Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-02
2003-12-16
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S250000, C544S281000
Reexamination Certificate
active
06664261
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to pyrazolopyrimiidines 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 functions. 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 pathophysiology 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. CRF receptor antagonists have been reported in for example, U.S. Pat. No. 5,063,245 disclosing substituted 4-thio-5-oxo-3-pyrazoline derivatives and Australian Patent No. AU-A-41399/93, disclosing substituted 2-aminothiazole derivatives. WO-92/18504 and JP-32104877 disclose pyrazolo[1,5-a]pyrimidines as antiinflammatory agents. Also, WO-94/13676, WO-94113677 and WO-95/33750 disclose pyrrolopyrimidines, pyrazolo[3,4-d]pyrimidines and substituted purines as CRF receptor antagonists. Arylpyrazolo[1,5-a]pyrinidines have been described as xanthine oxidase inhibitors (Robins et al., J. Heterocyclic Chem. 22:601-634, 1985). JP-42/011,753 discloses 7-methylamino-pyrazolo[1,5-a]pyrimidine derivatives useful as sedative and antiphlogistic agents. And JP-61/057,587 discloses pyrazolo[1,5-a]pyrimidine derivatives useful as antiulcer agents.
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.
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 NR
4
R
5
or OR
5
;
R
2
is C
1-6
alkyl, C
1-6
alkyloxy or C
1-6
alkylthio;
R
3
is hydrogen, C
1-6
alkyl, C
1-6
alkylsulfonyl, C
1-6
alkylsulfoxy or C
1-6
alkylthio;
R
4
is hydrogen, C
1-6
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 or C
1-6
alkyloxyC
1-6
alkyl;
R
5
is C
1-8
alkyl, mono- or di(C
3-6
cycloalkyl)methyl, Ar
1
CH
2
, C
1-6
alkyloxyC
1-6
alkyl, hydroxyC
1-6
alkyl, C
3-6
alkenyl, thienylmethyl, furanylmethyl, C
1-6
alkylthioC
1-6
alkyl, morpholinyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, di(C
1-6
alkyl)amino, C
1-6
alkylcarbonylC
1-6
alkyl, C
1-6
alkyl substituted with imidazolyl; or a radical of formula —Alk—O—CO—Ar
1
;
or R
4
and R
5
taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group, optionally substituted with C
1-6
alkyl or C
1-6
alkyloxyC
1-6
alkyl; and
Ar is phenyl; phenyl substituted with 1, 2 or 3 substituents 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; pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C
1-6
alkyl, trifluoromethyl, hydroxy, cyano, C
1-6
alkyloxy, benzyloxy, C
1-6
alkylthio, nitro, amino, mono- or di(C
1-6
alkyl)amino and piperidinyl; and wherein said substituted phenyl may optionally be further substituted with one or more halogens;
Ar
1
is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy, di(C
1-6
alkyl)aminoC
1-6
alkyl, trifluoromethyl and C
1-6
alkyl substituted with morpholinyl; or pyridinyl; and
Alk is C
1-6
alkanediyl.
In a further aspect the invention concerns novel compounds of formula (I) as defined above, with the proviso that 5-methyl-3-phenyl-7-(phenylmethoxy)-pyrazolo[1,5-a]-pyrimidine and 2,5-dimethyl-7-(methylamino)-3-phenyl-pyrazolo[f,5-a]pyrimidine are not included
The proviso is intended to exclude compounds disclosed in JP-61/057,587 and JP-42/011,753.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
1-6
alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; C
1-2
alkyl defines straight saturated hydrocarbo
Chen Chen
Huang Charles
McCarthy James R.
Moran Terence J.
Webb Thomas R.
Neurocrine Biosciences Inc.
Seed IP Law Group PLLC
Truong Tamthom N.
LandOfFree
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