Glucocorticoid receptor modulators

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S231200, C514S247000, C514S256000, C514S364000, C514S396000, C514S408000, C514S277000, C544S106000, C544S224000, C544S242000, C546S329000, C546S339000, C548S131000, C548S335100, C548S400000

Reexamination Certificate

active

06699893

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides non-steroidal compounds which are selective modulators (i.e., agonists and antagonists) of a steroid receptor, specifically, the glucocorticoid receptor. The present invention also provides pharmaceutical compositions containing these compounds and methods for using these compounds to treat animals requiring glucocorticoid receptor agonist and/or antagonist therapy. Glucocorticoid receptor modulators are useful to treat diseases, such as obesity, diabetes, inflammation and others as described below. The present invention also provides intermediates and processes for preparing these compounds.
BACKGROUND OF THE INVENTION
Nuclear receptors are classically defined as a family of ligand dependent transcription factors, that are activated in response to ligand binding (R. M. Evans, 240 Science, 889 (1988)). Members of this family include the following receptors: glucocorticoid, mineralocorticoid, androgen, progesterone and estrogen. Naturally occurring ligands to these receptors are low molecular weight molecules that play an important role in health and in many diseases. Excesses or deficiencies of these ligands can have profound physiological consequences. As an example, glucocorticoid excess results in Cushing's Syndrome, while glucocorticoid insufficiency results in Addison's Disease.
The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells where it resides in the cytosol in an inactive state until it is stimulated by an agonist. Upon stimulation the glucocorticoid receptor translocates to the cell nucleus where it specifically interacts with DNA and/or protein(s) and regulates transcription in a glucocorticoid responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NF&kgr;-B. Such interactions result in inhibition of API- and NF&kgr;-B-mediated transcription and are believed to be responsible for some of the anti-inflammatory activity of endogenously administered glucocorticoids. In addition, glucocorticoids may also exert physiologic effects independent of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid receptor agonists exist including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and eliciting GR mediated events, including transcription. RU486 is an example of a non-selective glucocorticoid receptor antagonist.
U.S. Pat. No. 3,683,091 discloses phenanthrene compounds, specifically certain di-7-hydroxy or methyl-2,3,4,4a,9,10-hexahydrophenanthren-2-one and 4a-alkyl derivatives, hydrogenated derivatives, functional derivatives and optically active isomers thereof useful as specific anti-acne agents.
Japanese Patent Application, Publication No. 45014056, published May 20, 1970, discloses the manufacture of 1,2,3,4,9,10,11&agr;, 12-octahydro-7-methoxy-12&bgr;-butylphenanthren-2&bgr;-ol and certain of its derivatives useful as antiandrogenic and antianabolic drugs.
Japanese Patent Application, Publication No. 6-263688, published Sep. 20, 1994, discloses certain phenanthrene derivatives which are interleukin-1 (IL-1) inhibitors. It also discloses their preparation and certain intermediates thereto. International Patent Application Publication No. WO 95/10266, published Apr. 20, 1995, discloses the preparation and formulation of certain phenanthrene derivatives as nitrogen monoxide synthesis inhibitors.
Japanese Patent Application, Publication No. 45-36500, published Nov. 20, 1970, discloses a method of making certain optically active phenanthrene derivatives which are useful as antiandrogenic agents.
European Patent Application, Publication No. 0 188 396, published Jul. 23, 1986, discloses certain substituted steroid compounds, certain processes and intermediates for preparing them, their use and pharmaceutical compositions containing them. These compounds are disclosed to possess antiglucocorticoid activity, and some of them have glucocorticoid activity.
C. F. Bigge et al., J. Med. Chem. 1993, 36, 1977-1995, discloses the synthesis and pharmacolgical evaluation of a series of octahydrophenanthrenamines and certain of their heterocyclic analogues as potential noncompetitive antagonists of the N-methyl-D-aspartate receptor complex.
P. R. Kanjilal et al., J. Org. Chem. 1985, 50, 857-863, discloses synthetic studies toward the preparation of certain complex diterpenoids.
G. Sinha et al., J. Chem. Soc., Perkin Trans. I (1983), (10), 2519-2528, discloses the synthesis of the isomeric bridged diketones cis-3,4,4a,9,10,10a-hexahydro-1,4a-ethanophenanthren-2(1H),12-dione and trans-3,4,4a,9,10,10a-hexahydro-3,4a-ethanophenanthren-2(1H),1,2-dione by highly regioselective intramolecular aldol condensations through the stereochemically defined cis- and trans-2,2-ethylenedioxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-4a-ylacetaldehydes.
U. R. Ghatak, M. Sarkar and S. K. Patra, Tetrahedron Letters No. 32, pp. 2929-2931, 1978, discloses a simple stereospecific route to certain polycyclic bridged-ring intermediates useful in preparing some complex diterpenoids.
P. N. Chakrabortty et al., Indian J. Chem. (1974), 12(9), 948-55, discloses the synthesis of 1&agr;-methyl-1&bgr;,4a&bgr;-dicarboxy-1,2,3,4,4a,9,10,10a&bgr;-octahydro-phenanthrene, an intermediate in the synthesis of certain diterpenoids and diterpene alkaloids, and of 1&bgr;,4a&bgr;-dicarboxy-1,2,3,4,4a,9,10,10a&bgr;-octahydrophenanthrene.
E. Fujita et al., J. Chem. Soc., Perkin Trans. I (1974), (1), 165-77, discloses the preparation of enmein from 5-methoxy-2-tetralone via ent-3-&bgr;,2-epoxy-3-methoxy-17-norkaurane-6&agr;,16&agr;-diol.
H. Sdassi et al., Synthetic Communications, 25(17), 2569-2573 (1995) discloses the enantioselective synthesis of (R)-(+)-4a-cyanomethyl-6-methoxy-3,4,9,10-tetrahydrophenanthren-2-one, which is a key intermediate in morphinan synthesis.
T. Ibuka et al., Yakugaku Zasshi (1967), 87(8), 1014-17, discloses certain alkaloids of menispermaceous plants.
Japanese Patent 09052899, dated Feb. 25, 1997, discloses certain diterpene or triterpene derivatives which are leukotriene antagonists obtained by extraction from
Tripterygium wilfordii
for therapeutic use.
U.S. Pat. No. 5,696,127 discloses certain nonsteroidal compounds, such as 5H-chromeno[3,4-f]quinolines, which are selective modulators of steroid receptors.
U.S. Pat. No. 5,767,113 discloses certain synthetic steroid compounds useful for concurrently activating glucocorticoid-induced response and reducing multidrug resistance.
Published European Patent Application 0 683 172, published Nov. 11, 1995, discloses certain 11,21-bisphenyl-19-norpregnane derivatives having anti-glucocorticoid activity and which can be used to treat or prevent glucocorticoid dependent diseases.
D. Bonnet-Delpon et al., Tetrahedron (1996), 52(1), 59-70, discloses certain CF
3
-substituted alkenes as good partners in Diels-Alder reactions with Danishefsky's diene and in 1,3-dipolar cycloadditions with certain nitrones and non-stabilized azomethine ylides.
International Patent Application Publication No. WO 98/26783, published Jun. 25, 1998, discloses the use of certain steroid compounds with anti-glucocorticoid activity, with the exception of mifepristone, for preparing medicaments for the prevention or treatment of psychoses or addictive behavior.
International Patent Application Publication No. WO 98/27986, published Jul. 2, 1998, discloses methods for treating non-insulin dependent Diabetes Mellitus (NIDDM), or Type II Diabetes, by administering a combination of treatment agents exhibiting glucocorticoid receptor type I agonist activity and glucocorticoid receptor type II antagonist activity. Treatment agents such as certain steroid compounds having both glucocorticoid receptor type I agonist activity and glucocorticoid receptor type II antagonist activity are also disclosed.
Interna

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