Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-25
2002-04-30
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235200, C514S323000, C514S414000, C514S415000, C540S602000, C544S144000, C546S201000, C548S456000, C548S491000
Reexamination Certificate
active
06380185
ABSTRACT:
The present invention relates to new N-substituted benzoyl indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds.
BACKGROUND OF THE INVENTION
Estrogen replacement therapy has been well established as the treatment of choice in women for the prevention of osteoporosis. [C. Christiansen, R. Lindsay, Estrogen, Bone Loss and Preservation, Osteoporosis International, 1, 15-21 (1990)] The downside to this therapy is that when estrogen is given alone i.e. without the opposing effects of progestins, proliferative effects on the uterus may result and thereby can put the patient at risk for endometrial cancer. Although less clear, hormone replacement therapy has been implicated in increasing the incidence of breast tumor formation. Non-steroidal antiestrogen drugs such as tamoxifen have been used in the treatment of breast cancer. The drug also is known to maintain bone mass, acting as a bone-sparing estrogen agonist, however it is also an agonist in uterine tissue. A more recent antiestrogen drug, Lilly's raloxifene, is a non-steroidal antiestrogen which appears to be more tissue selective. While having the desirable property of sparing bone, it has been demonstrated to stimulate uterine growth in animal models to a lesser degree than tamoxifen. Additionally, recent clinical data reveal no endometrial hyperplasia. A review on the tissue selective action of estrogen analogs has recently appeared. [G. L. Evans and R. T. Turner, Tissue Selective Actions of Estrogen Analogs, Bone, 17, no. 4, 1815-1905 (1995)].
The use of indoles as estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983), Abstract No. 53886u. Also, see, J. Med. Chem. 1990, 33, 2635-2640; J. Med. Chem. 1987, 30, 131-136. Also see Ger. Offen., DE 3821148 A1 891228 and WO 96/03375. These prior art compounds share some structural similarities with the present compounds, but are functionally different. For compounds containing a basic amine, there is no phenyl group to ridgidify the side chain. The reported data for these compounds indicates that they may have a weaker binding to estrogen receptor than the compounds of the present invention and the basic side chain containing compounds show some uterotrophic effect in the rat uterus.
WO A 95 17383 (Kar Bio AB) describes indole antiestrogens with long straight chains. Another related patent WO A 93 10741 describes 5-hydroxyindole with a generic descriptor incorporating other side chains.
U.S. Pat. No. 5,496,844 (Inai, et al.) teaches substituted N-indole compounds having potent antiestrogenic activity which are useful in the treatment of estrogen-dependent diseases, such as anovulatory infertility, prostatic hypertrophy, osteoporosis, breast cancer, endometrial cancer and melanoma.
Jones et al., in their article Antiestrogens. 2.
1
Structure-Activity Studies in a Series of 3-Aroyl-2-arylbenzo[b]thiophene Derivatives Leading to [6-Hydroxy-2-(4-hydroxyphenyl)benzo[b] thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone Hydrochloride (LY156758), a Remarkably Effective Estrogen Antagonist with Only Minimal Intrinsic Estrogenicity, J. Med. Chem. 1984, 27, 1057-1066, disclose a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives which act as non-steroidal antiestrogens.
The compounds described in the present invention are mixed estrogen agonists/antagonists and have potential use in treating osteoporosis, endometriosis, prostatic hypertrophy, breast cancer and endometrial cancer.
DESCRIPTION OF THE INVENTION
The present invention provides N-substituted indoles of Formula (I):
wherein
R
1
, R
2
and R
3
are independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —CF
3
, —NO
2
, cyano, C
1
-C
6
alkyl (straight chain or branched), trifluoromethyl, —OH or the C
1
-C
12
esters (straight chain or branched) or C
1
-C
12
alkyl ethers (straight chain or branched or cyclic) thereof, halogens, or C
1
-C
6
halogenated ethers, preferably C
1
-C
3
halogenated ethers, including trifluoromethyl ether and trichloromethyl ether;
R
4
and R
5
are independently selected from H or benzyl, the benzyl group being optionally substituted by C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —CF
3
, or halogen;
X is H, C1-C
6
alkyl, or CF
3
;
Z is O or S;
n is 2 or 3;
Y is selected from:
a) a moiety of the formula:
wherein R′ is C
1
-C
6
lower alkyl; or
b) a moiety selected from the group of:
or a pharmaceutically acceptable salt thereof.
A preferred group of this invention are those compounds of Formula I wherein R
1
, R
2
and R
3
are independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —CF
3
, or —NO
2
; and R
4
, R
5
, X, Z, n, and Y are as defined above, or a pharmaceutically acceptable salt thereof.
Another preferred group of compounds of this invention are those in which Z is oxygen and R
1
, R
2
, R
3
, R
4
and R
5
are H, or a pharmaceutically acceptable salt thereof. Among the most preferred compounds of these generic and subgeneric groups are those in which Y is a piperidine ring.
This invention includes acceptable salt forms formed from the addition reaction with either inorganic or organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful. Among the preferred salts of the compounds herein are the HCl, HBr, and acetate salts.
The compounds of the invention are partial estrogen agonists and display high affinity for the estrogen receptor. Unlike many estrogens, however, many of these compounds do not cause the increases in uterine wet weight normally associated with natural or synthetic estrogens. These compounds are antiestrogenic in the uterus and antagonize the trophic effects of estrogen agonists in uterine tissue. In addition, the compounds may be used as estrogen agonists in bone tissue. Due to the tissue selective nature of these compounds, they are useful in treating or preventing in a mammal disease states or syndromes which are caused or associated with an estrogen deficiency or an excess of estrogen.
The present compounds have the ability to behave like estrogen agonists by lowering cholesterol and preventing bone loss. These compounds are useful for treating many maladies which result from estrogen excess or deficiency including osteoporosis, prostatic hypertrophy, male pattern baldness, ovarian cancer, infertility, breast cancer, endometrial cancer, cardiovascular disease, contraception, Alzheimer's disease, cognitive decline and other CNS disorders, as well as certain cancers, including melanoma, prostrate cancer, cancers of the colon, CNS cancers, among others. Additionally, these compounds can be used for hormone replacement therapy in post-menopausal women or in other estrogen deficiency states where estrogen supplementation would be beneficial.
The compounds of this invention may also be used in methods of treatment for bone loss, which may result from an imbalance in an individual's formation of new bone tissues and the resorption of older tissues, leading to a net loss of bone. Such bone depletion results in a range of individuals, particularly in post-menopausal women, women who have undergone hysterectomy, those receiving or who have received extended corticosteroid therapies, those experiencing gonadal dysgenesis, and those suffering from Cushing's syndrome. Special needs for bone replacement can also be addressed using these compounds in individuals with bone fractures, defective bone structures, and those receiving bone-related surgeries and/or the implantation of prosthesis. In addition to those problems described above, these compounds can be used in t
Koko Marci C.
Santilli Arthur A.
Ullrich John W.
American Home Products Corporation
Coleman Brenda
Milowsky Arnold S.
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