WO2007120079A2 - Dérivés de 4-aminométhyl-6-brome-5-hydroxyindol-3-carboxylates - Google Patents

Dérivés de 4-aminométhyl-6-brome-5-hydroxyindol-3-carboxylates Download PDF

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Publication number
WO2007120079A2
WO2007120079A2 PCT/RU2007/000179 RU2007000179W WO2007120079A2 WO 2007120079 A2 WO2007120079 A2 WO 2007120079A2 RU 2007000179 W RU2007000179 W RU 2007000179W WO 2007120079 A2 WO2007120079 A2 WO 2007120079A2
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Prior art keywords
alkyl
formula
hydroxy
bromo
derivatives
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PCT/RU2007/000179
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English (en)
Russian (ru)
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WO2007120079A3 (fr
Inventor
Rakhimdzhan Akhmetdzhanovich Roziev
Jury Grigorievich Verkhovsky
Fedor Alexandrovich Trofimov
Nina Gavrilovna Tsyshkova
Elena Sergeevna Shevchenko
Elena Ivanovna Burtseva
Anatoliy Fedorovich Tsyb
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Obschestvo S Ogranichennoy Otvetstvennostju 'mbf'
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Publication of WO2007120079A2 publication Critical patent/WO2007120079A2/fr
Publication of WO2007120079A3 publication Critical patent/WO2007120079A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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

  • the invention relates to medicine and relates to antiviral prophylactic and therapeutic agents and methods for their preparation.
  • antiviral drugs are generally only active against certain viruses. And since more than a thousand varieties of viruses have already been discovered, and about half of them are dangerous to humans, the creation of new antiviral drugs is simply necessary.
  • the mechanism of action of modern antiviral drugs is to block one of the stages of reproduction of viruses in the cells of the virus carrier (human), which includes the step of attaching the virus to the cell and penetrating inside it, embedding the nucleic acid of the virus in the genome of the host cell, synthesis of its own DNA and RNA, synthesis and assembly own proteins of the virus.
  • Most of the available antiviral drugs are nucleoside analogues.
  • WO05 / 87729 describes 5-hydroxyind o derivatives of l-3-carboxylates of the general formula M:
  • Y means a group NR 3 R 4 in which R 3 and R 4 can be hydrogen, C 1-10 alkyl, C3 -7 cycloalkyl, C2-ioalkenyl or C 2-1 O alkynyl or R 3 and R 4 together with N form a 5-10 membered heterocycle, which may additionally contain N, 0 or S as a heteroatom,
  • R 1 may be C 1-5 alkyl, C 3-7 cycloalkyl,
  • R 2 may mean C 1-5 alkyl
  • R 1 may denote C 1-10 Alkyl, C 3- 7 tsikloalkil,
  • R 2 may be C 1-4 alkyl
  • R 5 may be C ⁇ alkyl
  • R 3 and R 3 may be hydrogen, alkyl, etc., or R 3 and R 3 together with N form a ring.
  • the compounds have a high inhibitory effect in influenza virus and acute respiratory
  • SUBSTITUTE SHEET (RULE 26) diseases and can be used as anti-influenza agents for the treatment and prevention of acute respiratory disease virus. Also described is a pharmaceutical composition and method for producing compounds.
  • CN1482118 describes compounds of general formula N, wherein Z -H, CH2-S-R5 , b SNgNR RSyoalkyu ⁇ Sg.ioalkenil or C 2-10 alkynyl which may be used as anti-influenza agents and for the treatment and prevention of acute virus with respiratory disease . Also described is a pharmaceutical composition and method for producing compounds.
  • JP63-188665 describes b-halogen-5-hydroxy-indole-3-carboxylates of the formula P:
  • R 1 and R 2 are hydrogen ; alkyl, aralkyl or together with a nitrogen atom form a heterocyclic group, Rz-alkyl, aralkyl, R 4 -H, alkyl, cycloalkyl, aryl or aralkyl X-halogen, and their acid addition salts.
  • Rz-alkyl, aralkyl, R 4 -H alkyl, cycloalkyl, aryl or aralkyl X-halogen, and their acid addition salts.
  • methyl 1-cyclohexyl-4-piperidinomethyl-6-bromo-5-hydroxy-indole-3-carboxylate and methyl-1-benzyl-4-piperidinomethyl-6-bromo-5-hydroxyl are disclosed.
  • the compounds of formula P can be used to treat circulating diseases, such as blood diseases, possess anticoagulation effect, 5-lipogenase inhibitory properties, etc.
  • Jurpaal IPdiam Chemical Company, 1994.71 (4), 175-8 describes the synthesis and antimicrobial activity of derivatives of 5-hydroxyindoles, in particular 6-bromo-5-hydroxy-2-methyl-l- (phenylmethyl) ethyl ester - (l-pyropolidinylmethyl) -Sh-indole-3-carboxylic acid and 6-bromo-5-hydroxy-2-methyl-l- (phenylmethyl) -4- (l-piperidinylmethyl) -Sh-indole-3 ethyl ester carboxylic acid.
  • SUBSTITUTE SHEET (RULE 26) dimethylaminomethyl-l-methyl-2-phenylthiomethylindinol-3-carboxylic acid (Arbidol), which has an antiviral, interferon-inducing and immunomodulating effect, its production method and pharmaceutical composition.
  • the drug "Apbidol" is not effective enough for some strains of viruses.
  • the problem solved by the invention is new compounds with a wide spectrum of antiviral activity, a method for their preparation, pharmaceutical composition and use of the compounds. None of the known documents disclose specific compounds of the general formula I indicated below, or the use of the compounds of the general formula I for the treatment or prophylaxis of influenza A and B.
  • R is alkyl, aryl, cyclohexyl, cycloheptyl, R 1 is Ci-C3-alkyl, CH 2 -X-Ci-C 5 -alkyl, CH 2 -X-Ci-C 5 -apyl, CH 2 -X-Ci- A C 5 getqcycle, X is N, O or S, R 2 is Ci-C 5 alkyl, R 3 , R 4 have the same meaning and are selected from CH 3 or Q-Cs alkyl, NR 3 R 4 - 5-10 member heterocycle, which may contain N, O, S. as a heteroatom
  • the most preferred compounds are derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindole selected from:
  • SUBSTITUTE SHEET (RULE 26) Salts can be prepared by conventional methods, for example, by treating a compound of formula I with an appropriate acid.
  • Salts include, for example, hydrochlorides, mesylates, oxalates, etc.
  • a process for preparing compounds of Formula I, Where R ⁇ -Indicates Q-Cs-alkyl comprising the steps of: a) obtained by the known reaction of derivatives of 2-C 1 -Cz-Alkyl-5- gidpookciindol-3-kapbookcilata formula II:
  • R, R 1 , R 2 have the above meanings, they are brominated with a brominating agent in an acidic medium to obtain the corresponding 2-alkyl-6-bromo-5-hydroxy-indole-3-carboxylates of the formula III:
  • a method of obtaining compounds of formula I, where R 1 means CH 2 -X-Cj -C 3 -alkyl, CH 2 -XC ! -C 3 -apyl, CH 2 -X-Ci-C 3 -heterocycle, X-N, O, S includes the steps of: a) bromination of derivatives of 2-methyl-5-hydroxy-indole-3-carboxylate of formula II:
  • the proposed antiviral compounds have been shown to be effective against various strains of the influenza virus. However, there are differences in the effectiveness of the proposed drugs and analogue (Arbidol) in relation to different strains.
  • the inventive drugs were effective against other viruses.
  • the claimed drugs are not analogues of nucleosides, which allows us to hope that they will replenish the list of drugs with another softer, not affecting the metabolic processes in cells mechanism of action. Thus, a technical result is achieved.
  • the synthesis method of this compound is carried out according to the following scheme:
  • the available l-benzyl-5-hydroxy-2-methyl-3-ethoxycarbonylindinol used as a starting material is brominated with bromine in acetic acid at room temperature
  • Example 1 l-benzyl-5-hydroxy-2-methyl-3-ethoxycarbonylindole (II). 26.0 (0.2 mol) of acetoacetate and 25.7 (0.24 mol) of benzylamine are dissolved in 50 ml of toluene. To the resulting solution, add 1 drop of concentrated hydrochloric acid and the water released as a result of the reaction is distilled off in the form of an azeotropic mixture with toluene with a Dean-Stark nozzle.
  • Example 3 l-benzyl-6-bromo-5-hydroxy-2-methyl-4-piperidinomethyl-3-ethoxycarbonylindole (I). To 0.17 g (0.002 mol) of piperidine was added 0.4 ml of acetic acid, then 0.34 ml of a 40% formalin solution was cooled with ice water. To the resulting cold mixture, 0.78 g (0.002 mol) of 1-benzyl-6-bromo-5-hydroxy-2-methyl-3-ethoxycarbonylindinol (III) and 2 ml of dioxin are added. The mixture is heated until dissolved and left overnight.
  • 6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindole has the structure shown in the formula:
  • the synthesis is carried out by bromination of 5-hydroxy-2-methyl-l-cyclohexyl-3-ethoxycarbonylindole to the 6th position with bromine in acetic acid or N-bromosuccinimide in chloroform. The resulting 6-bromo-5-hydroxy-2-methyl-l-
  • SUBSTITUTE SHEET (RULE 26) cyclohexyl-3-ethoxycarbonylindinol after treatment with acetic anhydride is brominated into the side chain with N-bromosuccinimide, preferably in CCl 4 medium, in the presence of a radical initiating catalyst (benzene peroxide) and lighting. Then, the resulting product is treated with potassium thiophenolate in an organic solvent medium and then hydrolyzed with a solution of mineral acid in an organic solvent. The resulting compound is subjected to aminomethylation with bis- (dimethylamino) methane in an organic solvent.
  • Example 11 5-acetoxy-6-bromo-2-methyl-1-cyclorexyl-3-ethoxycarbonylindinol (V).
  • a mixture of 2.3 g (0.006 mol) of IV, 0.61 ml of acetic anhydride and 0.7 ml of pyridine is boiled for 3 hours.
  • the reaction mixture is cooled, water is added, the precipitate is filtered off, washed with water.
  • Example 12 5-Acetoxy-6-bromo-2-bromomethyl-l-cyclohexyl-3-ethoxycarbonylindole (VI).
  • a mixture of 1.9 g (0.0045 mol) V, 0.8 g (0.0045 mol) of N-bromosuccinimide, 0.04 g of benzoyl peroxide in 10 ml of carbon tetrachloride is boiled for 4 hours under a 300 W lamp. Succinimide was filtered off from the hot solution, washed with hot CCl 4. After evaporation of the solvent, 2 g of VI (88.8%) were isolated, mp. 140-141 0 C (from heptane). Found,%: C 48.27; H 4.94; N, 3.14. C 20 H 23 Br 2 NO 4. Calculated,%: C 47.93; H 4.63; N, 2.79.
  • Example 13 6-bromo-5-hydroxy-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindole (VII).
  • VI 6-bromo-5-hydroxy-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindole
  • Example 14 6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindinol (C).
  • a mixture of 0.74 g (0.0015 mol) of VII, 0.25 ml of bis- (dimethylamino) methane in 5 ml of dioxane is boiled for 4 hours. After evaporation of the dioxane, water is added, extracted with chloroform. The chloroform solution was washed with water, dried b / in Na 2 SO 4 , chloroform was evaporated in vacuo, hexane was added to the residue. The precipitate is filtered off.
  • the cytotoxicity of the claimed compounds was studied by applying them in different concentrations (100; 50; 25; 12.5; 6.0; 3.0 and 1.5 ⁇ g / ml) on a monolayer of MDCK cell culture (transplantable dog kidney tissue culture cells) on 96-night panels.
  • the number of viable cells was determined by comparing the intensity of staining the solution in the control and experimental wells with the addition of neutral red and incubation of the panels for 72 hours at 37, O 0 C.
  • a study of the effects of the compounds on influenza A and B viruses was carried out in an MDCK cell culture. The study was carried out according to the following scheme: a substance was added to a monolayer of a 96-well panel (previously dissolved in DMSO, then a nutrient medium) at various concentrations (12.5; 10.0; 7.5; 5.0 ⁇ g / ml), incubated 2 -3 hours at 37.0 ° C, and then virus dilutions were added (10 -1, 10-2, 10-3, 10-4).
  • the panels were incubated for 24 hours at 37 ° C, and then the reaction was completed by enzyme-linked immunosorbent assay, sequentially applying mouse monoclonal antibodies to influenza A or B viruses, conjugate (goat antibodies to monoclonal mouse antibodies labeled with horseradish peroxidase), substrate (orthophenylenediamine), The results were taken into account when comparing the optical density in the control, (virus) and experimental wells (virus + the claimed compound).
  • Tables 1, 2, and 3 show the results of suppressing the reproduction (%) of influenza A and B viruses in the presence of compounds of structure A, B, and C. It should be emphasized that the study included influenza viruses that had epidemic activity in the 2003-2004 and 2001 seasons. -2005, as well as the reference strain of influenza virus -
  • SUBSTITUTE SHEET (RULE 26) A / California / 7/04 (HZN2). The degree of sensitivity of viruses was determined by their strain.

Abstract

L'invention concerne la médecine et notamment des agents antiviraux prophylactiques et thérapeutiques ainsi que leurs procédés de fabrication. Les agents de l'invention se présentent sous la forme de dérivés de 4-aminométhyl-6-brome-5-hydroxyindol-3-carboxylates correspondant à la formule générale (I), dans laquelle R est alkyle, aryle, cyclohexyle, cycloheptyle, alkyle R1-C1-C3, alkyle CH2-X-C1-C5, aryle CH2-X-C1-C5, hétérocycle CH2-X-C1-C5, X est N, O, S, R2 est alkyle C1-C5, R3 et R4 ont une valeur égale CH3 ou alkyle C1-C5, NR3R4 est un hétérocycle à 5-10 membres, qui peut contenir en tant qu'hétéroatome N, O ou S. L'invention porte sur des procédés de fabrication desdits dérivés ainsi que sur leur utilisation et l'utilisation de leurs sels à des fins de préparation de médicaments destinés à traiter la grippe de type A ou de type B. L'invention permet d'élargir le spectre d'action antivirale.
PCT/RU2007/000179 2006-04-18 2007-04-13 Dérivés de 4-aminométhyl-6-brome-5-hydroxyindol-3-carboxylates WO2007120079A2 (fr)

Applications Claiming Priority (2)

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RU2006112818/04A RU2330018C2 (ru) 2006-04-18 2006-04-18 Производные 4-аминометил-6-бром-5-гидроксииндол-3-карбоксилатов, способы их получения (варианты) и применение
RU2006112818 2006-04-18

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WO2007120079A3 WO2007120079A3 (fr) 2008-01-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009131493A3 (fr) * 2008-04-23 2010-01-21 Общество С Ограниченной Ответственностью "Биhatex" Dérivés de 5-hydroxy-4-aminométhyl-1-cyclohexyl (ou cycloheptyl)-3-alkoxycarbonyl indoles, leurs sels pharmaceutiquement acceptables qui possèdent une activité antivirale
EP2213660A1 (fr) * 2007-10-31 2010-08-04 Obschestvo S Ogranichennoy Otvetstvennostju "Binatekh" Dérivés 5-substitués de l'acide indol-3-carbonique possédant une activité antivirale, procédé de fabrication et d'utilisation
WO2012047133A1 (fr) * 2010-10-05 2012-04-12 Общество С Ограниченной Ответственностью "Научно-Исследовательская Компания "Медбиофарм" Médicament contre le virus de la grippe b

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RU2435582C1 (ru) * 2010-10-05 2011-12-10 Общество С Ограниченной Ответственностью "Научно-Исследовательская Компания "Медбиофарм" Средство против вируса гриппа в

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2213660A1 (fr) * 2007-10-31 2010-08-04 Obschestvo S Ogranichennoy Otvetstvennostju "Binatekh" Dérivés 5-substitués de l'acide indol-3-carbonique possédant une activité antivirale, procédé de fabrication et d'utilisation
EP2213660A4 (fr) * 2007-10-31 2010-12-01 Obschestvo S Ogranichennoy Otv Dérivés 5-substitués de l'acide indol-3-carbonique possédant une activité antivirale, procédé de fabrication et d'utilisation
WO2009131493A3 (fr) * 2008-04-23 2010-01-21 Общество С Ограниченной Ответственностью "Биhatex" Dérivés de 5-hydroxy-4-aminométhyl-1-cyclohexyl (ou cycloheptyl)-3-alkoxycarbonyl indoles, leurs sels pharmaceutiquement acceptables qui possèdent une activité antivirale
EA018346B1 (ru) * 2008-04-23 2013-07-30 Ооо "Научно-Исследовательская Компания "Медбиофарм" Производные 5-гидрокси-4-аминометил-1-циклогексил(или циклогептил)-3-алкоксикарбонилиндола и их фармацевтически приемлемые соли, обладающие противовирусной активностью в отношении вируса гриппа а
WO2012047133A1 (fr) * 2010-10-05 2012-04-12 Общество С Ограниченной Ответственностью "Научно-Исследовательская Компания "Медбиофарм" Médicament contre le virus de la grippe b

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