Piritramide

Piritramide[2](R-3365, trade names Dipidolor, Piridolan, Pirium and others) is a synthetic opioid analgesic (narcotic painkiller) that is marketed in certain European countries including: Austria, Belgium, Czech Republic, Slovenia, Germany and the Netherlands.[3] It comes in free form, is about 0.75x times as potent as morphine and is given parenterally (by injection) for the treatment of severe pain.[3][4] Nausea, vomiting, respiratory depression and constipation are believed to be less frequent with piritramide than with morphine (the gold standard opioid against which other opioids are compared and contrasted), and it produces more rapid-onset analgesia (pain relief) when compared to morphine and pethidine. After intravenous administration the onset of analgesia is as little as 1–2 minutes, which may be related to its great lipophilicity.[5] The analgesic and sedative effects of piritramide are believed to be potentiated with phenothiazines and its emetic (nausea/vomiting-inducing) effects are suppressed.[5] The volume of distribution is 0.7-1 L/kg after a single dose, 4.7-6 L/kg after steady-state concentrations are achieved and up to 11.1 L/kg after prolonged dosing.[5]

Piritramide
Clinical data
Trade namesDipidolor
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • No teratogenic effects in preclinical studies; but, as with other opioids it may cause reversible adverse effects in the newborn.
Routes of
administration		Oral, IM, IV
ATC code
Legal status
Legal status
  • AU: S8 (Controlled drug)
  • CA: Schedule I
  • DE: Anlage III (Special prescription form required)
  • US: Schedule I
Pharmacokinetic data
Protein binding95%[1]
MetabolismLiver
Elimination half-life4-10 hours (acute dosing), 17.4 hours (chronic dosing)
Identifiers
IUPAC name
  • 1-(3-Cyano-3,3-diphenyl-propyl)-4-(1-piperidyl)piperidine-4-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.569
Chemical and physical data
FormulaC27H34N4O
Molar mass430.596 g·mol−1
3D model (JSmol)
SMILES
  • N#CC(C1=CC=CC=C1)(CCN2CCC(N3CCCCC3)(CC2)C(N)=O)C4=CC=CC=C4
InChI
  • InChI=1S/C27H34N4O/c28-22-26(23-10-4-1-5-11-23,24-12-6-2-7-13-24)14-19-30-20-15-27(16-21-30,25(29)32)31-17-8-3-9-18-31/h1-2,4-7,10-13H,3,8-9,14-21H2,(H2,29,32) Y
  • Key:IHEHEFLXQFOQJO-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Piritramide was developed and patented in Belgium, at Janssen, in 1960. It is part of an eponymous two-member class of opioids in clinical use with the other being bezitramide (Burgodin). The closest chemical and structural relatives of piritramide in clinical use include the diphenoxylate family, fentanyl (both Janssen discoveries) and somewhat more distantly alphaprodine.

Not being in clinical use in the United States, it is a Schedule I Narcotic controlled substance with a DEA ACSCN of 9642 and manufacturing quota of zero.[6]

Synthesis
Patents:[7][8][9] Modern:[10]

The last step in the synthesis consists of attachment of the sidechain by an Sn2 alkylation between 4-bromo-2,2-diphenylbutanenitrile [39186-58-8] (1) and 1,4'-bipiperidine-4'-carboxamide [39633-82-4] (2) catalyzed by KI (Finkelstein reaction) in the presence of sodium carbonate base and in anhydrous toluene solvent yielding Piritramide (3)..

References
  1. Jage J, Laufenberg-Feldmann R, Heid F (May 2008). "[Drugs for postoperative analgesia: routine and new aspects: Part 2: opioids, ketamine and gabapentinoids]" [Drugs for postoperative analgesia: routine and new aspects: Part 2: opioids, ketamine and gabapentinoids]. Der Anaesthesist (in German). 57 (5): 491–8. doi:10.1007/s00101-008-1327-9. PMID 18409073.
  2. US Patent 3080366
  3. Brayfield A, ed. (23 September 2011). "Piritramide". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 22 April 2014.
  4. Kay B (December 1971). "A clinical investigation of piritramide in the treatment of postoperative pain". British Journal of Anaesthesia. 43 (12): 1167–71. doi:10.1093/bja/43.12.1167. PMID 4945251. S2CID 17729725.
  5. "FACHINFORMATION (Zusammenfassung der Merkmale des Arzneimittels)" [PROFESSIONAL INFORMATION (Summary of Product Characteristics)] (PDF). Janssen. Janssen - Cilag Pharma GmbH. November 2013. Retrieved 9 April 2014.
  6. "DEA Diversion Control Division".
  7. Paul A J Janssen, U.S. Patent 3,080,366 (1963 to).
  8. Med Paul Adriaan Jan Jansse Dr, DE 1238472 (1967 to Janssen Pharmaceutica Nv).
  9. Paul Adriaan Jan Janssen, BE 606850 (1961).
  10. Ivan Kakalík, et al. EP 2354133 (2011 to hameln rds GmbH).
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