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WO2021049980A1 - Nouvelles formulations pour le traitement et la prévention de maladies virales - Google Patents

Nouvelles formulations pour le traitement et la prévention de maladies virales Download PDF

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Publication number
WO2021049980A1
WO2021049980A1 PCT/RU2020/050219 RU2020050219W WO2021049980A1 WO 2021049980 A1 WO2021049980 A1 WO 2021049980A1 RU 2020050219 W RU2020050219 W RU 2020050219W WO 2021049980 A1 WO2021049980 A1 WO 2021049980A1
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Prior art keywords
imidazol
diseases
composition according
composition
pentanediamide
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English (en)
Russian (ru)
Inventor
Владимир Евгеньевич НЕБОЛЬСИН
Антон Петрович ПЕРЕВЕРЗЕВ
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Valenta Intellect LLC
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Valenta Intellect LLC
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Priority claimed from RU2019128667A external-priority patent/RU2745265C2/ru
Priority claimed from RU2020113506A external-priority patent/RU2746692C1/ru
Application filed by Valenta Intellect LLC filed Critical Valenta Intellect LLC
Publication of WO2021049980A1 publication Critical patent/WO2021049980A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention relates to the field of medicine, pharmacology and the chemical and 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.
  • 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.
  • 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 recurrence 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].
  • ARVI acute respiratory viral infections
  • 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].
  • influenza 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].
  • ARVI Usually the symptoms of ARVI 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 antibacterial resistance of the organism. With the correct choice of treatment tactics for ARVI, the risk of complications is noticeably reduced [1, 3-5].
  • ARVI and influenza viruses 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 are most susceptible to seasonal morbidity. So, in Russia, 30-40 million cases of infectious diseases are annually registered, from 70% to 90% of which are influenza and acute infections of the respiratory tract of viral and unspecified etiology [2].
  • 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.
  • 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 disease is characterized by an acute onset and severe course: high (40 ° C and 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].
  • 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 is an inflammation of the mucous membrane of the nasal cavity and paranasal sinuses (ROS), 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.
  • 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.
  • the traditional route of administration for inactivated vaccines is subcutaneous or intramuscular injection.
  • allergenicity development of symptoms of infection - headache, fever, malaise
  • allergenicity a number of contraindications (age over 50 years, acute diseases, internal diseases organs, immunosuppression and others).
  • inactivated vaccines for mass prevention of influenza, inactivated vaccines.
  • 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%.
  • 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.
  • pandemic 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.
  • the situation with the COVID-19 pandemic around the world has shown [19]
  • 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.
  • the priority belongs to etiotropic drugs that have a direct antiviral effect, disrupting various phases of the replicative cycle of viruses.
  • M2 channel blockers amantadine and rimantadine and neuraminidase inhibitors oseltamivir and zanamivir
  • 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].
  • 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.
  • rimantadine should not be long-term (for prevention, it is recommended to use 50 mg 1 time per day for 10-15 days).
  • oseltamivir phosphate oseltamivir
  • zanamivir oseltamivir phosphate
  • neuraminidase inhibitors The widespread use of neuraminidase inhibitors is limited by their high cost.
  • 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.
  • H274Y and N294S a large number of influenza A virus strains of the H5N 1 subtype acquired resistance to oseltamivir due to the replacement of one amino acid in neuraminidase [17-18].
  • 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].
  • 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].
  • 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.
  • 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] ...
  • 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 reduced density of interferon receptors by restoring or increasing the density of interferon receptors to overcome resistance to interferon therapy [23-25].
  • 2- (imidazol-4-yl) -ethanamide of pentanedioic-1, 5 acid Due to its pronounced antiviral and anti-inflammatory activity, 2- (imidazol-4-yl) -ethanamide of pentanedioic-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).
  • compositions of 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid in solid dosage form in the form of tablets or capsules with viral sotropic and immunogenic activity characterized in that it includes 2- ( imidazol-4-yl) -ethanamide pentanedioic acid 1, 5 acid, as auxiliary substances lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide (Aerosil 300) and calcium stearate [26-27].
  • 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.
  • trace amounts of transition metal impurities for example, ions of iron (II), iron (III), Ni (0) , Zn (II), etc.
  • metals with the configuration d 8 and d 10 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.
  • 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 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.
  • compositions containing pentanedioic acid 2- (imidazol-4-yl) -ethanamide in combination with N, N'-6nc- [2- (1 H-imidazol-4-yl ) ethyl] pentanediamide exhibits long-term (within 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:
  • 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 tract diseases, which has antiviral activity, containing 2- (imidazol-4-yl) -ethanamide of pentanedioic acid and M, M ' -bis- [2- (1H-imidazol-4-yl) ethyl] pentanediamide, or their pharmaceutically acceptable salts in an effective amount and, optionally, auxiliary substances.
  • Medical principle drug substance, 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'-6nc- [2- (1 H-imidazole-4- yl) ethyl] pentanediamide ohm 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.
  • suspending agents examples include 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, 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.
  • 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).
  • fillers are lactose, milk sugar, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate, and the like.
  • various organic and inorganic acids can be used, such as malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids.
  • dispersing agents and distributing agents are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium stearate, sodium lauryl sulfate, talc, colloidal silicon dioxide, and high molecular weight polyethylene glycol. weight.
  • 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, and 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.
  • organic bases from which 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.
  • 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.
  • compositions can include pharmaceutically acceptable excipients.
  • 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.
  • terapéuticaally 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.
  • 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.
  • compositions for the treatment and / or prevention of respiratory diseases which has antiviral activity, including 2- (imidazol-4-yl) -ethanamide of pentanedioic acid and N, N'-6nc- [2- (1 H-imidazol-4-yl) ethyl_] pentanediamide and / or their pharmaceutically acceptable salts, and the above composition contains N, N'-6nc- [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 1P, M'-bis- [2- (1H-imidazole-4- yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts.
  • composition characterized in that it contains N.N'-6nc- [2- (l H-imidazol-4-yl) ethyl] pentanediamide and / or its pharmaceutically acceptable salts in an amount of not more than 10.00 wt%.
  • composition characterized in that it contains N.N'-6nc- [2- (l H-imidazol-4-yl) ethyl] pentanediamide and / or its pharmaceutically acceptable salts in an amount from 0.0001% to 10, 00% of the mass.
  • composition characterized in that it contains N.N'-6nc- [2- (l H-imidazol-4-yl) ethyl] pentanediamide and / or its pharmaceutically acceptable salts in an amount from 0.0001 to 1.00 % mass.
  • composition characterized in that said composition contains N, N'-6nc- [2- (1 N-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'-6nc- [2- (1 H-imidazol-4-yl) ethyl] pentanediamide in an amount of 0.10 to 0.30 wt%.
  • composition characterized in that said composition contains N, N'-6nc- [2- (1 H-imidazol-4-yl) ethyl] pentanediamide in an amount from 0.10 to 0.20 wt%.
  • composition characterized in that said composition contains N, N'-6nc- [2- (1 H-imidazol-4-yl) ethyl] pentanediamide in an amount of not more than 0.15% of the mass.
  • composition characterized in that said composition contains pentanedioic acid 2- (imidazol-4-yl) ethanamide in an amount of more than 96.00 wt%.
  • composition characterized in that the diseases are diseases of the upper respiratory tract.
  • composition characterized in that the diseases are selected from the group consisting of ARVI and influenza.
  • composition characterized in that the respiratory tract diseases are caused by a viral infection.
  • composition characterized in that it is intended for the prevention of complications of respiratory diseases caused by a viral infection.
  • composition characterized in that it is intended for the prevention of concomitant diseases in case of respiratory tract infection with a viral infection.
  • 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.
  • 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.
  • 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, herp virus.
  • 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, herp 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 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid and M,] '-bis - [2- (1H-imidazol-4-yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.
  • compositions can include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are meant diluents, auxiliary agents and / or carriers used in the pharmaceutical field.
  • 2- (l H-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.
  • 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 a 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'-6nc-
  • 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'-onc- [2- (l H-imidazol-4-yl) ethyl] pentanediamide and / or their pharmaceutically acceptable salts, pharmaceutical composition according to the present invention or the medicament of 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.
  • Example 1 Obtaining 2- (imidazol-4-yl) -ethanamide of pentanedioic acid-1,5 acid.
  • 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.
  • Example 3 Obtaining new compositions of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid containing N, N'-6iic- [2- (l H-imidazol-4-yl) ethyl] pentanediamide.
  • Example 4 Obtaining a medicinal product in the form of capsules.
  • 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 (within 10 years) stability of the new formulations of 2- (imidazol-4-yl) - ethanamide of pentanedioic-1,5 acid was assessed by the content of 2- (imidazol-4-yl) - ethanamide of pentanedioic-1,5 acid and was 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.
  • compositions obtained according to example 3 including 2- (imidazol-4-yl) -ethanamide pentand new -1.5 acid with content of 0.01 May. %, 0.05 May. %, May 0.10. %, 0.15 May. %, 0.20 May. %, 0.30 May. %, May 1.0. % and 10.0 May.
  • N, N'-6nc- [2- (1 H-imidazol-4-yl) ethyl] pentandamide 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 logKl> 5 with respect to transition metal ions [31].
  • N, N'-6nc- [2- (l H-imidazol-4- yl) ethyl] pentanediamide is able to bind impurities of metal ions, thereby reducing their ability to catalyze oxidation reactions of 2- (imidazole-4- yl) -ethanamide of pentanedioic-1,5 acid.
  • imidazole rings are present in the structure of N, N'-6nc- [2- (l H-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.
  • N, N'-6HC- [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 effect of new formulations of 2- (imidazol-4-yl) -ethanamide of pentanedioic-1,5 acid according to the present invention, additionally containing N.N'-6nc- [2- (l H-imidazol-4-yl) ethyl] pentanediamide.
  • compositions 1, 2, 3 , 4, 5, 6, 7, 8, respectively were prepared according to example 3.
  • mice 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.
  • PC virus human respiratory syncytial virus
  • Mice pre-anesthetized with ether, infected with the PC virus intranasally.
  • compositions according to the present invention containing pentanedioic acid 2- (imidazol-4-yl) -ethanamide and N, N'-6HC- [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].
  • CPE cytopathic effect or action
  • 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'-6nc- [2- (l H-imidazol-4-yl) ethyl] pentanediamide, have antiviral activity, which is confirmed by a decrease in viral titers in the lungs of mice compared to with mice of the control group receiving placebo. Antiviral action of the new compositions according to the present invention against influenza virus.
  • mice 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.
  • a human influenza virus type A, strain Aichi (allantoic fluid), previously titrated in mice. Mice pre-anesthetized with ether were infected intranasally with rhinovirus.
  • compositions according to the present invention containing pentanedioic acid 2- (imidazol-4-yl) -ethanamide and N, N'-6HC- [2- (1H-imidazol-4-yl) ethyl] pentanediamide were judged by the change in the average life span (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.
  • ALE average life span
  • 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 that received treatment with a drug containing 2- (imidazol-4-yl) - pentanedioic acid-1.5 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 formulations according to the present invention, containing N.N'-6nc- [2- (l H-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 by compared with placebo-treated control mice.
  • mice 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.
  • human rhinovirus previously titrated in mice. Mice pre-anesthetized with ether were infected intranasally with rhinovirus.
  • 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 1-5) significant difference between the infectious titer of the virus in the lungs of mice of the experimental groups (compositions 1-5) from the infectious titer of the virus in the lungs of the mice of the control group that received placebo.
  • 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'-6nc- [2- (l H-imidazol-4-yl) ethyl] pentanediamide, have antiviral activity, which is confirmed by a decrease in viral titers in the lungs of mice compared to with mice of the control group receiving placebo.
  • the invention can be used in medicine, chemistry, pharmaceutical industry.
  • Gendon YZ "Etiology of acute respiratory diseases” // Vaccination, N ° 5 (17), 2001, S. 4-5; 5.
  • Ershov FI, Garashchenko TI “Is it possible to control acute respiratory diseases in children? (A new look at the old problem) "// Actual problems of pediatric otorhinolaryngology and pharmacotherapy of diseases of the ENT organs. Jubilee collection of scientific papers, Moscow, 2001;
  • Zaitsev A. A "Directions of pharmacotherapy and prevention of acute respiratory viral infections” // Russian Medical Journal, T. 17, N ° 23, 2009, S. 1525;
  • Hayden F.G . "Prevention and treatment of influenza in immunocompromised patients” // The American Journal of Medicine, V. 102 (3A), JV ° 17, 1997, P. 55-60;
  • Bochnev PR "Complexation and catalytic activity” // Publishing house “Mir”, M., pp. 151-153;
  • Gubler EV "Computational methods of analysis and recognition of pathological processes” // M., Nauka, 1978, 365 p.

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Abstract

L'invention se rapporte au domine de la médecine et de l'industrie pharmaceutique et chimique, et concerne notamment de nouvelles formulations pour le traitement et la prévention de maladies respiratoires, qui comprennent de l'acide 2-(imidazol-4-yl)-éthylamide pentanedione - 1,5 et du N,N'-bis-[2-( 1 Н- imidazol-4- yl)éthyl]pentandiamide et/ou leurs sels pharmaceutiquement acceptables, une composition pharmaceutique à base desdites formulations, un agent thérapeutique à base desdites formulations ou de ladite composition pharmaceutique, et une forme médicamenteuse prête à base desdites formulations, de ladite composition pharmaceutique ou dudit agent thérapeutique. L'invention concerne également l'utilisation desdites formulations, de ladite composition pharmaceutique, dudit agent thérapeutique ou de ladite forme médicamenteuse prête pour le traitement et la prévention de maladies des voies respiratoires.
PCT/RU2020/050219 2019-09-12 2020-09-10 Nouvelles formulations pour le traitement et la prévention de maladies virales Ceased WO2021049980A1 (fr)

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RU2019128667A RU2745265C2 (ru) 2019-09-12 2019-09-12 Новые составы 2-(имидазол-4-ил)-этанамида пентандиовой-1,5 кислоты для лечения и профилактики вирусных заболеваний
RU2019128667 2019-09-12
RU2020113506A RU2746692C1 (ru) 2020-04-14 2020-04-14 Новые составы 2-(имидазол-4-ил)-этанамида пентандиовой-1,5 кислоты для лечения и профилактики вирусных заболеваний
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023177328A1 (fr) * 2022-03-17 2023-09-21 Treamid Therapeutics Gmbh Dérivé bisamide d'acide dicarboxylique destiné à être utilisé dans la restauration de la fonction respiratoire externe après une infection à coronavirus

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RU2141483C1 (ru) * 1997-07-04 1999-11-20 Небольсин Владимир Евгеньевич Производные пептидов или их фармацевтически приемлемые соли, способ их получения, применение и фармацевтическая композиция
EA020283B1 (ru) * 2009-05-21 2014-10-30 Общество С Ограниченной Ответственностью "Валента-Интеллект" Средство для профилактики и лечения высокопатогенных инфекционных заболеваний
EA029461B1 (ru) * 2011-10-11 2018-03-30 Общество С Ограниченной Ответственностью "Валента-Интеллект" Применение глутарилгистамина для лечения заболеваний дыхательных путей
RU2665688C2 (ru) * 2013-04-12 2018-09-04 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Производные бисамидов дикарбоновых кислот, их применение, фармацевтическая композиция на их основе, способы их получения

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2141483C1 (ru) * 1997-07-04 1999-11-20 Небольсин Владимир Евгеньевич Производные пептидов или их фармацевтически приемлемые соли, способ их получения, применение и фармацевтическая композиция
EA020283B1 (ru) * 2009-05-21 2014-10-30 Общество С Ограниченной Ответственностью "Валента-Интеллект" Средство для профилактики и лечения высокопатогенных инфекционных заболеваний
EA029461B1 (ru) * 2011-10-11 2018-03-30 Общество С Ограниченной Ответственностью "Валента-Интеллект" Применение глутарилгистамина для лечения заболеваний дыхательных путей
RU2665688C2 (ru) * 2013-04-12 2018-09-04 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Производные бисамидов дикарбоновых кислот, их применение, фармацевтическая композиция на их основе, способы их получения

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023177328A1 (fr) * 2022-03-17 2023-09-21 Treamid Therapeutics Gmbh Dérivé bisamide d'acide dicarboxylique destiné à être utilisé dans la restauration de la fonction respiratoire externe après une infection à coronavirus

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