CN114380753B - 芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物及其抗菌用途 - Google Patents
芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物及其抗菌用途 Download PDFInfo
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- CN114380753B CN114380753B CN202011130881.0A CN202011130881A CN114380753B CN 114380753 B CN114380753 B CN 114380753B CN 202011130881 A CN202011130881 A CN 202011130881A CN 114380753 B CN114380753 B CN 114380753B
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- Prior art keywords
- quinoxaline
- diamine
- chlorobenzyl
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- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 25
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 24
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 12
- -1 quinoxaline-2, 3-diamine compound Chemical class 0.000 title claims description 429
- 238000002360 preparation method Methods 0.000 claims abstract description 141
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 20
- LUDZVVVPVCUUBP-UHFFFAOYSA-N quinoxaline-2,3-diamine Chemical class C1=CC=C2N=C(N)C(N)=NC2=C1 LUDZVVVPVCUUBP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 241000191963 Staphylococcus epidermidis Species 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical group 0.000 claims abstract description 13
- 241000588724 Escherichia coli Species 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims description 61
- 238000000034 method Methods 0.000 claims description 29
- 238000001704 evaporation Methods 0.000 claims description 16
- 241000894006 Bacteria Species 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 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 14
- 229960003085 meticillin Drugs 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 241000194031 Enterococcus faecium Species 0.000 claims description 11
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 241000194032 Enterococcus faecalis Species 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 108010059993 Vancomycin Proteins 0.000 claims description 8
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims description 8
- 229960003165 vancomycin Drugs 0.000 claims description 8
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 108090000204 Dipeptidase 1 Proteins 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 5
- 102000006635 beta-lactamase Human genes 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 241000606161 Chlamydia Species 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 241000193163 Clostridioides difficile Species 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 241000233866 Fungi Species 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 241000204031 Mycoplasma Species 0.000 claims description 2
- 241000588652 Neisseria gonorrhoeae Species 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 241000606701 Rickettsia Species 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 241000589970 Spirochaetales Species 0.000 claims description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
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- 229910052740 iodine Inorganic materials 0.000 claims description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
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- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
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- 150000004987 o-phenylenediamines Chemical class 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
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- 150000003141 primary amines Chemical class 0.000 claims description 2
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- 125000001725 pyrenyl group Chemical group 0.000 claims description 2
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract
本发明属于医药技术领域,涉及芳基或杂芳基取代的喹喔啉‑2,3‑二胺类化合物及其抗菌用途,具体涉及一类芳基或杂芳基取代的喹喔啉‑2,3‑二胺类化合物、制备方法及其在制备抗菌药物的用途。所述化合物如式(1)所示,其中Ar代表取代或非取代的芳基或杂芳基,所述取代基选自卤素、卤代C1‑8烷基中的一种或多种;R1代表取代或非取代的芳基或杂芳基、C3‑8环烷基、杂环基,所述取代基选自卤素、卤代C1‑8烷基中的一种或多种;R2、R3、R4、R5各自独立地选自氢、卤素、C1‑8烷基;本发明化合物对耐药的金黄色葡萄球菌、表皮葡萄球菌、肠球菌、大肠杆菌具有较强的抑制作用。
Description
技术领域
本发明属于医药技术领域,具体涉及芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物、制备方法及其作为抗菌药物的用途。
背景技术
抗生素耐药性已成为21世纪的主要公共卫生问题之一。几十年来,引起严重感染的耐药细菌已不同程度地对每种上市的抗生素产生耐药性,而抗菌药物研发放缓,极少有抗菌药物上市。面对这种情况,研究新结构类型或新作用机制的抗菌药物以应对不断发展的全球健康威胁势在必行。由金黄色葡萄球菌、大肠杆菌、淋球菌、肺炎克雷伯菌和铜绿假单胞菌等为代表的耐药性菌株引起的感染逐年攀升,针对以上耐药性病原微生物研发新型抗生素具有很高的应用价值与临床意义。
本专利涉及的化合物属于芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物,为新结构化合物。本专利涉及的化合物具有很强的抗革兰氏阳性菌耐药菌活性,若干代表性化合物同时具有抗革兰氏阴性菌活性。代表性化合物对标准及临床分离耐药金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌菌株的最低抑菌浓度(minimum inhibitoryconcentration,MIC)在0.05-32μg/mL水平,对标准及临床分离耐药大肠埃希菌、铜绿假单胞杆菌、肺炎克雷伯菌的最低抑菌浓度在2-32μg/mL水平。因此,该专利所涉及的化合物有进一步开发成为临床用抗菌药物的价值。
发明内容
本发明解决的技术问题是克服现有技术中抗耐药菌药物不足的缺陷,提供芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物、制备方法及其作为抗菌药物的用途。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面,提供了一种芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物,它是如式(1)所示的化合物:
其中:
Ar代表取代或非取代的芳基或杂芳基,所述取代基选自卤素、卤代C1-8烷基中的一种或多种;
R1选自取代或非取代的芳基或杂芳基、C3-8环烷基、杂环基,所述取代基选自卤素、卤代C1-8烷基中的一种或多种;
R2、R3、R4、R5各自独立地选自氢、卤素、C1-8烷基;
n选自0、1、2;
除非另有说明,否则上面所述的芳基包含6-16个碳原子;杂芳基是5-至15-元杂芳基;杂环基是3-至12-元杂环基;杂芳基或杂环基含有选自N、O或S中的一个或多个杂原子。
优选地,所述卤素选自氟、氯、溴、碘;所述卤代代表任意取代位置的单卤代、相同或不同卤素原子的多卤代;所述C1-8烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、直链或含支链的戊基、直链或含支链的己基、直链或含支链的庚基、直链或含支链的辛基,所述烷基代表任意取代位置的单烷基、相同或不同烷基的多烷基取代;所述C3-8环烷基选自环丙基、环丁基、环戊基、环己基、环庚基、环辛基;所述芳基选自苯基、萘基、蒽基、菲基或芘基;杂芳基选自呋喃、噻吩、噁唑、噻唑、异噁唑、噁二唑、噻二唑、吡咯、吡唑、咪唑、吡啶、嘧啶、吡嗪、哒嗪、酞嗪、喹啉、异喹啉、喋啶、嘌呤、吲哚、异吲哚、苯并呋喃基、苯并噻吩基、苯并咪唑酮、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基或苯并酞嗪基。
优选地,Ar选自取代或非取代的苯基、呋喃、噻吩;所述取代基选自氟、氯、溴、三氟甲基的一种或多种;R1选自取代或非取代的苯基、苯并咪唑酮、苯并咪唑、吲哚、喹啉、喹喔啉、C3-8环烷基、哌啶基,所述取代基选自氟、氯、溴、三氟甲基的一种或多种;R2、R3、R4、R5各自独立地选自氢、卤素、甲基;n选自0或1。
作为优选,本发明提供的芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物为:
N2-(4-氯苄基)-N3-(4-氯苯基)喹喔啉-2,3-二胺(L1)
5-((3-((4-氯苄基)氨基)喹喔啉-2-基)氨基)-1H-苯并[d]咪唑-2(3H)-酮(L2)
N2-(4-氯苄基)-N3-(1H-吲哚-4-基)喹喔啉-2,3-二胺(L3)
N2,N3-双(4-氯苄基)喹喔啉-2,3-二胺(L4)
N2-(4-氯苄基)-N3-环己基喹喔啉-2,3-二胺(L5)
N2-(1H-苯并[d]咪唑-6-基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L6)
N2-(4-溴苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L7)
N2-(4-氟苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L8)
N2-(4-溴-2-氟苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L9)
N2-(4-氯苄基)-N3-环戊基喹喔啉-2,3-二胺(L10)
5-(((3-((3-氯苄基氨基)喹喔啉-2-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(L11)
N2-(3,4-二氯苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L12)。
N2-(3-氯苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L13)
5-(((3-((2-氯苄基)氨基)喹喔啉-2-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(L14)
N2-(2,4-二三氟甲基苄基)-N3-(哌啶-4-基)喹喔啉-2,3-二胺(L15)
N2-(1H-苯并[d]咪唑-5-基)-N3-(2-氯苄基)喹喔啉-2,3-二胺(L16)
N2,N3-双(2-氯苄基)喹喔啉-2,3-二胺(L17)
N2-(2-氯苄基)-N3-(1H-吲哚-4-基)喹喔啉-2,3-二胺(L18)
N2-(2-氯苄基)-N3-(喹喔啉-6-基)喹喔啉-2,3-二胺(L19)
N2-(1H-苯并[d]咪唑-5-基)-N3-(3-氯苄基)喹喔啉-2,3-二胺(L20)
N2-(4-氯苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L21)
N2-(4-氯苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L22)
N2-(3,4-二氟苯基)-N3-(4-氟苄基)喹喔啉-2,3-二胺(L23)
N2,N3-双(4-氟苄基)喹喔啉-2,3-二胺(L24)
N2-(3,4-二氟苄基)-N3-环庚基喹喔啉-2,3-二胺(L25)
N2-(4-氯苄基)-N3-(4-(三氟甲基)苯基)喹喔啉-2,3-二胺(L26)
N2-(4-溴苄基)-N3-(3,4,5-三氯苯基)喹喔啉-2,3-二胺(L27)。
N2-(4-氟苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L28)
N2-(2,4-二三氟甲基苄基)-N3-(3,4-二氟苯基)喹喔啉-2,3-二胺(L29)
N2-(3,4-氟苄基)-N3-(3,4-氟苄基)喹喔啉-2,3-二胺(L30)
N2-(3,4-二氟苄基)-N3-(3,4-二氯苯基)喹喔啉-2,3-二胺(L31)
N2-(3,4-二氟苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L32)
6,7-二氯-N2-(3,4-二氟苄胺)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L33)
6,7-二氯-N2-(3,4-二氟苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L34)
N2-(4-氯苄基)-6-甲基-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L35)
N2-(4-氯苄基)-6-甲基-N3-(3,4,5-三氯苯基)喹喔啉-2,3-二胺(L36)
N2-(4-氯苄基)-6-甲基-N3-(3,4-二氯苯基)喹喔啉-2,3-二胺(L37)
6,7-二氯-N2-(3,4,5-三氟苯)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L38)
N2-(4-氯苄基)-N3-环己基-6,7-二氟喹喔啉-2,3-二胺(L39)
N2-(3,4-二氯苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L40)
N2-(4-氟苯基)-N3-(噻吩-2-基甲基)喹喔啉-2,3-二胺(L41)
N2-(3,4,5-三氟苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L42)
N2-(4-氯苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L43)
6,7-二氯-N2-(3,4-二氯苯基)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L44)
N2-(3,4-二氟苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L45)
N2-(4-氯苄基)-N3-环庚基喹喔啉-2,3-二胺(L46)
6,7-二氯-N2-(3,4-二氟苯基)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L47)
N2-(3,4-二氟苄基)-N3-环己基喹喔啉-2,3-二胺(L48)
6,7-二氯-N2-环庚基-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L49)
N2-(3,4-二氯苯基)-N3-(3,4-二氯苄基)喹喔啉-2,3-二胺(L50)
本发明技术方案的第二方面,提供了通式化合物(1)的制备方法,它包括如下步骤:
(1)将1当量的R2、R3、R4、R5取代的邻苯二胺与1当量的无水草酸溶解于4当量的盐酸水溶液中,搅拌并加热回流8小时,旋转蒸发,将溶剂蒸干,将残余物用乙醇洗涤并干燥,得到中间体(a);
(2)将中间体(a)溶于氯化亚砜(SOCl2)中,反应混合物在70℃下搅拌回流4小时,调节pH至中性,旋转蒸发,将溶剂蒸干,用正己烷洗涤固体,干燥,得到中间体(b);
(3)将1当量的中间体(b)溶于无水乙醇中,向溶液中加入1当量的芳基或芳杂基甲胺,加热回流8小时,旋转蒸发,将溶剂蒸发干,柱层析分离得到中间体(c);
(4)将1当量的中间体(c)与1当量R1取代的伯胺溶解于二甲基甲酰胺(DMF)中,加入1当量的无水三氯化铝,加热至110℃,搅拌8小时,向溶液中加入一定体积的蒸馏水,乙酸乙酯萃取3次,合并有机层,无水硫酸钠干燥30分钟,过滤取滤液,旋转蒸发,将溶剂蒸发干,得到的固体经柱层析分离得到权利要求1所述的化合物(1)。
其中,Ar、R1、R2、R3、R4、R5、n的定义如前所述。
本发明技术方案的第三方面,提供了上述芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物在制备抗菌药物中的应用。
作为优选,所述的抗菌用途为治疗和预防细菌、支原体、衣原体、立克次体、螺旋体、真菌等病原微生物所引起的人或动物的感染性疾病。
进一步优选地,所述的细菌为金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌、肺炎链球菌、艰难梭菌、淋病奈瑟菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌等,所述的支原体为肺炎支原体、溶脲脲原体、人型支原体、生殖器支原体等,所述的衣原体为肺炎衣原体、鹦鹉热衣原体、沙眼衣原体和牛衣原体等。
进一步优选地,所述的金黄色葡萄球菌包括甲氧西林敏感型金黄色葡萄球菌、甲氧西林耐药金黄色葡萄球菌、万古霉素中度敏感金黄色葡萄球菌,所述的表皮葡萄球菌包括甲氧西林敏感型表皮葡萄球菌、甲氧西林耐药表皮葡萄球菌,所述的粪肠球菌和屎肠球菌包括万古霉素敏感型粪肠球菌和屎肠球菌、万古霉素耐药粪肠球菌和屎肠球菌,所述大肠埃希菌选自非产超广谱β-内酰胺酶的肺炎克雷伯菌、产超广谱β-内酰胺酶的大肠埃希菌,所述肺炎克雷伯菌选自非产超广谱β-内酰胺酶的肺炎克雷伯菌。
本发明技术方案的第四方面,提供了一种抗菌药物组合物,该药物组合物含有上述的芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体。
进一步地,所述载体包括药学领域常规的赋形剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
作为优选,该药物给药剂型为注射剂、片剂、丸剂、胶囊、悬浮剂、乳剂或软膏,给药途径选自静脉或肌肉注射、口服、经皮给药、粘膜给药、直肠给药、阴道给药等。
与现有技术相比,本发明具有如下有益效果:
本发明的芳基或杂芳基取代的喹喔啉-2,3-二胺类化合物为新结构的抗菌药物,实验已证实该系列化合物对多种耐药菌有效,尤其对甲氧西林耐药金黄色葡萄球菌(MRSA)、甲氧西林耐药表皮葡萄球菌(MRSE)和万古霉素耐药的肠球菌(VRE)和耐药大肠埃希菌具有很强的抑制作用,具有深入研究的价值。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但实施例仅用于说明本发明,而不是对本发明进行限制。实施例中所用实验方法如无特殊说明,均为常规方法;所使用的材料、试剂等如无特殊说明,为可从商业途径得到的试剂和材料。
一、化合物的制备和检测
实施例1:化合物L1的制备和检测
在250mL圆底烧瓶中将邻苯二胺(5.4g,0.05mol)和无水草酸(4.5g,0.05mol)溶解于4N HCl(100mL)水溶液中。溶液在搅拌下,回流8小时。旋转蒸发,将溶剂蒸发干,将残余物用乙醇(50ml)洗涤并干燥,得到1,4-二氢喹喔啉-2,3-二酮,为白色固体(产率:68.2%)。
取化合物1,4-二氢喹喔啉-2,3-二酮(1.62g,0.01mol)于100mL的圆底烧瓶中,溶于SOCl2(20ml)中。反应混合物在70℃下搅拌4h,调节pH=7.0,旋转蒸发,将溶剂蒸发干。用正己烷(50mL)洗涤固体,干燥,得到2,3-二氯喹喔啉,为浅黄色固体(产率:65.6%)。
取化合物2,3-二氯喹喔啉(1.98g,0.01mol)于100mL的圆底烧瓶,溶于无水乙醇(40ml)中,向溶液中加入4-氯苄胺(1.41g,0.01mol),加热回流8h,旋转蒸发,将溶剂蒸发干,得到淡黄色固体。柱层析(乙酸乙酯:石油醚=20:1),得到3-氯-N-(4-氯苄基)喹喔啉-2-胺,为白色固体(产率:71.6%)。
取化合物3-氯-N-(4-氯苄基)喹喔啉-2-胺(1.01g,33mmol),无水AlCl3(0.45g,33mmol)和4-氯苯胺(0.42g,33mmol)于100mL的圆底烧瓶,溶于无水DMF(40ml)中,加热至110℃,搅拌8h,向溶液中加入蒸馏水20ml,萃取(乙酸乙酯40ml×3)合并有机层,加入Na2SO4干燥30min,过滤得到黄色澄清溶液,旋转蒸发,将溶剂蒸发干,得到淡黄色固体。柱层析(乙酸乙酯:石油醚=20:1,得到N2-(4-氯苄基)-N3-(4-氯苯基)喹喔啉-2,3-二胺(L1)。
白色固体,收率54.3%。ESI-MS(m/z):395.03[M+H]+.1H NMR(500MHz,DMSO-d6)δ8.92(s,1H),7.98(d,J=8.5Hz,2H),7.78(t,J=5.3Hz,1H),7.55(d,J=7.7Hz,1H),7.52(d,J=8.1Hz,2H),7.47(s,1H),7.45(dd,J=8.3,4.9Hz,5H),7.32(t,J=7.4Hz,1H),7.28(d,J=7.4Hz,1H),4.78(d,J=4.9Hz,2H)。
实施例2:化合物L2的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和5-氨基-1,3-二氢-2H-苯并[d]咪唑-2-酮为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到5-((3-((4-氯苄基)氨基)喹喔啉-2-基)氨基)-1H-苯并[d]咪唑-2(3H)-酮(L2)。
淡黄色固体,收率61.2%。ESI-MS(m/z):417.21[M+H]+.1H NMR(500MHz,DMSO-d6)δ10.61(s,1H),10.52(s,1H),8.67(s,1H),7.75(d,J=7.9Hz,2H),7.52(d,J=8.2Hz,2H),7.46(td,J=8.6,5.5Hz,4H),7.35(dd,J=8.4,2.1Hz,1H),7.30-7.22(m,2H),6.94(d,J=8.4Hz,1H),4.78(d,J=5.0Hz,2H).
实施例3:化合物L3的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和1H-吲哚-4-胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-(1H-吲哚-4-基)喹喔啉-2,3-二胺(L3)。
棕黄色固体,收率70.2%。ESI-MS(m/z):400.12[M+H]+.1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.54(s,1H),7.98(t,J=5.4Hz,1H),7.61(d,J=7.6Hz,1H),7.55(d,J=8.0Hz,2H),7.46(t,J=9.6Hz,3H),7.38(d,J=7.9Hz,1H),7.32(s,1H),7.21-7.28(m,3H),7.14(t,J=7.9Hz,1H),6.52(s,1H),4.81(d,J=5.1Hz,2H).
实施例4:化合物L4的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和4-氯苄胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2,N3-双(4-氯苄基)喹喔啉-2,3-二胺(L4)。
淡黄色固体,收率60.1%。ESI-MS(m/z):409.09[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.51-7.37(m,12H),7.19(dd,J=6.1,3.6Hz,2H),4.71(d,J=5.0Hz,4H).
实施例5:化合物L5的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和环己胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-环己基喹喔啉-2,3-二胺(L5)。
淡黄色固体,收率71.1%。ESI-MS(m/z):367.13[M+H]+.1H NMR(500MHz,DMSO-d6)δ6.71(m,2H),6.64(d,J=8.2Hz,2H),6.56(d,J=8.2Hz,2H),6.42(s,2H),3.96(d,J=5.0Hz,2H),3.35(tt,J=11.3,4.0Hz,1H),1.38-1.32(m,2H),1.09-1.02(m,2H),0.95(d,J=13.3Hz,1H),0.77-0.66(m,2H),0.60--0.42(m,3H).
实施例6:化合物L6的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和1H-苯并[d]咪唑-6-胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(1H-苯并[d]咪唑-6-基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L6)。
棕黄色固体,收率57.4%。ESI-MS(m/z):401.03[M+H]+.1H NMR(500MHz,DMSO-d6)δ12.50(s,1H),8.83(s,1H),8.49(s,1H),8.22(s,1H),7.86(s,1H),7.61(d,J=8.6Hz,1H),7.57-7.40(m,7H),7.32-7.23(m,2H),4.80(s,2H).
实施例7:化合物L7的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和4-溴苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-溴苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L7)。
淡黄色固体,收率48.4%。ESI-MS(m/z):439.03[M+H]+.1H NMR(500MHz,DMSO-d6)δ8.08-7.97(m,2H),7.65-7.53(m,6H),7.44(d,J=8.0Hz,2H),7.35(q,J=7.2Hz,2H),4.84(s,2H).
实施例8:化合物L8的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和4-氟苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氟苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L8)。
灰白色固体,收率71.2%。ESI-MS(m/z):379.06[M+H]+.1H NMR(500MHz,DMSO-d6)δ8.84(s,1H),7.95(t,J=6.4Hz,2H),7.76(d,J=5.4Hz,1H),7.52(d,J=7.9Hz,3H),7.50-7.41(m,3H),7.33-7.21(m,4H),4.79(d,J=5.0Hz,2H).
实施例9:化合物L9的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和4-溴-2-氟苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-溴-2-氟苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L9)。
灰白色固体,收率64.4%。ESI-MS(m/z):457.03[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.61(s,1H),8.62(s,1H),8.52(d,J=2.6Hz,1H),8.32(d,J=2.0Hz,1H),7.78(t,J=5.3Hz,1H),7.73(dd,J=8.7,2.6Hz,1H),7.44-7.39(m,3H),7.26-7.19(m,2H),6.88(d,J=8.8Hz,1H),4.75(d,J=5.0Hz,2H).
实施例10:化合物L10的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和环戊胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-环戊基喹喔啉-2,3-二胺(L10)。
淡黄色固体,收率77.3%。ESI-MS(m/z):353.23[M+H]+.1H NMR(500MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ7.50-7.34(m,7H),7.15(dq,J=6.5,3.8,2.8Hz,2H),6.77(d,J=6.2Hz,1H),4.69(d,J=5.2Hz,2H),4.44(h,J=6.6Hz,1H),2.13-2.01(m,2H),1.79-1.68(m,2H),1.60(td,J=7.2,3.8Hz,2H),1.56-1.47(m,2H).
实施例11:化合物L11的制备和检测
以3-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3-氯苄基)喹喔啉-2-胺(产率:71.3%)。
以3-氯-N-(3-氯苄基)喹喔啉-2-胺和5-氨基-1,3-二氢-2H-苯并[d]咪唑-2-酮为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到5-(((3-((3-氯苄基氨基)喹喔啉-2-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(L11)。
棕黄色固体,收率53.1%。ESI-MS(m/z):417.03[M+H]+,1H NMR(500MHz,DMSO-d6)δ10.62(s,1H),10.53(s,1H),8.74(s,1H),7.76(s,1H),7.71(t,J=4.9Hz,2H),7.62-7.56(m,1H),7.56-7.50(m,1H),7.47(td,J=9.0,7.3,4.2Hz,2H),7.36(q,J=3.4,3.0Hz,3H),7.26(dd,J=6.1,3.5Hz,2H),6.95(d,J=8.3Hz,1H),4.86(s,2H).
实施例12:化合物L12的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和3,4-二氯苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氯苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L12)。
白色固体,收率54.1%。ESI-MS(m/z):429.03[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.37(d,J=2.5Hz,1H),7.87(dd,J=8.9,2.6Hz,1H),7.74(t,J=5.4Hz,1H),7.62(d,J=8.8Hz,1H),7.56(dd,J=7.8,1.8Hz,1H),7.52-7.46(m,3H),7.44-7.39(m,2H),7.36-7.31(m,1H),7.29(td,J=7.4,1.8Hz,1H),4.76(d,J=5.0Hz,2H).
实施例13:化合物L13的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和3-氯苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3-氯苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L13)。
淡黄色固体,收率59.9%。ESI-MS(m/z):395.04[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.17(t,J=2.1Hz,1H),7.85-7.80(m,1H),7.77(t,J=5.4Hz,1H),7.55(dd,J=7.6,1.8Hz,1H),7.52-7.49(m,2H),7.47(dd,J=7.6,1.8Hz,1H),7.44-7.37(m,3H),7.35-7.30(m,1H),7.30-7.25(m,1H),7.10(m,1H),4.76(d,J=5.1Hz,2H).
实施例14:化合物L14的制备和检测
以2-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(2-氯苄基)喹喔啉-2-胺(产率:63.3%)。
以3-氯-N-(2-氯苄基)喹喔啉-2-胺和5-氨基-1,3-二氢-2H-苯并[d]咪唑-2-酮为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到5-(((3-((2-氯苄基)氨基)喹喔啉-2-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(L14)。
棕色固体,收率46.1%。ESI-MS(m/z):417.08[M+H]+.1H NMR(500MHz,DMSO-d6)δ10.62(s,1H),10.53(s,1H),8.74(s,1H),7.76(s,1H),7.71(t,J=4.9Hz,2H),7.62-7.56(m,1H),7.56-7.50(m,1H),7.47(td,J=9.0,7.3,4.2Hz,2H),7.36(q,J=3.4,3.0Hz,3H),7.26(dd,J=6.1,3.5Hz,2H),6.95(d,J=8.3Hz,1H),4.86(d,J=5.1Hz,2H).
实施例15:化合物L15的制备和检测
以2,4-二三氟甲基苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(2,4-二三氟甲基苄胺)喹喔啉-2-胺(产率:57.8%)。
以3-氯-N-(2,4-二三氟甲基苄胺)喹喔啉-2-胺和4-氨基哌啶-1-羧酸叔丁酯为起始原料,合成方法同实施例1中提到的产物L1的制备,得到N2-(2,4-二三氟甲基苄基)-N3-(1-叔丁氧羰基哌啶-4-基)喹喔啉-2,3-二胺(产率:53.1%)。
以N2-(2,4-二三氟甲基苄基)-N3-(1-叔丁氧羰基哌啶-4-基)喹喔啉-2,3-二胺为起始原料,溶于三氟乙酸15ml中,加热回流2h,加入饱和NaHCO3水溶液,调节PH至中性,析出白色固体,过滤得到N2-(2,4-二三氟甲基苄基)-N3-(哌啶-4-基)喹喔啉-2,3-二胺(L15)。
淡黄色固体,收率为36.6%。ESI-MS(m/z):470.71[M+H]+.1H NMR(500MHz,DMSO-d6)δ8.19(s,2H),8.03(s,1H),7.70(t,J=5.6Hz,1H),7.48-7.36(m,2H),7.26-7.16(m,2H),6.82(d,J=6.5Hz,1H),4.88(d,J=5.3Hz,2H),4.30(dq,J=10.9,5.9Hz,1H),3.32-3.30(m,1H),3.05(t,J=12.0Hz,2H),2.24-2.15(m,2H),1.67(q,J=11.0,10.3Hz,2H).
实施例16:化合物L16的制备和检测
以2-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(2-氯苄基)喹喔啉-2-胺(产率:67.4%)。
以3-氯-N-(2-氯苄基)喹喔啉-2-胺和1H-苯并[d]咪唑-5-胺为原料合成方法同实施例1中提到的终产物L1的制备,得到N2-(1H-苯并[d]咪唑-5-基)-N3-(2-氯苄基)喹喔啉-2,3-二胺(L16)。
棕黄色固体,收率42.4%。ESI-MS(m/z):401.12[M+H]+.1H NMR(500MHz,DMSO-d6)δ12.40(s,1H),8.86(s,1H),8.46(s,1H),8.19(s,1H),7.85-7.72(m,1H),7.68-7.57(m,2H),7.57-7.52(m,2H),7.47(s,2H),7.37(q,J=5.1,4.5Hz,2H),7.27(q,J=9.0,6.4Hz,2H),4.88(d,J=5.1Hz,2H).
实施例17:化合物L17的制备和检测
以2-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(2-氯苄基)喹喔啉-2-胺(产率:67.4%)。
以3-氯-N-(2-氯苄基)喹喔啉-2-胺和2-氯苄基为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2,N3-双(2-氯苄基)喹喔啉-2,3-二胺(L17)。
淡黄色固体,收率80.2%。ESI-MS(m/z):409.11[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.56-7.52(m,2H),7.52-7.50(m,2H),7.48(d,J=5.4Hz,2H),7.42(dd,J=6.1,3.6Hz,2H),7.34(p,J=5.5Hz,4H),7.19(dd,J=6.1,3.5Hz,2H),4.81(d,J=5.2Hz,4H).
实施例18:化合物L18的制备和检测
以2-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(2-氯苄基)喹喔啉-2-胺(产率:67.4%)。
以3-氯-N-(2-氯苄基)喹喔啉-2-胺和4-氨基吲哚为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(2-氯苄基)-N3-(1H-吲哚-4-基)喹喔啉-2,3-二胺(L18)
黄色固体,收率为37.1%。ESI-MS(m/z):400.03[M+H]+.1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),8.55(s,1H),7.98(t,J=5.5Hz,1H),7.65-7.57(m,2H),7.48(t,J=7.6Hz,2H),7.43(t,J=7.8Hz,1H),7.40-7.34(m,2H),7.32(d,J=2.9Hz,1H),7.27(t,J=7.3Hz,1H),7.22(q,J=7.4Hz,2H),7.14(t,J=7.8Hz,1H),6.52(t,J=2.5Hz,1H),4.83(s,2H).
实施例19:化合物L19的制备和检测
以2-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(2-氯苄基)喹喔啉-2-胺(产率:63.1%)。
以3-氯-N-(2-氯苄基)喹喔啉-2-胺和6-氨基喹喔啉为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(2-氯苄基)-N3-(喹喔啉-6-基)喹喔啉-2,3-二胺(L19)。
淡黄色固体,收率为43.3%。ESI-MS(m/z):413.08[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.37(s,1H),9.05(d,J=2.5Hz,1H),8.91(d,J=1.8Hz,1H),8.82(d,J=1.9Hz,1H),8.19(dd,J=9.0,2.7Hz,1H),8.11(d,J=9.1Hz,1H),7.88(t,J=5.1Hz,1H),7.70-7.66(m,1H),7.65-7.60(m,1H),7.54(dd,J=8.8,4.6Hz,2H),7.41-7.31(m,5H),4.90(d,J=4.9Hz,2H).
实施例20:化合物L20的制备和检测
以3-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3-氯苄基)喹喔啉-2-胺(产率:59.6%)。
以3-氯-N-(3-氯苄基)喹喔啉-2-胺和5-氨基苯并咪唑为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(1H-苯并[d]咪唑-5-基)-N3-(3-氯苄基)喹喔啉-2,3-二胺(L20)。
棕色固体,收率54.2%。ESI-MS(m/z):401.11[M+H]+.1H NMR(500MHz,DMSO-d6)δ12.40(s,1H),8.82(s,1H),8.49(s,1H),8.18(d,J=8.2Hz,1H),7.87-7.77(m,1H),7.66-7.57(m,2H),7.50(dd,J=21.9,6.8Hz,4H),7.42(t,J=7.7Hz,1H),7.37(d,J=7.9Hz,1H),7.32-7.24(m,2H),4.82(d,J=5.1Hz,2H).
实施例21:化合物L21的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和5-氨基吲哚为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L21)。
棕黄色固体,收率49.4%。ESI-MS(m/z):400.15[M+H]+.1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.62(s,1H),8.17(s,1H),7.75(t,J=5.3Hz,1H),7.53-7.49(m,2H),7.45-7.38(m,6H),7.34(t,J=2.7Hz,1H),7.25-7.18(m,2H),6.44(t,J=2.4Hz,1H),4.77(d,J=5.1Hz,2H).
实施例22:化合L22的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和3,4,5-三氟苯基为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L22)。
灰白色固体,收率60.1%。ESI-MS(m/z):415.09[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.11(s,1H),7.93(dd,J=11.0,6.4Hz,2H),7.72(t,J=5.3Hz,1H),7.65(d,J=8.0Hz,1H),7.54(t,J=7.2Hz,3H),7.47(d,J=8.1Hz,2H),7.39(t,J=7.5Hz,1H),7.34(t,J=7.6Hz,1H),4.80(s,2H).
实施例23:化合物L23的制备和检测
以4-氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氟苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-氟苄胺)喹喔啉-2-胺(产率:58.7%)。
以3-氯-N-(4-氟苄胺)喹喔啉-2-胺和3,4-二氟苯胺为原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氟苯基)-N3-(4-氟苄基)喹喔啉-2,3-二胺(L23)。
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淡黄色固体,收率60.2%。ESI-MS(m/z):381.13[M+H]+.1H NMR(500MHz,DMSO-d6)δ8.98(s,1H),8.31-8.22(m,1H),7.69(t,J=5.2Hz,1H),7.60-7.55(m,2H),7.55-7.49(m,2H),7.45(q,J=9.5Hz,1H),7.34(t,J=7.4Hz,1H),7.29(t,J=7.5Hz,1H),7.21(t,J=8.8Hz,2H),4.77(s,2H).
实施例24:化合物L24的制备和检测
以4-氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-氟苄胺)喹喔啉-2-胺(产率:58.7%)。
以3-氯-N-(4-氟苄胺)喹喔啉-2-胺和4-氟苄胺为起始原料合成方法同实施例1中提到的终产物L1的制备,得到N2,N3-双(4-氟苄基)喹喔啉-2,3-二胺(L24)。
淡黄色固体,收率74.9%。ESI-MS(m/z):377.09[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.48(dd,J=8.4,5.6Hz,4H),7.45-7.38(m,4H),7.19(dd,J=10.3,7.2Hz,6H),4.70(d,J=5.2Hz,4H).
实施例25:化合物L25的制备和检测
以3,4-二氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:74.8%)。
以3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺和环庚胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氟苄基)-N3-环庚基喹喔啉-2,3-二胺(L25)。
灰白色固体,收率58.2%。ESI-MS(m/z):383.62[M+H]+.1H NMR(500MHz,DMSO-d6)δ8.18(s,2H),8.03(s,1H),7.65(t,J=5.6Hz,1H),7.44-7.40(m,1H),7.39-7.34(m,1H),7.23-7.14(m,2H),6.62(d,J=7.0Hz,1H),4.87(d,J=5.3Hz,2H),4.18-4.02(m,1H),2.12-2.04(m,2H),1.80(dt,J=13.0,3.9Hz,2H),1.67(d,J=12.8Hz,1H),1.47-1.18(m,7H).
实施例26:化合物L26的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和4-三氟甲基苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-(4-(三氟甲基)苯基)喹喔啉-2,3-二胺(L26)。
淡黄色固体,收率为31.2%。ESI-MS(m/z):429.13[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.13(s,1H),8.16(d,J=8.4Hz,2H),7.83(t,J=5.3Hz,1H),7.75(d,J=8.5Hz,2H),7.60(d,J=7.9Hz,1H),7.55-7.48(m,3H),7.44(d,J=8.1Hz,2H),7.36(t,J=7.3Hz,1H),7.31(t,J=7.5Hz,1H),4.79(s,2H).
实施例27:化合物L27的制备和检测
以4-溴苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-溴苄基)喹喔啉-2-胺(产率:62.6%)。
以3-氯-N-(4-溴苄基)喹喔啉-2-胺和3,4,5-三氯苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-溴苄基)-N3-(3,4,5-三氯苯基)喹喔啉-2,3-二胺(L27)。
灰白色固体,收率为51.1%。ESI-MS(m/z):506.81 1H NMR(500MHz,DMSO-d6)δ9.15(s,1H),8.28(s,2H),7.68(t,J=5.3Hz,1H),7.60(d,J=7.7Hz,1H),7.57(d,J=8.3Hz,2H),7.51(d,J=8.1Hz,1H),7.46(d,J=8.1Hz,2H),7.38(t,J=7.4Hz,1H),7.33(t,J=7.6Hz,1H),4.75(s,2H).
实施例28:化合物L28的制备和检测
以4-氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-氟苄胺)喹喔啉-2-胺(产率:64.2%)。
以3-氯-N-(4-氟苄胺)喹喔啉-2-胺和3,4,5-三氟苯胺为起始原料,合成方法同实施例1中提到的产物L1的制备,得到N2-(4-氟苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L28)。
淡黄色固体,收率为49.6%。ESI-MS(m/z):399.23[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.08(s,1H),7.90(dd,J=11.0,6.4Hz,2H),7.67-7.60(m,2H),7.57-7.50(m,3H),7.37(t,J=7.5Hz,1H),7.31(t,J=7.5Hz,1H),7.21(t,J=8.7Hz,2H),4.77(d,J=5.0Hz,2H).
实施例29:化合物L29的制备和检测
以2,4-二三氟甲基苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(2,4-二三氟甲基苄胺)喹喔啉-2-胺(产率:57.8%)。
以3-氯-N-(2,4-二三氟甲基苄胺)喹喔啉-2-胺和3,4,5-三氟苯胺起始原料,合成方法同实施例1中提到的产物L1的制备,得到N2-(2,4-二三氟甲基苄基)-N3-(3,4-二氟苯基)喹喔啉-2,3-二胺(L29)。
白色固体,收率为52.9%。ESI-MS(m/z):517.63[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.22(d,J=1.7Hz,2H),8.01(s,1H),7.92-7.83(m,3H),7.61(dd,J=7.9,1.7Hz,1H),7.46(dd,J=8.0,1.6Hz,1H),7.38-7.33(m,1H),7.30(ddd,J=8.6,7.0,1.7Hz,1H),4.91(d,J=5.2Hz,2H).
实施例30:化合物L30的制备和检测
以3,4-二氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:68.3%)。
以3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺和3,4-二氟苄基为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-氟苄基)-N3-(3,4-氟苄基)喹喔啉-2,3-二胺(L30)。
淡黄色固体,收率为75.7%。ESI-MS(m/z):412.11[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.60-7.52(m,2H),7.46(dt,J=7.6,4.4Hz,6H),7.34(t,J=6.7Hz,2H),7.24(dt,J=7.0,3.4Hz,2H),4.75(d,J=5.1Hz,4H).
实施例31:化合物L31的制备和检测
以3,4-二氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:68.3%)。
以3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺和3,4-二氯苄基为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氟苄基)-N3-(3,4-二氯苯基)喹喔啉-2,3-二胺(L31)。
灰白色固体,收率为62.6%。ESI-MS(m/z):431.02[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.03(s,1H),8.38(d,J=2.5Hz,1H),7.89(dd,J=9.0,2.6Hz,1H),7.75(t,J=5.3Hz,1H),7.64(d,J=8.9Hz,1H),7.58(d,J=8.5Hz,2H),7.51(d,J=8.0Hz,1H),7.44(dt,J=10.9,8.4Hz,1H),7.34(m,3H),4.77(d,J=5.2Hz,2H).
实施例32:化合物L32的制备和检测
以3,4-二氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:62.3%)。
以3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺和3,4,5-三氟苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氟苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L32)。
淡黄色固体,收率为39.1%。ESI-MS(m/z):417.32[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.07(s,1H),7.90(dd,J=11.0,6.5Hz,2H),7.70(t,J=5.5Hz,1H),7.62(d,J=7.9Hz,1H),7.57(ddd,J=11.3,8.2,2.1Hz,1H),7.51(d,J=8.0Hz,1H),7.47-7.40(m,1H),7.39-7.27(m,3H),4.77(d,J=5.3Hz,2H).
实施例33:化合物L33的制备和检测
以4,5-二氯苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到2,3,6,7-四氯喹喔啉(产率:66.2%)。
以3,4-二氟苄胺和2,3,6,7-四氯喹喔啉为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:49.7%)。
以3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺和3,4-二氟苄胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到6,7-二氯-N2-(3,4-二氟苄胺)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L33)。
白色固体,收率为48.1%。ESI-MS(m/z):481.04[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.74(t,J=5.5Hz,2H),7.60(s,2H),7.56-7.49(m,2H),7.49-7.38(m,2H),7.30(t,J=6.4Hz,2H),4.69(s,4H).
实施例34:化合物L34的制备和检测
以4,5-二氯苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到2,3,6,7-四氯喹喔啉(产率:61.2%)。
以3,4-二氟苄胺和2,3,6,7-四氯喹喔啉为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:63.6%)。
以3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺和5-氨基吲哚为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到6,7-二氯-N2-(3,4-二氟苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L34)。
棕黄色固体,收率为47.1%。ESI-MS(m/z):470.08[M+H]+.1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.89(s,1H),8.18(s,1H),8.08(t,J=5.5Hz,1H),7.63(d,J=7.7Hz,2H),7.59(t,J=10.0Hz,1H),7.49-7.43(m,1H),7.43-7.39(m,2H),7.39-7.33(m,2H),6.48(t,J=2.3Hz,1H),4.77(d,J=5.0Hz,2H).
实施例35:化合物L35的制备和检测
以4-甲基苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到6-甲基喹喔啉(产率:68.2%)。
以6-甲基喹喔啉和4-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-氯苄基)-6-甲基喹喔啉-2-胺(产率:54.3%)。
以3-氯-N-(4-氯苄基)-6-甲基喹喔啉-2-胺和3,4,5-三氟苯胺为起始原料,合成方法同实施例1中提到的提到的终产物L1的制备,得到N2-(4-氯苄基)-6-甲基-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L35)。
棕色固体,收率22.4%。ESI-MS(m/z):429.07[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.03(s,1H),7.96-7.82(m,2H),7.65(t,J=5.3Hz,1H),7.58-7.48(m,3H),7.44(d,J=8.3Hz,2H),7.31(s,1H),7.15(d,J=8.2Hz,1H),4.76(s,2H),2.42(s,3H).
实施例36:化合物L36的制备和检测
以4-甲基苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到6-甲基喹喔啉(产率:65.4%)。
以6-甲基喹喔啉和4-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-氯苄基)-6-甲基喹喔啉-2-胺(产率:62.6%)。
以3-氯-N-(4-氯苄基)-6-甲基喹喔啉-2-胺和3,4,5-三氯苯胺为起始原料,合成方法同实施例1中提到的提到的终产物L1的制备,得到N2-(4-氯苄基)-6-甲基-N3-(3,4,5-三氯苯基)喹喔啉-2,3-二胺(L36)。
棕色固体,收率为17.7%。ESI-MS(m/z):477.03[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.10(s,1H),8.26(s,2H),7.64(t,J=5.3Hz,1H),7.50(t,J=8.0Hz,3H),7.46-7.39(m,3H),7.32(s,1H),7.17(d,J=8.1Hz,1H),4.75(s,3H),2.42(s,3H).
实施例37:化合物L37的制备和检测
以4-甲基苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到6-甲基喹喔啉(产率:61.7%)。
以6-甲基喹喔啉和4-氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-氯苄基)-6-甲基喹喔啉-2-胺(产率:52.3%)。
以3-氯-N-(4-氯苄基)-6-甲基喹喔啉-2-胺和3,4-二氯苯胺为起始原料,合成方法同实施例1中提到的提到的终产物L1的制备,得到N2-(4-氯苄基)-6-甲基-N3-(3,4-二氯苯基)喹喔啉-2,3-二胺(L37)。
棕色固体,收率为24.2%。ESI-MS(m/z):443.41[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.02(s,1H),8.41(s,1H),7.94-7.87(m,1H),7.73(t,J=5.5Hz,1H),7.65(dd,J=8.8,3.3Hz,1H),7.54(d,J=8.1Hz,2H),7.50(d,J=8.2Hz,1H),7.46(d,J=8.1Hz,2H),7.34(s,1H),7.24-7.15(m,1H),4.79(d,J=4.9Hz,2H),2.45(s,3H).
实施例38:化合物L38的制备和检测
以4,5-二氯苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到2,3,6,7-四氯喹喔啉(产率:65.2%)。
以3,4-二氟苄胺和2,3,6,7-四氯喹喔啉为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:53.3%)。
以3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺和3,4,5-三氟苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到6,7-二氯-N2-(3,4,5-三氟苯)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L38)。
淡黄色固体,收率66.9%。ESI-MS(m/z):485.24[M+H]+.1H NMR(500MHz,DMSO-d6)δ6.95(dd,J=10.5,6.4Hz,2H),6.90(s,1H),6.84(s,1H),6.62(dd,J=11.3,8.2Hz,1H),6.54-6.42(m,2H),3.97(s,2H).
实施例39:化合物L39的制备和检测
以4,5-二氟苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到2,3-二氯-6,7-二氟喹喔啉(产率:69.3%)。
以3,4-二氟苄胺和2,3-二氯-6,7-二氟喹喔啉为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(4-氯苄基)-6,7-二氟喹喔啉-2-胺(产率:62.1%)。
以3-氯-N-(4-氯苄基)-6,7-二氟喹喔啉-2-胺和环己胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-环己基-6,7-二氟喹喔啉-2,3-二胺(L39)。
淡黄色固体,收率70.7%。ESI-MS(m/z):403.21[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.62(t,J=5.3Hz,1H),7.42(s,2H),7.42-7.39(m,2H),7.31(ddd,J=12.1,8.5,6.9Hz,2H),6.80(d,J=7.1Hz,1H),4.66(d,J=5.3Hz,2H),4.09-3.98(m,1H),2.01(dt,J=12.4,3.8Hz,2H),1.76(dt,J=13.0,3.6Hz,2H),1.64(dd,J=9.9,6.3Hz,1H),1.38(qt,J=12.4,3.1Hz,2H),1.30-1.18(m,3H).
实施例40:化合L40的制备和检测
以2-呋喃苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(呋喃-2-基甲基)喹喔啉-2-胺(产率:63.7%)。
以3-氯-N-(呋喃-2-基甲基)喹喔啉-2-胺和3,4-二氯苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氯苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L40)。
棕色固体,收率45.1%。ESI-MS(m/z):385.09[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.37(d,J=2.6Hz,1H),7.87(dd,J=8.9,2.6Hz,1H),7.67-7.59(m,3H),7.58-7.52(m,2H),7.35(td,J=7.5,1.7Hz,1H),7.30(td,J=7.4,1.7Hz,1H),6.49-6.43(m,2H),4.76(d,J=4.7Hz,2H).
实施例41:化合物L41的制备和检测
以2-噻吩苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(噻吩-2-基甲基)喹喔啉-2-胺(产率:60.2%)。
以3-氯-N-(噻吩-2-基甲基)喹喔啉-2-胺和4-氟苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氟苯基)-N3-(噻吩-2-基甲基)喹喔啉-2,3-二胺(L41)。
淡黄色固体,收率为50.4%。ESI-MS(m/z):351.26[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.97-7.92(m,2H),7.81(t,J=5.3Hz,1H),7.54(dd,J=7.8,1.7Hz,2H),7.44-7.39(m,3H),7.34(td,J=7.4,1.7Hz,1H),7.31-7.26(m,1H),7.19(dd,J=3.5,1.2Hz,1H),7.00(dd,J=5.1,3.4Hz,1H),4.93(d,J=5.2Hz,2H).
实施例42:化合物L42的制备和检测
以2-呋喃苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(呋喃-2-基甲基)喹喔啉-2-胺(产率:63.7%)。
以3-氯-N-(呋喃-2-基甲基)喹喔啉-2-胺和3,4,5-三氟苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4,5-三氟苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L42)。
棕色固体,收率为53.1%。ESI-MS(m/z):370.16[M+H]+,1H NMR(500MHz,DMSO-d6)δ9.10(s,1H),7.91(dd,J=11.0,6.5Hz,2H),7.67(s,1H),7.62(d,J=8.0Hz,1H),7.60-7.54(m,2H),7.38(t,J=7.5Hz,1H),7.32(t,J=7.5Hz,1H),6.53-6.44(m,2H),4.78(d,J=5.2Hz,2H).
实施例43:化合物L43的制备和检测
以2-呋喃苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(呋喃-2-基甲基)喹喔啉-2-胺(产率:63.7%)。
以3-氯-N-(呋喃-2-基甲基)喹喔啉-2-胺和4-氯苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L43)。
白色固体,收率为63.4%。ESI-MS(m/z):351.07[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.90-7.86(m,2H),7.77(t,J=5.4Hz,1H),7.51(ddd,J=9.6,7.8,1.7Hz,2H),7.37(dd,J=5.1,1.3Hz,1H),7.32(dd,J=7.2,1.8Hz,1H),7.29(dd,J=4.0,1.8Hz,1H),7.26(dd,J=7.3,1.7Hz,1H),7.23-7.18(m,2H),7.18-7.16(m,1H),7.01-6.95(m,1H),4.91(d,J=5.1Hz,2H).
实施例44:化合物L44的制备和检测
以4,5-二氯苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到2,3,6,7-四氯喹喔啉(产率:66.9%)。
以3,4-二氟苄胺和2,3,6,7-四氯喹喔啉为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺的制备,得到3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:50.4%)。
以3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺和3,4-二氯苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到6,7-二氯-N2-(3,4-二氯苯基)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L44)。
淡黄色固体,收率为73.1%。ESI-MS(m/z):499.32[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.27(d,J=2.5Hz,1H),8.07(t,J=5.4Hz,1H),7.90(dd,J=8.9,2.5Hz,1H),7.76(s,1H),7.67(s,1H),7.62(d,J=8.9Hz,1H),7.56(ddd,J=11.8,7.8,2.1Hz,1H),7.43(dt,J=10.7,8.4Hz,1H),7.33(t,J=6.5Hz,1H),4.73(d,J=5.0Hz,2H).
实施例45:化合物L45的制备和检测
以3,4-二氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:72.3%)。
以3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺和5-氨基吲哚为起始原料,合成方法同实施例1中提到终产物L1的制备,得到N2-(3,4-二氟苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L45)。
棕色固体,收率为63.7%。ESI-MS(m/z):402.21[M+H]+.1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.62(s,1H),8.17(s,1H),7.76(t,J=5.4Hz,1H),7.56(ddd,J=11.9,7.9,2.1Hz,1H),7.48-7.38(m,5H),7.34(m,J,2H),7.23(qd,J=6.8,3.5Hz,2H),6.44(t,J=2.5Hz,1H),4.76(d,J=5.0Hz,2H).
实施例46:化合物L46的制备和检测
以3-氯-N-(4-氯苄基)喹喔啉-2-胺和环庚胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(4-氯苄基)-N3-环庚基喹喔啉-2,3-二胺(L46)。
淡黄色固体,收率为34.5%。ESI-MS(m/z):381.66[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.49(t,J=5.4Hz,1H),7.44(d,J=8.8Hz,2H),7.42-7.38(m,2H),7.38-7.36(m,1H),7.35(d,J=2.4Hz,1H),7.18-7.10(m,2H),6.67(d,J=7.0Hz,1H),4.68(d,J=5.3Hz,2H),4.25(td,J=8.8,4.3Hz,1H),2.01(dd,J=13.7,5.7Hz,2H),1.73-1.63(m,3H),1.62-1.48(m,7H).
实施例47:化合物L47的制备和检测
以4,5-二氯苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到2,3,6,7-四氯喹喔啉(产率:73.3%)。
以3,4-二氟苄胺和2,3,6,7-四氯喹喔啉为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:72.1%)。
以3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺和3,4-二氟苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到6,7-二氯-N2-(3,4-二氟苯基)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L47)。
淡黄色固体,收率为34.3%。ESI-MS(m/z):467.12[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.74(t,J=5.5Hz,2H),7.60(s,2H),7.56-7.49(m,2H),7.49-7.38(m,2H),7.30(t,J=6.4Hz,2H),4.69(s,4H).
实施例48:化合物L48的制备和检测
以3,4-二氟苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:72.3%)。
以3-氯-N-(3,4-二氟苄基)喹喔啉-2-胺和环己胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氟苄基)-N3-环己基喹喔啉-2,3-二胺(L48)。
淡黄色固体,收率为53.2%。ESI-MS(m/z):369.13[M+H]+.1H NMR(500MHz,DMSO-d6)δ6.71(ddd,J=16.2,7.5,2.2Hz,2H),6.60-6.51(m,1H),6.46-6.34(m,4H),3.93(s,2H),3.34(ddt,J=11.0,7.7,3.9Hz,1H),1.35(dd,J=12.7,4.0Hz,2H),1.05(dt,J=13.5,3.9Hz,2H),0.94(dt,J=13.0,3.8Hz,1H),0.75-0.67(m,2H),0.57-0.45(m,3H).
实施例49:化合物L49的制备和检测
以4,5-二氯苯-1,2-二胺为起始原料,合成方法同实施例1中提到的中间体2,3-二氯喹喔啉的制备,得到2,3,6,7-四氯喹喔啉(产率:66.4%)。
以3,4-二氟苄胺和2,3,6,7-四氯喹喔啉为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺(产率:62.7%)。
以3,6,7-三氯-N-(3,4-二氟苄基)喹喔啉-2-胺和环庚胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到6,7-二氯-N2-环庚基-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L49)。
淡黄色固体,收率为43.3%。ESI-MS(m/z):451.14[M+H]+.1H NMR(400MHz,DMSO-d6)δ7.83(t,J=5.4Hz,1H),7.54(s,2H),7.48(ddd,J=11.7,7.9,2.2Hz,1H),7.43-7.39(m,1H),7.29-7.23(m,1H),7.01(d,J=7.0Hz,1H),4.66(d,J=5.2Hz,2H),4.27-4.18(m,1H),2.05-1.95(m,2H),1.71-1.61(m,3H),1.61-1.46(m,7H).
实施例50:化合物L50的制备和检测
以3,4-二氯苄胺为起始原料,合成方法同实施例1中提到的中间体3-氯-N-(4-氯苄基)喹喔啉-2-胺的制备,得到3-氯-N-(3,4-二氯苄基)喹喔啉-2-胺(产率:48.2%)。
以3-氯-N-(3,4-二氯苄基)喹喔啉-2-胺和3,4-二氯苯胺为起始原料,合成方法同实施例1中提到的终产物L1的制备,得到N2-(3,4-二氯苯基)-N3-(3,4-二氯苄基)喹喔啉-2,3-二胺(L50)。
白色固体,收率为53.8%。ESI-MS(m/z):463.12[M+H]+.1H NMR(500MHz,DMSO-d6)δ9.03(s,1H),8.38(d,J=2.4Hz,1H),7.89(dd,J=8.9,2.5Hz,1H),7.77(d,J=4.6Hz,2H),7.63(d,J=8.8Hz,2H),7.58(d,J=7.8Hz,1H),7.53-7.47(m,2H),7.36(t,J=7.2Hz,1H),7.32(d,J=7.7Hz,1H),4.78(s,2H).
二、抗菌活性测定
实验例1:化合物的抗金黄色葡萄球菌标准菌株ATCC29213的活性测定
1.供试菌液的准备
接种金黄色葡萄球菌标准菌株ATCC 29213至20mL胰蛋白胨大豆肉汤培养基中,于37℃培养箱中以220转/分的速度振荡培养12小时。当澄清的培养基变混浊时,表明细菌增殖明显,生长旺盛。此时,将菌液用新的胰蛋白胨大豆肉汤培养基中进行稀释,使其OD600值介于0.3至0.5之间,再次用新的胰蛋白胨大豆肉汤培养基等倍稀释105倍作为供试菌液。
2.确定最低抑菌浓度
取洁净无菌的96孔细胞培养板,第一列各孔中加入制备好的供试菌液200μL,第二列至十二列各孔中加入供试菌液100μL。取预先配制好的5mg/ml的待测样品DMSO溶液4μL加入第1列各孔中(每个样品三重复),另设置阳性对照组(即同浓度的左氧氟沙星4μL)和空白对照(即不加药)。从第一列各孔开始,依次用8道微量移液器中从前一列吸100μL样品依次加入到后一列各孔中进行2倍梯度稀释,设置100、50、25、12.5、6.25、3.13、1.56、0.78、0.39、0.20、0.10、0.05μg/mL共12个不同浓度的化合物溶液。将96孔细胞培养板置于37℃培养箱,培养18小时后,观察96孔板各孔中的金黄色葡萄球菌的生长状况。对于每个化合物,未见细菌生长的孔对应的化合物浓度即该化合物的最低抑菌浓度(Minimal InhibitoryConcentration,MIC)。
3.代表性化合物抗金黄色葡萄球菌标准菌株ATCC29213的活性见表1。
实验例2:化合物的抗菌谱测定
1.菌种类别
ATCC标准菌株或四川地区收集的临床分离致病菌,包括金黄色葡萄球菌10株(甲氧西林耐药金黄色葡萄球菌:MRSA15-1、MRSA15-2、MRSA15-3、ATCC33591;甲氧西林敏感金黄色葡萄球菌:MSSA15-1、MSSA15-2、MSSA15-3;万古霉素敏感金黄色葡萄球菌:ATCC25923;万古霉素中度敏感金黄色葡萄球菌:ATCC700699、ATCC700788)、表皮葡萄球菌5株(甲氧西林耐药表皮葡萄球菌:MRSE15-1、MRSE15-2;甲氧西林敏感表皮葡萄球菌:MSSE15-3、MSSE15-4)、粪肠球菌4株(万古霉素敏感粪肠球菌:EFA15-1;万古霉素耐药粪肠球菌:ATCC700802、ATCC51575),大肠埃希菌4株(ATCC25922、ATCC35218、ECO+15-1、ECO-15-1),铜绿假单胞杆菌4株(PAE15-4、PAE15-5、PAE15-8、ATCC27853),肺炎克雷伯菌3株(KPN-15-1、KPN-15-2、KPN-15-3)。
2.培养基及培养条件
葡萄球菌:MH肉汤,35-37℃孵育18-24h观察结果。
其它菌种:常规MH肉汤,35-37℃孵育18-24h观察结果。
MH肉汤配方:蛋白胨1%,牛肉粉0.3%,NaCl 0.5%。
3.测试方法
(1)方法依据
采用美国临床和实验室标准协会(Clinical and Laboratory StandardsInstitute,CLSI)抗菌药物敏感性试验操作规程【Methods for Dilution AntimicrobialSucceptibility Tests for Bacteria That Grow Aerobically;Approved Standard-Eleventh Edition,M07-A11,2018】推荐的微量肉汤稀释法测定各受试样品对所试菌株的MIC值。
(2)具体操作步骤
分别吸取100μL各不同浓度的受试样品溶液加到灭菌的96孔聚苯乙烯板中的第1至第12孔内,使药物终浓度分别为64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03μg/mL(具体浓度范围根据药品量来计算)。再于各孔内加入100μL的受试菌液(每孔容量200μL),菌液最终浓度约为105CFU/mL。密封后置于35-37℃培养箱内培养18-24h,判断结果。以在小孔内完全抑制细菌生长的最低药物浓度为受试样品的MIC。同时设立不加任何样品的空白菌对照和加DMSO的溶媒对照。
4.化合物的抗革兰氏阳性菌的抗菌谱见表2。
5.化合物的抗革兰氏阴性菌的抗菌谱见表3。
表1.代表性化合物对金黄色葡萄球菌的最低抑菌浓度
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表2.代表性化合物对革兰氏阳性菌不同菌株的最低抑菌浓度MIC(μg/mL)。
表3.代表性化合物对革兰氏阴性菌不同菌株的最低抑菌浓度MIC(μg/mL)
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Claims (13)
1.如式(1)所示的化合物或其药学上可接受的盐,
其中:
Ar代表取代的芳基或杂芳基,所述取代基选自卤素、卤代C1-8烷基中的一种或多种;
R1选自取代或非取代的芳基或杂芳基、C3-8环烷基、杂环基,所述取代基选自卤素、卤代C1-8烷基中的一种或多种;
R2、R3、R4、R5各自独立地选自氢、卤素、C1-8烷基;
n选自0、1、2;
上面所述的芳基包含6-16个碳原子;杂芳基是5-至15-元杂芳基;杂环基是3-至12-元杂环基;杂芳基或杂环基含有选自N、O或S中的一个或多个杂原子。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
所述卤素选自氟、氯、溴、碘;
所述卤代代表任意取代位置的单卤代、相同或不同卤素原子的多卤代;
所述C1-8烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、直链或含支链的戊基、直链或含支链的己基、直链或含支链的庚基、直链或含支链的辛基;
所述C3-8环烷基选自环丙基、环丁基、环戊基、环己基、环庚基、环辛基;
芳基选自苯基、萘基、蒽基、菲基或芘基;
杂芳基选自呋喃、噻吩、噁唑、噻唑、异噁唑、噁二唑、噻二唑、吡咯、吡唑、咪唑、吡啶、嘧啶、吡嗪、哒嗪、酞嗪、喹啉、异喹啉、喋啶、嘌呤、吲哚、异吲哚、苯并呋喃基、苯并噻吩基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基或苯并酞嗪基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,Ar选自取代的苯基、呋喃、噻吩;所述取代基选自氟、氯、溴、三氟甲基的一种或多种。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R1选自取代或非取代的苯基、苯并咪唑酮、苯并咪唑、吲哚、喹啉、喹喔啉、C3-8环烷基、哌啶基,所述取代基选自氟、氯、溴、三氟甲基的一种或多种。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R2、R3、R4、R5各自独立地选自氢、卤素、甲基。
6.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述的化合物选自如下群组:
N2-(4-氯苄基)-N3-(4-氯苯基)喹喔啉-2,3-二胺(L1)
5-((3-((4-氯苄基)氨基)喹喔啉-2-基)氨基)-1H-苯并[d]咪唑-2(3H)-酮(L2)
N2-(4-氯苄基)-N3-(1H-吲哚-4-基)喹喔啉-2,3-二胺(L3)
N2,N3-双(4-氯苄基)喹喔啉-2,3-二胺(L4)
N2-(4-氯苄基)-N3-环己基喹喔啉-2,3-二胺(L5)
N2-(1H-苯并[d]咪唑-6-基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L6)
N2-(4-溴苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L7)
N2-(4-氟苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L8)
N2-(4-溴-2-氟苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L9)
N2-(4-氯苄基)-N3-环戊基喹喔啉-2,3-二胺(L10)
5-(((3-((3-氯苄基氨基)喹喔啉-2-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(L11)
N2-(3,4-二氯苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L12)
N2-(3-氯苯基)-N3-(4-氯苄基)喹喔啉-2,3-二胺(L13)
5-(((3-((2-氯苄基)氨基)喹喔啉-2-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(L14)
N2-(2,4-二三氟甲基苄基)-N3-(哌啶-4-基)喹喔啉-2,3-二胺(L15)
N2-(1H-苯并[d]咪唑-5-基)-N3-(2-氯苄基)喹喔啉-2,3-二胺(L16)
N2,N3-双(2-氯苄基)喹喔啉-2,3-二胺(L17)
N2-(2-氯苄基)-N3-(1H-吲哚-4-基)喹喔啉-2,3-二胺(L18)
N2-(2-氯苄基)-N3-(喹喔啉-6-基)喹喔啉-2,3-二胺(L19)
N2-(1H-苯并[d]咪唑-5-基)-N3-(3-氯苄基)喹喔啉-2,3-二胺(L20)
N2-(4-氯苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L21)
N2-(4-氯苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L22)
N2-(3,4-二氟苯基)-N3-(4-氟苄基)喹喔啉-2,3-二胺(L23)
N2,N3-双(4-氟苄基)喹喔啉-2,3-二胺(L24)
N2-(3,4-二氟苄基)-N3-环庚基喹喔啉-2,3-二胺(L25)
N2-(4-氯苄基)-N3-(4-(三氟甲基)苯基)喹喔啉-2,3-二胺(L26)
N2-(4-溴苄基)-N3-(3,4,5-三氯苯基)喹喔啉-2,3-二胺(L27)
N2-(4-氟苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L28)
N2-(2,4-二三氟甲基苄基)-N3-(3,4-二氟苯基)喹喔啉-2,3-二胺(L29)
N2-(3,4-氟苄基)-N3-(3,4-氟苄基)喹喔啉-2,3-二胺(L30)
N2-(3,4-二氟苄基)-N3-(3,4-二氯苯基)喹喔啉-2,3-二胺(L31)
N2-(3,4-二氟苄基)-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L32)
6,7-二氯-N2-(3,4-二氟苄胺)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L33)
6,7-二氯-N2-(3,4-二氟苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L34)N2-(4-氯苄基)-6-甲基-N3-(3,4,5-三氟苯基)喹喔啉-2,3-二胺(L35)
N2-(4-氯苄基)-6-甲基-N3-(3,4,5-三氯苯基)喹喔啉-2,3-二胺(L36)
N2-(4-氯苄基)-6-甲基-N3-(3,4-二氯苯基)喹喔啉-2,3-二胺(L37)
6,7-二氯-N2-(3,4,5-三氟苯)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L38)N2-(4-氯苄基)-N3-环己基-6,7-二氟喹喔啉-2,3-二胺(L39)
N2-(3,4-二氯苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L40)
N2-(4-氟苯基)-N3-(噻吩-2-基甲基)喹喔啉-2,3-二胺(L41)
N2-(3,4,5-三氟苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L42)
N2-(4-氯苯基)-N3-(呋喃-2-基甲基)喹喔啉-2,3-二胺(L43)
6,7-二氯-N2-(3,4-二氯苯基)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L44)N2-(3,4-二氟苄基)-N3-(1H-吲哚-5-基)喹喔啉-2,3-二胺(L45)
N2-(4-氯苄基)-N3-环庚基喹喔啉-2,3-二胺(L46)
6,7-二氯-N2-(3,4-二氟苯基)-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L47)N2-(3,4-二氟苄基)-N3-环己基喹喔啉-2,3-二胺(L48)
6,7-二氯-N2-环庚基-N3-(3,4-二氟苄基)喹喔啉-2,3-二胺(L49)
N2-(3,4-二氯苯基)-N3-(3,4-二氯苄基)喹喔啉-2,3-二胺(L50)。
7.权利要求1所述的化合物的制备方法,其特征在于,包括如下步骤:
(1)将1当量的R2、R3、R4、R5取代的邻苯二胺与1当量的无水草酸溶解于4当量的盐酸水溶液中,搅拌并加热回流8小时,旋转蒸发,将溶剂蒸干,将残余物用乙醇洗涤并干燥,得到中间体(a);
(2)将中间体(a)溶于氯化亚砜(SOCl2)中,反应混合物在70℃下搅拌回流4小时,调节pH至中性,旋转蒸发,将溶剂蒸干,用正己烷洗涤固体,干燥,得到中间体(b);
(3)将1当量的中间体(b)溶于无水乙醇中,向溶液中加入1当量的芳基或芳杂基甲胺,加热回流8小时,旋转蒸发,将溶剂蒸发干,柱层析分离得到中间体(c);
(4)将1当量的中间体(c)与1当量R1取代的伯胺溶解于二甲基甲酰胺(DMF)中,加入1当量的无水三氯化铝,加热至110℃,搅拌8小时,向溶液中加入一定体积的蒸馏水,乙酸乙酯萃取3次,合并有机层,无水硫酸钠干燥30分钟,过滤取滤液,旋转蒸发,将溶剂蒸发干,得到的固体经柱层析分离得到权利要求1所述的化合物(1);
其中,Ar、R1、R2、R3、R4、R5、n的定义同权利要求1。
8.一种药物组合物,其特征在于,其包括权利要求1-6任一项所述的化合物或其药学上可接受的盐、以及药学上可接受的载体。
9.根据权利要求8的药物组合物,其特征在于,所述的药物组合物选自注射剂、片剂、丸剂、胶囊、悬浮剂、乳剂或软膏,给药途径选自静脉或肌肉注射、口服、经皮给药、粘膜给药、直肠给药、阴道给药。
10.权利要求1-6任一项所述的化合物或其药学上可接受的盐在制备抗菌药物中的应用。
11.根据权利要求10的应用,其特征在于,所述的制备抗菌药物中的应用是指制备治疗或预防细菌、支原体、衣原体、立克次体、螺旋体、真菌所引起的人或动物的感染性疾病的药物中的应用。
12.根据权利要求11的应用,其特征在于,所述的细菌包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌、肺炎链球菌、艰难梭菌、淋病奈瑟菌、大肠埃希菌、铜绿假单胞菌、肺炎克雷伯菌。
13.根据权利要求12的应用,其特征在于,所述的金黄色葡萄球菌包括甲氧西林敏感型金黄色葡萄球菌、甲氧西林耐药金黄色葡萄球菌、万古霉素中度敏感金黄色葡萄球菌,所述的表皮葡萄球菌包括甲氧西林敏感型表皮葡萄球菌、甲氧西林耐药表皮葡萄球菌,所述的粪肠球菌和屎肠球菌包括万古霉素敏感型粪肠球菌和屎肠球菌、万古霉素耐药粪肠球菌和屎肠球菌,所述大肠埃希菌选自非产超广谱β-内酰胺酶的肺炎克雷伯菌、产超广谱β-内酰胺酶的大肠埃希菌,所述肺炎克雷伯菌选自非产超广谱β-内酰胺酶的肺炎克雷伯菌。
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---|
CAS号451523-92-5;CA;REGISTRY;CAS号451523-92-5 * |
Synthesis and Antimicrobial Activity of Some New Substituted Quinoxalines;Mohamed A. El-Atawy等;Molecules;第4198(1-16)页,Scheme 1.、Table 1.、Table 2. * |
Synthesis and Late-Stage Functionalization of Complex Molecules through C−H Fluorination and Nucleophilic Aromatic Substitution;Patrick S. Fier等,;J. Am. Chem. Soc.;第10139−10147页 * |
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