U.S. patent application number 10/339780 was filed with the patent office on 2004-05-06 for crf receptor antagonists and methods relating thereto.
This patent application is currently assigned to Neurocrine Biosciences, Inc.. Invention is credited to Dyck, Brian P., Guo, Zhiqiang, Haddach, Mustapha, Huang, Charles Q., McCarthy, James R., Nelson, Jodie.
Application Number | 20040087589 10/339780 |
Document ID | / |
Family ID | 24297480 |
Filed Date | 2004-05-06 |
United States Patent
Application |
20040087589 |
Kind Code |
A1 |
Haddach, Mustapha ; et
al. |
May 6, 2004 |
CRF receptor antagonists and methods relating thereto
Abstract
CRF receptor antagonists are disclosed which have utility in the
treatment of a variety of disorders, including the treatment of
disorders manifesting hypersecretion of CRF in a warm-blooded
animals, such as stroke. The CRF receptor antagonists of this
invention have the following structure: 1 including stereoisomers
and pharmaceutically acceptable salts thereof, wherein n, m, A, B,
C, R, R.sub.1, R.sub.2 and Ar are as defined herein. Compositions
containing a CRF receptor antagonist in combination with a
pharmaceutically acceptable carrier are also disclosed, as well as
methods for use of the same
Inventors: |
Haddach, Mustapha; (San
Diego, CA) ; Dyck, Brian P.; (San Diego, CA) ;
Huang, Charles Q.; (San Diego, CA) ; Nelson,
Jodie; (San Diego, CA) ; Guo, Zhiqiang; (San
Diego, CA) ; McCarthy, James R.; (Zionsville,
IN) |
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: |
24297480 |
Appl. No.: |
10/339780 |
Filed: |
January 8, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10339780 |
Jan 8, 2003 |
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09574751 |
May 18, 2000 |
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6531475 |
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09574751 |
May 18, 2000 |
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09439840 |
Nov 12, 1999 |
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6514982 |
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09439840 |
Nov 12, 1999 |
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09401364 |
Sep 21, 1999 |
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09401364 |
Sep 21, 1999 |
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09370837 |
Aug 9, 1999 |
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09370837 |
Aug 9, 1999 |
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09191073 |
Nov 12, 1998 |
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Current U.S.
Class: |
514/250 ;
514/267; 544/250; 544/251; 544/346 |
Current CPC
Class: |
C07D 487/16 20130101;
A61P 25/22 20180101; C07D 471/16 20130101 |
Class at
Publication: |
514/250 ;
514/267; 544/250; 544/251; 544/346 |
International
Class: |
A61K 031/519; A61K
031/498; C07D 487/14 |
Claims
1. A compound having the following structure: 498including
stereoisomers, prodrugs and pharmaceutically acceptable salts
thereof, wherein: n is 1 or 2; A and C are each independently
nitrogen, carbon or CH; B is nitrogen or CR.sub.3; with the
provisos that at least one of A, B and C is nitrogen; A, B and C
are not all nitrogen; and either A--B or B--C is a double bond; X
is nitrogen or CR.sub.q; R.sub.q is hydrogen, alkyl or halo; Ar is
aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R is
an optional substituent which, at each occurrence, is independently
alkyl, alkylidenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,
wherein m is 0, 1, 2 or 3 and represents the number of R
substituents; R.sub.1 is --C(H).sub.0,1(R.sub.4)(R.sub.5) or
--SO.sub.2R.sub.5; R.sub.2 is hydrogen, alkyl, haloalkyl or cyano
R.sub.3 is hydrogen, alkyl or haloalkyl; R.sub.4 is hydrogen, oxo,
alkyl, substituted alkyl, alkylidenyl or halo; and R.sub.5 is a
radical of the formula --Y--Z--R.sub.6, wherein Y is an alkanediyl,
substituted alkanediyl, or a direct bond, Z is NH, --N(R.sub.7), O,
S, SO.sub.2, C(.dbd.O), C(.dbd.O)O, OC(.dbd.O), NHC(.dbd.O),
C(.dbd.O)NH, NH(SO.sub.2), (SO.sub.2)NH, NR.sub.8C(.dbd.O)O, or a
direct bond; R.sub.6 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, heterocyle,
substituted heterocycle, heterocyclealkyl, or substituted
heterocylcealkyl; R.sub.7 and R.sub.8 are alkyl, substituted alkyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heterocyle, substituted heterocycle, heterocyclealkyl, or
substituted heterocylcealkyl; or R.sub.5 and R.sub.7 taken together
with the nitrogen atom to which they are attached form a heterocyle
ring or substituted heterocyle ring; or R.sub.4 and R.sub.5 taken
together with the carbon atom to which they are attached form
cycloalkyl, substituted cycloalkyl, cycloalkylcycloalkyl,
substituted cycloalkylcycloalkyl, cycloalkylaryl, substituted
cycloalkyaryl, cycloalkylheterocycle, or substituted
cycloalkylheterocycle.
2. The compound of claim 1 wherein n is 1 and having one of the
following structures: 499500
3. The compound of claim 1 wherein n is 2 and having one of the
following structures: 501
4. The compound of claim 1 having one of the following structures:
502
5. The compound of claim 4 wherein X is CR.sub.q and having one of
the following structures: 503
6. The compound of claim 4 wherein X is nitrogen and having one of
the following structures: 504
7. The compound of claim 1 wherein Ar is phenyl or substituted
phenyl.
8. The compound of claim 7 wherein substituted phenyl is
2,4-dichlorophenyl, 2-chloro-4-methyl-phenyl,
2-methyl-4-chloro-phenyl, 2,4,6-trimethyl-phenyl,
2-chloro-4-methoxy-phenyl, 2-methyl-4-methoxy-phenyl, or
2,4-dimethoxy-phenyl.
9. The compound of claim 1 wherein Ar is heteroaryl or substituted
heteroaryl.
10. The compound of claim 9 wherein heteroaryl is pyridinyl.
11. The compound of claim 9 wherein substituted heteroaryl is
4-methyl-6-dimethylamino-pyridin-3-yl,
4-dimethylamino-6-methyl-pyridin-3- -yl or
6-dimethylamino-pyridin-3-yl.
12. The compound of claim 1 wherein m is zero.
13. The compound of claim 1 wherein R is alkyl.
14. The compound of claim 1 wherein R is arylalkyl.
15. The compound of claim 1 wherein R.sub.1 is
--CH(n-propyl).sub.2, --CH(n-propyl)(CH.sub.2OCH.sub.3),
--CH(phenyl)(CH.sub.2OCH.sub.3), --CH(CH.sub.2OR').sub.2,
--CH(CH.sub.2OR')(ethyl), --CH(CH.sub.2OR')(n-butyl),
--CH(CH.sub.2OR')(tert-butyl), --CH(CH.sub.2OR')(4-chloro-phenyl),
--CH(CH.sub.2OR)(CH.sub.2CH.sub.2SCH.- sub.3),
--CH(CH.sub.2CH.sub.3)(CH.sub.2Ophenyl), where each occurrence of
R' is independently selected from C.sub.1-6alkyl.
16. The compound of claim 1 wherein R.sub.1 is
--SO.sub.2R.sub.5.
17. The compound of claim 1 wherein R.sub.1 is
--C(H).sub.0,1(R.sub.4)(R.s- ub.5).
18. The compound of claim 17 wherein R.sub.1 is
--CH.sub.2R.sub.5.
19. The compound of claim 17 wherein R.sub.1 is
--C(.dbd.O)R.sub.5.
20. The compound of claim 17 wherein R.sub.1 is
--CH(R.sub.4)(R.sub.5).
21. The compound of claim 1 wherein R.sub.4 is hydrogen.
22. The compound of claim 1 wherein R.sub.4 is alkyl.
23. The compound of claim 1 wherein R.sub.4 is keto.
24. The compound of claim 1 wherein Y is alkanediyl or substituted
alkanediyl.
25. The compound of claim 1 wherein Y is a direct bond.
26. The compound of claim 1 wherein Z is NH, --N(R.sub.7), O, S,
SO.sub.2, C(.dbd.O), C(.dbd.O)O, OC(.dbd.O), NHC(.dbd.O),
C(.dbd.O)NH, NH(SO.sub.2), (SO.sub.2)NH or NR.sub.8C(.dbd.O)O.
27. The compound of claim 1 wherein Z is a direct bond.
28. The compound of claim 1 wherein R.sub.6 is hydrogen, alkyl or
substituted alkyl.
29. The compound of claim 1 wherein R.sub.6 is aryl, substituted
aryl, arylalkyl or substituted arylalkyl.
30. The compound of claim 1 wherein R.sub.6 is heterocyle,
substituted heterocycle, heterocyclealkyl or substituted
heterocylcealkyl.
31. The compound of claim 1 wherein R.sub.2 is methyl.
32. The compound of claim 1 wherein R.sub.2 is ethyl.
33. The compound of claim 1 having the structure: 505
34. The compound of claim 33 wherein Ar is 2,4-dichlorophenyl,
2-chloro-4-methylphenyl, 2-trifluorometyl-4-chlorophenyl, or
2-methoxy-4-trifluoromethyl.
35. The compound of claim 33 wherein m is 0.
36. The compound of claim 33 wherein R.sub.1 is
CH(alkyl)(alkyl).
37. The compound of claim 36 wherein R.sub.1 is
CH(n-propyl).sub.2.
38. The compound of claim 36 wherein R.sub.1 is
CH(n-butyl).sub.2.
39. The compound of claim 33 wherein m is 1 and R is alkyl.
40. The compound of claim 39 wherein R is methyl, ethyl or
n-propyl.
41. The compound of claim 40 wherein R.sub.1 is
--CH.sub.2(cycloalkyl).
42. The compound of claim 41 wherein R.sub.1 is
--CH.sub.2(cyclopropyl).
43. The compound of claim 40 wherein R.sub.1 is
CH(alkyl)(alkyl).
44. The compound of claim 43 wherein R.sub.1 is CH(n-propyl).sub.2
or CH(n-butyl).sub.2.
45. A composition comprising a compound of claim 1 in combination
with a pharmaceutically acceptable carrier or diluent.
46. A method for treating a disorder manifesting hypersecretion of
CRF in a warm-blooded animal, comprising administering to the
animal an effective amount of the pharmaceutical composition of
claim 45.
47. The method of claim 46 wherein the disorder is stroke.
48. The method of claim 46 wherein the disorder is depression.
49. The method of claim 46 wherein the disorder is anxiety.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/439,840, filed Nov. 12, 1999; which is a
continuation-in-part of U.S. application Ser. No. 09/401,364, filed
Sep. 21, 1999; which is a continuation-in-part of U.S. application
Ser. No. 09/370,837, filed Aug. 9, 1999; which is a
continuation-in-part of U.S. application Ser. No. 09/191,073, filed
Nov. 12, 1998 (which applications are hereby incorporated by
reference in their entirety).
TECHNICAL FIELD
[0002] This invention relates generally to CRF receptor
antagonists, and to methods of treating disorders by administration
of such antagonists to a warm-blooded animal in need thereof.
BACKGROUND OF THE INVENTION
[0003] 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).
[0004] 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 224:1449-1451, 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). The receptor for CRF has now been
cloned from rat (Perrin et al., Endo 133(6):3058-3061, 1993), and
human brain (Chen et al., PNAS 90(19):8967-8971, 1993; Vita et al.,
FEBS 335(1):1-5, 1993). This receptor is a 415 amino acid protein
comprising seven membrane spanning domains. A comparison of
identity between rat and human sequences shows a high degree of
homology (97%) at the amino acid level.
[0005] 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.
[0006] 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. 278:332, 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 suggests that CRF may be hypersecreted
in the brain in depression, anxiety-related disorders, and anorexia
nervosa. (DeSouza, Ann. Reports in Med. Chem. 25:215-223, 1990).
Accordingly, clinical data suggests 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.
[0007] The first CRF receptor antagonists were peptides (see, e.g.,
Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al., Science
224:889, 1984). While these peptides established that CRF receptor
antagonists can attenuate the pharmacological responses to CRF,
peptide CRF receptor antagonists suffer from the usual drawbacks of
peptide therapeutics including lack of stability and limited oral
activity. More recently, small molecule CRF receptor antagonists
have been reported. For example, substituted
4-thio-5-oxo-3-pyyrazoline derivatives (Abreu et al., U.S. Pat. No.
5,063,245) and substituted 2-aminothiazole derivatives
(Courtemanche et al., Australian Patent No. AU-A-41399/93) have
been reported as CRF receptor antagonists. These particular
derivatives were found to be effective in inhibiting the binding of
CRF to its receptor in the 1-10 .mu.M range and 0.1-10 .mu.M range,
respectively.
[0008] More recently, numerous small molecule CRR receptor
antagonists have been proposed, including the compounds disclosed
in the following patent documents: WO 94/13643, WO 94/13644, WO
94/13661, WO 94/13676, WO 94/13677, WO 95/10506, WO 95/33750, WO
96/35689, WO 97/00868, WO 97,35539, WO 97/35580, WO 97,35846, WO
97/44038, WO 98/03510, WO 98/05661, WO 98/08846, WO 98/08847, WO
98/11075, WO 98/15543, WO 98/21200 and WO 98/29413.
[0009] Due to the physiological significance of CRF, the
development of 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.
[0010] While significant strides have been made toward achieving
CRF regulation through administration of CRF receptor antagonists,
there remains a need in the art for effective small molecule CRF
receptor antagonists. There is also a need for pharmaceutical
compositions containing such CRF receptor antagonists, as well as
methods relating to the use thereof to treat, for example,
stress-related disorders. The present invention fulfills these
needs, and provides other related advantages.
SUMMARY OF THE INVENTION
[0011] In brief, this invention is generally directed to CRF
receptor antagonists, and more specifically to CRF receptor
antagonists having the following general structure (I): 2
[0012] including stereoisomers, prodrugs and pharmaceutically
acceptable salts thereof, wherein n, m, A, B, C, X, R, R.sub.1,
R.sub.2, and Ar are as defined below.
[0013] The CRF receptor antagonists of this invention have utility
over a wide range of therapeutic applications, and may be used to
treat a variety of disorders or illnesses, including stress-related
disorders. Such methods include administering an effective amount
of a CRF receptor antagonist of this invention, preferably in the
form of a pharmaceutical composition, to an animal in need thereof.
Accordingly, in another embodiment, pharmaceutical compositions are
disclosed containing one or more CRF receptor antagonists of this
invention in combination with a pharmaceutically acceptable carrier
and/or diluent.
[0014] These and other aspects of the invention will be apparent
upon reference to the following detailed description. To this end,
various references are set forth herein which describe in more
detail certain procedures, compounds and/or compositions, and are
hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention is directed generally to compounds
useful as corticotropin-releasing factor (CRF) receptor
antagonists.
[0016] In a first embodiment, the CRF receptor antagonists of this
invention have the following structure (I): 3
[0017] including stereoisomers, prodrugs and pharmaceutically
acceptable salts thereof,
[0018] wherein:
[0019] n is 1 or 2;
[0020] A and C are each independently nitrogen, carbon or CH;
[0021] B is nitrogen or CR.sub.3;
[0022] with the provisos that at least one of A, B and C is
nitrogen; A, B and C are not all nitrogen; and either A--B or B--C
is a double bond;
[0023] X is nitrogen or Cr.sub.q;
[0024] R.sub.q is hydrogen, alkyl or halo;
[0025] Ar is aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0026] R is an optional substituent which, at each occurrence, is
independently alkyl, alkylidenyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, wherein m is 0, 1, 2 or 3 and represents the
number of R substituents;
[0027] R.sub.1 is --C(H).sub.0,1(R.sub.4)(R.sub.5) or
--SO.sub.2R.sub.5;
[0028] R.sub.2 is hydrogen, alkyl, haloalkyl or cyano;
[0029] R.sub.3 is hydrogen, alkyl or haloalkyl;
[0030] R.sub.4 is hydrogen, oxo, alkyl, substituted alkyl,
alkylidenyl or halo; and
[0031] R.sub.5 is a radical of the formula --Y--Z--R.sub.6,
wherein
[0032] Y is an alkanediyl, substituted alkanediyl, or a direct
bond,
[0033] Z is NH, --N(R.sub.7), O, S, SO.sub.2, C(.dbd.O),
C(.dbd.O)O, OC(.dbd.O), NHC(.dbd.O), C(.dbd.O)NH, NH(SO.sub.2),
(SO.sub.2)NH, NR.sub.8C(.dbd.O)O, or a direct bond;
[0034] R.sub.6 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, heterocyle,
substituted heterocycle, heterocyclealkyl, or substituted
heterocyclealkyl;
[0035] R.sub.7 and R.sub.8 are alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, heterocyle,
substituted heterocycle, heterocyclealkyl, or substituted
heterocylcealkyl; or
[0036] R.sub.6 and R.sub.7 taken together with the nitrogen atom to
which they are attached form a heterocyle ring or substituted
heterocyle ring;
[0037] or R.sub.4 and R.sub.5 taken together with the carbon atom
to which they are attached form cycloalkyl, substituted cycloalkyl,
cycloalkylcycloalkyl, substituted cycloalkylcycloalkyl,
cycloalkylaryl, substituted cycloalkyaryl, cycloalkylheterocycle,
or substituted cycloalkylheterocycle.
[0038] As used herein, the above terms have the following
meaning:
[0039] "Alkyl" means a straight chain or branched, noncyclic or
cyclic, unsaturated or saturated aliphatic hydrocarbon containing
from 1 to 10 carbon atoms, while the term "lower alkyl" has the
same meaning as alkyl but contains from 1 to 6 carbon atoms.
Representative saturated straight chain alkyls include methyl,
ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while
saturated branched alkyls include isopropyl, sec-butyl, isobutyl,
tert-butyl, isopentyl, and the like. Representative saturated
cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, --CH.sub.2cyclopropyl, --CH.sub.2cyclobutyl,
--CH.sub.2cyclopentyl, --CH.sub.2cyclohexyl, and the like; while
unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl,
and the like. Cyclic alkyls, also referred to as "homocyclic
rings," and include di- and poly-homocyclic rings such as decalin
and adamantyl. Unsaturated alkyls contain at least one double or
triple bond between adjacent carbon atoms (referred to as an
"alkenyl" or "alkynyl", respectively). Representative straight
chain and branched alkenyls include ethylenyl, propylenyl,
1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl,
3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and
the like; while representative straight chain and branched alkynyls
include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,
2-pentynyl, 3-methyl-1 butynyl, and the like.
[0040] "Alkylidenyl" represents a divalent alkyl from which two
hydrogen atoms are taken from the same carbon atom, such as
.dbd.CH.sub.2, .dbd.CHCH.sub.3, .dbd.CHCH.sub.2CH.sub.3,
.dbd.C(CH.sub.3)CH.sub.2CH.sub.- 3, and the like.
[0041] "Alkanediyl" means a divalent alkyl from which two hydrogen
atoms are taken from the same carbon atom or from different carbon
atoms, such as --CH.sub.2-- --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH(CH.sub.3)CH.sub.2--, and the
like.
[0042] "Aryl" means an aromatic carbocyclic moiety such as phenyl
or naphthyl.
[0043] "Arylalkyl" means an alkyl having at least one alkyl
hydrogen atoms replaced with an aryl moiety, such as benzyl,
--CH.sub.2-(1 or 2-naphthyl), --(CH.sub.2).sub.2phenyl,
--(CH.sub.2).sub.3phenyl, --CH(phenyl).sub.2, and the like.
[0044] "Heteroaryl" means an aromatic heterocycle ring of 5- to 10
members and having at least one heteroatom selected from nitrogen,
oxygen and sulfur, and containing at least 1 carbon atom, including
both mono- and bicyclic ring systems. Representative heteroaryls
include (but are not limited to) furyl, benzofuranyl, thiophenyl,
benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl,
pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl,
benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl,
benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
[0045] "Heteroarylalkyl" means an alkyl having at least one alkyl
hydrogen atom replaced with a heteroaryl moiety, such as
--CH.sub.2pyridinyl, --CH.sub.2pyrimidinyl, and the like.
[0046] "Heterocycle" (also referred to herein as a "heterocycle
ring") means a 5- to 7-membered monocyclic, or 7- to 14-membered
polycyclic, heterocycle ring which is either saturated, unsaturated
or aromatic, and which contains from 1 to 4 heteroatoms
independently selected from nitrogen, oxygen and sulfur, and
wherein the nitrogen and sulfur heteroatoms may be optionally
oxidized, and the nitrogen heteroatom may be optionally
quaternized, including bicyclic rings in which any of the above
heterocycles are fused to a benzene ring as well as tricyclic (and
higher) heterocyclic rings. The heterocycle may be attached via any
heteroatom or carbon atom. Heterocycles include heteroaryls as
defined above. Thus, in addition to the aromatic heteroaryls listed
above, heterocycles also include (but are not limited to)
morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,
hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
[0047] "Heterocyclealkyl" means an alkyl having at least one alkyl
hydrogen atom replaced with a heterocycle, such as
--CH.sub.2morpholinyl, and the like.
[0048] "Cycloalkyl" means a saturated or unsaturated (but not
aromatic) carbocyclic ring containing from 3-8 carbon atoms, such
as cyclopentane, cyclohexane, cycloheptane, cyclohexene, and the
like.
[0049] "Cycloalkylcycloalkyl" means a cycloalkyl ring fused to a
cycloalkyl ring, such as decalin.
[0050] "Cycloalkylaryl" means a cycloalkyl ring fused to aryl, such
as tetralin.
[0051] "Cycloalkylheterocycle" means a cycloalkyl ring fused to a
heterocycle ring.
[0052] The term "substituted" as used herein means any of the above
groups (e.g., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycle, heterocyclealkyl, etc.) wherein at least one hydrogen
atom is replaced with a substituent. In the case of a keto
substituent ("--C(.dbd.O)--") two hydrogen atoms are replaced. When
substituted, "substituents" within the context of this invention
include halogen, hydroxy, cyano, nitro, amino, alkylamino,
dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl, substituted
heteroarylalkyl, heterocycle, substituted heterocycle,
heterocyclealkyl, substituted heterocyclealkyl, --NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --N.sub.aC(.dbd.O)NR.sub.aNR.sub.b,
--NR .sub.aC(.dbd.O)OR.sub.b --NR.sub.aSO.sub.2R.sub.b, --OR.sub.a,
--C(.dbd.O)R.sub.a --C(.dbd.O)OR.sub.a, --C(.dbd.O)NR.sub.aR.sub.b,
--OC(.dbd.O)NR.sub.aR.su- b.b, --SH, --SR.sub.a, --SOR.sub.a,
--S(.dbd.O).sub.2R.sub.a, --OS(.dbd.O).sub.2R.sub.a,
--S(.dbd.O).sub.2OR.sub.a, wherein R.sub.a and R.sub.b are the same
or different and independently hydrogen, alkyl, haloalkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycle, substituted heterocycle,
heterocylealkyl or substituted heterocyclealkyl.
[0053] "Halogen" means fluoro, chloro, bromo and iodo.
[0054] "Haloalkyl" means an alkyl having at least one hydrogen atom
replaced with halogen, such as trifluoromethyl and the like.
[0055] "Alkoxy" means an alkyl moiety attached through an oxygen
bridge (i.e., --O-alkyl) such as methoxy, ethoxy, and the like.
[0056] "Alkylthio" means an alkyl moiety attached through a sulfur
bridge (i.e., --S-alkyl) such as methylthio, ethylthio, and the
like.
[0057] "Alkylsulfonyl" means an alkyl moiety attached through a
sulfonyl bridge (i.e., --SO.sub.2-alkyl) such as methylsulfonyl,
ethylsulfonyl, and the like.
[0058] "Alkylamino" and "dialkylamino" mean one or two alkyl moiety
attached through a nitrogen bridge (i.e., --N-alkyl) such as
methylamino, ethylamino, dimethylamino, diethylamino, and the
like.
[0059] "Hydroxyalkyl" means an alkyl substituted with at least one
hydroxyl group.
[0060] "Mono- or di(cycloalkyl)methyl" represents a methyl group
substituted with one or two cycloalkyl groups, such as
cyclopropylmethyl, dicyclopropylmethyl, and the like.
[0061] "Alkylcarbonylalkyl" represents an alkyl substituted with a
--C(.dbd.O)alkyl group.
[0062] "Alkylcarbonyloxyalkyl" represents an alkyl substituted with
a --C(.dbd.O)Oalkyl group or a --OC(.dbd.O)alkyl group.
[0063] "Alkyloxyalkyl" represents an alkyl substituted with a
--O-alkyl group.
[0064] "Alkylthioalkyl" represents a alkyl substituted with a
--S-alkyl group.
[0065] "Mono- or di(alkyl)amino" represents an amino substituted
with one alkyl or with two alkyls, respectively.
[0066] "Mono- or di(alkyl)aminoalkyl" represents a alkyl
substituted with a mono- or di(alkyl)amino.
[0067] As used in the context of this invention, 4
[0068] of structure (I) represents --CH.sub.2CH.sub.2-- or
--CH.dbd.CH-- optionally substituted with 1 or 2 R substituents
(i.e., when n=1 and m=1 or 2), or --CH.sub.2CH.sub.2CH.sub.2--
optionally substituted with 1, 2 or 3 R substituents (i.e., when
n=2 and m=1, 2 or 3). Moieties in this regard are
--CH.sub.2CH(R)--, --CH(R)CH.sub.2--, --CH(R)CH(R)--,
--CH.dbd.C(R)--, --C(R).dbd.CH--, --C(R).dbd.C(R)--,
--CH.sub.2CH.sub.2CH(R)--, --CH.sub.2CH(R)CH.sub.2--,
--CH(R)CH.sub.2CH.sub.2--, --CH(R)CH.sub.2CH(R),
--CH(R)CH(R)CH.sub.2 and --CH.sub.2CH(R)CH(R)--, wherein each
occurrence of R is the same or different and independently selected
from the R groups as set forth above.
[0069] Thus, representative compounds of this invention include the
following structures (Ia) through (In): 567
[0070] In one embodiment, n is 1 and m is 0 and the CRF receptor
antagonists of this invention have structure (Ia). In another
embodiment, n is 1 and m is 1 and the CRF receptor antagonists of
this invention have structure (Ib) or (Ic).
[0071] Depending upon the choice of the A, B and C moieties, the
CRF receptor antagonists of this invention include compounds having
the following structures (I-1), (I-2), (I-3) and (I-4): 8
[0072] When X of compounds (I-1), (I-2), (I-3) and (I-4) is
CR.sub.q, representative compounds of this invention include the
following compounds (I-1a), (I-2a), (1-3a), and (I-4a); and when X
of compounds (I-1), (I-2), (I-3) and (I-4) is nitrogen,
representative compounds of this invention include the following
compounds (I-1b), (I-2b), (I-3b) and (I-4b): 910
[0073] In one embodiment, R.sub.1 is --SO.sub.2R.sub.5, as
represented by the following structure: 11
[0074] In another embodiment, R.sub.1 is
--C(H).sub.0,1(R.sub.4)(R.sub.5) which represents both
--CH(R.sub.4)(R.sub.5) and --C(R.sub.4)(R.sub.5). Representative
embodiments in this regard include the following R.sub.1 moieties
(i), (ii) and (iii): 12
[0075] Representative R.sub.4 moieties of this invention include,
but are not limited to, hydrogen, oxo (i.e., .dbd.O), halogen
(fluoro, chloro, bromo and iodo), methyl, ethyl, n-propyl, n-butyl,
n-penty, .dbd.CH.sub.2, .dbd.CHCH.sub.3, and
.dbd.CHCH.sub.2CH.sub.3. Thus, representative R.sub.1 moieties
include (but are not limited to) the following: 13
[0076] In the embodiment where the R.sub.4 and R.sub.5 groups of
R.sub.1 taken together form a cycloalkyl, the resulting R.sub.1
group has the structure: 14
[0077] Cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl,
and the like. Similarly, substituted cycloalkyls are cycloalkyls
having one or more substituents as defined above. For example, in
one embodiment, the cycloalkyl is substituted with one or more
alkyl groups, and representative RI moieties include the following:
15
[0078] wherein R' and R" are the same or different and
independently selected from, for example, alkyl such as methyl or
ethyl.
[0079] In the embodiment where the R.sub.4 and R.sub.5 groups of
R.sub.1 taken together form a cycloalkylaryl, and the resulting
R.sub.1 group include compounds having the structure: 16
[0080] including optionally substituted analogs thereof as defined
above.
[0081] In still further embodiments, R.sub.4 and R.sub.5 are taken
together to form a cycloalkylcycloalky or cycloalkylheterocycle,
and the resulting R.sub.1 group include, for example, compounds
having the structure: 17
[0082] including optionally substituted analogs as defined
above.
[0083] As noted above, in one embodiment, R.sub.5 is a radical of
the formula --Y--Z--R.sub.6, wherein
[0084] Y is an alkanediyl, substituted alkanediyl, or a direct
bond,
[0085] Z is NH, --N(R.sub.7), O, S, SO.sub.2, C(.dbd.O),
C(.dbd.O)O, OC(.dbd.O), NHC(.dbd.O), C(.dbd.O)NH, NH(SO.sub.2),
(SO.sub.2)NH, NR.sub.8C(.dbd.O)O, or a direct bond;
[0086] R.sub.6 is hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, heterocyle,
substituted heterocycle, heterocyclealkyl, or substituted
heterocylcealkyl; or
[0087] R.sub.7 and R.sub.8 are the same or different and
independently alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, heterocyle, substituted
heterocycle, heterocyclealkyl, or substituted heterocylcealkyl;
or
[0088] R.sub.6 and R.sub.7 taken together with the nitrogen atom to
which they are attached form a heterocyle ring or substituted
heterocyle ring.
[0089] In one embodiment, the R.sub.5 moiety has Y as an
alkanediyl, Z as a direct bond, and R.sub.6 as hydrogen. Such R,
moieties include alkyl, saturated alkyl, unsaturated alkyl, lower
alkyl, lower saturated alkyl, lower unsaturated alkyl, saturated
straight chain alkyls, saturated branched chain alkyls, saturated
cyclic alkyl, unsaturated cyclic alkyl, alkenyl, straight chain
alkenyl, branched chain alkenyl, alkynyl, straight chain alkynyl,
and branched chain alkynyl. Representative examples are methyl,
ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl,
1-ethylpropyl (i.e., --CH(Et).sub.2) n-pentyl, n-hexyl, iso-hexyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
[0090] In another embodiment, the R.sub.5 moiety has Y and Z being
direct bonds while R.sub.6 includes an aromatic ring, such as aryl,
substituted aryl, arylalkyl, substituted arylalkyl. Representative
examples are phenyl, and chlorophenyl.
[0091] In another embodiment, the R.sub.5 moiety has Y being a
direct bond, Z being NH and R.sub.6 being as defined above. Thus,
R.sub.6 may be hydrogen such that R.sub.5 is amino. Alternatively,
R.sub.6 may be alkyl, such that R.sub.5 is an alkyl-substituted
amino group, e.g., isopropylamino, and ethylamino. Alternatively,
R.sub.6 may be an aryl or substituted aryl, such that R.sub.5 is an
arylamino or substituted arylamino group, e.g.,
(methoxyphenyl)amino, ((trifluoromethoxy)phenyl)am- ino, (phenyl
substituted phenyl)amino (also known as (biphenyl)amino), and
(di(trifluoromethyl)phenyl)amino. Alternatively, R.sub.6 may be
arylalkyl or substituted arylalkyl, such that R.sub.5 is an
(arylalkyl)amino or (substituted arylalkyl)amino, e.g.,
(benzyl)amino (also known as (phenylmethyl)amino),
(cyclopropylphenyl)amino, and (phenylethyl)amino. Accordingly to
this embodiment, a preferred R.sub.4 is carbonyl.
[0092] In another embodiment, the R.sub.5 moiety has Y being
alkanediyl, Z being N(R.sub.7) and R.sub.6 being as defined above,
where R.sub.7 is also as defined above. Accordingly, R.sub.5 is
--Y--N(R.sub.7)(R.sub.6), i.e., includes a disubstituted amino
moiety. In one embodiment, Y is methylene, i.e., --CH.sub.2--, so
that R.sub.5 is --CH.sub.2--N(R.sub.7)(- R.sub.6). As defined
above, R.sub.6 and R.sub.7 are each selected from alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl,
or substituted heterocyclealkyl, where R.sub.6 may additionally be
hydrogen. In one embodiment, R.sub.6is hydrogen.
[0093] Either one or both of the R.sub.6 and R.sub.7 groups of
--N(R.sub.6)(R.sub.7) group may be alkyl or substituted alkyl,
including saturated alkyl, unsaturated alkyl, lower alkyl, lower
saturated alkyl, lower unsaturated alkyl, saturated straight chain
alkyls, saturated branched chain alkyls, saturated cyclic alkyl,
unsaturated cyclic alkyl, alkenyl, straight chain alkenyl, branched
chain alkenyl, alkynyl, straight chain alkynyl, and branched chain
alkynyl. Representative examples are methyl, ethyl, n-propyl,
iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e.,
--CH(Et).sub.2) n-pentyl, n-hexyl, iso-hexyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
[0094] Either one or both of the R.sub.6 and R.sub.7 groups of
--N(R.sub.6)(R.sub.7) group may include an aromatic ring, such as
aryl, substituted aryl, arylalkyl, substituted arylalkyl.
Representative examples are phenyl, and chlorophenyl.
[0095] Thus, --N(R.sub.6)(R.sub.7) may be, for example,
(propyl)(cyclopropylmethyl) amino, (2-cyanoethyl)(methyl)amino,
(2-cyanoethyl)(benzyl)amino,
(ethyl)((2-(dimethylamino)ethyl))amino,
(2-hydroxyethyl)(benzyl)amino, di(2-hydroxyethyl)amino,
(propyl)(2-hydoxyethyl)amino, (cyclohexyl)(ethyl)amino,
(carboxymethyl)(methyl)amino, di(benzyl)amino, and
((2-hydroxy)(2-phenyl)ethyl))(methyl)amino.
[0096] As stated above, R.sub.6 and R.sub.7 taken together with the
nitrogen atom to which they are both attached may form a
heterocycle ring or substituted heterocycle ring. Thus,
--N(R.sub.6)(R.sub.7) may represent a heterocycle ring, such as
aziridinyl, methyl-substituted aziridinyl, 18
[0097] or a substituted heterocycle such as 19
[0098] A heterocycle, as defined above, may include more
heteroatoms (i.e., non-carbon atoms) than the nitrogen of
--N(R.sub.6)(R.sub.7). For instance, the heterocycle may
additionally include a second nitrogen, or an oxygen, or a sulfur.
When a second nitrogen is present, the heterocycle will have two
nitrogens, as in, e.g., piperazinyl. When an oxygen is present, the
heterocycle will have both an oxygen and a nitrogen, as in, e.g.,
morpholinyl. When a sulfur is present, the heterocycle will have
both a sulfur and a nitrogen, as in, e.g., thiomorpholinyl. These
heterocycles having two or more heteroatoms may be substituted or
non-substituted. For instance, the morpholinyl group may be
substituted with two alkyl group, e.g., one methyl group on either
side of the morpholinyl oxygen atom. When the heterocycle is a
piperazinyl group, the nitrogen atom not explicitly shown in the
formula --N(R.sub.6)(R.sub.7) may be substituted, where exemplary
substituents are, for example, alkyl (e.g., methyl), substituted
alkyl (e.g., 2-hydroxyethyl), or arylalkyl (e.g., benzyl).
[0099] In another embodiment, Y is substituted alkanediyl, Z is a
heteroatom or a direct bond, and R.sub.6 is as defined above. In a
preferred embodiment, R.sub.4 is hydrogen. Thus, Y is an alkanediyl
having a substituent, where the substituent may be, for example,
hydroxy. The alkanediyl may be, for example, ethylene (i.e.,
--CH.sub.2--CH.sub.2--), or n-propylene (i.e.,
--CH.sub.2CH.sub.2CH.sub.2- --), such that a substituted alkanediyl
may be, e.g., --CH(OH)--CH.sub.2--, or
--CH.sub.2--CH(OH)--CH.sub.2--.
[0100] In another embodiment, Y is alkanediyl, e.g., methylene
(--CH.sub.2--), Z is amido, i.e., --NHC(.dbd.O)-- or
--C(.dbd.O)NH--, and R.sub.6 is as defined above. In a preferred
embodiment, R.sub.4 is hydrogen. Thus, in one embodiment, R.sub.5
is --CH.sub.2--NHC(.dbd.O)--R.- sub.6.
[0101] In another embodiment, Y is alkanediyl, e.g., methylene
(--CH.sub.2--), Z is sulfonylamido, i.e., --NHSO.sub.2-- or
--SO.sub.2NH--, and R.sub.6 is as defined above. In a preferred
embodiment, R.sub.4 is hydrogen. Thus, in this embodiment, R.sub.5
is --CH.sub.2--NHSO.sub.2--R.sub.6.
[0102] In another embodiment, Y and Z are direct bonds and R.sub.6
is as defined above. Thus, in this embodiment, R.sub.5 is
--R.sub.6. In one embodiment, R.sub.4 is alkyl when R.sub.5 is
--R.sub.6. In another embodiment, R.sub.4 is carbonyl when R.sub.5
is --R.sub.6. The R.sub.6 moiety may be alkyl, saturated alkyl,
unsaturated alkyl, lower alkyl, lower saturated alkyl, lower
unsaturated alkyl, saturated straight chain alkyls, saturated
branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic
alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl,
alkynyl, straight chain alkynyl, and branched chain alkynyl.
Representative examples are methyl, trifluoromethyl, ethyl,
n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, 1-ethylpropyl
(i.e., --CH(Et).sub.2)n-pentyl, n-hexyl, iso-hexyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl. The R.sub.6 may
be substituted alkyl, where a substituted alkyl may have one, two,
or more substituents.
[0103] In another embodiment, Y and Z are direct bonds and R.sub.6
is as defined above. Thus, in this embodiment, R.sub.5 is
--R.sub.6. In one embodiment, R.sub.4 is hydrogen when R, is
--R.sub.6. In another embodiment, R.sub.4 is alkyl when R.sub.5 is
--R.sub.6.
[0104] In another embodiment, Y is a direct bond, Z is an ester
group, i.e., --C(.dbd.O)O-- or --OC(.dbd.O)--, and R.sub.6 is as
defined above. In this embodiment, R.sub.5 is -ester-R.sub.6, and
preferably R.sub.5 is --C(.dbd.O)--O--R.sub.6. In a one embodiment,
R.sub.4 is hydrogen. The R.sub.6 moiety may be alkyl, preferably
lower saturated alkyl, e.g., methyl, ethyl, propyl, etc.
[0105] In another embodiment, Y is substituted alkanediyl, Z is a
direct bond or oxygen, and R.sub.6 is as defined above. In this
embodiment, R.sub.4 is preferably H. In an alternative embodiment,
R.sub.4 is preferably alkyl. The alkanediyl may be a
C.sub.1-C.sub.6 alkanediyl, e.g., methylene, ethylene, propylene,
etc., and the substituent on the alkanediyl may be, e.g., hydroxy,
halogen, amino, alkyl, etc. Accordingly, Y may be --CH(OH)-- or
--CH(OH)--CH.sub.2--, etc. In one embodiment, R.sub.6 is aryl or
substituted aryl, e.g., phenyl or chlorophenyl. In another
embodiment, R.sub.6 is alky or substituted alkyl, e.g., methyl or
fluoromethyl.
[0106] In another embodiment, R.sub.1 is SO.sub.2R.sub.5, where Y
is a direct bond, Z is a direct bond, and R.sub.6 is as defined
above. Accordingly, in this embodiment, R.sub.1 is
--SO.sub.2--R.sub.6.
[0107] In another embodiment, Y is alkanediyl, Z is O or S, and
R.sub.6 is as defined above. For example, R.sub.5 may be
--CH.sub.2--O--CH.sub.3 where Y is methylene, Z is O, and R.sub.6
is an alkyl, and specifically methyl. In a preferred embodiment,
R.sub.4 is carbonyl. In another preferred embodiment, R.sub.4 is
hydrogen. In yet another preferred embodiment, R.sub.4 is
alkyl.
[0108] In another embodiment, Y is a direct bond, Z is a direct
bond, and R.sub.6 is alkyl or substituted alkyl of the formula
.dbd.CH.sub.2, .dbd.CH--CH.sub.3, .dbd.CH--CH.sub.2--CH.sub.3,
.dbd.CH--CH(CH.sub.3)--CH- .sub.3, and homologs thereof. The
substituent on the substituted alkyl may be, for example, hydroxyl
or halogen (e.g., fluoro).
[0109] The R.sub.6 moiety may be alkyl, saturated alkyl,
unsaturated alkyl, lower alkyl, lower saturated alkyl, lower
unsaturated alkyl, saturated straight chain alkyls, saturated
branched chain alkyls, saturated cyclic alkyl, unsaturated cyclic
alkyl, alkenyl, straight chain alkenyl, branched chain alkenyl,
alkynyl, straight chain alkynyl, and branched chain alkynyl.
Representative examples are methyl, ethyl, n-propyl, iso-propyl,
n-butyl, t-butyl, iso-butyl, 1-ethylpropyl (i.e.,
--CH(Et).sub.2)n-pentyl, n-hexyl, iso-hexyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and ethynyl.
[0110] The R.sub.6 moiety may be substituted alkyl, where
substituted alkyls may have one or may substituents. Suitable
substituents include trifluoromethyl, hydroxy, and halogen (i.e.,
fluoro, chloro, bromo, iodo).
[0111] The R.sub.6 moiety may include an aromatic ring, such as
aryl, substituted aryl, arylalkyl, substituted arylalkyl.
Representative examples are phenyl, methoxyphenyl, and
chlorophenyl.
[0112] The R.sub.6 moiety may be heterocycle, heterocyclealkyl,
substituted heterocycle, substituted heterocyclealkyl, e.g.,
furanyl, furanylmethyl, and thienyl, thienymethyl.
[0113] In a preferred embodiment, R.sub.4 is hydrogen when R.sub.5
is --R.sub.6 and R.sub.6 is alkyl as set forth above. In another
embodiment, R.sub.4 is alkyl when R.sub.5 is --R.sub.6 and R.sub.6
is alkyl as set forth above. In a preferred embodiment, R.sub.4 is
hydrogen when R.sub.5 is --R.sub.6 and R.sub.6 includes an aromatic
ring as set forth above. In another embodiment, R.sub.4 is alkyl
when R.sub.5 is --R.sub.6 and R.sub.6 includes an aromatic ring as
set forth above.
[0114] Representative R.sub.1 groups of this invention specifically
include each of the R.sub.1 groups disclosed in the Examples, as
well as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, --CH(ethyl).sub.2,
--CH(n-propyl).sub.2, --CH(n-butyl).sub.2,
--CH.sub.2CH.sub.2OCH.sub.3, --CH(methyl)(CH.sub.2OCH.sub.3),
--CH(ethyl)(CH.sub.2OCH.sub.3), --CH(n-propyl)(CH.sub.2OCH.sub.3),
--CH(n-butyl)(CH.sub.2OCH.sub.3), --CHC.ident.CH,
--CH(methyl)(ethyl), --CH(methyl)(n-propyl), --CH(methyl)(n-butyl),
--CH(methyl)(n-pentyl), --CH(methyl)(CH.sub.2CH.su-
b.2CH.sub.2CH(CH.sub.3).sub.2), --CH(ethyl)(n-propyl),
--CH(ethyl)(n-butyl), --CH(ethyl)(n-pentyl), ),
--CH(n-propyl)(n-butyl), --CH(n-propyl)(n-pentyl), cyclopropyl,
cyclobutyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl,
1,2,3,4-tetrahydronaphthyl (1 and 2), benzyl, 2-chlorobenzyl,
--CH(methyl)(benzyl), --CH(ethyl)(benzyl), --CH(n-propyl)(benzyl),
--CH(n-butyl)(benzyl), --CH.sub.2(cyclopropyl),
--CH.sub.2(cyclobutyl), --CH.sub.2CH(methyl)CH.sub.2CH.sub.3,
--CH.sub.2CH(ethyl)CH.sub.2CH.sub.3, --CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2C.ident.CH, --CH.sub.2C(.dbd.O)CH.sub.2CH.sub.3,
--C(.dbd.O)cyclopropyl, --C(.dbd.O)NHbenzyl,
[0115] Representative optional R groups of this invention include,
when present, methyl, ethyl, n-propyl, iso-propyl, iso-butyl,
.dbd.CH.sub.2, .dbd.CHCH.sub.3 and phenyl.
[0116] In more specific embodiments of this invention,
representative Ar groups of this invention include (but are not
limited to) the Ar groups identified in the Examples, as well as
2,4-dichlorophenyl, 2,4-dimethyl-phenyl, 2-chloro-4-methylphenyl,
2-methyl-4-chlorophenyl, 2,4,6-trimethylphenyl,
2-chloro-4-methoxyphenyl, 2-methyl-4-methoxyphenyl- ,
2,4-dimethoxyphenyl, 2-trifluoromethyl-4-chlorophenyl,
3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl,
2-methoxy-4-trichloromethylphenyl, 2-methoxy-4-isopropylphenyl,
2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl,
2-methoxy-4-methylphenyl, 4-methyl-6-dimethylaminopyridin-3-yl,
4-dimethylamino-6-methyl-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl
and 4-dimethylamino-pyridin-3-yl.
[0117] In another embodiment, compounds of this invention have
structure (I) above, wherein R.sub.4 is hydrogen, keto,
C.sub.1-6alkyl, 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, or
C.sub.1-6alkyloxyC.sub.1-6alkyl; R.sub.5 is hydrogen, Ar,
C.sub.1-6alkylAr, OAr, C.sub.1-8alkyl, C.sub.3-6cycloalkyl,
O(C.sub.1-8alkyl), mono- or di(C.sub.3-6cycloalkyl)methyl,
C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxyAr,
hydroxyC.sub.1-6alkyl, thienylC.sub.1-6alkyl,
furanylC.sub.1-6alkyl, C.sub.1-6alkylthioC.sub.1-6alkyl,
morpholinyl, mono- or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, amino,
(C.sub.1-6alkyl)amino, di(C.sub.1-6alkyl)amino,
(C.sub.1-6alkylAr)amino, (C.sub.1-6alkyl)(Ar)amino,
C.sub.1-6alkylcarbonylC.sub.1-6alkyl, sulfonyl(C.sub.1-8alky),
--C(.dbd.O)C.sub.1-6alkyl, C.sub.1-6alkyl substituted with
imidazolyl, or a radical of the formula
--(C.sub.1-6alkanediyl)--O--(CO).sub.0,1--Ar; or R.sub.4 and
R.sub.5 taken together form a C.sub.3-8cycloalkyl or a
C.sub.5-8cycloalkyl fused to Ar optionally substituted with one or
more substituents independently selected from C.sub.1-6alkyl; and
Ar is, at each occurrence, independently phenyl or naphthyl,
optionally substituted with 1, 2 or 3 substituents independently
selected from halo, C.sub.1-6alkyl, triflouromethyl, cyano,
C.sub.1-6alkyloxy, benzyloxy, C.sub.1-6alkylthio, nitro, amino, and
mono- or di(C.sub.1-6alkyl)amino; or an aromatic
C.sub.3-12heterocycle optionally substituted with 1, 2 or 3
substituents independently selected from halo, C.sub.1-6alkyl,
triflouromethyl, hydroxy, cyano, C.sub.1-6alkyloxy, benzyloxy,
C.sub.1-6alkylthio, nitro, amino, mono- or di(C.sub.1-6alkyl)amino,
and piperidinyl.
[0118] The compounds of the present invention may be prepared by
known organic synthesis techniques, including the methods described
in more detail in the Examples, and may generally be utilized as
the free base. Alternatively, the compounds of this invention may
be used in the form of acid addition salts. Acid addition salts of
the free base amino compounds of the present invention may be
prepared by methods well known in the art, and may be formed from
organic and inorganic acids. Suitable organic acids include maleic,
fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic,
oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic,
mandelic, cinnamic, aspartic, stearic, palmitic, glycolic,
glutamic, and benzenesulfonic acids. Suitable inorganic acids
include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric
acids. Thus, the term "pharmaceutically acceptable salt" of
structure (I) is intended to encompass any and all acceptable salt
forms.
[0119] In general, the compounds of structure (I) may be made
according to the organic synthesis techniques known to those
skilled in this field, as well as by the representative methods set
forth in the Examples. For example, the synthesis of structure (I)
will generally proceed by synthesis of the desired sub-structure
(I-1), (1-2), (I-3) or (I-4), as represented below. In turn,
synthesis of each of these sub-structures is exemplified in the
Examples. 2021
[0120] In addition, compounds of structure (I-1) and (I-4) may be
made by the following Reaction Scheme A by synthesis of
intermediate 4, which is then converted to the corresponding
structure (I-1) (structure "10") or (I-4) (structure "8"): 22
[0121] Compounds of structures (I-1) and (I-4) may also be made
according to the following Reaction Schemes B and C: 23 24
[0122] In addition, compounds of structure (I-1) may be made by the
following Reaction Scheme D: 25
[0123] Further, compounds of structure (I-3) and (I-4) may be
prepared by the following Reaction Schemes E and F, respectively:
26
[0124] 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. Neuroscieice 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-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 "K.sub.i" value calculated by the
following equation: 1 K i = IC 50 1 + L / K D
[0125] where L=radioligand and K.sub.D=affinity of radioligand for
receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099,
1973).
[0126] 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)).
[0127] 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). As set forth in
greater detail below, the K.sub.i values of representative
compounds of this invention were assayed by the methods set forth
in Example 9. Preferred compounds having a K.sub.i of less than 1
.mu.M are compound numbers I-2a-1 to I-2a-6, I-2a-8, I-2a-9,
I-2a-12 to I-2a-25, I-2a-27 to I-2a-44, I-2a-46 to I-2a-76,
I-2a-92, I-2a-173, I-4b-1 and I-4b-2. More preferred compounds
having a K.sub.i of less than 250 nM are compound numbers I-2a-1 to
I-2a-4, I-2a-6, I-2a-8, I-2a-9, I-2a-12 to I-2a-18, I-2a-20 to
I-2a-25, I-2a-28 to I-2a-36, I-2a-38 to I-2a-43, I-2a-46 to
I-2a-73, I-2a-76, I-4b-1 and I-4b-2.
[0128] 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, 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).
[0129] 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 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.
[0130] 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, such as those disclosed in Remington's
Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton,
Pa. 1990.
[0131] In addition, prodrugs are also included within the context
of this invention. Prodrugs are any covalently bonded carriers that
release a compound of structure (I) in vivo when such prodrug is
administered to a patient. Prodrugs are generally prepared by
modifying functional groups in a way such that the modification is
cleaved, either by routine manipulation or in vivo, yielding the
parent compound. Prodrugs include, for example, compounds of this
invention wherein hydroxy, amine or sulfhydryl groups are bonded to
any group that, when administered to a patient, cleaves to form the
hydroxy, amine or sulffiydryl groups. Thus, representative examples
of prodrugs include (but are not limited to) acetate, formate and
benzoate derivatives of alcohol and amine functional groups of the
compounds of structure (I). Further, in the case of an carboxylic
acid (--COOH), esters may be employed, such as methyl esters, ethyl
esters, and the like.
[0132] With regard to stereoisomers, the compounds of structure (I)
may have chiral centers and may occur as recemates, reacemic
mixtures and as individual enantiomers or diastereomers. All such
isomeric forms are included within the present invention, including
mixtures thereof. Furthermore, some of the crystalline forms of the
compounds of structure (I) may exist as polymorphs, which are
included in the present invention. In addition, some of the
compounds of structure (I) may also form solvates with water or
other organic solvents. Such solvates are similarly included within
the scope of this invention.
[0133] 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 flavorants, 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.
[0134] 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, unstable angina, reactive
hypertension, anorexia nervosa, bulimia, irritable bowel syndrome,
stress-induced immune suppression, stroke, inflammation, Cushing's
disease, infantile spasms, epilepsy, and substance abuse or
withdrawal.
[0135] The following examples are provided for purposes of
illustration, not limitation.
EXAMPLES
[0136] The CRF receptor antagonists of this invention may be
prepared by the methods disclosed in Examples 1-12. Example 13
presents a method for determining the receptor binding activity
(K.sub.i), and Example 14 discloses an assay for screening
compounds of this invention for CRF-stimulated adenylate cyclase
activity.
Example 1
Synthesis of Representative Compounds of Structure (I-1)
[0137] 27
[0138] Compound (2)
[0139] 2,4-dichloro-6-methyl-3-ethylester pyridine (1) (5.0 g,
21.36 mmoles), 4-heptylamine (21.36 mmoles) and triethyl amine
(2.97 ml, 21.36 mmole) in ethanol were heated at reflux over night.
Ethanol was evaporated and the residue was dissolved in ethyl
acetate, washed with saturated solution of bicarbonate and brine.
The organic layer was dried over sodium carbonate and concentrated
in vacuum. Compound (2) was separated from (1) and (3) by silica
gel column eluting with ethyl acetate-hexane.
[0140] Compound (4)
[0141] Compound (2) (20.0 mmoles) and hydrazine (25.0 mmoles) in
ethanol was refluxed over night. Ethanol was evaporated and the
residue was dissolved in ethyl acetate, washed with water, dried
over sodium sulfate and concentrated in vacuum to give compound (4)
which was used in the next step without further purification.
[0142] Compound (5)
[0143] A mixture of compound (4) (15.0 mmoles) and phosphorus
oxychloride (15 ml) was refluxed for 3 hours, cooled, poured onto
ice and neutralized by 1N NaOH. The aqueous layer was extracted by
ethyl acetate. The organic layer was washed with brine, dried under
sodium sulfate, and concentrated to yield the desired compound
(5).
[0144] Compound (6)
[0145] To a solution of compound (5) (15.0 mmoles) in THF were
added tri-n-butyl (1-ethoxy) vinyl tin (10.0 mmoles) and
bis(triphenylphosphine) palladium (II) chloride (10% mole). The
mixture was refluxed for 24 hours. The solution was partitioned
between ethyl acetate and water. The organic phase washed with
brine dried over sodium sulfate and concentrated in vacuum. The
residue was dissolved in CCl.sub.4 and added at ice bath
temperature to a suspension of pyridinium perbromide (75.0 mmoles)
in CCl.sub.4. The temperature was raised to room temperature and
stirred for 4 hours. The mixture was diluted with chloroform and
washed successively with brine, hydrochloric acid solution (10%),
saturated solution of bicarbonate, dried over sodium carbonate and
concentrated in vacuum. Compound (6) was purified by silica gel
column.
[0146] Compound (7)
[0147] To a solution of compound (6) (10.0 mmoles) in THF was added
1 M lithium hexamethyldisilizane in THF (11.0 mmoles) and the
mixture was stirred at room temperature over night. The mixture was
neutralized by 1N HCl diluted with ethyl acetate. The organic layer
was washed with brine, dried over sodium sulfate and concentrated
in vacuum. The residue was dissolved in THF and BH.sub.3-THF (1M)
was added and the reaction was refluxed for 8 hours. The mixture
was hydrolyzed with 1N HCl and diluted with ethyl acetate, the
organic layer was washed with saturated solution of sodium
bicarbonate and brine then concentrated in vacuum to give compound
(7).
[0148] Compound (8) (I-1a-1)
[0149] To a solution of compound (7) (0.5 mmoles) in DMF was added
NaH (0.6 mmoles) followed by 2,3-chloro-5-trifluomethyl-pyridine
(0.6 mmoles). The mixture was heated at 90.degree. C. over night.
The reaction mixture was neutralized with 1N HCl and partitioned
between water and ethyl acetate. The organic layer was washed with
saturated solution of sodium bicarbonate and brine and concentrated
in vacuum. Compound (8) was purified by silica gel column eluting
with ethyl acetate-hexane.
[0150] Alternatively, compounds of structure (I-1a) may be made by
the following reaction scheme. 28
2,4-Dichloro-3-hydroxymethyl-6-methylpyridine (10)
[0151] Ethyl 2,4-dichloro-6-methylnicotinate (9) (8.04 g, 34.3
mmol) was dissolved in THF (40 mL) and added to a stirred
suspension of LAH (6.52 g, 0.170 mmol) in THF (80 mL) at
-78.degree. C. The mixture was stirred for 6 hours at this
temperature and for 1 hour at -30.degree. C. followed by cautious
treatment with water (5.5 mL), 15% aqueous NaOH (5.5 mL) and water
(16.5 mL) with vigorous stirring. The mixture was warmed to room
temperature and filtered. The white precipitate was washed
liberally with ethyl acetate. The combined organic portions were
dried (MgSO.sub.4) and concentrated under vacuum to afford 6.40 g
(97%) of (10) as a colorless oil which solidified on standing: LCMS
(MH.sup.+, 192).
2,4-Dichloro-6-methylpyridine-3-carboxaldehyde (11)
[0152] DMSO (14.2 mL, 200 mmol) was added to a stirred solution of
oxalyl chloride (8.7 mmol, 99 mmol) in dichloromethane (100 mL) at
-70.degree. C. After 15 min, alcohol (10) (6.40 g, 33.3 mmol) in
dichloromethane (25 mL) was added, followed by triethylamine (56
mL). The mixture was allowed to warm to room temperature and was
stirred for 1 hour. The mixture was washed with aqueous sodium
bicarbonate (75 mL), dried (MgSO.sub.4), and concentrated under
vacuum. The residue was purified by column chromatography (elution
with 10% ethyl acetate in hexanes) to afford 5.00 g (78%) of (11)
as a pale yellow oil which solidified on standing: LCMS (MH.sup.+,
190), R.sub.f 0.48 (20% ethyl acetate in hexanes).
2,4-Dichloro-6-methyl-3-[1-(1-hydroxyallyl)]pyridine (12)
[0153] Vinylmagnesium bromide in THF (1.0 M, 6.7 mL, 6.7 mmol) was
added to a stirred solution of aldehyde (11) (1.15 g, 6.05 mmol) in
THF (20 mL) at -78.degree. C. The mixture was stirred at this
temperature for 30 min, warmed to room temperature and quenched
with aqueous sodium bicarbonate (40 mL). The mixture was extracted
with ethyl acetate (2.times.50 mL) and the combined extracts were
dried (MgSO.sub.4) and concentrated under vacuum to afford 1.37 g
of crude (12) a yellow oil: LCMS (MH.sup.+, 218), R.sub.f 0.28 (20%
ethyl acetate in hexanes).
2,4-Dichloro-6-methyl-3-(vinylcarbonyl)pyridine (13)
[0154] The above material (12) and N-methylmorpholine N-oxide (NMO,
1.06 g, 9.05 mmol) were dissolved in dichloromethane (27 mL) and
treated with 4 angstrom molecular sieves (1.3 g). The mixture was
stirred for 20 min, and tetrapropylammonium perruthenate (TPAP, 65
mg) was added. The mixture was stirred for 1 hour. Some starting
material persisted so additional NMO (1.06 g) and TPAP (65 mg) were
added, and stirring was continued for 1 hour. The mixture was
filtered (Celite), concentrated under vacuum, and the residue was
purified on a silica gel column (elution with 10% ethyl acetate in
hexanes) to afford 0.50 g (38%) of (13) as a pale yellow oil: LCMS
(MH.sup.+, 216), R.sub.f 0.52 (20% ethyl acetate in hexanes).
5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-4-one (14) and
5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin-4-one (15)
[0155] Enone (13) (920 mg, 4.26 mmol) was dissolved in ethanol (20
mL) and treated with 4-heptylamine (0.64 mL, 4.3 mmol). The mixture
was heated at 60.degree. C. for 16 hours and then was concentrated
under vacuum. The residue was taken up in ethyl acetate (50 mL),
washed with aqueous sodium bicarbonate (20 mL), dried (MgSO.sub.4),
and again concentrated. The residue was purified on a silica gel
column (elution with 5% ethyl acetate in hexanes for (14) and 25%
ethyl acetate in hexanes for (15)) to afford 314 mg (25%) of (14)
as a yellow oil followed by 214 mg (17%) of (15) as white solid.
5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-- 4-one (14):
NMR.sub.5 LCMS (MH.sup.+, 295), R.sub.f 0.70 (30% ethyl acetate in
hexanes); 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin--
4-one (15): mp 82-85.degree. C., NMR, LCMS (MH.sup.+, 295),
R.sub.f0.14 (30% ethyl acetate in hexanes).
[0156] Compound (16) (I-1a-2)
[0157] Compound (15) (68 mg, 0.23 mmol), TsOH.H.sub.2O (50 mg, 0.26
mmol) and hydrazone (93 mg, 0.35 mmol) were heated at 140.degree.
C. for 5 hours The mix was cooled to room temperature, diluted with
aqueous NaHCO.sub.3 (2 mL) and extracted with EtOAc (4.times.2 mL).
The combined extracts were dried (MgSO.sub.4), concentrated in
vacuo the residue was purified by prep. TLC (elution with 30%
EtOAc/hexane) to afford compound (16) (21 mg, 22%), LCMS (MH+,
417).
[0158] Further representative compounds were prepared by the above
procedure, the structure and analytical data for which are set
forth in the following Table 1.
1TABLE 1 Analytical Data for Representative Compounds 29 Cpd. No.
Ar R.sub.1 LCMS (I-1a-3) 2-chloro-4- trifluorophenyl 30 451
(MH.sup.+) (I-1a-4) 4-chloro-2- methylphenyl 31 397 (MH.sup.+)
(I-1a-5) 2,4- dimethylphenyl 32 377 (MH.sup.+) (I-1a-6) 2,4-
dichlorophenyl 33 417 (MH.sup.+) (I-1a-7) 2-chloro-4-
trifluorophenyl 34 451 (MH.sup.+) (I-1a-8) 4-chloro-2- methylphenyl
35 397 (MH.sup.+) (I-1a-9) 2,4- dichlorophenyl 36 377 (MH.sup.+)
(I-1a-10) 2,4- difluorophenyl 37 385 (MH.sup.+)
[0159] Compounds of structure (I-1b) may be made in the same manner
as compound (8) above, but using 2,4-dichloro-6-methyl-3-ethylester
pyrimidine (1') in place of the corresponding pyridine (1), as
illustrated by the following reaction scheme. 38
[0160] Compound (4')
[0161] Compound (2') (20.0 mmoles) and 2,4-dichlorophenlyhydrazine
(25.0 mmoles) in ethanol was refluxed overnight. Ethanol was
evaporated and the residue was dissolved in ethyl acetate, washed
with water, dried over sodium sulfate and concentrated in vacuum to
give compound (4') which was used in the next step without further
purification.
[0162] Compound (5')
[0163] A mixture of (4') (15.0 mmoles) and phosphorus oxychloride
(15 ml) was refluxed for 3 hours, cooled, poured onto ice and
neutralized by 1N NaOH. The aqueous layer was extracted by ethyl
acetate. The organic layer was washed with brine, dried under
sodium sulfate, concentrated to yield the desired product (5').
[0164] Compound (6')
[0165] To a solution of compound (5') (15.0 mmoles) in THF were
added tri-n-butyl (1-ethoxy) vinyl tin (10.0 mmoles) and
bis(triphenylphosphine) palladium (II) chloride (10.0% mole). The
mixture was refluxed for 24 hours. The solution was partitioned
between ethyl acetate and water. The organic phase washed with
brine dried over sodium sulfate and concentrated in vacuum. The
residue was dissolved in CC14 and added at ice bath temperature to
a suspension of pyridinium perbromide (75.0 mmoles) in CC14. The
temperature was raised to room temperature to a suspension of
pyridinium perbromide (75.0 mmoles) in CC14. The temperature was
raised to room temperature and stirred for 4 hours. The mixture was
diluted with chloroform and washed successively with brine,
hydrochloric acid solution (10%), saturated solution of
bicarbonate, dried over sodium carbonate and concentrated in
vacuum. The compound (6') was purified by silica gel column.
[0166] Compound (7')
[0167] To a solution of (6') (10.0 mmoles) in THF was added sodium
hydride (11.0 mmoles) and the mixture was stirred at room
temperature overnight. The mixture was neutralized by 1N HCl
diluted with ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate and concentrated in vacuum. The
residue was dissolved in THF and BH.sub.3-THF (1M) was added and
the reaction was refluxed for 8 hours. The mixture was hydrolyzed
with 1N HCl and diluted with ethyl acetate, the organic layer was
washed with saturated solution of sodium bicarbonate and brine then
concentrated in vacuum to give compound (7').
Example 2
Synthesis of Representative Compounds of Structure (I-2)
[0168] 39
.alpha.-Phthalimide-2,4-trichloroacetophenone (1)
[0169] .alpha.-2,4-trichloroacetophenone (15 gms, 67 mmol) was
added with stirring to a suspension of potassium phtalimide (16
gms, 86 mmol) in N,N-dimethylformamide (70 ml) at 5.degree. C.
After 5 min., the resulting solution was allowed to warm to room
temperature, followed by heating for 0.5 hr at 50.degree. C. After
heating the solution was concentrated on pump and the resulting
solid was partitioned between ethyl acetate/sodium bicarbonate
solution and the resulting organic layers were combined. These were
dried and all solvent removed to yield solid. This solid was
recrystallized from methylene chloride and ether to yield compound
(1), 9.6 gms.
[0170] Compound (2)
[0171] A solution of .alpha.-phthalimide-2,4-trichloroacetophenone
(1) (9.6 gms) in dimethylformamide dimethyl acetal (30 ml) and
refluxed for 1 hour. After reflux, t.l.c. indicate the completion
of the reaction and all solvent was removed on high vacuum to yield
tan solid (2).
2-(2',4'-Dichlorophenyl)-3-aminopyrazole (3)
[0172] To a suspension of compound (2) (14 g, 36 mmol) in dry
ethanol (300 mL) was added anhydrous hydrazine (1.2 g, 36 mmol).
The tan suspension slowly turned into a clear dark brown solution.
The solution was stirred at room temperature for 1 hr and more
anhydrous hydrazine (1.2 g, 36 mmol) was added. The solution was
heated to reflux for 2 hrs and a white solid formed. The reaction
mixture was cooled to room temperature and the solid was filtered
off. The filtrate was concentrated and partitioned between aqueous
saturated sodium bicarbonate solution and ethyl acetate. The ethyl
acetate layer was washed with Brine, dried by sodium sulfate,
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel to provide the desired product (3) as
a brown sticky solid (7.7 g, 33.8 mmol, 94%), which was confirmed
by GC/MS.
2-Methyl-4-hydroxy-7-(2',440 -dichlorophenyl)-pyrrozolepyridine
(4)
[0173] A solution of compound (3) (7.7 g, 33.8 mmol), ethyl
acetoacetate (8.4 g, 65 mmol) and 120 mg of p-tolunesulfonic acid
monohydrate in 200 mL of benzene was refluxed for 2 hrs. The
reaction mixture was concentrated and dissolved in 20 mL of
diphenylether. The diphenylether was heated to 240.degree. C. for
10 minutes, cooled and the solid was collected by filtration, and
rinsed with diethyl ether. The product (4) was obtained as a brown
solid (2.5 g, 8.4 mmol, 25%), which was confirmed by .sup.1H
NMR.
2-Methyl-4-chloro-7-(2',4'-dichlorophenyl)-pyrrozolepyridine
(5)
[0174] A mixture of compound (4) (2.0 g, 6.8 mmol) and phosphorous
oxychloride (10 mL) as refluxed for 2 hr, cooled, poured onto a
crack ice, neutralized by 1N NaOH. The aqueous layer was extracted
by ethyl acetate. The organic layer was washed with brine, dried
under sodium sulfate, concentrated to yield a yellow solid which
was triturated in ether. The desired product (5) was obtained as a
pale yellow solid (1.1 g, 3.2 mmol, 47%), which was identified by
GC/MS, Elemental Analysis and .sup.1H NMR.
2-Methyl-4-(N-4-heptyl)-7-(2',4'-dichlorophenyl)-pyrrozolepyridine
(6)
[0175] A mixture of (5) (0.3 g, 0.96 mmol) and p-toluenesulfonic
acid monohydrate (250 mg) in 0.8 mL of 4-heptylamine in a 5 mL
Reacti-Vials was refluxed at 180.degree. C. for 6 hours. The
reaction mixture was cooled, partitioned between ethyl acetate and
water. The organic layer was washed with Brine, dried under sodium
sulfate, concentrated, purified by flash chromatography on silica
gel (Hexane/EtOAc, 1:1) to provide the desired product (6) as a
yellow oil (140 mg, 0.36 mmol, 37%), which was identified by GC/MS
and .sup.1H NMR.
[0176] Compound (7) (I-2a-1)
[0177] A mixture of
2-methyl-4-(N-4-heptyl)-7-(2',4'-Dichlorophenyl)-pyrro-
zolepyridine (6) (43.9 mgs, 0.11 mmoles), potassium carbonate (31.0
mgs, 0.22 mmoles) and 1,2-dibromoethane in butanone (2 ml) was
heated to 85.degree. C. overnight. The solvent was removed in
vacuum and the residue was partitioned between ethyl acetate and
water, the organic layer was dried over magnesium sulfate, filtered
and concentrated in vacuum. Compound (7) was purified by silica gel
column eluting with dichloromethane-methanol (10-1), and identified
by LC/MS. .sup.1H NMR (CDCl.sub.3, TMS):0.93 (t, 6H); 1.37 (m, 4H);
1.61 (m, 4H); 2.58 (5, 3H); 3.67 (t, 24); 3.82 (m, 1H); 4.45 (t,
2H);6.22 (s, 1H); 7.35 (d, 1H); 7.53 (s, 1H); 7.86 (d, 1H).
[0178] Compound (8)
[0179] A solution of compound (7) (43 mg, 0.1 mmol) in toluene (2
ml) was treated with activated manganese dioxide catalyst (100 mg)
at reflux for 16 hrs. The catalyst was removed by filtration
through a Celite pad and the filtrate was evaporated to dryness and
purified by Prepative TLC (silica gel) with ethyl acetate:hexane
(1:1) to provide compound (8).
[0180] Alternatively, compounds of structure (I-2a) may be prepared
by the following procedure. 4041
4-Nitropyrazole (9)
[0181] Pyrazole (Lancaster) (30.0 g, 441 mmol) was portionwise
added to 220 ml of sulfuric acid 97% in an ice-bath. The mixture
was heated at 55.degree. C. and 30 ml of nitric acid 70% (0.5mol,
1.1 eq.) were added slowly. The reaction mixture was then stirred
at 55.degree. C. for 3 hours (reaction checked by TLC
Ethylacetate/Hexane 1/1 pyrazole R.sub.f=0.4, I.sub.2 active,
nitropyrazole R.sub.f=0.6, UV active), cooled down, poured into 600
ml of ice-water and neutralized with 6N NaOH solution (pH=7). The
product was then extracted with ethyl acetate (5.times.150 ml). The
organic phases were combined, washed with water (100 ml), a brine
solution (100 ml) and dried with sodium sulfate, filtered and
concentrated by vacuum to yield the desired product (9) as a white
solid (37.0 g, 326 mmol, 74%). GC/MS: m/z=113 (100%).
4-Aminopyrazole (10)
[0182] The 4-nitropyrazole (9) (15.0 g, 133 mmol) was added to a
suspension of palladium on carbon 10% (7.0 g, 6.65 mmol, 5% mmol)
in ethanol (100 ml). The mixture was shaken for 3 hours under
hydrogen pressure (40 psi) at room temperature. The end of reaction
checked by TLC (Ethylacetate/Hexane 1/1, 4-nitropyrazole
R.sub.f=0.6, UV active, 4-aminopyrazole R.sub.f 0.1, UV active).
The catalyst was removed by filtration through a pad of Celite and
the solvent was evaporated. The product (10) was obtained as a
burgundy oil (10.5 g, 126 mmol, 95%), which was used in the
following step without purification. GC/MS: m/z=83 (100%).
Imine (11)
[0183] A solution of 4-aminopyrazole (10) (10.5 g, 126 mmol),
ethylacetoacetate (18.0 g, 140 mmol, 1.05 eq.) and a catalytic
amount of para-toluenesulfonic acid monohydrate (1.3 g, 6.65 mmol,
5%) in 100 mL of benzene was refluxed with a Dean-Stark trap for
about 1 hour. The end of reaction checked by TLC
(Ethylacetate/Hexane 1/1, 4-aminopyrazole R.sub.f=0.1, imine
R.sub.f=0.5, UV active, brown after overnight). Solvents were
removed under vacuum and the imine was purified by running through
a short silica chromatography column to give the desired product
(11) as a tan solid (22.4 g, 125 mmol, 91%). GC/MS: m/z=195
(100%).
5-Methyl-7-hydroxy-pyrazolo[4,3-b]pyridine (12)
[0184] The imine (11) (7.03 g, 35.9 mmol) was added to a boiling
solution of dioxane (30 mL) and diphenyl ether (30 mL). The mixture
was heated until solid formed (5min). The reaction mixture was
continued heating for 2 more minutes. Heating was stopped. The end
of the cylcization was checked by LC/MS (disappearance of 196).
After cooling down at room temperature, 300 ml of diethyl ether
were added the reaction mixture was stirred for 15 minutes. The
solid was rinsed with diethyl ether. The desire product (12) was
obtained as a tan crystalline solid (5.09 g, 34.1 mmol, 95%).
LC/MS: [M+H]'=150.
5-Methyl-7-chloro-pyrazolo[4,3-b]pyridine (13)
[0185] The cyclized compound (12) (4.58 g, 30.7 mmol) in phosphorus
oxychloride (30 mL) was heated at 110.degree. C. for 30 minutes.
The end of the reaction was checked by LC/MS (disappearance of 150,
appearance of 168). After cooling down at room temperature, the
reaction mixture was poured on ice and pH was adjusted with a 6N
NaOH solution to pH=5. The solid was collected with filtration and
the mother aqueous layer was extracted with ethyl acetate
(3.times.250 ml). The above solid was dissolved in the combined
organic phases, washed with a brine solution (1.times.250 ml) and
dried with sodium sulfate, filtered and concentrated. The crude
product was purified by running through a short silica gel
chromatography column to give the desired product (13) as a pale
yellow solid (4.50 g, 26.8 mmol, 87%). GC/MS: m/z=167 (100%);.
LC/MS: [M+H]'=168.
3-Bromo-5-methyl-7-chloro-pyrazolo[4,3-b]pyridine (14)
[0186] The chloro compound (13) (600 mg, 3.58 mmol) was dissolved
in a mixture of water/methanol (12 mL/12mL) in an ice-bath. A
solution of bromine (629 mg, 3.94 mmol, 1.1 eq.) in a solution of
H.sub.2O/MeOH 1 mL/1 mL) was added dropwise to the cooled mixture.
After 10 minutes, the solution was clearer and the LC/Ms showed no
more chloro compound. The reaction mixture was concentrated to
remove the MeOH. The crude reaction mixture was extracted with
ethyl acetate (3.times.50 ml). The organic phases were combined,
washed with a brine solution (1.times.100 ml) and dried with sodium
sulfate, filtered and concentrated by vacuum. The desired product
(14) was obtained as a pale yellow solid. GC/MS: m/z=245, 247
(100%); LC/MS: [M+H]'=246, 248.
3-Bromo-5-methyl-7-(5-aminononane)-pyrazolo[4,3b]pyridine (15)
[0187] Compound (14) (1.0 g, 0.4 mmol) and 5-aminononane (1.7 g, 12
mmol) and p-toluenesulfonic acid (1.5 g, 8 mmol) were heated in
reaction vial at 160.degree. C. over night. The residue was
dissolved in ethyl acetate, washed with saturated solution of
sodium bicarbonate, brine, dried with MgSO4 and concentrated in
vacuum. The residue was triturated with toluene and the solid
formed was isolated and dried in vacuum to give 912 mg of product
(15) as a white solid. LCMS: (M+H)=353, 354.
3-(2,4-dichlorophenyl)-5-methyl-7-(5-aminononane)-pyrazolo[4,3b]pyridine
(16)
[0188] A mixture of compound (15) (100 mg, 0.27 mmol),
2,4-dichlorophenylboronic acid (63.7 mg), ethanol (0.6 ml), 2M
solution of sodium carbonate (0.6 ml), Pd(PPh.sub.3).sub.4 (10 mg)
and toluene (1.6 ml) was heated at 160.degree. C. over night. The
solution was partitioned between EtOAc and water. The organic layer
was dried with MgSO.sub.4 and concentrated in vacuum. The residue
was purified by chromatography on silica gel to give 34 mg of
product (16). LCMS (M+H)=419, 420.
[0189] Compound (17) (I-2a-2)
[0190] To compound (16) (34 mg, 0.08 mmol) in 2-butanone (3 ml) was
added potassium carbonate (67.18 mg, 0.48 mmol) and dibromoethane
(30.48 mg, 0.16 mmol) and the mixture was heated at reflux over
night. The mixture was partitioned between ethyl acetate and water.
The organic layer was dried with magnesium sulfate and concentrated
in vacuum. The crude product was purified by chromatography on
silica gel eluting with ethyl acetate-hexane (I-1) to give 10 mg of
product (17) (referred in Table 2 below as "Cpd. No. (I-2a-2)".
LC/MS (M+H)=445, 446
[0191] Further representative compounds of this invention were
prepared by the procedures set forth in the above examples, the
analytical data for which are set forth in the following Table
2.
2TABLE 2 Analytical Data for Representative Compounds 42 Cpd. No.
Ar R.sub.1 Analytical Data (I-2a-1) 2,4-dichloro- phenyl 43 0.93(t,
6H); 1.37(m, 4H); 1.61(m, 4H); 2.58(5, 3H); 3.67(t, 24); 3.82(m,
1H); 4.45(t, 2H); 6.22(s, 1H); 7.35(d, 1H); 7.53(s, 1H); 7.86(d,
1H). (I-2a-2) 2,4-dichloro- phenyl 44 LC/MS (M + H) = 445, 446
(I-2a-3) 2,4-dichloro- phenyl 45 LC/MS (MH+) = 376 (I-2a-4)
2,4-dichloro- phenyl 46 LC/MS (M + H) = 387 (I-2a-5) 2,4-dichloro-
phenyl 47 LC/MS (M + H) = 401 (I-2a-6) 2,4-dichloro- phenyl 48
LC/MS (M + H) = 415 (I-2a-7) 2,4-dichloro- phenyl 49 LC/MS (M + H)
= 415 (I-2a-8) 2,4-dichloro- phenyl 50 LC/MS (M + H) = 449 (I-2a-9)
2,4-dichloro- phenyl 51 LC/MS (M + H) = 431 (I-2a-10) 2,4-dichloro-
phenyl 52 LC/MS (M.sup.+ + 1) = 409 (I-2a-11) 2,4-dichloro- phenyl
53 7.87(d, J=8.4Hz, 1H), 7.54(d, J=2.1Hz, 1H), 7.42-7.29(m, 6H),
6.29(s, 1H), 5.83(t, J=7.7Hz, 1H), 4.51(dd, J=5.7, 5.1Hz, 2H),
3.86(dd, J=5.4, 4.8Hz, 2H), 2.51(s, 3H), 2.41-2.31(m, 2H), 1.14(t,
J=7.7Hz, 3H); LCMS(M.sup.+ + 1) = 449. (I-2a-12) 2,4-dichloro-
phenyl 54 LC/MS 405 (MH+) (I-2a-13) 2,4-dichloro- phenyl 55 LC/MS
(MH+) = 390 (I-2a-14) 2,4-dichloro- phenyl 56 LC/MS (MH+) = 418
(I-2a-15) 2,4-dichloro- phenyl 57 LC/MS (MH+ = 419 (I-2a-16)
2,4-dichloro- phenyl 58 LC/MS 417 (MH+) (I-2a-17) 2-chloro-4-
methylphenyl 59 LC/MS (MH+) = 397 (I-2a-18) 2-chloro-4-
methylphenyl 60 LC/MS (MH+) = 397 (I-2a-19) 2-chloro-4-
methoxyphenyl 61 LC/MS (MH+) = 413 (I-2a-20) 2-chloro-4-
methylphenyl 62 LC/MS (MH+) = 385
[0192] In another alternative embodiment, compounds of structure
(I-2a) may be made by the following procedure: 63
[0193] Compound (19)
[0194] Combined substituted chloropyrazolopyridine (18) (100 mg,
0.33 mmol), aminophenylethanol (133 mg, 0.97 mmol) and
p-toluenesulfonic acid (124 mg, 0.65 mmol) in a sealed vial and
heated at 120.degree. C. for 3 hours. LCMS showed product peak (19)
(MH.sup.+=413) and no starting material. The reaction mixture was
used, as is, in the following step.
[0195] Compound (20)
[0196] A 48% aqueous solution of HBr (0.5 mL) was added to the
reaction mixture containing (19) and the resulting mixture was
heated overnight at 80.degree. C. LCMS shows the product peak at
MH.sup.+=395. The reaction mixture was poured onto ice, made basic
with sodium hydroxide, and extracted with ethyl acetate. The
organic layer was evaporated and dried to give (20) (134 mg,
quantitative yield).
[0197] Compound (21) (I-2a-21)
[0198] A solution of (20) (105 mg, 0.268 mmol) in DMF (3 mL) was
cooled in an ice bath. NaH (95%, 8 mg, 0.321 mmol) was added and
the reaction mixture was stirred for 30 minutes. Added
4-bromoheptane (58 mg, 0.321 mmol) and stirred overnight. The
reaction was quenched with aqueous NH.sub.4Cl and was concentrated.
Brine and ethyl acetate were added followed by concentration of the
organic layer. Prep TLC gave product compound (21) (6 mg, MS
ion=493).
[0199] Compounds of structure (I-2b) may be made by the following
reaction scheme: 64
[0200] Compound (2')
[0201] A mixture of (1') (4.50 g, 30 mmol)(T. Huynh-Dinh et al., J.
Org. Chem. 40: 2825-2830, 1975) and phosphorous oxychloride (15 mL)
was refluxed for 3 hrs, cooled, poured onto a crack ice,
neutralized by 1N NaOH. The aqueous layer was extracted by ethyl
acetate. The organic layer was washed with brine, dried under
sodium sulfate, concentrated to yield the desired product (2').
[0202] Compound (3')
[0203] To a mixture of (2') (3.37 g, 20 mmol) in methanol (20 mL)
and water (20 mL) was added bromine (3.84 g, 24 mmol) in methanol
(10 mL) and water (10 mL). The reaction mixture was stirred at room
temperature for 2 hrs. The reaction mixture was washed with sodium
thiosulfate aqueous solution, extracted with ethyl acetate. The
residue was purified by flash chromatography on silica gel to
provide the desired product (3').
[0204] Compound (4')
[0205] A mixture of (3') (2.50 g, 10 mmol) and p-toluenesulfonic
acid monohydrate (100 mg) in 3 mL of 4-heptylamine was refluxed by
120.degree. C. for 5 hours. The reaction mixture was cooled,
partitioned between ethyl acetate and sodium bicarbonate aqueous
solution. The organic layer was washed with brine, dried under
sodium sulfate, concentrated, purified by flash chromatography on
silica gel to provide the desired product (4').
[0206] Compound (5')
[0207] To a stirring solution of (4') (1.63 g, 5mmol) in 10 mL of
toluene was added tetrakis(triphenylphosphine)-(palladium(0) (578
mg, 0.5 mmol, 10% mol) and 2.0M aqueous sodium carbonate solution
(8 mL) followed by addition of 2,4-dichloro-benzeneboronic acid
(1.14 g, 6 mmol) in ethyl alcohol (8 mL). The resulting mixture was
refluxed under nitrogen overnight. The reaction mixture was cooled,
diluted with ethyl acetate and washed with saturated ammonium
chloride solution once. The organic layer was dried by sodium
sulfate, filtered, concentrated. The residue was purified by flash
chromatography on silica gel to provide the desired product
(5').
[0208] Compound (6')
[0209] A mixture of (5') (390 mg, 1 mmol), 1,2-dibromoethane (1 mL)
and potassium carbonate (276 mg, 2 mmol) in 10 ML 2-butanol was
refluxed for 4 hours. The reaction mixture was cooled, partitioned
between ethyl acetate and sodium bicarbonate aqueous solution. The
organic layer was washed with brine, dried under sodium sulfate,
concentrated, purified by flash chromatography on silica gel to
provide the desired product (6').
Example 3
Synthesis of Representative Compounds of Structure (I-3)
[0210] 6566
N-oxide (4)
[0211] A mixture of compound (3) (7.31 g, 50 mmol) prepared by the
technique disclosed by Clayton and Kenyon (J. Chem. Soc., 2952-57,
1950), mCPBA (9.49 g, 55 mmol) in dichloromethane (200 mL) was
stirred at room temperature for 2 hours. The reaction mixture was
partitioned between dichloromethane and water. The dichloromethane
was dried under sodium sulfate, filtered and concentrated to yield
N-oxide (4) as the desired product.
[0212] Compound (5)
[0213] A mixture of N-oxide (4) (4.87 g, 30 mmol) and phosphorous
oxychloride (15 mL) was refluxed for 3 hours, cooled, poured onto a
crack ice, and neutralized by 1N NaOH. The aqueous layer was
extracted by ethyl acetate. The organic layer was washed with
brine, dried under sodium sulfate, and concentrated to yield
compound (5).
[0214] Compound (6)
[0215] To a mixture of compound (5) (3.61 g, 20 mmol) in methanol
(20 mL) and water (20 mL) was added bromine (3.84 g, 24 mmol) in
methanol (10 mL) and water (10 mL). The reaction mixture was
stirred at room temperature for 2 hours. The reaction mixture was
washed with sodium thiosulfate aqueous solution, and extracted with
ethyl acetate. The ethyl acetate layers were combined, dried by
sodium sulfate, filtered and concentrated. The residue was purified
by flash chromatography on silica gel to provide compound (6).
[0216] Compound (7)
[0217] A mixture of (6) (2.60 g, 10 mmol) and p-toluenesulfonic
acid monohydrate (100 mg) in 3 mL of 4-amino-heptane was refluxed
at 120.degree. C. for 5 hours. The reaction mixture was cooled,
partitioned between ethyl acetate and sodium bicarbonate aqueous
solution. The organic layer was washed with Brine, dried under
sodium sulfate, concentrated, purified by flash chromatography on
silica gel to provide compound (7).
[0218] Compound (8)
[0219] To a stirring solution of compound (7) (1.69 g, 5 mmol) in
10 mL of toluene was added
tetrakis(triphenylphosphine)-palladium(0) (Lancaster) (578 mg, 0.5
mmol, 10% mol) and 2.0M aqueous sodium carbonate solution (8 mL)
followed by addition of 2,4-dichloro-benzeneboronic acid (1.14 g, 6
mmol) in ethyl alcohol (8 mL). The resulting tan mixture was
refluxed overnight. The reaction mixture was cooled, diluted with
ethyl acetate and washed with saturated ammonium chloride solution
once. The organic layer was dried by sodium sulfate, filtered,
concentrated. The residue was purified by flash chromatography on
silica gel to provide compound (8).
[0220] Compound (9)
[0221] A mixture of compound (8) (404 mg, 1 mmol),
1,2-dibromoethane (1 ml) and potassium carbonate (276 mg, 2 mmol)
in 10 mL 2-butanol was refluxed for 4 hours. The reaction mixture
was cooled, partitioned between ethyl acetate and sodium
bicarbonate aqueous solution. The organic layer was washed with
Brine, dried under sodium sulfate, concentrated, purified by flash
chromatography on silica gel to provide compound (9).
[0222] Alternatively, compounds of structure (I-3a) may be made by
the following procedure: 6768
[0223] Compound (11)
[0224] Under nitrogen atmosphere, ethyl formate (7.38 g, 99.6 mmol)
in anhydrous THF (100 mL) was added dropwise to a stirred mixture
of NaH (1.75 g, 72.9 mmol) and compound (10) (6.93 g, 37.5 mmol) in
THF (100 mL). The mixture was stirred over night. Additional
portions of NaH and HCO.sub.2Et (2 equiv each) were added, and the
mixture was refluxed for 30 min and then stirred at room
temperature overnight. After solvent evaporation, the residue in
ice cold water (100 mL) was adjusted to pH 6 with cold 6 N HCl and
was extracted with CHCl.sub.3 (3.times.100 mL). The extract was
washed with water (100 mL), dried (Na.sub.2SO.sub.4), and
evaporated. The residue was triturated with hexane, which was
decanted. Column chromatography of the residue on silica gel (using
CHCl.sub.3 as eluant) led to compound (11).
[0225] Compound (12)
[0226] A solution of compound (11) (1.13 g, 5.31 mmol), methyl
glycinate hydrochloride (1.00 g, 7.97 mmol), and sodium acetate
(0.654 g, 7.97 mmol) in MeOH (40 mL) and H.sub.2O (10 mL) was
stirred at room temperature for 48 hr. The mixture was extracted
with CHCl.sub.3 (2.times.25 mL), and the organic extract was washed
with water (20 mL), dried (Na.sub.2SO.sub.4), and evaporated to
give compound (12).
[0227] Compound (13)
[0228] A solution of compound (12) (1.27 g, 4.5 mmol) in dry
CH.sub.2Cl.sub.2 (25 mL) was cooled to 0.degree. C. and treated
with 1,5-diazabicyclo(4.3.0)non-5-ene (DBN, 1.12 g, 9.04 mmol)
followed by ethyl chloroformate (0.735 g, 6.78 mmol). After
refrigeration for 24 h, 0.2 mL of DBN and 0.1 mL of ClCO.sub.2Et
were added to consume the small quantity of remaining starting
material, then an additional equivalent of DBN (0.6 g) was added,
and the mixture was refrigerated for 20 h. Solvent was evaporated
and the gummy residue was chromatographed on a silica gel column
(CHCl.sub.3 eluant) to give compound (13).
[0229] Compound (14)
[0230] A solution of compound (13) (2.9 g, 9.9 mmol), ethyl
acetoacetate (9.9 mmol) and p-toluenesulfonic acid monohydrate
(0.01 mmol) in 10 mL of xylene was refluxed for 2 hrs. Half of
solvent was removed by slow distillation over 1 hr. The solution
was allowed to cool to room temperature and a solution of potassium
t-butoxide (9.8 mmol) in 24 mL of ethanol was added. This mixture
was heated to 80.degree. C. for 2 hrs. The mixture was diluted with
ethyl acetate and washed with saturated NaCl solution. The organic
layer was dried with sodium sulfate and concentrated in vacuo. The
residue was triturated with ether and used in the next step without
further purification. The solid obtained was treated with an
aqueous solution of LiOH (18 mL, 1M) in methanol and the mixture
was heated at reflux for 18 hr. The solution was poured into a
solution of 1M HCl (18 mL). The solution was extracted with ethyl
acetate, washed with brine, dried with sodium sulfate and
concentrated in vacuo to give a solid which was heated in diphenyl
ether at 230.degree. C. for 1.5 hr. The solid obtained after
diluting with ether was dried in vacuo. The solid was heated at 100
C in POCl.sub.3 for 2 hrs then allowed to cool to room temperature
and poured into ice and neutralized with NaHCO.sub.3. The solution
was extracted with ethyl acetate. The organic layer was washed with
brine, dried with sodium sulfate and concentrated in vacuo.
Compound (14) was purified by flash chromatography on silica gel
silica gel eluting with ethyl acetate-hexane (1:3).
[0231] Compound (15)
[0232] A mixture of (14) (0.15 g, 0.5 mmol), p-toluenesulfonic acid
monohydrate (1 mmol) and 2-amino butanol was heated at 160.degree.
C. over night. The reaction mixture was cooled and purified by
flash chromatography on silica gel (Hexane/EtOAc, 5:1) to give
compound (15).
[0233] Compound (16)
[0234] Compound (15) (0.1 g, 0.28 mmol) was dissolved in 48% HBr
and heated at 130.degree. C. for 3 days. The mixture was cooled to
room temperature, cautiously basified with solid NaOH, and
extracted with ethyl acetate. The combined extracts were dried
(MgSO.sub.4) and concentrated in vacuo to afford compound (16).
[0235] Compound (17)
[0236] Sodium hydride mineral oil dispersion (60%, 0.1 mmol) was
added to stirred solution of compound (16) (30 mg, 0.09 mmol) in
DMF. After 15 min, 1-bromopropane was added and stirring was
continued for 10 minutes. The mixture was diluted with saturated
sodium bicarbonate, and extracted with ethyl acetate. The combined
extracts were concentrated in vacuo, and the residue was purified
by preparative TLC (elution with 10% methanol in dichloromethane)
to afford compound (17).
[0237] Compounds of structure (I-3b) may be made by the following
reaction scheme. 69
[0238] Compound (2')
[0239] To a mixture of (1')(Imai, Chem Pharm. Bull. 12:1030-1039,
1964) (3.34 g, 20 mmol) in methanol (20 mL) and water (20 mL) was
added bromine (3.84 g, 24 mmol) in methanol (10 mL) and water (10
mL). The reaction mixture was stirred at room temperature for 2
hrs. The reaction mixture was washed with sodium thiosulfate
aqueous solution, extracted with ethyl acetate. The ethyl acetate
layers were combined, dried by sodium sulfate, filtered and
concentrated. The residue was purified by flash chromatography on
silica gel to provide the desired product (2').
[0240] Compound (3')
[0241] A mixture of (2') (2.48 g, 10 mmol) and p-toulenesulfonic
acid monohydrate (100 mg) in 3 mL of 4-heptylamine was refluxed at
120.degree. C. for 5 hours. The reaction mixture was cooled,
partitioned between ethyl acetate and sodium bicarbonate aqueous
solution. The organic layer was washed with brine, dried under
sodium sulfate, concentrated, purified by flash chromatography on
silica gel to provide the desired product (3').
[0242] Compound (4')
[0243] To a stirring solution of (3') (1.63 g, 5mmol) in 10 mL of
toluene was added tetrakis(triphenylphosphine)-(palladium(0) (578
mg, 0.5 mmol, 10% mol) and 2.0M aqueous sodium carbonate solution
(8 mL) followed by addition of 2,4-dichloro-benzeneboronic acid
(1.14 g, 6 mmol) in ethyl alcohol (8 mL). The resulting mixture was
refluxed under nitrogen overnight. The reaction mixture was cooled,
diluted with ethyl acetate and washed with saturated ammonium
chloride solution once. The organic layer was dried by sodium
sulfate, filtered, concentrated. The residue was purified by flash
chromatography on silica gel to provide the desired product
(4').
[0244] Compound (5')
[0245] A mixture of (4') (390 mg, 1 mmol), 1,2-dibromoethane (1 mL)
and potassium carbonate (276 mg, 2 mmol) in 10 ML 2-butanol was
refluxed for 4 hours. The reaction mixture was cooled, partitioned
between ethyl acetate and sodium bicarbonate aqueous solution. The
organic layer was washed with brine, dried under sodium sulfate,
concentrated, purified by flash chromatography on silica gel to
provide the desired product (5').
[0246] Alternatively, compounds of structure (I-3b) may be made by
the following procedure: 7071
[0247] Compound (7')
[0248] Under nitrogen atmosphere, ethyl formate (7.38 g, 99.6 mmol)
in anhydrous THF (100 mL) was added dropwise to a stirred mixture
of NaH (1.75 g, 72.9 mmol) and compound (6') (6.93 g, 37.5 mmol) in
THF (100 mL). The mixture was stirred over night. Additional
portions of NaH and HCO.sub.2Et (2 equiv each) were added, and the
mixture was refluxed for 30 min and then stirred at room
temperature overnight. After solvent evaporation, the residue in
ice cold water (100 mL) was adjusted to pH 6 with cold 6 N HCl and
was extracted with CHCl.sub.3 (3.times.100 mL). The extract was
washed with water (100 mL), dried (Na.sub.2SO.sub.4), and
evaporated. The residue was triturated with hexane, which was
decanted. Column chromatography of the residue on silica gel (using
CHCl.sub.3 as eluant) led to compound (7').
[0249] Compound (8')
[0250] A solution of compound (7') (1.13 g, 5.31 mmol), methyl
glycinate hydrochloride (1.00 g, 7.97 mmol), and sodium acetate
(0.654 g, 7.97 mmol) in MeOH (40 mL) and H.sub.2O (10 mL) was
stirred at room temperature for 48 hr. The mixture was extracted
with CHCl.sub.3 (2.times.25 mL), and the organic extract was washed
with water (20 mL), dried (Na.sub.2SO.sub.4), and evaporated to
give compound (8').
[0251] Compound (9')
[0252] A solution of compound (8') (1.27 g, 4.5 mmol) in dry
CH.sub.2Cl.sub.2 (25 mL) was cooled to 0.degree. C. and treated
with 1,5-diazabicyclo(4.3.0)non-5-ene (DBN, 1.12 g, 9.04 mmol)
followed by ethyl chloroformate (0.735 g, 6.78 mmol). After
refrigeration for 24 h, 0.2 mL of DBN and 0.1 mL of ClCO.sub.2Et
were added to consume the small quantity of remaining starting
material, then an additional equivalent of DBN (0.6 g) was added,
and the mixture was refrigerated for 20 h. Solvent was evaporated
and the gummy residue was chromatographed on a silica gel column
(CHCl.sub.3 eluant) to give compound (9').
[0253] Compound (10')
[0254] HCl gas was bubbled into a solution of compound (9') and
acetonitrile in dioxane at room temperature. The reaction was
monitored by TLC until all starting material was consumed. The
mixture was basified with 10% aqueous ammonium hydroxide and then
was extracted with ethyl acetate. The solid obtained was washed
with water and dried to give brown solid. The solid was then
treated with POCl.sub.3 and heated at 100.degree. C. for 2 hrs.
POCl.sub.3 was evaporated in vacuo and the residue obtained was
neutralized with 2N NaOH, and extracted with ethyl acetate. The
organic layer was dried with MgSO.sub.4 and concentrated in vacuo.
The residue obtained was purified by flash chromatography on silica
gel (Hexane/EtOAc, 4:1) to give compound (10').
[0255] Compound (11')
[0256] A mixture of (10') (0.15 g, 0.5 mmol), p-toluenesulfonic
acid monohydrate (1 mmol) and 2-amino butanol was heated at
160.degree. C. over night. The reaction mixture was cooled and
purified by flash chromatography on silica gel (Hexane/EtOAc, 5:1)
to give compound (11').
[0257] Compound (12')
[0258] Compound (11') (0.1 g, 0.28 mmol) was dissolved in 48% HBr
and heated at 130.degree. C. for 3 days. The mixture was cooled to
room temperature, cautiously basified with solid NaOH, and
extracted with ethyl acetate. The combined extracts were dried
(MgSO.sub.4) and concentrated in vacuo to afford compound
(12').
[0259] Compound (13')
[0260] Sodium hydride mineral oil dispersion (60%, 0.1 mmol) was
added to stirred solution of compound (12') (30 mg, 0.09 mmol) in
DMF. After 15 min, 1-bromopropane was added and stirring was
continued for 10 minutes. The mixture was diluted with saturated
sodium bicarbonate, and extracted with ethyl acetate. The combined
extracts were concentrated in vacuo, and the residue was purified
by preparative TLC (elution with 10% methanol in dichloromethane)
to afford compound (13').
Example 4
Synthesis of Representative Compounds of Structure (I-4)
[0261] 7273
2-Amino-5-methyl-1-(2,4,6-trimethylphenyl)-1H-pyrrole-3-carbonitrile
(3)
[0262] A solution of acetol (1) (20.0 mL, 0.260 mol),
2,4,6-trimethylaniline (2) (36.5 mL, 0.260 mol), and
4-toluenesulfonic acid monohydrate (0.20 g) were refluxed in
benzene (115 mL) using a Dean-Stark trap to remove water. After 2
hours, malonitrile (16.4 mL, 0.260 mol) was added and heating was
continued for 14 hours. The mixture was cooled to room temperature,
concentrated, and the residue chromatographed (elution with 15%
ethyl acetate in hexanes) to afford 27.0 g (43%) of compound (3) as
a brown oil.
N-[3-Cyano-5-methyl-1-(2,4,6-trimethylphenyl)-1H-pyrrol-2-yl]acetamide
(4)
[0263] A mixture of compound (3) (25.3 g, 0.106 mol) and acetic
anhydride (11.0 mL, 0.117 mol) were refluxed in acetic acid (25 mL)
for 45 minutes, cooled to room temperature, poured onto crushed ice
and extracted with ethyl acetate. The organic layer was washed with
aqueous sodium bicarbonate, dried, and concentrated to give 33.6 g
(100%) of compound (4) as a yellow foam.
2,6-Dimethyl-7-(2,4,6-trimethylphenyl)-3,7-dihydro-pyrrol[2,3-d]pyrimidin--
4-one (5)
[0264] A mixture of compound (4) (32.1 g, 0.144 mol) and 85%
phosphoric acid (30 mL) was heated at 130.degree. C. for 30
minutes. The resulting mixture was cooled to room temperature,
poured into ice water with vigorous stirring, and the resulting
precipitate was filtered and dried under vacuum to afford 21.6 g
(67%) of compound (5) as a pink solid.
4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-3,7-dihydro-pyrrol[2,3-d]p-
yrimidine (6)
[0265] A mixture of compound (5) (18.3 g, 65.0 mmol) in POCl3 (30
mL) was refluxed for 3 hours, cooled to room temperature, poured
into ice water, and extracted with ethyl acetate. The combined
organic extracts were washed with aqueous sodium bicarbonate,
dried, and concentrated under vacuum. The residue was
chromatographed (elution with 10% ethyl acetate in hexanes) to
afford 16.3 g (84%) of compound (6) as a tan powder.
4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetyl)-3,7-dih-
ydropyrrolo[2,3-d]pyrimidine (7)
[0266] Compound (6) (11.2 g, 37.4 mmol) was added to a chloroform
solution (150 ml) or 20 equivalents of aluminum chloride and 25
equivalents of chloracetyl chloride. The solution was heated at
reflux for 16 hrs. The organic layer was departed and the water
layer extracted with methylene chloride. The combined organic
layers were dried over sodium sulfate and evaporated in vacuo to
yield compound (7).
4-(4-heptylamino)-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetyl-
)-3,7-dihydropyrrolo[2,3-d]pyrimidine (8)
[0267] A mixture of compound (7) (730 mg, 2 mmol), 4-aminoheptane
(250 mg, 2.2 mmol) and triethylamine (250 mg, 2.5 mmol) were
stirred at ambient temperature for 16 hours. The solution was
diluted with ethyl acetate and washed with brine. The organic layer
was dried over sodium sulfate and evaporated to dryness to provide
compound (8).
[0268] Compound (9)
[0269] A solution of (8) (440 mg, 1 mmol) in THF (10 ml) was cooled
to 0.degree. C. and a 1M solution of lithium hexamethyldisilizane
in THF (1 ml) was slowly added. The reaction was heated at reflux
for 16 hrs, evaporated to dryness, and purified by flash
chromatography with ethyl acetate and hexane to provide compound
(9).
[0270] Alternatively, compounds of structure (I-4b) may also be
prepared according to the following reaction. 7475
5-Allyl-4,6-dichloro-2-methylpyrimidine (10)
[0271] Acetamidine hydrochloride (11.2 g, 119 mmol) was added to a
stirred solution of sodium methoxide (6.41 g, 119 mmol) in methanol
(180 mL). After 5 min, diethyl allylmalonate (18 mL, 91 mmol) was
added and the mixture was heated to reflux for 15 h, cooled to rt,
and concentrated under vacuum to afford 20 g of the crude
pyridinone as a white solid. This material was heated to reflux in
phosphorus oxychloride (100 mL) for 5 h. The mixture was cooled to
rt, poured over crushed ice (200 mL), neutralized with powdered
NaHCO.sub.3, and extracted with ethyl acetate. The combined
extracts were dried (MgSO.sub.4), concentrated in vacuo, and the
residue was chromatographed (elution with 10% ethyl acetate in
hexanes) to afford 7.32 g (30%) of pyrimidine (10) as a pale yellow
oil.
5-Allyl-4-chloro-6-(2,4-dichloroanilino)-2-methylpyrimidine
(11)
[0272] Sodium hydride mineral oil dispersion (60%, 1.38 g, 34.5
mmol) was added to a stirred solution of pyrimidine (10) (3.50 g,
17.2 mmol) and 2,4-dichloroaniline (3.07 g, 18.9 mmol) in DMF (40
mL). After 25 min, the mixture was poured into water (100 mL) and
extracted with dichloromethane. The combined extracts were dried
(MgSO.sub.4), concentrated under vacuum, and the residue was
chromatographed (elution with dichloromethane) to afford 2.09 g
(37%) of pyrimidine (11) as a white powder.
4-Chloro-1-(2,4-dichlorophenyl)-6-methyl-5,7-diazaindole (12)
[0273] Sodium periodate (3.83 g, 17.9 mmol) was added to a stirred
solution of (11) (1.94 g, 5.90 mmol) in 3:1 acetone-water (55 mL).
The mixture was heated briefly to obtain homogeneity, and a 2.5%
solution of osmium tetroxide in t-butanol (0.4 mL) was added. After
20 h, the mixture was diluted with water (50 mL) and saturated
sodium thiosulfate (50 mL), and extracted with ethyl acetate. The
combined extracts were concentrated under vacuum, and the residue
was stirred in dichloromethane (40 mL) and 4 N HCl (5 mL) for 4 h.
The mixture was poured into saturated NaHCO.sub.3, extracted with
dichloromethane, dried (MgSO.sub.4), and concentrated in vacuo. The
residue was chromatographed (elution with dichloromethane) to
afford 0.929 g (50%) of diazaindole (12) as a white solid.
3-Bromo-1-(2,4-dichlorophenyl)-4-(4-heptylamino)-6-methyl-5,7-diazaindole
(13)
[0274] Bromine (0.077 mL, 1.5 mmol) was added to a stirred solution
of (12) (214 mg, 0.685 mmol) in dioxane (21 mL). After 4 hours, the
mixture was diluted with aqueous NaCl, and extracted with ethyl
acetate. The combined extracts were dried (MgSO.sub.4) and
concentrated under vacuum to afford the crude bromide. This
material was taken up 4-heptylamine (3 mL) and heated at 90.degree.
C. for 45 min. The resulting mixture was cooled to room
temperature, concentrated under vacuum, and the residue was
purified by preparative TLC (elution with 15% ethyl acetate in
hexanes) to afford 227 mg (70%) of (13) as a yellow oil which
solidified on standing.
N-Allyl-3-bromo-1-(2,4-dichlorophenyl)-4-(4-heptyl)amino-6-methyl-5,7-diaz-
aindole (14)
[0275] Sodium hydride mineral oil dispersion (60%, 80 mg, 2.0 mmol)
was added to a stirred solution of (13) (186 mg, 0.396 mmol) in DMF
(5 mL). After 10 min, allyl iodide (0.15 mL, 1.6 mmol) was added,
and stirring was continued for 90 min. The mixture was diluted with
water and aqueous NaCl, and extracted with ethyl acetate. The
combined extracts were dried (MgSO.sub.4), concentrated under
vacuum, and the residue was purified by preparative TLC (elution
with 5% ethyl acetate in hexanes) to afford 117 mg (58%) of (14) as
a white solid.
[0276] Compound (15) (I-4b-1)
[0277] Tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol)
was added to a stirred solution of (14) (83 mg, 0.16 mmol) and
potassium acetate (85 mg, 0.87 mmol) in DMF (3 ml), and the
resulting mixture was heated at 83.degree. C. for 45 min. The
mixture was cooled to room temperature, poured into aqueous NaCl,
and extracted with ethyl acetate. The combined extracts were
concentrated under vacuum, and the residue was purified by
preparative TLC (elution with 15% ethyl acetate in hexanes) to
afford 59 mg (86%) of (15) as a colorless oil. .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 7.57 (d, J=2.4 Hz, 1H), 7.49 (d, J=8.4 Hz,
1H), 7.38 (dd, J=8.6, 2.3 Hz, 1H), 6.98 (s, 1H), 5.38 (br s, 1H),
5.12 (br s, 1H), 4.93 (h, J=5.0Hz, 1H), 4.03 (br s, 2H), 2.54 (s,
3H), 1.71-1.48 (m, 4H), 1.38-1.26 (m, 4H), 0.92 (t, J=7.4 Hz, 6H);
LCMS (MH.sup.+, 429).
[0278] Compound (16) (I-4b-2)
[0279] Olefin (15) (9.4 mg, 0.022 mmol) and 10% palladium on
activated charcoal (3 mg) were stirred in ethyl acetate (2 mL)
under a balloon of hydrogen for 5 h. The mixture was filtered
through a plug of Celite, concentrated under vacuum, and the
residue was purified by preparative TLC (elution with 15% ethyl
acetate in hexanes) to afford 4.9 mg (52%) of (16) as a colorless
oil: .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.55 (d, J=2.7 Hz,
1H), 7.48 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.7, 2.7 Hz, 1H), 6.63 (br
s, 1H), 4.85 (h, J=4.9 Hz, 1H), 3.43 (dd, J=12.3, 4.8 Hz, 1H),
3.23-3.19 (m, 1H), 3.22 (dd, J=12.0, 9.6 Hz, 1H), 2.54 (s, 3H),
1.68-1.43 (m, 4H), 1.39-1.25 (m, 7H), 0.95-0.89 (m, 6H); LCMS
(MH.sup.+, 431).
[0280] Compounds of structure (I-4a) may be made by the following
reaction scheme. 7677
Ethyl
2-amino-5-methyl-1-(2,4,6-trimethylphenyl)-1H-pyrrole-3-carboxylate
(3')
[0281] A solution of acetol (1') (20 mL, 0.26 mol),
2,4,6-trimethylaniline (2') (36.5 mL, 0.260 mol), and
4-toluenesulfonic acid monohydrate (0.21 g) were refluxed in
benzene (115 mL) using a Dean-Stark trap to remove water. After 2
hours, ethyl cyanoacetate (27.7 mL, 0.26 mol) was added and heating
was continued for 14 hours. The mixture was cooled to room
temperature, concentrated, and the residue chromatographed (elution
with 15% ethyl acetate in hexanes) to afford 21.4 g (29%) of
compound (3') as a yellow oil.
3-Carboethoxy-4-hydroxy-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-1H-pyrrolo[-
2,3-b]pyridine (4')
[0282] A solution of compound (3') (12.3 g, 43.0 mmol), ethyl
3-ethoxycrotonate (6.79 g, 43.0 mmol) and 4-toluenesulfonic acid
monohydrate (0.50 g) in xylene (100 mL) were refluxed for 30
minutes. The solvent was distilled off over an additional 30
minutes, and the mixture was cooled to room temperature. Potassium
t-butoxide (4.82 g, 43.0 mmol) in absolute ethanol (50 mL) was
added and the mixture was heated at 80.degree. C. for 3 hours,
cooled to room temperature, treated with acetic acid (2.50 mL) and
concentrated under vacuum. The residue was taken up in ethyl
acetate, and treated with diethyl ether to precipitate 6.91 g (46%)
of compound (4') as a white powder.
4-Hydroxy-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-1H-pyrrolo
[2,3-b]pyridine (5')
[0283] Compound (4') (4.11 g, 11.7 mmol) in 1.0 M lithium hydroxide
(25 mL) and ethanol (15 mL) was heated at reflux for 17 hours. The
mixture was cooled to room temperature, neutralized with dilute
aqueous hydrochloric acid, and extracted with ethyl acetate. The
combined organic extracts were washed with aqueous sodium chloride,
dried, and concentrated under vacuum. This material was heated at
200.degree. C. for 2 hours in diphenyl ether (2.5 mL), cooled to
room temperature, and crystallized from methanol-ethyl acetate to
afford 1.41 g (43%) of compound (5') as a white powder.
4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-1H-pyrrolo[2,3-b]pyridine
(6')
[0284] Compound (6') was prepared from compound (5') according to
the same procedure as above used in the preparation of compound
(6).
4-Chloro-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetyl)-1H-pyrr-
olo[2,3-b]pyridine (7')
[0285] Compound (7') was prepared from compound (6') according to
the same procedure as disclosed above in the preparation of
compound (7).
4-(4-Heptylamino)-2,6-dimethyl-7-(2,4,6-trimethylphenyl)-5-(2-chloroacetyl-
)-1H-pyrrolo[2,3-b]pyridine (8')
[0286] Compound (8') was prepared from compound (7') according to
the same procedure as disclosed above in the preparation of
compound (8).
[0287] Compound (9')
[0288] Compound (9') was prepared from compound (8') according to
the same procedure as used above in the preparation of compound
(9). Similar compounds wherein the 2,4,6-trimethylphenyl group is
replaced with 4-methoxyphenyl (MS/MH.sup.+=392), or with
2-trifluoromethyl-4-isopropylp- henyl (MS/MH.sup.+=458), may be
made by the same procedure, but employing the
appropriately-substituted starting material 2' in place of
2,4,6-trimethylaniline.
[0289] Alternatively, compounds of structure (I-4a) may be made by
the following procedure: 7879
2,4-Dichloro-3-hydroxymethyl-6-methylpyridine (11')
[0290] Ethyl 2,4-dichloro-6-methylnicotinate (10') (8.04 g, 34.3
mmol) was dissolved in THF (40 mL) and added to a stirred
suspension of LAH (6.52 g, 170 mmol) in THF (80 mL) at -78.degree.
C. The mixture was stirred for 6 h at this temperature and 1 h at
-30.degree. C. and treated cautiously with water (5.5 mL), 15%
aqueous NaOH (5.5 mL) and water (16.5 mL) with vigorous stirring.
The mixture was warmed to room temperature and filtered. The white
precipitate was washed liberally with ethyl acetate. The combined
organic portions were dried (MgSO.sub.4) and concentrated under
vacuum to afford 6.40 g (97%) of (11') as a colorless oil which
solidified on standing: LCMS (MH.sup.+, 192).
2,4-Dichloro-6-methylpyridine-3-carboxaldehyde (12')
[0291] DMSO (14.2 mL, 200 mmol) was added to a stirred solution of
oxalyl chloride (8.7 mmol, 99 mmol) in dichloromethane (100 mL) at
-70.degree. C. After 15 min, alcohol (11') (6.40 g, 33.3 mmol) in
dichloromethane (25 mL) was added, followed by triethylamine (56
mL), and the mixture was allowed to warm to room temperature and
stirred for 1 h. The mixture was washed with aqueous sodium
bicarbonate (75 mL), dried (MgSO.sub.4), and concentrated under
vacuum. The residue was purified by column chromatography (elution
with 10% ethyl acetate in hexanes) to afford 5.00 g (78%) of (12')
as a pale yellow oil which solidified on standing: LCMS (MH.sup.+,
190), R.sub.f 0.48 (20% ethyl acetate in hexanes).
2,4-Dichloro-6-methyl-3-(vinylcarbonyl)pyridine (14')
[0292] Vinylmagnesium bromide in THF (1.0 M, 6.7 mL, 6.7 mmol) was
added to a stirred solution of aldehyde (12') (1.15 g, 6.05 mmol)
in THF (20 mL) at -78.degree. C. The mixture was stirred at this
temperature for 30 min, warmed to room temperature and quenched
with aqueous sodium bicarbonate (40 mL). The mixture was extracted
with ethyl acetate (2.times.50 mL) and the combined extracts were
dried (MgSO.sub.4) and concentrated under vacuum to afford 1.37 g
of crude (13') a yellow oil: LCMS (MH.sup.+, 218), R.sub.f 0.28
(20% ethyl acetate in hexanes).
[0293] The above material and N-methylmorpholine N-oxide (NMO, 1.06
g, 9.05 mmol) were dissolved in dichloromethane (27 mL) and treated
with 4 angstrom molecular sieves (1.3 g). The mixture was stirred
for 20 min, and tetrapropylammonium perruthenate (TPAP, 65 mg) was
added. The mixture was stirred for 1 h. Some starting material
persisted so additional NMO (1.06 g) and TPAP (65 mg) were added,
and stirring was continued for 1 h. The mixture was filtered
(Celite), concentrated under vacuum, and the residue was purified
on a silica gel column (elution with 10% ethyl acetate in hexanes)
to afford 0.50 g (38%) of (14') as a pale yellow oil: LCMS
(MH.sup.+, 216), R.sub.f 0.52 (20% ethyl acetate in hexanes).
5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyridin-4-one (15') and
5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin-4-one (16')
[0294] Enone (14') (920 mg, 4.26 mmol) was dissolved in ethanol (20
mL) and treated with 4-heptylamine (0.64 mL, 4.3 mmol). The mixture
was heated at 60.degree. C. for 16 h and concentrated under vacuum.
The residue was taken up in ethyl acetate (50 mL), washed with
aqueous sodium bicarbonate (20 mL), dried (MgSO.sub.4), and again
concentrated. The residue was purified on a silica gel column
(elution with 5% ethyl acetate in hexanes for (15') and 25% ethyl
acetate in hexanes for (16') to afford 314 mg (25%) of (15') as a
yellow oil followed by 214 mg (17%) of (16') as white solid.
5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,8)naphthyri- din-4-one (15'):
NMR, LCMS (MH.sup.+, 295), R.sub.f 0.70 (30% ethyl acetate in
hexanes); 5-Chloro-1-(4-heptyl)-7-methyl-1H-(1,6)naphthyridin--
4-one (16'): mp 82-85.degree. C., LCMS (MH.sup.+, 295), R.sub.f
0.14 (30% ethyl acetate in hexanes).
[0295] Compound (17')
[0296] LDA in THF (0.325M, 0.83 ml, 0.27 mmol) was added to a
stirred solution of the phosphine oxide (66 mg, 0.27 mmol) in THF
(2 mL) at -25.degree. C. After 15 min, compound (16') (11 mg, 0.034
mmol) in THF (1 mL) was added and the mixture was stirred for 15
min. NaH (30 mg) was added, the mixture was warmed to room
temperature and stirred for 16 hrs. The mixture was diluted with
water (15 mL) and extracted with EtOAc (4.times.10 mL) . The
combined extracts were dried (MgSO.sub.4), concentrated in vacuo
and the residue was purified by preparative TLC (elution with 30%
EtOAc/Hex.) to afford compound (17') as a colorless oil. (4.6 mg,
42%), LCMS (MH+, 323).
[0297] Compound (18')
[0298] Compound (17') (4.6 mg, 0.014 mmol), TsOH.H.sub.2O (4.2 mg,
0.022 mmol) and the aniline (12 mg, 0.085 mmol) was heated at
130.degree. C. for 16 hrs. The mixture was cooled to room
temperature, diluted with aqueous NaHCO.sub.3 (2 mL) and extracted
with EtOAc (4.times.2 mL). The combined extracts were dried
(MgSO.sub.4), concentrated in vacuo and the residue was purified by
preparative TLC to afford compound (18') as a yellow oil. (1.0 mg,
18%), LCMS (MH.sup.+, 396).
Example 5
Synthesis of Further Representative Compounds of Structure
(I-2A)
[0299] Additional representative compounds of this invention were
made by the following reaction scheme. 80
[0300] Compound (2)
[0301] Compound (1) (270 mg, 0.86 mmol), p-toluenesulfonic acid
monohydrate (225 mg, 1.18 mmol) and DL-2-amino-1-pentanol (1 mL)
were heated at 160.degree. C. for 3 hours. The mixture was cooled
to room temperature, diluted with dichloromethane, and purified on
a silica gel column (elution with 10% methanol in dichloromethane)
to afford 408 mg (100%) of compound (2) as a yellow solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.76 (d, J=4.8 Hz. 1H), 7.53 (br
s, 1H), 7.24-7.12 (m, 2H), 7.20 (d, J=7.8 Hz, 1H), 6.12 (s, 1H),
3.76-3.67 (m, 3H), 2.49 (s, 3H), 1.63-1.56 (m, 2H), 1.45-1.32 (m,
3H), 0.89 (t, J=7.1 Hz, 3H); LC/MS (MH.sup.+, 379).
[0302] Compound (3)
[0303] Compound (2) (478 mg, 0.86 mmol) was dissolved in 48% HBr (5
mL) and heated at 110.degree. C. for 4 days. The mix was cooled to
room temperature, cautiously basified with solid NaOH, and
extracted with ethyl acetate. The combined extracts were dried
(MgSO.sub.4) and concentrated under vacuum to afford 159 mg (51%)
of compound (3) as a yellow foam: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.86 (d, J=8.4 Hz. 1H), 7.52 (d, J=2.1 Hz, 1H), 7.34 (dd,
J=8.1, 2.1 Hz, 1H), 6.30 (s, 1H), 4.69 (br s, 1H), 4.60 (dd,
J=12.0, 3.6 Hz, 1H), 4.10 (dd, J=12.2, 8.6 Hz, 1H), 3.88-3.85 (m,
1H), 2.58 (s, 3H), 1.78-1.55 (m, 4H), 1.05 (t, J=7.4 Hz, 3H); LC/MS
(MH.sup.+, 361).
[0304] Compound (4)
[0305] Sodium hydride mineral oil dispersion (60%, 10 mg, 0.25
mmol) was added to a stirred solution of compound (3) (16 mg, 0.044
mmol) in DMF (0.5 mL). After 5 min, 1-bromopropane (0.050 mL, 0.55
mmol) was added and stirring was continued for 10 minutes. The
mixture was cautiously diluted with saturated sodium bicarbonate,
and extracted with ethyl acetate. The combined extracts were
concentrated under vacuum, and the residue was purified by
preparative TLC (elution with 10% methanol in dichloromethane) to
afford 7 mg (40%) of compound (4) where R.sub.1 is n-propyl as a
yellow oil.
[0306] This technique is representative of the synthesis of the
compounds presented in Table 3.
3TABLE 3 Analytical Data for Representative Compounds 81 Cpd. No. R
R.sub.1 Analytical Data (I-2a-21) n-propyl 82 7.91(d, J=8.4Hz, 1H),
7.53(d, J=2.1Hz, 1H), 7.35(dd, J=8.4, 2.1Hz, 1H), 6.14(s, 1H),
4.52(dd, J=12.2, 1.2Hz, 1H), 4.34(dd, J=12.3, 3.9Hz, 1H),
3.80-3.74(m, 1H), 3.63-3.54(m, 1H), 3.21-3.11(m, 1H), 2.59(s, 3H),
1.86-1.60(m, 4H), 1.56-1.34(m, 2H), 1.01(t, J=7.4Hz, 3H), 0.94(t,
J=7.2Hz, 3H); LCMS(MH+, 403) (I-2a-22) n-propyl 83 7.91(d, J=8.4Hz,
1H), 7.53(d, J=2.1Hz, 1H), 7.36(dd, J=8.4, 2.1Hz, 1H), 6.13(s, 1H),
4.52(dd, J=12.2, 2.0Hz, 1H), 4.33(dd, J=12.3, 4.2Hz, 1H),
3.80-3.74(m, 1H), 3.65-3.56(m, 1H), 3.23-3.14(m, 1H), 2.59(s, 3H),
1.80-1.60(m, 5H), 1.55-1.34(m, 5H), 0.97-0.91(m, 6H); LCMS (MH+,
431). (I-2a-23) n-propyl 84 7.91(d, J=8.4Hz, 1H), 7.54(d, J=2.4Hz,
1H), 7.36(dd, J=8.4, 2.1Hz, 1H), 6.11(s, 1H), 4.54(dd, J=12.5,
1.4Hz, 1H), 4.37(dd, J=12.5, 4.1Hz, 1H), 3.76-3.70(m, 1H), 3.48(dd,
J=14.4, 6.3Hz, 1H), 2.90(dd, J=14.1, 8.7Hz, 1H), 2.59(s, 3H),
2.13-2.04(m, 1H), 2.0-1.25(m, 4H), 1.01(d, J=6.3Hz, 3H), 0.99(d,
J=6.9Hz, 3H), 0.93(t, J=7.2Hz, 3H); LCMS(MH+, 417) (I-2a-24)
n-propyl 85 7.91(d, J=8.4Hz, 1H), 7.53(d, J=2.1Hz, 1H), 7.35(dd,
J=8.3, 2.0Hz, 1H), 6.18(s, 1H), 4.56(dd, J=12.6, 1.8Hz, 1H),
4.36(dd, J=12.5, 4.1Hz, 1H), 4.02-3.96(m, 1H), 3.57(dd, J=14.4,
6.0Hz, 1H), 3.05(dd, J=14.6, 7.4Hz, 1H), 2.59(s, 3H), 1.86-1.34(m,
4H), 1.13-1.09(m, 1H), 0.94(t, J=7.2Hz, 3H), 0.70-.61(m, 2H),
0.37-0.27(m, 2H); LCMS (MH+, 415) (I-2a-25) n-propyl 86 7.90(d,
J=8.1Hz, 1H), 7.54(d, J=2.4Hz, 1H), 7.36(dd, J=8.4, 2.1Hz, 1H),
6.15(s, 1H), 4.50(dd, J=12.2, 1.7Hz, 1H), 4.34(dd, J=12.2, 4.1Hz,
1H), 3.92-3.88(m, 1H), 3.78-3.72(m, 1H), 3.64-3.60(m, 2H),
3.51-3.42(m, 1H), 3.37(s, 3H), 2.59(s, 3H), 1.69-1.25(m, 4H),
0.94(t, J=7.4Hz, 3H); LCMS(MH+, 419). 7.90(d, J=8.1Hz, 1H), 7.54(d,
J=2.4Hz, 1H), 7.36(dd, J=8.4, 2.1Hz, 1H), 6.15(s, 1H), # 4.50(dd,
J=12.2, 1.7Hz, 1H), 4.34(dd, J=12.2, 4.1Hz, 1H), 3.92-3.88(m, 1H),
3.78-3.72(m, 1H), 3.64-3.60(m, 2H), 3.51-3.42(m, 1H), 3.37(s, 3H),
2.59(s, 3H), 1.69-1.25(m, 4H), 0.94(t, J=7.4Hz, 3H); LCMS(MH+, 419)
(I-2a-26) n-propyl 87 7.93(d, J=8.4Hz, 1H), 7.54(d, J=2.1Hz, 1H),
7.41-7.30(m, 6H), 6.23(m, 1H), 4.86(d, J=15.6Hz, 1H), 4.51(dd,
J=12.6, 2.1Hz, 1H), 4.37(d, J=16.2Hz, 1H), 4.33(dd, J=12.0, 4.2Hz,
1H), 3.75-3.71(m, 1H), 2.57(s, 3H), 1.71-1.32(m, 4H), 0.91(t,
J=7.2Hz, 3H); LCMS(MH+, 451) (I-2a-27) n-propyl 88 7.55(d, J=2.4Hz,
1H), 7.48-7.20(m, 5H), 6.16(s, 1H), 4.85(d, J=16.5Hz, 1H),
4.58-4.51(m, 2H), 4.40(dd, J=12.6, 3.9Hz, 1H), 3.82-3.74(m, 1H),
2.56(s, 3H), 1.76-1.25(m, 4H), 0.94(t, J=7.4Hz, 3H); LCMS (MH+,
485) (I-2a-28) n-propyl 89 7.92(dd, J=8.1Hz, 1H), 7.53(d, J=1.8Hz,
1H), 7.35(dd, J=8.6, 2.3Hz, 1H), 6.18(s, 1H), 4.59(dd, J=12.2,
1.4Hz, 1H), 4.10(dd, J=12.5, 3.5Hz, 1H), 3.83(d, J=10.8Hz, 1H),
3.70(pent, J=7.0Hz, 1H), 2.59(s, 3H), 1.81-1.18(m, 12H), 1.01(t,
J=7.2Hz, 3H), 0.93(t, J=7.1Hz, 3H), 0.89(t, J=7.2Hz, 3H); LCMS(MH+,
459) (I-2a-29) n-propyl 90 7.90(d, J=8.4Hz, 1H), 7.53(d, J=2.1Hz,
1H), 7.36(dd, J=8.3, 2.2Hz, 1H), 6.15(s, 1H), 4.53(dd, J=12.5,
1.7Hz, 1H), 4.32(dd, J=12.5, 4.1Hz, 1H), 3.80-3.72(m, 1H), 3.63(dd,
J=14.6, 6.6Hz, 1H), 3.23(dd, J=14.3, 8.0Hz, 1H), 2.77-2.70(m, 1H),
2.61(s, 3H), 2.16-1.26(m, 6H), 0.94(t, J=7.2Hz, 3H), 1.01-0.83(m,
4H); LCMS(MH.sup.+, 429). (I-2a-30) ethyl(S) 91 7.90(d, J=8.1Hz,
1H), 7.53(d, J=2.1Hz, 1H), 7.36(dd, J=8.3, 2.3Hz, 1H), 6.12(s, 1H),
4.58(dd, J=12.5, 1.4Hz, 1H), 4.36(dd, J=12.8, 3.5Hz, 1H),
3.68-3.65(m, 1H), 3.50(dd, J=14.0, 6.2Hz, 1H), 2.92(dd, J=14.0,
8.6Hz, 1H), 2.59(s, 3H), 2.11-2.06(m, 1H), 1.80-1.57(m, 2H),
1.04-0.98(m, 9H), LCMS(MH.sup.+, 403). (I-2a-31) ethyl(S) 92
7.91(d, J=8.4Hz, 1H), 7.53(d, J=2.1Hz, 1H), 7.34(dd, J=8.3, 2.3Hz,
1H), 6.19(s, 1H), 4.59(dd, J=12.5, 2.0Hz, 1H), 4.36(dd, J=12.3,
3.6Hz, 1H), 3.94-3.90(m, 1H), 3.59(dd, J=14.3, 5.9Hz, 1H), 3.06(dd,
J=14.4, 7.2Hz, 1H), 2.59(s, 3H), 1.78-1.74(m, 1H), 1.67-1.59(m,
1H), 1.13-1.11(m, 1H), 1.02(t, J=7.5Hz, 3H), 0.70-0.61(m, 2H),
0.34-0.30(m, 2H); LCMS(MH.sup.+, 401). (I-2a-32) ethyl(R) 93
7.90(d, J=8.1Hz, 1H), 7.53(d, J=2.1Hz, 1H), 7.36(dd, J=8.3, 2.3Hz,
1H), 6.12(s, 1H), 4.58(dd, J=12.5, 1.4Hz, 1H), 4.36(dd, J=12.8,
3.5Hz, 1H), 3.68-3.65(m, 1H), 3.50(dd, J=14.0, 6.2Hz, 1H), 2.92(dd,
J=14.0, 8.6Hz, 1H), 2.59(s, 3H), 2.11-2.06(m, 1H), 1.80-1.57(m,
2H), 1.04-0.98(m, 9H), LCMS(MH.sup.+, 403). (I-2a-33) ethyl(R) 94
7.91(d, J=8.4Hz, 1H), 7.53(d, J=2.1Hz, 1H), 7.34(dd, J=8.3, 2.3Hz,
1H), 6.19(s, 1H), 4.59(dd, J=12.5, 2.0Hz, 1H), 4.36(dd, J=12.3,
3.6Hz, 1H), 3.94-3.90(m, 1H), 3.59(dd, J=14.3, 5.9Hz, 1H), 3.06(dd,
J=14.4, 7.2Hz, 1H), 2.59(s, 3H), 1.78-1.74(m, 1H), 1.67-1.59(m,
1H), 1.13-1.11(m, 1H), 1.02(t, J=7.5Hz, 3H), 0.70-0.61(m, 2H),
0.34-0.30(m, 2H); LCMS(MH.sup.+, 401). (I-2a-34) iso-propyl 95
7.90(d, J=8.4Hz, 1H), 7.53(d, J=2.1Hz, 1H), 7.36(dd, J=8.4, 2.1Hz,
1H), 6.22(s, 1H), 4.67(dd, J=12.3, 2.0Hz, 1H), 4.31(dd, J=12.5,
4.4Hz, 1H), 3.82-3.73(m, 2H), 3.00(dd, J=14.6, 7.7Hz, 1H), 2.60(s,
3H), 2.14(m, 1H), 1.14-1.07(m, 1H), 1.02(d, J=6.6Hz, 3H), 0.85(d,
J=6.6Hz, 3H), 0.64-0.55(m, 2H), 0.37-0.23(m, 2H); LCMS(MH.sup.+,
415). (I-2a-35) iso-propyl 96 7.90(d, J=8.1Hz, 1H), 7.53(d,
J=1.8Hz, 1H), 7.36(dd, J=8.4, 2.1Hz, 1H), 6.15(s, 1H), 4.64(dd,
J=12.6, 1.8Hz, 1H), 4.28(dd, J=12.6, 4.5Hz, 1H), 3.77-3.68(m, 1H),
3.57-3.52(m, 1H), 3.24-3.14(m, 1H), 2.59(s, 3H), 2.17-2.10(m, 1H),
1.76-1.64(m, 2H), 1.03(d, J=6.9Hz, 3H), 0.98(t, J=7.4Hz, 3H),
0.88(d, J=6.9Hz, 3H); LCMS(MH.sup.+, 403). (I-2a-36) iso-propyl 97
LC/MS 417 (MH+) (I-2a-37) ethyl 98 LC/MS 432 (MH+) (I-2a-38)
ethyl(S) 99 LC/MS 445 (MH+)
Example 6
Further Representative Compounds of Structure (I-2A)
[0307] The representative compounds of Table 4 were made by the
procedures set forth above in Example 5.
4TABLE 4 Analytical Data for Representative Compounds 100 Cpd. No.
R R.sub.1 Analytical Data (I-2a-39) ethyl(S) 101 7.82(d, J=8.1Hz,
1H), 7.29-7.25(m, 2H), 6.18(s, 1H), 4.55(dd, J=12.3, 2.0Hz, 1H),
4.32(dd, J=12.3, 3.6Hz, 1H), 3.94-3.89(m, 1H), 3.59(dd, J=14.4,
5.7Hz, 1H), 3.06(dd, J=14.4, 7.2Hz, 1H), 2.59(s, 3H), 2.53(s, 3H),
1.83-1.71(m, 1H), 1.67-1.57(m, 1H), 1.15-1.10(m, 1H), 1.02(t,
J=7.5Hz, 3H), 0.71-0.61(m, 2H), 0.39-0.28(m, 2H); LCMS(MH.sup.+,
381). (I-2a-40) ethyl(S) 102 7.83(d, J=8.1Hz, 1H), 7.30-7.25(m,
2H), 6.11(s, 1H), 4.53(dd, J=12.3, 1.2Hz, 1H), 4.33(dd, J=12.5,
4.1Hz, 1H), 3.68-3.63(m, 1H), 3.49(dd, J=14.1, 6.3Hz, 1H), 2.91(dd,
J=14.1, 8.7Hz, 1H), 2.59(s, 3H), 2.54(s, 3H), 2.16-2.05(m, 1H),
1.77-1.57(m, 2H), 1.04-0.98(m, 9H); LCMS(MH.sup.+, 383). (I-2a-41)
ethyl(S) 103 7.82(d, J=8.7Hz, 1H), 7.30-7.25(m, 2H), 6.17(s, 1H),
4.56(dd, J=12.3, 0.9Hz, 1H), 4.42(dd, J=12.3, 3.3Hz, 1H),
3.64-3.60(m, 1H), 3.47(d, J=14.4Hz, 1H), 2.91(d, J=15.0Hz, 1H),
2.58(s, 3H), 2.54(s, 3H), 1.77-1.63(m, 1H), 1.61-1.53(m, 1H),
1.02(s, 9H), 1.07-0.98(m, 3H); LCMS(MH.sup.+, 397). (I-2a-42)
ethyl(S) 104 7.82(d, J=8.4Hz, 1H), 7.29-7.25(m, 2H), 6.17(s, 1H),
4.60(dd, J=12.3, 1.2Hz, 1H), 4.06(dd, J=11.9, 3.5Hz, 1H),
3.75-3.68(m, 2H), 2.59(s, 3H), 2.54(s, 3H), 1.78-1.44(m, 7H),
1.36-1.21(m, 3H), 1.05-0.96(m, 6H), 0.90(t, J=7.2Hz, 3H); LCMS
(MH.sup.+, 425). (I-2a-43) ethyl(S) 105 LC/MS 365 (MH+) (I-2a-44)
iso- butyl(S) 106 LC/MS 397 (MH+) (I-2a-45) iso- butyl(S) 107 LC/MS
409 (MH+) (I-2a-46) ethyl(S) 108 LC/MS 397 (MH+) (I-2a-47) ethyl(S)
109 7.90(d, J=8.4Hz, 1H), 7.33-7.28(m, 3H), 5.30-5.20(m, 1H),
4.59(dd, J=13.2, 1.2Hz, 1H), 4.50(dd, J=12.6, 3.6Hz, 1H), 2.71(s,
3H), 2.54(s, 3H), 2.30-2.21(m, 1H), 1.74-1.41(m, 4H), 1.25-0.97(m,
2H), 0.97(t, J=7.5Hz, 3H); LCMS(MH.sup.+, 395). (I-2a-48) ethyl(S)
110 7.82(d, J=7.8Hz, 1H), 7.29-7.24(m, 2H), 6.46(s, 1H), 4.54(dd,
J=12.2, 0.8Hz, 1H), 4.27(dd, J=12.3, 4.2Hz, 1H), 3.80-3.74(m, 1H),
2.73-2.68(m, 1H), 2.62(s, 3H), 2.52(s, 3H), 1.93-1.82(m, 2H),
1.64-1.54(m, 1H), 1.05(t, J=7.5Hz, 3H), 0.90-0.67(m, 3H);
LCMS(MH.sup.+, 367).
Example 7
Synthesis of Further Representative Compounds of Structure
(I-2A)
[0308] The representative compounds of Table 5 were made by the
following procedure (R=ethyl or hydrogen): 111
5TABLE 5 Analytical Data for Representative Compounds 112 Cpd. No.
Ar R R.sub.1 Analytical Data (I-2a-49) 2-trifluoromethyl-
4-chlorophenyl ethyl(S) 113 LC/MS 439 (MH+) (I-2a-50)
2-trifluoromethyl- 4-chlorophenyl ethyl(S) 114 LC/MS 435 (MH+)
(I-2a-51) 2-trifluoromethyl- 4-chlorophenyl ethyl(S) 115 LC/MS 514
(MH+) (I-2a-52) 2-methoxy-4- trifluromethyl- phenyl ethyl(S) 116
7.77(d, J=8.4Hz, 1H), 7.32(d, J=2.7Hz, 1H), 7.15(dd, J=8.4, 2.7Hz,
1H), 6.18(s, 1H), 4.54(dd, J=12.3, 1.8Hz, 1H); 4.33(dd, J=11.9,
4.1Hz, 1H), 3.95-3.90(m, 1H); 3.89(s, 3H), 3.58(dd, J=14.4, 6.0Hz,
1H), 3.05(dd, J=14.4, 7.2Hz, 1H); 2.57(s, 3H); 1.86-1.73(m, 1H),
1.67-1.57(m, 1H), 1.57-1.06(m, 1H), 1.01(t, J=7.4Hz, 3H),
0.70-0.61(m, # 2H); 0.37-0.28(m, 2H); LCMS(MH.sup.+, 431).
(I-2a-53) 2-trifluoromethyl- 4-chlorophenyl H 117 LC/MS 451 (MH+)
(I-2a-54) 2,5-dimethoxy-4- chlorophenyl H 118 7.60(s, 1H); 7.07(s,
1H); 6.27(s, 1H); 4.49(t, 2H); 3.93(s, 3H); 3.91(s, 3H); 3.86(m,
1H); 3.73(t, 2H); 2.73(s, 3H); 1.60-1.75(m, 4H); 1.20-1.40(m, 4H);
0.95(t, 6H). LC/MS m + 1(443, 445). (I-2a-55) 2-methoxy-4-
trifluoromethyl- phenyl H 119 7.75(d, J=8.4Hz, 1H); 7.32(d,
J=2.7Hz, 1H); 7.15(dd, J=8.7, 2.7Hz, 1H); 6.21(s, 1H); 4.42(t,
J=5.3Hz, 2H); 3.89(s, 3H); 3.86-3.80(m, 1H); 3.65(t, J=5.3Hz, 2H);
2.56(s, 3H); 1.76-1.58(m, 4H); 1.41-1.24(m, 4H); 0.94(t, J=7.2Hz,
6H); LCMS (MH.sup.+, 447). (I-2a-56) 2-methoxy-4- methylphenyl H
120 7.79(d, J=7.5Hz, 1H); 6.89(d, J=7.5Hz, 1H); 6.86(br s, 1H);
6.21(s, 1H); 4.46(t, J=5.3Hz, 2H); 3.92(s, 3H); 3.88-3.83(m, 1H);
3.66(t, J=5.3Hz, 2H); 2.66(s, 3H); 2.41(s, 3H); 1.71-1.53(m, 4H);
1.41-1.25(m, 4H); 0.93(t, J=7.4Hz, 6H); LCMS (MH.sup.+, 393).
(I-2a-57) 4-methyl-6- dimethylamino- pyridin-3-yl H 121 8.58(s,
1H); 6.46(s, 1H); 6.20(s, 1H); 4.41(t, 2H); 3.86(m, 1H); 3.66(t,
2H); 3.12(s, 6H); 2.58(s, 3H); 2.48(s, 3H); 1.50-1.72(m, 4H);
1.28-1.44(m, 4H); 0.96(t, 6H). LC/MS m + 1(407). (I-2a-58)
2-methoxy-4- isopropylphenyl H 122 LC/MS 421 (MH+) (I-2a-59)
2-methoxy-4- methylphenyl H 123 LC/MS 393 (MH+) (I-2a-59-1) 2-4-
di(trifluoromethyl)- phenyl H 124 -- (I-2a-60) 2,4-dimethyl- phenyl
ethyl(S) 125 LC/MS 361 (MH+) (I-2a-61) 2-methoxy-4- isopropylphenyl
ethyl(S) 126 LC/MS 405 (MH+) (I-2a-62) 2-formyl-4- methoxyphenyl
ethyl(S) 127 LC/MS 391 (MH+) (I-2a-63) 2,4,6-trimethyl- phenyl
ethyl(S) 128 LC/MS 375 (MH+) (I-2a-64) 2,4,6-trimethyl- phenyl H
129 LC/MS 391 (MH+) (I-2a-65) 2-chloro-4- (C(.dbd.O)OCH.sub.3)-
phenyl ethyl(S) 130 LC/MS 425 (MH+) (I-2a-66) 2-chloro-4-
C(OH)(CH.sub.3).sub.2- phenyl ethyl(S) 131 LC/MS 425 (MH+)
(I-2a-67) 2-trifluoromethyl- 4-isopropyl- phenyl ethyl(S) 132 LC/MS
443 (MH+) (I-2a-68) 2-chloro-4,6- dimethylphenyl ethyl(S) 133 LC/MS
395 (MH+) (I-2a-69) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S)
134 1.00(9H, t), 1.66(2H, m), 2.10(1H, m), 2.55(3H, s), 2.90(1H,
q), 3.48(1H, q), 3.65(1H, m), 3.89(3H, s), 4.33(1H, m), 4.53(1H,
d), 6.12(1H, s), 7.15(1H, m), 7.32(1H, d), 7.78(1H, d). (I-2a-70)
2,4,6-trimethyl- phenyl ethyl(S) 135 1.01(9H, t) 1.65(2H, m),
2.12(7H, m), 2.30(3H, s), 2.52(3H, s), 2.90(1H, m), 3.47(1H, m),
3.64(1H, m), 4.32(1H, d), 4.50(1H, d), 6.07(1H, s), 6.91(2H, s).
(I-2a-71) 2,4-dimethyl- phenyl ethyl(S) 136 1.00(9H, m), 1.65(2H,
m), 2.09(1H, m), 2.35(3H, s), 2.51(3H, s), 2.57(3H, s), 2.90(1H,
m), 3.48(1H, m), 3.63(1H, m), 4.31(1H, m), 5.51(1H, d), 6.09(1H,
s), 7.09(2H, m), 7.72(1H, d). (I-2a-72) 2-methoxy-4-
trifluoromethyl- phenyl ethyl(S) 137 LC/MS 468 (MH+) (I-2a-73)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 138 LC/MS 417 (MH+)
(I-2a-74) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 139 LC/MS
449 (MH+) (I-2a-75) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S)
140 LC/MS 489 (MH+) (I-2a-76) 2-methoxy-4- trifluoromethyl- phenyl
ethyl(S) 141 LC/MS 485 (MH+) (I-2a-77) 2-methoxy-4-
trifluoromethyl- phenyl ethyl(S) 142 LC/MS 445 (MH+) (I-2a-78)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 143 LC/MS 435 (MH+)
(I-2a-79) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 144 LC/MS
470 (MH+) (I-2a-80) 2-methoxy-4- trifluoromethyl- phenyl methyl(S)
145 -- (I-2a-81) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 146
-- (I-2a-82) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 147 --
(I-2a-83) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 148 417
(I-2a-84) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 149 --
(I-2a-85) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 150 421
(I-2a-86) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 151 461
(I-2a-87) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 152 531
(I-2a-88) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 153 --
(I-2a-89) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 154 --
(I-2a-90) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 155 453
(I-2a-91) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 156 403
(I-2a-92) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 157 433
(I-2a-93) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 158 481
(I-2a-94) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 159 --
(I-2a-95) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 160 --
(I-2a-96) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 161 473
(I-2a-97) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 162 --
(I-2a-98) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 163 --
(I-2a-99) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 164 --
(I-2a-100) 2-methoxy-4- trifluoromethyl- phenyl ethyl 165 --
(I-2a-101) 2-methoxy-4- trifluoromethyl- phenyl ethyl 166 --
(I-2a-102) 2-methoxy-4- trifluoromethyl- phenyl ethyl 167 --
(I-2a-103) 2-methoxy-4- trifluoromethyl- phenyl ethyl 168 --
(I-2a-104) 2-methoxy-4- trifluoromethyl- phenyl ethyl 169 --
(I-2a-105) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 170 LC/MS
405 (MH+) (I-2a-106) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S)
171 LC/MS 419 (MH+) (I-2a-107) 2-methoxy-4- trifluoromethyl- phenyl
ethyl(S) 172 LC/MS 491 (MH+) (I-2a-108) 2-methoxy-4-
trifluoromethyl- phenyl ethyl(S) 173 LC/MS 547 (MH+) (I-2a-109)
2-methoxy-4- trifluoromethyl- phenyl ethyl 174 LC/MS 449 (MH+)
(I-2a-110) 2-methoxy-4- trifluoromethyl- phenyl ethyl 175 LC/MS 459
(MH+) (I-2a-111) 2-methoxy-4- trifluoromethyl- phenyl ethyl 176
LC/MS 473 (MH+) (I-2a-112) 2-methoxy-4- trifluoromethyl- phenyl
ethyl 177 LC/MS 487 (MH+) (I-2a-113) 2-methoxy-4- trifluoromethyl-
phenyl ethyl 178 LC/MS 417 (MH+) (I-2a-114) 2-methoxy-4-
trifluoromethyl- phenyl ethyl 179 LC/MS 430 (MH+) (I-2a-115)
2-methoxy-4- trifluoromethyl- phenyl ethyl 180 LC/MS 447 (MH+)
(I-2a-116) 2-methoxy-4- trifluoromethyl- phenyl ethyl 181 LC/MS 513
(MH+) (I-2a-117) 2-methoxy-4- trifluoromethyl- phenyl ethyl 182
LC/MS 493 (MH+) (I-2a-118) 2-methoxy-4- trifluoromethyl- phenyl
ethyl 183 LC/MS 551 (MH+) (I-2a-119) 2-methoxy-4- trifluoromethyl-
phenyl ethyl 184 LC/MS 545 (MH+) (I-2a-120) 2-methoxy-4-
trifluoromethyl- phenyl methyl(S) 185 LC/MS 431 (MH+) (I-2a-121)
2-methoxy-4- trifluoromethyl- phenyl methyl(S) 186 LC/MS 459 (MH+)
(I-2a-122) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 187 LC/MS
419 (MH+) (I-2a-123) 2-methoxy-4- trifluoromethyl- phenyl methyl(S)
188 LC/MS 433 (MH+) (I-2a-124) 2-methoxy-4- trifluoromethyl- phenyl
methyl(S) 189 LC/MS 447 (MH+) (I-2a-125) 2-methoxy-4-
trifluoromethyl- phenyl methyl(S) 190 LC/MS 431 (MH+) (I-2a-126)
2-methoxy-4- trifluoromethyl- phenyl methyl(S) 191 LC/MS 447 (MH+)
(I-2a-127) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 192 LC/MS
461 (MH+) (I-2a-128) 2-methoxy-4- trifluoromethyl- phenyl methyl(S)
193 LC/MS 489 (MH+) (I-2a-129) 2-methoxy-4- trifluoromethyl- phenyl
methyl(S) 194 LC/MS 435 (MH+) (I-2a-130) 2-methoxy-4-
trifluoromethyl- phenyl methyl(S) 195 LC/MS 458 (MH+) (I-2a-131)
2-methoxy-4- trifluoromethyl- phenyl methyl(S) 196 LC/MS 391 (MH+)
(I-2a-132) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 197 LC/MS
403 (MH+) (I-2a-133) 2-methoxy-4- trifluoromethyl- phenyl methyl(S)
198 LC/MS 419 (MH+) (I-2a-134) 2-methoxy-4- trifluoromethyl- phenyl
methyl(S) 199 LC/MS 447 (MH+) (I-2a-135) 2-methoxy-4-
trifluoromethyl- phenyl methyl(S) 200 LC/MS 417 (MH+) (I-2a-136)
2-methoxy-4- trifluoromethyl- phenyl methyl(S) 201 LC/MS 431 (MH+)
(I-2a-137) 2-methoxy-4- trifluoromethyl- phenyl methyl(S) 202 LC/MS
447 (MH+) (I-2a-138) 2-methoxy-4- trifluoromethyl- phenyl methyl(S)
203 LC/MS 491 (MH+) (I-2a-139) 2-methoxy-4- trifluoromethyl- phenyl
methyl(S) 204 LC/MS 405 (MH+) (I-2a-140) 2-methoxy-4-
trifluoromethyl- phenyl methyl(S) 205 LC/MS 506 (MH+) (I-2a-141)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 206 LC/MS 421 (MH+)
(I-2a-142) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 207 LC/MS
433 (MH+) (I-2a-143) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S)
208 LC/MS 461 (MH+) (I-2a-144) 2-methoxy-4- trifluoromethyl- phenyl
ethyl(S) 209 LC/MS 503 (MH+) (I-2a-145) 2-methoxy-4-
trifluoromethyl- phenyl ethyl(S) 210 LC/MS 472 (MH+) (I-2a-146)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 211 LC/MS 445 (MH+)
(I-2a-147) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 212 LC/MS
461 (MH+) (I-2a-148) 2-methoxy-4- trifluoromethyl- phenyl ethyl(S)
213 LC/MS 447 (MH+) (I-2a-149) 2-trifluoromethyl- 4-methoxy-phenyl
H 214 -- (I-2a-150) 2-trifluoromethyl- 4-methoxy-phenyl ethyl(S)
215 -- (I-2a-151) 2-trifluoromethyl- 4-methoxy-phenyl ethyl(S) 216
-- (I-2a-152) 2-trifluoromethyl- 4-methoxy-phenyl ethyl(S) 217 --
(I-2a-153) 2-methoxy-4- trifluoromethyl- phenyl ethyl 218 LC/MS 419
(MH+) (I-2a-154) 2-methoxy-4- trifluoromethyl- phenyl ethyl 219
LC/MS 461 (MH+) (I-2a-155) 2-methoxy-4- trifluoromethyl- phenyl
ethyl 220 LC/MS 475 (MH+) (I-2a-156) 2-methoxy-4- trifluoromethyl-
phenyl ethyl 221 LC/MS 539 (MH+) (I-2a-157) 2-methoxy-4-
trifluoromethyl- phenyl ethyl 222 LC/MS 463 (MH+) (I-2a-158)
2-methoxy-4- trifluoromethyl- phenyl ethyl 223 LC/MS 523 (MH+)
(I-2a-159) 2-methoxy-4- trifluoromethyl- phenyl ethyl 224 LC/MS 511
(MH+) (I-2a-160) 2-methoxy-4- trifluoromethyl- phenyl ethyl 225
LC/MS 517 (MH+) (I-2a-161) 2-methoxy-4- trifluoromethyl- phenyl
ethyl 226 LC/MS 549 (MH+) (I-2a-162) 2-methoxy-4- trifluoromethyl-
phenyl ethyl 227 LC/MS 531 (MH+) (I-2a-163) 2-methoxy-4-
trifluoromethyl- phenyl ethyl 228 LC/MS 531 (MH+) (I-2a-164)
2-methoxy-4- trifluoromethyl- phenyl ethyl 229 LC/MS 501 (MH+)
(I-2a-165) 2-methoxy-4- trifluoromethyl- phenyl ethyl 230 LC/MS 503
(MH+) (I-2a-166) 2-chloro-4- methoxyphenyl ethyl(S) 231 7.81(d,
J=8.7Hz, 1H), 7.07(d, J=3.0Hz, 1H), 6.93(dd, J=8.7, 3.0Hz, 1H),
6.17(s, 1H), 4.57(12.3, 1.8Hz, 1H), 4.34(dd, J=12.3, 4.2Hz, 1H),
3.93-3.88(m, 1H), 3.84(s, 3H), 3.58(dd, J=14.1, 6.0Hz, 1H),
3.05(dd, J=14.6, 7.1Hz, .sub.----H); LC/MS 397 (MH+) (I-2a-167)
2-methyl-4- chlorophenyl ethyl(S) 232 7.79(d, J=8.4Hz, 1H),
7.29-7.27(m, 2H), 6.19(s, 1H), 4.56(dd, J=12.3, 1.8 Hz, 1H),
4.33(dd, J=12.3, 4.2Hz, 1H), 3.97-3.91(m, 1H), 3.63(dd, J=14.1, 5.7
Hz, 1H), 3.08(dd, J=14.4, 7.5Hz, 1H), 2.62(s, 3H), 2.52(s, 3H),
1.88-1; LC/MS 381 (MH+) (I-2a-168) 2-methyl-4- chlorophenyl H 233
7.75(d, J=8.4Hz, 1H), 7.28-7.21(m, 2H), 6.21(s, 1H), 4.42(dd,
J=5.4, 5.1Hz, 2H), 3.89-3.81(m, 1H), 3.65(dd, J=5.4, 5.1Hz, 2H),
2.57(s, 3H), 2.51(s, 3H), 1.74-1.53(m, 4H), 1.43-1.24(m, 4H),
0.94(t, J=7.4Hz, 6H); LC/MS 397 (MH+) (I-2a-169) 2,4-dimethyl-
phenyl H 234 7.66(d, J=7.5Hz, 1H), 7.11-7.08(m, 2H), 6.20(s, 1H),
4.42(dd, J=5.5, 4.8Hz, 2H), 3.89-3.81(m, 1H), 3.65(dd, J=5.4,
5.1Hz, 2H), 2.58(s, 3H), 2.48(s, 3H), 2.35(s, 3H), 1.72-1.53(m,
4H), 1.43-1.30(m, 4H), 0.94(t, J=7.2Hz, 6H); LC/MS 377 (MH+)
(I-2a-170) 2,4-dimethyl-6- chlorophenyl H 235 7.15(s, 1H), 7.01(s,
1H), 6.20(s, 1H), 4.50-4.39(m, 2H), 3.89-3.81(m, 1H), 3.67(dd, t,
J=5.3Hz, 2H), 2.56(s, 3H), 2.33(s, 3H), 2.17(s, 3H), 1.72-1.54(m,
4H), 1.44-1.32(m, 4H), 0.95(t, J=7.5Hz, 6H); LC/MS 411 (MH+)
(I-2a-171) 2-chloro-4- trifluoromethyl- phenyl ethyl(S) 236 8.13(d,
J=8.4Hz, 1H), 7.79(s, 1H), 7.62(d, J=8.1Hz, 1H), 6.21(s, 1H),
4.61(dd, J=12.6, 1.8Hz, 1H), 4.39(dd, J=12.5, 3.8Hz, 1H),
3.95-3.93(m, 1H), 3.60(dd, J=14.4, 5.7Hz, 1H), 3.06(dd, J=14.1,
7.2Hz, 1H), 2.60(s, 3H); LC/MS 435 (MH+) (I-2a-172) 2-chloro-4-
trifluoromethyl- phenyl H 237 8.10(d, J=8.4Hz, 1H), 7.78(s, 1H),
7.62(d, J=8.4Hz, 1H), 6.24(s, 1H), 4.48(dd, J=6.0, 4.8Hz, 2H),
3.91-3.82(m, 1H), 3.67(dd, J=5.4, 5.1Hz, 2H), 2.59(s, 3H),
1.74-1.54(m, 4H), 1.43-1.31(m, 4H), 0.94(t, J=7.2Hz, 6H); LC/MS 451
(MH+) (I-2a-173) 2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 238
1.01(9H, t), 1.28(6H, d), 1.63(2H, m), 2.15(1H, m), 2.56(3H, s),
2.95(2H, m), 3.49(1H, m), 3.65(1H, m), 4.36(1H, m), 4.53(1H, m),
6.51(1H, s), 7.48(1H, d), 7.63(1H, s), 7.76(1H, d) (I-2a-174)
2-methyl-4- methoxyphenyl ethyl(S) 239 0.31(2H, m), 0.64(2H, m),
1.02(3H, t), 1.10(1H, m), 1.63(1H, m), 1.75(1H, m), 2.06(1H, s),
2.53(3H, s), 2.58(3H, s), 3.04(1H, q), 3.57(1H, q), 3.83(3H, s),
4.29(1H, m), 4.53(1H, d), 6.16(1H, s), 6.84(2H, m), 7.78(1H, d)
(I-2a-175) 2-chloro-4- fluorophenyl ethyl(S) 240 0.32(2H, m),
0.65(2H, m), 1.02(3H, t), 1.10(1H, m), 1.67(2H, m), 2.58(3H, s),
3.05(1H, q), 3.59(1H, q), 3.92(1H, m), 4.35(1H, m), 4.57(1H, d),
6.19(1H, s), 7.10(1H, m), 7.27(1H, m), 7.90(1H, m) (I-2a-176)
2-(2-chloro-4- fluorophenyl)-4- fluorophenyl ethyl(S) 241 LC/MS 379
(MH+) (I-2a-177) 4-fluorophenyl ethyl(S) 242 0.31(2H, m), 0.64(2H,
m), 1.01(3H, t), 1.10(1H, m), 1.65(2H, m), 2.62(3H, s), 3.04(1H,
q), 3.57(1H, q), 3.89(1H, m), 4.28(1H, m), 4.53(1H, d), 6.18(1H,
s), 7.16(2H, t), 8.45(2H, m) (I-2a-178) 2-methoxy-4- chlorophenyl
ethyl(S) 243 0.31(2H, m), 0.63(2H, m), 1.01(3H, t), 1.10(1H, m),
1.70(2H, m), 2.58(3H, s), 3.04(1H, q), 3.57(1H, q), 3.87(1H, m),
3.90(3H, s), 4.32(1H, m), 4.58(1H, d), 6.16(1H, s), 7.02(1H, d),
7.08(1H, d), 8.06(1H, d) (I-2a-179) 2-methyl-4- methoxyphenyl
ethyl(S) 244 1.00(9H, q), 1.68(2H, m), 2.09(1H, m), 2.53(3H, s),
2.57(3H, s), 2.90(1H, q), 3.48(1H, q), 3.63(1H, m), 3.83(3H, s),
4.30(1H, m), 4.51(1H, d), 6.08(1H, s), 6.84(2H, m), 7.77(1H, d)
(I-2a-180) 2,4-dimethoxy- phenyl ethyl(S) 245 0.30(2H, m), 0.63(2H,
m), 1.01(3H, t). 1.09(1H, m), 1.70(2H, m), 2.09(1H, s), 2.58(3H,
s), 3.03(1H, q), 3.57(1H, q), 3.86(3H, s), 3.88(3H, s), 4.30(1H,
m), 4.57(1H, d), 6.15(1H, s), 6.62(2H, m), 8.03(1H, d) (I-2a-181)
2-methoxy-4- chlorophenyl H 246 0.93(6H, t), 1.34(4H, m), 1.63(4H,
m), 2.58(3H, s), 3.62(2H, d), 3.84(1H, m), 3.90(3H, s), 4.45(2H,
t), 6.20(1H, s), 7.04(2H. m), 8.00(1H, d) (I-2a-182) 2-chloro-4-
methoxyphenyl H 247 0.94(6H, t), 1.36(4H, m), 1.63(4H, m), 2.58(3H,
s), 3.65(2H, t), 3.84(4H, m), 4.44(2H, t), 6.21(1H, s), 6.32(1H,
d), 7.07(1H, d), 7.79(1H, d) (I-2a-183) 2-chloro-4- carboxyphenyl H
248 0.78(6H, t), 1.20(5H, m), 1.43(3H, m), 2.33(3H, s), 3.43(2H,
m), 3.67(1H, m), 4.25(2H, m), 6.01(1H, s), 7.45(1H, d), 7.86(1H,
d), 7.97(1H, s) (I-2a-184) 2,6-dimethyl-4- methoxyphenyl H 249
0.95(6H, t), 1.40(4H, m), 1.64(4H, m), 2.16(6H, s), 2.54(3H, s),
3.66(2H, t), 2.81(4H, m), 4.41(2H, t), 6.18(1H, s), 6.67(2H, s)
(I-2a-185) 2,6-dimethyl-4- methoxyphenyl ethyl(S) 250 0.34(2H, m),
0.66(2H, m), 1.02(3H, t), 1.13(1H, m), 1.74(4H, m), 2.15(5H, s),
2.54(3H, s), 3.05(1H, q), 3.58(1H, m), 3.81(3H, s), 3.92(1H, m),
4.32(1H, m), 4.52(1H, d), 6.16(1H, s), 6.67(2H, s) (I-2a-186)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 251 -- (I-2a-187)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 252 -- (I-2a-188)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 253 -- (I-2a-189)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 254 -- (I-2a-190)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 255 -- (I-2a-191)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 256 -- (I-2a-192)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 257 -- (I-2a-193)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 258 -- (I-2a-194)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 259 -- (I-2a-195)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 260 -- (I-2a-196)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 261 -- (I-2a-197)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 262 -- (I-2a-198)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 263 -- (I-2a-199)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 264 -- (I-2a-200)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 265 -- (I-2a-201)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 266 -- (I-2a-202)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 267 -- (I-2a-203)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 268 -- (I-2a-204)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 269 -- (I-2a-205)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 270 -- (I-2a-206)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 271 -- (I-2a-207)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 272 -- (I-2a-208)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 273 -- (I-2a-209)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 274 -- (I-2a-210)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 275 -- (I-2a-211)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 276 -- (I-2a-212)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 277 -- (I-2a-213)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 278 -- (I-2a-214)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 279 -- (I-2a-215)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 280 -- (I-2a-216)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 281 -- (I-2a-217)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 282 -- (I-2a-218)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 283 -- (I-2a-219)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 284 -- (I-2a-220)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 285 -- (I-2a-221)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 286 -- (I-2a-222)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 287 -- (I-2a-223)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 288 -- (I-2a-224)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 289 -- (I-2a-225)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 290 -- (I-2a-226)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 291 -- (I-2a-227)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 292 -- (I-2a-228)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 293 -- (I-2a-229)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 294 -- (I-2a-230)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 295 -- (I-2a-231)
2-methoxy-4- trifluoromethyl- phenyl ethyl(S) 296 -- (I-2a-232)
2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 297 -- (I-2a-233)
2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 298 -- (I-2a-234)
2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 299 -- (I-2a-235)
2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 300 -- (I-2a-236)
2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 301 -- (I-2a-237)
2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 302 -- (I-2a-238)
2-trifluoromethyl- 4-isopropylphenyl ethyl(S) 303 --
Example 8
Synthesis of Further Representative Compounds of Structure
(I-2A)
[0309] The representative compounds of Table 6 were made by the
following procedure: 304
6TABLE 6 Analytical Data for Representative Compounds 305 Cpd. No.
Ar R.sub.1 Analytical Data (I-2a-239) 2-methyl-4- methoxyphenyl 306
LC/MS 421 (MH+) (I-2a-240) 2-methyl-4- methoxyphenyl 307 LC/MS 365
(MH+) (I-2a-241) 2-methyl-4- methoxyphenyl 308 LC/MS 393 (MH+)
(I-2a-242) 2,4-dimethoxy- phenyl 309 LC/MS 409 (MH+) (I-2a-243)
2-methyl-4- methoxyphenyl 310 LC/MS 393 (MH+)
Example 9
Synthesis of Further Representative Compounds of Structure
(I-2A)
[0310] The representative compounds of Table 7 were made by the
following procedure: 311
7TABLE 7 Analytical Data for Representative Compounds 312 Cpd. No.
COR'/SO.sub.2R' (I-2a-244) 313 (I-2a-245) 314 (I-2a-246) 315
(I-2a-247) 316 (I-2a-248) 317 (I-2a-249) 318 (I-2a-250) 319
(I-2a-251) 320 (I-2a-252) 321 (I-2a-253) 322 (I-2a-254) 323
(I-2a-255) 324 (I-2a-256) 325 (I-2a-257) 326 (I-2a-258) 327
(I-2a-259) 328 (I-2a-260) 329 (I-2a-261) 330 (I-2a-262) 331
(I-2a-263) 332 (I-2a-264) 333 (I-2a-265) 334 (I-2a-266) 335
(I-2a-267) 336 (I-2a-268) 337 (I-2a-269) 338
Example 10
Synthesis of Further Representative Compounds of Structure
(I-2A)
[0311] The representative compounds of Table 8 were made by the
following procedure: 339
8TABLE 8 Analytical Data for Representative Compounds 340 Cpd. No.
R' (I-2a-270) 341 (I-2a-271) 342 (I-2a-272) 343 (I-2a-273) 344
(I-2a-274) 345 (I-2a-275) 346 (I-2a-276) 347 (I-2a-277) 348
(I-2a-278) 349 (I-2a-279) 350 (I-2a-280) 351 (I-2a-281) 352
(I-2a-282) 353
Example 11
Synthesis of Further Representative Compounds of Structure
(I-2A)
[0312] The representative compounds of Table 9 were made by the
following procedure: 354
9TABLE 9 Analytical Data for Representative Compounds 355 LC/MS
Cpd. No. R' (MH.sup.+) (I-2a-283) 356 -- (I-2a-284) 357 486
(I-2a-285) 358 562 (I-2a-286) 359 -- (I-2a-287) 360 508 (I-2a-288)
361 -- (I-2a-289) 362 530 (I-2a-290) 363 -- (I-2a-291) 364 554
(I-2a-292) 365 600 (I-2a-293) 366 -- (I-2a-294) 367 -- (I-2a-295)
368 536 (I-2a-296) 369 472 (I-2a-297) 370 474 (I-2a-298) 371 518
(I-2a-299) 372 -- (I-2a-300) 373 490 (I-2a-301) 374 486 (I-2a-302)
375 565 (I-2a-303) 376 583 (I-2a-304) 377 517 (I-2a-305) 378 503
(I-2a-306) 379 579 (I-2a-307) 380 533 (I-2a-308) 381 490 (I-2a-309)
382 518 (I-2a-310) 383 -- (I-2a-311) 384 546 (I-2a-312) 385 488
(I-2a-313) 386 -- (I-2a-314) 387 -- (I-2a-315) 388 518 (I-2a-316)
389 516 (I-2a-317) 390 -- (I-2a-318) 391 -- (I-2a-319) 392 --
(I-2a-320) 393 516 (I-2a-321) 394 518 (I-2a-322) 395 504 (I-2a-323)
396 580 (I-2a-324) 397 560 (I-2a-325) 398 -- (I-2a-326) 399 --
(I-2a-327) 400 578 (I-2a-328) 401 -- (I-2a-329) 402 571 (I-2a-330)
403 531 (I-2a-331) 404 542 (I-2a-332) 405 536 (I-2a-333) 406 502
(I-2a-334) 407 448 (I-2a-335) 408 -- (I-2a-336) 409 538 (I-2a-337)
410 581 (I-2a-338) 411 -- (I-2a-339) 412 -- (I-2a-340) 413 --
(I-2a-341) 414 552 (I-2a-342) 415 532 (I-2a-343) 416 462 (I-2a-344)
417 538 (I-2a-345) 418 476 (I-2a-346) 419 519 (I-2a-347) 420 --
(I-2a-348) 421 -- (I-2a-349) 422 476 (I-2a-350) 423 504 (I-2a-351)
424 -- (I-2a-352) 425 -- (I-2a-353) 426 560 (I-2a-354) 427 588
(I-2a-355) 428 -- (I-2a-356) 429 502 (I-2a-357) 430 -- (I-2a-358)
431 488 (I-2a-359) 432 -- (I-2a-360) 433 552 (I-2a-361) 434 490
(I-2a-362) 435 602 (I-2a-363) 436 -- (I-2a-364) 437 -- (I-2a-365)
438 -- (I-2a-366) 439 -- (I-2a-367) 440 -- (I-2a-368) 441 553
(I-2a-369) 442 567 (I-2a-370) 443 539 (I-2a-371) 444 -- (I-2a-372)
445 -- (I-2a-373) 446 557 (I-2a-374) 447 -- (I-2a-375) 448 583
(I-2a-376) 449 -- (I-2a-377) 450 567 (I-2a-378) 451 572 (I-2a-379)
452 -- (I-2a-380) 453 504 (I-2a-381) 454 -- (I-2a-382) 455 552
(I-2a-383) 456 552 (I-2a-384) 457 488 (I-2a-385) 458 -- (I-2a-386)
459 -- (I-2a-387) 460 -- (I-2a-388) 461 517 (I-2a-389) 462 583
(I-2a-390) 463 -- (I-2a-391) 464 504 (I-2a-392) 465 -- (I-2a-393)
466 581 (I-2a-394) 467 -- (I-2a-395) 468 598 (I-2a-396) 469 --
(I-2a-397) 470 -- (I-2a-398) 471 -- (I-2a-399) 472 -- (I-2a-400)
473 531 (I-2a-401) 474 599 (I-2a-402) 475 602 (I-2a-403) 476 --
(I-2a-404) 477 -- (I-2a-405) 478 478 (I-2a-406) 479 -- (I-2a-407)
480 492 (I-2a-408) 481 574 (I-2a-409) 482 517 (I-2a-410) 483 --
(I-2a-411) 484 517 (I-2a-412) 485 -- (I-2a-413) 486 --
Example 12
Synthesis of Further Representative Compounds of Structure
(I-2A)
[0313] The representative compounds of Table 10 were made by the
following procedure: 487
10TABLE 10 Analytical Data for Representative Compounds Cpd. No. R'
LC/MS (MH.sup.+) (I-2a-414) 488 462 (I-2a-415) 489 448 (I-2a-416)
490 526 (I-2a-417) 491 632 (I-2a-418) 492 510 (I-2a-419) 493 524
(I-2a-420) 494 572 (I-2a-421) 495 476 (I-2a-422) 496 580 (I-2a-423)
497 536
Example 13
Representative Compounds Having CRF Receptor Binding Activity
[0314] The compounds of this invention may be 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.
[0315] More specifically, the binding assay is 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 receives
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 .about.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 is 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 are
cut just above the pellet and monitored in a gamma counter for
radioactivity at approximately 80% efficiency. All radioligand
binding data may be analyzed using the non-linear least-square
curve-fitting program LIGAND of Munson and Rodbard (Anal. Biochem.
107:220, 1990).
Example 14
CRF-stimulated Adenylate Cyclase Activity
[0316] The compounds of the present invention may also be evaluated
by various functional testing. For example, the compounds of the
present invention may be screened for CRF-stimulated adenylate
cyclase activity. An assay for the determination of CRF-stimulated
adenylate cyclase activity may be performed as generally described
by Battaglia et al. (Synapse 1:572, 1987), with modifications to
adapt the assay to whole cell preparations.
[0317] More specifically, the standard assay mixture may contain
the following in a final volume of 0.5 ml: 2 mM L-glutamine, 20 mM
HEPES, and 1 mM IMBX in DMEM buffer. In stimulation studies, whole
cells with the transfected CRF receptors are plated in 24-well
plates and incubated for 1 h at 37.degree. C. with various
concentrations of CRF-related and unrelated peptides in order to
establish the pharmacological rank-order profile of the particular
receptor subtype. Following the incubation, the media is aspirated,
the wells rinsed once gently with fresh media, and the media
aspirated. To determine the amount of intracellular cAMP, 300 .mu.l
of a solution of 95% ethanol and 20 mM aqueous hydrochloric acid is
added to each well and the resulting suspensions are incubated at
-20.degree. C. for 16 to 18 hours. The solution is removed into 1.5
ml Eppendorf tubes and the wells washed with an additional 200
.mu.l of ethanol/aqueous hydrochloric acid and pooled with the
first fraction. The samples are lyophilized and then resuspended
with 500 .mu.l sodium acetate buffer. The measurement of cAMP in
the samples is performed using a single antibody kit from
Biomedical Technologies Inc. (Stoughton, Mass.). For the functional
assessment of the compounds, a single concentration of CRF or
related peptides causing 80% stimulation of cAMP production is
incubated along with various concentrations of competing compounds
(10.sup.-12 to 10.sup.-6 M).
[0318] It will be appreciated that, although specific embodiments
of the invention have been described herein for purposes of
illustration, various modifications may be made without departing
from the spirit and scope of the invention. Accordingly, the
invention is not limited except as by the appended claims.
* * * * *