CN106083817B - Pirfenidone derivative and preparation method thereof - Google Patents
Pirfenidone derivative and preparation method thereof Download PDFInfo
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Abstract
The invention discloses I compound represented of formula or its pharmaceutically acceptable salt, crystal form, hydrate or solvates: where R1、R2、R3、R4、R5Separately or concurrently it is selected from H, halogen, hydroxyl, nitro, carbonyl or C1~C8 alkyl；R6、R7Separately or concurrently it is selected from H or C1~C8Alkyl, and R6、R7It is connected and constitutes five-membered ring or hexatomic ring containing 3~17 carbon atoms.Compared with pirfenidone, noval chemical compound of the present invention has different ring structures, and the anti-fibrosis activity of noval chemical compound of the present invention is significantly better than pirfenidone, especially, noval chemical compound of the present invention is to the inhibiting rate of fibroblast proliferation, relative to pirfenidone increase rate at least 30% or more, simultaneously, noval chemical compound of the present invention is also significantly better than pirfenidone to the inhibitory effect of fibroblasts to secrete fibronectin, has good industrialization prospect.
Description
Technical field
The present invention relates to pirfenidone derivatives and preparation method thereof.
Background technique
Fibrosis refers to the reduction of patient organ's parenchyma as caused by various pathogenic factors or necrosis, organizes outside inner cell
Matrix increases the pathologic process with diffusivity over-deposit, and continuing advances can lead to the destruction and hypofunction of organ structure, directly
To failure.Fibrosis can betide a variety of organs, and clinically most commonly seen fibrosis mainly has: (1) pulmonary fibrosis；(2) liver
Fibrosis；(3) cardiac fibrosis；(4) kidney fibrosis and (5) pancreatic fibrosis；In addition, eye, blood vessel, nervous system may also be sent out
Raw fibrosis.
Anti-fibrosis medicine refers to the drug for the treatment of and/or prevention of fibrotic diseases, such as: (marketed drug produces pirfenidone
Product), however, the compound is only capable of the inhibiting rate of fibroblast proliferation to reach 8.15%, anti-fibrosis poor activity.
In order to preferably serve fibrotic disease patient, ensures the life and health of numerous people, need to existing anti-fibre
The drug of dimensionization improves, and develops a kind of anti-fibrosis activity more preferably noval chemical compound.
Summary of the invention
The purpose of the present invention is to provide pirfenidone derivatives shown in formula I.
I compound represented of formula provided by the invention or its pharmaceutically acceptable salt, crystal form, hydrate or solvent close
Object:
Wherein,
R1、R2、R3、R4、R5Separately or concurrently it is selected from H, halogen, hydroxyl, nitro, carbonyl or C1~C8Alkyl；
R6、R7Separately or concurrently it is selected from H or C1~C8Alkyl, and R6、R7Be connected five yuan constituted containing 3~17 carbon atoms
Ring or hexatomic ring.
Further, R1、R2、R3、R4、R5Separately or concurrently it is selected from H or C1~C8Alkyl；Preferably, R1、R2、R3、R4、R5
Separately or concurrently it is selected from H or C1~C4Alkyl；It is furthermore preferred that R1Selected from H or C1~C4Alkyl；R2、R3、R4、R5It is simultaneously H.
Further, I compound represented of formula is
Wherein, R8、R9、R10、R11、R12Separately or concurrently it is selected from H or C1~C4Alkyl.
Further, R8、R9、R10、R11、R12Separately or concurrently it is selected from H or methyl, ethyl.
Further, the compound is
The present invention also provides the preparation methods of above compound, comprising the following steps:
1., compound a reacted under conditions of alkali, catalyst and nitrogen-containing solvent with compound b, obtain compound
c；
Wherein, R1、R2、R3、R4、R5Separately or concurrently it is selected from H, halogen, hydroxyl, nitro, carbonyl or C1~C8Alkyl, X are
Halogen；
2., compound c reacted under conditions of alkali, catalyst and alcohols solvent with diamines, obtain change shown in formula I
Close object；
Wherein, the diamines isR8、R9、R10、R11、R12Separately or concurrently select
From H or C1~C4Alkyl.
Further, compound a -1 is in 50% sulfuric acid, NaNO2Under conditions of reacted, obtain compound a；
Wherein, R1Selected from H, halogen, hydroxyl, nitro, carbonyl or C1~C8Alkyl；
The w/v of the compound a -1 and 50% sulfuric acid is 1:3.4~5.0g/ml, the compound a -1 with
NaNO2Molar ratio be 1:2.5~3.0.
Further, step 1. in, the molar ratio of the compound a and compound b are 1:1.0~1.2, the compound
The molar ratio of a and alkali is 1:5~10, and the molar ratio of the compound a and catalyst is 1:0.25~0.30, the compound a
W/v with nitrogen-containing solvent is 1:50g/ml.
Further, step 1. in, the alkali be selected from potassium carbonate or sodium carbonate, the catalyst be selected from cuprous iodide
Or cuprous bromide, the nitrogen-containing solvent are selected from n,N-Dimethylformamide or n,N-dimethylacetamide.
Further, step 2. in, the molar ratio of the compound c and diamines is 1:1.2~1.5, the compound c with
The molar ratio of alkali is 1:3~3.5, and the molar ratio of the compound c and catalyst is 1:2.2-2.6, the compound c and alcohols
The w/v of solvent is 1:30~45g/ml.
Further, step 2. in, the alkali be selected from potassium carbonate or sodium carbonate, the catalyst be selected from iodine or N- bromine
For succimide, the alcohols solvent is the tert-butyl alcohol.
Further, step 2. in, the temperature of the reaction is 70~80 DEG C.
Further, R1、R2、R3、R4、R5Separately or concurrently it is selected from H or C1~C8Alkyl；Preferably, R1、R2、R3、R4、R5
Separately or concurrently it is selected from H or C1~C4Alkyl；It is furthermore preferred that R1Selected from H or C1~C4Alkyl；R2、R3、R4、R5It is simultaneously H.
Further, R8、R9、R10、R11、R12Separately or concurrently it is selected from H or methyl, ethyl.
Further, the halogen is selected from fluorine, chlorine, bromine or iodine.
The present invention also provides a kind of pharmaceutical composition, it be with above-mentioned compound or its pharmaceutically acceptable salt,
Crystal form, hydrate or solvate are active constituent, in addition the system that pharmaceutically common auxiliary material or complementary ingredient are prepared
Agent.
Compared with pirfenidone, noval chemical compound of the present invention has different ring structures, and the anti-fibre of noval chemical compound of the present invention
Dimensionization activity is significantly better than pirfenidone, in particular, inhibiting rate of the noval chemical compound of the present invention to fibroblast proliferation, relative to
Pirfenidone increase rate at least 30% or more, meanwhile, noval chemical compound of the present invention is to fibroblasts to secrete fibronectin
White inhibitory effect is also significantly better than pirfenidone, has good industrialization prospect.
Compound and derivative provided in the present invention can according to IUPAC (International Union of Pure and Applied Chemistry) or
The name of CAS (chemical abstracts service, Columbus, OH) naming system.
About the definition of the invention using term: unless otherwise indicated, group or term herein provide initial
Definition is suitable for group or term of entire description；For the term being not specifically defined herein, it should according to open
Content and context, their meaning 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 value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix Ca~CbAlkyl table
Bright any alkyl containing " a " to " b " a carbon atom.Thus, for example, C1~C4Alkyl refers to the alkyl comprising 1~4 carbon atom；
Substituted C1~C4Alkyl refers in alkyl comprising 1~4 carbon atom, the carbon atom number of substituent group is not counted.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual
In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " salt " and " pharmaceutical salt " refer to above compound or its stereoisomer, with inorganic and/or organic acid
The acid and/or basic salt formed with alkali also includes amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.This
A little salt can be to be directly obtained in being finally separating and purify of compound.It is also possible to by by above compound or it is vertical
Body isomers is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may be in the solution
It forms precipitating and is collected with filter method, or recycle obtain after the solvent evaporates, or be freeze-dried after reacting in an aqueous medium
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.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
Abbreviation:
DMF:N, dinethylformamide；TLC: thin-layer chromatography；3T3L1: Development of Mouse Embryos lung fibroblast；FBS(fetal
Bovine serum): fetal calf serum；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): MTT method；IC50(half maximal inhibitory
Concentration): half-inhibitory concentration.
The synthesis of embodiment 1, the compounds of this invention 5b
Synthetic route:
1, the synthesis of compound 3 (5- methyl -2- (1H)-pyridone)
50% sulfuric acid of 3.40mL (v/v) is first added in 25mL reaction flask, 1.00g (10mmol) 2- amino-is then added
5- picoline (compound 1), ice salt bath are cooled to 10 DEG C hereinafter, after stirring a few minutes, and reaction solution becomes milky；Then delay
It is slow that 1.72g (25mmol) NaNO is added dropwise2With 3mL H2The mixed solution of O composition, there is the irritant smell of brown color during being added dropwise
Gas generates, and finishes, and reaction solution becomes faint yellow, and with 10% dilute sulfuric acid tune pH to 7-8, return stirring reacts 20min or so,
Most of water is spun off, appropriate 300 mesh silica gel is added thereto, is spin-dried for, pours into glass sand core funnel, ethyl acetate rinse filters,
Filtrate is spin-dried for obtain the final product crude product (compound 3), it is not purified, it is directly used in and reacts in next step.
2, the synthesis of compound 4 (5- methyl-1-(4- formylphenyl)-2- (1H) pyridone)
0.10g (1mmol, 1quiv.) compound 3 is added in 25mL round-bottomed flask, 0.17g (1mmol, 1quiv.) is right
Bromobenzaldehyde, 1.4g (10mmol, 10equiv.) K2CO3, 0.05g (0.26mmol, 0.26equiv.) CuI, 5mL DMF make molten
Agent, return stirring react 1h, and TLC tracking, reaction is finished, cooling, are added 30mL water, the extraction of 3 × 20mL ethyl acetate, organic layer without
Aqueous sodium persulfate is dry, is spin-dried for, and the separation of 300 mesh silica gel column chromatographies, eluent petroleum ether: ethyl acetate=1:3 (v/v) obtains pale yellow
Color solid: compound 4.
3, the synthesis of compound 5b
0.22g (1mmol, 1equiv.) compound 4 is added in the 25mL round-bottomed flask for filling the 10mL tert-butyl alcohol,
0.086g (1.2mmol, 1.2equiv.) 1,2- propane diamine (R, S mixed object), 0.32g (2.5mmol, 2.5equiv.) simple substance
Iodine, 0.43g (3mmol, 3.0equiv.) potassium carbonate react 3h at 70 DEG C, and reaction is finished, and adjust pH to 7-8, are spin-dried for upper prop, first use stone
Oily ether: ethyl acetate=1:2 (v/v) eluant, eluent rinse out not completely reacted compound 4 and 1,2- propane diamine, then directly
Directly product elution is gone out with ethyl alcohol (dissolved with 3-5 drop triethylamine), merges eluent, is spin-dried for get yellow compound 5b, the step
Rapid single step yield is 66%.
Compound 5b:1- (4- (5- methyl -4,5- dihydro -1H- imidazoles -2- base) phenyl) -5- picoline -2 (1H) -
Ketone, yellow solid, m.p.180-182 DEG C；
1H NMR (400MHz, DMSO) δ 7.99 (t, J=7.6Hz, 2H), 7.58-7.42 (m, 4H), 6.44 (d, J=
9.3Hz,1H),3.99–3.88(m,1H),3.51–3.41(m,2H),2.05(s,3H),1.83(s,3H)1.77(m,1H)；
13C NMR(101MHz,DMSO)δ173.38,170.41,162.29,160.46,143.61,135.61,128.54,
127.14,120.34,114.77,60.31,46.75,22.33,16.46；
HRMS(ESI)calcd for C16H17N3O[M+H]+268.1451,found 268.1450。
The synthesis of embodiment 2, the compounds of this invention 5c
According to the similar method of embodiment 1, using ethylenediamine as raw material in step 3, compound 5c is prepared, step 3
Single step yield is 69%.
Compound 5c:1- (4- (4,5- dihydro -1H- imidazoles -2- base) phenyl) -5- picoline -2 (1H) -one, yellow are solid
Body, m.p.252-254 DEG C；
1H NMR (400MHz, DMSO) δ 8.01 (d, J=8.5Hz, 2H), 7.68 (d, J=8.5Hz, 2H), 7.55-7.31
(m, 2H), 6.45 (d, J=9.3Hz, 1H), 4.02-3.25 (m, 4H), 2.05 (s, 3H), 1.86 (dd, J=12.6,9.6Hz,
1H)；
13C NMR(101MHz,DMSO)δ164.04,160.29,144.87,143.66,135.37,129.01,127.50,
125.22,123.22,120.32,114.84,69.80,45.61,16.42；
HRMS(ESI)calcd for C15H15N3O[M+H]+254.1294 found 254.1289.
The synthesis of embodiment 3, the compounds of this invention 5d
According to the similar method of embodiment 1, with 1,3- propane diamine for raw material in step 3, it is prepared compound 5d, the 3rd
The single step yield of step is 54%.
Compound 5d:1- (4- (Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidine -2- bases) phenyl) -5- picoline -2 (1H) -one, yellow are solid
Body, m.p.265-267 DEG C；
1H NMR (400MHz, DMSO) δ 7.83 (d, J=8.5Hz, 2H), 7.68 (d, J=8.5Hz, 2H), 7.51-7.40
(m, 2H), 6.45 (d, J=9.3Hz, 1H), 3.51 (m, 6H), 2.93 (dd, J=14.7,7.4Hz, 1H), 2.05 (d, J=
13.5Hz,3H)；
13C NMR(101MHz,DMSO)δ160.21,158.66,144.51,143.61,135.29,128.51,127.95,
127.39,120.27,114.62,45.76,17.60,16.37,11.06；
HRMS(ESI)calcd for C16H17N3O[M+H]+268.1451 found 268.1449.
The synthesis of embodiment 4, the compounds of this invention 7b
With compound 1'(2- aminopyridine in step 1) it is raw material, according to the similar method of embodiment 2, being prepared
Object 7b is closed, the single step yield of step 3 is 56%.
Compound 7b:1- (4- (4-5- dihydro -1H- imidazoles -2- base) phenyl) pyridine -2 (1H) -one, yellow solid,
m.p.237-239℃；
1H NMR (400MHz, DMSO) δ 8.00 (d, J=8.6Hz, 2H), 7.69 (dd, J=12.3,5.2Hz, 3H),
7.57-7.51 (m, 1H), 6.50 (d, J=9.2Hz, 1H), 6.37 (td, J=6.7,1.1Hz, 1H), 3.56-3.10 (m, 4H),
1.87(s,1H)；
13C NMR(101MHz,DMSO)δ170.27,163.97,160.98,144.55,141.07,138.51,128.93,
127.49,120.63,106.14,45.90,45.74；
HRMS(ESI)calcd for C14H13N3O[M+H]+240.1138 found 240.1138.
The synthesis of embodiment 5, the compounds of this invention 7c
With compound 1'(2- aminopyridine in step 1) it is raw material, with 1,3- propane diamine for raw material in step 3, according to reality
The similar method of example 4 is applied, compound 7c is prepared, the single step yield of step 3 is 56%.
Compound 7c:1- (4- (Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidine -2- bases) phenyl) pyridine -2 (1H) -one, yellow solid,
m.p.146-148℃；
1H NMR (400MHz, DMSO) δ 8.10 (d, J=8.6Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 7.65 (d, J
=8.4Hz, 1H), 7.57-7.51 (m, 1H), 6.48 (d, J=9.3Hz, 1H), 6.37 (td, J=6.7,1.1Hz, 1H),
3.53-3.41 (m, 6H), 2.94 (dd, J=14.7,7.4Hz, 1H)；
13C NMR(101MHz,DMSO)δ170.34,165.08,162.01,161.64,159.06,141.64,138.91,
129.13,128.63,127.82,120.99,106.76,46.31,37.27,35.33；
HRMS(ESI)calcd for C15H15N3O[M+H]+254.1294,found 254.1292。
The synthesis of comparative example, pirfenidone
0.10g (1mmol, 1quiv.) compound 3,0.17g (1mmol, 1quiv.) bromine are added in 25mL round-bottomed flask
Benzene, 1.4g (10mmol, 10equiv.) K2CO3, 0.05g (0.26mmol, 0.25equiv.) CuI, 5mL DMF makees solvent, flows back
It is stirred to react 1h, TLC tracking, reaction is finished, and it is cooling, 30mL water, the extraction of 3 × 20mL ethyl acetate, organic layer anhydrous slufuric acid is added
Sodium is dry, is spin-dried for, and the separation of 300 mesh silica gel column chromatographies, 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)δ160.41,142.98,141.01,136.04,128.96,127.92,126.71,
120.21,114.01,16.30。
Illustrate the beneficial effect of the compounds of this invention below by way of test example.
Test example 1, the anti-fibrosis activity of the compounds of this invention
1, cell culture
By 3T3L1 cell inoculation in the cell culture medium containing 10%FBS, 100IU/mL penicillin and strepto- is added
Element is placed in 37 DEG C of incubators containing 5% carbon dioxide and cultivates, and after cell growth converges, is digested with 0.25% pancreatin
Passage takes the cell in 3-10 generation for testing.Pirfenidone, the compounds of this invention are dissolved with DMSO, 0.22 μm of membrane filtration removes
Bacterium, -20 DEG C of preservations, thaws before use.
2, cell proliferation rate/inhibiting rate evaluation
With the DMEM culture solution containing 10%FBS by 3T3L1 cell inoculation in 96 orifice plates, concentration is adjusted to 8 × 104/ hole, in
The present invention for being separately added into 100,200,400 tri- concentration of μ g/mL for 24 hours is cultivated in 37 DEG C of environment containing 5% carbon dioxide
Compound is used as positive control with pirfenidone (pirfenidone, PFD), the DMEM culture solution of equivalent as blank control,
Every group sets 5 parallel holes, is placed in 37 DEG C of environment containing 5% carbon dioxide and continues to cultivate, and 24,20 μ L are added after 48h
MTT (5mg/mL) continues prevention and treatment and hatches 4h in the incubator, discards supernatant liquid, and 150 μ L DMSO are added in every hole, mixes 10min,
Each hole absorbance value is read at microplate reader 570nm, proliferation rate/inhibiting rate of cell is calculated according to absorbance O.D. value, is inhibited
Rate is worth the O.D. of difference and control group that ratio is worth to indicate with experimental group with control group O.D..
24, after 48h, the compounds of this invention that mtt assay detects 100,200,400 tri- concentration of μ g/mL increases 3T3L1 cell
The evaluation result for growing inhibiting rate, is shown in Table 1.
Table 1, the compounds of this invention are to the inhibiting rate result of fibroblast proliferation
Illustrate: inhibiting rate is higher, shows that its anti-fibrosis activity is better；The inhibitory activity of blank control is 0, pirfenidone
Make positive control.
The above results show compared with pirfenidone (PFD), inhibiting rate of the compounds of this invention to 3T3L1 cell Proliferation
It is obviously improved, increase rate is at least 30% or more.
3, to the evaluation of 3T3L1 cell secretion Fn (fibronectin, fibronectin) inhibitory activity
The expression of ElISA kit measurement Fn.Containing 10%FBS DMEM culture solution adjustment adjustment cell concentration be 8 ×
104/ hole is simultaneously inoculated on 96 orifice plates, is cultivated for 24 hours in 37 DEG C of environment containing 5% carbon dioxide, be separately added into 100,
200, the compounds of this invention of 400 tri- concentration of μ g/mL, using pirfenidone as positive control, the DMEM culture solution of equivalent is made
For blank control, continue to take cell supernatant that instrument connection is added after cultivating 48h in 37 DEG C of environment containing 5% carbon dioxide
In, absorbance O.D. value is measured at microplate reader 450nm with standard curve control obtains the numerical value of Fn.
ELISA kit detects the compounds of this invention of 100,200,400 tri- concentration of μ g/mL to 3T3L1 respectively after 48h
Cell secretion Fn's as a result, the results are shown in Table 2.
Table 2, the compounds of this invention secrete the evaluation result of Fn inhibitory activity to 3T3L1 cell
Illustrate: Fn value is smaller, shows to inhibit the activity of Fn expression stronger, anti-fibrosis activity is also stronger；Blank control
The numerical value of middle Fn is 1389.10ng/mL, and pirfenidone makees positive control.
The above results show that the compounds of this invention is significantly better than pirfenidone to the inhibitory effect of 3T3L1 cell secretion Fn
(PFD)。
The anti-tumor activity of test example 2, the compounds of this invention
1, cell culture
MDA-MB-231 cell, HeLa cell, MCF7 cell are routinely cultivated with without phenol red culture medium, are added in culture medium
Enter 5% fetal calf serum (FBS), 4mM glutamate, 1mM Sodium Pyruvate, 100IU/mL penicillin, 100 μ g/mL streptomysins and
0.25 μ g/mL anphotericin；LnCAP prostate gland cancer cell is routinely cultivated in RPIM-1640 culture solution, is separately added 10%
FBS, 4mM glutamate, 1mM Sodium Pyruvate, 100IU/mL penicillin, 100 μ g/mL streptomysins and 0.25 μ g/mL anphotericin；
Cell culture is in 37 DEG C of environment containing 5% carbon dioxide.
2, cell survival rate, proliferation rate evaluation
MDA-MB-231 cell is inoculated in six orifice plates containing 5%FBS culture medium by the concentration of every 50000 cells in hole
In, then 10 are added thereto-5M、10-6The compounds of this invention of M, isometric DMSO is as blank control, by cell at 37 DEG C
It is cultivated 5 days in environment containing 5% carbon dioxide；Flow cytometer (Beckman-Coulter) counts cell number, survival rate
It is indicated by the processed cell number of compound/blank control group cell number.
HeLa, LnCAP and MCF7 cell are inoculated in by the concentration of every 20000 cells in hole containing 10%FBS culture medium
In 24- orifice plate, 6 various concentrations (0.01 μM to 10 μM) addition reference substance pirfenidone, the compounds of this invention are pressed in hole, waits bodies
Long-pending DMSO is as blank control, flow cytomery cell number, cell number/blank that cell survival rate treated with medicaments is crossed
Control cell number indicates, IC is obtained from dose-effect curve50Value.
3, anti-tumor activity test result
The compounds of this invention is to the proliferation inhibition activity primary dcreening operation of MDA-MB-231 cell as a result, the results are shown in Table 3.
Table 3, the compounds of this invention are to the inhibitory activity effect of MDA-MB-231 cell
Based on pirfenidone, the compounds of this invention to the primary dcreening operation of MDA-MB-231 cell as a result, 0.01 μM to 10 μM of setting
6 various concentrations carry out compound and react screening to the dose-dependant of HeLa, LnCAP and MCF7 cell, from dose-effect curve
On obtain IC50Value, the results are shown in Table 4.
Table 4, the compounds of this invention are to the inhibitory activity effect of HeLa, LnCAP and MCF7 cell
The above results show that the anti-tumor activity effect of the compounds of this invention and pirfenidone is substantially suitable.
In conclusion noval chemical compound of the present invention has different ring structures, and the new chemical combination of the present invention compared with pirfenidone
The anti-fibrosis activity of object is significantly better than pirfenidone, in particular, inhibition of the noval chemical compound of the present invention to fibroblast proliferation
Rate, relative to pirfenidone increase rate at least 30% or more, meanwhile, noval chemical compound of the present invention is to fibroblasts to secrete fibre
The inhibitory effect of dimension connection albumen is also significantly better than pirfenidone, has good industrialization prospect.
Claims (19)
1. I compound represented of formula or its pharmaceutically acceptable salt:
、
Formula I
Wherein,
R1、R2、R3、R4、R5Separately or concurrently it is selected from H, halogen, hydroxyl, nitro or C1~C8Alkyl；
R8、R9、R10、R11、R12Separately or concurrently it is selected from H or C1~C4Alkyl.
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that: R1、R2、R3、R4、R5Point
Not or it is simultaneously selected from H or C1~C8Alkyl.
3. compound according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that: R1、R2、R3、R4、R5Point
Not or it is simultaneously selected from H or C1~C4Alkyl.
4. compound according to claim 3 or its pharmaceutically acceptable salt, it is characterised in that: R1Selected from H or C1~C4
Alkyl；R2、R3、R4、R5It is simultaneously H.
5. compound according to claim 4 or its pharmaceutically acceptable salt, it is characterised in that: R8、R9、R10、R11、R12
Separately or concurrently it is selected from H or methyl, ethyl.
6. compound according to claim 5 or its pharmaceutically acceptable salt, it is characterised in that: the compound is、、、、、、
、。
7. the preparation method of compound described in claim 1, it is characterised in that: the following steps are included:
, compound a reacted under conditions of alkali, catalyst and nitrogen-containing solvent with compound b, obtain compound c；
Wherein, R1、R2、R3、R4、R5Separately or concurrently it is selected from H, halogen, hydroxyl, nitro or C1~C8Alkyl, X are halogen；
, compound c reacted under conditions of alkali, catalyst and alcohols solvent with diamines, obtain I compound represented of formula；
Wherein, the diamines isOr, R8、R9、R10、R11、R12Separately or concurrently selected from H or
C1~C4Alkyl.
8. preparation method according to claim 7, it is characterised in that: stepIn, the compound a is by following steps
Be prepared: compound a -1 is in 50% sulfuric acid, NaNO2Under conditions of reacted, obtain compound a；
Wherein, R1Selected from H, halogen, hydroxyl, nitro or C1~C8Alkyl；
The w/v of the compound a -1 and 50% sulfuric acid is 1:3.4~5.0 g/ml, the compound a -1 and NaNO2's
Molar ratio is 1:2.5~3.0.
9. preparation method according to claim 7, it is characterised in that: stepIn, the compound a is with compound b's
Molar ratio is 1:1.0~1.2, and the molar ratio of the compound a and alkali is 1:5~10, mole of the compound a and catalyst
Than for 1:0.25~0.30, the w/v of the compound a and nitrogen-containing solvent is 1:50 g/ml.
10. preparation method according to claim 7, it is characterised in that: stepIn, the alkali is selected from potassium carbonate or carbon
Sour sodium, the catalyst are selected from cuprous iodide or cuprous bromide, and the nitrogen-containing solvent is selected from n,N-Dimethylformamide
Or DMAC N,N' dimethyl acetamide.
11. preparation method according to claim 7, it is characterised in that: stepIn, the compound c and diamines rub
, than being 1:1.2~1.5, the molar ratio of the compound c and alkali is 1:3~3.5, mole of the compound c and catalyst for you
Than for 1:2.2-2.6, the w/v of the compound c and alcohols solvent is 1:30~45g/ml.
12. preparation method according to claim 7, it is characterised in that: stepIn, the alkali is selected from potassium carbonate or carbon
Sour sodium, the catalyst are selected from iodine or N- bromo-succinimide, and the alcohols solvent is the tert-butyl alcohol.
13. preparation method according to claim 7, it is characterised in that: stepIn, the temperature of the reaction is 70~80 DEG C.
14. preparation method according to claim 7 or 8, it is characterised in that: R1、R2、R3、R4、R5Separately or concurrently it is selected from H
Or C1~C8Alkyl.
15. preparation method according to claim 14, it is characterised in that: R1、R2、R3、R4、R5Separately or concurrently selected from H or
C1~C4Alkyl.
16. preparation method according to claim 15, it is characterised in that: R1Selected from H or C1~C4Alkyl；R2、R3、R4、R5Together
When be H.
17. preparation method according to claim 7, it is characterised in that: R8、R9、R10、R11、R12Separately or concurrently selected from H or
Methyl, ethyl.
18. preparation method according to claim 7, it is characterised in that: the halogen is selected from fluorine, chlorine, bromine or iodine.
19. a kind of pharmaceutical composition, it is characterised in that: it is with compound described in claim 1~6 any one or its medicine
Acceptable salt is active constituent on, in addition the preparation that pharmaceutically common auxiliary material is prepared.
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| CN103012254A (en) * | 2005-05-10 | 2013-04-03 | 英特芒尼公司 | Pyridone derivatives for modulating stress-activated protein kinase system |
| CN103570630A (en) * | 2012-07-18 | 2014-02-12 | 广东东阳光药业有限公司 | Heterocyclic nitrogen derivative and application thereof in medicines |
| WO2016065326A2 (en) * | 2014-10-24 | 2016-04-28 | Bristol-Myers Squibb Company | Modified fgf-21 polypeptides and uses thereof |
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| CN103012254A (en) * | 2005-05-10 | 2013-04-03 | 英特芒尼公司 | Pyridone derivatives for modulating stress-activated protein kinase system |
| CN103570630A (en) * | 2012-07-18 | 2014-02-12 | 广东东阳光药业有限公司 | Heterocyclic nitrogen derivative and application thereof in medicines |
| WO2016065326A2 (en) * | 2014-10-24 | 2016-04-28 | Bristol-Myers Squibb Company | Modified fgf-21 polypeptides and uses thereof |
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