RU2790376C1 - DIMETHYL 7-METHYL-2-(PYRROLIDINE-1-yl)-4-PHENYLPYRROLO[2,1-ƒ][1,2,4]TRIAZINE-5,6-DICARBOXYLATE AND DIMETHYL 7-METHYL-2-(4-R1-PHENYL)-4-(4-R2-PHENYL)PYRROLO[2,1-ƒ][1,2,4]TRIAZINE-5,6-DICARBOXYLATES EXHIBITING ANTIVIRAL ACTIVITY - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the field of biologically active compounds exhibiting antiviral effect against the strain of influenza virus A/Puerto Rico/8/34 (H1N1) and constituting dimethyl 7-methyl-2-(pyrrolidine-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate by the formula (7)

and dimethyl 7-methyl-2-(4-R¹-phenyl)-4-(4-R²-phenyl)pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylates by the formula (8)

, wherein R¹ is Me and R² is Me; or R¹ is Cl and R² is Me; or R¹ is H and R² is Cl.

EFFECT: creation of new chemical compounds of the azoloazine series — dimethyl 7-methyl-2-(pyrrolidine-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate by the formula (7) and dimethyl 7-methyl-2-(4-R¹-phenyl)-4-(4-R²-phenyl)pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylates by the formula (8), exhibiting a significant antiviral effect against the strain of influenza virus A/Puerto Rico/8/34 (H1N1).

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Description

The invention relates to the field of biologically active compounds, which are dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate and dimethyl 7-methyl-2-(4-R ¹ -phenyl)-4-(4-R ² -phenyl) pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylates having antiviral activity against influenza virus strain A/Puerto Rico/8/34 (H1N1).

The invention can find application in medicine and veterinary medicine.

Influenza is an acute high-contact respiratory viral infection caused by influenza viruses type A, B and C (family Orthomyxoviridae, genus Influenzavirus). This infection has a propensity for epidemic spread and affects all age groups of the population in various geographical conditions. Type A virus is the most common and is the cause of major pandemics. A large number of cases of severe/complicated influenza, as well as deaths, are recorded annually, which is associated with high morbidity and involvement in the epidemic process of people from risk groups for an unfavorable course of the disease [1].

Influenza and ARVI remain practically uncontrolled diseases due to the high antigenic variability of circulating influenza viruses and the heterogeneity of ARVI pathogens. An example of this is the causative agent of the influenza A / H1N1 virus, called "swine flu" and circulating in the epidemic season of 2009-2010. The A/H1N1/2009 influenza pandemic revealed quite serious problems in the treatment of this infection, namely: the lack of the required amount of antiviral therapy and the limited use of drugs due to resistance.

There are three main groups of anti-influenza drugs with proven clinical efficacy and approved by WHO: _M2 -channel blockers - amantadine and rimantadine, viral neuraminidase inhibitors - oseltamivir (Tamiflu) and zanamivir (Relenza) and an inhibitor of the endonuclease activity of the influenza virus polymerase complex - baloxavir marboxil ( Xofluza).

The antiviral effect of amantadine and rimantadine is realized by blocking the M ₂ ion channels of the influenza A virus, which impairs the ability of the virus to penetrate the target cell and release the viral ribonucleoprotein (there is no lysis of the virus envelope). Thus, an important step in viral replication, the release of the viral genome, is inhibited. The disadvantages of drugs in this group include a narrow spectrum of action (the drugs are active against influenza A viruses, but not effective against influenza B viruses), relatively high toxicity and the rapid formation of resistance.

The target of drugs of the second group is neuraminidase, one of the key enzymes involved in viral replication. They bind to the hydrophobic "pocket" of the active site of neuraminidase (sialidase) of influenza A and B viruses and block the removal of sialic acid residues from the surface of infected cells. As a result of inhibition of neuraminidase, the ability of viruses to penetrate into healthy cells is impaired, the release of virions from infected cells is inhibited, and their resistance to the inactivating effect of respiratory secretions decreases. In addition, neuraminidase inhibitors reduce the production of pro-inflammatory cytokines, thereby preventing the development of a local inflammatory response and attenuating the clinical manifestations of a viral infection. The disadvantages of drugs of the second group include the presence of numerous side effects (allergic reactions, complications from the gastrointestinal tract and neurological disorders) [2].

Baloxavir marboxil blocks the viral enzyme endonuclease, which cleaves the primer from cellular mRNA. This blockage prevents transcription of the viral genome and the production of viral proteins. When analyzing viruses isolated from patients treated with baloxavir, it was found that some of them carry an amino acid substitution, leading to a decrease in the sensitivity of the virus to the drug by several tens of times.

Given the duration of the use of drugs related to _M2 -protein blockers and neuraminidase inhibitors in clinical practice for 20-40 years, as well as the emergence of new virus mutations, the development of effective drugs for the treatment and prevention of influenza is one of the priorities of modern medicinal chemistry and virology.

The scientific literature describes the antiviral effect of pyrrolo[2,1-ƒ][1,2,4]triazines nucleosides against various RNA viruses: hepatitis C, Ebola virus, parainfluenza, measles, endemic mumps, human immunodeficiency and norovirus [3] .

Remdesivir (GS-5734) (I), whose structural fragment is pyrrolo[2,1-ƒ][1,2,4]triazine, developed by Gilead Sciences (Foster City, California, USA) to combat the epidemic of the disease, caused by the Ebola virus in West Africa in the mid-2010s, has also demonstrated activity against Marburg hemorrhagic fever virus (MARV), SARS-coV and MERS-coV) [4, 5].

C-nucleoside pyrrolo[2,1-ƒ][1,2,4]triazine II showed inhibitory activity against respiratory syncytial virus (RSV) and corresponding selectivity towards mitochondrial RNA and DNA polymerases [6].

The Gilead Sciences patent describes the pyrrolo[2,1-ƒ][1,2,4]triazine III nucleotide for the treatment of infections caused by parainfluenza virus of the Paramyxoviridae family [7].

The essence of the invention

The technical result of this invention is the creation of new chemical compounds of the azoloazinium series - dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazin-5,6- dicarboxylate 7 and dimethyl 7-methyl-2-(4-R ¹ -phenyl)-4-(4-R ² -phenyl)pyrrolo[2,1-ƒ][1,2,4]triazine-5,6- dicarboxylates 8a-8c, which have a pronounced antiviral effect against the A/Puerto Rico/8/34 (H1N1) influenza virus strain. These compounds can be used to create domestic antiviral drugs.

Compounds 7 and 8a-c, methods for their preparation, and physicochemical characteristics are not described in the literature.

The essence of the invention is illustrated by the following materials:

On FIG. 1 shows the chemical scheme for the synthesis of the claimed compounds 7, 8a-c.

On FIG. 2 is a table showing data on cytotoxicity and antiviral activity of compounds 7, 8a-c, rimantadine and ribavirin against influenza virus A/Puerto Rico/8/34 (H1N1) in cell culture.

Method for obtaining dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (7) and dimethyl 7-methyl- 2-(4-R ¹ -phenyl)-4-(4-R ² -phenyl)pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylates (8a-c).

The claimed compounds are dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (7) and dimethyl 7-methyl -2-(4-R ¹ -phenyl)-4-(4-R ² -phenyl)pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylates (8a-c), received in two stages. Synthesis of the starting compounds - 3,5-disubstituted 1,2,4-triazines (1 and 2) was carried out according to modified procedures described in the literature [8, 9].

The corresponding 1,2,4-triazines 1,2a-c are treated with Meerwein's reagent (triethyloxonium tetrafluoroborate) and the corresponding N(1)-ethyl-1,2,4-triazinium salts 3, 4a-c are obtained. Further, from N(1)-ethyl-1,2,4-triazinium cations 3, 4a-c under the action of triethylamine in absolute dioxane, ylides 5, 6a-c are generated in situ, which enter into the 1,3-dipolar cycloaddition reaction with dimethylacetylenedicarboxylate to form target compounds - pyrrolo[2,1-ƒ][1,2,4]triazines 7 and 8a-c (Figure 1).

The characteristics of the new compounds are given in the examples of a specific implementation. The structure of the obtained compounds was confirmed by ^1H NMR spectra, mass spectra and elemental analysis. The melting points of the compounds were determined on a Stuart SMP3 instrument (Barloworld Scientific).

^1H NMR spectra in DMSO-d ₆ and CDCl ₃ were recorded on a Bruker DRX-400 instrument, Me ₄ Si was used as an internal standard. Chemical shifts (δ) are given in parts per million (ppm), spin-spin coupling constants (J) - in Hertz.

Mass spectra were recorded on a Varian MAT-311A spectrometer. Recording conditions: accelerating voltage 3 kV, energy of ionizing electrons 70 eV, direct injection of the sample into the source.

Elemental analysis was performed on an automatic CHNS-O analyzer PE 2400 series II (Perkin Elmer).

Example 1 Synthesis of dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (7).

Stage 1. Obtaining 1-ethyl-3-(pyrrolidin-1-yl)-5-phenyl-1,2,4-triazinium tetrafluoroborate (3).

To a solution of 1.3 g (6.63 mmol) of triethyloxonium tetrafluoroborate in 7.0 ml of absolute dichloroethane is added 1.0 g (4.42 mmol) of 3-(pyrrolidin-1-yl)-5-phenyl-1,2, 4-triazine (1). The reaction mixture was stirred at room temperature for 3 h, the precipitate formed was filtered off and recrystallized from absolute ethanol. 1-Ethyl-3-(pyrrolidin-1-yl)-5-phenyl-1,2,4-triazinium tetrafluoroborate (3) (1.15 g, 64%) is obtained.

Step 2. Preparation of dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (7).

To a suspension containing 806 mg (2.36 mmol) of 1-ethyl-3-(pyrrolidin-1-yl)-5-phenyl-1,2,4-triazinium tetrafluoroborate (3) in 4 ml of absolute dioxane and 402 mg ( 2.83 mmol) of dimethylacetylenedicarboxylate, 250 mg (2.47 mmol) of triethylamine are added dropwise. The reaction mass is kept for 2 days at room temperature.

The precipitate that formed was filtered off and recrystallized from aqueous ethanol. Yellow crystals of dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (7) (409 mg; 44%). T pl. 126-127°C.

Found, %: С 64.01; H 5.73; N 14.17. Calculated, % for C ₂₁ H ₂₂ N ₄ O ₄ (M 394.43): C 63.95; H, 5.62; N, 14.20.

^1H NMR spectrum (DMSO-d ₆ /CCl ₄ ): 1.99 (br. s, 4H, (CH ₂ ) ₂ ); 2.65 (s, 3 H, Me); 3.29 (s, 3H, CO ₂ Me); 3.58 (br. s, 4H, N(CH ₂ ) ₂ ); 3.77 (s, 3H, CO ₂ Me); 7.48-7.58 (m, 5H, Ph).

Mass spectrum, m/z (%): 395 [M+1] ⁺ (24), 394 [M] ⁺ (100), 366 (15), 363 (10), 362 (9), 307 (10) , 275 (24), 165 (13), 70 (52).

Example 2 Synthesis of dimethyl 7-methyl-2,4-di(4-methylphenyl)-[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8a).

Stage 1. Preparation of 1-ethyl-3,5-di(4-methylphenyl)-1,2,4-triazinium tetrafluoroborate (4a).

To a solution of 1.3 g (6.89 mmol) of triethyloxonium tetrafluoroborate in 20.0 ml of absolute dichloroethane is added 1.2 g (4.60 mmol) of 3,5-di(4-methylphenyl)-1,2,4-triazine (2a). The reaction mass was stirred at room temperature for 4 h, the precipitate formed was filtered off and recrystallized from absolute ethanol. 1-Ethyl-3,5-di(4-methylphenyl)-1,2,4-triazinium tetrafluoroborate (4a) (1.21 g; 70%) is obtained.

Stage 2. Preparation of dimethyl 7-methyl-2,4-di(4-methylphenyl)-pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8a).

To a suspension containing 1.2 g (3.18 mmol) of 1-ethyl-3,5-di(4-methylphenyl)-1,2,4-triazinium tetrafluoroborate (4a) in 5 ml of absolute dioxane and 0.54 g (3.82 mmol) of dimethylacetylenedicarboxylate, 0.35 g (3.50 mmol) of triethylamine are added dropwise. The reaction mass is kept for 4 days at room temperature. The precipitate that formed was filtered off and recrystallized from ethanol. Yellow crystals of dimethyl 7-methyl-2,4-di(4-methylphenyl)-pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8a) (247 mg, 18 %). T pl. 185-187°C.

Found, %: С 70.05; H, 5.47; N 9.64. Calculated, % for C ₂₅ H ₂₃ N ₃ O ₄ (M 429.48): C 69.92; H, 5.40; N 9.78.

^1H NMR spectrum (CDCl ₃ ): 2.43 (s, 3H, 4-Me-C ₆ H ₄ ); 2.46 (s, 3H, 4-Me-C ₆ H ₄ ); 2.91 (s, 3H, Me); 3.48 (s, 3H, CO ₂ Me); 3.90 (s, 3H, CO ₂ Me); 7.29 (d, 2H, 4-Me-C ₆ H ₄ , J=8.0 Hz); 7.33 (d, 2H, 4-Me-C ₆ H ₄ , J=8.0 Hz); 7.69 (d, 2H, 4-Me-C ₆ H ₄ , J=8.0 Hz); 8.35 (d, 2H, 4-Me-C ₆ H ₄ , J=8.0 Hz).

Mass spectrum, m/z (%): 430 [M+l] ⁺ (28), 429 [M] ⁺ (100), 398 (12), 397 (18), 382 (10), 366 (28) , 365 (15), 310 (18), 215 (24).

Example 3 Synthesis of dimethyl 7-methyl-4-(4-methylphenyl)-2-(4-chlorophenyl)-[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8b).

Stage 1. Preparation of 1-ethyl-5-(4-methylphenyl)-3-(4-chlorophenyl)-1,2,4-triazinium tetrafluoroborate (4b).

To a solution of 1.52 g (7.99 mmol) of triethyloxonium tetrafluoroborate in 20.0 ml of absolute dichloroethane is added 1.5 g (5.32 mmol) of 5-(4-methylphenyl)-3-(4-chlorophenyl)-1, 2,4-triazines (2b). The reaction mixture was stirred at room temperature for 2 h, the precipitate formed was filtered off and recrystallized from absolute ethanol. 1-Ethyl-5-(4-methylphenyl)-3-(4-chlorophenyl)-1,2,4-triazinium tetrafluoroborate (4b) (1.61 g; 76%) is obtained.

Stage 2. Preparation of dimethyl 7-methyl-4-(4-methylphenyl)-2-(4-chlorophenyl)-[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8b).

To a suspension containing 0.9 g (2.26 mmol) of 1-ethyl-5-(4-methylphenyl)-3-(4-chlorophenyl)-1,2,4-triazinium tetrafluoroborate (4b) in 4 ml of absolute dioxane and 0.39 g (2.72 mmol) of dimethylacetylenedicarboxylate, 0.25 g (2.49 mmol) of triethylamine are added dropwise. The reaction mass is kept for 4 days at room temperature. The precipitate formed is filtered off and recrystallized from ethanol. Yellow crystals of dimethyl 7-methyl-4-(4-methylphenyl)-2-(4-chlorophenyl)-[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8b) are obtained ( 338 mg; 33%). T pl.=167-168°C.

Found, %: С 64.11; H 4.53; No. 9.14. Calculated, % for C ₂₄ H ₂₀ ClN ₃ O ₄ (M 449.90): C 64.07; H 4.48; N 9.34.

^1H NMR spectrum (CDCl ₃ ): 2.46 (s, 3H, 4-Me-C ₆ H ₄ ); 2.91 (s, 3H, Me); 3.49 (s, 3H, CO ₂ Me); 3.91 (s, 3H, CO ₂ Me); 7.34 (d, 2H, 4-Me-C ₆ H ₄ , J=8.0 Hz); 7.46 (d, 2H, 4-Cl-C ₆ H ₄ , J=8.8 Hz); 7.69 (d, 2H, 4-Me-C ₆ H ₄ , J=8.0 Hz); 8.41 (d, 2H, 4-Cl-C ₆ H ₄ , J=8.8 Hz).

Mass spectrum, m/z (%): 451 [M+2] ⁺ (38), 450 (28), 449 [M] ⁺ (100), 418 (14), 417 (22), 386 (32) , 385 (21), 330 (16), 225 (17).

Example 4 Synthesis of dimethyl 7-methyl-2-phenyl-4-(4-chlorophenyl)-[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8c).

Stage 1. Preparation of 1-ethyl-3-phenyl-5-(4-chlorophenyl)-1,2,4-triazinium tetrafluoroborate (4c).

1.5 g (5.60 mmol) of 3-phenyl-5-(4-chlorophenyl)-1,2,4- triazine (2c). The reaction mixture was stirred at room temperature for 2 h, the precipitate formed was filtered off and recrystallized from absolute ethanol. 1-Ethyl-3-phenyl-5-(4-chlorophenyl)-1,2,4-triazinium tetrafluoroborate (4c) (1.35 g; 63%) is obtained.

Stage 2. Preparation of dimethyl 7-methyl-2-phenyl-4-(4-chlorophenyl)-[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8c).

To a suspension containing 0.81 g (2.11 mmol) of 1-ethyl-3-phenyl-5-(4-chlorophenyl)-1,2,4-triazinium tetrafluoroborate (4c) in 4 ml of absolute dioxane and 0.36 g (2.53 mmol) of dimethylacetylenedicarboxylate, 0.24 g (2.32 mmol) of triethylamine are added dropwise. The reaction mass is kept for 2 days at room temperature. The precipitate that formed was filtered off and recrystallized from ethanol. Yellow crystals of dimethyl 7-methyl-2-phenyl-4-(4-chlorophenyl)-[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (8c) (202 mg; 22 %). T pl. 140-142°C.

Found, %: С 63.42; H 4.23; N 9.57. Calculated, % for C ₂₃ H ₁₈ ClN ₃ O ₄ (M 435.87): C 63.38; H 4.16; N9.64.

^1H NMR spectrum (DMSO-d ₆ /CCl ₄ ): 2.86 (s, 3H, Me); 3.48 (s, 3H, CO ₂ Me); 3.85 (s, 3H, CO ₂ Me); 7.48-7.51 (m, 3H, Ph); 7.59 (d, 2H, 4-Cl-C ₆ H ₄ , J=8.4 Hz); 7.72 (d, 2H, 4-Cl-C ₆ H ₄ , J=8.4 Hz); 8.35-8.39 (m, 2H, Ph).

Mass spectrum, m/z (%): 438 (9), 436 (27), 435 (100), 405 (28), 404 (31), 403 (68), 372 (19), 316 (25) , 218(16), 186(16).

Evaluation of the antiviral activity of dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate (7) and dimethyl 7-methyl -2-(4-R ¹ -phenyl)-4-(4-R ² -phenyl)pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylates (8a-c)

The toxicity and antiviral activity of the compounds were studied in cell culture against influenza virus A/Puerto Rico/8/34 (H1N1). As a result of testing were calculated 50% cytotoxic dose (CC ₅₀ ), 50% effective dose (IC ₅₀ ) and selectivity index (SI). Known antiviral drugs with different mechanisms of action - rimantadine and ribavirin - were used as reference drugs.

Example 5. Study of the toxicity of the claimed compounds

The toxicity of the claimed compounds was studied in relation to MDCK cells (dog kidney cells). MDCK cells were seeded in 96-well plates and cultured at 36° C. in MEM medium supplemented with 10% bovine serum under 5% CO ₂ until a monolayer was obtained. Stock solutions of concentration 10 mg/ml in dimethyl sulfoxide were prepared from the studied compounds, after which a series of threefold dilutions in MEM medium from 300 to 3.7 μg/ml was prepared. The dissolved compounds were added to the wells of the plates and incubated for 3 days at 36°C. After this period, the cells were washed 2 times for 5 minutes with phosphate-buffered saline, and the number of living cells was assessed using the microtetrazolium test (MTT). For this purpose, 100 μl of a solution (5 mg/ml) of 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (ICN Biochemicals Inc., Aurora, Ohio) in physiological saline was added to the wells of the plates. Cells were incubated at 36°C in an atmosphere of 5% CO ₂ for 2 hours and washed for 5 minutes with phosphate-buffered saline. The precipitate was dissolved in DMSO (100 µl per well), after which the optical density in the wells of the plates was measured on a Thermo Multiskan FC multifunctional reader (Thermo Fisher Scientific, USA) at a wavelength of 540 nm. According to the results of the test for each compound, a 50% cytotoxic concentration (CC ₅₀ ) was determined, i.e. the concentration of the compound that causes the death of 50% of the cells in culture. The results are shown in Figure 2. The data obtained indicate a relatively low cytotoxicity of the claimed compounds.

Example 6. Study of the antiviral activity of the claimed compounds

The evaluation of the antiviral activity of the compounds was carried out using the test to reduce the degree of cytopathic action. In the experiments used influenza virus A/Puerto Rico/8/34 (H1N1). The studied substances in the concentration range of 300-3.7 μg/ml were applied to the cells in the wells of the tablet, incubated for 1 hour, then the cells were infected with the virus at a dose of 0.01 TCID ₅₀ per cell. Cells were incubated for 72 hours, after which cell survival was analyzed using the MTT assay as described above. Based on the data obtained, a 50% inhibitory concentration (IC ₅₀ ) was calculated for each compound; concentration, which reduced the degree of viral destruction of cells by 50%, and the selectivity index SI - the ratio of 50% of the cytotoxic concentration of SS ₅₀ to 50% of the inhibitory concentration of IC ₅₀ .

As a result of the study of inhibition of the reproduction of influenza virus A/Puerto Rico/8/34 (H1N1) for the claimed compounds 7 and 8a-c, selectivity indices were obtained, in some cases exceeding those of the comparison drugs - rimantadine and ribavirin under similar conditions (Figure 2). The data obtained indicate a high virus-inhibiting activity of the claimed compounds.

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Claims (7)

1. Dimethyl 7-methyl-2-(pyrrolidin-1-yl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate of formula (7)

, having antiviral activity against influenza virus strain A/Puerto Rico/8/34 (H1N1). 2. Dimethyl 7-methyl-2-(4-R ¹ -phenyl)-4-(4-R ² -phenyl)pyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylates general formula (8)

, where R ¹ - Me and R ² - Me; or R ¹ - Cl and R ² - Me; or R ¹ - H and R ² - Cl, having antiviral activity against influenza virus strain A/Puerto Rico/8/34 (H1N1).

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