CN107417628A - Diaryl quianzolinones, its preparation method and its medical usage and the pharmaceutical composition comprising such compound - Google Patents
Diaryl quianzolinones, its preparation method and its medical usage and the pharmaceutical composition comprising such compound Download PDFInfo
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- CN107417628A CN107417628A CN201710508033.0A CN201710508033A CN107417628A CN 107417628 A CN107417628 A CN 107417628A CN 201710508033 A CN201710508033 A CN 201710508033A CN 107417628 A CN107417628 A CN 107417628A
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- 0 *c1ccccc1 Chemical compound *c1ccccc1 0.000 description 2
- CPNMAYYYYSWTIV-UHFFFAOYSA-N CCOC(c1ccccc1[N+]([O-])=O)=O Chemical compound CCOC(c1ccccc1[N+]([O-])=O)=O CPNMAYYYYSWTIV-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to a kind of a kind of quianzolinones or its pharmaceutically acceptable salt as shown in following formula I, its preparation method, and for preparing treatment tumour, antibacterial, AntiHIV1 RT activity, tranquilizing soporific, anticonvulsion, treating tuberculosis, anti-Parkinson syndrome, anti-inflammatory, the purposes brought down a fever, adjust the medicines such as the cardiovascular and active function of regulation cell and enzyme.
Description
Technical field
The invention belongs to study of pharmacy field, and in particular to a kind of quianzolinones or its is pharmaceutically acceptable
Salt, its preparation method, and for preparing treatment tumour, antibacterial, AntiHIV1 RT activity, tranquilizing soporific, anticonvulsion, treating tuberculosis, anti-Parkinson
Syndrome, anti-inflammatory, the purposes brought down a fever, adjust the medicines such as the cardiovascular and active function of regulation cell and enzyme.
Background technology
PI3K is a kind of phosphatidyl inositol kinase for making the 3rd di of inositol ring.Tied according to PI3K p110
Structure feature can be classified as three major types with substrate molecule difference：Ith, II, III totally 3 hypotypes.It is energy wherein to study most commonly used
The I type PI3K activated by cell surface receptor, the heterodimeric that it is made up of a catalytic subunit and a regulation subunit
Body.I type PI3K catalytic subunit is divided into two hypotypes of I A and I B again in mammalian cell.They connect from EGFR-TK respectively
Acceptor connects acceptor with G-protein and transmits signal.Recent study shows generation of the PI3K-Akt signal paths in kinds of tumors
Played an important role in development.PI3K-Akt is mainly to be made by influenceing wide variety of effector molecules downstream to play its anti-apoptotic
.At present, PI3K, Akt and related gene are suppressed by small-molecule drug, blocks it to a variety of anti-apoptotic effector molecules in downstream
Activation, promote Apoptosis, effectively suppress tumour growth, have become oncotherapy research focus.
Quianzolinones are as a kind of new polycyclic nitrogen-containing heterocycle compound, because of the changeability and height of its structure
The bioactivity of wide spectrum is imitated, is had a wide range of applications in medicine and pesticide field.In field of medicaments, quinazolinone is mainly manifested in
Antibacterial, antitumor, anticancer, anti-HIV-1 and treating tuberculosis etc., but also with it is quiet, bring down a fever, anti-inflammatory, hypnosis, it is anticonvulsion,
Anti-Parkinson syndrome, regulation is cardiovascular and adjusts the active function of cell and enzyme；In terms of agricultural chemicals research and development, quinazolinone master
Show desinsection, sterilization, weeding and antiviral etc..And 4 (3H)-quinazolinones and its derivative are a kind of critically important
Alkaloid, they can be extracted from extensive animals and plants, microorganism, possess many pharmacology and bioactivity, such as from harmel
The pegamine III of middle extraction separation, has cytotoxicity feature.4 (3H)-quinazolinone mother nucleus structures also have in medicine
Applied, such as methaqualone IV, be a kind of hypnotic sedative agent for being once used to treat insomnia, after 1985 due to its is additive and by
Disabling.Also halofuginone hydrobromide V, for treating malaria, cancer, good effect particularly is shown in chicken coccidiasis is treated, is
A kind of broad-spectrum anti-parasite medicine.Cause interest and the attention of chemistry, pharmacy and field of biology people always for many years, especially
It is one of focus of organic synthesis, medicine, agricultural chemicals and the research and development of other field of fine chemical in recent years to be.
The content of the invention
The one side of patent of the present invention is to provide a kind of quianzolinones shown in Formulas I or its is pharmaceutically acceptable
Salt.
Wherein, R1For hydrogen；By in hydroxyl, amino, halogen, cyano group, nitro, carboxyl and formamido 1 to 3 substitution
Base substitution or unsubstituted C1-6 alkyl；
R2And R3Be each independently substitution either unsubstituted five yuan to ten yuan aryl or substitution or it is unsubstituted containing
In S, N and O 1 to 3 heteroatomic five yuan to ten unit's heteroaryls, substituted five yuan to the ten yuan aryl or substituted five
Member to the substituent in ten unit's heteroaryls can be 1 to 3, and selected from C1-4 alkyl, hydroxyl, amino, halogen, cyano group,
Nitro, carboxyl and formamido.
Preferably, R1For hydrogen；By 1 to 3 taking in hydroxyl, amino, halogen, cyano group, nitro, carboxyl and the formamido
For base substitution or unsubstituted C1-4 alkyl.
It is further preferred that R1For hydrogen；Unsubstituted C1-4 alkyl.
It is further preferred that R1For hydrogen, methyl, ethyl or propyl group.
It is further preferred that R1For hydrogen or methyl.
Preferably, R2And R3Substitution or unsubstituted five yuan to seven yuan aryl are each independently, or substitutes or does not take
In generation, contains in S, N and O 1 to 3 heteroatomic five yuan to seven unit's heteroaryls, five yuan to the seven yuan substituted aryl or
Substituent in five yuan to seven unit's heteroaryls of substitution can be 1 to 3, and alkyl, hydroxyl, amino, halogen selected from C1-3
Element, cyano group, nitro, carboxyl and formamido.
It is further preferred that R2And R3Be each independently substitution or unsubstituted five yuan to seven yuan aryl, or substitution or
Person it is unsubstituted containing in S, N and O 1,2 or 3 heteroatomic five yuan to seven unit's heteroaryls, described substituted five yuan to seven
Substituent in first aryl or substituted five yuan to seven unit's heteroaryls can be 1,2 or 3, and alkyl or halogen selected from C1-3
Element.
It is further preferred that R2And R3Be each independently substitution or unsubstituted five yuan to seven yuan aryl or substitution or
Person it is unsubstituted containing in S, N and O 1,2 or 3 heteroatomic five yuan to seven unit's heteroaryls, described substituted five yuan to seven
Substituent in first aryl or substituted five yuan to seven unit's heteroaryls can be 1 or 2, and be selected from methyl, ethyl or halogen.
It is further preferred that R2And R3Be each independently substitution or unsubstituted five yuan to seven yuan aryl or substitution or
Unsubstituted heteroatomic five yuan containing selected from S or N of person five yuan to the seven yuan substituted aryl or is taken to seven unit's heteroaryls
Substituent in five yuan of generation to seven unit's heteroaryls can be 1 or 2, and be selected from methyl, ethyl or halogen.
The halogen is selected from F, Cl, Br or I, preferably F, Cl or Br, more preferably F or Cl.
According to the more preferably following compound of a kind of quianzolinones shown in the Formulas I of the present invention：
2,3- diphenyl quinazoline -4 (3H) -one
8- methyl -2- (pyridin-4-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
6- methyl -2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
2- (4- fluorophenyls) -3- phenylquinazolines -4 (3H) -one
2- (3- chlorphenyls) -3- phenylquinazolines -4 (3H) -one
Tolyl -3- (pyridin-3-yl) quinazoline -4 (3H) -one between 2-
Tolyl -3- phenylquinazolines -4 (3H) -one between 2-
2- (3- fluorophenyls) -3- phenylquinazolines -4 (3H) -one
(3H) -one of 2- p-methylphenyl -3- phenylquinazolines -4
2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
8- methyl -2- (5- methylthiophene -3- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
2- (2- chlorphenyls) -3- phenylquinazolines -4 (3H) -one
8- methyl -2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
(3H) -one of 8- methyl -2- (pyridin-4-yl) -3- phenylquinazolines -4
6- methyl -2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
6- methyl -2- (pyridin-4-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
8- methyl -2- (5- methylthiophene -2- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
(3H) -one of 6- methyl -2- (pyridin-3-yl) -3- phenylquinazolines -4
2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
(3H) -one of 2- (pyridin-3-yl) -3- phenylquinazolines -4
2- (2,4- 3,5-dimethylphenyls) -3- phenylquinazolines -4 (3H) -one
6- methyl -2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
2- (4- hydroxy phenyls) -3- phenylquinazolines -4 (3H) -one
(3H) -one of 2- (pyridin-4-yl) -3- phenylquinazolines -4
2- (3,4- 3,5-dimethylphenyls) -3- phenylquinazolines -4 (3H) -one
8- methyl -2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
6- methyl -2- (5- methylthiophene -2- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
Tolyl quinazoline -4 (3H) -one between 2- (pyridin-3-yl) -3-
" pharmaceutically acceptable salt " forms conventional for logical formula (I) compound with inorganic acid or organic acid reaction
Nontoxic salts.For example, the conventional nontoxic salts can be made by logical formula (I) compound with inorganic acid or organic acid reaction, it is described
Inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and the organic acid includes citric acid, wine
Stone acid, lactic acid, pyruvic acid, acetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids, ethyl sulfonic acid, naphthalenedisulfonic acid, maleic acid,
Malic acid, malonic acid, fumaric acid, butanedioic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutter acid, hydroxymaleic acid, phenylacetic acid,
Benzoic acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, Aspirin and isethionic acid etc.；Or
Logical formula (I) compound and propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, lemon
Acid, aspartic acid or glutamic acid form sodium salt, sylvite, calcium salt, aluminium salt or the ammonium salt formed again with inorganic base after ester；Or formula
(I) methylamine salt, ethylamine salt or the ethanolamine salt that compound is formed with organic base；Or logical formula (I) compound and lysine, smart ammonia
Acid, ornithine formed ester after again with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid formed corresponding inorganic acid salt or
The corresponding acylate formed with formic acid, acetic acid, picric acid, methanesulfonic acid and ethyl sulfonic acid.
The another further aspect of patent of the present invention there is provided a kind of quianzolinones shown in Formulas I or it pharmaceutically may be used
The novel preparation method of the salt of receiving.Reaction process is as follows：
Using substitution or unsubstituted 2- nitrobenzoic acids as raw material, process is amide condensed, reduction, Schiff base condensation and adds
Hot cyclization (b), obtain target product 4 (3H)-quinazolinone analog derivative.Wherein amide condensed, reduction, Schiff base condensation are each
The specific reaction condition of step can be carried out according to design conventional in the art, such as described amide condensed be referred to document
(J.Org.Chem.27(11):3851-3855.), the reduction is referred to document (Bioorganic＆Medicinal
Chemistry Letters, 20 (3), 1128-1133), the Schiff base condensation be referred to document (Tetrahedron
Letters,45(17):3475-3476), the heating cyclization (b) is referred to document (Synthesis, 45 (24):3349-
3354)。
Selectively, four steps ring-closure reaction can also use Cu photocatalysis ring-closure reactions (a), in this step with copper
Salt 365-480nm light irradiation, reacts at room temperature 2-5 hours, 2- (aryl methylene amino)-N- aryl-aryls as catalyst
Intramolecular cyclisation occurs for formamide, obtains cyclised products quinazoline -4 (3H) -one derivative I.
Preferably, the mantoquita as catalyst is selected from copper chloride, copper bromide, copper acetate and trifluoracetic acid copper etc..
Wherein substituent R 1, R2 and R3 are as defined above.
Another aspect of the present invention is to provide compound shown in Formulas I or the medical usage of its pharmaceutically acceptable salt.Bag
Include for preparing treatment tumour, bacterial-infection resisting, AntiHIV1 RT activity infection, tranquilizing soporific, anticonvulsion, treating pulmonery tuberculosis bacillus infection, anti-pa
The gloomy syndrome of gold, anti-inflammatory, the purposes brought down a fever, adjust the medicines such as the cardiovascular and active function of regulation cell and enzyme.
The fourth aspect of the present invention be to provide contain compound shown in Formulas I or its pharmaceutically acceptable salt as activity into
The pharmaceutical composition divided.According to the pharmaceutical composition of the present invention, described pharmaceutical composition includes Formulas I shownization of therapeutically effective amount
Compound or its pharmaceutically acceptable salt and excipient substance.Term " effective dose " can refer to realize the agent needed for expected effect
Amount and the effective amount of period.This effective dose may produce different changes because of some factors, species or treatment such as disease
When disease illness, construction, individual patient size or the seriousness of disease or symptom of the specific target organ being administered.This
Field has the effective dose that usually intellectual does not need excessively experiment to determine specific compound by rule of thumb.It is described that " medicine is auxiliary
Material " refers to the various auxiliary materials routinely used in medicine, such as excipient, controlled release agent, stabilizer etc., and this belongs to people in the art
Member's Conventional wisdom scope.
Pharmaceutical composition according to the present invention can be following formulation：Tablet is such as, but not limited to conventional tablet, speed
Release piece, sustained release tablets, controlled release tablet, Film coated tablets, sugar coated tablet, buccal tablet, sublingual tablet, biological adhesive tablet etc.；Capsule is for example but not
It is limited to hard shell capsules, soft capsule etc.；Injection is such as, but not limited to sterile or bacteriostatic agent aqueous injections, oily injection
Agent, freezing dry powder injection, microsphere for injection etc.；Spray is such as, but not limited to oral spray, nasal mist, local skin
Spray etc.；Aerosol is such as, but not limited to lung inhalation aerosol, local skin aerosol etc.；Nasal drop is such as, but not limited to
Collunarium solution, drop nasal gel etc.；Powder spray is such as, but not limited to cavity powder spray, nasal cavity powder spray, local skin
With powder spray etc.；Other cavities of the human body such as suppository of vagina, rectum, ear chamber etc., patch, gel.The preparation of these preparations
Technique is that those skilled in the art can prepare according to existing knowledge or with reference to pertinent texts or reference book or document
's.
Beneficial effect
The compound preparation technology of the present invention is simple, and committed step combination reaction uses cheap metal copper catalysis, and yield is more
Height, energy consumption is lower, more environmentally friendly.The methodological science for the quinazolinone analog derivative shown in formula I that patent of the present invention provides closes
Reason, has the characteristics that easy to operate, cost is cheap, the reaction time is short.Antitumorization of the compound of the present invention as new mechanism
Compound, show good potentiality to be exploited.
Brief description of the drawings
Fig. 1 is the figure of representation compound inducing acute marrow series leukemia cell differentiation experiment of the present invention in embodiment 32
Embodiment
Hereinafter, it will be described in detail the present invention.Before doing so, it should be appreciated that in this specification and appended
Claims in the term that uses should not be construed as being limited to general sense and dictionary meanings, and inventor should allowed
On the basis of appropriate definition term is to carry out the principle of best interpretations, according to implication corresponding with the technical elements of the present invention and generally
Thought explains.Therefore, description presented herein is not intended to limitation originally merely for the sake of the preferred embodiment for illustrating purpose
The scope of invention, it will thus be appreciated that without departing from the spirit and scope of the present invention, it can be obtained by it
His equivalents or improved procedure.
Experimental method in following embodiments, it is conventional method unless otherwise specified.
Material used, reagent etc., unless otherwise specified, are commercially obtained in following embodiments.
Embodiment 1：The synthesis of 2,3- diphenyl quinazoline -4 (3H) -one
The first step：The preparation of N- phenyl -2- nitrobenzamides
O-nitrobenzoic acid 10g (59.8mmol), EDCI 12.618g (65.8mmol), HOBT 8.894g
(65.8mmol), DMAP 0.366g (3mmol) are placed in 250ml reaction bulbs, add 150ml dichloromethane and 10mlDMF, drop
Enter aniline, be warming up to 60 DEG C and stir 1 day, lamellae monitoring observation reacting phenomenon, raw material point is wholly absent, and the removing that is concentrated under reduced pressure is big
Partial solvent, DCM is added, washed five times, saturation NaCl is washed once, dries organic phase.Remove drier, removal of solvent under reduced pressure.
Use ethyl acetate:Petroleum ether (2:1) column chromatography, yellow solid 12.975g, yield 90%.
Second step：The preparation of N- phenyl -2- amido benzamides
N- phenyl -2- nitrobenzamides 12.975g (53mmol), ammonium formate 10.133g (161mmol), palladium carbon
1.298g (10%, w/w) is placed in 250ml reaction bulbs, adds 150ml ethanol, is warming up to 70 DEG C and is stirred 1 day.Lamellae monitors
Observing response phenomenon, raw material point are wholly absent, and are filtered and are removed palladium carbon, obtain transparent settled solution, and vacuum rotary steam removes solvent, yellow
Solid.This solid is placed in 100ml reaction bulbs, adds methanol:Water (1:1) 20ml, 80 DEG C of stirrings are warming up to, methanol is added dropwise extremely
All solids are dissolved, and stir 30min, and reaction solution is slowly dropped into room temperature, separates out white solid, filters, dry cake, obtains white
Solid 6.351g；Filtrate decompression concentration is removed into most of solvent, filtered, obtains white solid 1.037g, merging filters institute twice
Obtain the common 7.388g of solid, yield 65%.
3rd step：(E) preparation of -2- (benzylideneamino)-N- phenylbenzamaides
N- phenyl -2- amido benzamide 3.16g (14.9mmol) are placed in 250ml reaction bulbs, add 100ml ethanol and
Benzaldehyde 1.89g (17.8mmol), it is warming up to 80 DEG C and stirs 1 day.Lamellae monitoring observation reacting phenomenon, raw material point disappear completely
Lose, stand cooling, separate out white solid, filter, obtain white solid 2.656g, yield 60%.
4th step：The synthesis of 2,3- diphenyl quinazoline -4 (3H) -one
(E) -2- (benzylideneamino)-N- phenylbenzamaides 300mg (1mmol) is placed in 250ml light reaction generators
In, the stirring of 250ml acetone is added, adds copper chloride 13.4mg (0.1mmol), cesium carbonate 325mg (1mmol), 300W illumination 4h.
Lamellae monitoring observation reacting phenomenon, raw material point are wholly absent, and are concentrated under reduced pressure and are removed solvent, ethyl acetate is added into reaction solution
And be transferred in separatory funnel, saturated ammonium chloride is washed three times, and organic phase is dried, and removes drier, and decompression rotation removes solvent, uses oil
Ether:Ethyl acetate (6:1) column chromatography, yellow solid 238mg, yield 80%.1H NMR(400MHz,CDCl3):8.37-8.35
(d, 1H, J=8.0Hz), 7.85-7.79 (m, 2H), 7.56-7.52 (m, 1H), 7.35-7.18m, 8H), 7.16-7.14 (m,
2H)；HRMS(m/z)(M+1)calcd for C20H14N2O:299.1140,found 299.1179.
Embodiment 2：8- methyl -2- (pyridin-4-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, it is light yellow
Solid, yield 63%.1H NMR(400MHz,CDCl3):8.51-8.50 (d, 2H, J=3Hz), 8.42-8.40 (m, 1H),
8.22-8.20 (d, 1H, J=7.8Hz), 7.83-7.79 (m, 1H), 7.70-7.68 (m, 1H), 7.49-7.44 (m, 2H),
7.30-7.26(m,3H),2.67(s,3H)；HRMS(m/z)(M+1)calcd for C19H14N4O:315.1201,
found315.1240.
Embodiment 3：6- methyl -2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, it is light yellow
Solid, yield 82%.1H NMR(400MHz,CDCl3):8.59-8.58 (d, 1H, J=1.68Hz), 8.49-8.47 (d, 1H, J
=4.76Hz), 8.45-8.43 (m, 1H), 8.15 (s, 1H), 7.81-7.77 (m, 1H), 7.74-7.72 (m, 2H), 7.67-
7.64 (m, 1H), 7.42-7.40 (d, 1H, J=7.88Hz), 7.28-7.25 (m, 1H), 7.19-7.16 (dd, 1H, J1=
7.88Hz,J2=4.76Hz), 2.54 (s, 3H)；HRMS(m/z)(M+1)calcd for C19H14N4O:315.1201,found
315.1240.
Embodiment 4：2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, it is light yellow
Solid, yield 70%.1H NMR(400MHz,CDCl3):8.28-8.26 (d, 2H, J=8.0Hz), 7.79-7.74 (m, 2H),
7.75-7.53 (m, 3H), 7.47-7.43 (m, 1H), 7.34-7.32 (m, 2H), 6.44-6.43 (d, 2H, J=4.0Hz),
6.08-6.07 (d, 2H, J=4.0Hz), 2.41 (s, 3H)；HRMS(m/z)(M+1)calcd for C18H15N3OS:
319.0860,found 319.0900.
Embodiment 5：2- (4- fluorophenyls) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 60%.1H NMR(400MHz,CDCl3):8.36-8.35 (d, 1H, J=8.0Hz), 7.82-7.81 (d, 2H, J=
4.0Hz), 7.57-7.53 (m, 1H), 7.36-7.29 (m, 5H), 7.16-7.14 (d, 2H, J=8Hz), 6.93-6.89 (t, 2H,
J=8.0Hz)；HRMS(m/z)(M+1)calcd for C18H15N3OS:317.1045,found 317.1086.
Embodiment 6：2- (3- chlorphenyls) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 62%.1H NMR(400MHz,CDCl3):8.36-8.34 (d, 1H, J=7.8Hz), 7.83-7.82 (m, 2H),
7.59-7.52(m,1H),7.43-7.42(t,1H),7.38-7.29(m,3H),7.24-7.21(dt,1H,J1=7.28Hz, J2
=1.96Hz), 7.17-7.09 (m, 4H)；HRMS(m/z)(M+1)calcd for C20H13ClN2O:334.0687,found
333.0789.
Embodiment 7：Tolyl -3- (pyridin-3-yl) quinazoline -4 (3H) -one between 2-
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 80%.1H NMR(400MHz,CDCl3):8.43-8.42 (d, 1H, J=4.48Hz), 8.39-8.37 (d, 1H, J=
8.0Hz), 7.87-7.80 (m, 2H), 7.65-7.61 (t, 1H, J=7.8Hz), 7.59-7.54 (t, 1H, J=8.0Hz),
7.49-7.47 (d, 1H, J=7.8Hz), 7.18-7.13 (m, 2H), 7.05-7.04 (m, 2H), 6.96-6.94 (d, 1H, J=
7.8Hz),2.27(s,3H)；HRMS(m/z)(M+1)calcd for C20H15N3O:314.1249,found 314.1288.
Embodiment 8：Tolyl -3- phenylquinazolines -4 (3H) -one between 2-
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 82%.1H NMR(400MHz,CDCl3):8.36-8.34(dd,1H,J1=8.0Hz, J2=2.0Hz), 7.84-
7.78(m,2H),7.54-7.50(m,1H),7.33-7.25(m,3H),7.22(s,1H),7.16-7.14(m,2H),7.05-
7.04(m,3H),2.24(s,3H)；HRMS(m/z)(M+1)calcd for C21H16N2O:312.372,found 313.1336.
Embodiment 9：2- (3- fluorophenyls) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 78%.1H NMR(400MHz,CDCl3):8.36-8.34 (d, 1H, J=8.0Hz), 7.82-7.81 (t, 2H),
7.58-7.51 (m, 1H), 7.36-7.28 (m, 3H), 7.19-7.14 (m, 3H), 7.11-7.07 (m, 1H), 6.98-6.92 (m,
1H)；HRMS(m/z)(M+1)calcd for C20H13N2OF:316.3354,found 317.1093.
Embodiment 10：(3H) -one of 2- p-methylphenyl -3- phenylquinazolines -4
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 85%.1H NMR(400MHz,CDCl3):8.35-8.33 (d, 2H, J=8.0Hz), 7.81-7.78 (t, 2H),
7.53-7.50 (m, 1H), 7.34-7.27 (m, 3H), 7.23-7.21 (d, 2H, J=8.0Hz), 7.16-7.13 (m, 2H),
7.01-6.99 (d, 2H, J=8.0Hz), 2.26 (s, 3H)；HRMS(m/z)(M+1)calcd for C21H16N2O:312.3720,
found 313.1335.
Embodiment 11：2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 62%.1H NMR(400MHz,CDCl3):8.47 (s, 1H), 8.40-8.39 (d, 1H, J=8.0Hz), 8.01-8.00
(d, 1H, J=8.0Hz), 7.88-7.85 (t, 1H), 7.75-7.71 (t, 1H), 7.63-7.59 (m, 1H), 7.34-7.28 (m,
4H),7.24-7.22(m,3H)；HRMS(m/z)(M+1)calcd for C21H16N2O:299.333,found 300.1131.
Embodiment 12：8- methyl -2- (5- methylthiophene -3- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 70%.1H NMR(400MHz,CDCl3):8.70-8.69(dd,1H,J1=4.8Hz, J2=1.5Hz), 8.12-
8.10 (d, 1H, J=8.0Hz), 7.94-7.89 (m, 1H), 7.61 (d, 1H, J=8.0Hz), 7.49-7.44 (m, 2H), 7.35-
7.31 (t, 1H) 6.43-6.42 (m, 1H), 5.88 (d, 1H, J=4.0Hz), 2.68 (s, 3H), 2.41 (s, 3H)；HRMS(m/z)
(M+1)calcd for C18H15N3OS:333.409,found 334.1010.
Embodiment 13：2- (2- chlorphenyls) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 31%.1H NMR(400MHz,CDCl3):8.40-8.38 (d, 1H, J=8.0Hz), 7.87-7.83 (t, 2H),
7.59-7.55 (m, 1H), 7.42-7.40 (d, 1H), 7.30-7.01 (m, 9H)；HRMS(m/z)(M+1)calcd for
C20H13N2OCl:333.0789,found 333.0790.
Embodiment 14：8- methyl -2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 36%.1H NMR(400MHz,CDCl3):8.64 (s, 1H), 8.50-8.49 (d, 1H, J=4.0Hz), 8.45-8.43
(d, 1H, J=4.8Hz), 8.22-8.19 (d, 1H, J=7.8Hz), 7.82-7.78 (m, 1H), 7.74-7.71 (m, 1H),
7.69-7.67 (d, 1H, J=7.28Hz), 7.47-7.43 (m, 2H), 7.29-7.26 (m, 1H), 7.19-7.15 (m, 1H),
2.68(s,3H)；HRMS(m/z)(M+1)calcd for C19H14N4O:315.1201,found 315.1240.
Embodiment 15：(3H) -one of 8- methyl -2- (pyridin-4-yl) -3- phenylquinazolines -4
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 31%.1H NMR(400MHz,CDCl3):8.51-8.49 (d, 2H, J=5.0Hz), 8.22-8.20 (d, 1H, J=
7.8Hz), 7.69-7.68 (d, 1H, J=7.28Hz), 7.48-7.44 (t, 1H, J=7.32Hz), 7.37-7.33 (m, 3H),
7.26-7.25(m,2H),7.18-7.16(m,2H),2.67(s,3H)；HRMS(m/z)(M+1)calcd for C20H15N3O:
314.1249,found 314.1288.
Embodiment 16：6- methyl -2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 50%.1H NMR(400MHz,CDCl3):8.40-8.39 (d, 1H, J=4.8Hz), 8.16 (s, 1H), 7.77-7.75
(d, 1H, J=8.0Hz), 7.65-7.59 (m, 2H), 7.50-7.48 (d, 1H, J=7.8Hz), 7.31-7.24 (m, 3H),
7.20-7.18(d,2H),7.16-7.13(dd,1H,J1=7.6Hz, J2=5.0Hz), 2.53 (s, 3H)；HRMS(m/z)(M+1)
calcd for C20H15N3O:314.1249,found 314.1288.
Embodiment 17：6- methyl -2- (pyridin-4-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 50%.1H NMR(400MHz,CDCl3):8.51 (s, 2H), 8.42-8.40 (d, 1H, J=4.8Hz), 8.15 (s,
1H), 7.82-7.78 (m, 1H), 7.74-7.72 (d, 1H, J=8.4Hz), 7.67-7.65 (d, 1H, J=8.1Hz), 7.46-
7.44 (d, 1H, J=7.8Hz), 7.29-7.26 (m, 3H), 2.54 (s, 3H)；HRMS(m/z)(M+1)calcd for
C19H14N4O:315.1201,found 315.1240.
Embodiment 18：8- methyl -2- (5- methylthiophene -2- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 33%.1H NMR(400MHz,CDCl3):8.71-8.69 (d, 1H, J=4.8Hz), 8.12-8.10 (d, 1H, J=
7.8Hz), 7.95-7.90 (t, 1H, J=7.56Hz), 7.63-7.61 (d, 1H, J=7.28Hz), 7.50-7.45 (m, 2H),
7.36-7.32 (t, 1H, J=7.56Hz), 6.43-6.42 (d, 1H, J=3.92Hz), 5.89-5.88 (d, 1H, J=
3.92Hz),2.68(s,3H),2.42(s,3H)；HRMS(m/z)(M+1)calcd for C19H15N3OS:334.0969,found
334.1010.
Embodiment 19：(3H) -one of 6- methyl -2- (pyridin-3-yl) -3- phenylquinazolines -4
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 70%.1H NMR(400MHz,CDCl3):8.64 (s, 1H), 8.49-8.48 (d, 1H, J=4.2Hz), 8.15 (s,
1H), 7.73-7.71 (d, 1H, J=8.4Hz), 7.67-7.64 (d, 1H, J=8.4Hz), 7.62-7.59 (m, 1H), 7.38-
7.31(m,3H),7.18-7.13(m,3H),2.54(s,3H)；HRMS(m/z)(M+1)calcd for C20H15N3O:
314.1249,found314.1288.
Embodiment 20：2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 39%.1H NMR(400MHz,CDCl3):8.60 (s, 1H), 8.50-8.49 (d, 1H, J=4.2Hz), 8.45-8.43
(d, 1H, J=4.76Hz), 8.38-8.36 (d, 1H, J=7.6Hz), 7.87-7.74 (m, 4H), 7.60-7.56 (m, 1H),
7.43-7.41 (d, 1H, J=7.84Hz), 7.29-7.26 (m, 1H), 7.21-7.17 (dd, 1H, J1=7.84Hz, J2=
5.0Hz)；HRMS(m/z)(M+1)calcd for C18H12N4O:301.1045,found 301.1084.
Embodiment 21：(3H) -one of 2- (pyridin-3-yl) -3- phenylquinazolines -4
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 63%.1H NMR(400MHz,CDCl3):8.65 (s, 1H), 8.50-8.49 (d, 1H, J=4.5Hz), 8.38-8.36
(d, 1H, J=7.6Hz), 7.87-7.82 (m, 2H), 7.63-7.61 (m, 1H), 7.60-7.56 (m, 1H), 7.39-7.30 (m,
3H),7.18-7.14(m,3H)；HRMS(m/z)(M+1)calcd for C19H13N3O:300.1092,found 300.1131.
Embodiment 22：2- (2,4- 3,5-dimethylphenyls) -3- phenylquinazolines -4 (3H) -one
Target compound, yellow solid, yield 56% are prepared according to the method for embodiment 1.1H NMR(400MHz,
CDCl3):8.38-8.36 (d, 1H, J=7.8Hz), 7.82-7.81 (d, 2H, J=3.4Hz), 7.57-7.53 (m, 1H),
7.30-7.22 (m, 3H), 7.13-7.12 (d, 2H, J=6.4Hz), 7.00-6.98 (d, 1H, J=7.8Hz), 6.87 (s, 1H),
6.83-6.81 (d, 1H, J=7.8Hz), 2.26 (s, 3H), 2.20 (s, 3H)；HRMS(m/z)(M+1)calcd for
C22H18N2O:327.1453,found 327.1492.
Embodiment 23：6- methyl -2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one (yield)
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 76%.1H NMR(400MHz,CDCl3):8.05 (s, 1H), 7.73-7.71 (d, 1H, J=7.6Hz), 7.61-7.58
(d, 1H, J=7.0Hz), 7.54-7.53 (m, 3H), 7.34-7.31 (m, 2H), 6.45-6.44 (d, 1H, J=3.4Hz), 6.17
(s,1H),2.49(s,3H),2.40(s,3H)；HRMS(m/z)(M+1)calcd for C20H16N2OS:333.1017,
found333.1052.
Embodiment 24：2- (4- hydroxy phenyls) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 47%.1H NMR(400MHz,CDCl3):8.34-8.32 (d, 1H, J=8.0Hz), 7.82-7.79 (m, 2H),
7.55-7.51 (t, 1H, J=7.8Hz), 7.35-7.28 (m, 3H), 7.14-7.12 (d, 4H, J=8.4Hz), 6.51-6.49
(d, 2H, J=8.6Hz)；HRMS(m/z)(M+1)calcd for C20H14N2O2:315.1089,found 315.1129.
Embodiment 25：(3H) -one of 2- (pyridin-4-yl) -3- phenylquinazolines -4
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 55%.1H NMR(400MHz,CDCl3):8.52-8.50 (d, 2H, J=5.8Hz), 8.38-8.36 (d, 1H, J=
8.0Hz),7.87-7.81(m,2H),7.61-7.57(m,1H),7.38-7.33(m,3H),7.25-7.23(m,2H),7.18-
7.15(m,2H)；HRMS(m/z)(M+1)calcd for C19H13N3O:300.1092,found 300.1132.
Embodiment 26：2- (3,4- 3,5-dimethylphenyls) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 63%.1H NMR(400MHz,CDCl3):8.36-8.33 (d, 1H, J=8.7Hz), 7.86-7.78 (m, 2H),
7.54-7.50 (t, 1H, J=7.8Hz), 7.36-7.28 (m, 3H), 7.21 (s, 1H), 7.17-7.15 (m, 2H), 6.97-6.90
(m,2H),2.17-2.15(d,6H)；HRMS(m/z)(M+1)calcd for C22H18N2O:327.1453,
found327.1492.
Embodiment 27：8- methyl -2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 37%.1H NMR(400MHz,CDCl3):8.12-8.10 (d, 1H, J=7.0Hz), 7.63-7.61 (d, 1H, J=
7.3Hz), 7.55-7.54 (m, 3H), 7.36-7.32 (m, 3H), 6.43-6.42 (d, 1H, J=3.9Hz), 5.98-5.97 (d,
1H, J=3.9Hz), 2.70 (s, 3H), 2.42 (s, 3H)；HRMS(m/z)(M+1)calcd for C20H16N2OS:333.1017,
found333.1055.
Embodiment 28：6- methyl -2- (5- methylthiophene -2- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 61%.1H NMR(400MHz,CDCl3):8.69-8.68 (d, 1H, J=5.0Hz), 8.05 (s, 1H), 7.93-7.88
(m, 1H), 7.69-7.67 (d, 1H, J=8.4Hz), 7.60-7.58 (d, 1H, J=8.4Hz), 7.48-7.45 (dd, 1H, J1=
7.6Hz,J2=4.8Hz), 7.44-7.42 (d, 1H, J=7.8Hz), 6.44-6.43 (d, 1H, J=3.6Hz), 6.07-6.06
(d, 1H, J=3.0Hz), 2.49 (s, 3H), 2.40 (s, 3H)；HRMS(m/z)(M+1)calcd for C19H15N3OS:
334.0969,found 334.1009.
Embodiment 29：2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 69%.1H NMR(400MHz,CDCl3):8.44 (s, 1H), 7.85-7.84 (m, 2H), 7.66-7.62 (t, 1H, J=
7.0Hz), 7.59-7.55 (t, 1H, J=7.8Hz), 7.32-7.18 (m, 6H)；HRMS(m/z)(M+1)calcd for
C19H13N3O:300.1092,found 300.1131.
Embodiment 30：Tolyl quinazoline -4 (3H) -one between 2- (pyridin-3-yl) -3-
In addition to replacing corresponding reaction initiation material, target compound is prepared according to the method for embodiment 1, yellow is solid
Body, yield 30%.1H NMR(400MHz,CDCl3):8.37-8.36 (d, 1H, J=7.56Hz), 7.87-7.81 (m, 2H),
7.71-7.69 (d, 1H, J=7.28Hz), 7.59-7.55 (m, 1H), 7.25-7.21 (t, 1H, J=7.56Hz), 7.14-7.12
(d, 1H, J=7.56Hz), 7.02 (s, 1H), 6.94-6.92 (d, 1H, J=7.8Hz), 2.30 (s, 3H)；HRMS(m/z)(M+
1)calcd for C20H15N3O:314.1249,found 314.1288.
Test example 1：The suppression experiment of compound on tumor cell propagation
Subject cell:MDA-MB-231, LM3 (are donated) by Radiation Medical Science Inst., Chinese Academy of Military Medical Science.Cell culture
And experimental method:Inoculating cell (supplement mycillin stoste 5ml/ in the DMEM cell culture fluids containing 10% hyclone
500ml), 37 DEG C are placed in containing 5% CO2Cell culture incubator in, per changing within 1-2 days liquid once, 0.25% Trypsin Induced, pass
Generation and collection cell.By exponential phase cell, suitable concentration is configured to the DMEM cell culture fluids containing 10% hyclone
Cell suspension, be added to by every 2500-4000 cell in hole (100 μ l) in 96 porocyte culture plates, after overnight incubation, per hole
The μ l of culture medium 100 containing various concentrations tested material are added, each concentration sets 4 parallel holes.After cell dosing culture 72 hours
Supernatant is abandoned, the serum-free medium for the 0.5-0.55mg/ml tetrazoles blue (MTT) that 100 μ l are newly configured, 37 DEG C of cultures are added per hole
Supernatant is abandoned after 4h, 200 μ l DMSO Rong Xie formazans are added per hole, ELIASA determines absorbance under 570nm wavelength.At data
Reason:Data are usedRepresent；Inhibiting rate=(control group OD values-administration group OD values)/control group OD value × 100%；Compound is imitated
Answer index half-strength (IC50) represent, and list actual measurement maximal percentage inhibition (Imax).Mapped with Origin softwares, and this is soft
Four parameter Logistic programs fitting growth of tumour cell curve in part, obtains half effect concentration (IC50, μ g/ml).As a result such as table
Shown in 1, compound prepared in accordance with the present invention show it is very strong suppress the high tumour cell MDA-MB-231 of grade malignancy and
The ability of LM3 propagation, there is good potentiality to be exploited.
Table 1
Test example 2：Representation compound inducing acute marrow series leukemia (AML) cell differentiation is tested
Using the generation of flow cytomery cell surface molecule mark CD11b expression analysis AML cell differentiations.Set
Blank control and compound treatment group, the cell in growth period of taking the logarithm is with 1.5 × 108/ L is inoculated with 2ml to 6 orifice plates, each group difference
Respective concentration medicine is added, blank control group adds isometric DMSO, after medicine acts on 72h, single cell suspension is collected by centrifugation
(500 × g, 5min), the anti-CD11b antibody of phycoerythrin mark is added, put incubation at room temperature 30min, added 1ml PBS and wash two
Time, it is collected by centrifugation single cell suspension (500 × g, 5min), machine testing on flow cytometer, calculates induction differentiation rate.
As shown in figure 1, it can be existed according to the representative compound of the present invention with inducing leukemia cell differentiation, effective dose
Differentiation rate is induced to reach 80-90% when 10uM or so, 80uM, and dose-dependence is clear and definite, therefore, according to being somebody's turn to do for the present invention
Class compound it is also possible to provide a kind of medicament for treatment of leukemia of the non-cytotoxicity of new mechanism.
Claims (10)
1. quianzolinones or its pharmaceutically acceptable salt shown in a kind of Formulas I：
Wherein, R1For hydrogen；Taken by hydroxyl, amino, halogen, cyano group, nitro, carboxyl and formamido 1 to 3 substituent
Generation or unsubstituted C1-6 alkyl；
R2And R3Be each independently substitution either unsubstituted five yuan to ten yuan aryl or substitution or it is unsubstituted containing selected from
S, in N and O 1 to 3 heteroatomic five yuan to ten unit's heteroaryls, five yuan to the ten yuan substituted aryl or substituted five yuan are extremely
Substituent in ten unit's heteroaryls can be 1 to 3, and the alkyl selected from C1-4, hydroxyl, amino, halogen, cyano group, nitro,
Carboxyl and formamido.
2. quianzolinones according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that described
R1For hydrogen, by 1 to the 3 substituent substitution in hydroxyl, amino, halogen, cyano group, nitro, carboxyl and formamido or not
Substituted C1-4 alkyl；Preferably, R1For hydrogen or unsubstituted C1-4 alkyl；It is further preferred that R1For hydrogen, methyl, second
Base or propyl group；It is further preferred that R1For hydrogen or methyl.
3. quianzolinones according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that described
R2And R3It is each independently substitution or unsubstituted five yuan to seven yuan aryl, or substitution or unsubstituted containing selected from S, N
With 1 to 3 in O heteroatomic five yuan to seven unit's heteroaryls, five yuan to the seven yuan substituted aryl or substituted five yuan to seven
Substituent in unit's heteroaryl can be 1 to 3, and alkyl, hydroxyl, amino, halogen, cyano group, nitro, carboxylic selected from C1-3
Base and formamido；It is further preferred that R2And R3It is each independently substitution or unsubstituted five yuan to seven yuan aryl or takes
Generation or it is unsubstituted containing in S, N and O 1,2 or 3 heteroatomic five yuan to seven unit's heteroaryls, described substituted five yuan
Substituent into seven yuan of aryl or substituted five yuan to seven unit's heteroaryls can be 1,2 or 3, and the alkyl selected from C1-3
Or halogen；It is further preferred that R2And R3Be each independently substitution either unsubstituted five yuan to seven yuan aryl or substitution or
It is unsubstituted containing in S, N and O 1,2 or 3 heteroatomic five yuan to seven unit's heteroaryls, described substituted five yuan to seven yuan
Substituent in aryl or substituted five yuan to seven unit's heteroaryls can be 1 or 2, and be selected from methyl, ethyl or halogen；Enter
One step preferably, R2And R3It is each independently substitution either unsubstituted five yuan to seven yuan aryl or substitution or unsubstituted
Containing heteroatomic five yuan selected from S or N to seven unit's heteroaryls, five yuan to the seven yuan substituted aryl or substituted five yuan are extremely
Substituent in ten unit's heteroaryls can be 1 or 2, and be selected from methyl, ethyl or halogen.
4. quianzolinones as claimed in any of claims 1 to 3 or its pharmaceutically acceptable salt, its
It is characterised by, the halogen is selected from F, Cl, Br or I, preferably F, Cl or Br, more preferably F or Cl.
5. quianzolinones according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that described
Quianzolinones shown in Formulas I are selected from following compound：
2,3- diphenyl quinazoline -4 (3H) -one
8- methyl -2- (pyridin-4-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
6- methyl -2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
2- (4- fluorophenyls) -3- phenylquinazolines -4 (3H) -one
2- (3- chlorphenyls) -3- phenylquinazolines -4 (3H) -one
Tolyl -3- (pyridin-3-yl) quinazoline -4 (3H) -one between 2-
Tolyl -3- phenylquinazolines -4 (3H) -one between 2-
2- (3- fluorophenyls) -3- phenylquinazolines -4 (3H) -one
(3H) -one of 2- p-methylphenyl -3- phenylquinazolines -4
2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
8- methyl -2- (5- methylthiophene -3- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
2- (2- chlorphenyls) -3- phenylquinazolines -4 (3H) -one
8- methyl -2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
(3H) -one of 8- methyl -2- (pyridin-4-yl) -3- phenylquinazolines -4
6- methyl -2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
6- methyl -2- (pyridin-4-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
8- methyl -2- (5- methylthiophene -2- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
(3H) -one of 6- methyl -2- (pyridin-3-yl) -3- phenylquinazolines -4
2- (pyridin-3-yl) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
(3H) -one of 2- (pyridin-3-yl) -3- phenylquinazolines -4
2- (2,4- 3,5-dimethylphenyls) -3- phenylquinazolines -4 (3H) -one
6- methyl -2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
2- (4- hydroxy phenyls) -3- phenylquinazolines -4 (3H) -one
(3H) -one of 2- (pyridin-4-yl) -3- phenylquinazolines -4
2- (3,4- 3,5-dimethylphenyls) -3- phenylquinazolines -4 (3H) -one
8- methyl -2- (5- methylthiophene -2- bases) -3- phenylquinazolines -4 (3H) -one
6- methyl -2- (5- methylthiophene -2- bases) -3- (pyridine -2- bases) quinazoline -4 (3H) -one
2- (pyridine -2- bases) -3- phenylquinazolines -4 (3H) -one
Tolyl quinazoline -4 (3H) -one between 2- (pyridin-3-yl) -3-.
6. the preparation method of the quianzolinones or its pharmaceutically acceptable salt shown in a kind of Formulas I, methods described is such as
Lower progress：
Using substitution or unsubstituted 2- nitrobenzoic acids as raw material, process is amide condensed, reduction, Schiff base condensation and heating ring
Close (b), obtain target product 4 (3H)-quinazolinone analog derivative, wherein substituent R 1, R2 and R3 is as defined above.
7. preparation method according to claim 6, it is characterised in that four steps ring-closure reaction uses Cu photocatalysis cyclizations
React (a), in this step using mantoquita as catalyst, 365-480nm light irradiation, react at room temperature 2-5 hours, 2- (aryl
Methene amido)-N- aryl-aryls formamide generation intramolecular cyclisation, obtain cyclised products quinazoline -4 (3H) -one and spread out
Biological I, wherein substituent R 1, R2 and R3 definition are as described in the appended claim 1.
8. preparation method according to claim 7, it is characterised in that the mantoquita as catalyst be selected from copper chloride,
Copper bromide, copper acetate and trifluoracetic acid copper.
9. quianzolinones as claimed in any of claims 1 to 5 or its pharmaceutically acceptable salt, use
Tumour, bacterial-infection resisting, AntiHIV1 RT activity infection, tranquilizing soporific, anticonvulsion, treating pulmonery tuberculosis bacillus infection, anti-Parkinson are treated in preparing
Syndrome, anti-inflammatory, the purposes brought down a fever, adjust cardiovascular and the active function of regulation cell and enzyme medicine.
10. a kind of pharmaceutical composition, described pharmaceutical composition include effective dose according to any one institute in claim 1 to 5
The quianzolinones stated or its pharmaceutically acceptable salt are as active component and excipient substance.
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| CN108822046A (en) * | 2018-08-28 | 2018-11-16 | 河南大学 | The method of one pot process quianzolinones |
| CN110041272A (en) * | 2019-05-29 | 2019-07-23 | 中国人民解放军军事科学院军事医学研究院 | 2- (2- chlorphenyl) quinazoline -4 (3H) -one analog derivative and its preparation method and application |
| CN110041273A (en) * | 2019-05-29 | 2019-07-23 | 中国人民解放军军事科学院军事医学研究院 | 2- (the chloro- 4- aminomethyl phenyl of 2-) quinazoline -4 (3H) -one class compound and its medical usage |
| CN110724153A (en) * | 2019-09-11 | 2020-01-24 | 广西师范大学 | Quinazolinone derivative and preparation method and application thereof |
| US10751339B2 (en) | 2018-01-20 | 2020-08-25 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
| CN115260164A (en) * | 2021-05-01 | 2022-11-01 | 杭州星鳌生物科技有限公司 | Preparation method and structural composition of novel 4 (3H) -quinazolinone analogue and application of analogue in antitumor drugs |
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| US10751339B2 (en) | 2018-01-20 | 2020-08-25 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
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| CN108822046B (en) * | 2018-08-28 | 2021-07-06 | 河南大学 | Method for synthesizing quinazolinone compound by one-pot method |
| CN110041272A (en) * | 2019-05-29 | 2019-07-23 | 中国人民解放军军事科学院军事医学研究院 | 2- (2- chlorphenyl) quinazoline -4 (3H) -one analog derivative and its preparation method and application |
| CN110041273A (en) * | 2019-05-29 | 2019-07-23 | 中国人民解放军军事科学院军事医学研究院 | 2- (the chloro- 4- aminomethyl phenyl of 2-) quinazoline -4 (3H) -one class compound and its medical usage |
| CN110041273B (en) * | 2019-05-29 | 2020-10-20 | 中国人民解放军军事科学院军事医学研究院 | 2- (2-chloro-4-methylphenyl) quinazoline-4 (3H) -ketone compound and medical application thereof |
| CN110041272B (en) * | 2019-05-29 | 2020-10-30 | 中国人民解放军军事科学院军事医学研究院 | 2- (2-chlorphenyl) quinazoline-4 (3H) -ketone derivative and preparation method and application thereof |
| WO2020239050A1 (en) * | 2019-05-29 | 2020-12-03 | 中国人民解放军军事科学院军事医学研究院 | 2-(2-chloro-4-methylphenyl)quinazoline-4(3h)-ketone compound and medical use thereof |
| CN110724153A (en) * | 2019-09-11 | 2020-01-24 | 广西师范大学 | Quinazolinone derivative and preparation method and application thereof |
| CN115260164A (en) * | 2021-05-01 | 2022-11-01 | 杭州星鳌生物科技有限公司 | Preparation method and structural composition of novel 4 (3H) -quinazolinone analogue and application of analogue in antitumor drugs |
| CN115260164B (en) * | 2021-05-01 | 2024-03-26 | 杭州星鳌生物科技有限公司 | Preparation method, structural composition and application of novel 4 (3H) -quinazolinone analogue in antitumor drugs |
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