E. G. Paronikyan

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 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 ad Some Conversions of Partially Hydrogenated 1-Aminopyrano(thiopyrano)[4,3-d]pyrazolo[3,4-b]pyridines and Pyrazolo[3,4-c]isoquinolines

We have synthesized derivatives of pyrano(thiopyrano)[4,3-d]pyrazolo[3,4-b]pyridine and pyrazolo[3,4-c]isoquinoline, and we have also carried out some conversions with them.

Synthesis of derivatives of pyrido[2,3-d]pyrimidines condensed with tetrahydropyran and tetrahydrothiopyran

Methods have been developed for obtaining derivatives of W-amino(oxo)-, 8,10-dioxo-, and 10-amino-8-oxo(thio)pyrano(thiopyrano) [4′,3′:4,5]pyrido[2,3-d]pyrimidine on the basis of 3-amino(benzylamino)-4-cyano (carbamoyl)pyrano(thiopyrano)[3,4-c]-pyridines.

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 of derivatives of tetrazolo[1,5-a]- and oxazolo[4,5-b]pyrano(thiopyrano)[3,4-c]pyridines

Tetrazolo[1,5-a]- and oxazolo[4,5-b]pyrano(thiopyrano)[3,4-c]pyridines, which are new heterocyclic systems, have been synthesized from pyrano[3,4-c]pyridine derivatives.