Patent GB-835886-A (GB)
Title: A new antibiotic angolamycin, and its preparation by fermentation, hydrogenation and fission products thereof and salts of these compounds
Filed: 1956-06-08
Abstract: <PICT:0835886/IV (b)/1> A new antibiotic angolamycin is prepared by cultivating an angolamycin-producing strain of Streptomyces eurythermus nov. spec. in an aqueous nutrient solution containing a source of carbon, nitrogen and inorganic salts under aerobic, preferably submerged, conditions.  A temperature of 20 DEG  to 50 DEG C. and duration of 36 to 120 hours is employed.  Specified nutrients are aminoacids, peptides and proteins and their hydrolysates such as peptone or tryptone, meat extracts, water-soluble constituents of cereal grains, distillation residues from manufacture of alcohol or yeasts, soya bean, cottonseed, glucose, lactose, saccharose, starch; chlorides, nitrates, carbonates and sulphates of alkali metals and alkaline earth metals, magnesium, iron, zinc and manganese. Angolamycin is isolated from the clarified broth by (a) extraction with a water-immiscible solvent such as ethyl acetate, chloroform, ether or butyl alcohol as a pH preferably above 7.0; (b) adsorption on activated carbon or fuller's earth followed by elution with an acid aqueous solution or with a partially water-miscible organic solvent such as butanol; (c) by precipitation as a salt with an organic sulphonic acid or picric acid.  Further purification is by (1) distribution between an acid aqueous solution and an organic solvent immiscible with water e.g. aqueous buffer of pH 3.15 and chloroform (1:1), especially countercurrent distribution; (2) chromatography on e.g. aluminium oxide using benzene, chloroform and mixtures of chloroform and methanol; (3) crystallization from solvents.  Angolamycin forms salts with inorganic and organic acids, both acid and neutral salts being formed; specified are salts with hydrochloric, sulphuric, acetic, valeric, palmitic, oleic, succinic, reinecke citric, mandelic, glutamic and pantothenic acids.  The salts may be produced by double decomposition between a salt of the acid and a salt of angolamycin.  Hydrogenation of angolamycin using (a) a palladium-calcium carbonate catalyst in ethanol yields dihydroangolamycin and (b) a platinum oxide catalyst in glacial acetic acid yields hexahydroangolamycin.  Hydrolysis with aqueous sulphuric acid for 5 hours at 100 DEG C. yields ethyl acetate insoluble fission products having Rf values of 0.28 and 0.65 (mixture of butanol and glacial acetic acid (10:1) saturated with water). Angolamycin is used medicinally (see Group VI). Angolamycin is a base; effective against certain gram-positive bacteria; occurs in two crystal forms, one of m. pt. 133-136 DEG  C. and the other of m. pt. 165 DEG  to 168 DEG  C.; specific rotation [a ]21D-64 DEG  (C = 1.3 in chloroform); C = 60.49%; H = 8.93%; N = 1.66%, CH3O = 8.80%, CH3(N) = 3.66%, CH3 (C) = 11.55%; empirical formula C50-1H89-2 O18N; exhibits a strong band in ultraviolet at 240 mm ; exhibits characteristic bands in infra red at 2.93, 3.53, 5.84, 5.92, 6.15, 6.81, 7.06, 7.25, 7.59, 7.87, 8.16, 8.56, 9.16, 9.34, 10.02, 10.29, 11.00, 11.91, 12.66 and 13.20 microns.  The antibiotic is distinguished from erythromycin and carbomycin.ALSO:A pharmaceutical preparation comprises a carrier and an antibiotic angolamycin, a salt thereof with an inorganic or an organic acid, a hydrogenation product particularly the dihydro- or hexahydro-compound, an aqueous acid hydrolysis product, or a mixture thereof (see Group IV (b)).  The preparations may be in the form of a tablet, dragee, powder, salve, cream, suppository, solution, suspension or emulsion. Specified carriers are gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly and cholesterol. Preserving, stabilizing, wetting or emulsifying agents and other drugs may be present.  Specified salts are those with hydrochloric, sulphuric, acetic, valeric, palmitic, oleic, succinic, reinecke citric, mandelic, glutamic and pantothenic acids.  The salts may be acid or neutral salts.