B. Ya. Syropyatov

Synthesis and biological activity of amides and nitriles of 2-arylamino-5-carboxy(carbethoxy)-6-methylnicotinic acids and 1-aryl-6-carbethoxy-7-methyl-4-oxo-1,4-dihydropyrido[2,3-d]pyrimidines

of diester (VIII) to considerably increase the locomotive activity and to improve the preservation of CRPA in rats. Further examination of the distinct antagonism of diester (XIII) to corazole is required, which makes it possible to assume that this compound has anticonvulsive properties, possibly as a result of antagonism to Glu. We may assume that the differences in the pharmacological properties of diesters (VIII-XIII) are connected with the different rate of generating Glu from them under influence of blood enzymes.

Substituted Amides and Hydrazides of Dicarboxylic Acids. Part 14. Synthesis and Antimicrobial and Antiinflammatory Activity of 4-Antipyrylamides, 2-Thiazolylamides, and 1-Triazolylamides of Some Dicarboxylic Acids

In continuation of our search for new biologically active substances among substituted amides of dicarboxylic acids [1], we have synthesized a series of 4-antipyrylamides, 2-thiazolylamides, and 1-triazolylamides of succinic (Ia – Ic), maleic (IIa – IIc), citraconic (IIIa – IIIc), and phthalic (IVa – IVc) acids. Compounds I – IV were obtained by acylating the corresponding dicarboxylic acid heterylamides with succinic, maleic, citraconic, or phthalic anhydrides under mild conditions using the well-known procedure described previously [2]. The proposed structures of the synthesized compounds were confirmed by the results of spectroscopic measurements (Table 1).

Synthesis and antiaggregant and hypotensive activity of benzo-annelated azabicyclo[m.n.0]alkanes

Three-component condensation of veratrole, isobutylene oxide, and aliphatic ω-chloronitriles via the Ritter reaction leads to 1-(ω-chloroalkyl)-6,7-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinolines, the reduction of which with NaBH4 yields benzoannelated azabicyclo[m.n.0]alkanes. The synthesized compounds have been tested for hypotensive and antiaggregant activity.

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%.

Synthesis of 1-aroylmethyl-and 1-aryloxymethyl-3,4-dihydroisoquinolines and their effects on blood clotting

Acylation of a number of tertiary enamines with aroylchlorides was used to synthesize 1-aroylmethyl-3,4-dihydroisoquinolines. Reaction of 1-chloromethyl-3,3-dimethyl-3,4-dihydroisoquinoline with phenols with interphase catalysis was also used to make 1-aryloxymethyl-3,4-dihydroisoquinoline derivatives. 1-Aroylmethylisoquinolines characteristically had a hemostatic effect, while 1-aryloxymethyl-3,4-dihydroisoquinolines had an anticoagulant effect. The most active compound increased blood clotting by 17.7%.

Synthesis and anticoagulant activity of 1-aryl derivatives of tetrahydroisoquinolines

A series of 1-aryl-3,3-dimethyl-3,4-dihydroisoquinolines were obtained by three-component (one-pot) condensation of veratrole, isobutylene oxide, and aromatic nitriles and then reduced to the corresponding 1,2,3,4-tetrahydroisoquinolines. Hydrochlorides of the synthesized compounds were tested for anticoagulant activity.

Substituted Amides and Hydrazides of Dicarboxylic Acids. Part 9. Pharmacological Activity of the Products of Interaction of 2-Aminopyridines and 2-Aminopyrimidine with Dicarboxylic Acid Anhydrides

There is evidence that some heterylamides of maleic, citraconic, succinic, and phthalic acids, obtained by acylating certain heterocyclic amines with the corresponding acid anhydrides, possess hypoand hypertensive, hypoand hyperglycemic, analgesic, antiinflammatory, and antibacterial properties [1 – 10]. At the same time, the pharmacological activity of pyridyland pyrimidylamides of dicarboxylic acids was insufficiently studied. It was reported almost half a century ago [11] that the interaction of 2-aminopyridine with citraconic acid anhydride yields the corresponding 2-pyridylamide, but this structure was not confirmed by spectroscopic data. Later [12 – 15], it was unambiguously established that 2-aminopyridines can be acylated by interaction with esters and chloroanhydrides of unsaturated carboxylic acids, leading to the formation of oxo derivatives of pyrido[1,2-a]pyrimidine. The reactions of 2-aminopyrimidine and its derivatives with electron-deficient alkenes (in particular, with dicarboxylic acid anhydrides) possessing two vicinal carbonyl groups were not studied in detail (only the aforementioned paper [11] is available, which presented insufficiently convincing data). In this context, we studied the interaction of 2-aminopyridine, 2-amino-5-bromopyridine, and 2-amino-4-picoline with citraconic anhydride (see Scheme 1). The reaction proceeded in ethyl acetate at room temperature and was accompanied by instantaneous crystallization of the products (Ia – Ic). The structures of these compounds were established based on spectroscopic data. I – III: R = R = H (a); R = H, R = Br (b); R = CH3, R 2 = H (c). The H NMR spectra of the reaction products contained a clear signal due to diastereotopic geminal protons of the 3-CH 2 methylene group, representing two doublets of the AB-system in the regions of 2.89 – 2.97 and 3.21 – 3.27 ppm (J 2 = 18.0 – 19.0 Hz). This fact, in the absence of a signal due to amide NH groups, was indicative of the formation of 4-methyl-2-oxo-3,4-dihydropyrido[1,2-a]pyrimidine-4-carboxylic acids (Ia – Ic) rather than pyridylamides of citraconic acid (which could be expected based on the data from [11]). Moreover, the presence of the characteristic signal due to the 3-CH 2 group allowed us to reject the possible isomer structure of 3-methyl-2-oxo-3,4-dihydropyrido[1,2-a]pyrimidine4-carboxylic acids (II, Scheme 1). The structure of compounds Ia – Ic indicates that the acylation reaction (proceeding at the amino group of 2-aminopyridine) involves the lactone carbonyl group re-

Substituted Amides and Hydrazides of Dicarboxylic Acids. Part 17. Synthesis and Antibacterial and Anticonvulsant Activity of Some Amides and Acylhydrazides of Phthalic Acid

Previously, we have reported on a series of substituted amides and acylhydrazides of phthalic acid possessing hypertensive [2] and hypoglycemic [3, 4] activity. We have studied a series of substituted monoamides and acylhydrazides of phthalic acid (I – XI) that can be also of interest as potential antibacterial agents [5, 6] and anticonvulsants [7 – 12]. Compounds I – XI were obtained by acylating the corresponding substituted amines and hydrazides of carboxylic acids with phthalic anhydride under mild conditions using the well-known procedure [2 – 4]. The proposed structures of the newly synthesized compounds were confirmed by spectroscopic data (Table 1).

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 Analgesic Activity of N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides

A three-component reaction of acetoacetanilides with a mixture of an aromatic aldehyde and thiourea was used to synthesize previously unknown N,6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides, which had high analgesic activity and low acute toxicity.