CN103739615A - Ketone compound with antitumor activity and application of ketone compound - Google Patents
Ketone compound with antitumor activity and application of ketone compound Download PDFInfo
- Publication number
- CN103739615A CN103739615A CN201310714286.5A CN201310714286A CN103739615A CN 103739615 A CN103739615 A CN 103739615A CN 201310714286 A CN201310714286 A CN 201310714286A CN 103739615 A CN103739615 A CN 103739615A
- Authority
- CN
- China
- Prior art keywords
- compound
- general formula
- application
- ketone compounds
- tumor
- 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.)
- Granted
Links
- 0 CC1C(c2ccccc2*(C)(C)CC(C)(C)O)=C(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(CO2)=O)C2=NC1 Chemical compound CC1C(c2ccccc2*(C)(C)CC(C)(C)O)=C(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(CO2)=O)C2=NC1 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines and particularly relates to a ketone compound with antitumor activity and an application of the ketone compound. The invention discloses the ketone compound as shown in the general formula (I), an isomer of the compound as shown in the general formula (I) and a salt of the compound as shown in the general formula (I), wherein R1, R2 and R3 can be same or different and are all selected from hydrogen, halogen, a cyano group, a halogenated alkyl group, an alkoxy group, an alkoxyalkyl group, an alkylamino group or an alkylaminoalkyl group, and X is an oxygen, sulfur, carbon or nitrogen atom. A pharmacological activity screening result proves that the compound provided by the invention has a favorable inhibiting effect on MCF-7 (human breast cancer cells), HeLa (human cervical cancer cells) and Bel7402 (human hepatoma cells) and has favorable development and application prospects in the anti-cancer aspect.
Description
Technical field
The invention belongs to medical technical field, specifically a kind of ketone compounds and application thereof with anti-tumor activity.
Background technology
Malignant tumour is as one of larger public health problem in the whole world, the health of harm humans greatly, and will become the first killer of the new millennium mankind.From world wide, global new cases of cancer 1,010 ten thousand in 2000, dead 6,200,000,2008 pathogenesis of cancer numbers and death toll rise to respectively 1,266 ten thousand and 7,560,000, and estimating 2015 will have 15,000,000 new cases.Meanwhile, malignant tumour is the serious disease of advanced industrial country no longer just, and developing country is faced with larger disease burden.Within 2008, Incidence number developing country accounts for 56%; The cancer patients of 2009 80% concentrates on middle and low income country rank, and by 2015, developing country estimated at 9,000,000 people and dies from cancer.New drug demonstrates wider antitumor spectra in recent years, efficient, easily tolerance, the various characteristics that waits easy to use.In the future, searching has no side effect and efficient new antitumoral medicine may become a main development direction, antimetabolite, topoisomerase enzyme inhibitor and Antitubulin will further develop, molecular targeted agents is if angiogenesis inhibitor, protein tyrosine kinase inhibitor etc. are by fast development, gene therapy medicament will complications develop, but new type antineoplastic medicine research and development will reach real healing tumour, also needs a very long process.
Summary of the invention
The object of the present invention is to provide a kind of ketone compounds and application thereof with anti-tumor activity.
For achieving the above object, the technical solution used in the present invention is:
A ketone compounds with anti-tumor activity, ketone compounds is as the salt of logical formula I, general formula (I) compound isomers or general formula (I) compound;
Wherein: R
1, R
2and R
3can be identical can be different, be selected from hydrogen, halogen, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl; X is oxygen, sulphur, carbon or nitrogen-atoms.Wherein haloalkyl is be selected from the cyclic saturated hydrocarbon of 3～6 saturated carbon atoms formation or have the straight or branched saturated hydrocarbyl that 1～6 saturated carbon atom forms, and the halogen in haloalkyl is fluorine, chlorine, the substituting group of bromine or iodine.
Described sulfamide compound is compound (1), compound (2), compound (3), compound (4), compound (5), compound (6), compound (7) or compound (8), and concrete structure formula is as follows:
Have an application for the ketone compounds of anti-tumor activity, described general formula (I) compound, its salt or isomer are for the preparation of anti-tumor drug.
Using one or more application for the preparation of anti-tumor compositions as active ingredient in general formula (I) compound, its salt or isomer.
The weight percentage of the active ingredient in described anti-tumor compositions is 30-80%.
Described anti-tumor compositions is tablet, capsule, powder, pill, granule or emulsion.
The present invention has advantages of: the compound that the present invention obtains, has good restraining effect to tumor cell line, and compound and one or more pharmaceutical carriers or vehicle are prepared into tablet, capsule, powder, pill, granule or emulsion.
Accompanying drawing explanation
The compound that Fig. 1 provides for the embodiment of the present invention (1) H NMR collection of illustrative plates;
The compound that Fig. 2 provides for the embodiment of the present invention (2) H NMR collection of illustrative plates;
The compound that Fig. 3 provides for the embodiment of the present invention (3) H NMR collection of illustrative plates;
The compound that Fig. 4 provides for the embodiment of the present invention (4) H NMR collection of illustrative plates;
The compound that Fig. 5 provides for the embodiment of the present invention (5) H NMR collection of illustrative plates;
The compound that Fig. 6 provides for the embodiment of the present invention (6) H NMR collection of illustrative plates;
The compound that Fig. 7 provides for the embodiment of the present invention (7) H NMR collection of illustrative plates;
The compound that Fig. 8 provides for the embodiment of the present invention (8) H NMR collection of illustrative plates.
Embodiment
Following synthetic example, pharmacology embodiment, comparative example result can be used to further illustrate the present invention, but do not mean that restriction the present invention, in the present invention except as otherwise outside indicating, raw materials used all have commercially available.
The ketone compounds with anti-tumor activity obtains according to following synthetic route preparation, the fluoro-4-iodine pyridine of the 2-phenyl aldehyde of specifically take is starting raw material, under palladium chloride and potassium alkaline, carry out alkylated reaction with dihydroxyl boron compound, then carry out condensation dehydration reaction with the aminotoluene base replacing, reduction, under hydrochloric acid condition, carry out again corresponding substitution reaction, under triethylamine condition, become acid amides with chloroacetyl chloride, cyclization under last alkaline condition, gets final product to obtain target compound.
Synthetic route 1:
The present invention includes compound that above-mentioned general formula I comprises and be preparation composition that activeconstituents is mixed with and the preparation that forms of preparation.Formulation preparation method is: the compound dissolution that the present invention is contained makes formulation soln in the tensio-active agent of water miscible organic solvent, nonionic, water miscible lipoid, various cyclodextrin, lipid acid, fatty acid ester, phosphatide or its combination solvent; Add physiological saline to obtain the carbohydrate of 1-20%.Described organic solvent comprises polyoxyethylene glycol (PEG), ethanol, the combination solvent of propylene glycol or these solvents.
The compound of containing in general formula I of the present invention and prodrug are for the preparation for the treatment of, prevention or alleviate antitumor drug or pharmaceutical preparation, and active constituents of medicine is the compound shown in one or more general formula Is.Be particularly useful for the cancer that treatment or alleviation tissue or organ tumor cell cause.The preferred colorectal carcinoma of indication cancer, liver cancer, lymphoma, lung cancer, the esophageal carcinoma, mammary cancer, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, kidney, leukemia, prostate cancer, carcinoma of the pancreas, bladder cancer, the rectum cancer or cancer of the stomach etc.
The synthetic compound of the present invention can be used for the activeconstituents of antitumor drug, can use separately, also can, antiviral drug combination antitumor with other.In the drug combination therapeutic process of indication of the present invention, comprise use at least one the compounds of this invention with and one or more anti-tumor virus drugs of reactive derivative and other together with use to increase general curative effect.Dose during drug combination and administration time should be determined according to rational therapy effect obtained in different situations.
The medicament compatibility of containing comprises the effective dose of the compound in general formula I." effective dose " herein refers to the consumption that can produce required this compound of result for the treatment of for institute's treatment target.This effective dose or dosage can be by having experience person according to the suggestion of different situations difference.Such as, the tumour kind for the treatment of is different, and the usage of medicine is different; Whether share etc. as other antitumor drugs or antiviral with other methods for the treatment of, dosage all can change.Can make any spendable preparation formulation.If some has alkalescence or acidic cpd and can form avirulent acid or salt, can use the form of the salt of this compound.In pharmacy, spendable organic acid salt comprises spendable anion salt on physiology, as toluenesulfonate, metilsulfate, acetate, benzoate, Citrate trianion, malate, tartrate, maleate, succinate, ascorbate salt or glycerophosphate etc.; Spendable inorganic salt comprise muriate, bromide, fluorochemical, iodide, vitriol, nitrate, supercarbonate, carbonate or phosphoric acid salt etc.; If any the alkaline compound as amine and suitable acid, can make the form of described salt; The compound of carboxylic-acid can form spendable salt with basic metal or alkaline-earth metal.
The compound of containing in formula of I of the present invention is general soluble in the mixed solvent of organic solvent, water-soluble solvent and organic solvent and water-soluble solvent and water.Water-soluble solvent preferred alcohols, poly ethylene glycol, N-methyl-2-pyrrolinone, N,N-dimethylacetamide, DMF, methyl-sulphoxide, acetonitrile with and share.Described alcohol particular methanol, ethanol, Virahol, glycerol or ethylene glycol.The compounds of this invention can mix with conventional preparations carrier and make preparation.Compound dissolution is in water miscible organic solvent, non-protonic solvent, water-soluble lipid, cyclodextrin, lipid acid, phosphatide or in the mixed solvent of these solvents and make drug solution; Add again physiological saline to obtain the carbohydrate of 1-20%, as the aqueous solution of glucose.The preparation stabilization making therefrom for animal and clinical.
The compound in above-mentioned general formula I of take is the product medicine that active fraction preparation becomes, can be by oral or parenteral route administration, also can be by transplant medicine pump in body and additive method administration, the parenteral route administration of indication herein refers to subcutaneous intracutaneous, intramuscular, intravenously, intra-arterial, atrium in, in synovial membrane, in breastbone, in sheath, interior, the intracranial injection of wound site or drip infusion technique etc.By technician, use conventional method proportioning, mix and finally become needed pharmaceutical dosage form.Can be the outstanding solution of tablet, pill, capsule, electuary, syrup, injection liquid, freeze-dried powder formulation, emulsion, pulvis, lyophilized powder, dripping pill, emulsion suspension liquid, water, the aqueous solution, colloid, colloidal solution, sustained release preparation, nanometer formulation or with other forms of formulation for animal or clinical.
Compound in general formula I of the present invention is used for the treatment of or alleviates the preparation of the cancer drug of a certain tissue or organ.Indication cancer comprises but is not only limited to colorectal carcinoma, liver cancer, lymphoma, lung cancer, the esophageal carcinoma, mammary cancer, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, kidney, leukemia, prostate cancer, carcinoma of the pancreas, bladder cancer, the rectum cancer or cancer of the stomach etc.
Embodiment 1: compound (1) synthetic
2-fluoro-4-iodine pyridine phenyl aldehyde 300mg (1.20mmol, 1.00equiv) is dissolved in to DMF 10mL, then adds respectively 2-fluorobenzoic boric acid 180mg (1.29mmol, 1.10equiv), PdCl
2(dppf) 44mg (0.06mmol; 0.05equiv); salt of wormwood 500mg (3.62mmol; 3.00equiv) 90 ℃ of stirring 2h under nitrogen protection condition; reaction is finished; add ethyl acetate 100mL dilution; with the washing of saturated sodium-chloride water solution 100mL * 3, anhydrous sodium sulfate drying, concentrating under reduced pressure; finally adopt silica gel column chromatography separating-purifying; eluent is petrol ether/ethyl acetate=10:1, obtains the fluoro-4-of light yellow oil 2-(2-fluorophenyl) pyridine phenyl aldehyde 0.2g, yield 76%; (ES, m/z): 220.2[M+H]
+ 1, 222.2[M+H+2]
+ 1.
By above-mentioned light yellow oil 1.73g (7.89mmol, 1.00equiv) be dissolved in dehydrated alcohol 30mL, add respectively again (the bromo-3-of 4-(trifluoromethyl l) phenyl) methylamine 2g (7.87mmol, 1.00equiv), acetic acid 1.2g (20.00mmol, 2.20equiv)., whole system adds NaBH (OAc) after 10 ℃ of stirring 1h again
33.7g (17.45mmol2.20equiv), rise to stirred overnight at room temperature, reaction is finished, concentrating under reduced pressure, and with sodium carbonate, adjusting system pH is 8.0, with ethyl acetate 100mL * 3, wash, use again the washing of saturated sodium-chloride water solution 100mL * 3, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain yellow oil N-(the bromo-3-of 4-(trifluoromethyl) benzyl) (the fluoro-4-of 2-(2-fluorophenyl) pyridine-3) methylamine crude product 3.5g, directly cast single step reaction.
By above-mentioned yellow oil 150mg (0.33mmol, 1.00equiv) be placed in the round-bottomed flask of 50mL, add 6mol/L hydrochloric acid 4mL, whole system is heated to 100 ℃ of backflow 4h again, and reaction is finished, solid collected by filtration, use again this solid of ethyl acetate crystallization, obtain off-white color solid 3-((the bromo-3-of 4-(trifluoromethyl) benzamido group) methyl)-4-(2-fluorophenyl) pyridine-2-alcohol 70mg, yield 47%, (ES, m/z): 455.2[M+H]
+ 1, 457.2[M+H+2]
+ 1.
By above-mentioned off-white color solid 3.11g (6.83mmol, 1.00equiv) be placed in the round-bottomed flask of 100mL, add methylene dichloride 30mL, triethylamine 3.45g (34.11mmol, 5.00equiv) and 0 ℃ of stirring, simultaneously again toward dripping the 2-chloroacetyl chloride 1.16g (10.27mmol diluting with 10mL methylene dichloride in it, 1.50equiv), dropping finishes rear continuation and stirs 3h, reaction is finished, with methylene dichloride 200mL dilute reaction solution, use again the washing of saturated sodium-chloride water solution 200mL * 3, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain white solid N-(the bromo-3-of 4-(trifluoromethyl) benzyl) the chloro-N-of-2-((4-(2-fluorophenyl)-2 hydroxy pyrimidine-3-) methyl) ethanamide 3.27g, yield 90%, (ES, m/z): 531.2[M+H]
+ 1, 533.2[M+H+2]
+ 1.
By above-mentioned white solid 70mg (0.13mmol, 1.00equiv) be dissolved in 50mL acetone, add salt of wormwood 55mg (0.40mmol, 3.00equiv), whole system is heated to 60 ℃ and stirs 3h, reaction is finished, with saturated common salt water washing and purified water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, finally adopts silica gel column chromatography separating-purifying, eluent is that petrol ether/ethyl acetate=2:1 obtains white solid compound (1) 23.7mg, yield 30%, (ES, m/z): 495.2[M+H]
+ 1, 497.2[M+H+2]
+ 1.H?NMR(300MHz,CD
3OD)δ:8.204(d,J=5.1Hz,1H),7.358(d,J=8.4Hz,1H),7.4657.529(m,1H),7.1657.289(m,3H),7.072(d,J=8.4Hz,1H),6.989(d,J=5.1Hz,1H),6.909(t,J=6Hz,J=7.5Hz,1H),5.287(d,
J=11.7Hz,1H),4.890(s,1H),4.7884.838(m,2H),4.243(d,J=13.8Hz,1H),4.243(d,J=5.7Hz,1H)。See Fig. 1.
4-bromo-3-(trifluoromethyl) cyanophenyl 300mg (1.20mmol, 1.00equiv) is dissolved in the round-bottomed flask of 25mL with 3mL tetrahydrofuran (THF), and 0 ℃ of stirring, simultaneously again toward dripping BH in it
3/ THF (1mol/L) (4mL, 3.00equiv), after dropping finishes, rise to room temperature and continue to stir 3h, add the quencher of 10mL methyl alcohol, reaction is finished, and concentrating under reduced pressure, obtains white oily solid (the bromo-3-of 4-(trifluoromethyl) phenyl) methylamine 260mg, yield approximately 85%, needn't be further purified and directly cast single step reaction.
Embodiment 2: compound (2) synthetic
Difference from Example 1 is, employing phenylo boric acid is raw material, according to the synthetic method of embodiment 1, is synthetic route I, can make compound (2), and concrete structure formula is as follows:
(ES, m/z): 615.2[M+H]
+ 1, 617.2[M+H+2]
+ 1; H NMR (300MHz, CDCl
3) δ: 8.16 (d, J=5.1Hz, 1H), 7.85 (s, 1H), 7.48～7.39 (m, 3H), 7.09～6.91 (m, 3H), 6.68～6.65 (m, 1H), 5.41 (d, J=14.1Hz, 1H), 5.26～5.07 (m, 2H), 4.87～4.80 (m, 1H), 4.30 (d, J=15.3Hz, 1H), 4.19～4.14 (m, 1H), 4.07～4.03 (m, 1H), 3.89 (d, J=17.1Hz, 1H), 3.75～3.71 (m, 2H), 3.66～3.50 (m, 5H), 3.34～3.32 (m, 1H), are shown in Fig. 2.
Embodiment 3: compound (3) synthetic
Adopt identical starting raw material with embodiment 2, but in the condensation reaction of second step, adopting (the bromo-3-of 4-(trifluoromethyl) phenyl) methylamine is raw material, according to the synthetic method of embodiment 2, be synthetic route I again, can make compound (3), concrete structure formula is as follows:
(ES, m/z): 571.2[M+H]
+ 1, 573.2[M+H+2]
+ 1; H NMR (300MHz, CDCl
3) δ: 8.16-8.14 (d, J=5.1Hz, 1H), 7.85 (s, 1H), 7.48 (s, 2H), 7.45-7.39 (d, J=8.4Hz, 1H), 7.08-7.05 (m, 1H), 6.95-6.91 (m, 2H), 6.67-6.64 (m, 3H), 5.64-5.59 (m, 1H), 5.35-5.29 (m, 1H), 5.09-5.04 (m, 1H), 4.79-4.75 (m, 1H), 4.32-4.27 (m, 1H), 4.21-4.16 (m, 1H), 4.08-4.03 (m, 1H), 3.87-3.81 (m, 1H), 3.75-3.68 (m, 2H), 3.64-3.61 (m, 2H), 3.52-3.48 (m, 2H), see Fig. 3.
Embodiment 4: compound (4) synthetic
Difference from Example 1 is, adopting the fluorine-based phenylo boric acid of 2-is raw material, according to the synthetic method of embodiment 1, is synthetic route I, can make compound (4), and concrete structure formula is as follows:
(ES, m/z): 495.2[M+H]
+ 1, 497.2[M+H+2]
+ 1; H NMR (300MHz, CDCl
3) δ: 8.22-8.20 (d, J=4.8Hz, 1H), 7.73 (s, 1H), 7.75-7.49 (m, 1H), 7.35 (s, 1H), 7.28-7.18 (m, 3H), 7.01-7.00 (d, J=5.1Hz, 1H), 6.95-6.90 (m, 1H), 5.34 (s, 1H), 4.97 (s, 1H), 4.85 (s, 1H), 4.42 (s, 1H), 4.25 (s, 1H), are shown in Fig. 4.
Embodiment 5: compound (5) synthetic
Adopt identical starting raw material with embodiment 1, but in the condensation reaction of second step, adopting 3-(3-(aminomethyl)-5-(trifluoromethyl) phenyl) propyl group-2-alkynes-1-alcohol is raw material, according to the synthetic method of embodiment 1, be synthetic route I again, can make compound (5), concrete structure formula is as follows:
(ES, m/z): 471.2[M+H]
+ 1, 473.2[M+H+2]
+ 1; H NMR (300MHz, CDCl
3) δ: 8.20-8.19 (d, J=4.8Hz, 1H), 7.57 (s, 1H), 7.53-7.49 (m, 1H), 7.28-7.19 (m, 4H), 6.99-6.97 (d, J=5.1Hz, 1H), 6.94-6.88 (m, 1H), 5.33 (s, 1H), 4.94 (s, 1H), 4.85 (s, 2H), 4.44 (s, 2H), 4.37-4.33 (m, 1H), 4.21-4.16 (m, 1H), is shown in Fig. 5.
Embodiment 6: compound (6) synthetic
Adopt identical starting raw material with embodiment 1, but 3-(3-(aminomethyl)-5-(trifluoromethyl) phenyl) propyl group-2-alkynes-1-methyl ether that adopts tetraethoxy to replace in the condensation reaction of second step is raw material, according to the synthetic method of embodiment 1, be synthetic route I again, can make compound (6), concrete structure formula is as follows:
(ES, m/z): 661.2[M+H]
+ 1, 663.2[M+H+2]
+ 1; H NMR (300MHz, CDCl
3) δ: 8.20 (s, 1H), 7.59 (s, 1H), 7.55-7.49 (m, 1H), 7.27-7.19 (m, 4H), 6.98-6.88 (m, 2H), 5.32 (s, 1H), 4.94 (s, 1H), 4.85 (s, 1H), 4.47 (s, 2H), 4.44-4.39 (m, 1H), 4.22-4.17 (m, 1H), 3.77-3.75 (d, J=4.8Hz, 4H), 3.68-3.61 (m, 10H), 3.55-73.52 (m, 2H), 3.36 (s, 3H), are shown in Fig. 6.
Embodiment 7: compound (7) synthetic
Adopt identical starting raw material with embodiment 1, but in the condensation reaction of second step, adopting 3-(3-(aminomethyl)-5-(trifluoromethyl) phenyl) propyl group-1-alcohol is raw material, according to the synthetic method of embodiment 1, be synthetic route I again, can make compound (7), concrete structure formula is as follows:
(ES, m/z): 475.2[M+H]
+ 1, 477.2[M+H+2]
+ 1; H NMR (300MHz, CDCl
3) δ: 8.18-8.16 (d, J=4.8Hz.1H), 7.52-7.47 (m, 1H), 7.39 (s, 1H), 7.22-7.17 (m, 2H), 7.06-7.03 (m, 2H), 6.94-6.93 (d, J=5.2Hz, 1H), 6.85-6.81 (m, 1H), 5.38-5.34 (m, 1H), 4.84-4.81 (m, 2H), 4.36-4.33 (m, 1H), 4.21-4.17 (m, 1H), 3.55-3.52 (m, 2H), 2.65-2.61 (m, 2H), 1.73-1.66 (m, 2H), is shown in Fig. 7.
Embodiment 8: compound (8) synthetic
Adopt identical starting raw material with embodiment 1, but 3-(3-(aminomethyl)-5-(trifluoromethyl) phenyl) propyl group-1-methyl ether that adopts tetraethoxy to replace in the condensation reaction of second step is raw material, according to the synthetic method of embodiment 1, be synthetic route I again, can make compound (8), concrete structure formula is as follows:
(ES,m/z):665.2[M+H]
+1，667.2[M+H+2]
+1;H?NMR(300MHz,CDCl
3)δ:8.19-8.18(d,J=3.4Hz,1H),7.537.48(m,1H),7.39(s,1H),7.22-7.18(m,2H),7.03(s,2H),6.95-6.94(d,J=4.4Hz,1H),6.87-6.82(m,1H),5.34(s,1H),4.99-4.95(m,1H),4.86-4.80(m,2H),4.38-4.31(m,1H),4.22-4.18(m,1H),3.66-3.57(m,15H),3.53-3.50(m,2H),3.43-3.41(m,2H),3.35-3.33(m,3H),2.66-2.63(m,2H),1.76-1.75(m,2H)。See Fig. 8.
Embodiment 9: compound pharmacological evaluation
Testing compound is to MCF-7 (human breast cancer cell), and HeLa (human cervical carcinoma cell) tumour cell and BeL7402 (human liver cancer cell), as research object, adopt tetramethyl-azo azoles salt colorimetry, i.e. mtt assay.Active in half-inhibition concentration (IC
50) represent, unit is μ M, take 5 FU 5 fluorouracil as contrast medicine.Take MCF-7 cell as example:
Get the MCF-7 cell of 0.25% tryptic digestion monolayer culture, with the RPMI1640 containing 10% foetal calf serum, nutrient solution is made into single cell suspension, is inoculated in 96 orifice plates, and every hole 200 μ L(are containing 3 * 10
4-5 * 10
4individual cell).Culture plate is put into CO
2incubator, at 37 ℃, 5%CO
2under condition, after culturing cell is adherent, add the testing compound of different concns, 4 concentration (1 * 10 of each compound test
-5, 1 * 10
-6, 1 * 10
-7, 1 * 10
-8mol/L), control group adds and the isopyknic solvent of administration group.Continuation is at CO
2in incubator in 37 ℃, 5%CO
2under condition, cultivate 72h.Every hole adds 20 μ L MTT solution (5mg/mL), in 37 ℃, continue to hatch 4h, end to cultivate, discard culture supernatant in hole, every hole adds 150 μ L DMSO, gentle agitation 10min, select 570nm wavelength, in microplate reader, measure each hole absorbance value (OD value), use the inhibiting rate of formula computerized compound to tumour cell below, and calculate IC
50.Repeated test 3 times, averages as net result.
Should be understood that, for those of ordinary skills, can be improved according to the above description or convert, and all these improvement and conversion all should belong to the protection domain of claims of the present invention.
Claims (6)
1. a ketone compounds with anti-tumor activity, is characterized in that: ketone compounds is as the salt of logical formula I, general formula (I) compound isomers or general formula (I) compound;
Wherein: R
1, R
2and R
3can be identical can be different, be selected from hydrogen, halogen, cyano group, hydroxyl, haloalkyl, alkoxyl group, alkoxyalkyl, alkylamino radical or alkylamino radical alkyl; X is oxygen, sulphur, carbon or nitrogen-atoms.
2. by the ketone compounds with anti-tumor activity claimed in claim 1, it is characterized in that: described sulfamide compound is compound (1), compound (2), compound (3), compound (4), compound (5), compound (6), compound (7) or compound (8), and concrete structure formula is as follows:
3. an application with the ketone compounds of anti-tumor activity claimed in claim 1, is characterized in that: described general formula (I) compound, its salt or isomer are for the preparation of anti-tumor drug.
4. by the application with the ketone compounds of anti-tumor activity claimed in claim 3, it is characterized in that: using one or more application for the preparation of anti-tumor compositions as active ingredient in general formula (I) compound, its salt or isomer.
5. by the application with the ketone compounds of anti-tumor activity claimed in claim 4, it is characterized in that: the weight percentage of the active ingredient in described anti-tumor compositions is 30-80%.
6. by the application with the ketone compounds of anti-tumor activity claimed in claim 5, it is characterized in that: described anti-tumor compositions is tablet, capsule, powder, pill, granule or emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310714286.5A CN103739615B (en) | 2013-12-20 | 2013-12-20 | A kind of ketone compounds and application thereof with anti-tumor activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310714286.5A CN103739615B (en) | 2013-12-20 | 2013-12-20 | A kind of ketone compounds and application thereof with anti-tumor activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103739615A true CN103739615A (en) | 2014-04-23 |
| CN103739615B CN103739615B (en) | 2015-10-28 |
Family
ID=50496700
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310714286.5A Expired - Fee Related CN103739615B (en) | 2013-12-20 | 2013-12-20 | A kind of ketone compounds and application thereof with anti-tumor activity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103739615B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006056881A (en) * | 2004-07-21 | 2006-03-02 | Takeda Chem Ind Ltd | Fused ring compound |
| US20110136788A1 (en) * | 2008-08-07 | 2011-06-09 | Minoru Maruyama | Therapeutic agent for irritable bowel syndrome |
| CN102558058A (en) * | 2012-01-19 | 2012-07-11 | 陕西理工学院 | 1-aryl-3-substituent-5-substituted amino-4-pyrazole formamide compound and application thereof |
-
2013
- 2013-12-20 CN CN201310714286.5A patent/CN103739615B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006056881A (en) * | 2004-07-21 | 2006-03-02 | Takeda Chem Ind Ltd | Fused ring compound |
| US20110136788A1 (en) * | 2008-08-07 | 2011-06-09 | Minoru Maruyama | Therapeutic agent for irritable bowel syndrome |
| CN102558058A (en) * | 2012-01-19 | 2012-07-11 | 陕西理工学院 | 1-aryl-3-substituent-5-substituted amino-4-pyrazole formamide compound and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103739615B (en) | 2015-10-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105473595A (en) | Carboxylic acid compounds in treatment of diabetes mellitus | |
| CN101787064B (en) | Cytarabine derivatives and purposes thereof in resisting cancers and tumors | |
| CN110381950A (en) | Substituted [5,6] ring -4 (3H)-pyrimidone as anticancer agent | |
| CN105237533A (en) | Tetrahydropyridine [4,3-d] miazines Hsp90 inhibitor and medical application thereof | |
| CN105263501A (en) | Sugar-analog phosphorus-containing heterocycles having an anti-metastatic activity | |
| CN101230045A (en) | Aromatic triazin derivatives and uses thereof | |
| CN103739615B (en) | A kind of ketone compounds and application thereof with anti-tumor activity | |
| CN103755695B (en) | A kind of amides and application thereof with anti-tumor activity | |
| CN101863901A (en) | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof | |
| CN104672213A (en) | Amide compound with antitumor activity, and application thereof | |
| CN1962658B (en) | Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug | |
| CN111171018B (en) | Chalcone compound and application thereof | |
| PT2699240E (en) | Acadesine derivatives, products and compositions including same, therapeutic uses thereof, and methods for synthesizing same | |
| CN103012380B (en) | Chroman compound, and preparation method and application thereof | |
| CN103772374B (en) | A kind of heterocyclic compound and application thereof | |
| CN105541792A (en) | Polycyclic PI3K inhibitors | |
| CN101787065B (en) | Cytarabine prodrug derivatives and purposes thereof in resisting cancers and tumors | |
| CN103755652B (en) | A kind of sulfamide compound and application thereof | |
| CN101423513B (en) | Amine pyrimidine derivates, and production method thereof, and medicament composition and use | |
| CN103172578A (en) | 4-ring end substituted 2-1,2,3-triazole phenylamines compound, preparation and purpose | |
| CN101684115B (en) | 4-(5-((2-(4-morpholinyl-6-phenylamino group-1,3,5-triazine-2-base) hydrazono) methyl) furan-2-base) benzoic acid, preparing method and application thereof | |
| CN103172606A (en) | Coumarin compound with anti-tumor activity | |
| CN103772262B (en) | A kind of different phthalimide derivatives and application thereof with anti-tumor activity | |
| CN104693182A (en) | Amide compounds having antineoplastic activity and application thereof | |
| CN101845052A (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application 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 | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151028 Termination date: 20161220 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |