10 Etozolin: A Novel Diuretic G. SATZINGER, M . HERRMANN, K.-O. VOLLMER, A. MERZWEILER, and H . GOMAHR Goedecke Research Institute, Goedecke AG, D-78 Freiburg (in Breisgau), West Germany O. HEIDENREICH and J. GREVEN Pharmacological Department, Rhein.-Westf. Technical University of Aachen, West Germany
Introduction - Investigations to date seem to indicate that choleresis i s , to some extent, part of the extrarenal effect of diuretic substances. However, more detailed studies, p a r t i c ularly with furosemide and ethacrynic acid, have proved that b i l i a r y osmolality i s not affected hereby (1-4). The question as to whether choleretics, which do not influence the b i l i a r y electrolyte concentration, would make suitable models in the search for novel diuretic substances has never been investigated. We have recently described (5) some highly potent diuretic and well-tolerated compounds which were discovered in the course of investigating a new class of heterocycles (Structure 1), many of which possess choleretic properties.
One of these compounds, ethyl Z-[3-methyl-4-oxo-5-(1-piperidinyl)-2-thiazolidinylidene]acetate (Compound 3, etozolin), has been introduced as a therapeutic agent on the German market under the trademark Elkapin . Table I summarizes the current synthetic work i n the f i e l d of 2-acylmethylene-4-thiazolidinones. Table II shows the substitution pattern of the compounds of type 1 which are active diuretics. As a consequence of these findings, six other series of heterocycles were synthesized and tested (Table III). None of the representatives of these heterocycles exhibited diuretic a c t i v i t y , even when the successful substitution pattern shown in Table II was employed (as far as this was feasible and led to stable compounds). R
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DIURETIC
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AGENTS
TABLE I Synthesized and Tested D e r i v a t i v e s of 1
Substituent
Notes
Groups H, a l k y l , a r a l k y l , (CH ) X 2
CH X,
X = f u n c t i o n a l groups such as -OR, -NR acyl (R = lower a l k y l ) 2>
2
H, a l k y l , a r y l , a r a l k y l , CH X, ( C H ) X ; NHCOCH ; 2
2
2
3
C0 R
only f o r R
= CH„
CH
only f o r R
= C0 R
2
3
2
-C0 H, -C0 R, R-CO-, 2
2
ArCO-, R-S0 ~, A r S 0 ~ , 2
2
>NCO-, -HNCO-, R NC0-,
AR = a r y l , h e t e r o aryl
2
-CN; p y r i d y l , benzimidazolyl, indolyl H, a l k y l ,
RV
aryl 2
>CR
-N
