CN105311008B - The purposes of stearoyl amino acid or its pharmaceutical salts - Google Patents
The purposes of stearoyl amino acid or its pharmaceutical salts Download PDFInfo
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- CN105311008B CN105311008B CN201410334003.9A CN201410334003A CN105311008B CN 105311008 B CN105311008 B CN 105311008B CN 201410334003 A CN201410334003 A CN 201410334003A CN 105311008 B CN105311008 B CN 105311008B
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Abstract
The invention discloses a kind of purposes of stearoyl amino acid or its officinal salt in slimming medicine is prepared, the stearoyl amino acid has the structural formula shown in following formula (I), wherein, R1Represent H or the aromatic radical or C that can be substituted by one or more substituents1‑4Straight chain or alkyl with side chain, the substituent is alcoholic extract hydroxyl group or phenolic hydroxyl group;R2Represent C11‑25Saturation or unsaturated aliphatic hydrocarbyl moiety.The invention also discloses the pharmaceutical composition for including stearoyl amino acid or its officinal salt.The stearoyl amino acid or its pharmaceutical salts of the present invention, confirms through preclinical Pharmacokinetic experiments, can not only significantly reduce obesity mice body weight, and safe, is expected to turn into clinical slimming medicine, has a extensive future.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of stearoyl amino acid or the new application of its pharmaceutical salts.
Background technology
Obesity is to cause diabetes, the first cause of the disease such as cardiovascular and cerebrovascular disease and NASH.The whole world into
People's obesity rates show year by year drastically elevated trend, 2013 up to 22%.Although appetite inhibitor sibutramine, Rimonabant etc.
Can effectively it lose weight, but the side effect such as depression ultimately results in both slimming drugs and removes city.And the slimming drugs of FDA approvals
Orlistat is in the fourth phase clinical monitoring it has also been found that rare hepatic injury case.Because the obesity cause of disease is complicated, therefore, preferably
Slimming medicine should have good security, and can promote lipolysis, suppression by adjusting a plurality of associated metabolic path in vivo
Fat absorption processed and synthesis.At present, the research both at home and abroad for Bariatric medicine focuses primarily upon discovery promotion beta oxidation (fat
The main path of fat catabolism) natural products, but such natural products can not often obtain the phase on fat animal model
The effect of prestige, meanwhile, its safety evaluation result also limit the development of such medicine.Thus, it is found that mechanism of action novelty
Slimming medicine does not only have great social demand, it may have important theory significance.
The N- stearoyls amino acid (such as NSTyr, NsTyr) or its officinal salt (such as N- of this laboratory research and development
Stearoyl tyrosine di-potassium, NST-2K) be endocannabinoids (anandamide, AEA) novel analogs, it passes through dry
The metabolism link of pre- Endogenous cannabinoid system (ECS) plays neuroprotection.
The research to stearoyl amino acid and its salt focused on the neuroprotection of the compound in the past, there is no pass so far
It is used as the open report of slimming medicine in stearoyl amino acid or its pharmaceutical salts.
The content of the invention
The invention solves the technical problem for lacking safe and effective slimming drugs at present, there is provided a kind of stearoyl amino acid or its
Purposes of the pharmaceutical salts in slimming medicine is prepared.
In order to solve the above-mentioned technical problem, the present invention is achieved through the following technical solutions:
In one aspect of the invention, there is provided a kind of stearoyl amino acid or its officinal salt are in slimming medicine is prepared
Purposes, the stearoyl amino acid has the structural formula shown in following formula (I):
Wherein, R1Represent H or the aromatic radical or C that can be substituted by one or more substituents1-4Straight chain or with side chain
Alkyl, the substituent is alcoholic extract hydroxyl group or phenolic hydroxyl group;R2Represent C11-25Saturation or unsaturated aliphatic hydrocarbyl moiety.
Above-mentioned C1-4Alkyl refer to the straight or branched alkyl with 1~4 carbon atom, such as:Methyl, ethyl, third
Base, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl.It is preferred that the alkyl with 1~2 carbon atom.
Above-mentioned C11-25Aliphatic group refer to saturation or unsaturated aliphatic hydrocarbyl moiety with 11~25 carbon atoms, wherein,
Saturated fat alkyl refers to straight chain or alkyl with side chain, cycloalkyl, such as dodecyl, octadecyl, cyclo-dodecyl, ring
Octadecyl etc., and unsaturated aliphatic hydrocarbyl moiety refers to alkenyl, alkynyl or alkadienyl, alkenyl such as 1- laurylenes base, 2- ten
Dialkylene, alkynyl such as 1- octadecynes base, 2- octadecyne bases, alkadienyl such as 1,3- octadecylenes base, 7,9- octadecylene bases etc..It is preferred that
Straight or branched alkyl with 17~25 carbon atoms, particularly preferably there is the straight chained alkyl of 17 carbon atoms.
Preferably, the stearoyl amino acid is the NSTyr of following formula (II) structural formula:
Preferably, the stearoyl amino-acid salt has the structural formula of following formula (III) or formula (IV):
Wherein, the M in formula (III) is monovalent metal cation or NH4 +, the M in formula (IV) is divalent metal.
Preferably, the M in the formula (III) is selected from K+、Na+Or NH4 +。
Preferably, the M in the formula (IV) is selected from Ba2+、Ca2+Or Mg2+。
In another aspect of this invention, a kind of pharmaceutical composition for being used to lose weight is additionally provided, the composition includes peace
The stearoyl amino acid or its officinal salt and pharmaceutically acceptable carrier of full effective dose.
Above-mentioned acceptable carrier is nontoxic, can aid in using and stearoyl amino acid or its officinal salt are controlled
Therapeutic effect has no adverse effect.Examples of such carriers can be any solid excipient, the liquid that those skilled in the art usually leads to
Body excipient, semisolid excipient can be gaseous excipients in aerosol combination.Solid pharmaceutical excipients include
Starch, cellulose, talcum, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, tristearin
Sour sodium, glyceryl stearate acyl ester, sodium chloride, anhydrous skimmed milk etc..Liquid and semisolid excipient can be selected from glycerine, propane diols,
Water, ethanol and various oil, including those come from oil, animal, plant or artificial synthesized oil, for example, peanut oil, soya-bean oil, ore deposit
Thing oil, sesame oil etc., preferable liquid-carrier, particularly for Injectable solution, including water, salt solution, D/W
And glycol.It can in addition contain add other assistant agents such as flavouring agent, sweetener etc. in the composition.
The stearoyl amino acid or its officinal salt of the present invention is applied with the effective dose treated, and its method of application can be
Orally, systemic administration (for example, transdermal, nasal inhalation or with suppository) or parenteral administration are (for example, intramuscular, quiet
It is in arteries and veins or subcutaneous).Preferable method of application is oral, and it can be adjusted according to disease degree.
The present invention stearoyl amino acid or its officinal salt actual amount of application (i.e. active component) depend on it is many because
Element, such as seriousness of disease to be treated, the age for the treatment of target and relative health, used compound efficiency, apply
With approach and form, and other factors.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the conventional method of pharmaceutical field.Such as make the tristearin
Acylamino- hydrochlorate (active component) mixes with one or more kinds of carriers, is then made into required formulation, such as tablet, medicine
Ball, capsule, semisolid, powder, slow release formulation, solution, suspension, ingredients, aerosol etc..
In another aspect of this invention, stearoyl amino acid or its officinal salt are additionally provided and is preparing treatment fatty liver medicine
Purposes in thing.
The stearoyl amino acid or its pharmaceutical salts of the present invention is small when being administered orally to KM in preclinical Pharmacokinetic experiments
Mouse, as a result showing, the stearoyl amino acid or its pharmaceutical salts can not only significantly reduce obesity mice body weight, and safe,
It is expected to turn into clinical slimming medicine, application prospect is boundless.
Brief description of the drawings
The present invention is further detailed explanation with reference to the accompanying drawings and detailed description.
Fig. 1 is diet intervention each group mouse weight variation diagram during 11 weeks of the embodiment of the present invention 1;
Fig. 2 is diet intervention each group mouse average food intake block diagram during 11 weeks of the embodiment of the present invention 1;
Fig. 3 is each group mouse weight variation diagram during the administration of the embodiment of the present invention 2 is handled 4 weeks;
Fig. 4 is each group mouse average food intake block diagram during the administration of the embodiment of the present invention 2 is handled 4 weeks;
Fig. 5 is the mouse peritoneal fat photo figure of the embodiment of the present invention 3;
Fig. 6 is epididymal adipose section H&E dyeing microphoto (engineer's scale=100 μm) figures of the embodiment of the present invention 4;
Fig. 7 is the epididymis tissue fat cell size block diagram of the embodiment of the present invention 4;
Fig. 8 is liver tissue slices H&E dyeing microphoto (engineer's scale=50 μm) figures of the embodiment of the present invention 4;
Fig. 9 is the equilbrium solubility curve of the embodiment of the present invention 5 and apparent lipid curve map;
Figure 10 is that the rat oral of the embodiment of the present invention 5 takes the blood concentration-time curve after gavage NST-2K, NsTyr
Figure.
In Fig. 3~8, ND, standard feed blank control group;HFD I, high lipid food blank control group;HFD II, low dosage
NST-2K groups (20mg/kg/day);HFD III, middle dosage NST-2K group (60mg/kg/day);HFD IV, high dose NST-2K groups
(100mg/kg/day);HFD V, positive controls (Orlistat100mg/kg/day).
Embodiment
The foundation of the Mice model of obesity of embodiment 1
1. purpose:Establish the Mice model of obesity for testing stearoyl amino acid or its pharmaceutical salts anti-obesity activity.
2. method:60 C57BL/6 mouse (3 week old, male ,~8.3g) are fed with 12%kcal standard feeds adaptability
After one week, 6 groups are randomly divided into, each group 10.One group (ND) continues with fed standard chow, remaining five groups (HFD I~V) with
45%kcal high lipid foods are fed.Each group average weight and food intake dose are recorded weekly until body weight has between two kinds of feed groups
There is significant difference, while there was no significant difference for body weight between five groups of high lipid food groups, and maintain the stable state 3 weeks, it can recognize
To model successfully.
Whole experiment process Mouse feeder is in following environment:23 ± 3 DEG C of temperature, humidity 50 ± 5%, light and shade alternate cycle
12h/12h, whole process mouse ad lib drinking-water.
3. result:
1) as shown in figure 1, using DIFFERENT FEED feed to the 9th week (in Fig. 1 abscissa as 10 position because abscissa 0~
1 stage was that adaptability feeds the stage, and six groups of this stage are just used with fed standard chow, the stage later from abscissa 1
DIFFERENT FEED is fed), five groups of high lipid food group (HFD I~V) mouse weights are significantly higher than standard feed group (ND), and five groups are high
Between fat feed group (HFD I~V), there was no significant difference for mouse weight.After above-mentioned weight differences state continues 3 weeks, fat mould
Type is successfully established (DIFFERENT FEED feed 11 weeks), and now standard feed group (ND) average weight is about 28.3g, five groups of high lipid foods
Group (HFD I~V) average weight is about 32.8g.In Fig. 1, all numerical value are represented in the form of mean ± standard error, n=10,
Different letters represent there is significant difference (P between the two<0.05).
2) as shown in Fig. 2 during 11 weeks of diet intervention (during i.e. DIFFERENT FEED is fed), standard feed group (ND) mouse
Per day food ration is significantly higher than each high lipid food group (HFD I~V), but (HFD I~V) mouse day between each high lipid food group
There was no significant difference for average food ration.In fig. 2, all numerical value are represented in the form of mean ± standard error, n=10, and * * * are represented
With significant difference (P compared with ND<0.001).
4. conclusion:Mouse obese model is successfully established, and the modelling phase, mouse between high lipid food each group (HFD I~V)
Appetite is similar.
The administration experiment of embodiment 2
1. purpose:(the present embodiment is observation N- stearoyls amino-acid salt with NSTyr di-potassium, NST-2K
Example) influence to obesity mice body weight after administration, and compared with positive drug Orlistat.
2. method:ND and HFD I gives 0.5% carboxymethyl fibre respectively as standard feed and high lipid food blank control group
Tie up plain sodium water solution (5ml/kg/day);HFD II~IV is used as tested group, gives NST-2K (20,60,100mg/kg/day);
HFD V is used as positive controls, gives Orlistat (100mg/kg/day).All medicines are dissolved in 0.5% carboxymethyl cellulose
Gastric infusion after plain sodium water solution.Administration continues 4 weeks, records each group average weight and food intake dose weekly until the administration stage
Terminate.
3. result:
1) as shown in figure 3, administration stage, administration fat group HFD II, HFD III and the increased weights of HFD V are fatter than blank
HFD I is slow, but at the end of the whole administration stage, still there was no significant difference for body weight between this four groups of mouse;Fat group HFD IV is administered
As administration time extends, body weight is on a declining curve, and at the end of the whole administration stage, body weight is substantially less than HFD I.In Fig. 3,
All numerical value represent that n=10, different letters represent there is significant difference (P between the two in the form of mean ± standard error<
0.05)。
2) as shown in figure 4, during administration is handled 4 weeks, the per day food ration of standard feed group (ND) mouse is significantly higher than respectively
High lipid food group (HFD I~V), but (HFD I~V) per day food ration of mouse is poor without conspicuousness between each high lipid food group
It is different.In Fig. 4, all numerical value are represented in the form of mean ± standard error, n=10,***Represent compared with ND with significant difference
(P<0.001)。
4. conclusion:
1) (20,60mg/kg/day) and positive drug Orlistat (100mg/kg/ from the figure 3, it may be seen that low, middle dosage NST-2K
Day obesity mice increased weight can) be suppressed, high dose NST-2K (100mg/kg/day) can reduce obesity mice body weight.
Under Isodose (100mg/kg/day), NST-2K anti-obesity activities are significantly better than Orlistat.
2) stage as shown in Figure 4, is administered, mouse appetite is similar between high lipid food each group (HFD I~V), shows NST-
2K and Orlistat is non-to play antiobesity action by appetite-suppressing.
The collection and observation of the experimental animal of embodiment 3 fat and liver organization
1. purpose:Each group mouse peritoneal fat content is observed, and separates liver and adipose tissue, is dyed for follow-up H&E
Observation.
2. method:After administration terminates, mouse fasting overnight, abdominal cavity is opened, observe each group mouse peritoneal fat content, separation
Epididymal adipose tissues, perirenal fat and liver, and weigh.
3. result:
1) as shown in figure 5, standard feed group mouse (ND) build and abdominal cavity fat pad are significantly less than each high lipid food group
(HFD I~V), as NST-2K dosages increase (HFD II~IV), abdominal cavity fat pad is compared with blank fat group (HFD I)
The trend reduced is shown, wherein HFD IV (high dose NST-2K groups) effect is the most obvious, better than HFD V (Orlistat groups).
2) as shown in table 1, between each high lipid food group (HFD I~V) there was no significant difference for liver percent mass, but significantly it is low
In standard feed group (ND);HFD III, HFD IV, the epididymises of HFD V and perirenal fat percent mass are substantially less than blank fat group
(HFDⅠ);HFD II (low dosage NST-2K groups) is compared with HFD I, and epididymis and perirenal fat percent mass are without significant difference.
The mouse liver of table 1 and adipose tissue percent mass[a]
[a] all numerical value represent in the form of mean ± standard error, n=10.**、***Represent to have compared with ND respectively to show
Write sex differernce (P<0.01, P<0.001).#、##、###P<0.001 represents compared with HFD I with significant difference (P respectively<
0.05, P<0.01, P<0.001).ND, standard feed blank control group;HFD I, high lipid food blank control group;HFD II, low dose
Measure NST-2K groups (20mg/kg/day);HFD III, middle dosage NST-2K group (60mg/kg/day);HFD IV, high dose NST-2K
Group (100mg/kg/day);HFD V, positive controls (Orlistat100mg/kg/day).
4. conclusion:NST-2K can reduce obesity mice abdominal cavity fat quality, and liver mass is influenceed without conspicuousness.On an equal basis
Under dosage (100mg/kg), NST-2K reduces abdominal cavity fat mass effect and is better than Orlistat.
Embodiment 4H&E dyeing observation fat and liver organization form
1. purpose:Microexamination fat and liver organization form.
2. method:Epididymal adipose tissues and liver fix 48 hours with 10% neutral formalin solution, make 5 μm after FFPE
Section, hematoxylin eosin staining (H&E dyeing), om observation adipocyte size, liver cell structure and fat accumulation.
3. result:
1) such as Fig. 6, shown in Fig. 7, the adipocytes of HFD I are noticeably greater than ND, and administration group HFD III, HFD IV and HFD V are fatty
Cell is substantially reduced compared with HFD I;Low dosage NST-2K (HFD II) processing can not be substantially reduced adipocyte.In Fig. 7, institute
There is numerical value to be represented in the form of mean ± standard error, n=10,***Represent compared with ND with significant difference (P<0.001),###
Represent compared with HFD I with significant difference (P<0.001).
2) as shown in figure 8, the liver organizations of HFD I have a serious fat accumulation phenomenon, at NST-2K or Orlistat administrations
After reason, as dosage increases, alleviation trend is presented in liver fat accumulation.
4. conclusion:NST-2K can reduce obesity mice adipocyte size, alleviate the change of obesity mice liver fat.
The test experiments of embodiment 5N- stearoyl amino-acid salt physicochemical constants and pharmacokinetic parameters
1. equilbrium solubility and apparent lipid
NsTyr (NSTyr), NST-2K (NSTyr dipotassiums when determining 37 DEG C using fask oscillating method
Salt), equilbrium solubility in NST-2Na (NSTyr disodium salt) water.NsTyr solubility is less than 100 μ g/100ml water,
NST-2K, NST-2Na solubility are respectively 513.704 μ g/100ml water, 926.551 μ g/100ml water;NST-2K、NST-2Na
Apparent lipid logp be respectively 1.512,1.477.NST-2K, NST-2Na equilbrium solubility are surveyed under different pH
Examination data are shown in Table 2, apparent lipid and are shown in Table 3.Equilbrium solubility curve and apparent lipid curve such as Fig. 9 institutes
Show.
The equilbrium solubility of table 2NST-2K, NST-2Na in different pH buffer solution
PH value | NST-2K(mg/L) | NST-2Na(mg/L) |
2.0 | 49.290 | 66.938 |
3.0 | 58.504 | 66.334 |
4.0 | 188.155 | 195.371 |
5.0 | 220.693 | 232.102 |
6.0 | 243.482 | 274.629 |
7.0 | 251.430 | 318.016 |
7.4 | 270.414 | 374.484 |
8.0 | 285.935 | 463.902 |
9.0 | 369.807 | 512.644 |
The apparent lipid of table 3NST-2K, NST-2Na in different pH buffer solutions
PH value | NST-2K Ko/w | LogP | NST-2Na Ko/w | LogP |
2.0 | 76.020 | 1.881 | 49.913 | 1.698 |
3.0 | 30.571 | 1.485 | 28.980 | 1.462 |
4.0 | 16.020 | 1.205 | 15.224 | 1.183 |
5.0 | 21.934 | 1.341 | 18.710 | 1.272 |
6.0 | 28.935 | 1.461 | 19.963 | 1.300 |
7.0 | 37.855 | 1.578 | 31.436 | 1.497 |
7.4 | 16.674 | 1.222 | 29.286 | 1.467 |
8.0 | 13.797 | 1.140 | 28.704 | 1.458 |
9.0 | 13.140 | 1.119 | 21.872 | 1.340 |
It is low in stomach by being understood with upper table 2, the equilbrium solubility of table 3 and the data of apparent lipid, and Fig. 9
PH makes a large amount of NST-2K, NST-2Na be reduced into prototype medicine NsTyr presence, is absorbed through biomembrane and plays drug effect;Into intestinal segment
Afterwards, its equilbrium solubility increased dramatically, and apparent lipid rapid drawdown, medicine mainly exists in the form of an ion, it is difficult to passes through
Biomembrane absorbed into serum.It is improved compared with prototype medicine NsTyr, NST-2K, NST-2Na solubility.
2. absorption dynamics data
10 150-180g SD rats are randomly divided into 2 groups, every group 5, male and female dual-purpose.Gavage gives 200mg/kg's
After NsTyr and NST-2K normal saline solutions, mean blood plasma concentration-time graph is shown in Figure 10 respectively.SD Oral Administration in Rats 200mg/
Pharmacokinetics Parameter after kg NsTyr and NST-2K is shown in Table 4.
Pharmacokinetics Parameter after the Oral Administration in Rats 200mg/kg NsTyr of table 4 and NST-2K
Parameter | NsTyr | NST-2K |
AUClast(h*μg/ml) | 0.13 | 3.49 |
AUCinf(h*μg/ml) | 0.14 | 3.69 |
MRTlast(h) | 1.38 | 2.19 |
T1/2(h) | 1.49 | 2.90 |
Tmax(h) | 0.75 | 0.60 |
Cmax(μg/ml) | 0.11 | 2.40 |
By comparing both Pharmacokinetics Parameters, NST-2K increases 30 times compared to NsTyr TG-AUCs AUC, phase
Bioavilability is significantly improved, half-life period is obviously prolonged (nearly twice);Cmax Cmax's is substantially improved (about 20 times) and reaches
Peak time Tmax's falls sharply, and prompts NST-2K that absorption rate is big in vivo, can suitably reduce dosage, advantageously reduces malicious pair
React occurrence probability, increase treatment window and safety coefficient.Prepare in formulation, suspension is can be made into by solubility limit NsTyr
Form;Solubility high salt NST-2K, NST-2Na can be prepared into homogeneous solution.
Embodiment described above only expresses embodiments of the present invention, and its description is more specific and detailed, but can not
Therefore it is interpreted as the limitation to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art,
Without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection model of the present invention
Enclose.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (5)
1. the purposes of NSTyr or its officinal salt in slimming medicine is prepared shown in formula (II)
2. purposes according to claim 1, it is characterised in that the officinal salt of the NSTyr has following
The structural formula of formula (III) or formula (IV):
Wherein, the M in formula (III) is monovalent metal cation or NH4 +, the M in formula (IV) is divalent metal.
3. purposes according to claim 2, it is characterised in that the M in the formula (III) is selected from K+、Na+Or NH4 +。
4. purposes according to claim 2, it is characterised in that the M in the formula (IV) is selected from Ba2+、Ca2+Or Mg2+。
5. NSTyr shown in formula (II) or its officinal salt are preparing the purposes in treating fatty liver medicament
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CN201410334003.9A CN105311008B (en) | 2014-07-14 | 2014-07-14 | The purposes of stearoyl amino acid or its pharmaceutical salts |
PCT/CN2014/090381 WO2015103901A1 (en) | 2014-01-08 | 2014-11-05 | Stearoyl amino acid salt, and preparation method therefor and uses thereof |
US15/110,228 US9914698B2 (en) | 2014-01-08 | 2014-11-05 | Stearoyl amino acid salt and preparation method and application thereof |
US15/877,838 US20180215703A1 (en) | 2014-01-08 | 2018-01-23 | Stearoyl amino acid salt and method of use thereof |
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