Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-09
2003-02-11
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S303000, C514S252020, C544S236000, C544S239000, C548S300100, C548S303400
Reexamination Certificate
active
06518271
ABSTRACT:
FIELD OF THE INVENTION
This invention relates a 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, by administration of certain 1H-imidazo[4,5-d]pyridazin-7-ones, 3H-imidazo-[4,5-c]pyridin-4-ones and corresponding thiones.
BACKGROUND OF THE INVENTION
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al.,
Proc. Nat. Acad. Sci
. (
USA
) 80:4851 (1983); W. Vale et al.,
Science
213:1394 (1981)]. 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 [W. Vale et al.,
Rec. Prog. Horm. Res.
39:245 (1983); G. F. Koob,
Persp. Behav. Med.
2:39 (1985); E. B. De Souza et al.,
J. Neurosci.
5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock,
Physiological Reviews
69:1 (1989); J. E. Morley,
Life Sci.
41:527 (1987)].
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 [for review see E. B. De Souza,
Hosp. Practice
23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al.,
Science
226:1342 (1984); C. M. Banki et al.,
Am. J. Psychiatry
144:873 (1987); R. D. France et al.,
Biol. Psychiatry
28:86 (1988); M. Arato et al.,
Biol Psychiatry
25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al.,
Arch. Gen. Psychiatry
45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al.,
Am J. Psychiatry
141:619 (1984); F. Holsboer et al.,
Psychoneuroendocrinology
9:147 (1984); P. W. Gold et al.,
New Eng. J. Med.
314:1129 (1986)]. 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 [R. M. Sapolsky,
Arch. Gen. Psychiatry
46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al.,
Neuropsychopharmacology
2:53 (1989)].
There has also been a role postulated for CRF 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 [D. R. Britton et al.,
Life Sci.
31:363 (1982); C. W. Berridge and A. J. Dunn
Regul. Peptides
16:83 (1986)]. Preliminary studies using the putative CRF-receptor antagonist a-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 [C. W. Berridge and A. J. Dunn
Horm. Behav.
21:393 (1987),
Brain Research Reviews
15:71 (1990)]. 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 [K. T. Britton et al.,
Psychopharmacology
86:170 (1985); K. T. Britton et al.,
Psychopharmacology
94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al.,
Psychopharmacology
88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), 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 (FG7142) enhanced the actions of CRF [K. T. Britton et al.,
Psychopharmacology
94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (&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 [for review see G. F. Koob and K. T. Britton, In:
Corticotropin
-
Releasing Factor: Basic and Clinical Studies of a Neuropeptide
, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.
SUMMARY OF THE INVENTION
In accordance with one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of in
Bakthavatchalam Rajagopal
Gilligan Paul Joseph
Bristol--Myers Squibb Company
Goddard Christine A.
Patel Sudhaker R.
Raymond Richard L.
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