CN103864765B - Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use - Google Patents

Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use Download PDF

Info

Publication number
CN103864765B
CN103864765B CN201410078487.5A CN201410078487A CN103864765B CN 103864765 B CN103864765 B CN 103864765B CN 201410078487 A CN201410078487 A CN 201410078487A CN 103864765 B CN103864765 B CN 103864765B
Authority
CN
China
Prior art keywords
compound
acceptable salt
pharmacy acceptable
preparation
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410078487.5A
Other languages
Chinese (zh)
Other versions
CN103864765A (en
Inventor
刘登科
祁浩飞
刘颖
穆帅
田军
张力婉
王景阳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Institute of Pharmaceutical Research Co Ltd
Original Assignee
Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin Institute of Pharmaceutical Research Co Ltd filed Critical Tianjin Institute of Pharmaceutical Research Co Ltd
Priority to CN201410078487.5A priority Critical patent/CN103864765B/en
Publication of CN103864765A publication Critical patent/CN103864765A/en
Application granted granted Critical
Publication of CN103864765B publication Critical patent/CN103864765B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses benzazepine compounds and pharmacy acceptable salt thereof that a class with structure shown in formula I contains five-membered ring, 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, by the phenyl that fluorine, chlorine, bromine replace, alkoxyl phenyl, ester group, aldehyde radical, carboxyl, cyano group.The invention also discloses the preparation method of above-claimed cpd, and also disclose using this compound or its pharmacy acceptable salt as the pharmaceutical composition of active ingredients, and they are as antitumor drug, particularly for the preparation of the application in treatment mammary cancer, lung cancer, gastric cancer medicament.

Description

Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use
Technical field
The invention belongs to medical art, or rather, relate to class compound with antitumor action and its production and use.
Background technology
Cancer has become a large chronic disease of serious harm human health at present.The people of annual suffers from cancer has 9,000,000 in the world according to statistics, and the patient dying from cancer is 6,000,000, almost just has a cancer death p.s..China's cancer year number of the infected, about 1,200,000, dies from the number of cancer up to more than 900,000, and patient to be treated more than 1,500,000, and has the trend risen year by year.Therefore cancer has now become the second largest killer being only second to cardiovascular disorder.Clinical treatment tumour, generally adopts operation, radiotherapy, the large therapy of chemotherapy three.Though embolic chemotherapy is comparatively quick, curative ratio is very low.The many cancer therapy drugs of clinical discovery exist significantly to damage and the toxic side effect of normal body simultaneously, such as mutagenesis and genetoxic.Therefore, to 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 containing five-membered ring of a class novel texture.
Another object of the present invention is, discloses a class and contains the benzazepine compounds of five-membered ring and the preparation method of pharmaceutical salts thereof.
Another object of the present invention is, open contains with a class pharmaceutical composition that the benzazepine compounds of five-membered ring and pharmaceutical salts thereof are main active ingredient.
A further object of the invention is, discloses a class and contains the application as medicine for resisting malignant tumors of the benzazepine compounds of five-membered ring and pharmaceutical salts thereof, particularly for the preparation of the purposes in treatment mammary cancer, lung cancer, gastric cancer medicament.
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 structure shown in formula I:
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.
Preferred 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, by the phenyl that fluorine, chlorine, bromine replace, 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-base) ethylamino)-1H-pyrroles-2-carboxylic acid, ethyl ester
I-2.2-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-base) ethylamino)-1H-pyrroles-3-formonitrile HCN
I-3.1-(3-(the fluoro-1H-pyrroles of 4--3-base is amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-is amino
I-4.3-(2-(5-(dimethylamino)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-base) ethylamino) furans-2-formaldehyde
I-5.1-(3-(furans-3-base is 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-base) ethylamino)-5-benzofurane-2-formonitrile HCN
I-7.1-(3-(2,4-thioxene-3-base is 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-base) ethylamino) thiophene-2-carboxylic acid methyl esters
I-9.N, N-dimethyl-1-(2-(thiene-3-yl-is amino) ethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine
Type 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 type I compound is as follows:
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, with the aliphatic alcohols compound of bromo 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 DEG C of obtained intermediate III of reaction.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 DEG C 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, with the five-membered heterocycles (V) replaced 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 DEG C of obtained final product compound I of reaction.
The obtained various compound of reaction or products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, DMSO or ether drip mineral acid, pharmacy acceptable salt made by organic acid.
Specifically various compound is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drips ethereal HCI to pH=2, make hydrochloride; Or various compound is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, mole taurine such as to add, heated and stirred obtains its taurate; Or various compound is dissolved in the one in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, under ice-water bath, drips the vitriol oil to pH=3, make vitriol.
This compounds is effective for treatment human malignancies.Although compound of the present invention can without the direct administration of any preparation, described various compounds preferably use in the form of a pharmaceutical preparation, and route of administration can be parenteral route (as vein, intramuscular delivery) 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 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 such as injection, pulvis etc.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, usually, the weight range of active compound is 0.5% ~ 90% (weight) of composition.Another preferred scope is 0.5%-70%.
Compound or its pharmacy acceptable salt with structure shown in formula I 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.Such as infrared spectra (IR) can be adopted subsequently, nuclear magnetic resonance spectrum ( 1hNMR, 13cNMR), high resolution mass spectrum (HRMS) etc. further confirm its structure.
reference example 1:
Intermediate III-1
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, 2.5g (0.020mol) ethylene bromohyrin is added under stirring, 2.5.g (0.025mol) triethylamine, back flow reaction 15h, TLC display reacts completely, steaming desolventizes, residue 50ml methylene dichloride dissolves, saturated common salt water washing (10ml × 3), steaming desolventizes, residue sherwood oil and ethyl acetate mixtures recrystallization, 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, 2.78g (0.02mo1) 3-bromopropyl alcohol is dripped under stirring, back flow reaction 12h, TLC display reacts completely, filter insolubles, filtrate is poured in distilled water, ethyl acetate (15ml × 3) extracts, merge organic layer, anhydrous sodium sulfate drying, steaming desolventizes, residue silica gel column chromatography is separated, obtain yellow solid, yield 82.5%, purity 97.5% (HPLC normalization method), ESI-MS (m/z): 248.2.
reference example 3:
Intermediate IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add 2.34g (0.01mol) intermediate III-1,50ml pyridine stirs and makes it dissolve, solution controls below-5 DEG C, add 2.28g (0.012mol) Tosyl chloride in batches, 0 DEG C of reaction 10h, TLC display reacts completely, and is poured into by reaction solution in cold water, solid is had to separate out, filter, filter cake through saturated aqueous common salt (50ml × 3) washing after, 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
Stirring is being housed, condenser, in the reaction flask of thermometer, add 2.48g (0.01mol) intermediate III-2, 50mlN, dinethylformamide and 2.52g (0.025mol) triethylamine, stirring makes it dissolve, solution controls below-5 DEG C, add 2.28g (0.012mol) Tosyl chloride in batches, 0 DEG C of reaction 10h, TLC display reacts completely, reaction solution is poured in cold water, solid is had 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-base) ethylamino)-1H-pyrroles-2-carboxylic acid, ethyl ester (chemical compounds I-1)
In the reaction flask that stirring, condenser, thermometer are housed, add 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 successively, back flow reaction 6h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, 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-base) ethylamino)-1H-pyrroles-3-formonitrile HCN (chemical compounds I-2)
In the reaction flask that stirring, condenser, thermometer are housed, add 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 successively, back flow reaction 7h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, 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-(the fluoro-1H-pyrroles of 4--3-base is amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amino (chemical compounds I-3)
In the reaction flask that stirring, condenser, thermometer are housed, add 4.02g (0.01mol) intermediate IV-2,2.00g (0.02mol) saleratus, 30ml tetrahydrofuran (THF) and the fluoro-3-amino of 1.00g (0.01mol) 4--1H-pyrroles successively, back flow reaction 7h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, 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-base) ethylamino) furans-2-formaldehyde (chemical compounds I-4)
In the reaction flask that stirring, condenser, thermometer are housed, add 3.88g (0.01mol) intermediate IV-1,2.00g (0.02mol) saleratus, 30mlN successively, dinethylformamide and 1.11g (0.01mol) 3-amino furan-2-formaldehyde, reflux 80 DEG C of reaction 7h, TLC display reacts completely, elimination insolubles, remove solvent under reduced pressure, residue silica gel column chromatography is separated, 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 is amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (chemical compounds I-5)
In the reaction flask that stirring, condenser, thermometer are housed, add 4.02g (0.01mol) intermediate IV-2,2.00g (0.02mol) saleratus, 30ml methyl alcohol and 0.83g (0.01mol) 3-amino furan successively, back flow reaction 8h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, 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-base) ethylamino)-5-benzofurane-2-formonitrile HCN (chemical compounds I-6)
In the reaction flask that stirring, condenser, thermometer are housed, add 3.88g (0.01mol) intermediate IV-1,2.02g (0.02mol) triethylamine, 30mlN successively, dinethylformamide and 1.84g (0.01mol) 3-amino-5-phenyl furans-2-formonitrile HCN, 80 DEG C of reaction 5h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, 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 is amino) propyl group)-N, N-dimethyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-5-amine (chemical compounds I-7)
In the reaction flask that stirring, condenser, thermometer are housed, add 4.02g (0.01mol) intermediate IV-2,2.02g (0.02mol) triethylamine, 30ml acetonitrile and 1.27g (0.01mol) 2 successively, 4-dimethyl-3-aminothiophene, back flow reaction 8h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, 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-base) ethylamino) thiophene-2-carboxylic acid methyl esters (chemical compounds I-8)
In the reaction flask that stirring, condenser, thermometer are housed, add 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 successively, back flow reaction 8h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, obtain 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-is amino) ethyl)-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidenes-5-amine (chemical compounds I-9)
In the reaction flask that stirring, condenser, thermometer are housed, add 3.88g (0.01mol) intermediate IV-1,2.00g (0.02mol) saleratus, 30ml acetonitrile and 1.56g (0.01mol) 3-aminothiophene successively, back flow reaction 8h, TLC display reacts completely, elimination insolubles, steaming desolventizes, residue silica gel column chromatography is separated, obtain 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 becomes 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 DEG C, and dripping 11.1% ethereal HCI solution is 2 to pH, continues at stir about 1h under ice-water bath.Filter, vacuum-drying, obtains white solid powder.
embodiment 11:
Chemical compounds I-2 becomes taurate: get chemical compounds I-2 white solid product 2.0g, be dissolved in 10ml anhydrous methanol.To add etc. mole taurine after being heated to backflow, continue at stirred at reflux and react about 1.5h.React complete, in left at room temperature 24h.Separate out Light yellow crystals, filter, vacuum-drying.
embodiment 12:
Chemical compounds I-5 becomes vitriol: get chemical compounds I-5 white solid product 2.0g, be dissolved in 15ml acetone.Ice-water bath is cooled to 0 DEG C, and dripping concentrated sulfuric acid solution is 3 to pH, continues at stir about 1h under ice-water bath.Filter, obtain white solid.
embodiment 13:
Chemical compounds I-11 becomes lactic acid salt: get I-11 white solid product 3.4g, be dissolved in 22mL anhydrous methanol.To add etc. molar lactic acid after being heated to backflow, continue at stirred at reflux and react about 1h.React complete, in left at room temperature 24h.Separate out Light yellow crystals, filter, vacuum-drying.
In order to the pharmaceutical composition of the benzazepine compounds containing five-membered ring of the present invention is described more fully, provide following example of formulations below, described embodiment only for illustration of, instead of for limiting the scope of the invention.Described preparation can use any active compound in the compounds of this invention and salt thereof, preferably uses the compound described in embodiment 1-13.
embodiment 14:
Hard gelatin capsule is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 100 mesh sieves for subsequent use.After mentioned component being mixed by recipe quantity, be packed in hard gelatin capsule.
embodiment 15:
Tablet is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 100 mesh sieves for subsequent use.First the auxiliary material of recipe quantity is fully mixed.Be added in auxiliary material by bulk drug to increase progressively dilution method, each added-time fully mixes 2-3 time, ensures that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry particle crosses the whole grain of 16 mesh sieve, measure intermediates content, mix, compressing tablet on tabletting machine.
embodiment 16:
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection dissolving polysorbate and propylene glycol, adds medicinal basic adjust ph to 4 ~ 8 and makes it dissolve.Add gac, whip attachment 30min, carbon removal, essence 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, makes it dissolve by medicinal basic adjust ph to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving, add gac by the requirement of injection, adopt filtering with microporous membrane, filtrate carries out packing, adopts freeze-drying, and obtained loose block, 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 that invention Compounds in vitro is cultivated.
(2) experiment material:
Laboratory sample: type I compound is made by oneself by contriver and provided.During experiment, sample is with DMSO hydrotropy, and plasma-free DMEM medium is diluted to desired concn, and sample segment solution is suspension.
Main agents: the packing of MTT, Amresco company, lot number: 04M0904; Complete DMEM substratum, Gibco Products, 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 KingYork Amino Acid Co., Ltd..
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO 2incubator, Thermo company, model: HERACell150; Inverted microscope, CarlZeiss 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 containing 10% calf serum, in the DMEM nutrient solution of 100IU/ml penicillin G sodium salt and 100 μ g/ml Vetstreps, be placed in 37 DEG C, 100% relative humidity, containing 5%CO 2incubator in, go down to posterity for subsequent use after 3 times.
Mtt assay measures: the cell in vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution containing 10% calf serum, single cell suspension is blown and beaten into gently, with blood cell counts plate numeration viable cell under microscope with glass dropper.(cell concn is adjusted to 6 ~ 10 × 10 to 96 well culture plate every hole inoculating cell suspension 90 μ L 4individual/ml), 37 DEG C, 100% relative humidity, containing 5%CO 2, 95% air incubator cultivate after 24h, every hole adds 10 μ L liquids (final concentration is set to: 40 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml and 2.5 μ g/ml, five concentration).In addition, each concentration establishes 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, after continuing to cultivate 4h, carefully sucks supernatant liquor (suspension cell needs first centrifugal, then sucks supernatant).Every hole adds 100 μ LDMSO, and put micro oscillator concussion 5min and dissolve completely to make crystallization, microplate reader 492nm Single wavelength colorimetric, measures OD value.Inhibitory rate of cell growth is calculated 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 pair vitro culture 50(μ g/ml)
(5) conclusion:
According to above-mentioned in vitro tests result, we can find out that the compound with structure shown in formula I has stronger restraining effect to above-mentioned 3 kinds of human tumor cells.

Claims (9)

1. there is compound or its pharmacy acceptable salt of structure shown in formula I:
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 be optionally substituted 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. have compound or its pharmacy acceptable salt of structure shown in formula I as claimed in claim 1, described compound is:
3. have compound or its pharmacy acceptable salt of structure shown in formula I as claimed in claim 1, its pharmacy acceptable salt is: formula I and mineral acid, organic acid salify.
4. there is compound or its pharmacy acceptable salt of 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. there is in claim 1 preparation method of the compound of structure shown in formula I, 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, with the aliphatic alcohols compound of bromo under the catalysis of acid binding agent, 0 ~ 130 DEG C of obtained intermediate III of reaction; Intermediate III and Tosyl chloride in methylene dichloride, trichloromethane, ethyl acetate, acetonitrile, pyridine, acetone, benzene or toluene-20 ~ 30 DEG C react, generation intermediate IV; Intermediate IV is at methyl alcohol, ethanol, methylene dichloride, trichloromethane, acetone, N, in dinethylformamide, ethyl acetate, acetonitrile, pyridine, benzene or toluene solvant, with the five member ring heterocyclic compound (V) replaced under the catalysis of acid binding agent, 0 ~ 130 DEG C of obtained final product compound I of reaction
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, has the compound of structure shown in formula I or its pharmacy acceptable salt and one or more pharmaceutical carriers described in any one of claim 1 ~ 2 that it comprises treatment significant quantity.
8. the compound of any one of claim 1 ~ 2 or its pharmacy acceptable salt are for the preparation of the application in antitumor drug.
9. apply as claimed in claim 8, for the preparation for the treatment of mammary cancer, lung cancer, purposes in gastric cancer medicament.
CN201410078487.5A 2014-03-05 2014-03-05 Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use Active CN103864765B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410078487.5A CN103864765B (en) 2014-03-05 2014-03-05 Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410078487.5A CN103864765B (en) 2014-03-05 2014-03-05 Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use

Publications (2)

Publication Number Publication Date
CN103864765A CN103864765A (en) 2014-06-18
CN103864765B true CN103864765B (en) 2016-02-10

Family

ID=50903835

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410078487.5A Active CN103864765B (en) 2014-03-05 2014-03-05 Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use

Country Status (1)

Country Link
CN (1) CN103864765B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111433201B (en) * 2017-12-21 2022-05-27 江苏恒瑞医药股份有限公司 Benzepine derivative, process for preparing the same and use thereof in medicine
CN112121051B (en) * 2020-09-30 2021-06-18 郑州大学 Application of mozavatan in preparation of anti-digestive tract tumor medicine
CN112778201B (en) * 2021-01-14 2023-07-11 合肥工业大学 Benzo [ b ] azepine-chalcone hybrid and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668671A (en) * 1985-04-26 1987-05-26 Smith Kline & French Laboratories Limited Tricyclic derivatives and pharmaceutical use
US5962449A (en) * 1995-04-07 1999-10-05 Novo Nordisk A/S Tricyclic compounds in treating hyperalgesic conditions and NIDDM
CN1261880A (en) * 1997-07-02 2000-08-02 布里斯托尔-迈尔斯斯奎布公司 Inhibitors of farnesyl protein transferase
CN1273529A (en) * 1997-09-24 2000-11-15 史密丝克莱恩比彻姆公司 Vitronection receptor antagonist

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668671A (en) * 1985-04-26 1987-05-26 Smith Kline & French Laboratories Limited Tricyclic derivatives and pharmaceutical use
US5962449A (en) * 1995-04-07 1999-10-05 Novo Nordisk A/S Tricyclic compounds in treating hyperalgesic conditions and NIDDM
CN1261880A (en) * 1997-07-02 2000-08-02 布里斯托尔-迈尔斯斯奎布公司 Inhibitors of farnesyl protein transferase
CN1273529A (en) * 1997-09-24 2000-11-15 史密丝克莱恩比彻姆公司 Vitronection receptor antagonist

Also Published As

Publication number Publication date
CN103864765A (en) 2014-06-18

Similar Documents

Publication Publication Date Title
CN103044395B (en) Desloratadine-containing amino acid derivative as well as preparation method and application thereof
CN103864765B (en) Benzazepine analog derivative containing five-membered ring, Preparation Method And The Use
CN102911118B (en) Benzo-azepine type derivative and preparation method and purpose thereof
CN101974016A (en) Amide compound and preparation method and applications thereof
CN101845051A (en) Nitrogen-containing heterocyclic thienopyridine compounds and preparation method and application thereof
CN101863901B (en) 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof
CN104292211A (en) Desloratadine nitric oxide donor, and preparation method and application thereof
CN104926804B (en) One kind has compound, the preparation method and use of antitumor action
CN102786458B (en) Pyrrole formamide derivative, and preparation method and application thereof
CN102746212B (en) Beta-elemene indole derivative, preparation and application thereof
CN103804367B (en) Benzazepine derivant, Preparation Method And The Use
CN103880793B (en) Containing furan imine compound and its production and use
CN103304556B (en) Schiff bases compounds containing chromene, Preparation Method And The Use
CN102796140A (en) Phosphate-containing isoxazoline derivatives and their preparation method and use
CN101845052B (en) Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof
CN102276626B (en) Isoxazole-containing compound
CN102276625B (en) Thiadiazole derivative
CN105037345B (en) Antitumoral compounds, preparation method and use
CN102838652B (en) A kind of oleanolic acid derivate with anticarcinogenesis and its production and use
CN103288805B (en) Pyrimidines containing benzofuran and its production and use
CN104292210B (en) Nitric oxide donors class compound containing pyridine, preparation method and the usage
CN102417514B (en) Pyridine derivatives, preparation method thereof, and purpose thereof
CN101805355B (en) Thienopyridone derivative, preparation method and uses thereof
CN102329327B (en) Furan derivatives and preparation method and application thereof
CN102358742B (en) Thiazole compound with antitumor activity

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant