V. S. Shklyaev

Heterocyclization of 1,1-dicyano-2-(trifluoromethyl)ethylenes with 1,3,3-trimethyl-3,4-dihydroisoquinoline and its derivatives

Abstract1,3,3-Trimethyl-3,4-dihydroisoquinolines react with 1,1-dicyano-2,2-bis(trifluoromethyl)ethylene to give 4-amino-6,6-dimethyl-2,2-bis(trifluoromethyl)-3-cyano-6,7-dihydro-2H-benzo[a]quinolizines. The reaction of 3,3-dimethyl-1-cyanomethylidene-1,2,3,4-tetrahydroisoquinoline and the methyl ester of 3,3-dicyano-2-(trifluoromethyl)acrylic acid leads to 5,5-dimethyl-3-oxo-2-(trifluoromethyl)-2-(dicyanomethyl)-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline.

Reaction of 2,3-dioxopyrrolo[2,1-a]isoquinolines with o-phenylenediamine

Reaction of 1,2,3,4-tetrahydroisoquinoline enaminoamides with oxalyl chloride gives 2,3-dioxpyrrolo[2,1-a]isoquinolines which react with o-phenylenediamine to give spiro benzimidazolines or condensed quinoxalines, depending on the conditions used.

SYNTHESIS AND ANTICOAGULANT AND ANTIARRHYTHMIC ACTIVITY OF OXIMES OF ISOQUINOLYL-1-GLYOXYLIC ACID DERIVATIVES

As is known, isoquinoline derivatives possess antiarrhythmic and and anticoagulant properties [ 1 8]. Previously we have reported on these types of activity in 3,4-dihydroisoquinoline derivatives [9, 10]. The purpose of this work is to synthesize a series of oximes of 3,3-disubstituted 3,4-dihydroisoquinoline derivatives and study their antiarrhythmic and and anticoagulant activity. Aleksandrov et al. [11, 12] showed that oximes of this type can be obtained by treating monoand disubstituted derivatives of 1,3,3-trimethyl-3,4-dihydroisoquinoline with nitrous acid, whereby one of the substituents is eliminated in the form of alcohol. Since 1,3,3-trimethyl-3,4-dihydroisoquinoline derivatives containing carbonyl, carbamoyl, or ester groups can be formally considered as analogs of I]-dicarbonyl compounds, it was expected that these derivatives would readily interact with nitrous acid to form the corresponding nitroso compounds. These intermediate products can be subsequently rearranged to form the oximes of 3,3-dialkyl-3,4-dihydroisoquinolyl-l-glyoxylic acid derivatives and related compounds. Indeed, treatment of the solutions of the carbonyl-containing derivatives of 3,3-dialkyl-3,4-dihydroisoquinoline in 10% aqueous HCI with a sodium nitrite equivalent, followed by neutralization of the reaction mass, led to a high yield of the expected oximes with the characteristics listed in Table 1. It must be noted that, in contrast to what was reported in [12], we failed to isolate the intermediate nitroso compounds.

Synthesis of 1-substituted-3,3-dimethyl-3,4-dihydroisoquinolines

The Ritter reaction between Β-substituted propionitriles and dimethylbenzylcarbinols gives 3,3-dimethyl-3,4-dihydroisoquinolines containing substituents in the 1-position corresponding to those in the starting nitrile.

Salts of alkyl-substituted 3,4-dihydroiso-quinolines with 2-acetylcyclopentane-1,3-dione

Reactions of alkyl-substituted 3,4-dihydroisoquinolines, with 2-acetylcyclopentane-1,3-dione were used to prepare 3,4-dihydroisoquinolinium 2-acetylcyclopentane-1, 3-dionates, which could not be converted into ABCD-tetracyclic derivatives of the 8-azagonane series (benzo[a]cyclopentano[f]quinolizines). The salts obtained were studied and characterized by physicochemical methods. It was shown by combining the NMR and H/D-isotope exchange methods that for 1-alkyl-3,4-dihydroisoquinolines and their salts in solutions, an imine-enamine (iminium-enaminium), and for the 2-acetylcyclopentane-1,3-dione anion, a keto-enol tautomeric equilibrium takes place.

Polyazole systems based on 3,4-dihydroisoquinoline

The reaction of 1-methylthio-3,3-dimethyl-6,7-di-R-dihydroisoquinolines with carboxylic acid hydrazides gives the corresponding hydrazides converted into derivatives of 1,2,4-triazolo[3,4-alisoquinoline. Reaction of these dihydroisoquinolines with hydrazine hydrate gives the corresponding 1-hydrazinoderivatives which with NaNO2 give tetrazolo[5,1-aisoquinolines, and with oxalyl chloride (where R = H), 1,2,4-triazino[5,1-aJisoquinoline.

Synthesis, antiaggregational and hypotensive activity of some isoquinolines

It has been reported [3, 4, 8] that compounds containing the isoquinoline ring show high antiaggregational activity with respect to thrombocytes, but the pharmacological activity of these compounds is low, being no greater than that of papaverine. It was therefore of interest to carry out a further search for novel isoquinolines in order to establish structure-activity relationships. Hypotensive activity is a classical feature of isoquinolines [7]. It would be particularly useful if antiaggregational and hypotensive activity, for example, were possessed by the same compound. The aim of the present investigation was to identify such compounds. With this in mind, some novel isoquinolines have been synthesized, in which the sub-

Reaction of dichlorocarbene with substituted 3,4-dihydroisoquinolines and 1-methylene-1,2,3,4-tetrahydroisoquinolines

Reaction of dichlorocarbene with 3,3-dialkyl-3,4-dihydroisoquinolines results in the formation of gemdichloroazirino[2,1-a]isoquinolines, which are in turn converted to 3-benzazepinones upon hydrolysis. Reaction of dichlorocarbene with the ethyl ester or amide of (3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-ylidene)acetic acid is accompanied by rearrangement of the intermediate carbene adducts at the enamine C=C bond and results in the formation of a 1-azadiene, 3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-3-chloroacrylic acid ethyl ester, and a spirolactam, 3,3-dimethyl-3-chlorospiro[1,2,3,4-tetrahydroisoquinoline-1,2′-pyrrole]-5′(2′H)-one, respectively.

Synthesis and spasmolytic activity of hydrogenated derivatives of 3,3-dimethylisoquinoline

The structure of compounds III-X was confirmed by PMRand IR-spectroscopic data. The enamine structure of the bases III-V was confirmed by the presence of vinyl proton singlets in the PMII spectrum (4.85-5.07 ppm) and singlets of the associated NH-ring proton (9.80-10.92 ppm) which upon the addition of CF~COOH shifted to the weak field by 4-5 ppm. The IR-spectra of bases III-X were recorded in CHCI3 at a concentration of 0.01 M. The bands of the C=O and NH groups were broadened and shifted to the long wave region (1615-1630 and 3150-3200 cm -z respectively) which confirms the presence of an internal molecular hydrogen bond (IMHB) between the CO oxygen group and the proton of the NH-ring. The 1640-1650 cm -: region exhibited a C=C conjugation bond band that was weaker than the carbonyl [5]. The PMR-spectra of the basis VI-X, in contrast to the enamines III-V lack vinyl proton and NH-cycle proton signals, but have a multiplet CH2 group on the first carbon atom of the isoquinoline ring. In contrast to the enamines Ill-V, the IR-spectrum of the bases VI-X lack NH-ring bands, but do have C=N bands (1635-1640 cm-~). Thus, in contrast to the amides Ill-V, the bases VI-X are characterized by an azomethine form. The existence of compounds III-V in an enamine form is due to the fact tha= this form is stabilized by an acceptoramide substitutent and the IMHB. In the case of the VI-X amines stabilization is lacking so they exist in the azomethine form.