Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-19
2002-03-19
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S099000, C544S095000
Reexamination Certificate
active
06358947
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nonsteroidal tetracyclic compounds that are modulators (i.e. agonists and antagonists) of progesterone receptors, and to methods for the making and use of such compounds.
BACKGROUND OF THE INVENTION
Progesterone receptor (PR) modulators have been widely used in regulation of female reproduction systems and in treatment of female hormone dependent diseases. The effectiveness of known steroidal PR modulators is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of synthetic progestins, such as norgestrel, as female birth control agents must be weighed against the increased risk of breast cancer and heart disease to women taking such agents. Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could cause homeostatic imbalances in a patient due to its inherent cross-reactivity as a glucocorticoid receptor (GR) antagonist. Accordingly, identification of compounds that have good specificity for PR, but have reduced or no cross-reactivity for other steroid receptors, would be of significant value in the improvement of women's health.
Nonsteroidal molecules that contain a di- or tetrahydroquinoline ring as the core pharmacophore have been described as steroid receptor modulator compounds. {See for example: “Preparation of Quinolines and Fused Quinolines as Steroid Receptor Modulators”, T. K. Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, L. G. Hamann, R. L. Davis, L. J. Farmer, PCT Int. Appl. Pub. No. WO 96/19458; “Steroid Receptor Modulator Compounds and Methods”, T. K Jones, D. T. Winr, L. Zhi, L. G. Hamann, C. M. Tegley, C. L. F. Pooley, U.S. Pat. No. 5,688,808; “Steroid Receptor Modulator Compounds and Methods”, T. K Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, U.S. Pat. No. 5,688,810; “Steroid Receptor Modulator Compounds and Methods”, T. K Jones, C. M. Tegley, L. Zhi, J. P. Edwards, S. J. West, U.S. Pat. No. 5,693,646; “Steroid Receptor Modulator Compounds and Methods”, T. K Jones, L. Zhi, C. M. Tegley, D. T. Winn, L. G. Hamann, J. P. Edwards, S. J. West, U.S. Pat. No. 5,693,647; “Steroid Receptor Modulator Compounds and Methods”, T. K Jones, L. Zhi, J. P. Edwards, C. M. Tegley, S. J. West, U.S. Pat. No. 5,696,127; “Steroid Receptor Modulator Comnpounds and Methods”, T. K Jones, D. T. Winn, M. E. Goldman, L. G. Hamann, L. Zhi, L. J. Farmer, R. L. Davis, U.S. Pat. No. 5,696,130; “Steroid Receptor Modulator Compounds and Methods”, T. K Jones, M. E. Goldman, C. L. F. Pooley, D. T. Winn, J. P. Edwards, S. J. West, C. M. Tegley, L. Zhi, L. G. Hamann, L. J. Farmer, R. L. Davis, U.S. Pat. No. 5,696,133.} Molecules containing a bicyclic heterocycle have been reported as cardiotonic agents. {See: “A Novel Class of Cardiotonic Agents: Synthesis and Biological Evaluation of 5-Substituted 3,6-Dihydrothiadiazin-2-ones with Cyclic AMP Phosphoidesterase Inhibiting and Myofibrillar Calcium Sensitizing Properties”, M.-C. Forest, P. Lahouratate, M. Martin, G. Nadler, M. J. Quiniou, R G. Zimmermann,
J. Med. Chem.
35 (1992) 163-172; “Heteroatom Analogues of Bemoradan: Chemistry and Cardiotonic Activity of 1,4-Benzothiazinylpyridazinones”, D. W. Combs, M. S. Rampulla, J. P. Demers, R. Falotico, J. B. Moore,
J. Med. Chem.,
35 (1992) 172-176.}
SUMMARY OF THE INVENTION
The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by PR. More particularly, the invention relates to nonsteroidal compounds and compositions that are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for progesterone receptors. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.
These and various other advantages and features of novelty that characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof However, for a better understanding of the invention, its advantages, and objects obtained by its use, reference should be had to the accompanying descriptive matter, in which preferred embodiments of the invention are described.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The terms alkyl, alkenyl, alkynyl and allyl include optionally substituted straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, and combinations thereof.
The term haloalkyl refers to alkyl structures, including straight-chain, branched-chain, or cyclic structures, or combinations thereof, that are substituted with one or more fluorines, chlorines, bromines or iodines, or combinations thereof.
The term heteroalkyl includes straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, or combinations thereof, in which one or more skeletal atoms is oxygen, nitrogen, sulfur, or combinations thereof.
The term aryl refers to an optionally substituted six-membered aromatic ring.
The term heteroaryl refers to an optionally substituted, aromatic five-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, or to an optionally substituted, aromatic six-membered heterocyclic ring containing one or more nitrogens.
The substituents of an “optionally substituted” structure include, but are not limited to, one or mnore of the following preferred substitutents: F, Cl, Br, I, CN, NO
2
, NH
2
, NCH
3
, OH, OCH
3
, OCF
3
, CH
3
, CF
3
.
Compounds of the present invention are defined as those having the formula:
wherein:
R
1
through R
6
are independently hydrogen, F, Cl, Br, I, NO
2
, CN, OR
10
, NR
10
R
11
, SR
10
, COR
12
, CO
2
R
12
, CONR
10
OR
11
, optionally substituted C
1
to C
6
alkyl or heteroalkyl, C
1
to C
6
haloalkyl, optionally substituted C
3
to C
8
cycloalyl, optionally substituted C
2
to C
6
alkenyl or allynyl, optionally substituted allyl, optionally substituted aryl or heteroaryl, or optionally substituted arylmethyl, where R
10
and R
11
are independently hydrogen, C
1
to C
6
alkyl or heteroalkyl or haloalkyl, aryl, heteroaryl, optionally substituted allyl, optionally substituted arylmethyl, COR
13
, SO
2
R
13
or S(O)R
13
, where R
12
is hydrogen, C
1
to C
6
aLkyl or heteroalkyl or haloalkyl, aryl, heteroaryl, optionally substituted allyl or optionally substituted arylmethyl, where R
13
is hydrogen, C
1
to C
6
alkyl or haloalkyl, aryl, heteroaryl, optionally substituted allyl or optionally substituted arylmethyl;
R
7
is hydrogen, C
1
to C
6
alkyl or haloalkyl or heteroalkyl, aryl, arylmethyl, heteroaryl, COR
12
, CO
2
R
12
, SO
2
R
12
, S(O)R
12
or CONR
10
R
11
, where R
10-12
have the same definitions given above;
R
8
and R
9
are independently hydrogen, C
1
to C
6
alkyl or haloalkyl or heteroalkyl, optionally substituted C
2
to C
6
alkenyl or alkynyl, optionally substituted allyl, optionally substituted arylmethyl, optionally substituted aryl or optionally substituted heteroaryl;
X is OCH
2
, SCH
2
, NHCH
2
, OC(O), SC(O), NHC(O), CH
2
O, CH
2
S, CH
2
NH, C(O)O, C(O)S or C(O)NH;
Y is O, S or NR
10
, where R
10
has the same definition given above; and
Z is O, S, NR
14
, CR
14
R
15
, CR
14
R
15
CR
16
R
17
, OCR
14
R
15
, SCR
14
R
15
, CR
14
R
15
S, NR
14
CR
15
R
16
, or CR
14
R
15
NR
16
, where R
14
through R
17
each independently are hydrogen, C
1
to C
6
alkyl or haloalkyl or heteroalkyl, optionally substituted C
2
to C
6
alkenyl or alkynyl, optionally substituted allyl, optionally substituted arylmethyl, optionally substituted aryl or optionally substituted heteroaryl;
or a pharmaceutically acceptable salt thereof.
In a p
Edwards James P.
Fensome Andrew
Jones Todd K.
Tegley Christopher M.
Wrobel Jay E.
American Home Products Corporation
Berch Mark L.
Habte Kahsay
Howson and Howson
LandOfFree
Tetracyclic progesterone receptor modulator compounds and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tetracyclic progesterone receptor modulator compounds and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tetracyclic progesterone receptor modulator compounds and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2857965