Derivatives of estradiol

Estramustine is used to treat prostate cancer. It is a derivative of estradiol with an nitrogen mustard-carbamate ester moiety. 

Estramustine is a conjugated derivative of estradiol and chlormethine, mainly used to treat prostate cancer (5,6). 

Reduction of derivatives of estradiol 3-methyl ether (I) and hydrolysis of the initially formed enol ether II provides an efficient route to 19-norsteroids (111) of considerable importance in hormone therapy. A. J. Birch, who introduced the method (1949), used sodium in liquid ammonia with ethanol as proton donor. A. L. Wilds and N.A. Nelson (1953) found that yields are improved by use of lithium in place of sodium and that lithium is effective in some cases where sodium is not. The Wilds-Nelson procedure, which became the standard one, employs ether as co-solvent and involves adding the ethanol lust terminal decomposition is done with water after evaporation of ammonia, Since this reaction is the key step in processes developed by O. D. Searleand Co. for the production of two I V-norsteroids... 

Jordan, V.C. and Koch, R. (1989) Regulation of prolactin synthesis in vitro by estrogenic and antiestrogenic derivatives of estradiol and estrone. Endocrinology, 124, 1717-1726. 

Hepatic metabolism of tamoxifen produces N-desmethyltamoxifen, which has affinity for ER comparable to that of tamoxifen, and lesser amounts of the highly active metabolites 4-hydroxytamoxifen and endoxifen, which have 25-50 times higher affinity for both ERa and ERfi. Raloxifene is a nonsteroidal, polyhydroxylated conpound. Clomiphene has two isomers zuclomiphene (cis-clomiphene), a weak estrogen agonist, and enclomiphene (tcans-clomiphene), a potent antagonist. Fulvestrant is a 7a-alkylamide derivative of estradiol. 

A number of derivatives of estradiol have been employed in the control and management of oestrogenic activity and these are summarized in Table 23.2. 

This key problem was solved in 1985 by Jaouen et ai, who were able to stabilize Cr(CO)3 derivatives of estradiol and, by using radioactive complexes, to confirm the identity of ERa as the primary target of these organometallic... 

Scheme 3.5 Selected platinum derivatives of estradiol, 10 and 11 and of hexestrol 12.

Here again, ferrocene alone is not toxic. In addition, it has been shown that derivatives of estradiol bearing a ferrocenyl substituent in position 17a, 32 and 33 have an estrogenic effect in vitro, and are devoid of any cytotoxic effect either on hormone-dependent or hormone-independent ceUs [71]. Simply delivering an estrogenic molecule bearing a ferrocenyl substituent payload into the interior of a target cell is not sufficient to obtain a cytotoxic effect. The production of this effect seems to be linked to a spedfic structure that allows the ferrocenyl - double bond - phenol pattern to come into play. 

The female contraceptive pill contains the hormone progesterone (often called the pregnancy hormone) combined with an estrogen, usually a derivative of estradiol called ethynyl estradiol. High levels of progesterone such as those in the pill are usually only found when a woman is... 

The preparation of a number of photosensitive azide and diazo derivatives of estradiol, estrone, and hexestrol has been described. 

The exceptionally high potency of a new synthetic estrogen, B.D.H. 619 7, reported to be 250 —SOO mes more potent than ethynylestradiol, was briefly mentioned. B.D.H. patents 0 29 substituted 17a-butadiynyl derivatives of estradiol have appeared. 

Estrogens are a group of naturally occurring steroid sex hormones which are characterized by their ability to induce estms in the female mammal. They are derivatives of the planar tetracycHc stmcture estra-l,3,5(10)-trien-3-ol [53-63-4](V) and the three principal estrogens in humans are estrone [56-16-7] (E ) (2), estradiol [50-28-2] (E2) (3), andestriol [50-27-1] (E ) (4). 

The application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

A remarkable feature of the Birch reduction of estradiol 3-methyl ether derivatives, as well as of other metal-ammonia reductions, is the extreme rapidity of reaction. Sodium and -butyl alcohol, a metal-alcohol combination having a comparatively slow rate of reduction, effects the reduction of estradiol 3-methyl ether to the extent of 96% in 5 minutes at —33° lithium also effects complete reduction under the same conditions as is to be expected. Shorter reaction times were not studied. At —70°, reduction with sodium occurs to the extent of 56 % in 5 minutes, although reduction with lithium is virtually complete (96%) in the same time. (The slow rates of reduction of compounds of the 5-methoxytetralin type is exemplified by 5-methoxy-tetralin itself with sodium and f-butyl alcohol reduction occurs to the extent of only 50% in 6 hours vs. 99+% with lithium.) The iron catalyzed reaction of sodium with alcohols must be very fast since it competes so well with the rapid Birch reduction. One cannot compensate for the presence of iron in a Birch reduction mixture containing sodium by adding additional metal to extend the reaction time. The iron catalyzed sodium-alcohol reaction is sufficiently rapid that the aromatic steroid still remains largely unreduced. 

Isotope labeling by derivative formation with deuterated reagents is useful for the preparation of analogs such as dg-acetonides, da-acetates, da-methyl ethers, dg-methyl esters, etc. The required reagents are either commercially available or can be easily prepared. (The preparation of da-methyl iodide is described in section IX-F. Various procedures are reported in the literature for the preparation of dg-acetone, da-diazometh-ane57.i63.i73 and da-acetyl chloride. ) These reactions can be carried out under the usual conditions and they need no further discussion. A convenient procedure has been reported for the da-methylation of sterically hindered or hydrogen bonded phenolic hydroxyl functions by using da-methyl iodide and sodium hydroxide in dimethyl sulfoxide solution. This procedure should be equally applicable to the preparation of estradiol da-methyl ether derivatives. 

Several flaoraza reagents shown in Tables 3a and 3b (B, C, E, F, J, and K) are reactive enough to fluorinate an aromatic ring (Table 1). The ortho isomer predominates in the o/mlp mixture Reagent K has been used to prepare fluorinated derivatives of tyrosine and estradiol [77 (equation 35) (Table 1, entry 10)... 

For the synthesis of estradiol methyl ether 4-319, the cydobutene derivative 4-317 was heated to give the orthoquinonedimethane 4-318 which cydized in an intramolecular Diels-Alder reaction [109]. The thermally permitted, conrotatory elec-trocyclic ring-opening of benzocyclobutenes [110] with subsequent intramolecular cycloaddition also allowed the formation of numerous complex frameworks (Scheme 4.70). 

ICI 164384. This is the first pure antiestrogen discovered (Wakeling and Bowler 1987). This compound is a 7o -alkylamine derivative of 17/i-estradiol, with a 16-atom carbon chain in the la position. 

Fulvestrant. Also called ICI 182780 and Faslodex, this compound is also a 7o -alkylamine derivative of 17 -estradiol, developed from ICI 164384... 

The PEs of BPA and BP-5 in a normal experimental medium, 5% CDFBS-supplemented medium and synthetic ITDME medium are presented in Table 7.3.5. The addition of 0.1 p.M BPA to 10% CDHuS or 5% CDFBS supplemented medium increases cell proliferation as effectively as estradiol. BPA was also tested in the presence of an antiestrogen, producing inhibition of the PE associated with BPA. The PEs of chlorinated bisphenols are shown in Table 7.3.5. It was significantly greater than one for all the compounds tested. In comparison with the RPE of estradiol, all the positive compounds showed a full to partial agonistic response, producing cell yields that ranged from 85% of estradiol-induced yield for bisphenol-A to 30% for the bisphenol-A derivative tetrachlorine. 

J. Patel, M. J. Katovich, K. B. Sloan, S. H. Curry, R. J. Prankerd, A Prodrug Approach to Increasing the Oral Potency of a Phenolic Drug. Part 2. Pharmacodynamics and Preliminary Bioavailabihty of an Orally Administered O-(Imidomethyl) Derivative of 17/3-Estradiol , J. Pharm. Sci. 1995, 84, 174- 178. 

Some compounds fluoroalkylated in position 7a of estradiol have also been prepared by electrophilic fluoroalkylation of corresponding enol derivatives (cf. Figure 2.37 in Chapter 2, and Figure 8.74 in Chapter... 

Oxcarbazepine is a keto derivative of carbamazepine but offers several advantages over carbamazepine. Oxcarbazepine does not require blood cell count, hepatic, or serum drug level monitoring. It causes less cytochrome P450 enzyme induction than does carbamazepine (but may decrease effectiveness of oral contraceptives containing ethinyl estradiol and levonorgestrel). As opposed to carbamazepine, oxcarbazepine does not induce its own metabolism. These properties, combined with its similarity to carbamazepine, led many clinicians to use this medication for the treatment of bipolar disorder. Randomized controlled trials suggested efficacy in the treatment of acute mania compared with lithium and haloperidol, but these trials were quite small and did not include a placebo control (Emrich 1990). 

Absorption of orally administered, relatively lipophilic compounds, such as estrone or estradiol, occurs mainly in the intestine. The bacteria that colonize the gut are, however, particularly adept at converting those compounds by attack at the 17 position to very water-soluble derivatives that defy absorption. Alkylation of that position avoids this catabolic pathway and consequently enhances bioavailability on oral administration. The reaction of 17-keto steroids with nucleophiles illustrates the high degree of stereospecifity that is maintained in many steroid reactions approach of that carbonyl group from the (3 face is virtually forbidden by the presence of the adjacent 18 methyl. The reaction products consequently consist of almost pure isomers from attack at the a face. Reaction of estradiol with lithium acetylide thus gives ethynylestradiol (9-2) [9] the corresponding alkylation of estradiol 3-methyl ether (9-1) leads to mestranol (9-3) [10]. Both compounds are potent orally active... 

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