T. A. Sapozhnikova

Synthesis and Antiarrhythmic Activity of N-(2-Hydroxyethyl)cytisine Hydrochloride and 3-(2-Hydroxyethyl)-1,5-dinitro-3-azabicyclo-[3.3.1]non-6-ene Hydrochloride

Synthetic analogs of natural 3-azabicyclo[3.3.1]nonanes have drawn the attention of researchers as potential drugs [1 – 3]. This study was aimed at the synthesis of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene (II) and N-(2-hydroxyethyl)cytosine (IV) and evaluation of the antiarrhythmic activity of these compounds in the form of hydrochlorides. The synthesis of compound II was based on the reduction of 1,3-dinitrobenzene with sodium borohydride to 1,3-dinitrocyclohexene disodium salt (I). This intermediate compound was introduced (without isolation from the reaction mixture) into the Mannich condensation reaction with formaldehyde and monoethanolamine, which led to the formation of target compound II (isolated with a 70% yield) [4].

Antiinflammatory and Antiulcer Properties of Betulin bis-Hemiphthalate

Triterpenoids of the lupane group (betulin and derivatives) were reported to possess hepatoprotector, bile-expelling, antimicrobial, antifungal, and antitumor properties [1 – 3]. Recently, betulonic acid derivatives were identified as a new class of potential selective HIV inhibitors [4]. An analysis of the published data shows that the best prospects in the search for highly active agents among lupane derivatives are related to compounds with ester and amide bonds. For this reason, we have synthesized a series of esters, including bis-cinnamate, bis-hemisuccinate, and bis-hemiphthalate of betulin and studied their hepatoprotector activity [5]. Recently, we also studied the pharmacological properties of betulin 3,28-di-O-nicotinate [6]. The aim of this study was to characterize betulin bis-hemiphthalate (I) with respect to antiinflammatory and antiulcer properties.

New (−)−Cytisine Derivatives with Nootropic Activity

The mnestic and antihypoxic effects of new derivatives of the quinolizidine alkaloid (−)-cytisine on acquisition of a conditioned passive avoidance reflex (CPAR) were studied in rats; effects on normobaric (jar) hypoxia were studied in mice. Screening studies showed that the benzamide and the N-(12-methylcytidin-3-yl)-N′-phenylurea not only improved learning and memory, but also increased the resistance of the brain to hypoxia.

Nootropic Activity of a Novel (-)-Cytisine Derivative (3aR,4S,8S,12R, 12aS,12bR)-10-Methyl-2-Phenyloctahydro-1H-4,12a-Etheno-8,12-Methanopyrrolo[3’,4’:3,4]Pyrido[1,2-a] [1,5]Diazocine-1,3,5(4H)-Trione

We performed screening of nootropic properties of 10 new derivatives of quinolizidine alkaloid (-)-cytisine. Compounds with β-endo stereochemistry were more active than α-endo-isomers. Under stress conditions (3aR,4S,8S,12R,12aS,12bR)-10-methyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3’,4’:3,4]pyrido[1,2-a] [1,5]diazocine-1,3,5(4H)-trione enhanced memory and had a positive effect on cognitive functions of rats. According to molecular docking data, the nootropic activity of the compound can be associated with its affinity for the glutamate-binding subunits GluK1 and GluR2 of the kainate and AMPA receptor, respectively.

Synthesis and Local Anesthetic Activity of ortho-(Cyclopentenyl)- and ortho-(Cyclopentyl)-aniline Derivatives

Recently [1, 2], we reported on the synthesis of compounds possessing local anesthetic and analgesic properties in the series of -aminoacetyl derivatives of 2-pentenyland 2-cyclopentenylanilines. In continuation of the research in this direction, we have synthesized and characterized a series of -aminoacetanilide hydrochlorides obtained from ortho-(cyclopent-1and -2-enyl)anilines and cyclopentylanilines and N-piperidinylacetocyclopent[b]indoline hydrochloride. In the first step, we obtained 2-methyl(I), 2,4-dimethyl-6-(cyclopenten-2 -yl)(II), and 2,2-di(cyclopenten-2 l)anilines (III) using the well-known method The subsequent reduction of double bonds in the alkenyl fragment of arylamines I – III readily proceeds on skeletal nickel catalyst Nisk) in ethyl alcohol with a quantitative yield of ortho-(cyclopentyl)anilines IV – VI. The only disadvantage of this method is the impossibility of regenerating used nickel catalyst subject to rapid poisoning. Heating compound I with KOH at 300°C leads to a vinyl shift of the double bond toward the aromatic nucleus (as described in [5]), which results in the formation of 2-methyl-6-(cyclopent-1 enyl)aniline (VII) with an almost quantitative yield. Indoline VIII was synthesized from aniline and 3-chlorocyclopentene as described in [6] By chloroacetylating arylamines I – VIII, we obtained 2-methyl-6(IX), 2,4-dimethyl(cyclopenten-2 -yl)(X), 2-methyl-6-(cyclopenten-1 -yl)(XI), 2-methyl-6(XII), 2,4-dimethyl-6-(cyclopentyl)(XIII), and 2,6-di(cyclopentyl)(XIV) -N-chloroacetanilides, as well as N-chloroacetyl-1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (XV). The condensation of chloroacetanilides IX – XIV and indoline XV with piperidine in toluene leads to the formation of N-[2 -methyl-6 (XVI), N-[2 -dimethyl-6 -(cyclopen ten-2 -yl)](XVII), N-[2 -methyl-6 -(cyclopent-1 -enyl)phenyl](XVIII), N-[2 -methyl-6 (XIX), N-[2 -dimethyl-6 -(cyclopentyl)-phenyl](XX), N-[2 ,6 -di(cyclopentyl)phenyl](XXI) -amino-2-oxoethylpiperidines and N-(1,2,3,3a,4,8b-hexahydrocyclopent[b]indolyl)-2-oxoethylpiperidine (XXII). Bubbling gaseous HCl through hexane solutions of amines XIV – XXII leads to precipitation of hydrochlorides XXIII – XXIX, the aqueous solutions of which were tested for local anesthetic activity.

Hepatoprotective and Choleretic Properties of Levopimaric Acid Derivatives

The hepatoprotective and choleretic activities of three levopimaric acid derivatives were studied experimentally using a CCl4-induced acute hepatitis model in rats. It was established that all investigated levopimaric acid derivatives tended to increase bile secretion whereas (5R,9R,13S,18S)-20-isopropyl-5,9-dimethyl-17-{[(4-methylphenyl)sulfonyl]imino}-14-oxopentacyclo[10.6.2.01, 10.04, 9.013, 18]eicosa-15,19-diene-5-carboxylic acid (I) and dimethyl (4bS,8R)-2-isopropyl-3′-4b,8-trimethyl-2′,4′-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10a-ethanophenanthrene-11,5′-[1,3]thiazolidine]-8,12-dicarboxylate (II) reduced transaminase enzyme levels in blood serum.

Composition and Pharmacological Activity of Neutral Lipids from Rhizomes with Roots of the Introduced Plants Helleborus abchasicus and H. caucasicus

The compositions of neutral lipids (NL) and fatty acids (FA) from subterranean parts of the introduced plants Helleborus abchasicus and H. caucasicus (Ranunculaceae) were established and compared with those of the wild species. The FA from diacyl- and triacylglycerides and free FA from these introduced species had elevated contents of unsaturated acids because of 18:2. The lipid-soluble NL constituents included 10 identified sterols, the major ones of which were cholesterol, sitosterol, and lanosterol. NL from H. abchasicus (introduced and wild) and H. caucasicus (wild) exhibited pronounced anti-inflammatory activity at the level of Voltaren and moderate wound-healing activity.

Choleretic activity of 2-demethoxycarbonyl-2-ethoxycarbonyl-11-deoxymisoprostol on the model of CCl4-induced hepatitis.

Therapeutic administration of 11-deoxymisoprostol had a hepatoprotective effect, which manifested in a decrease in the content of alanine transaminase and aspartate transaminase in blood plasma, and produced a choleretic effect in rats with CCl4-induced toxic hepatitis.

Gastroprotective properties of 11-deoxymisoprostol (prostaglandin E1 analog) and its effect on the level of sialic acids in gastric tissue of rats with peptic ulcer.

Abstract11-Deoxymisoprostol (prostaglandin E1 analog) exhibited a pronounced gastroprotective effect on various models of experimental ulcers induced by nonsteroid antiinflammatory drugs. A relationship between high resistance of the gastroduodenal mucosa under the effect of 11-deoxymisoprostol and changes in the level of sialic acid was detected.

Prostanoids. Part LXXIV. Antiulcerous activity of misoprostol and its 11-deoxy analog. Misoprostol synthesis

Ermisoprostol (I), a racemic analog of the natural prostaglandin is successfully used in medical practice for preventing stomach ulceration during the administration of nonsteroidal antiintlammatory drugs [1, 2]. In the previous communication [3], we showed good prospects for the search of new antiulcerous agents in the series of readily accessible 11deoxy-modified analogs of compound I and reported on the synthesis of compound II representing this series.