Epostane: Difference between revisions

Epostane
Clinical data
Other names	WIN-32729
Identifiers
	IUPAC name 4α,5α-Epoxy-3,17β-dihydroxy-4β,17α-dimethylandrost-2-ene-2-carbonitrile;
CAS Number	80471-63-2;
PubChem CID	6917713;
ChemSpider	5292942;
UNII	6375T36951;
ChEMBL	ChEMBL2106218;
CompTox Dashboard (EPA)	DTXSID001001267 ;
Chemical and physical data
Formula	C22H31NO3
Molar mass	357.494 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C)O)CC[C@]45[C@@]3(CC(=C([C@]4(O5)C)O)C#N)C;
	InChI InChI=1S/C22H31NO3/c1-18-8-6-16-14(15(18)7-9-20(18,3)25)5-10-22-19(16,2)11-13(12-23)17(24)21(22,4)26-22/h14-16,24-25H,5-11H2,1-4H3/t14-,15-,16-,18-,19+,20-,21+,22-/m0/s1; Key:CETKWEWBSMKADK-GSXVSZIWSA-N;

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Epostane (INN, USAN, BAN) (developmental code name WIN-32729) is an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) that was developed as a contraceptive, abortifacient, and oxytocic drug but was never marketed.^[1]^[2]^[3] By inhibiting 3β-HSD, epostane blocks the biosynthesis of progesterone from pregnenolone (and also the conversion of dehydroepiandrosterone to androstenedione), thereby functioning as an antiprogestogen and terminating pregnancy.^[1] The drug was trialed and in a study was found to be slightly more effective at inducing abortion relative to mifepristone.^[4]

Synthesis

Note that the last step in the synthesis is identical to that used to make Cyanostane from Androisoxazole.

Reaction of methyltestosterone (1) with formaldehyde and thiophenol leads to the 4-thiomethyl derivative [71507-77-2] (2). The removal of sulfur by means of Raney nickel gives 4,17alpha-dimethyltestosterone [28626-76-8] (3). Mixed aldol reaction of that intermediate with methyl formate in the presence of sodium methoxide gives the 2-formyl derivative 17beta-Hydroxy-2-(hydroxymethylene)-4,17-dimethylandrost-4-en-3-one [38539-99-0] (4). Reaction of the beta dicarbonyl function with hydroxylamine affords isoxazole [71507-21-6] (5). Epoxidation with peracid (mCPBA) proceeds as expected from the alpha side to give [71507-78-3] (6). Treatment with sodium methoxide leads initially to removal of the sole proton on the isoxazole moiety. Ring opening of the resulting carbanion gives, after protonation of the enol oxygen at the 3 position, the enol-nitrile array in epostane (7).

References

^ ^a ^b Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 492–. ISBN 978-1-4757-2085-3.
^ Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 113–. ISBN 978-94-011-4439-1.
^ Milne GW (8 May 2018). Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. pp. 23–. ISBN 978-1-351-78989-9.
^ Lachelin GC (11 September 2013). Introduction to Clinical Reproductive Endocrinology. Elsevier Science. pp. 198–. ISBN 978-1-4831-9380-9.
^ Castaer, J.; Hillier, K.; Blancafort, P.; Serradell, MN; WIN-32,729. Drugs Fut 1982, 7, 9, 661.
^ Christiansen, Rokbert G.; Neumann, Helmut C.; Salvador, U. Joseph; Bell, Malcolm R.; Schane, H. Philip; Creange, John E.; Potts, Gordon O.; Anzalone, A. J. (1984). "Steroidogenesis inhibitors. 1. Adrenal inhibitory and interceptive activity of trilostane and related compounds". Journal of Medicinal Chemistry. 27 (7): 928–931. doi:10.1021/jm00373a021.
^ DE2855091 idem Robert G. Christiansen, U.S. patent 4,160,027 (1979 to Sterling Drug).

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[Elks2014-1] Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 492–. ISBN 978-1-4757-2085-3.

[MortonHall2012-2] Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 113–. ISBN 978-94-011-4439-1.

[Milne2018-3] Milne GW (8 May 2018). Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. pp. 23–. ISBN 978-1-351-78989-9.

[Lachelin2013-4] Lachelin GC (11 September 2013). Introduction to Clinical Reproductive Endocrinology. Elsevier Science. pp. 198–. ISBN 978-1-4831-9380-9.

[5] Castaer, J.; Hillier, K.; Blancafort, P.; Serradell, MN; WIN-32,729. Drugs Fut 1982, 7, 9, 661.

[6] Christiansen, Rokbert G.; Neumann, Helmut C.; Salvador, U. Joseph; Bell, Malcolm R.; Schane, H. Philip; Creange, John E.; Potts, Gordon O.; Anzalone, A. J. (1984). "Steroidogenesis inhibitors. 1. Adrenal inhibitory and interceptive activity of trilostane and related compounds". Journal of Medicinal Chemistry. 27 (7): 928–931. doi:10.1021/jm00373a021.

[7] DE2855091 idem Robert G. Christiansen, U.S. patent 4,160,027 (1979 to Sterling Drug).

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 ==Synthesis==
+Note that the last step in the synthesis is identical to that used to make [[Cyanostane]] from [[Androisoxazole]].
 [[File:Epostane synthesis.svg|thumb|center|700px|[https://www.chemdrug.com/article/8/3284/16419390.html ChemDrug] Synthesis:<ref>Castaer, J.; Hillier, K.; Blancafort, P.; Serradell, MN; WIN-32,729. Drugs Fut 1982, 7, 9, 661.</ref><ref>Christiansen, Rokbert G.; Neumann, Helmut C.; Salvador, U. Joseph; Bell, Malcolm R.; Schane, H. Philip; Creange, John E.; Potts, Gordon O.; Anzalone, A. J. (1984). "Steroidogenesis inhibitors. 1. Adrenal inhibitory and interceptive activity of trilostane and related compounds". Journal of Medicinal Chemistry. 27 (7): 928–931. doi:10.1021/jm00373a021.</ref> Patent:<ref>DE2855091 idem Robert G. Christiansen, {{US patent|4160027}} (1979 to Sterling Drug).</ref>]]
 Reaction of methyltestosterone ('''1''') with formaldehyde and thiophenol leads to the 4-thiomethyl derivative [71507-77-2] ('''2'''). The removal of sulfur by means of Raney nickel gives 4,17alpha-dimethyltestosterone [28626-76-8] ('''3'''). Mixed aldol reaction of that intermediate with methyl formate in the presence of sodium methoxide gives the 2-formyl derivative 17beta-Hydroxy-2-(hydroxymethylene)-4,17-dimethylandrost-4-en-3-one [38539-99-0] ('''4'''). Reaction of the beta dicarbonyl function with hydroxylamine affords isoxazole [71507-21-6] ('''5'''). Epoxidation with peracid (mCPBA) proceeds as expected from the alpha side to give [71507-78-3] ('''6'''). Treatment with sodium methoxide leads initially to removal of the sole proton on the isoxazole moiety. Ring opening of the resulting carbanion gives, after protonation of the enol oxygen at the 3 position, the enol-nitrile array in epostane ('''7''').
 ==See also==
 * [[Nisterime]]