Δ4-Tibolone

Last updated
Δ4-Tibolone
D4-Tibolone.svg
D4-Tibolone molecule ball.png
Clinical data
Other namesIsotibolone; ORG-OM-38; Delta-4-Tibolone; 7α-Methylnorethisterone; 7α-Methyl-17α-ethynyl-19-nortestosterone; 17α-Ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one
Identifiers
  • (7R,8R,9S,10R,13S,14S,17R)-17-Ethynyl-17-hydroxy-7,13-dimethyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C21H28O2
Molar mass 312.453 g·mol−1
3D model (JSmol)
  • C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]3[C@@H]1[C@@H]4CC[C@]([C@]4(CC3)C)(C#C)O
  • InChI=1S/C21H28O2/c1-4-21(23)10-8-18-19-13(2)11-14-12-15(22)5-6-16(14)17(19)7-9-20(18,21)3/h1,12-13,16-19,23H,5-11H2,2-3H3/t13-,16+,17-,18+,19-,20+,21+/m1/s1
  • Key:WAOKMNBZWBGYIK-KIURNNQRSA-N

δ4-Tibolone (developmental code ORG-OM-38; also known as isotibolone, 7α-methylnorethisterone, or 7α-methyl-17α-ethynyl-19-nortestosterone) is a synthetic androgen and progestin which was never marketed. [1] [2] The compound is a major active metabolite of tibolone, which itself is a prodrug of δ4-tibolone along with 3α-hydroxytibolone and 3β-hydroxytibolone (which, in contrast to δ4-tibolone, are estrogens). [1] Tibolone and δ4-tibolone are thought to be responsible for the androgenic and progestogenic activity of tibolone, while 3α-hydroxytibolone and 3β-hydroxytibolone are thought to be responsible for its estrogenic activity. [1]

Contents

Activity

Isotibolone exhibited both estrogenic and progestogenic properties in several biological test systems and was found to be 10 to 40 times as potent as norethindrone in comparative assays. Tested for androgenic activity, it stimulated growth of seminal vesicles and the levator ani but was relatively inactive in stimulating prostate gland growth. [3]

Synthesis

Isotibolone, mibolerone, bolasterone, and calusterone all appear in the same patent file. [4] The specific entry for the synthesis of isotibolone is Example 31. Note that these agents were all produced by Upjohn whereas Tibolone is the subject of an Organon patent. [5]

The organic synthesis of these agents related to isotibolone are summarized in textbooks published by Daniel Lednicer (& Lester Mitscher): [6] [7] [8] [9] [10]

The enanthate ester of isotibolone was also prepared in a separate patent. [11]

See also

References

  1. 1 2 3 Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324.
  2. ↑ Escande A, Servant N, Rabenoelina F, Auzou G, Kloosterboer H, Cavaillès V, Balaguer P, Maudelonde T (2009). "Regulation of activities of steroid hormone receptors by tibolone and its primary metabolites". J. Steroid Biochem. Mol. Biol. 116 (1–2): 8–14. doi:10.1016/j.jsbmb.2009.03.008. PMID   19464167. S2CID   18346113.
  3. ↑ Pharriss, B. B. (February 1970). "Biological properties of 17-ethinyl-7α-methyl-19-nortestosterone (U-13,851)". Contraception. 1 (2): 87–100. doi:10.1016/0010-7824(70)90049-1.
  4. ↑ John C Babcock & Campbell J Allan, U.S. patent 3,341,557 (1967 to Pharmacia and Upjohn Co).
  5. ↑ NL 6406797 idem Jongh Hendrik Paul De, Nicolaas Pieter Van Vliet, U.S. patent 3,340,279 (1967 to Organon).
  6. ↑ Lednicer, D. (2011). Steroid chemistry at a glance (1. publ ed.). Wiley. ISBN   9780470660843.
  7. ↑ Lednicer, D., Mitscher, L. A. (1980). The organic chemistry of drug synthesis. 2. Wiley. ISBN   9780471043928.
  8. ↑ Lednicer, D. (2009). Strategies for organic drug synthesis and design (2nd ed.). John Wiley & Sons. ISBN   9780470190395.
  9. ↑ Lednicer, D., Mitscher, L. A. (1977). The organic chemistry of drug synthesis. 1. Wiley. ISBN   9780471521419.
  10. ↑ Lednicer, D. (2015). Antineoplastic drugs: organic syntheses. John Wiley & Sons. Ltd. ISBN   9781118892572.
  11. ↑ Richard Blye & Hyun K. Kim, U.S. patent 4,308,265 (1981 to Government of the United States of America).


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