WO2004047925A2

WO2004047925A2 - Therapeutic oxidation catalysts

Info

Publication number: WO2004047925A2
Application number: PCT/GB2003/005095
Authority: WO
Inventors: Claus Jacob; Gregory Giles; Fiona Fry
Original assignee: Exeter Antioxidant Therapeutics Ltd
Current assignee: Exeter Antioxidant Therapeutics Ltd
Priority date: 2002-11-22
Filing date: 2003-11-24
Publication date: 2004-06-10
Anticipated expiration: 2005-05-22
Also published as: AU2003302365A1; WO2004047925A3; GB0227348D0

Abstract

The present invention relates to the use of organotelenium and organotellerium GPx mimics for use as pro-oxidant catalysts and anti-oxidants.

Description

THERAPEUTIC OXIDATION CATALYSTS

The present invention relates to a series of organoselenium and organotellurium redox catalysts. Glutathione peroxidase (GP_X) is known as a natural redox catalyst. It has now been surprisingly found that organoselenium or organotellurium catalysts which mimic the activity of GP_X have useful therapeutic properties.

The present invention therefore provides the use of an organoselenium or organotellurium GP_X mimic in the manufacture of a medicament for use as a pro- oxidant catalyst. Also provided is a method of freating a patient in need of a pro- oxidant catalyst, which method comprises the administration thereto of an effective amount of an organoselenium or organotellurium GP_X mimic.

In a first embodiment of the invention, the organoselenium or organotellurium GP_X mimic is a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein: each R and R' is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιoalkyl)amino, di(Cι-Cιo allcyl)amino, -CO₂-(C₁-Cι₀ alkyl) or -NH-CO-(d-C₁₀ alkyl); n and m are the same or different and each represent 0, 1, 2, 3, 4 or 5; and - X represents -A-(L-B)_P-, wherein A and B are the same or different and each represent Se or Te, p is 0 or 1 and L is a direct bond or a C₁-C₁₂ alkylene group which is unsubstituted or substituted by a hydroxy group or a halogen atom, or L is a group -L'-Ar-L"- wherein L' and L" are the same or different and each represent a direct bond or -Cβ alkylene group and Ar is a phenyl ring which is optionally fused to a pyridine ring and which is unsubstituted or substituted by 1 or 2 substituents selected from Cι-C alkyl, amino and hydroxy substituents. Typically in the compound of formula (I), each R and R' is same or different and represents Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Cι-C₆ alkyl) or -NH-CO-(d-C₆ alkyl). Preferably each R and R' is the same or different and represents hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino. More preferably, each R and R' is the same or different and represents methoxy, hydroxy or amino.

Typically in the compound of formula (I), n and m are the same or different and each represent 0, 1, 2 or 3.

Typically in the compound of formula (I), p is 1 and L is a direct bond or a C_\- C₆ alkylene group. Preferably, when p is 1, A and B are the same.

Preferably the compound of formula (I) is a compound of formula (la),

wherein: - each R and R' is the same or different and represents hydrogen, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino; and X is as defined above for a compound of formula (I), provided that at least one R or one R' group is not hydrogen.

Typically, in the compound of formula (la), each R and R' are the same or different and represents methoxy, hydroxy or amino.

It is further preferred that the compound of formula (I) is a compound of formula (lb),

wherein: each R" is the same or different and represents hydrogen, methyl, ethyl, n- propyl, iso-propyl, hydroxy, COCH₃, COC₂H₅ or amino;

X' represents Se or Te; and n is an integer not greater than 3 provided that (a) when n is an integer greater than 1, the X' groups are optionally linked by a linker moiety L which is a (CH₂)_m group where m is an integer up to 4 and (b) at least one R" group on each phenyl moiety is not hydrogen.

In a second embodiment of the invention, the organoselenium or organotelluriam GP_X mimic is a compound of fonnula (II), or a pharmaceutically acceptable salt thereof,

wherein

H and J are the same or different and each represent -CR- or -N-, wherein R represents hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cι₀ alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι- Cio alkyl) or -NH-CO-(Cι-Cι₀ alkyl); each Ri is the same or different and represents Ci-Cio aUcyl, hydroxy, thio, Ci- Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo allcyl)amino, -CO₂-(Cι-Cιo alkyl) or -NH-CO-(Cι-Cι₀ alkyl); q represents 0, 1 or 2; and

R₂ and R₃ are the same or different and each represents hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl), -NH-CO-(Cι-Cι₀ alkyl) or a group of formula (II'):

wherein:

X is Se or Te; each R_t is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Q- Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, mono(Cι-Cιo aUcyl)amino, di(Cι-Cι₀ alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cιo alkyl); and s represents 0, 1, 2, 3, 4 or 5; provided that at least one of R₂ and R₃ is a group of formula (IL). Typically in the compound of fonnula (II), H and J are the same or different and represent -CH- or -N-. Preferably one of H and J is N, the other being -CH-. More preferably, H and J are the same and are -CH-.

Typically in the compound of formula (II), q is 0.

Typically R₂ and R₃ are the same or different and each represent Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Cι-C₆ alkyl), -NH-CO-(Cι-C₆ alkyl) or a group of formula (IL). Preferably, R₂ represents Cι-C₆ alkyl, hydroxy, Cχ-C₆ alkoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Cι-C₆ aUcyl) or-NH-CO-(Cι-C₆ alkyl). It is further preferred that R₃ is a group of formula (IP). Typically, in the formula (II), each R-_t is the same or different and represents hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

Typically in the compound of formula (II), s is 0 or 1. When s is other than 0, for example when s is 1, it is preferred that at least one R-j group is present at the 4 position of the phenyl ring. Preferably the compound of formula (II) is a compound of formula

(Ha),

wherein: each R" is the same or different and represents hydrogen, methyl, ethyl, n- propyl, iso-propyl, hydroxy, COCH₃, COC₂H₅ or amino; and

X' is Te or Se, provided that at least one R" group on each phenyl moiety is not hydrogen.

A third embodiment of the invention is the use, in the manufacture of a medicament for use as a pro-oxidant, of a conjugate in which a compound of foimula (I), (la), (lb), (II) or (Ila), as defined above, or a compound of formula (Ic), is linked to a moiety Z, wherein Z is a earner or targeting moiety

wherein : - X' is Se or Te;

R and n are as defined above for a compound of formula (I); and — * is the point of attachment to the rest of the conjugate. Typically, the compound of formula (Ic) is a compound of formula (Ic'):

wherein: each R" is the same or different and represents hydrogen, methyl, ethyl, n- propyl, iso-propyl, hydroxy, COCH₃, COC₂H₅ or amino; X' is Se or Te; and — * is the point of attachment to the rest of the conjugate, provided that at least one R" on the phenyl moiety is not hydrogen.

Typically, when the conjugate comprises a compound of formula (I), (la) or (lb), said compound is linked to the moiety Z via the 4-position of either of the two phenyl moieties.

Typically, when the conjugate comprises a compound of formula (II) or (Ila), said compound is linked to the moiety Z via the non-fused phenyl moiety. More preferably the compound of fonnula (II) or (Ila) is linked to the moiety Z at the 4- position of the phenyl moiety. In one embodiment the compound of formula (I), (la), (lb), (II), (Ila) or (Ic) is directly attached to Z, for example via a covalent bond. Z is typically a carrier or targeting moiety, and is preferably a peptide, protein, enzyme, polymer or polynucleotide. Z will generally enhance the effectiveness of the compound of the invention, for example by decreasing elimination of the compound from the circulation (which may occur through renal filtration, enzymatic degradation, uptake by the reticuloendothelial system (RES) and accumulation in non-targeted organs and tissues) or retaining the compound within the target tissue/cell or aid uptake into the cell, which could be important when targeting a drug to brain or liver tissue.

Z may be a polymer, typically having a molecular weight of at least 0.5 kDa, such as at least 1, 2, 5, 10, 20, 50 100, 150 or 200 kDa. Suitable polymers are known in the art. hi one embodiment the polymer is polyethylene glycol) (PEG). PEG is commercially available in a variety of molecular weights and in chemically activated, ready-for-use forms for covalent attachment to the compound to be delivered. In one embodiment the polymer is a polysaccharide. In one embodiment Z is a polymer which is able to bind to a plasma protein, such as plasma albumin. Poly(styrene-co-maleic acid anhydride) (SMA) is an example of such a polymer.

In one embodiment Z is a targeting (vector) moiety that is capable of directing the compound of the invention to, for example, a cancer to be treated. The moiety will typically have affinity toward ligands that are characteristic for target cancer tissues. Moieties capable of recognizing tumors include cytokines, antibodies, peptides, lectins, saccharides, hormones and some low molecular weight compounds, such as folate and vitamins. The moiety may be any of the types of moiety described in G. Gregoriadis, Targeting of drugs. Nature 265 (1977), pp. 407-411. hi particular antibody moieties may be used against ovarian cancer, prostate cancer, pancreatic cancer and colorectal cancer (for example as described in N.P. Torchilin, Editor, Handbook of Targeted Delivery of Imaging Agents, CRS Press (1995). The antibodies may be humanized versions of antibodies, or their fragments, for example humanized version of rodent-derived antibodies where rodent-derived binding sites and human constant regions are combined using recombinant technology. The antibodies may also be monoclonal antinuclear autoantibodies (AΝAs) with nucleosome-restricted specificity (for example as described in L. lakoubov et al, Anti- nuclear autoantibodies of the aged reactive against the surface of tumor but not noπnal cells. Immunol. Lett. 47 (1995), pp. 147-149 and L.Z. lakoubov and N.P. Torchilin, A novel class of antitumor antibodies: nucleosome-restricted antinuclear autoantibodies (ANA) from healthy aged nonautoimmune mice. Oncol. Res. 9 (1997), pp. 439-446. In one embodiment the moiety is anti-HER-2/neu monoclonal antibody or a fragment thereof which retains binding ability. In one embodiment Z is a growth factor or cytokine (for example as described in

R. Niv et al, Antibody engineering for targeted therapy of cancer: recombinant Fv- immunotoxins. Curr. Pharm. Biotechnol. 2 (2001), pp. 19-46).

In one embodiment Z is able to deliver the compound by transduction. Transduction is the ability of certain peptides to feπy conjugated macromolecules or large diameter particles (such as 40-nm dextran-coated iron oxide colloidal particles or 200-nιn) across cell membranes directly into the cytoplasm. Thus Z could be such a peptide, for example a peptide derived from a protein of a virus or Drosophila Antennapedia transcription factor. Such a peptide may as small as 10-16 amino acid longs. Generally the peptide directly targets the lipid bilayer of cell membranes, and penetrates it in a receptor- and/or transporter-independent fashion.

The peptide may be as described in D.A. Mann and A.D. Frankel , Endocytosis and targeting of exogenous HIV-1 Tat protein. EMBO J. 10 (1991), pp. 1733-1739, D.R. Gius et al, Transduced pl6INK4a peptides inhibit hypophosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of Cdk2 complexes in late Gl. Cancer Res. 59 (1999), pp. 2577-2580, A. Vocero-Akbani et al,

Transduction of full-length Tat fusion proteins directly into mammalian cells: analysis of T cell receptor activation-induced cell death. Methods Enzymol. 322 (2000), pp. 508- 521, N. Soga et al, Rho family GTPases regulate VEGF-stimulated endothelial cell motility. Exp. Cell Res. 269 (2001), pp. 73-87, J. Zezula et al, p21cipl is required for the differentiation of oligodendrocytes independently of cell cycle withdrawal. EMBO Rep. 2 (2001), pp. 27-34, CN. Hsia et al, c-Rel regulation of the cell cycle in primary mouse B lymphocytes. Int. Immunol. 14 (2002), pp. 905-916, or S.R. Schwarze et al, In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285 (1999), pp. 1569-1572. Peptides which can cause transduction may be conjugated to liposomes.

In one embodiment Z enhances the ability of the compound to cross an epithelial barrier. This may be required when, for example, the compound administered nasally. Thus Z may be a surfactant, such as laureth-9, a bile salt and bile salt derivative such as sodium taurodihydrofusidate, a fatty acid or fatty acid derivative, a phospholipid or a cyclodextrin. Z may be a chitosan, such as a chitosan glutamate salt of a mean molecular weight around 250 kDa.

Z may utilise a peptide transporter in the cancer/tumour to be treated, such as peptide transporter 1 (PEPT1, SLC15A1) or peptide transporter 2 (PEPT2, SLC15A2). Thus Z may be a substance which can be transported by the transporter, such as a peptide (e.g. dipeptide or tripeptide), or -amino fatty acid (-AFA) (such as one with more than four backbone carbon units).

As mentioned above the compound of the invention may be attached to Z via a linker. Typically the linker is covalently bonded to both the compound and Z. Suitable linkers are known in the art. The linker typically comprises a carbon chain or is a polynucleotide or polypeptide. The linker typically comprises a thioether, disulphide, amide or hydrazide bond. The linker may comprise Ν-hydroxysuccinimide, polyethyleneglycol (PEG), m-maleimidobenzoyl Ν-hydroxysuccinimide ester or Ν- succinimidyl-3-2-pyridyldithio propionate. Typically, the linker attaching the compound of formula (I), (la), (lb), (II), (Ila) or (Ic) to the moiety Z is a -(CH₂)_m- group where m is an integer up to 4.

As used herein, a Ci-Cio alkyl group or moiety is a linear or branched Ci-Cio alkyl group or moiety. Suitable such alkyl groups and moieties include Cι-C₆ alkyl groups and moieties, for example methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Methyl, ethyl, n-butyl and t-butyl , n-pentyl and n-hexyl preferred. Preferred such alkyl groups and moieties include -C₄ alkyl such as Cι-C₃ alkyl. As used herein, a C1-C12 alkylene group is a straight or branched C1-C₁₂ aUcylene group, for example, Cι-C₆ alkylene group. Examples of suitable Cι-C₆ alkylene groups include methylene, ethylene, propylene, butylenes, pentylene and hexylene groups. groups. Preferred such alkylene groups include Cι-C alkylene such as Cι-C alkylene groups.

A halogen atom is typically a chlorine, fluorine, bromine or iodine atom. It is preferably chlorine or fluorine.

As used herein, a said alkoxy group is typically a said alkyl group attached to an oxygen atom. A said alkylthio group is typically a said alkyl group attached to a thio group.

Phaπnaceutically acceptable salts of the compounds of the formulae (I), (la),

(Lb), (II), (Ila) and the conjugates of compounds of formula (I), (la), (lb), (II) (Ila), and

(Ic), are also suitable organoselenium and organotelluriam GP_X mimics for use in the present invention. Suitable such salts include salts with pharmaceutically acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, disphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succininc, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be formed with pharmaceutically acceptable bases such as alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.

Particularly prefeπed compounds of the invention are set out below.

4-(4-hydroxyphenylselanyl)phenol,

4-(4-hydroxyphenyltellanyl)phenol, bis(4-methoxyphenyl)selane, bis(4-methoxyphenyl)tellane, l,2-bis(4-methoxyphenyl)diselane,

1 ,2-bis(4-methoxyphenyl)ditellane,

2-(2-(2-aminophenyl)diselanyl)benzenamine, 1 -(3 -(4-methoxyphenyltellanyl)propyltellanyl-4-methoxybenzene,

1 ,2-bis(4-acetoxyphenyl)tellane,

(2,5-dimethoxyphenyl)(phenyl)tellane,

4-(4-methoxyphenyltellanyl)benzenamine, 2-(4-methoxyphenylselanyl)-3 -methylnaphthalene- 1 ,4-dione,

2-methyl-3 -(phenylselanyl)naphthalene- 1 ,4-dione,

2-(4-methoxyphenylltellanyl)-3 -methylnaphthalene- 1 ,4-dione,

2-methyl-3 -(phenyltellanyl)naphthalene- 1 ,4-dione, 2,3-bis(phenylselanyl)naρhthalene- 1 ,4-dione,

2-methoxy-3 -(phenylselanyl)naphthalene- 1 ,4-dione,

2-ethoxy-3 -(phenylselanyl)naphthalene- 1 ,4-dione,

2-(<frmethylainino)-3-(phenylselanyl)naphthalene-l,4-dione,

1 ,4-dihydro- 1 ,4,dioxo-2-(phenylselanyl)naphthalene-3 -yl-N-methylacetamide, 2-(ethylthio)-3 -phenylselanyl)naphthalene- 1 ,4-dione,

6-(phenylselanyl)quinoline-5,8-dione,

7-(jphenylselanyl)quinoline-5,8-dione ,

3-(4-methoxyphenyltellaryl)propan- 1 -amine,

1 ,2-diphenyldiselane, 1,2-diphenylditellane,

1 ,2-di- tolyldiselane,

4-(2-(4-aminophenyl)diselanyl)benzenamine,

1 ,2-dimesityldiselane, 1 -(4-methoxyphenyl)-2-phenyldiselane

1 ,2-bis(4-hydroxyphenyl)ditellane, 1,2-di- -tolylditellane,

4-(2-(4-aminophenyl)ditellanyl)benzenamine,

1,2- bis(4-ethoxyphenyl)ditellane,

1 ,2-di-o-tolylditellane, l,2-bis(2-methoxyphenyι)ditellane, 2-(2-(2-aminophenylditellanyl)benzenamine, 2-(2-(2-

(dimethylamino)phenyl)ditellanyl)-N.N-dimethylbenzenamine,

1 ,2-dimesitylditellane,

1 ,2-di-m-tolylditellane,

(2,5-dihydroxyphenyl)(4-hydroxyphenyl)selane and and (2,5-dihydroxyphenyl)(4-hydroxyphenyl)tellane.

Symmetrical compounds of formula (I) in which p is 0 can be prepared by the following reaction scheme. NaH + X (powdered) NMP/Argon

Na₂X

110°C

X = selenium or telurium halogen is preferably iodine or bromine

Typically, the sodium selenide or sodium telluride is made in situ by heating sodium hydride (NaH) (2 mole equivalents) with the chalcogen powder (1 mole equivalent) at 110°C with stirring in dry NMP (l-methyl-2-pyrrolidinone) in an atmosphere of argon for approximately 60 minutes.

The halophenyl reagent (2 mole equivalents) can then be added and left to react overnight. Following that reaction, the product can be recovered by adding saturated NH₄C1, pouring the reaction into ethyl acetate and agitating the mixture. The mixture can then be filtered under vacuum and the residue washed with ethyl acetate. The aqueous layer can be decanted and the organic layer dried over MgSO₄, filtered and the solvent removed in vacuo. The product can be purified by chromatograpliy.

Asymmetric compounds of formula (I) in which p is 0 can be prepared by the following reaction scheme. The preparation of the bisphenyldichalcogen starting material used in the reaction scheme is given below.

Typically, 'ϊ.u-Li is added dropwise to the halogenated phenyl reagent in a solvent such as dry THF at -78°C under an argon atmosphere. The bisphenyldichalogen reagent can then be added dropwise under argon, and the reaction mixture can be left overnight. An aqueous solution of potassium ferricyanide can then be added slowly to the mixture and stirred for 10 minutes.

The product can be extracted using DCM, washed with water and dried over Na₂SO₄. Purification can be effected using column chromatograpliy.

Symmetrical compounds of formula (I) in which p is 1 and L is a direct bond can be prepared according to the following reaction scheme.

2 tert-Butyl lithium

Argon

halogen is preferably iodine or bromine Selenium or Telluriurr (X) powder Argon

Typically, the reaction is conducted by adding *BuLi in a solvent such as pentane dropwise to the halogenated phenyl reagent in a solvent such as dry THF at -78°C under an argon atmosphere. The thus obtained reaction mixture can then be stirred for 60 minutes.

The mixture can then be allowed to warm to room temperature over 30 minutes. Telluriun/selenium powder can then be added while a brisk stream of argon is flowing through the system. The mixture can then be stirred under argon overnight. An aqueous solution of potassium fenicyanide can then be added slowly to the mixture.

The product can be extracted from the filtrate using DCM. The combined DCM extractions can be washed with water and then dried using Na₂SO₄. After filtration, the mixture can be evaporated to dryness, leaving the product, which can be purified by column chromatograpliy.

An alternative synthesis of such compounds involves dissolving (Se/Te)Cl (1 mole equivalent) in freshly distilled dry ether and adding an appropriately substituted phenol (2 mole equivalents). The reaction mixture can be stirred and then added to a flask containing CH₂C1 and an aqueous solution of K₂S₂O₅ (1.5 mole equivalents). NaHCO₃ can then be added until gas evolution ceases and the organic phase can be separated after removal of any insoluble matter.

The solution can then be dried over MgSO , filtered and the solvent removed in vacuo. The residue can be dissolved in a minimum volume of absolute ethanol, followed by addition of hexane, and the solution can be left at -20°C for 2 days. After this time a solid deposits, which can be collected, washed with petroleum ether and dried under vacuum in the dark.

A third procedure for preparing compounds of formula (I) in which p is 1 and L is a direct bond involves the following reactions.

(R)n Mg turnings (R)n

-halogen dry THF iodine crystal (eg)

Selenium or halogen is preferably bromine or iodine Telurium shot

Typically, the reaction proceeds by adding a solution of halogenated phenyl compound in dry THF dropwise to magnesium turnings and iodine under argon, keeping a gentle reflux. After addition, the solution can be heated to reflux for 30 mins. The solution can be cooled to room temperature and selenium or tellurium can be added. Reflux can be maintained for a further 30 mins, and the resulting solution can be cooled and quenched dropwise with saturated ammonium chloride solution until no more gas is released. The resulting solution can be filtered, extracted into diethyl ether (2 x 50 mL) and dried over MgSO₄.

Compounds of formula (I) in which p is 1, L is a direct bond and A and B are different can, of course, be prepared via the above reaction schemes by using a mixture of selenium and tellurium powder or shot, and isolating the desired product from the mixture thereby obtained.

Compounds of formula (I) in which p is 1, L is a direct bond and the two phenyl moieties are different can be obtained by reducing and re-oxidising a mixture of corresponding compounds with identical phenyl moieties. Thus, the reaction could, for example, proceed as follows.

Purification of the desired product from the mixture resulting from the reduction and subsequent re-oxidation can be effected by standard techniques, for example column chromatography.

Compounds of formula (I) in which p is 1 and L is other than a direct bond can be prepared from corresponding compounds in which L is a direct bond as follows.

1. NaBH argon, absolute ethanol

2. Haloge — L — Halogen

The diaryldichalcogen (1 mole equivalent) is typically dissolved in absolute ethanol under an argon atmosphere. Sodium borohydride (3 mole equivalents) can then rapidly be added and the solution stirred under argon for 1 hr. The dihalogen compound (0.5 mole equivalent) can be added via a syringe and the solution stirred for a further 3 hr. The solvent can be removed in vacuo and the residue dissolved in ethyl acetate and washed with water. The organic layer can be dried over MgSO and the solvent removed in vacuo. The product can then be dissolved in CHC1₃ and purified by silica column chromatography

Compounds of formula (II) can be prepared via the following reaction scheme.

Ri, R₂, R , R , s, H and J in the above reaction scheme are as defined above for the formula (II). Compounds of formula (II) in which both R₂ and R₃ respesent a moiety (II) can, of course, be prepared by using a benzoquinone intermediate which has a bromine leaving group at both the R₂ and the R₃ positions.

Typically, the above reaction is effected by sonicating the diaryldichalcogen (1 mole equivalent) and π-tributylphosphine (slight excess) in THF under argon for 15 mins. 10% NaOH (aq) (2 mole equivalents) can then be added, and the solution can be stirred until it becomes homogeneous (-15 mins) before being added dropwise to a solution of the quinone-type compound in THF under argon. The solution can then be stfrred for a further 10 mins, then poured into brine and the desired product can be extracted into DCM. The product can be dried over MgSO₄ and solvents removed in vacuo. The residue can be purified by flash chromatography to give the desired compound.

Alternatively, compounds of formula (II) can be prepared according to the following reaction scheme.

(i) NaBH₄/Ethanol/Argon

Again, compounds of formula (II) in which both R₂ and R₃ represent a moiety (II ) can be prepared according to the above section scheme by using a dibromo benzoquinone intermediate.

Typically, the above reaction is effected by adding NaBELj to degassed absolute ethanol and stirring under argon until all the solid dissolves. The dichalcogen can then be added and the solution stirred for 20 minutes at room temperature to generate the chalcogen anion. The quinone can then be added to the reaction mixture and left stirring overnight. The product can be purified by chromatograpliy (silica gel).

The starting materials used in the above reaction schemes are known compounds, or may be prepared by known methods. The compounds of the invention may, of course, be salified by known methods. They may also be linked to a moiety Z, as defined above, by techniques known in the art.

The present invention provides a new use for organoselenium and organotelluriam GPx mimics. Organoselenium and organotelluriam GPx mimics can be identified using a catalytic metallothionein assay conducted using a working volume of 800 μl in a quartz cuvette according to established literature (Jacob et al, Proceedings of the National Academy of Sciences of the United States of America 1999, 96, 1910- 1914 and Jacob et al Chemical Research in Toxicology 2000, 13, 3-9).

Thus, typically, an organoselenium or organotelluriam GPx mimic is a compound which has an IC₅₀ of 1000 nM or less, preferably 500 nM or less, more preferably 100 nM or less, most preferably 50 nM or less, when assessed by a catalytic metallothionein assay conducted using a working volume of 800 μl in a quartz cuvette, which assay comprises: incubating metallothionein (0.5 μM) in HEPES (20 mmol, pH 7.4, N₂ purged) containing PAR (4-(2-pyridylazo)resorcinol) ((100 μM), the candidate catalyst, and tert-butyl hydroperoxide (500 μM) at 25°C for 60 minutes; and continuously measuring the rate of zinc release spectrophotometrically (ε₅oo ⁼ 65 000 M^"1 cm^"1), the total zinc content being measured by incubation with ebselen (50 μM) for 1 hour at 25°C, the concentrations given being final concentrations in the 800 μl cuvette. An organoselenium or organotelluriam GPx mimic can also be defined as a compound which provokes a maximum zinc release of at least 20%, preferably at least 30%, more preferably at least 50%, most preferably at least 75%, in a catalytic metallothionein assay conducted using a working volume of 800 μl in a quartz cuvette, which assay comprises: - incubating metallothionein (0.5 μM) in HEPES (20 mmol, pH 7.4, N₂ purged) containing PAR (4-(2-pyridylazo)resorcinol) ((100 μM), 200 nM of the candidate catalyst, and tert-butyl hydroperoxide (500 μM) at 25°C for 60 minutes; measuring maximum zinc release spectrophotometrically (ε₅oo = 65 000 M^"1 cm^"1); and - determining maximum zinc release as a percentage of the total zinc content of metallothionein as measured by incubation with ebselen (50 μM) for 1 hour at 25°C, the concentrations given being final concentrations in the 800 μl cuvette. The organoselenium and organotelluriam GP_X mimics are useful as pro-oxidants catalysts. In particular, the GP_X mimics used in the present invention can induce apoptosis in cells subjected to an oxidising cellular environment. The interior of a tumour is often a highly oxidising micro-environment, and thus, the GP_X mimics used in the present invention are therefore useful in inducing cell death, for example via apoptosis or necrosis in malignant neoplasms.

Accordingly, the said medicament is typically for use in the treatment of, and the said patient is typically suffering from, a cancer. Typically, the cancer is one wherein the malignant cells exhibit an oxidising cellular environment, as compared with healthy cells from the same tissue type. Examples of such cancers include kidney cancer, prostate cancer, lung carcinoma, skin cancer, colon cancer or breast cancer.

The cancer which is treated is generally one in which the levels of antioxidant enzymes are either elevated or decreased compared with healthy cells from the same tissue. Other substances which are affected by the redox state of the cell may also be present in elevated or decreased levels compared with healthy cells from the same tissue. Thus the cancer may have elevated or decreased levels of manganese superoxide dismutase, coper-zinc oxide dismutase or catalase. The cancer may have a decreased level of glutathione. Ln one embodiment the cancer has elevated levels of reactive oxygen species, such as elevated levels of hydrogen peroxide. Levels of antioxidant enzyme may be determined by using a immunohistochemical or enzyme activity assay. Levels of glutathione may be determined using an enzyme assay or by ELIS A. Levels of hydrogen peroxide may be determined using an enzyme assay. The present invention also provides compounds of formulae (A), (A¹),

(B), (D), (E), (F), (G) and (H), and pharmaceutically acceptable salts thereof, as described below.

The compounds of fonnula (A) are defined as

wherein:

A and A' are the same or different and represent Se or Te; r and t are the same or different and each represent 0, 1, 2, 3, 4, or 5; - each R and R' is the same or different and represents Ci-Cio alkyl, hydroxy, thio,

Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cιo aUcyl); L is a C₁-C₁2 alkylene group which is unsubstituted or substituted by a hydroxy group or a halogen atom, or L is a group -L'-Ar-L"- wherein L' and L" are the same or different and each represent a direct bond or Cι-C₆ alkylene group and Ar is a phenyl ring which is optionally fused to a pyridine ring and which is unsubstituted or substituted by 1 or 2 substituents selected from Cι-C₄ alkyl, amino and hydroxy substituents, provided that when r and t are 1 and R is OMe, L is not n-propylene.

Typically in the compound of fonnula (A), each R and R' are as defined above for a compound of fonnula (I). Typically, A and A' are the same and preferably A and A' are Te.

Typically, t and r are the same or different and represent 1, 2 or 3. Preferred compounds of formula (A) are compounds of formula (A')

wherein:

A, A' and L are as defined above for a compound of formula (A); and each R and R' is the same or different and represents hydrogen, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino; provided that at least one R or one R' group is not hydrogen. The compounds of formula (B) are defined as

wherein: each R and R' is the same or different and represents Ci-Cio alkyl, hydroxy, thio,

Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(C₂-Cι₀ alkyl); k and 1 may be the same or different and are selected from 0, 1, 2, 3 or 4; - Rt is selected from hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-

Cio alkyl) or -NH-CO-(Cι-Cι₀ alkyl),

R4¹ is selected from Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl) or -NH-CO-(Cι-Cιo alkyl), provided that when k and 1 are 0, either _t and R_t' are different or R_t and Ri' are the same and are C₂-Cιo alkyl, hydroxy, thio, C₂-Cιo alkoxy, Ci-Cio alkylthio, mono(Cι-Cιo alkyl)amino, di(C₂-Cι₀ alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(C₂-Cι₀ alkyl).

Typically in the compound of formula (B), R and R' are as defined above for a compound of formula (I).

Typically, k and 1 are the same or different are 0, 1 or 2.

Typically, _t is selected from hydrogen, Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

Typically, R is selected from Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

Preferred examples of compounds of formula (B) include 4-(4- hydroxyphenylselanyl)phenol and 2-amino,4'-methoxy-diphenylselenide.

The compounds of fonnula (C) are defined as

wherein: each R and R' is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cι₀ alkyl); - s and t are the same or different and are selected from 0, 1, 2, 3 or 4; R is selected from hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-

Cio alkyl) or -NH-CO-(Cι-Cι₀ alkyl),

Rf is selected from Ci-Cio alkyl, hydroxy, thio, Ci-Cio ahcoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl) or

-NH-CO-(Cι-Cιo alkyl), provided that (a) when R_t and R_t' are different, s and/or t is other than 0 and (b) when R_t and _t' are the same, s and/or t is other than 0 and R is not methyl.

Typically in the compound of formula (C) , each R and R' are as defined above for a compound of formula (I).

Typically, s and t are the same or different and are 0 or 1.

R_t in the formula(C) is typically Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino. t> in the formula (C) is typically hydrogen, Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino. A preferred example of a compound of formula (C) is 4-(4- methoxyphenyltellanyl)benzenamine.

The compounds of formula (D) are defined as

wherein: each R' is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Ci-

Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo allcyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cι₀ alkyl); and t is 1, 2, 3, 4 or 5.

Typically in the compound of formula (D) each R' is same or different and represents Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(C C₆ alkyl) or -NH-CO-(Cι-C₆ alkyl). Preferably each R' is the same or different and represents hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino. More preferably, each R' is the same or different and represents methoxy, hydroxy or amino. Typically t in the formula (D) is 1 or 2. A prefened example of a compound of formula (D) is (2,5- dimethoxyphenyl)(phenyl)tellane.

The compounds of formula (E) are defined as

wherein

H and J are the same or different and each represent -CR- or -N-, wherein R represents hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι- Cio alkyl) or -NH-CO-(Cι-Cιo alkyl); each Ri is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Ci- Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cιo alkyl); q represents 0, 1 or 2; and

R₂ and R₃ are the same or different and each represents hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl), -NH-CO-(Cι-Cι₀ alkyl) or a group of formula (E'):

wherein:

X is Te; each R_t is the same or different and each represent Ci-Cio alkyl, hydroxy, thio,

Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or - H-CO-(Cι-Cιo alkyl); and s represents 0, 1, 2, 3, 4 or 5; provided that at least one of Ri and R₂ is a group of formula (E'). Typically in the compound of formula (E), H and J and/or q are as defined above for a compound of formula (II).

Typically in the compound of formula (E), R and R are the same or different and each represents Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Cι-C₆ alkyl), -NH-CO-( -C₆ alkyl) or a group of formula (E'). Preferably R₂ represents Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl) amino, -CO₂- (Cι-C₆ alkyl) or-NH-CO-(Cι-C₆ alkyl). More preferably R₃ is a group of formula (E').

Typically _t in the formula (E) represents hydroxy, Cι-C alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

Typically s in the formula (E) is 0, 1, 2 or 3. Preferably s is 0 or 1. It is further preferred that, when s is other than 0, for example when s is 1, that at least one _t group is present at the 4 position of the phenyl ring.

Preferred examples of the compounds of formula (E) include those when q is 0, H and J are both -CH-, R₂ is Me and R₃ is a group of formula (E') wherein X is Te, s is 1 and the R_t group is either hydrogen or methoxy and is present at the 4 position of the phenyl ring.

The compounds of formula (F) are defined as

wherein:

Ri, q, H and J are as defined above for a compound of formula (E) R_2' is hydrogen, C₁-C₁₀ alkyl, hydroxy, thio, C₁-C₁₀ alkoxy, C₁-C1₀ alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl), NH-CO-(Cι-Cιo alkyl); each R₄ is the same or different and represents Cj-Cio alkyl, hydroxy, thio, Q- C10 alkoxy, C1-C10 alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cι₀ alkyl); and v is 1, 2, 3, 4 or 5. Typically in the compound of formula (F), R₂ s Cι-C₆ alkyl, hydroxy, Q- C₆ alkoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆alkyl)amino, -CO₂-(C_!-C₆ alkyl) or -NH-CO-(C C₆ alkyl). _t in the formula (F) is typically hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

In the compound of fonnula (F), v is typically 1.

Typically, in the fonnula (F), at least one R_t group is present at the 4 position of the phenyl ring. For example, when v is 1 the R₄ group is preferably present at the 4 position of the phenyl ring.

A preferred example of a compound of fonnula (F) is when q is 0, H and J are both -CH-, Ri" is methyl, v is 1, R_t is methoxy and is present at the 4 position of the phenyl ring. The compounds of formula (G) are defined as

wherein: each R and R' is the same or different and represents C1-C₁₀ alkyl, hydroxy, thio, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo aUcyl)amino, -CO₂-(Cι-Cιo alkyl) or -NH-CO-(C Cι₀ alkyl); and a and b are the same or different and each represent 0, 1, 2, 3, 4 or 5; provided that the compound is not 1,2-diρhenyldiselane, l,2-bis(4- methoxyphenyl)diselane, 1 ,2-dip-tolyldiselane, 4-(2-(4- aminophenyl)diselanyl)benzenamine, 1,2-dimesityldiselane or l-(4-mefhoxyphenyι)-2- phenyldiselane.

Typically in the compound of formula (G), each R and R' is the same or different and represents C -Cιo alkyl, hydroxy, thio, C2-C1₀ alkoxy, C₁- ₀ alkylthio, mono(Cι-C_!o alkyl)amino, di(Cι-Cι₀ alkyl)amino, -CO₂-(Cι-Cιo alkyl) or - NH-CO-(Cι-Cιo alkyl). Preferably each R and R' is the same or different and represents C₂-C₆ alkyl, hydroxy, C2-C6 alkoxy, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)arιιino. Typically, a and b in the formula (G) are the same or different and represent 0, 1, 2 or 3.

The compounds of formula (H) are defined as

wherein:

R, R', a and b are as defined above for a compound of formula (G), provided that the compound is not l,2-bis(4-methoxyphenyl)ditellane, l,2-bis(4- hydroxyphenyl)ditellane, l,2-di-/ tolylditellane, 4-(2-(4- aminophenyl)ditellanyl)benzenamine, 1,2- bis(4-ethoxyphenyl)ditellane, 1,2-di-o- tolylditellane, l,2-bis(2-methoxyphenyl)ditellane, 2-(2-(2- aminophenylditellanyl)benzenamine, 2-(2-(2-(dimethylamino)phenyl)ditellanyl)-N,N- dimethylbenzenamine, 1,2-dimesitylditellane, or 1,2-di-m-tolylditellane. Typically, in the formula (H), each R and R' is the same or different and represents C₂-C₆ alkyl, C₃-C₆ alkoxy, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ aUcyl)amino, -

CO₂-(Cι-C₆ alkyl) or -NH-CO-(Cι-C₆ alkyl).

Compounds of the invention may be administered in a variety of dosage forms.

Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, either subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginte, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

In one embodiment the compound is administered in the foπn of a microreservoir (microparticulate) carrier. These types of systems include liposomes, micelles, polymer microparticles and cell ghosts. The use of such carriers generally results in a much higher active moiety: carrier ratio compared with "direct" molecular conjugates. They generally also provide a higher degree of protection against enzymatic degradation and other destructive factors upon parenteral administration because the carrier wall completely isolates drug molecules from the enviromnent.

Liposomes are vesicles formed by concentric spherical phospholipid bilayers encapsulating an aqueous space. These particles are generally biocompatible, biologically inert and cause little toxic or antigenic reactions. Their inner aqueous compartment encapsulates the compound. The liposomes may be in the form of surface-modified long-circulating liposomes grafted with a flexible hydrophilic polymer, usually PEG (for example as described in A.L. Klibanov et al, Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBSLett. 268 (1990), pp. 235-237).

The micelles that are used may be phannaceutical micelles or polymeric micelles, including those prepared from amphiphilic PEG-phospholipid conjugates (for example as described in V.S. Trubetskoy and V.P. Torchilin, Use of polyoxyethylene- lipid conjugates as long-circulating carriers for delivery of therapeutic and diagnostic agents. Adv. DrugDeliv. Rev. 16 (1995), pp. 311-320). Micelles are generally smaller than liposomes and lack the internal aqueous space. To load the micelles the compound may be attached to the surface of these particles or incorporated into them, typically via a chemically attached hydrophobic "anchor".

Vector (targeting) molecules can be used for the targeting of microreservoir delivery systems, for example in the form of an immuniliposome (a liposome targeted by antibody or antibody fragment). In a preferred embodiment PEG-modified, immunoliposomes targeted with anti-HER-2/neu monoclonal antibody fragments are used.

The microreservoir carrier may enhance delivery of the compound to the intracellular compartment of the cancer/tumour cell. In one embodiment the carrier promotes delivery into cells by receptor-mediated endocytosis. This process involves attachment of the carrier to specific ligands on target cell membranes, followed by the energy-dependent formation of endosomes. In one embodiment the carrier is also conjugated to a lytic peptide (for example as described in H. Kamata et al, Amphiphilic peptides enhance the efficiency of liposome-mediated DNA transfection. Nucleic Acids Res. 22 (1994), pp. 536-537, P. Midoux et al, Membrane permeabilization and efficient gene transfer by a peptide containing several histidines. Bioconjug. Chem. 9 (1998), pp. 260-267, or E. Mastrobattista et al. , Functional characterization of an endosome- disruptive peptide and its application in cytosolic delivery of immunoliposome- entrapped proteins. J Biol Chem. 277 (2002), pp. 27135-27143), pH-sensitive polymer (for example as described in CA. Lackey et al, A biomimetic pH-responsive polymer directs endosomal release and intracellular delivery of an endocytosed antibody complex. Bioconjug. Chem. 13 (2002), pp. 996-1001) or a swellable dendritic polymers (for example as described in O.L. Padilla De Jesus et al, Polyester dendritic systems for drug delivery applications: in vitro and in vivo evaluation. Bioconjug. Chem. 13 (2002), pp. 453-461). hi one embodiment the compound of the invention is administered in the fonn of a lipocore (for example as described in Perkins et al, h t. J. of Pharmaceutics 200 (2000), pp. 27-39), a microsphere (for example as described in Benoit et al, J. Controlled Release 65 (2000), pp 285-96) or a hydrogel (for example as described in Bouhadir et al, Biomaterials 22 (2001), pp. 2625-33). A therapeutically effective amount of a compound of the invention is administered to a patient. A typical daily dose is from about 0.1 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of adn inisfration. Preferably, daily dosage levels are from 0.5 mg to 1 g, more preferably 1 mg to 1 g.

In one aspect the present invention accordingly provides a compound of general formula (A), (A'), (B), (C), (D), (E), (F), (G) or (II) or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body. The compounds of the invention are also active as antioxidants. Accordingly, the invention also provides the use of a compound of general formula (A), (A*), (B), (C), (D), (E), (F), (G) or (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as an anti-oxidant or pro-oxidant, in particular where the medicament is for use in the treatment or prevention of neurodegenerative disease, inflammation, microbial infection, rheumatoid arthritis, Auto-hnmune Deficiency Syndrome, intestinal disorders, lung disorders, over-trained athlete's syndrome, trauma, heart disease and cancer. Preferred examples of neurodegenerative disease include Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Creuzfeld- Jacob disease. Further, the present invention provides a method of treating a human or animal patient in need of a pro-oxidant or anti-oxidant, which method comprises the adminisfration thereto of an effective amount of a compound of general formula (A), (A'), (B), (C), (D), (E), (F), (G) or (II) or a pharmaceutically acceptable salt thereof. Typically, the patient in need of a pro-oxidant or anti-oxidant is suffering from neurodegenerative disease, inflammation, microbial infection, rheumatoid arthritis, Auto-Immune Deficiency Syndrome, intestinal disorders, lung disorders, over-trained athlete's syndrome, trauma, heart disease or cancer. Prefened examples of neurodegenerative disease include Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Creuzfeld- Jacob disease. In a further embodiment, the present invention provides compounds for use in therapy, the compounds comprising at least one aromatic moiety linked to a selenium or tellurium moiety. In another aspect of this embodiment, the invention provides a pharmaceutical composition comprising a compound as hereinbefore described and a pharmaceutically-acceptable binder, extender, diluent or excipient.

Ln yet another aspect of this embodiment, the invention provides the use of a compound as hereinbefore described in the preparation of a medicament for the treatment of neurodegenerative diseases and other conditions including rheumatoid arthritis and cancer or malignant neoplasms.

In yet a further aspect of this embodiment, the invention provides a method of treatment of neurodegenerative diseases and other conditions including rheumatoid arthritis and cancer or malignant neoplasms comprising administering to a human or animal body an effective amount of a compound as hereinbefore described. Compounds according to or for use in the invention in this embodiment may broadly be sub-classified in one of three groups, as follows.

Group I. Chalcogen Catalysts

The compounds of this group have a general utility for freating diseased cells under oxidative stress conditions and may be used for treatment of Alzheimer's disease, cancer, rheumatoid arthritis and mental dementia. They show unusually high antioxidant activity at very low catalyst concentrations in the low nanomolar range. The compounds become toxic in the absence of glutathione, thus indicating responsiveness to the immediate redox environment. The compounds thus have the potential for use as antioxidants, to protect healthy cells, and pro-oxidants, to attack diseased cells, at the same time.

Compounds of Group I may be presented by the general fonnula:

in which R represents one or more of H, lower alkyl (for example methyl, ethyl, n- propyl, iso-propyl), alkoxide, hydroxy, halocarbonyl, lower alkyl carbonyl (for example COCH₃, COC₂H₅), amino and nitro, provided that each phenyl moiety has at least one substituent group which is other than H; X represents Se or Te and n is an integer, preferably not greater than 3 wherein, if n is greater than 1, the X groups are optionally joined by a linker moiety L.

Compounds of Group I in which R represents OCH₃ in the 4,4' positions, otherwise H, and n is 1 or 2, and in which when X is Te and n is 2 the Te atoms are linked by a trimethylene moiety, and also when R represents OH in the 4,4' positions when X is Te and n is 1, have already been proposed for the treatment of Alzheimer's disease.

Group II. Integrated Catalysts

This group again comprises an electron-rich selenium or tellurium atom linked to two aryl groups to create broad-band antioxidants or integrated catalysts which combine both electron-transfer and atom-transfer redox systems in the one molecule. Preferably, the aryl groups are different and include substituent groups which are electron-donating so that the electron availability over the respective aryl groups is different. For example, one aryl group may be 4-hydroxylphenyl and the other aryl group may be 2,5- dihydroxyphenyl, or one phenyl group may carry methoxy substitution additional to or instead of the hydroxy substitution. More preferably, at least one of the aromatic moieties comprises a conjugated cyclic diketone such as a 1,4-benzoquinone derivative or a 1,6-naphthoquinone derivative. Such diketone systems not only provide an integrated catalyst but also enhance the catalytic activity and solubility of the chalcogen redox system to which it is coupled, hitegrated catalysts may also comprise compounds in which a selenide or telluride group is linked to an aromatic moiety via an aliphatic amino chain. Integrated catalysts combine the catalytic activity of glutathione peroxidase with other known antioxidant systems, for example vitamin E or the quinone electron redox-systems derived from co-factor Q. Integrated benzoquinone and naphthoquinone antioxidants may be represented respectively by the following general formulae: Integrated Benzoquinone Antioxidants

Oxidised Form Reduced Fonn

Integrated Napthoquinone Antioxidants

Oxidised Form

Reduced Form

in which the R and X groups are as defined above. As shown, such compounds may be provided either in the reduced or oxidised form, the eventual status being dependent on the cellular redox environment.

Group III. Targeted Catalysts

This group of compounds is intended to transport antioxidant species to a desired site in the body, to render the active species more effective in being more concentrated at the site in question or enabling the dose to be reduced. The compounds can therefore be attached to specific peptides, proteins and enzymes to generate antioxidants that mimic the catalytic activity of glutathione peroxidase while travelling along the path of other proteins as the carrier species. Thus, the compounds preferably contain electron- rich selenium or tellurium atoms and aryl metabolic stabilizing groups and have a terminal moiety for attachment to a protein or enzyme. Carrier species may comprise any component of blood plasma, for example serum albumin.

Compounds of Group III may be represented by the general formula either

or

in which the R and X groups are as defined above and A represents NH₂, SH, OH or halogen.

The compound of Group III according to the second formula above in which R represents OCH₃ in the 4-position, X is Te and A is Br, and the linker moiety is trimethylene, has been proposed for the treatment of Alzheimer's disease.

In compounds for use in the present invention, linker moieties L will be known to those skilled in the art and typically comprise (CH₂)_m groups where m may be an integer up to 4.

Examples of compounds according to or for use in the invention are as follows:

Group II

Group III

Of the above compounds, compound (1) includes a tellurium atom which is susceptible JO

of oxidation by an oxidising agent and re-reduction by a thiol group, for example present in the cellular peptide glutathione. hi compound (2), the quinone moiety enhances the catalytic and solubility of the adjacent selenium-phenyl system. Compounds (3) and (4), in which X represents Se or Te, are analogous to compound (1) and compound (5) includes a phenolic redox system; the compound is symmetrical above the X-X bond where, again, X represents Se or Te. Compound (6) includes a nitrogen binding site for pro-oxidant metals such as iron and copper; the compound additionally could act as a metal-exchange complex to release beneficial metals such as zinc and to take up toxic metals such as cadmium and copper. The compounds of Group III include an amino moiety for attachment to peptides, proteins or enzymes. Compounds (9), in which X represents Se or Te, is shown coupled through the amino residue to a protein or enzyme for transportation in vivo to a specific target organ such as the liver, kidney or brain or other disease site. Human serum albumin is one such plasma carrier. The Examples which follow illustrate the invention.

EXAMPLES

Example 1 : Synthesis of 4-(4-hydroxyphenyIselanyl)phenol

SeCl₄ (1.12g, 5 mmol) was disolved in freshly distilled dry ether (10 ml) and phenol (0.95 g, 10 mmol) was added. The reaction mixture was refluxed with stirring for 3 hours. The reaction mixture was then added to a flask containing CH₂C1₂ (30 ml) and an aqueous solution of K₂S₂O₅ (3.37 g, 15 mmol) (30 ml). NaHCO₃ was added until gas evolution ceased and the orange organic phase was separated after removal of some insoluble matter. The solution was dried over MgSO , filtered and the solvent removed in vacuo giving a brown/orange oil. The oil was dissolved in a minimum volume of absolute ethanol, followed by addition of hexane and the solution was left at -20°C for 2 days. After this time a yellow solid has deposited and was collected, washed with petroleum ether and dried under vacuum in the dark. The solid was stored at -20°C and after 4 days the yellow solid had turned red. TLC (20% ethyl acetate in chloroform) showed the presence of only one product. Melting point: 143-144°C; 1H NMR (DMSO) δ 6.79 (d, 4H), 7.34 (d, 4H), 9.78 (s, 2H); Anal. Calcd for Cι₂Hι₀O₂Se: C 54.34; H 3.80. Found: C 53.02; H 3.71.

Example 2: Synthesis of l-(3-(4-methoxyphenyltelIanyl)propyltellanyl)-4- methoxybenzene

l,2-bis(4-methoxyphenyl)ditellane (100 mg, 0.2 mmol) was dissolved in absolute ethanol (40 ml) under an argon atmosphere. Sodium borohydride (23 mg, 0.6 mmol) was rapidly added and the solution stined under argon for 1 hr. 1,3- Dibromopropane (34 μl, 0.33 mmol) was added via a syringe and the solution stiπed for o

a further 3 hr. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (50 ml) and washed with water (3 x 30 ml). The organic layer was dried over MgSO₄ and the solvent removed in vacuo. The product was then dissolved in CHC1 (1 ml) and further purified by silica column chromatography (20% ether : petrol) then dried over silica gel to yield compound 7 as a yellow oil (57 mg, 0.11 mmol, 57% yield). R_f = 0.35 (20% ether : petrol). 1H NMR (CDC1₃) δ7.66 (d, J = 8.8 Hz, 4H), 6.77 (d, J = 8.7 Hz, 4H), 3.82 (s, 6H) 2.86 (t, J = 7.4 Hz, 4H), 2.20-2.10 (m, 2H); ¹³H NMR (CDC1₃) 6160.12, 141.53, 115.51, 100.67, 55.52, 33.38, 11.09; m/z (M+H) calcd. 516.9666, found 516.9667.

Example 3: Synthesis of l,2-bis(4-acetoxyphenyl)tellane

4,4'-dihydroxydiphenyltelluride (100 mg, 0.32 mmol) was dissolved in acetic anhydride (40 ml) and triethylamine (220 μl, 1.6 mmol) was added. The solution was stined overnight and then extracted into ethyl acetate (60 ml). The mixture was washed with saturated aqueous NaHCO₃ (3 x 30 ml) and H₂O (3 x 30 ml) and then dried over MgSO . The crude material was purified by column chromatography (CHCI₃) then dried over silica gel to yield compound 3 as a cream coloured solid (83 mg, 0.21 mmol, 66 % yield). R_f - 0.42 (CHC1₃). Melting point 155.6 - 165.5°C; 1H NMR (CDC1₃) 57.72 (d, J = 8.8 Hz, 4H), 6.99 (d, J = 8.7 Hz, 4H), 2.32 (s, 6H); ). ¹³C NMR (CDCI3) 5169.41, 150.94, 139.45, 123.11, 111.07, 21.32; m/z (M+H) calcd. 401.0032, found 401.0008.

Example 4: Synthesis of )2,5-dimethoxyphenyl)(phenyI)tellane

n-Butyllithium (1.6 M in hexane, 2.5 ml, 3.7 mmol) was added dropwise to a stiπed solution of l-bromo-2,5-dimethoxybenzene (0.5 ml, 0.72g, 3.3 mmol) in THF (2 ml) at -78 °C under argon. After one hour the solution was added dropwise to a stirred solution of diphenylditelluride (0.250g, 0.61 mmol) in THF (6 ml) at 0°C under argon until a colour change from red to pale yellow was observed (1.9 ml was needed). The resulting solution was left to stir under argon overnight and then separated using column chromatography Ether Petroleum Ether 40-60°C, (1:9). The solvent was evaporated under vacuum to give the title compound as a pale yellow crystalline solid. C H₁₄O₂Te. M_τ 341.86, Exact Mass 344.01. Yield 36%. Melting Point 57.6. Elemental analysis CHN. Found, C 48.91, H 4.02 (Calc. C. 49.2, H. 4.13). MS (El): m/z (%) 344 (M\ 41), 214 (39), 199 (100), 184 (46), 77, (62). 1H NMR (300 MHz, CDC1₃) δ, 7.91 (d, 2H, J= 8.1,1.6Hz,) δ, 7.45-7.27 ( , 3H) δ, 6.70 (m, 2H), δ, 6.49 (dd, 1H, J= 2.4,1.3Hz,) δ,3.8 (s, 3 H) δ, 3.5 (s, 3H). ¹³C NMR (400 MHz, CDC1₃) δ, 141.32 (s, C) δ, 129.72 (s, C) δ, 128.84 (s, C) δ, 55.55 (s, C) δ, 110.01 (s, C) δ, 112.41 (s, C) δ, 56.52 (s, C) δ, 119.30 (s, C) δ, 108.96 (s, C) δ, 154.93 (s, C) δ, 112.03 (s, C) δ, 112.03 (s, C).

Example 5: Synthesis of 4-(4-methoxyphenyltellanyl)benzenamine

^fBuLi (6 ml) was added dropwise to 4-iodoanisole (0.935g, 4 mmol) dissolved in dry THF (25 ml) at -78 °C under an argon atmosphere, giving an opaque, bright yellow liquid, which was stirred for 60 minutes. The mixture was allowed to warm to room temperature over 30 minutes. 4-(2-(4-aminophenyl)ditellanyl)benzenamine (0.878g, 2 mmol) was dissolved in THF (5 ml) under argon and added dropwise, and the reaction mixture turned colourless on addition. The mixture was then stiπed under argon overnight for 1 hour, yielding orange/red mixture. An aqueous solution of potassium ferricyanide (50 ml, 1.6g, 4.9 mmol) was added slowly to the mixture and stirred for 10 minutes. The product was extracted from the filtrate using DCM (100 ml, 2 x 50 ml). The combined DCM extractions were washed with water (3 x 10 ml) and then dried using Na₂SO₄. After filtration, the mixture was evaporated to dryness, leaving a brown oil. TLC using DCM to reveal 3 possible products which could be visualised using ninhydrin RpO (stationary spot) Rf=0.26 and R_f=0.17. The oil was then purified by column chromatography Hexane/CHC1₃ (4:6). Fractions collected and combined, the product was identified as R =0.17. Yield 9%. d₃Hι₃NOTe. M_r 326.85. Exact Mass 329.01. Elemental Analysis CHN. C 47.58 H 3.78 N 4.02 (Calc. C 47.46, H 3.95, N 4.2). MS (El): m/z (%) 329.93 (100), 327.93 (90), 325.92 (60), 324.92 (25). 1H NMR (300MHz, CDC1₃) δ: 7.59 - 7.52 (d,d 4H, J= 8.85 Hz,), 6.76 -6.73 (d, 2H, aromatic H, J- 8.7), 6.56 -6.54 (d, 2H, J= 8.7) 3.7 (s, 3H), 3.6 (br, 2H, NH₂). ¹³C NMR (400 MHz, CDCl₃) δ: 159.43, 146.57, 140.43, 138.94, 116.34, 115.28, 104.91, 100.82, 55.12.

Example 6: Synthesis of 2-amino,4'-methoxy-diphenylselenide

^lBuLi (6 ml) was added dropwise to iodoanisole (0.934g, 4 mmol) dissolved in dry THF (15 ml) at -78 °C under an argon atmosphere, this was stiπed for 60 minutes. The mixture was allowed to warm to room temperature over 30 minutes. 2-(2-(2- aminophenyl)diselanyl)benzenamine, (0.5g, 1.8 mmol) was dissolved in THF (dry) (2 ml) and added dropwise which decolourised on contact with the reaction. The mixture was then stirred under argon An aqueous solution of potassium ferricyanide (50 ml, 1.6g, 4.9 mmol) was added slowly to the mixture. The product was extracted from the filtrate using DCM (100 ml + 2 x 50 ml). The combined DCM extractions were washed with water (3 x 10 ml) and then dried using sodium sulfate. After filtration, the mixture was evaporated to dryness, leaving a red oil TLC R_f=0.37, the spot was visualised with UV followed by ninhydrin to distinguish the product from other reactant and side reactions. The oil was then purified by column chromatography CHC1₃/Hexane (1:9) on Alumina (basic). Yield 49%. Cι₃Hι₃NOSe. M_r 278.21. Exact Mass 279.02. Melting point 61.2 C. Elemental Analysis CHN. C 55.7, H 4.61, N 4.93. Calcd C 56.12, H 4.71, N 5.03. MS (El): m/z (%) 281.1 (100) 279 (40). 1H NMR (300MHz, CDC1₃) δ: 7.6 (dd, H, aromatic H, J= 1.6 Hz,), 7.34 (dd, 2H, aromatic H), 7.24 (m, H, aromatic H), 6.86 (dd, 2H, aromatic H, J= 8.7 Hz), 6.80 (dd, 2H, aromatic H, J= 14.9 Hz), 6.76-6.71 (ddd, 2H, aromatic H), 4.26 (br., 2H, NH₂), 3.75 (s, 3H, CH₃). Example 7: Synthesis of 2-(4-methoxyphenylselanyl)-3-methylnaphthalene-l,4- dione

Synthesis was followed according to the procedure as outlined by Sakakibara et al (Journal of the Chemical Society-Perkin Transactions 1 1991, 1231-1234). 7_?[4-Methoxyphenyl] diselenide (0.22 g, 1.1 mmol) and «-tributylphosphine (0.24 g, 1.2 mmol) in THF (5 mL) was sonicated under argon for 15 mins. 10% NaOH (aq) (90 μL, 2.2 mmol) was added and the solution was stirred until it became homogeneous (-15 mins) before being added dropwise to a solution of 2-bromo-3-methyl- [l,4]naphthoquinone (0.5 g, 2.0 mmol) in THF (5 mL) under argon. The solution was stirred for a further 10 mins, then poured into brine (-100 L) and the desired product was extracted into DCM (2 x 50 mL). Product was dried over MgSO₄, solvents were removed en vacuo to give a dark red oil. The oil was purified by flash chromatography (ethyl acetate:pet spirit, 25:75) to give the desired compound (0.61 g, 85 %). For the purposes of analysis the compound is purified by RPHPLC (methanol : water 15:85) and has a retention time of 14 minutes; 1H NMR (300 MHz, CDC1₃) δ 8.01 (m, 2H, ArH), 7.64 (m, 2H, quinine-ArH), 7.44 (d, 2H, Se-ArH), 6.75 (d, 2H, MeO-ArH), 3.73 (s, 3H, O-CH₃), 2.10 (s, 3H, Ar-CH_.3); m z (ESL): 464.9 (100 %, MB^Ag ;

Example 8 : Synthesis of (2,5-dihydroxyphenyl)(4-hydroxyphenyl)selane and (2,5- dihydroxyphenyl)(4-hydroxyphenyl)tellane

X=Se, Te

These compounds can be made in a procedure analogous to that used in Example 7. (2,5-dihydroxy)chlorobenzene is used as reagent (iii) and 4-(4- hydroxyphenylselanyl)phenol is used as the starting dichalcogen when X is Se or 4-(4- hydroxyphenyltellanyl)phenol is used as the starting dichalcogen when X is Te.

Example 9: Synthesis of (2,5-dihydroxy-3,4-dimethoxyphenyl)(4- hydroxyphenyl)selane and 2,5-dihydroxy-3,4-dimethoxyphenyl)(4- hydroxyphenyl)tellane

These compounds can be made in a procedure analogous to that used in

Example 7. (2,5-dihydroxy-3,4-dimethyl)chlorobenzene (prepared according to the procedure in Wilbur, D. S. Journal of Heterocyclic Chemistry 1984, 21, 801-807) is used as reagent (iii) and 4-(4-hydroxyphenylselanyl)phenol is used as the starting dichalcogen when X is Se or 4-(4-hydroxyphenyltellanyl)phenol is used as the starting dichalcogen when X is Te.

Example 10: Synthesis of 3-(4-methoxyphenyItellaryl)propan-l-amine

l,2-Bis(4-methoxyphenyl)ditellane (469mg, 1 mmol) was dissolved in absolute ethanol (40 ml) at room temperature under argon. Sodium borohydride (190 mg, 5 mmol) and sodium hydroxide (NaOH) (0.2 g, 5 mmol) were dissolved in EtOH (absolute) (10 ml) were added and the ethanolic solution via syringe. The solution became colourless and was stirred at room temperature under argon for 30 minutes. 3- Chloropropyl a ine hydrochloride (0.26 g, 2 mmol) was dissolved in absolute ethanol (15 ml), added via syringe and the solution refluxed at 70°C for 4 hrs under argon. CHC1₃ (100 ml) and aqueous NaOH (50 ml, IM, 50 mmol) were added to the solution, the phases separated and the aqueous phase extracted with CHCl₃.The organic phases were combined and dried with Na₂SO₄. The solution was concentrated under vacuum to a final volume of 10 ml and n-hexane (800 ml) was added. The solution was cooled in an ice bath and a fine white precipitate formed. The suspension was centrifuged and the liquid pipetted off. The white precipitate was washed with CHC1₃ (3 x 1 ml) and dried under vacuum to give the title compound as a fine white solid.

CioHisNOTe. M_r 292.02. Exact Mass 295.02. Yield 4.2 %. Melting Point 76.9 °C. The compound was insoluble in normal organic solvents therefore no NMR spectrum was recorded.

Example 11 : Coupling of 3-(4-methoxyphenyltellaryl)propan-l-amine to Human Serum Albumin (HSA)

Human Serium Albumin (HSA) (9 mg, 136 nmol) was dissolved in tris buffer pH = 8.6 (0.9 ml), dithothreitol (DTT) (3.5 mg, 22.6 μmol) was added and the solution heated at 40°C for 30 minutes. The reduced HSA solution was eluted through a PD 10 column (Hepes buffer). The first two HSA fractions were identified by UV abs at 280 nm, combined and eluted through another PD 10 column (Hepes buffer). Again the first two HSA fractions were identified by UV abs at 280 nm and combined. The free thiol content was determined by DNTB assay. 3-(4-Methoxyphenyltellaryl)propan-l-amine (1 mg, 3.4 μmol) was partially dissolved in dry THF (0.6 ml) and triethyl amine (40 μl, 0.3 μmol). Succinimidyl trans-4- maleimidylmethyl cyclohexand 1-carboxylate (SMCC) (2.9 mg, 8.6 μmol) was dissolved in dry THF (789 μl) to make a stock solution (11 μM). SMCC stock solution (100 μl, 1.1 μmol) was injected into the solution of 3-(4-Methoxyphenyltellaryl)propan- 1-amine in THF and left in ice for 5^lA hrs. Conjugate Fraction 1

SMCC-mimic solution (200 μl, 0.3 μmol) was injected into the reduced HSA solution (1 ml), the solution shaken and left at room temperature for 13 hrs. The HSA conjugate was eluted through a PD 10 column (Hepes buffer). The first two HSA fractions were identified by UV abs at 280 nm, combined and eluted through another PD 10 column (Hepes buffer). The first two HSA fractions were again identified by UV abs at 280 nm and combined to give the conjugate as a transparent solution (3 ml). The free thiol content was determined by DNTB assay. Conjugate Fraction 2

SMCC solution (200 μl, 0.3 μmol) was injected into reduced HSA solution (1 ml), the solution shaken and left at 4 °C for 13 hrs. The HSA conjugate was eluted through a PD 10 column (Hepes buffer). The first two HSA fractions were identified by UV abs at 280 nm, combined and eluted through another PD 10 column (Hepes buffer). The first two HSA fractions were again identified by UV abs at 280 nm and combined to give the conjugate as a transparent solution (3 ml). The free thiol content was determined by DNTB assay. Conjugate Fraction 3

SMCC solution (200 μl, 0.3 μmol) was injected into reduced HSA solution (1 ml), the solution shaken and left at -18 °C for 13 hrs. The HSA conjugate was eluted through a PD 10 column (Hepes buffer). The first two HSA fractions were identified by UV abs at 280 nm, combined and eluted through another PD 10 column (Hepes buffer). The first two HSA fractions were again identified by UV abs at 280 nm and combined to give the conjugate as a transparent solution (3 ml). The free thiol content was determined by DNTB assay.

Activity Data Example 12

The zinc form of ZFPF (Znl-ZFPF, molecular weight=3396 Da) was prepared according to an established metal-incorporation procedure (Nasak, M. (1991) Methods Enzymol. 205, 41-44). The concentration of peptide was determined by parallel measurement of thiol (specfrophotometric 2,2'-dithiodipyridine assay) and amino content (specfrophotometric ninhydrin assay). The number of zinc ions bound per ZFPF was determined by atomic absorption spectroscopy. Cyclic voltammetry was performed on a 100 B/W workstation (BAS, Chichester, UK). Voltammograms of organochalcogens (50-100 μM) were recorded as described in the literature (Giles, G.I., Tasker, K.M., Johnson, R.J.K., Jacob, C, Green,K.Ν. and Peers, C. (2001) Chem. Commun. 23, 2490-2491).

For the ZFPF stability assays, Znl-ZFPF (5 μM) and H₂O₂ (250 μM) were incubated in the presence of varying concentrations of catalyst in Tris-HCl (20 mM, pH 7.4) at 37°C for 10 min. The reaction was terminated by a 2-min incubation with catalase to remove excess H O₂. 5,5'-Dithiobis(2-nitrobenzoic acid) (DTNB) was added (100 μM final concentration) and the reaction of the remaining ZFPF thiols was monitored at 412 nm ( ε₄ι =13 600 M^"1 cm^"1) using a UN/VIS spectrophotometer.

For the cell survival assays, rat adrenal PC12 cells were cultured in RPMI 1640 suspension according to Kearns et al. (Kearns, S. and Dawson Jr., R. (2000) Adv. Exp. Med. Biol. 483,563-570), supplemented with glutamine (2 mM) and gentamicin (250 U/ml). Cells were fed three times a week and subcultured every 7 days. For experimentation, undifferentiated cells were plated at 100 000 cells (100 μl) per well and pre-incubated for 1 h with test compounds (see Table 1: 10 μM) at 37°C and 5% CO₂, in a Sanyo CO₂ incubator, followed by addition of varying concentrations of H₂O₂ (50-500 μM) and overnight incubation. A H₂O₂ dose-response curve in the absence of test compounds and a 'catalyst only' incubation at the highest catalyst concentration used were established as controls. The effect of H O (200 μM) on the standard GPx mimic ebselen (2-phenyl-l,2-benzisoselenazol-3(2H)-one, 10 WM) was also examined. Cell viability was measured using the standard MTT assay (Mossman, T. (1983) J. Immunol. Methods 65, 55-63) and a Dynex technologies MRX microplate reader. Individual treatments consisted of six wells per experiment and experiments were replicated at least four times. Table 1

Coπelation between the oxidative capacity (IC₅o) of compounds and Epa

The cyclic voltammograms were recorded at a scan rate of 200 mV/s. For the in vitro experiments, the Zni-ZnF (5 μM) was incubated with catalysts (nM range) and H₂O₂ (250 μM) in Tris-HCl (20mM, pH 7.4) at 37°C for 10 min. Catalase (1 nM), followed by DTNB (100 μM), was added to the mixture and the formation of TNB^" measured at 412 nm. Experimental eπor 10% (n =3).

Example 13

The effect of 4-(4-hydroxyphenyltellanyl)phenol and H₂O₂ on PC 12 cell survival was investigated. PC 12 cells were freated with increasing concentrations of H₂O₂ only (50-500 μM, ■). The experiment was then repeated in the presence of 4-(4- hydroxyphenyltellanyl)phenol (10 μM, o) . After an overnight incubation the %cell survival was measured using the MTT assay. The results are shown in Figure 1. Example 14

The effect of 2-methyl-3-(phenyltellanyl)naphthalene-l,4-dione on PC 12 cell survival was investigated in the absence of H₂O (■) and in the presence of H₂O₂ (200 μM, o) . The results are shown in Figure 2. Eπor bars represent the standard deviation (n=12).

Claims

1. Use of an organoselenium or organotellerium GPx mimic in the manufacture of a medicament for use as a pro-oxidant catalyst.

2. Use according to claim 1, wherein the organoselenium or organotellerium GPx mimic is a compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein: each R and R' is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cι₀ alkyl); - n and m are the same or different and each represent 0, 1, 2, 3, 4 or 5; and

X represents -A-(L-B)_P-, wherein A and B are the same or different and each represent Se or Te, p is 0 or 1 and L is a direct bond or a -C₁₂ alkylene group which is unsubstituted or substituted by a hydroxy group or a halogen atom, or L is a group -L'-Ar-L"- wherein L' and L" are the same or different and each represent a direct bond or Cι-C₆ alkylene group and Ar is a phenyl ring which is optionally fused to a pyridine ring and which is unsubstituted or substituted by 1 or 2 substituents selected from Cι-C alkyl, amino and hydroxy substituents.

3. Use according to claim 2 wherein each R and R' is same or different and represents Cι-C₆ alkyl, hydroxy, Cι-C₆ aUcoxy, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ allcyl)amino, -CO₂-(Cι-C₆ alkyl) or -NH-CO-(Cι-C₆ alkyl).

4. Use according to claim 3, wherein each R and R is the same or different and represents hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

5. Use according to claim 4 wherein each R and R' are the same or different and represents methoxy, hydroxy or amino.

6. Use according to any one of claims 2 to 4, wherein n and m are the same or different and each represent 0, 1, 2 or 3.

7. Use according to any one of claims 2 to 6, wherein A and B are the same.

8. Use according to any one of claims 2 to 7, wherein L is a direct bond or a Cι-C₆ alkylene group .

9. Use according to any one of claims 2 to 8, wherein p is 1 and L is a direct bond.

10. Use according to any one of claims 2 to 6 wherein p is 0.

11. Use according to claim 2, wherein the organoselenium or organotellerium GPx mimic is a compound of fonnula (la):

wherein: each R and R' is the same or different and represents hydrogen, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino; and X is as defined in any one of claims 2 to 10, provided that at least one R or one R' group is not hydrogen.

12. Use according to claim 2 wherein the organoselenium or organotellerium GPx mimic is a compound of formula (lb):

X' represents Se or Te; and n is an integer less than 3 provided that (a) when n is an integer greater than 1, the X' groups are optionally linked by a linker moiety L which is a (CH )_m group where m is an integer up to 4 and (b) at least one R" group on each phenyl moiety is not hydrogen.

13. Use according to claim 1, wherein the organoselenium or organotellerium GPx mimic is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein

H and J are the same or different and each represent -CR- or -N-, wherein R represents hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo aUcyl)amino, -CO₂-(Cι- Cio aUcyl) or -NH-CO-(Cι-Cι₀ alkyl); each Ri is the same or different and represents Ci-Cio aUcyl, hydroxy, thio, - Cio aUcoxy, Ci-Cio alkylthio, amino, mono(Ci-CioaUcyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl) or -NH-CO-(Cι-Cιo alkyl); q represents 0, 1 or 2; and R₂ and R₃ are the same or different and each represents hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo aUcyl)amino, -CO₂-(Cι-Cι₀ alkyl), -NH-CO-(Cι-Cιo alkyl) or a group of formula (IL):

wherein:

X is Se or Te; each _t is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Ci- Cio aUcoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cι₀ alkyl)amino, -CO₂-(Cι-Cι₀ aUcyl) or -NH-CO-(Cι-Cι₀ aUcyl); and s represents 0, 1, 2, 3, 4 or 5; provided that at least one of R₂ and R₃ is a group of formula (IT).

14. Use according to claim 13, wherein H and J are the same or different and represent -CH- or -N-.

15. Use according to claim 14, wherein H and J are the same and are -CH-.

16. Use according to claim 14, wherein one of H and J is N, the other being -CH-.

17. Use according to any one of claims 13 to 16, wherein q is 0.

18. Use according to any one of claims 13 to 17, wherein R₂ and R₃ are the same or different and each represent Cι-C₆ aUcyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Cι-C₆ alkyl), -NH-CO-(Cι-C₆ aUcyl) or a group of formula (II').

19. Use according to any one of claims 13 to 17, wherein R₂ represents Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ alkyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Cι-C₆ alkyl) or-NH-CO-(Cι-C₆ alkyl).

20. Use according to any one of claims 13 to 17 or 19 wherein R₃ is a group of formula (IT).

21. Use according to any one of claims 13 to 20, wherein each is the same or different and represents hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ aUcyl)amino or di(Cι-C₆ alkyl)amino.

22. Use according to any one of claims 13 to 21, wherein s is 1.

23. Use according to any one of claims claim 13 to 22, wherein the R-_t group is present at the 4 position of the phenyl ring.

24. Use according to any one of claims 13 or claim 23, wherein s is 0.

25. Use according to claim 13 wherein the organoselenium or organotellerium GPx mimic is a compound of formula (Ila):

26. Use, in the manufacture of a medicament for use as a pro-oxidant, of a conjugate in which a compound of formula (L), (la), (lb), (II) or (Ila), as defined in any one of claims 2 to 25, or a compound of formula (Ic), is linked to a moiety Z, wherein Z is a carrier or targeting moiety

wherein :

X' is Se or Te; - R and n are as defined in any one of claims 2 to 10; and

— * is the point of attachment to the rest of the conjugate,

27. Use according to claim 26, wherein the linker which joins the compound of formula (I), (la), (lb), (II), (Ila) or (Ic) to Z is a covalent bond, a carbon chain, a polynucleotide or polypeptide.

28. Use according to claim 26 or 27, wherein the compound of formula (Ic) is a compound of fonnula (Ic'):

X' is Se or Te; and

— * is the point of attachment to the rest of the conjugate, provided that at least one R" on the phenyl moiety is not hydrogen.

29. Use according to any one of claims 26 to 28 wherein the linker attaching the compound of formula (I), (la), (lb), (II), (Ila) or (Ic') to the moiety Z is a -(CH₂)m- group where m is an integer up to 4.

30. Use according to claim 26 or claim 27, wherein the conjugate comprises a compound of formula (I), (la) or (lb) linked to the moiety Z via the 4-position of either of the two phenyl moieties .

31. Use according to claim 26 or 27, wherein the conjugate comprises a compound of formula (II) or (Ila) linked to the moiety Z via the non-fused phenyl moiety.

32. Use according to claim 31, wherein the compound of formula (II) or (Ila) is linked to the moiety Z at the 4-position of the phenyl moiety.

33. Use according to any one of the previous claims, wherein the medicament is for use in the treatment of cancer.

34. Use according to claim 33, wherein the cancer is kidney cancer, prostate cancer, skin cancer, lung carcinoma, colon cancer or breast cancer.

35. A method of treating a human or animal patient in need of a pro-oxidant, which method comprises the administration thereto of an effective amount of an organosellenium or organotellerium GPx mimic.

36. A method according to claim 35, wherein the organoselenium or organotellerium GPx mimic is a compound as defined according to any one of claims 2 to 25 or a conjugate as defined according to any one of claims 26 to 32.

37. A method according to claim 35 or 36, wherein the patient is suffering from cancer.

38. A method according to claim 37, wherein the cancer is kidney cancer, prostate cancer, skin cancer, lung carcinoma, colon cancer or breast cancer.

39. A compound of formula (A) or a pharmaceutically acceptable salt thereof:

wherein: - A and A' are the same or different and represent Se or Te; r and t are the same or different and each represent 0, 1, 2, 3, 4, or 5; each R and R is the same or different and represents Ci-Cio aUcyl, hydroxy, thio, Ci-C ιo aUcoxy, Ci-Cio aUcylthio, amino, mono(Cι-Cιo aUcyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl) or -NH-CO-(Cι-Cι₀ alkyl); - L is a C₁-C₁₂ alkylene group which is unsubstituted or substituted by a hydroxy group or a halogen atom, or L is a group -L'-Ar-L"- wherein L' and L" are the same or different and each represent a direct bond or Cι-C₆ alkylene group and Ar is a phenyl ring which is optionally fused to a pyridine ring and which is unsubstituted or substituted by 1 or 2 substituents selected from Cι-C₄ aUcyl, amino and hydroxy substituents, provided that when r and t are 1 and R is OMe, L is not n-propylene.

40. A compound according to claim 39, wherein each R and R are as defined in any one of claims 2 to 5.

41. A compound according to claim 39 or 40, wherein A and A' are the same.

42. A compound according to claim 41, wherein A and A' are Te.

43. A compound according to any one of claims 39 to 42, wherein t and r are the same or different and represent 1, 2 or 3.

44. A compound of formula (A')

wherein:

A, A' and L are as defined in any one of claims 39, 41 or 42; and each R and R' is the same or different and represents hydrogen, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino; provided that at least one R or one R' group is not hydrogen.

45. A compound of formula (B) or a pharmaceutically acceptable salt thereof:

wherein: each R and R' is the same or different and represents Ci- o aUcyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo allcyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(C₂-Cι₀ al yl); k and 1 may be the same or different and are selected from 0, 1, 2, 3 or 4; R_t is selected from hydrogen, Ci-Cio aUcyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio aUcylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo aUcyl)amino, -CO₂-(Cι- Cio alkyl) or -NH-CO-(Cι-Cιo alkyl), - R_t' is selected from Ci-Cio aUcyl, hydroxy, thio, Ci-Cio aUcoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo aUcyl)amino, di(Cι-Cιo aUcyl)amino, -CO₂-(Cι-Cιo aUcyl) or -NH-CO-(Cι-Cιo alkyl), provided that when k and 1 are 0, either _t and R_t' are different or R and R₄' are the same and are C₂-Cιo alkyl, hydroxy, thio, C₂-Cιo alkoxy, C1-C10 aUcylthio, mono(Cι-Cιo aUcyl)amino, di(C₂-Cι₀ alkyl)amino, -CO₂-(Cι-Cιo aUcyl) or -NH-CO-(C₂-Cιo alkyl).

46. A compound according to claim 45, wherein R and R' are as defined in any one of claims 2 to 5.

47. A compound according to claim 45 or 46, wherein lc and 1, which are the same or different are 0, 1 or 2.

48. A compound according to any one of claims 45 to 47, wherein R-, is selected from hydrogen, Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ allcyl)amino or di(Cι-C₆ aUcyl)amino.

49. A compound according to any one of claims 45 to 48 wherein _t' is selected from Cι-C₆ alkyl, hydroxy, Cι-C₆ aUcoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι~ C₆ aUcyl)amino.

50. A compound according to claim 47 which is 4-(4-hydroxyphenylselanyl)phenol or 2-amino,4 ' -methoxy-diphenylselenide.

51. A compound according to formula (C) or a pharmaceutically acceptable salt thereof:

wherein: each R and R' is the same or different and represents Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo aUcyl) or -NH-CO-(Ct-Cι₀ alkyl); s and t are the same or different and are selected from 0, 1, 2, 3 or 4; _t is selected from hydrogen, Ci-Cio alkyl, hydroxy, thio, Ci-Cio alkoxy, Cj-Cio aUcylthio, amino, mono(Cι-Cιo aUcyl)amino, di(Cι-Cι₀ aUcyl)amino, -CO₂-(Cι- Cio alkyl) or -NH-CO-(Cι-Cι₀ alkyl), R^ is selected from Ci-Cio alkyl, hydroxy, thio, Ci-Cio aUcoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl) or

-NH-CO-(Cι-C₁₀ alkyl), provided that (a) when R_t and _t' are different, s and/or t is other than 0 and (b) when R₄ and R ' are the same, s and/or t is other than 0 and R is not methyl.

52. A compound according to claim 51, wherein each R and R' are as defined in any one of claims 2 to 5.

53. A compound according to claim 51 or 52, wherein s and t are the same or different and are 0 or 1.

54. A compound according to any one of claims 51 to 53 wherein _t is selected from Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ allcyl)amino or di(Cι-C₆ alkyl)amino.

55. A compound according to any one of claims 51 to 54 wherein R-» is selected from Cι-C₆ aUcyl, hydroxy, Cι~C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

56. A compound according to claim 51, which is 4-(4- methoxyphenyltellanyl)benzenamine,

57. A compound of formula (D) or a pharmaceutically acceptable salt thereof:

wherein: - each R is the same or different and represents C₁-C₁₀ alkyl, hydroxy, thio, Ci-

C₁₀ alkoxy, C1-C10 alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo aUcyl)amino, -CO₂-(Cι-Cι₀ aUcyl) or -NH-CO-(Cι-Cι₀ aUcyl); and t is 1, 2, 3, 4 or 5.

58. A compound according to claim 57, wherein R' is as defined in any one of claims 2 to 5.

59. A compound according to claim 59, wherein t is 1 or 2.

60. Compound according to claim 59, which is (2,5- dimethoxyphenyl) (phenyl)tellane.

61. A compound of fonnula (E) or a pharmaceutically acceptable salt thereof:

wherein : - H and J are the same or different and each represent -CR- or -N-, wherein R represents hydrogen, Ci-Cio aUcyl, hydroxy, thio, Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo aUcyl)amino, -CO₂-(Cι-

Cio aUcyl) or -NH-CO-(Cι-Cιo alkyl); each Ri is the same or different and represents Ci-Cio aUcyl, hydroxy, thio, Ci- Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo aUcyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ aUcyl) or -NH-CO-(Cι-Cιo alkyl); q represents 0, 1 or 2; and

R₂ and R₃ are the same or different and each represents hydrogen, C₁-C₁₀ alkyl, hydroxy, thio, C₁-C₁₀ aUcoxy, C₁-C₁₀ aUcylthio, amino, mono(Cι-Cιo aUcyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cιo alkyl), -NH-CO-(Cι-Cιo alkyl) or a group of formula (E^?):

wherein: - X is Te each R₄ is the same or different and each represent C1-C₁0 alkyl, hydroxy, thio, C1-C10 alkoxy, C1-C10 alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cι₀ aUcyl); and s represents 0, 1, 2, 3, 4 or 5; provided that at least one of Ri and R₂ is a group of formula (E').

62. A compound according to claim 61, wherein H and J and/or q are as defined in any one of claims 14 to 17.

63. A compound according to claim 61 or 62, wherein R₂ and R₃ are the same or different and each represents Cι-C₆ alkyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ aUcylthio, amino, mono(Cι-C₆ aUcyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Ci-C₆ aUcyl), -NH-CO- (Cι-C₆ alkyl) or a group of formula (E').

64. A compound according to any one of claims 61 to 63, wherein ₂ represents - C₆ aUcyl, hydroxy, Cι-C₆ aUcoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ aUcyl)amino, di(Cι-C₆ alkyl)amino, -CO₂-(Cι-C₆ alkyl) or-NH-CO-(d-C₆ alkyl).

65. A compound according to any one of claims 61, 62 or 64 wherein R₃ is a group of formula (E').

66. A compound according to claim 65, wherein s is 0, 1, 2 or 3.

67. A compound according to claim 65 or 66, wherein s is 1.

68. A compound according to any one of claims 65 to 67, wherein _t represents hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ aUcyl)amino or di(Cι-C₆ alkyl)amino.

69. A compound according to claim 69, wherein the _t group is present at the 4 position of the phenyl ring.

70. A compound according to claim 65 or claim 66, wherein s is 0.

71. A compound according to claim 61, wherein q is 0, H and J are both -CH-, R₂ is Me and R₃ is a group of formula (E') wherein X is Te, s is 1 and the R_t group is either hydrogen or methoxy and is present at the 4 position of the phenyl ring.

72. A compound according to formula (F) or a pharmaceutically acceptable salt thereof:

wherein: - Ri, q, H and J are as defined according to claim 61 or 62;

R₂> is hydrogen, C₁-C₁₀ alkyl, hydroxy, thio, C₁-C₁₀ alkoxy, C₁-C₁₀ aUcylthio, amino, mono(Cι-Cιoalkyl)amino, di(Cι-Cιoalkyl)amino, -CO₂-(Cι-Cιo aUcyl),

NH-CO-(Cι-Cιo alkyl); each t is the same or different and represents C₁-C₁₀ alkyl, hydroxy, thio, Ci- C10 alkoxy, C1-C10 alkylthio, amino, mono(Cι-Cιo aUcyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(Cι-Cι₀ alkyl) or -NH-CO-(Cι-Cι₀ alkyl); and v is 1, 2, 3, 4 or 5.

73. A compound according to claim 72 wherein R - is Cι-C₆ alkyl, hydroxy, Q- C₆ aUcoxy, Cι-C₆ alkylthio, amino, mono(Cι-C₆ aUcyl)amino, di(Cι-C₆ aUcyl)amino, -CO₂-(Cι-C₆ alkyl) or -NH-CO-(Cι- C₆ aUcyl).

74. A compound according to claims 72 or 73, wherein ₄ represents hydroxy, Cι-C₆ alkoxy, amino, mono(Cι-C₆ alkyl)amino or di(Cι-C₆ alkyl)amino.

75. A compound according to any one of claims 72 to 74, wherein v is 1.

76. A compound according to claim 75, wherein the R₄ group is present at the 4 position of the phenyl ring.

77. A compound according to claim 77 wherein q is 0, H and J are both -CH-, Rr is methyl, v is 1, t is methoxy and is present at the 4 position of the phenyl ring.

78. A compound of formula (G) or a phannaceutically acceptable salt thereof

wherein: each R and R' is the same or different and represents Ci-Cio aUcyl, hydroxy, thio,

Ci-Cio alkoxy, Ci-Cio alkylthio, amino, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO₂-(C₁-Cι₀ alkyl) or -NH-CO-(Cι-Cι₀ alkyl); and a and b are the same or different and each represent 0, 1, 2, 3, 4 or 5; provided that the compound is not 1,2-diphenyldiselane, l,2-bis(4- methoxyphenyl)diselane, 1 ,2-di-/ tolyldiselane, 4-(2-(4- aminophenyl)diselanyl)benzenamine, 1,2-dimesityldiselane or l-(4-methoxyphenyl)-2- phenyldiselane.

79. A compound according to claim 78, wherein each R and R is the same or different and represents C2-C1₀ alkyl, hydroxy, thio, C2-C10 alkoxy, C1-C10 alkylthio, mono(Cι-Cιo alkyl)amino, di(Cι-Cιo alkyl)amino, -CO2-(Ci-Cio alkyl) or - NH-CO-(Cι-Cιo alkyl).

80. A compound according to claim 79 wherein each R and R' is the same or different and represents C₂-C₆ alkyl, hydroxy, C₂-C₆ alkoxy, mono(Cι-C₆ aUcyl)amino or di(Cι-C₆ aUcyl)amino.

81. A compound according to any one of claims 78 to 80, wherein a and b are the same or different and represent 0, 1, 2 or 3.

82. A compound of formula (H) or a phannaceutically acceptable salt thereof

wherein: - R, R', a and b are as defined according to any one of claims 78 to 81 provided that the compound is not l,2-bis(4-methoxyphenyl)ditellane, l,2-bis(4- hydroxyphenyι)ditellane, l,2-di-/ tolylditellane, 4-(2-(4- aminophenyl)ditellanyl)benzenamine, 1,2- bis(4-ethoxyphenyl)ditellane, 1,2-di-o- tolylditellane, l,2-bis(2-methoxyphenyl)ditellane, 2-(2-(2- aminophenylditellanyl)benzenamine, 2-(2-(2-(dimethylamino)phenyl)ditellanyl)-N,N- dimethylbenzenamine, 1,2-dimesitylditellane, or 1,2-di-rn-tolylditellane.

83. A compound according to claim 82, wherein each R and R' is the same or different and represents C₂-C₆ alkyl, C₃-C₆ alkoxy, mono(Cι-C₆ alkyl)amino, di(Cι- C₆ aUcyl)amino, -CO₂-(Cι-C₆ aUcyl) or -NH-CO-(Cι-C₆ alkyl).

84. A pharmaceutical composition comprising a compound of formula (A), (A'), (B), (C), (D), (E), (F) or (G) as defined in accordance with any one of claims 39 to 83 or a compound of formula (II) as defined according to any one of claims 13 to 25, or a pharmaceutically acceptable salt thereof, and a phannaceutically acceptable diluent or carrier.

85. A compound of formula (A), (A'), (B), (C), (D), (E), (F) or (G) as defined in accordance with any one of claims 39 to 83 or a compound of formula (II) as defined according to any one of claims 13 to 25, or a phannaceutically acceptable salt thereof, for use in the treatment of the human or animal body.

86. Use of a compound of formula (A), (A'), (B), (C), (D), (E), (F) or (G) as defined in accordance with any one of claims 39 to 83 or a compound of formula (II) as defined according to any one of claims 13 to 25, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as an anti-oxidant or pro-oxidant.

87. Use according to claim 86 wherein the medicament is for use in the treatment or prevention of neurodegenerative disease, inflammation, microbial infection, rheumatoid arthritis, Auto-Immune Deficiency Syndrome, intestinal disorders, lung disorders, overtrained athlete's syndrome, trauma, heart disease and cancer.

88. Use according to claim 87 wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis or Creuzfeld- Jacob disease.

89. A method of treating a human or animal patient in need of a pro-oxidant or anti- oxidant, which method comprises the administration thereto of an effective amount of a compound of general formula (A), (A'), (B), (C), (D), (E), (F) or (G) as defined in accordance with any one of claims 39 to 83 or a compound of fonnula (II) as defined according to any one of claims 13 to 25, or a pharmaceutically acceptable salt thereof.

90. A method according to claim 89, wherein the patient is suffering from neurodegenerative disease, inflammation, microbial infection, rheumatoid arthritis, Auto-Lmmuiie Deficiency Syndrome, intestinal disorders, lung disorders, over-trained athlete's syndrome, trauma, heart disease or cancer.

91. A method according to claim 90, wherein the neurodegenerative disease is

Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis or Creuzfeld- Jacob disease.