CN107118176B - N-（5-苄基噻唑-2-基）吗啉基酰胺及其医药用途 - Google Patents
N-（5-苄基噻唑-2-基）吗啉基酰胺及其医药用途 Download PDFInfo
- Publication number
- CN107118176B CN107118176B CN201710319980.5A CN201710319980A CN107118176B CN 107118176 B CN107118176 B CN 107118176B CN 201710319980 A CN201710319980 A CN 201710319980A CN 107118176 B CN107118176 B CN 107118176B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- benzylthiazol
- pharmaceutically acceptable
- present
- amides
- 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.)
- Expired - Fee Related
Links
- -1 N-(5-benzylthiazol-2-yl)morpholino amides Chemical class 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 claims abstract description 6
- 239000002911 sialidase inhibitor Substances 0.000 claims abstract description 6
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 6
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 36
- 239000001257 hydrogen Substances 0.000 abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 8
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 abstract description 6
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 102000005348 Neuraminidase Human genes 0.000 description 7
- 108010006232 Neuraminidase Proteins 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JRXCZLQOJDMBKB-UHFFFAOYSA-N 5-benzyl-1,3-thiazole Chemical compound C=1C=CC=CC=1CC1=CN=CS1 JRXCZLQOJDMBKB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- DYTMLFRCOLHTIO-UHFFFAOYSA-N N-[4-tert-butyl-5-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-yl]-2-chloroacetamide Chemical compound ClCC(=O)NC=1SC(=C(N=1)C(C)(C)C)CC1=CC=C(C=C1)OC DYTMLFRCOLHTIO-UHFFFAOYSA-N 0.000 description 1
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000009459 hedgehog signaling Effects 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- MKQLBNJQQZRQJU-UHFFFAOYSA-N morpholin-4-amine Chemical class NN1CCOCC1 MKQLBNJQQZRQJU-UHFFFAOYSA-N 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- RXHUTPXPHGTYRS-UHFFFAOYSA-N n-[4-tert-butyl-5-[(4-chlorophenyl)methyl]-1,3-thiazol-2-yl]-2-chloroacetamide Chemical compound N1=C(NC(=O)CCl)SC(CC=2C=CC(Cl)=CC=2)=C1C(C)(C)C RXHUTPXPHGTYRS-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及化学结构式Ⅰ所示的N‑（5‑苄基噻唑‑2‑基）吗啉基酰胺及其药学上可接受的盐，以及其在制备流感病毒神经氨酸酶抑制剂中的应用。I式中R选自：氢、C1~C2烷基；R1选自：C1~C2烷基、C3~C4直链烷基或C3~C4支链烷基；R2选自：氢、C1~C2烷基、C3~C4直链烷基；X选自：4‑甲氧基、4‑乙氧基、4‑氟、4‑氯、4‑溴或4‑碘；n选自：1、2、3、4或5。
Description
技术领域
本发明涉及一类化合物及其应用，具体是N-（5-苄基噻唑-2-基）吗啉基酰胺及其在制备流感病毒神经氨酸酶抑制剂的应用。
背景技术
世界发明专利[WO 2014145642A2，2014-9-18公开]描述了一系列以核转录因子Nrf2为靶点的抗癌化合物，其中化合物1对人肺癌细胞A549和H1437的抑制活性评分为B级（5 μM＜IC50＜25 μM）。中国发明专利[CN 103524535A, 2014-1-22公开]描述了刺猬信号通道拮抗剂2，2对表达GRE-荧光素的NIH3T3细胞的IC50为134.3 nM，与阳性对照物维莫德吉接近:
Wittayanarakul等[Medicinal Chemistry Letters, 2010, 1(8): 376-380]描述了化合物3的制备及其与DNA的亲和力:
3
发明内容
本发明解决的技术问题是提供一类N-（5-苄基噻唑-2-基）吗啉基酰胺及其制备方法与用途。
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是提供了一类如结构式Ⅰ所示的N-（5-苄基噻唑-2-基）吗啉基酰胺及其在药学上可接受的盐：
I
式中R选自：C1~C2烷基；R1选自：C1~C2烷基、C3~C4直链烷基或C3~C4支链烷基； R2选自：氢、C1~C2烷基、C3~C4直链烷基；X选自：4-甲氧基、4-乙氧基、4-氟、4-氯、4-溴或4-碘；n选自：1、2、3、4或5。
或R选自：氢、C1~C2烷基；R1选自：C1~C2烷基、C3~C4直链烷基或C3~C4支链烷基；R2选自：C1~C2烷基、C3~C4直链烷基；X选自：4-甲氧基、4-乙氧基、4-氟、4-氯、4-溴或4-碘；n选自：1、2、3、4或5。
进一步的，优选的化合物选自：N-[4-叔丁基-5-(4-氯苄基)噻唑-2-基]-2-吗啉基乙酰胺或N-[4-叔丁基-5-(4-甲氧基苄基)噻唑-2-基]-2-吗啉基乙酰胺。
本发明技术方案的第二方面是提供了N-（5-苄基噻唑-2-基）吗啉基酰胺的制备方法，其特征在于它的制备反应如下：
I
式中R选自：C1~C2烷基；R1选自：C1~C2烷基、C3~C4直链烷基或C3~C4支链烷基；R2选自：氢、C1~C2烷基、C3~C4直链烷基；X选自：4-甲氧基、4-乙氧基、4-氟、4-氯、4-溴或4-碘；n选自：1、2、3、4或5。
或R选自：氢、C1~C2烷基；R1选自：C1~C2烷基、C3~C4直链烷基或C3~C4支链烷基；R2选自：C1~C2烷基、C3~C4直链烷基；X选自：4-甲氧基、4-乙氧基、4-氟、4-氯、4-溴或4-碘；n选自：1、2、3、4或5。
本发明技术方案的第三方面是提供含有第一方面所述化合物及其药学上可接受的盐的药物组合物，该药物组合物含有治疗有效量的本发明的N-（5-苄基噻唑-2-基）吗啉基酰胺及其药学上可接受的盐，以及任选的含有药用载体。其中所述的药用载体指药学领域常用的药用载体；该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物及其药学上可接受的盐与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂组合，制成适于人或动物使用的任何剂型。本发明化合物及其药学上可接受的盐在其药物组合物中的含量通常为0.1%~95 %重量百分比。
本发明化合物及其药学上可接受的盐或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂（包括真溶液和胶体溶液）、乳剂（包括o/w型、w/o型和复乳）、混悬剂、注射剂（包括水针剂、粉针剂和输液）、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂（包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片）、胶囊剂（包括硬胶囊、软胶囊、肠溶胶囊）、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气（粉）雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物及其药学上可接受的盐可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物及其药学上可接受的盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。
为将本发明化合物及其药学上可接受的盐制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明技术方案的第四方面是提供N-（5-苄基噻唑-2-基）吗啉基酰胺（I）及其药学上可接受的盐以及第三方面所述药物组合物在制备流感病毒神经氨酸酶抑制剂方面的应用:
式中R选自：氢、C1~C2烷基；R1选自：C1~C2烷基、C3~C4直链烷基或C3~C4支链烷基；R2选自：氢、C1~C2烷基、C3~C4直链烷基；X选自：4-甲氧基、4-乙氧基、4-氟、4-氯、4-溴或4-碘；n选自：1、2、3、4或5。
有益技术效果：本发明的N-（5-苄基噻唑-2-基）吗啉基酰胺在制备流感病毒神经氨酸酶抑制剂方面的应用。
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例 1
N-[4-叔丁基-5-(4-氯苄基)噻唑-2-基]-2-吗啉基乙酰胺的制备
1 mmol N-[4-叔丁基-5-(4-氯苄基)噻唑-2-基]-2-氯乙酰胺、2 mmol吗啉和1mmol吡啶溶于5 mL四氢呋喃中，室温反应16h，TLC监测；反应结束后，减压脱四氢呋喃，分别用二氯甲烷、饱和食盐水洗，无水硫酸钠干燥，脱溶，加石油醚析出固体，抽滤，石油醚洗，干燥得淡黄色固体N-[4-叔丁基-5-(4-氯苄基)噻唑-2-基]-2-吗啉基乙酰胺，收率73.5 %，m.p. 115~116 ℃；1H NMR（400 MHz，CDCl3）δ：1.36（s，9H，3×CH3），2.61（t，J = 4.4 Hz，4H，吗啉环 2,6-H），3.20（s，2H，COCH2），3.81（t，J = 4.4 Hz，4H，吗啉环 3,5-H），4.21（s，2H，CH2），7.11（d，J = 8.4 Hz，2H，C6H4 2,6-H），7.25（d，J = 8.4 Hz，2H，C6H4 3,5-H）。
实施例 2
N-[4-叔丁基-5-(4-甲氧基苄基)噻唑-2-基]-2-吗啉基乙酰胺的制备
1 mmol N-[4-叔丁基-5-(4-甲氧基苄基)噻唑-2-基]-2-氯乙酰胺、2 mmol吗啉和1 mmol吡啶溶于5 mL四氢呋喃中，室温反应16h，TLC监测；反应结束后，减压脱四氢呋喃，分别用二氯甲烷、饱和食盐水洗，无水硫酸钠干燥，脱溶，加石油醚析出固体，抽滤，石油醚洗，干燥得乳白色固体N-[4-叔丁基-5-(4-甲氧基苄基)噻唑-2-基]-2-吗啉基乙酰胺，收率95.5 %，m.p. 143~144 ℃；1H NMR（400 MHz，CDCl3） δ：1.38（s，9H，3×CH3），2.60（t，J =4.0 Hz，4H，吗啉环 2,6-H），3.18（s，2H，COCH2），3.79（s，3H，OCH3），3.80（t，J = 4.0 Hz，4H，吗啉环 3,5-H），4.18（s，2H，CH2），6.82（d，J = 8.0 Hz，2H，C6H4 3,5-H），7.10（d，J = 8.0Hz，2H，C6H4 2,6-H）。
实施例 3
N-（5-苄基噻唑-2-基）吗啉基酰胺的抗流感病毒神经氨酸酶活性
1. 实验原理
化合物MUNANA是神经氨酸酶的特异性底物，在神经氨酸酶作用下产生的代谢产物在360 nm照射激发下，可产生450 nm荧光，荧光强度的变化可以灵敏地反映神经氨酸酶活性。酶均来自A/PR/8/34（H1N1）病毒毒株。
2. 实验方法
在酶反应体系中，一定浓度样品与流感病毒神经氨酸酶NA悬浮于反应缓冲液中（pH 6.5），加入荧光底物MUNANA启动反应体系，37˚C孵育40分钟后，加反应终止液终止反应。在激发波长360 nm和发射波长为450 nm的参数条件下，测定荧光强度值。根据荧光强度的减少量可以计算化合物对NA活性的抑制率。
3. 检测样品：实施例化合物
4．活性结果
在反应系统中检测浓度40.0 μg/mL时，N-[4-叔丁基-5-(4-氯苄基)噻唑-2-基]-2-吗啉基乙酰胺和N-[4-叔丁基-5-(4-甲氧基苄基)噻唑-2-基]-2-吗啉基乙酰胺对神经氨酸酶的抑制率分别为31%和30%。
N-（5-苄基噻唑-2-基）吗啉基酰胺具有良好的抗流感病毒神经氨酸酶活性，可用于制备流感病毒神经氨酸酶抑制剂。
Claims (1)
1.N-[4-叔丁基-5-(4-氯苄基)噻唑-2-基]-2-吗啉基乙酰胺或N-[4-叔丁基-5-(4-甲氧基苄基)噻唑-2-基]-2-吗啉基乙酰胺及其在药学上可接受的盐在制备流感病毒神经氨酸酶抑制剂中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710319980.5A CN107118176B (zh) | 2017-05-09 | 2017-05-09 | N-（5-苄基噻唑-2-基）吗啉基酰胺及其医药用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710319980.5A CN107118176B (zh) | 2017-05-09 | 2017-05-09 | N-（5-苄基噻唑-2-基）吗啉基酰胺及其医药用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107118176A CN107118176A (zh) | 2017-09-01 |
| CN107118176B true CN107118176B (zh) | 2019-08-06 |
Family
ID=59726644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710319980.5A Expired - Fee Related CN107118176B (zh) | 2017-05-09 | 2017-05-09 | N-（5-苄基噻唑-2-基）吗啉基酰胺及其医药用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107118176B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013052845A1 (en) * | 2011-10-05 | 2013-04-11 | The Board Of Trustees Of The Leland Stanford Junior University | Pi-kinase inhibitors with broad spectrum anti-infective activity |
| CN105055405A (zh) * | 2015-08-31 | 2015-11-18 | 南华大学 | N-（4-烷基-5-苄基噻唑-2-基）卤代烷酰胺作为抗癌药的应用 |
| CN106467498A (zh) * | 2015-08-18 | 2017-03-01 | 湖南大学 | N-（噻唑-2-基）氨基酰胺衍生物及其制备方法与应用 |
-
2017
- 2017-05-09 CN CN201710319980.5A patent/CN107118176B/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013052845A1 (en) * | 2011-10-05 | 2013-04-11 | The Board Of Trustees Of The Leland Stanford Junior University | Pi-kinase inhibitors with broad spectrum anti-infective activity |
| CN106467498A (zh) * | 2015-08-18 | 2017-03-01 | 湖南大学 | N-（噻唑-2-基）氨基酰胺衍生物及其制备方法与应用 |
| CN105055405A (zh) * | 2015-08-31 | 2015-11-18 | 南华大学 | N-（4-烷基-5-苄基噻唑-2-基）卤代烷酰胺作为抗癌药的应用 |
Non-Patent Citations (3)
| Title |
|---|
| N-(4-叔丁基-5-苄基噻唑-2-基)乙酰胺衍生物的合成与抗肿瘤活性;丁娜;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20170315(第3期);正文第30页和第52页表4.3 |
| N-(4-叔丁基-5-苄基噻唑-2-基)氨基乙酰胺的合成与抗肿瘤活性;唐玉婷 等，;《有机化学》;20161212;第37卷(第3期);表1，图2 |
| 新型流感病毒神经氨酸酶抑制剂的设计、合成与初步活性研究;刘瑜;《中国博士学位论文全文数据库 医药卫生科技辑》;20111115;E079-4 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107118176A (zh) | 2017-09-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105777664B (zh) | 2‑(2‑苄亚肼基)噻唑‑5‑羧酸酯及其制备方法与医药用途 | |
| CN105622558B (zh) | 含苯并呋喃环的酰腙衍生物及其制备方法与应用 | |
| CN108440468B (zh) | 2-(苯并呋喃-5-基)苯酚及其作为抗癌药物的应用 | |
| CN105693665B (zh) | 含苯并呋喃环的芳甲酰腙衍生物及其制备方法与医药用途 | |
| CN107987033A (zh) | 香草醛及其异构体在制备na抑制剂中的应用 | |
| CN111153898B (zh) | 硫脲衍生物及其制备方法与应用 | |
| CN108503604A (zh) | (4-烷基-5-酰基-2-噻唑)腙衍生物及其医药用途 | |
| CN107118176B (zh) | N-（5-苄基噻唑-2-基）吗啉基酰胺及其医药用途 | |
| CN105541591B (zh) | 1‑（4‑羟基‑3‑芳基苯基）‑2‑丙酮及其制备方法与应用 | |
| CN105669589B (zh) | 2‑(5‑酰基噻唑‑2‑亚氨基)‑4‑噻唑啉酮及其制备方法与应用 | |
| CN108530439B (zh) | 呋喃甲酰胺衍生物及其制备方法与应用 | |
| CN106188030B (zh) | N-(5-胡椒基噻唑-2-基)二氯酰胺衍生物 | |
| CN107286149A (zh) | N‑（5‑胡椒基噻唑‑2‑基）哌啶基酰胺及其应用 | |
| CN107286147A (zh) | N‑[5‑（1,2,4‑三唑‑1‑基）噻唑‑2‑基]吗啉基酰胺及其医药用途 | |
| CN105777739B (zh) | 萘氨基噻唑甲基喹啉酮衍生物及其医药用途 | |
| CN107011337B (zh) | N-[5-(1,2,4-三唑-1-基)噻唑-2-基]哌啶基酰胺及其医药用途 | |
| CN110229081A (zh) | 2,4-二硝基苯腙衍生物及其制备方法与应用 | |
| CN110950856B (zh) | 8-(苯并呋喃-5-基)苯并噁嗪二酮及其作为抗癌药物的应用 | |
| CN107286115B (zh) | N-(5-芳甲基噻唑-2-基)哌嗪基酰胺及其作为na抑制剂的应用 | |
| CN105541752B (zh) | 2‑(4‑氧代噻唑啉‑2‑亚氨基)噻唑‑4‑乙酸衍生物的制备方法与应用 | |
| CN108864073B (zh) | N-噻唑基吡啶甲酰胺衍生物及其制备方法与应用 | |
| CN110183349B (zh) | 乙二酰腙衍生物及其制备方法与应用 | |
| CN108689961B (zh) | 2-(5-硝基噻唑-2-基)亚氨基-4-噻唑啉酮衍生物及其制备方法与应用 | |
| CN108003152B (zh) | 4-苯基-5-(1,2,4-三唑基)-2-吡啶氨基噻唑衍生物及其医药用途 | |
| CN107141267A (zh) | N‑（5‑酰基噻唑‑2‑基）酰胺及其制备方法与应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190806 Termination date: 20200509 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |