CN107805246A - A kind of application of imidazolone derivatives in the medicine of anti-dengue virus is prepared - Google Patents

A kind of application of imidazolone derivatives in the medicine of anti-dengue virus is prepared Download PDF

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CN107805246A
CN107805246A CN201710828099.8A CN201710828099A CN107805246A CN 107805246 A CN107805246 A CN 107805246A CN 201710828099 A CN201710828099 A CN 201710828099A CN 107805246 A CN107805246 A CN 107805246A
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imidazolone derivatives
medicine
hydrogen atom
application
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饶子和
杨诚
郭宇
蔡岩
汪颖
毛永红
赵佩佩
贺万丽
赵杨杨
楚会萌
刘高盼
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TIANJIN INTERNATIONAL JOINT ACADEMY OF BIOMEDICINE
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TIANJIN INTERNATIONAL JOINT ACADEMY OF BIOMEDICINE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a kind of application of imidazolone derivatives in the medicine of anti-dengue virus is prepared, the structural formula of the imidazolone derivatives is：Wherein, R1Selected from amino, C1‑3Alkyl amino, C1‑3Acyl amino, hydroxyl, C1‑3Alkoxy, hydrogen atom or oxygen atom；R2Selected from C1‑3Alkyl, aromatic ring, aryl-heterocyclic or hydrogen atom；R3Selected from C1‑3Alkyl, alkoxy or hydrogen atom；R4Selected from O alkyl first oxime, O alkyl hydroxylamine, oxadiazole rings, trifluoromethyl substitution oxadiazole rings, C1‑5Wan bases substitution oxadiazole rings, C1‑5Alkyl-substituted imidazole ring, C1‑5Alkyl-substituted triazole ring, C1‑5Alkyl-substituted Thiadiazole, N hydroxyformamides, N alkoxies formamide, hydrogen atom, cyano group or N hydroxyl amidino groups；X is selected from carbon atom or nitrogen-atoms；And Y is selected from C1‑4Alkyl, C5‑6Cycloalkyl or C1‑3Alkynyl.Such compound has higher selective inhibitory on a cellular level, to dengue fever virus, has good prospect on treatment dengue fever virus sense medicine is prepared.

Description

A kind of application of imidazolone derivatives in the medicine of anti-dengue virus is prepared
Technical field
The present invention relates to pharmaceutical field, and anti-dengue virus is being prepared more particularly, to a kind of imidazolone derivatives Application in medicine.
Background technology
Dengue fever (Dengue fever) is a kind of acute biography caused by dengue fever virus (Dengue virus, DENV) Catch an illness, initially betide torrid areas.DENV is a kind of flavivirus (flavivirus) by mosquitoes spread, according to statistics, its Infection causes 5,000 ten thousand to 1 hundred million cases of dengue fever per annual meeting, and the whole world there are about 2,500,000,000 people can be by the prestige of this virus infection The side of body.There is the clinical manifestation that degree differs, the lighter in non-evident sympton, i.e. subclinical infection as infection DENV is latter, only some patientss It can behave as generating heat, vomit headache, arthralgia, courbature, fash and Neuroleptic Leukocytopenia etc., belong to self limiting mostly, because of DENV The characteristic symptoms such as ostalgia can be caused, be otherwise known as dengue fever (dengue fever, DF) dengue；Severe patient can trigger DF, Dengue hemorrhagic fever, dengue shock syndrome, organ failure, blood plasma ooze out even dead.After superinfection xenogenesis DENV, even if again Infecting the third, even the 4th kind of serotype DENV, the situation for having symptom Dengue disease be not common.However, to being at present Only, clinically also without effective medicine come the infection that prevents or treat dengue fever virus.In addition in order to prevent to go out in the last few years Existing bioterrorist can utilize this viral transmission disease, how to prevent and treat its infection and cause scientists again Concern.DENV has four kinds of virus types：DF-1, DF-2, DF-3 and DF-4, and they are likely to occur genetic mutation, and this gives The research and development of corresponding vaccine and medicine bring very big difficulty.It is public by August, 2016, only French Sai Nuofei Pasteurs Take charge of the DF vaccines Dengvaxia of (Sanofi Pasteur) research and development
(CYD-TDV) in the multinational approval listing successively such as Mexico, Philippine and Brazil.By the end of current, still without complete Face is applied to clinical anti-dengue virus medicine.In general antiviral drugs, such as lamifudin, Tamiflu, small radix bupleuri, Radix Isatidis are only Prevention can be played a part of and part is treated.And during for dengue fever virus vaccine research, most candidate's epidemic diseases Seedling fails to provide four kinds of serotype DENV balanced protective effect, causes part research only to proceed to I or II clinical trial phase Stage halts.Therefore, research and development anti-dengue virus medicine just becomes more urgent and important.
The content of the invention
For problems of the prior art, the invention provides a kind of imidazolone derivatives to prepare anti-dengue disease Application in the medicine of poison, the structural formula of the imidazolone derivatives are：
Wherein, R1Selected from amino, C1-3Alkyl amino, C1-3Acyl amino, hydroxyl, C1-3Alkoxy, hydrogen atom or oxygen are former Son；R2Selected from C1-3Alkyl, aromatic ring, aryl-heterocyclic or hydrogen atom；R3Selected from C1-3Alkyl, alkoxy or hydrogen atom；R4Selected from O- alkane Base first oxime, O- alkyl hydroxylamine, oxadiazole rings, trifluoromethyl substitution oxadiazole rings, C1-5Wan bases substitution oxadiazole rings, C1-5Alkane Imidazole ring, the C of base substitution1-5Alkyl-substituted triazole ring, C1-5Alkyl-substituted Thiadiazole, N- hydroxyformamides, N- alkane Epoxide formamide, hydrogen atom, cyano group or N- hydroxyl amidino groups；X is selected from carbon atom or nitrogen-atoms；And Y is selected from C1-4Alkyl, C5-6Ring Alkyl or C1-3Alkynyl.
In above-mentioned application, X is nitrogen-atoms, and the imidazolone derivatives are selected from the chemical combination with following structural formula Thing：
In above-mentioned application, the imidazolone derivatives are selected from the compound with following structural formula：
In above-mentioned application, the medicine of the anti-dengue virus includes：The imidazolone derivatives, the imidazolone spread out The pharmaceutically acceptable salt of biology, ester, hydrate or their one or more combination and auxiliary material.
In above-mentioned application, pharmaceutically acceptable salt is organic salt to the imidazolone derivatives.
In above-mentioned application, pharmaceutically acceptable salt is mesylate, formates, acetic acid to the imidazolone derivatives Salt, trifluoroacetate, maleate, tartrate, succinate, fumarate, citrate, benzene sulfonate, to methylbenzene One or more kinds of combinations in sulfonate, naphthalene sulfonate, lactate or benzoate.
In above-mentioned application, stating imidazolone derivatives, pharmaceutically acceptable salt is inorganic salts.
In above-mentioned application, pharmaceutically acceptable salt is hydrochloride, hydrobromate, sulfuric acid to the imidazolone derivatives One or more kinds of combinations in salt or phosphate.
In above-mentioned application, the formulation of the medicine of the anti-dengue virus is selected from tablet, capsule, pill, suppository, gas Mist agent, oral liquid, granule, powder, injection, syrup, vina, tincture, distillate medicinal water, film or combinations thereof.
In above-mentioned application, the administering mode of the medicine of the anti-dengue virus includes：Orally, inject, be implanted into, be outer With, spraying, suction or combinations thereof.
The invention provides a kind of imidazolone derivatives as dengue fever virus inhibitor and the analog derivative are medicinal Salt, such inhibitor have higher selective inhibitory on a cellular level, to dengue fever virus, and Dengue is treated preparing There is good prospect on fever virus sense medicine.
Brief description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, below will be to institute in embodiment The accompanying drawing needed to use is briefly described.
Fig. 1 shows the hydrogen nuclear magnetic spectrogram of compound 7；
Fig. 2 shows the 13C nuclear magnetic spectrograms of compound 7；
Fig. 3 shows the mass spectrogram of compound 7；
Fig. 4 shows the EC of compound 750Value；And
Fig. 5 shows the CC of compound 750Value.
Embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete Site preparation describes, it is clear that described embodiment is only part of the embodiment of the present invention, rather than whole embodiments.It is based on Embodiment in the present invention, the every other embodiment that those of ordinary skill in the art are obtained, belong to what the present invention protected Scope.
These are only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all the present invention spirit and Within principle, any modification, equivalent substitution and improvements made etc., it should be included in the scope of the protection.
The building-up process of selected chemicals 7 of the present invention is as specific embodiment, to the tool of imidazolone derivatives of the present invention Body synthetic route illustrates, but the selection of embodiment is not meant to any restrictions of the preparation method of the present invention.
The specific building-up process of compound 7 is as follows：
Its preparation method comprises the following steps：
(1) the 4mL chloro- 2- ethyl isocyanates of 1- and the bromo- 4- amino pyrroles of 2g 2- is added into the there-necked flask with condenser pipe Pyridine, the system stirring reaction 5h at 50 DEG C, TLC monitoring reaction terminate.Solvent is spin-dried for, obtains brown oil, silicagel column is pure Change to obtain 1- (2- bromopyridine -4- bases) -3- (2- chloroethyls) urea, i.e. intermediate A (light yellow solid, 1.6g, yield 50%).
(2) weigh 1g intermediate As be placed in 20mL drying DMF in, system cools down under ice bath, after under stirring 0.3g 60%NaH are added, stirring reaction 2h at room temperature after addition.After reaction is finished, a small amount of water quenching is added to go out reaction, will be molten Agent is spin-dried for, and adds a large amount of water stirrings, and system separates out solid, by solid collected by suction, washes filter cake.Filtration cakes torrefaction is product 1- (2- bromopyridine -4- bases) imidazoline -2- ketone, i.e. intermediate B (lightpink powder, 0.7g, yield 80%).
(3) 2g intermediate Bs and 2.69g NaN are weighed3It is added in 15mL DMSO, is then added under stirring 1.2mL acetic acid, and reaction solution is heated to 120 DEG C of stirring reaction 3h.After reaction terminates, reaction solution is cooled to room temperature, and incline Pour into mixture of ice and water, be stirred for 1h, there is solid precipitation, filter, filter cake water wash, collect filter cake and in infrared drying oven Middle drying, obtain 1- (2- nitrine pyridin-4-yl) imidazoline -2- ketone, i.e. intermediate C (brown solid, 1.45g, yield 86%).
(4) weigh 8.1g intermediates C to be placed in 100mL dry DMF, system cools down under ice bath, is added portionwise afterwards 3.6g60%NaH, after addition, system stirs 10min under ice bath, and 14.5g1, the bromo- 3- methylpentanes of 5- bis-, drop is added dropwise After adding, reaction 6h, TLC detection reaction is stirred at room temperature and finishes, reaction solution is poured into 1000g mixture of ice and water, and stir 1h is mixed, is filtered after 1h, filter cake is eluted with water and ethyl acetate successively, is collected solid and is dried in infrared drying oven, obtaining 1-, (2- is folded Nitrogen pyridin-4-yl) -3- (the bromo- 3- methylpentanes of 5-) imidazoline -2- ketone, i.e. intermediate D (brownish-yellow powder, 8g, yield 55%).
(5) weigh 8g intermediates D to be dissolved in 100mL ethanol, 17.3g SnCl are separately added under stirring2With 3.2mL hydrochloric acid, Reaction is heated to 70 DEG C of stirring reaction 6h, TLC detection reactions and finished, and is cooled to room temperature, rotation removes ethanol, adds 200ml water, is stirring PH=10 is adjusted with the 10% NaOH aqueous solution and continue to stir 30min, filtering, aqueous phase ethyl acetate (100mL* under state 3) extract, filter cake is beaten multiple, suction filtration with EA, until existing in filtrate without product, merges and collects ethyl acetate phase, with anhydrous sulphur Sour sodium is dried.Obtain 1- (PA -4- bases) -3- (the bromo- 3- methylpentanes of 5-) imidazoline -2- ketone, i.e. intermediate E (white Powder, 5.3g, yield 71.33%).
(6) 5.3g intermediate Es are weighed and 4.27g intermediate F and 10.73g Anhydrous potassium carbonates are added in 50mL acetonitriles, Heating reflux reaction 6h.TLC detection reactions are finished, and reaction solution is filtered while hot, and filter cake is eluted with DCM, is merged organic phase, is spin-dried for, Silica gel column separating purification, obtain 1- (PA -4- bases) -3- (5- (4- ((ethyoxyl imines) methyl) phenoxy group) -3- first Base amyl group)-imidazoline -2- ketone, i.e. compound 7 (white solid, 6.1g, yield 92.3%).
Compound 71H modal datas are as follows：
1H-NMR(400MHz,CDCl3):δ 8.06 (s, 1H), 7.98 (d, J=5.2Hz, 1H), 7.54 (d, J=8.2Hz, 2H), 6.99-6.85 (m, 3H), 6.78 (d, J=4.6Hz, 1H), 4.45 (s, 2H), 4.24 (q, J=6.8Hz, 2H), 4.07 (d, J=4.1Hz, 2H), 3.75 (t, J=7.4Hz, 2H), 3.57-3.46 (m, 2H), 3.45-3.29 (m, 2H), 1.97-1.77 (m, 2H), 1.71 (dd, J=12.8,6.3Hz, 2H), 1.48 (dd, J=13.1,5.9Hz, 1H), 1.36 (t, J=6.9Hz, 3H), 1.07 (d, J=6.2Hz, 3H).
The corresponding hydrogen nuclear magnetic spectrogram of compound 7 is referring to Fig. 1.
Compound 713C modal datas are as follows：
13C-NMR(101MHz,CDCl3)δ160.22,159.36,156.93,148.65,148.47,147.95, 128.39,124.98,114.61,102.79,94.74,69.54,65.89,41.77,41.54,41.34,35.92,34.16, 27.50,19.46,14.63。
The corresponding 13C nuclear magnetic spectrograms of compound 7 are referring to Fig. 2.
The mass spectrometric data of compound 7:For C23H31N5O3,[M+H]+426.24 theoretical value 426.40.
The corresponding mass spectrogram of compound 7 is referring to Fig. 3.
The anti-dengue virus activity and cytotoxicity detection process of pyridine imidazolone derivatives cellular level are as follows：
A) culture of BHK-21 cells
After being thawed in 37 DEG C of water-baths of the BHK-21 cells frozen in liquid nitrogen (being purchased from ATCC), it is added to and fills 12mL In the culture dish of culture medium, medium component is DMEM (Dulbecco's modified eagle medium)+10% tire ox Serum (Fetal Bovine Serum, FBS)+1% penicillin and streptomysin (Penicillin-Streptomycin, PS), 37 DEG C, 5%CO2Culture.
B) amplification of Dengue-GLuc viruses
When BHK-21 cell growths full scale is to 90%, viral (the Tsing-Hua University's Lou Zhiyong teacher's favours of Dengue-GLuc are added Give) 1mL, 37 DEG C, 5%CO2Culture.Lesion takes place in cell after 72h, and supernatant, 4000rpm are collected after the complete lesion of cell 10min is centrifuged, -80 DEG C are stored in after packing is dispensed.
C) virus titer determines
A549 cells (being purchased from ATCC) are according to 3 × 105Individual/ml is inoculated in 96 orifice plates, 37 DEG C, 5%CO2After cultivating 24h, The μ L of virus 100 of 10 times of dilutions are added in the hole cell of first row 3, add 20 times of virus diluted 100 μ L in the hole of secondary series 3, the 3rd The μ L of virus 100 of 40 times of dilutions are added in the hole of row 3, the μ L of virus 100 of 50 times of dilutions are added in the hole of the 4th row 3, are added after culture 48h Enter fluorogenic substrate and carry out data determination, virus titer of the GLuciferase readings between 10,000-20,000 is the most suitable.
D) culture of A549 cells
100 μ L A549 cells are pressed 3 × 105Individual/ml is inoculated in 96 orifice plates, to prevent side caused by culture medium evaporation Edge effect, 96 orifice plates make a circle outside adds 200 μ L phosphate buffers (Phosphate Buffered Saline, PBS), and 37 DEG C, 5%CO2Cultivate 24h.
E) preparation of compound
Compound is dissolved in 95% dimethyl sulfoxide (DMSO) (Dimethyl sulfoxide, DMSO), is configured to 10mM storages Liquid.Above-mentioned aminooimidazole assimilation compound is configured into 100 μM, 20 μM and 4 μM with culture medium DMEM+10%FBS+1%PS to carry out Preliminary screening, screening process are following f)：.
F) one piece of 96 orifice plate can detect 6 compounds, the culture medium in 100 μ L cells be siphoned away, the 2nd of 96 orifice plates the 100 μM of 50 μ L the first compound is added in the hole cell of row BCD rows 3, adds 20 μM of 50 μ L's in the 3rd 3 holes of row BCD rows Compound, the 4th arranges the compound that 4 μM of 50 μ L are added in 3 holes of BCD rows, and 100 μM of 50 μ L are added in the 5th 3 holes of row BCD rows Second of compound, be added to 3 holes of the 9th row of 96 orifice plates by that analogy, the rows 9 of EFG 3 row add another 3 kinds of compounds, the 11 holes of row 6 are set to virus control and cell controls.
G) inhibitor first mixes 2h with cell, then with culture medium by 20 times of Dengue-GLuc viral dilutions, then per hole 50 μ L viruses are added, cumulative volume is changed into 100 μ L, and therefore, the concentration of inhibitor is changed into the 1/2 of compound concentration, 37 DEG C, 5%CO2Training Support 48h.
H) after cell culture 48h, cell conditioned medium is siphoned away, with PBS cell twice, adds the μ of 1X cell pyrolysis liquids 20 L, room temperature are placed 15min and slowly rocked, until cell cracks completely, cell lysate moved in white ELISA Plate, then Add 100 μ L renilla luciferase substrates, the reading numerical values in micropore board detector, numerical value be shown renilla luciferase with Chemical light caused by chemical reaction occurs for substrate, and the inhibition that numerical value is smaller to represent inhibitor is better.
I) inhibitor for being chosen at inhibiting rate more than 50% under the conditions of 10 μM carries out definite EC50Measure.Its method is as follows：
1) 100 μ L A549 cells are pressed 3 × 105Individual/ml is inoculated in 96 orifice plates, and periphery is closed with 200 μ L PBS, is prevented Only edge effect, 37 DEG C, 5%CO224h is cultivated in incubator.
2) 2 times of gradient dilutions of micromolecular compound 10mM liquid storages culture medium in filtering out are into 200 μM -0.78 μM 9 Individual concentration.
3) after the cell conditioned medium in 96 orifice plates is siphoned away, add the 50 above-mentioned concentration of μ L inhibitor, while set virus and Cell controls.
4) after adding inhibitor 2h, by 10 times of Dengue-GLuc viral dilutions, 50 μ L viruses are added into 96 orifice plates with the volley of rifle fire In, 37 DEG C, 5%CO248h is cultivated in incubator.
5) cell conditioned medium is siphoned away, with PBS, cell, the μ L of addition 1X cell pyrolysis liquids 20, room temperature place 15min twice And slowly rock, until cell cracks completely, cell lysate is moved in white ELISA Plate, it is glimmering then to add 100 μ L sea pansies Light element zymolyte, the reading numerical values in micropore board detector, and mapped with GraphPad Prism.
J) aminooimidazole ketone Compound Cytotoxicity (CC50) measure:
1) 100 μ lL A549 cells press 3 × 105Individual/ml is inoculated in 96 orifice plates, 37 DEG C, 5%CO2Cultivate 24h.
2) aminooimidazole assimilation compound is diluted to 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μ with culture medium M, 3.125 μM, 1.56 μM and 0.78 μM 9 concentration.
3) cell conditioned medium in 96 orifice plates is siphoned away, the inhibitor of the 100 above-mentioned concentration of μ L is added per hole, each concentration repeats 3 Hole, the 10th concentration are cell controls.
4) after inhibitor effect 24h, the cytotoxicity of inhibitor is detected with mtt assay, 15 μ L MTT are added per hole and are lived Cell dyeing.
5) supernatant is sucked after 4h, and read after adding the 150 fully dissolving crystallized things of μ L DMSO under ELIASA 490nM Fluorescent value.
Table 1
Compound number EC50(μM) CC50(μM)
7 4.251 29.01
9 8.215 >50
11 6.534 >50
12 1.861 >50
13 2.217 >50
18 4.71 >50
21 3.964 >50
The inhibitory activity data of part preferred compound are shown in upper table 1.And show respectively in figures 4 and 5 The EC of compound of having anticipated out 750Value and CC50Value.It is can be seen that from above-mentioned experimental result by inhibitor activity preliminary screening The pyridine imidazolone derivatives and its pharmaceutical salts gone out carry out the inhibitory activity and cytotoxicity test of cellular level, find to stepping on Leather fever virus has selective inhibitory, its medium effective concentration EC50Respectively less than 10 μM, there is stronger anti-dengue virus Act on and cytotoxicity is relatively low, the CC of majority of compounds50Value is all higher than 50 μM.Therefore the pyridine miaow being related in patent of the present invention Trazodone derivative and its pharmaceutical salts have certain druggability, can effectively suppress the activity of dengue fever virus, are stepped on preparing treatment There is good prospect on leather fever virus sense medicine.

Claims (10)

  1. A kind of 1. application of imidazolone derivatives in the medicine of anti-dengue virus is prepared, it is characterised in that the imidazolone The structural formula of derivative is：
    Wherein, R1Selected from amino, C1-3Alkyl amino, C1-3Acyl amino, hydroxyl, C1-3Alkoxy, hydrogen atom or oxygen atom；
    R2Selected from C1-3Alkyl, aromatic ring, aryl-heterocyclic or hydrogen atom；
    R3Selected from C1-3Alkyl, alkoxy or hydrogen atom；
    R4Selected from O- alkyl first oxime, O- alkyl hydroxylamine, oxadiazole rings, trifluoromethyl substitution oxadiazole rings, C1-5It is alkyl-substituted Oxadiazole rings, C1-5Alkyl-substituted imidazole ring, C1-5Alkyl-substituted triazole ring, C1-5Alkyl-substituted Thiadiazole, N- hydroxyls Base formamide, N- alkoxies formamide, hydrogen atom, cyano group or N- hydroxyl amidino groups；
    X is selected from carbon atom or nitrogen-atoms；And
    Y is selected from C1-4Alkyl, C5-6Cycloalkyl or C1-3Alkynyl.
  2. 2. application according to claim 1, it is characterised in that X is nitrogen-atoms, and the imidazolone derivatives are selected from tool There is the compound of following structural formula：
  3. 3. application according to claim 2, it is characterised in that the imidazolone derivatives are selected from following structural formula Compound：
  4. 4. application according to claim 1, it is characterised in that the medicine of the anti-dengue virus includes：The imidazoles Pharmaceutically acceptable salt, ester, hydrate or their the one or more combinations of ketone derivatives, the imidazolone derivatives And auxiliary material.
  5. 5. application according to claim 4, it is characterised in that pharmaceutically acceptable salt is the imidazolone derivatives Organic salt.
  6. 6. application according to claim 5, it is characterised in that pharmaceutically acceptable salt is the imidazolone derivatives Mesylate, formates, acetate, trifluoroacetate, maleate, tartrate, succinate, fumarate, citric acid One or more kinds of combinations in salt, benzene sulfonate, toluenesulfonate, naphthalene sulfonate, lactate or benzoate.
  7. 7. application according to claim 4, it is characterised in that pharmaceutically acceptable salt is the imidazolone derivatives Inorganic salts.
  8. 8. application according to claim 7, it is characterised in that pharmaceutically acceptable salt is the imidazolone derivatives One or more kinds of combinations in hydrochloride, hydrobromate, sulfate or phosphate.
  9. 9. according to the application any one of claim 1-8, it is characterised in that the agent of the medicine of the anti-dengue virus Type is selected from tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup, wine Agent, tincture, distillate medicinal water, film or combinations thereof.
  10. 10. according to the application any one of claim 1-8, it is characterised in that the medicine of the anti-dengue virus Administering mode includes：Orally, injection, implantation, external application, spraying, suction or combinations thereof.
CN201710828099.8A 2017-09-14 2017-09-14 A kind of application of imidazolone derivatives in the medicine of anti-dengue virus is prepared Pending CN107805246A (en)

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Cited By (1)

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CN109303779A (en) * 2018-04-11 2019-02-05 天津国际生物医药联合研究院 Aminopyridine imidazolone derivative application in preparation of anti-tumor drugs

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