Heterocyclics phthalazines

Aldehyde oxidase, a non-microsomal enzyme discussed in more detail below, may also be involved in the oxidation of quinoline to give 2-hydroxyquinoline (Fig. 4.14). The heterocyclic phthalazine ring in the drug hydralazine is oxidized by the microsomal enzymes to phthalazinone. The mechanism, which may involve nitrogen oxidation, is possibly involved in the toxicity of this drug (see chap. 7). Again, other enzymes may also be involved (Fig. 4.15). 

Purine oxidation. The oxidation of purines and purine derivatives is catalyzed by xanthine oxidase. For example, the enzyme oxidizes hypoxanthine to xanthine and thence uric acid (Fig. 4.34). Xanthine oxidase also catalyzes the oxidation of foreign compounds, such as the nitrogen heterocycle phthalazine (Fig. 4.35). This compound is also a substrate for aldehyde oxidase, giving the same product. 

R] Simpson, ]. C. E. Cinnolines. In The Chemistry of Heterocyclic Compounds. Condensed Pyridazine and Pyrazine rings (Cinnolines, Phthalazines, and Quinoxalines)-, Weissberger, A. Ed. Interscience Publishers New York-London, 1953 p3. 

R] Singerman, G. M. Cinnolines. In Heterocyclic Compounds. Condensed Pyridazines Including Cinnolines and Phthalazines-, Weissberger, A., Taylor, E. C. Eds. John Wiley Sons New York-London, 1973 pi. 

Triazine (38) is ideal for inverse electron-demand Diels-Alder cycloadditions, for example, with azulene to give a l,4-bis(CF3)phthalazine (89CB711). A rare example of the synthesis of a five-membered heterocycle originating from [4 + 1] cycloaddition followed by [4 + 2] cycloreversion was reported using (38). The intermediate tetraazanorbomadienimine (39) is highly strained and eliminates N2 [82AG(E)284]. 

The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine once again played a central role in many investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible. 

AO is also effective in metabolizing a wide range of nitrogen-containing heterocycles such as purines, pyrimidines, pteridines, quinolines, and diazanaphthalenes (95). For example, phthalazine is rapidly converted to 1-phthalazinone by AO and the prodrug, 5-ethynyl-2-(l//)-pyrimidone, is oxidized to the dihydropyrimidine dehydrogenase mechanism-based inhibitor, 5-ethynyluracil, by AO (Fig. 4.40) (96). 

Reissert compounds (>70%), derived from benzimidazole, phthalazine, quinoline and isoquinoline, have been prepared by a simple catalysed one-pot N-acylation of the appropriate heterocycle, followed by reaction with cyanide ion [e.g. 101-103],... 

Nagarapu L, Bantu R, Mereyala HB (2009) TMSCl-mediated one-pot, three-component synthesis of 2H-indazolo 2, 1-b phthalazine-triones. J Heterocycl (Them 46 728-731... 

Arene oxide-oxepin systems have also been reported to undergo [2 + 4] or [4 + 6] pericyclic cycloaddition reactions with heterocyclic dienes like the tetrazine 279 and the triazine 280. 65 Thus 86 96 reacts with 279 and 280 to yield the dihydrooxepino [4,5-d] pyridazine 281 and the oxepino [4,5-c] pyridine 282, respectively, via a [2 + 4] cycloaddition as well as the phthalazine 283 and isoquinoline 284, respectively, probably via a [6 + 4] cycloaddition reaction. However, 157 gives only 285 and 286 arising from a [2 + 4] cycloaddition reaction. 

Isolated and benzo-fused diazine rings are key structural elements in many natural and synthetic compounds of current, active interest. This contribution relates highlights from many of the studies on the diazines pyridazine, pyrimidine, pyrazine, and their benzo-fused derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine published in English in the journal literature during 1995, as covered by Chem. Abstr. through volume 124, issue 9. Review articles published in 1994 and not cited in Prog. Heterocycl. Chem. have been included. 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

Next to the quinazolines, phthalazines represent the most important heterocyclic series in this class of PDE5 inhibitors. At least two compounds from this category have reached clinical trials E4010 (32) [38] and BMS341400 (33) [39], Both compounds show subnanomolar PDE5 inhibition. Again, a chloromethoxybenzyl substituent seems to be among the preferred substituents in the top part of the molecule polar substituents in the bottom part also characterize this series. 

Ring closure and annelation occurs when the heterocyclic carbodiimide 628 is generated in the presence of phthalazine to give the new heterocycle 629. ... 

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