WO2016120332A1 - Silver complex compound, the method of preparation of the complex compound and the use of the complex compound - Google Patents

Silver complex compound, the method of preparation of the complex compound and the use of the complex compound Download PDF

Info

Publication number
WO2016120332A1
WO2016120332A1 PCT/EP2016/051710 EP2016051710W WO2016120332A1 WO 2016120332 A1 WO2016120332 A1 WO 2016120332A1 EP 2016051710 W EP2016051710 W EP 2016051710W WO 2016120332 A1 WO2016120332 A1 WO 2016120332A1
Authority
WO
WIPO (PCT)
Prior art keywords
silver
compound
metronidazole
acid
complex compound
Prior art date
Application number
PCT/EP2016/051710
Other languages
French (fr)
Inventor
Justyn Ochocki
Urszula Kalinowska-Lis
Original Assignee
Uniwersytet Medyczny W Lodzi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Uniwersytet Medyczny W Lodzi filed Critical Uniwersytet Medyczny W Lodzi
Publication of WO2016120332A1 publication Critical patent/WO2016120332A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/16—Heavy metals; Compounds thereof

Definitions

  • the invention relates to a silver complex compound, a method of preparation of the silver compound and the use of the silver compound.
  • compositions containing metronidazole and silver compounds are known.
  • International application WO 97/02038 discloses pharmaceutical compositions containing metronidazole and a stabilised silver composition prepared from silver nitrate and sodium chloride (proportion of chloride ions and silver ions - 18.5: 1) in poly(ethylene glycol).
  • Compositions according to WO 97/02038 are intended to combat pathogenic microorganisms.
  • the aim of the invention is to provide a complex compound of silver and metronidazole, a method of preparation of the silver compound and the use of the silver complex compound.
  • the silver complex compound is a complex compound of silver and metronidazole.
  • the complex comprises silver and metronidazole in a molar ratio of 1 :2.
  • the compound comprises silver in a formal oxidation state of +1, coordinated by metronidazole, and comprises a counterion which is an anion of an acid selected from the group consisting of hardly oxidisable oxygen inorganic acids, tetrafluoroboric acid, optionally-halogenated carboxylic acids, optionally-halogenated organic sulphonic acids.
  • the counterion is, in particular, an anion of an acid selected from the group consisting of nitric (V) acid, chloric (VII) acid, trifluoroacetic acid, tetrafluoroboric acid, methanesulphonic acid.
  • the method of preparation of the complex compound of silver and metronidazole according to the invention is characterised in that metronidazole and a silver (I) compound are used as reagents, wherein the silver (I) compound is at least partially soluble in a reaction medium, the reagents are introduced together to a reaction medium comprising a hydroxylic solvent at a temperature of 5-90°C, the reaction is conducted for 1-180 minutes while maintaining the temperature of 5-90°C, optionally mechanically stimulating the reaction medium, and then the complex compound of silver and metronidazole is extracted.
  • At least one hydroxylic solvent is used, wherein it is selected from the group consisting of inorganic hydroxylic solvents, organic hydroxylic solvents and mixtures thereof, and in particular a hydroxylic solvent selected from the group consisting of water, lower aliphatic alcohols and mixtures thereof.
  • the silver (I) compound and metronidazole in a molar ratio of 1 : 2 are used, and the reaction is conducted for 5-120 minutes while maintaining a temperature of 40-80°C, in particular for 30 minutes at a temperature of 60°C.
  • a compound selected from the group consisting of silver (I) nitrate (V), silver (I) chloride (VII), silver (I) trifluoroacetate, silver (I) tetrafluoroborate, silver (I) methanesulphonate is used as the silver (I) compound.
  • the compound as defined above, is used for the preparation of a formulation for inhibiting the growth of pathogenic microorganisms, in the prophylaxis or treatment of the animal or human organism.
  • the silver complex compound is prepared by the method according to the invention, in a preferred embodiment in a one-step process, particularly preferably in a mixture of water and ethanol, and therefore without having to use toxic organic solvents. Furthermore, the process is highly effective, fast and is conducted under mild conditions, and therefore does not require sophisticated equipment and service.
  • the silver complex compound according to the invention has preferable therapeutic and physicochemical properties (for example, it is easily dissolved in water, but also in organic solvents), which facilitates the use of the compound according to the invention as an additive to formulations or medical materials, such as formulations and materials intended for use, among others, in dermatology, dentistry, laryngology, ophthalmology and surgery.
  • the compound according to the invention may be used as a bactericidal and/or fungicidal agent added to ointments, gels, lotions, etc. intended for external use, and as an active ingredient introduced into wound dressing materials.
  • Fig. 1 shows the structure of compound 1 according to the invention
  • Fig. 2 shows the structure of compound 2 according to the invention
  • Fig. 3 shows the structure of compound 3 according to the invention
  • Fig. 4 shows the crystal structure of compound 4 according to the invention
  • Fig. 5 shows the crystal structure of compound 5 according to the invention.
  • a silver complex compound according to the invention is prepared in the reaction of a silver (I) compound with metronidazole, i.e. 1- (2-hydroxyethyl) -2- methyl-5-nitroimidazole of the following formula I,
  • reaction medium comprising at least one hydroxylic polar solvent
  • metronidazole is also denoted by symbol: MTZ.
  • hydroxylic solvent comprises a solvent having a hydroxyl group (-OH) and not containing nitrogen substituents with nitrogen atoms having a lone pair of electrons (since the presence of these groups may adversely affect the reaction of the silver (I) compound with metronidazole).
  • the hydroxylic solvent is a solvent selected from the group consisting of inorganic hydroxylic solvents and organic hydroxylic solvents, and also mixtures thereof, and in particular a solvent selected from the group consisting of water, lower aliphatic alcohols and any mixtures of water and lower aliphatic alcohols.
  • the hydroxylic solvent is selected from the group consisting of water, especially purified water, such as demineralised water or distilled water, ethanol and mixtures of water and ethanol.
  • the silver (I) compound used in the method according to the invention is a silver (I) compound at least partially soluble in a reaction medium comprising at least one hydroxylic solvent.
  • the silver (I) compound has a counterion which is an anion of an acid selected from the group consisting of hardly oxidisable oxygen inorganic acids, tetrafluoroboric acid, optionally-halogenated carboxylic acids, optionally-halogenated organic sulphonic acids.
  • Examples of the acid selected from the group consisting of hardly oxidisable oxygen inorganic acids are acids in which the central atom of the element, surrounded by oxygen atoms, is in oxidation state of +5, +6 or +7, such as chloric (V) acid, chloric (VII) acid, sulphuric(VI) acid, nitric (V) acid.
  • optionally-halogenated carboxylic acid examples include optionally-halogenated monocarboxylic acid, dicarboxylic acid and tricarboxylic acid, such as lactic acid, acetic acid, trifluoroacetic acid, succinic acid, tartaric acid, citric acid.
  • optionally-halogenated sulphonic acid examples include methanesulphonic acid, ethanesulphonic acid, trifluoromethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid.
  • the silver compound is a compound selected from the group consisting of silver (I) nitrate (V), silver (I) chloride (VII), silver (I) trifluoroacetate, silver (I) acetate, silver (I) tetrafluoroborate, silver (I) methanesulphonate, silver (I) trifluoromethanesulphonate.
  • the reagents i.e. the silver (I) compound and metronidazole
  • the silver (I) compound and metronidazole are introduced together to a reaction medium in substantially any ratio.
  • the silver (I) compound and metronidazole are introduced together in a molar ratio close to 1 :2, preferably around 1 :2.
  • the molar ratio should be understood as the ratio of the number of moles of silver ions Ag + to the number of moles of metronidazole.
  • the reaction is conducted at a temperature of 5-90°C, for 1-180 minutes, optionally with mechanical stimulation of the reaction medium, for example by stirring.
  • the reaction is conducted for 5-120 minutes at a temperature of 40-80°C, especially at the temperature of approximately 60°C for about 30 minutes.
  • the silver complex compound is extracted, for example by evaporating a part of the solvent under reduced pressure and leaving the concentrated solution to crystallise.
  • a special property of silver complex compounds according to the invention is the presence, in the structure of the molecule, of two different factors inhibiting the growth of microorganisms, i.e. ionised silver and metronidazole.
  • the ionised silver has a very broad spectrum of antimicrobial, antibacterial and antiviral actions (which is disclosed by N. Grier, "Silver and Its Compounds", in Disinfection, Sterilisation and Preservation, ed. 3, S.S. Block, Philadelphia Ch., p. 395, 1983).
  • WO 97/02038 discloses that a composition containing silver ions and metronidazole exhibits, among others, action against Staphylococcus aureus and Escherichia coli (p. 44). Therefore, silver complex compounds according to the invention can be used as bactericidal and fungicidal compounds, among others, in dermatology, dentistry, laryngology, ophthalmology and surgery.
  • An advantageous feature of the compounds according to the invention is good solubility in water, which ensures easier application and more effective operation in aqueous medium, and therefore also in the environment of bodily fluids.
  • Example 1 Compound 1 - [Ag(MTZ) 2 N0 3 ] Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C. The reaction flask with this solution is placed on a magnetic stirrer. 10.5 ml of ethanol-aqueous solution (in the volume ratio of EtOH/H 2 0 of 20: 1) of silver (I) nitrate (V) AgNOs (1 mmol, 0.170 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes.
  • reaction mixture is protected against light with a cover of aluminum foil. Then, the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume. The concentrated solution is allowed to crystallise at room temperature. The resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 87%).
  • Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C.
  • the reaction flask with this solution is placed on a magnetic stirrer.
  • 15 ml of ethanol solution of silver (I) chlorate (VII) AgC10 4 (1 mmol, 0.208 g) is once added to the solution of metronidazole, and it is stirred at the temperature of 60°C for 30 minutes.
  • the reaction mixture is protected against light with a cover of aluminum foil.
  • the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume.
  • the concentrated solution is allowed to crystallise at room temperature.
  • the resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 78%).
  • Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C.
  • the reaction flask with this solution is placed on a magnetic stirrer.
  • 15 ml of ethanol solution of silver (I) trifluoroacetate Ag(CF 3 COO) (1 mmol, 0.221 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes.
  • the reaction mixture is protected against light with a cover of aluminum foil.
  • the reaction mixture is evaporated in a rotary evaporator under reduced pressure at the temperature of 60°C to half its volume.
  • the concentrated solution is allowed to crystallise at room temperature.
  • the resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 77%).
  • Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C.
  • the reaction flask with this solution is placed on a magnetic stirrer.
  • 15 ml of ethanol solution of silver (I) tetrafluoroborate AgBF 4 (1 mmol, 0.195 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes.
  • the reaction mixture is protected against light with a cover of aluminum foil.
  • the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume.
  • the concentrated solution is allowed to crystallise at room temperature.
  • the resulting crystals are separated from the solution, by decanting it, are washed with dry diethyl ether, and are dried in air (efficiency of 88%).
  • Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C.
  • the reaction flask with this solution is placed on a magnetic stirrer.
  • 20 ml of ethanol-aqueous solution (in the volume ratio of EtOH/H 2 0 of 1 : 1) of silver methylsulphonate AgS0 3 CH 3 (1 mmol, 0.203 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes.
  • the reaction mixture is protected against light with a cover of aluminum foil.
  • the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume.
  • the concentrated solution is allowed to crystallise at room temperature.
  • the resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 83%

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pest Control & Pesticides (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Epidemiology (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a complex compound of silver and metronidazole, a method of preparation of this compound and the use of the compound for the preparation of a formulation for inhibiting the growth of pathogenic microorganisms, in the prophylaxis or treatment of the animal or human organism. In the method of preparation of the complex compound of silver and metronidazole, metronidazole and a silver (I) compound are used as reagents, wherein the silver (I) compound is at least partially soluble in a reaction medium. The reagents are introduced together to a reaction medium comprising a hydroxylic solvent at a temperature of 5-90°C, the reaction is conducted for 1-180 minutes while maintaining the temperature of 5-90°C, optionally mechanically stimulating the reaction medium, and then the complex compound of silver and metronidazole is extracted.

Description

Silver complex compound, the method of preparation of the complex compound and the use of the complex compound
The invention relates to a silver complex compound, a method of preparation of the silver compound and the use of the silver compound.
Pharmaceutical compositions containing metronidazole and silver compounds are known. International application WO 97/02038 discloses pharmaceutical compositions containing metronidazole and a stabilised silver composition prepared from silver nitrate and sodium chloride (proportion of chloride ions and silver ions - 18.5: 1) in poly(ethylene glycol). Compositions according to WO 97/02038 are intended to combat pathogenic microorganisms.
The aim of the invention is to provide a complex compound of silver and metronidazole, a method of preparation of the silver compound and the use of the silver complex compound.
According to the invention, the silver complex compound is a complex compound of silver and metronidazole. Preferably, the complex comprises silver and metronidazole in a molar ratio of 1 :2. In particular, the compound comprises silver in a formal oxidation state of +1, coordinated by metronidazole, and comprises a counterion which is an anion of an acid selected from the group consisting of hardly oxidisable oxygen inorganic acids, tetrafluoroboric acid, optionally-halogenated carboxylic acids, optionally-halogenated organic sulphonic acids. The counterion is, in particular, an anion of an acid selected from the group consisting of nitric (V) acid, chloric (VII) acid, trifluoroacetic acid, tetrafluoroboric acid, methanesulphonic acid.
The method of preparation of the complex compound of silver and metronidazole according to the invention is characterised in that metronidazole and a silver (I) compound are used as reagents, wherein the silver (I) compound is at least partially soluble in a reaction medium, the reagents are introduced together to a reaction medium comprising a hydroxylic solvent at a temperature of 5-90°C, the reaction is conducted for 1-180 minutes while maintaining the temperature of 5-90°C, optionally mechanically stimulating the reaction medium, and then the complex compound of silver and metronidazole is extracted. Preferably, at least one hydroxylic solvent is used, wherein it is selected from the group consisting of inorganic hydroxylic solvents, organic hydroxylic solvents and mixtures thereof, and in particular a hydroxylic solvent selected from the group consisting of water, lower aliphatic alcohols and mixtures thereof.
Preferably, the silver (I) compound and metronidazole in a molar ratio of 1 : 2 are used, and the reaction is conducted for 5-120 minutes while maintaining a temperature of 40-80°C, in particular for 30 minutes at a temperature of 60°C. In particular, a compound selected from the group consisting of silver (I) nitrate (V), silver (I) chloride (VII), silver (I) trifluoroacetate, silver (I) tetrafluoroborate, silver (I) methanesulphonate is used as the silver (I) compound.
According to the invention, the compound, as defined above, is used for the preparation of a formulation for inhibiting the growth of pathogenic microorganisms, in the prophylaxis or treatment of the animal or human organism.
The silver complex compound is prepared by the method according to the invention, in a preferred embodiment in a one-step process, particularly preferably in a mixture of water and ethanol, and therefore without having to use toxic organic solvents. Furthermore, the process is highly effective, fast and is conducted under mild conditions, and therefore does not require sophisticated equipment and service.
The silver complex compound according to the invention has preferable therapeutic and physicochemical properties (for example, it is easily dissolved in water, but also in organic solvents), which facilitates the use of the compound according to the invention as an additive to formulations or medical materials, such as formulations and materials intended for use, among others, in dermatology, dentistry, laryngology, ophthalmology and surgery. Furthermore, the compound according to the invention may be used as a bactericidal and/or fungicidal agent added to ointments, gels, lotions, etc. intended for external use, and as an active ingredient introduced into wound dressing materials. The object of the invention is illustrated in the accompanying drawing, wherein Fig. 1 shows the structure of compound 1 according to the invention, Fig. 2 shows the structure of compound 2 according to the invention, Fig. 3 shows the structure of compound 3 according to the invention, Fig. 4 shows the crystal structure of compound 4 according to the invention, and Fig. 5 shows the crystal structure of compound 5 according to the invention.
A silver complex compound according to the invention is prepared in the reaction of a silver (I) compound with metronidazole, i.e. 1- (2-hydroxyethyl) -2- methyl-5-nitroimidazole of the following formula I,
Figure imgf000004_0001
Formula I
by introducing said reagents together to a reaction medium comprising at least one hydroxylic polar solvent.
Within the description of the invention, metronidazole is also denoted by symbol: MTZ.
Within the description of the invention and the patent claims, term hydroxylic solvent comprises a solvent having a hydroxyl group (-OH) and not containing nitrogen substituents with nitrogen atoms having a lone pair of electrons (since the presence of these groups may adversely affect the reaction of the silver (I) compound with metronidazole). Preferably, the hydroxylic solvent is a solvent selected from the group consisting of inorganic hydroxylic solvents and organic hydroxylic solvents, and also mixtures thereof, and in particular a solvent selected from the group consisting of water, lower aliphatic alcohols and any mixtures of water and lower aliphatic alcohols. Particularly preferably, the hydroxylic solvent is selected from the group consisting of water, especially purified water, such as demineralised water or distilled water, ethanol and mixtures of water and ethanol. The silver (I) compound used in the method according to the invention is a silver (I) compound at least partially soluble in a reaction medium comprising at least one hydroxylic solvent. Preferably, the silver (I) compound has a counterion which is an anion of an acid selected from the group consisting of hardly oxidisable oxygen inorganic acids, tetrafluoroboric acid, optionally-halogenated carboxylic acids, optionally-halogenated organic sulphonic acids.
Examples of the acid selected from the group consisting of hardly oxidisable oxygen inorganic acids are acids in which the central atom of the element, surrounded by oxygen atoms, is in oxidation state of +5, +6 or +7, such as chloric (V) acid, chloric (VII) acid, sulphuric(VI) acid, nitric (V) acid.
Examples of the optionally-halogenated carboxylic acid are optionally- halogenated monocarboxylic acid, dicarboxylic acid and tricarboxylic acid, such as lactic acid, acetic acid, trifluoroacetic acid, succinic acid, tartaric acid, citric acid.
Examples of the optionally-halogenated sulphonic acid are methanesulphonic acid, ethanesulphonic acid, trifluoromethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid.
Particularly preferably, the silver compound is a compound selected from the group consisting of silver (I) nitrate (V), silver (I) chloride (VII), silver (I) trifluoroacetate, silver (I) acetate, silver (I) tetrafluoroborate, silver (I) methanesulphonate, silver (I) trifluoromethanesulphonate.
To prepare the compound according to the invention, the reagents, i.e. the silver (I) compound and metronidazole, are introduced together to a reaction medium in substantially any ratio. However, to achieve high efficiency (relative to the level of charge of the two reagents) and to ensure a high purity of the final silver complex compound, the silver (I) compound and metronidazole are introduced together in a molar ratio close to 1 :2, preferably around 1 :2. The molar ratio should be understood as the ratio of the number of moles of silver ions Ag+ to the number of moles of metronidazole.
The reaction is conducted at a temperature of 5-90°C, for 1-180 minutes, optionally with mechanical stimulation of the reaction medium, for example by stirring. Preferably, the reaction is conducted for 5-120 minutes at a temperature of 40-80°C, especially at the temperature of approximately 60°C for about 30 minutes. Then, the silver complex compound is extracted, for example by evaporating a part of the solvent under reduced pressure and leaving the concentrated solution to crystallise.
Thereby, according to the invention, complex compounds of silver and metronidazole are provided. A special property of silver complex compounds according to the invention is the presence, in the structure of the molecule, of two different factors inhibiting the growth of microorganisms, i.e. ionised silver and metronidazole. The ionised silver has a very broad spectrum of antimicrobial, antibacterial and antiviral actions (which is disclosed by N. Grier, "Silver and Its Compounds", in Disinfection, Sterilisation and Preservation, ed. 3, S.S. Block, Philadelphia Ch., p. 395, 1983). The combination of different agents exhibiting anti-microorganism activity provides a wide range of actions, which in the case of the compounds according to the invention can allow for treatment of mixed infections, i.e. those caused by both aerobic and anaerobic bacteria, as the second component, metronidazole, exhibits actions against anaerobic bacteria. WO 97/02038 discloses that a composition containing silver ions and metronidazole exhibits, among others, action against Staphylococcus aureus and Escherichia coli (p. 44). Therefore, silver complex compounds according to the invention can be used as bactericidal and fungicidal compounds, among others, in dermatology, dentistry, laryngology, ophthalmology and surgery. An advantageous feature of the compounds according to the invention (in contrast to the known agent which is the reference drug - silver sulphadiazine: Flamazine, Dermazin) is good solubility in water, which ensures easier application and more effective operation in aqueous medium, and therefore also in the environment of bodily fluids.
The invention is illustrated in greater detail by the following examples according to which complex compounds of silver and metronidazole are prepared. Example 1. Compound 1 - [Ag(MTZ)2N03] Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C. The reaction flask with this solution is placed on a magnetic stirrer. 10.5 ml of ethanol-aqueous solution (in the volume ratio of EtOH/H20 of 20: 1) of silver (I) nitrate (V) AgNOs (1 mmol, 0.170 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes. The reaction mixture is protected against light with a cover of aluminum foil. Then, the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume. The concentrated solution is allowed to crystallise at room temperature. The resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 87%).
Properties of the compound: colourless crystals (melting point of 151- 152°C); soluble in water, methanol, ethanol, acetone, dimethyl sulphoxide.
The thus obtained product was subjected to elemental analysis on the content of C, H and N, the results of which confirm the total formula of compound [Ag(MTZ)2N03] (Ci2Hi8N709Ag).
Elemental analysis: Ci2Hi8N709Ag (512.24)
Calculated: %C 28.14 %H 3.55 %N 19.14
Determined: 28.36 3.24 18.99
The structure of the resulting complex was fully determined by nuclear magnetic resonance spectroscopy NMR (¾ 13C) and by infrared spectroscopy IR (4000-400 cm"1), and by electrospray ionisation mass spectrometry (ESI-MS):
!H NMR (600 MHz, D20): δ 2.63 (s, 6H, 2xCH3), 3.95 (t, 4H, 2xCH2-0, J = 5.2 Hz), 4.57 (t, 4H, 2xN-CH2, J= 5.2 Hz), 8.10 (s, 2H, 2x CH-N).
13C NMR (151 MHz, D20): δ 153.14 (N=C-N), 138.50 (C-N02), 132.92
(CH-N), 60.15(CH2-O), 48.88 (N-CH2), 14.77 (CH3-im).
IR (KBr) vmax (cm 1): (O-H, C-H) 3399(s), 3265(w), 3149(m), 3102(w), 2989(w), 2880(w); (C=N, C=C) 1544(s); (N02, C-H) 1469 (s), (N03, N02, C-H) 1370(vs),1349 (vs); (C-O) 1054(m) (vs: very strong; s: strong; m: medium; w: weak).
ESI+-MS (CH3OH) m/z: 450 [Ag(MTZ)2]+. Example 2. Compound 2 - [Ag(MTZ)2C104]
Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C. The reaction flask with this solution is placed on a magnetic stirrer. 15 ml of ethanol solution of silver (I) chlorate (VII) AgC104 (1 mmol, 0.208 g) is once added to the solution of metronidazole, and it is stirred at the temperature of 60°C for 30 minutes. The reaction mixture is protected against light with a cover of aluminum foil. Then, the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume. The concentrated solution is allowed to crystallise at room temperature. The resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 78%).
Properties of the compound: colourless crystals (melting point of 130- 132°C); soluble in water, methanol, ethanol, acetone, dimethyl sulphoxide.
The thus obtained product was subjected to elemental analysis on the content of C, H and N, the results of which confirm the total formula of compound [Ag(MTZ)2C104] (Ci2Hi8N6OioClAg).
Elemental analysis: Ci2Hi8N6OioClAg (549.68)
Calculated: %C 26.22 %H 3.31 %N 15.29
Determined: 26.34 3.00 15.05
The structure of the resulting complex was fully determined by nuclear magnetic resonance spectroscopy NMR (¾ 13C) and by infrared spectroscopy IR (4000-400 cm"1), and by electrospray ionisation mass spectrometry (ESI-MS):
!H NMR (600 MHz, D20): δ 2.62 (s, 6H, 2xCH3), 3.95 (t, 4H, 2xCH2-0, J = 5.2 Hz), 4.57 (t, 4H, 2x N-CH2, J= 5.2 Hz), 8.10 (s, 2H, 2x CH-N).
13C NMR (151 MHz, D20): δ 153.11 (N=C-N), 138.49 (C-N02), 132.92
(CH-N), 60.16(CH2-O), 48.85 (N-CH2), 14.73 (CH3-im).
IR (KBr) vmax (cm"1): (O-H, C-H) 3459(vs), 3223(w), 3143(m), 3102(w), 2942(w), 2900(w); (C=N, C=C) 1544(s); (N02, C-H) 1468 (s, br), (N02, C-H) 1369(s); (C104, C-O) 1075(s, br) (vs: very strong; s: strong; m: medium; w: weak; br: broad).
ESI+-MS (CH3OH) m/z: 450 [Ag(MTZ)2]+. Example 3. Compound 3 - [Ag(MTZ)2CF3COO]
Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C. The reaction flask with this solution is placed on a magnetic stirrer. 15 ml of ethanol solution of silver (I) trifluoroacetate Ag(CF3COO) (1 mmol, 0.221 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes. The reaction mixture is protected against light with a cover of aluminum foil. Then, the reaction mixture is evaporated in a rotary evaporator under reduced pressure at the temperature of 60°C to half its volume. The concentrated solution is allowed to crystallise at room temperature. The resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 77%).
Properties of the compound: colourless crystals (melting point of 148- 151°C dec); soluble in water, methanol, ethanol, acetone, dimethyl sulphoxide.
The thus obtained product was subjected to elemental analysis on the content of C, H and N, the results of which confirm the total formula of compound [Ag(MTZ)2CF3COO] (Ci-iHigNeOgFsAg).
Elemental analysis: Ci4Hi8N60gF3Ag (563.25)
Calculated: %C 29.85 %H 3.23 %N 14.92
Determined: 30.05 2.87 15.00
The structure of the resulting complex was fully determined by nuclear magnetic resonance spectroscopy NMR (¾ 13C) and by infrared spectroscopy IR (4000-400 cm"1), and by electrospray ionisation mass spectrometry (ESI-MS):
!H NMR (600 MHz, D20): δ 2.60 (s, 6H, 2xCH3), 3.94 (t, 4H, 2xCH2-0, J = 5.2 Hz), 4.56 (t, 4H, 2x N-CH2, J= 5.2 Hz), 8.09 (s, 2H, 2x CH-N).
13C NMR (151 MHz, D20): δ 163.05 (CF3COO) (weak intensity), 153.11 (N=C-N), 138.48 (C-N02), 132.90 (CH-N), 119.57, 117.39, 115.46, 113.53 (CF3COO) (weak intensity), 60.14(CH2-O), 48.88 (N-CH2), 14.78 (CH3-im).
IR (KBr) vmax (cm"1): (O-H, C-H) 3384(m), 3222(m), 3143(w), 2958(w), 2900(w); (C=0) 1677(vs); (C=N, C=C) 1544(s); (N02, C-H) 1475 (s), (CF3COO) 1432(s); (NO2, C-H) 1369(s); (-CF3) 1267(s), 1126(s); (C-O) 1060(m) (s: strong; m: medium; w: weak).
ESI+-MS (CH3OH) m/z: 450 [Ag(MTZ)2]+.
Example 4. Compound 4 - [Ag(MTZ)2]BF4
Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C. The reaction flask with this solution is placed on a magnetic stirrer. 15 ml of ethanol solution of silver (I) tetrafluoroborate AgBF4 (1 mmol, 0.195 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes. The reaction mixture is protected against light with a cover of aluminum foil. Then, the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume. The concentrated solution is allowed to crystallise at room temperature. The resulting crystals are separated from the solution, by decanting it, are washed with dry diethyl ether, and are dried in air (efficiency of 88%).
Properties of the compound: colourless crystals (melting point of 137-
139°C dec); soluble in water, methanol, ethanol, acetone, dimethyl sulphoxide.
The thus obtained product was subjected to elemental analysis on the content of C, H and N, the results of which confirm the total formula of compound [Ag(MTZ)2]BF4
Elemental analysis:
Figure imgf000010_0001
37,04)
Calculated: %C 26.84 %H 3.39 %N 15.65
Determined: 27.12 3.16 15.24
The structure of the resulting complex was fully determined by nuclear magnetic resonance spectroscopy NMR (¾ 13C) and by infrared spectroscopy IR (4000-400 cm"1), and by electrospray ionisation mass spectrometry (ESI-MS):
!H NMR (600 MHz, D20): δ 2.66 (s, 6H, 2xCH3), 3.97 (t, 4H, 2xCH2-0, J = 5.2 Hz), 4.60 (t, 4H, 2x N-CH2, J= 5.2 Hz), 8.14 (s, 2H, 2x CH-N).
13C NMR (151 MHz, D20): δ 153.13 (N=C-N), 138.49 (C-NO2), 132.75 (CH-N), 60.13(CH2-O), 48.97 (N-CH2), 14.89 (CH3-im). IR (KBr) vmax (cm 1): (O-H, C-H) 355 l(s), 3350(s), 3160(m), 3102(w), 2938(w), 2884(w); (C=N, C=C) 1557(s); (N02, C-H) 1484 (s), (N02, C-H) 1373(s); (BF4, C-O) 1195(s), 1074(s), 1032(m) (s: strong; m: medium; w: weak).
ESI+-MS (CHsOH) m/z: 450 [Ag(MTZ)2]+.
Example 5. Compound 5 - [Ag(MTZ)2S03CH3]
Metronidazole (MTZ) (2 mmol, 0.342 g) is dissolved in 20 ml of ethanol at a temperature of 60°C. The reaction flask with this solution is placed on a magnetic stirrer. 20 ml of ethanol-aqueous solution (in the volume ratio of EtOH/H20 of 1 : 1) of silver methylsulphonate AgS03CH3 (1 mmol, 0.203 g) is once added to the solution of metronidazole, and it is stirred at a temperature of 60°C for 30 minutes. The reaction mixture is protected against light with a cover of aluminum foil. Then, the reaction mixture is evaporated in a rotary evaporator under reduced pressure at a temperature of 60°C to half its volume. The concentrated solution is allowed to crystallise at room temperature. The resulting crystals are separated from the solution, by decanting, are washed with dry diethyl ether, and are dried in air (efficiency of 83%).
Properties of the compound: colourless crystals (melting point of 148- 149°C); soluble in water, methanol, ethanol, acetone, dimethyl sulphoxide.
The thus obtained product was subjected to elemental analysis on the content of C, H and N, the results of which confirm the total formula of compound [Ag(MTZ)2S03CH3] (Ci3H2iN609SAg).
Elemental analysis: Ci3H2iN609SAg (545.34)
Calculated: %C 28.63 %H 3.89 %N 15.41
Determined: 28.89 3.81 15.18
The structure of the resulting complex was fully determined by nuclear magnetic resonance spectroscopy NMR (¾ 13C) and by infrared spectroscopy IR (4000-400 cm"1), and by electrospray ionisation mass spectrometry (ESI-MS):
!H NMR (600 MHz, D20): δ 2.63 (s, 6H, 2xCH3), 2.79 (s, 3H, CH3S03), 3.95 (t, 4H, 2xCH2-0, J = 5.2 Hz), 4.57 (t, 4H, 2x N-CH2, J = 5.2 Hz), 8.10 (s, 2H, 2x CH-N). 13C NMR (151 MHz, D20): δ 153.14 (N=C-N), 138.49 (C-N02), 132.91 (CH-N), 60.14 (CH2-O), 48.91 (N-CH2), 38.55 (CH3SO3), 14.84 (CH3-im).
IR (KBr) vmax (cm"1): (O-H, C-H) 3226(m), 3129(w), 3101(w); (C=N, C=C) 1537(s); (N02, C-H) 1474 (s), (N02, C-H) 1368(s); (S03) 1187(vs), (C-O) 1058(m), 1040(m) (s: strong; m: medium; w: weak).
ESI+-MS (CH3OH) m/z: 450 [Ag(MTZ)2]+.

Claims

Claims
1. A complex compound of silver and metronidazole.
2. The complex compound according to claim 1, characterised in that it comprises silver and metronidazole in a molar ratio of 1 :2.
3. The complex compound according to claim 2, characterised in that it comprises silver in a formal oxidation state of +1, coordinated by metronidazole, and comprises a counterion which is an anion of an acid selected from the group consisting of hardly oxidisable oxygen inorganic acids, tetrafluoroboric acid, optionally-halogenated carboxylic acids, optionally- halogenated organic sulphonic acids.
4. The complex compound according to claim 2 or 3, characterised in that the counterion is an anion of an acid selected from the group consisting of nitric (V) acid, chloric (VII) acid, trifluoroacetic acid, tetrafluoroboric acid, methanesulphonic acid.
5. A method of preparation of complex compound of silver and metronidazole, characterised in that metronidazole and a silver (I) compound are used as reagents, wherein the silver (I) compound is at least partially soluble in a reaction medium, the reagents are introduced together to a reaction medium comprising a hydroxylic solvent at a temperature of 5-90°C, the reaction is conducted for 1-180 minutes while maintaining a temperature of 5-90°C, optionally with mechanical stimulation of the reaction medium, and then the complex compound of silver and metronidazole is extracted.
6. The method according to claim 5, characterised in that at least one hydroxylic solvent is used, wherein said hydroxylic solvent is selected from the group consisting of inorganic hydroxylic solvents, organic hydroxylic solvents and mixtures thereof.
7. The method according to claim 6, characterised in that a hydroxylic solvent selected from the group consisting of water, lower aliphatic alcohols and mixtures thereof is used.
8. The method according to any claim 5 to 7, characterised in that the silver (I) compound and metronidazole in a molar ratio of 1 :2 are used.
9. The method according to any claim 5 to 8, characterised in that the reaction is conducted for 5-120 minutes while maintaining a temperature of 40- 80°C, preferably for 30 minutes at a temperature of 60°C.
10. The method according to any claim 5 to 9, characterised in that a compound selected from the group consisting of silver (I) nitrate (V), silver (I) chloride (VII), silver (I) trifluoroacetate, silver (I) tetrafluoroborate, silver (I) methanesulphonate is used as the silver (I) compound.
11. The use of the compound defined in any claim 1 to 4 for the preparation of a formulation for inhibiting the growth of pathogenic microorganisms, in the prophylaxis or treatment of the animal or human organism.
12. The compound as defined in any claim 1 to 4 for the preparation of a formulation for inhibiting the growth of pathogenic microorganisms, in the prophylaxis or treatment of the animal or human organism.
PCT/EP2016/051710 2015-01-27 2016-01-27 Silver complex compound, the method of preparation of the complex compound and the use of the complex compound WO2016120332A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP.411078 2015-01-27
PL411078A PL411078A1 (en) 2015-01-27 2015-01-27 Complex silver compound, method for producing a complex compound and application of a complex compound

Publications (1)

Publication Number Publication Date
WO2016120332A1 true WO2016120332A1 (en) 2016-08-04

Family

ID=55236377

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/051710 WO2016120332A1 (en) 2015-01-27 2016-01-27 Silver complex compound, the method of preparation of the complex compound and the use of the complex compound

Country Status (2)

Country Link
PL (1) PL411078A1 (en)
WO (1) WO2016120332A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4803066A (en) * 1986-03-22 1989-02-07 Smith & Nephew Associated Companies P.L.C. Antibacterial and/or antifungal compositions for topical application
WO1997002038A1 (en) 1995-06-30 1997-01-23 Capelli Christopher C Silver-based pharmaceutical compositions
WO1998006260A1 (en) * 1996-08-16 1998-02-19 Capelli Christopher C Silver-based antimicrobial compositions
US6093414A (en) * 1997-08-11 2000-07-25 Christopher C. Capelli Silver-based antimicrobial compositions
CN102688258A (en) * 2012-06-16 2012-09-26 李泽红 Medicine for external use for treating psoriasis, leucoderma, fungus infection and bromhidrosis
EP2848608A1 (en) * 2013-07-08 2015-03-18 Uniwersytet Medyczny W Lodzi Silver complex compounds, method for their production and their use

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4803066A (en) * 1986-03-22 1989-02-07 Smith & Nephew Associated Companies P.L.C. Antibacterial and/or antifungal compositions for topical application
WO1997002038A1 (en) 1995-06-30 1997-01-23 Capelli Christopher C Silver-based pharmaceutical compositions
US5744151A (en) * 1995-06-30 1998-04-28 Capelli; Christopher C. Silver-based pharmaceutical compositions
WO1998006260A1 (en) * 1996-08-16 1998-02-19 Capelli Christopher C Silver-based antimicrobial compositions
US6093414A (en) * 1997-08-11 2000-07-25 Christopher C. Capelli Silver-based antimicrobial compositions
CN102688258A (en) * 2012-06-16 2012-09-26 李泽红 Medicine for external use for treating psoriasis, leucoderma, fungus infection and bromhidrosis
EP2848608A1 (en) * 2013-07-08 2015-03-18 Uniwersytet Medyczny W Lodzi Silver complex compounds, method for their production and their use

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
N. GRIER: "Disinfection, Sterilisation and Preservation", 1983, article "Silver and Its Compounds", pages: 395
URSZULA KALINOWSKA-LIS ET AL: "Influence of selected organic counter-ions on the structure and antimicrobial properties of silver(I) complexes with imidazole-containing ligands", NEW JOURNAL OF CHEMISTRY, vol. 40, no. 1, 1 January 2016 (2016-01-01), GB, pages 694 - 704, XP055252193, ISSN: 1144-0546, DOI: 10.1039/C5NJ02514A *
URSZULA KALINOWSKA-LIS ET AL: "Synthesis, characterization and antimicrobial activity of silver(I) complexes of hydroxymethyl derivatives of pyridine and benzimidazole", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 749, 1 January 2014 (2014-01-01), pages 394 - 399, XP055167851, ISSN: 0022-328X, DOI: 10.1016/j.jorganchem.2013.10.035 *
URSZULA KALINOWSKA-LIS ET AL: "Synthesis, characterization and antimicrobial activity of water-soluble silver(i) complexes of metronidazole drug and selected counter-ions", DALTON TRANSACTIONS: THE INTERNATIONAL JOURNAL FOR INORGANIC, ORGANOMETALLIC AND BIOINORGANIC CHEMISTRY, vol. 44, no. 17, 25 March 2015 (2015-03-25), GB, pages 8178 - 8189, XP055251129, ISSN: 1477-9226, DOI: 10.1039/C5DT00403A *

Also Published As

Publication number Publication date
PL411078A1 (en) 2016-08-01

Similar Documents

Publication Publication Date Title
FI61609B (en) SAETT ATT FRAMSTAELLA EN BAKTERIER DOEDANDE JODOFORFOERENING OCH AVLAEGSNA FRAON ETT PHARMACEUTISKT PREPARAT JOD- OCH JODIDFOERORENINGAR
EP2753613B1 (en) Derivatives of xanthone compounds
US10570097B2 (en) Antimicrobial imidazolium compounds
WO2016120332A1 (en) Silver complex compound, the method of preparation of the complex compound and the use of the complex compound
WO2011061272A2 (en) A di(4-chloro-phenyldiguanido) derivative which is free of potential genotoxicity and a process for reducing the residual amount of p-chloroaniline in said di(4-chloro-phenyldiguanido) derivative
FI84421C (en) SAMMANSAETTNINGAR AV KONSERVERINGSAEMNEN OCH ANVAENDNINGAR AV DESAMMA.
Czerniak et al. Synthesis and properties of gallate ionic liquids
Gulea et al. Coordination compounds of copper with 2-formylpyridine 4-(dimethylphenyl) thiosemicarbazones
CN112515989B (en) Compound low-alcohol disinfectant and preparation method thereof
EP2848608B1 (en) Silver complex compounds, method for their production and their use
EP3004064B1 (en) Pharmaceutical compositions based on photochemically stable silver complexes, chlorexidine and cationic surfactants
EP2880978B1 (en) Herbicidal quaternary ammonium salts of (4-chloro-2-methylphenoxy)acetic acid
EP0359076B1 (en) pH-neutral aqueous solutions of quinolone-carboxylic acids
US4496589A (en) Anti-inflammatory, disinfectant and anti-bacterial compound
WO2024176264A1 (en) Ionic liquid, its formulations and method of synthesis thereof
RU2653597C1 (en) Method for preparation of n-benzyl [1-(dodecinoylamino)-3-(dimethylamino)]propane ammonium chloride monohydrate
IL32324A (en) Phenazine derivatives and their preparation
SarveAhrabi Single-step synthesis of 1, 3, 4-oxadiazoles containing fluorophenyl ring and evaluation of their antibacterial effect on gram-negative pathogens in vitro
RU2655603C1 (en) Antiseptic on the basis of dodecanic acid
Cardoso Synthesis and antifungal activity of 8-hydroxyquinoline derivatives bearing 1, 2, 3-triazole moiety
PL445210A1 (en) Ethyl 2-ethoxy-2-oxo-2H-benzo[e][1,2]oxaphosphinine-3-carboxylate for use in bactericidal and fungicidal preparations
US3980664A (en) 1-[(5-Nitro-2-furoyl)methyl]-2(1H) pyridone
JP2011006346A (en) Antibacterial agent
WO2018056902A1 (en) Imidazolium compounds, methods of synthesis and uses thereof
US3338912A (en) 5-(4-pyridyl)-5-methyl-1, 3, 2-dioxathiane-2-oxide and derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16701662

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16701662

Country of ref document: EP

Kind code of ref document: A1