Istvan Hermecz

Lipophilicity of antibacterial fluoroquinolones

Abstract The octanol/water partition coefficients of nine antibacterial fluoroquinolones and nalidixic and oxolinic acids were investigated. The pH-partition profile of amphoteric fluoroquinolones obtained between pH 4 and 10 showed maximum partitioning at the isoelectric point. From the two microspecies (zwitterionic and nonionic forms) which exist predominantly at this pH, the nonionic form is assumed to be transferred into the octanol phase. A relationship is derived between the apparent and true partition coefficients, valid for ampholyte compounds capable of forming zwitterions and having nonionic microspecies present in significant amounts. On the bases of true partition coefficients, three groups of examined fluoroquinolones are distinguished: lipophilic compounds (e.g., pefloxacin and amifloxacin), molecules of intermediate lipophilicity (such as ciprofloxacin and ofloxacin, etc.) and hydrophilic derivatives (e.g., norfloxacin and lomefloxacin, etc.). The influence of structural modification on the lipophilicity of these drugs is discussed.

Nitrogen bridgehead compounds part 16. Facile total synthesis of 7,8-dihydro-13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-one (Rutecarpine).☆

Rutecarpine 1 has been synthetised from hydrazone 2, in high yield by Fischer indole synthesis, Hydrazone 2 has been prepared from 3 with benzenediazonium chloride or 5 with phenylhydrazine. 2 Shows a solvent dependent E-Z isomerism.

Chemistry of Pyrido[1,2-a]pyrimidines

Publisher Summary This chapter surveys the primary chemical literature of Pyrido [1,2- a ]pyrimidines. Certain types of pyrido[1,2- a ]pyrimidines have aroused much interest owing to their valuable pharmacological properties. They are also used as synthetic intermediates or as additives to photographic materials and dyes. The chapter presents methods for the preparation of different pyrido[1,2-a]pyrimidines such as (1) pyrido[1,2- a ] pyrimidinium salts, (2) 2-oxo-2 H -pyrido[1,2- a ]pyrimidines, (3) 4-oxo-4 H -pyrido [1,2- a ]pyrimidines, (4) 3,4-dihydro-2 H -pyrido[1,2- a ]pyrimidines (5) 2-oxo-3,4-dihydro-2 H - and 4-oxo-2,3-dihydro-4 H - pyrido[1,2- a ]pyrimidines, and (6) miscellaneous pyrido[1,2- a ]pyrimidines. In addition, the chapter discusses the stability of the bicyclic ring system; and the hydrogenation, reduction, dehydrogenation, oxidation, and quaternization of the compounds. The substitution reactions affecting the pyrido[1,2- a ]pyrimidine ring, transformations of the side chains, and ring transformation reactions are outlined and the characteristic physicochemical properties of pyrido[1,2- a ]pyrimidines are enlisted in the chapter. Pyrido[1,2- a ]pyrimidines are being studied because of the valuable biological properties.

Chemistry of Diazabicycloundecene (DBU) and Other Pyrimidoazepines

Publisher Summary This chapter focuses on the chemistry of diazabicycloundecene (DBU) and other pyrimidoazepines. The general family of pyrimidoazepines encompasses seven distinct heterocyclic systems. This chapter illustrates that on the pyrimido azepines, the chemistry of 2,3,4,6,7,8,9,10-octahydropyrimi azepine, generally called diazabicyclo is treated in a separate subsection, as DBU has proved to be a useful reagent in synthetic organic chemistry and an important catalyst in the synthesis of macromolecules. The applications of DBU have rapidly increased because of its favorable nonnucleophilic, yet strongly basic, properties. It can therefore be applied for the preparation of even relatively sensitive molecules. This chapter also discusses the synthesis, reactions, physicochemical properties, and briefly the applications of further pyrimido[1,2-a]azepine derivatives. This chapter concludes that the treatment of the chemistry of the other pyrimidoazepines follows an essentially identical pattern to that for the pyrimido azepines.

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 4. 1 → 3 N→C-acyl migration. Part 2

Ring closure of 2-substituted 3-(2-pyridylamino)acrylates (1) in phosphoryl chloride–polyphosphoric acid gives pyrido[1,2-a]pyrimidines (2), whereas (6-substituted 2-pyridyl) derivatives in Dowtherm A afford pyrido[1,2-a]-pyrimidines (2) and 1,8-naphthyridines (3). The 6-substituted pyrido[1,2-a]pyrimidines (2) can be converted thermally into 1,8-naphthyridines (3) by 1 → 3 N→C-acyl migration. Similar acyl migrations can be observed in other such systems.

An alternative total synthesis of rutaecarpine and vasicolinone alkaloids

Abstract Rutaecarpine ( 6 ) and vasicolinone ( 9 ) alkaloids were alternatively prepared by Fischer indolization of 3-(phenylhydrazonomethyl)pyrroloquinazoline ( 4 ) under thermal and acidic conditions, respectively.

Determination of partition coefficients of pyrido[1,2-a]pyrimidin-4-one derivatives by traditional shake, thin-layer chromatographic and gas—liquid chromatographic methods

Abstract In the investigation of quantitative structure—activity relationships, one of the most important linear free-energy related parameters is the logarithmic value of water—1-octanol partition coefficients (log P ) and π values derived from that. Partition coefficients of eighteen pyrido[1,2- a ]pyrimidin-4-one compounds were measured for the water—1-octanol solvent system by spectrophotometric methods. R M values and corrected Δ I values of the compounds were also determined by thin-layer chromatographic and gas—liquid chromatographic methods, respectively. The excellent correlations found between these log P, R M and corrected Δ I values prove that liquid—liquid partition data can be obtained not only by thin-layer chromatography or high-performance liquid chromatography but also by gas—liquid chromatography.

Syntheses of indolyl-4(3H)-quinazolinones

2-(1H-Indol-2-yl)-4(3H)-quinazolinones (10, 11) and 2-(2-ethoxy-carbo- nyl-1H-indol-3-yl)-4(3H)-quinazolin-4-one (15) are prepared by the Fis- cher indolization of 2-(1-phenylhydrazonoalkyl)- (8, 9) and 2-(2-phenyl- hydrazono-2-ethoxycarbonylethyl)-4(3H)-quinazolinones (14), respecti- vely, by heating in PPA. When 2-phenylhydrazone derivative (14) is hea- ted in 85% phosphoric acid at 180°C, besides indolization ester hydro lysis and decarboxylation also occurred to yield 2-(1H-indol-3-yl)-4(3H) -quinazolinone (16). The 3-(1H-indol-3-yl)-4(3H)-quinazolinone (24) is prepared either from the isomeric 3-indolyl derivatives of anthranila- mide (21, 23) by heating in 98% formic acid, or in «one pot» procedure from 2-[1-(N-methyl-N-phenylamino)ethyl]-4(3H)-quinazolinone (17) by heating in 98% formic acid in the presence of a few drops of conc. hy- drochloric acid. The reaction mechanism is discussed

Saturated heterocycles. Part 88. Synthesis of a new ring system: dipyrido[1,2-a:4,3-d]pyrimidin-11-one derivatives

The synthesis of 1,2,3,4-tetrahydro-11H-dipyrido[1,2-a:4,3-d]pyrimidin-11-one derivatives (6a–s), a new class of ‘pyracridones’, i.e. 2-azapyracridones, was performed by the condensation of 3-methoxycarbonyl-4-piperidones (5) and 2-aminopyridines in polyphosphoric acid. Catalytic reduction of compounds (6) or ring closure of (5) with 2-iminopiperidine was found to give the 1,2,3,4,6,7,8,9-octahydro-11H-dipyrido[1,2-a:4,3-d]pyrimidin-11-ones (7a)–(7c). The seven-membered ring C homologue derivatives (7d), (7e) have also prepared by the latter method.