Patent GB-712828-A (GB)
Title: Therapeutically active bismuth organic compounds
Filed: 1951-01-29
Abstract: The invention comprises bismuth compounds which contain at least one ring of formula  <FORM:0712828/IV (b)/1> The compounds are made by reacting ionizable metallic bismuth or a bismuth compound with an organic vicinal dimercapto compound in the presence of a liquid reaction medium.  The reaction may be effected in water or in an organic solvent in which at least one of the reactants is soluble or in a liquid dithiol.  Reaction may take place in a pH range of from 4N HCl to N NaOH.  Aqueous media of pH 1-10 are preferred.  Organic solvents mentioned include chlorbutanol, benzyl alcohol, glycerol, methanol, olive and peanut oils, ethyl oleate or methyl-acetamide. Compounds made in acidic media are more stable than those obtained in neutral or weakly alkaline media.  In strong alkalies ring splitting at the Bi-S link may occur.  2,3-Dimercaptopropanol and 2,3-dimercaptopropionic acid are preferred dithiols, others mentioned including those of formula <FORM:0712828/IV (b)/2> where R may be present or absent and represents any aliphatic group containing up to 17 C atoms, Z is always present as H, -OH, -COOH, -COO-alkyl, -O-alkyl, CH3 or a glucose radicle and R1 is H or alkyl, and dithiols of formula  <FORM:0712828/IV (b)/3> Other preferred dithiols are HS.CH2CH2SH; HS.CH2CH(SH)X, where X is -CH2OH, -COOH, -CH2OCH3, -CH2O-glucose, -CH2OCOCH3, -CH2OCOC6H5, -CH2OCO C6H4CH3, -(CH2)nOH, -CH2O-alkyl, -CH2O-acyl and -(CH2)nCOOH. Representative of specified dithiols are 2,3-dimercaptopropionate, 2,3-dimercaptopropyl ethyl ether, 2,3-dimercaptopropyl urea, 2,3-dimercaptopropyl urethane, 2,3-dimercaptopropyglucoside, 2,3-dimercaptopropyl dodecyl sull phide, 2,3-dimercaptopropylamine, 2,3-dimercaptopropyl chloride, 2,3-dimercaptopropionic acid, ammonium 2,3-dimercaptopropionate, 3,4-dimercaptotetrahydrothiophene - 1 - dioxide, N - phenylaminopropane - 2,3 - dithiol hydrochloride, 1,2 - dimercaptopropane, dithiocatechol, phenylethanedithiol - 1,2, cyclohexanedithiol - 1,2; diethanolaminomethyl dithioglycerol - 1,2, methyl - glucaminomethyl dithioglycerol - 1,2, bis - S - (N - ethylacetamidomethyl) dithioglycerol-1,2, bis-S-(N-ethylacetamidomethyl) dithio-glycerol-1,2 and the glucose mercaptal of dithioglycerol-1,2.  Representative of specified bismuth compounds are bismuth potassium sodium tartrate, bismuth sodium p-aminophenylarsenate, bismuth subgallate, finely-divided metallic bismuth, bismuth nitrate, chloride, oxychloride and hydroxide, bismuth tribenzoate and bismuth salicylate.  Reaction is preferably effected at room temperatures although temperatures of 2-60 DEG  C. are indicated.  About 1/2 to 4 mols. of dimercapto compound are used per atom of bismuth. In examples: 2,3-dimercaptopropanol is reacted with (1) bismuth sodium citrate in aqueous ammonia and ethanol to yield a compound of formula <FORM:0712828/IV (b)/4> (2) Bl2O3 in aqueous methanol containing hydrochloric acid to yield <FORM:0712828/IV (b)/5> (3) sodium tribromethyl tartrate in aqueous sodium hydroxide under nitrogen to yield <FORM:0712828/IV (b)/6> (4) bismuth ammonium citrate in aqueous ethanol; (5) bismuth hydroxide in aqueous sodium hydroxide to yield the product of (1); in (6) bismuth sodium tartrate in aqueous sodium hydroxide is reacted with 2,3-dimercaptopropionic acid; (7) 1,2-dithioethane is reacted with bismuth hydroxide in aqueous ethanol to yield <FORM:0712828/IV (b)/7> (8) dithiocatechol is reacted with bismuth hydroxide in aqueous hydrochloric acid and ethanol to yield <FORM:0712828/IV (b)/8> (9) bismuth ammonium citrate is reacted in aqueous ammonia with 2,3-dimercaptopropanolglucoside; (10) 2,3-dimercaptopropanol is reacted with a -carboxyethyl-b -methyl nonoate of bismuthyl in peanut oil; and (11) 2,3-dimercaptopropanol is reacted with bismuth thiolaurate in ethyl oleate.ALSO:The invention comprises therapeutically active bismuth compounds which contain at least one ring of formula <FORM:0712828/VI/1> which may be prepared in the form of a medicinal or veterinarial composition by reacting a bismuth compound with an organic ricinol dimercapto compound in the presence of a liquid reaction medium. Thus bismuth hydroxide (2 mols) may be reacted with 2.3-dimercaptopropanol (3 mols) in water, peanut oil, ethyl oleate or methyl - acetamide, 2, 3 - dimercapto-propanol and -propionic acid are preferred dithiols, others mentioned including those of formula <FORM:0712828/VI/2> , where R may be present or absent and represents any aliphatic group containing up to 17 C atoms, Z is always present, is H, -OH, -COOH, -COO alkyl, -O-alkyl, -CH3 or a glucose radicle and R1 is H or alkyl and dithiols of formula <FORM:0712828/VI/3> Other preferred dithiols are HSCH2 CH2SH; HS, CH2CH(SH)X, where X is -CH2OH, -COOH, -CH2OCH3, -CH2O-glucose, -CH2O COCH3, -CH2O CO C6 H5, -CH2OCOC7H7, -(CH2)nOH, -CH2O-alkyl, -CH, O-acyl and -(CH2)n COOH. Representative of specified dithiols are 2, 3-dimercapto-propionate, propyl ethyl ether, propyl chloride and propionic acid, ammoside, propyl dodecyl sulphide, propylamine, propyl chloride and propionic aid, ammonium 2, 3-dimercaptopropionate, 3, 4-dimercapto -tetrahydrothiophene -1 -dioxide, N-phenylaminopropane-2, 3-dithiol hydrochloride, 1, 2-dimercapto-propane, dithiocatechol, phenylethandithiol-1, 2, cyclohexanedithiol-1, 2, diethanolaminomethyl dithioglycerol-1, 2, methyl-glucaminomethyldithioglycerol-1, 2, bis-s- (N-ethylacetamidomethyl) dithioglycerol-1, 2, and the glucose mercaptal of dithioglycerol-1, 2.  Representative of specified bismuth compounds are bismuth potassium sodium tartrate, bismuth sodium p-aminophenylarsonate, bismuth ascorbate, bismuth subgallate, finely divided metallic bismuth, bismuth nitrate, chloride, oxychloride and hydroxide, bismuth tribenzoate and bismuth salicylate.  Aqueous media of pH 1-10 are preferred.  Organic liquids specified include chlorbutanol, benzyl alcohol, glycerol, methanol, olive and peanut oils, ethyl oleate, methyl acetamide and excess liquid dithiol.  Compounds made in acidic media contain a single pentatomic ring and are more stable than those obtained in neutral or weakly alkaline media when if an excess of dithiol is used compounds containing more than one ring are obtained.  In strong alkalis ring splitting at the Bi-S link may occur.  The reaction is described in Group IV(b) about 1/2 -\ba1/4 mols of dithiol being used per atom of bismuth.