CN1590378A - Quinoxaline derivative and its preparation method and use - Google Patents
Quinoxaline derivative and its preparation method and use Download PDFInfo
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- CN1590378A CN1590378A CNA031506623A CN03150662A CN1590378A CN 1590378 A CN1590378 A CN 1590378A CN A031506623 A CNA031506623 A CN A031506623A CN 03150662 A CN03150662 A CN 03150662A CN 1590378 A CN1590378 A CN 1590378A
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Abstract
A series of quinoxaline derivatives with high immunosuppression activity can be used for organ transplantation and preventing and treating immunopathy, such as nephrotic syndrome, aplastic anemia, rheumatoid arthritis, AIDS, diabetes, SARS, etc. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to the synthetic and purposes of organic compound, more specifically refer to a class quinoxaline derivatives, preparation method and be used for immunosuppressor and antiviral treatment, particularly the treatment in treatment severe acute respiratory syndrome (SARS).
Background technology
Because the improvement of surgery operating technology and the raising of treatment level, the organ transplantation success ratio greatly increases.China's organ transplantation work has leapt to the first place, Asia, and the key of organ transplantation success is the control to immune rejection.Since ciclosporin was applied to clinical immunologic rejection, most of immune rejection can be controlled effectively, and made organ transplantation postoperative survival rate obtain significant raising.Clinical immunosuppressive drug commonly used has S-Neoral, adrenocortical hormones, alkylating agent and antimetabolite etc.
The immunosuppressive drug of clinical application at present has extensive use: can be used for the parenchymatous organ and transplants, and prevention kidney, liver, the heart, cardiopulmonary associating, homoioplastic rejections such as lung or pancreas, other immunosuppressor patient's graft-rejection was accepted in treatment in the past; Bone marrow transplantation, the different primitive marrow of kidney, lung, liver and acute leukemia is transplanted; Can be used for autoimmune disorder, as nephrotic syndrome, aplastic anemia, systemic lupus erythematosus.Also can be used for anti-inflammatory such as psoriatic, rheumatoid arthritis, endogenous uveitis.Can be used for the disease that parasite, schistosomicide and malaria cause; Also can be used for treatment or prevention AIDS, diabetes, multiple sclerosis; Also can be used for tumor treatment and prevention; Also can be used for treating xerophthalmia.
Though the immunosuppressive drug purposes of clinical application at present is extensive, it all has various deficiencies.Mostly show tangible renal toxicity.Have also have all if any headache, weak, apocleisis, meropresthesia, tremble, side reactions such as hypertension, hypercholesterolemia, hyperglycemia, gastrointestinal discomfort, amenorrhoea, fash, hair hyperplasia and gum hypertrophy.And the best ciclosporin of clinical effectiveness costs an arm and a leg, and general patient can't bear.Therefore neotype immunosuppressant has great demand.Various novel immunosuppressor constantly are found.As having reported that in patent US 4540693 compound that contains quinoxaline ring has certain immunosuppressive action.
Though the research of antibacterials has had very big progress, because the interactional complicacy of virus host, so most of antiviral are lower to human body toxigenicity or antiviral effect when the performance therapeutic action.The Symmetrel compound relevant with some has been used for the treatment of influenza, but their activity also only limits to resisiting influenza virus A.Interferon, rabbit has the RNA virus resisting activity, but the duplicating of ucleosides interfere RNA virus, but they are all invalid to severe acute respiratory syndrome virus.Have the report immunosuppressor to can be used for improving the symptom that some virus causes in addition, but it is applied to the virus disease treatment seldom.
Discover that a series of quinoxaline derivatives have the effect of anti-sars type pneumonitis virus (sars coronavirus).
Summary of the invention
The purpose of this invention is to provide quinoxaline derivative and give birth to acceptable salt;
Another object of the present invention is the preparation method who discloses this compounds;
A further object of the present invention is the medical usage that discloses this compounds.
The present invention designed and synthesized quinoxaline derivatives that following general formula is arranged with and physiologically acceptable salt:
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen etc.;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl etc. as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl etc. as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.; Or a plurality of methylene radical form contain or do not contain just like heteroatomic 3～7 Yuans rings such as oxygen, nitrogen, sulphur;
R5 is the substituting group on the heterocycle, is H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, amino, hydroxyl etc.;
X is
n＝0～8
Y is O, S.
Z is C
1-C
4Alkyl, C3～C6 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl etc. as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.
Quinoxaline derivatives of the present invention can prepare by the following method:
Reaction formula 1
Reaction formula 1 has provided among the quinoxaline derivatives Q as X
And the general synthetic method during Y=O.Wherein compound 5 can be buied or be reoxidized by benzoic condensation by aromatic aldehyde and obtain by commodity.As shown in the figure: the amino acid/11 of Boc protection and amine 2 are in inert solvent, and condensation obtains acid amides 3 in the presence of condensing agent and alkali, and the deprotection base obtains amino amides 4 under the acid effect then.In this reaction, used solvent is generally tetrahydrofuran (THF) (THF), ether (Et
2O), methylene dichloride (CH
2Cl
2), chloroform (CHCl
3), benzene, toluene, N, N-diformamide inert solvents such as (DMF); Used condensing agent has dicyclohexyl carbon imide (DCC), di-isopropyl carbon imide carbon imide class condensing agents such as (DIC), phosphorus oxychloride (POCl
3), thionyl chloride (SOCl
2), organic-inorganic acyl chlorides such as p-methyl benzene sulfonic chloride (TsCl), oxalyl chloride and isobutyl chlorocarbonate; Used alkali is generally Trimethylamine 99 (Me
3N), triethylamine (Et
3N), diisopropylethylamine organic tertiary amines such as (DIPEA).Temperature of reaction is between-78 ℃～50 ℃.Used acid has hydrochloric acid, sulfuric acid, trifluoroacetic acid (TFA) etc.Resulting compound 4 does not generally need purifying directly to can be used for next step reaction.
Compound 5 reacts in polar solvent with compound 6 and obtains compound 9 in addition.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF), N, N-diformamide etc., and protic solvent such as ethanol (EtOH), methyl alcohol (MeOH), n-propyl alcohol (n-PrOH), propyl carbinol (n-BuOH), Virahol (i-PrOH) etc., be generally methyl alcohol and ethanol.Reaction conditions is generally at the reflux temperature of solvent.Compound 9 can also react polar solvent from compound 5 and compound 7 and obtain nitro-compound 8, and reduction obtains then.Reduce general method and catalysis process here, used reductive agent has iron powder (Fe), zinc powder (Zn), tin (Sn), tin protochloride (SnCl in the general method
2) and the reductive agent of sulfur-bearing etc.Catalyzer in the catalysis process has palladium (Pd), platinum (Pt) and Ranny nickel (Ranny Ni) etc.Resulting compound 9 obtains isocyanic ester 10 with phosgene or the processing of three surpalites in inert solvents such as methylene dichloride, chloroform, benzene, toluene.Compound 10 obtains urea I～II with compound 4 condensation in polar solvent then.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF), N, and N-diformamide etc., and protic solvent such as ethanol, methyl alcohol, n-propyl alcohol, propyl carbinol, Virahol etc. are generally methyl alcohol and ethanol.Reaction conditions generally carries out between 0～100 ℃, carries out at ambient temperature usually.The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.
Reaction formula 2
This reaction formula 2 has provided above-mentioned another method of quinoxaline carbamide derivative synthetic.As shown in the figure: compound 4 in inert solvents such as methylene dichloride, chloroform, benzene, toluene and organic tertiary amines such as Trimethylamine 99, triethylamine, diisopropylethylamine in the presence of handle with phosgene or three surpalites and to obtain chloroformyl amine compound 11, this compound and compound 9 be at tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene, toluene, N, in the inert solvents such as N-diformamide and carry out condensation reaction under the existence of organic tertiary amine such as Trimethylamine 99, triethylamine, diisopropylethylamine and obtain urea I～II.Reaction conditions generally carries out between-78～100 ℃, carries out under 0 ℃ of condition usually.The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.
Reaction formula 3
Reaction formula 3 has provided among the quinoxaline derivatives Q as X
And the general synthetic method during Y=S.Shown in reaction formula: compound 9 is converted into lsothiocyanates 12 earlier, this can obtain by several different methods, such as compound 9 in inert solvents such as tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene, toluene and organic basess such as Trimethylamine 99, triethylamine, diisopropylethylamine in the presence of, earlier with dithiocarbonic anhydride (CS
2) handle and then obtain compound 12 with the processing of acyl chlorides such as phosphorus oxychloride, thionyl chloride and Vinyl chloroformate; Perhaps thiocyanate-and Benzoyl chloride form intermediate earlier and are obtaining lsothiocyanates 12 with compound 9 reactions.This lsothiocyanates 12 obtains thiocarbamide III～IV with amine 4 condensation in polar solvent.Here used polar solvent has non-protonic solvent such as tetrahydrofuran (THF), N, and N-diformamide etc., and protic solvent such as ethanol, methyl alcohol, n-propyl alcohol, propyl carbinol, Virahol etc. are generally methyl alcohol and ethanol.Reaction conditions generally carries out between 0～100 ℃, carries out at ambient temperature usually.The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.
Can synthesize by same or similar method and to obtain quinoxaline urea or quinoxaline thiourea derivative V～XVI
Reaction formula 4
This reaction formula 4 has provided in the quinoxaline derivatives as X
And the general synthetic method during Y=O.Wherein compound 13 can be buied or obtained by monoamideization or obtained by 4 reactions of dicarboxylic anhydride and amine by diacid by commodity.As shown in the figure: compound 9 and compound 13 are in inert solvent, and condensation can obtain acid amides XVII～XVIII in the presence of condensing agent and alkali.In this reaction, used solvent is generally tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene, toluene, N, inert solvents such as N-diformamide; Used condensing agent has carbon imide class condensing agents such as dicyclohexyl carbon imide, di-isopropyl carbon imide, organic-inorganic acyl chlorides such as phosphorus oxychloride, thionyl chloride, p-methyl benzene sulfonic chloride, oxalyl chloride and isobutyl chlorocarbonate; Used alkali is generally organic tertiary amines such as Trimethylamine 99, triethylamine, diisopropylethylamine.Temperature of reaction is between-78 ℃～50 ℃.Perhaps compound 9 forms compound 15 with acid anhydrides 14 reactions, and this compound 15 obtains acid amides XVII～XVIII with the amine condensation.The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.
Biological activity determination
By certain biophysics technology (as, surface plasma resonance biological sensing technology Biacore 3000, methods such as fluorescent quenching) it is significantly active with combining of people's cyclophilin A to find that this compounds shows, immunosuppressive activity with possibility, with the purposes that is applicable to that other immunosuppressive drug has: transplant as the essence sexual organ, autoimmune disorder such as nephrotic syndrome, aplastic anemia, systemic lupus erythematosus, inflammation such as psoriatic, rheumatoid arthritis, the endogenous uveitis, parasite, the disease that schistosomicide and malaria cause, AIDS, diabetes, multiple sclerosis and tumor treatment and prevention etc.
In addition, this compounds shows stronger antiviral activity, and it can suppress some common diseases such as influenza, parotitis, viral hepatitis, poliomyelitis, epidemic hemorrhagic fever and simplexvirus etc.Especially can obviously suppress particularly severe acute respiratory syndrome virus of coronavirus.Therefore this compounds can be used for antiviral, is widely used in the disease that various viruses cause, and is particularly useful for the treatment of severe acute respiratory syndrome.
1, (Cyclophilin A, balance CypA) is understood constant K for fluorescent quenching method research DDC838 and recombinant human cyclophilin A
d
Experimental technique
Adopt literature method (Li Fangqiu etc., microorganism journal, 1998,38,193) expression, purification of recombinant human CypA, use instrument and material: (1) spectrophotofluorometer HITACHI (F-2500); (2) CypA, 200 μ M; (3) use damping fluid (Buffer): 20mM Tris-HCl, pH=7.8,1mM EDTA; 4) DDC838 is dissolved in DMSO, makes 10mM.
Operation steps
In the total system 3000 μ L that contain 4 μ M CypA, measure adding 0,0.3,0.6 respectively, 1.2,2.4,4.8,9.6,19.2 behind the DDC838 of μ L, CypA is subjected to the emissioning light spectrum that 280nm excites, and (sweep limit: 300nm-380nm), the DMSO that adds equal volume respectively in contrast.
Experimental result
1) fluorescent quenching experiment
The results are shown in accompanying drawing one.
2) with 340nm as eigenwert, deduction DMSO influences data (Compound D DDC838 does not produce fluorescence at the 340nm place) and with data preparation in Table 1, with Δ Fc/C as X-coordinate, Δ Fc is as ordinate zou, curve plotting, the match linear equation is seen (accompanying drawing two).The slope of calculated curve obtains K
dBe 5.79 μ M.
Table 1: cancellation experimental result (λ
Ex=280nm, λ
Em=340nm)
| Compound concentration C (μ M) | Cancellation fluorescent value F | ?ΔF | Contrast fluorescent value F ' | ΔF’ | Fc (F+ΔF’) | ΔFc | ?ΔFc/C |
| ?0 ?1 ?2 ?4 ?8 ?16 ?32 ?64 | ?116.6 ?98.94 ?81.63 ?63.23 ?41.22 ?20.33 ?6.297 ?1.142 | ?0 ?17.66 ?34.97 ?53.37 ?75.38 ?96.27 ?110.303 ?115.458 | ?115.2 ?110.5 ?107.6 ?107.3 ?107 ?106.3 ?105.7 ?105.6 | ?0 ?4.7 ?7.6 ?7.9 ?8.2 ?8.9 ?9.5 ?9.6 | ?116.6 ?103.64 ?89.23 ?71.13 ?49.42 ?29.23 ?15.797 ?10.742 | ?0 ?12.96 ?27.37 ?45.47 ?67.18 ?87.37 ?100.803 ?105.858 | ?-- ?12.96 ?13.685 ?11.3675 ?8.3975 ?5.46062 ?3.15009 ?1.65403 |
Linear?fit：
K
d＝5.79μM
2, utilize surface plasma resonance (Surface Plasmon Resonance, SPR) interaction of biosensor technique Biacore 3000 research Compound D DDC838 and CypA.
Experimental technique
(BIACORE AB, Uppsala, Sweden) (Amersham), compound combine experiment and at room temperature finish BIACORE3000 with people's cyclophilin A (CypA).Chip and buffering solution is as, CM5 chip, EDC, NHS, Ethanolamine, HBS-EP available from BIACORE AB company (Uppsala, Sweden).CypA presses literature method (Li Fangqiu etc., microorganism journal, 1998,38,193) and expresses and purifying.
Operation steps
Compound D DDC838 dissolves with DMSO, is diluted to respective concentration with HBS-EP, and the content of DMSO is 0.4%.The albumen of purifying is connected on the chip by the amino coupled method, and compound dissolves with DMSO, is diluted to required concentration successively with HBS-EP, carries out dynamic experiment with the dynamic analysis Wizard of BIACORE 3000, carries out the Collection and analysis of data.
Experimental result
See accompanying drawing three;
Accompanying drawing threeBe Compound D DDC-838 and CypA bonded kinetic curve, according to 1: 1Langmuir bindingmodel analytical data, the series of results that obtains as shown in Table 2.
Table 2, DDDC-838 and CypA bonded kinetic constant are analyzed
| k on(M -1s -1) | k off(s -1) | KD(μM) a | Chi2 |
| 746±12.4 | 3.25± 0.03×10 -3 | 4.36 | 0.386 |
aKD＝k
off/k
on
3. utilize surface plasma resonance (Surface Plasmon Resonance, SPR) experiment that combines of biosensor technique Biacore 3000 research Compound D DDC838 blocking-up sars coronavirus nucleocapsid proteins (SARS_CoV-NP) and people CypA.
Operation steps
Utilize surface plasma resonance biological sensing technology BIACORE3000 research Compound D DDC838 to stop SARS-CoV-NP albumen to combine, relevant the same relative section of experimental implementation with human body CyPA.
Experimental result
The result is shown in accompanying drawing four, and along with the increase of the concentration of Compound D DDC838, SARS-CoV-NP albumen combines reduction with human body CypA, shows that DDDC838 can suppress SARS-CoV-NP albumen and combine with human body CypA.
4, the anti-SARS-CoV virus activity test of DDDC838
Test philosophy: as virus host cell (permissive cell), specimen is to the provide protection of virus infected cell with the Vero-E6 cell, and detecting index is cytopathy reaction (CPE) and observation cells infected protection ratio.
Testing method:
The Vero-E6 cell inoculation in 96 well culture plates, is put 37 ℃, and the 5%CO2 incubator is cultivated, add the SARS virus of different weaker concns and the Compound D DDC838 of different concns, observe CPE, and measure OD value, calculation sample anti-SARS virus active function with toluylene red dyeing.
Test result:
In the anti-SARS virus activity experiment of virus-cell levels model, SARS virus with different effective concentration infects the Vero-E6 cell, and the result shows that Compound D DC838 has than obvious suppression SARS virus infection Vero-E6 cell activity (the results are shown in accompanying drawing five).
Description of drawings
Fig. 1 is the fluorescent quenching figure of Compound D DDC838 to CypA.(along with DDDC838 concentration increases, the CypA fluorescent value descends, and in the experiment, CypA concentration remains 4 μ M, Compound D DC838 concentration: a wherein, 0 μ M; B, 1 μ M; C, 2 μ M; D, 4 μ M; E, 8 μ M; F, 16 μ M; G, 32 μ M.)
Fig. 2 is cancellation experimental result coordinate figure.
Fig. 3 is DDDC-838 and CypA bonded kinetic curve, and compound concentrations is followed successively by 3.45,4.92,7.03,10.0,14.35 from the bottom to top, and 20.50 μ M
Fig. 4 Compound D DDC838 suppresses SARS-CoV-NP albumen and human body CypA binding kinetics test result.CypA is fixed on the CM5 chip, and the proteic concentration of N is 0.5 μ M, and the concentration of Compound D DDC838 is followed successively by 0,0.5,1.0,2.0,4.0,8.0,16.0,32.0,64.0 and 128.0,256.0 μ M.
Fig. 5 Compound D DDC838 protection Vero-E6 cell is avoided SARS-CoV and is infected (shown in the solid line) and cytotoxicity (shown in the dotted line) thereof. (EC50=1.9 μ M, CC50=13.2 μ M.
Embodiment
Embodiment 1 N-{6-[2,3-(2-difuryl)-quinoxaline] base }-preparation of 3-dimethylamine acylpiperidine-1-methane amide:
1-a:1-tertiary butyloxycarbonyl phenylpiperidines-3-formic acid 20.0 gram nipecotic acid are dissolved in the 155ml water, add 6.2 gram sodium hydroxide and 24.8 gram yellow soda ash, and the dissolving back adds 100 milliliters of dioxane.This mixture cools off in frozen water, slowly drips the solution of 41.0 gram Boc acid anhydrides in 60 milliliters of dioxane.Adding the back stirring spends the night.Add water and make reactants dissolved, with 100 milliliters of petroleum ether 3 times, the cooling of water layer frozen water, slowly with the dilute hydrochloric acid pH=2.0 that neutralizes, with ethyl acetate extraction (250 milliliters of X3), organic layer anhydrous sodium sulfate drying, evaporate to dryness obtain white solid 34.2 and restrain.Productive rate 96.5%.
1-b:N, N-dimethyl-piperidines-above-mentioned product of 3-carboxamide hydrochloride 1.0 grams is dissolved in 15 milliliters of methylene dichloride, adds 1.1 gram exsiccant dimethylamine hydrochloride and 3.0 milliliters of diisopropylethylamine.The frozen water cooling adds 1.2 gram dicyclohexyl carbon imide.Stir then and spend the night.Drip 0.1 milliliter of acetate, stir half an hour, filter.Filtrate successively with 5% citric acid washing 2 times, water washing once, saturated sodium bicarbonate washing 3 times, saturated common salt water washing once, the organic layer anhydrous sodium sulfate drying.Boil off most of solvent up to about 5 milliliters of liquid, add the saturated ethyl acetate solution of 8 milliliters of hydrogenchloride in this liquid, stirring spends the night separates out solid, and filtering also, the vacuum-drying solid obtains white product 0.9 gram.
1-c:2,3-difuryl-6-aminoquinoxaline
One: 3.2 gram of method joins furan acyl and 5 grams 1,2, and 4-benzene triamine is dissolved in 70 milliliters of hot ethanols and refluxed 32 hours.Cold filtration obtains red solid.With ethyl alcohol recrystallization 2 times, obtain yellow solid 2.1 grams.HPLC：99％；EMS：278(100，M+1)
Method two: 20.0 gram connection furan acyls and 16.1 gram 4-nitro O-Phenylene Diamines are suspended in 420 milliliters of ethanol reflux 24 hours.Cold filtration, the solid ethyl alcohol recrystallization obtains yellow solid 31.1 grams.This solid suspension adds palladium-carbon (Pd-C) catalyzer of 5.4 grams 10% in 390 milliliters of ethanol, reduction is 36 hours under 1atm hydrogen and under 60 ℃.Filter, solid is extremely almost colourless with the hot ethanol washing.Filtrate concentrates evaporate to dryness, and uses ethyl alcohol recrystallization, obtains yellow solid product 25.2 grams.HPLC：99.5％；EMS：278(100，M+1)。
1-d:N-{6-[2,3-(2-difuryl)-quinoxaline] base }-3-dimethylamine acylpiperidine-1-methane amide
One: 0.17 gram of method, three surpalites are dissolved in 15 milliliters of methylene dichloride, 0.3 gram 2, and 3-difuryl-6-aminoquinoxaline and 0.19 milliliter of diisopropylethylamine are dissolved in 80 milliliters of methylene dichloride and slowly are added drop-wise in the above-mentioned solution.Add back restir half an hour, 0.4 gram N, N-dimethyl-piperidines-3-carboxamide hydrochloride and 0.55 milliliter of diisopropylethylamine are dissolved in 10 milliliters of methylene dichloride, and this solution is added in the above-mentioned reaction solution apace.Stir half an hour, reaction solution washes with water 3 times, anhydrous sodium sulfate drying, evaporate to dryness solution.Residuum is crossed post with 25 gram silica gel (200～300 order), uses ethyl acetate: sherwood oil (1: 1 to 2: 1) drip washing.Obtain yellow solid 0.38 gram.HPLC：98.1％；EMS：460(100，M+1)。
Method two: 0.18 gram three surpalites and 0.3 gram N, N-dimethyl-piperidines-3-carboxamide hydrochloride is blended in 5 milliliters of methylene dichloride, and 0.24 milliliter of pyridine is dissolved in 4 milliliters of methylene dichloride and slowly is added drop-wise to said mixture.Add the back and stirred 48 hours, obtain colourless solution.This solution slowly is added drop-wise to and contains 0.5 gram 2, and 3-difuryl-6-aminoquinoxaline and 0.4 milliliter of diisopropylethylamine are dissolved in the solution of 50 milliliters of tetrahydrofuran (THF)s, adds the back and stirs half an hour.Boil off solvent, residuum pours in 50 ml waters, with using ethyl acetate extraction (60 milliliters of X3).The organic layer anhydrous sodium sulfate drying boils off solvent, and (silica gel dress post is used ethyl acetate: sherwood oil (1: 1 to 2: 1) drip washing), obtain yellow solid 0.32 gram to the residuum column chromatography purification.HPLC：98.5％；EMS：460(100，M+1)。
Similar aforesaid method is synthetic to obtain following compound:
Table 3: quinoxaline carbamide compounds I and II
| NO. | ?R????R1 | R2 | R3 | R4 | n | ?P * |
| I-1 | ?H????H | H | Methyl | Methyl | 0 | ?2- |
| I-2 | The H furyl | Furyl | Methyl | Methyl | 0 | ?2- |
| I-3 | The H furyl | Furyl | Methyl | Methyl | 1 | ?3- |
| I-4 | The H furyl | Furyl | Methyl | Methyl | 2 | ?3- |
| I-5 | ?H | Furyl | Furyl | Ethyl | Ethyl | 2 | ?3- |
| I-6 | ?H | H | H | H | H | 3 | ?3- |
| I-7 | ?H | H | H | Methyl | Methyl | 3 | ?3- |
| I-8 | ?H | Furyl | Furyl | Methyl | Methyl | 3 | ?3- |
| I-9 | ?H | Furyl | Furyl | Ethyl | Ethyl | 3 | ?3- |
| I-10 | ?H | Furyl | Furyl | H | Methyl | 3 | ?3- |
| I-11 | ?H | Furyl | Furyl | H | Ethyl | 3 | ?3- |
| I-12 | ?H | Furyl | Furyl | H | Propyl group | 3 | ?3- |
| I-13 | ?H | Furyl | Furyl | H | Butyl | 3 | ?3- |
| I-14 | ?H | Furyl | Furyl | H | Sec.-propyl | 3 | ?3- |
| I-15 | ?H | Furyl | Furyl | H | Isobutyl- | 3 | ?3 |
| I-16 | ?H | Furyl | Furyl | H | The tertiary butyl | 3 | ?- |
| I-17 | ?H | Furyl | Furyl | H | Cyclopropyl | 3 | ?3- |
| I-18 | ?H | Furyl | Furyl | H | Cyclopentyl | 3 | ?3- |
| I-19 | ?H | Furyl | Furyl | H | Cyclohexyl | 3 | ?3- |
| I-20 | ?H | Furyl | Furyl | H | Benzyl | 3 | ?3- |
| I-21 | ?H | Furyl | Furyl | H | The 2-furyl | 3 | ?3- |
| I-22 | ?H | Furyl | Furyl | H | Phenyl | 3 | ?3- |
| I-23 | ?H | Thienyl | Thienyl | Ethyl | Ethyl | 3 | ?3- |
| I-24 | ?H | Pyrryl | Pyrryl | Ethyl | Ethyl | 3 | ?3- |
| I-25 | ?H | Furyl | Furyl | Propyl group | Propyl group | 3 | ?3- |
| I-26 | ?H | Furyl | Furyl | Methyl | Methyl | 3 | ?2- |
| I-27 | ?H | Furyl | Furyl | Ethyl | Ethyl | 3 | ?2- |
| I-28 | ?H | Furyl | Furyl | Propyl group | Propyl group | 3 | ?2- |
| I-29 | ?H | Furyl | Furyl | Methyl | Methyl | 3 | ?4- |
| I-30 | ?H | Furyl | Furyl | Ethyl | Ethyl | 3 | ?4- |
| I-31 | ?H | Furyl | Furyl | Propyl group | Propyl group | 3 | ?4- |
| II-1 | ?H | Furyl | Furyl | Methyl | Methyl | 3 | ?3- |
| II-2 | ?H | Furyl | Furyl | Ethyl | Ethyl | 3 | ?3- |
| II-3 | ?H | Furyl | Furyl | Propyl group | Propyl group | 3 | ?3- |
Annotate: 1, *---this column of figure is represented the position of methane amide on this cycloaliphatic ring.
2, I represents the 6-position of urea groups at quinoxaline ring; II represents the 5-position of urea groups at quinoxaline ring
Example 2:N-{6-[2,3-(2-difuryl)-quinoxaline] base }-preparation of 3-dimethylamine acylpiperidine-1-thioformamide:
0.5 restrain 2,3-difuryl-6-aminoquinoxaline is dissolved in 25 milliliters of tetrahydrofuran (THF)s, add 0.56 milliliter of triethylamine, the ice-water bath cooling, slowly drip the solution of 0.12 milliliter of dithiocarbonic anhydride in 5 milliliters of tetrahydrofuran (THF)s, be warmed up to room temperature after adding, stirred 5 hours, reaction solution frozen water cooling again, 0.19 milliliter of Vinyl chloroformate is dissolved in 5 milliliters of tetrahydrofuran (THF)s and slowly is added drop-wise to above-mentioned reaction solution.Adding the back stirring spends the night.0.5 gram N, N-dimethyl-piperidines-3-carboxamide hydrochloride and 0.65 milliliter of diisopropylethylamine are dissolved in 5 milliliters of N, and in the N-diformamide, this solution is added in the above-mentioned reaction solution apace.Stirring at room 1 hour, refluxed 2 hours then.Pressure reducing and steaming solvent, residuum are poured in the water, with ethyl acetate extraction (60 milliliters of X3).The organic layer anhydrous sodium sulfate drying boils off solvent, and (silica gel dress post is used ethyl acetate: sherwood oil (1: 1 to 2: 1) drip washing), obtain yellow solid 0.24 gram to the residuum column chromatography purification.HPLC：98.3％；EMS：476(100，M+1)。
Similar aforesaid method is synthetic to obtain following compound:
Table 4: quinoxaline thiourea III and IV
| ?NO. | ?R | R1 | R2 | R3 | R4 | n |
| ?III-1 | ?H | Furyl | Furyl | Methyl | Methyl | 2 |
| ?III-2 | ?H | Furyl | Furyl | Ethyl | Ethyl | 2 |
| ?III-3 | ?H | Furyl | Furyl | Methyl | Methyl | 3 |
| ?III-4 | ?H | Furyl | Furyl | Ethyl | Ethyl | 3 |
| ?III-5 | ?H | Furyl | Furyl | Propyl group | Propyl group | 3 |
| ?IV-1 | ?H | Furyl | Furyl | Methyl | Methyl | 3 |
| ?IV-2 | ?H | Furyl | Furyl | Ethyl | Ethyl | 3 |
| ?IV-3 | ?H | Furyl | Furyl | Propyl group | Propyl group | 3 |
Annotate: 1, methane amide is all in the 3-position of cycloaliphatic ring.
2, III represents the 6-position of urea groups at quinoxaline ring; IV represents the 5-position of urea groups at quinoxaline ring
Example 3,6-[2,3-(2-difuryl)-quinoxalinyl]-urea groups }-N, N-dimethyl-3-benzamide
3-a:N-tertiary butyloxycarbonyl-3-benzaminic acid 20.0 gram 3-benzaminic acid are suspended in the 200ml water, add 7.2 gram sodium hydroxide and 30.0 gram yellow soda ash, and the dissolving back adds 100 milliliters of dioxane.This mixture cools off in frozen water, slowly the solution of Dropwise 5 0.0 gram Boc acid anhydrides in 60 milliliters of dioxane.Adding the back stirring spends the night.Add water and make reactants dissolved, with 100 milliliters of petroleum ether 3 times, the cooling of water layer frozen water slowly with the dilute hydrochloric acid pH=2.0 that neutralizes, is separated out solid, obtains white solid 28.2 with ethyl acetate-sherwood oil recrystallization and restrains.
3-b:N, N-dimethyl-above-mentioned product of 3-aminobenzoyl amine hydrochlorate 5.0 grams is dissolved in 50 milliliters of methylene dichloride, adds 5.1 gram exsiccant dimethylamine hydrochloride and 12 milliliters of diisopropylethylamine.The frozen water cooling adds 6.5 gram dicyclohexyl carbon imide.Stir then and spend the night.Drip 0.5 milliliter of acetate, stir half an hour, filter.Filtrate successively with 5% citric acid washing 2 times, water washing once, saturated sodium bicarbonate washing 3 times, saturated common salt water washing once, the organic layer anhydrous sodium sulfate drying.Boil off most of solvent up to about 15 milliliters of liquid, add the saturated ethyl acetate solution of 30 milliliters of hydrogenchloride in this liquid, stirring spends the night separates out solid, and filtering also, the vacuum-drying solid obtains white product 4.1 grams.
3-c:{6-[2,3-(2-difuryl)-quinoxalinyl]-urea groups }-N, N-dimethyl-3-benzamide 0.17 gram three surpalites are dissolved in 15 milliliters of methylene dichloride, 0.3 restrain 2,3-difuryl-6-aminoquinoxaline and 0.19 milliliter of diisopropylethylamine are dissolved in 80 milliliters of methylene dichloride and slowly are added drop-wise in the above-mentioned solution.Add back restir half an hour, 0.5 gram N, N-dimethyl-3-aminobenzoyl amine hydrochlorate and 0.6 milliliter of diisopropylethylamine are dissolved in 10 milliliters of methylene dichloride, and this solution is added in the above-mentioned reaction solution apace.Stir half an hour, reaction solution washes with water 3 times, anhydrous sodium sulfate drying, evaporate to dryness solution.Residuum is crossed post with 25 gram silica gel (200～300 order), uses ethyl acetate: sherwood oil (1: 1 to 2: 1) drip washing.Obtain yellow solid 0.38 gram.HPLC：99.4％；EMS：468(100，M+1)。
Example 4:{6-[2,3-(2-difuryl)-quinoxalinyl]-thioureido }-N, N-dimethyl-3-benzamide
0.5 restrain 2,3-difuryl-6-aminoquinoxaline is dissolved in 25 milliliters of tetrahydrofuran (THF)s, add 0.56 milliliter of triethylamine, the ice-water bath cooling, slowly drip the solution of 0.12 milliliter of dithiocarbonic anhydride in 5 milliliters of tetrahydrofuran (THF)s, be warmed up to room temperature after adding, stirred 5 hours, reaction solution frozen water cooling again, 0.19 milliliter of Vinyl chloroformate is dissolved in 5 milliliters of tetrahydrofuran (THF)s and slowly is added drop-wise to above-mentioned reaction solution.Adding the back stirring spends the night.0.5 gram N, N-dimethyl-3-aminobenzoyl amine hydrochlorate and 0.65 milliliter of diisopropylethylamine are dissolved in 5 milliliters of N, and in the N-diformamide, this solution is added in the above-mentioned reaction solution apace.Stirring at room 1 hour, refluxed 5 hours then.Pressure reducing and steaming solvent, residuum are poured in the water, with ethyl acetate extraction (60 milliliters of X3).The organic layer anhydrous sodium sulfate drying boils off solvent, and (silica gel dress post is used ethyl acetate: sherwood oil (1: 1 to 2: 1) drip washing), obtain yellow solid 0.24 gram to the residuum column chromatography purification.HPLC：99.3％；EMS：484(100，M+1)。
Method according to example 3, example 4 has been synthesized following series compound:
Table 5: amine formylphenyl quinoxalinyl urea and thiourea
| ?NO. | ?Y | R1 | R2 | R3 | R4 | P |
| ?V-1 | ?O | Furyl | Furyl | Methyl | Methyl | 2- |
| ?V-2 | ?O | Furyl | Furyl | Ethyl | Ethyl | 2- |
| ?V-3 | ?O | Furyl | Furyl | Methyl | Methyl | 3- |
| ?V-4 | ?O | Furyl | Furyl | Ethyl | Ethyl | 3- |
| V-5 | ?O | Furyl | Furyl | Propyl group | Propyl group | 3- |
| V-6 | ?O | Furyl | Furyl | Methyl | Methyl | 4- |
| V-7 | ?O | Furyl | Furyl | Ethyl | Ethyl | 4- |
| V-8 | ?O | Furyl | Furyl | Propyl group | Propyl group | 4- |
| V-9 | ?O | Pyrryl | Pyrryl | Ethyl | Ethyl | 3- |
| VI-1 | ?O | Furyl | Furyl | Methyl | Methyl | 3- |
| VI-2 | ?O | Furyl | Furyl | Ethyl | Ethyl | 3- |
| VI-3 | ?O | Furyl | Furyl | Propyl group | Propyl group | 3- |
| VII-1 | ?S | Furyl | Furyl | Methyl | Methyl | 3- |
| VII-2 | ?S | Furyl | Furyl | Ethyl | Ethyl | 3- |
| VII-3 | ?S | Furyl | Furyl | Propyl group | Propyl group | 3- |
| VIII-1 | ?S | Furyl | Furyl | Methyl | Methyl | 3- |
| VIII-2 | ?S | Furyl | Furyl | Ethyl | Ethyl | 3- |
| VIII-3 | ?S | Furyl | Furyl | Propyl group | Propyl group | 3- |
Annotate: V and VII represent the 6-position of urea groups at quinoxaline ring; VI and VIII represent the 5-position of urea groups at quinoxaline ring
Example 5:{6-[2,3-(2-difuryl)-quinoxalinyl]-urea groups }-N, the N-diethyl acetamide
5-a:N, N-diethylamino acetamide hydrochloride 5.2 gram N-t-butoxycarbonyl glycines are dissolved in 50 milliliters of ethyl acetate, add 2.2 gram exsiccant diethylamine.The frozen water cooling adds 6.5 gram dicyclohexyl carbon imide.Stir then and spend the night.Drip 0.5 milliliter of acetate, stir half an hour, filter.Filtrate successively with 5% citric acid washing 2 times, water washing once, saturated sodium bicarbonate washing 3 times, saturated common salt water washing once, the organic layer anhydrous sodium sulfate drying.Boil off most of solvent up to about 15 milliliters of liquid, add the saturated ethyl acetate solution of 30 milliliters of hydrogenchloride in this liquid, stirring spends the night separates out solid, and filtering also, the vacuum-drying solid obtains white product 6.8 grams.
5-b:{6-[2,3-(2-difuryl)-quinoxalinyl]-urea groups } N, N-diethyl acetamide 0.17 gram three surpalites are dissolved in 15 milliliters of methylene dichloride, 0.3 restrain 2,3-difuryl-6-aminoquinoxaline and 0.19 milliliter of diisopropylethylamine are dissolved in 80 milliliters of methylene dichloride and slowly are added drop-wise in the above-mentioned solution.Add back restir half an hour, 0.5 gram N, N-diethylamino acetamide hydrochloride and 0.6 milliliter of diisopropylethylamine are dissolved in 10 milliliters of methylene dichloride, and this solution is added in the above-mentioned reaction solution apace.Stir half an hour, reaction solution washes with water 3 times, anhydrous sodium sulfate drying, evaporate to dryness solution.Residuum is crossed post with silica gel (200～300 order), uses ethyl acetate: sherwood oil (2: 1 to 4: 1) drip washing.Obtain yellow solid 0.35 gram.HPLC：98.8％；EMS：434(100，M+1)。
Example 6:{6-[2,3-(2-difuryl)-quinoxalinyl]-thioureido }-N, the N-diethyl acetamide
0.5 restrain 2,3-difuryl-6-aminoquinoxaline is dissolved in 25 milliliters of tetrahydrofuran (THF)s, add 0.56 milliliter of triethylamine, the ice-water bath cooling, slowly drip the solution of 0.12 milliliter of dithiocarbonic anhydride in 5 milliliters of tetrahydrofuran (THF)s, be warmed up to room temperature after adding, stirred 5 hours, reaction solution frozen water cooling again, 0.19 milliliter of Vinyl chloroformate is dissolved in 5 milliliters of tetrahydrofuran (THF)s and slowly is added drop-wise to above-mentioned reaction solution.Adding the back stirring spends the night.0.5 gram N, N-diethylamino acetamide hydrochloride and 0.65 milliliter of diisopropylethylamine are dissolved in 5 milliliters of N, and in the N-diformamide, this solution is added in the above-mentioned reaction solution apace.Stirring at room 1 hour, refluxed 1 hour then.Pressure reducing and steaming solvent, residuum are poured in the water, with ethyl acetate extraction (60 milliliters of X3).The organic layer anhydrous sodium sulfate drying boils off solvent, and (silica gel dress post is used ethyl acetate: sherwood oil (2: 1 to 4: 1) drip washing), obtain yellow solid 0.24 gram to the residuum column chromatography purification.HPLC：97.5％；EMS：450(100，M+1)。
Obtain following series compound according to example 5, example 6 methods are synthetic:
Table 6: the quinoxalinyl urea and the thiourea that contain common amino acid
| ????NO. | ????Y | ????n | ????R3 | ????R4 | ????R5 |
| ????IX-1 | ????O | ????0 | Methyl | Methyl | ????H |
| ????IX-2 | ????O | ????0 | Ethyl | Ethyl | ????H |
| ????IX-3 | ????O | ????0 | Propyl group | Propyl group | ????H |
| ????IX-4 | ????O | ????1 | Methyl | Methyl | ????H |
| ????IX-5 | ????O | ????1 | Ethyl | Ethyl | ????H |
| ????IX-6 | ????O | ????1 | Propyl group | Propyl group | ????H |
| ????IX-7 | ????O | ????2 | Ethyl | Ethyl | ????H |
| ????IX-8 | ????O | ????3 | Ethyl | Ethyl | ????H |
| ????IX-9 | ????O | ????4 | Ethyl | Ethyl | ????H |
| ????IX-10 | ????O | ????7 | Ethyl | Ethyl | ????H |
| ????IX-11 | ????O | ????0 | Ethyl | Ethyl | Methyl |
| ????IX-12 | ????O | ????0 | Ethyl | Ethyl | Ethyl |
| ????IX-13 | ????O | ????0 | Ethyl | Ethyl | Sec.-propyl |
| ????IX-14 | ????O | ????0 | Ethyl | Ethyl | Methylol |
| ????IX-15 | ????O | ????0 | Ethyl | Ethyl | Benzyl |
| ????IX-16 | ????O | ????0 | Ethyl | Ethyl | Isobutyl- |
| ????IX-17 | ????O | ????0 | Ethyl | Ethyl | Methylthio ethyl |
| ????IX-18 | ????O | ????0 | Ethyl | Ethyl | The carboxamide ethyl |
| ????IX-19 | ????O | ????0 | Ethyl | Ethyl | To hydroxybenzyl |
| ????IX-20 | ????O | ????0 | Ethyl | Ethyl | The tertiary butyl |
| ????X-1 | ????O | ????0 | Ethyl | Ethyl | ????H |
| ????X-2 | ????O | ????1 | Ethyl | Ethyl | ????H |
| ????X-3 | ????O | ????2 | Ethyl | Ethyl | ????H |
| ????XI-1 | ????S | ????0 | Ethyl | Ethyl | ????H |
| ????XI-2 | ????S | ????1 | Ethyl | Ethyl | ????H |
| ????XI-3 | ????S | ????2 | Ethyl | Ethyl | ????H |
| ????XII-1 | ????S | ????0 | Ethyl | Ethyl | ????H |
| ????XII-2 | ????S | ????1 | Ethyl | Ethyl | ????H |
| ????XII-3 | ????S | ????2 | Ethyl | Ethyl | ????H |
Annotate: IX and XI represent the 6-position of urea groups at quinoxaline ring; X and XII represent the 5-position of urea groups at quinoxaline ring
Example 7:N-ethamine formyl radical-2,3-difuryl-6-aminoquinoxaline
Method one, 0.17 gram, three surpalites are dissolved in 15 milliliters of methylene dichloride, 0.3 gram 2, and 3-difuryl-6-aminoquinoxaline and 0.19 milliliter of diisopropylethylamine are dissolved in 80 milliliters of methylene dichloride and slowly are added drop-wise in the above-mentioned solution.Add back restir half an hour, 0.5 milliliter of ethamine is dissolved in 10 milliliters of methylene dichloride, and this solution is added in the above-mentioned reaction solution apace.Stir half an hour, reaction solution washes with water 3 times, anhydrous sodium sulfate drying, evaporate to dryness solution.Residuum is crossed post with silica gel (200～300 order), uses ethyl acetate: sherwood oil (1: 1 to 3: 1) drip washing.Obtain yellow solid 0.31 gram.HPLC：98.8％；EMS：349(100，M+1)。
Method two, 0.3 gram 2,3-difuryl-6-aminoquinoxaline is dissolved in 5 milliliters of N, and in the N-diformamide, frozen water cooling adds 0.1 gram ethyl isocyanate, then stirring at room 2 hours.Reaction solution is poured in the water, separates out solid, uses ethyl alcohol recrystallization, obtains yellow solid 0.32 gram.HPLC：98.5％；EMS：349(100，M+1)。
Method three, 0.3 gram 2,3-difuryl-6-aminoquinoxaline is dissolved in 5 milliliters of N, and in the N-diformamide, the frozen water cooling adds 0.5 milliliter of triethylamine, drips the solution of 0.1 gram N-ethylamino formyl chloride in 1 milliliter of tetrahydrofuran (THF) then., add the back stirring at room 2 hours.Reaction solution is poured in the water, separates out solid, uses ethyl alcohol recrystallization, obtains yellow solid 0.28 gram.HPLC：98.5％；EMS：349(100，M+1)。
Example 8:N-ethamine thioformyl-2,3-difuryl-6-aminoquinoxaline
Method one, 0.5 gram 2,3-difuryl-6-aminoquinoxaline is dissolved in 25 milliliters of tetrahydrofuran (THF)s, add 0.56 milliliter of triethylamine, the ice-water bath cooling, slowly drip the solution of 0.12 milliliter of dithiocarbonic anhydride in 5 milliliters of tetrahydrofuran (THF)s, be warmed up to room temperature after adding, stirred 5 hours, reaction solution frozen water cooling again, 0.19 milliliter of Vinyl chloroformate is dissolved in 5 milliliters of tetrahydrofuran (THF)s and slowly is added drop-wise to above-mentioned reaction solution.Adding the back stirring spends the night.0.5 gram ethamine is added in the above-mentioned reaction solution apace.Stirring at room 1 hour, refluxed 1 hour then.Pressure reducing and steaming solvent, residuum are poured in the water, with ethyl acetate extraction (60 milliliters of X3).The organic layer anhydrous sodium sulfate drying boils off solvent, and (silica gel dress post is used ethyl acetate: sherwood oil (1: 1 to 2: 1) drip washing), obtain yellow solid 0.24 gram to the residuum column chromatography purification.HPLC：97.5％；EMS：365(100，M+1)。
Method two, 0.3 gram 2,3-difuryl-6-aminoquinoxaline is dissolved in 5 milliliters of N, and in the N-diformamide, the frozen water cooling adds 0.15 gram ethyl mustard oil, is warmed up to 80 ℃ in 2 hours then in stirring at room and stirs 1 hour.Reaction solution is poured in the water, separates out solid, uses ethyl alcohol recrystallization, obtains yellow solid 0.33 gram.HPLC：98.5％；EMS：365(100，M+1)。
Obtain following compound according to the method for example 7, example 8 is synthetic
Table 7: simple quinoxalinyl urea and thiourea
| ????NO. | ?Y | ??R1 | ????R2 | ????R3 | ????R4 |
| XIII-1 | ?O | Furyl | Furyl | H | Methyl |
| XIII-2 | ?O | Furyl | Furyl | H | Ethyl |
| XIII-3 | ?O | Furyl | Furyl | H | Propyl group |
| XIII-4 | ?O | Furyl | Furyl | H | Butyl |
| XIII-5 | ?O | Furyl | Furyl | H | Sec.-propyl |
| XIII-6 | ?O | Furyl | Furyl | H | Isobutyl- |
| XIII-7 | ?O | Furyl | Furyl | H | The tertiary butyl |
| XIII-8 | ?O | Furyl | Furyl | H | Cyclopropyl |
| XIII-9 | ?O | Furyl | Furyl | H | Cyclopentyl |
| XIII-10 | ?O | Furyl | Furyl | H | Cyclohexyl |
| XIII-11 | ?O | Furyl | Furyl | H | Benzyl |
| XIII-12 | ?O | Furyl | Furyl | H | The 2-furyl |
| XIII-13 | ?O | Furyl | Furyl | H | Phenyl |
| XIII-14 | ?O | Furyl | Furyl | Methyl | Methyl |
| XIII-15 | ?O | Furyl | Furyl | Methyl | Ethyl |
| XIII-16 | ?O | Furyl | Furyl | Ethyl | Ethyl |
| XIII-17 | ?O | Furyl | Furyl | Propyl group | Propyl group |
| XIII-18 | ?O | Furyl | Furyl | Piperidines | |
| XIII-19 | ?O | Thienyl | Thienyl | Ethyl | Ethyl |
| XIII-20 | ?O | Pyrryl | Pyrryl | Ethyl | Ethyl |
| XIV-1 | ?O | Furyl | Furyl | Methyl | Methyl |
| XIV-2 | ?O | Furyl | Furyl | Ethyl | Ethyl |
| XIV-3 | ?O | Furyl | Furyl | Propyl group | Propyl group |
| XV-1 | ?S | Furyl | Furyl | Methyl | Methyl |
| XV-2 | ?S | Furyl | Furyl | Ethyl | Ethyl |
| XV-3 | ?S | Furyl | Furyl | Propyl group | Propyl group |
| XVI-1 | ?S | Furyl | Furyl | Methyl | Methyl |
| XVI-2 | ?S | Furyl | Furyl | Ethyl | Ethyl |
| XVI-3 | ?S | Furyl | Furyl | Propyl group | Propyl group |
Annotate: XIII and XV represent the 6-position of urea groups at quinoxaline ring; XIV and XVI represent the 5-position of urea groups at quinoxaline ring
Example 9:N-{6-[2,3-(2-difuryl)-quinoxaline] base }-N ', N '-diethyl succinic diamide
Method one, 7.3 gram diethylamine are dissolved in 20 milliliters of tetrahydrofuran (THF)s, and the ice-water bath cooling slowly adds 10.0 gram Succinic anhydrieds, add the back stirring at room 3 hours.Reactant pours in 100 milliliters of frozen water, separates out solid, filters, and the solid ethyl alcohol recrystallization obtains white crystal 16.8 grams.
Be dissolved in 5 milliliters of anhydrous tetrahydro furans 0.2 restrain above-mentioned product, add 0.2 milliliter of oxalyl chloride, stirred overnight at room temperature.Boil off solvent, obtain white solid.This solid is dissolved in 5 milliliters of tetrahydrofuran (THF)s, slowly is added drop-wise to contain 0.3 gram 2 under the frozen water cooling, and 5 milliliters of N of 3-difuryl-6-aminoquinoxaline and 0.5 milliliter of triethylamine are in the N-diformamide solution.Add the back stirring at room 2 hours, pour in 100 milliliters of cold water, separate out solid, use ethyl alcohol recrystallization, obtain yellow solid 3.8 and restrain.HPLC：99.3％；EMS：433(100，M+1)。
Method two, 0.56 gram 2,3-difuryl-6-aminoquinoxaline and 0.25 gram Succinic anhydried are blended in 50 milliliters of tetrahydrofuran (THF)s, reflux 2 hours.Yellow solid is separated out in cooling.Use ethyl alcohol recrystallization, obtain yellow solid 0.65 gram.Be dissolved in 5 milliliters of N 0.38 restrain this solid, in the N-diformamide, add 0.1 gram diethylamine.The frozen water cooling slowly adds 0.22 gram dicyclohexyl carbon imide, then in stirred overnight at room temperature.Solids removed by filtration, filtrate pour in the cold water, separate out yellow solid, use ethyl alcohol recrystallization, obtain yellow solid 0.38 gram.HPLC：98.3％；EMS：433(100，M+1)。
The method of reference example 9 has been synthesized following compound
Table 8: quinoxaline amide derivatives
Annotate: XVII represents the 6-position of amide group at quinoxaline ring; XVIII represents the 5-position of amide group at quinoxaline ring
Claims (14)
1, a class has the quinoxaline carbamide derivative of following general structure:
Or
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain 3～7 Yuans rings just like oxygen, nitrogen, sulfur heteroatom;
R5 is the substituting group on the heterocycle, is H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, amino, hydroxyl;
X is:
Y is O, S;
Z is C
1-C
4Alkyl, C3～C6 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl.
2, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was O, X was:
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.; Or a plurality of methylene radical form contain or do not contain 3～7 Yuans rings just like oxygen, nitrogen, sulfur heteroatom;
R5 is the substituting group on the heterocycle, is H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, amino, hydroxyl.
3, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was S, X was
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl etc.;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain just like heteroatomic 3～7 Yuans rings such as oxygen, nitrogen, sulphur;
R5 is the substituting group on the heterocycle, is H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, amino, hydroxyl.
4, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was O, X was
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain just like heteroatomic 3～7 Yuans rings such as oxygen, nitrogen, sulphur;
R5 is H, C
1-C
4Alkyl, hydroxyl, halogen, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl.
5, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was S, X was
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain 3～7 Yuans rings just like oxygen, nitrogen, sulfur heteroatom;
R5 is H, C
1-C
4Alkyl, hydroxyl, halogen, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl.
6, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was O, X was
Wherein R is H, C
1-C
4Alkyl, halogen, C
1-C
4Alkoxyl group, C
1-C
4Alkyloyl, nitro, amino, cyano group, thiocyanogen;
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain just like heteroatomic 3～7 Yuans rings such as oxygen, nitrogen, sulphur;
R5 is H, C
1-C
4Alkyl, hydroxyl and the various substituting groups that constitute natural amino acid.
7, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was S, X was
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain 3～7 Yuans rings just like oxygen, nitrogen, sulfur heteroatom;
R5 is H, C
1-C
4Alkyl, hydroxyl and the various substituting groups that constitute natural amino acid.
8, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was O, X was
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain just like heteroatomic 3～7 Yuans rings such as oxygen, nitrogen, sulphur.
9, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was S, X was
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain just like heteroatomic 3～7 Yuans rings such as oxygen, nitrogen, sulphur.
10, quinoxaline carbamide derivative according to claim 1 is characterized in that when Y was O, X was
Wherein R is H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C
1-C
4Alkyloyl, halogen, nitro, amino, hydroxyl, cyano group, thiocyanogen;
R1, R2 are identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl;
R3, R4 can be identical or different, are H, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Alkynyl, C3～C8 cycloalkyl, benzyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl; Or a plurality of methylene radical form contain or do not contain 3～7 Yuans rings just like oxygen, nitrogen, sulfur heteroatom;
Z is C
1-C
4Alkyl, C3～C6 cycloalkyl perhaps contain 0～4 identical or different heteroatomic five Yuans or six Yuans aryl as phenyl, furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, pyridyl.
11, quinoxaline carbamide derivative according to claim 1 and preparation method thereof comprises by the following step and forming:
A) O-Phenylene Diamine compounds, by with 1,2-dicarbonyl compound condensation prepared quinoline derivative;
B) the quinoxaline aminated compounds is by intermediate and other amine condensation prepared urea or thiourea derivatives such as isocyanic ester, lsothiocyanates, carbamates; Or other aminated compounds is by isocyanic ester, lsothiocyanates, carbamate intermediate and quinoxaline aminated compounds condensation prepared urea or thiourea derivative;
C) organic replacing acid is by condensing agent, acyl chlorides, mixed acid anhydride isoreactivity intermediate and quinoxaline aminated compounds condensation prepared amide derivatives; Or the quinoxaline aminated compounds prepares amide derivatives with aminated compounds again after connecting a carboxylic group.
12, quinoxaline carbamide derivative according to claim 1 and its production and use can be used for immunosuppression.
13, quinoxaline derivative and physiologically acceptable salt thereof, be used for immunosuppression, can be used for the parenchymatous organ and transplant, prevention kidney, liver, the heart, cardiopulmonary associating, the rejection of lung or homotransplant of pancreas, other immunosuppressor patient's graft-rejection was accepted in treatment in the past; Bone marrow transplantation, the different primitive marrow of kidney, lung, liver and acute leukemia is transplanted; Can be used for autoimmune disorder, as nephrotic syndrome, aplastic anemia, systemic lupus erythematosus; Also can be used for anti-inflammatory such as psoriatic, rheumatoid arthritis, endogenous uveitis; Can be used for the disease that parasite, schistosomicide and malaria cause; Also can be used for treatment or prevention AIDS, diabetes, multiple sclerosis; Also can be used for tumor treatment and prevention; Also can be used for treating xerophthalmia.
14, quinoxaline derivative and physiologically acceptable salt thereof are used for antiviral.Can be widely used in the various diseases that the disease that caused by various viruses such as influenza, parotitis, viral hepatitis, poliomyelitis, epidemic hemorrhagic fever and simplexvirus cause.Especially can be used for treating or improving various diseases or the symptom that causes by coronavirus, HIV (human immunodeficiency virus), disease or symptom that special severe acute respiratory syndrome virus causes.
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|---|---|---|---|
| CNA031506623A CN1590378A (en) | 2003-08-29 | 2003-08-29 | Quinoxaline derivative and its preparation method and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031506623A CN1590378A (en) | 2003-08-29 | 2003-08-29 | Quinoxaline derivative and its preparation method and use |
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| Publication Number | Publication Date |
|---|---|
| CN1590378A true CN1590378A (en) | 2005-03-09 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| Country | Link |
|---|---|
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100448445C (en) * | 2005-08-01 | 2009-01-07 | 复旦大学 | Application of kuianchun family compound in anti-tumor drug preparing process |
| CN1966500B (en) * | 2005-11-17 | 2011-03-30 | 中国科学院上海药物研究所 | Quinoxaline derivative, preparation method and uses |
| WO2012071414A2 (en) * | 2010-11-22 | 2012-05-31 | Board Of Regents Of The University Of Nebraska | Quinoxaline compounds and uses thereof |
| WO2013047701A1 (en) * | 2011-09-29 | 2013-04-04 | 小野薬品工業株式会社 | Phenyl derivative |
| JP2013515037A (en) * | 2009-12-21 | 2013-05-02 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | New inhibitors of cyclophilin and their use |
| US9676719B2 (en) | 2013-03-26 | 2017-06-13 | Ono Pharmaceutical Co., Ltd. | Phenyl derivative |
| CN115337308A (en) * | 2022-07-15 | 2022-11-15 | 山东省农业科学院家禽研究所（山东省无特定病原鸡研究中心） | Application of ACSS2 inhibitor in preparation of medicine for resisting H1N1 subtype swine influenza virus |
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2003
- 2003-08-29 CN CNA031506623A patent/CN1590378A/en active Pending
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100448445C (en) * | 2005-08-01 | 2009-01-07 | 复旦大学 | Application of kuianchun family compound in anti-tumor drug preparing process |
| CN1966500B (en) * | 2005-11-17 | 2011-03-30 | 中国科学院上海药物研究所 | Quinoxaline derivative, preparation method and uses |
| JP2016128488A (en) * | 2009-12-21 | 2016-07-14 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | New inhibitors of cyclophilins and uses thereof |
| JP2013515037A (en) * | 2009-12-21 | 2013-05-02 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | New inhibitors of cyclophilin and their use |
| US8993758B2 (en) | 2010-11-22 | 2015-03-31 | Board Of Regents Of The University Of Nebraska | Substituted quinoxalines and uses thereof |
| WO2012071414A2 (en) * | 2010-11-22 | 2012-05-31 | Board Of Regents Of The University Of Nebraska | Quinoxaline compounds and uses thereof |
| WO2012071414A3 (en) * | 2010-11-22 | 2012-08-16 | Board Of Regents Of The University Of Nebraska | Quinoxaline compounds and uses thereof |
| US9353094B2 (en) | 2010-11-22 | 2016-05-31 | Board Of Regents Of The University Of Nebraska | Substituted quinoxalines as kinase inhibitors |
| US9340499B2 (en) | 2011-09-29 | 2016-05-17 | Ono Pharmaceutical Co., Ltd. | Phenyl derivative |
| JPWO2013047701A1 (en) * | 2011-09-29 | 2015-03-26 | 小野薬品工業株式会社 | Phenyl derivatives |
| US8975409B2 (en) | 2011-09-29 | 2015-03-10 | Ono Pharmaceutical Co., Ltd. | Phenyl derivative |
| CN103958465A (en) * | 2011-09-29 | 2014-07-30 | 小野药品工业株式会社 | Phenyl derivative |
| WO2013047701A1 (en) * | 2011-09-29 | 2013-04-04 | 小野薬品工業株式会社 | Phenyl derivative |
| CN103958465B (en) * | 2011-09-29 | 2016-08-31 | 小野药品工业株式会社 | Phenyl derivatives |
| JP2017036309A (en) * | 2011-09-29 | 2017-02-16 | 小野薬品工業株式会社 | Phenyl derivative |
| US9820980B2 (en) | 2011-09-29 | 2017-11-21 | Ono Pharmaceutical Co., Ltd. | Phenyl derivative |
| US10117861B2 (en) | 2011-09-29 | 2018-11-06 | Ono Pharmaceutical Co., Ltd. | Phenyl derivative |
| US10835520B2 (en) | 2011-09-29 | 2020-11-17 | Ono Pharmaceutical Co., Ltd. | Phenyl derivative |
| US9676719B2 (en) | 2013-03-26 | 2017-06-13 | Ono Pharmaceutical Co., Ltd. | Phenyl derivative |
| CN115337308A (en) * | 2022-07-15 | 2022-11-15 | 山东省农业科学院家禽研究所（山东省无特定病原鸡研究中心） | Application of ACSS2 inhibitor in preparation of medicine for resisting H1N1 subtype swine influenza virus |
| CN115337308B (en) * | 2022-07-15 | 2024-03-22 | 山东省农业科学院家禽研究所（山东省无特定病原鸡研究中心） | Application of ACSS2 inhibitor in preparation of anti-H1N 1 subtype swine influenza virus drugs |
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