CN113717143A - 一类瑞香素衍生物的合成方法和应用 - Google Patents
一类瑞香素衍生物的合成方法和应用 Download PDFInfo
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- CN113717143A CN113717143A CN202110816357.7A CN202110816357A CN113717143A CN 113717143 A CN113717143 A CN 113717143A CN 202110816357 A CN202110816357 A CN 202110816357A CN 113717143 A CN113717143 A CN 113717143A
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- daphnetin
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- chloride
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- ATEFPOUAMCWAQS-UHFFFAOYSA-N 7,8-dihydroxycoumarin Chemical class C1=CC(=O)OC2=C(O)C(O)=CC=C21 ATEFPOUAMCWAQS-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000010189 synthetic method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- -1 Boc group Chemical group 0.000 claims abstract description 17
- YBGKGTOOPNQOKH-UHFFFAOYSA-N daphnetin Natural products OC1=CC=CC2=C1OC(=O)C=C2O YBGKGTOOPNQOKH-UHFFFAOYSA-N 0.000 claims abstract description 17
- 102100024295 Maltase-glucoamylase Human genes 0.000 claims abstract description 16
- 108010028144 alpha-Glucosidases Proteins 0.000 claims abstract description 16
- 230000000694 effects Effects 0.000 claims abstract description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001408 amides Chemical class 0.000 claims abstract description 10
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 7
- 238000006266 etherification reaction Methods 0.000 claims abstract description 6
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 13
- 239000012153 distilled water Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000012544 monitoring process Methods 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 claims description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 5
- 229940125773 compound 10 Drugs 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 5
- 229960001680 ibuprofen Drugs 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 229920006395 saturated elastomer Chemical class 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 4
- OFTKFKYVSBNYEC-UHFFFAOYSA-N 2-furoyl chloride Chemical compound ClC(=O)C1=CC=CO1 OFTKFKYVSBNYEC-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 claims description 3
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- 238000004440 column chromatography Methods 0.000 claims 2
- 230000005764 inhibitory process Effects 0.000 abstract description 10
- 238000012216 screening Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
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- 239000002994 raw material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 239000010410 layer Substances 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
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- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229960002632 acarbose Drugs 0.000 description 3
- 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 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 241000934856 Daphne Species 0.000 description 1
- 241001163443 Daphne giraldii Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 208000016097 disease of metabolism Diseases 0.000 description 1
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- 230000002068 genetic effect Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 239000005017 polysaccharide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
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- 210000003296 saliva Anatomy 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域。本发明公开了一种瑞香素衍生物及其制备方法和医药用途,涉及结构通式(I)所示的7‑OH、8‑OH位取代的瑞香素衍生物,该衍生物通过瑞香素与N‑Boc溴乙胺发生醚化反应得到中间体II,中间体II再与三氟乙酸反应脱去Boc基团得到中间体III,中间体III再与能够改善化合物的生物利用度的取代基团发生酰胺缩合反应制备得到。经活性筛选试验证明,本发明的化合物具备α‑葡萄糖苷酶抑制作用,且活性优于原料瑞香素,具有治疗II型糖尿病的相关医用用途,且本发明提供的瑞香素衍生物的制备方法步骤简单,条件温和,可操作性和可控性较强。现有技术没有公开过本发明衍生物及其制备方法和医药用途。
Description
技术领域
本发明属于天然药物化学领域,涉及新的天然化合物衍生物,具体涉及一种瑞香素衍生物及其制备方法和医药用途。
背景技术
糖尿病是全球常见的临床疾病,严重威胁着人类的健康。目前已经成为公共卫生系统的一大挑战,虽然许多科学家致力于开发新的治疗方法用于治疗糖尿病,但它仍然是全球关注的临床热点和难点。糖尿病是一种由多种疾病引起的以慢性高血糖为特征的终身性代谢疾病,分为I型糖尿病和II型糖尿病,I型或II型糖尿病均具有遗传特性。研究表明,餐后高血糖水平是导致II型糖尿病发展和发展的主要因素。近年来,大量的治疗II型糖尿病药物被研发,其中大部分都是天然产物或其衍生物。
瑞香素又名祖师麻甲素,是从植物祖师麻中提取的有效成分,主要存在于瑞香科属植物中,具有消炎镇痛、抑制α-葡糖糖苷酶的药理作用。但是由于瑞香素存在着水溶性差、生物利用度低、稳定性差等局限,使得瑞香素在医药上的应用受到限制。所以本发明决定以天然植物中的有效成分为先导物进行结构修饰,对瑞香素进行结构改造修饰,以期望获得稳定性更好、生物利用度更高的化合物。
本发明通过对瑞香素进行结构修饰,得到了一系列衍生物。并通过初步的药理实验基本达到了上述目的,有望为治疗II型糖尿病提供相关的医药用途且具有良好的应用前景。
发明内容
本发明的目的之一在于提供一类瑞香素衍生物。
本发明的另一目的是提供上述一类瑞香素衍生物的制备方法。
本发明的又一目的是提供上述瑞香素衍生物的医药用途。
为了实现上述发明目的,本发明提供了一类结构通式(I)所示的7-OH、8-OH位取代的瑞香素衍生物,并通过α-葡糖糖苷酶抑制活性筛选,发现大多数化合物具有良好的体外活性,可作为进一步开发为α-葡糖糖苷酶抑制剂的前体化合物。
本发明提供的7-OH、8-OH位取代的瑞香素衍生物用结构通式(I)表示:
结构通式(I)中,取代基R选自下列能够改善化合物生物利用度的取代基团化合物:苯甲酰氯、丙酰氯、噻吩甲酰氯、丁酰氯、环丙基甲酰氯、呋喃甲酰氯、乙酰氯、布洛芬、川芎嗪、吡啶;
其中:化合物1:R1=R2=苯甲酰基;化合物2:R1=R2=丙酰基;
化合物3:R1=R2=噻吩甲酰基;化合物4:R1=R2=丁酰基;
化合物5:R1=R2=环丙基甲酰基;化合物6:R1=R2=呋喃甲酰基;
化合物7:R1=R2=乙酰基;
化合物8:R1=H、R2=2-(4-异丁基苯)丙酰基;
化合物9:R1=H、R2=2,3,5-三甲基吡嗪甲酰基;
化合物10:R1=H、R2=2-吡啶甲酰基;
本发明中7-OH、8-OH取代瑞香素衍生物制备方法包括:醚化反应,酰胺缩合反应。
本发明还提供了上述瑞香素7-OH、8-OH衍生物的制备方法,它包括如下操作步骤:
步骤a、瑞香素与N-Boc溴乙胺发生醚化反应,得到如下结构式所示的中间体II;
步骤b、中间体II与三氟乙酸反应脱去Boc基团,使氨基裸露出来,得到如下结构式所示中间体III;
步骤c、中间体III再与上述连接基团发生酰胺缩合反应制备化合物1-化合物7;
步骤d、中间体III再与上述连接基团发生酰胺缩合反应制备化合物8-化合物10;
优选地,步骤a中醚化反应条件包括:以碘化钾(KI)为催化剂,以碳酸钾(K2CO3) 作碱,反应温度为80℃。
更优选地,步骤a包括:首先将瑞香素(1eq)、K2CO3(3eq)和KI(0.1eq)溶于无水DMF中,磁力搅拌。80℃加热40min后缓慢滴加N-Boc溴乙胺(3eq),之后在80℃下回流反应,回流装置顶端加N2保护装置。待TLC监测反应进程;反应完成后,先加入适量稀盐酸搅拌中和至酸性,再用乙酸乙酯萃取三次,收集乙酸乙酯层;乙酸乙酯层再用蒸馏水、饱和食盐水各洗涤三次,无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经过硅胶柱色谱分离纯化,得到中间体II。
优选地,步骤b中脱Boc反应条件包括:以三氟乙酸(CF3COOH)为脱Boc基团试剂,常温反应。
更优选地,步骤b包括:取上述中间体II(1eq)置于单颈烧瓶中,采用CH2Cl2溶解后,再加入过量CF3COOH(30eq),放置室温搅拌反应2h,TLC板监测反应进程;待反应完成后,缓慢加入饱和NaHCO3溶液调至反应溶液为碱性,再用正丁醇萃取,收集正丁醇层;正丁醇层采用蒸馏水,饱和食盐水洗涤三次,收集正丁醇层用无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经过硅胶柱色谱分离纯化,得到中间体III。
优选地,步骤c中酰胺缩合反应条件包括:以三乙胺(Et3N)为碱,常温反应。
更优选地,步骤c包括:将中间体III(1eq)溶于二氯甲烷(CH2Cl2)置于单口烧瓶中,加入Et3N(3eq),缓慢加入不同取代基的酰氯化物(1.5eq),将混合物在室温反应8h,用 TLC板监测反应进程;待反应完成后,收集CH2Cl2层;CH2Cl2层采用蒸馏水,饱和食盐水各洗涤三次,收集CH2Cl2层用无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经过硅胶柱色谱分离纯化,得到目标化合物1-化合物7。
优选地,步骤d中酰胺缩合反应条件包括:以1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)、1-羟基苯并三唑(HOBt)为缩合剂,N,N-二异丙基乙胺(DIPEA)为碱,常温反应。
更优选地,步骤d包括:在单口圆底烧瓶(50mL)中,加入EDCI(1.5eq),HOBt(1.5eq), DIPEA(2.5eq),取代羧酸(1eq),并用N,N-二甲基甲酰胺(DMF)溶解上述化合物,置于室温反应1h,然后将上述中间体III(1eq)溶于DMF中再加入到反应体系中,TLC板监测反应结束后,加水淬灭并稀释,用乙酸乙酯萃取3次,合并乙酸乙酯层,用蒸馏水、饱和食盐水各洗涤三次,最后用无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经过硅胶柱色谱分离纯化,得到目标化合物8-化合物10。
本发明所制备的7-OH、8-OH位取代的瑞香素衍生物在开发成α-葡萄糖苷酶抑制剂及在慢性高血糖等疾病方面的预防和治疗,是以α-葡萄糖苷酶抑制活性的筛选为载体,以此来评价化合物治疗II型糖尿病的活性。
化合物的α-葡萄糖苷酶抑制活性的筛选采用α-葡萄糖苷酶(购买自西格玛奥德里奇(上海)贸易有限公司)。
本发明所制备的7-OH、8-OH位取代的瑞香素衍生物,经α-葡萄糖苷酶活性筛选,部分化合物在20μmol/L浓度下仍表现出较明显的抑制活性。
根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明技术思想的前提下,还可以做出其他多种形式的修改,替换和变更。
以下通过实施例对上述内容作进一步补充说明,但不应该理解为本发明范围仅限于以下实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
通过以下实施例以更好的说明本发明。但本发明不受下述实施例的限制。
工艺流程如下所示,制备方法中的“室温”或“rt”均指代“常温”:
实施例1
化合物1的合成
(1)中间体II的合成
称取瑞香素(178mg,1mmol)和无水碳酸钾(K2CO3,414mg,3mmol),碘化钾(KI,16.6mg,0.1mmol)加入到圆底烧瓶中,100mL N,N-二甲基甲酰胺(DMF)做为溶剂,回流装置顶端加N2保护装置,磁力搅拌。80℃加热40min后缓慢滴加N-Boc溴乙胺(508.7μL,3 mmol),回流反应72h,待TLC板监测反应结束后,终止反应。将反应混合物放置室温缓慢冷却,加入20mL蒸馏水稀释,并加入3mol/L稀盐酸调至酸性,用乙酸乙酯萃取,收集乙酸乙酯层,用蒸馏水、饱和食盐水各洗涤三次,收集有机层,用无水硫酸钠干燥,抽滤回收溶剂得粗产品。用石油醚∶乙酸乙酯=3∶1(V∶V)为洗脱剂硅胶柱层析得到黄色固体物(134.4 mg,0.4mmol),产率:40%。
(2)中间体III的合成
取上述中间体II(134.4mg,0.4mmol)置于单颈烧瓶中(50mL),加入二氯甲烷(6mL)溶解后,再加入过量三氟乙酸(CF3COOH,174μL,12mmol),放置室温搅拌反应2h,TLC 板监测反应进程,待反应结束后,慢慢加入饱和NaHCO3溶液调至反应溶液为碱性。用正丁醇萃取,收集正丁醇层,用蒸馏水、饱和食盐水各洗涤三次,收集有机层用无水硫酸钠干燥,抽滤回收溶剂得粗产品,用二氯甲烷∶甲醇=10∶1(V∶V)为洗脱剂硅胶柱层析得到淡黄色固体(66mg,0.3mmol),产率:75%。
(3)化合物1的合成
将中间体III(66mg,0.3mmol)溶于10mL CH2Cl2置于单口烧瓶(50mL)中,加入三乙胺(75μL,0.9mmol),缓慢加入苯甲酰氯(0.45mmol),将混合物在室温反应8h,用TLC 板监测反应进程,待反应结束后,用蒸馏水、饱和食盐水各洗涤二氯甲烷层三次,收集二氯甲烷层用无水硫酸钠干燥,抽滤回收溶剂得粗产品。粗产物经硅胶柱色谱(氯仿∶丙酮=10∶1,V∶V)纯化得到白色固体产物纯品。总产率:20.0%,熔点:140-142℃。GF254nm硅胶板薄层展开为一点。1H-NMR(600MHz,CDCl3):δH 8.14(m,2H),7.77(dd,J=8.1,1.4Hz,2H),7.72(d, J=9.6Hz,1H),7.62(td,J=7.4,1.2Hz,1H),7.45(t,J=7.6Hz,3H),7.38(t,J=7.6Hz,2H),7.29(d,J=8.4Hz,1H),7.16(d,J=8.4Hz,1H),6.43(d,J=9.6Hz,1H),4.42(t,J=4.9Hz,2H). 13C-NMR(150MHz,CDCl3):δC167.50,164.48,159.37,147.92,146.39,143.45,138.34,134.29, 133.99,131.39,130.29,128.86,128.45,128.16,127.12,122.70,119.47,118.17,116.12,73.46, 40.11.HR-ESI-MS:m/z 430.1284[M+H]+(calcd for C25H20NO6,430.1284).
实施例2
化合物2的合成
参照实施例1,步骤3用丙酰氯代替苯甲酰氯,其他条件与实施例1相同,制得白色固体产物纯品。总产率:21.5%,熔点:160-162℃。GF254nm硅胶板薄层展开为一点。1H-NMR(500MHz,CDCl3):δH 7.69(d,J=9.6Hz,1H),7.23(d,J=8.5Hz,1H),7.02(d,J=8.5Hz,1H),6.40(d,J=9.6Hz,1H),4.23(t,J=5.0Hz,2H),3.63(q,J=5.2Hz,2H),2.67(q,J=7.5Hz,2H), 2,31(q,J=7.6Hz,2H),1.30(t,J=7.6Hz,3H),1.18(t,J=7.6Hz,3H).13C-NMR(125MHz, CDCl3):δC174.27,172.12,159.32,147.91,146.36,143.44,138.28,122.68,119.35,117.99,116.01, 73.57,39.61,29.64,27.54,9.81,9.09.ESI-MS:m/z 356.1[M+Na]+(calcd for C17H19NNaO6, 356.1).
实施例3
化合物3的合成
参照实施例1,步骤3用噻吩甲酰氯代替苯甲酰氯,其他条件与实施例1相同,制得白色固体产物纯品。总产率:20.5%,熔点:126-130℃。GF254nm硅胶板薄层展开为一点。1H-NMR (600MHz,CDCl3):δH 7.96(dd,J=3.8,1.2Hz,1H),7.72(d,J=9.6Hz,1H),7.66(dd,J=5.0,1.2 Hz,1H),7.57(dd,J=3.8,1.0Hz,1H),7.44(dd,J=5.0,1.1Hz,1H),7.28(d,J=8.5Hz,1H), 7.18(d,J=8.5Hz,1H),7.14(dd,J=5.0,3.8Hz,1H),7.04(dd,J=5.0,3.8Hz,1H),6.43(d,J= 9.6Hz,1H),4.41(t,J=4.8Hz,2H),3.76(q,J=5.2Hz,2H).13C-NMR(150MHz,CDCl3):δC 162.06,159.74,159.41,147.87,145.92,143.47,138.93,138.27,135.62,134.55,131.15,130.14, 128.41,128.10,127.67,122.67,119.47,118.22,116.16,73.49,40.00.ESI-MS:m/z 464.1[M+ Na]+(calcd for C21H15NNaO6S2,464.1).
实施例4
化合物4的合成
参照实施例1,步骤3用丁酰氯代替苯甲酰氯,其他条件与实施例1相同,制得白色固体产物纯品。总产率:23.5%,熔点:155-160℃。GF254nm硅胶板薄层展开为一点。1H-NMR(500MHz,CDCl3):δH 7.74(d,J=9.6Hz,1H),7.28(d,J=8.5Hz,1H),7.07(d,J=8.4Hz,1H),6.45(d,J=9.5Hz,1H),4.28(t,J=4.9Hz,2H),3.68(q,J=5.1Hz,2H),2.66(t,J=7.4Hz,2H), 2.31(t,J=7.5Hz,2H),1.86(p,J=7.4Hz,2H),1.75(p,J=7.4Hz,2H),1.12(t,J=7.4Hz,3H), 1.00(t,J=7.4Hz,3H).13C-NMR(125MHz,CDCl3):δC 173.64,171.40,159.42,148.03,146.45, 143.57,138.43,122.80,119.52,118.10,116.12,73.76,39.71,38.68,36.08,19.29,18.58,13.91, 13.77.HR-ESI-MS:m/z 362.1600[M+H]+(calcd forC19H24NO6,362.1598).
实施例5
化合物5的合成
参照实施例1,步骤3用环丙基甲酰氯代替苯甲酰氯,其他条件与实施例1相同,制得白色固体产物纯品。总产率:27.6%,熔点:166-170℃。GF254nm硅胶板薄层展开为一点。1H-NMR(600MHz,CDCl3):δH 7.72(d,J=9.6Hz,1H),7.25(d,J=8.5Hz,1H),7.06(d,J=8.5Hz,1H),6.42(d,J=9.5Hz,1H),4.28(t,J=4.9Hz,2H),3.68(q,J=5.2Hz,2H),1.94(tt,J=8.3, 4.6Hz,1H),1.59(tt,J=7.9,4.6Hz,1H),1.24(dt,J=6.9,3.6Hz,2H),1.13(dq,J=7.6,4.2Hz, 2H),0.98(dt,J=6.6,3.4Hz,2H),0.76(dq,J=7.2,3.9Hz,2H).13C-NMR(150MHz,CDCl3):δC 173.94,172.75,159.43,147.83,146.32,143.53,138.36,122.63,119.40,117.94,115.93,73.70, 39.81,14.61,12.82,9.74,7.25.ESI-MS:m/z 380.1[M+Na]+(calcd for C19H19NNaO6,380.1).
实施例6
化合物6的合成
参照实施例1,步骤3用呋喃甲酰氯代替苯甲酰氯,其他条件与实施例1相同,制得白色固体产物纯品。总产率:24.1%,熔点:178-180℃。GF254nm硅胶板薄层展开为一点。1H-NMR (600MHz,CDCl3):δH 7.72(d,J=9.6Hz,1H),7.65(d,J=1.7Hz,1H),7.42(m,2H),7.28(t,J= 4.3Hz,2H),7.17(d,J=8.5Hz,1H),7.09(d,J=3.4Hz,1H),6.56(dd,J=3.6Hz,1.7Hz,1H), 6.48(dd,J=3.5,1.8Hz,1H),6.44(d,J=9.6Hz,1H),4.41(t,J=5.0Hz,2H),3.79(q,J=5.3Hz, 2H).13C-NMR(150MHz,CDCl3):δC 159.30,158.46,155.86,147.90,147.79,147.70,145.46, 144.08,143.33,142.92,138.41,122.65,120.55,119.26,118.27,116.26,114.11,112.46,111.88, 73.37,39.29.ESI-MS:m/z 432.1[M+Na]+(calcdfor C21H15NNaO8,432.1).
实施例7
化合物7的合成
参照实施例1,步骤3用乙酰氯代替苯甲酰氯,其他条件与实施例1相同,制得白色固体产物纯品。总产率:30.0%,熔点:140-145℃。GF254nm硅胶板薄层展开为一点。1H-NMR(600MHz,CDCl3):δH 7.69(d,J=9.6Hz,1H),7.24(d,J=8.5Hz,1H),7.02(d,J=8.4Hz,1H),6.40(d,J=9.6Hz,1H),4.23(t,J=4.9Hz,2H),3.62(q,J=5.2Hz,2H),2.37(s,3H),2.08(s,3H). 13C-NMR(150MHz,CDCl3):δC 170.76,168.68,159.44,147.96,146.28,143.59,138.36,122.87, 119.41,118.17,116.15,73.58,39.86,23.35,20.88.ESI-MS:m/z 328.1[M+Na]+(calcd for C15H15NNaO6,328.1).
实施例8
化合物8的合成
参照实施例1,步骤1和步骤2相同,步骤3为在单口圆底烧瓶(50mL)中,加入EDCI(86mg,0.45mmol),HOBt(61mg,0.45mmol),DIPEA(131μL,0.75mmol),布洛芬(0.45 mmol),并用6mL DMF溶解上述化合物,置于室温反应1h,然后将步骤2得到的中间体III (66mg,0.3mmol)溶于8mL DMF中再加入到反应体系中,TLC板监测反应结束后,加水淬灭并稀释,用乙酸乙酯萃取3次,合并乙酸乙酯层,用蒸馏水洗涤,再用饱和食盐水洗涤,最后用无水硫酸钠干燥,抽滤回收溶剂得到粗产品,粗产物经过硅胶柱色谱(石油醚∶乙酸乙酯=1∶1,V∶V)纯化得到淡黄色固体产物纯品。总产率:11.4%,熔点:120-122℃。GF254nm 硅胶板薄层展开为一点。1H-NMR(600MHz,CDCl3):δH 7.64(d,J=9.5Hz,1H),7.25(d,J=8.0 Hz,2H),7.15(d,J=7.9Hz,2H),7.11(d,J=8.5Hz,1H),6.92(d,J=8.5Hz,1H),6.19(d,J=9.5 Hz,1H),4.28(m,2H),3.70(q,J=7.2Hz,1H),3.53(m,2H),2.47(d,J=7.1Hz,2H),1.87(dp,J =13.6,6.8Hz,1H),1.59(d,J=7.2Hz,3H),0.89(d,J=6.6Hz,6H).13C-NMR(150MHz, CDCl3):δC 177.11,160.73,153.84,147.52,144.37,141.05,137.97,133.86,129.81,127.52,123.35, 113.48,112.46,111.90,75.56,46.82,45.01,40.95,30.17,22.41,18.52.ESI-MS:m/z 432.2[M+ Na]+(calcd for C24H27NNaO5,432.2).
实施例9
化合物9的合成
参照实施例8,步骤3用川芎嗪代替布洛芬,其他条件与实施例8相同,制得白色固体产物纯品。总产率:15.2%,熔点:215-220℃。GF254nm硅胶板薄层展开为一点。1H-NMR(600MHz,CDCl3):δH 7.62(d,J=9.4Hz,1H),7.09(d,J=8.6Hz,1H),6.90(d,J=8.6Hz,1H),6.20(d,J=9.4Hz,1H),4.48(m,2H),3.79(dt,J=6.7,4.8Hz,2H),2.95(s,3H),2.59(s,3H),2.55(s, 3H).13C-NMR(150MHz,CDCl3):δC 167.32,160.77,154.93,153.79,151.91,148.12,147.61, 144.44,138.35,133.98,123.43,113.48,112.66,112.16,75.88,40.81,23.14,22.17,21.51.ESI-MS: m/z 392.1[M+Na]+(calcd for C19H19N3NaO5,392.1).
实施例10
化合物10的合成
参照实施例8,步骤3用吡啶代替布洛芬,其他条件与实施例8相同,制得白色固体产物纯品。总产率:20.1%,熔点:146-150℃。GF254nm硅胶板薄层展开为一点。1H-NMR(500MHz,CDCl3):δH 8.71(m,1H),8.57(m,1H),8.25(d,J=7.8Hz,1H),7.87(td,J=7.7,1.7Hz,1H),7.61(d,J=9.5Hz,1H),7.46(ddd,J=7.5,4.8,1.2Hz,1H),7.08(d,J=8.5Hz,1H),6.90(d, J=8.5Hz,1H),6.19(d,J=9.5Hz,1H),4.48(m,2H),3.81(dt,J=6.6,4.7Hz,2H).13C-NMR (125MHz,CDCl3):δC 166.47,160.76,153.77,149.16,148.24,147.52,144.37,137.61,133.89, 126.69,123.32,122.69,113.48,112.53,111.98,75.69,40.95.ESI-MS:m/z 349.1[M+Na]+(calcd for C17H14N2NaO5,349.1).
实施例11
瑞香素衍生物α-葡萄糖苷酶酶抑制活性的测定
实验原理:食物中的淀粉(多糖)经口腔唾液、胰淀粉酶消化成含少数葡萄糖分子的低聚糖(或称寡糖)以及双糖与三糖,进入小肠经α-葡萄糖苷酶作用下分解为单个葡萄糖,为小肠吸收。在生理状态下,小肠上、中、下三段均存在α-葡萄糖苷酶,在服用α-葡萄糖苷酶抑制剂后上段可被抑制,而糖的吸收仅在中、下段,故吸收面积减少,吸收时间后延,从而对降低餐后高血糖有益,在长期使用后亦可降低空腹血糖,估计与提高胰岛素敏感性有关。对硝基苯-α-D-葡萄糖苷(pNPG)经α-葡萄糖苷酶水解可产生对硝基苯酚,呈黄色,其在405nm 下有特异性吸收,因此可以通过检测对硝基苯酚的生成量检测α-葡萄糖苷酶抑制活性。
测定方法:据文献报道,采用改良版pNPG法用于测定化合物的α-葡萄糖苷酶抑制活性。取10μL 0.1U/mL的α-葡萄糖苷酶溶液置于96孔板中,然后加入5μL样品溶液和145μL0.1 M PBS缓冲液,放入37℃恒温水浴中孵育10min,再加入40μL 2M pNPG溶液开始反应,在37℃下继续孵育20min,最后加入50μL 0.2M Na2CO3溶液终止反应。通过在405nm下测定吸光度来定量酶活性。阳性对照品选择阿卡波糖进行实验。平行操作3次(做3复孔),取均值,样品对α-葡萄糖苷酶的抑制活性以抑制率来表示。
抑制率计算公式:抑制率%=[1-(Aj-Aj0)/(Ai-Ai0)]×100%
其中Aj为待测样品组的吸光度值;A0为样品空白对照组的吸光度值;其中Ai为100%酶活性对照组的吸光度值;Ai0为空白对照组的吸光度值;
对于抑制率较好的化合物样品继续选择9个浓度测定其抑制率,每个化合物样品的每个浓度水平均设置3个复孔,并采用GraphPad Prism 5软件计算化合物样品的IC50值。
表1:α-葡萄糖苷酶酶抑制活性的测定结果
名称 | 50μmol/L的抑制率(%) | IC<sub>50</sub>(μmol/L) |
实施例1 | 41.42 | 76.91 |
实施例2 | 46.33 | 80.23 |
实施例3 | 36.73 | 96.82 |
实施例4 | 41.42 | 101.87 |
实施例5 | 39.10 | 105.91 |
实施例6 | 39.48 | 106.86 |
实施例7 | 32.58 | 136.74 |
实施例8 | 35.33 | 111.81 |
其中阳性药阿卡波糖IC50约为183.99μmol/L。
测定结果表明,本发明公开的部分化合物对α-葡萄糖苷酶具有较好的抑制作用,且活性优于阿卡波糖。
以上各实施例仅用以介绍本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,但本领域的技术人员应当知道:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围,不应将本发明的保护范围局限于以上具体实施例。
Claims (11)
1.一种瑞香素7-OH、8-OH衍生物,其结构通式如下:
结构通式(I)中,取代基R选自下列能够改善化合物生物利用度的取代基团化合物:苯甲酰氯、丙酰氯、噻吩甲酰氯、丁酰氯、环丙基甲酰氯、呋喃甲酰氯、乙酰氯、布洛芬、川芎嗪、吡啶。
其中:化合物1:R1=R2=苯甲酰基;化合物2:R1=R2=丙酰基;
化合物3:R1=R2=噻吩甲酰基;化合物4:R1=R2=丁酰基;
化合物5:R1=R2=环丙基甲酰基;化合物6:R1=R2=呋喃甲酰基;
化合物7:R1=R2=乙酰基;
化合物8:R1=H、R2=2-(4-异丁基苯)丙酰基;
化合物9:R1=H、R2=2,3,5-三甲基吡嗪甲酰基;
化合物10:R1=H、R2=2-吡啶甲酰基。
3.根据权利要求2所述的制备方法,其特征在于,步骤a中醚化反应条件包括:以碘化钾为催化剂,以碳酸钾作碱,反应温度为80℃。
4.根据权利要求3所述的制备方法,其特征在于,步骤a包括:首先将瑞香素、碳酸钾和碘化钾溶于无水DMF中,磁力搅拌。80℃加热40min后缓慢滴加N-Boc溴乙胺,之后在80℃下回流反应,回流装置顶端加N2保护装置。用TLC监测反应进程;反应完成后,先加入适量稀盐酸搅拌中和至酸性,再用乙酸乙酯萃取三次,收集乙酸乙酯层;乙酸乙酯层再用蒸馏水、饱和食盐水各洗涤三次,无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经柱色谱分离纯化,得到中间体II。
5.根据权利要求2所述的制备方法,其特征在于,步骤b中反应条件包括以三氟乙酸(CF3COOH)为脱Boc基团试剂,常温反应。
6.根据权利要求5所述的制备方法,其特征在于,步骤b包括:取上述中间体II置于单颈烧瓶中,采用二氯甲烷(CH2Cl2)溶解后,再加入过量CF3COOH,置于室温搅拌反应2h,TLC板监测反应进程;待反应完成后,缓慢加入饱和NaHCO3溶液调至反应溶液为碱性,再用正丁醇萃取,收集正丁醇层;正丁醇层采用蒸馏水,饱和食盐水各洗涤三次,收集正丁醇层用无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经柱色谱分离纯化,得到中间体III。
7.根据权利要求2所述的制备方法,其特征在于,步骤c中酰胺缩合反应条件包括以三乙胺(Et3N)为作碱,常温反应。
8.根据权利要求7所述的制备方法,其特征在于,步骤c包括:将中间体III溶于CH2Cl2置于单口烧瓶中,加入Et3N,缓慢加入不同取代基的酰氯化物,将混合物在室温反应8h,用TLC板监测反应进程;待反应完成后,收集CH2Cl2层;CH2Cl2层采用蒸馏水,饱和食盐水各洗涤三次,收集CH2Cl2层用无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经过硅胶柱色谱分离纯化,得到目标化合物1-化合物7。
9.根据权利要求2所述的制备方法,其特征在于,步骤d中酰胺缩合反应条件包括以1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)、1-羟基苯并三唑(HOBt)为缩合剂,N,N-二异丙基乙胺(DIPEA)为碱,常温反应。
10.根据权利要求9所述的制备方法,其特征在于,步骤d包括:在单口圆底烧瓶中,加入EDCI、HOBt、DIPEA、取代羧酸,并用N,N-二甲基甲酰胺(DMF)溶解上述化合物,置于室温搅拌反应1h,然后将中间体III溶于DMF中再加入到反应体系中,TLC板监测反应结束后,加水淬灭并稀释,用乙酸乙酯萃取3次,合并乙酸乙酯层,用蒸馏水洗涤、饱和食盐水各洗涤三次,最后用无水硫酸钠干燥,抽滤,滤液减压旋干,残留物经过硅胶柱色谱分离纯化,得到目标化合物8-化合物10。
11.权利要求1所述的瑞香素7-OH、8-OH衍生物具有抑制α-葡萄糖苷酶的作用,以及治疗II型糖尿病的相关医用用途。
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