WO2008079055A1 - Sels de 1-hydroxyhermatrane avec des acides oxy-, céto- et polycarboxyliques - Google Patents

Sels de 1-hydroxyhermatrane avec des acides oxy-, céto- et polycarboxyliques Download PDF

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Publication number
WO2008079055A1
WO2008079055A1 PCT/RU2007/000735 RU2007000735W WO2008079055A1 WO 2008079055 A1 WO2008079055 A1 WO 2008079055A1 RU 2007000735 W RU2007000735 W RU 2007000735W WO 2008079055 A1 WO2008079055 A1 WO 2008079055A1
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WIPO (PCT)
Prior art keywords
hydroxy
compounds
azatracyclo
acid
salts
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PCT/RU2007/000735
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English (en)
Russian (ru)
Inventor
Alexander Dmitrievich Isaev
Svetlana Alexanderovna Bashkirova
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Alexander Dmitrievich Isaev
Bashkirova Svetlana Alexandero
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Application filed by Alexander Dmitrievich Isaev, Bashkirova Svetlana Alexandero filed Critical Alexander Dmitrievich Isaev
Publication of WO2008079055A1 publication Critical patent/WO2008079055A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages
    • 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

Definitions

  • This invention relates to organoelement chemistry, chemical technology, specifically, to new salts of 1-hydroxyhydroxy acid, hydroxy, keto-and dicarboxylic acids, namely 1-hydroxy-1-herma-2,8,9-trioxy-5-azatracyclo [3.3.3] reducing the carboxylates of formula (I):
  • Patent RU 2104032 [000 "BLACK BAPC”, SCHERBININ B.B., Chernyshev EA] 08/17/1998, C07F 7/30, A61K 31/28 and Patent RU 2104033 [000
  • R is OH, or an organic radical, or an organoelemental radical, including a drug or in accordance with formula (III), written in general form
  • R 1 ⁇ R 12 is H, or an organic radical
  • X is O or S.
  • Derivatives of a 1-hydroxyhydramate (II, R is OH, or an organic radical, or an organoelemental radical) containing acetylsalicylic acid, ampicillin as an acid substituent in [Patent RU 2104032 [000 “BLACK BAPC”, SHCHERBININ BB, CHERNISHEV EA] 08/17/1998, C07F 7/30, A61 K 31/28] are named germanyl ethers (see table 9 [Patent RU 2104032 [LLC “BLACK BAPC” ”, SHCHERBININ BB, CHERNYSHEV EA] 08/17/1998, C07F 7/30, A61 K 31/28]), and in [Patent RU 2104033 [LLC“ CHEZHNY BAPC ”, SHCHERBININ BB, CHERNYSHEV EA] 08/17/1998, C07F 7
  • Organic germanium compounds with organic acid are known (see [Patent RU 2233286 [SOLOVYOV EB, SHCHERBININ BB, CHERNYSHEV EA, KOTRELEV M.V.] 17.08.1998, C07F 7/30, A61 K 31/28]), in which complexes are considered organogermanium compounds with drugs or biologically active substances of the general formula C (GOC) m (Pac.) n (IV), where L is a drug or biologically active substance (including acetylsalicylic acid, nicotinic acid, amino acids, etc. .), k> 1, m> 1, n> 0, Mort.
  • GOS is an organo-germanium compound (III, R is OH, or thiohydroxyl, or an organic radical, or an elementorganic radical, R ⁇ R 12 is H or organic radical, or oxygen (as a substituent, R 1 R 2 , RsR b and Rg ⁇ R 10 ), X is O or sulfur).
  • Patent RU 2233286 [SOLOVYOV EB, SHCHERBININ BB, CHERNYSHEV EA, KOTRELEV MB] 08/17/1998, C07F 7/30, A61K 31/28] on p.5 mentions the possibility of a donor-acceptor interaction of the nitrogen atom in the GOS molecule with carboxyl (thiocarboxyl) group of a drug or biologically active substance, but the compound L in formulas (IV) coordinates with the Ge atom.
  • Patent RU 2233286 [SOLOVYOV E.B., SHCHERBININ V., CHERNYSHEV EA, KOTRELEV M.B.] 08.17.1998, C07F 7/30, A61 K 31/28] only complexes of organo-germanium compounds with organic acids are considered.
  • a known method of obtaining a complex of formula (IV) with acetylsalicylic acid [Patent RU 2233286 [SOLOVYOV EB, SHCHERBININ BB, CHERNYSHEV EA 1 KOTRELEV MB] 08/17/1998, C07F 7/30, A61 K 31/28], p.14) is carried out by mixing a 0.1 M solution of acetylsalicylic acid in ethanol (100 ml of ethanol) and a 0.1 M solution of 1-ethyl-1-herma-2,8,9-trioxa-5-azatracyclo [3.3.3.0 1 5 ] - indecane -3,7,10-trione (75 ml of ethanol) on a magnetic stirrer for 14 hours at room temperature and separation from the solution on a rotary evaporator. Yield 89%, melting point T pl. equal to 230-231 0 C.
  • the technical result of the proposed invention is the creation of new substances of high purity, expanding knowledge about the structure of compounds of 1-hydroxyhydroxy compounds, namely, compounds of 1-hydroxyhydroxy with hydroxy, keto and dicarboxylic acids (with malic, ⁇ -ketoglutaric, oxalic acetic, succinic, succinic ), the expansion of a number of classes of compounds of 1-hydroxy compounds, the expansion of the class of salts.
  • formula (I) takes on view [hereinafter referred to as the "form (lb)"]: -
  • the difference of the proposed compounds of formula (I) is that new, previously unknown compounds of 1-hydroxy compounds are proposed, united by a single concept.
  • the proposed compounds of 1-hydroxyhermatran (I) are salts of 1-hydroxyhydraman with hydroxy, keto and dicarboxylic acids, (hereinafter “salts of 1-hydroxyhermtrane (l)”, and when considering salts with each acid separately, “salt 1- hydroxyhermatran with (appropriate) acid (Ia - Ie), respectively))).
  • the technological implementation of the invention is not difficult, very simple and technologically advanced, based on well-known technological chemical processes for the production of chemical compounds, which meets the criterion ((industrial applicability *.
  • the product is ground and packaged in a sealed container.
  • the PMR proton magnetic resonance spectrum (20% solution in D 2 O, standard CH 3 CN), obtained on a Bguer AM-360 instrument, has 2 triplets characteristic of the hermatran structure ( ⁇ , ppm): CH 2 N 3.41 t; OCH 2 3.89 t (see table 2).
  • the preparation is carried out according to the procedure described in example 1, only 29.2 g (0.2 mol) of ⁇ -ketoglutaric acid are charged.
  • the reaction mixture was stirred at 45 ° C for 30 minutes.
  • the preparation is carried out according to the procedure described in example 1, only 23.2 g (0.2 mol) of fumaric acid are charged, the reaction mixture is stirred at a temperature of 50 0 C for 60 minutes. After drying, 45.1 g of the salt of 1-hydroxyhydramate with fumaric acid of the formula (I, X —CH ⁇ CH—) (Ie) are obtained. The yield is 61.0%.
  • salts of 1-hydroxyhydraman (I) of formulas (Ia) - (Ia) are white powders, soluble in water. They do not melt, but decompose when heated.
  • the inability of the proposed salts of 1-hydroxyhermatran (I) of formulas (Ia) - (Ia) to give a stable liquid phase upon heating and their insolubility in such solvents as chloroform, benzene, toluene, ether, and dioxane are, of course, not typical for simple covalently constructed compounds.
  • influenza A virus the reference strain recommended by WHO experts for the production of diagnostic and vaccine preparations - A / New Kaledonia / 20/99 (H1 N1), sensitive to remantadine and arbidol, and
  • Acute toxicity was determined on nonlinear white male mice weighing 18-20 g with a single intragastric (iv) administration in doses of 1000, 2000, 3000, 4000 and 5000 mg / kg of a 20% aqueous solution of 0.1, 0, 2, 0.3, 0.4 and 0.5 ml per 20 g of mouse weight, respectively.
  • iv intragastric
  • a 20% aqueous solution of 0.1, 0, 2, 0.3, 0.4 and 0.5 ml per 20 g of mouse weight, respectively.
  • Each of the compounds 1-hydroxy-1-herma-2,8,9-thioxo-5-azatracyclo [3.3.3] was reduced, each of the carboxylates of the formulas (Ia-Ie), separately.
  • mice the LD 50 value for the studied compounds (Ia-Ie) was more than 5000 mg / kg, which allows them to be classified as hazard class IV in accordance with the hazard classification of substances according to the degree of exposure to the organism according to
  • the obtained new compounds - salts of 1-hydroxyhydramine with hydroxy-, keto-, dicarboxylic acids are used in industry, in particular in the chemical industry, and, as studies have shown, the said proposed salts are biologically active substances, can find application as new agents in pharmacotherapy, medicine, medical, pharmaceutical and food industries, including baby food, for water treatment, in cosmetology, perfumery, dentistry.

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

Abstract

L'invention concerne la chimie organique des éléments et la technologie chimique. Elle porte sur de nouveaux sels de 1-hydroxyhermatrane avec des acides oxy-, céto- et polycarboxyliques, et notamment des 1-hydroxy-1-herma-2,8,9-trioxa-5-azatricyclo[3.3.3]undécane carboxylates. On a crée de nouvelles substances de pureté élevée, on a élargi les connaissances sur la structure des compositions de 1-hydroxyhermatrane avec des acides oxy-, céto- et polycarboxyliques, on a élargi un certain nombre de classes de compositions de 1-hydroxyhermatrane ainsi que la classe des sels. Les nouveaux sels sont bioactifs et possèdent une gamme d'action étendue; ils peuvent s'utiliser en tant que nouveaux produits en thérapie pharmaceutique, en médecine, dans les industries médicale, pharmaceutique ou alimentaire, notamment dans les aliments pour enfants, pour la purification d'eau, en industrie cosmétique, en parfumerie et en stomatologie.
PCT/RU2007/000735 2006-12-26 2007-12-26 Sels de 1-hydroxyhermatrane avec des acides oxy-, céto- et polycarboxyliques WO2008079055A1 (fr)

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RU2006146303/04A RU2333912C1 (ru) 2006-12-26 2006-12-26 Соли 1-гидроксигерматрана с окси-, кето- и дикарбоновыми кислотами
RU2006146303 2006-12-26

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250138A (zh) * 2011-06-08 2011-11-23 广东药学院 一种杂氮锗三环类化合物及其制备方法和应用
WO2013113930A1 (fr) 2012-02-03 2013-08-08 Dsm Ip Assets B.V. Copolymère à blocs, procédé et composition correspondants
RU2741229C1 (ru) * 2020-10-12 2021-01-22 Федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр реабилитации и курортологии» Министерства здравоохранения Российской Федерации (ФГБУ «НМИЦ РК» Минздрава России) Способ коррекции атерогенеза в эксперименте с помощью 1-гидроксигерматрана

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2104032C1 (ru) * 1997-03-11 1998-02-10 Общество с ограниченной ответственностью "Снежный барс" Способ усиления лечебного эффекта лекарственных средств
RU2108096C1 (ru) * 1995-06-26 1998-04-10 Владимир Флорович Миронов Средство, стимулирующее в эксперименте синтез иммуноглобулинов
RU2171259C2 (ru) * 1996-09-05 2001-07-27 Праймамедик Лимитед Комплекс 1:2 германия и 2,6-пиридиндикарбоновой кислоты, способ его получения, фармацевтическая композиция
RU2272624C1 (ru) * 2005-06-10 2006-03-27 Общество с ограниченной ответственностью "Сафрон" Применение 1-гидроксигерматрана (моногидрата) в качестве средства актопротекторного действия и стимулирующего тканевое дыхание в организме и способ его получения

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2108096C1 (ru) * 1995-06-26 1998-04-10 Владимир Флорович Миронов Средство, стимулирующее в эксперименте синтез иммуноглобулинов
RU2171259C2 (ru) * 1996-09-05 2001-07-27 Праймамедик Лимитед Комплекс 1:2 германия и 2,6-пиридиндикарбоновой кислоты, способ его получения, фармацевтическая композиция
RU2104032C1 (ru) * 1997-03-11 1998-02-10 Общество с ограниченной ответственностью "Снежный барс" Способ усиления лечебного эффекта лекарственных средств
RU2272624C1 (ru) * 2005-06-10 2006-03-27 Общество с ограниченной ответственностью "Сафрон" Применение 1-гидроксигерматрана (моногидрата) в качестве средства актопротекторного действия и стимулирующего тканевое дыхание в организме и способ его получения

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250138A (zh) * 2011-06-08 2011-11-23 广东药学院 一种杂氮锗三环类化合物及其制备方法和应用
CN102250138B (zh) * 2011-06-08 2014-04-23 广东药学院 一种杂氮锗三环类化合物及其制备方法和应用
WO2013113930A1 (fr) 2012-02-03 2013-08-08 Dsm Ip Assets B.V. Copolymère à blocs, procédé et composition correspondants
RU2741229C1 (ru) * 2020-10-12 2021-01-22 Федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр реабилитации и курортологии» Министерства здравоохранения Российской Федерации (ФГБУ «НМИЦ РК» Минздрава России) Способ коррекции атерогенеза в эксперименте с помощью 1-гидроксигерматрана

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