CN113480536B - 螺环哌啶酮类衍生物 - Google Patents
螺环哌啶酮类衍生物 Download PDFInfo
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- CN113480536B CN113480536B CN202110431920.9A CN202110431920A CN113480536B CN 113480536 B CN113480536 B CN 113480536B CN 202110431920 A CN202110431920 A CN 202110431920A CN 113480536 B CN113480536 B CN 113480536B
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Abstract
本发明涉及医药技术领域,具体涉及螺环哌啶酮类衍生物:
Description
技术领域
本发明涉及医药技术领域,具体涉及一类具有抗肿瘤活性的 KRAS-PDEδ蛋白蛋白相互作用(PPIs)抑制剂及其药学上可接受的 盐类,以及制备方法,以及化合物抗肿瘤活性,可用于治疗KRAS依 赖型的相关癌症。
背景技术
胰腺癌恶性程度极高,早期病程难以发现,是全球致死率最高 的实体瘤之一。KRAS基因的突变对胰腺癌的发生发展有重要的影 响。然而靶向KRAS蛋白的药物研发进展缓慢,先后有多种靶向 KRAS的药物在临床试验阶段失败。近期,KRASG12C共价结合抑制 剂显示了优秀的治疗效果,但是KRAS基因在胰腺癌细胞系中主要 的突变形式为KRASG12D,因此并没有给胰腺癌的治疗带来变革。
KRAS-PDEδ蛋白-蛋白相互作用是靶向KRAS蛋白的新靶点, 对KRAS依赖的肿瘤株有效,有望为胰腺癌提供新的治疗策略。小分 子抑制剂通过阻断两者的相互作用,抑制PDEδ蛋白对KRAS蛋白的 转运,干扰KRAS在细胞膜上的正确定位,从而实现对KRAS信号 通路的阻断。然而,现有的KRAS-PDEδ小分子抑制剂存在代谢和选 择性等问题,因此需要进一步筛选发现全新结构类型的小分子抑制 剂,丰富抑制剂的结构类型,从而发现体内活性好,成药性佳的全新 小分子抑制剂。
发明内容
1.要解决的技术问题
本发明的目的是为了解决现有技术中的问题,而提出的螺环哌啶 酮类衍生物。
2.技术方案
为了实现上述目的,本发明采用了如下技术方案:
螺环哌啶酮类衍生物,
优选地,其中X是苯环、脂肪环或氢原子。
优选地,其中R1表示:甲基、乙基、丙基、异丙基、正丁基、 异丁基、叔丁基、正戊基、异戊基、叔戊基或正己基;三氟甲基、三 氟甲氧基、甲氧基、乙氧基、丙氧基、异丙氧基或丁氧基;氢、腈基、 低级卤代烷基、低级烷基、低级羟基烷基、低级烷氧基、低级烷基氨基、低级卤代烷基氨基、低级环烷基氨基、低级链炔基氨基、酰胺基、 低级环烷基酰胺基、低级酰胺基烷基、苯基或取代苯基、苄基或取代 苄基。
优选地,R2表示:各类饱和烷基,包括但不限于甲基、乙基、丙 基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基或 正己基、环丙基及取代环丙基、环丁基及取代环丁基、环戊基及取代 环戊基、环己基及取代环己基;优选为环丙甲基;氢、低级烷基、低级卤代烷基、低级羟基烷基、苯环或取代苯环、苄基或取代苄基。
优选地,所述的“低级”是指含1至6个碳原子的直链或支链饱和 脂肪烃基团;所述的环烷基是指含3至7个碳的环。
优选地,上述通式的化合物药学上可接受的盐类是有机酸盐或无 机酸盐。所述的无机酸包括(但不限于)盐酸、硫酸、磷酸、二磷酸、 氢溴酸或硝酸等;所述的有机酸包括(但不限于)乙酸、马来酸、富 马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸或草酸等。
本发明还提供了上述化合物的制备方法,该方法如下;
Scheme 1
Reagent and conditions:(a)AcOH,rt,2.5h;(b)98%H2SO4,rt.,18h; (c)DMF-DMA,MeOH,55℃,16h;(d)NaBH4,MeOH,rt.,2h;(e)H2, 20%Pd(OH))2,MeOH,rt.,overnight;(f)4-Chlorobutyryl chloride,TEA, DCM,rt.,2h;(g)18,TEA,KI,Acetonitrile,90℃,24h.
Scheme 2
Reagents and conditions:(h)MgSO4,NaBH4,MeOH,rt.,overnight;(i)γ-butyro- lactone,trimethylaluminum,toluene,80℃,12h;(j)DMP,DCM,rt.,2h;(k)18,MgSO4,NaBH4,MeOH,rt.,overnight.
具体步骤
化合物23系列的制备
A.化合物14的制备
苯胺、1-苄基哌啶-4-酮、三甲基硅乙腈置于冰醋酸中常温反应4 小时,得目标中间体。
B.化合物15的制备
中间体14在浓硫酸中常温反应18小时,经氨水淬灭后得目标产 物。
C.化合物16系列的制备
以甲醇做溶剂,将化合物15、DMA在55℃下反应16小时得目 标产物。
D.化合物17-18系列的制备
以甲醇做溶剂,用NaBH4常温下还原化合物16反应2小时得中间 体17,在20%Pd(OH)2和氢气催化下脱去苄基得目标产物。
化合物23系列的制备
A.化合物22a-22e制备
不同的伯胺和4-氯丁酰氯反应,以三乙胺为缚酸剂,二氯甲烷为 溶剂,常温下反应得化合物22a-22e。
B.化合物23a-23e制备
以乙腈为溶剂,将中间体22a、18和碘化钾在90℃油浴中回流反 应。2小时后再次加入22a,并继续反应24小时得目标产物。
化合物G系列的制备
以取代的醛31和苯胺通过还原氨化反应制得仲胺中间体33,随后 33与丁内酯反应得到伯醇中间体34,经戴斯马丁试剂氧化得到化 合物35,最后,中间体35和18经还原氨化反应制得36系列化合 物。
本发明的化合物可进一步制备药学上可接受的盐。
本发明的化合物可通过手性柱拆分的方法制备d-型或l-型异构体。
本发明的第三方面,是提供了上述一类螺环哌啶酮衍生物,包括 消旋体、d-型或l-型异构体、及其在药学上可接受的盐在KRAS-PDEδ 蛋白蛋白相互作用抑制剂方面的应用。将目标产物进行PDEδ蛋白亲 和力的测试。测试方法采用荧光偏振法。具体实验方法和实验结果 参照实施例X。
本发明还提供了上述的一类螺环哌啶酮衍生物,包括其消旋体、 d-型或l-型异构体,及其药学上可接受的盐在制备抗肿瘤药物中的应 用。
所述的肿瘤为KRAS依赖型肿瘤珠,如胰腺癌等。
(1)对本发明的化合物进行了肿瘤细胞增殖抑制试验,试验方 法采用常规的CCK8法,细胞株选用MiaPaCa-2(人胰腺导管癌细胞)。 培养液为DMEM+10%FBS+2.5%HS+双抗。以上实验结果表明,本发明的化合物具有良好的抗肿瘤活性,部分化合物的抗肿瘤活性优于阳 性药,同时表现出KRAS依赖型肿瘤珠的选择性。因此本发明化合物及其盐类可以用于制备抗肿瘤药物。
附图说明
图1为化合物36l在小鼠胰腺癌PDX模型中的体内药效结果。
具体实施方式
现结合实施例和附图,对本发明作详细描述,但本发明的实施不 仅限于此。本发明所用试剂和原料均市售可得或可按文献方法制备。
下列实施例中未注明具体条件的实验方法,通常按照常规条件, 或按照制造厂商所建议的条件。
以下实施例所涉化合物对应通式Ⅰ的化学结构式、1H-NMR和MS 数据详见表1。
表1:本发明部分优选化合物的1H-NMR和MS数据
实施例1:1-苄基-4-(苯氨基)哌啶-4-腈(14)
称取化合物11(3.0g,15.8mmol)和12(1.48g,15.8mmol)溶 于20mL冰醋酸,而后转移至冰浴,冷却后缓慢滴加化合物13(4.7 g,47.4mmol)。加入完毕转移至常温反应。4小时后反应结束,加入 2N NaOH溶液淬灭反应,并调节pH至10。而后DCM萃取(30 mL×3),合并有机相并用饱和食盐水洗涤后旋干并用***打浆得产 物。白色固体,2.8g,收率60.9%。
实施例2:1-苄基-4-(苯氨基)哌啶-4-羧酰胺(15)
称取化合物14(2.8g,9.6mmol)溶于14mL浓硫酸,而后常温反应。18小 时后反应结束,将反应液逐滴加入冰浴的25%氨水溶液80mL,加入完毕调节pH 至10以上。过滤,保留固体并烘干,而后甲醇打浆得产物。白色固体,2.2g, 收率94.2%。
实施例3:1-苄基-4-(苯氨基)哌啶-4-羧酰胺(16)
称取化合物15(2.16g,7mmol)溶于15mL甲醇,超声助溶后转移至55℃下 搅拌,缓慢滴加DMA(2.5g,21mmol),之后继续在55℃下反应。16小时停 止反应并旋干反应液,粗品用***打浆得产物。白色固体,1.53g,收率68.6%。
实施例4:1-苯基-1,3,8-三氮螺环[4.5]癸-4-酮(18)
称取化合物16(1.5g,4.76mmol)溶于25mL甲醇,超声助溶后转移至冰 浴下搅拌,缓慢加入NaBH4(0.23g,5.95mmol),之后在常温下反应。4小时停 止反应并加水1mL淬灭反应。旋干反应液,粗品用DCM 50mL溶解并用水(20 mL×2)洗涤。保留有机相,减压除去溶剂得17。化合物17用30mL甲醇溶解, 滴加少量甲酸,加入20%Pd(OH)2(0.3g,20%)并在氢气保护下常温反应。48 小时后停止反应并用硅藻土过滤,保留滤液,加入硅胶拌样并用柱层析纯化 (DCM:MeOH=100:7,含0.1%TEA)。白色固体,0.65g,收率59.1%。
实施例5:4-氯-N-苯基丁酰胺(22a)
将原料苯胺21a(470mg,1eq,5mmol)、TEA(850mg,1.2eq,6mmol)溶 于20mL DCM,冰水浴下逐滴加入4-氯丁酰氯(1.01g,2eq,10mmol),之后常 温反应。2小时后加水淬灭并用饱和Na2CO3溶液洗涤,保留有机相并旋干得粗 品。快速柱色谱纯化(PE:EA=75:25)得产物。化合物22b-22e合成参考中间 体22a的合成方法。
实施例6:4-(4-氧-1-苯基-1,3,8-三氮杂螺[4.5]癸-8基)-N-苯基丁酰胺(23a)
将中间体22a(400mg,2eq,2mmol)、18(230mg,1eq,1mmol)和碘化钾 (17mg,0.1eq,0.1mmol)溶于10mL乙腈,而反应瓶置于90℃油浴中回流反 应。2小时后再次加入22a(200mg,1eq,1mmol)并继续反应24小时。反应结 束后,将反应液倒入清水20mL并加入乙酸乙酯(30mL×3)萃取。合并有机 相,饱和NaCl溶液洗涤后并旋干得粗品。快速柱色谱纯化(DCM:MeOH= 100:7)得目标产物。化合物23b-23e合成参考中间体22a的合成方法。
实施例7:N-(2-氟苄基)-4-羟基-N-苯基丁酰胺(34a)
将仲胺33a(600mg,1eq,3mmol)溶于干燥的甲苯10mL,而后体系密闭 并用氮气保护。冰浴下缓慢加入三甲基铝的甲苯溶液(2M in toluene,2eq,3 mL),加入完毕在常温下活化2小时。取γ-丁内酯(510mg,2eq,6mmol)加入 上述反应体系并将反应瓶转移至65℃反应24小时。反应结束后,转移至冰浴 并加入甲醇、饱和酒石酸钾钠溶液淬灭反应。反应体系缓慢倒入乙酸乙酯溶液, 有机相依次用清水、饱和食盐水洗涤。保留有机相,旋干得粗品。快速柱色谱纯化(PE:EA=40:60~0:100)得中间体34a。34b-34o均按此法制得。
实施例8:N-(2-氟苄基)-4-氧代-N-苯基丁酰胺(35a)
取伯醇34a(145mg,1eq,0.5mmol)溶于干燥的DCM 15mL,冰浴下缓慢 加入戴斯马丁试剂(425mg,2eq,1mmol),加入完毕转移至常温下反应1小时。 反应结束后,加入饱和硫代硫酸钠溶液和饱和Na2CO3溶液淬灭反应。水相用 DCM(10mL×3)洗涤。合并有机相并旋干得粗品。快速柱色谱纯化(PE:EA =75:25)得中间体35a。35b-35o的制备参照35a的合成路线。
实施例9:N-(2-氟苄基)-4-(4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸-8基)-N-苯基 丁酰胺(36a)
取中间体35a(142mg,1eq,0.5mmol)、18(115mg,1eq,0.5mmol)和无 水MgSO4(300mg,2.5mmol)置于25mL圆底烧瓶,加入甲醇10mL溶解并在 常温反应过夜。冰浴下缓慢加入NaBH4(12mg,0.3mmol),而后转移至常温反 应2小时。反应结束,加入清水淬灭反应并用硅藻土过滤。旋干滤液得产物粗 品。C18快速柱色谱纯化(H2O(0.1%TFA):MeOH=40:60~80:20)得目标产物。 终产物36b-36o参照36a的合成方法制备纯化。
实施例10:本发明化合物荧光偏振法测定KRAS-PDEδ蛋白结合抑 制活性
实验材料:
阿托伐他汀荧光探针(Atrovastatin-PEG3-FITC),缓冲液(0.1 M PBS,0.05%chaps,0.5%DMSO),PDEδ蛋白,黑色96孔板
1.FITC探针与PDEδ蛋白的结合常数测定
a.取黑色96孔板1块,平衡至室温;
b.用缓冲液将阿托伐他汀荧光探针稀释至100nM;
c.用缓冲液稀释PDEδ蛋白,蛋白浓度依次为1000nM、500nM、 250nM、125nM、62.5nM、31.25nM、15.63nM、7.81nM、3.90 nM、1.85nM;
d.三复孔测量,在96孔板中1-10孔依次加入配好的PDEδ蛋白 溶液50uL,1-11孔中加入稀释的探针溶液50uL(11孔为空白对照,) 用缓冲液补充每孔溶液体积至200uL,加毕30℃下避光孵育2小时;
e.用Biotek Synergy H2酶标仪读取荧光各向异性值(激发波长: 485,检测波长535),探针与PDEδ蛋白的结合常数根据荧光各向异 性值的非线性回归拟合得到Mathamatica 9(Wolfram Research Inc.),公式如下:
公式中,F为荧光探针(Atrovastatin-PEG3-FITC)结合比例,A 为荧光偏振各向异性测量值,Q值是指探针与浓度最高组蛋白结合的 荧光强度同自由状态的荧光强度的比值,AB值为结合状态下的探针 各向异性值,AF值为自由状态下的探针的各向异性值,LST为荧光探 针浓度,Rt为蛋白浓度,KD1为FITC探针的蛋白结合常数。
根据曲线确定测量化合物结合常数时选定的蛋白浓度为160 nM,探针浓度为100nM
2.化合物与PDEδ蛋白的结合常数测定
a.取黑色96孔板1块,平衡至室温;
b.用缓冲液分别将阿托伐他汀荧光探针和PDEδ蛋白稀释至100 nM和160nM;
c.用DMSO溶解化合物,并用含0.2%Tween-80的缓冲液稀释化 合物浓度依次为10uM、5uM、2.5uM、1.25uM、0.625uM、312.5 nM、156.3nM、78.12nM、39.1nM、19.5nM;
d.三复孔测量,在96孔板中1-1孔依次加入PDEδ蛋白溶液50 uL,1-12孔中加入FITC探针溶液50uL,1-10孔分别加入配好的化 合物溶液100uL,其余孔用缓冲液补充每孔溶液体积至200uL,加 毕30℃下避光孵育10小时;
e.用Biotek Synergy H2酶标仪读取荧光各向异性值(激发波长: 485,检测波长535),化合物与蛋白的结合常数根据荧光各向异性 值的非线性回归拟合得到Mathamatica9(Wolfram Research Inc.),公 式如下:
d=KD1+KD2+LST+LT-RT;
e=(LT-RT)×KD1+(LST-RT)×KD2+KD1×KD2;
f=-KD1×KD2×RT;
公式中,F为荧光探针(Atrovastatin-PEG3-FITC)结合比例,A 为荧光偏振各向异性测量值,Q值是指探针与浓度最高组蛋白结合的 荧光强度同自由状态的荧光强度的比值,AB值为结合状态下的探针 各向异性值,AF值为自由状态下的探针的各向异性值,LST为荧光探 针浓度,Rt为蛋白浓度,KD1为FITC探针的蛋白结合常数,KD2为 化合物的蛋白结合抑制常数。
实施例11:本发明化合物体外抗肿瘤活性测试:
1、试验细胞株
Mia PaCa-2(人胰腺癌细胞),购自中科院上海生化细胞所。
培养液为DMEM+10%FBS+2.5%HS+双抗。
2、仪器
5%CO2培养箱、96孔板(WHB)、Biotek Synergy H2酶标仪
3、试验方法
受试化合物样品液配制:用DMSO(Merck)溶解后,加入含FBS 的培养基溶液配成100μM的溶液或均匀的混悬液,然后用 0.1%DMSO的培养基稀释,最终浓度分别为100μM、33.3μM、11.1 μM、3.70μM、1.23μM、0.41μM。
将文献报道的KRAS-PDEδ抑制剂Deltazinone(DZ)以同样的条 件配成对照品溶液。
本实验方法采用的是CCK8法。为96孔板每孔加入浓度为7×104个/mL的细胞悬液100μL,即5000个细胞/孔,置37℃、5%CO2培 养箱内。24小时后,去除上层培养液,分别加入受试化合物样品液 和对照品液,100μL孔,37℃作用72小时。每孔加入10mg/mL的 CCK8(2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑 单钠盐)溶液10μL,作用2小时后用酶标仪测570nm OD值,计算半数抑制浓度IC50。
抑制率=(空白对照孔OD值-给药孔OD值)/空白对照孔OD值 ×100%。根据各个浓度的IC%值,用GraphPad软件进行非线性回归, 算出各化合物抑制50%细胞生长的浓度,即IC50。
化合物的抗肿瘤活性详见下表,其中,样品是指相应实施例中制 备的二氢喹唑啉酮类化合物。
阳性药选取文献报道的KRAS-PDEδ抑制剂Deltazinone(DZ)作 为对照。
体外抗肿瘤实验结果显示,大部分化合物表现对KRAS依赖型肿 瘤株有较强的抑制活性特点,部分发明的化合物结果优于对照药 Deltazinone。
实施例12:本发明化合物在裸鼠胰腺癌PDX模型中显著抑制肿瘤生 长:
利用胰腺癌的PDX模型进一步评价36l的体内药效。基于此,首 先筛选敏感临床原代细胞系。选择4种不同的原代胰腺癌细胞株进 行筛选,分别为0001、0037、0034和0043。以CCK8法分别测定细胞在不同浓度的36l作用后生长曲线。化合物36l能够呈浓度依赖地 抑制原代细胞的生长,且对0001、0037及0034的抑制作用较0043 细胞株更为敏感。相比之下,阳性对照2对4株细胞系均没有显著的 抑制活性
根据原代细胞的体外抗肿瘤活性结果,选择敏感细胞株0034进行 PDX模型的构建。在肿瘤体积至100mm3左右开始给药。化合物36l 按照50mg/kg的剂量,腹腔给药,一天给药一次。鉴于化合物2体 内代谢稳定性差,阳性对照选择胰腺癌的一线药物吉西他滨,按10mg/kg的剂量尾静脉给药,每三天给药一次。实验结果(图1中的A-C) 表明,化合物36l显著抑制PDX肿瘤的生长,其抑瘤率达到57.3%。 从肿瘤重量和体积变化来看,药物组和空白组有显著的差异(P<0.05。)尽管化合物36l的抑瘤率不如吉西他滨,但36l是现有的KRAS- PDEδ抑制剂中抑瘤率最高的,而且也是在胰腺癌PDX模型中唯一有 效的KRAS-PDEδ抑制剂。这个结果进一步验证KRAS-PDEδ相互作 用的成药潜力,对发掘KRAS-PDEδ抑制剂的临床应用具有十分重要 的意义。
为进一步验证药物对肿瘤组织的作用,将体内实验的PDX肿瘤 制成组织切片,并进行染色分析。首先用苏木素-伊红染色 (hematoxylin and eosin stain,H&E stain)来评价肿瘤组织的病理学变 化。如图1所示,36l组与和空白组相比,肿瘤组织中有明显的透明质变增多的现象,证明化合物36l在体内诱导肿瘤细胞的老化和死亡。 进一步用Ki-67免疫组化染色检测肿瘤组织中增殖细胞的数量,以评 价不同组肿瘤增殖能力的强弱。结果显示(图1中的D-E),36l的用药组 的肿瘤切片中能够明显增殖细胞数量的减少,而吉西他滨组的肿瘤切 片也能观察到同样的抑制作用。组织切片染色结果进一步证明化合物36l能够在体内显著抑制胰腺癌的增殖。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并 不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范 围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都 应涵盖在本发明的保护范围之内。
Claims (2)
1.螺环哌啶酮类衍生物,其特征在于,
其中X是苯环,其中R1表示:氢或苯,R2表示:环丙基、环丁基、环戊基、环己基、苯环或苄基。
2.螺环哌啶酮类衍生物,其特征在于,衍生物为
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