CN115124528A - 一种吡咯并吡啶类化合物及其制备方法和医药应用 - Google Patents
一种吡咯并吡啶类化合物及其制备方法和医药应用 Download PDFInfo
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- CN115124528A CN115124528A CN202210850237.3A CN202210850237A CN115124528A CN 115124528 A CN115124528 A CN 115124528A CN 202210850237 A CN202210850237 A CN 202210850237A CN 115124528 A CN115124528 A CN 115124528A
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- ring
- compound
- pharmaceutically acceptable
- phenyl
- solvate
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Abstract
Description
技术领域
本发明属于药物化学和药物治疗学技术领域,具体涉及一种吡咯并吡啶类化合物。该类化合物可用于制备与PAK5有关疾病的药物。本发明还涉及该类化合物的制备方法以及含有它们的药物组合。
背景技术
吡咯[2,3-b]并吡啶是一类重要的含氮杂环类化合物,与吲哚,嘌呤等结构类似,成为后两类化合物的生物电子等排体,在医药,农药等领域有着广泛的用途。天然产物中含有吡咯并吡啶结构的化合物是一类重要的生物碱,具有抗癌、抗菌、抗精神病等生理活性。吡咯并吡啶衍生物具有蛋白激酶抑制作用,在抗组胺和抗多巴胺等方面都体现潜在的生物活性及药用价值。随着研究的不断深入,以吡咯并吡啶为骨架的抗肿瘤小分子已被FDA批准上市。Vemurafenib(维罗非尼),一种BRAF选择性抑制剂,其BRAF半数抑制浓度达到31nM,于2011年8月被FDA批准用于治疗晚期转移性或手术无法切除的黑色素瘤。GSK1070916,是以吡咯并吡啶为骨架的ATP竞争型极光激酶抑制剂,它对极光激酶B与极光激酶C的Ki分别为0.38±0.29nM、1.5±0.4nM,肿瘤增殖抑制活性评价实验显示GSK1070916对肺癌细胞半数抑制浓度为7nM,有效抑制了肿瘤细胞的增殖。异种移植瘤实验显示,GSK1070916可以抑制人结肠癌Colo205、HL-60的组蛋白H3的磷酸化,目前该小分子处于临床I期试验。
抗肿瘤靶点PAK5被证明在肿瘤细胞的侵袭转移、增殖、存活及凋亡等方面发挥着重要作用,因而其抑制剂的研发被认为是肿瘤治疗行之有效的策略,然而II类PAKs抑制剂大多处于生物测试研究阶段。但基于大量的分子生物学和结构生物学研究成果,目前II类PAKs抑制剂特别是选择性的II类PAKs抑制剂的发现与开发处于快速发展阶段,将有望开发出新一代抗肿瘤药物,特别是PAK5的蛋白晶体结构已经得到解析,相信开发PAK5抑制剂将势在必行。
因此,如何提供一种可有效抑制PAK5活性的蛋白激酶抑制剂,是本领域技术人员亟需解决的问题。
发明内容
本发明的目的是在现有技术的基础上,基于丝/苏氨酸激酶PAK5,利用基于片段的药物设计原理获得了一类吡咯并吡啶类化合物,药理实验证明,该类化合物具有良好的PAK5抑制活性,具体对肾癌细胞、肝癌细胞、结直肠癌细胞和乳腺癌细胞等肿瘤细胞也有较强的抗肿瘤活性。
本发明的另一目的是提供一种上述吡咯并吡啶类化合物的制备方法。
本发明的另一目的是提供一种上述吡咯并吡啶类化合物在医药方面的用途,具体涉及在制备与丝/苏氨酸激酶PAK5有关疾病的药物方面的应用;其中,丝/苏氨酸激酶PAK5有关疾病为结直肠癌、肝癌、胃癌、乳腺癌、肾癌或***。
本发明的技术方案如下:
式I所示的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐:
其中,
R1代表氢、C1-C4烷基、C1-C4烷氧基、丙烯酰基、丙烯基或叔丁氧羰基;
R2代表氢、羟基、C1-C4烷基、C1-C4烷氧基、卤素或三氟甲基;
L1代表-CH2-、-CO-NH-、-CO-NH-CH2-C(OH)-、乙烯基、乙炔基、氮原子、酰肼基或磺酰肼基;
n代表0、1或2;
环A代表哌啶、哌嗪、吗啉、吡咯或呋喃;
环B代表苯基或含氮五元杂环;
环C代表苯基、萘基或联苯基;
环D代表氧原子、苯基、环戊烷、环己烷、吡啶或嘧啶。
在一种优选方案中,R1代表氢、甲基、乙基、甲氧基或乙氧基。
在一种更优选方案中,R1代表甲基。
在一种优选方案中,R2代表氢、羟基、甲基、乙基、甲氧基或乙氧基。
在一种更优选方案中,R2代表氢、羟基或甲氧基。
在一种优选方案中,L1代表-CH2-、-CO-NH-、-CO-NH-CH2-C(OH)-、乙烯基、乙炔基或酰肼基。
在一种更优选方案中,L1代表-CH2-、-CO-NH-、-CO-NH-CH2-C(OH)-或乙炔基。
在一种优选方案中,n代表0或1。
在一种更优选方案中,n代表0。
在一种优选方案中,环A代表哌啶、哌嗪或吗啉。
在一种更优选方案中,环A代表哌啶。
在一种优选方案中,环B代表苯基、吡唑、噁唑、噻唑、咪唑或吡咯。
在一种更优选方案中,环B代表吡唑。
在一种优选方案中,环C代表苯基。
在一种优选方案中,环D代表氧原子、苯基、环戊烷、环己烷、吡啶或嘧啶。
在一种更优选方案中,环D代表氧原子、苯基、环戊烷、环己烷或吡啶。
进一步地,R1代表甲基;R2代表氢、羟基或甲氧基;L1代表-CH2-、-CO-NH-、-CO-NH-CH2-C(OH)-或乙炔基;n代表0;环A代表哌啶;环B代表吡唑;环C代表苯基;环D代表氧原子、苯基、环戊烷、环己烷或吡啶。
更进一步地,在通式I所述化合物、异构体、水合物、溶剂化物或其药学上可接受的盐,其中,所述化合物选自:
在一种优选方案中,当环A代表哌啶、环B代表吡唑、环C代表苯基、L1代表乙炔基和R1代表甲基时,通式I所示化合物的制备方法包括以下步骤:
本发明提及的中间体或目标化合物均可按照常规分离技术加以纯化,并且根据需要将其转化为与可药用酸的加成盐。
除非另外说明,在说明书和权利要求中使用的以下术语具有下面讨论的含义:
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括:
(1)与酸成盐,通过母体化合物的游离碱与无机酸或有机酸的反应而得,无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等,有机酸包括乙酸、三氟乙酸、丙酸、丙烯酸、己酸、环戊烷丙酸、羟乙酸、丙酮酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、抗坏血酸、樟脑酸、苯甲酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、肉桂酸、十二烷基硫酸、葡糖酸、谷氨酸、天冬氨酸、硬脂酸、扁桃酸、琥珀酸、戊二酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐,金属例子例如碱金属离子、碱土金属离子或铝离子,有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺、奎宁等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分,例如药学上可接受的载体,混合。药物组合物的目的是促进给药给动物的过程。
“药用载体”或“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分,例如但不限于:碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
“烷基”表示1-20个碳原子的饱和的脂烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“1-20”,是指该基团,此时为烷基,可以含1个碳原子、2个碳原子、3个碳原子等,直至包括20个碳原子)。更优选的是,烷基是有1-10个碳原子的中等大小的烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。最好是,烷基为有1-8或1-6个碳原子的低级烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。当是取代的烷基时,该取代基优选是一或多个,更优选1-3个,最优选1或2个取代基。
含氮五元杂环表示5个环原子的单环,含有一个、两个、三个或四个N杂原子,其余环原子是C,例如,吡唑、噁唑、噻唑、咪唑或吡咯。
“羟基”表示-OH基团。
“三氟甲基”表示-CF3基团。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“卤素”表示氟、氯、溴或碘,优选为氟或氯。
本发明提供了一种药物组合物,它以本发明的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐为活性成分或主要活性成分,辅以药学上可接受的载体。
本发明的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐可应用于制备与丝/苏氨酸激酶PAK5有关疾病的药物方面,其中,丝/苏氨酸激酶PAK5有关疾病为结直肠癌、肝癌、胃癌、乳腺癌、肾癌或***。
采用本发明的技术方案,优势如下:
1、本发明提到化合物对人结肠癌HCT-116细胞、人肾透明细胞癌786O细胞、人乳腺癌MCF-7细胞和人肝癌HepG2细胞均有较好的抑制作用。其中,化合物III5对四种肿瘤细胞的半数抑制浓度均在纳摩尔水平,抑制效果优于舒尼替尼(Sunitinib);在1μM浓度下,正常细胞人肾皮质近曲小管上皮细胞HK-2细胞的存活率接近80%,说明本发明提供的以吡咯并吡啶为骨架的衍生物对肿瘤细胞具有较强的抑制作用,同时具有较好的生物安全性。
2、使用均相时间分辨荧光(HTRF)STK-S2试剂盒(62ST2PEB,Cisbio)评价目标化合物对PAK5蛋白的抑制作用,整体处于纳摩尔水平。其中化合物III5对PAK5的IC50为8±0.40nM。
3、HepG2异种移植瘤裸鼠实验证明目标化合物III5组的肿瘤体积和瘤重明显小于阳性对照药组,抑瘤率达到了91.21%
4、给药结束后,裸鼠心脏、肝脏、脾脏、肺和肾脏组织的HE染色切片未见病理性结构改变,说明化合物III5的具有较好的生物安全性。
附图说明
图1是化合物III5对正常细胞HK-2细胞生存率的影响;其中,化合物III5的浓度在1μM时,正常细胞人肾皮质近曲小管上皮细胞HK-2细胞的存活率接近80%;
图2是化合物III5对HepG2裸鼠移植瘤模型的抑制作用;图2中A为各治疗组给药16天后剥离得到的裸鼠肿瘤照片;图2中B为给药后肿瘤体积的变化曲线;图2中C为给药后瘤重的变化曲线;目标化合物III5组的肿瘤体积和瘤重明显小于阳性对照药组,抑瘤率达到了91.21%;
图3是给药期间裸鼠体重变化曲线;其中,化合物III5的高中低三个剂量组对裸鼠体重影响较小,说明该化合物毒性较小;
图4是化合物III5对裸鼠的正常组织的影响;其中,给药结束后,裸鼠心脏、肝脏、脾脏、肺和肾脏组织的HE染色切片未见病理性结构改变,说明化合物III5的毒性较小
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅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。
鉴于本发明保护的吡咯并吡啶类化合物种类较多,申请人仅列举其中的一些化合物,其它化合物均能达到如下技术效果。
实施例1化合物III5的结构式和详细的制备方法如下:
制备方法如下:
4-(4-(1氢-吡咯[2,3-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯的合成(10)
称取原料5-溴-7氮杂吲哚(3.94g,20mmol),1-(1-叔丁氧羰基)-哌啶基-4-硼酸酯-吡唑(8.67g,24mmol)投入茄形瓶中,再称取Pd(PPh3)4(1.2g,1mmol),Na2CO3(4.24g,40mmol)投入混合溶剂(二氧六环:水=4:1)10mL,搅拌溶解,氮气保护,80℃反应,TLC监测(DCM:MeOH=30:1)。待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=50:1)得黄色固体。1H NMR(400MHz,CDCl3)δ9.39(s,1H),8.43(s,1H),8.00(d,J=2.0Hz,1H),7.80(d,J=2.4Hz,1H),7.68(d,J=1.2Hz,1H),7.33–7.30(m,1H),4.34–4.31(m,1H),2.97–2.87(m,2H),2.22–2.16(m,2H),2.01–1.96(m,2H),1.86–1.80(m,2H),1.48(s,9H).
4-(4-(3-碘代-1氢-吡咯[2,3-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯的合成(11)
称取原料10(3.67g,10mmol)投入茄形瓶中,二氯甲烷溶解,置于室温,开始搅拌,5min后,多次分批称取N-碘代丁二酰亚胺(2.7g,12mmol),分批投入,30min内投完,继续搅拌,TLC监测(DCM:MeOH=30:1),待反应结束,淬灭反应,乙酸乙酯萃取,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=50:1),分离得黄色固体。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.55(d,J=2.0Hz,1H),8.43(s,1H),8.00(s,1H),7.82(d,J=2.0Hz,1H),7.70(d,J=2.5Hz,1H),4.42–4.33(m,1H),4.09–4.02(m,2H),2.99–2.89(m,2H),2.11–2.05(m,2H),1.86–1.78(m,2H),1.43(s,9H).
4-(4-(3-碘代-1-甲基-苯磺酰基-1氢-吡咯[2,3-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯的合成(12)
称取原料11(4.93g,10mmol)投入茄形瓶中,10mL DMF溶解,置于冰浴,开始搅拌,多次分批称取氢化钠(287.97mg,12mmol)分批投入,30min投完,继续搅拌1h,称取对甲基苯磺酰氯(2.29g,12mmol)投入,继续搅拌,TLC监测(DCM:MeOH=50:1),待反应结束,将反应液转移至冰水中,搅拌30min,抽滤,滤渣水洗,得灰白色固体。1H NMR(400MHz,DMSO-d6)δ8.65(d,J=2.0Hz,1H),8.45(s,1H),8.07(s,1H),8.02(d,J=1.4Hz,1H),7.98(s,1H),7.96(s,1H),7.86(d,J=2.1Hz,1H),7.58(d,J=8.3Hz,1H),7.42–7.35(m,1H),4.37–4.26(m,1H),2.48–2.44(m,2H),2.37–2.34(m,2H),2.28(s,3H),2.04–1.97(m,2H),1.79–1.73(m,2H),1.37(s,9H).
3-碘代-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1-甲基-苯磺酰基-1H-吡咯[2,3-b]吡啶的合成(13)
称取原料12(3.24g,5mmol)投入茄形瓶中,甲醇溶解,室温搅拌,取盐酸,缓慢滴加至过量,TLC监测(DCM:MeOH=20:1),待反应结束,反应液浓缩准备下一步反应。
3-碘代-5-(1-(1-甲基-哌啶-4-基)-1H-吡唑-4-基)-1-甲基-苯磺酰基-1H-吡咯[2,3-b]吡啶的合成(14)
原料13用甲醇溶解,加入搅拌子,室温开始搅拌,加入催化量的乙酸,取7mL甲醛溶液,逐滴缓慢加入,室温继续搅拌2h,反应液直接萃取,有机相干燥、浓缩得白色固体。
取白色固体投入25mL茄形瓶,甲醇溶解,分批多次称取氰基硼氢化钠(378mg,1.2mmol),分批加入,室温搅拌,TLC监测(DCM:MeOH=20:1),待反应结束,反应液淬灭,萃取,有机相干燥、浓缩,硅胶制砂,柱层析分离(MeOH:DCM=50:1),得白色固体。1H NMR(400MHz,CDCl3)δ8.57(d,J=2.1Hz,1H),8.10(d,J=8.4Hz,2H),7.87(s,1H),7.81(s,1H),7.75(s,1H),7.67(d,J=2.1Hz,1H),7.31(d,J=7.8Hz,2H),4.23–4.17(m,1H),3.06–3.00(m,2H),2.39(s,3H),2.38(s,3H),2.23–2.20(m,2H),2.14–2.09(m,2H),1.30–1.24(m,2H).
1-((3-溴-苯基)乙炔基)环己基-1-醇的合成(III5a)
称取间溴碘苯(1.41g,5mmol),1-乙炔基环己醇(745.1mg,6mmol),碘化亚铜(95.23mg,0.5mmol),三乙胺(1.01g,10mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(183mg,0.25mmol),5mL四氢呋喃溶解,氮气保护,70℃反应。TLC监测(PE:EA=5:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=5:1),得黄色固体。1HNMR(400MHz,CDCl3)δ7.58(t,J=1.8Hz,1H),7.44(m,1H),7.35(m,1H),7.17(t,J=8.0Hz,1H),2.08–1.95(m,4H),1.64–1.56(m,6H).
1-(3-硼酸酯基-苯基)-乙炔基-环己烷-1-醇的合成(III5b)
称取III5a(1.4g,5mmol),联硼酸频那醇酯(1.52g,6mmol),乙酸钾(981.42mg,10mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(183mg,0.25mmol),5mL DMSO溶解,氮气保护,90℃反应。TLC监测(PE:EA=5:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=5:1),得白色固体。1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.76(m,1H),7.54(m,1H),7.34(t,J=7.5Hz,1H),1.78–1.72(m,4H),1.63–1.54(m,6H),1.37(s,12H).
1-((3-(5-(1-(1-甲基-哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯[2,3-b]吡啶-3-基)苯基)乙炔基)环己基-1-醇的合成(III5)
称取原料III5b(200g,0.35mmol),14(140mg,0.14mmol),碳酸钠(75mg,0.70mmol)投入100ml的圆底烧瓶,称取四(三苯基膦)钯(40mg,0.035mmol)投入反应瓶中,以混合溶剂(二氧六环:水=4:1)溶解,氮气保护,80℃反应,TLC监测(DCM:MeOH=20:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到淡白色固体。
取前一步得到的产物(100mg,0.15mmol),碳酸钾(23mg,0.15mmol)投入50ml的圆底烧瓶,以混合溶剂(甲醇:水=4:1)溶解,60℃回流反应5h,TLC监测(DCM:MeOH=15:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到白色固体。
化合物III5,白色固体产物,0.512g,收率65.07%。1H NMR(400MHz,MeOD)δ8.50(d,J=2.0Hz,1H),8.38(d,J=2.0Hz,1H),8.20(s,1H),7.92(s,1H),7.77–7.68(m,3H),7.46(t,J=7.7Hz,1H),7.35(m,J=7.7Hz,1H),4.25(m,J=5.1Hz,1H),3.23(s,1H),3.05(d,2H),2.37(s,3H),2.28(t,J=3.3Hz,2H),2.23–2.11(m,4H),2.02(d,2H),1.78(d,J=4.3Hz,1H),1.69(t,3H),1.63(d,J=7.2Hz,1H),1.35(s,1H),1.30(s,1H).HRMS(ESI)m/z[M-H]+:478.2607,found:478.2593.Retention time 2.612min,HPLC purity=98.255%.
实施例2化合物III4的结构式和详细的制备方法如下:
制备方法如下:
其中III4a的制备方法参照实施例1,将1-乙炔基环己醇替换为1-乙炔基环戊醇,合成路线如下:
称取间溴碘苯(1.41g,5mmol),1-乙炔基环戊醇(660.94mg,6mmol),碘化亚铜(95.23mg,0.5mmol),三乙胺(1.01g,10mmol),[1,1'-双(二苯基膦基)二茂铁],二氯化钯(183mg,0.25mmol),四氢呋喃溶解,氮气置换5min,70℃反应过夜。TLC检测(PE:EA=5:1),至原料反应完全,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=5:1),得黄色固体。
其中III4b的制备方法参照实施例1,合成路线如下:
称取III4a(1.2g,5mmol),联硼酸频那醇酯(1.52g,6mmol),乙酸钾(981.42mg,10mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(183mg,0.25mmol),5mL DMSO溶解,氮气保护,90℃反应。TLC监测(PE:EA=5:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=5:1),得白色固体。1H NMR(400MHz,CDCl3)δ7.89(d,J=1.6Hz,1H),7.72(m,1H),7.50(m,1H),7.30(t,J=7.6Hz,1H),2.03(m,4H),1.86–1.84(m,2H),1.81–1.74(m,2H),1.34(s,12H).
其中III4的制备方法参照实施例1,合成路线如下:
称取原料III4b(198mg,0.63mmol),14(300mg,0.53mmol),碳酸钠(112mg,1.06mmol)投入100ml的茄形瓶,称取四(三苯基膦)钯(31mg,0.026mmol)投入反应瓶中,以混合溶剂(二氧六环:水=4:1)溶解,氮气保护,80℃反应,TLC监测(DCM:MeOH=20:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到白色固体。
取前一步得到的产物(100mg,0.16mmol),碳酸钾(72mg,0.48mmol)投入50ml的圆底烧瓶,以混合溶剂(甲醇:水=4:1)溶解,60℃回流反应5h,TLC监测(DCM:MeOH=15:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到白色固体III4。
1-((3-(5-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯[2,3-b]吡啶-3-基)苯基)乙炔基)环戊烷-1-醇(III4),白色固体,0.37g,收率50.07%,1H NMR(400MHz,MeOD)δ8.48(d,J=2.0Hz,1H),8.36(d,J=2.0Hz,1H),8.18(s,1H),7.91(s,1H),7.72-7.65(m,3H),7.43(t,J=7.7Hz,1H),7.32(d,J=7.7Hz,1H),3.21(s,1H),3.07-2.99(m,2H),2.35(s,3H),2.31-2.22(m,2H),2.19-2.12(m,4H),2.03(d,J=6.5Hz,4H),1.90-1.76(m,4H).HRMS(ESI)m/z[M-H]+:464.2456,found:464.2430.Retention time 2.55min,HPLCpurity=97.681%.
实施例3化合物III1的结构式和详细的制备方法如下:
化合物14的制备过程同实施例1,其中III1b的制备方法参照实施例1,合成路线如下:
称取(3-溴苯基)甲醇(935.18mg,5mmol),联硼酸频那醇酯(1.52g,6mmol),乙酸钾(981.42mg,10mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(183mg,0.25mmol),5mLDMSO溶解,氮气保护,90℃反应。TLC监测(PE:EA=5:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=5:1),得白色固体。
其中III1的制备方法参照实施例1,合成路线如下:
称取原料III1b(150mg,0.64mmol),14(300mg,0.53mmol),碳酸钠(112mg,1.06mmol)投入100ml的圆底烧瓶,称取四(三苯基膦)钯(31mg,0.026mmol)投入反应瓶中,以混合溶剂(二氧六环:水=4:1)溶解,氮气保护,80℃反应,TLC监测(DCM:MeOH=20:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到淡黄色固体。
取前一步得到的产物(150mg,0.28mmol),碳酸钾(129mg,0.84mmol)投入50ml圆底烧瓶,以混合溶剂(甲醇:水=4:1)溶解,60℃回流反应5h,TLC监测(DCM:MeOH=15:1)。待反应结束,乙酸乙酯萃取,干燥有机相、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到白色固体粉末。
(3-(5-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)甲醇(III1)白色固体粉末,0.131g,收率68.11%,1H NMR(400MHz,CDCl3)δ10.74(s,1H),8.54(s,1H),8.24(d,J=1.8Hz,1H),7.97(s,1H),7.78(d,J=0.7Hz,1H),7.66(d,J=2.0Hz,1H),7.61–7.57(m,1H),7.50–7.45(m,2H),7.33(d,J=7.7Hz,1H),4.80(s,2H),4.32–4.26(m,1H),2.25–2.17(m,4H),1.87(s,4H).HRMS(ESI)m/z[M-H]+:386.1986,found:386.2004.Retention time 2.091min,HPLC purity=98.713%.
实施例4化合物III2的结构式和详细的制备方法如下:
制备方法如下:
化合物14的制备过程同实施例1,合成路线如下:
称取(3-溴苯基)甲醇(935.18mg,5mmol),联硼酸频那醇酯(1.52g,6mmol),乙酸钾(981.42mg,10mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(183mg,0.25mmol),5mLDMSO溶解,氮气保护,90℃反应。TLC监测(PE:EA=5:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=5:1),得白色固体。
其中III2b的制备方法参照实施例1,合成路线如下:
称取3-硼酸酯基-苯甲酸(496.17mg,2mmol),3-氨基-2-甲氧基-吡啶(297.94mg,2.4mmol),HATU(564.65mg,2,4mmol),DIPEA(516.97mg,4mmol),3mL DMF溶解,室温搅拌,TLC监测(PE:EA=1:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=1:1),得白色固体。1H NMR(400MHz,CDCl3):δ8.72(d,J=9.6Hz,1H),8.42(s,1H),8.28(s,1H),7.99(d,J=9.1Hz,2H),7.90(d,J=1.9Hz,1H),7.51(t,J=7.6Hz,1H),6.95(dd,J=7.8,5.0Hz,1H),4.05(s,3H),3.97(s,1H),1.36(s,12H).
其中III2的制备方法参照实施例1,合成路线如下:
称取原料III2b(227mg,0.64mmol),14(300mg,0.53mmol),碳酸钠(112mg,1.06mmol)投入100ml的圆底烧瓶,称取四(三苯基膦)钯(31mg,0.026mmol)投入反应瓶中,以混合溶剂(二氧六环:水=4:1)溶解,氮气保护,80℃反应,TLC监测(DCM:MeOH=20:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到淡黄色固体。
取前一步得到的产物(150mg,0.23mmol),碳酸钾(106mg,0.69mmol)投入50ml的圆底烧瓶,以混合溶剂(甲醇:水=4:1)溶解,60℃回流反应5h,TLC监测(DCM:MeOH=15:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到白色固体粉末III2。
N-(2-甲氧基吡啶-3-基)-3-(5-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)苯甲酰胺(III2),白色固体,0.62g,收率61.37%,1H NMR(400MHz,CDCl3)δ10.75(s,1H),8.78(dd,J=7.8,1.7Hz,1H),8.63(d,J=2.0Hz,1H),8.49(s,1H),8.30(d,J=2.0Hz,1H),8.20(t,J=1.8Hz,1H),8.06(s,1H),7.92–7.76(m,4H),7.65–7.60(m,2H),6.98(dd,J=7.8,5.0Hz,1H),4.04(s,3H),2.51(s,3H),2.36–2.14(m,4H).HRMS(ESI)m/z[M-H]+:506.2304,found:506.2322.Retention time 2.439min,HPLC purity=98.867%.
实施例5化合物III3的结构式和详细的制备方法如下:
制备方法如下:
化合物14的制备过程同实施例1,其中III3a的制备方法参照实施例1,合成路线如下:
称取(3-溴苯基)甲酸(1.05g,5mmol),联硼酸频那醇酯(1.52g,6mmol),乙酸钾(981.42mg,10mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(183mg,0.25mmol),5mLDMSO溶解,氮气保护,90℃反应。TLC监测(PE:EA=5:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=5:1),得黄色固体。
其中III3b的制备方法参照实施例1,合成路线如下:
称取3-硼酸酯基-苯甲酸(496.17mg,2mmol),2-氨基-1-(329.24mg,2.4mmol),HATU(564.65mg,2,4mmol),DIPEA(516.97mg,4mmol),3mL DMF溶解,室温搅拌,TLC监测(PE:EA=1:1),待反应结束,萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(PE:EA=1:1),得白色固体。1H NMR(400MHz,CDCl3):δ8.13(t,J=1.4Hz,1H),7.98–7.91(m,2H),7.47–7.34(m,6H),6.91(s,1H),3.94–3.86(m,1H),3.56–3.48(m,1H),1.35(s,12H).
其中III2的制备方法参照实施例1,合成路线如下:
称取原料III3b(235mg,0.64mmol),14(300mg,0.53mmol),碳酸钠(112mg,1.06mmol)投入100ml的圆底烧瓶,称取四(三苯基膦)钯(31mg,0.026mmol)投入反应瓶中,以混合溶剂(二氧六环:水=4:1)溶解,氮气保护,80℃反应,TLC监测(DCM:MeOH=20:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到淡黄色固体。
取前一步得到的产物(150mg,0.22mmol),碳酸钾(101mg,0.66mmol)投入50ml的圆底烧瓶,以混合溶剂(甲醇:水=4:1)溶解,60℃回流反应5h,TLC监测(DCM:MeOH=15:1),待反应结束,乙酸乙酯萃取反应液,有机相干燥、浓缩,硅胶制砂,柱层析分离(DCM:MeOH=40:1),得到白色固体粉末III3。
(S)-N-(2-羟基-2-苯乙基)-3-(5-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)苯甲酰胺(III3),白色固体,0.33g,收率51.98%,1H NMR(400MHz,CDCl3)δ8.48(d,J=2.0Hz,1H),8.36(d,J=2.0Hz,1H),8.18(s,1H),7.92(s,1H),7.71–7.65(m,3H),7.44(t,J=7.7Hz,1H),7.32(d,J=7.7Hz,1H),7.17–7.11(m,5H),5.36(s,1H),5.34(s,1H),4.30(t,J=6.7Hz,1H),3.49(s,2H),2.54(d,J=16.0Hz,4H),2.00(d,J=6.6Hz,4H).HRMS(ESI)m/z[M-H]+:519.2508,found:519.2521.Retention time 2.105min,HPLC purity=98.397%.
下面是本发明的代表化合物的部分药理试验及结果:
1、CCK-8法检测目标化合物对肿瘤细胞的增殖抑制影响
胰酶消化肿瘤细胞,细胞计数板计数,96孔板四周的36个孔只加100μL PBS防止水分蒸发,其余每孔铺5000-10000个细胞。细胞贴壁后,加入含有特定浓度化合物的完全培养基,置37℃,5%CO2细胞培养箱中培养48h。48h后弃去96孔板中培养基,每孔避光加入90μL完全培养基和10μL CCK-8溶液,混匀。将96孔板置于细胞培养箱中孵育0.5,1,2,4h。酶标仪波长设定为450nm测定OD值,重复实验三次。相对抑制率=(OD对照组-OD实验组)/(OD对照组-OD空白组)×100%。按照寇氏计算法,计算IC50值,即细胞生长抑制率为50%的药物浓度。具体增殖抑制效果如表1所示。
表1化合物对不同肿瘤细胞系抗增殖能力的影响
通过表1的CCK-8实验结果得知,本发明提供的化合物对人结直肠癌细胞HCT-116、人乳腺癌细胞MCF-7、人肾癌细胞786O和人肝癌细胞HepG2的均有显著的增殖抑制作用。
其中化合物III2对MCF-7细胞和786O细胞的半数抑制浓度分别为0.44和0.83μM;化合物III4对786O细胞的半数抑制浓度为0.95μM;化合物III5对HCT-116细胞、MCF-7细胞、786O细胞和HepG2细胞的半数抑制浓度分别为0.44μM、0.27μM、0.65μM和0.45μM,抑制效果优于阳性对照药舒尼替尼(Sunitinib)和5-氟尿嘧啶(5-FU),说明本发明提供的以吡咯并吡啶为骨架的衍生物对肿瘤细胞具有较强的抑制作用,整体达到纳摩尔水平。
2、HTRF KinEASE试剂盒考察化合物对PAK5激酶活性抑制作用
该方法分为两步:第一步为酶促反应步骤,将PAK5激酶底物-2-生物素复合物与酶一起温育,加入ATP以开始酶促反应。第二步监测试剂捕获磷酸化的底物。最终获得的TR-FRET信号与磷酸化水平成正比,加入标记有Eu3+-Cryptate的抗体和链菌素-XL665终止激酶活性。抑制率=(max-test)/(max-min)×100%(“max”是指无化合物对照,“min”是指无化合物无激酶对照)。
我们使用HTRF KinEASE试剂盒评价了化合物对PAK5激酶的抑制效果。在100nM的条件下,化合物对PAK5的抑制率均达到了50%,在1μM的条件下化合物III1、III2、III3对PAK5的抑制率均达到了80%以上,其他未列举的化合物也具有类似的效果。我们选择抑制效果较好的化合物III4、III5进行半数抑制评价,发现化合物III4、III5对PAK5的半数抑制浓度分别达到了14nM和8nM,与阳性对照药舒尼替尼相似(结果见表2)。
表2化合物对PAK5激酶的抑制活性
a激酶活性被抑制一半时化合物对应的浓度,实验重复三次,结果表示为平均值±标准偏差(Mean±SD)。
3、CCK-8法测定化合物对正常细胞的细胞毒性
胰酶消化培养皿中处于对数生长期的正常人肾小管上皮细胞HK-2细胞,计数板计数,接种于96孔板中。除周边孔只加200μL PBS外,其余每孔铺3000-6000个细胞;设置4个复孔,每孔加10%FBS的完全培养基100μL;细胞贴壁后,倒扣弃去96孔板中培养基,加入含有不同浓度的化合物的培养基,置37℃,5%CO2培养箱中培养48h;48h后弃去96孔板中旧培养基,每孔加入90μL无血清培养基,10μL CCK-8溶液,混匀,避光操作;放入培养箱中继续孵育0.5、1、2、4h;使用酶标仪读取位于450nm波长处测量光密度(OD),重复三次。
我们采用CCK-8法考察了目标化合物III5和III4对正常人肾小管上皮细胞HK-2的细胞毒性,结果如图1所示。化合物浓度为1μM时,III4和III5组HK-2细胞的存活率分别为70.48%和76.33%,高于5-FU的细胞存活率63.75%;当化合物浓度为5μM时,III4和III5组的细胞存活率为30%,接近于5-FU组的34.95%,差异具有统计学意义,说明化合物具有较好的安全性。本发明其他化合物也具有类似的效果。
4、异种移植瘤裸鼠模型考察化合物的体内抑瘤效果
为进一步评价目标化合物III5在动物体内的抗肿瘤效果。我们采用HepG2细胞裸鼠皮下瘤的体内实验,评价化合物III5的体内抑瘤效果。取30只BALB/C裸鼠(雄性,SPF级,18-22g),在每只裸鼠的右腋皮下接种5×106个HepG2细胞,成立荷瘤动物模型。等皮下肿瘤长至100-140mm3后,将裸鼠随机分成5组,分别为对照组(Vehicle)、阳性对照药舒尼替尼(20mg/kg)组和目标化合物III5的高中低浓度组(50mg/kg、35mg/kg和20mg/kg)。尾静脉注射方式给药,每天一次,给药连续给药16天,每天测量每只裸鼠的肿瘤大小及其体重,测定小鼠肿瘤的长径(a)和短径(b)。在给药16天后使用脱颈的方法处死裸鼠,取出肿瘤组织和正常组织,进行苏木素-伊红染色(H&E)。根据肿瘤体积计算公式:V=1/2×a×b2,计算肿瘤体积并得出抑瘤率,同时进行统计学t检验分析。结果如图2-4所示。
图2A为裸鼠体内肿瘤图。如图所示,化合物III5组比空白对照组的肿瘤明显缩小。在相同给药剂量下,20mg/k化合物III5给药组的肿瘤大小与阳性对照药舒尼替尼组治疗效果相当。高浓度化合物III5(50mg/kg)给药组的肿瘤体积最小,说明存在剂量依赖关系。
图2B为肿瘤体积变化图。如图所示,空白组的肿瘤体积随时间的延长呈指数增长,而给药组肿瘤体积明显小于对照组。在相同给药浓度下,化合物III5组较阳性对照药组抑瘤率有所提升,呈剂量依赖关系。
图2C为肿瘤重量变化图。如图所示,给药组瘤重比空白组有不同程度的降低。相同等给药浓度下,化合物III5给药组比阳性对照药舒尼替尼组平均瘤重降低了0.15g。随着给药剂量的增加,瘤重不断降低,当给药量为50mg/kg时,抑瘤率达到了91.21%。
图3为给药期内各组荷瘤裸鼠的体重变化曲线。如图所示,给药期间裸鼠体重并未发生明显的变化,表明化合物III5具有较低的毒性。
图4为给药结束后裸鼠正常组织的HE染色切片,其中苏木精染料主要将肿瘤细胞的细胞核染为蓝紫色,而伊红染料主要将细胞质及细胞外基质染成红色。结果显示,每组均有较为致密的细胞团,细胞核完整且细胞形态正常,表明化合物III5并未对裸鼠的心脏、肝脏、脾脏、肺、肾脏等主要脏器造成病理性损伤,具有体内生物安全性。
以上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:其依然可能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 (10)
2.根据权利要求1所述的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐,其中,R1代表氢、甲基、乙基、甲氧基或乙氧基;优选地,R1代表甲基;R2代表氢、羟基、甲基、乙基、甲氧基或乙氧基;优选地,R2代表氢、羟基或甲氧基。
3.根据权利要求1所述的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐,其中,L1代表-CH2-、-CO-NH-、-CO-NH-CH2-C(OH)-、乙烯基、乙炔基或酰肼基;优选地,L1代表-CH2-、-CO-NH-、-CO-NH-CH2-C(OH)-或乙炔基;n代表0或1;优选地,n代表0。
4.根据权利要求1所述的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐,其中,环A代表哌啶、哌嗪或吗啉;优选地,环A代表哌啶;环B代表苯基、吡唑、噁唑、噻唑、咪唑或吡咯;优选地,环B代表吡唑。
5.根据权利要求1所述的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐,其中,环C代表苯基;环D代表氧原子、苯基、环戊烷、环己烷、吡啶或嘧啶;优选地,环D代表氧原子、苯基、环戊烷、环己烷或吡啶。
6.根据权利要求1所述的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐,其中,R1代表甲基;R2代表氢、羟基或甲氧基;L1代表-CH2-、-CO-NH-、-CO-NH-CH2-C(OH)-或乙炔基;n代表0;环A代表哌啶;环B代表吡唑;环C代表苯基;环D代表氧原子、苯基、环戊烷、环己烷或吡啶。
9.一种药物组合物,它以权利要求1-7中任一项所述的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐为活性成分或主要活性成分,辅以药学上可接受的载体。
10.权利要求1-7中任一项所述的化合物、异构体、水合物、溶剂化物或其药学上可接受的盐在制备与丝/苏氨酸激酶PAK5有关疾病的药物方面的应用;优选地,所述丝/苏氨酸激酶PAK5有关疾病为结直肠癌、肝癌、胃癌、乳腺癌、肾癌或***。
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