Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-22
2004-12-14
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S359100
Reexamination Certificate
active
06831093
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to non-steroidal ligands of the glucocorticoid receptor, methods for making non-steroidal ligands compositions of non-steroidal ligands, and methods for using non-steroidal ligands, and methods for using compositions of non-steroidal ligands. More specifically, the present invention relates to derivatives of Wieland-Miescher ketone, methods for making derivatives of Wieland-Miescher ketone, compositions of derivatives of Wieland-Miescher ketone, methods for using derivatives of Wieland-Miescher ketone, and methods for using compositions of derivatives of Wieland-Miescher ketone.
BACKGROUND OF THE INVENTION
The glucocorticoid receptor is a member of the steroid/thyroid nuclear hormone receptor superfamily, which includes, but is not limited to, mineralcorticoid, androgen, progesterone and estrogen receptors. The glucocorticoid receptor is activated in vivo by binding of natural agonists such as cortisol and corticosterone. The glucocorticoid receptor may also be activated by binding of synthetic agonists such as dexamethasone, prednisone and prednisilone. Many synthetic antagonists of glucocorticoid receptors (e.g., RU-486) are also known.
Since the presence or absence of ligand binding to the glucocorticoid receptor may have profound physiological consequences (e.g., lead to Cushing's syndrome or Addison's disease), drugs that target the glucocorticoid receptor are clinically relevant. Consequently, selective glucocorticoid receptor ligands that either activate (i.e., agonists) or inactivate (i.e., antagonists) glucocorticoid mediated response are compounds of pharmaceutical interest.
The glucocorticoid receptor, when activated by ligand, mediates biological processes (e.g., metabolism, electrolyte balance, organ and tissue systems, etc.) by binding to specific regulatory DNA sequences (i.e., response elements) in the promoter of cortisol-regulated genes. The glucocorticoid receptor may thus activate or repress transcription of cortisol-regulated genes. At least three different response elements exist for glucocorticoid receptor regulation: (1) the glucocorticoid response element (GRE); (2) an AP-1/GRE; and (3) a NF&kgr;B/GRE. Agonist binding to the glucocorticoid receptor leads to transcriptional activation of the GRE and transcriptional repression of AP-1/GRE and NF&kgr;B/GR.
Currently available drugs that bind to the glucocorticoid receptor are typically cortisol analogues, which produce undesired side effects that are caused by: (1) unselective binding to other steroid receptors; and (2) failure to disassociate the different response elements when binding to the glucocorticoid receptor. Thus, there exists a need for compounds that selectively bind to the glucocorticoid receptor and selectively disassociate the different response elements of the glucocorticoid receptor.
SUMMARY OF THE INVENTION
The present invention addresses these and other needs by providing non-steroidal ligands for the glucocorticoid receptor, methods for making non-steroidal ligands of the glucocorticoid receptor, compositions of non-steroidal ligands of the glucocorticoid receptor and methods of using non-steroidal ligands and compositions of non-steroidal ligands of the glucocorticoid receptor for treating or preventing diseases (e.g., obesity, diabetes, depression, neurodegeneration or an inflammatory disease) associated with glucocorticoid binding to the glucocorticoid receptor. In principle, the current invention allows for the preparation of either agonist or antagonist compounds and either or both of these pharmacological modes of action may be useful for certain therapeutic treatments.
The compounds of the instant invention include a carbocyclic ring system, which may be unsaturated and may be annelated with a heterocyclic ring. In particular, the carbocyclic ring systems may be an indan (i.e., a six membered carbocyclic ring fused with a five membered carbocyclic ring), a dehydro-decalin (i.e., a six membered carbocyclic ring fused with a six membered carbocyclic ring) or a dehydro [4.5.0] bicyclo undecane (i.e., a six membered carbocyclic ring fused with a seven membered carbocyclic ring) ring system. When the carbocylic ring system comprises a carbocyclic ring system annelated with a heterocyclic ring, the heterocyclic ring is typically attached to the six membered ring fragment—say of an indan or a dehydro-decalin—and has at least one oxygen, nitrogen or sulfur atom.
In a first aspect, the present invention provides compounds of formula (I):
or a pharmaceutically available salt, solvate or hydrate thereof wherein:
A, B and C are independently carbon, nitrogen, oxygen or sulfur provided that at least one of A, B and C is nitrogen, oxygen or sulfur and that no more than one of A, B and C are oxygen or sulfur;
W is carbon, oxygen, nitrogen, or sulfur and, when W is other than carbon and nitrogen, one or more of R
8
, R
9
and R
10
is absent so that a normal valence on W is maintained;
R
1
is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl or substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl;
R
2
, R
3
, R
5
, R
6
, R
6
′, and R
7
are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy;
R
2
′, R
3
′, R
5
′, R
7
′ and R
8
are absent or are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy;
R
4
is absent or is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl;
R
9
is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, carboxy, cyano, halo, oxo, thio, hydroxy or is absent;
R
10
is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or is absent;
R
10
and R
2
may bond directly to one another to form a ring, and an additional ring such as a benzene ring, which may itself be substituted with an alkyl, alkoxy, halo
Scanlan Thomas S.
Shah Nilesh
Lambkin Deborah C.
Morgan & Lewis & Bockius, LLP
The Regents of the University of California
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