CN107814773B - Quinazolinone-containing diaryl urea compound and preparation method and application thereof - Google Patents
Quinazolinone-containing diaryl urea compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN107814773B CN107814773B CN201711117383.0A CN201711117383A CN107814773B CN 107814773 B CN107814773 B CN 107814773B CN 201711117383 A CN201711117383 A CN 201711117383A CN 107814773 B CN107814773 B CN 107814773B
- Authority
- CN
- China
- Prior art keywords
- quinazolinone
- reaction
- ketone
- preparing
- aminophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The diarylurea compounds containing quinazolinone can obviously inhibit LAD2 cells from releasing β -hexosaminidase, show obvious dose correlation, can be used for preparing antiallergic drugs, particularly can be used for preparing drugs antagonizing LAD2 cells from releasing β -hexosaminidase, and relieve the pain and the burden of patients.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a diaryl urea compound containing quinazolinone, and a preparation method and application thereof.
Background
The anaphylactoid reaction of the drugs means that a plurality of drugs used in clinic are neither antigens nor haptens, and react when the drugs are contacted with the organism for the 1 st time, the clinical performance is similar to the anaphylactoid reaction, which is called anaphylactoid reaction, the anaphylactoid reaction occupies a large proportion in the drug anaphylactoid case, the anaphylactoid reaction of the drugs not only limits the normal use of a plurality of drugs, influences the treatment of patients, but also aggravates the pain and the burden of the patients, the detection of the release amount of β -hexosaminidase is widely applied to the characterization and evaluation of the anaphylactoid reaction at the clinical and laboratory levels, therefore, the preparation of the compound for antagonizing the LAD2 cell release β -hexosaminidase for developing the medicine for antagonizing the anaphylactoid reaction is one of the difficulty and the hot problem in the current research field.
Disclosure of Invention
The invention aims to provide a diaryl urea compound containing quinazolinone, a preparation method and application thereof, and the compound can inhibit β -hexosaminidase released by human mast cells and can be applied to preparation of antiallergic drugs.
The invention is realized by the following technical scheme:
a diaryl urea compound containing quinazolinone, which has the following structural formula:
wherein R is1、R2Is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy or halogen.
Preferably, the halogen is fluorine or chlorine.
Preferably, the alkyl is an alkyl of 1 to 4 carbon atoms; the alkoxy is an alkoxy containing 1 to 3 carbon atoms; the halogenated alkyl is trifluoromethyl, and the halogenated alkoxy is trifluoromethoxy.
Preferably, the structural formula of the diarylurea compound containing quinazolinone is as follows:
the preparation method of the diarylurea compound containing quinazolinone comprises the following steps:
1) preparing 7-fluoroquinazolin-4 (3H) -one from 2-amino-4-fluorobenzoic acid and formamide through cyclization reaction;
2) preparing 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone by nucleophilic substitution reaction of 7-fluoroquinazoline-4 (3H) -ketone and p-aminosulfol;
3) phenyl isocyanate containing substituent groups reacts with 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone to obtain the diaryl urea compound containing quinazolinone.
Preferably, in step 2) of the above-mentioned production method,
under the protection of inert gas, 7-fluoroquinazoline-4 (3H) -ketone and K2CO3Adding the mixture into dimethyl sulfoxide, and heating to 110-120 ℃; dropwise adding a dimethyl sulfoxide solution of p-aminophenol into a reaction system, reacting for 0.8-1.5H, pouring the reaction solution into ice water, extracting with ethyl acetate, and performing column chromatography separation and purification to obtain 7- ((4-aminophenyl) thio) quinazoline-4 (3H) -ketone;
wherein, according to molar weight, the ratio of 7-fluoroquinazolin-4 (3H) -one: k2CO3: 1, para-aminophenol ═ 1: (1.3-1.8): (1.2-2.0).
The preparation method of the diarylurea compound containing quinazolinone comprises the following steps:
1) preparing 7-bromoquinazoline-4 (3H) -ketone by cyclization reaction of 2-amino-4-bromobenzoic acid and formamide;
2) reacting 7-bromoquinazolin-4 (3H) -one with p-nitrothiophenol to prepare 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one;
3) preparing 7- ((4-aminophenyl) thio) quinazolin-4 (3H) -one from 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one by a reduction reaction;
4) phenyl isocyanate containing substituent groups and 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone are subjected to nucleophilic reaction to obtain the diaryl urea compound containing quinazolinone.
Preferably, in step 2) of the above-mentioned production method,
under the protection of inert gas, 7-bromoquinazoline-4 (3H) -ketone, p-nitrothiophenol and K2CO3Heating the mixture of Cu to 130 ℃, and reacting for 6 h; cooling to room temperature, separating out a solid, and performing suction filtration to obtain 7- ((4-nitrophenyl) sulfenyl) quinazoline-4 (3H) -ketone;
wherein, according to molar weight, 7-bromoquinazolin-4 (3H) -one: para nitro sulfurPhenol: k2CO3：CuI＝1：(2～4)：(1～1.5)：(0.005～0.1)。
The diaryl urea compound containing quinazolinone is applied to preparing antiallergic drugs.
Preferably, the antiallergic agent is an agent which antagonizes β -hexosaminidase released from human mast cells.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention provides a diaryl urea Compound containing quinazolinone, a preparation method and an application thereof, and experiments prove that the Compound can obviously inhibit β -hexosaminidase released by LAD2 cells caused by Compound 48/80 and Substance P and has obvious dose correlation, so the Compound can be used for preparing antiallergic drugs, in particular for preparing drugs for antagonizing β -hexosaminidase released by LAD2 cells, which can reduce the worry of patients and doctors about the anaphylactoid reaction of the drugs, obtain more and more efficient treatment schemes and relieve the pain and the burden of the patients.
Drawings
FIG. 1 is a first scheme of the synthesis of diarylureas containing quinazolinones of the present invention.
FIG. 2 is a second scheme of the synthesis of diarylureas containing quinazolinones of the present invention.
FIG. 3 shows the release rate of β -hexosaminidase from human primary mast cells (LAD2 cells) treated with different concentrations of B10-S when Compound 48/80 was used as a sensitizing component.
FIG. 4 shows the release rate of β -hexosaminidase from human primary mast cells (LAD2 cells) treated with different concentrations of B10-S when Presence P was used as a sensitizing component.
Detailed Description
The present invention will now be described in further detail with reference to specific examples, which are intended to be illustrative, but not limiting, of the invention.
The invention provides a diaryl urea compound containing quinazolinone, which has the following chemical structural formula:
wherein R is1、R2Is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy or halogen.
The preparation method of the diaryl urea compound containing quinazolinone comprises 2 preparation methods, namely preparation methods 1 and 2
The preparation method 1 of the diarylurea compound containing quinazolinone comprises the following steps:
1) preparing 7-fluoroquinazolin-4 (3H) -one from 2-amino-4-fluorobenzoic acid and formamide through cyclization reaction;
2) preparing 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone by nucleophilic substitution reaction of 7-fluoroquinazoline-4 (3H) -ketone and p-aminosulfol;
3) phenyl isocyanate containing substituent groups and 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone are subjected to nucleophilic reaction to obtain the diaryl urea compound containing quinazolinone.
Preferably, in step 1) of preparation method 1, 2-amino-4-fluorobenzoic acid is dissolved in formamide and reacted at 160 ℃ under the protection of nitrogen, after the reaction is finished, the reaction solution is poured into ice water, filtered, and a filter cake is recrystallized by methanol to obtain 7-fluoroquinazolin-4 (3H) -one.
Preferably, in step 2) of preparation method 1, 7-fluoroquinazolin-4 (3H) -one and K2CO3Adding the mixture into dimethyl sulfoxide, performing argon protection, heating to 115 ℃, dropwise adding a dimethyl sulfoxide solution of p-aminophenol into the reaction solution, reacting for 1H, pouring the reaction solution into ice water after the reaction is finished, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, performing reduced pressure concentration to obtain a crude product, and performing column chromatography separation and purification to obtain 7- ((4-aminophenyl) thio) quinazolin-4 (3H) -one.
Preferably, in step 3) of preparation method 1, the compound 7- ((4-aminophenyl) thio) quinazolin-4 (3H) -one, phenyl isocyanate containing substituent, is dissolved in anhydrous tetrahydrofuran, reacted at room temperature, and detected by TLC. And after the reaction is finished, evaporating the solvent under reduced pressure to obtain a crude product, and separating the crude product by using a chromatographic column to obtain the diaryl urea compound containing quinazolinone.
The preparation method 2 of the diarylurea compound containing quinazolinone comprises the following steps:
1) preparing 7-bromoquinazoline-4 (3H) -ketone by cyclization reaction of 2-amino-4-bromobenzoic acid and formamide;
2) preparing 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one from 7-bromoquinazolin-4 (3H) -one and p-nitrothiophenol through a substitution reaction;
3) preparing 7- ((4-aminophenyl) thio) quinazolin-4 (3H) -one from 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one by a reduction reaction;
4) phenyl isocyanate containing substituent groups and 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone are subjected to nucleophilic reaction to obtain the diaryl urea compound containing quinazolinone.
Preferably, in step 1) of the preparation method 2, 2-amino-4-bromobenzoic acid is dissolved in formamide, microwave reaction is carried out under the protection of nitrogen, after the reaction is finished, the reaction solution is added into ice water, ethyl acetate is used for extraction, the solvent is evaporated under reduced pressure after the extracted organic phase is washed and dried to obtain a crude product, and the crude product is separated by a chromatographic column to obtain 7-bromoquinazolin-4 (3H) -one.
Preferably, in step 2) of preparation Process 2, 7-bromoquinazolin-4 (3H) -one, p-nitrothiophenol, K2CO3Adding CuI into a round-bottom flask, vacuumizing under the ice bath condition, protecting nitrogen, then heating to 130 ℃, and reacting for 6 hours. After the reaction is finished, cooling to room temperature, separating out solid, and performing suction filtration to obtain the 7- ((4-nitrophenyl) sulfenyl) quinazoline-4 (3H) -ketone.
Preferably, in step 3) of preparation method 2, 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one is dissolved in anhydrous methanol, then 10% (w/w) Pd/C is added, a catalytic amount of hydrazine hydrate is added, hydrogen gas is used for protection, and stirring is carried out at room temperature overnight. And (7) detecting by TLC. Filtering, concentrating the filtrate to obtain crude product, and separating by column chromatography to obtain 7- ((4-aminophenyl) thio) quinazoline-4 (3H) -ketone.
The preparation method of the diaryl urea compound containing quinazolinone is a new preparation method, and has the advantages of easily available raw material sources, mild reaction conditions, simple reaction process operation, and cheap and easily available reagents.
Example 1 was carried out:
1) preparing 7-fluoroquinazolin-4 (3H) -one (compound 2) from 2-amino-4-fluorobenzoic acid (compound 1) and formamide through cyclization reaction;
weighing 110.0 g of compound, dissolving in 30mL of formamide, reacting for 6h at 160 ℃ under the protection of nitrogen, pouring the reaction solution into ice water after the reaction is finished, filtering, and recrystallizing a filter cake with methanol to obtain the compound 2.
2) Preparing 7- ((4-aminophenyl) thio) quinazolin-4 (3H) -one (compound 4) from 7-bromoquinazolin-4 (3H) -one (compound 2) and p-aminosulfophenol (compound 3) through a substitution reaction;
compound 22.0 g, K2CO3Adding 1.26g of the mixture into 10mL of dimethyl sulfoxide, and heating to 115 ℃ under the protection of argon; and (3) dropwise adding a dimethyl sulfoxide (5mL) solution of 31.14 g of p-aminophenol into the reaction solution, reacting for 1h, pouring the reaction solution into ice water after the reaction is finished, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and separating and purifying by column chromatography to obtain the compound 4.
3) Phenyl isocyanate (compound 5) containing substituent groups and 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone (compound 4) are subjected to nucleophilic reaction to obtain the biphenyl urea compound containing quinazolinone.
As a specific example, 40.21 g of the compound was dissolved in an appropriate amount of anhydrous tetrahydrofuran solution, and 0.17g of 4-chloro-3-trifluoromethylphenylisonitrile ester was added with stirring. The reaction was stirred at room temperature overnight and checked by TLC. After the reaction is finished, the solvent is evaporated under reduced pressure to obtain a crude product. Separating the crude product by column chromatography to obtain compound 6(B10-S), wherein R1Is trifluoromethyl, R2Is chlorine. Mp>300℃；EI-MS(m/z)491.00[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),9.30(s,1H),9.21(s,1H),8.13(d,J＝4.0Hz,1H),8.03(s,1H),8.00(d,J＝8.0Hz,1H),7.64-7.67(m,4H),7.55(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,1H),7.11(d,J＝4.0Hz,1H).
Example 2 was carried out:
1) preparing 7-bromoquinazolin-4 (3H) -one (compound 8) by cyclization reaction of 2-amino-4-bromobenzoic acid (compound 7) and formamide;
5.1g of Compound 7 are weighed into a 250mL round-bottom flask using an analytical balance and 100mL of formamide solution, N2Microwave reaction (150 ℃ for 1.45h) under protection; after the reaction is finished, ice water is added while the mixture is hot, ethyl acetate is used for extraction, the organic phase is concentrated, stood to separate out solid, and filtered. The filter cake obtained is compound 8.
2) Reacting 7-bromoquinazolin-4 (3H) -one (Compound 8) with p-nitrothiophenol (Compound 9) to produce 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one (Compound 10);
80.5 g of compound, 1.02g of p-nitrothiophenol, K2CO30.3g of CuI and 0.02g of CuI are added into a 100mL round-bottom flask, and the mixture is vacuumized and protected by nitrogen under the ice bath condition, and then the temperature is raised to 130 ℃ for reaction for 6 hours; after the reaction is finished, cooling to room temperature, separating out solid, and performing suction filtration to obtain a compound 10.
3) Preparation of 7- ((4-aminophenyl) thio) quinazolin-4 (3H) -one (compound 4) by reduction of 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one (compound 10);
100.1 g of the compound and 0.01g of Pd/C were put in a 50mL round-bottomed flask, 20mL of anhydrous methanol was added, and then 100. mu.L of hydrazine hydrate (80%) was added, and the mixture was reacted overnight at room temperature under hydrogen gas. And (4) detecting by TLC, filtering after the reaction is finished, concentrating the filtrate, and performing column chromatography separation to obtain a compound 4.
4) Phenyl isocyanate (compound 5) containing substituent groups and 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone (compound 4) are subjected to nucleophilic reaction to obtain the biphenyl urea compound containing quinazolinone.
As a specific example, 40.21 g of the compound was dissolved in an appropriate amount of anhydrous tetrahydrofuranTo the solution, 0.17g of 4-chloro-3-trifluoromethylphenylisonitrile acid ester was added under stirring. The reaction was stirred at room temperature overnight and checked by TLC. After the reaction is finished, the solvent is evaporated under reduced pressure to obtain a crude product. Separating the crude product by column chromatography to obtain compound 6(B10-S), wherein R1Is trifluoromethyl, R2Is chlorine. Mp>300℃；EI-MS(m/z)491.00[M+H]+.1H NMR (400MHz, DMSO-d6) δ 12.22(s,1H),9.30(s,1H),9.21(s,1H),8.13(d, J ═ 4.0Hz,1H),8.03(s,1H),8.00(d, J ═ 8.0Hz,1H),7.64-7.67(m,4H),7.55(d, J ═ 8.0Hz,2H),7.24(d, J ═ 8.0Hz,1H),7.11(d, J ═ 4.0Hz, 1H). The structure of the obtained target compound 6(B10-S) is as follows:
the following screens and descriptions will be made on the pharmaceutical activity of the quinazolinone-containing diaryl urea compounds prepared by the present invention.
And (3) screening the antiallergic activity of the biphenyl urea compound containing quinazolinone.
The inhibitory activity of the diarylurea compound (B10-S) containing quinazolinone on mast cell degranulation is tested by adopting a human primary mast cell LAD2 cell β -hexosaminidase release rate determination experiment.
Example 3 of implementation:
1) reagent
0.1% Triton X-100 lysate: mu.L of Triton X-100 was dissolved in 10mL of PBS to obtain 0.1% Triton X-100 lysate.
0.1mol/L citric acid/sodium citrate buffer solution (pH 4.5): 2.101g of citric acid monohydrate is weighed and dissolved in 100mL of triple distilled water to obtain 0.1mol/L citric acid solution, and the solution is stored at 4 ℃ in a dark place. 2.941g of sodium citrate was weighed and dissolved in 100mL of triple distilled water to obtain 0.1mol/L sodium citrate solution, which was stored at 4 ℃ in the dark. Before use, according to the proportion of 0.1mol/L citric acid: 0.1mol/L sodium citrate 10.4: 9.6(v/v) to give a 0.1mol/L citric acid/sodium citrate buffer solution.
1mmol/L β -hexosamine solution 0.034g of β -hexosamine was weighed and dissolved in 100mL of 0.1mol/L citric acid/sodium citrate buffer solution to give 1mmol/L β -hexosamine solution.
0.1mol/L Na2CO3/NaHCO3Stop solution (pH 11.0): weighing 1.055g Na2CO3Dissolved in 100mL of triple distilled water to obtain 0.1mol/L of Na2CO3The solution was stored at 4 ℃ in the dark. 0.84g NaHCO was weighed3Dissolving in 40mL of triple distilled water to obtain 0.1mol/L NaHCO3And (3) solution. Before use, the ratio of Na is 0.1mol/L2CO3：0.1mol/L NaHCO39: 1(v/v) to obtain 0.1mol/L Na2CO3/NaHCO3And (4) stopping the solution.
TM buffered saline solution (TM-buffer): 6.954g NaCl, 0.353g KCl and 0.282g CaCl were weighed2、0.143g MgSO4、0.162g KH2PO42.383g HEPES, 0.991g glucose and 1g BSA, adding 800mL of triple distilled water, stirring for dissolving, adding the triple distilled water to the final volume of 1L, adjusting the pH value to 7.3, filtering and sterilizing by using a sterilized 0.22 mu m microporous filter membrane in a super clean bench, and storing at 4 ℃.
2) Experimental procedure
The cell suspension was diluted to a final concentration of 5X 105cells/mL, 100. mu.L per well, were seeded in 96-well plates (final cell mass per well was 5X 10)4Individual cells). Place 96-well plate in CO2In the incubator, the cells are incubated overnight (2 hours in primary cell culture) and the cells are allowed to adhere.
The next day, after centrifugation, the original medium was aspirated from each well, and the cells were grouped according to different groups, with different reagents added:
negative control group (control): adding 100 μ L TM buffer solution;
experimental cell groups: adding 100 μ L TM buffer solution containing B10-S, setting different gradients for the final concentration of B10-S;
blank cell group (Blank): adding 100 μ L TM buffer solution;
incubate in incubator for 30 min. After 30min, the supernatant was discarded by centrifugation. The negative control group and the experimental cell group were added with TM buffer solution containing 30. mu.g/mL Compound 48/80 or 4. mu.g/mL Substance P, and the blank cell group was added with 100. mu.L of TM buffer solution.
Adding reagent, culturing each group of cells at 37 deg.C for 30min, stopping on ice for 10min, collecting supernatant, and centrifuging at 4 deg.C for 10min at 1000rpm to obtain corresponding cell culture medium supernatant; and (3) completely sucking the culture medium supernatant of the blank cell group cells, then using 0.1% Triton X-100 to crack the blank cell group cells for 5min, stopping on ice for 10min, uniformly blowing the lysate, and centrifuging at the temperature of 4 ℃ and the rpm of 1000 for 10min to obtain the blank cell group cell lysate.
Respectively adding 50 μ L of positive control group cell culture medium supernatant, experimental cell group cell culture medium supernatant, blank cell group cell culture medium supernatant and blank cell group cell lysate into a blank 96 pore plate, adding 50 μ L of β -hexosamine with a substrate of 1mmol/L into each pore, incubating for 90min in an incubator at 37 ℃, and adding 150 μ L of 0.1mol/LNa into each pore after incubation is completed2CO3/NaHCO3Placing a 96-well plate on a room temperature shaking table, shaking and uniformly mixing for 2min, and detecting the absorbance value (OD) of each sample to be measured on an enzyme-labeling instrument at 405nm, β -hexosaminidase release rate:
β -hexosaminidase release rate (%). is absorbance (OD)/(absorbance of supernatant of cell culture medium of blank cell group (OD blank extracellular) + absorbance of lysate of cell of blank cell group (OD blank intracellular)) x 100% of sample to be measured, wherein the sample to be measured is supernatant of cell culture medium of positive control group, supernatant of cell culture medium of experimental cell group, supernatant of cell culture medium of blank cell group and lysate of cell of blank cell group.
The results are shown in FIGS. 3 and 4, wherein control is a positive control group and β -hexosaminidase release rate caused by the sensitizing component, and different concentrations represent different experimental cell groups, wherein the concentration is B10-S concentration and is β -hexosaminidase release rate in the presence of the sensitizing component, Blank cell group is β -hexosaminidase release rate when not stimulated by the sensitizing component, wherein the sensitizing component used in FIG. 3 is Compound 48/80, and the sensitizing component used in FIG. 4 is Substance P.
The experimental result shows that B-10S can remarkably antagonize β -hexosaminidase released by LAD2 cells caused by Compound 48/80 and Substance P, has antagonistic effect at a lower dose, and the antagonistic effect is in positive correlation with the dosage of the medicine.
Claims (7)
1. A diarylurea compound containing quinazolinone, which is characterized in that the structural formula is as follows:
wherein R is1、R2Is fluorine, chlorine or trifluoromethyl.
2. The quinazolinone-containing diaryl urea compound of claim 1, wherein the structural formula is as follows:
3. the method of preparing quinazolinone-containing diaryl ureas according to claim 1, comprising the steps of:
1) preparing 7-fluoroquinazolin-4 (3H) -one from 2-amino-4-fluorobenzoic acid and formamide through cyclization reaction;
2) preparing 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone by nucleophilic substitution reaction of 7-fluoroquinazoline-4 (3H) -ketone and p-aminosulfol;
3) phenyl isocyanate containing substituent groups reacts with 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone to obtain the diaryl urea compound containing quinazolinone.
4. The process for preparing quinazolinone-containing diaryl ureas according to claim 3, wherein in step 2),
under the protection of inert gas, 7-fluoroquinazoline-4 (3H) -ketone and K2CO3Adding the mixture into dimethyl sulfoxide, and heating to 110-120 ℃; to pairDropwise adding a dimethyl sulfoxide solution of aminothiophenol into a reaction system, reacting for 0.8-1.5H, pouring the reaction solution into ice water, extracting with ethyl acetate, and performing column chromatography separation and purification to obtain 7- ((4-aminophenyl) thio) quinazoline-4 (3H) -one;
wherein, according to molar weight, the ratio of 7-fluoroquinazolin-4 (3H) -one: k2CO3: 1, para-aminophenol ═ 1: (1.3-1.8): (1.2-2.0).
5. The method of preparing quinazolinone-containing diaryl ureas according to claim 1, comprising the steps of:
1) preparing 7-bromoquinazoline-4 (3H) -ketone by cyclization reaction of 2-amino-4-bromobenzoic acid and formamide;
2) reacting 7-bromoquinazolin-4 (3H) -one with p-nitrothiophenol to prepare 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one;
3) preparing 7- ((4-aminophenyl) thio) quinazolin-4 (3H) -one from 7- ((4-nitrophenyl) thio) quinazolin-4 (3H) -one by a reduction reaction;
4) phenyl isocyanate containing substituent groups and 7- ((4-aminophenyl) sulfenyl) quinazoline-4 (3H) -ketone are subjected to nucleophilic reaction to obtain the diaryl urea compound containing quinazolinone.
6. The process for preparing quinazolinone-containing diaryl ureas according to claim 5, wherein in step 2),
under the protection of inert gas, 7-bromoquinazoline-4 (3H) -ketone, p-nitrothiophenol and K2CO3Heating the mixture of Cu to 130 ℃, and reacting for 6 h; cooling to room temperature, separating out a solid, and performing suction filtration to obtain 7- ((4-nitrophenyl) sulfenyl) quinazoline-4 (3H) -ketone;
wherein, according to molar weight, 7-bromoquinazolin-4 (3H) -one: p-nitrothiophenol: k2CO3：CuI＝1：(2～4)：(1～1.5)：(0.005～0.1)。
7. The use of quinazolinone-containing diaryl ureas according to claim 1 in the preparation of antiallergic agents, which antagonize β -hexosaminidase released from human mast cells.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711117383.0A CN107814773B (en) | 2017-11-13 | 2017-11-13 | Quinazolinone-containing diaryl urea compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711117383.0A CN107814773B (en) | 2017-11-13 | 2017-11-13 | Quinazolinone-containing diaryl urea compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107814773A CN107814773A (en) | 2018-03-20 |
| CN107814773B true CN107814773B (en) | 2020-05-22 |
Family
ID=61608940
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711117383.0A Active CN107814773B (en) | 2017-11-13 | 2017-11-13 | Quinazolinone-containing diaryl urea compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107814773B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112076185A (en) * | 2020-08-17 | 2020-12-15 | 西安交通大学 | Halogenated diaryl urea compounds and application thereof in preparation of antiallergic drugs |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103102315A (en) * | 2012-11-01 | 2013-05-15 | 云南大学 | Quinazoline arylurea and preparation method and application thereof |
| CN103339138A (en) * | 2010-12-23 | 2013-10-02 | 阿勒克图治疗公司 | Selective glycosidase inhibitors and uses thereof |
| CN105007909A (en) * | 2013-03-06 | 2015-10-28 | 阿勒根公司 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
| CN105503744A (en) * | 2016-01-12 | 2016-04-20 | 西安交通大学 | Diphenyl urea compound containing quinazolinone and preparation method and application of diphenyl urea compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI1478358T1 (en) * | 2002-02-11 | 2013-09-30 | Bayer Healthcare Llc | Sorafenib tosylate for the treatment of diseases characterized by abnormal angiogenesis |
-
2017
- 2017-11-13 CN CN201711117383.0A patent/CN107814773B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103339138A (en) * | 2010-12-23 | 2013-10-02 | 阿勒克图治疗公司 | Selective glycosidase inhibitors and uses thereof |
| CN103102315A (en) * | 2012-11-01 | 2013-05-15 | 云南大学 | Quinazoline arylurea and preparation method and application thereof |
| CN105007909A (en) * | 2013-03-06 | 2015-10-28 | 阿勒根公司 | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
| CN105503744A (en) * | 2016-01-12 | 2016-04-20 | 西安交通大学 | Diphenyl urea compound containing quinazolinone and preparation method and application of diphenyl urea compound |
Non-Patent Citations (1)
| Title |
|---|
| 抗组胺药物的抗过敏作用研究进展;宋洪杰 等;《中国临床药理学杂志》;20030831;第19卷(第4期);第315-318页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107814773A (en) | 2018-03-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102634720B1 (en) | Methods for partitioning benzodiazepine-2-one and benzoazepine-2-one derivatives | |
| EP2949647B1 (en) | Deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing same | |
| CN101772494B (en) | 4-pyrimidinesulfamide derivative | |
| CN105980389B (en) | A kind of crystal form of disulfate of jak kinase inhibitor and preparation method thereof | |
| RU2720810C2 (en) | Salts of a quinazoline derivative and a method for production thereof | |
| CN112125911B (en) | CDK9 inhibitor and preparation method and application thereof | |
| CN107814773B (en) | Quinazolinone-containing diaryl urea compound and preparation method and application thereof | |
| EP3369733B1 (en) | Crystal form of 4h-pyrazolo[1,5- ]benzoimidazole compound, preparation method therefor and intermediate thereof | |
| EP2493892B1 (en) | Quinuclidine compounds as alpha-7 nicotinic acetylcholine receptor ligands | |
| CN112028880A (en) | Oxitinib dimer, preparation method and application thereof | |
| WO2023284804A1 (en) | Huperzine b crystal and preparation and application thereof | |
| KR20200097771A (en) | Salt forms and crystal forms thereof as Akt inhibitors | |
| US8729130B2 (en) | Methods of using novel solid forms of tacedinaline | |
| CN110194741B (en) | 4-benzoyl piperazine-3-nitro-1, 8-naphthalimide derivative and preparation method and application thereof | |
| CN110078706B (en) | Imatinib derivative and preparation method and application thereof | |
| WO2012003413A1 (en) | Novel solid forms of tacedinaline | |
| CN112300235B (en) | Benzimidazole derivative BI321 and preparation method and application thereof | |
| CN112812145B (en) | Benzimidazole derivative BI293 and preparation method and application thereof | |
| CN114106000B (en) | Imidazo [4,5-d ] pyrimidinone tricyclic derivative and antitumor application thereof | |
| CN112703190B (en) | Crystal forms of HDAC6 selective inhibitor and uses thereof | |
| CN112375112B (en) | Benzimidazole derivative BI361 and preparation method and application thereof | |
| CN103709146B (en) | One class is containing the quinolin-4-amines derivative of benzimidazole structure, its method for making and medicinal use | |
| WO2022237682A1 (en) | Salt form of pyrrolotriazine compound, crystal form thereof, and preparation method therefor | |
| CN116354967A (en) | Crystal form of nucleoside compound and preparation method and application thereof | |
| CN112920241A (en) | Benzimidazole derivative BI308 and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |