Indacrinone

Indacrinone is a loop diuretic. It can be used in patients of gout with hypertension as an antihypertensive because it decreases reabsorption of uric acid, while other diuretics increase it.

Chirality and biological activity
Indacrinone is a chiral drug, with one chiral center and hence exists as mirror-image twins. (R)-enantiomer, the eutomer, is diuretic whereas the mirror-image version (S)-enantiomer counteracts side effect of the eutomer. Here both the enantiomers contribute to the overall desired effect in different ways.

As indicated earlier, the (R)- enantiomer is the pharmacologically active diuretic. Like most other diuretics, the (R)-isomer possesses an undesirable side-effect of retaining uric acid. But the (S)-enantiomer, the distomer, has the property of assisting uric acid secretion (uricosuric effect), and, therefore, antagonizing the undesirable side-effects of the eutomer (uric-acid retention). It affords a good argument for the marketing of a racemic mixture. But studies exemplify that 9:1 mixture of the two enantiomers provides optimal therapeutic value.

Synthesis
The Friedel-Crafts acylation of 2,3-dichloroanisole [1984-59-4] (1) with phenylacetyl chloride [103-80-0] (2) gives 2,3-dichloro-4-phenylacetylanisole [59043-83-3] (3). A variation of the Mannich reaction is performed employing tetramethyldiaminomethane [51-80-9] (this is an aminal of dimethylamine and formaldehyde). The intermediate reaction product (5), which is not isolated, would undergo a β-Hydride elimination with concomitant loss of dimethylamine and formation of the corresponding enone, 2,3-Dichloro-4-(2-phenylacryloyl)anisole (PC10924810) (6). Acid catalyzed (H2SO4) intramolecular cyclization gives the indanone (PC10990444) (7). This is O-demethylated under acidic conditions to give 2-Phenyl-5-hydroxy-6,7-dichloro-1-indanone, PC12774089 (8). The phenol thus obtained is then alkylated on oxygen by iodoacetic acid [64-69-7] (9) affording PC20520826 (10). Alkylation with iodomethane [74-88-4] in the presence of sodium hydride completed the synthesis of indacrinone (11).