Patent GB-1004664-A (GB)
Title: Mercapto tetracyclines
IPC: C07C233/00
Filed: 1962-05-11
Abstract: The invention relates to (1) compounds of the formula <FORM:1004664/C2/1> wherein A is hydrogen or hydroxy and R is hydrogen, a primary or secondary alkyl of from one to twelve carbon atoms, R11CO where R11 is alkyl containing from 1 to 3 carbon atoms, phenyl, mono- or disubstituted phenyl, benzoyl, trifluoromethyl or R1CH2- wherein R1 is mono or disubstituted alkyl, carboxy, carbalkoxy, halo, phenyl, mono- or disubstituted phenyl or furyl, each substituent of said mono- or disubstituted alkyl being selected from hydroxy, alkoxy, carboxy, carbalkoxy, halo or amino, provided that where two of said substituents are joined to the same carbon atom at least one is carboxy or carbalkoxy and each substituent of said mono- or disubstituted phenyl being selected from alkyl, hydroxy, alkoxy, carboxy, carbalkoxy, nitro or amino; acid addition salts thereof, and the pharmaceutically acceptable metal salts or complexes thereof, (11) compounds of the formula <FORM:1004664/C2/2> where A is as above and R is as above except that it does not represent hydrogen, the acid addition salts thereof, and the pharmaceutically acceptable metal salts or complexes thereof, and (iii) compounds of formula <FORM:1004664/C2/3> and <FORM:1004664/C2/4> the acid addition salts thereof and the pharmaceutically acceptable metal salts thereof.  Compounds of formula I are prepared by reacting the corresponding 6-deoxy-6-demethyl-tetracycline with a thiol of formula RSH with or without a catalyst e.g. peroxides, oxygen, light or a ,a 1-azodibutyronitrile.  Compounds of formula I are converted to those of formula III by treatment with hydrogen peroxide.  Compounds of formula I in which R is hydrogen are obtained by acid hydrolysis of compounds of formula I in which R is acyl, when this procedure is applied to 6-deoxy-13-benzyl mercaptotetracycline sulphoxide compounds of formulae IX and X are obtained which are separated by fractional crystallisation from alkanols.  Chlorination of 6-deoxy-13-mercapto tetracycline or the corresponding 5-hydroxy compound gives the corresponding 6-deoxy-13-(S-chloromercapto) tetracycline, and where the 5-hydroxy compound is obtained treatment with a base yields <FORM:1004664/C2/5> otherwise the compound of formula IX is obtained. The compounds of formulae I, III, IX and X and their salts are converted to 6-epi-6-deoxytetracycline and 6-epi-6-deoxy-5-oxytetracycline or salts thereof by treatment with Raney nickel containing hydrogen formed during manufacture at 20 DEG to 130 DEG  C. in a reaction inert solvent.  Specified acid addition salts are those formed with p-toluene-sulphonic acid, sulphosalicylic acid, hydrochloric acid, naphtalene sulphonic acid, hydroiodic acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulphuric, tartaric, acetic citric, malic, benzoic, glycollic, gluconic, gulonic, succinic perchloric and hydrofluoric acids.  Specified metal salts or complexes are those formed with sodium, potassium, alkaline earths, magnesium, aluminium, zinc, iron, manganese, lithium, cobalt, tin, cadmium, silver, palladium, cerium, titanium, platinum, vanadium, lead, chromium and nickel.  The tetracycline derivatives are used in pharmaceutical compositions e.g. ointments for topical application or in veterinary feeds. Specifications 995,031 and 995,032 are referred to.