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a synthetic progestational hormone (trade name Norlutin) used in oral contraceptives and to treat endometriosis (同)norethindrone_acetate, norethandrolone, Norlutin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/07/12 00:58:26」(JST)

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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.^[1] 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.^[2] It was the progestin used in one of the first three oral contraceptives. Its related ester, norethisterone acetate, is used for the same indications.

Synthesis

Norethisterone synthesis:^[2]^[3]

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),^[3] 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).^[2]

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 synthesis:^[4]^[5]^[6] U.S. Patent 2,744,122 U.S. Patent 2,774,777

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.

Ethynerone

Ethynerone synthesis:^[7] J. Fried and T. S. Bry U.S. Patent 3,096,353 (1963, Merck & Co. Inc).

References

^ 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.
^ ^a ^b ^c 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.
^ ^a ^b 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.
^ p165 Lednicer Mitscher book 1 and p146 (2)

UpToDate Contents

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1. 避妊用のプロゲスチン単剤ピル（POP） progestin only pills pops for contraception
2. 月経抑制のためのホルモン避妊法 hormonal contraception for suppression of menstruation
3. 子宮内膜増殖症のマネージメント management of endometrial hyperplasia
4. 重度または持続性子宮出血のマネージメント managing an episode of severe or prolonged uterine bleeding
5. 子宮内膜症の治療の概要 overview of the treatment of endometriosis

English Journal

Sorption and desorption of diverse contaminants of varying polarity in wastewater sludge with and without alum.

Morissette MF1, Vo Duy S, Arp HP, Sauvé S.
Environmental science. Processes & impacts.Environ Sci Process Impacts.2015 Feb 12. [Epub ahead of print]
Sewage sludge sorption and desorption measurements were conducted for nine diverse contaminants of varying polarity: caffeine, sulfamethoxazole, carbamazepine, atrazine, estradiol, ethinylestradiol, diclofenac, and, for the first time desethylatrazine and norethindrone. Two types of sorption behavio
PMID 25672802

Effects of progesterone and norethindrone on female fathead minnow (Pimephales promelas) steroidogenesis.

Petersen LH1, Hala D, Carty D, Cantu M, Martinović D, Huggett DB.
Environmental toxicology and chemistry / SETAC.Environ Toxicol Chem.2015 Feb;34(2):379-90. doi: 10.1002/etc.2816. Epub 2015 Jan 6.
As knowledge of contaminants capable of adversely modulating endocrine functions increases, attention is focused on the effects of synthetic progestins as environmental endocrine disrupters. In the present study, effects of exposure to a synthetic progestin (norethindrone, 168 ± 7.5 ng/L) and
PMID 25470578

Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy.

DuBois BN1, Atrio J2, Stanczyk FZ3, Cherala G4.
Contraception.Contraception.2015 Jan;91(1):71-5. doi: 10.1016/j.contraception.2014.08.009. Epub 2014 Aug 30.
OBJECTIVE: Pharmacokinetics of norethindrone in combination oral contraceptive regimen are well described among HIV+ women treated with ritonavir-boosted protease inhibitor therapies; however, such characterization is lacking in women using progestin-only contraception. Our objective is to character
PMID 25245190

Japanese Journal

重度の反復する下部消化管出血に対して大腸血管拡張症を疑った犬の1例

日本獣医師会雑誌 67(10), 767-772, 2014
NAID 130004709672

A semi-automated 96-well plate method for the simultaneous determination of oral contraceptives concentration in human plasma using ultra performance liquid chromatography coupled with tandem mass spectrometry

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 852(1), 69-76, 2007-06-01
NAID 10025801403

Simultaneous determination of norethindrone and ethinyl estradiol in human plasma by high performance liquid chromatography with tandem mass spectrometry-experiences on developing a highly selective method using derivatization reagent for enhancing sensitivity

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 825(2), 223-232, 2005-10-25
NAID 10016977972

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リンク元	「ノルエチステロン」「ノルエチンドロン」

「ノルエチステロン」

Norethisterone
Systematic (IUPAC) name
	(17β)-17-ethynyl-17-hydroxyestr-4-en-3-one;; (8R,9S,10R,13S,14S,17S)-17-ethynyl-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a604034
Pharmacokinetic data
Bioavailability	64%
Protein binding	>95%
Biological half-life	7 hours
Identifiers
CAS Number	68-22-4
ATC code	G03AC01 (WHO) G03DC02 (WHO)
PubChem	CID 6230
IUPHAR/BPS	2880
DrugBank	DB00717
ChemSpider	5994
UNII	T18F433X4S
KEGG	D00182
ChEBI	CHEBI:7627
ChEMBL	CHEMBL1162
Chemical data
Formula	C20H26O2
Molar mass	298.419 g/mol
	SMILES O=C4\C=C3/[C@@H]([C@H]2CC[C@]1([C@@H](CC[C@]1(C#C)O)[C@@H]2CC3)C)CC4 ;
	InChI InChI=1S/C20H26O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,12,15-18,22H,4-11H2,2H3/t15-,16+,17+,18-,19-,20-/m0/s1 ; Key:VIKNJXKGJWUCNN-XGXHKTLJSA-N ;
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　　[★]

英: norethisterone、norethisterone acetate
ラ: norethisteronum
同: ノルエチンドロン norethindrone
商: オーソ777-21、オーソM-21、シンフェーズT28、ソフィアA配合、ソフィアC配合、ノアルテン、ビホープＡ、プリモルトN、メノエイドコンビ、ルナベル配合
関

「ノルエチンドロン」

　　[★]

英: norethindrone
関: ノルエチステロン

[Elks2014-1] 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-2] 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.

[Colton-3] Frank B. Colton, U.S. Patent 2,655,518 (1952 to Searle & Co).

[4] 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.

[5] 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.

[6] Onken, D; Heublein, D (1970). "Ethinylated steroids". Die Pharmazie 25 (1): 3–9. PMID 4914401.

[7] 165 Lednicer Mitscher book 1 and p146 (2)

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norethindrone