Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-01-07
2002-01-29
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S275000, C544S323000, C544S324000, C544S330000, C544S331000, C544S332000
Reexamination Certificate
active
06342503
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds, compounds and pharmaceutical compositions thereof, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy eating feeding disorders, irritable bowel syndrome, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, and fertility problems.
2. Description of the Related Art
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 demonstrating that CRF may also play 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 have demonstrated that CRF may have implications in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and eating 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 number 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 &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 (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 p.221 (1990)).
In order to study these specific cell-surface receptor proteins, compounds must be identified that can interact with the CRF receptor in a specific manner dictated by the pharmacological profile of the characterized receptor. Toward that end, there is evidence that the direct CRF antagonist compounds and compositions of this invention, which can attenuate the physiological responses to stress-related disorders, will have potential therapeutic utility for the treatment of depression and anxiety-related disorders. All of the aforementioned references are hereby incorporated by reference.
U.S. Pat. Nos. 4,788,195 and 4,876,252 teach the synthesis of compounds with the general formula (A):
The utility of these compounds is described as treatment of asthma, allergic diseases, inflammation, and diabetes in mammals.
PCT application WO 89/01938 describes the synthesis and utility of compounds with the formula (B):
These compounds can be utilized in the treatment of neurologic diseases, having an effect of regenerating and repairing nerve cells and improving and restoring learning and memory.
U.S. Pat. No. 4,783,459 describes the utility and synthesis of compounds with the following general formula (C):
The compounds have activity as fungicides, especially against fungal diseases of plants.
U.S. Pat. No. 4,992,438 discloses the utility and synthesis of compounds with the following general formula:
The utility of these compounds is described as fungicides with a broad spectrum activity against plant pathogenic fungi.
European Patent Application 0 013 143 A2 discloses the utility and synthesis of compounds with the following general formula:
These compounds are described as pre- and post-emergence herbicides.
U.S. Pat. No. 5,063,245 discloses a method of producing CRF antagonism with compounds with the general formulae:
PCT application WO 91/18887 discloses compounds of the general formula:
wherein R
2
may be C
1
-C
4
alkyl and R
3
may be substituted phenyl, said compounds being useful for the inhibition of gastric acid secretion.
European patent application EP 0588762 A1 discloses compounds of the general formu
Aldrich Paul Edward
Arvanitis Argyrios Georgios
Cheeseman Robert Scott
Chorvat Robert John
Christos Thomas Eugene
Black Robert W.
DuPont Pharmaceuticals Company
Fuzail Kalim S.
Rao Deepak R.
Rubin Kenneth B.
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