CN115611818B - 一种含双环单萜结构嘧啶胺化合物及其制备方法与应用 - Google Patents
一种含双环单萜结构嘧啶胺化合物及其制备方法与应用 Download PDFInfo
- Publication number
- CN115611818B CN115611818B CN202211157933.2A CN202211157933A CN115611818B CN 115611818 B CN115611818 B CN 115611818B CN 202211157933 A CN202211157933 A CN 202211157933A CN 115611818 B CN115611818 B CN 115611818B
- Authority
- CN
- China
- Prior art keywords
- compound
- pyrimidine
- reaction
- pyrimidylamine
- compounds
- 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
Links
- -1 Pyrimidine amine compound Chemical class 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims abstract description 11
- 241000723346 Cinnamomum camphora Species 0.000 claims abstract description 11
- 229930008380 camphor Natural products 0.000 claims abstract description 11
- 229960000846 camphor Drugs 0.000 claims abstract description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 10
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 9
- 229960000789 guanidine hydrochloride Drugs 0.000 claims abstract description 8
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 125000003277 amino group Chemical class 0.000 claims abstract description 5
- 229910052731 fluorine Chemical group 0.000 claims abstract description 4
- 239000011737 fluorine Chemical group 0.000 claims abstract description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 26
- XZFDKWMYCUEKSS-UHFFFAOYSA-N 6,6-Dimethylbicyclo[3.1.1]heptan-2-one Chemical compound C1C2C(C)(C)C1CCC2=O XZFDKWMYCUEKSS-UHFFFAOYSA-N 0.000 claims description 18
- 210000004027 cell Anatomy 0.000 claims description 16
- 150000001604 bicyclic monoterpene derivatives Chemical group 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 11
- 239000011541 reaction mixture Substances 0.000 claims description 11
- 241000222122 Candida albicans Species 0.000 claims description 9
- 241000588724 Escherichia coli Species 0.000 claims description 9
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 241000191967 Staphylococcus aureus Species 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 150000003230 pyrimidines Chemical class 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 150000002773 monoterpene derivatives Chemical group 0.000 claims description 7
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 6
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000000844 anti-bacterial effect Effects 0.000 claims description 6
- 230000001580 bacterial effect Effects 0.000 claims description 6
- 229940095731 candida albicans Drugs 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 241000193755 Bacillus cereus Species 0.000 claims description 5
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 5
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical group COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 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 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 230000002538 fungal effect Effects 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 229960003085 meticillin Drugs 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical group [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims description 4
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims description 3
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 210000002540 macrophage Anatomy 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- MNFZZNNFORDXSV-UHFFFAOYSA-N 4-(diethylamino)benzaldehyde Chemical compound CCN(CC)C1=CC=C(C=O)C=C1 MNFZZNNFORDXSV-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000005882 aldol condensation reaction Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims 1
- 241000233866 Fungi Species 0.000 abstract description 8
- 241000894006 Bacteria Species 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 150000001350 alkyl halides Chemical class 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 8
- 229960004821 amikacin Drugs 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 5
- UZDOMJBWUXDEBS-UHFFFAOYSA-N 8-methylquinazolin-2-amine Chemical compound N1=C(N)N=C2C(C)=CC=CC2=C1 UZDOMJBWUXDEBS-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229960004125 ketoconazole Drugs 0.000 description 4
- 231100000053 low toxicity Toxicity 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000607534 Aeromonas Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000193998 Streptococcus pneumoniae Species 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 2
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 2
- HZZMAAQLRLRCAG-UHFFFAOYSA-N 8-methoxyquinazolin-2-amine Chemical compound N1=C(N)N=C2C(OC)=CC=CC2=C1 HZZMAAQLRLRCAG-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- DSZGTLXKOLXXSZ-UHFFFAOYSA-N CC(C)(C(C1)C2)C1C1=C2C(C(C=C2)=CC=C2OC)=NC(NCCOC)=N1 Chemical compound CC(C)(C(C1)C2)C1C1=C2C(C(C=C2)=CC=C2OC)=NC(NCCOC)=N1 DSZGTLXKOLXXSZ-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000123650 Botrytis cinerea Species 0.000 description 1
- ONMYLFQJGFWOGV-UHFFFAOYSA-N CC(C)(C(C1)C2)C1C1=C2C(C(C=C2)=CC=C2OC)=NC(NCC2=CC=CC=C2)=N1 Chemical compound CC(C)(C(C1)C2)C1C1=C2C(C(C=C2)=CC=C2OC)=NC(NCC2=CC=CC=C2)=N1 ONMYLFQJGFWOGV-UHFFFAOYSA-N 0.000 description 1
- 241000395107 Cladosporium cucumerinum Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 239000005784 Fluoxastrobin Substances 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000005828 Pyrimethanil Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical compound [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008952 bacterial invasion Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- UFEODZBUAFNAEU-NLRVBDNBSA-N fluoxastrobin Chemical compound C=1C=CC=C(OC=2C(=C(OC=3C(=CC=CC=3)Cl)N=CN=2)F)C=1C(=N/OC)\C1=NOCCO1 UFEODZBUAFNAEU-NLRVBDNBSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004362 fungal culture Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930003658 monoterpene Natural products 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- ZLIBICFPKPWGIZ-UHFFFAOYSA-N pyrimethanil Chemical compound CC1=CC(C)=NC(NC=2C=CC=CC=2)=N1 ZLIBICFPKPWGIZ-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- USSIUIGPBLPCDF-KEBDBYFISA-N pyriminobac-methyl Chemical group CO\N=C(/C)C1=CC=CC(OC=2N=C(OC)C=C(OC)N=2)=C1C(=O)OC USSIUIGPBLPCDF-KEBDBYFISA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于生物医药领域,涉及一种含双环单萜结构嘧啶胺化合物及其制备方法与应用。所述含双环单萜结构嘧啶胺化合物的结构式为式1或式2所示,其中,R1为C1‑C4烷氧基或C1‑C4烷基取代的胺基;R2为碳原子数2‑4的烷氧基烷基、苄基或氟取代的苄基。本发明利用诺蒎酮或樟脑为起始原料,与取代芳醛缩合、盐酸胍环合反应得到蒎烷基嘧啶或樟脑基嘧啶类化合物,继续与卤代烷取代反应得到蒎烷基嘧啶胺衍生物或樟脑基嘧啶胺衍生物。生物活性研究结果表明,目标化合物对7种细菌和真菌具有普遍的抑制活性。
Description
技术领域
本发明属于生物医药领域,具体地,涉及一种含双环单萜结构嘧啶胺化合物,该含双环单萜结构嘧啶胺化合物的制备方法与应用。
背景技术
杂环化合物是一类重要的有机化合物,在医药、农药、染料、食品、功能材料等领域有着广泛的应用。在众多的含氮和含硫的多杂环化合物中,六元含氮杂环化合物的数量占了绝大多数,并且具有各种不同的生物活性。嘧啶胺类衍生物芳环中含有2个N原子,环外含有取代氨基,因其具有抑菌、抗病毒、抗过敏和抗肿瘤等功效,在农药、医药领域具有重要应用价值。嘧啶胺类杀菌剂通过抑制真菌体内甲硫氨酸的生物合成和细胞壁降解酶的分泌,从而抑制病菌侵入宿主细胞发挥抑菌作用,对灰葡萄孢引起的各种病害防治效果突出,具有活性高、毒性低、不易耐药等特点。已上市的嘧啶胺抑菌剂,如嘧菌胺、嘧霉胺、嘧螨醚和氟嘧菌胺等,可防治灰霉病、白粉病、黑星病、锈病等多种病害。然而,多数嘧啶胺类化合物因为毒性高、污染大等问题,导致难以进入产业化或市场竞争力不强。
诺蒎酮和樟脑因其具有独特的双环结构和环外不饱和羰基,因而化学性质特别活泼,可通过异构化、还原、缩合和酯化等反应合成结构丰富的生物活性物质。例如,蒎烷基噻唑衍生物对由脂多糖所致人脐静脉内皮细胞炎性损伤具有显著的抗炎作用(CN 105646394A),蒎烷基嘧啶衍生物对人乳腺癌细胞、人肺癌细胞、人肝癌细胞具有一定的抗肿瘤活性(CN103965118 A)。樟脑基缩氨基硫脲类化合物(CN 110551049 A)和樟脑基嘧啶对人多发性骨髓瘤细胞(RPMI-8226)、人乳腺癌细胞(MDA-MB-231)和人非小细胞肺癌细胞(A549)具有较好的抑制活性(CN 110551070 A)。因此,利用了蒎烷基和樟脑基结构单元具有良好细胞渗透性、优异的生物相容性和低毒性的特点,设计并制备蒎烷基嘧啶胺类化合物和樟脑基嘧啶胺类衍生物的抑菌活性研究,开发新型结构的绿色、高效、低毒、特异性的抑菌剂对于嘧啶胺类新农药创制具有重要意义。
发明内容
针对现有技术中存在的不足,本发明的目的在于探求一种来源于天然产物的诺蒎酮和樟脑为原料,制得具有抑菌活性并且低毒的含双环单萜结构嘧啶胺化合物。
为了实现上述目的,本发明提供一种含双环单萜结构嘧啶胺化合物,所述的双环单萜结构嘧啶胺化合物为蒎烷基结构N-取代-4-(4-(二乙氨基)苯基)-7,7-二甲基-5,6,7,8-四氢-6,8-甲基喹唑啉-2-胺和樟脑基结构N-取代-4-(4-甲氧基苯基)-8,9,9-三甲基-5,6,7,8-四氢-5,8-甲基喹唑啉-2-胺,其结构式为式1或式2所示:
其中,R1为C1-C4烷氧基或C1-C4烷基取代的胺基;R2为碳原子数2-4的烷氧基烷基、苄基或氟取代的苄基。
所述C1-C4烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
所述C1-C4烷氧基包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基。
所述C1-C4烷基取代的胺基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基单取代或多取代的胺基。
所述碳原子数2-4的烷氧基烷基包括但不限于甲氧基甲基、甲氧基乙基、甲氧基丙基、乙氧基甲基、乙氧基乙基、丙氧基甲基。
所述氟取代的苄基为单氟取代或多氟取代的苄基。
根据本发明一种优选实施方式,R1为-OCH3或-N(C2H5)2;R2为2-甲氧基乙基、苄基、3-氟苄基或2,4-二氟苄基。
更优选地,所述含双环单萜结构嘧啶胺化合物选自以下化合物中的一种:
本发明的另一目的是提供一种含双环单萜结构嘧啶胺化合物的制备方法,反应式如下,烯酮中间体不经分离,具有制备简单、得率较高等优点。
具体地,所述的含双环单萜结构嘧啶胺化合物的制备方法,包括如下步骤:
(1)以诺蒎酮或樟脑为起始原料,甲醇钠或叔丁醇钾为催化剂,分别与芳香醛衍生物进行羟醛缩合反应,得到3-芳亚甲基蒎烷类化合物或3-芳亚甲基樟脑类化合物,产物不经分离直接与盐酸胍发生环化反应,得到蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物;
(2)蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物在氢化钠或叔丁醇钾催化下,于四氢呋喃溶剂中与卤代烃缩合反应,得到式1或式2所示的含双环单萜结构嘧啶胺化合物。
根据本发明一种优选实施方式,步骤(1)包括:
i)在三口烧瓶中,依次加入诺蒎酮或樟脑、芳香醛衍生物、叔丁醇和叔丁醇钾,开启搅拌器,加热回流反应数小时;
ii)反应结束后,反应液加入干燥剂(无水Na2SO4)搅拌干燥,过滤后,向滤液中加入盐酸胍,加热回流反应数小时;
iii)反应结束后,反应液经浓缩除去叔丁醇,再依次经乙酸乙酯萃取、洗涤、干燥、过滤、浓缩后得到蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物的粗产物;
iv)粗产物经纯化(重结晶或柱层析),得到蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物。
根据本发明一种更具体的实施方式,步骤(1)包括:
i)在配有磁力搅拌器、温度计和回流冷凝管的50mL三口烧瓶中,依次加入诺蒎酮或樟脑(14mmol),芳香醛(14mmol)、叔丁醇(30mL)和叔丁醇钾(30~60mmol),开启搅拌器,加热回流反应数小时,至原料转化率达到95%以上(GC跟踪检测);
ii)反应液加入Na2SO4(20mmol)搅拌干燥5min,经过滤后的滤液加入盐酸胍(14mmol),加热回流反应数小时,TLC跟踪检测完成;
iii)反应结束后,反应液经浓缩除去叔丁醇,加入乙酸乙酯,分别用蒸馏水和饱和食盐水洗涤至中性,再用无水的Na2SO4干燥,经过滤、浓缩后得到樟脑基嘧啶类化合物粗产物;
iv)粗产物经重结晶纯化,得到蒎烷基嘧啶或樟脑基嘧啶类化合物。
根据本发明的方法,所述芳香醛衍生物的结构根据目标化合物的结构确定,例如为对甲氧基苯甲醛、对二乙氨基苯甲醛。
根据本发明一种优选实施方式,步骤(2)包括:
i)冷阱中控制0℃以内,N2保护下向三口烧瓶中加入THF、蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物,缓慢分批加入NaH,加毕,继续搅拌;
ii)反应体系中加入卤代烃,将反应混合物控制在65℃下搅拌数小时,TLC跟踪反应基本完全;
iii)反应结束后,冷却至室温,将反应混合物倒入冰水中,用乙酸乙酯萃取,滤液依次经洗涤、干燥、过滤、浓缩、除去乙酸乙酯得到粗品,最后经纯化(柱层析),得到式1或式2所示的含双环单萜结构嘧啶胺化合物。
根据本发明一种更具体的实施方式,步骤(2)包括:
i)冷阱中控制0℃以内,N2保护下向25mL三口烧瓶中加入THF(10mL)、加入蒎烷基嘧啶或樟脑基嘧啶类化合物(1.0mmol),缓慢分批加入NaH(4.0mmol),加毕,继续搅拌30min;
ii)反应体系中加入卤代烃(1.1mmol),将反应混合物控制在65℃下搅拌数小时,TLC跟踪反应基本完全;
iii)反应结束后,冷却至室温,将反应混合物倒入冰水中,用EtOAc(2×20mL)萃取,滤液分别用蒸馏水和饱和食盐水洗涤至中性,再用无水的Na2SO4干燥,过滤,经浓缩除去乙酸乙酯得到粗品,最后经柱层析纯化(石油醚/乙酸乙酯=4/1),得到蒎烷基嘧啶胺衍生物或樟脑基嘧啶胺衍生物。
根据本发明的方法,本领域技术人员能够根据目标化合物的结构确定所述卤代烃的结构。
本发明还有一目的是提供该含双环单萜结构嘧啶胺化合物在抑菌方面的应用。
本发明所述含双环单萜结构嘧啶胺化合物可用于制备抗炎化合物,这得益于其具有细菌或真菌抑制活性,所述细菌或真菌包括肺炎克雷伯菌、铜绿假单孢菌、金黄色葡萄球菌、大肠杆菌、耐甲氧西林金黄色葡萄球菌、蜡状芽孢杆菌和白色念珠球菌中的至少一种。
本发明所述含双环单萜结构嘧啶胺化合物还具有对单核巨噬细胞白血病细胞的抗炎活性。
本发明利用诺蒎酮和樟脑为起始原料,与取代芳醛缩合、盐酸胍环合反应得到蒎烷基嘧啶类化合物和樟脑基嘧啶类化合物,继续与卤代烷取代反应得到蒎烷基嘧啶胺衍生物和樟脑基嘧啶胺衍生物,优点如下:
(1)诺蒎酮和樟脑原料廉价易得,来源丰富,有利于工业化生产;
(2)合成蒎烷基嘧啶或樟脑基嘧啶类化合物的过程中,中间体无需分离纯化,工艺简单,溶剂消耗少,产率较高,符合清洁工艺与可持续发展的要求;
(3)含双环单萜结构嘧啶胺衍生物对细菌和真菌具有显著的抑制活性。生物活性研究结果表明,目标化合物对7种细菌和真菌具有普遍的抑制活性,其中,化合物1a对肺炎链球菌(S.pneumoniae)和大肠杆菌(E.coli)的最低抑制浓度均为1μg/mL,优于阿米卡星;2d对肺炎克雷伯菌(K.pneumoniae)最低抑制浓度为32μg/mL,与阿米卡星相当,对铜绿假单孢菌(P.aeruginosa)最低抑制浓度为16μg/mL,优于阿米卡星。在真菌的抑制活性中,目标化合物1d活性最好,对白色念珠球菌(C.albicans)最低抑制浓度为16μg/mL,与酮康唑相当。此外,抑菌效果较好的1a和2d对小鼠单核巨噬细胞白血病细胞(RAW)具有抗炎活性,其中2d(IC50=1.87)的活性优于对照品阿司匹林(IC50=1.91)。
本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。
具体实施方式
下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式,然而应该理解,可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。
实施例1:
7,7-二甲基-N-(2-甲氧基乙基)-4-(4-甲氧基苯基)-5,6,7,8-四氢-6,8-桥亚甲基喹唑啉-2-胺(1a)的合成:
步骤A:在50mL三口烧瓶中加入30mL叔丁醇,开启磁力搅拌,加入14mmol诺蒎酮,14mmol对甲氧基苯甲醛,58mmol叔丁醇钾,升温至回流,反应6-7h,反应完成,用Na2SO4干燥,过滤,收集滤液,加入14mmol盐酸胍,升温至回流反应10h。将反应混合物用乙酸乙酯萃取三次(10mL×3),合并的有机层用饱和盐水洗涤至中性,用Na2SO4干燥,浓缩,得到黄色粗产物,柱层析纯化(石油醚/乙酸乙酯=3/1混合溶剂洗脱),得到浅黄色粉末中间体A,收率:86.0%,熔点:173-175℃.1H NMR(400MHz,DMSO-d6,ppm)δ:0.65(s,3H),1.22-1.24(m,1H),1.34(s,3H),2.27-2.30(m,1H),2.58-2.60(m,1H),2.61-2.66(m,1H),2.71-2.76(m,1H),2.83-2.87(m,1H),3.80(s,3H),6.21(s,2H),7.00(dd,J=2.8,8.8Hz,2H),7.64-7.68(m,2H),13C NMR(100MHz,DMSO-d6,ppm)δ:175.72,162.40,161.82,160.05,131.50,130.44,113.84,111.99,55.62,50.07,38.61,29.88,29.73,26.08,21.51.HRMS-ESI:296.1763calcd for C18H22N3O[M+H]+,found:296.1765.
步骤B:冷阱中控制0℃以内,N2保护下向25mL三口烧瓶中加入10mL THF、1.02mmol中间体A、4.06mmol NaH,搅拌30min。然后加入1.12mmol 2-溴乙基甲基醚并将反应混合物在65℃下搅拌3h。冷却至室温,将反应混合物倒入冰水中,用EtOAc(2×20mL)萃取。合并的有机层用盐水洗涤,用Na2SO4干燥,过滤,浓缩得到粗品,经柱层析纯化(PE/EA=4/1)得到类白色固体,收率:79.8%,熔点:125-127℃.1H NMR(400MHz,DMSO-d6,ppm)δ:0.69(s,3H),1.23(d,J=9.2,1H),1.36(s,3H),2.29-2.32(m,1H),2.51-2.67(m,2H),2.75-2.91(m,2H),3.26(s,3H),3.46-3.47(m,4H),3.82(s,3H),6.67-6.69(m,1H),7.01-7.04(m,2H),7.01-7.04(d,J=8.4,2H),13C NMR(100MHz,DMSO-d6,ppm)δ:21.55,26.07,29.78,29.87,38.61,50.25,55.66,58.35,71.20,111.88,113.93,130.48,131.65,160.13,160.60,175.68.HRMS-ESI:354.2182calcd for C21H28N3O[M+H]+,found:354.2183.
实施例2:
N-(3-氟苄基)-4-(4-甲氧基苯基)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基喹唑啉-2-胺(化合物1b)的制备:
参照化合物1a合成方法,得到类白色固体,收率:66.4%.熔点:112-115℃.1H NMR(400MHz,DMSO-d6,ppm)δ:7.68(d,J=2.0,6.8Hz,2H),7.34-7.39(m,3H),7.09-7.14(m,2H),7.00(dd,J=2.0,7.2Hz,2H),4.48-4.50(m,2H),3.81(s,3H),2.79-2.86(m,2H),2.50-2.67(m,2H),2.29-2.30(m,1H),1.35(s,3H),1.23(d,J=9.3,1H),0.68(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ:175.79,161.60(d,J=216.3Hz),160.27,160.15,137.58(d,J=3.0Hz).131.59,130.51,129.67,129.59,115.22(d,J=21Hz),113.91,112.14,55.64,50.26,43.93,40.66,29.84,29.81,26.05,21.53.HRMS-ESI:404.2138calcd for C25H27FN3O[M+H]+,found:404.2132.
实施例3:
N-苄基-4-(4-甲氧基苯基)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基喹唑啉-2-胺(化合物1c)的合成:
参照化合物1a合成方法,得到黄色固体,收率:65.1%,熔点:128-130℃.1H NMR(400MHz,DMSO-d6,ppm)δ:7.69(d,J=8.8Hz,2H),7.34-7.36(m,3H),7.30(t,J=7.5Hz,2H),7.00(d,J=8.8Hz,2H),4.51-4.53(m,2H),3.80(s,3H),2.79-2.90(m,2H),2.67(t,J=5.5Hz,1H),2.57-2.62(m,1H),2.28-2.32(m,1H),1.35(s,3H),1.23(d,J=9.4,1H),0.69(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ:175.74,160.61,160.13,141.43,131.61,130.51,128.53,127.73,126.84,113.90,112.03,55.64,50.26,44.61,29.86,29.82,26.06,21.54.HRMS-ESI:386.2232calcd for C25H28N3O[M+H]+,found:386.2227.
实施例4:
N-(2,4-二氟苄基)-4-(4-甲氧基苯基)-7,7-二甲基-5,6,7,8-四氢-6,8-桥亚甲基喹唑啉-2-胺(化合物1d)的合成:
参照化合物1a合成方法,得到灰色固体,收率:40.0%,熔点:125-126℃.
1H NMR(400MHz,DMSO-d6,ppm)δ:7.68(dd,J=2.0,6.8Hz,2H),7.44(q,J=6.8Hz,1H),7.34(t,J=6.6Hz,1H),7.15-7.20(m,1H),6.99-7.03(m,3H),4.52-4.53(m,2H),3.81(s,3H),2.80-2.87(m,2H),2.67(t,J=5.6Hz,1H),2.51-2.59(m,1H),2.28-2.32(m,1H),1.35(s,3H),1.23(d,J=9.2,1H),0.68(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ:175.86,161.59(d,J=256.5Hz),162.73,160.54(d,J=258.5Hz),161.70,160.39,160.19,131.50,131.16,131.07(d,J=3.0Hz),131.00,130.52,124.26(dd,J=15.0,3.0Hz),113.92,112.40,111.50(dd,J=20.9,3.6Hz),103.86(t,J=25.6Hz),55.65,50.25,38.61,37.97(d,J=3.9Hz),29.83,26.04,21.52.HRMS-ESI:422.2044calcd for C25H26F2N3O[M+H]+,found:422.2046.
实施例5:
N-苄基-4-(4-(二乙氨基)苯基)-7,7-二甲基-5,6,7,8-四氢-6,8-甲基喹唑啉-2-胺(化合物1e)的合成:
参照化合物1a合成方法步骤A,得到黄色白色固体中间体B,收率:78.5%,熔点:146-148℃.1H NMR(400MHz,DMSO-d6,ppm)δ:7.63(d,J=8.0Hz,2H),6.68(d,J=8.0Hz,2H),6.13(s,2H),2.96-2.74(m,2H),2.70-2.54(m,2H),2.40(d,J=81.4Hz,2H),1.34(s,4H),1.22(d,J=7.5Hz,2H),1.11(t,J=6.0Hz,7H),0.67(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ:175.26,162.36,161.64,148.16,130.50,125.35,111.39,110.81,50.07,44.09,38.54,30.29,29.92,26.09,21.49,12.92.HRMS-ESI:337.2392calcd for C21H29N4[M+H]+,found:337.2390.
参照化合物1a合成方法步骤B,中间体B与氯化苄反应,收率:46.5%,熔点:57-60℃.1H NMR(400MHz,DMSO-d6,ppm)δ:7.66(d,J=8.6Hz,2H),7.28-7.36(m,4H),7.18-7.22(m,2H),6.68(d,J=8.6Hz,2H),4.47-4.58(m,2H),3.33-3.40(m,4H),2.88(qd,J=48.9,16.2,3.2Hz,2H),2.64(t,J=5.5Hz,1H),2.55-2.61(m,1H),2.30-2.33(m,1H),1.35(s,3H),1.22(d,J=9.2Hz,1H),1.11(t,J=6.9Hz,6H),0.68(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ:174.79,159.97,147.72,141.20,130.05,128.02,127.20,126.31,124.97,110.87,110.34,49.76,44.06,40.08,38.04,29.90,29.41,25.56,21.01,12.44.HRMS-ESI:427.2862calcd for C28H35N4[M+H]+,found:427.2877.
实施例6:
N-(2-甲氧基乙基)-4-(4-甲氧基苯基)-8,9,9-三甲基-5,6,7,8-四氢-5,8-甲氧基喹唑啉-2-胺(化合物2a)的合成:
参照1a的合成方法中的步骤A,以樟脑和4-甲氧基苯甲醛为原料,得到浅黄色晶体中间体C,收率:56.8%,熔点:97-98℃.1H NMR(400MHz,DMSO-d6,ppm)δ:7.45-7.48(m,2H),7.22(s,1H),6.93-6.96(m,2H),3.86(s,3H),3.11(d,J=4.4Hz,1H),2.18-2.22(m,1H),1.76-1.82(m,1H),1.53-1.65(m,2H),1.02-1.05(m,6H),0.83(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ:9.31,18.40,20.55,25.92,30.85,46.79,49.23,55.33,57.03,114.18,127.35,128.30,131.39,140.07,160.11,208.27.HRMS-ESI:271.1698calcd for C18H23O2[M+H]+,found:271.1700.
参照1a的合成方法中的步骤B,中间体C与2-溴乙基甲基醚反应,得到黄色油状物,收率:73.0%.1H NMR(400MHz,DMSO-d6,ppm)δ:0.56(s,3H),0.96(s,3H),1.15(s,3H),1.24(m,2H),1.88-2.02(m,1H),2.16-2.18(m,1H),3.08(d,J=3.6Hz,1H),3.31(s,3H),3.49-3.50(m,4H),3.82(s,3H),6.70(s,1H),7.05-7.07(m,2H),7.80(d,J=8.8Hz,2H).13C NMR(100MHz,DMSO-d6,ppm)δ:10.04,19.08,20.01,26.02,31.93,41.37,49.97,53.93,55.32,55.60,58.69,71.65,113.76,123.89,129.79,131.15,154.95,160.51,161.08,181.34.HRMS-ESI:368.2338calcd for C22H30N3O2[M+H]+,found:368.2397.
实施例7:
N-(3-氟苄基)-4-(4-甲氧基苯基)-8,9,9-三甲基-5,6,7,8-四氢-5,8-甲氧基喹唑啉-2-胺(化合物2b)的制备:
参照化合物1a的合成方法,得到灰色固体,收率:39.1%,熔点:93-96℃.
1H NMR(400MHz,DMSO-d6,ppm)δ:0.54(s,3H),0.96(s,3H),1.16-1.27(m,5H),1.87-1.90(m,1H),2.16-2.17(m,1H),3.07-3.08(m,1H),3.81(s,3H),4.49-4.52(m,2H),7.02-7.05(m,2H),7.09-7.14(m,2H),7.39-7.43(m,3H),7.75-7.78(m,2H),13C NMR(100MHz,DMSO-d6,ppm)δ:10.64,19.19,20.19,26.20,32.06,44.24,49.85,53.96,55.45,55.70,114.34,115.19(d,J=21.13Hz),123.04,129.78,129.86,130.93,137.72-137.75(d,J=3.0Hz),160.25,160.44,161.14-162.65(d,J=151.9Hz),181.20.HRMS-ESI:418.2295calcd for C26H29FN3O[M+H]+,found:418.2296.
实施例8:
N-苄基-4-(4-甲氧基苯基)-8,9,9-三甲基-5,6,7,8-四氢-5,8-甲基喹唑啉-2-胺(化合物2c)的合成:
参照化合物1a的合成方法,得到黄色固体,收率:44.2%,熔点:114-115℃.1H NMR(400MHz,DMSO-d6,ppm)δ:1H NMR(400MHz,DMSO-d6):0.55(s,3H),0.96(s,3H),1.24-1.25(m,5H),1.85-1.90(m,1H),2.14-2.18(m,1H),3.07-3.08(m,1H),3.81(s,3H),4.50-4.54(m,2H),7.02-7.05(m,2H),7.18-7.19(m,1H),7.21-7.31(m,2H),7.38-7.39(m,3H),7.75-7.79(m,2H).13C NMR(100MHz,DMSO-d6,ppm)δ:10.66,19.20,20.20,49.86,53.96,55.70,114.33,122.95,126.84,127.96,128.51,129.86,141.60,160.63(d,J=39.24Hz),161.14,162.65,181.20.HRMS-ESI:400.2389calcd for C26H30N3O[M+H]+,found:400.2395.
实施例9:
N-(2,4-二氟苄基)-4-(4-甲氧基苯基)-8,9,9-三甲基-5,6,7,8-四氢-5,8-甲基喹唑啉-2-胺(化合物2d)的合成:
参照化合物1a的合成方法,得到灰色固体,收率:43.3%,熔点:59-61℃.1H NMR(400MHz,DMSO-d6,ppm)δ:0.54(s,3H),0.96(s,3H),1.16-1.26(m,5H),1.87-1.88(m,1H),2.16-2.17(m,1H),3.07-3.08(m,1H),3.81(s,3H),4.52-4.55(m,2H),7.02-7.05(m,3H),7.15-7.20(m,1H),7.44-7.50(m,2H),7.74-7.77(m,2H).13C NMR(100MHz,DMSO-d6,ppm)δ:10.02,19.05,19.99,25.91,31.88,39.07(d,J=4.0Hz),49.97,54.06,55.35,55.74,103.47(t,J=25.0Hz),110.88(dd,J=4.0,17.1Hz),113.83,122.85(d,J=4.0Hz),124.29,129.83,131.07(dd,J=6.0,7.0Hz),159.90,160.55,160.66,161.09(d,J=259.8Hz),162.04(d,J=247.5Hz),181.73.HRMS-ESI:436.2200calcd for C26H28F2N3O[M+H]+,found:436.2203.
测试例1:
含双环单萜结构嘧啶胺类化合物对肺炎克雷伯菌、铜绿假单孢菌、金黄色葡萄球菌、大肠杆菌、耐甲氧西林金黄色葡萄球菌(MRSA)、蜡状芽孢杆菌和白色念珠球菌抑制活性实验,测试方法如下:
以酮康唑和阿米卡星作为抑制真菌和抑制细菌的对照药物,本发明合成的化合物的抑菌活性采用二倍稀释法测试。选用的菌种为肺炎克雷伯菌(K.pneumoniae)、肺炎链球菌(S.pneumoniae)、铜绿假单孢菌(P.aeruginosa)、金黄色葡萄球菌(S.aureus)、大肠杆菌(E.coli)、耐甲氧西林金黄色葡萄球菌(MRSA)、蜡样芽孢杆菌(B.cereus)和白色念珠球菌(C.albicans)。在96孔分析板上,首先将第2孔到第12孔加入100μL纯化水,再将待测化合物1a~1e、2a~2d、阳性对照品酮康唑和阿米卡星用甲醇配成100μg/mL的溶液100μL加入到第1孔,将目标化合物和阳性对照品分别在96孔分析板上进行二倍稀释,从第1到第12孔配成一系列的浓度梯度(1024~1.0μg·mL-1),每孔含100μL溶液,以纯的DMSO作为参照,再向每个孔中加入100μL预先配好的菌悬液,充分混匀。最后将96孔分析板置于37℃孵化箱中,细菌培养24h,真菌培养48h,以不产生混浊的最低浓度的孔对应的浓度作为该样品对该测试菌的最低抑菌浓度。每个样品对每种测试菌重复三次,记录实验数据,结果取其平均值,如表1所示。
由表1的抑菌结果可知:目标化合物对7种细菌和真菌具有普遍的抑制活性,其中,目标化合物1a对肺炎链球菌(S.pneumoniae)和大肠杆菌(E.coli)的最低抑制浓度均为1μg/mL,优于阿米卡星;2d对肺炎克雷伯菌(K.pneumoniae)最低抑制浓度为32μg/mL,与阿米卡星相当,对铜绿假单孢菌(P.aeruginosa)最低抑制浓度为16μg/mL,优于阿米卡星。在真菌的抑制活性中,目标化合物1d活性最好,对白色念珠球菌(C.albicans)最低抑制浓度为16μg/mL,与酮康唑相当。因此本发明所设计的双环单萜嘧啶胺结构衍生物可作为抑菌剂应用。
测试例2:
采用MTT法检测化合物对RAW细胞活力的影响。RAW以每孔5×104个细胞均匀接种于96孔板中,孵育12小时,使细胞贴壁。10mmol/L的待测化合物母液用无血清培养基稀释为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.8μM的含药培养基。弃细胞上清,将含药培养基加入到96孔板中,阳性对照组和阴性对照组均加入相同体积的培养基,继续孵育12小时。弃细胞上清液,加入5μg/mL的LPS无血清培养基,继续培养24小时。随后,于酶标仪上检测每孔在492nm下的吸光度,所得数据均用SPSS软件计算细胞存活率,结果如表2所示。
表2化合物对RAW的抗炎活性
由表2结果可知,化合物1a和2d对RAW细胞均有明显的抗炎活性,其中化合物2d(IC50=1.87)的活性优于对照品阿司匹林(IC50=1.91)。
以上已经描述了本发明的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。
Claims (10)
1.一种含双环单萜结构嘧啶胺化合物,其结构式为式1或式2所示:
其中,R1为C1-C4烷氧基或C1-C4烷基取代的胺基;R2为2-甲氧基乙基、苄基或氟取代的苄基。
2.根据权利要求1所述的含双环单萜结构嘧啶胺化合物,其中,R1为-OCH3或-N(C2H5)2;R2为2-甲氧基乙基、苄基、3-氟苄基或2,4-二氟苄基。
3.根据权利要求2所述的含双环单萜结构嘧啶胺化合物,其中,所述含双环单萜结构嘧啶胺化合物选自以下化合物中的一种:
4.权利要求1-3中任意一项所述的含双环单萜结构嘧啶胺化合物的制备方法,包括如下步骤:
(1)以诺蒎酮或樟脑为起始原料,甲醇钠或叔丁醇钾为催化剂,分别与芳香醛衍生物进行羟醛缩合反应,得到3-芳亚甲基蒎烷类化合物或3-芳亚甲基樟脑类化合物,产物不经分离直接与盐酸胍发生环化反应,得到蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物;
(2)蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物在氢化钠或叔丁醇钾催化下,于四氢呋喃溶剂中与卤代烃缩合反应,得到式1或式2所示的含双环单萜结构嘧啶胺化合物。
5.根据权利要求4所述的含双环单萜结构嘧啶胺化合物的制备方法,其中,步骤(1)包括:
i)在三口烧瓶中,依次加入诺蒎酮或樟脑、芳香醛衍生物、叔丁醇和叔丁醇钾,开启搅拌器,加热回流反应数小时;
ii)反应结束后,反应液加入干燥剂搅拌干燥,过滤后,向滤液中加入盐酸胍,加热回流反应数小时;
iii)反应结束后,反应液经浓缩除去叔丁醇,再依次经乙酸乙酯萃取、洗涤、干燥、过滤、浓缩后得到蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物的粗产物;
iv)粗产物经纯化,得到蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物。
6.根据权利要求5所述的含双环单萜结构嘧啶胺化合物的制备方法,其中,所述芳香醛衍生物为对甲氧基苯甲醛、对二乙氨基苯甲醛。
7.根据权利要求4所述的含双环单萜结构嘧啶胺化合物的制备方法,其中,步骤(2)包括:
i)冷阱中控制0℃以内,N2保护下向三口烧瓶中加入THF、蒎烷基嘧啶类化合物或樟脑基嘧啶类化合物,缓慢分批加入NaH,加毕,继续搅拌;
ii)反应体系中加入卤代烃,将反应混合物控制在65℃下搅拌数小时;
iii)反应结束后,冷却至室温,将反应混合物倒入冰水中,用乙酸乙酯萃取,滤液依次经洗涤、干燥、过滤、浓缩、除去乙酸乙酯得到粗品,最后经纯化,得到式1或式2所示的含双环单萜结构嘧啶胺化合物。
8.权利要求1-3中任意一项所述的含双环单萜结构嘧啶胺化合物在制备抑菌化合物和/或抗炎药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述含双环单萜结构嘧啶胺化合物具有细菌或真菌抑制活性,所述细菌或真菌为肺炎克雷伯菌、铜绿假单孢菌、金黄色葡萄球菌、大肠杆菌、耐甲氧西林金黄色葡萄球菌、蜡状芽孢杆菌和白色念珠球菌中的至少一种。
10.根据权利要求8所述的应用,其特征在于,所述含双环单萜结构嘧啶胺化合物对单核巨噬细胞白血病细胞具有抗炎活性。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2022111550122 | 2022-09-21 | ||
CN202211155012 | 2022-09-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115611818A CN115611818A (zh) | 2023-01-17 |
CN115611818B true CN115611818B (zh) | 2024-03-29 |
Family
ID=84859596
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211157933.2A Active CN115611818B (zh) | 2022-09-21 | 2022-09-22 | 一种含双环单萜结构嘧啶胺化合物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115611818B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103333122A (zh) * | 2013-06-25 | 2013-10-02 | 南京林业大学 | 蒎烷基-2-氨基嘧啶类化合物及其合成和应用 |
CN103965118A (zh) * | 2014-05-26 | 2014-08-06 | 南京林业大学 | 一类蒎烷基-2-氨基嘧啶类化合物及其合成方法和应用 |
CN105085413A (zh) * | 2015-09-01 | 2015-11-25 | 南京林业大学 | 四氢喹唑啉-2-胺希夫碱类化合物及其合成方法和应用 |
CN110551070A (zh) * | 2018-05-30 | 2019-12-10 | 南京林业大学 | 樟脑基嘧啶类化合物的合成及其抗肿瘤活性 |
-
2022
- 2022-09-22 CN CN202211157933.2A patent/CN115611818B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103333122A (zh) * | 2013-06-25 | 2013-10-02 | 南京林业大学 | 蒎烷基-2-氨基嘧啶类化合物及其合成和应用 |
CN103965118A (zh) * | 2014-05-26 | 2014-08-06 | 南京林业大学 | 一类蒎烷基-2-氨基嘧啶类化合物及其合成方法和应用 |
CN105085413A (zh) * | 2015-09-01 | 2015-11-25 | 南京林业大学 | 四氢喹唑啉-2-胺希夫碱类化合物及其合成方法和应用 |
CN110551070A (zh) * | 2018-05-30 | 2019-12-10 | 南京林业大学 | 樟脑基嘧啶类化合物的合成及其抗肿瘤活性 |
Non-Patent Citations (3)
Title |
---|
Synthesis and Antibacterial Activity of Pinanyl-2-amino Pyrimidines;JUN WU等;《ASIAN JOURNAL OF CHEMISTRY》;第26卷(第22期);7769-7775 * |
新型蒎烷基含氮杂环化合物的合成及抑菌活性研究;魏柏松,等;《有机化学》;第33卷;2196-2204 * |
新型蒎烷基噻唑衍生物的合成及其生物活性研究;孙楠,等;《有机化学》;第36卷;2489-2495 * |
Also Published As
Publication number | Publication date |
---|---|
CN115611818A (zh) | 2023-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Rai et al. | Novel chromeno [2, 3-b]-pyrimidine derivatives as potential anti-microbial agents | |
SK2212000A3 (sk) | Enantiomérne čisté deriváty kyseliny chinolónkarboxylovej a naftyridónkarboxylovej, spôsob ich výroby, liečivá tieto látky obsahujúce a ich použitie | |
WO2005085252A1 (en) | Imidazo ‘1,2-a’ pyrazine compounds which interact with protein kinases | |
El Azab et al. | Synthesis and reactivity of enaminone of naphtho [b] 1, 4-oxazine: One pot synthesis of novel isolated and heterocycle-fused derivatives with antimicrobial and antifungal activities | |
Fathalla et al. | Synthesis of new 2-thiouracil-5-sulfonamide derivatives with biological activity | |
CN103333122A (zh) | 蒎烷基-2-氨基嘧啶类化合物及其合成和应用 | |
Aksinenko et al. | Synthesis of bis (trifluoromethyl) pyrimido [4, 5-d] pyrimidine-2, 4-diones and evaluation of their antibacterial and antifungal activities | |
Fujisaki et al. | Antibacterial activity of 5-dialkylaminomethylhydantoins and related compounds | |
CN115611818B (zh) | 一种含双环单萜结构嘧啶胺化合物及其制备方法与应用 | |
CN111518104B (zh) | 一种含硫脲嘧啶的1,2,4-三氮唑并[1,5-a]嘧啶类化合物及其制备方法和应用 | |
Szennyes et al. | The first general synthesis of 2-C-(β-D-glycopyranosyl) pyrimidines and their evaluation as inhibitors of some glycoenzymes | |
CN103113375B (zh) | 一类吡唑并[3,4‑d]嘧啶类化合物及其制备方法 | |
WO2005075477A1 (en) | Antibacterial compounds | |
CN107540627B (zh) | 一类具有抗菌活性的脱氢枞酸噁二嗪杂环衍生物及其制备方法和用途 | |
CN105924397A (zh) | 一种1,5-二芳基-3-甲酸酯吡唑类化合物、制备方法及用途 | |
CN108610302B (zh) | 诺蒎酮噻唑腙类化合物及其制备方法和应用 | |
CN115417879B (zh) | 一种n-嘧啶基环亚胺二苯并[1,5]二氮杂环辛衍生物及其制备和应用 | |
Bhatt et al. | Synthesis, characterization and anti-microbial activity of pyrazole capped 2-azitidinone derivatives | |
Sathe et al. | Synthesis of anti-bacterial activity of some synthesized 2 [21-phenyl-41-benzidinyl-51-oxo-imidazoline1yl-amino]-6 fluoro-7-substituted (1, 3) benzothiazoles | |
CN109897052B (zh) | 一种n-嘧啶基-1,3-氧氮杂桥环化合物及其制备方法和应用 | |
Suresh et al. | Synthesis and Antibacterial Activities of 1, 2, 3, 4, 6, 7, 8, 9-octahydro-1, 3, 7, 9-tetraphenyl 5-pyrrolo-2, 4, 6, 8-tetraoxo-10H, 5H pyrido [2, 3-d; 6, 5-d'] dipyrimidine | |
CN113683608B (zh) | 具有杀菌活性的n-取代-2-氨基-4-糖精取代甲基噻唑类化合物、制备方法和应用 | |
HACIALİOĞLU et al. | Synthesis and Some Reactions of Pyrazole-3-carboxylic acid Having Trifluoromethyl Unit. | |
CN114716344B (zh) | 2-((2-乙酰氨基苯基)氨基)乙酰芳胺类化合物及其制备方法和用途 | |
Bhiruda et al. | Synthesis of 4-(2-(substituted phenyl) diazenyl)-1-phenylpyrazolidine-3, 5-dione catalyzed by L-proline and their biological activity |
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 |