Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-01
2001-07-10
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S212010, C514S422000, C514S443000, C540S536000, C546S202000, C548S525000
Reexamination Certificate
active
06258826
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations and applications thereof for the treatment of estrogen deficiencies, in particular, formulations containing 2-aryl-3-halobenzo[b]thiophenes.
BACKGROUND OF THE INVENTION
The term “estrogen deprivation syndrome” has been used in the art to describe various pathological conditions which frequently affect women who have insufficient levels of the hormone estrogen. The most common cause of estrogen deprivation in women is the natural cessation of menses with age, i.e., menopause. Additionally, non-natural circumstances including surgical ovariectomy, chemotherapy causing the cessation of hormone production or pharmacologic action, and the like, may induce estrogen deprivation. Although numerous pathologies are contemplated by the use of this term, the greatest long-term medical concerns resulting from estrogen deprivation syndrome are osteoporosis and cardiovascular effects, especially hyperlipidemia.
Osteoporosis describes a group of diseases which arise from diverse etiologies; however, all of the diseases within the group can be characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass is the failure of the skeleton to provide adequate structural support for the body i.e. bone fracture. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an overall increase of the bone resorption and bone formation cycle where the resorptive cycle is more dominant. The obvious result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Although osteoporosis is not generally thought of as a life threatening condition, twenty percent (20%) to thirty percent (30%) of the mortality rate for elderly women is attributed to hip fractures. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis.
Estrogen deficiencies has also been attributed to cardiovascular disease in women. Throughout pre-menopausal time, most women have less incidence of cardiovascular disease than age-matched men. However, following menopause, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the reduced ability for estrogen to regulate the levels of serum lipids. The mechanism by which estrogen regulates serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Estrogen also appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
In addition to the major estrogen deprivation pathologies (supra), there are many serious, but less common maladies as well as a larger number of less serious, yet significant sequela. For example, serious pathologies include: neuro-degenerative diseases such as Alzheimer's disease and various autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and the like. These pathologies are more prevalent in women, particularly in post-menopausal women as opposed to pre-menopausal. Less serious conditions, such as, urinary incontinence, skin and hair quality deterioration, vaginal dryness, hot flashes, and the like, also, occur more frequently in women past menopause.
Although estrogen replacement therapy is often prescribed for the estrogen deprivation syndrome, current treatments suffer from poor patient compliance as many women object to some of the side-effects and the inconvenience of the pharmaceutical forms of the medication. For example, 17-&bgr;-estradiol is often administered via a transdermal patch because of its poor oral absorption. As a result, a majority of women cease taking estrogen within the first year of estrogen replacement therapy.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical formulation which comprises a compound having the following structure:
wherein: R and R′ are independently hydrogen, hydroxy, —O(C
1
-C
4
alkyl), —OCH
2
Ar, —OCO(C
1
-C
6
alkyl), —OCOAr,
where Ar is phenyl or substituted phenyl; X is F, Cl, Br, or I; Y is S or S—O; and pharmaceutically acceptable solvates thereof; in combination with Compound II (depicted below).
R
6
and R
7
are independently hydrogen, —(C
1
-C
4
alkyl), —CO(C
1
-C
6
alkyl), —CH
2
Ar, or —COAr; R
8
is pyrolidin-1-yl, piperidin-1-yl, or hexamethyleneimin-1-yl (the nitrogen of the R
8
group may optionally be oxidized to the N-oxide); and pharmaceutically acceptable salts or solvates thereof.
In another embodiment of the present invention, a method is provided for inhibiting estrogen deprivation syndrome which comprises administering to a mammal (including humans) in need of such treatment, an effective amount of Compound I in combination with Compound II.
In yet another embodiment of the present invention, an article of manufacture is provided which comprises a package having deposited thereon a label describing the contents of the package and having deposited therein a pharmaceutically active material having the pharmaceutical formulation described above.
As used herein, the term “alkyl” refers to a hydrocarbon radical of the general formula C
n
H
2n+1
. The alkane radical may be straight, branched, cyclic, or multi-cyclic. For example, the term “C
1
-C
6
alkyl” refers to monovalent, straight, branched, or cyclic aliphatic group containing 1 to 6 carbons atoms (e.g., methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, pentyl, neopentyl, cyclopentyl, hexyl, 2-methylpentyl, cyclohexyl, and the like). The alkane radical may be substituted or unsubstituted.
The term “halo” refers to chloride, bromide, fluoride, or iodide.
The term “substituted phenyl” refers to a phenyl group having one or more substituents attached to the aromatic ring. Preferably, the phenyl group has one to three substituents selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
4
alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl.
The term “solvate” refers to an aggregate that comprises one or more molecules of the solute, such as an aggregate of compounds I or II, with one or more molecules of solvent. Suitable solvent molecules are those commonly used in the pharmaceutical art, which are known to be non-detrimental to the recipient, e.g., water and ethanol.
DETAILED DESCRIPTION
Estrogen deprivation syndrome includes those pathologies and conditions brought about by the loss of ovarian function (either natural, surgically, or chemically induced) and specifically to the loss of the ovarian hormones, especially estrogen. Since loss of estrogen is causative or contributive for the symptoms of the syndrome, administration of a pharmaceutical formulation that effects the symptoms may be useful in the treatment of estrogen deprivation syndrome. Applicants have discovered that each of the symptoms associated with estrogen loss responds to the replacement of the lost estrogen hormone through the administration of compounds having structure I (described below). Thus, formulations based on Compound I in combination with Compounds II (described below) are useful and beneficial in treating or preventing estrogen deficiency symptoms, which include but are not limited to osteoporosis, hyperlipidemia, atherosclerosis, vasom
Cullinan George Joseph
Muehl Brian Stephen
Thrasher Kenneth Jeff
Boudreaux William R.
Chang Ceila
Eli Lilly and Company
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