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The hepatoprotective activity of 8,8-dimethyl-5-p-tolyl-3,4,7,8-tetrahydro-2H-pyrido[4,3,2-de]cinnolin-3-one was studied in vivo using a model of CCl4-induced acute toxic hepatitis. It was found that this compound affected indices determining the level of free-radical oxidation, i.e., levels of malondialdehyde (MDA) and diene conjugates (DC), and the activities of the key antioxidant enzymes superoxide dismutase (SOD) and catalase. Hepatoprotective activity was analyzed using the activity levels of the enzymes alanine aminotransferase (AlAT), aspartate aminotransferase (AsAT), and alkaline phosphatase and the bilirubin level. The mechanism of the antioxidant activity was determined from the effect of this compound on the expression levels of the gene katG encoding catalase-hydroperoxidase I and the gene sodA encoding Mn-superoxide dismutase. It was found that 8,8-dimethyl-5-p-tolyl-3,4,7,8-tetrahydro-2H-pyrido[4,3,2-de]-cinnolin-3-one exhibited antioxidant activity by increasing the SOD and catalase levels.

The reactions of 1-benzoyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine with methyl 1-bromocycloalkanecarboxylates and zinc, followed by hydrolysis of the reaction mixtures, resulted in the formation of spiro-δ-lactams bearing a 2-(N-benzoylamino)phenyl substituent at the nitrogen atom. The product structures were confirmed by X-ray structural analysis, and a mechanism was proposed for the product formation.

A study of ion-molecular reactions of fluoro-substituted phenyl cations with benzopyridine derivatives demonstrated the following: (a) at present only the nuclear-chemical method enables the reaction of a direct phenylation of the nitrogen atom in benzopyridine derivatives, which makes it possible to obtain previously unknown quaternized structures, and (b) generation of nucleogenic phenyl cations with various substituents leads to a simultaneous introduction of the required substituents into the aromatic ring at the nitrogen heteroatom. Quantum-chemical calculations additionally confirmed the assumption about the pathways of the ion-molecular reactions with nucleogenic phenyl cations.

Quinazoline derivatives are well known to have a diverse array of therapeutic activities. Unfortunately, “classic” chemical synthesis does not provide an opportunity for the formation of N-phenyl quaternary 1,3-diazinium compounds. A devised nuclear-chemical method of synthesis based on chemical effects of nuclear transformations enables a new way of the direct nitrogen atom phenylation by the nucleogenic (generated by tritium β-decay) phenyl cations in 1,3-diazines, furnishing, based on our prediction, formation of previously unknown derivatives with N-phenyl quaternary quinazolinium scaffold.

Reformatsky reaction of methyl 1-bromocyclopentanecarboxylate with 1-aryl-3-(2-hydroxyphenyl)-prop-2-en-1-ones afforded 6-substituted 4-(2-aryl-2-oxoethyl)-2H,4H-spiro[chromene-3,1′-cyclopentan]-2-ones. A probable reaction mechanism was proposed on the basis of DFT/TZVP quantum chemical calculations.

Ethyl 2-amino-5-(2-aryl-2-oxoethylidene)-4-oxo-1H-4,5-dihydrofuran-3-carboxylates and 2-amino- 5-(2-aryl-2-oxoethylidene)-4-oxo-1H-4,5-dihydrofuran-3-carbonitriles reacted with alcohols in the presence of a catalytic amount of concentrated aqueous HCl to give the corresponding 5-alkoxy-2-amino-5-(2-aryl-2- oxoethyl)-4-oxo-1H-4,5-dihydrofuran-3-carboxylic acid derivatives. A probable reaction mechanism was proposed on the basis B3LYP/6-311G(d) quantum chemical calculations.

The developed nuclear-chemical method allows direct phenylation of the nitrogen atom in the isoquinoline molecule and one-step synthesis of tritium-labeled biomarkers containing previously unknown N-(p-difluorophenyl)isoquinolinium fragment with high radiochemical yield.

Physicochemical properties of 4,5-(aryl, alkyl)-3-substituted 2-sulfonylaminothiophenes have been studied. The effect of the nature of the substituents in the thiophene ring on acid-base properties, solubility, and chemical stability was investigated.

2-(Arylimino)-5-(het)arylfuran-3(2H)-ones were synthesized by reaction of 5-(het)arylfuran-2,3-diones with N-(triphenyl-λ5-phosphanylidene)anilines, and their aminolysis afforded N-aryl-4-amino-4-(het)aryl-2-oxobut-3-enamides.

The use of nuclear-chemical synthesis, based on the generation of free nucleogenic phenyl cations, allowed for the direct phenylation of the nitrogen atom in 1,4-diazines. The presence of two methyl substituents in the quinoxaline substrate leads to a marked increase of diazine salt radiochemical yield. On the basis of quantum-chemical calculations the possibility of synthesizing 2,3-dimethyl-1,4-di-phenylquinoxalinium dication is proposed.

Reformatsky reaction of methyl 1-bromocyclopentane-1-carboxylic acid with 3-aryl-2-cyanoprop-2-enamides and their N-methyl derivatives afforded 10-aryl-6,8-dioxo-7-azaspiro[4.5]decane-9-carbonitriles and 10-aryl-7-methyl-6,8-dioxo-7-azaspiro[4.5]decane-9-carbonitriles, respectively.

Substituted [1, 2]oxazino[5,4,3-de]quinolines and pyrido[4,3,2-de]cinnolines were obtained by the reaction of 2-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with hydroxylamine and N-ethyl-, phenyl-, pentafluorophenyl-, and tosylhydrazines, respectively. The structures of the synthesized compounds were confirmed using IR and PMR spectroscopy. The antioxidant activity of the synthesized compounds was studied in Escherichia coli BW 25113 cells for an oxidative stress model induced by H2O2. Three of the six compounds exhibited moderate antioxidant activity, which enabled compounds with antioxidant activity to be sought among the reaction products of substituted 5,6,7,8-tetrahydroquinoline-4-carboxylic acids and nucleophilic reagents.

The phenylation of methylquinolines by nucleogenic phenyl cations was studied. This reaction led to a product mixture through electrophilic addition and electrophilic substitution, with composition depending on the methyl substituent position. In the case of 4-methylquinoline, the electron-donating methyl group in the para position markedly increased the yield of N-phenylquinolinium derivative, while the low yield of the quinolinium salt in the case of 8-methylquinoline was due to the two factors - low basicity of the nitrogen atom in comparison to 4-methylquinoline and steric hindrance by the methyl group, which led to predominant electrophilic substitution.

The reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with hydrazine was studied. This reaction gave 5-substituted 8,8-dimethyl-3,7,8,9-tetrahydro-2H-pyrido-[4,3,2-de]cinnolin-3-ones in good yields. A possible reaction mechanism was discussed using nonempirical quantum-chemical calculations.

The reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with hydroxylamine results in the formation of 5-substituted 8,8-dimethyl-8,9-dihydro-3H,7H-[1,2]ox-azino[5,4,3-de]quinolin-3-ones. The structure of the 5-phenyl derivative has been established by X-ray structural analysis. A possible mechanism of the reaction has been proposed on the basis of nonempirical quantum-chemical calculations.

Methyl 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylates were obtained as a result of 3-amino-5,5-dimethylcyclohex-2-enone reaction with the methyl esters of acyl(aroyl)pyruvic acids. The structure of methyl 7,7-dimethyl-5-oxo-2-phenyl-5,6,7,8-tetrahydroquinoline-4-carboxylate was established by X-ray structural analysis.

Methyl 1-bromocyclohexanecarboxylate reacts with zinc and amides or methylamides of 3-aryl-2-cyanopropenoic acids to give 5-aryl-1,3-dioxo-2-azaspiro[5.5]undecane-4-carbonitriles or 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5.5]undecane-4-carbonitriles.

2-Substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids were synthesized by reaction of acyl- and aroylpyruvic acids with 3-amino-5,5-dimethylcyclohex-2-en-1-one. A plausible mechanism of their formation was proposed on the basis of ab initio quantum-chemical calculations.

Reformatsky reaction of methyl 1-bromocyclobutane-, 1-bromocyclopentane-, 1-bromocyclohexane-, and 1-bromocycloheptanecarboxylates with 2,5-bis(arylmethylidene)cyclopentanones gave the corresponding 4′-aryl-7′-arylmethylidene-4′,5′,6′,7′-tetrahydro-2′H-spiro[cycloalkane-1,3-cyclopenta[b]pyran]-2′-ones.

The synthesis, properties, structure, and analgesic activities of the products of the interaction of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with benzoic acid hydrazides are described. The significance of the structure-function relationship is discussed.

Methyl 1-bromocyclopentane-, 1-bromocyclohexane-, and 1-bromocycloheptanecarboxylates react with zinc and 2,6-bis(arylmethylene)cyclohexanones to afford 4-aryl-8-(arylmethylene)-5,6,7,8-tetrahydrospiro[chromene-3,1′-cyclopentan]-2(4H)-ones, 4-aryl-8-(arylmethylene)-5,6,7,8-tetrahydrospiro[chromene-3,1′-cyclohexan]-2(4H)-ones, and 4-aryl-8-(arylmethylene)-5,6,7,8-tetrahydrospiro[chromene-3,1′-cycloheptan]-2(4H)-ones, respectively.

Publications on derivatives of 2-imino-2H-furan-3one are not numerous. In recyclization reactions with binucleophiles they form new heterocyclic systems [1]. It was shown formerly that the reaction of Nsubstituted 5-aryl-2-imino-2Н-furan-2-ones with оphenylenediamine via the opening of the furan ring after the attack of the primary amino group on the С 2 atom of the heterocycle led to the formation of 2-[3amino-quinoxalin-2(1Н)-ylidene]-1-phenylethanone 1 [2]. Aiming at the preparation of 1-(4-methylphenyl)2-{-3-[(2-methylphenyl)imino]piperazin-2-ylidene}ethanone 2 we attempted to bring into the reaction instead of о-phenylenediamine a structural analog of the biologically active compound “mephepyron,” 3[2-oxo-2-(4-methylphenyl)ethylidene]piperazin-2-one 3 [3]. To this end from (4-methylbenzoyl)ketene, generated in situ by thermal decarbonylation of 5-(4-methylphenyl)furan-2,3-dione 4, and 1-isocyano-2-methylbenzene we prepared 5-(4-methylphenyl)-2-[(2-methylphenyl)

Methods for the synthesis of various heterocyclic compounds based on 3-amino-5,5-dimethylcyclohex-2-enone are discussed.

Reaction of methyl 1-bromocyclobutanecarboxylate with zinc and 1-aryl-2-(arylimino)ethanones leads to 4,6a-diaryl-3,3:6,6-dipropano- tetrahydro-2H-furo[3,2-b]pyrrole-2,5(3H)-diones. Structure of one of these compounds is confirmed by X-ray analysis.

The Reformatsky reagents derived from methyl 1-bromocyclohexane-or 1-bromocyclopentanecarboxylate and zinc add to benzoin to afford the corresponding 4-hydroxy-3,4-diphenyl-2-oxaspiro[4.5]decan-1-one and 4-hydroxy-3,4-diphenyl-2-oxaspiro[4.4]nonan-1-one.

A series of substituted amides of 3-carboxypicolinic acid have been synthesized via the interaction of quinolinic acid anhydride with alkyl(aryl)amines. Their structures were studied by 1H and 13C NMR spectroscopy. The direction of the reaction was explained by quantum-chemistry methods. Three compounds demonstrated hemostatic activity. Two substances exhibited anticoagulant properties. Most substances also exhibited weak bacteriostatic activity.

Dimethyl 2-(1-bromocyclohexylcarbonyl)-, 2-(1-bromocyclopentylcarbonyl)-, and 2-(1-bromocyclobutylcarbonyl)-2-methylmalonates reacted with zinc and aromatic aldehydes to give the corresponding methyl 1-aryl-4-methyl-3,5-dioxo-2-oxaspiro[5.5]undecane-4-, 6-aryl-9-methyl-8,10-dioxo-7-oxaspiro[4.5]-decane-9-, and 5-aryl-8-methyl-7,9-dioxo-6-oxaspiro[3.5]nonane-8-carboxylates.

Applying the quantum-chemical calculations by MP2/6-31G* method molecular structures of trichlorophosphazenes Cl3P=NCOCX3 with X = F and Cl were determined and barriers to intramolecular reorientation of PCl3 group relative to P=N bond and of CF3 and CCl3 groups relative to C-C bond were estimated. The values of potential barriers to internal rotation calculated for isolated molecules were compared with the values of the barriers obtained from the data of NQR and NMR spectroscopy of the compounds in the crystalline state. The structural and dynamic features of the studied molecules are discussed.

Zinc enolates obtained from substituted 1-aryl-2,2-dibromoalkanones and zinc react with alkyl 3-oxo-1,3-dihydrobenzo[c]oxepine-4-carboxylate to give the alkyl 1-alkyl-1-aroyl-2-oxo-4,8b-dihydro-1H-3-oxabenzo[a]cyclopropa[c]cycloheptene-1a-carboxylate.

3-Aroyl-2,4-dihydro-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with N-unsubstituted and N-substituted 3-amino-5,5-dimethylcyclohex-2-en-1-ones to give 3′-aroyl-4′-hydroxy-1′-(o-hydroxy-phenyl)-6,6-dimethyl-6,7-dihydrospiro[indole-3,2′-pyrrole]-2,4,5′(1H,1′H,5H)-triones. The molecular and crystalline structure of the 1-cyclohexyl-substituted derivative was studied by X-ray analysis.

1-R-3,3-Dimethyl-2-azaspiro[5.5]undeca-1,7,10-trien-9-ones were synthesized by condensation of 4-(p-methoxyphenyl)-2-methylbutan-2-ol with nitriles RCN in the presence of a concn. sulfuric acid.

Reformatsky reagent generated from methyl 1-bromocyclohexane-1-carboxylate reacted with N-aryl-2-oxochromene-3-carboxamides and N-aryl-6-bromo-2-oxochromene-3-carboxamides to give, depending on the conditions, the corresponding N-aryl-(6-bromo)-4-(1-methoxycarbonylcyclohexyl)-2-oxochroman-3-carboxamides or 3-aryl-(9-bromo)-1,1-pentamethylene-2,3,4,4a,5,10b-hexahydro-1H-chromeno[3,4-c]pyridine-2,4,5-triones. The products were isolated as a single diastereoisomer.

Zinc enolates formed from 1-aryl-2-bromo-2-phenylethanones and zinc react with dimethyl 2-(1-arylmethylene)malonates to afford dimethyl 2-(1,3-diaryl-3-oxo-2-phenylpropyl)malonates. The latter react with cyclohexylamine, piperidine, or morpholine to give the corresponding monosubstituted amides. The zinc enolate derived from 2-bromoindanone and zinc reacts with dimethyl 2-(4-bromobenzylidene)malonate, yielding dimethyl 2-[(4-bromophenyl)(1-oxoindan-2-yl)methyl]malonate. The final products largely form as a single diastereomer.

Aroylketenes, generated by the thermolysis of 5-aryl-2,3-dihydro-2,3-furandiones, react with S-methyl-N-cyano-N′-phenylisothiourea, N-cyano-N′,N′-dimethylformamidine, and N,N-bis(β-cyanoethyl)-cyanamide with the formation of 6-aryl-2-[(methylthio)(phenylamino)methylene]amino-, 6-aryl-2-dimethylaminomethyleneamino-, and 6-aryl-2-[N,N-bis(β-cyanoethyl)amino]-4H-1,3-oxazin-4-ones respectively. Modeling has been carried out of the interaction of benzoylketene with the indicated cyano compounds by the SSP MO LCAO semiempirical method using the MNDO-PM3 approach. A mechanism is proposed for the formation of substituted 4H-1,3-oxazin-4-ones.

We have used X-ray diffraction to establish the structure of 6-p-tolyl-2-triphenylphosphinimino-4H-1,3-oxazin-4-one. We have modeled its formation from 5-p-toluoylketene and N-cyanotriphenylphosphinimine using the semiempirical SCF MO LCAO method in the MNDO-PM3 approximation. We show that the reaction occurs according to a concerted mechanism.

The Reformatskii reagents formed from alkyl esters of α-bromoacetic, α-bromopropanoic, and α-bromoisobutyric acids and zinc react with N-arylamides of 2-oxochromene-3-carboxylic acid, yielding 3-R1-1-R2-1-R3-4a,10b-dihydro-1H-chromeno[3,4-c]pyridine-2,4,5-triones.

Zinc enolates formed from 1-aryl-2-bromoalkanones react with methyl esters of substituted 2-oxochromene-3-carboxylic acids to give methyl esters of 6-bromo- or 6,8-dibromo-4-(2-aryl-2-oxo-1-R- ethyl)-2-oxochromane-3-carboxylic acids as mixtures of two diastereomers.

As reported previously, 1-substituted 4-acyl-5-arylpyrrolidine-2,3-diones possess antiinflammatory [1], analgesic [2], antiviral [3], nootropic [2], and antibacterial activity [4]. In continuation of the search for biologically active compounds in the class of substituted pyrrolidine-2,3-diones, we have attempted at introducing a substituent, whose structure is significantly different from that of acyl group, into position 4. The aim was to study how this structural change will modify the chemical properties and antibacterial activity of pyrrolidine-2,3-diones. In this context, we have studied the reactions of 1-aryl5-methyl-5-ethoxycarbonylpyrrolidine-2,3-diones (I – V) with aryldiazonium salts. The results showed that treatment of compounds I – V with aryldiazonium chloride in an ethyl alcohol – dioxane mixture leads to the formation of 4-arylhydrazones of 1-Aryl-5-methyl-5-ethoxycarbonylpyrrolidine-2,3,4-triones (VI – XX). Compounds VI – XX appear as red or orange crystalline substances soluble in ethanol, DMF, and DMSO and insoluble in water. The yields, melting points, and empirical formulas of the synthesized compounds are listed in Tables 1 and 2. The 1 H NMR spectra of compounds VI – XX contain (i) a triplet and a quadruplet from protons of the ethoxy group at = 1.18 – 1.25 and 4.22 – 4.25 ppm, respectively; (ii) a singlet due to the methyl group in position 5 of the heterocycle (1.71 – 1.76 ppm); (iii) signals from aromatic protons (7.00 – 7.77 ppm); and a signal due to protons of the NH group (12.90 – 13.21 ppm). The IR spectra of compounds VI – XX display absorption bands due to lactam and ketone carbonyl groups in the regions of 1710 – 1716 cm –1 , ester carbonyls at 1740 cm –1 , azomethine group at 1653 – 1662 cm –1 , and a band due to the stretching vibrations of NH bonds in the region of 3192 – 3200 cm –1 .

Reaction of methyl 1-bromocyclobutanecarboxylate with zinc and 1-aryl-2-(arylimino)ethanones leads to 4,6a-diaryl-3,3:6,6-dipropano- tetrahydro-2H-furo[3,2-b]pyrrole-2,5(3H)-diones. Structure of one of these compounds is confirmed by X-ray analysis.

3-Reactions of 5-aryl, 5-heteryl, and 5-styryl-2,3-dihydro-2,3-furandiones with phenylbenzoyldiazomethane gave rise to 5-substituted 3-dipenylmethylene-2,3-dihydro2-furanones. The possible intermediates and reaction products were investigated by semiempirical SCF MO LCAO method in AM1 approximation.

Treatment of methyl 1-(2-bromo-4-methoxy-1,4-dioxobutyl)cyclohexanecarboxylate with zinc followed by aromatic aldehydes affords methyl 1-(2-aryl-5-oxotetrahydrofuran-3-carbonyl)cyclohexanecarboxylates.

The reactions of 1-(p-methoxyphenyl)-2-methylpropan-1-ol or α-cyclohexyl-p-methoxybenzyl alcohol with nitriles RCN in concentrated sulfuric acid afforded 1-R-3,3-dialkyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones. The stability of the latter toward the dienone-phenolic rearrangement depends on the nature of the substituent R. The reaction mechanism was studied by the semiempirical quantum-chemical AM1 method.

The interaction of 1,2- or 1,4-dimethoxybenzene with isobutylene oxide and nitriles RCN leads to 1-R-6,7- or 1-R-5,8-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinolines. In the case of 1,2-dimethoxybenzene and cyclohexene oxide the similar reaction is accompanied by rearrangement and 1-R-3,3-tetramethylene-3,4-dihydroisoquinolines are formed in low yield. On using cyanoacetic acid ester and any oxide derivatives of tetrahydroisoquinolylideneacetic acid are formed.

Benzoyl- and cinnamoylpyruvic acids have been investigated by X-ray diffraction. In crystals these acids exist as 2-hydroxy-4-oxo-4-phenyl-3(Z)-butenic and 4-hydroxy-2-oxo-6-phenyl-3(Z),5(E)-hexadienic acids, respectively, stabilized by intramolecular hydrogen bonding.

Reformatsky reagent prepared from methyl 1-bromocyclopentanecarboxylate and zinc reacted with 2-oxochromen-and 6-bromo-2-oxochromen-3-carboxylic acids N-arylamides yielding 3-aryl-1,1-tetramethylene-and 3-aryl-9-bromo-1,1-tetramethylene-2,3,4,4a,5,10b-hexahydro-1H-chromeno[3,4-c]pyridine-2,4,5-triones as single diastereomers.

6 Title compounds of type (II) are prepared and the reaction mechanism is discussed using also the results of quantum-chemical calculations.

The reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with hydrazine was studied. This reaction gave 5-substituted 8,8-dimethyl-3,7,8,9-tetrahydro-2H-pyrido-[4,3,2-de]cinnolin-3-ones in good yields. A possible reaction mechanism was discussed using nonempirical quantum-chemical calculations.

Reformatsky reagents generated from alkyl esters of bromoacetic, α-bromopropionic, α-bromobutyric, and α-bromoisobutyric acids react with alkyl esters of 6,8-dibromo-2-oxochromene-3-carboxylic acid to form alkyl esters of 6,8-dibromo-4-(1-alkoxycarbonylalkyl)-2-oxochromane-3-carboxylic acid.