RU2746692C1 - Novel 2-(imidazol-4-yl)-ethanamide pentanedioic-1,5 acid compositions for treating and preventing viral diseases - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: invention relates to medicine, pharmacology and chemical-pharmaceutical industry, specifically to novel compositions for treating and preventing respiratory diseases containing 2-(imidazol-4-yl)-ethanamide of pentane dihydro-1,5-acid and N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]pentane diamide and/or their pharmaceutically acceptable salts, a pharmaceutical composition based on said compositions, a medicinal agent based on said compositions or said pharmaceutical composition and a ready dosage form based on said compositions, said pharmaceutical composition or said medicinal agent. Invention also relates to the use of said compositions, a pharmaceutical composition, a medicinal agent or a ready dosage form for treating and preventing influenza and ARVI.EFFECT: treatment and prevention of viral diseases.13 cl, 6 ex, 4 tbl

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 of pentanedioic acid-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 its pharmaceutically acceptable salts, a pharmaceutical composition based on said compositions, a drug 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 in people around the world, of which viral diseases account for the majority. Among viral infections, herpes viruses occupy one of the leading places due to their widespread distribution. According to the WHO, about 90% of the world's population has manifestations of herpes infection, and mortality from these infections is in second place after viral hepatitis, so the problem of herpes diseases is especially urgent today. Today, science knows more than 100 types of herpes virus, of which 8 antigenic varieties cause diseases in humans (herpes simplex viruses of the 1st and 2nd types, chickenpox and herpes zoster (Varicella zoster), cytomegalovirus, Epstein virus -Barr, human herpes viruses type 6, 7 and 8). Herpes viruses are capable of being in the human body for life and cause diseases with various manifestations from asymptomatic carriage to severe forms with the development of herpetic encephalitis, meningitis, which are fatal. Localization of herpetic eruptions is different - skin, mucous membranes of the mouth and genitals, cornea, internal organs. For the treatment and prevention of recurrences of herpes infection, there is a large selection of drugs with a pronounced antiviral effect, but these drugs have a number of side effects, including a decrease in the body's resistance to viruses [1].

Many viruses infect the respiratory tract, nasal passages, throat, bronchi, 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 they are separated into a separate group due to the fact that they affect the entire body systemically. More than 200 different viruses, representatives of 4 families of RNA-containing viruses (orthomyxoviruses, paramyxoviruses, coronaviruses and picornaviruses) and 2 families of DNA-containing viruses (adenoviruses and herpes viruses) can be the cause of ARVI [1, 5]. In terms of the frequency of infection, 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 diseases and 65% of all registered diseases [1-2].

All acute respiratory viral infections are characterized by symptoms of general intoxication (headache, weakness, muscle pain, loss of appetite), fever, catarrhal phenomena (nasal congestion, runny nose, cough, sore throat). Localization of the lesion focus largely depends on the type of pathogen. So, rhinoviral diseases are characterized by the predominance of rhinitis, adenovirus infections - rhinopharyngitis, parainfluenza is characterized by pharyngitis, and for influenza - tracheitis, respiratory syncytial virus affects the bronchi. Other symptoms are also possible, for example, adenoviruses can cause conjunctivitis and keratitis. Usually the symptoms of SARS persist for 3-7 days (the cough can be observed for a longer time), the possible duration of the flu 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, bronchitis and pneumonia may develop. The main causes of complications are disorders of the immune defense, leading to long-term immunodeficiencies, combined with a sharp decrease in the antibacterial resistance of the body. With the correct choice of treatment tactics for ARVI, the risk of complications is noticeably reduced [1, 3-5].

Despite the advances achieved in medicine over the past decades, in particular in the treatment of infectious diseases, ARVI and influenza viruses continue to be a serious public health problem for most countries of the world due to the extremely high incidence rate, usually of the nature of seasonal epidemics. ARVI and influenza occupy leading positions in terms of medical care for children and adults, temporary disability, the amount of drugs consumed during the period of illness. Children, the elderly, people with concomitant diseases (various immunodeficiency states, diseases of the lungs, cardiovascular system, liver, kidneys, diabetes mellitus, etc.) are most susceptible to seasonal morbidity. So, in Russia annually 30-40 million cases of infectious diseases are registered, from 70% to 90% of which are influenza and acute infections of the respiratory tract of viral and unspecified etiology [2]. The reasons for such a high incidence are considered to be the high population density in large cities, poor ecology, high population mobility, incomplete coverage of pathogens through vaccinations or refusal of vaccinations, low hygienic culture of people, the presence of a large amount of stress, insufficient time spent on sleep and rest, smoking , alcohol abuse, as well as malnutrition and malnutrition [6].

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

The mortality rate from some forms of influenza, even with high-tech treatments, is over 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-fast 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 frequent 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 lighter short course. This is due to the fact that rhinoviruses mainly affect 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, bronchiolitis. Pneumonia is a rare complication of rhinovirus infection, but develops in 5-30% of patients with influenza A and 10% of patients with influenza B [9].

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

Vaccination is still the most effective way to control seasonal influenza morbidity. However, there is no vaccine effective against rhinovirus infection. Influenza vaccines, depending on the manufacturing technology, are divided into two classes: live and inactivated. Live vaccines are administered intranasally, the traditional route of administration for inactivated vaccines is subcutaneous or intramuscular injection. Despite the promising non-invasive route of administration and the low cost of live vaccines, their use is limited due to their 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 the compliance of the antigenic composition with the influenza virus strains relevant in the given epidemiological season [9].

The main disadvantage of vaccination and specific antiviral prophylaxis is that their action is limited only by influenza viruses, there is no protection against other pathogens of ARVI. A promising direction of prevention is the use of funds to activate the nonspecific resistance of the organism [9]. The prophylactic efficacy of antiviral agents during an outbreak is high and reaches 70-80%. At the same time, prophylaxis with antiviral agents can be carried out both for immunized individuals and for those who have not been vaccinated.

Treatment and prophylaxis with antiviral drugs is indicated in the following cases [9]: 1) as an addition to late vaccination in risk groups in the first 2 weeks after vaccination (for the period of antibody production); 2) for children who are vaccinated for the first time: taking medications is indicated within 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, in case of allergic reactions to chicken protein); 5) in the elderly, for whom the effectiveness of vaccination decreases, as an adjunct to vaccination; 6) for unvaccinated persons in contact with sick relatives and neighbors; 7) in case of 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 early design of effective vaccines is difficult, therefore it is important to have in the arsenal of drugs 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 around the world has shown [19], in order to provide citizens with antiviral drugs in a timely manner in a pandemic, it is advisable to create state reserves of such funds. Strategic government reserves for 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 in order to extend the shelf life and reduce government costs for creating and updating strategic reserves of antiviral agents.

Among the drugs used for influenza and acute respiratory viral infections, the priority belongs to etiotropic drugs that have a direct antiviral effect, disrupting various phases of the replicative cycle of viruses.

Agents with 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. Amantadine and rimantadine have been widely used in influenza therapy [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 representative 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 seizures. It also has an adverse effect on the liver, 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 adverse events (nausea, loss of appetite, dizziness, insomnia; among the contraindications - acute liver and kidney disease). In this regard, the use of rimantadine should not be long-term (for prevention, it is recommended to use 50 mg 1 time per day for 10-15 days). Currently, inhibitors of neuraminidase of influenza A and B viruses are widely used - oseltamivir phosphate (oseltamivir) and zanamivir (zanamivir), which, connecting with the hydrophobic site of the active center of the influenza virus neuraminidase, block the ability of the latter 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 significant side effects on the central nervous system. Zanamivir is available only in inhalation form, therefore it is not used for prophylaxis. The widespread use of neuraminidase inhibitors is limited by their high cost. In addition, the growing 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 reports, occur in about 30% of cases. So, recently, a large number of influenza A virus strains of the H5N1 subtype 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 available therapeutic forms for the treatment and prevention of influenza and ARVI.

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

It is known to use pentanedioic acid 2- (imidazol-4-yl) -ethanamide 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) due to type IV coronavirus [21].

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

It is also known to use pentanedioic acid 2- (imidazol-4-yl) -ethanamide or its pharmaceutically acceptable salt as an agent for the prevention and / or treatment of diseases associated with a decreased density of interferon receptors by restoring or increasing the density of interferon receptors to overcome resistance to interferon therapy [23-25].

Due to its pronounced antiviral and anti-inflammatory activity, 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid has found wide application 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).

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

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

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

2- (imidazol-4-yl) -ethanamide pentanedioic-1,5 acid in the presence of water can undergo hydrolysis at the intramolecular amide bond with the formation of histamine and glutaric acid. In addition, during the production of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid, trace amounts of transition metal impurities (for example, ions of iron (II), iron (III), Ni (O) , Zn (II), etc.). It is known from the prior art that metals with the configuration d8 and d10 are catalysts for the oxidation of organic substances with atmospheric oxygen, and even a small amount of them can initiate the oxidation reaction [29], which can negatively affect the stability of the drug during storage.

Thus, the object of the present invention was to develop a stable, during long-term storage, economically feasible, industrially sold preparative composition of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 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 drugs that have antiviral effects and are suitable for creating strategic state reserves in case of pandemics.

The inventors of the present invention have surprisingly found that a composition containing pentanedioic acid 2- (imidazol-4-yl) -ethanamide in combination with N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide exhibits long-term (over 10 years) stability of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid, which is currently used in the pharmaceutical industry. Such a long shelf life will reduce government spending on the creation and renewal of strategic reserves in the event of viral disease pandemics and ensure an increase in the biological safety of citizens.

The technical results of the claimed invention are:

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

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

The problem is solved, and the result is achieved by creating a stable composition for oral administration for the treatment and / or prevention of respiratory diseases, which has antiviral activity, containing 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and N, N ' -bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide, or their pharmaceutically acceptable salts in an effective amount and, optionally, auxiliary substances.

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

"Medicinal principle" (drug substance, drug 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 drug (means ).

"Drug (preparation)" - 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 for the restoration, correction or change of physiological functions in humans and animals, as well as for treatment and disease prevention, diagnostics, anesthesia, cosmetology and others.

"Pharmaceutical composition" means a composition comprising a novel formulation of pentanedioic acid 2- (imidazol-4-yl) ethanamide in combination with N, N'-bis- [2- (1H-imidazol-4-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, auxiliary, dispensing agents, delivery agents such as preservatives, stabilizers, fillers, disintegrants , humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavors, antibacterial agents, fungicides, lubricants, sustained 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, such as benzyl alcohol, urotropine, 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 such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents slowing down the absorption of the active principle, for example, such as hydrophilic polymer release agents, for example, cellulose derivatives, polyethylene oxide, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginates, carbomers, hydrophobic release retardants such as glycerolate, aluminum monostearate. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, buffers, 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 adjust the pH, various organic and inorganic acids can be used, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids. Examples of dispersing agents and distributing agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, colloidal silicon dioxide, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local 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 administration form, as a mixture with traditional pharmaceutical carriers. Suitable unit forms of administration 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 acids and bases as claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation, or purification of compounds, or they can be prepared specially. In particular, base salts can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid.

Examples of the salts obtained in this way 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 a 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 derived are sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which the salts of the claimed acids can be obtained, amines and amino acids are selected that are basic enough to form a stable salt and are suitable for medical use (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. Basic amino acids - lysine, ornithine and arginine - can be used as amino acids.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliary agents and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the active substance according to 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 an 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 particular disease, condition, or disorder described herein.

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

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

The problem is solved, and the technical result is achieved by creating a composition for the treatment and / or prevention of respiratory diseases, which has antiviral activity, including 2- (imidazol-4-yl) -ethanamide of pentanedioic-1, 5 acid and N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts, said composition comprising N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount from 0.0001% to 10.00% of the mass.

The task is also achieved, and the technical result is achieved by creating a pharmaceutical composition for the treatment and / or prevention of respiratory diseases, and said composition contains in a therapeutically effective amount any of the above composition and at least one pharmaceutically acceptable carrier.

The task is also achieved, and the technical result is achieved by creating a drug for the treatment and / or prevention of respiratory diseases, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, and the said agent contains in a therapeutically effective amount any of the aforementioned composition or the aforementioned pharmaceutical composition.

The subject of the present invention is a composition for the treatment and / or prevention of viral diseases, comprising 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and N, N'-bis- [2- (1H-imidazole-4- yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts.

More preferred is a composition characterized in that it contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or its pharmaceutically acceptable salts in an amount of not more than 10.00 wt%.

More preferred is a composition characterized in that it contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or its pharmaceutically acceptable salts in an amount from 0.0001% to 10.00 % mass.

More preferred is a composition characterized in that it contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or its pharmaceutically acceptable salts in an amount from 0.0001 to 1.00% masses.

More preferred is a composition characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount of 0.05 to 1.00 wt%.

More preferred is a composition characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount of 0.10 to 0.30 wt%.

More preferred is a composition characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount from 0.10 to 0.2 0% of the mass.

More preferred is a composition characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount of not more than 0.15% of the mass.

More preferred is a composition characterized in that said composition contains 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid in an amount of more than 96.00% of the mass.

More preferred is a composition characterized in that the diseases are diseases of the upper respiratory tract.

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

More preferred is a composition characterized in that the respiratory tract diseases are caused by a viral infection.

More preferable is the composition, characterized in that it is intended for the prevention of complications of respiratory diseases caused by a viral infection.

More preferable is the composition, characterized in that it is intended for the prevention of concomitant diseases in case of respiratory tract infection with a viral infection.

More preferred is a composition characterized in that the diseases are selected from the group consisting of rhinitis, sinusitis, rhinosinusitis, pharyngitis, nasopharyngitis, tonsillitis, diseases of the vocal folds and larynx, vasomotor and allergic rhinitis, bronchitis, bronchiolitis, pneumonia, bronchial asthma, chronic obstructive lung disease, cystic fibrosis.

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.

The subject of the present invention is also a pharmaceutical composition for the treatment and / or prevention of respiratory diseases, which contains a therapeutically effective amount of said composition comprising pentanedioic acid 2- (imidazol-4-yl) -ethanamide and N, N'-bis - [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

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

If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with conventional pharmaceutical carriers.

The carriers used in the pharmaceutical compositions of the present invention are those used in the pharmaceutical field to produce 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; in local forms, bases, diluents, lubricants, antiseptic agents are used.

The subject of the present invention is also a medicament for the treatment and / or prevention of respiratory diseases, in the form of tablets, capsules or solution for injection, placed in a pharmaceutically acceptable package, containing in a therapeutically effective amount a composition comprising 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts, or the pharmaceutical composition according to the present invention.

The subject of the present invention is also a finished dosage form for the treatment and / or prevention of respiratory tract diseases, in the form of tablets, capsules, solution or suspension, syrup, solution for injection, placed in a pharmaceutically acceptable package, containing in a therapeutically effective amount a composition comprising 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts, the pharmaceutical composition of the present invention or a medicament according to the present invention.

The subject of the present invention is also the use of the composition according to the present invention for the treatment and / or prophylaxis of diseases of the respiratory tract.

The subject of the present invention is also the use of a pharmaceutical composition according to the present invention,

a medicament according to the present invention or a finished dosage form according to the present invention for the treatment and / or prevention of respiratory diseases.

The subject of the present invention is also a method for the treatment and / or prevention of respiratory diseases, comprising the administration by a patient having a viral disease or a risk of contracting a viral disease, a pharmaceutical composition of the present invention, a medicament of the present invention, or a finished dosage form of the present invention.

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

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

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

HPLC: individual peak, retention time 14.36 min.

1H-NMR spectrum (D2O), δ, ppm: (m, 2H, (3- CH2), 2.18 (m, 4H, α, γ- CH2), 2.85 (t, 2H, (3- CH2- HA), 3.5 (t, 2H, α-CH2-HA), 7.25 (s, 1H, CH-4-Im), 8.5 (s, 1H, CH-2-Im).

Mass spectrum, m / z: [М + 1Н] + 226.1.

Highly pure samples of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid were prepared preparatively by the method of ion-exchange chromatography.

Example 2. Obtaining N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide.

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

HPLC: individual peak, retention time 5.58 min.

1H-NMR spectrum (400, 13 MHz, DMSO-d16, δ, ppm, J / Hz): 1.70 (pent., 2H, CH2CH2CH2, J = 7.3 Hz), 2.03 (t , 4H, CH2CH2CH2, J = 7.3 Hz), 2.61 (t, 4H, CCH2CH2N, J = 7.5 Hz), 3.26 (q, 4H, CCH2CH2N, J = 7.5 Hz), 6.76 (br s, 2H, CCH), 7.50 (s, 2H, NCHN), 7.94 (br t, 2H, NH).

Mass spectrum, m / z: [М + 1Н] + 319.

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

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

Compositions of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid containing N, N'-bis- [2- (1H-imidazol-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% May. according to the present invention were obtained in two ways:

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

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

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

Mixed 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. The resulting mixture was poured into appropriately sized capsules. 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-4-yl) -ethanamide of pentanedioic acid-1,5 acid.

The long-term (over 10 years) stability of the new formulations of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid was evaluated by the content of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and compared with long-term (within 10 years) stability of the prototype - especially pure (2- (imidazol-4-yl) -ethanamide of pentanedioic acid-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 climatic chamber under standard test conditions ((25 ± 2) ° C and (60 ± 5)% relative humidity). The active ingredient 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 up to 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 acid-1.5 with a content of 0.01 wt. %, 0.05 wt. %, 0.10 wt. %, 0.15 wt. %, 0.2 0 wt. %, 0.3 0 wt. %, 1.0 wt. % and 10.0 wt. % N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide (formulations 1, 2, 3, 4, 5, 6, 7, 8, respectively), have increased stability with long-term ( within 10 years) storage in comparison with the prototype - very pure (2- (imidazol-4-yl) -ethanamide with pentanedioic-1,5 acid The results are presented in table 1.

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

The authors suggest that the increased stability of the combination is a result of the chemical properties of N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide. One of these properties is the ability to complex or chelate metal ions. This compound has several functional groups that can act as electron donors during complexation, for example, a carboxyl group, imido, amido groups, and is a ligand that specifically interacts with metal ions, for example, with ions of zinc, copper, iron, magnesium. This is confirmed by high values of 1dK1≥5 with respect to transition metal ions [31].

Due to its high capacity for complexation, N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide is able to bind impurities of metal ions, thereby reducing their ability to catalyze oxidation reactions of 2- (imidazol-4-yl ) -ethanamide of pentanedioic acid-1,5 acid.

In addition, imidazole rings are present in the structure of N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide. They include two types of nitrogen atoms with different properties. One nitrogen atom exhibits basic properties, the second - acidic, due to the presence of a bond with hydrogen. Due to the presence of hydrogen on these nitrogen atoms, N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide is able to form associates with water through hydrogen bonds, thereby binding residual moisture that can remain upon drying product, which prevents the hydrolysis reaction of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid [32].

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

Investigated the antiviral effect of new compositions for the treatment and prevention of viral diseases, including 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1, 5 acid with a content of 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 pentanedioic acid 1, 5. The formulations were prepared according to example 3.

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

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

Compositions 6-8 also reduced the infectious titer of the virus in the lungs of mice in the experimental groups, which indicates that they also have antiviral activity. The presented data confirm that the new formulations according to the present invention, containing N, N'-bis- [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 of the control group receiving placebo.

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

The experiment was carried out on white outbred mice of both sexes weighing 8-10 g, which were randomly divided into 10 groups, each group had 10 animals: composition 1, composition 2, composition 3, composition 4, composition 5, composition 6, composition 7, composition 8, prototype and placebo control group. The animals were housed five individuals in temperature-controlled boxes (with an average temperature of 21 ° C) with a 12-hour day and night cycle and with sufficient water and food. For the research, we used a human influenza virus, type A, strain Aichi (allantoic fluid), previously titrated in mice. Mice pre-anesthetized with ether were infected intranasally with rhinovirus. On the antiviral efficacy of new compositions according to the present invention containing pentanedioic acid 2- (imidazol-4-yl) -ethanamide and N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide were judged by the change in the average lifespan (ALE) of mice, the survival rate of the mice, and the degree of protection provided by the drug against the lethal dose of viral infection. 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 pentanedioic acid 2- (imidazol-4-yl) -ethanamide, and the number of surviving animals (in percent) in the placebo control group. The animals were treated with the formulations 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 of the control group received placebo [20, 33].

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

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

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

Compositions 6-8 also reduced the infectious titer of the virus in the lungs of mice in the experimental groups, which indicates that they also have antiviral activity. The presented data confirm that the new formulations according to the present invention, containing N, N'-bis- [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 of the control group receiving placebo.

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

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Claims (13)

1. Composition for the treatment and / or prevention of influenza and acute respiratory viral diseases, including 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and N, N'-bis- [2- (1H-imidazole- 4-yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts, said composition comprising N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount from 0.01 to 10, 00 wt%. 2. The composition according to claim 1, characterized in that it contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or its pharmaceutically acceptable salts in an amount from 0.01 to 1 , 00 wt%. 3. Composition according to claim 2, characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount from 0.05 to 1.00 wt.% ... 4. Composition according to claim 3, characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount from 0.10 to 0.30 wt.% ... 5. Composition according to claim 4, characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount from 0.10 to 0.20 wt.% ... 6. Composition according to claim 2, characterized in that said composition contains N, N'-bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide in an amount of not more than 0.15 wt.%. 7. Composition according to claim 1, characterized in that said composition contains 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid in an amount of more than 96.00 wt.%. 8. Composition according to any one of paragraphs. 1-7, 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, adenovirus, metapneumovirus, coronavirus, bocavirus, Coxsackie virus, enterovirus, herpes virus. 9. Pharmaceutical composition for the treatment and / or prevention of influenza and acute respiratory viral diseases, and said composition contains in an effective amount a composition according to any one of claims. 1-8 and at least one pharmaceutically acceptable carrier. 10. A drug for the treatment and / or prevention of influenza and acute respiratory viral diseases in the form of tablets, capsules or syrup, and the said agent contains in an effective amount a composition according to any one of claims. 1-8 or a pharmaceutical composition according to claim 9. 11. Dosage form for the treatment and / or prevention of influenza and acute respiratory viral diseases in the form of tablets, capsules or syrup, and the said agent contains in an effective amount a composition according to any one of claims. 1-8, a pharmaceutical composition according to claim 9, or a medicament according to claim 10. 12. The use of the composition according to any one of paragraphs. 1-8 for the treatment and / or prevention of influenza and acute respiratory viral diseases. 13. The use of a pharmaceutical composition according to claim 9, a medicament according to claim 10 or a dosage form according to claim 11 for the treatment and / or prevention of influenza and acute respiratory viral diseases.