Derivatives of 3-mercaptoindole - synthesis of a potent vasoconstrictor,3-(2-imidazolin-2-ylthio)indole (Tinazoline)

Nagarajan, K. ; Arya, V. P. ; Parthasarathy, T. N. ; Shenoy, S. J. ; Shah, R. K. ; Kulkarni, Y. S. ; Ciba-Geigy, (1981) Derivatives of 3-mercaptoindole - synthesis of a potent vasoconstrictor,3-(2-imidazolin-2-ylthio)indole (Tinazoline) Indian Journal of Chemistry, 20B . pp. 672-679. ISSN 0019-5103

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Indoles are oxidatively coupled with various cyclic and acyclic thioureas using iodine to give rise to 3-(2-imida-zolin-2-yIthio)indole, 1-30, 32 and 36-40. Similar products 33, 34 and 35 are respectively obtained from benz[g]-indole, 1, 6, 6-trimethyl-4,5,6,7-tetrahydroindole and 7-azaindole, while alkylation of 3-mercaptoindole 44 with chloromethyl imidazoline leads to 31. Among the products so obtained, 3-(2-imidazolin-2-y!thio)indoIe is a potent vasoconstrictor and the hydrochloride salt forms the active ingredient of Varsyl®. 3-Mercaptoindole (44) readily obtained by alkali treatment of S-(3-mdoiyi)isothiourea (36) is converted into amine derivatives.47 and 52 and to the acids 53-55. Acid-catalysed cyclisatioa of 55 affords the expected thiopyranone (57), as well as the interesting isomeric ketone (58). A mechanism is proposed for this novel rearrangement. 3-Mercaptoindole (44) is also converted to a-methyl-aminoacid (64) via the hydantoin (63). 3-MercaptoindoIe-2-carboxylic acid (65) obtained from 10 is transformed to a variety of methylated derivatives 66-72. The amino acid 75 arising by the actioa of ethylenimine on 65 is esterified to 76 and cyclised to the condensed thiazepinone (77).

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