New antibiotics foromacidins a, b, c and d, hydrogenated foromacidins and forocidinsa, b, c and d and process for their manufacture

摘要

Foromacidins A, B, C and D, four closely related antibiotics active against bacteria and especially penicillin resistant microorganisms are prepared by cultivating Streptomyces aureofaciens NRRL 2531 or NRRL 2532, or a mutant thereof, in a nutrient solution containing inorganic salts, nitrogen containing compounds and carbohydrates under surface or submerged aerobic conditions. A pH of 6 to 8, a temperature of 22 to 32 and duration of cultivation of 36 to 120 hours is used. Specified nutrients are amino acids, peptides, proteins and their hydrolipates, meat extracts, grain extracts, distillers solubles, yeast extract, soybean extract, cottonseed extract, glucose, saccharose, lactose, starch, chlorides, nitrates, carbonates or sulphates of alkali metals, alkaline earth metals, magnesium, iron, zinc or magnesium. The mixed antibiotics are isolated from the clarified broth by extraction and/or adsorption. The extraction is a pH above 7.0, e.g. pH 8.5, with a water-immiscible solvent such as ethyl acetate, ethylene chloride, chloroform, methyl isopropyl ketone, butyl alcohol and ethyl ether. Adsorption is with activated carbon or fuller's earth, followed by elution with aqueous acid or an organic solvent such as butanol. The individual antibiotics are separated from the crude mixture so obtained by distribution between an acid aqueous solution, e.g. a citrate buffer of pH 5 and an organic solvent immiscible with water, e.g. chloroform. Further purification is by crystallization from a solvent, e.g. a mixture of ether and petroleum ether. The foromacidins A, B, C and D can be hydrogenated using a platinum PICT:0832627/IV (b)/1 PICT:0832627/IV (b)/2 PICT:0832627/IV (b)/3 PICT:0832627/IV (b)/4 or palladium catalyst to produce antibioticallyactive tetrahydro- or hexahydro-foromacidin A, B, C or D. Acid hydrolysis, e.g. with dilute mineral acid of foromacidin A, B, C and D gives antibiotically-active water-insoluble forocidins A, B, C and D. Alkaline hydrolysis, e.g. with dilute sodium hydroxide of foromacidins gives the production of dimethylamine, formic acid and acetic acid (formacidin B) or propionic acid (formacidin C). The foromacidins, their tetrahydro and hexahydro derivatives, and the forocidins form salts with inorganic and organic acids such as hydrochloric, sulphuric, acetic, propionic, valeric, palmitic, oleic, citric, mandelic, glutamic and pantothenic acids. The salts may be neutral or acid. The above antibiotics and their salts may be used medicinally (see Group VI). Foromacidin A, B, C and D having the following properties: TABS:0832627/IV (b)/1 FOROMACIDINALSO:The antibiotically active foromacidins A, B, C and D, the tetrahydro- and hexahydro-derivatives thereof, the forocidins A, B, C and D which are the acid hydrolysis products of the said foromacidins A, B, C and D, or the salts of these compounds with inorganic and organic acids (see Group IV (b)), as such or in admixture with one another, are incorporated into pharmaceutical preparations for enteral, parenteral and topical use. The preparations may be in the form of tablets, ampoules, dragees, powders, salves, creams, suppositories, solutions, suspensions or emulsions. Suitable carriers are gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, polyalkylene glycols, cholesterol and petroleum jelly. Specified salts are those with hydrochloric, sulphuric, acetic, propionic, valeric, palmitic, oleic, citric, mandelic, glutamic and pantothenic acids.