Patent Evaluation: Novel Oxamide Derivatives as TNF Inhibitors

Summary

Novelty: Novel oxamide derivatives and a process for their preparation are disclosed. These compounds are said to inhibit the production of TNF and are potentially useful for the treatment of disease states mediated or exacerbated by TNF production. The compounds are also said to inhibit PDE(IV).

Biology: In vitro TNF production by human monocytes showed IC₅₀ values in the range of 0.01-<3.0. The inhibition of TNF production in a mammal is also demonstrated. Also reported is the phosphodiesterase inhibitory activity, IC50 values range from 0.05 μM to 40μM.

Chemistry: Preferred novel compounds have the generic structure below. Nine compounds are specifically claimed. Representative of these is N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-ethyl]-N-methyl oxamide, which is prepared by a multistep process. The preparation of oxamide derivatives and intermediates are illustrated in forty-seven examples.

Structure: