Moracizine

Moracizine^[1] or moricizine, sold under the trade name Ethmozine, is an antiarrhythmic of class IC.^[2] It was used for the prophylaxis and treatment of serious and life-threatening ventricular arrhythmias,^[3] but was withdrawn in 2007 for commercial reasons.^[4]

Moracizine

Clinical data
Trade names	Ethmozine
Other names	Moricizine (USAN US)
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a601214
Pregnancy category	B (U.S.)
ATC code	C01BG01 (WHO)
Pharmacokinetic data
Bioavailability	34–38%
Protein binding	95%
Elimination half-life	3–4 hours (healthy volunteers), 6–13 hours (cardiac disease)
Identifiers
IUPAC name ethyl [10-(3-morpholin-4-ylpropanoyl)-10H-phenothiazin-2-yl]carbamate
CAS Number	31883-05-3^Y
PubChem CID	34633
IUPHAR/BPS	7244
DrugBank	DB00680^N
ChemSpider	31872^Y
UNII	2GT1D0TMX1
KEGG	D05077^Y
ChEBI	CHEBI:6997^Y
ChEMBL	ChEMBL1075^Y
CompTox Dashboard (EPA)	DTXSID4023335
ECHA InfoCard	100.046.216
Chemical and physical data
Formula	C22H25N3O4S
Molar mass	427.52 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C(OCC)Nc2cc1N(c3c(Sc1cc2)cccc3)C(=O)CCN4CCOCC4
InChI InChI=1S/C22H25N3O4S/c1-2-29-22(27)23-16-7-8-20-18(15-16)25(17-5-3-4-6-19(17)30-20)21(26)9-10-24-11-13-28-14-12-24/h3-8,15H,2,9-14H2,1H3,(H,23,27)^Y Key:FUBVWMNBEHXPSU-UHFFFAOYSA-N^Y
^NY (what is this?)  (verify)

Pharmacology

Moracizine, a phenothiazine derivative, undergoes extensive first-pass metabolism and is also extensively metabolized after it has entered the circulation. It may have pharmacologically active metabolites. A clinical study has shown that moracizine is slightly less effective than encainide or flecainide in suppressing ventricular premature depolarizations.^{[citation needed]} Compared with disopyramide and quinidine, moracizine was equally or more effective in suppressing premature ventricular contractions, couplets, and nonsustained ventricular tachycardia.^{[citation needed]}

In the Cardiac Arrhythmia Suppression Trial (CAST), a large study testing the influence of antiarrhythmics on mortality, showed a statistically non-significant increase of mortality from 5.4 to 7.2% under moracizine. This is in line with other class IC antiarrhythmics.^[5]

Synthesis

Note: The carbamate structure reminds the reader of Gastrophenzine or particularly Ethacizine.

 

Synthesis:^[6] Patents:^[7][8][9]

The amide formation between Phenothiazine-2-ethylcarbamate [37711-29-8] (1) and 3-Chloropropionyl chloride [625-36-5] (2) gives ethyl N-[10-(3-chloropropanoyl)phenothiazin-2-yl]carbamate [119407-03-3] [34749-22-9] (3). Displacement of the remaining ω-halogen by morpholine (4) then completes the synthesis of Moricizine (5).

References

1. "The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances" (PDF). World Health Organization. 2009. p. 103.
2. Ahmmed GU, Hisatome I, Kurata Y, Makita N, Tanaka Y, Tanaka H, et al. (March 2002). "Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block". Vascular Pharmacology. 38 (3): 131–41. doi:10.1016/S1537-1891(02)00213-6. PMID 12402511.
3. British National Formulary (59th ed.). British Medical Journal Publishing Group, Pharmaceutical Press. 2010.
4. . Heart Rhythm Society. Archived from the original on December 10, 2011. Retrieved January 12, 2012.
5. Cardiac Arrhythmia Suppression Trial II Investigators (July 1992). "Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction". The New England Journal of Medicine. 327 (4): 227–33. doi:10.1056/NEJM199207233270403. PMID 1377359.
6. Gritsenko, A.N., Ermakova, Z.I. & Zhuravlev, S.V. Pharm Chem J (1972) 6: 575.
7. Anna Nikitichna Gritsenko, 5 More », U.S. patent 3,740,395 (1973).
8. Gary O. Page, U.S. patent 5,202,435 (1993 to Roberts Laboratories Inc, Bristol Myers Squibb Pharma Co).
9. L.P. Nikitenkov, et al. RU 2159771  (2000 to).