|Systematic (IUPAC) name|
|AHFS/Drugs.com||International Drug Names|
|Biological half-life||7 hours|
|ATC code||G03AC01 (WHO) G03DC02 (WHO)|
|Molar mass||298.419 g/mol|
Norethisterone (INN, BAN), also known as norethindrone (USAN), as well as 19-nor-17α-ethynyltestosterone, but more commonly known under its trade name Utovlan®, is a steroidal progestin used in some combined oral contraceptive pills and progestogen-only pills, and also available as a standalone drug. It can be used to treat premenstrual syndrome, painful periods, abnormal heavy bleeding, irregular periods, menopausal syndrome (in combination with estrogen), or to postpone a period. It is also commonly used to help prevent uterine hemorrhage in complicated non-surgical or pre-surgical gynecologic cases and in treating non responsive cyclical mastalgia. Norethisterone was the first orally highly active progestin to be synthesized.
It was synthesized for the first time by chemists Luis Miramontes, Carl Djerassi, and George Rosenkranz at Syntex in Mexico City in 1951. It was the progestin used in one of the first three oral contraceptives. Its related ester, norethisterone acetate, is used for the same indications. Norethisterone was first introduced, as Norlutin, in 1957.
Estradiol methyl ether (1, EME) is partially reduced to the 1,5-diene (2) as also occurs for the first step in the synthesis of nandrolone. Oppenauer oxidation then transforms the 17β alcohol into a ketone functionality (3). This is then reacted with metal acetylide into the corresponding 17α-ethynyl compound (4). Hydrolysis of the enolether under mild conditions leads directly to (5), which appears to be noretynodrel (although Lednicer states that it is Ethynodrel in his book. This search term was corrected to Etynodiol in chemspider. Ethynodrel is with a chlorine atom attached.) an orally active progestin. This is the progestational component of the first oral contraceptive to be offered for sale (ie Enovid, 'the pill'). Treatment of the ethynyl enol ether with strong acid acid leads to yet another oral progestin employed as a contraceptive, norethindrone (6).
In practice, these and all other so-called combination contraceptives are mixtures of 1-2% mestranol or ethynylestradiol and an oral progestin. It has been speculated that the discovery of the necessity of estrogen in addition to progestin for contraceptive efficacy is due to the presence of a small amount of unreduced EME (1) in early batches of 2. This when subjected to oxidation and ethynylation, would of course lead to mestranol (3). In any event, the need for the presence of estrogen in the mixture is now well established experimentally.
Norethindrone, 17α-Ethynyl-19-nortestosterone, is made from Estr-4-ene-3,17-dione, which in turn is synthesized by partial reduction of the aromatic region of the 3-O-methyl ether of estrone with lithium in liquid ammonia, and simultaneously of the keto group at C17 to a hydroxy group, which is then oxidized back to a keto group by chromium trioxide in acetic acid. The congugated C4-C5 olefin and the carbonyl group at C3 is then transformed to dienol ethyl ether using ethyl orthoformate. The obtained product is ethynylated by acetylene in the presence of potassium tert-butoxide. After HCl hydrolysis of the formed O-potassium derivative, during which the enol ether is also hydrolyzed, and the remaining double bond is shifted, the desired norethindrone is obtained.
- J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 886–. ISBN 978-1-4757-2085-3.
- Djerassi, C.; Miramontes, L.; Rosenkranz, G.; Sondheimer, F. (1954). "Steroids. LIV.1Synthesis of 19-Nov-17α-ethynyltestosterone and 19-Nor-17α-methyltestosterone2". Journal of the American Chemical Society. 76 (16): 4092. doi:10.1021/ja01645a010.
- William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 2935–. ISBN 978-0-8155-1856-3.
- Frank B. Colton, U.S. Patent 2,655,518 (1952 to Searle & Co).
- Ringold, H. J.; Rosenkranz, G.; Sondheimer, F. (1956). "Steroids. LXXX.11-Methyl-19-nortestosterone and 1-Methyl-17α-ethinyl-19-nortestosterone". Journal of the American Chemical Society. 78 (11): 2477. doi:10.1021/ja01592a037.
- Ueberwasser, H.; Heusler, K.; Kalvoda, J.; Meystre, C.; Wieland, P.; Anner, G.; Wettstein, A. (1963). "19-Norsteroide II. Ein einfaches Herstellungsverfahren für 19-Norandrostan-Derivate. über Steroide, 193. Mitteilung". Helvetica Chimica Acta. 46: 344. doi:10.1002/hlca.19630460135.
- Onken, D; Heublein, D (1970). "Ethinylated steroids". Die Pharmazie. 25 (1): 3–9. PMID 4914401.