Synthesis and antitumor properties of new 4-methyl-substituted- pyrido[4,3-b]indoles (gamma-carbolines).

A new class of antineoplastic agents, 4-methyl-pyrido[4,3-b]indoles (5) and the related 4-hydroxymethyl derivatives (7), has been synthesized by a new pathway. Key transformations include regiospecific chlorination at the C(4)-position of 3-nitro-4-hydroxy-5-methyl-pyridin-2-(1H)-one (11) and photochemical cyclization of the intermediate triazolopyridones (15). This new synthesis was developed since an attempt to prepare 4-hydrazino-5-ethoxymethyl-pyridin-2-(1H)-one (10b) by the method previously used to obtain 4-hydrazino-5-methyl-pyridin-2-(1H)-one (10a) failed. The biological results obtained in different in vitro and in vivo models indicate that the substitution of the 4-CH3 by a 4-CH2OH group leads to a decrease of the antitumor properties.