[Use of crystal conversion reactions in the synthesis of pentacyclic alkaloid analogues]. / Kristály-átalakulási reakciók felhasználása pentaciklusos alkaloid analógok szintézisében.

During investigation of substitution of debenzorutaecarpine derivatives thermal cyclization reactions was observed to produce new fused heterocyclic systems. The optimal temperature of cyclizations was determined by differential calorimetric measurements of crystals of intermediate products. The thermolysis of 2-azido-3-formil-debenzorutaecarpine gave, after elimination nitrogen, izooxazolo-debenzorutaecarpine in good yield. The cyclization of the 2-azido-3-nitroso-debenzorutaecarpine readily led to oxadiazolo E-ring analogue of rutaecarpine. The thermal cyclization of 2-hydroxy-debenzorutaecarpines gave 2-oxo- and 4-oxo-pyrano E-ring analogues of rutaecarpine. The structure of substances was confirmed by spectroscopic methods. The synthesised compounds are considered as first representatives of new heterocyclic ring systems.

[Synthesis of carboline alkaloid analogues]. / Karbolinvázas alkaloid analógok szintézise.

Hybrid compounds were synthesized combining the structural features of two isomer natural indolalkaloids rutaecarpine (1) and nauclefine (2). These aza-bioisosteric analogues are the first representatives of a new heterocyclic ring system. Two alternative reaction routes were developed for the synthesis of pentacyclic compounds (4, 5) in which the key step is the Fischer indolization of the 6-phenylhydrazono-dipyrido[1,2-a;4,3-d]pirimidine-11-ones. In the case of E-ring substituted derivatives the synthesis was carried out via preparation and chemical transformation of pyrido[1,2-a]pirimidine-4-ones (14, 15) to 2-substituted-3-aza-rutaecarpines (17-20). Finally, the nucleophilic displacement of the chlorine atom of 2-chloro-3-aza-rutaecarpine (18) by dialkylaminoethylamine provided the 2-amino-substituted derivative (20) having improved physico-chemical properties and increased antitumour activity. The new compounds are characterized by UV, IR, 1H, 13C NMR spectroscopy.

Prolyl endopeptidase inhibitors.

Selective prolyl endopeptidase inhibitors were elaborated by modification of the structure of SUAM-1221, by using a CoMFA study and protein crystallography. The most active representatives of omega-(N-hetaryl)alkanoylprolylpyrrolidines, containing 2- or 3-methylene chain links have high activity (IC50 10(-9)-10(-11)) and exhibit significant in vivo activities.

A new potent calmodulin antagonist with arylalkylamine structure: crystallographic, spectroscopic and functional studies.

An arylalkylamine-type calmodulin antagonist, N-(3, 3-diphenylpropyl)-N'-[1-R-(3, 4-bis-butoxyphenyl)ethyl]-propylene-diamine (AAA) is presented and its complexes with calmodulin are characterized in solution and in the crystal. Near-UV circular dichroism spectra show that AAA binds to calmodulin with 2:1 stoichiometry in a Ca(2+)-dependent manner. The crystal structure with 2:1 stoichiometry is determined to 2.64 A resolution. The binding of AAA causes domain closure of calmodulin similar to that obtained with trifluoperazine. Solution and crystal data indicate that each of the two AAA molecules anchors in the hydrophobic pockets of calmodulin, overlapping with two trifluoperazine sites, i.e. at a hydrophobic pocket and an interdomain site. The two AAA molecules also interact with each other by hydrophobic forces. A competition enzymatic assay has revealed that AAA inhibits calmodulin-activated phosphodiesterase activity at two orders of magnitude lower concentration than trifluoperazine. The apparent dissociation constant of AAA to calmodulin is 18 nM, which is commensurable with that of target peptides. On the basis of the crystal structure, we propose that the high-affinity binding is mainly due to a favorable entropy term, as the AAA molecule makes multiple contacts in its complex with calmodulin.

[7-aza analogs of quinazolino-carboline alkaloids. Synthesis, structure, characterization]. / Kinazolino-karbolinvázas alkaloidok 7-aza-analóg származékai szintézis, szerkezet, jellemzés.

The synthesis, structure and characterization of 8-substituted-7-azarutaecarpines (2) is described. These compounds were prepared by Fischer indolization of 3-amino-2-(1-phenylhydrazonoethyl)-4(3H)-quinazolin-one (5), followed by cyclocondensation with a series of aliphatic or aromatic aldehydes and formic acid or a Vilsmeyer-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 position. Semiempirical MO calculations support these conformational preferences.

[Pseudopolymorphism of NO-SPA, 1-(3,4-diethoxy-benzyl)-6,7-diethoxy-3,4-dihydro-isoquinoli ne hydrochloride]. / A No-Spa, 1-(3,4-dietoxibenzil)-6,7-dietoxi-3,4-dihidroizokinolin hidroklorid, pszeudopolimorfiájáról.

The spasmolytic agent No-Spa, 1-(3,4-diethoxybenzyl)-6,7-diethoxy-3,4-dihydroisoquinoli ne hydrochloride (1) is a synthetic analogue of the naturally occurring alkaloid papaverine. (1) is prone to form stoichiometric crystalline solvates with a number of solvents causing technological and stability problem. Present paper describes the X-ray structure determination of the hemiethanol, hemibenzene and hemihydrochloride structures being the most important and interesting from both practical and theoretical point of view. The solvate formation is facilitated by the presence of the flexible ethoxy group encapsulating the solvent and by the quasi perpendicular position of the isoquinoline and phenyl group.

[Synthesis and reactivity of debenzorutaecarpine derivatives]. / Debenzorutekarpin származékok szintézise és reaktivitása.

A series of 7,12-dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones was prepared by Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one s. Quantumchemical calculations (ab initio and AM1) indicate that position 3 of 7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-one can be involved in electrophilic substitutions, while position 2 is sensitive towards nucleophilic attack. Bromination of 6-methyl-7,12-dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-o ne (16) with bromine afforded 3-bromo derivative (25), which was reacted with cyclic amines to give 2-amino-7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones (26-30) in an addition-elimination reaction. Vielsmeier-Haack formylation of compound (16) give 12-formyl (31) and 3,12-diformyl (32) derivatives (an N-formyl-1-aza derivative of nauclefidine alkaloid (34) at 60 degrees C and 100 degrees C, respectively. 3,12-dformyl compound (32) was oxidized to 3-carboxyl derivative (33). The quaternary salt (35), obtained from compound (16) with dimethyl sulphate, suffered a ring opening on the action of aqueous sodium hydroxide. The new compounds have been characterized by elemental analyses uv, 1H nmr and in some cases by 13C ruler, CD spectra and X-ray investigations.

[Molecular modeling studies of prolyl endopeptidase inhibitors]. / Prolil endopeptidáz inhibitorok molekulaszerkezeti vizsgálata.

Prolyl endopeptidase, a serine protease is considered to play an important role in the degradation of neuropeptides capable of changing the performance in learning and memory tasks in both animal and human. The inhibitors seem to be promising drug candidates to treat and prevent diseases with associated memory loss such as senile dementia. In the last decade advanced and improved new technologies have appeared to stimulate ideas in the design and synthesis of new drug molecules. The goal of this short communication is to review our results and observations, exemplified by our research on the inhibitors of prolyl endopeptidase. Among them qualitative and quantitative structure-activity relationship studies using conformational analyses, NMR measurements, pharmacophoric plots and CoMFA models are summarised.

[Synthesis of hetero-condensed quinazolones: 1,2,4-triazino[6,1-b]- and 1,2,5-triazino[2,3-b]quinazolones]. / Heterokondenzált kinazolonok szintézise: 1,2,4-triazino[6,1-b]- és 1,2,5-triazepino[2,3-b]kinazolonok elöállítása.

In the course of the systematic investigation of heterocondensed quinazolones derivatives of a new heterocyclic ring system, [1,2,5]triazepino[2,3-b]quinazolone have been developed as potential biologically active agents, which are new bioisoteric analogues of cholecystokinin antagonist diazepino[2,1-b]quinazolones. The authors worked out an original synthetic route for preparation of ring analogue [1,2,4]triazino[6,1-b]quinazolines from intermediates of the synthesis, too. Starting 2-alkyl-3-amino-quinazolones are easily prepared by reaction of 2-alkyl-benzoxazone with hydrazine hydrate. In the next step bromination reaction of the alpha-methylene group of 2-alkyl-substituents gave a mono-bromo derivative as major product. In the reaction of the bromo compound with N-nucleophyles 2-alkylamino-3-amino-quinazolones were obtained which reacted with alpha-halogeno-carbonyl compounds and led to the tricyclic quinazolones in ring closure reaction. The structural properties of the heterocyclic compounds were characterized by UV-VIS and NMR data and molecular modelling calculation.

Ipriflavone, an antiostheophorotic agent.

The antiostheophorotic agent ipriflavone [7-(1-methyl-ethoxy)-3-phenyl-4H-1-benzopyran-4-one, C18H16O3] is an important member of the isoflavone family. The structure of the molecule is dominated by the dihedral angle (50 degrees) between the planes of the phenyl and benzo-pyran moieties. A structural comparison with other related published structures is represented.

Investigations of indomethacin-induced gastric ulcer in rats.

The pathogenesis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced ulceration is still not completely understood, but it is possible that these effects are associated with a cytoprotective prostaglandin deficiency. Visible marks of gastric mucosa erosions induced by 25 mg/kg indomethacin in rats were determined parallel with the changes of PGE2, PGI2, TxA2 and leukotrienes content in gastric mucosa at various intervals. Beside the decreased level of the so-called cytoprotective prostaglandins caused by the inhibition of cyclooxygenase enzyme an overproduction of 5-lipoxygenase products (leukotrienes) was also found. To investigate the hypothesis that the gastric damage caused by NSAIDs is due not only to the decreased level of cyclooxygenase products but to the increased level of lipoxygenase products as well, different lipoxygenase inhibitors and leukotriene antagonists were tested. A lipoxygenase inhibitor and the structurally similar phenidone inhibited the ulcerogenic effect of indomethacin at the same high dose range. The selective lipoxygenase inhibitor nordihydroquaiaretic acid and dual inhibitors can reduce the severity of ulcer formation in lower concentrations as well. The first specific antagonist of SRS-A and a potent and selective antagonist of LTD4 produced a significant gastroprotective effect at i.p. treatment only at high doses. All of these results suggest that an overproduction of leukotrienes and other lipoxygenase products, following cyclooxygenase blockade induced by NSAIDs, may play a role in the development of gastric mucosal damage.

[Correlation between the structures and physicochemical properties of chemotherapeutic fluoroquinolone agents]. / Osszefüggés kemoterápiás fluorokinolonok szerkezete és fiziko-kémiai tulajdonságai között.

The acid-base properties, the lipophilicity and the HPLC behaviour of nine antibacterial fluoroquinolone derivatives were studied to reveal relationship between these physico-chemical parameters and the chemical structure. Basicity of compounds with two proton-binding sites is depicted here in terms of protonation macro- and microconstants. The concentrations of microspecies (cation, zwitterion, neutral and anion) were calculated in the function of pH. The microspeciation of fluoroquinolones were used to derive relationship between the apparent and true octanol/water partition coefficients. An analysis of structure-chromatographic behaviour has been performed utilizing the retention values was determined in a chromatographic system methanol-aqueous phosphate buffer/ODS. Close correlation was found between the lipophilicity and chromatographic behaviour of the tested compounds when pH dependence and the influence of an ionpairing agent were investigated.

[A drug ahead of its time: the success story of selegiline]. / Egy gyógyszer, amely megelözte korát: a selegilin siker története.

The racemic form of Selegiline was investigated in clinics a short time after its discovery in the sixties. However its fate seemed to be sealed by the so-called "cheese effect" associated with the applications of other MAO inhibitors. In the seventies the (-) enantiomer, called Selegiline was investigated again in European Clinics, and was finally introduced into therapy as an adjuvant of L-Dopa treatment for Parkinsonism. In the eighties its launch to the market of the USA was influenced by events known as the "MPTP Story" and the "Orphan Drug Act". Further clinical investigations of Selegiline are expected to clarify the real therapeutic value of Selegiline.

[Synthesis of selegiline, its potential impurities and metabolites]. / Selegilin, valamint lehetséges szennyezéseinek és metabolitjainak elöállítása.

Selegiline is prepared in a three-step synthesis starting from phenylacetone and methylamine. Its possible impurities may be the (+)-isomer and compounds formed in side reactions. The syntheses of selegiline's metabolites are also described.

[Thermoanalytic determination of the enantiomeric purity of selegiline]. / A selegilin enantiomertisztaságának vizsgálata termoanalitikai módszerekkel.

The thermal behaviour of Selegiline (a chiral, non racemic pharmaceutical used in the therapy of Parkinson disease) was studied by differential scanning calorimetry (DSC) for determining the enantiomeric purity (e.p.) of the bulk substance. It has been found, that (i) the binary phase diagram (melting point phase diagram) of the R/S enantiomer mixtures is characteristic to that of the true racemic compounds; (ii) the melting behaviour of the R/S binary mixtures follows the thermodynamic laws (i.e. the Schröder-Van Laar and the Prigogine-Defay equations); (iii) the e.p. of the highly purified bulk substance can be expressed as "DSC purity" (this latter is obtained from the Van't Hoff equation) and the microcalorimetric method as above gives good reproducibility; (iv) due to the minor impurities (other than the S(-) enantiomer) the obtained e.p. (expressed as DSC purity) can be higher but not lower than the actual e.p. of the investigated substance.

[Positron emission tomography of C-11-labelled selegiline]. / Vizsgálatok pozitron emissziós tomográfia és 11C jelzett selegilin alkalmazásával.

The combination of C-11-labelled Selegiline with PET gives the possibility of a non-invasive method for the determination of the distribution, activity and turnover of MAO-B enzyme and all the enzyme-related changes in the brain as well as for the early detection of Parkinson's disease.

Comparative studies of drotaverine--acephyllinate (Depogen) and pentoxifylline (Trental).

Pentoxifylline is an orally active agent for the treatment of peripherial and cerebral vascular diseases. Pentoxifylline increases the deformability of red blood cells in vitro, reduces blood viscosity and decreases platelet aggregation and thrombus formation. Depogen has shown antiaggregatory effect both in vitro and in ex vivo. The inhibitory effect of Pentoxifylline was about 3-5 times weaker than that of Depogen. IC50 = 900/micrograms/ml for Depogén and 3600/micrograms/ml for Pentoxifylline on human platelet rich plasma. Depogen has shown ex vivo antiaggregatory effect on anesthetised rabbits, ID50 = 7 mg/kg in case of iv. administration, and ID50 = 300 mg/kg in case of orally administration. Both compound inhibit the release of platelet precoagulation factor, but the effect of Pentoxifylline was slighter.

Synthesis and gastroprotective activity of 4H-pyrido[1,2-a]pyrimidin-4-ones.

The cytoprotective effect of different types of 4h-pyrido[1,2-a]pyrimidin-4-one derivatives was investigated. Short synthesis of the investigated compounds was depicted. The gastroprotective effect was determined against acidified ethanol induced mucosal lesions in rats. The most effective compounds belong to unsaturated 4-oxo-4h-pyrido[1,2-a]pyrimidine-3-carboxamide derivatives, and the most active one contains a methyl group in position 6 and a cyclopentyl group on the nitrogen of the carboxamide group. Further pharmacological, biochemical and clinical studies may justify, that the representative of this type of compounds may be useful as prophylactic agents against gastric damage caused by non-steroidal antiinflammatory agents.

The mechanism of cytoprotective effect of CHINOIN-127.

According earlier, investigations nitrogen bridgehead compounds make a representative group of non-prostaglandin type gastroprotective agents. One member of this group is CHINOIN-127 (1,6-dimethyl-4-oxo-1, 6, 7, 8, 9, 9a-hexahydro-4H-pyrido-(1, 2a)-pyrimidine-3-carbox-amide). CHINOIN-127 is a potent non-narcotic analgesic and antiinflammatory agent and has a remarkable protective effect on indomethacin induced ulcer (ED50 = 25 mg/kg p.o.) and on acidified ethanol induced ulcer (ED50 = 26 mg/kg p.o.). In this study we examined the mechanism of action of cytoprotective effect of this drug and we made a comparison between the cytoprotective effect of 20% ethanol and 25 mg/kg CHINOIN-127. In the gastric mucosa of control rats we observed a balance between TxA2 and PGI2 (PGI2/TxA2 = 3.8) and between the cytoprotective prostaglandins (PGI2 and PGE2) and ulcerogen eicosanoids (TxA2 and leukotrienes) (PGI2 + PGE2/TxA2 + LTs = 3.9). 100% ethanol treatment causes disintegration of this balance, shifting the synthesis towards the ulcerogen eicosanoids production. CHINOIN-127 and 20% ethanol pretreatment improves the deranged balance between cytoprotective prostaglandins and ulcerogen eicosanoids. Our results demonstrate that CHINOIN-127 and 20% ethanol have a similar mechanism of cytoprotective action on ethanol induced ulcer in rats.