Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists

Abstract

There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [(35)S]GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [(35)S]GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [(35)S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.

Figure 1

Compound 10a (CPK color scheme) docked into the kappa-opioid receptor ligand binding site (PDB: 4DJH). The observed configuration of JDTic (yellow) shown for comparison. Electrostatic interactions indicated by yellow (hydrogen-bonds involving water) or orange (interactions with Asp 238) dashed lines.

Figure 2

Compound 11e (CPK color scheme) docked into the kappa-opioid receptor ligand binding site (PDB: 4DJH). The observed configuration of JDTic (yellow) shown for comparison. Electrostatic interactions indicated by yellow (hydrogen-bonds involving water) or orange (interaction with Asp 238) dashed lines.

Scheme 1.^a

Synthesis of 10a ^aReagents: (a) N-Boc-L-valine, BOP, Et₃N, THF; (b) BH₃•THF, THF; (c) conc. HCl; (d) Boc-D-7-hydroxy-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, BOP, THF, 0 °C; (e) CF₃CO₂H, CH₂Cl₂; (f) HBTU, RCO₂H, CH₃CN, Et₃N.

Scheme 2.^a

Synthesis of 10b ^aReagents: (a) 1 N HCl, THF; (b) N-Boc-L-valine, BOP, Et₃N, THF; (c) BH₃•S(CH₃)₂, THF; (d) 6 N HCl; (e) 48% HBr; (f) Boc- D-7-hydroxytetrahydroquinoline-3-carboxylic acid, BOP, Et₃N, THF.

Scheme 3^a

^a Reagents and conditions: (a) ArCO₂H, HBTU, Et₃N, CH₃CN.

Scheme 4^a

^a Reagents and conditions: (a) KOH, DMF, 175 °C, 20 min; (b) CrO₃, aq. H₂SO₄, acetone; (c) aq. KOH, reflux; (d) HBr, AcOH, reflux; (e) HBTU, NEt₃, CH₃CN; (f) 16, BOP, NEt₃, CH₂Cl₂; (g) 16, EDC•HCl, cat. HOBt, NEt₃, CH₂Cl_2.

Scheme 5^a

^a Reagents and conditions: (a) KOH, DMF, 175 °C, 20 min; (b) CrO₃, aq. H₂SO₄, acetone; (c) aq. KOH, reflux; (d) HBr, AcOH, reflux; (e) conc. HCl, THF/iPrOH; (f) 16, EDC•HCl, cat. HOBt, NEt₃, CH₂Cl₂.

Scheme 6^a

^a Reagents and conditions: (a) bis(pinacolato)diborane, Pd(dppf)Cl₂, KOAc; (b) Oxone, aq. acetone.

Scheme 7^a

^a Reagents and conditions: (a) mCPBA, DCM; (b) Ac₂O, AcOH, 150 °C, 5 min; (c) aq. K₂CO₃, MeOH; (d) KMnO₄, acetone; (e) 16, HBTU, NEt₃, CH₃CN.

Scheme 8^a

^a Reagents and conditions: (a) TMSCHN₂, tol., MeOH; (b) Cs₂CO₃, PhOH, CH₃CN, reflux; (c) aq. LiOH, MeOH; (d) 16, EDC•HCl, cat. HOBt, NEt₃, CH₂Cl₂.

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