CN104098574A - Azetidine substituted pyrimidine compounds and use thereof - Google Patents

Azetidine substituted pyrimidine compounds and use thereof Download PDF

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Publication number
CN104098574A
CN104098574A CN201310125827.0A CN201310125827A CN104098574A CN 104098574 A CN104098574 A CN 104098574A CN 201310125827 A CN201310125827 A CN 201310125827A CN 104098574 A CN104098574 A CN 104098574A
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黄传满
解美娜
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KEJIE-BIO (SUZHOU) PHARMACEUTICAL Co Ltd
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KEJIE-BIO (SUZHOU) PHARMACEUTICAL Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The invention provides a preparation method and a use of pyrimidine compounds. The pyrimidine compounds are azetidine substituted pyrimidine compounds represented by general formula I. The compounds represented by general formula I and salts thereof have an inhibition effect on human lung cancer cells, human stomach cancer cells, human prostate cancer cells and myelomas, and can be used for preparing medicines for treating the human lung cancer cells, human stomach cancer cells, human prostate cancer cells and myelomas.

Description

Azetidine substituted pyrimidines compounds and uses thereof
Technical field
The present invention relates to azetidine substituted pyrimidines compounds and uses thereof, belong to medical preparing technical field.
Background technology
Tumour is common, the most serious a kind of disease that the world today jeopardizes human life, the whole world has up to ten million people to die from tumour every year, traditional chemicals is when killing tumour, also destroyed human normal cell, research and develop novel, efficiently become the task of top priority with the antitumor drug of low toxicity.
Pyrimidines has good pharmacologically active, can be used for the treatment of kinds of tumors.CGP-59326 and BIBX-1382 are pyrimidine kinase inhibitors, and CGP-59326 is developed by Novartis company, for treatment (Med Res Rev, 2001,21 (6): 499-512) of prostate cancer; BIBX-1382 is developed by Boehringer Ingelheim company, for treatment (Europ J ofCancer2002,38 (8): 1072-1080) of head and neck cancer.But clinical demonstration CGP-59326 has strong toxic side effect, mainly contain diarrhoea, feel sick and transaminase rising etc.; BIBX-1382 oral administration biaavailability is low, and meta-bolites does not have pharmacologically active.
Therefore, the pyrimidines of synthesizing new, to improve bioavailability and to reduce toxic side effect, seems very necessary.The pyrimidines that the synthetic azetidine of the present invention replaces, has good biological utilisation way and anti-tumor activity, is expected to become the antitumor drug of novel, efficient and low toxicity.
Summary of the invention
The present invention seeks to find the pyrimidine compound that a class is novel, efficient, low toxicity has anti-tumor activity.
Pyrimidines of the present invention, for thering is the azetidine substituted pyrimidines compounds of general formula I:
In general formula I, R1 represent hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, butyl, cyclopentyl,
R2 represents following group:
R3 is the substituting group that contains pyridine, represents following group:
Azetidine substituted uracil compound and salt thereof that the present invention has general formula I have the purposes for the preparation for the treatment of human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells and myelomatosis medicine.
The syntheti c route of the azetidine substituted pyrimidines compounds of general formula I is as follows:
In the synthetic general formula scheme1 of compound 4a series: the solvent of compound 2 synthetic use, including but not limited to dioxane, ethanol, propyl alcohol, Virahol, acetonitrile, propyl carbinol and DMF etc., with alkali including but not limited to triethylamine, diisopropylethylamine, diethylamine, pyridine, salt of wormwood and sodium carbonate etc., temperature of reaction is in room temperature to 120 ℃; The solvent of compound 3 synthetic use is including but not limited to DMF, dioxane, Virahol, propyl carbinol, tetrahydrofuran (THF) and acetonitrile etc., with alkali including but not limited to salt of wormwood, sodium carbonate, sodium hydride, potassium tert.-butoxide and sodium tert-butoxide etc., temperature of reaction is at 0 ℃ to 80 ℃; Compound 4a is synthetic is linked reaction, 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 80-110 ℃.
In the synthetic general formula scheme2 of compound 6a series: the solvent of compound 5 synthetic use is including but not limited to ethylene dichloride, methylene dichloride, Virahol, propyl carbinol and dioxane etc., and the alkali of use is including but not limited to sodium carbonate, salt of wormwood and cesium carbonate etc.; Compound 6a is synthetic is linked reaction, 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 solvent of reaction use is including but not limited to dioxane-water,, DMF-water, alcohol-water and toluene-water etc., temperature of reaction is at 80-110 ℃.
The salt that compound 4a becomes with 6a series is including but not limited to hydrochloride, vitriol, oxalate, fumarate, tartrate, maleate, Citrate trianion, mesylate, benzene sulfonate, lactic acid salt and malate etc.; During salify, reaction solvent is including but not limited to ethanol, Virahol, acetonitrile and ethyl acetate etc., and temperature of reaction is in room temperature to 100 ℃.
The present invention has following beneficial effect:
1, azetidine substituted pyrimidines compounds of the present invention is novel, the efficient target kinase inhibitor of a class, and tumour cell is had to obvious restraining effect.
2, azetidine substituted pyrimidines compounds of the present invention, owing to containing azelidinyl, has improved bioavailability and oral absorption effect in body.
3, azetidine substituted pyrimidines compounds of the present invention, owing to having targeting, greatly reduces toxic side effect, less to human normal cell's injury.
Embodiment
Embodiment 1: synthetic compound 2
In reaction flask, add 3-bromo-4-chlorine pyrazolopyrimidine (500mg, 2.15mmol), 1-(3-azetidine)-4-ethyl piperazidine (728mg, 4.30mmol), triethylamine (0.5mL) and dioxane (10mL), be heated to 80 ℃, react 3 hours, be cooled to room temperature, be concentrated into dry, add water (10mL), jolting, suction filtration, washing, be dried to obtain white solid compound (2) 640mg, productive rate: 81.3%.EI-MS?MS(m/z)：366.1(M +)
Embodiment 2: synthetic compound 3
In reaction flask, add compound 2 (400mg, 1.10mmol), Anhydrous potassium carbonate (304mg, 2.20mmol) and DMF (3mL), be heated to 55 ℃ and stir half an hour, add bromo propane (270mg, 2.20mmol), this thermotonus 3 hours, cooling, add water (10mL), jolting, suction filtration, washing, is dried to obtain off-white color solid chemical compound (3) 420mg, productive rate: 93.5%.
1H-NMR(CDCl 3，400MHz)：δ8.25(s，1H)，5.06～5.02(m，1H)，4.33～4.29(m，4H)，3.29～3.27(m，1H)，2.61～2.39(m，10H)，1.45(d，6H)，1.04(t，3H).
Embodiment 3: synthetic compound 4a
In reaction flask, add compound 3 (300mg; 0.74mmol), 2-amido-benzoxazoles-5-borate hydrochlorate (238mg; 1.11mmol), four triphenyl phosphorus palladium (68mg; 0.059mmol), sodium carbonate (392mg; 3.70mmol) and dioxane-water (10mL-3mL); under nitrogen protection, be heated to reflux; react 3 hours, cooling, suction filtration; ethyl acetate (100mL) extraction; saturated common salt (30mL) water washing, anhydrous sodium sulfate drying, is concentrated into dry; rapid column chromatography (silica gel 200～300 orders) obtains faint yellow solid compound (4a) 240mg, productive rate: 70.3%.EI-MS?MS(m/z)：462.3(M +)
1H-NMR(CDCl 3，400MHz)：δ8.42(s，1H)，7.59(s，1H)，7.37～7.31(m，2H)，5.60(br，2H)，5.22～5.18(m，1H)，3.75～3.72(m，4H)，3.09～3.07(m，1H)，2.45～2.31(m，10H)，1.61(d，6H)，1.09(t，3H).
Embodiment 4: compound 4a salify
In reaction flask, add compound (4a) (100mg, 0.22mmol) and 2.8MHCl/EtOH (2mL, 5.6mmol), stirred overnight at room temperature, suction filtration, ethyl acetate (10mL) washing, be dried to obtain off-white color solid (4a) hydrochloride 98mg, productive rate: 89.1%.
Embodiment 5: synthetic compound 5
In reaction flask, add Salicylaldoxime (198mg, 1.09mmol), dipyridyl (170mg, 1.09mmol) and ethylene dichloride (10mL), stir, be heated to 60 ℃, add compound 2 (398mg, 1.09mmol), cyclopropylboronic acid (187mg, 2.17mmol) and anhydrous sodium carbonate (231mg, mixture 2.17mmol), be heated to 70 ℃, react 4 hours, be chilled to room temperature, add ethylene dichloride (50mL), organic phase is used respectively ammoniacal liquor (25mL * 2) and saturated aqueous common salt (25mL * 2) washing, anhydrous sodium sulfate drying, be concentrated into dry, rapid column chromatography (silica gel 200～300 orders) obtains off-white color solid chemical compound (5) 320mg, productive rate: 72.3%.
EI-MS?MS(m/z)：406.1(M +)
Embodiment 6: synthetic compound 6a
In reaction flask, add compound 5 (140mg; 0.34mmol), 2-amido-benzoxazoles-5-borate hydrochlorate (110mg; 0.51mmol), four triphenyl phosphorus palladium (32mg; 0.028mmol), sodium carbonate (183mg; 1.72mmol) and dioxane-water (10mL-3mL); under nitrogen protection, reflux is 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) white solid compound (6a) 82mg, productive rate: 52.6%.EI-MS?MS(m/z)：460.2(M +)
1H-NMR(CDCl 3，400MHz)：δ8.45(s，1H)，7.56(s，1H)，7.35～7.27(m，2H)，5.26(br，2H)，3.82～3.78(m，2H)，3.08～3.05(m，1H)，2.43～2.41(m，5H)，2.27～2.26(m，4H)，1.72～1.70(m，4H)，1.36～1.34(m，2H)，1.18～1.16(m，2H)，1.07(t，3H).
Embodiment 7: compound 6a salify
In reaction flask, add compound (6a) (50mg, 0.11mmol) and 2.8MHCl/EtOH (1mL, 2.8mmol), stirred overnight at room temperature, suction filtration, ethyl acetate (10mL) washing, be dried to obtain off-white color solid (6a) hydrochloride 48mg, productive rate: 88.9%.
The compound 4a-4r for preparing general formula I according to the method in Scheme1 embodiment, structural formula is as shown in table 1.
Table 1
The compound 6a-6j for preparing general formula I according to the method in Scheme2 embodiment, structural formula is as shown in table 2.
Table 2
Embodiment 8: 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 myeloma cell strain RPMI8226.
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 ℃, 5%CO 2) middle cultivation, every 2～3 days, go down to posterity 1 time.Cell is inoculated in 96 well culture plates, and cell density is 5000/hole.After cell attachment, add different concns medicine (medicine dissolves with DMSO, 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:
1. attached cell adopts mtt assay (human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells): after drug treating 48h, put into 37 ℃, 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 by microplate reader, surveys absorbancy (OD) value under 570nm, and experiment in triplicate.
2. suspension cell adopts CCK-8 method (myeloma cell):
After drug treating 48h, add CCK-8 to put into 37 ℃, 5%CO 2in incubator, continue to cultivate 2h, by microplate reader, survey the OD value under 450nm, experiment in triplicate.
Assessment contrasts as table 3:
Table 3 (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 3, the compound of general formula I has restraining effect to human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells and myelomatosis etc., can be used for the medicine of preparation treatment human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells and myelomatosis.

Claims (5)

1. pyrimidines, is characterized in that, for thering is the azetidine substituted pyrimidines compounds of general formula I:
Wherein,
R1 represent hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, butyl, cyclopentyl,
R2 represents following group:
R3 represents following group:
2. azetidine substituted uracil compound and the salt thereof as claimed in claim 1 with general formula I have the purposes for the preparation for the treatment of human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells and myelomatosis medicine.
3. in the synthetic general formula scheme1 of compound 4a series: the solvent of compound 2 synthetic use, including but not limited to dioxane, ethanol, propyl alcohol, Virahol, acetonitrile, propyl carbinol and DMF etc., with alkali including but not limited to triethylamine, diisopropylethylamine, diethylamine, pyridine, salt of wormwood and sodium carbonate etc., temperature of reaction is in room temperature to 120 ℃; The solvent of compound 3 synthetic use is including but not limited to DMF, dioxane, Virahol, propyl carbinol, tetrahydrofuran (THF) and acetonitrile etc., with alkali including but not limited to salt of wormwood, sodium carbonate, sodium hydride, potassium tert.-butoxide and sodium tert-butoxide etc., temperature of reaction is at 0 ℃ to 80 ℃; Compound 4a is synthetic is linked reaction, 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 80-110 ℃.
4. in the synthetic general formula scheme2 of compound 6a series: the solvent of compound 5 synthetic use is including but not limited to ethylene dichloride, methylene dichloride, Virahol, propyl carbinol and dioxane etc., and the alkali of use is including but not limited to sodium carbonate, salt of wormwood and cesium carbonate etc.; Compound 6a is synthetic is linked reaction, 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 solvent of reaction use is including but not limited to dioxane-water,, DMF-water, alcohol-water and toluene-water etc., temperature of reaction is at 80-110 ℃.
5. compound 4a and 6a series can salifies, after this compounds salify, can increase solubleness, improve the bioavailability in human body; The salt becoming is including but not limited to hydrochloride, vitriol, oxalate, fumarate, tartrate, maleate, Citrate trianion, mesylate, benzene sulfonate, lactic acid salt and malate etc.; During salify, reaction solvent is including but not limited to ethanol, Virahol, acetonitrile and ethyl acetate etc., and temperature of reaction is in room temperature to 100 ℃.
CN201310125827.0A 2013-04-12 2013-04-12 Azetidine substituted pyrimidine compounds and use thereof Pending CN104098574A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0366059A2 (en) * 1988-10-25 1990-05-02 Bristol-Myers Squibb Company Carbocyclic nucleoside analogs
WO2011146313A1 (en) * 2010-05-19 2011-11-24 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
CN102690270A (en) * 2012-05-28 2012-09-26 吴雁 Pyrimidine compound and purpose thereof
WO2012168817A1 (en) * 2011-06-07 2012-12-13 Pfizer Inc. Pyrazolo[3,4-d]pyrimidine compounds and their use as pde2 inhibitors and/or cyp3a4 inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0366059A2 (en) * 1988-10-25 1990-05-02 Bristol-Myers Squibb Company Carbocyclic nucleoside analogs
WO2011146313A1 (en) * 2010-05-19 2011-11-24 The University Of North Carolina At Chapel Hill Pyrazolopyrimidine compounds for the treatment of cancer
WO2012168817A1 (en) * 2011-06-07 2012-12-13 Pfizer Inc. Pyrazolo[3,4-d]pyrimidine compounds and their use as pde2 inhibitors and/or cyp3a4 inhibitors
CN102690270A (en) * 2012-05-28 2012-09-26 吴雁 Pyrimidine compound and purpose thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JING LIU, ET AL.,: "UNC1062, a new and potent Mer inhibitor", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

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