Indacrinone

Indacrinone
Identifiers
	IUPAC name [(6,7-Dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid;
CAS Number	56049-88-8;
PubChem CID	42266;
ChemSpider	38545;
UNII	B926Y9U4QN;
CompTox Dashboard (EPA)	DTXSID60866624 ;
ECHA InfoCard	100.054.496
Chemical and physical data
Formula	C18H14Cl2O4
Molar mass	365.21 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1(Cc2cc(c(c(c2C1=O)Cl)Cl)OCC(=O)O)c3ccccc3;
	InChI InChI=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); Key: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,^[1] while other diuretics increase it.

Chirality and biological activity[edit]

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).^[2]^[3] 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.^[4]

Synthesis[edit]

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).

References[edit]

^ Vlasses PH, Rotmensch HH, Swanson BN, Irvin JD, Johnson CL, Ferguson RK (1984). "Indacrinone: natriuretic and uricosuric effects of various ratios of its enantiomers in healthy men". Pharmacotherapy. 4 (5): 272–7. doi:10.1002/j.1875-9114.1984.tb03374.x. PMID 6504708. S2CID 19743065.
^ Ariëns, Everardus J. (1986). "Stereochemistry: A source of problems in medicinal chemistry". Medicinal Research Reviews. 6 (4): 451–466. doi:10.1002/med.2610060404. ISSN 0198-6325. PMID 3534485. S2CID 36115871.
^ Kannappan, Valliappan. "Indacrinone – Chiralpedia". Retrieved 2022-08-28.
^ The impact of stereochemistry on drug development and use. Hassan Y. Aboul-Enein, Irving W. Wainer. New York: Wiley. 1997. ISBN 0-471-59644-2. OCLC 35262289.{{cite book}}: CS1 maint: others (link)
^ Castaer, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179.
^ 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.
^ Edward J. Cragoe, Jr. & Otto W. WOLTERSDORF, Jr., U.S. patent 4,096,267 (1978 to Merck and Co Inc).
^ Edward H. Blaine, et al. U.S. patent 4,510,322 (1985 to Merck and Co Inc).
^ 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.

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[1] Vlasses PH, Rotmensch HH, Swanson BN, Irvin JD, Johnson CL, Ferguson RK (1984). "Indacrinone: natriuretic and uricosuric effects of various ratios of its enantiomers in healthy men". Pharmacotherapy. 4 (5): 272–7. doi:10.1002/j.1875-9114.1984.tb03374.x. PMID 6504708. S2CID 19743065.

[2] Ariëns, Everardus J. (1986). "Stereochemistry: A source of problems in medicinal chemistry". Medicinal Research Reviews. 6 (4): 451–466. doi:10.1002/med.2610060404. ISSN 0198-6325. PMID 3534485. S2CID 36115871.

[3] Kannappan, Valliappan. "Indacrinone – Chiralpedia". Retrieved 2022-08-28.

[4] The impact of stereochemistry on drug development and use. Hassan Y. Aboul-Enein, Irving W. Wainer. New York: Wiley. 1997. ISBN 0-471-59644-2. OCLC 35262289.{{cite book}}: CS1 maint: others (link)

[5] Castaer, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179.

[6] 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.

[7] Edward J. Cragoe, Jr. & Otto W. WOLTERSDORF, Jr., U.S. patent 4,096,267 (1978 to Merck and Co Inc).

[8] Edward H. Blaine, et al. U.S. patent 4,510,322 (1985 to Merck and Co Inc).

[9] 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.

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Chirality and biological activity[edit]

Synthesis[edit]

See also[edit]

References[edit]