CN109456254A - 1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其制备方法和应用 - Google Patents
1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN109456254A CN109456254A CN201811486551.8A CN201811486551A CN109456254A CN 109456254 A CN109456254 A CN 109456254A CN 201811486551 A CN201811486551 A CN 201811486551A CN 109456254 A CN109456254 A CN 109456254A
- Authority
- CN
- China
- Prior art keywords
- derivative
- compound
- formula
- preparation
- dnj
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 150000001788 chalcone derivatives Chemical class 0.000 title claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 235000013305 food Nutrition 0.000 claims abstract description 14
- 230000000291 postprandial effect Effects 0.000 claims abstract description 13
- 239000008280 blood Substances 0.000 claims abstract description 12
- 210000004369 blood Anatomy 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000000470 constituent Substances 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- -1 amino, phenyl Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000005587 carbonate group Chemical group 0.000 claims description 4
- 230000001276 controlling effect Effects 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- LXBIFEVIBLOUGU-UHFFFAOYSA-N Deoxymannojirimycin Natural products OCC1NCC(O)C(O)C1O LXBIFEVIBLOUGU-UHFFFAOYSA-N 0.000 abstract description 20
- 102100024295 Maltase-glucoamylase Human genes 0.000 abstract description 18
- 108010028144 alpha-Glucosidases Proteins 0.000 abstract description 18
- 229960002632 acarbose Drugs 0.000 abstract description 14
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 238000012360 testing method Methods 0.000 abstract description 8
- 235000021257 carbohydrate digestion Nutrition 0.000 abstract description 7
- 102000004190 Enzymes Human genes 0.000 abstract description 6
- 108090000790 Enzymes Proteins 0.000 abstract description 6
- 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 abstract description 5
- 239000008103 glucose Substances 0.000 abstract description 5
- 230000003389 potentiating effect Effects 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 230000002829 reductive effect Effects 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 150000001789 chalcones Chemical class 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 10
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000011812 mixed powder Substances 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960001729 voglibose Drugs 0.000 description 6
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 201000001421 hyperglycemia Diseases 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229960001110 miglitol Drugs 0.000 description 5
- 239000000837 restrainer Substances 0.000 description 5
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 4
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000013016 Hypoglycemia Diseases 0.000 description 4
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 4
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 235000005513 chalcones Nutrition 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 239000002532 enzyme inhibitor Substances 0.000 description 4
- 229940125532 enzyme inhibitor Drugs 0.000 description 4
- 230000031700 light absorption Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 4
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 4
- 229940013618 stevioside Drugs 0.000 description 4
- 235000019202 steviosides Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IFBHRQDFSNCLOZ-IIRVCBMXSA-N 4-nitrophenyl-α-d-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC1=CC=C([N+]([O-])=O)C=C1 IFBHRQDFSNCLOZ-IIRVCBMXSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 108090000637 alpha-Amylases Proteins 0.000 description 3
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000001573 invertase Substances 0.000 description 3
- 235000011073 invertase Nutrition 0.000 description 3
- 238000004519 manufacturing process 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
- 239000012074 organic phase Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011122 softwood Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000004382 Amylase Substances 0.000 description 2
- 102000013142 Amylases Human genes 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 description 2
- 102100022624 Glucoamylase Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 102000004139 alpha-Amylases Human genes 0.000 description 2
- 229940024171 alpha-amylase Drugs 0.000 description 2
- 235000019418 amylase Nutrition 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- SISAYUDTHCIGLM-UHFFFAOYSA-N bromine dioxide Inorganic materials O=Br=O SISAYUDTHCIGLM-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 235000012149 noodles Nutrition 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 230000011218 segmentation Effects 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KQTFPHGJDWNEQY-TYHBFTGESA-N (9e,13e,17e)-18-bromooctadeca-9,13,17-trien-5,7,15-triynoic acid Chemical compound OC(=O)CCCC#CC#C\C=C\CC\C=C\C#C\C=C\Br KQTFPHGJDWNEQY-TYHBFTGESA-N 0.000 description 1
- ATWLRNODAYAMQS-UHFFFAOYSA-N 1,1-dibromopropane Chemical compound CCC(Br)Br ATWLRNODAYAMQS-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- LXBIFEVIBLOUGU-JGWLITMVSA-N 1-Deoxynojirimycin Natural products OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-JGWLITMVSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- NTIGNJOEVBTPJJ-UHFFFAOYSA-N 3,3-dibromopentane Chemical compound CCC(Br)(Br)CC NTIGNJOEVBTPJJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102400000471 Isomaltase Human genes 0.000 description 1
- 108010059881 Lactase Proteins 0.000 description 1
- BGMYHTUCJVZIRP-UHFFFAOYSA-N Nojirimycin Natural products OCC1NC(O)C(O)C(O)C1O BGMYHTUCJVZIRP-UHFFFAOYSA-N 0.000 description 1
- 108010026867 Oligo-1,6-Glucosidase Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102100029677 Trehalase Human genes 0.000 description 1
- 108010087472 Trehalase Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940116108 lactase Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000000110 microvilli Anatomy 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- BGMYHTUCJVZIRP-GASJEMHNSA-N nojirimycin Chemical compound OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O BGMYHTUCJVZIRP-GASJEMHNSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
- A23L5/10—General methods of cooking foods, e.g. by roasting or frying
- A23L5/13—General methods of cooking foods, e.g. by roasting or frying using water or steam
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L7/00—Cereal-derived products; Malt products; Preparation or treatment thereof
- A23L7/10—Cereal-derived products
- A23L7/104—Fermentation of farinaceous cereal or cereal material; Addition of enzymes or microorganisms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
本发明涉及医药和食品领域,具体涉及1‑脱氧野尻霉素‑羟基查尔酮杂合体衍生物及其制备方法和应用。1‑脱氧野尻霉素‑羟基查尔酮杂合体衍生物具有式(I)所示结构,经体外试验证明,该类化合物为α‑葡萄糖苷酶强效抑制剂,对α‑葡萄糖苷酶的抑制活性显著高于目前最常用的餐后血糖控制剂‑阿卡波糖。其中,DC‑5和DC‑2这两个化合物的活性还显著高于1‑脱氧野尻霉素。由于此类化合物能强效抑制α‑葡萄糖苷酶等糖类消化酶的活性,能够有效地降低餐后血糖,因此在降糖药物和辅助降糖食品中具有非常好的应用前景。
Description
技术领域
本发明涉及医药和食品领域,具体涉及1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其制备方法和应用。
背景技术
根据国际糖尿病联盟(IDF)的统计,2013年全世界糖尿病患者约3.82亿,糖耐量受损者3.16亿,每年耗费了5480亿美元的医疗费用,占总医疗费用的11%;我国约有5000万糖尿病患者,居世界第二位;近年来,由于饮食习惯、生活方式和环境的改变,高血糖和糖尿病患者持续增长,呈现加速上升的趋势。高血糖、糖尿病及其并发症严重损害了人们的身体健康,大大降低了他们的生活质量,同时还给家庭、社会造成了沉重的经济负担。膳食中碳水化合物的消化吸收是影响餐后血糖的关键因素,为了防止餐后高血糖,患者必须控制日常饮食中碳水化合物的摄入量,严重影响了患者的生活质量。服用α-葡萄糖苷酶和淀粉酶等糖类消化酶抑制剂是控制餐后血糖和治疗Ⅱ型糖尿病的首选方法之一,因此研发高活性糖类消化酶抑制剂具有十分重要的意义。
已报道的糖类消化酶抑制剂主要是通过天然产物筛选来发现的,从自然资源特别是具有降糖活性作用的天然动植物和微生物资源中发掘α-葡萄糖苷酶抑制剂,是近几十年来食品和医药研究者开发抑制餐后高血糖新型化合物和功能食品最为常用的方法和手段。目前,国内市场上常见的α-葡萄糖苷酶抑制剂主要有阿卡波糖(Acarbose)、伏格列波糖(Voglibose)和米格列醇(Miglitol),均为低聚糖或单糖结构类似物。阿卡波糖是一种生物合成的假性四糖,能竞争性地抑制小肠上皮刷状缘上的葡萄糖淀粉酶、麦芽糖酶、蔗糖酶及α-淀粉酶,延缓淀粉、蔗糖等的消化吸收,从而达到抑制餐后高血糖的效果。伏格列波糖是一种氨基糖类似物,主要抑制双糖水解酶,如蔗糖酶、麦芽糖酶和异麦芽糖酶,而对淀粉酶的抑制作用较小。米格列醇的抑制作用比阿卡波糖及伏格列波糖更为广泛,对麦芽糖酶、异麦芽糖酶、葡萄糖淀粉酶、蔗糖酶、α-淀粉酶、海藻糖酶及乳糖酶均有抑制效果。
阿卡波糖、伏格列波糖和米格列醇是目前最常见的三种α-葡萄糖苷酶抑制剂,为低聚糖或单糖结构类似物,是竞争性的抑制剂,但这三种抑制剂均可能引起胃肠胀气、腹泻、腹痛等胃肠道反应,伏格列波糖相对较轻;偶有低血糖出现;服用阿卡波糖及伏格列波糖后偶尔会出现转氨酶升高的现象,而米格列醇排泄快,对肝脏无损害。因此,高效、低副作用的新型糖类消化酶抑制剂的研发成为了行业关注的焦点。1-脱氧野尻霉素(1-DNJ)是当前研究较多的一种亚氨基糖类,其具有与葡萄糖类似的化学结构,与α-葡萄糖苷酶的亲和力大于二糖,可阻碍二糖的分解,为强效的竞争性α-葡萄糖苷酶抑制剂,但该物质在体内吸收速度快,很快地被代谢,因此体内抑制餐后血糖升高的效果一般。基于此,研究开发1-脱氧野尻霉素的结构衍生物来发现新的降糖活性成分非常必要。
发明内容
本发明的目的在于提供一系列结构新颖的1-脱氧野尻霉素-羟基查尔酮杂合体衍生物,本发明还提供该衍生物的制备方法,其是以1-脱氧野尻霉素和羟基查尔酮为主要原料,通过化学合成制备得到。本发明提供的上述衍生物,经体外试验证明,该类化合物为强效α-葡萄糖苷酶抑制剂,对α-葡萄糖苷酶的抑制活性显著高于目前最常用的餐后血糖控制剂-阿卡波糖。其中,DC-5和DC-2这两个化合物的活性还显著高于1-脱氧野尻霉素。由于此类化合物能强效抑制α-葡萄糖苷酶等糖类消化酶的活性,能够有效地降低餐后血糖,因此在降糖药物和辅助降糖食品中具有非常好的应用前景。
本发明的上述目的是采用以下技术方案来实现:
本发明提供一种具有式(I)结构的1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其药学上可接受的盐:
其中,M表示C1-C30的直链或者支链的烷基;
R1、R2、R3、R4、R5和R6各自独立地表示氢、卤素原子、羟基、羧基、氨基、苯基、C1-C5的直链或支链烷基或C1-C5的直链或支链的取代烷基;且R1和R2可以各自独立地在苯环任意可能的位置。
需要说明的是,上述的取代烷基上的取代基例如可以是卤素原子、羟基、羧基、氨基和苯基等;M表示C1-C30的直链或者支链的烷基非限制性实施例包括,甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正壬基…,及其各种支链异构体等。
本发明优选方案,所述M为C1-C30的直链烷基;所述R1、R2、R3、R4、R5和R6为氢。在本发明中,1-脱氧野尻霉素母核基团和羟基查尔酮母核基团之间的连接桥的C原子个数,取值为1-30之间的整数,其相对应的30个化合物的命名分别为DC-1、DC-2、DC-3、……、DC-30,以此类推。
进一步优选地,所述衍生物为
经体外实验证明,DC-5和DC-2这两个化合物对α-葡萄糖苷酶的抑制活性显著高于目前最常用的餐后血糖控制剂-阿卡波糖,也显著高于1-脱氧野尻霉素,并且上述化合物在体内可能具有更慢的代谢速度。
本发明还提供一种制备上述衍生物的方法,包括以下步骤:
(1)将式(II)化合物与式(III)化合物进行取代反应制备得到式(IV)化合物;
(2)式(IV)化合物与式(V)化合物进行取代反应得到式(I)化合物;
其中:
X表示卤族元素;
M表示C1-C30的直链或者支链的烷基;
R1、R2、R3、R4、R5和R6各自独立地表示氢、卤素原子、羟基、羧基、氨基、苯基、C1-C5的直链或支链烷基或C1-C5的直链或支链的取代烷基;且R1和R2可以各自独立地在苯环任意可能的位置。
在式(V)化合物中,当R2、R3、R4和R5为氢时,式(V)化合物为1-脱氧野尻霉素(1-DNJ)。
需要说明的是,卤族元素非限制性实施例包括氟、氯、溴、碘;优选地,该卤族元素为溴。
本发明优选方案,步骤(1)所述反应的反应溶剂为丙酮,催化剂为碳酸盐,反应温度为45~90℃。
本发明优选方案,步骤(2)所述反应的溶剂为DMF,催化剂为碳酸盐,反应温度为60~100℃。
本发明还提供含所述衍生物的药物组合物、保健品或食品,其含有至少一种式(I)所述化合物作为活性成分。
本发明的优选方案,其活性成分为DC-2和/或DC-5;在具体的实施方式中,药物组合物的剂型为固体制剂或液体制剂。进一步优选地,所述药物组合物为片剂、胶囊剂或冲剂。
在具体的实施方式中,所提供的药物组合物为片剂,其处方包括:活性成分DC-5和DC-2;辅料:微晶纤维素、环糊精、玉米淀粉、甜菊糖和硬脂酸镁。按活性成分计,片剂的规格为50mg/片。
在另一具体的实施方式中,所提供的药物为胶囊,其处方包括:活性成分DC-5或DC-2,辅料微晶纤维素和环糊精。按活性成分计,胶囊的规格为50mg/个。
在另一具体的实施方式中,所提供的药物组合物为冲剂,其处方包括:活性成分DC-5或DC-2,辅料β-环糊精、甜菊糖和乙醇。
在另一具体的实施方式中,所述食品是以淀粉为主要成分的原料加工而成的制品,例如以各种谷物为原料加工获得的米面制品,例如馒头、面条、蛋糕等等,本发明提供的具体实施例为馒头。
本发明还提供所述衍生物在制备降低餐后血糖或调控血糖的药物、保健品或食品中的应用。
本发明提供的1-脱氧野尻霉素-羟基查尔酮杂合体衍生物的优点:本发明公开的一系列新颖的1-脱氧野尻霉素-羟基查尔酮类衍生物,是α-葡萄糖苷酶等糖类消化酶的强效抑制剂,以其中的一个、两个或多个的组合物为主要活性成分制成药物或制剂可有效地降低餐后血糖或调控血糖,具有非常好的效果。对α-葡萄糖苷酶的抑制活性显著高于目前最常用的餐后血糖控制剂-阿卡波糖。其中,DC-5和DC-2这两个化合物的活性还显著高于1-脱氧野尻霉素。检测结果表明,DC-5的抑制常数Ki仅为阿卡波糖的1/30、1-DNJ的1/8。本发明公开的1-脱氧野尻霉素-羟基查尔酮类衍生物能强效抑制α-葡萄糖苷酶等糖类消化酶的活性,能够有效地降低餐后血糖,因此在降糖药物和辅助降糖食品中具有非常好的应用前景。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。本发明的己知的起始原料可以采用或按照本领域已知的方法来合成。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1:1-脱氧野尻霉素-羟基查尔酮杂合体衍生物的制备(DC-2)
(1)接入连接桥的羟基查尔酮的中间体制备:
往100mL的圆底烧瓶里加入2g(13.5mmol)2’-羟基查尔酮和7.62g(40.5mmol)1,2-二溴乙烷原料,再加入3.7g(27mmol)碳酸钾和50mL丙酮,于65℃的条件下搅拌进行反应,直至反应结束;反应结束后,将上述反应液倒入水中,以20mL乙酸乙酯进行萃取,重复萃取3次,合并有机相;以无水硫酸钠进行干燥,然后脱溶拌样,采用硅胶柱层析法进行分离,洗脱剂为石油醚/乙酸乙酯=20:1,制得接入了2个碳原子的连接桥的羟基查尔酮的中间体;1HNMR(500MHz,DMSO)δ7.77(d,J=3.6Hz,1H),7.76(d,J=2.2Hz,1H),7.61(d,J=3.7Hz,2H),7.58(dd,J=7.5,1.8Hz,1H),7.55–7.52(m,1H),7.45–7.42(m,3H),7.19(d,J=8.4Hz,1H),7.10(t,J=7.3Hz,1H),4.50–4.45(m,2H),3.83–3.79(m,2H).13C NMR(125MHz,DMSO)δ191.96,156.95,142.69,135.13,133.78,130.86,130.51,129.39,129.35,129.08,127.43,121.61,113.66,68.95,31.73.HRMS(ESI)m/z:calcd for C17H15BrO2[M+H]+330.0257,found330.0260。
(2)目标物DC-2的制备:
往100mL的圆底烧瓶中加入1g(3.3mmol)上述中间体和0.5g(3mmol)1-DNJ原料,再加入0.8g(6mmol)碳酸钾和50mL DMF,在80℃条件下连续搅拌,直至反应结束;反应结束后,进行脱溶拌样,然后以硅胶柱层析分离,洗脱剂为二氯甲烷/甲醇=25:2,制得目标化合物DC-2。1H NMR(500MHz,DMSO)δ7.77–7.71(m,2H),7.54(s,1H),7.53(s,2H),7.52(s,1H),7.45(d,J=1.9Hz,1H),7.44(d,J=1.8Hz,2H),7.23(d,J=8.2Hz,1H),7.06(t,J=7.4Hz,1H),4.70(s,3H),4.30–4.17(m,3H),3.78(d,J=11.5Hz,1H),3.53(d,J=9.6Hz,1H),3.22(s,2H),3.04–2.98(m,1H),2.93(d,J=7.0Hz,2H),2.13(s,1H),2.09(s,2H).13C NMR(125MHz,DMSO)δ192.24,157.83,142.52,135.11,133.68,130.84,130.20,129.47,129.37,128.95,127.46,121.10,113.86,79.53,77.60,73.25,70.89,69.24,67.40,65.80,57.52,51.50,45.21.HRMS(ESI)m/z:calcd for C23H27NO6[M+Na]+435.1731,found 435.1744。
实施例2:1-脱氧野尻霉素-羟基查尔酮杂合体衍生物的制备(DC-5)
(1)接入连接桥的羟基查尔酮的中间体制备:
往100mL的圆底烧瓶里加入2g(13.5mmol)2’-羟基查尔酮和9.31g(40.5mmol)1,5-二溴戊烷原料,再加入3.7g(27mmol)碳酸钾和50mL丙酮,于65℃的条件下搅拌进行反应,直至反应结束;反应结束后,将上述反应液倒入水中,以20mL乙酸乙酯进行萃取,重复萃取3次,合并有机相;以无水硫酸钠进行干燥,然后脱溶拌样,采用硅胶柱层析法进行分离,洗脱剂为石油醚/乙酸乙酯=20:1,制得接入了5个碳原子的连接桥的羟基查尔酮的中间体。1HNMR(500MHz,DMSO)δ7.78–7.63(m,2H),7.52(dd,J=14.1,6.3Hz,4H),7.47–7.39(m,3H),7.16(d,J=8.5Hz,1H),7.04(t,J=7.4Hz,1H),4.07(t,J=5.9Hz,2H),3.33(t,J=6.7Hz,2H),1.77–1.60(m,2H),1.55–1.44(m,2H).1.13-1.27(m,2H).13C NMR(125MHz,DMSO)δ192.49,157.79,142.23,135.13,133.70,130.85,130.17,129.42,129.34,128.84,127.76,121.01,113.51,68.42,35.00,32.43,28.39,24.89.HRMS(ESI)m/z:calcd for C20H21BrO2[M+H]+372.0798,found 372.0796.
(2)目标物DC-5的制备:
往100mL的圆底烧瓶中加入1g(2.68mmol)上述中间体和0.4g(2.5mmol)1-DNJ原料,再加入0.69g(5mmol)碳酸钾和50mL DMF,在80℃条件下连续搅拌,直至反应结束;反应结束后,进行脱溶拌样,然后以硅胶柱层析分离,洗脱剂为二氯甲烷/甲醇=25:2,制得目标化合物DC-5。1H NMR(500MHz,DMSO)δ7.72(dd,J=7.1,2.3Hz,2H),7.53(s,1H),7.52(s,1H),7.51(s,1H),7.49(s,1H),7.45(d,J=1.9Hz,1H),7.44(d,J=1.8Hz,1H),7.32–7.26(m,1H),7.18(d,J=8.1Hz,1H),7.06(t,J=7.4Hz,1H),4.75(s,3H),4.09(t,J=6.2Hz,2H),4.04(t,J=6.2Hz,1H),3.64(d,J=10.8Hz,1H),3.55(dd,J=13.1,3.4Hz,1H),3.18(s,1H),3.09(d,J=7.3Hz,1H),2.95(d,J=7.7Hz,1H),2.79(s,1H),2.66(dd,J=8.7,4.1Hz,1H),2.41–2.27(m,1H),2.09(s,2H),1.75–1.67(m,2H),1.39–1.27(m,4H).13C NMR(125MHz,DMSO)δ192.44,157.86,142.31,137.59,135.12,133.68,131.09,130.87,130.37,130.17,129.66,129.45,129.34,129.00,128.82,128.47,127.69,120.98,120.78,113.60,68.66,52.29,49.07,31.13,29.11,23.95.HRMS(ESI)m/z:calcd for C26H33NO6[M+H]+455.2381,found 455.2376。
实施例3:1-脱氧野尻霉素-羟基查尔酮杂合体衍生物的制备(DC-3)
(1)接入连接桥的羟基查尔酮的中间体制备:
往100mL的圆底烧瓶里加入2g(13.5mmol)2’-羟基查尔酮和8.18g(40.5mmol)1,3-二溴丙烷原料,再加入3.7g(27mmol)碳酸钾和50mL丙酮,于65℃的条件下搅拌进行反应,直至反应结束;反应结束后,将上述反应液倒入水中,以20mL乙酸乙酯进行萃取,重复萃取3次,合并有机相;以无水硫酸钠进行干燥,然后脱溶拌样,采用硅胶柱层析法进行分离,洗脱剂为石油醚/乙酸乙酯=20:1,制得接入了3个碳原子的连接桥的羟基查尔酮的中间体;1HNMR(500MHz,DMSO)δ7.74(d,J=3.7Hz,1H),7.73–7.72(m,1H),7.56–7.51(m,3H),7.46(s,1H),7.45–7.42(m,3H),7.20(d,J=8.2Hz,1H),7.08(t,J=7.4Hz,1H),4.20(t,J=5.8Hz,2H),3.56(t,J=6.7Hz,2H),2.23(p,J=6.3Hz,2H).13C NMR(125MHz,DMSO)δ192.46,157.30,142.71,134.96,133.63,130.95,130.17,129.46,129.44,128.92,127.43,121.27,113.49,66.46,32.31,31.47.HRMS(ESI)m/z:calcd for C18H17BrO2[M+H]+344.0485,found344.0482.
(2)目标物DC-3的制备:
往100mL的圆底烧瓶中加入1g(2.90mmol)上述中间体和0.42g(2.6mmol)1-DNJ原料,再加入0.72g(5.2mmol)碳酸钾和50mL DMF,在80℃条件下连续搅拌,直至反应结束;反应结束后,进行脱溶拌样,然后以硅胶柱层析分离,洗脱剂为二氯甲烷/甲醇=25:2,制得目标化合物DC-3。1H NMR(500MHz,DMSO)δ7.73(dd,J=7.2,2.2Hz,2H),7.54–7.53(m,1H),7.52(d,J=3.2Hz,2H),7.51(s,1H),7.45(d,J=2.1Hz,1H),7.44(s,1H),7.32–7.24(m,1H),7.20–7.16(m,1H),7.06(t,J=7.4Hz,1H),4.66(d,J=8.0Hz,3H),4.11(d,J=4.5Hz,2H),4.09(s,1H),3.68(d,J=11.4Hz,1H),3.49(d,J=12.0Hz,1H),3.19(d,J=3.7Hz,1H),3.02(t,J=8.6Hz,1H),2.90(d,J=8.0Hz,2H),2.76(dd,J=11.0,4.7Hz,1H),2.49–2.43(m,1H),2.09(s,2H),1.89(d,J=10.6Hz,2H).13C NMR(125MHz,DMSO)δ192.34,157.84,142.47,135.11,133.68,130.85,130.20,129.46,129.31,128.87,128.44,127.58,121.00,113.65,79.58,71.24,69.82,67.57,67.14,59.61,57.48,49.20,31.13,25.42.HRMS(ESI)m/z:calcd for C24H29NO6[M+Na]+449.1887,found449.1899。
实施例4:药效试验例
为了验证本发明提供的1-脱氧野尻霉素-羟基查尔酮杂合体衍生物对α-葡萄糖苷酶的抑制活性,下面以DC-2和DC-5为例进行试验:
(1)试剂配制
①0.1mmol/L磷酸缓冲液(PB)配制:取4.559g磷酸氢二钾和7.646g磷酸氢二钾,以超纯水溶解,定容至500mL,调pH至6.8,4℃冷藏备用。
②10mmol/L PNPG配制:取PNPG 0.0301g,以PB缓冲液溶解,定容至10mL,4℃冷藏备用。
③α-葡萄糖苷酶:将α-葡萄糖苷酶冻干粉溶于含50%甘油的PB中,配制成100U/mL的酶溶液,分装,-20℃冻存备用。
④待测抑制剂溶液:以DMSO溶解,Triton X-100助溶,PB缓冲液稀释。
(2)PNP测定标准曲线的绘制
吸取不同体积的PNP标准溶液,加入到96孔板中,以PB补足至200μL,得到0、0.15、0.03、0.06、0.15、0.3、0.6、1.5、0.8、3、6、12、24、48、96(×10-6mmol)的系列标准浓度;于405nm波长下测定吸光值;测定设置4个平行,取平均值,以吸光值(OD值)为横坐标,PNP物质的量为纵坐标,绘制测定标准曲线。所得的测定用线性回归方程为Y=48.5782*X,R2=0.999,式中Y表示PNP物质的量,X表示吸光值,R2表示决定系数。
(3)抑制常数Ki的测定
依次往96孔板中加入160μL PB缓冲液、待测样(DC-5终浓度梯度设置为0.04mM、0.02mM、0.012mM;DC-2浓度终浓度梯度设置为为0.2mM、0.1mM、0.06mM;参照物阿卡波糖和1-DNJ终浓度梯度设置为1.0mM、0.5mM、0.3mM)和α-葡萄糖苷酶(1U/mL)10μL,37℃孵育20min;加入PNPG(终浓度分别设置为1.00mM、0.90mM、0.75mM、0.60mM、0.45mM、0.30mM、0.25mM),37℃孵育反应9min,于405nm波长下测定吸光值;每个待测样设置4个平行测试,重复测定3次;按照上述(2)所述的测定回归方程计算PNP的生成速度,据此计算反应速度;采用Lineweaver-Burk方法,计算各待测物的抑制常数Ki。
(4)测定结果
经检测,DC-5、DC-2、阿卡波糖、1-DNJ的抑制常数Ki分别为0.01mM、0.052mM、0.30mM、0.08mM;可见,DC-5和DC-2这两个化合物的活性显著高于1-脱氧野尻霉素和阿卡波糖,且DC-5的抑制常数Ki仅为阿卡波糖的1/30、1-DNJ的1/8。
实施例5:以DC-5为活性成分制备的降糖胶囊
(1)制粒:按2:4:4的质量比例分别称取实施例2制备得到的化合物DC-5化合物、微晶纤维素和环糊精,混匀机中混匀10分钟,置于干法制粒机进行制粒,过20目筛,制得的颗粒用于胶囊灌装;
(2)灌制胶囊:以2号胶囊进行灌装,装量控制在250mg,制得以1-脱氧野尻霉素-羟基查尔酮杂合体衍生物DC-5为主要活性成分的胶囊。
实施例6:以DC-5和DC-2为活性成分制备的降糖片剂
(1)按4:4:2的质量比例分别称取微晶纤维素、环糊精、玉米淀粉,再加入0.18%的甜菊糖,得到混合粉1;
(2)以6:1:1的比例称取上述混合粉1、实施例2制备得到的化合物DC-5和实施例1制备得到的化合物DC-2,混匀得混合粉2;
(3)称取上述混合粉2,加入2%的硬脂酸镁,混匀后得混合粉3;
(4)称取上述混合粉3,按200mg每片的规格压片,制得以1-脱氧野尻霉素-羟基查尔酮杂物DC-5和DC-2为活性成分的片剂。
实施例7:以DC-5为活性成分制备的降糖冲剂
(1)按6:1的质量比例分别称取β-环糊精和实施例2制备得到的DC-5化合物,再称取0.8%甜菊糖,混匀;
(2)以50%的乙醇调整上述混合物料的湿度,制得软材,软材的软硬度以手捏成团、轻压则散为宜。
(3)将制好的上述软材投入到摇摆式颗粒机中,进行造粒;
(4)将上述造好的颗粒过16目筛网,得湿颗粒;
(5)将上述湿颗粒置于干燥机中干燥,80℃干燥20分钟,制得以1-脱氧野尻霉素-羟基查尔酮类杂合体化合物DC-5为主要活性成分的冲剂。
实施例8:以DC-5化合物为活性成分的低血糖生成指数食品的制备
以“低血糖生成指数馒头”为例,制作工艺和主要操作步骤如下:
制作工艺:主辅原料→称量→混合→和面→发酵→压面→分割→整形→醒发→蒸制→成品馒头。
主要操作步骤:
(1)称量、混合:称取面粉2000g、DC-5化合物1.5g,加入20g酵母,混合均匀;
(2)和面:往上述混合粉中加入适量的水,置于和面机中慢速搅拌3分钟,再快速搅拌10分钟;
(3)发酵:将上述和好的面团放置于醒发箱中,在37℃、90%的相对湿度的条件下发酵1小时;
(4)压面:将上述发酵好了的面团置于压面机中,压10次;
(5)分割、整形:将压好的面团分割至适当太小,手搓成型;
(6)醒发:将上述成形的馒头放置于醒发箱中,在37℃、90%的相对湿度的条件下进行醒发,时间为15分钟;
(7)蒸制:将上述醒发好了的生馒头放进沸腾的蒸锅中,蒸制30分钟,制得成品--低血糖生成指数馒头。
以上所描述的实施例是本发明一部分实施例,而不是全部的实施例。本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围,而是仅仅表示本发明的选定实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
Claims (10)
1.一种具有式(I)结构的1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其药学上可接受的盐:
其中,M表示C1-C30的直链或者支链的烷基;
R1、R2、R3、R4、R5和R6各自独立地表示氢、卤素原子、羟基、羧基、氨基、苯基、C1-C5的直链或支链烷基或C1-C5的直链或支链的取代烷基;且R1和R2可以各自独立地在苯环任意可能的位置。
2.根据权利要求1所述衍生物,其特征在于,所述M为C1-C30的直链烷基;所述R1、R2、R3、R4、R5和R6为氢。
3.根据权利要求2所述衍生物,其特征在于,所述衍生物为
4.一种制备权利要求1~3任一项所述衍生物的方法,其特征在于,包括以下步骤:
(1)将式(II)化合物与式(III)化合物进行取代反应制备得到式(IV)化合物;
(2)式(IV)化合物与式(V)化合物进行取代反应得到式(I)化合物;
其中:
X表示卤族元素;
M表示C1-C30的直链或者支链的烷基;
R1、R2、R3、R4、R5和R6各自独立地表示氢、卤素原子、羟基、羧基、氨基、苯基、C1-C5的直链或支链烷基或C1-C5的直链或支链的取代烷基;且R1和R2可以各自独立地在苯环任意可能的位置。
5.根据权利要求4所述的制备方法,其特征在于,步骤(1)所述反应的反应溶剂为丙酮,催化剂为碳酸盐,反应温度为45~90℃。
6.根据权利要求4所述的制备方法,其特征在于,步骤(2)所述反应的溶剂为DMF,催化剂为碳酸盐,反应温度为60~100℃。
7.含权利要求1~4任一项所述衍生物的药物组合物、保健品或食品,其特征在于,含有至少一种式(I)所述化合物作为活性成分。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物为固体制剂或液体制剂,优选地,所述药物组合物为片剂、胶囊剂或冲剂。
9.根据权利要求7所述的食品,其特征在于,所述食品是以淀粉为主要成分的原料加工而成的制品。
10.权利要求1~4任一项所述衍生物在制备降低餐后血糖或调控血糖的药物、保健品或食品中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811486551.8A CN109456254B (zh) | 2018-12-06 | 2018-12-06 | 1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811486551.8A CN109456254B (zh) | 2018-12-06 | 2018-12-06 | 1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109456254A true CN109456254A (zh) | 2019-03-12 |
CN109456254B CN109456254B (zh) | 2020-06-30 |
Family
ID=65612643
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811486551.8A Active CN109456254B (zh) | 2018-12-06 | 2018-12-06 | 1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109456254B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112898300A (zh) * | 2021-01-11 | 2021-06-04 | 河北大学 | 可自组装的苝酰亚胺-野尻毒素类降糖衍生物及其制备方法和应用 |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0437554A1 (en) * | 1989-06-02 | 1991-07-24 | Searle & Co | PHARMACEUTICAL COMPOSITION AND METHOD OF INHIBITING VIRUS. |
CN101108206A (zh) * | 2006-07-17 | 2008-01-23 | 北京北大维信生物科技有限公司 | 一种具有糖苷酶抑制作用的桑白皮提取物的制备方法 |
CN101654428A (zh) * | 2009-09-11 | 2010-02-24 | 成都市金医生科技健康产业有限公司 | 天然产物中提取分离高纯1-脱氧野尻霉素的方法 |
CN101671293A (zh) * | 2009-10-12 | 2010-03-17 | 南开大学 | 蚕沙总生物碱中的α-糖苷酶抑制剂化合物及其应用 |
CN101696186A (zh) * | 2009-10-29 | 2010-04-21 | 同济大学 | 一类1-脱氧野尻霉素衍生物的合成方法 |
CN102166210A (zh) * | 2011-03-22 | 2011-08-31 | 复旦大学 | 1-脱氧野尻霉素衍生物作为α-葡萄糖苷酶抑制剂的应用 |
CN102190615A (zh) * | 2011-04-08 | 2011-09-21 | 长沙华诚生物科技有限公司 | 一种从桑叶中提取分离1-脱氧野尻霉素的方法 |
CN102225907A (zh) * | 2011-05-25 | 2011-10-26 | 同济大学 | 一种含双键的1-脱氧野尻霉素衍生物的合成方法 |
JP2016011350A (ja) * | 2014-06-27 | 2016-01-21 | Jx日鉱日石エネルギー株式会社 | イソブチレン系共重合体およびその製造方法、これを含んでなるゴム組成物および架橋ゴム組成物。 |
CN106748970A (zh) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | N‑芳基‑1‑脱氧野尻霉素衍生物及其在制备治疗糖尿病药物中的应用 |
-
2018
- 2018-12-06 CN CN201811486551.8A patent/CN109456254B/zh active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0437554A1 (en) * | 1989-06-02 | 1991-07-24 | Searle & Co | PHARMACEUTICAL COMPOSITION AND METHOD OF INHIBITING VIRUS. |
CN101108206A (zh) * | 2006-07-17 | 2008-01-23 | 北京北大维信生物科技有限公司 | 一种具有糖苷酶抑制作用的桑白皮提取物的制备方法 |
CN101654428A (zh) * | 2009-09-11 | 2010-02-24 | 成都市金医生科技健康产业有限公司 | 天然产物中提取分离高纯1-脱氧野尻霉素的方法 |
CN101671293A (zh) * | 2009-10-12 | 2010-03-17 | 南开大学 | 蚕沙总生物碱中的α-糖苷酶抑制剂化合物及其应用 |
CN101696186A (zh) * | 2009-10-29 | 2010-04-21 | 同济大学 | 一类1-脱氧野尻霉素衍生物的合成方法 |
CN102166210A (zh) * | 2011-03-22 | 2011-08-31 | 复旦大学 | 1-脱氧野尻霉素衍生物作为α-葡萄糖苷酶抑制剂的应用 |
CN102190615A (zh) * | 2011-04-08 | 2011-09-21 | 长沙华诚生物科技有限公司 | 一种从桑叶中提取分离1-脱氧野尻霉素的方法 |
CN102225907A (zh) * | 2011-05-25 | 2011-10-26 | 同济大学 | 一种含双键的1-脱氧野尻霉素衍生物的合成方法 |
JP2016011350A (ja) * | 2014-06-27 | 2016-01-21 | Jx日鉱日石エネルギー株式会社 | イソブチレン系共重合体およびその製造方法、これを含んでなるゴム組成物および架橋ゴム組成物。 |
CN106748970A (zh) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | N‑芳基‑1‑脱氧野尻霉素衍生物及其在制备治疗糖尿病药物中的应用 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112898300A (zh) * | 2021-01-11 | 2021-06-04 | 河北大学 | 可自组装的苝酰亚胺-野尻毒素类降糖衍生物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN109456254B (zh) | 2020-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Sui et al. | In vitro and in silico studies of the inhibition activity of anthocyanins against porcine pancreatic α-amylase | |
KR101622915B1 (ko) | 프룩토실화 푸에라린 및 이의 제조 방법 및 이의 용도 | |
CN104431883B (zh) | 一种马铃薯渣无面筋蛋白烤馕及加工方法 | |
CN103228668A (zh) | 抗糖尿病的苯基丙酮酸烯醇糖苷 | |
CN102086172A (zh) | 沙格列汀的药用盐及其制备方法 | |
Khan et al. | Peptide conjugates of 18β-glycyrrhetinic acid as potent inhibitors of α-glucosidase and AGEs-induced oxidation | |
CN109456254A (zh) | 1-脱氧野尻霉素-羟基查尔酮杂合体衍生物及其制备方法和应用 | |
CN111773194B (zh) | 一种卡格列净片剂及其制备方法 | |
Zhao et al. | Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors | |
JPH09188625A (ja) | 医薬組成物 | |
CN103936726A (zh) | 晶体、制备方法及其用途 | |
CN109757652A (zh) | 一种青稞产品及其制备方法和用途 | |
CN109232684A (zh) | 17-aag葡萄糖苷及其制备方法和在制备抗肿瘤药物中的应用 | |
CN101015597A (zh) | 厚朴制剂在制备治疗糖尿病和肥胖症药物中的应用 | |
CN103204898B (zh) | 抗癌化合物及其应用 | |
CN110051678A (zh) | 一种预防和/或治疗糖尿病的药物及用途 | |
JP7101781B2 (ja) | Akt阻害剤としての塩形態及びその結晶形態 | |
CN109293564B (zh) | 1-脱氧野尻霉素-羟基肉桂酸甲酯杂合体衍生物及其制备方法和应用 | |
JP5822251B2 (ja) | 抗腫瘍剤、カスパーゼ阻害剤、イボタケ属担子菌抽出物およびその製造方法 | |
WO2021204193A1 (zh) | Sirt1受体激动剂及包含其的药物 | |
CN106397207A (zh) | 树豆酮酸a结构类似物、其组合物及其在药物中的应用 | |
CN105399725B (zh) | 曲格列汀化合物其盐、晶体、药物组合物和用途 | |
CN104610208B (zh) | (1s)‑1,6‑二脱氧‑1‑[4‑甲氧基‑3‑(反式‑4‑正丙基环己基)甲基苯基]‑d‑吡喃葡萄糖的晶型a及其制备方法和应用 | |
CN111214514B (zh) | 续断及续断中活性组分在降糖中的应用 | |
CN110467624B (zh) | 一类黄烷与二苯乙烯类化合物骈合而成的加合物 |
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 |