{{Short description|Chemical compound}} {{Infobox drug | drug_name = | IUPAC_name = [(6,7-Dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1''H''-inden-5-yl)oxy]acetic acid | image = Indacrinone.svg | image_class = skin-invert-image | alt = | caption =
<!-- Clinical data --> | tradename = | Drugs.com = | MedlinePlus = | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category= | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM --> | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_status = | routes_of_administration =
<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | onset = | elimination_half-life = | excretion =
<!-- Identifiers --> | CAS_number = 56049-88-8 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = B926Y9U4QN | ChemSpiderID = 38545 | ATCvet = | ATC_prefix = <!-- 'none' if uncategorised --> | ATC_suffix = | PubChem = 42266 | DrugBank =
<!-- Chemical data --> | 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,<ref>{{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 }}</ref> while other diuretics increase it.
== Chirality and biological activity == alt=Indacrinone enantiomeric pair exhibiting therapeutic advantage|thumb| '''Indacrinone - Chiral twins'''|center|507x507px 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).<ref>{{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 }}</ref><ref>{{Cite web |last=Kannappan |first=Valliappan |title=Indacrinone – Chiralpedia |url=https://chiralpedia.com/blog/indacrinone/ |access-date=2022-08-28 |language=en-US}}</ref> 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.<ref>{{Cite book |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}}</ref> ==Synthesis== [[File:Indacrinone synthesis.svg|thumb|center|700px|[https://www.chemdrug.com/article/8/3284/16419186.html ChemDrug] Synthesis:<ref>Castaer, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179.</ref><ref>Desolms, S. J.; Woltersdorf, O. W.; Cragoe, E. J.; Watson, L. S.; Fanelli, G. M. (1978). "(Acylaryloxy)acetic acid diuretics. 2. (2-Alkyl-2-aryl-1-oxo-5-indanyloxy)acetic acids". Journal of Medicinal Chemistry 21 (5): 437. doi:10.1021/jm00203a006.</ref> Patent:<ref>Edward J. Cragoe, Jr. & Otto W. WOLTERSDORF, Jr., {{US patent|4096267}} (1978 to Merck and Co Inc).</ref> Use patent:<ref>Edward H. Blaine, et al. {{US patent|4510322}} (1985 to Merck and Co Inc).</ref> Enantioselective method:<ref>Dolling, Ulf H.; Davis, Paul; Grabowski, Edward J. J. (1984). "Efficient catalytic asymmetric alkylations. 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis". Journal of the American Chemical Society. 106 (2): 446–447. doi:10.1021/ja00314a045.</ref>]] 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 (H<sub>2</sub>SO<sub>4</sub>) 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 ==
* Chiral drugs * Chirality * Eudisimic ratio
== References == {{Reflist}}
Category:Diuretics Category:Carboxylic acids Category:Chloroarenes
{{cardiovascular-drug-stub}}
{{Diuretics}}
{{DEFAULTSORT:Loop Diuretic}} *