3,3-azo structure

Methyldiazirinol

Structural Image:

Nomenclature:
3,3-azo-17a-methyl-5a-androstan-17b-ol or
3,3-azo-17α-methyl-5α-androstan-17β-ol

Synonyms:
Methyldiazirinol

History:
This compound was first synthesized by researchers at Lederle Laboratories, a subsidiary of American Cyanamid, who were examining a series of diazirines and diaziridines (the steroid in question is a diazirine). Their results were reported in 1965. [1] They patented the invention in 1966. [2]
Lederle/American Cyanamid also synthesized (appropriately enough) some 2a-cyano-substituted compounds similar to the Anabolic Innovations ‘prohormone’ Cynostane, [3][4] though their major contribution to the field of steroids was the 16-oxygenated corticosteroid triamcinolone in the late 1950s. [5]

US Patent #19640392022 [2]
Methyldiazirinol was one of the many steroids listed in Julius Vida’s Androgens and Anabolic Agents. In a section detailing “Compounds displaying decreased androgenic activity coupled with increased anabolic activity”, the 3,3-azo steroid is listed alongside steroids such as oxandrolone (anavar), methenolone (primobolan), stanozolol (winstrol) and norbolethone (one version of “the Clear”). [6]

Prog Med Chem. 1991;28:233-300. [7]
Anabolic:Androgenic Ratio:
According to the Lederle Laboratories researchers, the 3,3-azo has an oral anabolic:androgenic ratio of 300:20 (levator ani:ventral prostate) when compared to methyl testosterone, giving it a “Q factor” of 15.

Androgens and Anabolic Agents. 1969. Academic Press, p90. [6]
This gives it a dissociation of anabolic to androgenic effects similar to the recently-banned methasterone (superdrol), which was reported to have an anabolic:androgenic ratio of 400:20.

3,3-azo vida
Androgens and Anabolic Agents. 1969. Academic Press, p194. [8]

Structure and Function:
Many active steroids (including the natural androgens testosterone and DHT) have a ketone function at the three position (usually written in the nomenclature as a “3-one”). It was once believed that this was necessary for anabolic activity, but since 1959 many steroids have been discovered that have significant activity despite the absence of a 3-ketone.

    • Stanozolol (Winstrol) has a pyrazole heterocyclic ring fused to the steroid at carbons 2 and 3.
    • Furazabol has a furazane ring at the same position.
    • Methylepitiostanol (“Epistane”) has an episulphide moiety at carbons 2 and 3.
    • Methyldiazirinol has a diazirine moiety at carbon 3.
methyldiazirinol comparison
Heterocyclic steroids

Receptor bonding in these cases has been improved by the substitution of the 3-ketone for a more highly nucleophilic heteroatom; either sulphur or nitrogen. Methylepithiostanol has a sulphur atom in the place of the oxygen function of the natural steroids, while stanozolol, furazabol, and methyldiazirinol possess a nitrogen atom.

Stability
Diazirines are not terribly stable chemical structures, being known to be susceptible to decay from both ultraviolet light and heat. This relative instability is partly due to the ring strain on three membered rings, and partly due to the nucleophilic nature of the nitrogen atoms.
Instability in UV light is not something that is unique to diazirines, or to this steroid; many steroids have been found to be subject to photodegradation, including testosterone, testosterone propionate, methyltestosterone, nandrolone, dienolone, and trenbolone. [9][10][11][12]
The American Cyanomid Company discovered that the 3,3-azo steroids pyrolized largely to 2-ene compounds at 135°+ (via a singlet state carbene), though that is not expected to happen in vivo. This degradation with heat is not unique to methyldiazirinol either; the structurally similar steroid methylepitiostanol (epistane) also pyrolizes under heat (to the same 2-ene compound, desoxymethyltestosterone), making accurate testing by GC/MS impossible. [13][14]
In practice this ‘instability’ is likely to be of little consequence. The Lederle researchers found that “Unlike the diaziridines, the diazirines were found to be very stable, relatively nonpolar compounds”. [1] The same storage advice should be heeded as with all other steroidal products: keep in a cool, dark, dry place.

Availability
Methyldiazirinol was never commercialised by its inventors, though they continued to explore the possibilities of the diazirine group in other (non-steroidal) molecules. [15][16]

triumphalis methyldiazirinolIn 2013 methyldiazirinol was released onto the dietary supplement market as Iron Legion Triumphalis.

References:
[1] Church RFR, Kende AS, Weiss MJ. Diazirines. I. Some Observations on the Scope of the Ammonia-Hydroxylamine-O-sulfonic Acid Diaziridine Synthesis. The Preparation of Certain Steroid Diaziridines and Diazirines. J. Am. Chem. Soc. 1965 Jun 1;87(12):2665–71.
[2] Church RFR. 2,2 And 3,3-Hydrazi-Steroids of the Androstane and Pregnane Series. 1969
[3] Kissman H, Hoffman A, Weiss M. Communications- Synthesis of Certain Steroidal α-Cyano Ketones. J. Org. Chem. 1961 Jul 1;26(7):2610–1.
[4] Kissman HM, Hoffman AS, Weiss MJ. The Synthesis of Certain α-Cyano Keto Steroids. J. Org. Chem. 1962 Sep 1;27(9):3168–75.
[5] Bernstein S. Historic reflection on steroids: Lederle and personal aspects. Steroids. 1992 Aug;57(8):392–402.
[6] Androgens and Anabolic Agents. 1969. Academic Press, p90.
[7] Singh H, Jindal DP, Yadav MR, Kumar M. Heterosteroids and drug research. Prog Med Chem. 1991;28:233–300.
[8] Androgens and Anabolic Agents. 1969. Academic Press, p194.
[9] Albini A, Fasani E, Albini A, Fasani E. Photochemistry of drugs: An overview and practical problems. Drugs Photochemistry and Photostability. 2007.
[10] Van der Merwe PJ, Pieterse JW. Stability of zeranol, nandrolone and trenbolone in bovine urine. Analyst. 1994 Dec;119(12):2651–3.
[11] Debono M. The photodimerization of 17β-hydroxy-estra-4,9(10)-dien-3-one. Steroids. 1968 Oct;12(4):485–9.
[12] Qu S, Kolodziej EP, Cwiertny DM. Phototransformation rates and mechanisms for synthetic hormone growth promoters used in animal agriculture. Environ. Sci. Technol. 2012 Dec 18;46(24):13202–11.
[13] Okano M, Sato M, Ikekita A, Kageyama S. Analysis of non-ketoic steroids 17α-methylepithiostanol and desoxymethyl- testosterone in dietary supplements. Drug Testing and Analysis. 2009;1(11-12):518–25.
[14] Does “Epistane” convert to “Phera”? – Total Flex Blog.
[15] Church RFR, Weiss MJ. Diazirines. II. Synthesis and properties of small functionalized diazirine molecules. Observations on the reaction of a diaziridine with the iodine-iodide ion system. J. Org. Chem. 1970 Aug 1;35(8):2465–71.
[16] Church RFR, Maleike RR, Weiss MJ. Diazirines. 3. Synthesis of a series of diazirine-containing molecules and their pharmacological evaluation. J. Med. Chem. 1972 May 1;15(5):514–8.

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