CN102786467A - N-substitutional aryl pyridine ketone compound as well as preparation method and application of N-substitutional aryl pyridine ketone compound - Google Patents
N-substitutional aryl pyridine ketone compound as well as preparation method and application of N-substitutional aryl pyridine ketone compound Download PDFInfo
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Abstract
The invention discloses an N-substitutional aryl pyridine ketone compound with a structure shown by a formula I and pharmaceutically acceptable salt of the N-substitutional aryl pyridine ketone compound. The invention further discloses a preparation method of the N-substitutional aryl pyridine ketone compound, which is characterized in that pirfenidone as anti-fibrotic medicine is used as a pilot compound, on the basis of maintaining a pyridone mother nucleus, different amine methylene ether structures are introduced onto the fourth bit of N-substitutional aryl, and a series of N-(4-amine methylene ether) aryl pyridone is obtained. The method has the advantages that the raw material source is wide, the preparation is easy, the operation of the method is simple, the condition is mild, the control is easy, the cost is low, the method is suitable for industrial production, and the like. The invention also discloses the N-substitutional aryl pyridine ketone compound and application of the pharmaceutically acceptable salt of the N-substitutional aryl pyridine ketone compound to the treatment of idiopathic lung fibrosis diseases, the novel compound has a better inhibition effect on human embryonic lung fibroblast, and better lung fibrosis resistance application prospects are realized.
Description
Technical field
The present invention relates to a kind of verivate of pyridone, be specifically related to a kind of N-substituted aryl pyridinone compounds, pharmacy acceptable salt and preparation method and application.
Background technology
Fibrotic disease is one type of serious harm human life and healthy important diseases, like pulmonary fibrosis, renal fibrosis, hepatic fibrosis, myocardial fibrosis etc.Along with global industriallization and people live, the change of diet style, the sickness rate of fibrotic disease significantly increases.
Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis; IPF); Claim cryptogenic fibrosing alveolitis (cryptogenic fibrosing alveolitis again; CFA), for agnogenio, be confined to lung, be the fiber voltinism interstitial lung disease of the chronic progressive external development of pathological characters with the coventional type interstitial pneumonia.IPF invades alveolus wall, alveolar space and then can develop into diffuse interstitial pulmonary fibrosis, finally can cause breathing decay and death.Relevant statistics shows that the intermediate value survival time of idiopathic pulmonary fibrosis patient after disease is examined out be 2-5 only, and 5 annual survival rates have only 20%.This disease prognosis mala still lacks the efficacious therapy method at present, belongs to one of listed difficult disease of WHO.
Along with development of social industrialization, IPF has the trend of obvious rising in recent years, and this area presses for exploitation effectively new compound and the medicine of treatment IPF.The medicine that can be used for fibrotic disease treatment at present seldom so far, has found that pyridine compounds is one type of effective fibrosis compound, and wherein, pirfenidone is a representative compound wherein.
Pirfenidone (Pirfenidone) is a kind of fibrosis new drug, for IPF provides new treat-ment.Pirfenidone is the micromolecular compound of finding the seventies in 20th century, and its chemical name is 5-methyl isophthalic acid-phenyl-2 (1H)-pyridone.The initial pirfenidone of discovering has certain anti-inflammatory, analgesic activity.Afterwards, the investigator finds that pirfenidone has restraining effect for the fibrosis of multiple tissues such as the heart, lung, kidney, liver, and increasing experimental result has confirmed the significant curative effect of pirfenidone aspect fibrosis.Pirfenidone is is at first researched and developed by U.S. Marnac company, after give American I nterMune company with global development power permission.In December, 2008, pirfenidone tablets (trade(brand)name Pirespa) authorizes the wild adopted company of Japanese salt at first to go on the market in Japan by InterMune company.In October, 2010, the imitated pirfenidone tablets (trade(brand)name Pirfenex) of selling of India Cipla company.In March, 2011, EU Committee has ratified the pirfenidone tablets (trade(brand)name Esbriet) of InterMune company exploitation, is used for the mild to moderate IPF patient of treatment adult.Pirfenidone is first idiopathic pulmonary fibrosis medicine of getting permission clinical application so far in European Union.
But pirfenidone has more spinoff clinically as a kind of oral medicine, comprises gastrointestinal upset (like vomiting, maldigestion, diarrhoea, apocleisis), weak and photoallergic dermatitis etc.Research shows: above these spinoffs are relevant with the high dosage of pirfenidone.Pharmacokinetic is found its plasma half-life short (healthy volunteer is oral, plasma half-life 2-2.5h).In order to keep effective plasma concns in the pirfenidone body, high dosage has just become essential treatment scheme with the high frequency medication.Present stage, people can only be through reducing dosage or stopping to treat the spinoff that alleviates pirfenidone.
Therefore, be necessary pirfenidone is further optimized, the pulmonary fibrosis resistant medicine of novel high-efficiency low-toxicity is provided.
Summary of the invention
In prior art; Many spinoffs such as the gastrointestinal upset that idiopathic pulmonary fibrosis disease therapeuticing medicine high dosage causes, weak and photoallergic dermatitis, the present invention provide a kind of pulmonary fibrosis resistant compound N-substituted aryl pyridone and pharmacy acceptable salt thereof of efficient, low toxicity.
A kind of N-substituted aryl pyridinone compounds has suc as formula structure shown in the I:
Wherein, R
1, R
2Be independently selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl, C
1-C
10Haloalkyl, cyanic acid, halogen or hydroxyl; R
3Be selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group, hydroxyl or sulfydryl; X
3Be Y (CH
2)
nR
4, wherein Y is O or S, n is 1-10; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from the straight or branched alkane that contains 1-3 carbon atom, or R
5, R
6With R
4In N constitute five yuan, hexa-atomic or seven-membered ring, described five yuan, hexa-atomic or seven-membered ring are oxazole, pyrroles, imidazoles, pyrazoles, piperidines, piperazine, N-METHYL PIPERAZINE, morpholine or high piperidines.
Compound with structure shown in the formula I has good in-vitro to suppress proliferation function to HELF HFL-I, has significant fibrosis effect.
As preferably, described R
1Be H, F, Cl, cyanic acid or hydroxyl; R
2Be methyl, ethyl, sec.-propyl, trifluoromethyl, difluoromethyl, vinyl or cyanic acid; R
3Be H, vinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, hydroxyl or sulfydryl; X
3Be Y (CH
2)
nR
4, wherein Y is O or S, n is 1-6; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from methyl, ethyl, propyl group, sec.-propyl, or R
5, R
6With R
4In N constitute pyrroles, imidazoles, piperidines, N-METHYL PIPERAZINE, morpholine or high piperidines.
Further preferred, described N-substituted aryl pyridinone compounds is selected from:
1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(2-diethylin-oxyethyl group) phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
1-[4-(2-U-4527-1-base-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-phenyl }-1H-pyridin-2-ones,
1-[4-(3-dimethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(3-diethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-piperidines-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-morpholine-4-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
1-[4-(4-dimethylin-butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(4-diethylin-butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-tetramethyleneimine-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-piperidines-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[4-(4-methyl-piperazine-1-yl)-butoxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-morpholine-4-base-butoxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(5-dimethylin-pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(5-diethylin-pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-tetramethyleneimine-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[5-(4-methyl-piperazine-1-yl)-pentyloxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-morpholine-4-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(6-dimethylin-hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(6-diethylin-hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-tetramethyleneimine-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[6-(4-methyl-piperazine-1-yl)-hexyloxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-morpholine-4-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(2-diethylin-oxyethyl group) phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-phenyl }-1H-pyridin-2-ones,
1-[4-(3-dimethylin-propoxy-)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(3-diethylin-propoxy-)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-piperidines-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-morpholine-4-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
1-[4-(4-dimethylin-butoxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(4-diethylin-butoxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-tetramethyleneimine-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-piperidines-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[4-(4-methyl-piperazine-1-yl)-butoxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-morpholine-4-base-butoxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(5-dimethylin-pentyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(5-diethylin-pentyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-tetramethyleneimine-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[5-(4-methyl-piperazine-1-yl)-pentyloxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-morpholine-4-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(6-dimethylin-hexyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(6-diethylin-hexyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-tetramethyleneimine-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[6-(4-methyl-piperazine-1-yl)-hexyloxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-morpholine-4-base-hexyloxy)-phenyl]-1H-pyridin-2-ones.
The present invention also provides a kind of preparation method of described N-substituted aryl pyridinone compounds, has the starting material wide material sources, advantages such as cost is low, method is simple to operate, mild condition.
A kind of preparation method of N-substituted aryl pyridinone compounds; With the pyriphenanthrenone as anti-fibrosis medicine is lead compound; Keeping on the pyridone parent nucleus basis; Through on 4 of N-substituted aryl, introducing the methylene ether structure, further obtain a series of N-(4-amine methylene ether) aryl pyridinones again with the secondary amine reaction with the nucleophilic substitution reaction of halohydrocarbon.Specifically comprise the steps:
(1) will suc as formula the compound of II with as the compound of formula III in organic solvent, acid binding agent exists to react down and obtains the compound suc as formula IV, temperature of reaction is room temperature～backflow, 6～12 hours reaction times;
(2) suc as formula the compound of IV with suc as formula the secondary amine of V in organic solvent, catalyzer exists down with acid binding agent, reacts to obtain the target compound suc as formula I, temperature of reaction is room temperature～70 ℃, 3～14 days reaction times;
Wherein, R
1, R
2Be independently selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl, C
1-C
10Haloalkyl, cyanic acid, halogen or hydroxyl; R
3Be selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group, hydroxyl or sulfydryl; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from the straight or branched alkane that contains 1-3 carbon atom, or R
5, R
6With R
4In N constitute five yuan, hexa-atomic or seven-membered ring, described five yuan, hexa-atomic or seven-membered ring are oxazole, pyrroles, imidazoles, pyrazoles, piperidines, piperazine, N-METHYL PIPERAZINE, morpholine or high piperidines, n is 1-10, Y is O or S.
Compound III, V are the commercial goods, and compound I I can be that 200810201706.9 Chinese invention patent disclosed method makes according to application number.
Organic solvent in the said step (1) is acetone, butanone or ethanol; Acid binding agent is salt of wormwood, yellow soda ash or Potassium monofluoride.
As preferably, the organic solvent in the said step (1) is an acetone; Acid binding agent is a salt of wormwood.
Organic solvent in the said step (2) is acetone or N, dinethylformamide; Acid binding agent is salt of wormwood or yellow soda ash; Catalyzer is potassiumiodide, Soiodin.
As preferably, the solvent in the said step (2) is N, dinethylformamide; Acid binding agent is a salt of wormwood; Catalyzer is a Soiodin.
The various N-substituted aryl pyridinone compounds that reaction is made are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol, the ETHYLE ACETATE, and dropping inorganic acid or organic acid solution are processed pharmacy acceptable salt.
Specifically be that various N-substituted aryl pyridinone compounds are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol or the ETHYLE ACETATE, the dripping hydrochloric acid ethyl acetate solution is processed hydrochloride under ice-water bath; Or various N-substituted aryl pyridinone compounds are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol or the ETHYLE ACETATE, drip and wait a mole methylsulfonic acid, its mesylate; Or various N-substituted aryl pyridinone compounds are dissolved in a kind of in ether, acetone, methyl alcohol, ethanol or the ETHYLE ACETATE, drip concentrated sulfuric acid solution down in ice-water bath and process vitriol, or the like.
The invention also discloses the application in preparation treatment idiopathic pulmonary fibrosis disease medicament of described N-substituted aryl pyridinone compounds and pharmacy acceptable salt thereof.Preliminary pharmacological testing finds that these compounds great majority have good in-vitro to suppress proliferation function to HELF HFL-I, suppress proliferation function and are better than pirfenidone greatly.
The present invention is to be lead compound with the pyriphenanthrenone as anti-fibrosis medicine, is keeping on the pyridone parent nucleus basis, on 4 of N-substituted aryl, introduces different amine methylene ether structures and obtains a series of N-(4-amine methylene ether) aryl pyridinones.Have the starting material wide material sources, be easy to preparation, simple to operate, the mild condition of method, cost is low, is suitable for advantages such as suitability for industrialized production.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1,1-(4-hydroxyl-phenyl)-5-methyl isophthalic acid H-pyridin-2-ones (IIa): according to application number is that 200810201706.9 Chinese invention patent disclosed method makes.m.p.167-169℃。
1HNMR(δ，CDCl
3)：7.34-7.37(m，1H)，7.14(s，1H)，6.97-7.00(d，2H)，6.68(s，1H)，6.62-6.66(m，2H)，2.12(s，3H)。
Embodiment 2,1-[4-(3-chlorine propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVb):
Compound I Ia 5.4g (26.9mmol), salt of wormwood 7.3g (53.8mmol) are placed the 250mL three-necked bottle, add acetone 200mL, refluxing and stirring 30min; Add 1-bromo-3-chloro-propane (IIIb) 6mL (60.8mmol), back flow reaction 8 hours is filtered; Filter cake is with washing with acetone 3 times; Merge diafiltration liquid, be concentrated into part, add the sherwood oil crystallization and spend the night.Filter, washing, drying gets incarnadine solid IVb, yield 93%.m.p.107-108℃。
1HNMR(δ，CDCl
3)：7.08-7.29(m，4H)，6.99(d，2H)，6.60(d，1H)，4.14(t，2H)，3.75(t，2H)，2.25(m，2H)，2.09(s，3H)。
Embodiment 3,1-[4-(4-chlorine butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVc):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-4-chloro-butane (IIIc).Obtain light yellow cured article IVc, yield 97%.m.p.57-58℃。
1HNMR(δ，CDCl
3)：7.11-7.30(m，4H)，6.99(d，2H)，6.62(d，1H)，4.04(t，2H)，3.64(t，2H)，2.11(s，3H)，1.99(m，4H)。
Embodiment 4,1-[4-(2-chloroethoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVa):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-2-chloro-ethane (IIIa).Obtain light yellow cured article IVa, yield 82%.m.p.118-120℃。
1HNMR(δ，CDCl
3)：7.10-7.31(m，4H)，6.99-7.02(d，2H)，6.59-6.62(d，1H)，4.27(t，2H)，3.84(t，2H)，2.11(s，3H)。
Embodiment 5,1-[4-(2-chlorine pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVd):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-5-chloro-pentane (IIId).Obtain white solid IVd, yield 54%.m.p.87-88℃。
1HNMR(δ，CDCl
3)：7.10-7.29(m，4H)，6.98(d，2H)，6.62(d，1H，)，4.01(t，2H)，3.59(t，2H)，2.10(s，3H)，1.62-1.89(m，6H)。
Embodiment 6,1-[4-(2-chlorine hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (IVe):
Operating process replaces 1-bromo-3-chloro-propane (IIIb) referring to embodiment 2 with 1-bromo-6-chloro-hexane (IIIe).Obtain white solid IVe, yield 90%.m.p.67-68℃。
1HNMR(δ，CDCl
3)：7.10-7.29(m，4H)，6.98(d，2H)，6.62(d，1H，)，4.00(t，2H)，3.57(t，2H)，2.10(s，3H)，1.52-1.84(m，10H)。
Embodiment 7,1-[4-(3-dimethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (1b)
With compound IV b 500mg (1.8mmol), N, TMSDMA N dimethylamine hydrochloride 323mg (3.96mmol), salt of wormwood 995mg (7.2mmol), sodium iodide 90mg (0.6mmol) place the 50mL three-necked bottle, add DMF (25mL) under the N2 atmosphere, 70 ℃ of reactions of oil bath 3 days.Be cooled to room temperature, add 50mL water, stir 30min, ethyl acetate extraction 3 times; Merge organic phase, wash 2 times, anhydrous sodium sulfate drying filters; Be concentrated into small volume,, obtain faint yellow solid powder 1b, yield 28% with eluent (ETHYLE ACETATE+0.3% triethylamine) column chromatography.m.p.46-47℃。
1HNMR(δ，CDCl
3)：7.08-7.27(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.04(t，2H)，2.45(t，2H)，2.56(s，6H)，2.09(s，3H)，1.97(m，2H)。
Embodiment 8,1-[4-(3-diethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (2b)
Operating process is used N referring to embodiment 7, and TMSDEA N diethylamine replaces N, TMSDMA N dimethylamine hydrochloride.Obtain yellow oil 2b, yield 51%.
1HNMR(δ，CDCl
3)：7.08-7.27(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.03(t，2H)，2.52-2.63(m，6H)，2.09(s，3H)，1.94(m，2H)，1.04(t，6H)。
Embodiment 9,5-methyl isophthalic acid-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones (3b)
Operating process replaces N referring to embodiment 7 with Pyrrolidine, the TMSDMA N dimethylamine hydrochloride.Obtain white solid 3b, yield 46%.m.p.125-126℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.05(t，2H，)，2.62(t，2H)，2.52(s，4H)，2.09(s，3H)，2.01(m，2H)，1.79(s，4H)。
Embodiment 10,5-methyl isophthalic acid-[4-(3-piperidines-1-base-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (4b)
Operating process replaces N referring to embodiment 7 with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain white-yellowish solid 4b, yield 49%.m.p.97-98℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.96-6.98(d，2H)，6.57-6.60(d，1H)，4.02(t，2H)，2.48(t，2H)，2.41(s，4H)，2.08(s，3H)，1.97(m，2H)，1.59(m，4H)，1.44(d，2H)。
Embodiment 11,5-methyl isophthalic acid-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones (5b)
Operating process replaces N, TMSDMA N dimethylamine hydrochloride referring to embodiment 7 with the 4-N-METHYL PIPERAZINE.Obtain white-yellowish solid 5b, yield 33%.m.p.94-95℃。
1HNMR(δ，CDCl
3)：7.08-7.28(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，1H)，4.04(t，2H)，2.51-2.55(m，10H)，2.30(s，3H)，2.09(s，3H)，1.98(m，2H)。
Embodiment 12,5-methyl isophthalic acid-[4-(3-morpholine-4-base-propoxy-)-phenyl-1 h-pyridin-2-ketone (6b)
Operating process is replaced N, TMSDMA N dimethylamine hydrochloride referring to embodiment 7 with morpholino.Obtain pale yellow solid 6b, yield 77%.m.p.87-88℃。
1HNMR(δ，CDCl
3)：7.08-7.28(m，4H)，6.96-6.98(d，2H)，6.58-6.60(d，2H)，4.05(t，2H)，3.72(t，4H)，2.52(t，2H)，2.47(s，4H)，2.09(s，3H)，1.98(m，2H)。
Embodiment 13,1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (1a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, obtains yellow solid 1a, yield 29%, m.p.90-92 ℃.
1HNMR(δ，CDCl
3)：7.09-7.28(m，4H)，6.97-6.99(d，2H)，6.58-6.61(d，1H)，4.10(t，2H)，2.75(t，2H)，2.35(s，6H)，2.09(s，3H)。
Embodiment 14,1-[4-(2-diethylin-oxyethyl group) phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (2a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, uses N, and TMSDEA N diethylamine replaces N, and the TMSDMA N dimethylamine hydrochloride obtains yellow oil 2a, yield 19%.
1HNMR(δ，CDCl
3)：7.09-7.28(m，4H)，6.97-6.99(d，2H)，6.58-6.61(d，1H)，4.08(t，2H)，2.90(t，2H)，2.68(q，4H)，2.10(s，3H)，1.08(t，6H)。
Embodiment 15,5-methyl isophthalic acid-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones (3a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N with Pyrrolidine, and the TMSDMA N dimethylamine hydrochloride obtains yellow solid 3a, yield 43%.m.p.106-108℃。
1HNMR(δ，CDCl
3)：7.07-7.26(m，4H)，6.96-6.98(d，2H)，6.56-6.58(d，1H)，4.12(t，2H)，2.86(t，2H)，2.59-2.63(m，4H)，2.07(s，3H)，1.18-1.78(m，4H)。
Embodiment 16,5-methyl isophthalic acid-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones (4a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain light yellow solid 4a, yield 74%.m.p.107-108℃。
1HNMR(δ，CDCl
3)：7.08-7.21(m，4H)，6.96-6.99(d，2H)，6.57-6.59(d，1H)，4.13(t，2H)，2.78(t，2H)，2.50(s，4H)，2.09(s，3H)，1.58-1.63(m，4H)，1.46(d，2H)。
Embodiment 17,1-[4-(2-U-4527-1-base-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones (5a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N with U-4527, the TMSDMA N dimethylamine hydrochloride.Obtain yellow oil 5a, yield 77%.
1HNMR(δ，CDCl
3)：7.09-7.21(m，4H)，6.96-6.99(d，2H)，6.58-6.60(d，1H)，4.09(t，2H)，2.95(t，2H)，2.79(t，4H)，2.09(s，3H)，1.60-1.66(m，8H)。
Embodiment 18,5-methyl isophthalic acid-[4-(2-morpholine-4-base-oxyethyl group)-phenyl-1 h-pyridin-2-ketone (6a)
Operating process replaces compound IV b referring to embodiment 7 with compound IV a, replaces N, TMSDMA N dimethylamine hydrochloride with morpholino.Obtain pale yellow crystals 6a, yield 15%.m.p.118-119℃。
1HNMR(δ，CDCl
3)：7.08-7.28(m，4H)，6.97-6.99(d，2H，6-H)，6.58-6.60(d，1H)，4.14(t，2H)，3.73-3.75(m，4H)，2.82(t，2H)，2.58(s，4H)，2.09(s，3H)。
Embodiment 19,5-methyl isophthalic acid-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones (4d)
Operating process replaces compound IV b referring to embodiment 7 with compound IV d, replaces N with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain white solid 4d, yield 91%.m.p.92-93℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.93-6.96(d，2H)，6.57-6.59(d，1H)，3.97(t，2H)，2.29-2.37(m，6H)，2.08(s，3H)，1.81(m，2H)，1.43-1.59(m，10H)。
Embodiment 20,5-methyl isophthalic acid-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones (4e)
Operating process replaces compound IV b referring to embodiment 7 with compound IV e, replaces N with piperidines, the TMSDMA N dimethylamine hydrochloride.Obtain white solid 4e, yield 64%.m.p.67-68℃。
1HNMR(δ，CDCl
3)：7.08-7.26(m，4H)，6.94-6.96(d，2H)，6.57-6.60(d，1H)，3.97(t，2H)，2.29-2.37(m，6H)，2.08(s，3H)，1.79(m，2H)，1.33-1.61(m，12H)。
The hydrochloride of embodiment 21, compound 4b
Get compound 4b 1.0g, be dissolved in 10mL ETHYLE ACETATE, be cooled to 0 ℃ in the ice-water bath, drip saturated HCl ethyl acetate solution, centrifugal, get white solid, yield 70%.
Embodiment 22, pulmonary fibrosis resistant biological activity test method:
HELF's isolated culture: choose HELF HFL-I, contain conventional cultivation of α-MEM substratum of 10%FBS.
Mtt assay is measured the vitro inhibition effect of N-substituted aryl pyridinone compounds to HELF HFL-I:
The cell strain in vegetative period of taking the logarithm, the adjustment concentration of cell suspension is 1 * 10
5/ mL, every hole 100 μ L cell suspension inoculations in 96 porocyte culture plates, the inoculation 24h after administration (100 μ L/ hole); Establish blank group, cell control group and 5 concentration respectively and tried drug group (1.67,3.33,5.00; 6.67,10.00 μ mol/mL), each concentration is established 3 multiple holes.After after the dosing 20 hours, every hole adds 100 μ LMTT (1mg/mL is with α-MEM nutrient solution dissolving); Cultivate 4h for 37 ℃; Discard and add 150 μ L acidifying Virahols (containing 0.04mol/L HCl) in each hole behind the liquid, lucifuge placement 30min, ELIASA mensuration 570nm place absorbancy; Calculating receives the proliferation inhibition rate of reagent thing to the HFL-I cell, and with
Software (GraphPad
TMSoftware Inc) computer program match inhibition curve calculation is tried the half-inhibition concentration (IC of thing to HELF HFL-I propagation (24h)
50).The gained result sees table 1:
Table 1 compound is to the IC of HELF HFL-I
50Value
From table 1, can find out: (1) most of new compounds have certain restraining effect to HELF HFL-I.(2) 9 new compound IC
50Less than the positive control pirfenidone.(3) 4b has higher cell proliferation inhibition rate, IC
50Value is little 8 times than pirfenidone.(4) generally speaking, such new compound has pulmonary fibrosis resistant application prospect preferably, thereby has good commercial value.
Need not further to set forth in detail, believe and adopt the disclosed content in front, those skilled in the art can use the present invention to greatest extent.Therefore, the embodiment of front is interpreted as only illustrating, but not limits scope of the present invention by any way.
Claims (10)
1. the N-substituted aryl pyridinone compounds that has formula I structure:
Wherein, R
1, R
2Be independently selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl, C
1-C
10Haloalkyl, cyanic acid, halogen or hydroxyl; R
3Be selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group, hydroxyl or sulfydryl; X
3Be Y (CH
2)
nR
4, wherein Y is O or S, n is 1-10; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from the straight or branched alkane that contains 1-3 carbon atom, or R
5, R
6With R
4In N constitute five yuan, hexa-atomic or seven-membered ring, described five yuan, hexa-atomic or seven-membered ring are oxazole, pyrroles, imidazoles, pyrazoles, piperidines, piperazine, N-METHYL PIPERAZINE, morpholine or high piperidines.
2. N-substituted aryl pyridinone compounds as claimed in claim 1 is characterized in that described R
1Be H, F, Cl, cyanic acid or hydroxyl; R
2Be methyl, ethyl, sec.-propyl, trifluoromethyl, difluoromethyl, vinyl or cyanic acid; R
3Be H, vinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, hydroxyl or sulfydryl; X
3Be Y (CH
2)
nR
4, wherein Y is O or S, n is 1-6; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from methyl, ethyl, propyl group, sec.-propyl, or R
5, R
6With R
4In N constitute pyrroles, imidazoles, piperidines, N-METHYL PIPERAZINE, morpholine or high piperidines.
3. N-substituted aryl pyridinone compounds as claimed in claim 1 is characterized in that, described N-substituted aryl pyridinone compounds is selected from:
1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(2-diethylin-oxyethyl group) phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
1-[4-(2-U-4527-1-base-oxyethyl group)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-phenyl }-1H-pyridin-2-ones,
1-[4-(3-dimethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(3-diethylin-propoxy-)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-piperidines-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(3-morpholine-4-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
1-[4-(4-dimethylin-butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(4-diethylin-butoxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-tetramethyleneimine-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-piperidines-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[4-(4-methyl-piperazine-1-yl)-butoxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(4-morpholine-4-base-butoxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(5-dimethylin-pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(5-diethylin-pentyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-tetramethyleneimine-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[5-(4-methyl-piperazine-1-yl)-pentyloxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(5-morpholine-4-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(6-dimethylin-hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
1-[4-(6-diethylin-hexyloxy)-phenyl]-5-methyl isophthalic acid H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-tetramethyleneimine-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-methyl isophthalic acid-{ 4-[6-(4-methyl-piperazine-1-yl)-hexyloxy]-phenyl }-1H-pyridin-2-ones,
5-methyl isophthalic acid-[4-(6-morpholine-4-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(2-dimethylin-oxyethyl group)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(2-diethylin-oxyethyl group) phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-phenyl }-1H-pyridin-2-ones,
1-[4-(3-dimethylin-propoxy-)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(3-diethylin-propoxy-)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-tetramethyleneimine-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-piperidines-1-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[3-(4-methyl-piperazine-1-yl)-propoxy-]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(3-morpholine-4-base-propoxy-)-phenyl]-1H-pyridin-2-ones,
1-[4-(4-dimethylin-butoxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(4-diethylin-butoxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-tetramethyleneimine-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-piperidines-1-base-butoxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[4-(4-methyl-piperazine-1-yl)-butoxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(4-morpholine-4-base-butoxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(5-dimethylin-pentyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(5-diethylin-pentyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-tetramethyleneimine-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-piperidines-1-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[5-(4-methyl-piperazine-1-yl)-pentyloxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(5-morpholine-4-base-pentyloxy)-phenyl]-1H-pyridin-2-ones,
1-[4-(6-dimethylin-hexyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
1-[4-(6-diethylin-hexyloxy)-phenyl]-5-Trifluoromethyl-1 H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-tetramethyleneimine-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-piperidines-1-base-hexyloxy)-phenyl]-1H-pyridin-2-ones,
5-Trifluoromethyl-1-{ 4-[6-(4-methyl-piperazine-1-yl)-hexyloxy]-phenyl }-1H-pyridin-2-ones,
5-Trifluoromethyl-1-[4-(6-morpholine-4-base-hexyloxy)-phenyl]-1H-pyridin-2-ones.
Like each described N-substituted aryl pyridinone compounds of claim 1～3 at pharmacy acceptable salt, it is characterized in that: described pharmacy acceptable salt is described N-substituted aryl pyridinone compounds and mineral acid, organic acid reaction salify.
5. N-substituted aryl pyridinone compounds as claimed in claim 4 is characterized in that at pharmacy acceptable salt: described pharmacy acceptable salt is hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, oxalate, tartrate, mesylate, tosilate, fumarate, taurate, Citrate trianion or SUMATRIPTAN SUCCINATE.
6. like the preparation method of each described N-substituted aryl pyridinone compounds of claim 1～3, it is characterized in that, may further comprise the steps:
(1) suc as formula the compound of II with as the compound of formula III in organic solvent, acid binding agent exists to react down and obtains the compound suc as formula IV, temperature of reaction is room temperature～backflow, 6～12 hours reaction times;
(2) suc as formula the compound of IV with suc as formula the secondary amine of V in organic solvent, catalyzer exists to react down with acid binding agent and obtains the target compound suc as formula I, temperature of reaction is room temperature～70 ℃, 3～14 days reaction times;
Wherein, R
1, R
2Be independently selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl, C
1-C
10Haloalkyl, cyanic acid, halogen or hydroxyl; R
3Be selected from H, C
1-C
10Alkyl, C
1-C
10Thiazolinyl or amino; X
1, X
2, X
4And X
5Be independently selected from H, halogen, C
1-C
10Alkyl, C
1-C
10Alkoxyl group, hydroxyl or sulfydryl; Described R
4Be open chain or cyclic tertiary amine structure NR
5R
6, R wherein
5, R
6Be independently selected from the straight or branched alkane that contains 1-3 carbon atom, or R
5, R
6With R
4In N constitute five yuan, hexa-atomic or seven-membered ring, described five yuan, hexa-atomic or seven-membered ring are oxazole, pyrroles, imidazoles, pyrazoles, piperidines, piperazine, N-METHYL PIPERAZINE, morpholine or high piperidines, n is 1-10, Y is O or S.
7. the preparation method of N-substituted aryl pyridinone compounds as claimed in claim 6; It is characterized in that; Used organic solvent selects for use in acetone, butanone, the ethanol any or mixture, acid binding agent to select in salt of wormwood, yellow soda ash, the Potassium monofluoride any or mixture for use in the said step (1).
8. the preparation method of N-substituted aryl pyridinone compounds as claimed in claim 6; It is characterized in that; Solvent is selected acetone, N for use in the said step (2); In the dinethylformamide any, acid binding agent selects for use in salt of wormwood, the yellow soda ash any, catalyzer to select in potassiumiodide, the Soiodin any for use.
9. like the application of each described N-substituted aryl pyridinone compounds of claim 1～3 in preparation treatment idiopathic pulmonary fibrosis disease medicament.
10. treating the application in the idiopathic pulmonary fibrosis disease medicament like claim 4 or 5 described N-substituted aryl pyridinone compounds at pharmacy acceptable salt.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130884A (en) * | 2015-07-30 | 2015-12-09 | 四川大学 | 5-methyl-2(1H)pyridone derivatives, preparation method and applications thereof |
| CN105175326A (en) * | 2015-08-19 | 2015-12-23 | 四川国康药业有限公司 | 5-methyl-2(1H)pyridone derivatives, preparation method and application |
| CN105998016A (en) * | 2016-06-14 | 2016-10-12 | 四川大学 | Application of pirfenidone derivative to pharmacy |
| WO2017177974A1 (en) * | 2016-04-14 | 2017-10-19 | 南京明德新药研发股份有限公司 | Pyridone derivative comprising heteroatomic ring butane substituent, for treating fibrosis and inflammatory diseases |
| CN113476448A (en) * | 2021-07-09 | 2021-10-08 | 中南大学 | Application of meflonizone in preparation of medicine for treating acute lung injury |
| WO2024012531A1 (en) * | 2022-07-14 | 2024-01-18 | 广州嘉越医药科技有限公司 | Use of pyridone derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1930126A (en) * | 2004-03-05 | 2007-03-14 | 万有制药株式会社 | Pyridone derivative |
| WO2010135972A1 (en) * | 2009-05-25 | 2010-12-02 | 中南大学 | Preparation methods and uses of 1-(substituted aryl)-5-trifluoromethyl-2-(1h)-pyridone compounds and their salts |
-
2012
- 2012-08-15 CN CN2012102896132A patent/CN102786467A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1930126A (en) * | 2004-03-05 | 2007-03-14 | 万有制药株式会社 | Pyridone derivative |
| WO2010135972A1 (en) * | 2009-05-25 | 2010-12-02 | 中南大学 | Preparation methods and uses of 1-(substituted aryl)-5-trifluoromethyl-2-(1h)-pyridone compounds and their salts |
Non-Patent Citations (1)
| Title |
|---|
| 欧春艳等: "生物电子等排及其在新药设计中的应用综述", 《湛江海洋大学学报》, vol. 24, no. 4, 31 August 2004 (2004-08-31) * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105175326A (en) * | 2015-08-19 | 2015-12-23 | 四川国康药业有限公司 | 5-methyl-2(1H)pyridone derivatives, preparation method and application |
| CN105175326B (en) * | 2015-08-19 | 2018-02-27 | 四川国康药业有限公司 | 5 methyl 2 (1H) Pyridione derivatives and its production and use |
| WO2017177974A1 (en) * | 2016-04-14 | 2017-10-19 | 南京明德新药研发股份有限公司 | Pyridone derivative comprising heteroatomic ring butane substituent, for treating fibrosis and inflammatory diseases |
| CN109311859A (en) * | 2016-04-14 | 2019-02-05 | 石家庄智康弘仁新药开发有限公司 | For treating the Pyridione derivatives of the substituent group of butane containing heteroatomic ring of fibrosis and inflammatory disease |
| US10604513B2 (en) | 2016-04-14 | 2020-03-31 | Shijiazhuang Sagacity New Drug Development Co., Ltd. | Pyridone derivative comprising heteroatomic ring butane substituent, for treating fibrosis and inflammatory diseases |
| RU2738844C2 (en) * | 2016-04-14 | 2020-12-17 | Гуанчжоу Джойо Фарматек Ко., Лтд | Containing a substitute, which is butane, in the heterocyclic ring a pyridone derivative for treating fibrosis and inflammatory diseases |
| CN109311859B (en) * | 2016-04-14 | 2022-01-21 | 广州嘉越医药科技有限公司 | Heteroatom cyclobutane substituent containing pyridone derivatives for the treatment of fibrotic and inflammatory diseases |
| CN105998016A (en) * | 2016-06-14 | 2016-10-12 | 四川大学 | Application of pirfenidone derivative to pharmacy |
| CN105998016B (en) * | 2016-06-14 | 2020-08-11 | 四川大学 | Application of pirfenidone derivative in pharmacy |
| CN113476448A (en) * | 2021-07-09 | 2021-10-08 | 中南大学 | Application of meflonizone in preparation of medicine for treating acute lung injury |
| WO2024012531A1 (en) * | 2022-07-14 | 2024-01-18 | 广州嘉越医药科技有限公司 | Use of pyridone derivative |
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