WO2005095425A1

WO2005095425A1 - Dithiophosphato-platinum-complexes for the treatment of cancers

Info

Publication number: WO2005095425A1
Application number: PCT/GB2005/001251
Authority: WO
Inventors: Anthony Lowe; Mark Whittaker; Petra Dieterich; Mario Eugenio Cosimino Polywka
Original assignee: Pharminox Limited
Priority date: 2004-03-31
Filing date: 2005-03-31
Publication date: 2005-10-13
Also published as: GB0407351D0

Abstract

Complex of formulas: (I), (II) or (III): which are suitable for the treatment of tumors.

Description

DITHIOPHOSPHATO-PLATINUM-COMP EXES FOR THE TREATMENT OF CANCERS

This invention relates to platinum complexes and to their use as inhibitors of thioredoxin reductase, particularly in the treatment of tumours and of rheumatoid arthritis. At present, cancerous diseases are usually treated by drug therapy and/or radiotherapy before and/or after surgery. Oncotherapy by pharmaceuticals, i.e. chemotherapy, uses compounds influencing cancer growth in various ways. However, chemotherapy is often accompanied by serious side-effects unpleasant for patients, such as hair loss, nausea, vomiting, tiredness and damage to bone marrow and white blood cells. This applies particularly to the platinum compounds used so far, such as cis-platin and carbo-platin. More or less serious secondary infections also occur frequently. In addition, not all of the tumour kinds respond to chemotherapy, e.g. renal cell carcinoma or tumours of the gastrointestinal tract. One of the other maj or limitations to clinical use of cancer therapeutic agents is the development of resistance to such agents. The problem of pharmaceutical resistance has been observed with numerous drugs, including the platinum complexes used to treat certain types of solid tumours and leukaemias. Despite development of resistance, cis-platin is a clinically important anti- neoplastic agent with particular utility in the treatment of testicular and ovarian cancer. Several derivatives of cis-platin have been synthesised in an attempt to overcome these disadvantages and some progress has been made in identifying certain platinum compounds with high aqueous solubility, lowered nephrotoxicity and high anti-tumour activity. Despite the large number of platinum complexes available for clinical use, the development of resistance and toxicity remains a major problem. There is therefore a need to develop platinum pharmaceuticals which have improved anti-tumour activity and toward which tumours do not readily display cross resistance. Accordingly, the present invention provides a compound which is a complex offormula (I), (II) or (III):

(I)

(II)

(HI)

wherein: p is 1 and either

(a) each R, which are the same or different in a given compound, is a direct bond or is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene and alkynylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or

(b) each R, which are the same or different in a given compound, is a direct bond or is independently selected from arylene, aralkylene and alkarylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, halogen, nitro, cyano, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or p is 0, and

(c) the two R groups attached indirectly via X atoms to the same P or Si atom together form, with the X atoms to which they are directly attached, a 5- or 6- membered saturated cyclic diol or dithiol which is unsubstituted or substituted by one or more saturated substituents containing one or more heteroatoms selected from O and N; each m, which are the same or different in a given compound, is 0 or 1 ; each n, which are the same or different in a given compound, is 0 or 1 ; and X is O or S; or a pharmaceutically acceptable salt thereof; for use in a method of treatment of the human or animal body by therapy. In a further aspect the invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active agent, a compound as defined above. Compounds of the above formula (I) in which each X is bonded to an unsubstituted alkyl group are known. The remainder of the compounds are novel. Accordingly, the present invention further provides a compound which is a complex of formula (I), (II) or (III):

(I)

(II)

(Ill)

wherein p is 1 and either (a) each R, which are the same or different in a given compound, is a direct bond or is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene and alkynylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or (b) each R, which are the same or different in a given compound, is a direct bond or is independently selected from arylene, aralkylene and alkarylene; ancl each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, halogen, nitro, cyano, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from allcyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy ancl aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ -tnd R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturatec-L or unsaturated, 1,2- ring system; or p is 0, and

(c) the two R groups attached indirectly via X atoms to the same P or Si ato-m together form, together form, together with the X atoms to which they aire directly attached, a 5- or 6-membered saturated cyclic diol or dithiol which is unsubstituted or substituted by one or more saturated substituents containing one or more heteroatoms selected from O and N; each m, which are the same or different in a given compound, is 0 or 1; each n, which are the same or different in a given compound, is 0 or 1 ; and

X is O or S; or a pharmaceutically acceptable salt thereof; provided that, when p is 1 in formula (I), at least one of the moieties of formula -R-

(0)_m-(K\-R -R-(O)_m-(R)_n-R² , -R-(O)_m-(R)_n-R³ and -R-(O)_m-(R)_n-R⁴ does not represent an unsubstituted alkyl group. In one embodiment of formulae (I) to (III) as defined above, parameter f> is 1 and R is other than a direct bond. Accordingly, the invention further provides a compound which is a complex of formula (I'), (IF) or (III'):

(I¹)

(ΠT)

wherein

(a) each R, which are the same or different in a given compound, is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene and alkynylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or (b) each R, which are the same or different in a given compound, is independently selected from arylene, aralkylene and alkarylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, halogen, nitro, cyano, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; and each m, which are the same or different in a given compound, is 0 or 1; each n, which are the same or different in a given compound, is 0 or 1 ; and

X is O or S; or a pharmaceutically acceptable salt thereof; for use in a method of treatment of the human or animal body by therapy. The invention also provides compounds of formulae (F), (IF) and (IIF) as defined above as novel compounds provided that, in formula (F), at least one of the moieties of formula ^-(O^- R- R¹, -R-(O)_m-(R)_n-R² , -R-(O)_m-(R)_n-R³ and

-R-(O)_m-(R)_n-R⁴ does not represent an unsubstituted alkyl group. In the above definitions a halogen is fluorine, chlorine, bromine or iodine.

Preferably it is chlorine or fluorine. X is preferably O. An alkyl group is an unsubstituted or substituted, straight or branched chain saturated hydrocarbon radical. Typically it is -Cg alkyl, for instance C_rC₆ alkyl.

Preferably it is C_rC₄ alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s- butyl or n-butyl. It may also be pentyl, hexyl, heptyl, octyl and the various branched chain isomers thereof. When an alkyl group is substituted it typically bears one or more substituents, for instance one or two substituents, each independently selected from alkyl which is unsubstituted, aryl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, alkylthio, aralkoxy, amino, alkylamino and carboxy. Preferably the substituent is selected from unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, halogen, haloalkyl, hydroxy, unsubstituted alkoxy, unsubstituted alkythio, unsubstituted aralkoxy, amino and carboxy. Examples of substituted alkyl groups include haloalkyl (other than monohaloalkyl), hydroxyalkyl, aminoalkyl and alkoxyalkyl groups. A haloalkyl group in the context of the present invention is an alkyl group as defined above, substituted by two or more halogen atoms. It can be a perhaloalkyl group, for instance trifluoromethyl. A hydroxyalkyl group is an alkyl group as defined above, substituted by one or more hydroxy groups. An aminoalkyl group is an alkyl group as defined above, substituted by one or more amino groups. It may be, for instance, monoaminoalkyl or diaminoalkyl. An alkoxyalkyl group is an alkyl group as defined above, substituted by an alkoxy group as defined above. An alkoxyalkyl group is conveniently represented as -alk-O-alk in which alk is -Cg alkylene which is unsubstituted or substituted, as defined below, and alk is C_rC₈ alkyl which is unsubstituted or substituted, as defined above. An alkylene group is unsubstituted or substituted, straight or branched chain saturated divalent hydrocarbon group. Typically it is C_rC_g alkylene, for instance C C₆ alkylene. Preferably it is C_rC₄ alkylene, for example methylene, ethylene, i- propylene, n-propylene, t-butylene, s-butylene or n-butylene. It may also be pentylene, hexylene, heptylene, octylene and the various branched chain isomers thereof. When an alkylene group as defined above is substituted it typically bears one or more substituents selected from alkyl, aryl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, aralkoxy, amino, alkylamino, carbonyl and carboxy. Preferably the substituent is selected from unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, halogen, haloalkyl, hydroxy, unsubstituted alkoxy, unsubstituted aralkoxy, amino and carboxy. Examples of substituted alkylene groups include haloalkylene, hydroxyalkylene, and aminoalkylene groups. A haloalkylene group is an alkylene group as defined above, substituted by one or more halogen atoms. It can be a perhaloalkylene group, for instance trifluoromethylene. A hydroxyalkylene group is an alkylene group as defined above, substituted by one or more hydroxy groups. An aminoalkylene group is an alkylene group as defined above, substituted by one or more amino groups. It may be, for instance, monoaminoalkylene or diaminoalkylene. An alkylamino group is an amino group substituted by one or two unsubstituted alkyl groups as defined above. It is a monoalkylamino group or a dialkylamino group. An alkoxy group is unsubstituted or substituted and is typically C_rC₆ alkoxy, preferably -C₄ alkoxy, for example methoxy, ethoxy, i-propoxy, n-propoxy, t- butoxy, n-butoxy or s-butoxy. An alkoxy group can be substituted by one or more substituents, for instance one or two substituents, each independently selected from alkyl, aryl, cycloalkyl, halogen, haloalkyl, hydroxy,alkoxy, aralkoxy, amino, alkylamino and carboxy. Preferably the substituent is selected from unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, halogen, haloalkyl, hydroxy, unsubstituted alkoxy, unsubstituted aralkoxy, amino and carboxy. Unsubstituted alkoxy is a particularly preferred substituent. An alkylthio group is typically C C₆ alkylthio, preferably -C₄ alkylthio, for example methylthio, ethylthio, i-propylthio, n-propylthio, t-butylthio, n-butylthio or s-butylthio. An alkanoyl group is C_rC₈ alkanoyl, for instance C_rC₆ alkanoyl, such as formyl, acetyl, propionyl or butyryl. An alkanoyloxy group is is C_j-Cg alkanoyloxy, for instance C_rC₆ alkanoyloxy, such as formyloxy, acetoxy or propanoyloxy. A cycloalkyl group is aC₃-C₈ cycloalkyl group, for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. A cycloalkyl group is unsubstituted or substituted, for instance as specified above for alkyl. When the cycloalkyl group is substituted it typically bears one or more substituents, for instance one or two substituents, each independently selected from alkyl, aryl, halogen, haloalkyl, hydroxy, aralkoxy, amino, alkylamino, carbonyl and carboxy. Preferably the substituent is selected from unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, halogen, haloalkyl, hydroxy, unsubstituted alkoxy, unsubstituted aralkoxy, amino and carboxy An alkenyl group is an unsubstituted or substituted, straight or branched chain hydrocarbon radical having one or more double bonds. Typically it is C₂-C₈ alkenyl, for instance C₂-C₆ alkenyl, such as allyl, butenyl, butadienyl, pentenyl or hexenyl. When the alkenyl group is substituted it typically bears one or more achiral alkyl groups, for instance one or two achiral alkyl groups, such as defined above, preferably unsubstituted C_rC₄ alkyl, for example methyl, ethyl, i-propyl, n-propyl, t- butyl, s-butyl or n-butyl. An alkenylene group is an unsubstituted or substituted, straight or branched chain divalent hydrocarbon group containing one or more double bonds. Typically it is C₂-C₈ alkenylene, for instance C₂-C₆ alkenylene, such as allylene, butenylene, butadienylene, pentenylene or hexenylene. When the alkenylene group is substituted it typically bears one or more achiral alkyl groups, for instance one or two achiral alkyl groups, such as defined above, preferably unsubstituted Cj-C₄ alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n-butyl. An alkynyl group is an unsubstituted or substituted, straight or branched chain hydrocarbon radical having one or more triple bonds. Typically it is C₂-C₈ alkynyl, for instance C₂-C₆ alkynyl, such as ethynyl, propynyl or butynyl. When the alkynyl group is substituted it typically bears one or more achiral alkyl groups such as defined above, preferably unsubstituted C,-C₄ alkyl, for example methyl, ethyl, i- propyl, n-propyl, t-butyl, s-butyl or n-butyl. An alkynylene group is an unsubstituted or substituted, straight or branched chain divalent hydrocarbon group having one or more triple bonds. Typically it is C₂-C₈ alkynylene, for instance C₂-C₆ alkynylene, such as ethynylene, propynylene or butynylene. When the alkynylene group is substituted it typically bears one or more achiral alkyl groups, for instance one or two achiral alkyl groups, such as defined above, preferably unsubstituted C_rC₄ alkyl, for example methyl, ethyl, i-propyl, n- propyl, t-butyl, s-butyl or n-butyl. A cycloalkenyl group means a substituted or unsubstituted carbocyclic hydrocarbon group including one or more double bonds. Typically it is C₄-C₈ cycloalkenyl, for instance cyclopentenyl or cyclooctadienyl. When the cycloalkenyl group is substituted it typically bears one or more substituents, for instance one or two substituents, independenly selected from aryl, cycloalkyl, halogen haloalkyl, hydroxy, alkoxy, aralkoxyl, amino, alkylamino, carbonyl or carboxy. An aryl group is a substituted or unsubstituted, monocyclic or bicyclic aromatic group which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion. Examples include phenyl, naphyl, indenyl and indanyl groups. An aryl group is unsubstituted or substituted. When an aryl group as defined above is substituted it typically bears one or more substituents, for instance one or two substituents, independenly selected from C_j-Cg alkyl, C_rC₆ alkoxyl, haloalkyl, halogen, carboxy, sulfonic acid or sulfonic acid salt, sulfonyl and hydroxy. Preferably the substituent is selected from unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, halogen, haloalkyl, hydroxy, unsubstituted alkoxy, unsubstituted aralkoxy, amino and carboxy. An aryl group substituted by alkyl is preferably substituted by unsubstituted C_rC₄ alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n-butyl. Examples of substituted aryl groups include haloaryl, hydroxyaryl and aminoaryl groups. A haloaryl group is an aryl group as defined above, substituted by one or more halogen atoms. It can be a perhaloaryl group, for instance trifluoroaryl. A hydroxyaryl group is an aryl group as defined above, substituted by one or more hydroxy groups. An aminoaryl group is an aryl group as defined above, substituted by one or more amino groups. It may be, for instance, monoaminoaryl or diaminoaryl. An arylene group is an unsubstituted or substituted, monocyclic or bicyclic, aromatic divalent group which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion. Examples include phenylene, naphylene, indenylene and indanylene groups. An arylene group is unsubstituted or substituted. When an arylene group as defined above is substituted it typically bears one or more substituents, for instance one or two substituents, independenly selected from Cj-Cg alkyl, C_rC₆ alkoxyl, haloalkyl, halogen, carboxy, sulfonic acid or sulfonic acid salt, sulfonyl and hydroxy. An arylene group substituted by alkyl is preferably substituted by C_rC₄ alkyl, for example methyl, ethyl, i-propyl, n-propyl, t- butyl, s-butyl or n-butyl. Examples of substituted arylene groups include haloarylene, hydroxyarylene and aminoarylene groups. A haloarylene group is an arylene group as defined above, substituted by one or more halogen atoms. It can be a perhaloarylene group, for instance trifluoroarylene. A hydroxyarylene group is an arylene group as defined above, substituted by one or more hydroxy groups. An aminoarylene group is an arylene group as defined above, substituted by one or more amino groups. It may be, for instance, monoaminoarylene or diaminoarylene. An alkaryl group is an aryl group as defined above which is substituted by one or more alkyl groups as defined above. Examples include methylphenyl, ethylphenyl and methylnaphphyl groups. An alkarylene group is an arylene group as defined above which is substituted by one or more alkyl groups, for instance one or two alkyl groups, as defined above. Examples include methylphenylene, ethylphenylene and methylnaphphylene groups. An aryloxy group is a group Ar-O- in which Ar is an aryl group as defined above. Typically it is C₆-C₁₂ aryloxy, preferably C₆-C₁₀ aryloxy, for example phenoxy or napthoxy. An arylthio group is a group Ar-S- in which Ar is an aryl group as defined above. Typically it is C₆-C₁₂ arylthio, preferably C₆-C₁₀ arylthio, for example phenylthio or napthylthio. An aralkyl group is an alkyl group as defined above which is substituted by one or more aryl groups as defined above. Examples include benzyl, triphenylmethyl and phenethyl groups. An aralkylene group is an alkylene group as defined above which is substituted by one or more aryl groups as defined above. Examples include benzyl, diphenylmethyl, triphenylmethyl and phenethyl groups, each of which is unsubstituted or substituted in the phenyl ring by one or more of the groups specified above as substituents for an aryl group. An aroyl group is a group Ar-C(O)- in which Ar is an aryl group as defined above. Examples include benzoyl, napthoyl and salicyl groups, each of which is unsubstituted or substituted by one or more, for instance one or two, of the groups specified above as sustituents for an aryl group. An aroyloxy group is a group Ar- C(O)-O- in which Ar is an aryl group as defined above. Examples include benzoyloxy, napthoyloxy and a salicycloxy (the residue of salicylic acid). A heterocyclyl group is a 3- to 7-membered, typically 4- to 7-membered, for instance 5- to 7-membered saturated or unsaturated heterocyclic ring which contains at least one heteroatom selected from N, O and S and which is optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclic ring or to an aryl group as defined above. Typically the heterocyclyl group contains 1, 2 or 3 heteroatoms, for instance 1 or 2 heteroatoms. An unsaturated heterocyclic ring may be, for example, pyridine, furan, thiophene, pyrrole, pyrimidine, pyrazine, pyridazine, pyrazole, indazole, thiazole, isothiazole, thiadiazole, thioxazole, thiadioxazole, oxazole, isoxazole, indole, isoindole or a cyclic ether such as a sugar, for instance glucose or fructose. A saturated heterocyclic ring may be, for example, morpholine, thiomorpholine, piperidine, pyrrolidine, tetrahydrofuran, tetrahydropyran, quinoline or isoquinoline. A 5- or 6-membered saturated cyclic diol is typically substituted, for instance by any of the groups specified above as options for R¹ to R⁴. Particularly suitable substituents are those containing one or more heteroatoms selected from O and N, such as -(CH₂)_q-OR'_; -(CH₂)_q-NR'R' ' and -CO₂ R', wherein q is 0 or an integer of 1 to 6 and R' and R" are each independently H or C_rC₆ alkyl. A hydroxy group is free or protected. A protected hydroxy group is a hydroxy group protected by any suitable protecting group. A carboxy group is -COOH. A thiocarboxy group is -CSOH. A protected carboxy or thiocarboxy group is a carboxy or thiocarboxy group linked to any suitable protecting group. An amino group is free or protected. A protected amino group is an amino group linked to any suitable protecting group. Examples of protecting groups for hydroxy, carboxy, thiocarboxy and amino groups are known in the art, for instance as described in "Protective Groups for Organic Chemistry", Third Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999. A hydroxy group can be protected as an acetal, a substituted acetal, an ester, a xanthate, an ether or a silyl ether. The acetal is preferably tetrahydropyran. Typically the ester group is of formula -OC(=O)R', the xanthate group is of formula -OC(=S)- OR', the ether group is of formula -OR', and the silyl ether group is of formula

-OSi(R')₃, wherein each R', which may be the same or different if more than one is present, is an alkyl, aryl, alkaryl, aralkyl or cycloalkyl group as defined above, which group is unsubstituted or substituted as defined above. Preferred examples of R' in the ester, xanthate, ether and silyl ether groups include C_rC₆ alkyl such as methyl, ethyl, iso-propyl and t-butyl; aryl such as phenyl; and aralkyl such as benzyl. The silyl ether is preferably trimethylsilyl ether, t-butyl dimethylsilyl ether, triiso-propylsilyl ether or t-butyldiphenyl-silyl ether. A carboxy or thiocarboxy group may be protected with an alkyl, alkoxyalkyl, aryl, alkaryl, aralkyl or cycloalkyl group as defined above, which group is unsubstituted or substituted as defined above. Specific examples of such carboxy and thiocarboxy protecting groups include methyl, ethyl, n-propyl and t-butyl groups; and benzyl, 4-methoxybenzyl,4-methylthiobenzyl, 4-methylbenzyl, diphenylmethyl, benzyloxymethyl and benzylthiomethyl groups. A carboxy group may also be protected as an ester group -C(=O)-OR' or a thioester group -C(=O)-SR', wherein each R' is as defined above. Preferred examples of R' in the ester and thioester groups include C_rC₆ alkyl such as methyl, ethyl and t- butyl; aryl such as phenyl; and aralkyl such as benzyl. A thiocarboxy group may also be protected as a thiono ester group -C(=S)-OR' or a dithioester group -C(=S)-SR', wherein each R' is as defined above. Preferred examples of R' in the thiono ester and dithioester groups include C_rC₆ alkyl such as methyl, ethyl and t-butyl; aryl such as phenyl; and aralkyl such as benzyl. An amino group can be protected as an amide such as N-methylacetamide, a thioamide such as N-methylacetathioamide, a carbamate, a thiocarbamate, an imide, urea, thiourea or guanidine. Typical examples of amino protecting groups thus include phthalimidoyl, tetrachlorophthalimidoyl, dithiasuccinoyl and trifluoroacetyl groups; methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl, benzyloxycarbonyl, 9- fluorenylmethyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl and 2,2,2- trichloroethoxycarbonyl groups; and methylthiocarbonyl, ethylthiocarbonyl, t- butylthiocarbonyl, benzylthiocarbonyl, 9-fluorenylmethylthiocarbonyl, 2- (trimethylsilyl)ethylthiocarbonyl and 2,2,2-trichloroethylthiocarbonyl groups. Other examples of amino protecting groups include sulfonyl groups, for instance 2- (trimethylsilyl)ethylsulfonyl; alkyl and aryl groups as defined above, for instance methyl, ethyl, n-propyl, n-butyl, benzyl, diphenylmethyl, trityl and 9- phenylfluoromethyl groups. An amino group may also be protected as an imine derivative, for instance an imine with a bis(methylthio)methylene or diphenylmethylene group; or as a hydroxylamine, for instance N-t-butyl hydroxylamine or biphenyl ether N-formyl-hydroxylamine. The term "divalent 1,2-ring system" means a cycloalkyl, cycloalkenyl or aryl group as defined above, two adjacent ring carbon atoms of which bond directly to adjacent moieties of the platinum complex in question. A phenyl group which is unsubstituted or substituted is a preferred example. Parameters m and n are each, independently, 0 or 1. When both m and n are 0 in compounds where p is 1, each R is bonded directly to one of R¹, R², R³ and R⁴. For instance, if R is a direct bond in this embodiment, each of R¹, R², R³ and R⁴ is bonded directly to X. In one embodiment R¹ , R²_ R³ and R⁴ are each, independently, selected from hydrogen, halogen, hydroxy which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, alkyl which is unsubstituted or substituted, alkoxy which is unsubstituted or substituted, alkanoyl which is unsubstituted or substituted, aryl which is unsubstituted or substituted, aroyl which is unsubstituted or substituted and carboxy; each R is independently selected from alkylene, alkenylene and alkynylene, each of which is unsubstituted or substituted; each m is 0 or 1 ; each n is 0 or 1 ; and X is O or S. When, in this embodiment, each R in formula (I) or (F) is unsubstituted alkylene, then it is preferred that at least one of the following conditions apply in formula (I): (a) m is 1, or (b) one of R¹, R² R³ and R⁴ is other than unsubstituted alkyl. In a further embodiment R¹ , R² R³ and R⁴ are each, independently, selected from hydrogen, halogen, hydroxy which is free or protected, carboxy which is free or protected, thiocarbonyl which is free or protected, alkyl which is unsubstituted or substituted, alkoxy which is unsubstituted or substituted, alkanoyl which is unsubstituted or substituted, aryl which is unsubstituted or substituted, aroyl which is unsubstituted or substituted and carboxy; each R is independently selected from alkylene, alkenylene and alkynylene, each of which is unsubstituted or substituted; at least one of m is 1 and the others of m are 0; each n is 0; and X is O or S. In this embodiment one, two, three or four of the integers m are 1. Preferably each m is 1. In another embodiment R¹ , R² R³ and R⁴ are each, independently, selected from hydrogen, hydroxy which is free or protected, alkanoyloxy, aroyloxy and alkoxy which is unsubstituted or substituted by alkoxy; each R is alkylene or alkenylene; each m is 0 or 1; each n is 0; and each X is O or S. In one embodiment of formulae (I), (II) and (III), in particular of formula (I), p is 0 and the two R groups attached indirectly via X to the same P or Si atom together form a 5-membered cyclic diol or dithiol which is unsubstituted or substituted by a substituent containing one or more heteroatoms selected from O and N. In this embodiment the compound of formula (I) typically has the following structure (la):

(la)

wherein each of R⁵, R⁶, R⁷ and R⁸, which are the same or different, is hydrogen, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted. Typically each of R⁵ to R⁸ is hydrogen or a substituent containing one or more heteroatoms selected from O and N. In one aspect of formula (la) R⁵ and R⁸ are both H and R⁶ and R⁷ are both a substituent containing one or more heteroatoms. Alternatively R⁶ and R⁷ are both H and R⁵ and R⁸ are both a substituent containing one or more heteroatoms. In another aspect R⁵, R⁶, R⁷ and R⁸ are all a substituent containing one or more heteroatoms, typically the same substituent. For instance, in formula (la) R⁵ and R⁸ may each be a group -(CH₂)_q-NR'R" as defined above, such as -CH₂N(CH₃)₂ , or a group -(CH₂)_q-OR' as defined above, such as -CH₂-OCH₃ while R⁶ and R⁷ are both H. Alternatively, each of R⁵ to R⁸ may be a group -CO₂R' as defined above, such as -CO₂Et. As noted above, it is possible in complexes of the invention for both m and n to be 0 such that each of R¹ to R⁴ is directly bonded to group R. For instance, in this embodiment, R may be C_t - C₄ alkylene and each of R¹ to R⁴, which are the same, is selected from - C₆ alkoxy which is unsubstituted or substituted by - C₆ alkoxy, amino, a 3- to 7-membered saturated heterocyclic ring which contains 1, 2 or 3 heteroatoms selected from O and N and C_j - C₆ alkyl which is unsubstituted or substituted by one or two - C₆ alkoxy groups. In this embodiment R is typically a direct bond, methylene or ethylene and each of R¹ to R⁴ is selected from methoxy, 2-methoxyethoxy, morpholine, tetrahydrofuran, tetrahydropyran, dimethyla ino and dimethoxymethyl. In the general formulae (I), (F), (II), (II'), (HI) and (IIF), and in the preferred embodiments above, aroyloxy is preferably a salicyloxy or benzoyloxy group. Alkoxy which is substituted is typically alkoxy substituted by alkoxy; it is preferably methoxy, ethoxy or n-propoxy, each of which is substituted by alkoxy such as methoxy, ethoxy or n-propoxy. Most preferably alkoxy substituted by alkoxy is a group Alk-O-(CH₂)_p-O- in which p is 1, 2 or 3 and Alk is unsubstituted C_rC₆ alkyl. Preferred examples of complexes of formula (I) are: Bis(O,O'-diethane(dithiophosphate)platinum(II), Bis(O,O'-di(3-hydroxy)ethane(dithiophosphate)platinum (II), Bis(O,O^,-di(2-ethoxyethoxy)ethane(dithiophosphate)platinum (II), Bis(O,O^,-di(2-hydroxybenzoyl)ethane(dithiophosphate)platinum (II) Bis(O, O '-di-(2-methoxyethyl)dithiophosphato)platinum(II). Bis((O,O')-di-[2-(2-methoxyethoxy)ethyl]dithio-phosphate)platinum(II) Bis(4-methoxymethyl-2-thioxo-2λ⁵-[l,3,2]dioxaphospholane-2-thiol)platinum(II) Bis(diethyl 2-mercapto- 1 ,3,2-dioxaphospholane-4,5-dicarboxylate)-platinum(II) Bis(O,O-bis(tetrahydrofuran-2-ylmethyl)hydrogen dithiophosphate)platinum(II)

Bis(O,O-bis[2-(2-methoxyethoxyethoxy)ethyl] hydrogen dithiophosphate)platinum(II) Bis(O,O-di(tetrahydro-2H-pyran-4-yl)hydrogen dithio-phosphate)platinum(II) Bis(O,O-di(tetrahydrofuran-3-yl)hydrogen dithiophosphate)platinum(II) and the pharmaceutically acceptable salts thereof. It is preferred that the complexes of the invention are not chiral since this facilitates their synthesis. The groups R, R¹ , R²^ R³ and R⁴ therefore preferably lack any optically active centres. In the complexes of the invention any salt-forming group may be salified. A compound of the invention may thus be present in the form of a pharmaceutically acceptable salt. The complexes may be converted into pharmaceutically acceptable salts, and salts may be converted into the free compound, by conventional methods. Pharmaceutically acceptable salts of compounds with a basic centre include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, nitrates and salts of organic acids such as acetic acid, oxalic acid, malic acid, methanesulfonic acid, trifluoroacetic acid, benzoic acid, citric acid and tartaric acid. In the case of compounds of the invention bearing a free carboxy or sulphonic acid substituent, suitable salts include salts of alkali metal and alkaline earth metal cations such as sodium, potassium, calcium and magnesium, and ammonium and alkylammonium cations. The complexes of formulae (I), (F), (II) and (II') are soluble in polar media, for instance dimethyl sulphoxide (DMSO), water and DMSO/water mixtures. This facilitates their formulation into pharmaceutical compositions. Their solubility in solvents such as DMSO, which penetrates the stratum corneum, makes them suitable for administration in topical form. The solubility of the compounds of the invention is enhanced when one or more of R¹ to R⁴ is a water solubilising group. R¹ to R⁴ groups which contain an increased number of O and/or N heteroatoms tend to render the complexes more soluble. Examples of suitable solubilising groups include sulfonyl, alkanoyloxy, aroyloxy (for instance salicyloxy), hydroxy, morpholine, diol and amine groups. Compounds of the invention may be prepared by methods known in the art. In particular, the lack of chiral substituents in R¹, R², R³ and R⁴ simplifies such syntheses. For further ease of synthesis R¹, R², R³ and R⁴are preferably the same. The compounds of formulae (I) and (II) may be prepared by methods described in the literature (e.g. Casero, W.R. et al Inorganica Chim Acta 229 (2000) pp. 199-208). Accordingly, a compound of formula (I) wherein p is 1, or a compound of formula (F), may be prepared by a first process which comprises: (a) combining phosphorus pentasulphide with one or more alcohols of formulae R^OH, R²-OH, R³-OH and R⁴-OH, wherein R-¹ to R⁴ are the same or different and are as defined above for formula (I), to yield the corresponding dithiophosphoric acids of formulae (IN) and (N) shown in the scheme below; (b) treating the resulting dithiophosphoric acids with ammonia, to yield the corresponding dithiophosphates;

(c) treating the dithiophosphates with a platinum (II) salt in aqueous solution to yield a complex of formula (I); and (d) if required, removing one or more protecting groups from the product of step

(c) to yield a corresponding deprotected complex of formula (I). A suitable example of a Pt (II) salt for use in step (c) is K₂PtCl₄. Alternatively, a compound of formula (I) wherein p is 1, or a compound of formula (F), may be prepared by a second process which comprises: (a') combining phosphorus pentasulphide with one or more alcohols of formulae

R'-OH, R²-OH, R³-OH and R⁴-OH, wherein R¹ to R⁴ are the same or different and are as defined above for formula (I), to yield the corresponding dithiophosphoric acids of formulae (IN) and (V) shown in the scheme below;

(b') diluting the resulting dithiophosphoric acids with water, adjusting the resulting solution to a mildly alkaline pH and treating that solution with KΝO₂ and sulphuric acid to yield a compound of formula (VI) shown in the scheme below;

(c') treating the compound of formula (VI) with a solution of tris(styrene) platinum (0), to yield a complex of formula (I); and

(d') if required, removing one or more protecting groups from the product of step (c) to yield a deprotected complex of formula (I). Following either process described above, the resulting complex may be purified by chromatography. The final compound may be converted to a pharmaceutically acceptable salt by conventional methods, for instance a salt as described above. The above processes are summarised in the reaction scheme outlined below.

Analogous processes may be used to prepare complexes of formulae (II), (IF), (III) and (III') as defined above.

Tris(styrene)platinuiri(0)

If R¹, R², R³ and R⁴ are different substituents in the above process, then mixtures of complexes of formula (I) are obtained. These may be separated and purified by methods known in the art, for example by HPLC. Where R¹, R², R³ and R⁴ are or contain protecting groups (as defined above) the protecting groups may be individually or collectively removed, by methods known in the art, to R⁵, R⁶, R-⁷ and R⁸, which, respectively, correspond, to deprotected R¹, R², R³ and R⁴. Analogous deprotection strategies can be used to prepare additional complexes of formulae (π), (IF)_. (πi) and (IIF). Compounds of the present invention have been found in biological tests to have activity as anti-tumour agents. In particular, they show cytotoxicity against a number of cancer cell lines including K-562, L1210, NCI-H460, A-549, MCF-7, MDA-MB-231, PC-3, DU-145, ONCAR-3, SK-ON-3, IGRON-1, IGRON-1/CDDP, HT29, LS, 174T, U-87MG, CGL3, A375-SM, LB1319-MEL, PAΝC-1, BxPC-3, LB796-BLC, LB831-BLC, BB30-HNSLC, LB831-BCC, LB1047-RCC and LB996- RRC. The compounds, in particular Bis(O,O'-diethane(dithiophosphate)platinum(II), also exhibit comparable cytotoxicity towards tumour cell lines from various histological types and the IGRON-1 /CDDP ovarian carcinoma cell line (which is resistant to cis-platin) was sensitive to this platinum complex. Such activity may be due to intercalation with DΝA but platination of an enzyme is more probable. It is likely that the anti-rumour activity is in part due to the inhibition of thioredoxin reductase. Thioredoxin is a small protein which, in its reduced state, is the specific reductant in the conversion of ribonucleotides to 2'-deoxyridonucleotides by ribonucleotide reductase. As such it is essential for the generation in eukaryotes of the 2'-deoxyridonucleotides required for DΝA synthesis. Since human thioredoxin reductase contains the rare selenocysteine residue in its active site, it is likely that this is the site of platination. DΝA synthesis is consequently inhibited, which creates the potential for anti-tumour activity. Accordingly a human or animal suffering from cancer may be treated by administering thereto a compound which is a complex of formula (I), (II) or (III) as defined above or a pharmaceutically acceptable salt thereof. The compound is administered in an amount which is non-toxic and therapeutically effective. The condition of the human or animal may thereby be ameliorated. Tumours can thus be treated. Examples of types of cancer that the present compounds can be used to treat include leukaemias, lymphomas, sarcomas, carcinomas and adenocarcinomas. Specific examples include cancers of the lung, prostate, ovary, breast, colon, intestine, pancreas, bladder or kidney, more particularly human leukaemias, lung carcinomas, prostate carcinomas, ovarian and mammary gland adenocarcinomas, colon adenocarcinomas, human melinomas, pancreas carcinomas, pancreas adenocarcinomas, bladder cell and renal cell carcinomas. Typically, these compounds are capable of treating cis-platin resistant cancers or tumours. Human thioredoxin reductase is now considered to be the site of action of organogold compounds such as aurothioglucose (S. Gromer et al., J. Biol. Chem., 1998, 273, 20096-20101) and auranofin which are used in the treatment of rheumatoid arthritis. It is thus expected a compound which is a complex of formula (I), (II) or (III) as defined above, or a phannaceutically acceptable salt thereof, will be useful in the treatment of rheumatoid arthritis. Accordingly, a human or animal suffering from rheumatoid arthritis may be treated, by administering thereto a compound of the invention as defined above. The compound is administered in an amount which is therapeutically effective and non-toxic. In another aspect the present invention provides the use of a compound of the invention as defined above, in the manufacture of a medicament for use as an anti- rheumatoid arthritis agent or an anti-tumour agent. In another aspect the present invention provides a pharmaceutical composition comprising a compound of the invention as defined above in association with a pharmaceutically acceptable carrier, excipient or other additive. The pharmaceutical composition containing a compound of the invention may be prepared in a conventional way by employing conventional non-toxic pharmaceutical carriers or diluents in a variety of dosage forms and ways of administration. In particular, the compounds of the invention can be administered: A) orally, for example, as tablets, troches, lozenges, aqueous or oily suspension, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such composition may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring and preserving agents in order to provide elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch or alginic acid; binding agents, for example maize starch, gelatin or acacia, and lubricating agents, for example magnesium stearate or stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxyacetamol, or condensation products of ethylene oxide with partial esters derived from fatty acids and an hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and an hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol anhydrides, for example polyoxysorbitan monooleate. The said aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, one or more sweetening agents such as sucrose or saccharin. An oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, coconut oil or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacid or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxytethylene sorbitan monooleate.

The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose.

Such formulations may also contain a demulcent, a preservative, colouring and flavouring agents.

B) parenterally, either subcutaneously or intramuscularly, or intrasternally, or by infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or olagenous suspensions. These suspensions may be formulated according to the known art us ng those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloiride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. C) Topically, in the form of creams, ointments, jellies, coUyriums, solutions or suspensions. For this purpose any bland fixed oils may be conventionally employed including synthetic mono or diglycerides. Also topical administrations canb>e made employing various mixtures of dimethyl sulphoxide in water. In addition fatty acids such as oleic acid find use in the preparation of injectables. The daily dose varies according to the activity of the specific compo md, the age, weight, and conditions of the subject to be treated, the type and the severity of the disease, and the frequency and route of administration. Typically the daily dLose is from 0.1 to 100 mg per kg of body weight for an adult human, more typical y 0.1 to 50 mg per kg of body weight for an adult human. The amount of active ingredient that may be combined with the carried materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration may contain from 5 "to 95% of the total composition. Dosage unit forms will generally contain from 5 to 5O0 mg of the active compound. The Examples which follow further illustrate the present invention.

Example 1 : Synthesis of Bis(O.O'-diethane(dithiophosphate) platinum (II) by first process Phosphorus pentasulphide (4.44g, 20 mmol of P₂S₅) and ethanol (80 rnmol, or excess) were stirred together at room temperature with an evolution of heat. The mixture was warmed gently for 1-5 hours to complete the reaction, and then filtered through celite, washing with ethanol (2 x 10 ml) and dichloromelhane (1 x 10 ml). Solvents were removed by evaporation, and the residual greenish oil was taken up in light petrol ether or hexane. Anhydrous ammonia (freshly generated by heating aqueous ammonia and passing the gas over solid KOH pellets) was bubbled in until the stirred solution turned white. The resulting compound was filtered off, washed with hexane, and air-dried. The resulting solid (2 mmol) was dissolved in warm water (deionised) and to it was added K₂PtCl₄ (1 mmol) dissolved in the minimum volume of water. The two were stirred together at room temperature for 3 hours until the reaction was complete by tic (dichloromethane elution on silica) and electrospray mass spectrometry. The light brown precipitate was isolated by filtration and washed wit-h small aliquots of water. The product was purified by precipitation from the mini-rium volume of warm dichloromethane, using excess HPLC-grade hexane as the precipitant. The preparation of the title compound by the second process used in the invention is described in Example 5.

Example 2: Synthesis of bisfO.O'-di-O- methoxyethyUdithiophosphato)platinum(II

Preparation of (0.0 -di-(2-methoxyethyl ithiophosphate

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirre-r was charged with 2-methoxyethanol (5.33g, 70mmol). Phosphorus pentasulfide (4.44g, 20mmol) was charged in one portion. The reaction mixture exothermed to 52°C liberating gasses which were scrubbed with a bleach solution. The reaction mixture was heated at 70°C for 3 hours, cooled and filtered to give the title compound as a pale yellow oil (8g, 93%th.uncorrected).

Preparation of potassium (O.O^r)-di-(2-methoxyethyDdithiophosphate

(0,0 j-Di-(2-methoxyethyl)dithiophosphate (1.5g, 6. Immol) and diethyl ether (25mL) were charged to a 50mL round bottomed flask. Potassium carbonate (0.84g, 6.1π---mol) was charged and the reaction mixture stirred under a nitrogen balloon overnight. The reaction mixture was filtered, washed with diethyl ether (2x 20mL) and pulled dry to give the title compound as a white solid (1.5g).

Preparation of bisCO. O '-di- 2-methoxyethvDdithiophosphato)platinum(II

A 50ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with potassium (O, O -di-(2-methoxyethyl)dithiophosphate (0.4 lg, 1.45mmol) and water (24mL). The reaction mixture was stirred, potassium tetrachloroplatinate(II) (0.2g, 0.48mmol) charged and the reaction mixture heated at 40°C for 1 hour and concentrated. The residue was purified by column chromatography on silica gel (14g, t.l.c eluent=MeOH:DCM; 0.5:99.5;R_fproduct 0.5) using methanohdichloromethane (1 :99) as eluent to give the title compound as an orange oil (0.12g, 24%th.) which solidified on standing.

Η NMR (360 MHz, CHLOROFORM-D) ppm 3.39 (s, 12 H, 4x CH₃) 3.62 - 3.73 (m, 8 H, 4x CH₂) 4.28 - 4.42 (m, 8 H, 4x CH₂).

Example 3: Synthesis of bis((O-O^,)-di-[2-(2-methoxyethoxy)ethvndit-ιio- phosphate)platinum(ll)

Preparation of (O. O ^r)-di-[2-(2-methoxyethoxy^')ethyl]dithiophosphate

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with di(ethyleneglycol)methyl ether (8.41 g, 70mmol). Phosphorus pentasulfide (4.44g, 20mmol) was charged in one portion, the reaction mixture exothermed to 42°C liberating gasses which were scrubbed with a bleach solution.

The reaction mixture was heated at 70°C for 3 hours, cooled and filtered to give the title compound as a pale yellow oil (9.5g, 81%th.uncorrected). Preparation of potassium (O. O 'Vdi-[2-f2-methoxyethoxykthyl]dithiophosphate

(O.O ;-Di-[2-(2-methoxyethoxy)ethyl]dithiophosphate (2g, 6mmol) and diethyl ether (25mL) were charged to a 50mL round bottomed flask. Potassium carbonate (0.83g-- 6mmol) was charged and the reaction mixture stirred under a nitrogen atmosphere overnight. The reaction mixture was filtered, washed with diethyl ether (2x 20mL) and pulled dry to give the title compound as a white solid (2g).

Preparation of bis(YO O ^-di-P-^-methoxyethoxy^ethylldithio-phosphate^platinumril

A 50ml-reaction vessel equipped with a digital thermometer, condenser and stirrer ^as charged with potassium (O,O -di-[2-(2-methoxyethoxy)ethyl]dithiophosphate (0.54g, 1.45mmol) and water (24mL). The reaction mixture was stirred, potassium tetrachloroplatinate(II) (0.2g, 0.48mmol) charged, the reaction mixture heated at 40°C for 1 hour and concentrated. The residue was purified by column chromatography on silica gel (14g, t.l.c eluent=MeOH:DCM; 1:99 , R_fproduct 0.4) using methano dichloromethane (1:99) as eluent to give the title compound as an orange oil (O.lg, 16%th.). Η NMR (360 MHz, CHLOROFORM-D) ppm 3.38 (s, 12 H, 4x OCH₃) 3.49 - 3.59 (rn, 8 H, 4x CH₂) 3.62 - 3.69 (m, 8 H, 4x CH₂) 3.74 - 3.86 (m, J=4.77 Hz, 8 H, 4x CH₂) 4.29 - 4.43 (m, 8 H, 4x CH₂) Example 4: Synthesis of bis(4-methoxymethyl-2-thioxo-2λ⁵-[1.3,21dioxaphos- pholane-2-thiol)platinum(II)

Preparation of 4-methoxymethyl-2-thioxo-2λ⁵-[l .3.21dioxaphospholane- 2-thiol

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with 3 -methoxy- 1,2-propanediol (4.24g, 40mmol). Phosphorus pentasulfi.de (4.44g, 20mmol) was charged in one portion. The reaction mixture exothermed to 42°C liberating gasses which were scrubbed with a bleach solution. The reaction mixture was heated at 60°C for 3 hours, cooled and filtered to give the title compound as a pale yellow oil (7g, 88%th.uncorrected).

Preparation of bis(4-methoxymethyl-2-thioxo-2λ⁵-[l-3,21dioxaphospholane-2- thiol platinum(lD

A 50ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with 4-methoxymethyl-2-thioxo-2λ⁵-[l,3,2]dioxaphospholane-2-thiol (0.29g, 1.45mmol) and water (24mL). The reaction mixture was stirred, potassium tetrachloroplatinate(II) (0.2g, 0.48mmol) charged, the reaction mixture heated at 40°C for 1 hour and concentrated. The residue was purified by column chromatography on silica gel (15g) using dichloromethane as eluent to give the title compound as an orange oil (0.02g, 5%th.).

Η NMR (360 MHz, CHLOROFORM-D) ppm 3.42 (s, 6 H, 2x OCH₃) 3.61 (d, J=4.09 Hz, 4 H, 2x CH₂) 4.33 - 4.44 (m, 2 H, 2x CH) 4.45 - 4.56 (m, 2 H, 2x CH) 4.75 - 4.88 (m, 2 H, 2x CH)

Example 5: Synthesis of bis(O,O'-diethyldithiophosphato pIatinum(II) by second process

Preparation of (O,O' diethyldithiophosphate.

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with ethanol (3.22g, 70mmol). Phosphorus pentasulfide (4.44g, 20mmol) was charged in one portion. The reaction mixture exothermed to 59°C liberating gasses which were scrubbed with a bleach solution. The reaction mixture was heated at 70°C for 3 hours, cooled and filtered to afford the desired compound as a pale yellow oil (6.3g, 97%th.).

Preparation of bisfO.O ' -diethylthiophosphoryl)disulfide

A 250ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with (O,O')-diethyldithiophosphate (6.3g, 34mmol) and water (lOOmL). The reaction was stirred under nitrogen and the pH adjusted to 8 using 1M potassium hydroxide solution. Potassium nitrite (3.86g, 40mmol) was charged in one-portion followed by drop-wise addition of concentrated sulphuric acid (4.96g, 40mmol). The reaction mixture was heated at 50°C for 2 hours, cooled and the product extracted with dichloromethane (3x lOOmL). The combined organics were dried over magnesium sulphate (lOg) filtered and concentrated to give the crude product as a yellow oil (3g, 49%th.). The product was purified by column chromatography on silica gel (20g, t.l.c eluent=DCM; R_fproduct 0.8) with dichloromethane as eluent to give a pale yellow oil (2.9g, 46%th.).

Preparation of bisCOO'-diethyldithiophosphato^platinumflD

Bis(O,O'-diethylthiophosphoryl)disulfide (0.185g, 0.5mmol) was charged to a 25mL reaction vessel and stirred under nitrogen. Pt(0) in styrene (14mL, 0.5mmol) was charged and the reaction mixture stirred at room temperature for 20 minutes. The reaction mixture was concentrated and purified by column chromatography on silica gel (20g, t.l.c eluent=DCM:hexanes; 1:1, R_fproduct 0.5) using dichloromethane :hexanes (1 : 1) as eluent to give the title compound as an orange solid (0.17g, >100%th.uncorrected).

Η NMR (360 MHz, CHLOROFORM-D) ppm 1.35 (t, 12 H, 4x CH₃) 4.17 - 4.30 (m, 8 H, 4x CH₂) Example 6: Synthesis of bis(O,O^,-di-(2- methoxyethyl)dithiophosphato)platinunι(II)

Preparation of (0.0' ydi-f2-methoxyethyl dithiophosphate

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with 2-methoxyethanol (5.33g, 70mmol). Phosphorus pentasulfide (4.44g, 20mmol) was charged in one portion. The reaction mixture exothermed to 52°C liberating gasses which were scrubbed with a bleach solution. The reaction mixture was heated at 70°C for 3 hours, cooled and filtered to give the title compound as a pale yellow oil (8g, 93%th.uncorrected).

Preparation of bisr O.O^-di-^-methoxyethyπdithiophosphryl isulfide

A 250ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with (O,O')-di-(2-methoxyethyl)dithiophosphate (4.23g, 17.2mmol) and water (70mL). The reaction was stirred under nitrogen and the pH adjusted to 8 using 1M potassium hydroxide solution. Potassium nitrite (1.62g, 19mmol) was charged in one- portion followed by the drop-wise addition of concentrated sulphuric acid (1.9g, 19mmol). The reaction mixture was heated at 50°C for 2 hours, cooled and the product extracted with dichloromethane (3x 70mL). The combined organics were dried over magnesium sulphate (4g) filtered and concentrated to give the crude product as a yellow oil (3.4g). The product was purified by column chromatography on silica gel (25g, t.l.c eluent=MeOH:DCM; 1:99, R_fproduct 0.45) with methano dichloromethane (1:99) as eluent to give a yellow oil (1.5g, 36%th.).

Preparation of bis(O-O'-di-r2-methoxyethyl dithiophosphato platinum(ID

Bis((O,O')-di-(2-methoxyethyl)dithiophosphoι l)disulfide (0.25g, 0.5mmol) was charged to a 25mL reaction vessel and stirred under nitrogen. Pt(0) in styrene (14mL, 0.5mmol) was charged and the reaction mixture stirred at room temperature for 20 minutes. The reaction mixture was concentrated and purified by column chromatography (25g, t.l.c eluent=DCM; R _product 0. ) on silica gel using methanohdichloromethane (0.25:99.75) as eluent to give the title compound as an orange oil (0. lg, 29%th.uncorrected).

Η MR (360 MHz, CHLOROFORM-D) ppm 3.39 (s, 12 H, 4x CH₃) 3.62 - 3.73 (m, 8 H, 4x CH₂) 4.28 - 4.42 (m, 8 H, 4x CH₂). Example 7 Synthesis of bis(O,O-di(tetrahydro-2-H-pyran-4-yl)hydrogen dithio- phosphate)platinum(ID

Preparation of O-( -di(tetrahydro-2H-pyran-4-yl hvdrogen dithiophosphate

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with tetrahydro-4H-pyran-4-ol (3g, 29mmol) and toluene (lOmL). The reaction mixture was stirred and phosphorus pentasulfide (1.63g, 7.3mmol) charged in one portion. The resultant was stirred at room temperature for 2 hours and heated at 60°C for 3 hours (the liberated gasses scrubbed with a bleach solution). The reaction mixture was cooled to room temperature, filtered and concentrated at 40 to 45 °C under reduced pressure to give the title compound as a pale yellow oil which solidified on standing (2g, 46%th. containing 4% tetrahydro-4H-pyran-4-ol).

Preparation of bisCO-O-di(tetrahydro-2H-pyran-4-yl hvdrogen dithio- phosphate platinum(Tf)

A 50ml-reaction vessel equipped Λvith a digital thermometer, condenser and stirrer was charged with O,O-di(tetrahydro-2iJ-pyran-4-yl)hydrogen dithiophosphate (0.43g, 1.45mmol, corrected) and water (20mL). The reaction mixture was stirred at room temperature and potassium tetrachloroplatinate(H) (0.2g, 0.48mmol) charged. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure at 40°C. The residue was purified by column cliromatography on silica gel (25g) using methanol: dichloromethane (1:99) as eluent to give the title compound as an orange oil (0.3g, 53%th.).

Η NMR (360 MHz, CHLOROFORM-D) ppm 1.73 - 1.96 (m, 8 H, 4x CH₂) 1.97 - 2.15 (m, 8 H, 4x CH₂) 3.38 - 3.69 (m, 8 H, 4x CH₂) 3.79 - 4.10 (m, 8 H, 4x CH₂) 4.63 - 5.08 (m, 4 H, 4x CH)

Example 8: Synthesis of bis( ,O-bis(tetrahydrofnran-2-ylmethvI)hvdrogen dithiophosphate)platinum(II)

Preparation of O,O-bis(tetrahvdrofuran-2-ylmethyDhydrogen dithiophosphate

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with tetrahydrofurfuryl alcohol (7.15g, 70mmol). The reaction mixture was stirred and phosphorus pentasulfide (4.44g, 20mmol) charged in one portion giving an exotherm to 60°C. The resultant was stirred and maintained at 60 to 70°C for 4 hours (the liberated gasses scrubbed with a bleach solution), cooled to room temperature, diluted with dichloromethane (50mL), filtered and concentrated at 40 to 45°C under reduced pressure to give the title compound as an orange oil (lOg, 95%th.). Preparation ofbisrO.O-bis tefrahydrofuran-2-ylmethyl hydrogen dithiophosphate platinumOD

A 50ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with O,O-bis(tetrahydrofuran-2-ylmethyl)hydrogen dithiophosphate (0.43g, 1.45mmol, corrected) and water (20mL). The reaction mixture was stirred at room temperature and potassium tetrachloroplatinate(II) (0.2g, 0.48mmol) charged, the resultant stirred at room temperature for 60 minutes and heated at 40°C for a further 60 minutes. The reaction mixture was extracted with ethyl acetate (3x 50mL), the organics combined, dried over magnesium sulphate (5g), filtered and concentrated under reduced pressure at 40°C. The residue was purified by column chromatography on silica gel (20g) using methanol: dichloromethane (1:99) as the eluent. Further chromatography on silica gel (20g) was required using tert-butyl methyl ether as the eluent to give the title compound as an orange oil (O.lg, 18%th.). Η NMR (360 MHz, CHLOROFORM-D) ppm 1.64 - 1.79 (m, 4 H, 4x CH) 1.81 - 2.11 (m, 12 H, 6x CH₂) 3.72 - 3.93 (m, 8 H, 4x CH₂) 4.08 - 4.25 (m, J=6.81 Hz, 12 H, 6x CH₂)

Example 9: Synthesis of bis((λ,0-b is f2-(2-methoxy ethoxy ethoxytethyl] hydrogen dithiophosphate)platiιmm(ID

Preparation of O.,O-bis[2-(2-methoxyethoxyethoxy)ethyll hydrogen dithiophosphate

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with triethyleneglycol monomethyl ether (1 1.5g, 70m_.no 1). The reaction mixture was stirred at room temperature and phosphorus pentasulfide (4.44g, 20mmol) charged in one portion resulting in an exotherm to 41 °C over 10 minutes. The reaction mixture was heated at 60 to 70°C for 5 hours (the liberated gasses scrubbed with a bleach solution) cooled to room temperature and filtered to give the title compound as a pale yellow oil (14g, 90%th.).

Preparation of bisfO,O-bis[2-(2-methoxyethoxyethoxy ethyl] hydrogen dithiophosphate^platinumfl

A 50ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with O,O-bis[2-(2-methoxyethoxyethoxy)ethyl] hydrogen dithiophosphate (0.61g, 1.45mmol) and water (20mL). The reaction -mixture was stirred at room temperature, potassium tetrachloroplatinate(II) (0.2g, 0.48mmol) charged and the resultant stirred at room temperature for 60 minutes and heated at 40°C for 30 minutes. Water was removed by freeze drying and the residue was purified by column chromatography on silica gel (25g) using methanol: dichloromethane (2:98) as eluent to give the title compound as an orange oil (0.1 lg, 15%th.).

Η NMR (360 MHz, CHLOROFORM-D) ppm 3.33 - 3.39 (m, 12 H, 4x OCH₃) 3.52 - 3.83 (m, 40 H, 20x CH₂) 4.23 - 4.40 (m, 8 H, 4x CH₂)

Example 10: Synthesis of bis(0,O-di(tetrahvdrofuran-3-yl)hydrogen dithiophosphate)platinum(ID

Preparation of O.O-di(tetrahydrofuran-3-v hydrogen dithiophosphate

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with 3-hydroxytetrahydrofuran (6.16g, 70mmol). The reaction mixture was stirred at room temperature and phosphorus pentasulfide (4.44g, 20mmol) charged in one portion resulting in an exotherm to 35°C. The reaction mixture was heated at 60 to 70°C for 3 hours (the liberated gasses scrubbed with a bleach solution) and cooled to room temperature to afford a solid. The resultant was diluted with dichloromethane (lOmL), warmed to 30 to 35°C giving a yellow solution, filtered and concentrated under reduced pressure at 35 to 40°C to give the title compound as a yellow oil (7g, 74%th.).

Preparation of bisf O, O-di(tetrahydrofuran-3 -yPhvdro gen dithiophosphate^platinumflD

A 50ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with O,O-di(tetrahydrofuran-3-yl)hydrogen dithiophosphate (0.39g, 1.45mmol) and water (20mL). The reaction mixture was stirred at room temperature and potassium tetrachloroplatinate(IT) (0.2g, 0.48mmol) charged. The resultant was stirred at room temperature for 60 minutes and heated at 40°C for a further 60 minutes. Water was removed by freeze drying and the residue purified by column chromatography on silica gel (25g) using methanol: dichloromethane (1:99) as eluent. Further chromatography on silica gel (25g) was required using tert-butyl methyl ether as the eluent to give the title compound as a yellow oil which partially solidified on standing (0.08g, 18%th.).

Η NMR (360 MHz, CHLOROFORM-D) ppm 2.01 - 2.39 (m, 8 H, 4x CH₂) 3.80 - 4.10 (m, 16 H, 8x CH₂) 5.18 - 5.45 (m, 4 H, 4x CH)

Example 11: Synthesis of bisfdiethyl 2-mercapto-l,3.,2-dioxaphospholane-4,5- dicarboxylate)platinum(II)

Preparation of diethyl 2-mercapto-1.3.2-dioxaphospholane-4.5-dicarboxylate 2-sulfide

A 25ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with (+)-diethyl L-tartrate (8.25g, 40mmol) and toluene (15mL). The reaction mixture was stirred, phosphorus pentasulfide (4.44g, 20mmol) charged in one portion (no exotherm) and the resultant heated to and maintained at 60°C for 3 hours. The reaction mixture was cooled to room temperature, filtered and concentrated at 40 to 45°C under reduced pressure to give the title compound as a pale yellow oil (1 lg, 92%th. uncorrected).

Preparation of bisf diethyl 2-mercapto-1.3.2-dioxaphospholane-4-5- dicarboxylate^platinumfll)

A 50ml-reaction vessel equipped with a digital thermometer, condenser and stirrer was charged with diethyl 2-mercapto-l,3,2-dioxaphospholane-4,5-dicarboxylate 2-sulfide (0.43g, 1.45mmol) and water (20mL). The reaction mixture was stirred and potassium tetrachloroplatinate(H) (0.2g, 0.48mmol) charged. The reaction mixture was stirred at room temperature for 30 minutes, heated at 40°C for a further 30 minutes and concentrated under reduced pressure at 40°C. The residue was purified by column chromatography on silica gel (15g) using dichloromethane as eluent to give the title compound as an orange oil (0.19g, 33^oth.). Η NMR (360 MHz, CHLOROFORM-D) ppm 1.35 (t, J=7.15 Hz, 12 H, 4x CH₃) 4.24 4.44 (m, 8 H, 4x CH₂) 5.18 (d, J=18.62 Hz, 4 H, 4x CH) Example 12: Anti-tumour studies of the complex Bis(O,O'- diethane(dithiophosphate)platinum(ID.

Test Substances Bis(O,O'-diethane(dithiophosphate)platinum(II), prepared as described in Example 1 or 5, was dissolved in ethanol (CARLO ERBA, batch No. 0C037200C). A stock solution was prepared at 10 mM concentration in ethanol (23.0 mg of Bis(O,O'- diethane(dithiophosphate)platinum(II) in 4071 μl ethanol), aliquoted (aliquots of ~500μl) and stored at -20°C.

Tumour cell lines and culture conditions

The following cancer cell lines and culture media were studied:

Tumour cells were grown as a monolayer or in suspension at 37°C in a humidified atmosphere (5% CO₂, 95% air). The culture medium was RPMI 1640 (ref. BE12-702F, batch No. 2MB0207, Cambrex, Verviers, Belgium) supplemented with 2mM L-glutamine and 5% fetal bovine serum- (ref. DE14-801E, batch No. 1SB0020, Cambrex). For experimental use, the ac herent human tumour cells were detached from the culture flask by 10 minutes treatment with trypsin-versene (ref. 02-007E, batch No. 2MB0240, Cambrex), in Hant s' medium without calcium or magnesium (ref. BE10-543F, batchNo. 2MB0245, Cambrex). The cells were counted in a hemocytometer and their viability was assessed by 0.25% trypan blue exclusion. All cell lines were checked negative fo - mycoplasma contamination. EXPERIMENTAL DESIGN AND TREATMENTS

Cell lines amplification and plating Tumour cells (5,000 to 10,000 cell per well depen-ding on their doubling time) were plated in 96-wells flat-bottomed microtifration plat&s (Nunc, Rosklide, Denmark) at 37°C for 24 hours before treatment in 100 pΛ of drug-free RPMI 1640 medium supplemented with 10% FBS (Fetal Bovine Sentm). Tumour cell implantation densitities are summarised in the following table.

Step 1 : IC_5P pre-determination Tumour cells were incubated for 96 hours with 5 log-spaced concentrations of platinum (II) complex Bis(O,O'-diethane(dithiophosphate)platinum(II) starting at the upper concentration of 10 μM. The test substance stock dilution (lOmM) was diluted at l/10^e in ethanol and then at l/50^e in RPMI 1640 supplem-ented with 10% FCS (2% of solvent). Every other concentration was then obtained from 1/3 successive dilutions in RPMI 1640 supplemented with 10% FCS. The cells (100 μϊ) were incubated in a 200 l final volume of RPMI 1640 supplemented with 10% FCS containing at 37°C under 5% CO₂ for 96 hours. An experiment was performed once, each assay being issued from quadruplicate. Control cells were treated with vehicle alone.

Step 2: IC_S0 determination The five most sensitive tumour cell lines were chosen and were incubated for 96 hours with 10 various concentrations in a range of concentrations determined according to results obtained previously. The Bis(O,O'~ diethane(dithiophosphate)platinum(II) stock dilution (10 m-M) was diluted in ethanol and then in RPMI 1640 supplemented with 10% FCS. The pH of the Bis(O,O'- diethane(dithiophosphate)platinum(II) solutions was adjusted to 6.8 using HC1 IN before cells were treated. Cells were then incubated in 200 1 of RPMI 1640 supplemented with 10% FCS containing Bis(O,O'- diethane(dithiophosphate)platinum(II) or vehicle at 37 °C under 5% CO₂ for 96 -hours without medium removal. Experiments were repeated three times, each assay b eing issued from quadruplicate. Control cells were treated with vehicle alone.

MTT assay The in vitro cytotoxic activity of Bis(O,O'- diethane(dithiophosphate)platinum(II) was revealed by a MTT assay. At the end of cell treatment, 20 l of a 5 mg/ml solution tetrazolium reagent (MTT, Aldricli, France) in Phosphate Buffered Saline (PBS, Cambrex, Walkersville, MA, USA), 0.22 μm filtered, were added in each well. Culture plates were incubated for 4 ti at 37 °C. The resulting supernatant was removed and formazan crystals dissolved "with 200μl of dimethylsulfoxide (DMSO, Ref. D-8779, batch No. 100K3729, Sigma, St. Louis, MO, USA). Absorbency (OD) was measured in each well on a single wavelength spectrophotometer plate reader at 570 nm (Multiskan, Labsystem, Helsinki, Finland) and the results plotted with Genesis software (Labsystem, Helsinki, Finland). Results were expressed as the concentration of drug that inh abits 50% of the cell growth (IC₅₀) as compared to non-treated control cells.

RESULTS

IC_5P determination

The dose response inhibition of proliferation (IC) was expressed as following:

OD drug-exposed wells IC= X 100 OD drug-free wells IC₅₀: drug concentration to obtain a 50% inhibition of cell proliferation

Each value of IC₅₀ is the mean of 4 measurements. The dose-response curves were plotted using XLFit 3 (IDBS, United Kingdom). The IC₅₀ determination values were calculated using the XLFit 3 from semi-log curves.

IC_SQ pre-determination

Values are given in Table I below.

iα„ - Determination for the BxPC-3. CGL3. LB1319-MEL. ONCAR-3 and PC-3 cell lines

Values are given in Table II below.

SUMMARY

Platinum complex Bis(O,O'-diethane(dithiophosphate)platinum(II) showed a marked cytotoxicity on the majority of the cell lines tested, except on the F3L-60 and L1210/CDDP leukemia cell lines. Bis(O,O'-diethane(dithiophosph_ate)platinum(II) showed comparable cytotoxicity towards tumour cell lines from various histological types. The IGROV-1/CDDP ovarian carcinoma cell line resistant Xo cis-platin was as sensitive to Bis(O,O'-diethane(dithiophosphate)platinum(II) as the IGROV-1 parental cell line.

Table I: Summary table of the IC₅₀ pre-determination values (μM) for Bis(O,O'- diethane(dithiophosphate)platinum(II) obtained in a single experiment. Each value is the mean of 4 experimental measurements.

Table II: Summary table of the IC₅₀ determination values (μM) for Bis(O,O'- diethane(dithiophosphate)platinum(II) obtained in 3 experiments on five cell lines. Each value is the mean of 4 experimental measurement.

Example 13: Tablet composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention were manufactured as follows: Composition for 10.000 tablets Compound of the invention (250 g) Lactose (800 g) Corn starch (415g) Talc powder (30 g)

Magnesium stearate (5 g)

The compound of the invention, lactose and half of the corn starch were mixed. Ttie mixture was then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste was used to granulate the powder. The granulate was dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium was added, carefully mixed and processed into tablets.

Example 14: Injectable Formulation

Compound of the invention 200mg Hydrochloric Acid Solution 0.1M or

Sodium Hydroxide Solution 0.1M q.s. to pH 4.0 to 7.0 Sterile water q.s. to 10 ml

The compound of the invention was dissolved in most of the water (35°-40° C) and tfcie pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate. The batch was then made up to volume with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.

Example 15 Intramuscular Injection

Compound of the invention 200 mg Benzyl Alcohol 0.10 g

Glycofurol 75 1.45 g

Water for inj ection q. s to 3.00 ml

The compound of the invention was dissolved in the glycofurol. The benzyl alcohol was then added and dissolved, and water added to 3 ml. The mixture was then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (type 1).

Example 16: Syi rup Formulation

Compound of invention 250 mg

Sorbitol Solution 1.50 g

Glycerol 2.00 g

Sodium benzoate 0.005 g Flavour 0.0125 ml

Purified Water q.s. to 5.00 ml

The compound of the invention was dissolved in a mixture of the glycerol and most of the purified water. An aqueous solution of the sodium benzoate was then added to the solution, followed by addition of the sorbitol solution and finally the flavour. The volume was made up with purified water and mixed well.

Claims

1. A compound which is a complex of formula (I), (II) or (III):

(I)

(II)

(III)

wherein p is 1 and either (a) each R, which are the same or different in a given compound, is a direct bond or is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene and alkynylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or

(b) each R, which are the same or different in a given compound, is a direct bond or is independently selected from arylene, aralkylene and alkarylene; and

R², R³ and R⁴, which are the same or different, is hydrogen, halogen, nitro, cyano, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or p is O, and

(c) the two R groups attached indirectly via X atoms to the same P or Si atom together form, with the X atoms to which they are directly attached, a 5- or 6- membered saturated cyclic diol or dithiol which is unsubstituted or substituted by one or more saturated substituents containing one or more heteroatoms selected from O and N; each m, which are the same or different in a given compound, is 0 or 1; each n, which are the same or different in a given compound, is 0 or 1; and

X is O or S; or a pharmaceutically acceptable salt thereof; for use in a method of treatment of the human or animal body by therapy.

2. A compound as claimed in claim 1 wherein, in formulae (I), (II) and (III),

R¹, R² R³ and R⁴ are each, independently, selected from hydrogen, halogen, hydroxy which is free or protected, thiocarbonyl which is free or protected, carboxy which is free or protected, alkyl which is unsubstituted or substituted, alkoxy which is unsubstituted or substituted, alkanoyl which is unsubstituted or substituted, aryl which is unsubstituted or substituted, aroyl which is unsubstituted or substituted and carboxy; each R is independently selected from alkylene, alkenylene, alkynylene and arylene, each of which is unsubstituted or substituted; each m is 0 or 1 ; each n is 0 or 1 ; and X is O or S.

3. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a complex of formula (I), (II) or (III) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof.

A compound which is a complex of formula (I), (II) or (III):

(I)

(II)

(III) wherein p is 1 and either

(a) each R, which are the same or different in a given compound, is a direct bond or is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene and alkynylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or (b) each R, which are the same or different in a given compound, is a direct bond or is independently selected from arylene, aralkylene and alkarylene; and each of R¹ R², R³ and R⁴, which are the same or different, is hydrogen, halogen, nitro, cyano, hydroxy which is free or protected, amino which is free or protected, carboxy which is free or protected, thiocarboxy which is free or protected, amido, azido, aziridino, or a group which is selected from alkyl, alkoxy, alkylthio, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, aralkyl, alkaryl, alkanoyl, alkanoyloxy, aroyl, aroyloxy and aralkoxy, and which is unsubstituted or substituted; or R¹ and R², or R³ and R⁴, are adjacent carbon atoms on a substituted or unsubstituted, saturated or unsaturated, 1,2- ring system; or p is 0, and

(c) the two R groups attached indirectly via X atoms to the same P or Si atom together form, with the X atoms to which they are directly attached, a 5- or 6- membered saturated cyclic diol or dithiol which is unsubstituted or substituted by one or more saturated substituents containing one or more heteroatoms selected from O and N; each m, which are the same or different in a given compound, is 0 or 1; each n, which are the same or different in a given compound, is 0 or 1 ; and X is O or S; or a pharmaceutically acceptable salt thereof; provided that, when p is 1 in formula (I), at least one of the moieties of formula -R- (O- R¹. -R-(O)_m-(R)_n-R², -R-(O)_m-(R)_n-R³and -R-(O)_m-(R)_n-R⁴ does not represent an unsubstituted alkyl group.

5. A compound as claimed in claim 4 wherein, in formulae (I), (II) and (III):

R¹ , R² R³ and R⁴ are each, independently, selected from hydrogen, halogen, hydroxy which is free or protected, thiocarbonyl which is free or protected, carboxy which is free or protected, alkyl which is unsubstituted or substituted, alkoxy which is unsubstituted or substituted, alkanoyl which is unsubstituted or substituted, aryl which is unsubstituted or substituted, aroyl which is unsubstituted or substituted and carboxy; each R is independently selected from alkylene, alkenylene and alkynylene arylene, each of which is unsubstituted or substituted; each p is 1 ; each m is 0 or 1; each n is O or 1; and

X is O or S; provided that, when each R in formula (I) is unsubstituted alkylene, at least one of the following conditions apply in formula (I): (a) m is 1, or (b) one of R¹, R² R³ and

R⁴ is other than unsubstituted alkyl.

6. A compound as claimed in claim 1 or claim 4 which is selected from: Bis(O,O'-diethane(dithiophosphate)platinum(II), Bis(O,O'-di(3-hydroxy)ethane(dithiophosphate)platinum (II), Bis(O,O'-di(2-ethoxyethoxy)ethane(dithiophosphate)platinum (II), Bis(O,O^,-di(2-hydroxybenzoyl)ethane(dithiophosphate)platinum (II) Bis(O, O -di-(2-methoxyethyl)dithiophosphato)platinum(II). Bis((O,O')-di-[2-(2-methoxyethoxy)ethyl]dithio-phosphate)platinum(II) Bis(4-methoxymethyl-2-thioxo-2λ⁵-[ 1 ,3,2]dioxaphospholane-2-thiol)platinum(II) Bis(diethyl 2-mercapto-l,3,2-dioxaphospholane-4,5-dicarboxylate)-platinum(II) Bis(O,O-bis(tetrahydrofuran-2-ylmethyl)hydrogen dithiophosphate)platinum(II) Bis(O,O-bis[2-(2-methoxyethoxyethoxy)ethyl] hydrogen dithiophosphate)platinum(II) Bis(O,O-di(tetrahydro-2H-pyran-4-yl)hydrogen dithio-phosphate)platinum(II) Bis(O,O-di(tetrahydrofuran-3-yl)hydrogen dithiophosphate)platinum(π) and the pharmaceutically acceptable salts thereof.

7. Use of a compound as defined in claim 1 in the manufacture of a medicament for use as an inhibitor of thioredoxin reductase.

8. Use according to claim 7 wherein the medicament is for use as an anti- rheumatoid arthritis agent or anti-tumour agent.

9. A method of treating a patient in need of an inhibitor of thioredoxin reductase, which method comprises the administration thereto of a compound as defined in claim

1.

10. A method according to claim 9 wherein the patient is in need of an anti- rheumatoid arthritis agent or anti-tumour agent.