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The aim of this work was to study the systemic antinociceptive and anti-inflammatory effects and to evaluate the gastropathic effects of L-proline and L-tryptophan sulfamide derivatives on experimental models in rodents as compared to diclofenac. The target compounds were synthesized by the reaction of 4-(tert-butyl)-benzenesulfonyl chloride, which was previously obtained from tert-butylbenzene and chlorosulfonic acid, with the amino acids L-tryptophan and L-proline in aqueous NaOH solution. The target sulfamic acids were obtained in high yields and did not require further purification. The acids were converted to water-soluble sodium salts for subsequent pharmacological tests. The investigational compounds and diclofenac were administered intragastrically in doses of 10 mg/kg of body weight. The L-tryptophan sulfamide derivative demonstrated an antinociceptive effect close to that of diclofenac in the acetic acid-induced writhing test in mice. The number of writhings in each group decreased by 97% as compared with the control (p = 0.03 for diclofenac; p > 0.05 for the tryptophan derivative). The anti-inflammatory activity of the L-tryptophan sulfamide derivative on a formalin-induced paw edema model in rats exceeded that of diclofenac by 78% (p = 0.02). The L-proline sulfamide derivative did not exhibit antinociceptive and anti-inflammatory activity in the studied dose. In addition, L-proline and especially L-tryptophan sulfamide derivatives administered for 14 d had significantly lower ulcerogenic effects in rats as compared to diclofenac when assessing the degree of gastric ulceration and the percentage of rats that developed gastric ulcers. The L-tryptophan sulfamide derivative appears to be a promising compound from the viewpoint of balancing the analgesic and anti-inflammatory activities and gastrointestinal safety. [ABSTRACT FROM AUTHOR]