WO2012047131A1 - Anti-viral agent against influenza b - Google Patents

Anti-viral agent against influenza b Download PDF

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WO2012047131A1
WO2012047131A1 PCT/RU2011/000773 RU2011000773W WO2012047131A1 WO 2012047131 A1 WO2012047131 A1 WO 2012047131A1 RU 2011000773 W RU2011000773 W RU 2011000773W WO 2012047131 A1 WO2012047131 A1 WO 2012047131A1
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influenza
virus
drug
viruses
viral agent
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Владимир Константинович ПОДГОРОДНИЧЕНКО
Анатолий Федорович ЦЫБ
Рахимджан Ахметджанович РОЗИЕВ
Анна Яковлевна ГОНЧАРОВА
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Общество С Ограниченной Ответственностью "Научно-Исследовательская Компания "Медбиофарм"
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Priority to EA201370058A priority Critical patent/EA021443B1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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, namely to pharmacology and the creation of medicines and can be used to treat influenza caused by influenza B viruses.
  • Influenza viruses in 60-65% cause epidemic and infectious diseases in the world. According to the World Health Organization (WHO), every year during the epidemic of influenza and similar diseases in the world, up to 100 million people are sick, and up to 500 thousand people die. Since vaccination, which is the main means of combating influenza, does not allow a significant number of cases to prevent the incidence of influenza, etiotropic chemotherapy drugs that suppress the reproduction of the virus remain an important means of combating this disease. Currently, several such drugs are used in the world.
  • the first generation includes drugs of the adamantane series: Amantadine (1-aminoadamantane hydrochloride and its derivative rimantadine (alpha-methyl-1-adamantane-methylamine hydrochloride), which are ion channel blockers formed by the M2 protein of the influenza virus.
  • drugs derivatives of adamantane are therapeutically and prophylactically effective against influenza A virus but not effective against influenza virus In (Douglas RG 1990. Prophylaxis and treatment of influenza. New Engl. J. Med., 322,443-450 Review, Hayden FG1996, Amantadine and rimantadine-clinical aspects. In: Richman, DD (Ed) Antiviral Drug Resistance.
  • Second-generation drugs which include the neuraminidase inhibitors zanamivir, used in the form of an aerosol, and oseltamivir, used in the form of capsules or suspensions for children, are effective against both influenza A virus and influenza B virus (Von Itzstein M., Wu, WY , Kok GKet al 1993 Rational design of potent sialidase-based inhibitors of influenza virus protection. Nature 363, 418-423, Kim CU, Lew W., Williams MA 1997, Influenza neuraminidase inhibitors possessing a novel hydrophobic interactions in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J. Am. Chem. Soc 1 19, 681-690) are also often associated with their use obochnyh effects.
  • Arbidol (1-methyl-2-phenyl-thiomethyl-3-carbotoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate) inhibits the reproduction of influenza A and B virus in cell culture and protects against the death of mice infected with influenza virus.
  • Arbidol acts in the early stages of viral reproduction, inhibiting the fusion of the viral lipid membrane with cell membranes, and prevents the virus from entering the cell.
  • the antiviral activity of Arbidol has been proven in numerous clinical studies.
  • the present invention is based on the discovery by the authors of an anti-influenza agent claimed by them of Hydrochloride 1 - ⁇ [6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-n-indol-3-yl] carbonyl ⁇ -4-benzylpiperazine (hereinafter drug), effectively suppressing the reproduction of influenza A viruses, the ability to suppress the reproduction of influenza B viruses.
  • This drug has the following structure:
  • the antiviral effect of the drug against influenza B viruses was demonstrated in an experiment to study the effect of the drug on the reproduction of influenza B viruses in a culture of MDS cells (transplantable cells of a dog kidney tissue culture).
  • Tests of the antiviral activity of the drug were carried out on strains of influenza B viruses under conditions of the same multiplicity of virus infection.
  • the antiviral activity of the drug was studied on the basis of its ability to suppress the reproduction of viruses when used at a concentration of 10 ⁇ g / ml.
  • the anti-influenza drug Arbidol was used as a reference drug.
  • the study was carried out according to the following scheme: a drug and Arbidol at a concentration of 10 ⁇ g / ml were added to a monolayer of MDSK cells in a 96 well panel, incubated for 2-3 hours at 37 ° C, and then infected with viruses with the same multiplicity. The panels were incubated 24 hours at 37 ° C.
  • mice monoclonal antibodies to influenza B viruses, horseradish peroxidase conjugate and antibodies to mouse antibodies, a substrate for peroxidase were sequentially introduced into the wells of the panels. After the reaction was stopped, the results were taken into account when comparing the density indices in the control (virus) and experimental wells (virus + preparation). The results of the study of the effect of the drug on the reproduction of influenza B viruses are shown in table 1.

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  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to the field of medicine, more specifically pharmacology and the creation of drugs, and can be used for treating influenza caused by influenza B viruses. An anti-viral agent against influenza B is proposed which comprises 1-{[6-bromine-1-methly-5-methoxy-2-phenylthiomethyl-1-n-indole-3-yl] carbonyl}-4-benzyl-piperazine hydrochloride.

Description

Средство против вируса гриппа В  Influenza B virus
Изобретение относится к области медицины, а именно к фармакологии и созданию лекарственных средств и может быть использовано для лечения гриппа, вызываемого вирусами гриппа В. The invention relates to medicine, namely to pharmacology and the creation of medicines and can be used to treat influenza caused by influenza B viruses.
Вирусы гриппа в 60-65% являются причиной эпидемических и инфекционных заболеваний в мире. По данным Всемирной Организации Здравоохранения (ВОЗ), ежегодно во время эпидемии гриппа и подобных ему заболеваний в мире болеют до 100 миллионов, а умирают до 500 тысяч человек. Поскольку вакцинация, являющая основным средством борьбы с гриппом, не позволяет в значительном числе случаев предупредить заболеваемость населения гриппом, важным средством борьбы с этим заболеванием остаются этиотропные химиопрепараты, подавляющие репродукцию вируса. В настоящее время в мире используется несколько таких препаратов. К первому поколению относятся препараты адамантанового ряда: Амантадин (1-аминоадамантан гидрохлорид и его производное римантадин (альфа-метил- 1- адамантан-метиламин гидрохлорид), являющихся блокаторами ионных каналов, образованных М2 белком вируса гриппа. Широко используемые препараты производные адамантана терапевтически и профилактически эффективны в отношении вируса гриппа А, но не эффективны в отношении вируса гриппа В (Douglas R.G. 1990. Prophylaxis and treatment of influenza. New Engl.J.Med., 322,443-450 Review, Hayden F.G.1996, Amantadine and rimantadine-clinical aspects. In: Richman, D.D. (Ed) Antiviral Drug Resistance. John Wiley and Sons, Ltd, New York, pp 43-51, Zlydnikov D.M., Kubar O.I., Kovaleva T.P. et al 1981. Study of rimantadine in the USSR: a review of the literature. Rev. Infect. Dis.3, 408-421) и кроме того вызывают возникновение ряда побочных эффектов. Препараты второго поколения, к которым относятся ингибиторы нейраминидазы занамивир, используемый в форме аэрозоля, и озельтамивир, применяемый в виде капсул или суспензии для детей, эффективны в отношении как вируса гриппа А, так и вируса гриппа В (Von Itzstein М., Wu, W-Y, Kok G.K.et al 1993 Rational design of potent sialidase-based inhibitors of influenza virus protection. Nature 363, 418-423, Kim C.U., Lew W., Williams M.A. 1997, Influenza neuraminidase inhibitors possessing a novel hydrophobic interactions in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J. Am. Chem. Soc 1 19, 681-690) по их применению также часто сопряжено с возникновением побочных эффектов. Influenza viruses in 60-65% cause epidemic and infectious diseases in the world. According to the World Health Organization (WHO), every year during the epidemic of influenza and similar diseases in the world, up to 100 million people are sick, and up to 500 thousand people die. Since vaccination, which is the main means of combating influenza, does not allow a significant number of cases to prevent the incidence of influenza, etiotropic chemotherapy drugs that suppress the reproduction of the virus remain an important means of combating this disease. Currently, several such drugs are used in the world. The first generation includes drugs of the adamantane series: Amantadine (1-aminoadamantane hydrochloride and its derivative rimantadine (alpha-methyl-1-adamantane-methylamine hydrochloride), which are ion channel blockers formed by the M2 protein of the influenza virus. Widely used drugs derivatives of adamantane are therapeutically and prophylactically effective against influenza A virus but not effective against influenza virus In (Douglas RG 1990. Prophylaxis and treatment of influenza. New Engl. J. Med., 322,443-450 Review, Hayden FG1996, Amantadine and rimantadine-clinical aspects. In: Richman, DD (Ed) Antiviral Drug Resistance. John Wiley and Sons, Ltd, New York, pp 43-51, Zlydnikov DM, Kubar OI, Kovaleva TP et al 1981. Study of rimantadine in the USSR: a review of the literature. Rev. Infect. Dis. 3, 408-421) and In addition, they cause a number of side effects. Second-generation drugs, which include the neuraminidase inhibitors zanamivir, used in the form of an aerosol, and oseltamivir, used in the form of capsules or suspensions for children, are effective against both influenza A virus and influenza B virus (Von Itzstein M., Wu, WY , Kok GKet al 1993 Rational design of potent sialidase-based inhibitors of influenza virus protection. Nature 363, 418-423, Kim CU, Lew W., Williams MA 1997, Influenza neuraminidase inhibitors possessing a novel hydrophobic interactions in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J. Am. Chem. Soc 1 19, 681-690) are also often associated with their use obochnyh effects.
В России широкое распространение получил отечественный препарат Арбидол, созданный совместными усилиями ученых Медицинского Центра Химии лекарственных средств (ЦХАС-ВНИХФИ, г. Москва) и НИИ эпидемиологии и микробиологии им. Пастера (г. Санкт-Петербург). Антивирусный W In Russia, the domestic drug Arbidol, created by the joint efforts of scientists of the Medical Center for Chemistry of Medicines (TsHAS-VNIHFI, Moscow) and the Research Institute of Epidemiology and Microbiology named after Pasteur (St. Petersburg). Antivirus W
3 3
препарат Арбидол ( 1-метил-2-фенил-тиометил-3-карботокси-4- диметиламинометил-5-гидрокси-6-бромоиндолгидрохлорид моногидрат) ингибирует репродукцию вируса гриппа А и В в культуре клеток и защищает от гибели мышей, инфицированных вирусом гриппа. Арбидол действует на ранних стадиях вирусной репродукции, ингибируя слияние вирусной липидной оболочки с клеточными мембранами, предотвращаяет проникновение вируса внутрь клетки. Противовирусная активность Арбидола доказана в многочисленных клинических исследованиях.  Arbidol (1-methyl-2-phenyl-thiomethyl-3-carbotoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate) inhibits the reproduction of influenza A and B virus in cell culture and protects against the death of mice infected with influenza virus. Arbidol acts in the early stages of viral reproduction, inhibiting the fusion of the viral lipid membrane with cell membranes, and prevents the virus from entering the cell. The antiviral activity of Arbidol has been proven in numerous clinical studies.
Поскольку длительное применение противовирусных препаратов, как правило, приводит к усилению резистентности к ним вирусов гриппа и тем самым к снижению терапевтической эффективности, совершенно очевидно, что только новые препараты могут обеспечить прогресс в лечении гриппа.  Since long-term use of antiviral drugs, as a rule, leads to an increase in the resistance of influenza viruses to them and thereby to a decrease in therapeutic effectiveness, it is clear that only new drugs can ensure progress in the treatment of influenza.
Предлагаемое изобретение основано на обнаружении авторами у заявленного ими противогриппозного средства Гидрохлорид 1 - { [6-бром- 1 -метил-5 -метокси-2-фенилтиометил- 1 - н-индол-3-ил]карбонил}-4-бензилпиперазин (далее препарат), эффективно подавляющего репродукцию вирусов гриппа А, способности подавлять репродукцию вирусов гриппа В. Указанный препарат имеет следующую структуру: The present invention is based on the discovery by the authors of an anti-influenza agent claimed by them of Hydrochloride 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-n-indol-3-yl] carbonyl} -4-benzylpiperazine (hereinafter drug), effectively suppressing the reproduction of influenza A viruses, the ability to suppress the reproduction of influenza B viruses. This drug has the following structure:
Figure imgf000005_0001
Figure imgf000005_0001
Противовирусное действие препарата в отношении вирусов гриппа В продемонстрировано в эксперименте по изучению влияния препарата на репродукцию вирусов гриппа В в культуре клеток МДСК (перевиваемые клетки культуры ткани почки собаки). The antiviral effect of the drug against influenza B viruses was demonstrated in an experiment to study the effect of the drug on the reproduction of influenza B viruses in a culture of MDS cells (transplantable cells of a dog kidney tissue culture).
В предварительных экспериментах было исследовано цитотоксическое действие препарата для установления минимально токсической концентрации, которая составила 50 мкг/мл.  In preliminary experiments, the cytotoxic effect of the drug was studied to establish a minimally toxic concentration, which was 50 μg / ml.
Испытания противовирусной активности препарата были проведены на штаммах вирусов гриппа В в условиях одинаковой множественности заражения вирусом. Противовирусная активность препарата изучена на основании его способности подавлять репродукцию вирусов при использовании в концентрации 10 мкг/мл. В качестве препарата сравнения был использован противогриппозный препарат Арбидол. Исследование выполнялось по следующей схеме: на монослой клеток МДСК в 96 луночной панели вносили препарат и Арбидол в концентрации 10 мкг/мл, инкубировали 2-3 часа при 37°С, а затем заражали вирусами с одинаковой множественностью. Панели инкубировали 24 часа при 37°С. Затем осуществляли постановку иммуноферментного анализа для определения концентрации вируса. С этой целью в лунки панелей последовательно вносили мышиные моноклональные антитела к вирусам гриппа В, конъюгат пероксидазы хрена и антител к мышиным антителам, субстрат для пероксидазы. После остановки реакции проводили учет результатов при сравнении показателей плотности в контрольных (вирус) и опытных лунках (вирус + препарат). Результаты исследования влияния препарата на репродукцию вирусов гриппа В приведены в таблице 1. Tests of the antiviral activity of the drug were carried out on strains of influenza B viruses under conditions of the same multiplicity of virus infection. The antiviral activity of the drug was studied on the basis of its ability to suppress the reproduction of viruses when used at a concentration of 10 μg / ml. The anti-influenza drug Arbidol was used as a reference drug. The study was carried out according to the following scheme: a drug and Arbidol at a concentration of 10 μg / ml were added to a monolayer of MDSK cells in a 96 well panel, incubated for 2-3 hours at 37 ° C, and then infected with viruses with the same multiplicity. The panels were incubated 24 hours at 37 ° C. An enzyme-linked immunosorbent assay was then performed to determine the concentration of the virus. To this end, mouse monoclonal antibodies to influenza B viruses, horseradish peroxidase conjugate and antibodies to mouse antibodies, a substrate for peroxidase were sequentially introduced into the wells of the panels. After the reaction was stopped, the results were taken into account when comparing the density indices in the control (virus) and experimental wells (virus + preparation). The results of the study of the effect of the drug on the reproduction of influenza B viruses are shown in table 1.
Таблица 1Table 1
Сравнительная эффективность действия препарата и Арбидола на вирус гриппа В Comparative efficacy of the drug and Arbidol on influenza B virus
Figure imgf000007_0001
Figure imgf000007_0001
Кроме этого для оценки противовирусной активности препарата были определены концентрации (мкг/мл), ингибирующие вирусную репродукцию вируса гриппа В Москва 79/08 на 50% (ИК5о). Результаты определения ИК50 препарата для вируса гриппа В в клетках MDCK в сравнении с Арбидолом приведены в таблице 2. Таблица 2In addition, to assess the antiviral activity of the drug, concentrations (μg / ml) were determined that inhibit the viral reproduction of influenza virus B Moscow 79/08 by 50% (IR 5 °). The results of determining the IC 50 of the drug for influenza B virus in MDCK cells in comparison with Arbidol are shown in table 2. table 2
Противовирусная активность препарата в отношении вируса гриппа В в клетках MDCK Antiviral activity of the drug against influenza B virus in MDCK cells
Figure imgf000008_0001
Figure imgf000008_0001
Из данных, приведенных в таблицах 1 и 2, видно, что препарат в отношении вируса гриппа В обладает специфической активностью, соизмеримой с активностью препарата сравнения - Арбидола. From the data shown in tables 1 and 2, it can be seen that the drug against influenza B virus has a specific activity that is comparable with the activity of the reference drug - Arbidol.

Claims

Формула изобретения Claim
Средство против вируса гриппа В, представляющее собой гидрохлорид 1 - { [6-бром- 1 -метил-5-метокси-2-фенилтиометил- 1 - н-индол-3-ил] карбонил} -4-бензилпиперазин следующей структурной формулы: The anti-influenza B virus agent, which is 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-n-indol-3-yl] carbonyl} -4-benzylpiperazine hydrochloride of the following structural formula:
Figure imgf000009_0001
Figure imgf000009_0001
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