Movatterモバイル変換

[0]ホーム
URL:

Jump to content
WikipediaThe Free Encyclopedia
Search

Chlorotrianisene

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
Chlorotrianisene
Clinical data
Trade namesTace, Estregur, Anisene, Clorotrisin, Merbentyl, Triagen, others
Other namesCTA; Trianisylchloroethylene; tri-p-Anisylchloroethylene; TACE; tris(p-Methoxyphenyl)-chloroethylene; NSC-10108
AHFS/Drugs.comMultum Consumer Information
Routes of
administration		By mouth[1][2]
Drug classNonsteroidal estrogen
ATC code
Pharmacokinetic data
MetabolismMono-O-demethylation (liverCYP450)[3][4]
MetabolitesDesmethylchlorotrianisene[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
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.008.472Edit this at Wikidata
Chemical and physical data
FormulaC23H21ClO3
Molar mass380.87 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 checkY
  • Key:BFPSDSIWYFKGBC-UHFFFAOYSA-N checkY
  (verify)

Chlorotrianisene (CTA), also known astri-p-anisylchloroethylene (TACE) and sold under the brand nameTace among others, is anonsteroidal estrogen related todiethylstilbestrol (DES) which was previously used in the treatment ofmenopausal symptoms andestrogen deficiency in women andprostate cancer in men, among other indications, but has since been discontinued and is now no longer available.[5][6][7][1][8] It is takenby mouth.[1][2]

CTA is anestrogen, or anagonist of theestrogen receptors, thebiological target of estrogens likeestradiol.[7][1][9][10] It is a high-efficacypartial estrogen and shows some properties of aselective estrogen receptor modulator, with predominantlyestrogenic activity but also someantiestrogenic activity.[11][12] CTA itself is inactive and is aprodrug in the body.[2][13]

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

Medical uses

[edit]

CTA has been used in the treatment ofmenopausal symptoms andestrogen deficiency in women andprostate cancer in men, among other indications.[7][1] It has been used to suppresslactation in women.[16] CTA has been used in the treatment ofacne as well.[17][18][19]

Estrogen dosages for prostate cancer
Route/formEstrogenDosage
OralEstradiol1–2 mg 3x/day
Conjugated estrogens1.25–2.5 mg 3x/day
Ethinylestradiol0.15–3 mg/day
Ethinylestradiol sulfonate1–2 mg 1x/week
Diethylstilbestrol1–3 mg/day
Dienestrol5 mg/day
Hexestrol5 mg/day
Fosfestrol100–480 mg 1–3x/day
Chlorotrianisene12–48 mg/day
Quadrosilan900 mg/day
Estramustine phosphate140–1400 mg/day
Transdermal patchEstradiol2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IMTooltip Intramuscular orSC injectionEstradiol benzoate1.66 mg 3x/week
Estradiol dipropionate5 mg 1x/week
Estradiol valerate10–40 mg 1x/1–2 weeks
Estradiol undecylate100 mg 1x/4 weeks
Polyestradiol phosphateAlone: 160–320 mg 1x/4 weeks
With oralEE: 40–80 mg 1x/4 weeks
Estrone2–4 mg 2–3x/week
IV injectionFosfestrol300–1200 mg 1–7x/week
Estramustine phosphate240–450 mg/day
Note: Dosages are not necessarily equivalent.Sources: See template.

Side effects

[edit]
See also:Estrogen (medication) § Side effects

In men, CTA can producegynecomastia as aside effect.[20][21] Conversely, it does not appear to lowertestosterone levels in men, and hence does not seem to have a risk ofhypogonadism and associated side effects in men.[22]

Pharmacology

[edit]
Testosterone levels with no treatment and with various estrogens in men with prostate cancer.[23] Determinations were made with an earlyradioimmunoassay (RIA).[23] Source was Shearer et al. (1973).[23]

CTA is a relatively weakestrogen, with about one-eighth the potency of DES.[2][12] However, it is highlylipophilic and is stored infat 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 aprodrug todesmethylchlorotrianisene (DMCTA),[3][4] a weak estrogen that is formed as ametabolite via mono-O-demethylation of CTA in theliver.[2][13] As such, the potency of CTA is reduced if it is givenparenterally instead of orally.[2]

Although it is referred to as a weakestrogen and was used solely as an estrogen in clinical practice, CTA is a high-efficacypartial agonist of theestrogen receptor.[12] As such, it is aselective estrogen receptor modulator (SERM), with predominantly estrogenic effects but also withantiestrogenic effects, and was arguably the first SERM to ever be introduced.[11] CTA can antagonizeestradiol at the level of thehypothalamus, resulting in disinhibition of thehypothalamic–pituitary–gonadal axis and an increase in estrogen levels.[12]Clomifene andtamoxifen were both derived from CTA viastructural modification, and are much lower-efficacy partial agonists than CTA and hence much more antiestrogenic in comparison.[12][9] As an example, chlorotrianisene producesgynecomastia 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 inhibitsovulation in almost all women.[27] Conversely, it has been reported that CTA has no measurable effect on circulating levels oftestosterone in men.[22] This is in contrast to other estrogens, likediethylstilbestrol, which can suppress testosterone levels by as much as 96%—or to an equivalent extent ascastration.[22] These findings suggest that CTA is not an effectiveantigonadotropin in men.[22]

Chemistry

[edit]

Chlorotrianisene, also known as tri-p-anisylchloroethylene (TACE) or as tris(p-methoxyphenyl)chloroethylene, is asyntheticnonsteroidalcompound of thetriphenylethylene group.[5][7][1] It is structurally related to the nonsteroidal estrogendiethylstilbestrol and to the SERMsclomifene andtamoxifen.[1][12][9]

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

Chlorotrianisene is prepared by the halogenation of a compound calledtrianisylethylene [7109-27-5]. An improved version for the synthesis of this precursor is by the treatment ofchloroacetyl 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 withdesoxyanisoin.[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 overEstrobin.[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 frommethoxychlor &anisole in a single step.[39]

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

History

[edit]

CTA was introduced for medical use in theUnited States in 1952, and was subsequently introduced for use throughoutEurope.[14][6] It was the firstestrogenic compound of the triphenylethylene series to be introduced.[11] In comparison a commercial advertisement forGynosone was made in 1946.[41] CTA was derived fromestrobin (DBE), aderivative of the very weakly estrogenic compoundtriphenylethylene (TPE), which in turn was derived from structural modification ofdiethylstilbestrol (DES).[2][12][24][42] The SERMsclomifene andtamoxifen, as well as theantiestrogenethamoxytriphetol, were derived from CTA via structural modification.[12][9][43][44]

Society and culture

[edit]

Generic names

[edit]

Chlorotrianisene is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name.[5][6][7] It is also known astri-p-anisylchloroethylene (TACE).[5][6][7]

Brand names

[edit]

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

Availability

[edit]

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

References

[edit]
  1. ^abcdefghiSweetman 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. ^abcdefghMeikle AW (24 April 2003).Endocrine Replacement Therapy in Clinical Practice. Springer Science & Business Media. pp. 486–.ISBN 978-1-59259-375-0.
  3. ^abcRuenitz 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. ^abcJordan VC (1986).Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. p. 212.ISBN 978-0-299-10480-1.
  5. ^abcdeElks 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. ^abcdefgIndex Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 219–.ISBN 978-3-88763-075-1.
  7. ^abcdefMorton 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. ^abcdLuniwal 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. ^abcFischer 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. ^abcdefghiSneader W (23 June 2005).Drug Discovery: A History. John Wiley & Sons. pp. 198–.ISBN 978-0-471-89979-2.
  13. ^abHadden J (9 November 2013).Pharmacology. Springer Science & Business Media. pp. 249–.ISBN 978-1-4615-9406-2.
  14. ^abcdWilliam Andrew Publishing (22 October 2013).Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 980–.ISBN 978-0-8155-1856-3.
  15. ^abhttp://www.micromedexsolutions.com/micromedex2/[permanent dead link]
  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. ^abLi 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. ^abcdGhanadian R (6 December 2012).The Endocrinology of Prostate Tumours. Springer Science & Business Media. pp. 70–.ISBN 978-94-011-7256-1.
  23. ^abcShearer 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. ^abJordan 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. ^abRobert S Shelton, Jr Marcus G Van Campen,U.S. patent 2,430,891 (1947 to Wm S Merrell Co).
  30. ^abShelton, 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. ^abCrenshaw, 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.
Estrogens
ERTooltip Estrogen receptor agonists
Progonadotropins
Antiestrogens
ERTooltip Estrogen receptor antagonists
(incl.SERMsTooltip selective estrogen receptor modulators/SERDsTooltip selective estrogen receptor downregulators)
Aromatase inhibitors
Antigonadotropins
Others
ERTooltip Estrogen receptor
Agonists
Mixed
(SERMsTooltip Selective estrogen receptor modulators)
Antagonists
GPERTooltip G protein-coupled estrogen receptor
Agonists
Antagonists
Unknown
Retrieved from "https://en.wikipedia.org/w/index.php?title=Chlorotrianisene&oldid=1333697959"
Categories:
Hidden categories:
[8]ページ先頭
©2009-2026 Movatter.jp