EP0153307A4 - Utilisation de composes contenant du selenium pour annuler les effets toxiques des composes d'or utilises dans le traitement de l'arthrite rhumatoide, et nouveau compose d'or contenant du selenium et son utilisation comme medicament contre l'arthrite rhumatoide. - Google Patents

Utilisation de composes contenant du selenium pour annuler les effets toxiques des composes d'or utilises dans le traitement de l'arthrite rhumatoide, et nouveau compose d'or contenant du selenium et son utilisation comme medicament contre l'arthrite rhumatoide.

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Publication number
EP0153307A4
EP0153307A4 EP19830902851 EP83902851A EP0153307A4 EP 0153307 A4 EP0153307 A4 EP 0153307A4 EP 19830902851 EP19830902851 EP 19830902851 EP 83902851 A EP83902851 A EP 83902851A EP 0153307 A4 EP0153307 A4 EP 0153307A4
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European Patent Office
Prior art keywords
selenium
gold
stands
compound
unsubstituted
Prior art date
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Application number
EP19830902851
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German (de)
English (en)
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EP0153307A1 (fr
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Richard F Stockel
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Individual
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Individual
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Publication of EP0153307A1 publication Critical patent/EP0153307A1/fr
Publication of EP0153307A4 publication Critical patent/EP0153307A4/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/242—Gold; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C391/00—Compounds containing selenium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals

Definitions

  • the present invention relates to a method of negating the toxic effects of gold compounds. More particularly, the present invention relates to a method of negating the toxic effects of gold compounds used in the treatment of rheumatoid arthritis, which method comprises administering to a patient a selenium-containing compound.
  • the present invention is also concerned with a novel selenium-containing gold compound which can be effectively used as a so-called gold compound type anti-rheumatoid arthritis medicine which can self-detoxify gold toxicity.
  • rheumatoid arthritis The most common form of chronic inflammatory arthritis is rheumatoid arthritis, which is characterized by symmetrical inflammatory polyarthritis, morning stiffness and positive rheumatoid fact ⁇ r. Over more than 100 diseases have been classified as. arthritis, in addition to chronic inflammatory arthritis.
  • gold compounds used in gold therapy are most effective as anti-rheumatoid agents, and the gold therapy should be considered in patients with active disease who fail to respond to the plethora of drugs previously mentioned to reduce inflammation.
  • Active adult and juvenile rheumatoid arthritis are the principal indications where administration of these agents are used, but beneficial effects have also been obtained in some patients with psoriatic arthritis. Although their exact mechanism of action is unknown, the gold compounds exert an anti-inflammatory effect in these disorders, and unlike other anti-arthritic drugs may affect the course of the disease.
  • the gold therapy using the gold compounds as described above is effective in the treatment of rheumatoid arthritis, but is accompanied by side effects. Therefore, the gold compounds should be used with extreme cautions. In order to be effective, high doses of gold compounds are required. General irethod of administering to a patient gold compounds in the treatment of rheumatoid arthritis is described below.
  • the recommended dosages involve 1 mg/kg of body weight weekly for 20 weeks and the same dose at 2 to 4 week intervals thereafter for as long as therapy is beneficial and there are no signs of toxicity.
  • Single dosages for children and all but the largest adolescent should not exceed 25 mg.
  • Pruritus may signify the early development of a skin reaction. When a pruritic skin lesion occurs, whose etiology is not certain, it appears gold therapy must be discontinued immediately, for another dose may produce a much more severe skin reaction. Anaphylactoid reactions may also occur with gold therapy, but they are probably caused as much by the vehicle, as is caused by the gold compounds. Nausea, vomiting and weakness sometimes result from this treatment. Toxic effects may be observed after the first injection, during the course of therapy, or several months after gold therapy has been discontinued. Their incidence in severity appear to depend upon dosage. Although they may occur at any time, severe toxic effects of the gold compounds are most common after 300 to 500 milligrams have been administered.
  • Gold compounds should be used with extreme cautions in patients with impaired renel or hepatic function, blood disorders, skin rash or marked hypertension. They are contraindicated in patients with severe debilitation, systemic lupus erythematosus, or previous signs of gold toxicity. They are seldom needed during pregnancy but if their use is contemplated, the benefit/risk ratio should be considered. Diabetes mellitus or congestive heart failure should be under control before initiating gold therapy.
  • a blood sample is examined for its hemoglobin content and white blood cell count.
  • Another side effect is the possibility of a skin rash. When this occurs it is almost always itchy and usually also red and scaly, with tiny bumps. They may appear anywhere on the body, or even inside the mouth; but the most frequent locations are the chest, arms and legs. This rash can be quite severe and uncomfortable at times.
  • liver damage and intestinal cramps or diarrhea have also been reported in patients treated with gold but these reactions are extremely rare. However, a blood sample is analyzed every few months to detect any possible threat of liver damage.
  • the present inventors have made extensive and intensive studies in order to obtain a medicine excellent in detoxification effect against the gold toxicity. As a result, the present inventors have found that selenium-containing compounds has excellent effects of detoxification against the gold toxicity. Further, the present inventors have made extensive and intensive studies with a view to obtaining so-called gold compound type anti-rheumatoid arthritis medicine which possesses a self-detoxification effect against the gold toxicity resulting from the gold therapy of rheumatoid arthritis but does not sacrifice the anti-rheumatoid arthritis activity.
  • a novel selenium-containing gold compound of the latermetioned formula (1) can be effectively used as a gold compound type anti-rheumatoid arthritis medicine which is not only effective in the treatment of rheumatoid arthritis but also possesses a self-detoxification effect against the gold toxicity.
  • the present invention has been completed based on the above.
  • Mechanisms may involve a direct binding between selenium and the heavy metal; a direct binding between selenium metal and other small molecules or macro-molecules; or an indirect stoichiometric or catalytic effect of selenium mediated by other molecules, such as an enzyme.
  • selenium has protective effects against the toxicity of several specific heavy metals.
  • a seleniumcontaining compound has a detoxification effect against the gold toxicity, and as mentioned before, the present inventors have found for the first time that the selenium-containing compound has an excellent detoxification effect against the gold toxicity.
  • an object of the present invention to provide a method of negating the toxic effects of gold compounds used in the treatment of rheumatoid arthritis, which comprises administering to a patient a selenium-containing compound.
  • Another object of the present invention is to provide a novel selenium-containing gold compound which can be effectively used as a gold compound type anti-rheumatoid arthritis medicine which can self-detoxify gold toxicity.
  • a method of negating the toxic effects of gold compounds which comprises administering to a patient an effective amount of a selenium-containing compound adapted to negate the toxic effects of gold compounds used in the treatment of rheumatoid arthritis.
  • selenium-containing compounds to be used in the present invention there can be mentioned an alkali metal salt of selenious acid, an alkali metal salt of selenic acid, a selenoamino acid, an ⁇ -selenocarboxylic acid, a selenocarbohydrate, selenium yeast and a protein containing selenium.
  • selenium-containing compounds are effective for negating the gold toxicity resulting from the gold therapy especially of rheumatoid arthritis.
  • alkali metal salt of selenious acid to be used in the present invention there may mentioned sodium selenite.
  • alkali metal salt of selenic acid there may be mentioned sodium selenate.
  • selenoamino acid to be used in the present invention there may be mentioned amino acids containing selenium which has replaced sulfur in the thio or disulfide groups of sulfur-containing amino acids such as selenomethionine, selenocysteine, Semethylselenocysteine, selenocystine and selenohomomethionine.
  • ⁇ -selenocarboxylic acid there may be mentioned compounds of the formula HSe(CH 2 ) n COOH (where n > 5).
  • protein containing selenium there may be mentioned proteins containing selenium which has replaced sulfur in the thio or disulfide groups of sulfur-containing amino acids. The above mentioned selenium-containing compounds are known.
  • the selenium-containing compounds to be used in the present invention can be administered orally or parenterally, for example, in the form of ah intravenous injection, a hypodermical injection or a suppository.
  • the dosage may vary depending upon ages, severities and body weights of patients, but a selenium-containing compound as an active ingredient may be usually administered in a daily dose of from about 1 to about 500 mg for adults, if necessary, in divided dosage forms.
  • the selenium-containing compounds to be used in the present invention can be used concomitant with the gold therapy of rheumatoid arthritis, or alternatively the selenium-containing compounds can be administered prior to treatment with the gold compounds to build up levels of selenium in the body that will mitigate the toxic side effects of the gold compounds. Even though selenium itself at high levels in the body can be toxic, the body can tolerate low levels and the selenium compounds can detoxify gold poisoning particularly in the renal system and liver, where gold concentrates after gold therapy.
  • the selenium-containing compound as such may be administered.
  • a pharmaceutical composition which comprises a seleniumcontaining compound as an active ingredient is usually administered.
  • the composition or preparation may be in the form of, for example, capsule, granule, powder, tablet, pill, ointment, syrup, injection, suppository or the like.
  • excipients such as white sugar, lactose, glucose, starch, corn starch, mannite, sorbite, cellulose, talc, cyclodextrin and the like; binding agents such as cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, gelatin, gum arabic, polyethylene glycol, white sugar, starch and the like; disintegrators such as starch, carboxymethylcellulose, calcium salts of carboxymethylcellulose and the like; lubricants such as talc and the like; preservatives such as sodium benzoate, sodium bisulfite and the like; suspending agents such as methylcellulose, aluminum stearate, magnesium stearate and the like; and bases such as polyethylene glycol, Witepsol, white petrolatum and the like.
  • excipients such as white sugar, lactose, glucose, starch, corn starch, mannite, sorbite, cellulose, talc, cycl
  • compositions sodium selenite 6.3 mg lactose 20.3 mg corn starch 7.0 mg hydroxypropylcellulose 1.4 mg carboxymethylcellulose calcium 1.1 mg magnesium stearate 0.2 mg
  • Composition 2 sodium selenate 6.3 mg hydroxypropylmethylcellulose 8.0 mg crystalline cellulose 76.0 mg carboxymethylcellulose calcium 64.0 mg magnesium stearate 4.0 mg
  • composition 3 selenomethionine 4.0 mg lactose 178.0 mg corn starch 37.0 mg talc 5.0 mg
  • R 1 stands for an unsubstituted or substituted glucose radical, an unsubstituted or substituted malic acid radical, an unsubstituted or substituted malate radical, or an unsubstituted or substituted phenylcarbamoylmethy radical; and R 2 stands for a linear or branched alkyl group having 1 to 4 carbon atoms.
  • the unsubstituted or substituted glucose radical in the above general formula (1) is represented by the following general formula:
  • R 3 , R 4 , R 5 and R 6 each independently stand for H, an acetyl group, a propionyl group or a butyryl group.
  • Specific examples of the selenium-containing gold compound represented by the formula (1) in which R 1 stands for an unsubstituted or substituted glucose radical of the formula (2) include (tetra-O-acetyl-1- ⁇ -D-glucopyranosyl)seleno (triethylphosphine) gold and (1- ⁇ -D-glucopyranosyl)seleno (triethylphosphine) gold.
  • the former compound is given when R 1 in the formula (1) stands for a 2, 3, 4, 6-tetra-0-acetyl1- ⁇ -D-glucopyranosyl radical represented by the formula
  • R 1 in the formula (1) stands for a 1- ⁇ -D-glucopyranosyl radical represented by
  • R 2 in the formula (1) stands for an ethyl group.
  • the unsubstituted or substituted malic acid radical (radical A) or the unsubstituted or substituted malate radical (radical S) in the above general formula (1) is represented by the following general formula:
  • R 7 , R 8 and R 9 each independently stand for H or an alkyl group having 1 to 4 carbon atoms and M and M' each stand for H for radical A or an alkali metal for radical S).
  • Specific examples of the selenium-containing gold compound represented by the formula (1) in which R 1 stands for an unsubstituted or substituted malate radical of the formula (5) include triethylphosphine gold sodium selenomalate. This compound is given when R 1 in the formula (1) stands for sodium malate radical represented by
  • R 2 in the formula (1) stands for an ethyl group.
  • R 10 and R 11 each independently stand for H or an alkyl group having 1 to 4 carbon atoms.
  • Specific examples of the selenium-containing gold compound represented by the formula (1) in which R 1 stands for an unsubstituted or substituted phenylcarbamoylmethyl radical of the formula (7) include [ (phenylcarbamoyl)methyl]seleno (triethylphosphine) gold. This compound is given when R 1 in the formula (1) stands for a phenylcarbamoylmethyl radical represented by the formula
  • R 2 in the formula (1) stands for an ethyl group.
  • the selenium-containing gold compound of the present invention having the formula (1) as mentioned hereinbefore is a novel and unknown compound.
  • the method for preparing the selenium-containing gold compound according to the present invention will be described below.
  • the selenium-containing gold compound represented by the above-mentioned general formula (1) wherein R 1 stands for an unsubstituted or substituted glucose radical and R 2 stands for a linear or branched alkyl group having 1 to 4 carbon atoms can be prepared as follows.
  • R 13 , R 14 , R 15 and R 16 stands for H, an acetyl group, a propionyl group or a butyryl group, and X stands for a halogen
  • selenourea is reacted with selenourea according to the method as described in Wagner, G. and Nuhn, P., Arch. Pharm., 297, 461 (1964) to obtain a corresponding derivative of selenoisourea.
  • an acylbromoglucose is reacted with selenourea to form an acylglucose selenoisourea hydrobromide.
  • the above-mentioned reaction is carried out in a.
  • ketone as a reaction solvent such as acetone, methylethylketone or the like at room temperature to 100°C, generally at the boiling point of the solvent to be employed, for 10 minutes to 5 hours.
  • Selenourea may be employed in an amount of about one equivalent to an acylbromoglucose.
  • the thus formed selenoisourea derivative (acylglucose selenoisourea hydrobromide) is reacted with trialkylphosphine gold chloride [ClAuP(R) 3 , wherein R stands for a linear or branched alkyl group having 1 to 4 carbon atoms] according to the method of Sutton et al [M. Sutton, E. McGurty, D.
  • an acylglucose selenoisourea hydrobromide is dissolved in an aqueous solution containing 1.0 to 1.5 moles of potassium carbonate relative to one mole of the acylglucose selenoisourea hydrobromide, and then subjected to reaction with a trialkylphosphine gold chloride of an equimolar amount to the acylglucose selenoisourea hydrobromide, there by to prepare the intended selenoacylglucose trialkylphosphine gold compound.
  • the above-mentioned reaction is carried out at -20°C to room temperature.
  • the trialkylphosphine gold chloride may be dissolved in an alcohol such as ethanol, methanol and isopropanol, which contains a small amount of methylene chloride, and subjected to the reaction.
  • the reaction time is 30 minutes to 5 hours.
  • the thus obtained selenoacylglucose trialkylphosphine gold compound may be deacylated using an excess amount of sodium methoxide in methanol, thereby to obtain the intended selenoglucose trialkylphosphine gold compound.
  • the selenium-containing gold compound represented by the above-mentioned general formula (1) wherein R 1 stands for an unsubstituted or substituted malic acid radical, or an unsubstituted or substituted malate radical and R 2 stands for a linear or branched alkyl group having 1 to 4 carbon atoms can be prepared as follows. A halogen derivative of an unsubstituted or substituted malic acid is reacted with selenourea according to the above-mentioned method of Wagner to obtain a derivative of selenoisourea.
  • an unsubstituted or substituted 2-bromo-2-deoxy-malic acid is reacted with selenourea, thereby to form an unsubstituted or substituted malic acid selenoisourea hydrobromide.
  • the above-mentioned reaction is carried out in a ketone as a reaction solvent such as acetone, methylethylketone or the like at room temperature to 100°C, generally at the boiling point of the solvent to be employed, for 10 minutes to 5 hours.
  • Selenourea may be employed in an amount of about one equivalent to an unsubstituted or substituted 2-bromo-2-deoxy-malic acid.
  • selenoisourea derivative an unsubstituted or substituted malic acid selenoisourea hydrobromide
  • a trialkyl-phosphine gold chloride [ClAuP(R) 3 , wherein R stands for a linear or branched alkyl group having 1 to 4 carbon atoms]
  • the unsubstituted or substituted malic acid selenoisourea hydrobromide is dissolved in an aqueous solution containing potassium carbonate in a molar amount of 1 to 2.5 times that of the unsubstituted or substituted malic acid selenoisourea hydrobromide and subjected to reaction with a trialkylphosphine gold chloride of an equimolar amount to the unsubstituted or substituted malic acid selenoisourea hydrobromide, thereby to obtain the intended unsubstituted or substituted selenomalic acid trialkylphosphine gold compound.
  • the above-mentioned reaction is carried out at -20°C to room temperature.
  • trialkylphosphine gold chloride may be dissolved in an alcohol such as ethanol, methanol or isopropanol, which contains a small amount of methylene chloride, and subjected to the reaction.
  • the reaction time is 30 minutes to 5 hours.
  • the thus formed unsubstituted or substituted selenomalic acid trialkylphosphine gold compound may be reacted with an alkali metal salt such as Na 2 CO 3 In water according to the customary method, thereby to obtain an unsubstituted or substituted selenomalate trialkyl-phosphine gold compound.
  • R 2 stands for a linear or branched alkyl group having 1 to 4 carbon atoms
  • R 2 stands for a linear or branched alkyl group having 1 to 4 carbon atoms
  • An unsubstituted or substituted phenylcarbamoylmethyl halogen derivative is reacted with selenourea according to the method of Wagner as mentioned before, thereby to obtain a corresponding derivative of selenoisourea.
  • selenourea an unsubstututed or substituted phenylcarbamoylmethyl bromide is reacted with selenourea, thereby to form a corresponding derivative of selenoisourea (an unsubstituted or substituted phenylcarbamoylmethyl selenoisourea hydrobromide).
  • the above-mentioned reaction is carried out in a ketone as a reaction solvent such as acetone, methylethylketone or the like at room temperature to 100°C, generally at the boiling point of the solvent to be employed, for 10 minutes to 5 hours.
  • Selenourea may be employed in an amount of about one equivalent to the unsubstituted or substituted phenylcarbamoylmethyl bromide.
  • selenoisourea derivative an unsubstituted or substituted phenylcarbamoylmethyl selenoisourea hydrobromide
  • a trialkylphosphine gold chloride [ClAu-P (R) 3, wherein R stands for a linear or branched alkyl group having 1 to 4 carbon atoms ] according to the method of Sutton et al as mentioned above, thereby to obtain the intended unsubstituted or substituted selenophenylcarbamoylmethyl trialkylphosphine gold compound.
  • an unsubstituted or substituted phenylcarbamoylmethyl selenoisourea hydrobromide is dissolved in an aqueous solution containing potassium carbonate in a molar amount of 1 to 1.5 times that of the unsubstituted or substituted phenylcarbamoylmethyl selenourea hydrobromide, and then subjected to reaction with a trialkylphosphine gold chloride of an equimolar amount to the unsubstituted or substituted phenylcarbamoylmethyl selenoisourea hydrobromide, thereby to obtain the intended unsubstituted or substituted selenophenylcarbamoylmethyl trialkylphosphine gold compound.
  • the above-mentioned reaction is carried out at -20°C to room temperature.
  • the trialkylphosphine gold chloride may be dissolved in an alcohol such as ethanol, methanol, isopropanol or the like, which contains a small amount of methylene chloride, and then subjected to the reaction.
  • the reaction time is 30 minutes to 5 hours.
  • a method of treating a patient suffering from rheumatoid arthritis which comprises administering to a patient an effective amount of the selenium-containing gold compound of the formula (1) as defined above.
  • the seleniumcontaining gold compound of the present invention represented by the above-mentioned general formula (1) can be effectively used as a gold compound type anti-rheumatoid arthritis medicine which can self-detoxify gold toxicity.
  • the seleniumcontaining gold compound of the present invention can be administered orally or parenterally, for example, in the form of an intravenous injection, a hypodermical injection or suppository.
  • the dosage may vary depending upon ages, severities and body weights of patients, but a seleniumcontaining gold compound as an active ingredient may be usually administered in a daily does of from about 1 to about 500 mg for adults, if necessary, in divided dosage forms.
  • the selenium-containing gold compound as such may be administered.
  • a pharmaceutical composition which comprises a selenium-containing gold compound as an active ingredient is usually administered.
  • the composition or preparation may be of the form of, for example, capsule, granule, powder, tablet, pill, ointment, syrup, injection, suppository or the like.
  • excipients such as white sugar, lactose, glucose, starch, corn starch, mannite, sorbite, cellulose, talc, cyclodextrin and the like; binding agents such as cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, gelatin, gum arabic, polyethylene glycol, white sugar, starch and the like; disintegrators such as starch, carboxymethylcellulose, calcium salts of carboxymethylcellulose and the like; lubricants such as talc and the like; preservatives such as sodium benzoate, sodium bisulfite and the like; suspending agents such as methylcellulose, aluminum stearate, magnesium stearate and the like; and bases such as polyethylene glycol, Witepsol, white petrolatum and the like. According to the kinds of forms of the pharmaceutical composition, appropriate pharmaceutical agents are used.
  • the selenium-containing gold compound of the present invention can also be employed as an antidote for gold toxicity in the gold therapy of rheumatoid arthritis. It was found that the mice which have been received the selenium-containing gold compounds shows high resistance to the gold toxicity due to the administration of a gold compound, for example, Na 3 Au (S 2 O 3 ) 2 -2H 2 O.
  • a gold compound for example, Na 3 Au (S 2 O 3 ) 2 -2H 2 O.
  • mice were given sodium selenite in their drinking water over an extended period of time. Periodically, the mice were sacrificed and the kidney and liver were analyzed to monitor the accumulation of selenium. When observed selenium levels in the liver were on the order of 5 ppm, the remaining animals were given the gold compound at levels slightly exceeding the reported LD 50 value.
  • mice were given dosages of gold compounds at the reported LD 50 value and were then injected with sodium selenite.
  • mice were fed other type selenium compounds, which were sodium selenate, selenium yeast and selenocystine. Periodically, one would be sacrificed and the selenium concentration of the kidney and liver would be determined. When above 5 to about 7 ppm selenium concentrations were obtained, the remaining mice were given injections of Na 3 Au(S 2 O 3 ) 2 .2H 2 O at the reported LD 50 value. A control group that received no dietary selenium was maintained. This control group was given the gold salt at the same time as the selenium accumulated mice. The toxic effects of the gold was then compared in the two groups of mice.
  • selenium compounds which were sodium selenate, selenium yeast and selenocystine.
  • mice that recieved selenium in their diet, followed by the administration of Na 3 Au (S 2 O 3 ) 2 .2H 2 O nad a significantly lower mortality rate than the corresponding control group.
  • the higher survival rate of the selenium group indicates that these selenium compounds also are effective in reducing gold toxicity.
  • Example 3 1.4g (2 mmol) of (tetra-O-acetyl-1- ⁇ -D-glucopyranosyl) seleno (triethylphosphine) gold obtained in Example 3 was dissolved in 10 ml of absolute methanol. 540 mg (10 mmol) of CH 3 ONa was added to the thus obtained solution, and then stirred for 2 hours on ice. After completion of the reaction, the mixture was slightly acidified with 0.1N HCl. To the mixture was added 10 ml of water to form a precipitate. The thus obtained precipitate was separated by filtration and dried. Thus, 890 mg (1.6 mmol) of (1- ⁇ -D-glucopyranosyl) seleno (triethylphosphine) gold was obtained.

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EP19830902851 1983-08-10 1983-08-10 Utilisation de composes contenant du selenium pour annuler les effets toxiques des composes d'or utilises dans le traitement de l'arthrite rhumatoide, et nouveau compose d'or contenant du selenium et son utilisation comme medicament contre l'arthrite rhumatoide. Withdrawn EP0153307A4 (fr)

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Application Number Priority Date Filing Date Title
PCT/US1983/001239 WO1985000747A1 (fr) 1983-08-10 1983-08-10 Utilisation de composes contenant du selenium pour annuler les effets toxiques des composes d'or utilises dans le traitement de l'arthrite rhumatoide, et nouveau compose d'or contenant du selenium et son utilisation comme medicament contre l'arthrite rhumatoide

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EP0153307A1 EP0153307A1 (fr) 1985-09-04
EP0153307A4 true EP0153307A4 (fr) 1987-03-12

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US4645756A (en) * 1985-09-27 1987-02-24 Smith Kline Beckman Corporation [α,ω-bis(diphenylphosphino)hydrocarbon]bis[(thiosugar)gold] and bis[(selenosugar)gold] derivatives, pharmaceutical compositions and method of use
CN114949242B (zh) * 2022-01-27 2023-09-22 暨南大学 含硒化合物在制备破骨细胞分化抑制剂中的应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE757672A (fr) * 1969-10-28 1971-04-19 Smith Kline French Lab Complexes d'auro-trialcoylphosphine de 1-beta-D-glucopyranosides
US3792165A (en) * 1971-04-27 1974-02-12 Smithkline Corp Phosphine or phosphite gold complexes of thiomalic acid in treating arthritis
US3718679A (en) * 1971-04-27 1973-02-27 Smith Kline French Lab Phosphine or phosphite gold complexes of thiomalic acid
US3718680A (en) * 1971-06-07 1973-02-27 Smith Kline French Lab Phosphine or phosphite gold complexes of thioethanol and derivatives thereof
US3784687A (en) * 1971-06-07 1974-01-08 Smithkline Corp Phosphine or phosphite gold complexes of thioethanol and derivatives thereof to treat arthritis
US3883546A (en) * 1973-08-01 1975-05-13 Smithkline Corp S-heterocyclic derivatives of phosphine or phosphite gold mercaptides
US4096250A (en) * 1977-02-25 1978-06-20 Smithkline Corporation Tri-substituted phosphinegold(I) 1-thio-β-D-glucopyranosides
US4340590A (en) * 1977-08-02 1982-07-20 Lundy Research Laboratories, Inc. Method for reducing or inhibiting ecchymosis in skin tissues with inorganic selenium compositions

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* Cited by examiner, † Cited by third party
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No relevant documents have been disclosed *

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