Etynodiol diacetate

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Etynodiol diacetate
Ethynodiol diacetate.svg
Clinical data
Trade names Continuin, Demulen, Femulen, Luteonorm, Luto-Metrodiol, Metrodiol, Ovulen, others
Synonyms Ethynodiol diacetate; Norethindrol diacetate; 3β-Hydroxynorethisterone 3β,17β-diacetate;[1] 17α-Ethynylestr-4-ene-3β,17β-diyl diacetate; CB-8080; SC-11800
Routes of
administration
By mouth
Drug class Progestin; Progestogen; Progestogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
ECHA InfoCard 100.005.496 Edit this at Wikidata
Chemical and physical data
Formula C24H32O4
Molar mass 384.509 g/mol
3D model (JSmol)

Etynodiol diacetate, or ethynodiol diacetate, sold under the brand names Demulen and Femulen among others, is a progestin medication which is used in birth control pills.[2][3][4] The medication is available only in combination with an estrogen.[5] It is taken by mouth.[6]

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.[7][8] It has weak androgenic and estrogenic activity and no other important hormonal activity.[9][10][10][11] The medication is a prodrug of norethisterone in the body, with etynodiol occurring as an intermediate.[7][12][8]

Etynodiol, a related compound, was discovered in 1954, and etynodiol diacetate was introduced for medical use in 1965.[13][14] The medication remains available today only in the United States, Canada, and a few other countries.[4][5]

Medical uses[edit]

Etynodiol diacetate is used in combination with an estrogen such as ethinylestradiol or mestranol in combined oral contraceptives for women.[6]

Side effects[edit]

Pharmacology[edit]

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.[7][12][8] Upon oral administration and during first-pass metabolism in the liver, etynodiol diacetate is rapidly converted by esterases into etynodiol,[12] which is followed by oxygenation of the C3 hydroxyl group to produce norethisterone.[8] In addition to its progestogenic activity, etynodiol diacetate has weak androgenic activity,[9][10] and, unlike most progestins but similarly to norethisterone and noretynodrel,[15] also has some estrogenic activity.[10][11]

Chemistry[edit]

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.[3][4][1] 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.[3][4] Etynodiol diacetate is the 3β,17β-diacetate ester of etynodiol (17α-ethynylestr-4-ene-3β,17β-diol).[3][4]

Synthesis[edit]

Ethynodiol diacetate synthesis:[16] 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:[17]

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).[16]

History[edit]

Etynodiol was first synthesized in 1954, via reduction of norethisterone, and etynodiol diacetate was introduced for medical use in 1965.[13][14]

Society and culture[edit]

Generic names[edit]

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.[3][4][5] It is also known by its former developmental code names CB-8080 and SC-11800.[3][4][5]

Brand names[edit]

Etynodiol diacetate is or has been marketed under brand names including Conova, Continuin, Demulen, Femulen, Kelnor, Luteonorm, Luto-Metrodiol, Metrodiol, Ovulen, Soluna, Zovia, and others.[3][4][5]

Availability[edit]

Etynodiol diacetate remains marketed in only a few countries, including the United States, Canada, Argentina, and Oman.[5]

References[edit]

  1. ^ a b Schindler, Adolf E; Campagnoli, Carlo; Druckmann, René; Huber, Johannes; Pasqualini, Jorge R; Schweppe, Karl W; Thijssen, Jos H.H (2003). "Classification and pharmacology of progestins". Maturitas. 46: 7–16. doi:10.1016/j.maturitas.2003.09.014. ISSN 0378-5122. PMID 14670641. 
  2. ^ Donna Shoupe; Florence P. Haseltine (6 December 2012). Contraception. Springer Science & Business Media. pp. 21–. ISBN 978-1-4612-2730-4. 
  3. ^ a b c d e f g J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 522–. ISBN 978-1-4757-2085-3. 
  4. ^ a b c d e f g h Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 422. ISBN 978-3-88763-075-1. Retrieved 30 May 2012. 
  5. ^ a b c d e f https://www.drugs.com/international/etynodiol.html
  6. ^ a b Robert W. Blum (22 October 2013). Adolescent Health Care: Clinical Issues. Elsevier Science. pp. 216–. ISBN 978-1-4832-7738-7. 
  7. ^ a b c Hammerstein J (1990). "Prodrugs: advantage or disadvantage?". Am. J. Obstet. Gynecol. 163 (6 Pt 2): 2198–203. PMID 2256526. 
  8. ^ a b c d 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. 
  9. ^ a b Armen H. Tashjian; Ehrin J. Armstrong (21 July 2011). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. pp. 523–. ISBN 978-1-4511-1805-6. 
  10. ^ a b c d Kenneth L. Becker (24 April 2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. p. 1004. ISBN 978-0-7817-1750-2. Retrieved 30 May 2012. 
  11. ^ a b Allan H. Goroll; Albert G. Mulley (27 January 2009). Primary Care Medicine: Office Evaluation and Management of the Adult Patient. Lippincott Williams & Wilkins. p. 876. ISBN 978-0-7817-7513-7. Retrieved 30 May 2012. 
  12. ^ a b c Stanczyk FZ (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Rev Endocr Metab Disord. 3 (3): 211–24. doi:10.1023/A:1020072325818. PMID 12215716. 
  13. ^ a b Progress in Medicinal Chemistry. Butterworth-Heinemann. 21 September 2011. pp. 180–. ISBN 978-0-08-086256-9. 
  14. ^ a b William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1516–. ISBN 978-0-8155-1856-3. 
  15. ^ Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 36–. ISBN 978-3-642-73790-9. 
  16. ^ a b Klimstra, P.; Colton, F. (1967). "The synthesis of 3β-hydroxyestr-4-en-17-one and 3β-hydroxiandrost-4-en-17-one". Steroids. 10 (4): 411–424. doi:10.1016/0039-128X(67)90119-5. 
  17. ^ Sondheimer, F.; Klibansky, Y. (1959). "Synthesis of 3β-hydroxy analogues of steroidal hormones, a biologically active class of compounds". Tetrahedron. 5: 15–26. doi:10.1016/0040-4020(59)80066-1.