I. P. Skrastin'sh

Bromination of 4-aryl-3,5-dialkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines

Abstract4-Aryl-3,5-dialkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines are brominated by N-bromosuccinimide in methanol at room temperature at the methyl groups at positions 2 and 6 to form mono-, di-, tri-, and tetrabromo derivatives. When the N-unsubstituted bromomethyl-1,4-dihydropyridines are heated they are easily converted to tetrahydrofuropyridines, but in the case of the analogous N-substituted-1,4-dihydropyridines cyclization does not occur. The 2,6-bis(bromomethyl)-substituted products easily replace bromine under the influence of nucleophilic reagents.

Cardiovascular activity of difuropyridines

The UV spectra of compounds I-VI possess an absorption maximum around 320 nm. In the IR spectra the stretching vibrations of the CO group of the lactone ring are observed in the region of 1741-1764 hm. The PMR spectra also confirm the structure of comounds I-VI. The signals of the methylene protons give a singlet at 4.87-5.02 ppm. The spectral characteristics of compounds I-VI are analogous to those for difuropyridines that we synthesized previously [I].

Some substitution and heterocyclization reactions based on 1,4-dihydropyridines

Data on the bromination, chlorination, and bromolactonization of 4-aryl-1,4-dihydropyridines are correlated. The reactions of the products of bromination of 4-aryl-1,4-dihydropyridines with various nucleophilic agents (amines and iodide, azide, and thiocyanate ions) and reactions involving the heterocyclization of the products of substitution of the 2,6-methyl groups of 4-aryl-1,4-dihydropyridines, which lead to condensed furo-, difuro-, pyrrolo-, dipyrrolo-, furopyrrolo-, and furothiazolopyridines and thiazolopyridothiadiazines are examined.

Reactions of N-chlorosuccinimide with 4-phenyl-1,4-dihydropyridines

The action was studied of N-chlorosuccinimide on 2,6-dimethyl-3,5-dialkoxycarbonyl-4-phenyl-1,4-dihydropyridines. 3,4,5,6-Tetrahydropyridines having various degrees of chlorination were obtained according to the ratio between the reagents.

Nitration of 3,5-dicarbonyl derivatives of 4-phenyl-1,4-dihydropyridine

The nitration of the phenyl ring of 4-phenyl-1,4-dihydropyridines with retention of the 1,4-dihydropyridine structure was accomplished.

Cardiovascular activity of amino derivatives of foridon

To search for new cardiovascular agents in the 1,4-dihydropyridine series, we synthesized previously unknown 2,6-disubstituted 1,4-dihydropyridines (Ilia-g) -analogs of the cardiovascular drug foridon (I) [1]. It was shown earlier [2-4] that the halogen atom in the products ofbromination of the 2,6-methyl groups of 1,4-dihydropyridines enters into nucleophilic substitution reactions with the formation of 2,6-disubstituted 1,4-dihydropyridines. In the bromination of foridon by N-bromosuccinimide (NBS) in methanol at room temperature, 2,6-dibromomethyl-3,5dimethoxycarbonyl-4-(2-difluoromethoxyphenyl)-l,4-dihydropyridine (II) was obtained [4]. The latter, in reaction with primary and secondary amines, as well as with NaN, gives substitution products (Ilia-e, h). In the reaction of II with pyridine and thiourea, substitution products are isolated in the form of salts (IIIf, g).

Synthesis and pharmacological activity of silicon-containing 1,4-dihydropyridines

Highly active cardiovascular preparations are to be found among the 4-aryl derivatives of 1,4-dihydropyridine [i, 3, 5] and 4-furyl-l,4-dihydropyridines exhibiting hypotensive and coronary dilatation activity have been synthesized [2, 6]. There are also reports describing 1,4-dihydropyridines containing silicon in the 3,5-substituents of the 1,4-dihydropyridine ring [4, 7, 8]. Nevertheless, the cardiovascular activity of these compounds is appreciably lower than that of the well-known 1,4-dihydropyridine preparation nifedipine [9].

Synthesis and cardiovascular activity of 2-methyl-5-oxo-1,4-dihydroindeno[l,2-b]pyridines

Compounds I-VIII were prepared by condensation of 2-arylidene-l,3-indandiones with derivatives of t3-aminocrotonic acid in acetic acid with short heating according to [3] (Table 1). The structure of the compounds was determined with UV, IR, and PMR spectroscopy. UV spectra of I-VIII are similar to spectra of compounds that have been prepared earlier [1, 2]; the long-wave absorption maximum is found in the region 469487 nm. In IR spectra the position of the absorption bands of the CO and NH groups corresponds with published data [1, 2] (1691-1713 and 3291-3200 cm -1, respectively). The vibration band of the CN group is found at about 2200 cm -1 (for compounds VII and VIII).

Effect of 1,4-dihydropyridine derivatives on the cardiovascular system

Almost no vasoselectivity was exhibited by the first cardiovascular preparations of the 1,4-dihydropyridine series. Alterations in their structure resulted in the synthesis of calcium channel blockers such as intrendipine [I], nimodipine [2], and nicardipine [3] which primarily act upon peripheral vessels. Recent searches for compounds exhibiting pronounced selectivity resulted in the synthesis of 1,4-dihydropyridines which contain halide methyl groups in position 2 [4-7]. Some of these compounds exhibit a high degree of selectivity [6] or more extended activity [7]. There are data that show that halide derivatives of intrendipine exhibit less negative inotropic action, although in some cases their vasodilatory action is even greater than in nitrendipine [8].

Synthesis and pharmacological activity of analogs of the hypotensive drug Foridon

The synthesized 1,4-dihydropyridines are colorless crystalline substances: Compounds le-g have a yellowish color. The UV spectra exhibit two absorption maxima, at 240 and 350-370 ran. The introduction of an amide group into position 5 (Id) induced a hypsochromic shift of the longwave absorption maximum (A ~ 15 nm) in comparison to the complex ester group. Replacement of the oxygen atom by a sulfur atom in the aryl substituent (le-g) results in a certain bathochromic shift of the longwave maximum which diminishes as the lengths of the alkyl groups in positions 3 and 5 increaser