CN101774922A - 2,3-dyhydroxyl parabens compound as well as preparation and application thereof - Google Patents
2,3-dyhydroxyl parabens compound as well as preparation and application thereof Download PDFInfo
- Publication number
- CN101774922A CN101774922A CN201010103098A CN201010103098A CN101774922A CN 101774922 A CN101774922 A CN 101774922A CN 201010103098 A CN201010103098 A CN 201010103098A CN 201010103098 A CN201010103098 A CN 201010103098A CN 101774922 A CN101774922 A CN 101774922A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- normal hexane
- application
- dyhydroxyl
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 59
- 239000003814 drug Substances 0.000 claims abstract description 30
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 26
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000741 silica gel Substances 0.000 claims abstract description 5
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 5
- 238000010298 pulverizing process Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 15
- 210000005036 nerve Anatomy 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 241000246500 Gentianella aspera Species 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims 1
- 229960004217 benzyl alcohol Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 20
- 229930014626 natural product Natural products 0.000 abstract description 16
- 238000000034 method Methods 0.000 abstract description 15
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 5
- 230000004770 neurodegeneration Effects 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 3
- 241001071795 Gentiana Species 0.000 abstract 2
- 239000012043 crude product Substances 0.000 abstract 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000000401 methanolic extract Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 108010025020 Nerve Growth Factor Proteins 0.000 description 24
- 102000015336 Nerve Growth Factor Human genes 0.000 description 21
- 230000014759 maintenance of location Effects 0.000 description 13
- 230000008569 process Effects 0.000 description 12
- 238000002199 high-resolution Fourier transform ion cyclotron resonance mass spectrometry Methods 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 8
- 229960001138 acetylsalicylic acid Drugs 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000004069 differentiation Effects 0.000 description 6
- 102000012440 Acetylcholinesterase Human genes 0.000 description 5
- 108010022752 Acetylcholinesterase Proteins 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229940022698 acetylcholinesterase Drugs 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- ZRJBHWIHUMBLCN-UHFFFAOYSA-N Shuangyiping Natural products N1C(=O)C=CC2=C1CC1C(=CC)C2(N)CC(C)=C1 ZRJBHWIHUMBLCN-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- ZRJBHWIHUMBLCN-YQEJDHNASA-N huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@H]1\C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-YQEJDHNASA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- ZRJBHWIHUMBLCN-BMIGLBTASA-N rac-huperzine A Natural products N1C(=O)C=CC2=C1C[C@@H]1C(=CC)[C@@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-BMIGLBTASA-N 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 102000007072 Nerve Growth Factors Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229940053128 nerve growth factor Drugs 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 239000003900 neurotrophic factor Substances 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- ZRJBHWIHUMBLCN-SEQYCRGISA-N Huperzine A Natural products N1C(=O)C=CC2=C1C[C@H]1/C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-SEQYCRGISA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- APLHEOBEIBHCHW-YQEJDHNASA-N Selagine Natural products O=C1NC2=C([C@]3(N)/C(=C/C)/[C@@H](CC(C)=C3)C2)C=C1 APLHEOBEIBHCHW-YQEJDHNASA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000009514 concussion Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229960003530 donepezil Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 229960004136 rivastigmine Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000486199 Gentiana rigescens Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 208000008350 Pruritus Vulvae Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010056530 Vulvovaginal pruritus Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 201000003352 adrenal gland pheochromocytoma Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 101150031224 app gene Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 description 1
- 229960000876 cinnarizine Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 231100000895 deafness Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229930183966 gentiside Natural products 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 230000007472 neurodevelopment Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000006919 peptide aggregation Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000001551 total correlation spectroscopy Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960002726 vincamine Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for separating, extracting and preparing 2,3-dyhydroxyl parabens natural compound from traditional Chinese medicine gentian. The preparation method comprises the following steps of: pulverizing the traditional Chinese medicine gentian, extracting with carbinol, and carrying out suction filteration and concentration to obtain a methanol extract crude product, extracting and separating with 80 percent methanol water solution and normal hexane to obtain normal hexane layer crude sample; and separating the crude sample through a silica gel opening column and separating through an ODS opening column, and purifying by using a reverse HPLC to obtain a target compound. The naturally-separated 2,3-dyhydroxyl parabens compound used as a micromolecule compound represents obvious NGF mimics activity in an in-vitro screening model PC 12 cells for senile dementia, and can be applied to preparing medicaments for preventing neurodegenerative diseases of senile dementia and the like. A structure formula of the compound is shown as the following formula.
Description
Technical field
The invention belongs to the preparation method and the application of compound, relate to a kind of 2, the preparation method of 3-dyhydroxyl parabens natural compounds, and the application of this compounds in nerve degenerative diseases such as prevention and treatment senile dementia.
Background technology
Senile dementia is broadly divided into the three major types type: the dementia of Alzheimer's disease (Alzheimer ' s disease, be called for short AD), vascular dementia and other types.Along with increasing of the aged, the morbidity of senile dementia obviously raises, and has become the 4th major cause that causes grownup's death, is only second to heart trouble, cancer, apoplexy.China senile dementia patient estimates to surpass 5,000,000, accounts for 1/4 of the total case load in the world; And along with the quickening of China's aging population process, this numeral will be more huge, bring great influence for social stability and development.According to statistics, the sickness rate over-65s of Chinese senile dementia is to be to be 30% more than 10%, 80 years old more than 5%, 70 years old, to more than 85 years old then up to 40%.After 20 years, middle-aged people of today will step into the elderly's ranks, and dementia patient's quantity will sharply increase, and the elderly's health also will be related to the stable and development of entire society.Therefore, the medicine of researching and developing nerve degenerative diseases such as effective prophylactic treatment senile dementia has become the medical problem that the whole world presses for solution.
In senile dementia three macrotaxonomies, AD is that sickness rate is the highest, also is most important a kind of dementia form disease.AD is a kind of nerve degenerative diseases, is main clinical disease with memory and Cognitive function damage, can cause can't take care of oneself when serious.The definite pathomechanism of AD it be unclear that, and at present main academic viewpoint has following several: 1. beta-amyloyd polypeptide (A β) toxicity and deposition; 2. cholinergic lacks theory; 3. nerve retrograde affection (Neurodegeneration); 4. other multiple factor is as transgenation theory, oxidative stress theory.
A β deposition and toxicity are one of principal elements of Alzheimer's disease morbidity.The unusual adjusting of the app gene in the neurone causes the gathering of toxicity A β in neurocyte, causes the cascade reaction of pathological change, and then causes the degeneration of neurocyte.The focus of research concentrates on the generation that reduces A β both at home and abroad, thereby the configuration that suppresses A beta peptide aggregation, change A β reduces its neurotoxicity, has had several drugs to enter clinical trial at present.
The medicament categories of present stage treatment AD is a lot of, mainly contain cholinergic agent, acetylcholinesterase (Acetylcholinesterase wherein, AChE) inhibitor, the medicine of main listing has tacrine (tacrine), tartrate rivastigmine (rivastigmine), selagine (huperzine A), E2020 (donepezil) etc.; β, gamma secretase Depressant; The brain metabolism regulators is as vincamine, nimodipine, cinnarizine; Influence the medicine of Radical Metabolism, as vitamins C in conjunction with vitamin-E etc.But these medicines can only delay the progress of the AD course of disease, and reduce gradually with the PD curative effect of medication, side effect is arranged, old friends turn to sight the research and development of new anti senile dementia drug, searching becomes the focus and the difficult point of current research at the medicine and the method for the AD cause of disease.
Studies show that neurotrophic factor all has significant effects to the neurodevelopment and the neural lysis of growing up.In the neurodegeneration animal model, find that (nerve growthfactor NGF) can stop or reduce neuronic regression to nerve growth factor.NGF is human first neurotrophic factor of finding, also is most important neurotrophic factor; It is the biologically active polypeptides that there is the important regulating and controlling effect aspects such as a kind of growth to neurocyte, growth, differentiation and function maintenance; Treatment to sacred diseases such as neuratorphy, neurodegeneration, wound reparations has unusual effect.Discover that NGF to a certain degree can stop the AD progress, it promotes that nerve growth and neuroprotective are the long term studies focuses.Yet it is a polypeptide of being made up of more than 100 amino acid; Reasons such as big and polarity is strong owing to molecular weight, can not pass through hemato encephalic barrier (Blood Brain Barrier), and it is all multifactor to be difficult to mass preparation etc., has limited to its practical clinical, and NGF does not directly also find better methods of treatment the dispensing except that operation in the brain.Therefore, seek and to have similar NGF activity (NGF mimics) and maybe can strengthen its activity (NGFenhancer) and can just become the research focus naturally by the low molecular compound of hemato encephalic barrier.Because PC12 cell (Pheochromocytoma cells, the clone obtains from the rat adrenal pheochromocytoma) has the general feature of neurocyte and the characteristics that can go down to posterity, cell can stop division under the effect of NGF, grows projection, changes into neuron cell.Therefore, the function PC12 cell at cellular and molecular level research NGF is a good model.At present, NGF mimics has been arranged in the phase iii clinical trial stage.
Herbal medicine is the basic substance of Chinese materia medica, is the cornucopia of natural radioactivity organic compound.There is traditional Chinese medical science civilization in several thousand in China, and vast territory and abundant resources, and the famous-region drug of a lot of preciousnesses are arranged, because utilizing of Chinese material medicine resource is more convenient, so also just very important to its new composition and new active research.Studies show that Chinese medicine has significant curative effect to senile dementia, wherein foremost is alkaloid one selagine (huperzine A) that extracts from Herba Lycopodii serrati, and it is the original new drug with independent intellectual property right of Chinese Academy of Sciences institute of materia medica exploitation; It is not only a kind of acetylcholinesterase (AChE) Depressant of efficient highly selective, and can also reduce the nerve cell death that L-glutamic acid brings out; Has the response to oxidative stress that significant protection neurocyte antagonism beta-amyloyd polypeptide (A β) produces; Can be to inductive nerve cell apoptosis effects such as resistive to hydrogen peroxide, inhibitors of protein kinase C; It is one of optimal drug of the senile dementia of whole world treatment at present.
Rough gentian, another name: Radix Gentianae, courage grass.Spring, Qiu Erji excavate, cleaning, drying.Nature and flavor, hardship, cold.Return liver, gallbladder channel.Introduce in 2005 editions pharmacopeia, the function of rough gentian cures mainly: heat-clearing and damp-drying drug, purging the liver of pathogenic fire courage fire.Be used for jaundice due to damp-heat, swelling of vulva pruritus vulvae, band down, persistent erection, eczema itch, hot eyes, deafness, hypochondriac pain, bitter taste, convulsion with spasms.Kind had remarkable similar nerve growth factor active 2 surplus separation and purification obtained ten from the extract of the dry root and rhizome of hard rough gentian Gentianarigescens Franch. under the guiding of PC12 cell bio-activity identification systems, 3-dyhydroxyl parabens new compound, called after gentisides.Up to now, about 2, the 3-dyhydroxyl parabens compound has only the aliphatic chain of chemosynthesis to contain the bibliographical information that carbon number is lower than 11 or 16 carbon; European patent (EP 1 930 002 A1) has been described the application of benzoate compounds formula aspect treatment and prophylaxis of viral infections; Chinese patent (CN 1411339A) and the described benzoic acid derivative of United States Patent (USP) are mainly used in antibacterial, as foodstuff additive etc.
Acetylsalicylic acid (Aspirin, have another name called acetylsalicylic acid), with 2 of natural acquisition, the 3-dyhydroxyl parabens compound has similar parent nucleus, it is classical small molecules NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), clinical application is lasting always for over 100 years more than a hundred years, has stronger analgesic, analgesia, anti-inflammatory, anti rheumatism action.Aspirin has unique effects to anticoagulant, can stop thrombosis, prevents and treats cerebral apoplexy, coronary heart disease etc. with it, all can receive certain effect.In recent years, along with the research that deepens continuously to the NSAIDs pharmacological action, its novel clinical use is also constantly excavated.Epidemiological study shows that the old man who often takes acetylsalicylic acid suffers from the dangerous of AD and cognitive disorder and obviously reduces, and prompting NSAIDs has the potential using value of treatment AD.Research thinks that this possible mechanism is: acetylsalicylic acid can be prevented and treated the inflammatory process of AD and can directly regulate the metabolism of A β.
Aspirin is at the active testing of in-vitro screening model PC 12 cell systems, find that it does not have tangible similar NGF activity, separation and purification obtains from the Chinese medicine rough gentian natural 2, though the parent nucleus of 3-dyhydroxyl parabens compound is similar to the structure of Aspirin, but can cause a high proportion of PC12 cell generation nervous process elongation phenomenon, show naturally 2,3-resorcylic acid ester has good similar NGF activity, has the value of exploitation anti-senile dementia prophylactic treatment medicine.In addition, rough gentian has wide material sources, the advantages such as facility of drawing materials, obtain easily a large amount of 2, the 3-dyhydroxyl parabens compound.With 2, the 3-dyhydroxyl parabens compound is as active guide's thing, and the new drug of nerve degenerative diseases such as research and development prevention and treatment senile dementia is significant.
Summary of the invention
The purpose of this invention is to provide a kind ofly 2, the 3-dyhydroxyl parabens compound has formula (I) general structure:
It is described 2 that another object of the present invention provides, and the preparation method of 3-dyhydroxyl parabens compound realizes by following steps:
1) pulverizing and lixiviate:
After the Chinese medicine rough gentian was pulverized, with lixiviate under methyl alcohol (technical grade) room temperature 4～5 days (concussion once in a while), suction filtration concentrated, and gets methyl alcohol extractive substance study, separates with n-hexane extraction with 80% methanol aqueous solution again, obtains normal hexane layer study;
2) separation and purifying:
(200-300 order, solvent systems are normal hexane: ethyl acetate) through twice silica gel opening column separation earlier with normal hexane layer study; The sample that contains target compound separates by octadecyl silane chromatographic column (ODS) opening column further that (solvent systems is a methyl alcohol: water, methyl alcohol: chloroform); Use reverse hplc purifying twice at last again, moving phase is methanol aqueous solution for the first time, and moving phase is aqueous ethanolic solution for the second time, finally obtains the purpose compound.
A further object of the present invention provides 2, the application of 3-dyhydroxyl parabens compound formula (I) in the medicine of nerve degenerative diseases such as preparation prevention senile dementia.It mainly is the application in preparation treatment Alzheimer's disease nerve degenerative diseases medicines such as (AD).
The present invention further also provides a kind of pharmaceutical composition that prevents nerve degenerative diseases such as senile dementia, and this pharmaceutical composition contains 2 shown in (I) of physiology significant quantity, 3-dyhydroxyl parabens compound and pharmaceutically acceptable carrier or thinner.
Pharmaceutically acceptable carrier described here is meant the pharmaceutical carrier of pharmaceutical field routine, and for example thinner, vehicle wait in this way, weighting agent such as starch, sucrose, Microcrystalline Cellulose etc.; Tackiness agent such as starch slurry, hydroxypropylcellulose, gelatin, polyoxyethylene glycol etc.; Wetting agent such as Magnesium Stearate, micropowder silica gel, polyethylene glycols etc.; Absorption enhancer gathers sorb fat, Yelkin TTS etc., and tensio-active agent poloxamer, smooth, the poly-sorb fat of lipid acid sorb or the like can also add other assistant agent such as flavouring agent, sweeting agent etc. in addition in composition.
Of the present invention 2,3-dyhydroxyl parabens natural compounds can be with the unit dosage form administration, and route of administration can be enteron aisle and non-enteron aisle, comprises oral, muscle, subcutaneous and nasal cavity.
Compound administration approach of the present invention can be intravenously administrable.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and acupoint injection therapy.
The various formulations of pharmaceutical composition of the present invention can for example make activeconstituents mix with one or more carriers according to the conventional production method preparation of pharmaceutical field, are made into required formulation then.
Form of administration can be solid preparation, capsule or liquid preparation, comprises tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder, ointment, liniment or suppository.
Of the present invention 2,3-dyhydroxyl parabens natural compounds has the activity of significant similar nerve growth factor, can obtain to use in nerve degenerative diseases such as prevention senile dementia.Of the present invention 2, the separation and purification from the Chinese medicine rough gentian of 3-dyhydroxyl parabens compound obtains, and is that the class found in the natural product has the compound of new chemical structure (Compound I-C is the compound of known structure, but does not have the report of natural origin.)。As micromolecular compound, natural isolating 2, the 3-dyhydroxyl parabens compound shows significant NGF mimics activity in the in-vitro screening model PC of senile dementia 12 cells., optimize structure as guide's thing with this compounds,, will have important practical significance for the new drug development of prevention and nerve degenerative diseases such as treatment senile dementia etc. carries out basic research.
2, the preparation process of 3-dyhydroxyl parabens compound is to obtain by serial flow processs such as organic solvent lixiviate, solvent distribution, the separation of opening chromatographic column, high performance liquid chromatography (HPLC) purifying, the preparation method has simply, fast, the compound purity advantages of higher that obtains.
Description of drawings
Fig. 12, the HPLC preparation of 3-dyhydroxyl parabens natural compounds.
Fig. 2 adds natural compounds I-A and I-B, the variation that the nervous process differentiation rate of PC 12 cells increases with dosage after 48 hours.
Fig. 3 adds natural compounds I-A and I-B, the Photomicrograph of PC 12 cellular neural projections after 48 hours.
Fig. 4 adds natural compounds I-C～L, the nervous process differentiation rate of PC 12 cells after 48 hours.
Embodiment
Below again foregoing of the present invention is described in further detail by embodiment and the accompanying drawing that such some particular compound is prepared example, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Separation and Extraction 2 from the Chinese medicine rough gentian, the preparation method of 3-dyhydroxyl parabens natural compounds formula (I), and concrete steps are:
1) pulverizing and lixiviate:
After 1980g Chinese medicine rough gentian is pulverized, with lixiviate under 10L methyl alcohol (technical grade) room temperature 5 days (concussion once in a while).Suction filtration obtains methyl alcohol extractive substance study 353.6g after concentrating, and it is divided into two parts extracts, and replaces extracting and separating twice with 80% methanol aqueous solution (1500m1) and normal hexane (500ml).Obtain normal hexane layer study 14.6g altogether.
2) separation and purifying:
(200-300 order, following solvent systems are separated into normal hexane for the first time: ethyl acetate=100: 0,90: 10,85: 15,80: 20,70: 30,50: 50 all by volume through twice silica gel opening column separation earlier with normal hexane layer study; Be separated into for the second time normal hexane: ethyl acetate=90: 10,85: 15); Then, the sample that will contain target compound separates with the ODS opening column further that (solvent systems is methyl alcohol by volume: water=80: 20,85: 15,90: 10,100: 0, methyl alcohol: chloroform=1: 1); At last, the sample (203.4mg) that contains target compound is used the reverse hplc purifying, chromatographic condition again: permaphase ODS-HG-5 (
10/250mm), flow velocity 3ml/min detects wavelength 210nm, and moving phase is methyl alcohol: water=98: 2 obtains the compound behind the HPLC purifying for the first time, referring to Fig. 1.The retention time of Compound I-A～L is followed successively by: 47.1min, 55.8min, 20.0min, 21.5min, 25.1min, 26.9min, 36.8min, 40.0min, 43.3min, 51.0min, 55.8min, 71.7min.
The chromatographic condition of secondary HPLC purifying is: flow velocity 3ml/min, detect wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains Compound I-A (14.8mg, retention time is 43.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 90-100% aqueous ethanolic solution in the 90min, obtains Compound I-B (24.2mg, retention time is 31.9min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 80-95% aqueous ethanolic solution in the 60min, obtains Compound I-C (1.4mg, retention time is 37.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 60min, obtains Compound I-D (4.8mg, retention time is 26.1min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 60min, obtains Compound I-E (1.6mg, retention time is 29.2min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 120min, obtains Compound I-F (2.3mg, retention time is 37.3min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 60min, obtains Compound I-G (2.9mg, retention time is 32.2min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains Compound I-H (2.2mg, retention time is 43.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains Compound I-I (3.2mg, retention time is 44.7min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 85-100% aqueous ethanolic solution in the 90min, obtains Compound I-J (1.0mg, retention time is 47.0min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 90-100% aqueous ethanolic solution in the 60min, obtains Compound I-K (0.2mg, retention time is 36.1min); Flow velocity 3ml/min detects wavelength 210nm, and moving phase is the linear gradient of 90-100% aqueous ethanolic solution in the 60min, obtains Compound I-L (0.2mg, retention time is 39.6min).
Embodiment 2
To the physicochemical characteristics of embodiment 1 gained Compound I-A～L and the qualitative evaluation of chemical structure:
The structure of Compound I-A and I-B through MS, HR MS,
1H NMR,
13C NMR, DEPT, H-HCOSY, HMBC, HSQC and HOHAHA determine.
The structure of Compound I-C～L through MS, HR MS,
1H NMR tests, and determines after comparing with the structure of Compound I-A and I-B.
The physico-chemical property of Compound I-A: white solid, molecular formula are C
29H
50O
4HR FT-ICR MS:m/z 485.3610[M+Na]
+, theoretical value C
29H
50O
4Na:485.3601.Infrared spectra (KBr) value: 3469,2920,1671,1469,1311 and 1155cm
-1UV spectrum (solvent is an acetonitrile): maximum absorption wavelength 318nm; Hydrogen spectrum and carbon spectrum data see Table-1.
The physico-chemical property of Compound I-B: white solid, molecular formula are C
30H
52O
4Specific rotation light value: [α]
D 22+ 2.4 ° (c 2.04, CHCl
3); Infrared spectra (KBr) value: 3476,2920,1674,1468,1309,1153cm
-1UV spectrum (solvent is an acetonitrile): maximum absorption wavelength 318nm; HR FT-ICR MS m/z:499.3775[M+Na]
+, theoretical value C
30H
52O
4Na:499.3758.Hydrogen spectrum and carbon spectrum data see Table-1.
Table-1. hydrogen spectrum and the carbon of natural compounds I-A and I-B are composed data (CDCl
3)
aIn the 500MHz, bracket is coupling constant (J in Hz);
b125MHz.；
cChemical displacement value is: 27.4,29.2,29.5,29.6,29.7,30.0;
dChemical displacement value is: 27.1,29.2,29.5,29.6,29.7, and 30.1.
Determine (hydrolysis reaction of Compound I-B) to Compound I-B aliphatic chain steric configuration
With Compound I-B (8mg), anhydrous K
2CO
3(20mg), 10ml methyl alcohol places the 25ml round-bottomed flask, stirring at room 27 hours.With thin-layer chromatography (developping agent: chloroform) follow the tracks of reaction, after reaction stops, steaming methyl alcohol, thick product 10ml water dissolution, 10ml n-hexane extraction three times.Merge the normal hexane layer, concentrate, silica gel column chromatography (developping agent: chloroform), get Compound I-B-2 (4.2mg, yield: 74%).The steric configuration of Compound I-B aliphatic chain is further determined in the affirmation of the steric configuration of the hydrolysate I-B-2 of Compound I-B.Reaction formula is as follows:
The physico-chemical property of Compound I-B-2: white solid, [α]
D 25+ 3.7 ° (c 1.40, CHCl
3),
1HNMR (500MHz, CDCl
3) δ: 3.64 (t, 2H, J=6.5Hz, H-1 '), 1.57 (m, 2H, H-2 '), 1.25～1.35 (m, 35H, H-3 '～21 '), 1.06～1.14 (m, 2H, H-19 ', 21 '), 0.85 (t, 3H, J=7.5Hz, H-22 '), 0.84 (d, 3H, J=6Hz, H-23 ').
Compound I-C:
White solid, molecular formula are C
23H
38O
4 1H NMR (500MHz, CDCl
3) δ: 11.00 (s, 1H, 2-OH), 7.37 (dd, 1H, J=1.5,8.0Hz, H-6), 7.10 (dd, 1H, J=1.0,8.0Hz, H-4), 6.80 (t, 1H, J=8.0Hz, H-5), 5.63 (s, 1H, 3-OH), 4.34 (t, 2H, J=6.5Hz, H-1 '), 1.77 (m, 2H, H-2 '), 1.43 (m, 2H, H-3 '), 1.25～1.35 (m, 24H, H-4 '～15 '), 0.88 (t, 3H, J=7.0Hz, H-16 '); MS (m/z): 377.39[M-H]
-.
Compound I-D:
White solid, molecular formula are C
24H
40O
4HR FT-ICR MS:m/z 391.2844, theoretical value C
24H
39O
4[M-H]: 391.2854.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，7.5Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.64(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.78(m，2H，H-2’)，1.44(m，2H，H-3’)，1.10～1.38(m，22H，H-4’～15’)，1.08(m，1H，H-15’)，0.86(t，3H，J＝7.0Hz，H-16’)，0.84(d，3H，J＝6.0Hz，H-17’).
Compound I-E:
White solid, molecular formula are C
25H
42O
4HR FT-ICR MS:m/z 405.2999, theoretical value C
25H
41O
4[M-H]: 405.3010.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，8.0Hz，H-6)，7.10(dd，1H，J＝1.0，7.5Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.51(m，1H，H-16’)，1.45(m，2H，H-3’)，1.23～1.36(m，22H，H-4’～14’)，1.14(m，2H，H-15’)，0.86(d，6H，J＝6.5Hz，H-17’，18’).
Compound I-F:
White solid, molecular formula are C
25H
42O
4HR FT-ICR MS:m/z 405.2999, theoretical value C
25H
41O
4[M-H]: 405.3010.
1H?NMR(500MHz，CDCl
3)δ：11.01(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝7.5Hz，H-5)，5.64(s，1H，3-OH)，4.34(t，2H，J＝6.0Hz，H-1’)，1.77(m，2H，H-2’)，1.42(m，2H，H-3’)，1.25～1.34(m，28H，H-4’～17’)，0.88(t，3H，J＝7.0Hz，H-18’).
Compound I-G:
White solid, chemical formula are C
26H
44O
4HR FT-ICR MS:m/z 419.3154, theoretical value C
26H
43O
4[M-H]: 419.3167.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，8.0Hz，H-6)，7.10(dd，1H，J＝1.0，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.10～1.38(m，26H，H-4’～17’)，1.08(m，1H，H-17’)，0.86(m，3H，J＝6.5Hz，H-18’)，0.84(d，3H，J＝6.5Hz，H-19’).
Compound I-H:
White solid, molecular formula are C
27H
46O
4HR FT-ICR MS:m/z 433.3310, theoretical value C
27H
45O
4[M-H]: 433.3323.
1H?NMR(500MHz，CDCl
3)δ：11.01(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝7.5Hz，H-5)，5.64(s，1H，3-OH)，4.31(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.10～1.38(m，28H，H-4’～18’)，1.08(m，1H，H-18’)，0.85(m，3H，J＝6.5Hz，H-19’)，0.84(d，3H，J＝6.0Hz，H-20’).
Compound I-I:
White solid, molecular formula are C
28H
48O
4HR FT-ICR MS:m/z 447.3463, theoretical value C
28H
47O
4[M-H]: 447.3480.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.0，8.0Hz，H-6)，7.10(dd，1H，J＝1.0，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.10～1.38(m，30H，H-4’～19’)，1.08(m，1H，H-19’)，0.85(m，3H，J＝7.5Hz，H-20’)，0.84(d，3H，J＝6.5Hz，H-21’).
Compound I-J:
White solid, chemical formula are C
28H
48O
4HR FT-ICR MS:m/z 447.3464, theoretical value C
28H
47O
4[M-H]: 447.3480.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.42(m，2H，H-3’)，1.25～1.34(m，34H，H-4’～20’)，0.88(t，3H，J＝6.5Hz，H-21’).
Compound I-K:
White solid, molecular formula are C
29H
50O
4HR FT-ICR MS:m/z 461.3627, theoretical value C
29H
49O
4[M-H]: 461.3636.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.45(m，2H，H-3’)，1.25～1.34(m，36H，H-4’～21’)，0.88(t，3H，J＝7.0Hz，H-22’).
Compound I-L:
White solid, molecular formula are C
31H
54O
4HR FT-ICR MS:m/z 489.3931, theoretical value C
31H
53O
4[M-H]: 489.3949.
1H?NMR(500MHz，CDCl
3)δ：11.00(s，1H，2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，H-6)，7.10(dd，1H，J＝1.5，8.0Hz，H-4)，6.80(t，1H，J＝8.0Hz，H-5)，5.63(s，1H，3-OH)，4.34(t，2H，J＝6.5Hz，H-1’)，1.77(m，2H，H-2’)，1.43(m，2H，H-3’)，1.25～1.34(m，40H，H-4’～23’)，0.88(t，3H，J＝6.5Hz，H-24’).
2 of rough gentian source, the biological activity of 3-resorcylic acid alkane ester.
In the neurodegeneration animal model, discover that NGF can stop or reduce neuronic regression, to a certain degree can stop the AD progress, have the nerve growth of promotion and neuroprotective.Because the PC12 cell has the general feature of neurocyte, the PC12 cell can stop division under the effect of NGF, grows projection, changes into neuron cell.Therefore, can cause the PC12 cell transformation to become the compound of neuron cell to have the using value of nerve degenerative diseases such as prevention and treatment senile dementia.
Experimental technique:
1) cultivation of PC 12 cells: connect 20 * 10
4Individual PC 12 cells contain 10ml DMEM substratum (wherein containing 10% horse serum, 5% foetal calf serum) in the culture dish of 100mm, change a subculture two days later, after three days subcultures.Earlier cell is washed twice, add 10ml PBS again in culture dish with PBS, at 37 ℃, 5%CO
2Incubator in cultivated 10 minutes, purge is transferred to the disposable centrifuge tube of 15ml, counts on the blood counting chamber of centrifugal back.The every hole of 24 porocyte culture plates adds the DMEM substratum that 1ml contains serum earlier, and after the cell counting, every hole connects 2 * 10
4Individual cell, CO
2Incubator is cultivated application of sample after 24 hours.
2) active testing: with the negative contrast of DMSO, the positive contrast of NGF 40ng, the DMSO solution that the natural compounds I-A and the I-B of main content is configured to different concns.The DMEM solution (not containing serum) that contains 1%DMSO and sample with 1ml is put into 37 ℃, 5%CO after the former substratum in every hole of 24 porocyte plates is replaced
2Incubator in cultivate.Under the inverted microscope every 24 hours, continuous 6 days observation of cell metamorphosis, the nervous process differentiation rate of record cell (nervous process is longer than the ratio of total cell number under the cell number of one times of cell space diameter and the visual field), about 100 cells under each visual field, picked at random 3 places, and statistics mapping analysis.
3) experimental result:
1. under the concentration of 1-30 μ M, 48 as a child latter two compound all demonstrate good NGF-mimics activity.By Fig. 2, Fig. 3 as seen, the DMSO with 1% is as negative control, Compound I-A and I-B are under the condition of optimal concentration 10 μ M, the nervous process rate of inducing PC 12 cells to produce can surpass positive control NGF inductive projection rate; This experimental result also shows simultaneously, and Compound I-A and I-B compare, and the group difference of the long aliphatic chain end of compound does not influence the biological activity of this type of material as can be known, and concentration can cause cytotoxicity above optimal concentration.Fig. 2 adds natural compounds I-A and I-B, the variation that the nervous process differentiation rate of PC 12 cells increases with dosage after 48 hours, the negative contrast of C:1%DMSO among the figure; The positive contrast of NGF (40ng/ml), the concentration unit M of I-A and I-B.Fig. 3 adds natural compounds I-A and I-B, the Photomicrograph of PC 12 cellular neural projections after 48 hours, figure a, the negative contrast of 1%DMSO; Figure b, the positive contrast of NGF 40ng/ml; Figure c, Compound I-A (10M); Figure d, Compound I-B (1M).
2. natural compounds I-C～L is under the concentration of 1-30 μ M, and 48 all demonstrate significant NGF mimics activity after as a child.Referring to Fig. 4, DMSO with 1% is as negative control, Compound I-C～L is under the optimal concentration condition, and the nervous process rate of inducing PC 12 cells to produce can be compared with positive control NGF inductive nervous process rate, and the too high meeting of compound concentration causes cytotoxicity.Fig. 4 adds natural compounds I-C～L, the nervous process differentiation rate of PC 12 cells after 48 hours, the wherein negative contrast of C:1%DMSO; The positive contrast of NGF (40ng/ml), the concentration unit of I-C～L: M.
Claims (6)
1. one kind 2, the 3-dyhydroxyl parabens compound has following general structure (I):
2. claim 1 is described 2, and the preparation method of 3-dyhydroxyl parabens compound realizes by following steps:
(1) pulverizing and lixiviate:
After the Chinese medicine rough gentian was pulverized, with lixiviate under the industrial grade benzenemethanol room temperature 4～5 days, suction filtration concentrated, and gets methyl alcohol extractive substance study, separates with n-hexane extraction with 80% methanol aqueous solution again, obtains normal hexane layer study;
(2) separation and purifying:
Normal hexane layer study separated through silica gel opening column earlier, solvent systems is a normal hexane: ethyl acetate, the sample that contains the purpose compound further separates by the octadecyl silane chromatographic column, solvent systems is a methyl alcohol: water, methyl alcohol: chloroform, use reverse hplc purifying twice at last again, moving phase is methanol aqueous solution for the first time, moving phase is aqueous ethanolic solution for the second time, finally obtains the purpose compound.
3. according to claim 12, the application of 3-dyhydroxyl parabens compound in the medicine of preparation prevention senile dementia nerve degenerative diseases.
4. application according to claim 3 is characterized in that, the application in preparation treatment Alzheimer disease drug.
5. according to claim 3 or 4 described application, it is characterized in that the route of administration of described medicine is enteron aisle and non-enteron aisle.
6. according to claim 3 or 4 described application, it is characterized in that the formulation of described medicine is solid preparation or liquid preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010103098 CN101774922B (en) | 2010-01-29 | 2010-01-29 | 2,3-dyhydroxyl parabens compound as well as preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010103098 CN101774922B (en) | 2010-01-29 | 2010-01-29 | 2,3-dyhydroxyl parabens compound as well as preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101774922A true CN101774922A (en) | 2010-07-14 |
| CN101774922B CN101774922B (en) | 2012-12-26 |
Family
ID=42511539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010103098 Expired - Fee Related CN101774922B (en) | 2010-01-29 | 2010-01-29 | 2,3-dyhydroxyl parabens compound as well as preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101774922B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188477A (en) * | 2011-05-16 | 2011-09-21 | 浙江大学 | Preparation method and application of active component of radix gentianae extractive |
| CN103743828A (en) * | 2013-10-24 | 2014-04-23 | 云南省农业科学院药用植物研究所 | Determination method of benzoic acid ester compounds in traditional Chinese medicine gentianae radix et rhizoma |
| CN106608824A (en) * | 2015-10-21 | 2017-05-03 | 复旦大学 | Aromatic acid ester compound and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100447139C (en) * | 2003-07-08 | 2008-12-31 | 诺瓦提斯公司 | Benzenesulfonylamino compounds and pharmaceutical compositions containing these compounds |
| DE10335726A1 (en) * | 2003-08-05 | 2005-03-03 | Bayer Cropscience Gmbh | Use of hydroxyaromatics as safener |
| UA88792C2 (en) * | 2004-11-10 | 2009-11-25 | Таргасепт, Інк. | Hydroxybenzoate salts of metanicotine compounds |
-
2010
- 2010-01-29 CN CN 201010103098 patent/CN101774922B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102188477A (en) * | 2011-05-16 | 2011-09-21 | 浙江大学 | Preparation method and application of active component of radix gentianae extractive |
| CN102188477B (en) * | 2011-05-16 | 2013-03-13 | 浙江大学 | Preparation method and application of active component of radix gentianae extractive |
| CN103743828A (en) * | 2013-10-24 | 2014-04-23 | 云南省农业科学院药用植物研究所 | Determination method of benzoic acid ester compounds in traditional Chinese medicine gentianae radix et rhizoma |
| CN106608824A (en) * | 2015-10-21 | 2017-05-03 | 复旦大学 | Aromatic acid ester compound and preparation method and application thereof |
| CN106608824B (en) * | 2015-10-21 | 2019-12-20 | 复旦大学 | Aromatic acid ester compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101774922B (en) | 2012-12-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI648257B (en) | Compounds from antrodia camphorata, method for preparing the same and use thereof | |
| WO2011140676A1 (en) | Rhizoma gastrodiae plant extract used to prevent and treat alzheimer disease and vascular dementia and mixed type diseases thereof and preparative method thereof | |
| CN103642887A (en) | Preparation method for celastrol derivatives, products and application thereof | |
| CN101774922B (en) | 2,3-dyhydroxyl parabens compound as well as preparation and application thereof | |
| CN103360456B (en) | Triterpene compound and Synthesis and applications | |
| CN103627772B (en) | The preparation method of a kind of triptolide alcohol derivative and product thereof and application | |
| CN106905281B (en) | Inhibit acetyl and the flavone compound of butyrylcholine esterase and application thereof in thick fruit precipice beans rattan | |
| CN104513290B (en) | Triptolidenol derivative and its application | |
| US10093695B2 (en) | Sterol derivative, preparation method therefor and use thereof | |
| TW201309661A (en) | Compound isolated from monascus purpureus, preparation method therefor and uses thereof | |
| JPH0748255A (en) | Medicinal composition for medical treatment of asthma or inflammation air way disease, containing pyrimidone derivative and similar compound | |
| CN108659089B (en) | Sterol compound with antioxidant effect and application thereof in preparation of medicines | |
| CN103360451B (en) | The preparation of cucurbitane compound and pharmaceutical use thereof | |
| CN106236792B (en) | The preparation of Folum Ilicis extract and anti-alzheimer's disease purposes | |
| CN102188477B (en) | Preparation method and application of active component of radix gentianae extractive | |
| CN113717190B (en) | Indole alkaloid and pharmaceutical composition thereof, and preparation method and application thereof | |
| CN111848638B (en) | Acyl phloroglucinol hetero-terpenoid and application thereof in pharmacy | |
| CN103288914A (en) | Preparation method of traditional Chinese medicine manyflower tickclove herb extract and application in anti-senile dementia medicaments | |
| CN106674086A (en) | Piperidone alkaloid compounds as well as preparation method and application thereof | |
| CN108314618B (en) | Sesquiterpenoids, extraction method and medical application of sesquiterpenoids in resisting Alzheimer's disease | |
| CN102351934B (en) | Steroidal alkaloid compounds and pharmaceutical composition thereof, as well as preparation methods and applications of steroidal alkaloid compounds and pharmaceutical composition of compounds | |
| CN101014560B (en) | Wikstroemia indeca extract, their production and use in the production of anti-inflammatory pharmaceutical | |
| JPS62175476A (en) | Novel sesquiterpene | |
| CN103450323A (en) | Radix ophiopogonis nerve growth factor activity simulating component and compound and preparation | |
| US20050222245A1 (en) | Pyranocoumarin derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: NANJING MEDICAL UNIVERSITY |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Qi Jianhua Inventor after: Chen Ling Inventor after: Gao Lijuan Inventor after: Luo Yan Inventor after: Li Jinyou Inventor before: Qi Jianhua Inventor before: Gao Lijuan Inventor before: Luo Yan Inventor before: Li Jinyou |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: QI JIANHUA GAO LIJUAN LUO YAN LI JINYOU TO: QI JIANHUA CHEN LING GAO LIJUAN LUO YAN LI JINYOU |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20110126 Address after: 310027 Hangzhou, Zhejiang Province, Xihu District, Zhejiang Road, No. 38, No. Applicant after: Zhejiang University Co-applicant after: Nanjing Medical University Address before: 310027 Hangzhou, Zhejiang Province, Xihu District, Zhejiang Road, No. 38, No. Applicant before: Zhejiang University |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121226 Termination date: 20190129 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |