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WO2009091291A1 - Sel d'argent de n-(6-méthyl-2,4-dioxo-1,2,3,4-tétrahydro-5h-pyrimidinesulfone)-isonicotinoyl hydrazide - Google Patents

Sel d'argent de n-(6-méthyl-2,4-dioxo-1,2,3,4-tétrahydro-5h-pyrimidinesulfone)-isonicotinoyl hydrazide Download PDF

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Publication number
WO2009091291A1
WO2009091291A1 PCT/RU2008/000809 RU2008000809W WO2009091291A1 WO 2009091291 A1 WO2009091291 A1 WO 2009091291A1 RU 2008000809 W RU2008000809 W RU 2008000809W WO 2009091291 A1 WO2009091291 A1 WO 2009091291A1
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WO
WIPO (PCT)
Prior art keywords
cristaphone
silver salt
silver
mixture
activity
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/RU2008/000809
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English (en)
Russian (ru)
Inventor
Lev Davidovich Rasnetsov
Iakov Yudelevich Shvartsman
Olga Konstantinovna Yashnova
Nina Borisovna Melnikova
Yulia Viktorovna Chudetskaya
Aleksandr Aleksandrovich Volkov
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Individual
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Individual
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Publication of WO2009091291A1 publication Critical patent/WO2009091291A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P31/04—Antibacterial 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/10—Antimycotics
    • 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

Definitions

  • the invention relates to medicine, namely to the creation of medicines based on new biologically active substances, in particular to the silver salt of N- (6-methyl-2,4-dioxo-l, 2,3,4-tetrahydro-5H- pyrimidine cyclone) is an N "isonicotinoyl hydrazide exhibiting immunotropic, antimicrobial, antifungal (antimycotic) activity, the method for its preparation and a drug based on it.
  • the first characteristic of the state of public health in the world is a decrease in immunoreactivity: according to various sources, up to 50-70% of people have immunity disorders. And the second feature arising from the first is an increase in the frequency of diseases caused by opportunistic microbiota.
  • drugs with a dual effect - immunomodulatory and antimicrobial have become particularly relevant.
  • the disadvantage of the isofone immunomodulator with antimycobacterial activity is the low biological activity due to poor solubility in water, as evidenced by an experiment on animals (rabbits), in which It is estimated that about 50% of the isophone remains unchanged in the waste products.
  • the immunomodulator has the widespread trade name "KPISTAFOH”.
  • Isodinafon is prepared by reacting equimolar amounts of isophone and sodium hydroxide in water, followed by precipitation of the reaction product with ethanol.
  • the drug as an active substance contains isodinafon in an amount of 0.01-2 g and can be used in the form of capsules, tablets, injections and ointments.
  • the use of isodinafon as a drug can reduce the dose of the drug used, thereby reducing the cost of treatment.
  • a compound of this kind despite the advantages in the solubility of the drug in water, easily decomposes into two parts according to the hydrazine moiety: sulfopyrimidine derivative
  • the problem to which the invention is directed is to obtain a new compound based on derivatives of pyrimidone and isonicotinic acid hydrazide, exhibiting enhanced immunotropic, antimicrobial, antifungal (antimycotic) activity in comparison with cristaphone and isophone, and the creation of a drug on its basis facilities.
  • the problem is solved by a group of inventions, united by a single inventive concept, namely: the development of a new compound - cristaphone silver salt, a method for producing this compound and the creation of a medicine based on it.
  • the silver salt of cristaphone may be a compound of formula I
  • the problem is achieved by the method of obtaining silver salt of cristaphone, which consists in the fact that silver nitrate is added to an aqueous suspension of cristaphone, intensively mixed until homogeneous, with a molar ratio of cristaphone to silver nitrate from 1: 1 to 1: 4, then the reaction mixture without light stirred until a homogeneous bulk Nogo precipitate, the resulting precipitate was filtered, washed several times with double distilled water and dried at a temperature of 50-80 0 C.
  • krista- background in finely dispersed state.
  • the problem is also solved by the creation of a drug having immunotropic, antimicrobial, antifungal (antimycotic) activity, containing an active substance, which, according to the invention, contains silver as an active substance cristaphone salt or a mixture of cristaphone and its silver salt in a ratio of 1: 1 to 4: 1.
  • the drug can be made in the form of tablets, capsules, ointments, suppositories.
  • the essence of the proposed invention lies in the fact that to enhance the immunotropic, antimicrobial, antifungal (antimycotic) activity due to the additional action of silver, it is proposed to use a substance that is a silver salt of cristaphone.
  • Silver has a powerful bactericidal, immunomodulatory, astringent, analgesic properties and has a stimulating effect on the blood-forming organs. Most widely used in medicine is the ability of silver to have a bactericidal effect in small doses, and only silver ions have activity. Bactericidal activity is already apparent at a concentration of 0.0001%. The spectrum of action of silver preparations is much wider than many antibiotics and sulfonamides. It includes both gram-positive and gram-negative bacteria (including antibiotic-resistant strains), viruses and fungi. Thus, based on the above properties, silver exhibits an oligodynamic effect.
  • Cristaphone in aqueous solution is characterized by lactim-lactam (prototropic) tautomerism, and, in fact, cristaphone, when passing into solution, exists in two tautomeric forms - lactam (keto form) and lactim (enol form).
  • the lactim enol form acquires an aromatic character
  • the hydroxyl group in the pyrimidine ring acquires the properties of a phenolic hydroxyl.
  • the interaction of a suspension of cristaphone in water with silver nitrate AgNO 3 forms a silver salt (isomers).
  • a silver ion is present in the silver salt molecule of cristaphone, which can extremely slowly dissociate in a lipophilic medium, releasing silver ions, which ensures a prolonged effect of the preparations.
  • the critical factor for the bactericidal action in the wound is the required local concentration and the possibility of achieving this level by systemic administration or local application. If local blood supply is compromised, for example, with limb ischemia, tissue edema, or thermal coagulation, as well as with scab and / or lipoderma sclerosis, the chances of systemic therapy to achieve therapeutic concentrations are significantly reduced, while silver salts can provide the necessary concentration due to long-term preservation in lipid tissues (V.
  • Example 1 A method for producing the silver salt of N- (6-methyl-2,4-dioxol, 2,3,4-tetrahydro-5-pyrimidine-cyclone) -N'-isonicotinoylhydrazide (cristaphone).
  • aqueous suspension containing 2 g (0.0061 mol) of cristaphone they are preliminarily treated with ultrasound at a frequency of 22-44 kHz until a homogeneous dispersion is added, silver nitrate 4.2 g (0.0244 mol) is added. Then, without access to light, the reaction mixture is sonicated to obtain a homogeneous volumetric precipitate. The precipitate obtained is filtered, washed repeatedly with bidistilled water and dried in a vacuum oven (100-200 mmHg) at a temperature of 50-80 0 C. A white or white powder with a grayish tint is obtained.
  • the structure of the cristaphone silver salt was determined by comparing the IR spectra of the cristaphone and its silver salt. Analysis of infrared spectra was carried out for two reference bands in the 3307 cm “and 1743 cm” '(CO at position 2) characterizing the carbonyl group in the pyrimidine ring kristafona keto form as well as the group of strong bands in the region 3200-3000 cm " 1 (NH at position 3). In the IR spectrum of the silver salt of cristapho the band 1743 cm "1 disappears, and the absorption intensity of the group of bands 3200-
  • Example 2 A method for producing silver salt of cristaphone. An aqueous suspension containing 1 g (0.003 mol) of cristaphone is pre-mixed thoroughly on a mechanical stirrer 3000 rpm until a uniform dispersion is added, silver nitrate 1.03 g (0.006 mol) is added. Then, without access to light, the reaction mixture is stirred on a mechanical stirrer until a homogeneous volumetric precipitate is obtained. The precipitate obtained is filtered, washed many times with double-distilled water and dried in a vacuum oven (100-200 mm Hg) at a temperature of 50-80 0 C. A white or white powder with a grayish tint is obtained.
  • Example 3 A method for producing silver salt of cristaphone. An aqueous suspension containing 1 g (0.003 mol) of cristaphone is preliminarily mixed thoroughly on a mechanical stirrer from 1000 to 3000 rpm to a uniform dispersion, silver nitrate 0.516 g (0.003 mol) is added. Then, without access to light, the reaction mixture is stirred on a mechanical stirrer until a homogeneous volumetric precipitate is obtained. The precipitate obtained is filtered, washed many times with double-distilled water and dried in a vacuum oven (100-200 mm Hg) at a temperature of 50-80 0 C. A white or white powder with a grayish tint is obtained.
  • silver salt of cristaphone (examples 1-3) and their mixtures taken in the ratio specified in examples 4-5, suppositories based on polyethylene oxide and Vitepsol based in weight of 1.5 g were made.
  • Each suppository contains 0 , 2 g of substance (cristaphone, its silver salt or a mixture thereof).
  • a cristaphone or its silver salt, or a mixture of them, previously ground in a mortar, is introduced in an amount of 2 g.
  • the resulting mixture was thoroughly and vigorously stirred until a homogeneous suspension.
  • the resulting suspension is poured into the nests of the mold for the manufacture of suppositories, after solidification, the suppositories are removed from the mold and packaged.
  • Example 7 The results of preclinical trials of preparations containing cristaphone, silver salt of cristaphone and their mixture for the presence of antimicrobial and antifungal activity in experiments in vitro.
  • control strain number 906 obtained from the GISK named after Tarasevich
  • E. coli M-17 - museum (control strain) number B-8208 obtained from the GISK named after Tarasevich;
  • S. aires type 7M strain (NNIEM, N. Novgorod)
  • E. coli strain 782-2
  • S. aires type 7M strain (NNIEM, N. Novgorod)
  • E. coli strain 782-2
  • the study of the microbiocidal activity of the preparations was carried out by the method of serial dilutions according to the previously described recommendations (Medical Microbiology, 1999; Encyclopedia of Clinical Laboratory Tests, 1997; Laboratory Research Methods in the Clinic, 1987).
  • Table 2 presents the results of changes in the cytological picture of vaginal smears of rats in points.
  • cytological examination adhered to the following criteria when scoring: 1 - single bacterial cells; 2 - few cells; 3- moderate number of cells; 4- many cells.
  • Table 3 presents the results of microbiological studies in the treatment of bacterial vaginitis in rats in comparison with the known drug Betadine.
  • the silver salt of cristaphone in the form of a powder or in the form of a powder in capsule form, where the auxiliary substance is lactose (ip-vitro results) and vaginal suppositories (preclinical test results), has close immunomodulating, antimicrobial, antifungal (antimycotic) activity.
  • Capsules the active principle of cristaphone, its silver salt and mixtures thereof, taken in the ratio specified in examples 4-5 to 100 mg, 200 mg, 500 mg, in the first two cases, lactose was used as a filler.
  • Tablets the active principle of cristaphone, the silver salt of cristaphone and their mixtures, taken in the ratio specified in examples 4-5-200 mg, fillers: starch 30 mg, talc 5 mg, lactose 15 mg.
  • Ointment the active principle of cristafon, its silver salt and their mixtures, taken in the ratio specified in examples 4-5 - 3 g, base: emulsion wax - 20 g, liquid paraffin - 20 g, petrolatum - 10 g, POE 400 - 10 g, distilled water - 37 g.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un nouveau sel d'argent de N-(6-méthyl-2,4-dioxo-1,2,3,4-tétrahydro-5h-pyrimidinesulfone)-isonicotinoyl hydrazide manifestant une activité immunotropique, antimicrobienne, et antifongique (antimycosique). On obtient le sel en ajoutant à une suspension aqueuse de nitrate d'argente de N-(6-méthyl-2,4-dioxo-1,2,3,4-tétrahydro-5h-pyrimidinesulfone)-isonicotinoyl hydrazide, que l'on a intensément remué au préalable pour obtenir un état homogène, le rapport molaire entre l'hydrazide et le nitrure d'argent étant entre 1:1 et 1 :4, sans accès à la lumière, jusqu'à obtenir un résidu volumique homogène qui est ensuite filtré et rincé avec de l'eau
PCT/RU2008/000809 2008-01-09 2008-12-29 Sel d'argent de n-(6-méthyl-2,4-dioxo-1,2,3,4-tétrahydro-5h-pyrimidinesulfone)-isonicotinoyl hydrazide Ceased WO2009091291A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2008100493/04A RU2368609C1 (ru) 2008-01-09 2008-01-09 Серебряная соль n-(6-метил-2,4-диоксо-1,2,3,4-тетрагидро-5h-пиримидинсульфон)-n'-изоникотиноилгидразида, проявляющая иммунотропную, противомикробную, противогрибковую (противомикотическую) активность, и лекарственное средство на ее основе
RU2008100493 2008-01-09

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WO2009091291A1 true WO2009091291A1 (fr) 2009-07-23

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RU (1) RU2368609C1 (fr)
WO (1) WO2009091291A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113333772A (zh) * 2021-06-18 2021-09-03 南昌大学 金纳米簇的制备方法及其在2,4,6-三硝基苯酚检测的应用

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MD4075C1 (ro) * 2009-12-31 2011-07-31 Анатолий ЭФКАРПИДИС Procedeu de obţinere a argintului coloidal de înaltă dispersie
RU2440817C1 (ru) * 2010-09-22 2012-01-27 Открытое Акционерное Общество Завод Экологической Техники И Экопитания "Диод" Средство для лечения бактериального вагиноза
RU2706357C1 (ru) * 2018-05-22 2019-11-18 Федеральное государственное бюджетное образовательное учреждение высшего образования "Пермская государственная фармацевтическая академия" Министерства здравоохранения Российской Федерации (ПГФА) Серебряные соли 3,4-диарил-5-[4-(ацетиламиносульфонил)фенил]-4,6-дигидропирроло[3,4-с]пиразол-6-онов, проявляющие противогрибковую активность

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2141322C1 (ru) * 1997-08-12 1999-11-20 Голощапов Николай Михайлович Иммуномодулятор с антимикобактериальной активностью "изофон", способ его получения и применения
RU2191015C2 (ru) * 1999-11-05 2002-10-20 Общество с ограниченной ответственностью "Центр бифункциональных иммуномодуляторов" Динатриевая соль n-(6-метил-2,4-диоксо-1,2,3,4-тетрагидро-5h-пиримидинсульфон)-n'- изоникотиноилгидразида, проявляющая антимикробную и иммунотропную активность, и лекарственное средство на ее основе

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2141322C1 (ru) * 1997-08-12 1999-11-20 Голощапов Николай Михайлович Иммуномодулятор с антимикобактериальной активностью "изофон", способ его получения и применения
RU2191015C2 (ru) * 1999-11-05 2002-10-20 Общество с ограниченной ответственностью "Центр бифункциональных иммуномодуляторов" Динатриевая соль n-(6-метил-2,4-диоксо-1,2,3,4-тетрагидро-5h-пиримидинсульфон)-n'- изоникотиноилгидразида, проявляющая антимикробную и иммунотропную активность, и лекарственное средство на ее основе

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113333772A (zh) * 2021-06-18 2021-09-03 南昌大学 金纳米簇的制备方法及其在2,4,6-三硝基苯酚检测的应用
CN113333772B (zh) * 2021-06-18 2023-01-03 南昌大学 金纳米簇的制备方法及其在2,4,6-三硝基苯酚检测的应用

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RU2368609C1 (ru) 2009-09-27
RU2008100493A (ru) 2009-07-20

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