Abstract
1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK(1) receptor antagonist with a long central duration of action and a solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.
MeSH terms
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Administration, Oral
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Amines / chemical synthesis
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Amines / chemistry
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Amines / pharmacology
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Animals
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Animals, Newborn
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Antidepressive Agents / chemical synthesis*
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Antidepressive Agents / chemistry
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Antidepressive Agents / pharmacology
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Antiemetics / chemical synthesis*
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Antiemetics / chemistry
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Antiemetics / pharmacology
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Brain / drug effects
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Brain / metabolism
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Dogs
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Ferrets
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Gerbillinae
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Guinea Pigs
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In Vitro Techniques
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Injections, Intravenous
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Macaca mulatta
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / pharmacology
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Neurokinin-1 Receptor Antagonists*
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Radioligand Assay
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Rats
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Solubility
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / chemistry
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Triazoles / pharmacology
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Vocalization, Animal / drug effects
Substances
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1-(5-((2-((1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-3-(4-fluorophenyl)morpholin-4-yl)methyl)-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine
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Amines
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Antidepressive Agents
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Antiemetics
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Morpholines
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Neurokinin-1 Receptor Antagonists
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Triazoles