CN105777520A - Novel chalcone compound Chalcone-1203, and composition, preparation method and application thereof - Google Patents
Novel chalcone compound Chalcone-1203, and composition, preparation method and application thereof Download PDFInfo
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- CN105777520A CN105777520A CN201410811493.7A CN201410811493A CN105777520A CN 105777520 A CN105777520 A CN 105777520A CN 201410811493 A CN201410811493 A CN 201410811493A CN 105777520 A CN105777520 A CN 105777520A
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Abstract
The invention relates to a novel chalcone compound Chalcone-1203, and also relates to a preparation method for the compound, a composition using the compound as an active component and application of the compound in preparation of an antidepressant drug. The novel chalcone compound Chalcone-1203 provided by the invention has substantial anti-depression effect. Results of animal testing in the embodiments show that Chalcone-1203 can substantially reduce immobility time of mice in forced swimming test and tail suspension test of the mice, has fast action and small toxic and side effect (TD50>2000 mg/kg), is suitable for long-term usage and shows valuable antidepressant pharmacological properties. The novel chalcone compound uses widely-available and cheap raw materials, is simple to prepare and can be used for preparation of antidepressant drugs of a variety of dosage forms.
Description
Technical field
The present invention relates to a kind of novel chalcone compound, particularly relate to Chalcone-1203 [1-(2-hydroxyl-4-iso-amylene oxygen base)-phenyl-3-(naphthalene-1-base)-2-propylene-1-ketone], and relate to its preparation method, with its compositions being active component and the application in treatment antidepressant drug.
Background technology
Depression is also known as depressive disorder, low for main clinical characteristics with significantly lasting mental state, being the main Types of mood disorders, clinical visible mental state is low unbecoming with its situation, and the downhearted of emotion can from depressed to extremely grieved, feel oneself inferior depression, even pessimistic and worldweary, can there be suicidal attempt or behavior, even occur numb, some cases has obvious anxiety and mobility intense, and the psychotic symptoms such as hallucination, vain hope occurs in severe patient.The function such as the digestion of people, immunity and nervous system can be produced impact by depression, even causes damage, and this disease has high incidence, refractory more and the feature such as high relapse rate.
In current clinical practice, existing multi-medicament is available for depression use, if Ah rice is for flat, clomipramine, moclobemide, fluoxetine, paroxetine, Sertraline, citalopram etc., although these medicines can both in varying degrees for treating or alleviate the misery of various depressive patients, but there is side effect and feeling bad property in it, thus limiting their life-time service.In order to eliminate or reduce toxic and side effects, improve therapeutic effect, it is necessary to there is new architectural feature and the new compound of the new mechanism of action.
Flavone compound is widely present in medicinal plants, veterinary antibiotics, herbage and lichen, it is some secondary metabolites of producing in long-term natural selection process of plant, flavone compound has pharmacologically active and the low toxicity of wide spectrum, as antitumor, antioxidation, antiinflammatory, to cardiovascular regulatory function and antibacterial, antivirus action, it has also become both at home and abroad natural drug develops the focus of research.Particularly in recent years its chemical constitution and bioactive correlation research increasingly being paid attention to, this is to finding flavone lead compound from nature and carrying out structure of modification or modification, and Development of New Drugs is all significant.
Summary of the invention
First technical problem to be solved by this invention is to provide the novel chalcone compound Chalcone-1203 that a kind of antidepressant effect is better and toxic and side effects is low.
The preparation method that second technical problem to be solved by this invention is to provide a kind of above-mentioned novel chalcone compound.
3rd technical problem to be solved by this invention is to provide the compositions that the above Chalcone-1203 of stating is active component.
4th technical problem to be solved by this invention is to provide the application in treatment antidepressant drug of the above-mentioned novel chalcone compound.
This invention address that the technical scheme that first technical problem adopts is: a kind of novel chalcone compound, it is characterised in that described novel chalcone compound is the compound shown in formula (1).
This invention address that the technical scheme that second technical problem adopts is: described novel chalcone compound is prepared with the compounds I in formula (2) for starting material.
Further, the preparation method of above-mentioned novel chalcone compound is:
Adding 1-naphthaldehyde in described compounds I, drip the 14%KOH solution being made into by dehydrated alcohol and KOH solid, room temperature reaction 7～8h after mix homogeneously, the mass ratio of described compounds I, 1-naphthaldehyde and KOH is 1:0.84～0.86:9～10；Reaction terminates, and is poured into by reactant liquor in frozen water, is adjusted to neutrality with 3mol/LHCl, is filtrated to get yellow solid, dries to obtain thick product, thick product 95% ethyl alcohol recrystallization, obtains described novel chalcone compound.
This invention address that the 3rd technical scheme that technical problem adopts is: a kind of for antidepressant pharmaceutical composition, the as claimed in claim 1 novel chalcone compound as active component including effective dose, with at least one pharmaceutically acceptable excipient, described pharmaceutically acceptable excipient is inert non-toxic excipient, this pharmaceutical composition refers in particular to and is suitable for being administered orally, those tablets of non-bowel (vein or skin test) and nasal administration or sugar coated tablet, sublingual tablet, gelatine capsule, suppository, cream, ointment, skin gel, injectable formulation or drinkable suspension etc..Specifically mentioned can be suitable for those tablets or sugar coated tablet, sublingual tablet, gelatine capsule, suppository, cream, ointment, skin gel, injectable formulation or the drinkable suspension etc. of oral, non-bowel (vein or skin test) and nasal administration.
4th technical scheme that technical problem adopts to be solved by this invention is: the application in antidepressant drug of the above-mentioned novel chalcone compound.
Compared with prior art, it is an advantage of the current invention that: the novel chalcone compound Chalcone-1203 in the present invention has significant antidepressant effect, shown by the animal experiment in embodiment: Chalcone-1203 can significantly reduce mouse forced swimming test and the dead time of tail-suspention test small mouse, and instant effect, toxic and side effects little (TD50 > 2000mg/kg), can life-time service, it is shown that have valuable as antidepressant pharmacological properties effect；This novel chalcone compound abundant raw material source, cheap simultaneously, preparation method is simple, can be made into the antidepressant drug of various dosage form or prescription common with other drug, makes the antidepressant compound medicine of Mutiple Targets.
Accompanying drawing explanation
Fig. 1 is the Chalcone-1203 impact on mouse forced swimming test in the embodiment of the present invention 2；
Fig. 2 is the Chalcone-1203 impact (intraperitoneal injection) on Tail suspension test in the embodiment of the present invention 2；
Fig. 3 is the Chalcone-1203 impact (gastric infusion) on Tail suspension test in the embodiment of the present invention 2；
Fig. 4 is the Chalcone-1203 impact on mice opening pharmacological evaluation in the embodiment of the present invention 3.
Detailed description of the invention
Below in conjunction with accompanying drawing embodiment, the present invention is described in further detail.
Embodiment 1: the preparation of novel chalcone compound (Chalcone-1203)
Adding 0.425g3.82mmol1-naphthaldehyde in 0.5g3.18mmol compounds I, after mix homogeneously, dropping is made into the solution of 14%KOH, room temperature reaction 8h by 35mL dehydrated alcohol and 4.9gKOH.Reaction terminates, and is poured into by reactant liquor in 60mL frozen water, adjusts pH to neutral with 3mol/LHCl, is filtrated to get yellow solid, dry, and thick product 95% ethyl alcohol recrystallization obtains yellow crystals, namely required novel chalcone compound (Chalcone-1203).
Productivity 85.4%, fusing point 137.5-138.5 DEG C.1HNMR(CDCl3) δ:1H-NMR(CCl3D) δ: 1.70 (s, 3H ,-CH3), 1.75 (s, 3H ,-CH3), 4.51 (d, 2H ,-CH2), 5.42 (t, 1H ,=CH), 6.45-7.86 (m, 3H ,-C6H3), 7.49 (d, 1H, J=15Hz ,=CH), 7.19-7.49 (m, 7H ,-C12H7), 8.68 (d, 1H, J=15Hz ,=CH), 13.43 (s, 1H ,-OH)；IR(KBr)cm-1:3216,1638,1571,1224,966；MSm/z:359(M+1).
Embodiment 2: the antidepressant pharmacological evaluation of novel chalcone compound
The present embodiment, by the mice injecting above-mentioned novel chalcone compound (Chalcone-1203) carries out forced swimming test and mice rotation tail experiment screening, evaluates its antidepressant effect and safety.
Experiment material: healthy Balb/e mice, male, body weight 18-20g, Zhejiang Medical academy of science animal experimental center provide, raise under 25 DEG C of conditions.Keeping during experiment freely drinking water and taking food, feeding environment temperature is 24 ± 1 DEG C, and humidity is 55 ± 5%, and adaptability is tested after feeding 5-7 days, and every animal only uses once.
Positive control medicine: FLU (fluoxetine), it is purchased from Lilly company of the U.S., before drug use in following test 2.1,2.2, fluoxetine normal saline is configured to solution, chalcone compound (Chalcone-1203) is with DMSO wiring solution-forming for lumbar injection, and gastric infusion is made into suspension with 0.2% sodium carboxymethyl cellulose.
All experiments all carry out between at 5 in afternoon at 11 in the morning.
2.1 mouse forced swimming test
Balb/e mice is randomly divided into 5 groups, often group 10, namely blank group, positive drug group (fluoxetine, 10mg/kg), novel chalcone compound Chalcone-1203 high (10mg/kg), in (5mg/kg), low (1mg/kg) dosage group.Each group is all by 0.10ml/20g body weight intraperitoneal injection, the DMSO of blank group injection equivalent.
After intraperitoneal injection 30 minutes, mice is put into XSC-mice constant temperature swimming instrument (depth of water 10cm, diameter 34cm bucket, water temperature 25 ± 2 DEG C), mice swimming situation in observing 6 minutes, swimming accumulation dead time (stopping of motionless i.e. mice is struggled or mice is floating state, and mice extremity have mild action to keep head at the water surface) in 4 minutes after statistics mice.Result of the test is as shown in Figure 1, it is seen that the antidepressant activity of this novel chalcone compound is similar to positive drug control FLU (fluoxetine), and the very low (TD of neurotoxicity50> 2000mg/kg), safety is significantly high.Chalcone-1203 lumbar injection has significant difference (p < 0.001) under 1mg/kg, 5mg/kg, 10mg/kg dosage compared with blank group, wherein during lumbar injection 5mg/kg dosage, it suppresses the dead time similar to positive drug control group.
2.2 Tail suspension tests
Balb/e mice is randomly divided into 5 groups, often group 10, namely blank group, positive drug group (fluoxetine, 10mg/kg), novel chalcone compound Chalcone-1203 high (10mg/kg), in (5mg/kg), low (1mg/kg) dosage group.Each group is all by 0.10ml/20g body weight intraperitoneal injection, the DMSO of blank group injection equivalent.
After intraperitoneal injection 30 minutes, being about 1cm place adhesive plaster from mouse tail tip and be affixed on outstanding boot (30cm × 30cm × 25cm) support, make mice become reversal of the natural order of things state, its head is about 5cm from bottom, hangs 2 mices 1 time, and centre dividing plate separates.The suspension time is 6 minutes, outstanding tail accumulation dead time in 4 minutes after statistics mice (motionless state and mice stop struggling motionless or without any activity).Experimental result is as shown in Figure 2, this novel chalcone compound visible is at 1mg/kg, 5mg/kg, there is under 10mg/kg dosage significant difference (p < 0.001) compared with blank group, wherein 5mg/kg group induction dead time (63.3%) is similar to so (61.5%) to positive drug, illustrate that novel chalcone compound Chalcone-1203 has antidepressant activity, additionally, as shown in Figure 3, chalcone compound Chalcone-1203 passes through gastric infusion (0.1ml/10g), there is significant difference (p < 0.001) under 30mg/kg dosage compared with blank group, display antidepressant activity, illustrate that this compound oral absorption effect is fine.
Embodiment 3: mice opening experiment
Opening experiment is mainly for assessment of the autonomic activities behavior of laboratory animal, in the present embodiment, opening experiment device is an opaque plastic box (80cm × 60cm × 30cm), the square lattice of 48 10cm × 10cm sizes it is divided into bottom plastic box, plastic box is placed in quiet room, giving illumination with 60W bulb, bulb is higher than plastic box center about 1m.
Take male Balb/e mice 20, be randomly divided into 2 groups, often group 10, respectively blank group and medicine group.30min before test, is dissolved in DMSO solution by novel chalcone compound, with the dosage lumbar injection 0.10ml/20g of 10mg/kg, the DMSO solution of blank group lumbar injection same volume.Mice is placed in center grid at the bottom of plastic box, manually recorded mobile number of times (extremity both pass through grid) and erect number of times (standing with hind leg), record 3min.
Experimental result is as shown in Figure 4, experimental result display mice autonomic activities number of times does not significantly change compared with matched group, illustrate that this novel chalcone compound Chalcone-1203 will not change the autonomic activities of mice, eliminate the antidepressant false positive of compound Chalcone-1203.
Claims (5)
1. a novel chalcone compound, it is characterised in that described novel chalcone compound is the compound shown in formula (1).
2. the preparation method of a novel chalcone compound as claimed in claim 1, it is characterised in that: described novel chalcone compound is prepared with the compounds I shown in formula (2) for starting material.
3. the preparation method of novel chalcone compound as claimed in claim 2, it is characterized in that: in described compounds I, add 1-naphthaldehyde, the 14%KOH solution being made into by dehydrated alcohol and KOH solid is dripped after mix homogeneously, room temperature reaction 7～8h, the mass ratio of described compounds I, 1-naphthaldehyde and KOH is 1:0.84～0.86:9～10；Reaction terminates, and is poured into by reactant liquor in frozen water, is adjusted to neutrality with 3mol/LHCl, is filtrated to get yellow solid, dries to obtain thick product, last thick product 95% ethyl alcohol recrystallization, obtains described novel chalcone compound.
4. one kind is used for antidepressant pharmaceutical composition, it is characterised in that include the as claimed in claim 1 novel chalcone compound as active component of effective dose and at least one pharmaceutically acceptable excipient.
5. a novel chalcone compound as claimed in claim 1 application in antidepressant drug.
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| CN201410811493.7A CN105777520A (en) | 2014-12-23 | 2014-12-23 | Novel chalcone compound Chalcone-1203, and composition, preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146597A (en) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | A kind of saringosterol compound and extracting method, application |
| CN106146596A (en) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | A kind of Sargassum phyllocystum Tseng et Lu,Sargassum horneri (Turn.) C. Ag. (Fucus horneri (Turn.)C.Ag.,Spongocarpus horneri Kutz.) Sitosterolum compound and extracting method, application |
| CN107973708A (en) * | 2017-12-05 | 2018-05-01 | 王艳艳 | A kind of new chalcone compounds and its application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013054998A1 (en) * | 2011-10-13 | 2013-04-18 | 건국대학교 산학협력단 | Novel chalcone derivative and anticancer composition comprising same as active ingredient |
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2014
- 2014-12-23 CN CN201410811493.7A patent/CN105777520A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013054998A1 (en) * | 2011-10-13 | 2013-04-18 | 건국대학교 산학협력단 | Novel chalcone derivative and anticancer composition comprising same as active ingredient |
Non-Patent Citations (1)
| Title |
|---|
| LI-PING GUAN，ET AL.: "Evaluation of Potential Antidepressant-Like Activity of Chalcone-1203 in Various Murine Experimental Depressant Models", 《NEUROCHEM RES》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146597A (en) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | A kind of saringosterol compound and extracting method, application |
| CN106146596A (en) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | A kind of Sargassum phyllocystum Tseng et Lu,Sargassum horneri (Turn.) C. Ag. (Fucus horneri (Turn.)C.Ag.,Spongocarpus horneri Kutz.) Sitosterolum compound and extracting method, application |
| CN107973708A (en) * | 2017-12-05 | 2018-05-01 | 王艳艳 | A kind of new chalcone compounds and its application |
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