Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 3, 2010, Pages 836-840

  Qiang, Li ^a   Sasikumar, T K ^a   Burnett, Duane A ^a   Su, Jing ^a   Tang, Haiqun ^a   Ye, Yuanzan ^a   Mazzola Jr , Robert D ^a   Zhu, Zhaoning ^a   McKittrick, Brian A ^a   Greenlee, William J ^a   Fawzi, Ahmad ^a   Smith, Michelle ^a   Zhang, Hongtao ^a   Lachowicz, Jean E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Benzazepine; Dopamine antagonist; Ecopipam; Obesity; SCH 23390; SCH 39166

Indexed keywords

8 CHLORO 2,3,4,5 TETRAHYDRO 3 METHYL 5 PHENYL 1H 3 BENZAZEPIN 7 OL HYDROGEN MALEATE; DOPAMINE 1 RECEPTOR BLOCKING AGENT; DOPAMINE RECEPTOR; ECOPIPAM; BENZAZEPINE DERIVATIVE; DOPAMINE 1 RECEPTOR; DOPAMINE RECEPTOR BLOCKING AGENT;

ARTICLE; BINDING AFFINITY; BROMINATION; DERIVATIZATION; GEL CHROMATOGRAPHY; STRUCTURE ACTIVITY RELATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; COMPARATIVE STUDY; PHYSIOLOGY; RAT;

ANIMALS; BENZAZEPINES; DOPAMINE ANTAGONISTS; RATS; RECEPTORS, DOPAMINE D1;

EID: 74049162090     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.12.100     Document Type: Article

References (22)

1. Claudi F., Stefano A.D., Napolitani F., Cingolani G.M., Giorgioni G., Fontenla J.A., Montenegro G.Y., Rivas M.E., Rosa E., Michelotto B., Orlando G., and Brunetti L. J. Med. Chem. 43 (2000) 599
2. Kebabian J., and Calne D.B. Nature 277 (1979) 93
3. Sutton M., and Beninger R. Psychopharmacology 144 (1999) 95
4. Hoebel B., Hernandez L., Schwartz D., Mark G., and Hunter G. Ann. N. Y. Acad. Sci. 575 (1989) 171
5. Astrup A., Greenway F.L., Ling W., Pedicone L., Lachowicz J., Strader C.D., and Kwan R. Obesity 15 (2007) 1717
6. Gold, E. H.; Chang, W. K. U.S. Patent 4284555, 1981.
7. Iorio L.C., Barnett A., Leitz F.H., Houser V.P., and Korduba C.A. Pharmacology 226 (1983) 462
8. Barnett A., McQuade R.D., and Tedford C. Neurochem. Int. Suppl. 20 (1992) 119S
9. Berger J.G., Chang W.K., Clader J.W., Hou D., Chipkin R.E., and Mcphail A.T. J. Med. Chem. 32 (1989) 1913
10. McQuade R.D., Duffy R.A., Coffin V.L., Chipkin R.E., and Barnett A. J. Pharmacol. Exper. Ther. 257 (1991) 42
11. Tedford C.E., Coffin V.L., Ruperto V., Cohen M., McQuade R.D., Johnson R., Kim H.-K., and Lin C.-C. Psychophamacology 113 (1993) 199
12. Tedford C.E., Ruperto V., Coffin V.L., Cohen M., Libonati M., and Barnett A. Drug Dev. Res. 26 (1992) 389
13. Wu W.-L., Burnett D.A., Spring R., Greenlee W.J., Smith M., Favreau L., Fawzi A., Zhang H., and Lachowicz J.E. J. Med. Chem. 48 (2005) 680
14. Sasikumar, T. K.; Burnett, D. A.; Greenlee, W. J.; Smith, M.; Fawzi, A.; Zhang, H.; Lachowicz, J. E. Bioorg. Med. Chem. Lett. preceding paper.
15. Barnett J.R., Andrew L.J., and Keefer R.M. J. Am. Chem. Soc. 94 (1972) 6129
16. Similar but more limited SAR efforts were also explored with intermediate 5.
17. 1 receptor based on SCH 23390 have been reported earlier. See:. Monsma F.J., Barton A.C., Kang H.C., Brassard D.L., Haugland R.P., and Sibley D.R. J. Neuochem. 52 (1989) 1641
18. Gala D., Dahanukar V.H., Eckert J.M., Lucas B.S., Schumacher D.P., Zavialov I.A., Buholzer P., Kubisch P., Mergelsberg I., and Scherer D. Org. Process Res. Dev. 8 (2004) 754
19. A typical experimental method is given below: Compound 10 (0.17 g, 0.37 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 °C under atmosphere of nitrogen. Chlorosulfonic acid (2 ml, excess) was added dropwise to this solution. The reaction was then raised to room temperature and stirred for 3 h. The reaction was quenched with ice water and light brown solid was precipitated out from the solution. The liquid was descanted and the resulting solid was dried by forming the azeotropic solution with toluene. The crude solid material was redissolved in acetonitrile and added amines (excess amount) dropwise. The reaction mixture was left to stir at room temperature over night. Saturated ammonium chloride solution was used to quench the reaction followed by extraction with dichloromethane. The final product was isolated by preparative TLC with the yield ranging from 20-50%.
20. 2 (1.6 g, 12.9 mmol) and the reaction mixture was left to stir for 3 h. The reaction was then quenched with water and neutralized with saturated sodium bicarbonate solution. This mixture was extracted with dichloromethane and the solvent was evaporated under vacuum. The residue was redissovled in tetrahydrofuran/water solution (3:1), treated with 1 N LiOH aqueous solution and stir at room temperature for 3 h. The reaction mixture was then quenched with acetic acid, extracted with dichloromethane and dried with sodium sulfate. The solvent was evaporated and the resulting crude material was passed through a short silicon gel column to remove baseline material. The mixture was then purified by HPLC (silica gel column, eluting solvent 95% ethyl acetate/hexane, 0.25% triethylamine) to give three regioisomers.
21. 2 affinity. Two examples are shown as below:{A figure is presented}
22. Korfmacher W.A., Cox K.A., Ng K.J., Veals J., Hsieh Y., Wainhaus S., Broske L., Prelusky D., Nomeir A., and White R.E. Rapid Commun. Mass Spectrom. 15 (2001) 335