Synthesis and action on the central nervous system of 8-substituted 6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]-diazepine derivatives.

Selected 8-substituted 6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a] diazepine derivatives were synthesised and tested for their action on the central nervous system. The obtained results showed that the examined compounds type IV have sedative activity. The strongest effect was exerted by compound IV-f.

Histamine H1 receptor ligands: part II. Synthesis and in vitro pharmacology of 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives.

New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and tested in vitro as H1 receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the phenyl ring, showed weak H1-antagonistic activity (pA2: 4.62-5.04) and this activity was completely lost in the case of meta-methyl substituent (pA2 < 4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the resulting compounds exhibited slightly improved H1-antagonistic activity (at the meta-position pA2: 6.38-6.15; at the para-position pA2: 6.04-5.87).

Non-imidazole histamine H3 ligands, Part 2: New 2-substituted benzothiazoles as histamine H3 antagonists.

New, non-imidazole histamine H3 receptor antagonists were prepared and in vitro tested as H3 receptor antagonists measured as the electrically evoked contraction of the guinea-pig jejunum. The 2-(1-piperidinyl)- and 2-(1-pyrrolidinyl)benzothiazoles show no or very poor activity; 2-[1-(4-amino)piperidinyl]- and 2-(1,2-ethanediamino)- and 2-(1,3-propanediamino)derivatives of benzothiazole possess weak activity at H3 receptors, whereas 2-(4-piperidinyl)benzothiazoles and 2-[1-(4-piperazinyl)]benzothiazoles show moderate to good activity. Lipophilic and not-too-bulky substituents like n-propyl attached to the nitrogen at the piperazine or piperidine ring lead to potent H3 receptor antagonists with pA2 values ranging from 7.0 to 7.2. The structure-activity relationships for different substitution patterns are discussed.

Non-imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives as H3-antagonists with H1 blocking activities.

New 2-(1-Piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazoles were prepared and tested as H1- and H3-receptor antagonists. A number of compounds showed weak H1-antagonistic activity, with pA2 values ranging from 5.5 to 6.1. The simple alkyl substituted, 2-[1-(4-methyl and 4-ethyl)piperazinyl] analogues show increasing, moderate H3-antagonistic activity (pA2 = 6.0, and pA2 = 7.0). The compounds with 4-phenylalkyl substitution, for both the piperazinyl and the hexahydro-1H-1,4-diazepin-1-yl homologues series, regardless of the different physicochemical properties of the para substituents at the phenyl ring, showed weak H3-antagonistic activity with pA2 values ranging from 4.4 to 5.6.

Diazepinoquinazolines. Part II. Synthesis and pharmacological activity of some derivatives of 1,4-diazepino[2,1-b]quinazoline.

New derivatives of 1,4-diazepino[2,1-b]quinazoline were obtained. The diazepino quinazoline [IV] was obtained by the condensation of 2,5,6,7-tetrahydro-3-(methylthio)-1-phenyl-1H-1,4-diazepine with 5-chloroantranilic acid. Compounds was preparated in two steps from 2,3,4,5-tetrahydro-1,4-diazepino[2,1-b]quinazolin-7(1H)-one. The derivatives [II-IV], [VII], [VIII] were screened for their psychotropic activity.

Synthesis and action on the central nervous system of mescaline analogues containing piperazine or homopiperazine rings.

Structural juxtaposition of the 3,4,5-trimethoxyphenyl group in the same molecule with a piperazine or homopiperazine ring has been realized in a series of mescaline analogues (I-IV) as part of an investigation into the pharmacological properties of the seven-membered perhydro-1,4-diazepines (homopiperazines). The analogous six-membered piperazines were synthesized and tested as reference substances to determine whether the seven-membered ring conveyed special properties. A variety of pharmacological tests of action on the CNS showed that replacement of the amino group in mescaline by the heterocycles significantly alters the biological activity. In particular, both the piperazine and the homopiperazine derivatives displayed sedative activity to about the same extent.