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

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 alpha-amide derivative 13 was formed, but hydrolysis of the product provided N-methyl-DL-asparagine 9 via base catalyzed ring closure to DL-alpha-methylamino-succinimide 4, followed by selective ring opening. Efficient methods were developed for the preparation of NMA-alpha-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.

Photochemical and chemical oxidation of mexiletine and tocainide. Structure elucidation of the major products.

Mexiletine (mex) and tocainide (toc) are antiarrhythmic drugs of closely related structure. Several degradation products are formed by interaction with both light and oxidizing agents in the case of mex, and only by oxidants with toc. On the basis of the identified structures, the decomposition reactions can be classified into two types (Scheme 1). Type I is an oxidative cyclization reaction producing the oxazepine derivative 1 from mex and the diazepine derivative 3 from toc. In reaction type II side chain oxidized products (2 or 4 and 5) are formed. While tocainide.HCl has proved to be photostable, in solid mexiletine HCl the oxazepine derivative was observed after several days' exposure to direct sunlight. The pharmacopoeias (Ph.Eur.3, USP 23), however, do not prescribe light-protection for mex.HCl.

[Synthesis and investigation of protonation properties and lipophilicity of some new quinazolone-3-carboxylic acid derivatives]. / Kinazolon-3-karbonsav származékok szintézise, protonálódási és lipofilitási vizsgálata.

Several new quinazolone-carboxylic acid derivatives as potential NMDA and AMPA receptor antagonists have been synthesized, and the protonation properties and lipophilicity of some representative molecules have also been studied. The protonation macroconstants (logK) of 4(3H)-quinazolone (Q0) and two 2-methyl-4-oxo-3H-quinazoline-3-carboxylic acids (Q1, Q2) were determined by pH-potentiometry. The acid-base chemistry of Q1 and Q2, where protein-bindings take place in an overlapping fashion, was described in terms of protonation microconstants (logk) as well. Microspeciation was carried out by UV-pH titration and deductive method. Microspeciation revealed remarkable differences between the two homologue compounds (Q1 and Q2), namely insertion of a second methylene moiety into the aliphatic acid side-chain reversed the predominantly zwitterion-involved protonation pathway into neutral form-involved one. Lipophilicity of our molecules was described by the octanol-water partition coefficients. The apparent partition coefficients of Q1 and Q2 were determined by shake-flask method and converted into true logP values using the protonation microconstants. The unexpected differences between their true logP values were explained, similarly to the different protonation pathways with conformational preferences and formation of intramolecular interactions. Out of the other 15 monoprotic quinazolone compounds the lipophilicity of 10 molecules (Q8-Q17, experimental set) was determined by RP-TLC method with the help of a calibration set consisting of 12 standard molecules, five quinazolones (Q3-Q7, determined by shake-flask method) and seven pyrido[1,2a]pyrimidines (PP1-PP7). The obtained logP values proved mostly the expected structure-property relationships. These physico-chemical investigations are pieces of predictive information for the pharmacokinetics of our compounds. These are also discussed in the paper.

[In vitro interaction of selegiline, riboflavin and light. Sensitized photodegradation of drugs. I]. / Szelegilin, riboflavin és fény in vitro kölcsönhatása. Fotoszenzibilizált gyógyszerbomlások. I.

Selegiline (Deprenyl, Jumex, Movergan etc.) is primarily used in the therapy of Parkinson's disease due to its neuroprotective, antidepressive and oxidative stress-preventing activities. Its prime effect is based upon the inhibition of the monoamine oxidase enzyme (MAO-B). The cofactor of this flavoenzyme is riboflavin (vitamin B2). Riboflavin, on the other hand, is an effective photosensitizer, with the capacity to promote the photodegradation of molecules (drugs, biological systems) which are otherwise stable against daylight. It has been studied whether this property of riboflavin is expressed against selegiline as well. This experiments proved that in the presence of riboflavin, both daylight and the light of daylight-lamps are sufficient to significantly decompose selegiline. The major decomposition product is methamphetamine.

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.

[Chemistry of A-2545, an anti-arrhythmia drug candidate. I. Structure elucidation of its main hydrolysis product]. / Az A-2545 antiaritmiás gyógyszerjelölt kémiájához I. Hidrolízisvizsgálatok.

A great number of antiarrhythmic agents with 2,2,5,5-tetramethyl-3-pyrroline (and pyrrolidine)-3-carboxamide structure were synthesized. One of them A-2545 (1) was selected for further investigation aiming the elucidation of its chemical properties. The hydrolysis of 1 was studied, where theoretically seven hydrolysis products might be formed (2-8, Fig.1.). The hydrolysis takes place in aqueous solution of 1. HCl also at room temperature. In alkali-catalyzed process only one main product can be detected by TLC. This hydrolysis product was assigned as phthalamide acid (2) proved by chromatographic, thermic, GC-MS and NMR methods. An interesting behaviour of 2 upon GC-MS investigation (thermic and electron impact) is its recyclisation to 1 at the injector temperature (140 degrees) thus 2 appears in the mass spectrum as it would be A-2545 (Fig. 2. and 3.).

[Ion exchange interactions on silica gel in thin-layer chromatography. IV. Plate investigations by UV spectroscopy]. / Szilikagél rétegen végbemenö ioncserés kölcsönhatások. IV. On plate UV-spektroszkópos vizsgálatok.

The properties of silica gel as stationary phase are determined mainly by siloxane, silanol and metal-silanate functional groups. The metals (Na, Ca etc.) getting into the product as trace elements in the course of manufacture may cause the appearance of artefacts. In our previous studies the ion exchange interactions between salt-type analytes and silanol or metal-silanate groups were investigated. It was found in the TLC test of the salts of organic acids and N-bases that the acids and bases are separated from their counter ions and accept protons from or donate to the silica gel layer. In the present paper several analytes of above type have been investigated in situ by remission spectroscopy. These are: phenobarbital, sulfinpyrazone, sulfucetamide, benzoic acid, salicylic acid, (and their Na-salts) and papaverine hydrochloride. Remission spectra were registered from the start spot directly after application and then from the spot after development with the CHCl3EtOH (9 + 1) mobile phase. Based on the difference between the remission spectra of protonated and deprotonated forms of the analytes, the deviations from the initial state could be established. On the basis of the shift of lambda max values one can conclude to the approximate ratio of the protonated (acid) and deprotonated (anion, base) form present in the examined points (middle or edge) of the chromatographic spot. Significantly different protonation states of the analytes were found in the start spots and in the developed spots. These findings are interpreted by the ion exchange interactions between the pharmacon and silica gel. The results provide a deeper insight into the mechanisms of TLC process.

[Hydrophobic constant values (delta RMO) of functional groups. II. Interpretation of fragment interactions]. / Funkciós csoportok hidrofób konstans értékeinek (delta RM0) vizsgálata. II. Fragmens interakciók értelmezése.

The delta RM0(-CH2-) values have been calculated from fragment values of various alkyl groups (methyl, ethyl, n-propyl). On the basis of delta RM0(-CH2-) values it has been established that the value of the so-called "second" methyl group from aromatic ring has slightly differed from that of the so-called third methylene group and the value of methylene functional group is constant independently from positions of substituents and from electronic interactions. The delta RM0 Me values of methyl group--which is directly attached to aromatic ring--have been regarded as the so-called first methylene group from aromatic ring since value of free energy needed for transfer of methyl group as well as the other physico-chemical data (mole volume, parachor) are nearly the same as those of methylene group according to the literature. Fragment values of methyl groups substituted at various positions have been compared to relating delta RM0(-CH2-) value which is free practically from electronic interactions and it has been ascertained that fragment values have been higher as well as lower. In accordance with literature lower delta RM0 Me values have been interpreted with hyperconjugation effect of aromatic system. On the other hand lower methylene fragment values of alkyl substituted compounds at N1 atom have been attributed to sigma conjugation. In literature higher delta RM0 Me values than relating delta RM0(-CH2-) value are known only in case of orto position to another functional group or by a methyl group on a sterically hindered aromatic ring. Results of tests have shown that values of delta RM0 Me can substantially increase with extension of conjugated aromatic system or with simultaneous substitutions of methyl, methylene groups, respectively at certain locations. The authors have assigned that increase to change of solvate cuver which surrounds the molecule. The same has been manifested by methyl fragment values of quinazoline derivates (tetrahydropyrroloquinazoline, hexahydroazepinoquinazoline) of different electronic distributions. On basis of calculations it has been proved that delta RM0 2-Me and delta RM0 6-Me fragment values of monosubstituted pyrido (1,2-a)-pyrimidine (PP) derivatives have significantly differed from delta RM0 Me values of at other positions (3,7,8,9) methyl substituted compounds. Among disubstituted derivatives only delta RM0 7-Me and delta RM0 8-Me values of 2-phenyl- and 3-carbetoxymethyl-PP derivatives have not differed from each other but methyl fragment values of other positions (6,9) have significantly differed from each other and from other fragment values too.(ABSTRACT TRUNCATED AT 400 WORDS)

[Hydrophobic constant values (delta RM0) of functional groups. I. Comparative study of delta RM0 values determined in open (TLC) and closed (OPTLC) chromatographic systems]. / Funkciós csoportok hidrofób konstans értékeinek (delta RM0) vizsgálata. I. Nyílt (TLC) és zárt (OPTLC) kromatográfiás rendszerben meghatározott delta RM0 értékék összehasonlító vizsgálata.

delta RM0 values of functional groups (methyl, ethyl, n-propyl, methylene, phenyl, benzyl, saturation) of nitrogen bridgehead compounds [PP = pyrido(1,2-a)-pyrimidine, THPP = tetrahydropyrido(1,2-a)-pyrimidine, CTM-PP = 2,3-cyclotrimethylpyrido(1,2-a)-pyrimidine, CTM-THPP = 2,3-cyclotrimethylenetetrahydropyrido(1,2-a)-pyrimidine, CTRM-PP = 2,3-cyclotetramethylenepyrido(1,2-a)-pyrimidine, CTRM-THPP = 2,3-cyclotetramethylene-tetrahydropyrido(1,2-a)-pyrimidine, CTRM-THPP = 2,3-cyclotetramethylene-tetrahydropyrido(1,2-a)-pyrimidine, THPQ = tetrahydropyrroloquinazoline-, HHAQ = hexahydroazepinoquinazoline-derivates have been calculated from difference of retention values measured on RP-di-C1 stationary phase using methanol + water mobile phases of 6 (10 respectively) various compositions and of retention values (RM0) extrapolated to 0% organic phase. Retention data have been determined in normal chambers loaded with change of phase rate because of the vapour space of the developing chamber and in so-called pressurized ultramicro chamber which is free of change of phase rate and that of vapour space, respectively. It has been ascertained that delta RM0 values of same functional groups--that had been measured in the two different chamber systems--have not significantly differ from each other. It has also been established that opposite direction distortions of RM0 values--measured in normal chambers with mobile phases nearing or moving off 0% organic phase--have generally similar effects on delta RM0 values which are free of change of phase rate. Significant investigations were carried out by programs written on TEXAS SR-52 computer and work has always been done in 95% confidence interval.

[Ion exchange interactions on silica gel layers. II. Halogen salts of compounds containing organic tertiary and quaternary nitrogen]. / Szilikagél rétegen végbemenö ioncserés kölcsönhatások. II. Szerves tercier és kvaterner nitrogént vegyületek haloidsói.

Primary and secondary ion exchanges--of hydrochloric acid and hydrobromic acid salts of well hydrolyzing organic bases as well as quaternary ammonium bromide which are important drug substance--taking place on silica gel using methanol as mobile phase have been investigated by thin-layer chromatographic and spectrophotometric methods. In case of tertiary ammonium salts (hydrolyzing salts) basis linked to silanate ion and halogen acid have been formed by primary ion exchange. During secondary ion exchange halogen acid has exchanged metal ions linked to silanate ions on the layer. In case of non hydrolyzing salts, the quaternary ammonium bromide salts it could not surely be proved by the applied methods whether primary ion exchange had been followed by secondary ion exchange or only primary ion exchange had occurred.

[Ion exchange interactions on silica gel layers. III. Salts of organic bases with organic acids. Organic acids and sodium salts]. / Szilikagél rétegen vébemenö ioncserés kölcsönhatások. III. Szerves bázisok szerves savakkal alkotott sói. Szerves savak és nátriumsók.

By thin-layer chromatographic and spectroscopic (UV, IR) methods it has been proved that bass and acid are formed from salts of organic bases with organic acids during primary interaction because of the ion exchange behaviour of the silica gel layer. The organic acids formed have interacted with metals on the layer during secondary ion exchange and they migrate further as salts again. It has also been established that the extent of secondary ion exchange between metal silanate groups and acids depends on pKS values of acids. On the basis of investigations it can be ascertained with great probability that organic acids of pKS greater than 7 do not interact with metal silanate groups of silica gel layer. Sodium salts of organic acids of pKS less than 3 values similarly do not interact on the other hand sodium salts of organic acids of pKS greater than 3 values are able to interact with silanol groups. It has been established by flame atomic emission method that salicylic acid interacts with sodium ion and 86% of it migrates further as sodium salicylate.