Harold Mellon Taylor

Discovery and development of a novel class of nonsteroidal aromatase inhibitors

Efforts to develop a novel class of nonsteroidal aromatase inhibitors began with the discovery that the infertility in male rats exposed to high levels of the agricultural fungicide, fenarimol (alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidine-methanol), was attributable to the inhibition of aromatase activity within the central nervous system during the critical neonatal period. Although fenarimol was not particularly potent in inhibiting rat ovarian microsome aromatase activity in vitro (50% inhibition (IC50) = 4.1 microM). Subsequent testing of a number of analogues led to the identification of LY56110 (alpha,alpha-bis(4-chlorophenyl)-5-methylpyrimidine) which exhibited an IC50 of 29 nM. LY56110 was orally active, blocking the testosterone-induced increase of uterine weight and ovarian estrogen biosynthesis in immature female rats. In rats with established DMBA-induced mammary carcinoma, complete tumor regression was observed in 80% of the animals. Development of LY56110 was, however, stopped because of its effects on hepatic microsomal enzymes and an unacceptably long half-life. Structural modifications resulted in the development of the indenopyrimidines. LY113174 (8-chloro-5-(4-chlorophenyl)-5H-indeno less than 1, 2D greater than pyrimidine) was highly effective in vitro (IC50 = 24 nM) and in vivo but was far less potent than LY56110 with respect to induction of hepatic microsomal enzymes. LY113174 exhibited an acceptable biological half-life and had no effect on cholesterol side-chain cleavage. The indenopyrimidines appear to be a novel class of nonsteroidal aromatase inhibitors which may prove useful in the treatment of estrogen-dependent diseases.

A New Synthetic Approach to 4(1H)-Pyridone Derivatives. I. 1-Alkyl-3,5-diaryl-4(1H)-pyridones

Abstract Recent developments1–3 in the synthesis of 4(1H)-pyridone derivatives have prompted us to communicate a highly versatile synthesis of this class of heterocycles. Acylation of the styrylamine (I)4 (R1 = C2H5) with a substituted arylacetyl halide (II) in ether at O[ddot]-30[ddot]C in the presence of triethylamine or pyridine gave in 2 to 24 hours the enaminoketone (III) (75%-85% trans-isomer together with 25%-15% cis-isomer based on chemical shift of CH methine proton). Enaminoketone (III) could be readily converted to (IIIa) with aqueous methylamine in ethanol or to the bis-enaminoketone (IV) with N,N-dimethylformamide dimethyl acetal. The enaminoketone (IIIa) could be cyclized to pyridone (V) by refluxing with N,N-dimethylformamide dimethyl acetal; alternatively, the bis-enaminoketone (IV) could be cyclized to pyridone (V) by overnight reflux with methylamine hydrochloride in ethanol. yields based on styrylamine were 30%-65%. These transformations are outlined in Scheme 1. As an example, the synt...

New Synthetic Approaches to 4(1H)-Pyridones. II. Derivatives Having Nonaromatic Substituents

Abstract The preceding communication reports on the synthesis of 3,5-diaryl-4(1H)-pyridone derivatives via enaminoketones derived from the acylation of styrylamines with substituted arylacetyl chlorides. In this paper we describe methods for the preparation of 4(1H)-pyridones bearing carboxylic acid, ester, nitrile, cycloalkyl, cycloalkenyl, and derived functional groups in the 3-position.