CN106083702A - Pirfenidone derivant and preparation method thereof - Google Patents
Pirfenidone derivant and preparation method thereof Download PDFInfo
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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 discloses the compound shown in formula I or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate: wherein, R1、R2、R3、R4、R5Separately or concurrently selected from H, halogen, hydroxyl, nitro, carbonyl or C1～C8Alkyl；R6、R7Separately or concurrently selected from H, O=C NH2, S=C NH2, phenyl, methyl substituted phenyl, the substituted phenyl of ethyl, the phenyl of methoxy substitution, the substituted phenyl of ethyoxyl.Compared with pirfenidone, noval chemical compound of the present invention has specific C=N N structure, and the fibrosis activity of noval chemical compound of the present invention is significantly better than pirfenidone, particularly, the noval chemical compound of the present invention suppression ratio to fibroblast proliferation, relative to pirfenidone increase rate at least more than 50%, simultaneously, noval chemical compound of the present invention is also significantly better than pirfenidone to the inhibition of fibroblasts to secrete fibronectin, has good industrialization prospect.
Description
Technical field
The present invention relates to pirfenidone derivant and preparation method thereof.
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,
R1、R2、R3、R4、R5Separately or concurrently selected from H, halogen, hydroxyl, nitro, carbonyl or C1～C8Alkyl；
R6、R7Separately or concurrently selected from H, O=C-NH2, S=C-NH2, phenyl, methyl substituted phenyl, ethyl substituted
Phenyl, the phenyl of methoxy substitution, the substituted phenyl of ethyoxyl.
Further, R1、R2、R3、R4、R5Separately or concurrently selected from H or C1～C8Alkyl；Preferably, R1、R2、R3、R4、R5
Separately or concurrently selected from H or C1～C4Alkyl.
Further, R1Selected from H or C1～C4Alkyl；R2、R3、R4、R5It is H simultaneously.
Further, R6、R7In at least one be H.
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 react under conditions of alkali, catalyst and nitrogenous kind solvent with compound b, obtain compound
c；
Wherein, R1、R2、R3、R4、R5Separately or concurrently selected from H, halogen, hydroxyl, nitro, carbonyl or C1～C8Alkyl, X is
Halogen；
2., compound c react under conditions of catalyst and alcohols solvent with compound d, obtain the change shown in formula I
Compound；
Wherein, R6、R7Separately or concurrently selected from H, O=C-NH2, S=C-NH2, phenyl, methyl substituted phenyl, ethyl take
The phenyl in generation, the phenyl of methoxy substitution, the substituted phenyl of ethyoxyl.
Further, step 1. in, described compound a is to be prepared by following steps: compound a-1 is at 50% sulfur
Acid, NaNO2Under conditions of react, obtain compound a；
Wherein, R1Selected from H, halogen, hydroxyl, nitro, carbonyl or C1～C8Alkyl；
The w/v of described compound a-1 and 50% sulphuric acid is 1:3.4～5.0g/ml, described compound a-1 with
NaNO2Mol ratio be 1:2.5～3.0.
Further, step 1. 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 1. 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, step 2. in, the mol ratio of described compound c and compound d is 1:1.2～1.5, described compound
C is 1:60～80g/ml with the w/v of alcohols solvent.
Further, step 2. in, described catalyst be selected from hydrochloric acid or glacial acetic acid, described alcohols solvent be selected from ethanol
Or methanol.
Further, step 2. in, the temperature of described reaction is 15～25 DEG C.
Further, R1、R2、R3、R4、R5Separately or concurrently selected from H or C1～C8Alkyl；Preferably, R1、R2、R3、R4、R5
Separately or concurrently selected from H or C1～C4Alkyl；It is furthermore preferred that R1Selected from H or C1～C4Alkyl；R2、R3、R4、R5It is H simultaneously.
Further, described halogen is selected from fluorine, chlorine, bromine or iodine.
Further, R6、R7In at least one be H.
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.
Compared with pirfenidone, noval chemical compound of the present invention has a specific C=N-N structure, and noval chemical compound of the present invention
Fibrosis activity is significantly better than pirfenidone, particularly, the noval chemical compound of the present invention suppression ratio to fibroblast proliferation, phase
For pirfenidone increase rate at least more than 50%, meanwhile, noval chemical compound of the present invention is to fibroblasts to secrete fiber even
The inhibition connecing albumen is also significantly better than pirfenidone, has 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.
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): MTT method；IC50(half maximal inhibitory
Concentration): half-inhibition concentration.
Embodiment 1, the synthesis of the compounds of this invention 5f
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 4 (5-methyl isophthalic acid-(4-formylphenyl)-2-(1H) pyridone)
Adding 0.10g (1mmol, 1quiv.) compound 3 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 makees molten
Agent, return stirring reaction 1h, TLC follow the tracks of, reaction finish, cooling, add 30mL water, 3 × 20mL ethyl acetate extract, organic layer without
Aqueous sodium persulfate 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 pale yellow
Color solid: compound 4.
3, the synthesis of compound 5f
0.21g (1mmol, 1equiv.) compound 4, stirring is added in the 25mL reaction bulb fill 15mL dehydrated alcohol
To all dissolving, then dripping 0.13g (1.2mmol, 1.2equiv.) 30% hydrazine hydrate wherein, 3 concentrated hydrochloric acid make catalyst,
Reaction 3h is stirred at room temperature, and reaction is finished, is spin-dried for, ethyl alcohol recrystallization, obtains compound 5f, and the single step yield of this step is 76%.
Compound 5f:4-(5-methyl-2-oxo-pyridin-1 (2H)-yl) benzaldehyde hydrozone, white powder, m.p.150-152
℃；
1H NMR (400MHz, DMSO) δ 7.74 (s, 1H), 7.57 (d, J=8.5Hz, 2H), 7.41 (s, 1H), 7.38
7.30 (m, 3H), 6.95 (s, 2H), 6.42 (d, J=9.3Hz, 1H), 2.03 (s, 3H)；
13C NMR(101MHz,DMSO)δ160.47,143.02,139.77,136.98,136.17,135.98,126.82,
125.39,120.17,114.15,16.34；
HRMS(ESI)calcd for C13H13N3O[M+H]+228.1138,found 228.1134；[M+Na]+
250.0957；found 250.0963.
Embodiment 2, the synthesis of the compounds of this invention 5g
According to the method that embodiment 1 is similar, with phenylhydrazine or phenylhydrazine hydrochloride as raw material in step 3, prepare compound 5g,
The single step yield of the 3rd step is 72%.
Compound 5g:4-(5-methyl-2-oxo-pyridin-1 (2H)-yl) benzaldehyde-phenylhydrazone, buff powder,
m.p.139-141℃；
1H NMR (400MHz, DMSO) δ 7.95 (s, 1H), 7.74 (d, J=8.5Hz, 2H), 7.43 7.37 (m, 3H),
7.11 (d, J=7.6Hz, 2H), 7.00 (s, 2H), 6.92 (t, J=7.3Hz, 2H), 6.75 (t, J=7.2Hz, 1H), 6.46
(d, J=9.3Hz, 1H), 2.06 (s, 3H)；
13C NMR(101MHz,DMSO)δ160.47,145.70,145.22,143.30,140.10,136.11,135.70,
135.22,129.17,128.94,127.02,125.91,121.37,120.05,118.96,114.53,112.14,16.40；
HRMS(ESI)calcd for C19H17N3O[M+H]+304.1451,found 304.1447；[M+Na]+
326.1270,found 326.1268。
Embodiment 3, the synthesis of the compounds of this invention 5h
According to the method that embodiment 1 is similar, with semicarbazide hydrochloride as raw material in step 3, prepare compound 5h, the 3rd
The single step yield of step is 75%.
Compound 5h:N-(4-(5-methyl-2-oxo-pyridin-1 (2H)-yl) benzylidene) semicarbazides, white powder,
m.p.192-194℃；
1H NMR (400MHz, DMSO) δ 10.40 (s, 1H), 7.90 (s, 1H), 7.84 (d, J=8.5Hz, 2H), 7.45
(s, 1H), 7.42 7.35 (m, 3H), 6.58 (s, 2H), 6.42 (d, J=9.3Hz, 1H), 2.04 (s, 3H)；
13C NMR(101MHz,DMSO)δ160.44,156.78,143.18,141.16,138.23,135.88,134.49,
126.95,120.21,114.28,16.37；
HRMS(ESI)calcd for C14H14N4O2[M+H]+271.1196,found 271.1188；[M+Na]+
293.1015,found 293.1009。
Embodiment 4, the synthesis of the compounds of this invention 5i
According to the method that embodiment 1 is similar, with thiosemicarbazide as raw material in step 3, prepare compound 5i, the 3rd
The single step yield of step is 75%.
Compound 5i:N-(4-(5-methyl-2-oxo-pyridin-1 (2H)-yl) benzylidene) thiosemicarbazide, light yellow
Powder, m.p.224-226 DEG C；
1H NMR (400MHz, DMSO) δ 11.53 (s, 1H), 8.27 (s, 1H), 8.09 (d, J=8.2Hz, 2H), 7.92
(d, J=8.5Hz, 2H), 7.40 (ddd, J=11.8,8.0,1.6Hz, 4H), 6.43 (d, J=9.3Hz, 1H), 2.04 (s,
3H)；
13C NMR(101MHz,DMSO)δ178.10,160.39,143.19,141.82,141.13,135.78,133.86,
127.76,126.99,120.24,114.30,16.38；
HRMS(ESI)calcd for C14H14N4OS[M+H]+287.0967,found 287.0988。
Embodiment 5, the synthesis of the compounds of this invention 7d
With compound 1'(2-aminopyridine in step 1) as raw material, according to the similar method of embodiment 1, preparing
Compound 7d, the single step yield of the 3rd step is 69%.
Compound 7d:4-(2-oxo-pyridin-1 (2H)-yl) benzaldehyde hydrozone, yellow powder, m.p.164-166 DEG C；
1H NMR (400MHz, DMSO) δ 7.75 (s, 1H), 7.63 (ddd, J=6.8,2.0,0.5Hz, 1H), 7.61
7.55 (m, 2H), 7.53 7.46 (m, 1H), 7.39 7.30 (m, 2H), 6.95 (s, 2H), 6.48 (dd, J=9.2,0.5Hz,
1H), 6.30 (td, J=6.7,1.3Hz, 1H)；
13C NMR(101MHz,DMSO)δ161.21,140.54,139.59,138.98,136.86,136.33,126.84,
125.41,120.51,105.61；
HRMS(ESI)calcd for C12H11N3O[M+H]+214.0981,found 214.0981.[M+Na]+
236.0800,found 236.0809。
Embodiment 6, the synthesis of the compounds of this invention 7e
According to the method that embodiment 5 is similar, with phenylhydrazine or phenylhydrazine hydrochloride as raw material in step 3, prepare compound 7e,
The single step yield of the 3rd step is 62%.
Compound 7e:4-(2-oxo-pyridin-1 (2H)-yl) benzaldehyde-phenylhydrazone, yellow powder, m.p.208-210 DEG C；
1H NMR (400MHz, DMSO) δ 7.93 (s, 1H), 7.75 (d, J=8.5Hz, 2H), 7.65 (dd, J=6.9,
1.7Hz, 1H), 7.50 (ddd, J=9.0,6.6,2.1Hz, 1H), 7.40 (d, J=8.5Hz, 2H), 7.29 7.20 (m, 2H),
7.11 (d, J=7.6Hz, 2H), 7.02 6.88 (m, 1H), 6.76 (t, J=7.2Hz, 1H), 6.49 (d, J=9.0Hz, 1H),
6.32 (td, J=6.7,1.2Hz, 1H)；
13C NMR(101MHz,DMSO)δ161.21,145.60,145.15,140.60,140.01,138.95,135.73,
135.20,129.06,126.99,125.93,121.44,120.53,118.97,114.45,112.12,105.69；
HRMS(ESI)calcd for C18H15N3O[M+H]+290.1294,found 290.1292.[M+Na]+
312.1111,found 312.1104。
Embodiment 7, the synthesis of the compounds of this invention 7f
According to the method that embodiment 5 is similar, with semicarbazide hydrochloride as raw material in step 3, prepare compound 7f, the 3rd
The single step yield of step is 66%.
Compound 7f:N-(4-(2-oxo-pyridin-1 (2H)-yl) benzylidene) semicarbazides, buff powder,
m.p.230-232℃；
1H NMR (400MHz, DMSO) δ 10.38 (s, 1H), 7.89 (s, 1H), 7.85 (d, J=8.5Hz, 2H), 7.66
(dd, J=6.9,1.6Hz, 1H), 7.51 (ddd, J=9.0,6.6,2.0Hz, 1H), 7.41 (d, J=8.5Hz, 2H), 6.58
(s, 2H), 6.48 (d, J=9.1Hz, 1H), 6.32 (td, J=6.7,1.2Hz, 1H)；
13C NMR(101MHz,DMSO)δ161.16,157.83,156.74,141.00,140.66,138.92,138.11,
134.66,126.97,120.55,105.73；
HRMS(ESI)calcd for C13H12N4O2[M+H]+257.1039,found 257.1035。
Embodiment 8, the synthesis of the compounds of this invention 7g
According to the method that embodiment 5 is similar, with thiosemicarbazide as raw material in step 3, prepare compound 7g, the 3rd
The single step yield of step is 68%.
Compound 7g:N-(4-(2-oxo-pyridin-1 (2H)-yl) benzylidene) thiosemicarbazide, Lycoperdon polymorphum Vitt powder,
m.p.222-224℃；
1H NMR (400MHz, DMSO) δ 11.53 (s, 1H), 8.28 (s, 1H), 8.10 (d, J=8.6Hz, 2H), 7.93
(d, J=8.5Hz, 2H), 7.66 (dd, J=6.9,1.6Hz, 1H), 7.54 7.47 (m, 1H), 7.43 (d, J=8.5Hz, 2H),
6.49 (d, J=8.9Hz, 1H), 6.32 (td, J=6.7,1.2Hz, 1H)；
13C NMR(101MHz,DMSO)δ178.11,161.13,141.65,141.07,140.69,138.82,134.02,
127.80,127.00,120.58,105.78；
HRMS(ESI)calcd for C13H12N4OS[M+H]+273.0811,found 273.0815。
Embodiment 9, the synthesis of the compounds of this invention 7h
According to the method that embodiment 5 is similar, step 3 is former with 4-methoxyl group phenylhydrazine or 4-methoxyphenyl hydrazine hydrochloride
Material, prepares compound 7h, and the single step yield of the 3rd step is 63%.
Compound 7h:4-(2-oxo-pyridin-1 (2H)-yl) benzene methylene aldehyde (4-methoxyl group) phenylhydrazone, yellow powder,
m.p.204-206℃；
1H NMR (400MHz, DMSO) δ 10.31 (s, 1H), 7.86 (s, 1H), 7.72 (d, J=8.5Hz, 2H), 7.66
(dd, J=6.8,1.8Hz, 1H), 7.51 (ddd, J=8.9,6.6,2.1Hz, 1H), 7.39 (d, J=8.5Hz, 2H), 7.07
7.00 (m, 2H), 6.88 6.82 (m, 2H), 6.49 (d, J=9.1Hz, 1H), 6.32 (td, J=6.7,1.2Hz, 1H), 3.69
(s,3H)；
13C NMR(101MHz,DMSO)δ161.20,152.78,140.56,139.73,139.06,135.95(s),
134.02,126.95,125.67,120.52,114.67,113.13,105.64,55.27；
HRMS(ESI)calcd for C19H17N3O2[M+H]+320.1400,found 320.1394；[M+Na]+
342.1219,found 342.1209。
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)δ160.41,142.98,141.01,136.04,128.96,127.92,126.71,
120.21,114.01,16.30。
The beneficial effect of the compounds of this invention is described below by way of test example.
Test example 1, 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
Being obviously improved, increase rate is at least more than 50%.
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 substantially better than pirfenidone to the inhibition of 3T3L1 emiocytosis Fn
(PFD)。
Test example 2, 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
| growth rate | inhibition rate | |
| Compound | 1e-5Mol | 1e-5Mol |
| Blank (DMSO) | 0.987 | 0.013 |
| Positive control (PFD) | 0.642 | 0.358 |
| The compounds of this invention 5f | 0.632 | 0.368 |
| The compounds of this invention 5h | 0.757 | 0.243 |
| The compounds of this invention 5i | 0.134 | 0.866 |
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
| IC<sub>50</sub>[μM] | HeLa | LnCAP | MCF7 |
| Positive control (PFD) | >25 | >25 | >25 |
| The compounds of this invention 5f | >25 | 16.64 | >25 |
| The compounds of this invention 5h | >25 | >25 | >25 |
| The compounds of this invention 5i | 10.96 | 32.59 | 7.95 |
The above results shows, the compounds of this invention is the most suitable with the anti-tumor activity effect of pirfenidone；Wherein, chemical combination
The anti-tumor activity effect of thing 5f, 5i is better than pirfenidone.
In sum, compared with pirfenidone, noval chemical compound of the present invention has specific C=N-N structure, and the present invention is new
The fibrosis activity of compound is significantly better than pirfenidone, and particularly, noval chemical compound of the present invention is to fibroblast proliferation
Suppression ratio, relative to pirfenidone increase rate at least more than 50%, meanwhile, fibroblast is divided by noval chemical compound of the present invention
The inhibition secreting fibronectin is also significantly better than pirfenidone, has good industrialization prospect.
Claims (16)
1. the compound shown in formula I or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate:
Wherein,
R1、R2、R3、R4、R5Separately or concurrently selected from H, halogen, hydroxyl, nitro, carbonyl or C1～C8Alkyl；
R6、R7Separately or concurrently selected from H, O=C-NH2, S=C-NH2, phenyl, methyl substituted phenyl, the substituted phenyl of ethyl,
The substituted phenyl of the phenyl of methoxy substitution, ethyoxyl.
Compound the most according to claim 1 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate, its
It is characterised by: R1、R2、R3、R4、R5Separately or concurrently selected from H or C1～C8Alkyl；Preferably, R1、R2、R3、R4、R5Difference or same
Time selected from H or C1～C4Alkyl.
Compound the most according to claim 2 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate, its
It is characterised by: R1Selected from H or C1～C4Alkyl；R2、R3、R4、R5It is H simultaneously.
4. according to the compound described in claim 1 or 3 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate,
It is characterized in that: R6、R7In at least one be H.
Compound the most according to claim 4 or its pharmaceutically acceptable salt, crystal formation, hydrate or solvate, its
It is characterised by: the compound shown in formula I is
6. the preparation method of compound described in Claims 1 to 5 any one, it is characterised in that: comprise the following steps:
1., compound a react under conditions of alkali, catalyst and nitrogenous kind solvent with compound b, obtain compound c；
Wherein, R1、R2、R3、R4、R5Separately or concurrently selected from H, halogen, hydroxyl, nitro, carbonyl or C1～C8Alkyl, X is halogen；
2., compound c react under conditions of catalyst and alcohols solvent with compound d, obtain the chemical combination shown in formula I
Thing；
Wherein, R6、R7Separately or concurrently selected from H, O=C-NH2, S=C-NH2, phenyl, methyl substituted phenyl, ethyl substituted
Phenyl, the phenyl of methoxy substitution, the substituted phenyl of ethyoxyl.
Preparation method the most according to claim 6, it is characterised in that: step 1. in, described compound a is by following steps
Prepare: compound a-1 is at 50% sulphuric acid, NaNO2Under conditions of react, obtain compound a；
Wherein, R1Selected from H, halogen, hydroxyl, nitro, carbonyl or C1～C8Alkyl；
The w/v of described compound a-1 and 50% sulphuric acid is 1:3.4～5.0g/ml, described compound a-1 and NaNO2's
Mol ratio is 1:2.5～3.0.
Preparation method the most according to claim 6, it is characterised in that: step 1. 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 6, it is characterised in that: step 1. 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.
Preparation method the most according to claim 6, it is characterised in that: step 2. in, described compound c and compound d's
Mol ratio is 1:1.2～1.5, and described compound c is 1:60～80g/ml with the w/v of alcohols solvent.
11. preparation methoies according to claim 6, it is characterised in that: step 2. in, described catalyst selected from hydrochloric acid or
Glacial acetic acid, described alcohols solvent is selected from ethanol or methanol.
12. preparation methoies according to claim 6, it is characterised in that: step 2. in, the temperature of described reaction is 15～25
℃。
13. preparation methoies according to claim 6, it is characterised in that: R1、R2、R3、R4、R5Separately or concurrently selected from H or C1
～C8Alkyl；Preferably, R1、R2、R3、R4、R5Separately or concurrently selected from H or C1～C4Alkyl；It is furthermore preferred that R1Selected from H or C1~
C4Alkyl；R2、R3、R4、R5It is H simultaneously.
14. preparation methoies according to claim 6, it is characterised in that: described halogen is selected from fluorine, chlorine, bromine or iodine.
15. preparation methoies according to claim 6, it is characterised in that: R6、R7In at least one be H.
16. 1 kinds of pharmaceutical compositions, it is characterised in that: it is with the compound described in Claims 1 to 5 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.
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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 |
| CN114057630A (en) * | 2021-12-23 | 2022-02-18 | 郑州大学 | Pirfenidone derivative and synthetic method and application thereof |
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