CN101235030A - 1-substituted-5-trifluoromethyl-2-(1H)pyridone compound, preparation method and use thereof - Google Patents

Abstract

The invention relates to 1-substituted-5-trifluoromethyl-2-(1H) pyridone compound, a method for preparing the compound, and the medical application of the compound. The compounds provided by the present invention have the structure of formula (X). The compound has an anti-fibrotic effect.

Description

1-substituted-5-trifluoromethyl-2-(1H)pyridone compound, preparation method and use thereof

technical field

The invention relates to 1-substituted 5-trifluoromethyl-2-(1H)pyridone compounds, a method for preparing the compounds, and the medical application of the compounds.

Background technique

Pyridone compounds are a large family, which have different properties due to the different groups substituted on the pyridine ring.

German patent DE 4343528 has reported that a class of pyridone compounds have insecticidal effects in agriculture, and have the following structural formula I.

Structural Formula I

The above compound is synthesized by the following reaction formula.

European patent EP259048 discloses compounds having the following structural formula II.

Structural formula II

Wherein, R1, R2, R4, R5 are respectively selected from hydrogen, halogen, lower alkane or halogenated lower alkane, lower alkoxy or lower halogenated alkoxy and lower olefin or lower halogenated olefin; R3 is selected from halogen, ammonia, a Or two lower alkylamino, lower haloalkyl, lower haloalkoxy and lower alkenyl or lower haloalkenyl, as long as R3 is not monochloro or monobromomethyl; R6 is oxygen or sulfur; R7, R10 are selected from hydrogen, Halogen, lower alkane or halogenated lower alkane, lower alkoxy or lower haloalkoxy, etc.; R8 is also selected from hydrogen, halogen, lower alkane or halogenated lower alkane, lower alkoxy or lower haloalkoxy, etc., also includes Nitro, cyano, etc., but not trifluoromethyl;

EP367410 and EP398499 report that a class of compounds have insecticidal effects in agriculture, and have the following structural formula III.

Structural formula III

It includes a class of compounds whose structure _R1 is pyridone and has the structural formula IV.

Structural Formula IV

Wherein R ₁₀ is O or S.

European Patent EP 216541 reports that a class of compounds have insecticidal effects in agriculture, and have the following structural formula V.

Structural formula V

Where Z represents halogen atom or trihalomethane, X, Y are selected from halogen atom

Which includes a class of compounds of formula V:

Structural formula V

European patent EP488220 reports a class of compounds with herbicide action, having the following structural formula VI.

Structural formula VI

In the structures of the above compounds, no matter the pyridine ring or the benzene ring at the 1-position of the pyridine ring has multiple substituents, the structure is complex, and they are all used as insecticides or herbicides.

US Patents US3839346A, US4052509A, and US4042699 disclose 29 pyridone compounds having the following structural formula VIII.

Structural formula VIII

It is also disclosed that such pyridone has anti-inflammatory, antipyretic, lowering serum uric acid level, analgesic and other effects. Among them, 1-phenyl-5-methyl-2-(1H)-pyridone (5-methyl-1-phenyl-2(1H)-pyridone) has the best activity and lower toxicity.

US Patent US 5,310,562 first published 1-phenyl-5-methyl-2-(1H)pyridone in 1994, [5-methyl-1-phenyl-2(1H)-pyridone], also known as pyridone Pirfenidone (PFD) has anti-fibrosis biological activity. Then US patents US5,518,729 and US5,716,632 claimed that N-substituted 2(1H)-pyridone [N-substituted 2-(1H)pyridone], namely Structural formula VIII and N-substituted-3(1H)-pyridone [N-substituted 3-(1H)pyridone] also have the same anti-fibrosis effect as pirfenidone. And listed 44 compounds, most of which are known compounds cited from US Pat. No. 4,052,509. In these compounds, R ₁ , R ₂ , R ₃ , and R ₄ are all limited to methyl or ethyl. These two patents do not provide any experimental data on other compounds (including Chemical data and biological data) prove that there are two core structures of the above structural formula I and structural formula II, that is, N-substituted-2(1H)-pyridone and N-substituted-3(1H)-pyridone have anti-fibrosis effect.

The effectiveness of pirfenidone (pirfenidone, PFD) in anti-fibrosis has been confirmed by more in vitro and animal experiments. Experiments have shown that in renal fibrosis, pulmonary fibrosis animal experiments and clinical treatment of patients with specific pulmonary fibrosis, pirfenidone has the effect of preventing or even reversing ECM accumulation and preventing or even reversing the occurrence of fibrosis and scar formation (Shimizu T, Fukagawa M, Kuroda T, et al. Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partial nephrectomy. Kidney Int, 1997, 52 (Suppl 63): S239-243; Raghu G, Johnson WC, Lockhart D, et al . Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone. Am J Respir Crit Care Med, 1999, 159: 1061-1069). The mechanism of pirfenidone's anti-fibrosis effect is still under study, but a large number of studies have proved that pirfenidone is an effective cytokine inhibitor, which can inhibit the biological function of fibroblasts by participating in the regulation of certain factors. biological activity, leading to inhibition of cell proliferation and reduction of matrix collagen synthesis.

The inventor of the present application applied for Chinese patent ZL02114190.8, and provided a class of pyridone compounds (flufenidone for short) having the following structure IX.

Structural Formula IX

When n=1, the substituent R represents F, Br, I.

When n=2, the substituent R represents F, Cl, Br, I, saturated straight chain hydrocarbon group, oxo saturated straight chain hydrocarbon group, halogenated saturated straight chain hydrocarbon group.

The position of the substituent group R on the benzene ring has an ortho position, a meta position, a para position and the like.

The inventor of the present application also applied for the international patent PCT/CN2006/000651, providing a class of pyridone compounds with structure IX with broad-spectrum anti-hepatic, renal and pulmonary fibrosis.

Pirfenidone is metabolized in the body in the following ways:

brosis by pirfenidone and amiloride in DOCA-salthypertensive rats British Journal of Pharmacology 2002，135：961±968)，在犬口服给药时，半衰期为47分钟(王永升等，HPLC-UV法测定比格犬血浆中吡非尼酮浓度及其药代动力学中国药科大学学报2006，37(2)：146-149)。这些数据表明由于5位甲基容易代谢，使得吡非尼酮半衰期短，为了保证有效的血药浓度，临床给药为1天3次。有必要指出的是，因为所有的纤维化疾病都是慢性病，很可能需要长期的药物治疗。所以象任何需长期服用的药物一样，减少服药的次数，提高药物的疗效是有利于纤维化疾病的治疗。When administered intravenously in mice, the half-life 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), in When administered intravenously in rats, the half-life 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 administered orally in dogs, the half-life is 47 minutes (Wang Yongsheng, etc., HPLC-UV method for the determination of pirfenidone in beagle dog plasma Nidone concentration and its pharmacokinetics Journal of China Pharmaceutical University 2006, 37(2): 146-149). These data indicate that the half-life of pirfenidone is short due to the easy metabolism of the 5-methyl group. In order to ensure effective blood drug concentration, the clinical administration is 3 times a day. It is important to point out that because all fibrotic diseases are chronic, they are likely to require long-term medical treatment. Therefore, like any drug that needs to be taken for a long time, reducing the number of times of taking the drug and improving the curative effect of the drug is beneficial to the treatment of fibrotic diseases.

Contents of the invention

On the basis of the above prior art, the present invention modifies a methyl group into a trifluoromethyl group to obtain a new class of pyridone compounds, which are not metabolized in the body, and thus have the characteristics of long half-life and high curative effect. Its structure is as follows:

Structural formula X

In the structural formula X, A is: a mono- or di-substituted phenyl group, an aromatic heterocycle, or a substituted aromatic heterocycle.

Wherein when A is a substituted phenyl group, it has the structure of structural formula XI:

Structural Formula XI

In the formula: n=1-2, the substituent R is halogen, alkyl, alkoxy, oxoalkyl, haloalkyl, carboxyl, carboxylate, trifluoromethyl, amino, alkylamino.

According to the present invention, preferred compounds also include the following compounds:

In the 1-aryl-5-trifluoromethyl-2(1H)pyridone of formula (X),

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-quinolinyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-quinolinyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-quinolinyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2-pyrrolyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-pyrrolyl)-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-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=1, R=CH ₃ , such as:

1-(2-methylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-methylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-methylphenyl)-5-trifluoromethyl-2-(1H)pyridone; or

In the 1-substituted phenyl-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=1, R=F, Cl, Br, I, such 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-Chlorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-Chlorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-Chlorophenyl)-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-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=1, R=OCH ₃ , such as:

1-(2-methoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-methoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-methoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone; or

In the 1-substituted phenyl-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=1, R=COOH, such as:

1-(2-carboxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-carboxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-carboxyphenyl)-5-trifluoromethyl-2-(1H)pyridone; or

In the 1-substituted phenyl-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=1, R=COOR ₁ , such as:

1-(2-Methoxycarbonylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-Methoxycarbonylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-methoxycarbonylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2-ethoxycarbonylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3-ethoxycarbonylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-ethoxycarbonylphenyl)-5-trifluoromethyl-2-(1H)pyridinone; or

In the 1-substituted phenyl-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=2, R=F, Br or Cl, such as:

1-(2,3-Dibromophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,4-Dibromophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-Dibromophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,6-dibromophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,4-Dibromophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,5-Dibromophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,3-dichlorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,4-Dichlorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-Dichlorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,6-dichlorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,5-Dichlorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,3-difluorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,4-difluorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-Difluorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,6-Difluorophenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,5-difluorophenyl)-5-trifluoromethyl-2-(1H)pyridone; or

In the 1-substituted phenyl-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=1 or 2, R=trifluoromethyl, such as:

1-(2-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(4-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,3-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,4-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,6-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,4-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-trifluoromethylphenyl)-5-trifluoromethyl-2-(1H)pyridone; or

In the 1-substituted phenyl-5-trifluoromethyl-2(1H)pyridone of formula (XI), n=2, R=methyl, such as:

1-(2,3-Dimethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,4-Dimethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-Dimethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,6-Dimethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,4-Dimethylphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-Dimethylphenyl)-5-trifluoromethyl-2-(1H)pyridone; or

In the 1-substituted phenyl-5-trifluoromethyl-2(1H)pyridone of formula (XI), n2, R=methoxy, such as:

1-(2,3-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,4-dimethoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,5-dimethoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(2,6-dimethoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,4-dimethoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone;

1-(3,5-Dimethoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone.

The compounds provided by the present invention can be prepared through the following routes.

Route A

Route B:

Route C:

Wherein 5-trifluoromethylpyridone can be prepared according to the methods disclosed in US413167A1, US4230864A1 or US4249009A1.

Fibrosis can occur in various organs or tissues, causing parenchymal cells in organs or tissues to decrease and fibrous connective tissue to increase, which can eventually lead to organ or tissue structural damage, functional decline, and even organ failure. Extensive research has been done on the mechanism, diagnostic methods and prevention and treatment measures of organ or tissue fibrosis. In the prior art, considerable progress has been made in some aspects, but there are still some key problems that have not been resolved.

According to the introduction in the prior art, currently available anti-fibrosis compounds have been disclosed because the methyl group at the 5-position is easily metabolized in vivo, thus affecting the stability of the compounds in vivo.

According to the examples provided by the present invention, the compounds provided by the present invention are not metabolized in vivo because the CH3- is replaced by a CF3- group at the 5-position, which increases the stability of the compound.

Therefore, the present invention provides the pharmaceutical use of the compound of formula X with anti-fibrosis.

Detailed ways

Example 1

1-Phenyl-5-trifluoromethyl-2-(1H)pyridone

A dry and clean 250mL three-necked bottle was put into 120mL dry redistilled DMF, 5.0g 5-trifluoromethylpyridone and 1.4g sodium hydride, and after stirring for 10 minutes, 6.7g of iodobenzene was added and stirred at 100°C for the reaction, followed by TLC (acetic acid ethyl ester:petroleum ether=4:1), cooled, add 50mL water and stir for 5min, extract with ethyl acetate (100mL*3), wash the ethyl acetate layer with saturated sodium chloride solution (100mL*3), take ethyl acetate The ester layer was dried with anhydrous sodium sulfate for 4 hours, and the solvent was recovered to dryness to obtain an oily solution weighing 6.5 g, which was separated by silica gel column chromatography and eluted with ethyl acetate:petroleum ether=4:1 to obtain brown-yellow flaky crystals 1.7 g, total yield 29.3%, m.p.179～181°C.

Example 2

1-(4-Chlorophenyl)-5-trifluoromethyl-2-(1H)pyridone

Put 300mL dry redistilled DMF, 16.3g 5-trifluoromethylpyridone and 7.2g sodium hydride into a dry and clean 500mL three-necked bottle, stir and react for 10min, then put 28.0g p-chloroiodobenzene and stir at 100℃ for reaction, the same as below Example 1, 3.1 g of off-white solid was obtained, the total yield was 11.3%, m.p.179.1-180.2°C.

Example 3

1-Benzyl-5-trifluoromethyl-2-(1H)pyridone

Put 350mL of dry redistilled DMF, 32.4g of 5-trifluoromethylpyridone and 14.4g of sodium hydride into a dry and clean 500mL three-necked bottle, and stir for 10 minutes, then put in 25.3g of benzyl chloride and stir at 100°C for the reaction, the following is the same as the implementation In Example 1, 9.2 g of off-white solid was obtained, with a total yield of 18.2%, m.p.53.1-54.7°C.

Example 4

1-(2-Methoxyphenyl)-5-trifluoromethyl-2-(1H)pyridone

Put 300mL dry redistilled DMF, 19.0g 5-trifluoromethylpyridone and 8.6g sodium hydride into a dry and clean 500mL three-necked bottle, stir and react for 10 minutes, then put 32.6g 2-methoxyiodobenzene into the reaction at 100°C, The following is the same as Example 1 to obtain 5.2 g of brown-yellow solid, with a total yield of 20.5%, m.p.179.6-180.9°C.

Example 5

1-(3-fluorophenyl)-5-trifluoromethyl-2-(1H)pyridone

Put 200mL of dry redistilled DMF, 16.4g of 5-trifluoromethylpyridone and 4.6g of sodium hydride into a dry and clean 500mL three-necked bottle, stir for 10 minutes, then put in 24.1g of 3-fluoroiodobenzene and stir at 100°C for reaction, the same as below Example 1, 0.4 g brownish yellow solid was obtained, the total yield was 1.6%, m.p.132.6-134.5°C.

Example 6

1-(3-Methylphenyl)-5-trifluoromethyl-2-(1H)pyridone

Put 150mL of dry redistilled DMF, 21.8g of 3-methyl iodobenzene, 27.7g of 5-trifluoromethylpyridone, 15.2g of anhydrous potassium carbonate and 0.64g of copper powder into a dry and clean 250mL three-necked bottle, and stir the reaction at 120°C. TLC (ethyl acetate:petroleum ether=4:1) followed the reaction. DMF was recovered under reduced pressure at 120°C to dryness, 150 mL of toluene was refluxed for 20 min, filtered while hot, the filtrate was waved to dryness, separated by silica gel column chromatography, and eluted with ethyl acetate:petroleum ether=4:1 to obtain 1.6 g of yellow solid, total Yield 3.7%, m.p.65.7～67.2°C.

Example 7

1-(2-Formylmethylphenyl)-5-trifluoromethyl-2-(1H)pyridone

Dry and clean 250mL three-necked bottle is put into 100mL dry redistilled DMF, 13.7g 2-iodomethyl benzoate, 13.8g 5-trifluoromethylpyridone, 8.3g anhydrous potassium carbonate and 0.64 gram copper powder, the same as in the following examples 6. Obtained 0.8 g of white crystals, with a total yield of 5.4%, m.p.178.0-179.7°C.

Example 8

In the present invention, taking the following compound (coded by AKF010W) as an example, the anti-fibrosis activity of the compound provided by the present invention was tested.

Materials and methods:

1. Reagents:

1.1 Main Reagents Mouse kidney fibroblasts (NIH3T3) were provided by Tumor Research Institute of Xiangya School of Medicine, Central South University, thiazolyl blue (MTT) was a product of SIGMA, dimethyl sulfoxide (DMSO) was a product of SIGMA, and DMEM medium (High sugar type) is a product of SIGMA company, newborn bovine serum is a product of Sijiqing company, pancreatin is a product of SIGMA company, pirfenidone (PFD) is provided by the School of Pharmacy of Central South University, flufenidone (AKF-PD) is provided by this Applicant Synthesis.

1.2 Main equipment: ultra-clean bench, CO2 incubator, microplate reader, 0.22um filter, 96-well plate

2. Method: resuscitate NIH3T3, inoculate in 25cm ² culture flask and culture in 37°C, 5% CO2 box, replace the medium every 2-3 days, after the cells are congested, digest with 0.25% trypsin, and passage. Cells from passage 2-3 were used for experiments. Cells in the logarithmic growth phase were seeded in a 96-well plate, and 200ul of cell suspension was added to each well at a seeding density of 6×10 ⁴ /ml. Continue culturing in a 37°C, 5% CO2 incubator until the cells adhered to the wall Abandon the supernatant, add different concentrations of AKF-PD, PFD, AKF010 (100, 200, 400, 800, 1600ug/ml) respectively, the control group only adds DMEM medium containing 10% calf serum (200ul per hole), Set up 6 duplicate wells for each concentration, culture in a 37°C, 5% CO2 incubator, culture for 24, 48, and 72 hours respectively, add MTT 20ull (5mg/ml) to each well, put it in the incubator for 4 hours, and take it out for culture plate, discard the supernatant, add 150ul of DMSO to each well, measure the optical density value (A value) of each well at 490nm with a microplate reader, and the absorbance is directly proportional to the cell viability.

The results are shown in Table 1:

in conclusion:

Both AKF-PD and PFD can inhibit the proliferation of NIH3T3 cells, and the 48h time point has the best comparability, and the onset concentration and effect strength of AKF-PD are better than PFD.

Drug No. AKF010 has the effect of inhibiting the proliferation of NIH3T3 cells. Compared with AKF-PD and PFD (the second result), the cell inhibition rate and its effect can be ranked as follows: 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.