Home > Archives > IJSRST1731027 IJSRST-Library

Synthesis and Characterization of Related Substances Observed in Macitentan, an Endothelien Receptor Antagonist

Authors(3) :-Kunal M. Jagtap, Raghunath B. Toche, Vijayavitthal T. Mathad

During the process development of Macitentan (1), four related substance (impurities) were detected by high performance liquid chromatography (HPLC) in the final crude material ranging from 0.20 to 0.50% and these are identified by Liquid chromatography-mass spectrometry (LC–MS). All impurities were subsequently synthesized, characterized by spectroscopic techniques and further analyzed and confirmed by chromatographic techniques by spiking and purging study and this impurities are namely 2, 2’-{[5-(4-bromophenyl) pyrimidine-4,6-diyl]bis(oxy)}diethanol (8), 5-(4-bromo-phenyl)-4,6-bis-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]- pyrimidine (9), N-[5-(4-bromophenyl)-6-(2-{[5-(4-bromophenyl)-6-chloropyrimidin-4-yl]oxy}ethoxy)-4-pyrimidinyl] -N’-propylsulfamide (10) and 2-{[5-(4-bromophenyl)-6-{[(propylamino)sulfonyl]amino} pyrimidin-4-yl]oxy}ethylacetate (11).
Kunal M. Jagtap, Raghunath B. Toche, Vijayavitthal T. Mathad
Macitentan, Antagonist, Impurities, Synthesis.
  1. Hong, I.S., Coe, H.V., & Catanzaro, L.M. (2014). Macitentan for the treatment of pulmonary arterial hypertension. The Annals of Pharmacotherapy, 48, 1-10.
  2. Iglarz, M., Qiu, C., Fischli, W., Morrison, K., Binkert, C., Clozel, M., Hess, P., Capeleto, B., Buchmann, S., Boss, C., Bolli, M.H., Weller, T., Treiber, A., & Gatfield, J. (2008). Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. Journal of Pharmacology and Experimental Therapeutics, 327(3), 736-745
  3. Gatfield, J., Grandjean, C. M., Sasse, T., Clozel, M., & Nayler, O. (2012). Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS ONE, 7(10), e47662.
  4. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Goto K, Masaki T (1988) Nature 332:411
  5. Battistini B, Botting R, Endothelins (1995) Drug News Persp 8:365
  6. Kohan DE (2008) Curr Hypertens Rep 10:65
  7. Thorin E, Clozel M (2010) Adv Pharmacol 60:1
  8. International Conference on Harmonization guidelines Q3A (R) Impurities in New Drug Substances February 2002 (this guideline provides guidance for registration application on the content and qualification of impurities in new drug substances produced by the chemical synthesis) 18 October 2016.
  9. Bolli MH, Boss C, Binkert C, Clozel M, Fischli W, Weller T (2006) Sulfamide and their use as endothelin receptor antagonist. US Patent 7,094,781B2, Aug 22, 2006; (2006).
  10. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T (2012) J Med Chem 55:7849
Publication Details
  Published in : Volume 3 | Issue 10 | November-December 2017
  Date of Publication : 2017-12-31
License:  This work is licensed under a Creative Commons Attribution 4.0 International License.
Page(s) : 137-141
Manuscript Number : IJSRST1731027
Publisher : Technoscience Academy
PRINT ISSN : 2395-6011
ONLINE ISSN : 2395-602X
Cite This Article :
Kunal M. Jagtap, Raghunath B. Toche, Vijayavitthal T. Mathad, "Synthesis and Characterization of Related Substances Observed in Macitentan, an Endothelien Receptor Antagonist", International Journal of Scientific Research in Science and Technology(IJSRST), Print ISSN : 2395-6011, Online ISSN : 2395-602X, Volume 3, Issue 10, pp.137-141, November-December-2017.
Journal URL : http://ijsrst.com/IJSRST1731027

Article Preview