CN104086529B - A kind of quinazoline derivative, Its Preparation Method And Use - Google Patents
A kind of quinazoline derivative, Its Preparation Method And Use Download PDFInfo
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- CN104086529B CN104086529B CN201410209284.5A CN201410209284A CN104086529B CN 104086529 B CN104086529 B CN 104086529B CN 201410209284 A CN201410209284 A CN 201410209284A CN 104086529 B CN104086529 B CN 104086529B
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- cancer
- quinazoline derivative
- acceptable salt
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- pharmacy acceptable
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- 0 CCc(c(*C)c1)cc(C(C)=C)c1N=CC Chemical compound CCc(c(*C)c1)cc(C(C)=C)c1N=CC 0.000 description 2
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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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07D239/94—Nitrogen atoms
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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
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to antitumor relevant pharmaceutical field, provide quinazoline derivative or its pharmacy acceptable salt.Present invention also offers the preparation method of described quinazoline derivative or its pharmacy acceptable salt, pharmaceutical composition and treat glioblastoma as effective constituent in preparation, brain tumor, melanoma, lung cancer, prostate cancer, colorectal carcinoma, leukemia, mammary cancer, liver cancer, the application of the antitumor drug such as cancer of the stomach or carcinoma of the pancreas aspect.
Description
Technical field
The invention belongs to medical art, or rather, relate to a kind of quinazoline derivative, its preparation method, containing its pharmaceutical composition and the purposes for the preparation of antitumor drug thereof.
Background technology
Cancer is one of principal disease of current harm humans health and orthobiosis, particularly only over year, along with the deterioration of environment, there is significantly rising interesting gesture in the sickness rate of malignant tumour, the research and development of cancer therapy drug are the hot subjects that scientist selects always, and researching and developing antitumor drug that is novel, efficient and low toxicity becomes the task of top priority.
Contriver is in the process of research quinazoline derivative, and found that anti-tumor activity is strong, toxicity is low, has the quinazoline derivative of excellent pharmacokinetic properties, and this compounds cost is low, and synthesis technique is easy, and pollutes little.
Summary of the invention
One object of the present invention, is to provide a kind of quinazoline derivative or its pharmacy acceptable salt.
Another object of the present invention, is the preparation method providing a kind of quinazoline derivative or its pharmacy acceptable salt.
Another object of the present invention, is to provide a kind of pharmaceutical composition, and it comprises quinazoline derivative of the present invention or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.
A further object of the invention, be to provide quinazoline derivative or its pharmacy acceptable salt preparing the application in antitumor drug, described tumour particularly glioblastoma, brain tumor, melanoma, lung cancer, prostate cancer, colorectal carcinoma, leukemia, mammary cancer, liver cancer, cancer of the stomach or carcinoma of the pancreas.
The present invention relates to quinazoline derivative or its pharmacy acceptable salt of general formula (I) structure:
Wherein:
R
1, R
2be C independently
1-4alkyl, is optionally selected from halogen, cyano group, hydroxyl, amino, C by one, two or three
1-4thiazolinyl, C
1-4alkynyl, C
1-4alkylamino, two-C
1-4alkylamino, C
1-4alkoxyl group, C
6-10aryl or C
3-8the substituting group of heterocyclic radical replaces;
R
3for hydrogen, halogen, cyano group or hydroxyl;
A is C
6-10aryl or C
3-8heteroaryl, is optionally selected from halogen, cyano group, hydroxyl, amino, C by one, two or three
1-4alkylamino, two-C
1-4alkylamino, C
1-4alkoxyl group or C
1-4the substituting group of alkyl replaces;
B is C
3-8heterocyclylalkyl, is optionally selected from halogen, cyano group, hydroxyl, amino, C by one, two or three
1-4alkylamino, two-C
1-4alkylamino, C
1-4alkoxyl group, C
1-4the substituting group of alkyl ,-CONHR or COOR replaces; Wherein R is C
1-4alkyl.
In another preferred embodiment, halogen is preferably fluorine, chlorine or bromine;
In another preferred embodiment, C
1-4alkyl is preferably methyl, ethyl, n-propyl, sec.-propyl or butyl;
In another preferred embodiment, C
6-10aryl is preferably phenyl, naphthyl or tetralyl;
In another preferred embodiment, C
3-8heteroaryl is preferably pyridyl, pyridazinyl, pyrryl, pyrazolyl, thiazolyl, benzothiazolyl, benzimidazolyl-, indazolyl, indyl, quinolyl, quinazolyl, indolizinyl or acridyl;
In another preferred embodiment, C
3-8heterocyclylalkyl is preferably piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, dithiane base, pyridazinyl, pyrazinyl, triazinyl, homopiperazine base or homopiperidinyl;
In another preferred embodiment, C
3-8heterocyclic radical is preferably piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, dithiane base, pyridazinyl, pyrazinyl, triazinyl, homopiperazine base, homopiperidinyl, indolinyl or tetrahydric quinoline group.
Described compound is:
The pharmacy acceptable salt of the quinazoline derivative of general formula (I), for mineral acid or acetic acid, propionic acid, propanedioic acid, butyric acid, lactic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, toxilic acids such as the quinazoline derivative of general formula (I) and hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, the salt that the organic acids such as phenylformic acid, succsinic acid, picric acid, tartrate, citric acid, fumaric acid are formed.
The quinazoline derivative of general formula of the present invention (I) is synthesized by following steps:
Wherein, R
1, R
2, R
3, A, B definition with mentioned above.
This compounds is effective for treatment human tumor.Although compound of the present invention can without the direct administration of any preparation, described various compounds are preferably to use with pharmaceutically acceptable auxiliary material pharmaceutical compositions.Pharmaceutically acceptable auxiliary material comprises thinner, lubricant, tackiness agent, disintegrating agent, stablizer, solvent etc.
Thinner of the present invention includes but not limited to starch, Microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose etc.; Described lubricant includes but not limited to Magnesium Stearate, stearic acid, sodium-chlor, sodium oleate, sodium laurylsulfate, the husky mother in pool Lip river etc.; Described tackiness agent includes but not limited to water, ethanol, starch slurry, syrup, Vltra tears, Xylo-Mucine, sodium alginate, polyvinylpyrrolidone etc.; Described disintegrating agent includes but not limited to starch effervescent mixture and sodium bicarbonate and Citric Acid, tartrate, low-substituted hydroxypropyl cellulose etc.; Described stablizer includes but not limited to that polysaccharide is as kordofan gum, agar, alginic acid, ether of cellulose and carboxymethyl crusta ester etc.; Described solvent includes but not limited to the salts solution etc. of water, balance.
The difference that described composition needs according to treatment, can make various different preparation, comprise various solid orally ingestible, liquid oral medicine, injection etc.The acceptable oral preparation solid preparation of pharmaceutics has: conventional tablet, dispersible tablet, enteric coated tablet, particle, capsule, dripping pill, powder etc., and oral liquid has oral liquid, emulsion; Injection has: little liquid drugs injection, transfusion, freeze-dried powder etc.Each preparation can be prepared from according to the technique of routine.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, usually, the weight range of active compound is 1% ~ 90%(weight of composition).
Embodiment
Embodiment 1: the synthesis of compound 1
The synthesis of compound 1a:
By 6,7-dimethoxy-2-methylquinazolin-4-amine 2.19g and CH
2cl
2(10ml) add under nitrogen protection in 50ml three-necked bottle, after dissolving, drip the CH of CDI1.62g
2cl
2(10ml) solution, after reacting 16h, drips the CH of 1-methyl piperidine-4-amine 1.01g under normal temperature
2cl
2(10ml) solution, continues to stir 18h, and adularescent precipitation generates.Suction filtration, filter cake CH
2cl
2washing 2 × 10ml.Vacuum-drying, obtains product.Use tetrahydrofuran (THF) recrystallization.Obtain compound as white solid 1a3.04g, productive rate 94%.
ESI-MS：360.20[M+H]
+
Ultimate analysis: theoretical value/measured value, C (60.15/60.12), H (7.01/7.04), N (19.48/19.41), O (13.35/13.42).
The synthesis of compound 1:
By the compound 1a of 1.8g drying and 1.8g phenyl aldehyde mixed dissolution in 20ml glacial acetic acid, add the sodium acetate of catalytic amount, 130 DEG C of back flow reaction 8 hours, decompression remove portion acetic acid, is cooled to 0-5 DEG C, suction filtration, solid is with after 15ml washed with diethylether twice, dry, obtains white powdery solids.Thick product methyl alcohol/chloroform (volume ratio 1/50 to 1/10) by purification by silica gel column chromatography, obtains compound as white solid 1,1.99g, productive rate 89% as eluent.
ESI-MS：448.23[M+H]
+
Ultimate analysis: theoretical value/measured value, C (67.09/67.14), H (6.53/6.48), N (15.65/15.55), O (10.73/10.83).
1HNMR(400MHz，CDCl
3)δ9.50(s，1H)，7.60-7.24(m，7H)，6.98(d，2H)，6.0(s，1H)，3.83(s，6H)，3.6(m，1H)，2.50(t，4H)，2.26(s，3H)，1.85(m，4H)。
Embodiment 2: the synthesis of compound 2
Method, with embodiment 1, replaces phenyl aldehyde unlike with 1-naphthaldehyde, obtains light yellow solid.Productive rate: 72%.
ESI-MS：498.20[M+H]
+
Ultimate analysis: theoretical value/measured value, C (70.00/70.04), H (6.28/6.24), N (14.07/14.00), O (9.65/9.72).
Embodiment 3: the synthesis of compound 3
Method, with embodiment 1, unlike replacing 4-methyl piperidine-1-amine with 4-methylpiperazine-1-amine, obtains white solid.Productive rate: 70%.
ESI-MS：499.23[M+H]
+
Ultimate analysis: theoretical value/measured value, C (64.27/64.17), H (6.29/6.21), N (18.74/18.84), O (10.70/10.78).
Embodiment 4: the synthesis of compound 4
Method, with embodiment 1, unlike replacing 6,7-dimethoxy-2-methylquinazolin-4-amine with 7-methoxyl group-2-methyl-6-(3-morpholine-1-base propyl group) quinazoline-4-amine, obtains white solid.Productive rate: 68%.
ESI-MS：561.30[M+H]
+
Ultimate analysis: theoretical value/measured value, C (66.41/66.51), H (7.19/7.15), N (14.99/14.89), O (11.41/11.45).
Embodiment 5-18: synthesize following compound 5-18 according to similar approach
Table 1
Embodiment 19: anticancer experiment in vitro
Adopt classical cytotoxic activity vitro detection method mtt assay, test sample is to the cell proliferation toxicity of the human tumor cells of vitro culture.
During experiment, sample adds DMSO, is diluted to desired concn with RPMI1640 substratum, ultrasonic, is partly dissolved, and sample segment solution is suspension, with nutritive medium successively doubling dilution.
Cell strain: promyelocytic leukemia HL-60 cell; MCF-7 Breast Cancer Cell; Melanochrome G-361; Glioblastoma U-251.
Experimental technique:
Experiment adopts conventional MTT detection method.Inoculating cell: cell in vegetative period of taking the logarithm, adds the RPMI-1640 nutrient solution containing 10% embryo bovine serum, cell dilution is become single cell suspension after the trysinization of 0.25%, and adjustment cell count, is inoculated in 96 orifice plates, every hole 100 μ L.Postvaccinal cell put 37 DEG C, cultivate 24 hours in 5% CO2gas incubator.Dosing: test medicine RPMI-1640 nutrient solution is carried out doubling dilution, configures 6 concentration altogether.In 96 orifice plates, add survey product liquid, 100 μ L/ holes, each sample concentration establishes 4 multiple holes, and control group establishes 5 multiple holes, and sample concentration is 1 × 10-4mol/L.The RPMI-1640 nutrient solution of control group containing 10% foetal calf serum supplies residual volume, makes reaction volume be 200 μ L/ holes.After application of sample, cell put 37 DEG C, continue cultivation 68 hours in 5% CO2gas incubator.Add MTT: abandon supernatant, add MTT5mg/ml, dissolve with PBS, every hole adds 10 μ L.Put 37 DEG C of continuation cultivations to take out after 4 hours.Survey OD value: the supernatant liquor in reject 96 orifice plate, every hole adds DMSO150 μ L.Measure OD value at microplate reader 570nm, calculate inhibitory rate of cell growth with following formula:
Inhibiting rate=[(1-medication group mean OD value/control group mean OD value)] × 100%
Experimental result:
To the restraining effect of the tumour cell of vitro culture
Table 2
The power of the Tumor suppression activity of the compound in table 2 represents horizontally through " ++++", " +++ ", " ++ ", "+", wherein:
++++represent, inhibiting rate was more than 70%;
+++ represent that inhibiting rate is more than 60 to being less than 70%;
++ represent that inhibiting rate is more than 50 to being less than 60%;
+ represent that inhibiting rate is more than 40 to being less than 50%.
According to above in vitro tests result, the compound with general formula (I) structure has stronger restraining effect to above-mentioned 4 kinds of human tumor cells.
embodiment 20:urogastron (EGFR)-Tyrosylprotein kinase experiment
Table 3
The phosphorylation of the compounds of this invention to the tumour cell of EGFR overexpression has obvious restraining effect.
Anti-tumor in vivo is tested, and toxicity test, the preliminary experiment of pharmacokinetics etc. shows, the compounds of this invention has excellent characteristic in above-mentioned.
Claims (4)
1. the quinazoline derivative shown in following formula or its pharmacy acceptable salt:
2. a pharmaceutical composition, it comprises quinazoline derivative according to claim 1 or its pharmacy acceptable salt, and pharmaceutically acceptable auxiliary material.
3. quinazoline derivative according to claim 1 or its pharmacy acceptable salt are preparing the application in antitumor drug.
4. application according to claim 3, is characterized in that, described tumour is glioblastoma, brain tumor, melanoma, lung cancer, prostate cancer, colorectal carcinoma, leukemia, mammary cancer, liver cancer, cancer of the stomach or carcinoma of the pancreas.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101490016A (en) * | 2006-07-28 | 2009-07-22 | 诺瓦提斯公司 | 2,4-substituted quinazolines as lipid kinase inhibitors |
| CN101528702A (en) * | 2006-06-08 | 2009-09-09 | 阿雷生物药品公司 | Quinoline compounds and methods of use |
| WO2013143376A1 (en) * | 2012-03-26 | 2013-10-03 | 武汉盛云生物医药科技有限责任公司 | Quinoline compounds containing 1,2,4-triazine-3,5-dione and use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101528702A (en) * | 2006-06-08 | 2009-09-09 | 阿雷生物药品公司 | Quinoline compounds and methods of use |
| CN101490016A (en) * | 2006-07-28 | 2009-07-22 | 诺瓦提斯公司 | 2,4-substituted quinazolines as lipid kinase inhibitors |
| WO2013143376A1 (en) * | 2012-03-26 | 2013-10-03 | 武汉盛云生物医药科技有限责任公司 | Quinoline compounds containing 1,2,4-triazine-3,5-dione and use thereof |
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