EP2819517A2 - Small molecule having antiviral properties - Google Patents
Small molecule having antiviral propertiesInfo
- Publication number
- EP2819517A2 EP2819517A2 EP12868920.5A EP12868920A EP2819517A2 EP 2819517 A2 EP2819517 A2 EP 2819517A2 EP 12868920 A EP12868920 A EP 12868920A EP 2819517 A2 EP2819517 A2 EP 2819517A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- virus
- small molecule
- cells
- monolayer
- antiviral properties
- 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.)
- Withdrawn
Links
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Definitions
- the invention reiates to biologically active compounds possessing antiviral properties for the treatment and prevention of viral infections of animals and humans.
- the invention can be used in hospitals, research laboratories, as well as livestock and poultry.
- the closest in structure to the claimed compound from this series (1 ) can be regarded as a prototype.
- the compound (1 ) in a concentration of 40 ug / mi in in vitro experiments the infectious titer of influenza ⁇ / ⁇ 3 ⁇ 2 and influenza virus
- CC50 concentration at which 50% of the cells die
- the invention is the small molecule (2) which has antiviral activity.
- the small molecule (2) has demonstrated low toxicity.
- Fig. 1 shows a scaffold for a small molecule.
- Fig. 2 shows a small molecule based on the scaffold of Fig. 1 .
- the compound produced from this synthesis is a pale yellow crystaliine solid, soluble in water, methanol, dimethyl sulfoxide, insoluble in benzene, ether and most other solvents.
- the compound is orally ingestibie and show efficacy against viruses including the influenza virus.
- Viruses Used a one-day monolayer culture of epithelial cells MDCK (dog kidney) Viruses. To assess the antiviral activity of the virus used the reference A / Puerto Rico/8/34, as well as pandemic influenza virus H1 1 v A/San kt-Peterburg/2/09 (similar to the so-called virus "swine fiu» A/Caiifornia/7/09).
- the maximum tolerable concentrations of the compounds was determined by MTT test in ceil culture MDCK.
- Testing of toxicity was carried out as follows: weighed weigh weighing 5 mg in a sterile test tube 5 ml. and the diluted growth medium for the cells MDCK (a-MEM, Bioiot, St. Russia) to a concentration of 1 mg / mL, thus obtaining a basic solution. More of the same medium made eight consecutive binary dilutions (500, 250, 125, 82.5, 31 .25, 1 5.13, 7.56 and 3.78 mg / mi, respectively), which was used for toxicity testing. The experience set in the four parallels for each concentration. One-day cell culture MDCK, grown in 98 ⁇ vveli plates (Costar), checked visually in an inverted microscope on the integrity of the monolayer.
- the plates were washed twice with medium without serum, and then have made the test compound in appropriate concentrations in a volume of 100 ml in each well.
- the plates were incubated for 72 h at 37 ° C in the presence of 5% C02, and then recorded the results of the experiment visually assessing the integrity of the monolayer compared with control cells, and by the MTT (quantitatively evaluating the viability of the ceils) using the tablet reader Hydex Chameleon.
- Statistical analysis was performed using the program Statistica 6.0.
- the plates were incubated for 60 min at 37 ° C in the presence of 5% CO 2, and then washed with medium to remove unbound viral particles to cells. Continue to make the drug in the wells with virus dilutions in 100 mi of the appropriate concentration. Each concentration of test compound was placed in four parallels for each virus dilution. Control wells filled with growth medium in the same volume. Also, the wells were left to re-test toxicity used concentrations.
- the plates were incubated for 72 h at 37 0 G, and then recorded the results of the experiment visually assessing the integrity of the monolayer as compared to control ceils and the degree of cytopathic effect of virus in ceil culture, put hemagglutination reaction and MTT method was used to quantify cell viability using the tablet reader Hydex Chameleon.
- Evaluation of toxicity, as well as evaluation of the antiviral action of drugs produced by three methods 1 ) monitoring and evaluation of the integrity of the monolayer cells under an inverted microscope. Implies a comparison of cell morphology of control wells with experienced and registration of changes under the influence of an agent (drug, virus, etc.). The change of morphology could include violating the integrity of the monolayer, changes in cell shape, expression of cytopathic effect in virus infection.
- MTT The method used in the evaluation of drug sensitivity, based on the ability of dehydrogenases of living cells to restore the form of colorless 3- 4,5-dimethylthiazol-2-yl-2 ,5-difenilterarazola (MTT reagent) to blue crystalline farmazana soluble in DMSO or 96% alcohol. Saturation of color indicates the intensity of metabolic processes in cells, ie, the normal level of viability. The color intensity is recorded with a spectrophotometer and the absorbance values obtained can be used for statistical data processing.
- the concentration of the drug during that kills 50% of a monolayer of cells in a test on the MDCK cells was 177 pg / ml.
- Drug concentration at which all the cells survive the monolayer was 62.5 micrograms / ml, which was used to test the antiviral activity of the drug.
- connection (2) in much smaller concentrations, in comparison with toxic, has a pronounced antiviral activity, reducing the titers of virus A / Puerto Rico/8/34 virus and pandemic influenza HlNlv A/Sankt- Peterburg/2/09 (A/California/7/09-podobny) for 3,0 lg concentrations 62.5 and 125 ug / ml, respectively, then there is a more active antiviral compound than with a prototype.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
This patent disclosure describes a new scaffold for a small molecule having antiviral properties, molecule having antiviral properties with demonstrated low toxicity is disclosed.
Description
SMALL MOLECULE HAVING ANTIVIRAL PROPERTIES
Technical field to which the invention pertains.
The invention reiates to biologically active compounds possessing antiviral properties for the treatment and prevention of viral infections of animals and humans. The invention can be used in hospitals, research laboratories, as well as livestock and poultry.
There is evidence of antiherpetic action (VL, Ruthenians, ON Chupakhin, E. H Uiomsky and other RF Patent 2345080 from 27.01 .2009), as well as (ON Chupakhin, VL
Rusinov, EN Uiomsky and other RF Patent 2376307 from 20.12.2009, the). Antiviral activity against influenza virus types A and B have R = H, CHS, SCH3 (V.LRusinov, E. N. Uiomsky, S. Deev. And other RF Patent 2340614 from 10.12.2008; VL Rusinov, ON Chupakhin, C . L. Deev, TS Shestakova, EN Uiomsky, Li Rusinov, Ol Kiselev, EG Deeva Synthesis and antiviral activity of nucleoside analogues on the basis of 1 ,2,4- triazolo [ 3,2-c] [1 ,2,4] triazine-7 (4H)-ones Proceedings of the Academy of Sciences, Chemical Bulletin, 2010, Na 1 , p. 135-142.).
The closest in structure to the claimed compound from this series (1 ) can be regarded as a prototype. By using the compound (1 ) in a concentration of 40 ug / mi in in vitro experiments, the infectious titer of influenza Α/Ή3Ν2 and influenza virus
A/Gonkong/1 /68 A/H5N1 A / Duck / Singapore R/F1 19-3/97 reduced by 0,5-3,0 Ig. However, this compound at higher concentrations showed cytotoxicity. The
concentration at which 50% of the cells die (CC50) is 80 ug / mi.
SUMMARY OF THE INVENTION
The invention is the small molecule (2) which has antiviral activity.
The small molecule (2) has demonstrated low toxicity.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a scaffold for a small molecule.
Fig. 2 shows a small molecule based on the scaffold of Fig. 1 .
DETAILED DESCRIPTION OF THE INVENTION
Synthesis
Example 1. Obtained from 0.05 mo! of sodium salt of
-1 ,2,4-triazo!o [5,1 -c] 1 ,2,4-triazine-7-one dihydrate action hiormetiipiva!ata with 0.05 moi using D F as a solvent, a solution of one equivalent of cysteine in ethanol. After the reaction, the solvent was removed in vacuo and the resulting precipitate was purified by column chromatography (eluent - acetonitrile: water = 8:1 ).
Chemical synthesis of the proposed scheme of compound (2) has the following physico- chemical characteristics: TPL = 204 OS, 1 H NMR spectrum in D20 δ, ppm: 5.18 (d, 1 H, CH2), 5.13 (d, 1 H, CH2) , 4.19 (m, 1 H, CH), 3.91 (m, 1 Η, SSN2), 3.39 (m, 1 Η, SSN2), 2.69 (S, 3Η, CH3), 1 18 (d, 9H, C (CHS) 3). Found: C - 40.56, H - 4,77, N - 20,32. Gross formula - C14H20N6O5S2. Calculated: C - 40.38, H - 4,84, N - 20,18%.
The compound produced from this synthesis is a pale yellow crystaliine solid, soluble in water, methanol, dimethyl sulfoxide, insoluble in benzene, ether and most
other solvents. The compound is orally ingestibie and show efficacy against viruses including the influenza virus.
Antiviral properties of the molecule of Fig. 2
Example 2 Toxicity and antiviral activity of compounds against influenza virus
cells. Used a one-day monolayer culture of epithelial cells MDCK (dog kidney) Viruses. To assess the antiviral activity of the virus used the reference A / Puerto Rico/8/34, as well as pandemic influenza virus H1 1 v A/San kt-Peterburg/2/09 (similar to the so-called virus "swine fiu» A/Caiifornia/7/09).
The maximum tolerable concentrations of the compounds was determined by MTT test in ceil culture MDCK.
Testing of toxicity was carried out as follows: weighed weigh weighing 5 mg in a sterile test tube 5 ml. and the diluted growth medium for the cells MDCK (a-MEM, Bioiot, St. Petersburg) to a concentration of 1 mg / mL, thus obtaining a basic solution. More of the same medium made eight consecutive binary dilutions (500, 250, 125, 82.5, 31 .25, 1 5.13, 7.56 and 3.78 mg / mi, respectively), which was used for toxicity testing. The experience set in the four parallels for each concentration. One-day cell culture MDCK, grown in 98~vveli plates (Costar), checked visually in an inverted microscope on the integrity of the monolayer. The plates were washed twice with medium without serum, and then have made the test compound in appropriate concentrations in a volume of 100 ml in each well. The plates were incubated for 72 h at 37 ° C in the presence of 5% C02, and then recorded the results of the experiment visually assessing the integrity of the monolayer compared with control cells, and by the MTT (quantitatively evaluating the viability of the ceils) using the tablet reader Hydex Chameleon. Statistical analysis was performed using the program Statistica 6.0.
Assessment of antiviral activity were carried out for two concentrations: maximum concentration (dilutions of the binary), which survived for 100% of a monolayer of ceils, and a concentration equal to half the previous one. To assess the antiviral activity of the virus used the reference A / Puerto Rico/8/34. One-day cell culture MDCK, grown in 98-weli plates (Costar), checked visually in an inverted microscope on the integrity of the monolayer. Next, prepare ten-fold dilution of virus on
maintenance growth medium with the addition of trypsin (from -1 to -6). Plates with a monolayer of ceils were washed twice with medium without serum, after which the viral breeding have made the appropriate wells in a volume of 50 mi. Control wells filled with growth medium with an equal volume. The plates were incubated for 60 min at 37 ° C in the presence of 5% CO 2, and then washed with medium to remove unbound viral particles to cells. Continue to make the drug in the wells with virus dilutions in 100 mi of the appropriate concentration. Each concentration of test compound was placed in four parallels for each virus dilution. Control wells filled with growth medium in the same volume. Also, the wells were left to re-test toxicity used concentrations. The plates were incubated for 72 h at 37 0 G, and then recorded the results of the experiment visually assessing the integrity of the monolayer as compared to control ceils and the degree of cytopathic effect of virus in ceil culture, put hemagglutination reaction and MTT method was used to quantify cell viability using the tablet reader Hydex Chameleon.
Statistical analysis was performed using the program Statistica 6.0 [Borovikov VP, IP Borovikov Statistica. Statistical analysis and data processing in Windows. - M„, 1997. - S. 33-34], using regression analysis [Rokitskii PF Biological statistics. - Minsk, 1967. - S. 155]. The results are presented using graphs derived from the linear regression equation, which has the general form y = k + b * x, where y is expressed by the constant k and the angular coefficient b, multiplied by the variable x. At the same time on the graph indicates the coefficient of determination, r2, and designated as expressing the spread of values around the regression line relative to the total spread of values. The closer the value of r2 to 1 , the better the model explains the variability of the variables. The confidence interval for ail the regression equations was equal to
95%,
Evaluation of toxicity of the claimed compounds
Evaluation of toxicity, as well as evaluation of the antiviral action of drugs produced by three methods:
1 ) monitoring and evaluation of the integrity of the monolayer cells under an inverted microscope. Implies a comparison of cell morphology of control wells with experienced and registration of changes under the influence of an agent (drug, virus, etc.). The change of morphology could include violating the integrity of the monolayer, changes in cell shape, expression of cytopathic effect in virus infection.
2) Registration in the presence of the virus haemagglutinin with a suspension of chicken erythrocytes (0.75%). The reaction of hemagglutination (RHA) to evaluate the qualitative presence of the virus in the sample.
3) The method of MTT. The method used in the evaluation of drug sensitivity, based on the ability of dehydrogenases of living cells to restore the form of colorless 3- 4,5-dimethylthiazol-2-yl-2 ,5-difenilterarazola (MTT reagent) to blue crystalline farmazana soluble in DMSO or 96% alcohol. Saturation of color indicates the intensity of metabolic processes in cells, ie, the normal level of viability. The color intensity is recorded with a spectrophotometer and the absorbance values obtained can be used for statistical data processing.
The concentration of the drug during that kills 50% of a monolayer of cells in a test on the MDCK cells was 177 pg / ml. Drug concentration at which all the cells survive the monolayer was 62.5 micrograms / ml, which was used to test the antiviral activity of the drug.
In this test the viability of cells in the control was 0,571 ± 0,044. Thus, the absorbance value at which 50% of the surviving cell monolayer is 0.286. If you put this value on the y-axis graph, shown in Figure 1 , drawn through a line parallel to the x-axis, and then from the point of intersection of this line with the schedule to the viability of the perpendicular to the x-axis, we obtain a value corresponding to the concentration of the claimed compounds which killed 50% of a monolayer of cells (see Table 2)
Evaluation of antiviral activity
The proposed connection of all three methods of assessment (concentration = 62.5 mg / ml) had a pronounced antiviral activity, reducing viral titers at 3 Ig relative to the control of infectious virus activity.
3aBncn OCTb >KH3Hecnoco6Hoc™ OT OHLieHTpaLinn npenapaTa NMR 289
100 200 300 400 500 600
KoH_ieHTpau,n5i npenapaTa,
Table 1. Dependence of the viability of MDCK cells on the concentration of the claimed compounds. npenapaTa NMR 289
100 200 300 400 500 600
KoH_ieHTpau,n5i npenapaTa,
Table 2 Graphical calculation of the concentration of the claimed compounds in which the die 50% of the cell monolayer.
In constructing the graph corresponding to the action of the claimed compounds, the coefficient of determination r2 was equal to 0.86, which suggests that this model explains well the variation of the tested variables, namely, the effect of test compounds on cells infected with influenza virus. In constructing the perpendiculars through the points corresponding to an optical density at which 50% of surviving cells of the monolayer on the vertical axis and the intersection of the perpendicular to the line corresponding to the viability of cells in the drug, we have the following schedule as shown in Table 3.
Προτι iBOBi ipycHoe flei icTBi ie npenapaTaNMR 289
lg τι iTpa Bi ipyca
Table 3 The antiviral effect of the claimed compounds
From Table 3, it follows that the intersection point of the perpendicular to the x-axis corresponds to the dilution of the virus lg equal -3.5. Given the fact that the virus infects the drug in the absence of cell monolayer to a value equal to 10-6,5 (infectivity of the virus, clarified in a separate test for testing the biological properties of virus A/PR/8/34), we can say that the use of the drug under in vitro conditions reduces the activity of the infectious virus 31g.
The data presented above show that the prototype compound (1) is more toxic than the claimed connection (for connection (1) = 80mkg/ml SC50 and SC50 to the claimed compounds = 177 ug
/ ml). Compound (1) are active against a pandemic influenza virus A/HlNlv strain - A/Sankt- Peterburg/2/09 (A/Calif ornia/7/09-podobny). At the same time, the alleged connection (2) in much smaller concentrations, in comparison with toxic, has a pronounced antiviral activity, reducing the titers of virus A / Puerto Rico/8/34 virus and pandemic influenza HlNlv A/Sankt- Peterburg/2/09 (A/California/7/09-podobny) for 3,0 lg concentrations 62.5 and 125 ug / ml, respectively, then there is a more active antiviral compound than with a prototype.
10
Claims
1 . A molecular scaffold as shown in Fig 1 .
2. A small molecule having antiviral properties as shown in Fig. 2.
3. The small molecule of claim 2 in an orally ingestible form used to treat influenza infections in humans and animals.
4. The small molecule of claim 2 in an orally ingestible form used to treat viral infections.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2012/025070 WO2013122575A2 (en) | 2012-02-14 | 2012-02-14 | Small molecule having antiviral properties |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2819517A2 true EP2819517A2 (en) | 2015-01-07 |
Family
ID=48984871
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP12868920.5A Withdrawn EP2819517A2 (en) | 2012-02-14 | 2012-02-14 | Small molecule having antiviral properties |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP2819517A2 (en) |
| JP (1) | JP2015507007A (en) |
| WO (1) | WO2013122575A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015016818A1 (en) * | 2013-07-29 | 2015-02-05 | Ghias Asghar | Novel azolo-1,2,4-triazine derived antiviral oral therapeutic |
| US20190211024A1 (en) * | 2016-08-19 | 2019-07-11 | General Research Laboratory | Small molecules having antiviral properties |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4405619A (en) * | 1981-09-02 | 1983-09-20 | Diamond Shamrock Corporation | Antiinflammatory substituted-1,2,4-triazolo[4,3-b]-1,2,4-triazines |
| TWI335913B (en) * | 2002-11-15 | 2011-01-11 | Vertex Pharma | Diaminotriazoles useful as inhibitors of protein kinases |
| AU2005309019A1 (en) * | 2004-11-24 | 2006-06-01 | Novartis Ag | Combinations of JAK inhibitors and at least one of Bcr-Abl, Flt-3, FAK or RAF kinase inhibitors |
| RU2294936C1 (en) * | 2005-06-29 | 2007-03-10 | Государственное Образовательное Учреждение Высшего Профессионального Образования Уральский Государственный Технический Университет-УПИ | 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7(4h)-one sodium salt dihydrate possessing antiviral activity |
| JP2010510268A (en) * | 2006-11-23 | 2010-04-02 | ノバルティス アーゲー | 5-sulfanylmethyl- [1,2,4] triazolo [1,5-A] pyrimidin-7-ol as a CXCR2 antagonist |
| RU2343154C2 (en) * | 2007-01-31 | 2009-01-10 | Общество с ограниченной ответственностью Научно-техническое предприятие "Лиганд" | METHOD OF OBTAINING SODIUM SALT OF 2-METHYLTHIO-6-NITRO-1,2,4-TRIAZOLO[5,1-c]-1,2,4-TRIAZIN-7-ONE, DIHYDRATE |
| RU2345080C2 (en) * | 2007-02-16 | 2009-01-27 | ГОУ ВПО Уральский государственный технический университет-УПИ | 4-(4'-HYDROXYBUTYL)-6-PHENYL-1,2,4-TRIAZOLO[5,1-c][1,2,4]TRIAZIN-7-ON |
| RU2376307C1 (en) * | 2008-05-27 | 2009-12-20 | Институт органического синтеза им. И.Я. Постовского Уральского отделения Российской академии наук | 4-((Z)-4'-HYDROXYBUTENE-2'-YL)-2-R-6-FURYL-1,2,4-TRIAZOLO[5,1-c][1,2,4]TRIAZINE-7-ONS |
-
2012
- 2012-02-14 WO PCT/US2012/025070 patent/WO2013122575A2/en active Application Filing
- 2012-02-14 JP JP2014557606A patent/JP2015507007A/en active Pending
- 2012-02-14 EP EP12868920.5A patent/EP2819517A2/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2013122575A3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2015507007A (en) | 2015-03-05 |
| WO2013122575A3 (en) | 2014-05-01 |
| WO2013122575A2 (en) | 2013-08-22 |
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