CN1231175A - Fluoracyl melatonin and composition and preparation thereof - Google Patents
Fluoracyl melatonin and composition and preparation thereof Download PDFInfo
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- CN1231175A CN1231175A CN 98113892 CN98113892A CN1231175A CN 1231175 A CN1231175 A CN 1231175A CN 98113892 CN98113892 CN 98113892 CN 98113892 A CN98113892 A CN 98113892A CN 1231175 A CN1231175 A CN 1231175A
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Abstract
The present invention relates to 2-ethoxy formyl-5-methoxy-N-trifluoroacetyl tryptamine (fluoroacyl melatonin) and its composite and preparation. It can bring the bioregulation action into full play. Its composite contains 5-80 wt.% of fluoroacyl melatonin, 0-90 of calcium source, 0-5 of Vitamin B6, 0-20 of central depressant and 0-5 of matrix. Said invention can be used to made various medicinal preparations.
Description
The invention belongs to the preparation and the biological application of regulating of mammalian hormones analog.Be 2-ethoxycarbonyl-5-methoxy-N-TFA tryptamines (fluoracyl melatonin) and compositions and preparation specifically with induced hypnotic and immunoregulation effect.
Melatonin (Melatonin) is that U.S. scientist Lerner in 1958 purifies from the pineal gland of cattle first and identifies that its chemical constitution is acetyl 5-methoxytryptamine (C
13H
16N
2O
2), it is the excretory major hormone of pineal gland, carry out chemosynthesis in succession again, after this Wurtman of the U.S. (1961), Reiter (1961), the Li Jingcai professor (1978) of Canadian Brown (1971) and China, ten hundreds of finally various countries scientists furthers investigate pineal gland and melatonin function in succession.The result shows that the excretory hormone melatonin of body pineal gland is regulated by illumination, and illumination can suppress melatonin secretion, and therefore, melatonin is very low in voxel concentration on daytime, and then significantly raise night.Melatonin is expressed the environment periodic signal in vivo by its concentration change, and body is then regulated its function by experiencing melatonin concentration, thereby melatonin plays a crucial role in the information exchanging process between machine element and environment.Melatonin can be modulated the inherent moving law of body function, makes itself and environment cycle synchronisation, from cell until the powerful regulating action of body generation during integral level makes body keep homeostasis.Homeostasis is the basic assurance that vital movement is rely and carried out, and melatonin is kept homeostasis, also is called integration on life sciences, is core with this integration, and melatonin shows different biological activitys in different occasions.As calibrate the biological clock function, and induce ortho sleep, keep the ortho sleep cycle and the length of one's sleep, improve sleep quality.Melatonin also has enhance immunity, free radical resisting, adjusting sexual function and anti-aging effects.All these functions have important meaning to improving body quality of life.Because melatonin is the endogenous bioactive substance, sphere of action is very extensive, seeks to have the derivant that stresses in some aspects, and prior using value will be arranged.Therefore, world patent IP89/01472 and U.S. Pat P5,093,352 discloses the melatonin derivatives that is used for the treatment of depression; The disclosed melatonin derivatives of Chinese patent CN1107701A, be used for regulating sleep, all disclosed patent documentations all do not cover fluoracyl melatonin and analog thereof, the present invention will disclose the new melatonin derivatives as the formula I structure, 2-ethoxycarbonyl-5-methoxy-N-TFA tryptamines is used to improve immunologic function and induced hypnotic.The chemical compound that this invention is related does not see in disclosed document and the patent.
The purpose of this invention is to provide a kind of new melatonin derivatives, and it is formed compositions, make preparation and be used for raise immunity and regulate sleep.
The objective of the invention is to be achieved by the following scheme: it is to be the synthetic 2-ethoxycarbonyl of guide-5-methoxy-N-TFA tryptamines (fluoracyl melatonin), its structure such as formula I chemical compound with the melatonin
The formula I chemical compound
Compositions, is wherein formed in formula I chemical compound and calcium source, vitamin B6 or central inhibitor, and the weight proportion of each component is as follows: fluoracyl melatonin 5-80; Calcium source 0-90; Vitamin B6 0-5; Central inhibitor 0-20; Its matter 0-5.
Aforesaid goods is characterized in that the calcium source of using is any edible or medicinal calcium source or calcium chelate, and classical calcium source commonly used in enriching substance is as follows: calcium carbonate, calcium phosphate, calcium citrate, calcium gluconate, calcium oxalate, calcium glycine, animal bone calcium, Concha Ostreae calcium, activated calcium.If being absorbed by the body, other forms of calcium also can be used.
The central inhibitor that uses comprises barbiturates, the tall and erect class of benzene phenodiazine Asia puecon, the central inhibitor of clinical uses such as r aminobutyric acid.The vitamin B6 that uses is edible or pharmaceutical grades.
Substrate is some food and pharmacy industry adjuvant commonly used.Be used to dilute or the material of figuration as microcrystalline Cellulose, starch, dextrin, hydroxymethyl cellulose sodium, HYDROXY PROPYL METHYLCELLULOSE etc.
Preparation is the pharmacy common dosage forms, as tablet, controlled release tablet, capsule, electuary, patch, membrane, unguentum etc.
Invention is in the past compared, and the invention has the advantages that:
1, synthesized brand-new melatonin derivatives, introduced ethoxycarbonyl, introduced trifluoroacetyl group at tryptamines N place at 2.
2, confirmed that the formula I chemical compound is formed compositions better effect.
3, the formula I chemical compound is made various preparations.
4, the induced hypnotic and the immunoregulation effect of formula I chemical compound have been confirmed.
Biological activity test
Make preparation by 2-ethoxycarbonyl-5-methoxy-N-TFA tryptamines (abbreviation fluoracyl melatonin)
And it is as follows to test its effect:
I, hypnotic effect
One, material and method
1, tried thing:
The fluoracyl melatonin sheet is provided by Shenyang Pharmaceutical University, lot number 970806, and content 3mg/ sheet, for
The 90-110% of labelled amount.Facing the time spent tries with 0.3% Tween 80 aqueous solution dissolving confession.
2, animal:
Kunming mouse is provided by animal housing of Shenyang Pharmaceutical University, the animal quality certification number: No. 527, the real moving word of the Liao Dynasty.The weight of animals 20-23g, male and female half and half, ten group supports of every cage, the drinking-water of freely ingesting.
3, experimental technique:
3.1. the fluoracyl melatonin sheet is to the influence of mice behavioral activity:
Get 40 mices, be divided into 4 groups at random, 10 every group.Irritate stomach (ig) for first group and give fluoracyl melatonin sheet solvent 0.3% Tween 80 aqueous solution, 10ml/kg.The 2-4 group is ig fluoracyl melatonin sheet 400,200 respectively, 100mg/kg, capacity 10ml/kg.After irritating stomach, observe the active state of animal, whether righting reflex disappears and sleep quality.
3.2. the fluoracyl melatonin sheet is to the influence of mice autonomic activities:
Get 60 of mices, be divided into 6 groups at random, 10 every group.First group of ig fluoracyl melatonin sheet solvent 10ml/kg, the 2-5 group is ig respectively, fluoracyl melatonin sheet 400,200,100,50mg/kg, the 6th group of ig melatonin 400/mg/kg, capacity is 10ml/kg.Irritate Weihe after 30 minutes, respectively mice is put into toy spontaneous activity monitor, write down 10 minutes independent activity of animals number of times.
3.3. to the pentobarbital sodium influence of the length of one's sleep:
Get 60 of mices, be divided into 6 groups at random, 10 every group, first group of ig fluoracyl melatonin sheet solvent,
2-5 group ig fluoracyl melatonin sheet 50,25,5 and 0.5mg/kg, the 6th group of ig melatonin 50mg/kg, capacity is 10ml/kg, after 30 minutes, all the equal lumbar injection pentobarbital sodium of mice 45mg/kg writes down the length of one's sleep of respectively organizing mice thereafter
Two, result:
1, the fluoracyl melatonin sheet is to the influence of mice behavioral activity:
Give behind the fluoracyl melatonin sheet 400mg/kg 30 minutes, mice is movable to be reduced, and major part is lethargic state, and partly (1-2 only) animal still has activity, and righting reflex does not all disappear, and moving promptly wakes up.After the administration 90 minutes, mice still was the resting state of closing one's eyes, and 200mg/kg dosage group mice after the medication, movablely reduces not obviously, and 100mg/kg dosage does not have obvious difference to effect and the matched group of mice.
2, the fluoracyl melatonin sheet is to the influence of spontaneous activity in mice:
After the fluoracyl melatonin administration, the activity of animal reduces, and compares with matched group, and three dosage all can reduce the autonomic activities number of times of mice, and wherein 400, the 200mg/kg group has been compared highly significant difference, P＜0.01 with matched group; There were significant differences for the 100mg/kg group, P＜0.05.
The influence of spontaneous activity in mice when table 1, fluoracyl melatonin sheet (group dosage (mg/kg) the autonomic activities number of times of X ± SD) (inferior/10 minute) matched group 1752 ± 45 fluoracyl melatonin sheets 400 916 ± 375
*Fluoracyl melatonin sheet 200 1543 ± 91
*Fluoracyl melatonin sheet 100 1661 ± 106
*Fluoracyl melatonin sheet 50 1661 ± 106
*Melatonin sheet 400 1262 ± 271
*N=10 compares with matched group
*P＜0.01, * P＜0.05
3, the fluoracyl melatonin sheet is to the influence of pentobarbital sodium hypnosis time:
Give the animal of fluoracyl melatonin sheet, all the significant prolongation pentobarbital sodium hypnosis time (P＜0.01, table 2), prompting fluoracyl melatonin sheet has the effect that strengthens central depressant.
Table 2. fluoracyl melatonin sheet to the influence of pentobarbital sodium hypnosis time (during the group dosage (mg/kg) length of one's sleep (branch) of X ± SD) according to group 17.5 ± 6.7 fluoracyl melatonin sheets 50 69.2 ± 10.9
*Fluoracyl melatonin sheet 25 46.3 ± 17.9
*Fluoracyl melatonin sheet 5 29.5 ± 7.6
*Fluoracyl melatonin sheet 0.5 23.4 ± 8.3
*Melatonin sheet 50 52.9 ± 11.5
*N=10 compares * * P＜0.01 with matched group
Three, brief summary
The fluoracyl melatonin sheet is given the oral 100-400mg/kg of mice, and the autonomic activities number of times of animal is reduced, and is calmness and lethargic state, the same usefulness of 0.5-50mg/kg fluoracyl melatonin and pentobarbital sodium, then significant prolongation pentobarbital sodium hypnosis time.Illustrate that but the fluoracyl melatonin sheet has calmness, hypnosis, forms the effect of compositions enhanced activity with central depressant.
II. immunoregulation effect
Fluoracyl melatonin (FAMT) and other derivant influence 80 of mices to immunocompromised mice carbon clearance ability due to the cyclophosphamide (CY), are divided into 8 groups at random: normal saline group, 7 days 5ml/kg/d of lumbar injection (ip) continuous normal saline administration; CY group: ip CY20mg/kg/d5 days; The FAMT+CY group, ip CY while ip melatonin 40ug/kg/d7 days; 5 groups of ip5 melatonin derivatives in addition, the same melatonin of medication.After the last administration 12 hours, survey clearance in mice exponential sum phagocytic index, the results are shown in Table 3.By table 3 as seen, TCMMT, two groups of clearance in mice indexes of FAMMT and phagocytic index all are significantly higher than CY group (P＜0.01).Illustrate that TCMMT and FAMMT all can strengthen the phagocytic function of mononuclear phagocyte system, CY induced mice non-specific immunity is lowly significantly improved.
Table 3. melatonin derivatives is cleaned up the index phagocytic index to the group that influences of immunocompromised mice carbon clearance ability due to the cyclophosphamide (CY)
(K,×10
-2) (a)
NS 8.035±1.480 7.597±1.127
CY 4.768 ± 0.7967 5.979 ± 0.2930MT+CY 5.421 ± 1.278 6.654 ± 0.6947TAMMT+CY 5.334 ± 1.811 5.767 ± 0.8749TBMMT+CY 6.271 ± 1.456
*6.925 ± 0.7534TCMMT+CY 9.565 ± 2.211
*7.467 ± 0.9414
*FAMMT+CY 8.864 ± 1.602
*8.433 ± 0.8685
*FEMMT+CY 5.508 ± 1.725 6.162 ± 0.8551
*P＜0.05 vs CY group,
*P＜0.01 vs CY group I. toxicity test
Kunming kind healthy mice, 42 ages in days, body weight 18-21g is provided by animal housing of Shenyang Pharmaceutical University, No. the 527th, the real moving word of the animal quality certification number the Liao Dynasty.By 10 every group, random packet is placed on constant temperature (20 ± 1 ℃) with animal, constant humidity (55 ± 5%), and (07: 30-19: 30), 12 hours dark in the sound damping animal housing, are freely ingested, and drinking-water adapts to above-mentioned environment and is used for experiment after one week in illumination in 12 hours.
Measure LD with simplifying probit method
50
Get 100 mices, male and female half and half are divided into 5 groups at random by sex, each 10 of every group of male and female, and each group is by 1: 0.7 dose of distance, and dosage is respectively 4000,2800,1960,1372,960mg/kg (fluoracyl melatonin 0.3%CMC hydrotropy).All irritate stomach variable concentrations medicine by the 20ml/kg capacity.Fasting is fed water a night before the medication, observes the poisoning symptom of animal after the administration, writes down the death toll of animal in 14 days, calculates LD
50And 95% fiducial limit.
After the mouse stomach administration, animal activity reduces, and behind the high dose group animals administer 15 minutes, tiredly contracts one, idol has tic, and righting reflex loss is the anesthesia shape then, and death mostly occurred in 4 hours, dead animal is dissected, and enteral flatulence, surplus no abnormality seen are found in postmortem.Calculate LD with simplifying probit method
50, The acute toxicity tests such as table 4 show:
The LD of table 4. mouse stomach administration
50Dead moving LD of mortality rate probit of group dosage log10 dose number of animals and 95% fiducial limit
(mg/kg) thing number (mg/kg)
4,000 3.6021 10 10 1.00 7.400 male 2,800 3.4472 10 6 0.60 5.523
1,960 3.2922 10 6 0.60 5.523 2006.2 ± 286.6 property 1,372 3.1374 10 2 0.20 4.258
960 2.9823 10 0 0.00 2.600
4,000 3.6021 10 10 1.00 7.400 female 2,800 3.4472 10 6 0.60 5.523
1,960 3.2922 10 6 0.60 5.523 2059.6 ± 292.6 property 1,372 3.1374 10 1 0.10 3.718
The LD of 960 2.9823 10 0 0.00 2.600 male mices
50Be 2006.2 (1719.6-2292.8) mg/kg, female mice be 2059.6 (1776.9-2352.2) mg/kg, no significant sex difference.II. the preparation acute toxicity
Measure LD with simplifying probit method
50, owing to the restriction of administration capacity fails to measure, so measure the maximum tolerated dose behind the mice oral medication.With 40 mices, male and female half and half are divided into two groups at random, give Cmax, the maximum fluoracyl melatonin sheet (588mg/kg) that allows volume respectively, the behavior variation and the poisoning manifestations of observing 14 days animals thereafter continuously.
After the mouse stomach administration, since 10 minutes, animal activity reduced, is the sleep shape, but does not have righting reflex loss, continued about 5 hours, recovered normal thereafter, after this to 14 days, did not see other any changes, inferred the LD of melatonin sheet
50Greater than the 588mg/kg III. sub-acute toxicity test
Be further to disclose the toxic action of fluoracyl melatonin sheet, this test was taked orally give fluoracyl melatonin sheet continuous 30 days, observe after the mice medication variation and to drug reaction.
Get 60 mices, male and female half and half are divided into 3 groups at random, each 10 of every group of male and female, per os gives fluoracyl melatonin sheet solvent and fluoracyl melatonin sheet 50,200mg/kg respectively, every day gastric infusion once, continuous 30 days, the behavior variation and the poisoning manifestations of observing animal simultaneously.
Behind the mice oral administration, the activity of high dose group mice reduces to some extent, recovers in 4-5 hour, other states all do not have significant change, body weight normal growth (table 5,6), do not see any toxic reaction and death, prompting fluoracyl melatonin sheet is safe in the following dosage continuous application of 200mg/kg.
Table 5. fluoracyl melatonin sheet is on the impact of male mice body weight (time of X ± SD) (my god) control group fluoracyl melatonin sheet 50mg/kg fluoracyl melatonin sheet 200mg/kg 0 20.4 ± 1.3 20.5 ± 1.4 20.3 ± 1.0 1 22.1 ± 1.5 20.9 ± 1.6 21.5 ± 1.6 3 23.5 ± 1.9 23.6 ± 1.8 23.8 ± 1.5 5 25.3 ± 1.7 25.1 ± 1.7 24.9 ± 1.010 26.7 ± 1.8 26.8 ± 1.5 26.2 ± 1.3 20 30.2 ± 1.9 30.00 ± 2.3 29.0 ± 2.1 30 33.3 ± 2.1 32.1 ± 2.3 32.1 ± 2.9n=10, with the time according to group than * P＞0.05
Table 6. fluoracyl melatonin sheet is on the impact of female mice body weight (time of X ± SD) (my god) control group fluoracyl melatonin sheet 50mg/kg fluoracyl melatonin sheet 200mg/kg 0 20.3 ± 1.0 20.6 ± 1.2 20.9 ± 1.3 1 21.2 ± 1.2 21.5 ± 1.5 21.1 ± 1.1 3 22.4 ± 1.4 22.3 ± 0.9 22.2 ± 1.2 5 23.4 ± 1.3 23.1 ± 1.4 23.0 ± 1.6 10 25.4 ± 1.7 24.7 ± 1.3 25.8 ± 1.5 20 27.9 ± 1.6 27.7 ± 1.8 28.0 ± 1.6 30 29.8 ± 2.3 30.4 ± 2.1 29.3 ± 1.9n=10, with control group than P＞0.05
Embodiment
Following embodiment is for the better the present invention of elaboration, is not to be used for limiting scope of invention.
Embodiment 1
Make tablet by 2-ethoxycarbonyl-5-methoxy-N-TFA tryptamines (abbreviation fluoracyl melatonin) with the compositions that vitamin B6 and other adjuvant are formed.
The fluoracyl melatonin tablet recipe
Fluoracyl melatonin 3.0g
Vitamin B6 10.0g
Calcium carbonate 75.5g
The fine little plain 11.0g of crystallite
Magnesium stearate is an amount of
Make 1000 method for makings
Vitamin B6 is pulverized, crossed sieve No. 6, it is standby the more fine little element of crystallite to be put 80-100 ℃ of oven dry 2 hours.
In the prescription ratio, take by weighing former, adjuvant mixing, add the magnesium stearate mixing again, with 6mm punch die (flat square), direct powder compression
The prescription foundation
Vitamin B6 in the prescription is that the coenzyme of glutamate decarboxylase promotes the glutamic acid decarboxylation to become GABA and strengthens the induced hypnotic effect of fluoracyl melatonin.So it is added in the prescription.In the structure of fluoracyl melatonin, there is amide strong, circuitous water is easy to inactivation.We's every middle main component (fluoracyl melatonin, vitamin B6) content less (13mg altogether) can be by the deficiency that is used for remedying its physical property of adjuvant, and this point has been established the basis of prescription design for considering direct powder compression.With reference to the prescription of external similar products, all not sugaring, salt, starch, antiseptic and artificial color in its prescription also do not contain corn Semen sojae atricolor, Semen Tritici aestivi, yeast and milk product etc.Thereby, when we design prescription, do not add above-mentioned substance yet, only select no physiologically active for use, have filling preferably, compression forming, sticking and effect, calcium carbonate, the fine little element of crystallite is main adjuvant, adds an amount of magnesium stearate, can suppress up-to-standard tablet.
This product adopts technique of direct powder compression, can prevent light, wet, the heat destruction to fluoracyl melatonin etc., and can simplify working process, with low cost.The calcium carbonate that adopts in the prescription has good mobility, and proportion is bigger, and dust from flying is less during tabletting; Add the fine little element of an amount of crystallite, can increase the disintegrating property of tablet, increase the compressibility of tablet, prevent fragment.Evidence, whole prescription, technology is comparatively reasonable, is suitable for suitability for industrialized production
Description of the process
1. all are former, adjuvant all needed sieve No. 6, are beneficial to mixing of materials, and content is even.
2. when former, adjuvant mixes, should be strict be undertaken by " equivalent progressively increase dilution method ", guarantee fluoracyl melatonin, the uniformity of dosage units of vitamin B6 meets the requirements.
3. should guard against damp in producing, avoid light, heat radiation, the stability of assurance fluoracyl melatonin etc.
4. select for use packaging material to guard against damp and lucifuge.
Embodiment 2. fluoracyl melatonin sustained-release tablet recipes
Fluoracyl melatonin 3.0g
The fine little plain 11.0g of crystallite
The fine little plain 5.0g of ethyl
Enteric solubility acrylic resin (I) is an amount of
Enteric solubility acrylic resin (II) is an amount of
Magnesium stearate is an amount of
Starch is an amount of
Make 1000 method for makings
With fluoracyl melatonin 0.5g; starch 10g and microcrystalline Cellulose 3g sieve mix homogeneously with the particulate immediate release section of 10% starch slurry system; other gets the fine little plain 5.0g of ethyl; enteric solubility acrylate (I) and enteric solubility acrylic resin (II) dissolve with soak with ethanol in right amount; get the fine little plain 8g of the fluoracyl melatonin 2.5g crystallite mix homogeneously that sieves again; with above-mentioned solution system soft material; crossing 20 mesh sieves granulates; in 50 ℃ of dryings; granulate gets slow-released part, and rapid release and the mixing of slow-released part granule are added the magnesium stearate mixing again; with 6mm punch die (flat square), tabletting.Every fluorine-containing acyl melatonin 3mg.
Claims (6)
1. fluoracyl melatonin and compositions thereof and preparation is characterized in that: be the synthetic 2-ethoxycarbonyl of guide-5-methoxy-N-TFA tryptamines (fluoracyl melatonin), its structure such as formula I chemical compound with the melatonin
The formula I chemical compound
2, fluoracyl melatonin according to claim 1 and compositions thereof and preparation, it is characterized in that: described chemical compound is made up of formula I chemical compound, calcium source, vitamin B6 or central inhibitor, and wherein the weight proportion of each component is as follows: fluoracyl melatonin 5-80; Calcium source 0-90; Vitamin B6 0-5; Central inhibitor 0-20; Substrate 0-5.
3. fluoracyl melatonin according to claim 2 and compositions and preparation, it is characterized in that: the calcium source is any edible or medicinal calcium source or calcium chelate, classical calcium source commonly used in increasing plain agent is as follows: calcium carbonate, calcium phosphate, calcium citrate, calcium gluconate, calcium oxalate, calcium glycine, animal bone calcium, Concha Ostreae calcium, activated calcium also can be used if other forms of calcium can be absorbed by the body.
4, fluoracyl melatonin according to claim 2 and compositions thereof and preparation is characterized in that: described central inhibitor comprises barbiturates, Benzodiazepines, r aminobutyric acid.
5. fluoracyl melatonin according to claim 2 and compositions and preparation is characterized in that: substrate is some food and pharmacy industry adjuvant commonly used, as microcrystalline Cellulose, starch, dextrin, Carboxymethyl cellulose sodium, HYDROXY PROPYL METHYLCELLULOSE.
6. according to claim l or 2 described fluoracyl melatonins and compositions and preparation, it is characterized in that: its preparation is various pharmaceutical formulations.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98113892 CN1231175A (en) | 1998-04-08 | 1998-04-08 | Fluoracyl melatonin and composition and preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98113892 CN1231175A (en) | 1998-04-08 | 1998-04-08 | Fluoracyl melatonin and composition and preparation thereof |
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| CN1231175A true CN1231175A (en) | 1999-10-13 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103989711A (en) * | 2014-05-30 | 2014-08-20 | 江苏大学 | Health-care preparation containing melatonin and preparation method thereof |
| CN105085367A (en) * | 2014-05-03 | 2015-11-25 | 广东东阳光药业有限公司 | Substituted heteroaromatic compound, and composition and application thereof |
| CN105497029A (en) * | 2015-12-17 | 2016-04-20 | 范健身 | Capsules for improving sleep |
| CN111407761A (en) * | 2020-04-28 | 2020-07-14 | 广东润源中天生物科技有限公司 | Melatonin vitamin B6 tablet and production method thereof |
-
1998
- 1998-04-08 CN CN 98113892 patent/CN1231175A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085367A (en) * | 2014-05-03 | 2015-11-25 | 广东东阳光药业有限公司 | Substituted heteroaromatic compound, and composition and application thereof |
| CN105085367B (en) * | 2014-05-03 | 2019-05-21 | 广东东阳光药业有限公司 | Substituted heteroaryl compounds and compositions and uses thereof |
| CN103989711A (en) * | 2014-05-30 | 2014-08-20 | 江苏大学 | Health-care preparation containing melatonin and preparation method thereof |
| CN105497029A (en) * | 2015-12-17 | 2016-04-20 | 范健身 | Capsules for improving sleep |
| CN111407761A (en) * | 2020-04-28 | 2020-07-14 | 广东润源中天生物科技有限公司 | Melatonin vitamin B6 tablet and production method thereof |
| CN111407761B (en) * | 2020-04-28 | 2021-06-18 | 广东润源中天生物科技有限公司 | Melatonin vitamin B6 tablet and production method thereof |
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