CN104013638A - Application of swertisin and derivative thereof - Google Patents
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- CN104013638A CN104013638A CN201410217788.1A CN201410217788A CN104013638A CN 104013638 A CN104013638 A CN 104013638A CN 201410217788 A CN201410217788 A CN 201410217788A CN 104013638 A CN104013638 A CN 104013638A
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- ZIIAJIWLQUVGHB-UHFFFAOYSA-N COc1cc(OC(c(cc2)ccc2O)=CC2=O)c2c(O)c1OC Chemical compound COc1cc(OC(c(cc2)ccc2O)=CC2=O)c2c(O)c1OC ZIIAJIWLQUVGHB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a novel application of swertisin and a derivative thereof in preparing an antidepressant drug. The swertisin has an obvious antidepressant effect, can significantly improve functions of a monoamine neurotransmitter system, has an auxiliary therapeutic effect for depression and symptoms thereof, and provides a novel selection for treating depression clinically.
Description
Technical field
The present invention relates to the new purposes of swertisin and derivant thereof.
Background technology
Depression (depression) belongs to affective disorders (mood disorders), be a kind of low as principal character taking remarkable and lasting mental state, and weaken and the syndrome of multiple somatization performance with retardation of thinking, bulesis.Depression is the able-bodied commonly encountered diseases of harm humans, frequently-occurring disease, it is a global main spirits problem, its lifetime prevalence is 6.1%-9.5%, the people of about 13%-20% once had depressed experience all one's life, 15% major depressive disorder patient is dead because of suicide, and annual committed suicide Population size estimation is up to 1,000,000 people.World Health Organization (WHO) (WHO) estimates that approximately there is patients with depression 3.5 hundred million in the whole world, 1996, the investigation about " disease burden " that WHO announces shows: due to illness to cause disability (functional impairment) to add up, depression nineteen ninety occupies the 4th, accounts for 3.7% of the total burden of whole diseases; To be only second to ischemic heart desease to the year two thousand twenty and occupy second, account for 5.7% of the total burden of whole diseases.
Swertisin, is a kind of flavonoid glycoside composition, English name: Swertisin; Molecular weight is 446.41, and molecular formula is: C
22h
22o
10, chemical structural formula is as follows:
Swertisin is present in various plants, has at present comprising of report of acanthaceous rib Herba Rostellulariae, the Zantedeschia aethiopica Spreng. of Araeceae, and the larynx hair flower of Gentianaceae, Swertia franchetiana H.Smith, Swertia japonica, Herba Swertiae Mileensis, Swertia mussotii Franch., Iridaceae, in the plants such as Rhamnaceae.At present existing bibliographical information swertisin has liver-protecting activity, can suppress mouse liver sialidase, and to xanthine oxidase, influenza virus sialidase all has certain inhibitory action.
Have not yet to see the report that swertisin has antidepressant effect.
Summary of the invention
The object of the present invention is to provide the new purposes of swertisin and derivant thereof.
The invention provides compound shown in formula I or its pharmaceutically acceptable salt purposes in the antidepressant medicine of preparation,
Wherein, R1～R3 is independently selected from respectively H or glycosyl.
Further, R1 is H or glycosyl, and R2, R3 are H.
Further, R1 is glycosyl.
Wherein, described glycosyl is selected from glucosyl group, lactose base, galactosyl, malt-base, rhamanopyranosyl, aralino or xylosyl, comprises the arbitrary configuration of various glycosyls.
Further, described glycosyl is selected from glucosyl group, as glucopyranosyl or glucofuranose base.
Further, described glucosyl group is preferably glucopyranosyl.
Preferably, described structural formula of compound is as follows:
Preferably, the aglycon that described compound is swertisin, R1～R3 is H, and its structure is as follows:
This flavone aglycone can be hydrolyzed and be obtained by swertisin.
Wherein, described pharmaceutically acceptable salt is the salt of formula I compound and metal ion or acid formation.
Further, metal ion becomes potassium salt that many employings of salt form formula I compound and metal ion form, sodium salt, magnesium salt, iron salt, zinc salt etc., and conventional salify means are that formula I compound and corresponding alkali reaction are prepared from; Except with metal ion salify, formula I compound can also with sour salify, comprise and pharmaceutically common are machine acid or mineral acid, example hydrochloric acid salt, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, acetate, propionate, oxalates, succinate, fumarate, maleate, tartrate etc.
Further, described medicine is the medicine that improves monoamine neurotransmitter systemic-function; Preferably, described monoamine neurotransmitter system is 5-hydroxy tryptamine mediator system or norepinephrine mediator system.
Wherein, described medicine be compound shown in the formula I that contains effective dose or its pharmaceutically acceptable salt through gastrointestinal absorption dosage form, injection type or Transdermal absorption dosage form.
Above-mentioned various dosage form, is taking compound shown in formula I or its pharmaceutically acceptable salt as main activated feedstock, adds what pharmaceutically acceptable adjuvant or complementary composition were prepared from.
Pharmaceutically acceptable adjuvant of the present invention includes but are not limited to filler (diluent), lubricant (fluidizer or antitack agent), dispersant, wetting agent, binding agent, regulator, solubilizing agent, antioxidant, antibacterial, emulsifying agent, disintegrating agent etc.Binding agent comprises syrup, arabic gum, gelatin, sorbitol, tragacanth, cellulose and derivant thereof (as microcrystalline Cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methylcellulose etc.), gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Filler comprises water, lactose, Icing Sugar, dextrin, starch and derivant thereof, cellulose and derivant thereof, inorganic calcium salt (as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate etc.), sorbitol or glycine etc.; Lubricant comprises micropowder silica gel, magnesium stearate, Pulvis Talci, aluminium hydroxide, boric acid, hydrogenated vegetable oil, Polyethylene Glycol etc.; Disintegrating agent comprises starch and derivant (as carboxymethyl starch sodium, Explotab, pregelatinized Starch, modified starch, hydroxypropyl starch, corn starch etc.), polyvinylpyrrolidone or microcrystalline Cellulose etc.; Wetting agent comprises sodium lauryl sulphate, water or alcohol etc.; Antioxidant packages is containing sodium sulfite, sodium sulfite, sodium pyrosulfite, dibutyl benzoic acid etc.; Antibacterial comprises 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol etc.; Regulator comprises hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate and buffer agent (comprising phosphoric acid dioxy sodium and sodium hydrogen phosphate) etc.; Emulsifier package containing Tween-80, do not have that sour Pyrusussuriensis is smooth, pluronic gram F-68, lecithin, fabaceous lecithin etc.; Solubilizing agent comprises tween 80, bile, glycerol etc.
Described pharmaceutically acceptable complementary composition, it has certain physiologically active, but adding of this composition can not change the leading position of above-claimed cpd in disease treatment process, and only effect is assisted in performance, after combining use with above-claimed cpd, it can produce certain active summation action (not Synergistic), and these auxiliary effects are only the utilizations to this composition known activity, it is the usual auxiliary treatment mode of field of medicaments.If above-mentioned complementary composition and the compounds of this invention are used in conjunction with, still should belong to the scope of protection of the invention.
Except compound of the present invention and pharmaceutically acceptable salt thereof; the relevant pharmaceutical applications of described compound prodrug also should be included in protection scope of the present invention; wherein, described prodrug refers to formula I compound of the present invention obtains after chemical constitution is modified discharge active component and bring into play the compound of drug effect through the conversion of enzyme or non-enzyme in vivo.
In one embodiment of the present invention, present invention includes isotope-labeled formula I compound, described compound isotopically labelled refers to listed Compound Phase is same herein, but one or more atom is replaced by another atom, the atomic mass of this atom or mass number be different from occurring in nature common atomic mass or mass number.Isotope in can introduction-type I compound comprises hydrogen, carbon, nitrogen, oxygen, sulfur, i.e. 2H, 3H, 13C, 14C, 15N, 17O, 18O, 35S.The compound of the formula I that contains above-mentioned isotope and/or other atom isotope and stereoisomer thereof, and within the pharmaceutically useful salt of this compound, stereoisomer all should be included in the scope of the invention.
In some embodiments, one or more compounds of the present invention use that can combine with one another.Also can select compound of the present invention to be combined with any other active agent, for the preparation of medicine or the pharmaceutical composition of regulating cell function or treatment disease.If what use is one group of compound, can be by these compounds simultaneously, respectively or in an orderly manner study subject be carried out to administration.
All stereoisomers of the compounds of this invention, and racemic mixture is all also a part of the present invention.In addition, also comprise all geometric isomers or position isomer.
The present invention studies and shows, swertisin has obvious antidepressant effect, can significantly improve monoamine neurotransmitter systemic-function, and depression and symptom and sign thereof are had to auxiliary therapy effect, for clinical treatment depression provides a kind of new selection.
Obviously,, according to foregoing of the present invention, according to ordinary skill knowledge and the customary means of this area, not departing under the above-mentioned basic fundamental thought of the present invention prerequisite, can also make amendment, replacement or the change of other various ways.
The detailed description of the invention of form by the following examples, is described in further detail foregoing of the present invention again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
Detailed description of the invention
The swertisin structural formula using in the specific embodiment of the invention is as follows:
This compound can obtain by buying commercially available prod, also can extract purification by existing method, can also make by synthesizing mean.
The preparation of embodiment 1 tablet of the present invention
Raw material: swertisin 500mg, starch 500g, lactose 300g, magnesium stearate 50g.
Preparation method: swertisin, starch, lactose are mixed, and conventional method adds magnesium stearate granulate after granulating, and tabletting, makes 10000 altogether, obtains the every preparation containing swertisin 50 μ g.
The preparation of embodiment 2 capsules of the present invention
Raw material: swertisin 500mg, starch 2000g.
Preparation method: after swertisin is mixed homogeneously with starch, encapsulated with capsule, make altogether 10000, obtain the preparation of every capsules containing swertisin extract 50 μ g.
The preparation of embodiment 3 tablets of the present invention
Raw material: swertisin 1000mg, starch 500g, lactose 300g, magnesium stearate 50g.
Preparation method: swertisin, starch, lactose are mixed, and conventional method adds magnesium stearate granulate after granulating, and tabletting, makes 10000 altogether, obtains the every preparation containing swertisin 100 μ g.
Prove beneficial effect of the present invention by pharmacodynamics test below.
The impact of test example 1 swertisin on spontaneous activity in mice
Laboratory animal: 40 of male mice in kunming, body weight 20 ± 2g.
Experimental technique: utilize spontaneous activity in mice instrument to detect the impact of swertisin on spontaneous activity in mice after administration.Record the number of times of spontaneous activity in mice 5 minutes.
Experimental result: by the observation to spontaneous activity in mice, result shows, mice gives (oral administration gavage administration) after the swertisin of various dose, and spontaneous activity does not have significance to change.Illustrate that swertisin does not have innervation.The results are shown in Table 1.
The impact of table 1 swertisin on spontaneous activity in mice
Result shows, swertisin does not have a significant effect to spontaneous activity in mice, can determine that its antidepressant effect result is not caused by its excitation.
The impact of test example 2 swertisins on mouse tail suspension dead time and forced swimming dead time
Laboratory animal: 40 of male mice in kunming, body weight 20 ± 2g.
Experimental technique: with reference to Stern method, administration 14 days, 1h after last administration, is bonded at mouse tail higher than 6min on the batten of desktop 5cm with adhesive plaster, the actionless time of mice in 5min after record.
With reference to Porsolt method, will be through screening mice administration (oral administration gavage administration), administration 7 days, last administration 1h is placed on 7min in the lucite cylinder of about 10cm (25 DEG C of water temperatures) that is filled with water, in the rear 5min of record, the actionless time of mice.The results are shown in Table 2.
The impact of table 2 swertisin on mouse tail suspension dead time and forced swimming dead time
Note: compared with Normal group
*p<0.05,
*p<0.01
Experimental result: after mice administration, outstanding tail dead time and the obvious minimizing compared with blank group of forced swimming dead time, and be dosage according to lazy sexual relationship.In addition, wherein 400 μ g/kg groups have significant difference compared with blank group.Illustrate that swertisin can reduce the desperate time of the desperate model of animal behavior.
Test example 3 swertisins on injection reserpine after the impact of mouse temperature
Laboratory animal: 50 of Kunming mouses, male and female half and half, body weight 20 ± 2g.
Experimental technique: with reference to Alpermann method, measure basal body temperature administration (oral administration gavage administration).Administration 14 days, after last administration 1h, mouse peritoneal injection reserpine 2.5mg/kg, 1h after injection, 2h, 4h measures mouse temperature.Calculate temperature decline value.
Table 3 swertisin on injection reserpine after the impact of mouse temperature
Note: compared with Normal group
Δp<0.05,
Δ Δp<0.01, compared with model group
*p<0.05
Experimental result: after mouse peritoneal injection reserpine, body temperature declines gradually.And give after the swertisin of various dose, mouse temperature drop-out value and Normal group comparison, be the minimizing of dose dependent, and compare and have significant difference at the rainy Normal group of 200,400 μ g/kg dosage.Experimental result is in table 3.The monoamine exhaustion that swertisin energy antagonism reserpine causes is described.
Test example 4 swertisins get rid of on mice after injecting 5-HTP the impact that head reacts
Laboratory animal: 40 of Kunming mouses, male and female half and half, body weight 20 ± 2g.
Experimental technique: with reference to Kitanura Y method, administration 14 days (oral administration gavage administration), after last administration 1h, mouse mainline 5-HTP80mg/kg.In record injection 5-HTP10min, mice gets rid of the number of times of head.
Table 4 swertisin gets rid of on mice after injecting 5-HTP the impact that head reacts
Note: compared with Normal group
*p<0.05,
*p<0.01
Experimental result: after mouse mainline 5-HTP, head reaction has appearred comparatively significantly getting rid of in Normal group within observing time, but number of times is less; Obviously increase and the mice of swertisin administration group gets rid of a number of times, relatively have obvious significant difference with Normal group, experimental result is in table 4.Illustrate that swertisin has the effect that strengthens 5-HT mediator system.
The impact of test example 5 swertisins on Yohimbine toxicity
Laboratory animal: 40 of male mice in kunming, body weight 20 ± 2g.
Experimental technique: with reference to Quinton method, administration 14 days (oral administration gavage administration), after last administration 1h, mouse subcutaneous injection Yohimbine 30mg/kg, the mortality rate of mice after observation 24h.
The impact of table 5 swertisin on Yohimbine toxicity
Note: compared with Normal group
*p<0.05,
*p<0.01
Experimental result: after injection Yohimbine, each treated animal all occurs, after signs of toxicity 24h, recording dead animal number, result shows that in swertisin, dosage group, high dose group dead mouse quantity obviously increase, and has notable difference compared with Normal group, the results are shown in Table 5.Illustrate that swertisin has certain potentiation to norepinephrine (NE) mediator system.
The impact of test example 6 swertisins on rat tryptamines convulsions Enhancement test
Laboratory animal: 40 of SD rats, male and female half and half, body weight 200 ± 20g.
Experimental technique: administration 14 days, after last administration 1h (oral administration gavage administration), rat tail vein injection tryptamine hydrochloride 5mg/kg, after inserting needle, start timing, after observing injection, whether the interior rat forelimb performance of 5min there is patting the number of times that action and hunchbacked clonicity and clonic spasm occur, and mark according to its fierce degree, standards of grading: do not occur patting action: 0 point; Discontinuity is patted action: 1 point; Persistence is patted action, with hunchbacked phenomenon: 2 points; There is spasm phenomenon: 3 points.
The impact of table 6 swertisin on rat tryptamines convulsions Enhancement test
Experimental result shows, injects after tryptamine hydrochloride, and the each dosage group of swertisin rat faints from fear to mark does not have obvious difference with clonic spasm number of times compared with Normal group, shows that swertisin does not have obviously to suppress the effect of activity of monoamine oxidase.
Sum up:
To experimental studies have found that of swertisin antidepressant effect, swertisin is without central nervous excitation, but has obvious antidepressant activity, can obviously shorten mouse tail suspension dead time and forced swimming dead time.
Reserpine is by exhausting that monoamine neurotransmitter causes temperature decline, and swertisin can this effect of antagonism, points out it to have certain effect to monoamine transmitters system.The mice that further research discovery swertisin can increase 5-HTP induction gets rid of head, the toxicity of Yohimbine is had to certain potentiation, the antidepressant activity that swertisin is described may be with its inhibition 5-hydroxy tryptamine reuptake, strengthen neurotransmitter 5-HT function of nervous system in brain, affect the monoamine neurotransmitteies such as the interior norepinephrine of brain relevant.What swertisin was tested rat tryptophan convulsions affects result demonstration, and the inhibition of its metabolism to tryptamine hydrochloride does not have statistical significance, illustrates that the antidepressant activity of swertisin and the interior activity of monoamine oxidase of inhibition body have nothing to do.
In sum, swertisin has obvious antidepressant effect, and its antidepressant effect may be relevant with 5-HT, NE.Swertisin has desirable comprehensive pharmacological action aspect anti depressant therapy, both can treat the depression due to a variety of causes, also can bring into play the auxiliary therapeutic action of clinical satisfaction.The lateral reactivity composition that swertisin can be used as antidepressant drug is applied in the preparation of antidepressant drug, for clinical treatment depression provides a kind of new selection.
Claims (10)
1. compound shown in formula I or its pharmaceutically acceptable salt purposes in the antidepressant medicine of preparation,
Wherein, R1～R3 is independently selected from respectively H or glycosyl.
2. purposes according to claim 1, is characterized in that: R1 is H or glycosyl, and R2, R3 are H.
3. purposes according to claim 2, is characterized in that: R1 is glycosyl.
4. according to the purposes described in claim 1～3 any one, it is characterized in that: described glycosyl is selected from glucosyl group, lactose base, galactosyl, malt-base, rhamanopyranosyl, aralino or xylosyl.
5. purposes according to claim 4, is characterized in that: described glycosyl is selected from glucosyl group; Preferably, described glucosyl group is glucopyranosyl.
6. according to the purposes described in claim 1～5 any one, it is characterized in that: described structural formula of compound is as follows:
7. purposes according to claim 1, is characterized in that: R1～R3 is H.
8. purposes according to claim 1, is characterized in that: described pharmaceutically acceptable salt is the salt of formula I compound and metal ion or acid formation.
9. purposes according to claim 8, is characterized in that: described metal ion is potassium, sodium, magnesium, ferrum or zinc ion; Described acid is hydrochloric acid, sulphuric acid, citric acid, benzenesulfonic acid, hydrobromic acid, Fluohydric acid., phosphoric acid, acetic acid, propanoic acid, oxalic acid, succinic acid, fumaric acid, malic acid, maleic acid or tartaric acid.
10. purposes according to claim 1, is characterized in that: described medicine is the medicine that improves monoamine neurotransmitter systemic-function; Preferably, described monoamine neurotransmitter system is 5-hydroxy tryptamine mediator system or norepinephrine mediator system.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104000838B (en) * | 2014-06-23 | 2016-03-30 | 四川省中医药科学院 | The purposes of swertisin and pharmaceutical composition thereof |
| CN105467033A (en) * | 2015-12-15 | 2016-04-06 | 河北科技大学 | Method for building swertia pseudochinensis medicine material fingerprint spectrum and fingerprint spectrum and application thereof |
| CN115843807A (en) * | 2023-03-02 | 2023-03-28 | 云南省农业科学院生物技术与种质资源研究所 | Application of swertisin compound |
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| CN101396429A (en) * | 2007-09-27 | 2009-04-01 | 北京中研同仁堂医药研发有限公司 | Swertia diluta extract and preparation method and use thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104000838B (en) * | 2014-06-23 | 2016-03-30 | 四川省中医药科学院 | The purposes of swertisin and pharmaceutical composition thereof |
| CN105467033A (en) * | 2015-12-15 | 2016-04-06 | 河北科技大学 | Method for building swertia pseudochinensis medicine material fingerprint spectrum and fingerprint spectrum and application thereof |
| CN115843807A (en) * | 2023-03-02 | 2023-03-28 | 云南省农业科学院生物技术与种质资源研究所 | Application of swertisin compound |
| CN115843807B (en) * | 2023-03-02 | 2023-04-28 | 云南省农业科学院生物技术与种质资源研究所 | Application of swertia herb flavin compound |
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