CN101933933A - Application of 2-fluoro-beta-D-glucoside in treating depression - Google Patents
Application of 2-fluoro-beta-D-glucoside in treating depression Download PDFInfo
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Abstract
The invention discloses application of 2-fluoro-beta-D-glucoside compound or pharmaceutically-acceptable salts, ester or solvate thereof in preparing medicaments for treating depression. The structural formula of the 2-fluoro-beta-D-glucoside compound is shown in the specification. On two depressed behavior models and one pharmacological model, the compound respectively expresses the effect of cogent depression resistance after single oral administration at the dose of 45 mg/kg to different species of mice (KM and ICR species), and the effect of depression resistance is higher than that of equivalent hilieidum; and the determination on the spontaneous activities of the mice also indicates that the effective dose point does not express the effect of interfering the spontaneous activities of tested animals.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, particularly, the present invention relates to micromolecule phenol type glucoside compound 2-fluoro-beta-D-glucosides and officinal salt, ester and solvate thereof and be used to prepare the purposes for the treatment of depression.
Background technology
Depression (depression) is the main type of affective disorders (mood disorders), be a kind of low with remarkable and persistent mental state be the syndrome of principal character, clinical manifestation is depressed, pessimistic a, sleep disorder etc., and severe patient often has self inflicted injury impulsion or suicidal thought.
The choice drug of clinical treatment depression is selectivity 5-HT reuptake inhibitor (selective serotonin reuptakeinhibitors now, SSRIs), as fluoxetine (fluoxetine), paroxetine (paroxetine), Sertraline (sertraline) and citalopram (citalopram) etc., be characterized in specific inhibition 5-HT reuptake, and very low to other neurotransmitter receptor affinitys in the brain, compare toxicity with the antidepressants of general classics less; But its onset time is still longer, and finds in clinical trial, uses the patient 9-57% depressive symptom recurrence of SSRIs during keeping treatment.List of references is seen Zheng Minling, Huang Xiangyu, Zhou Min etc. the medication trend of Guangzhou antidepressants and development [J]. and Chinese Journal of New Drugs .2003,12 (3): 224-226.
Along with manifesting and the formation of people's " back to nature " theory in recent years of antidepressant Western medicine side effect, researcheres more and more pay attention to seeking, developing and develop the ideal medicament of treatment depression from natural plants.What foreign study was more at present is hypericin-Herba Hyperici perforati extract; Domestic researcher proves that also many compound recipes, folk prescription, effective ingredients in plant have therapeutical effect to depression.List of references is seen Yuan Changchun, and Yuan spends. anxiety and antidepressant natural drug progress [J]. and Chinese national folk medicine, drug research piece of writing .2009,22-25.The medicine of clinical practice at present need further be researched and developed and be improved not reaching promising result yet aspect drug effect, side reaction control, the addiction control but generally speaking.
Summary of the invention
The invention provides a kind of is 2-fluoro-beta-D glycoside compounds or its officinal salt, ester or the solvate of part with the following formula: compound, is used for the treatment of purposes in the medicine of depression in preparation:
Part is: adjacent fluorophenol
Wherein, glycosyl part is any pyranose or furanose, and representation compound is 2-fluoro-beta-D-galactopyranoside; From being numbered XH004, chemical structural formula is as follows:
This chemical compound is that white is to cream-coloured granular crystal, no special odor.Dissolving fully is partly dissolved in the methanol in water, ethanol, the dimethyl sulfoxine.Insoluble in the ether.The chemical compound 2-fluoro-beta-D-glucosides that relates among the present invention is to be the analog that parent is derived and got with micromolecule phenol glucosides gastrodine and helicide.
Helicide (helicid, PARA FORMALDEHYDE PRILLS(91,95) base benzene-O-β-D-A Luo pyranoside) chemical constitution and Gastrodine (gastrodin is to methylol benzene-O-β-D-pyranglucoside) similar (its structural formula See Figure).These two chemical compounds have similar chemical constitution, all are β-type pyranoside, and difference is the different of glycosyl and functional group.
Result of study about gastrodine and helicide antidepressant effect shows that this two chemical compound has embodied gentle constant antidepressant effect in the mouse anti depression model; Safe and effective, take continuously and do not find to poison or other side reaction.Its shortcoming be onset slowly, action intensity is weak, dosage is big, bioavailability is lower etc.List of references is seen Yang Rong, Xiao Han, wear smooth and explicit. helicide antidepressant effect research [J]. Pharmacology and Clinics of Chinese Materia Medica, 2007:23 (6): 22-23., Duan Lingyan, Xiao Han, Yuan Yan etc. the preliminary study of helicide antidepressant effect [J]. the practical medical .2008 of China, 10 (3): 107-108., Xie Xiaotian, Li Haiyan, Wang Qiang, Zheng Ping. Rhizoma Gastrodiae chemical constitution study overview [J]. the journal .2004 of Yunnan Normal University, 23 (3): 22-25. and Duan Lingyan. with the helicide is the micromolecule phenol monoglycosides chemical compound antidepressant activity screening study [D] of representative. the .2008. of Yunnan University
The present invention is reference with gastrodine and helicide, its chemical constitution is modified, and the neuropharmacology activity of such analog is screened, and has obtained having the analog XH004 of better antidepressant activity.
The purpose of this invention is to provide the purposes that is used to prepare the medicine for the treatment of the depression disease through the micromolecule phenol glycoside compounds 2-fluoro-beta-D-glucosides of structure optimization.
Studies show that through the inventor it is better that above-claimed cpd is used for the treatment of the depression effect.
Representation compound 2-fluoro-beta-D-galactoside (XH004) is on two depressed behavior models and pharmacological model, and different genera mice (KM and ICR kind) single gastric infusion 45mg/Kg all embodies practical antidepressant effect; Its antidepressant effect is higher than the equivalent helicide.Mensuration to spontaneous activity in mice shows that also this effective dose point does not embody the effect of disturbing the animal subject spontaneous activity.In sum, XH004 may become effective antidepressant prodrug.
At present, do not find the report that this chemical compound is applied to anti depressant therapy research.
Description of drawings
Fig. 1 is the experimental result picture that the experiment of KM kind mouse tail suspension can embody antidepressant activity among the present invention.
Fig. 2 is the experimental result picture that the experiment of ICR kind mouse tail suspension can embody antidepressant activity among the present invention.
Fig. 3 is the experimental result picture that the experiment of KM kind mice forced swimming can embody antidepressant activity among the present invention.
Fig. 4 is the experimental result picture that the experiment of ICR kind mice forced swimming can embody antidepressant activity among the present invention.
Fig. 5 is the experimental result picture that KM kind mice opens wild experiment among the present invention.
Fig. 6 is the experimental result picture that ICR kind mice opens wild experiment among the present invention.
The specific embodiment
Pharmacological evaluation is as follows:
One. be subjected to the reagent thing
Title: 2-fluoro-beta-D-galactoside.
Test-compound provides by this research is synthetic voluntarily, grinds suspendible with suspensoid before being tried.
Two. model and control drug
The reserpine injection (Reserpine Injection, RES), Guangdong Bangmin Pharmaceutical Co., Ltd., lot number: 060410;
Impamin (Imipromine hydrochloride, IMI), Sigma company product, article No. (Lot): 105K1319;
Gastrodine (Gastrodine, GAS), Kunming pharmaceutical factory, lot number 200610036;
Helicide (Helicid, HEL), Yuxi, Yunnan is natural drug company limited product incomparably, lot number: 040701;
Suspensoid: 0.02% sodium carboxymethyl cellulose solution (CMC-Na);
Blank solvent is a suspensoid.Positive control medicine imipramine concentration is 7.5mg/Kg, and glucosides class drug level is 45mg/Kg, and reserpine injection administration concentration is 5mg/Kg.The administration volume is 20mL/Kg BW.
Three. laboratory animal
KM (Kunming kind) mice, regular grade,
Body weight 18～22g provides credit number by unming Medical College's Experimental Animal Center (unming Medical College, Zhao Jiadui, Kunming): SCXK (Yunnan) 2008-2011.
The ICR mice, regular grade,
Body weight 18～22g is provided by Chinese Academy of Medical Sciences primate breeding base (clear ancestor, Kunming).Credit number: SDXK (Yunnan) 2005-0004.
The mice sub-cage rearing, 10 in every cage is all freely drunk water, is taken food except that experiment modeling specific (special) requirements, raises 20 ± 2 ℃ of room temperatures, and relative humidity 60 ± 10% keeps the 12h/12h circadian rhythm.
Each experiment mice all is used for experiment adapting to laboratory environment after seven days, fasting can't help being divided at random behind the water 18h blank group, positive controls and to be measured group, every group of at least 10 animals.
Four. data statistics is handled
Adopt SPSS 13.0 statistical packages as statistical tool, observed result adopts χ
2Check (Chi-Square) is its group difference relatively; All the other total datas adopt one factor analysis of variance (One-way ANOVA), and wherein homogeneity of variance person adopts the Dunnett method, and the heterogeneity of variance person adopts the significance of Dannett ' s T3 method check group difference.(x ± s) expression for statistical significance is arranged, is designated as " * " with P＜0.05 to data result with mean+SD; P＜0.01 is designated as " * * " for extremely significantly meaning is arranged.
Five. the drug evaluation model
Adopt two behavior models--the mouse tail suspension model (tail suspension test in mice, TST) and mice forced swimming model (forced swimming test in mice, FST); (reserpine reversal RR) verifies the antidepressant effect of compounds X H002 a pharmacology model--reserpine antagonism.Adopt the wilderness model carried out XH002 to the animal body nervus centralis untoward reaction test.Experiment is carried out between at 2 at 8 thirty to noon in the morning, and every animal is only used once.Concrete operation method as follows.
The experiment of A mouse tail suspension (Tail suspension test in mice, TST)
Reference material is seen Steru L, Chermat R, Thierry B, Simon P.The tail suspension test:A new methodfor screening antidepressant activity in mice[J] .Psychopharmacology, 1985,85:367-370.
At least 10 of every group of mices.Be subjected to the reagent single-dose, after mice is pressed the body weight random packet, fasting 16h, 1h before opening entry, each group is irritated the suspendible solvent of stomach respective concentration respectively or is subjected to the reagent suspension, and solvent is 0.02%CMC-Na; Positive control drug IMI is 30min single intraperitoneal injection administration before beginning to observe all, and solvent is 20 ℃ of distilled water.Positive control drug level imipramine is 7.5mg/Kg, and glucosides class drug level is 45mg/Kg.The administration volume is 20mg/Kg BW.
During experiment, use medical proof fabric that mouse tail is bonded on the horizontal cross bar of the outstanding boot of self-control at the about 2cm of distance tail point place, make animal become the reversal of the natural order of things state, its head is from the about 5cm of desktop, and the observer is to reduce ectocine (seeing accompanying drawing 2) dorsad.Laboratory observation 6min, record is also respectively organized the accumulative total dead time of mice in the 5min of back.When mice is in myasthenia of limbs, sagging naturally, the desperate status metric of the behavior that is considered as more than 2 seconds of stopping action.Observe the mice behavior whether unusual performance (for example health is undesiredly rolled up, spasm, shout etc.) is arranged simultaneously.
The experiment of B mice forced swimming (forced swimming test in mice, FST)
Reference material is seen Porsolt R, Le pichon M, Jalfre M.Depression:a new method animal modelsensitive to antidepressant treatments[J] .Nature, 1977,266:730 and Gong Mengjuan, Wang Liwei, Liu new people. the research overview [J] of big mouse swimming test method. Chinese comparative medicine magazine .2005,15 (5): 311-314.
During experiment mice is placed high 30cm, diameter 18cm, in the glass water vat of depth of water 10cm, 26 ± 1 ℃ of water temperatures are observed mice 6min, the accumulative total dead time in the 4min of record back.
In the experiment, each is organized mice and separates mutual sight line to avoid interference with the black paperboard, and experiment finishes and steams again after mice is dried with thermal oil heater in the back.
At least 10 of every group of mices.Be subjected to the reagent single-dose, mice is by after the body weight random packet, fasting 16h, and 1h before opening entry, what each group was irritated the stomach respective concentration respectively is subjected to reagent or suspendible solvent, and solvent is 0.02%CMC-Na; Positive control drug IMI is 30min single intraperitoneal injection administration before beginning to observe all, and solvent is 20 ℃ of distilled water.Positive control drug level imipramine is 7.5mg/Kg, and glucosides class drug level is 45mg/Kg.The administration volume is 20mg/Kg BW.
C reserpine antagonism (reserpine reversal, RR)
Reference material is seen Davood F, Nazanin M.Antidepressant-like effect of harmane and othercarbolines in the mouse forced swim test[J] .European Neuropsyehoph-armaeology.2006,16:324-328. and Shuji I, Mizuho T, Tetsuaki A.Immunohistochemical study of the serotonergieneuronal system in an animal model of the mood disorder[J] .Experimental Neurology, 2006,201:60-65.
Animal be can't help drinking water after by the body weight random packet, and each group is irritated stomach respectively by respective concentration and is subjected to reagent or distilled water, inserts animal anal 2cm place's survey anus temperature 3 times with 2202 type digital thermometers probe before the administration, and its mean is as basal body temperature (T
0).After this 1h lumbar injection (ip.) 5mg/kg BW reserpine per hour measures the anus temperature 1 time after the administration of mice last, amounts to 4h (T
1h, T
2h, T
3hAnd T
4h).Observe the difference that compares each time point administration group and the variation of matched group anus temperature.Positive control (IMI) treated animal is the 30min intraperitoneal injection before experiment.
1h rises behind the lumbar injection reserpine, surveys the preceding mice blepharoptosis of checking of anus temperature, is as the criterion with the eyelid state and marks
[44]: full cut-off eye, 4 minutes; Closed one's eyes 3/4,3 fen; Closed one's eyes 1/2,2 fen; Closed one's eyes 1/4,1 fen; Open eyes 0 fen entirely.Statistics adopts X 2 test.
When checking the mice blepharoptosis, the motion of observation mice can not, mice is placed on the central observation 15s that diameter is the circular blank sheet of paper of 7.5cm, relatively still stay in the number (akinesian) of the animal in the circle in administration group and the matched group, calculate resisted motion (anti-akinesia) percentage rate, its computing formula is as follows:
D open wild experiment (open field test, OFT)
List of references Barnett S.A.The rat:A study in behavior[M] .Chicago, IL:Aldine, 1966., PorsoltRD.Behacious despair[M] .Enna SJ, Malick JB, Richelson E.Antidepressants Neurochemical, behavioural and clinical perspectives.New York.Raven Press.1981:121] and Prut L, Belzung C.Theopen field as a paradigm to measure the effects of drugs onanxiety-like behaviors:a review[J] .Eur JPharmacol, 2003,46 (3): 3-33.
Autonomic activities experiment belongs to behavioristics's experiment, is by observing in the set time laboratory animal in the active situation that is not subjected under the external interference situation, thus the whether normal effective ways of test experience animal behavior.
The mice autonomic activities measure case that this experiment is used is long 40cm, wide 40cm, and the square plastic box of the no loam cake of high 25cm, bottom surface is divided into 25 lattice that area equates.
Single mice is put into the autonomic activities measure case, adapt to 1min after, in the record 5min mice by bottom center begin in grid pass through the lattice number (locomotions, LOCO), as the index of autonomic activities; After every mouse experiment finishes, all remove Excreta rapidly, and open wild frame bottom surface, the behavior generation of next mice is disturbed in order to avoid smell mark with 1 ‰ aqueous solution wipings of analytical pure acetic acid.
Six, experimental result
1. mouse tail suspension experiment
Compare with blank group mice, IMI (positive drug) and helicide group mouse tail suspension dead time significantly shorten (P＜0.05), and the model success is described.
For KM kind mice and ICR mice, administration group (XH004) mice significantly shortens (P＜0.05) than the blank group mouse tail suspension dead time.This explanation, in the TST model detected, XH004 all can embody antidepressant activity in the different genera mice.KM kind mouse experiment the results are shown in accompanying drawing 1, and ICR kind mouse experiment the results are shown in accompanying drawing 2.
2. mice forced swimming experiment
Compare with blank group mice, IMI (positive drug) and administration group mice non-swimming time significantly shorten (P＜0.01), and the model success is described.
For KM kind mice and ICR mice, administration group (XH004) mice significantly shortens (P＜0.05) than the blank group mouse tail suspension dead time.This explanation, in the FST model detected, XH004 all can embody antidepressant activity in the different genera mice.KM kind mouse experiment the results are shown in accompanying drawing 3, and ICR kind mouse experiment the results are shown in accompanying drawing 4.
3 reserpine antagonistic experiments
KM kind mice to single gastric infusion XH004 has carried out the reserpine antagonistic experiment, with the antidepressant mechanism of preliminary study XH004.Experimental result sees Table 1～table 2:
Table 1.KM kind mice gives the influence that XH002 descends to the inductive body temperature of RES
Result of study shows (seeing Table 1), and the IMI lumbar injection is after 2 hours, and administration group KM mice is subjected to the inductive body temperature speed of RES significantly to be lower than blank group KM mice (P＜0.05), illustrates that model is normal.
Claims (1)
1. be 2-fluoro-beta-D glycoside compounds or its officinal salt, ester or the solvate of part with the following formula: compound, be used for the treatment of purposes in the medicine of depression in preparation:
Part is: adjacent fluorophenol
Wherein, glycosyl part is any pyranose or furanose, and representation compound is:
2-fluoro-beta-D-galactopyranoside; Structural formula is as follows:
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153947A (en) * | 2019-08-21 | 2020-05-15 | 云南巅青生物科技有限公司 | Aromatic ring compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1428345A (en) * | 2002-11-22 | 2003-07-09 | 云大科技股份有限公司 | Chemical synthesis process for preparing gastrodin and its analogous henolic glycoside formula (I) |
| CN1507872A (en) * | 2002-12-16 | 2004-06-30 | 昆明贝克诺顿制药有限公司 | Application of p-benzaldehyde-O-beta-D-allopyranoside in treating depression |
| CN1951950A (en) * | 2006-11-17 | 2007-04-25 | 中国科学院昆明植物研究所 | Helicid modifier and its preparation method and uses |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1428345A (en) * | 2002-11-22 | 2003-07-09 | 云大科技股份有限公司 | Chemical synthesis process for preparing gastrodin and its analogous henolic glycoside formula (I) |
| CN1507872A (en) * | 2002-12-16 | 2004-06-30 | 昆明贝克诺顿制药有限公司 | Application of p-benzaldehyde-O-beta-D-allopyranoside in treating depression |
| CN1951950A (en) * | 2006-11-17 | 2007-04-25 | 中国科学院昆明植物研究所 | Helicid modifier and its preparation method and uses |
Non-Patent Citations (1)
| Title |
|---|
| 《中国药物化学杂志》 20090430 韩武建等 酚性2-乙酰氨基-2-脱氧-beta-D-吡喃葡萄糖苷的合成及抗抑郁活性 第19卷, 第2期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111153947A (en) * | 2019-08-21 | 2020-05-15 | 云南巅青生物科技有限公司 | Aromatic ring compound |
| CN111153947B (en) * | 2019-08-21 | 2021-03-09 | 云南巅青生物科技有限公司 | Aromatic ring compound |
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Application publication date: 20110105 |