WO2009144253A1 - Compounds comprising a 3-pyridinol or 5-pyrimidinol ring having an organoseleno or organotelluro substituent for use as antioxidants - Google Patents

Abstract

Compounds comprising a 3-pyridinol or 5-pyrimidinol ring carrying an organoseleno- or organotelluro- substituent on the pyridine or pyrimidine ring, exhibit useful antioxidant properties. The compounds may for example be in accordance with the following formula (I) as defined herein. Catalytic chain-breaking and hydroperoxide decomposing antioxidant properties are also disclosed. Furthermore the compounds may be used in combination with a reducing agent. The compounds are useful for the stabilization of man-made and natural materials, or for the prevention or treatment of disorders caused by or involving free radical-mediated or oxidative tissue damage.

Description

COMPOUNDS COMPRISING A 3-PYRIDINOL OR 5-PYRIMIDINOL RING HAVING AN ORGANOSELENO OR ORGANOTELLURO SUBSTITUENT FOR USE AS ANTIOXIDANTS

The present invention relates to compounds and their medical and non-medical uses as antioxidants. In particular the present invention relates to derivatives of 3-pyridinol and 5-pyrimidinol.

Antioxidants prevent or inhibit the oxidation of substances. Oxidation can result in damage to or degradation of biological systems as welt as man-made materials. Antioxidants can work via various mechanisms. Chain-breaking antioxidants intercept the radical cycle whereby organic material is oxidised. Antioxidants which reduce peroxyl radicals and decompose hydroperoxides are particularly useful in addressing the harmful effects that can be caused by such substances. There are a wide variety of applications including the treatment, prevention or amelioration of conditions or disorders caused by or involving free radical - mediated or oxidative tissue damage, or the stabilization or treatment of man-made or natural materials.

Over the years much research has been carried out to try to find antioxidants "which are suitable for various uses. For example, many known natural and man-made antioxidant systems are based on the phenol group (shown below). Alpha-tocopherol (shown below), a component of vitamin E, contains a phenol moiety fused to a further ring, and several structurally similar compounds have been targets for synthesis and testing as antioxidants.

Phenol A 1 ph a-tocopherol

All organic materials exposed to air undergo oxidative degradation. Reducing the rate of such processes by utilizing low concentrations of "antioxidants" is of paramount importance for aerobic organisms as well as for producers of most kinds of commercial products. In medicine the term "oxidative stress" has been introduced to describe a situation characterized by an elevation in the cellular steady-state concentration of reactive oxygen-derived species. This condition occurs if the balance between oxidants and various antioxidant defences is impaired. The recent interest in pharmaceutical antioxidants and "antioxidant pharmacotherapy" has emerged as a remedy for pathological conditions characterized by oxidative stress (chronic inflammatory disorders, atherosclerosis, cataract etc.). Food teclinolo gists use antioxidants to inhibit lipid peroxidation and, thus, rancidity in food materials. Polymer chemists use antioxidants to control polymerisation in the manufacture of rubber, plastics and paint and for the stabilization of polymeric materials during processing and use. The oil industry makes extensive use of antioxidants in the design of better automobile fuels and lubricating oils. Provided toxicity and environmental problems associated with increasing antioxidant use can be coped with, disease prevention/extending the lifetime of various materials is obviously of significant benefit to man and society.

Without wishing to be bound by theory, mechanistically, the chemical processes responsible for oxidative damage to biological material and the deterioration of the mechanical properties of a polymer during processing and use are very similar (Scheme 1, adopted from: Scott, G. in Free Radicals: Chemistry, Pathology and Medicine; Rice-Evans. C; Dormandy, T. Eds; Richelieu Press: London, 1988, p 103.). The catalytic cycle in the upper right of the scheme is a free radical chain process known as autoxidation. If not intercepted, this will in short time convert organic material (RH) to the corresponding alkylhydroperoxide (ROOH). Chain-breaking accepting antioxidants (CB-Λ) trap carbon centered radicals in competition with dioxygen. Chain-breaking donating antioxidants (CB-D) donate hydrogen atoms to peroxyl radicals before they can propagate the peroxidation reaction. The cycle to the left in Scheme 1 shows different ways of initiation of the autoxidation process. Preventive antioxidants keep initiation of new chains to a minimum by either destroying hydroperoxides (PD=peroxide decomposer) by absorbing ultraviolet light (UVΛ=UV-absorbers) or by complexing transition metals which would otherwise give rise to radicals via Fenton-like chemistry of hydroperoxides (MD- melal deactivator).

Scheme 1 Antioxidant mechanisms

heat, light, metal ions

In vivo, peroxide decomposition is brought about by enzymatic systems: Catalasc containing ferric haeme groups catalyze decomposition of hydrogen peroxide into oxygen and water. A family of closely related selenium-containing glutathione peroxidases (GPxs) catalyzes the reduction of hydrogen peroxide and organic hydroperoxides into water and alcohols, respectively. The stoichiometric reducing agent in these processes is the tripeptide glutathione, GSH (γ-glutamyl cysteinyl glycine) which is oxidized to the corresponding disulfide, GSSG (eqn 1).

ROOH/HOOH + 2 GSH — S ROH/H₂O + GSSG + H₂O (eqn 1)

Vitamin E is the most important lipophilic., chain-breaking antioxidant in vivo. Tts antioxidant activity stems from the ability to transfer the phenolic hydrogen to peroxyl radicals at a rate much faster than the chain-propagating H-atom transfer step of autoxidation (Scheme 1). Thus, it serves to protect DNA, proteins, lipids, carbohydrates and other important biomolecules from becoming oxidatively damaged by radical processes involving reactive oxygen and nitrogen species. α-Tocopherol (α-T0II), of formula:

is the most reactive component of Vitamin E₅ and is known to trap two peroxyl radicals before it is converted into non-radical products. It would therefore seem wise for Nature to provide a system for its regeneration and catalytic mode of action, especially within biological membranes where it is the only protective agent. Although it has been hard to establish conclusively that this regeneration process occurs in vivo, it is generally accepted that ascorbate as a coantioxtdant (CoAH) could

donate a hydrogen atom to the α-tocopheroxyl radical, α-TO , which results from the

interaction of α-TOII with peroxyl radicals (eqns 2-3).

ROO* + α-TOH *^■ ROOH + α-TO* (eqn 2) α-TO" + CoAH ^ α-TOH + CoA* (^©Qn 3) α-Tocopherol has also been shown to catalyze the reduction of peroxyl radicals (eqn 4)

ROO- + CoAH ^α"TQIj ROOH + CoA* (eqn 4) in the presence of lipid soluble coantioxidants such as ubiquinols, (z-tocopheryl hydroquinone, tlavonoids, phenothiazin.es, chatechols and phenols with sufficiently low O-H bond dissociation energies.

US 6,835,216 (Vanderbilt University) relates to antioxidants and discloses various 5- pyrimidinol and 3-pyridinol compounds. It theorises on the antioxidant activity of compounds in relation to natural vitamins including alpha-tocopherol, and discloses compounds which have a nitrogen- or oxygen- containing ring fused onto the pyrimidinc or pyridine ring. Various substitucnts arc disclosed, but the only heteroatoms which are attached to the pyrimidine or pyridine rings in this document are nitrogen or oxygen atoms.

Surprisingly, the present inventor has now found a group of antioxidants which are structurally different to compounds which have previously been shown to be antioxidants. Compounds of the present invention have non-medical and medical applications.

In a first aspect the present invention provides the use of a 3-pyridinol or 5- pyrimidinol compound carrying an organoseleno- or organotelluro- substitucnt on the pyridine or pyrimidine ring, as an antioxidant.

Thus the present invention relates to compounds which have the following cores:

wherein X is Te or Se, wherein R' is an organic moiety, and wherein there may be further substitucnts on the rings. The compound may also be in a salt form.

These compounds are significantly different to those which have previously been shown to have antioxidant properties. In particular, they are based on the heteroaromatic compounds pyridine and pyrimidine, have hydroxyl groups in particular positions, and contain selenium or tellurium which on one side is bonded to the heteroaromatic ring and on ihe other side to an organic group.

Having analyzed numerous compounds, the present inventors have discovered that compounds based on a 3-pyridinol or 5-pyiimidinol core carrying an organoseleno- or organotelluro- substituent on the pyridine or pyrimidine ring, are particularly effective antioxidants.

Optionally the compounds may be as defined in the following formula I:

wherein

X is selected from Te and Se;

Ri is selected from

- alkyl, optionally substituted with, OH, alkoxy, SH, NH₂, JV-alkylamino, N₁N- dialkylamino, COOH, aryl, optionally substituted with C₁-Cs alkyl, OH, alkoxy, SH, NH₂. JV-alkylamino, JV,JV-dialkylamino_; COOH_? CHO₅ NO₂, F, Cl, Br, I groups, and lieteroaryl which is optionally substituted with Ci-C₅ alkyl, OH, alkoxy, SH, NH₂, JV- alkylamino, JV.JV-dialkylamino, COOH, CHO, NO₂, F, Cl, Br. and I groups;

- aryl which is optionally substituted with C1-C₅ alkyl. OH, alkoxy, SH, NH₂, JV- alkylamino, jyJV-dialkylamino, COOH, CHO, NO₂, F, Cl, Br, and I groups; and

- heteroaryl, optionally substituted with C₁-Cs alkyl, OH, alkoxy, SH, NH₂, JV- alkylamino, ΛζJV-dialkylamino, COOII, CIIO, NO₂, F, Cl, Br, and I groups;

R₂, R3, and R4 arc the same or different and are each selected from

- hydrogen;

- alkyl, optionally substituted with, OH, alkoxy, SH, NH2, JV-alkylamino, JV₁JV- dialkylamino, COOH, ϊiryl which is optionally substituted with C1-C₅ alkyl, OH, alkoxy, SH, NII₂, JV-alkylamino, iV,JV-dialkylamino, COOH, CHO, NO₂, F, Cl, Br, I groups, and heteroaryl which is optionally substituted with C₁-Cs alkyl, OH, alkoxy, SH, NH₂, JV-alkylamino, N₁ JV-di alkyl amino, COOH, CHO, NO₂, F, Cl, Br, and I groups;

- alkoxy, JV-alkylamino, JV, JV-dialkylamino, alkylthio, wherein the alkyl groups are branched or unbranched and contain 1-5 carbon atoms, NH₂, OH, SH;

- aryl, optionally substituted with C1-C5 alkyl, OH, alkoxy, SH, NH₂, JV-alkylamino, 7V,JV-dialkylamino, COOH, CHO, NO₂. F, Cl, Br, and I groups;

- heteroaryl, optionally substituted with C₁-C₅ alkyl, OH, alkoxy, SH, NH₂, JV- alkylamino, jyJV-dialkylamino, COOII. CIIO, NO₂, F, Cl, Br, and I groups; wherein in any OfR₁, R₂, R₃ and R₄, unless otherwise specified, any alkyl moiety is a branched or unbranched C₁-C₃₀ alkyl, any aryl moiety is a C^-C_1O aryl, and any heteroaryl moiety is 5-6 membered and contains one or several heteroatoms selected

The compound according to formula I may be represented by any one of the following formulas II-VI:

IV V Vl

wherein

X, R₁, R₂, R3 and R4 are as defined herein above.

In one embodiment, X is Te.

In one embodiment, Ri is selected from branched or uiibranched alkyl and aryl.

In one embodiment, R₂, R₃ and R₄ are independently selected from H, alkyl, alkoxy, TV.N-dialkylamino and JV-alkylamino.

In one embodiment, the compound is according to formula TT, III or IV; in another embodiment the compound is according to formula V or VI. Tn one embodiment, in a compound as defined herein above, the group R₁X is in an ortho position in relation to the hydroxy group on the nitrogen-containing heteroaromatic ring.

In one embodiment, the compound is according to formula II as defined herein above, wherein R₂ and R₄ are hydrogen or alkyl and R₃ is an electron donating group such as JV,JV-dϊalkylamino, iV-alkylamino, alkoxy or alkyl.

In another embodiment, the compound is according to formula III as defined herein above, wherein one of R₂ and R3 is an electron donating group such as N₁N- dialkylamino, JV-aikylamino, alkoxy or alkyl and tlie other one is hydrogen or alkyl and R₄ is hydrogen or alkyl.

In still another embodiment, the compound is according to formula IV as defined herein above, wherein R₂ and R₄ are hydrogen or alkyl and R₃ is an electron donating group such as JV.iV-dialkylamino, JV-alkylamino, alkoxy or alkyl.

Tn still another embodiment, the compound is according to formula V as defined herein above, wherein R₂ is hydrogen or alkyl and R₃ is an electron donating group such as λ^JV-dialkylamino, jV-alkylamino, alkoxy or alkyl.

Finally, in one embodiment, the compound is according to formula VT as defined herein above, wherein one of R₂ and R₃ is an electron donating group such as N_rN- dialkyϊamino, iV-alkylamino, alkoxy or alkyl and the other one is hydrogen or alkyl.

The compounds of the present invention may be prepared by methods known to the person of ordinary skill within the field of synthetic organic chemistry. As an example, a compound of the invention according to formula 1 having a hydroxy group in position n and an R₁X group in position m on the nitrogen containing heteroaromatic cycle (pyridinol or pyrimidinol) may be prepared by a process comprising: - substituting a halogen for the hydroxy function of a pyridinol or pyrimidinol having said hydroxy function in the position corresponding to position m in the inventive compound ("in m position") and having a cyano moiety in the position corresponding to position n in the inventive compound ("in n position");

- transforming the cyano function to a carboxamidc function;

- transforming the carboxarrnde function to a primary amine function;

- transforming the primary amine function to a diazonium function;

- transforming the diazonium function to a hydroxy function;

- substituting lithium for the halogen in m position;

- reacting the lithiatcd species with elemental tellurium or selenium so as to provide a lithium tellurolate or selenolatc species; and

- reacting the tellurolate or selenolate with a compound capable of transferring an Ri moiety to the tellurium or selenium.

In general, it is preferred that R₁, i.e. the substituenL on Te or Se, is not aryl. Non-aryl substituents, for example alkyl substituents., arc preferred for R₁. In general, preferred alkyl lengths for R, are Ci-C₃₀ alkyl, C₁-C₁^ alkyl, C₁-C₁₆ alkyl, C_rC₈ alkyl, or C₂-C₆ alkyl. The alkyl may be straight-chain or branched. The alkyl may be saturated or unsaturated. For example, there may be no double bond present, or one, or more than one.

Whilst X may be Te or Se_? in general it is preferred that X is Te rather than Se.

In general it is preferred that XRi is ortho or para to the hydroxy group, and it is particularly preferred that XRj is bonded to a carbon atom which is both ortho to the hydroxy group and adjacent to a nitrogen atom of the heteroaromatic ring.

Furthermore_? in general it is preferred to have electron-donating substituents on the heteroaromatic ring, particularly in at least one of the ortho positions and/or in the para position. Suitable electron-donating groups are for example as defined above. For example, suitable electron-donating groups include alkyl (preferably Ci-Q alkyl, e.g. methyl), alkoxy (preferably C_\-C$ alkoxy, e.g. methoxy), dialkylamino (preferably where each alkyl is independently selected from Ci-C<; alkyl, e.g. methyl) or monoalkylamino (preferably where the alkyl is independently selected from Ci-Ce alkyl, e.g. methyl). Because there are potentially up to three "electron-donating" positions (depending on whether one of them is occupied by the XRi group), there may be zero, one, two or three electron-donating substitucnts on the heteroaromatic ring. Preferably the XRi group is ortho or para to the hydroxy group and there are one or two electron-donating substituents in the remaining ortho/para positions, preferably two. More preferably the XR] group is on a carbon atom which is both ortho to the hydroxy group and adjacent to a nitrogen of the heteroaromatic ring, and there is an electron-donating substituent in the other ortho position and/or in the para position relative to the hydroxy group.

Without wishing to be bound by theory, such groups in the ortho- and/or para- positions seem advantageous because they weaken the O-H bond and thus increase the rate of hydrogen atom transfer.

One particularly preferred group ofcompounds is as defined in formula VII:

VII wherein the moieties are as defined above for formula I.

A further preferred group ofcompounds are those of formula VIT wherein R₁ is C₁- C₃₀ alkyl, e.g. CpC₁₆ alkyl, C]-C₁₀ alkyl or C₂-Cs alkyl.

A further preferred group ofcompounds are those of formula VII wherein Ri is Ci- C30 alkyl, e.g. Ci-C₁S alkyl, C₁-CiO alkyl or C₂-Cg alkyl, and wherein z is CH or C- (C₁-C₆ alkyl), or C-(C₁-C₆ alkoxy). A further preferred group of compounds are those of formula VlT wherein R₁ is C₁- C₃₀ alkyl, e.g. Ci-C₁₆ alkyl, C₁-C10 alkyl or C₂-C₈ alkyl, wherein z is CH or CpC₆ , alkyl, preferably CH, and wherein R₂ and R₃ are the same or different and are selected from hydrogen, C₁-C_G alkyt, C₁-C₆ alkoxy, di-(Ci-Ce alkyl)-amino, or mono-(Ci-C₆ alkyl) amino; for example one of R₂ and R₃ may be hydrogen and the other may be other than hydrogen.

A further preferred group of compounds arc those of formula VII or any of the further preferred sub-groups of formula VII, wherein X is Tc. Alternatively X may be Se.

For example, the compound may be one of formula VII or any of the preferred subgroups of formula VIT, wherein R₂ is Me or II, R₃ is Me or H, z is CH or C-OMe, and Ri is C1-C1₆ alkyl for example ethyl or octyl, and optionally wherein X is Te.

Salt forms of the compounds of the compounds defined herein may also be used.

Optionally the compounds of the present invention may be as described herein, excluding 2-(mcthylseleno)-ρyridin-3-ol:

This compound was disclosed in Wakayama Kogyo Koto Senmon Gakko Kenkyu Kiyo 1989, 24, 52-56, K. Tokami, A. Mizumo and K. Tagaki, "Carbon-13 nuclear magnetic resonance spectroscopy of organic selenide and diselenide compounds". However, this document relates merely to a study of NMR spectra of compounds rather than any uses or combinations thereof.

Optionally the compounds of the present invention may be as described herein, excluding 2-(phenylseleno)-6-methyi-pyridin-3-ol and 2-(phenyltelluro)-6-methyl- pyridin-3-ol:

These compounds were amongst those disclosed in J Org. Chem. 2006, 71, 5400- 5403, S. Kumar and Lars Engman, "Microwave-assisted copper-catalyzed preparation of diaryl chalcogenides". However this document relates merely to a method of preparation and does not disclose antioxidant uses or combinations with other materials.

The 3-pyridinol or 5-pyrimidinol compound according to the present invention may optionally be used as a catalytic antioxidant. For example, it may be used under conditions which allow its regeneration, either because the system in which it is used inherently regenerates the compound and cycles the catalyst, or because an additional component is used to regenerate the catalyst.

Thus, the 3-pyridinol or 5-pyrimidinol compound according to the present invention may also be combined with, or used in combination with, a reducing agent. The reducing agent may for example be a mild reducing agent. For example, suitable reducing agents include those which are suitable for regenerating the catalyst without causing undesirable side-effects. One suitable class of suitable reducing agents is the class of thiols. Specific examples include N-acetylcystcinc, cysteine, dithiothreitol, glutathione, ascorbic acid and sodium ascorbate. Further examples arc given below.

Catalytic use is economically and environmentally advantageous and minimizes the preparation and use of potentially hazardous materials. It allows the use of reducing agents which are low-cost, readily available and safe.

The compounds of the present invention can be used in a stoichiometric sense, but in that case they only have a finite effect, and for example can only destroy a limited number of peroxyl radicals before they are themselves converted to inactive compounds. It is therefore preferable for them to be regenerated by cheap, nontoxic stoichiometric reducing agents in a similar fashion as has been proposed for the catalytic action of alpha-tocopherol in the presence of ascorbate and other co- reductants (eqn 2-4). It is advantageous that the compounds can act as chain-breaking antioxidants by catalyzing the decomposition of peroxyl radicals in the presence of mild reducing agents, and can also act as preventive peroxide-decomposing antioxidants by catalyzing the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents.

In accordance with the present invention, the antioxidant use may be the stabilization of a man-made or natural material, or the prevention or inhibition of oxidation or degradation of a man-made or natural material. Examples of man-made and natural materials include polymers, plastics, rubber, paint, oils, lubricants, greases, fuels, paper and pulp products.

The examples of the present invention show that compounds according to the present invention proved effective compounds, in a standard test for studying antioxidant properties; this test system is described in Vessman, K.; Ekstrόm, M.; Berglund, M.; Andcrsson, C-M.; Engman, L. J. Org. Chem. 1995, 60, 4461-4467, and discussed below under "catalytic chain-breaking antioxidant activity".

In a further aspect the present invention provides a man-made or natural material containing a compound according to the present invention, and optionally a reducing agent. It will be understood that the man-made or natural material may otherwise be more susceptible to degradation, oxidation or instability.

Furthermore, the compounds are also useful medically. As shown below, compounds of the present invention quench reactive oxygen species (ROS).

Thus, in a further aspect, the inventive compounds or pharmaceutically acceptable salts thereof may be used as medicaments for the treatment of disorders caused by or involving free radical-mediated or oxidative tissue damage, e.g. a disorder selected from ischemic or reperfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, artherosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis, Crohn's disease, cataract, respiratory distress syndrome, damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents, ischcmia/rcpcrfusion injury in the heart, kidney and CSN and post-operative ischemia/reperfiision injury. Additionally, the compounds may be used for organ preservation, to treat burn injury, or to treat IBS (irritable bowel syndrome).

In a further aspect the present invention provides a compound according to the present invention, optionally in combination with a reducing agent, for use in therapy. Medical uses of the compounds of the present invention have not hitherto been disclosed.

In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and additionally other components, for example a pharmaceutically acceptable diluent or other pharmaceutical additive or excipient.

The present invention relates to 3-pyridinol and 5-pyrimidϊnol compounds useful as chain-breaking antioxidants, ϊn particular, the invention relates to 3-pyridinol and 5- pyrimidinol compounds suitable for prevention or treatment of disorders caused by or involving free radical-mediated or oxidative tissue damage such as atherosclerosis, inflammation, Alzheimer's and Parkinson's disease, cataract and heart and lung disease.

Additionally, the invention also relates to the use of the inventive 3-pyridinol and 5- pyrimidinol compounds for the stabilization of man-made and natural materials such as polymers, plastics, rubber, paint, oils, lubricants, greases, fuels and paper and pulp products during processing and use.

One object of the present invention is to provide compounds capable of acting as chain-breaking antioxidants by catalyzing the decomposition of peroxyl radicals in the presence of mild reducing agents and capable also of acting as preventive peroxide- decomposing antioxidants by catalyzing the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents.

One further object of the present invention is to provide compounds capable of acting as chain-breaking antioxidants and capable also of acting as preventive peroxide- decomposing antioxidants, that may be regenerated by stoichiometric reducing agents, e.g cheap, nontoxic reducing agents.

The present inventors have discovered that compounds comprising a 3-pyridinol or 5- pyrimidinol core carrying an organoseleno- ot organogel luro- substituent on the pyridine or pyrimidine ring, act as effective regenerable chain-breaking antioxidants in the presence of suitable stoichiometric reducing agents. Thus, under these conditions, they act as catalysts for the quenching of peroxyl radicals.

As compared with compounds described in U.S. Patent 6835216, compounds of the invention have a significantly improved antioxidant performance. In contrast to compounds described in U.S. Patent 6835216, which act on a stoichiometric basis, the regenerability and catalytic mode of action of compounds of formula I allow their administration as protective agents in much lower concentrations, and the duration of the antioxidant protection in principle is determined by the amount of an inexpensive reducing agent present. An additional advantage, when protection in a biological system is considered, is that the reducing agent may already be present in substantial amounts (glutathione; ascorbate). A further advantage as compared with compounds described in U.S. Patent 6835216 is that compounds represented by the formula I have a capacity, due to the presence of readily oxidized organylseleno- or organyltelluro groups, to act as catalysts for the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents. Thus, compounds represented by the formula I act as catalytic, multifunctional (chain-breaking and peroxide decomposing) antioxidants.

Thus, the present invention relates to novel regenerable 3-pyridinol and 5-pyriniidmol compounds, or any salts or prodrugs thereof, which can act hi a catalytic fashion in the presence of mild reducing agents to quench peroxyl radicals and reduce hydrogen peroxide and organic hydroperoxides. The present invention also relates to the pharmacological use of the inventive compounds as well as pharmacological formulations containing them and to their use for the stabilization of man-made and natural organic materials, such as polymers, plastics, rubber, paint, oils, lubricants, greases j fuels and paper and pulp products during processing and use.

Without wishing to be bound by theory, the efficacy of compounds based on a 3- pyridinol or 5-pyriπύdinol core carrying an organoseleno- or organotelluro- substituent on the pyridine or pyrimidine ring, could in part be due to the favourable ionization potential and O-H bond dissociation enthalpy. The hydrogen atom of the hydroxy group may transfer to peroxyl radicals quickly, perhaps due to polar effects in the transition state of the atom transfer reaction,

In one embodiment, thus, a pharmaceutical composition is provided comprising a compound as defined herein above, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition suitably also comprises a pharmaceutically acceptable, mild reducing agent, e.g. ^-acetylcysteine, cysteine, dithiothreitol, glutathione, ascorbic acid or sodium ascorbate.

According to one aspect the invention relates to a compound for the treatment of a disorder caused by or involving free radical-mediated or oxidative tissue damage, e.g. a disorder selected from ischemic or rcpcrfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, artherosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis. Crohn's disease, cataract, respiratory distress syndrome, damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents, ischemia/reperfiision injury in the heart, kidney and CSN and post-operative ischemia/reperrusϊon injury, and to the use of the compound in the manufacture of a medicament for treatment of any of the diseases. According to still another aspect, the invention relates to an antioxidant composition comprising a compound according to the invention and a mild reducing agent, useful for preserving a liquid, solid or semi-solid organic material, e.g. a polymer, elastomer, oil, lubricant, grease, fuel or paint composition or a paper or pulp product against oxidative degradation.

The invention also provides such a liquid, solid or semi-solid material comprising the antioxidant composition of the invention.

According to another aspect, the invention relates to a method of preserving a polymer, elastomer, oil, lubricant, grease, fuel or paint composition or a paper or pulp product against oxidative degradation, by adding an. antioxidant composition according to the invention to the polymer, elastomer, oil, lubricant, grease fuel or paint composition or paper or pulp product.

Finally, the invention relates to a method of treatment of a mammal in need thereof, by administering to said mammal a therapeutically effective amount of a compound according to the invention

Compounds H-VI (or other compounds disclosed herein) can form salts with either acids or bases. All physiologically acceptable salts are contemplated as useful as active medicaments; however, sodium, potassium, ammonium, calcium and magnesium salts and salts with hydrochloric, hydrobromic, phosphoric and sulfuric acids and with organic acids such as oxalic, fumaric, tartaric, malonic, acetic, citric and succinic acids are preferred. Likewise preferred are organic bases such as lysine, argininc, choline, ethylendiamine, 2-amino-2-methyl-l,3-propanediol, cystamine, diethylaminc, ethanolamine and piperazine.

In the presence of mild reducing agents, compounds II- VI (or other compounds disclosed herein) of the present invention, or salts or prodrugs thereof, are regenerablc and act in a catalytic fashion to quench peroxyl radicals and to reduce hydrogen peroxide and organic hydroperoxides. The compounds which are going to act as stoichiometric reducing agents in the presence of the catalytically active compounds H-Vl either have to be present in the system where the antioxidant protection is desired or they have to be co-administered with the catalytic antioxidants. Mild reducing agents which have been found suitable to regenerate the catalytic antioxidants must have a capacity to donate hydrogen atoms or electrons. Such compounds include, but are not limited to, thiols, ascorbic acid or derivatives thereof such as sodium ascorbate, phenolic compounds, JV-hydroxy derivatives of certain amines and salts of readily oxidized metals.

A suitable thiol reducing agent is an alkane, an arene or a heteroarene containing one or several sulfhydryl (SH) groups, including all kinds ofpolymer-supported thiols or hyperbranched polyethcr, polyester or polyamide compounds with terminal sulfhydryl groups, wherein

- the alkane type compound is a straight or branched hydrocarbon chain with 1-30 carbon atoms, wherein the carbon atoms may be optionally substituted with one or several groups such as OH, alkoxyl, NH₂, iV-alkyiamino, ΛζiV-dialkylamuio, COOH, aryl which is optionally substituted with C₁-C₅ alkyl, OH, alkoxyl, SII, NII₂, N- alkylamino. ΛζJV-dialkylamino, COOH, CHO, NO₂, F, CI, Br, I groups, and heteroaryl which is optionally substituted with CpC₅ alkyl, OH, alkoxyl, SH, NH₂, N- alkylamino, N.-V-dialkylamino, COOH, CHO, NO₂, F, Cl, Br, and I groups;

- the arene type compound could be benzene, naphthalene or any other polyaromatic compound wherein the carbon atoms may be optionally substituted with one or several groups such as OH, alkoxyl, NH2, N-alkylamino, iV^-dialkylamino, COOH, aryl which is optionally substituted with C₁-C₅ alkyl, OH, alkoxyl, SH₅ NH₂, N- alkylamino, JV.iV-dialkylamino, COOIL, CITO, NO₂, V, CI, Br, 1 groups, and heteroaryl which is optionally substituted with C]-C₅ alkyl, OH, alkoxyl, SII₅ NI-I₂, N- alkylamino, iV,iV-dialkyIammo, COOH, CHO, NO₂, F, Cl, Br, and I groups;

- the heteroarene type compound could be furan, thiophene, pyrrole, pyridine or any other heteroaromatic compound wherein the carbon atoms may be optionally substituted with one or several groups such as OH, alkoxyl, NH₂, iV-alkylamino, N₁N- dialkylamino, COOH, aryl which is optionally substituted with C₁-Cs alkyl, OH, alkoxyl, SH, NH₂, JV-alkylamino, Λ/÷/V-dialkylamino, COOII, CIIO, NO₂, F, Cl, Br₁ 1 groups, and hctcroaryl which is optionally substituted with C₁-C₅ alkyl, OH, alkoxyi, SH, NH₂, iV-alkylamino, N,JV-dialkylamiao, COOH, CHO, NO₂, F, Cl, Br, and I groups.

Preferred mild reducing agents which have been found suitable to regenerate the catalytic antioxidants H-VI are N-acetylcysteine, cysteine, dithiothreitol. glutathione, ascorbic acid or sodium ascorbatc.

Further aspects and embodiments of the invention are as defined in the claims and will be apparent from the detailed description of the invention.

Figure 1 is a schematic illustration of a two-phase model used for studying regeneration of chain-breaking antioxidants;

Figure 2 is a graph showing peroxidation traces (Hnoleic acid hydroperoxide concentration vs time) recorded using compound 16a and α-TOH as antioxidants in the chlorobenzene layer in the presence of NAC (1 mM) in the aqueous phase;

Figure 3 is a graph showing concentration of ^-acetylcysteine in the aqueous phase with time during a normal peroxidation experiment using antioxidant 16a;

Figure 4 is a graph showing inhibition time recorded with compound 16a (40 μM) in the presence of various amounts of ^-acetylcysteine (1.0, 0.75, 0.5, 0.25, and 0 mM) in the aqueous phase.

Figure 5 is a graph showing reactive oxygen species (ROS) production in macrophages (THP-I) as a function of time as determined by luminescence measurements. Curves for telluride 17a (60 μM), NAC (0.1 mM) and the combination of 17a (60 μM) and NAC (0.1 mM) are shown together with a control (HBSS). In general all technical terms used herein should be given their ordinary meaning. However, definitions of some terms used hi the present context are given herein below.

As used herein, and unless specified otherwise, the term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to thirty carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, hexadecyl, and the like.

"Alkoxy" refers to a moiety of the formula -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy. isopropoxy, and the like.

'W-alkylamino" refers to a moiety of the formula -NRH wherein R is an alkyl moiety as defined herein. Examples of jY-alkylamino moieties include, but are not limited to, methylaminOi ethylamino, propylamino, and the like.

'W.N-dialkyϊamino" refers to a moiety of the formula -NR₂ wherein each R may be the same or different and is an alkyl moiety as defined herein. Examples of N₁N- dialkylamino moieties include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, mefhylpropylamino, cthylpropylamino, and the like.

The term "heteroaryl" refers to an monovalent aromatic cyclic radical of 5 or 6 ring atoms and containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyϊ, furanyl, thienyl_t thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, pyriinidinyl or pyrazinyl.

The term "pharmaceutically acceptable" refers to that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

A "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable, and that possesses the desired pharmacological activity of the parent compound. Such salts generally include: acid addition salts formed with inorganic acids; or formed with organic acids; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion or an alkaline earth ion; or coordinates with an organic or inorganic base, e.g. diethanolaminc, ethanolamine, N-methylglucamine, aluminum hydroxide, calcium hydroxide, sodium carbonate and sodium hydroxide, and the like.

it is contemplated that references to pharmaceutically acceptable sails also include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt.

A "mammal" as referred to herein is any member of the mammalia class including, but not limited to, humans; animals such as non-human primates, farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like.

"Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated j the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.

"Treating" or "treatment" of a disease includes e.g. preventing the disease, as well as inhibiting the disease state, Le,, arresting the development of the disease state or its clinical symptoms, and relieving the disease, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms. For the purpose of the present invention, the reference to a "compound of formula I" and "a compound according to formula 1" are used interchangeably with "a compound I" and thus a compound I is a compound that may be represented by the formula I, as defined herein. Similar considerations also apply analogously to the compounds II- Vl and VlL

Catalytic chain-breaking antioxidant activity

Azo-initiated peroxidation of linoleic acid or derivatives thereof has frequently been used for studying the anti oxidative properties of synthetic and natural compounds. A two-phase variant of this system has been designed which allows the study of antioxidant regeneration by water soluble co -antioxidants (Vessman_? K.; Ekstrom, M.; Berglund, M.; Andersson, C-M.; Engman, L. J Org. Cham. 1995, 60, 4461-4467), Tn the experimental setup used (schematically shown in Figure I)₅ linoleic acid and the antioxidant to be evaluated were vigorously stirred in chlorobenzene at 42⁰C with an aqueous solution of JV-acetylcysteine (NAC). 2,2'-Λzobis(2,4-dimetiiylvaIerorήtrile) (AMVN) was added as an initiator in the organic phase and the progress of peroxidation monitored by HPLC (conjugated diene hydroperoxide formation). For comparison of catalyst efficiency, the inhibited rate of peroxidation, R_inj_t, was determined by least-squares methods from absorbancc/time plots. The progress of peroxidation was followed and the duration of the inhibited phase, Tj_irι_r, determined graphically as lhe cross-point for the inhibited and the uninhibited lines (exemplified in Figure 2 ).

In a typical experiment linoleic acid in chlorobenzene (7.5 mL, 36.2 mM) was stirred (1100 rpm) in a 20 niL thermostated reaction vessel. To this solution the inhibitor in ethanol (107μL_f 3.0 mM; 40μM final concentration) was added by syringe followed by an aqueous thermostated solution of NAC (8.0 niL, 1.0 mM). After 25 min of stirring/equilibration, a thermostated solution of AMVN in chlorobenzene (0.5 mT,, 22.4 mM) was added. Samples were withdrawn (after interruption of the stirring and phase separation during 30 s ) and analyzed by straight-phase HPLC with UV- detection. After sampling, stirring was immediately resumed. The formation of conjugated dienes was monitored at 234 nm and the concentration determined by integration using an experimentally determined response factor,

α-Tocopherol (α-TOC), which is an excellent chain-breaking antioxidant, was used as a reference compound in the two-phase model. Whether (T_inf, = 90 min), or not (Ti_n/, = 80 min), NAC (1 mM) was present in the aqueous phase, α-tocopheroi inhibited peroxidation of linoleic acid for almost the same time in the lipid phase with the similar inhibited rates of peroxidation (24 and 22 μM/h, respectively). Obviously, under the conditions of the two-phase model, α-tocopherol is not regenerable.

Table 1 Inhibited rate of Linoleic Acid Peroxidation (Ri_n/,) and Inhibition Times (T_mh) for Antioxidants and Reference Compounds Tested in the Presence and Absence of JV- acetylcysteine and Initial Rates of Hydrogen Peroxide Reduction in the Presence of Thiophenol and Antioxidants and Reference Compounds

a Rate of peroxidation during the inhibited phase (uninhibited rate ca. 650 μM h^"1). b Duration of the inhibited phase of peroxidation. Reactions were monitored for ≤400 min. c Initial rate of hydrogen peroxide reduction in the presence of thiophenol and antioxidant. Initially, 3-pyridinols 7a-c (Tabic 1) substituted in the ό-position with octyltelluro-, octylseleno- and octylthio groups, respectively, and the corresponding 2-substHuted derivatives 8a-c were prepared starting from readily available 6-bromo- and 2-bromo- 3-pyridinol. The capacity of these antioxidants to inhibit AMVN-initiated peroxidation of linolcic acid to the corresponding hydroperoxide in the biphasic chlorobenzene/water system was much dependent on the experimental conditions (Tabϊc 1). In the absence of JV-acetylcysteine in the aqueous phase, the two organotelluriums 7a and 8a did not inhibit peroxidation at all. However, in the presence of the thiol reducing agent, the rale of linoleic acid hydroperoxide formation in the chlorobenzene layer. R_inh, was only slightly higher (32 and 27 μM/h, respectively) than that recorded using α-tocopherol

μM/h) as an antioxidant under identical conditions. Whereas the inhibition period for compound 7a was 70 min only, antioxidant 8a was clearly regenerable with an inhibition time, T_mh, of 200 min. The selenium (7b, 8b) and sulftir (7c, 8c) analogues were markedly poorer quenchers of peroxyl radicals (115< R^ <203 μM/h) than the organotelluriums and the addition of thiol to the aqueous phase always caused an increase (17-100 %) in ϊ)_nh (Table 1).

Introduction of additional electron releasing groups was investigated. Compounds 9a- c were prepared from commercially available 2-iodo-6-methyl-3-pyridinol and evaluated. As noted above, the organotelluiium derivative clearly outperformed the other chalcogen analogues when it comes to rate of inhibition and regenerability. Pyridinol 9a inhibited peroxidation as efficiently as α-tocopherol with an inhibition time exceeding 360 min in the presence of the thiol regenerating agent. Thus, regenerability was also improved by introduction of the methyl group.

The inventive compounds may be prepared by the method as generally outlined herein above. As an example, Scheme 1 represents the preparation of a 4,6-dimethylated derivative 16a from the commercially available 2-pyridinol 11. Scheme 1

In this approach, the 3-cyano-group serves as a source of a phenol via hydrolysis to an amide, IIofmann rearrangement and diazotization/aromatic iiucleophilic substitution. The chalcogen is introduced into the 2-position in the final step by lithiation, insertion of tellurium and alkylation of an arenetellurolate. Compound 16a quenched peroxyl radicals three times as efficiently as α-tocopherol

μM/h) in the presence of JV- acetyl-cysteine in the aqueous phase. Regenerability was also excellent (T_inh>409 min). Again, chain-breaking capacity and regenerability of the corresponding organo selenium and -sulfur compounds 16b and 16c could not match those of the organotelhirium derivative. Compound 17, carrying an cthyltelluro group in the 2- posilion, showed markedly poorer regenerability than compound 16a. Organoteilurium 18a, prepared in analogy with compound 16a, showed similar antioxidant characteristics and clearly outperformed its selenium analogue 18b. It is also noteworthy that compound 19a, carrying the phenolic moiety para to tellurium, showed rather poor antioxidativc capacity when it comes to regenerability. Bromopyridinol 15, which was tested as a chalcogen-free reference pyridinol did not inhibit peroxidation at all, whether or not NAC was present in the aqueous phase.

The peroxidation traces in Figure 2 show that compound 16a can clearly outperform α-tocopherol when it comes to the duration of the inhibited phase. In fact, the limitation is the availability of the thiol reducing agent. Sampling of the aqueous (instead of the chlorobenzene) phase at intervals during a normal peroxidation experiment showed that the thiol/disulfide ratio decreased linearly with time until complete consumption of ^-acetylcysteine after ca 400 min (Figure 3). Inhibition times were also recorded in the presence of smaller amounts of the thiol reducing agent (CL75_> 0.5, 0.25 mM). As shown in Figure 4, TM, decreases in a more or less linear fashion as the NAC concentration is lowered to zero. While keeping the concentration of JV-acetylcysteine constant (1 mM), the concentration of antioxidant 16a was also lowered from the 40 μM used in the standard assay. The inhibition of peroxidation did not change at the 20 μM level, decreased at 10 μM (7^=3 ϊ 0 min) and could not be observed at the 5 μM level.

The above results clearly demonstrate that the compounds of the invention act as catalysts for the quenching of peroxyl radicals in the presence of stoichiometric amounts of ^-acetylcysteine. Peroxyl radical quenching is likely to occur via donation of a hydrogen atom from the antioxidant (Scheme 2). The detailed mechanism for regeneration of the antioxidant from the corresponding phenoxyl radical is not known in detail. We hypothesize that it occurs via electron transfer from thiol RSH at or near the aqueous-lipid interphase, accompanied by transfer of a proton to produce a disulfide RSSR.

Scheme 2

ROO^* ROOH

Catalytic hydroperoxide-decomposing antioxidant activity Organochalcogen compounds seem to possess some unique properties which make them interesting as antioxidants. They are quite reactive towards hydrogen peroxide, organic hydroperoxides and a variety of other two-electron oxidizing agents such as peroxynitrite, hypochlorite, ozone and singlet oxygen. In all these processes the chalcogen is oxidized to the tetravalent state. The nice feature about these hypervalent species is that they can be reduced to the divalent state under very mild conditions by reductants such as thiols and ascorbate. This redox cycling is especially facile for organσtellurium compounds and allows for their use as catalysts for the decomposition of hydroperoxides. Thus, these materials are biomimetic in the sense that they can mimic the action of the selenium containing glutathione peroxidase enzymes. There are several methods in use for the assessment of glutathione peroxidase-likc activity of simple synthetic compounds, hi the method most commonly used today, the initial rate of reduction of hydrogen peroxide (v₀) is calculated by monitoring the formation of diphenyl disulfide from lhiophenol by UV spectroscopy at 305 ran (Iwaoka, M.; Toraoda, S. J. Am. Chem. Soc. 1994, 116, 2557- 2561 ). Thus, what is measured here is thiol peroxidase activity rather than glutathione peroxidase activity. Shown in Table 1 are initial rates recorded for the reduction of hydrogen peroxide (3.75 mM) in methanol by thiophenol (1 niM) in the presence of compounds 7a, 8a, 9a, 16a, 18a and 19a (0.01 mM) as recorded by UV spectroscopy at 305 nm where the extinction coefficient of diphenyl disulfide (ε-t .24 x 10³ M^-1Cm^{" l}) is much larger than for thiophenol (ε=9 M^-1Cm^"1). Initial rates were measured at least six times and calculated for the first 60 seconds of reaction. The rate of thiol formation was corrected for the slow spontaneous thiol oxidation by subtracting the rate of disulfide formation in a control experiment run without added catalyst. All investigated compounds showed a better thiol peroxidase activity (1.52<vo<17.80 μMmin^"') than diphenyl disclenide (0.67 μMmin^"1) which has often been used as a benchmark when catalytic activity of synthetic compounds were compared.

The above results clearly demonstrate that the compounds of the invention can act as catalysts for the decomposition of hydrogen peroxide and organic hydroperoxides in the presence of stoichiometric amounts of thiophenol. As exemplified in Scheme 3, the decomposition of hydrogen peroxide is likely to occur via nucleophilic attack of chalcogen on oxygen, resulting in the formation of a tellurium(IV)-oxide and a water molecule. Regeneration of the active antioxidant from the tellurium(rv^r)-spccies occult in the presence of thiophenol and is accompanied by disulfide and water formation. Scheme 3

H₂O₂ H₂O

Treatment of disorders caused by or involving free radical-mediated damage or oxidative tissue damage: effects on ROS-production in macrophages

In order to find evidence that the compounds of the invention could be useful for treatment of disorders caused by or involving free radical-mediated damage, their capacity to quench reactive oxygen species (ROS) produced by PMA-stimulatcd macrophages (THP-I cells) was studied. The total ROS (both extra- and intracellular production) was assessed by luminol enhanced chemiluniinescence measurements_* As can be seen (Figure 5), organotellurium 17 at 60 μM or NAC at 0, 1 mM both served to reduce ROS-production as compared to the medium control (HBSS). However, the ROS-inhibiting effect of the combination of organotellurium 17 (60 μM) and NAC (0.1 mM) was much larger than the added effect of the two components. We feel this synergistic effect is due to a catalytic mode of action of the antioxidant which is continuously being regenerated by the thiol reducing agent.

The present invention describes novel, regenerable compounds, and any acid or base addition salt or prodrug thereof, which are capable of acting as chain-breaking antioxidants by catalyzing the decomposition of peroxyl radicals in the presence of mild reducing agents and which act as preventive peroxide-decomposing antioxidants by catalyzing the reduction of hydrogen peroxide and organic hydroperoxides in the presence of mild reducing agents. Compounds according to the present invention interfere with pathophysiological^ important reactions in man and animals and thus effectively hamper the degradation of tissue constituent molecules as well as to act to remove harmful products from such degradation. The compounds possess a unique ability to protect tissues against oxidative damage induced by overreacting host defence systems. Compounds according to the present invention are therefore useful for the pharmacological treatment of diseases in which free radical-mediated or oxidative tissue degradation occurs or where oxidants trigger pro-inflammatory receptors on cell surfaces. The stoichiometric reducing agents required for a catalytic mode of action of compounds according to formula I could either be exogenous and present in the environment where the antioxidant effect is desired (for example glutathione or ascorbate) or they have to be supplemented together with compounds according to the present invention. Diseases such as inflammatory (including autoimmune inflammatory) conditions like asthma, bronchitis, various allergic skin and systemic disorders, Crohn's disease, ulcerative colitis, rheumatoid arthritis and other kinds of arthritis could be considered for such treatment. Compounds according to the present invention together with suitable stoichiometric reducing agents may also be used for intervention of cataract and the respiratory distress syndrome. Further, the involvement of oxidative damage in atherosclerosis and in ischemia/reperfusion injury in the heart, kidney, CSN or post-operative ischemia/reperfusion injury as well as in thrombosis and embolism makes these disorders liable to intervention by the compounds according to the present invention together with suitable stoichiometric reducing agents. The free radical dependent pathology of ageing and neoplasm development as well as disorders such as Parkinson's and Alzheimer's diseases may also be influenced in a favorable manner by the compounds according to the present invention together with suitable stoichiometric reducing agents. The oxidative damage to tissues caused by radiation, but also by antineoplastic or immunosuppressive agents and other xenobiotics can be prevented or limited by the use of compounds according to the present invention together with suitable stoichiometric reducing agents.

Compounds according to the present invention together with suitable stoichiometric reducing agents are also useful for the stabilization of man-made and natural materials such as polymers, plastics, rubber, paint, oils, lubricants, greases, fuels and paper and pulp products during processing and use. Consequently, according to a first aspect, the present invention provides a compound according to formula I

T; as defined herein above.

R₁ suitably is selected from branched or unbranchcd C1-C₃₀ alkyl and aryl, such as phenyl, in particular from C₁-Cs₀ alkyl. In one embodiment, the CJ-C30 alkyl is more specifically selected from C₁-C₁₁; alkyl, e.g. from C₁-C^ alkyl, from Q-C₁₀ alkyl or from CpCg alkyl.

In one embodiment, Ri is selected from C₃-C1₆ alkyl, e.g. from C₄-C^ alkyl or C₆-C_1O alkyl.

In one preferred embodiment, R₂, R3 and R4 are independently selected from H, Ci-C₆ alkyl, CI-C_O alkoxy, TV.JV-di-Ci-Cg alkylamino and N-C]-Ce alkylammo, e.g. from from H, C₁-Ce alkyl and CI-C_G alkoxy.

In R₂, R₃ and R4, any Ci-C₆ alkyl moiety (including those present in an alkoxy or amino function) more specifically may be selected from C₁-C₄ alkyl or from C₁-Cs alkyl.

The compound according to formula 1 may be represented by any of the formulas II- VI

Il III IV V Vl

as defined herein above, or by formula VII as discussed above..

Thus, in one embodiment, the compound is according to formula II, III or IV; in another the compound is according to formula V or VI.

In still another embodiment, R₁X is in an ortho position in relation to the OH group on the nitrogen-containing heteτoaromatic cycle, i.e. the pyridinol or pyrimidinol, viz. the compound is a compound according to formula II, IV or V, for example according to formula II or IV.

In one embodiment, the compound is according to formula II as defined herein above, wherein X is Te; Rj is alkyl; and R₂ and R₄ are hydrogen or alkyl and R₃ is an electron donating group such as iV,iV-dialkylammo, iV-alkylamino, alkoxy or alkyl.

For example, in one embodiment of a compound according to formula II, Ri is Ci-Cie alkyl; and R₂ and R₄ are hydrogen or Ci-C₆ alkyl; and R₃ is an electron donating group such as N,N~d\~CΛ-C6 alkylamino, JV-C1-C6 alkylamino, C1-C6 alkoxy or Cl- Cό alkyl.

In another embodiment, the compound is according to formula TII as defined herein above, wherein X is Te; Rj is alkyl; and one OfR₂ and R₃ is an electron donating group such as ΛζN-dialkylamino, iV-alkylamino, alkoxy or alkyl and the other one is hydrogen or alkyl and R₄ is hydrogen or alkyl.

For example, in one embodiment of a compound according to formula III, Rj is C₁- C₁₆ alkyl; and one of R2 and R₃ is an electron donating group such as N,N-di-C\-C6 alkylamino, /V-C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl and the other one is hydrogen or alkyl and R₄ is hydrogen or C1-C6 alkyl.

In still another embodiment, the compound is according to formula IV as defined herein above, wherein X is Te; Ri is alkyl; and R₂ and R₄ are hydrogen or alkyl and R₃ is an electron donating group such as ΛζiV-dialkylamino, N-alkylamino, alkoxy or alkyl.

For example, in one embodiment of a compound according to formula IV, Ri is Cr Ci₆ alkyl; and R₂ and R₄ are hydrogen or alkyl and R₃ is an electron donating group such as N,N-di- C1-C6 alkylamino, N- C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl.

In still another embodiment, the compound is according to formula V as defined herein above, wherein X is Te; R₁ is alkyl; and R₂ is hydrogen or alkyl and R₃ is an electron donating group such as JV, /V-diaϊkylamino, Λf-alkylamino, alkoxy or alkyl. For example, in one embodiment of a compound according to formula V, Ri is Ci-C^ alkyl; and R2 is hydrogen or C1-C6 alkyl and R₃ is an electron donating group such as N,N-di- C1-C6 alkylamino, N- C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl.

Finally, in one embodiment, the compound is according to formula VI as defined herein above, wherein X is Te; Rj is alkyl; and one OfR₂ and R₃ is an electron donating group such as ΛξJV-dialkylamino, Ν-alkyiamino, alkoxy or alkyl and the other one is hydrogen or alkyl.

For example, in one embodiment of a compound according to formula VI, R₁ is Cj- C] e alkyl; and one of R₂ and R₃ is an electron donating group such as N,N-άi- C1-C6 alkylamino, JV- C1-C6 alkylamino, C1-C6 alkoxy or C1-C6 alkyl and' the other one is hydrogen or C1-C6 alkyl . In any of R.₂, R₃ and R₄, it is contemplated that in any of the A^Af-dialkylamino, N- alkylamino, alkoxy and alkyl radicals, the alkyl may be more particularly selected from C1-C4 alkyl, or C1 -C3 alkyl., e.g. methyl, ethyl and propyl.

In one embodiment, any electron donating group in R₂, R₃ and/or R₄ is selected from alkoxy and alkyl as defined herein above.

Further preferred compounds and groups of compounds are as described above.

It is considered that the compounds according to formula I as defined herein may be prepared by the person of ordinary skill in the art, in the light of the teachings herein.

Thus, a compound according to formula I having a hydroxy group in position n and an RiX group in position m on the nitrogen-containing heteroaromatic cycle (pyrϊdinol or pyrimidinol) may be prepared, starting from a pyridinol or pyrimidmol, respectively, wherein the hydroxy function is in the position corresponding to position m in the inventive compound ("in m position"), and wherein the pyridinol or pyrimidinol additionally carries a cyano substitucnt in the position corresponding to position n in the inventive compound ("in n position"), by a method comprising a series of steps as outlined herein below.

Step 1 is a halogcnation, wherein a halogen, such as chlorine, bromine or iodine, is sub-stituted for the hydroxy group in m-position. Such substitution e.g. may be effected by reaction with tetrabutyl ammonium halogenide (Bu4NHal; Hal is Cl, Br or 1) in the presence of phosphorous pentoxide (P2O5).

Step 2 is the transformation of the cyano function in n-position into a carboxamide function. This may be achieved by acid hydrolysis, e.g. using a mineral acid such as sulfuric acid (H₂SO₄) and water. In step 3, the carboxamide function is transformed into a primary amine function by a Hofmann rearrangement (Ilofinann degradation), e.g. using Br₂ in an aqueous alkaline solution.

Step 4 is a diazotization reaction wherein the primary amine function is transformed into a diazonium function, e.g. by reacting with nitrous acid (HNO₂) or sodium nitrite (NaNO₂) in the presence of a mineral acid, such as tetrafiuoroboric acid (HBF₄). The diazonium function is then hydrolyzed to provide a hydroxy group in n position.

Step 5 is a lithium-halogen exchange reaction wherein the halogen in m position is replaced by a lithium atom using a suitable alkyllithium, such as fert-butyllithium.

In step 6, the lithiated species is reacted with elemental elemental tellurium or selenium so as to provide a lithium tellurolate or selenolate.

In step 7, finally, the lithium is replaced by the moiety Rj, e.g. in a nucleophilic substitution reaction.

The above sequence of steps may be modified in various ways depending e.g. on the contemplated number and identity of substituents in the compound according to formula I. For example, in some cases it may be necessary to protect different functional groups present in the molecule against the reactants used, by introducing protective groups and subsequently removing the same. Also it is contemplated that the order of some reaction steps may be changed or that further reaction steps may be undertaken, in addition to those outlined herein above. Finally, it is to be understood that the reactions may also be effected using other reactants than the ones exemplified herein above and used in the examples. It is considered well within the knowledge of the skilled person to undertake any such variation or modification as well as to select suitable solvents and reactions conditions for each step and effecting the necessary isolations and purifications of reactions products, if necessary taking guidance from the examples herein as well as from the relevant literature within the field. The inventive compounds may be used as a medicament, c.g for the treatment of a disorder caused by or involving free radical-mediated or oxidative tissue damage. The disorder may be e.g. selected from ischemic or reperfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, arthcrosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis, Crohn's disease, cataract, respiratory distress syndrome, damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents, ischemia/reperfusion injury in the heart, kidney and CSN and post-operative ischemia/reperfusion injury.

In one embodiment, thus, a pharmaceutical composition is provided comprising a compound as defined herein above, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition may comprise any pharmaceutically acceptable excipients including, for example, vehicles, adjuvants, carriers or diluents, as are well- known to those who are skilled in the art and readily available to the public. The pharmaceutically acceptable carrier may be one which is chemically inert to the active compounds and which have no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy. A. R. Gcnnaro, Editor. Lippincott, Williams and WiUάns, 20th edition (2000).

The composition according to the invention may be prepared for any route of administration, e.g. oral or parenteral, e.g. intravenous, intramuscular, by inhalation or intraperitoneal. The precise nature of the carrier or other material will depend on the route of administration. For a parenteral administration, a parenterally acceptable aqueous solution is suitably employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature.

The composition can be used in any standard dosage unit form, such as tablets, capsules, lozenges, elixirs, emulsions, suspensions and, in cases wherein topical application is preferred, by suppository or sub-lingual administration. For inhalation the pharmaceutical composition can be utilized as a micronized powder and administered from a powder-inhaler with or without pharmaceutically inert carrier.

The dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammaL over a reasonable lirne frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage/severity of the disease. The dose will also be determined by the route (administration form), timing and frequency of administration.

The compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of disorder caused by or involving tree radical-mediated or oxidative tissue damage. For example, if the disorder is a cancer, such an additional drug may be a cytostatic drug. In a combination therapy, the components may be in the same fonnulation or in separate formulations for administration simultaneously or sequentially. The compounds of the present invention may also be used or administered in combination with other treatment, such as e.g. irradiation for the treatment of cancer.

In one preferred embodiment, the pharmaceutical composition also comprises at least one pharmaceutically acceptable, mild reducing agent, as defined herein above.

For example, the reducing agent may be selected from //-acetylcysteine, cysteine, dithiothreitol, glutathione, ascorbic acid and sodium ascorbate.

According to still another aspect, the invention relates to an antioxidant composition comprising a compound according to the invention or a suitable salt thereof, and a mild reducing agent for use in the preservation of a liquid, solid or semi-solid material against oxidative degradation. The material to be preserved may be organic or inorganic and natural or synthetic, e.g. a polymer, elastomer, oil, lubricant, grease, fuel or paint composition oτ a paper or pulp product, comprising the antioxidant composition.

It is to be understood that for such non-pharmaceutical use, neither the salt of the compoound, nor the reducing agent need be pharmaceutically acceptabJe_? but suitably are environmentally acceptable, e.g. non-toxic and biodegradable. In general, of course, any of the salts and reducing agents mentioned in relation to the pharmaceutical use may also be used in the non-pharmaceutical context.

According to another aspect, the invention relates to a method of preserving a liquid_* solid or semi-solid organic material, as defined herein above, against oxidative degradation, by adding an antioxidant composition according to the invention to the polymer, elastomer, oil, lubricant, grease fuel or paint composition or paper or pulp product.

The antioxidant composition may suitably be added e.g. at the preparation or processing of the material or may be added al any point to an already prepared material with a view to preserving it against oxidative degradation.

In one embodiment, the antioxidant composition of the invention is added to a material susceptible to oxidative degradation, whereby a homogenous mixture of the material and the antioxidant composition is produced, e.g. using mixing equipment well-known to the skilled in the art.

The invention will be further illustrated by the following examples. These examples should not be construed as limiting the scope of the invention, but merely as illustrative, and it is contemplated numerous variations and modifications will present themselves to the skilled reader. EXAMPLES

Of the following examples, Examples 1, 12-19, 26 and 27 relate to the preparation of intermediary compounds, useful in the preparation of compounds according to the invention; Examples 2, 3, 5, 6, 8, 9, 2O₅ 21 _? 23, 24, 25, 28 and 29 relate to the preparation of compounds according to the invention; and Examples 4, 7, 10, 22 and 30 relate to the preparation of related compounds, not according to the invention.

General Experimental Details

For ¹H NMR analysis (CDCl₃), Varian 500, 400 and 300 MHz spectrometers were used. ¹³C spectra were recorded at 125, 100 and 75 MHz. NMR chemical shifts are reported in ppm referenced to the solvent peak of CDCb (7.26 ppm for ¹H and 77.16 ppm for ¹³C₃ respectively). Mass spectra reported are for ions of ⁸⁰Se. ES-MS data were obtained with an Sciex API ISO EX Spectrometer using direct inlet of a dilute methanol solution of compound. Microwave reactions were carried out in a Biotage Initiator 60 EXP focused microwave reactor equipped with an IR sensor for continuous monitoring of the reaction temperature. Melting points, obtained using a Stuart Scientific melting point apparatus, are unconⁿected. THF was dried by distillation over sodium/benzophenone.

Example 1

6-Bromo-3-pyridϊnoI. 3-Amino-6-bromopyridinc (1.73 g, 10 mmol) was dissolved in HBF4 (5 mL, 50 % aq.) and water (5 mL) was added. To the resulting brownish solution, cooled to O⁰C in an ice-bath, NaNO₂ (759 mg, 11 mmol) in water (5 mL) was added dropwisc. The resulting yellowish heterogenous reaction mixture was stirred for 1 h at this temperature. After addition of water (5 mL), the mixture was stirred in an oil -bath for 5 h at 100⁰C (gas evolution). The cooled reaction mixture was then neutralized by addition OfNaHCO₃ (5 % aq.) and the product extracted with ethyl acetate (5 x 35 mL). After drying (NaiSO₄) and evaporation in vacuo, the resulting brownish solid was purified by column chromatography (SiO₂) using pentane/ethyl acetate (9:1) to give 1.04 g (60 %) of the title compound, mp 137-138⁰C (lit. 135.5-136.5 ⁰C; den Hertog et al\ Rec. Tray. Chim. Pays-Bas 1959, 69, 1281). Example 2

5-Hydroxy-2-pyridyl «-Octyl Telluride (7a): To the solution of lithiated 6-bromo-3- pyridiaol prepared as described below (compound 7c), finely ground elemental tellurium (0.762 mg, 6 mmol) was added at -78 ⁰C. The cooling bath was then removed and stirring continued for an additional 4 h at room temperature. The reaction mixture was then poured onto crushed ice and kept in the open air overnight. After evaporation of the solvent in vacuo, the residue was washed with some pentane to remove any dialkyl ditelluridc present and dissolved in EtOII (10 niL). To the remaining stirred dark red solution of crude bis-(5-hydroxy-2-pyridyl)dite11uride under N₂, NaBH₄ (0.18 g, 5 mmol) was added in portions until the colour of the reaction mixture had permanently faded away. Octyl bromide (1.0 g, 5 mmol) was added and stirring continued for 1 h when the contents of the reaction flask was poured into brine and extracted with Et₂O (15 mL x 4). After drying over Na₂SO₄ and evaporation in vacuo the product was purified by column chromatography using pentane/ethyl acetate (86: 14) as an eluent The title compound was obtained as a colourless solid (0.442 g, 66 %), mp 56-57⁰C. ¹H NMR δ 8.18 (d, J = 3.1, IH), 7.52 (dm, J- 8.4, IH), 7.04 (dd, J = 8.4, 3.0, IH), 3.01 (t, J = 7.5, 2H)₃ 1.81 (m, 2H), 1.35- 1.19 (several peaks, 10H), 0.86 (I, J= 6.9, 311). ¹³C NMR δ 153.2, 139.0, 134.6, 126.1, 124.9, 32.2, 32.0, 32.0, 29.3, 29.0, 22.S₅ 14.2, 10.0. Anal, calcd for C₁₃H₂]NOTe: C 46.62; H 6.32. Found: C, 46.49; H, 6.25.

Example 3

5-Hydroxy-2-pyridyl « -Octyl Selenide (7b) was prepared according to the procedure for sulphide 7c, using di-rø-octyl diselenide instead of di-«-octyl disulfide. Yield: 65 %, mp 44-45 ⁰C ¹H NMR δ 8,13 (d, J = 3.0, IH), 7.34 (dm, J= 8.6, IH)₃ 7.15 (dd, J = 3.0, 8.6, IH), 3.02 (t, J= 7.6, 2H), 1.71 (m, 2H), 1.39-1.23 (several peaks, 10II), 0.86 (t, J = 7.1, 3H). ¹³C NMR δ 152.6, 143.5, 137.8, 128.5, 125.6, 31.9, 30.4, 30.0, 29.3, 29.2, 27.8, 22.8, 14.2. Anal, calcd for C₁₃H₂iNOSe: C 54.56; H 7.39. Found: C, 54.87; H, 7.39. Example 4

5-Hydroxy-2-pyridyl n-Octyl Sulfide (7c): To 6-bromo-3-pyridinol (348 mg, 2 mniol) in THF (10 mL) under N₂ at -78°C was added dropwise f-BuLi (3.5 mL 1.7 M solution inpentanc; 6 mmol). Then, di-n-octy] disulfide (872 mg, 3 mmol, 6 eq.) was added at -78⁰C and the reaction mixture stirred for 30 min at this temperature and an additional 3h at room temperature. After pouring the reaction mixture into NaHCU₃ (5 % aq.), extraction with Et₂O, drying over Na₂SO₄ and concentration in vacuo, the crude product was purified by column chromatography using pcntane/ethyl acetate (88:12) as an elucnt to yield the title compound as a colourless solid (403 mg, 84 %), mp 70-71 ⁰C. ¹H NMR 6 8.12 (d, J= 2.7, IH), 7.23 (dd, J= 8.6, 2.7, 1TI)_; 7.17 (d, J = 8.6, IH)₅ 6.68 (bs, IH)₅ 3.02 (t, J= 7.3, 2H), 1.63 (m, 2H), 1.43-1.30 (several peaks, 10H), 0.86 (t, J = 7.1, 3H). ¹³C NMR S 151.9, 148.8, 136.9, 125.9. 125.0, 32.7, 31.9, 29.4, 29,3, 29.3, 29.0, 22.8, 14.2. Anal, calcd for C₁₃H₂₁NOS: C 65.22; H 8.84. Found: C, 64.380; H, 8.68.

Example 5

3-Hydroxy-2-pyridyl »-Octyl Telluride (8a) was prepared from 2-bromo-3- pyridinol by using the procedure for telluride 7a. Yield: 62 %₅ mp 83-84 ⁰C. ¹HNMR δ 8.14 (dd, J= 4.6, 1.6, IH)₅ 7.15 (dd, J= 8.2, 1.6, IH), 7.08 (dd, J= 8.2. 4.6, IH), 3.02 (t, J = 7.5, 2H), 1.79 (m, 2H), 1.37-1.23 (several peaks. 1011), 0.86 (t₅ J= 6.9, 3H). ¹³C NMR δ 155.3, 142.8, 130.7, 123.3, 119.9, 32.2, 31.9, 31.9, 29.3, 29.0, 22.8, 14.2, 9.6. Anal, calcd for Ci₃H₂₁NOTe: C 46.62; H 6.32. Found: C, 46.66; H₃ 6.40.

Example 6

3-Hydroxy-2-pyridyl «-Octyl Selenide (8b) was prepared from 2-bromo-3-pyridmol by using the procedure for selenide 7b.Yield: 50 %, mp 88-89 ⁰C. ¹H NMR δ 8.15 (dd, J= 4.7, 1.5, IH), 7.29 (dm, J= 8.1, III), 7.13 (dd, J- 8.I₅4.8, IH), 5.30 (s, IH), 3.10 (t, J= 7.5, 2H), 1.70 (m, 2H), 1.43-1.24 (several peaks, 10H)₁ 0.86 (t, J= 7.1, 3H). ¹³C NMR δ 152.9, 142.2, 141.8, 123.0, 121.1, 31.9, 30.6, 30.0, 29.2, 29.1, 27.7, 22.7_} 14.2. Anal calcd for C₁₃H₂]NOSe: C 54.54; H 739. Found: C₅ 54.39; H, 7.48. Example 7

3-Hydroxy-2-pyridyl w-Octyl Sulfide (8c) was prepared from 2-bromo-3-pyridinol according to the procedure for sulphide 7c. Yield: 77 %, mp 101-103 ⁰C, ¹H NMR δ 8.13 <dd, J= 4.8, 1.5, IH), 7.22 (ddm, J= 8.1, 1.5, IH)₅ 7.06 (dd, J= 8.1, 4.8, III), 3.12 (t, J= 7.3, 2H)₅ 1.63 (m, 2H), 1.41-1,24 (several peaks, 10H), 0.87 (t, J= 7.1, 3H). ¹³C NMR δ 151.9, 144.4, 141.6, 122.6, 121.7, 33.2, 31 ,9, 29.9, 29.3, 29.2, 28.9, 22.8, 14.2. Anal, calcd for C13H21NOS: C 65.23; H 8.84. Found: C, 65.17; H, 9.09.

Example S

3-Hy<ϊroxy-6-methyϊ-2-pyridyI w-Octyl Telluride (9a) was prepared from 2-iodo-6- mcthyl-3-ρyridinol according to the procedure for telluride 7a. Yield: 54 %. ¹H NMR 5 7.03 (d, J = 8.2, IH), 6.90 (dm, J= 8.2, III), 2.97 (1, J = 7.4, 2H), 2.47 (s, 3H)₅ 1.80 (m, 2H), 1.23-1.34 (several peaks, 10H), 0.86 (t, J= 7.1, 3H). ¹³C NMR δ 152.8, 151.9, 128.7, 123.3, 120.1, 32.1, 32,0, 31.9, 29.3, 29.0, 23.4, 22.8, 14.2, 10.2. Anal Calcd for C₁₄H₂₃NOTe: C, 48.19, H, 6.64. Found: C, 48.34; H, 6.73.

Example 9

3-IIydroxy-6-methyl-2-pyridyl n-Octyl Selenide (9b) was prepared from 2-iodo-6- methyl-3-pyridinoi according to the procedure for sulphide 9c. using di-n-octyl diselenϊdc instead of di-«-octyl disulfide. Yield: 60 %. ¹H NMR δ 7.09 (d, J= 8.2, IH), 6.94 (dm, J= 8.2, IH), 3.01 (t, J= 7.3, 2H), 2.47 (s, 3H), 1.68 (m, 2H), 1.38- 1.24 (several peaks, 10 H), 0.87 (l, J= 6.9, 311). ¹³C NMR δ 151.2, 150.7, 139.6, 123.4, 121.6, 31.9, 30.8, 29.9, 29.2, 29.1, 28.9, 23.5, 22.8, 14.2. Anal Calcd for Cj₄H₂₃NOSe: C, 56.02; H, 7.72. Found: C₅ 56.25; H, 7.86.

Example 10

3-Hydroxy-6-methyl-2-pyridyl /i-Octyl Sulfide (9c). 2-Iodo-6-methyl-3-pyridinol (235 mg, 1.0 mmol) and di-K-octyl disulfide (290 mg, 1.0 mmol) were added to a stirred mixture of CuI (3 mg, 0.015 mmol), Mg turnings (48 mg, 2.0 mmol) and 2,2'- bipyridyl (2.3 mg, 0.015 mmol) in DMF (5 mL). This mixture was heated to 200 ⁰C in a scaled tube in a microwave reactor (300 W) for 6 h and then poured into water (15 mL). After extraction with Et₂O (20 mL x 4), the organic phase was washed with brine (50 mL), dried (MgSO₄), filtered, and evaporated in vacuo. Purification by flash chromatography using pentane/ethyl acetate (85:15) as eluent yielded 165 mg (65 %) of the title compound as an oil ¹H NMR δ 7.09 (d, J= 8.2, IH), 6.93 (d, J= 8.2, IH), 5.93 (bs, IH)₅ 3.08 (t, J= 7.3, 2H), 2.48 (s, 3H), 1.62 (m, 2H), 1.42-1.27 (several peaks, 10H)₃ 0.88 (1, 3H). ¹³C NMR S 150.8, 150.0, 142.4, 122.5, 122.0, 33.5, 31.9, 30.0, 29.3, 29.2, 28.9, 23.5, 22.8, 14.2. Anal Calcd for C₁₄H₂₃NOS: C, 66.36; H, 9.15. Found: C₅ 66.14; H, 9.01.

Example 12

2-Bromo-3-cyano-4,6-dimethylpyridine (12) was prepared according to the procedure for 2-biOmo-3-cyano-5-methoxy-4,6-dimethylpyridine below, using 3- cyano-4,6-dimethyl-2-pyridinol as a starting material. Yield: 96 %, mp 116-117 ⁰C. ¹H NMR 8 7.09 (m, IH), 2.56 (d, J=0.58, 3H), 2.53 (d, J=0.73, 3H). ^πC NMR δ 163.0, 154.3, 143.6, 123.6, 115.5, 111.8, 24.6, 20.9.

Example 13

2-Bromo-3-cyano-5-methoxy-4,6-dimethylpyrϊdine. Into a round-bottomed flask (200 mL) equipped with a refluxing condenser, 3-cyano-5-methoxy-4,6-dmietfiyl-2- pyridinol (1.90 g, 10.9 mmol), Bu₄NBr (4.80 g, 14.9 mmol), P₂O₅ (4.09 g, 28.8 rnmol), toluene (110 mL) and a stirring bar were placed. The mixture was heated for 14 h under reflux. The toluene layer was decanted and washed with a saturated solution of NaHCθ3 (30 mL) and then with water (50 mL). To the oily residue left in the flask was added water (50 mL) and then powdered NaHCO₃ portionwise until there were no further evolution of gas. The mixture was extracted with CH₂Cl₂ (ca. 250 mL), washed with brine (50 mL x 2) and then with water (30 mL). The toluene and CH₂Cl₂ solutions were combined and dried (MgSO₄). Removal of the solvent hi vacuo and filtration of the product through a short pad of silica (Φ4 cm x 7 cm) eluting with pentane/C^C^ (to remove any remaining tetrabutylammonium salts) afforded 2.23 g (84%) of the title compound as a white powder, mp 99-100 ⁰C. ¹H NMR S 3.76 (s, 3H), 2.54 (s, 3 H), 2.50 (s, 3 H). "C NMR δ 158.0, 152.7, 147.1, 137.0, 115.2, 113.2, 60.7, 19.8, 15.3. Example 14

2-Bromo-4,6-dimcthylpyridine-3-carboxyIic acid amide (13) was prepared according to the procedure for 2-bromo-5-methoxy-4₇6-dimcthylpyridinc-3- carboxylic acid amide below, using 2-bromo-3-cyano-4,6-dimethylpyridine as a starting material. Yield: 68 %, mp 179-180 ⁰C. ¹HNMR 5 6.99 (s, IH), 6.12 (bs, IH),

5.78 (bs, IH), 2.51 (s, 3H), 2.38 (s, 3H). ¹³C NMR δ 168.6, 160.2, 147.8, 137.5,

132.4, 124.4, 24.2, 19.5.

Example 15

2-Bromo-5-methoxy-4,6-dimethylpyridinc-3-carboxylic acid amide. To concentrated H₂SO₄ (2.16 mL 96%, IS M; 39.0 mmol) in an Erlenmeyer flask (50 niL) heated at 90 ⁰C in an oil bath, 2-bromo-3-cyano-5-methoxy-4,6-dimethylpyridine (2.70 g, 11.2 mmol) was added. The dark brown mixture was stirred at 100 ⁰C for 3 h and then cooled to ca 90 ⁰C. Water (7.0 mL) was added dropwise (CAUTION! Quick addition of water causes bumping) and the mixture quickly cooled down to 20 ⁰C, and poured slowly into water (30 mL) in a beaker (250 mL).To this mixture, powdered NaHCC>3 was added in small portions until the evolution of CO2 had ceased. After extraction with CI-I2CI2 (120 mL x 3), washing with brine (40 mL x 2), and drying over MgSU4 and evaporation of the solvent afforded 2.57 g (88%) of the title compound as colorless needles: ¹H NMR δ 6.07 (br s, 1 H), 5.82 (br s, 1 H), 3.73 (s, 3 H), 2.49 (s, 3 H), 2.34 (s, 3 H). ¹³C NMR δ 168.0, 154.4, 153.2, 140.6, 134.0, 130.7, 60.5, 19.3, 13.5.

Example 16

3-Amjno-2-bromo-4,6-dimcthylpyridine (14) was prepared according to the procedure for 3-amino-2-bromo-5-methoxy-4₅6-dimethylpyridine below, using 2- bromo-4,6-dimethylρyridine-3-carboxylic acid amide as a starting material Yield: 84 %, mp 61-62 ⁰C. ¹H NMR δ 6.82 (s, IH), 4.01 (bs₅ 2H), 2.41 (s, 3H), 2.19 (s, 3H). ¹³C NMR O 148.0, 137.5, 132.7, 128.6, 124.8, 22.9, 18.0. Example 17

3-Amino-2-bromo-5-methoxy-4,6-dimethylpyridiiie. To a solution of KOH (1.15 g,

20.6 mmol) in water (3 mL) in an Erlenmeyer flask (50 mL) at 0 ⁰C, Br₂ (0.623 g,

0.200 mL, 3.9 mmol) was added dropwise by syringe. The resulting lemon-yellow solution was stirred for 5 min at this temperature and 2-bromo-5-methoxy -4,6- dimethylpyridine-3-carboxylic acid amide (0.777 g, 3.0 mmol) was added. After stirring for another 5 min, a mixture of water and THF (1 mL of each) was added slowly to the resulting yellow suspension and stirring continued for 10 min at 0 ⁰C. The flask was then placed in an oil bath preheated to 70 ⁰C and stirred for 0.5 h (the color of the solution turned to reddish orange). The temperature of the oil-bath was raised to 90 ⁰C and stirring continued for another 3 h. The cooled brown residue was subjected to aqueous work-up. After extraction with CH₂Cl₂ (150 mL x 2), washing with brine (50 mL x 2), and drying over MgSC^, removal of the solvent afforded the title compound (0.693 g, -100%) as pale yellow needles, mp 96-97⁰C lH NMR δ 3.91 (br s, 211), 3.64 (s, IH), 2.33 (s, 3H), 2.09 (s, 3H)). 13c NMR δ 153.0, 141,6, 138.6, 125.4, 122.7, 60.5, 18.4, 10.9.

Example 18

2-Bromo-4,6-dimethyl-3-pyridiaol (15) was prepared according to the procedure for ό-bromo-3-ρyridinol, using 3-amino-2-bromo-4,6-dimethylpyridinc as a starting material. Yield: 43 %, mp 106-107 ⁰C. ^ιΗ NMR 6 6.84 (s, III), 5.78 (br s, IH), 2.39 (s, 3H), 2.24 (s, 3H). ¹³C NMR 150.6, 146.1, 135.4, 129.6, 125.8, 23.1, 16.5.

Example 19

2-Bromo-5-methoxy-4,6-dimethyI-3-pyridinol was prepared according to the procedure for 6-bromo-3-pyridinol_> using 3-amino-2-bromo-5-methoxy-4,6- dimethylpyridine as a starting material. Yield: 54 %, mp 103-104 ⁰C. lH NMR 6 5.79 (s₅ 111), 3.69 (s, 3H), 2,38 (s, 3H)₁ 2.21 (s, 3H). 13c NMR δ 153.7, 146.7, 144.5, 128.6, 123.4, 60.4₃ 18.5_f 10.2. Example 20

3"Hydroxy-4,6-dimethyl-2-pyridyI n-Octyl Telluridc (16a) was prepared according to the procedure for pyridinol 7a, using 2-bromo-4,ό-dimethyl-3-pyridinol as a starting material. Yield: 44 %. 1HNMR δ 6.80 (s, IH), 6.15 (bs, IH), 2.93 (t, J = 7.7, 2H)_S 2.43 (s, 3H), 2.22 (s, 3H), 1.76 (m, 2H), 1.35-1.23 (several peaks, 10H)₅ 0.86 (t, J = 7.2, 3H). ¹³C NMR δ 151.9, 151.6, 131.1, 127.8, 125.5, 32.0, 32.0, 31.9, 29.3, 29.0, 23.4, 22.8, 16.7, 14.2, 10.6. Anal, calcd for C,₅H_2sNOTe: C 49.64; H 7.02. Found: C, 49.46; H, 6.94.

Example 21

3-Hydroxy-4,6-dimethyl-2-pyridyl Λ-Octyl Selenide (16b) was prepared according to the procedure for pyridinol 7b, using 2-bromo-4_J6-dimethyl-3-pyridinol as a starting matcrial.Yield: 60 %. ¹HNMR δ 6.84 (s, IH), 6.10 (bs, IH)₇ 3.08 (t, J = 7.2, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.68 (m, 2 H), 1.37-1.23 (several peaks, 10H), 0.86 (t, J = 7.0, 3H). ¹³C NMR 5 150.6, 149.9. 138.1, 133.0, 125.6, 31.9, 30.8, 29.9, 29.5, 29.3, 29.1, 23.4, 22.8, 16.3, 14.2. Anal, calcd for C₁₅Il₂₅NOSe; C 57,32; H 8.02. N 4.46 Found: C, 57.37; H, 8.03 N 4.48.

Example 22

3-Hydroxy-4,6-dimethyl-2-pyridyl w-Octyl Sulfide (16c) was prepared according to the procedure for pyridinol 7c, using 2-bromo-4_J6-dimethy 1-3 -pyridinol as a starting material. Yield: 35 %, ¹H NMR 5 6.80 (s, IH), 5.91 (s, IH), 3.03 (t, J =7.4, 2H), 2.42 (s, 3H), 2.23 (s, 3H), 1.61 (m, 2H)₁ 1.41-1.20 (several peaks, 10 H), 0.87 (t, J = 7.I₅ 3H) . ¹³C NMR δ 150.3, 149.0, 140.7, 132.8, 124.8, 34.4, 31.9, 30.2, 29.3, 29.2, 28.9, 23.6, 22.8, 15.9, 14.22. EI-MS: 267.8 [M+HJ⁺, 290.0 [M+Na]⁺, 266.0 [M-H]\ Anal, calcd for Ci₅I-I₂₅NOS: C 67.4; H 9.4. N 5.2 Found: C, 67.0; H, 9.2 N 4.9.

Example 23

3-Hydroxy-4,6-dimetliyI-2-pyridyl Ethyl Telluride (17) was prepared according to the procedure for pyridinol 16a using ethyl bromide instead of «-octyl bromide. Yield 43 %. ¹H NMR δ 6.81 (s,lH), 5,99 (bs, IH), 2.91(q, J = 7.7, 2H), 2.43 fcs, 3H), 2.23 (s, 3H), 1 .63 (I, J = 7.7, 3H). ¹³C NMR δ 151.9, 151.7, 131.1, 127.7, 125.7, 23.5, 17.6, 16.7, 2.52. Anal, calcd for C₉Hi₃NOTe: C 38.8; H 4.7; N 5.0. Found: C, 39.0; H, 4.7; N 4.7.

Example 24

3-Hydroxy-5-methoxy-4,6-dϊmethyI-2-pyridyl n-Octyl Telluride (18a) was prepared according to the procedure for pyridinol 7a, using 2-bromo-5-methoxy-4,6- dimethyl-3 -pyridinol as a starting material. Yield: 54 %. ¹H NMR δ 5.98 (s, IH), 3.73 (s, 3H), 2.87 {t, J= 7.6, 2H)₅ 2.44 (s, 3H), 2.23 (s, 3H), 1.77 (m, 2H), 1 ,32-1.22 (several peaks, 10H), 0.86 (t, J= 7.2, 3H). ¹³C NMR (CDCl₃) δ 154.3, 152.7, 146.1, 124.2, 121.4, 60.5, 32.O₅ 31.9, 29.3, 29.0, 22.8, 22.5, 19.1 , 14.2, 10.7, 10.2.

Example 25

3-Hydroxy-5-mcthoxy-4,6-dimethyI-2-pyridyl «-Octyl Selcnidc (18b) was prepared according to the procedure for pyridinol 7b, using 2-bromo-5-methoxy-4,6- dimethy 1-3 -pyridinol as a starting material. Yield: 64 %. ¹HNMR 6 3.72 (s, 3H), 3.19 (t, J- 7.6, 2H), 2.44 (s, 3H), 2.20 (s, 3H), 1 .72 (m, 2H), 1 ,44-1.26 (several peaks, 10H), 0.88 (t, 3H). ¹³C NMR δ 154.1, 151.0, 144.9, 132.4, 126.1, 60.4, 31.9, 30.8, 29.9, 29.6, 29.2, 29.1, 22.7, 18.7, 14.1, 9.9. PJ-MS; 346.4 [M+H]^'1 (most abundant). Λnal. calcd for C₁₆H₂₇NO₂Sc: C 55.8; H 7.9; N 4.1. Found: C₁ 55.4; H₅ 7.7, N, 3.9

Example 26

2-Bromo-5-methoxy-4,6-dimethylpyridine: 3-Amino-2-bromo-5-methoxy-4,6- dimethylpyridine (231 mg, 1.00 mmol) was dissolved in HBF₄ (0.5 mL, 50 % aq. solution), water (0.5 mL) was added and the resulting brownish solution cooled to O⁰C. NaNO₂ (83 mg, 1.2 mmol) in water (0.5 mL) was added dropwise at O⁰C. The resulting solution was stirred for 1 Ii at this temperature when hypophosphorous acid (0.491 mL 50% in H₂O₅ 4.74 mmol) was quickly added. The mixture was then heated under reflux for 15 min, cooled to ambient temperature and neutralized with NaHCO₃ (5 % aq.). After extraction with CH₂Cl₂ (3 x 25 mL), drying (Na₂SO₄) and concentration in vacuo, the brown residue was purified by column chromatography (SiO₂) eluting with CH₂Cl₂ to give the title compound (80 mg, 37 % yield) in the first fraction, ¹HNMR δ 7.12 (s, IH). 3.71 (s, 3 H), 2.46 (s, 3 H), 2.43 (s. 3 H). ¹³C NMR δ 153.5, 153.2, 143.2, 134.8, 127.7, 60.2, 19.1 , 15.7. and 2-bromo-5-methoxy-4,6- dimelhy^]-3-pyridinol (87 mg, 38 % yield) in the second fraction.

Example 27

6-Bromo-2,4-dimethyl-3-pyridinol. To a solution of 2-bromo-5-methoxy-4,6- dimethylpyridine (216 mg, 1 mmol) in CH₂Cl₂ (10 mL), was added BBr₃ (2 mL 1.0 M solution in CH₂Cl₂; 2 mmol) at -7S⁰C under N₂. A Tier stirring for 30 min at this temperature and then 16 h at ambient temperature, the reaction mixture was poured into cold water (10 mL) and NaHCO₃ (5 % aq.) was added. After extraction with CH2CI2 (3 x 20 mL), drying over Na₂Sθ₄ and evaporation in vacuo, the resulting brownish solid was purified by column chromatography eluting with ethyl acetate/pentane (16:84), the title compound was obtained as a colourless solid (150 mg₅ 78 %), mp 105-106 ⁰C¹HNMR δ 7.1 (s, 1 H), 6.42 (br s₅ IH), 2.43 (s, 3 H), 2.23 (s, 3 Ii). ¹³C NMR δ 149.4, 146.4, 137.O₅ 130.3, 127.6, 18.7, 15.9.

Example 28

5-Hydro3sy-4,6-dimethyl-2-pyridyI n-Octyl Telluridc (19a) was prepared according to the procedure for pyridinol 7a_? using 6-bromo-2,4-dimethyl-3-pyridinol as a starting material. Yield: 47 %. ¹H NMR 3 7.2 l(s, IH), 3.04 (1, J= 7.7, 2H), 2.48 (s, 3H), 2.21 (s, 3H), 1.86 (m, 2H), 1.38-1.26 (several peaks, 10H)₅ 0.87 (t, J= 7.0, 3H). ¹³C NMR δ 148.2, 146.1, 132.9, 132.3, 127.4, 32.3, 32.2, 32.0, 29.3, 29.1, 22.8, 19.0, 15.2, 14.2, 9.7.

Example 29

5-Hydroxy-4,6-dimethyI-3-pyridyl w-Octyl Selenide (19b): To the solution of dilithiated 6-biOmo-2,4-dimethyl-3-pyridinol prepared as described below (compound 19c), finely ground elemental selenium (0.32 g, 4.0 mmol) was added and stirring continued for 2h. The reaction mixture was then poured onto crushed ice and kept in the open air for 2h when a solution of saturated aqueous NH₄CI was added. Extraction with Rt₂O (3 x 50 mL), drying and evaporation afforded crude bis-(5-hydroxy-4,6- dimethyl-3-pyridyl) diselenide which was dissolved in EtOH and cooled to O⁰C under N₂. NaBH₄ (0.34 g, 10 mmol) was added in one portion and the reaction mixture was stirred for 30 min al room temperature, resulting in a faint yellowish solution. ra-Octyl bromide (2.0 g. 10 mmol) was added by syringe and stirring continued for an additional 1 h when the reaction mixture was poured into water. Extraction with Et₂O (3 x 20 niL), drying over Na₂SO₄, evaporation and purification by column, chromatography eluting with pentane/ethyl acetate (90:10) afforded 0.185 g (54 %) of the title compound as a light yellow oil. H NMR δ 7.00 (s. IH), 4.78 (br s, IH), 3.06

(t, J = 7.6, 2H), 2.45 (s, 3H)₅ 2.20 (s, 3H), 1.74 (m, 2H), 1.42-1.23 (several peaks, 10 HH)),, 00..8877 ((tt,, JJ == 77..00,, 33HH)).. "ⁿcC NNMMRR δδ 114477..44,, 145.2, 143.7, 133.I₅ 126.4, 32.0, 30.7, 30.2, 29.3, 29.3, 27.0, 22.8₃ 18.9, 15.4, 14.

Example 30

5-Hydroxy-4,6-dimethyl-2-pyridyl M-Octyl Sulfide (19c): To a solution of 6-bromo- 2_s4-dimethyl-3-pyridinol (0.202 g, 1.0 mmol) in THF (15 mL) was added dropwise l~ BuLi (1.8 mL 1.7 M in pentane;3 mmol) at -78 °C. The solution was stirred for 20 min at this temperature and 15 min at room temperature. The reaction mixture was again cooled to -78 ⁰C and di-π-octyl disulfide (0.58 g, 2 mmol) was added dropwise and stirring was continued for ϊ h at room temperature. A saturated solution OfNH₄Cl was added and the mixture was extracted with ether (3 x 25 mL). Drying over Na2SO₄, removal of the solvent in vacuo and purification of the crude product by column chromatography using ethylacetatc/ pcntane (13:87) as eluent afforded the title compound (0.17 g, 64 %). ¹H NMR S 6.86 (s, IH), 4.82 (bs, 111), 3.04 (t, J- 7.6, 2H), 2.44 (s, 311), 2.20 (s, 3H), 1.64 (m, 2 H), 1.41-1.26 (several peaks, 10H), 0.87 (t, J = 7.0, 3H). ¹³C NMR 8 148.4, 146.8, 144.8, 133.3, 123.0, 32.0, 31 ,8, 29.7, 29.3, 29.3, 29.0, 22.8, 19.0. 15.7, 14.3.

HPLC Peroxidation Assay

Inhibition times (T_ιrιh) and inhibited rates of peroxidation (Rw,) were determined as previously described (Mahnstrom, J.; Jonsson, M.; Cotgreave, I. A.; Hammarstrδm, L.; Sjδdin, M.; Engman, L. J Am. Chem. Soc. 2001, 123, 3434-3440. Shanks, D.; Amorati, R.; Fumo, M. G.; Pedulli, G. F₁; Valgimigli, L.; Engman, L. J. Org. Chem. 2006, 71, 1033-1038). Assay for Thiol Peroxidase Activity

Thiol peroxidase activity was determined spectrophotometrically as recently described.

(Kumar, L. Engman, L. Valgimigli, R. Amorati, M. G. Fumo, G. K Pedulli, J. Org,

Chem, 2007, 72, 6046-6055).

Macrophage Assay

The generation of oxygen free radicals over time from macrophages (THP-I) was monitored for 180 minutes in 96-welϊ white optiplates (Greiner) using a 1ΕCΛN reader and a Diogenes chemilumincsccnce kit (National Diagnostics), Approximately 200 000 THP-I cells diluted in HBSS containing various amounts of organoteliurium 17 and JV-acetylcysteine (NAC) was added per well to a 96 well plate together with the Diogenes reagent 20 v/% (folio whig the manufacturer's recommendations) and 40 micro-M phorbol myristate acetate (PMA). Luminescence intensity was read every 6 min. All measurements were performed in quadruplicate (error-bars shown).

Claims

1. Use of a compound comprising a 3-pyridinol or 5-ρyrimidinol ring having an organoseleno- or organotelluro- substituent on the pyridine or pyrimidine ring, as an antioxidant.

2. Use as claimed in claim 1 wherein the compound is a compound according to formula I

1 wherein X is selected from Te and Sc;

Z is N or C-Ri;

R₁ is selected from

- alkyl, optionally substituted with, OH, alkoxy, SH, NH₂, W-alkylamino, N₁N- dialkylamino, COOH, aryl, optionally substituted with Ci-C₅ alkyl, Oil, alkoxy, SH, NH₂₅ JV-alkylammo, # JV-dialkylamino, COOH, CHO, NO₂, F₃ Ct, Br, I groups, and heteroaryl which is optionally substituted with Ci-C₅ alkyl, OH, alkoxy., SH, NII₂, N- alkylamino, Λ^iV-dialkylamino, COOH, CTIO, NO₂, F, Cl, Br, and I groups;

- aryl which is optionally substituted with Ci-C₅ alkyl, OH, alkoxy, SH, NH₂, N- alkylamino, W-dialkylamino, COOH, CHO₅ NO₂, F_} Cl₅ Br, and I groups; and

- heteroaryl, optionally substituted with Ci-C₅ alkyl. OH, alkoxy, SH, NH₂, N- alkylamino, iV;-V-dialkylamino, COOH₃ CHO, NO₂, F, Cl, Br, and I groups;

R₂, R3, and R₄ are the same or different and are each selected from - hydrogen;

- alkyl, optionally substituted with, OH, alkoxy, SH, NH₂, iV-alkylamϊno, N₁JV- dialkylamino, COOH, aryl which is optionally substituted with C1-C5 alkyl, OH, alkoxy, SH, NH₂, JV-alkylamino, N,JV-dialkylamino, COOH, CHO, NO₂, F, Cl, Br, I groups, and heteroaryl which is optionally substituted with C₁-C₅ alkyl, OH, alkoxy, SH, NH₂, JV-alkylamino, J^JV-dialkylamino, COOH₅ CHO, NO₂, F, Cl, Br, and I groups;

- alkoxy, JV-alkylamino, JV,7V-dialkylamino, alkylthio, wherein the alkyl groups are branched or unbranched and contain 1-5 carbon atoms, NH₂, OH₅ SH;

- aryl, optionally substituted with C₁-C₅ alkyl, OH, alkoxy, SH, NH₂, JV-alkylamino, N₃/V-dialkylamino, COOH₅ CHO, NO₂, F, Cl, Br, and I groups;

- heteroaryl, optionally substituted with C₁-C₅ alkyl, OH, alkoxy, SII, NTI₂, JV- alkylamino, JV,iV-dialkylamino, COOH, CHO, NO₂, F, Cl, Br, and I groups;

wherein in any of Ri, R₂, R₃ and R₄, unless otherwise specified, any alkyl moiety is a branched or unbranched C1-C30 alkyl, any aryl moiety is a C6-C10 aryl, and any heteroaryl moiety is 5-6 membered and contains one or several heteroatoras selected from N, O and S.

3. Use as claimed in claim 1 or claim 2, wherein X is Te.

4. Use as claimed in claim 2 or claim 3, wherein Rj is selected from branched or unbranched C₁-C₃₀ alkyl and phenyl.

5. Use as claimed in claim 4, wherein Ri is selected from branched or unbranched Ci- C₁₆ alkyl.

6. Use as claimed in any preceding claim, wherein the organoseleno- or organotelluro- substituent is alkylseleno- or alkyltelluro-, or wherein Ri is alkyl.

7. Use as claimed in any of claims 2 to 6, wherein R₂. JR.₃ and R₄ are independently selected from H, C_rC₆ alkyl, Ci-C₆ alkoxy, N,N-di-Cι-C₆ alkylamino and JV-Ci-C^ alkylamino.

8. Use as claimed in any of claims 2 to 7, wherein Z is CR₄.

9. Use as claimed in any of claims 2 to 8, wherein XRi is ortho or para to the hydroxy group.

10. Use as claimed in any of claims 2 to 9, wherein the group R₁X is in ortho position in relation to the hydroxy group on the nitrogen-containing heteroaromatic ring.

11. Use as claimed in any of claims 2 to 10, wherein XR₁ is bonded to a carbon atom which is both ortho to the hydroxy group and adjacent to a nitrogen atom of the heteroaromatic ring.

12. Use as claimed in any preceding claim, wherein the compound has an alkyl, alkoxy, dialkylamino or monoalkylamino substituent in one or more of the ortho and para positions relative to the hydroxy group.

13. Use as claimed in any of claims 2 to 12, wherein the compound is as defined in formula VII

VII wherein X, 2, Ri, R₂ and R₃ are as defined in any of claims 2 to 12.

14. Use as claimed in claim 13, wherein R₁ is C₂-C« alkyl.

15. Use as claimed in claim 13 or claim 14, wherein z is CH or C-(Ci-Cg alkyl), or C- (C₁-C₆ alkoxy).

16. Use as claimed in any of claims 13 to 15, wherein R.₂ and R₃ are the same or different and are selected from hydrogen, Ct-Q alkyl, Ci-C₆ alkoxy, di-fd-Cg alkyl)- amino, or mono-(Ci-Cg aikyl)ammo.

17. Use as claimed in any of claims 13 to 16, wherein X is Te.

18. Use as claimed in any of claims 13 to 17, wherein Ri is Ci-C₁₆ alkyl, R₂ is Me or H. R₃ is Me or H, 2 is CH or C-OMe, and X is Te.

19. Use as claimed in any of claims 2 to 5, wherein the compound, is according to formula II

wherein R₂ and R₄ are hydrogen or alkyl and R3 is an electron donating group such as JV,N-dialkyl amino, iV-alkylamino, alkoxy or alkyl.

20. Use as claimed in any of claims 2 to 5, wherein the compound is according to formula III

wherein one of R2 and R3 is an electron donating group such as N, N-dialkylamino, N- alkylamino, alkoxy or alkyl and the other one is hydrogen or alkyl and R₄ is hydrogen or alkyl.

21. Use as claimed in any of claims 2 to 5, wherein the compound is according to formula IV

IV wherein R2 and R₄ are hydrogen or alkyl and R₃ is an electron donating group sucli as Λ^N-diallcylarmno, JV-alkylamino, alkoxy or alkyl,

22. Use as claimed ..in. any.qf. claims.2. to .5, wherein .the .com pound is. according .to formula V

wherein R₂ is hydrogen or alkyl and R₃ is an electron donating group such as N₁N- dialkylamino, N-alkylamino, alkoxy or alkyl.

23. Use as claimed in any of claims 2 to 5, wherein the compound is according to formula VI

Vl wherein one of R2 and R₃ is an electron donating group such as ΛζN-dialkylamino, N- alkylamino, alkoxy or alkyl and the other one is hydrogen or alkyl.

24. Use as claimed in any preceding claim, wherein the compound is neither 2- (phenylseleno)-6-methyl-pyridin-3-ol nor 2-(phcnyltclluro)-6-methyl-ρyridin-3-ol.

25. Use of a compound as defined in any preceding claim as a catalytic antioxidant.

26. Use of a compound as defined in any preceding claim in combination with a reducing agent.

27. Use as claimed in claim 26. wherein the reducing agent is a thiol.

28. Use as claimed in claim 26, wherein the reducing agent is selected from Ν- acetylcysteine, cysteine, dithiothreilol, glutathione, ascorbic acid and sodium ascorbatc.

29. Use as claimed in any preceding claim, to stabilize a man-made or natural material, or prevent or inhibit oxidation or degradation of a man-made or natural material.

30. Use as claimed in claim 29, wherein the man-made or natural material is selected from a polymer, plastic, mbber, elastomer, paint, oil, lubricant, grease, fuel, paper or pulp product.

31. Use as claimed in any preceding claim, to preserve a liquid, solid or semi-solid material against oxidative degradation.

32. A man-made or natural material containing a compound the structure of which is as defined in any of claims 1 to 24, and optionally a reducing agent, as defined in any ofclaims 26 to 28.

33. A liquid, solid or semi-solid material comprising a compound the structure of which is as defined in any of claims 1 to 24, and optionally a reducing agent, as defined in any of claims 26 to 28.

34. A material as claimed in claim 33, selected from a polymer, elastomer, oil, lubricant, grease, fuel or paint composition or a paper or pulp product, comprising an antioxidant composition which comprises a compound the structure of which is as defined in any of claims 1 to 24_> and a mild reducing agent.

35. An antioxidant composition comprising a compound the structure of which is as defined in any of claims 1 to 24, and a reducing agent.

36. An antioxidant composition as claimed in claim 35, wherein the reducing agent is a mild reducing agent.

37. A compound, the structure of which is as defined in any of claims 1 to 24.

38. A compound, the structure of which is as defined in any of claims 1 to 24, with the proviso that said compound is not 2-(methylseleno)-pyrϊdin-3-ol.

39. A compound, the structure of which is as defined in any of claims 1 to 24, wherein the organ oseJeno- or organotelluro- substituent is an alkylseleno- or alkyltelluro- substituent.

40. A compound, the structure of which is as defined in any of claims 1 to 24, wherein the organoseleno- or organotelluro- substitucnt is an alkylseleno- or alkyltelluro- substituent, and with the proviso that said compound is not 2-(methylseleno)-pyridin- 3-ol.

41. A compound, the structure of which is as defined in claim 1, wherein the organoseleno- or organotelluro- substitucnt is an alkylseleno- or alkyl telluro- substituent, and with the proviso that said compound is not 2-(methylseleno)-pyridin- 3-ol.

42. A compound, the structure of which is as defined hi claim 2, wherein Ri is alkyl, and with the proviso that said compound is not 2-(melhγIseleno)-pyridin-3-ol.

43. A compound as claimed m claim 41 or claim 42, wherein said alkyl is C₁-Ci₆ alkyl.

44. A compound as defined in any of claims 1 to 24 or 37 to 43, or a pharmaceutically acceptable salt thereof, for use in therapy.

45. A compound as defined in any of claims 1 to 24 or 37 to 43, or a pharmaceutically acceptable salt thereof, in combination with a reducing agent, for use in therapy.

46. Λ compound as defined in any of claims 1 to 24 or 37 to 43, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable, mild reducing agent, for use in therapy.

47. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 24 or 37 to 43, or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition as claimed in claim 47, further comprising a reducing agent.

49. A pharmaceutical composition as claimed in claim 47, further comprising a pharmaceutically acceptable, mild reducing agent.

50. A pharmaceutical composition as claimed in claim 49, wherein the reducing agent is N-acetylcysteine, cysteine, dithiothreitol, glutathione, ascorbic acid or sodium ascorbate.

51. A pharmaceutical composition as claimed in any of claims 47 to 50, further comprising a pharmaceutically acceptable diluent, cxcipient or additive.

52. A compound as defined in any of claims 1 to 24 or 37 to 43 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any of claims 47 to 51, for the treatment of a disorder or condition caused by or involving free radical-mediated or oxidative tissue damage.

53. A compound as defined in any of claims 1 to 24 or 37 to 43 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any of claims 47 to 51, in combination with a pharmaceutically acceptable reducing agent, for the treatment of a disorder or condition caused by or involving free radical-mediated or oxidative tissue damage.

54. A compound as defined in any of claims 1 to 24 or 37 to 43 or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable reducing agent, or a pharmaceutical composition as defined in any of claims 47 to 51 , for the treatment of a disorder or condition selected from ischemic or reperfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, atherosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholitis, Crohn's disease, cataract, respiratory distress syndrome, damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents, ischemia/rcperfusion injury in the heart, kidney and CSN and post-operative ischemϊa/reperfusion injury, or for organ preservation, to treat burn injury, or to treat IBS (irritable bowel syndrome).

55. A compound as defined in any of claims 1 to 24 or 37 to 43 or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable reducing agent, or a pharmaceutical composition as defined in any of claims 47 to 51, for the treatment of a disorder selected from ischemic or reperfusion injuries, thrombosis, embolism, neoplasms, cancer, Parkinson's disease, Alzheimer's disease, atherosclerosis, allergic/inflammatory conditions such as bronchitis, asthma, rheumatoid arthritis, ulcerative cholϊtis, Crohn's disease, cataract, respiratory distress syndrome, damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents, ischemia/reperfusion injury in the heart, kidney and CSN and post-operative ischemia/reperfusion injury.

56. A method of treatment of a subject, for example a mammal, in need thereof, by administration of a therapeutically effective amount of a compound as defined in any of claims 1 to 24 or 37 to 43, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable reducing agent, or a pharmaceutical composition as defined in any of claims 47 to 51.

57. A method of treatment of a condition or disorder as defined in any of claims 52 to 55, comprising administering an effective amount of a compound as defined in any of claims 1 to 24 or 37 to 43, and optionally a pharmaceutically acceptable reducing agent, or a pharmaceutical composition as defined in any of claims 47 to 51.

58. The use of a compound as defined in any of claims 1 to 24 or 37 to 43, or of a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable reducing agent, or a pharmaceutical composition as defined in any of claims 47 to 51, in the manufacture of a medicament for treatment of a disorder caused by or involving free radical-mediated or oxidative tissue damage, for example a condition or disorder as defined in claim 54 or claim 55.