CN104341407A - Quinazoline compounds, preparation method and applications thereof - Google Patents

Quinazoline compounds, preparation method and applications thereof Download PDF

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Publication number
CN104341407A
CN104341407A CN201310312161.XA CN201310312161A CN104341407A CN 104341407 A CN104341407 A CN 104341407A CN 201310312161 A CN201310312161 A CN 201310312161A CN 104341407 A CN104341407 A CN 104341407A
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human
compound
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quinazoline compounds
cancer
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CN201310312161.XA
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黄传满
邵东
解美娜
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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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Abstract

The invention provides a preparation method and antitumor applications of quinazoline compounds, which are represented by a formula I, wherein in the formula I the R represents a group containing different substituent groups in a phenyl ring. The quinazoline compounds represented by the formula I and pharmaceutically acceptable salts/solvates thereof have an inhibiting effect on human liver cancer cells, human breast cancer cells, human lung cancer cells, human stomach cancer cells, human prostate cancer cells, and human myeloma cells, and can be used to prepare drugs for treating human liver cancer, human breast cancer, human lung cancer, human stomach cancer, human prostate cancer, and human myeloma.

Description

Quinazoline compounds and its production and use
Technical field
The present invention relates to quinazoline compounds and preparation method thereof and anticancer usage, belong to technical field of medicine preparation.
Background technology
Cancer is the disease of serious harm human health, the whole world has up to ten million people to die from cancer every year, traditional cancer therapy drug mainly cytotoxic drug, these medicine great majority are nonselective, while killing and wounding cancer cells, also can kill and wound the normal cell of body, there is poor selectivity, toxic side effect shortcoming that is strong, easily generation resistance.The research and development of cancer therapy drug deeply by the concern of scientists, research and develop novel, efficiently become the task of top priority with the antitumor drug of low toxicity.
Quinazoline compounds is widely used in biomedicine field, there are good antitumour activity and highly selective (Arch.Pharm.Pharm.Med.Chem.2001,334:357), this compounds is the inhibitor (EGFR-TKI) of class epidermal growth factor recipient tyrosine kinase comparatively early, a series of report demonstrates quinazoline compound by being combined with the binding site of ATP, high selectivity ground suppresses the phosphorylation of EGFR, thus the growth of inhibition tumor cell.The new drug of listing containing quinazoline structure unit has (the Bioscience Biotechnology Biochemistry such as Gefitinib (Gefitinib), Tarceva and lapatinibditosylate (Lapatinib) in recent years, 2005,69:2349; W02009016072), show and have good inhibition to tumour.
The present invention, by introducing 2-amido benzoxazoles group on 6 of quinazoline, has synthesized the active compound for anti tumor that a class is novel, the growth of the obvious inhibition tumor cell of this compounds energy, is expected to become antitumor drug that is efficient and low toxicity.
Summary of the invention
The present invention seeks to the quinazoline compounds that searching one class is novel, efficient, low toxicity has anti-tumor activity.
Quinazoline compounds of the present invention, for having the compound of general formula I:
In general formula I, R is the group containing different substituents on phenyl ring:
The quinazoline compounds of general formula I of the present invention and pharmacy acceptable salt thereof or solvate can be used for preparing the purposes for the treatment of including but not limited to people's liver cancer, human breast carcinoma, people's lung cancer, people's cancer of the stomach, human prostata cancer and human myeloma medicine.
The syntheti c route of the quinazoline compounds of general formula I is as follows:
With the bromo-4-chloro-quinazoline of 6-for starting raw material, obtained compound 3 is reacted containing the substituent compound 2 of distinct fragrance with on piperazine ring, reaction solvent is including but not limited to Virahol, ethanol, acetonitrile, propyl carbinol, dioxane, tetrahydrofuran (THF), DMF and toluene etc., alkali including but not limited to salt of wormwood, sodium carbonate, sodium hydride, cesium carbonate, potassium tert.-butoxide and sodium tert-butoxide, triethylamine, diisopropylethylamine etc., temperature of reaction is at 0-120 DEG C.
Compound I synthesis coupling reagent including but not limited to 2-amido-benzoxazoles-5-boric acid, 2-amido-benzoxazoles-5-borate hydrochlorate and 2-amido-benzoxazoles-5-boric acid ester, catalyzer including but not limited to four triphenyl phosphorus palladiums, tertiary butyl phosphorus palladium, PdCl 2(dppf), Pd 2(dba) 3with palladium etc., alkali including but not limited to sodium carbonate, salt of wormwood, sodium bicarbonate etc., reaction solvent is including but not limited to dioxane-water, DMF-water, alcohol-water, glycol dimethyl ether-water and toluene-water etc., and temperature of reaction is at 80-120 DEG C.
The quinazoline compounds with general formula I can become pharmacy acceptable salt, and the salt of one-tenth is including but not limited to hydrochloride, vitriol, oxalate, acetate, fumarate, tartrate, maleate, Citrate trianion, mesylate, benzene sulfonate, lactic acid salt, mandelate, succinate, fumarate and malate etc.
The quinazoline compounds with general formula I can become pharmaceutically acceptable solvate, and described solvate is organic solvent or hydrate, preferred alcohols compound or hydrate.
The quinazoline compounds with general formula I can deliver medicine to humans and animals, can oral, rectum, parenteral, topical.Described compound can be individually dosed, or with other pharmaceutically acceptable compound Combined Preparation.Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.Solid dosage such as tablet, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
Composition for parenteral injection comprises physiologically acceptable sterilized water or anhydrous solution, dispersion agent, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.
Formulation for topical comprises ointment, powder, propellant and inhalation.
The present invention has following beneficial effect:
Quinazoline compounds prepared by the present invention is the novel and efficient compound of a class, and have obvious restraining effect to kinds of tumor cells, such compound selective is good, and toxic side effect is little, is expected to the new drug being developed to treatment tumour.
Embodiment
This specific embodiment building-up process is as follows:
6-bromo-4-chloro-quinazoline (1) reference literature WO2008/89310 synthesizes;
1-(3-(2-(pyrrolidin-1-yl) ethylamino)-4-methyl-5-(piperazine-1-base) phenyl)
Acetone (2a) reference literature BMCL2012,22,2693 and CN102690270 synthesis;
2-amido-benzoxazoles-5-borate hydrochlorate (4) reference literature W02010/051042 synthesizes.
Embodiment 1: synthesis 1-(3-(2-(pyrrolidin-1-yl) ethylamino)-5-(4-(6-bromine quinazoline-4-base) piperazine-1-base)-4-aminomethyl phenyl) acetone (compound 3a)
The bromo-4-chloro-quinazoline of 6-(100mg, 0.41mmol), compound 2a (158mg, 0.46mmol), Anhydrous potassium carbonate (566mg, 4.1mmol) with DMF (3mL), stirred overnight at room temperature, add water (10mL), jolting, suction filtration, washing, dry faint yellow solid 1-(3-(2-(pyrrolidin-1-yl) ethylamino)-5-(4-(6-bromine quinazoline-4-base) piperazine-1-base)-4-aminomethyl phenyl) acetone (compound 3a) 135mg, productive rate: 59.7%.El-MS MS(m/z)：551.2(M +)
1H-NMR(CDCl 3，400MHz)：δ8.76(s，1H)，8.09(d，1H)，7.81～7.77(m，2H)，7.16(d，1H)，7.04(d，1H)，4.45(m，1H)，3.37(m，2H)，3.29(m，4H)，3.12(q，2H)，2.81(t，2H)，2.56(m，4H)，2.21(s，3H)，1.80～1.77(m，8H)，1.21(t，3H).
Embodiment 2: synthesis 1-(3-(2-(pyrrolidin-1-yl) ethylamino)-5-(4-(6-(2-amino benzoxazoles-5-base) quinazoline-4-base) piperazine-1-base)-4-aminomethyl phenyl) acetone (Compound I-a)
Compound 3a (105mg, 0.19mmol), 2-amido-benzoxazoles-5-borate hydrochlorate (53mg, 0.25mmol), four triphenyl phosphorus palladium (18mg, 0.016mmol), sodium carbonate (101mg, 0.95mmol) with dioxane-water (10mL-3mL), reflux 3 hours under argon shield, cooling, suction filtration, ethyl acetate (100mL) extracts, saturated aqueous common salt (30mL) washs, anhydrous sodium sulfate drying, be concentrated into dry, silica column purification (methylene dichloride: methyl alcohol=15: 1 wash-out), concentrate to obtain off-white color solid 1-(3-(2-(pyrrolidin-1-yl) ethylamino)-5-(4-(6-(2-amino benzoxazoles-5-base) quinazoline-4-base) piperazine-1-base)-4-aminomethyl phenyl) acetone (Compound I-a) 80mg, productive rate: 69.6%.EI-MS MS(m/z)：605.3(M +)
1H-NMR(DMSO-d6，400MHz)：δ8.66(s，1H)，8.15～8.11(m，2H)，7.88(d，1H)，7.61(s，1H)，7.52(s，2H)，7.45(d，1H)，7.38(d，1H)，7.05(s，1H)，6.94(s，1H)，5.01～4.98(m，1H)，3.98(br，4H)，3.28～3.24(m，2H)，3.03～2.96(m，6H)，2.73～2.70(m，2H)，2.55～2.50(m，4H)，2.15(s，3H)，1.71(br，4H)，1.06(t，3H).
Prepare the Compound I-a of general formula I to I-s according to the method for embodiment 1 and embodiment 2, structural formula is as shown in table 1.
Table 1
Embodiment 3: Tumor suppression Activity Assessment is tested
For examination target:
HepG2 cell lines, MCF-7 cell strainHJ2mm, human lung carcinoma cell line A549, human stomach cancer cell line SGC7901, Human Prostate Cancer Cells PC-3 and human myeloma cell strain RPMI8226.
Cell cultures and drug treating:
By freeze-stored cell recover after, add appropriate RPMI-1640 nutrient solution (containing 10% foetal calf serum, 100U/mL penicillin, 100U/mL Streptomycin sulphate) and be inoculated in culturing bottle, put incubator (37 DEG C, 5%CO 2) middle cultivation, went down to posterity every 2 ~ 3 days 1 time.Be inoculated in by cell in 96 well culture plates, cell density is 5000/hole, adds the compound solution (compound DMSO dissolves, then dilutes with nutrient solution) of different concns, and often kind of dosage establishes four repetitions.
Test method:
1. attached cell adopts mtt assay (human liver cancer cell, human breast cancer cell, human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells):
After drug treating 48h, every hole adds 0.25mg/mL MTT (Thiazolyl blue) reagent 10uL, puts into 37 DEG C, 5%CO 2continue in incubator to cultivate 4h, absorb nutrient solution, every hole adds 100uL DMSO dissolved particles, and then survey absorbancy (0D) value under 570nm by microplate reader, experiment in triplicate.Measure inhibiting rate, calculate suppression 50% Growth of Cells desired concn IC 50.
2. suspension cell adopts CCK-8 method (human myeloma cell):
After drug treating 48h, every hole adds CCK-8 (containing MTS0.19mg/ml) reagent 20uL, puts into 37 DEG C, 5%CO 2continue in incubator to cultivate 2h, survey the OD value under 450nm by microplate reader, experiment in triplicate.Measure inhibiting rate, calculate suppression 50% Growth of Cells desired concn IC 50.
Illustrate: IC 50be worth less, then the effect of compound Tumor suppression is better, more obvious.
Wherein:
IC 50< 1uM, with " ++++" represent;
IC 50=1-10uM, represents with " +++ ";
IC 50=10-50uM, represents with " ++ ";
IC 50> 50uM, represents with "+".
Assessment contrast is as table 2:
Table 2 (compound and Tumor suppression IC 50active table)
As described in Table 2, the quinazoline compounds with general formula I has restraining effect to human liver cancer cell, human breast cancer cell, human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells and human myeloma cell, can be used for the medicine preparing treatment people liver cancer, human breast carcinoma, people's lung cancer, people's cancer of the stomach, human prostata cancer and human myeloma.

Claims (6)

1. quinazoline compounds, is characterized in that, for having the compound of general formula I:
Wherein, R is the group containing different substituents on phenyl ring:
2. the quinazoline compounds of general formula I and pharmacy acceptable salt thereof or solvate can be used for preparing the purposes for the treatment of including but not limited to people's liver cancer, human breast carcinoma, people's lung cancer, people's cancer of the stomach, human prostata cancer and human myeloma medicine as claimed in claim 1.
3. there is the synthetic route of the quinazoline compounds of general formula I:
(a) with the bromo-4-chloro-quinazoline of 6-for starting raw material, obtained compound 3 is reacted with the compound 2 containing different benzene ring substitution group on piperazine ring, reaction solvent is including but not limited to Virahol, ethanol, acetonitrile, propyl carbinol, dioxane, tetrahydrofuran (THF), DMF and toluene etc., alkali including but not limited to salt of wormwood, sodium carbonate, sodium hydride, cesium carbonate, potassium tert.-butoxide and sodium tert-butoxide, triethylamine, diisopropylethylamine etc., temperature of reaction is at 0-120 DEG C.
(b) Compound I synthesis coupling reagent including but not limited to 2-amido-benzoxazoles-5-boric acid, 2-amido-benzoxazoles-5-borate hydrochlorate and 2-amido-benzoxazoles-5-boric acid ester, catalyzer including but not limited to four triphenyl phosphorus palladiums, tertiary butyl phosphorus palladium, PdCl 2(dppf), Pd 2(dba) 3with palladium etc., alkali including but not limited to sodium carbonate, salt of wormwood, sodium bicarbonate etc., reaction solvent is including but not limited to dioxane-water, DMF-water, alcohol-water, glycol dimethyl ether-water and toluene-water etc., and temperature of reaction is at 80-120 DEG C.
4. the quinazoline compounds with general formula I can become pharmaceutically acceptable inorganic salt or organic salt, including but not limited to hydrochloride, vitriol, oxalate, formate, acetate, fumarate, tartrate, maleate, Citrate trianion, mesylate, benzene sulfonate, lactic acid salt, mandelate, succinate, fumarate and malate etc.
5. the quinazoline compounds with general formula I can become pharmaceutically acceptable solvate, and described solvate is organic solvent or hydrate, preferred alcohols compound or hydrate.
6. the quinazoline compounds with general formula I can deliver medicine to humans and animals, can oral, rectum, parenteral, topical.Described compound can be individually dosed, or with other pharmaceutically acceptable compound Combined Preparation.Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
Composition for parenteral injection comprises physiologically acceptable sterilized water or anhydrous solution, dispersion agent, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.
Formulation for topical comprises ointment, powder, propellant and inhalation.
CN201310312161.XA 2013-07-24 2013-07-24 Quinazoline compounds, preparation method and applications thereof Pending CN104341407A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020518561A (en) * 2017-04-20 2020-06-25 ギリアード サイエンシーズ， インコーポレイテッド PD-1/PD-L1 inhibitor
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020518561A (en) * 2017-04-20 2020-06-25 ギリアード サイエンシーズ， インコーポレイテッド PD-1/PD-L1 inhibitor
JP7161491B2 (en) 2017-04-20 2022-10-26 ギリアード サイエンシーズ， インコーポレイテッド PD-1/PD-L1 inhibitor
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

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Application publication date: 20150211