Cyclic regimens using 2,1-benzisothiazoline 2,2-dioxides

Details Cyclic regimens using 2,1-benzisothiazoline 2,2-dioxides Cyclic regimens using 2,1-benzisothiazoline 2,2-dioxides

2000-04-19

2001-11-20

Moezie, Minna (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S223200, C514S222500, C514S226800, C514S228200, C514S223800

Reexamination Certificate

active

06319912

ABSTRACT:

BACKGROUND OF THE INVENTION
Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors” (R. M. Evans,
Science
240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound that inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann et al,
Ann. N.Y. Acad. Sci.
261, 248, 1995), in combination with a PR agonist (Kekkonen et al,
Fertility and Sterility
60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al,
J. Clin. Endo. Metab.
76, 513, 1993) and endometriosis (Kettel et al,
Fertility and Sterility
56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna et al,
Ann. N.Y. Acad. Sci.
761, 224, 1995).
Jones et al (U.S. Pat. No. 5,688,810) described the PR antagonist dihydroquinoline A.
Jones et al described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand.
Jones et al described compound C (U.S. Pat. No. 5,696,127) as a PR ligand.
Zhi et al described lactones D, E and F as PR antagonists (
J. Med. Chem.
41, 291, 1998).
Zhi et al described the ether G as a PR antagonist (
J. Med. Chem.
41, 291, 1998).
Combs et al disclosed the amide H as a ligand for the PR (
J. Med. Chem.
38, 4880, 1995).
Perlman et al described the vitamin D analog I as a PR ligand (
Tetrahedron. Lett.
35, 2295, 1994).
Hamann et al described the PR antagonist J (
Ann. N.Y. Acad. Sci.
761, 383, 1995).
Chen et al described the PR antagonist K (Chen et al, POI-37, 16
th
Int. Cong. Het. Chem., Montana, 1997).
Kurihari et al described the PR ligand L (
J. Antibiotics
50, 360, 1997).
There are several examples of 2,1-benzisothiazoline 2,2-dioxides (‘sultams’) in the chemical and patent literature which contain no reference to progesterone activity, and do not carry the correct substitution pattern for PR modulator activity.
Chiarino et al described the preparation of the parent 2,1-benzisothiazoline 2,2-dioxide, i.e., M (and derivatives, e.g., N), that was used in the present invention (
J. Heterocycl. Chem.
23(6), 1645-9, 1986).
Skorcz et al described a series of 5-(2-morpholinyl)-2,1-benzisothiazolines, e.g., O, which are useful as central nervous depressants (U.S. Pat. No. 3,635,964).
Kamireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q, useful for controlling undesired vegetation (WO 95/33746).
DESCRIPTION OF THE INVENTION
This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents. This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestins and progestins, an estrogen, such as ethinyl estradiol.
These regimens and combinations may be administered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake. The uses herein for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding.
The use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combination with an estrogen or progestin or both. These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins.
The progestins of these combinations may be administered alone or in combination with an estrogen for the first 14 to 24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 &mgr;g to about 150 &mgr;g levonorgestrel per day, preferably equal in activity to from about 35 &mgr;g to about 100 &mgr;g levonorgestrel per day. An antiprogestin may then be administered alone or in combination with an estrogen for a period of 1 to 11 days to begin on any cycle day between day 14 and 24. The anti-progestin in these combinations may be administered at a dose of from about 2 &mgr;g to about 50 &mgr;g per day and the estrogen may be administered at a dose of from about 10 &mgr;g to about 35 &mgr;g per day. In an oral administration, a package or kit containing 28 tablets will include a placebo tablet on those days when the antiprogestin or progestin or estrogen is not administered.
In a preferred embodiment of this invention, the progestins of this invention may be administered alone or in combination with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or in combination with an estrogen, for from 1 to 7 days.
The estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol.
Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone.
Examples of orally administered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 100 &mgr;g of levonorgestrel. An antiprogestin compound of this invention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration

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