Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-01-24
2002-04-23
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
active
06376687
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to sulfatase inhibitors and methods for making and using the same. These methods include use of these compounds in therapeutic and prophylactic treatments for estrogen dependent illnesses.
BACKGROUND OF THE INVENTION
Estrogen levels in breast tumors of post-menopausal women are at least ten times higher than estrogen levels in plasma. The high levels of estrogen in these tumors are due to in situ formation of estrogen, possibly through conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Inhibitors of estrone sulfatase are therefore potential agents for the treatment of estrogen-dependent breast cancers. Most estrone sulfatase inhibitors are steroidal in nature. Although estrone-3-O-sulfamate (EMATE) is believed to be the most potent inhibitor of estrone sulfatase, recent evidence indicates that this compound is a potent estrogen. This compound is therefore not useful in the treatment of estrogen dependent illnesses.
Reed and co-workers reported on sulfatase inhibitory activities of estrone-3-O-methylthiophosphonate, estrone-3-O alkyl and aryl sulfonates, estrone-3-O-phosphonates and thiophosphonates and estrone sulfamates 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 phosphate 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(5/6):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
., 59(1):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 derivatives of estra 1,3,5(10)trien-17-one, 3-amino compounds and methods for using these compounds in the treatment of estrogen dependent illnesses.
U.S. Pat. Nos. 5,556,847 and 5,763,492, are directed to steroidal and non-steroidal sulfatase inhibitors, respectively, and methods for using these inhibitors to effect memory enhancement. Use of these inhibitors in the treatment of estrogen dependent illnesses is not disclosed.
U.S. Pat. Nos. 5,616,574 and 5,604,215 disclose steroid sulphatase inhibitors and the methods of using the same. The disclosed compounds are potent estrogens and metabolize to form estrones, in contrast to the compounds of the present invention.
U.S. Pat. No. 5,763,432 discloses steroid inhibitors of estrone sulfatase; the patent does not appear to disclose the compounds of the present invention, or compounds in which the substituent at the C17 position of a steroid nucleus interacts with a lipid bilayer.
There remains a need for potent sulfatase inhibitors that are metabolically stable, more selective, and devoid of estrogenic activity.
SUMMARY OF THE INVENTION
The present invention has met the above described need by providing non-estrogenic compounds useful as steroid sulfatase inhibitors. These compounds generally comprise a substituted steroid ring system having 4 attached rings; in the compounds of the present invention this structure is generally depicted by formula 1:
wherein X and Y are both carbons and the bond between X and Y is either single or double, as is further described below. The compounds of the present invention can be generally described as sulfatase inhibitors, and derive this inhibition ability from the presence of an
group. The nitrogen in this group can be further substituted with one or more hydrogen atoms, one or more lower alkyl groups having 1 to 6 carbons, or combinations thereof. Thus, the present compounds comprise a sulfamate group or a 6-membered cyclic sulfamate group attached to the “A” ring of the steroid nucleus, thereby resulting in a compound with 5 attached rings. More specifically, the group can be attached to the “A” ring in the steroid nucleus in which case a sulfamate ester of the steroid would be represented. Alternatively, the “N”, “S ”, and the “O” attached to the S by a single bond can, together with a carbon attached to the N, form a fifth ring adjacent to the “A” ring of the steroid nucleus. The bond between the N and the carbon could be double, in which case an oxathiazine dioxide would be represented, or single, in which case a dihydro-oxathiazine dioxide ring would be represented.
The present invention is also directed to methods for synthesizing the steroid sulfatase inhibitors disclosed herein.
In addition, the present invention relates to methods for using these compounds as sulfatase inhibitors. These methods generally comprise incorporating one or more of the compounds into a suitable pharmaceutical carrier and administering a therapeutically or prophylactically effective amount of the compound to a patient.
It is an aspect of this invention to provide compounds for inhibiting the steroid sulfatase enzyme produced in the body.
It is a further aspect of the invention to provide estrone sulfatase inhibitor compounds having anti-tumor or synergistic activity with anti-estrogen and aromatase inhibitors.
It is a further aspect of the present invention to provide estrone sulfatase inhibitor compounds having activity against estrogen dependent illnesses.
Yet another aspect of the invention is to provide methods for therapeutically or prophylactically treating a patient with the sulfatase inhibitor compounds of the present invention.
It is another aspect of this invention to provide derivatives of sulfatase inhibitor compounds that are not metabolized to compounds that are estrogenic.
These and other aspects of the invention will be more fully understood to those skilled in the art upon review of the following description and appended claims.
REFERENCES:
patent: 5556847 (1996-09-01), Johnson et al.
patent: 5567831 (1996-10-01), Li
patent: 5571933 (1996-11-01), Li et al.
patent: 5604215 (1997-02-01), Reed et al.
patent: 5616574 (1997-04-01), Reed et al.
patent: 5763432 (1998-06-01), Tanabe et al.
patent: 5763492 (1998-06-01), Johnson et al.
patent: 5880115 (1999-03-01), Li et al.
patent: 86393 (1971-12-01), None
patent: WO 98/32763 (1998-07-01), None
patent: WO 99/33858 (1999-07-01), None
Howarth et al., “Phosphonates and Thiophosphonates As Sulfate Surrogates: Synthesis of Estrone 3-Methylthiophosphonate, A Potent Inhibitor of Estrone Sulfatase”,Bioorg. Med. Chem. Lett., vol. 3, pp. 313-318 (1993).
Duncan et al., “Inhibition of Estrone Sulfatase Activity by Estrone-3-methylthiophosphonate: A Potential Therapeutic Agent in Breast Cancer”,Cancer Res., vol. 53, pp. 298-302 (Jan. 15, 1993).
Li et al., “Synthesis and biochemical studies of estrone sulfatase inhibitors”,Steroids, vol. 58, pp. 106-111 (Mar. 1993).
Dibbelt et al., “Inhibition of Human Placental Sterylsulfatase by Synthetic Analogs of Estrone Sulfate”,J. Steroid Biochem. Molec. Biol., vol. 50, No. 5/6, pp. 261-266 (1994).
Howarth, et al., “Estrone Sulfamates: Potent Inhibitors of Estrone Sulfatase with Therapeutic Potential”,J. Med. Chem., vol.
Akinaga Shiro
Li Pui-Kai
Murakata Chikara
Anderson Debra Z.
Badio Barbara P.
Duquesne University of the Holy Ghost
Eckert Seamans Cherin & Mellott , LLC
Meyers Diane R.
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