Glutethimide: Difference between revisions

{{short description|Medication}}

{{drugbox

| Watchedfields = changed

| verifiedrevid = 416746257

| IUPAC_name = 3-ethyl-3-phenyl-piperidine-2,6-dione

| image = Glutethimide.svg

| width = 150

| image2 = Glutethimide ball-and-stick model.png

| width2 = 180

<!--Clinical data-->| tradename = Doriden, Elrodorm, Noxyron, others

| Drugs.com =

| pregnancy_category = C: (United States)

| legal_status =

| legal_AU = S8

| legal_BR = B1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = Schedule IV

| legal_US = Schedule II

| legal_UK = Class B

| legal_UN = P III

| legal_DE = Anlage II

| routes_of_administration = By mouth

| dependency_liability = Moderate - high

<!--Pharmacokinetic data-->| bioavailability = Variable ([[Cmax (pharmacology)|T_max]] = 1–6 hours)<ref>{{cite book|last1=Barceloux|first1=Donald G. | name-list-style = vanc |title=Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants|date=2012|publisher=John Wiley & Sons, Inc.|location=Hoboken, N.J.|isbn=978-0-471-72760-6|pages=492–493|oclc=814224300}}</ref>

| protein_bound = ~50%

| metabolism = Extensive [[Liver|hepatic]]

| elimination_half-life = 8–12 hours

| excretion = [[Kidney|Renal]]

<!--Identifiers-->| IUPHAR_ligand = 7192

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 77-21-4

| ATC_prefix = N05

| ATC_suffix = CE01

| PubChem = 3487

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01437

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 3367

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = C8I4BVN78E

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00532

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1102

<!--Chemical data-->| C = 13

| H = 15

| N = 1

| O = 2

| SMILES = O=C1NC(CCC1(CC)C2=CC=CC=C2)=O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C13H15NO2/c1-2-13(10-6-4-3-5-7-10)9-8-11(15)14-12(13)16/h3-7H,2,8-9H2,1H3,(H,14,15,16)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = JMBQKKAJIKAWKF-UHFFFAOYSA-N

| density =

| melting_point = 84

| solubility = 999 mg/L (30&nbsp;°C/86&nbsp;°F)

'''Glutethimide''' is a [[Sleep#Hypnotics|hypnotic]] [[sedative]] that was introduced by [[Ciba Specialty Chemicals|Ciba]]<ref name = "US2673205">{{ cite patent | title = 3-Disubstituted Dioxopiperidines and the Manufacture thereof | country = US | number = 2673205 | status = patent | inventor = Hoffmann K, Tagmann E | assign1 = CIBA | gdate = 23 March 1954 }}</ref> in 1954 as a safe alternative to [[barbiturates]] to treat [[insomnia]]. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similar [[Drug withdrawal|withdrawal]] symptoms. '''Doriden''' was the brand-name version. Current production levels in the United States (the annual quota for manufacturing imposed by the [[Drug Enforcement Administration|DEA]] has been three grams, enough for six Doriden tablets, for a number of years) point to its use only in small-scale research. Manufacturing of the drug was discontinued in the US in 1993 and discontinued in several eastern European countries in 2006.

[[Image:Glutethimide DOJ.jpg|frame|right]]

Long-term use rebound effects, which resemble those seen in barbiturate withdrawal, have anecdotally been described in patients who were still taking a stable dose of the drug. The symptoms include [[delirium]], [[hallucinosis]], [[convulsions]] and [[fever]].<ref>{{cite journal | vauthors = Cookson JC | title = Rebound exacerbation of anxiety during prolonged tranquilizer ingestion | journal = Journal of the Royal Society of Medicine | volume = 88 | issue = 9 | pages = 544 | date = September 1995 | pmid = 7562864 | pmc = 1295346 }}</ref>

Glutethimide is a [[CYP2D6]] enzyme inducer. When taken with [[codeine]], (known on the streets as "hits", "cibas and codeine", "Dors and 4s") it enables the body to convert higher amounts of the codeine to [[morphine]]. The general sedative effect of the glutethimide also adds to the effect of the combination.<ref>{{cite journal | vauthors = Shamoian CA | title = Codeine and glutethimide. Euphoretic, addicting combination | journal = New York State Journal of Medicine | volume = 75 | issue = 1 | pages = 97–99 | date = 1975| pmid = 1053824 }}</ref> It produces an intense, long lasting euphoria similar to IV heroin use.{{cn|date=April 2023}} A number of deaths have occurred from abuse of this combination.<ref>{{cite journal | vauthors = Havier RG, Lin R | s2cid = 45780806 | title = Deaths as a result of a combination of codeine and glutethimide | journal = Journal of Forensic Sciences | volume = 30 | issue = 2 | pages = 563–6 | date = April 1985 | pmid = 3998703 | doi = 10.1520/JFS11840J }}</ref> The effect was also used clinically, including some research in the 1970s in various countries of using it under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, e.g. as a ''Substitutionmittel'' that may be a useful alternative to [[methadone]].<ref>{{cite journal | vauthors = Popa D, Loghin F, Imre S, Curea E | title = The study of codeine-gluthetimide pharmacokinetic interaction in rats | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 32 | issue = 4–5 | pages = 867–77 | date = August 2003 | pmid = 12899973 | doi = 10.1016/s0731-7085(03)00189-4 }}</ref><ref>{{cite journal | vauthors = Khajawall AM, Sramek JJ, Simpson GM | title = 'Loads' alert | journal = The Western Journal of Medicine | volume = 137 | issue = 2 | pages = 166–8 | date = August 1982 | pmid = 7135952 | pmc = 1274052 }}</ref> The demand for this combination in Philadelphia, Pittsburgh, Newark, NYC, Boston, Baltimore, and surrounding areas of other states and perhaps elsewhere, has led to small-scale clandestine synthesis of glutethimide since 1984,<ref name=Gahlinger >{{cite book | first = Paul | last = Gahlinger | name-list-style = vanc | title = Illegal Drugs: A Complete Guide to Their History, Chemistry, Use, and Abuse | chapter = Methaqualone and Glutethimide |oclc=52269170|isbn=9780452285057| date = 2003}}</ref>{{rp|203}} a process that is, like [[methaqualone]] (Quaalude) synthesis, somewhat difficult and fraught with potential bad outcomes when amateur chemists manufacture the drugs with industrial-grade precursors without adequate quality control. The fact that the simpler clandestine synthesis of other extinct pharmaceutical depressants like [[ethchlorvynol]], [[methyprylon]], or the oldest barbiturates is not reported would seem to point to a high level of motivation surrounding a unique drug, again much like methaqualone. Production of glutethimide was discontinued in the US in 1993 and in several eastern European countries, most notably Hungary, in 2006. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, whereas purported methaqualone is in a significant majority of cases found to be inert, or contain [[diphenhydramine]] or [[benzodiazepines]].<ref name=Gahlinger/>

==Legal status==

Glutethimide is a Schedule II drug under the [[Convention on Psychotropic Substances]].<ref>{{cite web |url= http://www.incb.org/pdf/e/list/green.pdf |publisher=[[International Narcotics Control Board]] |title=List of psychotropic substances under international control |url-status=dead |archive-url=https://web.archive.org/web/20120831222336/http://www.incb.org/pdf/e/list/green.pdf |archive-date=2012-08-31 }}</ref> It was originally a Schedule III drug in the United States under the [[Controlled Substances Act]], but in 1991 it was upgraded to Schedule II,<ref>{{cite web | url = http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_12.htm | publisher = [[Drug Enforcement Administration]] | work = Title 21 Code of Federal Regulations | title = Section 1308.12 Schedules of Controlled Substances | access-date = 2011-10-07 | archive-date = 2015-08-04 | archive-url = https://web.archive.org/web/20150804042821/http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_12.htm | url-status = dead }}</ref> several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.<ref>{{cite journal | vauthors = Havier RG, Lin R | s2cid = 45780806 | title = Deaths as a result of a combination of codeine and glutethimide | journal = Journal of Forensic Sciences | volume = 30 | issue = 2 | pages = 563–6 | date = April 1985 | pmid = 3998703 | doi = 10.1520/JFS11840J }}</ref><ref>{{cite journal | vauthors = Feuer E, French J | title = Descriptive epidemiology of mortality in New Jersey due to combinations of codeine and glutethimide | journal = American Journal of Epidemiology | volume = 119 | issue = 2 | pages = 202–7 | date = February 1984 | pmid = 6695899 | doi = 10.1093/oxfordjournals.aje.a113738 }}</ref> It has a DEA ACSCN of 2550 and a 2013 production quota of 3&nbsp;g.

==Synthesis==

The (R) isomer has a faster onset and more potent anticonvulsant activity in animal models than the (S) isomer.<ref>{{cite journal | vauthors = Houlihan WJ, Bennett GB | title = Anti-Anxiety Agents, Anticonvulsants and Sedative-Hypnotics. | journal = Annual Reports in Medicinal Chemistry | date = January 1977 | volume = 12 | pages = 10–19 | publisher = Academic Press | doi=10.1016/S0065-7743(08)61540-7 }}</ref>

[[File:Glutethimide synthesis.svg|500px|center|thumb|[https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-07-0034 Thieme] Synthesis:<ref>

{{Cite journal | vauthors = Tagmann E, Sury E, Hoffmann K | title = Über Alkylenimin-Derivate. 2. Mitteilung | doi = 10.1002/hlca.19520350516 | journal = Helvetica Chimica Acta | volume = 35 | issue = 5 | pages = 1541–1548 | year = 1952 }}</ref><ref>{{cite journal | vauthors = Salmon-Legagneur F, Neveu C | title = Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques. | journal = Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences | date = January 1952 | volume = 234 | issue = 10 | pages = 1060–2}}</ref><ref>{{ cite journal | vauthors = Salmon-Legagneur F, Neveu C | title = Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques | journal = Bull. Soc. Chim. France | year = 1953|page=70 }}</ref> Patent:<ref>{{cite patent | country = DE | status = patent | number = 950193 | invent1 = Hoffmann K Tagmann E | assign1 = CIBA | title = Verfahren zur Herstellung neuer Dioxopiperidine | gdate = 4 October 1956 }}</ref><ref name = "US2673205" />]]

The base catalyzed conjugate addition of 2-phenylbutyronitrile [769-68-6] ('''1''') to [[ethyl acrylate]] ('''2''') gives ethyl 4-cyano-4-phenylhexanoate, [https://pubchem.ncbi.nlm.nih.gov/compound/139890735 CID:139890735] ('''3'''). Alkaline hydrolysis of the nitrile group into an amide group, and subsequent acidic cyclization of the product affords the desired glutethimide ('''4''').

== See also ==

*[[Aminoglutethimide]]

*[[Piperidione]]

*[[Methyprylone]]

*[[Pyrithyldione]]

== References ==

{{Reflist|2}}

{{Sedatives}}

{{GABAA receptor positive allosteric modulators}}

[[Category:Abandoned drugs]]

[[Category:CYP2D6 inducers]]

[[Category:Piperidines]]

[[Category:GABAA receptor positive allosteric modulators]]