Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-10-14
2004-02-24
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S291000, C514S242000, C514S243000, C514S255010, C514S256000, C514S259500, C514S267000, C514S292000, C514S299000, C514S300000, C514S301000, C514S302000, C514S303000, C514S314000, C514S312000, C514S311000
Reexamination Certificate
active
06696459
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to non-steroidal compounds that are modulators (i.e. agonists and antagonists) of steroid receptors (e.g., progesterone receptor, androgen receptor, estrogen receptor, glucocorticoid receptor and mineralocorticoid receptor), and to methods for the making and use of such compounds.
BACKGROUND OF THE INVENTION
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named “ligand dependent transcription factors.” R. M. Evans, 240
Science,
889 (1988). Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand which has the ability to selectively bind to the IR in a way that affects gene transcription.
Ligands to the IRs can include low molecular weight native molecules, such as the hormones progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as medroxyprogesterone acetate, diethylstilbesterol and 19-nortestosterone. These ligands, when present in the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell's nucleus, where it binds to a specific gene or genes present in the cell's DNA. Once bound to DNA, the complex modulates the production of the protein encoded by that gene. In this regard, a compound which binds an IR and mimics the effect of the native ligand is referred to as an “agonist”, while a compound that inhibits the effect of the native ligand is called an “antagonist.”
Ligands to the steroid receptors are known to play an important role in health of both women and men. For example, the native female ligand, progesterone, as well as synthetic analogues, such as norgestrel (18-homonorethisterone) and norethisterone (17&agr;-ethinyl-19-nortestosterone), are used in birth control formulations, typically in combination with the female hormone estrogen or synthetic estrogen analogues, as effective modulators of both PR and ER. On the other hand, antagonists to PR are potentially useful in treating chronic disorders, such as certain hormone dependent cancers of the breast, ovaries, and uterus, and in treating non-malignant conditions such as uterine fibroids and endometriosis, a leading cause of infertility in women. Similarly, AR antagonists, such as cyproterone acetate and flutamide have proved useful in the treatment of hyperplasia and cancer of the prostate.
The effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of progesterone and estrogen agonists, such as norgestrel and diethylstilbesterol respectively, 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 lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a GR antagonist. Accordingly, identification of compounds which have good specificity for one or more steroid receptors, but which have reduced or no cross-reactivity for other steroid or intracellular receptors, would be of significant value in the treatment of male and female hormone responsive diseases.
A group of quinoline analogs having an adjacent polynucleic ring system of the indene or fluorene series or an adjacent polynucleic heterocyclic ring system with substituents having a nonionic character have been described as photoconductive reducing agents, stabilizers, laser dyes and antioxidants. See e.g., U.S. Pat. Nos. 3,798,031; 3,830,647; 3,832,171; 3,928,686; 3,979,394; 4,943,502 and 5,147,844 as well as Soviet Patent No. 555,119; R. L. Atkins and D. E. Bliss, “Substituted Coumarins and Azacoumarins: Synthesis and Fluorescent Properties”, 43
J. Org. Chem.,
1975 (1978), E. R. Bissell et al., “Synthesis and Chemistry of 7-Amino-4-(trifluoromethyl)coumarin and Its Amino Acid and Peptide Derivatives”, 45
J. Org. Chem.,
2283 (1980) and G. N. Gromova and K. B. Piotrovskii, “Relative Volatility of Stabilizers for Polymer Materials,” 43
Khim, Prom
-
st.,
97 (Moscow, 1967). However, no biological activity of any kind has been ascribed to these compounds.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. More particularly, the invention relates to non-steroidal compounds and compositions which are high affinity, high specificity agonists, partial agonists and antagonists for the PR, AR, ER, GR and MR steroid receptors, as well as to compounds with combined activity on one or more of these 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 which 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 drawings and descriptive matter, in which there is illustrated and described preferred embodiments of the invention.
DEFINITIONS AND NOMENCLATURE
As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. The numbering system for the location of substituents on such compounds is also provided.
The term alkyl, alkenyl, alkynyl and allyl includes straight-chain, branched-chain cyclic, saturated and/or unsaturated structures, and combinations thereof.
The term aryl refers to an optionally substituted six-membered aromatic ring, including polyaromatic rings.
The term heteroaryl refers to an optionally substituted five-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of carbon, oxygen, nitrogen and sulfur, including polycyclic rings, or a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of carbon and nitrogen, including polycyclic rings.
A quinoline is defined by the following structure, and may be recognized as a benzannulated pyridine. Compounds of structures 4, 5, 13, 79, 83 and 86 herein are named as quinolines.
An indeno[1,2-g]quinoline is defined by the following structure. Compounds of structures 16 (X═C) and 20 herein are named as indeno[1,2-g]quinolines.
An indeno[2,1-f]quinoline is defined by the following structure. Compounds of structure 17 (X═C) herein are named as indeno[1,2-f]quinolines.
A benzo[b]furano[3,2-g]quinoline is defined by the following structure. Compounds of structure 16 (X═O) herein are named as benzo[b]furano[3,2-g]quinolines.
A benzo[b]furano[2,3-f]quinoline is defined by the following structure. Compounds of structure 17 (X═O) herein are named as benzo[b]furano[2,3-f]quinolines.
An indolo[3,2-g]quinoline is defined by the following structure. Compounds of structure 16 (X═N) herein are named as indolo[3,2-g]quinolines.
An indolo[2,3-f]quinoline is defined by the following structure. Compounds of structures 17 (X═N) and 29 herein are named as indolo[2,3-f]
Davis Robert L.
Edwards James P.
Farmer Luc J.
Goldman Mark E.
Hamann Lawrence G.
Huang Evelyn Mei
Ligand Pharmaceuticals Inc.
Paul Hastings Janofsky & Walker LLP
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