Isoxazolo [4,5-d] pyrimidines as CRF antagonists

Details Isoxazolo [4,5-d] pyrimidines as CRF antagonists Isoxazolo [4,5-d] pyrimidines as CRF antagonists

2002-03-27

2003-07-08

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S255000, C544S180000, C514S241000

Reexamination Certificate

active

06589958

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel isoxazolo[4,5-d] pyrimidines, pharmaceutical compositions containing the same and methods of using same in the treatment of psychiatric disorders and neurological diseases including affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing corticotropin releasing factor (CRF), including but not limited to disorders induced or facilitated by CRF.
BACKGROUND OF THE INVENTION
Corticotropin releasing factor, 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 provides 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 &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 (19.88)] 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)].
EP 0,778,277 (EP '277) describes a variety of CRF antagonists including those of the formula:
wherein A can be N or C, D can be N or C, E can be N or C, F can be N, C, S, or O, and G can be absent or a variety of groups. EP '277 does not disclose any isoxazolo[4,5-d]pyrimidines like those of the present invention.
WO 98/08847 (WO '847) describes a variety of CRF antagonists including those of the formula:
wherein A can be N or C, R
5
is an aromatic or heteroaromatic group, and R and R
3
can be a variety of groups. WO '847 does not disclose any isoxazolo[4,5-d]pyrimidines like those of the present invention.
WO 95/19774 (WO '774) describes a variety of CRF antagonists including those of the formula:
wherein A—B can be O, D can be N, and E can be C. However, WO '774 does not disclose any isoxazolo[4,5-d]pyrimidines like those of the present invention.
In view of the above, efficacious and specific antagonists of CRF are desired as potentially valuable therapeutic agents for the treatment of psychiatric disorders and neurological diseases. It is thus desirable to discover new CRF antagonists.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel isoxazolo[4,5-d] pyrimidines which are useful as CRF antagonists or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable

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