Synthesis of novel pyrazolopyrrolopyrazines is herein described with the aim to reach new specific PDE-5 inhibitors of potential clinical interest in male erectile dysfunction.J. Heterocyclic Chem., 38, 1045Chem., 38, (2001.Sildenafil [1] (1, VIAGRA®, Scheme 1) is a potent inhibitor of phosphodiesterase type 5 (PDE 5) [2] whose effectiveness in treating male erectile dysfunction was recently discovered. PDE5 is the primary cGMP hydrolyzing enzyme present in the corpus cavernosal smooth muscle of the penis. Upon sexual stimulation, nitric oxyde (NO) is released and activates guanylyl cyclase which produces cGMP [3]. The latter initiates a protein phosphorylation cascade that causes a decrease in intracellular calcium, resulting in vasorelaxation. Inhibition of PDE5 by sildenafil elevates levels of cGMP and hence leads to an improved erection. Despite the efficacy of 1, clinically notable adverse effects such as headache, nausea, cutaneous flushing and visual disturbance [4,5] have been noted with its use and attributed to its limited selectivity against other PDE enzymes. Thus, with the aim to reach more selective PDE5 inhibitors, devoid of such side effects, this paper describes the access to new Sildenafil analogs 2, belonging to the pyrrolopyrazine series, which were prepared in order to study the replacement of the pyrimidone moiety with a pyridopyrazine system.Compounds 2 were prepared according to a PictetSpengler-type reaction [6] starting from various 4-amino-5-pyrrolylpyrazoles 3 substituted or not in the 3-position.The unsubstituted ones were synthesized according to the following sequence (Scheme 2). Treatment of ethyl (ethoxymethylene)cyanoacetate with an appropriate N-substituted hydrazine yielded the expected ethyl 5-aminopyrazole-4-carboxylates [7,8] 4a-c. Compounds 4a-c, involved in a Clauson-Kaas reaction [9,10,11], followed by an alkaline hydrolysis, led to the 5-pyrrolylpyrazole-4-carboxylic acids 6a-c [11]. The latter were converted into the acyl azides 7a-c before being submitted to a Weinstock-Curtius rearrangement [12] in a refluxing aqueous hydrochloric acid solution. The sequence afforded finally the hydrochloric acid salts of the attempted 1-methyl-, 1-ethyl-and 1-(4-methoxyphenyl)-4-amino-5-pyrrolylpyrazoles 3a-c, with overall yields of 17%, 67% and 31% respectively from 4a-c.Access to the more closely related analog of Sildenafil 2d required the preparation of 1-methyl-3-propyl-4-amino-5-(pyrrol-1-yl)pyrazole 3d (Scheme 3). The latter was synthesized according to another pathway [13] starting from diethyloxalate and pentan-2-one that were reacted together in the presence of sodium to give the diketoester 8, under its enolic form. Treatment of 8 with methylhydrazine produced a mixture of the suitably substituted pyrazole derivative 9 and of its isomer 9a (60/40). The saponification in an alkaline medium led to a mixture of the carboxylic acids 10 and 10a, from which 10 was isolated by fractional crystallization. The subsequent nitration of the pyrazole ring of 10 yielded the nitro der...
