=8.3Hz,1H),6.29(d,J=8.1Hz,1H),5.76(s,1H),3.94(d,J=5.3Hz,3H),3.86(s,3H),3.73(s,3H),3.45(d,J=7.9Hz,4H),3.18(s,4H),3.08(d,J=9.3Hz,2H),2.54(d,J=6.7Hz,2H),2.10(s,2H)。
13C NMR(101MHz,DMSO-d6)δ170.64,160.64,157.23,142.98,142.29,139.68,139.03,130.92,123.98,121.74,121.32,119.52,117.67,112.79,109.35,101.10,100.14,63.63,55.92,53.86,53.41,51.40,33.65,29.73,19.38,15.63。
MS m/z(%)568(M+1,100)。
实施例21
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(吗啉-4-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐(13f·HCl)的合成
将13f制成盐酸盐化合物13f·HCl。合成过程参见实施例16。熔点:176.0-178.3℃
1H NMR(500MHz,DMSO-d6)δ10.69(s,1H),10.59(s,1H),9.31(s,1H),8.39(s,1H),8.15(d,J=8.4Hz,1H),8.09(s,1H),7.70(s,1H),7.42(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.29(d,J=8.3Hz,1H),5.76(s,1H),3.99(d,J=12.2Hz,3H),3.86(s,3H),3.79(t,J=11.9Hz,3H),3.73(s,2H),3.46(s,2H),3.44(s,2H),3.20–3.06(m,4H),3.00(s,2H)。
13C NMR(101MHz,DMSO-d6)δ168.37,167.59,160.65,157.23,143.02,142.25,139.70,131.00,124.08,121.72,119.59,112.80,109.40,101.10,65.38,63.63,55.39,53.86,52.29,51.62,49.05,36.83,30.72,29.83,24.56,15.60,12.01。
MS m/z(%)554(M+1,100)。
实施例22
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(N,N-二甲胺基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺(13g·HCl)的合成
将13g制成盐酸盐化合物13g·HCl。合成过程参见实施例16。熔点:164.0-170.0℃
1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),9.96(s,1H),9.33(s,1H),8.41(s,1H),8.22(s,1H),8.04(s,1H),7.73(s,2H),7.41(s,2H),6.29(d,J=8.3Hz,1H),4.22(s,2H),3.88(s,3H),3.73(s,3H),3.43(s,3H),2.92(s,6H)。
13C NMR(101MHz,DMSO-d6)δ163.66,160.66,157.24,143.11,142.15,139.74,137.64,131.16,124.32,121.62,119.79,118.53,112.98,112.69,109.56,101.11,100.68,65.38,58.48,53.87,53.40,43.80,29.79,15.64。
MS m/z(%)498(M+1,100)。
实施例23
利用本发明所制备出的部分咔唑磺酰胺衍生物前药或其可药用盐,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(即咔唑磺酰胺衍生物前药或其可药用盐)的药用功效。
一、本发明化合物体外抗肿瘤活性测定
1.1化合物抗肿瘤活性测定实验步骤
1.1.1细胞:MCF-7、MIA PaCa-2、HepG 2、Bel-7402,均可商购获得。
1.1.2试剂:
(1)培养基
MCF-7、MIA PaCa-2:
DMEM低糖培养基:Hyclone
+10%胎牛血清(FBS)
+1%青霉素/链霉素双抗溶液:Hyclone SV30010
+1%丙酮酸钠溶液:Gibco 11360-070
HepG 2:
MEM培养基:Corning
+10%胎牛血清(FBS)
+1%青霉素/链霉素双抗溶液:Hyclone SV30010
+1%NEAA:Gibco
Bel-7402:
1640培养基:Corning
+10%胎牛血清(FBS)
+1%青霉素/链霉素双抗溶液:Hyclone SV30010
+1%丙酮酸钠溶液:Gibco 11360-070
(2)胰酶:Hyclone SH30042.01
(3)磷酸盐缓冲液(PBS):Hyclone SH30256.01
(4)CCK-8细胞毒性检测试剂盒:博士德AR1160
(5)96孔板:Nucn
(6)CO2细胞培养箱:CO2浓度5%,温度37℃,饱和湿度
(7)酶标仪:PerkinElmer Victor X5多标记微孔板检测仪,检测波长:450nm。
1.1.3实验方法
当瓶中细胞生长铺满瓶底达80%~90%时,加胰酶消化,离心后用加血清的培养基新悬浮细胞沉淀,然后进行细胞计数,调整细胞浓度至30000个/mL,种入96孔板,每孔100μL,最终板内细胞浓度3000个/孔,96孔板最外面一圈加入100μL PBS,37℃在CO2细胞培养箱培养24h后,利用获得的细胞培养液进行实验。
以下以MCF-7细胞为例说明实验过程。
(1)药物溶解:
本发明化合物按质量及分子量用DMSO溶解至终浓度100mM,使用时可以按照需要以不同浓度添加至培养基中使用。
(2)分组:
A.对照组:分为对照空白组(只加培养基,不加细胞);以及对照组,在MCF-7细胞培养液中加10%胎牛血清(FBS)的相应培养基,培养48h;
B.实验组:分为实验调零组(只加本发明化合物,不加细胞);实验组(在MCF-7细胞培养液中加入不同浓度本发明化合物溶液(设置浓度100μM、10μM、1μM、0.1μM、0.01μM、0.001μM梯度)),然后培养48h。
(3)培养结束后,每孔加入CCK-8溶液10μL,37℃继续培养1.5h,用酶标仪测定每孔OD值,检测波长450nm,计算细胞存活率。
存活率=(A实验-A实验调零)/(A对照-A对照空白))
(4)根据各浓度下细胞存活率,获得各化合物针对MCF-7细胞的IC50。
1.2体外抗肿瘤活性
本申请化合物体外抗肿瘤活性数据如表1(空白组结果未测,NT为未测量)所示。其中实验15中阳性对照药为Podo(鬼臼毒素,市售抗肿瘤药),实验16中对照药为IMB105,结构式如下:
表1
由表1的活性数据可以看出,本发明提供的咔唑磺酰胺衍生物前药对四种肿瘤细胞均有良好的肿瘤抑制活性,尤其是,11e,11f的抗肿瘤活性与IMB-105相当,11e对HepG2细胞抗肿瘤活性优于IMB-105,11f对MCF-7的抗肿瘤活性优于IMB-105。
二、本发明化合物的裸鼠体内抗肿瘤试验
2.1主要试剂及仪器
2.2实验方法及步骤
建立肿瘤模型
皮下注射HepG2细胞成瘤雌性BALB/C-nu裸小鼠36只,待肿瘤生长至50-100mm3大小,将裸鼠分成6组,每组6只,分别为:
(1):细胞对照组,正常喂养;
(2):阳性对照组,正常喂养;同时给予药物CA-4P,50mg/Kg,隔天1次;
(3):11d-20mg/Kg组,正常喂养;同时给予本发明化合物11d 20mg/Kg,隔天1次;
(4):11d-10mg/Kg组,正常喂养;同时给予本发明化合物11d 10mg/Kg,隔天1次;
(5):11e-20mg/Kg组,正常喂养;同时给予本发明化合物11e 20mg/Kg,隔天1次;
(6):11e-10mg/Kg组,正常喂养;同时给予本发明化合物11e 10mg/Kg,隔天1次。
使用生理盐水按照浓度配制好以上药物溶液,尾静脉注射给药,每只单次注射50uL,开始给药算第1天,实验周期28天。每2天用游标卡尺测量瘤体最长径(a)和最短径(b),同时每3天测量裸鼠体重。停药后1天处死裸鼠,游标卡尺测量移植瘤瘤的体积V(mm3)=1/6πab2。
本实验以CA-4P为对照药说明本申请化合物的抗肿瘤效果。CA-4P的结构式如下:
2.3.4.肿瘤生长抑制率如表4所示。
计算肿瘤生长抑制率:肿瘤生长抑制率=(对照组平均瘤体积-用药组平均瘤体积)/对照组平均瘤体积×100%。其中对照组平均瘤体积指的是细胞对照组6只裸鼠的平均瘤体积;给药组包括:阳性对照组,11d-20mg/Kg组,11d-10mg/Kg组,11e-20mg/Kg组,11e-10mg/Kg组,各组平均瘤体积均为6只裸鼠的平均瘤体积。
表4
组别 | 抑瘤率 |
细胞对照组 | NA |
阳性对照组 | 72.61% |
11d-20mg/Kg组 | 63.04% |
11d-10mg/Kg组 | 26.93% |
11e-20mg/Kg组 | 70.91% |
11e-10mg/Kg组 | 50.99% |
由上表数据可以看出,阳性对照组CA-4P尾静脉注射50mg/kg 4周后人肝癌HepG2的瘤体积抑制率达到72.61%,化合物11d尾静脉注射20mg/kg,4周后对人肝癌HepG2的瘤体积抑制率达到63.04%,治疗效果显著,瘤体积抑制率略低于阳性对照组;化合物11e尾静脉注射20mg/kg时,4周治疗人肝癌HepG2的瘤体积抑制率达到70.91%,治疗效果显著,在剂量远远低于阳性对照药的情况下瘤体积抑制率与阳性对照组相当。11e尾静脉注射10mg/kg时,4周治疗人肝癌HepG2也达到了过半的瘤体积抑制率(50.99%)。与对照组相比,给药组裸鼠的体重未见显著变化。
综上,本申请提供的化合物具有显著的抗肿瘤活性,同时毒副作用小,具有良好的应用前景。
三、本发明化合物的水溶解度实验
1.测定本申请部分化合物(胺类前药)在pH=2.1和7.2两种条件下的水溶解度。
1.1标准曲线的绘制:
称取本申请化合物各1mg,用甲醇分别配制为1.0mg/mL、0.5mg/mL、0.25mg/mL、0.125mg/mL、0.0625mg/mL以及0.03125mg/mL的化合物溶液。用HPLC测定在254nm下吸收峰的面积,然后以浓度和峰面积做标准曲线。
1.2试验操作:
1)分别向带有搅拌子的玻璃瓶中加入1mL的pH 2.1的盐酸溶液和7.2的磷酸盐溶液;
2)将10μL配好的DMSO样品溶液(10mg/mL)在剧烈搅拌下滴加到1)中,室温下搅拌4小时;
3)将2)转移到离心管中,13.2×1000r/min离心10分钟;
4)取上层清夜用HPLC检测254nm下吸收峰的面积,计算溶解度。
1.3本申请部分胺类前药在不同pH的水溶解度结果如表5所示。
表5
2.测定本申请部分化合物(氨基酸前药、胺类前药的盐酸盐)在pH=7.0条件下的水溶解度
室温下,将少量所测化合物(大概2-3mg),加入到一定体积(0.5mL)的蒸馏水中溶解,10×1000r/min离心10min,将上清液倒出,干燥下层未溶的化合物,称量计算溶解的化合物质量,进一步测定该化合物的水溶解度(mg/ml)。
本申请部分氨基酸前药的水溶解度结果如表6所示。
表6
化合物 | 水溶解度(mg/mL)pH=7.0 |
11b | 2.0 |
11c | 0.5 |
11d | 2.0 |
11e | 4.0 |
11f | 2.8 |
11g | >4.33 |
IMB-105 | 0.11(ug/mL) |
本申请部分胺类前药的盐酸盐水溶解度结果如表7所示。
表7
化合物编号 | 水溶性(mg/mL)pH=7.0 |
13a﹒HCl | 4.75 |
13b﹒HCl | 25.00 |
13c﹒HCl | 27.00 |
13d﹒HCl | 9.00 |
13e﹒HCl | 6.83 |
13f﹒HCl | 13.00 |
13g﹒HCl | 11.00 |
由表5水溶性数据可以看出,胺类前药化合物的水溶性优于IMB-105,提高了10-130倍。由表6数据可以看出,氨基酸类前药成盐后,水溶性相比于IMB-105(溶解度0.11(ug/mL))提高2万-4万倍。进一步的,由表7数据可以看出,胺类前药制成盐酸盐后,水溶性也大大提高。水溶性提高使得本申请化合物能方便的采用各种剂型在体内进行给药,大大提高药物的利用度。
Claims (11)
1.一种咔唑磺酰胺衍生物前药或其可药用盐,其特征在于,具有如下通式(Ⅰ)的结构:
该式(Ⅰ)中,R–CO-NH-连接于咔唑环的2位或3位上,且,R的选择满足以下规则:
R–CO-NH-为氨基酸分子与-NH-结合得到的酰胺结构;或者,
R为–(CH2)n-NR1,其中,-NR1代表C1-C3的烷基叔胺基,或3-7元的含N杂环基团,n为选自1-6的整数,优选1-3。
2.根据权利要求1所述的咔唑磺酰胺衍生物前药或其可药用盐,其特征在于,所述氨基酸至少包括酪氨酸、甘氨酸、丝氨酸、缬氨酸、色氨酸或丙氨酸。
3.根据权利要求1所述的咔唑磺酰胺衍生物前药或其可药用盐,其特征在于,所述3-7元的含N杂环包括:所述C1-C3的烷基叔胺基包括:二甲基胺基、二乙基胺基或甲基乙基胺基。
4.根据权利要求1所述的咔唑磺酰胺衍生物前药或其可药用盐,其特征在于,所述可药用盐包括盐酸盐或三氟乙酸盐。
5.根据权利要求1-4任一项所述的咔唑磺酰胺衍生物前药或其可药用盐,其特征在于,包括:
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(4-羟基)苯基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·三氟乙酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-乙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-羟基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-甲基-丁酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-氨基-3-(吲哚-3-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-氨基-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-哌啶基-乙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(N,N-二甲胺基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(4-甲基哌嗪基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(4-甲基哌嗪基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(4-(吗啉-4-基)-丁酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(吗啉-4-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(N,N-二甲胺基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-哌啶基-丙酰氨基)-N-甲基-6-咔唑磺酰胺;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-哌啶基-乙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(N,N-二甲胺基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(4-甲基哌嗪基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(4-甲基哌嗪基)-乙酰氨基)-N-甲基-3-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(4-(吗啉-4-基)-丁酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(3-(吗啉-4-基)-丙酰氨基)-N-甲基-6-咔唑磺酰胺·盐酸盐;
N-(2,6-二甲氧基吡啶-3-基)-2-(2-(N,N-二甲胺基)-乙酰氨基)-N-甲基-6-咔唑磺酰胺。
6.权利要求1-5任一项所述的咔唑磺酰胺衍生物前药或其可药用盐在制备微管蛋白抑制剂中的应用。
7.权利要求1-5任一项所述的咔唑磺酰胺衍生物前药或其可药用盐在制备抗肿瘤药物中的应用。
8.一种抗肿瘤药物组合物,其包括权利要求1-5任一项所述的咔唑磺酰胺衍生物前药或其可药用盐,和药学上可接受的药用辅料。
9.权利要求1-5任一项所述的咔唑磺酰胺衍生物前药或其可药用盐的制备方法,包括使与含氮羧酸发生酰胺缩合反应的过程,其中,所述含氮羧酸选自氨基酸,或COOH(CH2)n-NR1,-NR1代表C1-C3的烷基叔胺基,或3-7元的含N杂环基团,n为选自1-6的整数,优选1-3。
10.根据权利要求9所述的制备方法,其包括:使与Boc-氨基酸发生酰胺缩合反应,以及使反应产物在酸性环境中脱保护基的过程。
11.根据权利要求9或10所述的制备方法,其包括:所述酰胺缩合反应的产物进一步成盐的过程。
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WO2014144125A1 (en) * | 2013-03-15 | 2014-09-18 | The Broad Institute, Inc. | Compounds for inducing proliferation and differentiation of cells, and methods of use thereof |
CN105418487A (zh) * | 2015-10-27 | 2016-03-23 | 山西普德药业股份有限公司 | 咔唑磺酰胺衍生物共晶及其制备方法 |
CN107382967A (zh) * | 2016-05-16 | 2017-11-24 | 中国医学科学院医药生物技术研究所 | 咔唑磺酰胺衍生物或其可药用盐及其制备方法和应用 |
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