Tibor Breining

Nitrogen bridgehead compounds. 44. New antiallergic 4H-pyrido[1,2-a]pyrimidin-4-ones. 4

The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbox yli c acid (1) in the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of an (arylamino)methylene moiety into position 9 of the pyridopyrimidine ring. Compound 34, (+)-6(S)-methyl-9-[(m-methylphenyl)-hydrazono]-4-oxo-4H-pyrido[1,2 -a] pyrimidine-3-carboxylic acid, displayed about 10 000 times the activity of the starting compound 1. A structure-activity relationship study of 9-[(arylamino)methylene]tetrahydropyridopyrimidine-3-carb ox ylic acids resulted in conclusions similar to those found for the 9-(arylhydrazono)tetrahydro-and 9-(arylamino)dihydropyridopyrimidine series. Replacement of the 3-carboxy group of 9-(phenylhydrazono)-tetrahydropyridopyrimidin-4-ones with an acrylic acid moiety caused slight increases in potency. In the 6-methyl-substituted series, a high stereospecificity was observed between the enantiomers with 6S and 6R absolute configurations, the former being responsible for the antiallergic activity. The effects of some 9-[(arylamino)-methylene]tetrahydropyridopyrimidine-3-car box ylic acids on the rat passive peritoneal anaphylaxis test were also investigated.

Nitrogen bridgehead compounds. Part 32. Absolute configuration and circular dichroism of 6-methyl-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones

From the resolved enantiomers of (1b), whose enantiomeric purities were determineed by 1H n.m.r., three types of 6-methyl-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one derivatives (1)–(3) were prepared in optically active form. The absolute configuration at the chiral centre C(6) was established on the basis of the anomalous X-ray scattering of the bromine atom of compound (–)-(5) synthesized from compound (+)-(5) synthesized from compound (+)-(1b). Analysis of the experimental u.v. and c.d. spectra led to the identification of two different types of chromophoric systems in molecules of types (1) and (2) on the one hand, and in those of type (3) on the other. The results of CNDO/S calculations for the energies, oscillator strengths, and rotational strengths due to the transitions of simple model molecules with geometries based on X-ray data were in good qualitative agreement with the experimental u.v. and c.d. spectra, and allowed the chiroptical properties of compounds (1)–(3) to be correlated with their known absolute geometries.

Nitrogen bridgehead compounds, part 49. Synthesis and stereochemistry of 9-aminotetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones.

The 9-phenylaminotetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones (4)–(9), synthesized from the 9-bromo compounds (1)–(3), displayed imine–enamine tautomerism. In solution (if R2≠ H) the equilibrium mixtures contain both cis- and trans-imines. The enamine form is stabilized by increasing polarity of the solvent and by increasing the electron-withdrawing effect of substituent R1. Owing to 1,3-allylic strain, in the derivatives where R2= Me the imine form is energetically less favoured than in the derivatives with R2= H. The chemical structures of the synthesized products were studied by u.v., 1H and 13C n.m.r. spectroscopy.