Etynodiol diacetate

Etynodiol diacetate
Clinical data
Routes of
administration		 Oral
ATC code G03DC06 (WHO)
G03AA01 (WHO) G03FA06 (WHO) (with an estrogen)
Legal status
Legal status
  • ℞ (Prescription only)
Identifiers
Synonyms 3β-Hydroxynorethisterone 3,17-diacetate[1]
CAS Number 297-76-7
8056-92-6
PubChem (CID) 92709270
DrugBank DB00823
ChemSpider 8913
Chemical and physical data
Formula C24H32O4
Molar mass 384.509 g/mol
3D model (Jmol) Interactive image

Etynodiol diacetate (sold as Continuin, Femulen, Luteonorm, Luto-Metrodiol, and Metrodiol), or ethynodiol diacetate (USAN, BAN, JAN), also known as norethindrol diacetate or 3β-hydroxynorethisterone diacetate,[2] is a steroidal progestin of the 19-nortestosterone group which is used as a hormonal contraceptive.[3][4] It is the 3β,17β-diacetate ester of etynodiol,[3][4] and acts as a rapidly converted prodrug to norethisterone,[5] with etynodiol occurring as an intermediate.[6][7] Etynodiol diacetate has weak androgenic activity,[8][9] and, unlike most progestins but similarly to norethisterone and noretynodrel,[10] also has some estrogenic activity.[9][11]

Pharmacology

Etynodiol diacetate is virtually inactive in terms of affinity for the progesterone and androgen receptors[6] and acts as a prodrug of etynodiol,[7] which in turn is a prodrug of norethisterone.[5] Upon oral administration and during first-pass metabolism in the liver, etynodiol diacetate is rapidly converted by esterases into etynodiol,[7] which is followed by oxygenation of the C3 hydroxyl group to produce norethisterone.[5]

Chemistry

Synthesis

Ethynodiol diacetate synthesis:[12] 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:[13]

Reduction of norethisterone (1) affords the 3,17-diol. The 3β-hydroxy compound is the desired product; since reactions at C-3 do not show nearly the stereoselectivity as those at C-17 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), one of the most potent oral progestins.[12]

See also

References

  1. ↑ 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.
  2. ↑ Donna Shoupe; Florence P. Haseltine (6 December 2012). Contraception. Springer Science & Business Media. pp. 21–. ISBN 978-1-4612-2730-4.
  3. 1 2 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. 1 2 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 422. ISBN 978-3-88763-075-1. Retrieved 30 May 2012.
  5. 1 2 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.
  6. 1 2 Hammerstein J (1990). "Prodrugs: advantage or disadvantage?". Am. J. Obstet. Gynecol. 163 (6 Pt 2): 2198–203. PMID 2256526.
  7. 1 2 3 Stanczyk FZ (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Rev Endocr Metab Disord. 3 (3): 211–24. PMID 12215716.
  8. ↑ 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.
  9. 1 2 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.
  10. ↑ 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.
  11. ↑ 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. 1 2 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. doi:10.1016/0039-128X(67)90119-5.
  13. ↑ Sondheimer, F.; Klibansky, Y. (1959). "Synthesis of 3β-hydroxy analogues of steroidal hormones, a biologically active class of compounds". Tetrahedron. 5: 15. doi:10.1016/0040-4020(59)80066-1.
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