WO2001080848A1 - Compositions destinees a inhiber la proliferation du virus d'immunodeficience humaine et methode d'inhibition de la proliferation de ce virus - Google Patents

Compositions destinees a inhiber la proliferation du virus d'immunodeficience humaine et methode d'inhibition de la proliferation de ce virus Download PDF

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Publication number
WO2001080848A1
WO2001080848A1 PCT/JP2001/003587 JP0103587W WO0180848A1 WO 2001080848 A1 WO2001080848 A1 WO 2001080848A1 JP 0103587 W JP0103587 W JP 0103587W WO 0180848 A1 WO0180848 A1 WO 0180848A1
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WIPO (PCT)
Prior art keywords
formula
hiv
inosose
compound
cells
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Application number
PCT/JP2001/003587
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English (en)
Japanese (ja)
Inventor
Tomio Takeuchi
Tuneya Ohno
Mariko Nakamura
Tsuyoshi Tamamura
Atsushi Takahashi
Original Assignee
Hokko Chemical Industry Co., Ltd.
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
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Application filed by Hokko Chemical Industry Co., Ltd., Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai filed Critical Hokko Chemical Industry Co., Ltd.
Publication of WO2001080848A1 publication Critical patent/WO2001080848A1/fr

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to a novel composition for inhibiting the growth of HIV against human immunodeficiency virus (HIV), and to a method for inhibiting the growth of HIV.
  • HIV human immunodeficiency virus
  • the present invention is useful for the prevention and treatment of acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • AIDS acquired immunodeficiency syndrome
  • AIDS therapeutics since immunostimulants are involved in the mechanism of HIV transmission to human hosts, they are described in the specifications of PCT International Publication Nos.W098 / 57620 and W090 / 00057.
  • Myo-inositol and scyllo-inositol are known to have an immunostimulatory activity, and in particular to have the activity of enhancing the proliferation of B cells and T cells. It is known to have an increasing effect.
  • an immunostimulant activates systemic immunity, which suggests that the immunostimulant is effective against acquired immunodeficiency syndromes (AIDS) caused by HIV infection of T cells. Be told. However, at present it is known that substances with immunostimulatory activity do not necessarily show high efficacy in treating AIDS when studied in in vivo studies. Also, in the international specification of the PCT application, the immunostimulant disclosed and proposed herein is disclosed. Has no direct antiviral effect on HIV. On the other hand, 3'-deoxy-3,1-azidothymidine (AZT), which has activity to inhibit the process of human immunodeficiency virus (HIV) infection and is actually used as a therapeutic drug in the clinical treatment of AIDS, It has been known.
  • AKT 3'-deoxy-3,1-azidothymidine
  • this AZT is a nucleic acid analog.
  • AZT is highly toxic and poses a problem because it has side effects such as bone marrow damage and acute inflammation caused by long-term administration.
  • the mechanism of action of AZT is due to its ability to inhibit the process of HIV infection via CD-4 receptors on the surface of T cells, etc.
  • the anti-HIV effect of AZT is not necessarily high. In fact, at present, even if AZT is administered as a treatment for AIDS in the clinical setting, it has not shown satisfactory therapeutic effects.
  • HIV protease inhibitors are known as clinical drugs for AIDS. This remedy also shows many side effects such as nausea and diarrhea, and the emergence of resistant virus is a problem.
  • dextran sulfate has the activity to strongly inhibit the binding of HIV particles to the CD4 receptor on the surface of T cells in in vitro tests, and may have low toxicity. It was hoped that it could exert anti-HIV effects.
  • dextran sulfate was determined to be ineffective in in vivo studies. The reasons why dextran sulfate does not exhibit anti-HIV effects in vivo are: (1) the possibility that it is a macromolecule and is not absorbed by the living body, or (2) it is degraded in the intestinal tract and inactivated.
  • new HIV agents that can be used for future development include T cells in HIV cells even after the infection of T cells has been established. Action to inhibit the growth of HIV There is still a strong demand for new anti-HIV agents that have low toxicity and low toxicity to human host cells. Disclosure of the invention
  • An object of the present invention is to have the activity of inhibiting the growth of HIV particles in T cells even after the infection of T cells with HIV, to have low toxicity to human hosts and human host cells, An object of the present invention is to provide a novel HIV growth inhibitor.
  • the present inventors focused on a substance having an activity or a mechanism of action that inhibits the growth of HIV particles present in T cells infected with HIV, and developed a blood cell system in which HIV has undergone chronic infection.
  • they succeeded in finding that L-epi-2-inosose and (+)-protoquercitol exhibited the expected HIV growth inhibitory activity against HIV particles infecting T cells.
  • LPE21-inosose and (+)-protoquercitol which have been found to have antiviral activity in the present invention, infect T cells and the like. It showed strong growth inhibitory activity against HIV particles and extremely low toxicity to human cells.
  • the present invention has been completed based on these findings.
  • myo-inositol and scyllo-inositol, analogs of L-epi-2-inosose and (+)-protalk elsitol are applied to the treatment of immune diseases caused by viruses such as AIDS through their immunostimulatory effects.
  • the mechanism of action of myo-inositol and scyllo-inositol is to secondaryly enhance systemic immunity.
  • the present inventors conducted an anti-HIV activity test to determine whether myo-inositol and scyllo-inositol have an activity of inhibiting the growth of HIV. As a result, it was found that myo-inositol and scyllo-inositol had a significantly lower activity of inhibiting the growth of HIV than L-epi-2f nosose and (+)-protalk ercitol, which was not practically useful. It was recognized by the present inventors.
  • a pharmaceutically acceptable solid or liquid carrier for the active ingredient for inhibiting the growth of the human immunodeficiency virus, characterized by containing monodoxy-inositol or inosose as an active ingredient and a pharmaceutically acceptable solid or liquid carrier for the active ingredient.
  • a pharmaceutical composition is provided.
  • the monodoxy-inositol used in the present invention has the following formula (I ⁇
  • (+) Preferably, protokerucitol, or it may be (en) one of its enantiomers, or it may be racemic (sat) of its racemic form. It can be talk elcitol.
  • the L-epi 1-2-inosose is represented by the following formula, or it can be the D-epi 1-2-inosose of the enantiomer, and the racemic DL-epi 2f It can be nosor.
  • the Protoquer citrate and Epi-2-inosose used in the present invention may be a synthetic product or a product obtained by a method of extraction from a natural product.
  • (+)-protoquercitol of the formula (1-1) can be prepared by allowing a microorganism belonging to the genus Salmonella or Agrobacterium to act on myo-inositol by the method described in JP-A-11-12210.
  • L-epi-2-inosose represented by the formula (1-2) can be prepared by adding Xanthomonas sp. To myo-inositol by the method described in PCT Application No. PCT / JP00 / 03687, International Publication WO 00 / 75355A1. It can be obtained with high purity by the action of strain AB10119 (FERM BP-7168) or other bacteria.
  • D L eppy 2-inosose can be synthesized by oxidizing myo-inositol with an oxidizing agent such as nitric acid (Helv. Chini. Acta 19, 1333, 1936). D-epi 2-inosose can be produced from D L-epi 2-inosose by using an appropriate optical resolution method.
  • the cyclic sugar alcohol type compound of the formula (I) or its oxo form used in the composition of the present invention especially the sugar alcohol of the formula (1-1) or its enantiomer or its racemic form, and the formula (I) 1-2) Inosource or its enantiomer or its racemate may be used for prevention or treatment of diseases due to HIV infection, such as immunodeficiency or carinii pneumonia, or AIDS in asymptomatic HIV carriers. It is useful for blocking.
  • the compound of the general formula (I) used as the active ingredient in the first composition of the present invention or the sugar alcohol of the formula (1-1) or its enantiomer or its racemate, or the formula (1-2)
  • oral administration or parenteral administration can also be used.
  • anal, nasal, topical (including sublingual), vaginal administration It can be injected (including intramuscular, intravenous, and subcutaneous injections) and can be applied topically.
  • the compound of the formula (I), the compound of the formula (1-1) or the formula (1-2) used in the present invention, or an enantiomer or a racemate of these compounds is By mixing with an organic or inorganic solid or liquid pharmaceutically acceptable carrier suitable for the administration method, it can be used in the form of conventional pharmaceutical preparations.
  • an organic or inorganic solid or liquid pharmaceutically acceptable carrier suitable for the administration method for example, lactose, kaolin, sucrose, crystalline cellulose, starch, talc, agar, pectin, magnesium stearate, lecithin, etc. are used. Oil, ethanol, aqueous ethanol, benzyl alcohol, propylene glycol, and the like are used.
  • Such preparations include, for example, solid preparations such as tablets, granules, capsules and the like, and liquid preparations such as liquid preparations, emulsions, suspensions and the like, or ointments.
  • solid preparations such as tablets, granules, capsules and the like
  • liquid preparations such as liquid preparations, emulsions, suspensions and the like, or ointments.
  • amount of the compound of the formula (I), the compound of the formula (1-1) or the formula (1-2), or the enantiomer or racemate thereof, to be incorporated in various preparations may vary depending on the patient's symptoms and Appropriately adjusted depending on the shape.
  • a compound of the formula (I), in particular, a compound of the formula (1-1) or a compound of the formula (1-1) can be administered at a dose of 0.1 mg to 800 mg, preferably 0.5 mg to 300 mg.
  • the compound of 1-2) or its enantiomer can be administered once, twice, three or more times per day.
  • a human host having T cells and / or monocytes / macrophages and / or other blood cell lines infected with human immunodeficiency virus (HIV)
  • HAV human immunodeficiency virus
  • HIV human immunodeficiency virus
  • the compound of the formula (I) administered in the second method of the present invention has the following formula (1-1)
  • the compound of the general formula (I), or the compound of the formula (1-1) or the formula (1-2) or its enantiomer or racemate is prepared in an amount of 0.1 mg to 800 mg, particularly 0.5 mg to 800 mg. It can be administered orally or parenterally once, twice or three times daily at a dose of 300 mg.
  • Parenteral administration of a compound of formula (I) or a compound of formula (1-1) or formula (1-2) or an enantiomer thereof may be performed by intramuscular, intravenous, subcutaneous injection or rectal administration, or It can be performed by mucosal administration.
  • the human immunodeficiency virus (HIV) T cells and / or monocytes / macrophages and / or other blood cells that are infected with the cells of the general formula (I)
  • the compound of formula (I) used is (+) — protoquercitol, or (1) one protalkositol or (P) one protalkositol, or L —Epi 2—Inno Source or D—Epi 2—Inno Source or DL—Epi 2—Inno Source.
  • the compound of the general formula (I) or the compound of the formula (1-1) or the formula (1-2) or an enantiomer or a racemate thereof is added in an amount of 0.2 ⁇ g / ml to 10 ⁇ .
  • Contacting HIV-infected cells in vitro at a concentration of g / ml can inhibit the growth of HIV in those cells.
  • (+) Protocol ercitol, or (1) One Protalk ercitol or (P) —Protalk ercitol, or the following formula (1-2)
  • (+) Protoque ercitol powder 5 g, sterile water 50 ml
  • the above (+) — protoque ercitol powder 5 g was dissolved in 50 ml of sterile water.
  • the obtained solution was filtered with a membrane filter for sterilization.
  • the filtered aseptic solution was dispensed under aseptic conditions into 5 ml aliquots of 10 ml brown vials, lyophilized aseptically, and sealed with nitrogen gas.
  • (+)-protoquercitol for intravenous injection was obtained.
  • the formulation in the vial was immediately and completely dissolved when added to 5 ml of sterile saline under aseptic conditions immediately before use for intravenous injection.
  • Got The aqueous solution contained (+)-protoquercitol at a concentration of 100 mg / ml and was suitable for intravenous administration.
  • L-Epi-2-inosose powder 5 g Sterile water 50 ml 5 g of the L-epi 1-2-inosose powder was dissolved in 50 ml of sterile water. The resulting solution was filtered through a membrane filter for sterilization. The filtered aseptic solution was dispensed under aseptic conditions into 5 ml aliquots of 10 ml brown vials, lyophilized aseptically, and sealed with nitrogen gas.
  • a freeze-dried preparation of L-epi-2-inosose for intravenous injection was obtained.
  • the formulation in a vial was immediately and completely dissolved when added to 5 ml of sterile saline under aseptic conditions immediately before use for intravenous injection.
  • the resulting aqueous solution contained L-epi-12-inosose at a concentration of 100 mg / ml and was suitable for intravenous administration.
  • (+)-protoquercinol which is used as an HIV growth inhibitor according to the present invention
  • L-epi1-2-inosose were used as test substances.
  • myo-inositol, scyllo-inositol and 3, -deoxy-3, -azidothymidine (AZT) were also used as test substances.
  • the human cells to be tested include human monocyte / macrophage-derived U937 cells or human T-cell derived H9 cells, which are prepared by persistently infecting human immunodeficiency virus HIV-1 IIIB with HIV-III-B. 1 II IB persistently infected U937 cells or H9 cells (AJ Chantal Petit et al., ⁇ J. Clin. Invest, j 79 Vol. 361-367 (1987)).
  • the following experiment was performed to examine the cytotoxicity of the test substance on the above-mentioned HIV-1 ⁇ persistently infected U937 cells or H9 cells used as an example of human cells.
  • test substance Dilute the test substance in dimethyl sulfoxide (DMS0) stepwise and dilute it in RPMI medium supplemented with 10% FBS to obtain various concentrations of the test substance.
  • a medium was prepared.
  • Cell culture medium containing the test substance was added to each well of a 96-well culture plate at a rate of 20 / l / well.
  • HIV-1 ⁇ persistently infected U937 cells or H9 cells were suspended in RPMI medium supplemented with 10% FBS, whereby 1 ⁇ 10 5 cells / ml of the U937 cells or H9 cells were suspended.
  • a cell suspension containing the cells was prepared.
  • the above cells are placed in each well of a 96-well culture plate containing a cell culture medium containing the test substance.
  • the suspension was added in 180 ⁇ 1 volumes and the mixture in each well was gently mixed.
  • the cell culture solution contained in each well of the culture plate was divided into two parts, and From the cell culture, 50 ⁇ 1 of the culture of the U937 cells or H9 cells in the treatment section cultured in the presence of the test substance was collected and transferred to each well of a new 96-well culture plate.
  • MTT [3- (4,5-dimethylthiazol-2-yl) -2 to a concentration of 5.0 mg / ml.
  • 5-diphenyltetrazolium bromide (Signa M-2128) in a phosphate buffer reagent was added, and the cells were cultured at 37 ° C for 4 hours.
  • MTT forms yellow to dark blue formazan when taken up by living cells.
  • the absorbance of the colored cell culture solution was measured by irradiating light having a test measurement wavelength of 570 nm and light having a reference measurement wavelength of 630 M1.
  • a standard curve showing the relationship between the concentration of the formazan solution and the absorbance in the MMT method was prepared, and was compared with the measured absorbance of the cell culture solution in the treated section. Then, the number of viable cells in the culture solution of the U937 cells persistently infected with HIV-1 II IB in each treatment group was calculated.
  • a where A means the number of viable U937 cells or H9 cells persistently infected with HIV-1 IIIB cultured in the absence of the test substance in the untreated plot, and B is the test in the treated plot The viable cell count of the cells cultured in the presence of the substance.
  • Table 1 shows the obtained test results.
  • test example 1 it was shown that the test substance used in test example 1 showed activity to inhibit the growth of HIV-1 IIIB virus in HIV-1 IIIB persistently infected U937 cells or H9 cells. Investigated by experiment.
  • the amount of HIV-1 particles present in U937 cells or H9 cells was determined by measuring the amount of reverse transcriptase (reverse transcriptase, abbreviated RT) produced by the virus particles. Measuring the potency of , paragraph
  • Test Example 1 On day 4 of culture of HIV-1 IIIB persistently infected U937 cells or H9 cells, the cell culture solution contained in each well of the culture plate was divided into two. One of the two cell culture solutions was used for measuring the number of living cells by the MMT method.
  • the supernatant from which the remaining viable cells of the cell culture solution thus obtained were removed was used in this test to measure the titer of HT produced by HIV virus particles.
  • a reaction solution containing a radiolabeled substance [ 3 H] dTTP (3'-deoxythymidine triphosphate) taken up by the RT of the HIV-1 IIIB virus was added to the supernatant of the previous period at 37 ° C. For 4 hours. By the action of RT, the radioactivity incorporated into the virus nucleic acid is measured with a scintillation counter.
  • the addition of the radiolabeled substance as described above was performed on the supernatant of the cultured cell solution in each well of the treated section.
  • a radiolabeled substance was similarly added to the supernatant of the culture cell solution in each well of the untreated section cultured in the absence of the test substance on the culture plate.
  • the growth inhibition rate (%) of the HIV-1 II IB virus in the treated area was calculated by the following formula. Virus growth inhibition rate (%) 2 (1—X I 0 0
  • A means the radioactivity value measured in the untreated section in which HIV-1 ⁇ persistently infected U937 cells or H9 cells were cultured in the absence of the test substance
  • B indicates the radioactivity of the test substance. It means the radioactivity value measured for the treated section in which the cells were cultured in the presence.
  • Test method Single-dose oral administration of 2000 mg / kg of (+)-Talk erucitol or L-epi 2-inosose using 4-week-old ICR mice (male, 5 mice per group) . Thereafter, the weight, life and death of the mice were observed for 2 weeks. As a result, the LD5 () value of the oral toxicity of (+)-protoquercitol and L-epi-2-inosose was more than 2000 mg / kg in both cases. Low toxicity. Industrial applicability
  • Protokerucitol or epi-2-inosose which has an activity of inhibiting the growth of HIV and has low toxicity is useful as a growth inhibitor of HIV.
  • the compounds are also useful for use in a method of inhibiting the growth of HIV.

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  • AIDS & HIV (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne (+)-proto-quercitol, (-)-proto-quercitol ou (?)-proto-quercitol représentés par la formule (I-1), ou L-épi-2-inosose, D-épi-2-inosose ou DL-épi-2-inosose représentés par la formule (I-2), qui présentent une activité d'inhibition de la prolifération de lymphocytes T porteurs du VIH et/ou des monocytes/macrophages humains et/ou d'autres hémocytes humains et, par conséquent, sont utiles comme inhibiteurs de prolifération du VIH. L'invention concerne en outre une méthode d'inhibition de la prolifération du VIH par traitement du virus avec les composés de formule (I-1), les composés de formule (I-2) ou des énantiomères ou des mélanges racémiques de ces derniers.
PCT/JP2001/003587 2000-04-25 2001-04-25 Compositions destinees a inhiber la proliferation du virus d'immunodeficience humaine et methode d'inhibition de la proliferation de ce virus WO2001080848A1 (fr)

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JP2000-123407 2000-04-25

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0422109A1 (fr) * 1988-06-30 1991-04-17 Abulkalam M Shamsuddin Reduction de la proliferation cellulaire et promotion de l'activite des cellules tueuses naturelles.
EP0685458A1 (fr) * 1994-05-31 1995-12-06 Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation) Des analoques de glycolipide comme inhibiteurs de glucosidese
JP2000086644A (ja) * 1998-09-14 2000-03-28 Hokko Chem Ind Co Ltd 新規アンヒドロデオキシイノシトールとグリコシダーゼ阻害剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0422109A1 (fr) * 1988-06-30 1991-04-17 Abulkalam M Shamsuddin Reduction de la proliferation cellulaire et promotion de l'activite des cellules tueuses naturelles.
EP0685458A1 (fr) * 1994-05-31 1995-12-06 Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation) Des analoques de glycolipide comme inhibiteurs de glucosidese
JP2000086644A (ja) * 1998-09-14 2000-03-28 Hokko Chem Ind Co Ltd 新規アンヒドロデオキシイノシトールとグリコシダーゼ阻害剤

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