2,7-Diazabicyclo[3.3.0]octanes as novel h5-HT(1D) receptor agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 17, 1999, Pages 2491-2496

  Russell, Michael G N ^a   Beer, Margaret S ^a   Stanton, Josephine A ^a   Sohal, Bindi ^a   Mortishire Smith, Russell J ^a   Castro, José L ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2,7 DIAZABICYCLO[3.3.0]OCTANE; PYRROLIDINE DERIVATIVE; SEROTONIN 1D AGONIST; SEROTONIN 1D RECEPTOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG ABSORPTION; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG CONFORMATION; DRUG SYNTHESIS; GASTROINTESTINAL ABSORPTION; NONHUMAN; ORAL DRUG ADMINISTRATION; PORTAL VEIN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BICYCLO COMPOUNDS, HETEROCYCLIC; CHO CELLS; CRICETINAE; RECEPTOR, SEROTONIN, 5-HT1D; RECEPTORS, SEROTONIN; RECOMBINANT PROTEINS; SEROTONIN AGONISTS;

EID: 0033530106     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00409-6     Document Type: Article

References (21)

1. Perry, C. M.; Markham, A. Drugs 1998, 55, 889-922.
2. Yevich, J. P.; Yocca, F. D. Curr. Med. Chem. 1997, 4, 295-312.
3. Longmore, J.; Dowson, A.; Hill, R. G. Current Opinion in CPNS Investigational Drugs 1999, 1, 39-53.
4. Russell, M. G. N. Idrugs 1999, 2, 37-43.
5. Connor, H. E.; Fenuik, W.; Beattie, D. T.; North, P. C.; Oxford, A. W.; Saynor, D. A.; Humphrey, P. P. A. Cephalagia 1997, 17, 145-152.
6. Glen, R. C.; Martin, G. R.; Hill, A. P.; Hyde, R. M.; Woollard, P. M.; Salmon, J. A.; Buckingham, J.; Robertson, A. D. J. Med. Chem. 1995, 38, 3566-3580.
7. Street, L. J.; Baker, R.; Davey, W. B.; Guiblin, A. R.; Jelley, R. A.; Reeve, A. J.; Routiedge, H.; Sternfeld, F.; Watt, A. P.; Beer, M. S.; Middlemiss, D. N.; Noble, A. J.; Stanton, J. A.; Scholey, K.; Hargreaves, R. J.; Sohal, B.; Graham, M. I.; Matassa, V. G. J. Med. Chem. 1995, 38, 1799-1810.
8. Ngo, J.; Rabasseda, X.; Castañer, J. Drugs of the Future 1997, 22, 221-224.
9. Goadsby, P. J. CNS Drugs 1998, 10, 271-286.
10. Cumberbatch, M. J.; Hill, R.; Hargreaves, R. J. Eur. J. Pharmacol. 1997, 328, 37-40.
11. Hartig, P. R.; Hoyer, D.; Humphrey, P. P. A.; Martin, G. R. Trends Pharmacol. Sci. 1996, 17, 103-105.
12. Longmore, J.; Shaw, D.; Smith, D.; Hopkins, R.; McAllister, G.; Pickard, J. D.; Sirinathsinghji, D. R. S.; Butler, A. J.; Hill, R. Cephalagia 1997, 17, 833-842.
13. Castro, J. L.; Street, L. J.; Guiblin, A. R.; Jelley, R. A.; Russell, M. G. N.; Sternfeld, F.; Beer, M. S.; Stanton, J. A.; Matassa, V. G. J. Med. Chem. 1997, 40, 3497-3500.
14. Sternfeld, F.; Guiblin, A. R.; Jelley, R. A.; Matassa, V. G.; Reeve, A. J.; Hunt, P. A.; Beer, M. S.; Heald, A.; Stanton, J. A.; Sohal, B.; Watt, A. P.; Street, L. J. J. Med. Chem. 1999, 42, 677-690.
15. This was performed using a Chiralpak AD (250 x 4.6 mm) column, eluting with 20% EtOH in 0.1% diethylamine/isohexane at 1 ml/min. The de's of 11 and 12 were determined to be 96.0% and 98.6% respectively.
16. Veldman, S. A.; Bienkowski, M. J. Mol. Pharmacol. 1992, 42, 439-444.
17. Schenke, T.; Peterson, U. European Patent 0393424 A2, 1992.
18. Stork, G.; Leong, A. Y. W.; Touzin, A. M. J. Org. Chem. 1976, 41, 3491-3493.
19. Castro Pineiro, J. L.; Russell, M. G. N. World Patent 09728162 A1, 1997.
20. A strong NOE from H-1 to H-5 defines the regiochemistry at the bridgehead to be cis. The relative magnitudes of NOE's between H-5 and H-4ax (large) and H-5 and H-4eq (small) indicate that H-4ax is on the same face of the bicycle as H-5. The relative magnitudes of NOE's between H-4ax and H-3 (small) and H-4eq and H-3 (large) then define the relative stereochemistry of the third centre. The relative stereochemistry is therefore (R,R,R) with the indolylmethyl group pseudoequatorial and on the same face as the bridgehead protons.
21. Russell, M. G. N.; Matassa, V. G.; Pengilley, R. R.; van Niel, M. B.; Sohal, B.; Beer, M. S.; Stanton, J. A.; Broughton, H. B.; Castro, J. L. unpublished results.