U.S. patent application number 10/650474 was filed with the patent office on 2004-06-24 for crf antagonistic pyrazolo[4,3-b]pyridines.
This patent application is currently assigned to Neurocrine Biosciences, Inc.. Invention is credited to Chen, Chen, Hadduch, Mustapha, Huang, Charles Q., McCarthy, James R., Wilcoxen, Keith M..
Application Number | 20040121999 10/650474 |
Document ID | / |
Family ID | 22137332 |
Filed Date | 2004-06-24 |
United States Patent
Application |
20040121999 |
Kind Code |
A1 |
Chen, Chen ; et al. |
June 24, 2004 |
CRF antagonistic pyrazolo[4,3-b]pyridines
Abstract
This invention concerns compounds of formula 1 including the
stereoisomers and the pharmaceutically acceptable acid addition
salt forms thereof, wherein R.sup.1 is C.sub.1-6alkyl,
NR.sup.5R.sup.6, OR.sup.6 or SR.sup.6; R.sup.2 is C.sub.1-6alkyl,
C.sub.1-6alkyloxy, or C.sub.1-6alkylthio; R.sup.3 is Ar.sup.1 or
Het.sup.1; R.sup.4 is hydrogen or C.sub.1-6alkyl; R.sup.5 is
hydrogen, C.sub.1-8alkyl, mono- or di(C.sub.3-6cycloalkyl)methyl,
C.sub.3-6cycloalkyl, C.sub.3-6alkenyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)amino- C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl; R.sup.6 is C.sub.1-8alkyl, mono-
or di(C.sub.3-6cycloalkyl)methyl, Ar.sup.2C.sub.1-6alkyl,
Ar.sup.2oxyC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.3-6alkenyl, thienylmethyl,
furanylmethyl, tetrahydrofuranylmethyl,
C.sub.1-6alkylthioC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.sub.1- -6alkyl, di(C.sub.1-6alkyl)amino,
or C.sub.1-6alkylcarbonylC.sub.1-6alkyl; or R.sup.5 and R.sup.6
taken together with the nitrogen atom to which they are attached
may form a pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,
or thiomorpholinyl group, optionally substituted with 1 or 2
substituents each independently selected from C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl; and and Ar.sup.1 and Ar.sup.2 are
each optionally substituted phenyl; and Het.sup.1 is optionally
substituted pyridinyl; having CRF receptor antagonistic properties;
pharmaceutical compositions containing such compounds as active
ingredients; methods of treating disorders related to
hypersecretion of CRF such as depression, anxiety, substance abuse,
by administering an effective amount of a compound of formula
(I).
Inventors: |
Chen, Chen; (San Diego,
CA) ; Wilcoxen, Keith M.; (San Diego, CA) ;
Huang, Charles Q.; (San Diego, CA) ; Hadduch,
Mustapha; (San Diego, CA) ; McCarthy, James R.;
(Solana Beach, CA) |
Correspondence
Address: |
SEED INTELLECTUAL PROPERTY LAW GROUP PLLC
701 FIFTH AVE
SUITE 6300
SEATTLE
WA
98104-7092
US
|
Assignee: |
Neurocrine Biosciences,
Inc.
San Diego
CA
|
Family ID: |
22137332 |
Appl. No.: |
10/650474 |
Filed: |
August 28, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10650474 |
Aug 28, 2003 |
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09623634 |
Feb 20, 2001 |
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6613777 |
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09623634 |
Feb 20, 2001 |
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PCT/EP99/01307 |
Feb 26, 1999 |
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60077311 |
Mar 6, 1998 |
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Current U.S.
Class: |
514/217.07 ;
514/227.8; 514/234.5; 514/303 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 25/00 20180101 |
Class at
Publication: |
514/217.07 ;
514/234.5; 514/303; 514/227.8 |
International
Class: |
A61K 031/55; A61K
031/541; A61K 031/5377; A61K 031/4745 |
Claims
1. Use of compounds of formula (I) 32including the stereoisomers
and the pharmaceutically acceptable acid addition salt forms
thereof, wherein R.sup.1 is C.sub.1-6alkyl, NR.sup.5R.sup.6,
OR.sup.6 or SR.sup.6; R.sup.2 is C.sub.1-6alkyl, C.sub.1-6alkyloxy,
or C.sub.1-6alkylthio; R.sup.3 is Ar.sup.1 or Het.sup.1; R.sup.4 is
hydrogen or C.sub.1-6alkyl; R.sup.5 is hydrogen, C.sub.1-8alkyl,
mono- or di(C.sub.3-6cycloalkyl)methyl, C.sub.3-6cycloalkyl,
C.sub.3-6alkenyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)amino- C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl; R.sup.6 is C.sub.1-8alkyl, mono-
or di(C.sub.3-6cycloalkyl)methyl, Ar.sup.2C.sub.1-6alkyl,
Ar.sup.2oxyC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.3-6alkenyl, thienylmethyl,
furanylmethyl, tetrahydrofuranylmethyl,
C.sub.1-6alkylthioC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.sub.1- -6alkyl, di(C.sub.1-6alkyl)amino,
or C.sub.1-6alkylcarbonylC.sub.1-6alkyl; or R.sup.5 and R.sup.6
taken together with the nitrogen atom to which they are attached
may form a pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,
or thiomorpholinyl group, optionally substituted with 1 or 2
substituents each independently selected from C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl; Ar.sup.1 is phenyl; naphtyl; or
phenyl substituted with 1, 2 or 3 substituents each independently
selected from halo, C.sub.1-6alkyl, trifluoromethyl, hydroxy,
cyano, C.sub.1-6alkyloxy, benzyl, benzyloxy, C.sub.1-6alkylthio,
nitro, amino and mono- or di(C.sub.1-6alkyl)amino; Het.sup.1 is
pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents each
independently selected from halo, C.sub.1-6alkyl, trifluoromethyl,
hydroxy, cyano, C.sub.1-6alkyloxy, benzyloxy, C.sub.1-6alkylthio,
nitro, amino, and mono- or di(C.sub.1-6alkyl)amino; and Ar.sup.2 is
phenyl; phenyl substituted with 1, 2 or 3 substituents each
independently selected from halo, hydroxy, C.sub.1-6alkyl,
C.sub.1-6alkyloxy, di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, or
trifluoromethyl; or pyridinyl; for the manufacture of a medicament
for treating physiological conditions or disorders arising from the
hypersecretion of corticotropin-releasing factor (CRF).
2. Use of a compound according to claim 1 wherein R.sup.1 is
NR.sup.5R.sup.6 wherein R.sup.5 is hydrogen or C.sub.1-8alkyl; and
R.sup.6 is C.sub.1-8alkyl or C.sub.3-6cycloalkylmethyl; or R.sup.1
is OR.sup.6 or SR.sup.6 wherein R.sup.6 is C.sub.1-6alkyl; R.sup.2
is C.sub.1-6alkyl; R.sup.3 is a phenyl substituted with 1, 2 or 3
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6alkyloxy or halo; or R.sup.3 is a pyridinyl substituted
with 1, 2 or 3 substituents each independently selected from halo,
amino, nitro, trifluoromethyl, mono- or di(C.sub.1-6alkyl)amino, or
C.sub.1-6alkyl; and R.sup.4 is hydrogen or C.sub.1-6alkyl.
3. A compound of formula (I-1) wherein R.sup.1 to R.sup.4 are
defined as in claim 1 and wherein at least R.sup.1 is
C.sub.1-6alkyl; OR.sup.6; SR.sup.6; or NR.sup.5R.sup.6 wherein
R.sup.5 is mono- or di(C.sub.3-6cycloalkyl)methyl,
C.sub.3-6cycloalkyl, C.sub.3-6alkenyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl, and R.sup.6 is mono- or
di(C.sub.3-6cycloalkyl)methyl, Ar.sup.2C.sub.1-6alkyl,
Ar.sup.2oxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.3-6alkenyl, thienylmethyl,
furanylmethyl, tetrahydrofuranylmethyl,
C.sub.1-6alkylthioC.sub.1-6alkyl,
C.sub.1-6alkylcarbonylC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.s- ub.1-6alkyl, or
di(C.sub.1-6alkyl)amino; or R.sup.5 and R.sup.6 taken together with
the nitrogen atom to which they are attached may form a
pyrrolidinyl, piperidinyl, or homopiperidinyl, each substituted
with 1 or 2 substituents independently selected from C.sub.1-6alkyl
or C.sub.1-6alkyloxyC.sub.1-6alkyl; or R.sup.5 and R.sup.6 taken
together with the nitrogen atom to which they are attached may form
a morpholinyl or a thiomorpholinyl group, optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-6alkyl
or C.sub.1-6alkyloxyC.sub.1-6alkyl; or at least R.sup.3 is
Het.sup.1 or Ar.sup.1 wherein Ar.sup.1 is naphtyl; or phenyl
substituted with 3 substituents each independently selected from
halo, C.sub.1-6alkyl, trifluoromethyl, hydroxy, cyano,
C.sub.1-6alkyloxy, benzyl, benzyloxy, C.sub.1-6alkylthio, nitro,
amino and mono- or di(C.sub.1-6alkyl)amino.
4. A compound according to claim 3 wherein R.sup.1 is a radical of
formula NR.sup.5R.sup.6 wherein R.sup.5 is mono- or
di(C.sub.3-6cycloalkyl)-methy- l, C.sub.3-6cycloalkyl,
C.sub.3-6alkenyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)amino- C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl, and R.sup.6 is mono- or
di(C.sub.3-6cycloalkyl)methyl, Ar.sup.2C.sub.1-6alkyl,
Ar.sup.2oxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkyloxyC.sub.- 1-6alkyl, C.sub.3-6alkenyl, thienylmethyl,
furanylmethyl, tetrahydrofuranylmethyl,
C.sub.1-6alkylthioC.sub.1-6alkyl,
C.sub.1-6alkylcarbonylC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.s- ub.1-6alkyl, or
di(C.sub.1-6alkyl)amino.
5. A compound according to claim 3 wherein R.sup.1 is a radical of
formula NR.sup.5R.sup.6 whereinor R.sup.5 and R.sup.6 taken
together with the nitrogen atom to which they are attached may form
a pyrrolidinyl, piperidinyl, or homopiperidinyl, each substituted
with 1 or 2 substituents independently selected from C.sub.1-6alkyl
or C.sub.1-6alkyloxyC.sub.1-6alkyl; or R.sup.5 and R.sup.6 taken
together with the nitrogen atom to which they are attached may form
a morpholinyl or a thiomorpholinyl group, optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-6alkyl
or C.sub.1-6alkyloxyC.sub.1-6alkyl.
6. A compound according to claim 3 wherein R.sup.3 is Het.sup.1 or
Ar.sup.1 wherein Ar.sup.1 is naphtyl; or phenyl substituted with 3
substituents each independently selected from halo, C.sub.1-6alkyl,
trifluoromethyl, hydroxy, cyano, C.sub.1-6alkyloxy, benzyl,
benzyloxy, C.sub.1-6alkylthio, nitro, amino or mono- or
di(C.sub.1-6alkyl)amino.
7. A composition comprising a pharmaceutically acceptable carrier,
and as active ingredient a therapeutically effective amount of a
compound as claimed in any one of claims 3 to 6.
8. A process for preparing a composition as claimed in claim 7
wherein a therapeutically effective amount of a compound as claimed
in any one of claims 3 to 6 is intimately mixed with a
pharmaceutically acceptable carrier.
9. A compound according to any one of claims 3 to 6 for use as a
medicine.
10. A process of preparing a compound of formula (I-1) as claimed
in claim 3 wherein a) intermediates of formula (VI) are reacted
with intermediates of formula (VII) under Suzuki coupling
conditions; 33b) an intermediate of formula (II) is reacted with an
intermediate of formula (III), wherein R.sup.1' has the meaning of
R.sup.1 other than C.sub.1-6alkyl, thereby yielding compounds of
formula (I-a); 34c) an intermediate of formula (IV) is O-alkylated
with an intermediate of formula (V) in a reaction-inert solvent and
in the presence of a suitable base, yielding compounds of formula
(I-b), defined as compounds of formula (I) wherein R.sup.1 is
OR.sup.6, 35d) an intermediate of formula (VII) is N-alkylated with
an intermediate of formula R.sup.6--W in a reaction-inert solvent
and in the presence of a suitable base, yielding compounds of
formula (I-c), which can be further N-alkylated with an
intermediate of formula R.sup.5--W 36wherein in the above reaction
schemes the radicals R.sup.1 to R.sup.6, are as defined in claim 1,
Z is bromo or iodo and W and W.sup.1 are appropriate leaving
groups; or, if desired, compounds of formula (I) are converted into
each other following art-known transformation reactions; and
further, if desired, compounds of formula (I) are converted into an
acid addition salt by treatment with an acid, or conversely, the
acid addition salt forms are converted into the free base by
treatment with alkali; and, if desired, preparing stereochemically
isomeric forms thereof.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to pyrazolo[4,3-b]pyridines which
possess CRF receptor antagonistic properties, to pharmaceutical
compositions containing these compounds as active ingredient, and
the use thereof in the treatment of endocrine, psychiatric and
neurologic conditions or illnesses, including stress-related
disorders in general.
[0002] The first corticotropin-releasing factor (CRF) was isolated
from ovine hypothalmi and identified as a 41-amino acid peptide
(Vale et al., Science 213:1394-1397, 1981). Subsequently, sequences
of human and rat CRF, were isolated and determined to be identical,
but different from ovine CRF in 7 of the 41 amino acid residues
(Rivier et al., Proc. Natl. Acad. Sci. USA 80:4851, 1983; Shibahara
et al., EMBO J. 2:775, 1983). CRF has been found to produce
profound alterations in endocrine, nervous and immune system
function. CRF is believed to be the major physiological regulator
of the basal and stress-release of adrenocorticotropic hormone
("ACTH"), .beta.-endorphin, and other pro-opiomelanocortin
("POMC")-derived peptides from the anterior pituitary (Vale et al.,
Science 213:1394-1397, 1981). Briefly, CRF is believed to initiate
its biological effects by binding to a plasma membrane receptor
which has been found to be distributed throughout the brain
(DeSouza et al., Science 221:1449-1451, 1984), pituitary (DeSouza
et al., Methods Enzymol. 124:560, 1986; Wynn et al., Biochem.
Biophys. Res. Comm. 110:602-608, 1983), adrenals (Udelsman et al.,
Nature 319:147-150, 1986) and spleen (Webster, E. L., and E. B.
DeSouza, Endocrinology 122:609-617, 1988). The CRF receptor is
coupled to a GTP-binding protein (Perrin et al., Endocrinology 118:
1171-1179, 1986) which mediates CRF-stimulated increase in
intracellular production of cAMP (Bilezikjian, L. M., and W. W.
Vale, Endocrinology 113:657-662, 1983).
[0003] In addition to its role in stimulating the production of
ACTH and POMC, CRF is also believed to coordinate many of the
endocrine autonomic, and behavioral responses to stress, and may be
involved in the pathophysiology of affective disorders. Moreover,
CRF is believed to be a key intermediary in communication between
the immune, central nervous, endocrine and cardiovascular systems
(Crofford et al., J. Clin. Invest. 90:2555-2564, 1992; Sapolsky et
al., Science 238:522-524, 1987; Tilders et al., Regul. Peptides
5:77-84, 1982). Overall, CRF appears to be one of the pivotal
central nervous system neurotransmitters and plays a crucial role
in integrating the body's overall response to stress.
[0004] Administration of CRF directly to the brain elicits
behavioral, physiological, and endocrine responses identical to
those observed for an animal exposed to a stressful environment.
For example, intracerebroventricular injection of CRF results in
behavioral activation (Sutton et al., Nature 297:331, 1982),
persistent activation of the electroencephalogram (Ehlers et al.,
Brain Res. 2/8332, 1983), stimulation of the
sympathoadrenomedullary pathway (Brown et al., Endocrinology
110:928, 1982), an increase of heart rate and blood pressure
(Fisher et al., Endocrinology 110:2222, 1982), an increase in
oxygen consumption (Brown et al., Life Sciences 30:207, 1982),
alteration of gastrointestinal activity (Williams et al., Am. J.
Physiol. 253:G582, 1987), suppression of food consumption (Levine
et al., Neuropharmacology 22:337, 1983), modification of sexual
behavior (Sirinathsinghji et al., Nature 305:232, 1983), and immune
function compromise (Irwin et al., Am. J. Physiol. 255:R744, 1988).
Furthermore, clinical data suggest that CRF may be hypersecreted in
the brain in depression, anxiety-related disorders, and anorexia
nervosa. (DeSouza, Ann. Reports in Med. Chem. 25:215-223,
1990).
[0005] Accordingly, clinical data suggest that CRF receptor
antagonists may represent novel antidepressant and/or anxiolytic
drugs that may be useful in the treatment of the neuropsychiatric
disorders manifesting hypersecretion of CRF.
[0006] Due to the physiological significance of CRF, the
development of further biologically active small molecules having
significant CRF receptor binding activity and which are capable of
antagonizing the CRF receptor remains a desirable goal. Such CRF
receptor antagonists would be useful in the treatment of endocrine,
psychiatric and neurologic conditions or illnesses, including
stress-related disorders in general.
[0007] CRF receptor antagonists have been reported in for example,
WO-94/13676, WO-94/13677, WO-95/33750 and WO-96/35689 which
disclose pyrrolopyrimidines, pyrazolo[3,4-d]pyrimidines and
substituted purines as CRF receptor antagonists. WO-98/03510,
published on 29 Jan. 1998, discloses azolotriazine and pyrimidine
derivatives as CRF antagonists. Also WO-97/29109, published 14 Aug.
1997, discloses CRF antagonistic pyrazolopyrimidines.
[0008] Structurally related pyrazolo[4,3-b]pyridines are also
disclosed in EP-0,239,191-A, published 30 Sep. 1987, as being
useful for treating inflammatory or allergic conditions.
[0009] Other structurally related compounds are disclosed in
Japanese Published (Kokai) patent application No. 52-077086 leaving
anti-inflammatory and anti-bacterial properties. Furthermore, J.
Heterocycl. Chem., 8(6), pp 1035-1037 (1971) describes
pyrazolopyridines having CNS antidepressant activity in mice.
[0010] The compounds of the present invention differ from the cited
art-known compounds structurally, by the nature of the substituents
on the pyrazolo[4,3-b]pyridine moiety and pharmacologically by the
fact that, unexpectedly, these compounds have CRF antagonistic
properties.
DESCRIPTION OF THE INVENTION
[0011] This invention concerns CRF antagonistic compounds of
formula (I) 2
[0012] including the stereoisomers and the pharmaceutically
acceptable acid addition salt forms thereof, wherein
[0013] R.sup.1 is C.sub.1-6alkyl, NR.sup.5R.sup.6, OR.sup.6 or
SR.sup.6;
[0014] R.sup.2is C.sub.1-6alkyl, C.sub.1-6alkyloxy, or
C.sub.1-6alkylthio;
[0015] R.sup.3 is Ar.sup.1 or Het.sup.1;
[0016] R.sup.4 is hydrogen or C.sub.1-6alkyl;
[0017] R.sup.5 is hydrogen, C.sub.1-8alkyl, mono- or
di(C.sub.3-6cycloalkyl)methyl, C.sub.3-6cycloalkyl,
C.sub.3-6alkenyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl;
[0018] R.sup.6 is C.sub.1-8alkyl, mono- or
di(C.sub.3-6cycloalkyl)methyl, Ar.sup.2C.sub.1-6alkyl,
Ar.sup.2oxyC.sub.1-6alkyl, C.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, C.sub.3-6alkenyl, thienylmethyl,
furanylmethyl, tetrahydrofuranylmethyl,
C.sub.1-6alkylthioC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.sub.1- -6alkyl, di(C.sub.1-6alkyl)amino,
or C.sub.1-6alkylcarbonylC.sub.1-6alkyl;
[0019] or R.sup.5 and R.sup.6 taken together with the nitrogen atom
to which they are attached may form a pyrolidinyl, piperidinyl,
homopiperidinyl, morpholinyl, or thiomorpholinyl group, optionally
substituted with 1 or 2 substituents each independently selected
from C.sub.1-6alkyl or C.sub.1-6alkyloxyC.sub.1-6alkyl;
[0020] Ar.sup.1 is phenyl; naphtyl; or phenyl substituted with 1, 2
or 3 substituents each independently selected from halo,
C.sub.1-6alkyl, trifluoromethyl, hydroxy, cyano, C.sub.1-6alkyloxy,
benzyl, benzyloxy, C.sub.1-6alkylthio, nitro, amino and mono- or
di(C.sub.1-6alkyl)amino;
[0021] Het.sup.1 is pyridinyl; pyridinyl substituted with 1, 2 or 3
substituents each independently selected from halo, C.sub.1-6alkyl,
trifluoromethyl, hydroxy, cyano, C.sub.1-6alkyloxy, benzyloxy,
C.sub.1-6alkylthio, nitro, amino, and mono- or
di(C.sub.1-6alkyl)amino; and
[0022] Ar.sup.2 is phenyl; phenyl substituted with 1, 2 or 3
substituents each independently selected from halo, hydroxy,
C.sub.1-6alkyl, C.sub.1-6alkyloxy,
di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, or trifluoromethyl; or
pyridinyl.
[0023] In an aspect this invention also concerns the novel
compounds of formula (I), which hereinafter and in the claims will
be referred to as compounds of formula (I-1) wherein R.sup.1 to
R.sup.4 are defined hereinabove and wherein
[0024] at least R.sup.1 is C.sub.1-6alkyl; OR.sup.6; SR.sup.6; or
NR.sup.5R.sup.6 wherein R.sup.5 is mono- or
di(C.sub.3-6cycloalkyl)methyl- , C.sub.3-6cycloalkyl,
C.sub.3-6alkenyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)amino- C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl, and R.sup.6 is mono- or
di(C.sub.3-6cycloalkyl)methyl, Ar.sup.2C.sub.1-6alkyl,
Ar.sup.2oxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkyloxyC.sub.- 1-6alkyl, C.sub.3-6alkenyl, thienylmethyl,
furanylmethyl, tetrahydrofuranylmethyl,
C.sub.1-6alkylthioC.sub.1-6alkyl,
C.sub.1-6alkylcarbonylC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.s- ub.1-6alkyl, or
di(C.sub.1-6alkyl)amino; or R.sup.5 and R.sup.6 taken together with
the nitrogen atom to which they are attached may form a
pyrrolidinyl, piperidinyl, or homopiperidinyl, each substituted
with 1 or 2 substituents independently selected from C.sub.1-6alkyl
or C.sub.1-6alkyloxyC.sub.1-6alkyl; or R.sup.5 and R.sup.6 taken
together with the nitrogen atom to which they are attached may form
a morpholinyl or a thiomorpholinyl group, optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-6alkyl
or C.sub.1-6alkyloxyC.sub.1-6alkyl;
[0025] or,
[0026] at least R.sup.3 is Het.sup.1 or Ar.sup.1 wherein Ar.sup.1
is naphtyl; or phenyl substituted with 3 substituents each
independently selected from halo, C.sub.1-6alkyl, trifluoromethyl,
hydroxy, cyano, C.sub.1-6alkyloxy, benzyl, benzyloxy,
C.sub.1-6alkylthio, nitro, amino and mono- or
di(C.sub.1-6alkyl)amino.
[0027] As used in the foregoing definitions and hereinafter, halo
is generic to fluoro, chloro, bromo and iodo; C.sub.1-6alkanediyl
defines bivalent straight and branched chained saturated
hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for
example, methylene, 1,2-ethanediyl, 1,3-propanediyl,
1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched
isomers thereof; C.sub.1-2alkyl defines straight saturated
hycrocarbon radicals having from 1 to 2 carbon atoms such as methyl
and ethyl; C.sub.2-4alkyl defines straight and branched chain
saturated hydrocarbon radicals having from 2 to 4 carbon atoms such
as ethyl, propyl, butyl, 1-methylethyl and the like; C.sub.3-4alkyl
defines straight and branched chain saturated hydrocarbon radicals
having from 3 to 4 carbon atoms such as propyl, butyl,
1-methylethyl and the like; C.sub.1-6alkyl includes C.sub.1-2alkyl
and C.sub.3-4alkyl radicals as defined hereinbefore and the higher
homologues thereof having from 5 to 6 carbon atoms such as, pentyl,
the pentyl isomers, hexyl and the hexyl isomers; C.sub.1-8alkyl
includes C.sub.1-6alkyl and the higher homologues thereof having
from 7 to 8 carbon atoms such as, for example, heptyl, octyl and
the like; C.sub.3-6alkenyl defines straight and branched chain
hydrocarbon radicals containing one double bond and having from 3
to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl,
2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; and where
said C.sub.3-6alkenyl is linked to a nitrogen or oxygen, the carbon
atom making the link preferably is saturated. C.sub.3-6cycloalkyl
comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
HydroxyC.sub.1-6alkyl refers to C.sub.1-6alkyl substituted with a
hydroxy group.
[0028] The pharmaceutically acceptable acid addition salts as
mentioned hereinabove are meant to comprise the therapeutically
active non-toxic acid addition salt forms which the compounds of
formula (I) are able to form. The compounds of formula (I) which
have basic properties can be converted in their pharmaceutically
acceptable acid addition salts by treating said base form with an
appropriate acid. Appropriate acids comprise, for example,
inorganic acids such as hydrohalic acids, e.g. hydrochloric or
hydrobromic acid; sulfuric; nitric; phosphoric and the like acids;
or organic acids such as, for example, acetic, propanioic,
hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.
butanedioic acid), maleic, fumaric, malic, tartaric, citric
methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic
and the like acids.
[0029] The term acid addition salts also comprises the hydrates and
the solvent addition forms which the compounds of formula (I) are
able to form. Examples of such forms are e.g. hydrates, alcoholates
and the like.
[0030] The term stereochemically isomeric forms of compounds of
formula (I), as used hereinbefore, defines all possible compounds
made up of the same atoms bonded by the same sequence of bonds but
having different three-dimensional structures which are not
interchangeable, which the compounds of formula (I) may possess.
Unless otherwise mentioned or indicated, the chemical designation
of a compound encompasses the mixture of all possible
stereochemically isomeric forms which said compound may possess.
Said mixture may contain all diastereomers and/or enantiomers of
the basic molecular structure of said compound. All
stereochemically isomeric forms of the compounds of formula (I)
both in pure form or in admixture with each other are intended to
be embraced within the scope of the present invention.
[0031] Some of the compounds of formula (I) may also exist in their
tautomeric forms. Such form is although not explicitly indicated in
the above formula are intended to be included within the scope of
the present invention. For instance, compounds of formula (I)
wherein R.sup.4 is hydrogen exist as tautomers as depicted below.
3
[0032] Whenever used hereinafter, the term "compounds of formula
(I)" is meant to include also the pharmaceutically acceptable acid
addition salts and all stereoisomeric forms.
[0033] The numbering of the bicyclic ring-system present in the
compounds of formula (I) is shown below: 4
[0034] Interesting groups of compounds within the invention are
those compounds of formula (I) wherein one or more of the radicals
have the following meaning:
[0035] a) R.sup.1 is NR.sup.5R.sup.6 wherein R.sup.5 is hydrogen or
C.sub.1-8alkyl; in particular C.sub.2-4alkyl; and R.sup.6 is
C.sub.1-8alkyl or C.sub.3-6cycloalkylmethyl; in particular
C.sub.2-4alkyl or cyclopropylmethyl;
[0036] b) R.sup.1 is OR.sup.6 or SR.sup.6 wherein R.sup.6 is
C.sub.1-6alkyl; in particular C.sub.1-4alkyl;
[0037] c) R.sup.2 is C.sub.1-6alkyl; in particular
C.sub.1-2alkyl;
[0038] d) R.sup.3 is a phenyl substituted with 1, 2 or 3
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6alkyloxy or halo; wherein the phenyl moiety is preferably
substituted in the 3-, 4-, 6-, 2,4- or 2,4,6-positions; or R.sup.3
is a pyridinyl substituted with 1, 2 or 3 substituents each
independently selected from halo, amino, nitro, trifluoromethyl),
mono- or di(C.sub.1-6alkyl)amino, or C.sub.1-6alkyl; wherein the
pyridinyl moiety preferably is connected via the 2- or 3-position
to the remainder of the molecule; and
[0039] e) R.sup.4 is hydrogen or C.sub.1-6alkyl.
[0040] Particular compounds are those compounds of formula (I)
wherein R.sup.1 is NR.sup.5R.sup.6 and R.sup.5 is C.sub.3-4alkyl,
preferably propyl; R.sup.6 is C.sub.3-4alkyl or cyclopropylmethyl,
preferably propyl; R.sup.2 is methyl; R.sup.3 is a phenyl
substituted with 1, 2 or 3 substituents each independently selected
from halo, methyl or methoxy; or R.sup.3 is pyridinyl substituted
with 1, 2 or 3 substituents each independently selected from halo,
methyl or dimethylamino; and R.sup.4 is hydrogen or methyl.
[0041] Other particular compounds are those compounds of formula
(I) wherein R.sup.3 is phenyl substituted on the 2- and 4-position
with C.sub.1-2alkyl or halo; in particular R.sup.3 is
2,4-dichlorophenyl.
[0042] Interesting novel compounds of formula (I-1) are those
compounds of formula (I-1) wherein one or more of the radicals have
the following meaning:
[0043] a) R.sup.1 is NR.sup.5R.sup.6 wherein R.sup.5 is hydrogen or
C.sub.1-8alkyl; in particular C.sub.2-4alkyl; and R.sup.6 is
C.sub.1-8alkyl or C.sub.3-6cycloalkylmethyl; in particular
C.sub.2-4alkyl or cyclopropylmethyl;
[0044] b) R.sup.1 is OR.sup.6 or SR.sup.6 wherein R.sup.6 is
C.sub.1-6alkyl; in particular C.sub.1-4alkyl;
[0045] c) R.sup.2 is C.sub.1-6alkyl; in particular
C.sub.1-2alkyl;
[0046] d) R.sup.3 is a phenyl substituted with 3 substituents each
independently selected from C.sub.1-6alkyl, C.sub.1-6alkyloxy or
halo; or R.sup.3 is a pyridinyl substituted with 1, 2 or 3
substituents each independently selected from halo, amino, nitro,
trifluoromethyl, mono- or di(C.sub.1-6alkyl)amino, or
C.sub.1-6alkyl; wherein the pyridinyl moiety preferably is
connected via the 2- or 3-position to the remainder of the
molecule; and
[0047] e) R.sup.4 is hydrogen or C.sub.1-6alkyl.
[0048] Particular novel compounds of formula (I-1) are those
compounds of formula (I-1) wherein R.sup.1 is a radical of formula
NR.sup.5R.sup.6 wherein R.sup.5 is mono- or
di(C.sub.3-6cycloalkyl)methyl, C.sub.3-6cycloalkyl,
C.sub.3-6alkenyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)amino- C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl, and R.sup.6 is mono- or
di(C.sub.3-6cycloalkyl)methyl, Ar.sup.2C.sub.1-6alkyl,
Ar.sup.2oxyC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkyloxyC.sub.- 1-6alkyl, C.sub.3-6alkenyl, thienylmethyl,
furanylmethyl, tetrahydrofuranylmethyl,
C.sub.1-6alkylthioC.sub.1-6alkyl,
C.sub.1-6alkylcarbonylC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminoC.s- ub.1-6alkyl, or
di(C.sub.1-6alkyl)amino.
[0049] Other particular novel compounds of formula (I-1) are those
compounds of formula (I-1) wherein R.sup.1 is a radical of formula
NR.sup.5R.sup.6 wherein R.sup.5 and R.sup.6 taken together with the
nitrogen atom to which they are attached may form a pyrrolidinyl,
piperidinyl, or homopiperidinyl, each substituted with 1 or 2
substituents independently selected from C.sub.1-6alkyl or
C.sub.1-6alkyloxyC.sub.1-6alkyl; or R.sup.5 and R.sup.6 taken
together with the nitrogen atom to which they are attached may form
a morpholinyl or a thiomorpholinyl group, optionally substituted
with 1 or 2 substituents independently selected from C.sub.1-6alkyl
or C.sub.1-6alkyloxyC.sub.1-6alkyl.
[0050] Still other particular novel compounds of formula (I-1) are
those compounds of formula (I-1) wherein R.sup.3 is Het.sup.1 or
Ar.sup.1 wherein Ar.sup.1 is naphtyl: or phenyl substituted with 3
substituents each independently selected from halo, C.sub.1-6alkyl,
trifluoromethyl, hydroxy, cyano, C.sub.1-6alkyloxy, benzyl,
benzyloxy, C.sub.1-6alkylthio, nitro, amino or mono- or
di(C.sub.1-6alkyl)amino.
[0051] The compounds of the present invention can generally be
prepared by reacting an intermediate of formula (VI), wherein Z is
bromo or iodo, with an intermediate of formula (VII) under Suzuki
coupling conditions. Appropriate Suzuki coupling conditions are for
example, stirring a solution of an intermediate (VI) and a
tetrakis(triphenylphosphine)pallad- ium catalyst in a
reaction-inert solvent, e.g. toluene, in the presence of an
appropriate base, e.g. sodium carbonate, while adding intermediate
(VII) dissolved in an alcohol, e.g. ethanol. 5
[0052] The above-mentioned Suzuki reaction, i.e. a
palladium-catalyzed cross-coupling reaction of a phenylboronic acid
derivative with a haloarene in the presence of a base, is
extensively described in Suzuki A. et al. Synthetic Communications,
11:513-519, 1981 and Suzuki A., Pure and Applied Chemistry, 66,
213-222 (1994).
[0053] Compounds of formula (I-a), defined as compounds of formula
(I) wherein R.sup.1' has the meaning of R.sup.1 other than
C.sub.1-6alkyl can be prepared by reacting an intermediate of
formula (II) with an intermediate of formula (III). In intermediate
(II), W is an appropriate leaving group such as halo, e.g. choro,
bromo, or a sulfonyloxy group, e.g. a mesyloxy or a tosyloxy group.
6
[0054] Said reaction can be performed in a reaction-inert solvent
such as, for example, acetonitrile, N,N-dimethylformamide, methyl
isobutylketone, tetrahydrofuran or dichloromethane; and in the
presence of a suitable base such as, for example, sodium carbonate,
sodium hydrogen carbonate or triethylamine. When the intermediates
of formula (III) are volatile amines, said reaction may also be
performed in a sealed reaction vial. Stirring may enhance the rate
of the reaction. The reaction may conveniently be carried out at a
temperature ranging between room temperature and reflux
temperature.
[0055] Compounds of formula (I) wherein R.sup.1 is OR.sup.6, said
compounds being represented by formula (I-b), may be prepared by
O-alkylating an intermediate of formula (IV) with an intermediate
of formula (V), wherein W.sup.1 is an appropriate leaving group
such as halo, e.g. chloro, bromo, or a sulfonyloxy group, e.g. a
mesyloxy or a tosyloxy group. 7
[0056] Said reaction for preparing compounds of formula (I-b) can
be performed in a reaction-inert solvent such as, for example,
N,N-dimethylformamide, and in the presence of a suitable base such
as, for example, sodium hydride, preferably at a temperature
ranging between room temperature and reflux temperature.
[0057] The compounds of formula (I) wherein R.sup.1 is --NHR.sup.6,
represented by formula (I-c), can be prepared by N-alkylating an
intermediate of formula (VIII) with an intermediate of formula
R.sup.6--W, wherein W is as previously defined. Compounds of
formula (I-c) can be further N-alkylated with an intermediate of
formula R.sup.5--W, wherein W is as previously defined, yielding
compounds of formula (I-d). These N-alkylations are conducted in a
reaction-inert solvent such as, for example, an ether e.g.
tetrahydrofuran and preferably in the presence of a strong base,
e.g. NaH. 8
[0058] As outlined below, compounds of formula (I) may be converted
into each other following art-known transformation procedures.
[0059] The compounds of formula (I) may also be converted into each
other via art-known reactions or functional group transformations.
For instance, compounds of formula (I) bearing a
hydroxyC.sub.1-6alkyl group may be converted into compounds of
formula (I) bearing a C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl
group, e.g. by treatment with an acid anhydride in an
reaction-inert solvent such as, e.g. dichloromethane, and
optionally in the presence of a base such as, e.g. pyridine.
[0060] The compounds of formula (I) bearing an C.sub.1-6alkylthio
group can be converted into compounds of formula (I) bearing an
C.sub.1-6alkylsulfonyl or C.sub.1-6alkylsulfoxy group by an
oxidation reaction, e.g. treatment with a peroxide such as
3-chloroperbenzoic acid in a reaction-inert solvent, e.g.
dichloromethane. By controlling the amount of oxidant and other
reaction parameters, either compounds of formula (I) bearing
C.sub.1-6alkylsulfonyl or C.sub.1-6alkylsulfoxy can be obtained, or
a mixture of both, which subsequently can be separated by
conventional methods, e.g. column chromatography.
[0061] Compounds of formula (I) bearing a nitro group may be
converted to compounds of formula (I) bearing an amino group and
subsequently to compounds of formula (I) having a mono- or
di(C.sub.1-6alkyl)amino group. Also, the amino group may be
converted using a diazotization reaction to a halo.
[0062] Further, the R.sup.3 group of compounds of formula (I) can
be halogenated using a halogenating agent such as, e.g. chlorine or
bromine, in a suitable solvent, e.g. acetic acid, and optionally
the reaction may be performed at a temperature ranging between room
temperature and the reflux temperature of the reaction mixture.
[0063] Furthermore, the compounds of formula (I) may also be
prepared as described in EP-0,239,191-A, on pages 6 to 12.
[0064] Intermediates of formula (II) can be prepared according to
the procedure as described in Robins et al., J. Heterocyclic Chem.
22:601-634, 1985. 9
[0065] Intermediates of formula (IX) are reacted with a .beta.-keto
ester (X), preferably under reflux conditions and in a suitable
reaction-inert solvent such as an ether, e.g. THF, yielding
intermediates of formula (IX) which are converted into
intermediates of formula (II) by converting the hydroxy group of
intermediate (VI) into leaving group W, e.g. by treating (IV) with
methanesulfonyloxy chloride or a halogenating reagent such as, e.g.
POCl.sub.3.
[0066] Intermediates of formula (VIII) are prepared by treating
intermediates of formula (II) with ammonia.
[0067] The intermediates of formula (IX) are prepared by reacting
an .alpha.-phthalimide compound (XI) with dimethylformamide
dimethyl acetal under reflux conditions. The intermediate of
formula (XII) is subsequently mixed with a hydrazine, preferably at
room temperature and in a suitable solvent such as ethanol. 10
[0068] The .alpha.-phthalimide intermediate (XI) is generated by
reacting a chloroacetyl compound (XIII) with potasium phthalimide
in N,N-dimethylformamide. 11
[0069] Compounds of formula (I) and some of the intermediates may
have one or more stereogenic centers in their structure, present in
a R or a S configuration.
[0070] The compounds of formula (I) as prepared in the hereinabove
described processes may be synthesized as a mixture of
stereoisomeric forms, in particular in the form of racemic mixtures
of enantiomers which can be separated from one another following
art-known resolution procedures. The racemic compounds of formula
(I) may be converted into the corresponding diastereomeric salt
forms by reaction with a suitable chiral acid. Said diastereomeric
salt forms are subsequently separated, for example, by selective or
fractional crystallization and the enantiomers are liberated
therefrom by alkali. An alternative manner of separating the
enantiomeric forms of the compounds of formula (I) involves liquid
chromatography using a chiral stationary phase. Said pure
stereochemically isomeric forms may also be derived from the
corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably if a specific stereoisomer is
desired, said compound will be synthesized by stereospecific
methods of preparation. These methods will advantageously employ
enantiomerically pure starting materials.
[0071] The effectiveness of a compound as a CRF receptor antagonist
may be determined by various assay methods. Suitable CRF
antagonists of this invention are capable of inhibiting the
specific binding of CRF to its receptor and antagonizing activities
associated with CRF. A compound of structure (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). As mentioned above,
suitable CRF antagonists include compounds which demonstrate CRF
receptor affinity. 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 CRF) to
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 "K.sub.i" value calculated by the
following equation: 1 K i = IC 50 I + L / K D
[0072] where L=radioligand and K.sub.D=affinity of radioligand for
receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099,
1973).
[0073] 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. Accordingly, CRF receptor antagonist activity may be
determined by assay techniques which generally include an initial
binding assay (such as disclosed by DeSouza (supra, 1987)) followed
by a cAMP screening protocol (such as disclosed by Battaglia
(supra, 1987)). With reference to CRF receptor binding affinities,
CRF receptor antagonists of this invention have a K.sub.i of less
than 10 .mu.M. In a preferred embodiment of this invention, a CRF
receptor antagonist has a K.sub.i of less than 1 .mu.M, and more
preferably less than 0.25 .mu.M (i.e., 250 nM).
[0074] The CRF receptor antagonists of the present invention
demonstrate activity at the CRF receptor site, and may be used as
therapeutic agents for the treatment of a wide range of disorders
or illnesses including endocrine, psychiatric, and neurologic
disorders or illnesses. More specifically, the CRF receptor
antagonists of the present invention may be useful in treating
physiological conditions or disorders arising from the
hypersecretion of CRF. Because CRF is believed to be a pivotal
neurotransmitter that activates and coordinates the endocrine,
behavioral and automatic responses to stress, the CRF receptor
antagonists of the present invention can be used to treat
neuropsychiatric disorders. Neuropsychiatric disorders which may be
treatable by the CRF receptor antagonists of this invention include
affective disorders such as depression; anxiety-related disorders
such as generalized anxiety disorder, panic disorder,
obsessive-compulsive disorder, abnormal aggression, social fobia,
cardiovascular abnormalities such as unstable angina and reactive
hypertension; and feeding disorders such as anorexia nervosa,
bulimia, and irritable bowel syndrome. CRF antagonists may also be
useful in treating stress-induced immune suppression associated
with various diseases states, as well as stroke. Other uses of the
CRF antagonists of this invention include treatment of inflammatory
conditions (such as rheumatoid arthritis, uveitis, asthma,
inflammatory bowel disease and G.I. motility), Cushing's disease,
infantile spasms, epilepsy and other seizures in both infants and
adults, and various substance abuse and withdrawal (including
alcoholism). Both prophylactic and therapeutic treatment are
envisaged.
[0075] In another embodiment of the invention, pharmaceutical
compositions containing one or more CRF receptor antagonists are
disclosed. For the purposes of administration, the compounds of the
present invention may be formulated as pharmaceutical compositions.
Pharmaceutical compositions of the present invention comprise a CRF
receptor antagonist of the present invention (i.e., a compound of
structure (I)) and a pharmaceutically acceptable carrier and/or
diluent. The CRF receptor antagonist is present in the composition
in an amount which is therapeutically effective to treat a
particular disorder, that is, in an amount sufficient to achieve
CRF receptor antagonist activity, and preferably with acceptable
toxicity to the patient. Preferably, the pharmaceutical
compositions of the present invention may include a CRF receptor
antagonist in an amount from 0.1 mg to 250 mg per dosage depending
upon the route of administration, and more preferably from 1 mg to
60 mg. Appropriate concentrations and dosages can be readily
determined by one skilled in the art.
[0076] Pharmaceutically acceptable carrier and/or diluents are
familiar to those skilled in the art. For compositions formulated
as liquid solutions, acceptable carriers and/or diluents include
saline and sterile water, and may optionally include antioxidants,
buffers, bacteriostats and other common additives. The compositions
can also be formulated as pills, capsules, granules, or tablets
which contain, in addition to a CRF receptor antagonist, diluents,
dispersing and surface active agents, binders, and lubricants. One
skilled in this art may further formulate the CRF receptor
antagonist in an appropriate manner, and in accordance with
accepted practices.
[0077] In another embodiment, the present invention provides a
method for treating a variety of disorders or illnesses, including
endocrine, psychiatric and neurologic disorders or illnesses. Such
methods include administering of a compound of the present
invention to a warm-blooded animal in an amount sufficient to treat
the disorder or illness. Such methods include systemic
administration of a CRF receptor antagonist of this invention,
preferably in the form of a pharmaceutical composition. As used
herein, systemic administration includes oral and parenteral
methods of administration. For oral administration, suitable
pharmaceutical compositions of CRF receptor antagonists include
powders, granules, pills, tablets, and capsules as well as liquids,
syrups, suspensions, and emulsions. These compositions may also
include flavorings, preservatives, suspending, thickening and
emulsifying agents, and other pharmaceutically acceptable
additives. For parental administration, the compounds of the
present invention can be prepared in aqueous injection solutions
which may contain, in addition to the CRF receptor antagonist,
buffers, antioxidants, bacteriostats, and other additives commonly
employed in such solutions.
[0078] As mentioned above, administration of a compound of the
present invention can be used to treat a wide variety of disorders
or illnesses. In particular, the compounds of the present invention
may be administered to a warm-blooded animal for the treatment of
depression, anxiety disorder, panic disorder, obsessive-compulsive
disorder, abnormal aggression, social fobia, unstable angina,
reactive hypertension, anorexia nervosa, bulimia, irritable bowel
syndrome, stress-induced immune suppression, stroke, inflammation,
Cushing's disease, infantile spasms, epilepsy, substance abuse or
withdrawal, and craving.
[0079] Hence, this invention provides the use of compounds of
formula (I) for the manufacture of a medicine for treating
physiological conditions or disorders arising from the
hypersecretion of corticotropin-releasing factor (CRF) and in
particular for treating the disorders or illnesses mentioned above;
and in a further embodiment the use of novel compounds of formula
(I) as a medicine is provided. Both prophylactic and therapeutic
treatment are envisaged.
EXPERIMENTAL PART
[0080] Hereinafter "THF" means tetrahydrofuran and "DCM" means
dichloromethane.
A. Preparation of the Intermediates
Example A.1
[0081] a) A solution of 2,4-dichloroacetophenone (3.78 g) in THF
(20 ml) was cooled to -78.degree. C. under a nitrogen atmosphere.
To this stirred solution was added lithium diisopropylamide (LDA)
(1.0 M, 22 ml) and the resulting solution was stirred at
-78.degree. C. for 15 minutes. Acetoxyacetyl chloride (2.3 ml) was
injected and the mixture was stirred for 1 hour and then allowed to
warm to room temperature. The reaction was quenched with 1N HCl and
the product was extracted with diethyl ether (200 ml). The organic
layer was dried, concentrated and recrystallized from
ether/hexanes, yielding ethyl
4-(2,4-dichlorophenyl)-2,4-diketobutyr- ate (intermediate 1).
[0082] b) Intermediate (1) (15.4 g) was dissolved in acetic acid
and sodium nitrite (3.8 g) in 15 ml water was added slowly. After
the exothermic reaction was complete, and the reaction mixture
began to cool, methyl hydrazine (6 ml) was added. The reaction
mixture was allowed to stir overnight, or until the mixture became
yellow. The mixture was concentrated to dryness, giving a yellow
oil. This oil was suspended between ether and 2N HCl. The aqueous
solution was separated and neutralized with sodium bicarbonate and
the slightly basic solution was extracted with ethyl acetate. The
ethyl acetate layer was dried and concentrated, yielding
1-methyl-3-carboxyethyl-4-amino-5-(2,4-dichlorophe- nyl)pyrazole
(intermediate 2), which was used without purification in the next
step.
[0083] c) A solution of intermediate (2) (5 g), ethyl-ethoxy
crotonate (2.6 g) and p-toluene-sulfonic acid (100 mg) was stirred
and refluxed in xylene (100 ml). After two hours reflux, the
reaction mixture was concentrated to a thick oil. This oil was
dissolved in 30 ml ethanol and refluxed for 3 hours in the presence
of potassium tert-butoxide (2 g). After reflux, the solution was
allowed to cool to room temperature and treated with acetic acid
(10 ml), then concentrated to dryness. This residue was suspended
in ethyl acetate and the resulting solid sodium acetate was
filtered off. The filtrate was concentrated to dryness and
5-methyl-6-carboxyethyl-7-hydroxy-2-methyl-4-(2,4-dichlorophenyl)pyrazolo-
[4,3-b]pyridine (intermediate 3) was obtained by recrystallisation
of the crude filtrate with ethyl ether.
[0084] d) A solution of intermediate (3) (1.7 g) and LiOH (1M, 17.5
ml) in ethanol (10 ml) was stirred and heated to reflux and stirred
for 16 hours; The solution was then allowed to cool, then poured
into HCl (1N, 20 ml). The compound was extracted out with ethyl
acetate, dried, and concentrated. The residue was suspended in
diphenyl ether (10 ml) and heated for 230.degree. C. for 3 hours.
The reaction mixture was allowed to cool, and
5-methyl-7-hydroxy-2-methyl-3-(2,4-dichlorophenyl)pyrazolo[4-
,3-b]pyridine (intermediate 4) was obtained by purification on a
silica column (eluens: ethyl acetate/methanol).
[0085] e) Intermediate (4) (400 mg) was suspended in phosphorous
oxychloride (2 ml) and refluxed for 2 hours. The reaction mixture
was concentrated, yielding
5-methyl-7-chloro-2-methyl-3-(2,4-dichlorophenyl)p-
yrazolo[4,3-b]pyridine (intermediate 5).
Example A.2
[0086] a) To a stirred suspension of potassium phtalimide (92.6 g)
in anhydrous DMF (200 ml) at 0.degree. C. was added slowly with
stirring trichloroacetophenone (100 g) while keeping the
temperature below 5.degree. C. After 1 hour, the reaction mixture
was allowed to warm to room temperature. After 16 hours, the
solution was concentrated and the resulting residue was partitioned
between HCl (1N) and DCM. The combined organic layers were dried,
concentrated, and the resulting residue was recrystallized from DCM
and diethyl ether, yielding
2-(2-oxo-2-(2,4-dichlorophenylethyl))-1H-indene-1,3(2H)-dione
(intermediate 6).
[0087] b) Intermediate (6) (50 g) was suspended in dimethyl
formamide dimethyl acetal (40 ml). This suspension was heated to
120.degree. C. for 12 hours. The reaction mixture was concentrated
and the resulting residue was suspended in diethyl ether and
filtered, yielding 1-methyl-4-amino-3-(2,4-dichlorophenyl)pyrazole
(intermediate 7).
[0088] c) Intermediate (7) (46 g) was suspended in absolute ethanol
(200 ml) and stirred under nitrogen. This suspension was heated to
35.degree. C. and one equivalent of methylhydrazine (5.52 g) was
added all at once with stirring. This solution was allowed to heat
for 10 minutes, followed by a second addition of methyl hydrazine
(7 g). The reaction mixture was refluxed for 3 hours, concentrated
to a viscous oil, yielding intermediate (8) which was immediately
used in the next step without further purification.
[0089] d) Crude intermediate (8) was dissolved in benzene (200 ml)
and refluxed with a dean-stark trap in the presence of
p-toluenesulfonic acid (30 mg). After 1 hour, the reaction mixture
was concentrated, and the resulting oil was used in the next step
without further purification (intermediate 9).
[0090] e) Intermediate (9) was dissolved in diphenyl ether (50 ml)
and heated to 250.degree. C. After 30 minutes, the mixture was
allowed to cool to room temperature, triturated with hexanes, and
concentrated, yielding
5-methyl-7-hydroxy-1-methyl-3-(2,4-dichlorophenyl)pyrazolo[4,3-b-
]pyridine (intermediate 10) which was used without further
purification.
[0091] f) Intermediate (10) was refluxed in the presence of
phosphorous oxychloride (45 ml) for 4 hours. The reaction mixture
was cooled to room temperature, concentrated and partitioned
between ethyl acetate and saturated sodium bicarbonate solution.
The aqueous layer was extracted with ethyl acetate. The combined
organic layers were dried, concentrated, and the residue was
purified over silica gel (eluent: 10% diethyl ether/hexanes),
yielding 5-methyl-7-chloro-1-methyl-3-(2,4-dichlorophenyl-
)-pyrazolo[4,3-b]pyridine (intermediate 11).
B. Preparation of the Final Compounds
Example B.1
[0092] Intermediate (5) was suspended in dipropylamine (1 ml) and
p-toluenesulflonic acid (30 mg) and heated to 200.degree. C. for 2
hours in a sealed tube. The reaction mixture was cooled and
partitioned between ethyl acetate and saturated sodium bicarbonate
solution. The organic layer was separated, dried and concentrated.
The residue was purified over silica gel (eluens: ethyl
acetate/hexanes), yielding
5-methyl-7-(dipropylamino)-2-methyl-3-(2,4-dichlorophenyl)pyrazolo[4,3-b]-
pyridine (compound 1).
[0093] Table F-1 to F-4 list the compounds that were prepared
accordingly and table F-5 lists the analytical data for these
compounds.
1TABLE F-1 12 Co. No. R.sup.5 R.sup.6 R.sup.4 1
--(CH.sub.2).sub.2CH.sub.3 --(CH.sub.2).sub.2CH.sub.3 2-CH.sub.3 2
H --(CH.sub.2).sub.3CH.sub- .3 1-CH.sub.3 3
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub- .3 1-CH.sub.3
4 --(CH.sub.2).sub.2CH.sub.3 --(CH.sub.2).sub.2CH.sub- .3
1-CH.sub.3 5 --(CH.sub.2).sub.2OCH.sub.3 --(CH.sub.2).sub.2OCH.s-
ub.3 1-CH.sub.3 6 --(CH.sub.2).sub.2OCH.sub.3 --CH.sub.3 1-CH.sub.3
7 --(CH.sub.2).sub.2CH.sub.3 --(CH.sub.2).sub.2OH 1-CH.sub.3 8
--(CH.sub.2).sub.2CH.sub.3 --CH.sub.3 1-CH.sub.3 9
--(CH.sub.2).sub.2OCH.sub.3 --(CH.sub.2).sub.2CH.sub.3 1-CH.sub.3
10 H --CH(CH.sub.2OH)((CH.sub.2).sub.2CH.sub.3) 1-CH.sub.3 11
--CH.sub.3 --CH(CH.sub.2OCH.sub.3)((CH.sub.2).sub.2CH.sub.3)
6-CH.sub.3 12 --(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3
H 13 --(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3
2-CH.sub.3 14 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.2CH.sub.3
1-CH.sub.3 15 --(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.2CH.sub.3
1-CH.sub.3 16 --(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3
1-CH.sub.2CH.sub.3 17 --(CH.sub.2).sub.3CH.sub.3
--(CH.sub.2).sub.3CH.sub.3 2-CH.sub.2CH.sub.3 18
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3
1-(CH.sub.2).sub.2CH.sub.3 19 --(CH.sub.2).sub.3CH.sub.3
--(CH.sub.2).sub.3CH.sub.3 2-(CH.sub.2).sub.2CH.sub.3 20
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3
1-CH(CH.sub.3).sub.2 21 --(CH.sub.2).sub.3CH.sub.3
--(CH.sub.2).sub.3CH.sub.3 2-CH(CH.sub.3).sub.2 22
--(CH.sub.2).sub.2CH.sub.3 13 --H 23 --(CH.sub.2).sub.2CH.sub.3 14
1-CH.sub.3 24 --(CH.sub.2).sub.2CH.sub.3 15 2-CH.sub.3 25
--(CH.sub.2).sub.2CH.sub.3 16 1-CH.sub.2CH.sub.3 26
--(CH.sub.2).sub.2CH.sub.3 17 2-CH.sub.2CH.sub.3 27
--(CH.sub.2).sub.3CH.sub.3 --CH.sub.2CH.sub.3 --H 28
--(CH.sub.2).sub.3CH.sub.3 --CH.sub.2CH.sub.3 2-CH.sub.3 29
--(CH.sub.2).sub.3CH.sub.3 --CH.sub.2CH.sub.3 1-CH.sub.2CH.sub.3 30
--(CH.sub.2).sub.3CH.sub.3 --CH.sub.2CH.sub.3 2-CH.sub.2CH.sub.3 31
--CH.sub.2CH.sub.3 --(CH.sub.2).sub.2OCH.sub.3 1-CH.sub.3 32
--CH(CH.sub.3).sub.2 --(CH.sub.2).sub.2OCH.sub.3 1-CH.sub.3 33 --H
4-hydroxyphenylmethyl 1-CH.sub.3 34 --H --(CH.sub.2).sub.2OCH.sub.-
3 1-CH.sub.3 35 --H 18 1-CH.sub.3 36 --(CH.sub.2).sub.3CH.sub.3
--(CH.sub.2).sub.2OCH.sub.3 1-CH.sub.3 37
--(CH.sub.2).sub.4CH.sub.3 --(CH.sub.2).sub.2OCH.sub.3 1-CH.sub.3
38 --(CH.sub.2).sub.5CH.sub.3 --(CH.sub.2).sub.2OCH.sub.3
1-CH.sub.3 39 --CH.sub.2CH(CH.sub.3).sub.2
--(CH.sub.2).sub.2OCH.sub.3 1-CH.sub.3 40
2-CH.sub.2C(.dbd.CH.sub.2)CH.sub.3 --CH.sub.2CH.sub.3 2-CH.sub.3 41
--(CH.sub.2).sub.2CH(CH.sub.3).su- b.2
--(CH.sub.2).sub.2CH(CH.sub.3).sub.2 1-CH.sub.3 42
--(CH.sub.2).sub.2N(CH.sub.3).sub.2 phenylmethyl 1-CH.sub.3 43
--CH.sub.2CH.sub.3 4-methylphenylmethyl 1-CH.sub.3 44
--CH.sub.2CH.sub.3 2-fluorophenylmethyl 1-CH.sub.3 45
--CH.sub.2CH.sub.3 19 1-CH.sub.3 46 --(CH.sub.2).sub.3CH.sub.3 20
1-CH.sub.3 47 --(CH.sub.2).sub.4CH.sub.3 21 1-CH.sub.3 48
--(CH.sub.2).sub.5CH.sub.3 22 1-CH.sub.3 49
--CH.sub.2CH(CH.sub.3).sub.2 23 1-CH.sub.3 50
--(CH.sub.2).sub.3CH.sub.3 4-hydroxyphenylmethyl 1-CH.sub.3 51
--(CH.sub.2).sub.3CH.sub.3 phenylmethyl 1-CH.sub.3 52
--(CH.sub.2).sub.2CH.sub.3 phenylmethyl 1-CH.sub.3 53
--CH.sub.2CH(CH.sub.3).sub.2 --CH.sub.2CH(CH.sub.3).sub.2
1-CH.sub.3 54 --CH.sub.2CH.sub.3 --(CH.sub.2).sub.3OCH.sub.3
1-CH.sub.3 55 --(CH.sub.2).sub.2CH.sub.3
--(CH.sub.2).sub.3OCH.sub.3 1-CH.sub.3 56
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3OCH.sub.3 1-CH.sub.3
57 --CH.sub.2CH.sub.3 --(CH.sub.2).sub.4CH.sub.3 1-CH.sub.3 58
--(CH.sub.2).sub.2CH.sub.3 --(CH.sub.2).sub.4CH.sub.3 1-CH.sub.3 59
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.4CH.sub.3 1-CH.sub.3 60
--(CH.sub.2).sub.3CH.sub.3 4-methoxyphenylethyl 1-CH.sub.3 61
--(CH.sub.2).sub.3CH.sub.3 2-pyridinylethyl 1-CH.sub.3 62
--(CH.sub.2).sub.3CH.sub.3 phenoxyethyl 1-CH.sub.3 63
--(CH.sub.2).sub.3CH.sub.3 isopentyl 1-CH.sub.3 64
--CH.sub.2CH.sub.3 --(CH.sub.2).sub.2CH.sub.3 1-CH.sub.3 65
--(CH.sub.2).sub.3CH.sub.3 2-methoxyphenylethyl 1-CH.sub.3 66
--(CH.sub.2).sub.3CH.sub.3 3-methoxyphenylethyl 1-CH.sub.3 67
--(CH.sub.2).sub.3CH.sub.3 4-pyridinylmethyl 1-CH.sub.3 68
--(CH.sub.2).sub.3CH.sub.3 4-pyridinylethyl 1-CH.sub.3 69
--(CH.sub.2).sub.3CH.sub.3 2-furanylmethyl 1-CH.sub.3 70
--(CH.sub.2).sub.3CH.sub.3 2-tetrahydrofuranylmethyl 1-CH.sub.3 71
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.2SCH.sub.3 1-CH.sub.3
72 --(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.2OCH(CH.sub.3).sub.2
1-CH.sub.3 73 --(CH.sub.2).sub.3CH.sub.3 4-methoxyphenylethyl
1-CH.sub.3
[0094]
2TABLE F-2 24 Co. No. R.sup.5 R.sup.6 R.sup.2 R.sup.4 74
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3
1-CH.sub.3 75 --(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.2CH.sub.-
3 --CH.sub.3 1-CH.sub.3 76 --(CH.sub.2).sub.3CH.sub.3
--CH.sub.2CH.sub.3 --CH.sub.3 1-CH.sub.3 77
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3 H
78 --(CH.sub.2).sub.2CH.sub.3 25 --CH.sub.3 H 79
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3
1-CH.sub.2CH.sub.3 80 --(CH.sub.2).sub.3CH.sub.3
--(CH.sub.2).sub.3CH.sub.3 --CH.sub.3 2-CH.sub.2CH.sub.3 81
--(CH.sub.2).sub.2CH.sub.3 26 --CH.sub.3 1-CH.sub.2CH.sub.3 82
--(CH.sub.2).sub.2CH.sub.3 27 --CH.sub.3 2-CH.sub.2CH.sub.3 83
--(CH.sub.2).sub.3OCH.sub.3 --CH.sub.2CH.sub.3 --CH.sub.3
1-CH.sub.3 84 --(CH.sub.2).sub.2CH.sub.3 --(CH.sub.2).sub.2CH.sub.-
3 --CH.sub.3 1-CH.sub.3 85 --(CH.sub.2).sub.2CH.sub.3
--CH.sub.2CH.sub.3 --CH.sub.3 1-CH.sub.3 86
--CH(CH.sub.3)(CH.sub.2CH.sub.3) --(CH.sub.2).sub.2CH.sub.3
--CH.sub.3 1-CH.sub.3 87 --(CH.sub.2).sub.2CH.sub.3 28 --CH.sub.3
1-CH.sub.3 88 --CH.sub.3 --(CH.sub.2).sub.2CH.sub.3 --CH.sub.3
1-CH.sub.3 89 --CH.sub.2CH.dbd.CH.sub.2 --CH.sub.2CH.dbd.CH.sub.2
--CH.sub.3 1-CH.sub.3 90 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3
--CH.sub.3 1-CH.sub.3 91 --CH.sub.3 --(CH.sub.2).sub.2OCH.sub.3
--CH.sub.3 1-CH.sub.3 92 --CH.sub.2CH.sub.3 --CH.sub.2CH.sub.3
--CH.sub.3 1-CH.sub.3
[0095]
3TABLE F-3 29 Co. No. R.sup.5 R.sup.6 R.sup.2 R.sup.4 93
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3
1-CH.sub.3 94 --(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.-
3 --CH.sub.3 2-CH.sub.3 95 --(CH.sub.2).sub.3CH.sub.3
--CH.sub.2CH.sub.3 --CH.sub.3 1-CH.sub.3 96 --CH.sub.2CH.sub.3
--(CH.sub.2).sub.3CH.sub.3 --CH.sub.3 H 97 --(CH.sub.2).sub.3CH.su-
b.3 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3 H 98
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3
2-CH.sub.2CH.sub.3 99 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.2CH.sub.3
--CH.sub.3 2-CH.sub.2CH.sub.3 100 --(CH.sub.2).sub.3CH.sub.3
--CH.sub.2CH.sub.3 --CH.sub.3 1-CH.sub.2CH.sub.3 101
--(CH.sub.2).sub.3CH.sub.3 --(CH.sub.2).sub.3CH.sub.3 --CH.sub.3
1-CH.sub.2CH.sub.3 102 --(CH.sub.2).sub.3CH.sub.3 30 --CH.sub.3
1-CH.sub.3 103 --(CH.sub.2).sub.2OCH.sub.3
--(CH.sub.2).sub.2OCH.sub.3 --CH.sub.3 1-CH.sub.3 104
--CH(CH.sub.3).sub.2 --CH.sub.2CH.sub.3 --CH.sub.3 1-CH.sub.3 105
--CH.sub.3 phenylmethyl --CH.sub.3 1-CH.sub.3
[0096]
4TABLE F-4 31 Co. No. R.sup.1 R.sup.4 R.sup.3 106
--N(CH.sub.2CH.sub.2CH.sub- .3).sub.2 2-CH.sub.3 2-chlorophenyl 107
--N(CH.sub.2CH.sub.2CH.sub.- 3).sub.2 2-CH.sub.3 phenyl 108
--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 1-CH.sub.3 2,4-bis(trifluoro-
methyl)phenyl 109 --N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2
1-CH.sub.3 2,4,6-trimethylphenyl 110
--N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).su- b.2 2-CH.sub.3
2,4,6-trimethylphenyl 111 4-methylpiperidin-1-yl 1-CH.sub.3
2-chloro-4,6-dimethyl- phenyl 112
--N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2 H
2-chloro-4-methoxyphenyl 113
--N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2 1-CH.sub.3
2-chloro-4-methoxyphenyl 114 --N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3)-
.sub.2 2-CH.sub.3 2-chloro-4-methoxyphenyl 115
2-methylpiperidin-1-yl 1-CH.sub.3 2-chloro-4-methylphenyl 116
2-methyl-5-ethyl- 1-CH.sub.3 2,4-dichlorophenyl piperidin-1-yl 117
--N(CH.sub.2CH.sub.2CH.sub.3).sub.2 1-CH.sub.3 4-chlorophenyl 118
N-thiomorpholinyl 5-CH.sub.3 2,4-dichlorophenyl 119
(N,N-ethylbutyl)amine 1-CH.sub.3 2-(dimethylamino)-4-meth-
yl-5-pyridinyl 120 (N,N-butylpentyl)amine 1-CH.sub.3
2,4,6-trimethylphenyl 121 (N,N-ethylbutyl)amine 1-CH.sub.3
2,4,6-trimethylphenyl 122 (N,N-methoxy- 1-CH.sub.3 1-naphtyl
ethylpropyl)amine 123 (N,N-ethylbutyl)amine 1-CH.sub.3
2-methyl-4-methoxyphenyl
[0097]
5TABLE F-5 Analytical data Co. No. .sup.1H NMR data (CDCl.sub.3) 1
.delta. 0.92(trp, 6H), 1.75(trp, 4H), 2.48(s, 3H), 3.71(m, 2H),
3.82(m, 2H), 4.00 (s, 3H), 6.01(s, 1H), 7.51(m, 3H) 2 .delta.
0.90(trp, 6H), 1.28(m, 4H), 1.53(m, 4H), 2.60(s, 3H), 3.22(trp,
4H), 4.29 (s, 3H), 6.69(s, 1H), 7.37(dd, 1H), 7.56(d, 1H), 7.79(d,
1H) 4 .delta. 0.89(trp, 6H), 1.58(m, 4H), 2.60(s, 3H), 3.20(trp,
4H), 4.29(s, 3H), 6.69 (s, 1H), 7.38(dd, 1H), 7.55(d, 1H), 7.80(d,
1H) 5 .delta. 2.61(s, 3H), 3.29(s, 6H), 3.52(trp, 8H), 4.31(s, 3H),
6.83(s, 1H), 7.36(dd, 1H), 7.41(d, 1H), 7.78(d, 1H) 6 .delta.
2.65(s, 3H), 2.97(s, 3H), 3.27(s, 3H), 3.41(m, 4H), 4.35(s, 3H),
6.78(s, 1H), 7.39(dd, 1H), 7.58(d, 1H), 7.81(d, 1H) 7 .delta.
0.92(trp, 3H), 1.61(m, 2H), 2.59(s, 3H), 3.23(m, 2H), 3.42(trp,
2H), 3.78 (m, 2H), 4.30(s, 3H), 6.75(s, 1H), 7.40(dd, 1H), 7.52(d,
1H), 7.76(d, 1H) 8 .delta. 0.95(trp, 3H), 1.71(m, 2H), 2.59(s, 3H),
2.88(s, 3H), 4.30(s, 3H), 6.67(s, 1H), 7.39(dd, 1H), 7.58(d, 1H),
7.76(d, 1H) 12 .delta. 0.97(t, 6H), 1.37-1.44(m, 4H), 1.64-1.72(m,
4H), 2.55(s, 3H), 3.62(t, 4H), 6.13(s, 1H), 7.35(dd, 1H), 7.49(d,
1H), 8.22(d, 1H) 13 .delta. 1.00(t, 6H), 1.39-1.47(m, 4H),
1.64-1.74(m, 4H), 2.54(s, 3H), 3.70-3.80(m, 2H), 3.80-3.92(m, 2H),
3.95(s, 3H), 5.95(s, 1H), 7.42(dd, 1H), 7.48(d, 1H), 7.57(d, 1H) 14
.delta. 0.88(trp, 3H), 1.05(trp, 3H), 1.41(m, 2H), 1.62(m, 2H),
2.60(s, 3H), 3.30 (trp, 2H), 3.32(m, 2H), 4.29(s, 3H), 6.68(s, 1H),
7.39(dd, 1H), 7.52(d, 1H), 7.73(d, 1H) 15 .delta. 0.93(m, 6H),
1.38(m, 2H), 1.40(m, 2H), 1.60(m, 2H), 2.59(s, 3H), 3.30(m, 4H),
4.30(s, 3H), 6.66(s, 1H), 7.38(dd, 1H), 7.50(d, 1H), 7.79(d, 1H) 16
.delta. 0.90(t, 6H), 1.26-1.34(m, 4H), 1.41(t, 3H), 1.48-1.54(m,
4H), 2.60(s, 3H), 3.21(t, 4H), 4.61(q, 2H), 6.70(s, 1H), 7.35(dd,
1H), 7.54(d, 1H), 7.80(d, 1H) 17 .delta. 1.00(t, 6H), 1.37-1.49(m,
4H), 1.67-1.77(m, 4H), 2.49(s, 3H), 3.68-3.77(m, 2H), 3.82-3.92(m,
2H), 4.05-4.15(m, 1H), 4.17-4.28(m, 1H), 5.94(s, 1H), 7.40(dd, 1H),
7.44(d, 1H), 7.56(d, 1H) 18 .delta. 0.84(t, 3H), 0.90(t, 6H),
1.26-1.34(m, 4H), 1.46-1.56(m, 4H), 1.80-1.90(m, 2H), 2.60(s, 3H),
3.21(t, 4H), 4.53(t, 2H), 6.70(s, 1H), 7.35(dd, 1H), 7.54(d, 1H),
7.77(d, 1H) 19 .delta. 0.79(t, 3H), 0.99(t, 6H), 1.38-1.47(m, 4H),
1.64-1.76(m, 4H), 1.82-1.90(m, 2H), 2.50(s, 3H), 3.65-3.75(m, 2H),
3.80-3.92(m, 2H), 3.96-4.06(m, 1H), 4.15-4.24(m, 1H), 5.94(s, 1H),
7.39-7.45(m, 2H), 7.57(d, 1H) 20 .delta. 0.89(t, 6H), 1.26-1.34(m,
4H), 1.46-1.54(m, 10H), 2.60(s, 3H), 3.19(t, 4H), 5.32-5.41(m, 1H),
6.70(s, 1H), 7.35(dd, 1H), 7.54(d, 1H), 7.82(d, 1H) 21 .delta.
1.00(t, 6H), 1.36(d, 3H), 1.40-1.48(m, 4H), 1.61(d, 3H),
1.68-1.79(m, 4H), 2.50(s, 3H), 3.68-3.92(m, 4H), 4.36-4.45(m, 1H),
5.92(s, 1H), 7.41(d, 2H), 7.57(dd, 1H) 22 .delta. 0.32-035(m, 2H),
0.59-0.64(m, 2H), 1.00(t, 3H), 1.14-1.22(m, 1H), 1.72-1.80 (m, 2H),
2.56(s, 3H), 3.60-3.65(m, 4H), 6.22(s, 1H), 7.40(dd, 1H), 7.52 (d,
1H), 8.32(d, 1H) 23 .delta. 0.06-0.09(m, 2H), 0.47-0.51(m, 2H),
0.93(t, 3H), 1.22-1.24(m, 1H), 1.50-1.62 (m, 2H), 2.60(s, 3H),
3.11(d, 2H), 3.32(d, 2H), 4.30(s, 3H), 6.75(s, 1H), 7.35(dd, 1H),
7.54(d, 1H), 7.79(d, 1H) 24 .delta. 0.34-0.38(m, 2H), 0.57-0.61(m,
2H), 1.00(t, 3H), 1.18-1.24(m, 1H), 1.73-1.81 (m, 2H), 2.55(s, 3H),
3.70-3.90(m, 4H), 3.95(s, 3H), 6.05(s, 1H), 7.43 (dd, 2H), 7.47(d,
1H), 7.57(d, 1H) 25 .delta. 0.06-0.08(m, 2H), 0.47-0.51(m, 2H),
0.93(t, 3H), 1.24-1.26(m, 1H), 1.42(t, 3H), 1.50-1.62(m, 2H),
2.61(s, 3H), 3.10(d, 2H), 3.31(d, 2H), 4.64(q, 2H), 6.77(s, 1H),
7.36(dd, 1H), 7.54(d, 1H), 7.80(d, 1H) 26 .delta. 0.36-0.38(m, 2H),
0.57-0.61(m, 2H), 1.00(t, 3H), 1.18-1.24(m, 1H), 1.45(t, 3H),
1.72-1.85(m, 2H), 2.54(s, 3H), 3.70-3.90(m, 4H), 4.06-4.30(m, 2H),
6.04(s, 1H), 7.42(dd, 2H), 7.45(d, 1H), 7.57(d, 1H) 27 .delta.
1.00(t, 3H), 1.31(t, 3H), 1.38-1.48(m, 2H), 1.67-1.77(m, 2H),
2.55(s, 3H), 3.63(t, 2H), 3.74(q, 2H), 6.14(s, 1H), 7.40(dd, 1H),
7.52(d, 1H), 8.35(d, 1H) 28 .delta. 1.00(t, 3H), 1.30(t, 3H),
1.39-1.47(m, 2H), 1.64-1.76(m, 2H), 2.51(s, 3H), 3.70-3.80(m, 2H),
3.80-3.96(m, 2H), 3.95(s, 3H), 5.97(s, 1H), 7.41(dd, 1H), 7.46(d,
1H), 7.57(d, 1H) 29 .delta. 0.91(t, 3H), 1.09(t, 3H), 1.30-1.38(m,
2H), 1.42(t, 3H), 1.50-1.58(m, 2H), 2.61(s, 3H), 3.19(t, 2H),
3.29(q, 2H), 4.62(q, 2H), 6.71(s, 1H), 7.36(dd, 1H), 7.54(d, 1H),
7.79(d, 1H) 30 .delta. 1.04(t, 3H), 1.34(t, 3H), 1.39-1.47(m, 5H),
1.64-1.78(m, 2H), 2.60(s, 3H), 3.75-4.00(m, 4H), 4.02-4.25(m, 2H),
5.96(s, 1H), 7.45(s, 1H), 7.46(s, 1H), 7.58(s, 1H) 74 .delta.
0.91(t, 6H), 1.30(m, 4H), 1.35(m, 4H), 2.50(s, 3H), 2.61(s, 3H),
3.23(m, 4H), 4.26(s, 3H), 6.69(s, 1H), 7.32(m, 2H), 7.75(d, 1H) 75
.delta. 0.90(t, 6H), 1.30(m, 2H), 1.34(m, 4H), 2.49(s, 3H), 2.60(s,
3H), 3.21(m, 2H), 4.27(s, 3H), 6.69(s, 1H), 7.31(m, 2H), 7.75(d,
1H) 76 .delta. 0.93(t, 3H), 1.09(t, 3H), 1.30(m, 2H), 1.34(m, 2H),
2.47(s, 3H), 2.59(s, 3H), 3.19(t, 2H), 3.29(q, 2H), 4.25(s, 3H),
6.67(s, 1H), 7.30(m, 2H), 7.71(d, 1H) 77 .delta. 0.97(t, 6H),
1.36-1.46(m, 4H), 1.63-1.73(m, 4H), 2.41(s, 3H), 2.54(s, 3H),
3.54(t, 4H), 6.18(s, 1H), 7.21(dd, 1H), 7.27(d, 1H), 7.62(d, 1H) 78
.delta. 0.28-0.33(m, 2H), 0.59-0.66(m, 2H), 0.98(t, 3H),
1.08-1.18(m, 1H), 1.70-1.78 (m, 2H), 2.44(s, 3H), 2.55(s, 3H),
3.49-3.54(m, 4H), 6.28(s, 1H), 7.25 (dd, 1H), 7.30(d, 1H), 7.69(d,
1H) 79 .delta. 0.90(t, 6H), 1.23-1.34(m, 4H), 1.41(t, 3H),
1.46-1.57(m, 4H), 2.49(s, 3H), 2.60(s, 3H), 3.20(t, 4H), 4.58(q,
2H), 6.69(s, 1H), 7.26-7.31(m, 2H), 7.78(d, 1H) 80 .delta. 1.00(t,
6H), 1.38-1.49(m, 4H), 1.67-1.77(m, 4H), 2.17(s, 3H), 2.57(s, 3H),
3.66-3.95(m, 4H), 4.05-4.16(m, 2H), 5.93(s, 1H), 7.22(d, 1H),
7.28(d, 1H), 7.37(s, 1H) 81 .delta. 0.05-0.08(m, 2H), 0.47-0.51(m,
2H), 0.92(t, 3H), 1.24-1.26(m, 1H), 1.41(t, 3H), 1.50-1.66(m, 2H),
2.48(s, 3H), 2.60(s, 3H), 3.09(d, 2H), 3.32(t, 2H), 4.61(q, 2H),
6.76(s, 1H), 7.26-7.31(m, 2H), 7.77(d, 1H) 82 .delta. 0.36-0.40(m,
2H), 0.57-0.62(m, 2H), 1.01(t, 3H), 1.18-1.22(m, 1H), 1.41(t, 3H),
1.72-1.85(m, 2H), 2.17(s, 3H), 2.60(s, 3H), 3.70-4.00(m, 4H),
4.06-4.20 (m, 2H), 6.03(s, 1H), 7.22(d, 2H), 7.29(d, 1H), 7.38(s,
1H) 83 .delta. 1.11(t, 3H), 2.47(s, 3H), 2.60(s, 3H), 3.31(s, 3H),
3.35(m, 2H), 3.43(m, 2H), 3.52(m, 2H), 4.27(s, 3H), 6.74(s, 1H),
7.30(m, 2H), 7.71(d, 1H) 84 .delta. 0.89(t, 6H), 1.56(m, 4H),
2.48(s, 3H), 2.58(s, 3H), 3.19(t, 4H), 4.25(s, 3H), 6.67(s, 1H),
7.30(m, 2H), 7.71(d, 1H) 85 .delta. 0.92(t, 3H), 1.09(t, 3H),
1.58(m, 2H), 2.48(s, 3H), 2.59(s, 3H), 3.17(t, 2H), 3.33(q, 2H),
4.27(s, 3H), 6.68(s, 1H), 7.30(m, 2H), 7.72(d, 1H) 86 .delta.
0.90(q, 6H), 1.17(d, 2H), 1.53(m, 2H), 2.49(s, 3H), 2.61(s, 3H),
3.10(m, 2H), 3.28(m, 1H), 4.27(s, 3H), 6.73(s, 1H), 7.30(m, 2H),
7.72(d, 1H) 87 .delta. 0.01-0.08(m, 2H), 0.47-0.50(m, 2H), 0.93(t,
3H), 1.55-1.62(m, 3H), 2.48(s, 3H), 2.59(s, 3H), 3.11(d, 2H),
3.33(t, 2H), 4.27(s, 3H), 6.74(s, 1H), 7.26(dd, 1H), 7.30(d, 1H),
7.73(d, 1H) 93 .delta. 0.91(t, 6H), 1.30(m, 4H), 1.35(m, 4H),
2.51(s, 3H), 2.48(s, 3H), 2.61(s, 3H), 3.23(q, 4H), 4.26(s, 3H),
6.66(s, 1H), 7.20(s, 1H), 7.75(s, 1H) 94 .delta. 0.90(trp, 3H),
0.97(trp, 3H), 1.24(m, 4H), 1.4(m, 2H), 1.71(m, 2H), 2.07 (s, 6H),
2.38(s, 3H), 1.42(s, 3H), 3.81(s, 3H), 3.81(trp, 4H), 5.93(s, 1H),
7.00 (s, 2H) 95 .delta. 0.93(t, 3H), 1.09(t, 3H), 1.30(m, 2H),
1.34(m, 2H), 2.38(s, 3H), 2.47(s, 3H), 2.59(s, 3H), 3.19(t, 2H),
3.29(q, 2H), 4.25(s, 3H), 6.67(s, 1H), 7.18(s, 1H), 7.76(s, 1H) 100
.delta. 0.93(t, 3H), 1.09(t, 3H), 1.29(t, 3H), 1.30(m, 2H), 1.34(m,
2H), 2.38(s, 3H), 2.47(s, 3H), 2.59(s, 3H), 3.19(t, 2H), 3.29(q,
2H), 4.60(q, 2H), 6.70(s, 1H), 7.20(s, 1H), 7.76(s, 1H) 102 .delta.
0.15(m, 2H), 0.50(m, 2H), 0.92(t, 3H), 1.25(m, 1H), 1.30(m, 2H),
1.49(m, 2H), 2.38(s, 3H), 2.49(s, 3H), 2.60(s, 3H), 3.15(d, 2H),
3.39(t, 2H), 4.30(s, 3H), 6.78(s, 1H), 7.2(m, 2H), 7.78(s, 1H) 103
.delta. 2.38(s, 3H), 2.42(s, 3H), 2.60(s, 3H), 3.28(s, 6H), 3.48(s,
8H), 4.35(s, 1H), 6.80(s, 1H), 7.19(s, 1H), 7.76(s, 1H) 106 .delta.
0.91(trp, 6H), 1.72(trp, 4H), 2.48(s, 3H), 3.70(m, 2H), 3.80(m,
2H), 3.98 (s, 3H), 6.03(s, 1H), 7.39(m, 2H), 7.55(m, 2H) 107
.delta. 0.99(trp, 6H), 1.76(trp, 4H), 2.47(s, 3H), 3.75(m, 4H),
4.09(s, 3H), 5.97(s, 1H), 7.35(d, 2H), 7.50(m, 2H), 7.71(d, 1H) 108
.delta. 0.87(trp, 6H), 1.56(m, 4H), 2.50(s, 3H), 3.06(m, 4H),
4.40(s, 3H), 6.36(s, 1H), 7.57(d, 1H), 7.71(m, 1H), 8.04(d, 1H) 110
.delta. 0.91(trp, 6H), 1.25(m, 4H), 1.52(m, 4H), 2.10(s, 6H),
2.31(s, 3H), 2.54(s, 3H), 3.24(trp, 4H), 4.22(s, 3H), 6.63(s, 1H),
6.93(s, 2H)
C. Pharmacological Examples
Example C.1: CRF Receptor Binding Activity
[0098] Compounds were evaluated for binding activity to the CRF
receptor by a standard radioligand binding assay as generally
described by DeSouza et al. (J. Neurosci. 7:88-100, 1987). By
utilizing various radiolabeled CRF ligands, the assay may be used
to evaluate the binding activity of the compounds of the present
invention with any CRF receptor subtype. Briefly, the binding assay
involves the displacement of a radiolabeled CRF ligand from the CRF
receptor.
[0099] More specifically, the binding assay was performed in 1.5 ml
Eppendorf tubes using approximately 1.times.10.sup.6 cells per tube
stably transfected with human CRF receptors. Each tube received
about 0.1 ml of assay buffer (e.g., Dulbecco's phosphate buffered
saline, 10 mM magnesium chloride, 20 .mu.M bacitracin) with or
without unlabeled sauvagine, urotensin I or CRF (final
concentration, 1 .mu.M) to determine nonspecific binding, 0.1 ml of
[.sup.125I] tyrosine-ovine CRF (final concentration approximately
200 pM or approximately the K.sub.D as determined by Scatchard
analysis) and 0.1 ml of a membrane suspension of cells containing
the CRF receptor. The mixture was incubated for 2 hours at
22.degree. C. followed by the separation of the bound and free
radioligand by centrifugation. Following two washes of the pellets,
the tubes were cut just above the pellet and monitored in a gamma
counter for radioactivity at approximately 80% efficiency. All
radioligand binding data was analyzed using a non-linear
least-square curve-fitting program.
[0100] Binding activity corresponds to the concentration (nM) of
the compound necessary to displace 50% of the radiolabeled ligand
from the receptor. Compounds 1-32, 36-41, 43-95, 97, 99-104, 106,
107, 109, 110, 112-116, 118-123 were found to have a
K.sub.i.ltoreq.250 nM.
* * * * *