indacrinone
{{Short description|Chemical compound}}
{{Infobox drug
| drug_name =
| IUPAC_name = [(6,7-Dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid
| image = Indacrinone.svg
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| CAS_number = 56049-88-8
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = B926Y9U4QN
| ChemSpiderID = 38545
| ATCvet =
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| PubChem = 42266
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| C=18 | H=14 | Cl=2 | O=4
| smiles = CC1(Cc2cc(c(c(c2C1=O)Cl)Cl)OCC(=O)O)c3ccccc3
| StdInChI = 1S/C18H14Cl2O4/c1-18(11-5-3-2-4-6-11)8-10-7-12(24-9-13(21)22)15(19)16(20)14(10)17(18)23/h2-7H,8-9H2,1H3,(H,21,22)
| StdInChIKey = PRKWVSHZYDOZLP-UHFFFAOYSA-N
}}
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,{{cite journal | vauthors = Vlasses PH, Rotmensch HH, Swanson BN, Irvin JD, Johnson CL, Ferguson RK | title = Indacrinone: natriuretic and uricosuric effects of various ratios of its enantiomers in healthy men | journal = Pharmacotherapy | volume = 4 | issue = 5 | pages = 272–7 | year = 1984 | pmid = 6504708 | doi = 10.1002/j.1875-9114.1984.tb03374.x | s2cid = 19743065 }} while other diuretics increase it.
Chirality and biological activity
File:Indacrinone Enantiomers.png
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).{{Cite journal |last=Ariëns |first=Everardus J. |date=1986 |title=Stereochemistry: A source of problems in medicinal chemistry |url=http://dx.doi.org/10.1002/med.2610060404 |journal=Medicinal Research Reviews |volume=6 |issue=4 |pages=451–466 |doi=10.1002/med.2610060404 |pmid=3534485 |s2cid=36115871 |issn=0198-6325|url-access=subscription }}{{Cite web |last=Kannappan |first=Valliappan |title=Indacrinone – Chiralpedia |url=https://chiralpedia.com/blog/indacrinone/ |access-date=2022-08-28 |language=en-US}} 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.{{Cite book |url=https://www.worldcat.org/oclc/35262289 |title=The impact of stereochemistry on drug development and use |date=1997 |publisher=Wiley |others=Hassan Y. Aboul-Enein, Irving W. Wainer |isbn=0-471-59644-2 |location=New York |oclc=35262289}}
Synthesis
File:Indacrinone synthesis.svg
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).
See also
References
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{{cardiovascular-drug-stub}}
{{Diuretics}}
{{DEFAULTSORT:Loop Diuretic}}