CN105130884B - 5 methyl 2 (1H) Pyridione derivatives and its production and use - Google Patents
5 methyl 2 (1H) Pyridione derivatives and its production and use Download PDFInfo
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- CN105130884B CN105130884B CN201510459029.0A CN201510459029A CN105130884B CN 105130884 B CN105130884 B CN 105130884B CN 201510459029 A CN201510459029 A CN 201510459029A CN 105130884 B CN105130884 B CN 105130884B
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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
Abstract
The invention discloses (1H) Pyridione derivatives of 5 methyl 2 or its crystal formation, pharmaceutically acceptable salt, hydrate, solvate or pro-drug shown in formula I；Wherein, R1Selected from hydrogen, halogen, C1~C6Alkyl, C1~C6Alkoxy, C2~C6Amide groups, C2~C6Aminoacyl or C3~C6Heterocyclic radical.The invention provides a kind of 5 new methyl 2 (1H) Pyridione derivatives, obvious inhibitory action is respectively provided with to fibroblast proliferation and fibroblasts to secrete fibronectin (Fn), can be used for preparing the medicines such as treatment or prevention fibrotic disease, tumour；The preparation method of compound shown in formula I, has the advantages that process is few, step is easy, reaction condition is gentle, energy consumption is low, efficiency high, cost are low, environmental protection, are especially suitable for the 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, alias：5- picoline -2- alcohol, 2- hydroxy-5-methyl yl pyridines, No. CAS：1003-
68-5, its chemical constitution is mainly used in the fields such as organic synthesis as shown in formula A.
United States Patent (USP) US3839346A discloses the pyridine compounds shown in formula B, and the compound has anti-inflammatory, solution
The effects such as heat, reduction serum uric acid level, analgesic；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).The U.S. is special
Sharp US4052509A also discloses that pirfenidone, and it has good anti-inflammatory and analgesic activity.
The A of Chinese patent CN 1386737 disclose the anti-fibrosis pyridone medicine shown in a kind of formula C, it be 1- more take
For phenyl -5- methyl -2- (1H) pyridinone compounds；Wherein, n is 1 or 2, R are F, Cl, Br, I, saturated straight chain alkyl, oxo
Saturated straight chain alkyl or halo saturated straight chain alkyl.
The A of Chinese patent CN 102786467 disclose the N- substituted aryl pyridinone compounds shown in a kind of formula D, and it is
Using pirfenidone as lead compound, retain pyridone parent nucleus, different amine methylene ethers are introduced on 4 of N- substituted aryls
Structure, obtains N- (4- amine methylene ether) aryl pyridinones；Wherein, X3For Y (CH2)nR4, Y is O or S, n are 1-10；Described R4
It is open chain or the tertiary amine structure NR of ring-type5R6, R5、R6Independently selected from the straight or branched alkane containing 1-3 carbon atom, or R5、
R6With R4In N constitute five-, six- or seven-membered ring, described five-, six- or seven-membered ring is oxazole, pyrroles, imidazoles, pyrazoles,
Piperidines, piperazine, methyl piperazine, morpholine or high piperidines.
The A of Chinese patent CN 101842355 disclose the N- aryl pyridinones of substitution shown in formula E；Wherein, R1、R2、R3、
R4、R5、R6、R7、R8、R9、R10And R11It is independently selected from the group being made up of hydrogen and deuterium；R1、R2、R3、R4、R5、R6、R7、R8、R9、R10With
R11In at least one be deuterium；And if R7、R8、R9、R10And R11Deuterium, then R1、R2、R3、R4、R5And R6In at least one be
Deuterium.
At present, it there are no the report of the Pyridione derivatives of 5- methyl -2 (1H) shown in formula I；Also it there are no the institute of formula I
Show the preparation method of 5- methyl -2 (1H) Pyridione derivatives and the report of purposes.
The content of the invention
It is an object of the invention to provide a kind of new 5- methyl -2 (1H) Pyridione derivatives.
(1H) Pyridione derivatives of 5- methyl -2 shown in the formula I that the present invention is provided or its crystal formation, pharmaceutically acceptable salt,
Hydrate, solvate or pro-drug：
Wherein, R1Selected from hydrogen, halogen, C1~C6Alkyl, C1~C6Alkoxy, C2~C6Amide groups, C2~C6Ammonia
Acyl group or C3~C6Heterocyclic radical.
Further, R1Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, butyl, methoxyl group, ethyoxyl, the third oxygen
Base or butoxy.
Further, the Pyridione derivatives of 5- methyl -2 (1H) shown in formula I are：
Another object of the present invention is to provide the preparation side of 5- methyl -2 (1H) Pyridione derivatives shown in above-mentioned formula I
Method.
A kind of preparation method for 5- methyl -2 (1H) Pyridione derivatives that the present invention is provided, the synthesis of the preparation method
Route is：
Wherein, R1Selected from hydrogen, halogen, C1~C6Alkyl, C1~C6Alkoxy, C2~C6Amide groups, C2~C6Ammonia
Acyl group or C3~C6Heterocyclic radical；
The preparation method comprises the following steps：
A, compound 1 and alcoholic solvent, inorganic base aqueous solution, compound 2 are taken, mix, react at room temperature, thin-layer chromatography prison
Control reaction is finished, and obtains reaction solution；
The mass volume ratio of compound 1 and alcoholic solvent is 0.02~0.04：1g/ml；Compound 1 and inorganic base aqueous solution
Mass volume ratio is 0.15~0.20：1g/ml；The mol ratio of compound 1 and compound 2 is 1：2.1~2.5；
Any one or two kind of the alcoholic solvent in ethanol, methanol；Inorganic base is in sodium hydroxide, potassium hydroxide
Any one or two kinds；
The mass fraction of inorganic base aqueous solution is 10%~30%；
B, reaction solution obtained by step a is isolated and purified, obtain the compound shown in formula I.
Further, in step a, the synthetic route of compound 1 is：
Compound 1 is prepared in accordance with the following steps：
1. 5- methyl -2 (1H) pyridone, inorganic base, p-bromobenzaldehyde and catalyst, are taken, is returned in organic solvent
Stream reaction, thin-layer chromatography monitoring reaction is finished, and obtains reaction solution；
The weight ratio of (1H) pyridone of 5- methyl -2 and inorganic base is 0.1：0.14~0.20；5- methyl -2 (1H) pyridone
Weight ratio with p-bromobenzaldehyde is 0.1：0.17~0.20；The weight ratio of (1H) pyridone of 5- methyl -2 and catalyst is 0.1:
0.02~0.05；The mass volume ratio of (1H) pyridone of 5- methyl -2 and organic solvent is 0.02~0.05g/ml；
Any one or two kind of the inorganic base in potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide with
On；
Any one or two kind of the catalyst in cuprous iodide, copper；
Organic solvent in N,N-dimethylformamide, tetrahydrofuran, pyridine any one or it is two or more；
2., to step, 1. gained reaction solution is isolated and purified, and obtains compound 1.
Further, step 1. in, the synthetic route of 5- methyl -2 (1H) pyridone is：
5- methyl -2 (1H) pyridone is prepared in accordance with the following steps：
I, 2- amino -5- picolines and aqueous sulfuric acid are taken, mixed, added sodium nitrite in aqueous solution and reacted, it is thin
Layer chromatography is monitored after completion of the reaction, adds water, and return stirring reaction 15min~30min obtains reaction solution；
The mass volume ratio of 2- amino -5- picolines and aqueous sulfuric acid is 1：3.2~3.6g/ml；2- amino -5- first
The mass volume ratio of yl pyridines and sodium nitrite in aqueous solution is 1：3.0~1：3.5g/ml；2- amino -5- picolines and water
Mass volume ratio is 1：7.5~1：8.0g/ml；
Aqueous sulfuric acid is mixed by isometric water and the concentrated sulfuric acid；The concentration of sodium nitrite in aqueous solution be 0.55~
0.65g/ml；
Ii, reaction solution obtained by step i is isolated and purified, obtain 5- methyl -2 (1H) pyridone.
Further, in step ii, it is to the method that reaction solution obtained by step i is isolated and purified：After reaction solution cooling,
Inorganic base is added, regulation pH is about 7, filtering obtains filtrate, removes the solvent in filtrate, obtains crude product, recrystallizes, obtains 5-
Methyl -2 (1H) pyridone；
The inorganic base in sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide any one or it is two or more.
Further, step 2. in, to step, 1. the method that is isolated and purified of gained reaction solution is：Reaction solution is carried out
Filtering, obtains filtrate；Filtrate is extracted with ethyl acetate, and by the concentrated post of organic phase, eluent is petroleum ether：Ethyl acetate=3:
1, solvent is removed, dries, obtains compound 1.
Further, in step a, described compound 2 is：
Further, in step b, it is to the method that reaction solution obtained by step a is isolated and purified：Adjust the pH of reaction solution
About 7, it is extracted with ethyl acetate, is added to silica gel concentration by organic, crosses post, eluent is petroleum ether：Ethyl acetate=3:1,
Solvent is removed, dries, obtains the compound shown in formula I.
Present invention also offers (1H) Pyridione derivatives of 5- methyl -2 shown in above-mentioned formula I or its crystal formation, pharmaceutically may be used
Salt, hydrate, solvate or the pro-drug of receiving, in treatment and/or prevention of fibrotic diseases, the medicine of tumour is prepared
Purposes.
(1H) Pyridione derivatives of 5- methyl -2 or its crystal formation, pharmaceutically acceptable salt, hydration shown in above-mentioned formula I
The purposes of thing, solvate or pro-drug in the medicine for the treatment of and/or prevention of fibrotic diseases or tumor disease is prepared.
Further, described fibrotic disease includes idiopathic pulmonary fibrosis, pulmonary fibrosis, interstitial lung disease, non-spy
After specific mesenchymal pneumonia, plain edition interstitial pneumonia, endomyocardial fibrosis, fibrosis of mediastinum, myelofibrosis, peritonaeum
Fibrosis, progressive bulk fibers, kidney systemic fibrosis disease, Crohn's disease, remote myocardial infarction, chorionitis/be
The hardening of system property, neurofibroma, Hermansky-Pudlak syndromes, nephrosis, kidney fibrosis, hypertrophic cardiac muscle
Disease, hypertension associated kidney disease, focal segmental glomerulosclerosis, the fibrosis of radiation induction, leiomyoma of uterus, Alcoholic
Hepatopathy, hepatic steatosis, hepatic fibrosis, hepatic sclerosis, infection with hepatitis C virus, Chronic organ transplant's rejection, skin
Skin fibrotic conditions, keloid, contracture of palmar fascia disease, Ehlers-Danlos syndromes, dystrophic epidermolysis pine
Any one or more in solution, oral submucosa fibrosis or Fibroproliferative illness.
The implication of above-mentioned fibrotic disease, with reference to the A of Chinese patent CN 104093408, or according to disclosure and upper
Hereafter, their implication can be given by providing those skilled in the art.
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition be with 5- methyl shown in above-mentioned formula I-
2 (1H) Pyridione derivatives or its crystal formation, pharmaceutically acceptable salt, hydrate, solvate or pro-drug for activity into
Point, 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 into fibre
Dimension cell eccrine fiber associated proteins (Fn) are respectively provided with obvious inhibitory action, can be used for preparing treatment or prevention fibrosis disease
The medicines such as disease, tumour；The preparation method of compound shown in formula I, with process is few, step is easy, reaction condition is gentle,
Energy consumption is low, efficiency high, low cost, environmental protection the advantages of, be especially suitable for the application in industry.
The compound and derivative provided in the present invention can according to IUPAC (IUPAC) or
CAS (chemical abstracts service, Columbus, OH) naming system is named.
Definition on the use term of the present invention：Unless otherwise indicated, what group or term herein were provided is initial
The group or term of definition suitable for entire description；For the term being not specifically defined herein, it should according to open
Content and context, their implication can be given by providing those skilled in the art.
" substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.
The minimum value and maximum of carbon content are represented by prefix in hydrocarbon group, for example, prefix (C a~b) alkane
The bright any alkyl containing " a " to " b " individual carbon atom of base table.Thus, for example, C1~C4Alkyl refers to comprising 1~4 carbon atom
Alkyl.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or the salt formed is usual
In chemistry or physically with constituting the other compatible into split-phase of certain pharmaceutical dosage form, and physiologically compatible with by body phase.
Term " salt " and " pharmaceutically useful salt " refer to above-claimed cpd or its stereoisomer, with inorganic and/or organic acid
The acid and/or basic salt formed with alkali, also including amphion salt (inner salt), in addition to quaternary ammonium salt, such as alkylammonium salt.This
A little salt can be directly obtained in being finally separating and purify of compound.Can also be that by by above-claimed cpd, or it is vertical
Body isomers, is obtained by mixing with a number of acid or alkali appropriate (such as equivalent).These salt may be in the solution
Form precipitation and collected with filter method, or reclaim and obtain after the solvent evaporates, or be freeze-dried in aqueous medium after reaction
It is made.Heretofore described salt can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, the hydrogen of compound
Fluorate, phosphate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleic acid
Salt, tartrate or trifluoroacetate.
In some embodiments of the present invention, present invention comprises the compound of isotope marks, the isotope marks
Compound refers to listed compound phase herein together, but one or more of atoms are replaced by another atom, should
The atomic mass or mass number of atom are different from atomic mass or mass number common in nature.Formula (I) chemical combination can be introduced
Isotope in thing includes hydrogen, carbon, nitrogen, oxygen, sulphur, i.e.,2H,3H、13C、14C、15N、17O、18O、35S.Containing above-mentioned isotope and/or
The compound and its stereoisomer of the formula (I) of other atom isotopes, and the compound, stereoisomer are pharmaceutically useful
Salt should be included within the scope of the invention.
Key intermediate and compound in the present invention are separated and purified, used mode be in organic chemistry often
Isolation and purification method and the example of methods described include filtering, extraction, dry, are spin-dried for and various types of chromatograms.Can
Selectively, it can make intermediate is not purified to carry out next step reaction.
In some embodiments, one or more compounds of the invention can be used in conjunction with one another.Also may be selected will
The compound of the present invention is used in combination with any other active agent, for preparing regulating cell function or treating the medicine of disease
Thing or pharmaceutical composition.If using one group of compound, can by these compounds simultaneously, respectively or in an orderly manner to tested
Object is administered.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes
(but being not limited to)：Orally, parenteral (intravenous, intramuscular is subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed with least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions are mixed：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) bond
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arabic gum；(c) NMF, example
Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid, some composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；Lubricant, for example, talcum, calcium stearate, tristearin (i)
Sour magnesium, solid polyethylene glycol, lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also be included
Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can using be coated and shell material prepare, such as casing and
Other materials well known in the art.They can include reactive compound or compound in opacifying agent, also, this composition
Release can discharge in certain part in a delayed fashion in alimentary canal.The example of adoptable embedding component is polymeric material
And Wax.If necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, and such as water or other solvents increase
Solvent and emulsifying agent, example knows, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these materials
Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste
Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Mixture of sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection composition can comprising physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
Formulation for the local the compounds of this invention being administered includes ointment, powder, patch, propellant and inhalant.
Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if necessary may need
Propellant be mixed together.
Pharmaceutically acceptable auxiliary material of the present invention, refers to the material being included in addition to the active ingredient (s in formulation.
Pharmaceutically acceptable complementary composition of the present invention, it has certain physiologically active, but the addition of the composition
Leading position of the aforementioned pharmaceutical compositions in treatment of diseases will not be changed, and only play auxiliary effect, these auxiliary
Effect is only the utilization to the composition known activity, is the usual adjuvant treatment modality of field of medicaments.If will be above-mentioned complementary
Composition is used cooperatively with pharmaceutical composition of the present invention, still should belong to the scope of protection of the invention.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be made, replaces or changes.
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
Embodiment 1
Wherein, " rf " is reflux abbreviation, and its Chinese implication is " backflow ".
In 25ml reaction bulbs, 3.4ml is first added by 17ml H2Solution (50%, volume of O and 17ml concentrated sulfuric acids composition
Fraction), 1g (0.01mol) 2- amino -5- picolines are then added, less than 10 DEG C are cooled to ice salt bath, a few minutes are stirred
Afterwards, reaction solution is changed into milky.Then it is slowly added dropwise by (1.72g NaNO2With 3mLH2O) the solution of mixing composition, during dropwise addition,
Irritative gas, completion of dropping are produced, reaction solution is changed into yellow solution, and TCL (thin-layer chromatography) monitoring to reaction is finished (about
40min).Then 8mL H are added2O, return stirring reaction 15min, cooling, stirring is lower to add anhydrous Na2CO3, make the reaction solution be in
Neutral (generation brown solid), filtering, gained filtrate is spin-dried for, then uses absolute ethyl alcohol dissolution filter, again by gained filtrate
It is spin-dried for, that is, obtains brown solid (5- methyl -2 (1H) pyridone) 0.87g.
(1H) pyridone of 0.1g (1mmol) 5- methyl -2,0.14g K are added in single port bottle2CO3, 0.17g p-bromobenzaldehydes,
0.05g CuI, 5ml DMF carry out return stirring reaction as solvent, and TCL is monitored to reaction and finished, and stop reaction, filter, filter
Liquid is extracted with EA (ethyl acetate), by the concentrated post (PE of organic layer：EA=3:1, volume ratio, PE is petroleum ether), obtain class yellow
Color or white flaky solid 0.08g, as compound 1.
In reaction bulb, add under 0.3g compounds 1 and 15ml absolute ethyl alcohols, magnetic agitation and 2mL10% (quality point is added dropwise
Number) the NaOH aqueous solution is until all dissolve, and cooling under ice bath adds 0.40g melilotal, removes ice-water bath, reaction temperature
Degree is warmed to room temperature, and after TLC monitoring reactions terminate, is adjusted to pH ≈ 7 with dilute HCl, is extracted with ethyl acetate, organic layer is added into 200
Mesh silica gel is concentrated, and crosses post (petroleum ether：Ethyl acetate=3:1), products obtained therefrom is spin-dried for, compound, yield shown in a of formula I is obtained
For 73%.
Compound shown in a of formula I：Yellow solid (yellow solid), fusing point (mp) is 94-95 DEG C；
1H NMR(400MHz,DMSO-d6)δ:7.96~8.11 (m, 1H, CH), 7.83 (m, 2H, ArH), 7.21~7.60
(m, 10H, ArH), 6.45 (d, J=8.0Hz, 1H, CH), 6.39 (d, J=9.6Hz, 1H, CH), 3.97 (m, 1H, CH), 3.40
(d, J=20Hz, 2H, CH2), 2.37 (s, 6H, CH3), 2.04 (d, J=21.1Hz, 3H, CH3)；
13C NMR(100MHz,DMSO-d6)197.85,160.34,143.50,136.06,134.19,129.19,
128.02,126.25,120.10,114.22,44.12,39.53,21.09,16.32；IR(KBr,n,cm-1):3390,2973,
1676,1610,1509,1412,1280,1185,1088,1048,882,820,590；
HRMS(ESI)calcd for C31H29NO3[M+Na]+463.2147found 486.2051。
Embodiment 2
According to the methods described of embodiment 1, " melilotal " is replaced with into " parachloroacetophenone ", b shownization of formula I is obtained
Compound.
Compound shown in the b of formula I：Yellow solid (yellow solid), fusing point (mp) is 66-67 DEG C；
1H NMR(400MHz,DMSO-d6)δ:8.02 (d, J=8.8Hz, 4H, ArH), 7.62 (d, J=8.4Hz, 4H,
), ArH 7.51 (d, J=8.4Hz, 2H, ArH), 7.37~7.40 (m, 2H, CH), 7.30 (d, J=8.4Hz, 2H, ArH), 6.43
(d, J=10.0Hz, 1H, CH), 3.97~4.03 (m, 2H, CH), 3.55 (d, J=6.8Hz, 4H, CH2),2.06(s,6H,
CH3)；
13C NMR(100MHz,DMSO-d6)197.40,160.34,143.95,139.04,136.02,135.26,
129.84,129.76,126.31,120.11,113.91,44.21,39.53,35.53,16.23；IR(KBr,n,cm-1):
3429,1673,1590,1400,1262,1091,804,590；
HRMS(ESI)calcd for C29H23Cl2NO3[M+Na]+503.1055found 526.0963。
Embodiment 3
According to the methods described of embodiment 1, " melilotal " is replaced with into " to fluoro acetophenone ", c shownization of formula I is obtained
Compound.
Compound shown in the c of formula I：Gray solid (gray solid), fusing point (mp) is 60-62 DEG C；
1H NMR(400MHz,DMSO-d6)δ:8.06 (dd, J1=6.0Hz, J2=8.4Hz, 4H, ArH), 7.48 (d, J
=8.4Hz, 2H, CH), 7.26~7.35 (m, 8H, ArH), 6.40 (d, J=10.0Hz, 1H, CH), 3.97~4.04 (m, 1H,
), CH 3.52 (d, J=6.8Hz, 4H, CH2),2.02(s,6H,CH3)；
13C NMR(100MHz,DMSO-d6)196.93,166.24,163.74,160.35,144.06,142.81,
139.02,136.01,133.37,130.95,128.14,126.30,120.11,115.73,113.91,44.17,39.11,
35.87,16.21；IR(KBr,n,cm-1):2925,1675,1596,1506,1410,1364,1277,1230,1156,990,
832,586；
HRMS(ESI)calcd for C29H23F2NO3[M+Na]+471.1646found 494.1549。
In order to illustrate beneficial effects of the present invention, the present invention provides tests below example：
Experiment material and instrument
1st, major experimental instrument
Biochemical cultivation case (SANYO)；
ELIASA (biorad)；
2nd, major experimental material and reagent
MRC-5 cell lines (human embryonic lung fibroblasts)；
MTT (sigma, Cat.No.M5655)；
DMSO, (sigma, Cat.No.67685)；
Fn ELISA Kit：Doctor's moral (Cat.No.EK0349)；
Test example 1
Influence (the mtt assay that detection compound is bred to human lung cancer cell A549：24 hours continuous action groups were held with 48 hours
Continuous effect group)；Detection compound secretes Fn influence (ELISA method) to human lung cancer cell A549.
Bibliography：
Tao Lijian, Zhang Jun, Hu Gaoyun, Chen Zhuo, Gong Juan .1- (3- fluorophenyls) -5- methyl -2- (1H) pyridones to mouse kidney into
The influence Central South University journal (medicine) of fibrocyte, 2004,29 (2)：139~141.
Xianchai Lin,Minbin Yu,Kaili Wu,Hongzhi Yuan,and Hua Zhong.Effects of
Pirfenidone on Proliferation,Migration,and Collagen Contraction of Human
Tenon’s Fibroblasts In Vitro.Investigative Ophthalmology & Visual Science,
August 2009,Vol.50,No.8：3763~3770.
Sample treatment：
Compound shown in pirfenidone and formula I is dissolved with DMSO respectively, 0.22 μm of membrane filtration is degerming, is made
The solution of various concentrations, -20 DEG C of preservations, thaws before use.
Cell culture：
MRC-5 cells (human embryonic lung fibroblasts) are inoculated in the DMEM nutrient solutions (100U/ml containing 10% hyclone
Penicillin, 100U/ml streptomysins) culture dish in, be placed in 5%CO2, cultivate in 37 DEG C of incubators.After cell growth is converged,
With 0.25% pancreatin had digestive transfer culture, the MRC-5 cells in 3-10 generations are taken to be used to test.
1st, mtt assay detection inhibiting rate
Mtt assay, also known as MTT colorimetric methods, are a kind of methods for detecting cell survival and growth.
It is 8 × 10 with the DMEM nutrient solutions adjustment MRC-5 cell concentrations containing 10% hyclone3/ hole, is inoculated in 96 holes
Plate, in 5%CO2, cultivate 24h in 37 DEG C of incubators, the DMSO for being separately added into compound shown in the formula I of various concentrations is molten
Liquid (100 μ g/ml, 500 μ g/ml, 1000 μ g/ml), with DMSO solution (the 100 μ g/ml, 500 μ of the pirfenidone of various concentrations
G/ml, 1000 μ g/ml) it is positive control, blank control group only adds the DMEM nutrient solutions of equivalent, and every group sets 5 parallel holes, will train
Foster plate is placed in 5%CO2, in 37 DEG C of incubators, continue to add 20 μ l MTT (5mg/ml) after cultivating 24h, 48h, then be placed in culture
4h is incubated in case, abandons and adds 150 μ l DMSO after supernatant per hole, 10min is mixed, each hole absorbance is read at ELIASA 570nm
A values.
Hyperplasia inhibiting rate is calculated according to absorbance A value, formula is as follows：
Inhibiting rate (%)=(blank control group A values-test group A values)/blank control group A value × 100%
Using statistic software SPSS 17.0 carry out statistical analysis, all quantitative datas with mean ± standard deviation (mean ±
S) represent, compare between group and use one-way analysis of variance, be that difference is statistically significant with P ＜ 0.05, P ＜ 0.01 are in the presence of poor
It is different in nature notable.
Mtt assay testing result is shown in Table 1.
Influence of the compound to MRC-5 cells shown in table 1, formula I
Compared with blank control group, * represents P<0.05, * * represents P<0.01；Compared with the μ g/mL of pirfenidone 500, △ tables
Show P<0.05, △ △ represents P<0.01.
Result of the test shows that compound shown in formula I has obvious inhibitory action to fibroblast proliferation, and
And with the increase of consumption, its inhibiting rate also increases therewith.
2nd, the detection of fibronectin (Fn) expression
Fn expression is determined using ELISA kit.
It is 8 × 10 with the DMEM nutrient solutions adjustment MRC-5 cell concentrations containing 10% hyclone3/ hole, is inoculated in 96 holes
Plate, in 5%CO2, cultivate 24h in 37 DEG C of incubators, the DMSO for being separately added into compound shown in the formula I of various concentrations is molten
Liquid (100 μ g/ml, 500 μ g/ml, 1000 μ g/ml), it is molten with the DMSO of the pirfenidone (PF refers to pirfenidone) of various concentrations
Liquid (100 μ g/ml, 500 μ g/ml, 1000 μ g/ml) is positive control, and blank control group only adds the DMEM nutrient solutions of equivalent, will trained
Foster plate is placed in 5%CO2, in 37 DEG C of incubators, continue to cultivate and take cell supernatant to add in instrument connection after 48h, according to Fn reagents
The method that box is provided is operated.ELIASA is determined after absorbance A value, with standard curve control, draws Fn contents.
Using statistic software SPSS 17.0 carry out statistical analysis, all quantitative datas with mean ± standard deviation (mean ±
S) represent, compare between group and use one-way analysis of variance, be that difference is statistically significant with P ＜ 0.05, P ＜ 0.01 are in the presence of poor
It is different in nature notable.
The result of the test of Fn expression is shown in Table 2.
The influence that compound shown in table 2, formula I is expressed Fn
Compared with blank control group, * represents P<0.05, * * represents P<0.01.
Result of the test shows that compound can suppress fibroblasts to secrete fibronectin shown in formula I
(Fn), and with the increase of consumption, its inhibitory action is also improved therewith.
In summary, the invention provides a kind of new 5- methyl -2 (1H) Pyridione derivatives, fibroblast is increased
Grow and fibroblasts to secrete fibronectin (Fn) is respectively provided with obvious inhibitory action, can be used for preparing treatment or pre-
The medicines such as lint disease, tumour；The preparation method of compound shown in formula I, with process is few, step is easy, anti-
The advantages of low mild condition, energy consumption, efficiency high, low cost, environmental protection is answered, the application in industry is especially suitable for.
Claims (14)
1. (1H) Pyridione derivatives of 5- methyl -2 shown in formula I or its pharmaceutically acceptable salt：
Wherein, R1Selected from hydrogen, halogen, C1~C6Alkyl or C1~C6Alkoxy.
2. (1H) Pyridione derivatives of 5- methyl -2 or its pharmaceutically acceptable salt, its feature according to claim 1 formula I
It is：R1Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, butyl, methoxyl group, ethyoxyl, propoxyl group or butoxy.
3. (1H) Pyridione derivatives of 5- methyl -2 or its pharmaceutically acceptable salt, its feature according to claim 1 formula I
It is：The Pyridione derivatives of 5- methyl -2 (1H) shown in formula I are：
4. a kind of preparation method of 5- methyl -2 (1H) Pyridione derivatives, it is characterised in that：The synthesis road of the preparation method
Line is：
Wherein, R1Selected from hydrogen, halogen, C1~C6Alkyl or C1~C6Alkoxy；
The preparation method comprises the following steps：
A, compound 1 and alcoholic solvent, inorganic base aqueous solution, compound 2 are taken, mix, react at room temperature, thin-layer chromatography monitoring is anti-
It should finish, obtain reaction solution；
The mass volume ratio of compound 1 and alcoholic solvent is 0.02~0.04: 1g/ml；Compound 1 and the quality of inorganic base aqueous solution
Volume ratio is 0.15~0.20: 1g/ml；The mol ratio of compound 1 and compound 2 is 1: 2.1~2.5；
Any one or two kind of the alcoholic solvent in ethanol, methanol；Inorganic base is any in sodium hydroxide, potassium hydroxide
It is one or two kinds of；
The mass fraction of inorganic base aqueous solution is 10%~30%；
B, reaction solution obtained by step a is isolated and purified, obtain the compound shown in formula I.
5. preparation method according to claim 4, it is characterised in that：In step a, the synthetic route of compound 1 is：
Compound 1 is prepared in accordance with the following steps：
1. 5- methyl -2 (1H) pyridone, inorganic base, p-bromobenzaldehyde and catalyst, are taken, carries out flowing back instead in organic solvent
Should, thin-layer chromatography monitoring reaction is finished, and obtains reaction solution；
The weight ratio of (1H) pyridone of 5- methyl -2 and inorganic base is 0.1: 0.14~0.20；(1H) pyridone of 5- methyl -2 with it is right
The weight ratio of bromobenzaldehyde is 0.1: 0.17~0.20；The weight ratio of (1H) pyridone of 5- methyl -2 and catalyst is 0.1:0.02
~0.05；The mass volume ratio of (1H) pyridone of 5- methyl -2 and organic solvent is 0.02~0.05g/ml；
Inorganic base in potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide any one or it is two or more；
Any one or two kind of the catalyst in cuprous iodide, copper；
Organic solvent in N,N-dimethylformamide, tetrahydrofuran, pyridine any one or it is two or more；
2., to step, 1. gained reaction solution is isolated and purified, and obtains compound 1.
6. preparation method according to claim 5, it is characterised in that：Step 1. in, the conjunction of 5- methyl -2 (1H) pyridone
It is into route：
5- methyl -2 (1H) pyridone is prepared in accordance with the following steps：
I, 2- amino -5- picolines and aqueous sulfuric acid are taken, mixed, added sodium nitrite in aqueous solution and reacted, thin layer color
Spectrum monitoring after completion of the reaction, adds water, and return stirring reaction 15min~30min obtains reaction solution；
The mass volume ratio of 2- amino -5- picolines and aqueous sulfuric acid is 1: 3.2~3.6g/ml；2- amino -5- methyl pyrroles
The mass volume ratio of pyridine and sodium nitrite in aqueous solution is 1: 3.0~1: 3.5g/ml；The quality of 2- amino -5- picolines and water
Volume ratio is 1: 7.5~1: 8.0g/ml；
Aqueous sulfuric acid is mixed by isometric water and the concentrated sulfuric acid；The concentration of sodium nitrite in aqueous solution be 0.55~
0.65g/ml；
Ii, reaction solution obtained by step i is isolated and purified, obtain 5- methyl -2 (1H) pyridone.
7. preparation method according to claim 6, it is characterised in that：In step ii, reaction solution obtained by step i is divided
Method from purifying is：After reaction solution cooling, inorganic base is added, regulation pH is about 7, filtering obtains filtrate, removes in filtrate
Solvent, obtains crude product, recrystallization, obtains 5- methyl -2 (1H) pyridone；
The inorganic base in sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide any one or it is two or more.
8. preparation method according to claim 5, it is characterised in that：Step 2. in, to step 1. gained reaction solution carry out
The method isolated and purified is：Reaction solution is filtered, filtrate is obtained；Filtrate is extracted with ethyl acetate, and organic phase is concentrated
Post, eluent is petroleum ether：Ethyl acetate=3:1, solvent is removed, dries, obtains compound 1.
9. preparation method according to claim 4, it is characterised in that：In step a, described compound 2 is：
10. preparation method according to claim 4, it is characterised in that：In step b, reaction solution obtained by step a is divided
Method from purifying is：The pH for adjusting reaction solution is about 7, is extracted with ethyl acetate, and is added to silica gel concentration by organic, crosses post,
Eluent is petroleum ether：Ethyl acetate=3:1, solvent is removed, dries, obtains the compound shown in formula I.
11. (1H) Pyridione derivatives of 5- methyl -2 shown in the formula I described in claims 1 to 3 any one or its pharmaceutically may be used
Purposes of the salt of receiving in the medicine for the treatment of and/or prevention of fibrotic diseases or tumor disease is prepared.
12. purposes according to claim 11, it is characterised in that：Described fibrotic disease includes pulmonary fibrosis, interstitial
Property tuberculosis, nonspecific interstitial pneumonia, plain edition interstitial pneumonia, endomyocardial fibrosis, fibrosis of mediastinum, marrow it is fine
Dimensionization, retroperitoneal fibrosis, progressive bulk fibers, kidney systemic fibrosis disease, Crohn's disease, old cardiac muscle stalk
Plug, chorionitis/systemic sclerosis, neurofibroma, Hermansky-Pudlak syndromes, nephrosis, kidney fibrosis,
Hypertrophic cardiomyopathy, hypertension associated kidney disease, focal segmental glomerulosclerosis, the fibrosis of radiation induction, uterine leio
Myomata, AML, hepatic steatosis, hepatic fibrosis, hepatic sclerosis, infection with hepatitis C virus, Chronic organ transplant
Rejection, fibrosis of skin illness, keloid, contracture of palmar fascia disease, Ehlers-Danlos syndromes, dystrophic
In epidermolysis bullosa, oral submucosa fibrosis or Fibroproliferative illness any one or it is two or more.
13. purposes according to claim 12, it is characterised in that：Described pulmonary fibrosis is idiopathic pulmonary fibrosis.
14. a kind of pharmaceutical composition, it is characterised in that：Described pharmaceutical composition is with described in claims 1 to 3 any one
Formula I shown in (1H) Pyridione derivatives of 5- methyl -2 or its pharmaceutically acceptable salt be active component, add and pharmaceutically may be used
The preparation that the auxiliary material of receiving is prepared from.
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