CRF receptor antagonists and methods relating thereto

Details CRF receptor antagonists and methods relating thereto CRF receptor antagonists and methods relating thereto

1999-11-12

2002-02-19

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S346000

Reexamination Certificate

active

06348466

ABSTRACT:

TECHNICAL FIELD
This invention relates generally to CRF receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof.
BACKGROUND OF THE INVENTION
The first corticotropin-releasing factor (CRF) was isolated from ovine hypothalmi and identified as a 41-amino acid peptide (Vale et al.,
Science
213:1394-1397, 1981). Subsequently, sequences of human and rat CRF were isolated and determined to be identical, but different from ovine CRF in 7 of the 41 amino acid residues (Rivier et al.,
Proc. Natl. Acad. Sci. USA
80:4851, 1983; Shibahara et al.,
EMBO J.
2:775, 1983).
CRF has been found to produce profound alterations in endocrine, nervous and immune system function. CRF is believed to be the major physiological regulator of the basal and stress-release of adrenocorticotropic hormone (“ACTH”), &bgr;-endorphin, and other pro-opiomelanocortin (“POMC”)-derived peptides from the anterior pituitary (Vale et al.,
Science
213:1394-1397, 1981). Briefly, CRF is believed to initiate its biological effects by binding to a plasma membrane receptor which has been found to be distributed throughout the brain (DeSouza et al.,
Science
224:1449-1451, 1984), pituitary (DeSouza et al.,
Methods Enzymol.
124:560, 1986; Wynn et al.,
Biochem. Biophys. Res. Comm.
110:602-608, 1983), adrenals (Udelsman et al.,
Nature
319:147-150, 1986) and spleen (Webster, E. L., and E. B. DeSouza,
Endocrinology
122:609-617, 1988). The CRF receptor is coupled to a GTP-binding protein (Perrin et al.,
Endocrinology
118:1171-1179, 1986) which mediates CRF-stimulated increase in intracellular production of cAMP (Bilezikjian, L. M., and W. W. Vale,
Endocrinology
113:657-662, 1983). The receptor for CRF has now been cloned from rat (Perrin et al.,
Endo
133(6):3058-3061, 1993), and human brain (Chen et al.,
PNAS
90(19):8967-8971, 1993; Vita et al.,
FEBS
335(1):1-5, 1993). This receptor is a 415 amino acid protein comprising seven membrane spanning domains. A comparison of identity between rat and human sequences shows a high degree of homology (97%) at the amino acid level.
In addition to its role in stimulating the production of ACTH and POMC, CRF is also believed to coordinate many of the endocrine, autonomic, and behavioral responses to stress, and may be involved in the pathophysiology of affective disorders. Moreover, CRF is believed to be a key intermediary in communication between the immune, central nervous, endocrine and cardiovascular systems (Crofford et al.,
J. Clin. Invest.
90:2555-2564, 1992; Sapolsky et al.,
Science
238:522-524, 1987; Tilders et al.,
Regul. Peptides
5:77-84, 1982). Overall, CRF appears to be one of the pivotal central nervous system neurotransmitters and plays a crucial role in integrating the body's overall response to stress.
Administration of CRF directly to the brain elicits behavioral, physiological, and endocrine responses identical to those observed for an animal exposed to a stressful environment. For example, intracerebroventricular injection of CRF results in behavioral activation (Sutton et al.,
Nature
297:331, 1982), persistent activation of the electroencephalogram (Ehlers et al.,
Brain Res.
278:332, 1983), stimulation of the sympathoadrenomedullary pathway (Brown et al.,
Endocrinology
110:928, 1982), an increase of heart rate and blood pressure (Fisher et al.,
Endocrinology
110:2222, 1982), an increase in oxygen consumption (Brown et al.,
Life Sciences
30:207, 1982), alteration of gastrointestinal activity (Williams et al.,
Am. J. Physiol.
253:G582, 1987), suppression of food consumption (Levine et al.,
Neuropharmacology
22:337, 1983), modification of sexual behavior (Sirinathsinghji et al.,
Nature
305:232, 1983), and immune function compromise (Irwin et al.,
Am. J. Physiol.
255:R744, 1988). Furthermore, clinical data suggests that CRF may be hypersecreted in the brain in depression, anxiety-related disorders, and anorexia nervosa. (DeSouza,
Ann. Reports in Med. Chem.
25:215-223, 1990). Accordingly, clinical data suggests that CRF receptor antagonists may represent novel antidepressant and/or anxiolytic drugs that may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF.
The first CRF receptor antagonists were peptides (see, e.g., Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al.,
Science
224:889, 1984). While these peptides established that CRF receptor antagonists can attenuate the pharmacological responses to CRF, peptide CRF receptor antagonists suffer from the usual drawbacks of peptide therapeutics including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported. For example, substituted 4-thio-5-oxo-3-pyyrazoline derivatives (Abreu et al., U.S. Pat. No. 5,063,245) and substituted 2-aminothiazole derivatives (Courtemanche et al., Australian Patent No. AU-A-41399/93) have been reported as CRF receptor antagonists. These particular derivatives were found to be effective ine inhibiting the binding of CRF to its receptor in the 1-10 &mgr;M range and 0.1-10 &mgr;M range, respectively.
More recently, numerous small molecule CRR receptor antagonists have been proposed, including the compounds disclosed in the following patent documents: WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676, WO 94/13677, WO 95/10506, WO 95/33750, WO 96/35689, WO 97/00868, WO 97,35539, WO 97/35580, WO 97,35846, WO 97/44038, WO 98/03510, WO 98/05661, WO 98/08846, WO 98/08847, WO 98/11075, WO 98/15543, WO 98/21200 and WO 98/29413.
Due to the physiological significance of CRF, the development of biologically-active small molecules having significant CRF receptor binding activity and which are capable of antagonizing the CRF receptor remains a desirable goal. Such CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general.
While significant strides have been made toward achieving CRF regulation through administration of CRF receptor antagonists, there remains a need in the art for effective small molecule CRF receptor antagonists. There is also a need for pharmaceutical compositions containing such CRF receptor antagonists, as well as methods relating to the use thereof to treat, for example, stress-related disorders. The present invention fulfills these needs, and provides other related advantages.
SUMMARY OF THE INVENTION
In brief, this invention is generally directed to CRF receptor antagonists, and more specifically to CRF receptor antagonists having the following general structure (I):
including stereoisomers and pharmaceutically acceptable salts thereof wherein m, n, X, R, R
1
, R
2
and Ar are as defined below.
The CRF receptor antagonists of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders or illnesses, including stress-related disorders. Such methods include administering an effective amount of a CRF receptor antagonist of this invention. preferably in the form of a pharmaceutical composition, to an animal in need thereof. Accordingly, in another embodiment, pharmaceutical compositions are disclosed containing one or more CRF receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain procedures, compounds and/or compositions, and are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed generally to compounds useful as corticotropin-releasing factor (CRF) receptor antagonists.
In a first embodiment, the CRF receptor antagonists of this invention have the following structure (I):
including stereoisomers and pharmaceutically acceptable salts thereof,
wherein:

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