Pyridazine Derivatives, VI. Synthesis and Hypotensive Activity of 3‐Hydrazinethieno(2,3‐h)Cinnoline and its Derivatives

Abstract

The preparation of new 3-hydrazinothieno(2,3-h)cinnolines is described togehter with their hypotensive effects in normotensive rats.Pyridazinderivate, 6. Mitt.: Synthese und antihypertensive Eigenschaften von 3-Hydrazinthieno(2,3-h)cinnolinen und ihrer Derivate Es werden die Darstellungen neuer 3-Hydrazinothieneo-(2,3-h)-cinnoline and ihrer Derivate sowie die bei der Untersuchung ihrer antihypertensiven Eigenschaften bei Normaldruckratten erhaltenen Ergebnisse beschrieben.Hydrazinephthalazines, discovered by Druey and Gross') in 1950, are drugs used clinically as antihypertensives, the most important being hyIt is nevertheless striking that few of the hydrazinepyridazincs investigated have thiophene substituted phenyl rings with the same isosterism as benzothiophene? As part of a more extensive study of the influence of such isosterism on the antihypertensive activity of hydrazinepyridazines, we report here the synthesis and hypotensive activity of 3-hydrazinethieno(2,3-h)cinnoline 8 and some of its derivatives. dralazine (Ia) (Apresoline) and dihydralazine (Ib) (Nepresol).Structure-activity studies have found significant antihypertensive activity to be exhibited by a number of related hydrazinepyridazines, and this group of compounds continues to be an object of prospection for new drugs with greater activity and fewer side-effects (the most serious of the latter being an increase in heart rate). In this laboratory, for example, we have synthesized series of hydrazinepyridazines based on 6-phenyl-5-aminomethyl-3-hydrazinepyridazine (II)z, 6-phenyl-5-amino-3-hydrazinepyridazine (III)3, 6-phenylamino-3-hydrazinepyridazine (IVY and 3-hydrazine-5,6-dihydrobenzo(h)cinnoline (VF, most of which proved to have considerable antihypertensive properties. IV Chemistry StrategyThe target compound 8 was prepared in three stages comprising 1) the preparation of the cycloalcanone 3,2) the addition of an acetic acid group to C-5 of 3, and 3) the formation of the pyridazine ring and subsequent introduction of the hydrazine group. 1) Preparation of cycloalcanone 3.A Friedel-Crafts reaction between thiophene and succinic anhydride with aluminium trichloride as catalyst afforded the acid 1, whose reduction in diethyleneglycol by hydrazine hydrate (Huang-Minlon procedure) gave the acid 2. This acid was finally cycliced to 3 following Nishimura et al.'), which consits in warming a solution of2 in acetic anhydride to 120-130 "C 'with a catalytic amount of 85 % phosphoric acid. 2) Addition of an acetic acid group to C-5 of 3.Two methods were used: a) reaction of 3 with glyoxylic acid generated in situ lo) afforded the hydroxyacid 4a; and b) alkylation of 3 with ethyl bromacetate in the presence of lithium di-isopropylamide afforded 4b in 45 % yield.3) Formation of the pyridazine ring and addition of hydrazine.A four stage process was employed: a) 4a and 4b were refluxed with hydrazine hydrate in ethanol to give the cor-

Stereoselective Aza Diels−Alder Reaction on Solid Phase: A Facile Synthesis of Hexahydrocinnoline Derivatives

“…Cinoxacin is a synthetic antimicrobial agent related to oxolinic and nalidixic acids and is used to treat urinary tract infections . Certain cinnoline-related compounds are useful as antianxiety and antihypertensive agents . Recently, two groups have demonstrated the usefulness of the epoxyquinol scaffold in the synthesis of a structurally diverse chemical library. , Some members of these libraries (Figure ), structurally similar to our hexahydro-1,2,4-triazolocinnoline-3,5-diones, inhibit the growth of human small-cell lung carcinoma (A549) and induction of heatshock protein (HSP 72).…”

Pyridazine Derivatives. 32: Stille-Based Approaches in the Synthesis of 5-Substituted-6-phenyl-3(2H)-pyridazinones.

“…Many of the pyridazines and 6-aryl-3(2H)-pyridazinones obtained in our laboratory during this period show antihypertensive action [8][9][10] or platelet inhibitory activity. [11][12][13] Of particular interest are our systematic studies on 5-substituted-3(2H)-pyridazinones, which have led to the development of new potent platelet antiaggregation agents.…”

Synthesis of New Ring Systems: Isomeric 1,2,4-Triazolopyrimido [4″,5″:4′,5′]thieno[3′,2′:5,6]pyrido[3,2c]cinnolines and Other Related Systems

“…IR, 1720 (CO) cm −1 . 1 ice/water. The precipitate was filtered, washed with water, and recrystallized from acetic acid as brown crystals, m.p.…”

“…IR, 3300 (NH 2 ), 3190 (NH), 1630 (C N) cm −1 . 1 (6) A mixture of 5 (0.001 mol) and triethylorthoformate (10 ml) in acetic acid (20 ml) was refluxed for 5 h. The precipitate was filtered and recrystallized from acetic acid as yellow crystals, m.p. > 360 • C, yield (70%).…”