CN104860919B - Benzimidizole derivatives containing piperidines and its production and use - Google Patents
Benzimidizole derivatives containing piperidines and its production and use Download PDFInfo
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- CN104860919B CN104860919B CN201510137918.5A CN201510137918A CN104860919B CN 104860919 B CN104860919 B CN 104860919B CN 201510137918 A CN201510137918 A CN 201510137918A CN 104860919 B CN104860919 B CN 104860919B
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- GYHXQMGNPFMACT-UHFFFAOYSA-N CCOCC[n]1c(cccc2)c2nc1C(CC1)CCN1S(c1cc(C#N)ccc1)(=O)=O Chemical compound CCOCC[n]1c(cccc2)c2nc1C(CC1)CCN1S(c1cc(C#N)ccc1)(=O)=O GYHXQMGNPFMACT-UHFFFAOYSA-N 0.000 description 1
- HDQNIIDIJJIWPZ-UHFFFAOYSA-N CCOCC[n]1c(cccc2)c2nc1C(CC1)CCN1S(c1ccccc1)(=O)=O Chemical compound CCOCC[n]1c(cccc2)c2nc1C(CC1)CCN1S(c1ccccc1)(=O)=O HDQNIIDIJJIWPZ-UHFFFAOYSA-N 0.000 description 1
- CBWHCYHAZOBKOT-UHFFFAOYSA-N O=S(c1ccc[o]1)(N(CC1)CCC1c1nc2ccccc2[nH]1)=O Chemical compound O=S(c1ccc[o]1)(N(CC1)CCC1c1nc2ccccc2[nH]1)=O CBWHCYHAZOBKOT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to hypoglycemic effect technical field of pharmaceuticals, there is provided there are the benzimidizole derivatives and its pharmaceutically acceptable salt containing piperidines of structure shown in formula I, wherein：R1、R2、R3Definition as used in the description.The invention further relates to the preparation method of above-claimed cpd, and also disclose using the compound or its pharmaceutically acceptable salt as the pharmaceutical composition of active ingredients, and their applications in terms of as hypoglycemic drug.
Description
Technical field
The invention belongs to pharmaceutical technology field, more precisely, being to be related to a kind of hypoglycemic compound and its preparation side
Method, the pharmaceutical composition containing them and the purposes as hypoglycemic drug.
Background technology
Diabetes (diabetes mellitus, DM) be it is a kind of relative to genetic related endogenous insulin or
DKA can occur for the whole body chronic disease of sugar, fat and protein metabolism disorder, severe patient definitely caused by deficiency,
Hyperosmolar coma, and easily merge multi-infection.With the extension of the course of disease, its metabolic disorder can cause eye, kidney, nerve, blood vessel and
The chronic disease of more tissues such as heart.Current about 2.85 hundred million diabetics in the world, account for the 6.4% of world population, in advance
Count to the year two thousand thirty, be up to 4.38 hundred million, and patient is concentrated mainly on the countries in Southeast Asia such as India and China, sugar in Chinese adult
The illness rate of patient is urinated already close to 10%.For individual level, diabetes will also than life loss caused by hypertension
Seriously, its case fatality rate is only second to angiocardiopathy, malignant tumour, the referred to as lethal cause of disease disease of the 3rd in developed country
With the continuous discovery for the treatment of diabetes novel targets, the mechanism of action of various treatment diabetes medicaments is different, drug effect
Also it is not quite similar with toxicity.At present, clinically mainly using the method for a variety of OHAs and insulin intensive treatment
To delay diabetes progression.In addition to insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitor, thiazolidinediones, benzoic acid
The medicines such as derivative are current clinical conventional treatment diabetes medicaments.The hypoglycemic action fastoperation of these medicines is strong, but in sugar
Still there are many vacancies in terms of urinating disease early stage, insulin resistance, complication at present, these medicines of patient's long-term use easily cause not
The shortcomings that long-term efficacy can be maintained, also easily cause hypoglycemia, increased weight, produce hepatotoxicity wind agitation and induce hypoglycemia angiocarpy disease
The side effects such as disease, there is no protective effect to the islet cells of damage yet.
Therefore, finding more safe and effective novel blood sugar lowing medicine turns into one of focus of researcher research.
The content of the invention
It is an object of the present invention to develop the benzimidizole derivatives containing piperidines of a kind of new structure and its medicinal
Salt.
It is another object of the present invention to disclose the preparation sides of benzimidizole derivatives and its pharmaceutical salts containing piperidines
Method.
Another object of the present invention is that it is main to disclose using the benzimidizole derivatives containing piperidines and its pharmaceutical salts
The pharmaceutical composition of active component.
A further object of the invention is, benzimidizole derivatives and its pharmaceutical salts containing piperidines is disclosed, as drop
Application in terms of hypoglycemic medicament, particularly for preparing prevention or treating pancreas function exhaustion, mistake because of caused by hyperglycaemia
Purposes in terms of the disease medicaments such as water and rock-soil coupling, nutritional deficiency, resistance decline, impaired renal function, DPN.
Understand that the compounds of this invention has a certain degree of superiority through Preliminary pharmacological test.
In conjunction with the object of the invention, present invention is described in detail.
Present invention relates particularly to the compound of logical structure shown in formula I and its pharmaceutically acceptable salt：
Wherein：
R1For：Hydrogen, fluorine, chlorine, bromine atoms, C1-C4Straight or branched alkyl；
R2For：Hydrogen, ethyoxyl alkyl；
R3For：(a)Wherein R4, R5It is at the same time or separately hydrogen, C1-C4Alkyl, halogen, nitro, cyano group, C1-
C4Alkoxy；
(b)Wherein X is O or S；R6, R7It is at the same time or separately hydrogen, C1-C4Alkyl, halogen, nitro, cyano group, C1-
C4Alkoxy.
Compound and its pharmaceutically acceptable salt of the present invention with logical structure shown in formula I are preferably：
Wherein：
R1For：Hydrogen, fluorine, chlorine, bromine atoms, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group；
R2For：Hydrogen, ethyoxyl alkyl；
R3For：(a)Wherein R4, R5At the same time or separately for hydrogen, methyl, ethyl, propyl group, isopropyl, butyl,
Isobutyl group, the tert-butyl group, fluorine, chlorine, bromine, nitro, cyano group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tertiary fourth oxygen
Base；
(b)Wherein X is O or S；R6, R7At the same time or separately for hydrogen, methyl, ethyl, propyl group, isopropyl, butyl,
Isobutyl group, the tert-butyl group, fluorine, chlorine, bromine, nitro, cyano group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tertiary fourth oxygen
Base.
The compound or its pharmaceutically acceptable salt with structure shown in formula I of the present invention, which part compound are：
I -1 2- (1- tosylpiperidin -4- bases) -1H- benzimidazoles
I -2 1- (2- ethoxyethyl groups) -2- (1- (benzenesulfonyl) piperidin-4-yl) -1H- benzimidazoles
I -3 2- (1- (3,4- dichloros benzenesulfonyl) piperidin-4-yl) -1H- benzimidazoles
I -4 3- (4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl) piperidin-1-yl sulfonyl) cyanophenyl
I -5 2- (1- (furans -2- bases sulfonyl) piperidin-4-yl) -1H- benzimidazoles
I -6 1- (2- ethoxyethyl groups) -2- (1- (5- methylfuran -2- bases sulfonyl) piperidin-4-yl) -1H- benzo miaows
Azoles
I -7 5- (4- (1H- benzimidazolyl-2 radicals-yl) piperidin-1-yl sulfonyl) furans -2- nitriles
I -8 1- (2- ethoxyethyl groups) -2- (1- (thiophene -2- bases sulfonyl) piperidin-4-yl) -1H- benzimidazoles
I -9 2- (1- (thiophene -2- bases sulfonyl) piperidin-4-yl) -1H-5- tolimidazoles
I -10 1- (2- ethoxyethyl groups) -2- (1- (5- methylthiophene -2- bases sulfonyl) piperidin-4-yl) -1H- benzos
Imidazoles
Generalformulaⅰcompound pharmaceutically acceptable salt refers to：Compound and inorganic acid, organic acid are into salt.It is wherein preferred：Hydrochloric acid
Salt, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, first sulphur
Hydrochlorate, tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate, ox sulphur
Hydrochlorate etc..
The syntheti c route of type I compound is as follows：
X is O, S；R1、R2、R3As defined above
Using dichloromethane, chloroform, ethyl acetate, N,N-dimethylformamide, 1,4- dioxane or acetonitrile to be molten
Agent, substituted 2- (piperidin-4-yl)-benzo [d] imidazoles is dissolved, in triethylamine, N, N- diisopropyl ethylenediamines, pyridine, carbon
Under the catalysis of the acid binding agents such as sour potassium, sodium carbonate, sodium acid carbonate, sodium hydroxide or potassium hydroxide, -30~80 DEG C be added dropwise sulfonic acid chlorides with
The mixed liquor of solvent, react and chemical compounds I is made.
Reaction is made various compounds or products therefrom is dissolved in into DMF, acetone, methanol, ethanol, isopropanol, ether, acetic acid
Inorganic acid is added dropwise in ethyl ester or DMSO, pharmaceutically acceptable salt is made in organic acid.
Specifically products therefrom is dissolved in DMF, acetone, methanol, ethanol, isopropanol, ether or DMSO, hydrochloric acid second is added dropwise
Hydrochloride is made to pH2 in ether.Or products therefrom is dissolved in DMF, acetone, methanol or ethanol, equimolar lactic acid is added, obtains its breast
Hydrochlorate.
Such compound is effective for disease caused by treatment hyperglycaemia.Although the compound of the present invention can be without
Any prepare is directly administered, but described various compounds preferably use in the form of a pharmaceutical preparation, and method of administration can be with right and wrong
Enteral routes (such as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition of the compounds of this invention prepares as follows：Using standard and conventional technique, make the compounds of this invention
Combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily with acceptable adjuvant on galenic pharmacy and
Excipient combines and is prepared into particulate or microballoon.Solid dosage forms includes tablet, discrete particles, capsule, sustained release tablets, sustained release pellet etc.
Deng.Solid carrier can be at least one material, and it can serve as diluent, flavouring agent, solubilizer, lubricant, suspending agent, viscous
Mixture, disintegrant and coating agent.Inert solid carrier includes magnesium phosphate, magnesium stearate, smoothers sugar, lactose, pectin, the third two
Alcohol, polyoxyethylene sorbitan monoleate, dextrin, starch, gelatin, cellulose substances such as methylcellulose, microcrystalline cellulose, low melting point stone
Wax, polyethylene glycol, mannitol, cocoa butter etc..Liquid dosage form includes solvent, suspension such as injection, pulvis etc..
The amount of the active component (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can be according to patient
The state of an illness, the situation of diagnosis be specifically applied, the amount or concentration of compound used are in a wider scope
Regulation.Generally, the scope of reactive compound amount is 0.5~90% (weight) of composition, another preferable scope is 0.5~
70%.
The compound or its pharmaceutically acceptable salt with structure shown in formula I of the present invention, has significantly at hypoglycemic aspect
Inhibitory action.
Embodiment
With reference to embodiment, the present invention is described further, and embodiment is only explanatory, is in no way intended to it
The scope limiting the invention in any way.Described compound is carried out through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC)
Detection.It can then use such as infrared spectrum (IR), nuclear magnetic resoance spectrum (1H NMR,13C NMR), mass spectrum (MS) etc. more enters one
Step confirms its structure.
Embodiment 1：
2- (1- tosylpiperidin -4- bases) -1H- benzimidazoles (compound I-1)
Equipped with stirring, condenser, thermometer reaction bulb in add 2- (piperidin-4-yl) -1H- benzos [d] imidazoles
(10.06g,
0.05mol), triethylamine (10.10g, 0.1mol) is added after being dissolved with 50ml dichloromethane, is stirred at -10 DEG C~5 DEG C
Mix, dichloromethane (30ml) solution of paratoluensulfonyl chloride (11.44g, 0.06mol) is added dropwise, (flaggy is shown anti-low-temp reaction 3h
Should be complete) after, distilled water washing reaction liquid (50ml × 3), organic layer anhydrous sodium sulfate drying, filtering, remove under reduced pressure organic
Solvent, residue are separated with silica gel column chromatography, produce near-white solid I-1 (16.44g, yield 92.50%), purity 98.91%
(HPLC).Rf=0.72 [single-point, solvent：V (petroleum ether):V (ethyl acetate)=1:3].ESI-HRMS:Calcd for
C19H22N3O2S(M+H)356.1427,found 356.1431.
With reference to the method for embodiment 1, target compound I -2~I -10 can be made.
Embodiment 2：
The hydrochloric acid salt of chemical compounds I -1：I -1 near-white solid product 4.0g is taken, is dissolved in 11mL anhydrous isopropyl alcohols.Ice-water bath is cold
But to 5 DEG C, it is 2 that 10.7% hydrochloric acid aqueous isopropanol, which is added dropwise, to pH, continues at stir about 1h under ice-water bath.Filtering, is obtained white solid
Body.
Embodiment 3：
The one-tenth sulfate of chemical compounds I -2：I -2 white solid product 4.3g is taken, is dissolved in 30mL acetone.Ice-water bath is cooled to 5 DEG C,
It is 3 that 9.8% sulfuric acid acetone soln, which is added dropwise, to pH, continues at stir about 1h under ice-water bath.Filtering, obtains white solid.
Embodiment 4：
The one-tenth lactate of chemical compounds I -5：I -5 white solid product 5.0g is taken, is dissolved in 20mL absolute methanols.After being heated to backflow
Equimolar lactic acid is added, continues at stirred at reflux reaction about 1h.Reaction finishes, and stands 24h at room temperature.Separate out faint yellow knot
Crystalline substance, filter, vacuum drying.
In order to which the pharmaceutical composition of the benzimidizole derivatives containing piperidines of the present invention is more fully explained, it is provided below down
Series preparation embodiment, the embodiment are merely to illustrate, rather than for limiting the scope of the present invention.The preparation can use
Any reactive compound and its salt in the compounds of this invention, preferably using the compound described in embodiment 1-4.
Embodiment 5：
Hard gelatin capsule is prepared with following compositions：
Preparation technology：Supplementary material is pre-dried, it is standby to cross 100 mesh sieves.After by recipe quantity, mentioned component is mixed, filling
Enter in hard gelatin capsule.
Embodiment 6：
Tablet is prepared with following compositions：
Preparation technology：Supplementary material is pre-dried, it is standby to cross 100 mesh sieves.First the auxiliary material of recipe quantity is fully mixed.By original
Material medicine is added in auxiliary material with incremental dilution method, and each added-time fully mixes 2-3 times, is ensured that medicine fully mixes with auxiliary material, is crossed 20 mesh
Sieve, dries 2h in 50 DEG C of ventilated drying ovens, and dry particl crosses the arrangement of 16 mesh sieves, determines intermediates content, is well mixed, in tablet press machine
Upper tabletting.
Embodiment 7：
The preparation of parenteral solution：
Preparation method：Take active component to be added in the water for injection for having dissolved sorbierite and propane diols, add medicinal basic
Regulation pH value makes its dissolving to 4~8.Add activated carbon, stirring and adsorbing 30min, carbon removal, refined filtration, embedding, sterilizing.
Embodiment 8：
The preparation of injection freeze-dried powder：
The 100mg of chemical compounds I -5
Medicinal basic 0.1-7.0%
Mannitol 55-85%
Preparation method：Take active component to add water for injection, make its dissolving with medicinal basic regulation pH value to 4-8.Add
Mannitol, autoclaving is carried out by the requirement of injection, adds activated carbon, using filtering with microporous membrane, filtrate is dispensed, and is adopted
With freeze-drying, loose block is made, sealing, produces.
Embodiment 9：
External insulin-sensitizing activity test
By 3T3-L1 cell culture in the DMEM nutrient solutions containing 10%NBS, passage in every 3 days is once.Cell is placed in 24 holes
In culture plate, with 0.5mmol/L IBMX and l μm of ol/L DEX and 1.0 μm of ol/L insulin processing 48h after covering with, add simultaneously
The test-compound of various dose (0.01,0.1 and l μm of ol/L), continue culture to experiment and terminate.Cell is collected, uses colorimetric method
The triglycerides and protein content in cell are determined, calculates the incrementss of intracellular triglyceride after administration.Positive control
Group selects rosiglitazone.Blank control group is the nutrient solution containing 0.1% dimethyl sulfoxide (DMSO).Fat before target compound stimulates
The Activity Results of fat cell differentiation lipoblast are shown in Table 1.
The target compound of table 1 stimulates the activity of PECTORAL LIMB SKELETON differentiation lipoblast
From can substantially suppress blood glucose rise with the pharmacological results of upper table 1, compound of the invention.
Claims (10)
1. compound or its pharmaceutically acceptable salt with structure shown in formula I：
Wherein：
R1For：Hydrogen, fluorine, chlorine, bromine, C1-C4Straight or branched alkyl；
R2For：Ethyoxyl alkyl；
R3For：(a)Wherein R4, R5It is at the same time or separately hydrogen, C1-C4 alkyl, halogen, nitro, cyano group, C1-C4 alkane
Epoxide；
(b)Wherein X is O or S；R6, R7It is at the same time or separately hydrogen, C1-C4 alkyl, halogen, nitro, cyano group, C1-C4 alkane
Epoxide.
2. there is the compound or its pharmaceutically acceptable salt of structure shown in formula I as claimed in claim 1：
Wherein：
R1For：Hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group；
R2For：Ethyoxyl alkyl；
R3For：(a)Wherein R4, R5It is at the same time or separately hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl
Base, the tert-butyl group, fluorine, chlorine, bromine, nitro, cyano group, methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy, tert-butoxy；
(b)Wherein X is O or S；R6, R7It is at the same time or separately hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl
Base, the tert-butyl group, fluorine, chlorine, bromine, nitro, cyano group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy.
3. the compound of following structure or its pharmaceutically acceptable salt：
Ⅰ-2
Ⅰ-4
Ⅰ-5
Ⅰ-6
Ⅰ-7
Ⅰ-8
Ⅰ-9
Ⅰ-10
4. having the compound or its pharmaceutically acceptable salt of structure shown in formula I as claimed in claim 1 or 2, it pharmaceutically may be used
The salt of receiving is：Compound of formula I and inorganic acid, organic acid are into salt.
5. having the compound or its pharmaceutically acceptable salt of structure shown in formula I as claimed in claim 4, its is pharmaceutically acceptable
Salt be：Hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate,
Lactate, mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, richness
Horse hydrochlorate, taurate.
6. the preparation method of the compound with structure shown in formula I as claimed in claim 1 or 2, it is characterised in that：Substituted benzo
For glyoxaline compound with sulfonic acid chloride class compound in the presence of acid binding agent, chemical combination is made in -30~80 DEG C of reactions in organic solvent
Thing I, wherein each substituent is as claimed in claim 1 or 2；
7. the preparation method of the compound with structure shown in formula I as claimed in claim 6, it is characterised in that：Described acid binding agent
It is selected from：Triethylamine, N, N- diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, sodium acid carbonate, sodium hydroxide or potassium hydroxide.
8. the preparation method of the compound with structure shown in formula I as claimed in claim 6, it is characterised in that：Described is organic molten
Agent is selected from：Ethyl acetate, dichloromethane, chloroform, toluene, DMF, DMSO or acetonitrile.
9. a kind of pharmaceutical composition, it has structure shown in formula I comprising therapeutically effective amount as described in any one of claim 1~2
Compound or its pharmaceutically acceptable salt and one or more pharmaceutical carriers.
10. if the compound of any one of claim 1~2 with structure shown in formula I or its pharmaceutically acceptable salt are for making
Application in terms of hypoglycemic medicament of making preparation for dropping.
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Cited By (1)
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| CN108289840A (en) * | 2015-11-30 | 2018-07-17 | 葛兰素史密斯克莱知识产权（第2号）有限公司 | Preparation for being injected intravenously Danirixin |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0882718T3 (en) * | 1995-12-28 | 2005-12-12 | Astellas Pharma Inc | benzimidazole |
| JPWO2002068407A1 (en) * | 2001-02-28 | 2004-06-24 | 山之内製薬株式会社 | Benzimidazole compounds |
| AR045496A1 (en) * | 2003-08-29 | 2005-11-02 | Schering Corp | ANALOLGES OF BENZIMIDAZOLPIPERIDINAS 2- SUBSTIZED AS ANTAGONISTS OF HORMONE RECEPTORS CONCENTRATING SELECTIVE MELANINE FOR THE TREATMENT OF OBESITY AND RELATED DISORDERS |
| CN101374813A (en) * | 2004-04-07 | 2009-02-25 | 凯利普西斯公司 | Aryl sulfonamide and sulfonyl compounds as modulators of PPAR and methods of treating metabolic disorders |
| US20100144591A1 (en) * | 2007-03-02 | 2010-06-10 | Schering Corporation | Benzimidazole derivatives and methods of use thereof |
| EP2440542B1 (en) * | 2009-06-08 | 2013-12-18 | Grünenthal GmbH | Substituted benzimidazoles, benzonthiazoles and benzoxazoles |
| AU2012267556B9 (en) * | 2011-06-09 | 2017-05-11 | Rhizen Pharmaceuticals Sa | Novel compounds as modulators of GPR-119 |
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| CN108289840A (en) * | 2015-11-30 | 2018-07-17 | 葛兰素史密斯克莱知识产权（第2号）有限公司 | Preparation for being injected intravenously Danirixin |
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