Vasodilators pyridazines

Dimethyl-l,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (41) is also an old product [7,11, 31] that has recently been found to react with GSH to give S-nitrosogluta-thione, NO and HNO [32]. It stimulates partially purified rat lung soluble guanylate cyclase, but not the heme-deficient enzyme. The activation is inhibited by ODQ. The product also displays significant vasodilator activity on rat thoracic aorta rings at nanomolar concentrations. Finally, [l,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide derivatives (42, R,Ri=CH3,H) release NO, detected as nitrite, in the presence of thiols. A mechanism for this release has been proposed [33]. 

A variety of tricylic compounds [indenopyridazinones (19)] have been prepared as rigid structural modifications of compounds like CI-930 (16) [28,29]. Most of them have been found to retain the positive inotropic and direct vasodilator activity of the freely rotating pyridazinones [28]. Also, hydrazinopyridazines of type (20) have been investigated as structural analogues of CI-914 and Cl-930, respectively. Whereas considerable inotropic activity has been observed in this series as well, ring closure to triazolo[4,3-h]pyridazines resulted in significantly less potent compounds [30]. 

In Japan, a variety of heterocyclylaminophenylpyridazinones as represented by the general formula (29) have been prepared and investigated [89-92]. Structure-activity relationships have been discussed [92] additional classes of compounds in which the heterocyclic substituent is separated from the aminophenyl ring by a carbon chain have been patented [93,94]. From these studies, a novel class of pyridazine-derived cardiotonics and vasodilators has emerged. 

Most of the cardiotonic pyridazine derivatives discussed in the preceding chapter also exhibit vasodilator effects. In addition, various dihydropyrida-zine derivatives like (52), structurally closely related to calcium-antagonistic Hantzsch-type dihydroypyridines, have been patented as coronary vasodilators [169-171]. Another type of pyridazine analogue of the previously mentioned dihydropyridines, namely compounds of type (53), in which the aryl substituent at C-4 is represented by a pyridazine nucleus, has been claimed in a patent [172]. Quite recently, pyridazinyldihydropyridine-3,5-dicarboxyl-ates (54,55) have been prepared in Austria [173]. 

There are numerous patents claiming 3-hydrazinopyridazine derivatives with amino-substituted alkoxy side-chains at C-6 as ff-blocking vasodilating agents [188,286-293]. Other 3-hydrazinopyridazine-derived antihypertensive agents are covered by patents [294-301], or described in the literature [302 306]. It should be noted that with structurally very simple hydrazino-pyridazines like 6-hydrazino-3-pyridazinecarboxamide (hydracarbazine, 2105 TH CAS 3164-47-9), antihypertensive activity has been observed. 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

Combined treatment is necessary in the long-term treatment of essential hypertension. p-Blocker and diuretic properties in a same molecule would present a great interest for hypertension management. Few attempts to synthesize hybrid molecules by combining the structures of a p-adrenoreceptor antagonist and a diuretic were described (Fig. 16.34). A hybrid sulfonamide was achieved by linking the (3-blocker propranolol derivative with the 2-chloroben-zene sulfonamide moiety of mefruside. In prizidilol a typical hydrazino pyridazine core, known for its vasodilator property, is combined with propanolol, leading to a dual vasodilator/(3-blocker. ... 

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