CN105884680A - Pirfenidone derivative and preparation method and use thereof - Google Patents
Pirfenidone derivative and preparation method and use thereof Download PDFInfo
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- CN105884680A CN105884680A CN201610431970.6A CN201610431970A CN105884680A CN 105884680 A CN105884680 A CN 105884680A CN 201610431970 A CN201610431970 A CN 201610431970A CN 105884680 A CN105884680 A CN 105884680A
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- 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
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Abstract
The invention relates to a pirfenidone derivative and a preparation method and use thereof and discloses a compound shown as in formula I or its pharmaceutically acceptable salt, crystal, hydrate or solvate, wherein R1 is selected from H or C1-C8 alkyl, R2, R3, R4, R5 and R6 are selected respectively or all from H or halogen, and at least one of the R2, R3, R4, R5 and R6 is halogen. The novel compound of the invention is significantly better than pirfenidone in anti-fibrosis activity and has an inhibitory rate of higher than 42% for fibroblast proliferation, as much as 5 times higher than 8.15% of pirfenidone, and the derivative has good industrial prospect.
Description
Technical field
The present invention relates to pirfenidone derivant and preparation method thereof and purposes.
Background technology
Fibrosis refers to that the patient organ's parenchyma caused by various paathogenic factors reduces or downright bad, outside tissue inner cell
Substrate increases and the pathological process of diffusivity over-deposit, and continuing advances may result in destruction and the hypofunction of organ structure, directly
To exhaustion.Fibrosis can betide multiple organ, and the most most commonly seen fibrosis mainly has: (1) pulmonary fibrosis；(2) liver
Fibrosis；(3) cardiac fibrosis；(4) renal fibrosis and (5) pancreatic gland fibrosis；Additionally, eye, blood vessel, nervous system are likely to send out
Raw fibrosis.
Anti-fibrosis medicine refers to treatment and/or the medicine of prevention of fibrotic diseases, such as: pirfenidone (produce by marketed drug
Product), but, this compound is only capable of reaching 8.15% to the suppression ratio of fibroblast proliferation, fibrosis poor activity.
In order to preferably serve fibrotic disease patient, ensure the life and health of numerous people, need existing anti-fibre
The medicine of dimensionization improves, and develops the noval chemical compound that a kind of fibrosis activity is more excellent.
Summary of the invention
It is an object of the invention to provide the pirfenidone derivant shown in formula I.
The compound shown in formula I or its pharmaceutically acceptable salt, crystal formation, hydrate or solvent that the present invention provides close
Thing:
Wherein,
R1Selected from H or C1～C8Alkyl；
R2、R3、R4、R5、R6Separately or concurrently selected from H or halogen, and R2、R3、R4、R5、R6In at least 1 be halogen.
Further, R1Selected from H or C1～C4Alkyl.
Further, R2、R3、R4、R5、R6In at least 2 be halogen；Preferably, R2、R3、R4、R5、R6In at least 2
Individual for halogen, and R4For halogen；It is furthermore preferred that R2、R3、R4、R5、R6In at least 2 be halogen, and R4For halogen, R2、R6In
At least 1 is halogen.
Further, R4For halogen, R2、R6In at least 1 be halogen, R3、R5It is H simultaneously；Preferably, described R4With institute
State R2、R6Selected halogen is different.
Further, described halogen is selected from fluorine, chlorine, bromine or iodine.
Further, the compound shown in formula I is
Present invention also offers the preparation method of above-claimed cpd, comprise the following steps:
1., compound a-1 is at 50% sulphuric acid, NaNO2Under conditions of react, obtain compound a；
2., compound a react under conditions of alkali, catalyst and nitrogenous kind solvent with compound b, obtain formula I institute
The compound shown；
Wherein,
R1Selected from H or C1～C8Alkyl；R2、R3、R4、R5、R6Separately or concurrently selected from H or halogen, and R2、R3、R4、R5、R6
In at least 1 be halogen；X is halogen.
Further, step 1. in, the w/v of described compound a-1 and 50% sulphuric acid is 1:3.4～5.0g/
Ml, described compound a-1 and NaNO2Mol ratio be 1:2.5～3.0.
Further, step 2. in, the mol ratio of described compound a and compound b is 1:1.0～1.2, described compound
A is 1:5～10 with the mol ratio of alkali, and described compound a is 1:0.25～0.30 with the mol ratio of catalyst, described compound a
It is 1:50g/ml with the w/v of nitrogenous kind solvent.
Further, step 2. in, described alkali be selected from potassium carbonate or sodium carbonate, described catalyst be selected from Hydro-Giene (Water Science).
Or cuprous bromide, described nitrogenous kind solvent is selected from DMF or N,N-dimethylacetamide.
Further, R1Selected from H or C1～C4Alkyl.
Further, R2、R3、R4、R5、R6In at least 2 be halogen；Preferably, R2、R3、R4、R5、R6In at least 2
Individual for halogen, and R4For halogen；It is furthermore preferred that R2、R3、R4、R5、R6In at least 2 be halogen, and R4For halogen, R2、R6In
At least 1 is halogen.
Further, R4For halogen, R2、R6In at least 1 be halogen, R3、R5It is H simultaneously；Preferably, described R4With institute
State R2、R6Selected halogen is different.
Further, described halogen is selected from fluorine, chlorine, bromine or iodine.
Present invention also offers a kind of pharmaceutical composition, it be with above-mentioned compound or its pharmaceutically acceptable salt,
Crystal formation, hydrate or solvate are active component, add the system that pharmaceutically conventional adjuvant or complementary composition prepare
Agent.
Present invention also offers above-mentioned compound or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate
Application in preparing anti-fibrosis medicine and/or antitumor drug.
Further, described anti-fibrosis medicine is the medicine of suppression fibroblast proliferation.
Further, described anti-fibrosis medicine is the medicine of suppression fibroblasts to secrete fibronectin.
Further, described fibroblast be embryo fibroblast, lung fibroblast, liver fibroblast,
In cardiac fibroblast, kidney fibroblast, pancreas fibroblast, eye fibroblast, Vascular fibroblasts
Any one or two or more.
Further, described antitumor drug is cancer therapy drug.
Further, described cancer therapy drug is appointing in treatment and/or Breast Cancer Prevention, cervical cancer, carcinoma of prostate
The medicine of one or more cancers of anticipating.
The fibrosis activity of noval chemical compound of the present invention is significantly better than pirfenidone, particularly, and noval chemical compound pair of the present invention
The suppression ratio of fibroblast proliferation has reached more than 42%, relative to the 8.15% of pirfenidone, increase rate reach 5 times it
Many, there is good industrialization prospect.
The compound provided in the present invention and derivant can according to IUPAC (IUPAC) or
CAS (chemical abstracts service, Columbus, OH) nomenclature is named.
The definition using term about the present invention: except as otherwise noted, herein group or term provide initial
Definition is applicable to this group or the term of entire description；For the term being not specifically defined herein, it should according to open
Content and context, provide those skilled in the art and can give their implication.
" replace " hydrogen atom referring in molecule to be replaced by other different atom or molecule.
In hydrocarbon group, minima and the maximum of carbon content are represented by prefix, such as, and prefix Ca～CbAlkyl table
Bright any alkyl containing " a " to " b " individual carbon atom.It is therefoie, for example, C1～C4Alkyl refers to comprise the alkyl of 1～4 carbon atom；
Substituted C1～C4Alkyl refers to comprise 1～4 carbon atom in alkyl, is not counted by the carbon number of substituent group.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, adjuvant, and/or the salt formed is usual
In chemistry or physically with constitute certain pharmaceutical dosage form other becomes split-phase compatibility, and physiologically mutually compatible with receptor.
Term " salt " and " pharmaceutically useful salt " refer to above-claimed cpd or its stereoisomer, with inorganic and/or organic acid
The acid formed with alkali and/or basic salt, also include amphion salt (inner salt), also include quaternary ammonium salt, such as alkylammonium salt.This
A little salt can be to directly obtain in purification being finally separating of compound.Can also be by by above-claimed cpd, or it stands
Body isomer, is obtained by mixing with a number of acid or alkali suitably (such as equivalent).These salt may be in the solution
Form precipitation and collect with filter method, or reclaim after the solvent evaporates and obtain, or in aqueous medium, react postlyophilization
Prepare.Heretofore described salt can be the hydrochlorate of compound, sulfate, citrate, benzene sulfonate, hydrobromate, hydrogen
Fluorate, phosphate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleic acid
Salt, tartrate or trifluoroacetate.
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): oral, parenteral (intravenous, intramuscular or subcutaneous) and topical.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulation
In type, reactive compound mixes with at least one conventional inert excipients (or carrier), such as sodium citrate or dicalcium phosphate, or with
Following compositions mixes: (a) filler or bulking agent, such as, and starch, lactose, sucrose, glucose, mannitol and silicic acid；B () bonds
Agent, such as, hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum；(c) wetting agent, example
As, glycerol；(d) disintegrating agent, such as, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate,
And sodium carbonate；(e) retarding solvent, such as paraffin；F () absorbs accelerator, such as, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Alcohol and glyceryl monostearate；(h) adsorbent, such as, Kaolin；(i) lubricant, such as, Talcum, calcium stearate, tristearin
Acid magnesium, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, dosage form also can comprise
Buffer agent.
Solid dosage forms such as tablet, sugar pill, capsule, pill and granule can use coating and shell material to prepare, such as casing and
Other material well known in the art.They can comprise opacifying agent, and, reactive compound or compound in this compositions
Release can discharge in the part of certain in digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And Wax.If desired, reactive compound also can form microencapsulation form with one or more 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 comprise the conventional inert diluent used in this area, such as water or other solvent, increases
Solvent and emulsifying agent, example knows, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formyl
Amine and oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or the mixture of these materials
Deng.
In addition to these inert diluents, compositions also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste
Agent, correctives and spice.
Except active ingredient beyond the region of objective existence, suspension can comprise suspending agent, such as, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or the mixture etc. of these materials.
Compositions for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or emulsion, and for being again dissolved into the sterilized powder of aseptic Injectable solution or dispersion liquid.Suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyhydric alcohol and suitable mixture thereof.
Dosage form for the compounds of this invention of topical includes ointment, powder, patch, propellant and inhalant.
Active component aseptically with physiologically acceptable carrier and any preservative, buffer agent, or if desired may need
Propellant be mixed together.
Pharmaceutically acceptable adjuvant of the present invention, refers to the material being included in addition to the active ingredient (s in dosage form.
Pharmaceutically acceptable complementary composition of the present invention, it has certain physiologically active, but the addition of this composition
Aforementioned pharmaceutical compositions leading position in treatment of diseases will not be changed, and only play auxiliary effect, these auxiliary
Effect is only utilization to this composition known activity, is 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 fall within the scope of protection of the invention.
Obviously, according to the foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, without departing from
Under the present invention above-mentioned basic fundamental thought premise, it is also possible to make the amendment of other various ways, replace or change.
The detailed description of the invention of form by the following examples, remakes the most specifically the foregoing of the present invention
Bright.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to Examples below.All based on foregoing of the present invention
The technology realized belongs to the scope of the present invention.
Detailed description of the invention
The raw material, the equipment that use in the specific embodiment of the invention are known product, obtain by buying commercially available prod.
Abbreviation:
DMF:N, dinethylformamide；TLC: thin layer chromatography；3T3L1: Development of Mouse Embryos lung fibroblast；FBS(fetal
Bovine serum): hyclone；DMSO: dimethyl sulfoxide；DMEM(dulbecco's modified eagle
Medium): DMEM culture medium；ElISA: enzyme-linked immunosorbent assay；MTT
(3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide): thiophene
Azoles indigo plant colorimetry；IC50(half maximal inhibitory concentration): half-inhibition concentration.
Embodiment 1, the synthesis of the compounds of this invention 6
Synthetic route:
1, the synthesis of compound 3 (5-methyl-2-(1H)-pyridone)
In 25mL reaction bulb, be initially charged 3.40mL 50% sulphuric acid (v/v), be subsequently adding 1.00g (10mmol) 2-amino-
5-picoline (compound 1), cryosel bath is cooled to less than 10 DEG C, and after stirring a few minutes, reactant liquor becomes milky；Then delay
Slowly 1.72g (25mmol) NaNO is dripped2With 3mL H2The mixed solution of O composition, has the irritant abnormal smells from the patient of brown color during dropping
Gas produces, and finishes, and reactant liquor becomes faint yellow, and the dilute sulfuric acid with 10% adjusts pH to 7-8, return stirring reaction about 20min,
Spin off major part water, be added thereto to appropriate 300 mesh silica gel, be spin-dried for, pour glass sand core funnel into, ethyl acetate rinse sucking filtration,
It is spin-dried for filtrate i.e. obtaining thick product (compound 3), the most purified, it is directly used in next step reaction.
2, the synthesis of compound 6
Addition 0.10g (1mmol, 1quiv.) compound 3 in 25mL round-bottomed flask, 0.17g (1mmol, 1quiv.) 1,
4-bis-bromo-2-fluorobenzene, 1.4g (10mmol, 10equiv.) K2CO3, 0.05g (0.26mmol, 0.26equiv.) CuI, 5mL DMF
Making solvent, return stirring reaction 1h, TLC follow the tracks of, and reaction is finished, cooling, adds 30mL water, and 3 × 20mL ethyl acetate extracts, organic
Layer anhydrous sodium sulfate is dried, and is spin-dried for, and 300 mesh silica gel column chromatographies separate, eluent petroleum ether: ethyl acetate=1:3 (v/v),
To compound 6, the single step yield of this step is 71%.
Compound 6:1-(4-bromo-2-fluorophenyl)-5-picoline-2 (1H)-one, white powder, m.p.144-146 DEG C；
1H NMR(400MHz,CDCl3) δ 7.58 (dd, J=8.4,7.6Hz, 1H), 7.20 (ddd, J=15.3,9.2,
2.4Hz, 2H), 7.03 (dd, J=6.9,1.5Hz, 2H), 6.50 (d, J=9.4Hz, 1H), 2.04 (s, 3H)；
13C NMR(101MHz,CDCl3)δ161.00,159.83,157.35,142.95,141.11,134.20,
133.64,123.36,121.19,115.59,108.88,108.67,16.81；
HRMS(ESI)calcd for C12H9BrFNO[M+H]+281.9931,found 281.9928,[M+Na]+
.303.9750,found 303.9750。
Comparative example, the synthesis of pirfenidone
0.10g (1mmol, 1quiv.) compound 3,0.17g (1mmol, 1quiv.) bromine is added in 25mL round-bottomed flask
Benzene, 1.4g (10mmol, 10equiv.) K2CO3, 0.05g (0.26mmol, 0.25equiv.) CuI, 5mL DMF makees solvent, backflow
Stirring reaction 1h, TLC follow the tracks of, and reaction is finished, cooling, adds 30mL water, and 3 × 20mL ethyl acetate extracts, organic layer anhydrous slufuric acid
Sodium is dried, and is spin-dried for, and 300 mesh silica gel column chromatographies separate, and eluent petroleum ether: ethyl acetate=1:3 (v/v) obtains pirfenidone,
Yield is 76%.
Pirfenidone: yellow crystals, m.p.121-123 DEG C；
1H NMR (400MHz, DMSO) δ 7.49 (t, J=7.4Hz, 2H), 7.44 7.32 (m, 5H), 6.43 (d, J=
9.3Hz,1H),2.03(s,3H)；
13C NMR(101MHz,DMSO)δ 160.41,142.98,141.01,136.04,128.96,127.92,
126.71,120.21,114.01,16.30。
Embodiment 2, the fibrosis activity of the compounds of this invention
1, cell is cultivated
3T3L1 cell is inoculated in the cell culture medium containing 10%FBS, adds 100IU/mL penicillin and strepto-
Element, is placed in 37 DEG C and cultivates containing in the incubator of 5% carbon dioxide, after cell growth converges, with the trypsinization of 0.25%
Pass on, take the cell in 3-10 generation for testing.Dissolving pirfenidone, the compounds of this invention with DMSO, 0.22 μm membrane filtration removes
Bacterium ,-20 DEG C of preservations, thaw before use.
2, cell proliferation rate/suppression ratio evaluation
With the DMEM culture fluid containing 10%FBS, 3T3L1 cell being inoculated in 96 orifice plates, concentration is adjusted to 8 × 104/ hole, in
37 DEG C, containing cultivating 24h in the environment of the carbon dioxide of 5%, are separately added into the present invention of 100,200,400 tri-concentration of μ g/mL
Compound, with pirfenidone (pirfenidone, PFD) as positive control, the DMEM culture fluid of equivalent as blank,
Often group sets 5 parallel holes, be placed on 37 DEG C containing the environment of the carbon dioxide of 5% continuing cultivate, 24, add 20 μ L after 48h
MTT (5mg/mL), continues preventing and treating and hatches 4h, abandoning supernatant in incubator, and every hole adds 150 μ L DMSO, mixes 10min,
Read each hole absorbance at microplate reader 570nm, calculate the rate of increase/suppression ratio of cell according to absorbance O.D. value, suppression
Rate experimental group is worth difference to be worth ratio to represent with the O.D. of matched group with matched group O.D..
24, after 48h, 3T3L1 cell is increased by the compounds of this invention of mtt assay detection 100,200,400 tri-concentration of μ g/mL
Grow the evaluation result of suppression ratio, be shown in Table 1.
Table 1, the compounds of this invention suppression ratio result to fibroblast proliferation
Illustrate: suppression ratio is the highest, show that its fibrosis activity is the best；The inhibitory activity of blank is 0, pirfenidone
Make positive control.
The above results shows, compared with pirfenidone (PFD), and the compounds of this invention suppression ratio to 3T3L1 cell proliferation
Having brought up to more than 42% from 8.15%, increase rate reaches 5 times more than.
3, the evaluation to 3T3L1 emiocytosis Fn (fibronectin, fibronectin) inhibitory activity
The expression of ElISA kit measurement Fn.DMEM culture fluid containing 10%FBS adjust cell concentration be 8 ×
104/ hole is also inoculated on 96 orifice plates, in 37 DEG C containing the environment of the carbon dioxide of 5% in cultivate 24h, be separately added into 100,
200, the compounds of this invention of 400 tri-concentration of μ g/mL, makees using pirfenidone as positive control, the DMEM culture fluid of equivalent
For blank, take cell supernatant after continuing to cultivate 48h in the environment of 37 DEG C of carbon dioxide containing 5% and add instrument connection
In, measure absorbance O.D. value at microplate reader 450nm, with standard curve control, draw the numerical value of Fn.
After 48h, ELISA kit detects the compounds of this invention of 100,200,400 tri-concentration of μ g/mL respectively to 3T3L1
The result of emiocytosis Fn, the results are shown in Table 2.
Table 2, the compounds of this invention evaluation result to 3T3L1 emiocytosis Fn inhibitory activity
Illustrating: Fn value is the least, showing that the activity suppressing Fn to express is the strongest, its fibrosis activity is the strongest；Blank
The numerical value of middle Fn is 1389.10ng/mL, and pirfenidone makees positive control.
The above results shows, the compounds of this invention is to the inhibition of 3T3L1 emiocytosis Fn and pirfenidone (PFD) base
This is quite.
Embodiment 3, the anti-tumor activity of the compounds of this invention
1, cell is cultivated
MDA-MB-231 cell, HeLa cell, MCF7 cell are cultivated routinely with without phenol red culture medium, add in culture medium
Enter 5% hyclone (FBS), 4mM glutamate, Glu, 1mM Sodium Pyruvate, 100IU/mL penicillin, 100 μ g/mL streptomycins and
0.25 μ g/mL amphotericin；LnCAP prostate gland cancer cell is cultivated in RPIM-1640 culture fluid routinely, separately adds 10%
FBS, 4mM glutamate, Glu, 1mM Sodium Pyruvate, 100IU/mL penicillin, 100 μ g/mL streptomycins and 0.25 μ g/mL amphotericin；
Cell is cultivated at 37 DEG C containing in the environment of the carbon dioxide of 5%.
2, cell survival rate, rate of increase evaluation
MDA-MB-231 cell is inoculated in six orifice plates containing 5%FBS culture medium by the concentration of 50000 cells in every hole
In, then it is added thereto to 10-5M、10-6The compounds of this invention of M, isopyknic DMSO is as blank, by cell at 37 DEG C
Cultivate 5 days containing in the environment of the carbon dioxide of 5%；Flow cytometer (Beckman-Coulter) statistics cell number, survival rate
The cell number crossed by compound treatment/blank group cell number represents.
HeLa, LnCAP and MCF7 cell is inoculated in containing 10%FBS culture medium by the concentration of 20000 cells in every hole
In 24-orifice plate, hole adds reference substance pirfenidone, the compounds of this invention by 6 variable concentrations (0.01 μM to 10 μM), waits body
Long-pending DMSO is as blank, flow cytomery cell number, cell number/blank that cell survival rate treated with medicaments is crossed
Compared with control cells number represents, obtains IC from dose-effect curve50Value.
3, anti-tumor activity test result
The compounds of this invention proliferation inhibition activity primary dcreening operation result to MDA-MB-231 cell, the results are shown in Table 3.
Table 3, the compounds of this invention inhibitory activity effect to MDA-MB-231 cell
Based on pirfenidone, the compounds of this invention primary dcreening operation result to MDA-MB-231 cell, arrange 0.01 μM to 10 μMs
6 variable concentrations, carry out compound and the dose-dependant of HeLa, LnCAP and MCF7 cell are reacted screening, from dose-effect curve
On draw IC50Value, the results are shown in Table 4.
Table 4, the compounds of this invention inhibitory activity effect to HeLa, LnCAP and MCF7 cell
| IC50[μM] | HeLa | LnCAP | MCF7 |
| Positive control (PFD) | >25 | >25 | >25 |
| The compounds of this invention 6 | >25 | >25 | >25 |
The above results shows, the compounds of this invention is the most suitable with the anti-tumor activity effect of pirfenidone.
In sum, the fibrosis activity of noval chemical compound of the present invention is significantly better than pirfenidone, and particularly, the present invention is new
Compound has reached more than 42% to the suppression ratio of fibroblast proliferation, relative to the 8.15% of pirfenidone, and increase rate
Reach 5 times more than, there is good industrialization prospect.
Claims (21)
1. the compound shown in formula I or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate:
Wherein,
R1Selected from H or C1～C8Alkyl；
R2、R3、R4、R5、R6Separately or concurrently selected from H or halogen, and R2、R3、R4、R5、R6In at least 1 be halogen.
Compound the most according to claim 1 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate, its
It is characterised by: R1Selected from H or C1～C4Alkyl.
Compound the most according to claim 1 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate, its
It is characterised by: R2、R3、R4、R5、R6In at least 2 be halogen；Preferably, R2、R3、R4、R5、R6In at least 2 be halogen,
And R4For halogen；It is furthermore preferred that R2、R3、R4、R5、R6In at least 2 be halogen, and R4For halogen, R2、R6In at least 1
For halogen.
Compound the most according to claim 3 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate, its
It is characterised by: R4For halogen, R2、R6In at least 1 be halogen, R3、R5It is H simultaneously；Preferably, described R4With described R2、R6Institute
The halogen of choosing is different.
5. according to the compound described in Claims 1 to 4 any one or its pharmaceutically acceptable salt, crystal formation, hydrate or
Solvate, it is characterised in that: described halogen is selected from fluorine, chlorine, bromine or iodine.
Compound the most according to claim 5 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate, its
It is characterised by: the compound shown in formula I is
7. the preparation method of compound described in claim 1～6 any one, it is characterised in that: comprise the following steps:
1., compound a-1 is at 50% sulphuric acid, NaNO2Under conditions of react, obtain compound a；
2., compound a react under conditions of alkali, catalyst and nitrogenous kind solvent with compound b, obtain shown in formula I
Compound；
Wherein,
R1Selected from H or C1～C8Alkyl；R2、R3、R4、R5、R6Separately or concurrently selected from H or halogen, and R2、R3、R4、R5、R6In at least
There is 1 for halogen；X is halogen.
Preparation method the most according to claim 7, it is characterised in that: step 1. in, described compound a-1 and 50% sulphuric acid
W/v be 1:3.4～5.0g/ml, described compound a-1 and NaNO2Mol ratio be 1:2.5～3.0.
Preparation method the most according to claim 7, it is characterised in that: step 2. in, described compound a and compound b's
Mol ratio is 1:1.0～1.2, and the mol ratio of described compound a and alkali is 1:5～10, described compound a and catalyst mole
It is 1:50g/ml than the w/v for 1:0.25～0.30, described compound a and nitrogenous kind solvent.
Preparation method the most according to claim 7, it is characterised in that: step 2. in, described alkali be selected from potassium carbonate or carbon
Acid sodium, described catalyst is selected from Hydro-Giene (Water Science). or cuprous bromide, and described nitrogenous kind solvent is selected from DMF
Or DMAC N,N' dimethyl acetamide.
11. preparation methoies according to claim 7, it is characterised in that: R1Selected from H or C1～C4Alkyl.
12. preparation methoies according to claim 7, it is characterised in that: R2、R3、R4、R5、R6In at least 2 be halogen；
Preferably, R2、R3、R4、R5、R6In at least 2 be halogen, and R4For halogen；It is furthermore preferred that R2、R3、R4、R5、R6In at least
2 is halogen, and R4For halogen, R2、R6In at least 1 be halogen.
13. preparation methoies according to claim 12, it is characterised in that: R4For halogen, R2、R6In at least 1 be halogen
Element, R3、R5It is H simultaneously；Preferably, described R4With described R2、R6Selected halogen is different.
14. according to the preparation method described in claim 7,12 or 13, it is characterised in that: described halogen selected from fluorine, chlorine, bromine or
Iodine.
15. 1 kinds of pharmaceutical compositions, it is characterised in that: it is with the compound described in claim 1～6 any one or its medicine
On, acceptable salt, crystal formation, hydrate or solvate are active component, add pharmaceutically conventional adjuvant or complementary one-tenth
Divide the preparation prepared.
Compound described in 16. claim 1～6 any one or its pharmaceutically acceptable salt, crystal formation, hydrate or solvent
Compound application in preparing anti-fibrosis medicine and/or antitumor drug.
17. application according to claim 16, it is characterised in that: described anti-fibrosis medicine is suppression fibroblast
The medicine of propagation.
18. application according to claim 16, it is characterised in that: described anti-fibrosis medicine is suppression fibroblast
Eccrine fiber connects the medicine of albumen.
19. according to the application described in claim 17 or 18, it is characterised in that: described fibroblast is that embryo fibroblast is thin
Born of the same parents, lung fibroblast, liver fibroblast, cardiac fibroblast, kidney fibroblast, pancreas fibroblast, eye
In fibroblast, Vascular fibroblasts any one or two or more.
20. application according to claim 16, it is characterised in that: described antitumor drug is cancer therapy drug.
21. application according to claim 20, it is characterised in that: described cancer therapy drug is treatment and/or prevention mammary gland
Any one or the medicine of two or more cancer in cancer, cervical cancer, carcinoma of prostate.
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Cited By (3)
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| WO2019028062A1 (en) | 2017-07-31 | 2019-02-07 | Washington University | Pirfenidone derivatives for modulation of b lymphocyte activity and organ protection |
| WO2022051984A1 (en) * | 2020-09-10 | 2022-03-17 | 苏州富德兆丰生化科技有限公司 | Synthesis method for pirfenidone |
| CN114790192A (en) * | 2021-01-26 | 2022-07-26 | 成都阿奇生物医药科技有限公司 | Anti-fibrosis compound and preparation method and application thereof |
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| CN102558040A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Method for preparing pirfenidone |
| WO2014036487A1 (en) * | 2012-08-31 | 2014-03-06 | Intermune, Inc. | Methods of administering pirfenidone therapy |
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| CN102099036A (en) * | 2008-06-03 | 2011-06-15 | 英特芒尼公司 | Compounds and methods for treating inflammatory and fibrotic disorders |
| CN102558040A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Method for preparing pirfenidone |
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| WO2019028062A1 (en) | 2017-07-31 | 2019-02-07 | Washington University | Pirfenidone derivatives for modulation of b lymphocyte activity and organ protection |
| WO2022051984A1 (en) * | 2020-09-10 | 2022-03-17 | 苏州富德兆丰生化科技有限公司 | Synthesis method for pirfenidone |
| CN114790192A (en) * | 2021-01-26 | 2022-07-26 | 成都阿奇生物医药科技有限公司 | Anti-fibrosis compound and preparation method and application thereof |
| CN114790192B (en) * | 2021-01-26 | 2023-12-08 | 成都阿奇生物医药科技有限公司 | Anti-fibrosis compound, preparation method and application thereof |
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