ACID-CATALYZED CYCLOCONDENSATION OF NITRILES. PART IV. SYNTHESIS AND SPASMOLYTIC ACTIVITY OF 1-SUBSTITUTED 3-AMINOISOQUINOLINES AND THEIR DERIVATIVES

Biologically active compounds with an isoquinoline nucleus are widely used in medicine (papaverine, No-Spa, salsoline, etc.). Earlier, we have developed a simple and efficient method for the synthesis of 3-aminoisoquinolines and the corresponding 3-iminocarbonylamino derivatives [ I, 2]. The purpose of this work was to obtain acyl derivatives of 3-aminoisoquinolines, substituted at the amino group, and study the spasmolytic activity of both 3-aminoisoquinolines and their derivatives. The initial 3-aminoisoquinolines (IIIa-IIIc) were synthesized using a method described previously [ 1, 2]. The first step of this procedure consists in the acid-catalyzed cyclocondensation of arylacetonitriles. This is a three-stage process (see Scheme 1) involving the formation of intermediate Nimidoylnitrilium ions (II) and 3-aminoisoquinoline (III); the reaction mechanism was considered in detail elsewhere [1 ]. Despite a rather hitch yield of final 3-aminoisoquinolinyl aminoimides IV (50 - 72%), the products always contain unreacted initial nitriles and 3-aminoisoquinolines (dimeric products) [1, 2]. Below we will demonstrate that increasing the duration of the first stage leads to more complete consumption of the reagents. Chromatographic estimates show that the content of IIIa in the reaction mass eventually decreases to 3 - 5%, while the yield of amidine IVa, with an allowance for the conversion of 3,4-dimethoxyphenylacetonitrile, amounts to 87%. The content of 3-aminoisoquinolines in the reaction mixture varies depending on the conditions, reaching a maximum by the end of the low-temperature reaction stage [3]. However, taking into account difficulties encountered in the isolation of these compounds, it is expedient to terminate reaction upon the stage of 3-aminoimidoylisoquinolines IV, with their subsequent conversion into corn