CN109824669A - 哌啶螺环酒石酸类化合物制备及应用 - Google Patents
哌啶螺环酒石酸类化合物制备及应用 Download PDFInfo
- Publication number
- CN109824669A CN109824669A CN201811571361.6A CN201811571361A CN109824669A CN 109824669 A CN109824669 A CN 109824669A CN 201811571361 A CN201811571361 A CN 201811571361A CN 109824669 A CN109824669 A CN 109824669A
- Authority
- CN
- China
- Prior art keywords
- compound
- piperidines
- pyridine
- spiral shell
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 piperidine spiro tartaric acid compounds Chemical class 0.000 title claims abstract description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title 1
- 150000003053 piperidines Chemical class 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 229920002101 Chitin Polymers 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 9
- 241000894006 Bacteria Species 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 241000233866 Fungi Species 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 11
- WMLBCGHQVFIUDI-UHFFFAOYSA-N pyrazolo[3,4-c]pyridine Chemical compound C1=NC=C[C]2C=NN=C21 WMLBCGHQVFIUDI-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 102000003960 Ligases Human genes 0.000 claims description 5
- 108090000364 Ligases Proteins 0.000 claims description 5
- 241000191967 Staphylococcus aureus Species 0.000 claims description 5
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 4
- 241000222122 Candida albicans Species 0.000 claims description 4
- 229940095731 candida albicans Drugs 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 244000005700 microbiome Species 0.000 claims description 4
- 241000894007 species Species 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 241000228197 Aspergillus flavus Species 0.000 claims description 3
- 241001225321 Aspergillus fumigatus Species 0.000 claims description 3
- 201000007336 Cryptococcosis Diseases 0.000 claims description 3
- 241000221204 Cryptococcus neoformans Species 0.000 claims description 3
- 241000588724 Escherichia coli Species 0.000 claims description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 3
- 229940091771 aspergillus fumigatus Drugs 0.000 claims description 3
- 229960003085 meticillin Drugs 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 230000001775 anti-pathogenic effect Effects 0.000 claims description 2
- 229960001270 d- tartaric acid Drugs 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000003413 spiro compounds Chemical class 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical class OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 abstract description 4
- 108090000790 Enzymes Proteins 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 3
- 241000192125 Firmicutes Species 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 230000001717 pathogenic effect Effects 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 230000002924 anti-infective effect Effects 0.000 abstract 1
- 150000004982 aromatic amines Chemical class 0.000 abstract 1
- 230000004071 biological effect Effects 0.000 abstract 1
- 230000001408 fungistatic effect Effects 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 34
- 239000007787 solid Substances 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 11
- BFJMHTOBRRZELQ-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-c]pyridine Chemical compound N1=CC=C2C(I)=NNC2=C1 BFJMHTOBRRZELQ-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 5
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 2
- 229930182764 Polyoxin Natural products 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010029768 Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate Proteins 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 230000001857 anti-mycotic effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000002543 antimycotic Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- YEBIHIICWDDQOL-YBHNRIQQSA-N polyoxin Polymers O[C@@H]1[C@H](O)[C@@H](C(C=O)N)O[C@H]1N1C(=O)NC(=O)C(C(O)=O)=C1 YEBIHIICWDDQOL-YBHNRIQQSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 108010049047 Echinocandins Chemical class 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical class COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了二氢螺[哌啶‑4,5'‑吡唑并[3,4‑c]吡啶]‑7'（6'H）‑酮D‑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：式中R1为氢；R2为：各类取代的芳胺、杂环芳胺。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
技术领域
本发明属医药领域，具体涉及一类 螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸衍生物类的设计合成及其在抗微生物方面的应用。
背景技术
近年来，随着医疗水平的不断提升和快速发展，许多顽固疾病得到了有效的治疗，但是由于抗生素的滥用致使微生物抗药性上升，造成患者免疫系统低下；此外，由于市场上流通的多烯类、唑类、烯丙胺类、吗啉类、棘白菌素类以及灰黄霉素类等抗真菌药物自身存在抗菌谱窄、副作用大等缺点，使得真菌感染引起的患者发病率与死亡率逐年上升，已对人类生命健康造成严重威胁。因此探索与合成一种新型、高效，广谱、小副作用的抗菌类药物在国内外医学领域备受关注。
螺环化合物因其两环平面相互垂直的结构、较强的刚性结构、异头效应、螺共轭效应及其螺超共轭效应等特殊结构，使其具备不仅可以提高配体与靶蛋白的亲和性与适应性，同时还可以增加生物代谢稳定性的优势，因此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。另外研究表明，通过胺与酸缩合形成的酰胺键，作为大量药物分子的药效基团，能有效改善药物活性并降低毒副作用，此外研究也发现含氮杂环结构在抗几丁质合成酶方面表现出较好的活性，这类研究文章可见：J. Med Chem. 2010, 53(5): 1937-1950；Bioorg. Med. Chem. Lett.2011, 21(4): 1270-1274；Bioorg. Med. Chem. Lett.2011, 21(6):1593-1597；Bioorg. Med. Chem.2001, 9(8):1999-2013。
本发明设计并合成了一类螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸类化合物，以多抗霉素B为对照，测定了该类化合物对几丁质合成酶的抑制作用，并测定了其在抗真菌、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抑制几丁质合成酶活性方面还未见报道，所以可将其作为几丁质合成酶的抑制剂，开发成新型的抗真菌制剂。
发明内容
本发明的目的之一在于提供一种螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸衍生物类；本发明的目的之二在于提供螺[哌啶-4, 5'-[5H]吡唑并[3,4-c]吡啶]-7'（6'H）-酮-D-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螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-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：
本发明所述的螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸衍生物类结构如通式1所示：
其中R1为H，R2为2-CH3O-4-O2NC6H3，4-BrC6H4，4-CH3C6H4，2-O2NC6H4，4-HOC6H5，Ph，6-CH3OC4H2N2，2- ClC6H4，4-O2NC6H4，4-F3CC6H4，3-O2NC6H4，3- BrC6H4，3-H3CC6H4，3-H3CC6H4，2-CH3OC6H4，2-H3CC6H4，2- BrC6H4，4-ClC6H4或3-ClC6H4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所示的螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸衍生物类为下述化合物的任意一种：
。
上述螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸衍生物类的合成方法，按如下进行：
如Scheme1所示
。
具体地说，上述Scheme1 反应条件如下：
a. 化合物2与化合物3a经EDC缩合成，然后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、四氢呋喃等，优选二氯甲烷；化合物2，3a，的摩尔比为1: 1.1~2，室温至45℃，反应6-8 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45℃反应8-12 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。
上述螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-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D-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（1.31g，6.0mmol）、1-羟基苯并三唑（0.81 g，6.0mmol）、二甲基氨基吡啶（0.73g，6.0mmol)、N,N-二环己基碳二酰亚胺（1.48g，7.2 mmol）加入干燥的二氯甲烷（25ml）中，室温搅拌30 min。再加入2-甲氧基-4-硝基苯胺即化合物3a（1.21g，7.2mmol），室温反应8 h。反应完毕后，分别用饱和碳酸氢钠溶液（20 mL×3）、5%稀盐酸（20 mL×3）、水（20mL×3）洗涤，无水硫酸钠干燥，旋干溶剂得粗产物1.21g，将粗产物（1.21 g，3.3mmol）溶于5mL 1,4-二氧六环中，加5 mL水，然后加入1 N氢氧化钠溶液（5 mL，4.9mmol），室温搅拌反应。待反应完毕后，用5%稀盐酸溶液调pH至2-3，二氯甲烷萃取（10 mL×3），合并有机相，无水硫酸钠干燥，旋干溶剂，柱层析得到化合物4a（0.70 g），黄色固体，收率64%；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-N-（2-甲氧基-4-硝基苯基）-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺（1a）的制备
在25 mL烧瓶中分别加入化合物4a（0.37 g，1.1 mmol）、三乙胺（0.47g，4.6mmol）、二氯甲烷10 mL，用注射器量取50%含量丙基磷酸三环酸酐的乙酸乙酯溶液（5.4 mL，9.1mmol）并加入到反应液，搅拌10 min。将化合物5（0.2 g，0.91mmol）加入反应瓶，室温搅拌30 min后45℃油浴回流反应。TLC监测反应大部分完成后，冷却至室温，加入10 mL饱和碳酸氢钠溶液，搅拌10 min后用二氯甲烷萃取（10 mL×3），合并有机相，无水硫酸钠干燥，过滤，旋干低沸点溶剂得粗产物白色固体（0.26 g）。将粗产物（0.26 g，0.48mmol）加入1 N稀盐酸溶液（3.5 mL，3.5 mmol）和10 mL甲醇的混合溶剂中，50℃油浴搅拌反应。待反应完全后冷却至室温，加10 mL水，用5%氢氧化钠溶液调pH至7-8，二氯甲烷萃取（10 mL×3），合并有机相，无水硫酸钠干燥，过滤，旋干溶剂，柱层析得白色固体（0.12 g）；收率67%；1H NMR (600 MHz,DMSO) δ 9.57 (s, 1H), 8.55 (d, J=8.6 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.86(s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 6.55 (s, 1H), 5.12 (d, J=75.0 Hz, 1H),4.75 (d, J=10.4 Hz, 1H), 4.36 (d, J=4.8 Hz, 1H), 4.03 (s, 3H), 3.87 (s, 3H),3.64 (d, J=77.8 Hz, 4H), 2.82–2.74 (m, 2H), 1.66 (d, J= 43.0 Hz, 4H). 13C NMR(151 MHz, DMSO) δ 171.64, 169.64, 161.51, 148.13, 143.20, 142.19, 133.63,129.07, 118.57, 117.81, 117.78, 106.43, 73.26, 70.84, 57.30, 54.83, 41.03,39.54, 38.62, 37.04, 36.92, 29.63.HRMS(ESI):calcd for C22H26N6O8[M+Na]+,525.1704,found, 525.1702。
按相同合成步骤，可得化合物1b-1r。
（2S,3S）-N-（4-溴苯基）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4-5'-吡唑并[3,4-c]吡啶]-1基-4-氧代丁酰胺（1b）
白色固体（0.10 g）；收率64%；1H NMR (600 MHz, MeOD) δ 7.63 (d, J = 7.4 Hz,2H), 7.49 (s, 1H), 7.23 (d, J = 7.3 Hz, 2H), 5.07 (s, 1H), 4.45 (s, 1H), 3.87(s, 3H), 3.77 (m, 4H), 2.96 (s, 2H), 1.81 (d, J = 64.6 Hz, 4H). 13C NMR (151MHz, MeOD) δ 172.34, 171.45, 166.05, 140.53, 139.10, 131.98, 131.31, 127.94,122.76, 121.21, 120.84, 119.06, 72.84, 69.89, 48.44, 41.75, 38.92, 38.84,37.01, 35.79, 28.73.LC-MS (ESI): m/z 507 [M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-4-氧代-N-（对甲苯基）丁酰胺 (1c)
白色固体（0.12 g）；收率63%；1H NMR (600 MHz, MeOD) δ7.54 (s, 2H), 7.49 (s,1H), 7.25 (s, 2H), 5.04 (s, 1H), 4.56 (s, 1H), 3.95 (s, 3H), 3.67 (d, J=37.0Hz, 4H), 2.84 (s, 2H), 2.61(s,3H), 1.75 (d, J=32.6 Hz, 4H). 13C NMR (151 MHz,MeOD) δ170.21, 169.06, 162.34, 140.12, 138.43, 133.94, 129.04, 125.04,124.41, 119.86, 119.52, 118.11, 70.06, 68.23, 48.31, 42.01, 41.94, 41.43,36.23, 35.21, 26.92.LC-MS (ESI): m/z 443 [M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-N-（2-硝基苯基）-4-氧代丁酰胺(1d)
黄色固体（0.10 g）；收率56%；1H NMR (600 MHz, MeOD) 8.76 (d, J=7.3 Hz, 1H),8.31 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.46 (s, 1H), 7.29 (t, J=8.2Hz, 1H), 5.03 (s, 1H), 4.49 (s, 1H), 3.97 (s, 3H), 3.81 (d, J=87.4 Hz, 4H),2.87 (s, 2H), 1.99 (d, J=21.7 Hz, 4H). 13C NMR (151 MHz, MeOD) δ 172.34,171.95, 145.92, 144.67, 138.59, 124.99, 124.64, 119.58, 116.94, 71.86, 69.86,49.05, 41.13, 39.90, 39.11, 32.34, 28.82.LC-MS (ESI): m/z 474 [M+H]+。
（2S,3S）-2,3-二羟基-N-（4-羟基苯基）-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4-，5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺 (1e)
白色固体（0.10 g）；收率53%；1H NMR (600 MHz, MeOD) δ8.01 (s, 1H), 7.44 (s,1H), 6.88 (t, J=7.4 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.72 (t, J=7.5 Hz, 1H),5.07 (s, 1H), 4.41 (s, 1H), 3.85 (s, 3H), 3.67 (dd, J=31.8, 17.6 Hz, 4H),2.83 (d, J=17.8 Hz, 2H), 1.76 (m, 4H). 13C NMR (151 MHz, MeOD) δ 170.80,170.28, 162.62, 141.29, 129.22, 125.05, 120.69, 119.28, 118.88, 114.70,72.82, 69.92, 48.18, 41.70, 38.59, 38.30, 36.27, 35.64, 29.50, 29.21.LC-MS(ESI): m/z 445 [M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-4-氧代-N-苯基丁酰胺 (1f)
白色固体（0.12 g）；收率57%；1H NMR (600 MHz, MeOD) δ7.79 (d, J=7.9 Hz, 2H),7.43 (s, 1H), 7.32 (t, J=7.8 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 5.05(t, J=5.4Hz, 1H),4.44 (m, 1H), 3.96 (s, 3H), 3.88-3.61 (m, 4H), 2.82 (d, J=10.3 Hz,2H), 1.94-1.72 (m, 4H). 13C NMR (151 MHz, MeOD) δ 169.50, 168.23, 162.56,141.89, 138.32, 129.12, 129.06, 124.37, 121.11, 118.98, 72.26, 70.44, 57.97,41.68, 38.74, 38.43, 36.21, 35.71, 28.89.LC-MS (ESI): m/z 429 [M+H]+。
（2S,3S）-2,3-二羟基-N-（6-甲氧基嘧啶-4-基）-4-（2'-甲基-7'-氧代-2'，4' ，6'，7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺 (1g)
淡黄色固体（0.09 g）；收率48%；1H NMR (600 MHz, MeOD) 9.06 (s, 1H), 8.30 (s,1H), 7.75 (s, 1H), 5.14 (s, 1H), 4.55 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H),3.81 (s, 4H), 2.98 (d, J=24.3 Hz, 2H), 1.88 (d, J=54.2 Hz, 4H). 13C NMR (151MHz, MeOD) δ171.86, 170.75, 166.32, 163.83, 143.97, 143.41, 130.49, 120.11,119.30, 99.59, 72.31, 69.73, 55.39, 48.52, 41.79, 38.91, 38.75, 36.33, 35.64,29.38.LC-MS (ESI): m/z 461 [M+H]+。
（2S,3S）-N-（2-氯苯基）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺 (1h)
白色固体（0.15 g）；收率64%；1H NMR (600 MHz, MeOD) δ7.90 (s, 1H), 7.78 (m,1H), 7.60 (m, 1H), 7.48 (s, 1H), 7.22 (s, J=6.2Hz, 1H), 5.29 (s, 1H), 4.90(s, 1H), 3.97 (s, 3H), 3.92 (m, 4H), 2.91 (s, 2H), 1.73 (d, J=3.1 Hz, 4H).13CNMR (151 MHz, MeOD )δ172.56, 171.85, 161.94, 141.61, 138.97, 131.01, 128.46,125.95, 124.47, 121.04, 120.17, 119.34, 118.17, 72.29, 69.64, 48.44, 40.89,40.02, 39.65, 31.65, 30.26, 29.61.LC-MS (ESI): m/z 463 [M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-N-（4-硝基苯基）-4-氧代丁酰胺 (1i)
褐色固体（0.13 g）；收率59%；1H NMR (600 MHz, MeOD) δ8.66 (s, 1H), 8.26 (d, J=9.0 Hz, 2H), 7.79 (m, 2H), 5.00 (d, J=5.5 Hz, 1H), 4.47 (s, 1H), 3.95 (s,3H), 3.72 (m, 4H), 2.96 (s, 2H), 2.01 (m, 4H). 13C NMR (151 MHz, MeOD) δ172.26, 171.85, 144.32, 143.72, 138.67, 125.11, 124.34, 118.98, 116.34,72.22, 70.02, 49.45, 40.23, 39.78, 38.91, 32.45, 29.12.LC-MS (ESI): m/z 474[M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-4-氧代-N-（4-（三氟甲基）苯基）丁酰胺 (1j)
褐色固体（0.09 g）；收率53%；1H NMR (600 MHz, MeOD) δ8.22 (s, 2H), 7.99 (s,2H), 7.67 (s, 1H), 5.25 (d, J=53.7 Hz, 1H), 4.59 (d, J=51.0 Hz, 1H), 3.98 (s,3H), 3.75 (m, 4H), 3.05-2.86 (m, 2H), 2.08-1.66 (m, 4H). 13C NMR (151 MHz,MeOD)δ170.74, 170.35, 163.25, 141.42, 138.62, 134.01, 131.02, 129.83, 124.46,120.37, 119.16, 118.75, 69.95, 69.73, 48.52, 41.77, 38.77, 38.62, 36.32,35.59, 29.30.LC-MS (ESI): m/z 497 [M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4', 6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-N-（3-硝基苯基）-4-氧代丁酰胺 (1k)
褐色白色固体（0.12 g）；收率64%；1H NMR (600 MHz, MeOD) δ8.61 (s, 1H), 7.90(s, 1H), 7.88 (s, 1H), 7.54 (s, 1H), 7.47 (t, J=7.7 Hz, 1H), 5.03 (s, 1H),4.46 (s, 1H), 4.11 (m, 1H), 3.87 (s, 3H), 3.78-3.61 (m, 4H), 2.85 (s, 2H),1.75 (d, J=40.7 Hz, 4H). 13C NMR (151 MHz, MeOD) δ 171.38, 170.41, 168.26,148.58, 138.83, 129.58, 129.29, 119.10, 118.97, 118.78, 118.54, 114.93,72.56, 69.90, 48.19, 38.37, 36.38, 35.66, 29.56, 29.03, 23.59.LC-MS (ESI): m/z 474 [M+H]+。
（2S,3S）-N-（3-溴苯基）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺 (1l)
白色固体（0.08g）；收率59%；1H NMR (600 MHz, MeOD) δ7.84 (s, 1H), 7.67-7.60(m, 1H), 7.53 (s, 1H), 7.31 (s, 1H), 7.14 (d, J=6.4 Hz, 1H), 5.20 (d, J=58.4Hz, 1H), 4.61-4.51 (m, 1H), 3.98 (s, 3H), 3.84-3.68 (m, 4H), 2.97 (s, 2H),1.88 (d, J = 57.9 Hz, 4H).13C NMR (151 MHz, MeOD) δ 172.12, 171.54, 162.65,141.34, 139.58, 130.38, 128.67, 126.29, 124.97, 120.98, 120.54, 119.73,117.87, 72.12, 69.43, 48.20, 40.27, 39.98, 39.61, 30.56, 31.25, 29.69.LC-MS(ESI): m/z 507 [M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-4-氧代-N-（间甲苯基）丁酰胺 (1m)
白色固体（0.08 g）；收率59%；1H NMR (600 MHz, MeOD) δ7.63 (s, 1H), 7.49 (s,1H), 7.37 (s, 1H), 7.18 (s, 1H), 6.98 (s, 1H), 5.09 (s, 1H), 4.44 (s, 1H),3.97 (s, 3H), 3.59 (d, J=27.0 Hz, 4H), 2.92 (s, 2H), 2.43(s,3H), 1.64 (d, J=37.6 Hz, 4H). 13C NMR (151 MHz, MeOD) δ 170.56, 168.66, 161.94, 139.04,138.71, 134.08, 129.77, 124.44, 124.09, 120.36, 120.07, 118.31, 69.86, 67.49,48.20, 41.68, 41.58, 41.20, 36.37, 35.78, 25.10.LC-MS (ESI): m/z 443 [M+H]+。
（2S,3S）-2,3-二羟基-N-（2-甲氧基苯基）-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺(1n)
白色固体（0.09 g）；收率56%；1H NMR (600 MHz, MeOD)δ7.85 (d, J=7.9 Hz, 1H),7.47 (s, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.10 (t, J=7.4 Hz, 1H), 7.07(t, J=7.6Hz, 1H), 5.07(t, J=5.4 Hz, 1H),4.84 (m, 1H), 3.96 (s, 3H), 3.88-3.61 (m, 4H),2.82 (d, J=10.3 Hz, 2H), 1.94-1.72 (m, 4H).13C NMR (151 MHz, MeOD) δ 169.50,168.23, 162.56, 141.89, 138.32, 129.12, 129.06 , 124.37, 121.11, 118.98,72.26, 70.44, 57.97, 41.68, 38.74, 38.43, 36.21, 35.71, 28.89.LC-MS (ESI): m/z 459 [M+H]+。
（2S,3S）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4,5'-吡唑并[3,4-c]吡啶] -1-基）-4-氧代-N-（邻甲苯基）丁酰胺 (1o)
白色固体（0.10 g）；收率57%；1H NMR (600 MHz, MeOD) δ7.48 (s, 1H), 7.29 (t, J= 7.6 Hz, 1H), 7.27(t, J=7.8 Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 7.09 (t, J=7.4Hz, 1H), 5.05 (s, 1H), 4.49 (s, 1H), 3.87 (s, 3H), 3.59 (m, 4H), 2.96 (s,2H), 2.24(s,3H), 1.64 (d, J=48.6 Hz, 4H). 13C NMR (151 MHz, MeOD) δ 171.80,170.76, 162.02, 135.84, 131.74, 130.88, 129.64, 125.98, 124.87, 123.98,120.07, 118.09, 72.96, 71.78, 48.67, 40.68, 40.08, 39.86, 36.34, 35.39,28.53, 18.34.LC-MS (ESI): m/z 443 [M+H]+。
（2S,3S）-N-（2-溴苯基）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4, 5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺 (1p)
白色固体（0.10 g）；收率48%；1H NMR (600 MHz, MeOD) δ7.87 (s, 1H), 7.74 (m,1H), 7.53 (m, 1H), 7.47 (s, 1H), 7.21 (s, J=6.2Hz, 1H), 5.24 (s, 1H), 4.84(s, 1H), 3.96 (s, 3H), 3.84 (m, 4H), 2.87 (s, 2H), 1.68 (d, J=46.9 Hz, 4H).13CNMR (151 MHz, MeOD )δ172.23, 171.05, 162.34, 141.22, 139.23, 130.87, 128.41,126.26, 124.37, 120.85, 120.47, 119.58, 117.87, 72.09, 69.29, 48.36, 40.87,39.82, 39.48, 31.65, 30.12, 29.23.LC-MS (ESI): m/z 507 [M+H]+。
（2S,S）-N-（4-氯苯基）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4',6',7'-四氢螺[哌啶-4, 5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺(1q)
白色固体（0.10 g）；收率58%；1H NMR (600 MHz, MeOD) δ7.56 (d, J=6.4 Hz, 2H),7.46 (s, 1H), 7.23 (d, J=7.3 Hz, 2H), 5.03 (s, 1H), 4.40 (s, 1H), 3.85 (s,3H), 3.77-3.60 (m, 4H), 2.84 (s, 2H), 1.75 (d, J=55.6 Hz, 4H). 13C NMR (151MHz, MeOD) δ170.75, 170.52, 162.65, 141.37, 138.10, 131.53, 131.02, 128.44,122.48, 121.89, 121.67, 118.96, 72.44, 69.79, 48.18, 41.51, 38.57, 38.30,36.27, 35.61, 29.10.LC-MS (ESI): m/z 463 [M+H]+。
（2S,3S）-N-（3-氯苯基）-2,3-二羟基-4-（2'-甲基-7'-氧代-2',4', 6',7'-四氢螺[哌啶-4, 5'-吡唑并[3,4-c]吡啶]-1基）-4-氧代丁酰胺 (1r)
白色固体（0.08 g）；收率54%；1H NMR (600 MHz, MeOD) δ7.84 (s, 1H), 7.66-7.56(m, 1H), 7.53 (s, 1H), 7.31 (s, 1H), 7.14 (d, J=6.4 Hz, 1H), 5.20 (d, J=58.4Hz, 1H), 4.62-4.51 (m, 1H), 3.98 (s, 3H), 3.73 (dd, J=53.2, 20.0 Hz, 4H),2.97 (s, 2H), 1.88 (d, J=57.9 Hz, 4H). 13C NMR (151 MHz, MeOD) δ 171.89,169.41, 163.20, 141.89, 141.59, 136.12, 130.95, 128.03, 125.47, 122.43,119.79, 116.34, 71.32, 69.80, 48.51, 41.54, 38.69, 38.51, 36.23, 35.67,29.58.LC-MS (ESI): m/z463 [M+H]+。
实施例3、二氢螺[哌啶-4, 5'-吡唑并[3, 4-c]吡啶]-7'（6'H）-酮D-酒石酸衍生物类的几丁质合成酶活性抑制实验
几丁质合成酶来源于啤酒酵母细胞膜，酶与底物在微孔板上一起孵化反应，产生的几丁质与板上包被的WGA结合在一起而被固定，然后加入WGA-HRP，WGA-HRP可与固定在板上的几丁质结合，将多余的试剂用蒸馏水洗掉，然后使用TMB底物溶液检测HRP的活性，使用2M的硫酸终止反应后在450 nm处检测其OD，计算出化合物的IC50值。化合物1a-r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, inhibitionpercentage）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，初筛结果和IC50值如表1所示。
实施例4、二氢螺[哌啶-4, 5'-吡唑并[3, 4-c]吡啶]-7'（6'H）-酮D-酒石酸衍生物类的体外抗微生物活性实验
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2制得的二氢螺[哌啶-4,5'-吡唑并[3, 4-c]吡啶]-7'（6'H）-酮D-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 N 315）、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）、铜绿假单胞菌（ATCC 9027）、变形杆菌（ATCC 8427））和真菌（白色念珠菌（ATCC 76615）、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2、表3。
Claims (7)
1.螺[哌啶-4, 5'-[5H]吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸衍生物类及其制备方法和应用，其特征在于：该螺环化合物9-位通过D-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：
。
2.如权利要求1所述，该类化合物中取代基为可为以基团：其中R1为H，R2为2-CH3O-4-O2NC6H3-，4-BrC6H4-，4-CH3C6H4-，2-O2NC6H4-，4-HOC6H5-，Ph-，6-CH3OC4H2N2-，2- ClC6H4-，4-O2NC6H4-，4-F3CC6H4-，3-O2NC6H4-，3- BrC6H4-，3-H3CC6H4-，3-H3CC6H4-，2-CH3OC6H4-，2-H3CC6H4-，2- BrC6H4-，4-ClC6H4-，3-ClC6H4-等。
3.如权利要求1所述化合物的合成方法，按Scheme1所示进行
。
4.如权利要求3所示，步骤(a)中，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2，3a，的摩尔比为1: 1.1~2，室温至45℃，反应6-8 h。
5.如权利要求3所示，步骤(b)中，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5，4a，的摩尔比1: 1.1~2，优选二氯甲烷为溶剂，室温至45℃反应8-12 h。
6.如权利要求2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，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。
7.如权利要求2所述 螺[哌啶-4, 5'-吡唑并[3, 4-c]吡啶]-7'（6'H）-酮-D-酒石酸衍生物类化合物在几丁质合成酶抑制剂药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811571361.6A CN109824669A (zh) | 2018-12-21 | 2018-12-21 | 哌啶螺环酒石酸类化合物制备及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811571361.6A CN109824669A (zh) | 2018-12-21 | 2018-12-21 | 哌啶螺环酒石酸类化合物制备及应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109824669A true CN109824669A (zh) | 2019-05-31 |
Family
ID=66859979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811571361.6A Pending CN109824669A (zh) | 2018-12-21 | 2018-12-21 | 哌啶螺环酒石酸类化合物制备及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109824669A (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113559013A (zh) * | 2021-09-01 | 2021-10-29 | 南充市中心医院 | 石胆酸类化合物在制备抗菌产品中的应用 |
| CN115925706A (zh) * | 2022-06-27 | 2023-04-07 | 西南大学 | 一类哌嗪乙酰-螺[吡咯烷-2,3`-喹啉]-2`-酮类衍生物的设计合成与应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103189377A (zh) * | 2010-10-29 | 2013-07-03 | 辉瑞大药厂 | N1/n2-内酰胺乙酰辅酶a羧化酶抑制剂 |
| CN106995418A (zh) * | 2016-01-26 | 2017-08-01 | 湖南师范大学 | 含5-氨基噻唑环核脲类化合物的制备和用途 |
| CN108467395A (zh) * | 2018-05-09 | 2018-08-31 | 大连理工大学 | 一种几丁质酶抑制剂及其应用 |
-
2018
- 2018-12-21 CN CN201811571361.6A patent/CN109824669A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103189377A (zh) * | 2010-10-29 | 2013-07-03 | 辉瑞大药厂 | N1/n2-内酰胺乙酰辅酶a羧化酶抑制剂 |
| CN106995418A (zh) * | 2016-01-26 | 2017-08-01 | 湖南师范大学 | 含5-氨基噻唑环核脲类化合物的制备和用途 |
| CN108467395A (zh) * | 2018-05-09 | 2018-08-31 | 大连理工大学 | 一种几丁质酶抑制剂及其应用 |
Non-Patent Citations (2)
| Title |
|---|
| ZHIQIANG GE ET AL.: "Synthesis and biological evaluation of novel 3-substituted amino-4-hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》 * |
| 张瑞: "新型酰亚胺螺环及其衍生物的合成与生物活性研究", 《西南大学硕士学位论文》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113559013A (zh) * | 2021-09-01 | 2021-10-29 | 南充市中心医院 | 石胆酸类化合物在制备抗菌产品中的应用 |
| CN115925706A (zh) * | 2022-06-27 | 2023-04-07 | 西南大学 | 一类哌嗪乙酰-螺[吡咯烷-2,3`-喹啉]-2`-酮类衍生物的设计合成与应用 |
| CN115925706B (zh) * | 2022-06-27 | 2024-04-12 | 西南大学 | 一类哌嗪乙酰-螺[吡咯烷-2,3’-喹啉]-2’-酮类衍生物的设计合成与应用 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5608082A (en) | Compounds useful as antiproliferative agents and GARFT inhibitors | |
| CN1850779B (zh) | β-榄香烯含氮衍生物及其制备方法和用途 | |
| KR20070045254A (ko) | 인돌리진 카르복사미드 및 그 아자 및 디아자유도체 | |
| CN101675052A (zh) | 作为蛋白酶c抑制剂的3-酰氨基-吡咯并[3,4-c]吡唑-5(1h,4h,6h)甲醛衍生物 | |
| US11780841B2 (en) | 3,6-methano-1H-pyrrolo[3,2-b]pyridine and 3,6-methano-1H-pyrrolo[3,2-c]pyridine compounds and medicaments using same | |
| KR102171120B1 (ko) | 치환된 2-티옥소-이미다졸리딘-4-온 및 이의 스피로 유사체, 전립선암 치료용 항암 활성 성분, 약학적 조성물, 약제 제조 방법 및 치료 방법 | |
| CN104341425A (zh) | 氘代乙炔衍生物、其药物组合物及应用 | |
| CN109824669A (zh) | 哌啶螺环酒石酸类化合物制备及应用 | |
| CN107459507B (zh) | 克林沙星唑烷酰衍生物及其制备方法和应用 | |
| CN113264949B (zh) | 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 | |
| CN104418820A (zh) | 作为溶血磷脂酸受体拮抗剂的羧酸衍生物 | |
| WO2018172925A1 (en) | Inhibitors of dna gyrase for treatment of bacterial infections | |
| Saour et al. | Synthesis of new levofloxacin derivatives and their biological activity | |
| CN109593089B (zh) | 二氮杂螺癸烷哌啶甲酰胺类化合物制备和应用 | |
| Ghaly et al. | Synthesis, antimicrobial activity, DNA-binding affinity and molecular docking of certain 1, 2, 4-triazolo [1, 5-a] pyrimidines as nalidixic acid isosteres | |
| US9540399B2 (en) | Quinolone derivatives | |
| CN102993105B (zh) | 1-甲基-2,4-喹唑啉二酮衍生物及其制备方法和应用 | |
| Altmann et al. | Natural Product-Based Drug Discovery–Epothilones as Lead Structures for the Discovery of New Anticancer Agents | |
| CN109400608A (zh) | 二氮杂螺[4，5]癸烷酒石酸类衍生物制备和应用 | |
| CN101553476A (zh) | 作为有丝分裂驱动蛋白抑制剂的二唑和噻二唑衍生物及其使用方法 | |
| WO2015042438A1 (en) | Selective inhibition of bacterial topoisomerase i | |
| CN107935950A (zh) | 一种三唑席夫碱类化合物及其制备方法与应用 | |
| CN106632282A (zh) | 1,3‑二甲基‑7‑取代喹唑啉‑2,4‑二酮含氟酰胺类化合物及其合成方法和应用 | |
| DE60013607T2 (de) | Bemzimidazolverbindungen und medikamente die diese enthalten | |
| Amer | Antibacterial activity of new synthesized derivatives 3-substituted imidazo benzothiazole from 2-amino-benzothiazole |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190531 |
|
| WD01 | Invention patent application deemed withdrawn after publication |