Synthesis of novel derivatives of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols with potential anti-inflammatory and immunomodulating activities

The synthesis of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols is described. These novel basic compounds have potent anti-inflammatory activity, significantly inhibiting rat paw oedema induced by a variety of phlogistic agents as a result of the release of inflammatory mediators such as histamine, 5-hydroxytryptamine, kinins, prostaglandins or leukotrienes. The biological activity of a selected, representative number of these compounds was examined on adjuvant-induced arthritis, a good animal model for rheumatoid arthritis in man. The results show that 3-(1-hydroxymethylpropylamino)-1-phenylpropan-1-one hydrochloride (2) and 3-(3-hydroxypiperidin-1-yl)-1-phenylpropan-1-one hydrochloride (4) effectively suppress the secondary lesions of adjuvant arthritis. 2-(3-Hydroxy-3-phenylpropylamino)-butan-1-ol hydrochloride (6) had no preventive activity in this animal model. In addition, several of the compounds suppressed the mitogenic responses of T-lymphocytes to concanavalin A, suggesting direct or indirect action on lymphocytes and therefore possible immunosuppressive properties. Finally, we investigated the in-vitro effects of compounds 2 and 4 on production of interleukins 1 and 2 (IL-1 and IL-2). We found that compound 4 suppressed the in-vitro production or action of IL-2 and IL-I. In contrast, compound 2 significantly increased the IL-1 activity of arthritic macrophages while reducing the ability of normal and arthritic splenocytes to produce or release IL-2. Our data suggest that compounds 2 and 4 have immunomodulatory properties that influence T lymphocyte functions.