3-Acyloxy-5-aryl-7-bromo-1,2-dihydro-3 H -1,4-benzodiazepin-2-ones ( 3 – 18 ) were synthesized and shown to possess (ED 50 = 0.05 – 5 mg/kg) hypnotic, sedative, anticonvulsant, and anxiolytic properties. The hypnotic activity of the tested compounds varied in the dose range 0.22 – 1.50 mg/kg i.p. in mice. The pharmacological properties of 3 – 14 were comparable to those of cinazepam (Levana ® IC) and its metabolite 3-hydroxyphenazepam. The CBDR affinity was shown to increase with acyl length in the series C2-C5 whereas it decreased significantly in the series C6-C8. The tested compounds were characterized by low toxicity with LD 50 > 650 mg/kg i.p. in mice.

Синтезированы производные 3-ацилокси-5-арил-7-бром-1,2-дигидро-3H-1,4-бенздиазепин-2-она (3 – 18). Показано, что изученные соединения (ЕД50 0,05 – 5 мг/кг) обладают снотворной, седативной, противосудорожной и анксиолитической активностью. Снотворная активность изученных соединений изменяется в интервале доз 0,22 – 1,50 мг/кг при внутрибрюшинном введении мышам. Соединения 3 – 14 по фармакологическим свойствам не уступают циназепаму (препарату Левана® ІС) и его метаболиту 3-гидроксифеназепаму. Показано, что в ряду 3-ацилпроизводных с длиной ацильного заместителя С2 – С5 наблюдается увеличение аффинитета к ЦБДР, а с длиной С6 – С8 — его значительное снижение. Исследуемые соединения являются малотоксичными, их LD50 > 650 мг/кг при внутрибрюшинном введении мышам.

A series of p-tert-butylcalix[4]arene derivatives containing 1,4(1,5)-benzodiazepinone fragments as substituents were prepared. The biological activity of the compounds, namely, their antispasmodic activity in mice, was evaluated by antagonism with a spasmodic agent, Corazol, upon transdermal administration. According to the data obtained, benzodiazepine derivatives of calixarenes show higher antispasmodic activity compared to 3-hydroxyphenazepam, taking into account their considerably higher molecular weight.

In order to establish the molecular targets of 1,4-benzodiazepin-2-ones mediating the influence on appetite, the ability of 18 representatives of this class of compounds to bind to the central and peripheral benzodiazepine, dopamine (D 1 , D 2 ), serotonin (5-HT 1A ) and cholecystokinin (CCK 2 )receptors in rat brain was studied. The anorexic activity of some compounds is related to their ability to CCK 2 receptor binding, while the orexigenic activity of 7-bromo-5-( о -chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one (phenazepam) is due to a high affinity to central benzodiazepine receptors.

In order to establish the molecular targets of 1,4-benzodiazepin-2-ones mediating their influence on the appetite, the ability of 18 representatives of this class of compounds to bind to the central and peripheral benzodiazepine, dopamine (D 1 , D 2 ), serotonin (5HT 1A ) and cholecystokinin (CCK 2 ) receptors in the rat brain has been studied. The anorexigenic activity of some compounds is related to their ability to bind to CCK 2 receptor, while the orexigenic activity of 7-bromo-5-( o -chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one (phenazepam) is due to its high affinity to central benzodiazepine receptors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

There were discovered the anti-aggregative properties of some psychotropic drugs as gidazepam, phenazepam and its derivatives 3-oxyphenazepam, esters of 3-oxyphenazepam, with IC50 values of 8.19-11 x 10(-4) M. On their anti-aggregative effects they exceed of the acetylsalicylic acid (IC50 = 21.3 x 10(-4) M). Only gidazepam, containing in its chemical structure hydrazide fragment, caused significant decrease in the content of MDA. The possibility of involvement of lipid peroxidation in mechanism of its anti-aggregative effect is discussed.

Literature data on inclusion compounds of psychotropic agents (hypno-sedative, anticonvulsive and antiepileptic drugs, neuroleptics and anxiolytics) with cyclodextrins and their derivatives are presented. Inclusion compounds of two novel psychotropic agents, gidazepam and cinazepam, withβ-cyclodextrin (1 : 1 and 1 : 2) were obtained. The structure of these complexes has been established by one- and two-dimensional1H-NMR (for solutions in DMSO) and IR (for solid state) spectroscopy.

Understanding the mechanisms of mutual recognition and complementary binding of molecules in guest-host complexes is based on analysis of their spatial structure. As guest-host complexes, we have synthesized inclusion compounds of 1,4-benzodiazepine anxiolytic agents gidazepam and cinazepam with β-cyclodextrin, in which these anxiolytic agents manifest increased biological accessibility. The spatial structure of the complexes was determined from the two-dimensional NOESY spectra and analysis of the fragmentary mobility of the guest and host molecules, characterized by spin-lattice relaxation times T1 of the13C nuclei. An analysis of d-contacts showed that the 5-phenyl ring is completely enclosed in the inner hydrophobic cavity of β-CD [(C2′ H-C4′ H)-CIIH(CIVH), CVH (CIIIH, CVIH2), CVIOH]. For the 1:1 complex, intense d-contracts of C8H with CVIOH indicate that C8H is located in the vicinity of both wide and narrow bases of the bracelet. This is only possible for the 2:2 complex, in which both β-CD molecules approach each other by their wide and narrow bases. A comparison between the schemes of d-contacts for the 2:2 and 2:1 associates proves that the β-CD molecules have the same spatial orientation in the dimer. The difference is in the fact that the hydrazinocarbonyl fragment of gidazepam and the hemisuccinate fragment of cinazepam penetrate into an empty molecule of the 2:1 β-CD complex (NH2-CIH contact). The intensities of the cross peaks were measured, due to which the interatomic distances between the guest and host molecules were calculated and the spatial structure of the clathrates was established. The benzodiazepine derivatives are embedded differently into the clathrate molecule, as shown by the value of the angle between the symmetry axis of β-CD and the axis through the centers of the aromatic rings: 0° for gidazepam and 60° for cinazepam. This is a consequence of the fact that the substituents forming hydrogen bonds with hydroxyl groups at the wide base of the β-CD bracelet lie in different positions: the hydrazinocarbonylmethyl fragment of gidazepam lies at N1, and the hemisuccinate fragment of cinazepam is at C3.

A metabolite of the anxiolytic, anticonvulsant, and soporific drug phenazepam, 3-oxyphenazepam (3-OPh), possesses strong anxiolytic action. In the present work, 3-OPh and its acetic, benzoic, nicotinic, hemisuccinic, hemiglutaric, and valproic esters were synthesized, and their interaction with benzodiazepine receptors of the rat central nervous system was investigated. The structure of the compounds is found to correlate with their affinity to benzodiazepine receptors (inhibition constants characterizing specific binding of3H-diazepam with the P fraction of synaptic membranes in the rat brain), as well as with their anxiolytic activities. The affinities of dicarbonic acid monoesters (hemisuccinate and, especially, hemiglutarate) and valproate were found to be lower than those of monocarbonic acid esters and 3-OPh itself. High pharmacological activity of 3-OPh hemisuccinate is hypothesized to be determined by its role as a 3-OPh precursor (the latter is a product of hemisuccinate hydrolysis).