Quinazoline cardiovascular agents (review)

Abstract

The chemistry of quinazoline compounds has a more than centuries-old history; however, the intensive search for biologically active substances in this series began only in the last few decades. The establishment of the quinazoline structure of the antimalarial alkaloid febrifugine [i], which was isolated from the Chinese plant aseru (Dichroa febrifuga Lout.), and the synthesis and study of its analogs [2-4], as well as quinazoline derivatives of the antimalarial quinoline and pyrimidine medicinal preparations [5-7] and azo compounds with chemotherapeutic action [8, 9], have served as an impetus for the initiation of the indicated studies. Earlier research in the nineteen fifties and sixties revealed the effectiveness in experiments of synthetic quinazolines not only with respect to malaria inducers but also in diseases induced by other protozoa [8, I0], as well as bacteria [9, ii] and viruses [12]. An important stage in the development of research on the biological activity of quinazoline compounds was the discovery of the considerable soporific and sedative action of 2methyl-3-aryl-4-quinazolone derivatives [13-16]. Synthesized on the basis of general concepts of the structure of analgesics far which the presence of a tertiary nitrogen atom and a quaternary carbon atom in the B position relative to it is characteristic [17], these substances [18] stimulated an extensive search for pharmacologically active quinazoline compounds. In the last 10-15 yr the search for quinazoline medieinals has been characterized by significant advances. Whereas only two quinazoline preparations, viz., the soporific and anticonvulsive agent methaqualone [2-methyl-3-(o-methylphenyl)-4-quinazolone] and the diuretic quinethazone (6-sulfamido-7-chloro-l,2,3,4-tetrahydro-4-quinazolone) [19], were used in medical practice in 1968, 50 quinazoline derivatives were being used in medicine in 1980 [20]. The preparations of this chemical class include medicinals with the most diverse types of biological action, viz., soporific, sedative, tranquilizing, analgesic, anticonvulsant, antitussive, myorelaxant, antirheumatic, hypotensive, antiallergic, bronehodilating~ antidiabetic, oholagogue, diuretic, cytostatic, antimalarial, spermatoeidal, etc. [20, 21]. A broad spectrum of chemotherapeutic activity (antiprotozoal, antifungal, antibacterial, and antivirus) in conjunction with anti-inflammatory action has been observed for 2-styryl-4aminoquinazoline derivatives [22-27]. The advances in the search for biologically active quinazoline compounds and medicinal preparations created on the basis of them have been reflected in several hundred patents that have been published in this period (see a previous review [28]) and in a large number of original papers and series of published reviews [4, 19, 20, 28-31]. Unfortunately, because of the volume and diversity of the general material on biologically active quinazoline compounds~ the more specific problem of the investigation of quinazoline cardiovascular agents has not been sufficiently completely reflected in these reviews. This served as the basis for the selection and correlation of the data on this important problem. Medicinal preparations that lower the arterial pressure [32, 33] occupy an important position among cardiovascular agents. In series of quinazoline derivatives the search for substances of this type was begun after the detection in the course of pharmacological screening of the hypotensive activity of 4-quinazolones that have a glycine amide or 8-alanine amide residue in the 3 position [34]. Unsubstituted 4-quinazolone and its derivatives with various substituents in the I, 2, and 3 positions and in the benzene fragment of the molecules have also been studied to determine the relationship between the structure and the biological activity in the indicated direction [35]. Most of the tested substances in the case