- Identification of ortho-Substituted Benzoic Acid/Ester Derivatives via the Gas-Phase Neighboring Group Participation Effect in (+)-ESI High Resolution Mass Spectrometry
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Benzoic acid/ester/amide derivatives are common moieties in pharmaceutical compounds and present a challenge in positional isomer identification by traditional tandem mass spectrometric analysis. A method is presented for exploiting the gas-phase neighbor
- Blincoe, William D.,Rodriguez-Granillo, Agustina,Saurí, Josep,Pierson, Nicholas A.,Joyce, Leo A.,Mangion, Ian,Sheng, Huaming
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p. 694 - 703
(2018/04/14)
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- 2,5-DISUBSTITUTED THIOMORPHOLINE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to 2,5-disubstituted thiomorpholine amide compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the 2,5-disubstituted thiomorpholine amide compounds described herein in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 37-38
(2013/05/09)
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- SUBSTITUTED PROLINES / PIPERIDINES AS OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to compounds that can modulate the bioactivity of an orexin receptor such as OX1 or OX2, or both; to pharmaceutical compositions and combinations comprising a compound of the invention; to methods of treatment of malconditions in patients wherein modulation of an orexin receptor is medically indicated; and to methods of preparation of compounds of the invention.
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Page/Page column 153; 154
(2013/08/28)
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- Enantioselective synthesis of a dual orexin receptor antagonist
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A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.
- Mangion, Ian K.,Sherry, Benjamin D.,Yin, Jingjun,Fleitz, Fred J.
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supporting information; experimental part
p. 3458 - 3461
(2012/08/08)
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- The first large-scale synthesis of MK-4305: A dual orexin receptor antagonist for the treatment of sleep disorder
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A new synthetic route to drug candidate 1, a potent and selective dual orexin antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-substituted benzoxazoles. A reductive amination was followed by a classical resolution to afford chiral diazepane (R)-11. Finally, coupling of (R)-11 with acid 5 furnished the desired drug candidate 1.
- Baxter, Carl A.,Cleator, Ed,Brands, Karel M. J.,Edwards, John S.,Reamer, Robert A.,Sheen, Faye J.,Stewart, Gavin W.,Strotman, Neil A.,Wallace, Debra J.
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experimental part
p. 367 - 375
(2012/05/19)
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- Discovery of the dual orexin receptor antagonist [(7 R)-4-(5-chloro-1,3- benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2 H -1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia
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Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
- Cox, Christopher D.,Breslin, Michael J.,Whitman, David B.,Schreier, John D.,McGaughey, Georgia B.,Bogusky, Michael J.,Roecker, Anthony J.,Mercer, Swati P.,Bednar, Rodney A.,Lemaire, Wei,Bruno, Joseph G.,Reiss, Duane R.,Harrell, C. Meacham,Murphy, Kathy L.,Garson, Susan L.,Doran, Scott M.,Prueksaritanont, Thomayant,Anderson, Wayne B.,Tang, Cuyue,Roller, Shane,Cabalu, Tamara D.,Cui, Donghui,Hartman, George D.,Young, Steven D.,Koblan, Ken S.,Winrow, Christopher J.,Renger, John J.,Coleman, Paul J.
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experimental part
p. 5320 - 5332
(2010/10/20)
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- 2,5-DISUBSTITUTED PIPERIDINE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to 2,5-disubstituted piperidine amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 38
(2010/05/13)
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- 2,3-DISUBSTITUTED PIPERIDINE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to 2,3-disubstituted piperidine amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin recepto
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Page/Page column 33
(2010/05/13)
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- SUBSTITUTED DIAZEPAN OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which orexin receptors are involved.
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Page/Page column 35
(2009/06/27)
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- SUBSTITUTED DIAZEPAN OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 30; 31
(2008/06/13)
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