CN101235030A - 1-substituted-5-trifluoromethyl-2-(1H)pyridone compound, preparation method and use thereof - Google Patents
1-substituted-5-trifluoromethyl-2-(1H)pyridone compound, preparation method and use thereof Download PDFInfo
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- CN101235030A CN101235030A CNA2007100343571A CN200710034357A CN101235030A CN 101235030 A CN101235030 A CN 101235030A CN A2007100343571 A CNA2007100343571 A CN A2007100343571A CN 200710034357 A CN200710034357 A CN 200710034357A CN 101235030 A CN101235030 A CN 101235030A
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Abstract
The invention relates to a 1-substituted-5-trifluoromethyl-2-(1H) pyridone compound, a corresponding preparation method and a pharmaceutical application of the compound, wherein the compound is represented as the formula (X) with anti-fibrosis function.
Description
Technical field
The present invention relates to 1-and replace 5-trifluoromethyl-2-(1H) pyridinone compounds, prepare the method for this compounds, and the medicinal use of this compounds.
Background technology
Pyridine compounds is a huge family, has different character owing to the group that is replaced on the pyridine ring is different.
German patent DE 4343528 has reported that a class pyridinone compounds has insecticidal action on agricultural, have following structural formula I.
Structural formula I
Above-claimed cpd is synthetic by following reaction formula.
European patent EP 259048 discloses the compound with following structural formula II.
Structural formula II
Wherein, R1, R2, R4, R5 are selected from hydrogen, halogen, lower paraffin hydrocarbons or halogenated lower alkane hydrocarbon, lower alkoxy or elementary halogenated alkoxy and light alkene or lower halogenated alkene respectively; R3 is selected from halogen, ammonia, one or two elementary alkyl amido, low-grade halogenated alkyl, elementary halogenated alkoxy and low-grade alkenyl or lower halogenated thiazolinyl, as long as R3 is not a chlorine or a brooethyl; R6 is oxygen or sulphur; R7, R10 are selected from hydrogen, halogen, lower paraffin hydrocarbons or halogenated lower alkane hydrocarbon, lower alkoxy or elementary halogenated alkoxy etc.; R8 also is selected from hydrogen, halogen, lower paraffin hydrocarbons or halogenated lower alkane hydrocarbon, lower alkoxy or elementary halogenated alkoxy etc., also comprises nitro, cyano group etc., but is not trifluoromethyl;
EP367410, EP398499 have reported that a compounds has insecticidal action on agricultural, have the compound of following structural formula II I.
Structural formula II I
Wherein comprised a class formation R
1Be pyridone, have the compound of structural formula IV.
Structural formula IV
R wherein
10Be O or S.
European patent EP 216541 has reported that a compounds has insecticidal action on agricultural, has following structural formula V.
Structural formula V
Wherein Z represents halogen atom or haloform, X, and Y is selected from halogen atom
The compound that has wherein comprised a class formation formula V:
Structural formula V
European patent EP 488220 has reported that a compounds has herbicide action, has following structural formula VI.
Structural formula VI
No matter these above compounds are on the phenyl ring of 1 of pyridine ring or pyridine ring multiple, a plurality of substituting groups to be arranged all in structure, and complex structure all is to use as sterilant or weedicide.
U.S. Pat 3839346A, US4052509A, US4042699 disclose 29 pyridine compounds with following structural VIII.
Structural formula VIII
And disclose this type of pyridone have anti-inflammatory, analgesic, reduce effects such as serum uric acid level, pain relieving.Wherein, 1-phenyl-5-methyl-2-(1H) pyridone (5-methyl-1-phenyl-2 (1H)-pyridone) has best active and lower toxicity.
U.S. Pat 5,310,562 have announced for the first time 1-phenyl-5-methyl-2-(1H) pyridone in 1994, [5-methyl-1-phenyl-2 (1H)-pyridone] claims pirfenidone (Pirfenidone again, PFD) having the biological activity of anti-fibrosis. U.S. Pat 5 subsequently, 518,729 and US5,716,632 declare that N-replaces-2 (1H)-pyridones [N-substituted 2-(1H) pyridone], be structural formula VIII, replace-3 (1H)-pyridones [N-substituted 3-(1H) pyridone] with N-and also have the same anti-fibrosis effect of pirfenidone (Pirfenidone).And enumerated 44 compounds, and major part wherein all is the known compound that draws from U.S. Pat 4052509, in these compounds, and R
1, R
2, R
3, R
4All be limited to methyl or ethyl.Except in the past in U.S. Pat 5,310, outside the experimental data of relevant 1-phenyl-5-methyl-2-(1H) pyridone (pirfenidone) that provides in 562, it is that N-replaces-2 (1H)-pyridones and N-and replaces-3 (1H)-pyridones and have anti-fibrosis effect that these two patents do not provide any experimental data (comprising chemistry data and biological information) of other compound to prove to have above structural formula I and two mother nucleus structures of structural formula II.
Pirfenidone, (pirfenidone, PFD), the validity aspect anti-fibrosis has obtained being confirmed in the how external and experimentation on animals.Experiment shows, in renal fibrosis, pulmonary fibrosis experimentation on animals and specificity pulmonary fibrosis patient's clinical treatment, pirfenidone all has prevention even reverses the effect of ECM accumulation and prevent even reverse fibrosis generation and cicatrization (Shimizu T, Fukagawa M, Kuroda T, et al.Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partialnephrectomy.Kidney Int, 1997,52 (Suppl 63): S239-243; Raghu G, Johnson WC, Lockhart D, et al.Treatment of idiopathic pulmonary fibrosis with a new antifibroticagent, pirfenidone.Am J Respir Crit Care Med, 1999,159:1061-1069).The mechanism of pirfenidone anti-fibrosis effect still is among the research, but it is a kind of effective cytokine inhibitor that a large amount of research has proved pirfenidone, can be by participating in regulating some factor, be suppressed to fibrocellular biologic activity, cause cell proliferation to be subjected to press down, matrix collagen is synthetic to be reduced.
The present application people has applied for Chinese patent ZL02114190.8, and a class pyridinone compounds is provided, and (abbreviation Fluorofenidone) has following structure I X.
Structural formula IX
When n=1, described substituent R is represented F, Br, I.
When n=2, described substituent R is represented F, Cl, Br, I, saturated straight chain alkyl, oxo saturated straight chain alkyl, halo saturated straight chain alkyl.
The position of described substituent group R on phenyl ring has modes such as ortho position, a position, contraposition.
The present application people has also applied for international monopoly PCT/CN2006/000651, provides the class pyridine compounds of structure IX to have anti-liver, kidney, the pulmonary fibrosis of wide spectrum.
Pirfenidone is metabolism in the following manner in vivo:
When the mouse mainline administration, transformation period is 8.6 minutes (Shri N.Giri et al.Pharmacokinetics and Metabolism of a Novel Antifibrotic Drug Pirfenidone, in MiceFollowing Intravenous Administration Biopharm.Drug Dispos.2002,23:203-211), when the rat intravenous injection administration, the transformation period is 37 minutes (Stevo Mirkovic et al.Attenuation of cardiac
Brosis by pirfenidone and amiloride in DOCA-salthypertensive rats British Journal of Pharmacology 2002,135:961 ± 968), when the dog oral administration, transformation period is 47 minutes (Wang Yongsheng etc., the HPLC-UV method is measured pirfenidone concentrations and pharmacokinetics China Medicine University journal 2006,37 (2) thereof in the beasle dog blood plasma: 146-149).These data show because 5 easy metabolism of methyl make that the pirfenidone transformation period short, and in order to guarantee effective Plasma Concentration, clinical administration is 1 day 3 times.It is important to point out,, need secular pharmacological agent probably because all fibrotic diseases all are chronic diseases.So the medicine as any need are taken for a long time reduces the number of times of taking medicine, the curative effect that improves medicine is the treatment that helps fibrotic disease.
Summary of the invention
The present invention is on above-mentioned prior art basis, and methyl is modified into trifluoromethyl, obtains the new pyridine compounds of a class, and they have not metabolism in vivo, thereby have long half time, the characteristics that curative effect is high.Its structure is as follows:
Structural formula X
Among the structural formula X, A is: one or the aromatic heterocycle of di-substituted-phenyl, aromatic heterocycle, replacement.
Wherein when A is substituted-phenyl, have the structure of structural formula XI:
Structural formula XI
In the formula: n=1～2,, described substituent R is halogen, alkyl, alkoxyl group, oxoalkyl group, haloalkyl, carboxyl, carboxylicesters, trifluoromethyl, amino, alkylamino.
According to the present invention, preferably compound also comprises following compounds:
In the 1-aryl of formula (X)-5-trifluoromethyl-2 (1H) pyridone,
1-(2-pyridyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-pyridyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-pyridyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-quinolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-quinolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-quinolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-pyrryl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-pyrryl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-imidazolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(5-imidazolyl)-5-trifluoromethyl-2-(1H) pyridone;
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=1, R=CH
3, as:
1-(2-aminomethyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-aminomethyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-aminomethyl phenyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=1, R=F, Cl, Br, I, as:
1-(2-fluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-fluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-fluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-chloro-phenyl-)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-chloro-phenyl-)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-chloro-phenyl-)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-bromophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-bromophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-bromophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-iodophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-iodophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-iodophenyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=1, R=OCH
3, as:
1-(2-p-methoxy-phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-p-methoxy-phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-p-methoxy-phenyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=1, R=COOH, as:
1-(2-carboxyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-carboxyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-carboxyl phenyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=1, R=COOR
1, as:
1-(2-methoxycarbonyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-methoxycarbonyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-methoxycarbonyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-carbethoxy phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-carbethoxy phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-carbethoxy phenyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=2, R=F, Br or Cl, as:
1-(2, the 3-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2,4 dichloro benzene base)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2,4 difluorobenzene base)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=1 or 2, the R=trifluoromethyl, as:
1-(2-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n=2, the R=methyl, as:
1-(2, the 3-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone; Or
In the 1-substituted-phenyl of formula (XI)-5-trifluoromethyl-2 (1H) pyridone, n2, the R=methoxyl group, as:
1-(2, the 3-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone.
The following approach that passes through of compound provided by the invention prepares.
Approach A
Approach B:
Approach C:
Wherein 5-5-flumethiazine ketone can be according to disclosed method preparation among US413167A1, US4230864A1 or the US4249009A1.
Fibrosis (fibrosis) can betide multiple organ or tissue, causes that parenchyma reduces in the organ or tissue, and fibrillar connective tissue increases, and finally can cause organ or tissue's structure deteriorate and hypofunction, even organ failure.At present extensive studies has been carried out in the Fibrotic mechanism of organ or tissue, diagnostic method and prophylactico-therapeutic measures, in the prior art, obtained significant progress in some aspects, but still had some key issues not solve.
According to introducing in the prior art, at present the compound of disclosed available anti-fibrosis because 5 methyl metabolism easily in vivo, thereby influenced compound stability in vivo.
Prove that according to embodiment provided by the invention compound provided by the invention has been owing to replaced CH3-with the CF3-base on 5, thereby, increased the stability of compound in vivo not by metabolism.
Therefore, the invention provides the medicinal use with anti-fibrosis of compound among the formula X.
Embodiment
Embodiment 1
1-phenyl-5-trifluoromethyl-2-(1H) pyridone
The 250mL three-necked bottle of dried and clean drops into the 120mL drying and heavily steams DMF, 5.0g 5-5-flumethiazine ketone and 1.4g sodium hydride, behind the stirring reaction 10min, drop into the 6.7g iodobenzene in 100 ℃ of stirring reactions, TLC follows the tracks of (ethyl acetate: sherwood oil=4: 1), cool off, add 50mL water and stir 5min, extract with ethyl acetate (100mL*3), ethyl acetate layer is got ethyl acetate layer anhydrous sodium sulfate drying 4h with saturated nacl aqueous solution (100mL*3) washing, reclaim solvent to doing, get an oily liquid, heavy 6.5g, silica gel column chromatography separates, ethyl acetate: sherwood oil=4: 1 wash-outs, pale brown color chips shape crystallization 1.7g, total recovery 29.3%, m.p.179～181 ℃.
Embodiment 2
1-(4-chloro-phenyl-)-5-trifluoromethyl-2-(1H) pyridone
The 500mL three-necked bottle of dried and clean drops into the 300mL drying and heavily steams DMF, 16.3g 5-5-flumethiazine ketone and 7.2g sodium hydride, behind the stirring reaction 10min, drop into 28.0g to chloroiodobenzone in 100 ℃ of stirring reactions, as follows embodiment 1,3.1g off-white color solid, total recovery 11.3%, m.p.179.1～180.2 ℃.
Embodiment 3
1-benzyl-5-trifluoromethyl-2-(1H) pyridone
The 500mL three-necked bottle of dried and clean drops into the 350mL drying and heavily steams DMF, 32.4g 5-5-flumethiazine ketone and 14.4g sodium hydride, behind the stirring reaction 10min, drop into the 25.3g benzyl chloride in 100 ℃ of stirring reactions, as follows embodiment 1,9.2g off-white color solid, total recovery 18.2%, m.p.53.1～54.7 ℃.
Embodiment 4
1-(2-p-methoxy-phenyl)-5-trifluoromethyl-2-(1H) pyridone
The 500mL three-necked bottle of dried and clean drops into the 300mL drying and heavily steams DMF, 19.0g 5-5-flumethiazine ketone and 8.6g sodium hydride, behind the stirring reaction 10min, drop into 32.6g2-methoxyl group iodobenzene in 100 ℃ of stirring reactions, as follows embodiment 1, the pale brown look solid of 5.2g, total recovery 20.5%, m.p.179.6～180.9 ℃.
Embodiment 5
1-(3-fluorophenyl)-5-trifluoromethyl-2-(1H) pyridone
The 500mL three-necked bottle of dried and clean drops into the 200mL drying and heavily steams DMF, 16.4g 5-5-flumethiazine ketone and 4.6g sodium hydride, behind the stirring reaction 10min, drop into 24.1g3-fluorine iodobenzene in 100 ℃ of stirring reactions, as follows embodiment 1, the pale brown look solid of 0.4g, total recovery 1.6%, m.p.132.6～134.5 ℃.
Embodiment 6
1-(3-aminomethyl phenyl)-5-trifluoromethyl-2-(1H) pyridone
The 250mL three-necked bottle of dried and clean drops into the 150mL drying and heavily steams DMF, 21.8g3-the methyl iodobenzene, 27.7g5-5-flumethiazine ketone, 15.2g Anhydrous potassium carbonate and 0.64 gram copper powder, in 120 ℃ of stirring reactions, TLC (ethyl acetate: sherwood oil=4: 1) follow the tracks of reaction.120 ℃ of reclaim under reduced pressure DMF are to doing, toluene 150mL backflow 20min, filtered while hot, filtrate is waved solvent to doing, silica gel column chromatography separates, ethyl acetate: sherwood oil=4: 1 wash-outs, yellow solid 1.6g, total recovery 3.7%, m.p.65.7～67.2 ℃.
Embodiment 7
1-(2-methyl-formiate base phenyl)-5-trifluoromethyl-2-(1H) pyridone
The 250mL three-necked bottle of dried and clean drops into the 100mL drying and heavily steams DMF, 13.7g2-iodo-benzoic acid methyl esters, 13.8g 5-5-flumethiazine ketone, 8.3g Anhydrous potassium carbonate and 0.64 gram copper powder, as follows embodiment 6 gets white crystal 0.8g, total recovery 5.4%, m.p.178.0～179.7 ℃.
Embodiment 8
Be example with following compound (is code name with AKF010W) among the present invention, tested the anti-fibrosis activity of compound provided by the invention.
Material and method:
1. reagent:
1.1 main agents mouse kidney inoblast (NIH3T3) is provided by Tumour Inst., Xiangya Medicine College, Zhongnan Univ., tetrazolium bromide (MTT) is a SIGMA company product, dimethyl sulfoxide (DMSO) (DMSO) is a SIGMA company product, DMEM substratum (high glycoform) is a SIGMA company product, new-born calf serum is a folium ilicis chinensis company product, pancreatin is a SIGMA company product, and pirfenidone (PFD) is provided by pharmaceutical college of Central South University, and Fluorofenidone (AKF-PD) is synthetic by the applicant.
1.2 main equipment: Bechtop, CO2 incubator, microplate reader, 0.22um filter, 96 orifice plates
2. method: recovery NIH3T3 is inoculated in 25cm
2In 37 ℃, 5%CO2 case, cultivate in the culturing bottle, changed a subculture in every 2-3 days, treat that cell covers with after, 0.25% trypsinase goes down to posterity in digestion.Get the cell that passes 2-3 generation and be used as experiment.The cell inoculation that is in logarithmic phase is in 96 orifice plates, and every hole adds cell suspension 200ul, and inoculum density is 6 * 10
4/ ml, 37 ℃, continue in the 5%CO2 incubator to cultivate, treat to abandon supernatant behind the cell attachment, add the AKF-PD of different concns respectively, PFD, AKF010 (100,200,400,800,1600ug/ml), control group only adds the DMEM substratum (every hole 200ul) that contains 10% calf serum, each concentration is established 6 multiple holes, in 37 ℃, cultivate in 5% the CO2 incubator, cultivate 24,48 respectively, every hole adds MTT 20ull (5mg/ml) behind the 72h, put and take out culture plate in the incubator behind the 4h, abandon supernatant, every hole adds DMSO150ul, measure each hole optical density value (A value) with microplate reader in 490nm, absorbancy is directly proportional with cell viability.
The results are shown in Table 1:
Conclusion:
AKF-PD and PFD all have the effect that suppresses NIH3T3 cell proliferation, and 48h time point comparability is best, and onset concentration and the action intensity of AKF-PD are better than PFD.
The AKF010 medicine all has the effect that suppresses propagation to the NIH3T3 cell, compare with AKF-PD and PFD (result for the second time), its effect power of cell inhibitory rate can do following ordering: AKF010AKF-PD＞PFD＞.
Claims (5)
1. the compound that has formula (X) structure
Wherein A is: one or the aromatic heterocycle of di-substituted-phenyl, aromatic heterocycle, replacement;
2. compound according to claim 1 is characterized in that having the structure of formula XI when A is substituted-phenyl:
In the formula: n=1～2,, described substituent R is halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Oxoalkyl group, C
1-C
6Haloalkyl, carboxyl, C
2-C
7Carboxylicesters, trifluoromethyl, amino, C
1-C
6Alkylamino.
3. compound according to claim 1 and 2 is characterized in that the compound that is preferably as follows:
1-(2-pyridyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-pyridyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-pyridyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-quinolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-quinolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-quinolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-pyrryl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-pyrryl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-imidazolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(5-imidazolyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-aminomethyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-aminomethyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-aminomethyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-fluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-fluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-fluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-chloro-phenyl-)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-chloro-phenyl-)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-chloro-phenyl-)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-bromophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-bromophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-bromophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-iodophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-iodophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-iodophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-p-methoxy-phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-p-methoxy-phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-p-methoxy-phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-carboxyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-carboxyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-carboxyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-methoxycarbonyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-methoxycarbonyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-methoxycarbonyl phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-carbethoxy phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3-carbethoxy phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-carbethoxy phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-dibromo phenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2,4 dichloro benzene base)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-dichlorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2,4 difluorobenzene base)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-difluorophenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(4-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-trifluoromethyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-3,5-dimethylphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 3-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 4-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 5-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(2, the 6-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 4-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone;
1-(3, the 5-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H) pyridone.
4. the method for the compound of preparation one of claim 1 to 3 is done prepared in reaction under the condition of catalyzer at Cu, KCO3 or NaH by 5-methyl-pyridone and aryl iodide.
5. the compound of one of claim 1 to 3 is used to prepare the medicine of anti-fibrosis.
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