R. 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 and Biological Activity of N-[3-(4-Substituted Phenyl)-3-hydroxypropyl]valines and -Tryptophans, and 3-{[3-Hydroxy-3-(4-substituted phenyl)propyl]amino}-3-phenylpropanoic Acids

Reduction of N-[β-(4-substituted benzoyl)ethyl]amino acids with sodium borohydride yielded arylaliphatic aminopropanols containing amino acid fragments – N-[3-(4-substituted phenyl)-3-hydroxypropyl]valines,-tryptophans, and 3-{[3-hydroxy-3-(4-substituted phenyl)propyl]amino}-3-phenylpropanoic acids. Studies of the biological activities of these compounds showed that some had anti-inflammatory and anticonvulsive activities.

Choline esters of N-subtituted amino acids. VIII. Synthesis and neurotropic properties of β-dimentylaminoethyl ester salts of N-(p-alkoxybenzoyl)-α,β-dehydrophenylalanines

Previously we have established that 5-oxazolone rings may open under the action of dialkylaminoalkyl alcohols to form the corresponding esters of N-substituted saturated or unsaturated amino acids [1, 2]. The purpose of this work was to synthesize 13-dimethylaminoethyl esters of N-(p-alkoxybenzoyl)-ct,13-dehydrophenylalanines ( I Ia-I I f ) and their saturated analogs (IIg I I i ) and study the pharmacological properties of their salts (III, IV). Because these compounds are analogs of acetylcholine, it was of interest to study their effect upon the cholinergic structures. The target aminoesters I I a I I f were synthesized by the azlactone method. The initial unsaturated oxazolones I a I f were obtained by the method described in [3], and the saturated oxazolones I g I i were obtained according to [4]. The yields and characteristics of previously unreported compounds are given in Table 1.

Synthesis and pharmacological activity of 1-(4-substituted phenyl)-1-alkyl(aryl)-3-piperidinopropanol hydrochlorides

Aminomethylation of substituted acetophenones with paraformaldehyde and piperidine hydrochloride yielded 4-substituted β-piperidinopropiophenones. Interaction of compounds I with the Grignard reagents in ether yielded 1-(4-substituted phenyl)-1-alkyl(aryl)-3-piperidinopropanols. The anti-inflammatory, analgesic, antipyretic, central m-cholinoblocking, and peripheral n-cholinoblocking actions of 1-(4-substituted phenyl)-1-alkyl(aryl)-3-piperidinopropanol hydrochlorides were studied. The study compounds were found to have marked central m-cholinoblocking and peripheral n-cholinoblocking activities. Only 1-(4-methoxyphenyl)-1-cyclohexyl-3-piperidinopropanol hydrochloride had anti-inflammatory activity.