Patent GB-800699-A (GB)
Title: Mono- and di-alkyl anhydrotetracyclines
IPC: C07C233/00
Filed: 1956-04-27
Abstract: Antimicrobial agents of general formula <FORM:0800699/IV (b)/1> wherein X is chlorine, when Y is H, and when X is hydrogen Y is OH or H, and R and R1 are alkyl groups or substituted alkyl groups which may be the same or different, are produced by condensing a tetracycline antibiotic with at least one molecular proportion of a compound which can provide a carbonium ion in the presence of a strong acid such as sulphuric acid, phosphoric acid, p-toluenesulphonic acid, benzene sulphonic acid and hydrogen chloride.  The reaction takes place in an inert solvent which may be polar, e.g. acetic acid, or non-polar, e.g. dioxane, tetrahydrofurane, dipropyl ether and diisobutyl ether.  Depending upon the nature of the starting materials, the temperature and duration of the reaction and the quantity of olefinic compound or compounds, the products produced are (a) C-alkyl anhydrotetracycline compounds of formula <FORM:0800699/IV (b)/2> having up to nine carbon atoms and at least one of the unsaturated carbon atoms is substituted by alkyl groups or by aryl; (b) N-alkyl anhydrotetracycline compounds of formula <FORM:0800699/IV (b)/3> and (c) C,N-dialkyl anhydrotetracycline compounds of formula <FORM:0800699/IV (b)/4> The tetracycline antibiotic starting material is tetracycline, chlortetracycline, and oxytetracycline, or a 5a-6 anhydro derivative thereof, as such, or in the form of a salt or the nitrile.  The compound, which can provide a carbonium ion, is, e.g., an olefine, which may be aryl substituted, e.g. isobutylene, diisobutylene, octenes, hexene or an alcohol such as t-butanol, sec.-amyl alcohol, benzyldimethyl carbinol and benzyl alcohol.  The compounds of the invention form salts with (a) inorganic acids such as sulphuric, hydrochloric, nitric and phosphoric; (b) alkali and alkaline earth metals, and (c) organic acids such as p-toluenesulphonic acid and benzenesulphonic acid. Complexes are formed with calcium chloride, nickel chloride, ferrous chloride and antimony trichloride.  Examples disclose the preparation of (a) tertiary-amylanhydro-oxytetracycline, (b) tertiary-butylanhydrochlortetracycline, (c) benzylanhydrochlortetracycline, (d) tertiary-butylanhydrotetracycline, (e) t - butylanhydrochlortetracycline, (f) di - tert. - butylanhydrochlortetracycline; (g) di-tert.-butylanhydrotetracycline, (h) tert. - amylanhydro-oxytetracycline, and (i) benzyl dimethylcarbinylanhydrochlortetracycline.  The antimicrobial agents of the invention, which are active against Trichomenas, may be used medicinally for the treatment of humans and animals (see Group VI). Specification 766,512 is referred to.ALSO:C-alkyl-, N-alkyl- and C,N-dialkyl-anhydrotetracyclines of formula <FORM:0800699/VI/1> wherein X is chlorine when Y is hydrogen, and when X is hydrogen Y is OH or H (i.e. chlortetracycline, oxytetracycline or tetracycline derivative) and R and R1 are alkyl or substituted alkyl groups which may be the same or different (see Group IV (b)), which are antimicrobial agents effective against Trichomonas, are used medicinally for the treatment of man and animals, in the form of compositions such as powders, tablets and suppositories. Specification 766,512, [Group IV (b)], is referred to.