CN108976235B - A kind of quianzolinones and application thereof - Google Patents
A kind of quianzolinones and application thereof Download PDFInfo
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- CN108976235B CN108976235B CN201811160910.0A CN201811160910A CN108976235B CN 108976235 B CN108976235 B CN 108976235B CN 201811160910 A CN201811160910 A CN 201811160910A CN 108976235 B CN108976235 B CN 108976235B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
This application discloses be related to having quianzolinones and its pharmaceutically acceptable salt, hydrate or prodrug shown in general formula I in technical field of organic chemistry.Wherein, substituent R 1, R2 have the meaning provided in the description.The invention further relates to general formula I
Description
Technical field
The present invention relates to technical field of organic chemistry, and in particular to Iatrochemistry quinazolinones framework compound and its medicine
Acceptable salt, hydrate or prodrug on, their preparation method and the pharmaceutical composition containing the compound.This hair
The bright application for further relating to such compound and composition in the drug of preparation treatment and/or pre- anti-cancer and IDO are extremely high
Express the application in the drug of diseases caused.
Background technique
Cancer, that is, malignant tumour is a kind of fatal disease for seriously endangering human health.The whole world has 14,000,000 at present
New cases of cancer, number of cancer deaths is up to 8,200,000.Wherein increase cases of lung cancer 1,800,000, death toll 1,590,000 newly.Therefore, pernicious
Tumour has become the mankind the second class killer for being only second to cardiovascular disease, seriously endangers human health.
Indole amine 2,3-dioxygenase (Indoleamin 2,3-Dioxygenase, IDO) is that tryptophan is catalyzed in human body
One of rate-limiting enzyme of metabolic breakdown is widely present in the various tissues of human body, and the great expression in tumor tissues, is tumour hair
The important factor in order of raw immunologic escape.IDO was most found in the enteron aisle of rabbit earlier than 1967, by the study found that its just
It is widely present in addition to liver in ordinary person's body, is concentrated mainly on the tissue such as Dendritic Cells, macrophage and placenta of immune system
It into the cell, can be by inflammation cell factor such as interferon-γ (IFN-γ), lipopolysaccharides (LPS), tumor necrosis factor (TNF)
Deng its high level expression of induction.
In inflammatory reaction, inflammation cell factor especially IFN-γ can induce IDO to express, and accelerate L-Trp's
Metabolism, a part of IDO as immune response protect host from disease by tryptophan necessary to consumption pathogenic growth
The infection of substance.And in tumor tissues, tumour cell can also utilize this function of IDO, inhibit the immune response of body anti-
It answers.IDO mainly passes through this 3 kinds of mechanisms mediate vivo immunizations inhibition functions of GCN2, m-TOR and AhR.The L- firstly, IDO degrades
Trp exhausts L-Trp in local organization microenvironment, and the tRNA for transporting L-Trp is caused to be in free state, at this time pressure response
Kinases (general control nonderepressible 2, GCN2) contains the allosteric tune for incuding free tRNA because of it
Section point and activated, the GCN2 kinases of activation makes -2 α (Eukaryotic of eukaryocyte transcription initiation factor in downstream
Translation initiation factor-2 α, eIF-2 α) phosphorylation, cause eIF-2 α to promote functional transcription reduction, thus
Inhibit the transcription of a variety of RNA and the translation process of protein in T cell；Secondly, the shortage of L-Trp is able to suppress amino acid induction
Kinases 1 (master amino acid-sensing kinase 1, GLK1), and then inhibit m-TOR signaling molecule, triggering T is thin
Born of the same parents' Immune anergy and autophagy.Therefore, both mechanism are by activation amino acid shortage signal (GCN2/eIF-2 α) and to inhibit
What amino acid abundance signal (GLK1/m-TOR) mediated.The third mechanism is situated between by L-Trp metabolite kynurenin (KYN)
It leads, IDO is caused in conjunction with AhR by being metabolized the endogenic ligand that the KYN that L-Trp is generated is aryl hydrocarbon receptor (AhR), KYN
Immature CD4+T cell differentiation is suppressor T lymphocyte (Treg), in addition, KYN also can induce the expression of IDO in conjunction with AhR,
Further suppress the immune response of T cell.
Currently, the research about IDO, it has already been proven that it is closely related with tumour, therefore, to the research of IDO inhibitor by
The concern of numerous scholar experts is arrived.The IDO inhibitor of early stage is mainly obtained with chemical synthesis means, mostly with IDO's in structure
Substrate tryptophan is basic framework.From after 2006, researcher begins trying to find the new of IDO inhibitor from natural products
Structural framework.In recent years, the drugmakers such as Bristol-Myers Squibb, Roche, Incyte, NewLink Genetics
By high flux screening and the drug based on target spot designs, it has been found that the IDO inhibitor of various new skeleton.
Couroupitine A (indoles simultaneously [2,1-b] quinazoline -6,12- diketone) derives from the natural production of medicinal plant indigo plant and woaded blue
Object, have extensive pharmacological effect, such as can inhibit microorganism and helminth growth and breeding, have immunoloregulation function,
Anti-inflammatory and anti-tumor activity.Couroupitine A, which has, inhibits oxidized azoethane induction F344 intestine in rats tumour to be formed, Yi Ji great
Amount experiment in vitro proves it with apparent anti-tumor effect.
Summary of the invention
For the present inventor using couroupitine A as lead compound, design has synthesized series of quinazoline ketone compounds, has good
Good inhibition IDO activity, and antitumor activity screening is carried out to various tumor cell strains in vitro, the results showed that have antitumor
Activity.
The main purpose of the present invention is to provide quianzolinones and its pharmaceutically acceptable salt, hydrate or
Its prodrug, as shown in general formula I:
Wherein, R1And R2It is identical or different, it is 1~3 substituent group, is each independently selected from hydroxyl, halogen, nitro, ammonia
Base, cyano, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, optionally by hydroxyl, amino or halogenated C1-C6
Alkyl or C1-C6Alkoxy, by 1-2 C1-C6Alkyl-substituted amino, C1-C6Alkylamidoalkyl, C1-C6Alkyl sulphinyl,
C1-C6Alkyl sulphonyl, C1-C6Alkyl acyl, carbamoyl, by 1-2 C1-C6Alkyl-substituted carbamoyl, C1-C3
Alkylenedioxy group, allyl and free, at salt, esterification and amidated carboxyl.
Preferably, R1And R2It is identical or different, it is 1~3 substituent group, is each independently selected from hydroxyl, halogen, nitro, ammonia
Base, cyano, C1-C4) alkyl, C2-C4) alkenyl, C2-C4Alkynyl, C1-C4Alkoxy, optionally by hydroxyl, amino or halogenated C1-C4
Alkyl or C1-C4Alkoxy, by 1-2 C1-C4Alkyl-substituted amino, C1-C4Alkylamidoalkyl, C1-C4Alkyl sulphinyl,
C1-C4Alkyl sulphonyl, C1-C4Alkyl acyl, carbamoyl, by 1-2 C1-C4Alkyl-substituted carbamoyl, C1-C3
Alkylenedioxy group, allyl and free, at salt, esterification and amidated carboxyl.
Preferably, R1And R2It is identical or different, it is 1~3 substituent group, is each independently selected from hydroxyl, halogen, nitro, ammonia
Base, cyano, C1-C4Alkyl, C1-C4Alkoxy.
Compound, optical isomer and its pharmaceutically acceptable salt described in general formula I of the present invention, hydrate or prodrug:
Particularly preferred following compound, but these compounds are not meant to any limitation of the invention:
Fluoro- 3- phenyl-[1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one of 6-；
- 9 (3H) -one of 3- (4- methoxyphenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the fluoro- 3- of 6- (4- methoxyphenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the chloro- 3- of 6- (4- aminomethyl phenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of 3- (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the fluoro- 3- of 6- (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the chloro- 3- of 6- (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of 3- (3- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the fluoro- 3- of 6- (3- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
Chloro- [1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one of 3- (3,4- difluorophenyl) -6-；
- 9 (3H) -one of 3- (4- fluorophenyl) -7- methoxyl group-[1,2,4] triazol [5,1-b] quinoline azoles；
Fluoro- [1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one of 3- (3,4- difluorophenyl) -6-.
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of general formula I
Object, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as pass through
Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" aryl " is
Refer to unsubstituted or is connected with the phenyl etc. of substituent group.
The present invention can the quianzolinones containing formula I above and its pharmaceutically acceptable salt, solvate work
For active ingredient, it is prepared by mixing into composition with pharmaceutically acceptable carrier or excipients, and is prepared into and is clinically subjected to
Dosage form, above-mentioned pharmaceutically acceptable excipients refer to any diluent that can be used for pharmaceutical field, adjuvant and/or load
Body.Derivative of the invention can be applied in combination with other active ingredients, if they do not generate other unfavorable effects, such as
Allergic reaction.
Clinical dosage of the quianzolinones of formula I above of the present invention for patient can basis: active constituent is in body
Age, gender, the disease phase of interior therapeutic efficiency and bioavilability, their metabolism and discharge rate and patient fit
Work as adjustment, but adult daily dosage generally should be 10-500mg, preferably 50-300mg.Therefore, when medicine of the invention
When compositions are made into unit dosage forms, it is contemplated that above-mentioned effective dose, per unit preparation should contain 10-500mg above formula I
Quianzolinones, preferably 50-300mg.According to the guidance of doctor or pharmacist, these preparations can divide at certain intervals
(preferably one to six time) is administered several times.
Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some common figurations in drug field
Agent.Several dosage form as described above can be using injection, tablet, capsule, aerosol, suppository, film, pill, outer
With drug forms such as liniment, ointments.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: adhesive, profit
Lubrication prescription, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent, preservative, solubilizer and matrix etc..
Pharmaceutical preparation can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) is administered, if some drugs
It is unstable under the conditions of stomach, enteric coated tablets can be configured to.
Passing through the active test method of vitro enzyme, it has been found that the compounds of this invention has certain anti-tumor activity, because
This compounds of this invention can be used for preparing the drug for the treatment of and/or the various cancers of prevention, such as mammary gland, lung, liver, kidney, knot
Intestines, rectum, stomach, prostate, bladder, uterus, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, esophagus
Cancer and leukaemia, neuroblastoma etc..
In addition, the compounds of this invention can be used for preparing treatment and/or prevent the medicine of IDO overexpression diseases caused
Application in object.
It is independent that reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-tumor drug
It uses, or can be with the anti-tumor drug (such as the platinum medicine cis-platinum, camptothecine Irinotecan, Changchun that have listed
Flower bases drug Noviburn, deoxidation born of the same parents' former times class drug gemcitabine, etoposide, taxol etc.) it is used in combination.Combination therapy is logical
Cross each therapeutic component simultaneously, sequence or separate administration to realize.
Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side
Method.It should be appreciated that the range of following embodiments and preparation example does not limit the scope of the invention in any way.
Following synthetic route describes the preparation of general formula I derivative of the invention, and all raw materials are all to pass through these
Method described in synthetic route, by organic chemistry filed it is well-known to the ordinarily skilled artisan method preparation or it is commercially available.
Whole final compounds of the invention are all by method described in these synthetic routes or by similar method system
Standby, these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole applied in these synthetic routes it is variable because
Definition in number definition as follows or such as claim.
General formula I derivative according to the invention, can be according to shown in route, using substituted aniline as starting material, through different sulphur
Polyisocyanate reactant obtains intermediate X 2, intermediate X 3 is then obtained with substituted ortho-aminobenzoic acid cyclization, then through methylation, hydrazine
Solution isomerization reaction obtains intermediate X 5, and last intermediate X 5 obtains target compound I through triethyl orthoformate cyclization.
Synthetic route:
Specific embodiment
Below by the further details of explanation of specific embodiment:
The nuclear magnetic resonance spectroscopy of compound use BrukerARX-400 type magnetic nuclear resonance analyzer measurement (DMSO-d6) for
Solvent, TMS are internal standard；Mass spectrum is measured using Agilent 1100LC/MS；Fusing point is measured using WRS-1A numeral melting point instrument, temperature
It spends not calibrated；Agents useful for same is that analysis is pure or chemical pure in experiment.
The preparation of fluoro- 3- phenyl-[1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one (I-1) of 1 6- of embodiment
The preparation of intermediate isothiocyano benzene (X2)
At room temperature, 10.0g (107.5mmol) X1,3.0g (268.8mmol) potassium carbonate is added to 150mL DMF/H2O
In (5:1).After mixing evenly, carbon disulfide is added dropwise in reaction solution by 20.3g (268.8mmmol), reacts at room temperature 3.5 h.It will
Reaction solution is cooled to 0 DEG C, and the dichloromethane solution (100mL) of 12.0g (64.5mmol) Cyanuric Chloride is added dropwise, and after reacting 1h, adds
2h is stirred at room temperature in the NaOH solution (100mL) for entering 6M, and methylene chloride extracts (100mL), separates organic layer, water layer dichloromethane
Alkane (100mL*3) extraction.Merge organic layer, dark red oil is obtained after being evaporated, column chromatographs to obtain colourless liquid, and yield 12.5g is received
Rate is 86.2%.
The preparation of thio -2,3- dihydroquinazoline -4 (1H) -one (X3) of the fluoro- 3- phenyl -2- of intermediate 6-
By 2.0g (14.8mmol) X2,2.3g (14.8mmol) 2- amino-5-fluorobenzoic acid, 4.1g (29.6mmol) carbon
Sour potassium is added in 25mL dehydrated alcohol, and 78 DEG C of reflux 2h, end of reaction has solid precipitation.Filter to obtain white solid 3.8g.
Yield is 98.9%.
The preparation of -4 (3H) -one (X4) of intermediate 6- fluoro- 2- (methyl mercapto) -3- phenylquinazoline
2.0g (7.4mmol) X3 is dissolved in the ethanol solution (4mL) of 2%NaOH, instills 1.1g (7.4mmol) iodine dropwise
Methane, reacts at room temperature 1h, and reaction terminates.Add 20mL water, methylene chloride extracts (10mL), separates organic layer, water layer dichloromethane
Alkane (100mL*3) extraction.Merge organic layer, white solid 1.4g is obtained after being evaporated.Yield is 66.7%.
The preparation of intermediate 3- amino -6- fluoro- 2- (phenylamino) quinazoline -4 (3H) -one (X5)
1g (3.5mmol) X4 is dissolved in 10mL isopropanol, instills 0.22mL hydrazine hydrate, back flow reaction 4h, reaction dropwise
Terminate.Obtain white solid 0.8g.Yield is 85.1%.
The preparation of fluoro- 3- phenyl-[1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one (I-1) of target compound 6-
0.2g (0.7mmol) X5 is dissolved in 5mL triethyl orthoformate, 25 DEG C of reaction 12h, reaction terminates.There is solid analysis
Out, it filters, thin layer separates to obtain white solid 0.08g.Yield is 38.7%.
According to the method for embodiment 1, using suitable raw materials and reagents, the compound that following general formula I is prepared (is implemented
Example 2 is to embodiment 12)
The preparation of -9 (3H) -one (I-2) of 2 3- of embodiment (4- methoxyphenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
Using ortho-aminobenzoic acid and P-nethoxyaniline as raw material, white is made in preparation method in accordance with the above-mentioned embodiment 1
Solid 0.07g, total recovery 26.7%.
- 9 (3H) -one (I-3) of the fluoro- 3- of 3 6- of embodiment (4- methoxyphenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
Preparation
Using 2- amino -4- fluobenzoic acid and para-fluoroaniline as raw material, white is made in preparation method in accordance with the above-mentioned embodiment 1
Solid 0.15g, total recovery 30.6%.
- 9 (3H) -one (I-4) of the chloro- 3- of 4 6- of embodiment (4- aminomethyl phenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
Preparation
Using 2- amino -4- chlorobenzoic acid and open-chain crown ether as raw material, preparation method in accordance with the above-mentioned embodiment 1 is made white
Color solid 0.14g, total recovery 29.6%.
The preparation of -9 (3H) -one (I-5) of 5 3- of embodiment (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
Using 2- aminobenzoic acid and para-fluoroaniline as raw material, white solid is made in preparation method in accordance with the above-mentioned embodiment 1
0.13g, total recovery 27.3%.
The system of -9 (3H) -one (I-6) of the fluoro- 3- of 6 6- of embodiment (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
It is standby
Using 2- amino -4- fluobenzoic acid and para-fluoroaniline as raw material, white is made in preparation method in accordance with the above-mentioned embodiment 1
Solid 0.14g, total recovery 28.0%.
The system of -9 (3H) -one (I-7) of the chloro- 3- of 7 6- of embodiment (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
It is standby
Using 2- amino -4- chlorobenzoic acid and para-fluoroaniline as raw material, white is made in preparation method in accordance with the above-mentioned embodiment 1
Solid 0.12g, total recovery 27.5%.
The preparation of -9 (3H) -one (I-8) of 8 3- of embodiment (3- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
Using 2- aminobenzoic acid and 3- fluoroaniline as raw material, white solid is made in preparation method in accordance with the above-mentioned embodiment 1
0.08 g, total recovery 21.2%.
The system of -9 (3H) -one (I-9) of the fluoro- 3- of 9 6- of embodiment (3- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles
It is standby
Using 2- amino -4- fluobenzoic acid and 3- fluoroaniline as raw material, white is made in preparation method in accordance with the above-mentioned embodiment 1
Solid 0.12g, total recovery 26.2%.
Chloro- -9 (3H) -one (I- of [1,2,4] triazol [5,1-b] quinoline azoles of 10 3- of embodiment (3,4- difluorophenyl) -6-
10) preparation
With 2- amino -4- chlorobenzoic acid and 3,4- difluoroaniline is raw material, and preparation method in accordance with the above-mentioned embodiment 1 is made
White solid 0.11g, total recovery 27.0%.
- 9 (3H) -one (I- of 11 3- of embodiment (4- fluorophenyl) -7- methoxyl group-[1,2,4] triazol [5,1-b] quinoline azoles
11) preparation
Using 2- amino -5- methoxy benzoic acid and para-fluoroaniline as raw material, preparation method in accordance with the above-mentioned embodiment 1 is made
White solid 0.13g, total recovery 27.7%.
Fluoro- -9 (3H) -one (I- of [1,2,4] triazol [5,1-b] quinoline azoles of 12 3- of embodiment (3,4- difluorophenyl) -6-
12) preparation
With 2- amino -4- fluobenzoic acid and 3,4- difluoroaniline is raw material, and preparation method in accordance with the above-mentioned embodiment 1 is made
White solid 0.12g, total recovery 27.2%.
The related data of target compound is as shown in table 1:
Table 1
The extracorporeal anti-tumor cell activity of product of the present invention
Using the active test method of vitro enzyme, kinases used is what Medicilon was provided for compound activity test
HIDO kinases.Method particularly includes: compound is concentrated in the buffer of 100 μ l, hIDO is eased up by the hIDO for preparing 20nM
Fliud flushing is preheated to 37 DEG C, and cultivates 30min at 37 DEG C.It is quenched later with 50 μ l, 30% trichloroacetic acid, continues at 52 DEG C and train
Support 30min.It is centrifuged at room temperature, takes 100 μ l supernatants to be mixed with 100 μ l Ehrlich ' s reagents, read number under 480nm wavelength
Value, and inhibiting rate is calculated according to the numerical value, activity data is shown in Table 2.
Table 2
From above-mentioned experimental result it should be apparent that the claimed compounds of formula I of the present invention, has centainly
Anti tumor activity in vitro.
It will be apparent to those skilled in the art that without departing from the structure of the invention, several deformations can also be made
And improvement, these also should be considered as protection scope of the present invention, these all will not influence the effect and patent that the present invention is implemented.
Claims (5)
1. quianzolinones and its pharmaceutically acceptable salt, which is characterized in that as shown in general formula I:
Wherein, R1For 1~3 substituent group, independently selected from hydroxyl, fluorine, chlorine, cyano, C1-C6 alkoxy；
R2For 1~3 substituent group, independently selected from hydroxyl, fluorine, cyano, C1-C6 alkoxy.
2. quianzolinones according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that R1It is 1
~3 substituent groups, independently selected from fluorine, chlorine, C1-C4 alkoxy；
R2For 1~3 substituent group, independently selected from fluorine, C1-C4 alkoxy.
3. following compounds and its pharmaceutically acceptable salt:
Fluoro- 3- phenyl-[1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one of 6-；
- 9 (3H) -one of 3- (4- methoxyphenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the fluoro- 3- of 6- (4- methoxyphenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；6- chloro- 3- (4- methylbenzene
Base)--9 (3H) -one of [1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of 3- (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the fluoro- 3- of 6- (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the chloro- 3- of 6- (4- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of 3- (3- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
- 9 (3H) -one of the fluoro- 3- of 6- (3- fluorophenyl)-[1,2,4] triazol [5,1-b] quinoline azoles；
Chloro- [1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one of 3- (3,4- difluorophenyl) -6-；
- 9 (3H) -one of 3- (4- fluorophenyl) -7- methoxyl group-[1,2,4] triazol [5,1-b] quinoline azoles；
Fluoro- [1,2,4] triazol [5,1-b] quinoline azoles -9 (3H) -one of 3- (3,4- difluorophenyl) -6-.
4. a kind of Pharmaceutical composition, the compound comprising any one of claims 1 to 3 and its pharmaceutically acceptable salt are made
For active constituent and pharmaceutically acceptable excipient.
5. the compound and its pharmaceutically acceptable salt of any one of claims 1 to 3 are in preparation treatment and/or pre- anti-cancer
Application in the drug of disease.
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|---|---|---|---|---|
| US4350695A (en) * | 1980-02-14 | 1982-09-21 | Roussel Uclaf | Antihistaminic and bronchospasmolytic triazoloquinazolinones |
| CN101506214A (en) * | 2006-06-20 | 2009-08-12 | 艾博特公司 | Pyrazoloquinazolinones as PARP inhibitors |
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2018
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