U.S. patent application number 10/427234 was filed with the patent office on 2003-11-27 for imidazo[1, 2-a] pyrazines for the treatment of irritable bowel syndrome.
Invention is credited to Bakthavatchalam, Rajagopal, Gilligan, Paul J., Wilde, Richard G..
Application Number | 20030220342 10/427234 |
Document ID | / |
Family ID | 22814709 |
Filed Date | 2003-11-27 |
United States Patent
Application |
20030220342 |
Kind Code |
A1 |
Bakthavatchalam, Rajagopal ;
et al. |
November 27, 2003 |
Imidazo[1, 2-a] pyrazines for the treatment of irritable bowel
syndrome
Abstract
Provided herein are methods for treating a subject afflicted
with irritable bowel syndrome comprising administering to the
subject a therapeutically effective amount of a pharmaceutical
composition that comprises a pharmaceutically acceptable carrier
and a compound of the formula 1 wherein: X is CHR.sup.5, NR.sup.5,
O, S, S(O).sub.n or a single bond, wherein n is equal to 0, 1 or 2;
D is aryl or heteroaryl attached through an unsaturated carbon atom
and wherein said aryl or heteroaryl is optionally substituted at
any available position with from 1-5 of A.sup.1, A.sup.2, A.sup.3,
A.sup.4 and A.sup.5; and R.sup.2 is C.sub.1-4 alkyl or C.sub.3-8
cycloalkyl, each of which is optionally substituted with from 1-3
hydroxy, halogen or C.sub.1-4 alkoxy, or wherein when X is a bond,
R.sup.2 is CN, CF.sub.3, or C.sub.2F.sub.5.
Inventors: |
Bakthavatchalam, Rajagopal;
(US) ; Wilde, Richard G.; (US) ; Gilligan,
Paul J.; (US) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
22814709 |
Appl. No.: |
10/427234 |
Filed: |
May 1, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10427234 |
May 1, 2003 |
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09905097 |
Jul 13, 2001 |
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6589952 |
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60218339 |
Jul 14, 2000 |
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Current U.S.
Class: |
514/249 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 487/04 20130101; A61P 25/22 20180101; A61P 25/24 20180101;
A61P 3/04 20180101 |
Class at
Publication: |
514/249 |
International
Class: |
A61K 031/498 |
Claims
What is claimed is:
1. A method of treating a subject afflicted with irritable bowel
syndrome comprising administering to said subject a therapeutically
effective amount of a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a compound of the formula
I: 10wherein: X is CHR.sup.5, NR.sup.5, O, S, S(O).sub.n or a
single bond, wherein n is equal to 0, 1 or 2; D is aryl or
heteroaryl attached through an unsaturated carbon atom and wherein
said aryl or heteroaryl is optionally substituted at any available
position with from 1-5 of A.sup.1, A.sup.2, A.sup.3, A.sup.4 and
A.sup.5; A.sup.1, A.sup.2, A.sup.3, A.sup.4 and A.sup.5 are each
independently H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, halo,
C.sub.1-4 haloalkyl, cyano, nitro, --OR.sup.12, SH,
--S(O).sub.nR.sup.13, --COR.sup.12, --CO.sub.2R.sup.12,
--OC(O)R.sup.13, --NR.sup.11COR.sup.12, --N(COR.sup.12).sup.2,
--NR.sup.11CONR.sup.12R.sup- .14, or wherein A.sup.1, A.sup.2,
A.sup.3, A.sup.4 and A.sup.5 are each independently phenyl or
phenyl substituted with from 1 to 4 of C.sub.1-3 alkyl, C.sub.1-3
alkoxy, halo, cyano, dimethylamino, CF.sub.3, C.sub.2F.sub.5,
OCF.sub.3, SO.sub.2Me or acetyl; R.sup.1 is C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-8 cycloalkyl,
C.sub.4-12 cycloalkylalkyl, NR.sup.6R.sup.7 or --C(R.sup.8)
(R.sup.9)--O--R.sup.10; R.sup.2 is C.sub.1-4 alkyl or C.sub.3-8
cycloalkyl, each of which is optionally substituted with from 1-3
hydroxy, halogen or C.sub.1-4 alkoxy, or wherein when X is a bond,
R.sup.2 is CN, CF.sub.3, or C.sub.2F.sub.5; R.sup.3 and R.sup.4 are
independently H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-5 cycloalkyl, C.sub.1-4 alkoxy, C.sub.1-4
haloalkyl, C.sub.1-4 haloalkoxy, halogen, CN, or NR.sup.6R.sup.7;
R.sup.5 is H, C.sub.1-4 alkyl or C.sub.3-8 cycloalkyl; R.sup.6 and
R.sup.7 are each independently H, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.3-6 cycloalkyl, C.sub.4-12
cycloalkylalkyl, aryl, aryl(C.sub.1-4 alkyl)-, heteroaryl or
heteroaryl(C.sub.1-4 alkyl)-; R.sup.8 and R.sup.9 are each
independently H or C.sub.1-4 alkyl, or R.sup.8 and R.sup.9 are
taken together as .dbd.CH.sub.2; R.sup.10 is H or C1-4 alkyl;
R.sup.11 is H, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-12
cycloalkylalkyl, phenyl or benzyl, each phenyl or benzyl optionally
substituted on the aryl moiety with 1-3 groups of C.sub.1-4 alkyl,
halogen, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4
haloalkoxy, or dimethylamino; and, R.sup.12, R.sup.13 and R.sup.14
are each independently H, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl,
C.sub.4-16 cycloalkylalkyl or C.sub.1-4 haloalkyl.
2. The method of claim 1, wherein X is a single bond.
3. The method of claim 1, wherein D is phenyl.
4. The method of claim 3, wherein the phenyl is 11and wherein each
of A.sup.1, A.sup.2 and A.sup.3 is independently H, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, halogen, C.sub.1-4 haloalkyl or
OR.sup.12.
5. The method of claim 4, wherein A.sup.1 is H, CH.sub.3 or Cl.
6. The method of claim 4, wherein A.sup.2 is Cl, --OCH.sub.3 or
--OCHF.sub.2.
7. The method of claim 4, wherein A.sup.3 is H or CH.sub.3.
8. The method of claim 4, wherein: A.sup.1 is H, CH.sub.3 or Cl;
A.sup.2 is Cl, --OCH.sub.3 or --OCHF.sub.2 and A.sup.3 is H or
CH.sub.3.
9. The method of claim 1, wherein R.sup.1 is
--C(R.sup.8)(R.sup.9)--O--R.s- up.10.
10. The method of claim 9, wherein each of R.sup.8, R.sup.9 and
R.sup.10 are independently H or C.sub.1-4 alkyl.
11. The method of claim 10, wherein R.sup.8 is H.
12. The method of claim 10, wherein R.sup.9 is C.sub.2H.sub.5 or
C.sub.3H.sub.7.
13. The method of claim 12, wherein R.sup.10 is H.
14. The method of claim 10, wherein R.sup.8 is H, R.sup.9 is
C.sub.2H.sub.5 or C.sub.3H.sub.7 and R.sup.10 is H.
15. The method of claim 1, wherein R.sup.2 is unsubstituted C1-4
alkyl.
16. The method of claim 15, wherein R.sup.1 is C.sub.2H.sub.5.
17. The method of claim 1, wherein each of R.sup.3 and R.sup.4 are
H 18. The method of claim 1, wherein R.sup.1 is
--C(R.sup.8)(R.sup.9)--O--R.sup- .10, R is unsubstituted C.sub.1-4
alkyl, each of R.sup.3 and R.sup.4 is H, X is a single bond and D
is phenyl of the formula 12wherein R.sup.8 is H, R.sup.9 is
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sup.10 is H, each of Al, is H,
A.sup.2 is Cl, --OCH.sub.3 or --OCHF.sub.2 and A.sup.3 is H.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S.
application Ser. No. 09/905,097, filed Jul. 13, 2001, now allowed,
which in turn claims priority of provisional application Serial No.
60/218,339. These priority applications are hereby incorporated
herein in their entireties.
FIELD OF THE INVENTION
[0002] This invention relates to compounds which are novel
imidazo[1,2-a]pyrazines, and to the use of such compounds as CRF
receptor antagonists in the treatment of various neurological
disorders.
BACKGROUND OF THE INVENTION
[0003] Corticotropin releasing factor (herein referred to as CRF),
a 41 amino acid peptide, is the primary physiological regulator of
proopiomelanocortin (POMC)-derived peptide secretion from the
anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci.
(USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In
addition to its endocrine role at the pituitary gland,
immunohistochemical localization of CRF has demonstrated that the
hormone has a broad extrahypothalamic distribution in the central
nervous system and produces a wide spectrum of autonomic,
electrophysiological and behavioral effects consistent with a
neurotransmitter or neuromodulator role in brain [W. Vale et al.,
Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med.
2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)].
There is also evidence that CRF plays a significant role in
integrating the response of the immune system to physiological,
psychological, and immunological stressors [J. E. Blalock,
Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527
(1987)].
[0004] Clinical data provide evidence that CRF has a role in
psychiatric disorders and neurological diseases including
depression, anxiety-related disorders and feeding disorders. A role
for CRF has also been postulated in the etiology and
pathophysiology of Alzheimer's disease, Parkinson's disease,
Huntington's disease, progressive supranuclear palsy and
amyotrophic lateral sclerosis as they relate to the dysfunction of
CRF neurons in the central nervous system [for review see E. B. De
Souza, Hosp. Practice 23:59 (1988)].
[0005] In affective disorder, or major depression, the
concentration of CRF is significantly increased in the cerebral
spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al.,
Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry
144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988);
M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the
density of CRF receptors is significantly decreased in the frontal
cortex of suicide victims, consistent with a hypersecretion of CRF
[C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In
addition, there is a blunted adrenocorticotropin (ACTH) response to
CRF (i.v. administered) observed in depressed patients [P. W. Gold
et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al.,
Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng.
J. Med. 314:1129 (1986)].
[0006] Preclinical studies in rats and non-human primates provide
additional support for the hypothesis that hypersecretion of CRF
may be involved in the symptoms seen in human depression [R. M.
Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is
preliminary evidence that tricyclic antidepressants can alter CRF
levels and thus modulate the numbers of CRF receptors in brain
[Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
[0007] It has also been postulated that CRF has a role in the
etiology of anxiety-related disorders. CRF produces anxiogenic
effects in animals and interactions between
benzodiazepine/non-benzodiazepine anxiolytics and CRF have been
demonstrated in a variety of behavioral anxiety models [D. R.
Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.
Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the
putative CRF receptor antagonist a-helical ovine CRF (9-41) in a
variety of behavioral paradigms demonstrate that the antagonist
produces "anxiolytic-like" effects that are qualitatively similar
to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav.
21:393 (1987), Brain Research Reviews 15:71 (1990)].
[0008] Neurochemical, endocrine and receptor binding studies have
all demonstrated interactions between CRF and benzodiazepine
anxiolytics, providing further evidence for the involvement of CRF
in these disorders. Chlordiazepoxide attenuates the "anxiogenic"
effects of CRF in both the conflict test [K. T. Britton et al.,
Psychopharmacology 86:170 (1985); K. T. Britton et al.,
Psychopharmacology 94:306 (1988)] and in the acoustic startle test
[N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats.
The benzodiazepine receptor antagonist (Ro15-1788), which was
without behavioral activity alone-in the operant conflict test,
reversed the effects of CRF in a dose-dependent manner while the
benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF
[K. T. Britton et al., Psychopharmacology 94:306 (1988)].
[0009] It has been further postulated that CRF has a role in
immunological, cardiovascular or heart-related diseases such as
hypertension, tachycardia and congestive heart failure, stroke,
osteoporosis, premature birth, psychosocial dwarfism,
stress-induced fever, ulcer, diarrhea, post-operative ileus and
colonic hypersensitivity associated with psychopathological
disturbance and stress.
[0010] The mechanisms and sites of action through which the
standard anxiolytics and antidepressants produce their therapeutic
effects remain to be elucidated. It has been hypothesized however,
that they are involved in the suppression of the CRF hypersecretion
that is observed in these disorders. Of particular interest is that
preliminary studies examining the effects of a CRF receptor
antagonist (a-helical CRF9-41) in a variety of behavioral paradigms
have demonstrated that the CRF antagonist produces
"anxiolytic-like" effects qualitatively similar to the
benzodiazepines [for review see G. F. Koob and K. T. Britton, In:
Corticotropin-Releasing Factor: Basic and Clinical Studies of a
Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press
p221 (1990)].
[0011] The following publications each describe CRF antagonist
compounds; however, none disclose the compounds provided herein:
WO95/10506; WO99/51608; WO97/35539; WO99/01439; WO97/44308;
WO97/35846; WO98/03510; WO99/11643; PCT/US99/18707; WO99/01454;
and, WO00/01675.
SUMMARY OF THE INVENTION
[0012] This invention provides a compound of the formula (I): 2
[0013] wherein: X is CHR.sup.5, NR.sup.5, O, S, S(O).sub.n or a
single bond, wherein n is equal to 0, 1 or 2; D is aryl or
heteroaryl attached through an unsaturated carbon atom and wherein
said aryl or heteroaryl is optionally substituted with from 1-5
A.sup.1-A.sup.5; R.sup.1 is C.sub.1-10 alkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-8 cycloalkyl, C.sub.4-12
cycloalkylalkyl, NR.sup.6R.sup.7 or
--C(R.sup.8)(R.sup.9)--O-R.sup.10; R.sup.2 is C.sub.1-4 alkyl or
C.sub.3-8 cycloalkyl, each of which is optionally substituted with
from 1-3 hydroxy, halogen or C.sub.1-4 alkoxy, or wherein when X is
a bond, R.sup.2 is optionally also CN, CF.sub.3, C.sub.2F.sub.5,
C.sub.1-4 alkyl or C.sub.3-8 cycloalkyl, each of which C.sub.1-4
alkyl or C.sub.3-8 cycloalkyl is optionally substituted with from
1-3 hydroxy, halogen and C.sub.1-4 alkoxy; R.sup.3 and R.sup.4 are
selected independently from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-5 cycloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, halogen, CN, or
NR.sup.6R.sup.7; R.sup.5 is H, C.sub.1-4 alkyl or C3-8 cycloalkyl;
R.sup.6 and R.sup.7 are each independently H, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.2-8 alkoxyalkyl, C.sub.3-6 cycloalkyl,
C.sub.4-12 cycloalkylalkyl, aryl, aryl(C.sub.1-4 alkyl)-,
heteroaryl or heteroaryl(C.sub.1-4 alkyl)-; R.sup.8 and R.sup.9 are
each independently H or C.sub.1-4 alkyl, or R.sup.8 and R.sup.9 are
taken together as .dbd.CH.sub.2, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl; and, R.sup.10 is H or C.sub.1-4 alkyl. Preferred
embodiments of this invention are set forth hereinbelow.
[0014] Said compounds antagonize CRF receptors, that is, they bind
to the receptors such that CRF is inhibited from binding to the
antagonized receptors. The compounds of this invention are thus
useful as therapeutic agents in conditions characterized by
excessive CRF expression, and this invention thus provides methods
of treating a subject afflicted with a disorder, e.g., an anxiety-
or depression-related disorder, characterized by CRF
overexpression.
DETAILED DESCRIPTION OF THE INVENTION
[0015] This invention provides a compound of the formula (I): 3
[0016] wherein the various substituents are as described
hereinbelow.
[0017] R.sup.1 is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10
alkynyl, C.sub.3-8 cycloalkyl, C.sub.4-12 cycloalkylalkyl,
NR.sup.6R.sup.7 or --C(R.sup.8) (R.sup.9)--O--R.sup.10. R.sup.2 is
C.sub.14 alkyl or C.sub.3-8 cycloalkyl, each of which is optionally
substituted with from 1-3 hydroxy, halogen or C.sub.1-4 alkoxy, or
wherein when X is a bond, R.sup.2 is optionally also CN, CF.sub.3,
C.sub.2F.sub.5, C.sub.1-4 alkyl or C.sub.3-8 cycloalkyl, each of
which C.sub.1-4 alkyl or C.sub.3-8 cycloalkyl is optionally
substituted with from 1-3 hydroxy, halogen and C.sub.1-4 alkoxy.
R.sup.3 and R.sup.4 are each selected independently from H,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-5
cycloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, halogen, CN, or NR.sup.6R.sup.7. R.sup.5 is H,
C.sub.1-4 alkyl or C.sub.3-8 cycloalkyl. R.sup.6 and R.sup.7 are
each independently H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
C.sub.2-8 alkoxyalkyl, C.sub.3-6 cycloalkyl, C.sub.4-12
cycloalkylalkyl, aryl, aryl(C.sub.1-4 alkyl)-, heteroaryl or
heteroaryl(C.sub.1-4 alkyl)-. R.sup.8 and R.sup.9 are each
independently H or C.sub.14 alkyl, or R.sup.8 and R.sup.9 are taken
together as .dbd.CH.sub.2, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl.
R.sup.10 is H or C.sub.14 alkyl. R.sup.11 is H, C.sub.1-4 alkyl,
C.sub.3-7 cycloalkyl, C.sub.4-12 cycloalkylalkyl, phenyl or benzyl,
each phenyl or benzyl optionally substituted on the aryl moiety
with 1-3 groups of C.sub.1-4 alkyl, halogen, C.sub.1-4 haloalkyl,
nitro, C.sub.1-4 alkoxy, C.sub.14 haloalkoxy, or dimethylamino.
R.sup.12, R.sup.13 and R.sup.14 are each independently H, C.sub.1-6
alkyl, C.sub.3-10 cycloalkyl, C.sub.4-16 cycloalkylalkyl or
C.sub.1-4 haloalkyl.
[0018] X is CHR.sup.5, NR.sup.5, O, S, S(O).sub.n or a single bond,
wherein n is equal to 0, 1 or 2. D is aryl or heteroaryl attached
through an unsaturated carbon atom, wherein said aryl is optionally
substituted at any available position with from 1-5 of, and said
heteroaryl is optionally substituted with from 1-4 of, A.sup.1,
A.sup.2, A.sup.3, A.sup.4 and A.sup.5 A.sup.1, A.sup.2, A.sup.3,
A.sup.4 and A.sup.5 are each independently H, C.sub.1-6 alkyl,
C.sub.3-6 cycloalkyl, halo, C.sub.1-4 haloalkyl, cyano, nitro,
--OR.sup.12, SH, --S(O).sub.nR.sup.13, --COR.sup.12, --CO.sub.2R
--OC(O)R.sup.13, --NR.sup.11COR.sup.12, --N(COR.sup.12).sub.2,
--N.sup.11CONR.sup.12R.sup.14, or wherein A.sup.1, A.sup.2,
A.sup.3, A.sup.4 and A.sup.5 are each independently phenyl or
phenyl substituted with from 1 to 4 of C.sub.1-3 alkyl, C.sub.13
alkoxy, halo, cyano, dimethylamino, CF.sub.3, C.sub.2F.sub.5,
OCF.sub.3, SO.sub.2Me or acetyl.
[0019] "Aryl" denotes either the 6-carbon benzene ring or the
condensed 6-carbon rings of other aromatic derivatives (see, e.g.,
Hawley's Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed.,
J. Wiley & Sons, Inc., New York (1997)); aryl includes, without
limitation, phenyl, napthyl, indanyl and indenyl. "Heteroaryl"
rings are aryl rings in which one or more, typically from 1-4, of
the ring-member carbon atoms is replace by an atom other than a
carbon atom, i.e., a heteroatom (typically O, N or S). Heteroaryl
includes, without limitation: pyridyl, pyrimidinyl, pyrazinyl,
triazolyl, tetrazolyl, indazolyl, thienyl, isoxazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzsothienyl,
2,3-dihydrobenzothienyl-S-oxide, indolinyl, benzoxazolin-2-on-yl
and benzodioxolanyl. "Alkyl" means saturated hydrocarbon chains,
branched or unbranched, having the specified number of carbon
atoms. "Alkenyl" means hydrocarbon chains of either a straight or
branched configuration and one or more unsaturated carbon-carbon
bonds, which may occur in any stable point along the chain, such as
ethenyl, propenyl, and the like. "Alkynyl" means hydrocarbon chains
of either a straight or branched configuration and one or more
triple carbon-carbon bonds, which may occur in any stable point
along the chain, such as ethynyl, propynyl and the like. "Alkoxy"
means an alkyl group of indicated number of carbon atoms attached
through an oxygen bridge. "Cycloalkyl" means saturated ring groups,
including mono-,bi- or polycyclic ring systems, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth.
"Halo" or "halogen" means fluoro, chloro, bromo, and iodo.
"Haloalkyl" means both branched and straight-chain alkyls having
the specified number of carbon atoms, substituted with 1 or more
halogens. "Haloalkoxy" means an alkoxy group substituted by at
least one halogen atom. "Substituted" means that one or more
hydrogen on the designated atom is replaced with a selection from
the indicated group, provided that the designated atom's normal
valency is not exceeded, and that the substitution results in a
stable compound. "Unsubstituted" atoms bear all of the hydrogen
atoms dictated by their valency. When a substituent is keto, then 2
hydrogens on the atom are replaced. Combinations of substituents
and/or variables are permissible only if such combinations result
in stable compounds; by "stable compound" or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0020] Preferably, R.sup.1 is --C(R.sup.8)(R.sup.9)--O--R.sup.10.
More preferably, presently, R.sup.8 is H, R.sup.9 is C.sub.2H.sub.5
or C.sub.3H.sub.7 and R.sup.10 is C.sub.2H.sub.5. Preferably,
R.sup.2 is unsubstituted C.sub.1-4 alkyl; more preferably,
presently, R.sup.2 is C.sub.2H.sub.5. R.sup.3 and R.sup.4 are
preferably each H. X is preferably a single bond.
[0021] D is preferably phenyl, more preferably a phenyl group of
the formula 4
[0022] wherein each of A.sup.1, A.sup.2 and A.sup.3 is selected
from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
halogen and C.sub.1-4 haloalkyl. Even more preferably: A.sup.1 is
H, CH.sub.3 or Cl; A is Cl, --OCH.sub.3 or --OCHF.sub.2; and,
A.sup.3 is H or CH.sub.3. Most preferably, presently, A.sup.1 is
C.sup.1 and A.sup.3 is H.
[0023] Each of R.sup.1-R.sup.12, X, D and A.sup.1-A.sup.5 are any
of the possible members of the groups listed hereinabove for these
substituents. R.sup.2, for example, being C1-4 alkyl or C3-8
cycloalkyl is each and every one of the members of these groups,
i.e., is C1, C2, C3 and C4 alkyl, as well as C3, C4, C5, C6, C7 and
C8 cycloalkyl. Moreover, selection of a substituent as a specific
member of one of its groups does not limit the choice of the other
substituents to less than all of the available selections.
[0024] R.sup.1 is preferably --CR.sup.8R.sup.9R.sup.10, and each of
R.sup.8, R.sup.9 and R10 is preferably H, C1, C2, C3 or C4 alkyl.
Moreover, each of the substituents is any one of these five
possibilities independently of the identity of the other
substituents. Thus, there are at least 125 groups of preferred
compounds, each of which is characterized by a different, but
preferred, combination of R.sup.8, R.sup.9 and R.sup.10 in R.sup.1.
These groups of compounds are listed in Tables A and B
(hereinbelow).
1 TABLE A R.sup.8 Alkyl R.sup.9 H C1 C2 C3 C4 H A1 A2 A3 A4 A5 C1
Alkyl A6 A7 A8 A9 A10 C2 Alkyl A11 A12 A13 A14 A15 C3 Alkyl A16 A17
A18 A19 A20 C4 Alkyl A21 A22 A23 A24 A25
[0025]
2 TABLE B R.sup.10 Alkyl R.sup.8 + R.sup.9 H C1 C2 C3 C4 X1 B1 B2
B3 B4 B5 X2 B6 B7 B8 B9 B10 X3 B11 B12 B13 B14 B15 X4 B16 B17 B18
B19 B20 X5 B21 B22 B23 B24 B25 X6 B26 B27 B28 B29 B30 X7 B31 B32
B33 B34 B35 X8 B36 B37 B38 B39 B40 X9 B41 B42 B43 B44 B45 X10 B46
B47 B48 B49 B50 X11 B51 B51 B53 B54 B55 X12 B56 B57 B58 B59 B60 X13
E61 B62 B63 B64 B65 X14 B66 B67 B68 B69 B70 X15 B71 B72 B73 B74 B75
X16 B76 B77 B78 B79 B80 X17 B81 B82 B83 B84 B85 X18 B86 B8 B88 B89
B90 X19 B91 B92 B93 B94 B95 X20 B96 B97 B98 B99 B100 X21 B101 B102
B103 B104 B105 X22 B106 B107 B108 B109 B110 X23 B111 B112 B113 B114
B115 X24 B116 B117 B118 B119 B120 X25 B121 B122 B123 B124 B125
[0026] Table A specifies the identity of the substituent "R.sup.8"
in preferred compounds provided herein; these are listed, in the
top row from left to right, as H, and then C1, C2, C3 and C4 alkyl.
The identity of the substituent "R.sup.9" in preferred compounds is
also given, along the left side, from top to bottom, as H, and then
C1, C2, C3 and C4 alkyl. Thus, each cell of the table identifies a
specific combination of R.sup.8 and R.sup.9 in a preferred
compound. Thus, each cell of the table identifies a specific
combination of R.sup.8 and R.sup.9 in a preferred compound. Each
cell is itself identified by an alphanumeric combination specifying
the cell's location within the table.
[0027] Table B specifies the identity of the substituent "R.sup.10"
in preferred compounds provided hererein; these are listed, in the
top row from left to right, as H, and then C1, C2, C3 and C4 alkyl.
Moreover, the R8/R9 combinations set forth in in Table 1 are listed
along the left side of the table, from top to bottom, in terms of
their cell number from Table A (e.g., "X1" refers to that set of
compounds wherein R.sup.8 and R.sup.9 are each H). Each cell of
Table B thus specifies a specific combination of R.sup.8, R.sup.9
and R.sup.10 (e.g., "B1" refers to that set of compounds wherein
each of R.sup.8, R.sup.9 and R.sup.10 are H)
[0028] R.sup.2 is preferably C1, C2, C3 or C4 alkyl (each being
unsubstituted). Table C hereinbelow lists the combinations of each
of these with each of the R.sup.8/R.sup.9/R.sup.10 combinations
from Table B:
3 TABLE C R.sup.1 ALKYL R.sup.8/R.sup.9/R.sup.10 C1 C2 C3 C4 B1 C1
C2 C3 C4 B2 C5 C6 C7 C8 B3 C9 C10 C11 C12 B4 C13 C14 C15 C16 B5 C17
C18 C19 C20 B6 C21 C22 C23 C24 B7 C25 C26 C27 C28 B8 C29 C30 C31
C32 B9 C33 C34 C35 C36 B10 C37 C38 C39 C40 B11 C41 C42 C43 C44 B12
C45 C46 C47 C48 B13 C49 C50 C51 C52 B14 C53 C54 C55 C56 B15 C57 C58
C59 C60 B16 C61 C62 C63 C64 B17 C65 C66 C67 C68 B18 C69 C70 C71 C72
B19 C73 C74 C75 C76 B20 C77 C78 C79 C80 B21 C81 C82 C83 C84 B22 C85
C86 C87 C88 B23 C89 C90 C91 C92 B24 C93 C94 C95 C96 B25 C97 C98 C99
C100 B26 C101 C102 C103 C104 B27 C105 C106 C107 C108 B28 C109 C110
C111 C112 B29 C113 C114 C115 C116 B30 C117 C118 C119 C120 B31 C121
C122 C123 C124 B32 C125 C126 C127 C128 B33 C129 C130 C131 C132 B33
C133 C134 C135 C136 B34 C137 C138 C139 C140 B35 C141 C142 C143 C144
B36 C145 C146 C147 C148 B37 C149 C150 C151 C152 B38 C153 C154 C155
C156 B39 C157 C158 C159 C160 B40 C161 C162 C163 C164 B41 C165 C166
C167 C168 B42 C169 C170 C171 C172 B43 C173 C174 C175 C176 B44 C177
C178 C179 C180 B45 C181 C182 C183 C184 B46 C185 C186 C187 C188 B47
C189 C190 C191 C192 B48 C193 C194 C195 C196 B49 C197 C198 C199 C200
B50 C201 C202 C203 C204 B51 C205 C206 C207 C208 B52 C209 C210 C211
C212 B53 C213 C214 C215 C216 B54 C217 C218 C2190 C220 B55 C221 C222
C223 C224 B56 C225 C226 C227 C228 B57 C229 C230 C231 C232 B58 C233
C234 C235 C236 B59 C237 C238 C239 C240 B60 C241 C242 C243 C244 B61
C245 C246 C2247 C248 B62 C249 C250 C251 C252 B63 C253 C254 C255
C256 B64 C257 C258 C259 C260 B65 C261 C262 C263 C264 B66 C265 C266
C267 C268 B67 C269 C270 C271 C272 B68 C273 C274 C275 C276 B69 C277
C278 C279 C280 B70 C281 C282 C283 C284 B71 C285 C286 C287 C288 B72
C289 C290 C291 C292 B73 C293 C294 C295 C296 B74 C297 C298 C299 C300
B75 C301 C302 C303 C304 B76 C305 C306 C307 C308 B77 C309 C310 C311
C312 B78 C313 C314 C315 C316 B79 C317 C318 C319 C320 B80 C321 C322
C323 C324 B81 C325 C326 C327 C328 B82 C329 C330 C331 C332 B83 C333
C334 C335 C336 B84 C337 C338 C339 C340 B85 C341 C342 C343 C344 B86
C345 C346 C347 C348 B87 C349 C350 C351 C352 B88 C353 C354 C355 C356
B89 C357 C358 C359 C360 B90 C361 C362 C363 C364 B91 C365 C366 C367
C368 B92 C369 C370 C371 C372 B93 C373 C374 C375 C376 B94 C377 C378
C379 C380 B95 C381 C383 C383 C384 B96 C385 C386 C387 C388 B97 C389
C390 C391 C392 B98 C393 C394 C395 C396 B99 C397 C398 C399 C400 B100
C401 C402 C403 C404 B101 C405 C406 C407 C408 B102 C409 C410 C411
C412 B103 C413 C414 C415 C416 B104 C417 C418 C419 C420 B105 C421
C422 C423 C424 B106 C425 C426 C427 C428 B107 C429 C430 C431 C432
B108 C433 C434 C435 C436 B109 C437 C438 C439 C440 B110 C441 C442
C443 C444 B111 C445 C446 C447 C448 B112 C449 C450 C451 C452 B113
C453 454 C455 C456 B114 C457 C458 C459 C460 B115 C461 C462 C463
C464 B116 C465 C466 C467 C468 B117 C469 C470 C471 C472 B118 C473
C474 C475 C476 B119 C477 C478 C479 C480 B120 C481 C482 C483 C484
B121 C485 C486 C487 C488 B122 C489 C490 C491 C492 B123 C493 C494
C495 C496 B124 C497 C498 C499 C500 B125 C501 C502 C503 C504
[0029] Also as described hereinabove, D is most preferably a phenyl
substituted with A.sup.1 (presently preferably H or CH.sub.3),
A.sup.2 (preferably Cl, --OCH.sub.3 or --OCHF.sub.2) and A.sup.3 (H
or CH.sub.3). Tables D and DD hereinbelow identify individual sets
of compounds containing each of the possible specific combinations
of these groupings. Table D lists combinations of A.sup.1 and
A.sup.3 (e.g., cell "D1" represents that set of compounds wherein
A.sup.1 and A.sup.3 are each H); Table DD lists combinations of
A.sup.1/A.sup.3 with the various presently preferred members of A
(e.g., cell "DD1" represents that set of compounds wherein A.sup.2
is Cl and the A.sup.1/A.sup.3 combination is represented by cell
"D1" (i.e., A.sup.1 and A.sup.3 are each H)):
4 TABLE D A.sup.3 A.sup.1 H CH.sub.3 H D1 D2 CH.sub.3 D3 D4
[0030]
5 TABLE DD A.sup.2 A.sup.1/A.sup.3 C1 --OCH.sub.3 --OCHF.sub.2 D1
DD1 DD2 DD3 D2 DD4 DD5 DD6 D3 DD7 DD8 DD9 D4 DD10 DD11 DD12
[0031] Furthermore, as described hereinabove, this invention
provides presently preferred compounds comprising combinations of
any of the preferred members of R.sup.1 and R.sup.2 (identified in
Table C hereinabove with the designations "C1-C500") with any of
the specific A.sup.1/A.sup.2/A.sup.3 combinations listed in Table
DD; these R.sup.1*R.sup.2/A.sup.1*A.sup.2*A.sup.3 combinations, and
hence, individual preferred compounds are listed specifically in
Table E hereinbelow. Across the top row of the table, from left to
right, are listed individual sets of compounds comprising
combinations of the various specific, individual A.sup.1, A.sup.2
and A.sup.3 substituents of the phenyl ring D, as identified by
their corresponding cell number in Table DD. The leftmost column of
the table lists individual sets of compounds comprising the various
specific, individual R.sup.1 and R.sup.2 substituents, as
identified by their corresponding cell number in table C. In this
regard, cell number Cl (and hence, compounds in which R.sup.1 is Cl
alkyl, R.sup.2 is --CR.sup.8R.sup.9OCR.sup.10, and R.sup.8, R.sup.9
and R.sup.10 are each H) corresponds to the individual compounds
listed in Table E as E1, E501, E1001, E1501, E2001, E2501, E3001,
E3501, E4001, E4501, E5001 and E5501; the other cells of Table C
(C2-C500) have a similar correspondence to the individual compounds
listed in Table E.
[0032] In addition to the compounds described and listed
hereinabove, this invention provides their corresponding
pharmaceutically acceptable salt, radiolabelled, various
stereoisomeric and prodrug forms. "Pharmaceutically acceptable
salts" of compounds of this invention are also provided herein. The
phrase "pharmaceutically acceptable" is employed to refer to those
compounds, materials, compositions, and/or dosage forms which are,
within the scope of sound medical judgment, suitable for use in
contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication, commensurate with a reasonable benefit/risk
ratio.
[0033] "Pharmaceutically acceptable salts" refer to derivatives of
the disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines, or alkali or
organic salts of acidic residues such as carboxylic acids.
[0034] Pharmaceutically acceptable salts include the conventional
non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. Such conventional nontoxic salts include those derived from
inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric and the like; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like.
[0035] Pharmaceutically acceptable salt forms of compounds provided
herein are synthesized from the parent compound which contains a
basic or acidic moiety by conventional chemical methods. Generally,
such salts are, for example, prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[0036] Radiolabelled compounds, i.e. wherein one or more of the
atoms described are replaced by a radioactive isotope of that atom
(e.g. C replaced by .sup.14C or by .sup.11C, and H replaced by
.sup.3H or .sup.18F), are also provided for herein. Such compounds
have a variety of potential uses, e.g. as standards and reagents in
determining the ability of a potential pharmaceutical to bind to
neurotransmitter proteins, or for imaging compounds of this
invention bound to biological receptors in vivo or in vitro.
[0037] Each of the stereoisomeric forms of this invention's
compounds is also provided for herein. That is, the compounds can
have one or more asymmetric centers or planes, and all chiral
(enantiomeric and diastereomeric) and racemic forms of the
compounds are included in the present invention. Many geometric
isomers of olefins, C=N double bonds, and the like can also be
present in the compounds, and all such stable isomers are
contemplated in the present invention. Compounds are isolated in
either the racemic form, or in the optically pure form, for
example, by chiral chromatography or chemical resolution of the
racemic form.
[0038] Prodrug forms of this invention's compounds are also
provided for herein. Such "prodrugs" are compounds comprising this
invention's compounds and moieties covalently bound to the parent
compounds such that the portions of the parent compound most likely
to be involved with toxicities in subjects to which the prodrugs
have been administered are blocked from inducing such effects.
However, the prodrugs are also cleaved in the subjects in such a
way as to release the parent compound without unduly lessening its
therapeutic potential. Prodrugs include compounds wherein hydroxy,
amine, or sulfhydryl groups are bonded to any group that, when
administered to a mammalian subject, cleaves to form a free
hydroxyl, amino, or sulfhydryl group, respectively. Examples of
prodrugs include, but are not limited to, acetate, formate, and
benzoate derivatives of alcohol, and amine functional groups in the
compounds of Formulae (I-III).
[0039] The compounds provided herein are, for example and without
limitation, made by the synthetic routes and schemes set forth
hereinbelow.
[0040] Synthesis
[0041] Imidazo[1,2-a]pyrazines (1) of the present invention may be
prepared from intermediate compounds of Formula (2) using the
procedures outlined in Scheme 1. 5
[0042] Compounds of Formula (2) (where L=leaving groups such as
halogen) may be treated with ammonia or aqueous ammonia in the
presence or absence an inert solvent such as alkyl alcohols, at
reaction temperatures ranging from -80.degree. C. to 250.degree. C.
to give products of Formula (3) (where L is halogen). Inert
solvents may include, but are not limited to, lower alkanenitriles
(1 to 6 carbons, preferably acetonitrile), dialkyl ethers
(preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably
N-methyl-pyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or
toluene), alkyl esters (preferably EtOAc) or haloalkanes of 1 to 10
carbons and 1 to 10 halogens (preferably dichloromethane).
[0043] The resulting intermediates (3) may then be reacted with
alpha haloketone derivatives in a solvent such as aliphatic
alcohols or an inert solvent at temperatures ranging from
-20.degree. C. to 150.degree. C. to give compounds of Formula (4).
Inert solvents may include, but are not limited to, polyethers
(preferably 1,2-dimethoxyethane), dialkyl ethers (preferably
diethyl ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane) or aromatic hydrocarbons (preferably benzene or
toluene).
[0044] The compounds of Formula (4) may be coupled to an aromatic
compound of Formula (5) to give a compound of formula (6), with
elimination of the leaving group (L). For compound (4), L
represents a halide, psuedohalide (such as mesylate, tosylate or
triflate), or thiomethyl. For compound (5), L represents groups
such as lithium, bromomagnesium, chlorozinc, (dihydroxy) boron,
(dialkoxy) boron, trialkylstannyl and the like. The coupling
reaction may be performed in the presence of an appropriate
catalyst, such as tetrakis(triphenylphosphine)palladium,
bis(triphenyl-phosphine)palladium dichloride,
[1,3-bis(diphenylphosphino)- propane]nickel dichloride, etc. Two
particularly useful methods involve the coupling of
chloroheterocycles with in-situ-prepared arylzinc reagents
according to the method of Negishi et al. (J. Org. Chem. 1977, 42,
1821), and the coupling with arylboronic esters according to the
method of Suzuki et al. (Chem. Letters 1989, 1405). Appropriate
solvents for reactions of this type usually include
tetrahydrofuran, diethyl ether, dimethoxyethane, dimethylformamide,
or dimethylsulfoxide. Typical temperatures range from ambient up to
the boiling point of the solvent.
[0045] The compound of formula (6) may be converted to a compound
of formula (7) by treatment with phosphorous oxyhalide in
dialkylformamide. Compounds of formula (8) may be obtained from a
compound of formula (7) by treatment with alkyllithiums,
alkylmagnesiumhalides, alkyllithiumcuprates or alkylzinc reagents
in an inert solvent such as tetrahydrofuran, diakylether or
aromatic hydrocarbons.
[0046] The compound of formula (8) can be converted to a compound
of invention (1) by alkylating the alcohol with alkyl halides in
the presence of a base in an inert solvent. Bases may include, but
are not limited to, alkali metal hydrides (preferably sodium
hydride).Inert solvents include, but are not limited to, dialkyl
ethers (preferably diethyl ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably
dimethylformamide), N,N-dialkylacetamides (preferably
dimethylacetamide), cyclic amides (preferably
N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably
dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or
toluene). Preferred reaction temperatures range from -20.degree. C.
to 100.degree. C.
[0047] Alternatively, imidazo[1,2-a]pyrazine (1) of the present
invention may be obtained by following the steps outlined in Scheme
2. A compound of Formula (4) may be converted to a compound of
Formula (9) by following similar conditions for the conversion of
compounds of formula (6) to (7) outlined in Scheme 1. Compound of
formula (10) may be obtained from compound (9) by following
conditions for the conversion of formula (7) to (8) as shown in
Scheme 1. Compound (10) may be alkylated to compound (11) by
similar conditions outlined for Formula (8) to (1) outlined in
scheme 1. Finally compound of formula (11) can be converted to
compound of invention (1) using the condition for the conversion of
Formula (4) to (6). 6
[0048] Alternatively, imidazo[1,2-a]pyrazines of the present
invention may be obtained by following the steps outlined in Scheme
3. The compound of Formula (7) may be oxidized to compound of
Formula (12) by following well known methods outlined in literature
(see: Comprehensive Organic Transformations by R. C. Larock, 1989,
pp 604-614). 7
[0049] The compound of Formula (12) may be subjected to Wittig or
Tebbe's reaction conditions to afford compound of Formula (13)
which may be reduced to compound of Formula (14).
[0050] The nitrogen containing side chain analogs of
imidazo[1,2-a]pyrazine derivatives can be synthesized by following
procedures outlined in Scheme 4. 8
[0051] The compound of the Formula (3) may converted to
3-aminoimidazo[1,2-a}pyrazine derivative of Formula (15) by a three
component condensation reaction consisting of primary amine,
aldehyde and isonitriles in the presence of an acid in an inert
solvent. Acids may include, but are not limited to alkanoic acids
of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids
(2-10 carbons, 1-10 halogens, such as trifluoroacetic acid),
alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic
acid), hydrochloric acid. Also acids include Lewis acids but not
limited to aluminum halides, borontrifluoride etherates,
LiBF.sub.4, Magnesium halides, tin halides, titanium halides,
titanium alkoxides, zinc halides and scandium triflates. Inert
solvents may include, but are not limited to, polyethers
(preferably 1,2-dimethoxyethane), dialkyl ethers (preferably
diethyl ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), haloalkanes or aromatic hydrocarbons (preferably
benzene or toluene). The compound of Formula (15) may be converted
to the compound of Formula (17) by following similar conditions
outlined in Scheme 1.
[0052] Moreover, in addition to compounds made by these routes and
schemes, this invention provides pharmaceutical compositions
comprising pharmaceutically acceptable carriers and therapeutically
effective amounts of the compounds. "Pharmaceutically acceptable
carriers" are media generally accepted in the art for the delivery
of biologically active agents to animals, in particular, mammals.
Such media are formulated according to a number of factors well
within the purview of those of ordinary skill in the art to
determine and account for. These include, without limitation: the
type and nature of the active agent being formulated; the subject
to which the agent-containing composition is to be administered;
the intended route of administration of the composition; and, the
therapeutic indication being targeted.
[0053] Pharmaceutically acceptable carriers include both aqueous
and non-aqueous liquid media, as well as a variety of solid and
semi-solid dosage forms. Such carriers can include a number of
different ingredients and additives in addition to the active
agent, such additional ingredients being included in the
formulation for a variety of reasons, e.g., stabilization of the
active agent, well known to those of ordinary skill in the art.
Descriptions of suitable pharmaceutically acceptable carriers, and
factors involved in their selection, are found in a variety of
readily available sources, e.g., Remington 's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the
contents of which are incorporated herein by reference.
[0054] Compounds provided herein are antagonists of receptors for
corticotropin releasing factor ("CRF"), a 41 amino acid peptide
that is the primary physiological regulator of pro-opiomelanocortin
(POMC)-derived peptide secretion from the anterior pituitary gland
[J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W.
Vale et al., Science 213:1394 (1981)]. Immunohistochemical
localization of CRF has also demonstrated that CRF has a broad
extrahypothalamic distribution in the central nervous system and
produces a wide spectrum of autonomic, electrophysiological and
behavioral effects consistent with a neurotransmitter or
neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res.
39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De
Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence
that CRF plays a significant role in integrating the response of
the immune system to physiological, psychological, and
immunological stressors [J. E. Blalock, Physiological Reviews 69:1
(1989); J. E. Morley, Life Sci. 41:527 (1987)].
[0055] CRF concentrations have been found to be significantly
increased in the cerebral spinal fluid (CSF) of drug-free
individuals afflicted with affective disorder or depression [C. B.
Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am.
J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry
28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)].
Furthermore, the density of CRF receptors is significantly
decreased in the frontal cortex of suicide victims, consistent with
a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen.
Psychiatry 45:577 (1988)]. Moreover, there is a blunted
adrenocorticotropin (ACTH) response to CRF (i.v. administered)
observed in depressed patients [P. W. Gold et al., Am J. Psychiatry
141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147
(1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)].
[0056] CRF produces anxiogenic effects in animals. Moreover,
interactions between benzodiazepine/non-benzodiazepine anxiolytics
and CRF have been demonstrated in a variety of behavioral anxiety
models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W.
Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary
studies using the putative CRF receptor antagonist alpha-helical
ovine CRF (9-41) in a variety of behavioral paradigms demonstrate
that the antagonist produces "anxiolytic-like" effects that are
qualitatively similar to the benzodiazepines [C. W. Berridge and A.
J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71
(1990)]. Neurochemical, endocrine and receptor binding studies have
all demonstrated interactions between CRF and benzodiazepine
anxiolytics, providing further evidence for the involvement of CRF
in these disorders. Chlordiazepoxide attenuates the "anxiogenic"
effects of CRF in both the conflict test [K. T. Britton et al.,
Psychopharmacology 86:170 (1985); K. T. Britton et al.,
Psychopharmacology 94:306 (1988)] and in the acoustic startle test
[N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats.
The benzodiazepine receptor antagonist (Ro15-1788), which was
without behavioral activity alone in the operant conflict test,
reversed the effects of CRF in a dose-dependent manner while the
benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF
[K. T. Britton et al., Psychopharmacology 94:306 (1988)]. The
contents of the above-cited documents are incorporated herein by
reference.
[0057] Thus, compounds provided herein which, because of their
antagonism of CRF receptors, alleviate the effects of CRF
overexpression are expected to be useful in treating these and
other disorders. Such treatable disorders include, for example and
without limitation: affective disorder, anxiety, depression,
headache, irritable bowel syndrome, post-traumatic stress disorder,
supranuclear palsy, immune suppression, Alzheimer's disease,
gastrointestinal diseases, anorexia nervosa or other feeding
disorder, drug addiction, drug or alcohol withdrawal symptoms,
inflammatory diseases, cardiovascular or heart-related diseases,
fertility problems, human immunodeficiency virus infections,
hemorrhagic stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis
and hypoglycemia.
[0058] This invention thus further provides a method of treating a
subject afflicted with a disorder characterized by CRF
overexpression, such as those described hereinabove, which
comprises administering to the subject a pharmaceutical composition
provided herein. Such compositions generally comprise a
therapeutically effective amount of a compound provided herein,
that is, an amount effective to ameliorate, lessen or inhibit
disorders characterized by CRF overexpression. Such amounts
typically comprise from about 0.1 to about 1000 mg of the compound
per kg of body weight of the subject to which the composition is
administered. Therapeutically effective amounts can be administered
according to any dosing regimen satisfactory to those of ordinary
skill in the art.
[0059] Administration is, for example, by various parenteral means.
Pharmaceutical compositions suitable for parenteral administration
include various aqueous media such as aqueous dextrose and saline
solutions; glycol solutions are also useful carriers, and
preferably contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer substances.
Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or
ascorbic acid, either alone or in combination, are suitable
stabilizing agents; also used are citric acid and its salts, and
EDTA. In addition, parenteral solutions can contain preservatives
such as benzalkonium chloride, methyl- or propyl-paraben, and
chlorobutanol.
[0060] Alternatively, compositions can be administered orally in
solid dosage forms, such as capsules, tablets and powders; or in
liquid forms such as elixirs, syrups, and/or suspensions. Gelatin
capsules can be used to contain the active ingredient and a
suitable carrier such as but not limited to lactose, starch,
magnesium stearate, stearic acid, or cellulose derivatives. Similar
diluents can be used to make compressed tablets. Both tablets and
capsules can be manufactured as sustained release products to
provide for continuous release of medication over a period of time.
Compressed tablets can be sugar-coated or film-coated to mask any
unpleasant taste, or used to protect the active ingredients from
the atmosphere, or to allow selective disintegration of the tablet
in the gastrointestinal tract.
[0061] This invention is described in the following examples, which
those of ordinary skill in the art will readily understand are not
limiting on the invention as defined in the claims which follow
thereafter.
EXAMPLES
[0062] Table 1 is a brief summary of compounds provided herein,
made according to the synthetic schemes described hereinabove and
the examples provided hereinbelow.
[0063] Analytical data were recorded for the compounds described
below using the following general procedures. Proton NMR spectra
were recorded on an Varian FT-NMR (300 MHz); chemical shifts were
recorded in ppm (.delta.) from an internal tetramethysilane
standard in deuterochloroform or deuterodimethylsulfoxide as
specified below. Mass spectra (MS) or high resolution mass spectra
(HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using
chemical ionization (CI) with NH.sub.3 as the carrier gas or gas
chromatography (GC) as specified below) or a Hewlett Packard 5988A
model spectrometer. Melting points were recorded on a Buchi Model
510 melting point apparatus and are uncorrected. Boiling points are
uncorrected. All pH determinations during workup were made with
indicator paper.
[0064] Reagents were purchased from commercial sources and, where
necessary, purified prior to use according to the general
procedures outlined by D. Perrin and W. L. F. Armarego,
Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon
Press, 1988). Chromatography (thin layer (TLC) or preparative) was
performed on silica gel using the solvent systems indicated below.
For mixed solvent systems, the volume ratios are given. Otherwise,
parts and percentages are by weight.
6TABLE 1 9 (Ex.) X Y Z R.sub.1 R.sub.2 mp (.degree. C.) (1) Cl Cl H
Et CH(Me)OH amorph (2) Cl Cl H Et CH(Me)OMe oil (3) Cl Cl H Et
CH(Me)OEt oil (4) Cl Cl H Et CH(Et)OH 70-71 (5) Cl Cl H Et
CH(Et)OMe oil (6) Cl Cl H Et CH(Et)OEt oil (7) Cl Cl H Et
CH(n-C.sub.3H.sub.7)OH 159-160 (8) Cl Cl H Et
CH(n-C.sub.3H.sub.7)OMe oil (9) Cl Cl H Et CH(n-C.sub.3H.sub.7)OEt
65-67 (10) Cl Cl H Et CH(C.ident.CMe)OH 81-82 (11) Cl Cl H Et
CH(C.ident.CMe)OMe oil (12) Cl Cl H Et CH(C.ident.CMe)OEt oil (13)
Cl Cl H Et CH(CPM)OH 131-132 (14) Cl Cl H Et CH(CPM)OEt oil (15) Cl
Cl H Et CH(allyl)OEt oil (16) Cl Cl H Et CH(n-Bu)OH oil (17) Cl Cl
H Et CH(n-Bu)OEt oil (18) Cl Cl H Et CH[CH(Me)Et]OH amorph. (19) Cl
Cl H Et CH[CH(Me)Et]OEt oil (20) Cl Cl H Me CH(n-C.sub.3H.sub.7)OH
amorph. (21) Cl Cl H Me CH(n-C.sub.3H.sub.7)OEt 110-111 (22) Cl OMe
H Et CH(Et)OH 145-146 (23) Cl OMe H Et CH(Et)OEt oil (24) Cl OMe H
Et CH(n-C.sub.3H.sub.7)OH 152-153 (25) Cl OMe H Et
CH(n-C.sub.3H.sub.7)OEt oil (26) Cl OCHF.sub.2 H Et CH(Et)OH
144-145 (27) Cl OCHF.sub.2 H Et CH(Et)OC.sub.2H.sub.5 oil (28) Cl
OCHF.sub.2 H Et CH(n-C.sub.3H.sub.7)OH 123-124 (29) Cl OCHF.sub.2 H
Et CH(n-C.sub.3H.sub.7)OEt 67-68 (30) Me OCHF.sub.2 Me Et
CH(n-C.sub.3H.sub.7)OEt 83-84 (31) Me OCHF.sub.2 H Et
CH(n-C.sub.3H.sub.7)OH 147-148 (32) Me OCHF.sub.2 H Et
CH(n-C.sub.3H.sub.7)OEt oil (33) Cl Cl H Et
C(.dbd.O)-n-C.sub.3H.sub.7 95-96 (34) Cl Cl H Et
C(.dbd.CH.sub.2)-n-C.sub.3H.sub.7 oil (35) H Cl H Et
N(Bz)-n-C.sub.3H.sub.7 oil (36) Cl Cl H Et N(Bz)-n-C.sub.3H.sub.7
oil (37) Cl Cl H Et NH(Bz) oil (38) Cl Cl H Et N(Bz)Et oil (39) Cl
Cl H Et N(Et)-n-Bu oil (40) Cl Cl H Et N(allyl)Et oil
Example 1
[0065]
8-(2,4-dichlorophenyl)-2-ethyl-3-(1-hyroxyethyl)imidazo[1,2-a]pyraz-
ine
[0066] Part A: Synthesis of 3-amino-2-chloropyrazine:
[0067] (Ref: S. Okada et al Chem. Pharm. Bull. 1971, 19(7),
1344-1357). A mixture of 2,3-dichloropyrazine (20 g, 0.134 moles)
and 28% aq. NH.sub.4OH (120 mL) was heated in a resealable pressure
tube at 140.degree. C. for 24 h. The solution was cooled and the
off-white crystals separated was filtered and dried to afford 16.6
g material (96%, mp 165-166.degree. C.). The crude was quite pure
by NMR and used in the next step without purification.
[0068] Part B: Synthesis of
8-chloro-2-ethylimidazo[1,2-a]pyrazine:
[0069] To a solution of 2-amino-3-chloropyrazine (19.5 g, fw=129,
0.15 moles) in dioxane (250.0 mL) was treated with 90%
1-bromo-2-butanone (25 g, fw=151, 1.1 moles, Aldrich) and stirred
under nitrogen for 4 h followed by reflux for 48 h. Brick red
colored solid separated from the mixture. TLC (1:50
MeOH/CH.sub.2Cl.sub.2) showed a new spot at Rf=0.30 along with
disappearance of starting material spot at Rf=0.42. The reaction
mixture was cooled to room temperature filtered the solid and
washed the solid with diethyl ether (2.times.100 mL). NMR of the
salt in DMS0-D6 revealed a clean product. The salt was dissolved in
water (500 mL), adjusted the pH to 8 using solid Na.sub.2CO.sub.3,
extracted with EtOAc, washed with brine, dried (MgSO.sub.4) and
concentrated in vacuum to afford pale yellow solid. The crude (20
g, 74% yield, mp 73-74.degree. C.) was found to be quite pure by
NMR and used without purification in the next step.
[0070] Part C: Synthesis of
8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]py- razine:
[0071] A mixture of 8-chloro-2-ethylimidazo[1,2-a]pyrazine (9.05 g,
0.05 mol, fw=181) and 2,4-dichlorobenzeneboronic acid (10.5 g,
0.055 mol, fw=190.81) in toluene (200.0 mL) was treated with 2M aq.
Na.sub.2CO.sub.3 (40.0 mL) and EtOH (20.0 mL). The reaction mixture
was degassed under vacuum and purged with nitrogen (repeated 3
times) and then added Pd(PPh.sub.3).sub.2Cl.sub.2 (740 mg, 0.001
mol, fw=738.18, 2 mol %). After the addition the reaction mixture
was degassed under vacuum and purged with nitrogen (repeated 3
times). The resultant mixture was refluxed under nitrogen for 24 h.
TLC (1:50 MeOH/CH.sub.2Cl.sub.2) showed two new spots at Rf=0.53
and 0.35 along with trace amount of starting material spot at
Rf=0.30. The reaction mixture was cooled to room temp and
partitioned between 200 ml of 1:1 EtOAc/water. The aq. layer was
extracted with EtOAc (2.times.150 mL), dried (MgSO.sub.4) and
concentrated in vacuum to afford yellow oil. The crude (15.1 g,
brown yellow solid) was purified by flash column chromatography on
a silica gel using 15% EtOAc/hexane to afford the top spot as pale
yellow solid (760 mg, mp 71-72.degree. C.) and characterized as
8-(4-chlorophenyl)-2-ethyli- midazo[1,2-a]pyrazine. HRMS calcd. for
C.sub.14H.sub.13N.sub.3Cl.sub.1: 258.0798. Found: 258.0788 (M+H).
Further elution of the column with 30% EtOAc/hexane gave desired
product (bottom spot) as white solid (8.6 g, 59% yield,
125-126.degree. C.). HRMS calcd. for C.sub.14H.sub.12N.sub.3Cl-
.sub.2: 292.0408. Found: 292.0409 (M+H).
[0072] Part D: Synthesis of
8-(2,4-dichlorophenyl)-2-ethyl-3-formyl-imidaz-
o[1,2-a]pyrazine:
[0073] POCl.sub.3 (99.6 g, 60.0 mL, 65.0 mmol, fw=153.33) was added
dropwise to a cooled (0.degree. C.) stirred solution of dry DMF
(200 mL). The resultant mixture was stirred for additional 15 min.
and then added 8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazine
(14.6 g, 50.0 mmol, fw=292) to the reaction mixture. The reaction
mixture was gradually brought to room temperature and stirred for 4
days. The reaction mixture appeared yellow in color. TLC (1:50
MeOH/CH.sub.2Cl.sub.2) revealed absence of starting material spot
(Rf=0.35) and showed a new spot at Rf=0.4. The reaction mixture was
quenched with ice (750 g), stirred the mixture for 30 min.,
neutralized with solid sodium carbonate and extracted with EtOAc
(3.times.200 mL), dried (MgSO.sub.4) and concentrated in vacuum to
afford yellow solid. The solid was purified by flash column
chromatography on a silica gel using 20% EtOAc/hexane to afford
11.7 g (73%, 93-94.degree. C.) of white solid. Anal. calcd. for
C.sub.15H.sub.11Cl.sub.2N.sub.3O: C, 56.27; H, 3.46; N, 13.12.
Found: C, 56.13; H, 3.38; N, 12.96.
[0074] Part E: Synthesis of title compound:
[0075] The aldehyde of Part D of Example 1 (0.320 g, 1.0 mmol) was
dissolved in anhydrous THF (5.0 mL) and cooled to #78 C under
nitrogen. To this mixture was added dropwise 1.4 M MeMgBr in
toluene/THF (3.0 mL, 4.2 mmol) and stirred at -78.degree. C. for 3
h. TLC (1:10 MeOH/CH.sub.2Cl.sub.2) revealed absence of starting
material spot (Rf=0.88) and showed a new spot at Rf=0.12. The
reaction mixture was quenched with satd. NH.sub.4Cl (10.0 mL),
stirred the mixture for 10 min., extracted with EtOAc (3.times.25
mL), dried (MgSO.sub.4) and concentrated in vacuum to afford yellow
oil. The residue was purified by flash column chromatography on a
silica gel using 2.5% MeOH/CH.sub.2Cl.sub.2 to afford 207 mg (62%)
of amorphous wet white solid. HRMS calcd. for
C.sub.16H.sub.16Cl.sub.2N.sub.3O: 336.0670. Found: 336.0678
(M+H).
Example 2
[0076]
8-(2,4-dichlorophenyl)-2-ethyl-3-(lmethoxyethyl)imidazo[1,2-a]pyraz-
ine
[0077] The alcohol from Part E of Example 1 (90.0 mg, 0.268 mmol)
was dissolved in dry DMF (2.0 mL) under nitrogen. To this mixture
was added 60% NaH (21.4 mg, 0.536 mmol, 2 equiv.) and stirred at
room temperature for 30 mins. MeI (excess) was added to the mixture
and stirred overnight. TLC (1:10 MeOH/CH.sub.2Cl.sub.2) revealed a
new spot (Rf=0.31). The reaction mixture was quenched with water
(5.0 mL), stirred the mixture for 10 mins., extracted with EtOAc
(3.times.15 mL), dried (MgSO.sub.4) and concentrated in vacuum to
afford yellow oil. The residue was purified by flash column
chromatography on a silica gel using 1% MeOH/CH.sub.2Cl.sub.2 to
afford yellow oil (32 mg, 34% yield. HRMS calcd. for
C.sub.17H.sub.18Cl.sub.2N.sub.3O: 350.0827. Found:350.0828
(M+H).
[0078] The compounds of examples 3-32 shown in Table 1 were
prepared by following the experimental conditions outlined in
Examples 1 & 2, hereinabove.
Example 33
[0079]
8-(2,4-dichlorophenyl)-2-ethyl-3-(1-oxo-butyl)imidazo[1,2-a]pyrazin-
e
[0080] Part A:
8-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxybutyl)imidazo[1,-
2-a]pyrazine:
[0081] The aldehyde (1.6 g, 5.0 mmol, Part D of Example 1) was
dissolved in anhydrous THF (25.0 mL) and cooled to -78.degree. C.
under nitrogen. To this mixture was added dropwise 2.0 M n-PrMgCl
in diethyl ether (6.7 mL, 14.4 mmol) and stirred at -78.degree. C.
for 4 h. TLC (1:10 MeOH/CH.sub.2Cl.sub.2) revealed absence of
starting material spot (Rf=0.88) and showed a new spot at Rf=0.05.
The reaction mixture was quenched with saturated NH.sub.4Cl (30.0
mL), stirred the mixture for 10 min., extracted with EtOAc
(3.times.1O0 mL), dried (MgSO.sub.4) and concentrated in vacuum to
afford yellow oil. The residue was purified by flash column
chromatography on a silica gel using 2.5% MeOH/CH.sub.2Cl.sub.2 to
afford 1.63 g (84%, mp 159-160.degree. C.) of desired product as
white solid.
[0082] Part B: Title compound: To a mixture of carbinol (1.1 g,
0.003 moles, fw364, Part A of Example 33) in toluene (25 mL) was
added MnO.sub.2 and refluxed under nitrogen for 24 h. TLC (1:10
MeOH/CH.sub.2Cl.sub.2) revealed absence of starting material spot
(Rf=0.5) and showed a new spot at Rf=0.86. The reaction mixture was
cooled to room temperature, filtered through celite, washed the
celite with EtOAc (3.times.50 mL), and concentrated in vacuum to
afford yellow oil. The residue was purified by flash column
chromatography on a silica gel using 1% MeOH/CH.sub.2Cl.sub.2 to
afford 580 mg (53%, mp 95-96.degree. C.) of white solid.
Example 34
[0083]
8-(2,4-dichlorophenyl)-2-ethyl-3-(1-propylvinyl)imidazo[1,2-a]pyraz-
ine
[0084] To a solution of keto imidazopyrazine (181 mg, 0.5 mmol,
Part B of Example 33) in THF (5.0 mL) at room temp was added 0.5 M
toluene solution of the Tebbe reagent (1.2 mL, 0.6 mmol) dropwise
under nitrogen atmosphere. The reaction mixture was slightly
exothermic during addition and continued stirring for 1 h. TLC (3:7
EtOAc/hexane) revealed absence of starting material (Rf=0.5) along
with a new spot (Rf=0.46). The reaction mixture was diluted with 15
mL of Et.sub.2O and then added 3-5 drops of 1.0 N Aq. NaOH. After
gas evolution ceases, the mixture was filtered through celite,
evaporated to dryness and purified by flash column chromatography
on a silica gel using 10% EtOAc/hexane to afford yellow oil (81 mg,
45%). HRMS calcd. for C.sub.19H.sub.20N.sub.3Cl.sub.2: 360.1034.
Found:360.1033
[0085] The compound of example 35 was prepared according to the
experimental conditions outlined in Examples 33 and 34,
hereinabove
Example 36
[0086] 8-(2,4-dichlorophenyl)-2-ethyl-3-(N-propylbenzylamino)
imidazo[1,2-a]pyrazine
[0087] Part A:
3-benzylamino-8-chloro-2-ethylimidazo[1,2-a]pyrazine:
[0088] To a solution of 2-amino-3-chloropyrazine (1.3 g, fw=129,
10.0 mmole) in MeOH (50.0 mL) was treated with propionaldehyde
(0.58 g, fw=58, 10.0 mmole, Aldrich), AcOH (1.2 g, 20 mmol, fw=60)
and benzyl isocyanide (STENCH, 1.17 g, 10.0 mmol, fw=117.15,
Aldrich). The resultant suspension was stirred at room temp
overnight. TLC (1:50 MeOH/CH.sub.2Cl.sub.2) showed a new spot at
Rf=0.24 along with unreacted starting material spot at Rf=0.42. The
unreacted isocyanide was destroyed by acidifying the reaction
mixture to pH 1 using 1N HCl. After acidification the reaction
mixture was stirred at room temp for 30 mins, evaporated to
dryness, residue dissolved in water, adjusted the pH to 8 using
KHCO.sub.3, extracted the reaction mixture with EtOAc (3.times.50
mL) and dried with anhydrous MgSO.sub.4. The solvent was evaporated
from the reaction mixture and the residue (pale yellow solid) was
partitioned between 50 ml of 1:1 EtOAc/aq. NaHCO.sub.3. The aq.
layer was extracted with EtOAc (2.times.15 mL), dried (MgSO.sub.4)
and concentrated in vacuum to afford pale yellow solid (3.0 g). The
crude was treated with CH.sub.2Cl.sub.2 and filtered the white
solid (0.75 recovered starting material). The filtrate was
evaporated and purified by flash column chromatography on a silica
gel using 30% EtOAc/hexane to afford 0.42 g (34% yield) desired
product as yellow oil.
[0089] Part B: N-Alkylation: A mixture of
3-benzyamino-8-chloro-2-ethylpyr- azine (415 mg, 0.00145 moles,
fw=286.45) in DMF (2.0 mL) was treated with 60% NaH (70 mg, 0.00174
moles, 1.2 equiv.) at room temp under nitrogen atmosphere and
stirred for 15 mins. To this mixture was added 1-iodopropane (0.296
g, 0.00174 moles, 1.2 equiv.) and stirred at room temp for 4 h. TLC
(1:50 MeOH/CH.sub.2Cl.sub.2) showed a new spot at Rf=0.33 along
with several minor spots below the product. Since the starting
material spot overlapped with one of the minor spots, the reaction
was allowed to continue over weekend. The solvent from the reaction
mixture was evaporated under vacuum, quenched with water, extracted
with EtOAc (3.times.10 mL), dried with MgSO.sub.4. The solvent from
the reaction mixture was evaporated and the crude was purified by
flash column chromatography on a silica gel using 15% EtOAc/hexane
to afford the desired product as yellow oil (170 mg, 35% yield).
HRMS calcd. for C.sub.18H.sub.22N.sub.4Cl.sub.1:329.1533. Found:
329.1530 (M+H).
[0090] Part C: Suzuki reaction: A mixture of above chloro compound
(0.140 g, 0.43 mmol, fw=328), 2,4-dichlorobenzeneboronic acid (95
mg, 0.65 mmol, fw=190.81) in toluene (5.0 mL) was treated with 2M
aq. Na.sub.2CO.sub.3 (2.0 mL) and EtOH (1 mL). The reaction mixture
was degassed under vacuum and purged with nitrogen (repeated 3
times) and then added Pd(PPh.sub.3).sub.2Cl.sub.2 (18. 5 mg, 0.005
mmol, fw=738.18). After the addition the reaction mixture was
degassed under vacuum and purged with nitrogen (repeated 3 times).
The resultant mixture was refluxed under nitrogen for 6 h. TLC
(1:50 MeOH/CH.sub.2Cl.sub.2) showed two new spots at Rf=0.75 and
0.5 along with small amount of starting material spot at Rf=0.33.
The reaction mixture was cooled to room temp and partitioned
between 20 ml of 1:1 EtOAc/water. The aq. layer was extracted with
EtOAc (2.times.15 mL), dried (MgSO.sub.4) and concentrated in
vacuum to afford yellow oil. The crude was purified by flash column
chromatography on a silica gel using 10% EtOAc/hexane to afford the
top spot as yellow solid (20 mg). Further elution of the column
with 15% EtOAc/hexane gave desired product (bottom spot) as yellow
oil (60 mg, 40% yield, 125-126.degree. C.). Also recovered 27.5 mg
of unreacted chloropyrazine derivative. Top spot was characterized
as mono chloro derivative of Example 35. HRMS calcd. for
C.sub.24H.sub.26N.sub.4Cl.sub.1:405.1846. Found: 405.1841 (M+H).
Bottom spot desired product. HRMS calcd. for
C.sub.24H.sub.25N.sub.4Cl.sub.2: 439.1456. Found: 439.1455
(M+H).
[0091] The compounds of examples 37 to 40 were prepared by
following experimental conditions outlined in Example 36,
hereinabove.
* * * * *