The investigation purpose. N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine (ALM-802 compounds) cardioprotective effect has been studied in rat models of subendocardial ischemia caused by isoproterenol and dobutamine. Material and methods. Acute subendocardial myocardial ischemia in anesthetized rats (urethane 1300 mg/kg, i.p.) was caused by infusion of isoproterenol (20 µg/kg/min i.v.) or dobutamine (80 µg/kg/min i.v.). Results. It was shown that in anesthetized rats, isoproterenol and dobutamine caused almost the same ST-segment depression in the II standard ECG lead. The compound ALM-802 (2 mg/kg i.v.), administered 2 minutes before the infusion start of isoproterenol or dobutamine, equally prevented the occurrence of ischemic changes on the ECG. Conclusion. The non-selective beta-adrenomimetic isoproterenol and the selective β1-adrenomimetic dobutamine cause subendocardial ischemia of the same intensity in anesthetized rats. The compound ALM-802 has a pronounced anti-ischemic effect on both models.

The anxiolytic and analgesic properties of compound ALM-802, a cardiotropic linear methoxyphenyltriazaalkane derivative, combining pharmacophore elements of p-FOX inhibitors trimetazidine and ranolazine were studied in vivo. In the elevated plus-maze test, ALM-802 after acute intraperitoneal administration in doses of 1-8 mg/kg dose-dependently prevented the development of anxiety in BALB/c mice. Chronic intraperitoneal administration of ALM-802 in a dose of 2 mg/kg to alcohol-preferring rats attenuated anxiogenesis induced by ethanol withdrawal. ALM-802 demonstrated antinociceptive activity in C57BL/6 mice during thermal stimulation of nociceptors in the hot plate test and during modeling of visceral pain in the acetic acid writhing test. Thus, ALM-802 exhibits anxiolytic and analgesic properties in the dose range corresponding to its anti-ischemic and antiarrhythmic effects.

A new series of bis-(2,3,4-trimethoxybenzyl)alkanediamines were obtained. Their anti-ischemic and antiarrhythmic activities were studied. Replacement of the central N atom of the triazaalkane linker in the previously studied compound ALM-802 by a carbon atom and shortening of the linker length led to preservation of the cardiotropic activity spectrum of the corresponding compounds. The most active compounds among the new series were ALM-844 [N1,N5-bis(2,3,4-trimethoxybenzyl)pentane-1,5-diamine dihydrochloride] and ALM-851 [N1,N3-bis(2,3,4-trimethoxybenzyl)propane-1,4-diamine dihydrochloride].

The cardioprotective activity of ALM-802 compound was demonstrated in model experiments simulating postinfarction chronic heart failure in rats forming in 90 days after anterior transmural myocardial infarction. ALM-802 decreased the left ventricle and improved its inotropic function (p=0.038). This effect was observed in case of systematic administration of ALM-802 over 28 days (starting from day 91 after infarction modeling). This is apparently the minimum time for the cardioprotective effect of ALM-802 to prevent or treat the resulting heart failure, because short-term systematic therapy (15 days) produced no positive effect.

Previously, ALM-802 (N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine trihydrochloride) and ALM-803 (N1-(3,4,5-trimethoxybenzyl)-N2-{2-[(3,4,5-trimethoxybenzyl) amino]ethyl}-1,2-ethanediamine trihydrochloride), which combined pharmacophores of the free fatty-acid oxidation inhibitors trimetazidine and ranolazine and the slow Ca2+-channel blocker verapamil, were synthesized by us. These compounds possessed anti-ischemic and antiarrhythmic activities. Herein, the new compound ALM-843 (N1-(3,4-dimethoxybenzyl)-N2-{2-[(3,4-dimethoxybenzyl)amino]ethyl}-1,2-ethanediamine trihydrochloride), which exhibited only antiarrhythmic activity, was prepared. The results led to the hypothesis that the antiarrhythmic activity of the linear alkoxyphenyltriazaalkanes was due to the presence of a 3,4-dimethoxyphenyl pharmacophore, which is also present in verapamil. This hypothesis was confirmed using molecular docking to show that the above alkoxyphenyltriazaalkanes bound similarly to the verapamil binding site of the voltage-gated Ca2+-channel.

New ortho-alkoxy analogs of the compound ALM-802 1a (N1-(2-methoxybenzyl)-N2-[2-((2-methoxybenzyl)amino)ethyl]ethane-1,2-diamine trihydrochloride) and 1b (N1-(2-ethoxybenzyl)-N2-[2-((2-ethoxybenzyl)amino)ethyl]ethane-1,2-diamine trihydrochloride), which differ from it by the presence of alkoxy groups in the phenyl rings only in the ortho positions. It was established that these structural changes lead to the disappearance of anti-ischemic activity. At the same time, antiarrhythmic activity was revealed in compound 1b on the models of aconitine and calcium chloride arrhythmias in rats (1 mg / kg, intravenously), which was absent in 1a.

Anti-ischemic activity of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino] ethyl}-1,2-ethanediamine (ALM-802) based on the structure of standard p-FOX inhibitors trimetazidine and ranolazine was studied on the model of endocardial ischemia in intact rats and animals with endothelial dysfunction. Acute endocardial myocardial ischemia was caused by infusion of isoproterenol (20 μg/kg/min intravenously). Endothelial dysfunction in rats was modeled by inducing hyperhomocysteinemia (3 g/kg methionine intragastrically one a day over 7 days). The reference drugs trimetazidine (30 mg/kg, intravenously) and ranolazine 10 mg/kg, intravenously) that were effective only in intact rats. In contrast, ALM-802 (2 mg/kg, intravenously) showed a pronounced anti-ischemic effect in animals with endothelial dysfunction, which suggests that the mechanisms of its cardioprotective action differ from those known for p-FOX inhibitors.

A group of new 1-(methoxybenzyl)-4-{2-[(methoxybenzyl)amino]ethyl}piperazines (1) were synthesized. The relationship of the structure of the triazaalkane linker and the cardiotropic activity in a series of these compounds was compared with that of previously studied linear and cyclic methoxyphenyltriazaalkanes. The most active compound in the group was 1e (1-(3,4,5-trimethoxybenzyl)-4-{2-[(3,4,5-trimethoxybenzyl)amino] ethyl}piperazine trihydrochloride) with statistically significant antiarrhythmic activity in aconitine and CaCl2 arrhythmia models.

A new group of potential pFOX inhibitors among linear methoxyphenyltriazaalkanes were designed and synthesized. Cardiotropic activity in rodent experiments was found for most of the synthesized compounds. The most active compound N-1-(2,3,4-trimethoxybenzyl)-N-2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine trihydrochloride (LM-1) combined anti-ischemic, antiarrhythmic, and antifibrillatory activities (1 mg/kg, i.v.) and low toxicity (LD50 = 119 mg/kg, mice, i.p.) and was selected for development as a potential cardiotropic drug.

Поиск новых оригинальных кардиотропных лекарственных средств, обладающих антарктической и антиишемической активностью, безусловно, является одной из наиболее актуальных задач, стоящих перед современной кардиофармакологией. В рамках решения этой проблемы впервые в ряду α, ω-диарилметильных производных бис- (ω -аминоалкил) аминов был проведён поиск соединений, обладающих подобной активностью.

A series of new substituted N-[2-(1-adamantylamino)-2-oxoethyl]-N-(ω-aminoalkyl)nitrobenzamides with an original spectrum of antiarrhythmic activity were synthesized. Their structure—activity relationship was studied. The most active compound, N-[2-(1-adamantylamino)-2-oxoethyl]-N-[3-(diethylamino)propyl]-4-nitrobenzamide hydrochloride, was selected as a potential lead drug for further detailed pharmacological and toxicological studies.

A series of new 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-one derivatives were synthesized from widely available furfurol, 3-aminopropionic acid, and amines. The antidepressant and anxiolytic properties of the obtained compounds were investigated. Results of Nomura and Porsolt forced swimming tests showed that some of the compounds exhibited antidepressant activity at doses of 7 μmol/kg (1.1 – 2.2 mg/kg). Use of the Vogel conflict test showed that several compounds possessed anxiolytic activity at the same doses. The activities of the most active compounds exceeded those of the reference drugs, antidepressant amitriptyline and daily tranquilizer medazepam, at doses of 10 mg/kg.

A series of new 1,2,4,5-tetrahydro-3 H -pyrrolo[1,2- a ][1,4]diazepin-3-one derivatives have been synthesized using widely available furfural, 3-aminopropionic acid, and amines. Antidepressant and anxiolytic properties of the obtained compounds were investigated. Results of the Nomura and Porsolt forced swimming tests showed some of the synthesized compounds to exhibit antidepressant activity in doses of 7 μmol/kg (1.1 – 2.2 mg/kg). Using the Vogel conflict test, several compounds were shown to possess anxiolytic activity in the same doses. The effects of most active compounds exceeded the activity of reference preparations — the antidepressant amitriptyline and daily tranquilizer medazepam in doses of 10 mg/kg.

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1′,2′:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2′,1′:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.

Magnetic properties and magnetocaloric effect of YNi4Si-type RNi4Si (R=Ce, Gd, Tb and Dy) compounds have been investigated. Magnetic measurements indicate the intermediate valence state of cerium in YNi4Si-type CeNi4Si. The magnetocaloric effect of GdNi4Si, TbNi4Si and DyNi4Si are calculated in terms of isothermal magnetic entropy change and they reach maximum values of −22.9 J/kg K, −13.5 J/kg K and −15.6 J/kg K for a field change of 140 kOe near ~28 K, 47 K and 27 K and they show maximum values of −12.7 J/kg K, −7.8 J/kg K and −9.3 J/kg K for a field change of 50 kOe near ~28 K, 42 K and 22 K, respectively. In contrast to GdNi4Si, the magnetization-field isotherms for TbNi4Si and DyNi4Si exhibit hysteresis loop at 2 K due to strong magnetocrystalline anisotropy.

ChemInformVolume 41, Issue 41 Heterocyclic Compounds ChemInform Abstract: Azacycloalkanes. Part 39. New Syntheses of 1H-Pyrrole-1-carboxylic Acid (III) and 1,2-Dihydropyrrolo[1,2-a]pyrazin-3(4H)-one Derivatives (VI). G. V. Mokrov, G. V. Mokrov Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this authorA. M. Likhosherstov, A. M. Likhosherstov Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this authorV. S. Troitskaya, V. S. Troitskaya Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this authorT. A. Gudasheva, T. A. Gudasheva Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this author G. V. Mokrov, G. V. Mokrov Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this authorA. M. Likhosherstov, A. M. Likhosherstov Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this authorV. S. Troitskaya, V. S. Troitskaya Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this authorT. A. Gudasheva, T. A. Gudasheva Zakusov State Inst. Pharmacol., Russ. Acad. Med. Sci., Moskva 125315, RussiaSearch for more papers by this author First published: 16 September 2010 https://doi.org/10.1002/chin.201041096Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume41, Issue41October 12, 2010 RelatedInformation

New procedures have been developed for the synthesis of α-(2-formyl-1 H -pyrrol-1-yl)-substituted carboxylic acids, α-(2-R-aminomethyl-1 H -pyrrol-1-yl)-substituted carboxylic acids, and 1,2-dihydropyrrolo-[1,2- a ]pyrazin-3(4 H )-ones on the basis of furfurol and α-amino acids.

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The reaction of 2,5-dimethoxy-2-dimethoxymethyltetrahydrofuran (I) with trimethylenediamine yields 3,4-dihydro-5H-pyrrolo[1,2-a]diazepine (II) or 1,3-bis-[N-(2-formylpyrryl)]propane (IV). Bicyclic compound II converts on standing into dimer V. The hydrolysis of compound V yields 6,7,12,13-tetrahydro-5H,14H-dipyrrolo[1,2-a;1′,2′-h][1,4,8,11]tetraazacyclotetradecin (VI). It is shown that bicycle II, pentacyclic dimer V, and tricyclic dimer VI can be readily converted into each other. The reduction of dimer VI with lithium alumohydride in ether yields stable 3,4,6,7,10,11,12,13-octahydro-5H,14H-dipyrrolo[1,2-a;1′,2′-h][1, 4, 8, 11]tetraazacyclotetradecin (VII). The hydrogenation of bicyclic monomer II, as well as of dimers V and VI, yields 1,2,3,4-tetrahydro-5H-pyrrolo[1,2-a]diazepine (VIII).

The reaction of 2,5-dimethoxy-2-dimethoxymethyltetrahydrofuran with trimethylenediamine yields 3,4-dihydro-5H-pyrrolo[1, 2-a]diazepine (II) or 1,3-bis-[N-(2-formylpyrril)propane. Bicyclic compound II converts on standing into dimer V. The hydrolysis of compound V yields 6,7,12,13-tetrahydro-5H,14H-dipyrrolo[1,2-a;1',2'-h][1,4,8,11]tetraazacyclotetradecin (VI). It is shown that bicycle II, pentacyclic dimer V, and tricyclic dimer VI can be readily converted into each other. The reduction of dimer VI with lithium alumohydride in ether yields stable 3,4,6,7,10,11,12,13-octahydro-5H,14H-dipyrrolo[1,2-a;1',2'-h][1,4,8,11]tetraazacyclotetradecin (VI). The hydrogenation of bicycle II and dimers V and VI yields 1,2,3,4-tetrahydro-5H-pyrrolo[1,2-a]diazepine.