Substituted azole derivatives as inhibitors of corticotropin...

Details Substituted azole derivatives as inhibitors of corticotropin... Substituted azole derivatives as inhibitors of corticotropin...

2001-09-17

2003-02-04

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S377000, C546S270700, C548S194000, C548S198000, C548S234000

Reexamination Certificate

active

06515005

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to thiazoles, oxazoles, imidazoles and pharmaceutical compositions comprising said compounds antagonizing the corticotropin releasing factor receptor (“CRF receptor”) and useful for the treatment of depression, anxiety, affective disorders, feeding disorders, post-traumatic stress disorder, headache, drug addiction, inflammatory disorders, drug or alcohol withdrawal symptoms and other conditions the treatment of which can be effected by the antagonism of the CRF-1 receptor.
BACKGROUND OF THE INVENTION
It has been shown that the neuropeptide, corticotropin releasing factor (“CRF”), acting through its binding to the CRF-1 receptor, is a primary mediator of stress- and anxiety-related physiological responses in humans and other mammals by stimulating ACTH secretion from the anterior pituitary gland. See A. J. Dunn, et al., Brain Res. Rev., 15: 71-100 (1990). Antagonists of the CRF-1 receptor, both peptides (J. Gulyas, et al., Proc. Natl. Acad. Sci. U.S.A., 92: 10575-10579 (1995) and small molecules (J. R. McCarthy, et al., Curr. Pharm. Design, 5: 289-315 (1999), have demonstrated the ability to ameliorate the effects of stressful stimuli in several animal models. In addition, marked elevations of CRF in cerebrospinal fluid have been detected in a large portion of individuals diagnosed with major depression and anxiety disorders, and the levels correlate with severity of the disease. See F. Holsboer, J. Psychiatric Res., 33: 181-214 (1999). Following antidepressant treatment, the increased CRF levels observed in depressed patients were reduced. See C. M. Banki, et al., Eur. Neuropsychopharmacol., 2: 107-113 (1992). CRF has also been shown to be a key mediator of several immune system functions through its effect on glucocorticoid plasma levels. See E. L. Webster, et al., Ann. N.Y. Acad. Sci., 840: 21-62 (1998). Recent reviews of the activity of CRF-1 antagonists, P. J. Gilligan, et al., J. Med. Chem., 43: 1641-1660 (2000) and J. R. McCarthy, et al., Ann. Rep. Med. Chem., 34: 11-20 (1999) are incorporated herein by reference. There appears a need to discover novel small molecule CRF antagonists in order to treat a wide variety of human disorders including depression, anxiety, bipolar disorder, and other stress-related illnesses. See WO 95/10506, WO 95/33750, WO 97/14684, WO 97/35580, WO 98/11075, WO 98/42699, WO 99/01439 and EP 773023.
SUMMARY OF THE INVENTION
Thus according to a first embodiment of the first aspect of the present invention are provided compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof
wherein
X is O, S, NH or N—C
1-6
alkyl;
W and W′ are each H or together are O or S;
Z and Z′ are independently CH or N
 provided that
if Z′ is N, then Z is CH;
if Z is N, then Z′ is CH;
R
1
and R
2
are each the same or different and selected from the group consisting of H, C
1-6
alkyl, C
1-6
haloalkyl, C
1-6
alkoxy, C
3-7
cycloalkyl, C
1-6
alkyl-C
3-7
cycloalkyl, C
2-6
alkenyl, C
3-6
alkynyl, C
1-6
cyanoalkyl, C
1-6
aralkyl, 5 or 6-membered heterocycle and 9 or 10-membered bicyclic fused heterocycle;
 wherein
said C
1-6
aralkyl is optionally substituted with one or more of the same or different halogens or with one or more of the same or different C
1-4
alkoxy groups;
said 5 or 6-membered heterocycle contains one to three of the same or different heteroatoms selected from the group consisting of O, N and S and said 5 or 6-membered heterocycle is optionally substituted with C
1-4
alkyl, C
1-4
thioalkyl, C
1-4
haloalkyl, halo, cyano or —O—C
1-4
alkyl;
 provided that if three of said heteroatoms are contained in said 5-membered heterocycle, said three heteroatoms are not all the same heteroatoms;
said 9 or 10-membered bicyclic fused heterocycle contains one to three of the same or different heteroatoms selected from the group consisting of O, N and S;
R
1
and R
2
together with the nitrogen to which they are attached form a five or six-membered heterocycle,
said heterocycle containing one to three of the same or different heteroatoms selected from the group consisting of N, S or O; and
said heterocycle optionally substituted with one or more C
1-6
alkyl, —C
1-6
alkyl-C
1-6
alkoxy or C
1-6
alkoxy groups;
R
3
is C
1-6
alkyl, C
1-6
haloalkyl, halo, cyano or C
1-6
alkoxy;
R
4
is H or C
1-6
alkyl; and
R
5
, R
6
and R
7
are each the same or different and selected from the group consisting of H, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
thioalkyl, CN, C
1-6
haloalkyl and halo.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein said 5 or 6-membered heterocycle is pyridyl, pryrimidinyl, thienyl, imidazolyl, C
1-3
thioalkyl-subsituted thiadiazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, thiazolyl, oxazolyl or furanyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein said 9 or 10-membered bicyclic fused heterocycle is benzofuranyl, indolyl, benzothiazolyl or benzimidazolyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
1
is not H and R
2
is not H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein the optionally substituted heterocycle formed by R
1
and R
2
together with the nitrogen to which they are attached is selected from the group consisting pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl and thiomorpholinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
1
and R
2
are each the same or different and selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, propenyl, cyclopropylmethyl, butyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, (CH
2
)
2
CF
3
, (CH
2
)
2
OCH
3
, CH
2
CH(CH
2
CH
3
)
2
, CH
2
CH(CH
2
CH
3
)(OCH
3
), CH
2
CH(CH
3
)
2
, CH(CH
3
)(CH
2
CH
3
), CH
2
CCH, CH
2
CN, CH
2
C(CH
2
)(CH
3
), (CH
2
)
2
CN, phenyl, methylphenyl, ethylphenyl, cyclobutylmethyl and propylphenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
5
, R
6
and R
7
are each the same or different and selected from the group consisting of H, Br, Cl, methyl, isopropyl, CF
3
and methoxy.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
4
is H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
4
is CH
3
or CH
2
CH
3
.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein X is S.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein X is O.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
3
is CF
3
.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
3
is methyl, R
4
is H, R
5-7
are each chloro and X is S.
According to another embodiment of the first aspect of the present invention are provided

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