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WO2025095813A1 - Nouveaux composés - Google Patents

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Publication number
WO2025095813A1
WO2025095813A1 PCT/RU2024/050280 RU2024050280W WO2025095813A1 WO 2025095813 A1 WO2025095813 A1 WO 2025095813A1 RU 2024050280 W RU2024050280 W RU 2024050280W WO 2025095813 A1 WO2025095813 A1 WO 2025095813A1
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Prior art keywords
crystalline form
diffraction pattern
powder
imidazol
propanediamide
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PCT/RU2024/050280
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English (en)
Russian (ru)
Inventor
Владимир Евгеньевич НЕБОЛЬСИН
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Valenta Intellect LLC
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Valenta Intellect LLC
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Priority claimed from RU2023128517A external-priority patent/RU2023128517A/ru
Application filed by Valenta Intellect LLC filed Critical Valenta Intellect LLC
Publication of WO2025095813A1 publication Critical patent/WO2025095813A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound is selected from the group or from hydrates of the indicated compounds.
  • the said chemical compounds are pharmaceutically acceptable salts of N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide.
  • 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.
  • 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 S.M.BERGE et al., Pharmaceutical salts, JOURNAL OF
  • 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),
  • 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
  • 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.
  • N,N'-Bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide can be represented as mesomeric structures.
  • Mesomeric structures include:
  • 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.
  • N,N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide the mesomeric effect is possible for two imidazole and two amide groups.
  • the salt form of the present invention may preferably be a solid crystalline form.
  • the present technical problem is solved and the indicated technical results are achieved also thanks to the crystalline form of N, N'-bis[2-(1H- imidazol-4-yl)ethyl] propanediamide, characterized by the following peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg (+ 0.2°): 21.5, 23.7, and 24.8.
  • the crystalline form is characterized by the following peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg (+ 0.2°): 17.4, 18.6, 21.5, 23.7, 24.8, 26.1, 28.6, and 30.4.
  • the crystalline form is characterized by a 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°.
  • 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, 2 ⁇ , deg (+ 0.2°): 21.4, 22.7 and 28.5.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg (+ 0.2°): 21.4, 22.7, 23.4, 24.1, 24.4, 27.3, 27.7 and 28.5.
  • 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°.
  • 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, 2 ⁇ , deg. (+ 0.2°): 14.8, 21.6 and 24.6.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg. (+ 0.2°): 14.8, 16.4, 19.4, 20.5, 21.6, 24.6 and 27.1.
  • 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°.
  • 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, 2 ⁇ , deg. (+ 0.2°): 20.4, 22.8, 24.6 and 25.7.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , 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.
  • 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°.
  • 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, 2 ⁇ , deg (+ 0.2°): 22.5, 23.5, 24.2, 25.7 and 27.5.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , 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.
  • 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°.
  • 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, 2 ⁇ , deg ( ⁇ 0.2°): 7.9, 11.1, 15.2, 18.1, 22.3, 23.6, 29.2 and 33.2.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 7.9, 1188..11 and 22.3.
  • 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°.
  • 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, 2 ⁇ , deg (+ 0.2°): 20.9, 25.1 and 25.8.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 11.4, 17.6, 18.0, 18.9, 20.9, 22.8, 25.1, 25.8 and 29.2.
  • 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°.
  • the present technical problem is solved and the indicated technical results are achieved also thanks to the crystalline form of N,N'-bis-[2-(lH-imidazol-4-yl)ethyl]propanediamide dimesylate, characterized by peak positions in powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 17.3, 20.0 and 21.9.
  • the crystalline form is characterized by peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 17.3, 18.0, 18.2, 20.0, 20.1, 21.4, 21.9, 22.4, 24.1 and 28.1.
  • 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 angle values (deg): 94.39° ⁇ 5.00°, 94.43° ⁇ 5.00°, 111.06° ⁇ 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-(1H-imidazol-4-yl)ethyl]propanediamide dibenzenesulfonate, characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 18.9, 21.4 and 22.9.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 15.7, 18.9, 19.5, 19.9, 21.4, 22.4, 22.9, 24.3 and 25.7.
  • 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°.
  • 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, 2 ⁇ , deg ( ⁇ 0.2°): 21.1, 24.0 and 24.7.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 18.4, 21.1, 23.1, 24.0, 24.7 and 29.7.
  • 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°.
  • 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, 2 ⁇ , deg ( ⁇ 0.2°): 20.8, 23.9 and 25.5.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 16.1, 19.7, 20.8, 22.0, 23.9 and 25.5.
  • 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, 2 ⁇ , deg ( ⁇ 0.2°): 18.2, 24.9 and 29.0.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 18.2, 20.1, 21.7, 22.2, 23.0, 23.2, 23.5, 24.9, 26.2 and 29.0.
  • 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°.
  • 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, 2 ⁇ , deg ( ⁇ 0.2°): 20.5, 22.1 and 25.2.
  • the crystalline form is characterized by the peak positions in the powder X-ray diffraction pattern, 2 ⁇ , deg ( ⁇ 0.2°): 20.0, 20.5, 22.1, 22.6, 23.4, 25.2 and 29.9.
  • 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°.
  • the method for preparing compound 1-48 involves reacting the compound N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide C with the appropriate acid.
  • 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, and in an even more preferred embodiment, in in a ratio of 1:1 to 1:2, even more preferably in a stoichiometric ratio.
  • 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, p-toluenesulfonic, tartaric, citric, benzoic, salicylic and glutamic.
  • a suitable solvent may be selected from an alcohol, ether, haloalkane, aromatic hydrocarbon or nitroalkane.
  • alcohol examples include methyl alcohol (methanol), ethyl alcohol (ethanol), propyl alcohol (propanol), isopropyl alcohol (isopropanol), n-butanol, etc.
  • ethers are diethyl ether (ethoxyethane), tetrahydrofuran (THF), dioxane.
  • haloalkanes are chloroform, methylene chloride.
  • aromatic hydrocarbons examples include benzene, toluene and xylenes.
  • nitroalkanes are nitromethane and nitroethane.
  • 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.
  • the solvent is removed, the residue is dried, and the product is isolated using known physicochemical methods.
  • the solvent is distilled off using a rotary evaporator, the residue is washed with hexane, and then dried to a constant weight.
  • 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.
  • a 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.
  • the pharmaceutical composition of the present invention will also include compositions containing one or more other active pharmaceutical substances.
  • a medicinal product is an active pharmaceutical substance or pharmaceutical composition in the form of a dosage form suitable for use in humans or animals.
  • 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.
  • compound 1-48 is in the pharmaceutical composition or medicinal product in an amount corresponding to the recommended dosage.
  • dosage 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.
  • the pharmaceutical composition and medicament of the present invention can be prepared using known conventional methods in the pharmaceutical field.
  • the pharmaceutical composition and the medicinal product is a composition in the form of a solid form.
  • solid dosage forms are powders, granules, briquettes, capsules, tablets, dragees, etc.
  • 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, possessing 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 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, most often obtained by pressing powders or granules containing one or more active substances with or without the addition of excipients.
  • 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.
  • the pharmaceutical composition is administered orally or sublingually.
  • 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.
  • 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.
  • filler or "diluent” means auxiliary substances used to impart a given volume or weight to solid dosage forms.
  • biners means substances included in the tablet mass to impart the required viscosity.
  • CMC carboxymethyl cellulose
  • OEC oxyethyl cellulose
  • OPMC oxypropyl methyl cellulose
  • PVC polyvinyl alcohol
  • PVP polyvinylpyrrolidone
  • alginic acid sodium alginate, gelatin, etc.
  • the group is not limited to this list.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition and drug is a composition in the form of a liquid form.
  • 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.
  • 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.
  • Routes of administration of liquid dosage forms include, but are not limited to, orally, intranasally, topically, and by injection.
  • 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.
  • 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.
  • solvent means auxiliary substances that allow the product to be brought to a state convenient for use, i.e. give it an optimal viscosity.
  • solvent carrier, diluent
  • water purified
  • ethanol isopropanol
  • polyalcohols buffer solutions
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate
  • thickeners and emulsifiers include, 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.
  • 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.
  • glycerin glycerol
  • PEG 300, PEG 400 polyethylene glycol
  • 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.
  • 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.
  • Corrigents are used to improve taste (sweetener) and smell (flavoring).
  • 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.
  • Compound 1-48 its active pharmaceutical substance, pharmaceutical composition and medicinal product of the present invention can be used 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.
  • the inflammation of the mucous membrane of the upper respiratory tract is associated with rhinitis, or is caused by rhinitis, or is rhinitis.
  • the 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.
  • rhinitis can be acute (acute rhinitis) or chronic (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.
  • inflammation of the mucous membrane of the upper respiratory tract is associated with sinusitis (rhinosinusitis), or caused by sinusitis (rhinosinusitis), or is sinusitis (rhinosinusitis).
  • 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.
  • inflammation of the mucous membrane of the upper respiratory tract is associated with pharyngitis, or is caused by pharyngitis, or is pharyngitis.
  • inflammation of the mucous membrane of the upper respiratory tract is caused by tonsillitis, pharyngotonsillitis or nasopharyngitis.
  • 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.
  • 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.
  • the cough, the treatment and/or prevention of which is the purpose 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.
  • the cough, the treatment and/or prevention of which is the purpose of the present invention refers to a dry cough.
  • 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.
  • 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.
  • 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.
  • Fig. 1 Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrochloride (C 13 H 18 N 6 O 2 * HCl) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • FIG. 2 General view of the unit cell of C 13 H 18 N 6 O 2 * HCl.
  • Fig. 3 Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride hydrate (C 13 H 18 N 6 O 2 * 2 ⁇ l * ⁇ 2 ⁇ ) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig. 5 Experimental diffraction pattern of N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrochloride (C 13 H 18 N 6 O 2 * 2 ⁇ l) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig. 7 Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dihydrobromide (C 13 H 18 N 6 O 2 * 2 HBr) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig. 8 General view of the unit cell of C 13 H 18 N 6 O 2 * 2 ⁇ .
  • Fig.13 Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide dimesylate (C 13 H 18 N 6 O 2 * 2CH3SO3H) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig.14 General view of the unit cell of C 13 H 18 N 6 O 2 * 2CH3SO3H.
  • Fig.15 Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl) ethyl ] propanediamide dibenzenesulfonate ( C13H18N6O2 * 2C6H5SO3H ) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig.16 General view of the unit cell of C 13 H 18 N 6 O 2 * 2C 6 H 5 SO 3 H.
  • Fig.17 Experimental diffraction pattern of N,N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide diformate (C 13 H 18 N 6 O 2 * 2HCOOH) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig.18 Experimental diffraction pattern of N ,N'-bis[2-(1H-imidazol-4-yl)ethyl ] propanediamide succinate ( C13H18N6O2 * C2H4 (COOH) 2 ) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig.19 Experimental diffraction pattern of N,N'-6uc[2-(lH-imidazol-4-yl)ethyl]propanediamide glutarate dihydrate (C 13 H 18 N 6 O 2 * C 3 H 6 (COOH) 2 * 2H 2 O) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig.20 Experimental diffraction pattern of N ,N'-bis[2-(1H-imidazol-4-yl)ethyl ] propanediamide fumarate ( C13H18N6O2 * C2H2 (COOH) 2 ) (blue curve) and theoretical diffraction pattern of the cell calculated for it (red line) and their difference curve (gray line). Vertical dashes indicate calculated peak positions.
  • Fig. 21 Effect of intranasal administration of C 13 H 18 N 6 O 2 * HCl solution on the number of coughs in a model of acute cough induced by capsaicin inhalation in guinea pigs.
  • Fig. 22 Effect of C 13 H 18 N 6 O 2 * HCl solution administered into the pharynx on the number of coughs in a model of acute cough induced by capsaicin inhalation in guinea pigs.
  • 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.
  • 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.
  • 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.
  • the concentration of the resulting solution is 0.4 mg/ml.
  • the shelf life of the solution is 24 hours.
  • 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.
  • Si is the peak area of N, N'-bis-[2-(1 H-imidazol-4-yl)ethyl]propanediamide on the chromatogram of the test solution;
  • P is the content of N, N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide in the substance sample, %.
  • Quantitative determination of the drug is carried out using the potentiometric titration method.
  • Titration is carried out with a 0.1 M sodium hydroxide solution.
  • 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.
  • M eq is the amount of acid ions equivalent to 1 ml of 0.1 M sodium hydroxide solution, g/ml;
  • V k is the volume of titrant used for titration of the control experiment, ml;
  • V i is the volume of titrant used to titrate the test sample, ml;
  • the X-ray phase study was performed on a Bruker D8 Advance X-ray diffractometer (copper radiation C u K ⁇ ) with a LynxEye position-sensitive detector, geometry in reflection, 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.
  • 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%.
  • 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.
  • 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%.
  • Fig. 5 shows the powder X-ray diffraction pattern of the resulting crystalline form.
  • the composition of the crystal is C 13 H 18 N 6 O 2 * 2 ⁇ 1.
  • N N'-bis-[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N 6 O 2 ) were added 10 ml of water with stirring, a suspension was obtained, and 0.76 ml (0.007 mol) of 48% hydrobromic acid, 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
  • 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%.
  • 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 the monoclinic cell.
  • the resulting solution was cooled to room temperature and added to 250 ml of acetone, left for 15 hours at room temperature, the formed precipitate was filtered off, washed with 20 ml of acetone, dried in vacuum over CaCl2 . A white crystalline powder was obtained.
  • 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%.
  • Table 7 lists the positions of the 2 ⁇ 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 is C 13 H 18 N 6 O 2 * 2 ⁇ . Table 7. Intensity and position of some peaks with a relative intensity greater than 3% for the sample.
  • the X-ray diffraction pattern of C 13 H 18 N 6 O 2 * 2 ⁇ Br showed the following intense peaks (maxima) at diffraction angles 2 ⁇ ( ⁇ 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.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 11.8 min.
  • 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%.
  • 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 release time of the individual peak of C 13 H 18 N 6 O 2 is 12.1 min.
  • Quantitative determination of the acid residue in the salt calculated 10.1%, found by acid-base titration method 8.02%.
  • 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%.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 12.1 min.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 12.1 min.
  • 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%.
  • Fig. 13 shows the powder X-ray diffraction pattern of the resulting crystalline form. Indexing of the diffraction pattern showed that the substance crystallizes in a triclinic cell.
  • 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%.
  • 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 using the Pauli method: sp. gr.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 10.2 min.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 10.2 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 12.1 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 12.1 min.
  • 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%.
  • 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 release time of the individual peak of C 13 H 18 N 6 O 2 is 12.1 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 11.5 min.
  • Fig. 18 shows the powder X-ray diffraction pattern of the resulting crystalline form.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 10.2 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 10.2 min.
  • 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%.
  • 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 release time of the individual peak of C 13 H 18 N 6 O 2 is 12.1 min.
  • 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%.
  • the resulting solution was cooled to room temperature and 200 ml of acetone were added to the solution, and the solution was left at room temperature for 24 hours.
  • the resulting precipitate was filtered, washed with 100 ml of acetone, and dried in a vacuum over CaCl 2 . A white crystalline powder was obtained.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 10.2 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 11.8 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 11.5 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 11.2 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 11.6 min.
  • 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%.
  • the release time of the individual peak of C 13 H 18 N 6 O 2 is 11.6 min.
  • 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%.
  • 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%.
  • N N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide malate (molar ratio 1:1)
  • N N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide (C 13 H 18 N 6 O 2 )
  • 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.
  • 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%.
  • Relative humidity 60 + 5%; Amount of substance 1.0 g
  • 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.
  • Example 1 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.
  • 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.
  • the concentration of the resulting solution is 8.0 ⁇ g/ml (histamine).
  • the stability study results are presented in Table 22.
  • the animals were inhaled with a capsaicin solution (30 ⁇ M) prepared in a mixture of ethanol and Tween-80 for 5 minutes using a compression nebulizer.
  • N, N'-bis[2-(1H-imidazol-4-yl)ethyl]propanediamide hydrochloride (C 13 H 18 N 6 O 2 * HCl) as a 1% solution was administered intranasally once, using a dispenser, 10 ⁇ l into each nostril, 5 minutes before capsaicin inhalation, and once, using a bottle with a spray dosing nozzle, into the throat in a volume of 50 ⁇ l, 5 minutes before capsaicin inhalation.
  • the control animals were administered the solvent.
  • the intact group was not administered anything.
  • Antitussive activity was assessed by counting the number of attacks cough within 15 minutes from the start of capsaicin inhalation. The results are shown in Fig. 21 and Fig. 22.

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Abstract

L'invention concerne des composés 1-48, des compositions pharmaceutiques les contenant, et des formulations médicamenteuses qui peuvent être utilisées pour le traitement et/ou la prévention de la toux. Le résultat technique consiste en une augmentation de la stabilité sous forme solide et en solution, une augmentation de l'efficacité thérapeutique et une amélioration de la biodisponibilité, une diminution du nombre d'effets secondaires, et la possibilité de produire une formulation médicamenteuse intra-nasale liquide stable.
PCT/RU2024/050280 2023-11-03 2024-11-01 Nouveaux composés Pending WO2025095813A1 (fr)

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WO2008135819A1 (fr) * 2007-03-16 2008-11-13 Pfizer Limited Sel hydrochlorure de 5-r3-f3-tivdroxyphénoxy)azétidin-1-yl]-5-méthyl-2,2- diphénylhexanamide
RU2665688C2 (ru) * 2013-04-12 2018-09-04 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Производные бисамидов дикарбоновых кислот, их применение, фармацевтическая композиция на их основе, способы их получения
WO2019226082A1 (fr) * 2018-05-24 2019-11-28 Общество с ограниченной ответственностью "Фарминтерпрайсез Аллерджи" Utilisation d'un dérivé bisamide d'acide malonique pour traiter des maladies allergique ou autres de l'humain et des animaux

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WO2008135819A1 (fr) * 2007-03-16 2008-11-13 Pfizer Limited Sel hydrochlorure de 5-r3-f3-tivdroxyphénoxy)azétidin-1-yl]-5-méthyl-2,2- diphénylhexanamide
RU2665688C2 (ru) * 2013-04-12 2018-09-04 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Производные бисамидов дикарбоновых кислот, их применение, фармацевтическая композиция на их основе, способы их получения
WO2019226082A1 (fr) * 2018-05-24 2019-11-28 Общество с ограниченной ответственностью "Фарминтерпрайсез Аллерджи" Utilisation d'un dérivé bisamide d'acide malonique pour traiter des maladies allergique ou autres de l'humain et des animaux

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