Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1998-10-01
2001-06-19
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S518000, C558S048000
Reexamination Certificate
active
06248780
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds for treatment of estrogen-dependent illnesses and methods for making and using the same. The compounds generally function by inhibiting sulfatase and/or blocking estrogen receptors. Methods of using these compounds provide both therapeutic and prophylactic treatment for estrogen dependent illnesses.
BACKGROUND OF THE INVENTION
Breast cancer is the most common malignancy in the United States. Clinically, breast cancer is divided into two types as defined by the amount of estrogen receptor (ER) present: estrogen dependent (ER+) and estrogen independent (ER−). It is estimated that approximately 30-40% of all breast cancers are estrogen dependent, and in postmenopausal women, the percentage is even higher. The most common treatment for estrogen-dependent breast cancers are endocrine treatments using an antiestrogen, such as tamoxifen, which blocks estrogen receptors. Progestins are also used although their mechanism of action is unknown. Other methods for treating estrogen-dependent breast cancer is through inhibition of estrogen biosynthesis with aromatase inhibitors. Aminoglutethimide, a non-steroidal aromatase inhibitor, and testolactone, a weak steroid aromatase inhibitor, are examples of compounds that have been used. Another non-steroidal aromatase inhibitor, CGS 16949A, and a steroidal aromatase inhibitor, 4-hydroxy-androstenedione, are at various stages of clinical trials.
All of the treatments described above deal with stopping the estrogen action through blocking estrogen receptors or inhibiting estrogen production. In estrogen dependent breast cancer patients, the estrogen levels in breast cancer cells are 5-10 times higher than in plasma. In postmenopausal women, the major pathway of estrogen production is through peripheral aromatization of circulating androstenedione (A) to estrone (E
1
), an estrogen with moderate biological activity. Estrone can be converted to estradiol (E
2
), the most potent endogenous estrogen, by 17&bgr;-hydroxysteroid dehydrogenase. The mean plasma levels of E
1
and E
2
in postmenopausal women are 100-150 pM and 30-40 pM, respectively.
Breast cancer cells accumulate high amounts of estrogens, even though studies have shown that there is no active uptake of estrogens by breast tumors. One of the possibilities to explain the high levels of estrogen is in situ production of estrogens from precursor substrates in the breast cancer cells. Indeed, aromatase has been found in breast cancer cells and conversion of androstenedione to estrone has been demonstrated. Another pathway for the in situ formation of estrogen is through the conversation of estrone sulfate (E
1
S) to estrone by the enzyme estrone sulfatase (estrone sulfatase pathway) as shown in FIG.
1
. Estrone sulfate is the most abundant circulating estrogen in women (1-2 nM), which may represent an important reservoir of active estrogens.
The plasma level of estrone sulfate in postmenopausal breast cancer patients is reported to be significantly higher than in normal subjects. In addition, the concentration of estrone sulfate in the breast cancer cells of postmenopausal breast cancer patients is significantly higher than in plasma. Furthermore, estrone sulfatase has been consistently found in human breast cancer cells. High concentrations of estrone sulfate in blood and in breast cancer cells may provide a high flux of free estrogen to mammary tumors. Vignon et al.,
Endocrinology
106:1079-1086 (1980), demonstrated that in the MCF-7 human breast cancer cell line, estrone sulfate entered the cells and was metabolized, yielding unconjugated estrone and estradiol which were finally bound to nuclear estrogen receptors and eventually induced proteins of 46,000 and 160,000 molecular weight. Wilking et al.,
Eur.J. Cancer
16:1339-1344 (1980), were able to demonstrate the conversion of [
3
H] estrone sulfate to [
3
H] estrone and [
3
H] estradiol by homogenates of mammary carcinoma tissue in vitro in 23 breast cancer patients. Pasqualini et al.,
J. Steroid Biochem.
34:155-163 (1989), reported that a high percentage of [
3
H] estrone sulfate was converted to estradiol in different hormone-dependent mammary cancer cell lines (MCF-7, R-27, T47D), but little or no conversion was found in the hormone-independent mammary cancer cell lines (MDA-MB-231, MDA-MB436). Santen et al.,
J. Clin. Endocrinol. & Metab.
59:29-33 (1984), and
Am. NY Acad. Sci.
464:126-137 (1986), evaluated the estrogen production from breast tumors via the estrone sulfate to estrone (sulfatase) pathway and compared it with the androstenedione to estrone (aromatase) pathway. When comparing the sulfatase with aromatase activity in human tumors at physiological levels of substrates, the amount of estrone produced through sulfatase was 10 times higher than through the aromatase pathway (2.8 pmol estrone/g protein vs 0.27 pmol/g protein) in human breast tumors. Santen suggested that this sulfatase pathway was significant and perhaps the primary means of local estrogen production in breast tumor tissues. In addition, despite the fact that aromatase inhibitors can cause a near total inhibition (95-98%) of peripheral aromatization of androstenedione to estrone, plasma levels of estrone and estradiol are sustained at a level of 45-65 % and estrone sulfate at 40-50%, the control levels in patients receiving aromatase inhibitor treatments. This residual amount of estrone sulfate may be a potential source of estrogens through the sulfatase pathway.
Preliminary reports indicate the importance of the estrone sulfatase pathway in supplying estrogenic steroids to support breast cancer growth. Inhibitors of this pathway may be potential therapeutic agents for the treatment of estrogen-dependent breast cancer. Among all the estrone sulfatase inhibitors, estrone-3-O-sulfamate (EMATE) is the most potent sulfatase inhibitor ever reported. It is classified as an active-site directed irreversible inhibitor. Estrone may be released during the inactivation of sulfatase by EMATE, however, thereby making the inhibitor itself estrogenic. This compound is therefore not useful in the treatment of estrogen-dependent illnesses.
Reed and co-workers reported the sulfatase inhibitory activities of estrone-3-O-methylthiophosphonate, estrone-3-O alkyl and aryl sulfonates, estrone-3-O-phosphonates and thiophosphonates and estrone sulfonates in: Duncan et al., “Inhibition of estrone sulfatase activity by estrone-3-methylthiophosphonate”,
Cancer Res.
53:298-303 (1993); Howarth et al., “Phosphonates and thiophosphonates as sulfate surrogates: Synthesis of estrone-3-methylthiophosphonate, a potent inhibitor of estrone sulfatase”, Bioorg. Med. Chem. Lett. 3:313-318 (1993); Howarth et al., “Estrone sulfamates: Potent inhibitors of estrone sulfatase with therapeutic potential”,
J. Med. Chem.
37:219-221 (1994); and Purohit, et al., “In vivo inhibition of Oestrone Sulphatase and Dehydroepiandrosterone Sulphatase by Oestrone-3-O-sulphamate”,
Int. J. Cancer,
63:106-111 (1995).
Li and co-workers reported the synthesis and sulfatase inhibitory activities of sulfonate and its analogues, methylene sulfonates and phosphates that contain the estrone nucleus in Li et al., “Synthesis and biochemical studies of estrone sulfatase inhibitors”,
Steroids,
58:106-111 (1993); Dibbelt et al, “Inhibition of human placental sterylsulfatase by synthetic analogs of estrone sulfate”,
J. Steroid Biochem. Molec. Biol.,
50 (516):261-266 (1994); and Li et al., “Estrone sulfate analogs as estrone sulfatase inhibitors”,
Steroids
60:299-306 (1995). Estrone-3-amino derivatives are reported in Selcer et al., “Inhibition of Placental Estrone Sulfatase Activity and MCF-7 Breast Cancer Cell Proliferation by Estrone-3-amino Derivatives”,
J. Steroid Biochem. Molec. Biol.,
591:83-91 (1996).
U.S. Pat. No. 5,567,831 is directed to the use of non-steroidal sulfatase inhibitor compounds in the treatment of estrogen dependent illnesses.
U.S. Pat. No. 5,571,933 is directed to derivati
Li Pui-Kai
Selcer Kyle W.
Barts Samuel
Duquesne University of the Holy Ghost
Eckert Seamans Cherin & Mellot LLC
Meyers Diane R.
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