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Metopimazine

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Metopimazine
Clinical data
Trade namesNortrip, Vogalen, Vogalene
Other namesEXP-999; NG-102; RP-9965
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.034.367 Edit this at Wikidata
Chemical and physical data
FormulaC22H27N3O3S2
Molar mass445.60 g·mol−1
3D model (JSmol)
  • O=S(=O)(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCC(C(=O)N)CC4)C
  • InChI=1S/C22H27N3O3S2/c1-30(27,28)17-7-8-21-19(15-17)25(18-5-2-3-6-20(18)29-21)12-4-11-24-13-9-16(10-14-24)22(23)26/h2-3,5-8,15-16H,4,9-14H2,1H3,(H2,23,26) checkY
  • Key:BQDBKDMTIJBJLA-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Metopimazine (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name), sold under the brand names Nortrip, Vogalen, and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting.[1][2][3][4][5][6] It is marketed in Europe, Canada, and South America.[2][5] As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.[6][5]

Metopimazine has antidopaminergic, antihistamine, and anticholinergic activity.[7] However, it has also been described as a highly potent and selective dopamine D2 and D3 receptor antagonist.[5] The D2 receptor antagonism of metopimazine is thought to underlie its antiemetic and gastroprokinetic effects.[5] It is said to not readily cross the blood–brain barrier and hence to have peripheral selectivity, in contrast to metoclopramide but similarly to domperidone.[5] Unlike domperidone however, metopimazine shows no hERG inhibition and hence is expected to have a more favorable cardiovascular profile.[5] In contrast to metoclopramide, metopimazine does not interact with serotonin 5-HT3 and 5-HT4 receptors.[5]

Synthesis

Thieme Patent:[8] Revised:[9]

For the first step, 2-Methylthiophenothiazine [7643-08-5] (1) is protected by sequential reaction with sodium amide and acetic anhydride to give 1-[2-(Methylthio)-10H-phenothiazin-10-yl]ethanone [23503-69-7] (2). Oxidation with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone. Upon hydrolysis of the acetate this affords 2-(methylsulfonyl)-10h-phenothiazine [23503-68-6] (3). Alkylation with 1-Bromo-3-chloropropane (4) gives 10-(3-chloropropyl)-2-methylsulfonylphenothiazine [40051-30-7] (5). Alkylation with piperidine-4-carboxamide (Isonipecotamide) [39546-32-2] (6) affords metopimazine (7).

References

  1. ^ J. Elks, ed. (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 817–. ISBN 978-1-4757-2085-3. OCLC 1058412474.
  2. ^ a b Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 683–. ISBN 978-3-88763-075-1.
  3. ^ I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 180–. ISBN 9789401144391. OCLC 1243535030.
  4. ^ Herrstedt J (September 1998). "Chemotherapy-induced nausea and vomiting with special emphasis on metopimazine". Danish Medical Bulletin. 45 (4): 412–22. PMID 9777292.
  5. ^ a b c d e f g h Heckroth M, Luckett RT, Moser C, Parajuli D, Abell TL (April 2021). "Nausea and Vomiting in 2021: A Comprehensive Update". J Clin Gastroenterol. 55 (4): 279–299. doi:10.1097/MCG.0000000000001485. PMC 7933092. PMID 33471485.
  6. ^ a b "Metopimazine - Neurogastrx - AdisInsight".
  7. ^ Bezin J, Noize P, Mansiaux Y, Jarne A, Pariente A (March 2021). "Antidopaminergic antiemetics and trauma-related hospitalization: A population-based self-controlled case series study". Br J Clin Pharmacol. 87 (3): 1303–1309. doi:10.1111/bcp.14510. ISSN 0306-5251. PMID 32737898. S2CID 220909387.
  8. ^ Robert Michel Jacob, Jacques Georges Robert, DE 1092476  (1960 to Rhone Poulenc Sa).
  9. ^ Karicherla, Venumanikanta; Phani, Kumar; Bodireddy, Mohan Reddy; Prashanth, Kumar Babu; Gajula, Madhusudana Rao; Pramod, Kumar (2017). "A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D2-Receptor Antagonist". Organic Process Research & Development. 21 (5): 720–731. doi:10.1021/acs.oprd.7b00052.



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