Synthesis, 5-HT1A and 5-HT2A receptor affinity of new 1-phenylpiperazinylpropyl derivatives of purine-2,6- and pyrrolidine-2,5-diones.

Two series of 1-phenylpiperazinylpropyl derivatives 10, 11, 16, 17 and 19-24, structurally related to previously described 5-HT1A or 5-HT2A ligands 4 and 1, respectively, were synthesized and their binding properties were determined. Structural modifications which involved 1,3-diazepine ring opening in 4 (compounds 10, 11, 15, 16) and replacement of spiroalkyl moiety in 1 by aryl substituent (19-24) did not improve binding affinity and selectivity of the tested compounds. The results showed, however, that the diazepine ring present in 4 or spiroalkyl ring in 1 are important for high 5-HT1A or 5-HT2A binding affinity and selectivity of these compounds.

Synthesis, physicochemical and anticonvulsant properties of new N-pyridyl derivatives of 3-phenyl- and 3,3-diphenyl-succinimides.

Synthesis and physicochemical properties of new N-pyridyl derivatives of 3-phenyl and 3,3-diphenylsuccinimides (1-12) have been described. The obtained compounds were evaluated in respect of their anticonvulsant activity. The N-pyridyl derivatives of 3-phenylsuccinimides (7-12) abolished the protection against MES- and scMET-induced seizures, whereas N-pyridyl derivatives of 3,3-diphenylsuccinimides (1-6) were inactive. After molecular modelling and quantum-chemistry calculations the theoretical activity test was applied (W. Kwiatkowski, J. Karolak-Wojciechowska, SAR and QSAR Envir. Res. 1 (1993) 233; Chem. Abstr. 120, 153001 (1994). J. Karolak-Wojciechowska, M. Blaszczyk, W. Kwiatkowski, J. Obniska, A. Zejc, J. Chem. Cryst. 27 (1997) 297; Chem. Abstr. 127, 277834k (1997)). The molecular electrostatic potential (MEP) of the active compounds differed significantly from that of the inactive ones.

Synthesis and anticonvulsant properties of new N-piperazinylalkyl imides of succinic acid.

A number of N-[(4-aryl)- or (4-methyl)-l-piperazinyl)alkyl]imides of 3-aryl or 3,3-pentamethylenesuccinic acid were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and pentylenetetrazole seizure threshold (scMet) tests. Structures of the novel compounds were confirmed by elemental and spectral analyses.

3-(omega-Aminoalkyl)-5,5-dialkyl(or spirocycloalkyl-1',5-)hydantoins as new 5-HT1A and 5-HT2A receptor ligands.

A series of new 3-(omega-aminoalkyl)-5,5-disubstituted hydantoins, containing 1-phenylpiperazine, 1-(o-methoxyphenyl)piperazine or 1,2,3,4-tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5-HT1A and 5-HT2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5-HT1A and 5-HT2A receptors due to the presence of a 1-arylpiperazine fragment however, the terminal hydantoin moiety plays an important role in stabilization of the receptor-ligand complex. It has also been found that the two 1-phenylpiperazine derivatives 32 and 36 are new selective 5-HT2A receptor ligands (Ki = 34 and 37 nM, respectively), whereas the derivative of 1-(o-methoxyphenyl)piperazine (38) is a new, highly potent 5-HT1A receptor ligand (Ki = 0.51 nM) with a moderate affinity for 5-HT2A receptors (Ki = 213 nM).

Search for new anticonvulsant compounds. Part 1: Synthesis, physicochemical and anticonvulsant properties of new derivatives of alpha-amino-gamma-phthalimidobutyric acid.

Synthesis and physicochemical properties of new derivatives of alpha-substituted gamma-phthalimidobutyric acid are described. N-substituted amides of alpha-(4-phenylpiperazine)-gamma- phthalimidobutyric acid were prepared by condensation of the acid with the corresponding derivatives of benzylamine in the presence of BOP reagent. 2-(4-Phenylpiperazine)- or 2-(4-benzylpiperidine)-4-phthalimidobutyric acid were esterified with alkyl bromide in the presence of DBU or tetrabutylammonium bromide as catalyst. The obtained compounds were evaluated for anticonvulsant activity. 2-(4-Phenylpiperazine)-4-phthalimidobutyric acid and three N-substituted amides of this acid displaced protection against MES and scMet-induced seizures.

Synthesis and antiarrhythmic properties of basic amide derivatives of imidazolidine-2,4-dione and pyrrolidine-2,5-dione II.

Basic amide derivatives of imidazolidine-2,4-dione and pyrrolidine-2,5-dione were synthesized as potential antiarrhythmic agents. Some of them have shown antiarrhythmic activity in the chloroform, barium chloride or adrenaline induced arrhythmia.

[Synthesis of 1-N-aryloacetamidobutanol derivatives with anti-seizure effect]. / Synteza 1-N-aryloacetamido-2-butanoli o przewidywanym dzialaniu przeciwdrgawkowym.

New derivatives of 1-N-aryloacetamidobutanols were obtained in the reaction of arylalkylcarboxylic acid chlorides with R, S, R(-), S(+) 1-amino-2-butanols. Structures of the obtained compounds have been confirmed by elemental analysis and IR-spectrometry. Results of pharmacological studies will be published elsewhere.

[1-amino-2-butanols derivates with antiarrhythmic effect]. / Pochodne 1-amino-2-butanolu o przewidywanym dzialaniu antyarytmicznym.

R(-), R, S, S(+)-1-N-theophylline-7-acetyl or ethyl/-amino-2-butanols were obtained in the reaction of 7-methoxycarbonylmethyltheophylline or 7-beta-chloroethyltheophylline with R(-), R, S, S(+) 1-amino-2-butanols. Compounds I and II tested for antiarrhythmic and hypotensive activity were inactive.

Synthesis and pharmacological investigation of new N-dimethylpyridyl and N-chloropyridyl substituted arylsuccinimides.

In the reaction of alpha-phenyl-, alpha-p-chlorophenyl-, alpha-m-chlorophenyl-, alpha-p-bromophenyl and alpha-m-bromophenyl succinic acids with various aminopyridines, N-(dimethylpyridine)-alpha- arylsuccinimides and N-(chloropyridine)-alpha-arylsuccinimides were obtained. The above compounds tested for their CNS activity did not show an anticonvulsant activity.

Synthesis and anticonvulsant properties of some arylsuccinate methylpyridylimides.

In reaction of alpha-phenyl, alpha-p-chlorophenyl and alpha-m-chlorophenylsuccinic acid with various aminopyridines, N-pyridyl-substituted succinimides (compounds 1-14) were obtained. These compounds were investigated for their CNS activity. Compounds 1, 2, 5, 6 and 7 displayed anticonvulsant properties in the maximum electroshock test. Compounds 5 and 6 were also active in the pentetrazole test.

Structures of three N-pyridyl-2-phenylsuccinimides and structural evidence for substituent effects on anticonvulsant properties.

T = 295 K, Mo K alpha with lambda = 0.70930 A. Compound (I-6): C15H12N2O2, Mr = 252.26, monoclinic, P2(1)/c, a = 8.441 (3), b = 15.269 (1), c = 9.745 (2) A, beta = 92.34 (2) degrees, V = 1254.9 (19) A3, Z = 4, Dx = 1.335 g cm-3, mu = 0.85 cm-1, F(000) = 528, R = 0.0345 for 1682 observed reflections. Compound (I-10): C16H14N2O2, Mr = 266.30, monoclinic, P2(1)/n, a = 11.637 (1), b = 5.793 (1), c = 20.778 (2) A, beta = 105.26 (1) degrees, V = 1351.3 (25) A3, Z = 4, Dx = 1.309 g cm-3, mu = 0.82 cm-1, F(000) = 560, R = 0.0379 for 1840 observed reflections. Compound (I-11): C16H13C1N2O2, Mr = 300.74, triclinic, P1, a = 9.076 (3), b = 9.366 (1), c = 10.477 (3) A, alpha = 118.27 (2), beta = 93.85 (2), gamma = 105.26 (1) degree, V = 737.2 (15) A3, Z = 2, Dx = 1.350 g cm-3, mu = 2.61 cm-1, F(000) = 312, R = 0.0528 for 2018 observed reflections. The three N-pyridyl-2-phenylsuccinimides [N-(3-methyl-2-pyridyl)-2-p-chlorophenylsuccinimide (I-11); N-(3-methyl-2-pyridyl)-2-phenylsuccinimide (I-10) and N-(3-pyridyl)-2-phenylsuccinimide (I-6)], examined by means of X-ray structure analysis, have been previously subjected to extensive pharmacological screening, with regard to their anticonvulsive activity. Pharmacological properties of the compounds examined are clearly connected with the conformation of the molecules. The conformation of the molecules of biologically active derivatives (I-10) and (I-11) differs from the conformation of the inactive molecule of (I-6). This difference involves relative positioning of the pyridyl ring and the succinimide moiety. The Cl atom in (I-11) has only a minor effect on the conformation and geometry of the molecule in comparison with (I-10).

Synthesis and pharmacological properties of new derivatives of 1-diphenylacetamide-2-butanol.

Newly synthesized derivatives of 1-diphenylacetamide-2-butanol were investigated pharmacologically for their central properties in mice and rats. The most active were 2 compounds: racemic (RS) and enantiomer S (+) form of N-diphenylacetamide-2-butanol which produced hypothermia in normothermic mice, showed anxiolytic action in the four-plate test and reversed reserpine-induced hypothermia.

Synthesis and pharmacological properties of diphenylimidazolidine acetic and propionic acids derivatives.

Several derivatives of diphenylimidazolidine-2,4-dione and diphenylimidazolidin-4-one acetic and propionic acids have been synthesized. Some of them were screened for their effect on the CNS in mice and rats. All the investigated compounds showed an analgesic activity. The most active one was 1-benzyl-5,5-diphenyl-3-imidazolidine-2,4-dione acetic acid. That compound exerted an inhibitory activity against the CNS, anxiety-relieving, anticonvulsant and antidepressive effects.

Pharmacological studies on the central action of novel benzylidene-imidazothiazolone derivatives.

Pharmacological studies on the central action of novel benzylidene-imidazothiazolone derivatives were carried out on mice and rats. The highest activity showed two compounds: a chloro- and a methoxy- derivative. They produced analgesic, anticonvulsant, anti-anxiety and "antidepressant" effects in mice.

Synthesis and pharmacological properties of phenoxyethylpiperazine derivatives.

Salts of new 1-phenoxyethylpiperazines 1-5, their 4-amidine derivatives 6-10 and 4-phenoxyacetyl derivatives 11-15 have been obtained. Some of them were screened for their cardiovascular activity.

Synthesis of amide derivatives of 5,5-diphenylhydantoin as potential antiarrhythmic agents. I.

5,5-Diphenylhydantoin derivatives containing amide groups at the position 3 were synthesized as potential antiarrhythmic agents. The most valuable was (X) whose antiarrhythmic activity is stronger than that of phenytoin.

Synthesis and anticonvulsant properties of N-methylpyridyl derivatives of m- and p-bromophenylsuccinimides.

The reaction of m- or p-bromophenylsuccinic acids with 2-aminomethylpyridines yielded respective N-methylpyridylimides 1-8. Only compounds 1 and 6 show anticonvulsant activity in the pentetrazole and electric seizures tests, but their therapeutic index is inferior to that of ethosuximide and valproic acid.

3-Alkyl(aryl)-piperazinoalkyl derivatives of 5,5-diphenylhydantoin.

The new obtained N3-alkyl- or arylpiperazinoalkyl substituted derivatives of 5,5-diphenylhydantoin weakly affect the spontaneous motility and the hypermotility induced by amphetamine. They did not show the anticonvulsive activity. Compounds containing the methyl (or phenyl)-piperazine moiety connected by the three-carbon chain with the N3 atom of the hydantoin ring show the strongest activity in the potentiation of the central effect of DOPA.