CN105085383A - 5-methyl-2(1H)pyridone derivatives, and preparation method and application thereof - Google Patents
5-methyl-2(1H)pyridone derivatives, and preparation method and application thereof Download PDFInfo
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- CN105085383A CN105085383A CN201510512370.8A CN201510512370A CN105085383A CN 105085383 A CN105085383 A CN 105085383A CN 201510512370 A CN201510512370 A CN 201510512370A CN 105085383 A CN105085383 A CN 105085383A
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- 0 CC(C=CC1O)=CN1c1ccc(CC=N*)cc1 Chemical compound CC(C=CC1O)=CN1c1ccc(CC=N*)cc1 0.000 description 3
- SOHMZGMHXUQHGE-UHFFFAOYSA-N Cc(cc1)cnc1O Chemical compound Cc(cc1)cnc1O SOHMZGMHXUQHGE-UHFFFAOYSA-N 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
Abstract
The invention discloses 5-methyl-2(1H)pyridone derivatives disclosed as Formula I, or crystal forms, pharmaceutically acceptable salts, hydrates, solvates or pro-drugs thereof. In the formula I, R is selected from hydroxy group, mercapto group, amino group or imino group. The invention provides the new 5-methyl-2(1H)pyridone derivatives; and the new 5-methyl-2(1H)pyridone derivatives have obvious inhibiting effects on fibroblast proliferation and fibroblast secretory fiber binding protein (Fn), and can be used for preparing drugs for treating or preventing fibrosis diseases, tumors and the like. The preparation method of the compounds disclosed as Formula I has the advantages of fewer procedures, simple steps, mild reaction conditions, low energy consumption, high efficiency, low cost, environment friendliness and the like, and is very suitable for application in industry.
Description
Technical field
The present invention relates to a kind of 5-methyl-2 (1H) Pyridione derivatives and its production and use.
Background technology
5-methyl-2 (1H) pyridone, another name: 5-picoline-2-alcohol, 2-hydroxy-5-methyl yl pyridines, No. CAS: 1003-68-5, its chemical structure, such as formula shown in A, is mainly used in the fields such as organic synthesis.
US Patent No. 3839346A discloses the pyridine compounds shown in formula B, and this compound has anti-inflammatory, antipyretic, effect such as reduction serum uric acid level, pain relieving etc.; Wherein, substituent R number be 0 or 1, R represent nitro, chlorine atom, alkyl, methoxyl group; When R is 0, compound shown in formula B is 1-phenyl-5-methyl-2-(1H) pyridone (i.e. pirfenidone).US Patent No. 4052509A also discloses pirfenidone, and it has good anti-inflammatory and analgesic activity.
Chinese patent CN1386737A discloses the anti-fibrosis pyridone medicine shown in a kind of formula C, and it is the polysubstituted phenyl of 1--5-methyl-2-(1H) pyridinone compounds; Wherein, n be 1 or 2, R be F, Cl, Br, I, saturated straight chain alkyl, oxo saturated straight chain alkyl or halo saturated straight chain alkyl.
Chinese patent CN102786467A discloses the N-substituted aryl pyridinone compounds shown in a kind of formula D, it take pirfenidone as lead compound, retain pyridone parent nucleus, 4 of N-substituted aryl are introduced different amine methylene ether structures, obtains N-(4-amine methylene ether) aryl pyridinones; Wherein, X
3for Y (CH
2)
nr
4, Y is O or S, n is 1-10; Described R
4the tertiary amine structure NR of open chain or ring-type
5r
6, R
5, R
6independently selected from the straight or branched alkane containing 1-3 carbon atom, or R
5, R
6with R
4in N form five yuan, hexa-atomic or seven-membered ring, described five yuan, hexa-atomic or seven-membered ring is oxazole, pyrroles, imidazoles, pyrazoles, piperidines, piperazine, methylpiperazine, morpholine or high piperidines.
Chinese patent CN101842355A discloses the N-aryl pyridinones replaced shown in formula E; Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10and R
11independently be selected from the group be made up of hydrogen and deuterium; R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10and R
11in at least one be deuterium; And if R
7, R
8, R
9, R
10and R
11deuterium, then R
1, R
2, R
3, R
4, R
5and R
6in at least one be deuterium.
At present, there are no the report of 5-methyl-2 shown in formula I (1H) Pyridione derivatives; Also there are no the preparation method of 5-methyl-2 shown in formula I (1H) Pyridione derivatives and the report of purposes.
Summary of the invention
The object of the present invention is to provide a kind of new 5-methyl-2 (1H) Pyridione derivatives.
5-methyl-2 (1H) Pyridione derivatives or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug shown in formula I provided by the invention:
Wherein, R is selected from hydroxyl, sulfydryl, amino, C
1~ C
6alkyl, C
1~ C
6alkoxyl group.
Further, shown in described formula I, 5-methyl-2 (1H) Pyridione derivatives is:
Another object of the present invention is to the preparation method that 5-methyl-2 (1H) Pyridione derivatives shown in above-mentioned formula I is provided.
The invention provides the preparation method of 5-methyl-2 (1H) Pyridione derivatives shown in above-mentioned formula I, the synthetic route of described preparation method is:
Wherein, R is selected from hydroxyl, sulfydryl, amino, C
1~ C
6alkyl, C
1~ C
6alkoxyl group;
Described preparation method comprises the following steps:
A, compound 1 react in alcoholic solvent with compound 2, and thin-layer chromatography monitoring reaction is complete, obtains reaction solution;
Compound 1 is 0.1:0.04 ~ 0.35 with the weight ratio of compound 2; Compound 1 is 0.1:5 ~ 10g/ml with the weightmeasurement ratio of alcoholic solvent;
B, separation and purification is carried out to step a gained reaction solution, obtain the compound shown in formula I.
Further, in step a, the synthetic route of compound 1 is:
Prepare compound 1 in accordance with the following steps:
1., get 5-methyl-2 (1H) pyridone, mineral alkali, p-bromobenzaldehyde and catalyzer, carry out back flow reaction in organic solvent, thin-layer chromatography monitoring reaction is complete, obtains reaction solution;
The weight ratio of 5-methyl-2 (1H) pyridone and mineral alkali is 0.1:0.14 ~ 0.20; The weight ratio of 5-methyl-2 (1H) pyridone and p-bromobenzaldehyde is 0.1:0.17 ~ 0.20; The weight ratio of 5-methyl-2 (1H) pyridone and catalyzer is 0.1:0.02 ~ 0.05; The weightmeasurement ratio of 5-methyl-2 (1H) pyridone and organic solvent is 0.02 ~ 0.05g/ml;
Mineral alkali be selected from salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide any one or two or more;
Catalyzer is selected from any one or two kinds in cuprous iodide, copper;
Organic solvent be selected from DMF, tetrahydrofuran (THF), pyridine any one or two or more;
2., to step 1. gained reaction solution carry out separation and purification, obtain compound 1.
Further, step 1. in, the synthetic route of 5-methyl-2 (1H) pyridone is:
Prepare 5-methyl-2 (1H) pyridone in accordance with the following steps:
I, get 2-amino-5-picoline and aqueous sulfuric acid, mixing, adds sodium nitrite in aqueous solution and reacts, and thin-layer chromatography monitoring after completion of the reaction, adds water, and return stirring reaction 15min ~ 30min, obtains reaction solution;
The weightmeasurement ratio of 2-amino-5-picoline and aqueous sulfuric acid is 1:3.2 ~ 3.6g/ml; The weightmeasurement ratio of 2-amino-5-picoline and sodium nitrite in aqueous solution is 1:3.0 ~ 3.5g/ml; The weightmeasurement ratio of 2-amino-5-picoline and water is 1:7.5 ~ 8.0g/ml;
Aqueous sulfuric acid is mixed by isopyknic water and the vitriol oil; The concentration of sodium nitrite in aqueous solution is 0.55 ~ 0.65g/ml;
Ii, separation and purification is carried out to step I gained reaction solution, obtain 5-methyl-2 (1H) pyridone.
Further, in step I i, the method for step I gained reaction solution being carried out to separation and purification is: after reaction solution cooling, add mineral alkali, regulate pH to be about 7, filter, obtain filtrate, the solvent in removing filtrate, obtain crude product, recrystallization, obtain 5-methyl-2 (1H) pyridone;
Described mineral alkali be selected from sodium carbonate, salt of wormwood, potassium hydroxide, sodium hydroxide any one or two or more.
Further, step 2. in, to the step method that 1. gained reaction solution carries out separation and purification be: reaction solution is filtered, obtains filtrate; Filtrate is extracted with ethyl acetate, and by concentrated for organic phase post, elutriant is sherwood oil: ethyl acetate=3:1, except desolventizing, dry, obtains compound 1.
Further, in step a, compound 2 is oxammonium hydrochloride; Alcoholic solvent is selected from any one or two kinds in dehydrated alcohol, methyl alcohol.
Further, in step b, the method for step a gained reaction solution being carried out to separation and purification is: in reaction solution, add rare NaOH aqueous solution, be adjusted to pH and be about 8, decompression steams solvent, add silica gel, be spin-dried for, cross post, elutriant is sherwood oil: ethyl acetate=1:2, collect elutriant, be spin-dried for, obtain compound shown in formula I a.
Present invention also offers 5-methyl-2 (1H) Pyridione derivatives or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug shown in above-mentioned formula I, prepare the purposes treated and/or prevented in the medicine of fibrotic disease, tumour.
The purposes treated and/or prevented in the medicine of fibrotic disease or tumor disease prepared by 5-methyl-2 (1H) Pyridione derivatives shown in above-mentioned formula I or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug.
Further, described fibrotic disease comprises idiopathic pulmonary fibrosis, pulmonary fibrosis, interstitial lung disease, nonspecific interstitial pneumonia, coventional type interstitial pneumonia, endomyocardial fibrosis, fibrosis of mediastinum, myelofibrosis, retroperitoneal fibrosis, Progressive symmetric erythrokeratodermia bulk fibers, kidney systemic fibrosis disease, Crohn disease, remote myocardial infarction, scleroderma/systemic sclerosis, neurofibroma, Hermansky-Pudlak syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy, hypertension associated kidney disease, focal segmental glomerulosclerosis, the fibrosis of radiation induction, leiomyoma of uterus, alcoholic liver disease, hepatic steatosis, hepatic fibrosis, liver cirrhosis, infection with hepatitis C virus, Chronic organ transplant's rejection, fibrosis of skin illness, keloid, contracture of palmar fascia is sick, Ehlers-Danlos syndrome, EBD, in oral submucosa fibrosis or Fibroproliferative illness any one or multiple.
The implication of above-mentioned fibrotic disease, with reference to Chinese patent CN104093408A, or according to disclosure and context, provides the implication that those skilled in the art can give them.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition be with 5-methyl-2 (1H) Pyridione derivatives shown in above-mentioned formula I or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug for activeconstituents, add the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
The invention provides a kind of new 5-methyl-2 (1H) Pyridione derivatives, to fibroblast proliferation and fibroblasts to secrete Fiberonectin (Fn), all there is obvious restraining effect, may be used for preparation treatment or the medicine such as prevention of fibrotic diseases, tumour; The preparation method of compound shown in formula I, has the advantages such as operation is few, step is easy, reaction conditions is gentle, energy consumption is low, efficiency is high, cost is low, environmental protection, is applicable to very much the application in industry.
The compound provided in the present invention and derivative can according to IUPAC (International Union of Pure and Applied Chemistry(IUPAC)) or the names of CAS (chemical abstracts service, Columbus, OH) naming system.
Definition about use term of the present invention: except as otherwise noted, the original definition that group or term provide herein is applicable to this group or the term of entire description; For the term be not specifically defined, according to disclosure and context, the implication that those skilled in the art can give them should be provided herein.
" replacement " refer to hydrogen atom in molecule by other different atom or molecule replace.
In hydrocarbon group, the minimum value of carbon content and maximum value are represented by prefix, such as, prefix (Ca ~ b) alkyl show any containing " a " to alkyl of " b " individual carbon atom.Therefore, such as, C
1~ C
4alkyl refers to the alkyl comprising 1 ~ 4 carbon atom.
Term " pharmaceutically acceptable " refers to certain carrier, load, thinner, auxiliary material, and/or the salt formed usually chemically or physically with form certain pharmaceutical dosage form other becomes phase-splitting compatibility, and mutually compatible with acceptor on physiology.
Term " salt " and " pharmaceutically useful salt " refer to above-claimed cpd or its steric isomer, and the acid formed with inorganic and/or organic bronsted lowry acids and bases bronsted lowry and/or subsalt also comprise zwitter-ion salt (inner salt), also comprise quaternary ammonium salt, such as alkylammonium salt.These salt can be directly obtain in the last abstraction and purification of compound.Also can be by by above-claimed cpd, or its steric isomer, with the acid of some amount or alkali suitably (such as equivalent) be obtained by mixing.These salt may form precipitation in the solution and collect with filter method, or reclaim after the solvent evaporates and obtain, or in water medium, react postlyophilization obtain.Salt described in the present invention can be the hydrochloride of compound, vitriol, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphoric acid salt, acetate, propionic salt, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
In some embodiment of the present invention, present invention comprises isotope-labeled compound, described compound isotopically labelled refers to listed Compound Phase is same herein, but one or more atom is replaced by another atom, the atomic mass of this atom or total mass number are different from the common atomic mass of occurring in nature or total mass number.Hydrogen, carbon, nitrogen, oxygen, sulphur can be comprised by isotropic substance in drawing-in system (I) compound, namely
2h,
3h,
13c,
14c,
15n,
17o,
18o,
35s.The compound of the formula (I) containing above-mentioned isotropic substance and/or other atom isotope and steric isomer thereof, and this compound, steric isomer pharmaceutically useful salt all should be included within the scope of the invention.
Key intermediate in the present invention and compound carry out abstraction and purification, and the mode used is Isolation and purification method conventional in organic chemistry and the example of described method comprises filtration, extraction, drying, is spin-dried for and various types of chromatogram.Selectively, can make intermediate not purified namely carry out next step reaction.
In some embodiments, one or more compounds of the present invention can combine with one another use.Also compound of the present invention can be selected to be combined with other active agent any, for the preparation of medicine or the pharmaceutical composition of regulating cell function or disease therapy.If use one group of compound, then can by these compounds simultaneously, respectively or in an orderly manner administration be carried out to study subject.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): oral, parenteral (intravenously, intramuscular or subcutaneous) and topical.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least one conventional inert excipients (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mix with following compositions: (a) filler or expanding material, such as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, such as, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, such as, glycerine; (d) disintegrating agent, such as, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, such as paraffin; F () absorbs accelerator, such as, and quaternary ammonium compound; (g) wetting agent, such as hexadecanol and glyceryl monostearate; (h) sorbent material, such as, kaolin; (i) lubricant, such as, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and in this composition, the release of active compound or compound can discharge in certain part in a delayed fashion in digestive tube.The example of adoptable embedding component is polymeric material and Wax.If desired, active compound also can form microencapsulation form with one or more in above-mentioned vehicle.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent adopted in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Except active ingredient beyond the region of objective existence, suspension can comprise suspension agent, such as, and the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials.
Composition for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
Formulation for the compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents aseptically with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need if desired is mixed together.
Pharmaceutically acceptable auxiliary material of the present invention, refers to the material be included in addition to the active ingredient (s in formulation.
Pharmaceutically acceptable complementary composition of the present invention, it has certain physiologically active, but adding of this composition can not change the dominant position of aforementioned pharmaceutical compositions in treatment of diseases, and only play auxiliary effect, these auxiliary effects are only the utilizations to this composition known activity, are the usual adjuvant treatment modality of field of medicaments.If by above-mentioned complementary composition and pharmaceutical composition of the present invention with the use of, still should belong to the scope of protection of the invention.
Obviously, according to foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, not departing under the present invention's above-mentioned basic fundamental thought prerequisite, the amendment of other various ways, replacement or change can also be made.
The embodiment of form by the following examples, is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
The raw material used in the specific embodiment of the invention, equipment are known product, obtain by buying commercially available prod.
Embodiment 1
Wherein, the abbreviation that " rf " is reflux, its Chinese implication is " backflow ".
In 25ml reaction flask, first add 3.4ml by 17mlH
2the solution (50%, volume fraction) of O and 17ml vitriol oil composition, then adds 1g (0.01mol) 2-amino-5-picoline, and be cooled to less than 10 DEG C with cryosel bath, after stirring several minutes, reaction solution becomes oyster white.Then slowly drip by (1.72gNaNO
2with 3mlH
2o) solution of mixing composition, during dropping, produce irritant gas, dropwise, reaction solution becomes yellow solution, and TCL (thin-layer chromatography) monitoring is to reacting complete (about 40min).Then 8mlH is added
2o, return stirring reaction 15min, cooling, adds anhydrous Na under stirring
2cO
3, make reaction solution be neutral (generation brown solid), filter, gained filtrate is spin-dried for, filter with anhydrous alcohol solution again, again gained filtrate is spin-dried for, namely obtains brown solid (5-methyl-2 (1H) pyridone) 0.87g.
0.1g (1mmol) 5-methyl-2 (1H) pyridone is added, 0.14gK in single port bottle
2cO
3, 0.17g p-bromobenzaldehyde, 0.05gCuI, 5mlDMF, as solvent, carries out return stirring reaction, and TCL monitoring is to reacting complete, stopped reaction, filter, filtrate extracts, by concentrated for organic layer post (PE:EA=3:1 with EA (ethyl acetate), volume ratio, PE is sherwood oil), obtain class yellow or white flaky solid 0.08g, be compound 1.
Get 0.04g oxammonium hydrochloride, be dissolved in 1ml water, add 0.05gNaHCO gradually
3, then add the 5ml dehydrated alcohol of the compound 1 dissolving 0.1g, react under ice bath, TLC detection, tracking are after completion of the reaction, add rare NaOH aqueous solution, be adjusted to pH and be about 8, decompression steams solvent, add silica gel, be spin-dried for, cross post (PE:EA=1:2), collect elutriant, be spin-dried for, obtain compound shown in formula I a.
Compound shown in formula I a: yellow product; Fusing point (mp) is 122-124 DEG C;
1HNMR(400MHz,DMSO-d6)δ：11.40(s,1H,N＝OH),8.21(s,1H,CH),7.71(d,2H,J＝8.4Hz,CH),7.37～7.45(m,4H,ArH),6.42～6.44(d,1H,J＝9.2Hz,CH),2.05(s,3H,CH
3)；
13CNMR(100MHz,DMSO-d6)160.31,147.32,143.09,136.75,132.68,126.79,120.16,114.15,40.13,39.51,38.88,16.28；
IR(KBr,n,cm
-1):3422,1566,1411,1265,1096,986,810,584；
HRMS(ESI)calcdforC
13H
12N
2O
2[2M+Na]
+228.0899found479.1679。
In order to beneficial effect of the present invention is described, the invention provides following test example:
Experiment material and instrument
1, major experimental instrument
Biochemical cultivation case (SANYO);
Microplate reader (biorad);
2, major experimental material and reagent
MRC-5 cell strain (human embryonic lung fibroblast);
MTT(sigma，Cat.No.M5655)；
DMSO，(sigma，Cat.No.67685)；
FnELISAKit: doctor's moral (Cat.No.EK0349);
Test example 1
The impact (mtt assay: 24 hours continuous action groups and 48 hours continuous action groups) that detection compound is bred human lung cancer cell A549; Detection compound is on the impact (ELISA method) of human lung cancer cell A549 secretion Fn.
Reference:
Tao Lijian, Zhang Jun, Hu Gaoyun, Chen Zhuo, Gong Juan .1-(3-fluorophenyl)-5-methyl-2-(1H) pyridone is on the fibroblastic impact of mouse kidney. Central South University's journal (medicine), 2004,29 (2): 139 ~ 141.
XianchaiLin,MinbinYu,KailiWu,HongzhiYuan,andHuaZhong.EffectsofPirfenidoneonProliferation,Migration,andCollagenContractionofHumanTenon’sFibroblastsInVitro.InvestigativeOphthalmology&VisualScience,August2009,Vol.50,No.8：3763～3770.
Sample preparation:
Dissolve compound shown in pirfenidone and formula I with DMSO respectively, 0.22 μm of membrane filtration is degerming, makes the solution of different concns, and-20 DEG C of preservations, thaw before use.
Cell cultures:
MRC-5 cell (human embryonic lung fibroblast) is inoculated in the culture dish containing the DMEM nutrient solution (100U/ml penicillin, 100U/ml Streptomycin sulphate) of 10% foetal calf serum, is placed in 5%CO
2, cultivate in 37 DEG C of incubators.After Growth of Cells converges, go down to posterity with 0.25% trysinization, get the MRC-5 cell in 3-10 generation for test.
1, mtt assay detects inhibiting rate
Mtt assay, also known as MTT colorimetry, is a kind of method detecting cell survival and growth.
Adjusting MRC-5 cell concn with the DMEM nutrient solution containing 10% foetal calf serum is 8 × 10
3/ hole, is inoculated in 96 orifice plates, in 5%CO
2, cultivate 24h in 37 DEG C of incubators, DMSO solution (the 100 μ g/ml of compound shown in the formula I adding different concns respectively, 500 μ g/ml, 1000 μ g/ml), with the DMSO solution of the pirfenidone of different concns (100 μ g/ml, 500 μ g/ml, 1000 μ g/ml) be positive control, blank group only adds the DMEM nutrient solution of equivalent, and often group establishes 5 parallel holes, and culture plate is placed in 5%CO
2, in 37 DEG C of incubators, after continuing to cultivate 24h, 48h, add 20 μ lMTT (5mg/ml), then be placed in incubator and hatch 4h, after abandoning supernatant, every hole adds 150 μ lDMSO, mixing 10min, in reading each hole, microplate reader 570nm place absorbance A value.
Calculate hyperplasia inhibiting rate according to absorbance A value, formula is as follows:
Inhibiting rate (%)=(blank group A value-test group A value)/blank group A value × 100%
Statistic software SPSS 17.0 is adopted to carry out statistical study, all quantitative datas all represent with mean ± standard deviation (mean ± s), employing one-way analysis of variance is compared between group, with P < 0.05 for difference has statistical significance, P < 0.01 for the property of there are differences remarkable.
Mtt assay detected result is in table 1.
Shown in table 1, formula I, compound is on the impact of MRC-5 cell
Compare with blank group, * represents P<0.05, and * * represents P<0.01; Compare with pirfenidone 500 μ g/ml, △ represents P<0.05, and △ △ represents P<0.01.
Test-results shows, shown in formula I, compound has obvious restraining effect to fibroblast proliferation, and along with the increase of consumption, its inhibiting rate also increases thereupon.
2, the detection expressed of Fiberonectin (Fn)
ELISA kit is adopted to measure the expression of Fn.
Adjusting MRC-5 cell concn with the DMEM nutrient solution containing 10% foetal calf serum is 8 × 10
3/ hole, is inoculated in 96 orifice plates, in 5%CO
2, cultivate 24h in 37 DEG C of incubators, DMSO solution (the 100 μ g/ml of compound shown in the formula I adding different concns respectively, 500 μ g/ml, 1000 μ g/ml), be positive control with the DMSO solution of the pirfenidone of different concns (PF refers to pirfenidone) (100 μ g/ml, 500 μ g/ml, 1000 μ g/ml), blank group only adds the DMEM nutrient solution of equivalent, and culture plate is placed in 5%CO
2, in 37 DEG C of incubators, get cell conditioned medium liquid after continuing to cultivate 48h and add in test hole, the method provided according to Fn test kit operates.Microplate reader with standard curve control, draws Fn content after measuring absorbance A value.
Statistic software SPSS 17.0 is adopted to carry out statistical study, all quantitative datas all represent with mean ± standard deviation (mean ± s), employing one-way analysis of variance is compared between group, with P < 0.05 for difference has statistical significance, P < 0.01 for the property of there are differences remarkable.
The test-results that Fn expresses is in table 2.
The impact that shown in table 2, formula I, compound is expressed Fn
Compare with blank group, * represents P<0.05, and * * represents P<0.01.
Test-results shows, compound shown in formula I can be suppressed to fibrocyte eccrine fiber associated proteins (Fn), and along with the increase of consumption, its restraining effect also improves thereupon.
In sum, the invention provides a kind of new 5-methyl-2 (1H) Pyridione derivatives, to fibroblast proliferation and fibroblasts to secrete Fiberonectin (Fn), all there is obvious restraining effect, may be used for preparation treatment or the medicine such as prevention of fibrotic diseases, tumour; The preparation method of compound shown in formula I, has the advantages such as operation is few, step is easy, reaction conditions is gentle, energy consumption is low, efficiency is high, cost is low, environmental protection, is applicable to very much the application in industry.
Claims (12)
1. (1H) Pyridione derivatives of 5-methyl-2 shown in formula I or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug:
Wherein, R is selected from hydroxyl, sulfydryl, amino, C
1~ C
6alkyl, C
1~ C
6alkoxyl group.
2. 5-methyl-2 (1H) Pyridione derivatives or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug shown in formula I according to claim 1, is characterized in that: shown in described formula I, 5-methyl-2 (1H) Pyridione derivatives is:
3. the preparation method of 5-methyl-2 shown in formula I (1H) Pyridione derivatives, is characterized in that: the synthetic route of described preparation method is:
Wherein, R is selected from hydroxyl, sulfydryl, amino, C
1~ C
6alkyl, C
1~ C
6alkoxyl group;
Described preparation method comprises the following steps:
A, compound 1 react in alcoholic solvent with compound 2, and thin-layer chromatography monitoring reaction is complete, obtains reaction solution;
Compound 1 is 0.1:0.04 ~ 0.35 with the weight ratio of compound 2; Compound 1 is 0.1:5 ~ 10g/ml with the weightmeasurement ratio of alcoholic solvent;
B, separation and purification is carried out to step a gained reaction solution, obtain the compound shown in formula I.
4. preparation method according to claim 3, is characterized in that: in step a, and the synthetic route of compound 1 is:
Prepare compound 1 in accordance with the following steps:
1., get 5-methyl-2 (1H) pyridone, mineral alkali, p-bromobenzaldehyde and catalyzer, carry out back flow reaction in organic solvent, thin-layer chromatography monitoring reaction is complete, obtains reaction solution;
The weight ratio of 5-methyl-2 (1H) pyridone and mineral alkali is 0.1:0.14 ~ 0.20; The weight ratio of 5-methyl-2 (1H) pyridone and p-bromobenzaldehyde is 0.1:0.17 ~ 0.20; The weight ratio of 5-methyl-2 (1H) pyridone and catalyzer is 0.1:0.02 ~ 0.05; The weightmeasurement ratio of 5-methyl-2 (1H) pyridone and organic solvent is 0.02 ~ 0.05g/ml;
Mineral alkali be selected from salt of wormwood, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide any one or two or more;
Catalyzer is selected from any one or two kinds in cuprous iodide, copper;
Organic solvent be selected from DMF, tetrahydrofuran (THF), pyridine any one or two or more;
2., to step 1. gained reaction solution carry out separation and purification, obtain compound 1.
5. preparation method according to claim 4, is characterized in that: step 1. in, the synthetic route of 5-methyl-2 (1H) pyridone is:
Prepare 5-methyl-2 (1H) pyridone in accordance with the following steps:
I, get 2-amino-5-picoline and aqueous sulfuric acid, mixing, adds sodium nitrite in aqueous solution and reacts, and thin-layer chromatography monitoring after completion of the reaction, adds water, and return stirring reaction 15min ~ 30min, obtains reaction solution;
The weightmeasurement ratio of 2-amino-5-picoline and aqueous sulfuric acid is 1:3.2 ~ 3.6g/ml; The weightmeasurement ratio of 2-amino-5-picoline and sodium nitrite in aqueous solution is 1:3.0 ~ 3.5g/ml; The weightmeasurement ratio of 2-amino-5-picoline and water is 1:7.5 ~ 8.0g/ml;
Aqueous sulfuric acid is mixed by isopyknic water and the vitriol oil; The concentration of sodium nitrite in aqueous solution is 0.55 ~ 0.65g/ml;
Ii, separation and purification is carried out to step I gained reaction solution, obtain 5-methyl-2 (1H) pyridone.
6. preparation method according to claim 5, it is characterized in that: in step I i, the method of step I gained reaction solution being carried out to separation and purification is: after reaction solution cooling, add mineral alkali, regulates pH to be about 7, filter, obtain filtrate, the solvent in removing filtrate, obtains crude product, recrystallization, obtains 5-methyl-2 (1H) pyridone;
Described mineral alkali be selected from sodium carbonate, salt of wormwood, potassium hydroxide, sodium hydroxide any one or two or more.
7. preparation method according to claim 4, is characterized in that: step 2. in, to the step method that 1. gained reaction solution carries out separation and purification be: reaction solution is filtered, obtains filtrate; Filtrate is extracted with ethyl acetate, and by concentrated for organic phase post, elutriant is sherwood oil: ethyl acetate=3:1, except desolventizing, dry, obtains compound 1.
8. preparation method according to claim 3, is characterized in that: in step a, and compound 2 is oxammonium hydrochloride; Alcoholic solvent is selected from any one or two kinds in dehydrated alcohol, methyl alcohol.
9. preparation method according to claim 3, it is characterized in that: in step b, the method for step a gained reaction solution being carried out to separation and purification is: in reaction solution, add rare NaOH aqueous solution, be adjusted to pH and be about 8, decompression steams solvent, add silica gel, be spin-dried for, cross post, elutriant is sherwood oil: ethyl acetate=1:2, collect elutriant, be spin-dried for, obtain compound shown in formula I a.
10. the purposes treated and/or prevented in the medicine of fibrotic disease or tumor disease prepared by 5-methyl-2 (1H) Pyridione derivatives shown in the formula I described in claim 1 ~ 2 any one or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug.
11. purposes according to claim 10, is characterized in that: described fibrotic disease comprises idiopathic pulmonary fibrosis, pulmonary fibrosis, interstitial lung disease, nonspecific interstitial pneumonia, coventional type interstitial pneumonia, endomyocardial fibrosis, fibrosis of mediastinum, myelofibrosis, retroperitoneal fibrosis, Progressive symmetric erythrokeratodermia bulk fibers, kidney systemic fibrosis disease, Crohn disease, remote myocardial infarction, scleroderma/systemic sclerosis, neurofibroma, Hermansky-Pudlak syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy, hypertension associated kidney disease, focal segmental glomerulosclerosis, the fibrosis of radiation induction, leiomyoma of uterus, alcoholic liver disease, hepatic steatosis, hepatic fibrosis, liver cirrhosis, infection with hepatitis C virus, Chronic organ transplant's rejection, fibrosis of skin illness, keloid, contracture of palmar fascia is sick, Ehlers-Danlos syndrome, EBD, in oral submucosa fibrosis or Fibroproliferative illness any one or two or more.
12. 1 kinds of pharmaceutical compositions, it is characterized in that: described pharmaceutical composition be with 5-methyl-2 (1H) Pyridione derivatives shown in the formula I described in claim 1 ~ 2 any one or its crystal formation, pharmacy acceptable salt, hydrate, solvate or prodrug for activeconstituents, add the preparation that pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
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