Amino substituted pyrimidines and triazines

Details Amino substituted pyrimidines and triazines Amino substituted pyrimidines and triazines

1998-04-15

2001-09-11

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S256000, C514S275000, C544S122000, C544S323000, C544S326000, C544S329000

Reexamination Certificate

active

06288060

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to aminopyrimidines and -triazines 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
213:13941397, 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-95/10506 discloses N-alkyl-N-arylpyrimidinamines and derivatives.
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 is directed to aminopyrimidines and -triazines having the following general structure (I):
including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein
R is C
1-6
alkyl, amino, mono- or diC
1-6
alkylamino;
R
1
is hydrogen, C
1-6
alkyl, C
3-6
alkenyl, hydroxyC
1-6
alkyl or C
1-6
alkyloxyC
1-6
alkyl;
R
2
is C
1-6
alkyl, mono- or diC
3-6
cycloalkylmethyl, phenylmethyl, substituted phenylmethyl, C
1-6
alkyloxyC
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
akyl, C
3-6
alkenyl;
or R
1
and R
2
taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, morpholinyl or piperidinyl group;
X is N or CR
3
;
R
3
is hydrogen or C
1-6
alkyl;
R
4
is phenyl or substituted phenyl;
A is
 or —CR
7
R
8
—
wherein R
5
and R
6
each independently are hydrogen or C
1-4
alkyl;
R
7
is hydrogen or OH;
R
8
is hydrogen or C
1-6
alkyl; and
substituted phenyl is phenyl substituted with 1, 2 or 3 substituents independently selected from halo, hydroxy, C
1-6
alkyloxy, benzyloxy, C
1-6
alkylthio, trifluoromethyl, C
1-6
alkyl and cyano.
As used in the foregoing definitions halo defines fluoro, chloro, bromo and iodo; C
1-2
alkyl defines straight saturated hydrocarbon radicals having from 1 to 2 carbon atoms such as methyl and ethyl; C
2-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl, propyl, butyl, 1-methylethyl and the like; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; C
1-6
alkyl defines C
1-4
alkyl radicals as defined hereinbefore and the higher homologs thereof having from 5 to 6 carbon atoms such as, pentyl, the pentyl isomers, hexyl and the hexyl isomers; C
3-6
alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 3,3-dimethyl-2-propenyl, hexenyl and the like. The carbon atom in the C
3-6
alkenyl moiety being substituted on the NR
2
R
3
-nitrogen preferably is saturated. When —NR
1
R
2
is a cyclic moiety, it preferably is linked to the pyrimidine or triazine ring through a nitrogen atom.
Depending on the nature of some of the substituents, the compounds of formula (I) may contain one or more asymmetric centers which may be designated with the generally used R and S nomenclature.
The compounds of the present invention are substituted amino compounds and, as such, can be utilized as the free base or in the form of acid addition salts. Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric aci

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