Fluoxymesterone

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Fluoxymesterone
Fluoxymesterone structure.svg
Systematic (IUPAC) name
9-fluoro-11,17-dihydroxy-10,13,17-trimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a682690
Pregnancy cat. X
Legal status Schedule III Controlled Substance
Pharmacokinetic data
Bioavailability 100% Oral
Metabolism Hepatic
Half-life 9.5 hours
Excretion urine
Identifiers
CAS number 76-43-7 YesY
ATC code G03BA01
PubChem CID 6446
IUPHAR ligand 2861
DrugBank DB01185
ChemSpider 6205 YesY
UNII 9JU12S4YFY YesY
KEGG D00327 YesY
ChEBI CHEBI:5120 YesY
ChEMBL CHEMBL1445 YesY
Chemical data
Formula C20H29FO3 
Mol. mass 336.441 g/mol
 YesY (what is this?)  (verify)

Fluoxymesterone (trade name Halotestin) is an anabolic steroid with strong androgenic properties that has been used in the treatment of male hypogonadism, delayed puberty in males, and in the treatment of breast neoplasms in women. It is approximately 5 times as potent as methyltestosterone.[citation needed] The antitumor activity of fluoxymesterone appears related to reduction or competitive inhibition of prolactin receptors or estrogen receptors or production.[citation needed]

Like many C-17 alpha alkylated steroids, fluoxymesterone has poor binding to the androgen receptor. Even so, its actions are mediated by the androgen receptor, most-likely due to its prolonged plasma half-life.[1]

It is considered a very toxic oral drug.

Though the half-life of fluoxymesterone is about 9.2 hours.[citation needed]

Synthesis: Part 1[edit]

The crucial importance of the presence of oxygen at the 11 position for adrenocorticoids activity, led to the development of methods for introducing that substituent by microbiological methods. Thus, fermentation of progesterone with soil organisms serves to oxidize the 11 position. Some of those same organisms were found to also hydroxylate simpler steroid substrates. Thus fermentation of andostene-3,17-dione obtained by Oppenauer oxidation of dehydroepiandrosterone affords the corresponding 11a hydroxyl derivative. Oxidation by means of Jones’ reagent leads to the 3,11,17-triketone. The difference in reactivity of carbonyl groups at the 3 and 17 positions attributable to the greater steric bulk near the 17 ketone. Ketones at the 11 position are so much less reactive than those at 17 that they are virtually inert to addition reactions. This lack of reactivity is due largely to the shielding effect of the two angular methyl groups, each of which bears a 1,3 diaxial relation to the carbonyl. Much of the work involved in steroid synthesis consists in taking advantage of these differences by juggling protecting groups so as to direct the reactions to the desired sites. Thus, reaction of triketone, also known as adrenosterone, with pyrrolidine occurs selectively at the 3 position to give the enamine. Condensation of that with methylmagnesium bromide followed by hydrolysis of the enamine results in the formation of the 17 methyl carbinol; the 11 ketone is, as expected, totally inert under the reaction conditions.

Preparation of Fluoxymesterone: Part 1

The potentiating effect of fluorine, particularly at the 9a position, on biological activity was first observed in the corticoids. Inclusion of that group starting from 11 oxygenated compounds involves a fairly standard set of transforms; the key starting intermediate usually possesses an 11b hydroxyl group. Conversion to the alcohol requires that the 3 ketone first be protected. The enamine at 3, lost during workup, is restored by reaction with pyrrolidine; exposure to [[lithium aluminum hydride]] leads to one of the few reactions that affect carbonyl groups at position 11. Thus reduction with LAH yields the 11b alcohol after removal of the enamine.

Synthesis: Part 2[edit]

Fluoxymesterone can be prepared from 11α-hydroxy-17-methyltestosterone:[2]

Preparation of Fluoxymesterone

Reaction of 11α-hydroxy-17-methyltestosterone with N-bromosuccinimide in an aqueous base leads to the addition of the elements of hypobromous acid. The stereochemistry of the reaction is, in all probability, determined by the initial formation of a bromonium derivative on the more open a face; diaxial opening by hydroxide leads to the bromohydrin. Reaction of this with a base results in the internal displacement of bromine by alkoxide to give the b epoxide. That compound is then allowed to react with hydrogen fluoride in THF. A diaxial opening of the intermediate oxiranium ion by fluoride anion completes the construction of the 9a-fluoro-11b-hydroxy moiety. There is thus obtained the potent androgenic agent fluoxymestrone.

References[edit]

  1. ^ Seth Roberts (2009). Anabolic Pharmacology .
  2. ^ Herr, M. E.; Hogg, J. A.; Levin, R. H. (1956). J. Amer. Chem. Soc. 78 (2): 501. doi:10.1021/ja01583a073. 

Further reading[edit]