U.S. patent application number 11/424073 was filed with the patent office on 2006-09-28 for substituted pyrimidine derivatives.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Jeffrey Wayne Corbett, Micheal Dalton Ennis, Kristine E. Frank, Jian-Min Fu, Robert Louis Hoffman, Patrick R. Verhoest.
Application Number | 20060217398 11/424073 |
Document ID | / |
Family ID | 33435238 |
Filed Date | 2006-09-28 |
United States Patent
Application |
20060217398 |
Kind Code |
A1 |
Corbett; Jeffrey Wayne ; et
al. |
September 28, 2006 |
SUBSTITUTED PYRIMIDINE DERIVATIVES
Abstract
This invention relates to compounds of Formula I, ##STR1## a
stereoisomer thereof, a pharmaceutically acceptable salt thereof, a
prodrug thereof, or a pharmaceutically acceptable salt of a prodrug
thereof. The compounds interact with CRF.sub.1 receptors, including
human CRF.sub.1 receptors. This invention also relates to methods
of using the compounds of the invention to treat a disorder or
condition, the treatment of which can be effected or facilitated by
antagonizing a CRF receptor, such as CNS disorders or diseases,
particularly anxiety-related disorders such as anxiety, and mood
disorders such as major depression.
Inventors: |
Corbett; Jeffrey Wayne;
(Niantic, CT) ; Ennis; Micheal Dalton;
(Chesterfield, MO) ; Frank; Kristine E.;
(Worcester, MA) ; Fu; Jian-Min; (Burnaby, CA)
; Hoffman; Robert Louis; (San Marcos, CA) ;
Verhoest; Patrick R.; (Old Lyme, CT) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
33435238 |
Appl. No.: |
11/424073 |
Filed: |
June 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10839055 |
May 5, 2004 |
7087617 |
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11424073 |
Jun 14, 2006 |
|
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60469487 |
May 9, 2003 |
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Current U.S.
Class: |
514/256 ;
514/340; 544/333; 546/268.1 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 25/34 20180101; A61P 29/00 20180101; A61P 3/08 20180101; A61P
25/30 20180101; A61P 9/00 20180101; A61P 13/06 20180101; A61P 25/08
20180101; A61P 25/28 20180101; A61P 37/06 20180101; C07D 239/42
20130101; A61P 25/04 20180101; A61P 5/14 20180101; A61P 25/06
20180101; A61P 25/22 20180101; A61P 25/02 20180101; A61P 17/00
20180101; A61P 7/04 20180101; A61P 35/00 20180101; A61P 25/00
20180101; C07D 213/72 20130101; A61P 43/00 20180101; A61P 1/00
20180101; A61P 25/18 20180101; A61P 11/06 20180101; A61P 37/04
20180101; A61P 17/14 20180101; A61P 17/06 20180101; A61P 3/00
20180101; A61P 1/14 20180101; A61P 31/18 20180101; A61P 21/00
20180101; A61P 25/20 20180101; A61P 25/24 20180101 |
Class at
Publication: |
514/256 ;
544/333; 514/340; 546/268.1 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 31/4439 20060101 A61K031/4439 |
Claims
1-3. (canceled)
4. A method of inhibiting the binding of CRF to the CRF.sub.1
receptor in vitro, the method comprising contacting, in the
presence of CRF, a solution comprising a compound of Formula I,
##STR13## a stereoisomer thereof, a pharmaceutically acceptable
salt thereof, a prodrug thereof form free hydroxyl, amino or
sulfhydry groups are bonded to any group that cleave to form free
hydroxyl, amino or sulfhydryl group respectively, or a
pharmaceutically acceptable salt of a prodrug thereof, wherein: X
is selected from --NR.sub.3R.sub.4, --OR.sub.3,
--CR.sub.3R.sub.5R.sub.5, --C(O)R.sub.3, --S(O).sub.mR.sub.3,
--NR.sub.3C(O)R.sub.4, or --NR.sub.3S(O).sub.mR.sub.4; m is 0, 1 or
2; G is selected from N or C(R.sub.2); R.sub.1 and R.sub.2 are
independently selected from --H, --NH(alkyl),
--N(alkyl).sub.2--NH(substituted alkyl), --N(substituted
alkyl).sub.2, --O(alkyl), --O(substituted alkyl), halogen, alkyl,
substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl,
aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted
heterocycloalkyl, substituted heteroaryl, --CR.sub.5R.sub.5Ar,
--OAr, --S(O).sub.mAr, --NR.sub.5Ar, --S(O).sub.malkyl,
--S(O).sub.msubstituted alkyl, --CN, --NO.sub.2, --OH, --NH.sub.2,
--SH, --C(O)NR.sub.4R.sub.5 and --C(S)NR.sub.4R.sub.5; R.sub.3 and
R.sub.4 are independently selected from heteroaryl, substituted
heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl,
heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl
heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl
heterocycloalkyl, substituted heteroaryl heterocycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, provided when
both R.sub.3 and R.sub.4 are present one of the R.sub.3 or R.sub.4
selected from a group provided herein above and the other R.sub.3
or R.sub.4 is selected from --H, alkyl, substituted alkyl,
haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,
heterocycloalkyl, substituted heterocycloalkyl, substituted
heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl,
heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl,
heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl
heterocycloalkyl, or substituted heteroaryl heterocycloalkyl; Ar is
selected from aryl, substituted aryl, heteroaryl, and substituted
heteroaryl; and R.sub.5 each is independently selected from --H,
alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted
with 1-3 substituents selected from halogen, --O(alkyl),
--NH(alkyl), --N(alkyl).sub.2, --CO(O)NH(alkyl),
--C(O)N(alkyl).sub.2, --NHC(O)alkyl, --N(alkyl)C(O)alkyl, and
--S(O).sub.malkyl, heterocycloalkyl, substituted heterocycloalkyl
and Ar, with cells expressing the CRF.sub.1 receptor, wherein the
compound is present in the solution at a concentration sufficient
to reduce levels of CRF binding to the cells in vitro.
5. A method of antagonizing a CRF.sub.1 receptor in a mammal,
comprising administering to the mammal, a therapeutically effective
amount of a compound of Formula I, ##STR14## a stereoisomer
thereof, a pharmaceutically acceptable salt thereof, a prodrug
thereof wherein hydroxyl, amine or sulfhydry groups are bonded to
any group that cleaves to form free hydroxyl, amino or sulfhydry
groups respectively, or a pharmaceutically acceptable salt of a
prodrug thereof, wherein: X is selected from --NR.sub.3R.sub.4,
--OR.sub.3, --CR.sub.3R.sub.5R.sub.5, --C(O)R.sub.3,
--S(O).sub.mR.sub.3, --NR.sub.3C(O)R.sub.4, or
--NR.sub.3S(O).sub.mR.sub.4; m is 0, 1 or 2; G is selected from N
or C(R.sub.2); R.sub.1 and R.sub.2 are independently selected from
--H, --NH(alkyl), --N(alkyl).sub.2, --NH(substituted alkyl),
--N(substituted alkyl).sub.2, --O(alkyl), --O(substituted alkyl),
halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl,
substituted cycloalkyl, aryl, heteroaryl, substituted aryl,
heterocycloalkyl, substituted heterocycloalkyl, substituted
heteroaryl, --CR.sub.5R.sub.5Ar, --OAr, --S(O).sub.mAr,
--NR.sub.5Ar, --S(O).sub.malkyl, --S(O).sub.msubstituted alkyl,
--CN, --NO.sub.2, --OH, --NH.sub.2, --SH, --C(O).sub.mAr,
--NR.sub.5 and --C(S)NR.sub.4R.sub.5; R.sub.3 and R.sub.4 are
independently selected from heteroaryl, substituted heteroaryl,
aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl
cycloalkyl, substituted heteroaryl cycloalkyl, aryl
heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl
heterocycloalkyl, substituted heteroaryl, heterocycloalkyl,
heterocycloalkyl or substituted heterocycloalkyl, provided when
both R.sub.3 and R.sub.4 are present one of the R.sub.3 or R.sub.4
is selected from a group provided herein above and the other
R.sub.3 or R.sub.4 is selected from --H, alkyl, substituted alkyl,
haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,
heterocycloalkyl, substituted heterocycloalkyl, substituted
heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl,
heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl
heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl
heterocycloalkyl, or substituted heteroaryl heterocycloalkyl; Ar is
selected from aryl, substituted aryl, heteroaryl, and substituted
heteroaryl; and R.sub.5 each is independently selected from --H,
alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted
with 1-3 substituents selected from halogen, --O(alkyl),
--NH(alkyl), --N(alkyl).sub.2, --C(O)NH(alkyl),
--C(O)N(alkyl).sub.2, --NHC(O)alkyl, --N(alkyl) C(O)alkyl, and
--S(O).sub.malkyl, heterocycloalkyl, substituted heterocycloalkyl
and Ar.
6. A method for screening for ligands for CRF.sub.1 receptors,
which method comprises: a) carrying out a competitive binding assay
with a CRF.sub.1 receptor, a compound of Formula I, ##STR15## a
stereoisomer thereof, a pharmaceutically acceptable salt thereof, a
prodrug thereof wherein hydroxyl, amine or sulfhydry groups are
bonded to any group that cleaves to form free hydroxyl, amino or
sulfhydryl group respectively, or a pharmaceutically acceptable
salt of prodrug thereof, wherein: X is selected from
--NR.sub.3R.sub.4, --OR.sub.3, --CR.sub.3R.sub.5R.sub.5,
--C(O)R.sub.3, --S(O).sub.mR.sub.3, --NR.sub.3C(O)R.sub.4, or
--NR.sub.3S(O).sub.mR.sub.4; m is 0, 1 or 2; G is selected from N
or C(R.sub.2); R.sub.1 and R.sub.2 are independently selected from
--H, --NH(alkyl), --N(alkyl).sub.2, --NH(substituted alkyl),
--N(substituted alkyl).sub.2, --O(alkyl), --O(substituted alkyl),
halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl,
substituted cycloalkyl, aryl, heteroaryl, substituted aryl,
heterocycloalkyl, substituted heterocycloalkyl, substituted
heteroalkyl, --CR.sub.5R.sub.5Ar, --OAr, --S(O).sub.mAr,
--NR.sub.5Ar, --S(O).sub.malkyl, --S(O).sub.msubstituted alkyl,
--CN, --NO.sub.2, --OH, --NH.sub.2, --SH, --C(O)NR.sub.4R.sub.5 and
--C(S)NR.sub.4R.sub.5; R.sub.3 and R.sub.4 are independently
selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl,
substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted
heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl
heterocycloalkyl, heteroaryl heterocycloalkyl, substituted
heteroaryl heterocycloalkyl, heterocycloalkyl or substituted
heterocycloalkyl, provided when both R.sub.3 and R.sub.4 are
present one of the R.sub.3 or R.sub.4 is selected from a group
provided herein above and the other R.sub.3 or R.sub.4 is selected
from --H, alkyl, substituted alkyl, haloalkyl, cycloalkyl,
substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl,
substituted heterocycloalkyl, substituted heteroaryl, aryl
cycloalkyl, substituted aryl, cycloalkyl, heteroaryl, cycloalkyl,
substituted heteroaryl cycloalkyl, aryl heterocycloalkyl,
substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or
substituted heteroaryl heterocycloalkyl; Ar is selected from aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; and
R.sub.5 each is independently selected from --H, alkyl, cycloalkyl,
and haloalkyl, wherein alkyl may be substituted with 1-3
substituents selected from halogen, --O(alkyl), --NH(alkyl),
--N(alkyl).sub.2, --C(O)NH(alkyl), --C(O)N(alkyl).sub.2,
--NHC(O)alkyl, --N(alkyl)C(O)alkyl, and --S(O).sub.malkyl,
heterocycloalkyl, substituted heterocycloalkyl and Ar, which is
labeled with a detectable label, and a candidate ligand; and b)
determining the ability of said candidate ligand to displace said
labeled compound.
7. A method of treating a disorder in a mammal the treatment of
which disorder can be effected or facilitated by antagonizing
CRF.
8. The method according to claim 7 wherein the disorder manifests
hypersecretion of CRF.
9. The method according to claim 8 wherein the mammal is a human
and the disorder is selected from anxiety-related disorders; mood
disorders, post-traumatic stress disorder; supranuclear palsy;
immune suppression; drug or alcohol withdrawal symptoms;
inflammatory disorders; pain; asthma; psoriasis and allergies;
phobias; sleep disorders induced by stress; fibromyalgia;
dysthemia; bipolar disorders; cyclothymia; fatigue syndrome;
stress-induced headache; cancer; human immunodeficiency virus
infections; neurodegenerative diseases; gastrointestinal diseases;
eating disorders; hemorrhagic stress; stress-induced psychotic
episodes; euthyroid sick syndrome; syndrome of inappropriate
antidiarrhetic hormone; obesity; infertility; head traumas; spinal
cord trauma; ischemic neuronal damage; excitotoxic neuronal damage;
epilepsy; cardiovascular and heart related disorders; immune
dysfunctions; muscular spasms urinary incontinence; senile dementia
of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral
sclerosis; chemical dependencies and addictions; psychosocial
dwarfism, hypoglycemia, and skin disorders; and hair loss.
10. The method according to claim 9 wherein the disorder is
selected from anxiety-related disorders; mood disorders; bipolar
disorders; post-traumatic stress disorder; inflammatory disorders;
chemical dependencies and addictions; gastrointestinal disorders;
and skin disorders.
11. The method according to claim 10 wherein the disorder is
selected from anxiety-related disorders or mood disorders and
wherein the anxiety-related disorder is generalized anxiety and
wherein the mood disorder is depression.
12. A method of promoting hair growth in a human, comprising
administering to the human in need thereof an effective amount of a
compound of Formula I, ##STR16## a stereoisomer thereof, a
pharmaceutically acceptable salt thereof, a prodrug thereof wherein
hydroxyl, amine or sulfylhydry groups are bonded to any group that
cleaves to form free hydroxyl, amino or sulfhydryl group
respectively, or a pharmaceutically acceptable salt of a prodrug
thereof, wherein; X is selected from --NR.sub.3R.sub.4, --OR.sub.3,
--CR.sub.3R.sub.5R.sub.5, --C(O)R.sub.3, --S(O).sub.mR.sub.3,
--NR.sub.3C(O)R.sub.4, or --NR.sub.3S(O).sub.mR.sub.4; m is 0, 1 or
2; G is selected from N or C(R.sub.2); R.sub.1 and R.sub.2 are
independently selected from --H, --NH(alkyl), --N(alkyl).sub.2,
--NH(substituted alkyl), --N(substituted alkyl).sub.2, --O(alkyl),
--O(substituted alkyl), halogen, alkyl, substituted alkyl,
haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,
substituted aryl, heterocycloalkyl, substituted heterocycloalkyl,
substituted heteroaryl, --CR.sub.5R.sub.5Ar, --OAr, --S(O).sub.mAr,
--NR.sub.5Ar, --S(O).sub.malkyl, --S(O).sub.msubstituted alkyl,
--CN, --NO.sub.2, --OH, --NH.sub.2, --SH, --C(O)NR.sub.4R.sub.5 and
--C(S)NR.sub.4R.sub.5; R.sub.3 and R.sub.4 are independently
selected from heteroaryl substituted heteroaryl, aryl cycloalkyl,
substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted
heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl
heterocycloalkyl, heteroaryl heterocycloalkyl, substituted
heteroaryl heterocycloalkyl, heterocycloalkyl or substituted
heterocycloalkyl, provided when both R.sub.3 and R.sub.4 are
present one of the R.sub.3 or R.sub.4 is elected from a group
provided herein above and the other R.sub.3 or R.sub.4 is selected
from --H, alkyl, substituted, alkyl, haloalkyl, cycloalkyl,
substituted, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,
substituted heterocycloalkyl, substituted heteroaryl, aryl
cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl,
substituted heteroaryl cycloalkyl, aryl heterocycloalkyl,
substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or
substituted heteroaryl heterocycloalkyl; Ar is selected from aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; and
R.sub.5 each is independently selected from --H, alkyl, cycloalkyl,
and haloalkyl wherein alkyl may be substituted with 1-3
substituents selected from halogen, --O(alkyl), --NH(alkyl),
--N(alkyl).sub.2, --CO(O)NH(alkyl), --C(O)N(alkyl).sub.2,
--NHC(O)alkyl, --N(alkyl)C(O)alkyl, and --S(O).sub.malkyl,
heterocycloalkyl, substituted heterocycloalkyl Ar.
13. A method of promoting smoking cessation in a human, comprising
administering to the human in need thereof an effective amount of a
compound of Formula I, ##STR17## a stereoisomer thereof, a
pharmaceutically acceptable salt thereof, a prodrug thereof wherein
hydroxyl, amine or sulfylhydry groups are bonded to any group that
cleaves to form free hydroxyl, amino or sulfhydryl group
respectively, or a pharmaceutically acceptable salt of a prodrug
thereof, wherein: X is selected from --NR.sub.3R.sub.4, --OR.sub.3,
--CR.sub.3R.sub.5R.sub.5, --C(O)R.sub.4, --S(O).sub.mR.sub.3,
--NR.sub.3C(O)R.sub.4, or --NR.sub.3S(O).sub.mR.sub.4; m is 0, 1 or
2; G is elected from N or C(R.sub.2); R.sub.1 and R.sub.2 are
independently selected from --H, --NH(alkyl), --N(alkyl).sub.2,
--NH(substituted alkyl), --N(substituted alkyl).sub.2, --O(alkyl),
--O(substituted alkyl), halogen, alkyl, substituted alkyl,
haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,
substituted aryl, heterocycloalkyl, substituted heterocycloalkyl,
substituted heteroaryl, --CR.sub.5R.sub.5Ar, --OAr, --S(O).sub.mAr,
--NR.sub.5Ar, --S(O).sub.malkyl, --S(O).sub.msubstituted alkyl,
--CN, --NO.sub.2, --NH.sub.2, --SH, --C(O)NR.sub.4R.sub.5 and
--C(S)NR.sub.4R.sub.5; R.sub.3 and R.sub.4 are independently
selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl,
substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted
heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl
heterocycloalkyl, heteroaryl heterocycloalkyl, substituted
heteroaryl heterocycloalkyl, heterocycloalkyl or substituted
heterocycloalkyl, provided when both R.sub.3 and R.sub.4 are
present one of the R.sub.3 or R.sub.4 is selected from a group
provided herein above and the other R.sub.3 or R.sub.4 is selected
from --H, alkyl, substituted alkyl, haloalkyl, cycloakyl,
substituted cycloalkyl, aryl, heteroaryl heterocycloalkyl,
substituted heterocycloalkyl, substituted heteroaryl cycloalkyl,
substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted
heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl
heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted
heteroaryl heterocycloalkyl; Ar is selected from aryl, substituted
aryl, heteroaryl, and substituted heteroaryl; and R.sub.5 each is
independently selected from --H, alkyl, cycloalkyl, and haloalkyl,
wherein alkyl may be substituted with 1-3 substituents selected
from halogen, --O(alkyl), --NH(alkyl), --N(alkyl).sub.2,
--C(O)NH(alkyl), --C(O)N(alkyl).sub.2, --NHC(O)alkyl,
--N(alkyl)C(O)alkyl, and --S(O).sub.malkyl, heterocycloalkyl,
substituted heterocycloalkyl and Ar.
14. (canceled)
15. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates generally to compounds that
bind to CRF receptors, and particularly to substituted pyrimidine
derivatives derivatives as CRF.sub.1 receptor antagonists and to
the use thereof as a treatment for disorders that are associated
with CRF or CRF.sub.1 receptors.
BACKGROUND OF THE INVENTION
[0002] Corticotropin releasing factor (CRF) is a 41 amino acid
peptide that is the primary physiological regulator of
proopiomelanocortin (POMC) derived peptide secretion from the
anterior pituitary gland [J. Rivier et al., Proc. Natl. Acad. Sci
(USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In
addition to its endocrine role at the pituitary gland, CRF is known
to have a broad extrahypothalmic distribution in the CNS,
contributing therein to a wide spectrum of autonomic behavioral and
physiological effects consistent with a neurotransmitter or
neuromodulator role in the brain [W. Vale et al., Rec. Prog. Horm.
Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E.
B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is evidence
that CRF plays a significant role in integrating the response in
the immune system to physiological, psychological, and
immunological stressors, in psychiatric disorders and neurological
diseases including depression, anxiety-related disorders and
feeding disorders, and in the etiology and pathophysiology of
Alzheimer's disease, Parkinson's disease, Huntington's disease,
progressive supranuclear palsy and amyotrophic lateral sclerosis,
as they relate to the dysfunction of CRF neurons in the central
nervous system [J. E. Blalock, Physiological Reviews 69: 1 (1989);
J. E. Morley, Life Sci. 41:527 (1987); E. B. De Souze, Hosp.
Practice 23:59 (1988)].
[0003] There is evidence that CRF plays a role in mood disorders.
Mood disorders, also known as affective disorders, are well
recognized in the art and include depression, including major
depression, single episode depression, recurrent depression, child
abuse induced depression, and postpartum depression; dysthemia;
bipolar disorders; and cyclothymia. It was shown that in
individuals afflicted with affective disorder, or major depression,
the concentration of CRF in the cerebral spinal fluid (CSF) is
significantly increased. [C. B. Nemeroff et al., Science 226:1342
(1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D.
France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al.,
Biol. Psychiatry 25:355 (1989)]. Furthermore, the density of CRF
receptors is significantly decreased in the frontal cortex of
suicide victims, consistent with a hypersecretion of CRF [C. B.
Memeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition,
there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v.
administered) observed in depressed patients [P. W. Gold et al.,
Am. J. Psychiatry 141:619 (1984); F. Holsboer et al.,
Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Engl.
J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human
primates provide additional support for the hypothesis that
hypersecretion of CRF may be involved in the symptoms seen in human
depression [R. M. Sapoisky, Arch. Gen. Psychiatry 46:1047 (1989)].
There is also preliminary evidence that tricyclic antidepressants
can alter CRF levels and thus modulate the numbers of receptors in
the brain [Grigoriadis et al., Neuropsychopharmacology 2:53
(1989)].
[0004] CRF has also been implicated in the etiology of
anxiety-related disorders. Anxiety disorders are a group of
diseases, recognized in the art, that includes phobic disorders,
anxiety states, post-traumatic stress disorder, generalized anxiety
disorder, social anxiety disorder, anxiety with co-morbid
depressive illness, panic disorder, obsessive-compulsive disorder,
and atypical anxiety disorders [The Merck Manual of Diagnosis and
Therapy, 16.sup.th edition (1992)]. Emotional stress is often a
precipitating factor in anxiety disorders, and such disorders
generally respond to medications that lower response to stress.
Excessive levels of CRF are known to produce anxiogenic effects in
animal models [see, e.g., Britton et al., 1982; Berridge and Dunn,
1986 and 1987]. Interactions between
benzodiazepine/non-benzodiazepine anxiolytics and CRF have been
demonstrated in a variety of behavioral anxiety models [D. R.
Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.
Dunn, Regul. Peptides 16:83 (1986)]. Studies using the putative CRF
receptor antagonist .alpha.-helical ovine CRF (9-41) in a variety
of behavioral paradigms demonstrates that the antagonist produces
"anxiolytic-like" effects that are qualitatively similar to the
benzodiazepines [C. W. Berridge and A. J. Dunn, Horm. Behav. 21:393
(1987), Brain Research Reviews 15:71 (1990); G. F. Koob and K. T.
Britton, In: Corticotropin-Releasing Factor: Basic and Clinical
Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds.,
CRC Press p. 221 (1990)]. Neurochemical, endocrine and receptor
binding studies have all demonstrated interactions between CRF and
benzodiazepine anxiolytics, providing further evidence for the
involvement of CRF in these disorders. Chlordiazepoxide attenuates
the "anxiogenic" effects of CRF both in the conflict test [K. T.
Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et
al., Psychopharmacology 94:306 (1988)] and in the acoustic startle
test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in
rats. The benzodiazepine receptor antagonist Ro 15-1788, which was
without behavioral activity alone in the operant conflict test,
reversed the effects of CRF in a dose-dependent manner while the
benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF
[K. T. Britton et al., Psychopharmacology 94:396 (1988)].
[0005] Use of CRF.sub.1 antagonists to treat of Syndrome X has also
been described in EP 1097709A2.
[0006] Use of CRF.sub.1 antagonists to treat congestive heart
failure is described in U.S. Pat. No. 6,043,260.
[0007] It has also been suggested that CRF.sub.1 antagonists are
useful for treating arthritis and inflammation disorders [E. L.
Webster et al., J. Rheumatol 29:1252 (2002); E. P. Murphy et al.,
Arthritis Rheum 44:782 (2001)]; stress-related gastrointestinal
disorders [K. E. Gabry et al., Molecular Psychiatry 7:474 (2002)];
and skin disorders [C. C. Zouboulis et al., Proc. Natl. Acad. Sci.
99:7148 (2002)].
[0008] It was disclosed recently that, in an animal model,
stress-induced exacerbation of chronic contact dermatitis is
blocked by a selective CRF.sub.1 antagonist, suggesting that
CRF.sub.1 is involved in the stress-induced exacerbation of chronic
contact dermatitis and that CRF.sub.1 antagonist may be useful for
treating this disorder [K. Kaneko et al., Exp Dermatol. 12:47
(2003)].
[0009] WO 01/60806 discloses aryl piperazines compounds that can
bind with high affinity and high selectivity to CRF.sub.1
receptors.
[0010] It is an object of the invention to provide novel
substituted pyrimidine derivative compounds.
[0011] It is another object of the invention to provide novel
substituted pyrimidine derivatives that are useful as CRF.sub.1
receptor antagonists.
[0012] It is another object of the invention to provide novel
substituted pyrimidine compounds as treatment of disorders or
conditions that are associated with CRF or CRF.sub.1 receptors,
such as anxiety disorders, depression, and stress related
disorders.
[0013] It is another object of the invention to provide a method of
treating disorders or conditions that are associated with CRF or
CRF.sub.1 receptors, such as anxiety-related disorders, mood
disorders, and stress related disorders.
[0014] It is yet another object of the invention to provide a
pharmaceutical composition useful for treating disorders or
conditions that are associated with CRF or CRF.sub.1 receptors,
such as anxiety-related disorders, mood disorders, and stress
related disorders.
[0015] There are other objects of the invention which will be
evident or apparent from the description of the invention in the
specification of the application.
SUMMARY OF THE INVENTION
[0016] The present invention provides a compound of Formula I,
##STR2## a stereoisomer thereof, a pharmaceutically acceptable salt
thereof, a prodrug thereof, or a pharmaceutically acceptable salt
of a prodrug thereof, wherein:
[0017] X is selected from --NR.sub.3R.sub.4, --OR.sub.3,
--CR.sub.3R.sub.5R.sub.5, --C(O)R.sub.3, --S(O).sub.mR.sub.3,
--NR.sub.3C(O)R.sub.4, or --NR.sub.2S(O).sub.mR.sub.4;
[0018] m is 0, 1 or 2;
[0019] G is selected from N or C(R.sub.2);
[0020] R.sub.1 and R.sub.2 are independently selected from --H,
--NH(alkyl), --N(alkyl).sub.2, --NH(substituted alkyl),
--N(substituted alkyl).sub.2, --O(alkyl), --O(substituted alkyl),
halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl,
substituted cycloalkyl, aryl, heteroaryl, substituted aryl,
heterocycloalkyl, substituted heterocycloalkyl, substituted
heteroaryl, --CR.sub.5R.sub.5Ar, --OAr, --S(O).sub.mAr,
--NR.sub.5Ar, --S(O).sub.malkyl, --S(O).sub.msubstituted alkyl,
--CN, --NO.sub.2, --OH, --NH.sub.2, --SH, --C(O)NR.sub.4R.sub.5 and
--C(S)NR.sub.4R.sub.5;
[0021] R.sub.3 and R.sub.4 are independently selected from
heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted
aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl
cycloalkyl, aryl heterocycloalkyl, substituted aryl
heterocycloalkyl, heteroaryl heterocycloalkyl, substituted
heteroaryl heterocycloalkyl, heterocycloalkyl or substituted
heterocycloalkyl, provided when both R.sub.3 and R.sub.4 are
present one of the R.sub.3 or R.sub.4 is selected from a group
provided herein above and the other R.sub.3 or R.sub.4 is selected
from --H, alkyl, substituted alkyl, haloalkyl, cycloalkyl,
substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl,
substituted heterocycloalkyl, substituted heteroaryl, aryl
cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl,
substituted heteroaryl cycloalkyl, aryl heterocycloalkyl,
substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or
substituted heteroaryl heterocycloalkyl. Ar is selected from aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; and
[0022] R.sub.5 each is independently selected from --H, alkyl,
cycloalkyl, and haloalkyl, wherein alkyl may be substituted with
1-3 substituents selected from halogen, --O(alkyl), --NH(alkyl),
--N(alkyl).sub.2, --C(O)NH(alkyl), --C(O)N(alkyl).sub.2,
--NHC(O)alkyl, --N(alkyl)C(O)alkyl, and --S(O).sub.malkyl,
heterocycloalkyl, substituted heterocycloalkyl and Ar.
[0023] In another aspect, the present invention provides a
pharmaceutical composition comprising a compound of Formula I, a
stereoisomer thereof, a pharmaceutically acceptable salt thereof, a
prodrug thereof, or a pharmaceutically acceptable salt of a prodrug
thereof. The compositions can be prepared in any suitable forms
such as tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols, and
ointments.
[0024] The compounds of the inventions are CRF.sub.1 receptor
antagonists. Thus, in another aspect, the present invention
provides a method of antagonizing CRF.sub.1 receptors in a
warm-blooded animal, comprising administering to the animal a
compound of the invention at amount effective to antagonize
CRF.sub.1 receptors.
[0025] In still another aspect, the present invention provides a
method for screening for ligands for CRF.sub.1 receptors, which
method comprises: a) carrying out a competitive binding assay with
CRF.sub.1 receptors, a compound of Formula I which is labeled with
a detectable label, and a candidate ligand; and b) determining the
ability of said candidate ligand to displace said labeled
compound.
[0026] In still another aspect, the present invention provides a
method for detecting CRF.sub.1 receptors in a tissue comprising: a)
contacting a compound of Formula I, which is labeled with a
detectable label, with a tissue, under conditions that permit
binding of the compound to the tissue; and b) detecting the labeled
compound bound to the tissue.
[0027] In yet another aspect, the present invention provides a
method of inhibiting the binding of CRF to CRF.sub.1 receptors in
vitro, comprising contacting a compound of the invention with a
solution comprising cells expressing the CRF.sub.1 receptor, such
as IMR32 cells, wherein the compound is present in the solution at
a concentration sufficient to inhibit the binding of CRF to the
CRF.sub.1 receptor.
[0028] Compounds of the invention are useful for treating, in a
warm-blooded animal, particularly a mammal, and more particularly a
human, various disorders that are associated with CRF or CRF.sub.1
receptors, or disorders the treatment of which can be effected or
facilitated by antagonizing CRF.sub.1 receptors. Examples of such
disorders include anxiety-related disorders (such as anxiety
states, generalized anxiety disorder, social anxiety disorder,
anxiety with co-morbid depressive illness, panic disorder, and
obsessive-compulsive disorder phobic disorders, post-traumatic
stress disorder, and atypical anxiety disorders); mood disorders,
also known as affective disorders (such as depression, including
major depression, single episode depression, recurrent depression,
child abuse induced depression, and postpartum depression;
dysthemia; bipolar disorders; and cyclothymia); post-traumatic
stress disorder; supranuclear palsy; immune suppression; drug or
alcohol withdrawal symptoms; substance abuse disorder (e.g.,
nicotine, cocaine, ethanol, opiates, or other drugs); inflammatory
disorders (such as rheumatoid arthritis and osteoarthritis);
fertility problems including infertility; pain; asthma; psoriasis
and allergies; phobias; sleep disorders induced by stress; pain
perception (such as fibromyalgia), dysthemia; bipolar disorders;
cyclothymia; fatigue syndrome; stress-induced headache; cancer;
human immunodeficiency virus (HIV) infections; neurodegenerative
diseases (such as Alzheimer's disease, Parkinson's disease and
Huntington's disease), gastrointestinal diseases (such as ulcers,
irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea,
and post operative ilius and colonic hypersensitivity associated by
psychopathological disturbances or stress); eating disorders (such
as anorexia and bulimia nervosa and other feeding disorders);
hemorrhagic stress; stress-induced psychotic episodes; euthyroid
sick syndrome; syndrome of inappropriate antidiarrhetic hormone
(ADH); obesity; head traumas; spinal cord trauma; ischemic neuronal
damage (e.g., cerebral ischemia such as cerebral hippocampal
ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular
and heart related disorders (such as hypertension, tachycardia and
congestive heart failure); stroke; immune dysfunctions including
stress induced immune dysfunctions (e.g., stress induced fevers,
porcine stress syndrome, bovine shipping fever, equine paroxysmal
fibrillation, and dysfunctions induced by confinement in chickens,
sheering stress in sheep or human-animal interaction related stress
in dogs); muscular spasms; urinary incontinence; senile dementia of
the Alzheimer's type; multiinfarct dementia; amyotrophic lateral
sclerosis, chemical dependencies and addictions (e.g., dependences
on alcohol, cocaine, heroin, benzodiazepines, or other drugs);
osteoporosis; psychosocial dwarfism, hypoglycemia, and skin
disorders (such as acne, psoriasis, chronic contact dermatitis, and
stress-exacerbated skin disorders). They are also useful for
promoting smoking cessation and hair growth, or treating hair
loss.
[0029] Thus, in yet a further aspect the present invention provides
a method of treating a disorder, in warm-blooded animal, the
treatment of which disorder can be effected or facilitated by
antagonizing CRF.sub.1 receptors, which method comprises
administration to a patient in need thereof an effective amount of
a compound of Formula I. In a particular embodiment the invention
provides a method of treating disorders that manifest
hypersecretion of CRF. Examples of disorders that can be treated
with the compounds of the invention include generalized anxiety
disorder; social anxiety disorder; anxiety; obsessive-compulsive
disorder; anxiety with co-morbid depressive illness; panic
disorder; and mood disorders such as depression, including major
depression, single episode depression, recurrent depression, child
abuse induced depression, postpartum depression, hair loss, and
contact dermatitis. It is preferred that the warm-blooded animal is
a mammal, and more preferred that the animal is a human.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention provides a compound of Formula I
described above.
[0031] Particularly preferred compounds of general Formula I are
those where X is --NR3R4.
[0032] Other preferred compounds of the invention are those of
general Formula I where X is --NR.sub.3R.sub.4 and one of R.sub.3
or R.sub.4 is aryl cycloalkyl or heteroaryl cycloalkyl.
[0033] Other preferred compounds of the invention are those of
general Formula I where X is --NR.sub.3R.sub.4 and one of R.sub.3
or R.sub.4 is aryl cycloalkyl or heteroaryl cycloalkyl and the
point of attachment is the cycloalkyl ring.
[0034] Other preferred compounds of the invention are those of
general Formula I where X is --NR.sub.3R.sub.4 and one of R.sub.3
or R.sub.4 is aryl cycloalkyl or heteroaryl cycloalkyl and the
point of attachment is the cycloalkyl ring and one of R.sub.3 or
R.sub.4 is hydrogen.
[0035] Other preferred compounds of the invention are those of
general Formula I where X is --R.sub.3R.sub.4 and one of R.sub.3 or
R.sub.4 is substituted aryl cycloalkyl or substituted heteroaryl
cycloalkyl and the point of attachment is the cycloalkyl ring and
one of R3 or R4 is hydrogen.
[0036] Other preferred compounds of the invention are those of
general Formula I where X is --NR.sub.3R.sub.4 and one of R.sub.3
or R.sub.4 is substituted aryl cycloalkyl or substituted heteroaryl
cycloalkyl where the substituent is either alkyl or alkoxy and is
on the cycloalkyl ring and the point of attachment is the
cycloalkyl ring and one of R.sub.3 or R.sub.4 is hydrogen.
[0037] Other preferred compounds of the invention are those of
general Formula I where X is --NR.sub.3R.sub.4 and one of R.sub.3
or R.sub.4 is substituted aryl cycloalkyl or substituted heteroaryl
cycloalkyl where the substituent is either alkyl or alkoxy and is
on the cycloalkyl ring and the absolute stereochemistry of these
ring substituents are either (R,R), (R,S), (S,R), or (S,S) and the
point of attachment is the cycloakyl ring and one of R.sub.3 or
R.sub.4 is hydrogen.
[0038] Particularly preferred compounds of the invention are those
of general Formula I where X is --NR.sub.3R.sub.4 and R.sub.3 is
2-substituted-1-indanyl and R.sub.4 is hydrogen.
[0039] Other particularly preferred compounds of the invention are
those of general Formula I where X is --NR.sub.3R.sub.4 and R.sub.3
is 2-alkoxy-1-indanyl and R.sub.4 is hydrogen.
[0040] Other particularly preferred compounds of the invention are
those of general Formula I where X is --NR.sub.3R.sub.4 and R.sub.3
is 2(S)-alkoxy-1(R)-indanyl and R.sub.4 is hydrogen.
[0041] Compounds provided herein can have one or more asymmetric
centers or planes, and all chiral (enantiomeric and diastereomeric)
and racemic forms of the compound are included in the present
invention. Many geometric isomers of olefins, C.dbd.N double bonds,
and the like can also be present in the compounds, and all such
stable isomers are contemplated in the present invention. Compounds
of the invention are isolated in either the racemic form, or in the
optically pure form, for example, by resolution of the racemic form
by conventional methods such as crystallization in the presence of
a resolving agent, or chromatography, using, for example, a chiral
HPLC column, or synthesized by a asymmetric synthesis route
enabling the preparation of enantiomerically enriched material. The
present invention encompasses all possible tautomers of the
compounds represented by Formula I.
[0042] The compounds of the present invention can be synthesized
using the methods outlined in Charts A-K and described below,
together with synthetic methods known in the art of synthetic
organic chemistry, or variations thereon as appreciated by those
skilled in the art. Those who are skilled in the art will recognize
that the starting materials may be varied and additional steps can
be employed to produce compounds encompassed by the invention.
##STR3##
[0043] Pyrimidine derivatives can be prepared as outlined in Chart
A, wherein R.sub.1 and R.sub.2 are as defined for Formula I and X
represents a halogen, preferably chloride or bromide. Compounds
such as A-I can be prepared according to a known literature
procedure [J. Org. Chem. 1983, 48, 1060]. Reduction of the nitro
group in A-I may be accomplished by a variety of methods known in
the art, including hydrogenation with hydrogen and transition metal
catalysts or the use of sodium hydrosulfite in aqueous solutions to
give A-II. Alternatively compounds such as A-II can be prepared by
alkylation of the amino group with suitable electrophiles (e.g.,
epoxides as descried in J. Med. Chem. 1997, 40, 24). The
aminopyridine A-II may be transformed into A-II by reductive
amination using aldehydes and reducing agents such as sodium
triacetoxyborohydride in inert solvents. The halopyridine A-III can
be converted to arylpyrimidine A-IV by a transition metal-catalyzed
coupling reaction with a metalloaryl reagent (Ar-[M]. More commonly
employed reagent/catalyst pairs include aryl boronic
acid/palladium(0) [Stille reaction: T. N. Mitchell, Synthesis 1992,
803], arylzinc/palladium(0) and aryl Grignard/nickel(II).
Palladium(0) represents a catalytic system mad of various
combinations of metal/ligan pairs, including, but not limited to,
tetrakis(triphenylphosphine)palladium(0),
palladium(II)acetate/tri(o-tolyl)phosphine,
tris(dibenzylideneacetone)dipallidium (0)/tri-tert-butylphosphine
and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium(0).
Nickel(II) represents a nickel-containing catalysts such as
[1,2-bis(diphenylphosphino)ehtanedichloronickel(II) and
[1,3-bis(dipehynlphosphino)propane]dichloronickel(II). ##STR4##
[0044] By changing the sequence of events in Chart A, but using the
same methods described for Chart A, compounds of formula B-IV can
also be prepared as outlined in Chart B. ##STR5##
[0045] An alternative method for introducing the substituents
R.sub.3 and R.sub.4 to give compounds of formula C-IV is outlined
in Chart C and may be accomplished by a variety of methods known in
the art. These methods include reaction of amine C-I with acid
chlorides or anhydrides in the presence of bases such as, but not
limited to, triethylamine or pyridine in inert solvents such as
dichloromethane or toluene. The N--H group may then be deprotonated
by a strong base such as, but not limited to, alkali metal hydride,
alkali metal amide, or alkali metal alkoxide in inert solvents such
as, but not limited to, tetrahydrofuran (THF), dimethylformamide
(DMF) or dimethyl sulfoxide. Alkylation may be conducted using
alkyl halide, suitably bromide or iodide, at temperatures ranging
from 0.degree. C. to 100.degree. C. Reduction of the amide C-III
with reducing agents such as, but not limited to, lithium aluminum
hydride, borane or diisobutylaluminum hydride in inert solvents
such as, bot not limited to, THF, ether, or toluene furnishes
compounds of formula C-IV. ##STR6##
[0046] Another method for preparing compounds of formula D-II is
illustrated in Chart D. Treatment of amine D-I with base such as,
but not limited to, alkali metal hyride, alkali metal amide, alkali
metal alkoxide or alkali metal carbonates in inert solvents such
as, but not limited to, THF, DMF dimethyl sulfoxide or acetonitrile
with or without the addition of alkali metal iodide, followed by
alkylation with alkyl halide, suitably bromide or iodide, or
sulfonate at temperatures ranging from 0.degree. C. to 100.degree.
C. affords compounds of formula D-II. ##STR7##
[0047] Pyridine compounds of the present invention can be prepared
by the routes outlined in Charts F-K. For instance, selective metal
catalyzed cross-couplings of the 2,5-dihalopyridine E-I affords
5-halo-2-pyridines E-II (hal=halogen). The desired
3-alkoxy-6-arylpyridine E-III is obtained by heating E-II with
alkoxide. Oxidation of E-III may be accomplished with a suitable
oxidant, such as m-chloroperoxybenzoic acid to afford E-IV. Heating
E-IV in POCl.sub.3 provides the halo-intermediate E-V. Conversion
of E-V provides the compounds, for example,
2,3-dialkoxy-6-arylpyridine E-VI by nucleophilic displacement,
2-alkyl-3-alkoxy-6-arylpyridine E-VII by cross coupling and
2-amino-3-alkoxy-6-arylpyridine E-VIII by amination. ##STR8##
[0048] 3-Alkoxypyridines are also prepared by alkylation of
3-pyridinols by the method shown in Chart F. Nitration of F-I using
methods known to one skilled in the art followed by hydroxy
dediazitization provides F-II. Treating F-II with hot POCl.sub.3
provides F-III. Cross-coupling of F-III with an appropriate aryl
unit affords F-IV. The nitro group of F-IV is subsequently reduced
using methods know to those in the art, including but not limited
to hydrogenation or SnCl.sub.2, provides F-V. Hydroxy
dediazitization of F-V provides F-VI. Alkylation of F-VI affords
the target 3-alkoxy-6-arylpyridine compounds F-VII. ##STR9##
[0049] Arylpyridines may also be prepared by construction of the
pyridine ring as shown n Chart G. Condensation of malonic acids G-I
with amines G-II gives dihydroxypyridine G-III. Treatment of G-III
with hot POCl.sub.3 affords G-IV. Selective cross coupling of G-IV
to the more highly activated halogen proceeds to afford
2-aryl-4-chloropyridine G-V. Incorporation of R.sub.2 proceeds via
nucleophilic substitution to provide G-VI. Hydrolysis of G-VI
affords carboxylic acid G-VII. Curtius rearrangement followed by
protection of the amine with a carbamate protecting group affords
G-VIII. Alkylation of the resultant amide provides G-IX.
Deprotection and, if desired, reductive alkylation affords the
target compound G-X. ##STR10##
[0050] An alternative synthesis of 2-amino-3-alkoxy-6-arylpyridines
is described in Chart H. Iodination of H-I provides H-II, which can
be alkylated to afford the corresponding 3-alkoxypyridine H-III. By
carefully applying chemoselectivity between 2-halo and 6-iodo,
halopyrazine H-III can be converted to arylpyrazine H-IV by a
transition metal-catalyzed coupling reaction with a metalloaryl
reagent (G-[M]). More commonly employed reagent/catalyst pairs
include aryl boronic acid/palladium(0) (Suzuki reaction; N. Miyaura
and A. Suzuki, Chemical Review 1995, 95, 2457), aryl
trialkylstannane/palladium(0) (Stille reaction; T. N. Mitchell,
Synthesis 1992, 803), arylzinc/palladium(0) and aryl
Grignard/nickel(II). Amination of H-IV in the presence of a
suitable transition metal catalyst such as, but not limited to,
palladium(II)acetate or tris(dibenzylideneacetone)dipalladium(0), a
ligand such as, but not limited to,
1,1'-bis(diphenylphosphine)ferrocene,
2,2'-bis(diphenylphosphine)-1,1'-binaphthyl,
dicyclohexyl(2-biphenyl)phosphine, tricyclohexylphosphine, or
tri-tert-butylphosphine, and a base such as sodium or potassium
tert-butoxide in inert solvents such as, but not limited to,
toluene, ethyleneglycol dimethyl ether, diglyme, DMF, or
N-methylpyrrolidinone at temperatures ranging from ambient to
100.degree. C. provides H-V. Halogenation of H-V followed by a
metal catalyzed cross-coupling reaction affords the target compound
H-VII. ##STR11##
[0051] Still another route to the pyridines of interest is outlined
in Chart J. Alkylation of 3-halo-5-pyridinol J-I provides J-II.
Metal catalyzed cross-coupling of J-II affords J-III. Halogenation
of J-III proceeds to deliver J-IV. Subsequent round of metal
catalyzed cross coupling to J-IV provides the trisubstituted
pyridine J-V. A second halogenation step gives J-VI. A final metal
catalyzed cross coupling delivers the target compound J-VII.
##STR12##
[0052] Still another route to pyridines of interest is outlined in
Chart K. Selective reaction of the activated bromine in the
2-position of commercially available K-I provides K-II. A Buchwald
coupling of a suitably substituted amine provides K-III. Finally,
alkylation in the presence of a suitable base would provide
K-IV.
[0053] The present invention also encompasses pharmaceutically
acceptable salts of compounds of Formula I. Examples of
pharmaceutically acceptable salts are salts prepared from inorganic
acids or organic acids, such as inorganic and organic acids of
basic residues such as amines, for example, acetic,
benzenesulfonic, benzoic, amphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, barbaric acid,
p-toluenesulfonic and the like; and alkali or organic salts of
acidic residues such as carboxylic acids, for example, alkali and
alkaline earth metal salts derived from the following bases: sodium
hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,
aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc
hydroxide, ammonia, trimethylammonia, triethylammonia,
ethylenediamine, lysine, arginine, ornithine, choline,
N,N-dibenzylethylenediamine, chloroprocaine, diethanolamine,
procaine, n-benzylphenethylamine, diethylamine, piperazine,
tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide,
and the like.
[0054] Pharmaceutically acceptable salts of the compounds of the
invention can be prepared by conventional chemical methods.
Generally, such salts are, for example, prepared by reacting the
free acid or base forms of these compounds with a stoichiometric
amount of the appropriate base or acid in water or in an organic
solvent, or in a mixture of the two; generally, non-aqueous media
like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
are preferred. Lists of suitable salts are found in Remington's
Pharmaceutical Sciences, 17.sup.th ed., Mack Publishing Company,
Easton, Pa., 1985, p. 1418, the disclosure of which is hereby
incorporated by reference.
[0055] In another aspect, the present invention provides a prodrug
of a compound of Formula I. The prodrug is prepared with the
objective(s) of improved chemical stability, improved patient
acceptance and compliance, improved bioavailability, prolonged
duration of action, improved organ selectivity (including improved
brain penetrance), improved formulation (e.g., increased
hydrosolubility), and/or decreased side effects (e.g., toxicity).
See e.g. T. Higuchi and V. Stella, "Prodrugs as Novel Delivery
Systems", Vol. 14 of the A.C.S. Symposium Series; Bioreversible
Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, (1987). Prodrugs
include, but are not limited to, compounds derived from compounds
of Formula I wherein hydroxy, amine or sulfhydryl groups, if
present, are bonded to any group that, when administered to the
subject, cleaves to form the free hydroxyl, amino or sulfhydryl
group, respectively. Selected examples include, but are not limited
to, biohydrolyzable amides and biohydrolyzable esters and
biohydrolyzable carbamates, carbonates, acetate, formate and
benzoate derivatives of alcohol and amine functional groups.
[0056] The prodrug can be readily prepared from the compounds of
Formula I using methods known in the art. See, e.g. See Notari, R.
E., "Theory and Practice of Prodrug Kinetics," Methods in
Enzymology, 112:309-323 (1985); Bodor, N., "Novel Approaches in
Prodrug Design," Drugs of the Future, 6(3):165-182 (1981); and
Bundgaard, H., "Design of Prodrugs; Bioreversible-Derivatives for
Various Functional Groups and Chemical Entities," in Design of
Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985); Burger's
Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp.
172-178, 949-982 (1995). For example, the compounds of Formula I
can be transformed into prodrugs by converting one or more of the
hydroxy or carboxy groups into esters.
[0057] The invention also includes isotopically-labeled compounds,
which are identical to those recited in Formula I, but for the fact
that one or more atoms are replaced by an atom having an atomic
mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine,
and chlorine, such as .sup.3H, .sup.11C, .sup.14C, .sup.18F,
.sup.123I, and .sup.125I. Compounds of Formula I that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of the invention. Isotopically-labeled compounds
of the present invention, for example those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in drug and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-14 i.e., .sup.14C isotopes are
particularly useful in PET (positron emission tomography), and
.sup.125I isotopes are particularly useful in SPECT (single photon
emission computed tomography); all useful in brain imaging.
Further, substitution with heavier isotopes such as deuterium,
i.e., .sup.2H, can afford certain therapeutic advantages resulting
from greater metabolic stability, for example increased in vivo
half-life or reduced dosage requirements and, hence, maybe
preferred in some circumstances. Isotopically labeled compounds of
Formula I of this invention can generally be prepared by carrying
out the synthetic procedures by substituting a isotopically labeled
reagent for a non-isotopically labeled reagent.
[0058] The compounds of Formula I are antagonists at the CRF.sub.1
receptor, capable of inhibiting the specific binding of CRF to
CRF.sub.1 receptor and antagonizing activities associated with
CRF.sub.1 receptor. The effectiveness of a compound as a CRF
receptor antagonist may be determined by various assay methods. A
compound of Formula I may be assessed for activity as a CRF
antagonist by one or more generally accepted assays for this
purpose, including (but not limited to) the assays disclosed by
DeSouza et al. (J. Neuroscience 7:88, 1987) and Battaglia et al.
(Synapse 1:572, 1987). CRF receptor affinity may be determined by
binding studies that measure the ability of a compound to inhibit
the binding of a radiolabeled CRF (e.g., [.sup.125I]tyrosine-CFR)
to its receptor (e.g., receptors prepared from rat cerebral cortex
membranes). The radioligand binding assay described by DeSouza et
al. (supra, 1987) provides an assay for determining a compound's
affinity for the CRF receptor. Such activity is typically
calculated from the IC.sub.50 as the concentration of a compound
necessary to displace 50% of the radiolabeled ligand from the
receptor, and is reported as a "Ki" value. IC.sub.50 and Ki values
are calculated using standard methods known in the art, such as
with the non-linear curve-fitting program GraphPad Prism (GraphPad
Software, San Diego, Calif.). A compound is considered to be active
if it has an Ki of less than about 10 micromolar (.mu.M) for the
inhibition of CRF.sub.1 receptors. The binding affinity of the
compounds of Formula I expressed as Ki values generally ranges from
about 0.5 nanomolar to about 10 micromolar. Preferred compounds of
Formula I exhibit Ki value of 1 micromolar or less, more preferred
compounds of Formula I exhibit Ki values of less than 100
nanomolar, still more preferred compounds of Formula I exhibit Ki
values of less than 10 nanomolar.
[0059] In addition to inhibiting CRF receptor binding, a compound's
CRF receptor antagonist activity may be established by the ability
of the compound to antagonize an activity associated with CRF. For
example, CRF is known to stimulate various biochemical processes,
including adenylate cyclase activity. Therefore, compounds may be
evaluated as CRF antagonists by their ability to antagonize
CRF-stimulated adenylate cyclase activity by, for example,
measuring cAMP levels. The CRF-stimulated adenylate cyclase
activity assay described by Battaglia et al. (supra, 1987) provides
an assay for determining a compound's ability to antagonize CRF
activity. Alternatively, adenylate cyclase activity or cAMP
production can be assessed in a 96/384-well format utilizing the
cAMP competitive ELISA system from Applied Biosystems (Bedford,
Mass.) according to the protocols provided. Briefly, a fixed amount
of diluted cAMP-alkaline phosphatase conjugate (cAMP-AP) is added
to 96 or 386-well plates containing samples from cells that were
stimulated with CRF in the presence or absence of inhibitors.
Anti-cAMP antibody is added to the mixture and incubated for 1 hr.
Following successive wash steps, the chemiluminescent
substrate/enhancer solution is added which then produces a light
signal that can be detected using a microplate scintillation
counter such as the Packard TopCount. cAMP produced by the cells
will displace the cAMP-AP conjugate from the antibody yielding a
decrease of detectable signal. An example of the CRF-stimulated
adenylate cyclase activity assay is provided in Example C
below.
[0060] Thus, in another aspect, the present invention provides a
method of antagonizing CRF.sub.1 receptors in a warm-blooded
animal, comprising administering to the animal a compound of the
invention at amount effective to antagonize CRF.sub.1 receptors.
The warm-blooded animal is preferably a mammal, and more preferably
a human.
[0061] In another aspect, the present invention provides a method
of treating a disorder in a warm-blooded animal, which disorder
manifests hypersecretion of CRF.sub.1 or the treatment of which
disorder can be effected or facilitated by antagonizing CRF.sub.1
receptors, comprising administering to the animal a therapeutically
effective amount of a compound of the invention. The warm-blooded
animal is preferably a mammal, and more preferably a human.
[0062] In another aspect, the present invention provides a method
for screening for ligands for CRF.sub.1 receptors, which method
comprises: a) carrying out a competitive binding assay with
CRF.sub.1 receptors, a compound of Formula I which is labeled with
a detectable label, and a candidate ligand, and b) determining the
ability of said candidate ligand to displace said labeled compound.
Assay procedure for competitive binding assay is well known in the
art, and is exemplified in Example A.
[0063] In another aspect, the present invention provides a method
for detecting CRF.sub.1 receptors in tissue comprising: a)
contacting a compound of Formula I, which is labeled with a
detectable label, with a tissue, under conditions that permit
binding of the compound to the tissue; and b) detecting the labeled
compound bound to the tissue. Assay procedure for detecting
receptors in tissues is well known in the art.
[0064] In another aspect, the present invention provides a method
of inhibiting the binding of CRF to CRF.sub.1 receptors, comprising
contacting a compound of the invention with a solution comprising
cells expressing the CRF.sub.1 receptor, wherein the compound is
present in the solution at a concentration sufficient to inhibit
the binding of CRF to the CRF.sub.1 receptor. An example of the
cell line that expresses the CRF.sub.1 receptor and can be used in
the in vitro assay is IMR32 cells known in the art.
[0065] Compounds of Formula I, or a stereoisomer, a
pharmaceutically acceptable salt, or a prodrug thereof, are useful
for the treatment of a disorder in a warm-blooded animal, which
disorder manifests hypersecretion of CRF, or the treatment of which
disorder can be effected or facilitated by antagonizing CRF.sub.1
receptors. Examples of such disorders are described herein above.
They are also useful for promoting smoking cessation or promoting
hair growth.
[0066] Thus, in still another aspect, the present invention
provides a method of treating a disorder described herein above,
comprising administering to a warm-blooded animal a therapeutically
effective amount of a compound of the invention. The warm-blooded
animal is preferably a mammal, particularly a human.
[0067] Particular disorders that can be treated by the method of
the invention preferably include the following anxiety-related
disorders, such as generalized anxiety disorder, social anxiety
disorder, anxiety with co-morbid depressive illness,
obsessive-compulsive disorder, and panic disorder, anxiety states,
phobic disorders: anxiety with co-morbid depressive illness,
obsessive-compulsive disorder, post-traumatic stress disorder, and
atypical anxiety disorders; mood disorders such as depression,
including major depression, single episode depression, recurrent
depression, child abuse induced depression, and postpartum
depression, bipolar disorders, post-traumatic stress disorder,
dysthemia, and cyclothymia; substance abuse disorder (e.g.,
nicotine, cocaine, ethanol, opiates, or other drugs); inflammatory
disorders such as rheumatoid arthritis and osteoarthritis;
gastrointestinal diseases such as irritable bowel syndrome, ulcers,
Crohn's disease, spastic colon, diarrhea, and post operative ilius
and colonic hypersensitivity associated by psychopathological
disturbances or stress; and skin disorders such as acne, psoriasis,
and chronic contact demertitis.
[0068] Particular disorders that can be treated by the method of
the invention more preferably include the following:
anxiety-related disorders, mood disorders, inflammation disorders;
and chronic contact demertitis.
[0069] Particular disorders that can be treated by the method of
the invention even more preferably include anxiety-related
disorders, particularly generalized anxiety, and mood disorders,
particularly major depression.
[0070] The therapeutically effective amounts of the compounds of
the invention for treating the diseases or disorders described
above in a warm-blooded animal can be determined in a variety of
ways known to those of ordinary skill in the art, e.g., by
administering various amounts of a particular agent to an animal
afflicted with a particular condition and then determining the
effect on the animal. Typically, therapeutically effective amounts
of a compound of this invention can be orally administered daily at
a dosage of the active ingredient of 0.002 to 200 mg/kg of body
weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one
to four times a day, or in sustained release formulation will be
effective in obtaining the desired pharmacological effect. It will
be understood, however, that the specific dose levels for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of administration, route of
administration, and rate of excretion, drug combination and the
severity of the particular disease. Frequency of dosage may also
vary depending on the compound used and the particular disease
treated. However, for treatment of most CNS disorders, a dosage
regimen of four-times daily or less is preferred. For the treatment
of stress and depression, a dosage regimen of one or two-times
daily is particularly preferred.
[0071] A compound of this invention can be administered to treat
the above disorders by means that produce contact of the active
agent with the agent's site of action in the body of a mammal, such
as by oral, topical, dermal, parenteral, or rectal administration,
or by inhalation or spray using appripropriate dosage forms. The
term "parenteral" as used herein includes subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques. The compound can be administered alone, but will
generally be administered with a pharmaceutically acceptable
carrier, diluent, or excipient.
[0072] Thus in yet another aspect, the present invention provides a
pharmaceutical composition comprising a compound of Formula I, a
stereoisomer thereof, a pharmaceutically acceptable salt thereof,
or a prodrug thereof, or a pharmaceutically acceptable salt of the
prodrug thereof. In one embodiment, the pharmaceutical composition
further comprises a pharmaceutically acceptable carrier, diluent,
or excipient therefore. A "pharmaceutically acceptable carrier,
diluent, or excipient" is a medium generally accepted in the art
for the delivery of biologically active agents to mammals, e.g.,
humans. Such carriers are generally formulated according to a
number of factors well within the purview of those of ordinary
skill in the art to determine and account for. These include,
without limitation, the type and nature of the active agent being
formulated; the subject to which the agent-containing composition
is to be administered; the intended route of administration of the
composition; and the therapeutic indication being targeted.
Pharmaceutically acceptable carriers and excipients include both
aqueous and non-aqueous liquid media, as well as a variety of solid
and semi-solid dosage forms. Such carriers can include a number of
different ingredients and additives in addition to the active
agent, such additional ingredients being included in the
formulation for a variety of reasons, e.g., stabilization of the
active agent, well known to those of ordinary skill in the art.
Descriptions of suitable pharmaceutically acceptable carriers, and
factors involved in their selection, are found in a variety of
readily available sources, e.g., Remington's Pharmaceutical
Sciences, 17.sup.th ed., Mack Publishing Company, Easton, Pa. 1985,
the contents of which are incorporated herein by reference.
[0073] Compositions intended for oral use may be in the form of
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsion, hard or soft capsules,
or syrups, or elixirs, and can be prepared according to methods
known to the art. Such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations.
[0074] Tablets contain the active ingredient in admixture with
non-toxic pharmaceutically acceptable excipients, which are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and a delay material such as glyceryl
monosterate or glyceryl distearate may be employed.
[0075] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0076] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexital
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more sweetening agents, such as
sucrose or saccharin.
[0077] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
soybean oil, sesame oil or coconut oil, or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening
agent, for example beeswax, hard paraffin or cetyl alcohol.
Sweetening agents such as those set forth above, and flavoring
agents may be added to provide palatable oral preparations. These
compositions may be preserved by the addition of an anti-oxidant
such as ascorbic acid.
[0078] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0079] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occuring gums, for example gum
acacia or gum tragacanth, naturally-occuring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0080] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents.
[0081] Suppositories for rectal administration of a compound of the
invention can be prepared by mixing the compound with a suitable
non-irritating excipient, which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Examples of such materials are cocoa
butter and polyethylene glycols.
[0082] Pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents, which have been
mentioned above. The sterile injectable solution or suspension may
be formulated in a non toxic parentally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringers's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0083] Dosage forms suitable for administration generally contain
from about 1 mg to about 100 mg of active ingredient per unit. In
these pharmaceutical compositions, the active ingredient will
ordinarily be present in an amount of about 0.5 to 95% by weight
based on the total weight of the composition. Examples of dosage
forms for administration of compounds of the invention includes the
following: (1) Capsules. A large number of units capsules are
prepared by filling standard two-piece hard gelatin capsules each
with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg
cellulose, and 6 mg magnesium stearate; (2) Soft Gelatin Capsules.
A mixture of active ingredient in a digestible oil such as soybean,
cottonseed oil, or olive oil is prepared and injected by means of a
positive displacement into gelatin to form soft gelatin capsules
containing 100 mg of the active ingredient. The capsules were
washed and dried; (3) Tablets. A large number of tablets are
prepared by conventional procedures so that the dosage unit was 100
mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of
magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of
starch, and 98.8 mg lactose. Appropriate coatings may be applied to
increase palatability or delayed adsorption.
[0084] In still another aspect, the present invention provides an
article of manufacture comprising: a) a packaging material; b) a
pharmaceutical agent comprising a compound of the invention
contained within said packaging material; and c) a label or package
insert which indicates that said pharmaceutical agent can be used
for treating a disorder described above.
Definitions and Conventions
[0085] The following definitions are used throughout the
application, unless otherwise described.
[0086] The term "halogen" meams a group selected from --F, --Cl,
--Br, --I;
[0087] The term "aryl cycloalkyl" means a bicyclic ring consisting
of 9 to 14 carbon atoms wherein one ring is aryl and the other ring
is cycloalkyl fused to the aryl ring, wherein either ring may act
as a point of attachment. The cycloalkyl ring may be fully or
partially saturated in the portion of the ring not fused to the
aryl ring.
[0088] The term "substituted aryl cycloalkyl" means an aryl
cycloalkyl group having 1-3 substituents independently selected
from halogen, --R.sub.5, --OR.sub.5, --S(O).sub.mR.sub.5,
--NR.sub.5R.sub.5, --C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5,
--NR.sub.5C(O)R.sub.5, --S(O).sub.2NR.sub.5R.sub.5,
--NR.sub.5S(O).sub.2R.sub.5, and --NO.sub.2;
[0089] The term "heteroaryl cycloalkyl" means a bicyclic ring
consisting of 9 to 14 atoms, wherein one ring is heteroaryl and the
other ring is cycloalkyl fused to the aryl ring, and wherein either
ring may act as a point of attachment. The cycloalkyl ring may be
fully or partially saturated in the portion of the ring not fused
to the aryl ring.
[0090] The term "substituted heteroaryl cycloalkyl" means a
heteroaryl cycloalkyl having 1-3 substituents independently
selected from halogen, --R.sub.5, --OR.sub.5, --S(O).sub.mR.sub.5,
--NR.sub.5R.sub.5, --C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5,
NR.sub.5C(O)R.sub.5, --S(O).sub.2NR.sub.5R.sub.5,
--NR.sub.5S(O).sub.2R.sub.5, and --NO.sub.2;
[0091] The term "aryl heterocycloalkyl" means a bicyclic ring
system containing 9 to 14 atoms, wherein one ring is aryl and the
other ring is heterocycloalkyl, wherein either ring may act as a
point of attachment.
[0092] The term "substituted aryl heterocycloalkyl" means an aryl
heterocycloalkyl having 1-3 substituents independently selected
from halogen, --R.sub.5, --OR.sub.5, --S(O).sub.mR.sub.5,
--NR.sub.5R.sub.5, --C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5,
--NR.sub.5C(O)R.sub.5, --S(O).sub.2NR.sub.5R.sub.5,
--NR.sub.5S(O).sub.2R.sub.5, and --NO.sub.2;
[0093] The term "heteroaryl heterocycloalkyl" means a bicyclic ring
containing 9 to 14 atoms, wherein one ring is heteroaryl and the
other ring is heterocycloalkyl, wherein either ring may act as a
point of attachment.
[0094] The term "substituted heteroaryl heterocycloalkyl" means a
heteroaryl heterocycloalkyl having 1-3 substituents independently
selected from halogen, --R.sub.5, --OR.sub.5, --S(O).sub.mR.sub.5,
--NR.sub.5R.sub.5, --C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5,
--NR.sub.5C(O)R.sub.5, --S(O).sub.2NR.sub.5R.sub.5,
--NR.sub.5S(O).sub.2R.sub.5, and --NO.sub.2.
[0095] The term "alkyl" means both straight- and branched chain
hydrocarbon moieties having from 1-10 carbon atoms.
[0096] The term "substituted alkyl" means an alkyl moiety having
1-3 substituents independently selected from halogen,
--S(O).sub.mR.sub.5, --NR.sub.5R.sub.5, --C(O)R.sub.5, --CN,
--C(O)NR.sub.5R.sub.5, --NR.sub.5C(O)R.sub.5,
--S(O).sub.2NR.sub.5R.sub.5, --NR.sub.5S(O).sub.2R.sub.5, --CN,
--NO.sub.2, and Ar provided that a halogen or halogens may not be
the only substituent(s) on the alkyl group.
[0097] The term "haloalkyl" means is an alkyl moiety having 1 to
(2v+1) independently selected halogen substituent(s) where v is the
number of carbon atoms in the moiety.
[0098] The term "cycloalkyl" means a monocyclic or bicyclic,
non-aromatic hydrocarbon moiety having from 3-10 carbon atoms. A
cycloalkyl may optionally contain 1 to 2 double bonds provided that
the double bonds are not cumulated;
[0099] The term "substituted cycloalkyl" means a cycloalkyl group
having 1-3 substituents independently selected from halogen,
--R.sub.5, --OR.sub.5, --S(O).sub.mR.sub.5, --NR.sub.5R.sub.5,
--C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5, --NR.sub.5C(O)R.sub.5,
--S(O).sub.2NR.sub.5R.sub.5, --NR.sub.5S(O).sub.2R.sub.5, and
--NO.sub.2;
[0100] The term "aryl" means either phenyl or napthyl.
[0101] The term "substituted phenyl" means a phenyl group having
1-3 substituents independently selected from halogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted heteroaryl, --OR.sub.5, SR.sub.5, --NR.sub.5R.sub.5,
--C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5, --NR.sub.5C(O)R.sub.5,
--S(O).sub.2NR.sub.5R.sub.5, --NR.sub.5S(O).sub.2R.sub.5, and
--NO.sub.2.
[0102] The term "substituted napthyl" means a napthyl group having
1-3 substituents independently selected from halogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroaryl,
substituted heteroaryl, --OR.sub.5, SR.sub.5, --NR.sub.5R.sub.5,
--C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5, --NR.sub.5C(O)R.sub.5,
--S(O).sub.2NR.sub.5R.sub.5, --NR.sub.5S(O).sub.2R.sub.5, and
--NO.sub.2.
[0103] The term "heteroaryl" means a radical of a monocyclic
aromatic ring containing five or six ring atoms consisting of
carbon and 1 to 4 heteroatoms each selected from the group
consisting of non-peroxide O, S, and N, with appropriate bonding to
satisfy valence requirements, wherein the attachment may be via a
ring carbon or nitrogen atom. The term "heteroaryl" also includes a
radical of a fused bicyclic heteroaromatic ring having about eight
to ten ring atoms consisting of carbon and 1 to 6 heteroatoms each
selected from the group consisting of non-peroxide O, S, and N,
with appropriate bonding to satisfy valence requirements, wherein
the attachment may be via a ring carbon or nitrogen atom.
Non-limiting examples of heteroaryl includes thienyl, benzothienyl,
pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,
furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,
benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and
benzoxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,
oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
purinyl, oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
benzothiazolyl, quinazolinyl, quinoxalinyl, naphthridinyl, and
furopyridinyl.
[0104] The term "substituted heteroaryl" means a heteroaryl group
having 1-3 substituents independently selected from halogen,
--R.sub.5, --OR.sub.5, --S(O).sub.mR.sub.5, --NR.sub.5R.sub.5,
--C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5, --NR.sub.5C(O)R.sub.5,
--S(O).sub.2NR.sub.5R.sub.5, --NR.sub.5S(O).sub.2R.sub.5, and
--NO.sub.2, phenyl, substituted phenyl, napthyl, substituted
napthyl, heteroaryl, and heteroaryl derivatives.
[0105] The term "heteroaryl derivatives" means a heteroaryl group
having 1-3 substituents independently selected from halogen,
--R.sub.5, --OR.sub.5, --S(O).sub.mR.sub.5, --NR.sub.5R.sub.5,
--C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5, --NR.sub.5C(O)R.sub.5,
--S(O).sub.2NR.sub.5R.sub.5, --NR.sub.5S(O).sub.2R.sub.5, and
--NO.sub.2.
[0106] The term "heterocycloalkyl" means a 4 to 8 membered
non-aromatic monocyclic ring or 6 to 12 membered non-aromatic
bicyclic ring, wherein 1 to 4 carbon atom(s) each is replaced with
a heteromember selected from oxygen, nitrogen, --NH--, or
--S(O).sub.m-- wherein m is zero, 1, or 2, wherein the ring
attachment can occur at either a carbon or nitrogen atom. A
heterocycloalkyl may optionally contain 1 to 3 double bonds.
Examples of heterocycloalkyl include tetrahydrofuranyl,
tetrahydropyranyl, morpholinyl, pyrrolidinyl, piperidinyl,
piperazinyl, [2.2.1]-azabicyclic rings, [2.2.2]-azabicyclic rings,
[3.3.1]-azabicyclic rings, quinuclidinyl, azetidinyl, azetidinonyl,
oxindolyl, dihydroimidazolyl, and pyrrolidinonyl.
[0107] The term "substituted heterocycloalkyl" means a
heterocycloalkyl group having 1-3 substituents independently
selected from halogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, --OR.sub.5, --S(O).sub.mR.sub.5,
--NR.sub.5R.sub.5, --C(O)R.sub.5, --CN, --C(O)NR.sub.5R.sub.5,
--NR.sub.5C(O)R.sub.5, --S(O).sub.2NR.sub.5R.sub.5,
--NR.sub.5S(O).sub.2R.sub.5, and --NO.sub.2.
[0108] The term "pharmaceutically acceptable," unless otherwise
described, refer to those compounds, materials, compositions,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic
response, or other problems or complications, commensurate with a
reasonable benefit/risk ratio.
[0109] The term "pharmaceutically acceptable salt" refers to a salt
which retains the biological effectiveness and properties of the
compounds of this invention and which is not biologically or
otherwise undesirable.
[0110] The term "stereoisomer" refers to a compound made up of the
same atoms bonded by the same bonds but having different
three-dimensional structures which are not interchangeable. The
three-dimensional structures are called configurations. As used
herein, the term "enantiomer" refers to two stereoisomers whose
molecules are nonsuperimposable mirror images of one another. The
term "chiral center" refers to a carbon atom to which four
different groups are attached. As used herein, the term
"diastereomers" refers to stereoisomers which are not enantiomers.
In addition, two diastereomers which have a different configuration
at only one chiral center are referred to herein as "epimers". The
terms "racemate" or "racemic mixture" refer to a mixture of equal
parts of enantiomers.
[0111] The term "prodrug" means compounds that are transformed in
vivo to yield a compound of Formula I. The transformation may occur
by various mechanisms, such as through hydrolysis in blood.
[0112] The term "therapeutically effective amount," "effective
amount," "therapeutic amount," or "effective dose" is meant that
amount sufficient to elicit the desired pharmacological or
therapeutic effects, thus resulting in effective prevention or
treatment of the disease.
[0113] The phrases "a compound of the invention," "a compound of
the present invention," "compounds of the present invention," or "a
compound in accordance with Formula I" and the like, refer to
compounds of Formula I, or stereoisomers thereof, pharmaceutically
acceptable salts thereof, or prodrugs thereof, or pharmaceutically
acceptable salts of a prodrug of compounds of Formula I.
[0114] The terms "treatment," "treat," "treating," and the like,
are meant to include both slowing or reversing the progression of a
disorder, as well as curing the disorder. These terms also include
alleviating, ameliorating, attenuating, eliminating, or reducing
one or more symptoms of a disorder or condition, even if the
disorder or condition is not actually eliminated and even if
progression of the disorder or condition is not itself slowed or
reversed. The term "treatment" and like terms also include
preventive (e.g., prophylactic) and palliative treatment.
Prevention of the disease is manifested by a prolonging or delaying
of the onset of the symptoms of the disease.
EXAMPLES
[0115] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, practice the
present invention to its fullest extent. Examples A-D are provided
to illustrate biological assays that can be used for determining
the biological properties of the compounds of the inventions. These
examples are not to be construed as limiting the invention in scope
or spirit to the specific procedures described in them. Those
skilled in the art will promptly recognize appropriate variations
from the procedures described in the examples.
Example A
In Vitro CRF.sub.1 Receptor Binding Assay for the Evaluation of
Biological Activity
[0116] The following is a description of a standard in vitro
binding assay for the evaluation of biological activity of a test
compound on CRF.sub.1 receptors. It is based on a modified protocol
described by De Souza (De Souza, 1987).
[0117] The binding assay utilizes brain membranes, commonly from
rats. To prepare brain membranes for binding assays, rat frontal
cortex is homogenized in 10 mL of ice cold tissue buffer (50 mM
HEPES buffer pH 7.0, containing 10 mM MgCl.sub.2, 2 mM EGTA, 1
.mu.g/mL aprotinin, 1 .mu.g/mL leupeptin and 1 .mu.g/mL pepstatin).
The homogenate is centrifuged at 48,000.times.g for 10 min, and the
resulting pellet rehomogenized in 10 mL of tissue buffer. Following
an additional centrifugation at 48,000.times.g for 10 min., the
pellet is resuspended to a protein concentration of 300
.mu.g/mL.
[0118] Binding assays are performed in 96 well plates at a final
volume of 300 .mu.L. The assays are initiated by the addition of
150 .mu.L membrane suspension to 150 .mu.L of assay buffer
containing .sup.125I-ovine-CRF (final concentration 150 pM) and
various concentrations of inhibitors. The assay buffer is the same
as described above for membrane preparation with the addition of
0.1% ovalbumin and 0.15 mM bacitracin. Radioligand binding is
terminated after 2 hours at room temperature by filtration through
Packard GF/C unifilter plates (presoaked with 0.3%
polyethyleneimine) using a Packard cell harvestor. Filters are
washed three times with ice cold phosphate buffered saline pH 7.0
containing 0.01% Triton X-100. Filters are assessed for
radioactivity in a Packard TopCount.
[0119] Alternatively, tissues and cells that naturally express CRF
receptors, such as IMR-32 human neuroblastoma cells (ATCC; Hogg et
al. 1996), can be employed in binding assays analogous to those
described above.
[0120] A compound is considered to be active if it has a Ki value
of less than about 10 .mu.M for the inhibition of CRF. Nonspecific
binding is determined in the presence of excess (10 .mu.M)
.alpha.-helical CRF.
Example B
Ex Vivo CRF.sub.1 Receptor Binding Assay for the Evaluation of
Biological Activity
[0121] The following is a description of a typical ex vivo
CRF.sub.1 receptor binding assay for assessing the biological
activity of a test compound on CRF.sub.1 receptors.
[0122] Fasted, male, Harlen-bred, Sprague-Dawley rats (170-210 g)
were orally dosed with test compound or vehicle, via gastric lavage
between 12:30 and 2:00 PM. Compounds were prepared in vehicle
(usually 10% soybean oil, 5% polysorbate 80, in dH20). Two hours
after drug administration, rats were sacrificed by decapitation,
frontal cortices were quickly dissected and placed on dry ice, then
frozen at -80.degree. C. until assayed; trunk blood was collected
in heparinized tubes, plasma separated by centrifugation (2500
RPM's for 20 minutes), and frozen at -20.degree. C.
[0123] On the day of the binding assay, tissue samples were weighed
and allowed to thaw in ice cold 50 mM Hepes buffer (containing 10
mM MgCl.sub.2, 2 mM EGTA, 1 .mu.g/mL aprotinin, 1 .mu.g/mL
leupeptin hemisulfate, and 1 .mu.g/mL pepstatin A, 0.15 mM
bacitracin, and 0.1% ovalalbumin, pH=7.0 at 23.degree. C.) and then
homogenized for 30 sec at setting 5 (Polytron by Kinematica).
Homogenates were incubated (two hours, 23.degree. C., in the dark)
with [.sup.125I] CRF (0.15 nM, NEN) in the presence of assay buffer
(as described above) or DMP-904 (10 uM). The assay was terminated
by filtration (Packard FilterMate, GF/C filter plates); plates were
counted in Packard TopCount LSC; total and nonspecific fmoles
calculated from DPM's. Data are expressed as % of vehicle controls
(specific fmoles bound). Statistical significance was determined
using student's t-test.
Example C
Inhibition of CRF Stimulated Adenylate Cyclase Activity
[0124] Inhibition of CRF-stimulated adenylate cyclase activity can
be performed as previously described [G. Battaglia et al., Synapse
1:572 (1987)]. Briefly, assays are carried out at 37.degree. C. for
10 min in 200 mL of buffer containing 100 mM Tris-HCl (pH 7.4 at
37.degree. C.), 10 mM MgCl.sub.2, 0.4 mM EGTA, 0.1% BSA, 1 mM
isobutylmethylxanthine (IBMX), 250 units/mL phosphocreatine kinase,
5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM
o-CRF, antagonist peptides (various concentrations) and 0.8 mg
original wet weight tissue (approximately 40-60 mg protein).
Reactions are initiated by the addition of 1 mM ATP/[.sup.32P]ATP
(approximately 2-4 mCi/tube) and terminated by the addition of 100
mL of 50 mM Tris-HCl, 45 mM ATP and 2% sodium dodecyl sulfate. In
order to monitor the recovery of cAMP, 1 mL of [.sup.3H]cAMP
(approximately 40,000 dpm) is added to each tube prior to
separation. The separation of [.sup.32P]cAMP from [.sup.32P]ATP is
performed by sequential elution over Dowex and alumina columns.
[0125] Alternatively, adenylate cyclase activity can be assessed in
a 96-well format utilizing the Adenylyl Cyclase Activation
FlashPlate Assay from NEN Life Sciences according to the protocols
provided. Briefly, a fixed amount of radiolabeled cAMP is added to
96-well plates that are precoated with anti-cyclic AMP antibody.
Cells or tissues are added and stimulated in the presence or
absence of inhibitors. Unlabeled cAMP produced by the cells will
displace the radiolabeled cAMP from the antibody. The bound
radiolabeled cAMP produces a light signal that can be detected
using a microplate scintillation counter such as the Packard
TopCount. Increasing amounts of unlabeled cAMP results in a
decrease of detectable signal over a set incubation time (2-24
hours).
Example D
In Vivo Biological Assay
[0126] The in vivo activity of a compound of the present invention
can be assessed using any one of the biological assays available
and accepted within the art Illustrative of these tests include the
Acoustic Startle Assay, the Stair Climbing Test, and the Chronic
Administration Assay. These and other models useful for the testing
of compounds of the present invention have been outlined in C. W.
Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990). A
compound may be tested in any species of rodent or small
mammal.
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