Cyclic regimens using cyclic urea and cyclic amide derivatives

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C514S230500, C514S224500, C514S229200, C514S293000, C514S300000

Reexamination Certificate

active

06399593

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both.
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 which 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 which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/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. 5719136). 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) describe the PR antagonist dihydroquinoline 1.
Jones, et al, described the enol ether 2 (U.S. Pat. No. 5,693,646) as a PR ligand.
Jones, et al, described compound 3 (U.S. Pat. No. 5,696,127) as a PR ligand.
Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J. Med. Chem, 41, 291, 1998).
Zhi, et al, described the ether 7 as a PR antagonist (J. Med. Chem., 41, 291, 1998).
Combs, et al., disclosed the amide 8 as a ligand for the PR (
J. Med. Chem
., 38, 4880, 1995).
Perlman, et. al., described the vitamin D analog 9 as a PR ligand (
Tet. Letters
, 35, 2295, 1994).
Hamann, et al, described the PR antagonist 10 (
Ann. N.Y. Acad. Sci
., 761, 383, 1995).
Chen, et al, described the PR antagonist 11 (Chen, et al, POI-37, 16
th
Int. Cong. Het. Chem., Montana, 1997).
Kurihari, et. al., described the PR ligand 12 (
J. Antibiotics
, 50, 360, 1997).
The patent by Christ et al. (WO 9814436) claims cyclo amide such as compound A as inhibitors of HIV reverse transcriptase. Other prior art includes pyridazine cyclo amide such as compound B by Turck et al. (
Tetrahedron
, 49(3), 599-606(1993)) and compound such as C by Canonne et al. (
J. heterocyclic Chem
. 26, 113(1989)). No activity data were reported in Turek's and Canonne' publications.
Regarding cyclic amides, Singh et al. and Kumar et al. (Singh et al.
J. Med. Chem
. 37(2), 248-254(1994); Kumar et al.
J. Org. Chem
. 57(25), 6995-6998(1992)) disclose compounds such as D and E claimed as cAMP PDE III inhibitors.
U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2-4 days to prevent breakthrough bleeding.
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 14-24 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.
E

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Cyclic regimens using cyclic urea and cyclic amide derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Cyclic regimens using cyclic urea and cyclic amide derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclic regimens using cyclic urea and cyclic amide derivatives will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-2906883

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.