Pyrimidine-, reversed

Basically, AZT is anabohcaHy phosphorylated to AZT mono-, di-, and tri-phosphates by various enzymes (kinases) of a target ceU (159). AZT-triphosphate competes with other phosphorylated pyrimidine nucleosides for incorporation into HIV DNA by the viral reverse transcriptase. Incorporation of the AZT-triphosphate into reverse transcriptase results in viral DNA chain termination. Reverse transcriptase is essential in the repHcative cycle of HIV. 

Preliminary IR spectral studies were said to suggest that pyrimidinones existed as pyrimidinols <50JCS3062) but this conclusion was promptly reversed <52JCS168) on better experimental evidence subsequent comparison with their N- and O-methyl derivatives showed that the pyrimidinones (39a R = H) and (40a R = H) along with their A-methyl derivatives (39a R = Me), (40a R = Me) and (40b R = Me) all exhibited vqo in the range 1600-1700 cm, whereas the methoxypyrimidines (39b R = Me) and (40c R = Me) showed no such absorptions <53JCS33l, 55JCS211). Closer analysis of the spectra for pyrimidin-4-one (40a R= H) showed that the ort/jo-quinonoid form (40a R = H) is the predominant tautomer (see Section 2.13.1.4). 

A reversal of the position of the substituents on the pyrimidine ring is involved in the reductive cyclization of 4-ketoalkyl-5-phenylazopyrimidines to give, e.g. 6-alkylpyrido[3,2- f]pyrimidines (76JHC439). 

The parent compounds undergo facile hydrolysis to aminoaldehydes subsequent to the covalent hydration and reversible ring-opening as described above for pyrido[4,3-d]pjrrimidines (Section IV, B). 2-(3-Pyridyl)pyTido[2,3-d]pyrimidine undergoes hydrolysis to yield 2-aminonicotinaldehyde and nicotinamide when treated with N—HCl under reflux for 3 hours. This mechanism also probably involves a covalent hydrate. 2-Methylpyrido[4,3-d]pyrimidin-4(3H)-one, although much more stable than the parent compound, is readily hydrolyzed with dilute acid, whereas the isomeric compounds from the other three systems are stable under such conditions. 

Quantitation of the oral bronehodilator 2,5-diethyl-7-(tetrahydro-l,4-thiazin-4-yl)-l,2,4-triazolo[l,5-c]pyrimidine (R-836) (195) in plasma and urine of humans and experimental animals utilized reversed-phase HPLC and UV deteetion (88MI1). 

Flash vacuum thermolysis (FVT) of 2-substituted 4//-pyrido[l,2-n]pyrimidin-4-ones 126 above 800 °C afforded (2-pyridyl)iminopropadie-none (130) (99JCS(P2)1087). These reactions were interpreted in terms of reversible ring opening of 4//-pyrido[l,2-n]pyrimidin-4-ones to imidoyl-ketenes 127. A 1,5-H shift in 127 generated the N(l)H-tautomeric methylene ketene 128, in which facile elimination of HX took place via a six-membered cyclic transition state 129 to yield 130. In the case of 2-methoxy derivative 126 (X = OMe) another competing pathway was also identified at lower temperature, which resulted in the formation C3O2 and 2-methylaminopyr-idine via mesoionic isomer 131 (Scheme 9). The products were identified by IR spectroscopy. 

Cyclocondensation of 2-iminopiperidine and 3-aryl-2-propynylnitriles in THE or 5% MeCN/THF afforded 4-aryl-2-imino-6,7,8,9-tetrahydro-2H- and 2-aryl-4-imino-6,7,8,9-terahydro-4//-pyrido[l,2-n]pyrimidines in 70-98% and 2-30% yields, respectively (00OL3389). When the reactions were carried out in the presence of 2 equiv of NaHMDS the product ratio was reversed. 

Cyclocondensation of 2-amino-6-bromopyridine and 4-chloroacetoace-tate in PPA at 100 °C for 4h afforded a mixture of 2-chloromethyl-, 2-bromomethyl-6-bromo-, and 2-chloromethyl-, 2-bromomethyl-6-chloro-4//-pyrido[l,2-n]pyrimidin-4-ones in 84% yield (99JHC1065). The pyrido-[l, 2-a]pyrimidin-4-ones were separated by preparative reversed phase HPFC. The pure 2-bromomethyl-6-bromo-4//-pyrido[l,2-n]pyrimi-din-4-one was prepared from 2-amino-6-bromopyridine with ethyl 4-bromoacetoacetate in 63% yield. Reaction of 2-aminomethylpyridines and ethyl 4-chloroacetoacetate in PPA at 110°C gave 2-chloromethyl-4//-pyrido[l,2-n]pyrimidin-4-ones (95FFS69, 01H(55)535). 

C. Lipschitz, H. Iith, G. J. de Jong, U. A. Th Brinkman and R. W. Frei, Trace emich-ment of pyrimidine nucleobases, 5-fluoro-uracil and bromacil on a silver-loaded tliiol stationaty phase with on-line reversed-phase high-perfomance liquid cliromatography , J. Chromatogr. 471 321-334 (1989). 

It was known that the K+ -competitive imidazopyridine compound, SCH28080, inhibits acid secretion. Then, many reversible inhibitors were developed. These contain protonatable nitrogens but have a variety of core structures such as imidazopyiidines, piperidinopyr-idines, substituted 4-phenylaminoquinolines, pyrrolo [3,2-c]quinolines, guanidinothiazoles, and 2,4-diamino-pyrimidine derivatives. Several reversible inhibitors have been in clinical trials. 

Balzarini J, Perez-Perez M-J, San-Felix A, Schols D, Perno C-F, Vandamme A-M, Camarasa M-J, De Clercq E. 2, 5 -Bis-0-(tert-Butyldimethylsilyl)-3 -spiro- 5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)pyrimidine (TSAO) nucleoside analogues highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proc Natl Acad Sci USA 1992 89 4392-4396. 

Formation of the photodimer is reversible, the dimer being split with high quantum yield with light of wavelength about 235 nm.(82> Similar dimerizations have been observed with several other pyrimidine derivatives, as... 

Cyclocondensation of 2-iminopiperidine and 3-aryl-2-propynylnitriles afforded 4-aryl-2-imino-6,7,8,9-tetrahydro-22/-pyrido[l,2- ]pyrimidines <20000L3389, 2002W002/00629>. The minor isomers, 2-aryl-4-imino-6,7,8,9-tetrahy-dro-4/7-pyrido[l,2- ]pyrimidines could also be isolated in 2-30% yields from the reaction mixtures <20000L3389>. When the reactions were carried out in the presence of 2 equiv of NaHMDS, the product ratio was reversed. From the reaction mixture of 2-aminopyridine and perfluoro-2-methylpent-2-ene in MeCN, a 9 1 mixture of 2,4-difluoro-2-pentafluoroethyl-3-trifluoromethyl-477- and the isomeric 2,4-difluoro-4-pentafluoroethyl-3-trifluoromethyl-277-pyr-ido[l,2- ]pyrimidine (64%), and 2-pentafluoroethyl-3-trifluoromethyl-47/-pyrido[l,2- ]-pyrimidine-4-one (20%) was isolated <2000JFC(103)105>. 

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