The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

The discovery of aminoglycoside 66-40C, a novel dimeric, unsaturated imine produced by Micromonospora inyoensis, afforded a versatile intermediate for the synthesis of a variety of sisomicin analogues modified at the 6' position. The conversion of 66-40C into sisomicin, antibiotic G-52, and a series of novel 6'-substituted analogues of sisomicin is described, and the biological activity of the products is discussed.

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A series of tylosins and acyl derivatives of 23-O-demycinosyltylosin (DMT) were initially tested for in vitro antibacterial activity and serum levels in squirrel monkeys (po) and mice (iv). Overall, the DMT compoundswere moreactive in vitro than the tylosins. Twotetraacylated DMTs,Sch 37644 and Sch 38646, were selected from the initial studies for further evaluation and compared to erythromycin and A-56268 (6-O-methyl erythromycin). Sch 37644 and Sch 38646 were 2 to 8-fold less potent in vitro against Gram-positive bacteria than erythromycin and A-56268. In squirrel monkeys, Sch 37644 (AUC, 19.7 fig-hour/ml) and A-56268 (21.6//g-hour/ml) had similar serum levels following po administration of 20 mg/kg, while Sch 38646 (1 1.8 fig à" hour/ml) and erythromycin (1.5 ,ug-hour/ml) had lower levels. In mice administered 200mg/kg orally, Sch 37644 (AUC, 19.4 fig-hour/ml) and Sch 38646 (15.4 fig-hour/ml) had higher serum levels than erythromycin (5.7 fighour/ml). A-56268 was the most active po macrolide in mouse protection studies (PD50s) against Staphylococci and Streptococci, while Sch 37644 and Sch 38646 were similar to erythromycin. 1131 Erythromycin, the most commonlyprescribed macrolide antibiotic for urinary tract and respiratory infections, has the disadvantage of being poorly absorbed after po administration. Therefore, a new series of macrolide antibiotics were prepared from tylosin and tested for improved po pharmacokinetics, as well as the retention of the good efficacy of erythromycin against Gram-positive infections. The derivatives were tested for in vitro antimicrobial activity, and pharmacokinetics in squirrel monkeys (po) and mice (iv). On the basis of initial results, two compounds were selected for further studies, 3,23,2'-triO -acetyl-23-0demycinosyl-4//^-/so-valeryltylosin (Sch 37644) and its 12,13-epoxy derivative (Sch 38646). These compoundswere compared to erythromycin and a new orally active erythromycin derivative, A-56268 (Abbott Laboratories, Abbott Park, IL). The data were presented in part at the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy0. Materials and Methods Antibiotics A series of tylosin derivatives were synthesized by Dr. Mallams in our laboratories2'3*. These derivatives consisted of two structurally related groups of compounds: Tylosin and 23-O-demycinosyltylosin (DMT) and their acyl, hydrazone, and 12,13-epoxy derivatives. The structures of the two selected derivatives, Sch 37644 and Sch 38646, are shown in Fig. 1.