Chemistry:Etynodiol diacetate

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Short description: Chemical compound
Etynodiol diacetate
Ethynodiol diacetate.svg
Clinical data
Trade namesOvulen, Demulen, others
Other namesEthynodiol diacetate; Norethindrol diacetate; 3β-Hydroxynorethisterone 3β,17β-diacetate;[1] 17α-Ethynylestr-4-ene-3β,17β-diyl diacetate; CB-8080; SC-11800
License data
Pregnancy
category
  • Contraindicated
Routes of
administration		By mouth
Drug classProgestogen; Progestin; Progestogen ester
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only [2][3]
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC24H32O4
Molar mass384.516 g·mol−1
3D model (JSmol)

Etynodiol diacetate, or ethynodiol diacetate, sold under the brand name Ovulen among others, is a progestin medication which is used in birth control pills.[4][5][6] The medication is available only in combination with an estrogen.[7] It is taken by mouth.[8]

Etynodiol diacetate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[9][10] It has weak androgenic and estrogenic activity and no other important hormonal activity.[11][12][13] The medication is a prodrug of norethisterone in the body, with etynodiol occurring as an intermediate.[9][10][14]

Etynodiol, a related compound, was discovered in 1954, and etynodiol diacetate was introduced for medical use in 1965.[15][16] The combination ethynodiol with mestranol (Ovulen) was approved for medical use in the United States in 1966.[17] The combination ethinylestradiol with ethynodiol (Demulen) was approved for medical use in the United States in 1970.[18]

In 2021, the combination with ethinylestradiol was the 276th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[19][20]

Medical uses

Etynodiol diacetate is used in combination with an estrogen such as ethinylestradiol or mestranol in combined oral contraceptives for women for the prevention of pregnancy.[8]

Side effects

Pharmacology

Norethisterone (3-ketoetynodiol), the active metabolite of etynodiol diacetate.

Etynodiol diacetate is virtually inactive in terms of affinity for the progesterone and androgen receptors and acts as a rapidly converted prodrug of norethisterone, with etynodiol occurring as an intermediate.[9][10][14] Upon oral administration and during first-pass metabolism in the liver, etynodiol diacetate is rapidly converted by esterases into etynodiol,[14] which is followed by oxygenation of the C3 hydroxyl group to produce norethisterone.[10] In addition to its progestogenic activity, etynodiol diacetate has weak androgenic activity,[11][12] and, unlike most progestins but similarly to norethisterone and noretynodrel,[21] also has some estrogenic activity.[12][13]

The pharmacokinetics of etynodiol diacetate have been reviewed.[22]

v · d · e Relative affinities (%) of norethisterone, metabolites, and prodrugs
Compound Typea PR AR ER GR MR SHBG CBG
Norethisterone – 67–75 15 0 0–1 0–3 16 0
5α-Dihydronorethisterone Metabolite 25 27 0 0 ? ? ?
3α,5α-Tetrahydronorethisterone Metabolite 1 0 0–1 0 ? ? ?
3α,5β-Tetrahydronorethisterone Metabolite ? 0 0 ? ? ? ?
3β,5α-Tetrahydronorethisterone Metabolite 1 0 0–8 0 ? ? ?
Ethinylestradiol Metabolite 15–25 1–3 112 1–3 0 0.18 0
Norethisterone acetate Prodrug 20 5 1 0 0 ? ?
Norethisterone enanthate Prodrug ? ? ? ? ? ? ?
Noretynodrel Prodrug 6 0 2 0 0 0 0
Etynodiol Prodrug 1 0 11–18 0 ? ? ?
Etynodiol diacetate Prodrug 1 0 0 0 0 ? ?
Lynestrenol Prodrug 1 1 3 0 0 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, estradiol for the ER, dexamethasone for the GR, aldosterone]] for the MR, dihydrotestosterone for SHBG, and cortisol for CBG. Footnotes: a = Active]] or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.

Chemistry

Etynodiol diacetate, also known as 3β-hydroxy-17α-ethynyl-19-nortestosterone 3β,17β-diaceate, 3β-hydroxynorethisterone 3β,17β-diacetate, or 17α-ethynylestr-4-ene-3β,17β-diol 3β,17β-diacetate, is a synthetic estrane steroid and a derivative of testosterone.[1][5][6] It is specifically a derivative of 19-nortestosterone and 17α-ethynyltestosterone, or of norethisterone (17α-ethynyl-19-nortestosterone), in which the C3 ketone group has been dehydrogenated into a C3β hydroxyl group and acetate esters have been attached at the C3β and C17β positions.[5][6] Etynodiol diacetate is the 3β,17β-diacetate ester of etynodiol (17α-ethynylestr-4-ene-3β,17β-diol).[5][6]

Synthesis

Ethynodiol diacetate synthesis:[23] F. B. Colton, U.S. Patent 2,843,609 (1958 to Searle). Prepn of the 3-acetate, 17-acetate, and diacetate: P. D. Klimstra, U.S. Patent 3,176,013 (1965 to Searle); see also:[24]

Chemical syntheses of etynodiol diacetate have been published.[22]

Reduction of norethisterone (1) affords the 3,17-diol. The 3β-hydroxy compound is the desired product; since reactions at C3 do not show nearly the stereoselectivity as those at C17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium tri-tert-butoxyaluminum hydride. Acetylation of the 3β,17β-diol affords etynodiol diacetate (3).[23]

History

Etynodiol was first synthesized in 1954, via reduction of norethisterone, and etynodiol diacetate was introduced for medical use in 1965.[15][16]

Society and culture

Generic names

Etynodiol diacetate is the generic name of the drug (the INN of its free alcohol form is etynodiol), while ethynodiol diacetate is its USAN, BAN, and JAN.[5][6][7] It is also known by its former developmental code names CB-8080 and SC-11800.[5][6][7]

Brand names

Etynodiol diacetate is or has been marketed under brand names including Conova, Continuin, Demulen,[18][25] Femulen, Kelnor,[3][25] Lo-Malmorede,[26] Luteonorm, Luto-Metrodiol, Malmorede,[27] Metrodiol, Ovulen,[17][25] Soluna, Zovia,[2] and others.[5][6][7]

Availability

Etynodiol diacetate is marketed in only a few countries, including the United States, Canada, Argentina, and Oman.[7]

References

  1. ↑ 1.0 1.1 "Classification and pharmacology of progestins". Maturitas 46 (Suppl 1): S7–S16. December 2003. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641. 
  2. ↑ 2.0 2.1 "Zovia 1/35- ethynodiol diacetate and ethinyl estradiol tablets kit". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d0d2a9e9-e9ce-4a42-b429-5c1f9a544795. 
  3. ↑ 3.0 3.1 "Kelnor 1/35- ethynodiol diacetate and ethinyl estradiol kit". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=96a73786-22b1-457e-be73-80b699996d40. 
  4. ↑ Contraception. Springer Science & Business Media. 6 December 2012. pp. 21–. ISBN 978-1-4612-2730-4. https://books.google.com/books?id=cpDhBwAAQBAJ&pg=PA21. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 522–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA522. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 422. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA422. Retrieved 30 May 2012. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Etynodiol". Drugs.com. https://www.drugs.com/international/etynodiol.html. 
  8. ↑ 8.0 8.1 Adolescent Health Care: Clinical Issues. Elsevier Science. 22 October 2013. pp. 216–. ISBN 978-1-4832-7738-7. https://books.google.com/books?id=36PpAgAAQBAJ&pg=PA216. 
  9. ↑ 9.0 9.1 9.2 "Prodrugs: advantage or disadvantage?". American Journal of Obstetrics and Gynecology 163 (6 Pt 2): 2198–2203. December 1990. doi:10.1016/0002-9378(90)90561-K. PMID 2256526. 
  10. ↑ 10.0 10.1 10.2 10.3 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 146–. ISBN 978-92-832-1291-1. https://books.google.com/books?id=aGDU5xibtNgC&pg=PA146. 
  11. ↑ 11.0 11.1 Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. 21 July 2011. pp. 523–. ISBN 978-1-4511-1805-6. https://books.google.com/books?id=kjCCMZHInigC&pg=PA523. Retrieved 11 October 2016. 
  12. ↑ 12.0 12.1 12.2 Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 24 April 2001. p. 1004. ISBN 978-0-7817-1750-2. https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1004. Retrieved 30 May 2012. 
  13. ↑ 13.0 13.1 Primary Care Medicine: Office Evaluation and Management of the Adult Patient. Lippincott Williams & Wilkins. 27 January 2009. p. 876. ISBN 978-0-7817-7513-7. https://books.google.com/books?id=bIZvJPcSEXMC&pg=PA876. Retrieved 30 May 2012. 
  14. ↑ 14.0 14.1 14.2 "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Reviews in Endocrine & Metabolic Disorders 3 (3): 211–224. September 2002. doi:10.1023/A:1020072325818. PMID 12215716. 
  15. ↑ 15.0 15.1 "Antifertility agents". Progress in Medicinal Chemistry 8 (2): 171–229. 1971. doi:10.1016/s0079-6468(08)70130-9. ISBN 9780408703147. PMID 4947236. https://books.google.com/books?id=CBk_ZfVPipUC&pg=PA180. 
  16. ↑ 16.0 16.1 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1516–. ISBN 978-0-8155-1856-3. https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1516. Retrieved 4 February 2018. 
  17. ↑ 17.0 17.1 "Ovulen: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=016029. 
  18. ↑ 18.0 18.1 "Demulen: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=016927. 
  19. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  20. ↑ "Ethinyl Estradiol; Ethynodiol - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/EthinylEstradiolEthynodiol. 
  21. ↑ Female Contraception: Update and Trends. Springer Science & Business Media. 6 December 2012. pp. 36–. ISBN 978-3-642-73790-9. https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA36. 
  22. ↑ 22.0 22.1 "Eigenschaften der Gestagene". Handbuch der Experimentellen Pharmakologie. Cham: Springer-Verlag. 27 November 2013. pp. 14–15,286. ISBN 978-3-642-99941-3. https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA14. 
  23. ↑ 23.0 23.1 "The synthesis of 3beta-hydroxyestr-4-en-17-one and 3beta-hydroxyandrost-4-en-17-one". Steroids 10 (4): 411–424. October 1967. doi:10.1016/0039-128X(67)90119-5. PMID 6064262. 
  24. ↑ "Synthesis of 3β-hydroxy analogues of steroidal hormones, a biologically active class of compounds". Tetrahedron 5: 15–26. 1959. doi:10.1016/0040-4020(59)80066-1. 
  25. ↑ 25.0 25.1 25.2 "Estrogen and Progestin (Oral Contraceptives)". https://medlineplus.gov/druginfo/meds/a601050.html. 
  26. ↑ "Lo-Malmorede". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209548. 
  27. ↑ "Malmorede". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209547. 



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