CA2134877A1 - Heteropolytungstates in the treatment of flavivirus infection - Google Patents

Abstract

Pharmaceutical compositions containing heteropolytungstates and pharmaceutically acceptable derivatives thereof. The use of such compounds or compositions in therapy for the treatment or prophylaxis of infections by viruses which are confirmed or probable members of the family Flaviviridae.

Description

WO93/21934 C~ 77 PCr/AlJ93/00192 H~ROPOLYTUNGSTAl~S IN T~ TRl~ATM~T ~ ~LAVIVIRUS INPBCIIONS.

The present inYennon rela~es to pharmaceu~c~l composi~ons containing s hetelopolytun~s2a2es and pharmaceu~cally acceptable denvahves thereof, and to ~hc use of these compounds in ~herapy for the treatmcnt or prophylalcis of infec~ons by ~iruses which are confi~ned or probable members of the family Flanvisidae, for example infec~ions such as yellow fev~r, dengue feves, Aus~liar~ encephali~s. Japanesc encephali~is ~d Hepa~s C.
Fa~n~scs are ~ell known to be thc causan:~rc agents of a numbes of humasl discases including the most importa~t arthropod-~oome vi~al af~ic~o~s of manldnd - dengue, yellow fever, and J~panese encephali~s. In addi~on, ~ight flaYi~riruses c~use disease in domes~c or wild animals of economic ~or~ce.
5 Yellowl fever and dengue fever are widesp~ead and well k~o~m as mosqLito borne diseases of tropical cou~mes~ Thcre arc betwcen 30 and 6û millioR
flaYi~nrus infcctions per year includ~ng one million Japanese encephali~s infec~ions. Thc extent of Hepa~s C is not hlown with ~tny de~e of c~y bccausc an infecdon can exîst for masly years without t~c pa~ient being aware of20 the symptos~ epa~s C produces a much higher rate of GhrOD,lC liYe~ fection WO 93~21934 PCI/AU93/00192 `; ~
3 ~

~an Hepa~s B which is a recog~ed hazard in many coun~ies. About 50% of pa~ents develop chronic infec~ons, compared with S tO lO~o of those i~fected with Hepan~s B. C~onic infec~on causes ci~hosis of the liver, Lmpa2rs liver func~on, and 20-30 years later causes li~rer failure. It has be~n es~mated tha~ the s ra~e of infechon approaches and may exceed 1% of the popula~on in Australia There is no proven cure or vacc~e for Hepatins C.

~ffec~ve vaccines are available for some viruses only, eg for yellow fever - Japanese encephalitis and ~cl~-borne encephali~s. Trea~e~t of dengue fever andl o Australian en~ephali~s relies on the pa~ent's own ~une defe~ces; infec~ons can be fatal.

An an~viral drug to con~ol iIlfec~ons with ~a~ri~es is thus highly desirable. Drugs which control or inhibit replication havc prove~ to be effective s in the control of some other viruses. However, beca~lse of tbe difficulty of inhibi~g viruses while leaving ~he non-infe~ted cells un~mpaired, few an~riral drugs are c~rently in widespread clinical use.

8 ~ 7 The family Flaviviridae is a newly-recognised large group (in excess of 70 speeies) of small. enveloped viIuses that contain a single s~and of positive-sense RNA of 10 kilobases. As a consequence of the difficulty rnen~ioned above and recent recognition of flavi~iruses as a unique g~oup with a unique replica~on s strategy, no attennon has been paid to an~Yiral compounds tO control flaviviral infections.

All members of the farnily Flavil iridae possess a unique replication strategy which is inhibited by the compositions of this invention. The non-0 structural genes NS3 and NSS which have been proposed to be involYed in replication share a great deal of sequence similanty ~etween sp~cies, and hence an inhibitor of replication should be active against all flaYiv~uses.

~ Prior Art Heteropolytungstate compounds have been known for over 100 ye~.
Most of ~heir applications stem from their redox chemistry and also ~eir high ionic weights and charges. Their redox chemistry has lead to their use as catalysts for the oxidation of organic substrates such as, for example, propylene to acrylic acid, ethylene to acetaldehyde. In the biological field 2o heteropolytungstates have found use as electron dense stains for electron microscopy, as analy~cal reagents for proteins and seYeral have also been shown to inhibit viral DNA and RNA polymerases. (J. C. Chennan, e~ al., Biochem.
Biophys. Res. Cornmun., 1975, 65, 1229; M. Hervé, et al., ibid, 1983, Il6, 222.)Thc heteropolynmgstates within the scope of this i~vention include the 2 5 Keggin and Dawson (also known as the Wells-Dawson) type strucn~es and compounds based on these structures in which one or more of the nmgsten atoms are removed and, in the majority of cases, exchanged by other metal atoms.
Vacancies in the structures are most often c~ea~ed by the extracaon of wo4+ or W3066+ from the Keggin (XW12040n-) or Dawson (P~W1gO62~) species.
Isomers of these unsaturated (lacunary) polyanions are possible, a consequence of the location of the vacancy. (R. Massart R. Conta~t, J. M. Fruc~art, J. M.
Ciabn~i. M. Foun~ier, lnorg. Chem. 1977, 16, 2916; T. L. Joms, M. Kozik, N.
Casan-Pastor, P. J. Domaille, R. G. Pin~e, W. K~ Mille$ and L. C. W. Baker, J.
Am. Chem. Soc. 1987, 109, 7402, T. J. R. Wea~ley, Polyhedron 1987t 6, 931;
3s R. Contant and J.-P. Ciabrini, J. Chem. Res. (S), 197?, 222; R. G. Fmke, M. W.
Droege and P. J. Domaille, lnorg. Chem." 1987, 26, 3886; M. T. Pope, "Het~ropoly and Isopoly Oxometalates", Springer-Verlag, Berlin, 1983.) The posi~on of the vaca~cy in P2W170611~ is defined by the prefix o~l- for a belt WO 93/21934 ~ 4 P~/AU93tO0192 . -vacancy or a2- for a cap vacancy. The rotation of W3-oxide triads in the seructures leads to a number of isomers. Thus a 60 rotation of a W3 triad cap can con~ert, for example, an a- isomer to the ~- isomer. In the trivacant polyanions of the type XW9O34n-, A- or B- forms are obtained, depending upon s whether a comer-linked W3 oxide triad is lost (A- fo~n) or an edge-linked W3 oxide triad has been removed(B- form).
Unsaturated heteropolyanions can behave as ligands by bonding, at their ~acant site, with metal ions. These me~al ions, when not stencally crowded, can ca~ry ligands such as water, organic coordinating species or arganometallic 0 groups. Organomet~llic moienes can also react with exposed oxygen a~oms on, for example, ~isubstituted Keggin or Dawson s~uctures (R. G. Finke and M. W.
Droege, J. Am. Chem. Soc., 1984, 106, 7274 and R. G. Finke, B. Rapko and P.
J. Domaille, Organome~allics 1986, 5, 17~). An oxygen atom on the Keggin structure can also be alkylated with reagents such as trimethyloxonium salts (W.5 H. Knoth and R. L. Harlow, J. Am. Chem. Soc. 1981, 103, 4265). Some of the oxygen atoms on heteropolytungstates can also be exchanged for fluorine aloms (F. Chauveau, P. Doppelt ~d J. Lefebvre, Inorg. Chem. 1980,19, 2803; T. L.
Joms, M. Kozik and I.. C. W. Baker, Inorg. ~hem. 1990, 29, 4584).
Other heteropolyanion species are formed by reac~ion of two WsolgH5-ions with metal ions such as the lanthanoids (R. D. Peacock and T. J. R. Weakley, J. Chem. Soc. A, 1971,1836). Heteropolyanions having PW7 phosphotungstate groups, generally bridged by phosphate group(s), are known (J. Fuchs and R.
Palm, Z. Naturforsch. 1988, 43b, 1529 and R. Acerete, J. Server-Ca~io, A.
Vegas and M. Mar~ez-Ripoll, J. Am. Chem. Soc., 1990, 112, 9386).
The central atom in the compounds can vary widely, especially in the case of the simpler Keggin type structures. The cent~al atom in the Dawson type struc~ures is most often phosphorus.
Heteropolytungstate species are often more stable in solution than the corresponding he~eropolymoly~dates. He~eropoly compounds of other metals, such as niobium and vanadium, have also been made but often are st~ble only over a more limited pH range.

We have now made the unexpected discovery that heteropolytungstate polyanions containing a "cent~al" species (designated X in the examples of 3s structural types listed below) are active against viruses belonging to the Flavivirid'ae family. In particular the~ inhibit the replication of such virusesstopping the developmen~ of an infection.

wo 93~21934 2 ~3 ~ ~ IJ7 7 pcr/Au93/oo192 ;. - .

Accordingly the present in~ention provides compositions for use in the treatment or prophyla~is of a f~avivirus associated infection having as active ing~edien~ one or more heteropolytungstate compounds selected from ~ormula 1 to ~below or a pha~naceutically acceptable derivative thereof. The compounds s of the invention are polyanions with associated cations (A) for electrical neutrality. They crystallize with a variable number of molecules of water of crystallization dependent upon the condi~ions of product recovery and subsequenttreatment; all such hydrates come within the scope of this invention.

0 By "a pharmaceutically acceptable derivative" is meant any pharrnaceutically acceptable salt, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of thc invention or an active metabolite or residue thereof.
-The pharmaceutical compositions of the present invention may comprise an effective amount of one or more compounds selected from Formulae 1-12 in associadon with one or more pharmaccutically acceptable ca~ners or diluents, - and optionally other therapeutic agen~s. Each ca~ier must be phannaceutically "acceptable" in the scnse of being compadble with the other ingredients of the composition and not injurious to the padent. It should be understood that in addition to the ingredients particularly mentioned, thc compositions of this invention may include other agents conventional in the art having regard to the ~- type of composition in qucstion, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and 2s flavou*ng agents.

-~ Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravcnous and intradesmal) adminis~ation. The compositions may conveniently be prescnted in unit dosage forrn and may be prepared by any methods well known in the art of pharmacy. Such methods include the stcp of b~inging into association thc acdvc ingredient with thc ca~rier which constitutes .t onc or more acccssory ingredients. In gencral, the compositions are prepared by unifonTlly and intimatcly bringing into association the active ingrcdient with 3 liquid ca~iers or finely divided solid ca~Tiers or both, and then if neccssary ~, shaping the product.

WO 93/21934 ~ r~ 6 PCI/AlJ93/00l97,................................. ~ j rne present inven~on also extends to a method for the treatment or prophylaxis of a flavivirus associated infec~ion, which comprises the adminis~a~on of a composition colltaining an effec~ve amount of one or more compounds selected from Formulae 1-12.
The compounds may be prepared by the literature methods or adaptions thereof, varying reactants and condi~ons as required to obtain the target compound. &eneral review articles, describing the prepara~on, structure and propemes of many of the compounds, include P. Souchay, "Ions Mi~eraux 10 Condensés", Masson, Paris, 1969; M. T. Pope, 'He~eropoly and Isopoly Oxometala~es", Springer-Verlag, Berlin, 1983; T. J. R. Weakley, Structure and Bonding, Springer-Verlag, Berlin, 1974,18, 131; ~vI. T. Pope and A. Muller, .Angew. Chem. Int. Ed. ~ngl. 1991, 30, 34.

lS The compounds of the inven~on useful as ac~ve ingredients, are listed as Formulae 1-12 below along with appropriate methods of preparanon for each su~type.

a. Compounds based on ~he Keggin st~ucture.
1.) An~YMXw11039]
Wherein X _ gIII, pV, SiIV, GeIV, ZnII~ CoII, Com, Fem, Gam, TirV, or zrIV, M = MnII, Mnm, FeII, FeIII, c~ , CoII, Com, Gam, NiII, znII, TiIV, zrIV, AlIII, Inm, VIv~ VV, MoVI, P~, NbV, Y = ligand (e.g. H20, OH-, o2-, NH3, NCS-, N02-, CN-, S032-, aromatic/~liphanc amines, or cyclopentadienyl group.) These compounds may be made by following the procedures descn~ed in the literan~re, e.g. C. M. Tousné, G. F.Toumé, S. A. Malik and T. J. R. Weakley, J.
inorg. nucl. Chem. 1970, 32, 3875-3890 and refe~ences ~herein; M. Bauchet, C. i M. Tourné and G. Tourné, C. R. Acad. Sci. Paris, 1972, C275, 4 Zonne~rijlle, C. M. Tou~né and G. F. Tou~né, Inorg. Chem. 1982, 21, 2742-3s 2750, 2751-2757 and references therein; P. J. Domaille, J. Am. Chem. Soc., 1984, 106, 7677; T. J. R. Wealdey, J. Chem. Soc., Dalton Trans. 1973, 341; L.
C. W. Bake~ and T. P~ McCutcheon, J. Am. Chem. Soc. 1956, 78, 4503 and subse~uent papers; M. Michelon and G. Hervé, C. R. Acad. Sci. Paris, 1972, WO 93/21934 7 2 1 3 ~ 3 7 7 PC[/AU93/00192 ; '''~ :
C274, 209; J. Liu, W. Wag, Z. Zhu, E. Wang and Z. Wang, Transition Met.
Chem. 1991, 16, 169; F. Ortéga and M. T. Pope, Ino~. Chem. 1984, 23, 3292.
The cyclopen~adienyl compounds were prepared by the methods of R. K. C. Ho and W. G. Klemperer, J. Am. Chem. Soc. 1978,100, 6772 or W. H. Knoth, J.
S Am. Chem. Soc. 1979,101, 2211.

2.) An[M(XW11O39)2 Wherein X = Gam. pV, SiIV, GeIV~ or TiIV.
0 M = L~II Cem, CeIV, PrIII, Smm, NdI~, Ell~, GdIll, Tbm, DyIII, Ho~ TmIII, or ybIII

The compounds may be made by following procedures given in the lite~ature, e.g. J. Liu, W. Wa~g, Z. Zhu, E. Wang and 7. Wang, Transition Met. Chem.
1991, 16, 169 and references therein; Gh. Marcu and M. Rusu, ~?ev. Roum.
Chim. 1977, 22, 227; .

3.) An~M2Wloo4o]
Wherein X = pV, SiIv~ or VV.
M = TiIV~ ZrIv, VV, ZnII, CoII, FeII, or Fem.

The compounds may be prepared by following the methods of P. J. Domaille, Inorg. Synth., 1990, 2~, 102-104. (Ed. A. P. Ginsberg) Whiley-Intesscience and 2s references therein; J. Canny, R. ThouvenQt, A. Tézé, G. HeNé, M. Leparu1~
Lofrus and M. T. Pope, Inorg. Chem. 1991, 30, 976; P. J. Domaille and W. H.
Knoth, Inorg. Chem. 1983, 22, 818; C. M. Tourné and G. F. Tourné, J.Chem.
Soc. Dal~on Tra~. 1988, 2411; C. M. Flynn Jr. and M. T. Pope, Inorg. Chem.
1971, 10, 2745.

4.) An[XM3WgO40]
Wherein X = P~, Fem, SiIv~ or VV
M = VV, Fem, NbV, CrIII, ZrIV, or TiIV.

The compo~mds may be prepared by following thc methods of P. J. Domaille, J.
Am. Chem. Soc., 1984,106, 7677; R. G. Fmke, C. A. Grcen and B. Ra~ko, Inorg. Synth., 1990,~7, 129.(Ed. A. P. Ginsbcrg) Whiley-Lnterscience and 3 ~ 8 pcr/Aus3/ools7 ._ references therein; P. Jun, Q. Lun-yu and C. Ya-guang, ~norg. Chim. Ac~a 1991,183, 157; D. J. Edlund, R. J. Saxton, D. K. Lyons and R. G. Finke, Organometallics 1988, 7, 1692; C. M. nynn Jr. and M. T. Pope, Inorg. CJ~em.
1971, 10, 2745.
s B. Satura~ed Compounds based on lhe Dawson struc~ure.

i.) An~x2Mwl7o62 Wherein o X=PV.
M = Co~, CoIII7 NiII, Zn~ MnIII, Fem, A1~, Ga~ [, InIII, TiIV, ZrIv~ VV, MoVI, or ~5-~C5H4Ti where R - organic residue.
.
lS The compounds may be obtained by the reac~ons of S. A. Malik and T. J. R.
Weakley, J. Chem. Soc., Chem. Commun. 1967, 1094; J. Chem. Soc. (A), 1968, 2647; D. K. Lyon, W. K. Miller, T. Novet, P. J. Domaille, E. Evitt, D. C.
Johnson and R. G. Finke, J. Am. Chem. Soc. 1991,113, 7209 and references therein; J. F. W. Keana and M. D. Ogan, J. Am. Ckem. Soc. 1986, 108, 7951.
6.) An~M(X2w17O6l)2]
Wherein X =pV
M = EUm, CeIII, CeIV, SmIII, or other sta~le 1antharloid metal ion.

The compounds may be made by the reac~ions of R. D. Peacock and T. J. R.
Wealdey, J. Chem. Soc. (A), 1g68, 1836; A. V. Botar and ReY. Roum. Chim.
1973, 18, 1155; Gh. Marcu, M. Rusu and A. V. Bo~ar,Rev. Roum. Chim. 1974, 19,82~.
7-) An~X2M3W1562]
Wherein X-pV ~' M = VY, TiIV, MoVl, or NbV

The compounds, M = V, may be made by following R. G. Fmke, B. Rapko, R. J.
Salcton and P. J. Domaille, J. A~z. Chem. Soc. 1986, 108, 2947. Ihe species, M
= Nb, the monomers and dimers, may be formed according to D. J. Edlund, R. J.

WO 93/21934 ~ 7 P~/AU93/00192 Saxton, D. K. Lyons and R. G. Finke, Organometallics 1988, 7, 1692. The compounds, LVI = Mo, may be made according to J. P. Ciabrini, R. Contant and J.
M. Fruchart, Polyhedron 1983, 2, 1229.

C. Compounds in which two or three trivacant A- or B-XW9034n- or two B-X~W15056n- polyanions are connected via ~ansition metal or lanthanoid me~l ion(s).

0 8.) An~M4(H2o)y(xw9o34)2 Wherein X = pV~ FeIII~ ZnII~ or CoII, ~I = MnII, FeII, CoII, NiII, CuII~ ZnII, ZrO, ~FeCu]1/2, tWZn3]lJ4 /4. [wzn~m2lll4~ 3~
~nIII3] 1/4, [wFeII3]~ [wFem3]~ 3]1/4, ~WCuII33 1/4, ~WZnV~2~ 1/4, [WZnIIFerl2~
[WZnIICoII~]1/4, WNi3II, [WZnIINi~]l~4, VIV2~i/4. [WZnIIPdII2]114~ 3~ /4.
~WCo~ 2]1/4. rWCoIIFem2~1/4. [WCo~ 2~1/4. or ~WC0~ 2]1/4-y is 1-6 most commonly 2.

These compounds may be made following the methods of H. T. Evans, C M~
Tou$né, G. F. Tou~é and T. J. R. Weakley, J. C~aem. Soc. Dalton Trans., 1986, 2699: R. G. Finke, M. W. Droege and P. J. Domai31e, Inorg. Chem." 1987, 26, 38~5; S. H. Wasfi, A. L. Reingold, GP.Kokoszka and A. S. Goldstein, Inorg.
Chem., 1987, 26, 2934; C. M. Toumé, G. F. Tou~é and F. Zonnevijlle, J.
Ckem. Soc. Dalton Tr~ns. 1991, 143.

9.) An[(Fe0A)4(PW9034)2]
The cbmpounds may be made by reflux of an aqueous mixture of ~-NagHPW9034 with an Fe(III) acetate species in a 1:2 molar ratio as descnbed t in Patent Application PCI/AU91/~0280. The structure of the polyanion is not known. An ICP analysis of, for exarnple, the potassium compound, gives a K: P
3s : ~e: W ra~o of 7: 1: 2: 9. An attempt was made to detenT~ine the crystal structure of the arnmonium salt, but the crystals were of insufficient quali~ toenable the atoms in the polyanion to be located with certainty. The unit ccll dimensions found were 32.36 x 27.30 x 24.42 A, with b = 112.28.

W093/Z1934 \g~l~ 10 PCI/AU93/1)0192 ~, 10.) An[Ma(XWgO34~2]
Wherein X - PV, or SiIV.
if a=l or2,M=WO2 if a = 3, M = Zr(OH), CeO, Cu, Cu(NO3)1/3, CU(N2)1/3, W2, ZnII, MnII, MnIII, FeII, FeIII, NiII CoII
[Fe2(W02)] 1/3. ~FeCo(W02)~ 1/3. [CoIICuIIW02.~
[CuII2CoII] 1/3 . [CuII2CoIIN03] 1/3, [Zn2(WO2)~ 1/3.
0 [Ni2(W02)]1/3, [co2(wo2)]~ or [11~5HsTiIv(oH2~J

The compounds may be made by the methods descnbed by R. G. Finke, B.
Rapk~ and T. J. R. Weakley, lnorg. Chem. 1989, 28, 1573 and references - therein; C. Tourné, A. Revel and G. Toumé, Rev. Chim. Miner~le 1977, 14, 537 ([Co2(W02)~1/3); C. M. Toumé and G. F. Toumé, J .Chem. Soc. Dalton Trans. 1988, 2411 .

11.) An[Cog(OH)3(H20)6(HPo4)~pw9o34)3~

M~y be prepared following the method of T. J. R. Weakley, .~. Chem. Soc., Chem. Commun. 19~4, 1406; J. Chem. Soc., Dalton Trans., 1986, 2699.

12.) An~M4(H20)2(X2W15056)2]
Wherein 2s x=pv M = MnII, FeII, CoII~ NiII, cUII or, ZnII.
These compounds may be made following the general method of R. G. Finke, M.
W. Droege and P. J. Domaille, Inorg. Chem." 1987, 26, 3886. When the cobalt compound (e.g. Na salt) is warmed in aqueous solution tO 80-90 for several hours, the ~d-brown compound that cIystallizes from the solution on cooling to room temperature is refe~Ted to as the 'high temp.' foIm of the compound.

In the compounds of formula 1-12, when a transition metal atom(s) replace(s) one or more tungsten atoms in thc structure, the oxygen on the transition metal atom(s) may be either doubly protonated (H20), singly protonated (OH), or completely deprotonated (O). The acidity of these protons, and the compounds that are obtained, as is }~own to one skilled in the ant of heteropolytungstate chernistry, depends on the nanlre of thc transition metal wo 93/21934 ~ 7 Pcr/Au93/ools~

atom, i~s oxidation state, the basicity of the polyanion formed and the basicity of the solution from which the compounds were isolated. In the compounds of the inven~on not all oxygen atoms are necessarily oxo groups and the charge (and hence the number of counter cations (A)) on the polyanion will depend on the s number of protons attached to the oxygen atom(s). Furthermore, compounds - containing groups such as, ~or example, MOH, may dimerize by an intermolecular condensa~on reaction. Dimers, where formed, of the compounds listed, are also included in the invention.
Many of the compounds of the invention can occur in a number of 0 isomenc forms. In fact, it is at times difficult to obtain isomerically pure compounds. All isomers or isomer mixtures are included in this invention.
Many of the compounds can undergo one or more electron reduclions.
The reduced compounds are also included in this invention.
T~te charge on the polyanions can vary, depending upon the extent of 5 protonation of the polyanions, as noted earlier, and upon the oxidation states of the metal atoms. The n~ber of associaled counter cations (A) will vary correspondingly. A ma~c be a proton, an aL~ali metal ion, an alkali ea~h ion, orammonium or a~l ammonium ion of type R4_nHnN+, where R is an alkyl chain of from 1 to 6 earbon atoms. The reguired cation is generally introduced into 20 the compound either by use of an ion exchange resin or by precipita~on with excess of a salt of that cation.
It is to be noted that, as one skilled in the art of heteropolyanion chemistry would l~ow, not all combina~ons of the elements given in ~rmulae 1 to 12 are 2 s isolable.

Preparation of Compositions Composi~ons of the present inven~ion suitable for oral ad~inistra~ion may be presented as discrete units such as capsules, sachets or tablets each containing a 30 predete~nined amount of the active in~edient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed table~s may be prepaled by compressing in a suitable machine the active ingredient in a free-flowing for~n such as a powder or granules, optionally mixed with a biIlder (e.g i~crt diluent, preservatiYe disintegrant (e.g. sodium starch glycollate, cross-lin~ed povidone, WO 93~1934 ~ L`~ 12 PCr/AI)93/00192 . `

cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.Moulded tablets may be made by moulding in a suitable machine a mixture of ~he powdered compound moistened with an inert ~iquid diluent. The table~s may opnonally be coated or scored amd may be fonnulated so as to provide slow or s controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying propor~ions to provide the desired release profile. Tablets may optionally b,e provided with an entenc coanng, to provide release in parts of the gut other than the stomach.

0 Compositions suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragac~nth gum; pastilles co~,nprising the active ingredient in aninert basis such as gelatin and glycerin, or sucrose and acacia gUITl; and ~ mQuth-vashes comprising the active ingredient in a suitable liquid ca~ier.

Composi~ons for rectal administration may be presen~ed as a suppository wi h a suitable base comprising, for example, cocoa butter or a salicylate.

Composltions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foa ns or spray formula~ons containingin addition to the active ingredient such carners as are known in the art to be appropriate.

Compositions suitable for parenteral adminis~ation include aqueous and 2S non-aqueous isotonic stenle injecdon solutions which rnay contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with ~eblood of the intended recipient; and aqueous and non-aqueo~s ste~ile suspensionswhich may include suspending agents and thic~cening agents. The compositions may be presented in unit-dose or mul~-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition re~uiring only the addidon of the sterile liquid ca~ier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage compositions are those containing a daily dose or unit daily sub-dose, as herein a~ove recited, or an appropriate fraction thereof, of an active ingredient.

.-.. WO 93/21934 13 '~ 7 7 PCI/AU93/00192 : . , The compounds according to the invennon may also be presented for use in the form of veterinary compositions, which may be prepared7 for example, by methods that are conven~ional in the art. Examples of such veteIinary 5 compositions include those adapted for:
(a) oral administla~on, external applicalion, for example drenches (e.g.
aqueous or non-aqueous solu~ions or suspensions); tablets or boluses; powders, granules or pellets for admixn~re with feed stuffs; pastes for application to the tongue;
0 (b) p~ren~eral adrninis~ration for example by subcutaneol~s, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramarnrnary injection where a suspension or solution isintroduced into the udder Yia the teat;
(c) topical application, e.g. as a cream, ointment or spray applied tO the 1S skin; or (d) intravaginally, e.g. as a pessary, cream or foarn.

It should be understood that in addition to the ingredients parncularly men~oned above, the compositions of this invention may include other agents 20 conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration rnay include such further agentsas sweeteners, thickeners and flavouring agents.

~.

WO 93/Z1934 ~ 14 Pcr/Au93/nolg~

Administration and dosage The compositions according to the invention may be adrr~inistered for therapy by any suitable route, including oral, rectal, nasal, topical (includingbuccal and sublingual), vaginal and parenteral (including su~cutaneous, s intramuscular, in~aYenous and intradermal~. Preferably, administration will be by the oral route, however it will be appreciated that the prefelTed route will vary with the condition and age of the recipient, the nature of the composition and the chosen active ingredient.

0 In general a suitable dose of the active ingredient will be in the range of 3.0 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg per kilogram body we;ght per day and most preferably in the range 15 to 60 mg per kilogram body weight per day. The desired dose is preferably presented as two, three, four, five, six or more su~doses administered at appropriate inteNals throughout the day. These sub-doses may be administered in unit dosage forrns, for exarnple, cont~g 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredien~
per unit dosage form Ideally the actiYe ingredient should be administered to achieve peak plasma concentrations of the active compound of ~om about 1 to a~out 100 ~lM, preferably about 2 to 50 IlM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the acave ingredient, optionally in saline, or oraIly administered as a bolus containing about 0.1 to about 100 mg/~cg of the active ingredient. Desirable blood levels may ~e maintained by a continuous infusion to containing about 0.4 to about 15 mg/mg of the acdve ingredient.

The following examples are intended for illus~ation only and are llot intended to limi~ the scope of the invention in any way. The term "active ingredient" as used in Examples 3 to 6 means one or more compounds of selected from Formulae 1-12 or a pharmaceutically acceptable derivative thereof.

W0 93~21g34 15 ~ 7 7 PCr/AU93/~019~
. . : ` !

EXAMPl,E 1 Compounds of the invention The compounds listed in Table 1 were prepared and dissolYed in doubly dis~illed water for tes~ng as described in Example 2 below:

Table 1 _ _ __ _ Anion Molecular Formula Acti~ritv ~
T~e Kun j in ¦ Denaue , ,., ., , ~ , 1-_~PW1 1 03 9 ] nH20 5 0-10 0 1I X~tC SiW1lO~nH~l nH~0 10 _ j ~ o ~ , , 1~CN~H6) 5 [c~ wl 14oH2] 'nH2 _ ~ 1o_5o 1 ¦ R6 t FePW1 1 0 4 o ] nH20 S 0 . _ _ 1 K8 tznznwllo4ol nH2 50 _ . .- . ~ , _ . .
. R7 tCOZnWl 1 040 ] nH20 5 . ~
1 K8 tFeFewllo4o] nH2~ >100 2 X11 tLa ~Pwllo39) 2~ _ 10-50 >100 _ 2 _ K13 [La (SiWll039) 2 1 ~nH~0 _ 10 2 _ R13 tNd~Tiwllo39) 2 1 ~nH20 _ O .5 3 X7Ti2PWI0040 nH2 _ _ 50-100 50 3 ¦ R6HZr2PW10040 nH20 ~ ~0-100 ~100 3 K7Zs2PW10040 n~2 __ 5-10 3 iC3HsZr2SiWI004on_2 _ _ _ _ 100 4 R6H7 tA-a-SiWgFe~040] nH20 5 ¦ _ 4 K6 tA--~-HSiWsV3040] ~nH2 _ _ 50-100 4 C~6 ta-l~ 2, 3-PWgV3040] n~20 _ _ 50-100 _4 tNMe3H) 3H6 tpwgzr3o4o] .nH?O 10-50 4 (N~e4) 3H7 tsiwszr3o4o] n 2 _ _ _ 50 1 _ 4 ~C6H4 ~A-a-siW9Ti3040] .nH20 _ 41 K6E~8 tF~WgFe~04o] nH2~____ 50-100 S R7 tC5H5TiP2W17061] nH~0 50 S R7tFe~ ~O 10-50 K7 tTiP2W17062Hl nH2 _ _ _ 10-50 K7 tZrP2W17062H] nE~2 _ _ __ 10--50 X? tAlP2wl70ç2H2l nH2~ 50 6 ~C~_ 50 7 R~HP2W1SV3062 nH2 _ 10-50 _ W 0 93/21g34 ~ ~ ~ 16 PCT/AU93/00l97~.

K8H4P2WlST'3062'nH20 _ I 10 ' 3 ~lo~co4~H2o)2(PWgO34)2]~n~2o- 5 5 Li~otco4tH2o)~(pwso34)2]~nH2o 1-2 8 ~lo~zn4(H2o)2(~wso34)2] nH20 ' 10 '.

9 ~Na.OtZn4(H20)2(PW90~4)2] nH20 ~ 10 i 8 ItNH4ll0tzn4~H2Q)2~pw~o34)2l~nH2o 1 10-50 8 XlotFe4~H2o)2tpw9o~4)2l nH20 lO-SO
8 Rlo~Mn4~H2o)2(pwgo34)2l nH2o _ 5-10 8 Kto tCu4tH20)2(PWgO34)21 nH2o 5 8 ~lotNi4ta2o)2(pwso34~)2l n~2o- 10.5-1 8 Na.2tZn~W~H20)2~ZnW9034)2] nH20 5 i 8 Na,2tCo~W~H20)2(CoWgO34~2] nH20 _ 1 i .
8 Nal2tZn~Fe20)W~H20)2~Znwso34)2] nH2o l-S 1, 9 Xlot~FeoK)4tpwso34)2]~nH2o 10 ilO
9 tNH4110ttFeONH4)q~PWgO34)2]~nH20 50 ! -9 Nalot~FeoNa)4~pwgo34)2] nH20 1-5 1 _ Xl2t(ceo)3~H2o)2(pwso~4)2] nH20 10 11 K16tCog~OH)3~H20)6(HPo4)2~pwso34)3~ nH20 10 !
11 [NH4]l6~co9(oH)3~H2o)6~Hpo4)2~pwgo34)3l~nH2o l-5 i 12 Nal6tZn4(H20)2(P2WlsO56)2] nH20 10-50 ilO
12 Nal6tFe4(H20)2tP2wl5os6)2 ~ 50 5 12 Nal6tMn4~H20)2~P2wlsos6)2] nH2o 1-5 12 ~il6[c04~H2o)2~p2wlsos6)2]-nH2o thl~h temp.l 5 ¦
12 Na~6tCo4~H20)2(P2W~5056)2] nH20 llow eemp.l S
12 Nal6tC04~H2)2(P2W150s6)2] nH20 [hi~h temp.l 10-50 . . . , , 5 f :, .

WO 93J21934 ~13 ~ ~ 7 7 PC~/AU93/00192 ,................................................................. ' 1i EXAMPLE 2: Antiviral Activitv The compounds listed in Example I were tested for their ability to inhlbit RNA
synthesis in an in vitro polymerase assay (Chu and Westaway, 1985, 1987; Brun and Bnnton, 1986). In this assay, flavivirus RNA comp$ising the genornic 44S
RNA, a double-s~anded replicanve form (RF) and a p~ y-double-stranded replicative intermediate (RI) are detected by the incorpora~ion of [a-32P]GTP.

A. Preparation of ~ir~s-infected Vero cell ex~racts Vero cells were infected at a multiplicity of infection of 7 for Type 2 dengue (DEN-2) v~rus (New Guinea C strain; Sabin and Schlesinger, 1945~ or Kunjin (KUN) virus (strain MRM 61C; Boulton and Westaway, 1972). Extracts containing RNA-dependent RNA polymerase (RDRP) acti~ty derived from DEN- 2 virus-infected cells were prepared at 30 to 36 h p.i., when polymerase activity was a~ a maximum. Similar1y, extracts of KUN virus-infe~ted cells were prepared at the time of maximum polymerase ac~vity at 24 h p.i. (Chu and Westaway, 1985).

The cells were pelleted by centrifugation and resuspended in 10 mM sodium acetate at a concentration of 2x107 cells/ml. They were then disrupted by passagmg 20 ~mes through a 21 gauge needle followed by 20 ~mes through a 26 gauge needle. The disrupted cells were centnfuged at 800 g for 7 min to obtain a supe~natant frac~on and a pellet of the nuclear-associated matenal. AIl RDRP
assays were performed using the supernat~nt ~ac~on, hereafter referred to as the cell ex~act, which was stored at -70C and used after only one cycle of freeze/thawing.

B. RNA-dependent RNA polymerase ass~y The RDRP activity in the cell ex¢act was assayed as prev~ously descn~ed with t the following modifications (Chu and Westaway, 1985). In each RDRP assay the virus-infected cell extract contained 4.~-6 mg/ml of protein. Ihe compound to be tested dissolved in double dis~lled water and RNasin (0~ units/ml, Promaga) were added to the cell extract for 10 min p~ior to the addition of the other components of the RDRP assay. The final reaction mixture (total ~olume of 50 111) contained 50 mM Tns-HCl pH 8.0, 10 mM magncsium acetate, 75 mM
potassaum acetate, 10 mM 2-mercaptoe~hanol, 6 ~Lg ac~nomycin D (AMD), S mM

wo 93/21934~ a~ 18 PCr/AU93/0019 phosphoenolpyruvate, 3 units/,LLl pyruvate kinase, 0.5 mM ATP, 0.5 mM CTP, 0.5 mM UTP, 25 ~M GTP, S ~Ci [a-32P]GTP (Amersham, specific activity 410 Ci/mmol), 0.5 units/ml RNasin, 30 ~1 of infected cell exl:ract and the test compound (from 0.5 to 100 ~ . The reaction was stopped after 30 min at 37C
5 by the addition of EDTA to a final concentration of 10 mM. An equal volume of TNE-SDS (50 mM Tris-acetate pH 7.6, 0.1 M sodium acetate, 1 rnM EDTA and 2% SDS) was added to disrupt membranes. The RNA was then extracted with phenol and precipitated by ethanol.

C. Electrophoresis of RNA

RNA samples were mixed with an equal volume of sample buffer containing 7 M
urea in TBE (89 mM Tris-HCl, 89 mM boIic acid, 2.5 snM EDTA) and 0.5~o bromophenol blue, and were separated by electrophoresis through 3%
polyacrylamide gels containing 7 M urea in TBE. The gels were fLl~ed in 10%
ace~c acid, dned and radiolabelled bands detected by au~oradiography.

Results The compounds tested inhibited the synthesis of both DEN-2 and K~ RF
RNA. There was also a decrease in the arnount of Rl dete~ted with increasing conc~ntrat~on of drug. The inhibito~y concentla~ons are given in Table 1.

References 2s BOULTON, R.W. AND WESTAWAY, E.G. ~1972).
Comparisons of Togavimses:Sindbis virus (Group A) and Kunjin virus (Group B).
Virology 49, 283-289.
CHU, P.W.G. AND WESTAWAY, E.G. (1985).
3 o Replication s~tegy of Kunjin v~us:c~ridence for recycling, role of thc replicative fo~n RNA as template in semiconservative and asymme~ic replication. Virology 140, 68-79.
CHU, P.W.G. AND WESTAWAY, E.G. (1987).
3 5 Charactcnzation of Kunjin virus RNA~ependent RNA polyme~asc reinitiadon of synthesis in vitro. Virology 157, 330-337.
GRUN, J.B. AND BRINTON, M.A. (1986).
Cha~cterisadon of West Nile virus RNA~ependent RNA polyme~se and cellular 4 o adenylyl and undylyl ~ansferases in cell-free extracts. Journal of Virology 60, 1 1 13-1124.
SABIN, A.B. AND SCHLESI~GER, R.W. tl945).
Production of immunity to dengue wi~ virus modified by propagation in mice.
4 5 Science lû1, 640-642.

- wo 93/21934 1 9 ~ 1 3 ~ ~ 7 7 PCl`/AU93/00192 EXAMPLF 3: Ta~let Formulations !

The ~ollowing formulatîon A may be prepared by wet granulation of the ingredients wi~h a solu~ion of poYidone, followed by addi~on of magnesium stearate 5 and compression.

mgltable~
Forrnulation A
(a) Ac~ve ingredient 250 250 (b) Lactose B.P. 210 26 (c) Povidone B.P. 15 9 (d) Sodiumstarch glycollate 20 12 (e) Magnesiumstearate 5 3 The following formula~ion B, may be prepared by direc~ compression of the admixed ingredients.
Fo. ~JIula~ion ~3 m~apsule . 20 Active ingredient 250 Pregela~inised sta~ch NF15 150 400 :

2s Fonnula~ion C ~Qntrolled release fo~mulaa~n~
This forrnul~tion may be prepar~d by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnes~um s~arate and compression.
m~/tablçt (a) Active ingredient 500 (b) Hydrox~opylmethylcellulose 112 (methocel K4M Premium) (c) Lactose B.P. 53 , (d) Povidone B.P.C. 28 -(e) Magnesium stearate 7 WO 93/21934 ~ 20 PCI`JAU93/00192 EXAMPLE 4: Capsule Formulations Forrnulation A
A capsule fonnulation may be prepared by admixing the ingredients of s Formulatian B in Example 3 above and filling into a two-part hard gelatin capsule.
Formulation B (infra) may be prepared in a similar marmer.

Fonnulation B
m~Lcapsule (a) Acti~e ingredient 250 (b) ~actose B.P. 143 (c) Sodiumstarch glycollate 25 (d) Magnesiumstearate 2 -Forrnula~ion (~ tCon~olled release capsule) The following controlled release capsule formulation may be prepared by 20 ex~uding ingredients a, b and c using an ex~ruder, followed by spheronisa~on of ~e extrudate and drying. The dried pellets may then be coated with release-controlling membr ne (d) and filled in~o a two-piece, hard gelatin capsule.
m~ap$ule (a) Ac~re ingredient 250 (b) Microcrystalline cellulose 125 (c) LactoseB.P. 125 (d) Ethyl cellulose 13 .

wo 93/21934 ~ ~ 3 ` 3 7 7 Pcr/Aus3/ool92 .... , . ~ I

EXAMPLE 5: Injec~able Formulation ~. `
Formulation:
Acnve ingredient 0.200 g Hydrochloric acid solution, 0.1M qs to pH 5.0-7.0 Sodium hydroxide solution, O.lM qs to pH 5.~7.0 Ste~ile water qs to lO ml The active ingredien~ may be dissolved in most of the water (35-40C) and the pH adjusted to between 5.0 and 7.0 with the hydrochloric acid or the sodium 0 hydroxide as appropnate. The batch may then be made up to volume with the water and filtesed through a sterile micropore filter into a sterile 10 ml amberglass vial (type 1) and sealed with sterile closures and overseals.

Claims (17)

CLAIMS:

1. A method for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises the administration to a patient in need of such treatment or prophylaxis of an effective amount of one or more compounds selected from Formulae 1 to 12 and dimers, isomers, solvates or reduced forms thereof:

1.) An [YMXW11O39]
Wherein X = BIII, PV, SiIV, GeIV, ZnII, CoII, CoIII, FeIII, GaIII, TiIV, or ZrIV.
M = MnII, MnIII, FeII, FeIII, CuII, CoII, CoIII, GaIII, NiII, ZnII, TiIV, ZrIV, AlIII, InIII, VIV, VV, MoVI, PbII, NbV, Y = ligand 2.) AD[M(XW11O39)2]
Wherein X = GaIII, PV, SiIV, GeIV, or TiIV.
M = LaIII, CeIII, ceIV, PrIII, SmIII, NdIII, EuIII, GdIII, TbIII, DyIII, HoIII, TmIII, or YbIII.

3.) An[XM2W1040]
Wherein X = PV, SiIV, or VV.
M = TiIV, ZrIV, VV, ZnII, CoII, FeII, or FeIII.

4.) AD [XM3W9o40]
Wherein X PV, FeIII, SiIV, or VV.
M = VV FeIII, NbV CrIII, ZrIV, or TiIV.

5.) An[X2MW17O62]
Wherein X = PV, M = CoII, CoIII, NiII, ZnII, MnII, MnIII, FeIII, AlIII, GaIII, InIII, TiIV, ZrIV, VV, MoVI, or ?5-RC5H4Ti where R= organic residue.
6.) An[M(X2W17O61)2]
Wherein X = pv M = Euiii, Ceiii, CeiV, Smiii, or other stable lanthanoid metal ion.

7.) An[X2M3W15O62]
Wherein X = PV, M = VV, TiIV, MoVI, or NbV

8.) An[M4(H2O)y(XW9O34) Wherein X = PV, FeIII, ZnII, or CoII, M = MnII, FeII, CoII, NiII, CuII, ZnII, ZrO, [FeCu]1/2, [WZn3]1/4, [WZnMII2]1/4, [WZnMnIII2]1/4, [WMnII3]1/4, [WMnIII3]1/4, [WFeII3]1/4, [WFeIII3]1/4, [WNiII3]1/4, [WCuII3]1/4, [WZnVIV2]1/4, [WZnIIFeII2]1/4, [WZnIICoII2]1/4, WNi3II, [WZnIINiII2]1/4, [WZnIIVIV2]1/4, [WZnIIPdII2]1/4, [WCo3II]1/4, [WCoIIMnII2]1/4, [WCoIIFeIII2]l1/4, [WCoIINiII2]1/4, or [WCoIIZnII2]1/4.
y is 1-6 9.) An((FeOA)4(PW9O34)2]

10.) An[Ma(XW9O34)2]

Wherein X = PV, or SiIV.
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, NiII, CoII, [Fe2(WO2)]1/3, [FeCo(WO2)]1/3, [CoIICuIIWO2]1/3, [CuII2CoII]1/3, [CuII2CoIINO3]1/3, [Zn2(WO2)]1/3, [Ni2(WO2)1/3, [Co2(WO2)]1,3, or [?-C5H5TiIV(OH2)].

11.) An[Co9(OH)3(H2O)6(HPO4)2(PW9O34)3]

12.) An[M4(H2O)2(X2W15O56)2]
Wherein X = PV
M = MnII, FeII, CoII, NiII, CuII or, ZnII.

and wherein in each of the above formulae, A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;

or pharmaceutically acceptable derivatives thereof.

2. A method as claimed in Claim 1, characterised in that A is a proton, an alkali metal, alkaline earth or ammonium cation, or an alkylammonium cation of the formula R4-mHmN+, where R is an alkyl chain of from 1 to 6 carbon atoms and m is 0, 1, 2 or 3.

3. A method as claimed in Claim 1 or Claim 2, characterised in that the compoundis administered in the form of a pharmaceutical composition which comprises the said compound in association with a pharmaceutically acceptable carrier or diluent.

4. The use in the manufacture of a medicament for the treatment or prophylaxis of a flavivirus associated infection of a compound as defined in Claim 1 or Claim 2.

5. A pharmaceutical composition for the treatment or prophylaxis of a flavivirusassociated injection, characterised in that it comprises a compound as defined in Claim 1 or Claim 2, in association with a pharmaceutically acceptable carrier or diluent.

6. A pharmaceutical composition for the treatment or prophylaxis of a flavivirusassociated infection, characterised in that it comprises one or more compounds of Formula 1 or dimers, isomers, solvates or reduced forms thereof:

1.) An [YMXW11O39]
Wherein X = BIII, PV, SiIV, GeIV, ZnII, CoII, CoIII, FeIII, GaIII, TiIV, or ZrIV.
M = MnII, MnIII, FeII, FeIII, CuII, CoII, CoIII, GaIII, NiII, ZnII, TiIV, ZrIV, AlIII, InIII, VIV, VV, MoVI, PbII, NbV, Y = ligand and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

7. A pharmaceutical composition for the treatment or prophylaxis of a flavivirusassociated infection, characterised in that it comprises one or more compounds of Formula 2 or dimers, isomers, solvates or reduced forms thereof:

2. An[M(XW11O39)2]
Wherein X = GaIII, PV, SiIV, GeIV, or TiIV.
M = LaIII, CeIII, CeIV, PrIII, SmIII, NdIII, EuIII, GdIII, TbIII, DyIII, HoIII, TmIII, or YbIII.

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

8. A pharmaceutical composition for the treatment or prophylaxis of a flavivirusassociated infection, characterised in that it comprises one or more compounds of Formula 3 or dimers, isomers, solvates or reduced forms thereof:

3.) An[XM2W10O40]
Wherein X = PV, SiIV, or VV.
M = TiIV, ZrIV, VV, ZnII, CoII, FeII, or FeIII.

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

9. A pharmaceutical composition for the treatment or prophylaxis of a flavivirusassociated infection, characterised in that it comprises one or more compounds of Formula 4 or dimers, isomers, solvates or reduced forms thereof:

4. An[XM3W9O40]
Wherein X = PV, FeIII, SiIV, or VV.
M = VV, FeIII, NbV, CrIII, ZrIV, or TiIV.

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises one or more compounds of Formula 5 or dimers, isomers, solvates or reduced forms thereof:

5.) An[X2MW17O62]
Wherein X = PV.
M = CoII, CoIII, NiII, ZnII, MnII, MnIII, FeIII, AlIII, GaIII, InIII, TiIV, ZrIV, VV, MoVI, or ?5-RC5H4Ti where R= organic residue.

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

11. A pharmaceutical composition for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises one or more compounds of Formula 6 or dimers, isomers, solvates or reduced forms thereof:

6.) AN[M(X2W17O61)2]
Wherein X = PV
M = EuIII, CeIII, CeIV, SmIII, or other stable lanthanoid metal ion.

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

12. A pharmaceutical composition for the treatment or prophylaxis of ?avivi??

associated infection, characterised in that it comprises one or more compounds of Formula 7 or dimers, isomers, solvates or reduced forms thereof:

7. An[X2M3W15O621]
Wherein X = PV.
M = VV, TiIV, MoVI, or NbV

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

13. A pharmaceutical composition for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises one or more compounds of Formula 8 or dimers, isomers, solvates or reduced forms thereof:

8.) An[M4(H2O)y(XW9O34))2]
Wherein X = PV, FeIII, ZnII, or CoII, M = MnII, FeII, CoII, NiII, CuII, ZnII, ZrO, [FeCu]1/2, [WZn3]1/4, [WZnMnII2]1/4, [WZnMnIII2]1/4, [WMnII3]1/4, [WMnIII3]1/4, [WFeII3]1/4, [WFeIII3]1/4, [WNiII3]1/4, [WCuII3]1/4, [WZnVIV2]1/4, [WZnIIFeII2]1/4, [WZnIICoII2]1/4, WNi3II, WZnIINiII2]1/4, [WZnIIVIV2]1/4, [WZnIIPdII2]1/4, [WCo3II]1/4, [WCoIIMnII2]1/4, [WCoIIFeIII2]1/4, [WCoIINiII2]1/4, or [WCoIIZnII2]1/4.
y is 1-6 and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;

or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

14. A pharmaceutical composition for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises one or more compounds of Formula 9 or dimers, isomers, solvates or reduced forms thereof:

9.) An(FeOA)4(PW9O34)2]

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;

or pharmaceutically acceptable derivatives thereof.

15. A pharmaceutical composition for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises one or more compounds of Formula 10 or dimers, isomers, solvates or reduced forms thereof:

10.) An[Ma(XW9O34)2]
Wherein X = PV, or SiIV.
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, NiII, CoII, [Fe2(WO2)]1/3, [FeCo(WO2)]1/3, [CoIICuIIWO2]1/3, [CuII2CoII]1/3, [CuII2CoIINO3]1/3, [Zn2(WO2)]1/3, [Ni2(WO2)]1/3, [Co2(WO2)]1/3, or [?-C5H5TiIV(OH2)].

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

16. A pharmaceutical composition for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises one or more compounds of Formula 11 or dimers, isomers, solvates or reduced forms thereof:

11.) An[Co9(OH)3(H2O)6(HPO4)2(PW9O34)3]

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.

17. A pharmaceutical composition for the treatment or prophylaxis of a flavivirus associated infection, characterised in that it comprises one or more compounds of Formula 12 or dimers, isomers, solvates or reduced forms thereof:

12.) An[M4(H2O)2(X2W15O56)2]

Wherein X = PV
M = MnII, FeII, CoII, NiII, CuII or, ZnII.

and A is a cation and n is the number of such cations necessary for electrical neutrality of the molecule;
or pharmaceutically acceptable derivatives thereof;
in association with a pharmaceutically acceptable carrier or diluent.