CN101284007B - Pharmaceutical use of aryl group substituted pyridone derivates in preparing medicine for tumour - Google Patents
Pharmaceutical use of aryl group substituted pyridone derivates in preparing medicine for tumour Download PDFInfo
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Abstract
The invention provides the uses of 6-aryl-3-methylene-pyridones and pharmaceutically-acceptable salts thereof in preparing antitumor medicines. The in vitro test shows that the 6-aryl-3-methylene-pyridones, with structure of piperazine derivatives, have inhibitory activity on the growth of the in vitro cultured human esophagus cancer cell line (Eca-109) and the murine lymphoid neoplasm cell line (P388D1); and can be used for preparing medicines for treating tumor diseases.
Description
Technical field
The invention belongs to pharmaceutical chemistry and area of pharmacology, be used to prepare the purposes of antitumor drug and pharmaceutical composition in particular to a class 6-aryl-3-substituted methylene-pyridine compounds.Test through pharmacologically active, this compounds has the activity of remarkable inhibition In vitro culture human esophagus cancer cell strain (Eca-109) and mouse lymph sample tumor cell strain (P388D1) growth, can expect as preventing and treating the esophageal carcinoma, leukemia and related neoplasms disease medicament purposes thereof.
Background technology
In recent years, chemotherapy of tumors has been obtained suitable progress, the tumor patient life span obviously prolongs, particularly the treatment to leukemia, malignant lymphoma etc. has had breakthrough, but treatment the most serious, that account for the solid tumor of malignant tumor more than 90% fails to reach satisfied effect to the harm humans life and health.Pharmacy man and oncologist are more and more profoundly recognized: improve the curative effect of oncotherapy, must set about from the mechanism of tumor development, just can obtain the new breakthrough progress.The development of molecular weight tumor in recent years,, molecular pharmacology is progressively illustrated tumor essence; The drug development process has been quickened in the invention and the application of advanced technologies such as extensive rapid screening, combinatorial chemistry, genetic engineering; The research and development of antitumor drug have entered a brand-new era.The development strategy of current antitumor drug has following characteristics: serve as the main attack object to account for the solid tumor of malignant tumor more than 90% 1.; 2. from natural product, seek active component; 3. at the mechanism of tumor development, seek new molecular action (enzyme, receptor, gene) target spot; 4. extensive rapid screening (High-throughput screening); 5. the importing of new technique and application: combinatorial chemistry, structure biology, computer-aided design, genetic engineering, DNA chip, pharmacogenomics (functional genomics combines with the pharmacology) etc.
Except the novel targets of the antitumor action of domestic and international concern and the new type antineoplastic medicine development at the too many levels effect of mechanism, traditional cytotoxicity antitumor drug is still in the treatment of cancer and the common indispensable first-line treatment measure of using of means such as radiotherapy.The industry cell toxicant class antineoplastic new material just under study for action that national cancer institute (NCI) is announced has manyly have been finished clinical experiment nearly or has come into the market, and it is effective to be used for the treatment of mouse leukemia as the Rebeccamycin Analogue (NSC 655649) of Bristol Myers Squibb development; The alkylating agent prodrug Bezelesin (NSC615291) that Pharmacia Upjohn releases is used for the treatment of colon cancer etc.; The guanine metabolism agent interfering (NSC686673) that Glaxo Wellcome releases is used for the treatment of leukemia, t cell lymphoma etc.; The KPN5500 (NSC650426) of Japan's kylin development is used for the treatment of people's gastric cancer, colon cancer, esophageal carcinoma or the like.Illustrate that all the cell toxicant series antineoplastic medicament still has market and definite curative effect comparatively widely.
Piperazine compounds has pharmacologically active widely, medication as usual: sedative hypnotic (Zopiclone), phosphodiesterase gamma inhibitors (Sildenafil), antimicrobial drug (Enoxacin, Ciprofloxacin) and antifungal agent (Ketoconazole, itraconazole).In early days, piperazine and piperazine derivative thereof have carried out extensive studies [Groszkowski as antitumor drug, S. etc., J.Med.Chem.1968,11,621], many in recent years antitumor drug that are used for contain piperazine fragment [Westwell, A.D.Drug Discovery Today 2003,8,229; Boschelli, D.H. etc., J.Med.Chem.2001,44,3965].
For further exploration discovery new efficient, wide spectrum cell toxicant type antitumoral compounds, the chemical compound that we contain piperazine ring and pyridone ring to time among the present invention has carried out studying at the cytotoxic activity of people and mouse tumor cell.We have selected In vitro culture human esophagus cancer cell strain (Eca-109) and mouse lymph sample tumor cell strain (P388D1) as the pharmacological testing evaluation model.
The inventor finds, 6-aryl-3-substituted methylene-pyridinone derivatives that we prepare has significant growth inhibitory activity for In vitro culture human esophagus cancer cell strain (Eca-109) and mouse lymph sample tumor cell strain (P388D1), illustrate that such 6-aryl-3-substituted methylene-pyridinone derivatives has the purposes that can expect as control related neoplasms disease medicament, finishes the present invention thus.
Summary of the invention
The purpose of this invention is to provide the purposes of a class aryl substituted pyridine ketones derivant in the preparation antitumor drug, described derivant is selected from a class 6-aryl-3-substituted methylene-pyridine compounds and an officinal salt thereof, has following array structure:
Chemical compound 1-a:3-(4-benzhydryl piperazidine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-b:3-[4-(4-luorobenzyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-c:3-[4-(4-fluorophenyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-d:4-{[6-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-yl] the methyl piperazine base }-the 1-Ethyl formate;
Chemical compound 1-e:3-[4-(3, the 4-Dichlorobenzene base) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-f:3-(4-benzyl diethylenediamine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-g:3-(4-ethyl piperazidine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-h:3-[4-(2-methoxyphenyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-i:3-(4-cyclohexyl piperazine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-j:3-[4-(3, the 4-dichloro benzyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones.
Described structural formula of compound is:
The prepared above-mentioned 6-aryl-3-substituted methylene-pyridine compounds of the present invention has important biological, in vitro tests shows that this type of chemical compound with piperazine derivative structure has growth inhibitory activity for In vitro culture human esophagus cancer cell strain (Eca-109) and mouse lymph sample tumor cell strain (P388D1), can expect as control related neoplasms disease medicament purposes.
The prepared compound or pharmaceutically acceptable salt thereof of the present invention can combine with adjuvant or carrier pharmaceutically commonly used, prepares the medicine with anticancer usage.Aforementioned pharmaceutical compositions can adopt injection, tablet, capsule, paster, the subcutaneous dosage forms such as burying agent of planting, or other adopt controlled release, slow release formulation and the nanometer formulation of known theory and technology preparation.
The specific embodiment
The present invention is further illustrated below by embodiment.Embodiment has provided the part activity data of representative compounds.Mandatory declaration, following pharmacology embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1:The preparation of starting material A (acetanisole):
Methoxybenzene (10.8 grams, 0.1 mole) is dissolved in 150 milliliters of dichloromethane, adds anhydrous chlorides of rase zinc powder (26.8 grams, 0.20 mole) then, drip acetic anhydride (15.3 grams, 0.15 mole) down at-15 ℃; After dropwising, reaction slowly was raised to room temperature reaction 7 hours, then reactant was carefully poured in 600 milliliters of frozen water, used ethyl acetate extraction 3 times; Organic facies anhydrous magnesium sulfate drying, filtering and concentrating get the colorless oil crude product, get starting material A (acetanisole) through too short silica gel column chromatography: 13.1 grams, yield 87%); White solid, fusing point: 35～38 ℃.Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm) δ 2.56 (unimodal, 3H, COCH
3), 3.87 (unimodal, 3H, OCH
3), 6.93 (bimodal, 2H, J=8.4Hz, H-3,5), 7.94 (bimodal, 2H, J=8.4Hz, H-2,6).
Embodiment 2:The preparation of intermediate B (3-cyano group-6-(4-methoxyphenyl)-2H-pyridin-2-ones):
With sodium metal (2.76 grams, 120 mMs) add in 250 milliliters of ether, drip 1 milliliter of ethanol, drip starting material A (acetanisole) (100 mM) and Ethyl formate (150 mM) mixture under ice bath, after dropwising, mixture stirred after 15 minutes, be warmed up to room temperature reaction 1 hour, after removing ether under reduced pressure, solid mixture adds cyanoacetamide (12.6 grams, 150 mMs) and water (400 milliliters).After mixture refluxed 8 hours, acidifying with acetic acid was used in cooling, filter xanchromatic solid, after the drying, head product recrystallization from ethanol obtains intermediate B (3-cyano group-6-(4-methoxyphenyl)-2H-pyridin-2-ones): yield: 56%, faint yellow solid, fusing point＞250 ℃; R
f(methylene chloride 20: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterated dimethyl sulfoxide, δ ppm): 3.82 (unimodal, MeO-4 '), 6.69 (bimodal, 1H, J=7.2Hz, H-5), 7.05 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.79 (bimodal, 2H, J=8.4Hz, H-2 ', 6 '), 8.06 is (bimodal, 1H, J=7.2Hz, H-4).
Embodiment 3:The preparation of intermediate C (3-cyano group-6-(4-methoxyphenyl)-2-methoxypyridine):
Intermediate B (3-cyano group-6-(4-methoxyphenyl)-2H-pyridin-2-ones) (10 mM) is at N, N-dimethylformamide dimethyl acetal (DMFDMA) (1.8 grams, 15 mMs) N, dinethylformamide (50 milliliters) vlil is spent the night, and mixture is to going in the frozen water.Produce xanchromatic solid precipitation, filter, with a spot of water washing filter cake, dry must thick product, recrystallization gets compound intermediate C (3-cyano group-6-(4-methoxyphenyl)-2-methoxypyridine) in ethanol: yield: 89%; White solid; Fusing point: 137～138 ℃; R
f(petrol ether/ethyl acetate 3: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.89 (unimodal, 3H, MeO-4 '), 4.15 (unimodal, 3H, MeO-2), 7.02 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.36 is (bimodal, 1H, J=8.0Hz, H-5), 7.87 is (bimodal, 1H, J=8.0Hz, H-4), 8.04 is (bimodal, 2H, J=8.4Hz, H-2 ', 6 ').
Embodiment 4: intermediate D, the i.e. preparation of chemical compound (2-methoxyl group-6-(4-methoxyphenyl) Nicotinicum Acidum):
In 100 milliliters of ethanol, the potassium hydroxide solution and 24 gram 3-cyano group-2-methoxyl group-6-(4-methoxyphenyl) pyridines that add 110 milliliter 30%, heat up and refluxed 12 hours, be cooled to room temperature, placement is spent the night, filter 2-methoxyl group-6-(4-methoxyphenyl) Nicotinicum Acidum sodium salt, after the careful neutralization of the hydrochloric acid of 6N, with dichloromethane extraction (5 * 150 milliliters), merge organic facies, the anhydrous calcium chloride drying, sucking filtration, rotary evaporation is removed dichloromethane, obtains white solid 21 grams, yield Y=80%.Starting material D (2-methoxyl group-6-(4-methoxyphenyl) Nicotinicum Acidum): fusing point: 186～187 ℃; R
f(methylene chloride 25: 1) 0.42; Proton nmr spectra
1H-NMR (400MHz, deuterated dimethyl sulfoxide, δ ppm): 3.83 (unimodal, 3H, MeO-4 '), 4.03 (unimodal, 3H, MeO-2), 7.06 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.58 (bimodal, 1H, J=7.6Hz, H-5), 8.10～8.17 (multiplet, 3H, H-4,2 ', 6 '); Carbon-13 nmr spectra
13C NMR (100MHz, deuterated dimethyl sulfoxide, δ ppm): 166.0,161.4,161.1,156.8,142.4,130.0,128.7 (* 2), 114.4 (* 2), 112.1,111.8,55.5,53.5.
Embodiment 5:Intermediate E, the i.e. preparation of chemical compound (2-methoxyl group-6-(4-methoxyphenyl)-3-hydroxymethylpyridine)
Bathe under the cooling condition in cryosel, in the oxolane suspension (140 milliliters) of 4.11 gram lithium aluminium hydride reductions, add 2-methoxyl group-6-(4-methoxyphenyl) Nicotinicum Acidum (intermediate D) 14 grams in batches, after adding, stirring at room 4 hours, be warmed up to 60 ℃, the cooling back adds saturated aqueous ammonium chloride (80 milliliters) in reaction system, with ethyl acetate (3 * 150 milliliters) extraction, merge organic facies, with saturated common salt water washing (3 * 20 milliliters), anhydrous sodium sulfate drying, sucking filtration, silica gel column chromatography (petrol ether/ethyl acetate: 5/1) obtain colorless solid 9.9 grams, yield Y=85%; Fusing point: 84～86 ℃; R
f(petrol ether/ethyl acetate 3: 1) 0.56; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.38 (wide unimodal, 1H, HO-CH
2), 3.88 (unimodal, 3H, MeO-4 '), 4.09 (unimodal, 3H, MeO-2), 4.67 (unimodal, 2H, CH
2-3), 6.98 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.28 is (bimodal, 1H, J=8.0Hz, H-5), 7.58 (bimodal, 1H, J=8.0Hz, H-4), 8.00 (bimodal, 2H, J=8.4Hz, H-2 ', 6 '). Electrospray Mass Spectrometry MS (ESI), m/e:246 ([M+1]
+).
Embodiment 6:Intermediate F, the i.e. preparation of chemical compound (3-chloromethyl-2-methoxyl group-6-(4-methoxyphenyl) pyridine)
In ice-water bath, 2-methoxyl group-6-(4-methoxyphenyl) pyridine-3-methanol (intermediate E) of 20 mMs is dissolved in the dichloromethane (40 milliliters), adds 3.0 milliliters of triethylamines, drip mesyl chloride 2.4 grams again, slowly be raised to room temperature, reaction is at room temperature stirred and is spent the night.After adding 40 milliliters of dilutions of dichloromethane, wash (2 * 40 milliliters) with water, the saturated common salt water washing, anhydrous sodium sulfate drying, rotary evaporation is removed dichloromethane, silica gel column chromatography (petrol ether/ethyl acetate: 20/1) obtain colorless solid 0.992 gram, yield Y=76%.Fusing point: 79～80 ℃ of .R
f(petrol ether/ethyl acetate 9: 1) 0.65; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.87 (unimodal, 3H, MeO-4 '), 4.10 (unimodal, 3H, MeO-2), 4.64 (unimodal, 2H, CH
2Cl-3), 6.98 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.28 (bimodal 1H, J=8.0Hz, H-5), 7.66 (bimodal, 1H, J=8.0Hz, H-4), 8.00 (bimodal, 2H, J=8.4Hz, H-2 ', 6 '). carbon-13 nmr spectra
13C-NMR (100MHz, deuterochloroform, δ ppm): 41.1,53.4,55.3,111.8,114.0,117.5,128.0,131.2,139.4,154.6,160.5,160.9.
Embodiment 7:The preparation of chemical compound 1-a (3-(4-benzhydryl piperazidine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones)
265 milligrams (3-chloromethyl-2-methoxyl group-6-(4-methoxyphenyl) pyridine) (being intermediate F) were dissolved in the acetonitrile (14 milliliters), add 504 milligrams of 1-benzhydryl piperazidines and 1114 milligrams of potassium carbonate, 60 ℃ of following reacting by heating 5 hours.Cooling is filtered, with dichloromethane filter wash cake, and after rotary evaporation removes and desolvates, silica gel column chromatography (dichloromethane～methylene chloride: 50/1) get 180 milligrams of white solids.Get in the hydrobromic acid aqueous solution (5 milliliters) that 120 milligrams of this white solids (0.25 mM) are dissolved in glacial acetic acid (5 milliliters) and 40%, mixture is 60 ℃ of reactions 6 hours down.The potassium carbonate neutralization is carefully arranged after the cooling, and dichloromethane (3 * 50 milliliters) extraction merges organic facies, with saturated common salt water washing (2 * 20 milliliters), and anhydrous sodium sulfate drying, sucking filtration; Silica gel column chromatography (methylene chloride: 50/1) get 108 milligrams of white solids.
Fusing point: 146～148 ℃ (acetonitrile), separation yield Y=92.7%.R
f(methylene chloride: 20/1): 0.28, proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.39～2.58 (multiplet, 8H, H-3 ', 4 ', 6 ', 7 '), 3.56 (unimodal, 2H, H-1 '), 3.85 (unimodal, 3H, MeO-4 "), 4.22 (bimodal, 1H; J=2.8Hz, H-8 '), 6.53 (wide bimodal, 1H, J=6.0Hz; H-5), 6.97 (bimodal, 2H, J=8.8Hz, H-12 '; 18 '), 7.15-7.28 (multiplet, 6H, H-10 ', 14 '; 16 ', 20 ', 3 ", 5 "), 7.41 (bimodal; 4H, J=8.0Hz, H-11 ', 13 ', 17 ', 19 '), 7.48 (bimodal, 1H, J=7.2Hz, H-4), 7.67 (bimodal, 2H, J=8.0Hz, H-2 ", 6 "); Electrospray Mass Spectrometry MS (ESI), m/e:466 (M+1)
+
Embodiment 8
Prepare each chemical compound shown below according to the similar approach with above embodiment, what list below is the physicochemical data of each chemical compound:
Chemical compound 1-b:3-[4-(4-luorobenzyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones; Buff powder, fusing point: 148～149 ℃ (acetonitrile recrystallization), R
f(methylene chloride: 20/1): 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.49～2.58 (wide bimodal, 8H, H-3 ', 4 ', 6 ', 7 '), 3.48 is (unimodal, 2H, H-1 '), 3.55 (unimodal, 2H, H-8 '), 3.86 (unimodal, 3H, MeO-4 "); 6.53 (bimodal, 1H, J=7.2Hz, H-5); 6.99 (triplet, 4H, J=8.8Hz, H-11 '; 13 ', 3 ", 5 "), 7.26～7.29 (multiplet; 2H, H-10 ', 14 '), 7.49 (bimodal; 1H, J=7.2Hz, H-4), 7.70 is (bimodal, 2H, J=8.4Hz, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 408 (M+1)
+
Chemical compound 1-c:3-[4-(4-fluorophenyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones; Buff powder, fusing point: 143～144 ℃ (acetonitrile recrystallization), R
f(methylene chloride: 20/1): 0.42; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.74 (wide unimodal, 4H, H-3 ', 7 '), 3.15 is (wide unimodal, 4H, H-4 ', 6 '), 3.60 (unimodal, 2H, H-1 '), 3.86 is (unimodal, 3H, MeO-4 "), 6.54 (bimodal, 1H, J=7.2Hz, H-5), 6.87 (multiplet; 2H, H-9 ', 13 '), 6.95～7.02 (multiplet, 4H, H-10 '; 12 ', 3 ", 5 "), 7.56 (bimodal, 1H, J=7.2Hz; H-4), 7.66 (bimodal, 2H, J=8.8Hz, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 394 (M+1)
+
Chemical compound 1-d:4-{[6-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-yl] the methyl piperazine base }-the 1-Ethyl formate; Buff powder, fusing point: 111～112 ℃ (acetonitrile), R
f(methylene chloride 30: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 1.26 (triplet, 3H, J=7.2Hz, H-11 '), 2.50 (wide unimodal, 4H, H-3 ', 7 '), (3.50 unimodal, 2H, H-1 '), 3.53 (wide unimodal, 4H, H-4 ', 6 '), 3.87 (unimodal, 3H, MeO-4 "), 4.13 (quartet, 2H, J=7.2; 14Hz, H-10 '), 6.49 (bimodal, 1H; J=7.2Hz, H-5), 6.99 (bimodal, 2H; J=8.8HZ, H-3 ", 5 "), 7.52 (bimodal; 1H, J=7.2HZ, H-4), 7.67 (bimodal; 2H, J=8.8HZ, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 372 (M+1)
+
Chemical compound 1-e:3-[4-(3, the 4-Dichlorobenzene base) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones; Buff powder, fusing point: 141～142 ℃ (acetonitrile), R
f(methylene chloride 20: 1) 0.41; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.70 (brs, 4H, H-3 ', 7 '), 3.19 (wide unimodal, 4H, H-4 ', 6 '), (3.58 unimodal, 2H, H-1 '), 3.85 (unimodal, 3H, MeO-4 "), 6.50 (bimodal, 1H, J=7.2HZ, H-5); 6.73 (double doublet, 1H, J=2.8,8.8Hz, H-13 '); 6.94 (bimodal, 1H, J=2.8Hz, H-9 '), 6.99 (bimodal; 2H, J=8.4Hz, H-3 ", 5 "), 7.26 (bimodal; 1H, J=8.8Hz, H-12 '), 7.57 (bimodal; 1H, J=7.2Hz, H-4), 7.68 is (bimodal, 2H, J=8.4HZ, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 444 (M+1)
+
Chemical compound 1-f:3-(4-benzyl diethylenediamine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones; Buff powder, fusing point: 139～140 ℃ (acetonitrile), R
f(methylene chloride 20: 1) 0.44; Proton nmr spectra
1H-NMR (400MHz, deuterated acetone, δ ppm): 2.57 (wide unimodal, 4H, H-3 ', 7 '), 2.67 (wide unimodal, 4H, H-4 ', 6 '), (3.54 unimodal, 2H, H-8 '), 3.62 (unimodal, 2H, H-1 '), 3.86 (unimodal, 3H, MeO-4 "), 6.57 (bimodal; 1H, J=7.2Hz, H-5), 6.99 (bimodal; 2H, J=8.8Hz, H-3 ", 5 "); 7.23～7.32 (multiplet, 5H, H-10 ', 11 '; 12 ', 13 ', 14 '), 7.56 (bimodal; 1H, J=7.2Hz, H-4), 7.65 is (bimodal, 2H, J=8.4Hz, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 390 (M+1)
+
Chemical compound 1-g:3-(4-ethyl piperazidine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones, buff powder, fusing point: 101～103 ℃ (acetonitrile), R
f(methylene chloride 20: 1) 0.28; Proton nmr spectra
1H-NMR (400MHz, deuterated acetone, δ ppm): 1.08 (triplet, 3H, J=7.2Hz, H-9 '), 2.42 (quartet, 2H, J=7.2Hz, H-8 '), 2.46～2.62 (multiplet, 8H, H-3 ', 4 ', 6 ', 7 '), (3.56 unimodal, 2H, H-1 '), 3.86 is (unimodal, 3H, MeO-4 "), 6.55 (bimodal, 1H; J=6.8Hz, H-5), 6.98 (bimodal, 2H; J=8.0Hz, H-3 ", 5 "), 7.49 (bimodal; 1H, J=6.8Hz, H-4), 7.69 (bimodal; 2H, J=8.0Hz, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 328 (M+1)
+
Chemical compound 1-h:3-[4-(2-methoxyphenyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones; Buff powder, fusing point: 151～152 ℃ (acetonitrile), R
f(methylene chloride 20: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.81 (wide unimodal, 4H, H-3 ', 7 '), 3.15 is (wide unimodal, 4H, H-4 ', 6 '), 3.66 (unimodal, 2H, H-1 '), 3.86 is (unimodal, 6H, MeO-4 ", 9 '), 6.58 (bimodal, 1H, J=6.8Hz; H-5), 6.85～7.01 (multiplet, 6H, H-10 ', 11 ', 12 '; 13 ', 3 ", 5 "), 7.57 (bimodal, 1H, J=6.8Hz; H-4), 7.67 (bimodal, 2H, J=8.4Hz, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 406 (M+1)
+
Chemical compound 1-i:3-(4-cyclohexyl piperazine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones; Buff powder, fusing point: 125～127 ℃ (acetonitrile), R
f(methylene chloride 20: 1) 0.30; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 1.08～1.90 (multiplet m, 10H, H-9 ', 10 ', 11 ', 12 ', 13 '), 2.24 is (wide unimodal, 1H, H-8 '), 2.64 (wide unimodal, 8H, H-3 ', 4 ', 6 ', 7 '), (3.56 s, 2H, H-1 '), 3.86 is (unimodal, 3H, MeO-4 "), 6.59 (bimodal, 1H; J=7.2Hz, H-5), 6.99 (bimodal, 2H; J=8.8Hz, H-3 ", 5 "), 7.48 (bimodal; 1H, J=7.2Hz, H-4), 7.67 (bimodal; 2H, J=8.8Hz, H-2 ", 6 "); Electrospray Mass Spectrometry ESIMS (m/e) 382 (M+1)
+
Chemical compound 1-j:3-[4-(3, the 4-dichloro benzyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones; Buff powder, fusing point: 149～150 ℃ (acetonitrile), R
f(methylene chloride 20: 1) 0.48; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.51～2.61 (multiplet, 8H, H-3 ', 4 ', 6 ', 7 '), 3.49 (unimodal, 2H, H-8 '), 3.56 (unimodal, 2H, H-1 '), 3.90 is (unimodal, 3H, MeO-4 "), 6.56 (bimodal, 1H, J=7.2Hz; H-5), 6.97 (bimodal, 2H, J=8.0Hz, H-3 ", 5 "), 7.16 (bimodal, 1H, J=7.6Hz, H-14 '); 7.37 (bimodal, 1H, J=7.6Hz, H-13 '); 7.43 (unimodal, 1H, H-10 '), 7.51 (bimodal; 1H, J=7.2Hz, H-4), 7.65 (bimodal; 2H, J=8.0Hz, H-2 ", 6 "). Electrospray Mass Spectrometry ESIMS (m/e) 458 (M+1)
+
Pharmacology embodiment 1: chemical compound 1-b is to the cytotoxic activity of human esophagus cancer cell
Human esophagus cancer cell (Eca-109) contains 5% calf serum, the streptomycin of 100U/ ml penicillin and 100U/ milliliter with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 4 * 10
3Concentration join in 96 orifice plates, in 37 ℃ of incubators that contain 5% carbon dioxide humid air, cultivated 24 hours.
The mensuration of cell survival rate is with improveing MTT (3-(4,5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt) method.Cell is through after 24 hours hatch, the dimethyl sulfoxide solution of the chemical compound 1-b that will newly join respectively joins in each hole with Concentraton gradient, make that the chemical compound ultimate density is respectively 100 mcg/ml in the hole, 33.3 mcg/ml, 11.1 mcg/ml and 3.7 mcg/ml.After 72 hours, the normal saline solution that adds 10 microlitre MTT (5 mg/ml), continue 37 ℃ of cultivations after 3 hours again, add 200 microlitre dimethyl sulfoxines in every hole, MTT crystal Jia Za (formazan) with dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.
Chemical compound 1-b is to Eca-109 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of chemical compound 1-b
50Be 63.4 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of Eca-109 cell with antitumor one line medication cisplatin (DDP) in this experiment
50Be 5.0 μ M.
This experiment shows that this type of 6-aryl-3-substituted methylene-pyridinone derivatives has stronger cytotoxicity to the Eca-109 cell, might develop into the new medicine with anti esophageal cancer and related neoplasms effect.
Pharmacology embodiment 2: chemical compound 1-h is to the cytotoxic activity of human esophagus cancer cell
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.
Wherein chemical compound 1-h is to Eca-109 cell 503nhibiting concentration (IC
50) obtain by dose effect curve.The IC of chemical compound 1-h
50Be 73.1 μ M; And the positive control cisplatin is to the IC of Eca-109 cell
50Be 5.0 μ M.
Experiment conclusion: this experiment shows that further this type of 6-aryl-3-substituted methylene-pyridinone derivatives has stronger cytotoxicity to human esophagus cancer cell, might develop into the new medicine with anti esophageal cancer effect and related neoplasms effect.
Pharmacology embodiment 3: chemical compound 1-b is to the cytotoxic activity of mouse lymph sample tumor
Mouse lymph sample tumor (P388D1) cell contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter streptomycin with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 5 * 10
3Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of humid air.
The assay method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the chemical compound 1-b that will newly join respectively joins in each hole with Concentraton gradient, makes that the ultimate density of chemical compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of humid air, add 150 microlitre dimethyl sulfoxines in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein chemical compound 1-b is to the half-inhibition concentration (IC of P388D1 cell
50) obtain by dose effect curve.
Chemical compound 1-b is to P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of chemical compound 1-b
50Be 42.9 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of P388D1 cell with antitumor one line medication cisplatin (DDP) in this experiment
50Be 7.2 μ M.
This experiment shows that this type of 6-aryl-3-substituted methylene-pyridinone derivatives has stronger cytotoxicity to the P388D1 cell, might develop into the new medicine with leukemia and related neoplasms effect.
Pharmacology embodiment 4: chemical compound 1-c is to the cytotoxic activity of mouse lymph sample tumor
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 3.
Chemical compound 1-c is to P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of chemical compound 1-c
50Be 68.0 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of P388D1 cell with antitumor one line medication cisplatin (DDP) in this experiment
50Be 7.2 μ M.
This experiment shows that further this type of 6-aryl-3-substituted methylene-pyridinone derivatives has stronger cytotoxicity to the P388D1 cell, might develop into the new medicine with leukemia and related neoplasms effect.
Pharmacology embodiment 5: chemical compound 1-a is to the cytotoxic activity of mouse lymph sample tumor
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 3.
Chemical compound 1-a is to P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of chemical compound 1-a
50Be 5.4 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of P388D1 cell with antitumor one line medication cisplatin (DDP) in this experiment
50Be 7.2 μ M.
This experiment shows that chemical compound 1-a also is eager to excel than positive control medicine cisplatin (DDP) to mouse lymph sample tumor P388D1 cytotoxicity, has potentiality and develops into the new medicine with leukemia and related neoplasms effect.
These compound or pharmaceutically acceptable salt thereofs of the present invention can with antitumor drug that has now gone on the market such as platinum medicine cisplatin (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), paclitaxel (Paclitaxel) etc. is united use, prepare and have tumor growth and suppress active cytotoxicity compositions, can be used for treating tumor disease, especially the esophageal carcinoma, leukemia and related neoplasms disease thereof.
Claims (4)
1. the application of aryl substituted pyridine ketones derivant in the preparation antitumor drug, it is characterized in that the application in preparation treatment lymph sample tumor and esophageal carcinoma medicine, described derivant is selected from a class 6-aryl-3-substituted methylene-pyridine compounds, has following structure:
Chemical compound 1-a:3-(4-benzhydryl piperazidine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-b:3-[4-(4-luorobenzyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridine-2 ketone;
Chemical compound 1-c:3-[4-(4-fluorophenyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-e:3-[4-(3, the 4-Dichlorobenzene base) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-f:3-(4-benzyl diethylenediamine-1-ylmethyl)-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-h:3-[4-(2-methoxyphenyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones;
Chemical compound 1-i:3-[4-(3, the 4-dichloro benzyl) piperazine-1-ylmethyl]-6-(4-methoxyphenyl)-2H-pyridin-2-ones.
2. the application of aryl substituted pyridine ketones derivant according to claim 1 in the preparation antitumor drug is characterized in that: the application of the officinal salt of described derivant in preparation treatment lymph sample tumor and esophageal carcinoma medicine.
3. the application of aryl substituted pyridine ketones derivant according to claim 1 and 2 in the preparation antitumor drug, it is characterized in that: the pharmaceutic adjuvant that described aryl substituted pyridine ketones derivant and officinal salt thereof and preparation allow is prepared into medicine.
4. the application of aryl substituted pyridine ketones derivant according to claim 3 in the preparation antitumor drug, it is characterized in that: the dosage form of described medicine is selected injection, tablet or capsule for use.
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