EA044475B1 - NEW COMPOSITIONS OF 2-(IMIDAZOL-4-YL)-ETHANAMIDE PENTANDIOIC-1,5 ACID FOR THE TREATMENT AND PREVENTION OF VIRAL DISEASES - Google Patents

Description

The invention relates to the field of medicine, pharmacology and the chemical-pharmaceutical industry, namely to new compositions for the treatment and/or prevention of viral diseases containing 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid or its pharmaceutically acceptable salt and at least one additional compound selected from the group consisting of 1,5-di[2(4-imidazolyl)ethylamide]pentadionic acid and pharmaceutically acceptable salts thereof, a pharmaceutical composition based on said compositions, a medicinal product based on said compositions or said pharmaceutical composition and a finished dosage form based on said compositions, said pharmaceutical composition or said medicinal product.

Infectious diseases are the third leading cause of death worldwide, with viral diseases accounting for the majority. Among viral infections, one of the leading places is occupied by herpes viruses due to their widespread distribution. According to WHO, about 90% of the world's population have manifestations of herpetic infection, and mortality from these infections is in second place after viral hepatitis, so the problem of herpetic diseases is especially relevant today. Today, science knows more than 100 types of herpes virus, of which 8 antigenic varieties cause diseases in humans (herpes simplex viruses type 1 and 2, chickenpox and herpes zoster (Varicella zoster), cytomegalovirus, Epstein virus -Barr, human herpes viruses types 6, 7 and 8). Herpes viruses can remain in the human body for life and cause diseases with a variety of manifestations from asymptomatic carriage to severe forms with the development of herpetic encephalitis, meningitis, ending in death. The localization of herpetic rashes is different - skin, mucous membranes of the oral cavity and genital organs, cornea, internal organs. To treat and prevent relapses of herpes infection, there is a large selection of drugs with a pronounced antiviral effect, however, these drugs have a number of side effects, including a decrease in the body’s resistance to viruses [1].

Many viruses affect the respiratory tract, nasal passages, throat, bronchi, and lungs, and therefore such viral infections are grouped into the group of acute respiratory viral infections (ARVI), since they also have common clinical symptoms. Influenza viruses also belong to the ARVI group, but are separated into a separate group due to the fact that they affect the entire body systemically. The cause of ARVI can be more than 200 different viruses, representatives of 4 families of RNA viruses (orthomyxoviruses, paramyxoviruses, coronaviruses and picornaviruses) and 2 families of DNA viruses (adenoviruses and herpesviruses) [1, 5]. In terms of infection frequency, influenza is about 15% (type A - 12%, B - 3%), parainfluenza and rhinoviruses up to 50%, adenovirus up to 5%, respiratory syncytial virus (PC) - 4%, mycoplasma - about 2%, enteroviruses - about 1%, mixed infections - about 23% of cases. The high-risk group includes children whose respiratory tract diseases account for up to 90% of all infectious pathologies and 65% of all registered diseases [1, 2].

All ARVIs are characterized by symptoms of general intoxication (headache, weakness, muscle pain, loss of appetite), fever, catarrhal symptoms (nasal congestion, runny nose, cough, sore throat). The localization of the lesion largely depends on the type of pathogen. Thus, rhinovirus diseases are characterized by a predominance of rhinitis, adenoviral infections - nasopharyngitis, parainfluenza is characterized by pharyngitis, and influenza - tracheitis, respiratory syncytial virus affects the bronchi. Other symptoms are also possible, for example, adenoviruses can cause conjunctivitis and keratitis. Typically, ARVI symptoms persist for 3-7 days (cough may persist for a longer time), the possible duration of influenza is 1-2 weeks. Complications include laryngitis, tonsillitis, pharyngitis and tracheitis of a bacterial nature, various forms of sinusitis (sinusitis, ethmoiditis, frontal sinusitis), as well as otitis media, eustachitis, and the possible development of bronchitis and pneumonia. The main causes of complications are violations of the immune defense, leading to long-term immunodeficiencies, combined with a sharp decrease in the body's antibacterial resistance. With the right treatment tactics for ARVI, the risk of complications is significantly reduced [1, 3-5].

Despite the advances made in medicine over the past decades, in particular in the treatment of infectious diseases, ARVI and influenza viruses continue to be a serious health problem for most countries of the world due to the extremely high incidence rate, usually in the nature of seasonal epidemics. ARVI and influenza occupy leading positions in terms of seeking medical help among children and adults, temporary loss of ability to work, and the number of medications consumed during the period of illness. Children, elderly people, people with concomitant diseases (various immunodeficiency conditions, diseases of the lungs, cardiovascular system, liver, kidneys, diabetes, etc.) are most susceptible to seasonal morbidity. Thus, in Russia, 30-40 million cases of infectious diseases are registered annually, from 70 to 90% of which are influenza and acute respiratory tract infections of viral and unspecified etiology [2]. The reasons for such a high incidence are considered to be high population density in large cities, poor ecology, high mobility of the population, incomplete coverage of pathogens through vaccines

- 1 044475 tions or refusal of vaccinations, low hygiene culture of people, the presence of a lot of stress, insufficient time allocated for sleep and rest, smoking, alcohol abuse, as well as unhealthy and inadequate nutrition [6].

Influenza A and B viruses are of greatest epidemic importance, causing annual epidemics, the economic damage from which amounts to billions of US dollars. In Russia, the annual total economic loss from influenza is estimated by experts at an amount reaching 40 billion rubles. Around the world, 250-500 thousand people die from influenza every year. Numerous studies have shown a consistent association between influenza and acute myocardial infarction [7].

The mortality rate for some forms of influenza, even with high-tech treatments, is more than 50%. In this case, the disease, however, like other forms of influenza of a different etiology, is characterized by an acute onset and severe course: high (40 ° C or more) temperature and prolonged fever with symptoms of intoxication - headache, insomnia, pain in muscles and joints, meningeal symptoms. One of the unfavorable currents is the lightning form, i.e. rapid development of hemorrhagic toxic pulmonary edema and death from respiratory and cardiovascular failure [8].

In some cases, a viral infection predisposes to the development of complications, the most common of which are otitis media (most often in children), sinusitis (in adults), exacerbation of chronic bronchitis/COPD or bronchial asthma.

ARVI of non-influenza etiology is often characterized by a milder, short-term course. This is due to the fact that rhinoviruses primarily infect the epithelium of the upper respiratory tract, while influenza viruses have a tropism for the epithelium of the lower respiratory tract and can cause the development of acute tracheobronchitis and bronchiolitis. Pneumonia is a rare complication of rhinovirus infection, but occurs in 5-30% of patients with influenza A and 10% of patients with influenza B [9].

Rhinosinusitis (RS) is an inflammation of the mucous membrane of the nasal cavity and paranasal sinuses, the problem of which is currently one of the most pressing in otorhinolaryngology [10]. The cause of rhinosinusitis is almost always stagnation of secretions, a block of the natural anastomosis of the SNP and a violation of their aeration, when the mucociliary clearance mechanism suffers, which is an important primary innate mechanism that protects the respiratory tract from the damaging effects of inhaled pollutants, allergens and pathogens.

Vaccination remains the most effective way to control seasonal influenza incidence to date. However, there is no vaccine effective against rhinovirus infection. Depending on the manufacturing technology, influenza vaccines are divided into two classes: live and inactivated. Live vaccines are administered intranasally, the traditional route of administration of inactivated vaccines is subcutaneous or intramuscular. Despite the promising non-invasive route of administration and the low cost of live vaccines, their use is limited due to high reactogenicity (development of symptoms of infection - headache, fever, malaise), allergenicity and a number of contraindications (age over 50 years, acute diseases, internal diseases organs, immunosuppression and others). In this regard, inactivated vaccines are recommended for mass prevention of influenza. The most important requirement for the vaccines used is that the antigenic composition corresponds to the influenza virus strains that are relevant in a given epidemiological season [9].

The main disadvantage of vaccination and specific antiviral prophylaxis is that their effect is limited only to influenza viruses; there is no protection against other ARVI pathogens. A promising area of prevention is the use of drugs to activate the body’s nonspecific resistance [9]. The preventive effectiveness of antiviral drugs during a disease outbreak is high and reaches 70-80%. In this case, prophylaxis with antiviral agents can be carried out both for immunized persons and for persons who have not been vaccinated.

Treatment and prevention with antiviral drugs is indicated in the following cases [9]: 1) as an addition to late vaccination in individuals at risk in the first 2 weeks after vaccination (during the period of antibody development); 2) for children who are vaccinated for the first time: medication is indicated for 6 weeks after the first vaccination (the final production of antibodies ends by 2 weeks after the second vaccination); 3) for persons with immunodeficiency who may give an insufficient immune response to vaccination; 4) for persons for whom vaccination is contraindicated (for example, with allergic reactions to chicken protein); 5) in elderly people for whom the effectiveness of vaccination is reduced, as an addition to vaccination; 6) for unvaccinated persons who are in contact with sick relatives and neighbors; 7) during a pandemic; 8) if the antigenic composition of the vaccine used does not correspond to the epidemic situation.

Considering that it is impossible to predict the antigenic structure of a future epidemic (pandemic) virus, the advance design of effective vaccines is difficult, therefore it is important to have in the arsenal medicines for the prevention and treatment of diseases caused by highly pathogenic strains of viruses. At the same time, as the situation with the COVID-19 pandemic showed in

- 2 044475 all over the world [19], for the timely provision of citizens with antiviral drugs in a pandemic, it is advisable to create state reserves of such drugs. Strategic state reserves in case of pandemics are subject to long-term storage and renewal after the expiration date of reserved medicines. In such a situation, it is extremely important to increase long-term stability to extend shelf life and reduce government costs for creating and updating strategic reserves of antiviral drugs.

Among the drugs used for influenza and ARVI, priority goes to etiotropic drugs that have a direct antiviral effect that disrupts various phases of the replicative cycle of viruses.

Drugs that have a direct effect on the influenza virus (M2 channel blockers amantadine and rimantadine and neuraminidase inhibitors oseltamivir and zanamivir) are used to treat and prevent influenza. M2 channel blockers are active against the influenza A virus. The drugs amantadine and rimantadine have been widely used in the treatment of influenza [11, 12]. The antiviral drug rimantadine has become widespread in the Russian Federation. It is used to treat and prevent infections caused by influenza A viruses [13]. However, rimantadine, as a member of the adamantane group, has limitations in its use. At high doses, side effects from the central nervous system occur; in particular, the drug can cause convulsions. It also has an adverse effect on the liver and kidneys, and therefore its use in people with diseases of these organs may be undesirable. The disadvantage of drugs in this group is the rapidly developing resistance of the virus to them and a number of possible undesirable effects (nausea, loss of appetite, dizziness, insomnia; contraindications include acute liver and kidney diseases). In this regard, the use of rimantadine should not be long-term (for prevention it is recommended to use it at a dose of 50 mg once a day for 10-15 days). Currently, neuraminidase inhibitors of influenza A and B viruses are widely used - oseltamivir phosphate (oseltamivir) and zanamivir (zanamivir), which, by combining with the hydrophobic site of the active site of the influenza virus neuraminidase, block the latter’s ability to cleave sialic acid residues from the surface of the infected cell, thereby suppressing the release of new formed virions from it. Neuraminidase inhibitors (oseltamivir, zanamivir) act on influenza A and B viruses and also have pronounced side effects on the central nervous system. Zanamivir is only available in inhaled form and is therefore not used for prophylaxis. The widespread use of neuraminidase inhibitors is limited by their high cost. In addition, increasing resistance of influenza viruses to these drugs has been reported in various regions of the world [9, 14–15]. This is due to mutations in the neuraminidase gene, which make the virus resistant to this class of compounds [16-18]. Mutations, according to some data, occur in approximately 30% of cases. Thus, recently, a large number of influenza A virus strains of the H5N1 subtype have acquired resistance to oseltamivir due to the replacement of one amino acid in neuraminidase (H274Y and N294S) [17, 18].

Consequently, there is a need to develop new agents and accessible therapeutic forms for the treatment and prevention of influenza and ARVI.

It is known to use 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid, which has pronounced antiviral activity against a wide range of viral pathogens, including the influenza virus [20].

2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid

It is known to use 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid or its pharmaceutically acceptable salt for the treatment and/or prevention of highly pathogenic infectious diseases such as highly pathogenic influenza A caused by viruses having a pathogenicity index of more than 1.2 , and severe acute respiratory syndrome (SARS) caused by type IV coronavirus [21].

It is also known to use 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid for the treatment of viral hepatitis C. This agent can also be administered in combination with pegylated interferon and ribavirin. The pharmaceutical composition of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid for the treatment of viral hepatitis C is also known, which has a pronounced antiviral effect and is effective in the treatment of viral hepatitis C, allowing to significantly reduce the incidence of side effects of antiviral therapy [22] .

It is also known to use 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid or a pharmaceutically acceptable salt thereof as a means for the prevention and/or treatment of diseases associated with a reduced density of interferon receptors by restoring or increasing the density of interferon receptors. receptors to overcome resistance to interferon therapy [2325].

Due to its pronounced antiviral and anti-inflammatory activity, 2-(imidazole-4

- 3 044475 yl)-ethanamide of pentanedioic-1,5 acid has found wide use in medicine as a means for the treatment and prevention of influenza A and B and other acute respiratory viral infections (adenoviral infection, parainfluenza, respiratory syncytial infection).

There is also a known pharmaceutical composition of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid in a solid dosage form in the form of tablets or capsules, which has viral tropic and immunogenic activity, characterized by the fact that it includes 2(imidazole) as an active principle -4-yl)-ethanamide of pentanedioic-1,5 acid, as excipients lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide (Aerosil 300) and calcium stearate [26, 27].

A structural analogue of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid, N,N'bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide, is also known, as well as its use for the treatment chronic diseases of the upper respiratory tract, in particular rhinosinusitis [31], which is a common complication of acute respiratory viral infection.

M,M'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide

One of the disadvantages of many drugs is the lack of stability of the active substance during shelf life. However, solid state stability and shelf life of the active components are very important factors. The drug and pharmaceutical compositions must be able to be stored for significant periods of time without exhibiting a significant change in the physicochemical properties of the active component (for example, its chemical composition, density, hygroscopicity and solubility).

Thus, the objective of the present invention was to develop a stable, long-term storage, economically feasible, industrially marketable preparative composition of 2(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid for the treatment and prevention of respiratory tract diseases, in particular, influenza and ARVI , providing high antiviral activity, as well as expanding the arsenal of medicines that have an antiviral effect and are suitable for creating strategic state reserves in case of pandemics.

The inventors of the present invention have unexpectedly discovered that a composition containing pentanedioic-1,5 acid 2(imidazol-4-yl)-ethanamide in combination with N,N'-bis-[2-(1H-imidazol-4yl)ethyl]pentanediamide exhibits long-term (10 years) stability of 2-(imidazol-4-yl)ethanamide pentanedioic-1,5 acid, which is currently used in the pharmaceutical industry. Such a long shelf life will reduce government costs for creating and updating strategic reserves in case of pandemics of viral diseases and ensure increased biological safety of citizens.

The technical results of the claimed invention are:

increasing the long-term (over 10 years) stability of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid;

expansion of the arsenal of antiviral agents and agents for the treatment and/or prevention of respiratory diseases, suitable for creating strategic, including government stocks in case of pandemics.

The problem is solved, and the result is achieved by creating a composition for the treatment and/or prevention of viral diseases of the respiratory tract, including 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid and N,N'-bis-[2-( 1H-imidazol-4-yl)ethyl]pentanediamide, or pharmaceutically acceptable salts thereof, wherein N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide is contained in an amount of from 0.01 to 1 .00 wt.%.

The following are definitions of terms that are used in the description of the present invention.

A medicinal principle (medicinal substance, medicinal substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, which has pharmacological activity and is the active principle of a pharmaceutical composition used for the production and manufacture of a medicinal product (drug).

Medicine (drug) - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready-made forms, intended to restore, correct or change physiological functions in humans and animals, as well as for treatment and prevention diseases, diagnostics, anesthesia, cosmetology and other things.

Pharmaceutical composition means a composition comprising a novel composition of 2(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid in combination with N,N'-bis-[2-(1H-imidazol-4

- 4 044475 yl)ethyl]pentanediamide and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliaries, distributing agents, delivery agents, such as preservatives, stabilizers , fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavors, flavors, antibacterial agents, fungicides, lubricants, extended delivery regulators, the choice and ratio of which depends on their nature, method of administration of the composition and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as other pharmaceutically acceptable surfactants, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, for example, benzyl alcohol, methenamine, ethylenediaminetetraacetic acid, benzoic acid, chlorobutanol, sorbic acid, parabens, alkylpyridinium, benzethonium and their pharmaceutically acceptable salts and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged action of the composition can be achieved using agents that retard the absorption of the active principle, for example, such as hydrophilic polymeric release retardants, for example, cellulose derivatives, polyethylene oxide, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginates, carbomers, hydrophobic release retardants, such as glyceryl behenate, aluminum monostearate. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohols, buffer solutions, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate and the like. To regulate pH, various organic and inorganic acids can be used, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, and sorbic acids. Examples of dispersing agents and distributing agents are starch, alginic acid and its salts, and silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, colloidal silica, and high molecular weight polyethylene glycol.

A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard form of administration, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions, elixirs or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous , intranasal or intraocular forms of administration and rectal forms of administration.

Pharmaceutically acceptable salt means the relatively non-toxic organic and inorganic salts of the acids and bases claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds or specially prepared. In particular, base salts can be prepared specifically starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like [30]. Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be prepared include sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. The organic bases from which salts of the claimed acids can be obtained are amines and amino acids that are sufficiently basic to form a stable salt and suitable for use for medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane and the like. In addition, tetraalkylammonium hydroxides, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. The basic amino acids that can be used as amino acids are lysine, ornithine and arginine.

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Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliaries and/or carriers used in the pharmaceutical field. The pharmaceutical composition, along with the active substance of the present invention or its pharmaceutically acceptable salt, may include other active substances, including those with activity, provided that they do not cause undesirable effects.

The term therapeutically effective amount means an amount of active substance that (1) treats or prevents a specific disease, condition or disorder, (2) reduces, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (3) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder set forth herein.

The term pharmaceutically acceptable means that the substance or composition to which the term is applied must be chemically and/or toxicologically compatible with the other ingredients in the drug and safe for the person being treated with the substance or composition.

The terms containing, contains means that the specified combinations, compositions and sets include the listed components, but do not exclude the inclusion of other components.

The stated task is also carried out, and the technical result is achieved by creating a pharmaceutical composition for the treatment and/or prevention of viral diseases of the respiratory tract, wherein said composition contains the above-mentioned composition and at least one pharmaceutically acceptable carrier in an effective amount.

The stated task is also carried out, and the technical result is achieved by creating a medicinal product for the treatment and/or prevention of viral diseases of the respiratory tract, and the said drug contains the above-mentioned composition or the above-mentioned pharmaceutical composition in a therapeutically effective amount.

The subject of the present invention is a composition for the treatment and/or prevention of viral diseases of the respiratory tract, including 2-(imidazol-4-yl)-pentanedioic-1,5 acid ethanamide and ^^-bis-[2-(1H-imidazol-4- yl)ethyl]pentanediamide and/or their pharmaceutically acceptable salts, wherein N-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide is contained in an amount of from 0.01 to 1.00 wt.%.

More preferred is a composition characterized in that it contains N,N'-6uc-[2-(1Himidazol-4-yl)ethyl]pentanediamide and/or pharmaceutically acceptable salts thereof in an amount of from 0.10 to 0.30 wt.% .

More preferred is a composition characterized in that it contains N,N'-6uc-[2-(1Himidazol-4-yl)ethyl]pentanediamide and/or pharmaceutically acceptable salts thereof in an amount of from 0.10 to 0.20 wt.% .

More preferred is a composition characterized in that it contains N,N'-6uc-[2-(1Himidazol-4-yl)ethyl]pentanediamide and/or its pharmaceutically acceptable salts in an amount of not more than 0.15 wt.%.

More preferable is a composition characterized in that the viral diseases are selected from the group consisting of ARVI and influenza.

More preferred is a composition characterized in that the diseases are caused by a virus selected from the group consisting of rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, including influenza A, B, C and D, adenovirus, noravirus, metapneumovirus, coronavirus, hantavirus, bocavirus, Coxsackie virus, ECHO group viruses, enterovirus, rotavirus, herpes virus.

Also the subject of the present invention is a pharmaceutical composition for the treatment and/or prevention of viral diseases of the respiratory tract, which contains an effective amount of the mentioned composition, including 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid and Ν,Ν'bis- [2-(1H-imidazol-4-yl)ethyl]pentanediamide (wherein N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide is contained in an amount from 0.01 to 1.00 wt. %) and/or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliaries and/or carriers used in the pharmaceutical field. A pharmaceutical composition along with a composition including 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid and N,N'-bis-[2-(1H-imidazol-4yl)ethyl]pentanediamide and/or their pharmaceutical acceptable salts, the present invention may include other active substances, including those with activity, provided that they do not cause undesirable effects.

If the pharmaceutical composition of the present invention is required to be used in clinical practice, it may be mixed with conventional pharmaceutical carriers.

The carriers used in the pharmaceutical compositions of the present invention are:

- 6 044475 are carriers that are used in the pharmaceutical field to obtain common forms, in particular, in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, flavoring agents are used; antiseptic agents, solubilizers, stabilizers are used in injection forms; topical forms use bases, diluents, lubricants, and antiseptic agents.

The subject of the present invention is also a medicinal product for the treatment and/or prevention of viral diseases of the respiratory tract, containing in an effective amount a composition comprising 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid and N,N'-bis- [2-(1H-imidαzol-4yl)ethyl]pentanediamide and/or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention.

The subject of the present invention is also a finished dosage form for the treatment and/or prevention of viral diseases of the respiratory tract, in the form of tablets, capsules or syrup, containing in a therapeutically effective amount a composition including 2-(imidazol-4-yl)-ethanamide pentanedium-1, 5 acids and N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide and/or pharmaceutically acceptable salts thereof, a pharmaceutical composition of the present invention or a drug of the present invention.

The subject of the present invention is also the use of a pharmaceutical composition according to the present invention, a medicinal product according to the present invention or a finished dosage form according to the present invention for the treatment and/or prevention of viral diseases of the respiratory tract.

The present invention also provides a method for treating and/or preventing respiratory tract diseases, comprising administering to a patient who has a viral disease or is at risk of contracting a viral disease, a pharmaceutical composition of the present invention, a medicinal product of the present invention, or a finished dosage form of the present invention.

The examples presented below illustrate, but do not cover all possible embodiments of the invention and do not limit the invention.

Example 1. Preparation of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid.

Glutaric anhydride was added to a solution of histamine in DMF. The reaction mixture was stirred for 3. and left for 20 hours at 20°C. The completeness of the reaction was monitored by TLC. The white precipitate was separated, dried in vacuum, and recrystallized.

HPLC: individual peak, retention time 14.36 min.

¹ H-NMR spectrum (D ₂ O), δ, ppm: (m, 2H, -CH2), 2.18 (m, 4H, α,γ-CH2), 2.85 (t, 2H, -CH2-HA ), 3.5 (t, 2H, αCH2-HA), 7.25 (s, 1H, CH-4-Im), 8.5 (s, 1H, CH-2-Im).

Mass spectrum, m/z: [M+1H]+ 226.1.

Ultrapure samples of 2(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid were obtained preparatively by ion-exchange chromatography.

Example 2. Preparation of NH-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide.

Histamine was added to glutaric acid dimethyl ester and heated until the release of methyl alcohol vapors stopped. The completeness of the reaction was monitored by TLC. The reaction mass was then suspended in isopropyl alcohol and left. The product was separated, washed with isopropyl alcohol, and dried.

HPLC: individual peak, retention time 5.58 min.

¹ H-NMR spectrum (400.13 MHz, DMSO-d6, δ, ppm, J/Hz): 1.70 (pent., 2H, CH ₂ CH ₂ CH ₂ , J=7.3 Hz) , 2.03 (t, 4H, CH ₂ CH ₂ CH ₂ , J=7.3 Hz), 2.61 (t, 4H, CCH2CH2N, J=7.5 Hz), 3.26 (q.v., 4H , CCH2CH2N, J=7.5 Hz), 6.76 (brs, 2H, CCH), 7.50 (s, 2H, NCHN), 7.94 (brt, 2H, NH).

Mass spectrum, m/z: [M+1H]+ 319.

Ultrapure samples of N,N'-bis-[2(1 H-imidazol-4-yl)ethyl]pentanediamide were obtained preparatively by ion exchange chromatography.

Example 3. Preparation of new compositions of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid containing N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide.

Compositions of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid containing N,N'-bis-[2-(1Nimidazol-4-yl)ethyl]pentanediamide 0.0001, 0.001, 0.01, 0.05, 0.10, 0.15, 0.20, 0.30, 1.0 and 10.0 wt.% according to the present invention were obtained by two methods.

1. From a sample of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid, prepared according to example 1, by adding to it the appropriate calculated amount of N,N'-bis-[2-(1Nimidazol-4-yl )ethyl]pentanediamide prepared according to example 2, and thoroughly mixing the resulting composition.

2. At the same time, by controlling the reaction of the directed synthesis of 2-(imidazol-4-yl)ethanamide pentanedioic-1,5 acid under special conditions.

Example 4. Preparation of a drug in the form of capsules.

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900 g of lactose monohydrate, 900 g of the composition obtained in example 3, 356 g of potato starch, 22 g of magnesium stearate and 22 g of colloidal silicon dioxide were mixed. The resulting mixture was scattered into capsules of suitable size. The mass of the mixture inside one capsule was 220 mg.

Example 5. Study of long-term storage stability of a new composition of 2-(imidazol-4yl)-ethanamide pentanedioic-1,5 acid.

The long-term (over 10 years) stability of new formulations of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid was assessed by the content of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid and compared with long-term (for 10 years) stability of the prototype - especially pure (2-(imidazol-4yl)-ethanamide of pentanedioic-1,5 acid by HPLC method during long-term storage.

All samples were stored in glass vials sealed with rubber stoppers with aluminum caps in a climate chamber under standard test conditions ((25±2)°C and (60±5)% relative humidity). The active substance content was determined by HPLC using standards every three months during the first year, every six months during the second and third years and every 12 months until the tenth year of storage.

As a result of research, it was found that the compositions obtained according to example 3, including 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid with a content of 0.01, 0.05, 0.10, 0.15, 0.20, 0.30, 1.0 and 10.0 wt. % K,K'-bis-[2-(III-imidazol-4-yl)ethyl]pentanediamide (compositions 1, 2, 3, 4, 5, 6, 7, 8, respectively), have increased long-term stability ( for 10 years) storage compared to the prototype - especially pure (2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid. The results are presented in Table 1.

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Table 1

Evaluation of the long-term stability of new formulations of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid containing N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide by HPLC at long-term storage compared to the prototype

Time stored Research Institute, months The amount of active substance detected by HPLC data in May. % of theoretical content Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Proto type 0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 3 99.9+0.01 99.9 100.0 100.0 100.0 100.0 99.9+0, 1 99.9+0, 1 99.9+0.1 6 99.9±0.1 99.9±0. 1 100.0 100.0 100.0 100.0 99.9±0.1 99.9±0.1 99.9+0.1 9 99.9+0.1 99.9+0, 1 100.0 100.0 100.0 100.0 99.9+0, 2 99.9+0, 1 99.8+0.2 12 99.7±0. 1 99.7±0. 1 99.9±0. 1 99.9±0. 1 99.9±0. 1 99.9±0. 1 99.8±0. 1 99.8±0. 2 99.6+0.2 18 99.4+ 0.1 99.6+0, 1 99.9+0, 1 99.9+0, 01 99.8±0. 1 99.8+0, 1 99.6+0, 2 99.5+0, 2 99.2+0.3 24 99.1+0, 3 99.4+0, 3 99.8+0, 1 99.8+0, 1 99.7±0. 1 99.7+0, 1 99.4+0, 3 99.2+0, 3 98.7+0.3 thirty 98.7+0, 1 99.0+0.1 99.8+0, 1 99.7+0, 1 99.5±0. 2 99.6+0, 2 99.2+0, 2 98.9+0, 2 98.1±0.2 36 98.5+0, 2 98.8+0, 2 99.8+0, 1 99.7+0, 1 98.9±0. 3 98.9+0, 2 98.8+0, 3 98.6+0, 3 97.7+0.3 48 98.2+0, 2 98.6+0, 2 99.8+0, 1 99.7+0, 1 98.8±0. 3 98.6+0, 2 98.5+0, 3 98.1+0, 3 97.4±0.3 60 98.1+0, 2 98.5+0, 2 99.8+0, 1 99.7+0, 1 98.7±0. 3 98.5+0, 2 98.3+0, 3 97.6+0, 3 97.0+0.2 72 98.0+0, 2 98.4+0, 2 99.8+0.1 99.7+0.1 98.6±0. 3 98.4+0, 2 98.1+0, 3 97.5+0, 3 96.8+0.3 84 97.9+0, 3 98.3+0, 2 99.7+0, 2 99.6+0, 2 98.5±0. 1 98.3+0, 2 97.9+0, 3 97.1+0, 3 96.2+0.3 96 97.6+0, 3 98.0+0, 2 99.6+0, 2 99.5+0, 2 98.5±0. 2 98.2+0, 3 97.5+0, 4 96.9+0, 4 95.8+0.4 108 97.4+0, 4 97.8+0, 3 99.5+0, 3 99.4+0, 3 98.4+0, 3 98.1+0, 4 97.4+0, 5 96.7+0, 3 95.6+0.3 120 97.1+0, 4 97.5+0, 3 99.5+0, 3 99.4+0, 3 98.4+0, 3 98.1+0, 4 97.2+0, 5 96.5+0, 4 95.4+0.3

It was found that after 10 years of storage under standard conditions ((25±2)°C and (60±5)% relative humidity), new formulations of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid the invention had increased stability compared to the prototype. The prototype substance remained stable for three years, then the content of 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid decreased by more than 2%.

Example 6. Antiviral effect of new compositions of 2-(imidazol-4-yl)-ethanamide pentanedioic 1,5 acid according to the present invention, additionally containing N,N'-bis-[2-(1H-imidazol4-yl)ethyl]pentanediamide.

We studied the antiviral effect of new compounds for the treatment and prevention of viral diseases, including 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid containing 0.01, 0.05, 0.10, 0.15, 0. 20, 0.30, 1.0 and 10.0% N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide (compositions 1, 2, 3, 4, 5, 6, 7, 8, respectively). The prototype contained highly pure 2-(imidazol-4-yl)-ethanamide pentane-1,5 acid. The compositions were prepared according to example 3.

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Antiviral effect of the new compositions according to the present invention against mouse-adapted human respiratory syncytial virus.

The experiment was carried out on outbred white mice of both sexes weighing 8-10 g, which were randomly divided into 10 groups, each group containing 10 animals: composition 1, composition 2, composition 3, composition 4, composition 5, composition 6, composition 7, composition 8, prototype and control group receiving placebo. Animals were housed in groups of five in temperature-controlled boxes (average temperature 21°C) on a 12-hour light/dark cycle and with sufficient water and food. To conduct the research, we used human respiratory syncytial virus (PC virus), previously adapted to grow in the lungs of mice. Mice, previously anesthetized with ether, were infected with PC virus intranasally. The antiviral efficacy of the new formulations of the present invention containing 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid and N,N'-bis-[2-(1H-imidazol-4yl)ethyl]pentanediamide was assessed by measuring the viral titer in the lungs of mice of experimental groups compared to the control group on the 5th and 7th days of infection by titrating an isolated 10% suspension of mouse lung tissue in cell culture according to the cytopathic effect or action (CPE). Animals received treatment with the compounds orally using a probe at a dose of 30 mg per person, once a day for 7 days, similarly, animals in the control group received placebo. Treatment began one day after infection [28].

table 2

Antiviral effect of new compositions of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid according to the present invention, containing N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide, in model of experimental respiratory syncytial virus infection in mice

Medicine Infectious titer of the virus in the lungs of mice on the 5th day after infection Placebo 4.68+0.41 Composition 1 3.14+0.46* Composition 2 3.11+0.42* Composition 3 3.09+0.36* Composition 4 3.04+0.31* Composition 5 3.07+0.49*

There was a significant difference between the infectious titer of the virus in the lungs of mice in the experimental groups (compositions 1-5) from the infectious titer of the virus in the lungs of mice of the control group receiving placebo.

Compositions 6-8 also reduced the infectious titer of the virus in the lungs of mice in the experimental groups, indicating that they also have antiviral activity. The data presented confirm that the new formulations of the present invention containing N,N'-6uc-[2(1H-imidazol-4-yl)ethyl]pentanediamide have antiviral activity, as evidenced by a decrease in viral titers in the lungs of mice compared to mice control group receiving placebo.

Antiviral effect of new compositions according to the present invention against influenza virus.

The experiment was carried out on outbred white mice of both sexes weighing 8-10 g, which were randomly divided into 10 groups, each group containing 10 animals: composition 1, composition 2, composition 3, composition 4, composition 5, composition 6, composition 7, composition 8, prototype and control group receiving placebo. Animals were housed in groups of five in temperature-controlled boxes (average temperature 21°C) on a 12-hour light/dark cycle and with sufficient water and food. To conduct the research, the human influenza virus, type A, strain Aichi (allantoic fluid), previously titrated in mice, was used. Mice, previously anesthetized with ether, were infected with rhinovirus intranasally. The antiviral efficacy of the new formulations of the present invention containing 2-(imidazol-4-yl)-ethanamide-pentanedioic-1,5 acid and N,N'-bis-[2-(1H-imidazol-4yl)ethyl]pentanediamide was assessed by changes in the average life expectancy (ALS) of mice, the survival rate of mice and the degree of protection from a lethal dose of viral infection provided by the drug. The degree of protection provided by the drug was calculated as the difference between the number of surviving animals (in percent) in the experimental group treated with a drug containing 2-(imidazol-4-yl)-pentanedioic-1,5 acid-ethanamide and the number of surviving animals (in percent) in the control group receiving placebo. Animals were treated with the compounds orally by gavage at a dose of 60 mg per person, once a day for 3 days before infection and 10 days after infection, similarly, animals in the control group received placebo [20, 33].

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Table 3

Antiviral effect of new compositions of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid according to the present invention, containing N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide, in models of experimental influenza infection in mice

Medicine SPZh, days Survival rate, % Placebo 5.68±0.2 15.9±0.6 Composition 1 11.84±0.3* 69.8±0.8* Composition 2 11.89+0.4* 71.2±0.9* Composition 3 11.94+0.2* 66.3±0.8* Composition 4 12.03+0.2* 68.6±0.7* Composition 5 11.93±0.4* 70.1±0.9*

There was a significant difference in the average life expectancy and survival rate in mice of experimental groups (compositions 15) from similar indicators in mice of the control group receiving placebo.

Formulations 6-8 also significantly increased survival in experimental mice, indicating that they also have antiviral activity. The presented data confirm that the new compositions according to the present invention containing N,N'-6uc-[2-(1Himidazol-4-yl)ethyl]pentanediamide have antiviral activity, as evidenced by an increase in life expectancy and survival of mice in experimental groups compared to mice control group receiving placebo.

Antiviral effect of new compositions according to the present invention against rhinovirus.

The experiment was carried out on outbred white mice of both sexes weighing 8-10 g, which were randomly divided into 10 groups, each group containing 10 animals: composition 1, composition 2, composition 3, composition 4, composition 5, composition 6, composition 7, composition 8, prototype and control group receiving placebo. Animals were housed in groups of five in temperature-controlled boxes (average temperature 21°C) on a 12-hour light/dark cycle and with sufficient water and food. Human rhinovirus, previously titrated in mice, was used to conduct the research. Mice, previously anesthetized with ether, were infected with rhinovirus intranasally. To evaluate the antiviral efficacy of new formulations according to the present invention containing 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid and N,N'-bis-[2-(1H-imidazol-4-yl)ethyl] pentanediamide, measured the viral titer in the lungs of mice of the experimental groups compared to the control group on the 2nd and 3rd days after infection by titrating the isolated pulmonary suspension of mice in cell culture according to the cytopathic effect or action (CPE). Animals received treatment with the compounds orally using a probe at a dose of 30 mg per person once a day for 5 days, similarly, animals in the control group received placebo. Treatment began one day after infection [28].

Table 4

Antiviral effect of new compositions of 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid according to the present invention, containing N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentanediamide, according to compared with the prototype in a model of experimental rhinovirus infection in mice

Medicine Infectious titer of the virus in the lungs of mice on day 2 after infection Placebo 4.12+0.44 Composition 1 2.24+0.46* Composition 2 2.21+0.37* Composition 3 2.20+0.41* Composition 4 2.19+0.43* Composition 5 2.22+0.49*

* significant difference between the infectious titer of the virus in the lungs of mice of experimental groups (compositions 1-5) from the infectious titer of the virus in the lungs of mice of the control group receiving placebo.

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Compositions 6-8 also reduced the infectious titer of the virus in the lungs of mice in the experimental groups, indicating that they also have antiviral activity. The data presented confirm that the new formulations of the present invention containing N,N'-6uc-[2(1H-imidazol-4-yl)ethyl]pentanediamide have antiviral activity, as evidenced by a decrease in viral titers in the lungs of mice compared to mice control group receiving placebo.

The invention can be used in medicine, chemistry, and the pharmaceutical industry.

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Claims (11)

20. RF Patent No. 2141483, November 20, 1999; 21. Patent EA No. 020283, 10/30/2014; 22. RF Patent No. 2496512, 10/27/2013; 23. RF Patent No. 2595862, 08/27/2016; 24. Application WO 2014035297, 03/06/2014; 25. Application WO 2013055258, 04/18/2013; 26. RF Patent No. 2546002, 01/20/2014, 27. Application WO No. 2015108440, 07/23/2015; 28. RF Patent No. 2562773, 09/10/2015; 29. Bochnev P.P.: “Complex formation and catalytic activity” // Publishing house “Mir”, M., pp. 151-153; 30. Berge S.M., Bighley L.D., Monkhouse D.C.: “Pharmaceutical Salts” // Journal of Pharmaceutical Sciences, V. 66, No. 1, 1977, P. 1-19; 31. RF Patent No. 2665688, 04/12/2013; 32. Antonova M.I., Berlyand A.S.: “Bioorganic chemistry, part VI, Heterocyclic compounds” // M., MGMSU, 2010, 63 S.; 33. Gubler E.V.: “Computational methods of analysis and recognition of pathological processes” // M., Nauka, 1978, 365 P. CLAIM 1. Composition for the treatment and/or prevention of viral diseases of the respiratory tract, including 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid and X,N'-bis-[2-(1H-imidazol-4yl) ethyl]pentanediamide and/or pharmaceutically acceptable salts thereof, wherein 1X,M-bis-[2-(1H-imidazol-4yl)ethyl]pentanediamide is contained in an amount of from 0.01 to 1.00% by weight. 2. The composition according to claim 1, characterized in that said composition contains N,N'-6hc-[2-(1Himidazol-4-yl)ethyl]pentanediamide in an amount of from 0.05 to 1.00 wt.%. 3. The composition according to claim 1, characterized in that said composition contains N,N'-6hc-[2-(1Himidazol-4-yl)ethyl]pentanediamide in an amount of from 0.10 to 0.30 wt.%. 4. The composition according to claim 1, characterized in that said composition contains N,N'-6hc-[2-(1Himidazol-4-yl)ethyl]pentanediamide in an amount of from 0.10 to 0.20 wt.%. 5. The composition according to claim 1, characterized in that said composition contains N,N'-6hc-[2-(1Himidazol-4-yl)ethyl]pentanediamide in an amount of not more than 0.15 wt.%. 6. The composition according to any one of claims 1-5, characterized in that the viral diseases are selected from the group consisting of ARVI and influenza. 7. Composition according to any one of claims 1 to 6, characterized in that the diseases are caused by a virus selected from the group consisting of rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, including influenza A and B, adenovirus, noravirus , metapneumovirus, coronavirus, hantavirus, bocavirus, Coxsackie virus, ECHO group viruses, enterovirus, rotavirus, herpes virus. 8. A pharmaceutical composition for the treatment and/or prevention of viral diseases of the respiratory tract, wherein said composition contains in an effective amount the composition according to any one of claims 1 to 7 and at least one pharmaceutically acceptable carrier. 9. A medicinal product for the treatment and/or prevention of viral diseases of the respiratory tract, wherein said drug contains in an effective amount a composition according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8. 10. Dosage form for the treatment and/or prevention of viral diseases of the respiratory tract, selected from tablets, capsules or syrup, containing in an effective amount the drug according to claim 9. 11. Use of a pharmaceutical composition according to claim 8, a medicinal product according to claim 9 or a finished dosage form according to claim 10 for the treatment and/or prevention of viral respiratory diseases. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2