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CN109593089B - 二氮杂螺癸烷哌啶甲酰胺类化合物制备和应用 - Google Patents

二氮杂螺癸烷哌啶甲酰胺类化合物制备和应用 Download PDF

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CN109593089B
CN109593089B CN201910070042.5A CN201910070042A CN109593089B CN 109593089 B CN109593089 B CN 109593089B CN 201910070042 A CN201910070042 A CN 201910070042A CN 109593089 B CN109593089 B CN 109593089B
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piperidine
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吉庆刚
李兵
王凯渊
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Abstract

本发明公开了1‑氧代‑2,8‑二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物及其制备方法和应用，所述化合物的结构如通式1所示：
Figure DEST_PATH_IMAGE001
式中R1为氢；R2为：各类取代的芳胺。经生物活性测试实验证明，部分化合物对革兰阳性菌、革兰阴性菌和真菌都有一定抑制活性，而且对几丁质合成酶抑制活性明显，抑菌效果较好，可用于制备抗病原微生物的药物。并且制备原料简单，廉价易得，对抗感染方面的应用具有重要意义。

Description

二氮杂螺癸烷哌啶甲酰胺类化合物制备和应用
技术领域
本发明属医药领域，具体涉及1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物的设计合成及其在抗微生物方面的应用。
背景技术
近些年，随着国内外医疗水平的快速发展，许多顽固疾病得到了有效的治疗，但由于抗生素的滥用、肿瘤放化疗、器官移植抗排斥和艾滋病等原因造成机体免疫力低下，使得由白色念珠菌、烟曲霉菌、新型隐球菌等常见真菌引起的真菌感染发病率与死亡率逐年上升，已严重威胁人类的健康。因此，探索与合成一种新型抗菌类药物已成为国内外医学领域学者的研究热点。
螺环结构是天然产物与药物化合物中常见的一种环状化合物，因其自身具备的独特结构及其特殊性质被广泛应用于医学、农药、不对称催化等各领域，且具有螺环结构的化合物生物活性均要高于非螺环化合物。研究发现，具有酰胺基团的分子在在抗癌、抗病毒、抗菌、消炎、抗抑郁、抗糖尿病等多方面均表现出了比较明显的生物活性，且临床上使用的众多药物均含有酰胺基团。此外，以哌啶甲酸作为linker的酰胺类衍生物也具备较高的几丁质合成酶抑制活性，在抗癌等医学领域均表现出了优异的活性。这类化合物的研究文章可见：Analytical Biochemistry. 2002, 305(1): 97-105；Eur. J.Med. Chem. 2012,50:370-375；Bioorg. Med. Chem. Lett. 2014, 24(16): 3673-3682；Cheminform. 2006,37(20)；Bioorg. Med. Chem.2016, 24(23):6206-6214。以上文献均未覆盖或包括本发明所涉及的新型化合物的结构、合成方法和用途。
本发明设计并合成了一类1-氧代-2,8-二氮杂螺[4. 5]癸烷哌啶甲酸酰胺类化合物，以多抗霉素B、氟康唑、链霉素和左氧氟沙星为对照，测定了该类化合物在抗真菌、抗细菌方面的活性，拓展了此类化合物的应用范围。到目前为止，本发明所涉及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的抗菌制剂。
发明内容
本发明的目的之一在于提供一种1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物；本发明的目的之二在于提供1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰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1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物在制备抗细菌/抗真菌药物中的应用。
为达到上述目的，本发明提供如下技术方案：
1、本发明所述的1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物结构如通式1所示：
Figure 783232DEST_PATH_IMAGE001
其中R1为H，R2为2-CH3OC6H4，4-ClC6H4，3-CH3C6H4，2,4-FC6H3，3-BrC6H4，Ph，4-FC6H4，3-F3CC6H4，3-Cl-4-FC6H3，CHCH3C6H5，4-CH3OC6H4，2-FC6H4，3-O2NC6H4，3,5-CH3C6H3，4-BrC6H4，3-CH3OC6H4，2-CH3C6H4，3,4-FC6H3等，具体地，通式1所示的1-氧代-2, 8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物为下述化合物的任意一种：
Figure 696961DEST_PATH_IMAGE002
Figure 926080DEST_PATH_IMAGE003
Figure 241655DEST_PATH_IMAGE004
Figure 107979DEST_PATH_IMAGE005
Figure 289431DEST_PATH_IMAGE006
Figure 40349DEST_PATH_IMAGE007
Figure 958233DEST_PATH_IMAGE008
Figure 933143DEST_PATH_IMAGE009
Figure 539573DEST_PATH_IMAGE010
上述1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物的合成方法，按如Scheme1所示进行：
Figure 625341DEST_PATH_IMAGE011
具体地说，上述Scheme 1 反应条件如下：
a. 化合物2与氯乙酰氯经取代反应生成化合物4。溶剂为二氯甲烷、三氯甲烷、四氢呋喃等，优选二氯甲烷；化合物2与氯乙酰氯的摩尔比为1: 1.1~2，0℃至45℃反应8-12h；
b. 化合物5与邻甲氧基苯胺经缩合反应，最后脱Boc生成化合物7a，溶剂为二氯甲烷、三氯甲烷、四氢呋喃等，优选二氯甲烷；化合物5与邻甲氧基苯胺的摩尔比1: 1.1~2，室温至45℃反应6-10 h；
c. 化合物4与化合物7a经取代反应生成化合物1, 溶剂为三氯甲烷、乙腈、DMF等，优选乙腈；化合物4与化合物7a的摩尔比为1: 1.1~2，室温至70℃反应4-8 h。
本领域普通技术人员均可按上述公开的制备方法制得相应的化合物。
上述1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类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，如大肠杆菌、金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、枯草杆菌、变形杆菌、铜绿色假单胞菌；白色念珠菌、新型隐球菌、黄曲霉菌、烟曲霉菌等。
具体实施方式
为了加深对本发明的理解，下面将结合实施例对本发明作进一步详述，该实施例仅用于解释本发明，并不构成对本发明保护范围的限定，但本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。
所有使用的试剂都是商业购买的分析纯或化学纯，如未说明则未经过特殊处理。反应进度通过TLC跟踪监测，在紫外灯254 nm处显色，部分用碘和浓硫酸显色。熔点使用X-4显微熔点仪测定。核磁共振氢谱和碳谱使用Bruker Av-600型傅立叶变换核磁共振仪测定，使用的氘代试剂有CDCl3，DMSO-d6和MeOD，内含内标物质TMS。化学位移δ单位为ppm，偶合常数J单位为Hz，s、d、t、q、m分别表示单峰、两重峰、三重峰、四重峰和多重峰。HRMS(ESI)使用Bruker impactⅡ测定。
实施例1、8-（2-氯乙酰基）-2,8-二氮杂螺[4.5]癸-1-酮4的制备
在50 mL圆底烧瓶中加入化合物2（0.62 g，4.0mmol），无水碳酸钾（0.66 g，4.8mmol），干燥的二氯甲烷（15 mL），室温下搅拌30min，冰浴滴加氯乙酰氯即化合物3（0.4 mL，4.8 mmol）的二氯甲烷溶液（15mL）。室温下搅拌过夜，然后回流30 min，冷却至室温，加入5%的碳酸氢钠溶液（20 mL），搅拌10 min后用二氯甲烷萃取（25 mL×2），合并有机层，无水硫酸钠干燥，抽滤，真空浓缩，柱层析后即得化合物4（0.39 g），白色粉末，收率42.5%，熔点：149.7-151.1℃；1H NMR (600 MHz, CDCl3) δ 6.62 (s, 1H, CONH), 4.14-4.02 (m, 2H,CH2), 4.01-3.81 (m, 2H, diazaspiro-CH2), 3.35-3.25 (m, 4H, diazaspiro-CH2),2.05-1.96 (m, 2H, diazaspiro-CH2), 1.93-1.78 (m, 2H, diazaspiro-CH2), 1.51-1.43 (m, 2H, diazaspiro-CH2).13C NMR (151 MHz, CDCl3) δ 180.12(1C), 164.08(1C), 42.14(1C), 40.58(1C), 39.99(1C), 37.95(1C), 37.76(1C), 31.95(1C), 31.87(1C), 30.87(1C). HRMS(ESI): calcd for C10H15ClN2O2[M+H]+, 231.0895, found,231.0899。
实施例2、N-（2-甲氧基苯基）哌啶-4-甲酰胺（7a）的制备
在100 mL 圆底烧瓶中加入1-（叔丁氧基羰基）哌啶-4-羧酸即化合物5（2.35 g，10.2 mmol），吡啶（2.1 mL，26.0mmol），二氯甲烷(30 mL)，充入氮气保护，在室温下加入氯化亚砜(0.9 mL， 12.4 mmol)，继续搅拌30 min，向其中缓慢滴加含有邻甲氧基苯胺（1.42g，11.5mmol），三乙胺（4.9 mL，35.3mmol），催化量DMAP的二氯甲烷溶液（30mL），滴加完毕后室温反应10 h，依次用1mol/mL的盐酸（30 mL×2）、饱和碳酸氢钠（30 mL×2）洗涤，用无水硫酸钠干燥，抽滤，真空浓缩，柱层析后即得中间体（2.47 g），将中间体（2.47 g）加入（50mL）乙酸乙酯中，搅拌溶解后，加入15%的盐酸（2.5 mL），在50℃下反应8 h，冷却至室温，抽滤，得白色固体，将白色固体溶于10mL水中，用15%的氢氧化钠溶液调节PH至8-9，有白色固体析出，用乙酸乙酯萃取（30 mL×2），有机层用无水硫酸钠干燥，抽滤，真空浓缩即得化合物7a（1.40 g），白色粉末，产率80.9%，熔点：96.8-97.8℃；1H NMR (600 MHz, CDCl3) δ8.32 (d, J=7.6 Hz, 1H, CONH), 7.78 (s, 1H, Ar-H), 6.96 (t, J=7.3 Hz, 1H, Ar-H), 6.88 (t, J=7.5 Hz, 1H, Ar-H), 6.80 (d, J=7.9 Hz, 1H, Ar-H), 3.81 (s, 3H,Ar-OCH3), 3.11 (d, J=11.9 Hz, 2H, piperidine-CH2), 2.61 (t, J=12.0 Hz, 2H,piperidine-CH2), 2.38-2.31 (m, 1H, piperidine-CH), 1.86 (d, J=12.3 Hz, 2H,piperidine-CH2), 1.74 (s, 1H, NH), 1.68-1.61 (m, 2H, piperidine-CH2).13C NMR(151 MHz, CDCl3)： δ 172.02(1C), 146.85(1C), 126.73(1C), 122.54(1C),120.13(1C), 118.80(1C), 108.88(1C), 54.70(1C), 45.07(2C), 44.17(1C), 29.02(2C)。
按照实施例2相同的方法，可制得化合物7b-7r：
实施例3、N-（2-甲氧基苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1a）的制备
在25 mL的圆底烧瓶中加入化合物7a（0.42 g，1.8 mmol），研磨后的碳酸钾（0.25g，1.8 mmol），催化量的KI（0.07 g，0.4 mmol），乙腈10 mL，室温搅拌30 min，加入化合物4（0.35 g，1.5mmol），加热到70℃反应8 h，过滤，真空浓缩，柱层析后即得化合物1a（0.25g），白色粉末，产率39.6%，熔点：136.3-137.5℃；1H NMR (600 MHz, CDCl3) δ 8.30 (d, J=7.9 Hz, 1H, CONH), 7.78 (s, 1H, Ar-H), 6.96 (t, J=7.7 Hz, 1H, Ar-H), 6.88 (t,J=7.7 Hz, 1H, Ar-H), 6.80 (d, J=8.1 Hz, 1H, Ar-H), 6.31 (s, 1H,CONH), 3.82(s, 3H,Ar-OCH3), 3.31-3.06 (m, 6H, diazaspiro-CH2), 2.90 (d, J=10.8 Hz, 2H,CH2), 2.20 (dd, J=16.1, 6.9 Hz, 1H, piperidine-CH), 2.12-1.97 (m, 4H,piperidine-CH2), 1.95-1.74 (m, 8H, diazaspiro-CH2, piperidine-CH2), 1.47-1.37(m, 2H, diazaspiro-CH2). 13C NMR (151 MHz, CDCl3) δ 180.10(1C), 171.93(1C),167.10(1C), 146.87(1C), 126.68(1C), 122.60(1C), 120.10 (1C), 118.81(1C),108.90(1C), 60.88(1C), 54.72(1C), 52.15(1C), 51.99(1C), 43.27 (1C), 41.40(1C), 40.70(1C), 37.66(1C), 37.53(1C), 32.15(1C), 31.74(1C), 31.15(1C), 28.08(1C), 27.96(1C). HRMS(ESI): calcd for C23H32N4O4[M+H]+, 429.2496, found,429.2497。
按照实施例3相同的方法，可制备如下化合物1b-1r：
N-（4-氯苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1b）
产率41.5%；白色粉末；熔点：253.2-254.6℃；1H NMR (600 MHz, CDCl3) δ 8.11(s, 1H, CONH), 7.46 (d, J=8.5 Hz, 2H, Ar-H), 7.17 (d, J=8.6 Hz, 2H, Ar-H),6.33 (s, 1H, CONH), 3.29 (t, J=6.8 Hz, 2H, diazaspiro-CH2), 3.24-3.03 (m, 4H,diazaspiro-CH2), 2.89 (d, J=9.1 Hz, 2H, CH2), 2.22-2.18 (m, 1H, piperidine-CH), 2.03 (ddd, J= 28.4, 22.2, 16.1 Hz, 6H, diazaspiro-CH2, piperidine-CH2),1.77 (dd, J=32.5, 18.8 Hz, 6H, piperidine-CH2), 1.41 (t, J=16.7 Hz, 2H,diazaspiro-CH2). 13C NMR (151 MHz, CDCl3) δ 179.99(1C), 172.51(1C), 167.05(1C),135.96(1C), 127.93(1C), 127.85(2C), 120.19(2C), 60.85(1C), 52.06(2C), 42.84(1C), 41.48(1C), 40.79(1C), 37.72(1C), 37.63(1C), 32.12(1C), 31.57(1C), 31.17(1C), 27.81(2C). HRMS(ESI): calcd for C22H29ClN4O3[M+H]+, 433.2001, found,433.2000。
（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）-N-（间甲苯基）哌啶-4-甲酰胺（1c）
产率43.6%；白色粉末；熔点：167.8-168.9℃；1H NMR (600 MHz, DMSO) δ 9.78(s, 1H, CONH), 7.60 (s, 1H, Ar-H), 7.45 (s, 1H, Ar-H), 7.37 (d, J=8.1 Hz, 1H,Ar-H), 7.15 (t, J=7.8 Hz, 1H, Ar-H), 6.84 (d, J=7.5 Hz, 1H, CONH), 3.35 (s,2H, diazaspiro-CH2), 3.25-3.04 (m, 6H, diazaspiro-CH2), 2.89-2.84 (m, 2H,CH2), 2.33-2.25 (m, 4H, diazaspiro-CH2, piperidine-CH2), 2.00 (dd, J=6.6, 4.0Hz, 4H, piperidine-CH), 1.77-1.47 (m, 6H, piperidine-CH2), 1.37 (dd, J=32.8,13.5 Hz, 2H, diazaspiro-CH2).13C NMR (151 MHz, DMSO) δ 180.19(1C), 173.89(1C),167.84(1C), 139.75 (1C), 138.20(1C), 128.88(1C), 124.12(1C), 120.21(1C),116.83(1C), 61.80(1C), 53.08 (1C), 52.89(1C), 42.97(1C), 42.62(1C), 42.18(1C), 38.50(1C), 38.38(1C), 32.89(1C), 32.05(1C), 31.60(1C), 29.01(2C), 21.64(1C). HRMS(ESI): calcd for C23H32N4O3[M+H]+, 413.2547, found,413.2547。
（2,4-二氟苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1d）
产率38.8%；白色粉末；熔点：155.6-156.7℃；1H NMR (600 MHz, MeOD) δ 7.74(dd, J=14.9, 8.8 Hz, 1H,Ar-H), 7.03 (dd, J=13.9, 5.5 Hz, 1H, Ar-H), 6.94 (t,J= 8.5 Hz, 1H, Ar-H), 3.49 (dd, J=13.2, 5.1 Hz, 2H, diazaspiro-CH2), 3.23-3.07 (m, 4H, diazaspiro-CH2), 2.81 (ddd, J=15.0, 12.0, 5.9 Hz, 2H,CH2), 2.15(t, J=6.9 Hz, 1H, piperidine-CH), 2.05-1.93 (m, 6H, diazaspiro-CH2, piperidine-CH2), 1.82-1.56 (m, 6H, piperidine-CH2), 1.40-1.22 (m, 2H,diazaspiro-CH2). 13C NMR (151 MHz, MeOD) δ 182.12(1C), 180.53(1C), 174.63(1C),126.32(1C), 121.90(1C), 110.56(1C), 103.64 (1C), 103.48(1C), 103.31(1C),59.46(1C), 49.83(1C), 49.71(1C), 48.48(1C), 44.75 (1C), 42.34(1C), 41.26(1C),40.60(1C), 38.36(1C), 31.96(1C), 31.02(1C), 28.95(1C), 28.13(1C). HRMS(ESI):calcd for C22H28F2N4O3[M+H]+, 435.2202, found, 435.2209。
（3-溴苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1e）
产率40.7%；白色粉末；熔点：180.3-181.6℃；1H NMR (600 MHz, CDCl3) δ 8.74(s, 1H, CONH), 7.74 (s, 1H, Ar-H), 7.46 (d, J=8.1 Hz, 1H, Ar-H), 7.12 (d, J=8.0 Hz, 1H,Ar-H), 7.07 (t, J=8.0 Hz, 1H, Ar-H), 6.29 (s, 1H, CONH), 3.28-2.96(m, 6H, diazaspiro-CH2), 2.74 (t, J=11.9 Hz, 2H, CH2), 2.54-2.48 (m, 1H,piperidine-CH), 2.13 -1.91 (m, 4H, piperidine-CH2), 1.89-1.58 (m, 8H,diazaspiro-CH2, piperidine-CH2), 1.36 (t, J=12.9 Hz, 2H, diazaspiro-CH2). 13CNMR (151 MHz, CDCl3) δ 181.01(1C), 172.09(1C), 167.25(1C), 138.86(1C), 129.21(1C), 125.88(1C), 121.86(1C), 121.40 (1C), 117.48(1C), 61.30(1C), 48.99(1C),48.76(1C), 44.23(1C), 42.39(1C), 40.76(1C), 40.39(1C), 37.78(1C), 31.20(2C),30.44(1C), 28.23(1C), 27.52(1C). HRMS(ESI): calcd for C22H29BrN4O3 [M+Na]+,499.1315, found, 499.1314。
（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）乙基）-N-苯基哌啶-4-甲酰胺（1f）
产率43.3%；白色粉末；熔点：246.7-247.6℃；1H NMR (600 MHz, DMSO) δ 9.84(s, 1H, CONH), 7.61-7.57 (m, 3H, Ar-H), 7.28 (t, J=7.9 Hz, 2H, Ar-H), 7.02(t, J=7.3 Hz, 1H, CONH), 3.15 (ddd, J=54.2, 29.4, 11.2 Hz, 6H, diazaspiro-CH2), 2.87 (d, J=11.0 Hz, 2H, CH2), 2.31 (ddd, J=15.3, 7.8, 3.6 Hz, 1H,piperidine-CH), 2.05-1.99 (m, 4H, piperidine-CH2), 1.83-1.41 (m, 8H,diazaspiro-CH2, piperidine-CH2), 1.40-1.32 (m, 2H, diazaspiro-CH2).13C NMR (151MHz, DMSO) δ 180.18(1C), 173.93(1C), 167.84 (1C), 139.85(1C), 129.05(2C),123.42(1C), 119.62(2C), 61.83(1C), 53.09(1C), 52.90 (1C), 43.02(1C), 42.62(1C), 42.17(1C), 38.50(1C), 38.38(1C), 32.92(1C), 32.06(1C), 31.62(1C), 29.02(2C). HRMS(ESI): calcd for C22H30N4O3[M+H]+, 399.2391, found,399.2383。
（4-氟苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1g）
产率37.6%；白色粉末；熔点：164.8-165.7℃；1H NMR (600 MHz, DMSO) δ 9.98(s, 1H, CONH), 7.62 (dd, J=8.9, 5.0 Hz, 2H, Ar-H), 7.53 (s, 1H, CONH), 7.12(t, J=8.9 Hz, 2H, Ar-H), 3.09 (dt, J=24.0, 9.3 Hz, 4H, diazaspiro-CH2), 2.77(s, 2H, CH2), 2.59 (ddd, J=16.8, 11.6, 8.2 Hz, 3H, diazaspiro-CH2, piperidine-CH), 2.12 (s, 2H, piperidine-CH2), 1.90 (d, J=6.8 Hz, 2H, piperidine-CH2),1.86-1.39 (m, 8H, diazaspiro-CH2, piperidine-CH2), 1.37-1.30 (m, 2H,diazaspiro-CH2). 13C NMR (151 MHz, DMSO) δ 180.68(1C), 173.30(1C), 159.16(1C),157.58(1C), 136.12(1C), 121.42(2C), 115.69 (1C), 115.54(1C), 61.67(1C), 50.04(1C), 49.79(1C), 45.17(1C), 43.00(1C), 41.55(1C), 41.22(1C), 38.32(1C), 32.03(2C), 31.30(1C), 29.43(1C), 28.74(1C). HRMS(ESI): calcd for C22H29FN4O3[M+H]+,417.2296, found, 417.2303。
（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）乙基）-N-（3-（三氟甲基）苯基）哌啶-4-甲酰胺（1h）
产率45.7%；白色粉末；熔点：132.8-134.6℃；1H NMR (600 MHz, CDCl3) δ 8.92(s, 1H, CONH), 7.79 (d, J=8.9 Hz, 2H, Ar-H), 7.33 (t, J=7.8 Hz, 1H, Ar-H),7.24 (d, J=7.7 Hz, 1H, Ar-H), 6.21 (s, 1H, CONH), 3.26-.01 (m, 5H,diazaspiro-CH2), 2.79 -2.67 (m, 3H, CH2, diazaspiro-CH2), 2.56 (ddd, J=14.6,10.8, 3.7 Hz, 1H, piperidine-CH), 2.10 (dd, J=27.5, 12.1 Hz, 2H, piperidine-CH2), 1.94 (dd, J=12.6, 6.4 Hz, 2H, piperidine-CH2), 1.92-1.48 (m, 8H,diazaspiro-CH2, piperidine-CH2), 1.36 (t, J=13.5 Hz, 2H, diazaspiro-CH2). 13CNMR (151 MHz, CDCl3) δ 180.96(1C), 172.23(1C), 167.24(1C), 138.13(1C), 130.12(1C), 128.42(1C), 122.04(1C), 119.40(1C), 115.60 (1C), 61.28(1C), 48.98(1C),48.76(1C), 44.22(1C), 42.38(1C), 40.72(1C), 40.38(1C), 37.74(1C), 31.20(2C),30.43(1C), 29.67(1C), 28.23(1C), 27.49(1C).HRMS(ESI): calcd for C23H29F3N4O3[M+H]+, 467.2265, found, 467.2270。
（3-氯-4-氟苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1i）
产率49.0%；白色粉末；熔点：173.2-174.8℃；1H NMR (600 MHz, CDCl3) δ 8.66(s, 1H, CONH), 7.68 (dd, J=6.5, 2.4 Hz, 1H, Ar-H), 7.39-7.35 (m, 1H, Ar-H),6.98 (t, J=8.8 Hz, 1H, Ar-H), 6.12 (s, 1H, CONH), 3.26 (t, J=6.9 Hz, 2H,diazaspiro-CH2), 3.15-2.99 (m, 3H, diazaspiro-CH2), 2.71 (dt, J=37.2, 11.4 Hz,3H, CH2, diazaspiro-CH2), 2.50 (ddd, J=14.6, 10.8, 3.7 Hz, 1H, piperidine-CH),2.21-2.05 (m, 4H, piperidine-CH2), 1.97-1.63 (m, 8H, diazaspiro-CH2, piperidine-CH2), 1.37 (t, J=12.3 Hz, 2H, diazaspiro-CH2). HRMS(ESI): calcd forC22H28ClFN4O3[M+H]+, 451.1907, found, 451.1909。
（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）-N-（1-苯乙基）哌啶-4-甲酰胺（1j）
产率44.5%；白色粉末；熔点：106.9-108.5℃；1H NMR (600 MHz, CDCl3) δ 7.23(d, J=9.2 Hz, 4H, Ar-H), 7.16 (t, J=6.4 Hz, 1H, Ar-H), 6.51 (d, J=7.1 Hz, 1H,CONH), 5.02 (p, J=7.0 Hz, 1H, CH), 3.35-2.90 (m, 6H, diazaspiro-CH2), 2.72(s, 2H, CH2), 2.57 (q, J=11.8 Hz, 1H, piperidine-CH), 2.09 (dd, J=21.8, 10.8Hz, 2H, piperidine-CH2), 2.02-1.42 (m, 10H, diazaspiro-CH2, piperidine-CH2),1.39 (dd, J=6.8, 2.6 Hz, 3H,CH3), 1.33 (d, J=8.7 Hz, 2H, diazaspiro-CH2 ). 13CNMR (151 MHz, CDCl3) δ 181.09(1C), 172.35(1C), 167.13(1C), 142.51(1C), 127.61(2C), 126.20(1C), 125.14 (2C), 61.20(1C), 48.86(2C), 47.52(1C), 44.23(1C),41.74(1C), 40.78(1C), 40.43(1C), 37.78(1C), 31.15(2C), 30.49(1C), 28.36(1C),27.59(1C), 20.83(1C). HRMS(ESI): calcd for C24H34N4O3[M+Na]+, 449.2523, found,449.2523。
（4-甲氧基苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1k）
产率48.2%；白色粉末；熔点：217.6-218.9℃；1H NMR (600 MHz, CDCl3) δ 7.62(s, 1H, CONH), 7.37 (d, J=8.9 Hz, 2H, Ar-H), 6.76 (d, J=8.9 Hz, 2H, Ar-H),6.18 (s, 1H, CONH), 3.71 (s, 3H, Ar-OCH3), 3.30-3.03 (m, 6H, diazaspiro-CH2),2.88 (s, 2H, CH2), 2.19-2.13 (m, 1H, piperidine-CH), 2.09-1.98 (m, 6H,diazaspiro-CH2, piperidine-CH2), 1.86-1.73 (m, 6H, diazaspiro-CH2, piperidine-CH2), 1.45-1.37(m, 2H, diazaspiro-CH2). 13C NMR (151 MHz, CDCl3) δ 179.96(1C),172.07(1C), 167.09(1C), 155.39 (1C), 130.24(1C), 120.79(2C), 113.15(2C),60.87(1C), 54.51(1C), 52.08(2C), 42.80 (1C), 41.46(1C), 40.67(1C), 37.61(2C),32.16(1C), 31.72(1C), 31.18(1C), 27.94(2C). HRMS(ESI): calcd for C23H32N4O4[M+H]+, 429.2496, found,429.2500。
（2-氟苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1l）
产率39.6%；白色粉末；熔点：151.4-152.7℃；1H NMR (600 MHz, DMSO) δ 9.68(s, 1H, CONH), 7.86 (t, J=8.6 Hz, 1H, Ar-H), 7.51 (s, 1H, CONH), 7.29-7.21(m, 1H, Ar-H), 7.14 (dd, J=4.9, 2.4 Hz, 2H, Ar-H), 3.34-3.13 (m, 6H,diazaspiro-CH2), 3.03 (t, J=11.6 Hz, 2H, piperidine-CH2), 2.75 (dd, J=12.1,9.1 Hz, 2H, CH2), 2.63 (t, J= 12.1 Hz, 1H, piperidine-CH), 2.08 (d, J=8.5 Hz,2H, piperidine-CH2), 1.87 (dt, J=32.1, 11.9 Hz, 4H, diazaspiro-CH2), 1.72-1.43(m, 4H, piperidine-CH2), 1.32 (d, J=9.3 Hz, 2H, diazaspiro-CH2). 13C NMR (151MHz, DMSO) δ 180.75(1C), 173.85(1C), 167.84(1C), 155.15(1C), 126.68(1C),125.74(1C), 125.00(1C), 124.69(1C), 115.93(1C), 61.92(1C), 50.04(1C), 49.76(1C), 45.22(1C), 42.42(1C), 41.64(1C), 41.21(1C), 38.33(1C), 32.17 (2C),31.26(1C), 29.52(1C), 28.84(1C). HRMS(ESI): calcd for C22H29FN4O3[M+Na]+,439.2116, found,439. 2119。
（3-硝基苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1m）
产率39.8%；白色粉末；熔点：118.5-119.7℃；1H NMR (600 MHz, DMSO) δ 10.82(s, 1H, CONH), 8.01 (d, J=8.2 Hz, 1H, Ar-H), 7.87 (dd, J=8.2, 1.5 Hz, 1H, Ar-H), 7.71 (s, 1H, Ar-H), 7.60 (d, J=8.2 Hz, 1H, Ar-H), 6.73 (s, 1H, CONH),3.26 (dt, J=12.5, 4.4 Hz, 2H, diazaspiro-CH2), 3.18-3.13 (m, 4H, diazaspiro-CH2 ), 2.97-2.92 (m, 2H, CH2), 2.01-1.78 (m, 4H, piperidine-CH2), 1.59-1.49(m, 8H, diazaspiro-CH2, piperidine-CH2), 1.30 (dd, J=13.8, 6.3 Hz, 2H,diazaspiro-CH2). 13C NMR (151 MHz, DMSO) δ 179.38(1C), 174.26(1C), 170.84(1C),148.38(1C), 130.48(1C), 125.62(1C), 123.10(1C), 118.00(1C), 113.68(1C), 63.94(1C), 49.01(1C), 49.76(1C), 44.22(1C), 42.62(1C), 41.84(1C), 40.16(1C), 38.34(1C), 31.99(2C), 30.63(1C), 29.91(1C), 28.93 (1C).HRMS(ESI): calcd forC22H29N5O5[M+H]+, 444.2241, found, 444.2242。
（3,5-二甲基苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1n）
产率51.3%；白色粉末；熔点：148.6-149.7℃；1H NMR (600 MHz, CDCl3) δ 7.83(s, 1H, CONH), 7.11 (s, 2H, Ar-H), 6.66 (s, 1H, Ar-H), 6.15 (s, 1H, CONH),3.24 (t, J=6.9 Hz, 2H, diazaspiro-CH2), 3.13 (s, 2H, diazaspiro-CH2), 2.75 (t,J=11.0 Hz, 2H, CH2), 2.44 (t, J=10.9 Hz, 1H, piperidine-CH), 2.20 (s, 6H, Ar-CH3), 2.16-2.09 (m, 6H, diazaspiro-CH2,piperidine-CH2), 1.96-1.84 (m, 6H,diazaspiro-CH2, piperidine-CH2 ), 1.68 (dd, J=44.9, 10.0 Hz, 2H, piperidine-CH2), 1.36 (dd, J=20.5, 8.5 Hz, 2H, diazaspiro-CH2). 13C NMR (151 MHz, CDCl3) δ180.98(1C), 171.59(1C), 167.20(1C), 137.61(2C), 136.89(1C), 124.99(1C),116.81(2C), 61.16(1C), 48.91(1C), 48.78(1C), 44.21(1C), 42.69(1C), 40.67(1C),40.39(1C), 37.71(1C), 31.19(2C), 30.55(1C), 28.32(1C), 27.64(1C), 20.35(2C).HRMS(ESI): calcd for C24H34N4O3[M+H]+, 427.2704, found, 427. 2712。
（4-溴苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1o）
产率35.5%；白色粉末；熔点：164.8-166.2℃；1H NMR (600 MHz, DMSO) δ 10.07(s, 1H, CONH), 7.59 (d, J=8.9 Hz, 2H, Ar-H), 7.47 (d, J=8.8 Hz, 2H, Ar-H),7.12 (s, 1H, CONH), 3.15 (t, J=6.8 Hz, 2H, diazaspiro-CH2), 3.03 (t, J=12.0Hz, 2H, diazaspiro-CH2), 2.76-2.71 (m, 2H, CH2), 2.65-2.58 (m, 2H, diazaspiro-CH2), 2.52-2.50 (m, 1H, piperidine-CH), 2.11-2.05 (m, 2H, piperidine-CH2),1.90 (d, J=6.8 Hz, 2H, piperidine-CH2), 1.85-1.44 (m, 8H, diazaspiro-CH2,piperidine-CH2), 1.33 (dd, J=10.5, 4.9 Hz, 2H, diazaspiro-CH2). 13C NMR (151MHz, DMSO) δ 180.75(1C), 173.60(1C), 167.84(1C), 139.12(1C), 131.89(2C),121.62(2C), 115.59(1C), 61.87(1C), 50.03(1C), 49.77(1C), 45.20(1C), 43.12(1C), 41.63(1C), 41.18(1C), 38.33(1C), 32.18(2C), 31.28 (1C), 29.41(1C),28.71(1C).HRMS(ESI): calcd for C22H29BrN4O3[M+H]+, 477.1496, found,477. 1487。
（3-甲氧基苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1p）
产率45.6%；白色粉末；熔点：109.8-111.0℃；1H NMR (600 MHz, DMSO) δ 10.00(s, 1H, CONH), 7.59 (s, 1H, Ar-H), 7.35 (s, 1H, Ar-H), 7.21-7.14 (m, 2H, Ar-H), 6.61 (d, J=6.6 Hz, 1H, CONH), 3.72 (s, 3H, Ar-OCH3), 3.30 (d, J=12.7 Hz,2H, diazaspiro-CH2), 3.18 (t, J=9.8 Hz, 4H, diazaspiro-CH2), 3.07-2.96 (m, 2H,piperidine-CH2), 2.65 (t, J=11.1 Hz, 2H, CH2), 1.92 (d, J=4.9 Hz, 2H,piperidine-CH2), 1.71 (ddd, J=43.1, 28.0, 12.6 Hz, 8H, diazaspiro-CH2,piperidine-CH2), 1.43 (s, 2H, diazaspiro-CH2). 13C NMR (151 MHz, DMSO) δ180.36(1C), 179.35(1C), 173.45(1C), 159.94 (1C), 140.94(1C), 129.82(1C),111.96(1C), 109.11(1C), 105.46(1C), 63.95(1C), 55.45 (1C), 50.04(1C), 49.84(1C), 44.99(1C), 42.95(1C), 41.28(1C), 38.33(1C), 31.90(1C), 31.44(2C), 29.31(1C), 29.00(1C), 28.67(1C).HRMS(ESI): calcd for C23H32N4O4[M+H]+, 429.2496,found,429.2493。
（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）-N-（邻甲苯基）哌啶-4-甲酰胺（1q）
产率42.8%；白色粉末；熔点：121.9-123.2℃；1H NMR (600 MHz, MeOD) δ 7.28(d, J=7.6 Hz, 1H, Ar-H), 7.22 (d, J=7.3 Hz, 1H, Ar-H), 7.18-7.11 (m, 2H, Ar-H), 3.24 (dt, J=23.4, 9.3 Hz, 4H, diazaspiro-CH2), 2.95 (d, J=7.2 Hz, 2H,diazaspiro-CH2), 2.77 (ddd, J=15.3, 12.9, 5.6 Hz, 2H, CH2), 2.35 (t, J=10.4Hz, 2H, piperidine-CH2), 2.23 (s, 3H, Ar-H), 2.06 (dd, J=7.4, 6.2 Hz, 2H,piperidine-CH2), 2.01-1.58 (m, 8H, diazaspiro-CH2, piperidine-CH2), 1.50 (d, J=11.1 Hz, 2H, diazaspiro-CH2). 13C NMR (151 MHz, MeOD) δ 182.32(1C), 174.56(1C), 168.09(1C), 135.42(1C), 133.20(1C), 130.21(1C), 126.14(1C), 125.93(1C),125.85(1C), 60.24(1C), 49.74(1C), 49.63(1C), 44.99(1C), 42.52(1C), 41.86(1C),41.30(1C), 38.44(1C), 31.42(2C), 31.09(1C), 29.20 (1C), 28.33(1C), 16.78(1C).HRMS(ESI): calcd for C23H32N4O[M+H]+, 413.2547, found, 413.2547。.
N-（3,4-二氟苯基）-1-（2-氧代-2-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）乙基）哌啶-4-甲酰胺（1r）
产率52.2%；白色粉末；熔点：203.7-205.1℃；1H NMR (600 MHz, CDCl3) δ 8.69(s, 1H, CONH), 7.57 (ddd, J=12.0, 7.2, 2.1 Hz, 1H, Ar-H), 7.15 (d, J=8.8 Hz,1H, Ar-H), 6.99 (q, J=9.1 Hz, 1H, Ar-H), 6.19 (s, 1H, CONH), 3.35-2.94 (m,6H, diazaspiro-CH2), 2.76 (dd, J=21.6, 10.0 Hz, 2H, CH2), 2.49 (td, J=10.9,5.4 Hz, 1H, piperidine-CH), 2.30-1.91 (m, 6H, diazaspiro-CH2, piperidine-CH2),1.87-1.63 (m, 6H, diazaspiro-CH2, piperidine-CH2), 1.37 (t, J=12.3 Hz, 2H,diazaspiro-CH2). 13C NMR (151 MHz, CDCl3) δ 180.99(1C), 171.90(1C), 167.26(1C), 148.97(1C), 145.73(1C), 134.03(1C), 116.02(1C), 114.59(1C), 108.63(1C),61.29(1C), 48.88(2C), 44.23(1C), 42.39(1C), 40.74(1C), 40.39(1C), 37.75(1C),31.22(2C), 30.42(1C), 28.23(1C), 27.50 (1C).HRMS(ESI): calcd for C21H28N4O3[M+H]+, 435.2202, found, 435.2200。
实施例4、1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物的几丁质合成酶活性抑制实验
从热带酵母细胞膜中提取的几丁质合成酶与底物UDP-GlcNAc在微孔板上发生孵化反应，产生的几丁质与微孔板上包被的WGA结合在一起，然后加入WGA-HRP与固定在板上的几丁质结合，将多余的试剂洗掉，然后使用TMB底物溶液检测HRP的活性，用2 M的硫酸终止反应，用ELISA检测仪在450 nm处检测其OD值，进而计算出抑制率和IC50值。
实施例3制得的化合物1a-1r都进行了几丁质合成酶抑制活性初筛，初筛的最高药物浓度为300 μg/mL，抑制率（IP, inhibition percentage）为该最高药物浓度对几丁质合成酶的抑制率，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：
Figure 400661DEST_PATH_IMAGE012
。
实施例5、1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合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，检查实施例3制得的1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物对革兰氏阳性菌（耐甲氧西林金黄色葡萄球菌（MRSA 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（JM109）、铜绿假单胞菌（ATCC 9027）、变形杆菌（ATCC 8427））和真菌（白色念珠菌（ATCC76615）、烟曲霉菌（GIMCC 3.19）、白色念珠菌（ATCC 90023）、黄曲霉菌（ATCC 16870）、新型隐球菌（ATCC 32719））的最低抑制浓度（MIC），将待测化合物用少量二甲亚砜溶解，用灭菌水配制成溶液备用，将96孔板，枪头等进行紫外灭菌，取稀释好的菌液100uL加入到96孔板中，用链霉素，左氧氟沙星；氟康唑和多抗霉素 B作为参比对照。细菌，真菌在37℃培养18~24h，观察现象，结果见表2~3：
Figure 874368DEST_PATH_IMAGE013
Figure 905778DEST_PATH_IMAGE014
由表可以看出，本发明制得的化合物1a-1r，对所测试的细菌和真菌均表现出一定的抑制作用，特别地， 1h分别对白色念珠菌（ATCC 76615）、烟曲霉菌、白色念珠菌（ATCC9002300）、新型隐球菌表现出较高的抗菌活性，MIC值都为16 µg/mL。部分化合物抗真菌活性与参考药物氟康唑相接近。

Claims (3)

1.1-氧代-2,8-二氮杂螺[4.5]癸烷哌啶甲酸酰胺类化合物，其特征在于：该螺环化合物8-位通过4-哌啶甲酸酰胺与一含氮的片断相连，组成如通式1所示结构的化合物：
Figure DEST_PATH_IMAGE002
其中R1为H；R2为2-CH3OC6H4，4-ClC6H4，3-CH3C6H4，2,4-FC6H3，3-BrC6H4，Ph，4-FC6H4，3-F3CC6H4，3-Cl-4-FC6H3，CHCH3C6H5，4-CH3OC6H4，2-FC6H4，3-O2NC6H4，3,5-CH3C6H3，4-BrC6H4，3-CH3OC6H4，2-CH3C6H4，3,4-FC6H3。
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，选自大肠杆菌、金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、枯草杆菌、变形杆菌、铜绿色假单胞菌；白色念珠菌、新型隐球菌、黄曲霉菌、烟曲霉菌。
3.如权利要求1所述化合物在制备几丁质合成酶抑制剂药物中的应用。
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