new series of ligands has been synthesized where the cinnamoyl group

new series of ligands has been synthesized where the cinnamoyl group of the 14-cinnamoylamino morphinones has been introduced to the 7α-substituent of the 6 14 PIK-90 oripavine series. prepared from your known thebaine adduct (9)8 in 3 actions (Plan 1). Treatment of 9 with hydroxylamine hydrochloride under reflux afforded the oxime with subsequent reduction using lithium aluminium hydride leading to amine 10. Catalytic hydrogenation of the olefin bond gave 7α-aminomethyl-6 14 (11) in an overall yield of 23%. Boron tribromide9 mediated 3-O-demethylation at room temperature gave 7α-aminomethyl-6 14 (12). Plan 1 Reagents and Conditions: (i) NH2OH.HCl EtOH/H2O (1:1) reflux 6 h 78 (ii) LiAlH4 THF reflux overnight 61 (iii) H2 Pd-C EtOH 50 °C 40 atm overnight 60 (iv) BBr3 DCM r.t. 0.25 h 65 (v) Rabbit Polyclonal to PKNOX2. Acid chloride NEt3 DCM r.t. immediately; … Acylation of 7α-aminomethyl-6 14 (11) using the appropriate acid chloride gave target compounds 5a – f while EDC promoted coupling with the appropriate acid furnished 5g – i. In the acylation of 7α-aminomethyl-6 14 (12) a second equivalent of the acid chloride was used to afford the bis-acylated derivative as an intermediate with subsequent hydrolysis giving the desired phenols 6a – f (Plan 1). As expected the 7α-cinnamylaminomethyl analogues 7 8 could not be accessed directly via an alkylation using the corresponding cinnamyl bromide owing to the predominant formation of the dialkylated tertiary amine product. Instead a reductive amination approach was utilized. A two-stage protocol treating amines 11 and 12 with the corresponding cinnamaldehyde followed by reduction of the imine intermediate using sodium borohydride was employed (Plan 1). C7 C8 ring-constrained analogues 18a and 18b were prepared as depicted in Plan 2. First cycloaddition of thebaine (13) with N-benzylmaleimide gave rise to 14 in quantitative yield with sequential reduction (to give 15) and debenzylation performed under standard hydrogenolysis conditions affording 16. PIK-90 This latter step proceeded in poor yield and under these conditions the 6 14 bridge was not reduced. Demethylation of 16 at C3 was best performed with boron tribromide affording 17 in good yield. BBr3 is known to demethylate opioid ligands at both C3 and C6 9 however the authors suggested that selective demethylations at C3 could be achieved with an aminomethyl group in the 7α-position which forms a complex with the boron atom thus blocking the reaction at C-6. It would appear that the constrained aminomethyl moiety of 16 was behaving similarly to the non-constrained example. In a similar manner to the synthesis of 5 and 6 the secondary amine was acylated to give rise to 18a and 18b in moderate PIK-90 yield. Plan 2 Reagents and Conditions: (i) N-benzylmaleimide toluene reflux 18 h quantitative; (ii) LiAlH4 THF reflux 16 h 74 (iii) 10% Pd/C EtOH HCl (conc.) H2 at 40 psi 5 days 22 (iv) BBr3 DCM 15 min 72 (v) Acid chloride NEt3 DCM r.t. immediately. … Results In displacement binding assays in recombinant human opioid receptors in which the displaced radioligands were [3H]DAMGO (MOR) [3H]”type”:”entrez-nucleotide” attrs :”text”:”U69593″ term_id :”4205069″ term_text :”U69593″U69593 (KOR) and [3H]Cl-DPDPE (DOR) 10 the new ligands (5 6 showed high affinity for MOR. This was particularly true for the oripavine derivatives (6) which all experienced subnanomolar MOR affinity (Table 1). They had affinity for KOR and DOR in the nanomolar range resulting in MOR selectivity which was higher for the unsubstituted cinnamoylamino ligand (6a) than for the substituted analogues (6b-6f). MOR affinity of the thebaine derivatives (5) was lower than that of the oripavine derivatives (6). The reduction in affinity was least in the 2′-chloro derivative (6c to 5c; 2.5-fold) and best in the 4’-methyl derivative (6d to 5d; 51-fold). Reduction in KOR PIK-90 and DOR affinity in the thebaine..