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

  • J Med Chem. 2001 Nov 22;44(24):4296-9. doi: 10.1021/jm0109558.
T Harrison  1 ,  A P Owens ,  B J Williams ,  C J Swain ,  A Williams ,  E J Carlson ,  W Rycroft ,  F D Tattersall ,  M A Cascieri ,  G G Chicchi ,  S Sadowski ,  N M Rupniak ,  R J Hargreaves
Affiliations
  • 1. The Neuroscience Research Centre, Merck, Sharp & Dohme, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. [email protected]
PMID: 11708932 DOI: 10.1021/jm0109558
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.

Products