Etacrynic acid

Structural formula
General
Non-proprietary name	Etacrynic acid
other names	Ethacrylic acid; [2,3-dichloro-4- (2-methylenebutanoyl) phenoxy] acetic acid ( IUPAC ) ;
Molecular formula	C 13 H 12 Cl 2 O 4
External identifiers / databases
EC number	200-384-1
ECHA InfoCard	100,000,349
PubChem	3278
ChemSpider	3163
DrugBank	DB00903
Wikidata	Q418571
Drug information
ATC code	C03 CC01
Drug class	Loop diuretic
properties
Molar mass	303.14 g mol −1
Physical state	firmly
Melting point	122.5 ° C
pK s value	3.50
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Caution
H and P phrases	H: 302-312-315-319-332-335
	P: 261-280-305 + 351 + 338
Toxicological data	1000 mg kg −1 ( LD 50 , rat , oral ) ; 43 mg kg −1 ( LD 50 , rat , ip ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Etacrynic acid (also: ethacrynic acid ) is a loop diuretic .

From a chemical and structural point of view, it is a derivative of 2,3-dichlorophenol, which is acylated in the 4-position of the aromatic with 2-methylenebutyric acid and substituted on the oxygen by acetic acid .

It differs from other loop diuretics in its luminal and capillary effects. Irreversible hearing damage was described as side effect. Studies indicate that etacrynic acid does not work directly, but only the phase II metabolite, the cysteine conjugate , has the effect. The conjugate is believed to have a mechanism of action similar to that of the furosemide- type loop diuretics .

history

Etacrynic acid was first described in the literature by EM Schultz in 1962. The substance class around etacrynic acid was filed for a patent in 1961 by Merck & Co.

presentation

The synthetic route starts from 2,3-dichlorophenoxyacetic acid , which is converted to 2,3-dichloro-4-butyrylphenoxyacetic acid in a Friedel-Crafts acylation with butyryl chloride in carbon disulfide (CS ₂ ) with activation of the acid chloride by aluminum chloride (AlCl ₃ ) . This is aminomethylated in a Mannich reaction (with paraformaldehyde , dry dimethylammonium chloride and catalytic amounts of acetic acid ) in the α-position to the keto group and then olefinated to the α, β-unsaturated ketone acrynic acid with cleavage of the amine by treatment with a base (aqueous sodium hydrogen carbonate ) .

Trade name

Hydromedine

Individual evidence

↑ David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Physical Constants of Organic Compounds, pp. 3-232.
↑ David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Dissociation Constants of Organic Acids and Bases, pp. 8-50.
↑ ^a ^b ^c ^d Datasheet Ethacrynic acid from Sigma-Aldrich , accessed on October 18, 2016 ( PDF ).
↑ Palfrey, HC and Leung, S. Am. J. Physiol. 1993, 264, C1270-C1277.
↑ Everett M. Schultz, Edward J. Cragoe, John B. Bicking, William A. Bolhofer, James M. Sprague: α, β- Unsaturated Ketone Derivatives of Aryloxyacetic Acids, a New Class of Diuretics . In: Journal of Medicinal and Pharmaceutical Chemistry . tape 5 , no. 3 , May 1962, pp. 660 , doi : 10.1021 / jm01238a030 .
↑ Patent US3255241 : (2-Alkylidene acyl) phenoxy- and (2-Alkylidene acyl) phenylmercaptocarboxylic acids. Applied January 19, 1961 , published June 7, 1966 , Applicants: Merck & Co. Inc., Inventors: Everett M. Schultz, James M. Sprague. ‌
↑ Ulrich Käppler: Synthesis and testing of non-peptide cysteine protease inhibitors - etacrynic acid as the lead structure . Dissertation, Würzburg, 2004. DNB 976079887/34 .

[1] David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Physical Constants of Organic Compounds, pp. 3-232.

[CRC90_8_50-2] David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Dissociation Constants of Organic Acids and Bases, pp. 8-50.

[Sigma-3] Datasheet Ethacrynic acid from Sigma-Aldrich , accessed on October 18, 2016 ( PDF ).

[4] Palfrey, HC and Leung, S. Am. J. Physiol. 1993, 264, C1270-C1277.

[5] Everett M. Schultz, Edward J. Cragoe, John B. Bicking, William A. Bolhofer, James M. Sprague: α, β- Unsaturated Ketone Derivatives of Aryloxyacetic Acids, a New Class of Diuretics . In: Journal of Medicinal and Pharmaceutical Chemistry . tape 5 , no. 3 , May 1962, pp. 660 , doi : 10.1021 / jm01238a030 .

[6] Patent US3255241 : (2-Alkylidene acyl) phenoxy- and (2-Alkylidene acyl) phenylmercaptocarboxylic acids. Applied January 19, 1961 , published June 7, 1966 , Applicants: Merck & Co. Inc., Inventors: Everett M. Schultz, James M. Sprague. ‌

[7] Ulrich Käppler: Synthesis and testing of non-peptide cysteine protease inhibitors - etacrynic acid as the lead structure . Dissertation, Würzburg, 2004. DNB 976079887/34 .