4-hydroxytamoxifen

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Structural formula
Structural formula of 4-hydroxytamoxifen
General
Non-proprietary name Afimoxifene
other names
  • 4 - [(1 Z ) -1- {4- [2- (dimethylamino) ethoxy] phenyl} -2-phenylbut-1-enyl] phenol ( IUPAC )
  • Hydroxytamoxifen
  • ( Z ) -hydroxytamoxifen
  • trans -hydroxytamoxifen
Molecular formula C 26 H 29 NO 2
External identifiers / databases
CAS number
  • 68047-06-3 ( Z )
  • 174592-47-3 ( E )
  • 68392-35-8 ( Z , E )
EC number 635-210-7
ECHA InfoCard 100.163.120
PubChem 449459
ChemSpider 395987
DrugBank DB04468
Wikidata Q4689254
Drug information
Drug class

Selective estrogen receptor modulator

Mechanism of action

competitive inhibition of estrogen receptors

properties
Molar mass 387.52 g · mol -1
Melting point
solubility

Water: 3.03 mg l −1 (25 ° C)

safety instructions
GHS labeling of hazardous substances
08 - Dangerous to health 07 - Warning

danger

H and P phrases H: 302-312-332-361
P: 280
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

4-Hydroxytamoxifen , also known as hydroxytamoxifen , abbreviated as 4-OHT, 4-HT, OHTAM, international non-proprietary name Afimoxifen , is a selective estrogen receptor modulator from the group of stilbene derivatives . Because of their anti-esterogenic activities, these are of interest both as contraceptives and therapeutics for the treatment of benign breast diseases and breast tumors .

history

The metabolism of tamoxifen was investigated in animal experiments as early as 1973 and in 1977 hydroxytamoxifen was confirmed as the main metabolite alongside desmethyl-hydroxytamoxifen ( endoxifen ) . Further studies from 1979 come to the same result and emphasize the strong receptor binding of 4-hydroxytamoxifen. As early as 1978 patent protection for a preparation and for the synthesis with application were filed.

Clinical information

Potential areas of application

4-Hydroxytamoxifen, like tamoxifen, is intended for the treatment of hormone-dependent tumors. Because of the much stronger effectiveness of 4-hydroxytamoxifen and, at the same time, faster metabolism after oral ingestion compared to tamoxifen, topical applications as a gel or transdermally as a patch are preferable. In the USA, the preparation TamoGel for the treatment of cycle-dependent breast pain in premenopausal women was investigated in a phase II study in 2007 , another 4-hydroxytamoxifen gel for reducing the radiographic breast tissue density in women with a tissue density of BI-RADS category C or D. in clinical phase III since August 2017.

Interactions

As a hormone receptor modulator, 4-hydroxytamoxifen, like tamoxifen, can potentially affect the effects of other hormone preparations. In particular, when estrogens are taken at the same time as tamoxifen derivatives, a mutual weakening of the effects can be observed.

chemistry

synthesis

The earlier synthesis of 4-hydroxy tamoxifen use the same principle as tamoxifen syntheses: By reaction of a 1,2-Diphenylbutanon derivative with an aryl - Grignard compound is built up the Triphenylbuten skeleton. Since the olefin is formed from the intermediate tertiary diphenylcarbinol by elimination of water according to an ionic reaction mechanism , Z / E mixtures always result in the ratio Z  : E = 3: 2. Isomer separation by means of chromatography is described.

Three strategies are used with different protecting groups for phenols :

Syntheses of 4-Hydroxxytamoxifen
  1. Introduction of the dimethylaminoethoxyphenyl group: The carbinol precursor of the formula (IV) of hydroxytamoxifen of the formula (V) is built up via the Grignard compound from dimethylaminoethoxybromobenzene of the formula (III) and 1-tetrahydropyranyloxyphenyl-2-phenylbutanone of the formula (II). The central component of the hydroxyphenyl-2-phenylbutanone of the formula (I) is made up of anisole and phenylacetic acid in several stages (see reaction scheme).
  2. Introduction of the phenol radical: In the case of the building block of the formula (I), the basic side chain can also be introduced using dimethylaminoethyl chloride. The ketone of the formula (VI) obtained, together with the Grignard compound from tetrahydropyranyloxybromobenzene of the formula (VII), likewise gives the carbinol of the formula (IV). This category also includes newer processes which start from a diphenylbutanone derivative of the formula (VII) with a chloroethoxy side chain. After a similar reaction sequence, the amino group is only introduced in the final stage.
  3. McMurry reaction to build up the olefin: In a formula- wise simple form, ( Z ) -4-hydroxytamoxifen of the formula (V) is to be formed by coupling the benzophenone derivative of the formula (VIII) with propiophenone by means of low-valent titanium compounds.

stability

It has long been known that the anti- estrogenic effect of 4-hydroxytamoxifen depends on its stereochemical purity, since the E-isomer acts as an estrogenic compound. However, hydroxytamoxifen is conformationally unstable both in solution and as a solid substance . Freshly synthesized ( Z ) -4-hydroxy tamoxifen should have a melting point of 142-144  ° C have. But after a storage time of a few weeks at room temperature, it drops by 4 ° C because the E content increases.

With ketones , especially with mesityl oxide , ( Z ) -4-hydroxytamoxifen forms stable solvates at room temperature, which are also suitable for cleaning. The isomer mixture is separated at the preliminary stage of the chloroethoxy compound (CAS number: 119757-57-2) after benzoylation of the phenol group with benzoyl chloride . Alcoholysis of the phenol ester leads, under kinetic control, to preferential precipitation of the sparingly soluble ( E ) -benzoyl compound. From this, after hydrolysis of the phenol ester and substitution of the chlorine atom by means of dimethylamine, the Z isomer can be obtained, which gives the corresponding purified solvate from the ketone.

literature

Individual evidence

  1. ↑ a b c d data sheet (Z) -4-Hydroxytamoxifen from Sigma-Aldrich , accessed on October 19, 2016 ( PDF ).
  2. ↑ Entry on (E) -4-Hydroxytamoxifen at ChemicalBook , accessed on December 3, 2017.
  3. ↑ (E / Z) -4-hydroxy tamoxifen (CAS number: 68392-35-8). In: caymanchem.com. Retrieved December 1, 2017 .
  4. ↑ a b c d Patent DE2807599 : Pharmaceutical compositions. Published August 31, 1978 , inventor: Dora Nellie Richardson. ‌
  5. ↑ a b c S. Gauthier, J. Mailhot, F. Labrie: New Highly Stereoselective Synthesis of (Z) -4-Hydroxytamoxifen and (Z) -4-Hydroxytoremifene via McMurry Reaction . In: The Journal of Organic Chemistry . tape 61 , no. 11 , 1996, pp. 3890-3893 , doi : 10.1021 / jo952279l .
  6. ↑ Entry on Afimoxifene in the DrugBank of the University of Alberta , accessed December 3, 2017.
  7. ↑ JM Fromson, S. Pearson, S. Bramah: The Metabolism of Tamoxifen (ICI 46,474) Part I: In Laboratory Animals . In: Xenobiotica . tape 3 , no. 11 , 1973, p. 693-709 , doi : 10.3109 / 00498257309151594 , PMID 4361333 .
  8. ↑ VC Jordan, Margret M. Collins, L. Rowsby, G. Prestwich: A Monohydroxylated Metabolite of Tamoxifen with Potent Antioestrogenic Activity . In: Journal of Endocrinology . tape 75 , no. 2 , 1977, ISSN  0022-0795 , pp. 305-316 , doi : 10.1677 / joe.0.0750305 , PMID 591813 .
  9. ↑ J.-L. Borgna, H. Rochefort: Biologie moléculaire. Occupation in vivo des réscepteurs estrogènes par des métabolites hydroxylés du tamoxifène. In: Comptes Rendus Des Seances De l'Academie Des Sciences. Series D, Sciences Naturelles . tape 289 , no. 15 , 1979, ISSN  0567-655X , p. 1141-1144 , PMID 121266 (French).
  10. ↑ a b Patent DE2835536 : Method for achieving an anti-oestrogenic effect in warm-blooded animals, compositions and compounds suitable for this purpose, and methods for producing these compounds. Published March 1, 1979 , Inventor: Dora Nellie Richardson. ‌
  11. ↑ Patent WO9524187 : Plaster-shaped transdermal system with a tamoxifen derivative. Published on September 14, 1995 , Applicant: Hexal Pharma GmbH, Inventor: W. Fischer, K. Klokkers. ‌
  12. ^ R. Mansel et al .: A phase II trial of Afimoxifene (4-hydroxytamoxifen gel) for cyclical mastalgia in premenopausal women. Breast Cancer Res. Treat. 106 (3): pp. 389-397 (2007). doi: 10.1007 / s10549-007-9507-x .
  13. ↑ Clinical study (phase III): Trial of 4-OHT Gel in Women Aimed at Reducing Dense Breast Tissue (4WARD) at Clinicaltrials.gov of the NIH .
  14. ↑ Afimoxifene. In: adisinsight.springer.com. Springer-Verlag, accessed on December 3, 2017 (English).
  15. ↑ a b c Peter C. Ruenitz, Jerome R. Bagley, Corwin M. Mokler: Estrogenic and antiestrogenic activity of monophenolic analogs of tamoxifen, [(Z) -2- [p- (1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethylethylamine. In: J. Med. Chem. Volume 25 , no. 9 , 1982, pp. 1076-1060 , doi : 10.1021 / jm00351a010 , PMID 7131484 (English).
  16. ↑ a b Patent EP0287690 : Stable solvent adducts of Z-1- (p-beta-dimethylamino-ethoxyphenyl) -1- (p-hydroxyphenyl) -2-phenylbut-1-ene. Published on October 26, 1988 , Applicant: Heumann Pharma GmbH Co., Inventor: Ingomar Grafe, Helmut Schickaneder, Peter W. Jungblut, Kurt Henning Ahrens. ‌
  17. ↑ a b Patent WO2008070463 : Endoxifen methods and compositions. Published on June 12, 2008 , Applicant: JINA PHARMACEUTICALS INC., Inventor: Ahmad Ateeq, Ali Shoukath M, Ahmad Moghis U, Sheikh Saifuddin, Ahmad Imran. ‌
  18. ↑ a b Shoukath M. Ali, Ateeq Ahmad, Syed Shahabuddin, Moghis U. Ahmad, Saifuddin Sheikh Imran: Endoxifen is a new potent inhibitor of PKC: A potential therapeutic agent for bipolar disorder. In: Bioorganic & Medicinal Chemistry Letters . tape 20 , no. 8 , 2010, p. 2665–2667 , doi : 10.1016 / j.bmcl.2010.02.024 , PMID 20227879 (English).
  19. ↑ Patent WO2010135703 : Endoxifen methods and compositions in the treadment of mammalian diseases. Published on March 28, 2012 , inventors: Ahmad, Ateeq; Ali, Shoukath M .; Ahmad, Moghis U .; Sheikh, Saifuddin; Ahmad, Imran (Jina Pharmaceuticals, Inc., USA). ‌