This report describes the discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". These agents are notable for their activity against a broad spectrum of tetracycline-susceptible and -resistant Gram-negative and Gram-positive aerobic and anaerobic bacteria possessing various classes of tetracycline-resistant determinants [tet B (efflux), tet M (ribosomal protection)]. The design and synthesis of a number of 7-substituted 9-substituted-amido 6-demethyl-6-deoxytetracyclines are described.

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3-Amino-4,5-bis(hydroxymethyI)pyridine Hydrochloride (III).-A suspension of 2.0 g. (0.011 mole) of 5-aminocinchomeronic acid in 30 ml. of methanol was treated wdth a solution of diazomethane in ether made from 5.6 g. (0.063 mole) of N-nitrosomethylurea. The reaction mixture was swirled occasionally and allowed to stand until no more nitrogen was evolved. The suspended solid was filtered off and found to be 1.0 g. of starting material. The ether filtrate was evaporated to a brown oil from which no solid product could be obtained. This 1.0 g. of crude ester in 50 ml. of anhydrous tetrahydrofuran was added slowly to a solution of 0.38 g. (0.010 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran. The resulting orange mixture was refluxed for 8 hr. and allowed to stand overnight at room temperature. The excess hydride was destroyed with 2 ml. of water and the insoluble salts were filtered off. The solid was washed three times with 30 ml. of boiling methanol and the combined filtrates were evaporated in vacuo to a tarry residue. Recrystallization of this from ethanol-ethyl acetate (decolorizing charcoal) gave a tan solid; yield 0.25 g. (34% on the basis of reacted acid); m.p. 135-140°( dec.). As purification of the base was difficult the hydrochloride was prepared. Recrystallization of a 100 mg. sample of the hydrochloride from ethanol and alcoholic hydrogen chloride yielded 40 mg. of a light tan solid; m.