JPH07506352A - Heteropolytungstates in the treatment of flavivirus infections - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Heteropolytungstate in the treatment of flavivirus infections The present invention Pharmaceutical products containing lopolitungstate and its pharmaceutically acceptable derivatives a composition, and the composition has been identified as a member of the flavivirus family. or anticipated viral infections, such as yellow fever, dengue fever, or Therapeutic use for the treatment or prevention of Laria encephalitis, Japanese encephalitis and hepatitis C. Regarding.

Flaviviruses are one of the most serious arthropod-borne viral diseases in humans. A substance that causes many human diseases, including dengue, yellow fever, and Japanese encephalitis. It is known as. In addition, eight brackenviruses are associated with regional disease or economic risks. causes important wildlife diseases. Yellow fever and dengue fever are widely spread. It is also well known that the disease is caused by mosquitoes in tropical regions. yearly, There are between 300 million and 600 million people infected with bracken virus, of which 1 million are in Japan. This is brain inflammation. The extent of the hepatitis C epidemic is unknown with any degree of certainty. This is because hepatitis C can remain dormant for many years without showing any symptoms. Because it can be done. Hepatitis C is more dangerous than hepatitis B, which is recognized as being more dangerous in many countries. , which is quite common and chronic. Approximately 50% of patients present with chronic infection In contrast, the chronic rate among people infected with hepatitis B is 5 to 10%. Chronic infection affects the liver This can lead to cirrhosis of the liver, decreased liver function, and even cause liver failure in 20 to 30 years. Ru.

Studies of infection rates estimate that more than 1% of Australia's population is infected. It is. There is no established treatment or vaccine for hepatitis C.

Effective vaccines are available for several viruses, such as yellow fever, Japanese encephalitis, and tick-borne brain infections. Only those against fire etc. can be obtained. Treatment of dengue fever and Australian encephalitis Treatment relies on the patient's own immune defenses. Infection can be fatal.

Antiviral drugs that control flavivirus infections are therefore highly desirable.

Drugs that control or inhibit virus reproduction also control some other viruses. It has been proven to be useful. However, without harming uninfected cells, It is difficult to inhibit viruses, and anti-virus drugs currently widely used in medical applications There are almost no antivirus drugs.

The family Flaviviridae is newly recognized, 10 km A small enveloped virus containing positive-sense RNA based on A large group (containing over 70 species). The above-mentioned difficulties and flaviviruses Recent findings indicate that the virus is a unique virus that exhibits a unique replication strategy. Therefore, caution should be taken when using antiviral compositions for controlling flavivirus infections. It wasn't paid.

All members of the Flaviviridae family are unibiotics that are inhibited by the compositions of the present invention. It has a unique replication path. Nonstructural gene NS3 thought to be involved in replication and NS5 have very large sequence homology between species and therefore inhibit replication. The harmful agent is effective against all flaviviruses.

Conventional technology Heteropolytungstate compounds have been known for over 100 years. its suitability Most of the reactions are due to redox chemistry and high ionic weight and charge.

Because this compound has redox ability, it can convert propylene to acrylic acid, ethylene to acrylic acid, etc. used as a catalyst for the oxidation of organic substrates, such as the oxidation of carbon to acetaldehyde. It is being In the field of biology, heteropolytungstates are It has been found that it can be used as an electron-dense dye for protein analysis and as a reagent for protein analysis. and some are derived from viral DNA and RNA polymerases. (J, C, Cherman). ) et al., Keggin ( Keggin) and Dawson (wells taurine) - also known as Dawson) type of structure; is where multiple tungsten atoms are removed and most often replaced with other metal atoms. Also included are compounds based on these structures that have been obtained. Vacancies in the structure is Keggin (XV/+zO4゜°-) or Dowlin (P2W+806□1) It is produced by extracting WO4' or W,066' from seeds. these The isomers of unsaturated polyanions (having vacancies) differ in the position of vacancies. (R, Massart), contant (R, Co ntant), Full/Yard (J, M, Fruchart), Schiabrini (J, M, C1abrini) and Fournières (M.

Fournier), Inorg Chew, 1 977, 16.2916; Joris (T, L.

Jorris), Kozik CM, Kozik), Kazan Pastor (N, C a5an-Pastor), Tomail (P.

J, Domaille), R,G, Finke, Miller (W, K, 1 liller) and Becker (L, C, ?bu (M, T, Pope) , “Heteropoly and Isopolyoxymetalates” Sbringer Fair Rug , Berlin, 1983). The position of the vacancy in P2W+tO,,+o- is determined by It can be defined by fixed belt vacancy α1 or cap vacancy α2. can. Several isomers are obtained by rotation of the W,-oxide triad in the structure. It will be done. That is, when the W3-triad element cap is rotated by 60°, for example, α-differential isomer can be converted to the β-isomer. XW, 0.4”-type 3-vacancy lattice Is the W3 oxide triad linked to the corner lost in polyanions? (A-form) or the W3 oxide triad linked to the edge is removed (B-form). Either form A or B can be obtained.

Unsaturated heteropolyanions can bind metal ions in their vacancies. and can act as a ligand. Metal ions are placed in a field that is not sterically crowded. In some cases, they can carry ligands such as water, three types of organic coordination compounds, or organometallic groups. Wear. Organometallic moieties can also be exposed on top of e.g. trisubstituted Keggin or Daurin structures. (Huisin and Drose, J.A.M.K.) Mu Tsuku, 1984.106, 7271: Huishin, Loveko and Tomail, Oru Ganometalysis, 1986, Rui, 175). The oxygen atom on the Keggin structure also It may also be alkylated by reagents such as trimethyloxonium salts (no (f, H, Knoth) and Barlow (R, L.

Harlot), J.A.M.C., 19g1,103.4265) . Some oxygen atoms on heteropolytungstate are replaced with fluorine atoms It is also possible to do this (Chauveau (F, Chauveau), Dolabert (P, Doppelt), Lefebvre (J, Lefebvre), Inorg. Kem, 1980.19.2803; Joris (T, L, Joris), Koschik and Becker), Inorg Kem, 1990. competition, 4584).

Other heteropolyanion species include the two W, O, H6- ions and the lanthanoids. It can be synthesized by reaction with metal ions such as peacock (R, D, Pea cock) Totsu Krey, J Chew A (J, Chew, So c, ^), 1971.1386). with pwt phosphotungstate base Heteropolyanions are generally crosslinked by phosphate groups and are known in the art. Aru (Fuchs 0. Fuchs) and Balm (R, Pa1m) set nature - Horsch (Z, Naturforsch) 1988.43b, 1529 and acelate (R, ^cerete), cervere-cario (J, 5er ver-Carrio), Vegas (A, Vegas) and Martinez Thuriball (M, Artinez-Ripoll), J Am Chem Tsuk, 19 90.112.9386).

Changing the central atom of a compound extensively, especially in simpler Keggin structures Can be done. The central atom in taurine-type structures is most often phosphorus.

Heteropolytungstate species are often synonymous with the corresponding heteropolymolybdates. It is more stable in solution. Other golds such as niobium and vandalium Although it is possible to create heteropoly compounds of the genus, it is often more restricted Stable only within the pH range.

We now have an unexpected discovery of the invention, namely the "core" species (of the structural types listed below). In the example, a heteropolytungstate polyanion containing He discovered that it has activity against viruses belonging to the family Flaviviridae.

In particular, they inhibit the replication of such viruses and stop the development of infection.

In the present invention, for the treatment or prevention of infectious diseases related to flaviviruses, one or more heteropolitans of formulas 1 to 12 below as active ingredients, Compositions containing ungstic acid compounds or pharmaceutically acceptable derivatives thereof provide. The composition of the present invention is combined with a cation (A) to make it electrically neutral. It is a polyanion. Depending on the conditions of product recovery and further processing, crystallization crystallizes with varying numbers of water molecules. All such hydrous compounds are also included in the invention. Within range.

"Pharmaceutically acceptable derivative" means a pharmaceutically acceptable salt or recipient compound. When the composition of the present invention or its active metabolite or residue thereof is administered to (directly or indirectly).

The pharmaceutical composition of the invention comprises one or more compounds selected from formulas 1-12. an effective amount, one or more pharmaceutically acceptable carriers or diluents, and Contained together with other components if desired. Each carrier is compatible with the other ingredients of the composition. is pharmaceutically "acceptable" in the sense that it does not cause harm to the patient. Especially the word In addition to the ingredients mentioned above, compositions of the invention may further include, for example, drugs suitable for oral administration. It is recognized by those skilled in the art that it may contain sweeteners, thickeners and flavoring agents. It may also contain components that are regularly added.

Oral, enteral, intranasal, topical (including buccal and sublingual), vaginal or parenteral (dermal) Compositions suitable for administration (including subcutaneous, intramuscular, intravenous, and subcutaneous) are included in the invention. set The formulation is easy to use in dosage unit form and is well known in the pharmaceutical field. It may be prepared using any method. Such methods contain the active ingredients in one or more the step of combining with a carrier containing at least one accessory component. Generally, group The composition comprises a homogeneous combination of the active ingredient and a liquid carrier or a finely divided solid carrier or both. , and by direct combination and subsequent shaping of the product if desired.

The invention further provides an effective amount of one or more compounds selected from formulas 1-12. or Concerning preventive methods.

Compounds can be prepared using methods described in the literature or using reactants and conditions to obtain targeted compounds. It can be produced by a modification thereof. Explains and explains the synthesis, structure and properties of various compounds. Xometalate, Sbringer-Verlag, Berlin 1983; Wekle Lee, Mueller, Angew, Chew, Int, Edgl, ), 1991. Includes viewing angle and 34°.

Compounds useful as active ingredients in compositions of the invention are represented by formulas 1-12 below for each subtype. A suitable method for preparing is listed.

A. Compounds based on Keggin structure 1) An[YMXWBo3sko During the ceremony, Y = ligand (e.g. H2O, OH-, 02-, NH3, NC5-, NO2-, OJ-, SO32-.

aromatic/aliphatic amines or noclopentadienyl group). For example, C,M,) Tourn. , G, F, Tourne (G, F, Tournuri, Maritsuk (S, A, Ma lik) and Waffle 0 and its references, Pawnett (M, Bauch et), C, M, Tourne and G, F,) Urfu, C, R Acad Sai Paris (C , R, Acad, Sci, Paris), 1972. C275,407;Zon Nebijour (F, Zonnevi jlle), C, M, Toru Futo GF Tourne, Impone Ke Liu), Wag (f, tag), Zhu (Z, Zhu ), E one (E, rang) and Z one (Z, Tang), tran- (R, K, C, Ha) and Klemperer (W, G, Klemperer), No. Aam chem tsuk.

197g, 100.6772, Matahanos, Noei am Kem Tsuk, 1 979. By the method of IOl, 2211! Ill be made.

2) An [M(XW1+03e)2] in the formula, This compound can be prepared by methods described in the following literature, for example Liu, W., Wang, Zoo and E. Wang, Trannonoyon Met Chem, 1991.16.169 and Reference sentence 3), to, [XMzW,. 04゜〕 This compound can be produced by the method described in the following literature. Tomail, Impon・ Inorg, 5ynth, 1990.27.102-104 (/ :zsberg (A, P, Ginsberg) Thiley~Interscience and its references: Ki Canny (J, Canny), Thouvenot (R), Tese (A, Teze), Herbe, Repallochem Tsuk Dalton Trans. 1988.2411: With Flynn Jr. (C, M, Flynn lr, ) Pawn, Import Kem, 1971. Io, 2745°4) An[XM3 WgO4o, co During the ceremony, The compounds can be prepared by methods described in the literature below. Tomail, J.A.M.K. Mu・References: Jun (P, Jun), Lun-yu (Su Lun-yu) and Ya C, Ya-guang, Inorg Kim Akta, Chill, Acta), 1991.183. +57: Nidorand (D, J.

Edlund), Saxton (R, J, 5axton), Lyons (D, K., Lyons) and Fifuku, Olga B. Taurine structure-based saturation Compound 5) An[X2MW+tOg! ] During the ceremony, (In the formula, R=organic residue) This compound can be synthesized by the reaction described in the following literature. Maritsuk and Wakeley , Jie Kem Tsuk, Kem Commun, 1967.1094: Noei Kem ・Tsuku (A), 1968.2647, Lion (D, K, Lyon), Mi Ra, Novet (T, Novet), Tomail, Evitt (E.

6) An[M(X2W+tOg+)z] in the formula, This compound is Peacock and Wakeley, J. Chem. Tsuk (^), 19 68.1836:7) A-[XzlVhW+5Osz in the formula, Among the above compounds, M=V can be produced by the method described in the following literature: Fisin , Loveco, Saxton and Tomail, Noei am Kem Tsuk, 1986.1 08.2947°M=Nb species, monomers and dimers are Nidland, Sa. Kuston, Lyons and Fifuku, Organometalysis, 19884.169 It can be produced by the method described in 2. Compounds where M=Mo are Noavry m:, contour Polyhedron of Nto and Furnoyat.

1983, 2.1229.

C, to 2 or 3 trivacancies - or B-XWoOs4'- or to 2 B -X2M/+5Oss'- polyanion with transition metal or lanthanide metal ion Compounds that are bonded via a bond.

8) A-[Ma(H2O)-(XW*08a)z] in the formula, y is 1-6, most preferably 2.

These compounds can be produced by methods described in the literature below. Evans, C.M. Tourne, G, F, l-Urne and Wakeley, Noei Kem Tsuk Dalton. ·Trance.

1986, 2699: Fifuku, Drose and Tomail, Inorg Kem, 19 87.26.3886. Wasfi (S, H, Ta5fi), Rain Cold ( ^, L, Reingold), Kokoszka (G, F, Kokoszka ) and Goldstein (^, S, Goldstein), Inorg Kem , 1987.26.2934; C, M, Torufu, G, F,) Urne and Ji 1991.143 ゜ 9) AJ(FeOA)4(PWeOz4)z This compound is registered in the international patent application PCT /At191100280 △-N a @HP Ws O3 By refluxing a mixed aqueous solution of 4 and F e (III) acetate species at a molar ratio of 1.2. Can be manufactured.

The structure of polyanions is unknown. For example, ICP analysis of potassium compounds It was found that the Rini:P:Fe:W ratio was 7:1:2:9. ammonium salt Attempts were made to determine the crystal structure of the polyanion, but the positions of the atoms within the polyanion could not be determined. The purity of the crystals was insufficient to make a true determination. The dimensions of the unit cell are 32.36 X 27.30X 24.42 people, b=112.28".

10) An[Ma(XW*03-)2] in the formula, x=pゝ or S1IV If a is 1 or 2, M=WO! If A is 3, 573 and its references 2C, Tourne (C, Tourne6), Level (^R evel) and G,) Urfu (G, Tour6), Rev Kim Mineral, 1977, 14.537 ([Co2(WO2)]+7z): C, M Tourne and G, F. Tourne, N.E.C. Dalton Trans., 1988.2 411.

11) An[Co*(OH)s(Hz○)s(HPO4)2(PWsO3s)3 ] It can be produced by the method described in the following literature. Wakeley, J.K.M.T.K. , Kem Commun, 1984.1406; Noei Kem Tsuk Dalton To Lance, 19°86.2699°12) An[1VL(H2O)2(XzW+s Osg)2] where, These compounds can be prepared by the following general methods described in the literature: Rose and Tomail, Inorg Chem, 19g7.26.3886゜Cobalt When a compound (e.g. sodium salt) is heated to 80-90°C for several hours in an aqueous solution , the reddish-brown compound crystallizes from the solution while cooling the solution to room temperature. It is called high tempform J.

In compounds of formulas 1 to 12, one or more tungsten atoms in the structure transition When replaced with a metal atom, the oxygen on the transition metal atom is either dihydrogenated (H2O ), - either hydrogenated (OH) or completely dehydrogenated (○) obtain. The acidity of these hydrogens and the resulting compound are heteropolytungsten As is well known to those skilled in the art of acid chemistry, the nature of transition metal atoms, their acid state, the basicity of the polyanion formed and the base of the solution from which the compound was isolated. Depends on gender. In the compounds of the invention, all oxygen atoms are the necessary oxo groups. There is also a charge on the polyanion (and therefore a counter charge). The number of thiones (A) will depend on the number of hydrogens bonded to this oxygen atom. Ma Furthermore, compounds with groups such as MOH can be diluted by intramolecular condensation reactions. can form a mer. Dimers of the listed compounds are also included within the scope of the invention. be caught.

Many compounds of the invention may contain several isomers. In fact, currently It is difficult to obtain compounds that do not yet contain isomers. All isomers or Mixtures of the sexes are also included in the invention.

Many compounds undergo one or more electron reductions. Reduced compounds are also included in the present invention. included.

The charge of the polyanion depends on the degree of hydrogenation of the polyanion, as described above. It can also vary depending on the oxidation state of the metal atom. Combining counter The number of cations (A) also varies accordingly. Even if A is hydrogen, it is an alkali metal ions, alkaline earth metal ions or ammonium, or R,, H, N' (wherein R is an alkyl chain having 1 to 6 carbon atoms) type of alkylammonium ion. The required cations are generally Use of ion exchange resin or precipitate with excess salt of the cation in the compound is introduced into the compound by

Those skilled in the art of heteropolyanion chemistry will appreciate that the elements shown in formulas 1 to 12 indicates that you know that not all combinations of Pick it up.

Preparation of the composition The composition for oral administration according to the present invention contains a predetermined amount of the active ingredient. discrete dosage forms (e.g. capsules, sachets, and tablets) etc.), powders, granules, solutions or suspensions in aqueous or non-aqueous liquids, Alternatively, it may be prepared in the form of an oil-in-water or water-in-oil emulsion. Yes The active ingredient may be prepared in the form of a lozenge, lozenge or paste.

Tablets are made by subjecting the composition to a compression or molding process along with one or more accessory ingredients. It may also be prepared by Compressed tablets may optionally contain a binder (e.g. an inert diluent). diluent, etc.), preservative, disintegrant (e.g., sodium starch glycolate, crosslinking agent, bidone and cross-linked carboxymethyl cellulose sodium, etc.), surfactants or applies the active ingredient in free-flowing form (e.g. powder or granules) mixed with a dispersant. It may also be prepared by compressing using a suitable compressor. Molded tablets are inert Molding a powdery mixture moistened with a liquid diluent using a suitable molding machine. It may be molded by These tablets may be optionally coated or scored. Alternatively, for example, hydroxypropyl methylcellulose The active ingredient can be released at the desired release rate by blending the bases in different proportions. It may also be prepared in sustained release form. Additionally, these tablets may optionally be used for consumption outside the stomach. It may also be coated with a soluble component to release the active ingredient in the tube.

Compositions for topical administration in the oral cavity are formulated with flavoring bases (usually sucrose and acacia). Drops containing active ingredients in rubber or gum tragacanth), inert base ( For example, gelatin and glycerin, or sucrose and gum acacia) Lozenges containing the active ingredient, or lozenges containing the active ingredient in a suitable liquid carrier. It may also be prepared in the form of a penetrating agent or the like.

Compositions for rectal administration may contain suitable bases, including, for example, cocoa butter or salicylates. It may also be prepared in the form of a suppository, etc., containing the active ingredient.

Compositions for vaginal administration may be formulated as a pellet containing the active ingredients in suitable carriers known in the art. saree, tampon, cream, gel, paste, foam or It may also be prepared in the form of a spray or the like.

Compositions for parenteral administration may be prepared from isotonic aqueous or non-aqueous sterile injection solutions, including , antioxidants, buffers, bacteriostatic agents, and the osmotic pressure of the injection solution at the recipe end (re). cipient), and Forms such as aqueous or non-aqueous sterile suspensions that may contain suspending agents or thickening agents. It may also be prepared in a form. Such compositions may be packaged in unit or multiple doses. It may also be enclosed in a sealed container, such as an ampoule or vial. , stored in a lyophilized state and immediately before use in a liquid sterile carrier, e.g. It may be used by adding water. Extemporaneously prepared injection solutions and suspensions may be prepared as described above. It may also be prepared from sterile powders, granules or tablets.

Preferred unit dosage form compositions contain the active ingredients per day, as described above. whether it is a composition containing an amount or subdose or a suitable division thereof. good.

The compounds according to the invention may be prepared in the form of veterinary compositions, which may include, for example For example, they may be prepared by methods conventional in the art. This type of veterinary composition includes: The following (a) to (d) are exemplified: (a) Oral or external compositions substances, e.g. trenches (e.g. aqueous or non-aqueous solutions or suspensions), tablets or pellets, powders, granules or pellets for mixing with feed, and (b) compositions for parenteral administration, e.g. subcutaneously, intramuscularly or Is a sterile solution for intravenous injection or! i&turbid fluid, if appropriate, from the nipple to the mammary gland Breast injection solutions or suspensions of (C) Compositions for topical administration, such as creams, ointments or spray, (d) Compositions for vaginal administration, such as pessaries, creams or foams.

In addition to the above-mentioned ingredients, the composition according to the invention also includes, depending on the type of composition in question. Accordingly, other components conventional in the art may be appropriately blended. For example, oral The composition for administration may contain sweeteners, thickeners, flavoring agents, and the like.

Administration and dosage The composition according to the invention can be administered by any suitable route for treatment, such as oral, rectal, nasal, Local (including buccal and sublingual), vaginal and parenteral (subcutaneous, muscular, venous and cortical) (including). Oral administration is generally preferred; The appropriate administration depends on the patient's condition and age, the characteristics of the composition, and the active ingredient selected. The routes are different.

In general, the appropriate daily dosage of the active ingredient (1 kg of body weight at the end of the recipe) 30 to 120 mg, preferably 6 to 90 g 1) It is 15 to 6011 g. The preferred method of administration is at appropriate intervals throughout the day. A method of administering the drug in 2, 3, 4, 5, 6 or more doses. It is. Such divided administration may involve unit doses, e.g. 10 to 150 doses of active ingredient. 0mg, preferably 20-1000mg, most preferably 50-70011g. This may be carried out by administering a unit dose comprising:

Ideally, the peak plasma of the active ingredient should be approximately 1 degree. The active ingredient is administered at a concentration of 1 to about 100 μM, preferably about 2 to 50 μM. Should.

Such administration may include, for example, 0.1 to 5 ml of active ingredient added to optionally physiological saline. % solution by intravenous injection or containing about 0.1 to about 100 mg/kg of the active ingredient. It may also be carried out by orally administering a bolus containing the drug. Desirable active ingredients Blood levels may be maintained at about 0.4 to about 15 mg/mg by continuous infusion.

The following examples are intended to illustrate the invention and do not limit the scope of the invention. It's not something you can do. ``Active ingredients'' used in Examples 3 to 6 The term grdient) J refers to compounds represented by formulas (1) to (12) and and one or more compounds selected from pharmaceutically acceptable derivatives thereof. means.

Example 1: Compound according to the invention The compounds shown in Table 1 below were commercially available for use in the tests described in Example 2 below. and dissolved in twice the amount of distilled water.

Table 1 Table 1 (continued) Example 2: Antiviral activity RN in an in vitro polymerase assay for the compound described in Example 1. A test was conducted on the ability to inhibit A synthesis [Chu and Westar Westaway, 1985, 1987 and Brinton, 1986]. In this assay, Genome 44S RNA, double-stranded replication type (RF) and partially double-stranded replication type intermediate ( R1) with [α-”PIGTP Detected by.

A. Preparation of virus-infected Vero cell extract type dengue fever (DEN-2) virus [New Guinea C strain; n) and Schlesinger, 1945] or Kunjin (KUN) virus [MRM61C strain; Boulton ) and Westaway, 1972] were infected seven times. DEN-2 virus an extract derived from cells infected with an RNA-dependent RNA polymer The extract with polymerase (RDRP) activity was added to the Prepared at ~35 hp, i. Similarly, cells infected with KUN virus Extracts of were prepared at 24 hp, i, when the polymerase activity was at its maximum ( Chu and Willsaway, 1985).

These cells were made into pellets by centrifugation, and then treated with 10% sodium acetate. Resuspended in oM solution at a concentration of 2X107 cells/ml. This is 21 gauge 20 times through a 26 gauge needle, and then 20 times through a 26 gauge needle. Therefore, it was crushed. The crushed cells were centrifuged at 800 g for 7 minutes. Therefore, the pellet containing the nucleus and the supernatant were separated. For all RDRP assays In this case, this supernatant (hereinafter referred to as cell extract) was stored at -70°C and frozen. After thawing once, it was used.

B, RNA-dependent RNA polymerase assay. RDRP activity of cell extracts was determined previously. (Chu and Wess) assay, 1985). In each RDRP assay, virus-infected cells were The cell extract contained 4.5-5 mg/ml protein. double amount of distilled water Test compound and RNN Asin 0.5 unit/111 dissolved in romaga)) and other compounds used in the RDRP assay. minutes before addition to the cell extract. The final reaction mixture (total volume 50 μm) contains the following components: as follows: 50mM) Lis-HCI (pH 8,0), 10mM Magnesium acetate. sodium, 75mM potassium acetate, 10oM 2-mercaptoethanol, 6μg acetate. Cutinomycin D (AMD), 5mM phosphoenolpyruvate, 3 units /μm pyruvate kinase, 0.51°C M ATPSo, 5wM CTP, 0. 5mM UTP.

25 μM GTP, 5 μCi [α-32P co-GTP [Amerunyam (A+oer sha11), specific activity 410 Ci/mmol: l, 0, 5 units/ ml'RNazine, 30μm infected cell extract, and test compound (05-100 μM). The reaction was carried out for 30 minutes at 37°C and then stopped by the addition of EDTA. (Final concentration of EDTA: 10mM). Equal volume of TNE-3DS [50mM Tris-acetate (pH 7,6), 0.1M sodium acetate, 1mM ED TA and 2% SDS] were added to the crushed membrane. RNA was extracted using phenol. After that, it was precipitated using ethanol.

C. RNA electrophoresis RNA samples were prepared in TBE (89mM Tris-HCl, 89mM boric acid, 2.5mM Equal volumes of sample buffer containing 7M urea in EDTA) and 0.5% bromof 3% polyacrylic containing 7M urea in TBE after mixing with phenol blue. Separation was performed by electrophoresis using an amide gel. This gel was fixed in 10% acetic acid. After drying, the radiolabeled band was detected by autoradiography.

result The test compound inhibited the synthesis of RF RNA by DEN-2 and KUN.

As the concentration of the compound increased, the amount of RI detected decreased. Table 1 shows the inhibitory concentration. Shown below.

References The details of the above document are as follows: (1) Boultin (R,W) and Westaway (W estavay, E.

G), “Toga virus, Sindbis virus (group A) and Kunjin virus (group B) "A comparison of the 9 pages (1972) (1i) Chu (P.W.G.) and Westaway, “Kunjin How viruses replicate, evidence of recycling, and templates in bioconservative and asymmetric replication. “The role of replicative RNA as a template”, Pyrology, Vol. 140, pp. 68-7. 9 (1985), (fi) Chu and Westaway, “Kunjingwi "Characteristics of reinitiation of in vitro synthesis by RNA-dependent RNA polymerase of M. russ", p. Irorono, Vol. 157, pp. 330-337 (1987) (tv) Grun (J, B,) and Brinton (S) M, A,), “RNA-dependent RNA polymerase of West Nile virus” and cell-free extraction of cellular adenylyl and uridylyl transferases. "Characteristics in Excerpts", Journal of Pyrology (Journal) ofv4rotogy), Vol. 60, pp. 1113-1124 (1986) ),and (v) SabinSA, B, and Schlesinger inger, R.W.), ``A modified virus that multiplies in the body of a mouse. "Development of immunity against dengue fever", Science, Vol. Volume 101, pages 640-642 (1945).

Example 3: Tablet formulation The ingredients according to the following formulation were subjected to wet crushing using povidone solution, and Tablet A was prepared by compressing after adding magnesium alinate. Active ingredient 250 250 Lactose B, P, 210 26 Povidone B, P, 15 9 Sodium starch glycolate 2o 12 magnesium stearate Tablet B was prepared by direct compression of a mixture consisting of the following ingredients: Active ingredient 250 Pre-gelatinized starch NF15' Made with a formulation of 150 or less The fraction was subjected to wet crushing using povidone solution to remove magnesium/umium stearate. Sustained release tablet C was prepared by adding and then compressing: Ingredients: Amount (mg/tablet) Active ingredient 500 Hydroxypropyl methylcellulose 112 [methocel K 4 M Blemium (P remiuw)] Lactose B, P, 53 Povidone B, P, 2 B Magnesium stearate Example 4: Capsule formulation The mixture consisting of the ingredients of Tablet B of Example 3 was put into two-split hard gelatin capsules. Capsule A was prepared by filling into a bottle.

Capsule B was prepared in the same manner as capsule A using the following ingredients: ・ Active ingredient 250 Lactose B, P, 143 Sodium starch glycolate 25 Magnesium stearate 2 Sustained-release capsule C was prepared as follows. Active ingredient 250mg/capsule, Fine quality cellulose 125 mg/capsule and lactose B, P, 125 After subjecting the mg/capsule to an extrusion process using an extruder and molding the extrudate into a spherical shape, , dried.

These spherical pellets were mixed with 13 mg/capsule of ethyl cellulose, which becomes a sustained release membrane. After coating, it was filled into two-piece hard gelatin capsules.

Example 5: Formulation of an injectable formulation An injectable formulation was prepared according to the following formulation.

Ingredients/Amount Active ingredient 0.200g O3IM hydrochloric acid solution Amount of 0.1M sodium hydroxide to adjust the pi-i of the system to 5.0 to 7.0 Amount of sterilized water to bring the pH of the system to 5.0 to 7.0. Bring the entire system to 10-1. amount The active ingredient is dissolved in a large amount of water (35-40°C) and the pH of the solution is adjusted by adding an appropriate amount of It was adjusted to 5.0 to 7.0 using an aqueous hydrochloric acid solution or a sodium hydroxide solution. child A batch of After that, inject into a 1 (bl) amber glass vial (type 1), and , sterile closure and oversea. 1) was used for sealing.

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Fe+vn to τ/IsA/2101cenl+nusuoe ofmem藺+h aw)Fuly 1992 Hitomi-■International Investigation Report-mlapp-N.

＝渭＝＝? 2=to: ern:+;on’l;=:c, “・・・′・−・”y　 members relating・to paLer+I@d・−・ ,. , Chase pariiculars which ar. merely given,,,,r,epo,n,Th story:sA:mAP=t (Xfi ee + s + n no way 1iable front page continuation (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.

TD, TG), AU, BB, BG, BR, CA, CZ.

FI, HU, JP, KP, KR, KZ, LK, MG, M (72) Inventor Verso Romeus, Ashigerin Ingrid Cowan Lo, South Overleve, Victoria, Commonwealth of Australia 3167 card number 28, unit 2 (72) Inventor Horan, George 86 Waugh Street, Brighton, Victoria, Commonwealth of Australia 3186 ) Inventor Marcucchio, Sebastian Mario Commonwealth of Australia 3976V 9 Stuart Avenue, Hampton Park, Ectoria ) Inventor: Wright, Beter James Commonwealth of Australia 3132 Victor Leah, Mitcham, 78 Orient Avenue

Claims (5)

[Claims] 1. For patients in need of treatment or prevention of flavivirus-related infections: Formula 1 below: ~12 compounds: 1) An [YMXW11O39] During the ceremony, X=BIII, PV, SiIV, GeIV, ZnII, CoII, CoIII, FeIII, GaIII, TiIV, or M=MnII, MnIII, FeI I, FeIII, CuII, CoII, CoIII, GaIII, II, Zn II, TiIV, ZrIV, AlIII, InIII, VIV, VV, MoVI , PbII, NbV, Y=ligand 2) An[M(XW11O39)2] During the ceremony, X=GaIII, PV, SiIV, GeIV or TiIV. M=LaII,C eIII, CeIV, PrIII, SmIII, NdIII, EuIII, Gd III, TdIII, DyIII, HOIII, TmIII, or YbIII ．． 3) An[XM2W10O40] During the ceremony, X=PV, SiIV or VV. M=TiIV, ZrIV, VV, ZnII, CoII, FeII, or FeI II. 4) An[XM3W9O40] During the ceremony, X=PV, FeIII, SiIV or VV. M=VV, FeIII, NbV, CrIII, ZrIV or TiIV. 5) An[X2MW17O62] During the ceremony, X=PV. M=CoII, CoIII, NiII, ZnII, MnII, MnIII, Fe III, AlIII, GaIII, InIII, TiIV, ZrIV, VV, M oVI, or ■5-RC5H4Ti (wherein R = organic residue) 6) An[M(X2W17O61)2] in the formula, X=PV M = EuIII, CeIII, CeIV, SmIII, or other stable lanter Noid metal ion 7) An[X2M3W15O62] During the ceremony, X=PV. M=VV, TiIV, MoVI, or NbV8) An[M4(H2O)y(X W9O34)2] where, X=PV, FeII, ZnII or CoII, M=MnII, FeII, Co II, NiII, CuII, ZnII, ZrO, [FeCu]1/2, [WZn 3] 1/4 [WZnMnII2] 1/4, [WZnMnIII2] 1/4, [W MnII3]1/4, [WMnIII3]1/4, [WFeII3]1/4, [ WFeIII3] 1/4, [WNiII3] 1/4 [WCuII3] 1/4, [ WZnVIV2]1/4, [WZnIIFeII2]1/4, [WZnIICo II2] 1/4, WNi3II, [WZnIINiII2] 1/4, [WZnI IVIV2] 1/4, [WZnIIPdII2] 1/4, [WCoIINiII 2] 1/4, or [WCoIIZnII2] 1/4, y is 1 to 6 9) An[(FeOA)4(PW9O34)2]10) An[Ma(XW9O3 4) 2] In the formula, X=PV or Si■■ If a=1 or 2, M=WO2 If a=3, M=Zr(OH), CeO, Cu, Cu(NO3)1/3, Cu(NO2)1/ 3, WO2, ZnII, MnII, MnIII, FeII, FeIII, NiI I, CoII, [Fe2(WO2)]1/3, [FeCo(WO2)]1/3, [CoIICuIIWO2]1/3,][CuII2CoII]1/3,[Cu II2CoIINO3]1/3, [Zn2(WO2)]1/3, [Ni2(WO 2)]1/3, [Co2(WO2)]1/3, or [■-C5H5TiIV( OH2)]11) An[CO9(OH)3(H2O)6(HPO4)2(PW9 O34)3]12) An[M4(H2O)2(X2W15O56)2] where, X=pV M=MnII, FeII, CoII, NiII, CuII or ZnII (as described above) In both formulas, A is a cation and n makes the molecule electrically neutral. number of cations required) and dimers, isomers, solvates or reduced forms thereof, or one or more compounds selected from the group consisting of pharmaceutically acceptable derivatives of A method for treating or preventing a flavivirus-associated infection, comprising administering an effective amount of Law. 2. A is hydrogen, alkali metal, alkaline earth metal or ammonium cation , or of the formula R4-mHmN+, where R is an alkyl chain of 1 to 6 carbon atoms, The first term is an alkylammonium cation (m is 0, 1, 2 or 3) Method described. 3. Pharmaceutical compositions containing the compound together with a pharmaceutically acceptable carrier or diluent 3. The method according to item 1 or 2, wherein the method is administered in the form of 4. Section 1 for the manufacture of drugs for the treatment or prevention of flavivirus-related infections or a method of using the compound specified in Section 2. 5. The compound described in paragraph 1 or the compound in a pharmaceutically acceptable carrier or diluted Pharmaceutical composition for treatment or prevention of flavivirus-related infections, containing together with a diluent .