Chlorotrianisene

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Chlorotrianisene
Chlorotrianisene.svg
Clinical data
Trade names Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Triagen, others
Other namesCTA; Trianisylchloroethylene; tri-p-Anisylchloroethylene; TACE; tris(p-Methoxyphenyl)-chloroethylene; NSC-10108
AHFS/Drugs.com Multum Consumer Information
Routes of
administration 		By mouth [1] [2]
Drug class Nonsteroidal estrogen
ATC code
Pharmacokinetic data
Metabolism Mono-O-demethylation (liver CYP450) [3] [4]
Metabolites Desmethylchlorotrianisene [3] [4]
Identifiers
  • 1,1',1''-(2-chloroethene-1,1,2-triyl)tris(4-methoxybenzene); 11-chloro-4,13-dimethoxy-12-(p-methoxyphenyl)stilbene
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.008.472 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H21ClO3
Molar mass 380.87 g·mol−1
3D model (JSmol)
  • COc1ccc(C(Cl)=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
  • InChI=1S/C23H21ClO3/c1-25-19-10-4-16(5-11-19)22(17-6-12-20(26-2)13-7-17)23(24)18-8-14-21(27-3)15-9-18/h4-15H,1-3H3 Yes check.svgY
  • Key:BFPSDSIWYFKGBC-UHFFFAOYSA-N Yes check.svgY
   (verify)

Chlorotrianisene (CTA), also known as tri-p-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications, but has since been discontinued and is now no longer available. [5] [6] [7] [1] [8] It is taken by mouth. [1] [2]

Contents

CTA is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. [7] [1] [9] [10] It is a high-efficacy partial estrogen and shows some properties of a selective estrogen receptor modulator, with predominantly estrogenic activity but also some antiestrogenic activity. [11] [12] CTA itself is inactive and is a prodrug in the body. [2] [13]

CTA was introduced for medical use in 1952. [14] It has been marketed in the United States and Europe. [14] [6] However, it has since been discontinued and is no longer available in any country. [1] [15]

Medical uses

CTA has been used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications. [7] [1] It has been used to suppress lactation in women. [16] CTA has been used in the treatment of acne as well. [17] [18] [19]

Estrogen dosages for prostate cancer
Route/formEstrogenDosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–3 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 100–480 mg 1–3x/day
Chlorotrianisene12–48 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IM Tooltip Intramuscular or SC injection Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

Side effects

In men, CTA can produce gynecomastia as a side effect. [20] [21] Conversely, it does not appear to lower testosterone levels in men, and hence does not seem to have a risk of hypogonadism and associated side effects in men. [22]

Pharmacology

Testosterone levels with no treatment and with various estrogens in men with prostate cancer. Determinations were made with an early radioimmunoassay (RIA). Source was Shearer et al. (1973). Testosterone levels with different estrogen therapies in men with prostate cancer.png
Testosterone levels with no treatment and with various estrogens in men with prostate cancer. Determinations were made with an early radioimmunoassay (RIA). Source was Shearer et al. (1973).

CTA is a relatively weak estrogen, with about one-eighth the potency of DES. [2] [12] However, it is highly lipophilic and is stored in fat tissue for prolonged periods of time, with its slow release from fat resulting in a very long duration of action. [2] [12] [24] CTA itself is inactive; it behaves as a prodrug to desmethylchlorotrianisene (DMCTA), [3] [4] a weak estrogen that is formed as a metabolite via mono-O-demethylation of CTA in the liver. [2] [13] As such, the potency of CTA is reduced if it is given parenterally instead of orally. [2]

Although it is referred to as a weak estrogen and was used solely as an estrogen in clinical practice, CTA is a high-efficacy partial agonist of the estrogen receptor. [12] As such, it is a selective estrogen receptor modulator (SERM), with predominantly estrogenic effects but also with antiestrogenic effects, and was arguably the first SERM to ever be introduced. [11] CTA can antagonize estradiol at the level of the hypothalamus, resulting in disinhibition of the hypothalamic–pituitary–gonadal axis and an increase in estrogen levels. [12] Clomifene and tamoxifen were both derived from CTA via structural modification, and are much lower-efficacy partial agonists than CTA and hence much more antiestrogenic in comparison. [12] [9] As an example, chlorotrianisene produces gynecomastia in men, [21] albeit reportedly to a lesser extent than other estrogens, [25] while clomifene and tamoxifen do not and can be used to treat gynecomastia. [26]

CTA at a dosage of 48 mg/day inhibits ovulation in almost all women. [27] Conversely, it has been reported that CTA has no measurable effect on circulating levels of testosterone in men. [22] This is in contrast to other estrogens, like diethylstilbestrol, which can suppress testosterone levels by as much as 96%—or to an equivalent extent as castration. [22] These findings suggest that CTA is not an effective antigonadotropin in men. [22]

Chemistry

Chlorotrianisene, also known as tri-p-anisylchloroethylene (TACE) or as tris(p-methoxyphenyl)chloroethylene, is a synthetic nonsteroidal compound of the triphenylethylene group. [5] [7] [1] It is structurally related to the nonsteroidal estrogen diethylstilbestrol and to the SERMs clomifene and tamoxifen. [1] [12] [9]

It is structurally related to a compound that is called Aminoxytriphene (Amotriphene).

Chlorotrianisene is prepared by the halogenation of a compound called trianisylethylene [7109-27-5]. An improved version for the synthesis of this precursor is by the treatment of chloroacetyl chloride with 3 equivalents of Grignard reagent. [28] Another synthetic pathway relies on Grignard addition to the corresponding benzophenone, [29] [30] or by the Grignard reaction with desoxyanisoin. [31] Crenshaw & Zimmer reported some interesting methods too. [32] E.g. Grignard reaction to alpha-chloro-4'-methoxyacetophenone [2196-99-8] was also demonstrated to work.

Trianisylethylene was also halogenated with bromine and found to give a,a,b-tri(p-anisyl)bromoethylene. [33] [34] [35] According to one SAR survey, this agent was said to be an improvement over Estrobin. [36] This earlier work accumulated in the synthesis of Chlorotrianisene. [37] At least three newer syntheses are also recorded in the pendant literature for Chlorotrianisene. [30] [29] [38] [32] In one adventitious discovery, it was found that chlorotrianisene could be made from methoxychlor & anisole in a single step. [39]

The halogenation step in this class of agents has the overall effect of replacing a vinylic hydrogen with a halogen atom. The reaction mechanism however can thought to be rationalized by a discrete halogenation step to give a vicinally dihalogenated compound, which is not isolated but then instead undergoes dehydrohalogenation step. [40]

History

CTA was introduced for medical use in the United States in 1952, and was subsequently introduced for use throughout Europe. [14] [6] It was the first estrogenic compound of the triphenylethylene series to be introduced. [11] In comparison a commercial advertisement for Gynosone was made in 1946. [41] CTA was derived from estrobin (DBE), a derivative of the very weakly estrogenic compound triphenylethylene (TPE), which in turn was derived from structural modification of diethylstilbestrol (DES). [2] [12] [24] [42] The SERMs clomifene and tamoxifen, as well as the antiestrogen ethamoxytriphetol, were derived from CTA via structural modification. [12] [9] [43] [44]

Society and culture

Generic names

Chlorotrianisene is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name. [5] [6] [7] It is also known as tri-p-anisylchloroethylene (TACE). [5] [6] [7]

Brand names

CTA has been marketed under the brand names Tace, Estregur, Anisene, Clorotrisin, Merbentyl, Merbentul, and Triagen among many others. [5] [6]

Availability

CTA is no longer marketed and hence is no longer available in any country. [1] [15] It was previously used in the United States and Europe. [14] [6]

References

  1. 1 2 3 4 5 6 7 8 9 Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2085. ISBN   978-0-85369-840-1.
  2. 1 2 3 4 5 6 7 8 Meikle AW (24 April 2003). Endocrine Replacement Therapy in Clinical Practice. Springer Science & Business Media. pp. 486–. ISBN   978-1-59259-375-0.
  3. 1 2 3 Ruenitz PC, Toledo MM (August 1981). "Chemical and biochemical characteristics of O-demethylation of chlorotrianisene in the rat". Biochem. Pharmacol. 30 (16): 2203–7. doi:10.1016/0006-2952(81)90088-5. PMID   7295335.
  4. 1 2 3 Jordan VC (1986). Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. p. 212. ISBN   978-0-299-10480-1.
  5. 1 2 3 4 5 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 263–. ISBN   978-1-4757-2085-3.
  6. 1 2 3 4 5 6 7 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 219–. ISBN   978-3-88763-075-1.
  7. 1 2 3 4 5 6 Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 73–. ISBN   978-94-011-4439-1.
  8. ↑ Cox RL, Crawford ED (December 1995). "Estrogens in the treatment of prostate cancer". The Journal of Urology. 154 (6): 1991–8. doi:10.1016/S0022-5347(01)66670-9. PMID   7500443.
  9. 1 2 3 4 Luniwal A, Jetson R, Erhardt P (2012). "Selective Estrogen Receptor Modulators". In Fischer J, Ganellin CR, Rotella DP (eds.). Analogue-Based Drug Discovery III. pp. 165–185. doi:10.1002/9783527651085.ch7. ISBN   9783527651085.
  10. ↑ Jordan VC, Lieberman ME (September 1984). "Estrogen-stimulated prolactin synthesis in vitro. Classification of agonist, partial agonist, and antagonist actions based on structure". Molecular Pharmacology. 26 (2): 279–85. PMID   6541293.
  11. 1 2 3 Fischer J, Ganellin CR, Rotella DP (15 October 2012). Analogue-based Drug Discovery III. John Wiley & Sons. pp. 5–. ISBN   978-3-527-65110-8.
  12. 1 2 3 4 5 6 7 8 9 Sneader W (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 198–. ISBN   978-0-471-89979-2.
  13. 1 2 Hadden J (9 November 2013). Pharmacology. Springer Science & Business Media. pp. 249–. ISBN   978-1-4615-9406-2.
  14. 1 2 3 4 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 980–. ISBN   978-0-8155-1856-3.
  15. 1 2 http://www.micromedexsolutions.com/micromedex2/%5B%5D
  16. ↑ Vorherr H (2 December 2012). The Breast: Morphology, Physiology, and Lactation. Elsevier Science. pp. 203–. ISBN   978-0-323-15726-1.
  17. ↑ Schirren C (1961). "Die Sexualhormone". Therapie der Haut- und Geschlechtskrankheiten. pp. 470–549. doi:10.1007/978-3-642-94850-3_6. ISBN   978-3-642-94851-0.{{cite book}}: ISBN / Date incompatibility (help)
  18. ↑ Kile RL (August 1953). "The treatment of acne with TACE". J Invest Dermatol. 21 (2): 79–81. doi: 10.1038/jid.1953.73 . PMID   13084969.
  19. ↑ Welsh AL (April 1954). "Use of synthetic estrogenic substance chlorotrianisene (TACE) in treatment of acne". AMA Arch Dermatol Syphilol. 69 (4): 418–27. doi:10.1001/archderm.1954.01540160020004. PMID   13147544.
  20. ↑ Dao TL (1975). "Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms". In Sartorelli AC, Johns DG (eds.). Antineoplastic and Immunosuppressive Agents. pp. 170–192. doi:10.1007/978-3-642-65806-8_11. ISBN   978-3-642-65806-8.
  21. 1 2 Li JJ (3 April 2009). Triumph of the Heart: The Story of Statins. Oxford University Press, USA. pp. 34–. ISBN   978-0-19-532357-3.
  22. 1 2 3 4 Ghanadian R (6 December 2012). The Endocrinology of Prostate Tumours. Springer Science & Business Media. pp. 70–. ISBN   978-94-011-7256-1.
  23. 1 2 3 Shearer RJ, Hendry WF, Sommerville IF, Fergusson JD (December 1973). "Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer". Br J Urol. 45 (6): 668–77. doi:10.1111/j.1464-410x.1973.tb12238.x. PMID   4359746.
  24. 1 2 Jordan VC, Mittal S, Gosden B, Koch R, Lieberman ME (September 1985). "Structure-activity relationships of estrogens". Environmental Health Perspectives. 61: 97–110. Bibcode:1985EnvHP..61...97J. doi:10.1289/ehp.856197. PMC   1568776 . PMID   3905383.
  25. ↑ Vitamins and Hormones. Academic Press. 18 May 1976. pp. 387–. ISBN   978-0-08-086630-7.
  26. ↑ Khan HN, Blamey RW (August 2003). "Endocrine treatment of physiological gynaecomastia". BMJ. 327 (7410): 301–2. doi:10.1136/bmj.327.7410.301. PMC   1126712 . PMID   12907471.
  27. ↑ Duncan CJ, Kistner RW, Mansell H (October 1956). "Suppression of ovulation by trip-anisyl chloroethylene (TACE)". Obstet Gynecol. 8 (4): 399–407. PMID   13370006.
  28. ↑ Г. Хухр нский Л. Н. Волове льский, SU213825 ().
  29. 1 2 Robert S Shelton, Jr Marcus G Van Campen, U.S. patent 2,430,891 (1947 to Wm S Merrell Co).
  30. 1 2 Shelton, R. S., Campen, M. G. V., Meisner, D. F., Parmerter, S. M., Andrews, E. R., Allen, R. E., Wyckoff, K. K. (November 1953). "Synthetic Estrogens. Halotriphenylethylene Derivatives". Journal of the American Chemical Society. 75 (22): 5491–5495. doi:10.1021/ja01118a008.
  31. ↑ Robert A. Magarian, Joseph T. Pento & Billy W. Day, U.S. patent 5,015,666 (1991 to University of Oklahoma).
  32. 1 2 Crenshaw, M. D., Zimmer, H. (August 1983). "Synthesis with .alpha.-heterosubstituted phosphonates. Part 13. Synthesis of trisubstituted vinyl chlorides". The Journal of Organic Chemistry. 48 (16): 2782–2784. doi:10.1021/jo00164a036.
  33. ↑ DAVIES J. S. H., AND ELSON L.A. GB549353 (1942 to Imperial Chemical Industries, Ltd.); Chem. Abstracts 38, 838 (1944).
  34. ↑ DAVIES, J. S. H. GB549200 (1942 to Imperial Chemical Industries, Ltd.); Chem. abstracts 38, 621 (1944).
  35. ↑ BASFORD, F. R., GB559374 (1944 to Imperial Chemical Industries Ltd).
  36. ↑ Solmssen, Ulrich V. (1945). "Synthetic Estrogens and the Relation Between their Structure and their Activity.". Chemical Reviews. 37 (3): 481–598. doi:10.1021/cr60118a004.
  37. ↑ Frederick Robert Basford, GB561508 (1944 to ICI Ltd.).
  38. ↑ Sisido, K., Okano, K., Isida, T., Nozaki, H. (December 1955). "Preparations of the Synthetic Estrogens. VII. 1 New Syntheses of 1,1,2-Tri-p-anisyl-2-chloroethylene". Journal of the American Chemical Society. 77 (24): 6580–6582. doi:10.1021/ja01629a046.
  39. ↑ Mitchell, R. H., Mazuch, L., Shell, B., West, P. R. (1 May 1978). "Constituents of commercial methoxychlor-III. The mechanism of tetraanisylethylene formation. unsym -Tetraarylethylenes (Ar 2 C=CAr 2 ′): synthesis from DT class pesticides, and conversion to phenanthrenes and dibenzo[ g,p ]chrysenes". Canadian Journal of Chemistry. 56 (9): 1246–1252. doi:10.1139/v78-207.
  40. ↑ Koelsch, C. Frederick. (1932). SYNTHESES WITH TRIARYLVINYLMAGNESIUM BROMIDES. TRIARYLACRYLIC ACIDS AND THE INDONES DERIVED FROM THEM. Journal of the American Chemical Society, 54(6), 2487–2493. doi:10.1021/ja01345a046
  41. ↑ ""Gynosone" A New Synthetic Oestrogen". Advertisement. Proc R Soc Med. 39 (11). Sep 1946. PMC   2181944 .
  42. ↑ Avendano C, Menendez JC (11 June 2015). Medicinal Chemistry of Anticancer Drugs. Elsevier Science. pp. 87–. ISBN   978-0-444-62667-7.
  43. ↑ Manni A (15 January 1999). Endocrinology of Breast Cancer. Springer Science & Business Media. pp. 286–287. ISBN   978-1-59259-699-7.
  44. ↑ Ravina E (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 178–. ISBN   978-3-527-32669-3.
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