Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-03-08
2003-12-09
Badio, Barbara P. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C552S615000
Reexamination Certificate
active
06660726
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the isolation of estrogenic compounds.
BACKGROUND OF THE INVENTION
Women, particularly menopausal and post-menopausal women, often experience a wide variety of conditions and disorders attributable to estrogen deprivation. Estrogen deprivation is most often the result of loss of ovarian function. Exemplary conditions are hot flashes, dryness of the vagina, including discomfort during intercourse, loss of bone mass, increased heart disease and the like.
Providing dosages of estrogen is an effective agent for the control or prevention of such conditions, particularly in controlling or preventing hot flashes and vaginal atrophy, along with retarding or preventing osteoporosis. Estrogen is typically administered alone or in combination with a progestin.
As detailed in U.S. Pat. No. Re. 36,247 to Plunkett et al., estrogen alone, given in small doses, on a continuous basis, is effective in most patients for the control of the above symptoms and problems associated therewith. However, although the vast majority of women taking continuous low-dose estrogen will not have bleeding for many months or even years, there is a distinct risk posed by this routine of silently (i.e. exhibiting no overt symptoms) developing “hyperplasia of the endometrium”. This term refers, of course, to an overstimulation of the lining of the uterus which can become pre-malignant, coupled with the possibility that the patient may eventually develop cancer of the uterine lining even under such a low-dose regimen (Gusberg et al., Obstetrics and Gynaecology, 17, 397-412, 1961).
Estrogen alone can also be given in cycles, usually 21-25 days on treatment and 5-7 days off treatment. Again, if small doses of estrogen are required to control the symptoms and it is used to this fashion, only about 10% of women will experience withdrawal bleeding between the cycles of actual treatment. However, one must again be concerned by the risk of developing endometrial hyperplasia and by the increased relative risk of developing cancer of the uterus (Research on the Menopause: Report of a W.H.O. Scientific Group, 53-68, 1981).
The addition of progestin for the last 7-10 days of each estrogen cycle may virtually eliminate the concern about developing endometrial hyperplasia and/or also reduce the risk of developing endometrial carcinoma below that of the untreated general population. However, withdrawal bleeding may occur regularly in this routine and this is highly unacceptable to most older women (Whitehead, Am. J. Obs/Gyn., 142,6, 791-795, 1982).
Still another routine for estrogen administration may involve a formulation such as those found in birth control pills which contain relatively small doses of estrogen over the full 20-21 day treatment cycle, plus very substantial doses of potent progestins over the same period of time. This routine, of course not only produces withdrawal bleeding on each cycle, but is further unacceptable because such formulations have been shown to carry an increased risk of developing arterial complications, such as stroke or myocardial infarction in older women about the age of 35-40. This is especially true if the individual is a smoker of cigarettes (Plunkett, Am. J. Obs/Gyn. 142,6, 747-751, 1982). There, however, remains a need for novel isolated estrogenic compounds.
SUMMARY OF THE INVENTION
Thus, as one aspect of the present invention, a compound represented by Formula I is provided.
where the bond represented by the wavy line may be a single or double bond such that when the wavy line is a single bond, R
1
may be selected from the group consisting of hydrogen, sulfate and glucoronide or other esters, and when the wavy line is a double bond, R
1
does not exist; R
2
is lower alkyl; R
3
may be selected from the group consisting of hydrogen, sulfate, and glucuronide or other esters; and R
4
through R
13
may independently be selected from the group consisting of hydrogen, hydroxy, ketone, lower alkyl (C
1
to C
4
), lower alkoxy (C
1
to C
4
), halogen, and carbonyl groups. When R
1
is hydroxy, the hydroxy or ester substituent may have either an &agr; or a &bgr; orientation, with the &bgr; orientation being preferred. R
2
is preferably C
1
to C
4
alkyl, and more preferably is methyl. R
4
through R
12
are preferably hydrogen. R
13
is preferably hydrogen or ethynyl. R
14
is hydrogen, sulfate, or glucoronide and other esters.
The compound represented by Formula I may be present in chemically pure form, namely greater than about 90% pure, preferably greater than about 95% pure, and most preferably greater than about 99% pure.
A preferred compound is illustrated in Formula II:
Another preferred compound is illustrated in Formula III:
In another aspect, the present invention provides a composition of matter. The composition of matter comprises a compound according to the present invention.
In still another aspect, the invention provides a method of treating mammals in need of treatment. The method comprises administering an effective amount of a composition of matter according to the present invention. Examples of treatments that are addressed by the compositions of the invention include vasomotor symptoms, atrophic vaginitis, and osteoporosis.
The invention is described in greater detail with respect to the preferred embodiments set forth hereinbelow.
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Hill Edward N.
Sancilio Frederick D.
Whittle Robert R.
Badio Barbara P.
Endeavor Pharmaceuticals
Myers Bigel & Sibley Sajovec, PA
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