Synthesis and Opioid Activity of 7-Oxygenated 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolinols

Abstract

3-(Cyclopropylmethyl)-9-hydroxy-7-oxo-2,3,4,4a alpha,5,6,7,7a alpha- octahydro-1H-benzofuro[3,2-e]isoquinoline (4b) containing the ACNO ring system of morphine and a 7-keto function on ring C has been synthesized and found to possess potent PQW (ED50 = 0.15 mg/kg sc) and anti-Straub tail (ED50 = 0.02 mg/kg sc) activity. As compared to its 7-deoxy analog 1b, introduction of the 7-keto group did not significantly affect binding to any of the three opioid receptors (mu, kappa, and delta), but caused a 34-fold reduction in sigma-binding, suggesting reduced propensity to induce psychotomimetic effects. The C/D cis isomer of 4b (4c) was much less potent at the three opioid receptors, while displaying a slight increase in sigma affinity. Both 7-hydroxy derivatives 4e and 4f were active in anti-Straub tail assay (ED50 < or = 0.8 mg/kg sc), but only the alpha-isomer 4e demonstrated analgesic activity (PQW ED50 = 0.37 mg/kg sc) in the dose range tested. In guinea pig ileum preparations, 4e was characterized as a selective full agonist at the kappa opioid receptor (IC50 = 2.8 nM); while its beta-isomer 4f was a partial agonist (78% at 1 microM), with antagonist activity observed at both mu- and kappa-opioid receptors.

Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-like Receptor 4 Antagonists and Opioid Ligands

“…TLC showed a single spot with traces of an unknown impurity at a slightly higher R f . Spectra matched those reported by Weller et al 9 …”

“…The stereoselective reduction of the trisubstituted alkene 15 was performed with 5% Pt/C rather than the more reactive PtO 2 , while the resulting 85:15 mixture of 4aH,9- O - trans : cis ring juncture isomers 16 were separated by crystallization of the desired trans isomer as a tosylate salt. Weller et al 9 reported a separation of the cis and trans isomers of racemic trans -(±)- 2 with recrystallization from benzene/hexane after subjecting crude 16 to acidic hydrolysis–decarboxylation. Acid hydrolysis led to the desired 4aH,9- O - trans -isoquinolinone 2 .…”

“…First, basic conditions (NaOEt at 19 °C) gave 33 . 9 The latter was subjected to NaH in refluxing THF to afford product 34 . We have now found that the quaternary amine 32 , under basic conditions (NaOEt, at 78 °C), afforded the Dieckmann condensation product 34 (4aH,9- O - trans- ethyl 3-(cyclopropylmethyl)-7-hydroxy-9-methoxy-5,7a-dihydro-3 H -benzofuro[3,2- e ]isoquinoline-6-carboxylate) directly.…”

“…The elimination of the isolation of the intermediate 33 enabled us to obtain 34 in 68% yield from 12 , rather than the <50% yield formerly obtained. The catalytic reduction of 34 (Scheme 7) and subsequent hydrolysis/de-esterification was performed as noted in the literature 9 and afforded 4aH,9- O - trans -(±)- 36 in 61% yield.…”

“…We now had the complete skeleton of the 10-nornaltrexone compound and it only remained to find a way to replace an N -methyl moiety with the 3-cyclopropylmethyl group in 1 , and that was done with cyanogen bromide, as shown in Scheme 6. After accomplishing that, we proceeded to shorten the procedure of Cheng et al 9 for the synthesis of 36 from 12 (Scheme 7). The racemate 36 was optically resolved, and each of its hitherto-unknown enantiomers were used to prepare (+)- and (−)- 1 .…”