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Toremifene

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Toremifene
File:Toremifene.svg
Systematic (IUPAC) name
2-{4-[(1Z)-4-chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy}-N,N-dimethylethanamine
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a608003
Pharmacokinetic data
Protein binding more than 99.5%
Half-life 5 days
Identifiers
89778-26-7 7pxY
L02BA02
PubChem CID 3005573
DrugBank DB00539 7pxY
ChemSpider 2275722 7pxY
UNII 7NFE54O27T 7pxY
KEGG D08620 7pxY
ChEBI CHEBI:9635 7pxY
ChEMBL CHEMBL1655 7pxY
Chemical data
Formula C26H28ClNO
405.959 g/mol
 14pxY (what is this?)  (verify)

Toremifene citrate is an oral selective estrogen receptor modulator (SERM) which helps oppose the actions of estrogen in the body. Licensed in the United States under the brand name Fareston, toremifene citrate is FDA-approved for use in advanced (metastatic) breast cancer. It is also being evaluated for prevention of prostate cancer under the brand name Acapodene.[1]

In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008[2]

An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,[3] and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.[4]

Synthesis

File:Toremifene synthesis.png
Toremifene synthesis: Prepn: R. J. Toivola et al., EP 95875 ; eidem, U.S. Patent 4,696,949(1983, 1987 both to Farmos).

Alkylation of desoxybenzoin (1) proper with the benzyl ether from 2-bromoethanol affords the intermediate (2). This is then condensed with the Grignard reagent from the THP ether of 4-bromophenol to give the corresponding 3° alcohol. The reaction is expected to consist of a single diastereomer (see Newman projection). The benzyl ether protecting group is then cleaved by hydrogen by hydrogen over palladium to yield diol (3). A strong acid leads to the formation of a THF ring by a condensation reaction between the 3° and 1° alcohol groups, as well as hydrolysis of the THP protecting group to give (4). Ring formation almost certainly starts by loss of the protonated benzhydryl hydroxyl group; the fact that the final olefin consists of preodominantly the Z isomer argues that stereochemical identity must be retained during ring formation. This can be rationalized by assuming that a loss of the benzhydryl hydroxyl occurs with the concomitant SN2 like attack of the 1° ROH. The requisite basic ether is then added by alkylation of the free phenol with 2-chloroethyl(dimethylamine) to afford (5). Treatment of this last intermediate with HCl leads to ring opening of the THF ring with simultaneous formation formation of the Z olefin; the terminal OH is converted to a chloro under the reaction conditions. THere is this obtained toremifene (6)

References

  1. ^ Price N, Sartor O, Hutson T, Mariani S. Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer 2005;3:211-4. PMID 15882476
  2. ^ "GTx's Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review" (Press release). GTx Inc. 2007-07-12. Retrieved 2006-07-14. 
  3. ^ "GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA" (Press release). 
  4. ^ "GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study". 2 Mar 2011. 



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