CN107879989A - 3,4,5 substitution ketone drug molecules of Benzodiazepine 2 with bioactivity and preparation method thereof - Google Patents

3,4,5 substitution ketone drug molecules of Benzodiazepine 2 with bioactivity and preparation method thereof Download PDF

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CN107879989A
CN107879989A CN201711220444.6A CN201711220444A CN107879989A CN 107879989 A CN107879989 A CN 107879989A CN 201711220444 A CN201711220444 A CN 201711220444A CN 107879989 A CN107879989 A CN 107879989A
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reaction
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benzodiazepine
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CN107879989B (en
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侯茜茜
毛伸
胡娅伦
刘国锋
穆开蕊
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Chongqing Academy of Chinese Materia Medica
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Henan Longhu Biological Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of 3,4,5 substitution ketone drug molecules of Benzodiazepine 2 with bioactivity and preparation method thereof, belong to medical synthesis technical field.Technical key point is：, wherein R1For methyl, pyridine radicals, phenyl or isopropyl, R2And R3It is each independently selected from methyl, ethyl or phenyl.The present invention has the advantages that compared with prior art：Synthetic method of the present invention is simple, molecular structure is novel and has inhibitory action to malignant myeloid cell lines K562 and breast cancer cell MCF 7, is expected to further genralrlization application.

Description

With bioactivity 3,4,5- substitution Benzodiazepine 2- ketones drug molecule and its Preparation method
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of 3,4,5- substitution benzos two with bioactivity Nitrogen Zhuo 2- ketone drug molecules and preparation method thereof.
Background technology
Tumour is a kind of most common, most serious disease that the world today directly jeopardizes human life, and it refers to that body exists Under the effect of various tumorigenesis factors, the cell paraplasm of local organization and the local lump that is formed, wherein malignant tumour are also known as Cancer.In recent years, the incidence of disease of tumour constantly rises, and turns into the common disease for seriously endangering human health, especially It is that threat of the fatal rate of malignant tumour to human life is just increasingly sharpening.The World Health Organization is according to regions of the world cancer The incidence of disease, the death rate and world population data estimate that dying from malignant tumour person every year on average in the population of the whole world more than 50 hundred million reaches 6900000 people, new cases are about 8,700,000, wherein nearly 60% die from lung cancer, stomach cancer, breast cancer, colorectal cancer, carcinoma of mouth, Liver cancer, cervical carcinoma and the cancer of the esophagus, it is the second largest cause of the death for being only second to angiocardiopathy.
Benzodiazepines compound is widely used in field of medicaments, for example as anxiolytic drugs, antiarrhymic Thing, vasopressin antagonists, hiv reverse transcriptase inhibitor and cholecystokinin antagonist.This research and design has synthesized a series of 3,4,5- substitution Benzodiazepine 2- ketone compounds, and antitumor activity test is carried out to these compounds, find such change Compound has good inhibitory activity to cancer cell, therefore has potential application value in terms of antitumor exploitation.
The content of the invention
Present invention solves the technical problem that it there is provided a kind of 3,4,5- substitution Benzodiazepines 2- with bioactivity Ketone drug molecule and preparation method thereof.
3,4,5- with bioactivity substitutes Benzodiazepine 2- ketones drug molecular structure as shown in formula I：
In formula I, R1For methyl, pyridine radicals, phenyl or isopropyl, R2And R3It is each independently selected from methyl, ethyl or benzene Base.
The preparation method of 3 with bioactivity, 4,5- substitution Benzodiazepine 2- ketone drug molecules, it is characterised in that Concretely comprise the following steps：
A, aniline is after pivaloyl chloride is acylated, under n-BuLi effect with R1- CHO occurs addition reaction and obtained
B、It is oxidized agent to aoxidize, after the hydroxyl generation carbonyl in its structure, takes off in acid condition Tertiary bytyry is gone to obtain
C、Reacted generation with dimethyl suflfate
D、With R2-NH2Substitution reaction generation occurs in the basic conditions
E、Annulation occurs with chloracetyl chloride to obtain
F, compoundWith R3- I or dimethyl suflfate react to obtain compound
Further limit, step A detailed process is：Aniline and triethylamine are added in anhydrous THF, delayed under room temperature condition It is slow that pivaloyl chloride is added dropwise, drip and finish stirring 2h, then n-butyllithium solution is slowly added dropwise, drip and finish stirring 30min, dissolved with R1- CHO's Anhydrous THF solution is slowly dropped in reaction solution, is warming up to back flow reaction 8h, TLC monitoring reaction and is finished, adds 10% ammonium chloride Reaction is quenched, then reaction solution is extracted with ethyl acetate, is obtained after organic phase is evaporated offCrude product, then through post layer Analyse isolated sterling；Wherein R1For pyridine radicals, phenyl or isopropyl.
Further limit, step B detailed process is：In reaction bulb,And metal onidiges It is added in chloroform, is heated to reflux temperature and reacts 1~4h, obtained after filtering and concentratingThe product is added Enter into the mixed solution of concentrated hydrochloric acid and methanol, be heated to back flow reaction 3h, methanol is evaporated off in vacuum concentration, then uses saturated sodium carbonate Solution regulation reaction solution pH>7, merge organic phase after dichloromethane extractive reaction liquid, be concentrated to giveCrude product, then Sterling is obtained through column chromatography for separation；Described metallic catalyst is MnO2、KMnO4Or BaMnO4。
Further limit, step C detailed process is：Dimethyl suflfate and alkali compounds add In reaction bulb, 3~8h is reacted under the conditions of 50 DEG C, TLC monitoring raw material reactions are complete, and reaction solution is cooled to room temperature, to reaction solution Middle addition ethyl acetate dilution, ammoniacal liquor stirring 20min is then added, organic phase is separated and is concentrated to giveDescribed alkali Property compound is NaH, KOH or DBU.
Further limit, step D detailed process is：In reaction bulb, R2-NH2It is added in hydrochloric acid solution, then adds Enter a certain amount of sodium chloride, at ambient temperature, sodium bicarbonate solution regulation reaction solution pH to 7~8 is slowly added dropwise, addsIt is complete in 9~10, TLC monitoring raw material reactions that reaction solution pH is adjusted again, and reaction solution is cooled to room temperature, pours into water Middle suction filtration obtainsWherein R2For methyl, ethyl or phenyl.
Further limit, step E detailed process is：In reaction bulb,It is molten that reaction is added to NaH In agent, chloracetyl chloride is slowly added dropwise at ambient temperature, keeping temperature reacts 2~10h, adds frozen water quenching reaction, separates Organic phase, obtained after concentrationDescribed reaction dissolvent is DMF, THF or pyridine.
Further limit, step F detailed process is：In reaction bulb,Dichloromethane is added with LDA In alkane, a certain amount of phosphoric acid is added, reaction temperature is down to 0 DEG C, is slowly added dropwise dissolved with R3- I or dimethyl suflfate dichloromethane Alkane solution, controlling reaction temperature are no more than 10 DEG C, react 2h after dripping under the conditions of 0 DEG C, and TLC monitoring raw material reactions are complete, After steaming solvent, frozen water quenching reaction is added, suction filtration obtains compoundWherein R3For methyl, ethyl, phenyl.
Compared with prior art, the present invention at least has advantages below and beneficial effect：
The present invention designs reaction scheme using aniline as raw material, screens reaction condition, has synthesized 3,4,5- substitution benzos first Phenodiazine Zhuo 2- ketone drug molecules.Such drug molecule compound has good antitumor activity, develops and leads in cancer therapy drug Domain has great potential, and preparation technology is simple, easily controllable, is established for the production of such drug molecule compound industry metaplasia Basis.
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair Bright scope.
Embodiment 1
In reaction bulb, aniline (10g, 0.107mol) and triethylamine (2g, 0.02mol) are added anhydrous THF 50mL In, pivaloyl chloride (14.24g, 0.118mol) is slowly added dropwise at ambient temperature, drips and finishes stirring 2h, then normal-butyl is slowly added dropwise Lithium (4.48g, 0.07mol) solution, drip to finish and stir 30min, the anhydrous THF dissolved with benzaldehyde (14.24g, 0.118mol) is molten Liquid is slowly dropped in reaction solution, is warming up to back flow reaction 8h, TLC monitoring reaction and is finished, adds 10% ammonium chloride 15mL and be quenched Reaction, then reaction solution is extracted with ethyl acetate, obtained after organic phase is evaporated offCrude product, then through post layer Analyse isolated sterling (19.7g, yield:64.98%) .MS (ESI) m/z:283.2(M+H+)；HNMR:(CDCl3)δ7.34- 7.38 (m, 8H, Ar-H), 7.12 (m, 1H, Ar-H), 6.55 (s, 1H, N-H), 5.02 (s, 1H), 1.85 (s, 9H)
Embodiment 2
In reaction bulb,(283mg, 1.0mmol) and MnO2(26mg, 0.3mmol) enter to In chloroform, 40 DEG C are reacted 4h, are obtained after filtering and concentratingThe product is added to concentrated hydrochloric acid and methanol (1:1) in mixed solution, back flow reaction 3h is heated to, methanol is evaporated off in vacuum concentration, then is adjusted instead with saturated sodium carbonate solution Answer liquid pH>7, merge organic phase after dichloromethane extractive reaction liquid, be concentrated to giveCrude product, then through post layer Analyse isolated sterling (132mg, yield:67.1%) .MS (ESI) m/z:197.1(M+H+).HNMR:(CDCl3)δ7.78(m, 2H, Ar-H), 7.22-7.32 (m, 4H, Ar-H), 7.06 (d, H, Ar-H), 6.81 (d, 1H, J=8Hz, Ar-H), 6.57 (m, 1H,Ar-H),5.88(s,2H,N-H).
Embodiment 3
In reaction bulb,(283mg, 1.0mmol) and KMnO4(26mg, 0.3mmol) enters to chloroform In, 3h is reacted under counterflow condition, is obtained after filtering and concentratingThe product is added to concentrated hydrochloric acid and methanol (1: 1) in mixed solution, back flow reaction 3h is heated to, methanol is evaporated off in vacuum concentration, then adjusts reaction solution with saturated sodium carbonate solution pH>7, merge organic phase after dichloromethane extractive reaction liquid, be concentrated to giveCrude product, then obtained through column chromatography for separation To sterling (78.8mg, yield:58.3%) .MS (ESI) m/z:135.2(M+H+).HNMR:(CDCl3)δ10.35(s,2H, NH),7.78(m,1H,Ar-H),7.24(m,1H,Ar-H),6.75-6.92(m,2H,Ar-H),2.5(s,3H,CH).
Embodiment 4
In reaction bulb,(284mg, 1.0mmol) and BaMnO4(46mg,0.18mmol) Enter into chloroform, 1h is reacted at 25 DEG C, is obtained after filtering and concentratingThe product is added to concentrated hydrochloric acid With methanol (1:1) in mixed solution, back flow reaction 3h is heated to, methanol is evaporated off in vacuum concentration, then uses saturated sodium carbonate solution Adjust reaction solution pH>7, merge organic phase after dichloromethane extractive reaction liquid, be concentrated to giveCrude product, then Sterling (165mg, yield are obtained through column chromatography for separation:83%) .MS (ESI) m/z:199.2(M+H+).HNMR:(CDCl3)δ 8.75-8.76 (m, 2H, Ar-H), 7.44 (d, 2H, Ar-H), 7.43 (d, 2H, Ar-H), 6.75 (d, 1H, J=8Hz, Ar-H), 6.57-6.61(m,1H,Ar-H),6.32(brs,2H,NH).
Embodiment 5
In reaction bulb,(135mg, 1mmol), dimethyl suflfate (101mg, 0.8mmol) and NaH (19.2mg, 0.8mmol) is added in reaction bulb, 5h is reacted under the conditions of 50 DEG C, TLC monitoring raw material reactions are complete, and reaction solution is cold But to room temperature, ethyl acetate 20mL dilutions are added into reaction solution, ammoniacal liquor 10mL stirring 20min is then added, separates organic phase It is concentrated to give(75.4mg,yield:49.84%) .MS (ESI) m/z:151.2(M+H+).HNMR:(DMSO-d6)δ 11.61(s,1H,NH),7.38(s,2H,Ar-H),6.88(m,2H,Ar-H),4.54(m,1H),3.17(s,3H,CH),2.22 (m,3H,CH).
Embodiment 6
In reaction bulb,(198mg, 1.0mmol), dimethyl suflfate (126mg, 1.0mmol) and KOH (33.6mg, 0.6mmol) is added in reaction bulb, 8h is reacted under the conditions of 50 DEG C, TLC monitoring raw material reactions are complete, reaction solution Room temperature is cooled to, ethyl acetate 20mL dilutions are added into reaction solution, ammoniacal liquor 10mL stirring 20min is then added, separates organic Mutually it is concentrated to give(126mg,yield:58.89%) .MS (ESI) m/z:214.3(M+H+).HNMR:(DMSO- d6)δ11.61(s,2H,NH),8.38(s,2H,Ar-H),7.54-7.58(m,4H,Ar-H),7.50(m,2H,Ar-H),5.41 (s,1H,CH),3.32(m,3H,CH).
Embodiment 7
In reaction bulb,(163mg, 1.0mmol), dimethyl suflfate (76mg, 0.6mmol) and DBU (45.6mg, 0.3mmol) is added in reaction bulb, 3h is reacted under the conditions of 50 DEG C, TLC monitoring raw material reactions are complete, and reaction solution is cold But to room temperature, ethyl acetate 20mL dilutions are added into reaction solution, ammoniacal liquor 10mL stirring 20min is then added, separates organic phase It is concentrated to give(128mg,yield:71.66%) .MS (ESI) m/z:179.3(M+H+).HNMR:(DMSO-d6)δ 11.46(s,2H,NH),7.33(m,1H,Ar-H),6.81(m,2H,Ar-H),6.55(m,1H,Ar-H),4.41(m,1H,CH), 3.27(s,3H,CH),2.87(m,1H,CH),1.91(m,6H,CH).
Embodiment 8
In reaction bulb, CH3NH2(62mg, 2.0mmol) is added in 10% hydrochloric acid solution 20mL, adds sodium chloride 0.5eq, at ambient temperature, sodium bicarbonate solution regulation reaction solution pH to 7~8 is slowly added dropwise, adds (179mg, 1.0mmol), then adjust reaction solution pH and react complete in 9~10, TLC monitoring raw materials, reaction solution cooling, it is poured into water Suction filtration obtains(160mg,yield:90.1%) .MS (ESI) m/z:178.3(M+H+).HNMR:(DMSO-d6)δ 11.46(s,2H,NH),8.99(m,1H,NH),6.86-7.02(m,4H,Ar-H),4.41(m,1H,CH),3.27(s,3H, CH),2.57(m,1H,CH),2.0(s,1H,NH),0.91(m,6H,CH).
Embodiment 9
In reaction bulb, CH3CH2NH2(68mg, 1.5mmol) is added in 10% hydrochloric acid solution 20mL, adds chlorine Change sodium 0.5eq, at ambient temperature, sodium bicarbonate solution regulation reaction solution pH to 7~8 is slowly added dropwise, adds(240mg, 1.0mmol), then adjust reaction solution pH and react complete in 9~10, TLC monitoring raw materials, reaction solution Cooling, is poured into water suction filtration and obtains(199mg,yield:87.9%) .MS (ESI) m/z:227.1(M+H+).HNMR:(DMSO-d6)δ9.55(s,2H,NH),8.78(m,2H,Ar-H),6.76-7.07(m,6H,Ar-H),5.28(m, 1H,CH),2.97(m,2H,CH),2.3(s,1H,NH),1.01(m,3H,CH).
Embodiment 10
In reaction bulb, aniline (168mg, 1.8mmol) is added in 10% hydrochloric acid solution 30mL, adds sodium chloride 0.5eq, at ambient temperature, sodium bicarbonate solution regulation reaction solution pH to 7~8 is slowly added dropwise, adds (213mg, 1.0mmol), then adjust reaction solution pH and react complete in 9~10, TLC monitoring raw materials, reaction solution cooling, it is poured into water Suction filtration obtains(181mg,yield:65.91%) .MS (ESI) m/z:274.1(M+H+).HNMR:(DMSO- d6)δ10.55(s,2H,NH),7.23-7.33(m,6H,Ar-H),6.98(m,2H,Ar-H),6.70-6.82(m,5H,CH), 5.99(s,1H,CH),4.28(s,1H,NH).
Embodiment 11
In reaction bulb,(274mg, 1.0mmol) and NaH (24mg, 1.0mmol) are added to THF In 10mL, chloracetyl chloride (203mg, 1.8mmol) is slowly added dropwise at ambient temperature, after keeping temperature reacts 10h, adds frozen water Quenching reaction, organic phase is separated after ethyl acetate 10mL extractions, is obtained after concentration(258mg,yield: 82.1%) .MS (ESI) m/z:314.1(M+H+).HNMR:(DMSO-d6)δ8.25(s,1H,NH),6.83-7.30(m,14H, Ar-H),5.28(s,1H,CH),4.35(m,2H,CH).
Embodiment 12
In reaction bulb,(178mg, 1.0mmol) and NaH (20mg, 0.8mmol) are added to In DMF10mL, chloracetyl chloride (168mg, 1.5mmol) is slowly added dropwise at ambient temperature, after keeping temperature reacts 6h, adds ice Water quenching reaction, separates organic phase after ethyl acetate 10mL extractions, is obtained after concentration(175mg,yield: 80.6%) .MS (ESI) m/z:218.1(M+H+).HNMR:(DMSO-d6)δ9.01(s,1H,NH),7.12-7.37(m,4H, Ar-H),3.89(t,1H,CH),3.35(m,2H,CH),2.45(m,1H,CH),2.15(m,3H,CH),1.66(m,6H,CH).
Embodiment 13
In reaction bulb,(228mg, 1.0mmol) and NaH (20mg, 0.8mmol) are added to pyrrole In pyridine 10mL, chloracetyl chloride (168mg, 1.5mmol) is slowly added dropwise at ambient temperature, after keeping temperature reacts 2h, adds ice Water quenching reaction, separates organic phase after ethyl acetate 10mL extractions, is obtained after concentration(227mg,yield: 85.7%) .MS (ESI) m/z:267.1(M+H+).HNMR:(DMSO-d6)δ9.37(brs,1H,NH),8.68(s,2H,Ar- ), H 7.54 (d, 1H, J=8Hz, Ar-H), 7.45 (s, 2H, Ar-H), 7.20-7.27 (m, 3H, Ar-H), 5.38 (s, 1H), 3.53(m,2H),2.88(m,2H),1.08(m,3H).
Embodiment 14
In reaction bulb,(267mg, 1.0mmol) and LDA (22mg, 0.2mmol) add dichloro In methane 15mL, 1eq phosphoric acid is added, reaction temperature is down to 0 DEG C, is slowly added dropwise dissolved with iodomethane (170mg, 1.2mmol) Dichloromethane solution, controlling reaction temperature is no more than 10 DEG C, reacts 2h after dripping under the conditions of 0 DEG C, and TLC monitoring raw materials are anti- Should be complete, after steaming solvent, frozen water quenching reaction is added, there are a large amount of solids to separate out, suction filtration obtains compound(187mg,yield:66.4%) .MS (ESI) m/z:281.1(M+H+).HNMR:(DMSO-d6)δ9.37 (brs,1H,NH),8.68(s,2H,Ar-H),7.10-7.30(m,6H,Ar-H),5.38(s,1H),3.53(m,1H),2.48 (m,2H),1.30(m,3H),1.08(m,3H).
Embodiment 15
In reaction bulb,(267mg, 1.0mmol) and LDA (22mg, 0.2mmol) add dichloro In methane 15mL, add 1eq phosphoric acid, reaction temperature is down to 0 DEG C, be slowly added dropwise dissolved with dimethyl suflfate (189mg, Dichloromethane solution 1.5mmol), controlling reaction temperature are no more than 10 DEG C, react 2h, TLC prisons after dripping under the conditions of 0 DEG C It is complete to control raw material reaction, after steaming solvent, adds frozen water quenching reaction, there are a large amount of solids to separate out, suction filtration obtains compound(168mg,yield:59.88%) .MS (ESI) m/z:281.1(M+H+).
Embodiment 16
In reaction bulb,(267mg, 1.0mmol) and LDA (22mg, 0.2mmol) add dichloromethane In alkane 15mL, 1eq phosphoric acid is added, reaction temperature is down to 0 DEG C, and two dissolved with iodobenzene (306mg, 1.5mmol) are slowly added dropwise Chloromethanes solution, controlling reaction temperature are no more than 10 DEG C, react 2h after dripping under the conditions of 0 DEG C, and TLC monitoring raw materials have reacted Entirely, after steaming solvent, frozen water quenching reaction is added, there are a large amount of solids to separate out, suction filtration obtains compound (140mg,yield:47.61%) .MS (ESI) m/z:294.2(M+H+).HNMR:(DMSO-d6)δ8.88(brs,1H,NH), 7.14-7.33(m,9H,Ar-H),4.88(s,1H),3.85(m,1H),2.48(m,1H),2.38(s,3H),1.28(m,6H).
Embodiment 17
In reaction bulb,(314mg, 1.0mmol) and LDA (44mg, 0.4mmol) add dichloro In methane 15mL, 1eq phosphoric acid is added, reaction temperature is down to 0 DEG C, is slowly added dropwise dissolved with iodoethane (234mg, 1.5mmol) Dichloromethane solution, controlling reaction temperature is no more than 10 DEG C, reacts 2h after dripping under the conditions of 0 DEG C, and TLC monitoring raw materials are anti- Should be complete, after steaming solvent, frozen water quenching reaction is added, there are a large amount of solids to separate out, suction filtration obtains compound (149mg, yield: 45.88%) .MS (ESI) m/z:342.2(M+H+).HNMR:(DMSO-d6)δ9.18(brs,1H,NH),6.79-7.30(m, 14H,Ar-H),5.58(s,1H),3.99(m,1H),2.08(m,2H),1.33(m,3H).
Embodiment 18
The method in embodiment 1~17 is repeated, difference is to use different initiation materials, so as to obtain a series ofization Compound, specifically it is shown in Table 1.
In formula I, R1For methyl, pyridine radicals, phenyl or isopropyl, R2And R3It is each independently selected from methyl, ethyl or benzene Base；
Embodiment 19
Antitumor activity is tested
In human leukemia cell line K562 and breast cancer cell MCF-7, the anticancer of compound 1~36 is determined with MTS methods Activity, cell is added in 96 porocyte culture plates with debita spissitudo, after cultivating 24h, in 37 DEG C, 5%CO2Under the conditions of with difference The compound effects 72h of concentration, it is then that MTS (ultimate density 2mg/mL) and DMS (30 μM of ultimate density) mixture is direct Add in celliferous culture medium.After acting on 4h, the metabolin that cell survival rate is acted on MTS by it is under 492nm wavelength Absorptivity measure.We select to carry out active testing to this series compound under 40 μM and 4 μM of concentration, detect thin to both The inhibiting rate of born of the same parents.
Preliminary biological activity test shows that such compound is in human leukemia cell line K562 and breast cancer cell MCF-7 In, there is certain inhibitory action to cancer cell, wherein chemical compounds I -10, I -16, I -30 pair of MCF-7 tumor cell line has aobvious The inhibitory action of work, chemical compounds I -18 and I -21 have good inhibitory action to both cells simultaneously, I -25 and I -27 pair K562 cell lines have good inhibitory action.
In summary, this patent provides a kind of 3,4,5- substitution Benzodiazepine 2- ketone chemical combination with bioactivity Thing, this is the discovery first of such compound purposes, has great research and development potentiality.
Embodiment above describes the general principle of the present invention, main features and advantages, the technical staff of the industry should Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within In the scope of protection of the invention.

Claims (9)

1. 3,4, the 5- substitution Benzodiazepine 2- ketone drug molecules with bioactivity, it is characterised in that its molecular structure For：Wherein R1For methyl, pyridine radicals, phenyl or isopropyl, R2And R3It is each independently selected from methyl, ethyl Or phenyl.
A kind of 2. system of the substitution Benzodiazepine 2- ketone drug molecules of the 3,4,5- with bioactivity described in claim 1 Preparation Method, it is characterised in that concretely comprise the following steps：
A, aniline is after pivaloyl chloride is acylated, under n-BuLi effect with R1- CHO occurs addition reaction and obtained
B、It is oxidized agent to aoxidize, after the hydroxyl generation carbonyl in its structure, sloughs tertiary fourth in acid condition Acyl group obtains
C、Reacted generation with dimethyl suflfate
D、With R2-NH2Substitution reaction generation occurs in the basic conditions
E、Annulation occurs with chloracetyl chloride to obtain
F, compoundWith R3- I or dimethyl suflfate react to obtain compound
A kind of 3. 3,4,5- substitution Benzodiazepine 2- ketone drug molecules with bioactivity according to claim 2 Preparation method, it is characterised in that step A detailed process is：Aniline and triethylamine are added in anhydrous THF, under room temperature condition Pivaloyl chloride is slowly added dropwise, drips and finishes stirring 2h, then n-butyllithium solution is slowly added dropwise, drips and finishes stirring 30min, dissolved with R1-CHO Anhydrous THF solution be slowly dropped in reaction solution, be warming up to back flow reaction 8h, TLC monitoring reactions finish, and add 10% chlorination Reaction is quenched in ammonium, then reaction solution is extracted with ethyl acetate, and is obtained after organic phase is evaporated offCrude product, then through post Chromatography obtains sterling；Wherein R1For pyridine radicals, phenyl or isopropyl.
A kind of 4. 3,4,5- substitution Benzodiazepine 2- ketone drug molecules with bioactivity according to claim 2 Preparation method, it is characterised in that step B detailed process is：In reaction bulb,Aoxidized with metal Agent is added in chloroform, and 1~4h is reacted at 25 DEG C to reflux temperature, is obtained after filtering and concentratingThis is produced Thing is added in the mixed solution of concentrated hydrochloric acid and methanol, is heated to back flow reaction 3h, methanol is evaporated off in vacuum concentration, then uses saturated carbon Acid sodium solution regulation reaction solution pH>7, merge organic phase after dichloromethane extractive reaction liquid, be concentrated to giveIt is thick Product, then obtain sterling through column chromatography for separation；Described metallic catalyst is MnO2、KMnO4Or BaMnO4。
A kind of 5. 3,4,5- substitution Benzodiazepine 2- ketone drug molecules with bioactivity according to claim 2 Preparation method, it is characterised in that step C detailed process is：：Dimethyl suflfate and alkali compounds add Enter in reaction bulb, 3~8h is reacted under the conditions of 50 DEG C, TLC monitoring raw material reactions are complete, and reaction solution is cooled to room temperature, to reaction Ethyl acetate dilution is added in liquid, ammoniacal liquor stirring 20min is then added, separates organic phase and be concentrated to giveDescribed Alkali compounds is NaH, KOH or DBU.
A kind of 6. 3,4,5- substitution Benzodiazepine 2- ketone drug molecules with bioactivity according to claim 2 Preparation method, it is characterised in that step D detailed process is：In reaction bulb, R2-NH2It is added in hydrochloric acid solution, then A certain amount of sodium chloride is added, at ambient temperature, sodium bicarbonate solution regulation reaction solution pH to 7~8 is slowly added dropwise, addsIt is complete in 9~10, TLC monitoring raw material reactions that reaction solution pH is adjusted again, and reaction solution is cooled to room temperature, pours into water Middle suction filtration obtainsWherein R2For methyl, ethyl or phenyl.
A kind of 7. 3,4,5- substitution Benzodiazepine 2- ketone drug molecules with bioactivity according to claim 2 Preparation method, it is characterised in that step E detailed process is：In reaction bulb,Reaction is added to NaH In solvent, chloracetyl chloride is slowly added dropwise at ambient temperature, keeping temperature reacts 2~10h, adds frozen water quenching reaction, point Go out organic phase, obtained after concentrationDescribed reaction dissolvent is DMF, THF or pyridine.
A kind of 8. 3,4,5- substitution Benzodiazepine 2- ketone drug molecules with bioactivity according to claim 2 Preparation method, it is characterised in that step F detailed process is：In reaction bulb,Dichloro is added with LDA In methane, a certain amount of phosphoric acid is added, reaction temperature is down to 0 DEG C, is slowly added dropwise dissolved with R3- I or dimethyl suflfate dichloro Dichloromethane, controlling reaction temperature are no more than 10 DEG C, react 2h after dripping under the conditions of 0 DEG C, and TLC monitoring raw materials have reacted Entirely, after steaming solvent, frozen water quenching reaction is added, suction filtration obtains compoundWherein R3For methyl, ethyl, benzene Base.
9. new 3,4,5- substitutions Benzodiazepine 2- ketones drug molecule as claimed in claim 1 is preparing antineoplastic In application.
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