CN105920004A - Application of 1,2,4-trisubstituted piperazine compound to preparation of anti-influenza virus medicine - Google Patents
Application of 1,2,4-trisubstituted piperazine compound to preparation of anti-influenza virus medicine Download PDFInfo
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- CN105920004A CN105920004A CN201610351594.XA CN201610351594A CN105920004A CN 105920004 A CN105920004 A CN 105920004A CN 201610351594 A CN201610351594 A CN 201610351594A CN 105920004 A CN105920004 A CN 105920004A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of a 1,2,4-trisubstituded piperazine compound to preparation of an anti-influenza virus medicine. Cell experiments prove that the 1,2,4-trisubstituded piperazine compound has a strong inhibiting effect on influenza virus a, the median inhibitory concentration IC50 of the 1,2,4-trisubstituded piperazine compound is 29.97 microns, and the 1,2,4-trisubstituded piperazine compound is low in toxicity to cells, the medicine use safety is high, and the cell median toxicity concentration CC50 of the 1,2,4-trisubstituded piperazine compound is 400 microns or above. Thus, the 1,2,4-trisubstituded piperazine compound has wide application background in treating influenza virus a infection diseases, and can be applied to preparing the anti-influenza virus medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to 1,2,4-tri-substituted piperazine like compound are in preparing anti-influenza virus medicament
Purposes.
Background technology
Influenza is called for short influenza, is the acute febrile respiratory infectious disease caused by influenza virus, and major transmission path is
With the spittle of influenza virus, entering internal through respiratory tract, minority also can infect through mediate contacts such as shared handkerchief, towels,
Clinical typical characteristic is projection fear of cold, high heat, headache, systemic pain, the weak and weary systemic toxicity profiles symptom such as weak, and respiratory tract disease
Shape is lighter.Influenza has that popular wide, infectiousness is strong, sickness rate high, infant, old people, has heart and lung diseases
And other patients with chronic diseases or immunologic hypofunction person can Complicating Pneumonia In Patients, prognosis is poor.
Influenza Virus orthomyxovirus section, is a kind of tunicary RNA viruses, in its envelope components containing hemagglutinin (HA) and
Neuraminidase (NA) two kinds of glycoprotein projection, both glycoprotein projections are respectively provided with antigenicity, and have hypospecificity.
The source of influenza virus variation is mainly due to the change of HA and NA antigenic structure.The whole world has 250,000-50 ten thousand people to die from every year
The complication that influenza or influenza infection cause.In recent years, along with the increasing of whole world species range of activity, the change of influenza virus
The opposite sex strengthens, and between people, fowl, pig and (or) other kinds, influenza virus interacts to produce and has highly pathogenic new variant virus,
The generation of Human Avian Influenza, neopathy poison crowd between highly infective and the high mortality of the infected, Zeng Yi
Degree causes the global range fear to influenza, has had a strong impact on daily life and the Stable Development in Economy of the mankind.
The major way answering infected by influenza is vaccine and Drug therapy.The effectiveness of vaccine prevention is built upon the Strain of vaccine
To just on the basis of popular strains of influenza viruses is similar, only known influenza virus sub-strain is had preventive effect, and for by
Antigenic drift or the produced novel influenza protective rate of antigenicity conversion are the highest or invalid, at present cannot by existing means
Prediction will be popular strains of influenza viruses, the therefore limited use of vaccine infected by influenza.Therefore, Tamiflu has all the time
Imitate influenza, the first line of defence of protection human health.The anti-influenza virus medicament of current many countries use is hydrochloric acid Buddha's warrior attendant
Alkanamine, including amantadine and rimantadine, can prevent influenza A virus, but the most invalid to Influenza B virus.In A type
During influenza pandemic, preventative give health adult or child's amantadine or rimantadine, for prevention influenza A virus tool
There are the effective percentage of 70%-90%, the infected to rise and give both medicines in 48h after being ill, also can play therapeutical effect, can alleviate
The state of an illness and the shortening course of disease.Neuraminidase inhibitor is the another kind of medicine that can be used for flu-prevention, can be popular influenza virus
Period tries out in health adult.But the common problem that this two classes anti-influenza virus medicament all faces at present is exactly often to occur
Drug resistance in various degree.Therefore, find and there is the novel anti-influenza virus medicament of preventive and therapeutic action just seem and be even more important
With urgent.
Summary of the invention
It is an object of the invention to provide 1,2,4-tri-substituted piperazine like compound purposes in preparing anti-influenza virus medicament.
1,2,4-tri-substituted piperazine like compound of the present invention are learned synthesis by Paris, FRA is the seventh-largest and provides, and its molecular formula is
C30H42N4O10, molecular weight is 627.68, has a structure as shown in formula (I):
1,2,4-tri-substituted piperazine like compound that the present invention provides can be applied individually to any prepares anti-influenza virus medicament, it is also possible to other
Have and prevent and treat the compounding compositions that formed of composition of influenza effect and be applied to prepare anti-influenza virus medicament.
Preferably, described influenza virus is influenza A virus.
Preferably, described anti-influenza virus medicament can be made into the dosage form that any one is suitable for using clinically, as make tablet,
Capsule, granule, powder, oral liquid, injection, injectable powder, injection or spray etc..
Compared with prior art, the beneficial effects of the present invention is first public 1,2,4-tri-substituted piperazine like compound of the present invention in preparation
Purposes in anti-influenza virus medicament.Cell experiment proves, influenza A virus is had stronger by 1,2,4-tri-substituted piperazine like compound
Inhibitory action, its half-inhibition concentration IC50It is 29.97 μMs, and 1,2,4-tri-substituted piperazine like compound are low to cytotoxicity, medicine
Thing is safe to use, its cell half toxic concentration CC50>=400 μMs, therefore, 1,2,4-tri-substituted piperazine like compound is in treatment
Influenza a virus infection disease has application background widely, can be applicable to prepare anti-influenza virus medicament.
Detailed description of the invention
Below by way of specific embodiment, the present invention is further detailed explanation.
In the embodiment of the present invention, described mdck cell (Madin-Darby canine kidney(cell line)) is that Ji'nan University and biological medicine base, south are from the cell deposited；
Described influenza virus is Influenza A/PR/8 (H1N1), sick from the influenza A deposited for Ji'nan University and biological medicine base, south
Poison, is inoculated in 10 age in days chick embryo allantois intracavity, and inoculum concentration is 200 μ L, cultivates for 35 DEG C and reclaims allantoic fluid after 2 days, in-80 DEG C
Save backup, virus tissue culture infective dose (TCID50)=10-5；Described 1,2,4-tri-substituted piperazine like compound are by method
State University Paris VII Denis Dideret synthesis and providing, 1,2,4-tri-substituted piperazine like compound powder through dimethyl sulfoxide (DMSO) (purchased from Sigma
Company) fully dissolve after-20 DEG C save backup.
Embodiment 11,2,4-tri-substituted piperazine like compound cytotoxic assay
It is 1.2 × 10 by cell density5The mdck cell of cells/mL is inoculated in 96 orifice plates, and every hole 100 μ L, containing volume
Percent concentration is the DMEM culture medium of the hyclone (purchased from Bai Wang bio tech ltd, Guangzhou) of 10% (v/v)
After (brand is gibco, purchased from Ying Weijie base trade Co., Ltd) cultivates 24h, draw and remove culture medium, by 1,2,4-tri-
The substituted piperazine like compound DMEM culture medium without serum does serial dilution (400 μMs-6.25 μMs) afterwards by dilute with 2 multiple proportions
Releasing order to be inoculated on the mdck cell in 96 orifice plates, every hole 100 μ L, each concentration be arranged in parallel 3 and tests multiple hole,
Set cell controls group simultaneously.At 37 DEG C, 5%CO2Detect with mtt assay, at 570nm after incubator cultivates 48h
Absorbance OD value is surveyed under wavelength, by drug study group calculating cell survival rate compared with the OD value of cell controls group, according to
Reed-Muench method calculates cell half toxic concentration CC50.It is repeated 4 times experiment, averages.
Experimental result: cell controls group cell is examined under a microscope, and cell attachment is tight, form is good.According to MTT result,
Reed-Muench method is used to calculate the cell half toxic concentration CC of 1,2,4-tri-substituted piperazine like compound50≥400μM。
Embodiment 21, the CPE of 2,4-tri-substituted piperazine like compound anti-influenza virus activities observes
It is 1.2 × 10 by cell density5The mdck cell of cells/mL is inoculated in 96 orifice plates, and every hole 100 μ L, containing volume
Percent concentration be the hyclone of 10% (v/v) DMEM culture medium in cultivate after 24h, draw and remove culture medium, will
1,2,4-tri-substituted piperazine like compound DMEM culture medium without serum does serial dilution (200 μMs-6.25 μMs) with 2 multiple proportions
Being inoculated on the mdck cell in 96 orifice plates by dilution order afterwards, every hole 100 μ L, each concentration be arranged in parallel 3 and tests
Multiple hole, after dosing, every hole adds the influenza virus 100 μ L of 100TCID50 as 1,2,4-tri-substituted piperazine like compound medicines realities
Test group, set cell controls group (i.e. Normal group) and virus control group simultaneously.By positive control drug ribavirin, (powder is criticized
Number is2013081301, purchased from Guangzhou Ai Chun Pharmaceutical Technology Co., Ltd, uses after DMSO fully dissolves) with without serum
DMEM culture medium do serial dilution (200 μMs-6.25 μMs) with 2 multiple proportions after be inoculated in 96 orifice plates by dilution order
On mdck cell, every hole 100 μ L, each concentration be arranged in parallel 3 and tests multiple hole, and after dosing, every hole adds 100TCID50
Influenza virus 100 μ L as positive control drug ribavirin drug study group.At 37 DEG C, 5%CO2Incubator is cultivated 48h
After, observe 1,2,4-tri-substituted piperazine like compound and the antiviral activity of ribavirin, and with Normal group and virus control group ratio
Relatively, observe and record cytopathy (CPE) situation.Experimental result is shown in Table 1.
Table 11, the CPE of 2,4-tri-substituted piperazine like compound and ribavirin observes
Note: compared with Normal group, "-": cell is without pathological changes；"+": cytopathy variability 0-24%；" ++ ": thin
Born of the same parents' pathological changes rate 25-49%；" +++ ": cytopathy variability 50-74%；" ++++": cytopathy variability 75-100%.
Experimental result: basis of microscopic observation, Normal group cell attachment is fine and close, form is good, and influenza virus is in MDCK
CPE strengthen with refractivity, downright bad, be broken for principal character.Drug study group respectively organizes cell, according to drug dilution gradient,
There is CPE in gradient rule, and CPE is with 1 as seen from the results in Table 1, and 2,4-tri-substituted piperazine like compound concentration reduce and gradually increase the weight of.
Meanwhile, by the antiviral activity of contrast 1,2,4-tri-substituted piperazine like compound with ribavirin, it appeared that 1,2,4-tri-replacement piperazine
Piperazine compound is compared with ribavirin, and 1,2,4-tri-substituted piperazine like compound antiviral activity is more preferable, lower to the activity of host cell.
Embodiment 31,2,4-tri-substituted piperazine like compound anti-influenza virus activities measure
It is 1.2 × 10 by cell density5The mdck cell of cells/mL is inoculated in 96 orifice plates, and every hole 100 μ L, containing volume
Percent concentration be the hyclone of 10% (v/v) DMEM culture medium in cultivate after 24h, draw and remove culture medium, will
1,2,4-tri-substituted piperazine like compound DMEM culture medium without serum does serial dilution (200 μMs-6.25 μMs) with 2 multiple proportions
Being inoculated on the mdck cell in 96 orifice plates by dilution order afterwards, every hole 50 μ L, each concentration be arranged in parallel 3 and tests again
Hole, after dosing, every hole adds the influenza virus 50 μ L of 100TCID50 as 1,2,4-tri-substituted piperazine like compound drug test groups,
Setting cell controls group, virus control group and positive controls, positive control drug is ribavirin simultaneously.At 37 DEG C, 5%CO2
Detect with mtt assay after incubator cultivates 72h, under 570nm wavelength, survey absorbance OD value, calculate medicine disease-resistant
Poison effective percentage (ER), computing formula is ER%=(drug treating group mean OD value-virus control group mean OD value)/(thin
Born of the same parents' matched group mean OD value-virus control group mean OD value) × 100%, calculate medicine to influenza according to Reed-Muench method
Virus causes CPE and produces the concentration of 50% suppression, i.e. half-inhibition concentration IC50, it is repeated 4 times experiment, averages, and according to
Formula TI=CC50/IC50Calculate drug therapeutic indices TI.
Experimental result: according to MTT result, the half using Reed-Muench method to calculate 1,2,4-tri-substituted piperazine like compound presses down
Concentration IC processed50It is 29.97 μMs, therapeutic index TI >=13.34.
Conclusion: 1,2,4-tri-substituted piperazine like compound has stronger inhibitory action, and drug use safety to influenza A virus
Height, therefore 1,2,4-tri-substituted piperazine like compound have application background widely in treatment influenza a virus infection disease, can
It is applied to prepare anti-influenza virus medicament.
Above content is to combine concrete preferred implementation further description made for the present invention, it is impossible to assert the present invention
Be embodied as be confined to these explanations.For general technical staff of the technical field of the invention, without departing from this
On the premise of inventive concept, it is also possible to make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Claims (4)
1.1,2,4-tri-substituted piperazine like compound purposes in preparing anti-influenza virus medicament, it is characterised in that described 1,2,4-tri-substituted piperazine like compound have a structure as shown in formula (I):
2. purposes as claimed in claim 1, it is characterised in that described influenza virus is influenza A virus.
3. purposes as claimed in claim 1, it is characterised in that described anti-influenza virus medicament makes tablet, capsule, granule, powder or oral liquid.
4. purposes as claimed in claim 1, it is characterised in that described anti-influenza virus medicament makes injection, injectable powder, injection or spray.
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| CN201610351594.XA CN105920004B (en) | 2016-05-24 | 2016-05-24 | Purposes of 1,2,4- tri- substituted piperazine like compound in preparing anti-influenza virus medicament |
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| CN201610351594.XA CN105920004B (en) | 2016-05-24 | 2016-05-24 | Purposes of 1,2,4- tri- substituted piperazine like compound in preparing anti-influenza virus medicament |
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| CN105920004B CN105920004B (en) | 2018-10-09 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2430966A1 (en) * | 2000-12-06 | 2002-06-13 | Signal Pharmaceuticals, Inc. | Anilinopyrimidine derivatives as jnk pathway inhibitors and compositions and methods related thereto |
| WO2005079799A1 (en) * | 2004-02-13 | 2005-09-01 | Glaxo Group Limited | 4-acyl-piperazines as anti-viral agents |
| US20110251215A9 (en) * | 2009-01-23 | 2011-10-13 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
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- 2016-05-24 CN CN201610351594.XA patent/CN105920004B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2430966A1 (en) * | 2000-12-06 | 2002-06-13 | Signal Pharmaceuticals, Inc. | Anilinopyrimidine derivatives as jnk pathway inhibitors and compositions and methods related thereto |
| WO2005079799A1 (en) * | 2004-02-13 | 2005-09-01 | Glaxo Group Limited | 4-acyl-piperazines as anti-viral agents |
| US20110251215A9 (en) * | 2009-01-23 | 2011-10-13 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
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