Ring fused pyrazole derivatives as CRF antagonists

Details Ring fused pyrazole derivatives as CRF antagonists Ring fused pyrazole derivatives as CRF antagonists

2002-12-03

2004-11-23

Desai, Rita (Department: 1625)

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

06821984

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to ring fused pyrazole derivatives with CRF activity, and associated pharmaceutical compositions, and methods for use as therapeutic agents.
BACKGROUND OF THE INVENTION
Corticotropin releasing factor (CRF) or hormone (CRH) is one of several neurohormones synthesized by specific hypothalamic nuclei in the brain where it activates the transcription of the pro-opiomelanocortin (POMC) gene resulting in release of adrenocorticotropic hormone (ACTH) and beta-endorphin from anterior pituitary cells (Vale et al,
Science
213, 1394-1397 (1981)). The fundamental role of CRF is to prepare the organism for an appropriate response to various stressors such as physical trauma, insults of the immune system and social interactions. CRF also has CNS effects by acting at higher centers in the brain, particularly cortical regions where there is a widespread distribution of CRF neurons. CRF is believed to be a key intermediary in communication between the immune, central nervous, endocrine and cardiovascular systems (Sapolsky et al,
Science
238, 522-524 (1987)). The role played by CRF in integrating the response of the immune system to physiological, psychological and immunological stressors has been described in the art, e.g. J. E. Blalock, Physiological Reviews 69, 1 (1989) and J. E. Morley,
Life Sci
. 41, 527 (1987).
CRF antagonists are effective in the treatment of a wide range of stress-related illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, bipolar disorder and cyclothymia; chronic fatigue syndrome; eating disorders such as obesity, anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; pain perception such as fibromyalgia; headache; stress-induced gastrointestinal dysfunction such as irritable bowel syndrome (IBS), colonic hypersensitivity or spastic colon; hemorrhagic stress; ulcers; stress-induced psychotic episodes; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; asthma; psoriasis; allergies; premature birth; hypertension; congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimer's disease, senile dementia, Parkinson's disease and Huntington's disease; head or spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; psychosocial dwarfism; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; stress-induced immune dysfunctions; immune suppression and stress-induced infections; cardiovascular or heart related diseases; fertility problems; and/or human immunodeficiency virus infections. Accordingly clinical data suggests that CRF receptor antagonists may represent novel antidepressants and/or anxiolytic drugs that may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF.
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.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula I or Formula II:
wherein:
R
1
is —OR
a
, —NR
a
R
b
, —CR
c
R
d
R
e
, CO
2
R
a
, or —C(O)NR
a
R
b
; or R
1
is hydrogen, halogen, cycloalkenyl, aryl, or heteroaryl, where each aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, C
1-6
alkylsulfonyl, halogen, haloalkyl, cyano, nitro, —C(O)NR
a
′R
b
′, and —NR
a
′R
b
′, where R
a
′ and R
b
′ are each independently selected from the group consisting of hydrogen, C
1-9
alkyl, and C
1-9
alkylcarbonyl;
R
2
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
3-6
cycloalkylalkyl, C
1-6
alkylcarbonyl, C
1-6
alkylsulfonyl, aryl, or arylalkyl, wherein said aryl or arylalkyl is optionally substituted with one or more substituents independently selected from C
1-6
alkyl, haloalkyl, C
1-6
alkoxy, and halogen;
R
3
and R
4
are each independently selected from hydrogen and C
1-6
alkyl, or R
3
and R
4
are taken together with the carbon to which they are attached to form a C
3-6
cycloalkyl ring;
Ar is aryl or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, C
1-6
alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and —NR
a
″R
b
″, where R
a
″ and R
b
″ are each independently selected from the group consisting of hydrogen, C
1-9
alkyl, and C
1-9
alkylcarbonyl;
R
a
and R
b
are each independently selected from the group consisting of hydrogen, C
1-9
alkyl, hydroxyalkyl, C
1-6
alkoxyalkyl, C
1-6
alkylthioalkyl, carboxyalkyl, C
1-6
alkoxycarbonyl, C
1-6
-alkoxy-C
1-3
alkylcarbonyl, acyl, C
3-6
cycloalkyl, C
3-6
cycloalkylalkyl, di-C
3-6
cycloalkylC
1-3
alkyl, C
1-6
heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C
5-8
heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenylalkyl, phenylsulfonyl optionally substituted as described for phenyl below, and C
1-3
alkyl substituted with both a C
3-6
cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C
1-6
alkyl, haloalkyl, C
1-6
alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl; or
R
a
and R
b
are taken together with the nitrogen to which they are attached form an heterocyclyl or heteroaryl ring selected from the group consisting of pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline, pyrrole, pyrazole, and imidazole, where each of said rings is optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl, aminocarbonylamino, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino, and phenyl, wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from C
1-6
alkyl, haloalkyl, C
1-6
alkoxy, amino, alkylamino, dialkylamino, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl, or is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group;
R
c
is hydrogen, hydroxy, C
1-6
alkoxy, or —NR
a
′″R
b
′″;
R
d
and R
e
are each independently selected from the group consisting of hydrogen, C
1-9
alkyl, hydroxyalkyl, C
1-6
alkoxyalkyl, C
1-6
alkylthioalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, C
3-6
cycloalkyl, C
3-6
cycloalkylalkyl, di-C
3-6
cycloalkyl-C
1-3
alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C
1-3
alkyl, and C
1-3
alkyl substituted with both a C
3-6
cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C
1-6
alkyl, haloalkyl, C
1-6
alkoxy, amino, alkylamino, dialkylamino, and halogen; or
R
c
and R
d
are taken together to form a divalent group selected from C
1-6
alkylidenyl, C
1-6
heteroalkylidenyl, C
3-6
cycloalkylidenyl,

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