A. N. Fomina

Synthesis and antiviral activity of 2-alkylaminomethyl derivatives of 5-oxyindole

The 2and 4-alkylaminomethyl derivatives of 5-oxyindole are known to have a broad spectrum of biological activity [1-5]. In that connection, we have continued studies on the synthesis of 2-alkylaminomethyl derivativesof 5-oxyindole and their biological activity. It has been shown earlier that l-methyl-2-dlethylaminomethyl-3-carbethoxy-5-tosyloxyindole causes a temporary reduction of arterial pressure and exhibits antiarrythmic, antiflbrillatory, and anticonvulsant activity [4].

Synthesis 6-formylbenzo(b)thiophene derivatives and their antiviral activity

Benzothiophenes containing a formyl group in the benzene ring are of interest as possible key intermediate products in the synthesis of potential biologically active compounds of this series. However, introduction of an aldehyde group (formylation) into the benzene ring of benzothiophene can be accomplished only in the presence of electron-donor substituents, for example the OH group [5, 6]. We found that by the action of the Vilsmeier reagent on the previously obtained 7-oxo-4,5,6,7-tetrahydrobenzo(b)thiophenes (I, II) [i, 4], 6-formyl-7-chloro derivatives ~IIl, IV are formed in a yield of 44.2-63.4%. The structure of the compounds obtained was confirmed by means of IR, PMR and mass spectra. In the IR spectra of compounds III,IV, the absorption band of the formyl group appears together with the ethoxycarbonyl group in the form of a broadened band at 1680 cm -l. In the PMR spectrum of aldehyde III the following signals are observed: 2.73 (t, 4-H), 3.08 (t, 5-H), 10.15 ppm (s, CHO), which corresponds to the proposed structure.

Synthesis and antiviral activity of 7-oxo- and 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene derivatives

26, 917-919 (1978). 22. N. J. Lewis, R. L. Inloes, J. Hes et al., J. Med. Chem., 21, 1070-1073 (1978). 23. I. Litchfield and F. Wilcoxon, J. Pharmacol. Exp. Ther., 96, 99 (1949). 24. I. R. Neher, A. Wettstein, and K. Miescher, Helv. Chim. Acta, 29, 1815-1829 (1946). 25. R. F. Nutt, F. W. Holly, C. Homnick et al., J. Med. Chem., 24, 692-698 (1981). 26. C. G. 0verberger, H. Ringsdorf, and B. Avchen, ibid., 8, 862-864 (1965). 27. J. C. Schwartz, Trends Neurosci., 6, 45-48 (1983).

Synthesis and antiviral activity of 1-alkyl[aryl]-2-alkylaminomethyl-3-ethoxycarbonyl-5-hydroxy-6-bromoindoles

Cu(2+)-l,8-Bis-(2-methoxycarbonylethylamino)-3,6-dithiaoctane Acetate (VII): A mixture of 2.1 g (6 mmole) of the diamine (III) and 0.54 g (3 mmole) of copper acetate in 50 ml of ethanol was stirred at 20~ for 3 h, the solution assuming a dark blue color. Most of the solvent was removed under reduced pressure, and the complex precipitated with ether. The oil which separated was kept under vacuum until it was converted into a glassy solid, yield 1.4 g (90%). IR spectrum, cm-*: 3200 (NH), 1730 (COOCHs). Found, %: C 40.1, H 6.2, N 4.9, S 11.6, Cu 11.5. C:.H3~N=OsS=Cu. Calculated, %: C 40.4, H 6.3, N 5.2, S 12.0, Cu 12.0.

Synthesis and antiviral activities of 5-(pyridyl-2)-oxyindole derivatives

the synthesized compounds and the reference preparation, are given in Table I. It is evident that with daily injection in a dose of 5 mg/kg for 7 days, all compounds studied inhibited the formation of granulomatous tissue by 25-30%. Prednisolone hemisuccinate and Vb were found to have the greatest thymolytic activity (35 and 27%, respectively); Va decreased the mass of the thymus by 19%. Compounds Va and Vb and the reference preparation caused the animals to gain weight to a similar degree, but did not decrease the weight of the adrenals. At the same time, it was found that the compounds synthesized did not change the content of corticosterone in blood plasma, in contrast to prednisolone hemisuccinate, subcutaneous administration of which changed the hormones concentration by 26%.

SYNTHESIS AND ANTIVIRAL ACTIVITY OF 2-PHENOXYMETHYL DERIVATIVES OF 5-HYDROXYINDOLE

As starting compound, we used the previously described l-methyl-2-bromomethyl-3-ethoxycarbonyl-5-acetoxy-6-bromoindole (I). When this was reacted in acetone with phenols and phenolamines containing methyl, bromo, or nitro groups at position 4, 2-phenoxymethyl derivatives of 5-acetoxyindole (II-V) were obtained. When unsubstituted phenol was used, we isolated •-methy•-2-phen•xy-3-eth•xycarb•ny•-5-(•-methy•-3-eth••ycarb•ny•-5-acet•xy-6-br•m•indolyl-2-methoxy)-6-bromoindole (VI) as a by-product. Carrying out the same reaction in aqueous dioxane in the presence of KOH leads to O-deacylation, shown by reacting 5-acetoxyindole (I) with 4-methoxyphenol, which resulted in the isolation of the 5-hydroxyindole derivative (X). Alkaline hydrolysis of 5-acetoxyindoles II-V gave the corresponding 5-hydroxyindoles VII-X.

Synthesis and antiviral activity of 2-anilinomethyl derivatives of 5-hydroxyindole

It was demonstrated earlier that 2-alkylaminomethyl derivatives of 5-acetoxy (hydroxy)indoles possessed antiviral activity [1, 2]. However, the literature holds not information on 2-arylaminomethyl derivatives of indole. In this connection it was of interest to study the antiviral activity of structures of compounds such as 2-anilinomethyl derivatives of 5-acetoxy (hydroxy)indole, the syntheses of which were brought about by alkylation of a substituted aniline with the bromomethyl derivative of 5-acetoxyindole (I), obtained earlier [2]. The condensation proceeded in benzene, both triethylamine and an excess of one of the reaction components, the corresponding aniline, may be used as accepter of the HBr produced. The yields of the anilinomethyl derivatives of the substituted 5-acetoxyindoles (IIVI) were 60-76%. In the preparation of indole III, a 3.2% yield of N,N-b is ( l -methy l -3-e thoxycarbonyl -5-ace toxy-6bromoindole) (VII) also was isolated. The yield of compound VII could be increased to 10% if the reaction is carried out not with aniline but with excess aniline hydrochloride in aqueous dioxane with heating. Basic hydrolysis of the substituted l -methyl -2-ani l inomethyl -3-e thoxycarbonyl-5-aee toxy-6-bromoindoles II-VI lead to the formation of the corresponding substituted 5-hydroxyindoles (VIII-XI). Aminomethylation of the latter have the 4-aminomethyl indole derivatives (XII-XV).

Aminoalkyl-5- and -6-hydroxyindoles and their antiviral activity

Bromination of (VII) with N-bromosuccinimide (NBS) in CC14 with illumination in the presence of benzoyl peroxide afforded l-phenyl-2-bromomethyl-3-ethoxy-carbonyl-6-acetoxyindole (VIII) o In the PMR spectrum of this compound, the position and multiplicity of the signals for the aromatic protons were similar to those for the same protons in the starting material (VII), and in addition a singlet signal was present at 6 = 4.93 ppm attributable to the protons of the methylene group in the 2-position of the indole ring. However, bromination of (VII) with bromine in acetic acid gave (IX), the PMR spectrum of which as compared with that of (VII) contained a singlet signal for the 2-methyl group at 2.53 ppm, signals for the protons in positions 4 and 7 with characteristic multiplicity, but no signal for a proton in the 5-position. Bromination of (VIII) with bromine in acetic acid gave the dibromide (X), which was also obtained by boiling (IX) with NBS in CCI~ with illumination in the presence of benzoyl peroxide. Reaction of (X) with thiophenol in alcohol in the presence of KOH gave the 2-phenylthiomethyl derivative of 6-hydroxyindole (XI), which on reaction with bis(dimethylamino)methane was converted into (XII).

Synthesis of benz[g]indole aminomethyl derivatives

Aminomethyl derivatives of indole have been found to include compounds with a high degree of antiviral [6] and antitubercular activity [4] as well as compounds which exhibit antiarrhythmic, antifibrillatory, and anticonvulsive activity [5]. At the same time there has been little study of the aminomethyl derivatives in the benz[g]indole series. A description has been given for the synthesis of N-methyl and N-phenyl-2-methyl-3-ethoxycarbonyl-4dimethylaminomethyl-5-oxybenz[g]indoles by treating corresponding derivatives of 5-oxybenz[g]indoles with bisdimethylaminomethane [i]. However, information about their biological activity is lacking.

SYNTHESIS AND ANTIVIRAL ACTIVITY OF 5-METHOXYBENZOFURANS

)propionic acid with PC15 in chloroform in the presence of dimethylformamide (DMF) gave the acid chloride, which was treated without further purification with diethylamine to give (2-methyl-5-methoxy-3benzofuryl)propionir diethylamide (V). Reaction of the acid chloride with ammonia failed to give the unsubstituted amide. (2-Methyl-5-methoxy-3-benzofuryl )propionamide (VI) was obtained by reducing the hydrazide (II) over Raney nickel. Amides (IV-VI) were reduced with LiAIH, to the amines, 3-y-hydroxyethyl aminopropyl- (VII), 3-y-diethylaminopropyl- (VIII), and 3-y-aminopropyl- (IX) 2-methyl-5-methoxybenzofurans. 2Methyl-3-y-piper idinopropyl-5-methoxybenzofuran (X) was obtained by replacing the hydroxygroup in (III) by the piperidine residue in the presence of a skeletal nickel catalyst. In addition to 3-aminopropyl derivatives of 5-hydroxybenzofurar~ we have obtained some 3aminoethyl derivatives. 2-Methyl-3-aminoethyl-5-methoxybenzofuran (XIII) has been obtained from the hydrazide (II) via 2-methyl-3-B-ethoxycarbonylaminoethyl-5-methoxybenzofuran (XI) and 2-methyl-3-(B,phthalimidoethyl)5-methoxybenzofuran (XII). Some of the above reactions were also carried out with (2-methyl-5-methoxy-3-benzofuryl )butyric acid. Esterification of ~he acid gave the ethyl ester (XIV). This served as the starting material for the preparation of (2-methyl-5-methoxy-3-benzofuryl )butyrohydrazide (XV) and (2-methyl-5-methoxy-3-benzofuryl )-butyric 8-hydroxyethylamide (XVI). In addition to the 3-aminoalkyl derivatives, we have obtained some 2-aminoalkyl-5methoxybenzofurans. The key intermediate in the preparation of these compounds was 2-bromo