Novel compounds

Abstract

The invention relates to compounds 1-48 and to pharmaceutical compositions and medicaments containing same, which can be used for the treatment and / or prophylaxis of cough. Technical result: increased stability in solid form and in solution; enhanced therapeutic efficiency; improved bioavailability; reduced side effects; the possibility of producing a stable liquid intransal dosage form.

Description

[0001] NEW CONNECTIONS

[0002] Field of technology

[0003] The invention relates to the fields of medicine, pharmacology and the chemical-pharmaceutical industry, namely to new salt forms of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide, pharmaceutical compositions and dosage forms containing them, which can be used to treat various diseases.

[0004] State of the art

[0005] The closest analogues of the invention under consideration are bisamides and a specific representative of bisamides, the compound N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, which were first disclosed in patents RU2665688C2 and RU2725881C2. The compounds were introduced into reactions with metal salts as chelators. The authors demonstrated the possibility of using bisamides for the treatment and / or prevention and / or cure of diseases associated with metal-dependent reactions of free radical oxidation, for example, iron-excess anemia, atherosclerosis, late porphyria, poisoning with transition metal salts, etc. N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide N, N'-Bis[2-(1H-imidazol-4-yl)ethyl]propanediamide can be obtained by the reaction of dimethyl malonate with histamine in a polar organic solvent at a temperature of 85-120°C (RU2679636C1).

[0006] In patent RU2685277C1 new properties of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide were discovered and studied in detail. It was shown that the compound is effective in suppressing the activity of the histamine receptor type III, in the treatment of allergic (such as perennial and persistent allergic rhinitis) and other diseases associated with excessive stimulation of the histamine receptor type III.

[0007] One of the key tasks of the modern pharmaceutical industry is the development of dosage forms with an increased rate of development of the therapeutic effect, which is necessary to prevent the occurrence of severe consequences. This is also true to a greater extent for symptomatic drugs. It should also be noted that the drug and pharmaceutical compositions must be able to be stored for significant periods of time without showing significant changes in the physicochemical properties of the active substance.

[0008] The technical problem that has not been solved is the insufficient technological and pharmacological parameters of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide.

[0009] Disclosure of the essence of the invention

[0010] Explanation of the technical solution

[0011] The inventors have unexpectedly discovered that the new salt forms of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, previously unknown in the prior art, have reduced hygroscopicity and increased stability during storage while maintaining good solubility. In addition, the pharmaceutical composition containing the said new salt form has improved compressibility with good flowability without noticeable electrostatic phenomena, while maintaining its therapeutic efficacy. The new salt forms of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide also have improved bioavailability, which is expressed, in particular, in the rapid development of the therapeutic effect. The said properties are also true for the pharmaceutical composition and drug containing the new salt forms of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide.

[0012] The technical results that the present invention is aimed at achieving are:

[0013] - increasing the stability and decreasing the hygroscopicity of the form of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide in solid form and in solution;

[0014] - increasing the therapeutic efficacy of the N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide form and the pharmaceutical composition and dosage form containing it; - improving bioavailability, in particular, as manifested in an increased rate of development of the therapeutic effect and improved pharmacokinetic parameters of the N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide form;

[0015] - reduction in the number of side effects, reduction in the number of adverse events during therapy using the form of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl] propanediamide;

[0016] - the possibility of obtaining a stable liquid intranasal dosage form without adding excipients;

[0017] - the possibility of obtaining a stable liquid dosage form for the treatment of cough;

[0018] - qualitative and / or quantitative changes in some types of biological activity and the manifestation of new unexpected properties;

[0019] Stability is understood as the ability of a form of substance, pharmaceutical composition and medicinal product to retain chemical, physical, microbiological and biopharmaceutical properties within certain limits over a selected period of time.

[0020] Hygroscopicity is the property of a substance to absorb water vapor (moisture) from the air. The degree and intensity of water vapor absorption depend on the chemical composition of the substance, the form of the substance, and the content of water vapor in the air.

[0021] Compressibility is understood as the ability of powder particles to cohesion under pressure to form a stable solid dosage form. Flowability of a dosage form characterizes the ability of the powder to uniformly fill a given form.

[0022] Bioavailability is the ability of a substance to be distributed, absorbed and metabolized in the body. It can be determined by changes in the concentration of the drug in the blood plasma being studied.

[0023] Therapeutic efficacy is the ability of a drug to produce a pharmacological effect. The therapeutic efficacy of any given drug can be determined by assessing the response of a patient or animal to the drug; a drug with high therapeutic efficacy will provide greater symptom relief and / or resolution than a drug with low therapeutic efficacy. Compounds 1-48

[0024] The present technical problem is solved and the indicated technical results are achieved thanks to connections 1-48 or their hydrates.

[0025] In a preferred embodiment, the compound is selected from the group or from hydrates of the indicated compounds.

[0026] The said chemical compounds are pharmaceutically acceptable salts of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide. The term "pharmaceutically acceptable salt" means relatively non-toxic organic and inorganic salts of acids and bases. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, salts of bases can be obtained starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts obtained in this way are hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, malates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (A detailed description of the properties of such salts is given in SMBERGE et al., Pharmaceutical salts, JOURNAL OF.

[0027] PHARMACEUTICAL SCIENCES, 1977, V.66, N.1, pp. 1-19). Preferred salts of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide are the salts of hydrochloric acid (chlorides), sulfuric acid (sulfates), acetic acid (acetates), propionic acid (propionates), hydrobromic acid (bromides), hydroiodic acid (iodides), formic acid (formates), succinic acid (succinates), lactic acid (lactates), glutaric acid (glutarates), malonic acid (malonates), oxalic acid (oxalates), methanesulfonic acid (methanesulfonates), biquinone (tartrates), p-toluenesulfonic acid (p-toluenesulfonates), benzenesulfonate (benzenesulfonates), maleic acid (maleates), fumaric acid (fumarates), L-malic acid (malates), citric acid (citrates), phosphoric acid (phosphates), benzoic acid (benzoates), salicylic (salicylates), glutamic (glutamates).The preferred ratio of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide with hydrochloric acid is 1:1 and 1:2; with sulfuric acid 1:0.5 and 1:1; with citric acid 1:0.(3), 1:0.(6) and 1:1; with tartaric acid 1:0.5 and 1:1; with maleic acid 1:0.5, 1:1 and 1:2; with fumaric acid 1:1 and 1:2; with phosphoric acid 1:0.(3), 1:0.(6) and 1:1; with acetic acid 1:1 and 1:2; With oxalic acid 1:0.5 and 1:1; with hydrobromic acid 1:1 and 1:2; with hydroiodic acid 1:1 and 1:2; with L-malic acid 1:1; with formic acid 1:1 and 1:2; with succinic acid 1:0.5 and 1:1; with lactic acid 1:1 and 1:2; with propionic acid 1:1 and 1:2; with para-toluene sulfonic acid 1:1 and 1:2; with methanesulfonic acid 1:1 and 1:2; with glutaric acid 1:0.5 and 1:1; with malonic acid 1:0.5 and 1:1; with benzenesulfonic acid 1:1 and 1:2; with benzoic acid 1:1 and 1:2, with salicylic acid 1:1 and 1:.

[0028] 2, with glutamic acid 1:1 and 1:2.

[0029] Pharmaceutically acceptable salts of compounds 1-48 can be both anhydrous and hydrates. Hydrates are understood to be the product of addition of water to compound 1-48. The hydrate can contain from 0.1 to 5 water molecules, preferably 0.5, 1, 1.5, 2, 3 water molecules.

[0030] Compounds 1-48 can also be acid adducts or addition products. N,N'-Bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide can be represented as mesomeric structures. Mesomeric structures include:

[0031]

[0032] For example, N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and N,N'-bis-[2-(1H-imidazol-5-yl)ethyl]propanediamide are mesomers. A mesomer (mesomeric structure) is a structure in chemical resonance theory that arises due to the conjugation of multiple bonds and / or unshared electron pairs in a molecule. In N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, the mesomeric effect is possible for two imidazole and two amide groups.

[0033] Taking into account the mesomeric effect, alternative names for N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide according to the present invention are:

[0034] Bis- 1 ,3-(T β -histaminyl)malonic acid;

[0035] N,N'-Bis-[2-(1H-imidazol-4-yl)ethyl]malonamide;

[0036] N,N'-Bis-[2-(1H-imidazol-5-yl)ethyl]malonamide; N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide; N,N'-bis-[2-(1H-imidazol-5-yl)ethyl]propanediamide.

[0037] The salt form of the present invention may preferably be a solid crystalline form.

[0038] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrochloride, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (+ 0.2°): 21.5, 23.7 and 24.8. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (+ 0.2°): 17.4, 18.6, 21.5, 23.7, 24.8, 26.1, 28.6 and 30.4. In addition, the crystalline form is characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 22.46 + 0.50 A, 11.16 + 0.50 A, 15.48 + 0.50 A; and the value of the angle (deg): 123.40° + 5.00°.

[0039] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride hydrate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (+ 0.2°): 21.4, 22.7 and 28.5. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (+ 0.2°): 21.4, 22.7, 23.4, 24.1, 24.4, 27.3, 27.7 and 28.5. In addition, the crystalline form is characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.79 + 0.50 A, 12.66 + 0.50 A, 29.78 + 0.50 A; and the value of the angle (deg): 93.43° + 5.00°.

[0040] The present technical problem is solved and the said technical results are also achieved thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg. (+ 0.2°): 14.8, 21.6 and 24.6. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg. (+ 0.2°): 14.8, 16.4, 19.4, 20.5, 21.6, 24.6 and 27.1. In addition, the crystalline form is characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 17.29 + 0.50 A, 4.76+ 0.50 A, 11.17+ 0.50 A; and the value of the angle (deg): 76.01° + 5.00°.

[0041] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrobromide, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg. (+ 0.2°): 20.4, 22.8, 24.6 and 25.7. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg. (+ 0.2°): 16.8, 17.6, 19.0, 20.2, 20.4, 22.8, 24.6, 25.1, 25.7, 27.0, 27.7, 28.1, 28.5, 28.7 and 31.0. In addition, the crystalline form is characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 8.04 + 0.50 A, 21.18 + 0.50 A, 9.69 + 0.50 A; and the value of the angle (deg): 97.51° + 5.00°.

[0042] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrobromide, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (+ 0.2°): 22.5, 23.5, 24.2, 25.7 and 27.5. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (+ 0.2°): 22.5, 22.9, 23.5, 24.2, 24.5, 25.7, 26.2, 27.5, 28.4, 29.8 and 31.8. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.89 + 0.50 A, 12.04 + 0.50 A, 15.71 + 0.50 A; and the values ​​of the angles (deg): 106.83° + 5.00°, 99.99° + 5.00°, 93.46° + 5.00°.

[0043] The present technical problem is solved and the specified technical results are achieved also thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydroiodide, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 7.9, 11.1, 15.2, 18.1, 22.3, 23.6, 29.2 and 33.2. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 7.9, 1188..11 and 22.3. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 5.00 ± 0.50 A, 12.39 + 0.50 A, 16.03 + 0.50 A and the values ​​of the angles (deg): 70.22 ° + 5.00°, 81.55 ° ± 5.00°, 87.11 ° ± 5.00°.

[0044] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis-[2-(lH-imidazol-4-yl)ethyl]propanediamide oxalate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (+ 0.2°): 20.9, 25.1 and 25.8. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 11.4, 17.6, 18.0, 18.9, 20.9, 22.8, 25.1, 25.8 and 29.2. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 7.09 ± 0.50 A, 8.03 ± 0.50 A, 15.81 ± 0.50 A; and the values ​​of the angles (deg): 107.61° ± 5.00°, 95.55° ± 5.00°, 86.97° ± 5.00°.

[0045] The present technical problem is solved and the specified technical results are achieved also thanks to the crystalline form of N,N'-bis-[2-(lH-imidazol-4-yl)ethyl]propanediamide dimesylate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 17.3, 20.0 and 21.9. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 17.3, 18.0, 18.2, 20.0, 20.1, 21.4, 21.9, 22.4, 24.1 and 28.1. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 8.57 ± 0.50 A, 9.07 ± 0.50 A, 14.93 ± 0.50 A; and the values ​​of the angles (deg): 94.39° ± 5.00°, 94.43° ± 5.00°, 111.06° ± 5.00°.

[0046] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide dibenzenesulfonate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 18.9, 21.4 and 22.9. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 15.7, 18.9, 19.5, 19.9, 21.4, 22.4, 22.9, 24.3 and 25.7. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 9.65 ± 0.50 A, 9.35 ± 0.50 A, 17.60 ± 0.50 A; and the values ​​of the angles (deg): 90.37° ± 5.00°, 110.70° ± 5.00°, 106.63° ± 5.00°.

[0047] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide diformate or its hydrate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 21.1, 24.0 and 24.7. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 18.4, 21.1, 23.1, 24.0, 24.7 and 29.7. In addition, the crystalline form is characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 16.32 ± 0.50 A, 4.70 ± 0.50 A, 12.08 ± 0.50 A; and the value of the angle (deg): 89.56° ± 5.00°.

[0048] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis-[2-(lH-imidazol-4-yl)ethyl]propanediamide succinate or its hydrate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 20.8, 23.9 and 25.5. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 16.1, 19.7, 20.8, 22.0, 23.9 and 25.5. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.72 ± 0.50 A, 12.98 ± 0.50 A, 18.20 ± 0.50 A; and the values ​​of the angles (deg): 116.57° ± 5.00°, 88.31° ± 5.00°, 81.78° ± 5.00°.The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis-[2-(lH-imidazol-4-yl)ethyl]propanediamide glutarate dihydrate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 18.2, 24.9 and 29.0. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 18.2, 20.1, 21.7, 22.2, 23.0, 23.2, 23.5, 24.9, 26.2 and 29.0. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.95 ± 0.50 A, 15.74 ± 0.50 A, 16.12 ± 0.50 A; and the values ​​of the angles (deg): 111.76° ± 5.00°, 74.07° ± 5.00°, 98.79° ± 5.00°.

[0049] The present technical problem is solved and the said technical results are achieved also thanks to the crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide fumarate, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 20.5, 22.1 and 25.2. In a preferred embodiment, the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg (± 0.2°): 20.0, 20.5, 22.1, 22.6, 23.4, 25.2 and 29.9. In addition, the crystalline form is characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.99 ± 0.50 A, 16.02 ± 0.50 A, 13.27 ± 0.50 A; and the values ​​of the angles (deg): 66.22° ± 5.00°, 87.61° ± 5.00°, 78.13° ± 5.00°.

[0050] Method of obtaining

[0051] Compounds 1-48 are obtained according to the following scheme:

[0052] The method for preparing compound 1-48 involves reacting the compound N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide C with the corresponding acid. In a preferred embodiment, N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and the acid are taken in a molar ratio of 5:1 to 1:5, even more preferably in a ratio of 1:1 to 1:2, and even more preferably in a stoichiometric ratio. In a preferred embodiment, the corresponding acid is selected from the group consisting of hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, formic, acetic, propionic, hydrobromic, oxalic, malonic, succinic, glutaric, maleic, fumaric, L-malic, methanesulfonic, benzenesulfonic, para-toluenesulfonic, tartaric, citric, benzoic, salicylic and glutamic.

[0053] The synthesis is carried out in any suitable organic solvent. A suitable solvent may be selected from an alcohol, ether, haloalkane, aromatic hydrocarbon or nitroalkane. Examples of alcohol are methyl alcohol (methanol), ethyl alcohol (ethanol), propyl alcohol (propanol), isopropyl alcohol (isopropanol), n-butanol, etc. Examples of ethers are diethyl ether (ethoxyethane), tetrahydrofuran (THF), dioxane. Examples of haloalkanes are chloroform, methylene chloride. Examples of aromatic hydrocarbons are benzene, toluene and xylenes. Examples of nitroalkanes are nitromethane and nitroethane. The concentration of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide can be from 0.1 mol / L (mmol / mL) to 1 mol / L (mmol / mL), such as 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, 0.8 mol / L, 0.9 mol / L, 1.0 mol / L.

[0054] After the reaction is complete, the solvent is removed, the residue is dried, and the product is isolated using known physicochemical methods. For example, the solvent is distilled off using a rotary evaporator, the residue is washed with hexane, and then dried to a constant weight. Or, for example, the reaction product is precipitated from the reaction mixture with acetone, the precipitate is filtered off, washed with acetone, and then dried in a vacuum to a constant weight.

[0055] Pharmaceutical composition and medicinal product

[0056] The present technical problem is solved, and the said technical results are also achieved thanks to a pharmaceutical composition and a medicinal product for the treatment and / or prevention of inflammation of the mucous membrane of the upper respiratory tract, symptomatic treatment of influenza, acute respiratory viral infections, allergies and allergic rhinitis, containing compound 1-48 and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is understood to be a composition (mixture, composition, etc.) suitable for use in humans or animals, including an active pharmaceutical substance. The active pharmaceutical substance in the pharmaceutical composition contains the active substance - compound 1-48 of the present invention. A person skilled in the art will understand that the pharmaceutical composition of the present invention will also include compositions containing one or more other active pharmaceutical substances.

[0057] A medicinal product (drug) is an active pharmaceutical substance or pharmaceutical composition in the form of a dosage form suitable for use in humans or animals.

[0058] The terms “includes” and “contains” in the context of the present invention mean that the said pharmaceutical compositions (medicines, groups of components, etc.) include the following listed components / ingredients, but do not exclude the inclusion of other components / ingredients.

[0059] In a preferred embodiment, compound 1-48 is contained in a pharmaceutical composition or a medicinal product and is used in a certain dosage. The dosage of compound 1-48 according to the present invention can be in the range of 1 mg to 1000 mg / day, preferably 5 mg to 100 mg. In a preferred embodiment, compound 1-48 is in the pharmaceutical composition or medicinal product in an amount corresponding to the recommended dosage.

[0060] The term "dosage" as used herein characterizes the content of one or more active substances in quantitative terms per unit volume, or unit mass in accordance with the dosage form, or the amount of active substance administered to the patient per unit time.

[0061] In some embodiments, the pharmaceutical composition and medicament of the present invention can be prepared using known conventional methods in the pharmaceutical field.

[0062] Solid dosage form

[0063] In one embodiment, the pharmaceutical composition and drug is a composition in the form of a solid form. Examples of solid dosage forms are powders, granules, briquettes, capsules, tablets, dragees, etc. In the most preferred embodiment, the solid form is a powder, granule, capsule or tablet. A powder is a solid non-dosed dosage form consisting of solid individual dry particles of varying dispersion, having the property of flowability. A capsule is a solid dosed or non-dosed dosage form, including a solid (usually gelatin) shell, inside which an encapsulate is enclosed, containing one or more active substances with or without the addition of excipients. A granule is a solid dosed dosage form in the form of grains (aggregates of powder particles) of round, cylindrical or irregular shape, containing one or more active substances with the addition of excipients.A tablet is a solid dosage form of medicine, most often obtained by pressing powders or granules containing one or more active substances with or without the addition of excipients.

[0064] The routes of administration of the pharmaceutical composition and the drug of the present invention include, but are not limited to, oral, inhalation, topical, transdermal, sublingual and rectal routes. In a preferred embodiment, the pharmaceutical composition is administered orally or sublingually.

[0065] The pharmaceutical composition and the drug of the present invention include at least one pharmaceutically acceptable excipient, which is a carrier of active substances, providing the required volume / weight and the necessary characteristics of the drug in a certain dosage form. In a preferred embodiment, the pharmaceutical composition and the drug include a pharmaceutically acceptable excipient, which is selected from the group consisting of a filler, a binder, a lubricant, a disintegrating agent, a sliding agent, a preservative, a flavoring agent and a coloring agent.

[0066] The term "filler" or "diluent" means auxiliary substances used to impart a given volume or weight to solid dosage forms. Starch, glucose, sucrose, lactose (milk sugar), basic magnesium carbonate, magnesium oxide, sodium chloride, sodium hydrogen carbonate, white clay (kaolin), gelatin, microcrystalline cellulose (MCC), methylcellulose (MC), sodium carboxymethylcellulose (Na CMC), calcium carbonate, dibasic calcium phosphate, glycine (aminoacetic acid), dextrin, amylopectin, sorbitol, mannitol, pectin, etc. can be used as fillers. The term "binders" means substances included in the tablet mass to impart the required viscosity to it.Water, ethyl alcohol, starch paste, sugar syrup, solutions of carboxymethyl cellulose (CMC), oxyethyl cellulose (OEC), oxypropyl methyl cellulose (OPMC); polyvinyl alcohol (PVC), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, gelatin, etc. are used as binding agents. The group is not limited to this list.

[0067] The term "lubricant" means auxiliary substances used in the technological process of tablet production at the pressing stage to improve the flowability of granules or powder by reducing friction between particles. The lubricant may be one or more of starch, talc, polyethylene oxide-4000, stearic acid, calcium and magnesium stearate, etc. The group is not limited to this list.

[0068] The term "lubricant" or "lubricant" means auxiliary substances that help reduce the friction force between the surface of the tablet and the walls of the punch tray in which the tablet is formed, used in the technological process of tablet production at the pressing stage. The lubricant may be one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethyleneglycol (with a molecular weight of over 3350), sodium lauryl sulfate, talc, mineral oil, leucine and poloxamer, etc. The group is not limited to this list.

[0069] The term "disintegrating agent" means substances used to improve disintegration or dissolution, providing mechanical destruction of tablets in a liquid medium, which is necessary for the fastest release of the active substance. Disintegrating agent mmoojjeett be represented by one or more of microcrystalline cellulose, sodium croscarmellose, crospovidone, sodium starch glycolate, starch, pectin, gelatin, amylopectin, ultra-amylopectin, agar-agar, alginic acid, potassium and sodium alginate, tween-80, etc. The group is not limited to this list.

[0070] Additional components, corrigents, are used to improve taste (sweetener) and smell (flavoring agent). These include, for example, sugar, cocoa, vanillin. Dyes (pigments) are used to improve the appearance of the pharmaceutical composition and dosage form. Examples of dyes are titanium dioxide, indigo carmine.

[0071] Liquid dosage form

[0072] In one embodiment, the pharmaceutical composition and drug is a composition in the form of a liquid form. In a preferred embodiment, the liquid dosage form is selected from the group comprising a solution, a concentrate for preparing a solution, a spray, a syrup, an infusion, drops, a suspension, an emulsion. In a more preferred embodiment, the liquid dosage form is selected from the group comprising a solution or a spray. The liquid dosage form can be an aqueous or aqueous-alcoholic solution, for example, an aqueous-ethanol solution, an alcohol concentrate.

[0073] Routes of administration of liquid dosage forms include, but are not limited to, orally, intranasally, topically, and by injection.

[0074] The pharmaceutical composition and the drug of the present invention include at least one pharmaceutically acceptable excipient, which is a carrier of active substances, providing the required volume / weight and the necessary characteristics of the drug in a certain dosage form. In a preferred embodiment, the pharmaceutical composition and the drug include one or more pharmaceutically acceptable excipients (auxiliaries), which are selected from the group including a solvent, a stabilizer, a thickener, an emulsifier, a preservative, a taste and / or odor corrigent, an acidity regulator, and a colorant.

[0075] The terms "solvent", "carrier" and "diluent" mean auxiliary substances that allow the product to be brought to a state convenient for use, i.e. give it an optimal viscosity. The following may be used as a solvent (carrier, diluent): water (purified), ethanol, isopropanol, polyalcohols, buffer solutions, as well as their mixtures, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). The group is not limited to this list.

[0076] The term "stabilizer" means an auxiliary substance that allows maintaining the quality or form of the original pharmaceutical product for a long time. Thickeners are intended to provide a certain viscosity of the liquid dosage form, and emulsifiers - to stabilize emulsions. The group of stabilizers, thickeners and emulsifiers includes, without limitation, alginic acid and its salts, agar, gums, chitosan, fatty acids and their salts, glycerin (glycerol) and its esters, polyoxyethylene (tween 20, tween 40, tween 60, tween 80), polyethylene glycol (PEG 300, PEG 400), propylene glycol, pectin, methylcellulose, carboxymethylcellulose. The group is not limited to this list.

[0077] Preservatives are substances that ensure the death or inhibition of the development of harmful microorganisms in a product. Preservatives include, without limitation, benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens (methylparaben, ethylparaben, propylparaben), alkylpyridinium, benzethonium and their pharmaceutically acceptable salts. The group is not limited to this list.

[0078] The term "acidity regulator" means substances that establish or maintain a certain pH value in a product. Acidity regulators include malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, phosphoric, aspartic, glutaric, glutamic, sorbic acids and their sodium, ammonium, potassium, calcium, magnesium salts, such as sodium citrate, potassium citrate, calcium citrate, magnesium citrate, sodium tartrate, potassium tartrate, sodium potassium tartrate, sodium phosphate, potassium phosphate, ammonium phosphate. The group is not limited to this list.

[0079] Corrigents are used to improve taste (sweetener) and smell (flavoring).

[0080] Sweeteners include, but are not limited to, maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin and its salts such as sodium saccharinate, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame (acesulfame potassium), neotame, lactitol and their pharmaceutically acceptable salts. The group is not limited to this list.

[0081] Pharmaceutical use

[0082] Compound 1-48, its active pharmaceutical substance, pharmaceutical composition and medicinal product of the present invention can be used for treatment and / or prevention of inflammation of the mucous membrane of the upper respiratory tract, symptomatic treatment of influenza, acute respiratory viral infections, allergies and allergic rhinitis. In one embodiment, inflammation of the mucous membrane of the upper respiratory tract is associated with rhinitis, or is caused by rhinitis, or is rhinitis. In a more specific embodiment, inflammation of the mucous membrane of the upper respiratory tract is caused by allergic rhinitis, infectious rhinitis (e.g., viral or bacterial rhinitis) or vasomotor rhinitis. In another embodiment, rhinitis can be in an acute form (acute rhinitis) or in a chronic form (chronic rhinitis).Rhinitis also includes atrophic, hypertrophic rhinitis, rhinitis caused by the use of vasoconstrictor or hormonal drugs, rhinitis associated with burns and damage to the mucous membrane or nosebleeds, etc.

[0083] In another alternative variant, inflammation of the mucous membrane of the upper respiratory tract is associated with sinusitis (rhinosinusitis), or caused by sinusitis (rhinosinusitis), or is sinusitis (rhinosinusitis). In a more specific variant, inflammation of the mucous membrane of the upper respiratory tract is caused by sinusitis (maxillary sinus sinusitis), frontal sinusitis (frontal sinus sinusitis), ethmoiditis (inflammation of the mucous membrane of the ethmoid labyrinth cells) and sphenoiditis (inflammation of the mucous membrane of the sphenoid sinus). Sinusitis can be acute (acute sinusitis) or chronic (chronic sinusitis). Sinusitis also includes traumatic, viral, bacterial, fungal, mixed, allergic sinusitis.

[0084] In another alternative variant, inflammation of the mucous membrane of the upper respiratory tract is associated with pharyngitis, or is caused by pharyngitis, or is pharyngitis. In a more specific variant, inflammation of the mucous membrane of the upper respiratory tract is caused by tonsillitis, pharyngotonsillitis or nasopharyngitis. In another variant, pharyngitis can be in an acute form (acute pharyngitis) or a chronic form (chronic pharyngitis). Pharyngitis also includes viral, bacterial, fungal, allergic, traumatic, catarrhal, hyperplastic, subatrophic, atrophic, mixed pharyngitis.

[0085] Compound 1-48, its active pharmaceutical substance, pharmaceutical composition and medicinal product of the present invention can also be used for the treatment and / or prevention of cough.

[0086] The cough, the treatment and / or prevention of which is the subject of the present invention, may relate to dry cough, refractory cough, chronic cough of unknown etiology, cough associated with respiratory tract diseases caused by bronchial asthma, COPD, idiopathic pulmonary fibrosis, lung cancer. In a preferred embodiment, the cough, the treatment and / or prevention of which is the subject of the present invention, relates to dry cough.

[0087] In another embodiment, the cough, the treatment and / or prevention of which is the purpose of the present invention, may relate to a cough caused by viral infections. In a preferred embodiment, the cough may be caused by an acute respiratory viral infection (ARVI). Acute respiratory viral infections are understood to be infectious diseases affecting the mucous membranes of the upper respiratory tract.

[0088] Compound 1-48, its active pharmaceutical substance containing, the pharmaceutical composition of the present invention can be used for the manufacture of the medicinal product of the present invention.

[0089] In a preferred embodiment of the present invention, the treatment of cough involves symptomatic treatment, i.e. treatment aimed at eliminating the symptom of cough regardless of the etiopathogenesis of other possible diseases.

[0090] Brief description of the drawings

[0091] Fig. 1. Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrochloride (C 13 H 18 N6O2* HCl) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0092] Fig.2. General view of the elementary cell C 13 H 18 N6O2* HCl.

[0093] Fig.3. Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride hydrate (C 13 H 18 N6O2* 2НСl * Н2О ) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated positions of the peaks.

[0094] Fig.4. General view of the elementary cell C 13 H 18 N6O2* 2НСl * Н2О.

[0095] Fig. 5. Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride (C 13 H 18 N6O2* 2НСl ) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions. Fig.b. Experimental diffraction pattern of N,N'-bis[2-(1Н-imidazol-4-yl)ethyl]propanediamide hydrobromide (C 13 H 18N6O2* HBr) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0096] Fig. 7. Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrobromide (C 13 H 18 N6O2* 2 HBr) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0097] Fig.8. General view of the elementary cell C 13 H 18 N6O2* 2НВг.

[0098] Fig.9. Experimental diffraction pattern of N, N'-bis[2-(lH-imidazol-4-yl)ethyl]propanediamide dihydrioiodide (C 13 H 18 N6O2* 2HI) and the theoretical diffraction pattern of the cell calculated for it

[0099] Fig.10. General view of the elementary cell C 13 H 18 N6O2* 2HI.

[0100] Fig. 11. Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide oxalate (C 13 H 18 N6O2* HOOC-COOH) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0101] Fig.12. General view of the elementary cell C 13 H 18 N6O2* HOOC-COOH.

[0102] Fig.13. Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dimesylate (C 13 H 18 N6O2* 2CH3SO3H) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0103] Fig.14. General view of the elementary cell C 13 H 18 N6O2*2CH3SO3H.

[0104] Fig.15. Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dibenzenesulfonate (C 13 H 18 N6O2* 2C6H5SO з H) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). The vertical dashes indicate the calculated positions of the peaks.

[0105] Fig.16. General view of the elementary cell C 13 H 18 N6O2* 2C6H5SO з N. Fig.17. Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide diformate (C 13 H 18 N6O2* 2НСООН) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0106] Fig.18. Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide succinate (C 13 H 18N6O2* C2H4(COOH)2) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0107] Fig.19. Experimental diffraction pattern of N,N'-6uc[2-(lH-imidazol-4-yl)ethyl]propanediamide glutarate dihydrate (C 13 H 18 N6O2* C3H6(COOH)2* 2H2O) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated positions of the peaks.

[0108] Fig.20. Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide fumarate (C 13 H 18 N6O2* C2H2(COOH)2) (blue curve) and the theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate the calculated peak positions.

[0109] Fig.21. Influence of C 13 H18 N6O2* HCl intranasally administered solution on the number of coughs in a capsaicin inhalation-induced acute cough model in guinea pigs.

[0110] Fig.22. Influence of C 13 H 18 N6O2* HCl when administered as a solution into the pharynx on the number of coughs in a model of acute cough induced by capsaicin inhalation in guinea pigs.

[0111] Implementation of the invention

[0112] The present invention is further illustrated, but not limited, by the following examples.

[0113] Example 1 Quantitative determination of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and acid residue was carried out by HPLC.

[0114] Chromatography conditions

[0115] Preparation of solutions

[0116] 0.035 M phosphate buffer. 4.76 g of potassium dihydrogen phosphate are dissolved in 900 ml of water for chromatography, the pH of the resulting solution is adjusted to 7.5 ± 0.05 potentiometrically using 20% ​​potassium hydroxide solution, the volume of the solution is adjusted to 1000.0 ml with water for chromatography, mixed and degassed in any convenient way.

[0117] Mobile phase A (MP A). Place 30 ml of methanol for chromatography in a 1000.0 ml measuring flask and bring the volume of the solution to the mark with 0.035 M phosphate buffer. Degas the solution in any convenient way.

[0118] Mobile phase B (MP B). Place 30 ml of methanol for chromatography and 250 ml of acetonitrile for chromatography in a 1000.0 ml measuring flask, bring the volume of the solution to the mark with 0.035 M phosphate buffer. Degas the solution in any convenient way.

[0119] Sample solvent: Place 100 ml of chromatographic grade acetonitrile in a 1000.0 ml volumetric flask and bring the volume up to the mark with chromatographic grade water.

[0120] Standard solution. About 40.0 mg (exactly weighed) of the substance N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide is placed in a 100.0 ml measuring flask, about 70 ml of solvent is added and mixed, the volume of the solution is brought up to the mark with the same solvent and mixed.

[0121] The concentration of the resulting solution is 0.4 mg / ml.

[0122] The shelf life of the solution is 24 hours.

[0123] Test solution. About 40.0 mg (exactly weighed) of the N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide salt sample is placed in a 100.0 ml volumetric flask, about 70 ml of solvent is added and mixed, the volume of the solution is brought up to the mark with the same solvent and mixed.

[0124] Calculation of the quantitative content of N,N'-6uc-(2-( 1 H-imidazol-4-yl)ethyl] propanediamide

[0125] Calculation of the content of the base N, N'-bis[-2-( 1 H-imidazol-4-yl)ethyl]propanediamide (x i in mg is produced according to the formula: Where:

[0126] Si is the peak area of ​​N, N'-bis-[2-(1 H-imidazol-4-yl)ethyl]propanediamide on the chromatogram of the test solution;

[0127] So is the area of ​​the peak of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide on the chromatogram of the standard solution; ao is the sample weight of the substance N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide, mg; ai is the sample weight of the test sample, mg; co is the water content in the test sample, %;

[0128] P is the content of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide in the substance sample, %.

[0129] Calculation of the quantitative content of acid residue

[0130] Quantitative determination of the drug is carried out using the potentiometric titration method.

[0131] Titration is carried out with a 0.1 M sodium hydroxide solution.

[0132] Test solution: About 100.0 mg (exactly weighed) of the N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide salt sample is placed in a 150 ml beaker, and the sample is dissolved in 100 ml of purified water.

[0133] Before titration, a control experiment is carried out under the conditions of the test solution. The arithmetic mean of the results of 2 parallel measurements is taken as the measurement result.

[0134] Calculation of the quantitative content of acid residue:

[0135] The calculation of the acid residue content of the salt N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (xi) in mg is carried out according to the formula: where: m i - mass of the test sample, g;

[0136] M eq- the amount of acid ions equivalent to 1 ml of 0.1 M sodium hydroxide solution, g / ml;

[0137] V k - the volume of titrant used for titration of the control experiment, ml;

[0138] V i - the volume of titrant used for titration of the test sample, ml;

[0139] % - stoichiometric coefficient, %.

[0140] The chemical structure of the obtained compounds was confirmed by X-ray phase and X-ray structural analysis.

[0141] X-ray phase analysis was performed on a Bruker D8 Advance X-ray diffractometer (copper radiation C u TO α ) with a LynxEye position-sensitive detector, reflection geometry, with rotation. Data collection was performed using the Bruker DIFFRACplus software package, analysis was performed using the EVA program and Topas V5.0. The crystal structure of the obtained phase was determined using the Pauli method.

[0142] For each of the structures, several variants of their arrangement of the cation and anion were found, which described the experimental diffractogram quite well. Then, from the set of solutions, the only one with the correct packing without implausibly short intermolecular contacts was selected.

[0143] The obtained atomic coordinates were used as the starting geometry for the Rietveld refinement with the assignment of parabolic constraints (restrains) on the values ​​of bond lengths and valence angles; also, for aromatic planar fragments, a penalty function flatten was specified, limiting the exit of atoms from the plane; this set of penalty functions was implemented using the Topas 5.0 program [Coelho, A.A. TOPAS and TOPAS -Academic: An Optimization Program Integrating Computer Algebra and Crystallographic Objects Written in C++. J. Appl. Cryst. 2018, 51, 210-218, doi: 10.1107 / S1600576718000183]. To determine the values ​​of the “desired” bond lengths and angles, a crystal calculation was performed in the VASP program [Kresse, G.; Hafner, J. Ab Initio Molecular Dynamics for Liquid Metals. Phys. Rev. B 1993, 47, 558-561, doi: 10.1103 / PhysRevB.47.558]. For each type of non-hydrogen atoms, a separate isotropic thermal parameter was specified.

[0144] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrochloride (molar ratio 1:1) To 2.0 g (0.007 mol) of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) * 68.9 ml (0.007 mol) of 0.1N hydrochloric acid solution in isopropanol were added with stirring and heating to 40°C, a suspension was obtained, 20 ml of methanol were added until a solution was obtained, the reaction mixture was stirred for 15 min. The solvent was removed in vacuo, 10 ml of methanol were added to the residue twice, and the solvent was removed again in vacuo. The resulting residue was dissolved in 1 ml of methanol and 20 ml of acetone were gradually added, and the mixture was left at room temperature for 24 hours. The formed precipitate was filtered off, washed with 40 ml of acetone, and dried in vacuo over CaCl2. A white crystalline powder was obtained.

[0145] Yield 2.1 g (92.1%). Individual peak C time 13 H 18 N6O211.9 min.

[0146] Quantitative determination of C 13 H 18 N6O2: calculated 88.8%, found by HPLC (internal normalization method) in terms of anhydrous substance 88.8%.

[0147] Quantitative determination of the acid residue in the salt: calculated 11.2%, found by acid-base titration method in terms of anhydrous substance 11.0%.

[0148] Next, the X-ray diffraction pattern of the resulting crystalline powder was recorded. Table 1 lists the positions of the 2θ angles and their relative intensities. Fig. 1 shows the powder X-ray diffraction pattern of the resulting crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a monoclinic C-centered cell. The results of refining the cell parameter values ​​using the Pauli method: space group

[0149] GOF = 1.40%. Based on the cell volume and its symmetry, it was determined that the crystal composition

[0150] Table 1. Intensity and position of some peaks with relative intensity greater than 0.5% for the sample.

[0151] On the radiograph C 13 H 18 N6O2*НС1 showed the following intense peaks (maxima) at diffraction angles 2θ (± 0.2°): 17.4, 18.6, 21.5, 23.7, 24.8, 26.1, 28.6 and 30.4. The most intense maxima were: 21.5, 23.7 and 24.8.

[0152] Detailed results of the X-ray structural study are presented in the table.

[0153] 1.

[0154] Table 2. Crystallographic data C 13 H 18 N6O2* НС1

[0155] General view of the unit cell C 13 H 18 N6O2* HCl is shown in Fig. 2. Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride hydrate (molar ratio 1:2)

[0156] To 3.0 g (0.01 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) was added 10 ml of 2-propanol, heated to a temperature of 65-75 ° C with stirring. To the resulting suspension, with stirring and a temperature of 65-75 ° C, 2.7 g of an ethanol solution of hydrochloride were added and stirred for 20 min. The reaction mixture was cooled to 20-25 ° C and stirred for 120-150 minutes. The precipitate that formed was filtered off, washed with 2-propanol. Drying in vacuum at a temperature of 60 ° C for 8 hours.

[0157] Yield 3.8 g (96.0%).

[0158] Individual peak C release time 13 H 18 N6O211.9 min.

[0159] Quantitative determination of C 13 H 18 N6O2: calculated 76.1%, found by HPLC (internal normalization method) in terms of anhydrous substance 75.9%.

[0160] Quantitative determination of the acid residue in the salt: 19.1% calculated, 19.2 found by acid-base titration in terms of anhydrous substance. Then the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 3 lists the positions of the 2θ angles and their relative intensities. Fig. 3 shows the powder X-ray diffraction pattern of the obtained crystalline form.

[0161] Indexing of the diffraction pattern showed that the substance crystallizes in a monoclinic cell. The results of refining the maximum parameters of the Pauli monoclinic cell: space group P2i / c, α = 4.78870(14) A, Ь = 12.6581(4) A, с = 29.7761(8) A, β = 93.4287(13)°, V = 1801.68(9) A 3 , R-Bragg = 0.316%, R exp = 4.61%, R wp = 6.19%, R P = 4.78%,

[0162] GOF = 1.34%. Based on the cell volume and its symmetry, the composition of the crystal was determined. 13 H 18 N6O2* 2НС1 * Н2О.

[0163] Table 3. Intensity and position of some peaks with relative intensity greater than 3% for the sample.

[0164] On the radiograph C 13 H 18 N6O2* 2НС1 * Н2О the following intense peaks (maxima) were observed at diffraction angles 2θ (± 0.2°): 21.4, 22.7, 23.4, 24.1, 24.4, 27.3, 27.7 and 28.5. The most intense maxima were: 21.4, 22.7 and 28.5.

[0165] Detailed results of the X-ray structural study are presented in the table.

[0166] 4.

[0167] Table 4. Crystallographic data C 13 H 18 N6O2* 2НС1 * Н2О

[0168] General view of the unit cell C 13 H 18 N6O2* 2НС1 * Н2О is shown in Fig.4

[0169] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride (molar ratio 1:2)

[0170] To 2.0 g (0.007 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) was added 137.9 ml (0.014 mol) of 0.1N hydrochloric acid solution in isopropanol with stirring, the reaction mixture was stirred for 35 min. The solvent was removed in vacuo, 50 ml of isopropanol were added to the resulting residue 3 times, and the solvent was removed in vacuo. The resulting residue was suspended in 10 ml of methanol, 100 ml of acetone were gradually added to the resulting suspension, and the mixture was left at room temperature for 3 hours. The resulting precipitate was filtered, washed with 100 ml of acetone, and dried in vacuo over CaCl2. A white crystalline powder was obtained.

[0171] Yield 2.3 g (92.1%).

[0172] Individual peak C release time 13 H 18 N6O211.9 min.

[0173] Quantitative determination of C 13 H 18N6O2: calculated 79.9%, found by HPLC (internal normalization method) in terms of anhydrous substance 80.8%.

[0174] Quantitative determination of the acid residue in the salt: calculated 20.1%, found by acid-base titration method in terms of anhydrous substance 19.6%.

[0175] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 5 lists the positions of the 2θ angles and their relative intensities. Fig. 5 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a C-centered cell (space group C2) with the parameters α = 17.2909(11) Å, b = 4.7630(4) Å, c = 11.1697(9) Å, β = 76.009(3)°, V = 892.61(11) Å 3 R-Bragg = 0.682%, R exp = 1.25%, R wp = 6.00%, R p = 3.59%, GOF = 4.79%. Based on the cell volume and its symmetry, it was determined that the crystal composition C 13 H 18N6O2* 2НС1.

[0176] Table 5. Intensity and position of some peaks with relative intensity greater than 3% for the sample.

[0177] On the radiograph C 13 H 18 N6O2* 2НС1 anhydrous the following intense peaks (maxima) were observed at diffraction angles 26 (± 0.2°): 14.8, 16.4, 19.4, 20.5, 21.6, 24.6 and 27.1. The most intense maxima: 14.8, 21.6 and 24.6.

[0178] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrobromide (molar ratio 1:1)

[0179] To 2.0 g (0.007 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) was added 10 ml of water with stirring, a suspension was obtained, 0.76 ml (0.007 mol) of 48% hydrobromic acid was added, the reaction mixture was stirred for 15 min. 50 ml of acetone were added to the resulting solution, the solvent was removed in a vacuum, the resulting residue was dissolved in 1 ml of water, and 10 ml (0.007 mol) of 48% hydrobromic acid was added to the resulting solution.

[0180] 50 ml of acetone, left for 3 hours at +4°C and 48 hours at room temperature. The precipitate was filtered, washed with 100 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0181] Yield 2.5 g (97%).

[0182] Individual peak C release time 13 H 18 N6O211.9 min.

[0183] Quantitative determination of C 13 H 18 N6O2: calculated 78.2%, found by HPLC (internal normalization method) in terms of anhydrous substance 77.7%.

[0184] Quantitative determination of the acid residue in the salt: calculated 21.8%, found by acid-base titration method in terms of anhydrous substance 21.9%.

[0185] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 6 lists the positions of the 2θ angles and their relative intensities. Fig. 6 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a monoclinic cell. The results of refining the values ​​of the Pauli monoclinic cell parameters: space group P2i / c, α = 8.03838(18) K, b = 21.1760(4) A, c = 9.6923(2) A, β = 97.5096(16)°, V = 1635.67(7) A 3 , R-Bragg = 0.222%, R exp = 3.14%, R wp = 5.54%, R p = 4.25%,

[0186] GOF = 1.76%. Based on the cell volume and its symmetry, it was determined that the crystal compositionC 13 H 18 N6O2* HBr.

[0187] Table 6. Intensity and position of some peaks with relative intensity greater than 3% for the sample.

[0188] On the radiograph C 13 H 18 N6O2* HBr showed the following intense peaks (maxima) at diffraction angles 2θ (± 0.2°): 16.8, 17.6, 19.0, 20.2, 20.4, 22.8, 24.6, 25.1,

[0189] 25.7, 27.0, 27.7, 28.1, 28.5, 28.7 and 31.0. The most intense maxima: 20.4, 22.8, 24.6 and

[0190] 25.7.

[0191] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrobromide (molar ratio 1:2) 3.0 g (0.010 mol) of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) was added to 10 ml of water with stirring, the resulting suspension was heated to +40°C and 2.54 ml (0.023 mol) of 48% hydrobromic acid were added, the reaction mixture was stirred for 5 min at +40°C. The resulting solution was cooled to room temperature and added to 250 ml of acetone, left for 15 hours at room temperature, the precipitate was filtered off, washed with 20 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0192] Yield 4.14 g (88.2%).

[0193] Individual peak C release time 13 H 18 N6O212.6 min.

[0194] Quantitative determination of C 13 H 18 N6O2: calculated 64.2%, found by HPLC (internal normalization method) in terms of anhydrous substance 64.9%.

[0195] Quantitative determination of the acid residue in the salt: calculated 35.8%, found by acid-base titration method in terms of anhydrous substance 34.9%.

[0196] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 7 lists the positions of the 2θ angles and their relative intensities. Fig. 7 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. Results of refining the cell parameters using the Pauli method: space group . Based on the cell volume and its symmetry, it was determined that the composition of the crystal C 13 H 18 N6O2* 2НВг. Table 7. Intensity and position of some peaks with relative intensity greater than 3% for the sample.

[0197] On the radiograph C 13 H 18N6O2* 2НВг the following intense peaks (maxima) were observed at diffraction angles 2θ (± 0.2°): 22.5, 22.9, 23.5, 24.2, 24.5, 25.7, 26.2, 27.5, 28.4, 29.8 and 31.8. The most intense maxima were: 22.5, 23.5, 24.2, 25.7 and 27.5.

[0198] Detailed results of the X-ray structural study are presented in the table.

[0199] 8.

[0200] Table 8. Crystallographic data C 13 H 18 N6O2* 2НВг

[0201] General view of the unit cell C 13 H 18 N6O2* 2НВг is shown in Fig.8

[0202] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydroiodide (molar ratio 1:1)

[0203] To 5.0 g (0.017 mol) N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) were added 20 ml of 2-propanol with stirring, to the resulting suspension with stirring were added 2.27 ml (0.017 mol) of 57% aqueous solution of hydroiodic acid. Stirred with heating at about +70-80 °C until a clear solution was obtained. The solvent was removed in a vacuum, 35 ml of 2-propanol were added to the resulting oily residue, heated until condensation appeared and crystallization began for about 5-10 minutes. The suspension was cooled to a temperature of +20-25 °C, added

[0204] 20 ml of 2-propanol and left at -20°C for 12 hours. The resulting precipitate was filtered, washed with 2x25 ml of 2-propanol, dried in a vacuum at +60°C. A white crystalline powder was obtained.

[0205] Yield 6.88 g (95.6%).

[0206] Individual peak C release time 13 H 18 N6O211.9 min.

[0207] Quantitative determination of C 13 H 18N6O2: calculated 69.4%, found by HPLC (internal normalization method) in terms of anhydrous substance 69.8%.

[0208] Quantitative determination of the acid residue in the salt: calculated 30.6%, found by acid-base titration in terms of anhydrous substance 30.4%. Obtaining N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydroiodide (molar ratio 1:2)

[0209] To 5.0 g (0.017 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) 20 ml of 2-propanol were added with stirring, 5.2 ml (0.034 mol) of 57% aqueous solution of hydroiodic acid were added to the resulting suspension.

[0210] Stirred while heating at about +70-80°C until a clear solution was obtained, cooled to +65°C, stirred for 5 min, the resulting suspension was left at -20°C for 12 hours. The precipitate that formed was filtered, washed with 2x25 ml of 2-propanol, dried in a vacuum at +60°C. A yellow-orange crystalline powder was obtained.

[0211] Yield 9.10 g (96.7%).

[0212] Individual peak C release time 13 H 18 N6O211.8 min.

[0213] Quantitative determination of C 13 H 18 N6O2: calculated 53.2%, found by HPLC (internal normalization method) in terms of anhydrous substance 52.7%.

[0214] Quantitative determination of the acid residue in the salt: calculated 46.8%, found by acid-base titration method in terms of anhydrous substance 45.6%.

[0215] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 9 lists the positions of the 2θ angles and their relative intensities. Fig. 9 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. The results of refining the cell parameters using the Pauli method: space group , ( ) , ( ) , ( ) , Based on the cell volume and its symmetry, it was determined that the composition of the crystal

[0216] Table 9. Intensity and position of some peaks with relative intensity greater than 1%.

[0217] On the radiograph C 13 H 18 N6O2*2НI the following intense peaks were observed

[0218] (maxima) at diffraction angles 2θ (± 0.2°): 7.9, 11.1, 15.2, 18.1, 22.0, 22.3, 23.6, 29.2 and

[0219] 33.2. The most intense maxima: 7.9, 18.1 and 22.3.

[0220] Detailed results of the X-ray structural study are presented in the table.

[0221] 10.

[0222] Table 10. Crystallographic data C 13 H 18 N6O2*2НI

[0223] General view of the unit cell C 13 H 18 N6O2*2НI is shown in Fig.10.

[0224] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide 1 / 3 phosphate (molar ratio 1:1 / 3)

[0225] To 2.00 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) were added 8 ml of water with stirring, 0.16 ml (0.0023 mol) of 85% orthophosphoric acid were added to the resulting suspension, the reaction mixture was stirred for 20 min at +40°C and 10 min at +50°C. The reaction mixture was cooled to room temperature and 80 ml of acetone were added to it and left for 15 hours at room temperature. The precipitate that formed was filtered off, washed with 50 ml of acetone, and dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0226] Yield 1.9 g (82.9%).

[0227] Individual peak C release time 13 H 18 N6O212,1 min.

[0228] Quantitative determination of C 13 H 18 N6O2: calculated 89.9%, found by HPLC (internal normalization method) 87.6%.

[0229] Quantitative determination of the acid residue in the salt: calculated 10.1%, found by acid-base titration method 8.02%.

[0230] Preparation of N,N'-6uc[2-(1H-imidazol-4-yl)ethyl]propanediamide 2 / 3 phosphate (molar ratio 1:2 / 3)

[0231] To 2.0 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) 4.1 ml (0.004 mol) of 1 M orthophosphoric acid solution were added with stirring, the reaction mixture was stirred for 10 min. The reaction mixture was poured into 90 ml of acetone and left for 72 hours at +4°C. The resulting precipitate was filtered, washed with 20 ml of acetone, and dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0232] Yield 2.41 g (90.1%). Individual peak C time 13 H 18 N6O211.2 min.

[0233] Quantitative determination of C 13 H 18 N6O2: calculated 77.7%, found by HPLC (internal normalization method) in terms of anhydrous substance 75.9%.

[0234] Quantitative determination of the acid residue in the salt: calculated 18.4%, found by acid-base titration method in terms of anhydrous substance 17.5%.

[0235] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide phosphate

[0236] (molar ratio 1:1)

[0237] To 2.0 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) were added 5 ml of water and 0.5 ml (0.007 mol) of 85% orthophosphoric acid with stirring, the reaction mixture was stirred for 25 min at room temperature. 70 ml of acetone were added to the resulting solution and left for 3 hours at +4°C. The precipitate that formed was filtered, washed with 20 ml of acetone, and dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0238] Yield 2.64 g (98.6%).

[0239] Individual peak C release time 13 H 18 N6O211.9 min.

[0240] Quantitative determination of C 13 H 18 N6O2: calculated 74.8%, found by HPLC (internal normalization method) in terms of anhydrous substance 73.0%.

[0241] Quantitative determination of the acid residue in the salt: calculated 25.2%, found by acid-base titration method in terms of anhydrous substance 24.4%.

[0242] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide ½ oxalate (molar ratio 1:0.5)

[0243] To 2.0 g (0.0070 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) and 0.4 g (0.0035 mol) of oxalic acid dihydrate were added with stirring 5 ml of water, the reaction mixture was stirred for 20 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 100 ml of acetone was added, left for 15 hours at room temperature. The precipitate that formed was filtered, washed with 100 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0244] Yield 2.2 g (92.5%). Individual peak C time 13 H 18 N6O212,1 min.

[0245] Quantitative determination of C 13 H 18 N6O2: calculated 86.6%, found by HPLC (internal normalization method) 83.9%.

[0246] Quantitative determination of the acid residue in the salt: calculated 13.4%, found by acid-base titration method 13.8%.

[0247] Preparation of N, N'-bis[2-( 1H-imidazol-4-yl)ethyl]propanediamide oxalate

[0248] (molar ratio 1:1)

[0249] To 2.0 g (0.007 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) and 0.9 g (0.007 mol) of oxalic acid dihydrate were added with stirring 5 ml of water, the reaction mixture was stirred for 15 min. 70 ml of acetone were added to the resulting solution and left for 3 hours at +4°C and for +24 hours at room temperature. The precipitate that formed was filtered, washed with 100 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0250] Yield 2.6 g (100.2%).

[0251] Individual peak C release time 13 H 18 N6O211.9 min.

[0252] Quantitative determination of C 13 H 18 N6O2: calculated 76.3%, found by HPLC (internal normalization method) 78.0%.

[0253] Quantitative determination of the acid residue in the salt: calculated 23.7%, found by acid-base titration method 22.9%.

[0254] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 11 lists the positions of the 2θ angles and their relative intensities. Fig. 11 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. The results of refining the cell parameter values ​​by the Pauli method: space group P1, α = 7.0882(3) K, b = 8.0274(2) A, c = 15.8146(6) A, α = 107.6061(16)°, β = 95.550(2)°, γ = 86.968(2)°, V = 853.41(5) A 3 , R-Bragg = 0.280%, R exp =

[0255] 4.01%, R wp = 5.85%, R p = 4.43%, GOF = 1.46%. Based on the cell volume and its symmetry, it was determined that the composition of the crystal C 13 H 18 N6O2*HOOC-COOH.

[0256] Table 11. Intensity and position of some peaks with relative intensity greater than 1%.

[0257] On the radiograph C 13 H 18 N6O2*HOOC-COOH showed the following intense peaks (maxima) at diffraction angles 2θ (± 0.2°): 11.4, 17.6, 18.0, 18.9, 20.9, 22.8, 25.1, 25.8 and 29.2. The most intense maxima were 20.9, 25.1 and 25.8.

[0258] Detailed results of the X-ray structural study are presented in the table.

[0259] 12.

[0260] Table 12. Crystallographic data C 13 H 18 N6O2*HOOC-COOH

[0261] General view of the unit cell C 13 H 18 N6O2*NOOC-COOH is presented in Figure 12.

[0262] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide mesylate

[0263] (molar ratio 1:1)

[0264] 2.0 g (0.007 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) was added to 5 ml of water with stirring, 0.5 ml (0.007 mol) of methanesulfonic acid was added to the resulting suspension, the reaction mixture was stirred for 5 min, the reaction proceeded with the release of heat, 5 ml of methanol was added and stirred for 10 min, cooled to room temperature. 200 ml of acetone were added to the reaction mixture and left at +4°C for 24 hours. The formed precipitate was filtered, washed with 100 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0265] Yield 2.51 g (93.6%).

[0266] Individual peak C release time 13 H 18 N6O212,1 min.

[0267] Quantitative determination of C 13 H 18 N6O2: calculated 75.1%, found by HPLC (internal normalization method) in terms of anhydrous substance 74.7%.

[0268] Quantitative determination of the acid residue in the salt: calculated 24.9%, found by acid-base titration in terms of anhydrous substance 25.8%. Obtaining N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dimesylate (molar ratio 1:2)

[0269] 2.00 g (0.007 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) was added to 7 ml of water with stirring, 0.91 ml (0.014 mol) of methanesulfonic acid was added to the resulting suspension, the reaction mixture was stirred for 10 min, the reaction proceeds with the release of heat. The solvent was removed in vacuo, 50 ml of isopropanol were added to the resulting residue 3 times and the solvent was removed in vacuo. The resulting residue was dissolved in 5 ml of methanol, 200 ml of acetone were added to the solution, the mixture was left for 4 hours at room temperature, the precipitate was filtered off, washed with 100 ml of acetone, and dried in vacuo over CaCl2. A white crystalline powder was obtained.

[0270] Yield 3.3 g (96.8%).

[0271] Individual peak C release time 13 H 18 N6O212,1 min.

[0272] Quantitative determination of C 13 H 18 N6O2: calculated 60.2%, found by HPLC (internal normalization method) in terms of anhydrous substance 60.8%.

[0273] Quantitative determination of the acid residue in the salt: calculated 39.8%, found by acid-base titration method in terms of anhydrous substance 39.4%.

[0274] Then the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 13 lists the positions of the 2θ angles and their relative intensities. Fig. 13 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. The results of refining the cell parameter values ​​by the Pauli method: space group P1, α = 8.5722(3) K, b = 9.0659(3) A, c = 14.9321(5) A, α = 94.385(2)°, β = 94.4268(19)°, γ = 111.0623(16)°, V = 1072.90(6) A 3 , R-Bragg = 0.232%, R exp = 3.82%, R wp = 4.87%, R p = 3.70%, GOF = 1.28%. Based on the cell volume and its symmetry, the composition of the crystal C was determined 13 H 18 N6O2*2СН з SO з N.

[0275] Table 13. Intensity and position of some peaks with relative intensity greater than 3%

[0276] On the radiograph C 13 H18 N6O2*2СН з SO з The following intense peaks (maxima) were observed at diffraction angles 2θ (± 0.2°): 17.3, 18.0, 18.2, 20.0, 20.1, 21.4, 21.9, 22.4, 24.1 and 28.1. The most intense maxima were: 17.3, 20.0 and 21.9.

[0277] Detailed results of the X-ray structural study are presented in the table.

[0278] 14. Table 14. Crystallographic data C 13 H 18 N6O2*2СН з SO з N

[0279] General view of the unit cell C 13 H 18 N6O2*2СН з SO з H is shown in Fig.14.

[0280] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dibenzenesulfonate (molar ratio 1:2)

[0281] To 2.0 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 N 18N6O2) and 2.2 g (0.014 mol) of benzenesulfonic acid were added 5 ml of water with stirring, the reaction mixture was stirred for 10 min, the reaction proceeded with the release of heat. The solvent was removed in vacuo, 100 ml of isopropanol were added to the resulting residue 5 times and the solvent was removed in vacuo. 100 ml of acetone were added to the resulting residue, left for 48 hours at +4°C, the precipitate was filtered off, washed with 100 ml of acetone, dried in vacuo over CaCl2. A white crystalline powder was obtained.

[0282] Yield 4.0 g (95.8%).

[0283] Individual peak C release time 13 H 18 N6O210.3 min. Quantitative determination of C 13 H 18 N6O2: calculated 47.9%, found by HPLC (internal normalization method) in terms of anhydrous substance 47.8%.

[0284] Quantitative determination of the acid residue in the salt: calculated 52.1%, found by acid-base titration method in terms of anhydrous substance 52.0%.

[0285] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 15 lists the positions of the 2θ angles and their relative intensities. Fig. 15 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. The results of refining the cell parameter values ​​by the Pauli method: space group P1, a = 9.6498(4) A, b = 9.3547(3) A, c = 17.6042(7) A, α = 90.367(2)°, β = 110.702(3)°, γ = 106.6286(19)°, V = 1414.08(10) A 3 , R-Bragg = 0.173%, R exp = 4.69%, R wp = 5.09%, R P = 3.82%,

[0286] GOF = 1.09%. Based on the cell volume and its symmetry, it was determined that the crystal composition C 13 H 18 N6O2*2С6Н5SO з N.

[0287] Table 15. Intensity and position of some peaks With relative intensity greater than 3% [%]

[0288] 22.895 3.88 100.0

[0289] On the radiograph C 13 H 18 N6O2*2С6Н5SO з The following intense peaks (maxima) were observed at diffraction angles 2θ (± 0.2°): 15.7, 18.9, 19.5, 19.9, 21.4, 22.4, 22.9, 24.3 and 25.7. The most intense maxima were: 18.9, 21.4 and 22.9.

[0290] Detailed results of the X-ray structural study are presented in the table.

[0291] 16.

[0292] Table 16. Crystallographic data C 13 H 18 N6O2*2С6Н5SO з N

[0293] General view of the unit cell C 13 H 18 N6O2*2С6Н5SO з H is shown in Fig.16.

[0294] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide maleate

[0295] (molar ratio 1:0.5)

[0296] 5 ml of methanol and 1 ml of water were added to 2.0 g (0.0070 mol) of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide and 0.4 g (0.0035 mol) of maleic acid, the reaction mixture was stirred for 30 min at +40°C. The reaction mixture was cooled to room temperature and 60 ml of acetone was added, and left for 15 hours at room temperature. The resulting precipitate was filtered off, washed with 50 ml of acetone, and dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0297] Yield 2.3 g (94.6%).

[0298] Individual peak C release time 13 H 18 N6O210.2 min.

[0299] Quantitative determination of C 13 H 18 N6O2: calculated 83.3%, found by HPLC (internal normalization method) in terms of anhydrous substance 81.91%.

[0300] Quantitative determination of the acid residue in the salt: calculated 16.7%, found by acid-base titration method in terms of anhydrous substance 15.3%.

[0301] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dimaleate (molar ratio 1:2)

[0302] To 2.0 g (0.0070 mol) of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide and 1.6 g (0.0140 mol) of maleic acid were added 20 ml of methanol and 4 ml of water, the reaction mixture was stirred for 30 min at a temperature of +40°C. The reaction mixture was cooled to room temperature and 200 ml of acetone was added, and left for 15 hours at room temperature. The resulting precipitate was filtered off, washed with 50 ml of acetone, and dried in a vacuum over CaCl2. A white crystalline powder was obtained. Yield 3.5 g (97.0).

[0303] Individual peak C release time 13 H 18 N6O210.2 min.

[0304] Quantitative determination of C 13 H 18N6O2: calculated 55.6%, found by HPLC (internal normalization method) in terms of anhydrous substance 54.9%.

[0305] Quantitative determination of the acid residue in the salt: calculated 44.4%, found by acid-base titration method in terms of anhydrous substance 43.9%.

[0306] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide formate

[0307] (molar ratio 1:1)

[0308] 2.00 g (0.007 mol) N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) was added to 7 ml of water with stirring, 0.26 ml (0.007 mol) of formic acid was added to the resulting suspension, the reaction mixture was stirred for 10 minutes, the reaction proceeded with the release of heat. 70 ml of acetone were added to the reaction mixture and left for 4 hours at +4°C, the precipitate was filtered off, washed

[0309] 50 ml of acetone were dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0310] Yield 2.3 g (98.9%).

[0311] Individual peak C release time 13 H 18 N6O212,1 min.

[0312] Quantitative determination of C 13 H 18 N6O2: calculated 86.3%, found by HPLC (internal normalization method) in terms of anhydrous substance 87.3%.

[0313] Quantitative determination of the acid residue in the salt: calculated 13.7%, found by acid-base titration method in terms of anhydrous substance 11.0%.

[0314] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide diformate (molar ratio 1:2)

[0315] 2.00 g (0.007 mol) N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) was added to 7 ml of water with stirring, 0.52 ml (0.014 mol) of formic acid was added to the resulting suspension, the reaction mixture was stirred for 10 min, the reaction proceeded with the release of heat. The solvent was removed in vacuo, 5 ml of methanol and 100 ml of acetone were added to the resulting residue, the solvent was removed in vacuo. The resulting residue was dissolved in 1 ml of water and 100 ml of acetone was added, left for 4 hours at room temperature, the precipitate was filtered off, washed with 100 ml of acetone, dried in vacuo over CaCl2. A white crystalline powder was obtained.

[0316] Yield 2.3 g (86.8%).

[0317] Individual peak C release time 13 H 18 N6O212,1 min.

[0318] Quantitative determination of C 13 H 18 N6O2: calculated 81.9%, found by HPLC (internal normalization method) in terms of anhydrous substance 83.8%.

[0319] Quantitative determination of the acid residue in the salt: calculated 13.0%, found by acid-base titration method in terms of anhydrous substance 13.7%.

[0320] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 17 lists the positions of the 2θ angles and their relative intensities. Fig. 17 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a monoclinic cell. The results of refining the maximum parameters of the Pauli monoclinic cell: space group P21, α = 16.3194(4) k, b = 4.70012(13) Å, c = 12.0793(3) Å, β = 89.5555(17)°, V = 926.49(5) Å 3 , R-Bragg = 0.165%, R exp = 1.65%, R wp = 3.99%, R P = 2.87%,

[0321] GOF = 2.42%. Based on the cell volume and its symmetry, it was determined that the crystal composition C 13 H 18 N6O2* 2HCOOH.

[0322] Table 17. Intensity and position of some peaks with relative intensity greater than 2% for the sample

[0323] On the radiograph C 13 H 18 N6O2*2HCOOH showed the following intense peaks (maxima) at diffraction angles 2θ (± 0.2°): 18.4, 21.1, 23.1, 24.0, 24.7 and 29.7. The most intense maxima were: 21.1, 24.0 and 24.7.

[0324] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide ½ succinate (molar ratio 1:0.5)

[0325] To 2.0 g (0.0070 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) and 0.4 g (0.0035 mol) of succinic acid were added with stirring 3 ml of water and 5 ml of methanol, the reaction mixture was stirred for 25 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 80 ml of acetone were added to the solution, left for 24 hours at room temperature. The precipitate that formed was filtered off, washed with 50 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0326] Yield 2.4 g (95.1%).

[0327] Individual peak C release time 13 H 18 N6O212,1 min.

[0328] Quantitative determination of C 13 H 18 N6O2: calculated 83.1%, found by HPLC (internal normalization method) in terms of anhydrous substance 87.5%.

[0329] Quantitative determination of the acid residue in the salt: calculated 16.9%, found by acid-base titration method in terms of anhydrous substance 16.4%.

[0330] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide

[0331] (molar ratio 1:1) To 2.0 g (0.007 mol) N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide

[0332] (C 13 H 18 N6O2) and 0.8 g (0.007 mol) of succinic acid were added with stirring 5 ml of methanol and 0.5 ml of water, the reaction mixture was stirred for 25 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 70 ml of acetone were added to the solution, left for 24 hours at room temperature. The precipitate that formed was filtered off, washed with 50 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0333] Yield 2.7 g (96.2%).

[0334] Individual peak C release time 13 H 18 N6O211.5 min.

[0335] Quantitative determination of C 13 H 18N6O2: calculated 71.1%, found by HPLC (internal normalization method) in terms of anhydrous substance 72.7%).

[0336] Quantitative determination of the acid residue in the salt: calculated 28.9%, found by acid-base titration method in terms of anhydrous substance

[0337] 28.8%.

[0338] Next, the X-ray diffraction pattern of the resulting crystalline powder was recorded. Table 18 lists the positions of the 2θ angles and their relative intensities. Fig. 18 shows the powder X-ray diffraction pattern of the resulting crystalline form.

[0339] Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. The results of refining the values ​​of the Pauli crystal cell parameters: space group P1, α = 4.71781(16) Α, b = 12.9796(4) Å, c = 18.2017(6) Å, α =

[0340] 116.5679(18)°, р = 88.308(2)°, γ = 81.7789(18)°, V = 981.13(6) A 3 , R-Bragg = 0.210%, Rexp =

[0341] 4.26%, R wp = 5.48%, R p = 4.07%, GOF = 1.29%. Based on the cell volume and its symmetry, it was determined that in the crystalline structure of the substance the composition of the crystal C 13 H 18 N6O2*C2H4(COOH)2or (C 13 H 18 N6O2*C2H4(COOH)2*H2O).

[0342] Table 18. Intensity and position of some peaks with relative intensity greater than 1%

[0343] On the radiograph C 13 H 18 N6O2*C2H4(COOH)2the following intense peaks (maxima) were observed at diffraction angles 2θ (± 0.2°): 16.1, 19.7, 20.8, 22.0, 23.9 and 25.5. The most intense maxima: 20.8, 23.9 and 25.5.

[0344] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide ½ glutarate (molar ratio 1:0.5)

[0345] To 2.0 g (0.0070 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) and 0.5 g (0.0035 mol) of glutaric acid were added with stirring 1 ml of water and 5 ml of methanol, the reaction mixture was stirred for 30 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 60 ml of acetone were added to the solution and left for 24 hours at room temperature. The precipitate that formed was filtered off, washed with 50 ml of acetone, dried in a vacuum over C a CI2. A white crystalline powder was obtained.

[0346] Yield 2.4 g (93.7%).

[0347] Individual peak C release time 13 H 18 N6O210.2 min.

[0348] Quantitative determination of C 13 H 18 N6O2: calculated 81.5%, found by HPLC (internal normalization method) in terms of anhydrous substance 85.6%.

[0349] Quantitative determination of the acid residue in the salt: calculated 18.5%, found by acid-base titration method in terms of anhydrous substance 15.4%.

[0350] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide glutarate dihydrate (molar ratio 1:1)

[0351] To 2.0 g (0.007 mol) N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) and 0.9 g (0.007 mol) of glutaric acid were added 7 ml of methanol and 1.5 ml of water, the reaction mixture was stirred for 10 min at +40°C. The resulting solution was cooled to room temperature and 85 ml of acetone was added and left for 24 hours at a temperature of +4°C. The precipitate that formed was filtered off, washed with 50 ml of acetone, dried in a vacuum over C a CI2. A white crystalline powder was obtained.

[0352] Yield 2.87 g (97.8%).

[0353] Individual peak C release time 13 H 18 N6O210.2 min.

[0354] Quantitative determination of C 13 H 18 N6O2: calculated 68.7%, found by HPLC (internal normalization method) in terms of anhydrous substance 68.9%.

[0355] Quantitative determination of the acid residue in the salt: calculated 31.3%, found by acid-base titration method in terms of anhydrous substance 29.1%.

[0356] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 19 lists the positions of the 2θ angles and their relative intensities. Fig. 19 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. The results of refining the cell parameter values ​​by the Pauli method: space group P1, α = 4.9541(3) A, b = 15.7371(10) A, c = 16.1193(11) A, α = 111.762(3)°, β = 74.066(3)°, γ = 98.785(3)°, V = 1120.47(13) A 3 , R-Bragg = 0.189%, R exp = 3.48%, R wp = 5.16%, R P = 3.84%,

[0357] GOF = 1.48%. Based on the cell volume and its symmetry, it was determined that the crystal composition C 13 H 18 N6O2*C зH6(COOH)2*2H2O.

[0358] Table 19. Intensity and position of some peaks with relative intensity greater than 3%. On the radiograph C 13 H 18 N6O2*C з H6(COOH)2*2H2O showed the following intense peaks (maxima) at diffraction angles 2θ (± 0.2°): 18.2, 20.1, 21.7, 22.2, 23.0, 23.2, 23.5, 24.9, 26.2 and 29.0. The most intense maxima were 18.2, 24.9 and 29.0.

[0359] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide ½ malonate (molar ratio 1:0.5)

[0360] To 2.0 g (0.0070 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) and 0.4 g (0.0035 mol) of malonic acid were added 5 ml of methanol and 0.5 ml of water, the reaction mixture was stirred for 10 min. 200 ml of acetone were added to the reaction mixture and the precipitated oil was ground. The resulting precipitate was filtered, washed with 100 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0361] Yield 2.2 g (93.9%).

[0362] Individual peak C release time 13 H 18 N6O212,1 min.

[0363] Quantitative determination of C 13 H 18 N6O2: calculated 84.8%, found by HPLC (internal normalization method) in terms of anhydrous substance 82.1%.

[0364] Quantitative determination of the acid residue in the salt: calculated 15.2%, found by acid-base titration method in terms of anhydrous substance 13.8%.

[0365] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide malonate (molar ratio 1:1)

[0366] To 2.0 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) and 0.7 g (0.007 mol) of malonic acid were added 5 ml of water, the reaction mixture was stirred for 10 min. The solvent was removed in vacuo, 50 ml of isopropanol were added to the resulting residue 3 times, and the solvent was removed in vacuo. The resulting residue was dissolved in a mixture of 0.5 ml of water and 5 ml of methanol with ultrasound treatment and heating to +40°C. The resulting solution was cooled to room temperature and 200 ml of acetone were added to the solution, and left at room temperature for 24 hours. The resulting precipitate was filtered, washed with 100 ml of acetone, and dried in vacuo over CaCl2. A white crystalline powder was obtained.

[0367] Yield 2.3 g (90.3%).

[0368] Individual peak C release time 13 H 18 N6O212.1 min. Quantitative determination of C 13 H 18N6O2: calculated 73.6%, found by HPLC (internal normalization method) in terms of anhydrous substance 74.2%.

[0369] Quantitative determination of the acid residue in the salt: calculated 26.4%, found by acid-base titration method in terms of anhydrous substance 26.0%.

[0370] Preparation of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide ½ fumarate (molar ratio 1:0.5)

[0371] To 2.0 g (0.0070 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide

[0372] ( C 13 H 18N6O2) and 0.4 g (0.0035 mol) of fumaric acid were added 5 ml of methanol and 1.5 ml of water, the reaction mixture was stirred for 30 min at a temperature of +40°C. The reaction mixture was cooled to room temperature and 65 ml of acetone was added, left for 3 hours at room temperature. The resulting precipitate was filtered, washed with 50 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0373] Yield 2.4 g (97.8%).

[0374] Individual peak C release time 13 H 18 N6O210.2 min.

[0375] Quantitative determination of C 13 H 18 N6O2: calculated 83.3%, found by HPLC (internal normalization method) in terms of anhydrous substance 81.7%.

[0376] Quantitative determination of the acid residue in the salt: calculated 16.7%, found by acid-base titration method in terms of anhydrous substance 16.7%.

[0377] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide fumarate

[0378] (molar ratio 1:1)

[0379] 2.0 g (0.007 mol) N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) was suspended in 6 ml of methanol with stirring and heating at +40°C, 0.9 g (0.008 mol) of fumaric acid was added to the suspension, the reaction mixture was stirred for 10 min at +40°C. The reaction mixture was cooled to room temperature and added to 100 ml of acetone, left for 15 hours at +4°C. The precipitate that formed was filtered off, washed with 100 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0380] Yield 2.8 g (98.8%). Individual peak C time 13 H 18 N6O211.8 min.

[0381] Quantitative determination of C 13 H 18N6O2: calculated 71.4%, found by HPLC (internal normalization method) in terms of anhydrous substance 70.68%.

[0382] Quantitative determination of acid residue in the salt composition: calculated 28.6%, found by acid-base titration method in terms of anhydrous substance

[0383] 28.93%.

[0384] Next, the X-ray diffraction pattern of the obtained crystalline powder was recorded. Table 20 lists the positions of the 2θ angles and their relative intensities. Fig. 20 shows the powder X-ray diffraction pattern of the obtained crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell. The results of refining the cell parameter values ​​using the Pauli method: space group P1, α = 4.9946(3) K, b = 16.0227(9) A, c = 13.2678(8) A, α =

[0385] 66.218(3)°, β = 87.614(3)°, γ = 78.134(2)°, V = 949.85(11) A 3 , R-Bragg = 0.132%, R exp = 4.95%, R wp = 5.48%, Rp = 4.11%, GOF = 1.11%. Based on the cell volume and its symmetry, it was determined that the composition of the crystal C 13 H 18 N6O2*C2H2(COOH)2.

[0386] Table 20. Intensity and position of some peaks with relative intensity greater than 1% ]

[0387] On the radiograph C 13 H 18 N6O2*C2H2(COOH)2the following intense peaks (maxima) were observed at diffraction angles 2θ (± 0.2°): 20.0, 20.5, 22.1, 22.6, 23.4, 25.2 and 29.9. The most intense maxima were: 20.5, 22.1 and 25.2.

[0388] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide difumarate

[0389] (molar ratio 1:2)

[0390] To 5.0 g (0.017 mol) N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) was added 50 ml of methanol with stirring. A solution of 4.6 g (0.039 mol) of fumaric acid in 50 ml of methanol, heated to a temperature of +50-60°C, was added to the resulting solution with stirring. The reaction mixture was stirred while boiling until precipitation began for approximately 90 min. The resulting suspension was left at -20°C for 2 hours. The precipitate that formed was filtered, washed with 2x25 ml of methanol, and dried in a vacuum at +60°C. A white crystalline powder was obtained.

[0391] Yield 9.10 g (65.7%).

[0392] Individual peak C release time 13 H 18 N6O211.8 min.

[0393] Quantitative determination of C 13 H 18 N6O2: calculated 55.6%, found by HPLC (internal normalization method) in terms of anhydrous substance 55.9%.

[0394] Quantitative determination of the acid residue in the salt: calculated 44.4%, found by acid-base titration method in terms of anhydrous substance 42.2%.

[0395] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide ½ tartrate (molar ratio 1:0.5)

[0396] To 2.0 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) and 0.5 g (0.003 mol) of tartaric acid were added with stirring 5 ml of methanol and 0.5 ml of water, the reaction mixture was stirred for 15 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 55 ml of acetone were added to the solution, the precipitated oil was triturated, and left for 24 hours at room temperature. The precipitate that formed was filtered, washed with 50 ml of acetone, and dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0397] Yield 2.6 g (85.2%).

[0398] Individual peak C release time 13 H18 N6O211.5 min.

[0399] Quantitative determination of C 13 H 18 N6O2: calculated 79.5%, found by HPLC (internal normalization method) in terms of anhydrous substance 74.3%.

[0400] Quantitative determination of the acid residue in the salt: calculated 20.5%, found by acid-base titration method in terms of anhydrous substance 19.4%.

[0401] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide lactate (molar ratio 1:1)

[0402] To 2.0 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) was added 8.27 ml (0.008 mol) of 1 M lactic acid solution, stirred for 15 min at +40°C. The resulting solution was cooled to room temperature and 80 ml of acetone were added to the solution, left for 15 hours at room temperature. The precipitate that formed was filtered, washed with 50 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0403] Yield 2.1 g (80.1%).

[0404] Individual peak C release time 13 H 18 N6O211.2 min.

[0405] Quantitative determination of C 13 H 18 N6O2: calculated 76.3%, found by HPLC (internal normalization method) in terms of anhydrous substance 81.1%.

[0406] Quantitative determination of the acid residue in the salt: calculated 23.7%, found by acid-base titration method in terms of anhydrous substance 19.9%.

[0407] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide tartrate (molar ratio 1:1)

[0408] To 2.0 g (0.007 mol) N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) and 1.1 g (0.007 mol) of tartaric acid were added with stirring 5 ml of methanol and 1.5 ml of water, the reaction mixture was stirred for 15 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 65 ml of acetone were added to the solution, the precipitated oil was triturated, and left for 3 hours at room temperature. The precipitate that formed was filtered, washed with 50 ml of acetone, and dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0409] Yield 2.4 g (80.0%).

[0410] Individual peak C release time 13 H 18 N6O211.6 min.

[0411] Quantitative determination of C 13 H 18N6O2: calculated 65.9%, found by HPLC (internal normalization method) in terms of anhydrous substance 64.6%.

[0412] Quantitative determination of the acid residue in the salt: calculated 34.1%, found by acid-base titration method in terms of anhydrous substance 36.3%.

[0413] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide sulfate

[0414] (molar ratio 1:0.5)

[0415] 2.0 g (0.007 mol) N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18N6O2) was added to 10 ml of water with stirring, the resulting suspension was heated to +40°C and 0.192 ml (0.004 mol) of 96% sulfuric acid was added, the reaction mixture was stirred for 15 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 50 ml of acetone was added to the solution, left for 2 hours at room temperature. The precipitate that formed was filtered, washed with 50 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0416] Yield 2.3 g (95.6%).

[0417] Individual peak C release time 13 H 18 N6O211.6 min.

[0418] Quantitative determination of C 13 H 18 N6O2: calculated 85.5%, found by HPLC (internal normalization method) in terms of anhydrous substance 84.6%.

[0419] Quantitative determination of the acid residue in the salt: calculated 28.9%, found by acid-base titration method in terms of anhydrous substance 27.5%.

[0420] Preparation of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide sulfate

[0421] (molar ratio 1:1)

[0422] 2.0 g (0.007 mol) N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) was added to 10 ml of water with stirring, the resulting suspension was heated to +40°C and 0.385 ml (0.007 mol) of 96% sulfuric acid was added, the reaction mixture was stirred for 15 min at a temperature of +40°C. The resulting solution was cooled to room temperature and 65 ml of acetone was added to the solution, left for 3 hours at room temperature. The precipitate that formed was filtered, washed with 60 ml of acetone, dried in a vacuum over CaCl2. A white crystalline powder was obtained.

[0423] Yield 2.6 g (98.6%).

[0424] Individual peak C release time 13 H 18 N6O211.4 min.

[0425] Quantitative determination of C 13 H 18 N6O2: calculated 74.7%, found by HPLC (internal normalization method) in terms of anhydrous substance 73.8%.

[0426] Quantitative determination of the acid residue in the salt: calculated 25.3%, found by acid-base titration method in terms of anhydrous substance 24.7%.

[0427] Preparation of N, N'-bis[2-(1H-imidazole-4-yl)ethyl]propanediamide malate (molar ratio 1:1) To 5.0 g (0.017 mol) of N, N'-bis[2-(1H-imidazole-4-yl)ethyl]propanediamide (C 13 H 18 N6O2) was added 25 ml of methanol with stirring. A solution of 2.3 g (0.017 mol) of L-malic acid in 25 ml of methanol was added to the resulting solution with stirring.

[0428] The reaction mixture was boiled for 60°C and left at -20°C for 12 hours. The resulting precipitate was filtered, washed with 2x5 ml of 2-propanol, and dried in a vacuum at +60°C.

[0429] A white crystalline powder was obtained.

[0430] Yield 5.48 g (75.0%).

[0431] Individual peak C release time 13 H 18 N6O211.9 min.

[0432] Quantitative determination of C 13 H 18 N6O2: calculated 68.4%, found by HPLC (internal normalization method) in terms of anhydrous substance 68.8%.

[0433] Quantitative determination of the acid residue in the salt: calculated 31.6%, found by acid-base titration method in terms of anhydrous substance 28.5%.

[0434] Example 2. Study of stability and hygroscopicity of compounds in solid form

[0435] The stability study was carried out under the following conditions:

[0436] Time period: 12 months;

[0437] Temperature: 25 ± 2°С;

[0438] Relative humidity: 60 + 5%; Amount of substance 1.0 g

[0439] Sample control was performed at the 3rd, 6th, 9th and 12th months (± 10 days);

[0440] Methods of sample analysis: determination of water by the Karl-Fischer method (GOST

[0441] 33593-2015) and the high-performance liquid chromatography (HPLC) method. The measurement results are presented in Table 21.

[0442] Table 21. Study of stability and hygroscopicity of compounds Additionally, a study of hygroscopicity was conducted in accordance with

[0443] European Pharmacopoeia under the following conditions: temperature 25 ± 1°C; relative humidity: 80 ± 2% for 24 hours.

[0444] The relative increase in mass for all studied salts was less than 0.2 wt.%, which allows us to classify the substances as non-hygroscopic.

[0445] Example 3. Study of the stability of compounds in solution

[0446] According to literature data (P.ARORA et al., Permeability issues in nasal drug delivery, DRUG DISCOVERY TODAY, 2002, V.7, NI 8, pp.967-975), a liquid dosage form with a pH in the range of 4.5-6.5 is preferable for intranasal administration. At the same time, the active substance must remain stable in solution.

[0447] Salt forms of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide were obtained similarly to Example 1. Then, 3 wt.% solutions of the indicated compounds were prepared and the amount of impurities was estimated by HPLC at a temperature of +25°C and a relative humidity of 60%. The composition of the mobile phases and the chromatography conditions are given in Example 1.

[0448] Impurity solution. About 16.6 mg (exactly weighed) of the histamine dihydrochloride impurity sample is placed in a 50.0 ml volumetric flask, about 40 ml of solvent is added and mixed, the volume of the solution is brought up to the mark with the same solvent and mixed. 1.0 ml of the resulting solution is placed in a 25.0 ml volumetric flask and the volume of the solution is brought up to the mark with solvent and mixed.

[0449] The concentration of the resulting solution is 8.0 μg / ml (histamine). The stability study results are presented in Table 22.

[0450] Table 22. Data from the stability study of 3% solutions N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide in free base form is unsuitable for the preparation of intranasal dosage forms due to low stability in solution. Similar conclusions are made with respect to salt forms not related to the present invention.

[0451] Example 4. Study of compound activity in an acute cough model

[0452] The study was conducted on male Agouti guinea pigs. The groups were formed by selection using body weight as the leading characteristic (the spread in initial weight between and within groups did not exceed ±10%). Each group consisted of 10 animals.

[0453] The animals were inhaled for 5 minutes using a compression nebulizer with a capsaicin solution (30 μM) prepared in a mixture of ethanol and Tween-80. N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrochloride (C 13 H 18N6O2* HCl) in the form of a 1% solution was administered intranasally once, using a dispenser, 10 μl into each nostril, 5 min before capsaicin inhalation and once, using a bottle with a spray dosing nozzle into the throat in a volume of 50 μl, 5 min before capsaicin inhalation. Control animals were administered the solvent. The intact group was not administered anything. Antitussive activity was assessed by counting the number of coughing fits within 15 minutes from the start of capsaicin inhalation. The results are shown in Fig. 21 and Fig. 22.

[0454] The results of the studies showed that with a single administration of C 13 H 18 N6O2*НС1 in the form of a 1% solution has been shown to reduce coughing in guinea pigs.

[0455] Similar studies were conducted with other compounds of the present invention. The results of the studies showed a decrease in cough intensity by 30-50% compared to the control.

Claims

Invention formula 1. Compound of chemical formula: Connection 3 Connection 4 Connection 7 Connection 8 Connection 9 Connection 10 Connection 13 Connection 14 Connection 17 Connection 18 Connection 19 Connection 20 Connection 23 Connection 24 Connection 27 Connection 28 Connection 29 Connection 30 Connection 31 Connection 32 Connection 33 Connection 34 Connection 35 Compound 37 Compound 38 th th 5 5 Connection 39 Connection 40 Connection 41 Connection 42 Connection 43 Connection 44 l D Connection 45 Connection 46 Compound 47 Compound 48 or its hydrate.

2. The compound according to claim 1, selected from or its hydrate.

3. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrochloride, characterized by peak positions in the powder X-ray diffraction pattern, 2θ, deg: 21.5 ± 0.2, 23.7 ± 0.2 and 24.8 ± 0.

2.

4. The crystalline form according to item 3, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 17.4 ± 0.2, 18.6 ± 0.2, 21.5 ± 0.2, 23.7 ± 0.2, 24.8 ± 0.2, 26.1 ± 0.2, 28.6 ± 0.2 and 30.4 ± 0.

2.

5. The crystalline form according to item 3, characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 22.46 ± 0.50 A, 11.16 ± 0.50 A, 15.48 ± 0.50 A; and the value of the angle (deg): 123.40° ± 5.00°.

6. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride hydrate, characterized by peak positions in powder X-ray diffraction pattern, 2θ, deg: 21.4 ± 0.2, 22.7 ± 0.2 and 28.5 ± 0.

2.

7. The crystalline form according to claim 6, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 21.4 ± 0.2, 22.7 ± 0.2, 23.4 ± 0.2, 24.1 ± 0.2, 24.4 ± 0.2, 27.3 ± 0.2, 27.7 ± 0.2 and 28.5 ± 0.

2.

8. Crystalline form according to item b, characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.79 ± 0.50 A, 12.66 ± 0.50 A, 29.78 ± 0.50 A; and the value of the angle (deg): 93.43° ± 5.00°.

9. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride, characterized by peak positions in powder X-ray diffraction pattern, 2θ, deg: 14.8 ± 0.2, 21.6 ± 0.2 and 24.6 ± 0.

2.

10. The crystalline form according to claim 9, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 14.8 ± 0.2, 16.4 ± 0.2, 19.4 ± 0.2, 20.5 ± 0.2, 21.6 ± 0.2, 24.6 ± 0.2 and 27.1 ± 0.

2.

11. The crystalline form according to claim 9, characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 17.29 + 0.50 A, 4.76+ 0.50 A, 11.17+ 0.50 A; and the value of the angle (deg): 76.01° + 5.00°.

12. A crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrobromide, characterized by the peak positions in the powder X-ray diffraction pattern, 2θ, deg: 20.4 + 0.2, 22.8 + 0.2, 24.6 + 0.2 and 25.7 + 0.

2.

13. The crystalline form according to I.12, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 16.8 + 0.2, 17.6 + 0.2, 19.0 + 0.2, 20.2 + 0.2, 20.4 + 0.2, 22.8 + 0.2, 24.6 + 0.2, 25.1 + 0.2, 25.7 + 0.2, 27.0 + 0.2, 27.7 + 0.2, 28.1 + 0.2, 28.5 + 0.2, 28.7 + 0.2 and 31.0 + 0.

2.

14. Crystalline form according to I.12, characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 8.04 + 0.50 A, 21.18 + 0.50 A, 9.69 + 0.50 A; and the value of the angle (deg): 97.51° + 5.00°.

15. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrobromide, characterized by ammonia-containing phase transition in powder X-ray diffraction pattern, 2θ, deg: 22.5 + 0.2, 23.5 + 0.2, 24.2 + 0.2, 25.7 + 0.2 and 27.5 + 0.

2.

16. The crystalline form according to I.15, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 22.5 + 0.2, 22.9 + 0.2, 23.5 + 0.2, 24.2 + 0.2, 24.5 + 0.2, 25.7 + 0.2, 26.2 + 0.2, 27.5 + 0.2, 28.4 + 0.2, 29.8 + 0.2 and 31.8 + 0.

2.

17. The crystalline form according to I.15, characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.89 + 0.50 A, 12.04 + 0.50 A, 15.71 + 0.50 A; and the values ​​of the angles (deg): 106.83° + 5.00°, 99.99° + 5.00°, 93.46° + 5.00°.

18. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydroiodide, characterized by ammonia-containing fluorescence in the powder X-ray diffraction pattern, 2θ, deg: 7.9+ 0.2, 18.1+ 0.2, and 22.3+ 0.

2.

19. The crystalline form according to I.16, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 7.9+ 0.2, 11.1+ 0.2, 15.2+ 0.2, 18.1 + 0.2, 22.3 + 0.2, 23.6 + 0.2, 29.2 + 0.2 and 33.2 + 0.

2.

20. Crystalline form according to I.16, characterized by triclinic syngony, crystal cell edge values, A (angstroms): 5.00 + 0.50 A, 12.39 + 0.50 A, 16.03 + 0.50 A and angle values ​​(deg): 70.22 ° + 5.00°, 81.55 ° + 5.00°, 87.11 ° + 5.00°.

21. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide oxalate, characterized by peak positions in powder X-ray diffraction pattern, 2θ, deg: 20.9 ± 0.2, 25.1 ± 0.2 and 25.8 ± 0.

2.

22. The crystalline form according to claim 21, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 11.4 ± 0.2, 17.6 ± 0.2, 18.0 ± 0.2, 18.9 ± 0.2, 20.9 ± 0.2, 22.8 ± 0.2, 25.1 ± 0.2, 25.8 ± 0.2 and 29.2 ± 0.

2.

23. The crystalline form according to claim 21, characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 7.09 ± 0.50 A, 8.03 ± 0.50 A, 15.81 ± 0.50 A; and the values ​​of the angles (deg): 107.61° ± 5.00°, 95.55° ± 5.00°, 86.97° ± 5.00°.

24. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dimesylate, characterized by peak positions in powder X-ray diffraction pattern, 2θ, deg: 17.3 ± 0.2, 20.0 ± 0.2 and 21.9 ± 0.

2.

25. The crystalline form according to claim 24, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 17.3 ± 0.2, 18.0 ± 0.2, 18.2 ± 0.2, 20.0 ± 0.2, 20.1 ± 0.2, 21.4 ± 0.2, 21.9 ± 0.2, 22.4 ± 0.2, 24.1 ± 0.2 and 28.1 ± 0.

2.

26. The crystalline form according to claim 24, characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 8.57 ± 0.50 A, 9.07 ± 0.50 A, 14.93 ± 0.50 A; and the values ​​of the angles (deg): 94.39° ± 5.00°, 94.43° ± 5.00°, 111.06° ± 5.00°.

27. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dibenzenesulfonate, characterized by peak positions in powder X-ray diffraction pattern, 2θ, deg: 18.9 ± 0.2, 21.4 ± 0.2 and 22.9 ± 0.

2.

28. The crystalline form according to claim 27, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 15.7 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, 19.9 ± 0.2, 21.4 ± 0.2, 22.4 ± 0.2, 22.9 ± 0.2, 24.3 ± 0.2 and 25.7 ± 0.

2.

29. The crystalline form according to claim 27, characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 9.65 ± 0.50 A, 9.35 ± 0.50 A, 17.60 ± 0.50 A; and the values ​​of the angles (deg): 90.37° ± 5.00°, 110.70° ± 5.00°, 106.63° ± 5.00°.

30. A crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide diformate or its hydrate, characterized by peak positions in the powder X-ray diffraction pattern, 2θ, deg: 21.1 ± 0.2, 24.0 ± 0.2 and 24.7 ± 0.

2.

31. The crystalline form according to claim 30, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 18.4 ± 0.2, 21.1 ± 0.2, 23.1 ± 0.2, 24.0 ± 0.2, 24.7 ± 0.2 and 29.7 ± 0.

2.

32. The crystalline form according to claim 30, characterized by monoclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 16.32 + 0.50 A, 4.70 + 0.50 A, 12.08 + 0.50 A; and the value of the angle (deg): 89.56° + 5.00°.

33. A crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide succinate or its hydrate, characterized by peak positions in the powder X-ray diffraction pattern, 2θ, deg: 20.8 + 0.2, 23.9 + 0.2 and 25.5 + 0.

2.

34. The crystalline form according to item 33, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 16.1 + 0.2, 19.7 + 0.2, 20.8 + 0.2, 22.0 + 0.2, 23.9 + 0.2 and 25.5 + 0.

2.

35. The crystalline form according to item 33, characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.72 + 0.50 A, 12.98 + 0.50 A, 18.20 + 0.50 A; and the values ​​of the angles (deg): 116.57° + 5.00°, 88.31° + 5.00°, 81.78° + 5.00°.

36. A crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide glutarate dihydrate, characterized by peak positions in the powder X-ray diffraction pattern, 2θ, deg: 18.2 + 0.2, 24.9 + 0.2 and 29.0 + 0.

2.

37. The crystalline form according to claim 36, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 18.2 + 0.2, 20.1 + 0.2, 21.7 + 0.2, 22.2 + 0.2, 23.0 + 0.2, 23.2 + 0.2, 23.5 + 0.2, 24.9 + 0.2, 26.2 + 0.2 and 29.0 + 0.

2.

38. The crystalline form according to claim 36, characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.95 ± 0.50 A, 15.74 + 0.50 A, 16.12 + 0.50 A; and the values ​​of the angles (deg): 111.76° + 5.00°, 74.07° + 5.00°, 98.79° + 5.00°.

39. Crystalline form of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide fumarate, characterized by peak positions in powder X-ray diffraction pattern, 2θ, deg: 20.5 + 0.2, 22.1 + 0.2 and 25.2 + 0.

2.

40. The crystalline form according to claim 39, characterized by the positions of the peaks in the powder X-ray diffraction pattern, 2θ, deg: 20.0 + 0.2, 20.5 + 0.2, 22.1 + 0.2, 22.6 + 0.2, 23.4 + 0.2, 25.2 + 0.2 and 29.9 + 0.

2.

41. The crystalline form according to claim 39, characterized by triclinic syngony, the values ​​of the edges of the crystal cell, A (angstroms): 4.99 + 0.50 A, 16.02 + 0.50 A, 13.27 + 0.50 A; and the values ​​of the angles (deg): 66.22° + 5.00°, 87.61° + 5.00°, 78.13° + 5.00°.

42. A method for producing a compound according to claim 1, comprising reacting N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide with a corresponding acid selected from the group consisting of hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, formic, acetic, propionic, hydrobromic, oxalic, malonic, succinic, glutaric, maleic, lactic, fumaric, methanesulfonic, benzenesulfonic, para-toluenesulfonic, tartaric, E-malic, citric in a molar ratio of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide and acid from 5:1 to 1:

5.

43. A pharmaceutical composition for the treatment and / or prevention of inflammation of the mucous membrane of the upper respiratory tract, symptomatic treatment of influenza, acute respiratory viral infections, allergies and allergic rhinitis, containing a compound according to claim 1 in a therapeutically effective amount and at least one pharmaceutically acceptable excipient.

44. The pharmaceutical composition according to claim 43, characterized in that the inflammation of the mucous membrane of the upper respiratory tract is caused by rhinitis.

45. A medicinal product for the treatment and / or prevention of inflammation of the mucous membrane of the upper respiratory tract, containing a compound according to claim 1 or a pharmaceutical composition according to claim 43.

46. ​​A medicinal product according to paragraph 45, characterized in that said product is a solid dosage form or a liquid dosage form.

47. A medicinal product according to item 45, characterized in that said product is a powder, granule or tablet.

48. A medicinal product according to claim 45, characterized in that said product includes at least one pharmaceutically acceptable excipient.

49. The medicinal product according to item 45, characterized in that the inflammation of the mucous membrane of the upper respiratory tract is caused by rhinitis.

50. Use of a compound according to claim 1 for the treatment and / or prevention of inflammation of the mucous membrane of the upper respiratory tract.

51. Use according to paragraph 50, characterized in that the inflammation of the mucous membrane of the upper respiratory tract is caused by rhinitis, sinusitis or pharyngitis.

52. Use of a compound according to claim 1 for the treatment and / or prevention of cough.

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