Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-08-26
2003-07-29
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, C514S238800, C514S428000, C514S609000, C514S651000, C540S609000, C544S106000, C546S205000, C548S576000, C564S347000
Reexamination Certificate
active
06599920
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the field of pharmaceutical and organic chemistry and provides naphthalene compounds, intermediates, formulations, and methods.
Osteoporosis describes a group of diseases which arises from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate support for the body. One of the most common types of osteoporosis is 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 increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among postmenopausal 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 to 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. Additionally, although osteoporosis is generally not thought of as a life threatening condition, a 20% to 30% mortality rate is related to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis.
The most generally accepted method for the treatment of postmenopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low, primarily because estrogen treatment frequently produces undesirable side effects. An additional method of treatment would be the administration of a bisphosphonate compound, such as, for example, Fosomax® (Merck & Co., Inc.).
Throughout premenopausal time, most women have less incidence of cardiovascular disease than men of the same age. Following menopause, however, 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 loss of estrogen's ability to regulate the levels of serum lipids. The nature of estrogen's ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can up regulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that serum lipid levels in postmenopausal women having estrogen replacement therapy return to concentrations found in the premenopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which regulates serum lipid levels in a manner analogous to estrogen, but which is devoid of the side effects and risks associated with estrogen therapy.
Another major estrogen associated pathology is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasms are not solely limited to a postmenopausal woman, they are more prevalent in the older, postmenopausal population. Current chemotherapy of these cancers have relied heavily on the use of anti-estrogen compounds, such as tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be counterproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an antiestrogenic compound having fewer or no estrogen agonist properties on reproductive tissues.
Thus, it would be a significant contribution to the art to provide novel compounds useful, for example, in the treatment or prevention of the disease states as indicated herein.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula I
wherein
R
1
is —H, —OH, —O(C
1
-C
4
alkyl), —OCO(C
1
-C
6
alkyl), —O—CO—O(C
1
-C
6
alkyl), —O—CO—Ar, —OSO
2
(C
2
-C
6
alkyl), —O—CO—OAr, where Ar is optionally substituted phenyl;
R
2
is —H, —Cl, —F, C
1
-C
4
alkyl, —OH, —O(C
1
-C
4
alkyl), —OCO(C
1
-C
6
alkyl), —O—CO—O(C
1
-C
6
alkyl), —O—CO—Ar, —OSO
2
(C
2
-C
6
alkyl), or —O—CO—OAr, where Ar is optionally substituted phenyl;
R
3
and R
4
are, independently, R
2
, with the proviso that R
3
and R
4
are not both hydrogen.
R
5
is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; and
n is 2 or 3;
or a pharmaceutically acceptable salt or solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention further relates to intermediate compounds of formula II which are useful for preparing the pharmaceutically active compounds of the present invention, and are shown below:
wherein
R
1a
is —H or —OR
6
in which R
6
is a hydroxy protecting group;
R
2a
, R
3a
, and R
4a
are, independently, —H, —Cl, —F, C
1
-C
4
alkyl, —OR
6
in which R
6
is a hydroxy protecting group;
n and R
5
have their previous meanings;
and further, wherein said compound is in the Z— or E— stereoisomeric form, and mixtures thereof.
Further, the present invention provides intermediate compounds of formula III which are useful for preparing the pharmaceutically active compounds of the present invention, and are shown below.
wherein
R
1a
, R
2a
, R
3a
, R
4a
, R
5
, and n have their previous meanings and provisions; and
R
7
is —OH or —OR
8
, where R
8
is a C
1
-C
6
alkyl sulfonyl or aryl sulfonyl.
The present invention further provides intermediate compounds of formula IX which are useful for preparing the pharmaceutically active compounds of the present invention, and are shown below:
wherein:
R
1a
, R
2a
, R
3a
, R
4a
, R
5
, and n have their previous meanings and provisions.
The present invention further relates to pharmaceutical compositions containing compounds of formula I.
Still further, the current invention provides methods for the therapeutic use of such compounds and compositions.
General terms used in the description of compounds herein described bear their usual meanings. For example, “C
1
-C
6
alkyl” refers to straight or branched aliphatic chains of 1 to 6 carbon atoms including moieties such as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like. Similarly, the term “—OC
1
-C
4
alkyl” represents a C
1
-C
4
alkyl group attached through an oxygen molecule and include moieties such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Of these alkoxy groups, methoxy is highly preferred in most circumstances.
Optionally substituted phenyl includes phenyl and phenyl substituted once or twice with C
1
-C
6
alkyl, C
1
-C
4
alkoxy, hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro)methyl.
The term, “hydroxy protecting group” contemplates numerous functionalities used in the literature to protect a hydroxyl function during a chemical sequence and which can be removed to yield the phenol. Included within this group would be acyls, mesylates, tosylates, benzyl, alkylsilyloxys, —OC
1
-C
4
alkyls, and the like. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works i
Bryant Henry Uhlman
Crowell Thomas Alan
Jones Charles David
Birch Gary M.
Chang Ceila
Eli Lilly and Company
Voy Gilbert T.
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