CN109678915A - The preparation method and its pharmaceutical usage of halogenated benzenediol glucoside - Google Patents
The preparation method and its pharmaceutical usage of halogenated benzenediol glucoside Download PDFInfo
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- CN109678915A CN109678915A CN201811444027.4A CN201811444027A CN109678915A CN 109678915 A CN109678915 A CN 109678915A CN 201811444027 A CN201811444027 A CN 201811444027A CN 109678915 A CN109678915 A CN 109678915A
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- Prior art keywords
- anhydrous
- solvent
- halogenated
- reaction
- benzenediol
- Prior art date
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- -1 halogenated benzenediol glucoside Chemical class 0.000 title claims abstract description 13
- 229930182478 glucoside Natural products 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 210000000274 microglia Anatomy 0.000 claims abstract description 12
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 230000001537 neural effect Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 10
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 9
- 108090001005 Interleukin-6 Proteins 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Substances Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 7
- 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 230000021736 acetylation Effects 0.000 claims description 6
- 238000006640 acetylation reaction Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- DUKURNFHYQXCJG-UHFFFAOYSA-N Lewis A pentasaccharide Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(CO)O2)O)C(NC(C)=O)C(OC2C(C(OC3C(OC(O)C(O)C3O)CO)OC(CO)C2O)O)OC1CO DUKURNFHYQXCJG-UHFFFAOYSA-N 0.000 claims description 5
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims description 5
- 229950006780 n-acetylglucosamine Drugs 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 2
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- 230000017858 demethylation Effects 0.000 claims 1
- 238000010520 demethylation reaction Methods 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
- 230000003285 pharmacodynamic effect Effects 0.000 claims 1
- 235000011056 potassium acetate Nutrition 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 10
- 102000004889 Interleukin-6 Human genes 0.000 description 8
- 229940100601 interleukin-6 Drugs 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 235000013824 polyphenols Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- LYFBZGKZAZBANN-UHFFFAOYSA-N 5-fluorobenzene-1,3-diol Chemical class OC1=CC(O)=CC(F)=C1 LYFBZGKZAZBANN-UHFFFAOYSA-N 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010029240 Neuritis Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000008442 polyphenolic compounds Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MUKYLHIZBOASDM-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid 2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound NC(=N)N(C)CC(O)=O.OCC(O)C(O)C(O)C(O)C(O)=O MUKYLHIZBOASDM-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 241000819233 Tribulus <sea snail> Species 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- NDQKGYXNMLOECO-UHFFFAOYSA-N acetic acid;potassium Chemical compound [K].CC(O)=O NDQKGYXNMLOECO-UHFFFAOYSA-N 0.000 description 1
- 210000001642 activated microglia Anatomy 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001272 acylglucoses Chemical class 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- KOPBYBDAPCDYFK-UHFFFAOYSA-N caesium oxide Chemical compound [O-2].[Cs+].[Cs+] KOPBYBDAPCDYFK-UHFFFAOYSA-N 0.000 description 1
- 229910001942 caesium oxide Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229940047183 tribulus Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of halogenated benzenediol glucosides, and as shown in logical formula (I), the preparation method of this kind of compound, this kind of compound and the pharmaceutical composition containing this kind of compound are in the new opplication for inhibiting neural microglia aspect of inflammation.
Description
Technical field
The invention belongs to drug fields, and in particular to the preparation method of halogenated benzenediol glucoside and its inhibit nerve
The new opplication of microglia aspect of inflammation.
Background technique
Neural microglia is the immunocyte resided in brain and spinal cord, protects central nervous system from invading
It attacks.In the case where neurodegenerative disease, headstroke and brain are wound, microglia is activated, and by chemotactic to sense
It contaminates position and external infection source or impaired tissue is cleared up by phagocytosis.Although the microglia of activation generates many beneficial
Effect, but it continues excessive inflammatory reaction can cause more unfavorable permanent damage to brain tissue[1].Academia is general
All over thinking that neuroinflamation Ahl tribulus sea silent sickness and Parkinson's disease caused by Activated Microglia are closely related[2]
Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) be in neuroinflamation main pro-inflammatory cellular because
Son[3].TNF-α is originally described as a kind of cytotoxicity substance, can selective killing tumour cell, later find
TNF-α also plays critical function during inflammatory reaction after cellular informatics transmitting, infection and wound.TNF-α can induce flower
The release of raw tetraenoic acid metabolin and the generation of lipoperoxide and oxygen radical, above-mentioned substance have serious damage cell membrane
Effect[4].IL-6 is not only important inflammatory molecule, but also increases amyloid precursor protein gene (APP) and generate, and promotes
Beta-amyloid protein (amyloid β-protein, A β) aggregation, all many-sided play such as activating complement damaged nerve cells are imitated
It answers[5]。
Due to weight of the neuroinflamation in terms of neurodegenerative disease (Alzheimer disease, Parkinson's disease etc.) occurrence and development
It acts on, inhibits inflammatory factor, alleviating neuroinflamation becomes the important channel for the treatment of neurodegenerative disease[4].Polyphenols chemical combination
Often have anti-oxidant, anti-inflammatory isoreactivity, natural polyphenol class compound, curcumin anti-neuroinflamation effect it is verified that[6]。
Bibliography
[1]Glass CK；Saijo K；Winner B；et al.Mechanisms underlying inflammation
in neurodegeneration[J].Cell,2010,140:918-934.
[2] Cai Zhiyou, Yan Yong Alzheimer disease microglia neurotoxicity progress [J] Aged in China is miscellaneous
Will, 2008, (04): 404-407.
[3]Tuppo EE；Arias HR.The role of inflammation in Alzheimer's disease
[J].Int J Biochem CellBiol,2005,37:289-305.
[4] Xiao Shuping .IL-6 and Alzheimer disease progress [J] brain and neurological disease magazine, 2003, (06):
380-381.
Effect [J] of the such as [5] Liu Hongcui, Zheng Minhua, Han Hua microglia in Parkinson's disease pathological evolution is modern
Biomedicine progress, 2011, (11): 2194-2196.
[6] Du Guohua, Wang Hongxu, mechanism [J] Aged in China magazine of Liu Ziliang turmeric extract for treating Parkinson's disease,
2017,(10): 2387-2390.
Summary of the invention
Technical problem to be solved by the present invention lies in provide a kind of novel halogenated benzenediol glucoside, its preparation side
Method.
Another technical problem to be solved by this invention is the provision of a kind of pharmaceutical composition, including as work
The compound and pharmaceutically acceptable carrier of the logical formula (I) of property ingredient.
Another technical problem to be solved by this invention is to provide above-mentioned halogenated benzenediol glucoside and combinations thereof
Object is in the new opplication for inhibiting neural microglia aspect of inflammation.
Halogenated benzenediol glucoside general structure of the present invention can be indicated with general formula I
Wherein, X F, Cl, I
Above compound is available but is not limited to following method preparation, and wherein the definition of X is as hereinbefore
The preparation method of compound of the present invention is as follows, and wherein the definition of X is as hereinbefore
Step a: starting material (1) is D-Glucose, prepares the full second of intermediate by acetylation process in anhydrous conditions
Acyl glucose (intermediate 2), preparing reagent and solvent used includes following combination: 1. acetylation reagents: sodium acetate, acetic acid
Potassium, solvent: acetic anhydride；2. acetylation reagent: acetic anhydride, chloroacetic chloride, solvent: anhydrous methylene chloride, anhydrous tetrahydro furan, anhydrous
DMF, acid binding agent: triethylamine, pyridine.Reaction temperature is 25 DEG C~coordinative solvent boiling point, and the reaction time is 1h~for 24 hours.
Step b: intermediate 2 is reacted with the acetic acid solution of hydrogen bromide generates the tetra-acetylated glucopyra of intermediate α-D- bromo
Sugared (intermediate 3), reacting hydrogen bromide solution concentration range used is 10%~50%, and reaction dissolvent is methylene chloride, three chloromethanes
Alkane, toluene, reaction temperature are 0 DEG C~60 DEG C, and the reaction time is 1h~for 24 hours.
Step c: preparing the resorcinol (intermediate 5) accordingly replaced by deprotection under acid condition by marketable material 4,
Acid used is BF3Or HBr, solvent for use are anhydrous ether, anhydrous tetrahydro furan, anhydrous dioxane.Reaction temperature is 0 DEG C
~60 DEG C, the reaction time is 1h~for 24 hours.
Step d: intermediate 3 replaces resorcinol to react generation halogeno-benzene diphenylol acetyl Portugal under alkaline condition with corresponding
Polyglycoside (intermediate 6), alkali used are sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate, and solvent for use is anhydrous third
Ketone, anhydrous methylene chloride, anhydrous tetrahydro furan, anhydrous dioxane, reaction temperature be 0 DEG C~60 DEG C, the reaction time be 1h~
24h。
Step e: intermediate 6 is deprotected under alkaline condition generates the halogenated benzenediol glucoside (7) of target product, used
Alkali is sodium methoxide, sodium ethoxide, and solvent for use is methanol, ethyl alcohol, tetrahydrofuran, and reaction temperature is 0 DEG C~40 DEG C, and the reaction time is
1h~12h.
Novel halogenated benzenediol glucoside of the present invention, which has, inhibits neural microglia inflammatory activity.In vitro
Anti-inflammatory experiment shows that such compound is able to suppress the mouse microglia strain BV-2 cellular inflammation of lipopolysaccharides (LPS) induction
The release of factor TNF-α, IL-6.
The present invention can be used for preparing the drug or pharmaceutical composition with anti-neural microglia inflammatory effect.
Specific embodiment
The following examples are used to further illustrate the present invention, but this does not imply that any limitation of the invention.
Embodiment 1 prepares full acetyl glucosamine
The addition 10g anhydrous sodium acetate in 250mL single-necked flask, 10gD- glucose, using acetic anhydride as solvent about 100ml,
100ml ice water is added after reaction in heating reflux reaction 2h, and stirring is extracted with ethyl acetate 3 times, merges organic phase, according to
Secondary saturation NaHCO3Solution, water washing, evaporating solvent under reduced pressure, 95% ethyl alcohol recrystallization of crude product.Yield 88%.
Embodiment 2 prepares the tetra-acetylated glucopyranose of α-D- bromo
Full acetyl glucosamine 10g is added, in 250ml single-necked flask with 100ml CH2Cl2As solvent, in condition of ice bath
33% hydrogen bromide acetic acid solution 40ml of lower addition, reacts 4h at room temperature, after reaction, ice water is added, stirs, stratification,
Lower organic layer, water layer CH are separated with separatory funnel2Cl2Extraction 2 times merges CH2Cl2Layer, successively with saturation NaHCO3Solution,
Solvent, crude product Diethyl ether recrystallization is evaporated off in water washing.Yield 55%.
The synthesis of the fluoro- 3,5- dihydroxy benzenes of 3 1- of embodiment
Fluoro- 3, the 5- dimethoxy benzene of 1.5g 1- is weighed, CH is used2Cl2Dissolution, is added dropwise BBr3/CH under condition of ice bath2Cl2
Solution 40ml, normal-temperature reaction is overnight, after with methanol be quenched excessive Boron tribromide, ice water is added, stirring removes under reduced pressure big
Part CH2Cl2After water phase is extracted with ethyl acetate three times, combined ethyl acetate layer is used, and saturated salt solution is dry, by ethyl acetate
It is spin-dried for, obtains product 1.2g, crude product directly uses without further purification.
4 1-3 ' of embodiment-fluoro- 5 '-hydroxy benzenes phenolic group -2,3,4,6-, four-O- acetyl group-β-D- glucopyranoside
Mono- hydronium(ion) cesium oxide (1.2equiv) of 1.9g, 2ml H are added in 100ml single-necked flask2O, by 1.2g 1-
Wherein, stirring is added catalytic amount KI (2%mmol) for fluoro- 3,5- dihydroxy benzenes dissolution, and the full acetyl glucosamine of 3.9g bromo is used
It being added in single-necked flask after 10ml acetone solution, a small amount of water is added into flask after reaction by room temperature reaction 12h, it stirs,
It is extracted with ethyl acetate three times, combined ethyl acetate phase is evaporated, and is obtained through column chromatography for separation (petroleum ether: ethyl acetate=4:1)
Product 1.5g, yield 34%.
5 1-3 ' of embodiment-fluoro- 5 '-hydroxy benzenes phenolic group-β-D- glucopyranoside
Fluoro- 5 '-hydroxy benzenes phenolic group -2,3,4,6-, the four-O- acetyl group-β-D- glucopyranoside of 1.5g 1-3 '-is used
The dissolution of 50ml methanol is injected 267mg sodium methoxide (sodium methoxide solid is dissolved in 10ml methanol) under nitrogen protection, reaction 6
Hour, it is evaporated under ice bath with concentrated hydrochloric acid tune PH to neutrality after reaction, column chromatography for separation (ethyl acetate: ethyl alcohol=15:1)
Obtain product 400mg, yield 41.7%.
1H NMR(DMSO-d6, 300MHz): δ 9.90 (s, 1H), δ 6.31 (d, 2H, J=10.8Hz), 6.21 (dd, 1H,
J1=1.8Hz, J2=10.8Hz), 5.30 (d, 1H, J=4.8Hz), 5.09 (d, 1H, J=4.2Hz), 5.02 (d, 1H, J=
5.1Hz), 4.79 (d, 1H, J=7.2Hz), 4.57 (t, 1H, J=5.4Hz), 3.69 (dd, 1H, J1=4.8Hz, J2=
11.4Hz),3.47(dd,1H, J1=5.7Hz, J2=11.7Hz), 3.33~3.14 (m, 4H)
13CNMR(DMSO-d6,75MHz):δ164.94,161.77,159.42,159.22,100.44,99.88,96.56,
96.24, 94.81,94.47,77.08,76.54,73.18,69.68,60.69；
TOF(ESI):C12H15O7F Na(M+Na+) Calculated m/z:313.0694；Found:313.0698
The external anti-neuroinflamation experiment of embodiment 6
Compound I~III be used to measure anti-neuritis activity.
Mouse microglia strain BV-2 cell be used to evaluate the anti-neuritis activity of each compound.The small colloid of mouse is thin
Born of the same parents' strain BV-2 is attached cell, is incubated at DMEM in high glucose culture medium (containing 10% fetal calf serum, 100unit/ml penicillin, 100 μ
G/ml streptomysin) in, condition of culture is 37 DEG C, 5%CO2, according to cell metabolism situation, 1-2d changes liquid, until it is raw to grow to index
It is long-term spare.
Mtt assay detects cell viability: with every hole 4 × 104A cell by BV-2 cell inoculation in 96 orifice plates, culture for 24 hours to
Cell is adherent, each compound is incubated for BV-2 cell for 24 hours with 100 μM of concentration, 20 μ l of MTT 5mg/ml is added in every hole, in 37 DEG C
Incubator is incubated for 4h, and 150 μ l of DMSO is added and precipitates purple and dissolves, microplate reader 490nm measures absorbance, measures cell survival
Rate.It the results are shown in Table 1.Each compound no cytotoxicity under 100 μM of concentration acts on as can be seen from the results.
Cell survival rate (%)=sample sets light absorption value/control group light absorption value × 100%
Influence of the 1 compound I-III of table for BV-2 cell survival rate
TNF-α, IL-6 release detection: each compound with 2 μM of concentration and LPS Co stituation BV-2 cell for 24 hours after, take supernatant
Liquid measures TNF-α, IL-6 secretory volume by kit the method.(TNF alpha Mouse ELISAKit, IL-6 Mouse
ELISAKit, Thermo Fisher company).It the results are shown in Table 2.As can be known from the results, each compound can be effective under 2 μM of concentration
Inhibit the release of inflammatory factor TNF-α, IL-6, there is anti-inflammatory effect.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (6)
1. halogenated benzenediol glucoside shown in logical formula (I):
X indicates F, Cl, I in structural formula.
2. the preparation method of compound as described in claim 1, it is characterised in that include the following steps:
A) D-Glucose is full acetylated, obtain full acetyl glucosamine；
B) by 1 acetoxyl group bromo of full acetyl glucosamine, the tetra-acetylated glucopyranose of α-D- bromo is obtained；
C) by halogenated -1,3 benzenediol dimethyl ether of 5- be deprotected, obtain corresponding 5- it is halogenated-Resorcinol；
D) by the tetra-acetylated glucopyranose of α-D- bromo and 5- it is halogenated-Resorcinol be coupled, obtain disubstituted benzenes phenolic group-acetyl
Base-β-D- glucopyranoside；
E) it is deprotected to obtain halogenated benzenediol glucoside.
3. according to the method described in claim 2, it is characterized by:
A) step a: acetylation reagent and solvent include following combination: (1) acetylation reagent is sodium acetate or potassium acetate, and solvent is
Acetic anhydride；(2) acetylation reagent is acetic anhydride or chloroacetic chloride, and solvent is anhydrous methylene chloride, anhydrous tetrahydro furan or anhydrous
DMF, acid binding agent are triethylamine or pyridine；Reaction temperature is 25 DEG C~coordinative solvent boiling point, and the reaction time is 1h~for 24 hours；
B) step b: bromo is carried out using hydrogen bromide acetic acid solution, bromination range of hydrogen concentrations is 10%~50%, and reaction dissolvent is
Methylene chloride, chloroform, toluene, reaction temperature are 0 DEG C~60 DEG C, and the reaction time is 1h~for 24 hours；
C) step c: demethylation in acid condition, acid used are BF3Or HBr, solvent for use are anhydrous ether, anhydrous tetrahydro furan
It mutters or anhydrous dioxane；Reaction temperature is 0 DEG C~60 DEG C, and the reaction time is 1h~for 24 hours；
D) step d: reacting under alkaline condition, and alkali used is sodium hydroxide, potassium hydroxide, cesium hydroxide or potassium carbonate, institute
It is anhydrous propanone, anhydrous methylene chloride, anhydrous tetrahydro furan or anhydrous dioxane with solvent, reaction temperature is 0 DEG C~60 DEG C,
Reaction time is 1h~for 24 hours；
E) step e: being deprotected under alkaline condition, and alkali used is sodium methoxide, sodium ethoxide, and solvent for use is methanol, ethyl alcohol, tetrahydro
Furans, reaction temperature are 0 DEG C~40 DEG C, and the reaction time is 1h~12h.
4. application of the compound described in claim 1 in terms of the drug that preparation inhibits neural microglia inflammation.
5. application of the compound described in claim 1 in terms of the drug that preparation inhibits neuroinflamation, it is characterised in that inhibit mind
Release through IL-6 and TNF-α during microglia inflammatory reaction.
6. a kind of pharmaceutical composition, it is characterised in that contain carrier acceptable in pharmacodynamics, and at least one claim 1 institute
The compound stated.
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| CN111269279A (en) * | 2020-02-24 | 2020-06-12 | 陕西师范大学 | Method for preparing halogenated sugar under mild condition |
| CN111991423A (en) * | 2020-09-30 | 2020-11-27 | 中国农业科学院特产研究所 | Preparation method and application of cornu Cervi Pantotrichum alcohol extract |
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| CN103977013A (en) * | 2014-03-21 | 2014-08-13 | 崔德华 | Application of catechol glycoside compounds to early-stage Alzhemier's disease |
| CN105418698A (en) * | 2015-12-21 | 2016-03-23 | 上海市第七人民医院 | Amide ethyoxyl-beta-D-glucoside compound and preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111269279A (en) * | 2020-02-24 | 2020-06-12 | 陕西师范大学 | Method for preparing halogenated sugar under mild condition |
| CN111269279B (en) * | 2020-02-24 | 2022-08-05 | 陕西师范大学 | Method for preparing halogenated sugar under mild condition |
| CN111991423A (en) * | 2020-09-30 | 2020-11-27 | 中国农业科学院特产研究所 | Preparation method and application of cornu Cervi Pantotrichum alcohol extract |
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