Diels-Alder Reaction of Pyrano[3,4-b]indolones with an Electron-deficient Pyridazinone: A New Pathway to Carbazole-fused Pyridazines

Abstract

Thermally induced [4+2] cycloaddition reactions of 5-ethanesulfonyl-2-methylpyridazin-3(2H)-one (2) with pyrano[3,4-b]indol-3(9H)-ones (1, 4) affords isomeric pyridazino[4,5-b]carbazolones (3a,b, 5a,b), the product ratio depending on the substitution pattern of the diene. Two carbazolocarbazoles (6, 7) were obtained as side products. The antineoplastic activity of ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) has stimulated considerable interest in the field of b-fused carbazoles and has led to the synthesis of a large number of derivatives of the natural lead compound, some of them with superior antitumor properties. 1,2 Among those congeners, also some aza-analogous ellipticines like 6,11-dimethyl-5H-pyrido[3',4':4,5]pyrrolo-[2,3-g]isoquinoline 3 (9-azaellipticine), the drug candidate pazelliptine, 4 or a series of 1,4-dialkoxypyridazino[4,5-b]carbazoles 5 have been described. Whereas the latter 3-azaellipticines had been found to be almost inactive, 5 several new representatives of this ring system were prepared in our laboratory recently 6 and some of them turned out to be remarkably active in an in-vitro assay. In this context, the examination of alternative pathways to this tetracyclic ring system became an object of interest. In particular, a cycloaddition reaction between a synthon with a preformed pyridazine ring and another component representing the remaining part of the tetracyclic system was considered a promising strategy. As an indole-derived diene, an appropriately substituted pyrano[3,4-b]indol-3(9H)-one should be a useful building block, as such compounds had already been employed for the construction of condensed or substituted carbazoles previously, e.g. by Plieninger, 7 Moody, 8 and Pindur. 9 As the dienophile, we chose the electron-deficient 5-ethanesulfonyl-2-methylpyridazin-3(2H)-one, 10 which-as well as one example of a nitro-substituted pyridazinone 11-had been shown to react with simple butadiene derivatives in a Diels-Alder fashion to afford (tetrahydro-)phthalazinones, due to its low LUMO energy. 12,13

The anticancer potential of various substituted pyridazines and related compounds

“…The compound (3) was a new 3-aza bioisoster of the natural product, olivacine (Haider and Sotelo.2002). The antitumor activity of polycyclic hetarenes, especially condensed carbazoles of the ellipticine/olivacine type (Haider, et al, 1999;Fidesser, et al, 2001;Haider. 2002) and polycyclic quinones (Spreitzer, et al, 2001;Spreitzer, and Puschmann.…”

“…Based on the naturally occurring lead compounds, numerous modifications of this system have been studied, leading to the development of drugs like elliptinium, datelliptium, retelliptine, or pazelliptine. Recently, the highly potent olivacine analogue, S16020, has attracted considerable attention due to its apparent ability to circumvent P-glycoprotein-mediated multidrug resistance (Haider, et al, 1999;Haider. 2002).…”

Convenient synthesis of new 3-aminocarbazole and pyrimido[5,4-b]carbazole derivatives

“…3 Another strategy consists in replacement of the pyridine ring by other heterocyclic substructures: the synthesis of several new pyridazino [4,3-b]carbazoles ("3azaellipticines"), some of them exhibiting significant antitumor activity, has been described by us recently. 4,5 In continuation of these investigations, we became interested in new 2,3-bifunctional 1-methylcarbazoles which should serve as intermediates in the synthesis of so far unknown types of heterocycle-annelated carbazoles. In particular, derivatives of 1-methylcarbazole-2-carboxylic acid with a (free or protected) amino function in position 3 were regarded as useful synthons for the construction of such tetracyclic systems.…”

Synthesis and In-vitro Antitumor Activity of 1-[3-(Indol-1-yl)prop-1-yn-1-yl]phthalazines and Related Compounds

“…During the course of a research program at our department, focusing on the synthesis and antitumor activity of polycyclic hetarenes, especially condensed carbazoles of the ellipticine/olivacine type [1][2][3][4][5] (cf. Figure 1) and polycyclic quinones [6][7][8], we recently described the preparation of novel pentacyclic ellipticine analogs via a route featuring an intramolecular inverse-electron-demand DielsAlder reaction of indolylpropyl-substituted 1,2-diazines as the key step (Scheme 1) [9].…”