New isothiazole derivatives: synthesis, reactivity, physicochemical properties and pharmacological activity.
The synthesis and biological investigation of the series of amide and ester derivatives 10-20 of 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid 5 are presented. Because the amide series of 5-benzoylamino-3-methyl-4-isothiazolecarboxylic acid 2 has been studied extensively and from this series denotivir (vratizolin) 4 became the antiviral drug. The influence of exchanging the N-benzoyl for a N-(4-chlorobenzoyl) group at position 5 of the isothiazole ring on the pharmacological activity of 5-benzoylamino-3-methyl-4-isothiazolecarboxylic acid 2 derivatives is dealt with here. The effect of structure modifications in the carboxylic group of the 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid 5 series of derivatives on their biological activity is discussed. Some of the tested 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylamides revealed significant anti-inflammatory activity in carrageenan induced edema and air-pouch inflammation tests. Physicochemical properties of 6-(4-chlorophenyl)-3-methylisothiazolo[5,4-d]-4H-1,3-oxazin-4-one 6 are described. Its use in the synthesis of isothiazole derivatives and its reactivity are also presented.
Regiec
Andrzej
A
Department of Organic Chemistry, Faculty of Pharmacy, Medical Academy of Wroclaw, Wroclaw, Poland. rykolf@mp.pl
Machoń
Zdzisław
Z
Miedzybrodzki
Ryszard
R
Szymaniec
Stanisław
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002351:Carrageenan; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004910:Erythrocyte Membrane / Q000187:drug effects; D005260:Female; D006614:Hindlimb / Q000187:drug effects; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C514572:5-(4-chlorobenzoyl)amino-N-(4-chlorophenyl)-3-methyl-4-isothiazolecarboxamide; C514573:5-(4-chlorobenzoyl)amino-N-(4-chlorophenyl)-N-methyl-3-methyl-4-isothiazolecarboxamide; C514574:5-(4-chlorobenzoyl)amino-N-(5-methyl-2-pyridyl)-3-methyl-4-isothiazolocarboxamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D013844:Thiazoles; D002351:Carrageenan; C109918:denotivir; D007052:Ibuprofen