CN101863898B - Thieno pyridinone derivative containing piperazidine and preparation method and applications thereof - Google Patents
Thieno pyridinone derivative containing piperazidine and preparation method and applications thereof Download PDFInfo
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- CN101863898B CN101863898B CN2010101831606A CN201010183160A CN101863898B CN 101863898 B CN101863898 B CN 101863898B CN 2010101831606 A CN2010101831606 A CN 2010101831606A CN 201010183160 A CN201010183160 A CN 201010183160A CN 101863898 B CN101863898 B CN 101863898B
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Abstract
The invention belongs to the technical field of antineoplastic medicines and provides thieno pyridinone derivative with the structure of the general formula I and salt thereof which are acceptable in pharmacy, wherein n, R1 and R2 are defined in the specification. The invention also relates to a preparation method of the compound, and discloses pharmaceutical composites using the compound or the salt thereof which are acceptable in pharmacy as active ingredient and the applications of the pharmaceutical composites used as the antineoplastic 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
Tumour is the common disease that threatens the human life, and according to statistics, annual global tumor mortality sum reaches 7,000,000 people, and China dies from tumour person more than 100 ten thousand people every year, and increases gradually, has become first cause of the death of urban population.Traditional chemotherapeutics result of treatment clinically is obvious, and shortcoming is: specificity is low, poor selectivity, cause obvious toxic and side effects, be easy to generate serious tumor multi-medicine drug-resistant phenomenon, limited Clinical Application, seek safety and effective antitumour medicine is pursuing one's goal of the world of medicine always.
Summary of the invention
One object of the present invention is, discloses thienopyridine ketones derivant and pharmaceutical salts thereof that a class contains piperazine.
Another object of the present invention is, disclosing the Thienopyridinone derivatives and the pharmaceutical salts thereof that contain piperazine with a class is the pharmaceutical composition of main active ingredient.
A further object of the present invention is, discloses a class and has contained the Thienopyridinone derivatives of piperazine and the preparation method of pharmaceutical salts thereof.
A further object of the invention is, Thienopyridinone derivatives and pharmaceutical salts thereof that one class contains piperazine are disclosed, as the application of medicine for resisting malignant tumors, particularly in the purposes that is used to prepare aspect treatment liver cancer, leukemia, colorectal carcinoma, the oral carcinoma 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) ethanoyl)-(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) ethanoyl)-(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) ethanoyl)-(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) ethanoyl)-(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) ethanoyl)-(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) propionyl)-(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) propionyl)-(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.
5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-ketone and halogen acyl halide, in methylene dichloride, trichloromethane or toluene equal solvent, 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 piperazine compounds 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 Compound 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 method 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, detection contains the cell proliferation toxicity of the thienopyridine ketones derivant of piperazine to the human tumor cells of vitro culture.
(2) experiment material:
Laboratory sample: the thienopyridine ketones derivant that contains piperazine 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: liver cancer SMMC-7721 cell, promyelocytic leukemia HL-60 cell, colorectal carcinoma SW-480 cell, oral carcinoma KB 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 100 μ L DMSO, 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 general formula (I) structure as can be seen has stronger restraining effect to above-mentioned 4 kinds of human tumor cells, especially more outstanding to the effect of colorectal carcinoma SW-480 cell inhibiting, I-3 is more outstanding to the restraining effect of 4 kinds of tumour cells.
Intravital antitumor action
(1) experiment material:
Sample: I-3 is provided by contriver's self-control.
Cell strain: liver cancer H22 cell, purchase Shanghai cell research institute of the white 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-3 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-3 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
Add 5,6,7 in the reaction flask that stirring, condenser, thermometer are housed, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone 15.5g also, with the 100mL methylene dichloride it is dissolved, and is cooled to-30 ℃ under stirring, and adds salt of wormwood 41.5g.Chloroacetyl chloride 11.3g is dissolved in the 50mL methylene dichloride, slowly is added dropwise to reaction system, dropwise, continue reaction 1.5h (the flaggy demonstration reacts completely) down in-10 ℃.With 3 * 200mL 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 light yellow oily product 20.3g (HPLC:99.6%).The Rf=0.35[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].
1H?NMR(CDCl
3，400MHz)δ：2.693～2.699(m，2H)，2.905～2.911(m，2H)，3.798～3.804(s，2H)，4.258～4.261(s，2H)，4.365～4.371(m，1H)，6.245(s，1H)。
Embodiment 2:
Intermediate
2Preparation
Add 5,6,7 in the reaction flask that stirring, condenser, thermometer are housed, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone 15.5g also, with the 100mL trichloromethane it is dissolved, and is cooled to-20 ℃ under stirring, and adds triethylamine 30.6g.Bromoacetyl bromide 20.2g is dissolved in the 50mL trichloromethane, slowly is added dropwise to reaction system, dropwise, continue reaction 2h (the flaggy demonstration reacts completely) down in-10 ℃.With 3 * 100mL 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 yellow oil product 22.4g (HPLC:99.0%).The Rf=0.32[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].
Embodiment 3:
Intermediate
3Preparation
Add 5,6,7 in the reaction flask that stirring, condenser, thermometer are housed, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone 15.5g also, with 150mL toluene it is dissolved, and is cooled to-25 ℃ under stirring, and adds potassium hydroxide 16.8g.Chlorpromazine chloride 12.7g is dissolved in the 50mL toluene, slowly is added dropwise to reaction system, dropwise, continue reaction 3h (the flaggy demonstration reacts completely) down in-5 ℃.With 3 * 150mL 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 20.7g (HPLC:99.4%).The Rf=0.28[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].
Embodiment 4:
Intermediate
4Preparation
Add 5,6,7 in the reaction flask that stirring, condenser, thermometer are housed, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone 15.5g also, with the 100mL methylene dichloride it is dissolved, and is cooled to-15 ℃ under stirring, and adds yellow soda ash 31.8g.Bromopropionyl bromide 21.6g is dissolved in the 50mL methylene dichloride, slowly is added dropwise to reaction system, dropwise, continue reaction 2.5h (the flaggy demonstration reacts completely) down in 0 ℃.With 3 * 150mL 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 oil product 23.5g (HPLC:98.9%).The Rf=0.30[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].
Embodiment 5:
(2-(4-phenylpiperazine-1-yl) ethanoyl)-(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 2.3g intermediate 1, it is dissolved, stir adding Anhydrous potassium carbonate 4.1g down with the 10mL methylene dichloride.The 1.62g methylpiperazine is added reaction system in batches.Add, continue reaction 5h (the flaggy demonstration reacts completely) down in 35 ℃.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 light yellow solid product (HPLC:99.2%).The Rf=0.53[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
1H?NMR(DMSO-d6，400MHz)δ：2.285～2.289(m，1H)，2.291～2.295(m，1H)，2.864～2.871(m，4H)，3.421～3.426(m，2H)，3.543～3.545(s，2H)，3.646～3.651(m，4H)，4.025～4.028(m，2H)，4.386～4.390(m，1H)，6.247(s，1H)，6.799～6.802(m，1H)，7.658～7.662(m，2H)，7.865～7.869(m，2H)。MS，m/Z：357.2(M)。
Embodiment 6:
(2-(4-p-methylphenyl piperazine-1-yl) ethanoyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-2) also for 5-
With reference to the method for embodiment 5, replace phenylpiperazine with the p-methylphenyl piperazine, with intermediate 1 reaction, get white solid product (HPLC:99.1%).The Rf=0.49[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 7:
(2-(the adjacent fluorophenyl piperazine of 4--1-yl) ethanoyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-3) also for 5-
In the reaction flask that stirring, condenser, thermometer are housed, add 2.8g intermediate 2, it is dissolved, stir adding triethylamine 3.0g down with the 15mL trichloromethane.The adjacent fluorophenyl piperazine of 1.8g is added 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 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:99.5%).The Rf=0.43[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 8:
(2-(4-(2, the 3-dichlorophenyl) piperazine-1-yl) ethanoyl)-(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 7, with 2,3-dichlorophenyl piperazine replaces adjacent fluorophenyl piperazine, with intermediate 2 reactions, gets white solid product (HPLC:99.7%).The Rf=0.47[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 9:
(2-(4-(3-trifluoromethyl) piperazine-1-yl) ethanoyl)-(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 7, replace adjacent fluorophenyl piperazine with the m-trifluoromethyl phenylpiperazine, with intermediate 2 reactions, get faint yellow solid product (HPLC:98.1%).The Rf=0.50[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 10:
(3-(4-(2, the 3-dichlorophenyl) piperazine-1-yl) propionyl)-(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 2.5g intermediate 3, it is dissolved, stir adding sodium hydroxide 1.2g down with 20mL toluene.With 2.3g2,3-dichlorophenyl piperazine adds reaction system in batches.Add, continue reaction 1.5h (the flaggy demonstration reacts completely) down in 90 ℃.With 3 * 15mL 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 white solid product (HPLC:98.6%).The Rf=0.45[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
1H?NMR(DMSO-d6，400MHz)δ：2.246～2.250(m，1H)，2.254～2.258(m，1H)，2.668～2.671(t，2H)，3.356～3.361(m，2H)，3.468～3.470(s，2H)，3.594～3.598(m，4H)，3.652～3.655(t，2H)，4.064～4.069(m，4H)，4.355～4.358(m，1H)，6.261(s，1H)，6.625～6.627(m，1H)，7.327～7.331(m，2H)。MS，m/Z：439.1(M)。
Embodiment 11:
(3-(4-(2-fluorophenyl) piperazine-1-yl) propionyl)-(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 10, replace 2 with 2-fluorophenyl piperazine, 3-dichlorophenyl piperazine with intermediate 4 reactions, gets white solid product (HPLC:98.8%).The Rf=0.55[single-point, developping agent: v (methylene dichloride): v (methyl alcohol)=1: 1].
Embodiment 12:
Compound I-2 one-tenth hydrochloride: get I-2 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 white solid.
Embodiment 13:
Compound I-4 one-tenth taurate: get I-4 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 4h of stirring reaction down that refluxes.Reaction finishes, and leaves standstill 24h under room temperature.Filter, get white solid.
Embodiment 14:
Compound I-6 one-tenth vitriol: get I-6 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 that contains the thienopyridine ketones derivant of piperazine 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 5～14.
Embodiment 15:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Compound I-3 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 16:
Prepare tablet with following compositions:
Consumption/sheet
The taurate 75mg of Compound I-4
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 whole grain of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 17:
The preparation of injection liquid:
The hydrochloride 45mg of Compound I-2
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 18:
The preparation of injection lyophilized powder:
The vitriol 50mg of Compound I-6
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. compound described in claim 1 and pharmacy acceptable salt thereof, wherein:
n＝1；
R
1, R
2Be hydrogen, methyl, fluorine, chlorine, trifluoromethyl.
3. compound described in claim 1 and pharmacy acceptable salt thereof, for:
(2-(4-phenylpiperazine-1-yl) ethanoyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for 5-;
(2-(4-p-methylphenyl piperazine-1-yl) ethanoyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for 5-;
(2-(the adjacent fluorophenyl piperazine of 4--1-yl) ethanoyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for 5-;
(2-(4-(2, the 3-dichlorophenyl) piperazine-1-yl) ethanoyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for 5-;
(2-(4-(3-trifluoromethyl) piperazine-1-yl) ethanoyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for 5-;
(3-(4-(2, the 3-dichlorophenyl) piperazine-1-yl) propionyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for 5-;
(3-(4-(2-fluorophenyl) piperazine-1-yl) propionyl)-(5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also for 5-.
4. compound as claimed in claim 1 and pharmacy acceptable salt thereof, its pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
5. compound as claimed in claim 4 and pharmacy acceptable salt thereof, its pharmacy acceptable 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.
6. the preparation method of claim 1 Chinese style I compound, it is characterized in that: 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-ketone and halogen acyl halide, at methylene dichloride, in trichloromethane or the toluene, at triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, the sodium hydroxide acid binding agent exists down,-30 ℃～35 ℃ reactions make key intermediate, intermediate again with piperazine compounds at methylene dichloride, in trichloromethane or the toluene, at triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, potassium hydroxide, the sodium hydroxide acid binding agent exists down, 0 ℃～90 ℃ reactions make Compound I
Wherein X is a halogen, n, R
1, R
2According to claim 1.
7. the pharmaceutical composition of an anti-malignant tumor, it comprises the formula I compound or its salt described in the claim 1 for the treatment of significant quantity and one or more pharmaceutical excipients.
Claim 1～5 in each formula I compound and salt 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 liver cancer, leukemia, colorectal carcinoma, the oral carcinoma medicine.
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