Synthesis of novel analogues of the delta opioid ligand SNC-80 using REM resin

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 9, 1999, Pages 1323-1328

  Cottney, J ^a   Rankovic, Z ^a   Morphy, J R ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [ALPHA (4 ALLYL 2,5 DIMETHYL 1 PIPERAZINYL) 3 METHOXYBENZYL] N,N DIETHYLBENZAMIDE; DELTA OPIATE RECEPTOR; DELTA OPIATE RECEPTOR AGONIST;

ANTINOCICEPTION; ARTICLE; BINDING AFFINITY; CHEMICAL MODIFICATION; CHEMICAL STRUCTURE; DRUG RECEPTOR BINDING; DRUG SYNTHESIS;

BENZAMIDES; INHIBITORY CONCENTRATION 50; PIPERAZINES; RECEPTORS, OPIOID, DELTA; RESINS, PLANT;

EID: 0033519307     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00173-0     Document Type: Article

References (12)

1. Rapaka, R.S.; Porreca F., Pharmacol. Res. 1991, 8, 1
2. Calderon, S.N.; Rothman, R.B.; Porreca, F.; Flippen-Anderson, McNutt R.W.; Xu, H.; Smith, L.E.; Bilsky, E.J.; Davis, P.; Rice, K.C. J. Med. Chem. 1994, 37, 2125
3. Morphy, J.R.; Rankovic Z.; Rees D.C. Tetrahedron Lett. 1996, 37, 3209
4. Calderon, S.N.; Rice, K.C.; Rothman, R.B.; Porreca, F.; Flippen-Anderson, J.L.; Kayakiri, H.; Xu, H.; Becketts, K.; Smith, L.E.; Bilsky, E.J.; Davis, P.; Horwath, R. J. Med. Chem., 1997, 40, 695
5. 3H]-U69593 (1.5nM) to guinea pig brain membranes.
6. 4 in refluxing toluene followed by Boc deprotection with KOH in boiling MeOH.
7. 2O (0.7mL), then eluted with heptane (2mL: eluted aliphatic impurity) then ethyl acetate (4mL: elutes product). Evaporation of the EtOAc provided the product as a colourless gum (18.4mg; 58%).
8. Brown, A.; Rees, D.C.; Rankovic, Z.; Morphy, J.R. J. Am. Chem. Soc. 1997, 119, 3288.
9. 4 (12 mg; 20 mol%) was added under argon atmosphere into a degassed DMF (2 mL) suspension of resin 13 (100mg; 0.052 mmol), LiCl (11 mg; 0.26 mmol) and arylbromide (0.26 mmol). After the reaction suspension was heated at 100°C for 18h, the resin was washed (3 × DMF, 3 × DCM, 3× MeOH) and dried at 45°C in vacuo.
10. Azizian H.; Eaborn C.; Pidcock A. J. Orgmet. Chem. 1981, 215, 49
11. 3, separated, and the solvent evaporated to give 0.66g of 4, in 47% overall yield and 97% HPLC purity.
12. During the course of this work, a report was published exploring the SAR around the diethylamide in which similar trends were described: Katsura, Y.; Zhang, X.; Homma, K.; Rice, K.C.; Calderon, S.N.; Rothman, R.B.; Yamamura, H.I.; Davis, P.; Flippen-Anderson, J.L.; Xu, H.; Becketts, K.; Foltz, E.J.; Porreca, F. J. Med. Chem., 1997, 40, 2936.