A series of novel compounds having a benzothiazoline skeleton was studied for their structure-activity relationship (SAR) with respect to Ca2+ antagonistic activity. As test compounds, analogues of 3-acyl-2-arylbenzothiazolines (3) were synthesized. Benzothiazoline derivatives (3) exerted higher Ca2+ antagonistic activity than the corresponding thiazolidine derivatives (2). Effects of substituents R1-R4, the substitution position of the aminoalkoxy group and R2, and the length of the methylene chain on biological activities were examined. Compound 4 [3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl ) amino]butoxy]phenyl]benzothiazoline hydrochloride] showed a potent Ca2+ antagonistic activity in vitro and dual inhibition on the fast Na+ inward channel and the slow Ca2+ inward channel in Langendorff perfused rabbit hearts. Compound 4 also showed a long-acting hypotensive effect in spontaneously hypertensive rats and prevented acute pulmonary thrombotic death in mice.

In order to search for anti-hepatitis drugs, we synthesized a series of eight- and nine-membered cyclic disulfides (1) and six- and seven-membered cyclic sulfides (2) and evaluated them for ability to reduce mortality in the model of acute hepatic failure induced by Propionibacterium acnes-lipopolysaccharide in mice. Compounds 1 were synthesized by oxidative cyclization of the corresponding dithiol derivatives (3) with diethyl bromomalonate or iodine. Compounds 2 were prepared from the methyl esters of 1 by desulfurization with tris(diethylamino)phosphine followed by deprotection. Compounds 1 were generally found to be more active than compounds 2. Compound 1b (SA3443) was found to exhibit potent protective activity. The synthesis and structure-activity relationships are discussed.

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Reaction of 4‐chloro‐2‐methyl‐5‐(1‐methylhydrazino)‐3(2H)‐pyridazinone (1) with carbon disulfide followed by alkylation yielded 2‐alkylthio‐4H‐pyridazino[4,5‐e][1,3,4]thiadiazine derivatives 2. Oxidative cyclization of 5‐(4‐substituted 1‐methylthiosemicarbazido)‐3(2H)‐pyridazinone derivatives 4 with N‐bromosuccinimide also gave 2‐substituted amino‐4H‐pyridazino[4,5‐e][1,3,4]thiadiazine derivatives 5. Heating of 2 and 5 resulted in ring contraction to afford the corresponding pyrazolo[3,4‐d]pyridazine derivatives 6, 7 via sulfur extrusion. A possible mechanism for the desulfurization reaction is discussed, comparing with a structural difference between a type of pyridazino[4,5‐e][1,3,4]thiadiazine (2,5) and another one (9,11,13,15).

Die Pyrazolo‐pyridazinthione (V) werden über eine photochemische Cyclisierung der N‐geschützten Pyridazin‐Derivate (II) hergestellt.