CN104803925A - 一类以 fgfr 为靶点的 2,4,5-三取代嘧啶类化合物及其制备方法和用途 - Google Patents
一类以 fgfr 为靶点的 2,4,5-三取代嘧啶类化合物及其制备方法和用途 Download PDFInfo
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- CN104803925A CN104803925A CN201510180883.3A CN201510180883A CN104803925A CN 104803925 A CN104803925 A CN 104803925A CN 201510180883 A CN201510180883 A CN 201510180883A CN 104803925 A CN104803925 A CN 104803925A
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Classifications
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明属于药物化学领域,具体涉及一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物及其制备方法和用途,该化合物可以选择性地抑制FGFR激酶的磷酸化从而用于治疗与此激酶密切联系的恶性肿瘤,同时能减少不良反应;能够用于治疗FGFR激酶相关的肿瘤或相关的疾病。2,4,5-三取代嘧啶类化合物的通式为:其中:以上R1、R2、R3可以多种取代基选择,R1、R2、R3取代基可以任意组合。本发明所述的以FGFR为靶点的2,4,5-三取代嘧啶类化合物对FGFR1激酶具有良好的抑制作用和对FGFR1依赖性肿瘤细胞株KG1细胞具有抗增殖作用;可用于制备抗肿瘤药物,且抗肿瘤效果较好。
Description
技术领域
本发明属于药物化学领域,具体涉及一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物及其制备方法和用途。
背景技术
在蛋白激酶这个领域,成纤维细胞生长因子受体FGFR家族是一个非常有吸引力的靶点在肿瘤治疗中。受体酪氨酸激酶的FGFR家族包括四个成员,分别是FGFR1,FGFR2,FGFR3和FGFR4。它们具有高度相似的序列同源性。FGFR激酶的失调与多种恶性肿瘤密切相关,如乳腺癌、膀胱癌、胃癌、***癌、直肠癌等多种癌症,因此肿瘤医学不断对其研究和对癌症的诊断和治疗。
抑制与疾病相关的蛋白激酶,阻断并破坏肿瘤细胞的信号传递,可通过多种方法来实现,但由于合成的反义寡核苷酸易受核酶的攻击而降解,RNA干扰技术存在安全性、稳定性和脱靶效应等问题,因此新药研发人员尝试从有机合成小分子中筛选FGFR的化学小分子抑制剂。迄今为止,已有多个小分子抑制剂进入临床试验阶段,如NVP-BGJ398,
BIBF-1120,TKI-258,BMS-582664,AZD-2171,AB-1010,TSU-68,AP-24534和E-7080。
目前研究最快的药物是NVP-BGJ398,其作为高选择性的FGFR抑制剂,用于治疗固体恶性肿瘤,正处于临床I期研究中。市场上尚未有以嘧啶为母核的FGFR抑制剂,故亟待研制出以嘧啶为母核的FGFR抑制剂。
发明内容
本发明的目的之一是为解决上述技术问题,提供一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物及其制备方法和用途,该化合物可以选择性地抑制FGFR激酶的磷酸化从而用于治疗与此激酶密切联系的恶性肿瘤同时能减少不良反应;能够用于治疗FGFR激酶相关的肿瘤或相关的疾病。
为实现上述技术效果,本发明的技术方案为:
一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物,具有下列通式:
其中:R1可以选自下列任一取代基团:
R2可以选自下列任一取代基团:
R3可以选自Cl或NO2中的任意一种;
以上R1、R2、R3中的取代基可以任意组合。
一种制备上述的一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的方法,包括如下步骤:
步骤一:称取2,4-二氯-5-硝基嘧啶,N,N-二异丙基乙胺和R1-NH2于烧瓶中,搅拌下加二氯甲烷使其溶解,室温反应5h,反应完毕后,加入饱和食盐水,混合物用二氯甲烷萃取,浓缩,得到红色固体粉末状的2-R1-氨-4-氯-5-硝基嘧啶。
步骤二:称取所述2-R1-氨-4-氯-5-硝基嘧啶和所述R2-NH2于烧瓶中,搅拌下加入仲丁醇使其溶解,回流2h,反应结束后,冷却至室温,加入碳酸氢钠中和,用乙酸乙酯萃取3次,浓缩,硅胶柱层析,洗脱剂为乙酸乙酯-甲醇,乙酸乙酯与甲醇的体积比为20∶1,得2-R1-氨-4-R2-氨-5-R3嘧啶。
其中,R3为硝基,R1和R2的定义与上述的定义相同,可有多种取代基选择。
进一步的,所述步骤一中每1g 2,4-二氯-5-硝基嘧啶用二氯甲烷20ml;物质的量之比:2,4-二氯-5-硝基嘧啶∶N,N-二异丙基乙胺∶R1-NH2=1∶1∶1。
进一步的,每500mg所述2-R1-氨-4-氯-5-硝基嘧啶用仲丁醇15-20ml,再将三氟乙酸滴入烧瓶中,物质的量之比:2-R1-氨-4-氯-5-R3嘧啶∶R2-NH2∶三氟乙酸为1∶1∶1。
一种制备上述的一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的方法,包括如下步骤:
步骤一:称取2,4,5-三氯嘧啶,无水碳酸钾和所述R1-NH2于烧瓶中,搅拌加入DMF使其溶解,每1g 2,4,5-三氯嘧啶用DMF 5-10ml,物质的量之比:2,4,5-三氯嘧啶∶无水碳酸钾∶R1-NH2=1∶2∶1,60℃反应2-3h,反应完毕后,冷却至室温,加入大量冰水,有固体析出,抽滤,干燥,得到2-R1-氨-4,5-二氯嘧啶;
步骤二:称取所述2-R1-氨-4-氯-5-二氯嘧啶和所述R2-NH2于烧瓶中,搅拌下加入所述仲丁醇使其溶解,每500mg所述2-R1-氨-4-氯-5-二氯嘧啶用仲丁醇20-30ml,再将三氟乙酸滴入烧瓶中,物质的量之比:2-R1-氨-4-氯-5-二氯嘧啶∶R2-NH2∶三氟乙酸=1∶1∶1,回流2h。反应结束后,冷却至室温,加入碳酸氢钠中和,用乙酸乙酯萃取3次,浓缩,硅胶柱层析,洗脱剂为乙酸乙酯-甲醇,乙酸乙酯与甲醇的体积比为20∶1,得2-R1-氨-4-R2-氨-5-R3嘧啶。
R3为氯,R1和R2的定义与上述的定义相同,可有多种取代基选择。
一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的用途,所述用途为制备抗肿瘤药物中的应用。
一种药物组合物,包括药用辅料和一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物。
含有一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的药物组合物,所述的药物组合物的制剂形式为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
本发明的有益效果包括:本发明所述的以FGFR为靶点的2,4,5-三取代嘧啶类化合物对FGFR1激酶具有良好的抑制作用和FGFR1依赖性肿瘤细胞株KG1细胞具有抗增殖作用。可用于制备抗肿瘤药物,且抗肿瘤效果较好。
具体实施方式
下文将结合具体实施例详细描述本发明。应当注意的是,下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的,它们可以被相互组合从而达到更好的技术效果。
实施例1 N-{4-{{2-{[4-甲基哌嗪-1-基]苯}胺}-5-硝基嘧啶-4-基}苯}乙酰胺(化合物1)的制备
(1)N-{4-[(2-氯-5-硝基嘧啶-4-基)胺]苯基}乙酰胺的制备
在冰浴的条件下,将2,4-二氯-5-硝基嘧啶(5g,25.7mmol)溶解于二氯甲烷(100ml)中,加N,N-二异丙基乙胺(4.3ml,25.7mmol)和对乙酰氨基苯胺(3.87g,25.7mmol)。撤掉冰浴,反应混合物在室温下反应5h,然后加入饱和食盐水(200ml)。混合物用二氯甲烷(300ml)萃取。有机层用无水硫酸镁进行干燥,浓缩得固体,产物不做进一步纯化,得到6.34g红色固体,收率90.0%。
(2)N-{4-{{2-{[4-甲基哌嗪-1-基]苯}胺}-5-硝基嘧啶-4-基}苯}乙酰胺(化合物1)的制备
称取N-{4-[(2-氯-5-硝基嘧啶-4-基)胺]苯基}乙酰胺(1g,3.25mmol),4-甲基哌嗪苯胺(746.0mg,3.90mmol)和三氟乙酸(0.25ml,3.25mmol)溶于仲丁醇(20ml),加毕100℃反应6h。冷却,减压浓缩体系,得到的油状物倒入冰水中,加入碳酸氢钠中和至中性,乙酸乙酯萃取,干燥,浓缩有机相得到粗品,柱层析(乙酸乙酯∶甲醇=20∶1)得到红色固体状产物2.78g,收率61.7%。
实施例2 N-{4-{{5-氯-2-{[4-(4-甲基哌嗪-1-基)苯]胺基}嘧啶-4-基}胺}苯基}乙酰胺(化合物2)的制备
(1)N-{4-[(2,5-二氯嘧啶-4-基)胺]苯基}乙酰胺的制备
称取对乙酰氨基苯胺(1.31g,8.72mmol)溶解于DMF(20ml),再加入无水碳酸钾(2.42g,17.5mmol)和2,4,5-三氯嘧啶(1.0ml,8.72mmol)。反应混合物加热到60℃反应2h。反应完毕后,冷却到室温,加入大量冰水,析出固体,抽滤,干燥,产物不做进一步纯化,得到2.3g,收率90%。
(2)N-{4-{{5-氯-2-{[4-(4-甲基哌嗪-1-基)苯]胺基}嘧啶-4-基}胺}苯基}乙酰胺的制备
称取N-{4-[(2,5-二氯嘧啶-4-基)胺]苯基}乙酰胺(1.6g,5.45mmol),4-甲基哌嗪苯胺(1.24g,6.46mmol)和三氟乙酸(0.42ml,5.45mmol)溶于仲丁醇(30ml),加热至100℃反应6h。冷却,减压浓缩体系,得到的油状物倒入冰水中,加入碳酸氢钠中和至中性,乙酸乙酯萃取,干燥,浓缩有机相得到粗品,柱层析(乙酸乙酯∶甲醇=20∶1)得到白色固体状产物1.47g,收率60.3%。
按实施例1或2任意一种方法,用2,4-二氯-5-硝基嘧啶或2,4,5-三氯嘧啶及不同的取代形式的苯胺为原料,合成了表1所列的以FGFR为靶点的2,4,5-三取代嘧啶类化合物1~26。
表1通式I中以FGFR为靶点的2,4,5-三取代嘧啶类化合物中各R基团
注:初始原料均购于aladdin公司。
实施例3 化合物对FGFR激酶活性的测定
通过LANCE ULTRA Assay方法测定化合物对FGFR1的抑制活性,并与阳性对照药比较,筛选出活性好的化合物。FGFR1为CARNA公司购买。
具体方法:所测试的化合物、ATP、特异性底物以及FGFR1激酶用激酶稀释液稀释。激酶反应混合物中含FGFR1、ATP、底物、HEPES(PH=7.5)、MgCl2、EGTA、Tween-20。不 加任何化合物组作100%磷酸化对照,加入FGFR1激酶后马上加EDTA终止反应组作为0%磷酸化对照。激酶反应混合物室温下共孵育1h后,加EDTA终止反应5分钟。再加入特异性抗体,室温下继续共孵育1h,用PerkinElmer Envision激酶仪检测激发光。根据激酶仪检测所得信号值,用公式计算得抑制率或者GraphPad计算受试化合物IC50值。
实施例4 化合物对KG1细胞抑制率的测定
化合物对KG1细胞的增殖抑制作用以CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下:处于对数生长期的KG1细胞按合适密度接种至96孔培养板中,每孔90μL,培养过夜后,加入不同浓度的化合物作用72h,并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后,化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测,每孔加入10μL CCK-8试剂,置于37℃培养箱中放置2-4h后,用全波长式微孔板酶标仪SpectraMax 190读数,测定波长为450nm。
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(%):
抑制率(%)=(OD对照孔-OD给药孔)/OD对照孔×100%
表2部分化合物的体外FGFR1激酶活性的测试结果
表3部分化合物体外FGFR1激酶活性已经对KG1细胞活性测试结果
(表中化合物代号对应于前面的化合物代号)
药理测试结果表明,本发明化合物15、16、17、18具有良好的FGFR1抑制活性,并且具有良好的抗肿瘤细胞活性,可用于预防或治疗与成纤维细胞生长因子受体激酶1抑制剂有关的临床疾病,这些疾病可以是:乳腺癌、膀胱癌、胃癌、***癌、直肠癌等多种癌症。
测定化合物代号为1~26的性状、产率、熔点、氢谱数据和质谱:
实施例5 N-{4-{{2-{[4-甲基哌嗪-1-基]苯}胺}-5-硝基嘧啶-4-基}苯}乙酰胺(1)的测定结果为:
红色粉末;产率61.7%;m.p:269.5-270.4℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.251(1H,s,-NH),10.206(1H,s,-NH),10.119(1H,s,-NH),8.998(1H,s,H-6),7.594(2H,d,J=8.4Hz,H-3″,H-5″),7.4 00(2H,d,J=8.4Hz,H-3′,H-5′),7.326(2H,d,J=9.0Hz,H-2″,H-6″),6.712(2H,d,J=9.0Hz,H-2′,H-6′),3.093(4H,s,-CH2N(aryl)CH2-),2.591(4H,s,-CH2N(CH3)CH2-),2.317(3H,s,-NCH3),2.063(3H,s,-NHCOCH3).13C NMR(600MHz,DMSO-d6):δ(ppm)168.77,159.18,157.73,155.08,147.33,137.25,132.37,130.52,126.12×2,121.94×2,119.50×2,115.48×2,54.43×2,48.01×2,45.26,24.12.ESI-MS m/z:463.1(M+H)+.
实施例6 N2-[4-(4-甲基哌嗪-1-基)苯]-N4-(4-***啉苯)-5-硝基嘧啶-2,4-二胺(2)测定结果为:
红色粉末;产率65.4%;m.p:253.4-255.6℃.1H NMR(600MHz,DMSO-d6):δ(ppm) 10.184(1H,s,-NH),10.168(1H,s,-NH),8.991(1H,s,H-6),7.335(2H,d,J=8.4Hz,H-2′,H-6′),7.312(2H,d,J=8.4Hz,H-2″,H-6″),6.974(2H,d,J=8.4Hz,H-2′,H-6′),6.702(2H,d,J=8.4Hz,H-3″,H-5″),3.128(8H,s,morpholine),3.098(3H,s,-NCH3),2.610(4H,s,-CH2N(aryl)CH2-),2.335(4H,s,-CH2N(CH3)CH2-).ESI-MS m/z:491.1(M+H)+.
实施例7 N2-[4-(4-甲基哌嗪-1-基)苯]-5-硝基-N4-[3-(三氟甲基)苯]嘧啶-2,4-二胺(3)的测定结果为:
红色粉末;产率71.2%;m.p:219.3-220.7℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.463(1H,s,-NH),10.303(1H,s,-NH),9.047(1H,s,H-6),7.914(1H,s,H-2″),7.823(1H,d,J=6.6Hz,H-6″),7.619(1H,t,J=7.2Hz,H-5″),7.613(1H,t,J=7.2Hz,H-4″),7.299(2H,d,J=9.0Hz,H-3′,H-5′),6.699(2H,d,J=9.0Hz,H-2′,H-6′),3.029(4H,s,-CH2N(aryl)CH2-),2.425(4H,s,-CH2N(CH3)CH2-),2.195(3H,s,-NCH3).ESI-MS m/z:474.2(M+H)+.
实施例8 N4-(9H-芴-2-基)-N2-[4-(4-甲基哌嗪-1-基)苯]-5-硝基嘧啶-2,4-二胺(4)的测定结果为:
棕色粉末;产率66.7%;m.p:248.9-250.4℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.487(1H,s,-NH),10.322(1H,s,-NH),9.066(1H,s,H-6),7.955(2H,d,J=7.8Hz,H-7″,H-8″),7.850(1H,s,H-2″),7.646(1H,d,J=7.2Hz,H-4″),7.476(1H,d,J=8.4Hz,H-9″),7.434(1H,t,J=7.8Hz,H-6″),7.354(1H,t,J=7.8Hz,H-5″),7.341(2H,d,J=8.4Hz,H-3′,H-5′),6.590(2H,d,J=8.4Hz,H-2′,H-6′),3.886(2H,s,-CH2-),3.443(4H,s,-CH2N(aryl)CH2-),2.793(4H,s,-CH2N(CH3)CH2-),2.515(3H,s,-NCH3).ESI-MS m/z:494.1(M+H)+.
实施例9 N4-(3-溴苯基)-N2-[4-(4-甲基哌嗪-1-基)苯基]-5-硝基嘧啶-2,4-二胺(5)的测定结果为:
红色粉末;产率69.8%;m.p:222.1-224.5℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.377(1H,s,-NH),10.319(1H,s,-NH),9.036(1H,s,H-6),7.877(1H,s,H-2′),7.482(1H,d,J=7.2Hz,H-6″),7.430(1H,d,J=7.8Hz,H-4″),7.369(2H,d,J=7.8Hz,H-3′,H-5′),7.335(1H,t,J=7.8Hz,H-5″),6.816(2H,d,J=9.0Hz,H-2′,H-6′),3.098(4H,s,-CH2N(aryl)CH2-),2.547(4H,s,-CH2N(CH3)CH2-),2.281(3H,s,-NCH3).ESI-MS m/z:474.9(M+H)+.
实施例10 N4-(1H-吲哚-5-基)-N2-[4-(4-甲基哌嗪-1-基)苯]-5-硝基嘧啶-2,4-二胺(6)的测定结果为:
黄色粉末;产率65.9%;m.p 269.8-271.5℃.1H NMR(600MHz,DMSO-d6):δ(ppm)11.288(1H,s,H-1″),10.362(1H,s,-NH),10.248(1H,s,-NH),9.041(1H,s,H-6),7.740(1H,s,H-4″),7.439(1H,d,J=9.0Hz,H-7″),7.370(1H,d,J=8.4Hz,H-2″),7.286(1H,d,J=9.0Hz,H-6″),7.142(1H,d,J=8.4Hz,H-3″),6.555(2H,d,J=8.4Hz,H-3′,H-5′),6.431(2H,d,J=8.4Hz,H-2′,H-6′),3.121(4H,t,J=7.8Hz,-CH2N(aryl)CH2-),3.019(4H,t,J=12Hz,-CH2N(CH3)CH2-),2.791(3H,s,-NCH3).ESI-MS m/z:445.1(M+H)+.
实施例11 N2-[4-(4-甲基哌嗪-1-基)苯基]-5-硝基-N4-(间甲苯基)嘧啶-2,4-二胺(7)的 测定结果为:
红色粉末;产率70.1%;m.p:218.3-219.8℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.318(1H,s,-NH),10.258(1H,s,-NH),9.021(1H,s,H-6),7.443(1H,d,J=9.6Hz,H-6″),7.384(2H,d,J=8.4Hz,H-3′,H-5′),7.297(1H,d,J=7.2Hz,H-4″),7.254(1H,t,J=7.8Hz,H-5″),7.053(1H,s,H-2″),6.760(2H,d,J=8.4Hz,H-2′,H-6′),3.058(4H,s,-CH2N(aryl)CH2-),2.444(4H,s,-CH2N(CH3)CH2-),2.250(3H,s,-NCH3),2.206(3H,s,-CH3).13C NMR(600MHz,DMSO-d6):δ(ppm)159.50,157.90,154.48,147.91,138.34,137.11,130.14,128.77,126.32,124.66,122.38×2,121.32,120.29,115.54×2,54.68×2,48.44×2,45.84.ESI-MS m/z:420.0(M-H)-.
实施例12 N4-(3,5-二甲氧基苯)-N2-[4-(4-甲基哌嗪-1-基)苯]-5-硝基嘧啶-2,4-二胺(8)的测定结果为:
棕色粉末;产率75.8%;m.p 188.1-190.5℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.304(1H,s,-NH),10.270(1H,s,-NH),9.029(1H,s,H-6),7.445(2H,d,J=9.0Hz,H-3′,H-5′),6.783(2H,d,J=8.4Hz,H-2″,H-6″),6.762(2H,d,J=8.4Hz,H-2′,H-6′),5.73(1H,s,H-4″),3.668(6H,s,3″-OCH3,5″-OCH3),3.070(4H,s,-CH2N(aryl)CH2-),2.487(4H,s,-CH2N(CH3)CH2-),2.250(3H,s,-NCH3).ESI-MS m/z:466.2(M+H)+.
实施例13 N2-[4-(4-甲基哌嗪-1-基)苯基]-5-硝基-N4-(3,4,5-三氟苯基)嘧啶-2,4-二胺(9)的测定结果为:
棕色粉末;产率80.7%;m.p 256.3-257.2℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.396(1H,s,-NH),10.375(1H,s,-NH),9.073(1H,s,H-6),7.680(2H,d,J=9.0Hz,H-2′,H-6′),7.340(2H,d,J=9.0Hz,H-3′,H-5′),6.847(2H,d,J=9.0Hz,H-2″,H-6″),3.109(4H,s,-CH2N(aryl)CH2-),2.497(4H,s,-CH2N(CH3)CH2-),2.269(3H,s,-NCH3).ESI-MS m/z:460.1(M+H)+.
实施例14 N4-(4-氟苄基)-N2-[4-(4-甲基哌嗪-1-基)苯]-5-硝基嘧啶-2,4-二胺(10)的测定结果为:
红色粉末;产率78.3%;m.p:221.7-223.5℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.285(1H,s,-NH),9.428(1H,s,-NH),8.967(1H,s,H-6),7.557(2H,d,J=7.8Hz,H-2″,H-6″),7.141(2H,d,J=9.0Hz,H-3″,H-5″),7.029(2H,d,J=9.0Hz,H-3′,H-5′),6.912(2H,d,J=7.8Hz,H-2′,H-6′),4.717(2H,s,-CH2-),3.477(4H,s,-CH2N(aryl)CH2-),3.126(4H,s,-CH2N(CH3)CH2-),2.785(3H,s,-NCH3).ESI-MS m/z:427.1(M+H)+.
实施例15 N-{4-{{2-{[4-(4-甲基哌嗪-1-基)苯]胺}-5-硝基嘧啶-4-基}胺}苯}丙烯酰胺(11)的测定结果为:
红色粉末;产率82.6%;m.p>320℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.571(1H,s,-NH),10.286(1H,s,-NH),10.254(1H,s,-NH),9.016(1H,s,H-6),7.770(2H,d,J=8.4Hz,H-3″,H-5″),7.430(2H,d,J=8.4Hz,H-3′,H-5′),7.331(2H,d,J=8.4Hz,H-2″,H-6″),6.698(2H,d,J=8.4Hz,H-2′,H-6′),6.586-6.541(1H,m,-CH=CH2),6.281(1H,d,J=16.8Hz,-CH=CH2), 6.149(1H,d,J=16.8Hz,-CH=CH2),3.034(4H,s,-CH2N(aryl)CH2-),2.408(4H,s,-CH2N(CH3)CH2-),2.206(3H,s,-CH3).ESI-MS m/z:475.1(M+H)+.
实施例16 (Z)-N-{4-{{2-{[4-(4-甲基哌嗪-1-基)苯]胺}-5-硝基嘧啶-4-基}胺}苯}-3-苯基丙烯酰胺(12)的测定结果为:
红色粉末;产率84.2%;m.p>320℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.375(1H,s,-NH),10.292(1H,s,-NH),10.229(1H,s,-NH),9.017(1H,s,H-6),7.781(1H,d,J=8.4Hz,-CH=CH-),7.684-7.618(5H,m,C-Ar-H),7.487-7.406(8H,m,A,B-H),7.295(1H,d,J=8.4Hz,-CH=CH-),2.998(4H,s,-CH2N(aryl)CH2-),2.325(4H,s,-CH2N(CH3)CH2-),2.027(3H,s,-CH3).ESI-MS m/z:551.3(M+H)+.
实施例17 4-氯-N-{4-{{2-{[4-(4-甲基哌嗪-1-基)苯]胺}-5-硝基嘧啶-4-基}胺}苯}苯甲酰胺(13)的测定结果为:
红色粉末;产率66.3%;m.p>320℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.444(1H,s,-NH),10.312(1H,s,-NH),10.249(1H,s,-NH),9.027(1H,s,H-6),8.038(2H,d,J=8.4Hz,H-2″′,H-6″′),7.830(2H,d,J=8.4Hz,H-3″′,H-5″′),7.658(2H,d,J=8.4Hz,H-3″,H-5″),7.468(2H,d,J=9.0Hz,H-3′,H-5′),7.337(2H,d,J=9.0Hz,H-2″,H-6″),6.715(2H,d,J=9.0Hz,H-2′,H-6′),2.992(4H,s,-CH2N(aryl)CH2-),2.285(4H,s,-CH2N(CH3)CH2-),2.150(3H,s,-NCH3).ESI-MSm/z:559.1(M)+.
实施例18 3-氯-N-{4-{{2-{[4-(甲基哌嗪-1-基)苯]胺}-5-硝基嘧啶-4-基}胺}苯}丙酰胺(14)的测定结果为:
红色粉末;产率74.2%;m.p 272.8-273.9℃.1H NMR(600MHz,DMSO-d6):δ(ppm)10.497(1H,s,-NH),10.298(1H,s,-NH),10.289(1H,s,-NH),9.032(1H,s,H-6),7.734(2H,d,J=8.4Hz,H-3″,H-5″),7.450(2H,d,J=8.4Hz,H-3′,H-5′),7.387(2H,d,J=9.0Hz,H-2″,H-6″),6.788(2H,d,J=9.0Hz,H-2′,H-6′),2.887(4H,s,-CH2N(aryl)CH2-),2.728(4H,s,-CH2N(CH3)CH2-),2.653(3H,s,-NCH3),2.499(4H,t,J=1.8Hz,-COCH2CH2Cl).ESI-MS m/z:511.0(M+H)+.
实施例19 N-{4-{{5-氯-2-{[4-(4-甲基哌嗪-1-基)苯]胺基}嘧啶-4-基}胺}苯基}乙酰胺(16)的测定结果为:
白色粉末;产率60.3%;m.p 250.9-252.7℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.028(1H,s,-NH),9.009(1H,s,-NH),8.683(1H,s,-NH),8.035(1H,s,H-6),7.545(4H,s,H-2″,H-6″,H-3′,H-5′),7.403(2H,d,J=7.8Hz,H-2′,H-6′),6.757(2H,d,J=7.8Hz,H-3″,H-5″),3.025(4H,s,CH2N(aryl)CH2-),2.454(4H,s,-CH2N(CH3)CH2-),2.222(3H,s,-NCH3),2.026(3H,s,-CH3).ESI-MS m/z:452.4(M+H)+.
实施例20 N-{2-氯-4-{{5-氯-2-[(4-(4-甲基哌嗪-1-基)苯)]胺}嘧啶-4-基}胺}苯}乙酰胺(17)的测定结果为:
白色粉末;产率83.5%;m.p:110.5-111.9℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.532(1H,s,-NH),9.135(1H,s,-NH),8.849(1H,s,-NH),8.095(1H,s,H-6),7.821(1H,s,H-2″), 7.583(2H,t,J=8.4Hz,H-5″,H-6″),7.404(2H,d,J=9Hz,H-3′,H-5′),6.821(2H,d,J=9Hz,H-2′,H-6′),3.033(4H,t,J=4.8Hz,-CH2N(aryl)CH2-),2.434(4H,t,J=4.8Hz,-CH2N(CH3)CH2-),2.209(3H,s,-NCH3),2.088(3H,s,-COCH3).ESI-MS m/z:486.0(M)+.
实施例21 N-{2,6-二氯-4-{{5-氯-2-{[4-(4-甲基哌嗪-1-基)苯]胺}嘧啶-4-基}胺}苯}乙酰胺(18)的测定结果为:
白色粉末;产率64.2%;m.p:112.5-114.3℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.679(1H,s,-NH),9.155(1H,s,-NH),8.970(1H,s,-NH),8.106(1H,s,H-6),7.950(1H,s,H-2″),7.827(1H,s,H-6″),7.402(2H,d,J=8.4Hz,H-2′,H-6′),6.839(2H,d,J=9.0Hz,H-3′,H-5′),3.029(4H,t,J=4.8Hz,-CH2N(aryl)CH2-),2.435(4H,t,J=4.8Hz,-CH2N(CH3)CH2-),2.209(3H,s,-NCH3),2.052(3H,s,-CH3).ESI-MS m/z:521.2(M)+.
实施例22 N-{4-{{5-氯-2-{[4-(4-甲基哌嗪-1-基)苯]胺}嘧啶-4-基}胺}-2-甲氧基苯基}乙酰胺(19)的测定结果为:
白色粉末;产率66.3%;m.p 113.5-115.9℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.116(1H,s,-NH),9.048(1H,s,-NH),8.701(1H,s,-NH),8.055(1H,s,H-6),7.805(2H,d,J=8.4Hz,H-3′,H-5′),7.414(2H,d,J=9.0Hz,H-5″,H-6″),7.283(1H,s,H-2″),6.767(2H,d,J=9.0Hz,H-3′,H-5′),3.718(3H,s,-OCH3),3.021(4H,t,J=4.8Hz,-CH2N(aryl)CH2-),2.438(4H,t,J=4.8Hz,-CH2N(CH3)CH2-),2.212(3H,s,-NCH3),2.072(3H,s,-CH3).ESI-MS m/z:482.0(M+H)+.
实施例23 N-{4-{{5-氯-2-{[4-(4-甲基哌嗪-1-基)苯]胺}嘧啶-4-基}胺}-2,5-二甲氧基苯}乙酰胺(20)的测定结果为:
白色粉末;产率55.2%;m.p 245.2-247.3℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.200(1H,s,-NH),9.021(1H,s,-NH),8.142(1H,s,H-6),8.051(1H,s,H-3″),7.848(1H,s,H-6″),7.498(1H,s,-NH),7.318(2H,d,J=7.2Hz,H-3′,H-5′),6.739(2H,d,J=8.4Hz,H-2′,H-6′),3.720(3H,s,2″-OCH3),3.632(3H,s,5″-OCH3),3.011(4H,s,-CH2N(aryl)CH2-),2.435(4H,s,-CH2N(CH3)CH2-),2.214(3H,s,-NCH3),2.103(3H,s,-CH3).ESI-MS m/z:512.2(M)+.
实施例24 N-{2-氯-4-{{5-氯-2-[(2-甲氧基-4-***啉苯基)胺]嘧啶-4-基}胺}苯}乙酰胺(21)的测定结果为:
白色粉末,产率77.5%;m.p:227.2-229.3℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.417(1H,s,-NH),8.770(1H,s,-NH),8.055(1H,s,-NH),7.942(1H,s,H-6),7.802(1H,s,H-2″),7.734(1H,d,J=9.0Hz,H-5″),7.666(1H,d,J=9.0Hz,H-6″),7.576(1H,s,H-3′),7.515(1H,d,J=8.4Hz,H-5′),7.444(1H,d,J=8.4Hz,H-6′),3.760(3H,s,-OCH3),3.741(4H,t,J=4.8Hz,-CH2OCH2-),3.087(4H,t,J=4.8Hz,-CH2NCH2-),2.075(3H,s,-COCH3).ESI-MS m/z:503.1(M+H)+.
实施例25 N-{2-氯-4-{{5-氯-2-{[2-甲氧基-4-(4-甲基哌嗪-1-基)苯]胺}嘧啶-4-基}胺}苯}乙酰胺(22)的测定结果为:
棕色粉末;产率71.5%;mp:177.3-179.2℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.467 (1H,s,-NH),8.777(1H,s,-NH),8.052(1H,s,H-6),7.935(1H,s,-NH),7.808(1H,s,H-2″),7.587(1H,d,J=8.4Hz,H-5″),7.500(1H,d,J=9Hz,H-2′),7.424(1H,d,J=9Hz,H-3′),6.604(1H,s,H-5′),6.442(1H,d,J=8.4Hz,H-6″),3.756(3H,s,-OCH3),3.144(4H,s,-CH2N(aryl)CH2-),2.535(4H,s,-CH2N(CH3)CH2-),2.282(3H,s,-NCH3),2.076(3H,s,-COCH3).ESI-MS m/z:516.1(M)+.
实施例26 N-{2,6-二氯-4-{{5-氯-2-{[2-甲氧基-4-(4-甲基哌嗪-1-基)苯]胺}嘧啶-4-基}胺}苯}乙酰胺(23)的测定结果为:
白色粉末;产率43.1%;m.p 115.4-116.7℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.668(1H,s,-NH),8.871(1H,s,-NH),8.098(1H,s,H-2″),8.088(1H,s,H-6″),7.950(1H,s,-NH),7.871(1H,s,H-6),7.361(1H,d,J=8.4Hz,H-2′),6.609(1H,s,H-5′),6.458(1H,d,J=9.0Hz,H-3′),3.756(3H,s,-OCH3),3.117(4H,s,-CH2N(aryl)CH2-),2.477(4H,s,-CH2N(CH3)CH2-),2.242(3H,s,-NCH3),2.044(3H,s,-CH3).ESI-MS m/z:551.2(M)+.
实施例27 N-{4-{{5-氯-2-[(2-甲氧基-4-***啉苯)胺]嘧啶-4-基}胺}-2-甲氧基苯}乙酰胺(24)的测定结果为:
白色粉末;产率74.7%;m.p 202.3-203.5℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.052(1H,s,-NH),8.642(1H,s,-NH),8.026(1H,s,-NH),7.950(1H,s,H-6),7.804(1H,s,H-2″),7.762(1H,d,J=9.0Hz,H-5″),7.524(1H,d,J=9.0Hz,H-2′),7.804(1H,s,H-5′),7.247(1H,d,J=8.4Hz,H-3′),6.386(1H,d,J=8.4Hz,H-6″),3.755(3H,s,-OCH3),3.741(4H,t,J=4.8Hz,-CH2N(aryl)CH2-),3.705(3H,s,-OCH3),3.077(4H,t,J=4.8Hz,-CH2N(CH3)CH2-),2.068(3H,s,-CH3).ESI-MS m/z:499.3(M+H)+.
实施例28 N-{4-{{5-氯-2-{[2-甲氧基-4-(4-甲基哌嗪-1-基)苯]胺}嘧啶-4-基}胺}-2-甲氧基苯}乙酰胺(25)的测定结果为:
白色粉末;产率72.5%;mp:122.3-123.5℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.068(1H,s,-NH),8.644(1H,s,-NH),8.019(1H,s,H-6),7.780(1H,s,-NH),7.753(1H,d,J=9Hz,H-5″),7.500(1H,d,J=9Hz,H-6″),7.314(1H,s,H-2″),7.244(1H,d,J=8.4Hz,H-2′),6.577(1H,s,H-5′),6.366(1H,d,J=7.2Hz,H-3′),3.748(3H,s,-OCH3),3.696(3H,s,-OCH3),3.095(4H,t,J=4.8Hz,-CH2N(aryl)CH2-),2.449(4H,t,J=4.8Hz,-CH2N(CH3)CH2-),2.221(3H,s,-CH3),2.064(3H,s,-COCH3).ESI-MS m/z:512.1(M)+.
实施例29 N-{4-{{5-氯-2-[(2-甲氧基-4-***啉苯)胺]嘧啶-4-基}胺}-2.5-二甲氧基苯}乙酰胺(26)的测定结果为:
棕色粉末;产率78.6%;m.p:243.7-245.3℃.1H NMR(600MHz,DMSO-d6):δ(ppm)9.155(1H,s,-NH),8.082(1H,s,-NH),8.03.7(1H,s,H-6),7.950(1H,s,-NH),7.831(1H,s,H-5″),7.819(1H,s,H-5′),7.430(1H,d,J=8.4Hz,H-2′),6.587(1H,d,J=2.4Hz,H-2″),6.357(1H,dd,J=9Hz,J=1.8Hz,H-3′),3.749(3H,s,-OCH3),3.738(3H,s,-OCH3),3.731(3H,s,-OCH3),2.888(4H,s,-CH2N(aryl)CH2-),2.729(4H,s,-CH2NOCH2-),2.089(3H,s,-COCH3).ESI-MS m/z: 429.0(M)+.
上述详细说明是针对发明的可行实施例的具体说明,该实施例并非用以限制本发明的专利范围,凡未脱离本发明的等效实施或变更,均应当包含于本发明的专利范围内。
另外,本领域技术人员还可在本发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然,这些依据本发明精神所做的各种修改、添加和替换等变化,都应包含在本发明所要求保护的范围之内。
Claims (9)
1.一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物,其特征在于,具有下列通式:
其中:R1可以选自下列任一取代基团:
R2可以选自下列任一取代基团:
R3可以选自Cl或NO2中的任意一种;
以上R1、R2和R3取代基可以任意组合。
2.一种制备权利要求1所述的一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的方法,其特征在于,包括如下步骤:
步骤一:称取2,4-二氯-5-硝基嘧啶,N,N-二异丙基乙胺和R1-NH2于烧瓶中,搅拌下加二氯甲烷使其溶解,室温反应,反应完毕后,加入饱和食盐水,混合物用二氯甲烷萃取,浓缩,得到红色固体粉末状的2-R1-氨-4-氯-5-硝基嘧啶;
步骤二:称取所述2-R1-氨-4-氯-5-硝基嘧啶和所述R2-NH2于烧瓶中,搅拌下加入仲丁醇使其溶解,回流,反应结束后,冷却至室温,加入碳酸氢钠中和,用乙酸乙酯萃取,浓缩,硅胶柱层析,洗脱剂为乙酸乙酯-甲醇,得2-R1-氨-4-R2-氨-5-R3嘧啶。
3.如权利要求2所述的一种制备权利要求1所述的一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的方法,其特征在于,所述步骤一中,室温反应时间为5h;每1g所述2,4-二氯-5-硝基嘧啶用二氯甲烷20ml;物质的量之比:2,4-二氯-5-硝基嘧啶:N,N-二异丙基乙胺:R1-NH2=1:1:1。
4.如权利要求2所述的一种制备权利要求1所述的一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的方法,其特征在于,所述步骤二中,每500mg所述2-R1-氨-4-氯-5-硝基嘧啶用仲丁醇15-20ml溶解,再将三氟乙酸滴入烧瓶中,物质的量之比:2-R1-氨-4-氯-5-R3嘧啶:R2-NH2:三氟乙酸=1:1:1;所述回流时间为2h,所述萃取次数为3次,所述洗脱剂为乙酸乙酯-甲醇,乙酸乙酯与甲醇的体积比为20:1。
5.一种制备权利要求1所述的一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的方法,其特征在于,包括如下步骤:
步骤一:称取2,4,5-三氯嘧啶,无水碳酸钾和所述R1-NH2于烧瓶中,搅拌加入DMF使其溶解,60℃反应2-3h,反应完毕后,冷却至室温,加入大量冰水,有固体析出,抽滤,干燥,得到2-R1-氨-4,5-二氯嘧啶;
步骤二:称取所述2-R1-氨-4-氯-5-二氯嘧啶和所述R2-NH2于烧瓶中,搅拌下加入所述仲丁醇使其溶解,回流,反应结束后,冷却至室温,加入碳酸氢钠中和,用乙酸乙酯萃取,浓缩,硅胶柱层析,洗脱剂为乙酸乙酯-甲醇,得2-R1-氨-4-R2-氨-5-R3嘧啶。
6.如权利要求5所述的一种制备一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的方法,其特征在于,所述步骤一中:每1g 2,4,5-三氯嘧啶用DMF 5-10ml溶解,物质的量之比:2,4,5-三氯嘧啶:无水碳酸钾:R1-NH2=1:2:1;所述步骤二中:每500mg所述2-R1-氨-4-氯-5-二氯嘧啶用仲丁醇15-20ml,再将三氟乙酸滴入烧瓶中,物质的量之比:2-R1-氨-4-氯-5-二氯嘧啶:R2-NH2:三氟乙酸=1:1:1,所述回流时间为2h,所述萃取次数为3次,所述洗脱剂乙酸乙酯与甲醇的体积比为20:1。
7.一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的用途,其特征在于,所述用途为制备抗肿瘤药物中的应用。
8.一种药物组合物,其特征在于,包括药用辅料和如权利要求1所述的一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物。
9.根据权利要求8所述的含有一类以FGFR为靶点的2,4,5-三取代嘧啶类化合物的药物组合物,其特征在于,所述的药物组合物的制剂形式为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
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