CN114656391A - Polyhydroxy pyrrolidine compound and preparation method and application thereof - Google Patents
Polyhydroxy pyrrolidine compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN114656391A CN114656391A CN202210333880.9A CN202210333880A CN114656391A CN 114656391 A CN114656391 A CN 114656391A CN 202210333880 A CN202210333880 A CN 202210333880A CN 114656391 A CN114656391 A CN 114656391A
- Authority
- CN
- China
- Prior art keywords
- formula
- solvent
- reaction
- compound
- reagent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 73
- -1 pyrrolidine compound Chemical class 0.000 title claims abstract description 47
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 30
- 102000006995 beta-Glucosidase Human genes 0.000 claims abstract description 23
- 108010047754 beta-Glucosidase Proteins 0.000 claims abstract description 23
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- 239000003316 glycosidase inhibitor Substances 0.000 claims abstract description 17
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 207
- 239000002904 solvent Substances 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 239000003153 chemical reaction reagent Substances 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 32
- 238000006722 reduction reaction Methods 0.000 claims description 31
- 239000003054 catalyst Substances 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 28
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- 238000005859 coupling reaction Methods 0.000 claims description 23
- 239000003638 chemical reducing agent Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 18
- 125000002524 organometallic group Chemical group 0.000 claims description 18
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- 238000006735 epoxidation reaction Methods 0.000 claims description 16
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 229940122069 Glycosidase inhibitor Drugs 0.000 claims description 13
- 108010028144 alpha-Glucosidases Proteins 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000003223 protective agent Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 150000002978 peroxides Chemical class 0.000 claims description 9
- 241000283690 Bos taurus Species 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 claims description 8
- 229910000085 borane Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 210000004185 liver Anatomy 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
- 102000005936 beta-Galactosidase Human genes 0.000 claims description 7
- 108010005774 beta-Galactosidase Proteins 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012190 activator Substances 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 239000010949 copper Substances 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 102100032487 Beta-mannosidase Human genes 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 claims description 4
- 108010060309 Glucuronidase Proteins 0.000 claims description 4
- 102000053187 Glucuronidase Human genes 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 208000015439 Lysosomal storage disease Diseases 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 102000005840 alpha-Galactosidase Human genes 0.000 claims description 4
- 108010030291 alpha-Galactosidase Proteins 0.000 claims description 4
- 108010061314 alpha-L-Fucosidase Proteins 0.000 claims description 4
- 102000012086 alpha-L-Fucosidase Human genes 0.000 claims description 4
- 108010044879 alpha-L-rhamnosidase Proteins 0.000 claims description 4
- 108010012864 alpha-Mannosidase Proteins 0.000 claims description 4
- 102000019199 alpha-Mannosidase Human genes 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 108010055059 beta-Mannosidase Proteins 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 150000003235 pyrrolidines Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 208000015872 Gaucher disease Diseases 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 239000011987 hoveyda–grubbs catalyst Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001979 organolithium group Chemical group 0.000 claims description 3
- 125000002734 organomagnesium group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- BOUARFRGCVOQDU-UHFFFAOYSA-M [Br-].[Zn+]C=C Chemical compound [Br-].[Zn+]C=C BOUARFRGCVOQDU-UHFFFAOYSA-M 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011984 grubbs catalyst Substances 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- IJMWREDHKRHWQI-UHFFFAOYSA-M magnesium;ethene;chloride Chemical compound [Mg+2].[Cl-].[CH-]=C IJMWREDHKRHWQI-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- PGOLTJPQCISRTO-UHFFFAOYSA-N vinyllithium Chemical compound [Li]C=C PGOLTJPQCISRTO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000004973 liquid crystal related substance Substances 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 abstract description 9
- 108010031186 Glycoside Hydrolases Proteins 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 80
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 description 17
- 102000016679 alpha-Glucosidases Human genes 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 238000010791 quenching Methods 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 244000309464 bull Species 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- KTZVZZJJVJQZHV-UHFFFAOYSA-N 1-chloro-4-ethenylbenzene Chemical compound ClC1=CC=C(C=C)C=C1 KTZVZZJJVJQZHV-UHFFFAOYSA-N 0.000 description 4
- LVJZCPNIJXVIAT-UHFFFAOYSA-N 1-ethenyl-2,3,4,5,6-pentafluorobenzene Chemical compound FC1=C(F)C(F)=C(C=C)C(F)=C1F LVJZCPNIJXVIAT-UHFFFAOYSA-N 0.000 description 4
- JWVTWJNGILGLAT-UHFFFAOYSA-N 1-ethenyl-4-fluorobenzene Chemical compound FC1=CC=C(C=C)C=C1 JWVTWJNGILGLAT-UHFFFAOYSA-N 0.000 description 4
- QEDJMOONZLUIMC-UHFFFAOYSA-N 1-tert-butyl-4-ethenylbenzene Chemical compound CC(C)(C)C1=CC=C(C=C)C=C1 QEDJMOONZLUIMC-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- LPNANKDXVBMDKE-UHFFFAOYSA-N 5-bromopent-1-ene Chemical compound BrCCCC=C LPNANKDXVBMDKE-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 2
- 241000705930 Broussonetia papyrifera Species 0.000 description 2
- 102000005575 Cellulases Human genes 0.000 description 2
- 108010084185 Cellulases Proteins 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- RYVMUASDIZQXAA-UHFFFAOYSA-N pyranoside Natural products O1C2(OCC(C)C(OC3C(C(O)C(O)C(CO)O3)O)C2)C(C)C(C2(CCC3C4(C)CC5O)C)C1CC2C3CC=C4CC5OC(C(C1O)O)OC(CO)C1OC(C1OC2C(C(OC3C(C(O)C(O)C(CO)O3)O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OCC(O)C(O)C1O RYVMUASDIZQXAA-UHFFFAOYSA-N 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- KIFPIAKBYOIOCS-UHFFFAOYSA-N 2-methyl-2-(trioxidanyl)propane Chemical compound CC(C)(C)OOO KIFPIAKBYOIOCS-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000005820 Prochloraz Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- TVLSRXXIMLFWEO-UHFFFAOYSA-N prochloraz Chemical compound C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl TVLSRXXIMLFWEO-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of glycosidase inhibitors, and discloses a polyhydroxy pyrrolidine compound, and a preparation method and application thereof. The structural formula of the polyhydroxy pyrrolidine compound is shown as a formula (1), wherein R1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, C3-C10 cycloalkyl, C1-C10 alkoxy and C1-C10 straight chain or branched chain alkyl; n is an integer of 1 to 20. Hair brushThe polyhydroxy pyrrolidine compound has high glycosidase inhibitory activity, particularly shows excellent inhibitory activity on beta-glucosidase, and can be used for preventing and treating various related diseases.
Description
Technical Field
The invention relates to the field of glycosidase inhibitors, and in particular relates to a polyhydroxy pyrrolidine compound, and a preparation method and application thereof.
Background
Imino sugars are widely distributed in the body of plants, and natural imino sugars can be classified into polyhydroxypyrrolidines, polyhydroxypiperidines, polyhydroxyindolizidines, polyhydroxypyrrolizidines, and polyhydroxydemethyltropanes, depending on their backbone structures. They show good inhibitory activity against different glycosidases, for example, broussonetia papyrifera alkali is a series of natural products separated from broussonetia papyrifera, and has good inhibitory activity against beta-glucosidase and beta-galactosidase, while its enantiomer shows good alpha-glucosidase inhibitory activity [ (a) m.shibano, s.kitagawa, g.kusano, chem.pharm.Bull.1997,45, 505-508; (b) shibano, s.kitagawa, s.nakamura, n.akazawa, g.kusano, chem.pharm.bull.1997,45, 700-705; (c) m.shibano, s.nakamura, n.akazawa, g.kusano, chem.pharm.bull.1998,46, 1048-; (d) m.shibano, s.nakamura, m.kubori, k.minoura, g.kusano, chem.pharm.ball.1998, 46, 1416-; (e) shibano, S.Nakamura, N.Motoya, G.Kusano, chem.pharm.Bull.1999,47, 472-476; (f) shibano, D.Tsukamoto, G.Kusano, chem.pharm.Bull.1999,47, 907-); (g) shibano, D.Tsukamoto, G.Kusano, Heterocycles 2002,57,1539-1553 ]. Such properties make them potentially valuable for pharmaceutical use in antiviral, lysosomal storage diseases, hyperglycemia, and diabetes. Therefore, the intensive research on the polyhydroxy pyrrolidine compounds is of great importance.
Disclosure of Invention
The invention aims to provide a polyhydroxy pyrrolidine compound, a preparation method and an application thereof, wherein the polyhydroxy pyrrolidine compound has high glycosidase inhibitory activity, especially has excellent inhibitory activity on beta-glucosidase, and can be used for preventing and treating various related diseases.
In order to achieve the above object, the present invention provides in a first aspect a polyhydroxypyrrolidine compound having the formula (1):
wherein R is1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, cycloalkyl of C3-C10, alkoxy of C1-C10 and straight chain or branched chain alkyl of C1-C10;
n is an integer of 1 to 20;
denotes a chiral carbon atom.
In a second aspect, the present invention provides a process for the preparation of polyhydroxypyrrolidines, comprising the steps of:
1) carrying out a first nucleophilic addition reaction on nitrone shown in a formula (2) and an organic metal reagent with vinyl under the condition of the first nucleophilic addition reaction to obtain hydroxylamine shown in a formula (3),
wherein R is6Is benzyl or benzyl with hydrogen on benzene ring being singly or fully substituted by hydroxyl, alkoxy, nitro or halogen;
represents a chiral carbon atom;
2) carrying out reduction reaction on hydroxylamine shown in a formula (3) obtained in the step 1) and a reducing agent under the reduction reaction condition, carrying out amino protection reaction on a product obtained by the reduction reaction and an amino protective agent under the amino protection reaction condition to obtain a compound shown in a formula (4),
wherein R is7Is a residue from the amino protecting agent;
preferably, R7Is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl or acetyl;
3) carrying out double bond epoxidation reaction on the compound shown in the formula (4) obtained in the step 2) and peroxide under the condition of double bond epoxidation reaction to obtain a mixture of the compound shown in the formula (5) and the compound shown in the formula (6),
4) reacting the compound represented by the formula (5) or the compound represented by the formula (6) with a compound having a-CH group in the mixture obtained in the step (3)2-(CH2)m-R8The organometallic reagent of (a) is subjected to a second nucleophilic addition reaction under a second nucleophilic addition reaction condition to obtain a compound represented by formula (7),
wherein m is an integer of 0 to 18;
R8is-CH ═ CH2or-CH ═ CHX, where X is halogen or substituted borane, the substituents in the substituted borane being selected from one of C1-6 alkyl, C1-6 alkoxy and potassium fluoroborate;
5) carrying out coupling reaction on the compound shown in the formula (7) obtained in the step 4) and the compound shown in the formula (8) under the coupling reaction condition to obtain a compound shown in the formula (9),
wherein R is1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, C3-C10 cycloalkyl, C1-C10 alkoxy and C1-C10 straight chain or branched chain alkyl;
6) carrying out catalytic hydrogenation reaction on a compound shown as a formula (9) and a hydrogen source under the catalytic hydrogenation reaction condition to obtain a compound shown as a formula (1),
wherein n is an integer of 0 to 20, and n is m + 2.
In a third aspect, the present invention provides a glycosidase inhibitor, wherein the glycosidase inhibitor comprises the polypyrrolidine compound according to the first aspect of the present invention or the polypyrrolidine compound prepared by the preparation method according to the second aspect of the present invention.
Preferably, the glycosidase inhibitor is used to inhibit one or more of alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-rhamnosidase, amyloglucosidase, and beta-glucuronidase; more preferably, the glycosidase inhibitor is used to inhibit β -glucosidase; further preferably, the glycosidase inhibitor is used for inhibiting bovine liver-derived β -glucosidase.
In a fourth aspect, the present invention provides a use of the polyhydroxy pyrrolidine compound according to the first aspect of the present invention or the polyhydroxy pyrrolidine compound prepared by the preparation method according to the second aspect of the present invention in preparation of a medicament, wherein the medicament is at least one selected from the following medicaments: 1) a medicament for the prophylaxis and/or treatment of diabetes; 2) a medicament for preventing and/or treating gaucher's disease; 3) a medicament for the prevention and/or treatment of lysosomal storage disorders; 4) drugs for preventing and/or treating tumors; 5) an antiviral drug.
The polyhydroxy pyrrolidine compound provided by the invention has good inhibitory activity on glycosidase, especially beta-glucosidase, and simultaneously has good selectivity on the beta-glucosidase. Therefore, the compound has the potential of preventing and treating diabetes, high-snow disease, lysosome storage disease, tumor and other diseases, and can also be applied to antiviral drugs.
In addition, the polyhydroxy pyrrolidine compound provided by the invention has excellent inhibitory activity on bovine liver-derived beta-glucosidase.
According to the test examples provided by the invention, the compound shown in the formula (1-1) and the compound shown in the formula (1-3) in the invention show very significant beta-glucosidase inhibitory activity for bovine liver, and the inhibitory activity is improved by more than ten times, even can be up to nearly thousand times compared with other compounds. Meanwhile, the compounds shown in the formula (1-1) and the compounds shown in the formula (1-3) also show obviously lower alpha-glucosidase inhibitory activity from maltase in rat small intestine, so that the influence of the compounds shown in the formula (1-1) and the compounds shown in the formula (1-3) on intestinal tracts is obviously reduced after being taken as medicine components, and the probability and degree of side effects such as diarrhea and the like are greatly reduced. Is very suitable to be used as a medicine component.
In addition, the preparation method of the polyhydroxy pyrrolidine compound provided by the invention is simple and feasible, has high yield and purity, and is very suitable for industrial production.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The first aspect of the present invention provides a polyhydroxy pyrrolidine compound, wherein the structural formula of the polyhydroxy pyrrolidine compound is represented by formula (1):
in the formula (1), R1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, cycloalkyl of C3-C10, alkoxy of C1-C10 and straight chain or branched chain alkyl of C1-C10;
n is an integer of 1 to 20;
denotes a chiral carbon atom.
In the present invention, the halogen may be, for example, fluorine, chlorine, bromine or iodine.
In the present invention, the cycloalkyl group having 3 to 10 may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc.
In the present invention, the alkoxy group having 1 to 10 may be, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, etc.
In the present invention, the linear or branched alkyl group having 1 to 10 may be, for example, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, isoheptyl, 2-methylhexyl, 2-ethylhexyl, 1-methylheptyl, 2-methylheptyl, isooctyl, isononyl, 3,5, 5-trimethylhexyl, or the like.
According to the first aspect of the present invention, in the formula (1), preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, C3-C8 cycloalkyl, C1-C8 alkoxy and C1-C8 straight chain or branched chain alkyl; more preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, fluorine, chlorine, bromine, amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C1-C6 straight chain or branched chain alkyl; further preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, fluorine, chlorine, methyl and tert-butyl.
Further, preferably, R1、R2、R3、R4And R5Not all hydrogen.
In the present invention, n is not particularly limited, and may be, for example, 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
Preferably, n is an integer from 1 to 10; more preferably, n is an integer from 1 to 6.
According to a particularly preferred embodiment of the present invention, wherein n is 5.
In the present invention, preferably, each is independently in R or S configuration;
in addition, the compound shown in the formula I has the spatial configuration of 2, 3, 4 and 5 carbon atoms of 2R, 3R, 4R and 5R or 2S, 3S, 4S and 5S.
In the present invention, preferably, the structure of the compound represented by formula i is any one of the following structures:
wherein F is fluorine.
When the compound shown in the formula I is any one of the structures shown in the formulas (1-1) to (1-20), the compound has good glycosidase inhibitory activity, particularly shows good inhibitory activity on beta-glucosidase, and shows very excellent inhibitory activity on bovine liver-derived beta-glucosidase.
In addition, the compound represented by the formula (1-1) and the compound represented by the formula (1-3) show very significant beta-glucosidase inhibitory activity against bovine liver, and the inhibitory activity is significantly improved compared to other compounds. Meanwhile, the compound shown in the formula (1-1) and the compound shown in the formula (1-3) also show obviously lower alpha-glucosidase inhibitory activity from maltase in rat small intestine, and show that the influence of the compound shown in the formula (1-1) and the compound shown in the formula (1-3) on intestinal tracts is obviously reduced after the compound shown in the formula (1-1) and the compound shown in the formula (1-3) are taken as medicine components, so that the probability and degree of side effects such as diarrhea and the like can be greatly reduced. Is very suitable to be used as a medicine component.
In a second aspect, the present invention provides a process for the preparation of a polyhydroxypyrrolidine compound according to the first aspect of the invention, which comprises the steps of:
1) carrying out a first nucleophilic addition reaction on nitrone shown in a formula (2) and an organic metal reagent with vinyl under the condition of the first nucleophilic addition reaction to obtain hydroxylamine shown in a formula (3),
wherein R is6Is benzyl or benzyl with hydrogen on benzene ring being singly or fully substituted by hydroxyl, alkoxy, nitro or halogen;
represents a chiral carbon atom;
2) carrying out reduction reaction on hydroxylamine shown in a formula (3) obtained in the step 1) and a reducing agent under the reduction reaction condition, carrying out amino protection reaction on a product obtained by the reduction reaction and an amino protective agent under the amino protection reaction condition to obtain a compound shown in a formula (4),
wherein R is7Is a residue from the amino protecting agent;
3) carrying out double bond epoxidation reaction on the compound shown in the formula (4) obtained in the step 2) and peroxide under the condition of double bond epoxidation reaction to obtain a mixture of the compound shown in the formula (5) and the compound shown in the formula (6),
4) reacting the compound represented by the formula (5) or the compound represented by the formula (6) with a compound having a-CH group in the mixture obtained in the step (3)2-(CH2)m-R8The organometallic reagent of (a) is subjected to a second nucleophilic addition reaction under a second nucleophilic addition reaction condition to obtain a compound represented by formula (7),
wherein m is an integer of 0 to 18;
R8is-CH ═ CH2or-CH ═ CHX, where X is halogen or substituted borane, the substituents in the substituted borane being selected from one of C1-6 alkyl, C1-6 alkoxy and potassium fluoroborate;
5) carrying out coupling reaction on the compound shown in the formula (7) obtained in the step 4) and the compound shown in the formula (8) under the coupling reaction condition to obtain a compound shown in the formula (9),
wherein R is1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, C3-C10 cycloalkyl, C1-C10 alkoxy and C1-C10 straight chain or branched chain alkyl;
6) carrying out catalytic hydrogenation reaction on a compound shown in a formula (9) and a hydrogen source under the catalytic hydrogenation reaction condition to obtain a compound shown in a formula (1),
wherein n is an integer of 0 to 20, and n is m + 2.
The method for producing the above-mentioned polyhydroxypyrrolidine compound is specifically described below.
First, the first nucleophilic addition reaction in step 1) will be described.
In the step 1), an organometallic reagent with a vinyl group in the nitrone shown in the formula (2) is subjected to a first nucleophilic addition reaction to obtain hydroxylamine shown in the formula (3) as a skeleton structure of the polyhydroxy pyrrolidine compound.
In the present invention, the nitrone represented by the formula (2) may have enantiomers represented by the following formulae (2-1) and (2-2), that is, in the present invention, the nitrone represented by the formula (2) may be a compound having only the structure represented by the formula (2-1), may be a compound having only the structure represented by the formula (2-2), or may be a mixture of compounds having the structures represented by the formulae (2-1) and (2-2).
The nitrone represented by formula (2) can be prepared by a conventional method in the art, or can be obtained commercially. With R6For benzyl, the nitrones of formula (2-1) or (2-2) can be obtained from Prochloraz technology, Inc.
In the present invention, preferably, R6Is a benzyl group.
According to the invention, in step 1), the first nucleophilic addition reaction is carried out in the presence of a first solvent; preferably, the first solvent is an anhydrous aprotic solvent; more preferably, the first solvent is an ether solvent and/or a halogenated alkyl solvent; further preferably, the first solvent is one or more of diethyl ether, tetrahydrofuran, dioxane and dichloromethane.
In the present invention, the amount of the first solvent may be determined according to the amount of the nitrone represented by formula (2). Preferably, the first solvent is used in an amount of 1 to 6mL, more preferably 2 to 4mL, relative to 1mmol of the nitrone represented by formula (2), whereby the reaction can be promoted.
According to the present invention, the organometallic reagent having a vinyl group is preferably one or more of an organomagnesium reagent having a vinyl group, an organozinc reagent having a vinyl group, an organolithium reagent having a vinyl group, an organocopper reagent having a vinyl group, and an organosilicon reagent having a vinyl group; more preferably, the organometallic reagent having a vinyl group is one or more of vinyl magnesium chloride, vinyl magnesium bromide, vinyl lithium and vinyl zinc bromide.
In a particularly preferred embodiment of the present invention, the organometallic reagent having a vinyl group is vinyl magnesium bromide, whereby the reaction efficiency can be further improved.
In the present invention, the amount of the organometallic reagent having a vinyl group can be determined depending on the amount of the nitrone represented by the formula (2). For example, the molar ratio of the nitrone of formula (2) to the organometallic reagent having a vinyl group may be 1: 1.2-3, preferably 1: 1.5-2.5. Thereby improving the reaction efficiency and ensuring the yield of the hydroxylamine shown in the formula (3).
According to the present invention, the conditions of the first nucleophilic addition reaction may include: the temperature is between 80 ℃ below zero and 20 ℃ and the time is between 0.2 and 3 hours; preferably, the conditions of the first nucleophilic addition reaction include: the temperature is-10 ℃ to 10 ℃ and the time is 0.5 to 2 hours. By carrying out the first nucleophilic addition reaction under the above conditions, smooth progress of the reaction can be promoted, and the reaction efficiency and yield can be improved.
In the present invention, the first nucleophilic addition reaction is preferably performed under the protection of an inert gas, which may be, for example, nitrogen, argon, helium, neon, or the like.
In addition, after the first nucleophilic addition reaction in step 1) is completed, the reaction may be quenched by a method conventional in the art, for example, saturated NH may be used4And (3) quenching the Cl aqueous solution, and refining the quenched product by adopting methods such as extraction and the like after quenching. For example, ethyl acetate may be used for extraction, and the organic phase may be washed, dried and concentrated after extraction as necessary. This is a routine operation in the art and will not be described in detail here.
Next, the reduction reaction and the amino group protection reaction described in step 2) will be described.
In the step 2), the hydroxylamine represented by the formula (3) obtained in the step 1) and a reducing agent are subjected to a reduction reaction under a reduction reaction condition to obtain the amine represented by the formula (3').
Wherein the reduction reaction is carried out in the presence of a second solvent.
In order to allow the reducing agent to react with an activating agent described later more favorably and thereby to perform the reduction reaction more favorably, it is preferable that the second solvent is an acidic solvent.
More preferably, the second solvent is one or more of acetic acid, propionic acid, butyric acid and formic acid, and further preferably acetic acid.
Further, the amount of the second solvent may be determined according to the amount of hydroxylamine represented by formula (3), and for example, the amount of the second solvent may be 20 to 80mL relative to 1mmol of hydroxylamine represented by formula (3). In order to further facilitate the reduction reaction, the amount of the second solvent to be used is preferably 30 to 50mL relative to 1mmol of the hydroxylamine represented by the formula (3).
According to the present invention, the reducing agent may use various reducing agents commonly used in the art for reducing hydroxylamine to amines, for example, one or more of zinc powder, iron powder, and lithium aluminum hydride may be used; preferably, the reducing agent is zinc powder. Thereby, the rate of the reduction reaction can be increased.
In addition, in order to ensure the reduction reaction is fully and smoothly performed, the amount of the reducing agent can also be determined according to the amount of hydroxylamine represented by formula (3), for example, the molar ratio of hydroxylamine represented by formula (3) to the reducing agent can be 1: 5-20; preferably 1: 10-15.
In the present invention, the reducing agent may be activated in advance or an activator may be added to the reduction reaction system in order to promote the reaction.
In the present invention, it is preferable that the reducing agent is activated in advance. When the reducing agent is activated in advance, the method may be performed by an activation method which is conventional in the art, and is not particularly limited, and for example, the reducing agent may be activated by hydrochloric acid.
The activator in the present invention is not particularly limited, and may be any of various activators commonly used in the art for activating a reducing agent, for example, Cu (OAc)2、AgOAc、CuSO4And CuCl2One or more of; preferably, the activator is Cu (OAc)2And/or AgOAc.
According to the present invention, in order to sufficiently activate the reducing agent, the amount of the activating agent may be determined according to the amount of the reducing agent, and for example, the molar ratio of the activating agent to the reducing agent may be 1: 80-200 parts of; preferably 1: 100-200.
In the present invention, the conditions of the reduction reaction may include: the temperature is 10-30 ℃, and the time is 2-12 h; preferably, the conditions of the reduction reaction include: the temperature is 20-30 ℃ and the time is 2-6 h.
According to the present invention, after the reduction reaction is completed, the product obtained by the reduction reaction can be purified by various methods generally used in the art for purification. For example, the reduction reaction product may be concentrated, dispersed in an organic solvent, and washed with an alkaline solution, for example, a saturated aqueous sodium bicarbonate solution may be used, and after washing with an alkaline solution, water may be used as necessary, and the washed aqueous phase may be extracted as necessary to increase the yield, and then the organic phase may be dried (for example, dried with anhydrous sodium sulfate) and concentrated to obtain a crude product of the amine having the structure represented by formula (3').
In the present invention, the crude product can be used directly for the next reaction.
Then, in step 2), the product obtained from the reduction reaction, namely the amine amino protecting agent with the structure shown in (3'), is subjected to an amino protection reaction under the amino protection reaction condition to obtain the compound shown in the formula (4).
In the present invention, the reaction of step 2) generates an acid, and thus, in order to neutralize the acid generated in the reaction and accelerate the reaction, it is preferable that the amino-protecting reaction is performed in the presence of a first base.
The first base may be various inorganic or organic bases commonly used in the art, and is preferably an inorganic base.
The inorganic base as the first base may be, for example, one or more of sodium bicarbonate, sodium hydroxide, potassium bicarbonate, and potassium hydroxide; more preferably, the first base is sodium bicarbonate.
In the present invention, the amount of the first base may be determined according to the amount of the reduction reaction product, and for example, the molar ratio of the reduction reaction product to the first base may be 1: 1.0-3.0; preferably 1: 1.5-2.0.
In addition, in the present invention, the amino group protection reaction is carried out in the presence of a third solvent.
The third organic solvent may employ various organic solvents commonly used in the art, without particular limitation.
However, when the first base is used and the first base is an inorganic base, in order to increase the solubility of the inorganic base, it is preferable that the third solvent is a mixed solvent of an organic solvent and water; for example, the third solvent may be a mixed solvent of water and one or more of diethyl ether, tetrahydrofuran, dioxane, and dichloromethane; preferably, the third solvent is a mixed solvent of tetrahydrofuran and water.
At this time, preferably, in the third solvent, the ratio of the organic solvent to water may be 1 to 10: 1, preferably 2 to 8: 1.
in the present invention, the amount of the third solvent may be determined according to the amount of the product obtained by the reduction reaction. For example, the amount of the third solvent is 5 to 20mL relative to 1mmol of the product obtained by the reduction reaction; preferably 8-12 mL.
According to the invention, the amino protective agent can be one or more of benzyl chloroformate, fluorenylmethoxycarbonyl chloride, allyl chloroformate and di-tert-butyl carbonate; preferably, the amino protecting agent is benzyl chloroformate.
Preferably, the amino protecting group R in the compound represented by the formula (4)7Is benzyloxycarbonyl.
In the invention, the molar ratio of the product obtained by the reduction reaction to the amino protective agent is 1: 1.0-3.0; preferably 1: 1.5-2.0.
In addition, the conditions of the amino protection reaction of the present invention are not particularly limited, and for example, the conditions of the amino protection reaction may include: the temperature is 0-40 ℃, and the time is 0.2-5 h; to further facilitate the amino protection reaction, preferably, the conditions of the amino protection reaction may include: the temperature is 0-30 ℃ and the time is 0.5-2 h.
Hereinafter, the double bond epoxidation reaction described in the step 3) is specifically performedDescription of the invention。
In the step 3), the compound shown in the formula (4) obtained in the step 2) and peroxide are subjected to double bond epoxidation reaction under the condition of double bond epoxidation reaction.
In step 3) of the present invention, the double bond epoxidation reaction is carried out in the presence of a fourth solvent.
The fourth solvent is preferably an organic solvent, and may be, for example, one or more of dichloromethane, 1, 2-dichloroethane, tert-butanol, acetonitrile, propionitrile, and butyronitrile; preferably, the fourth solvent is dichloromethane.
According to the present invention, the amount of the fourth solvent may be determined according to the amount of the compound represented by formula (4), for example, the fourth organic solvent is used in an amount of 5 to 30mL with respect to 1mmol of the compound represented by formula (4); preferably 10 to 20mL, whereby the smooth progress of the reaction can be further promoted.
In addition, in order to neutralize an acidic substance generated during the reaction, promote smooth progress of the reaction, and improve reaction efficiency and yield, it is preferable that the double bond epoxidation reaction is performed in the presence of a second base.
Here, the second base may be, for example, one or more of sodium bicarbonate, disodium hydrogen phosphate, sodium carbonate, potassium bicarbonate, and dipotassium hydrogen phosphate; sodium bicarbonate is preferred.
In the present invention, the amount of the second base may be determined according to the amount of the compound represented by formula (4), and for example, the molar ratio of the compound represented by formula (4) to the second base may be 1: 1-5; preferably 1: 2-3.
According to the invention, the peroxide in step 3) is one or more of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, Oxone and tert-butyl peroxy-alcohol; m-chloroperoxybenzoic acid is preferred. Thereby being more beneficial to the double bond epoxidation reaction and improving the yield.
In addition, the amount of the peroxide may be determined according to the amount of the compound represented by formula (4), and for example, the molar ratio of the compound represented by formula (4) to the peroxide may be 1: 1-5; preferably, the molar ratio of the compound represented by formula (4) to the peroxide is 1: 2-3.
In addition, in the present invention, the conditions of the double bond epoxidation reaction may include: the temperature is 5-50 ℃, and the time is 1-6 days; preferably, the temperature is 10-40 ℃ and the time is 2-4 days.
Thus, a mixture of the compound represented by the formula (5) and the compound represented by the formula (6) is obtained by the double bond epoxidation reaction.
After the reaction is completed, the compound represented by formula (5) and the compound represented by formula (6) in the mixture may be separated using a separation method that is conventional in the art. Selecting the compound shown in the formula (5) or the compound shown in the formula (6) according to the target product for subsequent steps.
The separation method may include, for example, column chromatography, beating, extraction, etc., which are conventional in the art and will not be described in detail in this specification.
Next, the second nucleophilic addition reaction in step 4) will be described。
In the step 4), the compound represented by the formula (5) or the compound represented by the formula (6) in the mixture obtained in the step (3) is reacted with a compound having a-CH2-(CH2)m-R8To perform a second nucleophilic addition reaction to obtain a compound represented by formula (7).
In the present invention, the second nucleophilic addition reaction is performed in the presence of a fifth organic solvent in order to allow the reaction to proceed more smoothly.
Preferably, the fifth organic solvent is an anhydrous aprotic solvent; more preferably, the fifth solvent is one or more of diethyl ether, tetrahydrofuran, dioxane and dichloromethane.
The amount of the fifth organic solvent to be used may be 5 to 20mL, preferably 10 to 15mL, based on 1mmol of the compound represented by formula (5) or the compound represented by formula (6).
According to the present invention, in order to promote the progress of the second nucleophilic addition reaction, it is preferable that the second nucleophilic addition reaction is carried out in the presence of the first catalyst.
The first catalyst may be various catalysts commonly used in the art for performing affinity addition reaction, and may be, for example, one or more of cuprous iodide, cuprous cyanide, cuprous chloride, and cuprous bromide; preferably cuprous iodide.
In addition, the amount of the first catalyst to be used may be adjusted depending on the amount of the compound represented by formula (5) or the compound represented by formula (6), for example, the molar ratio of the compound represented by formula (5) or the compound represented by formula (6) to the first catalyst is 1: 0.05-0.4; preferably 1: 0.08-0.15. Whereby the efficiency of the second nucleophilic addition reaction can be improved.
In the present invention, the compound having-CH2-(CH2)m-R8The organometallic reagent of (a) may be, for example, one or more of an organomagnesium reagent, an organozinc reagent, an organolithium reagent, an organocopper reagent, and an organosilicon reagent.
As described above, wherein R8May be-CH ═ CH2or-CH ═ CHX, where X is halogen or substituted borane.
The halogen is preferably chlorine, bromine or iodine, and the substituent in the substituted borane can be selected from one of C1-6 alkyl, C1-6 alkoxy and potassium fluoroborate.
In the present invention, preferably, R is8is-CH ═ CH2。
In addition, having a-CH2-(CH2)m-R8In the organometallic reagent of (2), m is an integer of 0 to 18, and the value of m can be selected according to the target product (i.e., the polyhydroxypyrrolidine compound). For example, to prepare a compound of formula (1-1), having a-CH2-(CH2)m-R8M in the organometallic reagent(s) of (2) should then be chosen to be 2.
According to the invention, preferably, said compound has a-CH2-(CH2)m-R8The organometallic reagent is MgBr-CH2-(CH2)2-CH＝CH2、MgBr-CH2-(CH2)3-CH＝CH2And ZnBr-CH2-(CH2)2-CH＝CH2One or more of (a).
Further, as described herein having a-CH2-(CH2)m-R8The organometallic reagent of (a) can be prepared by methods conventional in the art. With an organic magnesium reagent MgBr-CH2-(CH2)2For example, -CH or CH, may be adopted2-(CH2)2-CH＝CH2Of halogenated compounds, i.e. X-CH2-(CH2)2-CH＝CH2(X is chlorine, bromine or iodine) and magnesium, and the invention is not described in detail.
In the present invention, the compound represented by the formula (5) or the compound represented by the formula (6) and the compound having the formula-CH2-(CH2)m-R8The molar ratio of the organometallic reagent(s) of (a) may be 1: 1.2-3; preferably 1: 1.5-2.0.
According to the present invention, the conditions of the second nucleophilic addition reaction may include: the temperature is-10 to 30 ℃, and the time is 0.5 to 2 hours; preferably, the conditions of the second nucleophilic addition reaction include: the temperature is 10-25 deg.C, and the time is 0.5-1 h.
Furthermore, after the second nucleophilic addition reaction in step 4) is completed, the reaction may be quenched by conventional methods in the art, for example, saturated NH may be used4And (3) quenching the Cl aqueous solution, and refining the quenched product by adopting methods such as extraction and the like after quenching. For example, ethyl acetate may be used for extraction, and the organic phase may be washed, dried and concentrated after extraction as necessary. And will not be described in detail herein.
Thus, a compound represented by the formula (7) was obtained.
Next, the coupling reaction described in step 5) will be described。
In the step 5), the compound shown in the formula (7) obtained in the step 4) and the compound shown in the formula (8) are subjected to coupling reaction to obtain the compound shown in the formula (9).
In the formula (8), R1、R2、R3、R4And R5In keeping with the first aspect of the invention, the selection may be made accordingly based on the target product.
Preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, C3-C8 cycloalkyl, C1-C8 alkoxy and C1-C8 straight chain or branched chain alkyl; more preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, fluorine, chlorine, bromine, amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C1-C6 straight chain or branched chain alkyl; further preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, fluorine, chlorine, methyl and tert-butyl.
Further, preferably, R1、R2、R3、R4And R5Not all hydrogen.
According to the invention, the coupling reaction of step 5) is carried out in the presence of a sixth solvent.
The sixth solvent is not particularly limited, and may be various solvents conventionally used in the art for performing a coupling reaction. For example, the sixth solvent may be one or more of dichloromethane, 1, 2-dichloroethane, and toluene. Preferably, the sixth solvent is dichloromethane.
The amount of the sixth solvent may be adjusted according to the amount of the compound represented by formula (7), for example, the sixth solvent is used in an amount of 10 to 50mL per 1mmol of the compound represented by formula (7); preferably 20-30 mL.
Furthermore, according to the present invention, the coupling reaction may also be carried out in the presence of a second catalyst.
As the second catalyst, for example, a catalyst commonly used in the art for coupling reaction may be used, and for example, the second catalyst may be one or more of a palladium catalyst, a nickel catalyst, a Grubbs catalyst, and a Hoveyda-Grubbs catalyst.
In the experimental process, the inventor of the present invention found that when the catalyst is Hoveyda-Grubbs, the yield of the coupling and the reaction rate can be greatly improved, so that the yield of the prepared polyhydroxy pyrrolidine compound is improved, and the catalyst is very suitable for the coupling reaction described in the present application.
Therefore, in the present invention, it is particularly preferred to carry out the coupling reaction using a second generation Hoveyda-Grubbs catalyst as the second catalyst, which can be obtained commercially.
According to the present invention, the amount of the second catalyst used may be selected according to the total amount of the compound represented by formula (7) and the compound represented by formula (8), and preferably, the molar ratio of the total amount of the compound represented by formula (7) and the compound represented by formula (8) to the second catalyst is 1: 0.03-0.08; more preferably 1: 0.04-0.06. Therefore, the reaction rate of the coupling reaction can be ensured, and the yield is improved.
In the present invention, the molar ratio of the compound represented by formula (7) to the compound represented by formula (8) may be 1: 1.5-15; preferably 1: 3-10.
The coupling reaction is preferably carried out under the protection of an inert gas, and may be carried out under the protection of a gas such as nitrogen, argon, helium, or the like.
According to the present invention, the conditions of the coupling reaction may be conventional in the art, for example, the conditions of the coupling reaction include: the temperature is 30-50 ℃ and the time is 2-24 h; preferably, the conditions of the coupling reaction include: the temperature is 40-45 deg.C, and the time is 6-12 h.
The compound represented by the formula (7) is coupled with the compound represented by the formula (8) by the above coupling reaction to obtain the compound represented by the formula (9).
Next, the catalytic hydrogenation reaction of step 6) will be described。
And 6), carrying out catalytic hydrogenation reaction on the compound shown in the formula (9) and a hydrogen source to obtain the compound shown in the formula (1).
According to the invention, in step 6), the catalytic hydrogenation reaction is carried out in the presence of a seventh solvent.
The seventh solvent is not particularly required, and may be conventionally selected in the art, and for example, may be one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, and water; methanol is preferred.
In addition, the amount of the seventh solvent may be determined according to the amount of the compound represented by formula (9). For example, the seventh organic solvent may be used in an amount of 10 to 50mL with respect to 1mmol of the compound represented by formula (9); preferably, the seventh organic solvent may be used in an amount of 20 to 40mL with respect to 1mmol of the compound represented by formula (9).
According to the present invention, preferably, the catalytic hydrogenation reaction is carried out in the presence of a third catalyst.
The third catalyst may be a catalyst conventionally used in the art for catalytic hydrogenation, and may be, for example, one or more of Pd/C, palladium hydroxide, platinum oxide, and raney nickel, without particular limitation. Preferably, the third catalyst is Pd/C.
Further, the amount of the third catalyst to be used may be selected depending on the amount of the compound represented by formula (9), and for example, the molar ratio of the compound represented by formula (9) to the third catalyst may be 1: 0.03-0.2; preferably 1: 0.05-0.1.
In the present invention, the hydrogen source is not particularly limited, and may be, for example, one or more of hydrogen gas, ammonium formate, formic acid, ammonium acetate, sodium borohydride, cyclohexene, and cyclohexadiene; preferably hydrogen.
The amount of the hydrogen source is selected according to the amount of the compound represented by formula (9), for example, the molar ratio of the compound represented by formula (9) to the hydrogen source may be 1: 20-100; preferably 1: 50-70.
In the present invention, the conditions of the catalytic hydrogenation are not particularly limited and may be conventionally selected in the art, and for example, the conditions of the catalytic hydrogenation reaction include: the temperature is 15-30 ℃, and the time is 6-12 h; in order to improve the efficiency of the catalytic hydrogenation reaction, preferably, the conditions of the catalytic hydrogenation reaction include: the temperature is 20-30 ℃ and the time is 8-10 h.
By the above method, the polyhydroxypyrrolidine compound according to the first aspect of the present invention can be prepared.
In a third aspect, the present invention provides a glycosidase inhibitor comprising a polypyrrolidine compound according to the first aspect of the present invention or a polypyrrolidine compound prepared by the method according to the second aspect of the present invention.
According to a third aspect of the invention, the glycosidase inhibitor is used to inhibit one or more of alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-rhamnosidase, amyloglucosidase and beta-glucuronidase.
In the invention, the glycosidase inhibitor has very good inhibitory activity particularly to alpha-glucosidase, beta-glucosidase and beta-galactosidase.
In addition, the compounds represented by the formulae (1-1) to (1-20) of the present invention exhibit a good inhibitory effect on the above-mentioned glycosidase.
Accordingly, in a particularly preferred embodiment of the present invention, the present invention also provides the use of one or more of the compounds represented by the above formulae (1-1) to (1-20) as glycosidase inhibitors.
Particularly preferably, the invention provides the application of one or more compounds shown in the formulas (1-1) to (1-20) as glycosidase inhibitors in inhibiting alpha-glucosidase, beta-glucosidase and beta-galactosidase.
In a fourth aspect, the present invention provides the use of the polypyrrolidine compounds of the first aspect of the present invention or the polypyrrolidine compounds prepared by the method of the second aspect of the present invention for preparing a medicament, wherein the medicament is at least one selected from the following medicaments: 1) a medicament for the prophylaxis and/or treatment of diabetes; 2) a medicament for preventing and/or treating gaucher's disease; 3) a medicament for the prevention and/or treatment of lysosomal storage disorders; 4) drugs for preventing and/or treating tumors; 5) an antiviral drug.
According to the invention, when the polyhydroxy pyrrolidine compound is used for preparing the medicament, one or more pharmaceutically acceptable carriers can be added into the medicament. For example, the carrier may include one or more of various diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, and lubricants generally used in the pharmaceutical field, without particular limitation.
According to the present invention, the drug may be prepared into various forms that are conventional in the art, such as injection, tablet, powder, granule, capsule, oral liquid, ointment, cream, etc., without particular limitation.
In addition, according to the present invention, the drug prepared by using the polyhydroxy pyrrolidine compound of the present invention can be administered by various administration routes, including but not limited to oral administration, inhalation, rectal administration, transdermal administration, transmucosal administration, subcutaneous administration, intramuscular administration, intravenous administration, and the like.
The present invention will be described in detail below by way of examples.
In the following preparations and test examples, unless otherwise specified, the methods are all conventional in the art, and all reagents used are commercially available reagents.
Nitrones (2-1) and (2-2) used in the following preparations were purchased from Bailingwei science and technology Co.
Preparation example 1: preparation of Compound represented by the formula (1-1)
1) Dissolving nitrone (6.280g, 15mmol) shown in formula (2-1) in 50mL dry THF (tetrahydrofuran), slowly injecting vinyl magnesium bromide solution (30mmol) at 0 deg.C under argon protection, reacting at room temperature (25 deg.C, the same below) for 30min after dropwise addition, adding saturated ammonium chloride solution to quench reaction, extracting water phase with ethyl acetate for 3 times, combining organic phases, washing with saturated sodium chloride solution, adding anhydrous MgSO4Drying, filtering, and distilling under reduced pressure to remove the solvent to obtain 6.312g of a crude product, namely, hydroxylamine represented by the formula (3-1);
2) the crude product (15mmol) was dissolved in 50mL of acetic acid at 20 ℃ after which Cu (OAc) was added2(0.264g, 1.5mmol) and activated zinc powder (14.625g, 0.225mol, activated with 1mol/L hydrochloric acid), reacted at room temperature for 4h, and reactedAfter the reaction, the zinc powder was filtered, the zinc powder was repeatedly washed with ethyl acetate, the filtrate was spin-dried, then dissolved with ethyl acetate, neutralized with a saturated aqueous solution of sodium bicarbonate, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, and anhydrous MgSO was added4Drying, filtering and removing the solvent to obtain 6.301g of crude hydroxylamine reduced product;
the crude hydroxylamine-reduced product (15mmol) was dissolved in 50mL of THF, 10mL of water and sodium bicarbonate (2.52g, 30mmol) were added, CbzCl (3.839g, 22.5mmol) was slowly added dropwise, the solvent was removed after stirring at room temperature for 1h, after adding ethyl acetate and water to dissolve the resulting product, the aqueous phase was washed 3 times with ethyl acetate, after which the organic phases were combined and dried over anhydrous MgSO4Drying, spin-drying the solvent, and performing column chromatography to obtain 6.521g of a product shown in formula (4-1), wherein the total yield of the step is 77% from the nitrone shown in formula (2-1);
3) the above product, i.e., the compound represented by the formula (4-1) (2.748g, 4.878mmol) was dissolved in 50mL of dichloromethane, m-chloroperoxybenzoic acid (1.684g, 9.757mmol) and sodium bicarbonate (0.820g, 9.757mmol) were added, reaction was carried out at room temperature for 3 days, and after the reaction, excess Na was added2S2O3Quenching the solution, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, drying by spinning, and separating by column chromatography to obtain a compound represented by formula (5-1) (1.191g, 2.054mmol, yield 42%) and a compound represented by formula (6-1) (0.502g, 0.8660mmol, yield 17%);
4) magnesium turnings (0.234g, 9.73mmol) were added to a two-necked flask, 20mL of dry THF was added under argon, 5-bromo-1-pentene (1.208g, 8.11mmol) was slowly injected, a reaction was initiated with a bolus of iodine (ca. 50mg), heated to 45 deg.C and reacted for 30min to give the Grignard reagent (MgBr-CH) of 5-bromo-1-pentene2-(CH2)2-CH＝CH2) Standby;
the compound represented by the formula (5-1) (2.352g, 4.054mmol) obtained in step 3) was dissolved in 50mL of dry THF, and thenAfter CuI (77mg, 0.405mmol) was added, the Grignard reagent (6.2mmol) of 5-bromo-1-pentene obtained above was slowly injected at room temperature, reacted for 40min, and then saturated NH was slowly dropped4The reaction was quenched with aqueous Cl. Then adding ethyl acetate to extract the water phase, combining the organic phases, carrying out spin drying, and carrying out column chromatography separation to obtain 2.163g of the compound shown in the formula (7-1), wherein the yield of the step is 82%;
5) dissolving the product obtained in the step 4), namely the compound (128mg, 0.197mmol) shown in the formula (7-1) in dry dichloromethane (5mL), adding 4-methylstyrene (362mg, 0.985mmol) and a catalyst Hoveyda-Grubbs II (20mg, 0.002mmol), reacting overnight (about 8h) under the protection of argon, after the reaction is finished, spin-drying the solvent, and performing column chromatography to obtain 110mg of the compound shown in the formula (9-1), wherein the yield of the step is 75%;
6) dissolving the product obtained in the step 5), namely the compound (110mg, 0.148mmol) shown in the formula (9-1), in 10mL of methanol, adding HCl solution (1mL, 1mol/L) and Pd/C (10mg), reacting overnight (about 8h) under a hydrogen atmosphere, filtering off Pd/C, and spin-drying the solvent to obtain 50mg of the compound shown in the formula (1-1) with the yield of 100%.
1H NMR(400M,CD3OD)δ7.09–7.00(m,4H),4.23(t,J＝6.9Hz,1H),3.97(dd,J1＝6.9Hz,J2＝8.3Hz,1H),3.90–3.76(m,3H),3.43–3.37(m,2H),2.55(t,J＝7.52Hz,2H),2.27(s,3H),1.66–1.57(m,4H),1.54–1.46(m,1H).1.43–1.31(m,5H)13C NMR(100M,CD3OD)δ139.4,134.6,128.5,127.9,75.2,73.7,68.6,64.6,63.4,57.3,35.1,33.2,31.3,29.1,28.8,25.4,19.7；IR(neat,KBr,cm-1)3386,2926,2854,1729,1652,1647,1069.
Preparation example 2: preparation of Compound represented by the formula (1-3)
The procedure was as described in preparation example 1, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 2, 3, 4, 5, 6-pentafluorostyrene, to finally obtain 41mg of the compound represented by the formula (1-2) in a yield of 62%.
1H NMR(500M,CD3OD)δ4.24(t,J＝7Hz,1H,),3.98(t,J＝8.1Hz,1H),3.93–3.78(m,3H),3.41(t,J＝4.2Hz,2H),2.75–2.62(m,2H),1.66–1.56(m,4H)；1.56–1.48(m,1H),1.48–1.34(m,5H)13C NMR(125M,CD3OD)δ146.2–134.2(m),113.9(t,J＝19.2Hz),75.2,73.7,68.54,64.5,63.4,57.3,33.1,29.3,29.0,28.9,28.8,28.7,25.32,25.3,21.7,21.4.
Preparation example 3: preparation of Compound represented by the formula (1-3)
The procedure was as described in preparation example 1, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-chlorostyrene to finally obtain 42mg of the compound represented by formula (1-3).
1H NMR(400M,CD3OD)δ7.26(t,J＝7.4Hz,2H),7.19–7.13(m,2H),4.26(t,J＝7.0Hz,1H),3.99(t,J＝8.2Hz,1H),3.92–3.78(m,3H),3.45–3.38(m,2H),2.63(t,J＝7.5Hz,2H),1.71–1.61(m,4H),1.60–1.48(m,1H),1.48–1.35(m,5H)；13C NMR(100M,CD3OD)δ142.5,128.0,127.9,125.3,75.2,73.7,68.6,64.6,63.4,57.3,35.5,33.2,31.3,29.1,28.8,25.4.
Preparation example 4: preparation of Compound represented by formula (1-4)
The procedure was carried out as described in preparation example 1, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-tert-butylstyrene to finally obtain 52mg of the compound represented by the formula (1-4).
1H NMR(500M,CD3OD)δ7.28(d,J＝8.1Hz,2H),7.09(d,J＝8.1Hz,2H),4.25(t,J＝7.2Hz,1H),4.00(t,J＝6.8Hz,1H),3.94–3.79(m,3H),3.42(dd,J＝2Hz,J＝4.4Hz,2H),2.57(t,J＝7.5Hz,2H),1.68–1.59(m,4H),1.57–1.48(m,1H),1.45–1.36(m,5H),1.30(s,9H)；13C NMR(125M,CD3OD)δ148.0,139.4,127.7,124.7,75.2,73.7,68.6,64.5,63.4,57.3,35.0,33.8,33.2,31.3,30.6,29.1,28.9,25.4.
Preparation example 5: preparation of Compound represented by formula (1-5)
The procedure was as described in preparation example 1, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-fluorostyrene to finally obtain 55mg of the compound represented by the formula (1-5).
1H NMR(500M,CD3OD)δ7.16(dd,J1＝5.8Hz,J2＝8.4Hz,2H),6.96(t,J＝8.8Hz,2H),4.05(t,J＝6.4Hz,1H),3.82(t,J＝6.6Hz,1H),3.73–3.58(m,3H),3.08(dd,J1＝6.3Hz,J2＝10.7Hz,1H),2.99(dd,J1＝4.5Hz,J2＝6.7Hz,1H),2.59(t,J＝7.6Hz,2H),1.64–1.56(m,3H),1.56–1.46(m,2H),1.43–1.32(m,5H)；13C NMR(125M,CD3OD)δ161.2(d.J＝240Hz,),138.4,129.6(d,J＝7.7Hz),114.4(d,J＝21.1Hz),75.2,73.6,68.6,64.5,63.4,57.2,34.6,33.2,31.3,29.0,28.7,25.3.
Preparation example 6: preparation of Compound represented by formula (1-6)
The procedure was as described in preparation example 1, except that,
in step 4), the compound represented by the formula (5-1) was replaced with the same molar amount of the compound represented by the formula (6-1), to finally obtain 41mg of the compound represented by the formula (1-6).
1H NMR(500M,CD3OD)δ7.09–6.99(m,4H),4.24(t,J＝7.0Hz,1H),3.98(dd,J＝6.9Hz,J＝8.4Hz,1H),3.90–3.75(m,3H),3.40(dt,J＝5.0Hz,J＝9,2Hz,2H),2.57(t,J＝7.5Hz,2H),2.29(s,3H),1.67–1.55(m,4H),1.55–1.45(m,1H),1.45–1.32(m,5H)；13C NMR(125M,CD3OD)δ139.4,134.6,128.5,127.9,75.2,73.6,68.6,64.5,63.4,57.2,35.0,33.2,31.3,29.1,28.8,25.4,19.7,19.65.
Preparation example 7: preparation of Compounds represented by the formula (1-7)
The procedure was as described in preparation 6, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 2, 3, 4, 5, 6-pentafluorostyrene to finally obtain 39mg of the compound represented by the formula (1-7).
1H NMR(500M,CD3OD)δ4.24(t,J＝7Hz,1H,),3.98(t,J＝8.1Hz,1H),3.92–3.87(m,1H),3.86(dd,J＝3.6Hz,J＝12.2Hz,1H),3.84(dd,J＝5.2Hz,J＝11.9Hz,1H)3.43–3.37(m,2H),2.75(t,J＝7.4Hz,2H),1.66–1.59(m,4H)；1.55–1.48(m,1H),1.44–1.36(m,5H)13C NMR(125M,CD3OD)δ145.6–115.5(m),75.2,73.7,68.5,64.5,63.4,57.3,33.1,28.9,28.8,28.7,25.3,21.7.
Preparation example 8: preparation of Compounds represented by the formula (1-8)
The procedure was as described in preparation 6, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-chlorostyrene to finally obtain 55mg of the compound represented by formula (1-8).
1H NMR(500M,CD3OD)δ7.28(d,J＝4.4Hz,2H),7.19–7.13(m,2H),4.23(t,J＝6.4Hz,1H),3.97(t,J＝6.8Hz,1H),3.90–3.75(m,3H),3.43–3.35(m,2H),2.61(t,J＝5.5Hz,2H),1.66–1.57(m,4H),1.54–1.46(m,1H),1.43–1.33(m,5H)；13C NMR(125M,CD3OD)δ142.5,128.0,127.9,125.3,75.2,73.7,68.6,64.6,63.4,57.3,35.5,33.2,31.3,29.1,28.8,25.4.
Preparation example 9: preparation of Compound represented by the formula (1-9)
The procedure was carried out as described in preparation example 6, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-tert-butylstyrene to finally obtain 53mg of the compound represented by the formula (1-9).
1H NMR(500M,CD3OD)δ7.27(d,J＝8.2Hz,2H),7.07(d,J＝8.2Hz,2H),4.23(t,J＝7.0Hz,1H),3.96(dd,J＝6.8Hz,J＝8.4Hz,1H),3.90–3.85(m,1H),3.81(dq,J＝5.3Hz,J＝12Hz,2H),3.41–3.36(m,2H),2.56(t,J＝7.5Hz,2H),1.65–1.58(m,4H),1.54–1.46(m,1H),1.43–1.34(m,5H),1.29(s,9H)；13C NMR(125M,CD3OD)δ148.0,139.4,127.7,124.7,75.2,73.7,68.6,64.5,63.4,57.2,35.0,33.7,33.2,31.3,30.6,29.1,28.9,25.4.
Preparation example 10: preparation of Compounds represented by the formula (1-10)
The procedure was as described in preparation 6, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-fluorostyrene to finally obtain 55mg of the compound represented by the formula (1-10).
1H NMR(500M,CD3OD)δ7.17(dd,J1＝5.7Hz,J2＝8.4Hz,2H),6.97(t,J＝8.8Hz,2H),4.24(t,J＝7.1Hz,1H),3.98(dd,J＝6.9Hz,J＝8.4Hz,1H),3.90–3.86(m,1H),3.82(dq,J＝3.5Hz,J＝12.2Hz,2H)3.42–3.37(m,2H),2.60(t,J＝7.6Hz,2H),1.66–1.59(m,4H),1.53–1.46(m,1H),1.43–1.32(m,5H)；13C NMR(125M,CD3OD)δ161.2(d.J＝240.2Hz,),138.4(d,J＝3.2Hz),129.5(d,J＝7.7Hz),114.4(d,J＝21.2Hz),75.2,73.7,68.6,64.5,63.4,57.2,34.6,33.2,31.3,29.0,28.7,25.3.
Preparation example 11: preparation of Compounds represented by the formula (1-11)
The procedure was as described in preparation example 1, except that,
in the step 1), the nitrone shown in the formula (2-1) is replaced by the nitrone shown in the formula (2-2) with the same molar weight, and finally 55mg of the compound shown in the formula (1-11) is obtained.
1H NMR(500M,CD3OD)δ7.06(dd,J1＝2.4Hz,J2＝8.5Hz 4H),4.02(dt,J1＝6.4Hz,J2＝11.6Hz 2H),3.91–3.80(m,3H),3.40(d,J＝2.9Hz 1H),3.25(t,J＝5.8Hz 1H),2.57(t,J＝7.5Hz,2H),2.29(s,3H),1.66–1.48(m,6H),1.45–1.35(m,4H)；13C NMR(125M,CD3OD)δ139.4,134.6,128.5,127.9,75.9,74.7,67.5,66.3,63.6,57.5,35.0,34.0,31.3,29.0,28.8,25.1,19.7.
Preparation example 12: preparation of Compounds represented by the formulae (1-12)
The procedure was as described in preparation 11, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 2, 3, 4, 5, 6-pentafluorostyrene to finally obtain 36mg of the compound represented by the formula (1-12).
1H NMR(500M,CD3OD)δ4.01–3.95(m,2H),3.87–3.75(m,4H),3.21–3.15(m,1H),2.72(t,J＝7.2Hz,2H),1.65–1.52(m,5H),1.45–1.38(m,5H)；13C NMR(125M,CD3OD)δ76.4,75.2,68.0,66.2,63.5,58.2,34.0,29.1,28.8,28.7,25.0,21.7.
Preparation example 13: preparation of Compounds represented by the formula (1-13)
The procedure was as described in preparation 11, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-chlorostyrene to finally obtain 44mg of the compound represented by formula (1-13).
1H NMR(500M,CD3OD)δ7.23(t,J＝7.6Hz,2H),7.17–7.11(m,2H),4.01(dt,J＝6.4Hz,J＝9.7Hz,2H),3.89–3.80(m,3H),3.39(t,J＝3Hz,1H),3.25(t,J＝5.1Hz,1H),2.60(t,J＝7.5Hz,2H),1.67–1.49(m,6H),1.44–1.35(m,4H)；13C NMR(125M,CD3OD)δ142.5,128.0,127.9,125.2,75.9,74.7,67.5,66.4,63.6,57.5,37.6,35.5,34.1,33.2,26.4,26.1,25.1.
Preparation example 14: preparation of Compounds represented by the formulae (1-14)
The procedure was carried out as described in preparation example 11, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-tert-butylstyrene to finally obtain 57mg of the compound represented by the formula (1-14).
1H NMR(500M,CD3OD)δ7.17(d,J＝8.2Hz,2H),6.98(d,J＝8.2Hz,2H),3.90–3.85(m,2H),3.77–3.67(m,3H),3.26–3.22(m,1H),3.11–3.07(m,1H),2.47(t,J＝7.6Hz,2H),1.57–1.39(m,6H),1.38–1.25(m,4H),1.19(s,9H)；13C NMR(125M,CD3OD)δ148.0,139.4,127.7,124.7,76.3,75.1,67.8,66.2,63.5,58.0,34.9,33.7,31.3,30.5,29.0,28.9,25.1.
Preparation example 15: preparation of Compounds represented by the formula (1-15)
The procedure was as described in preparation 11, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-fluorostyrene to finally obtain 55g of the compound represented by the formula (1-15).
1H NMR(500M,CD3OD)δ7.17(dd,J＝5.6Hz,J＝8.4Hz,2H),6.97(t,J＝8.8Hz,2H),4.0–3.94(m,2H),3.90–3.74(m,3H),3.35–3.33(m,1H),3.21–3.14(m,1H),2.60(t,J＝7.6Hz,2H),1.69–1.47(m,6H),1.42–1.32(m,4H)；13C NMR(125M,CD3OD)δ162.2(d,J＝240.3Hz),138.4,129.5(d,J＝7.5Hz),114.4(d,J＝20.9Hz),76.4,75.1,67.9,66.2,63.5,58.1,34.6,34.1,31.3,29.0,28.7,25.1.
Preparation example 16: preparation of Compounds represented by the formulae (1-16)
The procedure was as described in preparation 11, except that,
in step 4), the compound represented by the formula (5-2) was replaced with the same molar amount of the compound represented by the formula (6-2), to finally obtain 46mg of the compound represented by the formula (1-16).
1H NMR(400M,CD3OD)δ7.09–7.02(m,4H),4.10–3.96(m,2H),3.95–3.82(m,3H),3.47–3.39(m,1H),3.31–3.25(m,1H),2.57(t,J＝7.6Hz,2H),2.29(s,3H),1.66–1.51(m,5H),1.47–1.34(m,5H)；13C NMR(125M,CD3OD)δ139.4,134.6,128.5,127.9,75.9,74.7,67.5,66.3,63.6,57.5,35.0,34.0,31.3,29.0,28.8,25.1,19.7.
Preparation example 17: preparation of Compounds represented by the formulae (1-17)
The procedure was as described in preparation 16, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 2, 3, 4, 5, 6-pentafluorostyrene to finally obtain 31mg of the compound represented by the formula (1-17).
1H NMR(500M,CD3OD)δ4.04–3.97(m,2H),3.88–3.81(m,3H),3.42–3.35(m,1H),3.26–3.19(m,1H),2.74(t,J＝7.4Hz,2H),1.65–1.52(m,5H),1.45–1.38(m,5H)；13C NMR(125M,CD3OD)δ76.0,74.8,67.7,66.3,63.5,57.5,35.5,33.9,28.9,28.7,25.0,21.7.
Preparation example 18: preparation of Compounds represented by the formulae (1-18)
The procedure was as described in preparation 16, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-chlorostyrene to finally obtain 48mg of the compound represented by formula (1-18).
1H NMR(500M,CD3OD)δ7.25(t,J＝7.6Hz,2H),7.17–7.11(m,2H),4.03(dt,J＝6.4Hz,J＝9.7Hz,2H),3.93–3.80(m,3H),3.44–3.40(m,1H),3.27(t,J＝5.1Hz,1H),2.62(t,J＝7.5Hz,2H),1.70–1.51(m,6H),1.40–1.39(m,4H)；13C NMR(125M,CD3OD)δ142.5,128.0,127.9,125.2,75.9,74.7,67.5,66.4,63.6,57.5,37.6,35.5,34.1,33.2,26.4,26.1,25.1.
Preparation example 19: preparation of Compounds represented by the formulae (1-19)
The procedure was as described in preparation 16, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-tert-butylstyrene to finally obtain 51mg of the compound represented by the formula (1-19).
1H NMR(500M,CD3OD)δ7.28(d,J＝8.2Hz,2H),7.09(d,J＝8.2Hz,2H),4.06–3.99(m,2H),3.91–3.81(m,3H),3.43–3.38(m,1H),3.26(t,J＝5.2Hz,1H),2.58(t,J＝7.6Hz,2H),1.68–1.50(m,5H),1.38–1.36(m,5H),1.31(s,9H)；13C NMR(125M,CD3OD)δ148.0,139.4,127.7,124.7,75.9,74.7,67.6,66.3,63.6,57.6,35.0,33.8,31.3,30.6,29.0,28.9,25.1.
Preparation example 20: preparation of Compounds represented by the formulae (1-20)
The procedure was as described in preparation 16, except that,
in step 5), 4-methylstyrene was replaced with the same molar amount of 4-fluorostyrene to finally obtain 47mg of the compound represented by the formula (1-20).
1H NMR(500M,CD3OD)δ7.16(t,J＝7.1Hz,2H),6.96(t,J＝8.4Hz,2H),4.50(q,J＝5.9Hz,2H),4.10(t,J＝5.6Hz,1H),3.79(t,J＝6.8,1H),3.75(dd,J＝3.8Hz,J＝11.7Hz,1H),3.67(dd,J＝4.1Hz,J＝11.6Hz,1H),3.56(q,J＝4.1Hz,1H),3.47(t,J＝6.0Hz,1H),2.59(t,J＝7.4Hz,2H),1.85–1.75(m,1H),1.75–1.67(m,1H),1.66–1.57(m,2H)1.53–1.27(m,6H)；13C NMR(125M,CD3OD)δ161.2(d,J＝240.1Hz),138.4(d,J＝3.3Hz),129.5(d,J＝7.5Hz),114.4(d,J＝21.3Hz),80.8,80.1,78.5,67.7,65.9,60.9,34.9,34.6,31.3,27.7,27.6,24.1.
Test example
(1) Test materials and sources
Test compounds: the preparation examples of the invention provide polyhydroxy pyrrolidine compounds shown in formulas (1-1) to (1-20).
Test materials: 4-Nitrophenol pyranoside matrix, disaccharides and various glycosidases (including alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-rhamnosidase, amyloglucosidase, and beta-glucuronidase) were purchased from Sigma-Aldrich.
(2) Test method
Kinetic studies were performed in sodium citrate/phosphate buffer (50mmol/L) at 37 ℃. According to different matrixes, the concentration of the prepared enzyme is 0.1-0.5 mg/mL. The activity test was carried out with 4-nitrophenol pyranoside as substrate, at the optimum activity pH for each enzyme. The substrate, enzyme solution and inhibitor (polyhydroxypyrrolidine compound of the present invention) were incubated at 37 ℃ for 30 minutes, and then the reaction was initiated in an ultraviolet-visible spectrophotometer to measure the absorption of 400nm wavelength light. Data analysis was finally performed using GraFit program [ see leather barrow, r.j.grafitt4.0; erithocus software: staines, UK,1998 ].
(3) Evaluation results
The inhibitory activity results of the polyhydroxy pyrrolidine compounds provided by the invention on glycosidase are shown in tables 1-4.
In the following table, IC50Represents the concentration of the inhibitor at which the inhibition rate of the enzyme is 50%; the percentage in parentheses indicates the inhibition rate of the enzyme at an inhibitor concentration of 1000. mu. mol/L.
TABLE 1
TABLE 2
TABLE 3
TABLE 4
As can be seen from the data in the above table, the polyhydroxypyrrolidine compounds of the present invention have good inhibitory activity against glycosidases. Especially has excellent inhibitory activity to beta-glucosidase and simultaneously shows good selectivity to beta-glucosidase.
In addition, among beta-glucosidases from various sources, the polyhydroxy pyrrolidine compound provided by the invention particularly shows excellent inhibitory activity on the beta-glucosidases from bovine livers.
According to the test examples provided by the invention, the compound shown in the formula (1-1) and the compound shown in the formula (1-3) prepared by the preparation examples of the invention show very significant beta-glucosidase inhibitory activity to bovine liver, and the inhibitory activity is improved by more than ten times, even can be as high as about thousand times compared with other compounds. Meanwhile, the compounds shown in the formula (1-1) and the compounds shown in the formula (1-3) also show obviously lower inhibitory activity on alpha-glucosidase derived from maltase of rat small intestine, so that the influence of the compounds shown in the formula (1-1) and the compounds shown in the formula (1-3) on intestinal tract after being taken as medicinal components is obviously reduced, and the probability and degree of side effects such as diarrhea and the like are greatly reduced. Is very suitable to be used as a medicine component.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A polyhydroxy pyrrolidine compound is characterized in that the structural formula of the polyhydroxy pyrrolidine compound is shown as a formula (1):
wherein R is1、R2、R3、R4And R5Each independently selected from hydrogen, halogen, amino, C3-C10 cycloalkyl,C1-C10 alkoxy and C1-C10 straight chain or branched chain alkyl;
n is an integer of 1 to 20;
denotes a chiral carbon atom.
2. The polyhydroxypyrrolidines according to claim 1, wherein R1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, C3-C8 cycloalkyl, C1-C8 alkoxy and C1-C8 straight chain or branched chain alkyl;
preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, fluorine, chlorine, bromine, amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C1-C6 straight chain or branched chain alkyl;
more preferably, R1、R2、R3、R4And R5Each independently selected from one of hydrogen, fluorine, chlorine, methyl and tert-butyl;
preferably, R1、R2、R3、R4And R5Not all hydrogen;
preferably, n is an integer from 1 to 10;
more preferably, n is an integer from 1 to 6;
preferably, each is independently in the R or S configuration;
preferably, the compound shown in the formula I has 2, 3, 4 and 5-carbon steric configurations of 2R, 3R, 4R and 5R or 2S, 3S, 4S and 5S.
3. A polyhydroxypyrrolidine compound according to claim 1 or 2, wherein the structure of the polyhydroxypyrrolidine compound is any one of the following structures:
4. a method for preparing polyhydroxy pyrrolidine compounds is characterized by comprising the following steps:
1) carrying out a first nucleophilic addition reaction on nitrone shown in a formula (2) and an organic metal reagent with vinyl under the condition of the first nucleophilic addition reaction to obtain hydroxylamine shown in a formula (3),
wherein R is6Is benzyl or benzyl with hydrogen on benzene ring being singly or fully substituted by hydroxyl, alkoxy, nitro or halogen;
denotes a chiral carbon atom;
2) carrying out reduction reaction on hydroxylamine shown in a formula (3) obtained in the step 1) and a reducing agent under a reduction reaction condition, carrying out amino protection reaction on a product obtained by the reduction reaction and an amino protective agent under an amino protection reaction condition to obtain a compound shown in a formula (4),
wherein R is7Is a residue from the amino protecting agent;
preferably, R7Is tert-butoxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl or acetyl;
3) carrying out double bond epoxidation reaction on the compound shown in the formula (4) obtained in the step 2) and peroxide under the condition of double bond epoxidation reaction to obtain a mixture of the compound shown in the formula (5) and the compound shown in the formula (6),
4) reacting the compound represented by the formula (5) or the compound represented by the formula (6) with a compound having a-CH group in the mixture obtained in the step (3)2-(CH2)m-R8The organometallic reagent of (a) is subjected to a second nucleophilic addition reaction under a second nucleophilic addition reaction condition to obtain a compound represented by formula (7),
wherein m is an integer of 0 to 18;
R8is-CH ═ CH2or-CH ═ CHX, where X is halogen or substituted borane, the substituents in the substituted borane being selected from one of C1-6 alkyl, C1-6 alkoxy and potassium fluoroborate;
5) carrying out coupling reaction on the compound shown in the formula (7) obtained in the step 4) and the compound shown in the formula (8) under the coupling reaction condition to obtain a compound shown in the formula (9),
wherein R is1、R2、R3、R4And R5Each independently selected from one of hydrogen, halogen, amino, C3-C10 cycloalkyl, C1-C10 alkoxy and C1-C10 straight chain or branched chain alkyl;
6) carrying out catalytic hydrogenation reaction on a compound shown as a formula (9) and a hydrogen source under the catalytic hydrogenation reaction condition to obtain a compound shown as a formula (1),
wherein n is an integer of 0 to 20, and n is m + 2.
5. The process for producing a polyhydroxypyrrolidine compound according to claim 4, wherein in step 1), the first nucleophilic addition reaction is carried out in the presence of a first solvent;
preferably, the first solvent is an anhydrous aprotic solvent;
preferably, the organometallic reagent having a vinyl group is one or more of an organomagnesium reagent having a vinyl group, an organozinc reagent having a vinyl group, an organolithium reagent having a vinyl group, an organocopper reagent having a vinyl group, and an organosilicon reagent having a vinyl group;
more preferably, the organometallic reagent having a vinyl group is one or more of vinyl magnesium chloride, vinyl magnesium bromide, vinyl lithium and vinyl zinc bromide;
preferably, in step 2), the reduction reaction is carried out in the presence of a second solvent;
more preferably, the second solvent is an acidic solvent;
further preferably, the second solvent is one or more of acetic acid, propionic acid, butyric acid and formic acid;
preferably, the reduction reaction is carried out in the presence of an activator;
more preferably, the activator is Cu (OAc)2、AgOAc、CuSO4And CuCl2One or more of;
preferably, the reducing agent is one or more of zinc powder, iron powder and lithium aluminum hydride;
preferably, in step 2), the amino protection reaction is carried out in the presence of a third solvent;
more preferably, the third solvent is a mixed solvent of an organic solvent and water;
further preferably, the third solvent is a mixed solvent of one or more of diethyl ether, tetrahydrofuran, dioxane and dichloromethane and water;
preferably, the amino protection reaction is carried out in the presence of a first base;
more preferably, the first base is one or more of sodium bicarbonate, sodium hydroxide, potassium bicarbonate and potassium hydroxide;
preferably, the amino protecting agent is one or more of di-tert-butyl carbonate, benzyl chloroformate, allyl chloroformate and fluorenylmethoxycarbonyl chloride;
preferably, the amino protecting group R in the compound represented by the formula (4)7Is benzyloxycarbonyl.
6. The process for producing a polyhydroxypyrrolidine compound according to claim 4, wherein in step 3), the double bond epoxidation reaction is carried out in the presence of a fourth solvent;
preferably, the fourth solvent is one or more of dichloromethane, 1, 2-dichloroethane, acetonitrile, propionitrile, butyronitrile and tert-butanol;
preferably, the double bond epoxidation reaction is carried out in the presence of a second base;
more preferably, the second base is one or more of sodium bicarbonate, disodium hydrogen phosphate, sodium carbonate, potassium bicarbonate and dipotassium hydrogen phosphate;
preferably, the peroxide is one or more of m-chloroperoxybenzoic acid, hydrogen peroxide, Oxone, t-butanol peroxide and peracetic acid;
preferably, in step 4), the second nucleophilic addition reaction is performed in the presence of a fifth organic solvent;
preferably, the fifth organic solvent is an anhydrous aprotic solvent;
more preferably, the fifth solvent is one or more of diethyl ether, tetrahydrofuran, dioxane and dichloromethane;
preferably, the second nucleophilic addition reaction is carried out in the presence of a first catalyst;
more preferably, the first catalyst is one or more of cuprous iodide, cuprous cyanide, cuprous bromide and cuprous chloride;
preferably, having a-CH2-(CH2)m-R8The organic metal reagent is one or more of organic magnesium reagent, organic zinc reagent, organic lithium reagent, organic copper reagent and organic silicon reagent;
more preferably still, the first and second liquid crystal compositions are,said has-CH2-(CH2)m-R8The organometallic reagent is MgBr-CH2-(CH2)2-CH＝CH2、MgBr-CH2-(CH2)3-CH＝CH2、ZnBr-CH2-(CH2)2-CH＝CH2One or more of (a).
7. The process for preparing a polyhydroxypyrrolidine compound according to claim 4, wherein in step 5), the coupling reaction is carried out in the presence of a sixth solvent;
preferably, the sixth solvent is one or more of dichloromethane, 1, 2-dichloroethane and toluene;
preferably, the coupling reaction is carried out in the presence of a second catalyst;
more preferably, the second catalyst is one or more of a palladium catalyst, a nickel catalyst, a Grubbs catalyst and a Hoveyda-Grubbs catalyst;
further preferably, the second catalyst is a Hoveyda-Grubbs catalyst;
preferably, in step 6), the catalytic hydrogenation reaction is carried out in the presence of a seventh solvent;
more preferably, the seventh solvent is one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran and water;
preferably, the catalytic hydrogenation reaction is carried out in the presence of a third catalyst;
more preferably, the third catalyst is one or more of Pd/C, palladium hydroxide, platinum oxide and raney nickel;
preferably, the hydrogen source is one or more of hydrogen gas, ammonium formate, formic acid, ammonium acetate, sodium borohydride, cyclohexene and cyclohexadiene.
8. A glycosidase inhibitor comprising the polypyrrolidine compound of any one of claims 1 to 3 or the polypyrrolidine compound prepared by the preparation method of any one of claims 4 to 7.
9. The glycosidase inhibitor according to claim 8, wherein the glycosidase inhibitor is for inhibiting one or more of alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, beta-mannosidase, alpha-L-fucosidase, alpha-trehalase, alpha-L-rhamnosidase, amyloglucosidase and beta-glucuronidase;
preferably, the glycosidase inhibitor is used to inhibit β -glucosidase;
more preferably, the glycosidase inhibitor is used to inhibit bovine liver-derived β -glucosidase.
10. Use of a polyhydroxypyrrolidine compound according to any one of claims 1 to 3 or a polyhydroxypyrrolidine compound prepared according to the preparation method of any one of claims 4 to 7 for the preparation of a medicament selected from at least one of the following: 1) a medicament for the prophylaxis and/or treatment of diabetes; 2) a medicament for preventing and/or treating gaucher's disease; 3) a medicament for the prevention and/or treatment of lysosomal storage disorders; 4) drugs for preventing and/or treating tumors; 5) an antiviral drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210333880.9A CN114656391B (en) | 2022-03-30 | 2022-03-30 | Polyhydroxy pyrrolidine compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210333880.9A CN114656391B (en) | 2022-03-30 | 2022-03-30 | Polyhydroxy pyrrolidine compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114656391A true CN114656391A (en) | 2022-06-24 |
| CN114656391B CN114656391B (en) | 2023-10-24 |
Family
ID=82033428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210333880.9A Active CN114656391B (en) | 2022-03-30 | 2022-03-30 | Polyhydroxy pyrrolidine compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114656391B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006225344A (en) * | 2005-02-18 | 2006-08-31 | Yoshimura Toshitsugu | 2-acylaminomethyl-3,4-dihydroxypyrrolidine type enzyme inhibitor |
| JP2006225343A (en) * | 2005-02-18 | 2006-08-31 | Yoshimura Toshitsugu | 2-aminomethyl-3,4-dihydroxypyrrolidine type glycosidase inhibitor |
| US20070244184A1 (en) * | 2006-01-09 | 2007-10-18 | Simon Fraser University | Glycosidase inhibitors and methods of synthesizing same |
| US20070275907A1 (en) * | 2006-05-23 | 2007-11-29 | Yuanwei Chen | Glucose transport inhibitors and methods of use |
| WO2011058975A1 (en) * | 2009-11-11 | 2011-05-19 | 国立大学法人富山大学 | Agent for ameliorating postprandial hyperglycemia, and pyrrolidine iminosugar or salt thereof |
| WO2012117219A1 (en) * | 2011-03-02 | 2012-09-07 | Summit Corporation Plc | Pyrrolidine derivatives as selective glycosidase inhibitors and uses thereof |
| CN106349141A (en) * | 2016-08-30 | 2017-01-25 | 中国科学院化学研究所 | Polyhydroxylated pyrrolidine compound as well as preparation method and application thereof |
-
2022
- 2022-03-30 CN CN202210333880.9A patent/CN114656391B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006225344A (en) * | 2005-02-18 | 2006-08-31 | Yoshimura Toshitsugu | 2-acylaminomethyl-3,4-dihydroxypyrrolidine type enzyme inhibitor |
| JP2006225343A (en) * | 2005-02-18 | 2006-08-31 | Yoshimura Toshitsugu | 2-aminomethyl-3,4-dihydroxypyrrolidine type glycosidase inhibitor |
| US20070244184A1 (en) * | 2006-01-09 | 2007-10-18 | Simon Fraser University | Glycosidase inhibitors and methods of synthesizing same |
| US20070275907A1 (en) * | 2006-05-23 | 2007-11-29 | Yuanwei Chen | Glucose transport inhibitors and methods of use |
| WO2011058975A1 (en) * | 2009-11-11 | 2011-05-19 | 国立大学法人富山大学 | Agent for ameliorating postprandial hyperglycemia, and pyrrolidine iminosugar or salt thereof |
| WO2012117219A1 (en) * | 2011-03-02 | 2012-09-07 | Summit Corporation Plc | Pyrrolidine derivatives as selective glycosidase inhibitors and uses thereof |
| CN106349141A (en) * | 2016-08-30 | 2017-01-25 | 中国科学院化学研究所 | Polyhydroxylated pyrrolidine compound as well as preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| BRENDAN J. BYATT,，ET AL.: "Synthesis and Structural Revision of Glyphaeaside C", vol. 23, no. 23, pages 4029 - 4033 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114656391B (en) | 2023-10-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1077566C (en) | 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effect | |
| WO1992009589A1 (en) | Method for preparing taxane derivatives, novel derivatives thereby obtained and pharmaceutical compositions containing same | |
| AU2006217293A1 (en) | Isoxazoline derivative and novel process for its preparation | |
| WO2021185192A1 (en) | Tegoprazan analogues and synthetic method thereof | |
| US20200039914A1 (en) | Cyclohexyl gpr40 agonists for the treatment of type ii diabetes | |
| Mishra et al. | Carbohydrate-based organocatalysts: recent developments and future perspectives | |
| CN111620903A (en) | C-nucleoside analogue, preparation method and application of nitrile-containing C-nucleoside compound for synthesizing Rudexilvir | |
| CN106349141B (en) | Polyhydroxy pyrrolidine compound and preparation method and application thereof | |
| US5434152A (en) | Asymmetric synthesis of (S)-(-)-6-chloro-4- cyclopropyl-3,4-dihydro-4-[(2-pyridyl)ethynyl]-2(1H)-quinazolinone | |
| FR2496103A1 (en) | NOVEL DERIVATIVES OF BENZOPYRAN AND BENZOTHIOPYRAN, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES | |
| WO2010106270A1 (en) | N-[(6-aza-bicyclo[3.2.1]oct-5-yl)-aryl-methyl]-heterobenzamide derivatives, preparation thereof, and therapeutic use of same | |
| CN114656391A (en) | Polyhydroxy pyrrolidine compound and preparation method and application thereof | |
| EP2331555B1 (en) | Ferrocene derivatives having antineoplastic activity | |
| CN115322065A (en) | Method for industrially producing deuterated pharmaceutical intermediate by adopting combination of immobilized nickel and organic base for catalysis | |
| CA2551501A1 (en) | Tolterodine, compositions and uses thereof, and preparation of the same | |
| CN106966943B (en) | C4 branched polyhydroxy pyrrolidine compound and preparation method and application thereof | |
| CN104860975B (en) | A kind of preparation method of bortezomib synthetic intermediate | |
| CN105085356B (en) | Small paper mulberry alkaloid compound and its preparation method and application | |
| CN107353256A (en) | The method of the triazole compounds of 4 acetyl group of one pot process 1,2,3 | |
| WO2012069566A1 (en) | Synthesis of n-heterocycles by reductive alkylation of cyan derivatives | |
| US20120004441A1 (en) | Method of enantioselective addition to imines | |
| CN1990478A (en) | 6-aryl-3-substituted methylene pyranone compounds, preparation process and use thereof | |
| WO2004043952A1 (en) | Novel 2,3-dihydro-4(1h)-pyridinone derivatives, method for production thereof and pharmaceutical composition comprising the same | |
| FR2670780A1 (en) | 4-(Acylamino)benzopyran derivatives, their preparation and their application in therapeutics | |
| CN106117101A (en) | A kind of little Broussonetia papyrifera alkali analog and preparation method thereof and glycosidase inhibitor and application |
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 |