Bulky amine analogs of ketoprofen: potent antiinflammatory agents

Abstract

Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.

Design and Synthesis ofN-(3,3-Diphenylpropenyl)alkanamides as a Novel Class of High-Affinity MT2-Selective Melatonin Receptor Ligands

“…Synthetic routes to the other target compounds are described in Schemes −3. Briefly, melatonin receptor ligands 9a − c and 11 were prepared by hydrogenation over Raney nickel of suitable nitriles (commercially available α-cinnamonitrile or its 3-methoxy analogue for 9a − c and 3-benzoyl-phenylacetonitrile for 11 ) and concomitant N -acylation with acetic or propionic anhydride (Scheme ). N -(2-Oxo-2-phenylethyl)acetamide was subjected to Wittig reaction conditions using benzyltriphenylphosphonium chloride in the presence of n -BuLi to give an E / Z mixture of N -(2,3-diphenylpropenyl)acetamide ( 10a , b ) from which each diastereoisomer was separated by flash chromatography (Scheme ).…”

“…A solution of (3-benzoylphenyl)acetonitrile 38 (0.15 g, 0.68 mmol) and propionic anhydride (1 mL, 7.8 mmol) in THF (7.5 mL) was hydrogenated over Raney nickel at 4 atm of H 2 for 5 h at 80 °C. The catalyst was filtered on Celite, the filtrate was concentrated in vacuo, and the residue was partitioned between EtOAc and 2 N NaOH.…”

“…Synthetic routes to the other target compounds are described in Schemes 1-3. Briefly, melatonin receptor ligands 9a-c and 11 were prepared by hydrogenation over Raney nickel of suitable nitriles (commercially available R-cinnamonitrile or its 3-methoxy analogue 37 for 9a-c and 3-benzoyl-phenylacetonitrile 38 for 11) and concomitant N-acylation with acetic or propionic anhydride (Scheme 1). N-(2-Oxo-2-phenylethyl)acetamide 39 was subjected to Wittig reaction conditions 40…”

Συνθεση Φαρμακοχημικη Μελετη Και Βιολογικος Ελεγχος Ενωσεων Με Πιθανη Δραση Στο Ανοσοβιολογικο Συστημα

“…Η πρώτη κατηγορία περιλαμβάνει παράγωγα της 2-(3-βενζουλοφαινυλο) προπυλαμίνης του τύπου Ι [2]: Οι βάσεις αντιδρούν με CH3I και μπορούν να δώσουν τεταρτοταγή προϊόντα. Προκαταρτικά πειράματα έδειξαν ότι η ένωση 5-(2,5-διμεθυλοφαινυλο)-4,1οξαζαδικυκλο [3.3.0] οκτάνιο έχει αντιφλεγμονώδη δράση [6,7].…”