4944 J. zyxwvutsrq Med. Chem. 1995,38, zyxwv 4944-4949 Notes The Furoxan System as a Useful Tool for Balancing “Hybrids”with Mixed al-Antagonist and NO-like Vasodilator Activities Roberta Fruttero, Donatella Boschi, Antonella Di Stilo, and Albert0 Gasco* Department zyxwvutsrqpo of “Scienza e Tecnologia del Farmaco”, Universita’ degli Studi di Torino, Facolta’ di Farmacia, Via P. Giuria 9, 10125 Torino, Italy Received March 16, 1995@ The design of new vasodilator derivatives in which two different pharmacophoric groups are present in a single molecule has been pursued by substitution of NO-prodrug furoxan moieties for the furanylcarbonyl function in Prazosin, a well-known al-receptor antagonist. The aim was to obtain new antihypertensive agents in which two vasodilation mechanisms, al-antagonist and NO-mediated, can operate in an appropriate balance. The al-antagonist activity was assessed on rat aortic strips in the presence and in the absence of oxyhemoglobin (HbOz), a well-known scavenger of nitric oxide. The resulting hybrids displayed different pharmacological behaviors. When the 4-furoxanylcarbonyl system, bearing an ester or an amide function at the 3-position, was present (derivatives 7a,b), hybrids with predominant al-antagonist activity were obtained. By contrast, in the derivative 7c, in which the nitrile function is linked to the 3-position of the furoxan ring, the NO-mediated vasodilating properties are predominant. Finally, the (furoxanylsulfony1)piperidine derivatives 13a,b showed NO vasodilation and a1- antagonist activities in an appropriate balance. For the furoxan derivatives, the NO-dependent vasodilating ability, assessed on the K+-depolarized aortic strip, and the NO release features under the action of thiol cofactors are also discussed. Introduction Recent results have shown that furoxan derivatives are able to activate the soluble guanylate cyclase by releasing nitric oxide under the action of thiol co- factor~.’-~ Since NO is involved in many bioregulatory processes,6the furoxan system 1 could be used in the design of a variety of “hybrid”molecules (Chart 1). We have recently synthesized the furoxans 3a-d, analogues of the Prazosin 2, in which the phenyl(or methy1)furoxanylcarbonyl system was substituted for the 2-furanylcarbonyl moiety’ (Chart 2). The aim was to obtain new vasodilators capable of displaying the typical NO-dependent effects on the micro- and macrovascular system, mixed with the al- antagonist activities. The vasodilating activity of these compounds was assessed on the epididymal portion of rat vas deferens, and the results showed that all of the hybrids were strongly (3b) or completely (3a,c,d) biased toward al-antagonist properties. In order to have better balanced hybrids, we have now changed the substitution pattern at the furoxan ring. In this paper, we report synthesis and vasodilating activities, assessed on rat aortic strips, of the Prazosin analogues 7a-c and 13a-c. We designed these com- pounds on the basis of the results of previous works on the vasodilating properties of series of furoxan deriva- tive~’,~ and their synthetic accessibility. By an iterative procedure, we characterized the derivatives 13a,b as two well-balanced hybrids. Chemistry Derivatives 7a-c were synthesized according to the pathway reported in Scheme 1. 4-Amino-6,7-dimethoxy- ~~ @ Abstract published in Advance ACS Abstracts, October 15, 1995. Chart 1 2 Chart 2 2-piperazinylquinazoline (6) was treated with the acti- vated ester 6, prepared in situ from 4, N-hydroxysuc- cinimide (NHS), and 1,3-dicyclohexylcarbodiimide (DCC), to afford the expected compound 7a. This derivative was transformed into zyxw 7b by ammonia. The amide function of 7b was easily dehydrated with trifluoroacetic anhydride (TFAA) in dry pyridine, giving 7c. Phenyl- furoxanylsulfonyl isomers 13a,b and the related furazan 13c were prepared according to the pathway reported in Scheme 2. The intermediates loa-c were obtained from 4-mercaptopiperidine and Sa, 9, and Sb, respec- tively, working in phase transfer conditions, using Aliquat 336. The compounds were oxidized, with 80% hydrogen peroxide in trifluoroacetic acid (TFA), to the corresponding sulfones 1 la-c, which, by reaction with 4-amino-2-chloro-6,7-dimethoxyquinazoline (121, af- forded the final products 13a-c. The latter reaction 0022-262319511838-4944$09.00/0 0 1995 American Chemical Society