WO1993016993A1 - Diaryltellures antioxydants - Google Patents

Diaryltellures antioxydants Download PDF

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Publication number
WO1993016993A1
WO1993016993A1 PCT/SE1993/000123 SE9300123W WO9316993A1 WO 1993016993 A1 WO1993016993 A1 WO 1993016993A1 SE 9300123 W SE9300123 W SE 9300123W WO 9316993 A1 WO9316993 A1 WO 9316993A1
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Prior art keywords
general formula
diaryl
formula
tellurides
compounds
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PCT/SE1993/000123
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English (en)
Inventor
Carl-Magnus Andersson
Mats Berglund
Ralph Brattsand
Ian Cotgreave
Lars Engman
Anders Hallberg
Peter Moldeus
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Aktiebolaget Astra
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Publication of WO1993016993A1 publication Critical patent/WO1993016993A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
    • C09K15/02—Anti-oxidant compositions; Compositions inhibiting chemical change containing inorganic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C395/00—Compounds containing tellurium

Definitions

  • ROMs reduced metabolites of oxygen
  • 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).
  • LDL low-density lipoprotein
  • 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,
  • the endogenous antioxidant network relies on a multitude of mechanisms for the prevention and limitation of damage caused by ROMs.
  • 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.
  • glutathione 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.
  • glutathione serving as the reducing agent.
  • Many 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].
  • 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].
  • 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.
  • 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.
  • 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 I - Te - Ar II where Ar and Ar represent, the same or different, substituted aryl groups carrying the substituents which are defined below.
  • R 11 , R 12 , R 13 , R 21 , R 22 and R 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 1 2 , NR 1 R 2 and SR 1 wherein R 1 and R 2 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 11 , R 12 or R 13 is OH, OR 1 , SH, NH 2 , NHR 1 , NR 1 2 , NR 1 R 2 or SR 1 , wherein R 1 and R 2 are as defined above, further provided that when one of R 11 , R 12 or R 13 is OR 1 or NR 1 2 then at least one of R 21 , R 22 or R 23 is selected from OH
  • R 14 , R 15 , R 24 and R 25 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.
  • 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.
  • organic bases such as lysine, arginine, choline, ethylenediamine, N,N'-dibenzylethylenediamine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methylpropanediol, benethamine, t-butylamine, cystamine, cysteamine, diethylamine, ethanolamine,
  • methenamine 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.
  • R 21 , R 22 and R 23 are as defined above.
  • diaryl tellurides as well as diaryl telluroxides or other tellurium (IV) derivatives of the same diaryl tellurides, such as dihalides, dicarboxylates and dialkoxides.
  • N-Methyl-N-propyl-4-amino-1,1'-tellurobisbenzene N,N'-Dimethyl-N,N'-dipropyl-2,2'-diamino-1,1 '-tellurobisbenzene
  • N-Methyl-4-amino-3,5-di(1,1-dimethylethyl)-1,1 '-tellurobisbenzene 4-Mercapto-3,5-di(1,1-dimethylethyl)-1,1'-tellurobisbenzene
  • diaryl tellurides as well as diaryl telluroxides or other tellurium (IV) derivatives of the same diaryl tellurides, such as dihalides, dicarboxylates and dialkoxides.
  • 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
  • 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.
  • 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.
  • 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 propagating 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.
  • physiologically relevant molecules such as fatty acids, e.g. linoleic or arachidonic acid
  • 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 peroxidase-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.
  • a physiologically relevant such as vitamine C, vitamine E or glutathione
  • synthetic such as N-acetylcysteine, N-isobutyrylcysteine, t-butyl mercaptan or octyl mercaptan
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 I to give diaryl tellurium products Ar-Te-Ar I 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.
  • OH, SH, NH 2 , NHR I and NHR II 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.
  • NHR 1 , NR 1 R 2 or N H2 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.
  • 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 I -Te-Te-Ar I formed as intermediates in the reaction are induced, by heat or copper powder, to lose one tellurium atom.
  • 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.
  • 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.
  • diaryl ditellurides Ar I -Te-Te-Ar I 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.
  • p) Treatment of diaryl ditellurides Ar I TeTeAr I with arenediazonium halides Ar II N 2 + X- (X Cl, Br, I) in acetone or acetone/acetonitrile.
  • the product is a 1 :1 mixture of diaryl telluride, Ar I -Te-Ar II , and diaryl tellurium dihalide,
  • 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.
  • 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.
  • Microsomal lipid peroxidation was performed in incubations constructed as follows: incubations (1 ml) in phosphate (50 mM) buffer, pH 7,4 containing microsomal protein (1mg), ADP (200 ⁇ M), FeSO 4 (1 ⁇ M) and vehicle/test substance, were preincubated for 5 min at 37° before addition of the initiation stimulus ascorbate (50 ⁇ M). For screening experiments the accumulation of thiobarbituric acid (TBA) reactive substances
  • 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. Eur J Biochem 25: 420-425, 1972].
  • MDA malondialdehyde equivalents
  • 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
  • the glutathione peroxidase-like activity of the compounds of formula 1 was determined by using a 1 H-NMR method.
  • 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 1 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 II. It is obvious that the compounds exemplified show a substantial catalytic effect as compared to the control.
  • 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-1,1'-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.
  • 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.
  • 2,2'-Dihydroxy-1,1'-tellurobisbenzene 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 3 Fe(CN) 6
  • N,N'-Dimethyl-4,4'-diamino-1 ,1'-tellurobisbenzene A 2:1-complex was prepared from N-methylaniline and TeCl 4 in analogy with a literature method [G.T. Morgan and H. Burgess, J. Chem. Soc. 1103 (1929)].
  • a solution of Na 2 S 2 O 5 (1.01 g, 5.33 mmol) in H 2 O (20 mL) was added to a suspension of the complex (1.29 g, 2.67 mmol) in CH 2 Cl 2 (20 mL). The red precipitate that was formed dissolved when the aqueous phase was
  • N,N'-dimethyl-4,4'-diamino-1,1'-tellurobisbenzene was 0.29 g (64%), ⁇ H (250 MHz; CDCl 3 ) 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 CH 2 CI 2 (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 CH 2 CI 2 (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%).
  • N,N'-Diphenyl-4,4'-diamino-1,1'-tellurobisbenzene The 2:1-complex of N-phenylaniline and TeCl 4 (3.0 g, 4.9 mmol), prepared in analogy with a literature procedure [G.T. Morgan and H. Burgess J. 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.
  • 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-1,1'-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 ⁇ 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.
  • 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.
  • 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.
  • the compounds of formula 1 can be administered in pharmaceutical formulations for inhalation;
  • Diaryltelluride was micronized to a particle size suitable for inhalation dierapy (mass median diameter ⁇ 5 ⁇ m).
  • 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.
  • Diaryltelluride was micronized to a particle size suitable for inhalation therapy (mass median diameter ⁇ 5 ⁇ m).
  • 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 ® inhaler (Fisons).
  • Diaryltelluride was micronized to a particle size suitable for inhalation therapy (mass median diameter ⁇ 5 ⁇ m).
  • the micronized powder was mixed with lactose monohydrate with an average particle size of 100 ⁇ m.
  • 20 mg of the mixed powder, containing 5 mg diaryltelluride, was filled into a gelatine capsule.
  • the gelatine capsule was loaded into a Spinmatic ® inhaler (Fisons).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention décrit de nouveaux diaryltellures selon la formule ArI - Te - ArII utiles en tant qu'antioxydants dans la prévention et le traitement de maladies causées par l'oxydation des tissus ou concernant des dégats dus à l'oxydation des tissus.
PCT/SE1993/000123 1992-02-20 1993-02-17 Diaryltellures antioxydants WO1993016993A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9200502-4 1992-02-20
SE9200502A SE9200502D0 (sv) 1992-02-20 1992-02-20 Novel antioxidants

Publications (1)

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WO1993016993A1 true WO1993016993A1 (fr) 1993-09-02

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CN (1) CN1083472A (fr)
AP (1) AP9300490A0 (fr)
AU (1) AU3580893A (fr)
HR (1) HRP930179A2 (fr)
IL (1) IL104683A0 (fr)
IS (1) IS3977A (fr)
MX (1) MX9300839A (fr)
SE (1) SE9200502D0 (fr)
SI (1) SI9300099A (fr)
TN (1) TNSN93018A1 (fr)
WO (1) WO1993016993A1 (fr)
ZA (1) ZA93781B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0747704A2 (fr) * 1995-06-07 1996-12-11 Johnson & Johnson Clinical Diagnostics, Inc. Elément d'essai immunologique contenant diaryl-telluride pour accroître la stabilité
US5928886A (en) * 1995-06-07 1999-07-27 Johnson & Johnson Clinical Diagnostics, Inc. Reduction in first slide bias and improved enzyme stability by incorporation of diaryl tellurides in the gravure layer of dry-film, immunoassay elements
WO2004047925A2 (fr) * 2002-11-22 2004-06-10 Exeter Antioxidant Therapeutics Limited Catalyseurs d'oxydation therapeutiques
EP1694313A2 (fr) * 2003-12-18 2006-08-30 Biomas Ltd. Derives du tellure pour la prevention et le traitement des processus neurodegeneratifs
WO2010076323A1 (fr) * 2009-01-02 2010-07-08 Rainbow Pharmaceutical Sa Utilisation de chlorure d'ammonium en thérapie
JP2011057637A (ja) * 2009-09-11 2011-03-24 Kitasato Institute 新規有機テルロニウムおよびセレノニウム化合物
US8048915B2 (en) 2001-11-22 2011-11-01 Biomas Ltd. Biologically active complex

Citations (2)

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Publication number Priority date Publication date Assignee Title
US2195539A (en) * 1938-08-12 1940-04-02 Standard Oil Dev Co Di-alkyl diphenol sulphides
EP0198277A1 (fr) * 1985-04-12 1986-10-22 A. Nattermann & Cie. GmbH Diséléno bisbenzamides d'amines primaires et secondaires, leurs procédés de préparation et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2195539A (en) * 1938-08-12 1940-04-02 Standard Oil Dev Co Di-alkyl diphenol sulphides
EP0198277A1 (fr) * 1985-04-12 1986-10-22 A. Nattermann & Cie. GmbH Diséléno bisbenzamides d'amines primaires et secondaires, leurs procédés de préparation et compositions pharmaceutiques les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
POLYMER DEGRADATION AND STABILITY, Volume 21, 1988, S.S. ABED-ALI et al., "Stabilisation of PVC with Organotellurium Compounds", page 211 - page 225. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0747704A2 (fr) * 1995-06-07 1996-12-11 Johnson & Johnson Clinical Diagnostics, Inc. Elément d'essai immunologique contenant diaryl-telluride pour accroître la stabilité
US5686254A (en) * 1995-06-07 1997-11-11 Johnson & Johnson Clinical Diagnostics, Inc. Reduction in first slide bias and improved enzyme stability by the incorporation of diaryl tellurides in thin-film immunoassay elements
EP0747704A3 (fr) * 1995-06-07 1998-06-17 Johnson & Johnson Clinical Diagnostics, Inc. Elément d'essai immunologique contenant diaryl-telluride pour accroítre la stabilité
US5928886A (en) * 1995-06-07 1999-07-27 Johnson & Johnson Clinical Diagnostics, Inc. Reduction in first slide bias and improved enzyme stability by incorporation of diaryl tellurides in the gravure layer of dry-film, immunoassay elements
AU736764B2 (en) * 1997-09-23 2001-08-02 Ortho-Clinical Diagnostics, Inc. Reduction in first slide bias and improved enzyme stability by incorporation of diaryl tellurides in the gravure layer of dry-film, immunoassay elements
US8048915B2 (en) 2001-11-22 2011-11-01 Biomas Ltd. Biologically active complex
WO2004047925A3 (fr) * 2002-11-22 2004-10-28 Exeter Antioxidant Therapeutic Catalyseurs d'oxydation therapeutiques
WO2004047925A2 (fr) * 2002-11-22 2004-06-10 Exeter Antioxidant Therapeutics Limited Catalyseurs d'oxydation therapeutiques
EP1694313A2 (fr) * 2003-12-18 2006-08-30 Biomas Ltd. Derives du tellure pour la prevention et le traitement des processus neurodegeneratifs
EP1694313A4 (fr) * 2003-12-18 2010-11-17 Biomas Ltd Derives du tellure pour la prevention et le traitement des processus neurodegeneratifs
WO2010076323A1 (fr) * 2009-01-02 2010-07-08 Rainbow Pharmaceutical Sa Utilisation de chlorure d'ammonium en thérapie
US8840934B2 (en) 2009-01-02 2014-09-23 Rainbow Pharmaceutical Sa Uses of ammonium chloride
EA024723B1 (ru) * 2009-01-02 2016-10-31 Рейнбоу Фармасьютикал С.А. Применение лекарственной формы хлорида аммония для профилактики или лечения вирусной инфекции и состояний, вызванных токсическими веществами
JP2011057637A (ja) * 2009-09-11 2011-03-24 Kitasato Institute 新規有機テルロニウムおよびセレノニウム化合物

Also Published As

Publication number Publication date
AP9300490A0 (en) 1994-08-18
ZA93781B (en) 1993-08-20
MX9300839A (es) 1993-09-01
SI9300099A (en) 1994-09-30
AU3580893A (en) 1993-09-13
CN1083472A (zh) 1994-03-09
IL104683A0 (en) 1993-06-10
IS3977A (is) 1993-08-21
TNSN93018A1 (fr) 1994-03-17
HRP930179A2 (en) 1994-10-31
SE9200502D0 (sv) 1992-02-20

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