CN102911118B - Benzo-azepine type derivative and preparation method and purpose thereof - Google Patents
Benzo-azepine type derivative and preparation method and purpose thereof Download PDFInfo
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- CN102911118B CN102911118B CN201210445465.9A CN201210445465A CN102911118B CN 102911118 B CN102911118 B CN 102911118B CN 201210445465 A CN201210445465 A CN 201210445465A CN 102911118 B CN102911118 B CN 102911118B
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- FBUIGUJNASSZSW-UHFFFAOYSA-N O=C(CCC1)c2cc(Cl)ccc2N1S(CCN(CCCl)CCCl)(=O)=O Chemical compound O=C(CCC1)c2cc(Cl)ccc2N1S(CCN(CCCl)CCCl)(=O)=O FBUIGUJNASSZSW-UHFFFAOYSA-N 0.000 description 2
- XDQDIIUTNAALRC-UHFFFAOYSA-N CCCN(CCC)CCS(N(CCC1)c2ccc(C(F)(F)F)cc2C1=O)(=O)=O Chemical compound CCCN(CCC)CCS(N(CCC1)c2ccc(C(F)(F)F)cc2C1=O)(=O)=O XDQDIIUTNAALRC-UHFFFAOYSA-N 0.000 description 1
- KBTKWRDBGSDFNA-UHFFFAOYSA-N CCCN(CCC)CCS(N(CCCC(c1c2)=O)c1ccc2Cl)(=O)=O Chemical compound CCCN(CCC)CCS(N(CCCC(c1c2)=O)c1ccc2Cl)(=O)=O KBTKWRDBGSDFNA-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N CCCNCCC Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- MBTYYEYQXKMFRN-UHFFFAOYSA-N Cc(cc1C(CCC2)=O)ccc1N2S(CCN(CCOC)CCOC)(=O)=O Chemical compound Cc(cc1C(CCC2)=O)ccc1N2S(CCN(CCOC)CCOC)(=O)=O MBTYYEYQXKMFRN-UHFFFAOYSA-N 0.000 description 1
- RPFSLOFGIVBYLP-UHFFFAOYSA-N O=C(CCC1)c(cc(C(F)(F)F)cc2)c2N1S(CCCl)=O Chemical compound O=C(CCC1)c(cc(C(F)(F)F)cc2)c2N1S(CCCl)=O RPFSLOFGIVBYLP-UHFFFAOYSA-N 0.000 description 1
- MUSCYPAKTJUJMV-UHFFFAOYSA-N O=C(CCC1)c2cc(Cl)ccc2N1S(CCCl)(=O)=O Chemical compound O=C(CCC1)c2cc(Cl)ccc2N1S(CCCl)(=O)=O MUSCYPAKTJUJMV-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a benzo-azepine type derivative and a preparation method and purposes thereof. The benzo-azepine type derivative has the structure of a general formula I, wherein in the formula I, R1 is any one among hydrogen, halogen, or halogen substituted C1-C4 alkyl, R2 is oxygen or hydroxyl, and R3 is any one among hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen or hydroxyl. According to the invention, compounds or pharmaceutically acceptable salts having the structure of the formula I are novel in chemical constitution, and have an obvious restraining effect, the same as fluorouracil generally used in clinical trials, for tumors, in particular to human lung adenocarcinoma cells, human breast cancer cells and human gastric carcinoma cells.
Description
Technical field
The present invention relates to medical technical field, particularly relate to class benzazepine analog derivative and its production and use.
Background technology
Cancer has become a large chronic disease of serious harm human health at present.Suffering from every year in the world according to statistics cancered people has 9,000,000, and the patient who dies from cancer is 6,000,000, almost just has cancer patients's death p.s..China's cancer year number of the infected, in 1,200,000 left and right, is died from the number of cancer up to more than 900,000, and patient to be treated surpasses 1,500,000, and has the trend rising year by year.Therefore cancer has now become the second largest killer who is only second to cardiovascular disorder.
Treat clinically tumour, generally adopt operation, radiotherapy, the large therapy of chemotherapy three.Though embolic chemotherapy is comparatively quick, curative ratio is very low, and meanwhile, clinical study finds that the cancer therapy drug using at present exists very large deficiency, finds the focus that novel cancer therapy drug has become new drug research.
Summary of the invention
The object of this invention is to provide a class benzazepine analog derivative.
Another object of the present invention is to provide the pharmaceutical salts of a class benzazepine analog derivative.
Another object of the present invention is to provide the preparation method of an a kind of class benzazepine derivative and pharmaceutical salts thereof.
A further object of the present invention is to provide a class and take the pharmaceutical composition that benzazepine derivative and pharmaceutical salts thereof be main active ingredient.
A further object of the invention is to provide a class benzazepine analog derivative and pharmaceutical salts thereof as the application of medicine for resisting malignant tumors, particularly in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
For realizing the technical scheme that object of the present invention adopts, be:
One class benzazepine analog derivative, has the structure of formula I:
In formula: described R
1for: the C that hydrogen, halogen, halogen replace
1-C
4alkyl in any;
Described R
2for: oxygen or hydroxyl;
Described R
3for hydrogen, C
1-C
4alkyl, C
1-C
4any in alkoxyl group, halogen, hydroxyl.
The present invention is following compound preferably:
1,1-(2-(dipropyl amino) ethylsulfonyl)-7-is chloro-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one
2,1-(2-(two (2-chloroethyl) amino) ethylsulfonyl)-7-is chloro-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one:
3,1-(2-(two (2-methoxyethyl) amino) ethylsulfonyl)-7-is chloro-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one:
4,1-(2-(two (2-hydroxyethyl) amino) ethylsulfonyl)-7-is chloro-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one:
5,1-(2-(dipropyl is amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one:
6,1-(2-(two (2-chloroethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one:
7,1-(2-(two (2-methoxyethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one:
8,1-(2-(two (2-hydroxyethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one:
9,1-(2-(dipropyl amino) ethylsulfonyl) 7-is chloro-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol:
10,1-(2-(two (2-chloroethyl) amino) ethylsulfonyl)-7-is chloro-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol:
11,1-(2-(two (2-methoxyethyl) amino) ethylsulfonyl)-7-is chloro-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol:
12,1-(2-(two (2-hydroxyethyl) amino) ethylsulfonyl)-7-is chloro-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol:
13,1-(2-(dipropyl is amino) ethylsulfonyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol:
14,1-(2-(two (2-chloroethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol:
15,1-(2-(two (2-methoxyethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol:
16,1-(2-(two (2-methoxyethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol
The compound of the formula I compound that pharmaceutically receivable salt is described formula I and mineral acid or organic acid salify.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, gluconate, amino acid salts.
The preparation method of the present invention's one class benzazepine analog derivative, comprises the steps:
(1) the benzazepine compounds of the replacement of general formula II reacts and makes intermediate III with 2-chloroethyl SULPHURYL CHLORIDE under alkaline condition;
(2) intermediate III reacts with two (2-replaces ethyl) amine of general formula IV the compound that makes general formula V;
(3) compound of general formula V is dissolved in alcoholic solvent, adds sodium borohydride, and reaction makes compound VI;
Synthetic route is as follows:
In formula: R
1for: the C that hydrogen, halogen, halogen replace
1-C
4alkyl in any;
Described R
2for: oxygen or hydroxyl;
Described R
3for hydrogen, C
1-C
4alkyl, C
1-C
4any in alkoxyl group, halogen, hydroxyl.
The concrete preparation method of the present invention's one class benzazepine analog derivative is: the benzazepine compounds of the replacement of general formula II dissolves, and under the catalysis of acid binding agent, in-30-50 ℃ a reaction, makes intermediate III with 2-chloroethyl SULPHURYL CHLORIDE; Two (2-replaces ethyl) amine of intermediate III and general formula IV react in-10-120 ℃ the compound that makes general formula V in solvent; The compound of general formula V is dissolved in solvent, controls temperature at-10-20 ℃, add excessive sodium borohydride, reaction obtains compound VI.
Wherein, for dissolving the solvent of benzazepine compounds of the replacement of general formula II, be methylene dichloride, trichloromethane, DMF, pyridine, acetonitrile, tetrahydrofuran (THF) or acetone; Described acid binding agent is triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide; Described intermediate III is methylene dichloride, trichloromethane, acetonitrile, acetone, benzene or toluene etc. with the solvent that two (2-replaces ethyl) amine of general formula IV react; For dissolving the solvent of the compound of general formula V, be methyl alcohol, ethanol or Virahol.
The one class benzazepine analog derivative pharmaceutically concrete preparation method of receivable salt is as follows: the compound of formula I is dissolved in solvent, drips salt acid ether to pH=2 under ice-water bath, make hydrochloride; Or the compound of formula I is dissolved in solvent, adding the equimolar taurine of compound with formula I, heated and stirred obtains taurate; The compound of formula I is dissolved in solvent, under ice-water bath, drips the vitriol oil to pH=3, make vitriol.
The antitumor medicine composition of one class benzazepine analog derivative, comprises and treats the claim 1 of significant quantity or 2 compound; Or the pharmacy acceptable salt of claim 3.
The compound compound of formula I of the present invention or pharmacy acceptable salt are in the application aspect antitumor drug.
Particularly in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
The compound that contains formula I of the present invention is effective for treatment human malignancies.The compound that contains formula I of the present invention can be without the direct administration of any preparation, and the compound that contains formula I is preferably used with the form of pharmaceutical preparation, and route of administration can be parenteral route (as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compound that contains formula I of the present invention is prepared as follows: use standard and conventional technology; compound that the present invention contains formula I acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one material in 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, such as 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 etc.
The amount of the active ingredient containing in pharmaceutical composition and unit dosage form (compound that the present invention contains formula I) can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of activeconstituents used or concentration regulate in a wider scope, conventionally, the weight range of activeconstituents is 0.5%～90%(weight of composition), preferred scope is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, chemical structure is novel, and tumour especially human lung adenocarcinoma cell, human breast cancer cell, gastric carcinoma cells are had to obvious restraining effect.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1:
The preparation of intermediate III-1:
In stirring, temperature are housed take into account the reaction flask of condenser, add 7-chloro-3,4-dihydro-1H-benzo [b] azatropylidene-5(2H)-one 3.91g(20mmol), pyridine 50mL, stirring and dissolving, at 0 ℃, drip 2-chloroethyl SULPHURYL CHLORIDE 2.91g(24mmol), keep-10 ℃-5 ℃ to stir 4h, the reaction of TLC detection display finishes (developping agent: ethyl acetate: sherwood oil=1:3).
By in 200ml25 ℃ of cold water of reaction solution impouring, stir, there is solid to separate out.Filter, filter cake washing, dry, obtains brown color solid crude product.By this crude product Virahol recrystallization, obtain pale solid and be intermediate III-1, purity 98.1%(HPLC normalization method), yield 81.0%.ES?I-MS：321.0。
Embodiment 2:
The preparation of intermediate III-2:
In stirring, temperature are housed take into account the reaction flask of condenser, add 7-trifluoromethyl-3,4-dihydro-1H-benzo [b] azatropylidene-5(2H)-one 4.58g(20mmo l), add acetonitrile 50mL, saleratus 5.0g(50mmo l) stir, at 0 ℃, stir, drip 2-chloroethyl SULPHURYL CHLORIDE 2.91g(24mmo l), keep 5 ℃-20 ℃ to stir 3h, the reaction of TLC detection display finishes (developping agent: ethyl acetate: sherwood oil=1:3).
By in 200mL10 ℃ of distilled water of reaction solution impouring, ethyl acetate extraction 3 times, each 50mL, anhydrous sodium sulfate drying, solvent evaporated, it is intermediate III-2 that silica gel column chromatography obtains white solid, purity 99.7%(HPLC normalization method), yield 85.8%.ES?I-MS：355.1。
Embodiment 3:
1-(2-(dipropyl amino) ethylsulfonyl)-7-is chloro-3, the preparation of 4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one and chemical compounds I-1:
Stirring is being housed, temperature is taken into account in the reaction flask of condenser and is added 3.22g(10mmol) intermediate III-1, 2.0g(20mmo l) saleratus, 2.02g(20mmo l) dipropylamine and 50mL acetonitrile, stir, after 80 ℃-90 ℃ reaction 12h, naturally cool to room temperature, elimination insolubles, filtrate is poured in 100mL distilled water, ethyl acetate extraction 3 times, each 50mL, merge organic phase, saturated common salt water washing 3 times for organic phase, each 50mL, anhydrous sodium sulfate drying, solvent is to the greatest extent steamed in decompression, silica gel column chromatography obtains white and is solid chemical compound I-1, purity 99.2% (HPLC normalization method), yield 81.6%, HRMS (m/z) [M+H]
+: 387.1504.
Embodiment 4:
1-(2-(two (2-chloroethyl) amino) ethylsulfonyl)-7-is chloro-3, and 4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one is the preparation of chemical compounds I-2:
In stirring, temperature are housed take into account the reaction flask of condenser, add 3.21g(10mmol) intermediate III-1,2.0g(20mmo l) triethylamine, 2.84g(20mmo l) Dichloroethyl amine and 50mL N, N dimethyl formamide, 110 ℃-120 ℃ reaction 10h, TLC shows the (developping agent: ethyl acetate: sherwood oil=1:3) that reacts completely.
Reaction solution is naturally cooled to after room temperature, pour in 15 ℃ of cold water, stir, have solid to separate out, the solids crude product ethyl alcohol recrystallization filtering out, obtains faint yellow solid and is chemical compounds I-2, purity 99.0% (HPLC normalization method), yield 77.5%, HRMS (m/z) [M+H]
+: 427.0412.
Embodiment 5:
1-(2-(two (2-methoxyethyl) amino) ethylsulfonyl)-7-is chloro-3, and 4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one is the preparation of chemical compounds I-3:
In stirring, temperature are housed take into account the reaction flask of condenser, add 3.21g(10mmol) intermediate III-1,2.0g(20mmo l) triethylamine, 2.66g(20mmo l) two (2-methoxy ethyl) amine and 50mL acetonitrile, 70 ℃-80 ℃ reaction 14h, TLC shows the (developping agent: ethyl acetate: sherwood oil=1:3) that reacts completely.After being naturally cooled to room temperature, pours in 100mL distilled water reaction solution ethyl acetate extraction 3 times, each 50mL into, merge organic phase, saturated common salt water washing 3 times for organic phase, each 50mL, anhydrous sodium sulfate drying, solvent is to the greatest extent steamed in decompression, silica gel column chromatography obtains faint yellow solid and is chemical compounds I-3,171 ℃-172.6 ℃ of fusing points, purity 98.5% (HPLC normalization method), yield 80.2%, HRMS (m/z) [M+H]
+: 419.1402.
Embodiment 6:
1-(2-(two (2-hydroxyethyl) amino) ethylsulfonyl)-7-is chloro-3, and 4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one is the preparation of chemical compounds I-4:
In stirring, temperature are housed take into account the reaction flask of condenser, add 3.21g(10mmol) intermediate III-1,50mL pyridine and 2.10g(20mmo l) 2,2 '-azanyl ethyl alcohol, 115 ℃ of reaction 12h, TLC shows the (developping agent: ethyl acetate: sherwood oil=1:3) that reacts completely, solvent evaporated, silica gel column chromatography obtains weak yellow liquid and is chemical compounds I-4, purity 99.5% (HPLC normalization method), yield 85.2%, HRMS (m/z) [M+H]
+: 391.1089.
Embodiment 7:
1-(2-(dipropyl is amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one is the preparation of chemical compounds I-5:
In stirring, temperature are housed take into account the reaction flask of condenser, add 3.56g(10mmol) intermediate III-2,2.0g(20mmol) saleratus, 2.02g(20mmol) dipropylamine and 50mL N, dinethylformamide, 60 ℃-70 ℃ reaction 12h, TLC shows the (developping agent: ethyl acetate: sherwood oil=1:3) that reacts completely.Reaction solution is naturally cooled to room temperature, elimination insolubles, filtrate is poured in cold water and is stirred, separate out yellow solid, filter, by the thick product ethyl alcohol recrystallization obtaining, obtain white solid and be chemical compounds I-5, purity 99.1% (HPLC normalization method), yield 75.9%, HRMS (m/z) [M+H]
+: 421.1768.
Embodiment 8:
1-(2-(two (2-chloroethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one is the preparation of chemical compounds I-6:
In stirring, temperature are housed take into account the reaction flask of condenser, add 3.56g(10mmol) intermediate III-2,2.76g(20mmol) salt of wormwood, 2.84g(20mmol) Dichloroethyl amine and 50ml trichloromethane, 50 ℃-60 ℃ reaction 15h, TLC shows the (developping agent: ethyl acetate: sherwood oil=1:3) that reacts completely.Remove by filter insolubles, filtrate is used saturated common salt water washing 3 times, each 50mL, anhydrous sodium sulfate drying, solvent is to the greatest extent steamed in decompression, and silica gel column chromatography obtains white solid and is chemical compounds I-6, purity 99.2% (HPLC normalization method), yield 83.7%, HRMS (m/z) [M+H]
+: 461.0675.
Embodiment 9:
1-(2-(two (2-methoxyethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one is the preparation of chemical compounds I-7:
Stirring is being housed, temperature is taken into account in the reaction flask of condenser and is added 3.56g(10mmol) intermediate III-2, 2.02g(20mmo l) triethylamine, 2.66g(20mmo l) two (2-methoxy ethyl) amine and 50mL acetonitrile, 10 ℃-20 ℃ reaction 12h, be cooled to room temperature, reaction solution is poured in distilled water, ethyl acetate extraction 3 times, each 50mL, merge organic phase, saturated common salt water washing 3 times for organic phase, each 50mL, anhydrous sodium sulfate drying, solvent is to the greatest extent steamed in decompression, silica gel column chromatography obtains white solid and is chemical compounds I-7, purity 99.5% (HPLC normalization method), yield 76.1%, HRMS (m/z) [M+H]+: 453.1666.
Embodiment 10:
1-(2-(two (2-hydroxyethyl) amino) ethylsulfonyl)-7-(trifluoromethyl)-3,4-dihydro-1H-benzo [b] azatropylidene-5 (2H)-one is the preparation of chemical compounds I-8:
In stirring, temperature are housed take into account the reaction flask of condenser, add 3.56g(10mmol) intermediate III-2,2.0g(20mmo l) saleratus, 2.10g(20mmo l) 2,2 '-azanyl ethyl alcohol and 50mL trichloromethane, 30 ℃-40 ℃ reaction 12h, be cooled to room temperature, elimination insolubles, filtrate is used saturated common salt water washing 3 times, each 50mL, anhydrous sodium sulfate drying, solvent is to the greatest extent steamed in decompression, and silica gel column chromatography obtains yellow liquid and is chemical compounds I-8, purity 99.0% (HPLC normalization method), yield 78.8%, HRMS (m/z) [M+H]+: 425.1353.
Embodiment 11:
1-(2-(dipropyl amino) ethylsulfonyl) 7-is chloro-2,3,4, and 5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-alcohol is the preparation of chemical compounds I-9:
In stirring, temperature are housed take into account the reaction flask of condenser, add 3.87g(10mmo l) chemical compounds I-1,50mL methyl alcohol, stirring and dissolving, adds 0.74 gram of (20mmol) NaBH
4, 5 ℃-15 ℃ are stirred 1h, and TLC shows the (developping agent: ethyl acetate: sherwood oil=2:1) that reacts completely.
Reaction solution is concentrated, and solid dissolves with 50mL trichloromethane, saturated common salt water washing 3 times, and each 30mL, merges organic layer, anhydrous sodium sulfate drying, standing over night.Filter insolubles, solvent is to the greatest extent steamed in decompression, obtains yellow oil.
To the mixed solvent that adds 36mL ether and methyl alcohol in yellow oil, in the mixed solvent of ether and methyl alcohol, the volume ratio of ether and methyl alcohol is 5:1, stirring at room 1h, there is solid to separate out, filter, obtain faint yellow solid and be chemical compounds I-9, purity 99.0% (HPLC normalization method), yield 93.0%, HRMS (m/z) [M+H]
+: 389.1660.
With reference to the method for embodiment 11, under-10 ℃ of-20 ℃ of conditions, can synthetic compound I-10～I-16.Specifically as shown in table 1.
Table 1
I-14,179.1 ℃-180.5 ℃ of fusing points; I-15,183.3 ℃-184.7 ℃ of fusing points.
Embodiment 12
Chemical compounds I-1 one-tenth hydrochloride: get chemical compounds I-1 white solid product 2.0g, be dissolved in 8mL anhydrous diethyl ether.Ice-water bath is cooled to 5 ℃, and hydrochloric acid diethyl ether solution to the pH value of dropping 11.1% is 2, continues at stir about 1h under ice-water bath.Filter, vacuum-drying, obtains the hydrochloride that white solid powder is chemical compounds I-1.
Adopt the method for embodiment 12, adopt chemical compounds I-2～I-16 can obtain the hydrochloride of chemical compounds I-2～I-16 as raw material.
Embodiment 13
Chemical compounds I-2 one-tenth taurate: get chemical compounds I-2 faint yellow solid product 2.0g, be dissolved in 10mL anhydrous methanol.After being heated to reflux, add and the equimolar taurine in chemical compounds I-2, continue at the lower about 1.5h of stirring reaction that refluxes.React complete, standing 24h under room temperature.Separate out light yellow crystallization and be the taurate of chemical compounds I-2, filter vacuum-drying.
Adopt the method for embodiment 13, adopt chemical compounds I-1, chemical compounds I-3～I-16 can obtain the taurate of chemical compounds I-1 and compound and I-3～I-16 as raw material.
Embodiment 14
Chemical compounds I-1 is dissolved in ether, under ice-water bath, drips the vitriol oil to pH value=3, make the vitriol of compound and I-1.
Adopt the method for embodiment 14, adopt chemical compounds I-2～I-16 can obtain the vitriol of chemical compounds I-2～I-16 as raw material.
The pharmaceutical composition of benzazepine compounds of the present invention can be used any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 1-14.
Embodiment 15:
By following compositions, prepare hard gelatin capsule:
Preparation technology: chemical compounds I-3, dry starch, Magnesium Stearate is dry in advance, cross 100 mesh sieves standby.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
Embodiment 16:
By following compositions, prepare tablet:
Preparation technology: chemical compounds I-4, starch, carboxymethyl starch sodium salt, Magnesium Stearate, talcum powder is dry in advance, cross 100 mesh sieves standby.First the supplementary product starch of recipe quantity, carboxymethyl starch sodium salt, Magnesium Stearate, talcum powder are fully mixed.Chemical compounds I-4 are added in the above-mentioned auxiliary material mixing to increase progressively dilution method, and each added-time fully mixes 2-3 time, guarantees that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dry particle is crossed the whole grain of 16 mesh sieves, mix compressing tablet on tabletting machine.
Embodiment 17:
The preparation of injection liquid:
Preparation method: polysorbate and propylene glycol are dissolved in distilled water.The hydrochloride of getting chemical compounds I-1 joins in the distilled water that dissolves polysorbate and propylene glycol as activeconstituents, adds sodium hydroxide to regulate pH value to 7, and the hydrochloride of chemical compounds I-1 dissolves.The gac that adds the hydrochloride 5% of chemical compounds I-1, whip attachment 30mi n, carbon removal, smart filter, embedding, sterilizing.
Embodiment 18:
The preparation of injection lyophilized powder:
The taurate 100mg of chemical compounds I-2
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get the taurate of chemical compounds I-2 as activeconstituents, add 5 times of amounts (quality) water for injection, regulate pH value to make its dissolving to 6-7 with sodium hydroxide.Add N.F,USP MANNITOL again, by the requirement of injection, carry out autoclaving, add the gac of the taurate 5% of chemical compounds I-2, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, and sealing, obtains.
External antitumor action:
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of the compounds of this invention to the human tumor cells of vitro culture.
(2) experiment material:
Laboratory sample: chemical compounds I-1-I-16 of preparing in the above embodiment of the present invention, during experiment, sample is with DMSO hydrotropy, 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 Jin Yao amino acid company limited.
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO
2incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
Cell strain: SPCA1 human lung adenocarcinoma cell line, MCF7 human breast cancer cell, SGC-7901 gastric carcinoma cells, all purchased from Shanghai cell research institute of the Chinese Academy of Sciences.
(3) experimental procedure:
Cell cultures: by SPCA1 human lung adenocarcinoma cell line, MCF7 human breast cancer cell, SGC-7901 gastric carcinoma cells, be seeded in respectively containing 10% calf serum, in the DMEM nutrient solution of 100I U/ml penicillin G sodium salt and 100 μ g/ml Vetstreps, be placed in 37 ℃, 100% relative humidity, containing 5%CO
2incubator in, go down to posterity standby after 3 times.
Mtt assay is measured: above-mentioned three kinds of tumour cells in the vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest) respectively, be suspended in containing in the DMEM nutrient solution of 10% calf serum, with glass dropper, blow and beat into gently single cell suspension, under microscope, use blood cell counts plate numeration viable cell.The 96 every hole of well culture plate inoculating cell suspension 90 μ L(cell concns are adjusted into 6～10 * 10
4individual/ml), at 37 ℃, 100% relative humidity, containing 5%CO
2, 95% air incubator cultivate after 24h, every hole adds 10 μ L liquids (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, then every hole adds the MTT solution 10 μ L of 5mg/ml, continues to cultivate after 4h, carefully suck supernatant liquor (suspension cell, need first centrifugal, then suck supernatant).Every hole adds 100 μ L DMSO, puts micro oscillator concussion 5min so that crystallization is dissolved completely, and the mono-wavelength colorimetric of microplate reader 492nm, measures OD value.The following method of usining is calculated inhibitory rate of cell growth as evaluation index.
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, with straight-line regression method, calculate IC
50value.
(4) experimental result is as shown in table 2:
Table 2: the IC to the tumour cell of vitro culture
50(μ g/ml)
| Group | SPCA1 cell | MCF7 cell | SGC-7901 cell |
| Ⅰ-1 | 12,53 | 10.36 | 10.12 |
| Ⅰ-2 | 14.70 | 13.00 | 11.83 |
| Ⅰ-3 | 10.89 | 9.54 | 10.27 |
| Ⅰ-4 | 16.44 | 11.97 | 13.01 |
| Ⅰ-5 | 15.37 | 12.33 | 13.21 |
| Ⅰ-6 | 13.55 | 10.64 | 11.59 |
| Ⅰ-7 | 13.52 | 9.78 | 11.52 |
| Ⅰ-8 | 14.36 | 12.13 | 12.67 |
| Ⅰ-9 | 16.63 | 11.67 | 11.79 |
| Ⅰ-10 | 13.96 | 11.06 | 10.51 |
| Ⅰ-11 | 11.54 | 10.16 | 9.78 |
| Ⅰ-12 | 13.91 | 11.78 | 10.15 |
| Ⅰ-13 | 12.44 | 10.44 | 13.91 |
| Ⅰ-14 | 10.58 | 9.01 | 10.85 |
| Ⅰ-15 | 9.73 | 9.11 | 12.68 |
| Ⅰ-16 | 14.97 | 12.35 | 11.70 |
| Fluracil | 16.49 | 12.82 | 13.16 |
(5) conclusion:
According to above-mentioned in vitro tests result, we can find out that the compound with formula I structure has more intense restraining effect to above-mentioned 3 kinds of human tumor cells, and restraining effect is suitable with the clinical Fluracil generally using.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a class benzazepine analog derivative or its pharmacy acceptable salt, is characterized in that, this benzazepine analog derivative has the structure of general formula I:
In formula: described R
1for: the C that hydrogen, halogen, halogen replace
1-C
4alkyl in any;
Described R
2for: oxygen or hydroxyl;
Described R
3for hydrogen, C
1-C
4alkyl, C
1-C
4any in alkoxyl group, halogen, hydroxyl.
2. a class benzazepine analog derivative according to claim 1, is characterized in that, comprises following compound:
3. an a class benzazepine analog derivative claimed in claim 1 receivable salt pharmaceutically, is characterized in that the compound of described general formula I and mineral acid or organic acid salify.
4. a preparation method for a class benzazepine analog derivative claimed in claim 1, is characterized in that, comprises the steps:
(1) the benzazepine compounds of the replacement of general formula I I reacts and makes intermediate III under alkaline condition with 2-chloroethyl SULPHURYL CHLORIDE;
(2) intermediate III reacts with two (2-replaces ethyl) amine of general formula I V the compound that makes general formula V;
(3) compound of general formula V is dissolved in alcoholic solvent, adds sodium borohydride, and reaction makes compound VI; That is:
In formula: R
1for: the C that hydrogen, halogen, halogen replace
1-C
4alkyl in any;
Described R
3for hydrogen, C
1-C
4alkyl, C
1-C
4any in alkoxyl group, halogen, hydroxyl.
5. the preparation method of a class benzazepine analog derivative according to claim 4, it is characterized in that, the benzazepine compounds of the replacement of general formula I I dissolves, and under the catalysis of acid binding agent, in-30-50 ℃ a reaction, makes intermediate III with 2-chloroethyl SULPHURYL CHLORIDE; Two (2-replaces ethyl) amine of intermediate III and general formula I V react in-10-120 ℃ the compound that makes general formula V in solvent; The compound of general formula V is dissolved in solvent, controls temperature at-10-20 ℃, add excessive sodium borohydride, reaction obtains compound VI.
6. the preparation method of a class benzazepine analog derivative according to claim 5, it is characterized in that, for dissolving the solvent of benzazepine compounds of the replacement of general formula I I, be methylene dichloride, trichloromethane, DMF, pyridine, acetonitrile, tetrahydrofuran (THF) or acetone; Described acid binding agent is triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide; Described intermediate III is methylene dichloride, trichloromethane, acetonitrile, acetone, benzene or toluene with the solvent that two (2-replaces ethyl) amine of general formula I V react; For dissolving the solvent of the compound of general formula V, be methyl alcohol, ethanol or Virahol.
7. a class benzazepine analog derivative claimed in claim 3 preparation method of receivable salt pharmaceutically, it is characterized in that, comprise the steps: the compound of general formula I to be dissolved in solvent, under ice-water bath, drip salt acid ether to pH=2, make hydrochloride; Or the compound of general formula I is dissolved in solvent, adding the equimolar taurine of compound with general formula I, heated and stirred obtains taurate; The compound of general formula I is dissolved in solvent, under ice-water bath, drips the vitriol oil to pH=3, make vitriol.
8. an antitumor medicine composition that contains benzazepine analog derivative described in claim 1 or 2 or pharmacy acceptable salt claimed in claim 3, comprises and treats the claim 1 of significant quantity or 2 compound; Or the pharmacy acceptable salt of claim 3.
9. the compound described in claim 1 or 2 or pharmacy acceptable salt claimed in claim 3 are in the application aspect antitumor drug.
10. application according to claim 9, in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
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| CN101035765A (en) * | 2004-07-13 | 2007-09-12 | 弗·哈夫曼-拉罗切有限公司 | Sulfonamide derivatives |
| CN101065361A (en) * | 2004-11-29 | 2007-10-31 | 艾文蒂斯药品公司 | Bengamides with a substituted caprolactame cycle, method forthe preparation thereof, compositions containing them and use thereof |
| CN101622232A (en) * | 2007-02-02 | 2010-01-06 | 弗·哈夫曼-拉罗切有限公司 | 6-oxo-6, 7-dihydro-5H-dibenzo [B, D] aza-7-yl derivative |
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| CN101035765A (en) * | 2004-07-13 | 2007-09-12 | 弗·哈夫曼-拉罗切有限公司 | Sulfonamide derivatives |
| CN101065361A (en) * | 2004-11-29 | 2007-10-31 | 艾文蒂斯药品公司 | Bengamides with a substituted caprolactame cycle, method forthe preparation thereof, compositions containing them and use thereof |
| CN101622232A (en) * | 2007-02-02 | 2010-01-06 | 弗·哈夫曼-拉罗切有限公司 | 6-oxo-6, 7-dihydro-5H-dibenzo [B, D] aza-7-yl derivative |
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