CN104072499A - Piperazine substituted pyrimidine compounds and applications thereof - Google Patents
Piperazine substituted pyrimidine compounds and applications thereof Download PDFInfo
- Publication number
- CN104072499A CN104072499A CN201310106011.3A CN201310106011A CN104072499A CN 104072499 A CN104072499 A CN 104072499A CN 201310106011 A CN201310106011 A CN 201310106011A CN 104072499 A CN104072499 A CN 104072499A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- synthetic
- human
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Abstract
The invention provides piperazine substituted pyrimidine compounds represented by the formula I and applications thereof. The pyrimidine compounds represented by the formula I have a prominent inhibiting effect on human lung cancer cells, human stomach cancer cells, human prostatic cancer cells, human colon cancer cells, human kidney cancer cells, and myeloma cells, and can be used to prepare drugs for treating human lung cancer, human stomach cancer, human prostatic cancer, human colon cancer, human kidney cancer, and myeloma.
Description
Technical field
The present invention relates to piperazine substituted pyrimidines compounds and uses thereof, belong to medical preparing technical field.
Background technology
Malignant tumour is the major disease of harm people life and health, and the whole world has up to ten million people to die from tumour every year, and the research and development of antitumor drug shoulder heavy responsibilities, and researching and developing antitumor drug novel, efficient and low toxicity has become the task of top priority.
Pyrimidines has shown good pharmacologically active aspect medical research, can be used for the treatment of kinds of tumors.Bibliographical information XL-418 has strong anti-tumor activity, can be used for treating the solid tumor such as lung cancer and prostate cancer (BMCL2012,22,2693-2697), BIBX-1382 can be used for the treatment (Strait Pharmaceutical Journal 2006,18:17-21) of head and neck cancer; But above-claimed cpd bioavailability is not high, absorption difference in vivo, the curative effect of impact in human body.Therefore, further this compounds is carried out to structure of modification, synthesizing new pyrimidines, to improve bioavailability and to reduce toxic side effect, seem very necessary, the piperazine substituted pyrimidines compounds that the present invention is synthetic, has good biological utilisation way and strong anti-tumor activity, is expected to become the antitumor drug of novel, efficient and low toxicity.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art part, a kind of piperazine substituted pyrimidines compounds and uses thereof is provided.
Pyrimidines of the present invention, for thering is the piperazine 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:
The piperazine substituted uracil compound with general formula I of pyrimidines of the present invention has the purposes for the preparation for the treatment of human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells, human colon cancer cell, human renal carcinoma cell and myelomatosis medicine.
Embodiment
The syntheti c route of the piperazine substituted pyrimidines compounds with general formula I of pyrimidines of the present invention is as follows:
Scheme1
Scheme2
The synthetic 2-piperazine-3-trifluoromethyl-pyridine (compound 2) of embodiment 1
In reaction flask, add the chloro-3-trifluoromethyl-pyridine of 2-(3.0g, 16.5mmol), Piperazine anhydrous (12g, 139mmol) and propyl carbinol (10mL), stir, be heated to back flow reaction 6 hours, cooling, concentrated, extract with methylene dichloride (150mL), water (30mL) washing secondary, anhydrous sodium sulfate drying, concentrate to obtain faint yellow oily matter, cross fast post (eluent: methylene chloride/methanol=20/1 of containing 1% ammoniacal liquor), obtain faint yellow oily matter 2-piperazine-3-trifluoromethyl-pyridine 2.8g, place and obtain every other day low melting point solid, productive rate: 73.6%.
1H-NMR(CDCl
3,400MHz):δ8.46~8.44(m,1H),7.89~7.87(m,1H),7.02~6.99(m,1H),3.47~3.31(m,4H),3.09~3.06(m,4H).
The synthetic bromo-4-[4-of 3-(3-trifluoromethyl-pyridine)-2-piperazine of embodiment 2)-pyrazolopyrimidine (compound 3)
In reaction flask, add the bromo-4-chlorine of 3-pyrazolopyrimidine (140mg, 0.60mmol), 2-piperazine-3-trifluoromethyl-pyridine (166mg, 0.72mmol), triethylamine (0.5mL) and dioxane (10mL), oil bath is slowly warming up to 80 DEG C, stir 3 hours, be cooled to room temperature, be concentrated into dry, add water (10mL), jolting, suction filtration, washing, be dried to obtain the bromo-4-[4-of white solid 3-(3-trifluoromethyl-pyridine)-2-piperazine)-pyrazolopyrimidine 193mg, productive rate: 75.1%.
1H-NMR(DMSO-d6,400MHz):δ14.06(br,1H),8.57(d,1H),8.37(s,1H),8.13(d,1H),7.27~7.24(m,1H),3.95~3.92(m,4H),3.40~3.37(m,4H).
The synthetic bromo-4-[4-of 1-sec.-propyl-3-(3-trifluoromethyl-pyridine)-2-piperazine of embodiment 3)-pyrazolopyrimidine (compound 4)
In reaction flask, add the bromo-4-[4-of 3-(3-trifluoromethyl-pyridine)-2-piperazine)-pyrazolopyrimidine (170mg, 0.40mmol), Anhydrous potassium carbonate (110mg, 0.80mmol) and DMF (3mL), be heated to 55 DEG C and stir half an hour, add bromo propane (98mg, 0.80mmol), again this thermotonus 3 hours, cooling, add water (10mL), jolting, suction filtration, washing, be dried to obtain the bromo-4-[4-of off-white color solid 1-sec.-propyl-3-(3-trifluoromethyl-pyridine)-2-piperazine)-pyrazolopyrimidine 151mg, productive rate: 80.3%.
1H-NMR(DMSO-d6,400MHz):δ8.57(d,1H),8.39(s,1H),8.13(d,1H),7.27~7.24(m,1H),5.09~5.06(m,1H),3.97~3.94(m,4H),3.39~3.37(m,4H),1.46(d,6H).
Embodiment 4 synthetic compound 5a and salt thereof
In reaction flask, add compound 4 (130mg, 0.28mmol), 2-amido-benzoxazoles-5-borate hydrochlorate (90mg, 0.42mmol) and dioxane-water (10mL-3mL), stir, add again four triphenyl phosphorus palladium (26mg, 0.022mmol) and sodium carbonate (148mg, 1.4mmol), find time, applying argon gas, in triplicate, oil bath is heated to 100 DEG C, reacts 3 hours.Cooling, suction filtration, ethyl acetate (100mL) extraction, saturated common salt (30mL) water washing, is concentrated into dryly, and the quick post of crossing, obtains off-white color solid chemical compound (5a) 105mg, productive rate: 71.6%.EI-MSMS(m/z):524.2(M
+)
1H-NMR(DMSO-d6,400MHz):δ8.49(s,1H),8.46(d,1H),7.85(d,1H),7.76(s,1H),7.51(d,1H),7.38(d,1H),7.02(t,1H),6.04(br,2H),5.25~5.22(m,1H),3.63~3.61(m,4H),3.18~3.16(m,4H),1.62(d,6H).
Compound 5a salify
In reaction flask, add compound (5a) (100mg, 0.19mmol), 2.8MHCl/EtOH (2mL, 5.6mmol), stirred overnight at room temperature, solid is separated out, suction filtration, dehydrated alcohol (10mL) washing, be dried to obtain off-white color solid (5a) hydrochloride 102mg, productive rate: 90.3%.
Embodiment 5 synthetic compounds 7
In reaction flask, add the chloro-pyrazolopyrimidine (500mg of the bromo-4-of 3-, 2.15mmol), p-toluene sulfonic acide (10mg, 0.05mmol), ethyl acetate (10mL) and 3,4-dihydropyrane (1mL), oil bath is heated to reflux 3 hours, cooling, ethyl acetate (50mL) extraction, use respectively saturated sodium bicarbonate (15mL) and saturated aqueous common salt (15mL) washing, anhydrous sodium sulfate drying, be concentrated into dry faint yellow solid compound (7) 620mg, productive rate: 91.2%.
Embodiment 6 synthetic compounds 8
In reaction flask, add compound (7) (101mg, 0.32mmol), 2-piperazine-3-trifluoromethyl-pyridine (74mg, 0.32mmol), triethylamine (0.5mL) and dioxane (10mL), oil bath is slowly warming up to 80 DEG C, stir 3 hours, be cooled to room temperature, be concentrated into dry, add water (10mL), ethyl acetate (50mL) extraction, saturated aqueous common salt (15mL) washing, anhydrous sodium sulfate drying, be concentrated into dry oily matter compound (8) 154mg, productive rate: 94.0%.
EI-MS?MS(m/z):512.1(M
+)
Embodiment 7 synthetic compounds 9
In reaction flask, add compound 8 (130mg, 0.25mmol), 2-amido-benzoxazoles-5-borate hydrochlorate (64mg, 0.30mmol) and dioxane-water (10mL-3mL), stir, add again four triphenyl phosphorus palladium (26mg, 0.022mmol) and sodium carbonate (133mg, 1.25mmol), find time, inflated with nitrogen, in triplicate, oil bath is heated to 100 DEG C, reacts 3 hours.Cooling, suction filtration, ethyl acetate (100mL) extraction, saturated common salt (30mL) water washing, is concentrated into dryly, and the quick post of crossing, obtains off-white color solid chemical compound (9) 98mg, productive rate: 69.5%.
EI-MS?MS(m/z):566.2(M
+)
Embodiment 8 synthetic compound 10a and salt thereof
In reaction flask, add compound (9) (80mg, 0.14mmol), 2.8MHCl/EtOH (3mL), stirred overnight at room temperature, solid is separated out, suction filtration, a small amount of absolute ethanol washing, dry off-white color solid (10a) hydrochloride that to obtain, is adjusted to alkalescence by above-mentioned hydrochloride with saturated sodium carbonate solution, suction filtration, washing, is dried to obtain gray solid compound (10a) 45mg, productive rate: 67.2%.
EI-MS?MS(m/z):482.2(M
+)
1H-NMR(DMSO-d6,400MHz):δ13.81(br,1H),8.42(s,1H),8.39(d,1H),7.65(d,1H),7.56(s,1H),7.32(d,1H),7.18(d,1H),6.86(t,1H),3.53~3.51(m,4H),3.11~3.08(m,4H).
The compound 5a-5p for preparing general formula I according to the method in embodiment Scheme1, structural formula is as shown in table 1.
Table 1
The compound 10a-10k for preparing general formula I according to the method in embodiment Scheme2, structural formula is as shown in table 2.
Table 2
Embodiment 9 suppresses 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, human colon cancer cell strain LoVo, human renal carcinoma cell strain A498 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, 100 μ g/mL Streptomycin sulphates) to be inoculated in culturing bottle, put incubator (37 DEG C, 5%CO
2) middle cultivation, go down to posterity 1 time every 2~3d.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:
1. attached cell adopts mtt assay (lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells, human colon cancer cell, human renal carcinoma cell):
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 100 μ L DMSO dissolve purple particles, then surveys absorbancy (OD) value under 570nm by microplate reader, and experiment in triplicate.
2. suspension cell adopts CCK-8 method (myeloma cell):
After drug treating 48h, add CCK-8 to put into 37 DEG C, 5%CO
2in incubator, continue to cultivate 2h, survey the OD value under 450nm by microplate reader, 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 significant restraining effect to human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells, human colon cancer cell, human renal carcinoma cell and myelomatosis etc., can be used for the medicine of preparation treatment human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells, human colon cancer cell, human renal carcinoma cell and myelomatosis.
Claims (5)
1. pyrimidines, is characterized in that, for thering is the piperazine 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 is the substituting group that contains pyridine, represents following group:
2. pyrimidines as claimed in claim 1, the described piperazine substituted uracil compound with general formula I has the purposes for the preparation for the treatment of human lung carcinoma cell, gastric carcinoma cells, Human Prostate Cancer Cells, human colon cancer cell, human renal carcinoma cell and myelomatosis medicine.
3. in the synthetic general formula scheme1 of compound 5a series: the solvent of compound 2 synthetic use can be propyl carbinol, can be also ethanol, propyl alcohol, Virahol, acetonitrile and dioxane etc.; The solvent of compound 3 synthetic use can be dioxane, also can be DMF, Virahol, propyl carbinol, ethanol, acetonitrile etc., with alkali can be triethylamine, can be also diisopropylethylamine, diethylamine, pyridine, salt of wormwood and sodium carbonate etc., temperature of reaction can be between room temperature to 100 DEG C; The solvent of compound 4 synthetic use can be DMF, can be also Virahol, tetrahydrofuran (THF) and acetonitrile etc., and the alkali of use can be salt of wormwood, can be also sodium hydrogen and sodium carbonate etc., and temperature of reaction can be between 0 DEG C to 80 DEG C; Compound 5 is synthetic is linked reaction, and the catalyzer of use can be four triphenyl phosphorus palladiums, can be also tertiary butyl phosphorus palladium, PdCl
2(dppf), palladium etc., the solvent of reaction use can be dioxane-water, can be also DMF-water, alcohol-water etc., temperature of reaction is at 80-110 DEG C.
4. in the synthetic general formula scheme2 of compound 10a series: the solvent of compound 7 synthetic use can be ethyl acetate, can be also ethanol, propyl alcohol, Virahol and dioxane etc.; The solvent of the synthetic use of compound 8 can be dioxane, can be also DMF, Virahol, propyl carbinol, ethanol, acetonitrile etc., and the alkali of use can be triethylamine, can be also diisopropylethylamine, salt of wormwood etc., and temperature of reaction can be between room temperature to 100 DEG C; Compound 9 is synthetic is linked reaction, and the catalyzer of use can be four triphenyl phosphorus palladiums, can be also tertiary butyl phosphorus palladium, PdCl
2(dppf) etc., the solvent of reaction use can be dioxane-water, can be also DMF-water, alcohol-water etc.; Compound 10 is synthetic is Deprotection, can in HCl-EtOH solution, carry out, and also can in the solution such as HCl-MeOH, HCl-dioxane, HCl-ethyl acetate, carry out, and temperature of reaction is between room temperature to 80 DEG C.
5. compound 5a and 10a series can salifies, after this compounds salify, can increase solubleness, thereby improve the bioavailability in human body, salify can be hydrochloride, also can be vitriol, oxalate, fumarate, tartrate, Citrate trianion, mesylate, benzene sulfonate, lactic acid salt and malate etc., reaction solvent can be ethanol, can be also Virahol, acetonitrile and ethyl acetate etc., and temperature of reaction is between room temperature to 100 DEG C.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310106011.3A CN104072499A (en) | 2013-03-29 | 2013-03-29 | Piperazine substituted pyrimidine compounds and applications thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310106011.3A CN104072499A (en) | 2013-03-29 | 2013-03-29 | Piperazine substituted pyrimidine compounds and applications thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN104072499A true CN104072499A (en) | 2014-10-01 |
Family
ID=51594143
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310106011.3A Pending CN104072499A (en) | 2013-03-29 | 2013-03-29 | Piperazine substituted pyrimidine compounds and applications thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104072499A (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005117909A2 (en) * | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
WO2009017838A2 (en) * | 2007-08-01 | 2009-02-05 | Exelixis, Inc. | Combinations of jak-2 inhibitors and other agents |
CN102653540A (en) * | 2012-03-22 | 2012-09-05 | 盛世泰科生物医药技术(苏州)有限公司 | New synthesis process of new antineoplastic drug INK128 |
CN102690270A (en) * | 2012-05-28 | 2012-09-26 | 吴雁 | Pyrimidine compound and purpose thereof |
CN102985425A (en) * | 2010-07-09 | 2013-03-20 | 利奥制药有限公司 | Novel homopiperazine derivatives as protein tyrosine kinase inhibitors and pharmaceutical use thereof |
-
2013
- 2013-03-29 CN CN201310106011.3A patent/CN104072499A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005117909A2 (en) * | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
WO2009017838A2 (en) * | 2007-08-01 | 2009-02-05 | Exelixis, Inc. | Combinations of jak-2 inhibitors and other agents |
CN102985425A (en) * | 2010-07-09 | 2013-03-20 | 利奥制药有限公司 | Novel homopiperazine derivatives as protein tyrosine kinase inhibitors and pharmaceutical use thereof |
CN102653540A (en) * | 2012-03-22 | 2012-09-05 | 盛世泰科生物医药技术(苏州)有限公司 | New synthesis process of new antineoplastic drug INK128 |
CN102690270A (en) * | 2012-05-28 | 2012-09-26 | 吴雁 | Pyrimidine compound and purpose thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105461695B (en) | Pyrimidine or pyrrolotriazine derivatives and its production and use | |
Moafi et al. | New HA 14-1 analogues: synthesis of 2-amino-4-cyano-4H-chromenes | |
CN106432202B (en) | Quinazoline derivative and its application | |
CN102603743B (en) | Anti-tumor benzazepine[f]azulene derivative, preparation method thereof, and purpose thereof | |
CN105175410A (en) | Triazine compound and preparing method and antineoplastic application thereof | |
CN103608341A (en) | N-aryl unsaturated fused ring tertiary amine compound, preparation method thereof and antitumor application thereof | |
CN102070595A (en) | Substituted benzoxanthone type compound and application thereof | |
CN102675323A (en) | Pyrrole-(2, 1-f) (1, 2 and 4) triazine derivative (I) and antitumor effect thereof | |
CN106432190A (en) | A class of 2-aminopyrimidine-containing naphthalimide compounds, preparation method and applications thereof | |
CN102690270B (en) | Pyrimidine compound and purpose thereof | |
CN106946868B (en) | Nitric oxide donator type coumarin derivative, preparation method and medical usage | |
CN104119330A (en) | Synthesis of berberine derivatives and application of berberine derivatives in preparing anti-tumor drug and anti-tumor drug composition in combination with adriamycin | |
CA2886744A1 (en) | Imatinib derivatives, their preparation and use to treat cancer and bacterial and viral infections | |
CN101967127A (en) | Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs | |
CN103396386A (en) | Di-substituted dinaphtho-[2,1-b:1',2'-d] furan derivative as well as preparation method and application thereof | |
CN1931869B (en) | Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use | |
CN104072499A (en) | Piperazine substituted pyrimidine compounds and applications thereof | |
CN103242321A (en) | Benzylpiperazine compound and anti-tumor application thereof | |
CN103435560B (en) | Synthesis and application of aceanthrylene [1,2-b] quinoxaline derivative with flexible side chain | |
CN104119343A (en) | 2-trifluoromethyl thiadiazole compound and application thereof | |
CN104341407A (en) | Quinazoline compounds, preparation method and applications thereof | |
CN104250250A (en) | 4-aromatic aminopyrimidine compound and anti-tumor use thereof | |
CN105061430A (en) | Preparation method of anti-tumor compound and application of compound | |
CN104230913A (en) | Piperazine-substituted quinazoline compound and use thereof | |
CN104177346A (en) | Quinazoline compound and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
DD01 | Delivery of document by public notice |
Addressee: Huang Chuanman Document name: Notification of Publication and of Entering the Substantive Examination Stage of the Application for Invention |
|
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20141001 |