WO2019112483A1 - Nobazit cristallin sous forme de système cristallographique en losange et procédé de sa fabrication - Google Patents

Nobazit cristallin sous forme de système cristallographique en losange et procédé de sa fabrication Download PDF

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Publication number
WO2019112483A1
WO2019112483A1 PCT/RU2018/000802 RU2018000802W WO2019112483A1 WO 2019112483 A1 WO2019112483 A1 WO 2019112483A1 RU 2018000802 W RU2018000802 W RU 2018000802W WO 2019112483 A1 WO2019112483 A1 WO 2019112483A1
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Prior art keywords
nobazite
nobasite
sample
rule
purity
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PCT/RU2018/000802
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English (en)
Russian (ru)
Inventor
Денис Владимирович РЕМЕНЯКО
Елена Васильевна Ткаченко
Юрий Андреевич КРЮКОВ
Алла Ивановна РОГОВА
Сергей Викторович СЫСОЛЯТИН
Original Assignee
Открытое акционерное общество "Авексима"
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Publication of WO2019112483A1 publication Critical patent/WO2019112483A1/fr

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • Nobazite K-methyl-4-benzylcarbamidopyridinium iodide, enisamium iodide
  • Nobazite K-methyl-4-benzylcarbamidopyridinium iodide, enisamium iodide
  • SUBSTITUTE SHEET (RULE 26) goals need to have a scalable, easily reproducible production process.
  • the invention SU 583612 (1975) describes the synthesis of nobazite for pharmaceutical use, but there is no description of the reproducibility of the preparation of the substance.
  • the objective of the claimed invention is to develop a method of obtaining nobazita in the form of a rhombic syngony, which would provide a substance with a high degree of purity that meets the requirements for subsequent pharmaceutical use.
  • the present invention relates to a novel crystalline form of nobazite in the form of a rhombic syngony and a method for producing it.
  • the following characteristics inherent in x-ray diffraction and X-ray phase analysis methods, are inherent in the nobazitu ristastic in the form of a rhombic syngony.
  • the Cambridge database has searched for crystal structures of compounds containing a cation similar to the cation of the claimed substance (CSD, version 5.38, November 2016 [Groom, S. R., Bruno, IJ, Lightfoot, M. R. & Ward, S. S. Acta Cryst, 2016, B72, 171-179.]). Crystal structures containing the cation [MeC 5 H 4 NCONHCH2C6H5] + were not found, which confirms the scientific novelty of the claimed invention.
  • the crystalline nobazite in the form of a rhombic system is obtained by a method which, in accordance with the present invention, consists of the following stages:
  • the solvent is selected from the group consisting of dimethyl sulfoxide, water, methanol, acetonitrile, acetone, dimethylformamide, ethanol and isopropanol, as well as mixtures thereof.
  • Nobazite crystal in the form of a rhombic syngony has the following parameters, determined using X-ray diffraction and X-ray phase analysis methods.
  • the crystal structure of nobazite is determined.
  • ⁇ -methyl-4-benzylcarbamidopyridinium iodide obtained in accordance with the present invention has a purity of at least 99.7% and preferably at least 99.9%, as determined by HPLC.
  • SUBSTITUTE SHEET (RULE 26) is 3.3% (Table 1).
  • Other data acquisition parameters (absorption coefficients, diffraction angles, number of collected and strong reflexes), shown in Table 1, also meet the standards for the qualitative determination of the structure.
  • the decryption of the crystal structure by the direct method was carried out in the SHELXS program, the refinement by the full-matrix least squares method in the SHELXL2014 / 6 program [Sheldrick, G.M. Acta Cryst., 2015, C71, 3-8]. All non-hydrogen atoms were refined in the anisotropic approximation. The position of the hydrogen of the amide group involved in the hydrogen bond was found from the difference Fourier synthesis, and it was refined in the isotropic approximation.
  • the independent part of the unit cell contains one cation of the organic molecule and one anion of iodine (Fig. 1). Cation and anion form
  • SUBSTITUTE SHEET (RULE 26) strong hydrogen bonded ion pair Thermal ellipsoids are shown at a 50% probability level. Hydrogen atoms are depicted with an arbitrary radius. The hydrogen bond is shown by a dashed blue line.
  • Table 2 shows the coordinates of the atoms in the independent part of the unit cell in fractions of the parameters of the unit cell and the equivalent or isotropic thermal parameters.
  • the thermal parameters of non-hydrogen atoms in the anisotropic approximation are presented in Table 3.
  • Symmetry codes (i) x + 1/2, -y + 1/2, -z + 1; (ii) x + 1, y, z.
  • the central part of the nobazite molecule obtained by the claimed method and the pyridine ring lie almost in the same plane (the exit of atoms from the N2-C8-O1-C9-C10-C11-N1-C12-C13 plane is on average 0.015 A, the maximum is 0.025 (3 ) BUT).
  • the iodine anion is located close to this plane (the distance to the N2 – C8 – O1 – C9 – C10 – C11 – N1 – C12 – C13 – 0.504 (3) A) plane.
  • the dihedral angle between the planes of the pyridine and benzene rings is 117.2 (1) ° (Fig. 2), or 62.8 (1) ° from a formal point of view.
  • the nobasite obtained in accordance with the present invention has a purity of at least 99.7% and preferably at least 99.9%, as determined by HPLC. Such a high degree of purity could not be obtained according to the prior art. This was made possible by using a method in accordance with the present invention to significantly reduce the intermediate substance in the final product.
  • Nobazite crystalline in the form of a rhombic syngony is obtained by a method which, in accordance with the present invention, consists of the following stages:
  • the product of the reaction namely 4-carbamidobenzpyridine, is released from the reaction mixture by the addition of toluene.
  • the reaction mixture is dissolved in toluene, filtered from unreacted 4-pyridinecarboxylic acid, cooled, and 4-carbamide-benzpyridine is filtered off.
  • T4-methyl-4-benzylcarbamidopyridinium iodide crystallizes in rhombic syngony using a wide range of solvents listed in Table 8:
  • FIG. 1 Molecular structure of nobasite with numbering of non-hydrogen atoms
  • FIG. 2 Type of nobazite molecule with planes of aromatic rings
  • FIG. 3 Fragments of the crystal structure of nobazite in a projection along the crystallographic axis b (a) and axis a (b). Hydrogen bonds are shown by a dotted line.
  • FIG. 4 Diffractogram of sample l of nobazite (Table 8). Crystallization from DMSO
  • FIG. 5 Diffraction pattern of sample M2 of nobazite (Table 8). Water crystallization
  • FIG. 6 The diffractogram of sample M3 of nobazite (Table 8). Crystallization from methanol
  • FIG. 7 Diffraction pattern of sample M4 of nobazite (Table 8). Crystallization from acetonitrile
  • FIG. 8 The diffractogram of sample No5 Basitum (Table 8). Crystallization from 90% acetone
  • FIG. 9 Diffractogram of sample MB of nobazite (Table 8). Crystallization from DMF
  • FIG. 10 Diffractogram of sample M7 of nobazite (Table 8).
  • FIG. 11 Diffraction pattern of sample M8 nobazite (Table 8).
  • FIG. 12 Diffractograms without background: a - theoretical, bs - samples
  • FIG. 13 Diffraction pattern of sample M9 nobazita (tab. 8). The theoretically calculated diffractogram is shown in red.
  • FIG. 14 IR spectra of sample Nobasite Ml (Table 8)
  • FIG. 15 IR spectra of sample No2 basitas (Table 8)
  • FIG. 17 IR spectra of sample no. 4 of nobasite (Table 8)
  • FIG. 18 IR spectra of sample no. 5 of nobazite (Table 8)
  • FIG. 19 IR spectra of sample Nobasite JV26 (Table 8)
  • FIG. 20 IR spectra of sample Ni »7 nobasite (tab. 8)
  • FIG. 21 IR spectra of sample no. 8 of nobazite (Table 8)
  • FIG. 22 DSC diagram of sample no. 1 of nobazite (Table 8)
  • FIG. 23 DSC diagram of sample N22 of nobazite (Table 8)
  • FIG. 24 DSC diagram of sample N "3 nobasite (Table 8)
  • FIG. 25 DSC-diagram of sample J ®4 nobasite (tab. 8)
  • FIG. 26 DSC-diagram of sample No5 nobasite (Table 8)
  • FIG. 27 DSC diagram of sample N "6 nobasite (Table 8)
  • FIG. 28 DSC diagram of sample e7 nobazite (Table 8)
  • FIG. 29 DSC diagram of sample no. 8 of nobazite (Table 8)
  • FIG. 30 PMR spectrum of nobasite
  • IR spectrum (cm): 611.27, 631.44, 703.72, 777.41, 759.32, 860.4, 920.77, 960.85, 1020.8, 1078.2, 1147.6, 1187.8, 1618.8, 1285.4, 1329.8, 1416.4, 1452.5, 1505.1, 1541.1, 1571.6, 1629.8, 1616.4, 1452.5, 1505.1, 1516.4, 1452.5, 1505.1, 1541.4, 1452.5, 1505.1, 1516.4, 1452.5, 1509.1, 1516.4, 1452.5, 1505.1, 1541.4, 1452.5, 1505.1, 1516.4, 1452.5, 1505.1, 1516.4, 1452.5, 1505.1, 1516.4, 1452.5, 1505.1, 1516.4 , 1828.1, 1950.9, 2828.6, 2936.6, 3040.4, 3237.6.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne une nouvelle forme cristalline d'iodure d'Enisamium (carbabenzpyride) ayant la formule (I) et notamment un système cristallographique en losange dans un groupe de symétrie spatiale Р2 1 2 1 2 1 avec les paramètres suivants de la cellule élémentaire : а = 9,2867(2) Å; b = 10,8741(2) Å; с = 14,3038(3) Å; V= 1444,46(5) Å3; Z = 4, et son procédé de fabrication. L'invention peut être utilisée en tant que substance pour produire des médicaments utilisés dans le traitement ou la prévention d'infections virales.
PCT/RU2018/000802 2017-12-06 2018-12-05 Nobazit cristallin sous forme de système cristallographique en losange et procédé de sa fabrication WO2019112483A1 (fr)

Applications Claiming Priority (2)

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EA201792455 2017-12-06
EA201792455A EA201792455A1 (ru) 2017-12-06 2017-12-06 Нобазит кристаллический в форме ромбической сингонии и способ его получения

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2815779C1 (ru) * 2022-11-14 2024-03-21 Открытое акционерное общество "Авексима" Применение композиции, включающей действующее вещество энисамия йодид

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2429230C1 (ru) * 2010-05-27 2011-09-20 Учреждение Российской академии наук Институт проблем химико-энергетических технологий Сибирского отделения РАН (ИПХЭТ СО РАН) Способ получения n-метил-4-бензилкарбамидопиридиния йодида
WO2011157743A1 (fr) * 2010-06-17 2011-12-22 Farmak International Holding Gmbh Forme cristalline alpha du carbabenzpyride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2429230C1 (ru) * 2010-05-27 2011-09-20 Учреждение Российской академии наук Институт проблем химико-энергетических технологий Сибирского отделения РАН (ИПХЭТ СО РАН) Способ получения n-метил-4-бензилкарбамидопиридиния йодида
WO2011157743A1 (fr) * 2010-06-17 2011-12-22 Farmak International Holding Gmbh Forme cristalline alpha du carbabenzpyride

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CAIRA ED - MONTCHAMP JEAN-LUC: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022 *
HILFIKER R (EDITOR) ED - HILFIKER R: "Polymorphism in the Pharmaceutical Industry", 1 January 2006, 20060101, PAGE(S) 1 - 19, ISBN: 978-3-527-31146-0, XP002528052 *
T A BUKHTIAROVA ET AL: "STRUCTURE AND ANTIINFLAMMATORY ACTIVITY OF ISONICOTINIC AND NICOTINIC AMIDES Physicochemical Properties and Antiinflammatory Activity of Pyridinecarboxylic Amides", 1 November 1997 (1997-11-01), pages 30 - 32, XP055579526, Retrieved from the Internet <URL:https://link.springer.com/content/pdf/10.1007/BF02464277.pdf> *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2815779C1 (ru) * 2022-11-14 2024-03-21 Открытое акционерное общество "Авексима" Применение композиции, включающей действующее вещество энисамия йодид

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