WO2023085979A1 - Novel derivatives of favipiravir - Google Patents

Abstract

The invention relates to the field of the chemical and pharmaceutical industry and medicine and concerns novel derivatives of favipiravir, and more particularly novel salts of favipiravir with amino acids, such as favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate, as well as a pharmaceutical composition and a drug containing the novel salts of favipiravir. The invention makes it possible to reduce the risks of an increase in liver transaminase levels during treatment, which is associated with hepatotoxicity.

Description

NEW FAVIPIRAVIR DERIVATIVES

The invention relates to the field of chemical-pharmaceutical industry and medicine, and represents new derivatives of favipiravir, namely, new salts of favipiravir with amino acids, as well as a pharmaceutical composition and a drug containing new salts of favipiravir.

One of the most urgent problems of modern medicine is the fight against viral infections. According to WHO, every year 2 billion people suffer from infectious diseases in the world, and for 17 million of them it is the cause of death. Every day in the world, 50 thousand deaths are caused by infectious diseases, which still remain among the leading causes of death and the first cause of premature death [Briko N.I., Mindlina A.Ya., Polybii R.V. The universality of changes in the manifestations of the epidemic process of anthroponotic infections over the past decades. Journal of Microbiology. 2015; 5:12-20].

Most viruses are viruses whose genome is encoded by a single strand of RNA and which use the viral RNA-dependent RNA polymerase for their replication. Examples of such viruses are influenza virus, coronavirus, picornavirus, arenavirus, flavivirus, bunyavirus, filovirus, phlebovirus, hantavirus, enterovirus, togavirus, calicivirus, respiratory syncytial virus, parainfluenza virus, rhinovirus, metapneumovirus, rotavirus, or noravirus.

Nucleoside analogues directly target blocking the activity of RNA-dependent RNA polymerase and block the synthesis of the viral RNA chain for a wide range of RNA viruses, including the human coronavirus family. For example, favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide), a guanine analogue approved in clinical practice for the treatment of influenza, effectively blocks the RNA-dependent RNA polymerase of influenza viruses (various types), Ebola virus, yellow fever, chikungunya, noroviruses, enteroviruses, etc. [De Clercq, E. New nucleoside analogues for the treatment of hemorrhagic fever virus infections. Chem. Asian J. 14, 3962-3968, 2019].

The universal mechanism of action of favipiravir, which specifically acts on the fundamental enzyme of the viral replication apparatus, suggests a wide spectrum of antiviral activity of this substance, which has been demonstrated in many studies listed below. Antiviral activity of favipiravir.

The effect of favipiravir against the influenza virus.

Influenza epidemics happen all over the world every year. The disease is caused by influenza virus strains of varying virulence. The highly pathogenic avian influenza A(H5N1) virus caused the first outbreak in Hong Kong in 1997. and continues to cause local outbreaks of this type of influenza every year. Avian influenza A(H7N9) epidemic in China in 2013 and the influenza A(H1N1) pandemic in 2009 resulted in 17,700 deaths, and influenza is still one of the major public health problems worldwide, not only in terms of incidence but also in the critical health complications it causes [Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection.- 2010,- N. Engl. J. Med.]. The A(H1N1) epidemic showed that this strain is resistant to ocetalmivir (Tamiflu), a neuramidase inhibitor, and to amantadine, an inhibitor of the non-structural protein M2. In this regard, in medical practice, a drug with a different mechanism of action is urgently needed.

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is effective against a wide range of influenza virus strains, including A(H1N1), A(H5N1) and A(H7N9), due to the fact that viral RNA -dependent RNA polymerase (PsRp) misidentifies the favipirovir-RTF metabolite as a purine nucleotide. Favipiravir has completed phase III trials in Japan and Phase II trials in the United States for the treatment of influenza.

In addition to antiviral activity against influenza, favipiravir inhibits the replication of arenaviruses, phleboviruses (Rift-Valle fever, phlebotomic fever and Punta Toro fever), hantaviruses (Maporal, Dobrava and Prospect Hill); flaviviruses (yellow fever and West Nile fever); enteroviruses (full and rhinoviruses); respiratory syncytium paramyxovirus and norovirus [Yousuke Furuta, Brian B. Gowen, KazumiTakahashi, Kimiyasu Shiraki, Donald F. Smee, Dale L. Barnard. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research, 2013, Volume 100, Issue 2].

The use of favipiravir in in vitro models of influenza.

In in vitro studies, favipiravir showed high antiviral activity against all strains of the influenza virus, A, B and C. Based on the calculation of plaque forming units (PFU) in MDCK cell culture, the effective concentration (hereinafter EC50) ranged from 0.014 to 0.55cg/ml [Furuta Y, Takahashi K., Fukuda Y, Kuno M., Kamiyama T., Kozaki K., Nomura N., Egawa H., Minami S., Watanabe Y, Narita H., Shiraki K. In vitro and in vivo activities of anti-influenza virus compound T-705.-2002,- Antimicrob Agents Chemother; 46(4), p. 977-981].

Favipiravir is known to be active against 53 strains of the influenza virus, including seasonal strains A(H1N1), A(H3N2), and strains of influenza type B; A(HlNl)pdmO9 pandemic virus, highly pathogenic avian influenza A(H5N1) isolated from humans, strains A(H1N1) and A(H1N2) isolated from pigs, and A(H2N2), A(H4N2), A(H7N2) .

The use of favipiravir in in vivo models of influenza.

In vivo, in mouse models of viral infection with lethal doses of strains H3N2 (A/Victoria/3/75), H3N2 (A/Osaka/5/70) or H5N1 (A/Duck/MN/1525/81), favipiravir was administered one hour after infection . Survival of mice at doses of 30 mg/kg/day 2 or 4 times a day was significant, while all infected control mice died.

When administered at 60 to 300 mg/kg/day, favipiravir has been shown to be effective in reducing the viral load in the lungs of H1N1-infected mice (A/ Califomia/04/09), as well as delayed use up to 96 hours post-infection [Takahashi K ., Furuta Y, Fukuda Y, Kuno M., Kamiyama T, Kozaki K., Nomura N., Egawa H., Minami S., Shiraki K. In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. antivirus. Chem. Chemother.- 2003; Sidwell R.W., Barnard D.L., Day C.W., Smee D.F., Bailey K.W., Wong M.H., Morrey J.D., Furuta Y. Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice.- 2007,- Antimicrob Agents Chemother], Favipiravir showed a significant therapeutic effect compared to ocetalmivir in mice that were injected with a dose of the virus 100 times more, and the treatment itself was delayed by 96 hours post-infection [Takahashi K, Furuta Y, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Shiraki K. Antivir Chem Chemother. In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. 2003].

Efficacy of favipiravir for other families of RNA viruses in in vitro and in vivo studies. Arenaviridae

Arenaviruses cause fatal human diseases [Moraz M.L., Kunz S. Pathogenesis of arenavirus hemorrhagic fevers. - 2011. - Expert Rev. Anti infection. Then-9(1), p. 49-59], for which there are no antiviral drugs, except for ribavirin, which has a pronounced toxic effect.

In vitro, favipiravir showed greater selectivity than ribavirin. When measuring the cytopathic effect in cell culture, the EC50 values for the drug were 0.79-0.94 cg/ml for Yunin, Pichinde and Takaribe viruses. Also, the viral load during the use of favipiravir significantly decreased by the third day. In the study by the method of counting hemolysis foci, 3K90s against the highly pathogenic Romero strain of the Guanarito virus JUNV (Romero) and the Machupo virus was 3.3-8.4 cg / ml (21-53 cM) [Mendenhall M, Russell A, Juelich T, Messina EL, Smee DF, Freiberg AN, Holbrook MR, Furuta Y, de la Torre JC, Nunberg JH, Gowen BB. Antimicrobial Agents Chem other. T-705 (favipiravir) inhibition of arenavirus replication in cell culture. - 2011, - Antimicrob Agents Chemother. - 55(2), p. 782-787].

When administered orally in a model line of hamsters infected with the Pichinde virus, favipiravir prevented death, reduced the number of viral titers in the blood and tissues, at dosages of 60 mg/kg/day, twice prevented liver damage when used for 7 days, starting from 4 hours post-infection [Gowen V.V., Wong M.N., Jung K.N., Sanders A.V., Mendenhall M., Bailey K.W., Furuta Y, Sidwell R.W. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob. Agents Chemother.- 2007,- 51(9), p. 3168-3176]. Viral load also decreased significantly at the start of treatment from days 4, 5 and 6 post-infection. When used in dosages of 100 mg / kg / day, the survival of animals significantly increased [Gowen V.V., Smee D.F., Wong M.N., Hall J.O., Jung K.H., Bailey K.W., Stevens J.R., Furuta Y, Morrey J.D. Treatment of stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin. - 2008, - PLoS One 3, e3725].

In a guinea pig infection model, favipiravir demonstrated its effectiveness even after the onset of acute symptoms of the disease [Mendenhall M., Russell A., Smee DF, Hall J. O., Skirpstunas R., Furuta Y, Gowen BB Effective oral favipiravir (T-705 ) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic fever.- 2011,- PLoS Negl. Trop. Dis. 5, el342]. When using favpiravir at a dose of 300 mg/kg/day, it showed significant effects on survival: 100% of the animals participating in the experiment survived, at a dose of 150 mg/kg/day, the indicators decreased to 50 and 25%, the animals maintained body weight, their temperature dropped to normal and all indicators were generally better than those for ribavirin at a dosage of 50 mg/kg/day. The concentration of aspartate aminotransferase (AST), a prognostic marker of the severity of the disease with Lassa fever in the blood, decreased significantly in a dose-dependent manner by the tenth day of the disease in the treatment with favipiravir. Mean infectious dose viremia per ml of eluate decreased to an average of 2.1, 1.3, and 1.6 logIO SS50/ml in the high and medium dose favipiravir and ribavirin groups, respectively.

The efficacy of oral administration of favipiravir has also been shown in models infected with the lethal Lassa virus in guinea pigs and mice [Safronetz D., et al. The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.- 2015,- Sci. Rep. 5, 14775]. The therapeutic effect was observed on the 2nd day after infection. Subcutaneous administration of favipiravir at doses of 300 mg/kg/day once a day reduced temperature, prevented weight loss, and increased animal survival. The effects of favipiravir were many times greater than those of ribavirin at a dose of 50 mg/kg/day. A significant improvement in the survival of Lassa virus-infected guinea pigs was observed even on days 5, 7 and 9 post-infection [Safronetz D., et al. The broadspectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.- 2015,- Sci. Rep. 5, 14775].

Bunyaviridae

Viruses of the Bunyaviride family, including La Croce virus (LACV), Rift Valley fever virus (RVFV), Crimean-Congo hemorrhagic fever virus (CCHFV), acute fever with thrombocytopenia syndrome virus (SFTSV), and hantavirus, cause severe hemorrhagic fevers with concomitant pulmonary and renal complications.

In vitro studies have shown the superiority of the use of favipiravir over other drugs in the direction, efficacy and speed of action against a number of such viruses [Yousuke Furuta, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. - 2013. - Antiviral Research. Volume 100; Gowen BB, et al. Efficacy of favipiravir (T-705) and T-1106 pyrazine derivatives in phlebovirus disease models.- 2010,- Antiviral Res., Volume 86, Issue 2]. EC50 values in Plaque Forming Units (PFU) studies in cell culture started in the range of 0.9-30 ng/mL of the drug for Lassa, Punta Toro, Reef Valle, Acute Fever (SFTSV), Phlebotomy Fever, and Dobrava, Maporal, and Prospect Hill Hantaviruses [Tani H., et al. Efficacy of T-705 (Favipiravir) in the treatment of infections with lethal severe fever with thrombocytopenia syndrome virus. - 2016. - m Sphere 1].

The use of favipiravir in in vitro and in vivo models of bunyaviruses.

Thrombocytopenic fever virus (SFTSV) emerged several years ago as a seasonal disease in China, Korea and Japan [Yu X., Liang M., et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. - 2011. - N. Engl. J. Med, 364, pp. 523-1532]. Favipiravir inhibited SFTSV replication in cell culture with EC values of 0.71-1.3 cg/mL.

The therapeutic effect of favipiravir has been demonstrated in interferon-a receptor knockout (IFNAR-/-) mouse models that do not develop an immediate immune response.

After oral administration of favipiravir at a dose of 300 mg/kg/day for 5 days, starting from day 3 post-infection, all experimental mice survived (P < 0.001), and starting from days 4 and 5 post-infection, there was a significant improvement in performance. group survival. Based on in vivo studies in Japan, the drug has entered clinical trials and has successfully completed them to date. Studies have shown the effectiveness of favipiravir even after the onset of the disease and the onset of clinical symptoms [Yousuke Furuta, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. - 2013. - Antiviral Research. Volume 100, Issue 2].

Flaviviridae.

Favipiravir blocks the replication of viruses of the flaviviride family, including yellow fever virus (YFV) and West Nile virus (WNV) [Julander JG, et al. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106. - 2009. - Antimicrob. Agents Chemother, 53(1), p. - 202-209; Morrey JD, et al. Efficacy of orally administered T-705 pyrazine analog on lethal West Nile virus infection in rodents. - 2008. - Antiviral Res., 80(3), p. 377-379], however, at higher concentrations than needed to block influenza virus activity. The EC90 of favipiravir against YFV is 51.8 cg/ml in in vitro studies to determine the release of active viral particles on Vero cell culture.

YFV-infected hamsters were treated orally with favipiravir at doses ranging from 200 to 400 mg/kg/day for 8 days starting treatment 4 hours prior to infection. This therapy significantly reduced the mortality rate of animals at the beginning of treatment [Julander J.G., et al. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106. - 2009. - Antimicrob. Agents Chemother, 53(1), p. 202-209].

Complete recovery was achieved with the introduction of 400 mg/kg/day, starting from the 2nd day of post-infection.

In vitro and in vivo, the antiviral efficacy of favipiravir against West Nile virus was achieved at EC50 concentrations of 53 cg/ml in Ver o cell culture.

Oral administration of favipiravir at doses of 400 mg/kg/day 2 times a day, 4 hours after infection, saved 90% of mice from death, and also significantly reduced the expression of viral proteins and viral RNA in brain tissues. The same efficacy was shown in lines infected with WNV, hamsters at the same doses. WNV envelope proteins were not detected in the brains of the treated animals.

Togaviridae

Favipiravir exhibits antiviral activity against Western equine encephalitis virus (WEEV) in Vero cell culture, reaching an EC90 at 49 cg/mL [Julander J.G., et al. Effect of T-705 treatment on western equine encephalitis in a mouse model. Antiviral Res, 82(3), p. 169-171].

In WEEV-infected mice, oral administration of favipiravir significantly increased survival and lifespan of infected animals when administered twice at a dose of 400 mg/kg/day for 7 days, starting at the 4th hour post-infection. Viral titers in the brain tissues were reduced on the 4th day post-infection.

Favipiravir showed antiviral activity against Chikungunya virus (CHIKV) in Vero cell culture, reaching an EC50 at 0.3-9.4 cg/mL. In CHIKV-infected mice, oral administration of favipiravir improved survival rates at double doses from 300 mg/kg/day starting 24 hours before or 4 hours before after infection [Delang L., et al. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. - 2014, - J. Antimicrob. Chemother, 69(10), p. 2770-2784].

Picornaviridae

Replication of enterovirus vesicular stomatitis was inhibited by favipirovir in in vitro studies with an EC50 of 14 cg/ml [Sakamoto K., et al. The inhibition of FMD virus excretion from the infected pigs by an antiviral agent, T-1105. FAO report of the research group of the standing technical committee of european commission for the control of Foot-and-Mouth Disease. - 2006. - Paphos, Cyprus. FAO Appendix 64; Furuta Y, et al. T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. - 2009, - Antiviral Res, ;82(3), p. 95-102].

Favipiravir also blocked poliovirus replication in Vero cell culture and rhinovirus in HeLa cell culture at 3K50s of 4.8 and 23 cg/ml, and with a selectivity index of 29 and >43, respectively [Furuta Y, et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. 2002. - Agents Chemother, 46(4), p. 977-981]. Favipiravir inhibited Enterovirus replication at an EC50 of 23 cg/mL [Wang Y, et al. In vitro assessment of combinations of enterovirus inhibitors against enterovirus 71,- 2016,- Antimicrob. Agents Chemother, 60(9), p. 5357-5367].

Caliciviridae.

Favipiravir is active against murine noravirus with EC50 values of 39 cg/mL in viral plaque scoring studies in the RAW 264.7 mouse macrophage cell line. Real-time PNR revealed blocking of RNA synthesis using favipiravir with EC50 from 19 cg/ml [Rocha-Pereira J., et al. Favipiravir (T-705) inhibits in vitro norovirus replication. - 2012. - Biochem. Biophys. Res. Commun, 424(4), p. 777-780].

The use of favipiravir in in vivo models of the noravirus genus from the Calicivirus family.

In a mouse model of persistent infection, oral administration of favpiravir at a dose of 600 mg/kg/day twice for 8 weeks, 4 weeks post-infection, resulted in a significant decrease in viral titers in the feces of mice and the number of norovirus-positive mice. Scientific evidence also confirms that favipiravir-RTF inhibits the RNA polymerase activity of human Noraviruses [Jin Z., et al. Biochemical evaluation of the inhibition properties of Favipiravir and 2'-C-methyl-cytidine triphosphates against human and mouse norovirus RNA polymerases. - 2015 Antimicrob. Agents Chem other],

filoviridae.

Favipiravir showed antiviral activity against the Zaire Ebola virus (Mayinga 1976 strain) in a Vero E6 cell culture with an EC50 of 10.5 cg/ml. In a strain of mice infected with the Mayinga 1976 strain lacking interferon-alpha receptor (IFNAR-/- C57BL/6), oral administration of favipiravir avoided death and reduced viral titers in the blood when administered twice from 300 mg/kg/day for 8 days from day 6 post-infection, while in the placebo group all mice died [Oestereich L., et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model.- 2014,- Antiviral Res, 105, p. 17-21]. Similarly, in IFNAR-/- interferon receptor knockout A129 strain E718 Ebola, treatment with favipiravir orally completely saved all infected mice from death when the drug was administered twice at a dose of 300 mg/kg/day for 14 days, starting from the 1st hour after infection [Smither S.J., et al.- Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model.- 2014,- Antiviral Res, Volume 104, Pages 153 -155].

During the Ebola outbreak in West Africa in 2014, the French Institute of Health and Medical Research and the government of Guinea conducted a clinical trial of favipiravir in patients [Mentre E, Taburet A.M. Dose regimen of favipiravir for Ebola virus disease. 2015 - Lancet Infect. Dis, VOLUME 15, ISSUE 2, R.150-151]. Favipiravir was well tolerated by patients and reduced the number of deaths in patients with low viral titers. A group of Chinese researchers also noted an increase in the survival rate of Ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone, 2016. Clin. Infect. Dis, 63(10), p.1288-1294].

Rhabdoviridae.

The activity of favipiravir against the rabies virus was detected in the cell line of mouse neuroblastoma Neuro-2a with 3K50s at 5.1-7.0 cg/ml [Yamada K., et al. Efficacy of Favipiravir (T-705) in rabies postexposure prophylaxis.- 2016,- J. Infect. Dis, 213(8), p. 1253-1261]. Favipiravir significantly reduced morbidity and mortality in RABV-infected mice when given orally at doses of 300 mg/kg/day twice for 7 days starting at 1 hour post-infection. Coronavirus.

According to the Global Substances Report, favipiravir has now entered clinical trials against COVID-19 disease based on its proven mechanism of action against viral RsRp. In a clinical study by the National Center for Clinical Research on Infectious Diseases in Shenzhen, favipiravir was administered to 340 patients (age groups and comorbidities not specified) in two doses (2 doses) of 1600 mg on the first day and two doses of 600 mg for the next 13 days in addition to an inhalation aerosol of interferon-alpha (5 million units * 2 / day). This dosage resulted in more rapid disappearance of the virus to undetectable values in the blood) than in the group of patients taking the combination of anti-HIV proteases - lopinavir / ritonavir, with a median clearance of viral particles of 4 days, versus 11, respectively, and was assessed by control CT chest section. According to the current study, the use of favipiravir reduces the number of detectable viral particles in the blood, which means that it effectively inhibits viral replication, delays the development of an aggressive course of COVID-19 or even prevents it.

A recent study showed the efficacy of favipiravir against SARS-CoV-2 (EC50 = 61.88 mM in Vero E6 cell culture) [Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res.- 2020,- 30, p. 269-271]. The study tested the co-administration of favipiravir with interferon-a and favipiravir with baloquavir marboxil (an influenza-approved cap-dependent endonuclease inhibitor) in patients with SARS-CoV-2.

All the generalized data described above on the undeniable efficacy of favipiravir against a very wide range of RNA viruses show that this drug perfectly “closes” the hitherto effectively uncovered niche of incurable, acute and fatal viral diseases, including a wide range of tropical fevers. Prior to studies on favipiravir, ribavirin and/or alpha-interferon were used against the above RNA infections, but the former has significantly less antiviral activity and efficacy against RNA viruses, and both drugs lead to debilitating side effects with long-term use. In view of the versatility and high efficacy demonstrated by favipiravir preparations, it seems necessary to use them during periods of epidemics.

The worldwide outbreak of SARS-CoV-2 and its associated consequences are a threat to the public health and economies of many countries. The lack of specific therapy against the new virus and its high variability require the creation of new drugs.

As part of the fight against a new infection, a number of preventive vaccines have been developed, as well as non-specific therapies that alleviate the course of the disease. However, in addition to existing therapies, specific drugs are needed that have a direct effect on the virus, leading to symptomatic relief, accelerated resolution of the disease, blocking transmission, and reducing the risk of clinical complications.

Favipiravir, relying on a wide spectrum and proven mechanism of its action, can also alleviate the course of viral diseases, if taken on time, and also significantly reduce the viral load in the course of diseases with complications. Despite the high efficacy of favipiravir against viral diseases, there are a number of difficulties associated with the physicochemical, technological and pharmacological characteristics of drugs based on favipiravir in free form, in particular, the solubility of favipiravir in free form in water is extremely low, which complicates the production of new dosage forms. , while the free-form favipiravir substance remains stable and shows acceptable performance, including hygroscopicity and flowability, for only about three years.

Also, one of the problems with the use of antiviral drugs, including favipiravir, is an increased risk of hepatotoxic effects during therapy (Barbara Styrt MD, Joel P. Freiman MD. Hepatotoxicity of antiviral agents // Gastroenterology Clinics of North America. - 1995. -V. 24, 1. 4, P. 839-852).

That is why today the problem of finding new compounds effective against viral diseases is very relevant.

Based on the foregoing, it seems necessary to create new antiviral compounds with an improved safety profile, as well as improved physicochemical, technological and pharmacological properties. Previously, researchers have made attempts to obtain compounds of favipiravir with various substances of a basic nature in order to improve their physicochemical properties.

Favipiravir derivatives with various substances of a basic nature are known from the prior art, namely, favipiravir compounds with meglumine (CN103209967, Toyama Chemical Co LTD) and favipiravir sodium salt (TW201934539, Fujifilm Toyama Chemical Co LTD).

As the closest analogue of the present invention, the authors consider the salt of favipiravir with arginine (CN111214446, Reyoung Pharmaceutical Co LTD et al.).

The objective of the present invention is to create new antiviral compounds, namely favipiravir derivatives, the substances and dosage forms of which have an improved safety profile, as well as improved physicochemical, technological and pharmacological properties. The problem is solved by creating new derivatives of favipiravir, in particular salts of favipiravir with amino acids, namely, compounds of formula I:

Formula I where X is an amino acid residue selected from the group: lysine, ornithine or histidine.

The technical results of the present invention are:

- reducing the risk of increased levels of hepatic transaminases during therapy associated with toxic liver damage;

- improving the physicochemical and technological properties of the substance in the form of new derivatives of favipiravir according to the present invention, pharmaceutical compositions and dosage forms that contain them. Below are the terms that are used in the description of the present invention. Unless otherwise indicated, all technical and technical terms used in the description have the meaning generally accepted in the art.

The term "pharmaceutical composition" means a composition comprising an amino acid salt of favipiravir in an effective amount, and also a pharmaceutical composition in the context of the present invention may additionally contain one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, such as, but not limited to specified, fillers, solubilizers, solvents, co-solvents, antioxidants, buffering agents, cryoprotectants, diluents, preservatives, stabilizers, humectants, emulsifiers, lubricants, lubricants, suspending agents, thickeners, sweeteners, fragrances, fragrances, antibacterial agents, fungicides, slow release regulators delivery, isotonic agents, pH adjusting agents, the choice and ratio of which depends on the nature, purpose and dosage of the drug.

Non-limiting (illustrative) examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, as well as mixtures of these substances.

Protection of the pharmaceutical composition from the action of microorganisms can be provided using a variety of antibacterial and antifungal agents, such as, but not limited to, sorbic acid, parabens (methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben and mixtures thereof) , chlorobutanol and similar compounds.

As isotonic agents, the pharmaceutical composition may include, but is not limited to, sugars, sodium chloride, sodium bicarbonate, etc. Prolonged action of the pharmaceutical composition can be provided, but not limited to, using agents that slow down the absorption of the active agent (for example, hydrophilic and hydrophobic polymeric release inhibitors).

Non-limiting (illustrative) examples of suitable fillers are lactose, various types of starch, microcrystalline cellulose, calcium carbonate and phosphate, and others. As solvents and diluents, water, suitable for parenteral forms, organic esters, ethanol, polyalcohols, and mixtures thereof can be used, but are not limited to. Examples of lubricants can be magnesium or calcium stearate, talc, sodium lauryl sulfate, sodium stearyl fumarate, etc. Silicon dioxide, talc, kaolin, bentonites, etc. can be used as lubricants. Various organic and inorganic acids or alkalis can be used to adjust the pH, such as, but not limited to, hydrochloric acid, malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids, sodium hydroxide, etc. Examples of dispersing agents and spreading agents are, but not limited to, starch, alginic acid and its salts, silicates.

The pharmaceutical composition can be administered to animals and humans orally, parenterally (intradermally, subcutaneously, intramuscularly, intravenously, intraarterially, in the cavity), sublingually, topically, including, but not limited to, ophthalmic, nasal administration, etc., rectally in a standard form of administration , as a mixture with traditional pharmaceutical carriers. Suitable unit forms of administration include (without limitation) oral forms: tablets, capsules, pellets, granules, powders, solutions, oral and nasal spray solutions, syrups, suspensions, etc., oral: solutions, suspensions, emulsions, concentrates for preparation of injection and infusion dosage forms, aerosols and powders for inhalation administration, powders and lyophilizates for the preparation of injection and infusion dosage forms; rectal: suppositories, capsules, etc.; as well as eye drops.

The term "excipient" in the context of the present invention characterizes substances of inorganic or organic origin used in the manufacturing process, the manufacture of drugs to give them the necessary physical and chemical properties.

"Pharmaceutical salt" means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention.

The term “pharmaceutically acceptable” in the context of the present invention means that the substance or composition to which the term is applied must be chemically and/or toxicologically compatible with other formulation ingredients and are safe for the person being treated with the substance or composition.

The term "amino acids" in the context of the present invention means organic substances, the molecules of which simultaneously contain carboxyl and amine groups, which can exist in the form of isomers and mixtures thereof.

The term "substance" in the context of the present invention means a synthesis product, which is any substance or mixture of substances of synthetic or other (biological, biochemical, mineral, plant, animal, microbial and other) origin, intended for the production of pharmaceutical compositions and medicines, which in during the production of a medicinal product (drug) becomes the active ingredient of this medicinal product and determines its effectiveness. Such substances are intended to exhibit pharmacological activity or other direct effect in the diagnosis, treatment, relief of symptoms, or prevention of disease and relief of symptoms, or to affect the structure or function of the body.

The term "drug" in the context of the present invention characterizes substances or combinations thereof that come into contact with the human or animal body, penetrate into the organs, tissues of the human or animal body, used for the prevention, treatment of diseases, obtained by synthetic methods. Medicines are medicines. The drug can be presented in the form of various ready-made forms intended for introduction into the animal or human body in various ways, for example, but not limited to, orally, sublingually, topically, rectally, parenterally.

Also for the purposes of the present invention, the terms "comprising", "comprises", "including" mean that the specified combinations, compositions and concentrate include the listed components, but do not exclude the inclusion of other components.

The term "therapeutically effective amount" in the context of the present invention means the amount of a substance (as well as a combination of substances) which, when administered to a subject for the treatment or prevention of a disease, or at least one of the clinical symptoms of the disease, or disorder, is sufficient to effect such treatment (prophylaxis ) to a disease, disorder, or symptom. The "therapeutically effective amount" may vary depending on the form of the substance (e.g., polymorph, salt, solvate, hydrate, etc.), disease, the disorder and/or symptoms of the disease or disorder, the severity of the disorder, disorder and/or symptoms of the disease or disorder, and the age and/or weight of the subject in need of such treatment (prophylaxis).

The terms "about", "approximately", "about" characterize plus or minus ten percent of the specified value.

The term "free form" of a substance in the context of the present invention means the form of a substance in which the molecules of the substance do not interact with other molecules and/or particles, in particular cations or anions, ligands or complexing agents through ionic or van der Waals interactions, while atoms in a given molecule are linked only by covalent bonds.

The term "bound form" of a substance in the context of the present invention means the form of a substance in which the molecules of a given substance interact with other molecules and/or particles, in particular cations or anions, ligands or complexing agents through ionic or van der Waals interactions. Examples of related compounds are organic and inorganic salts and complexes.

The term "derivatives of organic compounds" in the context of the present invention means a compound obtained from a compound of a similar structure (structural analogue) through a chemical reaction, if one or more atoms are replaced by other atoms (or a group of atoms), including functional groups; or there is an addition to the original molecule of acid or base residues, solvent molecules or other small molecules through chemical bonds or intermolecular interactions; or splitting off atoms or groups of atoms to form multiple bonds.

The term "physical properties of medicinal substances" in the context of the present invention characterizes the density, shape, size and nature of the surface of the particles, the specific surface of the particles, the forces of adhesion (adhesion on the surface) and cohesion (adhesion of particles inside the body), surface activity, melting point of medicinal substances and etc.

The term "chemical properties of medicinal substances" in the context of the present invention characterizes the solubility, stability, reactivity of medicinal substances, etc. The term "technological properties of medicinal substances" in the context of the present invention characterizes bulk density, degree of compaction, flowability, moisture content, fractional composition, dispersion, porosity, compressibility of medicinal substances, etc.

The problem is solved, and the claimed technical result is achieved by obtaining new salts of favipiravir with amino acids, in particular, favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate.

More preferably, the amino acids of the present invention are amino acids in the L or D configuration.

More preferably, the amino acid of the present invention is favipiravir L-lysinate.

More preferably, the amino acid of the present invention is favipiravir L-ornithinate.

More preferably, the amino acid of the present invention is favipiravir L-histidinate.

More preferably, the amino acid of the present invention is favipiravir D-lysinate.

More preferably, the amino acid of the present invention is favipiravir D-ornithinate.

More preferably, the amino acid of the present invention is favipiravir D-histidinate.

The novel compounds of the present invention may be administered in the form of prodrugs. The prodrug may include a covalently linked carrier that releases the active parent drug upon administration to a mammalian subject. Prodrugs can be prepared by modifying the functional groups present on the compounds such that the modifications are cleaved, either during routine manipulation or in vivo, to the parent compounds. Prodrugs include, for example, compounds in which a hydroxyl group is bonded to any group that, when administered to a subject, is cleaved to form a free hydroxyl group. Examples of prodrugs include, without limitation, acetate, formate and benzoate derivatives of alcohol functional groups in the compounds. Typical prodrugs form the active metabolite by converting the prodrug with hydrolytic enzymes, hydrolyzing amides, lactams, peptides, carboxylic acid esters, epoxides, or cleaving inorganic acid esters.

To obtain new favipiravir derivatives with amino acids according to the present invention, dioxane, dimethyl sulfoxide, ethylene glycol, tetrahydrofuran, alcohols (for example, but not limited to methanol, ethanol, isopropanol), dimethylacetamide, dimethylformamide, etc., as well as their mixtures in various proportions.

The problem is solved, and the claimed technical result is achieved by obtaining a pharmaceutical composition for the treatment and/or prevention of viral diseases, containing a compound in a therapeutically effective amount, which is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate.

The problem is solved, and the claimed technical result is achieved by obtaining a pharmaceutical composition for the treatment and/or prevention of viral diseases, containing in a therapeutically effective amount a compound representing favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate, and at least one pharmaceutically acceptable excipient.

One embodiment of the invention is a pharmaceutical composition in which the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 100 to 4000 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 100 to 3700 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from PO to 3300 mg.

More preferably, the amount of the compound which is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 120 to 3000 mg. More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 130 to 2700 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 140 to 2400 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 150 to 2100 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 160 to 1800 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 170 to 1500 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is from 180 to 1200 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is 190 to 900 mg.

More preferably, the amount of a compound that is favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate is 200 to 600 mg.

One embodiment of the invention is a pharmaceutical composition wherein the pharmaceutically acceptable excipients are selected from the group including, but not limited to, excipients, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, fragrances, fragrances, fungicides, sustained release regulators, co-solvents, diluents, fillers, emulsifiers, preservatives, antioxidants, buffering agents, cryoprotectants, pH adjusting agents, isotonicity or corrective agents. More preferably, the solvent of the present invention is, but is not limited to, saline, injection water, pyrogen-free water, distilled water, Ringer's solution, Hartman's solution, or glucose solution.

One of the embodiments of the invention is a pharmaceutical composition for the treatment and/or prevention of viral diseases, where the virus is an RNA-containing virus.

One of the embodiments of the invention is a pharmaceutical composition for the treatment and/or prevention of viral diseases, where the virus is a virus whose genome is encoded by a single-stranded sense (+)-strand, as well as an antisense (-)-strand of RNA and which uses a viral RNA-dependent -RNA polymerase for its replication.

More preferably, the virus of the present invention is an influenza virus, coronavirus, picornavirus, arenavirus, flavivirus, bunyavirus, filovirus, phlebovirus, hantavirus, enterovirus, togavirus, calicivirus, respiratory syncytial virus, parainfluenza virus, rhinoviruses, metapneumoviruses, rotavirus, or noravirus.

More preferably, the virus of the present invention is a highly virulent or low virulent virus.

More preferably, the virus of the present invention is SARS-CoV, SARS-CoV-2, MERS-CoV or Influenza A, B, C.

More preferably, the influenza virus of the present invention is, but not limited to, influenza A virus, including strains A (H1N1), A (H1N1) pdm09, A (H1N2), A (H3N2), A (H2N2), A (H4N2) , A (H7N2), swine influenza type A, avian influenza type A, including highly pathogenic strains (including H5N1 and H7N9).

The problem is solved, and the claimed technical result is achieved by obtaining a drug for the treatment and/or prevention of viral diseases, containing a pharmaceutical composition of the present invention.

The problem is solved, and the claimed technical result is achieved by obtaining a drug for the treatment and/or prevention of viral diseases, containing a pharmaceutical composition of the present invention and at least one pharmaceutically acceptable excipient. The problem is solved, and the claimed technical result is achieved by obtaining a drug for the treatment and/or prevention of viral diseases, containing the pharmaceutical composition of the present invention in a therapeutically effective amount.

One embodiment of the invention is a drug that is a solid drug.

More preferably, the solid drug of the present invention is, but not limited to, a tablet, capsule, pellet, sachet, dragee, powder, or lyophilisate.

Lyophilization (lyophilization) is a process of removing a solvent from a frozen material by sublimation (sublimation) of solvent crystals under vacuum, i.e. converting it to vapor, bypassing the liquid phase. The drug in the form of a lyophilizate fully retains its pharmacological activity.

The removal of the solvent during freeze-drying is carried out mainly by sublimation. Sublimation is the removal of a solvent from a frozen object without the formation of a liquid phase, it is carried out under vacuum or much less often in an inert gas. The freezing step is one of the determining steps for obtaining a quality drug in the form of a lyophilisate.

The auxiliary excipients used in freeze-dried medicinal preparations of the present invention include: solvents, solubilizers (EDTA, a-cyclodextrin, etc.), fillers (mannitol, glycine, glucose, sucrose, lactose, milk, etc.), preservatives ( benzyl alcohol, ethyl and methyl parahydroxybenzoate, etc.), pH regulators (buffer solutions, sodium hydroxide, hydrochloric acid), stabilizers, cryoprotectants (dextran, gelatin, hydroxyethyl starch, etc.).

In the form of lyophilisates according to the present invention, both individual medicinal substances and their mixtures with excipients can be presented.

One embodiment of the invention is a drug that is an oral drug. More preferably, the oral drug of the present invention is, but not limited to, a tablet, capsule, pellet, dragee, powder, suspension, syrup, or solution.

One embodiment of the invention is a drug that is a liquid drug.

More preferably, the liquid drug of the present invention is, but not limited to, a solution, a concentrate, a syrup, a suspension.

More preferably, the liquid drug of the present invention is a parenteral drug.

Parenteral drug administration is a way of introducing drugs into the body, in which they bypass the gastrointestinal tract, in contrast to the oral route of drug administration. Parenteral medicinal products are sterile preparations intended for administration by injection, infusion, inhalation or implantation into the human or animal body. These include solutions, emulsions, suspensions, aerosols, powders and tablets for the preparation of solutions and implantation, powders for inhalation, lyophilized preparations for the preparation of dosage forms administered parenterally (subcutaneously, intramuscularly, intravenously, intraarterially, into various cavities).

Parenteral routes of administration include administration into tissues (intradermally, subcutaneously, intramuscularly, intraosseously), into vessels (intravenously, intraarterially, into lymphatic vessels), into cavities (into the pleural, abdominal, cardiac and articular cavities), into the subarachnoid space, as well as inhalation , intranasal and subconjunctival administration.

More preferably, the parenteral drug is an infusion solution.

More preferably, the parenteral drug is an injectable solution.

One of the embodiments of the invention is a drug, which is an inhalation drug.

More preferably, the inhalation drug of the present invention is, but not limited to, an aerosol, powder, or pulverized powder. One of the embodiments of the invention is a drug, which is a drug for topical administration.

Local administration of drugs refers to the application of a medicinal product to mucous membranes (including ophthalmic, nasal, rectal, vaginal application, application to the gums, oral mucosa, etc.), as well as the introduction into the external auditory canal.

More preferably, the topical drug of the present invention is an ophthalmic, nasal, and rectal drug.

One embodiment of the invention is a drug that is a rectal drug.

More preferably, the rectal drug of the present invention is, but not limited to, suppositories or capsules.

One embodiment of the invention is a medicament wherein the pharmaceutically acceptable excipients are selected from the group including, but not limited to, excipients, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, perfumes, fragrances, fungicides, sustained release regulators, co-solvents, diluents, fillers, emulsifiers, preservatives, antioxidants, buffering agents, cryoprotectants, pH adjusting agents, isotonicity or corrective agents.

More preferably, the solvent of the present invention is, but is not limited to, saline, injection water, pyrogen-free water, distilled water, Ringer's solution, or glucose solution.

The problem is solved, and the claimed technical result is achieved through the use of new compounds of the present invention, which are favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate, to obtain a pharmaceutical composition for the treatment and/or prevention of viral diseases.

The problem is solved, and the claimed technical result is achieved through the use of the pharmaceutical composition of the present invention for obtaining a medicinal product for the treatment and/or prevention of viral diseases.

The problem is solved, and the claimed technical result is achieved through the use of new compounds of the present invention, which are favipiravir lysinate, favipiravir ornithinate or favipiravir histidinate, for the treatment and/or prevention of viral infections.

The problem is solved, and the claimed technical result is achieved through the use of a pharmaceutical composition or drug for the treatment and/or prevention of viral infections.

More preferably, the viral infection of the present invention is SARS-CoV, SARS-CoV-2, MERS-CoV or Influenza A, B C.

The problem is solved, and the claimed technical result is achieved by a method for the treatment and / or prevention of viral diseases, including the introduction to a patient in need of such treatment, a new compound of the present invention, which is favipiravir lysinate, favipiravir ornithinat or favipiravir histidinate, in a therapeutically effective amount .

The problem is solved, and the claimed technical result is achieved by a method for the treatment and/or prevention of viral diseases, including the introduction of a pharmaceutical composition of the present invention in a therapeutically effective amount to a patient in need of such treatment.

The problem is solved, and the claimed technical result is achieved by a method for the treatment and / or prevention of viral diseases, including the introduction of a patient in need of such treatment, the drug of the present invention, in a therapeutically effective amount.

The following are examples of the invention, which illustrate the invention, but do not cover all possible options for its implementation and do not limit the invention.

A person skilled in the art will understand that other private embodiments of the invention are possible.

Examples

Example 1. Obtaining new compounds of the present invention. General procedure for obtaining new compounds of the present invention, namely, compounds of general formula I:

Formula I where X is an amino acid residue selected from: lysine, ornithine histidine, tryptophan, hydroxylysine or leucine.

The reaction vessel was filled with distilled water and thermostated at a temperature of 40-45°C. Then, with stirring, the calculated amount of amino acid was gradually added to the water. The temperature of the reaction medium was raised to 60-70°C and the calculated amount of a mixture of favipiravir with dimethylformamide was added to the solution, provided that the total volume of this mixture a did not exceed 5-15% of the volume of the amino acid solution. The addition of favipiravir occurred in stages, namely four servings in a mass ratio of 4:2:1:0.5. At the same time, after adding the third portion of the mixture of favipiravir with dimethylformamide, the reaction vessel was kept in an ultrasonic bath for 5-10 minutes, after which the fourth portion of the mixture was added. Then the temperature of the reaction medium was raised to 75-80°C. The solution was kept under stirring and constant temperature, then the solvent was removed from the reaction mass by evaporation under reduced pressure. The temperature during evaporation did not exceed 50°C. As a result, a fine powder of favipiravir salt with the indicated amino acids was obtained.

Identification of new compounds of the present invention:

Favipiravir Lysinate:

NMR y (D ₂ O, 300 MHz) 5 (ppm): 1.56 - 1.34 (m, 2H), 1.69 (p, J= 7.62 Hz, 2H), 1.95 - 1.80 (t, 2H), 3.00 (t, J= 7.60 Hz, 1H), 3.73 (t, J= 6.08 Hz, 2H), 8.01 (d, J= 8.08 Hz). NMR I'C 5 (ppm): 22.10, 27.06, 30.64, 39.71, 55.18, 125.16, 135.23 (d, J = 41.18 Hz), 150.85 (d, J = 235.52 Hz), 165, 94, 169.49, 175.50. The measurement error of chemical shifts is 0.1 ppm, the spin-spin interaction constants are 0.3 Hz. Elemental analysis CHHISFNSC: calculated C 43.56%, H 5.98%, F 6.26%, N 23.09%, O 21.10%; found C 43.68%, H 6.09%, F 6.41%, N 22.96%, O 21.37%.

Comparison of ^13C NMR spectra of favipiravir lysinate (A), lysine (B), and favipiravir (C) is shown in Figure 1.

The structure of favipiravir lysinate was confirmed as a result of the analysis of the experiments performed by ¹³ C NMR spectroscopy of lysine, favipiravir and favipiravir lysinate. In particular, the formation of a lysine salt was confirmed by downfield shifts of the C(4) and C(5) signals of favipiravir from 122.8 to 125.1 ppm, from 160.2 to 165.9 ppm. respectively, and high-field shifts of favipiravir signals at C(2) and C(1) from 136.2 ppm. by 135.2 ppm, from 152.9 to 150.1 ppm, respectively. A shift of all signals in the ¹³ C NMR spectrum of lysine to the upfield was also found.

Favipiravir Ornithinat:

NMR y (D ₂ O, 300 MHz) 5 (ppm): 1.54 - 1.81 (m, 2H), 1.85 - 2.03 (m, 2H), 2.54 - 2, 94 (m, 2H), 3.74 - 3.87 (m, 2H), 7.80 (d, J = 7.7 Hz, 1H), 7.90 (t, J = 7.2 Hz, 3H). NMR ³³ C 5 (ppm): 22.3, 27.4, 30.9, 40.0, 55.4, 137.9, 140.5, 143.1, 159.1, 161.9 , 178.0. The error in measuring chemical shifts is 0.1 ppm, and the spin-spin interaction constants are 0.3 Hz.

Elemental analysis of CioHisFNsC: calculated C 41.52%, H 5.58%, F 6.57%, N 24.21%, O 22.12%; found C 41.40%, H 5.64%, F 6.71%, N 24.39%, O 21.97%.

Favipiravir histidinate:

NMR y (D ₂ O, 300 MHz) 5 (ppm): 3.53 - 3.71 (m, 2H), 4.06 - 4.23 (m, 1H), 4.51 (d, J = 15, 8 Hz, 2H), 7.80 (s, 1H), 8.79 - 8.94 (m, 1H). NMR ³³ C 5 (ppm): 38.1, 50.3, 50.1, 53.8, 138.4, 140.6, 143.1, 158.9, 161.3, 164.5 , 168.5, 171.8. The measurement error of chemical shifts is 0.1 ppm, the spin-spin interaction constants are 0.3 Hz.

Elemental analysis CiiHisFNeC: calculated C 42.31%, H 4.20%, F 6.08%, N 26.91%, O 20.49%; found C 42.04%, H 4.51%, F 5.90%, N 26.58%, O 20.75%.

Favipiravir hydroxylysinate:

NMR W (D ₂ O, 300 MHz) 5 (ppm): 1.55 - 2.07 (m, 4H), 2.80 - 3.04 (t, 1H), 3.58 - 4, 02 (t, 2H), 5.28 (d, J = 7.3 Hz, 1H), 7.71 - 7.95 (t, 4H), 8.03 (t, J = 6.9 Hz, 1H ). NMR ³³ C 5 (ppm): 26.1, 32.8, 50.1, 53.8, 74.2, 135.9, 142.7, 146.6, 163.0, 165.3 , 179.1.

Elemental analysis CieHieFNsC: calculated C 41.38%, H 5.68%, F 5.95%, N

21.93%, O 25.05%; found C 41.44%, H 5.61%, F 5.94%, N 21.87%, O 25.12%.

Favipiravir Leucinate: NMR w (D ₂ O, 300 MHz) 5 (ppm): 0.90 (d, J = 6.6 Hz, 6H), 1.67 - 2.24 (m, 3H), 3.83 - 4.09 (m, 1H), 7.59 - 7.97 (m, 3H), 10.2 (s, 1H). NMR 1'C 5 (ppm): 22.0, 22.3, 40.5, 58.1, 136.5, 142.7, 145.2, 160.9, 163.8, 172, 4.

Elemental analysis CieHieFNsOT calculated C 45.83%, H 5.94%, F 6.59%, N 19.44%, O 22.20%; found C 45.91%, H 5.86%, F 6.64%, N 19.50%, O 22.16%.

Favipiravir tryptophanate:

^13C NMR and elemental analysis showed no signals of favipiravir tryptophanate product.

At the same time, in a number of experiments, improved characteristics of new substances in the form of favipiravir derivatives of the present invention were noted, namely, improved solubility, stability (including photostability, accelerated and long-term stability), reduced hygroscopicity, improved compressibility while maintaining good flow characteristics without noticeable electrostatic phenomena.

Example 2. Obtaining dosage forms of new derivatives of favipiravir.

Injections

To prepare a solution for injection of new favipiravir derivatives according to the present invention, water for injection was first placed under sterile conditions in a container for preparing solutions. Next, the calculated amount of favipiravir salt according to the present invention was added to the container and stirred until complete dissolution of the active agent at a temperature of 50-70°C to obtain a transparent pharmaceutical composition in the form of a solution. Further, if necessary, the pH value was adjusted, filtered through a membrane filter, and the filtrate was placed in sterile containers and tightly sealed.

Pills

To obtain a solid drug in the form of a tablet containing new favipiravir derivatives as an active agent, a 10% humectant solution was initially prepared. Next, the low-substituted hyprolose, the favipiravir salt of the present invention, and half of the microcrystalline cellulose were sequentially loaded into the mixer granulator. The resulting mixture was stirred with a stirrer for 5 minutes, followed by the addition of a humidifier. The mixing process was continued until complete introduction of the humidifier. The resulting pharmaceutical composition was granulated, followed by drying of the granules in a fluidized bed unit. Next, the granules were calibrated through a sieve with a mesh size of 1 mm.

To obtain a finished pharmaceutical composition for tableting, the obtained granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer. The resulting pharmaceutical composition was powdered with stearic acid, followed by tableting on a rotary tablet press.

Example 3. Study of biochemical parameters of blood associated with liver damage.

To confirm the effect of reducing the risk of increasing the level of hepatic transaminases through the use of new favipiravir derivatives, namely favipiravir salts with amino acids selected from the group: lysine, hydroxylysine, ornithine, leucine or histidine, an experiment was conducted on laboratory animals. As a criterion for evaluating the positive effect of the presented composition, blood biochemical parameters were studied, such as the levels of alanine and aspartate aminotransferases, alkaline phosphatase and bilirubin, the increase of which in most cases is associated with liver damage.

The studies were carried out on 40 mature mice, which were divided into four groups of ten individuals each. Animals were divided into groups using body weight as a criterion, so that the individual weight of the animals did not differ by more than 10% from the average weight of the animals.

Injected drugs:

1st group: favipiravir lysinate preparation,

group 2: favipiravir ornithinat;

group 3: favipiravir histidinate;

group 4: favipiravir hydroxylysinate;

group 5: favipiravir leucinate;

6th group: favipiravir argininate preparation, obtained in accordance with the method described in the source CN111214446 (closest analogue).

Dosing of the drug to animals was carried out according to the following scheme: daily individuals from groups 1, 2, 3, 4, 5 and 6 were orally administered 1500 mg of the drug in terms of free favipiravir (dosage is per person) by gavage for 10 days.

On the 11th day of the experiment, the animals were subjected to simultaneous decapitation, taking into account the requirements of the ethical committee.

Serum separated by centrifugation of whole blood collected at the time of decapitation of animals was subjected to biochemical research. It determined the level of enzymes aspartic (AsAT) and alanine (AlAT) aminotransferases, alkaline phosphatase (AP) and bilirubin. The results obtained are presented in table 1.

Table 1. Biochemical parameters of blood serum of mice on the 11th day after oral administration of the study drugs.

* - a significant difference in blood biochemical parameters with the introduction of favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate compared with the effect of favipiravir argininate (p < 0.05)

As can be seen from the data of the biochemical parameters of the blood of mice, with the introduction of favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate there is no statistically significant deterioration in blood biochemical parameters caused by toxic damage to liver cells, in contrast to new favipiravir derivatives, such as favipiravir hydroxylysinate and favipiravir leucinate, as well as favipiravir arginate according to the prototype.

Thus, new salts of favipiravir with amino acids, namely, favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate, unexpectedly have an advantage over the first synthesized new favipiravir salts, namely favipiravir hydroxylysinate and favipiravir leucinate, as well as favipiravir arginate known in the prior art in terms of safety. use.

Example 4. Study of the therapeutic effect of new derivatives of favipiravir against the influenza virus.

Modeling of viral infection in mice was performed by intranasal administration of units of highly pathogenic H1N1 avian influenza virus. The experiment was carried out on 40 mature mice. The animals were kept under standard vivarium conditions and received sterile rodent food and sterile water.

In the course of the experiment, integral indicators (changes in animal weight) and clinical symptoms (fever, mucous discharge, activity level, respiration) were assessed daily.

The animals were divided into four groups of 10 individuals.

Injected drugs:

group 1: favipiravir lysinate preparation;

group 2: favipiravir ornithinat;

group 3: favipiravir histidinate;

4th group: microcrystalline cellulose (placebo).

Treatment was started 24 hours after infection. The drugs were administered orally as a suspension through a tube at a dosage of 400 mg 4 times a day for 5 days (dosages are given in terms of free favipiravir in terms of a person). Similarly, the fourth group received microcrystalline cellulose in suspension via gavage 4 times a day.

On day 6, the animals were sacrificed. For virus titration, we used a monolayer culture of sensitive Vero E6 cells grown in 96-well tablets. Previously, 10-fold dilutions of plasma were prepared on a nutrient medium. Infected cells were incubated for 7 days. The assessment of the presence of the virus was carried out according to the characteristic virus-induced changes in cell morphology. The virus titer was determined in tissue cytopathic doses (TCPD/50).

Nasal lavage virus titers were assessed daily throughout the experiment. The average results are shown in Figure 2.

The results of the experiment clearly demonstrate a significant decrease in the titer of the virus already on the 2nd day of the experiment. At the same time, no significant change in weight was observed in individuals in groups 1-3 during the treatment, while mortality throughout the entire experiment in groups 1-3 was zero. On the contrary, in group 4 (control group) the mortality was 80% by the end of the experiment.

Thus, new derivatives of favipiravir in the form of pharmaceutically acceptable salts of favipiravir with amino acids, namely, favipiravir lysinate, favipiravir ornithinate and favipiravir histidinate, exhibit highly effective antiviral activity.

Claims

CLAIMS OF THE INVENTION Compound of general formula I:

formula I, where X represents an amino acid residue selected from the group: lysine, ornithine or histidine. A compound according to claim 1, wherein the amino acid is an amino acid in the L or D configuration. A pharmaceutical composition for the treatment and/or prevention of viral diseases, containing a compound according to any of pi in a therapeutically effective amount. 1-2 and at least one pharmaceutically acceptable excipient. Pharmaceutical composition according to and. 3, in which the amount of compound according to any of pi. 1-2 is from 100 to 4000 mg. Pharmaceutical composition according to and. 4, in which the amount of compound according to any of pi. 1-2 is 100 to 3700 mg, PO to 3300 mg, 120 to 3000 mg, 130 to 2700 mg, 140 to 2400 mg, 150 to 2100 mg, 160 to 1800 mg, 170 to 1500 mg, 180 to 1200 mg, 190 to 900 mg, or 200 to 600 mg. Pharmaceutical composition according to and. 3, characterized in that the pharmaceutically acceptable excipients are selected from the group consisting of excipients, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, fragrances, flavors, fungicides, sustained delivery regulators, co-solvents, diluents, excipients, emulsifiers, preservatives, antioxidants, buffering agents, cryoprotectants, pH adjusting agents, isotonicity or corrective agents. Pharmaceutical composition according to and. 6, characterized in that the solvent is a saline solution, injection water, pyrogen-free water, distilled water, Ringer's solution, Hartmann's solution, or

GLUCOSE. Pharmaceutical composition according to and. 3, where the virus is an RNA containing virus. Pharmaceutical composition according to and. 8, wherein the virus is a virus whose genome is encoded by a single-stranded sense (+) strand as well as an antisense (-) strand RNA and which uses a viral RNA-dependent RNA polymerase for its replication. Pharmaceutical composition according to and. 8, where the virus is an influenza virus, coronavirus, picornavirus, arenavirus, flavivirus, bunyavirus, filovirus, phlebovirus, hantavirus, enterovirus, togavirus, calicivirus, respiratory syncytial virus, parainfluenza virus, rhinoviruses, metapneumoviruses, rotavirus or noravirus. Pharmaceutical composition according to and. 8, where the virus is a highly virulent or low virulent virus. Pharmaceutical composition according to and. 10, where the virus is SARS-CoV, SARS-CoV-2, MERS-CoV or Influenza A, B C. A drug for the treatment and/or prevention of viral diseases, containing a pharmaceutical composition according to any one of pi. 3-12. Medicinal product according to i. 13, characterized in that it is a solid drug. Medicinal product according to i. 14, characterized in that it is a powder or lyophilisate. Medicinal product according to i. 13, characterized in that it is an oral drug. Medicinal product according to i. 16, characterized in that it is a tablet, capsule, pellet or granule. Medicinal product according to i. 13, characterized in that it is a liquid drug. Medicinal product according to i. 18, characterized in that it is a solution, concentrate, syrup, suspension. Medicinal product according to i. 18, characterized in that it is a parenteral drug.

33 The drug according to claim 20, characterized in that it is an infusion solution. The drug according to claim 20, characterized in that it is an injection solution. The drug according to claim 13, characterized in that it is an inhalation drug. The drug according to claim 23, characterized in that the inhalation drug is an aerosol or pulmonary powder. The drug according to claim 13, characterized in that it is a rectal drug. The use of a compound according to any one of paragraphs. 1-2 to obtain a pharmaceutical composition according to any one of paragraphs. 3-12. The use of a pharmaceutical composition according to any one of paragraphs. 3-12 to obtain a medicinal product according to any one of paragraphs. 13-25. The use of a compound according to any one of paragraphs. 1-2 for the treatment and/or prevention of viral diseases. The use of a pharmaceutical composition according to any one of paragraphs. 3-12 or a drug according to any one of paragraphs. 13-25 for the treatment and/or prevention of viral diseases. Application according to any one of paragraphs. 28-29, where the viral infection is SARS-CoV, SARS-CoV-2, MERS-CoV or Influenza A, B C. A method for treating and/or preventing viral diseases, comprising administering to a patient in need of such treatment, a compound according to any from paragraphs. 1-2 in a therapeutically effective amount. A method for treating and/or preventing viral diseases, comprising administering to a patient in need of such treatment a pharmaceutical composition according to any one of paragraphs. 3-12 in a therapeutically effective amount. A method for treating and/or preventing viral diseases, comprising administering to a patient in need of such treatment a drug according to any one of paragraphs. 13-25 in a therapeutically effective amount.