Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-02-08
2003-06-24
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C560S013000, C560S027000, C560S043000, C560S044000, C562S437000, C562S457000, C564S086000, C564S087000, C564S373000
Reexamination Certificate
active
06583180
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to non-steroidal compounds which are selective modulators of steroid receptors, in particular, the glucocorticoid receptor. In particular, the present invention is directed to compounds and methods for using such compounds to treat mammals requiring glucocorticoid receptor modulation.
BACKGROUND OF THE INVENTION
Glucocorticoids are lipid soluble hormones synthesized in the adrenal cortex (Neville and O'Hare, The Adrenal Gland, James, Ed. New York, Raven, 1-65, (1979)). These molecules readily pass through cell membranes and enter the cytoplasm of target tissues, where they bind to glucocorticoid receptors sequestered in the cytoplasm by complexation with heat shock proteins. Upon binding of the hormone to its receptor, the receptor undergoes a conformational change which results in dissociation of heat shock proteins, and translocation of the ligand bound glucocorticoid receptor into the nucleus where it can either initiate or repress specific gene transcription. Transcriptional activation occurs when the ligand bound receptor complex homodimerizes, and the homodimeric receptor ligand complex binds to chromosomal deoxyribonucleic acid (DNA) at sequence specific sites in the promoter region of regulated genes (Beato, Cell, 56, 335-344 (1989); and Yamamato, Annu. Rev. Genet., 19, 209-215 (1989)). 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.
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.
Type II diabetes (also referred to as non insulin-dependent Diabetes Mellitus) is a debilitating disease characterized by an abnormal elevation of blood glucose levels driven by three factors: increased hepatic glucose production, inadequate clearance of glucose via insulin mediated pathways, and decreased uptake of circulating glucose by tissues (DeFronzo, Diabetes Review 5(3), 177-269, (1997)). Administration of agents that decrease hepatic glucose production are a fundamental approach to controlling blood glucose (De Feo et al., Am. J. Physiol. 257, E35-E42 (1989); Rooney, et al., J. Clin. Endocrinol. Metab. 77, 1180-1183 (1994); and Dinneen et al., J. Clin. Invest.,92, 2283-2290 (1993)). Glucocorticoids have been shown to have major influences on glucose production. Glucocorticoid excess aggravates established diabetes while glucocorticoid deficiency reduces blood glucose and improves glucose control in diabetic mice (Boyle, Diabetes Review, 1(3), 301-308, (1993); Naeser, Diabetologia, 9, 376-379 (1973); and Solomon et al., Horm, Metab. Res., 9, 152-156 (1977)). The underlying mechanism responsible for these effects is the glucocorticoid-induced upregulation of key hepatic enzymes required for gluconeogenesis (Exton et al., Recent Prog. Horm. Res., 26, 411-457 (1970); and Kraus-Friedmann, Physiol. Rev., 64, 170-259 (1984)).
Among the genes that glucocorticoids up-regulate are several genes that play key roles in gluconeogenesis and glycogenolysis, particularly phosphoenolpyruvyl carboxykinase (PEPCK) and glucose-6-phosphatase (Hanson and Patel, Adv. Enzymol., Meister, Ed. New York, John Wiley and Sons, Inc., 203-281 (1994); and Argaud et al., Diabetes 45, 1563-1571 (1996)). Mifepristone (RU486), a potent GR antagonist reduces messenger ribonucleic acid (mRNA), levels of PEPCK and glucose-6-phosphate in the liver, and causes a 50% reduction of plasma glucose levels in obese diabetic db/db transgenic mice (Friedman et al., J. Biol. Chem. 272(50), 31475-31481 (1997)). While steroid-based GR antagonists have been useful in demonstrating efficacy for in vivo glucose lowering effects, the utility of such agents is limited due to side effects resulting from potent cross-reactivity with other steroid receptors, in particular progesterone receptor (PR) and mineralocorticoid receptor (MR). U.S. Pat. No. 5,929,058 discloses a method for treating type II diabetes by administering a combination of steroidal-agents that exhibit mineralcorticoid receptor agonist activity and glucocorticoid receptor antagonist activity. Pharmaceutical agents that function as glucocorticoid receptor (GR) antagonists represent a novel approach to controlling type II diabetes.
Other examples of proteins that interact with the glucocorticoid receptor are the transcription factors AP-1 and NF&kgr;-B. Such interactions result in inhibition of AP-1- 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.
Glucocorticoid selective non-steroidal agents that antagonize functional activity mediated by the glucocorticoid receptor may be useful for treating mammals suffering from type II diabetes and for treating symptoms of type II diabetes including hyperglycemia, inadequate glucose clearance, obesity, hyperinsulinemia, hypertriglyceridemia and high circulating glucocorticoid levels. In addition to diabetes, glucocorticoid receptor modulators are useful to treat diseases such as obesity, Syndrome X, Cushing's Syndrome, Addison's disease, inflammatory diseases such as asthma, rhinitis and arthritis, allergy, autoimmune disease, immunodeficiency, anorexia, cachexia, bone loss or bone frailty, and wound healing.
U.S. Pat. No. 5,929,058 discloses a method for treating type II diabetes by administering a combination of steroidal-agents that exhibit mineralcorticoid receptor agonist activity and glucocorticoid receptor antagonist activity.
Although there are glucocorticoid receptor therapies in the art, there is a continuing need for and a continuing search in this field of art for selective glucocorticoid receptor therapies. Thus, the identification of non-steroidal compounds which have specificity for one or more steroid receptors, but which have reduced or no cross-reactivity for other steroid or intracellular receptors, is of significant value in this field.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention discloses compounds of formula (I) that are useful as glucocorticoid receptor modulators:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
L
A
is a covalent bond or C(X
A1
)(X
A2
);
L
D
is a covalent bond or C(X
D1
)(X
D2
);
X
A1
is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkoxyalkyl, alkyl, alkylcarbonyl, cyano, halogen, hydroxy, hydroxyalkyl, nitro and (NR
10
R
11
)carbonyl;
X
A2
is selected from the group consisting of hydrogen and alkyl;
or X
A1
and X
A2
together are oxo;
X
D1
is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkoxyalkyl, alkyl, alkylcarbonyl, cyano, halogen, hydroxy, hydroxyalkyl, nitro and (NR
10
R
11
)carbonyl;
X
D2
is selected from the group consisting of hydrogen and alkyl;
or X
D1
and X
D2
together are oxo;
L
B
is absent or selected from the group consisting of a covalent bond, alkenylene, alkylene, alkynylene, —(CH
2
)
m
C(O)(CH
2
)
n
—, —(CH
2
)
m
C(O)(CH
2
)
n
CH═CH—, —(CH
2
)
m
C(O)(CH
2
)
n
C≡C—, —(CH
2
)
m
CH(OH)(CH
2
)
n
—, —(CH
2
)
m
CH(OH)(CH
2
)
n
CH
2
CH═CH—, —(CH
2
)
m
CH(OH)(CH
2
)
n
CH
2
C≡C—, —(CH
2
)
m
O(CH
2
)
n
—, —(CH
2
)
m
O(CH
2
)
n
CH
2
CH═CH—, —(CH
2
)
m
O(CH
2
)
n
CH
2
C≡C—, —(CH
2
)
m
S(CH
2
)
n
—, —(CH
2
)
m
S(O)(CH
2
)
n
—, —(CH
2
)
m
S(O)
2
(CH
2
)
n
—, —(CH
2
)
m
N(R
7
)(CH
2
)
n
—, —(CH
2
)
m
N(R
7
)C(CH
2
)
n
—, —(CH
2
)
m
C(O)N(R
7
)(CH
2
)
n
—, —O(CH
2
)
m
C(O)N(R
7
)(CH
Arendsen David L.
Li Gaoquan
Link James T.
Patel Jyoti R.
Sorensen Bryan K.
Abbott Laboratories
O'Sullivan Peter
Rogers Christopher P.
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