CN115108999B - 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 - Google Patents
一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 Download PDFInfo
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- CN115108999B CN115108999B CN202210554025.0A CN202210554025A CN115108999B CN 115108999 B CN115108999 B CN 115108999B CN 202210554025 A CN202210554025 A CN 202210554025A CN 115108999 B CN115108999 B CN 115108999B
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- phenylpiperazine
- methoxyethoxy
- quinazoline
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Classifications
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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
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
本发明公开了一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途。该苯基哌嗪喹唑啉类化合物或其药学上可接受的盐具体如下通式(I)、(II)、(III)的结构。本发明的提供的这些化合物合成方法容易实现,成本较低,可从EGFR激酶抑制与整合素αvβ3受体抑制双靶点产生抗肿瘤作用。体内外实验研究表明,该类化合物在体内外均具有抗肿瘤活性,其中化合物QJJ‑12的体内抗肿瘤活性类似临床用药吉非替尼。该类化合物还可以抑制EGFR激酶或EGFR T790M/L858R双突变型激酶的活性,抑制HUVEC细胞的水平迁移能力,能够与αvβ3抗体竞争结合HUVEC细胞表面的整合素αvβ3受体。(I)(II)(III)。
Description
本申请为2019年7月26日申请的第201910680663.5号发明专利申请的分案申请。
技术领域
本发明属于医药领域,特别涉及一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途。
背景技术
癌症是严重威胁人类健康和社会发展的重大疾病,癌细胞***异常,过度增殖分化,并对人体正常细胞组织侵犯转移,对个人和社会都是沉重的负担。我国癌症发病前十位的是肺癌、胃癌、结直肠癌、肝癌、食管癌、女性乳腺癌、胰腺癌、淋巴瘤、膀胱癌以及甲状腺癌,占全部癌症发病的76.39%,而我国癌症死亡前十位的是肺癌、肝癌、胃癌、食管癌、结直肠癌、胰腺癌、乳腺癌、白血病、脑瘤以及淋巴瘤,占全部癌症死亡的84.27%。因此,研发新型、低毒高效并具有特异性的抗癌药物依然是目前药物研究的重点方向。
在许多肿瘤细胞的表面都有EGFR的表达或过度表达,EGFR是目前癌症领域研究最多的分子靶点之一。EGFR是原癌基因Cerb B的表达产物,EGFR家族包括ERBB1(HER1)、ERBB2(Neu/HER2)、ERBB3(HER3)和ERBB4(HER4)。ERBB受体表达在不同的细胞中,如上皮细胞,间叶细胞和神经元。ERBB1(HER1)与再生上皮细胞的增殖有关。ERBB2(Neu/HER2)在心脏的发育中起到重要作用,缺少ERBB2的胚胎会由于心室小梁的异常发育而死亡。ERBB3(HER3)缺少内在活性,至今也缺少ERBB3(HER3)同源二聚化的相关报道,ERBB3(HER3)的活化依赖于与配体的结合或者与其他ERBB受体的异源二聚化。ERBB4(HER4)的同源或异源二聚化在肺表面活性物质磷酸化的代谢以及肺细胞增殖中起重要调节作用,影响肿瘤的增殖、分化、存活、转化和凋亡。EGFR经过自身的磷酸化之后,胞内的信号通路传导启动,下游级联反应发生,主要的信号通路有PI3K/Akt途径、Ras/MARK途径以及STAT途径等。
喹唑啉类化合物是一类有效的EGFR抑制剂,受到了普遍的重视。针对这一特点,已经开发了吉非替尼(Gefitinib)、伊马替尼、埃罗替尼(Erlotinib)、埃克替尼(Icotinib)、索拉非尼、舒尼替尼和拉帕替尼等靶向EGFR激酶抑制剂的抗肿瘤药物。但是这些替尼类药物都是作用于单一的靶点,而且只能缓解症状并不能彻底的根治疾病,更重要的是,单一靶点抗肿瘤药物很容易产生耐药性,因此开发新型多靶点药物有着非常重要的意义。
整合素受体家族是异源二聚体跨膜糖蛋白,由胞外区,跨膜区和胞内区组成,至今发现其家族成员包括18种α亚基和8种β亚基,按照不同的组合形式可形成24种不同的整合素分子。其中,整合素αvβ3受体在多种恶性肿瘤细胞及其组织的新生血管内皮细胞膜表面上高度表达,而在正常组织中少表达或不表达。用于抑制肿瘤转移和肿瘤血管生长的苯基哌嗪类衍生物(公开号CN201110146835)公开了苯基哌嗪及其衍生物以整合素αvβ3为靶点,抑制肿瘤生长以及血管新生的用途。
整合素αvβ3受体参与肿瘤的粘附、转移、生存增殖和耐药等过程,尤其实在新生血管中效果尤其明显。整合素家族广泛表达在组织上,然而,整合素αvβ3在血管内皮细胞的重建以及病态组织中表达最为丰富。血管生长因子如纤维母细胞生长因子-2(growth factor-2,FGF-2)、TNF-α和白介素-8(interleukin-8,IL-8)能刺激整合素αvβ3受体在内皮细胞的表达。整合素αvβ3受体与酶解活化的MMP-2在新生的血管聚集,导致细胞介导的胶原蛋白降解以及ECM的重组。因此,整合素αvβ3受体与纤连蛋白、纤维蛋白原或者骨桥蛋白的结合会促进诱导内皮细胞的迁移。大多数整合素,包括表达在内皮细胞的整合素,都具有“开”和“关”的状态。整合素αvβ3受体胞外区弯曲折叠,把RGD结合区隐藏起来从而阻止与配体的结合。相反,与RGD结合的整合素αvβ3有着伸直的胞外区。虽然整合素胞质尾区比胞外区要小,但它对于整合素的信号通路发挥着至关重要的作用,胞质尾区的分离,扭转都影响着整合素的活化。在癌症的发生过程中,整合素αvβ3、αvβ5、α5β1、α6β4、α4β1和αvβ6受体与肿瘤的发生最为相关。在乳腺癌的发生中,整合素αvβ3受体的过度表达与骨转移有关,它与骨桥蛋白产生反应引起肿瘤的生长和侵袭。在恶性胶质瘤的发生中,整合素αvβ3受体过度表达在肿瘤的侵袭性边缘上,而且纤维蛋白的表达水平也会增高,这关系到肿瘤细胞运动性的增加以及抵制凋亡能力的提高。在胰腺癌的发生中,整合素αvβ3受体的过度表达关系到MMP-2的过度活化以及***的转移。在***癌的发生中,由于整合素与层粘连蛋白、纤连蛋白和骨桥蛋白的粘附转移发生作用联系,整合素αvβ3受体过度表达导致骨转移的发生。
目前,越来越多的研究者认为,分子靶向药物对于传统癌症过于简单,靶向攻击一个靶点对于抑制情况复杂的肿瘤的进展疗效并不理想,如***癌和结肠癌。目前的研究认为,肿瘤产生的信号通路存在交叉现象,从而导致这一现象的出现。EGFR和整合素的信号通路也是互相交叉关联,针对于此,有望设计出双靶点小分子药物以更好地治疗癌症。
EGFR的传统信号通路如上所述有Ras/Raf/MEK/ERK/MAPK和PI3K/PDK1/Akt,而整合素的下游信号通路主要是FAK/paxillin和p130cas。这两条信号通路的关联是目前最为热门的研究热点。EGFR和整合素通路对于肿瘤细胞的侵袭以及增殖是十分紧密关联的,如果想单只通过一个靶点阻断肿瘤细胞的增殖、转移及侵袭是十分困难的。据报道,在胰腺癌中,EGFR与整合素αvβ5相互发生作用,致使癌细胞发生侵袭和增殖。EGFR受到刺激被激活后,活化的不止ERK和PKB,也有整合素下游的FAK,paxillin和p130cas。因此,控制癌症发展进程,单从EGFR或者整合素一个靶点入手阻断远不如同时阻断两者信号通路或者它们的交叉点。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足,提供一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐。以期获得同时抑制EGFR和整合素αvβ3受体活性的新化合物结构类型。
本发明的另一目的在于提供所述苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法。
本发明的再一目的在于提供所述苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的用途,可作用于与EGFR和整合素αvβ3相关的癌症或疾病。
本发明的目的通过下述技术方案实现:一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐,具体如下通式(I)、(II)、(III)的结构:
其中,R为取代或未取代、有杂原子或无杂原子的直链、支链或环状的多至10个碳原子的烃基碳链(优选的碳原子数为1-8,更优选为1-4),取代或未取代的单环芳基、杂芳基;
所述的取代或未取代的单环芳基、杂芳基优选为苯基、对甲基苯基、对硝基苯基、对氟苯基、对溴苯基、邻甲氧基苯基、苯磺酰基、对甲基苯磺酰基、对甲氧基苯磺酰基、间硝基苯磺酰基、苄基或间氯苄基。
优选的,所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐选自但不限于如下化合物之一(QJJ-1~QJJ-28):
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法,包括以下步骤:
以吗啉为起始原料,将其与1-溴-3-氯丙烷溶于甲苯中,发生取代反应得到4-(3-氯丙基)吗啉(3a);在甲酸和甲酸钠的环境中,以异香兰素(3-羟基-4-甲氧基苯甲醛)为原料,通过与盐酸羟胺反应制备中间体化合物3-羟基-4-甲氧基苯甲腈(5a);然后4-(3-氯丙基)吗啉和3-羟基-4-甲氧基苯甲腈之间发生醚化反应生成4-甲氧基-3-(3-吗啉丙氧基)苯甲腈(6a);接着进行硝化,得到硝基化的化合物(7a);再使用三氯化铟作为催化剂,在微波反应仪中环化得到喹唑啉酮化合物(8a),最后与草酰氯反应得到氯代喹唑啉化合物(9a);氯代喹唑啉化合物分别与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物进行反应,得到化合物QJJ-1~QJJ-12;
以三甘醇为起始原料,将其与对甲苯磺酰氯(TsCl)溶于THF(四氢呋喃)中,发生取代反应得对甲基苯磺酰取代羟基的三甘醇(3c);在甲酸和甲酸钠环境中,以3,4-二羟基苯甲醛为原料,通过与盐酸羟胺反应制备3,4-二羟基苯甲腈(5c);将对甲基苯磺酰取代羟基的三甘醇和3,4-二羟基苯甲腈溶解在四氢呋喃中,然后用氢氧化钠和氢氧化锂环化,得到冠醚苯甲腈(6c);随后进行硝化反应,得到硝基化合物(7c),接着使用三氯化铟作为催化剂,在微波反应仪中反应得到喹唑啉酮类化合物(8c),再使用草酰氯作为氯化剂,氯仿作为溶剂,得到中间体氯代喹唑啉化合物(9c);最后将氯代喹唑啉化合物与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物反应,得到化合物QJJ-13~QJJ-18;
以乙二醇单甲醚为起始原料,将其与对甲基苯磺酰氯在四氢呋喃中发生亲核取代反应得到2-甲氧基乙基-4-甲基苯磺酸酯(3d);2-甲氧基乙基-4-甲基苯磺酸酯与3,4-二羟基苯甲醛在乙腈中,氮气保护下发生取代生成3,4-二-(2-甲氧乙氧基)苯甲醛(4d);3,4-二-(2-甲氧乙氧基)苯甲醛的醛基经盐酸羟胺还原得到3,4-二-(2-甲氧乙氧基)苯甲腈(5d);3,4-二-(2-甲氧乙氧基)苯甲腈低温下与浓硝酸反应,硝化得到4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈(6d);4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈经过在甲酰胺中,与三氯化铟微波环合(Niementowski环合)得到6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮(7d);6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮经草酰氯氯代后得到4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉(8d);4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉分别与取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物反应,得到化合物QJJ-19~QJJ-28。
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法,更优选包括以下步骤:
(1)将吗啉与1-溴-3-氯丙烷溶于甲苯中,加热至65~85℃回流反应2.5~6.5h,待反应结束后冷却至室温,过滤并用HCl溶液萃取去除甲苯,调pH至强碱性,油水层分离,再用***萃取,蒸去***,得到4-(3-氯丙基)吗啉(3a);将异香兰素(3-羟基-4-甲氧基苯甲醛)、盐酸羟胺、甲酸和甲酸钠混合均匀,加热至100℃回流反应5~7.5h,待反应结束后加入饱和食盐水,过滤,水洗,干燥,得到中间体化合物3-羟基-4-甲氧基苯甲腈(5a);将4-(3-氯丙基)吗啉、3-羟基-4-甲氧基苯甲腈、碳酸钾、碘化钾和乙腈混合均匀,加热至75~85℃回流反应3~7h,得到4-甲氧基-3-(3-吗啉丙氧基)苯甲腈(6a);将4-甲氧基-3-(3-吗啉丙氧基)苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中,保持0℃反应2~5h,然后加热至40~50℃回流3~6h,待反应结束后加入冰水洗涤,析出固体,过滤,正己烷洗涤,干燥,得到硝基化的化合物7a(4-甲氧基-5-(3-吗啉丙氧基)-2-硝基苯甲腈);将硝基化的化合物7a溶解到甲酰胺中,然后加入三氯化铟作为催化剂,在100~120℃,400W条件下微波反应40~70分钟,用二氯甲烷萃取,无水Na2SO4干燥,过滤并浓缩,硅胶柱分离,得到喹唑啉酮化合物8a(7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉-4(3H)-酮);将喹唑啉酮化合物8a和N,N-二甲基甲酰胺加入到氯仿中,然后加入草酰氯,加热至60~70℃反应1.5~3小时后,再加入饱和碳酸氢钠溶液直至观察到pH为10.0;乙酸乙酯萃取,有机层用无水Na2SO4干燥,过滤并浓缩,硅胶柱分离,得到氯代喹唑啉化合物9a(4-氯-7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉);将氯代喹唑啉化合物9a和取代物加入到N,N-二甲基甲酰胺中,加入三乙胺作为催化剂,在100~130℃,100W条件下微波反应15~30分钟,再加入饱和盐水,乙酸乙酯萃取,乙酸乙酯层用无水Na2SO4干燥,过滤并浓缩,硅胶柱分离,得到化合物QJJ-1~QJJ-12;其中,取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物;
(2)将三甘醇、四氢呋喃、氢氧化钠和水混合均匀,然后在冰浴下加入四氢呋喃溶解的对甲基苯磺酰氯(TsCl),在冰浴下继续反应2.5~4h,结束后蒸出四氢呋喃,冷却,抽滤,并依次用甲醇、乙醇和冰水洗涤,得到对甲基苯磺酰取代羟基的三甘醇(3c);将3,4-二羟基苯甲醛、盐酸羟胺、甲酸钠和甲酸混合均匀,加热至100℃回流反应5~7.5h,结束后加入饱和食盐水,过滤,水洗,干燥,得到3,4-二羟基苯甲腈(5c);将3,4-二羟基苯甲腈、四氢呋喃、氢氧化钠、氢氧化锂和水混合均匀,在氮气保护下,60~75℃反应1h,然后加入四氢呋喃溶解的对甲基苯磺酰取代羟基的三甘醇,继续反应60~80h,反应完毕后,蒸出四氢呋喃,残留部分用二氯甲烷萃取,蒸干溶剂,得到冠醚苯甲腈(6c);将冠醚苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中,保持0℃反应2~5h,然后加热至40~50℃回流3~6h,待反应结束后加入冰水洗涤,析出固体,过滤,正己烷洗涤,干燥,得到硝基化的化合物7c(12-氰基-13-硝基-2,3,5,6,8,9-六氢苯并[b][1,4,7,10]四氧环十二烷);将硝基化的化合物7c溶解到甲酰胺中,然后加入三氯化铟作为催化剂,在100~120℃,400W条件下微波反应40~70分钟,用二氯甲烷萃取,无水Na2SO4干燥,过滤并浓缩,硅胶柱分离,得到喹唑啉酮类化合物8c(7,8,10,11,13,14-六氢-[1,4,7,10]四氧环十二烷并[2,3-g]喹唑啉-4(3H)-酮);将喹唑啉酮类化合物8c和N,N-二甲基甲酰胺加入到氯仿中,然后加入草酰氯,加热至60~70℃反应1.5~3小时后,再加入饱和碳酸氢钠溶液直至观察到pH为10.0;乙酸乙酯萃取,有机层用无水Na2SO4干燥,过滤并浓缩,硅胶柱分离,得到中间体氯代喹唑啉化合物9c(4-氯-7,8,10,11,13,14-六氢-[1,4,7,10]四氧环十二烷并[2,3-g]喹唑啉);将氯代喹唑啉化合物9c和取代物加入到N,N-二甲基甲酰胺中,加入三乙胺作为催化剂,在100~130℃,100W条件下微波反应15~30分钟,再加入饱和盐水,乙酸乙酯萃取,乙酸乙酯层用无水Na2SO4干燥,过滤并浓缩,硅胶柱分离,得到化合物QJJ-13~QJJ-18;其中,取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物;
(3)将乙二醇单甲醚加入到THF(四氢呋喃)和水的混合液中,冰浴处理1~3小时后,加入THF溶解的对甲基苯磺酰氯,继续冰浴3~6小时,然后旋干THF,饱和食盐水水洗,二氯甲烷萃取,有机层加入无水Na2SO4干燥,减压浓缩,硅胶柱层析分离,真空干燥,得到2-甲氧基乙基-4-甲基苯磺酸酯(3d);将2-甲氧基乙基-4-甲基苯磺酸酯、3,4-二羟基苯甲醛、乙腈和碳酸钾混合均匀,抽真空,N2保护,70~85℃反应30~45h,抽滤,取滤液,旋干乙腈,用饱和食盐水水洗,乙酸乙酯萃取,有机层加入无水Na2SO4干燥,减压浓缩,硅胶柱层析分离,得到3,4-二-(2-甲氧乙氧基)苯甲醛(4d);将甲酸钠和3,4-二-(2-甲氧乙氧基)苯甲醛加入到甲酸中,加热至75~85℃后加入盐酸羟胺,反应4~7h后,冷至至室温,加入冷的饱和食盐水析出固体,过滤,乙酸乙酯重结晶,干燥得3,4-二-(2-甲氧乙氧基)苯甲腈(5d);将3,4-二-(2-甲氧乙氧基)苯甲腈用冰醋酸溶解后加入到0℃的硝酸溶液中,保持0℃反应2~5h,然后加热至40~50℃回流3~6h,待反应结束后加入冰水洗涤,析出固体,过滤,正己烷洗涤,干燥,得到4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈(6d);将4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈溶解到甲酰胺中,然后加入三氯化铟(Niementowski环合)作为催化剂,在100~120℃,400W条件下微波反应40~70分钟,反应结束后过滤,滤液用饱和食盐水水洗,乙酸乙酯萃取,有机层减压浓缩,再用乙酸乙酯重结晶,得到6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮(7d);将6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮溶于氯仿,加入N,N-二甲基甲酰胺,滴加草酰氯,60~70℃回流1.5~3h,用饱和碳酸氢钠水溶液洗涤,乙酸乙酯萃取,有机层加入无水Na2SO4干燥,减压浓缩,硅胶柱层析分离,真空干燥,得到4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉(8d);将4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉和取代物加入到N,N-二甲基甲酰胺中,加入三乙胺作为催化剂,在100~130℃,300W条件下微波反应15~30分钟,再加入饱和盐水,乙酸乙酯萃取,乙酸乙酯层用无水Na2SO4干燥,过滤并浓缩,硅胶柱分离,得到化合物QJJ-19~QJJ-28;其中,取代物为取代苯磺酰哌嗪、取代苯基哌嗪和取代苄基哌嗪化合物。
步骤(1)中所述的吗啉与1-溴-3-氯丙烷的体积比优选为1:1.15。
步骤(1)中所述的异香兰素与盐酸羟胺的质量比优选为1:1.1。
步骤(1)中所述的4-(3-氯丙基)吗啉和3-羟基-4-甲氧基苯甲腈的质量比优选为5.25:4。
步骤(1)、(2)和(3)中所述的硝酸溶液的浓度优选为质量百分比65%。
步骤(1)中所述的氯代喹唑啉化合物和取代物的摩尔比优选为1:1。
步骤(1)、(2)和(3)中所述的取代苯磺酰哌嗪是以取代苯磺酰氯与哌嗪为原料合成的取代苯磺酰哌嗪;优选为苯磺酰哌嗪(1-(phenylsulfonyl)piperazine)、对甲基苯磺酰哌嗪(1-tosylpiperazin)、对甲氧基苯磺酰哌嗪(1-((4-methoxyphenyl)sulfonyl)piperazine)、或间硝基苯磺酰哌嗪(1-((3-nitrophenyl)sulfonyl)piperazine)。
步骤(1)、(2)和(3)中所述的取代苯基哌嗪优选为苯基哌嗪(1-苯基哌嗪)、对甲基苯基哌嗪(1-(4-甲基苯基)哌嗪)、对硝基苯基哌嗪(1-(4-硝基苯基)哌嗪)、对氟苯基哌嗪(1-(4-氟苯基)哌嗪)、对溴苯基哌嗪(1-(4-溴苯基)哌嗪)、或邻甲氧基苯基哌嗪(1-(2-甲氧基苯基)哌嗪)。
步骤(1)、(2)和(3)中所述的取代苄基哌嗪化合物优选为苄基哌嗪(1-苄基哌嗪)或间氯苄基哌嗪(1-(3-氯苄基)哌嗪)。
步骤(2)中所述的三甘醇与对甲基苯磺酰氯的摩尔比优选为6.7:12。
步骤(2)中所述的3,4-二羟基苯甲醛与盐酸羟胺的质量比为13.8:16.7。
步骤(2)中所述的对甲基苯磺酰取代羟基的三甘醇和3,4-二羟基苯甲腈的质量比优选为3.73:1。
步骤(2)中所述的冠醚苯甲腈与硝酸溶液的摩尔比为1:10。
步骤(2)中所述的喹唑啉酮类化合物与草酰氯的摩尔比为0.3:0.86。
步骤(2)中所述的氯代喹唑啉化合物和取代物的摩尔比优选为1:1。
步骤(3)中所述的乙二醇单甲醚与对甲基苯磺酰氯的摩尔比为1:1.05
步骤(3)中所述的2-甲氧基乙基-4-甲基苯磺酸酯与3,4-二羟基苯甲醛的摩尔比为2:1。
步骤(3)中所述的3,4-二-(2-甲氧乙氧基)苯甲醛与盐酸羟胺的摩尔比为1:2.4。
步骤(3)中所述的4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉和取代物的摩尔比优选为1:2。
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用,本发明制备的苯基哌嗪喹唑啉类化合物以及其药学上可接受的盐可制备具有抗肿瘤的药物,作为肿瘤化疗药物和手术治疗中的辅助药物,或者与其它药剂组合用于各种癌症的治疗。
所述的肿瘤为包括且不局限于非小细胞肺癌、乳腺癌、***、脑瘤、胰腺癌、肝癌、结肠直肠癌、甲状腺髓样癌、神经胶质瘤、成神经细胞瘤、肾脏肿瘤(肾癌)、肺癌、胰腺癌、星细胞瘤、膀胱癌、卵巢癌、头颈癌、子***、胸腺癌、胃癌,卵巢癌和***癌;优选为非小细胞肺癌、肺腺癌或***。
所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐在制备抑制激酶的药物、抑制HUVEC细胞迁移的药物中的应用,本发明制备的苯基哌嗪喹唑啉类化合物以及其药学上可接受的盐可以抑制EGFR激酶或EGFR T790M/L858R双突变型激酶的活性,抑制HUVEC细胞的水平迁移能力,能够与αvβ3抗体竞争结合HUVEC细胞表面的整合素αvβ3受体。
所述的激酶为EGFR激酶或EGFR T790M/L858R双突变型激酶。
本文所用的术语“烃基”是指未被取代的或被取代的直链、支链或环状的多至10个碳原子的烃基碳链,或在链上含有至少一个杂原子(例如氮、氧或硫)的烃基。直链烃基的非限定性例子包括如甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基等饱和烃基,也包括含有烯键、炔键、羰基、氰基等取代基的不饱和烃基,还包括含杂原子的烃基如-CH2CH2OCH3、-CH2CH2N(CH3)2和-CH2CH2SCH3等。不含或含杂原子的支链烃基的非限定性例子包括如异丙基、仲丁基、异丁基、叔丁基、新戊基、-CH2CH(OCH3)CH3、-CH2CH(N(CH3)2)CH3和-CH2CH(SCH3)CH3。不含或含杂原子的环状烃基(“环烃基”)的非限定性例子包括如环丙基、环丁基、环戊基和环己基等,含O、N、S的六元环如-CH(CH2CH2)2O、-CH(CH2CH2)2NCH3和-CH(CH2CH2)2S等及相应的五元杂环等。烃基可被一个或多个取代基取代,上述取代基的非限定性例子包括-N(CH3)2、F、Cl、Br、I、-OCH3、-CO2CH3、-CN、-OH、芳基和杂芳基。
本文所用的术语“芳基”是指未被取代的或取代的芳香化合物、碳环基团和杂芳基。芳基或者是单环或者是多环稠合化合物。芳基可以被一个或多个取代基取代,取代基的非限制性的例子包括-N(CH3)2、F、Cl、Br、I、-OCH3、-CO2CH3、-CN、-OH、芳基和杂芳基。
杂芳基涉及到取代的或非取代的单环或多环的基团,环内至少包括一个杂原子,如氮、氧以及硫。举例来说,典型的杂环基团包括一个或多个氮原子譬如四唑基、吡咯基、吡啶基(如4-吡啶基,3-吡啶基,2-吡啶基等)、哒嗪基、吲哚基、喹啉基(如2-喹啉基,3-喹啉基等)、咪唑基、异喹啉基,吡唑基、吡嗪基、嘧啶基、吡啶酮基;典型的含一个氧原子的杂环基团包括2-呋喃基,3-呋喃基或苯并呋喃基;典型的硫杂原子基团包括噻吩基、苯并噻吩基;典型的混合杂原子基团包括呋吖基、噁唑基、异噁唑基、噻唑基和吩噻噁基。杂环基团能被一个或多个取代基取代,这些取代基包括-O-烷基、-NH-烷基、-N-(烷基)2、-NHC(O)-烷基、F、Cl、Br、I、-OH、-OCF3、-CO2-烷基、-CN以及芳基和多芳基。
本文使用的术语“药学上可接受的”指的是在化合物如盐或赋形剂中不具有不能接受的毒性。药学上可接受的盐包括无机阴离子,例如氯离子、溴离子、碘离子、硫酸根、亚硫酸根、硝酸根、亚硝酸根、磷酸根、磷酸氢根等。有机阴离子包括乙酸根、丙酸根、肉桂酸根、苯甲磺酸根、柠檬酸根、乳酸根、葡萄糖酸根、富马酸根、酒石酸根、琥珀酸根等。本发明涉及一类苯基哌嗪喹唑啉类化合物的烃基、芳基、杂芳基、硝酸酯基、卤代、磺酰基衍生物,可以一种药学可接受的盐或药物复合物的形式对病人给药。某个复合物可与适当载体或赋形剂混合形成药物组合物从而保证达到有效治疗剂。“有效治疗剂量”是指该种类化合物及其衍生物达到治疗效果所需的剂量。
与现有技术相比,本发明具有以下优点及有益效果:
(1)本发明提供的这些化合物,结构新颖、合成方法容易实现。体外抗肿瘤活性实验表明,该类化合物的抗肿瘤活性类似临床用药厄洛替尼。该类化合物以及其药学上可接受的盐可制备具有抗肿瘤的药物,可以制备治疗非小细胞肺癌、乳腺癌、肝癌和***药物,以及制备作为肿瘤化疗药物和手术治疗中的辅助药物。
(2)苯基哌嗪喹唑啉类化合物制备工艺简单,原料易得,成本较低,经济有效。
附图说明
图1是化合物1a~1d的合成路线图(图中a表示:哌嗪,三乙胺,二氯甲烷,冰浴反应,反应时间为3h,反应结束后恢复至室温)。
图2是化合物QJJ-1~QJJ-12的合成路线图(图中:A表示吗啉,甲苯,65~85℃,2.5~6.5h;B表示盐酸羟胺,甲酸钠,甲酸,100℃,5~7.5h;C表示碳酸钾,碘化钾,乙腈,75~85℃,3~7h;D表示65%硝酸,冰醋酸,0℃、2~5h,40~50℃、3~6h;E表示甲酰胺,三氯化铟,微波400w,100~120℃,40~70分钟;F表示草酰氯,N,N-二甲基甲酰胺,氯仿,60~70℃,1.5~3h;G表示各取代苯基哌嗪,三乙胺,N,N-二甲基甲酰胺,微波100w,100~130℃,15~30min;H表示1b/1c/1d/1a,三乙胺,N,N-二甲基甲酰胺,微波100w,100~130℃,15~30min;I表示各取代苄基哌嗪,三乙胺,N,N-二甲基甲酰胺,微波100w,100~130℃,15~30min)。
图3是化合物QJJ-13~QJJ-18的合成路线图(图中:A表示对甲基苯磺酰氯,四氢呋喃,氢氧化钠,水,冰浴,2.5~4h;B表示盐酸羟胺,甲酸钠,甲酸,100℃,5~7.5h;C表示四氢呋喃,氢氧化钠,氢氧化锂,水,N2保护,60~75℃,60~80h;D表示65%硝酸,冰醋酸,0℃、2~5h,40~50℃、3~6h;E表示甲酰胺,三氯化铟,微波400w,100~120℃,40~70分钟;F表示草酰氯,N,N-二甲基甲酰胺,氯仿,60~70℃,1.5~3h;G表示各取代苯基哌嗪,三乙胺,N,N-二甲基甲酰胺,微波100w,100~130℃,15~30min;H表示1a/1d,三乙胺,N,N-二甲基甲酰胺,微波100w,100~130℃,15~30min;I表示各取代苄基哌嗪,三乙胺,N,N-二甲基甲酰胺,微波100w,100~130℃,15~30min。
图4是化合物QJJ-19~QJJ-28的合成路线图(图中:A表示对甲基苯磺酰氯,四氢呋喃,氢氧化钠,水,冰浴,4~9h;B表示3,4-二羟基苯甲醛,碳酸钾,乙腈,N2保护,70~85℃;C表示盐酸羟胺,甲酸钠,甲酸,75~85℃,4~7h;D表示65%硝酸,冰醋酸,0℃、2~5h,40~50℃、3~6h;E表示甲酰胺,三氯化铟,微波400w,100~120℃,40~70分钟;F表示草酰氯,N,N-二甲基甲酰胺,氯仿,60~70℃,1.5~3h;G表示1a/1b/1c/1d,N,N-二甲基甲酰胺,三乙胺,微波300w,100~130℃,15~30min;H表示各取代苯基哌嗪,N,N-二甲基甲酰胺,三乙胺,微波300w,100~130℃,15~30min;I表示各取代苄基哌嗪,N,N-二甲基甲酰胺,三乙胺,微波300w,100~130℃,15~30min)。
图5是化合物QJJ-28抑制HUVEC人脐静脉内皮细胞迁移镜下图(10×10)。
图6是流式细胞术对QJJ-12结合整合素αvβ3受体的检测结果。
图7是流式细胞术对QJJ-28结合整合素αvβ3受体的检测结果。
图8是实验各组裸鼠体重变化曲线图。
图9是整个实验给药前后裸鼠体重的变化图(*p<0.05,**p<0.01,***p<0.001对比于给药前组)。
图10是实验各组裸鼠肿瘤组织图。
图11是实验各组裸鼠肿瘤生长曲线图(*p<0.05,**p<0.01,***p<0.001与Ctrl组对比;#p<0.05,##p<0.01,###p<0.001与Gefitinib组对比)。
图12是实验各组裸鼠的肿瘤生长抑制率(#p<0.05,##p<0.01,###p<0.001与Gefitinib组对比)。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。下列实施例中未注明具体实验条件的试验方法,通常按照常规实验条件或按照制造厂所建议的实验条件。除非特别说明,本发明所用试剂和原材料均可通过市售获得。
实施例1:化合物1-(phenylsulfonyl)piperazine(1a)的合成
称取无水哌嗪(3.24g,37.7mmol),三乙胺(2.10g,20.7mmol),溶于无水二氯甲烷(100mL)中,冰浴。30min后,滴加稀释苯磺酰氯(4.0g,22.6mmol)的无水二氯甲烷(20mL),冰浴下继续反应3h。TLC(薄层色谱)检测反应,反应完全后旋干二氯甲烷,饱和食盐水水洗,乙酸乙酯萃取,有机层加入无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(洗脱剂为:石油醚:乙酸乙酯=1:2(体积比),再加入1%(v/v)三乙胺),TLC跟踪收集,真空干燥,得白色固体1a(产率62%)(图1)。
ESI-MS:[M+H]+m/z 227.3。1H NMR(300MHz,CDCl3)δ:7.71–7.63(m,2H),7.57–7.42(m,3H),2.94–2.86(m,4H),2.85–2.78(m,4H),1.70(s,1H)。13C NMR(75MHz,CDCl3)δ:135.32,132.84,129.02,127.69,46.82,45.20。
实施例2:化合物1-tosylpiperazin(1b)的合成
化合物1b的具体合成方法可参照化合物1a的合成步骤。将对甲苯磺酰氯(4.0g,21.0mmol)替换实施例1中的苯磺酰氯,得白色固体1b(产率60%)(图1)。
ESI-MS:[M+H]+m/z 241.3。1H NMR(300MHz,CDCl3)δ7.61(t,J=9.4Hz,2H),7.37–7.27(m,2H),2.98(t,J=22.3Hz,8H),2.43(s,3H),1.77(s,1H)。13C NMR(75MHz,CDCl3)δ143.63,132.27,129.60,127.77,46.85,45.21,21.47。
实施例3:化合物1-((4-methoxyphenyl)sulfonyl)piperazine(1c)的合成
化合物1c的具体合成方法可参照化合物1a的合成步骤。将对甲氧基苯磺酰氯(4.0g,19.4mmol)替换实施例1中的苯磺酰氯,得淡黄色固体1c(产率79%)(图1)。
ESI-MS:[M+H]+m/z 257.1。1H NMR(300MHz,CDCl3)δ:7.59–7.46(m,2H),6.91–6.82(m,2H),3.72(s,3H),2.76(d,J=4.8Hz,8H),1.96–1.72(m,1H)。13C NMR(75MHz,CDCl3)δ:162.98,129.76,126.71,114.15,55.61,46.78,45.09。
实施例4:化合物1-((3-nitrophenyl)sulfonyl)piperazine(1d)的合成
化合物1d的具体合成方法可参照化合物1a的合成步骤。将间硝基苯磺酰氯(4.0g,18.2mmol)替换实施例1中的苯磺酰氯,得黄色固体1d(产率65%)(图1)。
ESI-MS:[M+H]+m/z 272.3,[M+Na]+m/z 284.3。1H NMR(300MHz,CDCl3)δ:8.57(dt,J=10.2,1.9Hz,1H),8.47(ddd,J=8.2,2.2,1.0Hz,1H),8.15–8.03(m,1H),7.84–7.74(m,1H),3.14–3.03(m,4H),3.02–2.92(m,4H),2.19–1.84(m,1H)。13C NMR(75MHz,CDCl3)δ:148.37,138.15,133.19,130.53,127.30,122.76,46.83,45.23。
实施例5:化合物4-(3-chloropropyl)morpholine(3a)的合成
在圆底烧瓶中依次加入吗啉(30ml),1-溴-3氯丙烷(34.4ml),甲苯(90ml),加热至80℃,回流6h,结束后冷却至室温,过滤得滤液,用3mol/L的HCl溶液萃取,除去甲苯,然后用10mol/L NaOH溶液调pH至强碱性,油水层分离,***萃取,蒸去***得无色液体3a(图2)。
ESI-MS:m/z 164.1([M+H]+)。1H NMR(300MHz,d6-DMSO)δ:3.75(s,2H),3.55(s,4H),2.44(s,2H),2.33(s,4H),2.03(s,2H)。13C NMR(75MHz,d6-DMSO)δ:67.08,53.71,53.07,41.28,29.15。
实施例6:化合物3-hydroxy-4-methoxybenzonitrile(5a)的合成
在圆底烧瓶中依次加入异香兰素2g,盐酸羟胺2.2g,甲酸钠1.7g,甲酸11ml,加热至100℃回流6h,结束后在反应液中加入饱和食盐水10ml,搅拌过滤,滤饼水洗(20ml×3),干燥,得灰色粉末5a(图2)。
ESI-MS:m/z 150.1([M+H]+)。1H NMR(300MHz,d6-DMSO)δ:7.66(s,1H),7.53(s,1H),6.94(s,1H),5.56(s,1H),3.86(s,3H)。13C NMR(75MHz,d6-DMSO)δ:153.91,147.34,125.90,118.82,117.41,113.77,104.59,56.83。
实施例7:化合物4-methoxy-3-(3-morpholinopropoxy)benzonitrile(6a)的合成
在圆底烧瓶中依次加入3a 0.525g,5a 0.4g,碳酸钾0.75g,碘化钾0.023g,乙腈2.2ml。搅拌溶解,加热至82℃,回流3~4h,结束后冷却至室温,过滤得滤液,蒸去乙腈,得粗品用硅胶柱分离(石油醚:乙酸乙酯=1:1,体积比),得无色液体6a(图2)。
ESI-MS:m/z 277.1([M+H]+)。1H NMR(300MHz,d6-DMSO)δ:7.59–7.27(m,3H),7.11(d,J=8.1Hz,1H),4.13–3.95(m,2H),3.84(s,3H),3.64–3.48(m,4H),2.38(dd,J=13.5,6.1Hz,6H),1.87(p,J=6.5Hz,2H)。13C NMR(75MHz,d6-DMSO)δ:153.25,148.17,126.46,119.44,116.10,112.68,102.72,67.23,66.18,55.84,54.84,53.46,26.00。
实施例8:化合物4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile(7a)的合成
在圆底烧瓶中加入质量分数65%的硝酸1.7ml,冷却至0℃,缓慢加入用5ml冰醋酸溶解的6a 0.66g,保持0℃4h,然后加热至50℃,回流4h,结束后反应液中加入冰水洗涤,析出黄色固体,过滤,正己烷洗涤,干燥,得黄色固体7a(产率49.3%)(图2)。
ESI-MS:m/z 322.1([M+H]+)。1H NMR(300MHz,d6-DMSO)δ:7.88(d,J=3.5Hz,1H),7.70(d,J=9.4Hz,1H),4.36–4.12(m,2H),4.06–3.91(m,3H),3.66–3.48(m,4H),2.48(s,2H),2.33(s,4H),1.83(s,2H)。13C NMR(75MHz,d6-DMSO)δ:154.41,151.95,151.86,117.76,117.08,111.45,104.54,67.91,67.08,56.83,53.07,52.49,28.13.
实施例9:化合物7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one(8a)的合成
将7a(1.56mmol,0.5g)加入到含有20ml甲酰胺的烧瓶中,搅拌使其完全溶解,加入三氯化铟(1.56mmol,0.35g)作为催化剂。反应在微波反应器中进行(110℃,400W),反应60分钟后终止反应。向混合物中加入少量的水,并用二氯甲烷萃取。将二氯甲烷层用无水Na2SO4干燥,过滤并浓缩,得到残余物,将其通过硅胶柱(乙酸乙酯:三乙胺=100:1,体积比)纯化,得到化合物8a(白色固体,产率30.2%)(图2)。
ESI-MS:m/z 319.3([M+H]+)。1H NMR(300MHz,d6-DMSO)δ:12.08(s,1H),7.98(s,1H),7.43(s,1H),7.13(s,1H),4.10(t,J=6.4Hz,2H),3.90(s,3H),3.60(dd,J=17.0,12.6Hz,4H),2.41(dd,J=16.6,9.6Hz,6H),1.92(p,J=6.6Hz,2H)。13C NMR(75MHz,d6-DMSO)δ:160.59,154.91,148.17,145.24,144.17,115.43,108.39,106.05,67.22,66.66,56.40,55.18,53.82,26.15。
实施例10:化合物4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(9a)的合成
将8a(3mmol,1g)和N,N-二甲基甲酰胺(0.22ml)加入到含有30ml氯仿的烧瓶中,当其完全溶解时,缓慢加入草酰氯(7.5mmol,0.67ml),加热至61℃,2小时后终止反应。加入饱和碳酸氢钠溶液直至观察到pH为10.0。混合物用乙酸乙酯萃取。有机层用无水Na2SO4干燥,过滤并浓缩,得到残余物,通过硅胶柱(石油醚:乙酸乙酯=1:1,体积比)纯化,得到化合物9a(白色固体,产率60.0%)。
ESI-MS:m/z 320.3([M+H]+)。1H NMR(300MHz,CDCl3)δ:8.86(s,1H),7.38(s,1H),7.32(s,1H),4.27(t,J=6.5Hz,2H),4.05(s,3H),3.78–3.66(m,4H),2.59(t,J=7.1Hz,2H),2.55–2.44(m,4H),2.13(p,J=6.7Hz,2H)。13C NMR(75MHz,CDCl3)δ:158.92,156.87,152.55,150.90,148.57,119.43,107.02,103.01,67.54,66.96,56.54,55.31,53.74,25.94。
实施例11:化合物4-(3-((7-methoxy-4-(4-phenylpiperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-1)的合成
将化合物9a(0.3mmol)和1-苯基哌嗪(0.3mmol)加入到含有20ml DMF(N,N-二甲基甲酰胺)的烧瓶中,完全溶解,加入三乙胺作为催化剂。将反应在微波反应器中进行,设置反应条件(120℃,100W),20分钟后终止反应。向混合物中加入少量饱和盐水,并用乙酸乙酯萃取。乙酸乙酯层用无水Na2SO4干燥,过滤并浓缩,得到残余物,通过硅胶柱(乙酸乙酯:石油醚=1:1,体积比)纯化,得到化合物QJJ-1,淡黄色固体,产率85%,m.p.119.6℃-120.5℃(图2)。
ESI-HRMS m/z:464.2656[M+H]+,calcd for C26H33N5O3 464.2654。1H NMR(300MHz,CDCl3)δ:8.69(s,1H),7.29(dd,J=7.2,1.3Hz,2H),7.25(s,1H),7.17(s,1H),6.99(d,J=7.9Hz,2H),6.90(t,J=7.3Hz,1H),4.21–4.11(m,2H),3.99(s,3H),3.79(dd,J=13.1,8.0Hz,4H),3.75–3.66(m,4H),3.45–3.35(m,4H),2.58(t,J=7.2Hz,2H),2.53–2.43(m,4H),2.09(dq,J=12.8,6.4Hz,2H)。13C NMR(75MHz,CDCl3)δ:163.93,154.54,152.87,150.89,148.85,148.18,128.81,119.73,115.73,111.05,109.67,107.71,104.33,67.21,66.55,56.16,55.14,53.48,49.72,49.14,25.99。
实施例12:化合物4-(3-((7-methoxy-4-(4-(p-tolyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-2)的合成
化合物QJJ-2(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-甲基苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-2。淡黄色固体,产率82%,m.p.122.0℃-124.8℃。
ESI-HRMS m/z:478.2813[M+H]+,calcd for C27H35N5O3 478.2811。1H NMR(300MHz,CDCl3)δ:8.70(s,1H),7.25(s,1H),7.17(s,1H),7.12(d,J=8.3Hz,2H),6.92(d,J=8.5Hz,2H),4.18(t,J=6.4Hz,2H),4.00(s,3H),3.88–3.66(m,8H),3.44–3.28(m,4H),2.59(t,J=7.2Hz,2H),2.51(d,J=4.1Hz,4H),2.30(s,3H),2.17–2.05(m,2H)。13C NMR(75MHz,CDCl3)δ:163.81,154.79,153.04,148.98,147.90,129.78,116.51,111.53,107.43,104.23,67.23,66.97,56.04,55.15,53.42,49.78,26.15,20.29。
实施例13:化合物4-(3-((7-methoxy-4-(4-(4-nitrophenyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-3)的合成
化合物QJJ-3(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-硝基苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-3。黄色固体,产率89%,m.p.90.2℃-91.4℃。
ESI-HRMS m/z:509.2507[M+H]+,calcd for C26H32N6O5 509.2511。1H NMR(300MHz,CDCl3)δ:8.69(s,1H),8.18–8.10(m,1H),7.27(s,1H),7.17(s,1H),6.91–6.83(m,1H),4.18(t,J=6.4Hz,1H),4.01(s,1H),3.87(dd,J=6.3,3.9Hz,2H),3.75–3.69(m,2H),3.66(dd,J=6.2,3.9Hz,2H),2.59(t,J=7.2Hz,1H),2.53–2.45(m,2H),2.16–2.07(m,1H)。13C NMR(75MHz,CDCl3)δ:163.42,155.16,154.66,152.82,149.14,148.23,138.75,125.96,112.65,111.29,107.66,104.05,67.40,66.93,56.21,55.42,53.72,48.96,46.65,26.12。
实施例14:化合物4-(3-((4-(4-(4-fluorophenyl)piperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-4)的合成
化合物QJJ-4(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-氟苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-4。白色固体,产率82%,m.p.131.7℃-133.2℃。
ESI-HRMS m/z:482.2562[M+H]+,calcd for C26H32FN5O3 482.2581。1H NMR(300MHz,CDCl3)δ:8.70(s,1H),7.26(s,1H),7.17(s,1H),7.08–6.88(m,4H),4.18(t,J=6.1Hz,2H),4.01(s,3H),3.81(s,4H),3.72(s,4H),3.33(s,4H),2.59(t,J=7.0Hz,2H),2.49(s,4H),2.17–2.05(m,2H)。13C NMR(75MHz,CDCl3)δ:163.80,155.03,153.04,149.17,148.10,147.74,118.13,118.03,115.83,115.53,111.55,107.67,104.33,67.39,66.98,56.17,55.43,53.75,50.16,49.77,26.19。
实施例15:化合物4-(3-((4-(4-(4-bromophenyl)piperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-5)的合成
化合物QJJ-5(图2)的合成同实施例11化合物QJJ-1的合成。将1-(4-溴苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-5。淡黄色固体,产率85%,m.p.145.5℃-147.2℃。
ESI-HRMS m/z:542.1761[M+H]+,calcd for C26H32BrN5O3 542.1783。1H NMR(300MHz,CDCl3)δ:8.70(s,1H),7.44–7.34(m,1H),7.26(s,1H),7.16(s,1H),6.90–6.82(m,2H),4.18(t,J=6.4Hz,2H),4.01(s,3H),3.84–3.69(m,8H),3.42–3.33(m,4H),2.61(t,J=7.2Hz,2H),2.55–2.49(m,4H),2.18–2.06(m,2H)。13C NMR(75MHz,CDCl3)δ:163.73,155.01,152.94,150.06,149.07,148.11,131.97,117.74,112.31,111.50,107.57,104.18,67.34,66.94,56.18,55.42,53.72,49.53,48.88,26.15。
实施例16:化合物4-(3-((7-methoxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-6)的合成
化合物QJJ-6(图2)的合成同实施例11化合物QJJ-1的合成。将1-(2-甲氧基苯基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-6。淡黄色固体,产率83%,m.p.87.9℃-88.7℃。
ESI-HRMS m/z:494.2762[M+H]+,calcd for C27H35N5O4 494.2768。1H NMR(300MHz,CDCl3)δ:8.69(s,1H),7.25(s,1H),7.18(s,1H),7.09–6.90(m,4H),4.16(q,J=6.1Hz,2H),4.01(s,3H),3.91(s,3H),3.87(dd,J=5.5,4.0Hz,4H),3.74–3.69(m,4H),3.35–3.23(m,4H),2.58(t,J=7.2Hz,2H),2.53–2.44(m,4H),2.15–2.02(m,2H)。13C NMR(75MHz,CDCl3)δ:163.78,154.86,153.09,152.27,149.12,147.85,140.88,123.38,121.09,118.34,111.41,107.59,104.58,67.36,66.98,56.16,55.45,53.75,50.63,49.98,26.18。
实施例17:化合物4-(3-((7-methoxy-4-(4-tosylpiperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-7)的合成
化合物QJJ-7(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1b(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-7。棕色固体,产率81%,m.p.164.4℃-167.7℃。
ESI-HRMS m/z:542.2432[M+H]+,calcd for C27H35N5O5S 542.2428。1H NMR(300MHz,CDCl3)δ:8.47(s,1H),7.75(s,1H),7.63(s,2H),7.43(s,2H),7.37(s,1H),4.03(s,2H),3.84(d,J=15.0Hz,7H),3.54(s,4H),3.04(s,4H),2.45(d,J=25.0Hz,5H),2.32(s,4H),1.83(s,2H)。13C NMR(75MHz,CDCl3)δ:156.55,152.80,149.95,143.56,141.08,135.58,129.69,127.53,112.87,110.65,109.09,67.91,67.08,56.83,53.07,52.49,48.73,45.75,28.13,21.15。
实施例18:化合物4-(3-((7-methoxy-4-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-8)的合成
化合物QJJ-8(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1c(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-8。棕色固体,产率86%,m.p.141.8-143.4℃。
ESI-HRMS m/z:558.2381[M+H]+,calcd for C27H35N5O6S 558.2368。1H NMR(300MHz,CDCl3)δ:8.49(s,1H),7.88(s,1H),7.78–7.61(m,2H),7.40(s,1H),7.18–6.93(m,2H),4.04(t,J=15.0Hz,2H),3.91–3.71(m,10H),3.55(t,J=9.4Hz,4H),3.05(t,J=10.2Hz,4H),2.48(t,J=11.0Hz,2H),2.33(t,J=9.4Hz,4H),1.83(tt,J=14.9,11.0Hz,2H)。13C NMR(75MHz,CDCl3)δ:163.15,154.97,152.66,149.20,148.21,129.87,127.04,114.39,111.08,107.62,104.03,67.41,66.94,56.16,55.63,55.29,53.73,48.96,45.56,26.14。
实施例19:化合物4-(3-((7-methoxy-4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-9)的合成
化合物QJJ-9(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1d(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-9。黄色固体,产率79%,m.p.191.5℃-194.0℃。
ESI-HRMS m/z:573.2126[M+H]+,calcd for C26H32N6O7S 573.2119。1H NMR(300MHz,CDCl3)δ:8.54(dt,J=15.0,3.1Hz,1H),8.49(s,1H),8.43(t,J=3.0Hz,1H),8.22(dt,J=15.0,3.1Hz,1H),7.97(t,J=15.0Hz,1H),7.79(s,1H),7.69(s,1H),4.04(t,J=15.2Hz,2H),3.85(dd,J=18.6,7.5Hz,7H),3.55(t,J=9.4Hz,4H),3.05(t,J=11.0Hz,4H),2.48(t,J=15.0Hz,2H),2.33(t,J=9.4Hz,4H),1.95–1.70(m,2H)。13C NMR(75MHz,CDCl3)δ:162.93,155.13,152.53,149.31,148.32,138.17,133.16,130.65,127.59,122.42,111.04,107.59,103.65,67.35,66.94,56.11,55.38,53.73,48.93,45.47,26.13。
实施例20:化合物4-(3-((7-methoxy-4-(4-(phenylsulfonyl)piperazin-1-yl)quinazolin-6-yl)oxy)propyl)morpholine(QJJ-10)的合成
化合物QJJ-10(图2)的合成同实施例11化合物QJJ-1的合成。将化合物1a(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-10。棕褐色固体,产率79%,m.p.159.1℃-160.6℃。
ESI-HRMS m/z:528.2275[M+H]+,calcd for C26H33N5O5S 528.2272。1H NMR(300MHz,CDCl3)δ:8.49(s,1H),8.07–7.77(m,3H),7.70–7.57(m,3H),7.38(s,1H),4.04(t,J=15.0Hz,2H),3.85(dd,J=17.9,7.6Hz,7H),3.55(t,J=9.3Hz,4H),3.05(t,J=10.2Hz,4H),2.48(t,J=11.0Hz,2H),2.33(t,J=9.4Hz,4H),1.83(tt,J=14.9,11.0Hz,2H)。13CNMR(75MHz,CDCl3)δ:163.04,155.27,152.79,149.17,148.13,135.80,133.09,132.78,129.07,128.94,127.73,111.07,107.74,103.91,67.48,66.95,56.18,55.38,53.61,48.93,46.83,45.55,45.29,26.13。
实施例21:化合物4-(3-((4-(4-benzylpiperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-11)的合成
化合物QJJ-11(图2)的合成同实施例11化合物QJJ-1的合成。将1-苄基哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-11。淡黄色油状,产率87%。
ESI-HRMS m/z:478.2813[M+H]+,calcd for C27H35N5O3 478.2808。1H NMR(300MHz,CDCl3)δ:8.49(s,1H),7.97(s,1H),7.79(s,1H),7.33–7.13(m,5H),4.04(t,J=15.0Hz,2H),3.87(dd,J=22.7,12.6Hz,7H),3.66(s,2H),3.55(t,J=9.4Hz,4H),2.62(t,J=10.2Hz,4H),2.48(t,J=11.0Hz,2H),2.33(t,J=9.4Hz,4H),1.83(tt,J=14.9,11.0Hz,2H)。13C NMR(75MHz,CDCl3)δ:163.23,154.91,152.57,148.86,147.88,137.51,129.16,128.15,127.44,111.03,107.71,104.65,67.36,66.96,63.10,56.10,55.46,53.73,52.95,49.68,26.12。
实施例22:化合物4-(3-((4-(4-(3-chlorobenzyl)piperazin-1-yl)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(QJJ-12)的合成
化合物QJJ-12(图2)的合成同实施例11化合物QJJ-1的合成。将1-(3-氯苄基)哌嗪(0.3mmol)替换实施例11中的1-苯基哌嗪,与化合物9a反应得到化合物QJJ-12。淡黄色油状,产率76%。
ESI-HRMS m/z:512.2423[M+H]+,calcd for C27H34ClN5O3 512.2418。1H NMR(300MHz,CDCl3)δ:8.49(s,1H),7.85(s,1H),7.48–7.30(m,4H),7.25–7.13(m,1H),4.04(t,J=15.0Hz,2H),3.87(dd,J=22.9,12.5Hz,7H),3.66(s,2H),3.55(t,J=9.4Hz,4H),2.62(t,J=10.4Hz,4H),2.48(t,J=11.0Hz,2H),2.33(t,J=9.4Hz,4H),1.83(tt,J=14.9,11.0Hz,2H)。13C NMR(75MHz,CDCl3)δ:163.22,154.51,152.86,149.23,147.49,139.85,133.80,129.60,129.00,127.41,127.14,111.26,107.45,104.55,67.34,66.95,62.40,56.12,55.38,53.71,52.90,49.64,26.13。
实施例23:化合物(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate)(3c)的合成
在圆底烧瓶中依次加入三甘醇(0.9mL,6.7mmol),四氢呋喃1.5mL,水4mL,氢氧化钠0.76g,冰浴下缓慢滴加2.2mL四氢呋喃溶解的对甲基苯磺酰氯(2.39g,12mmol),滴加完毕后冰浴下继续反应3h,结束后蒸出四氢呋喃,冷却,析出白色固体,抽滤并依次用甲醇、乙醇、冰水洗涤,干燥后得到白色固体3c(图3)。
ESI-MS:m/z 459.2[M+H]+。1H NMR(300MHz,CDCl3)δ:2.46(s,6H),3.54(s,4H),3.66(t,4H),4.15(t,4H),7.35(d,4H),7.80(d,4H)。13C NMR(75MHz,CDCl3)δ:144.9,132.9,129.9,128.0,70.7,69.2,68.7,21.7。
实施例24:化合物3,4-dihydroxybenzonitrile(5c)的合成
在圆底烧瓶中依次加入3,4-二羟基苯甲醛13.8g,盐酸羟胺16.7g,甲酸钠13.6g,甲酸50ml,加热至100℃回流6h,结束后在反应液中加入饱和食盐水,搅拌过滤,滤饼水洗,干燥,得灰色粉末5c(图3)。
ESI-MS:m/z 136.1[M+H]+。1H NMR(300MHz,CDCl3)δ:7.49(s,1H),7.36(s,1H),6.79(s,1H),3.05(s,1H),2.93(s,1H)。13C NMR(75MHz,CDCl3)δ:153.08,146.56,125.51,118.82,117.67,116.22,101.67。
实施例25:化合物2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carbonitrile(6c)的合成
在圆底烧瓶中依次加入5c 10g,四氢呋喃200mL,水40mL,氢氧化钠2.8g,氢氧化锂8.8g,氮气保护,70℃反应1h。1h后将四氢呋喃70mL溶解的3c 37.3g滴加到反应体系中,继续反应72h。反应完毕后,蒸出四氢呋喃,残留部分用二氯甲烷萃取,蒸干溶剂,得到黑色粘稠油状物。粗品经硅胶柱分离(石油醚:乙酸乙酯=4:1,体积比),可得白色固体6c(图3)。
ESI-MS:m/z 250.3[M+H]+。1H NMR(300MHz,d6-DMSO)δ:7.56(d,J=2.0Hz,1H),7.46(dd,J=8.4,2.0Hz,1H),7.21(d,J=8.4Hz,1H),4.23–4.13(m,4H),3.75–3.63(m,4H),3.58(s,4H)。13C NMR(75MHz,d6-DMSO)δ:155.29,150.54,128.20,122.64,119.32,117.93,104.19,72.73,70.99,70.69,70.36,69.11,68.92。
实施例26:化合物13-nitro-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carbonitrile(7c)的合成
在圆底烧瓶中加入质量分数65%的硝酸(38mmol,2.7ml),冷却至0℃,缓慢加入用5ml冰醋酸溶解的6c(3.8mmol,0.95g),保持0℃4h,然后加热至50℃,回流4h,结束后反应液中加入冰水洗涤,析出黄色固体,过滤,正己烷洗涤,干燥,得黄色固体7c(黄色固体,产率51%)(图3)。
ESI-MS:m/z 295.3[M+H]+。1H NMR(300MHz,CDCl3)δ:7.90(s,1H),7.37(s,1H),4.35(dd,J=8.4,4.3Hz,4H),3.98–3.80(m,4H),3.73(s,4H)。13C NMR(75MHz,CDCl3)δ:155.40,154.12,143.24,122.72,115.05,114.60,101.98,94.33,72.56,72.47,70.85,70.84,69.20,69.17。
实施例27:化合物7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4(3H)-one(8c)的合成
将7c(0.68mmol,0.2g)加入到含有20ml甲酰胺的烧瓶中,搅拌使其完全溶解,加入三氯化铟(0.68mmol,0.15g)作为催化剂。反应在微波反应器中进行(110℃,400W),反应60分钟后终止反应。向混合物中加入少量的水,并用二氯甲烷萃取。将二氯甲烷层用无水Na2SO4干燥,过滤并浓缩,得到残余物,将其通过硅胶柱(乙酸乙酯:三乙胺100:1,体积比)纯化,得到化合物8c(白色固体,产率25.6%)(图3)。
ESI-MS:m/z 293.3[M+H]+。1H NMR(300MHz,d6-DMSO)δ:12.07(s,1H),7.99(d,J=2.7Hz,1H),7.62(s,1H),7.22(s,1H),4.28–4.16(m,4H),3.81–3.66(m,4H),3.62(s,4H)。13CNMR(75MHz,d6-DMSO)δ:160.44,156.84,150.03,146.23,144.69,117.10,113.76,113.08,73.20,71.00,70.92,70.51,69.23,68.93。
实施例28:化合物4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline(9c)的合成
将8c(0.3mmol,0.1g)和N,N-二甲基甲酰胺(0.024ml)加入到含有30ml氯仿的烧瓶中,当其完全溶解时,缓慢加入草酰氯(0.86mmol,0.073ml),加热至61℃,2小时后终止反应。加入饱和碳酸氢钠溶液直至观察到pH为10.0。混合物用乙酸乙酯萃取。有机层用无水Na2SO4干燥,过滤并浓缩,得到残余物,通过硅胶柱(石油醚:乙酸乙酯=1:1,体积比)纯化,得到化合物9c(白色固体,产率65.0%)(图3)。
ESI-MS:m/z 311.7[M+H]+。1H NMR(300MHz,CDCl3)δ:8.88(s,1H),7.67(s,1H),7.41(s,1H),4.47–4.28(m,4H),4.03–3.85(m,4H),3.80(s,4H)。13C NMR(75MHz,CDCl3)δ:159.83,158.57,152.93,152.55,149.56,120.01,111.94,111.27,73.74,71.53,71.01,70.89,69.63,69.18。
实施例29:化合物4-(4-(4-fluorophenyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2,3-g]quinazoline(QJJ-13)的合成
化合物QJJ-13(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a,与1-(4-氟苯基)哌嗪(0.3mmol)合成化合物QJJ-13。淡黄色固体,产率83%,m.p.161.2℃-165.2℃。
ESI-HRMS m/z:455.2089[M+H]+,calcd for C24H27FN4O4 455.2092。1H NMR(300MHz,CDCl3)δ:8.49(s,1H),8.03(s,1H),7.81(s,1H),6.99–6.83(m,2H),6.78–6.63(m,2H),4.34–4.22(m,4H),3.88(dt,J=13.6,9.3Hz,4H),3.70(s,4H),3.65–3.47(m,8H)。13CNMR(75MHz,CDCl3)δ:163.96,156.41,153.51,150.21,149.19,147.70,118.19,118.09,115.83,115.53,113.46,111.88,111.13,74.12,71.69,70.82,69.92,69.77,69.32,50.23,49.76。
实施例30:化合物4-(4-(4-nitrophenyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2,3-g]quinazoline(QJJ-14)的合成
化合物QJJ-14(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a,与1-(4-硝基苯基)哌嗪(0.3mmol)合成化合物QJJ-14。黄色固体,产率81%,m.p.146.2℃-146.8℃。
ESI-HRMS m/z:482.2034[M+H]+,calcd for C24H27N5O6 482.2042。1H NMR(300MHz,CDCl3)δ:8.49(s,1H),8.04(s,2H),7.84(d,J=15.9Hz,2H),7.01(s,2H),4.28(d,J=10.2Hz,4H),3.93(s,2H),3.85(s,2H),3.65(s,4H),3.55(d,J=15.0Hz,8H)。13C NMR(75MHz,CDCl3)δ:163.58,156.42,154.56,153.47,150.16,149.36,138.72,125.87,113.26,112.50,111.83,111.14,74.08,71.66,70.71,69.92,69.75,69.19,48.93,46.65。
实施例31:化合物4-(4-(phenylsulfonyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxa-cyclododecino[2,3-g]quinazoline(QJJ-15)的合成
化合物QJJ-15(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a,与1a(0.3mmol)合成化合物QJJ-15。淡黄色固体,产率76%,m.p.162.1℃-163.9℃。
ESI-HRMS m/z:501.1802[M+H]+,calcd for C24H28N4O6S 501.1807。1H NMR(300MHz,CDCl3)δ:8.60(s,1H),7.78(dd,J=9.5,7.9Hz,2H),7.70–7.51(m,3H),7.31–7.24(m,2H),4.33–4.19(m,4H),4.03–3.91(m,2H),3.90–3.69(m,10H),3.29–3.13(m,4H)。13CNMR(75MHz,CDCl3)δ:156.28,152.73,151.20,141.08,137.97,134.30,129.96,128.95,112.87,110.50,109.36,70.17,68.31,48.73,45.75。
实施例32:化合物4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline(QJJ-16)的合成
化合物QJJ-16(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a,与1d(0.3mmol)合成化合物QJJ-16。黄色固体,产率75%,m.p.141.6℃-147.5℃。
ESI-HRMS m/z:546.1653[M+H]+,calcd for C24H27N5O8S 546.1659。1H NMR(300MHz,CDCl3)δ:8.58–8.50(m,1H),8.49(s,1H),8.43(t,J=3.0Hz,1H),8.22(dt,J=15.0,3.1Hz,1H),8.02–7.92(m,2H),7.85(s,1H),4.35–4.23(m,4H),3.96–3.79(m,8H),3.67(s,4H),3.05(t,J=10.2Hz,4H)。13C NMR(75MHz,CDCl3)δ:163.43,156.81,153.42,150.21,149.47,148.41,137.96,133.06,130.65,127.62,122.65,113.05,111.69,110.93,74.08,71.73,70.63,69.81,69.65,69.19,48.95,45.67。
实施例33:化合物4-(4-benzylpiperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclo-dodecino[2,3-g]quinazoline(QJJ-17)的合成
化合物QJJ-17(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a,与1-苄基哌嗪(0.3mmol)合成化合物QJJ-17。淡黄色油状,产率86%。
ESI-HRMS m/z:451.2340[M+H]+,calcd for C25H30N4O4 451.2353。1H NMR(300MHz,d6-DMSO)δ:8.49(s,1H),8.00(s,1H),7.85(s,1H),7.24(t,J=17.5Hz,5H),4.30(d,J=16.8Hz,4H),3.88(t,J=25.1Hz,8H),3.67(d,J=9.9Hz,6H),2.62(s,4H)。13C NMR(75MHz,d6-DMSO)δ:163.46,156.28,153.33,149.73,149.17,138.49,129.23,128.69,127.24,112.59,111.75,111.04,73.76,71.07,70.72,70.54,69.32,68.75,62.36,52.92,49.49。
实施例34:化合物4-(4-(3-chlorobenzyl)piperazin-1-yl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline(QJJ-18)的合成
化合物QJJ-18(图3)的合成同实施例11化合物QJJ-1的合成。即将化合物9c(0.3mmol)替换实施例11的9a,与1-(3-氯苄基)哌嗪(0.3mmol)合成化合物QJJ-18。淡黄色油状,产率85%。
ESI-HRMS m/z:485.1950[M+H]+,calcd for C25H29ClN4O4 485.1981。1H NMR(300MHz,CDCl3)δ:8.65(s,1H),7.39(d,J=4.8Hz,2H),7.31–7.23(m,4H),4.34–4.20(m,4H),4.02–3.93(m,2H),3.86(dd,J=4.6,3.1Hz,2H),3.81(s,4H),3.76–3.66(m,4H),3.57(s,2H),2.73–2.56(m,4H)。13C NMR(75MHz,CDCl3)δ:163.86,156.17,153.45,149.98,148.85,140.06,134.26,129.55,129.07,127.39,127.14,113.62,111.79,110.91,74.11,71.70,70.81,69.91,69.71,69.34,62.41,52.94,49.63。
实施例35:化合物2-methoxyethyl-4-methylbenzenesulfonate(3d)的合成
称取NaOH(14.4g,0.36mol),乙二醇单甲醚(22.8g,0.3mol),溶于THF(四氢呋喃)(90mL)和水(180mL)的混合液中,冰浴处理。2小时后,将对甲基苯磺酰氯(59.9g,0.315mol)溶于THF(150mL),滴加入上述体系,继续冰浴4h。TLC检测反应完全后,旋干THF,饱和食盐水水洗,二氯甲烷萃取,有机层加入无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(石油醚:乙酸乙酯=9:1,体积比),TLC跟踪收集,真空干燥,得油状化合物3d(产率47%)(图4)。
ESI-MS:[M+H]+m/z 231.0,[M+NH4]+m/z 248.3。1H NMR(300MHz,d6-DMSO)δ:7.79(d,J=8.3Hz,2H),7.48(d,J=8.0Hz,2H),4.16–4.08(m,2H),3.55–3.44(m,2H),3.18(s,3H),2.41(s,3H)。13C NMR(75MHz,d6-DMSO)δ:145.37,132.85,130.57,128.06,70.17,69.71,58.37,21.50。
实施例36:化合物3,4-bis(2-methoxyethoxy)benzaldehyde(4d)的合成
称取3,4-二羟基苯甲醛(6.9g,0.05mol),溶于乙腈(300mL),加入碳酸钾(13.8g,0.1mol)、化合物3d(23.1g,0.1mol),抽真空,N2保护,84℃反应36h。TLC检测反应完全后,抽滤,取滤液,旋干乙腈。饱和食盐水水洗,乙酸乙酯萃取,有机层加入无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(石油醚:乙酸乙酯=4:1,体积比)。TLC跟踪收集,真空干燥,得橙色油状化合物4d(产率80.3%)(图4)。
ESI-MS:[M+H]+m/z 255.3,[M+Na]+m/z 277.3。1H NMR(300MHz,CDCl3)δ:9.79(s,1H),7.40(dt,J=8.2,2.6,1.8Hz,2H),6.96(d,J=8.0Hz,1H),4.23–4.13(m,4H),3.76(dt,J=6.2,3.8Hz,4H),3.41(s,6H)。13C NMR(75MHz,CDCl3)δ:190.90,154.35,149.16,130.20,126.75,112.43,111.70,70.76,70.66,68.57,68.55,59.27,59.19。
实施例37:化合物3,4-bis(2-methoxyethoxy)benzonitrile(5d)的合成
称取甲酸钠(2.68g,39.9mmol)溶解于甲酸(1.63g,35.4mmol)中,加入化合物4d(5.0g,19.69mmol),加热至85℃后加入盐酸羟胺(3.3g,47.2mmol),反应5h后,冷至室温。将反应液倒入冷的饱和食盐水中,搅拌,析出大量白色固体,过滤得粗品,乙酸乙酯重结晶,干燥得白色固体化合物5d(产率75.5%)(图4)。
ESI-MS:[M+H]+m/z 252.3,[M+NH4]+m/z 269.3。1H NMR(300MHz,CDCl3)δ:7.27(dd,J=8.4,2.0Hz,1H),7.15(d,J=1.9Hz,1H),6.93(dd,J=8.4,2.7Hz,1H),4.25–4.13(m,4H),3.79(dt,J=4.3,3.1Hz,4H),3.45(d,J=0.9Hz,6H)。13C NMR(75MHz,CDCl3)δ:152.93,148.90,126.83,119.16,117.05,113.51,104.17,70.80,70.69,69.05,68.62,59.29,59.25。
实施例38:化合物4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile(6d)的合成
称取质量分数65%的硝酸(10.5mL),置于低温反应仪里,0℃预冷30min。将化合物5d(3.7g,14.8mmol)溶于冰醋酸(8.0mL)后,滴加入上述体系,0℃继续反应。4h后,升温至50℃继续反应。4h后,加入30mL冰水洗涤,过滤,滤饼用冰水洗涤、正己烷洗涤,干燥,得黄色固体化合物6d(产率50%)(图4)。
ESI-MS:[M+H]+m/z 297.3。1H NMR(300MHz,CDCl3)δ:7.87(s,1H),7.29(s,1H),4.31(td,J=6.2,4.6Hz,4H),3.88–3.79(m,4H),3.47(s,6H)。13C NMR(75MHz,CDCl3)δ:153.16,151.90,142.69,117.32,115.55,109.62,100.85,70.51,70.45,69.61,69.42,59.38。
实施例39:化合物6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one(7d)的合成
称取化合物6d(0.4g,1.35mmol),三氯化铟(0.3g,1.35mmol)溶于甲酰胺(20mL),进行微波反应1h,微波反应仪设置参数温度为110℃,功率为400w。反应结束后过滤,滤液用饱和食盐水水洗,乙酸乙酯萃取,有机层减压浓缩,再用少量乙酸乙酯重结晶,得白色固体化合物7d(产率50%)(图4)。
ESI-MS:[M+H]+m/z 295.3,[M+Na]+m/z 317.3。1H NMR(300MHz,CDCl3)δ:12.17(s,1H),8.04(s,1H),7.51(s,1H),7.09(s,1H),4.36–4.14(m,4H),3.83(s,4H),3.45(d,J=0.7Hz,6H)。13C NMR(75MHz,CDCl3)δ:162.39,154.74,148.62,145.33,142.76,115.65,109.06,106.47,70.63,70.48,68.50,68.43,59.27,59.23。
实施例40:化合物4-chloro-6,7-bis(2-methoxyethoxy)quinazoline(8d)的合成
称取化合物7d(0.13g,0.44mmol)溶于氯仿(20mL),加入N,N-二甲基甲酰胺(0.03g,0.38mmol)。滴加草酰氯(0.14g,1.1mmol),61℃回流2h。TLC检测反应完全后,用饱和碳酸氢钠水溶液洗涤,乙酸乙酯萃取,有机层加入无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(石油醚:乙酸乙酯=1:1,体积比)。TLC跟踪收集,真空干燥,得白色固体化合物8d(产率94%)(图4)。
ESI-MS:[M+H]+m/z 313.3。1H NMR(300MHz,d6-DMSO)δ:8.48(s,1H),7.47(s,1H),7.26(s,1H),4.24(ddd,J=9.3,5.3,3.7Hz,4H),3.74(ddd,J=9.1,8.0,4.6Hz,4H),3.35(dd,J=5.8,2.2Hz,6H)。13C NMR(75MHz,d6-DMSO)δ:159.40,154.75,148.92,146.05,139.75,115.35,107.24,106.06,70.55,70.39,68.85,68.73,58.81,58.76。
实施例41:化合物6,7-bis(2-methoxyethoxy)-4-(4-(phenylsulfonyl)piperazin-1-yl)quinazoline(QJJ-19)的合成
称取化合物8d(0.1g,0.32mmol),溶解于N,N-二甲基甲酰胺(20mL),加入化合物1a(0.15g,0.64mmol)和三乙胺(0.1mL),进行微波反应20min,微波反应仪设置参数温度为120℃,功率为300w。反应结束后用饱和食盐水水洗,乙酸乙酯萃取,有机层加入无水硫酸钠干燥,减压浓缩,硅胶柱层析分离(洗脱剂:石油醚:乙酸乙酯=1:1(体积比),再加入1%(v/v)三乙胺)。TLC跟踪收集,真空干燥,得白色固体化合物QJJ-19(产率50%),m.p.89.9~90.4℃(图4)。
ESI-MS:[M+H]+m/z 503.2。1H NMR(300MHz,CDCl3)δ:8.54(s,1H),7.78–7.72(m,2H),7.61–7.48(m,3H),7.16(s,1H),7.06(s,1H),4.26–4.14(m,4H),3.78(ddd,J=6.2,4.6,3.3Hz,4H),3.73–3.66(m,4H),3.40(d,J=6.4Hz,6H),3.21–3.13(m,4H)。13C NMR(75MHz,CDCl3)δ:163.26,154.51,152.80,149.26,148.24,135.56,133.11,129.24,127.69,111.28,108.49,105.81,71.11,70.38,69.22,68.25,59.27,59.22,48.97,45.66。ESI-HRMS m/z:503.1961[M+H]+,calcd for C24H30N4O6S 503.1959。
实施例42:化合物6,7-bis(2-methoxyethoxy)-4-(4-tosylpiperazin-1-yl)quinazoline(QJJ-20)的合成
化合物QJJ-20的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1b(0.15g,0.64mmol)替换化合物1a,得油状化合物QJJ-20(产率62%)(图4)。
ESI-MS:[M+H]+m/z 517.2。1H NMR(300MHz,CDCl3)δ:8.56(s,1H),7.72–7.65(m,2H),7.17(s,1H),7.08(s,1H),7.01–6.98(m,1H),6.98–6.95(m,1H),4.21(ddd,J=12.8,5.4,3.9Hz,4H),3.87–3.75(m,7H),3.75–3.67(m,4H),3.42(d,J=4.7Hz,6H),3.19–3.12(m,4H)。13C NMR(75MHz,CDCl3)δ:163.25,154.50,152.81,149.25,148.20,143.98,132.44,129.86,127.76,111.24,108.46,105.87,71.11,70.38,69.22,68.25,59.28,59.24,48.95,45.67,21.55。ESI-HRMS m/z:517.2124[M+H]+,calcd for C25H32N4O6S 517.2115。
实施例43:化合6,7-bis(2-methoxyethoxy)-4-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)quinazoline(QJJ-21)的合成
化合物QJJ-21的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1c(0.16g,0.64mmol)替换化合物1a,得油状化合物QJJ-21(产率65%)(图4)。
ESI-MS:[M+H]+m/z 533.5。1H NMR(300MHz,CDCl3)δ:8.56(s,1H),7.76–7.61(m,2H),7.17(s,1H),7.08(s,1H),7.02–6.94(m,2H),4.21(ddd,J=12.8,5.4,3.9Hz,4H),3.89–3.75(m,7H),3.74–3.67(m,4H),3.42(d,J=4.7Hz,6H),3.22–3.06(m,4H)。13C NMR(75MHz,CDCl3)δ:163.28,163.20,154.53,152.86,149.32,148.22,129.87,126.99,114.39,111.28,108.54,105.96,71.14,70.41,69.28,68.27,59.31,59.26,55.63,48.95,45.68。ESI-HRMS m/z:533.2089[M+H]+,calcd for C25H32N4O7S 533.2064。
实施例44:化合物6,7-bis(2-methoxyethoxy)-4-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)quinazoline(QJJ-22)的合成
化合物QJJ-22的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1d(0.17g,0.64mmol)替换化合物1a,得橙黄色固体化合物QJJ-22(产率64%),m.p.155.8~156.2℃(图4)。
ESI-MS:[M+H]+m/z 548.2。1H NMR(300MHz,CDCl3)δ:8.60(d,J=8.6Hz,2H),8.48(d,J=8.1Hz,1H),8.12(d,J=7.7Hz,1H),7.80(t,J=8.0Hz,1H),7.21(s,1H),7.09(s,1H),4.31–4.17(m,4H),3.88–3.71(m,8H),3.45(d,J=5.1Hz,6H),3.34–3.22(m,4H)。13CNMR(75MHz,CDCl3)δ163.17,154.62,152.79,149.29,148.43,148.39,138.15,133.15,130.78,127.60,122.73,111.30,108.51,105.61,71.15,70.40,69.24,68.31,59.33,59.27,48.94,45.62。ESI-HRMS m/z:548.1809[M+H]+,calcd for C24H29N5O8S 548.1810。
实施例45:化合物6,7-bis(2-methoxyethoxy)-4-(4-phenylpiperazin-1-yl)quinazoline(QJJ-23)的合成化合物QJJ-23的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-苯基哌嗪(0.1g,0.64mmol)替换化合物1a,得油状化合物QJJ-23(产率55%)(图4)。
ESI-MS:[M+H]+m/z 439.1。1H NMR(300MHz,CDCl3)δ:8.69(s,1H),7.38–7.23(m,4H),7.00(d,J=7.9Hz,2H),6.91(t,J=7.3Hz,1H),4.35–4.22(m,4H),3.93–3.75(m,8H),3.48(s,6H),3.45–3.36(m,4H)。13C NMR(75MHz,CDCl3)δ:163.82,154.41,153.08,151.08,149.15,148.11,129.24,120.22,116.24,111.55,108.52,106.08,71.11,70.48,69.13,68.31,59.39,59.32,49.70,49.19。ESI-HRMS m/z:439.2344[M+H]+,calcd for C24H30N4O4439.2340。
实施例46:化合物4-(4-(4-fluorophenyl)piperazin-1-yl)-6,7-bis(2-methoxyethoxy)quinazoline(QJJ-24)的合成
化合物QJJ-24的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(4-氟苯基)哌嗪(0.12g,0.64mmol)替换化合物1a,得油状化合物QJJ-24(产率50%)(图4)。
ESI-MS:[M+H]+m/z 457.5。1H NMR(300MHz,CDCl3)δ:8.68(s,1H),7.27(s,1H),7.25(s,1H),7.07–6.90(m,4H),4.37–4.19(m,4H),3.93–3.70(m,8H),3.48(s,6H),3.37–3.26(m,4H)。13C NMR(75MHz,CDCl3)δ:163.81,154.43,153.05,149.15,148.13,147.77,147.74,118.16,118.05,115.80,115.51,111.55,108.51,106.02,71.10,70.47,69.11,68.31,59.38,59.30,50.20,49.72。ESI-HRMS m/z:457.2245[M+H]+,calcd for C24H29FN4O4457.2246。
实施例47:化合物6,7-bis(2-methoxyethoxy)-4-(4-(2-methoxyphenyl)piperazin-1-yl)quinazoline(QJJ-25)的合成
化合物QJJ-25的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(2-甲氧基苯基)哌嗪(0.13g,0.64mmol)替换化合物1a,得油状化合物QJJ-25(产率59%)(图4)。
ESI-MS:[M+H]+m/z 469.4。1H NMR(300MHz,CDCl3)δ:8.65(s,1H),7.26(t,J=7.3Hz,2H),7.11–6.81(m,4H),4.32–4.17(m,4H),3.93–3.78(m,11H),3.45(s,6H),3.25(s,4H)。13C NMR(75MHz,CDCl3)δ:163.72,154.26,153.05,152.24,149.07,147.88,140.86,123.36,121.05,118.34,111.37,108.40,106.20,71.05,70.46,69.04,68.25,59.33,59.27,55.43,50.63,49.91。ESI-HRMS m/z:469.2446[M+H]+,calcd forC25H32N4O5469.2445。
实施例48:化合物6,7-bis(2-methoxyethoxy)-4-(4-(4-nitrophenyl)piperazin-1-yl)quinazoline(QJJ-26)的合成
化合物QJJ-26的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(4-硝基苯基)哌嗪(0.13g,0.64mmol)替换化合物1a,得橙黄色固体化合物QJJ-26(产率59%),m.p.140.4~141.9℃(图4)。
ESI-MS:[M+H]+m/z 484.4。1H NMR(300MHz,CDCl3)δ:8.65(d,J=4.7Hz,1H),8.16–8.01(m,2H),7.30–7.20(m,2H),6.91–6.77(m,2H),4.32–4.19(m,4H),3.91–3.76(m,8H),3.62(dd,J=6.2,3.9Hz,4H),3.45(d,J=1.0Hz,6H)。13C NMR(75MHz,CDCl3)δ:163.39,154.60,154.50,152.93,149.22,148.23,138.66,125.91,112.58,111.37,108.53,105.78,71.09,70.44,69.16,68.32,59.36,59.28,48.87,46.61。ESI-HRMS m/z:484.2186[M+H]+,calcd for C24H29N5O6 484.2191。
实施例49:化合物4-(4-benzylpiperazin-1-yl)-6,7-bis(2-methoxyethoxy)quinazoline(QJJ-27)的合成化合物QJJ-27的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-苄基哌嗪(0.12g,0.64mmol)替换化合物1a,得油状化合物QJJ-27(产率62%)(图4)。
ESI-MS:[M+H]+m/z 453.5。1H NMR(300MHz,CDCl3)δ:8.63(s,1H),7.38–7.25(m,5H),7.20(d,J=3.1Hz,2H),4.24(ddd,J=14.0,5.4,4.0Hz,4H),3.83(dd,J=9.6,5.0Hz,4H),3.71–3.63(m,4H),3.59(s,2H),3.46(s,6H),2.69–2.61(m,4H)。13C NMR(75MHz,CDCl3)δ:163.75,154.19,153.12,149.15,147.80,137.75,129.17,128.32,127.23,111.42,108.47,106.24,71.01,70.46,69.01,68.21,63.07,59.33,59.27,52.97,49.66。ESI-HRMSm/z:453.2493[M+H]+,calcd for C25H32N4O4 453.2496。
实施例50:化合物4-(4-(3-chlorobenzyl)piperazin-1-yl)-6,7-bis(2-methoxyethoxy)quinazoline(QJJ-28)的合成
化合物QJJ-28的具体合成方法可参照实施例41化合物QJJ-19的合成步骤。称取化合物1-(3-氯苄基)哌嗪(0.12g,0.64mmol)替换化合物1a,得油状化合物QJJ-28(产率65%)(图4)。
ESI-MS:[M+H]+m/z 487.3。1H NMR(300MHz,CDCl3)δ:8.64(s,1H),7.28(s,1H),7.24(dt,J=11.6,3.8Hz,5H),4.26(ddd,J=13.9,5.4,4.1Hz,4H),3.84(dd,J=9.5,5.5Hz,4H),3.72–3.63(m,4H),3.56(s,2H),3.48–3.44(m,6H),2.68–2.61(m,4H)。13C NMR(75MHz,CDCl3)δ:163.74,154.26,153.09,149.15,147.87,140.08,134.24,129.60,129.03,127.41,127.16,111.43,108.48,106.25,71.04,70.47,69.07,68.25,62.40,59.35,59.29,52.95,49.64。ESI-HRMS m/z:487.2108[M+H]+,calcd for C25H31ClN4O4487.2107。
实施例51:苯基哌嗪喹唑啉类化合物抗癌细胞增殖活性实验
本实施例选用的细胞为***Hela细胞系,人肺腺癌H1299细胞系,人肺腺癌A549细胞系(上海中国科学院细胞库),采用含1%(w/v)双抗(青霉素和链霉素)、10%(v/v)FBS(胎牛血清)血清的RPMI 1640培养基(Gibco)进行细胞培养,采用MTT法来检测细胞增殖及凋亡。试验方法简述如下:
(1)实验样品:化合物QJJ-1~QJJ-28及阳性对照厄洛替尼(Erlotinib)。
(2)配药:将上述化合物的浓溶液(母液浓度为200mmol/L)分别用培养基稀释到所需的一系列浓度,用于化合物对各肿瘤细胞的IC50(半数抑制浓度)的测定。
(3)种板:取对数生长期的所需细胞,以5×103/孔的密度种植在96孔板中,每孔100μL,边缘孔用100μL无菌PBS填充,将细胞放入37℃,5%CO2的恒温培养箱中培养过夜。
(4)加药:24h后,将96孔板中的原培养基小心吸掉,设置空白对照组和加药组。空白组加入不含药培养基100μL,实验组加入含药培养基100μL,每个浓度设置6个复孔,置于37℃,5%CO2的恒温培养箱中继续培养72h。
(5)加入MTT:作用72h后每孔再加入15μL MTT溶液(0.5%),恒温培养箱继续作用4h。
(6)DMSO溶解:4h后,将上清液吸干,小心不要破坏底部细胞,每孔加入150μL DMSO(二甲基亚砜)振摇10min,以使甲瓒充分溶解。
(7)IC50的测定:用多功能酶标仪在570nm波长处测定吸光值,计算细胞生长抑制率(%):生长抑制率=1-药物组A570nm值/对照组A570nm值;绘制曲线,计算IC50。
化合物QJJ-1~QJJ-28及厄洛替尼对三种癌细胞株的IC50值测定结果如表1所示。结果显示,本发明制备的苯基哌嗪喹唑啉类化合物QJJ-1~QJJ-28均对所考察的三种肿瘤细胞的生长有不同程度的抑制作用,一些化合物如QJJ-12、QJJ-18、QJJ-28显示出较好的体外抗癌活性。
表1化合物QJJ-1~QJJ-28及厄洛替尼对三种癌细胞的IC50值
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实施例52:EGFR野生型(EGFR wt)以及EGFR T790M/L858R双突变型激酶抑制实验
(1)实验样品:QJJ-12、QJJ-18、QJJ-28,阳性对照厄洛替尼(Erlotinib)。
(2)实验试剂盒:采用美国promega公司的ADP-GloTM Kinase Assay试剂盒,该ADP-GloTM Kinase Assay是发光法检测试剂盒,用于检测激酶反应中所形成的ADP(二磷酸腺苷);ADP被转化成ATP(三磷酸腺苷),然后ATP再被萤光素酶转化成光,发光信号与激酶活性正相关。按照试剂盒说明使用试剂盒中相应的组分准备反应组分,并进行相应的实验操作,测定待测化合物对激酶活性的影响。
(3)准备反应组分:
①取38.8μL超纯水,160μL 5×Reaction Buffer A,0.4μL DTT(100mM)和0.8μLMnCl2(2.5mM),在1.5ml离心管中配制成200μL的4×Reaction Buffer A+DTT+MnCl2,震荡混匀。
②取79.6μL超纯水,0.4μL 10mMΜLtra-Pure ATP,在1.5ml离心管中配制80μL的50uM ATP,震荡混匀。
③取62.5μL4×Reaction Buffer A+DTT+MnCl2,62.5μL 50uM ATP,125μL Poly(Glu:Tyr=4:1,w/w)peptide(1mg/ml),在1.5ml离心管中配制250μL的2.5×ATP/Substrate Mix,震荡混匀。
④取146μL超纯水,50μL4×Reaction Buffer A+DTT+MnCl2,4μL EGFR激酶(100ng/μL;Promega Corporation),在1.5ml离心管中配制200μL的EGFR激酶溶液,吹打混匀。
⑤取105μL超纯水,37.5μL 4×Reaction Buffer A+DTT+MnCl2,7.5μL EGFRT790M/L858R激酶(100ng/μL;Promega Corporation),在1.5ml离心管中配制150μL的EGFR激酶溶液,吹打混匀。
⑥取15μL超纯水,5μL 4×Reaction Buffer A+DTT+MnCl2,在1.5ml离心管中配制20μL的1×Reaction Buffer用作无激酶的对照,震荡混匀。
(4)将化合物进行梯度稀释:取299.5μL超纯水,80μL 5×Reaction Buffer A,0.2μL DTT(100mM),0.3μL MnCl2(2.5mM)和20μL DMSO,在1.5ml离心管中配制400μL的1×Reaction Buffer+5%DMSO,震荡混匀。将10μL上述液体加入下面384孔板的A2~A24:A1孔不加。取14μL超纯水,5μL 4×Reaction Buffer A+DTT+MnCl2和1μL化合物(DMSO溶解至1mM),在1.5ml离心管中,配制20μL的50μM抑制剂(5%DMSO)。震荡混匀,转移到A1孔(在激酶反应体系中的终浓度将为10μM,1%DMSO)。从A1孔吸出10μL转移至A2孔,吹打6~10次混匀(注意不要吹出气泡)。依次稀释至A21孔,每孔浓度依次是10000nM,5000nM,2500nM……0.04nM,0.02nM,0.01nM。不要向A22、A23和A24孔转移液体。
(5)激酶反应:将配制好的激酶溶液(步骤(3)④、⑤)每孔2μL加入B1至B23孔,B24孔不加。向无激酶的孔中加入2μL的1×Reaction Buffer(B24孔)。加入1μL梯度稀释的化合物,将反应板放在摇床上600rpm混匀1~2min,室温孵育10min。向所有的反应孔中加入2μL的2.5×ATP/Substrate Mix(来源于ADP-GloTM Kinase Assay试剂盒),将反应板放在摇床上600rpm混匀1~2min,室温孵育60min。
(6)ADP-Glo试剂检测生成的ADP:在室温融化ADP-Glo Reagent,向所有的反应孔中加入5μL ADP-Glo Reagent,将反应板放在摇床上600rpm混匀1~2min。室温孵育40min,按试剂盒说明书配制Kinase Detection Reagent,将Kinase Detection Buffer转移到Kinase Detection Substrate瓶中,颠倒数次混匀。向所有的反应孔中加入10μL KinaseDetection Reagent,将反应板放在摇床上600rpm混匀1~2min。室温孵育至少30min,用发光检测仪读取光信号值,分析数据。
结果表明,化合物QJJ-12、QJJ-18和QJJ-28都能抑制野生型EGFR,且QJJ-12与阳性药厄洛替尼无甚差异,QJJ-12和QJJ-28对EGFR T790M/L858R双突变型激酶抑制活性优于厄洛替尼。
表2待测化合物对EGFR野生型激酶及EGFR T790M/L858R双突变型激酶活性的影响
实施例53:细胞划痕试验
本项实验采用HUVEC人脐静脉内皮细胞(上海中乔新舟生物科技有限公司)作为研究对象。先用马克笔在6孔板背后,用直尺比着,均匀得划横线,大约每隔0.5cm至1cm一道,横穿过孔,每孔至少穿过3条线。每孔中加入约5×105个细胞,将细胞放入37℃,5%CO2的恒温培养箱中培养。24h后细胞铺满90%,用枪头比着直尺,尽量垂直于背后的横线划痕,枪头要垂直,不能倾斜。用PBS洗细胞3次,去除划下的细胞,空白组加入无血清培养基2mL,实验组加入QJJ-28(10ummol/L)无血清培养基2mL,放入37℃,5%CO2的恒温培养箱中培养。于0,6,12和24小时观察拍照,记录划痕宽度并计算每孔平均值,最后计算各时间点的平均划痕愈合率%,重复3次。
结果显示,6小时空白组愈合率为19%,加药组为11%;12小时空白组愈合率为23%,加药组为12%;24小时空白组愈合率为35%,加药组为13%。可以看出,化合物QJJ-28能抑制HUVEC细胞水平迁移能力,细胞迁移速度受到了明显的抑制(图5)。
实施例54:整合素αvβ3受体结合试验
采用竞争抑制实验测定化合物QJJ-12、QJJ-28与HUVEC细胞上整合素αvβ3受体的结合情况。取对数生长期的HUVEC细胞,以5×105/孔的密度种植在6孔板中,培养过夜。阴性对照组直接加入含血清不含药物的培养基,实验组分别加入终浓度为0、10、20、40μmol/L的含QJJ-12、QJJ-28以及40μmmol/L的含厄洛替尼的血清培养基。作用24h后,阴性对照组加入FITC标记小鼠IgG-1(2μL/mL细胞悬液,Millipore),实验组加入FITC-αvβ3(LM609)(2μL/mL细胞悬液,Millipore)。避光孵育1h后,上流式细胞仪检测,激发波长和发射波长分别为488和525nm,计算10000个细胞的阳性细胞率。实验重复3次。
流式细胞仪检测结果显示,随着化合物QJJ-12和QJJ-28浓度的降低,阳性细胞率逐渐升高,表明化合物QJJ-12和QJJ-28能够与αvβ3抗体竞争结合HUVEC细胞表面的整合素αvβ3受体(图6、7)。
实施例55:体内抗肿瘤活性研究
(1)取对数生长期A549细胞无菌操作下吸出所有培养基,并用PBS反复对细胞进行三次洗涤,为避免细胞脱落洗涤时尽量轻柔,以去除残余培养基中的蛋白成分,以0.25%胰酶对A549细胞进行消化成细胞悬液,然后将所有消化后的细胞放入离心管离心(1000r/min),离心后用基质胶溶解,溶液比例为:基质胶:PBS=1:1,v/v,100μL双抗/2ml,经计数后调整浓度为1.0×107细胞/毫升。每只裸鼠腋下皮下注射瘤液0.2毫升,即每鼠种植瘤细胞约为2.0×106细胞建立异体移植肿瘤模型。所有裸鼠在无特定病原体(SPF)条件下的层流架中饲养。经无菌处理的水和饲料供动物自由摄入,高温消毒的饲料,垫料每三天更换一次,笼具及饮水瓶每三天紫外线消毒一次,饮用无菌蒸馏水,更换饲养用品时严格遵循无菌原则操作。每日观察裸鼠精神、呼吸、运动以及肿瘤的生长情况。
待肿瘤生长至约100~200mm3后按照下列分组情况随机分组。将25只接种A549肿瘤细胞成功的裸鼠随机分为5组,每组5只,即:
①PBS对照组;
②QJJ-12组(0.034mmol/kg;QJJ-12L);
③QJJ-12组(0.102mmol/kg;QJJ-12M);
④QJJ-12组(0.306mmol/kg;QJJ-12H);
⑤吉非替尼组(Gefitinib,0.102mmol/kg)。
(2)各组接种后于第3、6、9、12、15、18天(间隔3~4天)分别尾静脉给予相应的化合物或PBS,每日称量小鼠体重,肿瘤体积,同时观察小鼠的生长状态,于接种21天后,将小鼠拉断颈椎处死,剥离瘤体,取各组织器官(包括脑,心,肝,脾,肺,肾),称瘤重,计算瘤重抑制率。将各组的抗肿瘤活性进行比较,评价化合物QJJ-12体内抗肿瘤作用。
①日常观察:接种肿瘤细胞和给药后,观察裸鼠的精神状态,饮食饮水等一般状况及死亡情况;详细观察记录移植部位有无感染,肿瘤或肿块出现的时间。
②裸鼠体重:每3日称量每只裸鼠的体重,记录好数据并绘制每组裸鼠体重变化曲线。
③肿瘤测量:每3日用精密游标卡尺测量移植瘤大小,按以下公式计算肿瘤体积(tumor volume,TV),计算公式为:TV=0.5×a×b2(其中a、b分别表示长、宽)。根据公式计算肿瘤体积并绘制生长曲线。实验结束时称瘤质量,计算各组的抑瘤率%。
给药后裸鼠体重变化曲线如图8所示。从图中可以看出给药后空白组体重明显上升,化合物QJJ-12组在低剂量组(QJJ-12L)的体重略有上升,中剂量组(QJJ-12M)体重变化无显著性差异,高剂量组(QJJ-12H)体重略有下降,而阳性药吉非替尼组从第二次给药开始体重下降明显。对比整个实验各组给药前后裸鼠体重的变化如图9所示。从图中可以看出给药前后空白组和化合物QJJ-12组在低剂量组体重上升明显,中剂量组和高剂量组体重略有下降,体重变化无显著性差异,而阳性药吉非替尼组体重下降明显。根据裸鼠体重测量结果,可知在实验选取的浓度范围内,化合物QJJ-12对实验裸鼠体重无显著性影响,而阳性药吉非替尼组使实验裸鼠体重显著下降。
给药结束后,解剖得到各组裸鼠肿瘤组织,如图10所示。在整个给药实验过程中,肿瘤体积生长曲线结果如图11所示,空白组肿瘤体积增长最快,QJJ-12低剂量组和中剂量组对肿瘤的增长抑制作用较弱,而高剂量组和阳性药吉非替尼组均能显著性抑制肿瘤体积的增长。
实验各组裸鼠的肿瘤生长抑制率结果如图12所示,可知QJJ-12低剂量组和中剂量组抑制率分别为25.15%、31.07%,而高剂量组和阳性药吉非替尼组抑制率均高于40%,分别为57.55%、52.46%,显示出良好的肿瘤生长抑制作用。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (7)
1.一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐,选自化合物QJJ-19- QJJ-21、QJJ-23- QJJ-25、QJJ-28的任一种: 。
2.权利要求1所述的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐的制备方法,包括以下步骤:
(1)以乙二醇单甲醚为起始原料,将其与对甲基苯磺酰氯在四氢呋喃中发生亲核取代反应,得到2-甲氧基乙基-4-甲基苯磺酸酯;
(2)2-甲氧基乙基-4-甲基苯磺酸酯与3,4-二羟基苯甲醛在乙腈中,氮气保护下发生取代,生成3,4-二-(2-甲氧乙氧基)苯甲醛;
(3)3,4-二-(2-甲氧乙氧基)苯甲醛的醛基经盐酸羟胺还原,得到3,4-二-(2-甲氧乙氧基)苯甲腈;
(4)3,4-二-(2-甲氧乙氧基)苯甲腈低温下与浓硝酸反应,硝化得到4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈;
(5)4,5-二-(2-甲氧乙氧基)-2-硝基苯甲腈经过在甲酰胺中,与三氯化铟微波Niementowski环合得到6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮;
(6)6,7-二-(2-甲氧基乙氧基)-3H-4-喹唑啉酮经草酰氯氯代后,得到4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉;
(7)4-氯-6,7-二-(2-甲氧基乙氧基)喹唑啉分别与1-苯磺酰基哌嗪、1-对甲苯磺酰哌嗪、1-(4-甲氧基苯磺酰)哌嗪、1-苯基哌嗪、1-(4-氟苯基)哌嗪、1-(2-甲氧基苯基)哌嗪、1-(3-氯苄基)哌嗪反应,即得。
3.权利要求1所述的苯基哌嗪喹唑啉类化合物或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***。
4.权利要求1中所述的苯基哌嗪喹唑啉类化合物QJJ-20或其药学上可接受的盐在制备抗肿瘤药物中的应用,所述的肿瘤为非小细胞肺癌H1299。
5.权利要求1中所述的苯基哌嗪喹唑啉类化合物QJJ-21、QJJ-23- QJJ-25、QJJ-28或其药学上可接受的盐在制备抗肿瘤药物中的应用,所述的肿瘤为非小细胞肺癌A549和H1299。
6.权利要求1中所述的苯基哌嗪喹唑啉类化合物QJJ-28或其药学上可接受的盐在制备抑制EGFR激酶的药物、抑制整合素αvβ3受体的药物、或抑制HUVEC细胞迁移的药物中的应用。
7.权利要求1中所述的苯基哌嗪喹唑啉类化合物QJJ-28或其药学上可接受的盐在制备抑制EGFR T790M/L858R双突变型激酶的药物中的应用。
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