CN101805355A - Thienopyridone derivative, preparation method and uses thereof - Google Patents
Thienopyridone derivative, preparation method and uses thereof Download PDFInfo
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Abstract
The invention, belonging to the technical field of anti-malignant tumor medicines, provides a thienopyridone derivative having the structure shown as formula I and pharmaceutically acceptable salts thereof, wherein R1 and R2 are defined as specification. The invention further relates a preparation method of the compound, and simultaneously discloses pharmaceutical compositions with the compound or pharmaceutically acceptable salts thereof as effective active ingredient as well as uses of the pharmaceutical compositions as anti-malignant tumor medicines,.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to a class and have compound of anticarcinogenesis and preparation method thereof.
Background technology
Cancer is one of main killer of human health, and its mortality ratio ranked second the position in China position of ranking forefront in the world.According to World Health Organization statistics, global cancer mortality number in 2007 reaches 7,900,000 (account for all death tolls 13%), and lung cancer, cancer of the stomach, liver cancer, colorectal carcinoma and breast cancer are the arch-criminals of annual most of cancer mortalities.In recent years, because the cancer risk factors such as abuse of urban air pollution, overweight or obesity, alcohol tobacco are on the rise, cause the sickness rate of cancer to rise year by year.In developing country, along with the reduction of transmissible disease death and child mortality, more people's life-time dilatations, the burden of cancer also increases thereupon.Pharmacological agent is one of main treatment means of cancer, and the searching of cancer therapy drug is the popular domain of scientists study always.At present being used for anticancer medicine clinically has hundreds of, prolong cancer patients's life effectively or improved cancer patients's life quality, but most drug is a cell toxicity medicament, selectivity is not high, when eliminating tumour cell, normal cell also there is major injury, cause the intensive toxic side effects, and have the resistance problem.In addition, existing chemicals is unsatisfactory to the result of treatment of most solid tumors.Therefore, seeking the new type anticancer medicine shoulders heavy responsibilities.
Summary of the invention
One object of the present invention is, open Thienopyridone analog derivative and pharmaceutical salts thereof.
Another object of the present invention is that disclosing with Thienopyridone derivative and pharmaceutical salts thereof is the pharmaceutical composition of main active ingredient.
A further object of the present invention is, discloses the preparation method of Thienopyridone derivative and pharmaceutical salts thereof.
A further object of the invention is, discloses Thienopyridone derivative and pharmaceutical salts thereof, as the application of medicine for resisting malignant tumors, particularly in the purposes that is used to prepare aspect treatment lung cancer, mammary cancer, liver cancer, the cancer of the stomach medicine.
The present invention is specifically related to the compound and the pharmacy acceptable salt thereof of general formula I structure:
Wherein:
n＝1，2；
R
1, R
2Be hydrogen, C
1-C
3Alkyl, halogen, halogenated methyl.
C of the present invention
1-C
3Alkyl and halogen, the concrete represent methylidene of halogenated methyl, ethyl, propyl group, sec.-propyl, fluorine, chlorine, trifluoromethyl etc.
The compound that the present invention relates to formula I structure, wherein part of compounds is:
(2-(4-phenylpiperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-1 5-;
(2-(4-p-methylphenyl piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-2 5-;
(2-(the adjacent fluorophenyl piperazine of 4--1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-3 5-;
(2-(4-(2, the 3-dichlorophenyl) piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-4 5-;
(2-(4-(3-trifluoromethyl) piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-5 5-;
(3-(4-(2, the 3-dichlorophenyl) piperazine-1-yl)-3-oxopropyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-6 5-;
(3-(4-(2-fluorophenyl) piperazine-1-yl)-3-oxopropyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-7 5-.
The compound with formula I structure or its pharmacy acceptable salt among the present invention mean: the salt that The compounds of this invention is become with mineral acid, organic acid.Wherein particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate or the like.
The preparation route of formula I compound:
Wherein X is a halogen.
Substituted-piperazinyl compounds and halogen acyl halide are in methylene dichloride, trichloromethane or toluene, in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide ,-30 ℃～35 ℃ reactions make key intermediate.Intermediate again with compound 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-ketone, in methylene dichloride, trichloromethane or toluene, in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, 0 ℃～90 ℃ reactions make I.
Reaction is made various intermediates or products therefrom be dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, dropping inorganic acid or organic acid solution are made pharmacy acceptable salt.
Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, the dripping hydrochloric acid diethyl ether solution is made hydrochloride to pH=2 under ice-water bath; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, and adding and wait a mole taurine, heated and stirred gets its taurate; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, drips concentrated sulfuric acid solution down to pH=3, make vitriol in ice-water bath, or the like.
This compounds is effective for the treatment human malignancies.Although compound of the present invention can be without the direct administration of any preparation, described all cpds preferably uses with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions of The compounds of this invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of used compound or concentration are regulated in the scope of a broad.Usually, the weight range of active compound is 0.5%～90% (weight) of composition, and another preferred range is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention has the obvious suppression effect to tumour in external, body.
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of Thienopyridinone derivatives the human tumor cells of vitro culture.
(2) experiment material:
Laboratory sample: Thienopyridinone derivatives is provided by contriver's self-control.Sample is with the DMSO hydrotropy during experiment, and serum-free DMEM substratum is diluted to desired concn, and sample segment solution is suspension.
Main agents: MTT, the packing of Amresco company, lot number: 04M0904; Complete DMEM substratum, Gibco company product, lot number: 1290007; Calf serum, Lanzhou people's marine life, lot number: 20060509; Trypsinase, the packing of Amresco company, lot number: 016B0604; Fluorouracil Injection, 0.25g/10mL (propping up), lot number: 0512022, Tianjin gold credit amino acid company limited.
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO
2Incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert 200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
Cell strain: lung cancer A-549 cell, liver cancer SMMC-7721 cell, mammary cancer MCF-7 cell, adenocarcinoma of stomach SGC-7901 cell, all available from Shanghai cell research institute of the Chinese Academy of Sciences.
(3) experimental procedure:
Cell cultures: tumor cell inoculation is containing 10% calf serum, in the DMEM nutrient solution of 100IU/mL penicillin G sodium salt and 100ug/mL Vetstrep, places 37 ℃, 100% relative humidity, contains 5%CO
2Incubator in, it is standby after 3 times to go down to posterity.
Mtt assay is measured: the cell in the vegetative period of taking the logarithm, behind 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution that contains 10% calf serum, blow and beat into single cell suspension gently, microscopically blood cell counts plate numeration viable cell with the glass dropper.(cell concn is adjusted into 6～10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ L
4Individual/mL), at 37 ℃, 100% relative humidity, contain 5%CO
2, 95% air incubator cultivate 24h after, every hole adds 10 μ L soups (final concentration is made as: 40 μ g/mL, 20 μ g/mL, 10 μ g/mL, 5 μ g/mL and five concentration of 2.5 μ g/mL).In addition, each concentration is established negative control (isoconcentration DMSO) and blank background (not adding cell), and each group is all established 6 multiple holes.Cultured continuously 24h again, every then hole adds the MTT solution 10 μ L of 5mg/mL, and after continuing to cultivate 4h, the careful suction removed supernatant liquor (suspension cell needs earlier centrifugally, inhales and removes supernatant).Every hole adds DMSO 100 μ L, puts micro oscillator concussion 5min so that crystallization is dissolved fully, and the single wavelength colorimetric of microplate reader 492nm is measured the OD value.Calculate inhibitory rate of cell growth as evaluation index with following method.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average)] * 100%.According to inhibitory rate of cell growth, calculate IC with the straight-line regression method
50Value.
(4) experimental result: see Table 1.
The IC of the tumour cell of table 1. pair vitro culture
50(μ g/mL)
(5) conclusion:
According to above-mentioned in vitro tests result, the compound that we have the general formula I structure as can be seen has stronger restraining effect to above-mentioned 4 kinds of human tumor cells.
Intravital antitumor action
(1) experiment material:
Sample: I-4 is provided by contriver's self-control.
Cell strain: liver cancer H22 cell, all available from Shanghai cell research institute of the Chinese Academy of Sciences.
Positive control drug: endoxan, lot number: 07020121, Hengrui Medicine Co., Ltd., Jiangsu Prov..
Instrument: PB303-N type thousandth electronic balance, Mettler Toledo Inc. produces.
Animal: Kunming mouse, the SPF level, male and female half and half, body weight 18-22g purchases in Institute of Radiation Medicine, Chinese Academy of Medical Sciences, conformity certification number: SCXK (Tianjin) 2005-0001.
(2) experimental technique:
Get abdominal cavity inoculation knurl strain 9 days, tumor growth is good, the tangible tumor-bearing mice of abdominal tympanites, ascites is drawn in aseptic technique down, be made into the cancer cells suspension by physiological saline dilution in 1: 3, in all experiment mice right fore armpit subcutaneous vaccinations (0.2mL/ mouse), all operations is finished in 30min.To inoculate knurl liquid mouse next day by the body weight random packet, i.e. lotus knurl control group, endoxan group (25mg/kg), I-4 organizes (100mg/kg, 50mg/kg).The equal intraperitoneal injection of each administration group, once a day, control group gives with volume physiological saline.Mouse successive administration 10 days behind the last administration 24h, takes off cervical vertebra and puts to death, and peels off tumour, takes by weighing knurl and weighs, and calculates and respectively organizes heavy mean value of mouse tumor and inhibiting rate.
Inhibiting rate=[(the average knurl of the average knurl weight-experimental group of control group is heavy)/average knurl of control group is heavy] * 100%
(3) result:
Table 2. pair H22 tumor-bearing mice knurl heavily reaches the influence of inhibiting rate
(4) conclusion:
From above-mentioned animal vivo test result as can be seen, I-4 has certain restraining effect to the tumor growth of H22 tumor-bearing mice.Wherein during 100mg/kg dosage group intraperitoneal injection, inhibition rate of tumor growth all is better than positive control.
Embodiment
Below in conjunction with embodiment the present invention is described further, embodiment only is indicative, means that never it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1H NMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Embodiment 1:
Intermediate
1Preparation
In the reaction flask that stirring, condenser, thermometer are housed, add 4-phenylpiperazine 16.2g, it is dissolved, be cooled to-30 ℃ under stirring, add Anhydrous potassium carbonate 41.5g with the 30mL methylene dichloride.Chloroacetyl chloride 11.3g is dissolved in the 25mL methylene dichloride, slowly is added dropwise to reaction system, dropwise, continue reaction 2 h (the flaggy demonstration reacts completely) down in-10 ℃.With 3 * 50mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets colorless oil product 21.0g (HPLC:98.5%).The Rf=0.56[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=2: 1].
1H?NMR(CDCl
3，400MHz)δ：3.452～3.457(m，2H)，3.460～3.465(m，2H)，3.628～3.633(m，4H)，4.298(s，2H)，6.543～6.545(m，1H)，6.722～6.725(m，2H)，7.436～7.440(m，2H)。
Embodiment 2:
Intermediate
2Preparation
In the reaction flask that stirring, condenser, thermometer are housed, add p-methylphenyl piperazine 17.6g, it is dissolved, be cooled to-20 ℃ under stirring, add triethylamine 30.4g with the 40mL trichloromethane.Bromoacetyl bromide 20.2g is dissolved in the 30mL trichloromethane, slowly is added dropwise to reaction system, dropwise, continue reaction 4h (the flaggy demonstration reacts completely) down in 0 ℃.With 3 * 80mL water washing reaction solution, divide and get the trichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets colorless oil product 26.8g (HPLC:98.9%).The Rf=0.60[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=2: 1].
1H?NMR(CDCl
3，400MHz)δ：2.517～2.519(s，3H)，3.453～3.458(m，2H)，3.462～3.466(m，2H)，3.631～3.636(m，4H)，4.301(s，2H)，6.629～6.631(d，2H)，7.138～7.140(d，2H)。
Embodiment 3:
Intermediate
3Preparation
With reference to the method for embodiment 1, replace the 4-phenylpiperazine with adjacent fluorophenyl piperazine, with the chloroacetyl chloride reaction, get colorless oil product (HPLC:99.6%).The Rf=0.58[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=2: 1].
Embodiment 4:
Intermediate
4Preparation
With reference to the method for embodiment 2, with 2,3-dichlorophenyl piperazine replaces the p-methylphenyl piperazine, with the bromoacetyl bromide reaction, gets yellow oil product (HPLC:99.0%).The Rf=0.63[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=2: 1].
Embodiment 5:
Intermediate
5Preparation
With reference to the method for embodiment 1, replace the 4-phenylpiperazine with 3-trifluoromethyl piperazine, with the chloroacetyl chloride reaction, get colorless oil product (HPLC:99.2%).The Rf=0.57[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=2: 1].
Embodiment 6:
Intermediate
6Preparation
Add 2 in the reaction flask that stirring, condenser, thermometer are housed, 3-dichlorophenyl piperazine 23.1g dissolves it with 50mL toluene, is cooled to-10 ℃ under stirring, and adds pyridine 23.7g.Chlorpromazine chloride 12.7g is dissolved in the 20mL toluene, slowly is added dropwise to reaction system, dropwise, continue reaction 3h (the flaggy demonstration reacts completely) down in 10 ℃.With 3 * 80mL water washing reaction solution, divide and get toluene layer, use the anhydrous sodium sulphate thorough drying, to filter, toluene is to the greatest extent steamed in decompression, promptly gets faint yellow oily product 29.6g (HPLC:99.1%).The Rf=0.64[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=2: 1].
Embodiment 7:
Intermediate
7Preparation
With reference to the method for embodiment 6, replace 2 with 2-fluorophenyl piperazine, 3-dichlorophenyl piperazine with the bromopropionyl bromide reaction, gets yellow oil product (HPLC:98.8%).The Rf=0.65[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=2: 1].
Embodiment 8:
(2-(4-phenylpiperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-1) also for 5-
In the reaction flask that stirring, condenser, thermometer are housed, add 2.4g intermediate 1, it is dissolved, stir adding Anhydrous potassium carbonate 4.3g down with the 10mL methylene dichloride.With 1.6g5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridines-2 (4H)-ketone adds reaction system in batches.Add, continue reaction 4h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 15mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets yellow solid product (HPLC:98.4%).The Rf=0.44[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
1H?NMR(DMSO-d6，400MHz)δ：2.042～2.045(m，1H)，2.113～2.116(m，1H)，2.864～2.871(m，4H)，3.386～3.389(m，2H)，3.441～3.444(s，2H)，3.523～3.528(m，4H)，3.875～3.878(m，2H)，4.381～4.383(m，1H)，6.243(s，1H)，6.786～6.788(m，1H)，7.392～7.395(m，2H)，7.552～7.554(m，2H)。MS，m/Z：357.2(M)。
Embodiment 9:
(2-(4-p-methylphenyl piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-2) also for 5-
In the reaction flask that stirring, condenser, thermometer are housed, add the 3.0g intermediate
2, with the 15mL trichloromethane it is dissolved, stir adding triethylamine 3.0g down.With 1.6g5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridines-2 (4H)-ketone adds reaction system in batches.Add, continue reaction 3h (the flaggy demonstration reacts completely) in refluxing down.With 3 * 20mL water washing reaction solution, divide and get the trichloromethane layer, use the anhydrous sodium sulphate thorough drying, to filter, trichloromethane is to the greatest extent steamed in decompression, promptly gets light yellow solid product (HPLC:98.9%).The Rf=0.45[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].MS，m/Z：371.2(M)。
Embodiment 10:
(2-(the adjacent fluorophenyl piperazine of 4--1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-3) also for 5-
With reference to the method for embodiment 8, use intermediate
3Replace intermediate
1, with 5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-reactive ketone also, gets white solid product (HPLC:99.6%).The Rf=0.50[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 11:
(2-(4-(2, the 3-dichlorophenyl) piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-4) also for 5-
With reference to the method for embodiment 9, use intermediate
4Replace intermediate
2, with 5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-reactive ketone also, gets white solid product (HPLC:99.0%).The Rf=0.48[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 12:
(2-(4-(3-trifluoromethyl) piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-5) also for 5-
With reference to the method for embodiment 8, use intermediate
5Replace intermediate
1, with 5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-reactive ketone also, gets light yellow solid product (HPLC:98.3%).The Rf=0.51[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 13:
(3-(4-(2, the 3-dichlorophenyl) piperazine-1-yl)-3-oxopropyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-6) also for 5-
In the reaction flask that stirring, condenser, thermometer are housed, add 3.2g intermediate 6, it is dissolved, stir adding pyridine 2.4g down with 15mL toluene.With 1.6g 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridines-2 (4H)-ketone adds reaction system in batches.Add, continue reaction 2h (the flaggy demonstration reacts completely) down in 90 ℃.With 3 * 20mL water washing reaction solution, divide and get toluene layer, use the anhydrous sodium sulphate thorough drying, to filter, toluene is to the greatest extent steamed in decompression, promptly gets light yellow solid product (HPLC:98.9%).The Rf=0.54[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
1H?NMR(DMSO-d6，400MHz)δ：2.248～2.252(m，1H)，2.255～2.258(m，1H)，2.670～2.673(t，2H)，3.355～3.360(m，2H)，3.467～3.470(s，2H)，3.602～3.606(m，4H)，3.650～3.654(t，2H)，4.065～4.070(m，4H)，4.357～4.360(m，1H)，6.262(s，1H)，6.626～6.628(m，1H)，7.329～7.334(m，2H)。MS，m/Z：439.1(M)。
Embodiment 14:
(3-(4-(2-fluorophenyl) piperazine-1-yl)-3-oxopropyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-7) also for 5-
With reference to the method for embodiment 14, use intermediate
7Replace intermediate
6, with 5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-reactive ketone also, gets light yellow solid product (HPLC:99.2%).The Rf=0.45[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 15:
Compound I-1 one-tenth hydrochloride: get I-1 solid product 2.0g, be dissolved in the 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 ℃, drip 25% hydrochloric acid diethyl ether solution to pH be 2, continue at stir about 1h under the ice-water bath.Filter, get light yellow solid.
Embodiment 16:
Compound I-3 one-tenth taurate: get I-3 solid product 2.0g, be dissolved in the 15mL dehydrated alcohol.Be heated to the back adding that refluxes and wait a mole taurine, continue at the about 2h of stirring reaction down that refluxes.Reaction finishes, and leaves standstill 24h under room temperature.Filter, get white solid.
Embodiment 17:
Compound I-5 one-tenth vitriol: get I-5 solid product 2.5g, be dissolved in the 20mL anhydrous methanol.Ice-water bath is cooled to 5 ℃, drip concentrated sulfuric acid solution to pH be 3, continue at stir about 1h under the ice-water bath.Filter, get light yellow solid.
For the pharmaceutical composition of Thienopyridinone derivatives of the present invention is described more fully, following example of formulations is provided below, described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment 8～17.
Embodiment 18:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Compound I-4 75mg
Pregelatinized Starch 100mg
Poloxamer 4mg
Sodium starch glycolate 10mg
Magnesium Stearate 20mg
10% polyvidone ethanolic soln is an amount of
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieves three times, add an amount of 10% polyvidone ethanol (95%) solution system softwood, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the whole grain of 16 mesh sieves, are packed in the hard gelatin capsule.
Embodiment 19:
Prepare tablet with following compositions:
Consumption/sheet
The hydrochloride 75mg of Compound I-1
Starch 45mg
Microcrystalline Cellulose 40mg
Carboxymethyl starch sodium salt 4.5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Poloxamer 3mg
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 20:
The preparation of injection liquid:
The taurate 45mg of Compound I-3
Propylene glycol 100mg
Polysorbate 80 is an amount of
Distilled water 300mL
Preparation method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and propylene glycol, add medicinal basic adjusting pH value to 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 21:
The preparation of injection lyophilized powder:
Vitriol 50 mg of Compound I-5
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-80%
Preparation method: get activeconstituents and add water for injection, regulate pH value to 4～8 with medicinal basic and make its dissolving.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals, promptly.
Claims (9)
1. the compound and the pharmacy acceptable salt thereof that have formula I structure:
Wherein:
n＝1，2；
R
1, R
2Be hydrogen, C
1-C
3Alkyl, halogen, halogenated methyl.
2. the compound of Formula I described in claim 1, preferred following compound:
n＝1；
R
1, R
2Be hydrogen, methyl, fluorine, chlorine, trifluoromethyl.
3. the compound of Formula I described in claim 2, represent following compound:
(2-(4-phenylpiperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-15-;
(2-(4-p-methylphenyl piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-25-;
(2-(the adjacent fluorophenyl piperazine of 4--1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-35-;
(2-(4-(2, the 3-dichlorophenyl) piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-45-;
(2-(4-(3-trifluoromethyl) piperazine-1-yl)-2-oxoethyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-55-;
(3-(4-(2, the 3-dichlorophenyl) piperazine-1-yl)-3-oxopropyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-65-;
(3-(4-(2-fluorophenyl) piperazine-1-yl)-3-oxopropyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for I-75-.
4. compound as claimed in claim 1, its pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
5. compound of Formula I pharmacy acceptable salt as claimed in claim 4 is preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate.
6. the preparation method of claim 1 Chinese style I compound, it is characterized in that: substituted-piperazinyl compounds and halogen acyl halide are in methylene dichloride, trichloromethane or toluene, in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide ,-30 ℃～35 ℃ reactions make key intermediate.Intermediate again with compound 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-ketone, in methylene dichloride, trichloromethane or toluene, in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide acid binding agent, 0 ℃～90 ℃ reactions make I.
Wherein X is a halogen.
7. the pharmaceutical composition of an anti-malignant tumor, it comprises formula I compound or its salt and one or more pharmaceutical excipients for the treatment of significant quantity.
8. claim 1～5 Chinese style I compound and salt thereof are in the application that is used to prepare medicine for resisting malignant tumors.
9. application as claimed in claim 8 is in the purposes that is used to prepare aspect treatment lung cancer, liver cancer, mammary cancer, the cancer of the stomach medicine.
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| CN103896962A (en) * | 2014-03-20 | 2014-07-02 | 天津药物研究院 | Substituent piperazinyl-containing thienopyridine ester derivatives as well as preparation method and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4681888A (en) * | 1984-11-16 | 1987-07-21 | Societe De Conseils De Recherches Et D'applications Scientifiques | Thienopyridine derivatives and anti-thrombotic compositions containing the same |
| CN101284838A (en) * | 2008-06-06 | 2008-10-15 | 天津药物研究院 | Ethylene imine derivates with thienopyridine, preparation method and applications thereof |
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| US4681888A (en) * | 1984-11-16 | 1987-07-21 | Societe De Conseils De Recherches Et D'applications Scientifiques | Thienopyridine derivatives and anti-thrombotic compositions containing the same |
| CN101284838A (en) * | 2008-06-06 | 2008-10-15 | 天津药物研究院 | Ethylene imine derivates with thienopyridine, preparation method and applications thereof |
Non-Patent Citations (1)
| Title |
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| 《中国药学杂志》 20091130 成碟等 含有取代哌嗪及哌啶结构的噻吩并吡啶类化合物的合成及活性研究 1752-1754 1-9 第44卷, 第22期 2 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896962A (en) * | 2014-03-20 | 2014-07-02 | 天津药物研究院 | Substituent piperazinyl-containing thienopyridine ester derivatives as well as preparation method and use thereof |
| CN103896962B (en) * | 2014-03-20 | 2016-09-14 | 天津药物研究院 | One class thienopyridine esters derivative containing substituted piperazinyl and its production and use |
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