Synthesis and Chemical Properties of 1-Aryl-substituted Pyrimido[5,4-b]indoles

Abstract

The class of isomeric pyrimidoindoles and their derivatives contain many compounds possessing biological activity of various types, including analgesic [1, 2], vasodilating [3], antihypoxant [4], antiinflammatory [5], inotropic [6], etc. Recently, it was also established that some derivatives of pyrimido[5,4-b]indoles are capable of inhibiting NO synthases — enzymes catalyzing the oxidation of L-arginine into citrulline and nitric oxide [7]. A number of NO synthase blockers have been found among the compounds containing amidine fragments – for example, imino derivatives of various heterocycles, including substituted pyrimidines [8]. Nitric oxide (NO) is capable of penetrating by means of simple diffusion through almost all biological membranes. For this reason, a large release of this biologically-active mediator gives rise to numerous (frequently, serious) pathological states. Such disorders include septic shock, neurodegenerative diseases, and various inflammatory processes. In order to avoid NO overproduction in the organism, it is necessary to use NO synthase inhibitors. This study was aimed at the synthesis and characterization of new 1-aryl-substituted pyrimido[5,4-b]indoles containing amidine fragments — potential NO synthase inhibitors. Methods most widely used for the synthesis of pyrimido[5,4-b]indoles are based on the cyclization of 3-aminoindole-2-carboxylic acid derivatives via reactions with “single-carbon” components such as dimethylformamide dialkyl acetals [9] and isocyanates [10, 11]. Recently [12, 13], we obtained a series of 1-aryl-2-oxo1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole-4-oxides (Ia – Id) and transformed a seven-member cycle of 4-oxide Ia into a six-member cycle under the action of PCl3 with the formation of 2-oxo-1-phenyl-3-formyl-2,3,4,5-tetrahydro-1H-pyrimido[5, 4-b]indole (IIa) [12]. In this study, by analogy with the above transformation of oxide Ia, we have also decreased the diazepine cycle of compounds Ib – Id and obtained the corresponding 1H-pyrimido[5,4-b]indoles (IIb – IId). The H NMR spectra of compounds IIb – IId exhibit doubling of most signals due to amide isomerism. The appearance of singlets at = 8.35, 8.46, and 8.82 – 8.85 ppm is indicative of the presence of N–CHO groups in these compounds. The physicochemical characteristics and parameters of the H NMR spectra of the newly synthesized compounds are presented in Tables 1 and 2. It should be noted that the transformation of 6-methyl-substituted 4-oxide of [1,4]diazepino[6,5-b]indole Id proceeds much more difficultly (a mixture of oxide Id and PCl3 is boiled for 4 h) than the analogous conversion of unsubstituted 4-oxides Ib and Ic, for which the reaction is completed within 10 min. We have also studied the transformations of 2-oxo-1phenyl-2,5-dihydro-1H-pyrimido[5,4-b]indole (III) obtained by boiling 3-formylpyrimidoindole IIa with piperidine in methanol. This reaction involves deformylation and subsequent aromatization of the pyrimidine ring