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J Med Chem. 2001 Nov 22;44(24):4296-9.

An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration.

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The Neuroscience Research Centre, Merck, Sharp & Dohme, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.


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.

[Indexed for MEDLINE]

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