CN104177346A - Quinazoline compound and use thereof - Google Patents
Quinazoline compound and use thereof Download PDFInfo
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- CN104177346A CN104177346A CN201310189863.3A CN201310189863A CN104177346A CN 104177346 A CN104177346 A CN 104177346A CN 201310189863 A CN201310189863 A CN 201310189863A CN 104177346 A CN104177346 A CN 104177346A
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- quinazoline
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- 0 C*c(cc1)cc(Cl)c1OCc1cccc(F)c1 Chemical compound C*c(cc1)cc(Cl)c1OCc1cccc(F)c1 0.000 description 7
- YSWLKKFRVKBNND-UHFFFAOYSA-N C=[Br]c1cc(N)ccc1 Chemical compound C=[Br]c1cc(N)ccc1 YSWLKKFRVKBNND-UHFFFAOYSA-N 0.000 description 1
- YDKXUEPKUPZERK-UHFFFAOYSA-N CC(C)C(Nc(cc(C)cc1)c1F)=O Chemical compound CC(C)C(Nc(cc(C)cc1)c1F)=O YDKXUEPKUPZERK-UHFFFAOYSA-N 0.000 description 1
- PAYWIMMOVUPBHF-UHFFFAOYSA-N CC(C)c(c(F)c1)ccc1Br Chemical compound CC(C)c(c(F)c1)ccc1Br PAYWIMMOVUPBHF-UHFFFAOYSA-N 0.000 description 1
- KOBUPESTYSBFQY-UHFFFAOYSA-N CC(C)c(cc1)ccc1NC(NCc1ccccc1)=O Chemical compound CC(C)c(cc1)ccc1NC(NCc1ccccc1)=O KOBUPESTYSBFQY-UHFFFAOYSA-N 0.000 description 1
- ALMHSXDYCFOZQD-UHFFFAOYSA-N CC(Nc1cccc(C)c1)=O Chemical compound CC(Nc1cccc(C)c1)=O ALMHSXDYCFOZQD-UHFFFAOYSA-N 0.000 description 1
- XBLAEKJXNKNGMJ-UHFFFAOYSA-N CCOC(c1c[s]c2cc(S(C)(C)=C)ccc12)=O Chemical compound CCOC(c1c[s]c2cc(S(C)(C)=C)ccc12)=O XBLAEKJXNKNGMJ-UHFFFAOYSA-N 0.000 description 1
- WCWARWHLMCDLPB-UHFFFAOYSA-N CC[IH]c1cccc(C#C)c1 Chemical compound CC[IH]c1cccc(C#C)c1 WCWARWHLMCDLPB-UHFFFAOYSA-N 0.000 description 1
- DIALINJAHQGNCR-UHFFFAOYSA-N Cc(c(Nc(nc1)ncc1-c1cccnc1)c1)ccc1S(C)C Chemical compound Cc(c(Nc(nc1)ncc1-c1cccnc1)c1)ccc1S(C)C DIALINJAHQGNCR-UHFFFAOYSA-N 0.000 description 1
- JWQUBAUGVPTBAE-UHFFFAOYSA-N Cc(cc(cc1)F)c1NC Chemical compound Cc(cc(cc1)F)c1NC JWQUBAUGVPTBAE-UHFFFAOYSA-N 0.000 description 1
- ZCQTXAKABYDEMG-UHFFFAOYSA-N Cc(cc1)ccc1NC(Nc1cc(C)ccc1F)=O Chemical compound Cc(cc1)ccc1NC(Nc1cc(C)ccc1F)=O ZCQTXAKABYDEMG-UHFFFAOYSA-N 0.000 description 1
- AVMCKOKAHTULEY-UHFFFAOYSA-N Cc(cc1)ccc1P(C)(C)=O Chemical compound Cc(cc1)ccc1P(C)(C)=O AVMCKOKAHTULEY-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N Cc1c(C)cccc1 Chemical compound Cc1c(C)cccc1 CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MPWFGAWFTAZWKZ-UHFFFAOYSA-N Ic(cc1)ccc1OCc1ccccc1 Chemical compound Ic(cc1)ccc1OCc1ccccc1 MPWFGAWFTAZWKZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method and antineoplastic use of a quinazoline compound. The quinazoline compound has a general formula I. The quinazoline compound shown in the general formula I and its pharmaceutically acceptable salt or solvate have effects of inhibiting human lung cancer cells, human stomach cancer cells, human prostate cancer cells and human colorectal cancer cells and can be used for preparation of drugs for treating human lung cancer, human stomach cancer, human prostate cancer and human colorectal cancer.
Description
Technical field
The present invention relates to quinazoline compounds and uses thereof, belong to medical preparing technical field.
Background technology
The whole world has up to ten million people to die from tumour every year, and the research and development of cancer therapy drug have been subject to the concern of scientists deeply, 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, has good pharmacologically active (Arch.Pharm.Pharm.Med.Chem.2001,334:357; CN102838600).Urogastron is a kind of Tyrosylprotein kinase, EGF-R ELISA (epidermal growth factor receptor EGFR) is the member of erbB family, these members' of EGFR family extracellular domain just can trigger same dimerization or the different dimerization of acceptor after being combined with aglucon, and activate Tyrosylprotein kinase, and then cause the autophosphorylation of acceptor and cause the propagation of cell and the activation of the relevant various signal transduction cascades of survival.Therefore, EGF-R ELISA becomes a novel targets (chemistry circular 2010, the 4:314 of oncotherapy; Synthetic chemistry 2013,1:92).
Quinazoline compounds is an effective EGFR inhibitor of class (TKI), has been subject to general attention.Quinazoline is the inhibitor (EGFR-TKI) of class epidermal growth factor recipient tyrosine kinase early, a lot of to this compounds research, a series of report has proved that quinazoline compound is by being combined with the binding site of ATP, high selectivity ground suppresses the phosphorylation of EGFR, thereby the growth of inhibition tumor cell, quinazoline compounds is proved to be good inhibition.The medicine (Bioscience Biotechnology Biochemistry, 2005, the 69:2349 that have now gone on the market; WO2009016072) have Gefitinib (Gefitinib), Tarceva (Erlotinib) and lapatinibditosylate (Lapatinib), also having Tandutinib (Tandutinib) and fork clip is all quinazoline compounds for Buddhist nun (Saracatinib).
The present invention, by introduce amido benzoxazole group on 6 of quinazoline, has synthesized the novel active compound for anti tumor of a class, and this compounds is the growth of inhibition tumor cell obviously, is expected to become the antitumor drug of efficient and low toxicity.
Summary of the invention
The present invention seeks to find the quinazoline compounds that a class is novel, efficient, low toxicity has anti-tumor activity.
Quinazoline compounds of the present invention, for thering is the compound of general formula I:
In general formula I, R represents following group:
The quinazoline compounds of general formula I of the present invention and pharmacy acceptable salt thereof or solvate can be used for the purposes of preparation treatment including but not limited to people's lung cancer, people's cancer of the stomach, human prostata cancer and human colon carcinoma medicine.
The syntheti c route of the quinazoline compounds of general formula I is as follows:
Scheme1
The reagent of compound 2 synthetic use is 2-amido-5-bromo-benzoic acid and methane amide, and temperature of reaction is at 160 DEG C-200 DEG C, and the reaction times is 6-12 hour.
The reagent of compound 3 synthetic use is 6-bromo-4-hydroxyl quinazoline and Phosphorus Oxychloride, and temperature of reaction is at 80 DEG C-120 DEG C, and the reaction times is 2-8 hour.
The solvent of compound 4 synthetic use is including but not limited to Virahol, ethanol, propyl carbinol, dioxane, DMF and toluene etc., and temperature of reaction is at 50-120 DEG C, and the reaction times is 1-24 hour.
The coupling reagent of the synthetic use of compound 5a is 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, and the catalyzer of use is including but not limited to four triphenyl phosphorus palladiums, tertiary butyl phosphorus palladium, PdCl
2(dppf), palladium etc., the alkali of use is 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 and toluene-water etc., 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 present invention has following beneficial effect:
1, quinazoline compounds of the present invention is the compound of novel, the efficient and low toxicity of a class, and tumour cell is had to obvious restraining effect.
2, quinazoline compounds of the present invention has bioavailability in good body, has improved oral absorption effect.
Embodiment
Embodiment 1: the synthetic bromo-4-hydroxyl of 6-quinazoline (compound 2)
2-amido-5-bromo-benzoic acid (5.4g, 25mmol) and methane amide (40mL) mixed solution be heated to 175 DEG C, react 7 hours, be chilled to room temperature, add water (100mL), jolting, suction filtration, washing, is dried to obtain the bromo-4-hydroxyl of off-white color needle-like crystal 6-quinazoline 4.7g, productive rate: 83.9%.EI-MS?MS(m/z)：225.0(M
+)
Embodiment 2: the synthetic bromo-4-chloro-quinazoline of 6-(compound 3)
6-bromo-4-hydroxyl quinazoline (3.2g, 14mmol) and POCl
3(24mL), heating reflux reaction 4 hours, cooling, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, concentrates to obtain the bromo-4-chloro-quinazoline of the cotton-shaped solid 6-of off-white color 2.8g, productive rate: 82.3%.
EI-MS?MS(m/z)：242.9(M
+)
1H-NMR(CDCl
3，400MHz)：δ9.08(s，1H)，8.46(d，1H)，8.06(dd，1H)，7.97(d，1H).
Embodiment 3: the synthetic bromo-4-of 6-(4-benzyloxy phenyl) amido quinazoline (compound 4)
The bromo-4-chloro-quinazoline of 6-(150mg, 0.62mmol), 4-benzyloxy-aniline (123mg, 0.62mmol) and Virahol (8mL), reflux 2 hours, cooling, suction filtration, washed with isopropyl alcohol, be dried to obtain the bromo-4-of golden yellow solid 6-(4-benzyloxy phenyl) amido quinazoline 210mg, productive rate: 83.7%.EI-MS?MS(m/z)：406.1(M
+)
Embodiment 4: synthetic 6-(2-amido-5-benzoxazole)-4-(4-benzyloxy phenyl) amido quinazoline (compound 5a)
The bromo-4-of 6-(4-benzyloxy phenyl) amido quinazoline (130mg, 0.32mmol), 2-amido-benzoxazoles-5-borate hydrochlorate (89mg, 0.42mmol), four triphenyl phosphorus palladium (30mg, 0.026mmol), sodium carbonate (170mg, 1.6mmol) and dioxane-water (10mL-3mL), under nitrogen protection, reflux 3 hours, cooling, suction filtration, ethyl acetate (100mL) extraction, saturated common salt (30mL) water washing, anhydrous sodium sulfate drying, be concentrated into dry, rapid column chromatography (silica gel 200～300 orders) obtains faint yellow solid 6-(2-amido-5-benzoxazole)-4-(4-benzyloxy phenyl) amido quinazoline 110mg, productive rate: 74.8%.EI-MS?MS(m/z)：460.2(M
+)
1H-NMR(DMSO-d6，400MHz)：δ9.87(s，1H)，8.80(s，1H)，8.51(s，1H)，8.17(d，1H)，7.82～7.69(m，4H)，7.52～7.34(m，9H)，7.09(d，1H)，5.14(s，2H).
The compound 5a-5p for preparing general formula I according to the method in Scheme1 embodiment, structural formula is as shown in table 1.
Table 1
Embodiment 5: suppress tumor promotion evaluation test
For trying target:
Human lung carcinoma cell line A549, human stomach cancer cell line SGC7901, Human Prostate Cancer Cells PC-3 and human colon cancer cell strain HCT116.
Cell cultures and drug treating:
By after freeze-stored cell recovery, add appropriate RPMI-1640 nutrient solution (containing 10% foetal calf serum, 100U/mL penicillin, 100U/mL Streptomycin sulphate) to be inoculated in culturing bottle, put incubator (37 DEG C, 5%CO
2) middle cultivation, went down to posterity 1 time every 2～3 days.Cell is inoculated in 96 well culture plates, and cell density is 5000/hole.After cell attachment, add different concns medicine (medicine DMSO dissolves, then dilutes with nutrient solution), in control group nutrient solution, containing the DMSO of same concentrations, every kind of dosage is established four repetitions.
Test method (mtt assay):
After drug treating 48h, put into 37 DEG C, 5%CO after adding MTT (0.25mg/mL)
2in incubator, continue to cultivate 4h, absorb nutrient solution, every hole adds 100uL DMSO dissolved particles, then surveys absorbancy (OD) value under 570nm by microplate reader, and experiment in triplicate.
Assessment contrasts as table 2:
Table 2 (compound and inhibition tumor promotion table)
Suppress tumor promotion:
++++anti-tumor activity is strong, and sample concentration is less than 1uM
+++ anti-tumor activity is stronger, and sample concentration is less than 10uM and is greater than 1uM
++ anti-tumor activity is general, and sample concentration is less than 50uM and is greater than 10uM
A little less than+anti-tumor activity, sample concentration is greater than 50uM
As described in Table 2, the quinazoline compounds with general formula I has restraining effect to human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells and human colon cancer cell, can be used for the medicine of preparation treatment people lung cancer, people's cancer of the stomach, human prostata cancer and human colon carcinoma.
Claims (5)
1. quinazoline compounds, is characterized in that, for thering is the compound of general formula I:
Wherein, R represents following group:
2. the quinazoline compounds of general formula I and pharmacy acceptable salt thereof or solvate can be used for the purposes of preparation treatment including but not limited to people's lung cancer, people's cancer of the stomach, human prostata cancer and human colon carcinoma medicine as claimed in claim 1.
3. there is the synthetic route of the quinazoline compounds of general formula I:
(a) reagent of compound 2 synthetic use is 2-amido-5-bromo-benzoic acid and methane amide, and temperature of reaction is at 160 DEG C-200 DEG C, and the reaction times is 6-12 hour.
(b) reagent of compound 3 synthetic use is 6-bromo-4-hydroxyl quinazoline and Phosphorus Oxychloride, and temperature of reaction is at 80 DEG C-120 DEG C, and the reaction times is 2-8 hour.
(c) solvent of compound 4 synthetic use is including but not limited to Virahol, ethanol, propyl carbinol, dioxane, DMF and toluene etc., and temperature of reaction is at 50-120 DEG C, and the reaction times is 1-24 hour.
(d) coupling reagent of the synthetic use of compound 5a is 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, and the catalyzer of use is including but not limited to four triphenyl phosphorus palladiums, tertiary butyl phosphorus palladium, PdCl
2(dppf), palladium etc., the alkali of use is 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 and toluene-water etc., temperature of reaction is at 80-120 DEG C.
4. 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.
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.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310189863.3A CN104177346A (en) | 2013-05-21 | 2013-05-21 | Quinazoline compound and use thereof |
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|---|---|---|---|
| CN201310189863.3A CN104177346A (en) | 2013-05-21 | 2013-05-21 | Quinazoline compound and use thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530436A (en) * | 2018-05-17 | 2018-09-14 | 黄传满 | A kind of pyrazole compound and its preparation method and application |
| CN110357852A (en) * | 2019-06-21 | 2019-10-22 | 中国药科大学 | Benzo pyridine compound, preparation method and purposes |
| CN116425743A (en) * | 2022-12-30 | 2023-07-14 | 贵州医科大学 | Benzo heterocyclic compound serving as PI3K alpha kinase inhibitor, and preparation method and application thereof |
Citations (5)
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| US20060036061A1 (en) * | 2004-08-11 | 2006-02-16 | Chong-Kyu Shin | Novel benzimidazole compound |
| US20090054405A1 (en) * | 2007-08-02 | 2009-02-26 | Amgen Inc. | PI3 kinase modulators and methods of use |
| CN102573846A (en) * | 2009-08-17 | 2012-07-11 | 因特利凯公司 | Heterocyclic compounds and uses thereof |
| WO2012148540A1 (en) * | 2011-02-23 | 2012-11-01 | Intellikine, Llc | Combination of kanase inhibitors and uses threof |
| WO2013071264A1 (en) * | 2011-11-11 | 2013-05-16 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
-
2013
- 2013-05-21 CN CN201310189863.3A patent/CN104177346A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060036061A1 (en) * | 2004-08-11 | 2006-02-16 | Chong-Kyu Shin | Novel benzimidazole compound |
| US20090054405A1 (en) * | 2007-08-02 | 2009-02-26 | Amgen Inc. | PI3 kinase modulators and methods of use |
| CN102573846A (en) * | 2009-08-17 | 2012-07-11 | 因特利凯公司 | Heterocyclic compounds and uses thereof |
| WO2012148540A1 (en) * | 2011-02-23 | 2012-11-01 | Intellikine, Llc | Combination of kanase inhibitors and uses threof |
| WO2013071264A1 (en) * | 2011-11-11 | 2013-05-16 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
Non-Patent Citations (2)
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|---|
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530436A (en) * | 2018-05-17 | 2018-09-14 | 黄传满 | A kind of pyrazole compound and its preparation method and application |
| CN108530436B (en) * | 2018-05-17 | 2020-12-29 | 黄传满 | Pyrazole compound and preparation method and application thereof |
| CN110357852A (en) * | 2019-06-21 | 2019-10-22 | 中国药科大学 | Benzo pyridine compound, preparation method and purposes |
| CN110357852B (en) * | 2019-06-21 | 2022-06-10 | 中国药科大学 | Benzopyrimidine compounds, preparation method and application |
| CN116425743A (en) * | 2022-12-30 | 2023-07-14 | 贵州医科大学 | Benzo heterocyclic compound serving as PI3K alpha kinase inhibitor, and preparation method and application thereof |
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