TECHNICAL FIELD

BACKGROUND OF THE INVENTION

It is well established that most cell types undergoing aerobic metabolism produce reduced metabolites of oxygen (ROMs), such as superoxide, hydrogen peroxide and hydroxyl radical, which possess considerable chemical reactivity. ROMs can induce the formation of secondary oxidative metabolites derived from tissue macromolecules for example during lipid peroxidation in cell membranes or in low-density lipoprotein (LDL). Under certain pathophysiological conditions these oxidants may be produced in extremely high concentrations locally in the tissues. During such episodes the ROM's contribute significantly to tissue destruction. Their secondary oxidative metabolites, such as hydroperoxides and aldehydes, are important chemokinetic and chemotactic messengers as well as inducers of a variety of enzyme activities and modulators of leucocyte adhesion and migration. Thus, ROM's can trigger pro-inflammatory receptors on important cells by direct oxidative interaction. ROM's and their secondary metabolites have been associated with a variety of disease states which include inflammatory disorders such as asthma, bronchitis and emphysema, various forms of autoimmune diseases including rheumatoid arthritis, ulcerative colitis,

Crohn's disease and synovitis as well as other pathophysiological conditions including atherosclerosis, cataract, ischemia/reperfusion damage in the heart, kidney or CNS, thrombosis and embolism and the adult respiratory distress syndrome. Thus, it is of considerable medicinal interest to develop suitable xenobiotic antioxidant molecules which protect against ROM's or augment the activity of the endogenous antioxidants.

The endogenous antioxidant network relies on a multitude of mechanisms for the prevention and limitation of damage caused by ROMs. Among the most prominent members of this network is vitamin E, which is a membrane associated chain breaking antioxidant. The vitamin serves to terminate free radical peroxidative destruction of membrane lipids by donation of hydrogen atoms to the propagating peroxyl species. It has been suggested, that the thus formed tocopheroxyl radicals become re-reduced to the operating vitamin by a relay mechanism involving vitamin C, glutathione and possibly also uric acid.

Another of the most important endogenous antioxidants, the enzyme gluta¬ thione peroxidase, contains at its active site a selenocysteine residue which is responsible for the redox activity of the molecule. The principal function of the enzyme is to reduce hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively, with glutathione serving as the reducing agent. Recently, several simple synthetic organoselenium compounds were claimed to possess glutathione peroxidase-like activity as well as free radical scavenging properties [EP 165,534, EP 44453, EP 198277]. The most well- documented of these compounds is Ebselen [EP 165,534]. Some diaryl diselenides, but not their corresponding diaryl selenides, were recently found to be more potent than Ebselen as glutathione peroxidase mimicing agents [WO 91/011 25].

PRIOR ART

In the prior art of th field there have appeared a few reports of the utilisation of tellurium containing organic compounds as oxidation or

peroxidation inhibitors. Thus, organotellurium compounds have been shown to be of use in the stabilisation of lubricants and as corrosion inhibitors [US 2 626 207, US 2 438 876, US 2 398 414, FR 805 666, GB 599 729, US 2 385 301, US 2 195 539, GB 790 281, GB 498 315, US 4 124 633]. There have also appeared numerous patents describing the use of diaryltellurides, and particularly their dihalide addition salts, in the area of photographic materials, more precisely their use as dry image forming materials [DE 2 005 462, US 4 113 496, US 4 144 062, JP 53-578 17, JP 53-142 222, JP 59-176 294]. A patent concerning the use of diaryltellurium (IV) compounds as oxidants has also appeared [US 4 013 730, GB 2 058 758].

A US patent, namely US 2,195,539 has claimed compounds of the general formula:

in which R and R' represent alkyl groups having at least four carbon atoms each, X represents an element of the sulfur family, consisting of sulfur, selenium and tellurium. The only example of synthesis, however, uses a method which cannot be applied in the case of tellurides since one of the starting materials would be tellurium dichloride. The existence of this compound in the solid state is, however, doubtful and therefore this method of synthesis does not enable the skilled man to synthesize the corresponding diaryl tellurides (Houben-Weyl: Methods of Organic Chemistry, Ed. D.

Klamann, Vol E 12 b, Thieme, Stuttgart 1990, page 2) which are the subject matter of the present invention. A publication disclosing compounds of the general formulas:

in which R represents H, OMe or OEt has appeared recently (Singh, A.K. et al., Polyhedron Vol 10, No 23,24, pp. 2693-2697, 1991). These compounds have been synthesized for scientific purposes and no technical application is disclosed.

DISCLOSURE OF THE INVENTION

The present invention relates to novel diaryl tellurides with antioxidant and/or glutathione peroxidase mimicing capacity, methods for their preparation and pharmacological use as well as pharmaceutical formulations containing them. The invention also relates to the application of diaryl tellurides, or salts or prodrugs thereof, generally for therapeutic purposes. In the definition aryl are included both substituted and unsubstituted aryls. Both new compounds according to formula 1 below and for technical applications previously known compounds are included. Such compounds are described in the prior art given above. The substituents can in addition to those defined below under formula 1 also be any substituent which can be attached to an

aryl nucleus. Especially preferred are those substituents defined under formula 1 and in addition those known from US 2,195,539 and Singh, A.K. et al. with the formulas given above.

The object of the invention is to provide an antioxidant and/or glutathione peroxidase mimicing diaryl telluride or a pharmaceutical composition thereof with activity against disorders caused by or involving oxidative tissue damage.

The compounds included in this invention are substituted diaryl tellurides of the general formula 1:

Ar ¹ - Te - Ar ¹¹

where Ar and Ar represent, the same or different, substituted aryl groups carrying the substituents which are defined below.

wherein Rj j, Rj2» ^13* ^21' ^22 ^an( ~ ^23 ^{are me same or} different and each selected from the group consisting of hydrogen, alkyl having 1-5 carbon atoms, OH, OR ¹ , SH, NH ₂ , NHR ¹ , NR ^! ₂ , NR ^J R ² and SR ¹ wherein R ¹ and R are different and each selected from the group consisting of an alkyl

having a carbon chain of 1 to 14 carbon atoms optionally carrying one or several hydrophilic groups, phenyl, phytyl or a cholesterol or phospholipid derivative

provided that at least one of R^j, -^12 ^or ^13 * ^s ®*-> ^R ' ^H> -^2' NHR ¹ , NR ¹ ^ NR ^! R ² or SR ¹ , wherein R ¹ and R ² are as defined above,

further provided that when one of R _{j j} , R^ or RJ is OR or NR 2 ^{tnen at} least one of R ₂ j, R ₂₂ ^or -^23 ^{ls se} l ^ectec -- fr° ^m OH, NH ₂ , SH, NHR , NR 1 R2 and SR 1 wherein R 1 and R2 are as defined above and still further provided that when Ar or Ar ¹ contains an OH group, then the remaining substituents on that aryl moiety must not represent a single methyl group.

R _j R _j 5, R ₂ 4 and R ₂ are the same or different and each selected from the group consisting of hydrogen, alkyl having 1-5 carbon atoms and alkoxy having 1-5 carbon atoms.

In the above alkyl shall mean groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butvl or amyl.

A carbon chain with 1-5 carbon atoms shall mean a straight or branched carbon chain, such as methyl, ethyl, propyl, iso-propyl, butyl or t-butyl.

A carbon chain with 1 to 14 carbon atoms shall mean a straight or branched carbon chain, such as methyl, ethyl, propyl, iso-propyl, butyl, octyl or tetradecyl.

Hydrophilic groups shall mean groups such as sulfonic, phosphonic or carboxylic acid, hydroxyl or amino groups.

Some of these compounds can form salts with either acids or bases. All physiologically acceptable salts are 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, arginine, choline, ethylenediamine, N,N'-dibenzylethylenediamine, 2-amino- 2-methyl-l,3-propanediol, 2-amino-2-methylpropanediol, benethamine, t- butylamine, cystamine, cysteamine, diethylamine, ethanolamine, methenamine, methyl nicotinate, nicotinamide, ethanolamine, piperazine, pyridoxine, spermidine, spermine, tromethamine, diethanolamine or triethanolamine.

The compounds or their salts can be administered together with supporting reducing equivalents of vitamines C or E or N-acetyl cysteine or salts thereof.

Also included in the invention are the corresponding diaryl telluroxides or other tellurium(IV) derivatives of the diaryl tellurides 1, such as dihalides, dicarboxylates and dialkoxides. Some of these derivatives are more soluble in water solution than their corresponding diaryl tellurides 1, and are readily reduced under physiological conditions to give the active antioxidant of formula 1. Such compounds may therefore be used as prodrugs.

The preferred compounds of the general formula 1 include those in which the aromatic groups carry substituents chosen according to one of the following criteria:

i) Ar ¹ = Ar ¹¹ and R _{j {} - R ₁₂ = R ₂₁ = R ₂₂ = H; R ₁₃ , R ₁₄ , R ₁₅ ,

R23, R ₇ 4 and R 5 are as defined above

ϋ) Ai Ar ¹¹ and R _I4 = R ₁₅ = R ₂₃ = R ₂₄ = R ₂₅ = H; R _u , R ₁₂ , R , defined above

iii) Ar*# AT ¹¹ and R _{χ l} = R ₁₂ = R ₂₁ = R ₂₂ = H; R ₁₃ , R ₁₄ , R ₁₅ ,

R ₂₄ and R ₂ ^ are as defined above

iv) Ar ¹ = Ar ¹¹ and R ₁₄ = R ₁₅ = R ₂₄ = R ₂₅ = H; R _{j {} , R _{2 , R ₁₃ ,

R I , R ₂₂ and R ₂₃ are as defined above.

Likewise preferred are salts of the above diaryl tellurides as well as diaryl telluroxides or other tellurium (IV) derivatives of the same diaryl tellurides, such as dihalides, dicarboxylates and dialkoxides.

Specifically preferred compounds according to the general formula 1 are those listed below:

4,4'-Dihydroxy- 1,1' -tellurobisbenzene

4-Hydroxy-l,l '-tellurobisbenzene

4- Amino-1, 1 '-tellurobisbenzene

2,4'-Dihydroxy- 1,1' -tellurobisbenzene

2,2' -Dihydroxy-1,1 '-tellurobisbenzene 4-(N-methylamino)- 1,1 '-tellurobisbenzene

N,N'-Dimethyl-4,4'-diamino-l, 1 '-tellurobisbenzene

N,N'-Dimethyl-2,4'-diamino- 1 , 1 '-tellurobisbenzene

N,N'-Dimethyl-2,2'-diamino- 1 , 1 '-tellurobisbenzene

N-Methyl-N-propyl-4-amino- 1, 1 '-tellurobisbenzene

N,N'-Dimethyl-N,N'-dipropyl-2,2'-diamino- 1,1 '-tellurobisbenzene 4-Mercapto- 1 , 1 '-tellurobisbenzene 4,4'-Dimercapto- 1 , 1 '-tellurobisbenzene N,N-Dimethyl-4-amino-4'-hydroxy- 1 , 1 '-tellurobisbenzene 4-Hydroxy-2,2',6,6'-tetramethyl- 1,1 '-tellurobisbenzene 4-Hydroxy-2,2',6,6'-tetramethoxy- 1 , 1 '-tellurobisbenzene 4-Hydroxy-2,2',6,6'-tetra-( 1 -methylethyl)- 1 , 1 '-tellurobisbenzene N-Methyl-4-amino-2,2',6,6'-tetramethyl- 1 , 1 '-tellurobisbenzene N-Methyl-4-amino-2,2',6,6'-tetramethoxy-l ,1 '-tellurobisbenzene N-Methyl-4-amino-2,2',6,6'-tetra(l-methylethyl)- 1,1 '-tellurobisbenzene 4-Mercapto-2,2',6,6'-tetramethyl- 1 ,1 '-tellurobisbenzene 4-Mercapto-2,2 ' ,6,6 '-tetramethoxy- 1,1' -tellurobisbenzene 4-Mercapto-2,2', 6,6 '-tetra(l -methylethyl)- 1,1 '-tellurobisbenzene 4,4'-Dihydroxy-2,2' ,6,6'-tetramethyl- 1 , 1 '-tellurobisbenzene 4,4'-Dihydroxy-2,2' ,6,6'-tetramethoxy- 1 , 1 '-tellurobisbenzene 4,4'-Dihydroxy-2,2'-dimethyl-6,6'-diethyl- 1 , 1 '-tellurobisbenzene 4,4'-Dihydroxy-2,2',6,6'-tetra( 1 -methylethyl)- 1 , 1 '-tellurobisbenzene N,N'-Dimethyl-4,4'-diamino- 2,2',6,6'-tetramethyl- 1,1 '-tellurobisbenzene N,N'-Dimethyl-4,4'-diamino-2,2',6,6'-tetramethoxy-l, -tellurobisbenzene N,N'-Dimethyl-4,4'diamino-2,2',6,6'-tetra( 1 -methylethyl)- 1,1'- tellurobisbenzene

4,4 ' -Dimercapto-2,2 ' ,6,6 ' -tetramethy 1- 1,1 ' -tellurobisbenzene 4,4'-Dimercapto-2,2' ,6,6 '-tetramethoxy- 1 , 1 '-tellurobisbenzene 4,4'-Dimercapto-2,2'-dimethyl-6,6'-di( 1 -methylethyl)- 1 , 1 '-tellurobisbenzene 4-Hydroxy-3,5-dimethyl- 1,1 '-tellurobisbenzene

4-Hydroxy-3,5-di( 1 -methylethyl)- 1 , 1 '-tellurobisbenzene 4-Hydroxy-3,5-di( 1 , 1 -dimethylethyl)- 1,1 '-tellurobisbenzene N-Methyl-4-amino-3,5-dimethyl- 1 , 1 '-tellurobisbenzene N-Methyl-4-amino-3 ,5-di( 1 , 1 -dimethylethyl)- 1 , 1 '-tellurobisbenzene

4-Mercapto-3,5-di(l , 1 -dimethylethyl)- 1 , 1 '-tellurobisbenzene 4,4'-Dihydroxy-3,3',5,5'-tetramethyl-l, -tellurobisbenzene 4,4'-Dihydroxy-3 ,3 ' ,5,5' -tetra( 1 , 1 -dimethylethyl)- 1 , 1 '-tellurobisbenzene 4,4'-Dimercapto-3,3',5,5'-tetramethyl-l, -tellurobisbenzene 4,4'-Dimercapto-3,3 ',5,5'-tetra(l , 1 -dimethylethyl)- 1 , 1 '-tellurobisbenzene N,N-Dimethyl-4,4'-diamino-3,3 ',5,5'-tetramethyl-l, 1 '-tellurobisbenzene N,N-Dimethyl-4,4'-diamino-3,3',5,5'-tetra(l,l-dimethylethyl) -l,l'- tellurobisbenzene 2,2'-Dihydroxy-6,6'-dimethyl- 1 , 1 '-tellurobisbenzene 2,2'-Dihydroxy-6,6'-di(l-methylethyl)-l,l '-tellurobisbenzene

N,N'-Dimethyl-2,2'-diamino-6,6'-di(l-methylethyl)-l,l '-tellurobisbenzene 2,2'-Dimercapto-6,6'-dimethyl- 1 , 1 '-tellurobisbenzene 2,2'-Di(methylthio)-4,4'-dimethoxy- 1 , 1 '-tellurobisbenzene 2-Hydroxy-4'-(methylthio)-l,l '-tellurobisbenzene 4,4'-dihydroxy-2,2',3,3',5,5',6,6'-octamethyl-l,r-tellurobis benzene 4-hydroxy-4'-methoxy-2,2',6,6'-tetramethyl- 1, 1 '-tellurobisbenzene 4-hydroxy-4'-butoxy-2,2',6,6'-tetramethyl-l ,1 '-tellurobisbenzene 4-hydroxy-4'-octyloxy-2,2',6,6'-tetramethyl- 1 , 1 '-tellurobisbenzene 4-hydroxy-4'-tetradecyloxy-2,2' ,6,6'-tetramethyl- 1 , 1 '-tellurobisbenzene N,N'-Diphenyl-4,4'-diamino- 1 , 1 '-tellurobisbenzene 4-Hydroxy-4'-tetradecyloxy- 1 , 1 '-tellurobisbenzene 4-Carboxymethoxy-4'-hydroxy-2,2\6,6'-tetramethyl-l , 1 '-tellurobisbenzene 4-Carboxymethoxy-4'-hydroxy-l,l '-tellurobisbenzene

Likewise preferred are salts of the above diaryl tellurides as well as diaryl telluroxides or other tellurium (IV) derivatives of the same diaryl tellurides, such as dihalides, dicarboxylates and dialkoxides.

According to the present invention, the compounds of the formula 1 have unexpectedly been found to possess extremely potent antioxidant capacity, some of them in combination with a unique ability to decompose hydroperoxides and hydrogen peroxide. Thus, the compounds of the invention show much higher efficacy than the corresponding sulfides and selenides in assays which assess the free radical scavenging action of such compounds. Examples of this property are provided below. Also, the compounds of the general formula 1 possess the unique ability to act in a catalytic way with respect to their free radical scavenging action, in a milieux where reducing equivalents are available. Such a milieux would be prevailing in a normal physiological system, such as in the cytosol, plasma or other compartments in mammalian organisms. When required due to disease conditions, supporting reducing equivalents such as vitamins C or E or a suitable thiol, such as glutathione or N-acetyl cysteine may be co- administrated with the compound of formula 1.

The present compounds are thus capable of reacting with the chain pro¬ pagating species, most importantly the peroxyl radical, of the free radical mediated peroxidation of physiologically relevant molecules such as fatty acids, e.g. linoleic or arachidonic acid, to produce a tellurium (IV) oxide. The so formed telluroxide can be reduced to a diaryl telluride in the presence of a suitable reducing agent. Relevant reducing agents which are present in a physiological situation include ascorbate, vitamin E, glutathione, cysteine and lipoic acid as well as a variety of protein thiols. Examples of this type of action are provided below.

Diaryl selenides have been shown to be devoid of any glutathione peroxida- se-like activity [WO 91/011 25]. It was therefore unexpected to find that certain diaryl tellurides, i.e. the compounds of the formula 1, display an ex-

tremely efficient such activity. Thus, in the presence of a physiologically relevant (such as vitamine C, vitamine E or glutathione) or synthetic (such as N-acetylcysteine, N-isobutyrylcysteine, t-butyl mercaptan or octyl mercaptan) reducing agent, the compounds of formula 1 rapidly decompose organic hydroperoxides or hydrogen peroxide with concomitant production of an alcohol or water. This reaction does not consume the telluride of formula 1. Examples of this type of catalytic action are provided below.

It will be appreciated by those skilled in the art, that the compounds of formula 1 differ in the relative expression of the two kinds of antioxidant action, i.e. radical chain breaking and glutathione peroxidase-like behaviour, which are disclosed above.

The compounds of formula 1 interfere with pathophysiologically important reactions in man or animals, and thus effectively hamper the degradation of tissue constituent molecules as well as act to remove harmful products from such degradation. The compounds possess a unique ability to protect tissues against excessive oxidative damage induced by overreacting host defence systems.

The compounds of formula 1 are therefore useful for the pharmacological treatment of diseases in which oxidative tissue degradation occurs or where oxidants trigger pro-inflammatory receptors on cell surfaces. Such diseases involve for instance inflammatory (including autoimmune inflammatory) conditions, like asthma, bronchitis, various allergic skin and systemic disorders, Crohn's disease, ulcerative colitis, coeliaci and rheumatoid arthritis and other kinds of arthritis.

The compounds of formula 1 may also be used for the intervention of cataract or the adult respiratory distress syndrome.

Further, the involvement of oxidative damage in artherosclerosis and in ischemia/reperfusion injury in the heart, kidney, CNS or post-operative ischemia/reperfusion injury as well as in thrombosis and embolism makes these disorders liable to intervention by the compounds of formula 1.

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 by the compounds of formula 1.

The oxidative damage to tissues caused by particularly radiation, but also by antineoplastic or immunosuppressive agents and other xenobiotics can be prevented or limited by the use of the compounds of formula 1.

The compounds of formula 1 are also useful for preventing oxidation in technical products such as oils, lubricants or polymers or as stabilisers or preservatives in foodstuffs.

METHODS OF PREPARATION

All compounds 1 described in the present invention are prepared according to one or several of the methods listed below:

a) Tellurium extrusion from compounds Ar-Te-Te-Ar to give diaryl tellurium products Ar-Te-Ar when the compound is heated above its melting point. This conversion can be effected almost quantitatively by refluxing the diaryl ditelluride with copper powder in toluene or dioxane. The

method is particularly suitable for the preparation of symmetrical compounds 1, (Ar = Ar^), however, by submitting a mixture of two different diaryl ditellurides Ar-TeTe-Ar and ArVTeTe-Ar ¹ to the reaction conditions, it is possible to isolate unsymmetrical diaryl tellurides Ar-Te-Ar^ in addition to the symmetrical diaryl tellurides.

b) Treatment of aryltellurenyl compounds Ar-TeX (where X = F, Cl, Br, I, SCN, CN, acetyloxy, C10 ₄ , N0 ₃ ) with organometallic compounds Ar^-M (where M = Li, MgBr, MgCl, Mgl) or diaryl cadmium compounds Ar ₂ Cd. The method is applicable to the preparation of symmetrical (Ar = Ar ¹ ) and unsymmetrical (Ar # Ar^) compounds 1. If present, OH, SH, NH ₂ , NHR and NHR groups are suitably protected in the reaction, preferably as trimethylsilyl or t-butyldimethylsilyl ethers, sulfides and amides, respectively. Deprotection is conveniently effected by treatment with tetrabutylammonium fluoride.

c) Treatment of diaryl ditellurides Ar-Te-Te-Ar with an equimolar amount of an organometallic reagent ArVM (where M = Li, MgBr, MgCl, Mgl). The method is applicable to the preparation of symmetrical ( Ar = Ar ¹ ) and unsymmetrical ( Ar # Ar ¹ ) compounds 1. If present, OH, SH, NH ₂ , NHR ¹ , and NHR ¹¹ groups are suitably protected in the reaction, preferably as trimethylsilyl or t-butyldimethylsilyl ethers, sulfides and amides, respectively. Deprotection is conveniently effected by treatment with tetrabutylammonium fluoride.

d) Treatment of l:2-complexes of TeX ₄ (where X = F, Cl, Br or I) and substituted aromatic amines Ar-H (where one of Rt , , Rι ₂ and R _j3 is

NHR 1 ¹ , or NH ₂ ) with a suitable reducing agent such as sodium sulfide, sodium or potassium disulfide, sodium borohydride, Ra-Ni, lithium

aluminium hydride, potassium sulfide, sodium or potassium sulfite, thiourea dioxide, zinc, hydrazine or sodium ascorbate. The unstable diaryl ditellurides Ar-Te-Te-Ar formed as intermediates in the reaction are induced, by heat or copper powder, to lose one tellurium atom. The method is applicable to the preparation of symmetrical compounds 1 (Ar = Ar ) carrying an NHR NR 1 R 2 or NH ₂ substituent as defined above.

e) Reduction of diaryl tellurium (IV) derivatives

X

I

Ar ¹ - Te - Ar ¹¹

(where X and Y are F, Cl, Br, I, OH, SCN, CN, alkoxy, thioalkyl, acetyloxy), or

Ar ¹ - Te - Ar ¹¹

(where X = O, S or NS0 ₂ Ph) with a reducing agent such as potassium sulfide, sodium or potassium hydrogen sulfite, thiourea dioxide, sodium sulfide, sodium or potassium disulfite, sodium borohydride, Ra-Ni, methyl magnesium iodide, lithium aluminium hydride, zinc, hydrazine or sodium ascorbate.

f) Reduction of aryl tellurium (IV) trihalides Ar-TeX ₃ (where X = F, Cl, Br, I) with a reducing agent such as sodium sulfide, sodium or potassium disulfite, sodium borohydride, potassium sulfide, sodium or potassium sulfite, thiourea dioxide, Ra-Ni, lithium aluminium hydride, zinc, hydrazine or sodium ascorbate and thermal or copper-induced tellurium extrusion of the so formed diaryl ditelluride. The method is applicable to the preparation of symmetrical compounds 1 (Ar = Ar^).

g) Reaction of two equivalents of an organometallic reagent Ar-M (where M = Li, MgBr, MgCl, Mgl) with a suitable Te(II) equivalent such as di(phenylethynyl)telluride or l,l-dichloro-2,5-dihydrotellurophene. The method is applicable to the preparation of symmetrical compounds 1 (Ar = A If present, OH, SH, NHR ¹ or NH ₂ groups are suitably protected during the reaction, preferably as trimethylsilyl or t-butyldimethylsilyl ethers, sulfides and amides, respectively. Deprotection is conveniently effected by treatment with tetrabutylammonium fluoride.

h) Treatment of aryldiazonium salts, ArN ₂ ⁺ X ^~ where X = Cl, Br,

BF ₄ , with potassium tellurocyanate or alkali metal tellurides M Te (M = Li, Na, K) in a polar solvent such as DMSO or DMF. The method is only applicable to the preparation of symmetrical compounds 1 (Ar = Ar ¹ ). Small amounts of diaryl ditellurides Ar-Te-Te-Ar are frequently formed as byproducts in the reaction. These can be conveniently induced to extrude one tellurium atom by heat or copper to give pure diaryl tellurides 1.

i) Treatment of alkali metal tellurides M ₂ Te (where M = Li, Na,

K) in polar aprotic solvents (like DMF, DMSO, THF) or liquid ammonia with aryl halides Ar-X (where X = Cl, Br, I). The method is only applicable to the preparation of symmetrical compounds 1 (Ar = Ar ¹¹ ).

j) Thermolysis of diaryl mercury compounds Ar ₂ Hg or tetraaryltin compounds Ar ₄ Sn with elemental tellurium in a sealed tube at 200-250°C. The method is only applicable to the preparation of symmetrical compounds 1 (Ar ¹ = Ar ¹¹ ).

k) Treatment of alkali metal tellurolates (M = Li, Na, K) in aprotic solvents or in liquid ammonia under UV-irradiation with aryl halides (where X = Cl, Br, I).

1) Treatment of alkali metal tellurolates (M = Li, Na, K) with arenediazonium salts Ar"N ₂ X (X = Cl, Br, I, BF ₄ ).

m) Treatment of trialkylphosphine tellurides R ₃ P=Te (R = Me, Et,

Pr, Bu) with diaryl mercury compounds Ar ₂ Hg. The method is only applicable to the preparation of symmetrical compounds 1 (Ar = Ar ).

n) Thermolysis of tetraaryl tellurium compounds Ar ₄ Te with elimination of Ar-Ar. The method is only applicable to the preparation of symmetrical diaryl tellurides 1 (Ar - Ar ¹ ).

o) Thermolysis of diaryl alkyl telluronium compounds

Ar Ar e ⁺ RX ^" (R = lower alkyl or benzyl group) or reduction of triaryltelluronium compounds Ar ₃ Te ⁺ X ^" (X = Cl, Br, I, F) with suitable reducing agents like alkylmagnesium halides or alkali metals.

p) Treatment of diaryl ditellurides ArTeTeAr with arenediazonium halides Ar ₂ ⁺ X ^" (X = Cl, Br, I) in acetone or acetone/acetonitrile. The product is a 1 :1 mixture of diaryl telluride, Ar-Te-Ar\ and diaryl tellurium dihalide,

Ar ¹ - Te - Ar ¹¹

After reduction with a suitable reducing agent (sodium or potassium sulfide, sodium or potassium hydrogen sulfite, thiourea dioxide, sodium borohydride, Ra-Ni, lithium aluminum hydride, zinc, hydrazine or sodium ascorbate) the unsymmetrical telluride Ar-Te-Ar^ will result. The method is also applicable to the preparation of symmetrical tellurides (Ar=Ar^).

q) Treatment of a diaryl telluride, Ar - Te - Ar _% containing one or several nucleophilic substituents (OH, SH, NH ₂ , NHR or NHR groups) with an alkylating agent to give mono-, di- or polyalkylation products. The alkylating agent may either be an unsubstituted alkyl halide or sulfonate containing 1-14 carbon atoms, or an alkyl halide or sulfonate containing one or several hydrophilic, suitably protected, substituents such as a carboxylic acid, sulfonic acid, phosphoric acid, or hydroxyl or amino groups.

PHARMACEUTICAL PREPARATIONS

The compounds of the present invention can be utilized both prophylactically and therapeutically. They are effective when administered within the range from 0.1 mg/kg to 50 mg/kg of body weight per day. For prophylactic administration, correspondingly lower doses can be utilized.

The compounds can be administered both orally, intravenously or by

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

ANTIOXIDANT ACTIVITY

The capacity of the compounds of formula 1 to express antioxidant activity with respect to both free radical mediated peroxidation processes and eliminating harmful prooxidant molecules was determined by using several standard assays. The effects are exemplified in tables I and II and in figure 1, where the antioxidant action is apparent in three independent model systems. The unique, catalytic mode of action expressed by the compounds of formula 1 is demonstrated in figures 2 through 4.

Lipid peroxidation in rat liver microsomes. The livers of male Sprague- Dawley rats were exsanguinated, excised and homogenized in an ice-cold sucrose (250 mM/phosphate (50 mM) buffer, pH = 4 using a polytron). The homogenate was centrifuged once at 12,000 g, at 4° for 30 min and the supernatant recentrifuged at 105,000 g at 4° for 60 min. The pellet was resuspended and washed twice with 150 mM KC1 before used in the experiments. Microsomes were prepared fresh before each batch of experiments.

Microsomal lipid peroxidation was performed in incubations constructed as follows: incubations (1 ml) in phosphate (50 mM) buffer, pH 7,4 containing

microsomal protein (lmg), ADP (200 μM), FeS0 ₄ (1 μM) and vehicle/test substance, were preincubated for 5 min at 37° before addition of the initiation stimulus ascorbate (50 μM). For screening experiments the accumulation of thiobarbituric acid (TBA) reactive substances (malondialdehyde equivalents) over 30 min of incubation in antioxidant- treated samples was compared to control levels in microsomes treated with DMSO vehicle only. Individual 50% inhibition concentrations (IC^Q values) were calculated from the best-fit curve of the effect of a range of concentra¬ tions of the compounds. Controls demonstrated that the compounds did not react with TBA-reactive substances in the system. In all cases the DMSO concentration of the incubations was less than 0.5% (v/v). This concentration of the vehicle did not affect the time course of peroxidation or the extent of peroxidation after 30 min.

Lipid peroxidation was assessed by assay of the accumulation of TBA- reactive substances in supematants of trichloracetic acid-precipitated samples of microsomes as described previously [Thurman RG, Ley HG and Scholz R. Hepatic microsomal ethanol oxidation. Hydrogen peroxide formation and the role of catalase. E r J Biochem 25: 420-425, 1972].

Briefly, aliquots (0.5 ml) of incubations were mixed with equal volumes of trichloroacetic acid (TCA) (10% v/v) containing 10 mM butylated hydroxytoluene and then reacted with TBA at 95° for 15 min. The samples were then centrifuged (1000 g, 5 min) and the absorbance determined at 535 nM. The concentration of malondialdehyde equivalents (MDA) was determined using a molar extinction coefficient of 1.56 x 10^ M ^"1 cm ^" .

The results given in Table I exemplify that micromolar, or even submicromolar concentrations of the compounds of formula 1 efficiently

inhibit peroxidative deterioration of physiologically relevant, membrane constituent molecules.

Glutathione peroxidase-like activity. The principal function of the enzyme glutathione peroxidase is to reduce hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively, in the presence of a thiol (glutathione) which serves as the stoichiometric reducing agent. Synthetic compounds which mimic this behaviour have been ascribed a glutathione peroxidase-like behaviour.

The glutathione peroxidase-like activity of the compounds of formula 1 was determined by using a H-NMR method. In this assay the catalyst to be evaluated was added to a rigorously cleaned NMR tube containing a thiol (N-acetylcysteine or t-butyl mercaptan) and hydrogen peroxide. The glutathione peroxidase-like activity was quantified by recording the H NMR spectrum of the solution at intervals and determination of the half-life of the thiol. These data, together with half-life data of the thiols in the absence of catalyst (control), are shown in Table π. It is obvious that the compounds exemplified show a substantial catalytic effect as compared to the control.

Inhibition of stimulated autoxidation of linoleic acid. The mechanism of action of the compounds of formula 1 was studied in a system utilising 2,2'- azobis (2-methylvaleronitril) as an inducer of peroxidation of linoleic acid in methanol [J.M. Braughler, J.F. Pregenzer Free Rad. Biol. Med. 1989, 7, 125]. In this system, 4,4'-dihydroxy-2,2',6,6'-tetramethyl- 1,1 '-tellurobisbenzene acts as an efficient inhibitor of lipid peroxidation, as demonstrated in Figure 1. The telluride is under these conditions cleanly and completely converted into the corresponding telluroxide during the chain-terminating reaction with the propagating peroxyl radical. This telluroxide is, however, very efficiently

reduced to the operating antioxidant, the telluride, by e.g. thiols, ascorbate or vitamin E. This catalytic behaviour is exemplified in Figures 2 and 3, obtained by monitoring the 4,4'-dihydroxy-2,2',6,6'-tetramethyl-l,r- tellurobisbenzene and its corresponding oxide during peroxidation of linoleic acid performed as above. The figures clearly demonstrate regeneration upon the addition of equimolar amounts of ascorbate or a thiol, respectively.

A situation facilitating recycling of the inhibitors of formula 1 would prevail under physiological conditions.

The catalytic cycle indicated in Figure 4 schematically summarises both the chain-breaking antioxidant activity and the glutathione peroxidase-like behaviour exerted by the compounds of formula 1.

Table I. Antioxidant Capacity of Diaryl Tellurides 1 in the Microsomal

Peroxidation Assay Compound 1 IC ₅ Q (μM) ¹

4-hydroxy- 1,1 ' -tellurobisbenzene 0, 13

2,2'-dihydroxy- 1 , 1 '-tellurobisbenzene 0, 17

N,N'-dimethyl-4,4'-diamino- 1 , 1 '-tellurobisbenzene 0, 18

N,N'-diphenyl-4,4'-diamino- 1 , 1 '-tellurobisbenzene 0,93

4,4'-dihydroxy-l,l '-tellurobisbenzene 0,21

4,4'-dihydroxy-3,3',5,5'-tetra(l,l-dimethylethyl) > 2,5

-1,1 '-tellurobisbenzene

4,4'-dihydroxy-2,2',6,6'-tetramethyl-l,l ' 0,85

-tellurobisbenzene

4,4'-dihydroxy-2,2',3,3',5,5',6,6'-octamethyl 0,40

-1,1 '-tellurobisbenzene

4,4'-dihydroxy-3,3 ',5,5 '-tetramethyl- 1,1 '- 0, 17 tellurobisbenzene

4-hydroxy-2,2\6,6'-tetramethyl- 1,1'- 1 ,05 tellurobisbenzene

4-hydroxy-4'-methoxy-2,2',6,6'-tetramethyl-l,l'- 1,15 tellurobisbenzene

4-hydroxy-4'-butoxy-2,2',6,6'-tetramethyl-l,l '- 0,83 tellurobisbenzene

4-hydroxy-4'-octyloxy-2,2\6,6'-tetramethyl- 1,1 '- > 2,5 tellurobisbenzene

4-hydroxy-4'-tetradecyloxy-2,2',6,6'- > 2,5 tetramethyl- 1 , 1 '-tellurobisbenzene

IC^g-values were determined from plots of twelve concentrations in the range 5nM - 2,5 μM

Table DL Glutathione Peroxidase-like Activity of Diaryl Tellurides 1 as Determined by the Ability to Catalyse the Oxidation of Thiols by H ₂ 0 ₂

Compound 1

4,4'-dihydroxy-l,l '-tellurobisbenzene 2,2' -dihydroxy-1,1 '-tellurobisbenzene N,N'-dimethyl-4,4'-diamino- 1,1 '-telluro¬ bisbenzene 5 128 N,N'-diphenyl-4,4'-diamino- 1 , 1 '-telluro¬ bisbenzene 232 14 4,4'-dihydroxy-3,3 ',5,5'-tetramethyl- 1,1 '-tellurobisbenzene 1 14

The half-life of the thiol was determined by integration in the H NMR spectrum. For N-acetylcysteine the disappearance of peaks at 4.62 ppm and the appearance of new peaks at 4.73 ppm were characteristic. For t-butyl mercaptan the disappearance of the singlet absoφtion at 1.40 ppm and the appearance of another singlet at 1.29 ppm were characteristic. The values in Table π are not corrected for the slow spontaneous oxidation of the thiols by H ₂ θ2 itself (= control).

To N-acetylcysteine (15 mg) in 750 μL of a 4/1 -mixture of D ₂ 0 and CD ₃ OD was added H ₂ 0 ₂ (4.7 μL, 30%) and the catalyst to be evaluated ( (22..77 xx 1100 ^""7 ' mmooll)) ddiissssoollvveedd iinn 1100 μ μLL ooff CCDD ₃ O0DD//CCHHQC1 ₃

To t-butyl mercaptan (10 μL) in 750 μL of CD ₃ OD was aa<dded H2O2 (4.7 μL; 30%) and the catalyst to be evaluated (2.7 x 10 ^~7 mol) dissolved in 10 μL of CD ₃ 0D/CDC1 ₃ .

Table II cont'd

4,4'-dihydroxy-2,2',6,6'-tetramethyl

-1,1 '-tellurobisbenzene 180 -

Control 3300 »5000

Not determined.

15 30 45 60 75 time/min

Figure 1. Formation of Conjugated Dienes by AMVN-induced Peroxidation of Linoleic Acid.

12 24 36 48 60 time/min

Figure 2. Regeneration of a ^' Telluride from its Telluroxide by the Addition (Arrow) of Ascorbate.

t/miπ

Figure 3. Regeneration of a Telluride from its Telluroxide by Additions (Arrows) of Captopril.

R 0 O ' (C hain. breaking) R O O H R O O H lβ SH ?ι activity) R O H

ArTeAr

Oxidised products Thiols (E .g. GSH) (E.g. GSSG, Ascorbate Dehydroascorbate) Vitamin E Etc

R= H, Alkyl, etc

Figure 4. Catalytic Antioxidant Behaviour of the Compounds of Formula 1.

WORKING EXAMPLES

Chemistry

Example Cl

4-Hvdroxy-l,V -tellurobisbenzene: A solution of phenyltellurenyl bromide was prepared under nitrogen at -78°C by addition of bromine (63 μL, 1.23 mol) to a solution of diphenyl ditelluride (0.50 g, 1.22 mmol) in dry THF (15 mL). To this solution was added by syringe a solution of I-lithio-4(t- butyldimethylsilyloxy)benzene, prepared from the reaction of t-butyllithium (2.9 mL; 1.7 M, 4.9 mmol) and l-bromo-4(t-butyldimethylsilyloxy)benzene (0.70 g, 2.4 mmol) in dry THF (10 mL) at -78°C. After lh at -78°C, the cooling-bath was removed and stirring continued for 2h. The work-up included evaporation of the solvent, extraction of the product into CH C , washing with water and drying of the organic phase. After evaporation the residue was dissolved in dry THF (10 mL) and treated with tetrabutylammonium fluoride (2 mL; 1 M, 2.0 mmol) in an ice-bath for 30 min to remove the silyl protecting group. Work-up as described above and chromatography (SiC^/C^C^) afforded a crude product. To remove some remaining phenol, the product was dissolved in C^C^/hexane (1/1) and SO2CI2 added until no more 4-hydroxy-l, -tellurobisbenzene dichloride was precipitated. The dichloride was then reduced with NzqS Qr in water/ether in a separatory funnel and the product passed through a short silica column (CH ₂ C1 ₂ ). The yield of 4-hydroxy-l,l'-tellurobisbenzene, m.p. 65°C, (Found: C, 48.62; H, 3.26. C ₁₂ H ₁₍₎ OTe requires C, 48.40; H, 3.38) δ _H (250 MHz; CDCI3) 4.81 (s, 1H), 6.73 (d, 2H), 7.14-7.26 (several peaks, 3H), 7.57 (m, 2H), 7.68 (d, 2H), was 0.10 g (14%).

Example C2 t-Butyllithium (10 mL, 1.7 M, 17.0 mmol) was added at-78°C under N2 to a stirred solution of 2-bromophenol (0.98 g, 5.7 mmol) in dry THF (40 mL). After lh the cooling-bath was removed and the temperature allowed to rise to ambient. Finely ground elemental tellurium (0.73 g, 5.7 mmol) was then added and stirring continued for lh when only trace-amounts of unreacted tellurium remained. The solution was then poured into water (100 mL) containing K Fe(CN)^ (1.87 g, 5.7 mmol) and acidified with acetic acid. Extraction with CH2CI2 (3 x 50 mL) afforded a mixture of telluride and ditelluride. This was heated at reflux in EtOH for 1.5 h to extrude elemental tellurium. Chromatography (Si0 ₂ ; CH ₂ C1 ₂ ) afforded 0.50 g (56%), of 2,2'-dihydroxy-l,l '- tellurobisbenzene, m.p. 133-4°C, (250 MHz; CDCI3) 5.85 (s, 2H), 6.78 (m, 2H), 6.96 (d, 2H), 7.25 (m, 2H), 7.51 (d, 2H) (Found: C, 46.05; H, 3.25. C ₁₂ H ₁₀ O ₂ Te requires C, 45.93; H, 3.25).

Example C3

N,N'-Dimeth l-4 ' -diamino-l.r -tellurobisbenzene: A 2: 1 -complex was prepared from N-methylaniline and TeCl^ in analogy with a literature method [G.T. Morgan and H. Burgess, /. Chem. Soc. 1103 (1929)]. A solution of Na2S2C>5 (1.01 g, 5.33 mmol) in H2O (20 mL) was added to a suspension of the complex (1.29 g, 2.67 mmol) in CH ₂ Cl2 (20 mL). The red precipitate that was formed dissolved when the aqueous phase was neutralized (pH = 7-8) by the addition of NaHCOg in portions. After separation, the aqueous phase was extracted with additional CH2CI2 (2 x 25 mL). The combined organic phases were dried (CaCl ₂ ) and evaporated. The semisolid residue was slowly transferred (10 h) through a silica gel column which darkened due to precipitation of elemental tellurium. However, TLC indicated that some ditelluride still remained in the product. The material was

therefore dissolved in dioxane (20 mL) and refluxed for 10 min with activated copper (1.1 g). The yield of N,N'-dimethyl-4,4'-diamino-l, - teUurobisbenzene was 0.29 g (64%), δp _j (250 MHz; CDCI3) 2.79 (s, 3H), 3.7-3.8 (bs, 1H), 6.45 (d, 2H), 7.54 (d, 2H). The telluride was converted to the corresponding Te,Te-dichloride, and analysed as such, by the following procedure: A solution of sulfuryl chloride (0.022 mL, 0.26 mmol) in CH2CI2 (0.5 mL) was added dropwise to an icecold solution of N,N'-dimethyl-4,4'- diamino- 1,1 '-tellurobisbenzene (0.09 g, 0.26 mmol) in CH2CI2 (3 mL). The solution immediately turned green. Hexane (10 mL) was added after 2 min and a green precipitate was formed. It was filtered off after 2 h in the freezer. Yield: 95 mg (89%). The analytical sample was obtained after two recrystallizations from EtOH, m.p. 140-50°C (dec), δ _jj (250 MHz, DMSO- d ₆ ) 2.70 (s, 3H), 6.35 (bs, 1H), 6.62 (d, 2H), 7.60 (d, 2H). (Found: C, 41.05; H, 3.79 C ₁₄ H ₁₆ Cl ₂ N ₂ Te requires: C, 40.93; H, 3.93).

Example C4

N,N'-DiOhenyl-4,4'-diamino-lJ' -tellurobisbenzene: The 2:1 -complex of N- phenylaniline and TeCl^ (3.0 g, 4.9 mmol), prepared in analogy with a litera¬ ture procedure [G.T. Morgan and H. Burgess /. Chem. Soc. 1103 (1929)], was treated as described in Example C3. The yield of N,N'-diphenyl-4,4'- diamino-1,1 '-tellurobisbenzene was 0.59 g (51%), m.p. 91°C, δg (250 MHz; CDCI3) 5.67 (s, 2H), 6.88 (d, 4H), 6.94 (m, 2H), 7.05 (d, 4H), 7.25 (m, 4H), 7.58 (d, 4H) (Found: C, 62.02; H, 4.26. C^H^^Te requires C, 62.12; H, 4.34).

Example C5

4.4' -Dihvdroxy-l.r -tellurobisbenzene: 4-Hydroxyphenyl tellurium tri¬ chloride (5.0 g, 15.3 mmol) was added to a separatory funnel containing Na ₂ S ₂ 0 ₅ (6.0 g, 31.6 mmol) in water (100 mL) and CH ₂ C1 ₂ (100 mL).

Vigorous shaking produced a reddish-black heterogeneous mixture which was filtered to remove insoluble material. This was extracted with boiling CH2CI2 (100 mL) and combined with the organic phase from the separatory funnel. After drying and evaporation the residue was dissolved in dioxane (30 mL) and heated at reflux with activated copper powder for 1 h. This treatment caused a decoloration of the solution. Filtration from Cu-residues, evaporation under reduced pressure and recrystallization from CH ₂ Cl ₂ /hexanes afforded 0.55 g (23%) of 4,4'-dihydroxy-l,l '- tellurobisbenzene, m.p. 102-3°C (Found: C, 45.67; H, 3.16. C ₁₂ H ₁₀ O ₂ Te requires C, 45.93; H, 3.21. δ _jj (250 MHz; CDCI3) 4.68 (s, 2H), 6.69 (d, 4H), 7.58 (d, 4H).

Example C6 2,6-Di-t-butylphenol (1.02 g, 4.94 mmol) and TeCl ₄ (1.33 g, 4.94 mmol) in CCI4 (25 mL) were refluxed for 30 min. Elemental tellurium precipitated and darkened the solution. A solution of (3.0 g, 15.8 mmol) in H2O (25 mL) was added. The mixture was stirred for 15 min, filtered and transferred to a separatory funnel with additional ^O (30 mL) and C^C (30 mL). The phases were separated and the aqueous phase was shaken with an additional portion of CH2CI2 (25 mL). The combined organic phases were dried (MgS0 ₄ ) and evaporated. The solid residue was dissolved in dioxane and refluxed for 30 min with activated copper. After cooling, the mixture was filtered with celite and evaporated. Flash chromatography (SiC^; CH ₂ Cl ₂ /hexanes 9/1 → 5/5) afforded 0.18 g (15%) of 4,4'-dihydroxy- 3,3',5,5'-tetra(l,l-dimethylethyl)-l,l '-tellurobisbenzene as a yellow microcrystalline powder, m.p. 121-2°C d, δ _H (250 MHz; CDCI3) 1.39 (s, 18H), 5.22 (s, 1H), 7.50 (s, 2H), (Found: C, 62.36; H, 7.80. C ₂₈ H ₄ 2θ ₂ Te requires: C, 62.48; H, 7.86.

Example C7

4.4' -Dihydroxy-22 6.6'-tetramethxl-l.V -tellurobisbenzene: To 4-bromo- 3,5-dimethylphenol (0.50 g, 2.49 mmol) in Et3N (3 mL) was added t-butyldi- methylsilyl chloride (0.40 g, 2.65 mmol). The reaction mixture was then heated rapidly to 90°C and stirred overnight at ambient temperature. Dry ethyl ether was added to the heterogenous system and after filtration from Et3NH ⁺ Cl ^" , the residue was evaporated and chromatographed on SiC»2 (CH ₂ C1 ₂ ) to give 0.76 g (97%) of 4-bromo-3,5-dimethyI-t- butyldimethylsilyloxybenzene. 2.75 g (8.7 mmol) of this material was dissolved in dry THF (50 mL) and t-butyllithium (10.3 mL, 1.7 M; 17.5 mmol) added under an Ar-atmosphere at -78°C. After 40 min the cooling- bath was removed and finely crushed elemental tellurium (1.11 g, 8.7 mmol) was added. When almost all tellurium had disappeared (~ lh) the solution was poured into water (100 mL) containing KgFe CN)^ (2.90 g, 8.7 mmol), and CH2CI2 (150 mL) added to extract the ditelluride formed. The crude product was dissolved in dioxane (50 mL) and heated with activated copper powder (5.5 g, 87 mmol) until the red colour of the ditelluride disappeared (1 h). Filtration and evaporation afforded 2.4 g (92%) of crude telluride. 2.2 g (3.68 mmol) of this material was dissolved in dry THF (25 mL) and tetrabutylammonium fluoride (15 mL, 1M; 15.0 mmol) was added at 0°C. After 30 min the reaction mixture was poured into water/C^Ck. The organic phase was separated, dried and evaporated and the product redissolved in QH^C^/EtOH. Addition of hexane caused the precipitation of 4,4'-dihydroxy-2,2',6,6'-tetramethyl-l,l'-tellurobisbenzene 1.28 g (94%), m.p. 170-80°C d (THF/hexanes) δ (250 MHz, CDCl ₃ /DMSO-d ₆ = 9/1) 2.32 (s, 12H), 6.57 (s, 4H), 8.61 (s, 2H). (Found: C, 51.74; H, 4.89. C ₁₆ H ₁₈ 0 ₂ Te requires C, 51.95; H, 4.90).

Example C8

4,4' -Oi xdroxx-2, 2' ,3.3' ,5,5' ,6,6' -octamethil-1,1' -tellurobisbenzene:

Tetrabutylammonium fluoride (1.13 mL, 1.0 M; 1.13 mmol) was added at 0°C to a solution of 4,4'-di(t-butyldimethylsilyloxy)-2,2\3,3',5,5',6,6'- octamethyl-l,l '-tellurobisbenzene (0.37 g, 0.57 mmol) in THF (15 mL). After 10 min, water (50 mL) was added and the solution extracted with methylene chloride (3 x 50 mL). The combined organic phases were concentrated at low temperature to a volume of 5-10 mL. After addition of hexane (50 mL) the solution was left over night in the freezer. 0.14 g (58%) of yellow crystals was filtered off, m.p. 150°C d, δ _jj (250 MHz; DMSO-d ₆ ) 2.07 (s, 6H), 2.31 (s, 6H), 8.07 (s, 1H). Due to decomposition, the material could not be further purified and analyzed.

Example C9 4 A' -Dihχdroxy-33',5, 5' -tetramethxl-1,1' -tellurobisbenzene: 2,6-Dimethyl- phenol (4.0 g, 32.8 mmol) and tellurium tetrachloride (4.4 g, 16.3 mmol) were stirred in CC1 ₄ (50 mL) for 70 h. The green solid formed was filtered off, washed with CC1 ₄ and dried to give 5.4 g of 4-hydroxy-3,5- dimethylphenyl tellurium trichloride. 2.0 g (5.6 mmol) of this material was dissolved in MeOH (30 mL), and sodium ascorbate (3.3 g, 16.8 mmol) in water (6 mL) was added dropwise with stirring. After 1.5 h CH2CI2 was added and the reaction mixture extracted with water. After evaporation of the organic layer, the resulting mixture of telluride and ditelluride was dissolved in dioxane (50 mL) and refluxed with copper (1.5 g) for 2 h. Flash chromatography (CH ₂ C1 ₂ ) of the product afforded 0.50 g (48%) of 4,4'- dihydroxy-3,3',5,5'-tetramethyl-l,r-tellurobisbenzene, m.p. 135°C, δ _H (250 MHz; CDCI3) 2.19 (s, 12H), 4.60 (s, 2H), 7.37 (s, 4H). (Found: C, 51.83; H, 4.92. C ₁₆ H ₁₈ 0 ₂ Te requires: C, 51.95; H, 4.90).

Example CIO

4-Hydroχy-4'-methoxy-2y2', 6,6' -tetramethyl-1,1' -tellurobisbenzene: DMSO (6 mL) was added to sodium hydride (0.018 g 80 %; 0.60 mmol) and 4,4'- dihydroxy-2,2',6,6'-tetramethyl-l,l '-tellurobisbenzene (0.185 g, 0.50 mmol) under an atmosphere of dry nitrogen. When the evolution of hydrogen had ceased (- 10 min), methyl iodide (37 μL, 0.60 mmol) was added and the mixture stirred for 2 h at 90°C. After dilution with water (30 mL), extraction with CH2CI2 (3 x 25 mL) drying (MgS0 ), evaporation and flash chromatography (Si0 ₂ /CH ₂ C1 ₂ ) 0.069 g (36%) of 4-hydroxy-4'-methoxy- 2,2',6,6'-tetramethyl-l,r-tellurobisbenzene was obtained, m. p. 181-2° C (CH ₂ Cl ₂ hexane). δ _jj (250 MHz; CDCI3), 2.35 (s, 6H), 2.37 (s, 6H), 3.76 (s, 3H), 4.51 (s, 1H), 6.56 (s, 2H), 6.62 (s, 2H).

Example Cll 4-Hydroχy-4'-butoχy-2J'. 6.6' -tetramethyl-1,1' -tellurobisbenzene: Following the procedure described in example CIO (methyl iodide exchanged for 1-bromobutane) the title compound was prepared in 41 % yield, m.p. 131-5° C (CH ₂ Cl ₂ /hexane). δ _R (250 MHz; CDCI3), 0.96 (t, 3H), 1.47 (m, 2H), 1.73 (m, 2H), 2.35 (s, 6H), 2.36 (s, 6H), 3.90 (t, 2H), 4.52 (s, 1H), 6.56 (s, 2H), 6.62 (s, 2H).

Example C12

4-Hydroχy-4'-(l-octyloχy)-2.2'. 6.6' -tetramethyl-1.1' -tellurobisbenzene:

Following the procedure described in example CIO (methyl iodide exchanged for 1-bromooctane) the title compound was prepared in 35 % yield, m.p. 87- 9° C (CH ₂ Cl ₂ /hexane). δg (250MHz; CDCI3), 0.66 (t, 3H), 1.20-1.50 (several peaks, 10H), 1.75 (m, 2H), 2.35 (s, 6H), 2.36 (s, 6H), 3.69 (t, 2H), 4.50 (s, 1H), 6.56 (s, 2H), 6.62 (s, 2H).

Example C13

4-Hydroχy-4'(l-tetradecyloχy)-2,2', 6.6' -tetramethyl-1,1' -tellurobisbenzene:

Following the procedure described in example CIO (methyl iodide exchange for 1-bromotetradecane; chromatography using hexanes/EtOAc = 9/1) the title compound was prepared in 13 % yield, m.p. 92-3° C (hexane). δ _jj (25 MHz; CDCI3), 0.68 (t, 3H), 1.20-1.50 (several peaks, 22H), 1.74 (m, 2H), 2.35 (s, 6H), 2.36 (s, 6H), 3.69 (t, 2H), 4.49 (s, 1H), 6.56 (s, 2H), 6.62 (s, 2H).

Example C14

4-Hydroχy-4' (l-tetradecyloxy)-l,V -tellurobisbenzene:

Following the procedure described in example CIO (methyl iodide exchange for 1-bromotetradecane and using 4,4'-dihydroxy- 1,1 '-tellurobisbenzene as the telluride starting material) the title compound was prepared in 36 % yield, m.p. 71-2° C (hexane). δ _H (250 MHz; CDCI3), 0.68 (t, 3H), 1.20-1.5 (several peaks, 22H), 1.76 (m, 2H), 3.92 (t, 2H), 4.70 (s, 1H), 6.69 (d, 2H), 6.75 (d, 2H), 7.57 (d, 2H), 7.62 (d, 2H).

Example C15 4-Carboχymethoxy-4' -hydroxy-2,2' , 6.6' -tetramethyl- l' -tellurobisbenzene: Sodium hydride (0.0115 g 80 %, 0.38 mmol) and 4,4'-dihydroxy-2,2',6,6'- tetramethyl- 1,1 '-tellurobisbenzene (0.120 g, 0.32 mmol) were placed under nitrogen in a flask equipped with a reflux condenser. Dry tetrahydrofuran (1 mL) was then added and the reaction mixture stirred until the gas-evolution had ceased (- 30 min). Methyl bromoacetate (62 mL, 0.65 mmol) was then added and the flask heated at reflex for 24 h. After cooling, dilution with water (50 mL), CH ₂ Cl ₂ -extraction (3 x 25 mL) drying (MgS0 ₄ ) of the organic phase, evaporation and flash chromatography (Siθ2; = 99/1), 0.058 g (41 %) of 4-carbomethoxymethoxy-4'-hydroxy-2,2',6,6'-

tetramethyl- 1,1 '-tellurobisbenzene was obtained, δ _jj (250 MHz, CDCI3), 2.34 (s, 6H), 2.36 (s, 6H), 3.60 (s, 3H), 4.59 (s, 2H), 6.57 (s, 2H), 6.62 (s, 2H). The above methyl ester (0.020 g, 0.045 mmol) was stirred with LiOH x H2O (0.003 g, 0.07 mmol) in THF/water = 3/2 (5 mL). After 21 h water (5 mL) was added followed by 2 M HC1 until the solution was acidic. Ether extractions, drying (MgS0 ₄ ) and evaporation of the solvent afforded 0.019 g (100%) of 4-carboxymethoxy-4'-hydroxy-2,2',6,6'-tetramethyl-l,r- teUurobisbenzene, m. p. 120° C dec (CH ₃ OH/H ₂ 0). δ (250 MHz, DMSO- d6), 2.23 (s, 6H), 2.27 (s, 6H), 4.61 (s, 2H), 6.51 (s, 2H), 6.66 (s, 2H), 9.35 (s, IH), 13.0 (br s, IH).

Example C16

4-Carboxymetkoxy-4'-hydroxy-l,l' '-tellurobisbenzene:

Following the procedure described in example C15, 4,4'-dihydroxy-l,l'- tellurobisbenzene was converted to 4-carbomethoxymethoxy-4'-hydroxy-l,l'- tellurobisbenzene in 35 % yield, δ _jj (250 MHz, CDCI3), 3.80 (s, 3H), 4.61 (s, 2H), 5.57 (s, 1 H), 6.69 (d, 2H), 6.74 (d, 2H), 7.57 (d, 2H), 7.59 (d, 2H). Hydrolysis as described in example C15 afforded the title compound in 88 % yield, m. p. 120-8° C dec (CH ₃ OH/H ₂ 0). δ _H (250 MHz, DMSO-d6), 4.65 (s, 2H), 6.68 (d, 2H), 6.80 (d, 2H), 7.51 (d, 2H), 7.53 (d, 2H), 9.67 (s, IH), 13.0 (br s IH).

Example C17

4-Hydroxy-l ' -tellurobisbenzene: To a stirred solution of 4-bromophenol (0.34 g, 1.97 mmol) in dry THF under argon, t-butyllithium (3.48 mL 1.7 M; 5.9 mmol) was added drop wise at -78°C. After 15 min a solution of phenylethynyl phenyl telluride (0.60 g, 1.97 mmol) in dry THF was added dropwise and stirring continued for 1 h. Work-up, including hydrolysis at -78 °C, warming of the reaction mixture,

dilution with water and C^C^-extraction, evaporation and recrystallization from CH ₂ Cl ₂ /hexanes afforded 0.42 g (72%) of 4-hydroxy-l,l '- tellurobisbenzene, m.p. 65°C.

Example C18

4-Hydroxy-2,2' -6,6' -tetramethyl-1,1' -tellurobisbenzene:

A solution of 2,6-dimemylphenyl tellurenyl bromide was prepared under nitrogen at ambient temperature by addition of bromine (0.189 g, 1.18 mmol) in hexanes (5 mL) to a solution of 2,6-dimethylphenyl ditelluride (0.55 g, 1.18 mmol) in a mixture of hexanes (30 mL) and THF (10 mL). To this solution was added by syringe at ambient temperature a solution of 1-lithio- 4-(t-butyldimethylsilyloxy) benzene, prepared from the reaction of t- butyllithium (2.8 mL; 1.7 M, 4.76 mmol) and l-bromo-2,6-dimethyl-4- (t- butyldimethylsilyloxy) benzene (0.75 g, 2.38 mmol) in THF (10 mL) at - 78°C. Work-up after 2 h, including addition of H2O/CH2CI2, separation of die organic phase, drying, evaporation and deprotection of the resulting product (dissolved in 3 mL THF) by addition of tetrabutylammonium fluoride (3.0 mL; 1.0 M, 3.0 mmol). After addition of H ₂ 0/CH ₂ C1 ₂ , separation, drying, evaporation and flash-chromatography (Siθ2; CH2CI2), the tide compound was obtained, contaminated by some 3,5-dimethylphenol.

2 Sublimation (20°C/10 mm Hg/15 h) removed the impurity and left 4- hydroxy-2,2',6,6'-tetramethyl-l,l '-tellurobisbenzene, 0.35 g (42%) (Found: C,

54.13; H, 5.08. C ₁₆ H ₁₈ OTe requires C, 54.30; H, 5.13) δ _H (250 MHz;

CDCI3) 2.34 (s, 6H), 2.37 (s, 6H), 4.56 (s, IH), 6.57 (s, 2H), 7.00-7.08 (several peaks, 3H). MP. 139-140°C.

Pharmaceutical formulations

The compounds of formula 1 can be administrated in oral pharmaceutical formulations for treatment of e.g. Crohn's disease, ulcerative colitis or rheumatoid arthritis.

Example PI Plain tablet

Diaryltelluride 100 mg

Lactose anhydrous 300 mg

Microcrystalline cellulose 60 mg

Magnesium stearate 8 mg

Example P2 Coated tablet

Diaryltelluride 100 mg

Lactose 300 mg

Polyvinylpyrrolidone 40 mg

Magnesium stearate 8 mg

Hydroxypropylmethylcellulose 8 mg Polyediyleneglycol 1 mg

Talc 1 mg

Titanium dioxide 1 mg

Example P4

Gastro-resistant extended release granules for the small intestine

Example P5

Gastro-resistant extended release granules for the colon

The compounds of formula 1 can be administrated in topical pharmaceutical formulations for the treatment of e.g. rheumatoid and other kinds of arthritis

The compounds of formula 1 can be administrated in rectal pharmaceutical formulations for the treatment of e.g. Crohn's disease or ulcerative colitis.

Example PI 1

Enema, medium viscous

The compounds of formula 1 can be administered in pharmaceutical formulations for inhalation;

Example P12

Diaryltelluride was micronized to a particle size suitable for inhalation dierapy (mass median diameter < 5 μm). The micronized powder was aggregated into soft spheres with a diameter of less than 1 mm. 150 mg of the aggregated powder was loaded into a powder-inhaler, Turbuhaler® (AB Astra). The dosing unit of the inhaler was constructed to give a nominal dose of 1.0 mg.

Example PI 3

Diaryltelluride was micronized to a particle size suitable for inhalation

therapy (mass median diameter < 5 μm). The micronized powder was aggregated into soft spheres with a diameter of less than 1 mm. 20 mg of the aggregated powder was filled into a gelatine capsule. The gelatine capsule was loaded into a Spinmatic (R) inhaler (Fisons).

Example P14

Diaryltelluride was micronized to a particle size suitable for inhalation therapy (mass median diameter < 5 μm). The micronized powder was mixed with lactose monohydrate with an average particle size of 100 μm. 20 mg of the mixed powder, containing 5 mg diaryltelluride, was filled into a gelatine capsule. The gelatine capsule was loaded into a Spinmatic (^R) inhaler (Fisons).