A. G. Mikhailovskii

Acylation reaction of the 3,3-dimethylisoquinoline series enaminonitrile and properties of 5,5-dimethyl- 2,3-dioxo-2,3,5,6-tetrahydropyrrolo[2,1-a]isoquinoline- 1-carbonitrile

2-(3,3-Dimethyl-3,4-dihydro-2H-isoquinolin-1-ylidene)acetonitrile containing an enamine fragment has been acylated using acetyl or benzoyl chlorides to give the corresponding enamino ketones. The acylation using oxalyl chloride gives 5,5-dimethyl-2,3-dioxo-2,3,5,6-tetrahydropyrrolo[2,1-a]-isoquinoline-1-carbonitrile. Reaction of the latter with guanidine carbonate or o-phenylenediamine is accompanied by opening of the pyrrole ring and heterocyclization to give the corresponding 2-amino-4-imidazolone and 2-quinoxalone derivatives. Linear amines were formed in similar reactions with m-toluidine, 1-aminoadamantane, o-aminophenol, and 2-amino-3-hydroxypyridine.

Synthesis of 2-(3,3-dimethyl-3,4-dihydroisoquinol-1-yl)propanoic acid amides and their influence on blood coagulation

A series of new 2-(3,3-dimethyl-3,4-dihydroisoquinol-1-yl)propanoic acid amides have been synthesized using the reaction of methyliodide with 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-idene)ethanamides that proceeds on the β-atom of the enamine fragment to form iodides of 2-(isoquinol-1-yl)propanoic acid derivatives. Investigation of the influence of the synthesized compounds on blood coagulation showed that all of them are hemostatics. The most active compounds possess radicals such as morpholine and 2-(3,4-dimethoxyphenyl)ethylamine, are not substituted at the amide fragment, and decrease the blood coagulation time by 14–16%.

Enamines of the 1,2,3,4-tetrahydroiso-quinoline series in the Chichibabin synthesis of pyrrolo[2,1-a]isoquinolines and in reaction with oxalyl chloride

It has been shown that the Chichibabin reaction of enamines of the 1,2,3,4-tetrahydroisoquinoline series and 1,2,3,4-tetrahydrobenzo[f]isoquinoline series with p-bromophenacyl bromide leads to pyrrolo[2,1-a]isoquinoline derivatives. The same heterocyclic system is obtained on interaction of 1-alkyl-3,4-dihydroisoquinolines or their benzo[f]-analogs with oxalyl chloride. The obtained dioxopyrrolines form derivatives of benzo[g]quinoxalino[2,3-b]indolizine on condensation with o-phenylenediamine.

Chloromethyl and Aryloxymethyl 3,4-Dihydroisoquinoline Derivatives: Synthesis and Study of Antiaggregant and Antihypoxant Properties

Previously we studied a series of isoquinoline derivatives exhibiting antiaggregant effect with respect to thrombocytes [1 – 5] and possessing hypotensive properties [6 – 8]. At the same time, derivatives of 1-chloromethylisoquinoline [9 – 11] are still not characterized with respect to pharmacological activity. To our knowledge, the properties of 1-methylisoquinoline esters were also never reported in the literature. When the ester residue represents an aromatic or benzyl fragment, such molecules differ from papaverine by the presence of an oxygen bridge. In this context, it was of interest to compare the pharmacological properties of these esters and papaverine. The aim of our study was to determine the effect of 1-chloromethyl-3,4-dihydroisoquinolines (II) and benzo[f]isoquinoline esters (IV) on the thrombocyte aggregation and arterial pressure in experimental animals. The latter compounds were selected as objects for the investigation because previously we observed a pronounced hypotensive activity in benzo[f]isoquinoline derivatives [7, 8]. The series of chloromethylisoquinolines IIa – IIe was synthesized by means of the interaction of carbinols Ia – Ie with chloroacetonitrile under the Ritter cyclocondensation conditions [1 – 3, 7, 8]. Esters IVa – IVf were obtained via reactions of compound III, obtained previously by the same method [7], with alcohols and phenols under conditions of phase-transfer catalysis [12]. In particular, the interaction of III with benzyl alcohol to yield compound IVa (R = PhCH2) [12] proceeds in a KOH/benzene system and is catalyzed by 18-crown-6. The interaction between III and phenols, proceeding in a 50 % NaOH/CH2Cl2 system and catalyzed by tetrabutylammonium hydrosulfate, led to phenyl esters IVb – IVf. Data on the yields, structures (R–R), and properties of the synthesized compound are presented in Tables 1 – 3.

Synthesis and study of antiaggregative and hypotensive activity of 3,3-dialkyl- isoquinoline azomethines and their derivatives

Some representatives of the class of isoquinoline derivatives were reported to exhibit antiaggregative activity [I -6] . In addition, a number of I-substituted isoquinolines, such as l-benzylisoquinolines, produce a hypotensive action [7, 8]. Allyl radical is close to the benzyl radical with respect to many chemical properties [9]. Therefore, it was of interest to compare the antiaggregative and hypotensive properties of some isoquinoline derivatives containing benzyl or allyl residues in position 1. Reactions of carbinols I a I e with the corresponding substituted benzyl cyanides lead to compounds lIIa-IIIc. Compound lIla can be reduced by LiA1H4 to tetrahydroisoquinoline IV. Interactions of carbinols I a Ie with HCN lead to azomethines I Ia I Ie [10-12], which can be readily iodoalkylated to form salts Va, Vb and compounds Via, VIb and VIIa, VIIb [12]. In order to obtain the 1-allyl derivatives of isoquinoline, we have carried out allylboriding of the above azomethines. Similarly to the processes studied previously for compounds IIa and IIb [13], the reactions of compounds I Ic IIe with triallylborane proceed under mild conditions (20~ and lead to the corresponding 1-allyl-l,2,3,4tetrahydroisoquinolines VIIla-VIIIe. Alcohol IX was obtained using a hydroboriding-oxidation reaction described elsewhere [l 3]. Analogous syntheses were carried out using other carbinols (Xa and Xb) as the initial compounds. The subsequent allylboriding of the products of these reactions led to the corresponding benzo[fJisoquinoline derivatives (XIIa and XIIb). All the newly synthesized compounds (Table 1) were isolated and studied in the form of soluble salts. The substances obtained previously were tested in the form of hydroiodides (IIa, Va, Vb, VIIa, and VIlb) and hydrochlorides (otherwise).

Allylboration of isatin and 2,3-dioxopyrrolo[2,1-a]isoquinolines

The reaction of triallylboron with isatin and derivatives 2,3-dioxopyrrolo[2,1-a]isoquinolines at room temperature proceeds regiospecifically at the ketone group to give the corresponding homoallyl alcohol. One of these, which contains a lactam and an amide in its structure, was reduced with lithium tetrahydroaluminate to a diamine.

Synthesis of 2-(3-spiro-cyclohexyl-3,4-dihydroisoquinolyl-1)acetic acid derivatives and their effects on blood clotting

Cyclocondensation of the esters and amides of cyanoacetic acid with 1-spiro-cyclohexylcarbinols yielded derivatives of 2-(3-spiro-cyclohexyl-3,4-dihydroisoquinolyl-1)acetic acid containing and not containing methylenedioxo groups at positions 6,7. Compounds containing this group were found to increase blood clotting; those without it, conversely, decreased clotting. The most active compounds had effects comparable to those of ethamsylate and heparin.

Synthesis of 1-alkyl-3,4-dihydroisoquinoline derivatives and study of their effect on arterial pressure

A series of 1-alkyl-3,4-dihydroisoquinolines and the related 4-alkyl-1,2-dihydro-benzo[f]isoquinolines was synthesized using reactions of dialkylbenzylcarbinols and their naphthyl analogs with alkylcyanides. Experiments showed that 1-alkyl-6,7-dimethoxy-3,4-dihydroisoquinolines typically produce a hypotensive action, while the benzo-annelated structures usually exhibit a hypertensive effects. The most active compound decreases the arterial pressure in cats by 52 Torr and the effect lasts for about 4 hours.

SYNTHESIS AND STUDY OF THE ANTIAGGREGANT AND HYPOTENSIVE PROPERTIES OF N-BENZYL-3,3- DIMETHYL-1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES

As is known, N-benzyl-1,2,3,4-tetrahydroisoquinoline derivatives are capable of influencing the blood coagulation process [1, 2]; tiklyd, representing a thiophene analog of N-benzylisoquinoline, is a selective antiaggregant with respect to thrombocytes [3, 4]. While compounds of the 1-benzylisoquinoline series were reported to exhibit hypotensive properties [3 – 8], this activity was not studied for 2-benzylisoquinolines (i.e., N-derivatives of the heterocycle). A comparison between properties of the two groups of isoquinoline derivatives would elucidate the dependence of their pharmacological properties on the position of the benzyl radical in the molecule. N-Benzylisoquinolines (IIIa – IIIg) were synthesized via reduction of the corresponding amides (IIa – IIg) with lithium aluminum hydride. The initial amides were obtained via benzoylation of compound I in the presence of triethylamine [9]:

Synthesis and Analgesic Activity of 1-substituted 3-methyl-6-methoxy-7( n -butoxy)-3,4-dihydroisoquinolines

Cyclocondensation of O-butylated eugenol with various nitriles was used to synthesize 1-substituted derivatives of 3-methyl-6-methoxy-7-(n-butoxy)-3,4-dihydroisoquinoline. Hydrochlorides of the study compounds were tested for analgesic activity using the “hot plate” test. The experiments showed that the study compounds had analgesic effects greater than those of metamizole sodium and similar to those of ibuprofen.