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CN103864765A - Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative - Google Patents

Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative Download PDF

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Publication number
CN103864765A
CN103864765A CN201410078487.5A CN201410078487A CN103864765A CN 103864765 A CN103864765 A CN 103864765A CN 201410078487 A CN201410078487 A CN 201410078487A CN 103864765 A CN103864765 A CN 103864765A
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compound
acceptable salt
formula
pharmacy acceptable
salt
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CN103864765B (en
Inventor
刘登科
祁浩飞
刘颖
穆帅
田军
张力婉
王景阳
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Tianjin Institute of Pharmaceutical Research Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a benzoazepine compound containing five-membered heterocycle with a structure shown in a formula I as well as a pharmaceutically acceptable salt of the derivative. In the formula I, n is equal to 1, 2, 3 or 4; X is N, O or S; R1 and R2 are simultaneously or separately hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tertiary butyl, trifluoromethyl, methylalkoxyl, ethylalkoxyl, phenyl, fluorine, chlorine or bromine substituted phenyl, alkoxylphenyl, ester group, formyl, carboxyl and cyano. The invention also discloses a preparation method of the compound and discloses a medicinal composition with the compound or the pharmaceutically acceptable salt thereof as an active ingredient and application of the compound or the pharmaceutically acceptable salt thereof as anti-tumor medicaments, particularly application in preparation of medicaments for treating breast cancer, lung cancer and gastric cancer.

Description

The benzazepine analog derivative, the Preparation Method And The Use that contain five-membered ring
Technical field
The invention belongs to medical technical field, or rather, relate to a class and there is compound of antitumor action 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 exceedes 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.There is significantly damage and the toxic side effect to normal body, for example mutagenesis and genetoxic in the many cancer therapy drugs of clinical discovery simultaneously.Therefore, find effectively and the cancer therapy drug with less body injury and toxic side effect has become the focus of new drug research.
Summary of the invention
One object of the present invention is, discloses its pharmaceutical salts of benzazepine compounds that contains five-membered ring of a class novel texture.
Another object of the present invention is, discloses benzazepine compounds that a class contains five-membered ring and the preparation method of pharmaceutical salts thereof.
A further object of the present invention is, the pharmaceutical composition that the benzazepine compounds that openly contains five-membered ring take a class and pharmaceutical salts thereof are main active ingredient.
A further object of the invention is, discloses the application as medicine for resisting malignant tumors of benzazepine compounds that a class contains five-membered ring and pharmaceutical salts thereof, particularly in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
Now, in conjunction with the object of the invention, content of the present invention is described in detail.
The present invention is specifically related to compound and the pharmacy acceptable salt thereof of formula I structure:
Figure BDA0000473202430000011
Wherein:
N=1,2,3 or 4;
X is N, O or S;
R 1, R 2be at the same time or separately: hydrogen, halogen, C 1-C 4direct-connected or branched-chain alkyl, halogenated alkane, alkoxyl group, phenyl, halogenophenyl, the phenyl that alkoxyl group replaces, ester group, aldehyde radical, carboxyl, cyano group.
Preferably following compound and pharmacy acceptable salt thereof:
Wherein:
N=1,2,3 or 4;
X is N, O or S;
R 1, R 2be at the same time or separately: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, trifluoromethyl, methyl alkoxy, ethyl alkoxyl group, phenyl, the phenyl being replaced by fluorine, chlorine, bromine, alkoxyl phenyl, ester group, aldehyde radical, carboxyl, cyano group.
More preferably its pharmacy acceptable salt of following compound:
I-1.3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino)-1H-pyrroles-2-carboxylic acid, ethyl ester
I-2.2-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino)-1H-pyrroles-3-formonitrile HCN
I-3.1-(3-(4-fluoro-1H-pyrroles-3-base amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amino
I-4.3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino) furans-2-formaldehyde
I-5.1-(3-(furans-3-base amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine
I-6.3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino)-5-benzofurane-2-formonitrile HCN
I-7.1-(3-(2,4-thioxene-3-base amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine
I-8. methyl 3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino) thiophene-2-carboxylic acid methyl esters
I-9.N, N-dimethyl-1-(2-(thiene-3-yl-amino) ethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine
Formula I compound pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.Wherein 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 syntheti c route of formula I compound is as follows:
Figure BDA0000473202430000031
N, X, R 1, R 2definition as previously mentioned.
N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (II), in methyl alcohol, ethanol, methylene dichloride, trichloromethane, ethyl acetate, DMF, acetonitrile or acetone equal solvent, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide or potassium tert.-butoxide, 0～130 ℃ of reaction makes intermediate III with the aliphatic alcohols compound of bromo.Intermediate III and Tosyl chloride are in methylene dichloride, trichloromethane, ethyl acetate, acetonitrile, pyridine, acetone, benzene or toluene, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide or potassium tert.-butoxide ,-20～30 ℃ of reactions generate intermediate IV.Intermediate IV is at methyl alcohol, ethanol, methylene dichloride, trichloromethane, acetone, N, in dinethylformamide, ethyl acetate, acetonitrile, pyridine, benzene or toluene equal solvent, under the catalysis of the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, 0～130 ℃ of reaction makes end product chemical compounds I with the five-membered heterocycles (V) replacing.
Reaction make various compounds or products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, DMSO or ether drip mineral acid, organic acid is made pharmacy acceptable salt.
Specifically various compounds are dissolved in to the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drip salt acid ether to pH=2, make hydrochloride; Or various compounds are dissolved in to the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, and mole taurine such as adding, heated and stirred obtains its taurate; Or various compounds are dissolved in to the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drip the vitriol oil to pH=3, make vitriol.
This compounds is effective for treatment human malignancies.Although compound of the present invention can be without the direct administration of any preparation, described various compounds preferably use 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 compounds of this invention is prepared as follows: use standard and conventional technology; the compounds of this invention 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, 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 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 (the compounds of this invention) containing in pharmaceutical composition and unit dosage form can specifically be applied according to the situation of patient's the state of an illness, diagnosis, the amount of compound used or concentration regulate in a wider scope, conventionally 0.5%～90%(weight that, the weight range of active compound is composition).Another preferred scope is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, has obvious restraining effect to tumour in vitro.
Embodiment
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that 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), high resolution mass spectrum (HRMS) etc. is further confirmed its structure.
reference example 1:
Intermediate III-1
Figure BDA0000473202430000041
Stirring is being housed, condenser, in the reaction flask of thermometer, add 1.9g (0.010mol) N, N-dimethyl-2, 3, 4, 5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (II) and 20ml dehydrated alcohol, under stirring, add 2.5g (0.020mol) ethylene bromohyrin, 2.5.g(0.025mol) triethylamine, back flow reaction 15h, TLC demonstration reacts completely, steaming desolventizes, residue dissolves with 50ml methylene dichloride, saturated common salt water washing (10ml × 3), steaming desolventizes, sherwood oil and ethyl acetate mixed solution recrystallization for residue, obtain faint yellow solid, yield 81.4%, purity 95.5%(HPLC normalization method), ESI-MS (m/z): 234.2.
reference example 2:
Intermediate III-2
Stirring is being housed, condenser, in the reaction flask of thermometer, add 1.9g (0.010mol) N, N-dimethyl-2, 3, 4, 5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (II), 2.0g(0.020mol) saleratus and 30ml acetonitrile, stir the lower 2.78g (0.02mo1) of dropping 3-bromopropyl alcohol, back flow reaction 12h, TLC demonstration reacts completely, filter insolubles, filtrate is poured in distilled water, ethyl acetate (15ml × 3) extraction, merge organic layer, anhydrous sodium sulfate drying, steaming desolventizes, residue silica gel column chromatography separates, obtain yellow solid, yield 82.5%, purity 97.5%(HPLC normalization method), ESI-MS (m/z): 248.2.
reference example 3:
Intermediate IV-1
Figure BDA0000473202430000052
Being equipped with in the reaction flask of stirring, condenser, thermometer, add 2.34g(0.01mol) intermediate III-1,50ml pyridine stirs and makes its dissolving, solution is controlled at below-5 ℃, add 2.28g(0.012mol in batches) Tosyl chloride, 0 ℃ of reaction 10h, TLC demonstration reacts completely, and reaction solution is poured in cold water, there is solid to separate out, filter, filter cake after saturated aqueous common salt (50ml × 3) washing, vacuum-drying, obtain white solid, yield 93.7%, purity 97.6%(HPLC normalization method), ESI-MS (m/z): 388.2.
reference example 4:
Intermediate IV-2
Figure BDA0000473202430000053
Stirring is being housed, condenser, in the reaction flask of thermometer, add 2.48g(0.01mol) intermediate III-2, 50ml N, dinethylformamide and 2.52g(0.025mol) triethylamine, stirring makes its dissolving, solution is controlled at below-5 ℃, add 2.28g(0.012mol in batches) Tosyl chloride, 0 ℃ of reaction 10h, TLC demonstration reacts completely, reaction solution is poured in cold water, there is solid to separate out, filter, filter cake is after saturated aqueous common salt (50ml × 3) washing, vacuum-drying, obtain faint yellow solid, yield 92.3%, purity 97.6%(HPLC normalization method), ESI-MS (m/z): 402.2.
embodiment 1:
3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino)-1H-pyrroles-2-carboxylic acid, ethyl ester (chemical compounds I-1)
Figure BDA0000473202430000061
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 3.88g(0.01mol) intermediate IV-1,0.8g(0.02mol) sodium hydroxide, 30ml ethanol and 1.54g(0.01mol) 3-amino-1H-pyrroles-2-carboxylic acid, ethyl ester, back flow reaction 6h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtain chemical compounds I-1: white solid, yield 78%, purity 99.4%(HPLC normalization method), HRMS (m/z) [M+H] +: 371.2442.
embodiment 2:
2-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino)-1H-pyrroles-3-formonitrile HCN (chemical compounds I-2)
Figure BDA0000473202430000062
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 3.88g(0.01mol) intermediate IV-1,2.76g(0.02mol) salt of wormwood, 30ml tetrahydrofuran (THF) and 1.07g(0.01mol) 2-amino-1H-pyrroles-3-formonitrile HCN, back flow reaction 7h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtain chemical compounds I-2: white solid, yield 84%, purity 99.5%(HPLC normalization method), HRMS (m/z) [M+H]+: 324.2183.
embodiment 3:
1-(3-(4-fluoro-1H-pyrroles-3-base amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amino (chemical compounds I-3)
Figure BDA0000473202430000063
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 4.02g(0.01mol) intermediate IV-2,2.00g(0.02mol) saleratus, 30ml tetrahydrofuran (THF) and 1.00g(0.01mol) the fluoro-3-amino-1H-pyrroles of 4-, back flow reaction 7h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtain chemical compounds I-3: white solid, yield 82%, purity 99.2%(HPLC normalization method), HRMS (m/z) [M+H] +: 331.2293.
embodiment 4:
3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino) furans-2-formaldehyde (chemical compounds I-4)
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 3.88g(0.01mol) intermediate IV-1,2.00g(0.02mol) saleratus, 30ml N, dinethylformamide and 1.11g(0.01mol) the amino furans-2-formaldehyde of 3-, 80 ℃ of reaction 7h reflux, TLC demonstration reacts completely, elimination insolubles, remove solvent under reduced pressure, residue separates with silica gel column chromatography, obtain chemical compounds I-4: white solid, yield 85%, purity 99.4%(HPLC normalization method), HRMS (m/z) [M+H] +: 328.2020.
embodiment 5:
1-(3-(furans-3-base amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (chemical compounds I-5)
Figure BDA0000473202430000072
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 4.02g(0.01mol) intermediate IV-2,2.00g(0.02mol) saleratus, 30ml methyl alcohol and 0.83g(0.01mol) the amino furans of 3-, back flow reaction 8h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtain chemical compounds I-5: white solid, yield 87%, purity 99.6%(HPLC normalization method), HRMS (m/z) [M+H]+: 314.2227.
embodiment 6:
3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino)-5-benzofurane-2-formonitrile HCN (chemical compounds I-6)
Figure BDA0000473202430000073
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 3.88g(0.01mol) intermediate IV-1,2.02g(0.02mol) triethylamine, 30ml N, dinethylformamide and 1.84g(0.01mol) 3-amino-5-phenyl furans-2-formonitrile HCN, 80 ℃ of reaction 5h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtain chemical compounds I-6: white solid, yield 80%, purity 99.5%(HPLC normalization method), HRMS (m/z) [M+H] +: 401.2336.
embodiment 7:
1-(3-(2,4-thioxene-3-base amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (chemical compounds I-7)
Figure BDA0000473202430000081
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 4.02g(0.01mol) intermediate IV-2,2.02g(0.02mol) triethylamine, 30ml acetonitrile and 1.27g(0.01mol) 2,4-dimethyl-3-aminothiophene, back flow reaction 8h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, and residue separates with silica gel column chromatography, obtain chemical compounds I-7: white solid, yield 84%, purity 99.5%(HPLC normalization method), HRMS (m/z) [M+H] +: 358.2311.
embodiment 8:
Methyl 3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-yl) ethylamino) thiophene-2-carboxylic acid methyl esters (chemical compounds I-8)
Figure BDA0000473202430000082
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 3.88g(0.01mol) intermediate IV-1,2.00g(0.02mol) saleratus, 30ml acetonitrile and 1.57g(0.01mol) 3-aminothiophene-2-carboxylate methyl ester, back flow reaction 8h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains chemical compounds I-8: white solid, yield 83%, purity 99.4%(HPLC normalization method), HRMS (m/z) [M+H] +: 347.1897.
embodiment 9:
N, N-dimethyl-1-(2-(thiene-3-yl-amino) ethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (chemical compounds I-9)
Being equipped with in the reaction flask of stirring, condenser, thermometer, add successively 3.88g(0.01mol) intermediate IV-1,2.00g(0.02mol) saleratus, 30ml acetonitrile and 1.56g(0.01mol) 3-aminothiophene, back flow reaction 8h, TLC demonstration reacts completely, elimination insolubles, steaming desolventizes, residue separates with silica gel column chromatography, obtains chemical compounds I-8: white solid, yield 84%, purity 99.5%(HPLC normalization method), HRMS (m/z) [M+H] +: 316.1842.
embodiment 10:
Chemical compounds I-1 one-tenth hydrochloride: get chemical compounds I-1 white solid product 2.0g, be dissolved in 10ml anhydrous diethyl ether.Ice-water bath is cooled to 5 ℃, drip 11.1% hydrochloric acid diethyl ether solution to pH be 2, continue at stir about 1h under ice-water bath.Filter, vacuum-drying, obtains white solid powder.
embodiment 11:
Chemical compounds I-2 one-tenth taurate: get chemical compounds I-2 white solid product 2.0g, be dissolved in 10ml anhydrous methanol.After being heated to reflux, adding and wait mole taurine, continue at time about 1.5h of stirring reaction of refluxing.React complete, under room temperature, leave standstill 24h.Separate out light yellow crystallization, filter vacuum-drying.
embodiment 12:
Chemical compounds I-5 one-tenth vitriol: get chemical compounds I-5 white solid product 2.0g, be dissolved in 15ml acetone.Ice-water bath is cooled to 0 ℃, drip concentrated sulfuric acid solution to pH be 3, continue at stir about 1h under ice-water bath.Filter, obtain white solid.
embodiment 13:
Chemical compounds I-11 one-tenth lactic acid salt: get I-11 white solid product 3.4g, be dissolved in 22mL anhydrous methanol.After being heated to reflux, the molar lactic acid such as add, continue at the lower about 1h of stirring reaction that refluxes.React complete, under room temperature, leave standstill 24h.Separate out light yellow crystallization, filter vacuum-drying.
For the pharmaceutical composition of the benzazepine compounds that contains five-membered ring of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, described embodiment is only for explanation, rather than for limiting the scope of the invention.Described preparation can use any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 1-13.
embodiment 14:
Prepare hard gelatin capsule by following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
embodiment 15:
Prepare tablet by following compositions:
Figure BDA0000473202430000092
Figure BDA0000473202430000101
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.First the auxiliary material of recipe quantity is fully mixed.Bulk drug is added in auxiliary material 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, measure intermediate content, mix compressing tablet on tabletting machine.
embodiment 16:
The preparation of injection liquid:
Figure BDA0000473202430000102
Preparation method: get activeconstituents and join in the water for injection that dissolves polysorbate and propylene glycol, add medicinal basic to regulate pH value to 4～8 to make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilizing.
embodiment 17:
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 activeconstituents and add water for injection, regulate pH value to make its dissolving to 4-8 with medicinal basic.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, and sealing, to obtain final product.
embodiment 18:
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of the human tumor cells of invention compound to vitro culture.
(2) experiment material:
Laboratory sample: formula I compound is provided by contriver's self-control.When 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; DMEM substratum completely, 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: tumor cell inoculation is containing 10% calf serum, in the DMEM nutrient solution of 100IU/ml penicillin G sodium salt and 100 μ g/ml Vetstreps, is placed in 37 ℃, 100% relative humidity, containing 5%CO 2incubator in, go down to posterity for subsequent use after 3 times.
Mtt assay is measured: the cell in the vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest), be suspended in containing in the DMEM nutrient solution of 10% calf serum, blow and beat into gently single cell suspension with glass dropper, 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), all establishes 6 multiple holes for each group.Cultured continuously 24h again, then every hole adds the MTT solution 10 μ L of 5mg/ml, continues to cultivate after 4h, carefully sucks supernatant liquor (suspension cell, need to be 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.Calculate inhibitory rate of cell growth as evaluation index using 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 straight-line regression method 50value.
(4) experimental result:
The IC of the tumour cell of table 1 to vitro culture 50(μ g/ml)
Figure BDA0000473202430000111
(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.

Claims (9)

1. there is compound or its pharmacy acceptable salt of formula I structure:
Wherein:
N=1,2,3 or 4;
X is N, O or S;
R 1, R 2be at the same time or separately: hydrogen, halogen, C 1-C 4alkyl, the C being replaced by halogen 1-C 4alkyl, C 1-C 4alkoxyl group, C 1-C 4carbalkoxy, phenyl, halogenophenyl, C 1-C 4alkoxyl phenyl, aldehyde radical, carboxyl, cyano group.
2. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1, described compound is:
Figure FDA0000473202420000012
Figure FDA0000473202420000021
3. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1, its pharmacy acceptable salt is: formula I compound and mineral acid, organic acid salify.
4. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 3; 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.
5. in claim 1, there is the preparation method of the compound of formula I structure, it is characterized in that: N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (II), at methyl alcohol, ethanol, methylene dichloride, trichloromethane, ethyl acetate, N, in dinethylformamide, acetonitrile or acetone solvent, under the catalysis of acid binding agent, 0～130 ℃ of reaction makes intermediate III with the aliphatic alcohols compound of bromo; Intermediate III and Tosyl chloride in methylene dichloride, trichloromethane, ethyl acetate, acetonitrile, pyridine, acetone, benzene or toluene-20～30 ℃ react, generate intermediate IV; Intermediate IV is at methyl alcohol, ethanol, methylene dichloride, trichloromethane, acetone, N, in dinethylformamide, ethyl acetate, acetonitrile, pyridine, benzene or toluene solvant, under the catalysis of acid binding agent, 0～130 ℃ of reaction makes end product chemical compounds I with the five member ring heterocyclic compound (V) replacing
Figure FDA0000473202420000031
N, X, R 1, R 2definition as claimed in claim 1.
6. preparation method as claimed in claim 5, described acid binding agent is selected from triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide or potassium tert.-butoxide.
7. an antitumor medicine composition, it comprises compound or its pharmacy acceptable salt and one or more pharmaceutical carriers described in claim 1～2 any one for the treatment of significant quantity with formula I structure.
8. the compound of claim 1～2 any one or its pharmacy acceptable salt are in the application aspect antitumor drug.
9. application as claimed in claim 8, in the purposes aspect treatment mammary cancer, lung cancer, cancer of the stomach medicine.
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CN111433201A (en) * 2017-12-21 2020-07-17 江苏恒瑞医药股份有限公司 Benzazepine derivatives, process for their preparation and their use in medicine
CN112121051A (en) * 2020-09-30 2020-12-25 郑州大学 Application of mozavatan in preparation of anti-digestive tract tumor medicine
CN112778201A (en) * 2021-01-14 2021-05-11 合肥工业大学 Benzo [ b ] azepine-chalcone heterozygote and preparation method and application thereof

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CN111433201A (en) * 2017-12-21 2020-07-17 江苏恒瑞医药股份有限公司 Benzazepine derivatives, process for their preparation and their use in medicine
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CN112778201A (en) * 2021-01-14 2021-05-11 合肥工业大学 Benzo [ b ] azepine-chalcone heterozygote and preparation method and application thereof
CN112778201B (en) * 2021-01-14 2023-07-11 合肥工业大学 A kind of benzo[b]azepine-chalcone hybrid compound and its preparation method and application

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