I. A. Dzhagatspanyan

Synthesis and Anticonvulsant Activity of isothiazolo[5,4-b]pyrano(thiopyrano)[4,3-d]pyridine and Isothiazolo[4,5-b]-2,7-naphthyridine Derivatives

Previously [1 – 3], we reported that pyrano(thiopyrano)[3,4-c]pyridine and 2,7-naphthyridine derivatives, as well as related heterocycles, possess anticonvulsant properties. In this context, we have developed a method for the synthesis of new heterocyclic systems based on isothiazolo[5,4-b]pyrano(thiopyrano)[4,3-d]pyridine and isothiazolo[4,5-b]-2,7-naphthyridine. According to this, isothiazolo[5,4-b]pyrano(thiopyrano)[4,3-d]pyridine (IIa, IIb) and isothiazolo[4,5-b]-2,7-naphthyridine (IIc) were obtained proceeding from 3-thio-4-cyano-pyrano(thiopyrano)[3,4-c]pyridines (Ia, Ib) and -2,7-naphthyridines (Ic) synthesized previously [4]. Interaction of the latter compounds with bromine results in the attachment of bromine to a nitrile group and intramolecular cyclization with formation of compounds IIa – IIc. In contrast to this, the interaction of 3-thio-4-cyanopyridines Ia – Ic with iodine in a basic medium leads to the corresponding disulfides IIIa – IIIc. Compounds Va – Vc were obtained by aminating 3-thio-4-cyano derivatives Ia – Ic with hydroxyaminosulfonic acid. The intermediate amination products, 3-sulfenamides IVa – IVc, exhibit cyclization in the presence of sodium ethylate to yield compounds Va – Vc. Benzoylation of 1-aminoisothiazolo[5,4-b]pyridines Va and Vb with benzoyl chloride yields the corresponding amides VIa and VIb. The H NMR spectra of compounds IVa – IVc dissolved in DMSO-d6 exhibit signals at 5.3 ppm characteristic of the amino group. In the spectra of tricyclic products Va – Vc, the signals of amino groups are observed in a somewhat lower field (5.8 – 5.9 ppm). EXPERIMENTAL CHEMICAL PART

Synthesis and Anticonvulsant Activity of Pyrazolo[3,4-b]pyrano(thiopyrano)[4,3-d]pyridine and Pyrazolo[3,4-c]isoquinoline Derivatives

Previously [1 – 3], we reported that pyrano(thiopyrano)[3,4-c]pyridine derivatives possess anticonvulsant properties. At the same time, pyrazolo[3,4-b]pyrano(thiopyrano)[4,3-d]pyridine and pyrazolo[3,4-c]isoquinoline derivatives were never described in the literature. For this reason and in continuation of our work on the search for new biologically active heterocyclic compounds [4, 5], we have developed a method for the synthesis of these condensed compounds, obtained a series of these substances, and studied their anticonvulsant properties. Initial compounds for the synthesis were the previously reported 3-chloro-4-cyano(carbamoyl)pyrano(thiopyrano)[3,4-c]pyridines (Ia – Ig, IIa – IIc) [1 – 3] and 5,6,7,8-tetrahydroisoquinoline derivatives (Ih – In, IId, IIe) obtained by analogous methods. Interacting with hydrazine hydrate, compounds I and II yield tricyclic 1-amino (IIIa – IIIn) and 1-hydroxy (IVa – IVe) derivatives, respectively: R = CN(I), CONH2 (II); I, III: X = O, R = R = CH3 (a); X = O, R = CH3, R 1 = C2H5 (b); X = O, R = CH3, R 1 = iso-C3H7 (c); X = O, R = CH3, R = (d); X = O, R = CH3, R 1 = C6H5 (e); X = S, R = R = CH3 (f); X = S, R = CH3, R 1 = C6H5 (g); X = CH2, R = H, R = CH3 (h); X = CH2, R = H, R 1 = C2H5 (i); X = CH2, R = H, R 1 = C3H7 (j); X = CH2, R = H, R 1 = iso-C3H7 (k); X = CH2, R = H, R 1 = C4H9 (l); X = CH2, R = H, R 1 = (m); X = CH2, R = H, R 1 = C6H5 (n); II, IV: X = O, R = R = CH3 (a); X = O, R = CH3, R 1 = C6H5 (b); X = S, R = R = CH3 (c); X = CH2, R = H, R 1 = C2H5 (d); X = CH2, R = H, R = iso-C3H7 (e).

Synthesis and Anticonvulsive Activity of 7-Amino-Substituted Cyclopenta[4′,5′]-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines

Methods for the synthesis of new cyclopenta[4′,5′]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine derivatives based on 3-oxo-derivatives of cyclopenta[c]pyridines were developed. O-alkylated derivatives of these latter compounds were cyclized to furo[2,3-b]pyridines, which were converted to furo[3,2-d]pyrimidin-7-ones with formamide. Subsequent chlorination and amination of 7-oxo derivatives yielded 7-amino derivatives. The anticonvulsive and predicted tranquillizer activities of the compounds synthesized here were assessed. Compounds with anticonvulsant properties were identified.

Derivatives of Condensed Thienopyrimidines: Synthesis and Neurotropic Activity of New Pyrano[4′,3′:4,5]thieno[3,2-e]triazolo[3,4-b]pyrimidine Derivatives

Previously [1,2], we reported on the synthesis of condensed thieno[2,3-d]pyrimidines possessing neurotropic properties. This study is aimed at the synthesis and characterization of pyrano[4 ,3 :4,5]thieno[3,2-e]triazolo[3,4-b]pyrimidines (II – IV). In the first step, triazolopyrimidine II was obtained via heterocyclization of 2-hydrazino-4-oxothienopyrimidine (I) with orthoformate. Then, alkylation of compound II with methyl iodide (or ethyl iodide) yielded 1-methyl(ethyl)-5oxothienopyrimidines III and IV.

Synthesis and Anticonvulsant Activity of Pyrano[4′,3′:4,5]pyrido[2,3-b]furo[3,2-d]pyrimidine and Pyrano[4′,3′:4,5]pyrido[2,3-b]furo[3,2-d]pyridine Derivatives

Previously [1], we reported on the synthesis of pyrano[4,3-d]furo[2,3-b]pyridines possessing anticonvulsant properties. This study continues the development of methods for obtaining derivatives of new condensed heterocycles, representing pyrano[4 ,3 :4,5]pyrido[2,3-b]furo[3,2-d]pyrimidines and pyrano[4 ,3 :4,5]pyrido[2,3-b]furo[3,2-d]pyridines. Furo[3,2-d]pyrimidines IIa – IIe were synthesized via interaction of 9-aminopyrano[4,3-d]furo[2,3-b]pyridines (Ia – Ic, If, Ig) [3] with formamide. Furo[3,2-d]pyridines IIIa – IIIe were obtained by the condensation of compounds Ib, Id, Ie – Ig [1] with acetoacetic acid ethyl ester, whereby the cyclization was accompanied by hydrolysis of the ester group. Optimum reaction conditions ensuring high yields of the target products were provided by boiling the initial compounds in m-xylene in the presence of zinc chloride.

Synthesis and Neurotropic Activity of New Pyrano[4′,3′:4,5]thieno[2,3:4″,5″]pyrimido[2,3-c]-(1,2,4)triazines

Previously we reported that some derivatives of condensed thienopyrimidines possess neurotropic properties [1, 2]. To our knowledge, the synthesis and biological properties of pyranothienopyrimidino(1,2,4)triazines were not described so far. We have developed a method for the synthesis of new thienopyrimidinotriazines, which are condensed with a tetrahydropyran ring, and studied their anticonvulsant activity. In the first stage, we used the reactions of 2-aminothiophene (I) [1] with isothiocyanates to obtain thioureido derivatives IIa and IIb. These products exhibit cyclization in the presence of potassium hydroxide with the formation of the corresponding 2-thio-4-oxothienopyrimidines (IIIa, IIIb). Boiled with hydrazine hydrate, compounds IIIa and IIIb yielded hydrazino derivatives IVa and IVb.

Synthesis and neurotropic properties of 2-amino-5,5-dimethyl(5,5,6-trimethyl)-4,5-dihydro-7h-pyrano(pyrido)[4,3-d]thiazoles

Methods for the synthesis of new 2-aminopyrano(pyrido)[4,3-d]thiazoles have been developed, a series of new compounds have been obtained and their neurotropic properties have been studied.

Synthesis and Neurotropic Activity of Pyrrolo[2,3-c]pyran(thiopyran, pyridine) and Pyrano(thiopyrano, pyrido)[4′,3′:4,5]pyrrolo-[1,2-b]asym-triazine Derivatives

In continuation of our previous investigations devoted to the synthesis of condensed pyrroles [1 – 3], we have developed a method for the synthesis of pyrrolo[2,3-c]pyran(thiopyran, pyridine) derivatives proceeding from 2,2-dimethyl-4-tetrahydropyranylidenemalonic acid dinitrile (Ia) and its thiopyran and pyridine analogs (Ib and Ic, respectively) [4]. The interaction of compounds Ia – Ic with substituted phenyl(furyl)diazomethylketones led to derivatives of pyrrolo[2,3-c]pyran(thiopyran, pyridine) derivatives (IIa – IIi). By treating compounds IIa – IIi with an ethanol solution of potassium hydroxide, we obtained a series of derivatives representing a new heterocyclic system: pyrano(thiopyrano, pyrido)[4 ,3 :4, 5]pyrrolo[1,2-b]asym-triazines (IIIa – IIIi). A special method developed for the synthesis of compounds IIIa – IIIi is based on the reactions of compounds Ia – Ic with diazomethyl ketones on heating to 70°C. Using this procedure, compounds IIIa – IIIi are obtained without isolating intermediate pyrroles IIa – IIi. I: X = O (a), S (b), N-CH3 (c); I, III: X = O, R = C6H5 (a); X = O, R = o-C6H4Cl (b); X = O, R = p-C6H4Cl (c); X = O, R = p-C6H4NO2 (d); X = O, R = p-C6H4CH3 (e); X = O, R = m-C6H4NO2 (f); X = O, R = (g), X = S, R = C6H5 (h);

Synthesis and neurotropic properties of 1-amino-2-substituted 8,9-dihydro-6h-pyrano(thiopyrano)[4,3-d]-thieno-[2,3-b]pyridines and- thieno[2,3-c]-2,7-naphthyridines

Thieno[2,3-b]pyfidines are widely used both as reagents for the synthesis of complex condensed heterocyclic systems [1 -3 ] and as pharmacologically active compounds [4, 5]. This class includes substances producing an anticonvulsive effect and possessing affinity with respect to benzodiazepine receptors [6, 7]. The purpose of this work was to synthesize l-amino-2substituted 8,9-dihydro-6H-pyrano(thiopyrano)[4,3-d]-thieno[2,3-b]pyridines and -thieno[2,3-c]-2,7-naphthyridines ( X XXI) and study their neurotropic properties.

Synthesis and Neurotropic Activity of New 7-Cyclohexyl-6,7,8,9-Tetrahydro-3 H -Pyrazolo[3,4- c ]-2,7-Naphthyridine-1,5-Diamines

A method for synthesizing new tricyclic heterocyclic 7-cyclohexyl-6,7,8,9-tetrahydro-3H-pyrazolo- [3,4-c]-2,7-naphthyridine-1,5-diamines from 1,3-dichloro-7-cyclohexyl-5,6, 7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile was elaborated. Investigation of the biological activity of the synthesized compounds showed that several of them exhibited pronounced neurotropic properties.