CN109400608B - 二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用 - Google Patents

二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用 Download PDF

Info

Publication number
CN109400608B
CN109400608B CN201811537842.5A CN201811537842A CN109400608B CN 109400608 B CN109400608 B CN 109400608B CN 201811537842 A CN201811537842 A CN 201811537842A CN 109400608 B CN109400608 B CN 109400608B
Authority
CN
China
Prior art keywords
diazaspiro
oxo
nmr
mhz
tartaric acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201811537842.5A
Other languages
English (en)
Other versions
CN109400608A (zh
Inventor
吉庆刚
李兵
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southwest University
Original Assignee
Southwest University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Southwest University filed Critical Southwest University
Priority to CN201811537842.5A priority Critical patent/CN109400608B/zh
Publication of CN109400608A publication Critical patent/CN109400608A/zh
Application granted granted Critical
Publication of CN109400608B publication Critical patent/CN109400608B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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L‑酒石酸衍生物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_IMAGE002
式中R1为氢；R2为：苯或取代苯。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，可用于制备抗细菌和/或抗真菌药物，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[4，5]癸烷酒石酸类衍生物制备和应用
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L-酒石酸衍生物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，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，使得菌类感染的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在国内外医学领域备受关注。
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，螺环化合物因其两环平面相互垂直的结构、杂环螺具备螺共轭、螺超共轭或异头效应等一般有机化合物不具备的特殊性质及其含有电负强的O，N等杂原子与其它分子之间能够形成的较大的分子间作用力等独特优势，被广泛应用于抗真菌、抗肿瘤、抗病毒、抗焦虑、抗糖尿病、消炎等医学领域。此外，以L-酒石酸作为linker的核苷糖类衍生物也具备较高几丁质合成酶抑制活性，同时L-酒石酸在TACE抑制剂，抗糖尿病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：Cheminform, 2006, 62(5):779-828.；Bioorg. Med. Chem.Lett.2012, 22(11):3643-364；Bioorg. Med. Chem.Lett. 2010, 20(16):4895-4900；Bioorg. Med. Chem.Lett.2008, 18(18):4997-5001；Bioorg. Med. Chem.Lett.2010, 20(16):4895-4900。
本发明设计并合成了一类1-氧代-2,8-二氮杂螺[4. 5]癸烷L-酒石酸衍生物类化合物，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，为人类的健康做出贡献。
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L-酒石酸衍生物类；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L-酒石酸衍生物类的制备方法；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L-酒石酸衍生物类在制备抗细菌/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L-酒石酸衍生物类结构如通式1所示：
Figure 3074DEST_PATH_IMAGE001
其中R1为H，R2为Ph，4-ClC6H4，2-CH3OC6H4，2,4-ClC6H3，2-BrC6H4，4-FC6H4，2-CH3C6H4，3,5-F3CC6H3，4-CH3OC6H4，3,4-FC6H3，2-FC6H4，4-O2NC6H4，3-F3CC6H4，3-Cl-4-FC6H3，3-CH3OC6H4，4-BrC6H4，2- ClC6H4或2,4-FC6H3等等，上述物质是分别唯一对应一个结构式的具体化合物，具体地，通式1所示的1-氧代-2, 8-二氮杂螺[4.5]癸烷L-酒石酸衍生物类为下述化合物的任意一种。
Figure 823263DEST_PATH_IMAGE002
Figure 175747DEST_PATH_IMAGE003
Figure 554513DEST_PATH_IMAGE004
Figure 992448DEST_PATH_IMAGE005
Figure 350748DEST_PATH_IMAGE006
Figure 761001DEST_PATH_IMAGE007
上述1-氧代-2,8-二氮杂螺[4.5]癸烷L-酒石酸衍生物类的合成方法，按如下进行：
如Scheme1所示
Figure 874450DEST_PATH_IMAGE008
具体地说，上述Scheme1 反应条件如下：
a. 化合物2与化合物3a经缩合，酯碱性条件下水解生成化合物4a。溶剂为二氯甲烷、三氯甲烷、四氢呋喃、二氧六环等，优选二氯甲烷；化合物2，3a，的摩尔比为1: 1.1~2，室温至50℃，反应4-8 h。
b. 化合物4a再与化合物5，经T3P缩合，最后脱羟基保护生成化合物1a，溶剂为二氯甲烷、三氯甲烷、四氢呋喃、二氧六环等，优选二氯甲烷；化合物5：4a摩尔比1: 1.1~2，优选二氯甲烷为溶剂，室温至50℃反应6-12 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L-酒石酸衍生物类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。
实施例1、（4S，5S）-2,2-二甲基-5-（苯基氨基甲酰基）-1,3-二氧戊环-4-羧酸（4a）的制备
依次称取保护的L-酒石酸【（4S，5S）-5-（乙氧基羰基）-2,2-二甲基-1,3-二氧戊环-4-羧酸】即化合物2（2.24 g，10.31 mmol）、1-羟基苯并三唑（1.39 g，10.31 mmol）、二甲基氨基吡啶（1.26 g，10.31 mmol）、N, N-二环己基碳二酰亚胺（2.34 g，11.34 mmol）加入干燥的二氯甲烷（50 ml）中，室温搅拌30 min。加入化合物3a（1.06 g，11.34 mmol），室温反应8 h。抽滤，滤液依次用饱和的碳酸氢钠、稀盐酸（0.01 mol/L）和水洗剂，无水硫酸钠干燥，抽滤，真空浓缩得到粗产物2.3 g，将粗产物（2.1 g，7.16 mmol）溶于1, 4-二氧六环和水（42 mL，1: 1v/v）的混合溶剂中，室温下滴加1 mol/L氢氧化钠溶液（7.2 mL，7.16mmol），滴加完毕后再室温反应3 h，用二氯甲烷萃取（15 mL×2），水层用1mol/L稀盐酸调PH到2-3，水层用二氯甲烷萃取（15 mL×2），合并有机层，无水硫酸钠干燥，抽滤，真空浓缩，柱层析后即得到化合物4a（1.2 g），浅黄色油状液体，收率65.0%；1H NMR (600 MHz, CDCl3) δ8.41 (s, 1H,CONH), 7.58 (d, J = 7.9 Hz, 2H,Ph-2,6-H), 7.39 (t, J = 7.9 Hz,2H,Ph-3,5-H), 7.21 (t, J=7.4 Hz, 1H,Ph-4-H), 4.79 (d, J=7.6 Hz, 1H,CH), 4.75(d, J=7.6 Hz, 1H,CH), 1.57 (d, J=2.9 Hz, 6H,C(CH3)2)。按相似的合成方法，可得化合物4b-4r。
实施例 2、（2S，3S）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）-N-苯基丁酰胺(1a)的制备
在25 mL 圆底烧瓶中加入化合物4a（0.68g，2.56mmol），二氯甲烷15 mL,三乙胺（0.47g，4.66mmol），丙基磷酸三环酸酐（2.96g，4.66mmol），室温搅拌20min后，加入2,8-二氮杂螺[4.5]癸-1-酮，即化合物5（0.36g，2.33 mmol），继续搅拌30 min后加热到45℃反应12h，冷却至室温，加入15mL饱和碳酸氢钠溶液，用二氯甲烷萃取（15 mL×2）, 合并有机层，无水硫酸钠干燥，抽滤，真空浓缩得到粗产物0.49g，将粗产物（0.49g，1.22mmol）溶于甲醇20mL和1mol/L稀盐酸（6.1mL）的混合溶剂中，50℃反应4h，冷却至室温，加水15 mL，用1mol/L氢氧化钠溶液调PH到7-8，二氯甲烷萃取（15 mL×2），合并有机层，无水硫酸钠干燥，抽滤，真空浓缩，柱层析得到化合物1a（0.21 g），白色粉末， 产率48.6%，熔点：106.3-107.5℃；1HNMR (600 MHz, MeOD) δ 7.62 (d, J=7.9 Hz, 2H,Ph-2,6-H), 7.33 (dd, J=10.8, 5.1Hz, 2H,Ph-3,5-H), 7.12 (t, J =7.4 Hz, 1H, Ph-4-H), 4.94 (d, J=5.4 Hz, 1H,OH),4.38 (d, J=11.6 Hz, 1H,OH), 4.35-4.27 (m, 1H,CH), 4.13-4.07 (m, 1H,CH), 3.40-3.30 (m, 4H,diazaspiro-7,9-H), 2.14 (t, J=6.9 Hz, 2H, diazaspiro-3-H), 1.90-1.76 (m, 2H, diazaspiro-6-H,), 1.60 -1.50 (m, 2H, diazaspiro-10-H), 1.34-1.27(m, 2H, diazaspiro-4-H).13C NMR (151 MHz, MeOD) δ 181.81(1C), 170.97(1C),170.20(1C) , 137.48(1C) , 128.44 (2C), 124.29(1C) , 120.19 (2C), 72.72(1C) ,69.82(1C) , 42.52(1C) , 41.85(1C) , 39.08(1C), 38.45(1C) , 32.24(1C), 31.29(2C).HRMS(ESI): calcd. for C18H23N3O5 [M+H]+ , 362.1710, found, 362.1716.
按相同合成步骤，可得化合物1b-1r。
（2S，3S）-N-（4-氯苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺（1b）
产率52.4%；白色粉末；熔点：130.2-131.2℃；1H NMR (600 MHz, CDCl3) δ 8.89(s, 1H,CONH), 7.47 (t, J=6.9 Hz, 2H,Ph-2,6-H), 7.15 (t, J=8.9 Hz, 2H,Ph-3,5-H), 6.52 (s, 1H,CONH), 4.96 (s, 1H,OH), 4.34 (s, 1H,OH), 4.21 (dd, J=26.8,13.3 Hz, 1H,CH), 4.00-3.87 (m, 1H,CH), 3.28-2.92 (m, 4H,diazaspiro-7,9-H),2.24-1.72 (m, 6H,diazaspiro-3,6,10-H), 1.42-1.33 (m, 2H,diazaspiro-4-H).13CNMR (151 MHz, CDCl3) δ 180.23(1C), 169.16(1C), 168.97(1C), 134.96(1C), 128.43(1C), 127.87(2C), 120.12(2C), 71.42(1C), 68.25(1C), 41.33(1C), 40.81(1C),38.49(1C), 37.86(1C),31.40(2C),30.72(1C).HRMS(ESI): calcd. for C18H22ClN3O5[M+H]+, 396.1321,found,396.1325.
（2S，3S）-2,3-二羟基-N-（2-甲氧基苯基）-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1c)
产率46.9%；白色粉末；熔点：124.9-125.8℃；1H NMR (600 MHz, CDCl3) δ 9.25(s, 1H,CONH), 8.34-8.30 (m, 1H,Ph-6-H), 7.00-6.96 (m, 1H,Ph-4-H), 6.87 (dt, J=11.9, 6.1 Hz, 1H,Ph-3-H), 6.80 (t, J=6.8 Hz, 1H,Ph-5-H), 6.53 (s, 1H,CONH),4.97 (s, 1H,OH), 4.32 (s, 1H,OH), 4.24-4.13 (m, 1H,CH), 4.02-3.92 (m, 1H,CH),3.78 (s, 3H,Ph-OCH3), 3.30- 3.00 (m, 6H, diazaspiro-3,7,9-H), 1.96-1.71 (m,4H, diazaspiro-6,10-H), 1.40 (t, J=20.1 Hz, 2H, diazaspiro-4-H).13C NMR (151MHz, CDCl3) δ 180.17(1C), 169.26(1C), 168.75(1C), 147.51(1C), 126.03(1C),123.22(1C), 119.89(1C), 118.67(1C), 109.23(1C), 71.54(1C), 68.00(1C), 54.82(1C), 41.19(1C), 40.84(1C), 38.39(1C), 37.80(1C), 31.64(2C), 30.83(1C). HRMS(ESI): calcd. for C19H25N3O6[M+Na]+,414.1636, found,414.1638.
（2S，3S）-N-（2,4-二氯苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1d)
产率60.1%；白色粉末；熔点：112.5-113.2℃；1H NMR (600 MHz, CDCl3) δ 9.18(s, 1H,CONH), 8.32 (d, J=8.8 Hz, 1H,Ph-6-H), 7.31 (s, 1H,Ph-3-H), 7.17 (d, J=8.3 Hz, 1H,Ph-5-H), 6.16 (s, 1H,CONH), 4.93 (s, 1H,OH), 4.35 (d, J=7.8 Hz,1H,OH), 4.18 (dd, J=53.4, 13.1 Hz, 1H,CH), 4.06=3.94 (m, 1H,CH), 3.37-3.08(m, 4H,diazaspiro-7,9-H), 2.08=1.56 (m, 6H,diazaspiro-3,6,10-H), 1.51-1.40(m, 2H diazaspiro-4-H,).13C NMR (151 MHz, CDCl3) δ 179.93(1C) , 169.01(1C) ,168.77(1C) , 131.88(1C), 128.47(1C), 127.87(1C), 126.78(1C), 122.96(1C),120.97(1C) , 71.49(1C) , 67.82(1C), 41.28(1C), 40.90(1C), 38.45(1C), 37.73(1C), 31.77 (2C), 30.99(1C).HRMS(ESI)：calcd. for C18H21Cl2N3O5 [M+H]+ ,430.0931, found,430.0937.
（2S，3S）-N-（3-溴苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1e)
产率56.2%；白色粉末；熔点：126.8-128.3℃；1H NMR (600 MHz, CDCl3) δ 8.92(s, 1H,CONH), 7.83 (d, J = 11.9 Hz, 1H,Ph-2-H), 7.39 (t, J = 5.8 Hz, 1H,Ph-4-H), 7.13 (t, J=8.4 Hz, 1H,Ph-5-H), 7.06 (q, J=7.8 Hz, 1H,Ph-6-H), 6.54 (s,1H,CONH), 4.94 (dd, J=23.2, 6.8 Hz, 1H,OH), 4.36-4.30 (m, 1H,OH), 4.26-4.15(m, 1H,CH), 4.00-3.87 (m, 1H,CH), 3.26-2.93 (m, 4H,diazaspiro-7,9-H), 2.15(s, 2H,diazaspiro-3-H), 1.97-1.71 (m, 4H, diazaspiro-6,10-H), 1.37 (dd, J=16.8, 8.5 Hz, 2H, diazaspiro-4-H). 13C NMR (151 MHz, CDCl3) δ 180.23, 169.16,168.93, 137.66, 129.18, 126.39, 121.77, 121.49, 117.36, 71.47, 68.27, 41.32,40.98, 40.82, 38.50 , 37.87, 31.43, 30.75.13C NMR (151 MHz, CDCl3) δ 180.23(1C), 169.16(1C), 168.93(1C), 137.66(1C), 129.18(1C), 126.39(1C), 121.77(1C),121.49(1C), 117.36(1C), 71.67(1C), 68.27(1C), 41.32(1C), 40.98(1C), 40.82(1C), 38.50(1C), 37.87(1C), 31.43(1C), 30.75(1C).HRMS(ESI): calcd. forC18H22BrN3O5 [M+Na]+, 462.0635, found,462.0632.
（2S，3S）-N-（4-氟苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1f)
产率47.8%；白色粉末；熔点：120.3-121.1℃；1H NMR (600 MHz, CDCl3) δ 8.78(s, 1H,CONH), 7.50-7.45 (m, 2H,Ph-2,6-H), 6.89 (t, J=8.0 Hz, 2H,PH-3,5-H),6.39 (s, 1H), 4.94 (s, 1H,OH), 4.33 (s, 1H,OH), 4.17 (d, J=13.4 Hz, 1H,CH),3.93 (d, J=13.8 Hz, 1H,CH), 3.34-2.97 (m, 5H,diazaspiro-3,7,9-H),2.00-1.73(m, 5H, diazaspiro-3,6,10-H), 1.39 (d, J=13.5 Hz, 2H, diazaspiro-4-H).13C NMR(151 MHz, CDCl3) δ 180.20(1C), 169.13(1C), 168.89(1C), 157.76(1C), 132.41(1C), 120.72(2C), 114.59(1C), 114.44(1C), 71.38(1C), 68.17(1C), 41.33(1C),40.91(1C), 38.51(1C), 37.82(1C), 31.56(2C), 30.85(1C).HRMS(ESI): calcd. forC18H22FN3O5 [M+Na]+ , 402.1436, found,402.1438.
（2S，3S）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）-N-（邻甲苯基）丁酰胺 (1g)
产率57.5%；白色粉末；熔点：115.4-116.5℃；1H NMR (600 MHz, CDCl3) δ 8.68(s, 1H,CONH), 7.94-7.90 (m, 1H), 7.17 (dd, J = 10.7, 6.1 Hz, 2H), 7.06 (q, J=7.0 Hz, 1H), 6.65 (s, 1H,CONH), 5.00 (s, 1H,OH), 4.43 (s, 1H,OH), 4.27 (dd, J=28.5, 13.2 Hz, 1H,CH), 4.03 (dd, J=33.9, 13.3 Hz, 1H,CH), 3.36-3.06 (m, 5H,diazaspiro-3,7,9-H), 2.27 (s, 3H,Ph-CH3), 2.04-1.76 (m, 5H, diazaspiro-3,6,10-H), 1.46 (dd, J=27.2, 14.0 Hz, 2H, diazaspiro-4-H).13C NMR (151 MHz, CDCl3)δ 181.22(1C), 170.17(1C), 169.87(1C), 135.17(1C), 130.44(1C), 129.03(1C),126.62(1C), 125.15 (1C), 122.28(1C), 72.48(1C), 69.06(1C), 42.27(1C), 41.85(1C), 39.40(1C), 38.83(1C), 32.54(2C), 31.87(1C), 17.53(1C).HRMS(ESI): calcd.for C19H25N3O5 [M+Na]+ , 398.1686,found, 398.1684.
（2S，3S）-N-（3,5-双（三氟甲基）苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）丁丁酰胺 (1h)
产率62.4%；白色粉末；熔点：127.8-129.2℃；1H NMR (600 MHz, MeOD) δ 8.36(s, 2H,Ph-2,6-H), 7.66 (s, 1H,Ph-4-H), 4.95 (d, J=9.4 Hz, 1H,OH), 4.45 (d, J=11.8 Hz, 1H,OH), 4.34 (dd, J=32.7, 12.6 Hz, 1H,CH), 4.12 (dd, J=25.2, 10.2Hz, 1H,CH), 3.37 (dd, J=43.6, 23.8 Hz, 5H,diazaspiro-3,7,9-H), 2.20-1.75 (m,5H diazaspiro-3,6,10-H), 1.57 (dd, J=34.4, 19.0 Hz, 2H, diazaspiro-4-H).13CNMR (151 MHz, MeOD) δ 181.83(1C), 171.98(1C), 169.94(1C), 139.83(1C), 131.91(1C), 131.69 (1C), 124.22(1C), 122.42(1C), 119.77(2C), 116.66(1C), 72.78(1C),69.98(1C), 42.53(1C), 41.78(1C), 39.11(1C), 38.45(1C), 32.27(1C), 31.45(2C).HRMS(ESI)：calcd.for C20H21F6N3O5 [M+H]+ ,498.1458,found,498.1458.
（2S，3S）-2,3-二羟基-N-（4-甲氧基苯基）-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1i)
产率54.3%；白色粉末；熔点：114.4-115.5℃；1H NMR (600 MHz, CDCl3) δ 8.69(s, 1H,CONH), 7.42 (t, J= 8.1 Hz, 2H,PH-2,6-H), 6.75 (d, J=7.7 Hz, 2H,3,5-H),6.50 (s, 1H,CONH), 4.94 (s, 1H,OH), 4.31 (s, 1H,OH), 4.19 (dd, J=34.4, 12.8Hz, 1H,CH), 3.96 (dd, J=44.5, 13.2 Hz, 1H,CH), 3.69 (s,3H,Ph-OCH3), 3.53-2.95(m, 6H,diazaspiro-3,7,9-H), 1.96-1.71 (m, 4H,diazaspiro-6,10-H), 1.39 (s, 2H,diazaspiro-4-H).13C NMR (151 MHz, CDCl3) δ 180.22 (1C), 169.23(1C), 168.65(1C), 155.60(1C), 129.55(1C), 120.63(2C), 113.13(2C), 71.34(1C), 68.11(1C),54.48(1C), 41.26(1C), 40.84(1C), 38.45(1C), 37.83(1C), 31.55(2C), 30.85(1C).HRMS(ESI)：calcd. for C19H25N3O6 [M+H]+ ,392.1816,found,392.1816.
（2S，3S）-N-（3,4-二氟苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1j)
产率45.8%；白色粉末；熔点：112.5-113.5℃；1H NMR (600 MHz, CDCl3) δ 8.79(s, 1H,CONH), 7.62 (d, J=8.2 Hz, 1H,PH-2-H), 7.09 (s, 1H,Ph-5-H), 7.04-6.95(m, 1H,Ph-6-H), 6.28 (s, 1H,CONH), 4.94 (s, 1H,OH), 4.33 (s, 1H,OH), 4.21(dd, J =34.5, 13.4 Hz, 1H,CH), 3.95 (d, J=12.4 Hz, 1H,CH), 3.35-2.97 (m, 6H,diazaspiro-3,7,9-H), 2.01 (d, J=17.9 Hz, 2H, diazaspiro-6-H), 1.94-1.75 (m,2H, diazaspiro-10-H), 1.44 (s, 2H, diazaspiro-4-H).13C NMR (151 MHz, CDCl3)δ180.01(1C), 169.12(1C), 168.90(1C), 141.22(1C), 133.36(1C), 122.98(1C),116.19(1C),114.60(1C), 108.68(1C), 71.18(1C), 68.041(1C), 41.33(1C), 40.86(1C), 38.56(1C), 37.78(1C), 31.42(2C), 30.87(1C).HRMS(ESI):calcd.forC18H21F2N3O5 [M+H]+, 398.1522, found,398.1522.
（2S，3S）-N-（2-氟苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1k)
产率55.3%；白色粉末；熔点：108.7-120.3℃；1H NMR (600 MHz, CDCl3) δ 8.91(s, 1H,CONH), 8.29-8.24 (m, 1H,PH-6-H), 7.07-6.96 (m, 3H,Ph-3,4,5-H), 6.36(s, 1H,CONH), 4.95 (d, J=5.4 Hz, 1H,OH), 4.35 (s, 1H,OH), 4.26-4.13 (m, 1H,CH), 4.03-3.93 (m, 1H,CH), 3.33-3.04 (m, 4H,diazaspiro-7,9-H), 2.02-1.96 (m,2H,diazaspiro-3-H), 1.95-1.78 (m, 4H,diazaspiro-6,10-H), 1.43 (t, J=14.9 Hz,2H,diazaspiro-4-H).13C NMR (151 MHz, CDCl3) δ 180.14(1C), 169.01(1C), 168.79(1C), 151.72(1C), 124.71(1C), 123.79(1C), 123.47(1C), 120.59(1C), 114.03(1C),71.43(1C), 67.96(1C), 41.25(1C), 40.87(1C), 38.42(1C), 37.79(1C), 31.69(2C),30.83(1C). HRMS(ESI): calcd. for C18H22FN3O5[M+H]+ , 380.1616, found, 380.1617.
（2S，3S）-2,3-二羟基-N-（4-硝基苯基）-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1l)
产率49.7%；白色粉末；熔点：111.8-113.0℃；1H NMR (600 MHz, MeOD) δ 8.24-8.19 (m, 2H,Ph-2,6-H), 7.93 (d, J=7.1 Hz, 2H,Ph-3,5-H), 4.94 (s, 1H,OH), 4.43(s, 1H,OH), 4.39-4.27 (m, 1H,CH), 4.11 (dd, J=28.3, 13.5 Hz, 1H,CH), 3.45-3.28 (m, 4H, diazaspiro-7,9-H), 2.17 (dd, J=15.4, 8.8 Hz, 2H,diazaspiro-3-H),1.93-1.75 (m, 2H,diazaspiro-6-H), 1.56 (dd, J=32.9, 16.5 Hz, 2H,diazaspiro-10-H), 1.37-1.25 (m, 2H,diazaspiro-4-H).13C NMR (151 MHz, MeOD) δ 181.81(1C),171.67(1C), 170.02(1C), 143.73(1C), 143.63(1C), 124.27(2C), 119.53(2C), 72.88(1C), 69.97(1C), 42.51(1C), 41.78(1C), 39.09(1C), 38.45(1C), 32.27(1C), 31.46(2C).HRMS(ESI): calcd.for C18H22N4O7 [M+Na]+ ,429.1381,found,429.1400.
（2S，3S）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基）-N-（3-（三氟甲基）苯基）丁酰胺 (1m)
产率56.3%；白色粉末；熔点：137.2-138.8℃；1H NMR (600 MHz, CDCl3) δ 9.09(s, 1H,CONH), 7.93 (d, J=15.1 Hz, 1H,Ph-2-H), 7.63 (d, J=7.6 Hz, 1H,PH-6-H),7.27 (t, J=8.2 Hz, 1H,Ph-5-H), 7.23-7.19 (m, 1H,Ph-4-H), 6.53 (s, 1H,CONH),4.98 (s, 1H,OH), 4.37 (s, 1H,OH), 4.26-4.15 (m, 1H,CH), 3.95 (dd, J=48.0,13.1 Hz, 1H,CH), 3.30-2.88 (m, 4H, diazaspiro-7,9-H), 2.40-1.70 (m, 6H,diazaspiro-3,6,10-H), 1.41 (dd, J=49.4, 15.3 Hz, 2H, diazaspiro-4-H).13C NMR(151 MHz, CDCl3)δ 180.34(1C), 169.37(1C), 168.91(1C), 136.92(1C), 130.25(1C),128.36(1C), 122.00(1C), 121.83(1C), 119.91(1C), 115.52(1C), 71.72(1C), 68.36(1C), 41.34(1C), 41.09(1C), 38.52(1C), 37.88(1C), 31.40(2C), 30.69(1C).HRMS(ESI):calcd. for C19H22F3N3O5 [M+Na]+ , 452.1404,found,452.1406.
（2S，3S）-N-（3-氯-4-氟苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺(1n)
产率63.7%；白色粉末；熔点： 128.5-129.4℃；1H NMR (600 MHz, CDCl3) δ 8.94(s, 1H,CONH), 7.76-7.70 (m, 1H,Ph-2-H), 7.33-7.28 (m, 1H,Ph-5-H), 6.95 (q, J=9.2 Hz, 1H,Ph-6-H), 6.51 (s, 1H,CONH), 4.94 (dd, J=24.5, 7.2 Hz, 1H,OH),4.33 (dd, J=21.6, 5.4 Hz, 1H,OH), 4.25-4.17 (m, 1H,CH), 4.02-3.88 (m, 1H,CH),3.30-2.94 (m, 4H,diazaspiro-7,9-H), 2.13 (s, 2H,diazaspiro-3-H), 1.99 (d, J=7.1 Hz, 2H,diazaspiro-6-H), 1.91-1.73 (m, 2H,diazaspiro-10-H), 1.45-1.35 (m,2H,diazaspiro-4-H).13C NMR (151 MHz, CDCl3) δ 180.17(1C), 168.99(1C), 168.90(1C), 154.64(1C), 133.04(1C), 120.98(1C), 119.98(1C), 118.54(1C), 115.52(1C),71.57(1C), 68.26(1C), 41.35(1C), 40.94(1C), 38.52(1C), 37.85(1C), 31.51(2C),30.77(1C).HRMS(ESI)：calcd. for C18H21ClFN3O5[M+H]+ , 414.1227 found, 414.1226.
（2S，3S）-2,3-二羟基-N-（3-甲氧基苯基）-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1o)
产率47.5%；白色粉末；熔点：118.6-120.0℃；1H NMR (600 MHz, CDCl3) δ 8.90(s, 1H,CONH), 7.36 (d, J=11.7 Hz, 1H,Ph-2-H), 7.19 (td, J=8.1, 4.1 Hz, 1H,Ph-5-H), 7.09 (t, J=8.6 Hz, 1H,Ph-6-H), 6.65 (d, J=6.0 Hz, 1H,Ph-4-H), 6.63 (s,1H,CONH), 5.04 (s, 1H,OH), 4.41 (s, 1H,OH), 4.32-4.23 (m, 1H,CH), 3.99 (d, J=13.8 Hz, 1H,CH), 3.78 (s, 3H,Ph-OCH3), 3.34-3.02 (m, 4H,diazaspiro-7,9-H),2.40 (s, 2H,diazaspiro-3-H), 2.03-1.79 (m, 4H,diazaspiro-6,10-H), 1.46 (t, J=12.4 Hz, 2H,diazaspiro-4-H).13C NMR (151 MHz, CDCl3) δ 181.22(1C), 170.08(1C),169.93(1C), 160.09(1C), 138.49(1C), 129.57(1C), 112.14(1C), 110.54(1C),105.53(1C), 72.42(1C), 69.14(1C), 55.29(1C), 42.25(1C), 41.94(1C), 39.45(1C),38.82(1C), 32.43(2C), 31.75(1C).HRMS(ESI):calcd. for C19H25N3O6 [M+Na]+ ,414.1636,found,414.1635.
（2S，3S）-N-（4-溴苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1p)
产率54.8%；白色粉末；熔点： 122.8-123.6℃；1H NMR (600 MHz, CDCl3) δ 8.88(s, 1H,CONH), 7.41 (t, J=7.3 Hz, 2H,PH-2,6-H), 7.30 (t, J=9.2 Hz, 2H,Ph-3,5-H), 6.48 (s, 1H,CONH), 4.95 (s, 1H,OH), 4.33 (s, 1H,OH), 4.25-4.17 (m, 1H,CH), 3.90 (d, J=13.9 Hz, 1H,CH), 3.32-2.85 (m, 6H, diazaspiro-3,7,9-H), 1.96-1.70 (m, 4H, diazaspiro-6,10-H), 1.37 (dd, J=18.2, 8.1 Hz, 2H,diazaspiro-4-H). 13C NMR (151 MHz, CDCl3) δ 180.24(1C), 169.01(1C), 168.95(1C), 135.46(1C),130.83(2C), 120.46(2C), 116.09(1C), 71.44(1C), 68.26(1C), 41.34(1C), 41.04(1C), 38.50(1C), 37.87(1C), 31.41(2C), 30.71(1C).HRMS(ESI):calcd. forC18H22BrN3O5 [M+Na]+ , 462.0635,found,462.0638.
（2S，3S）-N-（2-氯苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1q)
产率50.7%；白色粉末；熔点： 125.4-126.5℃；1H NMR (600 MHz, CDCl3) δ 9.24(s, 1H,CONH), 8.35 (dd, J=8.2, 3.0 Hz, 1H,Ph-6-H), 7.31-7.28 (m, 1H,Ph-3-H),7.20-7.17 (m, 1H,Ph-5-H), 6.98 (q, J=7.1 Hz, 1H,Ph-4-H), 6.38 (s, 1H,CONH),4.97-4.90 (m, 1H,OH), 4.36 (d, J=5.9 Hz, 1H,OH), 4.24-4.13 (m, 1H,CH), 4.06-3.93 (m, 1H,CH), 3.34-3.04 (m, 4H, diazaspiro-7,9-H), 2.02-1.75 (m, 6H,diazaspiro-4,6,10-H), 1.44 (dt, J = 20.2, 10.6 Hz, 2H, diazaspiro-4-H).13C NMR(151 MHz, CDCl3) δ 180.11(1C), 169.12(1C), 169.02(1C), 133.12(1C), 128.15(1C), 126.60(1C), 123.95(1C), 122.42(1C), 120.32(1C), 71.56(1C), 67.93(1C),41.26(1C), 40.89(1C), 38.44(1C), 37.78(1C), 31.70(2C), 30.93(1C).C18H22ClN3O5.HRMS: calcd. for C18H22ClN3O5 [M+Na]+, 418.1140, found, 418.1137.
（2S，3S）-N-（2,4-二氟苯基）-2,3-二羟基-4-氧代-4-（1-氧代-2,8-二氮杂螺[4.5]癸-8-基）丁酰胺 (1r)
产率46.4%；白色粉末；熔点：113.9-115.5℃；1H NMR (600 MHz, CDCl3) δ 8.80(s, 1H,CONH), 8.22-8.16 (m, 1H,Ph-3-H), 6.79 (s, 2H,Ph-5,6-H), 6.38 (d, J=9.0Hz, 1H,CONH), 4.95-4.88 (m, 1H,OH), 4.35 (s, 1H,OH), 4.20 (dd, J=43.6, 10.3Hz, 1H,CH), 4.07-3.92 (m, 1H,CH), 3.34-3.03 (m, 4H, diazaspiro-7,9-H), 2.06-1.75 (m, 6H, diazaspiro-3,6,10-H), 1.49-1.38 (m, 2H,diazaspiro-4-H).13C NMR(151 MHz, CDCl3) δ 180.16(1C), 169.11(1C), 168.79(1C), 156.91(1C), 151.10(1C). 121.72(1C), 121.12(1C), 110.88(1C), 102.84(1C), 71.36(1C), 67.98(1C),41.31(1C), 40.88(1C), 38.47(1C), 37.81(1C), 31.68 (2C), 30.86(1C).HRMS:calcd. for C18H21F2N3O5 [M+Na]+, 420.1341, found, 420.1344.
实施例3、1-氧代-2,8-二氮杂螺[4.5]癸烷L-酒石酸衍生物类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4制得的1-氧代-2,8-二氮杂螺[4.5]癸烷L-酒石酸衍生物类对革兰氏阳性菌（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，用灭菌水制成溶液备用，将96孔板，西林瓶，枪头等物品高压灭菌，用移液枪移取稀释好的菌液溶液100uL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24h，观察现象。结果见表1、表2。
Figure 737364DEST_PATH_IMAGE009
Figure 397890DEST_PATH_IMAGE010
由表可以看出，本发明实施例2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，其中对真菌的抑制作用优于细菌的，特别地，3,5-二双三氟甲基取代的1h分别对白色念珠菌（ATCC 76615）和新型隐球菌表现出较高的抗菌活性，MIC值分别为16 µg/mL和32 µg/mL。部分化合物抗真菌活性与参考药物氟康唑相接近。

Claims (2)

1.1-氧代-2,8-二氮杂螺[4.5]癸烷L-酒石酸衍生物，其特征在于：该螺环化合物8-位通过L-酒石酸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_IMAGE001
其中R1为H；R2为Ph，4-ClC6H4，2-CH3OC6H4，2,4-ClC6H3，2-BrC6H4，4-FC6H4，2-CH3C6H4，3,5-CF3C6H3，4-CH3OC6H4，3,4-FC6H3，2-FC6H4，4-O2NC6H4，3-CF3C6H4，3-Cl-4-FC6H3，3-CH3OC6H4，4-BrC6H4，2- ClC6H4，2,4-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，所述微生物为大肠杆菌、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、烟曲霉菌中的一种。
CN201811537842.5A 2018-12-15 2018-12-15 二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用 Active CN109400608B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811537842.5A CN109400608B (zh) 2018-12-15 2018-12-15 二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811537842.5A CN109400608B (zh) 2018-12-15 2018-12-15 二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用

Publications (2)

Publication Number Publication Date
CN109400608A CN109400608A (zh) 2019-03-01
CN109400608B true CN109400608B (zh) 2021-08-31

Family

ID=65459368

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811537842.5A Active CN109400608B (zh) 2018-12-15 2018-12-15 二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用

Country Status (1)

Country Link
CN (1) CN109400608B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116143782B (zh) * 2021-11-22 2024-04-12 西南大学 一类螺[吡咯烷-2,3'-喹啉]-2'-酮类衍生物的设计合成与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101426486A (zh) * 2005-12-01 2009-05-06 先灵公司 用于炎性疾病和微生物疾病治疗的化合物
CN103003233A (zh) * 2010-04-20 2013-03-27 大正制药株式会社 新型异羟肟酸衍生物
CN103068826A (zh) * 2010-08-13 2013-04-24 霍夫曼-拉罗奇有限公司 新型氮杂环化合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060035903A1 (en) * 2004-08-14 2006-02-16 Boehringer Ingelheim International Gmbh Storage stable perfusion solution for dihydropteridinones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101426486A (zh) * 2005-12-01 2009-05-06 先灵公司 用于炎性疾病和微生物疾病治疗的化合物
CN103003233A (zh) * 2010-04-20 2013-03-27 大正制药株式会社 新型异羟肟酸衍生物
CN103068826A (zh) * 2010-08-13 2013-04-24 霍夫曼-拉罗奇有限公司 新型氮杂环化合物

Also Published As

Publication number Publication date
CN109400608A (zh) 2019-03-01

Similar Documents

Publication Publication Date Title
KR102132574B1 (ko) 트라이사이클릭 자이라제 억제제
SK91795A3 (en) Six-member nitrogen-containing heteroaryl oxazolidinones their use and medicaments containing these matters
EP0132845A2 (en) Novel 1,8-Naphthyridine derivatives, and process for preparation thereof
HU219488B (hu) Kinolon-karbonsavszármazék, ezt tartalmazó gyógyszerkészítmény és eljárás előállításukra
ES2268011T3 (es) Oxazolidinonas que contienen un grupo sulfonimida como antibioticos.
CN105884752B (zh) 并环类回旋酶和拓扑异构酶iv抑制剂
JPS6323879A (ja) ニトロフラン誘導体
AU669948B2 (en) Bicyclic amine derivatives
JPS59206386A (ja) 三環式エーテル及びこれを含有する胃保護作用―及び胃酸分泌抑制剤
JP2016530250A (ja) トリサイクリックベンズオキサボロール化合物、その製造方法および用途
JPWO2005051949A1 (ja) 新規縮合イミダゾール誘導体
EP2367820B1 (en) Novel antimicrobial agents
CN109400608B (zh) 二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用
SK17022001A3 (sk) Deriváty a analógy galantamínu
CN109593089B (zh) 二氮杂螺癸烷哌啶甲酰胺类化合物制备和应用
JP2021534246A (ja) １，３，４，９−テトラヒドロ−２ｈ−ピリド［３，４−ｂ］インドール誘導体化合物及びその使用
US9643979B2 (en) Inhibitors of DNA gyrase for the treatment of bacterial infections
RU2041226C1 (ru) Замещенные производные изотиазол-пиридон ацетидинила и фармацевтическая композиция на их основе
KR100497942B1 (ko) 광학활성을 유발하는 7-피롤리딘 치환체를 갖는 광학활성의 퀴놀린 카르복실산 유도체 및 그의 제조방법
JPH02502455A (ja) ピリドンカルボン酸または酸誘導体を含有する抗生物質β‐ラクタム
EP0514268A1 (fr) Dérivés de pyridone amino acide azétidinyl substitués, leur préparation et leur application en tant que médicaments
KR100372978B1 (ko) 피리도[3,2,1-i,j][3,1]벤족사진유도체
Siddiqui et al. Effects of skeletal modifications of ciprofloxacin on antibacterial, antifungal and cytotoxic activities
AU704735B2 (en) Pyridonecarboxylic acid derivatives and intermediates for the synthesis thereo
CN116143782B (zh) 一类螺[吡咯烷-2,3'-喹啉]-2'-酮类衍生物的设计合成与应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant