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.
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 NFxcexaB/GRE. Agonist binding to the glucocorticoid receptor leads to transcriptional activation of the GRE and transcriptional repression of AP-1/GRE and NFxcexaB/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.
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 fragmentxe2x80x94say of an indan or a dehydro-decalinxe2x80x94and 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 R8, R9 and R10 is absent so that a normal valence on W is maintained;
R1 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;
R2, R3, R5, R6, R6xe2x80x2, and R7 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;
R2xe2x80x2, R3xe2x80x2, R5xe2x80x2, R7xe2x80x2 and R8 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;
R4 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;
R9 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, carboxy, cyano, halo, oxo, thio, hydroxy or is absent;
R10 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;
R10 and R2 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, alkyl, substituted alkyl, acyl, substituted acyl, cycloalkyl, or substituted cycloalkyl, may fuse to the bond between R10 and R2; and
R11 and R12 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, oxo, thio, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy.
The bonds in formula (I) that are shown with single and dashed lines are intended to represent alternative forms of the structure. That is, one or more, but preferably one, such bonds may be a double bond provided that normal valences of the atoms in the rings are satisfied.
In a second aspect, the present invention provides compositions of compounds of the invention. The compositions generally comprise one or more compounds of the invention, pharmaceutically acceptable salts, hydrates or solvates thereof and a pharmaceutically acceptable diluent, carrier, excipient and adjuvant. The choice of diluent, carrier, excipient and adjuvant will depend upon, among other factors, the desired mode of administration.
In a third aspect, the present invention provides methods for treating or preventing obesity, diabetes, depression, neurodegeneration or an inflammatory disease. The methods generally involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound and/or composition of the invention.
In a fourth aspect, the current invention provides compositions for treating or preventing obesity, diabetes, depression, neurodegeneration or an inflammatory disease in a patient in need of such treatment or prevention.
In a fifth aspect the current invention provides methods for selectively modulating the activation, repression, agonism and antagonism effects of the glucocorticoid receptor in a patient. The methods generally involve administering to patient in need of such treatment a therapeutically effective amount of a compound or composition of the invention.