CN109223741A - A kind of purposes of Rimantadine schiff bases - Google Patents
A kind of purposes of Rimantadine schiff bases Download PDFInfo
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- CN109223741A CN109223741A CN201811061512.3A CN201811061512A CN109223741A CN 109223741 A CN109223741 A CN 109223741A CN 201811061512 A CN201811061512 A CN 201811061512A CN 109223741 A CN109223741 A CN 109223741A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of purposes of Rimantadine schiff bases.The preparation step of Rimantadine schiff bases are as follows: through thionyl chloride chloride, then in the presence of trimethyl aluminium, cesium formate alkylated reaction occurs for adamantanecarboxylic acid, then oximate is at ketoxime, the reduction of palladium charcoal, then aldimine condensation occurs with cinnamic acid and reacts, obtain Rimantadine contracting cinnamic acid schiff bases.The route for having the beneficial effect that synthesizing adamantane methyl ketone before reaction route of the invention changes is reacted using cesium formate auxiliary trimethyl aluminium, makes mild condition, by-product is few.Synthetic method craft simple possible of the present invention, catalyst amount is few, environmentally friendly, and product yield is high.Rimantadine schiff bases produced by the present invention has antibacterial activity, antiviral activity, and anti-tumor activity can be used in the fields such as medicine, daily use chemicals, food, develop as the potential purposes for preparing antibacterial agent, antivirotic, antitumor agent.
Description
Technical field
The present invention relates to drug fields more particularly to a kind of Rimantadine schiff bases in antibacterial, antiviral and antitumor preparation
In purposes.
Background technique
Rimantadine is the aminoderivative of saturated tricyclic decane, entitled Alpha-Methyl tricyclic [3,3,1, the 1] decane-of chemistry
1- methylamine has antiviral and sedation effect, is clinically also used for the severe pain and morbilli for the treatment of burst, and feature is to absorb fastly,
Toxic side effect is small.Rimantadine is researched and developed by Bristol Myers Squibb company of the U.S., is listed for the first time in France within 1987,
U.S. FDA approval in 1993 is better than amantadine for preventing and treating influenza A infection, clinical efficacy.Rimantadine
Mechanism of action is the surface charge for changing host cell, inhibits virus to penetrate sensitive cells and discharges the process of nucleic acid, makes virus
Proliferation be suppressed.People had further research to the synthetic method of Rimantadine in recent years.
The synthesis key of rimantadine is the synthesis of intermediate adamantane methyl ketone, and conventional method is original with adamantane
1- bromo adamantane is first made, then under concentrated sulfuric acid existence condition, using distinct methods synthesizing adamantane methyl ketone, so in material
Catalytic hydrogenation obtains product Rimantadine afterwards.These method some use low-boiling acetylene, and some uses ether, industrial difficult
To recycle and have risk, the total recovery of product is low.
Cinnamic acid and its derivative are the important intermediates of fine chemical product, in terms of medicine, food, agrochemical
It has a wide range of applications.Currently, synthesizing Rimantadine schiff bases using Rimantadine and cinnamic acid as raw material, having not been reported.
Summary of the invention
The purpose of the present invention is to provide purposes of the Rimantadine schiff bases in antibacterial, antiviral and antitumor preparation,
Rimantadine schiff bases is reacted and is made through chloride, alkylation, oximate, the reduction of palladium charcoal, aldimine condensation by adamantanecarboxylic acid.
The present invention in view of the above technology in the problem of mentioning, the technical solution taken are as follows:
Purposes of the Rimantadine schiff bases in antibacterial, antiviral and antitumor preparation.
A kind of purposes of Rimantadine schiff bases, the Rimantadine schiff bases of preparation are Rimantadine contracting cinnamic acid Schiff
Alkali, its stereoisomer or pharmaceutically accessible salt, chemical structural formula are as follows:
A kind of purposes of Rimantadine schiff bases, the synthetic method of made Rimantadine schiff bases include the following steps:
The preparation of adamantane formyl chloride: taking adamantanecarboxylic acid and excessive thionyl chloride to be put into reaction flask, be heated to reflux, benzene extraction
It takes, obtains the benzole soln of adamantane formyl chloride, it is spare；
The preparation of adamantane methyl ketone: under nitrogen protection, trimethyl aluminium, cesium formate are added into reaction flask, gold is then added dropwise
The benzole soln of rigid alkane formyl chloride reacts adamantane formyl chloride with trimethyl aluminium and generates adamantane methyl ketone, reaction solution is poured into
In ice water, filtering, drying obtain adamantane methyl ketone, spare；Oxygen atom has strong in chlorine atom and C=O double bond in formyl chloride
Electron-withdrawing ability, is in elecrtonegativity, and the carbon atom being connected with chlorine atom and oxygen atom, with electropositive, easily with trimethyl aluminium
In carbonium ion or free radical combine, generate methyl ketone groups, since trimethyl aluminium activity is high, reaction fierceness be difficult to control
System, the collective effect of cesium formate and trimethyl aluminium cooperate benzole soln, can be initially formed complex, then form methyl ketone groups,
To slow down the severity of reaction, become reaction system environment mildly, it is easily controllable, while the generation of by-product is reduced,
Improve reaction yield；
The preparation of 1- adamantane methyl ketoxime: hydroxylamine hydrochloride, dehydrated alcohol, pyridine is taken to be put into reaction flask, heating stirring adds
Enter adamantane methyl ketone, back flow reaction distills to obtain solids, filtering, drying, obtains 1- adamantane methyl ketoxime, spare；
Rimantadine preparation: in autoclave pressure, 1- adamantane methyl ketoxime, glacial acetic acid, titanium dioxide-palladium charcoal catalysis is added
Agent and metatartaric acid, lead to hydrogen reaction, filtering, and filtrate concentration adds deionized water and sodium hydroxide tune pH9-10, methylene chloride extraction
It takes, dry, filter, obtain Rimantadine, it is spare；
The preparation of Rimantadine schiff bases: taking Rimantadine, dehydrated alcohol to be added in reaction flask, and cortex cinnamomi is added dropwise in stirring and dissolving
The ethanol solution of aldehyde, is heated to reflux, and reaction solution vacuum distillation, filters concentration, obtains Rimantadine contracting cinnamic acid schiff bases.
Preferably, cesium formate dosage is the 5-15% of trimethyl aluminium dosage in adamantane methyl ketone preparation step.
Preferably, hydroxylamine hydrochloride, pyridine and dehydrated alcohol are first to heat in 1- adamantane methyl ketoxime preparation step
It 90-110 DEG C and stirs to solution in homogeneous, adds adamantane methyl ketone and carry out back flow reaction.
Preferably, the dosage of metatartaric acid is titanium dioxide-palladium carbon catalyst dosage in Rimantadine preparation step
5-25%；Titanium dioxide-absorbent charcoal carrier surface is in weak acid, metatartaric acid and the presence of titanium dioxide-activated carbon composite carrier,
It can produce synergistic function, on the one hand improve the dispersion degree of active component and the surface nature of catalyst on complex carrier,
Meanwhile also make the Metal Palladium being supported on complex carrier occur Hydrogen spillover phenomenon, so as to shorten C=N double-bond hydrogenation reaction when
Between, reaction rate is improved, and increase catalyzing by metal palladium hydrogenation activity, improves reaction yield.
Further preferably, in Rimantadine preparation step, the pressure for being passed through hydrogen is 0.35-0.45MPa, and the reaction time is
12-24h, the concentration of sodium hydroxide are 0.5-1.5mol/L.
Preferably, the rate of addition of the ethanol solution of cinnamic acid is 0.5- in Rimantadine schiff bases preparation step
1mL/min, return time 3-6h.
Compared with the prior art, the advantages of the present invention are as follows: synthetic route such as Fig. 1 institute of Rimantadine schiff bases of the present invention
Show；The route of synthesizing adamantane methyl ketone before reaction route of the invention changes using trimethylaluminum reagent, and screens
The auxiliary reagent of reaction, discovery cesium formate is best to the auxiliaring effect of trimethyl aluminium, and cesium formate uses simultaneously with trimethyl aluminium, can
So that reaction condition is mild, by-product is few, product yield high；Reaction route of the invention is compound using titanium dioxide-active carbon
The palladium catalyst of load, while its synergistic catalytic activity of metatartaric acid is added, reductone to alcohol, dosage is few, and environmental protection；This
Inventing Rimantadine schiff bases obtained has antibacterial activity, antiviral activity, and anti-tumor activity can be used for medicine, daily use chemicals, food
In the fields such as product.
Detailed description of the invention
Fig. 1 is the reaction route schematic diagram of Rimantadine schiff bases synthetic method of the present invention；
Specific embodiment
The present invention program is described further below by embodiment:
Embodiment 1:
A kind of purposes of Rimantadine schiff bases, the Rimantadine schiff bases of preparation are Rimantadine contracting cinnamic acid Schiff
Alkali, its stereoisomer or pharmaceutically accessible salt, chemical structural formula are as follows:
A kind of purposes of Rimantadine schiff bases, the synthetic method of made Rimantadine schiff bases include the following steps:
The preparation of adamantane formyl chloride: adamantanecarboxylic acid 1.8g and 3.6mL thionyl chloride is added in three-necked flask, is heated to
80 DEG C, back flow reaction 2h, then vacuum distillation recycling thionyl chloride is added benzene 5mL × 2 and is extracted, gained extract liquor is direct
For reacting in next step；
Adamantane methyl ketone preparation: in three-necked flask be added 0.10g trimethyl aluminium, 0.01g cesium formate, then with
The benzole soln of adamantane formyl chloride is added dropwise in 0.25mL/min, reacts adamantane formyl chloride with trimethyl aluminium and generates adamantane methyl
Reaction solution is poured into obtain lurid compound in ice water after the reaction was completed by ketone, and then filtering, 100 DEG C of dry 5h, obtain light yellow
Precipitate adamantane methyl ketone 1.95g, yield 90%；Oxygen atom has strong suction electricity in chlorine atom and C=O double bond in formyl chloride
Sub- ability is in elecrtonegativity, and the carbon atom being connected with chlorine atom and oxygen atom, has electropositive, easily and in trimethyl aluminium
Carbonium ion or free radical combine, and generate methyl ketone groups, and since trimethyl aluminium activity is high, reaction fierceness is difficult to control, first
The collective effect of sour cerium and trimethyl aluminium cooperates benzole soln, can be initially formed complex, then forms methyl ketone groups, thus
The severity for slowing down reaction becomes reaction system environment mildly, easily controllable, while reducing the generation of by-product, improves
Reaction yield；
The preparation of 1- adamantane methyl ketoxime: in reaction flask, hydroxylamine hydrochloride 1.9g, pyridine 10mL and dehydrated alcohol is added
10mL is heated to 100 DEG C, and solution distills to obtain solids, 10mL is gone in homogeneous, addition 1.42g adamantane methyl ketone, reflux 2h
Ion is washed with water, filtered and dried drying, obtains 1- adamantane methyl ketoxime 1.57g, yield 97%；
Rimantadine preparation: in autoclave pressure, 1- adamantane methyl ketoxime 1.89g, glacial acetic acid 40mL, modified palladium charcoal is added
Catalyst 0.9g and metatartaric acid 0.1g, under room temperature and 0.40MPa Hydrogen Vapor Pressure, successive reaction 18h, Filtration of catalyst
And metatartaric acid, filtrate are concentrated into a quarter of original volume, add deionized water 30mL, then plus 1mol/L sodium hydroxide tune
PH9-10 is extracted three times with 45mL methylene chloride, and anhydrous magnesium sulfate dries, filters, and obtains Rimantadine 1.65g, yield 95%；Two
Titanium oxide-absorbent charcoal carrier surface is in weak acid, metatartaric acid and the presence of titanium dioxide-activated carbon composite carrier, be can produce
On the one hand synergistic function improves the dispersion degree of active component and the surface nature of catalyst on complex carrier, meanwhile, also make
Hydrogen spillover phenomenon occurs for the Metal Palladium being supported on complex carrier, so as to shorten the reaction time of C=N double-bond hydrogenation, improves anti-
Rate is answered, and increases catalyzing by metal palladium hydrogenation activity, improves reaction yield；
The preparation of Rimantadine schiff bases: being added 2.00g Rimantadine, 50mL dehydrated alcohol in round-bottomed flask, stirs molten
Solution, takes 1.32g cinnamic acid to be dissolved in 20mL dehydrated alcohol, stirs evenly, be added dropwise to round-bottomed flask with the speed of 0.5mL/min
In, it after being added dropwise, is heated to reflux 4 hours, reaction solution is evaporated under reduced pressure, be concentrated into liquid into sticky shape, slightly cold, suction filtration, nothing
Water-ethanol elution, obtains 2.48g yellow solid, is Rimantadine contracting cinnamic acid schiff bases, yield 85%.
Embodiment 2:
A kind of purposes of Rimantadine schiff bases, the Rimantadine schiff bases of preparation are Rimantadine contracting cinnamic acid Schiff
Alkali, its stereoisomer or pharmaceutically accessible salt, chemical structural formula are as follows:
A kind of purposes of Rimantadine schiff bases, the synthetic method of made Rimantadine schiff bases include the following steps:
The preparation of adamantane formyl chloride: being added adamantanecarboxylic acid and thionyl chloride in three-necked flask, is heated to 80 DEG C, reflux
2h is reacted, then vacuum distillation recycling thionyl chloride is added benzene and is extracted, gained extract liquor is directly used in react in next step；
The preparation of adamantane methyl ketone: trimethyl aluminium, cesium formate are added in three-necked flask, is then added dropwise with 0.1mL/min
The benzole soln of adamantane formyl chloride reacts adamantane formyl chloride with trimethyl aluminium and generates adamantane methyl ketone, after the reaction was completed
Reaction solution is poured into and obtains lurid compound in ice water, then filtering, 100 DEG C of dry 5h, obtain light-yellow precipitate adamantane first
Base ketone；
The preparation of 1- adamantane methyl ketoxime: in reaction flask, hydroxylamine hydrochloride, pyridine and dehydrated alcohol is added, is heated to 100
DEG C, solution distills to obtain solids, deionization is washed with water, filtered and dried drying, obtains 1- in homogeneous, addition adamantane methyl ketone, reflux 2h
Adamantane methyl ketoxime；
Rimantadine preparation: in autoclave pressure, be added 1- adamantane methyl ketoxime, glacial acetic acid, modified palladium carbon catalyst and
Metatartaric acid, under room temperature and 0.35MPa Hydrogen Vapor Pressure, successive reaction 12h, Filtration of catalyst and metatartaric acid, filtrate
Be concentrated into a quarter of original volume, add deionized water, then plus 0.5mol/L sodium hydroxide tune pH9-10, use methylene chloride
It extracts three times, anhydrous magnesium sulfate dries, filters, and obtains Rimantadine；
The preparation of Rimantadine schiff bases: being added Rimantadine, dehydrated alcohol in round-bottomed flask, and stirring and dissolving takes cortex cinnamomi
Aldehyde is dissolved in dehydrated alcohol, is stirred evenly, and is added dropwise in round-bottomed flask with the speed of 0.8mL/min, after being added dropwise, is heated back
Stream 5 hours, reaction solution is evaporated under reduced pressure, and is concentrated into liquid into sticky shape, slightly cold, suction filtration, dehydrated alcohol elutes, and it is solid to obtain yellow
Body is Rimantadine contracting cinnamic acid schiff bases.
Embodiment 3:
A kind of purposes of Rimantadine schiff bases, the Rimantadine schiff bases of preparation are Rimantadine contracting cinnamic acid Schiff
Alkali, its stereoisomer or pharmaceutically accessible salt, chemical structural formula are as follows:
A kind of purposes of Rimantadine schiff bases, the synthetic method of made Rimantadine schiff bases include the following steps:
The preparation of adamantane formyl chloride: being added adamantanecarboxylic acid and thionyl chloride in three-necked flask, is heated to 80 DEG C, reflux
2h is reacted, then vacuum distillation recycling thionyl chloride is added benzene and is extracted, gained extract liquor is directly used in react in next step；
The preparation of adamantane methyl ketone: trimethyl aluminium, cesium formate are added in three-necked flask, is then added dropwise with 0.5mL/min
The benzole soln of adamantane formyl chloride reacts adamantane formyl chloride with trimethyl aluminium and generates adamantane methyl ketone, after the reaction was completed
Reaction solution is poured into and obtains lurid compound in ice water, then filtering, 100 DEG C of dry 5h, obtain light-yellow precipitate adamantane first
Base ketone；
The preparation of 1- adamantane methyl ketoxime: in reaction flask, hydroxylamine hydrochloride, pyridine and dehydrated alcohol is added, is heated to 100
DEG C, solution distills to obtain solids, deionization is washed with water, filtered and dried drying, obtains 1- in homogeneous, addition adamantane methyl ketone, reflux 2h
Adamantane methyl ketoxime；
Rimantadine preparation: in autoclave pressure, it is multiple that 1- adamantane methyl ketoxime, glacial acetic acid, titanium dioxide-active carbon is added
The palladium catalyst and metatartaric acid of load are closed, under room temperature and 0.45MPa Hydrogen Vapor Pressure, successive reaction for 24 hours, is filtered to remove catalysis
Agent and metatartaric acid, filtrate are concentrated into a quarter of original volume, add deionized water, then plus 1.5mol/L sodium hydroxide tune
PH9-10 is extracted three times with methylene chloride, and anhydrous magnesium sulfate dries, filters, and obtains Rimantadine；
The preparation of Rimantadine schiff bases: being added Rimantadine, dehydrated alcohol in round-bottomed flask, and stirring and dissolving takes cortex cinnamomi
Aldehyde is dissolved in dehydrated alcohol, is stirred evenly, and is added dropwise in round-bottomed flask with the speed of 1mL/min, after being added dropwise, is heated to reflux
6 hours, reaction solution is evaporated under reduced pressure, is concentrated into liquid into sticky shape, slightly cold, suction filtration, dehydrated alcohol elutes, yellow solid is obtained,
For Rimantadine contracting cinnamic acid schiff bases.
Comparative example 1:
Trimethyl aluminium, cesium formate, rest part and embodiment 2 complete one are not added in adamantane methyl ketone preparation step
It causes.
Comparative example 2:
Trimethyl aluminium is not added in adamantane methyl ketone preparation step, rest part and embodiment 2 are completely the same.
Comparative example 3:
The catalyst that composite load is not used in Rimantadine preparation step uses activated carbon supported palladium as replacement
Catalyst, rest part and embodiment 2 are completely the same.
Embodiment 4:
It regard embodiment 2 as test group, comparative example 1, comparative example 2, comparative example 31, control group 2, control group as a control group
3, the yield of adamantane methyl ketone and Rimantadine is shown in Table 1.
The yield of table 1 adamantane methyl ketone and Rimantadine
| Project | Adamantane methyl ketone yield (%) | Rimantadine yield (%) |
| Test group | 90 | 95 |
| Control group 1 | 0 | 0 |
| Control group 2 | 83 | 95 |
| Control group 3 | 90 | 85 |
As shown in Table 1, the adamantane methyl ketone yield of test group and the yield of Rimantadine to be much higher than control group 1,
Control group 2, control group 3；Wherein, in control group 1, the yield of adamantane methyl ketone yield and Rimantadine is 0, illustrates not add
Add catalyst, reaction does not generate adamantane methyl ketone and Rimantadine；Adamantane methyl ketone yield is higher than control group in test group
2, illustrate that cesium formate plays the role of synergy to the catalytic efficiency of trimethyl aluminium；Rimantadine yield is higher than control group 3 in test group,
Illustrate that the catalytic efficiency of the metatartaric acid palladium catalyst activated carbon supported to titanium dioxide-has synergistic function.
Embodiment 5:
Using Escherichia coli, bacillus, staphylococcus aureus as pathogenic bacteria model, Ciprofloxacin is as Model of Bacterial
Positive control drug, preliminary assessment is carried out to the bacteriostatic activity of gained compound using filter paper doubling dilution.It the results are shown in Table
2。
The detection method (doubling dilution solvent diffusion method) of bacteriostatic activity:
Rimantadine schiff bases obtained is carried out to the screening and test of bacteriostatic activity, the screening of bacteriostatic activity uses the scraps of paper
The test of diffusion method, MIC uses doubling dilution.Specific step is as follows:
Indicator bacteria is recovered in liquid bouillon media from -80 DEG C of refrigerators, 37 DEG C of fermentations for 24 hours, are prepared into seed liquor.
After getting corresponding Solid media for plates ready, seed liquor is spread evenly across spare on plating medium.Take each sample to be tested
(diameter on the filter paper after sterilizing is added dropwise in (concentration of coarse extract is 10mg/mL, final compound concentration 0.1mg/mL) 10 μ L
5mm), it is gently attached at after sample dries on the spare plate for being coated with indicator bacteria, is placed in 28 DEG C of constant temperature in constant incubator
Stationary culture is for 24 hours.Fungistatic effect (i.e. inhibition zone size) is observed after culture.Two times need to be used for active compound
Dilution method continues to test its minimum inhibitory concentration (MIC), until sample concentration when filter paper is not infected just is MIC.
Inhibitory activity of the 2 Rimantadine schiff bases of table to drug-fast bacteria
The test result of table 2 shows: Rimantadine schiff bases is equal to Escherichia coli, bacillus and staphylococcus aureus
Strong inhibitory activity is shown, the MIC of inhibitory activity is respectively 1.2 μ g/mL, 1.5 μ g/mL, 3.0 μ g/mL, than Ciprofloxacin
Inhibitory activity is more preferable, and Rimantadine schiff bases of the present invention is prompted to can be used as potential antibacterial substance.
Embodiment 6:
Rimantadine schiff bases is used to treat inhibitory activity when H1N1 virus
Test procedure:
1) inoculation mdck cell is to 96 hole cell culture mediums, and culture is to growing up to single layer；
2) culture solution is abandoned, 100TCID is added in every hole50H1N1 100 μ L of virus, be incubated for 1 hour in 37 DEG C；
3) remove virus, the test medicine for having diluted concentration 200 μ L into cell is added in every hole；
4) it cultivates 48 hours for 37 DEG C, the inhibition with the Rimantadine schiff bases of mtt assay detection various concentration to H1N1 virus
Activity.Data result is shown in Table 3.
3 Rimantadine schiff bases of table treats inhibitory activity when H1N1 virus
| Rimantadine Schiff alkali concentration (μ g/mL) | To the inhibiting rate (%) of H1N1 virus |
| 500.00 | 17 |
| 250.00 | 38 |
| 125.00 | 62 |
| 62.50 | 90 |
| 31.25 | 75 |
| 15.63 | 36 |
As shown in Table 3, inhibitory activity of the Rimantadine schiff bases of 62.50 μ g/mL for when treating H1N1 virus is
90%, illustrate that Rimantadine schiff bases is obvious to the effect of the inhibitory activity for the treatment of H1N1 virus, prompts Rimantadine of the present invention
Schiff bases infected by influenza has preferable therapeutic effect.
Embodiment 7:
Using human lung cancer cell A549, human cervical carcinoma cell Hela cell, human liver cancer cell HepG2 cell as model, Ah mould
Element is positive control drug, carries out preliminary assessment using anti-tumor activity of the mtt assay to Rimantadine schiff bases.It the results are shown in Table 4.
The preparation method of MTT solution: weighing MTT0.5g, is dissolved in the phosphate buffer (PBS) of 100mL or without phenol red training
It supports in base, with 0.22 μm of membrane filtration to remove the bacterium in solution, puts 4 DEG C of refrigerators and be kept in dark place.It is preparing and is saving
During, container is encased with aluminium-foil paper, and the fluorescent lamp on super-clean bench is closed when experiment to be protected from light.
Mtt assay experimental procedure-attached cell
1 collects logarithmic phase cell, adjusts concentration of cell suspension, and 100 μ L are added in every hole, and bed board makes cell density to be measured
10000 every holes, (edge hole is filled with sterile PBS)；
2 5%CO2, it is incubated for 12 hours in 37 DEG C of insulating boxs, until cell is adherent, the drug of concentration gradient, every hole 100 is added
μ L sets 3 multiple holes；
3 5%CO2, it is incubated for 24 hours in 37 DEG C of insulating boxs, is observed under inverted microscope；
20 μ LMTT solution (5mg/mL, i.e. 0.5%MTT) are added in 4 every holes, continue to cultivate 4h；
5 terminate culture, carefully suck culture solution in hole.150 μ L dimethyl sulfoxides are added in every hole, set low-speed oscillation on shaking table
10min dissolves crystal sufficiently.The light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument OD570nm；
6 be arranged zeroing hole i.e. blank group (culture medium, MTT, dimethyl sulfoxide) simultaneously, control wells (cell, same concentrations
Drug dissolving medium, culture solution, MTT, dimethyl sulfoxide)；
7 take three hole mean OD values to calculate sample by IR%=(OD blank control-OD sample)/OD blank control × 100% formula
The inhibiting rate (IR%) of product cell proliferation, and half inhibiting rate IC50 is calculated using bliss method.
The anti-tumor activity of 4 Rimantadine schiff bases of table is tested
The test result of table 4 shows that Rimantadine schiff bases is thin to human lung cancer cell A549, human cervical carcinoma cell Hela
Born of the same parents, human liver cancer cell HepG2 show strong inhibitory activity, and the MIC of inhibitory activity is respectively 10 μ g/mL, 20 μ g/mL, 22 μ g/
ML prompts Rimantadine schiff bases to have certain anti-tumor activity.
Routine operation in operating procedure of the invention is well known to those skilled in the art, herein without repeating.
Technical solution of the present invention is described in detail in embodiment described above, it should be understood that the above is only
For specific embodiments of the present invention, it is not intended to restrict the invention, all any modifications made in spirit of the invention,
Supplement or similar fashion substitution etc., should all be included in the protection scope of the present invention.
Claims (7)
1. a kind of purposes of Rimantadine schiff bases, which is characterized in that the Rimantadine schiff bases is Rimantadine contracting cortex cinnamomi
Aldehyde schiff bases, its stereoisomer or pharmaceutically accessible salt, as effective component, in antibacterial, antiviral and antitumor preparation
In purposes, the chemical structural formula of Rimantadine contracting cinnamic acid schiff bases are as follows:
2. a kind of purposes of Rimantadine schiff bases according to claim 1, which is characterized in that the Rimantadine Schiff
The synthetic method of alkali includes the following steps:
1) prepared by adamantane formyl chloride: it takes adamantanecarboxylic acid and excessive thionyl chloride to be put into reaction flask, is heated to reflux, benzene extraction
It takes, obtains the benzole soln of adamantane formyl chloride, it is spare；
2) prepared by adamantane methyl ketone: under nitrogen protection, trimethyl aluminium, cesium formate being added into reaction flask, Buddha's warrior attendant is then added dropwise
The benzole soln of alkane formyl chloride reacts adamantane formyl chloride with trimethyl aluminium and generates adamantane methyl ketone, reaction solution is poured into ice
In water, filtering, drying obtain adamantane methyl ketone, spare；
3) prepared by 1- adamantane methyl ketoxime: taking hydroxylamine hydrochloride, dehydrated alcohol, pyridine to be put into reaction flask, heating stirring is added
Adamantane methyl ketone, back flow reaction distill to obtain solids, filtering, drying, obtain 1- adamantane methyl ketoxime, spare；
4) prepared by Rimantadine: in autoclave pressure, 1- adamantane methyl ketoxime, glacial acetic acid, titanium dioxide-palladium carbon catalyst is added
And metatartaric acid, lead to hydrogen reaction, filtering, filtrate concentration adds deionized water and sodium hydroxide tune pH9-10, methylene chloride extraction
It takes, dry, filter, obtain Rimantadine, it is spare；
5) prepared by Rimantadine schiff bases: taking Rimantadine, dehydrated alcohol to be added in reaction flask, cinnamic acid is added dropwise in stirring and dissolving
Ethanol solution, be heated to reflux, reaction solution vacuum distillation, concentration, filter, obtain Rimantadine contracting cinnamic acid schiff bases.
3. a kind of purposes of Rimantadine schiff bases according to claim 2, which is characterized in that the adamantane methyl ketone
In preparation step, cesium formate dosage is the 5-15% of trimethyl aluminium dosage.
4. a kind of purposes of Rimantadine schiff bases according to claim 2, which is characterized in that the 1- adamantane methyl
In ketoxime preparation step, it is in homogeneous that hydroxylamine hydrochloride, pyridine and dehydrated alcohol, which are first to heat to 90-110 DEG C and stir to solution, then plus
Enter adamantane methyl ketone and carries out back flow reaction.
5. a kind of purposes of Rimantadine schiff bases according to claim 2, which is characterized in that the Rimantadine preparation
In step, the dosage of metatartaric acid is titanium dioxide-palladium carbon catalyst dosage 5-25%.
6. a kind of purposes of Rimantadine schiff bases according to claim 2, which is characterized in that the Rimantadine preparation
In step, the pressure for being passed through hydrogen is 0.35-0.45MPa, and reaction time 12-24h, the concentration of sodium hydroxide is 0.5-
1.5mol/L。
7. a kind of purposes of Rimantadine schiff bases according to claim 2, which is characterized in that the Rimantadine Schiff
In alkali preparation step, the rate of addition of the ethanol solution of cinnamic acid is 0.5-1mL/min, return time 3-6h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111743897A (en) * | 2020-07-02 | 2020-10-09 | 河南工业大学 | Application of twenty-four-membered macrocyclic schiff base in preparation of methicillin-resistant staphylococcus aureus infection medicine |
| CN115894262A (en) * | 2022-11-23 | 2023-04-04 | 辽宁大学 | N-methylated amantadine reduction Schiff base derivative and preparation method and application thereof |
-
2018
- 2018-09-12 CN CN201811061512.3A patent/CN109223741A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111743897A (en) * | 2020-07-02 | 2020-10-09 | 河南工业大学 | Application of twenty-four-membered macrocyclic schiff base in preparation of methicillin-resistant staphylococcus aureus infection medicine |
| CN115894262A (en) * | 2022-11-23 | 2023-04-04 | 辽宁大学 | N-methylated amantadine reduction Schiff base derivative and preparation method and application thereof |
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