EA041030B1 - APPLICATION OF BISAMIDE DERIVATIVE OF MAALIC ACID FOR THE TREATMENT OF ALLERGIC AND OTHER DISEASES IN HUMAN AND ANIMALS - Google Patents

Description

Technical field

The invention relates to chemistry of organic compounds, pharmacology and medicine and concerns the treatment of diseases associated with excessive activation of histamine receptors, in particular for the treatment of pruritus and allergic diseases, preferably the treatment of year-round and persistent allergic rhinitis through the use of a compound that is effective in suppressing the activity of histamine receptors of the third H3 and fourth type H4, which are involved, in particular, in the processes of vasodilation, the development of edema and inflammation in the nasal cavity, and the occurrence of pain symptoms.

State of the art

Histamine receptors are a class of G protein coupled receptors (GPCRs) that bind histamine as a major endogenous ligand. Histamine receptors are involved in a number of physiological processes associated with the development of various pathological conditions. In particular, histamine H1 and H2 receptor antagonists are widely used in the treatment of allergies and gastrointestinal disorders (Br. J. Pharmacol. 2009 Mau; 157(1):24-33).

Type 3 histamine receptors were first discovered in 1983 in the human brain and a number of laboratory animals (Nature 1983; 302(5911):832-837). Histamine type 3 receptors are expressed in areas of the brain that are critical for cognition (cortex and hippocampus) and regulation of circadian rhythms (hypothalamus) (Expert Opin. Investig. Drugs 2004; 13(10): 1237-1248). Histamine is a highly active H3 receptor agonist. Activation of H3 receptors in the brain by H3 agonists regulates the release and synthesis of histamine and a number of other neurotransmitters that play a role in the regulation of attention, impulsivity, and food intake. Therefore, H3 receptor antagonists are currently being studied in several therapeutic areas, including cognitive disorders and sleep disorders (Expert Opin. Investig. Drugs 2007; 16(7):967-985). Thus, H3 receptors of the central nervous system are an attractive drug target for both research and pharmaceutical industry (Biochem. Pharmacol. 2007; 73(8): 1084-1096, Biochem. Pharmacol. 2006; 71(8): 1103 -1113). However, it should be noted that the effect on the H3 receptors in the brain can lead to a number of undesirable side effects, such as the development of depression, sleep disturbances, etc.

More recently, type 3 histamine receptors have also been found to be expressed in peripheral tissues and localized to the epithelium and nerves of the human nasal mucosa (Mol. Pharmacol. 1999; 55(6): 1101-1107). This discovery allowed us to consider peripheral histamine type 3 receptors as a promising target for the treatment of certain allergic conditions and, in particular, allergic rhinitis. An allergic reaction in the nasal cavity initiates mast cell degranulation and the release of histamine, which in turn acts on postsynaptic H1 receptors, causing extravasation with SH mesons, vasodilation, and mucus secretion. In addition, histamine induces vasodilation by activating presynaptic H3 receptors located on postganglionic sympathetic neurons, resulting in reduced noradrenaline release, increased vascular permeability, edema, and pain symptoms. In addition, activation of H3 receptors located on nociceptive sensory nerves induces the release of substance P, which in turn causes rhinorrhea and nasal congestion (Am. Rev. Respir. Dis. 1991; 144:630-5; J. Pharmacol. Sci. 2008; 108:206-11).

While the expression of type 3 histamine receptors in peripheral tissues is limited to the epithelium and nerve endings of the nasal mucosa, type 4 histamine receptors are widely expressed on the surface of cells of the immune system (Br. J. Pharmacol. 2009 Mau; 157(1):24-33 .). Activation of histamine quaternary receptors modulates eosinophil migration (Br. J. Pharmacol. 2004 Mau;142(1):161-71; Cytometry A. 2008;73:299-304) and selective recruitment of mast cells (J. Invest. Dermatol. 2004 Jul; 123(1): 116-23; J. Pharmacol. Exp. Ther. 2004; 309:404-413), leading to increased histamine-mediated immune response and ultimately to chronic inflammation.

In various animal models, as well as studies in healthy volunteers, it has been shown that simultaneous blockade of peripheral H3 and H4 receptors may have a beneficial effect in the treatment of allergic rhinitis as well as other inflammatory diseases. It has been shown that intranasal administration of a type 4 histamine receptor antagonist caused a significant reduction in nasal symptoms of the disease and a decrease in the level of interleukin 4 (Int. Immunopharmacol. 2009 Jun; 9(6):734-8). A similar intranasal administration of R-alpha-methylhistamine, an H3 receptor agonist, causes nasal blockade in humans, which is reduced by topical application of the H3 receptor antagonist thioperidamide (Br. J. Pharmacol. 2005 Mar; 144(6):867-74). In in vitro studies on tissue samples from pigs and humans, R-alpha-methylhistamine has been shown to cause vasodilation by decreasing the release of the vasoconstrictor norepinephrine from nasal sympathetic nerve endings (Eur. J. Pharmacol. 2004; 484:83-9; Eur J. Pharmacol 2002;452:339-45). It is important to note that in addition to suppressing the nasal symptoms of allergic rhinitis, peripheral histamine receptor antagonists of the fourth type can effectively suppress histamine.

- 1 041030 induced pruritus (J. Pharmacol. Exp. Ther. 2014 Jul;350(1): 181-7.)

Several histamine type 3 and 4 receptor antagonists (H3 and H4 receptors) have been studied in clinical trials for the treatment of allergic rhinitis. All three H3 antagonists have been shown to be effective in phase II clinical trials for symptom control of allergic rhinitis. However, since all three drugs have the ability to cross the blood-brain barrier and block the H3 receptors of the central nervous system, all data regarding drug candidates are more or less associated with the development of side effects. In addition, the selective H4 receptor antagonist JNJ-7777120 was effective in an animal model of allergic rhinitis.

To date, thioperamide is the only dual H3- and H4-receptor antagonist tested in clinical trials. It has been shown that it penetrates the blood-brain barrier and leads to the development of CNS side effects. Thus, the known H3 receptor antagonists either do not have the desired selectivity for H3 and H4 receptors, or penetrate the blood-brain barrier and are not suitable for the clinical development of drugs for the treatment of allergic rhinitis.

Thus, to date, no drug is known that acts as an antagonist of the histamine receptor of the third and fourth type, which would be used in the treatment of human allergic diseases. Therefore, there remains a need to create and introduce into the clinic new effective drugs based on type 3 histamine receptor antagonists.

This invention relates to the use of a chemical compound effective in suppressing the activity of histamine receptors in the treatment of allergic diseases (such as perennial and persistent allergic rhinitis), as well as other diseases associated with excessive stimulation of histamine receptors of the third and fourth type.

Disclosure of invention

The objective of the present invention is to develop a new drug that is an antagonist of histamine receptors of the third and fourth type, and effective for the treatment of pruritus and allergic diseases, preferably for the treatment of perennial and persistent allergic rhinitis, as well as other diseases associated with the activity of histamine receptors of the third and fourth type .

The technical result of this invention is the development and production of an effective antagonist of histamine receptors of the third and fourth type, characterized by high activity and pharmacokinetic characteristics, allowing the use of this compound, in particular, for oral and intranasal use for the treatment of pruritus and allergic diseases, such as perennial and persistent allergic rhinitis.

The specified technical result is achieved by using compound 1

or a pharmaceutically acceptable salt, hydrate or solvate thereof, as a type 3 and 4 histamine receptor antagonist. The object of the invention is the use of compound 1

or a pharmaceutically acceptable salt, hydrate or solvate thereof for the prevention and/or treatment of a disorder associated with type 3 and/or type 4 histamine receptor activity. The disorder includes pruritus or allergic disorders, in particular perennial or persistent allergic rhinitis.

Also the object of the invention is a method for preventing and/or treating a disorder associated with the activity of histamine receptors of the third and/or fourth type in a subject in need of such treatment, comprising administering a therapeutically effective amount to said subject of compound 1

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Also the object of the invention is a method for preventing and/or treating a disease selected from the group including pruritus and perennial or persistent allergic rhinitis in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of compound 1

- 2 041030

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Also the object of the invention is a method for reducing excessive activation of histamine receptors of the third and/or fourth type, including the introduction of an effective amount of compound 1

or a pharmaceutically acceptable salt, hydrate or solvate thereof. Also the object of the invention is the use of compound 1

or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the prevention and/or treatment of a disorder selected from the group consisting of pruritus and perennial or persistent allergic rhinitis.

The compound N,N'-bis(2-(1H-imidazol-5-yl)ethyl)malonamide is known and described in the patent application RU 2013/116822.

Detailed disclosure of the invention

The preparation of compound 1 is described in the application for invention RU 2013/116822. This patent application describes derivatives of dicarboxylic acid bisamides with the ability to complex or chelate metal ions, as well as their use as a means for the prevention and/or treatment of viral hepatitis, HIV infection, oncological, neurodegenerative, cardiovascular, inflammatory diseases, diabetes, gerontological diseases, diseases caused by toxins of microorganisms, as well as alcoholism, alcoholic cirrhosis of the liver, anemia, late porphyria, poisoning with transition metal salts.

The present inventor unexpectedly found that Compound I is a type 3 and 4 histamine receptor antagonist. The use of compound I is promising for the treatment of pruritus and allergic diseases, in particular for the treatment of perennial and persistent allergic rhinitis.

Thus Compound I can be used for the treatment of pruritus and allergic diseases such as perennial and persistent allergic rhinitis.

Terms and Definitions.

The term compound I refers to N,N'-bis(2-(1H-imidazol-5-yl)ethyl)malonamide (N,N'-6uc[2(1H-imidazol-4-yl)ethyl]propanediamide), also represented by the structural formula

The term C, when used with reference to temperature, means the centigrade scale or the Celsius temperature scale.

The term IC ₅₀ means the concentration of a test compound at which half-maximal enzyme inhibition is achieved.

The term pharmaceutically acceptable salts or salts includes salts of the active compounds which are prepared with relatively non-toxic acids. Examples of pharmaceutically acceptable non-toxic salts are salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, succinic, citric or malonic acids, or obtained by others. methods used in this area, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, hemi-fumarate, stearate, succinate, sulfate, tartrate, thiocyanate, ptoluenesulfonate (tosylate), undecanate, valeriate, and the like.

The term solvate is used to describe a molecular complex containing a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term hydrate is used when said solvent is water.

The term excipient means any pharmaceutically acceptable substance of inorganic or organic origin, which is part of the drug or used in the manufacturing process, the manufacture of the drug to give it the necessary physical and chemical properties.

The terms treatment, therapy cover the treatment of pathological conditions in mammals, preferably in humans, and include: a) reduction, b) blocking (suspension) of the course of the disease, c) alleviation of the severity of the disease, i. induction of regression of the disease, d) reversal of the disease or condition to which the term is applied, or one or more symptoms of the disease or condition.

The term prophylaxis encompasses the elimination of risk factors as well as the prophylactic treatment of subclinical stages of disease in a mammal, preferably in humans, to reduce the likelihood of occurrence of clinical stages of the disease. Patients for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increased risk of clinical stages of the disease compared with the general population. Preventive therapy refers to a) primary prevention and b) secondary prevention. Primary prevention is defined as prophylactic treatment in patients who have not yet reached the clinical stage of the disease. Secondary prevention is the prevention of the recurrence of the same or a similar clinical disease state.

Compound I is promising for the treatment of diseases associated with activity and in particular with excessive stimulation of the histamine receptor of the third type and/or the fourth type, in particular for the treatment of allergic diseases that are both systemic and local in nature, including those associated with various diseases or caused by long-term use of certain drugs.

Method for the therapeutic use of the compounds.

The subject matter of this invention also includes administering to a subject in need of appropriate treatment a therapeutically effective amount of a compound of the invention. By a therapeutically effective amount is meant that amount of a compound administered or delivered to a patient that is most likely to result in the desired response to treatment (prophylaxis) in the patient. The exact amount required may vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, the selected combination treatment regimen with other drugs, and the like.

Compound I or a pharmaceutical composition containing Compound I may be administered to the patient in any suitable amount (preferably, the daily dose of the active substance is up to 0.5 g per patient per day, most preferably the daily dose is 550 mg/day) and any by administration (preferably the oral route) effective for the treatment or prevention of the disease.

After mixing the drug with a specific suitable pharmaceutically acceptable carrier at the desired dosage, the compositions constituting the essence of the invention can be administered to humans or other animals orally, parenterally, topically, and the like.

The introduction can be carried out as a single, and several times a day, a week (or any other time interval), or from time to time. In addition, the compound may be administered to the patient daily for a period of days (eg 2-10 days) followed by a period without the substance (eg 1-30 days).

When Compound (I) is used as part of the components of a combination therapy regimen, the dose of each of the components of the combination therapy is administered during the desired treatment period. Compounds that are components of combination therapy can be administered to the patient both at the same time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.

pharmaceutical compositions.

The invention also relates to pharmaceutical compositions which contain a compound I (or a prodrug or other pharmaceutically acceptable derivative, in particular a salt, hydrate or solvate) and one or more pharmaceutically acceptable carriers, adjuvants, diluents and/or excipients, such as may be co-administered to the patient with Compound I, and which do not interfere with the pharmacological activity of that compound, and are non-toxic when administered at doses sufficient to deliver a therapeutic amount of Compound I.

Pharmaceutical compositions of this invention contain compound I together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, binders, lubricants etc. suitable for a particular dosage form. Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; 4 041030 latin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oils; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffer substances such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffer solutions. Other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, film formers, sweeteners, flavoring and flavoring agents, preservatives and antioxidants may also be included in the composition.

The subject of this invention is also drugs - a class of pharmaceutical compositions, the composition of which is optimized for a certain route of administration into the body in a therapeutically effective dose, for example, for administration to the body orally, topically, inhalation, for example, in the form of an inhaled spray, or intravascularly, intranasally , subcutaneously, intramuscularly, as well as by infusion, in the recommended dosages.

The medicaments of the present invention may contain formulations prepared by liposome techniques, microencapsulation techniques, nanoformulation techniques, or other methods known in the pharmaceutical art.

When preparing a drug, for example in the form of a tablet, the active principle is mixed with one or more pharmaceutically acceptable excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or similar compounds.

Tablets can be coated with sucrose, a cellulose derivative, or other materials suitable for coating. Tablets can be prepared in a variety of ways, such as direct compression, dry or wet granulation, or hot melting.

The drug in the form of a gelatin capsule can be obtained by mixing compound I with other components and filling the resulting mixture with soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used, which contain pharmacologically compatible agents, such as propylene glycol or butylene glycol.

Examples of pharmaceutical compositions.

Compound I can be used in the prevention and/or treatment of diseases in humans or animals in the form of the following formulations

Tablet I mg/tablet

Substance 2.0

Microcrystalline cellulose 73.2

Sodium carboxymethyl starch 4.0

Magnesium stearate 0.8

Tablet II mg/tablet

Substance 10.0

Microcrystalline cellulose 366.0

Sodium carboxymethyl starch 20.0

Magnesium stearate 4.0

Tablet III mg/tablet

Substance 20.0

Microcrystalline cellulose 732.0

Sodium carboxymethyl starch 40.0

Magnesium stearate 8.0

Tablet IV mg/tablet

Substance 50

Lactose Ph. EUR 223.75

Croscarmellose sodium 6.0

Cornstarch 15

Polyvinylpyrolidon (5% w/v paste) 2.25

Magnesium stearate 3.0

Tablet V mg/tablet

Substance 200

Lactose Ph. EUR 182.75

Croscarmellose sodium 12.0

- 5 041030

Corn starch (5% w/v paste) 2.25

Magnesium stearate 3.0

Capsule mg/capsule

Substance 10

Lactose Ph. EUR 488.5

Magnesia 1.5

Formulation for injection I (50 mg/ml)

Substance 5.0% w/v

1M sodium hydroxide solution 15.0% w/v

1M hydrochloric acid solution to pH 7.6

Polyethylene glycol 400 4.5% w/v

Water for injection up to 100%

Ointment (ml)

Substance 40 mg

Ethanol 300 µl

Water 300 µl

1-dodecylasecycloheptanone 50 µl

Propylene glycol up to 1 ml

Composition for intranasal administration I (mg/ml)

Substance 10.0

Sodium citrate dihydrate 3.823

Citric acid monohydrate 0.609

Glycerin 25.0

Dextrose 5.5

Benzyl alcohol 2.5

Water up to 100%

Composition for intranasal administration II (mg/ml)

Substance 10.0

Sodium citrate dihydrate 3.823

Citric acid monohydrate 0.609

Glycerin 25.0

Dextrose 5.5

Water up to 100%

Nasal Formulation III (mg/ml)

Substance 10.0

Sodium dihydrophosphate dihydrate 3.38

Disodium hydrophosphate dihydrate 2.08

Glycerin 25.0

Dextrose 5.5

Benzyl alcohol 2.5

Water up to 100%

Intranasal formulation IV (mg/ml)

Substance 10.0

Sodium dihydrophosphate dihydrate 3.38

Disodium hydrophosphate dihydrate 2.08

Glycerin 25.0

Dextrose 5.5

Benzyl alcohol 2.5

Water up to 100%

These compositions can be prepared in accordance with standard techniques. Tablets (I)-(V) may be enteric coated using, for example, cellulose acetate phthalate.

The use of compound I in combination therapy.

Although the compound I of the invention may be administered as a single active ingredient, it may also be used in combination with one or more other active ingredients, in particular the other active ingredient may be an antihistamine, sodium cromoglycate, intranasal glucocorticoid, ipratropium bromide, a vasoconstrictor, an antibiotic, a non-steroidal anti-inflammatory drug (NSAID) or other anti-inflammatory agent, etc. When co-administered orally, the therapeutic agents may be placed in different dosage forms administered simultaneously or sequentially at different times, or the therapeutic agents may be combined into a single dosage form.

The phrase combination therapy, in relation to the compounds of this invention in combination with other pharmaceutical agents, means the simultaneous or sequential administration of all agents, which in one way or another will provide a beneficial effect of the combination of drugs. Co-administration means in particular co-delivery, for example, in a single tablet, capsule, injection or other form, having a fixed ratio of active substances, as well as simultaneous delivery in several, separate dosage forms for each compound, respectively.

Thus, the administration of Compound I may be carried out in combination with additional treatments known to those skilled in the art of prevention and treatment of related diseases, including the use of antibacterial and anti-inflammatory drugs, drugs to suppress symptoms, or side effects of one of the drugs.

If the dosage form is a fixed dose, such a combination uses the compound of this invention in an acceptable dose range. Compound I of the invention can also be administered sequentially to the patient with other agents, when a combination of these drugs is not possible. The invention is not limited to the sequence of administration; compound I can be administered to the patient together, before or after administration of another drug.

Examples

Preparation of compound I.

The preparation of compound I is described in the application for invention RU 2013/116822. The same application describes the ability of compound I to complex or chelate metal ions.

Characterization of the biological activity of the compounds according to the invention.

The biological activity of compound I has been studied in various in vitro and in vivo experiments. In particular, when studying the activity of compound I in various in vitro and in vivo models, the inhibitory effect of compound I was shown in a model of ovalbumin-induced allergic rhinitis in guinea pigs. This biological activity of Compound I cannot be predicted or explained on the basis of prior knowledge of Compound I's ability to chelate metal ions.

Studies of the biological activity of compound I in vitro, made it possible to establish that compound I is an antagonist of the histamine receptor of the third type. Apparently, the activity of compound I in models of allergic rhinitis is associated with the action on the above receptor.

Example 1 Investigation of the effect of compound I on the activity of a third type histamine receptor.

Compound I was dissolved in DMSO to a concentration of 100 mm; then the stock solution was serially diluted with DMSO. The maximum starting concentration of the substance was 100 μM. The effect was determined at 8 concentrations of the test compound, each concentration was tested twice. In the experiment, CHO cells expressing the third type of human histamine receptor were used, which, after preincubation with histamine, were incubated with compound I. Receptor activity was determined by intracellular cAMP concentration by fluorescence spectroscopy (Lim H.D. et al. (2005) J. Pharmacol. Exp. Ther. , 314: 1310-1321).

As a result of the study, it was found that the compound I is an antagonist of the histamine receptor of the third type with IC ₅₀ =20 μm.

Example 2 Study of the effect of compound I on the binding of a radiolabeled ligand to a type 3 histamine receptor.

Compound I was dissolved in DMSO to a concentration of 300 mm; then the stock solution was serially diluted with DMSO. The maximum starting concentration of the substance is 300 μM. The effect was determined at 10 concentrations of the test compound, each concentration was tested twice. The experiment used CHO cells expressing the third type of human histamine receptor, which, after preincubation with [3H]Nα-methylhistamine (1 nM), were incubated with compound I.

The activity of compound I was determined by the concentration of displaced radiolabeled ligand (Lovenberg T.W. et al. (1999), Mol. Pharmacol., 55: 1101-1107).

As a result of the study, it was found that compound I binds to the third type histamine receptor with Ki=2.7 μM.

Example 3. Study of the effect of compound I on the binding of a radiolabeled ligand to a fourth type histamine receptor.

Compound I was dissolved in DMSO to a concentration of 300 mm; then the stock solution was serially diluted with DMSO. The maximum starting concentration of the substance was 300 μM. The effect was determined on 10 concentrations of the test compound, each concentration was tested twice. The experiment used HEK-293 cells expressing the fourth type of human histamine receptor, which, after preincubation with [3H]histamine (10 nM), were incubated with compound I. The activity of compound I was determined by the concentration of displaced radioactively labeled ligand (Liu

C. et al. (2001), J. Pharmacol. Exp. Ther., 299: 121-130).

As a result of the study, it was found that compound I binds to the fourth type histamine receptor with Ki=16 μM.

Example 4 Study of the activity of compound I in the ovalbumin-induced allergic rhinitis model in guinea pigs.

The model of allergic rhinitis was implemented according to the standard method [Thakare V.N., Osama M.M., Naik S.R. Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs. Int Immunopharmacol. 2013. V. 17(1). P. 18-25]. Guinea pigs (250-300 g) were immunized 4 times (on days 0, 7, 14 and 21) intraperitoneally with a mixture of ovalbumin (100 μg/gilt) and aluminum hydroxide (5 mg/gilt), diluted and suspended in saline. On the 28th day of the study, a solution of ovalbumin (60 mg/ml) was administered to the animals intranasally, 20 μl in each nostril. On the 35th day, the animals were injected with a solution of ovalbumin (200 µg/ml, 25 µl) intradermally, having previously shaved the area of the skin on the back. The presence of sensitization was confirmed by the formation of edema and redness at the injection site. On the 42nd day of the study, intranasal administration of an ovalbumin solution (60 mg/ml, 20 μl/nostril) was performed. In order to control the formation of precisely allergic inflammation, a group of falsely immunized animals was formed: on days 0, 7, 14 and 21, the pigs received a solution of aluminum hydroxide (5 mg/mumps), on the 28th and 35th days - physical. solution, on the 42nd ovalbumin (60 mg / ml, 20 μl / nostril). In table. 1 presents data on the clinical manifestations of pathology and the number of eosinophils in lavage in guinea pigs in an experimental model of allergic rhinitis when administered orally (M±m, n=10).

Table 1

Groups Dose, mg/kg Number of sneezes Number of nose scratches The number of eosinophils in 1 µl of lavage Intact - 1.0±0.4 5.3±1.1 87.4±14.0 False immunization - 4.1±0.9* 10.5±1.2* 601.6±52.0* Control - 20.2±1.8*# 29.6±4.2*# 1985.0±292.0*# 0.014 11.6±1.4*#& 16.1±2*#& 1300.5±93.8*#& 0.042 10.5±1.2*#& 16.2±2.7* & 1219.6±159.4*#& Compound I 0.14 8.3±0.9*#& 13.3±1.3* & 1141.5±128.5*#& 0.42 5.2±0.6* & 16.2±2.0*#& 1069.0±139.4*#& Notes: 1.4 6.9±0.8*#& 14.4±3.3* & 984.1±111.0*#& * - difference from the intact group according to Student's t-test at p<0.05 # - difference from the false immunization group according to Student's t-test at p<0.05. & - difference from the control group according to Student's t-test at p<0.05.

Compound I was administered intragastrically to animals 48, 24 and 1 h prior to intranasal administration of ovalbumin. Within 2 hours after the last injection of ovalbumin, the clinical manifestations of rhinitis were assessed: the number of sneezes and scratching of the nose was counted. In addition, the number of eosinophils in nasal lavage was determined.

Accounting for the clinical manifestations of allergic rhinitis within 2 hours after the last intranasal administration of ovalbumin to animals showed a pronounced increase in the number of sneezes and scratching of the nose in experimental animals, which indicates the correctness of the implemented model of allergic rhinitis. Intragastric administration of compound I reduced the number of clinical manifestations of rhinitis and the influx of eosinophils into the nasal cavity (Table 1). The results obtained give grounds to conclude that compound I, when administered orally, has a pronounced therapeutic effect in allergic rhinitis.

Example 5 Study of the activity of a 1% solution of compound I when administered nasally to guinea pigs in an allergic rhinitis model.

The model of allergic rhinitis was implemented according to the standard method [Thakare V.N., Osama M.M., Naik S.R. Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs. Int Immunopharmacol. 2013. V. 17(1). P. 18-25]. Guinea pigs (250-300 g) were immunized with 4-fold (on days 0, 7, 14 and 21) intraperitoneal administration of a mixture of ovalbumin (100 μg/gilt) and aluminum hydroxide (5 mg/gilt), diluted and suspended in physiological solution. On the 28th day of the study, a solution of ovalbumin (60 mg/ml) was administered to the animals intranasally, 20 μl in each nostril. On the 35th day, the animals were injected with a solution of ovalbumin (200 µg/ml, 25 µl) intradermally, having previously shaved the area of the skin on the back. The presence of sensitization was confirmed by the formation of edema and redness at the injection site. On the 42nd day of the study, intranasal administration of an ovalbumin solution (60 mg/ml, 20 μl/nostril) was performed. In order to control the formation of precisely allergic inflammation, a group of falsely immunized animals was formed: on days 0, 7, 14 and 21, the pigs received a solution of aluminum hydroxide (5 mg/mumps), on the 28th and 35th days - physical. solution, at 42 ovalbumin (60 mg/ml, 20 µl/nostril).

A 1% solution of compound I was administered to animals intranasally once 1 hour or 3 hours before intranasal administration of ovalbumin in a volume of 10 μl/nostril. Within 2 hours after the last injection of ovalbumin, the clinical manifestations of rhinitis were assessed: the number of sneezes and scratching of the nose was counted. In addition, the number of eosinophils in nasal lavage was determined.

In table. 2 shows the clinical manifestations of pathology and the number of eosinophils in lavage in guinea pigs in an experimental model of allergic rhinitis with nasal administration of Compound I (M±m, n=10).

table 2

Groups Mode of administration of Compound I Number of sneezes Number of nose scratches The number of eosinophils in 1 µl of lavage Intact 3.9+1.0 5.6+1.3 198.8+59.9 False immunization 7.4+0.8* 22.5+4.6* 497.1+112.8* Control Once, intranasally, 1 hour before the last intranasal administration of ovalbumin 16.3+1.4*# 40.8+3.5*# 2700.4+539.0*# Compound I (1% solution) 3.1+1.2 #& 14.5+4.4 & 1416.9+126.8*# & Control Once, intranasally, 3 hours before the last intranasal administration of ovalbumin 17.2+1.2*# 37.2+3.3*# 2560.5+306.6* Compound I (1% solution) 3.9+1.5 & 10.7+2.1 #& 1490.1+241.0*#&

Notes:

* - difference from the intact group according to Student's t-test at p<0.05 # - difference from the group of false immunization according to Student's t-test at p<0.05.

& - difference from the control group according to Student's t-test at p<0.05

Accounting for the clinical manifestations of allergic rhinitis within 2 hours after the last intranasal administration of ovalbumin to animals showed a pronounced increase in the number of sneezes and scratching of the nose in experimental animals, which indicates the correctness of the implemented model of allergic rhinitis. Intranasal administration of a 1% solution of compound I reduced the number of clinical manifestations of rhinitis and the influx of eosinophils into the nasal cavity (Table 2). The therapeutic effect was equally manifested in both modes of administration of a 1% solution of compound I: with a single injection 1 hour before the last intranasal administration of ovalbumin and with a single administration 3 hours before the last intranasal administration of ovalbumin.

The results obtained give grounds to conclude that compound I has a pronounced therapeutic effect in allergic rhinitis. The duration of the therapeutic effect is at least 3 hours.

Example 6 Study of the activity of a 1% solution of compound I when administered nasally in a model of histamine-induced nasal congestion in guinea pigs.

The model of histamine-induced nasal congestion in guinea pigs was implemented according to the standard method [Slack R.J.1, Russell L.J., Hall D.A., Luttmann M.A., Ford A.J., Saunders K.A., Hodgson S.T., Connor H.E., Browning C., Clark K.L. Pharmacological characterization of GSK1004723, a novel, long-acting antagonist at histamine H(1) and H(3) receptors.//Br. J Pharmacol. 2011. V. 164(6). P. 1627-1641]. Guinea pigs were anesthetized, the trachea was isolated and a cannula was inserted through it into the nasopharynx. The cannula was connected to a pressure transducer and an artificial respiration apparatus (Ugo Basile). Histamine solution was inhaled at a concentration of 0.2% for 3 min. Within 15 minutes after the end of inhalation of the histamine solution, the airflow resistance in the nasal passages was assessed. Compound I was administered to guinea pigs once intranasally as a 1% solution (10 μl/nostril) 1 and 4 hours before the start of histamine inhalation. For an objective assessment, an integral indicator was introduced - the area under the curve (AUC), which characterizes the resistance to air flow in the nasal passages at time points - 015 min.

In table. Figure 3 shows the results of a study of resistance to air flow in the nasal passages in guinea pigs on an experimental model of histamine-induced nasal congestion with nasal administration, cm H ₂ 0xc, AUC(M±m).

- 9 041030

Table 3

Groups Mode of administration Number of animals in the group Nasal resistance, AUC Intact thirty 164.47+13.87 Control Once, intranasally 1 hour before histamine inhalation thirty 467.94±38.4* Compound I (1% solution) thirty 317.95±24.49*& Intact 20 155.74+23.58 Control Once, intranasally 4 hours before histamine inhalation 20 479.75+46.28* Compound 1 (1% solution) 20 281.75+52.44*&

Notes:

* - difference from the intact group according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05.

A single intranasal administration of a 1% solution of compound I to guinea pigs in the model of histamine-induced nasal congestion significantly reduced the resistance to air flow in the nasal passages (Table 3). The therapeutic effect was manifested in both modes of administration of a 1% solution of compound I: when administered 1 hour before histamine inhalation and when administered 4 hours before histamine inhalation.

The obtained results give grounds to conclude that a 1% solution of compound I has a pronounced therapeutic effect on the model of histamine-induced nasal congestion in guinea pigs. The duration of the therapeutic effect is at least 4 hours.

Example 7. Study of the activity of a 1% solution of compound I when administered nasally in a model of histamine-induced nasal congestion in dogs.

The model of histamine-induced nasal congestion in dogs was implemented according to the standard method [Tiniakov R.L., Tiniakova O.P., McLeod R.L., Hey J.A., Yeates D.B. Canine model of nasal congestion and allergic rhinitis.//J. Appl. physiol. 2003. V. 94(5). P. 1821-1828]. Beagle dogs were injected with a 5% histamine solution in a volume of 250 μl/nostril into the nasal cavity. Before the administration of histamine, 5, 10, 15, 20, 30, 40, 50 and 60 minutes after the administration of histamine, the volume of the nasal cavity of the right and left nostrils was measured using a rhinometer. 5 experiments were carried out, in which compound I was administered intranasally once as a 1% solution in a volume of 50 μl at different time periods: 1) 5 minutes after the administration of histamine; 2) right before the introduction of histamine; 3) 3 hours before the administration of histamine; 4) 6 hours before the administration of histamine; 5) 8 hours before the administration of histamine.

The results of the study showed that inhalation of a 5% solution of histamine to dogs reduces the volume of the nasal cavity of the nostrils of animals. A single intranasal administration of a 1% solution of Compound I significantly increased the reduced volume of the nasal cavity of the nostrils of dogs in a dose-dependent manner. Table 4 measured the volume of the nasal cavity of the right and left nostrils in dogs in an experimental model of histamine-induced nasal congestion with nasal administration, cm ³ (M±m, n=9). The onset of the therapeutic effect of the introduction of compound I was no more than 5 minutes, the duration of the therapeutic effect was at least 8 hours.

Thus, compound I, when administered intranasally, is a strong decongestant with a high rate of onset of effect and a duration of action of at least 8 hours.

- 10 041030

Table 4

Group The introduction of the drug Before histamine administration Time after administration of histamine, minutes 5 10 15 20 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 5 minutes after administration of histamine 4.6+0.1 4.5+0.1 2.4+0.1$ $2.8+0.2 $2.1+0.2 $2.3+0.2 1.7±0.1$ $1.5+0.1 $1.6+0.2 $1.8+0.1 Compound 1 (1% solution) 3.9+0.4 3.8+0.3 4.2+0.4&$ 4.8+0.1&$ 4.3+0.2 & 4.7+0.2&$ 4.6+0.5 4.6+0.3 & 4.2+0.2 & 4.6+0.4 Control right before histamine administration 4.1+0.2 4.2+0.1 2.7+0.2$ 2.5+0.2 $ 2.0+0.2$ 2.0+0.2$ 1.3+0.1$ 1.3+0.1$ 1.6+0.1$ 1.5+0.1$ Compound 1 (1% solution 3.6+0.2 3.9+0.5 3.2+0.1 & 3.4+0.1 & 2.8+0.1&$ 2.7+0.1&$ 3.2+0.3 & 3.4+0.3 & 3.4+0.2 & 3.3+0.1 & Control 3 hours before the administration of histamine 5.1+0.3 5.2+0.2 2.8+0.3$ $2.6+0.3 2.6+0.4$ 2.7+0.4$ 1.6+0.2$ 1.8+0.2$ 1.2+0.1$ 1.3+0.1$ Compound 1 (1% solution 4.8+0.2 4.9+0.2 2.4+0.3$ $2.2+0.3 $2.9+0.3 3.3+0.4$ 2.7+0.4&$ 2.8+0.4&$ 2.2+0.2&$ 2.1+0.2 &$ Control 6 hours before the introduction of histamine 4.5+0.2 4.4+0.2 2.9+0.3$ $2.8+0.3 2.5+0.2$ 2.4+0.2$ $1.9+0.3 1.9+0.2$ 0.9+0.2$ 0.9+0.2$ Compound 1 (1% solution 4.5+0.2 4.1+0.2 3.6+0.2$ 3.4+0.2$ 3.8+0.2&$ 4+0.3&$ 3.9+0.5 & 3.5+0.2&$ 3.7+0.1&$ 3.6+0.2&$ Control 8 hours before the introduction of histamine 4.2+0.1 4.3+0.1 2.6+0.1$ $2.9+0.2 2.4+0.28 2.3+0.1$ 1.4+0.1$ 1.2+0.1$ 0.8+0.1$ 0.9+0.2$ Compound 1 (1% solution 4.5+0.1 4.1+0.1 3.0±0.2$ $2.8+0.2 2.9+0.1&$ 2.8+0.2&$ 2.0+0.1 &$ 1.9+0.2&$ 1.7+0.1&$ 1.8+0.2&$ Group Introduction drug Time after administration of histamine, minutes thirty 40 50 60 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 5 minutes after administration of histamine 2.5+0.1 $ $2.2+0.2 3.4+0.2$ 3.5+0.2 $ 3.3+0.1 $ 3.6+0.1$ 3.5+0.2 $ 3.3+0.1$ Compound 1 (1% solution 4.6+0.1 & 4.9±0.2&$ 4.5±0.3& 4.8±0.4& 4.4+0.2 & 4.1+0.4 5.2±0.5& 5.2±0.3&$ Control right before histamine administration 2.1+0.1$ 2.4+0.1$ 3.4+0.1$ 3.4+0.1$ 3.5+0.2$ 3.9+0.1 3.4+0.1$ 3.8+0.1$ Compound I (1% solution 3.1+0.2& 3.2±0.0& 4.1+0.3 4.0+0, I& 3.4+0.4 3.4+0.1 3.2+0.2 3.6+0.3 Control 3 hours before the administration of histamine 2.1+0.3$ 2.2+0.2$ 2.8±0.3$ 2.7+0.4$ 3.2+0.2$ 3.3+0.3 5.1+0.3 5.1+0.1 Compound 1 (1% solution 2.9±0.2&$ 3.0+0.1&$ 3.6+0.1&$ 3.6+0.1&$ $2.8+0.2 $2.7+0.2 5.0+0.2 5.2+0.3 Control 6 hours before the introduction of histamine 2.9+0.1$ 3.0+0.1$ 3.4+0.2$ 3.5+0.2$ 3.5+0.3$ 3.6+0.3$ 3.7+0.3 3.8+0.3 Compound I (1% solution 4.3+0.2& 3.8+0.1&$ 3.3+0.1 $ $3.8+0.2 $3.9+0.1 4.2+0.2 4.0+0.0 4.5+0.3$ Control 8 hours before the introduction of histamine 1.9+0.2$ 2.0+0.1$ 3.5+0.1$ 3.5+0.1$ 3.6+0.1 3.5+0.1$ 3.9+0.2 3.7+0.2$ Compound 1 (1% solution 2.7±0.2&$ 2.5±0.2&$ 3.6+0.2$ 3.5+0.2 $ 3.7+0.1 3.7+0.2 4.1+0.2 4+0.2$ Notes: $ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's not-test at p<0.05.

- 11 041030

Table 5

Group Dose, mg/kg Before histamine administration Time after administration of histamine, minutes 5 10 15 20 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 4.4+0.2 4.4+0.2 3.0+0.2$ 2.9+0.2$ 2.2+0.2$ 2.0+0.2$ 1.9+0.1$ 1.8+0.1$ 1.5+0.1$ 1.5+0.1$ Compound I 0.005 4.3+0.3 4.6+0.3 3.5+0.2$ 3.4+0.1$ 2.6+0.2 $ 2.5+0.2$ $2.2+0.2 2.1+0.2$ 1.9+0.3 $2.0+0.2 0.05 4.3+0.2 4.2+0.2 3.4+0.1$ 3.3+0.2$ 2.5+0.1 $ 2.4+0.2$ 2.8+0.1&$ 2.6±0.2&$ 3.3+0.1&$ 3.3±0.3&$ 0.54 4.5+0.1 4.5+0.3 2.9+0.1$ 3.0+0.2$ $2.6+0.1 2.5+0.1$ 3.7±0.3&$ 3.8+0.1&$ 3.8±0.2& 3.7+0.1& $

Notes:

$ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05.

Group Dose, mg/kg Time after administration of histamine, minutes thirty 40 50 60 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 2.1±0.1$ 2.2+0.2$ 3.5+0.1$ 3.3+0.1$ 3.6+0.1$ 3.4+0.2$ 4.0+0.1 3.9+0.2 Compound I 0.005 2.5+0.1&$ 2.8±0.2&$ 3.9+0.1& 3.8±0.2& 3.9+0.1& 4.0±0.2& 4.0+0.1 3.5+0.1$ 0.05 4.1±0.1& 3.8+0.1& 4.2±0.3& 4.2±0.2& 4.2+0.1& 4.5+0.1& 4.3+0.1 4.5+0.3 0.54 3.8+0.1&$ 3.8±0.2&$ 4.2±0.3& 4.2+0.3& $3.9+0.2 4.0+0.3 $4.0+0.1 4.2+0.3

Notes:

$ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05.

Table 6. The volume of the nasal cavity of the right and left nostrils in dogs in an experimental model of histamine-induced nasal congestion after oral administration 1 hour before the administration of histamine, ^cm3 (M±w, n=9)

Group Dose, mg/kg Before histamine administration Time after administration of histamine, minutes 5 10 15 20 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 4.2+0.2 4.1+0.1 3.4+0.4 3.3+0.1$ 2.3+0.2$ $2.2+0.3 1.9+0.2$ 1.6+0.2$ 1.6+0.2$ 1.4+0.2$ Compound 1 0.005 3.9+0.2 4.3+0.2 3.1+0.2$ 3.1+0.5$ $2.4+0.4 2.1+0.1$ 2.2+0.2$ 2.8+0.5$ 2.3+0.1&$ 2.6+0.4$ 0.05 4.0+0.3 4.2+0.2 2.8+0.1$ $2.8+0.3 3.1±0.2&$ 3.5±0.2&$ 3.1+0.1&$ 2.6+0.2$ 2.5+0.1& $ 2.5±0.1&$ 0.54 4D ±0.1 4.4+0.1 2.6+0.1$ 3.0+0.4$ 3.4+0.1&$ 3.0±0.2&$ 2.5+0.2$ 3.0±0.2&$ 2.5+0.2&$ 2.8±0.3&$ Notes: $ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05. Group Dose, mg/kg Time after administration of histamine, minutes thirty 40 50 60 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 2.4+0.2$ 2.5+0.3$ 3.0+0.2$ 3.0+0.1$ 3.4+0.2$ 3.1+0.2$ 3.2+0.1$ 3.2+0.2$ Compound I 0.005 $2.0+0.2 3.0+0.5 $ 3.6+0.2 3.4+0.2 $ 3.3+0.2 $ 3.7±0.2&$ 3.4+0.1 $ 3.5+0.2 $ 0.05 3.6+0.2 & 3.5±0.3& 3.7±0.3& 3.7±0.2& 3.2+0.1$ 3.2+0.1$ 3.2+0.1 $ 3.5+0.1$ 0.54 3.8+0.2 & 3.6±0.2&$ 3.6±0.1&$ 3.6±0.2&$ 3.3+0.3$ 3.4+0.1$ 3.3+0.2$ $3.2+0.2 Notes: $ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05.

- 12 041030

Table 7. The volume of the nasal cavity of the right and left nostrils in dogs in an experimental model of histamine-induced nasal congestion after oral administration 6 hours before the administration of histamine, ^cm3 (M±w, n=9)

Group Dose, mg/kg Before histamine administration Time after administration of histamine, minutes 5 10 15 20 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 4.4+0.1 4.5+0.1 2.5+0.1$ 2.4+0.2$ 2.2+0.2$ 2.2+0.1$ 1.5+0.1$ 1.5+0.1$ 1.4+0.1$ 1.4+0.1$ Compound 1 0.005 4.4+0.1 4.4+0.2 2.0+0.3$ 2.1+0.3$ $1.9+0.1 $2.0+0.1 2.4±0.2& $ 2.4+0.1&$ 3.2+0.2&$ 3.2±0.2&$ 0.05 4.2+0.2 4.1±0.1 2.2+0.1$ 2.2+0.2$ $2.4+0.2 $2.3+0.2 2.0±0.2&$ 2.0+0.1&$ 3.3+0.1&$ 3.2±0.2&$ 0.54 4.1+0.2 4.1+0.2 2.7+0.2$ $2.7+0.3 2.8±0.2&$ 2.8±0.2&$ 2.8+0.1& $ 2.8±0.2&$ 3.4+0.1&$ 3.5+0.1&$ Notes: $ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05. Group Dose, mg/kg Time after administration of histamine, minutes thirty 40 50 60 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 2.0+0.2$ 2.0+0.2$ 3.2+0.2$ 3.2+0.2$ 3.1+0.1$ 3.2+0.1$ 3.3+0.1$ 3.3+0.1$ Compound I 0.005 3.3+0.1&$ 3.4+0.1&$ 3.3+0.2 $ 3.4+0.1 $ 3.4+0.1 $ 3.5+0.2$ 3.6+0.2$ 3.4+0.2$ 0.05 3.4±0.2&$ 3.4+0.1&$ 3.1+0.1 $ 3.1+0.1$ 3.4+0.1$ 3.4+0.1 $ 3.6+0.1 $ 3.5+0.1 $ 0.54 3.5±0.2&$ 3.4+0.1&$ 3.5+0.1$ 3.5+0.1$ $2.9+0.1 $2.9+0.2 $2.9+0.1 3.0+0.1 $ Notes: $ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05.

Table 8. The volume of the nasal cavity of the right and left nostrils in dogs in an experimental model of histamine-induced nasal congestion after oral administration for 14 days, cm ³ (M±w, n=9)

Group Dose, mg/kg Before introduction histamine Time after administration of histamine, minutes 5 10 15 20 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 4.4+0.1 4.5+0.2 2.7+0.3$ 2.7+0.2$ 2.5+0.25 2.6+0.1$ 1.7+0.2$ 1.7+0.1$ 1.5+0.1$ 1.5+0.1$ Compound I 0.13 4.5+0.1 4.5+0.1 2.7+0.2$ 2.7+0.2$ 3.2+0.2*$ 3.3+0.2* $ 2.5+0.2*$ 2.5+0.1*$ 2.4+0.2*$ 2.4+0.2*$ 0.27 4.5+0.2 4.5+0.1 2.8+0.2$ 2.7+0.2$ 3.6+0.2*$ 3.6+0.2* $ 2.8+0.3 *$ 2.8+0.2*$ 2.7+0.1*$ 2.7+0.2*$ 0.54 4.4+0.1 4.2+0.1 3.1+0.3$ 2.7+0.2$ 3.4+0.2*$ 3.4+0.1* $ 2.6+0.1*$ 2.6+0.1*$ 2.5+0.2*$ 2.5+0.2*$ Notes: $ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05. Group Dose, mg/kg Time after administration of histamine, minutes thirty 40 50 60 Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Left nostril Right nostril Control 2.5+0.2$ 2.5+0.2$ 3.2+0.1$ 3.2+0.1$ 3.5+0.2$ 3.4+0.1$ 3.6+0.2$ 3.6+0.2$ Compound I 0.13 3.2+0.2*$ 3.2+0.2*$ 3.6+0.2*$ 3.6+0.2$ 3.7+0.2$ 3.7+0.2 $ $3.8+0.1 $3.8+0.1 0.27 3.3+0.2*$ 3.3+0.1*$ 3.8+0.2*$ 3.8+0.2*$ 3.7+0.1 $ 3.7+0.1$ $3.8+0.1 $3.8+0.1 0.54 3.5+0.1*$ 3.5+0.2*$ 3.7+0.1*$ 3.7+0.2*$ 3.7+0.1$ 3.7+0.2$ $3.8+0.1 $3.8+0.1 Notes: $ - difference from the background according to Student's t-test at p<0.05 & - difference from the control group according to Student's t-test at p<0.05.

While the invention has been described with reference to the disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail

Claims (7)

The statements are for the purpose of illustrating the present invention only and should not be construed as limiting the scope of the invention in any way. It should be clear that it is possible to carry out various modifications without departing from the essence of the invention. CLAIM 1. Application of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as a type 3 and 4 histamine receptor antagonist. 2. Application of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof for the prevention and/or treatment of a disorder associated with type 3 and/or type 4 histamine receptor activity. 3. Use according to claim 2, wherein the disorder includes pruritus or allergic disorders, in particular perennial or persistent allergic rhinitis. 4. A method for preventing and/or treating a disorder associated with the activity of histamine receptors of the third and/or fourth type in a subject in need of such treatment, comprising administering a therapeutically effective amount to said subject of compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. 5. A method for preventing and/or treating a disease selected from the group including pruritus and perennial or persistent allergic rhinitis in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. 6. A method for reducing excessive activation of type 3 and/or type 4 histamine receptors, comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof. 7. Application of Compound 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof for the prevention and/or treatment of a disease selected from the group consisting of pruritus and perennial or persistent allergic rhinitis. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2