CN111889080B - α-葡萄糖苷酶抑制剂及其应用 - Google Patents
α-葡萄糖苷酶抑制剂及其应用 Download PDFInfo
- Publication number
- CN111889080B CN111889080B CN202010748803.0A CN202010748803A CN111889080B CN 111889080 B CN111889080 B CN 111889080B CN 202010748803 A CN202010748803 A CN 202010748803A CN 111889080 B CN111889080 B CN 111889080B
- Authority
- CN
- China
- Prior art keywords
- alpha
- glucosidase
- cinnamic acid
- magnolol
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 title claims abstract description 23
- 239000003888 alpha glucosidase inhibitor Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000009098 adjuvant therapy Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 108010028144 alpha-Glucosidases Proteins 0.000 abstract description 57
- 102100024295 Maltase-glucoamylase Human genes 0.000 abstract description 55
- 230000005764 inhibitory process Effects 0.000 abstract description 27
- 230000000694 effects Effects 0.000 abstract description 22
- 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 abstract description 13
- 229960002632 acarbose Drugs 0.000 abstract description 13
- 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 abstract description 13
- 125000000217 alkyl group Chemical group 0.000 abstract description 12
- 239000003112 inhibitor Substances 0.000 abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 abstract description 6
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 6
- 150000002367 halogens Chemical class 0.000 abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 239000004480 active ingredient Substances 0.000 abstract description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 40
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- 102000004190 Enzymes Human genes 0.000 description 30
- 108090000790 Enzymes Proteins 0.000 description 30
- 238000000338 in vitro Methods 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 21
- 235000010290 biphenyl Nutrition 0.000 description 20
- VVOAZFWZEDHOOU-UHFFFAOYSA-N magnolol Chemical compound OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 230000002401 inhibitory effect Effects 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000000758 substrate Substances 0.000 description 18
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 14
- 235000013985 cinnamic acid Nutrition 0.000 description 12
- 229930016911 cinnamic acid Natural products 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 10
- 230000003993 interaction Effects 0.000 description 10
- 238000003032 molecular docking Methods 0.000 description 7
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000006911 enzymatic reaction Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000010413 mother solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 3
- -1 aromatic fatty acids Chemical class 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 150000001851 cinnamic acid derivatives Chemical class 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
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 3
- AFDXODALSZRGIH-QPJJXVBHSA-N (E)-3-(4-methoxyphenyl)prop-2-enoic acid Chemical compound COC1=CC=C(\C=C\C(O)=O)C=C1 AFDXODALSZRGIH-QPJJXVBHSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- ANRMAUMHJREENI-UHFFFAOYSA-N 3-[4-(trifluoromethyl)phenyl]prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=C(C(F)(F)F)C=C1 ANRMAUMHJREENI-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 230000009471 action Effects 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000010799 enzyme reaction rate Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229930005346 hydroxycinnamic acid Natural products 0.000 description 2
- DEDGUGJNLNLJSR-UHFFFAOYSA-N hydroxycinnamic acid group Chemical group OC(C(=O)O)=CC1=CC=CC=C1 DEDGUGJNLNLJSR-UHFFFAOYSA-N 0.000 description 2
- 235000010359 hydroxycinnamic acids Nutrition 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 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
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- CPDDDTNAMBSPRN-UHFFFAOYSA-N 3-(4-bromophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=C(Br)C=C1 CPDDDTNAMBSPRN-UHFFFAOYSA-N 0.000 description 1
- GXLIFJYFGMHYDY-UHFFFAOYSA-N 3-(4-chlorophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=C(Cl)C=C1 GXLIFJYFGMHYDY-UHFFFAOYSA-N 0.000 description 1
- ISMMYAZSUSYVQG-UHFFFAOYSA-N 3-(4-fluorophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=C(F)C=C1 ISMMYAZSUSYVQG-UHFFFAOYSA-N 0.000 description 1
- RURHILYUWQEGOS-UHFFFAOYSA-N 3-(4-methylphenyl)prop-2-enoic acid Chemical compound CC1=CC=C(C=CC(O)=O)C=C1 RURHILYUWQEGOS-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 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
- 108010011485 Aspartame Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 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 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 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
- 241001673966 Magnolia officinalis Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 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 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 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 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 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 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 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 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000170 anti-cariogenic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000026 anti-ulcerogenic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 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 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000021258 carbohydrate absorption Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 150000001893 coumarin derivatives Chemical class 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 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 description 1
- 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 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose 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
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 230000006961 mixed inhibition Effects 0.000 description 1
- JBLLRCOZJMVOAE-HSQYWUDLSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methoxy-1h-indole-2-carboxamide Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)C=1NC=2C=CC=C(C=2C=1)OC)C(=O)C=1SC2=CC=CC=C2N=1)[C@@H]1CCNC1=O JBLLRCOZJMVOAE-HSQYWUDLSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- 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 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- KKSDGJDHHZEWEP-SNAWJCMRSA-M trans-3-coumarate Chemical compound OC1=CC=CC(\C=C\C([O-])=O)=C1 KKSDGJDHHZEWEP-SNAWJCMRSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/24—Naturally occurring macromolecular compounds, e.g. humic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F1/00—Treatment of water, waste water, or sewage
- C02F1/28—Treatment of water, waste water, or sewage by sorption
- C02F1/286—Treatment of water, waste water, or sewage by sorption using natural organic sorbents or derivatives thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/40—Aspects relating to the composition of sorbent or filter aid materials
- B01J2220/48—Sorbents characterised by the starting material used for their preparation
- B01J2220/4806—Sorbents characterised by the starting material used for their preparation the starting material being of inorganic character
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/40—Aspects relating to the composition of sorbent or filter aid materials
- B01J2220/48—Sorbents characterised by the starting material used for their preparation
- B01J2220/4812—Sorbents characterised by the starting material used for their preparation the starting material being of organic character
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/40—Aspects relating to the composition of sorbent or filter aid materials
- B01J2220/48—Sorbents characterised by the starting material used for their preparation
- B01J2220/4812—Sorbents characterised by the starting material used for their preparation the starting material being of organic character
- B01J2220/485—Plants or land vegetals, e.g. cereals, wheat, corn, rice, sphagnum, peat moss
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F2101/00—Nature of the contaminant
- C02F2101/30—Organic compounds
- C02F2101/308—Dyes; Colorants; Fluorescent agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hydrology & Water Resources (AREA)
- Engineering & Computer Science (AREA)
- Environmental & Geological Engineering (AREA)
- Water Supply & Treatment (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了α‑葡萄糖苷酶抑制剂及其应用，所述α‑葡萄糖苷酶抑制剂包括具有如下结构式的化合物：
其中，R1独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基或羟基；所述R1位于苯环的邻位、间位或对位。该抑制剂的活性成分为一类肉桂酸‑厚朴酚衍生物，其具有较强的α‑葡萄糖苷酶抑制活性，其抑制活性可达阿卡波糖的25～50倍左右，可用于治疗或辅助治疗II糖尿病，具有良好的潜在医疗保健价值。
Description
技术领域
本发明涉及医药技术领域，具体涉及α-葡萄糖苷酶抑制剂及其应用。
背景技术
糖尿病是一种代谢性、终身性疾病，其并发症严重威胁着人类的健康。糖尿病是由于胰岛素分泌不足等原因而引起蛋白质、脂肪、水和电解质等一系列的代谢紊乱，其中以高血糖为主要标志。近年来，糖尿病的患病率较高，目前已成为继肿瘤、心血管疾病之后第三大类严重危害人类健康的慢性疾病。随着我国经济、社会的迅速发展，膳食结构和生活方式的改变，以及人口老龄化速度的加快，糖尿病的患病率也呈现快速增加的趋势。在糖尿病患病率快速上升的同时，我国糖尿病的知晓率、治疗率及控制率明显偏低。因此，糖尿病已成为一个严重危害我国人群健康的公共卫生问题，对经济社会发展产生越来越严重的影响。
α-葡萄糖苷酶抑制剂已被作为单纯饮食控制不佳II型糖尿病患者的首选降糖药物，以及I型糖尿病患者在使用胰岛素治疗时的首选辅助药物，临床上常用的α-葡萄糖苷酶抑制剂包括阿卡波糖，米格列醇和伏格列波糖等。它通过抑制碳水化合物在小肠内的吸收，降低餐后血糖及胰岛素水平，进而起到控制血糖的作用。近年来，大量临床调查研究表明，α-葡萄糖苷酶抑制剂能够延缓糖耐量异常患者向II型糖尿病转化的进程，并且在调节糖脂代谢、提高胰岛素敏感性、保护胰岛细胞功能及改善糖尿病血管并发症等方面具有更广阔的应用前景。
目前，临床上可选择的α-葡萄糖苷酶抑制剂均为化学合成，虽然有一定的降血糖效果，但其种类少、作用效果有限，因此，研究得到新的高效低毒的α-葡萄糖苷酶抑制剂，为临床应用提供更多的选择仍具有十分重要的意义。
厚朴酚是植物厚朴中的主要成分，因其结构简单且具有较好的生物活性而被广泛研究。厚朴酚具有广泛的生物活性，如抗肿瘤、抑菌、抗溃疡、抗过敏、止痛、消炎和防龋等作用。肉桂酸类化合物是水果、咖啡和葡萄酒中天然存在的芳香脂肪酸，其结构的共同特点是含有一个丙烯酸基团取代的苯环。目前，有研究表明，肉桂酸及其衍生物常作为消炎消肿等药物成分。但目前市场未见以上述药物化合制成的具有抑制α-葡萄糖苷酶活性的药物。然而，尚未有将肉桂酸与厚朴酚的拼合骨架，即肉桂酸-厚朴酚衍生物应用于抑制葡萄糖苷酶中的相关报道。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明提出一类具有肉桂酸-厚朴酚型活性成分的α-葡萄糖苷酶抑制剂，对α-葡萄糖苷酶具有较高的抑制活性。
本发明还提出了上述α-葡萄糖苷酶的应用。
根据本发明的第一方面实施方式的α-葡萄糖苷酶抑制剂，所述α-葡萄糖苷酶抑制剂包括具有如下结构式的化合物：
其中，R1独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基或羟基；
所述R1位于苯环的邻位、间位或对位。
根据本发明实施方式的α-葡萄糖苷酶抑制剂，至少具有以下有益效果：
本发明的抑制剂中的活性成分为一类肉桂酸-厚朴酚衍生物，其具有较强的α-葡萄糖苷酶抑制活性，其抑制活性可达阿卡波糖的25～50倍左右；本发明利用骨架拼接原理将厚朴酚结构与肉桂酸相连，由于两者的作用位点不同，制备得到的肉桂酸-厚朴酚衍生物能够增强抑制活性和提高选择性；该抑制剂的活性成分不仅毒性低，而且能够有效抑制α-葡萄糖苷酶的活性，具有良好的潜在医疗保健价值。
根据本发明的一些实施方式，所述R1独立地选自C1～10烷基、C1～10烷氧基或C1～10卤代烷基。
根据本发明的一些实施方式，所述R1独立地选自C1～4烷基、C1～4烷氧基或C1～4卤代烷基。
根据本发明的一些实施方式，所述R1独立地选自氢原子、羟基、卤素、甲基、甲氧基或三氟甲基。
根据本发明的一些实施方式，以下结构所示的化合物具有最好的α-葡萄糖苷酶抑制效果：
根据本发明的第一方面实施方式的应用，上述α-葡萄糖苷酶抑制剂治疗糖尿病药物的制备中。
根据本发明实施方式的应用，至少具有以下有益效果：本发明的α-葡萄糖苷酶抑制剂对α-葡萄糖苷酶表现出显著的抑制活性，可达阿卡波糖的25～50倍左右。
根据本发明的一些实施方式，所述糖尿病为II型糖尿病。
根据本发明的一些实施方式，所述药物的剂型选自片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、干混悬剂、滴丸剂、干浸膏剂、注射剂或输注剂。
根据本发明的一些实施方式，所述药物还包括药学上可接受的载体。
进一步地，所述药学上可接受的载体是指药学领域常规的药物载体，可以为任意合适的生理学或药学上可接受的药物辅料；优选地，所述药用辅料选自崩解剂、稀释剂、润滑剂、粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂或防腐剂中的至少一种；更优选地，所述崩解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙或藻酸中的至少一种；更优选地，所述稀释剂选自乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙或结晶纤维素中的至少一种；更优选地，所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉或无水硅胶中的至少一种；更优选地，所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素或聚乙烯吡咯烷酮中的至少一种；更优选地，所述湿润剂选自十二烷基硫酸钠；更优选地，所述矫味剂可以为阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇或柠檬酸中的至少一种；更优选地，所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟甲基纤维素或硬脂酸铝凝胶中的至少一种；更优选地，所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯或单硬脂酸甘油酯中的至少一种；更优选地，所述防腐剂选自对羟苯甲酸甲酯或对羟苯甲酸丙酯中的至少一种。
根据本发明的一些实施方式，还提供了一种用于辅助治疗糖尿病的药物，所述药物包括上述α-葡萄糖苷酶抑制剂。
进一步地，所述糖尿病为II型糖尿病。
本文中“C1～10烷基”是指碳原子个数为1至10的烷基，意指包括具有指定碳原子数目的支链和直链的饱和脂族烃基。例如，C1～10，如在“C1～10烷基”中定义为包括在直链或者支链结构中具有1、2、3、4、5、6、7、8、9或者10个碳原子的基团。例如，“C1～10烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基和癸基等。
“C1～4烷基”表示碳原子个数为1至4的烷基，例如包括甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基等。
类似地，“C1～10烷氧基”表示通过氧原子连接的如上文所定义的烷基，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基等。同理，“C1～10卤代烷基”指卤素取代如上文所定义的烷基。
术语“卤素”包括F、Cl、Br或I。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
图1为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的酶动力学图；
图2为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的酶动力学图；
图3为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的酶动力学图；
图4为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的底物动力学双倒数图；
图5为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的底物动力学斜率-浓度关系曲线图；
图6为本发明实施例中肉桂酸-厚朴酚衍生物5h在体外对α-葡萄糖苷酶的底物动力学截矩-浓度关系曲线图；
图7为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的底物动力学双倒数图；
图8为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的底物动力学斜率-浓度关系曲线图；
图9为本发明实施例中肉桂酸-厚朴酚衍生物5i在体外对α-葡萄糖苷酶的底物动力学截矩-浓度关系曲线图；
图10为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的底物动力学双倒数图；
图11为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的底物动力学斜率-浓度关系曲线图；
图12为本发明实施例中肉桂酸-厚朴酚衍生物5j在体外对α-葡萄糖苷酶的底物动力学截矩-浓度关系曲线图；
图13为本发明实施例中肉桂酸-厚朴酚衍生物5j与α-葡萄糖苷酶的相互作用的分子对接图；图中，(a)和(b)为5j与α-葡萄糖苷酶的对接模拟图，(c)显示了5j与活性口袋处的氨基酸残基的结合相互作用。
具体实施方式
为详细说明本发明的技术内容、所实现目的及效果，以下结合实施方式并配合附图予以说明。
实施例1：α-葡萄糖苷酶抑制剂及其制备
本发明实施例中的α-葡萄糖苷酶抑制剂均为肉桂酸-厚朴酚衍生物，肉桂酸-厚朴酚衍生物的结构式为：
其中，R1独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基或羟基；R1位于苯环的邻位、间位或对位。
具体地，在本发明的实施例中，包括如下表1所列出的化合物(分别记做4a～4j和5a～5j)：
表1.肉桂酸-厚朴酚衍生物
在本发明中，“2-”对应苯环的邻位，“3-”对应苯环的间位，“4-”对应苯环的对位。
表1中4a～4j的化合物对应单分子肉桂酸与厚朴酚拼合的如式I所示的化合物，其结构式为：
5a～5j的化合物对应双分子肉桂酸与厚朴酚拼合的如式II所示的化合物，其结构式为：
上表中的化合物可以通过下述步骤制备得到，由于基团对反应的影响，制备的方法有所不同：
制备方法一(适用于制备化合物4a～4g和5a～5g)：在1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)和4-二甲基氨基吡啶(DMAP)存在下，用等摩尔的厚朴酚2将取代的肉桂酸1酯化，可得到肉桂酸-厚朴酚衍生物(4a～4g)。而用双摩尔厚朴酚取代肉桂酸可制得肉桂酸-厚朴酚衍生物(5a～5g)。制备方法一的化学反应式如下所示：
上式中试剂和条件为：(a)EDCI，DMAP，DCM，
4h。
制备方法二(由于肉桂酸中羟基的影响，适用于制备化合物4h～j和5h～j)：首先用叔丁基二甲基氯硅烷(TBSCl)保护羟基肉桂酸3，得到TBSCl保护的肉桂酸x，TBSCl保护的肉桂酸x与不同摩尔厚朴酚2的酯化反应得到中间体y和z，中间体在HF存在下进行脱保护反应，最终分别生成肉桂酸-厚朴酚衍生物4h～j和5h～j。制备方法二的化学反应式如下所示：
上式中试剂和条件：(a)TBSCl，咪唑，DMAP，DMF，
(b)EDCI，DMAP，DCM，
4h；(c)HF，THF，室温，1h。
采用以上典型的合成策略以中等至良好的产率生产肉桂酸-厚朴酚衍生物4a-j和5a-j；以下为化合物的性状、产率、核磁和质谱结果表征：
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl cinnamate(4a,C27H24O3).白色固体；产率68.2％；mp:79-81℃；1H NMR(500MHz,氯仿-d)δ7.67(d,J＝16.0Hz,1H),7.54-7.45(m,2H),7.42-7.35(m,3H),7.29(dd,J＝8.2,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.20(d,J＝8.2Hz,1H),7.04(dd,J＝8.3,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.42(d,J＝15.9Hz,1H),5.95(dddt,J＝40.4,16.7,10.0,6.7Hz,2H),5.17-5.09(m,2H),5.05-4.94(m,2H),3.45(d,J＝6.8Hz,2H),3.30(d,J＝6.7Hz,2H).13C NMR(126MHz,氯仿-d))δ29.74,30.18(d),31.50(d),39.46(d),115.54,116.28,116.56(d),123.05,123.93,128.35,128.96,129.71(d),130.13,130.71(d),131.91,134.04,136.81,137.79,138.72,146.92(d),151.33,165.78,HRMS:calcd for C27H24O3[M+Na]+419.1617,found419.1615。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(p-tolyl)acrylate(4b,C28H26O3).白色固体；产率51.8％；mp:75-77℃,1H NMR(500MHz,氯仿-d)δ7.65(d,J＝16.0Hz,1H),7.38(d,J＝7.8Hz,2H),7.29(dd,J＝8.3,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(dd,J＝8.1,1.7Hz,3H),7.03(dd,J＝8.3,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.37(d,J＝16.0Hz,1H),5.95(dddt,J＝39.9,16.7,9.9,6.7Hz,2H),5.17-5.09(m,2H),5.04-4.96(m,2H),3.45(d,J＝6.8Hz,2H),3.30(d,J＝6.6Hz,2H),2.37(s,3H).13C NMR(126MHz,氯仿-d)δ166.00,146.97(d),141.32,138.64,137.80,136.83,131.89(d),131.33,130.66,130.18,129.67(d),128.37,123.99,123.08,116.41(d),115.48(d),39.46(d),21.56,HRMS:calcd for C28H26O3[M+H]+411.1954,found 411.1953。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-methoxyphenyl)acrylate(4c,C28H26O4).白色固体；产率52.8％；mp:87-88℃,1H NMR(500MHz,氯仿-d)δ7.63(d,J＝15.9Hz,1H),7.47-7.41(m,2H),7.28(dd,J＝8.2,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(d,J＝8.2Hz,1H),7.03(dd,J＝8.3,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.4Hz,3H),6.28(d,J＝16.0Hz,1H),5.95(dddt,J＝37.2,16.7,10.0,6.7Hz,2H),5.18-5.08(m,2H),5.05-4.95(m,2H),3.84(s,3H),3.44(d,J＝6.8Hz,2H),3.32-3.28(m,2H).13CNMR(126MHz,氯仿-d)δ166.16,161.77,151.39,147.04,146.63,138.58,137.81,136.85,131.88(d),130.68,130.23,130.11,129.65(d),126.81,124.07,123.10,116.41(d),115.53,114.39,113.92,55.43,39.46(d),29.74,HRMS:calcd for C28H26O4[M+H]+427.1903,found 427.1900。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-fluorophenyl)acrylate(4d,C27H23FO3).白色固体；产率88.1％；mp:89-90℃,1H NMR(500MHz,氯仿-d)δ7.63(d,J＝16.0Hz,1H),7.50-7.44(m,2H),7.29(dd,J＝8.3,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(d,J＝8.2Hz,1H),7.10-7.02(m,3H),6.97(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.33(d,J＝16.0Hz,1H),5.94(dddt,J＝40.3,16.7,10.0,6.6Hz,2H),5.19-5.08(m,2H),5.04-4.94(m,2H),3.45(d,J＝6.8Hz,2H),3.30(dd,J＝6.6,1.8Hz,2H).13CNMR(126MHz,氯仿-d)δ165.66,151.32,146.90,145.54,138.77,137.79,136.79,131.91(d),130.66,130.28(d),130.10,129.71(d),39.45(d),HRMS:calcd for C28H23FO3[M+H]+415.1703,found 415.1702。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-chlorophenyl)acrylate(4e,C27H23ClO3).白色固体；产率69.9％；mp:78-79℃,1H NMR(500MHz,氯仿-d)δ7.61(d,J＝16.0Hz,1H),7.43-7.39(m,2H),7.37-7.33(m,2H),7.29(dd,J＝8.3,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(d,J＝8.2Hz,1H),7.04(dd,J＝8.3,2.3Hz,1H),6.97(d,J＝2.2Hz,1H),6.89(d,J＝8.3Hz,1H),6.38(d,J＝16.0Hz,1H),5.94(dddt,J＝40.5,16.7,10.0,6.7Hz,2H),5.17-5.09(m,2H),5.03-4.95(m,2H),3.45(d,J＝6.8Hz,2H),3.32-3.27(m,2H).13C NMR(126MHz,氯仿-d)δ165.52,151.31,146.88,145.36,138.80,137.78,136.74(d),132.52,131.92,130.65,130.05,129.73(d),129.49,129.26,123.88,123.00,117.16,116.57,116.24,115.54,39.45(d),HRMS:calcd for C28H23ClO3[M+H]+431.1408,found431.1400。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-bromophenyl)acrylate(4f,C27H23BrO3).白色固体；产率61.1％；mp:100-102℃,1H NMR(500MHz,氯仿-d)δ7.59(d,J＝16.0Hz,1H),7.53-7.50(m,2H),7.36-7.32(m,2H),7.29(dd,J＝8.2,2.2Hz,1H),7.23(d,J＝2.2Hz,1H),7.19(d,J＝8.2Hz,1H),7.04(dd,J＝8.3,2.3Hz,1H),6.97(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.39(d,J＝16.0Hz,1H),5.94(dddt,J＝40.5,16.7,9.9,6.7Hz,2H),5.18-5.09(m,2H),5.07-4.92(m,2H),3.45(d,J＝6.8Hz,2H),3.29(d,J＝6.6Hz,2H).13C NMR(126MHz,氯仿-d)δ165.50,151.30,146.87,145.43,138.81,137.77,136.76,132.95,132.23,131.92,130.65,130.05,129.81-129.63(m),125.10,123.86,122.99,117.28,116.57,116.24,115.54,39.45(d),HRMS:calcd for C28H23BrO3[M+Na]+497.0722,found 497.0722。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-(trifluoromethyl)phenyl)acrylate(4g,C28H23F3O3).白色固体；产率65.6％；mp:74-76℃,1H NMR(500MHz,氯仿-d)δ7.68(s,1H),7.64(d,J＝8.4Hz,5H),7.58(d,J＝8.1Hz,4H),7.30(dd,J＝8.2,2.2Hz,2H),7.24(d,J＝2.2Hz,2H),7.20(d,J＝8.2Hz,2H),7.04(dd,J＝8.2,2.3Hz,2H),6.97(d,J＝2.3Hz,2H),6.89(d,J＝8.2Hz,2H),6.48(d,J＝16.0Hz,2H),5.94(dddt,J＝42.5,16.8,10.0,6.7Hz,4H),5.18-5.09(m,5H),5.04-4.95(m,4H),3.45(d,J＝6.8Hz,4H),3.30(dd,J＝6.7,1.6Hz,4H).13C NMR(126MHz,氯仿-d)δ165.18,151.28,146.80,144.84,138.93,137.76,136.73,131.95,130.64,129.99,129.77(d),128.44,125.93(d),123.78,122.95,119.20,116.61,116.21,115.55,39.45(d),HRMS:calcd forC28H23F3O3[M+H]+465.1672,found 465.1667。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(2-hydroxyphenyl)acrylate(4h,C27H24O4).淡黄色固体；产率85.5％；mp:107-109℃,1H NMR(500MHz,氯仿-d)δ7.97(d,J＝16.0Hz,1H),7.39(dd,J＝7.8,1.6Hz,1H),7.22(dd,J＝9.4,1.8Hz,2H),7.18(d,J＝8.3Hz,1H),7.02(dd,J＝8.2,2.3Hz,1H),6.99(d,J＝2.2Hz,1H),6.91-6.86(m,2H),6.77(dd,J＝8.1,1.1Hz,1H),6.57(d,J＝16.1Hz,1H),5.94(dddt,J＝36.1,16.8,10.0,6.7Hz,2H),5.15-5.09(m,2H),5.03-4.95(m,2H),4.13(d,J＝7.2Hz,1H),3.43(d,J＝6.7Hz,2H),3.29(dd,J＝6.6,1.6Hz,2H).13C NMR(126MHz,氯仿-d)δ166.81,155.51,151.24,146.99,142.54,138.64,137.78,136.84,132.04-131.86(m),130.76,130.28,129.76-129.44(m),124.02,123.06,121.30,120.81,116.90,116.49,116.33,115.56,60.60,39.60,39.28,HRMS:calcd for C27H24O4[M+H]+413.1747,found 413.1741。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(3-hydroxyphenyl)acrylate(4i,C27H24O4).淡黄色固体；产率87.4％；mp:110-112℃,1H NMR(500MHz,氯仿-d)δ7.58(d,J＝16.0Hz,1H),7.28(d,J＝2.2Hz,1H),7.25-7.21(m,2H),7.19(t,J＝8.4Hz,1H),7.02(td,J＝5.2,2.4Hz,2H),6.98(d,J＝2.2Hz,1H),6.92-6.87(m,2H),6.84(dd,J＝8.1,2.5Hz,1H),6.39-6.32(m,1H),5.93(dddt,J＝33.7,16.7,9.9,6.7Hz,2H),5.17-5.08(m,2H),5.03-4.95(m,2H),3.43(d,J＝6.8Hz,2H),3.29(dd,J＝6.5,1.6Hz,2H).13C NMR(126MHz,氯仿-d)δ166.01,156.06,151.24,146.80(d),138.79,137.76,136.79,135.48,131.97(d),130.71,130.14,129.72(d),123.89,122.98,121.11,118.02,116.80,116.55,116.33,115.59,114.63,39.44(d),HRMS:calcd for C27H24O4[M+H]+413.1747,found413.1740。
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl(E)-3-(4-hydroxyphenyl)acrylate(4j,C27H24O4).Light白色固体；产率58.6％；mp:114-116℃,1H NMR(500MHz,氯仿-d)δ7.60(d,J＝15.9Hz,1H),7.38-7.32(m,2H),7.22(d,J＝2.2Hz,1H),7.18(d,J＝8.2Hz,1H),7.03(dd,J＝8.2,2.3Hz,1H),6.98(d,J＝2.2Hz,1H),6.89(d,J＝8.2Hz,1H),6.81-6.76(m,2H),6.24(d,J＝15.9Hz,1H),5.94(dddt,J＝31.3,16.8,10.0,6.7Hz,2H),5.17-5.07(m,2H),5.04-4.94(m,2H),3.43(d,J＝6.7Hz,2H),3.29(d,J＝6.4Hz,2H).13C NMR(126MHz,氯仿-d)δ166.51(d),158.26(d),151.23(d),147.40-146.66(m),138.70(d),137.77,136.80,131.98(d),130.73(d),130.36,130.18(d),129.71(d),126.70(d),124.01,123.07,116.44(d),115.77(dd),113.66(d),39.45(d),HRMS:calcd for C27H24O4[M+H]+413.1747,found 413.1739。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-phenylacrylate)(5a,C36H30O4).白色固体；产率47.3％；mp:124-126℃,1H NMR(500MHz,氯仿-d)δ7.66(d,J＝16.0Hz,2H),7.50(dd,J＝6.6,2.9Hz,4H),7.39(hept,J＝3.7Hz,5H),7.20(dd,J＝4.4,1.9Hz,5H),6.47(d,J＝16.0Hz,2H),5.94(ddt,J＝16.8,10.1,6.7Hz,2H),5.08(q,J＝1.8Hz,1H),5.06-5.00(m,3H),3.39(d,J＝6.7Hz,3H).13C NMR(126MHz,氯仿-d)δ165.46,146.36(d),137.57,137.06,134.27,131.30,130.59,130.25,128.98(d),128.32,122.54,117.32,116.21,39.60,HRMS:calcd for C36H30O4[M+H]+527.2216,found 527.2211。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(p-tolyl)acrylate)(5b,C38H34O4).白色固体；产率50.4％；mp:132-134℃,1H NMR(500MHz,氯仿-d)δ7.64(d,J＝16.0Hz,2H),7.43-7.38(m,4H),7.22-7.15(m,10H),6.41(d,J＝15.9Hz,2H),5.94(ddt,J＝16.8,10.0,6.7Hz,2H),5.09-5.00(m,4H),3.43-3.36(m,4H),2.38(s,6H).13CNMR(126MHz,氯仿-d)δ165.66,146.49,141.05,137.47,137.08,131.56,131.29,130.27,129.66,128.96,128.32,122.58,116.19(d,J＝4.2Hz),39.60,21.56,HRMS:calcd forC38H34O4[M+H]+555.2529,found 555.2523。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-methoxyphenyl)acrylate)(5c,C38H34O6).白色固体；产率40.1％；mp:123-125℃,1H NMR(500MHz,氯仿-d)δ7.61(d,J＝15.9Hz,2H),7.49-7.43(m,4H),7.18(d,J＝2.0Hz,5H),6.93-6.87(m,4H),6.33(d,J＝15.9Hz,2H),5.93(ddt,J＝16.7,9.9,6.7Hz,2H),5.10-4.99(m,4H),3.84(s,5H),3.38(dd,J＝6.7,1.5Hz,4H).13C NMR(126MHz,氯仿-d)δ165.78,161.59,146.55,145.91,137.38,137.11,131.28,130.32,130.02,128.91,127.07,122.59,116.14,114.78,114.34,55.43,39.59,HRMS:calcd for C38H34O6[M+H]+587.2428,found587.2421。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-fluorophenyl)acrylate)(5d,C36H28F2O4).白色固体；产率44.2％；mp:121-122℃,1H NMR(500MHz,氯仿-d)δ7.60(d,J＝16.0Hz,2H),7.53-7.44(m,4H),7.23-7.15(m,6H),7.11-7.04(m,4H),6.38(d,J＝16.0Hz,2H),5.94(ddt,J＝16.8,10.0,6.7Hz,2H),5.08(q,J＝1.7Hz,1H),5.06-5.00(m,3H),3.39(dt,J＝6.7,1.5Hz,4H).13C NMR(126MHz,氯仿-d)δ165.29,146.42,144.91,137.60,137.03,131.30,130.52(d),130.20(d),129.00,122.48,117.06(d),116.19,116.03,39.58,HRMS:calcd for C36H28F2O4[M+H]+563.2028,found 563.2021。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-chlorophenyl)acrylate)(5e,C36H28Cl2O4).淡黄色固体；产率37.6％；mp:150-154℃,1H NMR(500MHz,氯仿-d)δ7.58(d,J＝16.0Hz,2H),7.46-7.40(m,4H),7.35(d,J＝8.5Hz,4H),7.24-7.15(m,6H),6.42(d,J＝15.9Hz,2H),5.94(ddt,J＝16.8,9.9,6.7Hz,2H),5.08(q,J＝1.7Hz,1H),5.06-5.00(m,3H),3.39(d,J＝6.7Hz,4H).13C NMR(126MHz,氯仿-d)δ165.17,146.38,144.78,137.66,137.01,136.52,132.73,131.30,130.20,129.34(d),129.03,122.46,117.87,116.22,39.57,HRMS:calcd for C36H28Cl2O4[M+H]+595.1437,found 595.1429。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-bromophenyl)acrylate)(5f,C36H28Br2O4).白色固体；产率53.9％；mp:158-159℃,1H NMR(500MHz,氯仿-d)δ7.56(d,J＝15.9Hz,2H),7.53-7.49(m,4H),7.38-7.33(m,4H),7.23-7.15(m,6H),6.43(d,J＝16.0Hz,2H),5.93(ddt,J＝16.8,10.0,6.7Hz,2H),5.08(q,J＝1.7Hz,1H),5.06-5.01(m,3H),3.39(d,J＝6.4Hz,4H).13C NMR(126MHz,氯仿-d)δ165.16,146.37,144.85,137.68,137.00,133.15,132.20,131.30,130.18,129.65,129.04,124.91,122.45,117.98,116.23,39.57,HRMS:calcd for C36H28Br2O4[M+H]+683.0427,found 683.0419。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-(trifluoromethyl)phenyl)acrylate)(5g,C38H28F6O4).白色固体；产率39.3％；mp:125-127℃,1H NMR(500MHz,氯仿-d)δ7.64(d,J＝8.1Hz,5H),7.60(t,J＝8.6Hz,5H),7.24-7.17(m,6H),6.54(s,1H),6.51(s,1H),5.94(ddt,J＝16.8,10.0,6.7Hz,2H),5.09(q,J＝1.7Hz,1H),5.07-5.01(m,3H),3.40(dd,J＝6.8,1.6Hz,4H).13C NMR(126MHz,氯仿-d)δ164.84,146.31,144.33,137.84,137.56,136.97,131.32,130.15,129.11,128.40,125.92(q),122.41,119.86,116.27,39.57,HRMS:calcd for C38H28F6O4[M+K]+701.1523,found701.1516。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-(trifluoromethyl)phenyl)acrylate)(5h,C36H30O6).白色固体；产率38.5％；mp:168-170℃,1H NMR(500MHz,DMSO-d6)δ10.34(s,2H),7.90(d,J＝16.1Hz,2H),7.58(dd,J＝7.9,1.7Hz,2H),7.26(ddd,J＝8.6,7.2,1.7Hz,2H),7.22(dd,J＝8.3,2.1Hz,2H),7.18(d,J＝8.2Hz,2H),7.13(d,J＝2.1Hz,1H),6.92(dd,J＝8.2,1.1Hz,2H),6.84(td,J＝7.6,1.2Hz,2H),6.62(d,J＝16.1Hz,2H),5.91(ddt,J＝16.9,10.0,6.8Hz,1H),5.05(dq,J＝17.0,1.7Hz,2H),4.97(dt,J＝10.0,1.6Hz,1H),3.36(d,J＝7.3Hz,4H).13C NMR(126MHz,DMSO-d6)δ165.92,157.55,146.59,142.33,137.69(d),132.64,131.21,130.22,129.52(d),123.58,120.94,119.93,116.58(t),HRMS:calcd for C36H30O6[M+H]+559.2115,found559.2108。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(3-hydroxyphenyl)acrylate)(5i,C36H30O6).淡黄色固体；产率47.5％；mp:181-182℃,1H NMR(500MHz,DMSO-d6)δ9.70(s,2H),7.57(d,J＝16.0Hz,2H),7.27-7.18(m,6H),7.17-7.10(m,4H),7.03(t,J＝2.1Hz,2H),6.86(dd,J＝8.3,2.4Hz,2H),6.52(d,J＝16.0Hz,2H),5.92(ddt,J＝16.8,10.0,6.8Hz,2H),5.05(dq,J＝17.0,1.7Hz,2H),4.98(dq,J＝10.0,1.4Hz,2H),3.37(s,4H).13C NMR(126MHz,DMSO-d6)δ165.29,158.22,146.67(d),137.78,135.47,131.23,130.52,130.16,129.49,123.48,119.94,118.54,117.24,116.58,115.26,HRMS:calcd for C36H30O6[M+H]+559.2115,found559.2109。
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl(2E,2'E)-bis(3-(4-hydroxyphenyl)acrylate)(5j,C36H30O6).白色固体；产率35.8％；mp:175-176℃,1H NMR(500MHz,DMSO-d6)δ10.11(s,2H),7.61-7.51(m,6H),7.21(dd,J＝8.4,2.1Hz,2H),7.17(d,J＝8.2Hz,2H),7.12(d,J＝2.2Hz,2H),6.83-6.78(m,4H),6.39(d,J＝15.9Hz,2H),5.90(ddt,J＝16.8,10.0,6.8Hz,2H),5.04(dq,J＝17.0,1.7Hz,2H),4.96(dq,J＝9.8,1.4Hz,2H),3.36(s,4H).13C NMR(126MHz,DMSO-d6)δ165.75,160.70,146.76(d),137.67(d),131.14(d),130.27,129.39,125.36,123.57,116.44(d),113.50,HRMS:calcd for C36H30O6[M+H]+559.2115,found 559.2109。
实施例2：化合物的α-葡萄糖苷酶抑制活性测试
一、微孔板法验证α-葡萄糖苷酶体外抑制活性：
1.1原理：α-葡萄糖苷酶催化水解4-硝基苯-α-D-吡喃葡萄糖苷(PNPG)，产生硝基苯酚(PNP，黄色物质，在405nm有最大吸收)，α-葡萄糖苷酶抑制剂可抑制α-葡萄糖苷酶与底物结合从而降低PNP的释放量，以一定时间内反应体系中PNP的含量变化来计算提取物的酶抑制活性。
(1)100mM pH6.8的磷酸缓冲液(PBS)的配制：分别取17.907g的磷酸氢二钠和6.804g的磷酸二氢钾混合溶解，然后加去离子水定容至1L，用pH计测定pH值。
(2)肉桂酸-厚朴酚系列衍生物溶液的配制：称取一定量的系列肉桂酸-厚朴酚衍生物加到二甲基亚砜(DMSO)溶液当中进行溶解，制得浓度为10mM的母液，然后根据所需浓度用100mM pH6.8的磷酸缓冲液进行稀释，实验当中DMSO的终浓度不超过5％。
(3)pNPG溶液的配制：准确称取0.006025g pNPG溶解于20mL的pH6.8的PBS中充分溶解，即得1mM的pNPG母液。
α-葡萄糖苷酶溶液的配制：将酶活力为100U的酶加适量100mM的PBS配成工作浓度分别为0.075U/mL、0.1U/mL、0.125U/mL、0.15U/mL并分装冷冻。
阿卡波糖溶液的配制：准确称取阿卡波糖0.06456g，置于10mL容量瓶中，
然后用100mM pH6.8的PBS溶液定容至刻度，即得到10mM的母液。
1.2实验步骤
(1)肉桂酸-厚朴酚衍生物4a～4j和5a～5j的α-葡萄糖苷酶抑制活性测定，具体步骤为：将10μLα-葡萄糖苷酶(终浓度为0.1U/mL)和10μL测试化合物添加到130μL PBS(0.1M磷酸盐，pH6.8)中，并将混合物在37℃下孵育10分钟。然后将PNPG(终浓度为0.25mM)添加到该混合物中，并使用Microplate reader测定其在405nm处的吸光度变化。所有实验均进行了四次测定。还分别测定了母体化合物肉桂酸和厚朴酚的α-葡萄糖苷酶抑制作用，以及阳性样品阿卡波糖的α-葡萄糖苷酶抑制作用。每种化合物的IC50值可从抑制率对化合物浓度的曲线得出。
(2)待测化合物的α-葡萄糖苷酶抑制活性根据如下公式计算：
抑制率抑制率(％)＝[((A1-A0)/A0]×100％，
其中A1和A0分别代表测试化合物和空白的吸光度变化，数据处理：使用MS Excel分析处理数据，并用Origin 9.1计算得到半数抑制浓度(IC50)，IC50代表在所述实验条件下，α-葡萄糖苷酶的活性被抑制50％时所需待测化合物的浓度。
1.3结果分析
本发明实施例应用体外酶学实验对合成得到的化合物进行α-葡萄糖苷酶抑制活性评价，结果表明，大多数衍生物均表现出优异的α-葡萄糖苷酶抑制活性，IC50的范围值为5.11±1.46至85.52±1.83μM。其中的阳性对照药阿卡波糖IC50为259.90±1.06μM。筛选出三个具有较好的α-葡萄糖苷酶抑制活性的衍生物(5h、5i、5j)，它们的抑制率分别是9.99±1.68μM、8.87±1.27μM、5.11±1.46μM，表明这些小分子化合物在与α-葡萄糖苷酶相互作用时表现出较强的结合亲和力。
由此可以推知，此类肉桂酸-厚朴酚型结构的化合物具有较好的α-葡萄糖苷酶抑制活性，且其毒性低、安全性高。
化合物与α-葡萄糖苷酶的体外抑制活性评价结果如下表2所示：
表2.化合物的α-葡萄糖苷酶体外抑制活性结果
二、体外酶动力学实验：
采用体外酶动力学实验对合成得到的活性化合物进行α-葡萄糖苷酶抑制活性动力学评价。
2.1试剂与标准溶液的配制
(1)100mM pH6.8的磷酸缓冲液(PBS)的配制：分别取17.907g的磷酸氢二钠和6.804g的磷酸二氢钾混合溶解，然后加去离子水定容至1L，用pH计测定pH值。
(2)系列肉桂酸-厚朴酚衍生物溶液的配制：称取一定量的系列肉桂酸-厚朴酚衍生物加到二甲基亚砜(DMSO)溶液当中进行溶解，制得浓度为10mM的母液，然后根据所需浓度用100mM pH6.8的磷酸缓冲液进行稀释，实验当中DMSO的终浓度不超过5％。
(3)pNPG溶液的配制：准确称取0.006025g pNPG溶解于20mL的pH6.8 PBS中充分溶解，即得1mM的pNPG母液。
α-葡萄糖苷酶溶液的配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度分别为0.075U/mL、0.1U/mL、0.125U/mL、0.15U/mL并分装冷冻。
阿卡波糖溶液的配制：准确称取阿卡波糖0.06456g，置于10mL容量瓶中，
然后用100mM pH6.8 PBS溶液定容至刻度，即得到10mM的母液。
2.2实验步骤
(1)根据先前的报告分析了动力学机理。选择了具有最强抑制活性的衍生物5h，5i和5j作为测试化合物。在5h，5i或5j存在的情况下，在405nm处测量了混合物α-葡萄糖苷酶(终浓度0.075、0.1、0.125和0.15U/mL)和PNPG(终浓度0.25mM)的吸光度变化。然后通过酶促反应速率与α-葡萄糖苷酶浓度的关系图确定抑制的类型。
(2)数据处理：使用MS Excel，Origin9.1分析处理数据，酶反应体系的反应速率为△OD/min。
2.3结果分析
通常根据抑制剂的类型，酶抑制剂可分为可逆抑制剂和不可逆抑制剂。不可逆抑制：在相同的抑制剂浓度下，酶浓度增加曲线的斜率不变，不同抑制剂浓度曲线相互平行。相反，可逆抑制剂被定义为多条曲线相交于原点。为了获得酶抑制剂与酶结合的原理，有必要研究酶抑制剂与酶的相互作用。选择有着最低IC50的化合物5h
5i/>
和5j/>
进行抑制动力学的研究，酶反应速率(V)vsα-葡萄糖苷酶生成一系列曲线。以5h为例分析，在不同浓度的5h存在下，改变酶的浓度，通过绘制不同浓度下剩余酶活性相对于酶的直线。图1～3分别为绘制出的5h、5i和5j的在体外对α-葡萄糖苷酶的酶动力学图，如图1至图3所示，所有的直线都有良好的线性关系，都经过原点。此外，图1中随着5h浓度的增加，直线的斜率逐渐减小。显然，5h的存在并没有改变酶的数量，而是降低了酶的活性。上面的结果清楚地表明，香豆素衍生物的抑制机制α-葡萄糖苷酶是可逆的。从图1～3可以看出，5i和5j属于类似于5h的可逆抑制。
三、体外底物动力学实验：
采用体外底物动力学实验对合成得到的活性化合物进行α-葡萄糖苷酶抑制活性动力学评价。
3.1试剂与标准溶液的配制
(1)100mM pH6.8的磷酸缓冲液(PBS)的配制：分别取17.907g的磷酸氢二钠和6.804g的磷酸二氢钾混合溶解，然后加去离子水定容至1L，用pH计测定pH值。
(2)系列肉桂酸-厚朴酚衍生物溶液的配制：称取一定量的系列肉桂酸-厚朴酚衍生物加到二甲基亚砜(DMSO)溶液当中进行溶解，制得浓度为10mM的母液，然后根据所需浓度用100mM pH6.8的磷酸缓冲液进行稀释，实验当中DMSO的终浓度不超过5％。
(3)pNPG溶液的配制：准确称取0.006025g pNPG溶解于20mL的pH6.8 PBS中充分溶解，即得1mM的pNPG母液。
α-葡萄糖苷酶溶液的配制：将酶活力为100U的酶加适量100mM PBS配成工作浓度分别为0.075U/mL、0.1U/mL、0.125U/mL、0.15U/mL并分装冷冻。
阿卡波糖溶液的配制：准确称取阿卡波糖0.06456g，置于10mL容量瓶中，
然后用100mM pH6.8 PBS溶液定容至刻度，即得到10mM的母液。
3.2实验步骤
(1)对于5h，5i和5j的抑制模式，在405nm下测量了α-葡萄糖苷酶(终浓度0.1U/mL)和PNPG(终浓度0.25、0.5、0.75、1mM)混合物的吸光度变化。5h，5i或5j。然后通过酶反应速率对PNPG浓度的Lineweaver-Burk图获得抑制模式。常数KI通过斜率与化合物浓度的关系图计算得出，常数KIS通过截距与化合物浓度的关系图计算得出。
(2)数据处理：使用MS Excel，Origin 9.1分析处理数据，酶反应体系的反应速率为△OD/min。
3.3结果分析
据报道，抑制剂的抑制类型可根据双倒数作图法的得到的Lineweaver-Burk直线来判断。象限内直线相交为混合抑制，平行或不相交为反竞争抑制，Y轴上直线相交为竞争抑制，X轴上直线相交为非竞争抑制。分别在存在5h，5i或5j的条件下，使用酶反应速率与PNPG浓度的Lineweaver-Burk双倒数图进一步研究了5h，5i和5j的抑制动力学行为。图4、7和10分别为5h、5i和5j在体外对α-葡萄糖苷酶的底物动力学双倒数图，从图4、7和10可以看出，这些图在第二象限中给出了具有不同斜率的直线相交的曲线，这表明5h，5i和5j的抑制动力学行为是混合类型。也就是说5h，5i和5j可以与游离酶以及酶-底物复合物结合以抑制α-葡萄糖苷酶的催化活性。同时，通过图5、8和11的底物动力学斜率-浓度关系曲线图，计算了抑制剂与游离酶(KI)，以及通过图6、9和12的底物动力学截矩-浓度关系曲线图计算得到化合物5h，5i和5j和酶-底物复合物(KIS)结合的平衡常数，并如表2所示。KI值高于KIS值，表明5h，5i和5j与游离酶的亲和力低于与酶-底物复合物的亲和力。同时，根据图4～12可以得知，化合物5h、5i、5j抑制常数KI分别为15.78、4.08、23.48。
四、分子对接模拟：
采用分子对接(Molecular docking)的方法分析活性化合物5h、5i、5j与α-葡萄糖苷酶的相互作用规律。
使用Sybyl 2.1.1(USA)和Pymol软件进行了分子对接研究，以了解α-葡萄糖苷酶酶和衍生物5j之间的结合相互作用，并具有最佳抑制活性。图13中(a)和(b)给出了α-葡萄糖苷酶酶和衍生物5j之间的对接模拟图，揭示了5j很好地插入了与活性位点残基相互作用的酶的活性口袋中。图13中(c)显示了5j与活性口袋处的氨基酸残基的结合相互作用。一种羟基肉桂酸的氢原子与氨基酸Asp215形成两个氢键相互作用。其他羟基肉桂酸的氢原子与氨基酸Lys156形成氢键相互作用，氧原子与氨基酸Ser241形成氢键相互作用。此外，在一种羟基肉桂酸的苯环与该蛋白质的Tyr158残基之间发现了π-π堆积相互作用。
本说明书的实施例，合成了一系列的肉桂酸-厚朴酚衍生物4a～j和5a～j，并确定了它们对α-葡萄糖苷酶的活性。结果表明，大多数合成的衍生物对α-葡萄糖苷酶表现出显著的抑制活性。特别是化合物5h、5i和5j表现出最强的α-葡萄糖苷酶抑制作用，IC50值分别为9.99±1.68μM、8.87±1.27μM、5.11±1.46μM，是阿卡波糖的25～50倍左右。
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书及附图内容所作的等同变换，或直接或间接运用在相关的技术领域，均同理包括在本发明的专利保护范围内。
Claims (6)
1. α-葡萄糖苷酶抑制剂，其特征在于，所述α-葡萄糖苷酶抑制剂包括具有如下结构式的化合物：
其中，R1为-CF3；
所述R1位于苯环的对位。
2.权利要求1所述的α-葡萄糖苷酶抑制剂在制备治疗糖尿病药物中的应用。
3.根据权利要求2所述的应用，其特征在于，所述糖尿病为II型糖尿病。
4.根据权利要求2所述的应用，其特征在于，所述药物还包括药学上可接受的载体。
5.一种用于辅助治疗糖尿病的药物，其特征在于，所述药物包括如权利要求1所述的α-葡萄糖苷酶抑制剂。
6.根据权利要求5所述的药物，其特征在于，所述糖尿病为II型糖尿病。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010748803.0A CN111889080B (zh) | 2020-07-30 | 2020-07-30 | α-葡萄糖苷酶抑制剂及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010748803.0A CN111889080B (zh) | 2020-07-30 | 2020-07-30 | α-葡萄糖苷酶抑制剂及其应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111889080A CN111889080A (zh) | 2020-11-06 |
| CN111889080B true CN111889080B (zh) | 2023-06-13 |
Family
ID=73182621
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010748803.0A Active CN111889080B (zh) | 2020-07-30 | 2020-07-30 | α-葡萄糖苷酶抑制剂及其应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111889080B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010202536A (ja) * | 2009-02-27 | 2010-09-16 | Erina Co Inc | 脂肪細胞分化促進剤、その促進剤を含有する糖尿病治療剤、その促進剤を含有する脂肪細胞分化促進用機能性食品及び健康食品 |
| US20160374944A1 (en) * | 2011-05-19 | 2016-12-29 | Rakesh Srivastava | Compositions and methods for treating and preventing cancer by targeting and inhibiting cancer stem cells |
| CN108997121A (zh) * | 2018-07-10 | 2018-12-14 | 中国科学院昆明植物研究所 | 厚朴酚衍生物在制备治疗中枢神经系统疾病药物中的应用 |
-
2020
- 2020-07-30 CN CN202010748803.0A patent/CN111889080B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010202536A (ja) * | 2009-02-27 | 2010-09-16 | Erina Co Inc | 脂肪細胞分化促進剤、その促進剤を含有する糖尿病治療剤、その促進剤を含有する脂肪細胞分化促進用機能性食品及び健康食品 |
| US20160374944A1 (en) * | 2011-05-19 | 2016-12-29 | Rakesh Srivastava | Compositions and methods for treating and preventing cancer by targeting and inhibiting cancer stem cells |
| CN108997121A (zh) * | 2018-07-10 | 2018-12-14 | 中国科学院昆明植物研究所 | 厚朴酚衍生物在制备治疗中枢神经系统疾病药物中的应用 |
Non-Patent Citations (2)
| Title |
|---|
| Structure–activity relationships of trans-cinnamic acid derivatives on a-glucosidase inhibition;Sirichai Adisakwattana et al.;《Bioorganic & Medicinal Chemistry Letters》;20041231;表1 * |
| α-葡萄糖苷酶抑制剂的筛选及其对糖尿病大鼠糖吸收抑制作用的研究;朱庆亚;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20111215;第44页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111889080A (zh) | 2020-11-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yoshioka et al. | Studies on hindered phenols and analogs. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation | |
| Scozzafava et al. | Carbonic anhydrase inhibitors. A general approach for the preparation of water-soluble sulfonamides incorporating polyamino− polycarboxylate tails and of their metal complexes possessing long-lasting, topical intraocular pressure-lowering properties | |
| AU2021205040B2 (en) | Compounds effective in treating hepatotoxicity and fatty liver diseases and uses thereof | |
| RU2431634C2 (ru) | Соединения флавоноидов и их применение | |
| CN101444496B (zh) | 用于治疗代谢失调的化合物 | |
| US20080221204A1 (en) | Materials and Methods for Treating Coagulation Disorders | |
| CN108635350A (zh) | 治疗血管渗漏综合征的方法 | |
| EP3838887B1 (en) | 2-(1-acyloxypentyl) benzoic acid salt formed by basic amino acid or aminoguanidine, preparation method therefor and uses thereof | |
| TW201607949A (zh) | 供治療代謝症候群或發炎性疾病的呲喃苯并吡喃基苯酚衍生物及醫藥組成物 | |
| EP0810221A1 (en) | Oxygen-containing heterocyclic derivatives | |
| US9695181B2 (en) | Hydroximic acid derivatives and medical applications therof | |
| CN111889080B (zh) | α-葡萄糖苷酶抑制剂及其应用 | |
| CN107151236B (zh) | 一种2,3-环氧丁二酰衍生物及其制备方法和用途 | |
| JP2008506722A (ja) | シス−１，２−置換スチルベン誘導体、および糖尿病の治療および／または予防のための薬剤の製造におけるそれらの使用 | |
| CN105732561A (zh) | 高异黄酮芳酸及芳酸酯类衍生物、其制备方法和医药用途 | |
| CN110305143A (zh) | 一种呋喃[2，3-c]并吡啶衍生物及其制备方法和用途 | |
| CN109793739A (zh) | 一种喹喔啉酮衍生物的结构、制备方法及用途 | |
| CN109956868A (zh) | 一类苯基羧酸衍生物、其制备方法及其用途 | |
| US7145020B2 (en) | Materials and methods for treating coagulation disorders | |
| CN111116452B (zh) | 具有α-葡萄糖苷酶抑制活性的吲哚酮类衍生物及其制备方法与应用 | |
| CN111057036A (zh) | 一种香豆素衍生物及其制备方法与应用 | |
| CN107586284A (zh) | 一种2‑芳基苯并呋喃类衍生物在制备痛风药物中的用途 | |
| CN110563690A (zh) | 树豆酮酸a结构类似物、其组合物及其在药物中的应用 | |
| CN112168817A (zh) | 3-芳基香豆素类化合物的应用 | |
| CN102070608A (zh) | 4-取代苯胺基-7-取代烷氧基-喹唑啉衍生物、其制备方法和用途 |
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 | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240502 Address after: Room 801, 85 Kefeng Road, Huangpu District, Guangzhou City, Guangdong Province Patentee after: Guangzhou Dayu Chuangfu Technology Co.,Ltd. Country or region after: China Address before: No.22, Dongcheng village, Pengjiang district, Jiangmen City, Guangdong Province Patentee before: WUYI University Country or region before: China Patentee before: INTERNATIONAL HEALTHCARE INNOVATION INSTITUTE (JIANGMEN) |