Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-20
2003-09-02
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S119000
Reexamination Certificate
active
06613777
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to pyrazolo[4,3-b]pyridines which possess CRF receptor antagonistic properties, to pharmaceutical compositions containing these compounds as active ingredient, and the use thereof in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general.
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
221:1449-1451, 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).
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 pathoplhysiology 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
. 2/8332, 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 suggest 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 suggest 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.
Due to the physiological significance of CRF, the development of further 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.
CRF receptor antagonists have been reported in for example, WO-94/13676, WO-94/13677, WO-95/33750 and WO-96/35689 which disclose pyrrolopyrimidines, pyrazolo[3,4-d]pyrimidines and substituted purines as CRF receptor antagonists. WO-98/03510, published on Jan. 29, 1998, discloses azolotriazine and pyrimidine derivatives as CRF antagonists. Also WO-97/29109, published Aug. 14, 1997, discloses CRF antagonistic pyrazolopyrimidines.
Structurally related pyrazolo[4,3-b]pyridines are also disclosed in EP-0,239,191-A, published Sep. 30, 1987, as being useful for treating inflammatory or allergic conditions.
Other structurally related compounds are disclosed in Japanese Published (Kokai) patent application No. 52-077086 having anti-inflammatory and anti-bacterial properties. Furthermore,
J. Heterocycl. Chem
., 8(6), pp 1035-1037 (1971) describes pyrazolopyridines having CNS antidepressant activity in mice.
The compounds of the present invention differ from the cited art-known compounds structurally, by the nature of the substituents on the pyrazolo[4,3-b]pyridine moiety, and pharmacologically by the fact that, unexpectedly, these compounds have CRF antagonistic properties.
DESCRIPTION OF THE INVENTION
This invention concerns CRF antagonistic compounds of formula (I)
including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein
R
1
is C
1-6
alkyl, NR
5
R
6
, OR
6
or SR
6
;
R
2
is C
1-6
alkyl, C
1-6
alkyloxy, or C
1-6
alkylthio;
R
3
is Ar
1
or Het
1
;
R
4
is hydrogen or C
1-6
alkyl;
R
5
is hydrogen, C
1-8
alkyl, mono- or di(C
3-6
cycloalkyl)methyl, C
3-6
cycloalkyl, C
3-6
alkenyl, hydroxyC
1-6
alkyl, C
1-6
alkylcarbonyloxyC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl or C
1-6
alkyloxyC
1-6
alkyl;
R
6
is C
1-8
alkyl, mono- or di(C
3-6
cycloalkyl)methyl, Ar
2
C
1-6
alkyl, Ar
2
oxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, hydroxyC
1-6
alkyl, C
3-6
alkenyl, thienylmethyl, furanylmethyl, tetrahydrofuranylmethyl, C
1-6
alkylthioC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, di(C
1-6
alkyl)amino, or C
1-6
alkylcarbonylC
1-6
alkyl;
or R
5
and R
6
taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, or thiomorpholinyl group, optionally substituted with 1 or 2 substituents each independently selected from C
1-6
alkyl or C
1-6
alkyloxyC
1-6
alkyl;
Ar
1
is phenyl; naphtyl; or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C
1-6
alkyl, trifluoromethyl, hydroxy, cyano, C
1-6
alkyloxy, benzyl, benzyloxy, C
1-6
alkylthio, nitro, amino and mono- or di(C
1-6
alkyl)amino;
Het
1
is pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents each independently selected from halo, C
1-6
alkyl, trifluoromethyl, hydroxy, cyano, C
1-6
alkyloxy, benzyloxy, C
1-6
alkylthio, nitro, amino, and mono- or di(C
1-6
alkyl)amino; and
Ar
2
is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, di(C
1-6
alkyl)aminoC
1-6
alkyl, or trifluoromethyl; or pyridinyl.
In an aspect this invention also concerns the novel compounds of formula (I), which hereinafter and in the claims will be referred to as compounds of formula (I-1) wherein R
1
to R
4
are defined hereinabove and wherein
at least R
1
is C
1-6
alkyl; OR
6
; SR
6
; or NR
5
R
6
wherein R
5
is mono- or di(C
3-6
cycloalkyl)methyl, C
3-6
cycloalkyl, C
3-6
alkenyl, hydroxyC
1-6
alkyl, C
1-6
alkylcarbonyloxyC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl or C
1-6
alkyloxyC
1-6
alkyl,
Chen Chen
Hadduch Mustapha
Huang Charles Q.
McCarthy James R.
Wilcoxen Keith M.
Coleman Brenda
Scully Scott Murphy & Presser
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