Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-19
2002-06-18
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S092000
Reexamination Certificate
active
06407101
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, alternatively they may be used in conjunction with a PR antagonist. 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.
Jones et al (U.S. Pat. No. 5,688,810) is 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 (U.S. Pat. No. 5,688,810) described the PR antagonist dihydroquinoline A.
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).
Chem et al described the PR antagonist K (Chen et al, POI-37, 16
th
Int. Cong. Het. Chen, Montana, 1997).
Kurihari et al described the PR ligand L (
J. Antibiotics
50, 360, 1997).
Kuhla et al claimed the oxindole M as a cardiotonic (WO 86/03749).
Weber claimed the oxindole N for cardiovascular indications (WO 91/06545).
Fischer et al claim a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516).
Singh et al described the PDE III inhibitor P (
J. Med. Chem.
37, 248, 1994).
Andreani et al described the cytotoxic agent Q (
Acta. Pharn. Nord.
2, 407, 1990).
Binder et al described structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767).
Walsh (A. H. Robins) described the oxindole S as an intermediate (U.S. Pat. Nos. 4,440,785, 4,670,566).
R
1
=F, Cl, Br, alky, NH
2
R
2
=alkyl, alkoxy, F, Cl, NH
2
, CF
3
.
Bohm et al claim the oxindole T as cardiovascular agents (WO 91/06545).
Bohm et al include the generic structure U (WO 91/04974).
A Japanese patent contains the generic structure V (JP 63112584 A).
Boar et al described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1).
Kende et al described methodology for preparing 3,3-substituted oxindoles, e.g., X, that was utilized in the present invention (
Synth. Commun.
12, 1, 1982).
There are numerous literature reports that disclose a number of benzoxazin-2-ones. However, none of these examples in these patents contain substituents necessary for the compounds to be active as progesterone receptor modulators.
Among these publications, Narr et al (German Patent, DE 3633861, CA 109:22973) claimed that imidazobenzoxazinones, e.g. Y, as cardotonics; Benzoxazin-2-ones, such as brofoxine (Z), being active as an anxiolytic was reported by Hartmann et al (
Proc. West. Pharmacol. Soc.
21, 51-55(1978)). More recently, a number of patents (e.g., Young et al WO95/20389; Christ et al. WO98/14436) claimed quinazolin-2-ones and benzoxazin-2-ones such as compounds AA and BB as inhibitors of HIV reverse transcriptase.
DESCRIPTION OF THE INVENTION
This invention provides progesterone receptor agonists of Formula 1 having the structure
wherein
T is O, S, or absent;
R
1
, and R
2
are each, independently, hydrogen, alky, substituted alkyl; or
R
1
and R
2
are taken together form a ring and together contain —CH
2
(CH
2
)
n
CH
2
—, —CH
2
CH
2
CMe
2
CH
2
CH
2
—, —O(CH
2
)
p
CH
2
—, —O(CH
2
)
q
O—, —CH
2
CH
2
OCH
2
CH
2
—, or —CH
2
CH
2
NR
7
CH
2
CH
2
—;
n=1-5;
p=1-4;
q=1-4
R
3
is hydrogen, OH, NH
2
, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR
A
;
R
A
is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R
4
is hydrogen, halogen, CN, NH
2
, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R
5
is hydrogen, alkyl, or substituted alkyl;
R
6
is hydrogen, alkyl, substituted alkyl, or COR
B
;
R
B
is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R
7
is hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof, which are useful for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Preferred compounds of this invention are those having the structure:
wherein
T is O, or absent;
R
1
, and R
2
are each, independently, hydrogen, alkyl, substituted alkyl; or
R
1
and R
2
are taken together form a ring and together contain —CH
2
(CH
2
)
n
CH
2
—;
n=1-5;
R
3
is hydrogen;
R
4
is hydrogen or halogen;
R
5
is hydrogen or alkyl;
R
6
is hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
The term “alkyl” is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms; “alkenyl” includes both straight- and branched-chain alkyl groups of 2-6 carbon atoms containing at least one carbon-carbon double bond; “alkynyl” group includes both straight- and branched-chain alkyl groups of 2-6 carbon atoms with at least one carbon-carbon triple bond.
The terms “substituted alkyl”. “substituted alkenyl”, and “substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as containing one or more substituents from the group including halogen, CN, OH, NO
2
, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term “thioalkyl” is used herein to refer to the SR group, where
Collins Mark A.
Edwards James P.
Jones Todd K.
Mackner Valerie A.
Tegley Christopher M.
American Home Products Corporation
Ford John M.
Howson and Howson
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