CN103980339B - Accumulated snow oxalyl-L-Trp and preparing the application in antidepressant drug - Google Patents
Accumulated snow oxalyl-L-Trp and preparing the application in antidepressant drug Download PDFInfo
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Abstract
The present invention relates to compound accumulated snow oxalyl-L-Trp (X4) and preparing the purposes in antidepressant drug, present invention also offers the pharmaceutical composition containing accumulated snow oxalyl-L-Trp.Experiment proves, accumulated snow oxalyl-L-Trp and pharmaceutical composition thereof are a kind of medicines of safe, efficient, stable, inexpensive prevention and therapy dysthymia disorders, have higher activity, are better than asiatic acid, fluoxetine, have good Development volue.
Description
Technical field
The present invention relates to compound accumulated snow oxalyl-L-Trp and preparing the purposes in antidepressant drug.
Background technology
Along with the increase of the quickening of people's rhythm of life, social pressures, Psychological Endurance reduce, the ratio of suffering from dysthymia disorders is growing on and on.Announce according to the World Health Organization, various patients with depression accounts for population in the world 3% ~ 5%.Expect the year two thousand twenty, dysthymia disorders will become the second largest common disease in the whole world.Therefore, in the urgent need to safety, efficient, cheap thymoleptic.
The medicine being used for the treatment of dysthymia disorders at present mainly contains: tricyclic antidepressants and oxidase inhibitor are as doxepin; Selectivity oxidase inhibitor is as moclobemide; Serotonin cell reabsorption inhibitor is as fluoxetine; Selective N E reuptake inhibitor is as Reboxetine; 5-HT and norepinephrine reuptake double inhibitor are as Venlafaxine; Norepinephrine and specificity 5-HT energy thymoleptic are as mirtazapine.But all there is untoward reaction in various degree, as drowsiness, blurring of vision, hypertension, convulsions and hyposexuality etc., thus limit it and widely use.Therefore, novel, that untoward reaction effect is little thymoleptic are found still imperative.
Herba Centellae total glycosides is primarily of centella asiatica glucoside (asiaticoside) and asiaticoside (madecassoside) composition, from samphire Herba Centellae (Centellaasiatica), extraction and isolation obtains, and has therapeutic action (see Chinese patent CN1387868A and CN1377649A) to depression.And asiatic acid (asiaticacid) and Madecassic acid (madecassicacid) are the aglycon of centella asiatica glucoside and asiaticoside respectively, also be obtained by extraction and isolation in samphire Herba Centellae, we apply for and obtain asiatic acid and derivative is preparing the license (see Chinese patent CN1256090C) of the application in antidepressant drug.We have synthesized again a series of asiatic acid derivative, comprise ester class, amides etc., have studied its antidepressant activity, find asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) there is antidepressant effect, antidepressant effect is better than asiatic acid, bioavailability is higher than asiatic acid, and toxic side effect is little, security is good, is expected to for the preparation of antidepressant medicine.
Summary of the invention
The technical issues that need to address of the present invention are open asiatic acid derivative X4(accumulated snow oxalyl-L-Trps) preparing the application in antidepressant drug, to meet the needs of people.
Have in the active skull cap components process of antidepressant effect in screening, contriver finds that non-volatile fatty contents (asiatic acid and Madecassic acid) also has very strong antidepressant effect in the chemical composition of Herba Centellae except volatile oil and the larger methods of glycosides of polarity.Meanwhile, contriver has prepared a series of amino acid derivative of asiatic acid, therefrom finds asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) there is very strong antidepressant activity, and disclose experimental data and analytical results in an embodiment.
First, the invention provides a kind of asiatic acid derivative X4, described X4 is accumulated snow oxalyl-L-Trp, and chemical structural formula is as follows:
Secondly, the invention provides asiatic acid derivative X4 and preparing the application in antidepressant drug, described asiatic acid derivative X4 is accumulated snow oxalyl-L-Trp.
Again, present invention also offers a kind of antidepressant composition, comprise the asiatic acid derivative X4 for the treatment of significant quantity and pharmaceutically acceptable carrier, described asiatic acid derivative X4 is accumulated snow oxalyl-L-Trp.Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp of addressing) patient needing treatment can also be applied in the form of compositions.
Said pharmaceutically acceptable carrier comprises vehicle, as starch, water etc.; Lubricant, as Magnesium Stearate etc.; Disintegrating agent, as Microcrystalline Cellulose etc.; Weighting agent, as lactose etc.; Caking agent, as pregelatinized Starch, dextrin etc.
Described composition is preferably the asiatic acid derivative X4(accumulated snow oxalyl-L-Trp of 0.1% ~ 99.9% containing weight percent).
In addition, present invention also offers the preparation method of a kind of accumulated snow oxalyl-L-Trp, it is characterized in that asiatic acid and L-Trp to react in tetrahydrofuran (THF).
Preferably, condensing agent 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate (PyBOP) is adopted;
Preferably, in reaction, also add alkali, such as DIPEA (DIEA).
The pharmaceutical composition X4(accumulated snow oxalyl-L-Trp of asiatic acid derivative) method well known in the art can be adopted to make various formulation, as tablet, capsule, granule, suspensoid, emulsion, solution, syrup, patch, sprays, suppository etc., the route of administration such as oral or Non-injective route (as Transdermal absorption, mucous membrane dialysis) are taked to carry out the treatment of dysthymia disorders.
During for patient, dosage is 1 ~ 50mg/kg.d, and this dosage determines according to the age of patient and the situation of body weight and symptom usually.
Experiment proves, asiatic acid derivative X4(accumulated snow oxalyl-L-Trp of the present invention), and pharmaceutical composition is a kind of medicine of safe, efficient, stable, inexpensive prevention and therapy dysthymia disorders, there is higher activity, activity is better than asiatic acid and fluoxetine (Prozac), has good Development volue.
Accompanying drawing explanation
Accompanying drawing 1 is the chemical structural formula of asiatic acid derivative X4.
Embodiment
Content of the present invention is illustrated below by embodiment.In the present invention, the example of the following stated is to set forth the present invention better, is not for limiting the scope of the invention.
Embodiment 1: the preparation of asiatic acid derivative X4
Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) synthetic method as follows: 200mg asiatic acid (JXCS) is dissolved in 10mL tetrahydrofuran (THF), add 220mgPyBOP successively, 100mgDIEA and 120mgL-tryptophane, room temperature reaction is after 5 hours, steaming desolventizes, after column chromatography, obtain product 98mg.Purity: 96%.[M+H]+：675.1。
1HNMR(300MHz,DMSO)：δ12.66–12.37(m,1H),10.82(s,1H),7.51(d,J=7.7Hz,1H),7.28(d,J=8.3Hz,1H),7.16(s,1H),7.11–6.99(m,2H),6.99–6.87(m,1H),4.96(s,1H),4.34(d,J=18.1Hz,2H),4.12(s,2H),3.43(s,1H),3.20–2.98(m,4H),2.02–1.92(m,1H),1.92–1.79(m,1H),1.67(d,J=12.0Hz,5H),1.26(d,J=17.5Hz,10H),1.07(s,2H),0.82(dd,J=41.7,8.1Hz,15H),0.64(s,3H),0.52(s,3H)。
The preparation of embodiment 2, accumulated snow oxalyl-L-Trp tablet
Technique:
Get recipe quantity accumulated snow oxalyl-L-Trp, pulverized 100 mesh sieves, then the starch of recipe quantity, lactose were pulverized 100 mesh sieves, mixing.In the starch that accumulated snow oxalyl-L-Trp, sodium starch glycolate are added mixing and lactose, mixing.Add appropriate 7% starch slurry to mix thoroughly, granulate through 16 order iron silk screen nets, less than 60 DEG C dry, whole grain, adds the mixing of appropriate Magnesium Stearate, compressing tablet after analysis content.Can be made into the tablet of 1000 every sheets containing accumulated snow oxalyl-L-Trp 30mg.
The preparation of embodiment 3, accumulated snow oxalyl-L-Trp capsule
Technique:
Get recipe quantity accumulated snow oxalyl-L-Trp, pulverized 100 mesh sieves, add in the starch of recipe quantity, starch silica gel, mixing, directly incapsulates, and can be made into 1000 every the capsule containing accumulated snow oxalyl-L-Trp 30mg.
The preparation of embodiment 4, accumulated snow oxalyl-L-Trp suspensoid
Technique:
Get recipe quantity accumulated snow oxalyl-L-Trp and be crushed to 200 orders, join in the CMC of swelling good recipe quantity, stir, add distilled water to 100000ml, stir into suspendible, obtain often milliliter of suspensoid containing accumulated snow oxalyl-L-Trp 3mg.
The pharmacokinetics of embodiment 5, accumulated snow oxalyl-L-Trp
Pharmacokinetic
12 SD rats are divided into 2 groups at random, often organize 6,
A group: X4(accumulated snow oxalyl-L-Trp) drug administration by injection;
B group: X4(accumulated snow oxalyl-L-Trp) gastric infusion;
Drug administration by injection dosage 2mg/kg, drug level is 1mg/mL;
Gastric infusion dosage 20mg/kg, drug level is 1mg/mL.
Get blood 0.5mL respectively at 0,5,10,15,30,45,60min, 2h, 3h, 4h, 6h, 8h, 12h, 24h eye socket, be placed in the EP pipe that 1.5mL scribbles heparin sodium, upper and lower jolting 3 times, 3500rpm is centrifugal, and 5min gets supernatant, saves backup to-20 DEG C of refrigerators.
Analysis condition
1) chromatographic condition
Shiseido 3.0 × 100mm3.0umC18 sample size: shunt 1:1 after 5 μ L flow velocity 0.8 posts
Moving phase: ACN:0.1%FA=80:20
2) Mass Spectrometry Conditions
NegativeX4,SIM=527.3Z3,SIM=637.4
DG=10L
Fragmentor=100V
Nb=40psig
Sample treatment
Inside being designated as Z3(concentration is 284ng/mL)
Be followed successively by the standardized solution of 5ug/ml, 2.5ug/ml, 1ug/ml, 0.5ug/ml, 0.25ug/ml, 0.1ug/ml by acetontrile concentration, obtain typical curve 1;
Add 180ul after a concentration 20ul adds 100ul plasma sample in label taking directrix curve 1 respectively and contain interior target acetonitrile solution, after vortex 30S, 12000rpm, centrifugal 10min, get the analysis of supernatant liquor sample introduction.
Same testing sequence carries out the pharmacokinetic of asiatic acid.
Test-results
The bioavailability of asiatic acid: F=AUC
igd
iv/ AUC
ivd
ig=0.83*2/0.34*20=24.41%.
Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) bioavailability:
F=AUC
ig?D
iv/AUC
iv?D
ig=14.974*2/1.9615*20=76.34%。
Conclusion (of pressure testing)
Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) bioavailability be significantly higher than asiatic acid, difference has statistical significance (P<0.01).
The antidepressant effect experiment of embodiment 6, accumulated snow oxalyl-L-Trp
Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) antidepressant effect adopt the desperate model (Tail suspension test and mouse forced swimming test) of acquired mouse to carry out detecting and verifying.
Test medicine
Title: asiatic acid derivative X4(accumulated snow oxalyl-L-Trp)
Proterties: white powder
There is provided unit: organic chemistry teaching and research room of pharmaceutical college of The 2nd Army Medical College
Solvent: 0.5% Xylo-Mucine (0.5%CMC-Na) solution.
Compound method: the suspension becoming desired concn with 0.5%CMC-Na solution preparation, fully stirs evenly gavage before use.
Tested material concentration: 1mg/ml, 2mg/ml, 4mg/ml.
Animal species, strain, sex, body weight, source, conformity certification
ICR mouse, male, body weight 16-18g, SPF level, is purchased from Shanghai Slac Experimental Animal Co., Ltd.'s [Quality of Experimental Animals conformity certification number: SCXK(Shanghai) 2007-0005].
Rearing conditions
All mouse, all freely look for food and drink water, and in room temperature (23 ± 2) DEG C, raise under natural lighting condition.
Dosage is arranged
Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) mouse stomach arranges three dosage groups: 10mg/kg, 20mg/kg, 40mg/kg.
Experimental control
Negative control: 0.5%CMC-Na solution
Positive control: fluoxetine, dosage 20mg/kg, asiatic acid 20mg/kg
Medication
Route of administration: gastric infusion
Administration volume: 10ml/kg
Administration number of times: every day 1 time, continuous 7 days
Every treated animal number: 10
Test key step
1. Tail suspension test
Experiment mice is divided into 6 groups at random, often organizes 10.Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) 3 dosage groups, be respectively 10,20,40mg/kg, fluoxetine group dosage is 20mg/kg, and asiatic acid group dosage is 20mg/kg, and negative control group gives 0.5%CMC-Na solution.Every day gavage once, gavage amount 0.1ml/10g, successive administration 7 days.1h after last administration, be fixed in a horizontal supports at animal tail end 2 centimetres of positions, make animal become reversal of the natural order of things state, upholder is positioned in an open top container, about 5 centimetres away from bottom surface be, its head.Dead time of latter 4 minutes in record mouse 6 minutes, each group mouse parallel running.
Mouse forced swimming test
Experiment mice is divided into 6 groups at random, often organizes 10.Asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) 3 dosage groups, be respectively 10,20,40mg/kg, fluoxetine group dosage is 20mg/kg, and asiatic acid group dosage is 20mg/kg, and negative control group gives 0.5%CMC-Na solution.Every day gavage once, gavage amount 0.1ml/10g, successive administration 7 days.1h after last administration, puts into separately cylinder shape glass jar that is high 20 centimetres, diameter 14 centimetres, the depth of water 10 centimetres in cylinder, water temperature 23-25 DEG C by mouse.When entering water postscript from mouse 6 minutes, record the accumulative dead time in latter 4 minutes, each group mouse parallel running.
Statistical procedures
Testing data SPSS13.0 software processes, and experimental data represents with ± s, adopts one-way analysis of variance (ONA-wayANOVA) inspection.Significance level a=0.05.
Test-results
Occur behavioral despair in mouse tail suspension process, show motionless state, the dead time is 109.0 ± 29.4 seconds.Compare with negative control group, X4(accumulated snow oxalyl-L-Trp) 3 dosage groups (10,20,40mg/kg) and fluoxetine group, asiatic acid group all can obviously shorten the mouse tail suspension dead time, difference has significant (P<0.05, P<0.01).The effect of the middle dosage group (20mg/kg) of X4 is better than asiatic acid group (20mg/kg), suitable with fluoxetine group (8mg/kg).The results are shown in Table 1.
Table 1, X4 are on the impact (± SD, n=10) of mouse tail suspension dead time
Occur behavioral despair in mouse forced swimming test process, show motionless state, the dead time is 94.5 ± 22.6 seconds.Compare with negative control group, X4(accumulated snow oxalyl-L-Trp) 3 dosage groups (10,20,40mg/kg) and fluoxetine, asiatic acid group all can obviously shorten the mouse forced swimming test dead time, difference has significant (P<0.05, P<0.01).The effect that in accumulated snow oxalyl-L-Trp, dosage group (20mg/kg) is organized is better than asiatic acid group (20mg/kg), suitable with fluoxetine group (8mg/kg).The results are shown in Table 2.
Table 2, accumulated snow oxalyl-L-Trp is on the impact (± SD, n=10) of mouse forced swimming test dead time
Conclusion (of pressure testing): asiatic acid derivative X4(accumulated snow oxalyl-L-Trp) there is antidepressant effect, during high dosage, activity is better than control drug fluoxetine.
Embodiment 7, X4(accumulated snow oxalyl-L-Trp) studies on acute toxicity
Experiment material
ICR mouse 20 (being provided by The 2nd Army Medical College animal center), male and female half and half, body weight 18 ~ 22g, animal is fed with granulated feed, freely ingests and drinks water.
X4(accumulated snow oxalyl-L-Trp) prepared by embodiment 1, be mixed with 0.5%CMC-Na the suspension that concentration is 500mg/mL respectively.
Experimental technique
ICR mouse, by the accumulated snow oxalyl-L-Trp of body weight single oral gavage 10ml/kg and 5g/kg, observes the toxic reaction in animal after administration 14 days and death condition.Found that, after the administration of mouse single oral gavage, mouse activity is slow, reposes and moves less, namely recovers normal after 30-50 minute.After administration in 14 days, there is not death in mouse, the 15th day, whole sacrifice, and dissect, each internal organs of visual control, are showed no obvious pathology.
Experimental result
Above-mentioned acute toxicity test result shows, gastric infusion maximum tolerated dose MTD is not less than 5g/Kg, illustrates that the acute toxicity of accumulated snow oxalyl-L-Trp is lower.
To sum up, the invention provides compound accumulated snow oxalyl-L-Trp and composition thereof, be expected to, for prevention and therapy dysthymia disorders, to there is higher activity, be better than asiatic acid and fluoxetine, and bioavailability has had remarkable lifting, has good Development volue.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (5)
1. an asiatic acid derivative X4, its structure is
。
2. an asiatic acid derivative X4 as claimed in claim 1 is preparing the application in antidepressant drug.
3. an antidepressant composition, comprises the asiatic acid derivative X4 according to claim 1 for the treatment of significant quantity and pharmaceutically acceptable carrier.
4. composition according to claim 3, is characterized in that: described asiatic acid derivative X4 is 0.1% ~ 99.9% at pharmaceutical composition weight percent.
5. a preparation method of asiatic acid derivative X4 as claimed in claim 1, is characterized in that asiatic acid and L-Trp to react in tetrahydrofuran (THF).
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543964A (en) * | 2003-11-25 | 2004-11-10 | 中国人民解放军第二军医大学 | Application in antidepressants preparation of asiatic acid and derivation |
| CN1582946A (en) * | 2004-06-09 | 2005-02-23 | 崔福贵 | Use of centellosic acid derivative in preparation of medicines for diseases of cardio-cerebral blood vessels |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543964A (en) * | 2003-11-25 | 2004-11-10 | 中国人民解放军第二军医大学 | Application in antidepressants preparation of asiatic acid and derivation |
| CN1582946A (en) * | 2004-06-09 | 2005-02-23 | 崔福贵 | Use of centellosic acid derivative in preparation of medicines for diseases of cardio-cerebral blood vessels |
Non-Patent Citations (1)
| Title |
|---|
| 3S-1,2,3,4-四氢-β-咔啉-3-羧酸的结构修饰和抗血栓活性研究;薛宝玉等;《首都医科大学学报》;20050228;第26卷(第1期);38 * |
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