Indolizidine derivatives as potential substance P antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 2, 1996, Pages 161-164

  Chan, Chuen ^a   Cocker, J Derek ^a   Davies, H Geoffrey ^a   Gore, Andrea ^a   Green, Richard H ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 (2 METHOXYBENZYLAMINO) 2 PHENYLPIPERIDINE; INDOLIZIDINE DERIVATIVE; NEUROKININ 1 RECEPTOR; SUBSTANCE P ANTAGONIST;

ARTICLE; CONTROLLED STUDY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; NUCLEAR MAGNETIC RESONANCE;

EID: 0030025430     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(95)00581-D     Document Type: Article

References (17)

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10. Cocker, J.D.; Davies, H.G. Morphan Based Substance P Antagonists. Bioorg. Med. Chem. Lett. Manuscript accepted for publication.
11. Conformational analysis on structure (1) was carried out by a Monte Carlo-style search and minimised with MM3 force field within MacroModel 4.5. Based on these studies (1b) was found to have 3.4 kJ/mol and (1c) 10.6 kJ/mol higher energy than the lowest energy conformer (1a). However these data could not exclude the accessibility of conformer (1b).
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15. Treatment of the ketopiperidine (2) with 1,3-diidopropane and sodium hydrogen carbonate at 21°C, without the exclusion of air, gave a complex mixture from which was isolated benzoic acid (i), pyrrolidine (ii) and the iodoester (iii):-(figure presented)
16. The ketone (4a, X = H,H) was converted into the corresponding methoxime and the amide function reduced with diborane. Hydrogenation of the resultant methoxime (i) in the presence of a platinum catalysts gave the cyclohexyl derivative (ii):-(figure presented)
17. 1 receptors from U-373MG human astrocytoma cell line. For details of the receptor binding protocol, see reference 10.