Patent GB-815517-A (GB)
Title: Dihydro novobiocin, its salts and other derivatives and pharmaceutical compositions containing same
IPC: C07H17/075
Filed: 1956-06-12
Abstract: <PICT:0815517/IV (b)/1> A broad spectrum antibiotic, dihydronovobiocin, which is active against resistant strains of staphyllococci, is non-toxic, readily absorbed and stable in aqueous preparations, is prepared by reacting novobiocin (also known as streptonivicin, albamycin and antibiotic 66a) in a solvent therefor with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel and platinum oxide.  The temperature is 0 DEG  to 100 DEG C., the pressure 0 to 100 lb. per square inch and the time 5 to 30 minutes or even up to 24 hours.  One molecule of hydrogen is absorbed per molecule of novobiocin.  The solvent is an aliphatic alcohol such as methanol and ethanol or an alkoxyethanol such as beta methoxyethanol, beta ethoxy ethanol or beta butoxyethanol. Dihydronovobiocin is recovered by filtering off the catalyst, diluting with water and acidifying to pH 1 to 2.  Recrystallization may be from a chlorinated solvent such as chloroform.  Alternatively, dihydronovobiocin may be recovered from the clarified reaction medium by the addition of a non-solvent e.g. a mixture of acetone and hexane.  Dihydronovobiocin forms mono- and di-salts with inorganic and organic bases.  Salts may also be formed by double decomposition between a salt of dihydronovobiocin and a salt of a weak acid, e.g. sodium acetate; or by the action of an alkoxide, e.g. sodium methoxide on the dihydronovobiocin in an anhydrous medium, e.g. acetone.  Specified salts are the alkali metal, e.g. sodium and potassium; the alkaline earth metal, e.g. calcium; magnesium; ammonium; and amine salts of mono-, di-, trimethyl (ethyl or propyl) amines, ethyldimethylamine; benzyldiethylamine; cyclohexylamine; benzylamine; dibenzylamine; N,N - dibenzylethylenediamine; bis (o-methoxyphenylisopropyl) amine; araliphatic amines up to and including 8 carbon atoms; heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine, and their alkyl derivatives, e.g. 1-methyl piperidine, 4-ethylmorpholine, 1 - isopropylpyrrolidine, 1,4-dimethylpiperazine, N - n - butyl piperidine, 2 - methylpiperidine and 1 - ethyl - 2 - methyl-piperidine; amines containing water-solubilizing or hydrophilic groups such as mono-, di- and tri-ethanolamines, ethyldiethanolamine, n-butylmonoethanolamine, 2 - amino - 1 - butanol, 2 - amino - 2 - ethyl - 1,3 - propanediol, 2-amino - 2 - methyl - 1 - propanol, tris (hydroxymethyl) amino methane, phenylmonoethanolamine, p - tert. amylphenyldiethanolamine; galactamine, N - methylglucamine, N - methylglucosamine, ephedrine, phenylephedrine, epinephrine, procaine; guanidine; quaternary ammonium hydroxides such as tetraethylammonium hydroxide; antibiotics such as neomycin and erythromycin.  Acyl derivatives are obtained by reacting dihydronovobiocin with an acid anhydride, e.g. acetic anhydride or an acid chloride.  Alkylated products are obtained by the action of a diazoalkane, e.g. diazomethane. Dihydronovobiocin, its salts, its alkyl and acyl derivatives are used medicinally (see Group VI), as an animal feed supplement (see Group I), and to control diseases in plants and slime caused by L. mesenteroides in sugar industry.  Dihydronovobiocin has a decomposition point of 163-5 DEG C.; optical rotation [a ]D23-26 degrees 63.0 (1 per cent ethanol); is soluble in water at pH 9.0 but solubility decreases to pH 5.0; is soluble in chloroform, acetone and amyl acetate; contains C = 60.3 per cent, hydrogen = 6.2 per cent and nitrogen 4.5 per cent; molecular weight 614; two acidic groups pKa, 4.3 and pKa2 9.1 in water; exhibits ultraviolet absorption maxima at 328 millimicrons in acidified aqueous ethanol; characteristic infra-red absorption spectrum of Fig. 1; has the formula <FORM:0815517/IV (b)/1> Specification 815,518 is referred to.ALSO:Dihydronovobiocin, a broad spectrum antibiotic, non-toxic and stable in aqueous vehicles (see Group IV(b)), its salts with inorganic or organic bases and its acyl and alkyl derivatives are used, either alone or in combination with other antibiotics, as feed supplements in promoting growth of animals and poultry. Specification 815,518 is referred to.ALSO:Dihydronovobiocin, a broad spectrum antibiotic which is active against resistant strains of staphyllococci, is non-toxic, readily absorbed and stable in aqueous vehicles (see Group IV (b)), its salts with inorganic or organic bases and its acyl and alkyl derivatives, are used in pharmaceutical preparations for parenteral, oral or topical administration in conjunction with a carrier.  The preparations may be in the form of tablets, effervescent tablets, powders, granules, capsules, suspensions in edible oils, aqueous suspensions, ointments, creams, emulsions, lotions, sprays, troches and suppositories for human use.  For veterinary use, the preparations may be in the form of bougies, mastitis ointments and oil suspensions.  Dihydronovobiocin (in all forms) may be admixed with (a) sulpha drugs such as sulphadiazine, sulphamerazine and sulphamethazine, (b) other antibiotics such as tetracydine, oxytetracycline and chlortetracycline, (c) vitamins such as thiamine, riboflavin, ascorbic acid, niacinamide, pyridoxine, pantothenic acid, pantothenates, Vitamin B12 and folic acid, (d) corticoids such as cortisone, hydrocortisone, and esters thereof; D 1-cortisone and D 1-hydrocortisone and their esters in the 21 position, e.g. acetate and cyclopentylpropionate; 2-methylhydrocortisone and its esters; and (e) other drugs. Examples relate to (a) an aqueous suspension for oral use containing dihydronovobiocin, citric acid, benzoic acid, methyl p-hydroxybenzoic acid, propyl p-hydroxy-benzoic acid, glycerin, tragacanth, sucrose and flavour, (b) an aqueous suspension similar to (a) but containing polyethylene glycol and sodium carboxymethyl celluse, (c) an aqueous suspension for injection containing dihydronovobiocin sodium carboxymethyl cellulose, polyvinylpyrrolidone, and preservative, (d) an aqueous suspension containing dihydronovobiocin, sulphadiazine, sulphamerazine, sulphamethazine, citric acid, preservative, saccharin, sucrose, tragacanth and flavour, (e) eye or ear drops containing dihydronovobiocin neomycin sulphate, hydrocortisone, sodium citrate, polyethylene glycol, polyvinylpyrrolidine, preservative and water. Specification 815,518 is referred to.