CN113264949B - 一类螺苯并噁嗪哌啶α,β-不饱和酮类衍生物的设计合成与应用 - Google Patents
一类螺苯并噁嗪哌啶α,β-不饱和酮类衍生物的设计合成与应用 Download PDFInfo
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Abstract
本文公开了一类螺苯并噁嗪哌啶α,β‑不饱和酮类衍生物及其制备方法和应用，所述化合物的结构如通式Ⅰ所示：
Description
技术领域
本发明属医药领域，具体涉及一类螺苯并噁嗪哌啶α,β-不饱和酮类衍生物的设计合成及其在抗微生物上的应用。
背景技术
具有高发病率和致死率的侵袭性真菌感染每年影响着全球数百万人的生命。现有抗真菌药物具有毒副作用大、易产生耐药性、抗菌谱窄等问题，临床上迫切需要新的抗真菌药物，以应对日益严重的真菌感染问题以及真菌耐药性问题。
几丁质是真菌细胞壁中必不可少的组成成分。阻断几丁质的合成会导致细胞渗透稳定性的改变、形态异常和生长停滞。几丁质的合成需要多种几丁质合成酶的作用。由于哺乳细胞中无几丁质生物合成途径，几丁质合成酶被认为是开发新型抗真菌药物的优质靶点。
螺苯并噁嗪酮类化合物是一种重要的氮杂环类化合物，是一种大量存在于多种生物活性分子中的医药母体结构，具有降压、防治偏头痛和血管舒张的作用。存在于自然界中α,β-不饱和酮片断的化合物，具有多种生理活性，如抗炎、抗癌、抗菌及抗糖尿病等作用。这类化合物的研究文章可见：Journal of Medical Chemistry，1983,26,657-661；ChemcicalReviews,2017,7762-7810；Medical Chemistry,2015.388-404。
为了寻找新的几丁质合成酶抑制剂，本发明设计合成了一类4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1,3]噁嗪-4,4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物，并以多抗霉素B、氟康唑、左氧氟沙星和氯霉素为阳性对照药物，测试了该类化合物的几丁质合成酶抑制活性及抗真菌、抗细菌活性。并提供这些化合物简便易行的实验方法及其在制药领域中的应用。
目前，此发明涉及到的新型化合物在抗微生物活性方面还未见报道、所以可将其开发成新型抗真菌剂，为人类健康做出贡献。
发明内容
本发明的目的之一在于提供一类4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1,3]噁嗪-4,4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物；本发明的目的之二在于提供一类4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1,3]噁嗪-4,4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物的制备方法；本发明的目的之三在于提供所述的4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1,3]噁嗪-4,4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物在制备抗细菌/真菌药物中的应用。
为达到上述目的，本发明提供以下技术方案：
1. 本发明所述的4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1,3]噁嗪-4,4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物结构如通式Ⅰ所示：
其中，R为-CH3、-CF3、-Cl、-OCH3，具体地说，通式Ⅰ所示的4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1，3]噁嗪-4，4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物为下述化合物的任意一种。
上述4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1，3]噁嗪-4，4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物和合成方法，如Scheme 1所示。
具体地说，上述Scheme 1反应条件如下：
步骤a 在反应容器中，以二氯甲烷为溶剂，加入顺丁烯二酸酐和苯胺类化合物，投料比为1.2：1，室温搅拌2h，反应完成后，抽滤得固体；
步骤b 以二氯甲烷为溶剂，将化合物3a-r、1-丙基磷酸酐和三乙胺以1：2：2.5的投料比投入反应器，保持室温反应20min，继续投入6-甲氧基螺[苯并[d][1，3]噁嗪-4，4’-哌啶]-2(1H)-酮，投料比为1.2：1，室温继续反应30min，提升温度至45℃回流反应16h。
本领域普通技术人员均可按上述公开的制备方法合成相应的化合物。
上述4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1，3]噁嗪-4，4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物在制备几丁质合酶抑制剂及抗真菌药物中的应用，所述真菌为白色念珠菌、新型隐球菌、烟曲霉菌、黄曲霉菌。
具体实施方式
为了加深对本发明的理解，下面对本发明作进一步详述。
所用试剂均为商业购买的分析纯或化学纯，反应进度经过TLC跟踪监测，化合物结构通过Bruker AV-600型傅立叶变换核磁共振仪确定。
实施例1、对氟苯胺3a的制备
在10mL圆底烧瓶中，加入溶剂二氯甲烷（3.5mL）和对氟苯胺（0.2g, 1.8mmol），室温下充分溶解后，加入顺丁烯二酸酐（0.176g, 1.8mmol）继续搅拌反应2h。混合物中有固体生成后，TLC检测反应进行程度。反应结束后，过滤分离出固体。固体用二氯/甲醇重结晶两次即可得到纯品白色固体；化合物3b-r的合成方法同实施例1。
实施例2、N-（4-氟苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）- 4-氧代丁-2-烯酰胺（1a）的制备
将化合物3a（0.144 g, 0.69 mmol）溶装有干燥二氯甲烷（5.8 mL）的25mL圆底烧瓶中，室温下加入三乙胺（0.240 mL, 1.725 mmol）将其溶解，继续加入1-丙基磷酸酐（0.32mL，1.38 mmol）的乙酸乙酯溶液，搅拌反应30 min后，加入6-甲氧基螺[苯并[d][1，3]噁嗪-4，4’-哌啶]-2(1H)-酮（0.133 g, 0.575 mmol），升温至45℃回流反应16 h，TLC检测反应彻底结束后，观察到有固体不溶物产生。饱和碳酸氢钠洗涤混合液三次，收集有机相，并用无水硫酸钠干燥，旋转蒸发仪除去溶剂，得混合物。用二氯/甲醇混合体系重结晶即可或获取产物（1a）。白色固体，产率51.3%。1H NMR (600 MHz, DMSO) δ 10.37 (s, 1H, CONH),10.11 (s, 1H, CONH), 7.72 – 7.64 (m, 2H, Ar-H), 7.31 – 7.12 (m, 2H, Ar-H),6.84 (dt, J = 8.5, 5.9 Hz, 2H, Ar-H), 6.79 (s, 1H, Ar-H), 6.64 (dd, J = 11.6,3.1 Hz, 1H, -CH=CH-), 6.26 (dd, J = 11.6, 3.2 Hz, 1H, -CH=CH-), 4.44 (d, J =12.3 Hz, 1H, Piperidine-CH2), 3.71 (d, J = 3.3 Hz, 3H, OCH3), 3.70 – 3.68 (m,1H, Piperidine -CH2), 3.40 (d, J = 13.3 Hz, 1H, Piperidine-CH2), 2.99 (t, J =12.7 Hz, 1H, Piperidine-CH2), 2.15 (t, J = 13.1 Hz, 1H, Piperidine-CH2), 2.09(t, J = 13.1 Hz, 1H, Piperidine-CH2), 1.99 (d, J = 13.6 Hz, 1H, Piperidine-CH2), 1.88 (d, J = 13.3 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ171.40 (1C), 170.70 (1C), 155.77 (1C), 150.79 (1C), 139.57 (1C), 129.12 (1C),128.58 (1C), 127.56 (1C), 126.38 (1C), 123.58 (1C), 119.57 (1C), 115.84 (1C),114.85 (1C), 109.66 (1C), 80.77 (1C), 55.95 (1C), 49.08 (1C), 37.14 (1C),35.03 (1C), 34.61 (1C), 31.92 (1C), 28.82 (1C), 27.84 (1C). HRMS (ESI): calcdfor C23H22FN3O5, [M+H]+, 440.1616, found, 440.1611。按相同步骤，可得化合物1b-1r。
N-（2-氯苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺环[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1' -基）-4-氧代丁-2-烯酰胺（1b)
白色固体，产率：52.7%。白色固体，产率：52.7%。1H NMR (600 MHz, DMSO) δ10.09 (s, 1H, CONH), 9.92 (s, 1H, CONH), 7.80 (d, J = 7.8 Hz, 1H, Ar-H), 7.51(d, J = 7.9 Hz, 1H, Ar-H), 7.33 (t, J = 7.6 Hz, 1H, Ar-H), 7.22 (t, J = 7.4Hz, 1H, Ar-H), 6.83 (q, J = 8.6 Hz, 2H, Ar-H), 6.74 (s, 1H, Ar-H), 6.68 (d, J = 11.8 Hz, 1H, -CH=CH-), 6.46 (d, J = 11.8 Hz, 1H, -CH=CH-), 4.41 (d, J =11.7 Hz, 1H, Piperidine-CH2), 3.70 (d, J = 11.2 Hz, 1H, Piperidine-CH2), 3.64(s, 3H, OCH3), 3.38 (t, J = 10.2 Hz, 1H, Piperidine-CH2), 2.96 (t, J = 11.6Hz, 1H, Piperidine-CH2), 2.16 (td, J = 13.4, 4.7 Hz, 1H, Piperidine-CH2), 2.05– 1.99 (m, 1H, Piperidine-CH2), 1.96 (d, J = 12.8 Hz, 1H, Piperidine-CH2),1.89 (d, J = 13.4 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.22(1C), 162.52 (1C), 155.07 (1C), 149.72 (1C), 135.81 (1C), 135.32 (1C), 131.24(1C), 130.30 (1C), 128.31 (1C), 126.02 (1C), 125.91 (1C), 125.77 (1C), 125.25(1C), 124.43 (1C), 115.18 (1C), 114.50 (1C), 108.82 (1C), 80.41 (1C), 55.26(1C), 41.41 (1C), 35.91 (1C), 34.22 (1C), 33.90 (1C), 17.81 (1C). HRMS (ESI):calcd for C24H25N3O5, [M+H]+, 436.1867, found, 436.1866。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）-N-（3-硝基苯基）-4-氧代丁-2-烯酰胺（1c)
白色固体，产率53.9%。1H NMR (600 MHz, DMSO) δ 10.84 (s, 1H, CONH),10.11 (s, 1H, CONH), 8.66 (s, 1H, Ar-H), 8.01 (d, J = 8.0 Hz, 1H, Ar-H), 7.96(dd, J = 8.1, 1.3 Hz, 1H, Ar-H), 7.63 (t, J = 8.2 Hz, 1H, Ar-H), 6.86 – 6.81(m, 2H, Ar-H), 6.74 (dd, J = 11.2, 6.8 Hz, 2H, Ar-H, -CH=CH-), 6.30 (d, J =11.8 Hz, 1H, -CH=CH-), 4.45 (d, J = 12.3 Hz, 1H, Piperidine-CH2), 3.70 (d, J = 11.4 Hz, 1H, Piperidine-CH2), 3.66 (s, 3H, OCH3), 3.40 (d, J = 13.2 Hz, 1H,Piperidine-CH2), 3.01 (t, J = 11.7 Hz, 1H, Piperidine-CH2), 2.15 – 2.05 (m,2H, Piperidine-CH2), 2.00 (d, J = 13.0 Hz, 1H, Piperidine-CH2), 1.89 (d, J =13.0 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.19 (1C), 163.31(1C), 155.39 (1C), 150.04 (1C), 148.27 (1C), 140.11 (1C), 137.29 (1C), 130.49(1C), 128.53 (1C), 126.12 (1C), 125.44 (1C), 118.37 (1C), 115.46 (1C), 114.45(1C), 113.61 (1C), 109.38 (1C), 80.58 (1C), 55.59 (1C), 41.59 (1C), 36.19(1C), 34.49 (1C), 34.11 (1C). HRMS (ESI): calcd for C23H22N4O7, [M+H]+,467.1561, found, 467.1556。
N-(4-氯-2，6-二甲氧基苯基)-4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1，3]恶嗪-4，4’-哌啶]-1’-基)-4-氧代-2-烯胺（1d）
白色固体，产率52.1% 1H NMR (600 MHz, DMSO) δ 10.10 (s, 1H, CONH), 9.68(s, 1H, CONH), 8.00 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 6.86 (d, J = 6.8 Hz,1H, Ar-H), 6.83 (d, J = 8.6 Hz, 1H, Ar-H), 6.71 (s, 1H, Ar-H), 6.63 (d, J =11.7 Hz, 1H, -CH=CH-), 6.53 (d, J = 11.9 Hz, 1H, -CH=CH-), 4.44 (d, J = 12.0Hz, 1H, Piperidine-CH2), 3.81 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.70 (d, J =13.8 Hz, 2H, Piperidine-CH2), 3.65 (s, 3H, OCH3), 2.99 (s, 1H, Piperidine-CH2), 2.16 – 2.10 (m, 2H, Piperidine-CH2), 2.07 – 2.02 (m, 2H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 170.84 (1C), 169.54 (1C), 166.17 (1C), 162.83(1C), 155.13 (1C), 153.06 (1C), 149.86 (1C), 148.15 (1C), 143.78 (1C), 135.81(1C), 128.27 (1C), 126.67 (1C), 126.01 (1C), 115.29 (1C), 113.80 (1C), 113.25(1C), 109.49 (1C), 80.37 (1C), 56.62 (1C), 56.33 (1C), 55.32 (1C), 41.43(1C), 35.95 (1C), 34.22 (1C), 33.88 (1C). HRMS (ESI): calcd for C25H26ClN3O7,[M+H]+, 516.1532, found, 516.1531。
N-（2-溴苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺环[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1' -基）-4-氧代丁-2-烯酰胺（1e)
白色固体，产率53.0%。1H NMR (600 MHz, DMSO) δ 10.08 (s,1H, CONH), 9.85(s, 1H, CONH), 7.70 – 7.63 (m, 2H, Ar-H), 7.37 (t, J = 7.7 Hz, 1H, Ar-H),7.17 (t, J = 7.6 Hz, 1H, Ar-H), 6.84 (dd, J = 8.6, 2.3 Hz,1H, Ar-H), 6.81 (d,J = 8.6 Hz, 1H, Ar-H), 6.72 (s, 1H, Ar-H), 6.67 (d, J =11.8 Hz, 1H, -CH=CH-),6.43 (d, J = 11.7 Hz, 1H, -CH=CH-), 4.40 (d, J =12.8Hz, 1H, Piperidine-CH2),3.70 (d, J = 9.5 Hz, 1H, Piperidine-CH2), 3.62(s, 3H,OCH3), 3.17 (d, J = 5.0Hz, 1H, Piperidine -CH2), 2.95 (t, J = 11.3 Hz, 1H, Piperidine-CH2), 2.17 (td,J = 13.4, 4.8 Hz, 1H, Piperidine-CH2), 2.03 – 1.97 (m, 1H, Piperidine-CH2),1.95 (d, J = 12.4 Hz, 1H, Piperidine-CH2), 1.88 (d, J = 13.4 Hz, 1H,Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.33 (1C), 164.52 (1C), 155.39(1C), 149.92 (1C), 145.61 (1C), 142.08 (1C), 133.17 (1C), 128.47 (1C), 127.72(1C), 126.30 (1C), 125.71 (1C), 115.41 (1C), 115.26 (1C), 114.88 (1C), 109.38(1C), 104.47 (1C), 102.53 (1C), 80.89 (1C), 55.75 (1C), 46.31 (1C), 42.00(1C), 36.36 (1C), 34.65 (1C). HRMS (ESI): calcd for C23H22BrN3O5, [M+H]+,500.0816, found, 500.0807。
N-（2-氯苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺环[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1' -基）-4-氧代丁-2-烯酰胺（1f）
白色固体，产率53.1%。1H NMR (600 MHz, DMSO) δ 10.09 (s, 1H, CONH), 9.92(s, 1H, CONH), 7.80 (d, J = 7.8 Hz, 1H, Ar-H), 7.51 (d, J = 7.9 Hz, 1H Ar-H),7.33 (t, J = 7.6 Hz, 1H, Ar-H), 7.22 (t, J = 7.4 Hz, 1H, Ar-H), 6.83 (q, J =8.6 Hz, 2H, Ar-H), 6.74 (s, 1H, Ar-H), 6.68 (d, J = 11.8 Hz, 1H, -CH=CH-),6.46 (d, J = 11.8 Hz, 1H, -CH=CH-), 4.41 (d, J = 11.7 Hz, 1H, Piperidine-CH2), 3.70 (d, J = 11.2 Hz, 1H, Piperidine-CH2), 3.64 (s, 3H, OCH3), 3.38 (t,J = 10.2 Hz, 1H, Piperidine-CH2), 2.96 (t, J = 11.6 Hz, 1H, Piperidine-CH2),2.16 (td, J = 13.4, 4.7 Hz, 1H, Piperidine-CH2), 2.05 – 1.99 (m, 1H,Piperidine-CH2), 1.96 (d, J = 12.8 Hz, 1H, Piperidine-CH2), 1.89 (d, J = 13.4Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.31 (1C), 163.02 (1C),155.34 (1C), 149.99 (1C), 136.55 (1C), 135.32 (1C), 134.69 (1C), 129.76 (1C),128.49 (1C), 127.63 (1C), 126.73 (1C), 126.48 (1C), 126.04 (1C), 125.65 (1C),125.47 (1C), 115.44 (1C), 114.69 (1C), 109.19 (1C), 80.64 (1C), 55.56 (1C),41.64 (1C), 36.16 (1C), 34.48 (1C), 34.18 (1C). HRMS (ESI): calcd forC23H22ClN3O5, [M+H]+, 456.1321, found, 456.1316。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）-4-氧代- N-（间甲苯基）丁-2-烯酰胺（1g）
白色固体，产率54.3%。 1H NMR (600 MHz, DMSO) δ 10.21 (s, 1H, CONH),10.10 (s, 1H, CONH), 7.49 (s, 1H, Ar-H), 7.44 (d, J = 7.9 Hz, 1H, Ar-H), 7.19(t, J = 7.8 Hz, 1H, Ar-H), 6.90 (d, J = 7.4 Hz, 1H, Ar-H), 6.87 – 6.81 (m,2H, Ar-H), 6.79 (s, 1H, Ar-H), 6.61 (d, J = 11.8 Hz, 1H, -CH=CH-), 6.26 (d, J = 11.8 Hz, 1H, -CH=CH-), 4.44 (d, J = 12.2 Hz, 1H, Piperidine-CH2), 3.76 -3.70 (m, 1H, Piperidine-CH2), 3.69 (s, 3H, OCH3), 3.39 (d, J = 12.0 Hz, 1H,Piperidine-CH2), 2.99 (t, J = 11.9 Hz, 1H, Piperidine-CH2), 2.29 (s, 3H, CH3),2.16 (td, J = 13.3, 4.6 Hz, 1H, Piperidine-CH2), 2.08 (td, J = 13.5, 4.6 Hz,1H, Piperidine-CH2), 1.98 (d, J = 13.2 Hz, 1H, Piperidine-CH2), 1.87 (d, J =13.2 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.23 (1C), 165.90(1C), 162.32 (1C), 156.01 (1C), 155.11 (1C), 149.76 (1C), 138.68 (1C), 138.01(1C), 135.80 (1C), 128.56 (1C), 128.27 (1C), 125.90 (1C), 125.81 (1C), 124.31(1C), 119.65 (1C), 116.37 (1C), 115.17 (1C), 114.22 (1C), 109.10 (1C), 80.39(1C), 55.33 (1C), 41.38 (1C), 35.87 (1C), 34.19 (1C), 33.86 (1C), 21.05 (1C).HRMS (ESI): calcd for C24H25N3O5, [M+H]+, 436.1867, found, 436.1866。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶]-1'-基）-N-（2-甲氧基苯基）-4-氧代丁-2-烯酰胺（1h)
白色固体，产率；52.7%。1H NMR (600 MHz, DMSO) δ 10.09 (s, 1H, CONH),9.56 (s, 1H, CONH), 8.03 (d, J = 7.9 Hz, 1H, Ar-H), 7.11 (t, J = 7.7 Hz, 1H,Ar-H), 7.05 (d, J = 8.1 Hz, 1H, Ar-H), 6.90 (t, J = 7.6 Hz, 1H, Ar-H), 6.84(dt, J = 17.0, 5.4 Hz, 2H, Ar-H), 6.77 (d, J = 1.6 Hz, 1H, Ar-H), 6.59 (d, J = 11.8 Hz, 1H, -CH=CH-), 6.52 (d, J = 11.8 Hz, 1H, -CH=CH-), 4.43 (d, J =10.8 Hz, 1H, Piperidine-CH2), 3.83 (s, 3H, OCH3), 3.69 (d, J = 10.8 Hz, 1H,Piperidine-CH2), 3.67 (s, 3H, OCH3), 3.38 (d, J = 12.8 Hz, 1H, Piperidine-CH2), 2.97 (t, J = 11.9 Hz, 1H, Piperidine-CH2), 2.15 (td, J = 13.4, 4.9 Hz,1H, Piperidine-CH2), 2.09 – 2.03 (m, 1H, Piperidine-CH2), 1.97 (d, J = 13.4Hz, 1H, Piperidine-CH2), 1.87 (d, J = 13.2 Hz, 1H, Piperidine-CH2). 13C NMR(151 MHz, DMSO) δ 166.31 (1C), 162.55 (1C), 155.09 (1C), 149.74 (1C), 149.61(1C), 135.39 (1C), 128.24 (1C), 126.85 (1C), 126.11 (1C), 125.84 (1C), 124.72(1C), 121.80 (1C), 131.17 (1C), 115.17 (1C), 114.38 (1C), 111.17 (1C), 108.96(1C), 80.40 (1C), 55.64 (1C), 55.33 (1C), 41.40 (1C), 35.89 (1C), 34.31 (1C),33.85 (1C). HRMS (ESI): calcd for C24H25N3O6, [M+H]+, 452.1816, found,452.1814。
N-（4-氯苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺环[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1' -基）-4-氧代丁-2-烯酰胺（1i）
白色固体，产率53.1%。1H NMR (600 MHz, DMSO) δ 10.45 (s, 1H, CONH),10.10 (s, 1H, CONH), 7.69 (d, J = 8.4 Hz, 2H, Ar-H), 7.37 (d, J = 8.7 Hz, 2H,Ar-H),6.86 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 6.82 (d, J = 8.6 Hz, 1H, Ar-H),6.79 (s, 1H, Ar-H), 6.65 (d, J = 11.7 Hz, 1H, -CH=CH-), 6.26 (d, J = 11.8 Hz,1H, -CH=CH-), 4.43 (d, J = 11.8 Hz, 1H, Piperidine-CH2), 3.70 (s, 3H, OCH3),3.68 (s, 1H, Piperidine-CH2), 3.39 (d, J = 12.7 Hz, 1H, Piperidine-CH2), 2.99(t, J = 12.1 Hz, 1H, Piperidine-CH2), 2.12 (dd, J = 15.4, 11.2 Hz, 1H,Piperidine-CH2), 2.09 – 2.03 (m, 1H, Piperidine-CH2), 1.98 (d, J = 12.9 Hz,1H, Piperidine-CH2), 1.87 (d, J = 13.1 Hz, 1H, Piperidine-CH2).13C NMR (151MHz, DMSO) δ 165.84 (1C), 162.23 (1C), 154.81 (1C), 149.47 (1C), 137.38 (1C),136.03 (1C), 128.38 (1C), 127.99 (1C), 126.91 (1C), 125.58 (1C), 125.15 (1C),131.49 (1C), 114.89 (1C), 113.96 (1C), 108.85 (1C), 80.08 (1C), 55.08 (1C),41.07 (1C), 35.61 (1C), 33.91 (1C), 33.55 (1C). HRMS (ESI): calcd forC23H22ClN3O5, [M+H]+, 456.1321, found, 456.1316。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）-N-（2 -硝基苯基）-4-氧代丁-2-烯酰胺（1j）
白色固体，产率49.3%。 1H NMR (600 MHz, DMSO) δ 10.58 (s, 1H, CONH),10.09 (s, 1H, CONH), 7.98 (d, J = 8.1 Hz, 1H, Ar-H), 7.77 – 7.69 (m, 2H, Ar-H), 7.41 (t, J = 7.5 Hz, 1H, Ar-H), 6.84 (qd, J = 8.6, 2.0 Hz, 2H), Ar-H,6.76 (s, 1H, Ar-H), 6.71 (d, J = 11.8 Hz, 1H, -CH=CH-), 6.36 – 6.32 (m, 1H, -CH=CH-), 4.41 (d, J = 12.5 Hz, 1H, Piperidine-CH2), 3.68 (d, J = 1.9 Hz, 3H,OCH3), 3.40 – 3.33 (m, 2H, Piperidine-CH2), 3.00 – 2.91 (m, 1H, Piperidine-CH2), 2.13 (t, J = 11.1 Hz, 1H, Piperidine-CH2), 1.97 (s, 2H, Piperidine-CH2),1.88 (d, J = 13.6 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 165.28(1C), 162.31 (1C), 154.84 (1C), 149.50 (1C), 141.94 (1C), 136.80 (1C), 133.69(1C), 130.49 (1C), 127.98 (1C), 125.52 (1C), 125.23 (1C), 125.05 (1C), 124.66(1C), 124.45 (1C), 114.91 (1C), 114.27 (1C), 108.59 (1C), 80.01 (1C), 55.04(1C), 40.95 (1C), 35.45 (1C), 33.78 (1C), 33.57 (1C). HRMS (ESI): calcd forC23H22N4O7, [M+H]+, 467.1561, found, 467.1553。
N-（3,5-二甲基苯基）-4-（6-甲氧基-2-氧-1,2-二氢螺基[苯并[d] [1,3]噁嗪-4,4'-哌啶]- 1'-基）-4-氧代丁-2-烯酰胺（1k）
白色固体，产率54.7%。 1H NMR (600 MHz, DMSO) δ 10.14 (s, 1H, CONH),10.10 (s, 1H, CONH), 7.26 (s, 2H, Ar-H), 6.85 (dd, J = 8.7, 2.4 Hz, 1H, Ar-H), 6.82 (d, J = 8.6 Hz, 1H, Ar-H), 6.77 (d, J = 2.0 Hz, 1H, Ar-H), 6.72 (s,1H, Ar-H), 6.58 (d, J = 11.8 Hz, 1H, -CH=CH-), 6.24 (d, J = 11.8 Hz, 1H, -CH=CH-), 4.43 (d, J = 11.2 Hz, 1H, Piperidine-CH2), 3.71 – 3.68 (m, 2H,Piperidine-CH2), 3.66 (s, 3H, OCH3), 2.98 (t, J = 11.8 Hz, 1H, Piperidine-CH2), 2.23 (s, 6H, CH3), 2.18 – 2.12 (m, 1H, Piperidine-CH2), 2.09 – 2.03 (m,1H, Piperidine-CH2), 1.97 (d, J = 12.9 Hz, 1H, Piperidine-CH2), 1.86 (d, J =13.6 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.38 (1C), 162.35(1C), 155.21 (1C), 149.93 (1C), 143.48 (1C), 138.67 (1C), 137.89 (1C), 135.74(1C), 133.71 (1C), 128.31 (1C), 126.04 (1C), 125.98 (1C), 125.27 (1C), 116.99(1C), 115.28 (1C), 114.14 (1C), 109.30 (1C), 80.47 (1C), 55.39 (1C), 41.44(1C), 35.93 (1C), 34.25 (1C), 33.92 (1C), 21.02 (1C). HRMS (ESI): calcd forC25H27N3O5, [M+H]+, 450.3123, found, 450.3123。
N-（2,4-双（三氟甲基）苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4' -哌啶] -1'-基）-4-氧代丁-2-烯酰胺（1l）
白色固体，产率51.6%。 1H NMR (600 MHz, DMSO) δ 10.14 (s, 1H, CONH),8.00 – 7.95 (m, 2H, Ar-H), 7.79 (d, J = 8.1 Hz, 1H, Ar-H), 6.84 – 6.80 (m,2H, Ar-H), 6.67 – 6.62 (m, 2H, Ar-H, -CH=CH-), 6.44 (d, J = 11.9 Hz, 1H, -CH=CH-), 4.41 (d, J = 12.9 Hz, 1H, Piperidine-CH2), 3.72 (d, J = 12.1 Hz, 1H,Piperidine-CH2), 3.56 (s, 3H, OCH3), 3.37 (t, J = 12.2 Hz, 1H, Piperidine-CH2), 2.99 – 2.92 (m, 1H, Piperidine-CH2), 2.12 (td, J = 13.4, 4.8 Hz, 1H,Piperidine-CH2), 1.99 (dd, J = 14.0, 4.6 Hz, 1H, Piperidine-CH2), 1.94 (d, J =12.4 Hz, 1H, Piperidine-CH2), 1.87 (d, J = 13.3 Hz, 1H, Piperidine-CH2). 13CNMR (151 MHz, DMSO) δ 165.91 (1C), 164.03 (1C), 155.04 (1C), 149.74 (1C),137.36 (1C), 135.70 (1C), 133.04 (1C), 132.82 (1C), 128.23 (1C), 127.87 (1C),125.75 (1C), 124.05 (1C), 123.75 (1C), 122.66 (1C), 122.24 (1C), 121.94 (1C),115.17 (1C), 114.33 (1C), 108.81 (1C), 80.28 (1C), 55.06 (1C), 41.29 (1C),35.83 (1C), 34.18 (1C), 33.94 (1C). HRMS (ESI): calcd for C25H21F6N3O5 [M+H]+,558.1458, found, 558.1449。
N-（2,6-二溴-4-甲氧基苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4' -哌啶] -1'-基）-4-氧代丁-2-烯酰胺（1m）
白色固体，产率52.7%。1H NMR (600 MHz, DMSO) δ 10.04 (d, J = 9.7 Hz, 2H,CONH), 7.38 – 7.29 (m, 2H, Ar-H), 6.86 – 6.81 (m, 2H, Ar-H), 6.67 (d, J = 1.9Hz, 1H, Ar-H), 6.64 (d, J = 11.8 Hz, 1H, -CH=CH-), 6.32 (d, J = 11.9 Hz, 1H,-CH=CH-), 4.41 (d, J = 13.0 Hz, 1H, Piperidine-CH2), 3.84 (s, 3H, OCH3), 3.73– 3.69 (m, 1H, Piperidine-CH2), 3.61 (s, 3H, OCH3), 3.42 – 3.37 (m, 1H,Piperidine-CH2), 2.94 (td, J = 13.2, 4.8 Hz, 1H, Piperidine-CH2), 2.26 (td, J = 13.5, 5.0 Hz, 1H, Piperidine-CH2), 1.94 (d, J = 11.1 Hz, 2H, Piperidine-CH2), 1.87 (d, J = 13.7 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ166.36 (1C), 163.03 (1C), 159.40 (1C), 155.57 (1C), 150.25 (1C), 137.03 (1C),128.70 (1C), 128.42 (1C), 126.27 (1C), 124.71 (1C), 124.50 (1C), 118.35 (1C),118.12 (1C), 115.63 (1C), 114.99 (1C), 109.49 (1C), 80.98 (1C), 56.70 (1C),55.77 (1C), 41.96 (1C), 40.96 (1C), 36.24 (1C), 34.65 (1C), 34.57 (1C). HRMS(ESI): calcd for C24H23Br2N3O6 [M+H]+,608.0026, found, 608.0024。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）-N-（3-甲氧基苯基）-4-氧代丁-2-烯酰胺(1n)
白色固体，产率53.6%。1H NMR (600 MHz, DMSO) δ 10.59 (s, 1H, CONH),10.18 (s, 1H, CONH), 7.34 (s, 1H, Ar-H), 7.24 (d, J = 7.7 Hz, 1H, Ar-H), 7.19(t, J = 8.0 Hz, 1H, Ar-H), 6.84 (s, 2H, Ar-H), 6.77 (s, 1H, Ar-H), 6.65 (d, J = 7.9 Hz, 1H), 6.59 (d, J = 11.7 Hz, 1H, -CH=CH-), 6.32 (d, J = 11.8 Hz, 1H,-CH=CH-), 4.44 (d, J = 11.5 Hz, 1H, Piperidine-CH2), 3.72 (s, 3H, OCH3), 3.69(s, 1H, Piperidine-CH2), 3.68 (s, 3H, OCH3), 3.37 – 3.35 (m, 1H, Piperidine-CH2), 2.99 (t, J = 12.6 Hz, 1H, Piperidine-CH2), 2.16 (dd, J = 12.7, 9.2 Hz,1H, Piperidine-CH2), 2.07 (dd, J = 13.4, 3.6 Hz, 1H, Piperidine-CH2), 1.98 (d,J = 13.7 Hz, 1H, Piperidine-CH2), 1.86 (d, J = 13.6 Hz, 1H, Piperidine-CH2).13C NMR (151 MHz, DMSO) δ 175.18 (1C), 166.78 (1C), 163.03 (1C), 160.03 (1C),155.63 (1C), 150.32 (1C), 140.57 (1C), 136.29 (1C), 129.99 (1C), 128.84 (1C),126.42 (1C), 115.78 (1C), 114.84 (1C), 112.12 (1C), 109.60 (1C), 109.44 (1C),105.52 (1C), 80.88 (1C), 55.83 (1C), 55.43 (1C), 41.92 (1C), 36.39 (1C),34.69 (1C), 34.37 (1C). HRMS (ESI): calcd for C24H25N3O6, [M+H]+, 452.1816,found, 452.1814。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）-4-氧代- N-（4-（三氟甲基）苯基）丁-2-烯酰胺（1o）
白色固体，产率49.6%。1H NMR (600 MHz, DMSO) δ 11.21 (s, 1H, CONH),10.19 (s, 1H, CONH), 8.10 (s, 1H, Ar-H), 7.96 (d, J = 7.2 Hz, 1H, Ar-H), 7.54(d, J = 7.8 Hz, 1H, Ar-H), 7.41 (d, J = 6.7 Hz, 1H, Ar-H), 6.85 (s, 2H, Ar-H), 6.77 (s, 1H, Ar-H), 6.68 – 6.64 (m, 1H, -CH=CH-), 6.41 – 6.36 (m, 1H, -CH=CH-), 4.45 (d, J = 12.3 Hz, 1H, Piperidine-CH2), 3.71 (d, J = 15.2 Hz, 1H,Piperidine-CH2), 3.68 (d, J = 3.6 Hz, 3H, OCH3), 3.42 (s, 1H, Piperidine-CH2),3.01 (t, J = 12.7 Hz, 1H, Piperidine-CH2), 2.14 (t, J = 13.0 Hz, 1H,Piperidine-CH2), 2.07 (d, J = 12.5 Hz, 1H, Piperidine-CH2), 1.99 (d, J = 13.5Hz, 1H, Piperidine-CH2), 1.89 (d, J = 13.5 Hz, 1H, Piperidine-CH2). 13C NMR(151 MHz, DMSO) δ 174.67 (1C), 166.07 (1C), 162.99 (1C), 155.11 (1C), 149.79(1C), 139.73 (1C), 136.34 (1C), 129.89 (1C), 128.32 (1C), 125.87 (1C), 125.62(1C), 124.92 (1C), 123.11 (1C), 122.83 (1C), 119.73 (1C), 115.23 (1C), 114.26(1C), 108.96 (1C), 80.27 (1C), 55.27 (1C), 41.30 (1C), 35.86 (1C), 34.31(1C), 33.82 (1C). HRMS (ESI): calcd for C24H22F3N3O5 [M+H]+, 490.1584, found,490.1581。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）-N-（2-甲氧基-4-硝基苯基）-4-氧代丁-2-烯酰胺(1p)
米色固体。产率52.1%， 1H NMR (600 MHz, DMSO) δ 10.21 (s, 2H, CONH),8.47 (d, J = 8.9 Hz, 1H, Ar-H), 7.89 (d, J = 9.0 Hz, 1H, Ar-H), 7.84 (s, 1H,Ar-H), 6.84 (d, J = 8.8 Hz, 2H, Ar-H), 6.76 (s, 1H, Ar-H), 6.71 (d, J = 11.8Hz, 1H, -CH=CH-), 6.64 (d, J = 11.8 Hz, 1H, -CH=CH-), 4.44 (d, J = 11.0 Hz,1H, Piperidine-CH2), 4.01 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.43 (s, 2H,Piperidine-CH2), 3.00 (t, J = 12.3 Hz, 1H, Piperidine-CH2), 2.07 (dd, J =15.7, 5.9 Hz, 2H,Piperidine-CH2 ), 1.99 (d, J = 12.9 Hz, 1H, Piperidine-CH2),1.88 (d, J = 13.6 Hz, 1H, Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.03(1C), 163.38 (1C), 155.05 (1C), 149.75 (1C), 148.93 (1C), 142.99 (1C), 136.80(1C), 133.90 (1C), 128.31 (1C), 125.84 (1C), 125.61 (1C), 119.88 (1C), 116.66(1C), 115.21 (1C), 114.04 (1C), 109.25 (1C), 105.98 (1C), 80.25 (1C), 56.48(1C), 55.35 (1C), 41.36 (1C), 35.91 (1C), 34.25 (1C), 33.80 (1C). HRMS (ESI):calcd for C24H24N4O8 [M+H]+, 497.1667, found, 497.1665。
N-（3-氯-4-氟苯基）-4-（6-甲氧基-2-氧代-1,2-二氢螺环[苯并[d] [1,3]噁嗪-4,4'-哌啶 ] -1'-基）-4-氧代丁-2-烯酰胺(1q)
白色固体，产率51.4%。1H NMR (600 MHz, DMSO) δ 10.52 (s, 1H, CONH),10.07 (s, 1H, CONH), 7.95 (s, 1H, Ar-H), 7.54 (s, 1H, Ar-H), 7.36 (t, J = 8.2Hz, 1H, Ar-H), 6.84 (d, J = 3.9 Hz, 2H, Ar-H), 6.77 (s, 1H, Ar-H), 6.67 (d, J = 11.6 Hz, 1H, -CH=CH-), 6.25 (d, J = 11.6 Hz, 1H, -CH=CH-), 4.44 (d, J =11.3 Hz, 1H, Piperidine-CH2), 3.69 (s, 4H, OCH3, Piperidine-CH2), 3.38 (t, J =12.6 Hz, 1H, Piperidine-CH2), 3.00 (t, J = 12.0 Hz, 1H, Piperidine-CH2), 2.11(d, J = 16.6 Hz, 1H, Piperidine-CH2), 2.06 (d, J = 10.0 Hz, 1H, Piperidine-CH2), 1.99 (d, J = 13.4 Hz, 1H, Piperidine-CH2), 1.89 (d, J = 13.3 Hz, 1H,Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 166.37 (1C), 164.05 (1C), 163.00(1C), 155.53 (1C), 150.17 (1C), 136.93 (1C), 128.67 (1C), 126.26 (1C), 125.73(1C), 121.01 (1C), 119.98 (1C), 119.58 (1C), 117.41 (1C), 117.27 (1C), 115.61(1C), 114.70 (1C), 109.39 (1C), 80.72 (1C), 55.75 (1C), 41.72 (1C), 36.29(1C), 34.61 (1C), 34.24 (1C). HRMS (ESI): calcd for C23H21ClFN3O5,[M+H]+,474.1227, found, 474.1231。
4-（6-甲氧基-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,4'-哌啶] -1'-基）-N-（4-硝基苯基）-4-氧代丁-2-烯酰胺（1r）
白色固体，产率52.8%。1H NMR (600 MHz, DMSO) δ 10.92 (s, 1H, CONH),10.07 (s, 1H, CONH), 8.22 (d, J = 8.3 Hz, 2H, Ar-H), 7.92 (d, J = 8.2 Hz, 2H,Ar-H), 6.86 (d, J = 6.3 Hz, 1H, Ar-H), 6.83 (d, J = 8.4 Hz, 1H, Ar-H), 6.79(s, 1H, Ar-H), 6.75 (d, J = 11.7 Hz, 1H, -CH=CH-), 6.34 (d, J = 11.7 Hz, 1H,-CH=CH-), 4.45 (d, J = 11.1 Hz, 1H, Piperidine-CH2), 3.72 (s, 3H), 3.70 –3.67 (m, 1H, Piperidine-CH2), 3.40 (t, J = 12.6 Hz, 1H, Piperidine-CH2), 3.01(t, J = 12.0 Hz, 1H, Piperidine-CH2), 2.10 (d, J = 9.2 Hz, 2H, Piperidine-CH2), 2.00 (d, J = 13.6 Hz, 1H, Piperidine-CH2), 1.89 (d, J = 13.4 Hz, 1H,Piperidine-CH2). 13C NMR (151 MHz, DMSO) δ 165.87 (1C), 163.18 (1C), 155.08(1C), 149.73 (1C), 144.85 (1C), 142.45 (1C), 137.39 (1C), 128.27 (1C), 125.84(1C), 125.08 (1C), 124.88 (1C), 119.02 (1C), 115.17 (1C), 114.05 (1C), 109.27(1C), 99.46 (1C), 80.28 (1C), 55.37 (1C), 54.81 (1C), 41.30 (1C), 35.90 (1C),34.22 (1C), 33.81 (1C). HRMS (ESI): calcd for C23H22N4O7,[M+H]+, 467.1561,found, 467.1555。
实施例3、螺苯并噁嗪哌啶α,β-不饱和酮类衍生物所示的几丁质合成酶抑制活性实验
将从热带酿酒酵母细胞膜中提取的几丁质合成酶与底物UDP-GlcNAc、测试化合物在96微孔板中孵化，产生的几丁质与微孔板上预先包被的WGA结合，加入过氧化酶标记的WGA（WGA-HRP）结合。冲去多余试剂后，加入HRP的TMB溶液显色，最后用2M的硫酸终止反应，以多抗霉素B为阳性对照。
化合物1a-1r都进行了几丁质合成酶活性初筛，选取300ug/ml的药物浓度，测试当前药物浓度对几丁质合成酶活性抑制率，对几丁质合成酶抑制活性较好的化合物进一步测试其IC50值，结果如表1所示：
实施例4、螺苯并噁嗪哌啶α,β-不饱和酮类衍生物的体外抗微生物活性
采用符合美国国家委员会制定的临床实验标准（Clinical and LaboratoryStandards Institute, CLSI）的96孔微量稀释法，测试实施例2制得的螺苯并噁嗪哌啶α,β-不饱和酮类化合物对革兰氏阳性菌（耐甲氧西林金黄色葡萄球菌（MRAS N315）、金黄色葡萄球菌（ATCC 25923）、枯草杆菌（ATCC 6633）、革兰氏阴性菌（大肠杆菌（JM 109）、铜绿假单孢菌（ATCC 9027）、变形杆菌（ATCC 8427、真菌（白色念珠菌（ATCC 76615）、烟曲霉菌（GIMCC3.19）、黄曲霉菌（ATCC 16870）、新型隐球菌（ATCC H99）的最低抑制浓度（MIC）。待测化合物用少量二甲基亚砜溶解，用灭菌水配制成相应浓度备用。使用的所有仪器均提前消毒灭菌备用，取稀释好的菌液100ul加入到96孔板中，左氧氟沙星、氯霉素、氟康唑、多抗霉素B为阳性对照药物。细菌、真菌均在37℃下培养24-72h，观察现象，结果见表2和表3：
本发明实化合物1a-1r对几丁质合成酶有较好的抑制作用，并且对所测试的微生物有一定的抑制作用，其中，化合物1q对白色念珠菌、烟曲霉菌、新型隐球菌都表现出较强抗菌活性，与参考药物多抗霉素B相近， 可用于制备几丁质合成酶抑制剂和抗真菌制剂。
Claims (4)
1.4-(6-甲氧基-2-氧代-1，2-二氢螺环[苯并[d][1，3]噁嗪-4，4’-哌啶]-1’-基)-4-氧代-N-苯基丁-2-烯胺类化合物，化合物的结构如通式Ⅰ所示:
其中，R为氢、卤素、甲基、甲氧基、硝基、三氟甲基，具体为：
2.如权利要求1所述化合物在制备抗病原微生物药物中的应用，所述微生物为病原细菌或病原真菌。
3.如权利要求1所述化合物在制备抗病原微生物药物中的应用，所述微生物为大肠杆菌、金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、枯草杆菌、铜绿色假单细胞菌、白色念珠菌、新型隐球菌、烟曲霉菌或黄曲霉菌。
4.如权利要求1所述化合物在制备几丁质合成酶抑制剂中的应用。
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| CA2730493A1 (en) * | 2008-07-14 | 2010-01-21 | Cropsolution, Inc. | Modulators of acetyl-coenzyme a carboxylase and methods of use thereof |
| US8975290B2 (en) * | 2013-03-01 | 2015-03-10 | Colorado State University Research Foundation | Methods and compositions for enhancing an immune response, blocking monocyte migration, amplifying vaccine immunity and inhibiting tumor growth and metastasis |
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