Dimethazine

Structure:

Nomenclature:
2a,17a-dimethyl-5a-androstan-17b-ol-3,3′-azine, or
2a,17a-dimethyl-5a-androstan-17b-ol-3-one-azine

Synonyms:
Dimethazine, dymethazine, Roxilon, mebolazine

History:
The synthesis of dimethazine was first reported by the Research Laboratories of Ormonoterapia Richter (Richter Hormone Therapy) in Milan, Italy in 1962. [1]

This research team had been testing the theory that increasing the electron density at and around carbon 3 would increase the dissociation between anabolic and androgenic effects. [2] This paralleled and built on research undertaken at Syntex that yielded such steroids as oxymetholone (Anadrol-50), desoxymethyltestosterone (pheraplex), and methasterone (superdrol), and research at Sterling-Winthrop that led to stanozolol (Winstrol). [3]

“We have prepared a number of steroidal derivatives where the normal carbonyl group at C3 was replaced with the group C=N- (less susceptible to deactivation at the 3-carbon) and to increase the electronic densification of C3, the 2 position has been replaced with a methyl group.” [Translated] [2]

De Ruggieri believed he had detected 2a,17a-dimethyl-5a-androstan-17b-ol-3-one in urine after administration of 17β-Hydroxy-17-methyl-5α-androstano[3,2-c]pyrazole. [4][5] Those drugs are better known as methasterone (superdrol) and stanozolol (winstrol). Believing ‘superdrol’ to be a metabolite of ‘winstrol’, he hypothesized the route of metabolism (drawn below), and postulated that some or all of the anabolic and androgenic activity of stanozolol may be due to the 3-hydrazone metabolite (II).

proposed metabolism of stanozolol (de ruggieri)

Proposed metabolism of stanozolol.
I. Stanozolol
II. Methasterone-hydrazone
III. Methasterone

More recent metabolic studies have failed to detect methasteron as a metabolite of stanozolol. [6]

To test their theories the Ormonoterapia Richter researchers prepared and tested a series of 2a-methyl-3-hydrazone, 2a-methyl-3,3′-azine, and 2a-methyl-3-guanidine steroids.

2a,17a-dimethyl-5a-androstan-17b-ol-3,3′-azine (dimethazine; mebolazine), and the non-17a-methylated congener 2a-methyl-5a-androstan-17b-ol-3,3′-azine (bolazine) were the most active, and both were brought to market by Ormonoterapia Richter and used clinically in Europe.

In 2008 dimethazine was released as a “dietary supplement” sold over the internet by iForce Nutrition, under the name Dymethazine.
iForce_Nutrition_DymethazineiForce Nutrition’s premises were raided by the FDA in 2009, and they were subsequently charged with selling unapproved drugs (including dimethazine), resulting in a fine of $125,000. [7] Despite this, dimethazine-containing products continue to be marketed online by other companies.

Anabolic/Androgenic Activity:
When tested by Syntex researchers Fred Kincl and Ralph Dorfman, dimethazine was fairly weakly active when administered by injection, with a ratio of 27:<6-<12. [8]

dimethazine structure and effect dorfman kincl

Pharmacol Ther B. 1975;1(2):233–75. [9]


Kincl and Dorfman observed:

“The azine derivative of 2,17a-dimethyldihydrotestosterone is particularly interesting, since the seminal vesicles and prostate did not respond at the dosage used although a highly significant levator ani response was found.” – Kincl & Dorfman [8]

De Ruggieri found that by oral administration dimethazine has an anabolic:androgenic ratio of 210:95-97.

Synthesis:
– In 1958 Syntex described how to synthesize 2-hydroxymethylene-androstane derivatives (including oxymetholone; ‘Anadrol’), and from them, 2a-methyl-androstane derivatives (including methasterone; ‘Superdrol’).
– In 1960 Sterling-Winthrop described how to synthesize steroids with a [3,2-c]pyrazole heterocyclic ring system (including stanozolol) from 2-hydroxymethylene-androstanes using hydrazine.
– In 1962 de Ruggieri reported the synthesis of the dimeric steroid dimethazine by applying a similar technique to 2a-methyl steroids as Sterling-Winthrop had previously applied to the 2-hydroxymethylenes.

synthesis of stanozolol and dimethazine

Synthesis of stanozolol and dimethazine

Dimethazine is formed from the condensation of two molecules of methasterone with one molecule of hydrazine (with the loss of water).

Structure and Function:
Dimethazine is what is known as a homodimer. That is, it is a chemical compound made from two identical subunits, joined together by a bond (in this case, a covalent nitrogen-nitrogen bond).
Although the ketazines dimethazine and the non-17a-methylated analogue bolazine (sold as “Roxilon inject”) are the only dimeric steroids commercially marketed to date, several steroids have been found to dimerize under ultra-violet light (including testosterone [10] and dienolone [11]), and dimeric, trimeric, and even tetrameric anabolic steroids have been synthesized experimentally.

Oligomeric steroids

Adapted from Journal of Steroid Biochemistry vol. 5 issue 4 June, 1974. p. 298

Effect
In 1978 dimethazine was tested for use in aquaculture (fish farming) to accelerate the growth of fish. After 60 days dimethazine at a dose of 2.5mg/kg caused a significant increase in bodyweight of rainbow trout relative to controls, [12] and similar increases in growth rate were reported in carp, in 1984. [13]

The Ormonoterapia Richter research group proudly declared of dimethazine:

“This new steroid is endowed with strong effectiveness in the protein-anabolic sense, which is matched by negligible androgenicity, a low incidence of side effects and an almost absolute lack of toxicity.” [Translated] [2]

An English-language journal article in 1964 summarized the Italians’ results thus:

“[Dimethazine] on oral administration, is stated to induce an appreciable weight gain in adult rats, to show greater myotrophic activity than methyltestosterone, oxymetholone, stanozolol or testosterone propionate in castrated rats and to induce greater nitrogen retention in adult male rats than methyltestosterone while exhibiting no oestrogenic, progestational or corticoid activity.” [14]

Metabolism:

“This compound [dimethazine]… can perhaps be regarded as an example of drug latentation, especially in view of the obvious parallel to the relationship between prontosil red and sulphanilamide.” [14]

Prontosil was the first commercial antibiotic, released in the 1930s. Its activity was due to metabolism of the latent drug, or prodrug, prontosil in the liver to the active drug sulphanilamide.

metabolism of prontosil

Metabolism of Prontosil

Protonsil is an imperfect model for predicting dimethazine metabolism however because it contains an azo group (R-N=N-R’) rather than an azine (R=N-N=R’). A better model may be dimethylketazine.
Dimethylketazine hydrolyzes to acetone + hydrazine, via acetone hydrazone, under acidic conditions, [15] which lends credence to the generally-accepted view that dimethazine functions as a pro-drug to methasterone (superdrol).

Legality:
Since 1996 mebolazine has been a Class C controlled drug in the United Kingdom, and a Schedule IV controlled drug in Canada. [16][17]
At the time of writing [September 2013] it remains unscheduled in the United States.

References:
[1] US Patent US3062847: Steroidal Azines. De Ruggiero, Pietro.
[2] De Ruggieri P, Gandolfi C, Chiaramonti D. A new series of steroids with protein anabolic action. Boll. Soc. Ital. Biol. Sper. 1962 Oct 31;38:985–7.
[3] Bowers, A. Ring A Modified Androstanes. New Classes of Anabolic Agents. Proceedings of the First International Congress on Hormonal Steroids, Volume 2, p132-141
[4] Cited in: Doorenbos NJ, Dorn CP Jr. Steroids 23. Synthesis of some ring A-fused heterocyclic steroids. J Pharm Sci. 1965 Aug;54(8):1219–21.
[5] Matscher, R., Lupo, C., and De Ruggieri, P. (1962). Excerpta Med. Intern. Congr. Ser. 51, 217. Cited in: Dorfman RI. Methods in hormone research IV. Academic Press; 1965 p40.
[6] Massé R, Ayotte C, Bi HG, Dugal R. Studies on anabolic steroids. III. Detection and characterization of stanozolol urinary metabolites in humans by gas chromatography-mass spectrometry. J. Chromatogr. 1989 Dec 29;497:17–37.
[7] FDA: Criminal Investigations – May 5, 2011: Dietary Supplements Manufacturer Sentenced
[8] Dorfman RI, Kincl FA. Relative Potency of Various Steroids in an Anabolic-Androgenic Assay Using the Castrated Rat. Endocrinology. 1963 Feb 1;72(2):259–66.
[9] Camerino B, Sciaky R. Structure and effects of anabolic steroids. Pharmacol Ther B. 1975;1(2):233–75.
[10] Reisch J, Ekiz-Gücer N, Takács M, Takács M, Henkel G. Photochemische Studien, 54. Photodimerisierung von Testosteronpropionat in kristallinem Zustand und Kristallstruktur von Testosteronpropionat. Liebigs Annalen der Chemie. 1989;1989(6):595–7.
[11] Debono M. The photodimerization of 17β-hydroxy-estra-4,9(10)-dien-3-one. Steroids. 1968 Oct;12(4):485–9.
[12] Matty AJ, Cheema IR. The effect of some steroid hormones on the growth and protein metabolism of rainbow trout. Aquaculture. 1978 Jun;14(2):163–78.
[13] K.p L, A.j M. Oral administration of an anabolic-androgenic steroid dimethazine increases the growth and food conversion efficiency and brings changes in molecular growth responses of carp (Cyprinus carpio) tissues. Nutrition Reports International. 1984;29.
[14] Martin-Smith M, Sugrue MF. Biological activity in steroids possessing nitrogen atoms: recent advances. Journal of Pharmacy and Pharmacology. 1964;16(9):569–95.
[15] Gilbert EC. Studies on hydrazine. The hydrolysis of dimethylketazine and the equilibrium between hydrazine and acetone. J Am Chem Soc. 1929 Nov 1;51(11):3394–409.
[16] The Misuse of Drugs Act 1971 (Modification) Order 1996
[17] Controlled Drugs and Substances Act, SC 1996, c 19

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