N-phenyl benzimidazolecarboxamide and N-phenyl...

Details N-phenyl benzimidazolecarboxamide and N-phenyl... N-phenyl benzimidazolecarboxamide and N-phenyl...

2001-08-13

2003-06-24

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S495000, C548S309700, C514S394000

Reexamination Certificate

active

06583169

ABSTRACT:

FIELD OF THE INVENTION
This invention relates N-phenyl benzimidazolecarboxamides and N-phenyl indolecarboxamides. When appropriately substituted, such compounds act as selective modulators of CRF1 receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. Additionally this invention relates to the use such compounds as probes for the localization of CRF1 receptors in cells and tissues.
BACKGROUND
Corticotropin releasing factor (CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors.
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system.
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression. There is also preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain.
CRF has also been implicated in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine
on-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models. Preliminary studies using the putative CRF receptor antagonist &agr;-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test and in the acoustic startle test in rats. The benzodiazepine receptor antagonist Ro 15-1788, which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner, while the benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF.
CRF has also been implicated in the pathogeneisis of certain immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke and osteoporosis, as well as in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.
The mechanisms and sites of action through which conventional anxiolytics and antidepressants produce their therapeutic effects remain to be fully elucidated. It has been hypothesized however, that they are involved in the suppression of CRF hypersecretion that is observed in these disorders. Of particular interest are that preliminary studies examining the effects of a CRF receptor antagonist peptide (&agr;-helical CRF
9-41
) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines.
SUMMARY OF THE INVENTION
The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I. Such compounds bind to cell surface receptors, preferably G-coupled protein receptors, especially CRF receptors and most preferably CRF1 receptors. Preferred compounds of the invention exhibit high affinity for CRF 1 receptors. Additionally, preferred compounds of the invention also exhibit high specificity for CRF1 receptors.
Preferred compounds of the present invention exhibit activity as corticotropin releasing factor receptor antagonists and appear to suppress the anxiogenic effects of CRF hypersecretion. The invention also provides methods of using compounds of Formula I for the suppression of CRF hypersecretion and for the treatment of anxiogenic disorders.
The invention further comprises methods of treating patients suffering from certain disorders that are responsive to modulation of CRF1 receptors with an effective amount of a compound of the invention. These disorders include CNS disorders, particularly affective disorders, anxiety disorders, stress-related disorders, eating disorders and substance abuse. Treatment of human patients suffering from such disorders as well as other animals (domesticated companion animals (pets) or livestock animals in encompassed by the invention.
In another aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I or the pharmaceutically acceptable salts or solvates thereof.
Additionally this invention relates to the use of the compounds of the invention (particularly labeled compounds of this invention) as probes for the localization of receptors in cells and tissues and as standards and reagents for use in determining the receptor-binding characteristics of test compounds. Labelled compounds of the invention may be used in in vitro studies such as is autoradiography of tissue sections or for in vivo methods, e.g. PET or SPECT scanning. Particularly, preferred compounds of the invention are useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF1 receptor.
Accordingly, a broad aspect of the invention provides compounds of general Formula I:
or the pharmaceutically acceptable non-toxic salts thereof wherein:
A represents N or C—Y, where Y is hydrogen or (C
1
-C
6
)alkyl;
G represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, hydroxy, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, —SH, (C
1
-C
6
)alkylthio-, thio(C
1
-C
6
)alkyl or (C
1
-C
6
)alkyl thio(C
1
-C
6
)alkyl;
R
1
represents hydrogen, (C
1
-C
6
)alkyl, or hydroxy(C
1
-C
6
)alkyl;
R
2
represents hydrogen or (C
1
-C
6
)alkyl, with the proviso that R
2
is hydrogen when A is C—Y;
R
3
and R
4
are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, hydroxy, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, —SH, (C
1
-C
6
)alkylthio, thio(C
1
-C
6
)alkyl or (C
1
-C
6
)alkyl thio(C
1
-C
6
)alkyl; and
R
5
, R
6
, R
7
and R
8
are the same or different and represent hydrogen, h

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