CN108752351A - 一种含哌嗪的吡唑并嘧啶类化合物或其药用盐及其制备方法与应用 - Google Patents
一种含哌嗪的吡唑并嘧啶类化合物或其药用盐及其制备方法与应用 Download PDFInfo
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- CN108752351A CN108752351A CN201811065796.3A CN201811065796A CN108752351A CN 108752351 A CN108752351 A CN 108752351A CN 201811065796 A CN201811065796 A CN 201811065796A CN 108752351 A CN108752351 A CN 108752351A
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- pyrazolo
- piperazin
- pyrimidin
- ethanone
- piperazine
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- -1 pyrazolopyrimidine compound Chemical class 0.000 claims abstract description 105
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- C—CHEMISTRY; METALLURGY
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
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- 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
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- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种含哌嗪的吡唑并嘧啶类化合物或其药用盐，其特征在于，具有如下通式Y：
Description
技术领域
本发明属于有机化合物合成及医药技术领域，具体涉及一种含哌嗪的吡唑并嘧啶类化合物或其药用盐及其制备方法与应用。
背景技术
Phosphatidylinositol 3-kinase(PI3K)/AKT/mTOR信号通路是目前研究活跃、肿瘤细胞突变频繁的通路，在细胞信号传导，促进细胞增殖、生存、分化和凋亡等过程中发挥重要作用。此信号通路过度激活在急、慢性白血病，淋巴瘤，骨髓瘤及卵巢癌、前列腺癌等肿瘤中十分常见。该信号通常由各种配体与多种受体[主要是受体酪氨酸激酶(receptortyrosine kinases，RTKs)和G蛋白偶联受体(G-protein-coupled receptors，GPCRs)]结合而激活；细胞外生长因子与RTKs结合激活RTKs；在细胞膜上活化的RTKs直接使磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase，PI3K)聚集并激活，活化的PI3K磷酸化PIP2的3-OH使其转化为PIP3；PIP3与AKT的PH域结合使其移位至细胞膜，AKT构象改变暴露出苏氨酸Thr308和丝氨酸Ser473两个磷酸化位点，继而分别被磷脂酰肌醇依赖性蛋白激酶1(phosphoinositide-dependent kinase 1，PDK1)和mTORC2磷酸化而使AKT完全活化；活化的AKT通过磷酸化一系列底物(包括mTORC1，糖原合成激酶3(GSK3)，细胞周期蛋白依赖性激酶抑制物p21Cip1和p27Kip1，转录因子家族Forkhead/FOXO和促凋亡蛋白Bad)促进细胞的增殖和存活、抑制凋亡(Fig.1)。因此，AKT是此信号通路的关键性激酶，在调节细胞存活、生长、增殖、凋亡中起到非常重要的作用，抑制AKT将有利于肿瘤的靶向治疗。
目前，AKT已经成为抗肿瘤药物重要靶点之一，到目前为止已有多种AKT抑制剂进入临床或者临床前研究。GSK690693是第一个进入临床研究的AKT抑制剂在移植BT474乳腺癌细的小鼠中腹腔注射GK690693大大减慢了肿瘤生长速度，静脉注射GSK690693治疗癌症病人引起了药物相关性高血糖症而使该药终止于临床I期；其他代表性AKT抑制剂如GSK2110183已经完成在血癌病人中的临床Ⅱ期研究；AZD5363已经完成治疗转移性前列腺癌的I期临床研究；GDC0068正进行与紫杉醇联合用药治疗转移性乳腺癌的Ⅱ期临床研究，尽管如此仍存在一些关键性问题未完全解决，如毒副作用、选择性等。因此，开发新型高效低毒、高选择性的AKT抑制剂任重而道远。
基于上述情况，本发明提出了一种含哌嗪的吡唑并嘧啶类化合物或其药用盐及其制备方法与应用。
发明内容
本发明的目的之一在于提供一种含哌嗪的吡唑并嘧啶类化合物或其药用盐，该类化合物具有一定的PC-3细胞生长抑制活性和AKT1激酶抑制活性。本发明的含哌嗪的吡唑并嘧啶类化合物或其药用盐，结构新颖，如通式Y所示，R3基团(取代氨基)的引入是提高化合物活性的必需基团，通过这种设计改造方式，具有AKT1激酶抑制活性，并且对前列腺癌细胞株(PC-3细胞)表现出抑制活性。
本发明通过下述技术方案实现：
一种含哌嗪的吡唑并嘧啶类化合物或其药用盐，具有如下通式Y：
其中，R1为氢、单卤素取代、双卤素取代、甲氧基或烷烃；R2为氢、氯或溴；R3为氢、氨基、取代氨基、取代哌啶或取代哌嗪基。
作为一种优选方案，所述通式Y中，R1为氢、4-氯、4-溴、4-氟或2,4-二氯；R2为氢、氯或溴；R3为氢、氨基、二甲氨基、N-甲基哌嗪、4-羟基哌啶或乙酰基哌嗪。
作为一种优选方案，所述通式Y是下列化合物之一：
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(4-甲基哌嗪-1-基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(4-甲基哌嗪-1-基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-氨基乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(二甲氨基)乙酮。
本发明的目的之二在于提供一种含哌嗪的吡唑并嘧啶类化合物或其药用盐的制备方法，以3-取代-1H-吡唑并[3,4-d]嘧啶为起始原料，在微波催化下与1-叔丁氧羰基-哌嗪发生亲核取代得中间体2，在酸性条件下脱去Boc保护基得到中间体3，中间体3与取代苯乙酸进行酰胺缩合，得目标产物Y。
该制备方法的合成路线如下：
其中，R1、R2、R3如通式Y中所述。
作为一种优选方案，包括如下步骤：
1)将3-取代-1H-吡唑并[3,4-d]嘧啶加入到DMF中，依次加入DIEA、1-叔丁氧羰基哌嗪，微波加热至85～95℃，反应20～30min，将反应液倒入冰水中，析出大量固体，乙酸乙酯萃取，有机相依次采用饱和氯化胺、饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，用石油醚/乙酸乙酯柱层析纯化，得中间体2；
2)将中间体2溶剂于THF中，加入浓盐酸，室温反应4～5h，过滤得中间体3；
3)将取代苯乙酸溶解在DMF中，依次加入HBTU、DIEA，室温搅拌15～20min，加入中间体3，室温反应，将反应液倒入冰水中，析出大量固体，乙酸乙酯萃取，合并有机相，依次采用饱和氯化铵、饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂得粗品，采用二氯甲烷/甲醇柱层析纯化得目标产物Y。
作为一种更优选方案，步骤1)中，所述3-取代-1H-吡唑并[3,4-d]嘧啶、DIEA和1-叔丁氧羰基哌嗪的摩尔比为1：1.3：1.1。
作为一种更优选方案，步骤2)中，所述THF和浓HCl的体积比3：1。
作为一种更优选方案，步骤3)中，所述中间体3、DIEA、HBTU和取代苯乙酸的摩尔比为1：1.5：1.05：1。
本发明的目的之三在于提供含哌嗪的吡唑并嘧啶类化合物或其药用盐在制备抗肿瘤药物中的应用。
作为一种优选方案，所述抗肿瘤药物是靶向AKT1的抗前列腺癌和淋巴瘤的药物。
本发明与现有技术相比，具有以下优点及有益效果：
本发明的含哌嗪的吡唑并嘧啶类化合物或其药用盐，结构新颖，如通式Y所示，R3基团(取代氨基)的引入是提高化合物活性的必需基团，通过这种设计改造方式，具有AKT1激酶抑制活性，并且对前列腺癌细胞株(PC-3细胞)表现出抑制活性。
具体实施方式
下面结合实施例对本发明作进一步地详细说明，但本发明的实施方式不限于此。实施例中采用的条件可以根据现有的设备条件做进一步调整，未注明的实施条件通常为常规实验中的条件。
本发明中所述化学试剂名称与简称对照：N，N-二异丙基乙胺(DIEA)，N,N-二甲基甲酰胺(DMF)，盐酸(HCl)，四氢呋喃(THF)，O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)。
本发明所述的室温为20～25℃。
实施例1：
化合物Y的制备
1)中间体2的制备：
将3-取代-1H-吡唑并[3,4-d]嘧啶(10mmol)溶解于DMF(15mL)中,依次加入DIEA(15mmol,2.5mL)，1-叔丁氧羰基哌嗪(10.5mmol)，90℃下微波反应20～30min，反应完毕，将反应液用冰水(150mL)淬灭反应，采用乙酸乙酯(3×30mL)萃取，合并有机相，依次采用饱和氯化胺(3×20mL)，饱和食盐水(3×20mL)洗涤有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂，柱层析纯化(石油醚：乙酸乙酯＝1：3)得中间体2。
制备的所述中间体2是下列几种化合物：
4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2a)
白色固体，产率89％，1H NMR(400MHz,DMSO)δ8.94(s,1H),8.60(s,1H)，4.32(s,4H),3.35(s,4H)，1.39(s,9H)
4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2b)
淡黄色固体，产率86％，1H NMR(400MHz,DMSO)δ8.36(s,1H)，3.93–3.79(m,4H),3.12–3.00(m,4H)，1.40(s,9H)
4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2c)
白色固体，产率88％，1H NMR(400MHz,DMSO)δ8.38(s,1H)，3.96–3.74(m,4H),3.20–3.07(m,4H)，1.41(s,9H)
2)中间体3的合成:
将中间体2(4.0g)溶解于四氢呋喃(12mL)中，加入浓盐酸(4mL)，室温反应4-5h。反应完毕，析出大量固体，过滤，得中间体3。
制备的所述中间体3是下列几种化合物：
4-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶二盐酸盐(3a)
类白色固体，产率84％，1H NMR(400MHz,DMSO)δ9.99(s,2H)8.97(s,1H),8.63(s,1H),4.32(s,4H),3.35(s,4H).
3-氯-4-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶二盐酸盐(3b)
灰白色固体，产率68％，1H NMR(400MHz,DMSO)δ8.36(d,J＝5.7Hz,1H),3.93–3.79(m,4H),3.12–3.00(m,4H).
3-溴-4-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶二盐酸盐(3c)
类白色固体，产率88％，1H NMR(400MHz,DMSO)δ8.38(s,1H),3.96–3.74(m,4H),3.20–3.07(m,4H).
3)目标化合物Y制备：
将取代苯乙酸(1mmol)，溶解于DMF(5mL)中，依次加入HBTU(1.05mmol),DIEA(2.0mmol)，常温搅拌15分钟，加入中间体3(1mmol)，室温反应6h。反应完毕，用冰水(50mL)淬灭，乙酸乙酯萃取(3×20mL)，合并有机相，依次用饱和氯化铵(3×20mL)，饱和食盐水(3×20mL)洗涤有机相，减压蒸除溶剂，得粗品，柱层析分离纯化，得目标产物Y，洗脱溶剂为二氯甲烷/甲醇＝50：1。
制备的所述目标产物Y是下列几种化合物：
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮(Y1)
白色固体，1H NMR(400MHz,MeOD)δ8.25(s,1H),8.19(s,1H),7.36–7.22(m,5H),4.07–4.01(m,2H),3.98–3.90(m,2H),3.85(s,2H),3.84–3.80(m,2H),3.80–3.75(m,2H).
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮(Y2)
白色固体，1H NMR(400MHz,DMSO)δ13.58(s,1H),8.27(d,J＝2.6Hz,2H),7.33–7.25(m,2H),7.20–7.09(m,2H),3.98(t,J＝14.7Hz,4H),3.78(s,2H),3.76–3.65(m,4H).13CNMR(101MHz,DMSO)δ169.69(s),160.24(s),156.95(s),155.99(s),155.12(s),134.15(s),132.39(s),131.55(2C),115.51(2C),99.93(s),46.33(2C),44.95(s),42.27(s),41.78(s).
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮(Y3)
白色固体，1H NMR(400MHz,MeOD)δ8.26(s,1H),8.22(s,1H),7.30(dd,J＝23.2,8.4Hz,4H),4.10–3.98(m,4H),3.84(s,2H),3.81(dd,J＝9.8,4.7Hz,4H).13C NMR(101MHz,DMSO)δ169.46(s),156.95(s),155.92(s),155.12(s),135.30(s),134.16(s),131.59(3C),128.55(2C),99.99(s),54.09(s),44.95(2C),41.19(s),39.07(s).
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮(Y4)
白色固体，1H NMR(400MHz,DMSO)δ13.57(s,1H),8.26(s,2H),7.50(d,J＝8.3Hz,2H),7.22(d,J＝8.3Hz,2H),4.01–3.91(m,4H),3.78(s,2H),3.75–3.63(m,4H).13C NMR(101MHz,DMSO)δ169.39(s),156.89(s),155.99(s),155.13(s),135.62(s),134.16(s),132.04(2C),131.55(2C),120.11(s),100.05(s),44.95(2C),41.19(s),39.14(2C).
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)乙酮(Y5)
白色固体，1H NMR(400MHz,DMSO)δ13.59(s,1H),8.29(s,1H),8.28(s,1H),7.60(d,J＝1.8Hz,1H),7.39–7.36(m,2H),4.11–4.03(m,2H),4.03–3.94(m,2H),3.89(s,2H),3.82–3.74(m,2H),3.71-3.68(m,2H).13C NMR(101MHz,DMSO)δ168.18(s),156.95(s),155.85(s),155.15(s),135.27(s),134.15(2C),133.78(s),132.48(s),128.83(s),127.55(s),99.93(s),46.33(2C),44.81(s),41.27(s),37.32(s).
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮(Y6)
白色固体，1H NMR(400MHz,CDCl3)δ8.42(s,1H),7.97(s,1H),7.37–7.31(m,2H),7.30–7.25(m,3H),3.93(d,J＝5.9Hz,2H),3.90–3.83(m,4H),3.80(s,2H),3.71–3.62(m,2H).13C NMR(101MHz,CDCl3)δ169.97(s),160.31(s),158.12(s),155.33(s),134.24(s),128.85(2C),128.59(2C),126.75(s),119.71(s),100.88(s),60.21(s),44.88(s),43.75(s),40.89(s),29.86(s).
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮(Y7)
白色固体，1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.97(s,1H),7.24(dd,J＝8.4,5.4Hz,2H),7.03(t,J＝8.6Hz,2H),3.96-3.84(m,4H),3.87-3.73(m,2H),3.76(s,2H),3.72–3.64(m,2H).13C NMR(101MHz,CDCl3)δ169.59(s),162.97(s),160.80(s),157.70(s),154.85(s),130.27(3C),119.91(s),115.84(s),115.56(s),100.59(s),61.31(s),45.33(s),41.16(s),39.62(s),29.07(s).
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮(Y8)
白色固体，1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.96(s,1H),3.98–3.90(m,4H),3.87-3.75(m,2H),3.75(s,2H),3.71–3.63(m,2H).13C NMR(101MHz,CDCl3)δ169.37(s),160.80(s),157.49(s),155.53(s),132.97,130.04(2C),128.45(2C),119.29(s),100.38(s),60.48(s),45.10(s),41.15(s),39.84(s),30.35(s).
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮(Y9)
白色固体，1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.97(s,1H),7.46(d,J＝8.4Hz,2H),7.15(d,J＝8.3Hz,2H),4.09-3.84(m,4H),3.90–3.83(m,2H),3.73(s,2H),3.70–3.61(m,2H).13C NMR(101MHz,CDCl3)δ169.58(s),160.80(s),157.28(s),155.32(s),133.35(s),131.95(2C),130.24(2C),121.04(s),119.28(s),101.50(s),60.71(s),45.10(s),40.89(s),38.71(s),30.62(s).
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(4-甲基哌嗪-1-基)乙酮(Y10)
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮(Y11)
白色固体，1H NMR(400MHz,CDCl3)δ13.86(s,1H),8.43(s,1H),7.37–7.31(m,2H),7.27(dd,J＝8.2,4.6Hz,3H),3.89(dd,J＝13.4,5.6Hz,4H),3.83(s,2H),3.69(dd,J＝19.0,5.7Hz,4H).13C NMR(101MHz,CDCl3)δ169.95(s),158.83(s),156.81(s),154.63(s),134.62(s),128.96(2C),128.53(2C),127.08(s),119.75(s),101.92(s),49.33(s),48.68(s),45.82(s),41.71(s),41.20(s).
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮(Y12)
白色固体，1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.26(d,J＝4.2Hz,2H),7.04(t,J＝8.6Hz,2H),3.92-3.86(m,4H),3.78(s,4H),3.69(s,2H).13C NMR(101MHz,CDCl3)δ169.77(s),163.12(s),160.68(s),158.87(s),156.80(s),154.67(s),130.25(2C),119.76(s),115.89(s),115.68(s),101.98(s),49.40(s),48.68(s),45.75(s),41.73(s),40.08(s).
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮(Y13)
白色固体，1H NMR(400MHz,CDCl3)δ13.70(s,1H),8.45(s,1H),7.31(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),3.92-3.86(m,4H),3.78(s,4H),3.68-3.65(m,2H).13C NMR(101MHz,MeOD)δ170.23(s),159.67(s),157.91(s),156.03(s),136.12(s),132.38(3C),129.45(2C),120.00(s),102.35(s),50.01,49.70,46.23(s),42.36(s),39.84(s).
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮(Y14)
白色固体，1H NMR(400MHz,CDCl3)δ13.48(s,1H),8.45(s,1H),7.47(d,J＝8.3Hz,2H),7.16(d,J＝8.2Hz,2H),3.92-3.87(m,4H),3.76(s,4H),3.67-3.65(m,2H).13C NMR(101MHz,DMSO)δ169.36(s),158.79(s),157.05(s),155.06(s),135.73(s),132.01(2C),131.57(2C),119.92(s),119.22(s),101.60(s),49.32(s),49.10(s),45.43(s),41.55(s),39.11(s).
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)乙酮(Y15)
白色固体，1H NMR(400MHz,DMSO-d6)δ14.09(s,1H),8.38(s,1H),7.59(s,1H),7.37(d,J＝3.8Hz,2H),3.90(s,2H),3.86(s,2H),3.80(s,4H),3.69(s,2H).13C NMR(101MHz,DMSO-d6)δ168.15(s),158.87(s),157.07(s),155.24(s),135.24(s),134.15(s),133.77(s),132.45(s),128.81(s),127.54(s),119.25(s),101.61(s),49.34(s),49.16(s),45.27(s),41.67(s),37.32(s).
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(4-甲基哌嗪-1-基)乙酮(Y16)
白色固体，1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.44(q,J＝8.5Hz,4H),4.65(s,1H),3.57-3.75(m,8H),2.42(s,4H),2.29(s,4H),2.12(s,3H).13C NMR(101MHz,DMSO-d6)δ169.00(s),158.84(s),157.14(s),155.12(s),135.62(s),132.77(s),131.46(2C),128.63(2C),119.09(s),101.60(s),68.17(s),63.07(s),55.35(s),52.50(s),50.23(s),46.17(s),46.09(s),45.24(s),41.86(s).
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-氨基乙酮(Y17)
白色固体，1H NMR(400MHz,DMSO)δ8.34(s,1H),7.40(s,4H),5.01(s,1H),3.84–3.60(m,6H),3.54–3.40(m,2H).13C NMR(101MHz,DMSO)δ167.36(s),158.85(s),157.06(s),155.18(s),146.69(s),134.41(s),130.72(2C),129.65(2C),119.11(s),101.67(s),53.54(s),49.18(s),48.97(s),46.00(s),44.81(s),42.23(s).
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(二甲氨基)乙酮(Y18)
白色固体，1H NMR(400MHz,DMSO-d6)δ14.01(s,1H),8.34(s,1H),7.45(s,4H),4.72(s,1H),3.89-3.85(m,1H),3.78–3.59(m,6H),3.57–3.47(m,1H),2.24(s,6H).13C NMR(101MHz,DMSO-d6)δ168.97(s),158.83(s),157.06(s),155.18(s),140.22(s),133.10(s),131.42(2C),128.85(2C),119.16(s),101.61(s),68.46(s),52.49(s),49.26(s),45.18(s),42.77(s),41.82(s).
实施例2：
化合物对AKT1激酶抑制活性、PC-3细胞的抗增殖活性的测定实验
将实例1中制备的目标化合物Y1至Y18按以下方法进行生物活性测定，结果见表1中。
化合物对AKT1激酶抑制活性、PC-3细胞的抗增殖活性采用文献报道的方法进行，具体参见：LIu Y,Yin Y,Zhang J,NomIe K,Zhang L,Yang D,Wang ML,ZhaoG.2016.DIscovery of 4-(PIperazIn-1-yl)-7H-pyrrolo[2,3-d]pyrImIdIneDerIvatIves as Akt InhIbItors.Arch Pharm(WeInheIm)349:356-362.LIu Y,Yin Y,Zhang Z,LI C.J,Zhang H,Zhang D,JIang C,NomIe K,Zhang L,Wang M.L,ZhaoG.2017.Structural optImIzatIon elaborates novel potent Akt InhIbItors wIthpromIsIng antIcancer actIvIty.Eur J Med Chem 138:543-551.
表1.目标化合物Y1至Y18对AKT1激酶抑制活性和PC-3细胞抗增殖活性
a化合物对AKT1激酶的半数抑制浓度(IC50)
bND＝not detected
实验结果表明，大部分化合物在1μM浓度下对AKT1激酶具有一定的抑制活性，其中，化合物Y10和Y16对AKT1激酶显示出最强的抑制活分别为94.3％和99.7％，它们对AKT1激酶的半数抑制浓度为31.8nM和23.5nM。Y10和Y16对前列腺癌PC-3细胞的生长抑制活性的半数抑制浓度11.5μM和6.4μM，因此，本发明的化合物可以作为靶向AKT1的抗前列腺癌的药物。
以上所述，仅是本发明的较佳实施例，并非对本发明做任何形式上的限制，凡是依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化，均落入本发明的保护范围之内。
Claims (10)
1.一种含哌嗪的吡唑并嘧啶类化合物或其药用盐，其特征在于，具有如下通式Y：
其中，R1为氢、单卤素取代、双卤素取代、甲氧基或烷烃；R2为氢、氯或溴；R3为氢、氨基、取代氨基、取代哌啶或取代哌嗪基。
2.根据权利要求1所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐，其特征在于，所述通式Y中，R1为氢、4-氯、4-溴、4-氟或2,4-二氯；R2为氢、氯或溴；R3为氢、氨基、二甲氨基、N-甲基哌嗪、4-羟基哌啶或乙酰基哌嗪。
3.根据权利要求1所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐，其特征在于，所述通式Y是下列化合物之一：
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(4-甲基哌嗪-1-基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-苯基乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(4-甲基哌嗪-1-基)乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-氨基乙酮、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-2-(二甲氨基)乙酮。
4.一种如权利要求1至3任一项所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐的制备方法，其特征在于，以3-取代-1H-吡唑并[3,4-d]嘧啶为起始原料，在微波催化下与1-叔丁氧羰基-哌嗪发生亲核取代得中间体2，在酸性条件下脱去Boc保护基得到中间体3，中间体3与取代苯乙酸进行酰胺缩合，得目标产物Y。
5.根据权利要求4所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐的制备方法，其特征在于，包括如下步骤：
1)中间体2的制备：
将3-取代-1H-吡唑并[3,4-d]嘧啶加入到DMF中，依次加入DIEA、1-叔丁氧羰基哌嗪，微波加热至85～95℃，反应20～30min，将反应液倒入冰水中，析出大量固体，乙酸乙酯萃取，有机相依次采用饱和氯化胺、饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，用石油醚/乙酸乙酯柱层析纯化，得中间体2；
2)中间体3的合成:
将中间体2溶剂于THF中，加入浓盐酸，室温反应4～5h，过滤得中间体3；
3)目标化合物Y制备：
将取代苯乙酸溶解在DMF中，依次加入HBTU、DIEA，室温搅拌15～20min，加入中间体3，室温反应，将反应液倒入冰水中，析出大量固体，乙酸乙酯萃取，合并有机相，依次采用饱和氯化铵、饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，减压蒸除溶剂得粗品，采用二氯甲烷/甲醇柱层析纯化得目标产物Y。
6.根据权利要求5所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐的制备方法，其特征在于，步骤1)中，所述3-取代-1H-吡唑并[3,4-d]嘧啶、DIEA和1-叔丁氧羰基哌嗪的摩尔比为1：1.3：1.1。
7.根据权利要求5所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐的制备方法，其特征在于，步骤2)中，所述THF和浓HCl的体积比3：1。
8.根据权利要求5所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐的制备方法，其特征在于，步骤3)中，所述中间体3、DIEA、HBTU和取代苯乙酸的摩尔比为1：1.5：1.05：1。
9.权利要求1至3任一项所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的含哌嗪的吡唑并嘧啶类化合物或其药用盐的制备方法，其特征在于，所述抗肿瘤药物是靶向AKT1的抗前列腺癌和淋巴瘤的药物。
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| CN117122602A (zh) * | 2023-09-26 | 2023-11-28 | 赣南创新与转化医学研究院 | 化合物在制备治疗和/或预防脂肪肝病及相关疾病的药物中的用途 |
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