Synthesis of some piperazinylpyrazolo[3,4‐b]pyridines as selective serotonin re‐uptake inhibitors

Abstract

A number of 3‐substituted 6‐piperazinylpyrazolo[3,4‐b]pyridines were synthesized from 2,6‐difluoropyridine by directed ortho metallation and sequential intra‐ and intermolecular displacement of fluorine. Three derivatives with a cyano group in the 3‐position showed activity as selective serotonin re‐uptake inhibitors.

Discovery of Riociguat (BAY 63‐2521): A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension

“…Our continuous efforts to optimize the unfavorable DMPK profile of previous sGC stimulators led to the identification of riociguat (20). Its pharmacodynamic and pharmacokinetic properties suggest that riociguat may offer a unique mode of action for the treatment of PH by inducing pulmonary vasodilation and thus decreasing the workload of the right heart.…”

“…Herein we describe our efforts to optimize the drug metabolism and pharmacokinetic (DMPK) profile of our sGC stimulators by an extended SAR exploration of the pyrimidine region, leading to the identification of riociguat (20), which is currently in advanced clinical development for the treatment of PH.…”

“…Riociguat (20) demonstrated a favorable safety profile and was well tolerated in healthy volunteers [15] and in patients with PH. [16] Orally administered riociguat was efficacious in a proof-of-concept study of patients with PH, decreasing pulmonary vascular resistance and increasing cardiac output to a significantly greater extent than inhaled NO at doses of 1 and 2.5 mg. [15] Neither dose produced any deterioration in gas exchange, indicating that ventilation/perfusion matching was maintained.…”

“…Subsequent cyclocondensation of the crude product with 3-dimethylaminoacrolein gave pyrazolopyridine 27 in 50 % overall yield. In the following highyielding steps the carboxylic ester moiety was transformed into the corresponding nitrile via classical amide formation and dehydration under standard conditions with trifluoroacetic acid anhydride, [20] providing compound 29. Subsequent Pinner reaction of the cyano group with sodium methanolate and substitution with ammonia gave access to amidine 23 in a total 35 % yield over five steps.…”

“…[16] Orally administered riociguat was efficacious in a proof-of-concept study of patients with PH, decreasing pulmonary vascular resistance and increasing cardiac output to a significantly greater extent than inhaled NO at doses of 1 and 2.5 mg. [15] Neither dose produced any deterioration in gas exchange, indicating that ventilation/perfusion matching was maintained. In a phase II study, riociguat (20) exerted strong effects on pulmonary hemodynamics and exercise capacity in subjects with the PH subforms of pulmonary arterial hypertension and chronic thromboembolic PH. [17] Syntheses Retrosynthetic analysis of scaffolds A, B, and C with none, one, or two amino groups as pyrimidine substituents, respectively, revealed amidine 23 as common precursor (Figure 4).…”