CN107176932B - 苯并恶嗪酮衍生物及其制备方法和用途 - Google Patents
苯并恶嗪酮衍生物及其制备方法和用途 Download PDFInfo
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- CN107176932B CN107176932B CN201710396333.4A CN201710396333A CN107176932B CN 107176932 B CN107176932 B CN 107176932B CN 201710396333 A CN201710396333 A CN 201710396333A CN 107176932 B CN107176932 B CN 107176932B
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- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- -1 carbomethoxy group Chemical group 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
- C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域,具体涉及苯并恶嗪酮衍生物及制备方法和在相关的疾病中的应用。本发明提供了苯并恶嗪酮衍生物,具体结构为式I或式II所示。本发明还提供了式I或式II所示的合成方法及其在相关的疾病中的应用,主要涉及到肿瘤、心血管疾病、神经退行性疾病、代谢类疾病、炎性疾病等。
Description
技术领域
本发明属于药物化学领域,具体涉及式I或式II所示的苯并恶嗪酮衍生物及其制备方法和其在相关疾病中的应用,主要涉及肿瘤、心血管疾病、神经退行性疾病、代谢性疾病、炎性疾病等。
背景技术
肿瘤是对人类健康危害最大的疾病之一,严重影响人们生活质量。近年来,化学药物作为治疗肿瘤的重要手段之一,已经取得巨大的进步和发展。目前,已开发出很多具有不同作用机制的抗肿瘤药物,但是这些药物在临床使用中表现出许多缺陷,比如选择性差、毒副作用大、快速产生耐药性等。因此,新型抗肿瘤药物的研究与开发尤为重要。
苯并恶嗪酮衍生物是一类重要的含氮杂环化合物,该骨架广泛存在于天然产物、生物活性分子和药物分子中。研究表明,此类化合物具有良好而广泛的药理活性,可用于抗炎、抗肿瘤、抗血栓形成、减肥、代谢紊乱和神经退行性疾病等的治疗。例如,化合物A是组蛋白去乙酰化酶(HDAC)抑制剂,用于治疗癌症和炎症。科特斯医药品公司开发的化合物CX-614正在处于研究阶段,有望成为帕金森综合症和阿尔茨海默症治疗药物。
由于苯并恶嗪酮衍生物在有机化学和医药领域具有重要的作用,因此关于该骨架的合成研究较多。传统的合成方法是利用官能化的邻羟基苯甲酰胺衍生物与醛或酮在酸性条件下反应。近年来,新的合成策略被报道,包括官能化邻羟基苯甲醛和亚胺的直接亚胺酰化反应(DIA),环化亚胺、邻氟代酰氯和含氧亲核试剂的三组分反应,以及过渡金属(如铜、钯、锡、钴等)催化的交叉脱氢偶联反应、分子内的多米诺反应、氧化脱芳化反应、脱乙酰化反应、自由化反应等。以上所述的合成方法由于反应条件苛刻、收率低、成本高、重金属残留等缺陷,无法实现工业化大量生产制备,限制了其在医药生产上的应用。
本发明合成一系列结构新颖的苯并恶嗪酮衍生物,并对其进行了肿瘤细胞毒性试验,证明该类苯并恶嗪酮衍生物具有肿瘤抑制活性。
苯并恶嗪酮衍生物结构新颖,表现出优良的抗肿瘤活性。目前还没有经济、高效的合成工艺,更无相关大批量生产制备工艺报道。本发明通过高效、经济、环保的合成方法提供苯并恶嗪酮衍生物,为肿瘤、心血管疾病、神经退行性疾病、代谢性疾病、炎性疾病等相关疾病的预防和治疗提供新策略。
发明内容
本发明针对现有技术的不足,提供了一系列结构新颖的苯并恶嗪酮衍生物及其制备方法和医药用途。
本发明提供的苯并恶嗪酮衍生物是式I或式II所示的化合物。
R1和R6相同或不相同代表氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环。
Y选自O或S中的一种。
Z选自O、NH或S中的一种。
X代表羟基、卤素、CN、OR7、OCF3、SCF3、SR7、NR7R8、NO2、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;其中所述R7和R8同时或不同时为氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环。
R2、R3、R4与R5相同或不相同,分别独立代表氢、卤素、CN、CH3、CF3、OR9、OCF3、SCF3、SR9、NR9R10、NO2、COR9、COOR9、CONR9R10、SO3R9、SO2NR9R10、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环;其中所述R9和R10同时或不同时为氢、C1-C8直链饱和烷基、C2-C8直链不饱和烷基、C3-C8支链饱和烷基、C3-C8支链不饱和烷基、C3-C6的环烷基、芳基、杂环芳基、饱和杂环。
所述芳基为苯基、取代苯基,其中取代苯基的取代基位于苯环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、硝基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
所述杂环芳基为呋喃、嘧啶、咪唑、吡唑、吡啶、三唑、噻唑、吲哚、吲唑、苯并咪唑,杂环上的取代基位于杂环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
所述饱和杂环为哌啶、哌嗪、甲基哌嗪、吡咯、吗啉,杂环上的取代基位于杂环的各个位置,是单取代或多取代,取代基为卤素、C1-C4直链烷基、C1-C4支链烷基、C1-C4直链烷氧基、C1-C4支链烷氧基、氰基、羟基、氨基、羧基、甲酯基、乙酯基、三氟甲基。
本发明另一个目的是提供式I或式II所示的化合物的制备方法:
式I或式II所示化合物的合成方法如下:
起始原料1与酰化试剂反应得到化合物2,其中所用酰化试剂选自氯化亚砜、草酰氯五氯化磷中的一种,用量为1-5当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的中的一种;温度为所用溶剂的回流温度。
中间体2与胺和碱在室温下反应得到化合物3,其中所用的碱选自三乙胺、N,N-二异丙基乙胺、吡啶中的一种,用量为4-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的中的一种;温度为室温。
中间体3与氧化剂和碱在加热条件下反应得到式I或式II化合物,其中所用的氧化剂选自过氧化氢、过氧化叔丁醇、过氧化二叔丁基、过氧化异丙苯、间氯过氧化苯甲酸、过硫酸钠中的一种,用量为2-10当量;碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、氢氧化锂、碳酸铯、甲醇钠、乙醇钠中的一种,用量为1-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃、乙酸乙酯、乙腈、1,2-二氯乙烷、1,4-二氧六环中的一种;温度为25~100℃。
本发明的又一目的在于提供上述化合物或其药学上可以接受的盐、酯或前药用于制备相关疾病的预防与治疗药物:主要涉及肿瘤、心血管疾病、神经退行性疾病、代谢类疾病、炎性疾病等。
具体实施方式
以下通过实施例对本发明作进一步阐述,但是本发明不限于下述的实施例。
实施例1 本发明部分化合物合成,包括Ia-Ih,以化合物Ia为例
N-苄基-2-羟基-5-甲氧基苯甲酰胺的制备:
将5-甲氧基水杨酸1g(5.95mmol)溶于溶于30ml无水二氯甲烷中,加入氯化亚砜2.14g(10.7mmol),N,N-二甲基甲酰胺1滴,升温至回流反应2h后,冷却至室温,旋干除去溶剂,用无水二氯甲烷溶解,滴加到含有三乙胺1.85g(17.80mmol)和苄胺0.76g(7.14mmol)的无水二氯甲烷溶液中。滴加完毕后室温搅拌5min,旋干得粗品,柱层析纯化的白色固体N-苄基-2-羟基-5-甲氧基苯甲酰胺1.27g,收率83%。1H NMR(300MHz,DMSO)δ12.62(s,1H),7.36-7.32(m,5H),7.22(d,J=9.3Hz,1H),6.47(d,J=1.8Hz,1H),6.37(dd,J=9.0,2.4Hz,1H),6.33(s,1H),4.61(d,J=5.7Hz,2H),3.80(s,3H);ESI-MS(m/z):258.2[M+H]+.
2-羟基-6-甲氧基-2-苯基-2,3-二氢-4H-苯并恶嗪酮的制备(Ia):
N-苄基-2-羟基-5-甲氧基苯甲酰胺1g(3.89mmol)溶于30ml 1,2二氯乙烷中,加入过氧化氢2.20g(19.45mmol),碳酸钾1.07g(7.78mmol),升温至50℃反应2h后,冷却至室温,旋干得粗品,柱层析纯化的白色固体2-羟基-6-甲氧基-3-苯基-2,3-二氢-4H-苯并恶嗪酮0.97g,收率93%。M.P.202-203℃,1H NMR(300MHz,DMSO)δ11.95(brs,2H),8.13-8.02(m,4H),7.85(d,J=6.6,Hz,1H),7.46(t,J=6.9Hz,1H),7.03-6.95(m,2H),3.90(s,3H);13CNMR(75MHz,DMSO)δ165.5,164.7,156.9,137.9,134.3,133.0,131.0,129.6,128.2,119.7,119.0,117.2,52.6;HRMS(ESI)calculated for C15H14NO4 +[M+H]+ 272.0917,found272.0918.
2-羟基-6-硝基-2-苯基-2,3-二氢-4H-苯并恶嗪酮(Ib)
参照Ia的合成方法,产物为棕红色固体,收率90%.m.p.218-219℃;1H NMR(300MHz,DMSO)δ15.62(brs,2H),8.71(s,1H),8.07-7.95(m,3H),7.61(s,3H),6.49(d,J=5.4Hz,1H);13C NMR(75MHz,DMSO)δ177.5,165.1,165.0,134.0,132.7,129.0,128.8,128.4,127.8,122.9,118.6,116.9;HRMS(ESI)calculated for C14H11N2O5 +[M+H]+ 287.0662,found287.0665.
N-苄基-2-羟基-2-苯基-3,4-二氢-2H-苯并恶嗪酮-6-磺酸胺(Ic)
参照Ia的合成方法,产物为黄色固体,收率83%.m.p.169-172℃;1H NMR(300MHz,DMSO)δ14.52(brs,2H),8.22(s,1H),8.01(d,J=7.2Hz,2H),7.81-7.79(m,1H),6.64-7.53(m,4H),7.25(brs,5H),6.78(d,J=8.7Hz,1H),3.90(d,J=5.7Hz,2H);13C NMR(75MHz,DMSO)δ168.8,165.6,138.4,134.5,133.1,131.9,131.0,129.7,129.3,129.0,128.6,128.3,128.0,127.5,125.6,121.0,118.6,46.6;HRMS(ESI)calculated for C21H19N2O5S+[M+H]+ 411.1009,found 411.1013.
2-羟基-2-(4-甲氧基苯基)-2,3-二氢-4H-苯并恶嗪酮(Id)
参照Ia的合成方法,产物为白色固体,收率68.9%.M.P.85-87℃,1H-NMR(300MHz,DMSO),δ11.18(s,1H),9.01(s,1H),7.34-7.29(m,3H),7.06-7.04(m,1H),4.01-3.96(t,J=6.3Hz,2H),1.74-1.69(m,2H),1.41(m,2H),1.26(m,8H),0.86-0.38(m,3H),13C NMR(75MHz,DMSO):δ164.37,159.03,134.58,129.94,119.43,117.86,113.02,68.05,31.69,29.19,29.12,29.09,25.96,22.54,14.48;HRMS(ESI)calculated for C15H24NO3[M+H]+ 266.1751,found 266.1747.
2-(1,3-苯并恶唑-5-基)-2-羟基--2,3-二氢-4H-苯并恶嗪酮(Ie)
参照Ia的合成方法,产物为黄色固体,收率91%.M.P.213-215℃;1H NMR(300MHz,DMSO)δ14.00(brs,2H),7.87-7.84(m,1H),7.62-7.60(m,1H),7.46(brs,1H),7.35-7.30(m,1H),7.07-7.04(m,1H),6.88-6.84(m,1H),6.78-6.74(m,1H),6.14(s,2H);13C NMR(75MHz,DMSO)δ166.3,151.0,147.8,134.0,132.2,130.5,123.3,118.6,118.1,117.3,116.8,115.9,108.2,107.6,102.0;HRMS(ESI)calculated for C15H12NO5 +[M+H]+ 286.0710,found286.0710.
2-羟基-2-(2-氯苯基)-2,3-二氢-4H-苯并恶嗪酮(If)
参照Ia的合成方法,产物为黄色固体,收率91%.M.P.137-138℃;1H NMR(300MHz,DMSO)δ11.99(brs,2H),7.71(d,J=7.8Hz,1H),7.50-7.42(m,3H),7.38-7.30(m,2H),6.86-6.77(m,2H);13C NMR(75MHz,DMSO)δ167.2,165.4,159.5,136.8,135.1,133.8,131.1,130.1,129.0,127.8,119.1,118.1,116.6;HRMS(ESI)calculated for C14H11ClNO3 +[M+H]+276.0422,found 276.0419.
4-(2-羟基-2,3-二氢-4H-苯并恶嗪酮)-苯甲酸甲酯(Ig)
参照Ia的合成方法,产物为黄色固体,收率98%.M.P.189-191℃;1H NMR(300MHz,DMSO)δ12.60(brs,2H),7.90(d,J=6.1Hz,2H),7.83(d,J=7.8Hz,1H),7.36(t,J=7.2Hz,1H),7.05(d,J=8.7Hz,2H),6.92(d,J=8.4Hz,1H),7.85(t,J=7.2Hz,1H);13C NMR(75MHz,DMSO)δ168.1,165.2,165.0,163.3,134.6,131.3,130.3,119.4,119.2,118.1,114.6,114.2,56.0;HRMS(ESI)calculated for C16H14NO5 +[M+H]+ 300.0866,found 300.0866.
2-羟基-2-(2-呋喃基)-2,3-二氢-4H-苯并恶嗪酮(Ih)
参照Ia的合成方法,产物为黄色固体,收率83%.M.P.202-203℃;1H NMR(300MHz,DMSO)δ14.00(brs,2H),7.87-7.85(m,1H),7.61(d,J=8.1Hz,1H),7.46(s,1H),7.35-7.30(m,1H),7.05-7.03(m,1H),6.87-6.84(m,1H),6.77-6.75(m,1H);13C NMR(75MHz,DMSO)δ151.5,148.3,134.5,130.9,124.0,119.1,118.6,117.8,116.5,108.6,108.2,102.5;HRMS(ESI)calculated for C12H9NO4Na+[M+Na]+ 254.0424,found 254.0426.
实施例2 化合物Ia-Ih抗肿瘤活性实验。
实验材料
细胞株:人宫颈癌细胞HeLa和人乳腺癌细胞MCF-7;样品:化合物Ia-Ih加入适量DMSO配置成浓度为10-2M溶液,临用前用培养基稀释至相应浓度。
实验方法
细胞消化、计数,每孔2.5×103个细胞,点在96孔板中,每孔总体积为100μl,培养24h;将待测样品用培养基稀释至适当的浓度,每孔100μl,设3复孔。培养72h后加入20μ15mg/ml MTT溶液,孵育4h后,将孔内液体全部吸出,加入100μl DMSO,全波长酶标仪测吸光度;抑制率=(1-给药组平均吸光度值/对照组平均吸光度值)×100%。
实验结果
化合物Ia-Ih在10μM时对人宫颈癌细胞HeLa和人乳腺癌细胞MCF-7有抑制作用,表明该类化合物具有较好的抗肿瘤活性。
具体结果如表所示:
表:本发明部分化合物的抗肿瘤活性
Claims (4)
2.根据权利要求1所述的苯并恶嗪酮衍生物及其药学上可接受的盐,其特征在于,式I所示化合物制备方法如下:
其中,起始原料1与酰化试剂反应得到化合物2,其中所用酰化试剂选自氯化亚砜、草酰氯、五氯化磷中的一种,用量为1-5当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的一种;温度为所用溶剂的回流温度;
中间体2与胺和碱在室温下反应得到化合物3,其中所用的碱选自三乙胺、N,N-二异丙基乙胺、吡啶中的一种,用量为4-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃中的中的一种;温度为室温;
中间体3与氧化剂和碱在加热条件下反应得到式I所示化合物,其中所用的氧化剂选自过氧化氢、过氧化叔丁醇、过氧化二叔丁基、过氧化异丙苯、间氯过氧化苯甲酸、过硫酸钠中的一种,用量为2-10当量;碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、氢氧化锂、碳酸铯、磷酸钾、甲醇钠、乙醇钠中的一种,用量为1-6当量;溶剂选自二氯甲烷、氯仿、四氢呋喃、乙酸乙酯、乙腈、1,2-二氯乙烷、1,4-二氧六环中的一种;温度为25~100℃。
3.一种根据权利要求1所述的苯并恶嗪酮衍生物及其药学上可接受的盐在制备抗肿瘤药物中的应用,所述的肿瘤为胃癌、肝癌、骨髓瘤、膀胱癌、前列腺癌、乳腺癌、直肠癌、头颈癌、肺癌、黑色素瘤、卵巢癌、宫颈癌或食道癌。
4.一种药物组合物,其中含有有效治疗量的权利要求1所述的苯并恶嗪酮衍生物及其药学上可接受的盐。
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CN110204506B (zh) * | 2019-02-20 | 2022-10-28 | 常州大学 | Co2作为c1来源合成1,4-二氢-2h-3,1-苯并恶嗪-2-酮衍生物 |
CN114450274A (zh) | 2019-07-11 | 2022-05-06 | 伊斯凯普生物公司 | 作为lrrk2抑制剂的吲唑及氮杂吲唑 |
CN113135884B (zh) * | 2020-01-20 | 2023-03-10 | 西华大学 | 一种异色烯类化合物及其制备方法和用途 |
CN111269197A (zh) * | 2020-04-08 | 2020-06-12 | 苏州大学 | 苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用 |
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