Norboletone

{{Short description|Chemical compound}} {{Drugbox | verifiedrevid = 444029421 | IUPAC_name = (8''R'',9''S'',10''R'',13''S'',14''S'',17''S'')-13,17-diethyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[''a'']phenanthren-3-one | image = Norboletone.svg | image_class = skin-invert-image | width = 225px

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 1235-15-0 | ATC_prefix = None | ATC_suffix = | PubChem = 66255 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 59638 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = U3BZU2241A | synonyms = Norbolethone; 17α-Ethyl-18-methyl-19-nortestosterone; 17α-Ethyl-18-methylestr-4-en-17β-ol-3-one; 13β-Ethyl-17α-hydroxy-18,19-dinorpregn-4-en-3-one

| C=21 | H=32 | O=2 | SMILES = O=C4\C=C3/[C@@H]([C@H]2CC[C@]1([C@@H](CC[C@@]1(O)CC)[C@@H]2CC3)CC)CC4 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C21H32O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h13,16-19,23H,3-12H2,1-2H3/t16-,17+,18+,19-,20-,21-/m0/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = FTBJKONNNSKOLX-XUDSTZEESA-N }}

'''Norboletone''' ({{abbrlink|INN|International Nonproprietary Name}}) (former proposed brand name '''Genabol'''), or '''norbolethone''', is a synthetic and orally active anabolic–androgenic steroid (AAS) which was never marketed.<ref name="Fainaru-WadaWilliams2006">{{cite book| vauthors = Fainaru-Wada M, Williams L |title=Game of Shadows: Barry Bonds, BALCO, and the Steroids Scandal that Rocked Professional Sports|url=https://books.google.com/books?id=AtXm74CbIJoC&pg=PT75|date=23 March 2006|publisher=Penguin Publishing Group|isbn=978-1-101-21676-7|pages=75–}}</ref> It was first developed in 1966 by Wyeth Laboratories and was investigated for use as an agent to encourage weight gain and for the treatment of short stature, but was never marketed commercially because of fears that it might be toxic.<ref name="Fainaru-WadaWilliams2006" /><ref name=sfgate>{{cite news| title = Inventor of 'clear' steroid gets 3 months in prison | url=https://www.sfgate.com/news/article/Inventor-of-clear-steroid-gets-3-months-in-2491732.php | work=The San Francisco Chronicle | vauthors = Lee HK | date=2006-08-04}}</ref> It subsequently showed up in urine tests on athletes in competition in the early 2000s.<ref>{{cite journal | vauthors = Catlin DH, Ahrens BD, Kucherova Y | title = Detection of norbolethone, an anabolic steroid never marketed, in athletes' urine | journal = Rapid Communications in Mass Spectrometry | volume = 16 | issue = 13 | pages = 1273–1275 | year = 2002 | pmid = 12112254 | doi = 10.1002/rcm.722 | bibcode = 2002RCMS...16.1273C }}</ref>

Norboletone was found to have been brought to the market by the chemist Patrick Arnold, of the Bay Area Laboratory Co-operative (BALCO), an American nutritional supplement company. It is reputed to have been the active ingredient in the original formulation of the "undetectable" steroid formulation known as "The Clear" before being replaced by the more potent drug tetrahydrogestrinone.<ref>{{cite press release |url=http://www.usdoj.gov/usao/can/press/2006/2006_08_04_arnold_sentencing%20press.htm |title=Chemist Who Created "The Clear" Sentenced |publisher=United States Attorney for the Northern District of California |date=2006-08-04 |access-date=2007-10-08 |url-status=dead |archive-url=https://web.archive.org/web/20061014084938/http://www.usdoj.gov/usao/can/press/2006/2006_08_04_arnold_sentencing%20press.htm |archive-date=2006-10-14 }}</ref><ref>{{cite journal | vauthors = Knight J | title = Drugs bust reveals athletes' secret steroid | journal = Nature | volume = 425 | issue = 6960 | pages = 752 | date = October 2003 | pmid = 14574369 | doi = 10.1038/425752a | s2cid = 4380612 | doi-access = free | bibcode = 2003Natur.425..752K }}</ref>

In 2002, Don Catlin, the founder and then-director of the UCLA Olympic Analytical Lab, identified norboletone for the first time in an athlete's urine sample. In the same year, U.S. bicycle racer Tammy Thomas was caught using it and was banned from her sport.<ref name=sfgate/> The following year, Catlin identified and developed a test for tetrahydrogestrinone (THG), the second reported designer anabolic sample—a key development in the BALCO Affair.<ref>{{cite news | title = Catlin has made a career out of busting juicers | url = https://www.usatoday.com/sports/olympics/2007-02-28-catlin-drug-lab_N.htm | newspaper = USA Today | date = 2007-02-28}}</ref>

Norboletone is on the World Anti-Doping Agency's list of prohibited substances,<ref>{{cite web | url=http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/2012/WADA_Prohibited_List_2012_EN.pdf | title=The World Anti-Doping Code: The 2012 Prohibited List | publisher=World Anti-Doping Agency | access-date=2012-07-17 | url-status=dead | archive-url=https://web.archive.org/web/20120513020202/http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/2012/WADA_Prohibited_List_2012_EN.pdf | archive-date=2012-05-13 }}</ref> and is therefore banned from use in most major sports.

==Chemistry== ===Synthesis=== Hughes & Smith reported the original synthesis of norboletone.<ref>Smith, Hercherl; Hughes, G. A.; Douglas, G. H.; Wendt, G. R.; Buzby, G. C.; Edgren, R. A.; Fisher, J.; Foell, T.; Gadsby, B.; Hartley, D.; Herbst, D.; Jansen, A. B. A.; Ledig, K.; McLoughlin, B. J.; McMenamin, J.; Pattison, T. W.; Phillips, P. C.; Rees, R.; Siddall, J.; Siuda, J.; Smith, Leland L.; Tokolics, J.; Watson, D. H. P. (1964). "856. Totally synthetic steroid hormones. Part II. 13β-Alkylgona-1,3,5(10)-trienes, 13β-alkygon-4-en-3-ones, and related compounds". J. Chem. Soc. 0 (0): 4472–4492. doi:10.1039/JR9640004472.</ref><ref>Gordon Alan Hughes & Herchel Smith, {{US patent|3959322}} (1976 to Individual).</ref><ref>Gordon Alan Hughes & Herchel Smith, {{US patent|4002746}} (1977 to Individual).</ref> Commercial:<ref>{{cite journal | journal=Chemical & Engineering News Archive | title=Total Synthesis of Steroids Shows Commercial: Method developed at Wyeth may compete with established partial syntheses of drugs containing steroid nucleus | volume=41 | issue=34 | pages=32–34 | date=26 August 1963 | url=https://pubs.acs.org/doi/abs/10.1021/cen-v041n034.p032 | doi=10.1021/cen-v041n034.p032| url-access=subscription }}</ref> NB: Although the synthesis has involved the formation of no fewer than 6 chiral centers, only two of the possible 64 possible isomers are formed.

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The halogenation of 3-(3-methoxyphenyl)propan-1-ol [7252-82-6] ('''1''') with phosphorus tribromide gives 1-(3-bromopropyl)-3-methoxybenzene [6943-97-1] ('''2'''). Treatment with monosodium acetylide gives 5-m-methoxyphenylpent-1-yne [1424-70-0] ('''3''') . ('''Ex 1''') The Mannich reaction gives 1-Diethylamino-6-m-methoxyphenylhex-2-yne, PC21485597 ('''4'''). ('''Ex 8''') The oxymercuration reaction with mercury(II) sulfate in aqueous sulfuric acid gives a mixture of 1-(Diethylamino)-6-(3-methoxyphenyl)hexan-3-one [3706-69-2] (5) and 6-m-Methoxyphenylhex-1-en-3-one, PC10798238 ('''6'''). ('''Ex 17''') Treatment with 2-Ethyl-1,3-cyclopentanedione [823-36-9] ('''7''') in the presence of pyridine base causes a Michael reaction to occur to give 2-Ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione, PC21485569 ('''8'''). ('''Ex 43''') The cyclodehydration step was achieved by refluxing with a catalytic amount of TsOH in a DS-trap to give [848-07-7] ('''9'''). ('''Ex 68''') Catalytic hydrogenation over Raney nickel gives ('''10'''). ('''Ex 83''') Ethynylation with ethynyl lithium gave ('''11'''). ('''Ex 96''') Catalytic hydrogenation gave ('''12'''). ('''Ex 104''') Reduction of the remaining olefin gave PC68145890 ('''13'''). Birch reduction gave PC68144974 ('''14'''). ('''Ex 172 & 188''') Hydrolysis of the enol ether in mineral acid completed the synthesis of norboletone ('''15''').

==See also== *Norgestrel is the unreduced alkyne (ethynyl group). == References == {{Reflist|2}}

Category:Abandoned drugs Category:Androgens Category:Estranes Category:Designer drugs Category:Hepatotoxins