József Kökösi

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.

A PAMPA study of the permeability-enhancing effect of new ceramide analogues

There is a major need in drug discovery for quick, precise, and cost‐effective high‐throughput screening (HTS) systems in the early stages of drug research. The Parallel Artificial Membrane Permeability Assay (PAMPA) aims at predicting the passive membrane properties of drugs. Since 1998, model membranes have been developed to predict gastro‐intestinal absorption or transport through the blood–brain barrier. This paper presents recent results in a project aiming to improve the prediction of transdermal penetration. Using the PAMPA system, we investigated the effect of four newly synthetized ceramide analogues (certramides) on the permeability of three model compounds (ciprofloxacin, nifedipine, and verapamil). The certramides differ in the length of one alkyl chain, while the other alkyl chain and the head group remained the same. A relationship between the membrane concentration of certramides (from 0 to 100%) and the permeability of compounds was found, and the results of different certramides were compared. The strongest effect on permeability was caused by the ceramide analogue CTR(C12–C16). The reproducibility of the experiments and the impact of presence or absence of organic solvents (dodecane and CHCl3) in the membrane were also investigated.

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.

Characterization of potential NMDA and cholecystokinin antagonists. II. Lipophilicity studies on 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acid derivatives.

The lipophilicity of 17 newly synthesized potential NMDA and cholecystokinin antagonist 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acid derivatives has been investigated. The apparent partition coefficients of two amphoteric compounds of overlapping protonation (Q1 and Q2) were determined by shake-flask method and converted into true log P values using the protonation microconstants. The difference between their lipophilicity expressed with the true partition coefficients was less, than it could be expected from the 2D structures and was explained with conformational preferences and formation of intramolecular interactions. Out of the other 15 monoprotic quinazolone compounds the lipophilicity of ten molecules (Q8-Q17, experimental set) was determined by TLC method with the help of a calibration set consisting of 12 standard molecules, five quinazolones (Q3-Q7) and seven pyrido[1,2-a]pyrimidines (PP1-PP7). In order to justify the suitability of pyrido-pyrimidines as standards for the chromatographic log P determination of quinazolones, first Q3-Q7 were examined by TLC and HPLC using PP1-PP7 for calibration. Data showed good agreement of results obtained by shake-flask and two different chromatographic methods indicating the similar chromatographic behavior of the two bicyclic systems and the relevance of PP1-PP7 to extend the calibration set of quinazolones. The obtained log P values proved mostly the expected structure-activity relationships. Some findings, however, have revealed specific partition behavior of the compounds providing useful information in the estimation of their pharmacokinetics, and these are discussed in the paper.

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

Nitrogen bridgehead compounds 87. Synthesis of 3-azarutecarpine (14-azanauclefine) and its 7-methyl derivative

Abstract 3-Azarutecarpine (14-azanauclefine) derivatives 2 were prepared by Fischer indolization of 6-phenylhydrazono-6,7,8,9-tetrahydro-11H-dipyrido[1,2-a;4,3-d]pyrimidine-11-ones8. Compounds 8 were obtained from 6,7,8,9-tetrahydro-11H-dipyrido-[1,2-a;4,3-d]pyrimidinones7 with phenyldiazonium chloride. New compounds are characterized by UV, IR, 1H and 13C NMR spectroscopy.

Synthesis of 8-substituted 7-azarutaecarpines

Abstract The synthesis of 8-substituted 7-azarutaecarpines 2 is described. These compounds were prepared by Fischer indolization of 3-amino-2-(1-phenylhydrazonoethyl)-4(3H)-quinazolinone 5, followed by cyclocondensation with a series of aliphatic, araliphatic or aromatic aldehydes and formic acid or a Vilsmeier–Haack reagent. The stereochemistry of compounds 2 was investigated by 1H NMR spectroscopy. It was found that the 8-substituents assume a quasi-axial position on the flattened boat conformation of ring C of 2, with the exception of ortho substituted phenyl groups, which occupy quasi-equatorial positions. Semi-empirical MO calculations support these conformational preferences.

Enantiomer separation of imidazo-quinazoline-dione derivatives on quinine carbamate-based chiral stationary phase in normal phase mode.

The normal phase mode liquid chromatographic enantiomer separation capability of a quinine tert-butyl-carbamate-type chiral stationary phase (CSP) has been investigated for a set of polar [1,5-b]-quinazoline-1,5-dione derivatives. This class of chiral heterocycles is currently under development as potential alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and/or N-methyl-D-aspartic acid (NMDA) receptor antagonists. The effect of the nature and concentration of polar modifier, i.e., ethanol and isopropanol, in n-hexane-based mobile phases, as well as the substituent pattern of the phenyl ring attached to the quinazolone framework on retention factor, enantioselectivity, and resolution was investigated. The Soczewiński competitive adsorption model was used to describe the relationship between the retention and the binary mobile phase compositions. According to this model, linear plots of the logarithms of retention factor versus molar fractions of the polar modifiers were obtained over a wide concentration range (X(B) between 0.15 and 0.35). Addition of equimolar ethanol yields higher resolution than isopropanol, R(S) values ranging between 1.54 and 2.75, whereas the latter allows to achieve moderately increased enatioselectivity. The resolution was further improved by using a ternary mixture of n-hexane:methanol:isopropanol/85:5:10 (v/v). The most pronounced selectivity factor alpha and resolution R(S) values were obtained for the para-hydroxy substituted compound, indicating that chiral recognition is sensitive to steric and stereoelectronic factors. In the course of optimization, the temperature-dependence on the chiral separation was also investigated. It turned out that the enantiomer separation is predominantly enthalpically driven in normal phase mode.

Structure elucidation of a process-related impurity of dapoxetine.

Unknown by-product associated with the synthesis of dapoxetine was isolated. The structure elucidation of this new compound using accurate mass data and NMR spectroscopy is presented herein. The unambiguous resonance assignment concluded to the formation of a tricyclic compound 4-phenyl-2H,3H,4H-naphtho[1,2-b]pyran, a new impurity of dapoxetine which has never been reported previously. A proposed mechanism for the formation of the new carbon-carbon bond is discussed. For the separation of dapoxetine and the process-related impurities, a gradient HPLC method was developed.

Methods for syntheses of N-methyl-DL-aspartic acid derivatives

Summary.A novel practical method for the synthesis of N-methyl-DL-aspartic acid 1 (NMA) and new syntheses for N-methyl-aspartic acid derivatives are described. NMA 1, the natural amino acid was synthesized by Michael addition of methylamine to dimethyl fumarate 5. Fumaric or maleic acid mono-ester and -amide were regioselectively transformed into beta-substituted aspartic acid derivatives. In the cases of maleamic 11a or fumaramic esters 11b, the α-amide derivative 13 was formed, but hydrolysis of the product provided N-methyl-DL-asparagine 9 via base catalyzed ring closure to DL-α-methylamino-succinimide 4, followed by selective ring opening. Efficient methods were developed for the preparation of NMA-α-amide 13 from unprotected NMA via sulphinamide anhydride 15 and aspartic anhydride 3 intermediate products. NMA diamide 16 was prepared from NMA dimethyl ester 6 and methylamino-succinimide 4 by ammonolysis. Temperature-dependent side reactions of methylamino-succinimide 4 led to diazocinone 18, resulted from self-condensation of methylamino-succinimide via nucleophyl ring opening and the subsequent ring-transformation.