Enallylpropymal

Enallylpropymal (INN)
Clinical data
Trade namesNarconumal, "Methyl Numal"
Other namesEnallylpropymal
Routes of
administration		IV, oral
ATC code
  • none
Legal status
Legal status
Identifiers
  • RS-1-Methyl-5-allyl-5-isopropyl-1,3-diazinane-2,4,6-trione
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.015.876 Edit this at Wikidata
Chemical and physical data
FormulaC11H16N2O3
Molar mass224.260 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • O=C1NC(=O)N(C)C(=O)C1(C(C)C)CC=C
  • InChI=1S/C11H16N2O3/c1-5-6-11(7(2)3)8(14)12-10(16)13(4)9(11)15/h5,7H,1,6H2,2-4H3,(H,12,14,16)
  • Key:AXJXURWWUFZZKN-UHFFFAOYSA-N
  (verify)

Enallylpropymal (INN; trade name Narconumal) is a rapid-acting anesthetic. It is an N-methylated barbiturate retaining an oxygen atom at the C2 position, in contrast to thiobarbiturates such as thiopentone. It acts as a central nervous system depressant with sedative and soporific effects and was used primarily in Europe as an intravenous anaesthetic induction agent. Chemically, it is N-methyl-5,5-allylisopropylbarbituric acid. The compound and its sodium salt were introduced as potent sedative-hypnotics and were protected by a United States patent granted to Hoffmann-La Roche in 1937. It was marketed principally under the trade name Narconumal and was also known colloquially as "Methyl Numal".

Chemistry

Enallylpropymal crystallizes in a single known crystalline form, consisting of centrosymmetric N–H⋯O hydrogen-bonded dimers built around an essentially planar barbiturate ring, as determined by X-ray crystallography. This distinguishes its solid-state packing from some other N-monosubstituted barbituric acid derivatives, which instead form hydrogen-bonded helical chains. An earlier thermomicroscopic and differential scanning calorimetry study had already established a melting point of 58–61 °C, notably low relative to other N-monosubstituted derivatives of barbituric acid, a finding the crystallographic study's own thermal measurements corroborated.

History

Enallylpropymal was developed by Otto Schneider at Hoffmann-La Roche in 1934 in Switzerland, molecularly identified as N-methyl-5,5-allyl-isopropyl-barbituric acid. The compound was synthesized as a sodium salt modification to improve water solubility and rapid onset for clinical administration.

Dundee and McIlroy (1982) described Narconumal as a "popular" choice of sedative in France, a characterization echoed independently by Ball and Westhorpe (2001) in their historical review of intravenous anaesthesia. Clinical use extended beyond France: Barron's 1962 induction trial (below) establishes that the drug was also supplied and used clinically in the United Kingdom, and case reports document its use for induction of anaesthesia across continental Europe through the late 1940s and early 1950s.

Clinical use across continental Europe

David Barron study

In 1961-62, David W. Barron at The Queen's University of Belfast compared the induction characteristics of enallylpropymal with a brominated oxybarbiturate analog Narcodorm, with thiopentone as a reference standard. For the trial, Narconumal was supplied by Roche Products Ltd. Both drugs produced a fairly high incidence of excitatory phenomena — more pronounced with atropine premedication than with opiate premedication — as well as hypotension. in 1982, Dundee and McIlroy separately reported that Barron had found a particularly high incidence of muscle movement associated with Narconumal's use during induction.

Federal drug policy of the United States designates 5-allyl-5-isopropyl-1-methylbarbituric acid and the trade name Narconumal as a "habit-forming" but "non-narcotic" derived from barbituric acid, thus a Schedule III controlled substance.

In the Philippines, the compound was separately listed as a Schedule B regulated drug under both the trade name "Narconumal-Enallylpropymal" and the generic name "Enallylpropymal".

Notes

  1. ↑ The same 1972 Philippine list also includes two variant spellings: "Emalilpropimal-Enallylpropymal" and "Enallynymalnatrium." The former appears to be a straightforward transcription variant of "Enallylpropymal." The latter's "-natrium" suffix (from the Latin natrium, sodium) is consistent with the naming convention used elsewhere in the same list for sodium-salt formulations, and may denote the sodium salt of the compound described above — though this identification is not independently confirmed.

References

  1. 1 2 3 "DDB Board Regulation No. 6, s. 1972 — List of Regulated Drugs Pursuant to the Provisions of Section 40 of Republic Act No. 6425, As Amended". Dangerous Drugs Board, Republic of the Philippines. 11 December 1972. National Administrative Register, Vol. 1, No. 2 (April–June 1990) – via Supreme Court E-Library.
  2. 1 2 US 2072829, Schnider O, "N-Methyl-5,5-allylisopropylbarbituric acid", published 1937-03-02, issued 2 March 1937, assigned to Hoffmann-La Roche Inc.
  3. 1 2 3 4 Gelbrich T, Zencirci N, Griesser UJ (2010). "Hydrogen-bond motifs in N-monosubstituted derivatives of barbituric acid: 5-allyl-5-isopropyl-1-methylbarbituric acid (enallylpropymal) and 1,5-di(but-2-enyl)-5-ethylbarbituric acid". Acta Crystallographica Section C. 66 (1): o55–o58. doi:10.1107/S0108270109054249. PMID 20048427.
  4. 1 2 3 Dundee JW (July 1982). "The methylated oxybarbiturates". Anaesthesia. 37 (7): 726–733. doi:10.1111/j.1365-2044.1982.tb01310.x. PMID 7049575.
  5. ↑ Ball C, Westhorpe R (August 2001). "The history of intravenous anaesthesia". Anaesthesia and Intensive Care. 29 (4): 323.
  6. ↑ Lerch K (June 1947). "[Experience of Intravenous Anesthesia with Narconumal]". Wiener Klinische Wochenschrift (in German). 59 (25): 418–420. PMID 20252420.
  7. ↑ Ceria G (May 1947). "[Intravenous narcosis with narconumal]". Clinica Odontoiatrica; Revista Mensile Di Operativa Dentaria, Chirurgia Orale, Ortodontia e Protesi (in Italian). 2 (5): 100–106. PMID 20259145.
  8. ↑ Kranz H (December 1952). "[Experiences with narconumal in 500 short narcoses]". Die Medizinische (in German). 20 (50): 1598–1599. PMID 13024624.
  9. 1 2 3 Barron DW (June 1962). "Clinical Studies of Induction Agents: II: A Comparison of the Incidence of Induction Complications With Two Methylated Oxybarbiturates, Narconumal and Narcodorm". BJA: British Journal of Anaesthesia. 34 (6): 391–394. doi:10.1093/bja/34.6.391.
  10. ↑ "21 CFR § 329.1 — Habit-forming drugs which are chemical derivatives of substances specified in section 502(d) of the Federal Food, Drug, and Cosmetic Act" (PDF). U.S. Government Publishing Office. 39 FR 11736.