Heterotricyclic systems. Part I. Synthesis of new dipyridopyrazines

Abstract

Pursuing our previous research on azaquinoxalinones (1,2‐dihydropyrido[2,3‐b]/[3,4‐b]pyrazinones) we prepared, through a reductive cyclization of N‐(3′‐nitropyridin‐2′‐yl)piperidine‐2‐carboxylic acids 3a‐c, a set of derivatives of a new tricyclic structure, 7,8,9,10‐tetrahydro‐5H‐dipyrido[1,2‐a:3′,2′‐e]pyrazin‐6(6aH)‐ones 4a‐c. Starting from these compounds we obtained substituted amides 5a‐c and, from 4a, the amidines 6a‐c. In the synthesis of 6, a dehydrogenation reaction occurred giving rise to 7. The compounds 9 and 10, characterized by a different ring‐fusion between the pyridine and pyrazine rings, were synthesized in a similar manner.

Synthesis of Kappa Opioid Antagonists Based On Pyrrolo[1,2-α]quinoxalinones Using an N-Arylation/Condensation/Oxidation Reaction Sequence

“…HRMS (ESI-TOF) calcd for C 11 H 14 N 3 O 1 [M + H] + : 204.1131, found 204.1130. This data is consistent with that previously reported …”

“…22 (ML190) vs 26 and 27). Furthermore, analogues that more closely resembled ML190 (22) such as 25 were more potent than the exploratory analogues. Disappointingly, none of the exploratory directions resulted in improved KOR antagonism either on the core scaffold (26−31) or on the side chain (32−33).…”

“…To illustrate the value of these compounds in medicinal chemistry discovery, we used the above building blocks in the syntheses of candidate KOR antagonists using the methods shown in Scheme 2 (specifically illustrated for ML190 (22); details and yields for other examples are provided in the Supporting Information). The final analogues synthesized are summarized in Figure 5.…”

“…We assessed KOR antagonism using one of two methods (Table 1). In the first, a standard GTPγS assay 18,19 provided IC 50 values from concentration-response curves (25−30) with our lead compound ML190 (22) provided for comparison. Alternatively, three-point screens using the Cellomics β-arrestin recruitment assay (31−33) provided values that are expressed as % U69,593 maximum stimulation remaining at given concentrations.…”

“…Alternatively, three-point screens using the Cellomics β-arrestin recruitment assay (31−33) provided values that are expressed as % U69,593 maximum stimulation remaining at given concentrations. We investigated analogues that retained the side chain from ML190 (22) as well as side chains inspired by the known KOR antagonist JDTic (32 and 33). The results indicate that the pyrrole is crucial for KOR antagonist activity as the unoxidized analogues were significantly less potent than the corresponding pyrroles (cf.…”